Helen grew up in a family of academics and found her way to business through Yale’s Biotechnology & Pharmaceutical Society while getting her Ph.D. at Yale. A mentor connected her to L.E.K., where she consulted for several years, including a stint in the Shanghai office. She joined Agios – one of the first Third Rock builds – when the company was still negotiating high-throughput screening contracts. Over the course of six years, she helped broker its second deal with Celgene focused on immunometabolism at the height of immuno-oncology. She left to take TCR² (an MPM Capital Newco), out of stealth alongside CEO Garry Menzel, building the corporate function and co-leading a $125 million crossover Series B. Next, at Blueprint Medicines she was promoted to Chief Business Officer, where she shaped the company’s corporate strategy and executed more than a dozen corporate transactions, including its global strategic partnership with Roche valued at $775 million upfront (plus $927 million in downstream payments and tiered royalties). Across Agios and Blueprint, she played a part in bringing five transformative drugs to patients. Now, as Chief Business and Strategy Officer at Parabilis (formerly FogPharma), she is building out the company’s flagship β-catenin franchise and broader pipeline of Helicons capable of targeting previously “undruggable” biology on the back of a $770 million IPO debut, the largest in biotech history.

In our interview, Helen discusses the Agios-Celgene’s co-development and co-commercialization partnerships (and why structures like it are in decline), her experience leading a company out of stealth, how the Blueprint playbook can generalize, and the potential and science behind Parabilis’ Helicon platform targeting undruggable drivers of cancer. Lastly, she provides practical advice for those starting out in biotech: how to practice the discipline of intentionality, what she looks for in the people she hires, and how the biotech community can support each other.

Share

Below is an interview with Dr. Helen Ho, Chief Business and Strategy Officer at Parabilis Medicines, from July 2026:

1. What drew you into science in the first place? Was academia the dream when you started out? How did you find your way from science to business?

I grew up in a family of scientists and academics, so that is how I got into science initially. For me, it has always been more about what I love, and in science, what I found was a passion for understanding the fundamentals. I believe that to make a difference in medicine, you need to understand things at the molecular level. That is what led me to study biochemistry as an undergraduate and to get my Ph.D. in cell biology. It is perhaps what kept pulling me toward precision medicine throughout my career — that conviction about understanding the root causes of disease and being able to tackle them head-on.

I had no exposure to business at all growing up. To be candid, pursuing academia was a bit of a default, since so many of my family members had Ph.D.s. I was very fortunate that I did love science, so I pursued it.

The shift came at Yale, where I was introduced to a student organization called Yale Biotechnology & Pharmaceutical Society focused on business and biotech. I was fascinated by the intersection of R&D and business. This was twenty-five years ago, when the line was drawn hard. You were an academic, or you went to the “the alternative career,” as people called it, in industry. Through that organization, and through mentors who were industry executives, I got excited about this other path. A mentor of mine connected me to a partner at L.E.K., and that is how I ended up there as a management consultant.

2. How did your Ph.D. advisors react when you started looking outside academia?

Again, this was now twenty years ago, when the expectation was that if you were a good scientist, you stayed on to be a postdoc and went into academia. There were professors who held that view very strongly. If you went into pharma or biotech, they would basically disown you. Times have changed significantly, and we are all better for it.

I was very fortunate. My advisor was Dr. Graham Warren, and I was in a lab run jointly with Ira Mellman’s, before he went to Genentech. They were supportive of students figuring out what we wanted to do with our scientific training. They were willing to let me explore my interests and passions, even though they may not have been completely sure what I was going to do. That support mattered enormously to me.

[Dr. Ira Mellman is a Biomarker alum. In our interview we discussed the importance of mentorship, lessons picked up from mentors, problems in oncology that motivate his current research and advice to those in science looking to have an impact.]

[On her Ph.D. thesis]

Going back to my belief that you have to understand the fundamentals — I studied how the Golgi apparatus is inherited in daughter cells, which is as fundamental as biology gets. I did that in Trypanosoma brucei because it has only a single Golgi apparatus, unlike human cells, which have many. We know how DNA duplicates and divides; I was asking whether the Golgi duplicates and divides too, or whether it is made de novo.

None of it was remotely relevant when I went into industry. I knew nothing about drug development. What carried over was the training in how to think analytically, and the interest in science itself — both rooted in my graduate study at Yale.

3. You spent time in L.E.K.’s Shanghai office. What was that experience like, both in terms of the skills and being in Asia?

Professionally, China twenty years ago, ten years ago, and today are three completely different places. A lot of what I learned then — and some of what carried into deals I have done with Chinese partners over the last ten years — is very different than how we look at the ecosystem now. What still holds is the experience of working cross-culturally between the US and Asia, which continues to help me as I think about how important that ecosystem has become in biotech.

Personally, it felt like life was coming full circle. My family immigrated to the US from Taiwan when I was about twelve, and we moved to South Georgia. I had not been back to Asia since, until I was transferred to the Shanghai office. Going back as an adult and working alongside people who shared my roots was life-changing.

4. Did you always intend to move to the operating side, or did that come into focus at L.E.K.?

I did not know. That is a bit of a theme in my career — I focus on what I love to do, and go where I can learn from the best people. I loved consulting. It was hard work, and we worked a lot of hours, but I did not mind. I found it fascinating to work across so many different business problems, even just within life sciences. One route would have been to be a career consultant and make Partner.

At some point, though, I realized that rolling up my sleeves and figuring out what it takes to actually develop a drug within a biotech company was exciting to me. I was fortunate to come across Agios in those early days, when biotech was not the ‘thing’ it is today. Agios was one of the first Third Rock companies. People usually went from consulting into big pharma — that was the path we knew. Few chose to go to a startup nobody had heard of, especially one that had only just been built. I was not sure where it would lead, but I knew I would be learning a ton from leaders like David Schenkein, John Evans who hired me, and other brilliant minds.

5. It was a remarkable time to join Agios — the IPO priced at $18, and the follow-on came a few years later at $110. What strikes us is that the cancer metabolism franchise went to Celgene, leaving Agios to develop a then-unproven PKR activator. How has that shaped the way you think about what to partner and what to keep?

At Agios we partnered with Celgene on cancer metabolism and eventually co-developed and co-commercialized our IDH inhibitor programs with them — a “co-co,” as opposed to out-licensing, which could have been another option. The idea behind the co-co was that we could use it as training wheels for the next wave of products coming through our pipeline. The deliberate decision was to share the rights, share the risks, learn from the big brother or big sister, and get support not just with R&D expertise but financially.

During my tenure, we also did the second Celgene deal, on immunometabolism, at the height of immuno-oncology. The rationale was the same: could we partner with a company that had expertise we did not? We were not an immuno-oncology company, but leveraging our platform to expand into that space was an opportunity partnership made achievable.

Broadening out — how should any company think about partnering versus going alone? I always go back to the big-picture question: what are you looking to solve for? That seems like a no-brainer, but a lot of companies go into the business development process without thinking hard about it. They get pushed by the board, by investors, or internally — you have got to go do a deal — and they just go out and start talking to companies.

You have to step back and answer that question specifically. How does a partner help you go bigger, better, faster, and potentially cheaper? How does a partner help you maximize the value not just of that program but of your whole portfolio? I mention that last piece because any deal should not be just about the program but about how it impacts your portfolio overall – how does it impact the value of the company.

So I go back to those questions. What is the right thing to partner? How do you partner? When do you partner? What is the right structure? How do you create long-term optionality? There is the near-term imperative that all companies have, but you also have to think about long-term optionality. Simple questions, but important ones.

6. By that point Agios had real momentum, not to mention all the relationships you built with your team there. What made you decide to leave for TCR²?

In my roughly six years at Agios, I had helped the company grow from a blank piece of paper to planning for pre-commercialization with Celgene. There was certainly still a lot to do, but I left to join TCR² because I was fascinated by the question of how you go back and do it again.

TCR² was an MPM Capital cell therapy company, still in stealth. I was drawn to the opportunity to join alongside Garry Menzel, who came in as CEO at the same time, and take the company out of stealth. In a very small company, my role was to figure out how you build it from the ground up. We had no processes. We had fantastic scientific ideas, but nothing else had been thought through — from investor and public relations to the website to corporate strategy and direction to our first indication.

Helping figure that out and set the direction for the company was an incredible experience as I thought about being a company builder in the long run — as was working with Garry to lead the $125 million crossover Series B. It taught me that at that stage, every little thing you do — the processes you set up, the people you hire — affects how you scale. That is very different from stepping into an established company and executing.

7. Agios had never commercialized anything, and Celgene had decades of track record. Are those co-development structures as common today — or does a company facing that choice now simply get acquired?

For companies with the ambition and long-term vision to build a pipeline and platform that produce a cadence of programs, a co-co is a great way to share risk, leverage expertise, and capture long-term value of the program. I certainly do not see this type of deal as often nowadays, and I have been reflecting on why. Over the last few years, the choice has narrowed to two paths: continue to take it on yourself (like Argenyx, Insmed or Vertex before them), which is the rarer path, or sell the whole asset outright.

I suspect three things. First, we all came out of an extremely challenging macro environment, and there is less willingness now — among a lot of leadership teams, board members, and investors — to take on that kind of long build alongside a partner.

Second, not many companies have a broad platform and a cadence of programs coming through. If you do not have that, and you are essentially a one-asset company, a co-co is hard to contemplate — because once you do it, what is next? Especially if you do not have full decision rights on those programs, the position becomes challenging.

Third, pharma also recognizes the difficulties of a co-co. Unless the smaller company has real leverage, pharma often prefers to take it on itself, because alliances are hard. It is a marriage you have to figure out how to maintain and grow, and not everybody wants to do that.

Those are the three main reasons the trend has shifted, but I do think co-co models can be useful in certain circumstances for certain companies – when partnering with pharma can help you do it bigger, better, faster, potentially cheaper, and maximize the value. But what your long-term build looks like becomes an important input into whether you co-co, out-license, or go it alone.

8. Blueprint ran with a compelling strategy: start with a well-validated target and compelling cell biology in a very small population — advanced systemic mastocytosis (ASM) — then have the vision to expand into a more indolent disease in indolent systemic mastocytosis (ISM) that a lot of people have but only thirty thousand are formally diagnosed with. With an eye to what Parabilis is doing, does that pattern generalize? Is it something you look for explicitly?

You are right that small to big is often the pattern. But I would not universally frame it as “go small, then go big”. It is more about where you have the highest conviction. It is about really understanding the biology of the disease, so you can go after an opportunity with a higher probability of success — and then leveraging that opportunity — big or small; in Blueprint’s case, small — to show quickly whether you have a drug or not. The size of the indication is secondary to understanding the biology. The goal is to go in and demonstrate that you have a drug.

Sometimes companies stop there. What we did at Blueprint, and what we are doing so deeply at Parabilis, is to expand. You become the disease expert — not just on the biology, but on development, on the patient journey, on what patients need. From there you decide what you actually do. Is it a combination? Is it expanding into a broader population?

That next step is not always as comfortable as the first one. For me, that is where a company needs boldness, establish good scientific insight and hypothesis, and do the right “go/no go” studies, preclinically or clinically, to test it.

[On spotting these indications]

A lot of these diseases are under the radar because there is no treatment option available. In many cases, rare diseases often seem even rarer than they really are for that reason; until there’s a treatment available, diagnosis often lags behind.

Across Agios, Blueprint, and the areas we are exploring now at Parabilis, it is not always that doctors did not know the diseases or could not describe them. Oftentimes, they did not have the tools to help patients. If there is nothing to offer, what is the doctor going to do? That is what leads to underdiagnosis. To the extent that we can understand the disease and the biology and develop novel tools to go after it, that is where you can have breakthrough impact — something very few companies are positioned to pursue.

For Parabilis, that is leveraging our Helicon platform to target disease-drivers that have historically been inaccessible to other modalities. These are all things people did not necessarily know how to get into, and you take a bold risk to figure out how.

Share

9. How did you come to Parabilis? Was there a mentor at the company, or did you see one target where the biology was really understood?

After Blueprint I took some time off — I call it my personal sabbatical — and spent a month in Chile, traveling the whole country with my husband, which was incredible. I took the time to reflect on the type of company I hoped to be part of next. I feel fortunate that through my time at Agios and Blueprint I have played a part in bringing five transformative drugs to patients. I wanted to focus on another company that can go a distance – a company with a broad platform that truly has the ability to exponentiate, a drug with the potential to help patients, a leadership team with the experience and ambition to build.

The combination of those four things, I realized, is extremely rare, especially over the past few years. We are all a bit traumatized by the years behind us, and not many leaders are interested in continuing to build for the long haul.

I was delighted to be connected with Mathai, whom I had known and respected, and with the team at Parabilis — a company that I had been following closely since its early days. As I learned more about what they have accomplished in the clinic, about the continued expansion of the platform, and about the incredible team they’ve built, I knew Parabilis is the rare company that has the combination of the four things I mentioned. It is an exciting time to be part of this company to decide what those next chapters look like for us.

10. What is on your list of top priorities now? And can you explain the Helicon platform and why β-catenin has been so hard to drug?

A key focus is how we further expand the β-catenin franchise, which is our flagship. That sits alongside our preclinical pipeline in prostate cancer and our recent collaboration with Regeneron to further expand the impact of our Helicon platform. We envision taking zolucatetide forward across a range of indications: desmoid tumors are the starting point, but we are also very focused on other Wnt/β-catenin-driven diseases such as familial adenomatous polyposis (FAP) and adamantinomatous craniopharyngioma (ACP). That is a key priority, in addition to advancing our next wave of programs in prostate cancer and broader discussions on how we expand and scale our platform to pursue additional ”undruggable” targets.

Let me provide some background on Helicons and why our industry has not been able to go into an area like β-catenin before now. Here’s the problem - Many of the drivers of disease are intracellular, and many of them do not have the kind of pocket that small molecules can bind.

β-catenin is a good example. It is an intracellular protein with a flat surface, which is hard to bind. Antibodies have an amazing ability to bind flat surfaces very selectively, but they cannot get into the cell. Small molecules can get into the cell, but they cannot bind flat surfaces. We engineered Helicons – which are stabliized α-helical peptides – an important new modality that can enter cells and bind flat surfaces. That opens up many of these historically undruggable drivers of disease. We understand the biology. If you know how to target it, you can change the treatment paradigm.

[On the indications Parabilis is pursuing]

We discovered and are now developing zolucatetide, the first β-catenin:TCF inhibitor that gets at the root cause of these diseases. We and others have known for thirty years that β-catenin is a “holy grail” target — a driver of about ten percent of solid tumors. But it was considered to be undruggable. With zolucatetide in clinical development, and a β-catenin degrader effort behind it as a potential follow-on, we feel a sense of responsibility to the field, and we are thinking about how to pursue diseases where our drugs can be applicable.

We are initially prioritizing a few key indications where the biology is especially clear and compelling. Our lead indication is in desmoid tumors, a type of soft tissue tumor that can cause severe pain, functional impairment and reduced quality of life, and are almost universally driven by dysregulated β-catenin signaling. We are also advancing zolucatetide in FAP — familial adenomatous polyposis — a cancer predisposing disease where hundreds to thousands of polyps grow in the GI tract and, if untreated, carry a near-inevitable risk of colorectal cancer and an increased risk of other GI cancers. That is a debilitating disease, often requiring life-altering multiple surgeries, with no medical treatment options, and it is driven by APC mutations, which sit upstream of β-catenin. A third area we are starting to move into is what we think of as “sleeper diseases” that few people know about. Adamantinomatous craniopharyngioma — ACP — is a slow-growing brain tumor that arises from the pituitary stalk and primarily impacts young patients, often causing vision loss, hormonal dysfunction, cognitive impairment and lifelong neurological complications. They are one hundred percent driven by β-catenin.

Following the science, we have been encouraged by the early clinical data, which show that we are able to shrink tumors in desmoid and in ACP and to significantly reduce polyp burden in FAP. Very early days, but quite remarkable data.

Going back to how you expand, there is a second wave: hepatocellular carcinoma (HCC); colorectal cancer, which is maybe more complex; and a range of other Wnt/β-catenin pathway-driven diseases that we have included within our trial.

Subscribe now

11. Tell us about the Regeneron collaboration and how you think about structuring these deals.

With our Helicon platform, we are able to go after the causal biology of disease, and our internal focus is principally in oncology and rare chronic disease. There is a lot we can do with our platform where our own expertise lies. But there is also a lot we could do outside those areas with the Helicon platform — immunology and inflammation, perhaps metabolism, other therapeutic areas entirely.

So, the reasons for the Regeneron deal were twofold. One is what I just mentioned: by leveraging their expertise, there is an opportunity to expand the application of the platform beyond oncology and the rare chronic diseases we are currently in.

The other is that Helicons have opportunities beyond what I would call the naked Helicon — standalone inhibitors, like zolucatetide, or degraders like we’re pursuing for β-catenin and in prostate cancer. An antibody-Helicon conjugate (AHC) is one good example. We are not a biologics company, but Regeneron is one of the world’s leading biologics and antibody-drug conjugate (ADC) companies. By complementing those two platforms, we believe we can expand the possibilities.

That ties back to the framework. Where are you being clear and honest with yourself about what you can do? Where do you invest? Where do you want to take on the risk? Where do you share some of it with another company that has a similar culture and scientific rigor, in a way that lets you do much more?

12. You are also on the board of advisors at GBH. How does public media connect back to your work?

I grew up with NOVA, the PBS science series, which GBH created. Sitting on the board of advisors there is one of my ways of giving back.

I think about its mission, which is how you make information accessible to people — and not just accessible but understandable, across science and culture. For me, communicating science is about providing that accessibility. How do you simplify in a way that people understand? Because I oversee corporate communications here at Parabilis, thinking about our audiences — investors, media, employees, patients — matters a great deal. You have to deeply understand the subject in order to know how to simplify and articulate it.

I am inspired by GBH’s mission of making that information available - it is probably more important than ever.

13. You have worked with some remarkable scientists and CEOs. When you are evaluating an opportunity, one part is the science — but the other part is clearly the people. How do you judge them? And what are you looking for when you are hiring?

For me, a lot of it is why they do what they do, and who it is for. There are brilliant people everywhere, but the ‘why’ is what matters to me, especially when I think about the leaders and colleagues I want to work with.

Specifically, I look for someone, such as Mathai, who has a genuine sense of responsibility for doing what is most impactful — not just for society and for patients, which fortunately we talk about a lot in this industry, but also for the people on the team. I do not think that last part gets discussed as much, and I feel strongly about it. I always say that in order to benefit patients, you have to think about how you develop your employees and make their careers fulfilling.

So I want to hear somebody talk to me about how the team is going to be the secret sauce of the company. How do we develop each other? How do we bring each other along? How do we motivate people and help them see the impact? We spend so much of our lives at work. That is why this matters so much to me.

14. Biotech leadership is still predominantly male. How can we all support women on this journey?

Twenty years ago, I was often the only woman at the negotiation table, and almost always the only Asian woman. I am glad that has changed significantly. There is still room to grow, but the change is real.

When thinking about how we support each other, it is not just men, but women have a responsibility to lift each other up. As I think about my female colleagues and the next generation of leaders, I ask how we advocate for one another, how we support one another, and how we serve as role models for one another.

When I was promoted to Chief Business Officer at Blueprint, many female colleagues came to me and said, “Thank you — thank you for showing that this is a position we could reach.” That stopped me, and taught me again that we have to keep showing up for each other. Not just men, not just women, but everybody. And not just gender, either — other types of diversity too. Diversity makes us better.

Subscribe now

Share

Johan’s career has spanned geographies (Sweden, Switzerland, the US, Denmark) and disciplines (basic neuroscience, drug development, clinical operations, executive leadership). Yet, when asked about his trajectory, Johan resists the framing of a planned path. “Maybe life is a planned path, and maybe there is someone planning yours,” he says, “but I never planned mine. Things came into my path that guided me. I dug where I stood, and things came out of it.”

Johan trained at the Karolinska Institute, where he discovered neuroscience through histology coursework and a charismatic teacher. He moved into industry when his PhD advisor was recruited to Astra, eventually heading a research lab there, and maintaining an academic affiliation that allowed him to mentor graduate students – one of whom worked on the project that produced the seminal Arctic APP paper (Camilla Nilsberth). Across Astra, Serono, Merck, and Eisai, Johan worked on three different BACE inhibitor programs through Phase 3, none of which ultimately led to a marketed drug. Yet these setbacks deeply informed his current views on biomarkers, Phase 2 de-risking, and the dangers of confusing target engagement for disease modification. At Lundbeck, he has overseen the first-ever Bayesian adaptive Phase 3 registration trial in neuroscience (in MSA), a positive Phase 2b in migraine using a novel PACAP1 mechanism, and the company’s continued expansion into pediatric epilepsy through the Longboard acquisition. He is an active advocate within the field of clinical trial design – earlier this year he made the case for Bayesian adaptive designs directly to the FDA commissioner during a listening tour, and a draft FDA guidance on the methodology has since appeared.

In our interview, Johan discusses his early forays into neuroscience, hard lessons from failed BACE programs, the mechanics and promise of Bayesian adaptive trials, where he sees the next decade of neuroscience innovation, and strategic advice for young scientists thinking about careers in biopharma. He shares an adage from his Astra days: “You need the right people, the right assets, the right drugs for the right indications, and the right decisions. Then…you need luck. The first four pave the way for the fifth.”

Share

Below is an interview with Dr. Johan Luthman, Head of Research & Development at Lundbeck, from April 2026:

Subscribe now

1. You’ve spent your career in neuroscience. What initially drew you into the field, and was there a teacher or mentor who shaped that early interest?

I never planned my career path. A few things pushed me toward neuroscience. The first was my older brother, five years ahead of me, who went into medicine and then PhD training at the Karolinska Institute. He was the smart one in the family, and I admired him. Watching him do science made it seem cool, even though I had no idea where it might lead.

Some years later, I ended up at the same institute as a student. In my second semester, we had a histology course that included neurology, and the teacher was deeply inspiring — really committed to communicating what was beautiful about science. I asked him whether I could do something in his lab. He told me to come up after class, and when I did we started talking, I got hooked, and that was the start of it.

If my brother had not been in science, I probably would not have thought about it. If I had not encountered that particular teacher, I probably would not have gone into neuroscience. They were chance events, and I built on them. I started working evenings and weekends in the lab while still studying. Lab work is practical, and I am a practical person — I liked it.

2. You eventually moved to Astra, where you ran a neuroscience research group. While there, you co-authored the paper describing the Arctic APP mutation — decades later, this work laid the foundation for lecanemab. Can you walk us through how that paper came together?

First, some context about the era. I was actually recruited to Astra to do schizophrenia research, but reorganizations were a daily matter and I ended up in neurology instead. The Astra unit was unusual, with fully integrated R&D, dedicated to brain science--so dedicated that it did not even include pain, which was in a different unit.

Back then, in some companies like Astra, it was acceptable to maintain academic ties. You could have a university affiliation and host PhD students who split their time between an industry lab and an academic one. I had that arrangement with the Karolinska Institute, a half-hour drive from the Astra site. There is less of that today, which is unfortunate.

One of the students who came through that arrangement was Camilla [Nilsberth], who started as a master’s student in our labs. She wanted a project, so I took her on. Around the same time, I reconnected with Lars Lannfelt, a professor at Karolinska who was working in genetics. He had actually learned some of his early genetics from my brother, which was another nice coincidence. Lars had identified a family with what would become known as the Arctic mutation. Camilla was paired with that project.

This was during the era when several dominant Alzheimer’s mutations were being identified – the Swedish mutation, the London mutation, and so on. I assumed at first that the Arctic mutation was just another in that series. But it had striking characteristics: it caused a very rapid and aggressive aggregation of the Aβ peptide. Because the aggregation was so fast, we could begin isolating the aggregated forms of Aβ and characterizing them. Lars later sent some of those aggregated forms to a company that raised a mouse antibody against them, and that work became the foundation of BioArctic. He started the company alongside his academic work. Camilla continued in academia and became a clinician – she is now a geriatric medicine specialist at Linköping, and she has spoken publicly about the privilege of being an[JL1] Alzheimer’s disease doctor, having first-authored the paper that characterized the mutation 25 years ago. That arc, in one person, is hard to beat.

The most striking reflection, looking back, is the time horizon. From that mutation to a drug on the market was a 25-year journey. There is one detail I will never forget: when BioArctic was being formed, there was internal discussion at Astra about whether we should participate. My boss at the time looked at me and said, “Jump off this one. This will never become a drug.” I have not seen him in many years, but I sometimes wonder what he would say now that the drug is on the market.

I later had the pleasure of returning to that very same biology when I joined Eisai, which had picked up the program fully already in during 2007, after a research partnership initiated in 2005, and had since then been running the entire development program.

3. From this story, what are the major lessons learned about neuroscience drug development?

The headline lesson is that even after the drug arrives, the work is not finished. You still need to identify the right patient populations, treat early enough to see benefit, and build the diagnostic and reimbursement infrastructure around the drug. The full benefit takes another arc beyond approval.

The longer lesson is about the structure of the business. In neuroscience, the time horizons are inherently long, and the success rates are inherently low. That makes it easy to lose conviction along the way — including, sometimes, from your own leadership. The BioArctic story is a reminder that strong opinions held with little information are dangerous, and that the people closest to the biology are often best positioned to judge what is worth pursuing.

For me personally, it is also a lesson in patience. The work I did in my late twenties became the foundation of a drug that reached patients in my late fifties. That is the rhythm of this field. If you cannot tolerate that, neuroscience is probably not where you should be working.

4. While you were running the lab at Astra, you also went through internal business training. Was that when your interest in management and broader R&D leadership took shape?

Honestly, I was not particularly interested in management at that point. I thought it was great to do lab work and run a small team — five or six people. The work itself was what energized me.

What changed was realizing I was working inside a company. The path from academia to industry is more challenging than people expect. The lab looks similar, but the work happens differently — performance reviews, structured planning, organizational expectations. After a while, I realized I needed to take leadership and management seriously, not as a passion, but as a basic part of doing the job well.

What was unique about Astra, and what I am genuinely grateful for, is that they invested in business training. They thought I had potential, so they put me through a series of courses, and by the end, I had effectively completed a mini-MBA inside the company. None of it came from a deliberate desire to acquire those skills — it came on the journey. Now I understand how important it is to “dig where you stand”. I did the work in front of me, and other things came my way.

5. After Astra and Serono, you joined Merck and worked on BACE inhibitors — a class that was, for a long time, considered one of the most exciting opportunities in Alzheimer’s disease. What did you learn from that experience?

The BACE story is one of the hardest learnings of my career, because the program looked, on paper, like the “ideal” Phase 2 trial.

The mechanism and scientific rationale was strong. BACE is a protease that generates Aβ peptide, and we had excellent target engagement biomarkers – you could measure Aβ in serum and CSF and watch it come down with dosing. We could build clean PK/PD models showing how much Aβ generation we were inhibiting at any given exposure. There was a strong belief that lowering Aβ would translate into clinical benefit.

That translation did not happen. We were blinded by something we should have appreciated earlier: BACE is extraordinarily promiscuous. It cleaves up to a hundred different substrates, and some of the off-target consequences only became visible late. One striking finding was hair and skin depigmentation, first in animals, then in humans, caused by BACE acting on a protein in melanocytes. No one would have predicted that from the canonical biology.

The deeper lesson is about trial design. There was a prevailing belief at the time that Phase 2 in Alzheimer’s was not worth doing, because you could not power it strongly enough to truly de-risk Phase 3. The argument was: just go straight to large Phase 3 trials. Those trials are enormous and take years. The discipline I would urge now is the opposite: do Phase 2 studies slowly and carefully. Build a real bridge between target engagement and disease-relevant biomarkers, not just mechanism-of-action biomarkers. We were measuring the biomarker for the mechanism, not the biomarker for the disease, and we let ourselves believe one implied the other.

I was involved in three BACE programs through Phase 3: two at Merck, one at Eisai. By the time I was running the third, the prior two had failed for safety reasons: liver toxicity in one, hints of brain volume loss and cognitive worsening in another. Running the last program knowing the others had collapsed was one of the most difficult professional situations I have ever been in. I left for Lundbeck before that program terminated. It is a situation I never want to be in again, and it is why I am so adamant now about disciplined Phase 1 and Phase 2 work.

The one consolation from that era is that the work was not entirely lost. At Merck, we had to build a great deal of infrastructure around those programs: diagnostic biomarkers, imaging biomarkers, blood-based biomarkers, companion diagnostic work. I was personally involved in validating some of those tools. The drugs failed, but the diagnostic infrastructure is still out there and is genuinely important in Alzheimer’s diagnosis today, including for identifying patients who can benefit from the antibody therapies that did make it through. That is the consolation prize of failure in this field: even when the molecule does not work, the surrounding science can outlive it.

6. With on-target toxicity that takes time to manifest, are there ways to detect it earlier — better assays, better trial designs — or does the field just have to accept that some toxicities only emerge with scale?

It is a bit of both. Some on-target toxicity simply requires time and patient numbers to surface, especially when the effect is subtle or delayed. That is why drugs sometimes reach the market and only then reveal issues at scale.

What you can do is invest aggressively early. In neuroscience specifically, we now have access to far more sensitive readouts — digital cognitive and motor measures, imaging biomarkers, fluid biomarkers — that let you cast a much tighter safety net early on than you could a decade ago. Combined with extensive preclinical safety work and the right kind of clinical pharmacology in Phase 1, you can catch a lot. But the size and duration of your studies still matter. The mechanism dictates how dense your safety net needs to be, and how long the drug has to be in patients before you trust it.

7. You’ve been a vocal advocate for Bayesian adaptive trial designs in neuroscience. What makes the methodology powerful, and where is it best applied?

Bayesian statistics is not new – it goes back to Reverend Thomas Bayes in the 18th century. But it never really took hold for clinical trials, because the computational power required to run the simulations did not exist. With modern computing, and especially with the work that underlies machine learning, the barriers have come down. The heart of what AI is doing today is, conceptually, what Bayes was doing: using past information to predict the future.

The simplest way to describe the contrast (with traditional trials) is with an analogy. A traditional frequentist trial is like driving a car blindfolded. You drive a fixed distance, then stop, take off the blindfold, and check where you landed. You either hit your target or you did not, and that is when you find out. A Bayesian adaptive trial is like driving with your eyes open. You continuously gather data, continuously update your model, and continuously adapt. You can do this without unblinding the trial — the algorithm operates behind the scenes, adjusting things like patient allocation, while the team running the study remains blinded to outcomes.

The other benefit is what you get out at the end. A frequentist trial gives you a p-value – essentially, how likely it is that the difference you observed could have occurred by chance under the null. A Bayesian trial gives you a posterior probability: given everything we knew before plus everything we learned during this trial, how likely is it that the drug works? If your posterior is 90%, that is a very different statement, and a far more useful one for a drug developer making the decision to advance.

The big caveat is the prior. The strength of a Bayesian readout depends on the strength and breadth of the information you bring into it: what populations it represents, what geographies it covers, how relevant it is to the patients you want to treat. A weak prior or design gives you a weak posterior, regardless of how the trial runs.

We are running a Bayesian Phase 3 in MSA right now. To my knowledge, it is the first ever Phase 3 registration trial in neuroscience designed this way. Getting there required naturally a supportive Phase 2 trial to build a prior, but we also did a natural history progression study to build further on the prior and a major scientific engagement with regulators, who are understandably quite conservative about novel statistical approaches. But through this trial we are establishing a meaningful precedent for the field.

The regulatory tailwind is also picking up. Earlier this year, I had three minutes to present to FDA Commissioner Marty Makary during a listening tour, and I used the brief time to make the case for Bayesian designs. He didn’t comment on it directly, but the FDA has since released a draft guidance on Bayesian methodology, which I was very glad to see. The methodology was held back for years by computational limits and regulatory caution; both constraints are now loosening at the same time.

8. The MSA Phase 2 read showed a roughly 20% slowing in disease in a less impaired subgroup, though the primary endpoint did not hit statistical significance. How did that data shape the Phase 3 design?

I had seen versions of this movie before in my Phase 2 BACE work, so I was attentive to certain patterns. What surprised me about the MSA data was the consistency. The signal was not just on UMSARS – it appeared in different MSA subtypes (parkinsonian and cerebellar), in early- versus late-stage subgroups, in quality-of-life measures, and in volumetric MRI. In a small trial, when you start slicing into subgroups you can find almost anything, so consistency across multiple lenses matters.

The other reframe is what a 15–20% slowing actually means in MSA. This is a rapidly progressive disease in which each step on the rating scale represents a meaningful loss: the ability to walk, the ability to swallow, the ability to live independently.

Unlike Parkinson’s disease, MSA does not have effective symptomatic treatments that confound disease-modification readouts. UMSARS is not muddied by patients being on dopaminergic therapy. That made the disease an ideal candidate for a Bayesian design built on natural history.

The Phase 2 itself was small, about 60 patients, and we were not powered to hit a frequentist primary. But it allowed us to build a much stronger prior. By the time we designed the Phase 3, we had natural history data, our own placebo-arm progression data, and a measured posterior probability from the Phase 2 of around 87–89%, against a target of 97.5%. That is the kind of input that justifies committing the resources of a Phase 3 in a rare, devastating disease.

9. Another of your programs recently hit its primary endpoint — a PACAP-targeting antibody for migraine. PACAP feels like it is opening up a new chapter after the CGRP class. Can you walk us through the biology and where this fits?

Migraine is one of the most underappreciated diseases in medicine. People who have it occasionally, say, after a glass of bad red wine, do not understand what it means to have it daily. There are patients, often young women, sometimes teenagers, with severe migraine attacks every day. That reshapes a life: school, work, relationships, family, all of it.

The vascular hypothesis of migraine has been around for a long time, and the family of drugs going back to the triptans engaged that biology. CGRP is a neuropeptide that acts on sensory neurons and on vascular tone, and it became an obvious place to intervene. I worked on CGRP for many years at Merck. We developed three small-molecule CGRP receptor antagonists – ‘gepants’. The first one failed in Phase 3 due to liver toxicity. The other two were eventually divested and ultimately reached the market through another company. So I know the class well.

When I came to Lundbeck, we entered the migraine space through an acquisition, which brought us a CGRP-targeting molecule and an early-stage program targeting PACAP, a related but broader-acting neuropeptide. PACAP affects not only pain pathways but also autonomic features: red eyes, lacrimation, and other signs that migraine patients report. The biology demonstrated a positive proof-of-concept in human experimental medicine more than 20 years ago, and one of the clinicians involved in that early work is now at Lundbeck. Our smaller proof-of-concept study supported the mechanism, and we have now obtained further support in a larger Phase 2b. We are advancing the program towards a Phase 3 program.

This matters because even within the CGRP class, a meaningful number of patients do not respond or cycle in and out of response. A second mechanism in a devastating, daily disease will be important. There has not been a new mechanism in migraine in 20 years.

The broader reflection is that even in an era of rational drug design, clinical observation still drives the field. The discovery that botulinum toxin helped migraine came from a plastic surgeon noticing that cosmetic patients reported their headaches had disappeared. That kind of serendipity is not going away.

It is also why I keep coming back to a saying I repeat often: in this business, you need the right people, the right assets, the right drugs for the right indications, and the right decisions. Then you need luck. The first four pave the way for the fifth. You can do everything we have been talking about – the biomarkers, the Bayesian designs, the disciplined Phase 2 work – and you are still, in the end, trying to put yourself in a position where serendipity has somewhere to land.

10. Lundbeck recently entered pediatric epilepsy through the Longboard acquisition. The lead asset is a selective 5-HT2C agonist for developmental and epileptic encephalopathies. Why this space, and why this molecule?

Several reasons, and they line up with strategy. Lundbeck is committed to severe diseases with high unmet medical need, particularly in neurology and increasingly in psychiatry, with a strong orientation toward rare diseases. Few patient populations are higher-need than children with developmental and epileptic encephalopathies: kids with devastating seizures, developmental impairment, meaningful mortality risk, and around-the-clock caregiving needs. If we are serious about going where the need is greatest, this is an example of an area we should engage in.

Lundbeck also has history in epilepsy. The company had a US presence in epilepsy for years, and we still have the anticonvulsants on the market such as clobazam for Lennox-Gastaut syndrome. So the institutional memory and some of the clinical relationships are intact, even though we had stepped back from the area. Personally, I worked on epilepsy at Eisai, including in Lennox-Gastaut, so the disease space is familiar to me. My CEO also has epilepsy experience from a prior company. It is a big leap into a complex space, but we have the people and the foundation.

Bexicaserin is a highly selective 5-HT2C agonist. The mechanism stimulates inhibitory interneurons through serotonin signaling and ultimately damps down excitability. This is also biology that Lundbeck knows well. We have deep history in monoamine pharmacology, and our scientists were able to characterize the molecule rigorously before the Longboard acquisition.

11. Looking out five to ten years, where do you see the most exciting opportunities in neuroscience? If you were building a wish list, what would be on it?

The honest answer is that there are too many interesting opportunities to handle. Neuroscience is roughly ten years behind oncology, but we are now where oncology was when biomarkers and precision medicine started to take over, and the field is moving fast. Ten or fifteen years ago, people worried we were running out of drug targets in neuroscience. That problem has reversed. We now have an embarrassment of riches. The constraint is not ideas, it is capital and focus.

Within that, a few areas stand out for me.

First, rare neurological diseases. Many of these are genetically defined, which means tighter populations, stronger biomarkers, and a more direct path to precision medicine. Lundbeck has more than 70 years in neuroscience, which positions us well in that space.

Second, neuro-endocrinology and the brain–body axis more broadly. We work on the HPA axis, and there is a lot of biology between the brain and the adrenal that we have barely begun to address therapeutically.

Third, sleep medicine. Almost everything we touch in neuroscience affects sleep, and sleep itself is reciprocally connected to nearly every other disease we care about. I think sleep is going to undergo something like the rejuvenation that obesity went through. For years obesity was a no-go area for drug developers; then GLP-1s, which, incidentally, act in the brain, changed the field. I expect something analogous in sleep.

Fourth, the truly hard chronic neurodegenerative diseases. Alzheimer’s, progressive MS, MSA, ALS, and Huntington’s. Huntington’s is a particularly painful example – it was the first disease for which a causal gene was identified, more than 30 years ago, and we still do not have a disease-modifying therapy. The time is ripe to deliver something there, and we now have a much richer set of tools: antisense oligonucleotides, gene therapy, AI-enabled small-molecule design. Recent data from gene therapy in Huntington’s deserves real scrutiny. There are reasons to be both encouraged and cautious, but the trajectory is clearly forward.

Finally, do not write off psychiatry. For example, schizophrenia is one of the most devastating diseases in medicine, and we have very little to offer beyond the antipsychotics that have been on the market for decades. I think there will be breakthroughs in psychiatry, and I think they will come from two directions. One is psychedelics, used in disciplined and increasingly sophisticated ways, primarily for treatment-resistant depression. The other is immunopsychiatry – autoimmune conditions like anti-NMDA receptor encephalitis that present with many symptoms, but commonly with severe psychosis but respond to immunotherapy. It is plausible that some patients carrying schizophrenia diagnoses today actually have autoimmune conditions we do not yet recognize.

Psychiatry is still built on a very crude diagnostic foundation: you tell us your symptoms, and if you have enough of them for long enough, you have the disease. If we can get to real biomarkers and real mechanisms, the field will look different in a decade. There is also a historical inversion worth keeping in mind. Psychiatry used to be the dominant field; neurology came in as the renegades. The pendulum has swung the other way for a long time now, but you can imagine it swinging back. Many neurological diseases present first in psychiatric clinics – Alzheimer’s with depression and aggression, anti-NMDA encephalitis with psychosis. Maybe what we will eventually discover is that a lot of psychiatry is really neurology.

12. For someone earlier in their career — an undergraduate, MD or PhD interested in neuroscience drug development — what skills and mindsets matter most?

The skill profile of the field is changing more rapidly than it ever has, so I would hold predictions loosely. But there are a few patterns that I think will hold.

For lab scientists, the highest-leverage skill increasingly is the ability to combine biological training with AI and computational fluency. We are designing drugs with AI now. We are running lab work guided by machine learning. People who can sit at the interface – a chemist who is also a competent ML engineer, a biologist who can build pipelines – are in extraordinarily high demand. Combining a traditional life-science degree with serious computer-science exposure is one of the strongest career bets right now.

A caveat on AI itself, because it is easy to get carried away. AI has all the past information, but the field still needs new information, and AI cannot generate that, at least not yet. The lab work, the clinical observation, the kind of serendipity I mentioned with botulinum toxin in migraine – those still come from people. Some of us have a Luddite reflex about every new technology, and that reflex is usually wrong. But the opposite reflex, that the tool replaces the work, is also wrong. AI is a powerful instrument inside a system that still depends on people generating new ideas.

For clinicians, the field still has a high need for physicians who are deeply scientific. MD-PhDs who understand the biology, who care about biomarkers, who can run experimental medicine studies – those are valuable people. The trade-off is real: when you move into industry, you generally stop seeing patients. That is a hard transition for some, and I would encourage anyone considering it to be honest about what they will miss.

Beyond skills, three things matter at least as much. The first is the willingness to follow what genuinely engages you. It sounds trite, but the difference in performance between people working out of curiosity and people working out of obligation is enormous. There is a caveat – “follow your passion” works better in fields with broad opportunity than in winner-take-all ones; the actor or artist with the same drive faces a much harder market. Drug development is broad enough that genuine drive almost always finds a place. The second is the willingness to move, across countries, across companies, across disciplines. A career that spans multiple geographies and multiple cultures builds a network you can draw on for the rest of your life. My own network spans Sweden, Switzerland, the US, Denmark, and Japan, and it has been one of the most enduring assets of my career.

The third piece is openness. Stay open to ideas, to people, to pathways you did not plan. You will not be able to script the most important moves of your career in advance. The people who do well are the ones who notice the doors when they appear and walk through them.

A parting observation, which is really an application of the Bayesian point. People love to repeat other people’s mistakes. No one likes to listen to the old generation – that is a classic, and I was in that seat myself. I did not listen either. But that may change, because AI is going to make accumulated experience much more queryable than it ever has been. Maybe it is less about old people like me lecturing and more about wisdom being accessible at your fingertips. I find that genuinely exciting.

Share

At Decibel Therapeutics, Joe and Adam led the development of DB-OTO, a one-time AAV gene therapy for otoferlin-mediated hearing loss — a condition in which children are born profoundly deaf despite having a structurally intact cochlea. Otoferlin is the protein responsible for triggering neurotransmitter release at the synapse between hair cell and auditory nerve: without it, sound enters the ear and simply stops. The challenge was formidable: “it was a risk for us, for the company and for patients,” Adam, now CSO of Source Bio, emphasizes. The otoferlin gene is too large to fit inside a single AAV, requiring a dual-vector approach in which two viral vectors deliver split halves of the gene that recombine inside the hair cell. And because AAV capsids inevitably transduce off-target cells, including immune cells that can mount a response against the foreign protein, the Decibel team drew on their deep single-cell genomics work to engineer hair-cell-specific promoters that restricted expression to exactly where it was needed. “The promoter work was probably the most important technological differentiator Decibel had,” Joe, now CEO of Source Bio, explains. That precision in expression control, combined with local delivery to the confined space of the inner ear, is what made the therapy’s safety and durability profile possible.

The results from Regeneron’s CHORD trials after acquiring Decibel’s otoferlin program have been striking. Children born profoundly deaf, registering no response on standard hearing tests, are recovering normal or near-normal hearing thresholds after a single injection. “When I heard about the clinical results and saw videos of these kids hearing sounds for the first time…we both stopped our day to watch it. I think I cried,” recounts Adam. The responses appear durable, and early speech perception data are encouraging. Teenagers are responding alongside younger children, suggesting a wider treatment window than many expected. “Some of these patients were going back to normal thresholds, which was absolutely incredible,” explains Joe. Now granted FDA-approval (April 2026) DB-OTO is the first FDA-approved genetic medicine for hearing loss — a condition that, by prevalence, dwarfs most other congenital disorders that have received far more biotech investment.

Joe and Adam are both trained scientists who came to the inner ear from different directions. Joe did his PhD work on cochlear hair cell regeneration and performed some of the first single-cell genomic profiling of the ear at NIH. Adam spent years at Genzyme (through its acquisition by Sanofi) working on gene therapy programs and building expertise in computational biology and genomics. They met through Third Rock Ventures, which founded Decibel in 2016 with the ambitious, largely unprecedented goal of building a therapeutics company focused on the ear. Together, they pushed the company toward gene therapy for genetic deafness, a direction the founding investors initially didn’t want to pursue, and built the scientific platform that made DB-OTO possible.

Today, both are co-founders of SourceBio, where they are applying the lessons of Decibel to a far broader canvas: using locally delivered, low-dose AAV gene therapies as “biofactories” that secrete therapeutic proteins for common chronic diseases. “We’ve gotten our first development candidate at Source for roughly ten to twenty times less than what it cost at Decibel,” says Joe, “and we like this candidate as much as we liked DB-OTO.” In our conversation, Joe and Adam reflect on the scientific journey from academic labs to a potentially landmark therapy, the state of gene therapy as a field, and what it will take to bring genetic medicines to common diseases that affect millions.

Share

Below is an interview with Joe Burns (CEO) and Adam Palermo (CSO) of SourceBio and formerly Decibel Therapeutics from April 2026:

Subscribe now

1. At Decibel, you two developed what is now officially the first FDA-approved medicine for a genetic hearing condition. Data from the CHORD trials showed that a single injection of DB-OTO can restore normal or near-normal hearing in children born deaf. And on top of all that, Regeneron is going to make it free in the US. Very few people in science or medicine get to be part of something like that. Before we get into the story of how it happened, how does it feel?

Joe: The two immediate reactions are joy and anticipation. Joy from being able to help patients and their families in such a profound way — it’s the best kind of joy you can get. And then anticipation, because — wow, this technology is really working, and I’m so excited about the potential of where it can go next. And how amazing for patients that such a complex medicine will be so accessible. What a bold move by Regeneron. The biggest theme you’ll see throughout this story is that it required a lot of risk-taking and fortitude from the very beginning all the way to the approval. It’s a one-of-a-kind story, and it’s really a testament to the power of genetic medicine if you do it right.

Adam: The first I heard about the clinical results was from Jonathon Whitton, who was co-lead on the program with me at Decibel and who then joined Regeneron after the acquisition and shepherded the program to approval. He sent us a video: one of these kids walking around, hearing what her parents said. We both just stopped our entire day to watch it. I think I cried. I’ve been involved in other drug approvals before, mainly when I was at Sanofi, but in those cases, the drug was so far along in development that I was just helping to understand what was going on in clinical trials. This one, we started from the beginning. We were the ones, along with others at Decibel, who decided to take on this huge risk. When you take a risk in this field, it can be many years before you know if it was the right call, and you’re taking that risk not just on behalf of yourself but on behalf of patients, the scientists whose shoulders you’re building on, the people you work with, and your investors. To see that bet actually pay off for all those people, especially the patients — that’s an amazing feeling. It’ll be exciting to see people growing up on this treatment now that it’s approved.

2. Joe, you studied the inner ear as a doctoral student. What initially drew you to this organ, and what kept you in the field?

Joe: I got my PhD in a biomedical engineering department, but did the work in a neuroscience lab. It was really my grad advisor, Jeff Corwin, who drew me into the field. In undergrad, I was taking a tissue engineering course, and he came in as a guest speaker and gave this fascinating talk about how non-mammals — sharks, fish, frogs, birds — all have the ability to regenerate the mechanosensory cells that detect sound and gravity in the inner ear, canonically known as “hair cells.” And it’s a robust regenerative capacity; for example, you can deafen birds by wiping out all their hair cells with loud sound, and they will fully regain their hearing over the course of a few months. However, mammals like humans, have lost that ability. We are born with our full complement of hair cells, and if they are damaged or lost, they never get replaced. Jeff was the person who discovered this remarkable difference between species, and he spent his entire career trying to figure out why mammals have lost their regenerative capabilities. I was hooked in that lecture. I joined his lab after getting into grad school, and the entire focus of my PhD revolved around that same question — why can’t mammals regenerate, and how do we get them to? I’m a very applied thinker, and the translational potential of this research was very alluring and captivated me for almost two decades. It doesn’t hurt that the inner ear is the most architecturally beautiful and fascinatingly complex organ in the body either…

3. Adam, you spent three years at Millennium Pharma doing research before going to grad school. What was that experience like, and did it cement your interest in an industry career early on?

Adam: I was different from a lot of the other students in my undergrad major, in that I didn’t want to go to medical school, and I didn’t want to be a consultant. I had always wanted to invent stuff. So I was drawn to science, but specifically applied science. I had no idea what a career in industry would look like when I was a college senior, but I did have an idea of what an academic career looked like, and it felt too theoretical. I wanted to be working on applied problems, so I went to industry initially.

I got into Millennium just as genomics was exploding in the late 90s, hoping I could make my career there and maybe never go back to grad school. It was a crazy time — investment felt easy for Millennium to come by in that era. We thought we could solve any problem just by collecting more and more sequencing and expression data. It took the field a lot of years to learn where the limitations were. But during that period, as long as you could do anything with confidence, it was easy to get a lot of responsibility, and that’s what happened to me. It was a great time and a great intro to industry — both the possibilities and the pitfalls. Eventually, I decided I needed more discipline in my project planning and thinking, and that’s what drove me to grad school. But I went knowing I was coming right back to industry as soon as I finished.

[Lessons Learned at Millennium]

Adam: When I started at the company, they were putting a huge emphasis on collecting expression profiling data across all kinds of contexts. I was in a subsidiary that was using that data to make multidimensional biomarkers. The belief was that we could collect data across every kind of cancer and build biomarkers that could tell you anything — stage the cancer, predict how a patient would progress, and so on. Meanwhile, the parent company had done an enormous deal worth half a billion dollars with Bayer, promising to deliver 200-plus new drug targets from all this profiling.

The main lesson, and everyone who was there will say the same thing, is that data alone isn’t enough. You need a huge amount of post-data-collection insight as well. A single data modality without a strong connection to the underlying cause probably won’t get you there. You need other information, other experimental capabilities to really make it work.

When Velcade came into Millennium through an acquisition, a lot of us were really excited. Here was something concrete. The path from basic biological understanding to a new target to a drug is incredibly long, but Velcade was already a drug, and we could believe in it. People gravitated to that, including me, and seeing how something very concrete could be married up with genomics and high-throughput data to produce real value has been a grounding principle for me ever since.

Share

4. What led each of you to Third Rock Ventures in 2016, and what did you take from your prior careers into your work at Decibel?

Joe: When I started my postdoc at NIH, I had become focused on identifying the molecular factors that control the identity of different cell types in the ear, with the hope of co-opting them to stimulate regeneration using gene therapy. The problem was the ear contains a vast array of different cell types, and we needed to be able characterize the gene expression patterns of each one. Fortunately, single-cell genomics was just starting to emerge thanks to the pioneering work of Aviv Regev, Evan Macosko, Stephen Quake, and others. In a single profiling run, you could deconvolve all the cells within a complex tissue like the ear and parse what each cell type was expressing. The NIH was a fantastic environment to work on cutting edge technologies like this, and I established the techniques and performed the first single-cell RNA-Seq experiments on the inner ear while there. It was a very exciting time, and the work received a lot of attention.

I was able to leverage this into a K99 grant and faculty position interviews and offers. Right as I was in the middle of the interview process, I got a call out of the blue from Third Rock Ventures. It turned out they were also interested in the single-cell technology I had been working on. The pitch was: we’re going to start the world’s first real hearing therapeutics company, do you want to join us? My first reaction was — who are you? I was down in the DC area and didn’t understand the Boston biotech ecosystem at all. I had always envisioned getting into biotech and starting my own company, but there just weren’t any companies working on hearing at the time. My plan was to run my own academic lab, discover something that restores the ear, and spin out a company from there.

I flew up and interviewed with the Third Rock team at their office on Newbury Street, and got exposed to VC for the first time. I’ll never forget interviewing with people like Kevin Starr, Stefan Vitorovic, and Craig Muir. It just had such a different vibe compared to academics, in a good way. I quickly started to appreciate that they were serious and were going to invest a lot of money. It was everything I wanted to do in my academic startup lab, but much better financed and much more applied. I debated the decision a lot, but it was a no-brainer in the end. So I moved up to Boston, bringing everything I had been training for over the last decade with me.

Adam: After grad school, I was at Genzyme, through its acquisition by Sanofi, for a bunch of years, and one of the major lessons I took away was just how powerful some of these gene therapy methods were. This was the late 2000s into the early 2010s — a relatively dark period for gene therapy. A lot of companies had divested for historical reasons, but Genzyme had kept its discovery programs going, mostly focused on neurodegeneration and skeletal muscle degeneration. I was looking at those results, getting really excited, and started thinking about how to apply my skills in computational biology and genomics to make these therapies better and more specific.

At the same time, the company went through a massive acquisition. Genzyme was a 10,000-person company that became part of a 100,000-person company. It was a big cultural transition. In a company of that size, decisions just tend to be hard and slow. Eventually, I got frustrated, and through connections to ex-Millennium folks at Third Rock like Craig Muir and John Kielty, I started exploring smaller companies where I might make a bigger difference.

So I was in the right place to try something new when I got introduced to Decibel. I’d worked on many different biological systems, but I didn’t know the inner ear, and as Joe said, it’s just so beautiful. The opportunity to understand this system was part of what got me excited. The other part was the people. When I was interviewing, Joe had just signed on, and after we talked, I thought, this guy is really good, and this team is going to be really good. That made the decision for me. I went in as an ear neophyte but as more of a genomics and gene therapy expert.

5. What were the early days of Decibel like, and what were the key decisions that set the company’s direction?

Joe: It was so dynamic and so much fun. It was also a bit out of the ordinary because there was almost nobody with prior ear experience who had worked in industry, and vice versa, so you had a mix of academic ear biologists and extremely experienced drug developers. There was so much learning going back and forth between the two groups. We were really co-dependent on each other.

Third Rock took a very big risk on Decibel. There had been no real attempts to develop therapeutics in that space, and it was a testament to their fortitude, especially people like Craig who was the initial champion within the firm. There are a lot of stories about how those early funds broke from the norm when conservatism dominated the investment community. They backed a lot of things nobody else had the stomach for, and it paid off in the long run.

Decibel is a good example. The biology was early, and the company’s focus wasn’t really set in stone. But Third Rock saw a huge unmet need, and they saw what was happening in the eye space — drugs starting to emerge, the biology being figured out — and they saw single-cell genomics starting to take off. They thought, maybe we can accelerate target discovery in this complex tissue and be the first to develop drugs for hearing loss.

Adam and I were in charge of setting up a target discovery engine based on single-cell genomics, and we had a very broad remit in terms of indications we could pursue. There was a lot of pressure to accelerate the biology and find something that could be drugged. The one thing Third Rock was certain about was that they didn’t want to work on gene therapy for genetic hearing loss. Adam and I spent the first six months scrambling to build a single-cell genomics platform that could profile the ear at a scale nobody in academia had achieved. We pulled it off — we had an incredible platform in place. But in parallel, publications were emerging showing that AAV-based gene therapies could correct specific mutations in mice and restore hearing. We both had gene therapy backgrounds, and we were so compelled by that data. Not long after, we started pushing the leadership: we really need to consider gene therapy for genetic deafness. We’ll keep chasing targets for bigger indications, but this is where the first therapies are going to come from. That ended up being one of the biggest early decisions. Looking back, that push was critical.

Adam: To support the case that an inner ear gene therapy company was viable, we made a range of arguments. There are more than 100 different genetic causes of deafness. If you can figure out how to address one efficiently and identify which others are tractable, you can build a platform that does many small things and adds them up. We also argued that once you figure out how to safely deliver genes into the inner ear, there might be ways to treat non-genetic populations with hearing or balance loss using the same tools. At the time, most people weren’t thinking about applying gene therapy to common indications, but we kept saying, “Look, this is a contained system.” It’s probably one of the safer places to apply gene therapy, and it might be the right place to start using these techniques to push regeneration of the hearing and balance organs, building on Joe’s academic work.

The other thing that helped us get over the hump was our conversation with Regeneron as a potential partner. They were interested in developing their own gene therapy capabilities, and when we proposed doing it together, they got really excited.

Share

6. Tell us about otoferlin — what the protein normally does, why its loss causes deafness, and what made it such an ideal target for gene therapy.

Joe: Hair cells detect noise when the long cilia that protrude from their surface are deflected by sound pressure waves. To relay that information to the brain, each hair cell is connected up to neurons that they communicate with via highly evolved synapses. Otoferlin is a large protein that is absolutely critical for that synaptic transmission. If you lose otoferlin function, sound information is not passed to the neurons, resulting in complete absence of hearing.

Hair cells are incredibly fragile, and many genetic mutations lead to rapid degeneration and loss of hair cells before the ear has finished developing in utero. So for inner ear gene therapy, one of the biggest questions is always the treatment window for the target gene/mutation: do the hair cells survive long enough that you can intervene after birth? That question was by far the biggest thing we needed to de-risk, and we were on the hunt for a Goldilocks gene.

We were exploring a bunch of different possibilities, asking the basic question: in mouse models with this mutation, does the ear remain intact once it’s mature? We created various models and evaluated all of them, including otoferlin. We were just starting to do work on the mutant otoferlin mice we had created when the definitive proof came from outside Decibel.

There’s an unsung hero in this story who doesn’t get talked about enough — a researcher named Omar Akil. I was at a conference in Morocco, and Omar presented work there he had done in collaboration with Bill Hauswirth and Larry Lusting showing that a) the ear in otoferlin knockout mice remains intact and pristine into adulthood, and b) if you deliver otoferlin gene therapy to an adult mouse with a fully mature ear — equivalent to a newborn human or older — you could completely restore hearing. It was such an amazing moment, I remember how much the room was buzzing throughout the presentation. I think everyone in the audience appreciated the enormous implications of Omar’s work. At that point, it was off to the races. I called our CSO, Michael Su, from Morocco and told him we have to get going!

7. From 2016 onward, what were the key scientific hurdles you had to clear, and what were the most important advances your team made in developing DB-OTO?

Adam: In gene therapy, people are really focused on the delivery vehicle — in this case, AAV. We did a lot of work figuring out the right AAV capsid, whether we should consider non-viral methods or other approaches. It turned out that AAV1, one of the most common and earliest-identified AAVs, is really good at getting into hair cells, especially in larger animals. Hair cells are easy to transduce with AAV1.

But once you solve the delivery question, many other issues remain. The first, partially solved by Omar and Bill, is that the otoferlin gene is too large to fit within a single AAV. An AAV has only about 4.5 kilobases of packaging capacity, which must include the promoter and all regulatory elements. So we needed to split the otoferlin gene across two separate AAVs that get delivered simultaneously, enter the cell, and recombine into an intact expression cassette. We spent a lot of time optimizing around various ideas about how to do that for maximum efficiency.

All of that is the baseline. But the real differentiator, and this was the major insight we had at Decibel, was expression control. Natural capsids have some cell specificity, but it’s not absolute. They have slight preferences, maybe tenfold, for one cell type over another. So when you deliver an AAV expressing otoferlin, you get expression in the inner hair cells where you want it, but also in all the other cells of the cochlea, including immune cells. Those immune cells exist specifically to find and identify proteins the body has never seen before and mount a response. For that reason, having otoferlin expression in those cells is detrimental to the durability of the therapy.

This is where our investment in single-cell genomics paid off. Because we had built this deep profiling capability for the inner ear, we knew every gene that was exclusively expressed in inner hair cells and where all the regulatory elements were. We repurposed that data to design cell-specific promoter-enhancer combinations, and that became Decibel’s calling card. When we expressed otoferlin using our hair-cell-specific promoter, we achieved very good durability in mice. Meanwhile, with a ubiquitous promoter that drives expression in many other cell types, similar durability wasn’t there. That was probably our single biggest insight.

The third challenge was delivery itself. One of the things that trips up some gene therapies is the idea of delivering a vector into the systemic circulation, even when you only need to hit a few specific cells. This means going in with a huge dose that gets everywhere. That’s led to serious safety issues. The inner ear is self-contained, which makes it a natural fit for local delivery that stays highly localized. We had to figure out how to access that space — it’s the hardest bone in the body and relatively difficult to reach — but the containment is a huge advantage.

Joe: I agree wholeheartedly with Adam that the promoter work was probably the most important technological differentiator Decibel had, and it’s carried forward into what we’re doing at Source Bio. The field has spent so much time engineering capsids to target particular cell types, but it’s impossible to make them fully specific. You always get AAV into immune cells, regardless of the compartment, and expression there risks antigen presentation and safety issues. A sufficiently specific promoter — and it needs to be really specific — can make a huge difference. We care enormously about getting the promoter right, and we believe that’s contributed majorly to the success of DB-OTO.

8. Funding for rare disease and gene therapy became increasingly difficult after 2022. Where was the science at that point, and how did Regeneron’s acquisition of the program come about? And now that the CHORD trial data are out — what impressed you most, and what did it feel like to see those results?

[On the Regeneron Partnership]

Joe: We had some pilot efforts into AAV delivery going when Adam and I started pushing on gene therapy, but it was the Regeneron partnership that let us go after it in a big way. A small team of us at Decibel, along with a couple of our counterparts at Regeneron, put together a slide deck of about 150 slides to convince both the Regeneron and Decibel leadership that this should be a critical piece of the partnership. The Regeneron collaboration was finalized relatively early in Decibel’s history, and they continued to be strong supporters of our gene therapy efforts throughout. Regeneron was building out their own gene therapy capabilities in parallel, so there were a lot of mutual interests. We eventually IPO’d, and the IPO financing was used to complete IND-enabling activities and push DB-OTO into the clinic. Just as we were standing up the trial, a few things were happening. The biotech financing market was starting to head south, and Decibel was getting short on cash and looking at all its options, including acquisition. Looking at the chessboard, Regeneron did not want to lose DB-OTO to a turbulent financial market, and they recognized the opportunity to move quickly to a first-of-its-kind gene therapy approval. So they went ahead and acquired Decibel.

[On the CHORD clinical trial results]

Joe: In the trial, participants from 11 months up to 16 years old with profound deafness due to biallelic mutations in otoferlin were enrolled — and DB-OTO was delivered directly into the inner ear using the same surgical approach as for a cochlear implant. Some participants had a cochlear implant in one ear, and some didn’t. It’s worth talking about cochlear implants for context. They’re the standard of care and the primary treatment for genetic deafness. You need severe hearing loss to qualify for one, and we shouldn’t discount what they’ve done for patients — they’re absolutely amazing devices. But they do have limitations in sound quality. They just don’t faithfully represent natural sound from your cochlea, and studies have shown that children with cochlear implants often lag behind their peers in various developmental milestones.

The first question for DB-OTO was safety — specifically, whether the ear would remain intact enough for a cochlear implant to still work if something went wrong with the gene therapy. Does the cochlear nerve, which is all you need for a cochlear implant, get damaged? DB-OTO generally appeared to be safe and most adverse events were temporary and associated with the surgical procedure.

In addition to safety, the trial also looked at efficacy. Pure-tone audiometry — playing tones at increasing loudness to determine the threshold when sound is first heard — is the primary objective measure of hearing recovery. There were also speech assessments, though those were still preliminary in the study.

What stood out and got us excited: first, the sheer extent of hearing threshold recovery. Some participants were showing normal thresholds. Wow. Keep in mind, otoferlin patients are born without any hearing — on a pure tone audiometry test, they don’t register any response at all. To see some of them return to normal thresholds was absolutely incredible. Second, the durability. So far, the responses have been steady and stable with no loss of effect. Third, the early speech perception assessments are also looking positive. You can watch the videos and appreciate that this is working at a fundamental level.

We were also really excited about the treatment window — how late you can treat and still see benefit. Newborn hearing screening isn’t universal, and many patients never get genetic testing. The ideal is to treat as early as possible after birth, which is also true for cochlear implants — the standard keeps getting pushed earlier, sometimes as early as a year old. But what about the patients who were never caught on testing, or the ones who got a cochlear implant in one ear, hoping a better therapy might come along, and are now teenagers? Preclinically at Decibel, we had treated geriatric mice, well over a year old, with DB-OTO and seen incredible hearing recovery.

One last detail that I find very cool: the neutralizing antibodies. Many patients had pre-existing neutralizing antibodies against AAV, which is always a concern because they can bind the virus and prevent it from entering cells. In some trials, patients are screened out if they’re positive. But we had data at Decibel suggesting it might not matter in the inner ear. Our data showed that even with high systemic neutralizing antibody titers, we could still get very good transduction of hair cells. This held up in the trial — some patients had pretty high pre-treatment titers and were still experiencing strong recovery.

Subscribe now

9. Zooming out to gene therapy more broadly — where have the successes been, and what made them work? Zolgensma is the obvious example.

Joe: We talk about this at Source Bio on a daily basis. Up to this point, the biggest successes have been in areas with high unmet need where there are few or no existing therapies. Naturally, this has been rare, severe diseases, with AAV gene therapies like Zolgensma and Elevidys and the HSV gene therapy Vyjuvek having the best sales. Paradoxically, the commercially successful AAV gene therapies have had poor safety profiles, with multiple deaths reported for both Zolgensma and Elevidys, and Elevidys sales in the US are currently paused. These are systemically administered AAVs that are delivered at astronomically high doses, up to 1×10¹⁴ vg/kg in many cases. So it’s not surprising at all that we’re seeing safety issues, the age-old saying in drug development of “the dose makes the poison” applies equally to gene therapy. This type of high-risk, high-reward profile is not acceptable for diseases where there are already safer options, even if AAV can provide quantitatively better efficacy and the massive benefits of a one-time format. I think this is precisely why the approved AAV therapies for hemophilia have struggled. While hemophilia antibody therapies like Hemlibra need to be dosed chronically, they are just safer, and AAV has struggled to compete. Zolgensma is also a fascinating case study here because it has initially done well despite having competition, sharing a comparable amount of the SMA market with the antisense oligonucleotide Spinraza. This could be because both products came onto the market at a similar time and Zolgensma was able to establish itself before Spinraza became entrenched. In addition, both products are delivered via an invasive intrathecal injection, and Spinraza needs to be delivered multiple times a year, so neither is a slam dunk when patients are considering the risks. Roche’s recently approved daily oral Evrysdi is rapidly gaining ground, and it will be interesting to see if this safer format option eventually takes over.

Adam: An additional point is that SMA is fairly large for a rare disease. What’s happening across gene therapy and rare disease more broadly is that the set of diseases that are both unaddressed and large enough to be commercially interesting is shrinking. So, where does gene therapy go next if no remaining rare disease is large enough to attract investment? For us at Source, the answer is everything else — all the common diseases — if you can figure out how to solve the safety and other issues we’ve been talking about.

10. What needs to happen for gene therapy to move beyond rare disease and into more common conditions?

Joe: This is a good segue to where we think successes will come in the future. Adam and I strongly believe that gene therapy could bring unbelievable benefits to a wider range of patients, and the biggest thing holding it back has been safety. Gene therapies have been safest when applied locally. Whether it’s DB-OTO in the ear, Luxturna in the eye, or Vyjuvek applied topically to the skin, small doses of gene therapy in contained compartments will naturally have the best safety profiles. The next evolution is to take this concept to larger patient populations and more competitive indications. We’re already seeing this happen in the eye, with AAVs for wet AMD and geographic atrophy advancing in the clinic.

There is also a lot of discussion about the high costs of gene therapy making it untenable for common disease. It’s true that just the manufacturing costs of AAV delivered at 1×10¹⁴ vg/kg can be hundreds of thousands of dollars per patient. But the dose of locally administered AAV can be 100 to 1,000 times lower, and you can do the math on how much that decreases the cost of goods. There’s a lot more that goes into price than manufacturing costs, but I think local dosing allows AAV to be price competitive with other modalities, making cost less of a barrier.

11. That brings us to Source Bio. What’s the core concept behind the company, and how does its approach sidestep the safety, efficacy, and funding challenges that have held gene therapy back from common chronic diseases?

Adam: We founded Source on the premise that local delivery and lower doses can categorically change the safety profile of gene therapy and make it more broadly deployable for common diseases. The company is still in stealth, so we can’t say too much, but we can give a teaser. The core concept is to use AAV to create small, contained in vivo biofactories that durably secrete therapeutic proteins into the systemic circulation. Our approach does this without transducing the liver, or any other tissues of safety concern, and we’ve used our promoter engineering approach to constrain the expression tightly to secretory cells and away from the immune system. We think many different chronically dosed therapeutic proteins could be replaced with our technology, from small peptides up to large antibodies, with cost of goods low enough to support competitive pricing.

Joe: We’ve unlocked some really fundamental insights about how to do this in a very targeted, scalable, and low-cost manner. Since we have effectively eliminated the gene therapy safety concerns, the bigger question is what therapeutic proteins would you want to stably expose a patient to for up to a decade?

The data we’ve generated thus far is so exciting, and we think that having your body produce its own medicine could be a new modality in the future. Imagine a world in which patients don’t have to worry about dosing themselves with their biologic on a daily, weekly, or monthly basis. The impact on long-term outcomes, access, and drug costs would be profound.

12. What advice would you give to scientists thinking about a career in industry — and what do you wish someone had told you earlier?

Adam: Patience plays a huge role. I’ve developed the patience to wait for things to play out over the kind of timelines this industry actually requires. That’s something you’ve got to have. But you also need patience for the ups and downs of data — in any field, there will be times when you’re convinced something is never going to work. Part of maturing into a leader in this industry means becoming the person with an “even keel” who keeps people on the right track — yourself and your team. With a team like Source’s, we’re the leadership, but we’re also in the science every day — in the conversations where we interpret data and decide how to respond. We’re showing people: okay, we got this data, let’s take a breath, figure out what we need to learn, how to understand what it means, and if it’s bad news, figure out how to change course and keep moving. A lot of our staff are fairly experienced, and some came over from Decibel once Source was up and running, so they know how to reach success even when not everyone sees the vision.

I keep coming back to Third Rock and folks like Stefan [Vitorovic], having the fortitude to invest in something like Decibel. Or to take another example: the lore within Genzyme was that when the company was starting, the idea of going after rare disease at all was anathema, and it was just a few people’s commitment to that idea that transformed our industry for the next forty years. So I’d encourage people to be careful not to let the first resistance derail a vision you believe in.

Joe: To add to that — maybe less what I’ve learned about myself and more what I’ve learned from other people: resilience and conviction. From the very beginning, there were a lot of doubts about the commercial viability of gene therapy for deafness. There were plenty of questions about whether it should be Decibel’s lead program, both internally and externally. But overall, the team’s commitment was incredible, and there were individuals who were deeply passionate about keeping it alive because of what it could mean for patients, and they remained deeply committed through thick and thin. In drug discovery, there’s always the instinct to get to the quick kill — to cut something and move onto the next thing. That’s true to some extent. But the other side of that coin is: how do you stick with something when it looks challenging, when it looks like it might not work? It’s easy to walk away. It’s really hard to maintain belief in a vision and have the tenacity to make it come to fruition.

Question 13: What lessons from Decibel are you applying at Source, and what’s the hardest part of running a biotech today?

Joe: Every biotech company will tell you that capital is the biggest challenge right now. Everyone’s trying to navigate through it. What’s been interesting for us is learning just how ridiculously capital-efficient you can be — a lot of that comes from the Decibel experience and everything we learned there. We’ve gotten to our first development candidate at Source for roughly 10 to 20 times less than it cost at Decibel, and we like this candidate as much as we liked DB-OTO. You can do a lot when capital is constrained. That efficiency is extra important right now as we watch China do things so efficiently and cheaply — it’s a real wake-up call for US biotech. But we feel like we can be competitive. And we’re hopefully at a point now where the company is starting to hit its exponential growth phase. The data we’ve collected is really compelling, and we’re very excited about it.

Subscribe now

Share

For Dr. Ranjan (Ron) Batra, Chief Scientific Officer at Dyne Therapeutics, his “problem” over the last two decades has been neuromuscular disease. During his PhD training, Dr. Batra worked on designing targeted therapies for DM1 and DMD. He studied how gain-of-function toxicity and splicing disruption leads to neuromuscular pathology. He helped develop RNA-targeting tools to correct these dysfunctional proteins that have been useful across academia and industry. He then moved from academia (eschewing offers to start his own lab at Case Western and Harvard) to translational roles at Verily and LocanaBio, where he helped build AAV-based RNA splicing-modifier therapies. He deepened his understanding of delivery and gene therapy in his work at Lexeo therapeutics, prior to being recruited to Dyne as CSO: “My motivation comes from the desire to create impact…I wanted depth around a particular human problem to successfully ‘debug the program’ and truly help patients.”

The conversation comes at a pivotal moment. Dyne recently reported topline data from the registrational expansion cohort of its DMD DELIVER trial, with robust dystrophin expression (to ~5.5% normal expression), durable safety, and sustained functional improvement from baseline across 6 clinical endpoints. Earlier in 2025, they also reported results from the ACHIEVE trial in DM1, showing robust splice correction of DMPK and functional improvements through 1 year. For Dr. Batra, what matters is whether patients and clinicians can feel the difference. “We asked patients and clinicians, in a more blinded manner, whether they thought patients were improving,” he says. “Patients felt their daily activities were better, and clinicians had the same assessment.”

Dr. Batra also dives into the technical questions shaping Dyne’s strategy. He explains why microdystrophin has struggled to deliver durable benefit, highlighting protein size thresholds, AAV dilution in growing muscle, lack of redosing, and genotype-phenotype data from Becker patients, and contrasts this with RNA-based approaches that preserve endogenous regulation.

He discusses that TfR1 mediated delivery is now a clinically validated approach to deliver oligonucleotide and antibody payloads to skeletal muscle. Yet not all TfR1 shuttles are equal. Design principles can impact safety (e.g., if disruption of endogenous function leads to anemia) and distribution (e.g., amount of delivery to the brain vs skeletal muscle) and Dyne’s FORCE platform stands out on both dimensions. He also reflects on how to weigh molecular biomarkers against functional endpoints in slowly progressive diseases, and why patient- and clinician-reported outcomes are critical to an early understanding of clinical impact.

Throughout the interview, he returns to the same mantra: chase impact and stay focused on execution. This mindset extends to leadership as well. “Individual excellence only takes you so far,” he notes. “If the team is moving left and right together, back and forth together, you’re going to win.” Despite his own contributions and Dyne’s progress, Dr. Batra remains sober: until patients have an approved therapy — the problem remains unsolved.

Below is an interview with Dr. Ranjan Batra, CSO of Dyne Therapeutics from January 2026:

Subscribe now

1. What first made you interested in pharmacology and research? Was there an early mentor or teacher who set you on this path?

My interest in pharmacology started early, and it was very concrete. My dad was a pharmacist, and he used to bring home these pharmacology magazines and compendia. In India, one of them was the Monthly Index of Medical Specialities (MIMS) — a Yellow Pages of small-molecule medicines. As soon as I could read, I studied it: what does a drug do, how do you dose it, which patient populations would you treat? Why does one molecule work for a headache, but another causes skeletal muscle relaxation? I got fascinated by the idea that a molecule could change the course of a disease.

At the same time, I’ve always liked gardening, and plants were another doorway into the same fascination. I grew up in New Delhi, India, and the common flowers growing around me, such as Vinca rosea, are precursors to some of the most important chemotherapies. That connection between nature, chemistry, and human biology felt almost unbelievable to me. I remember thinking: if I could spend my life solving these mysteries – finding drugs, building drugs, learning where they come from – I could change how people feel. That was the first real motivation.

[On going to the US for graduate training]

After earning an undergraduate degree in pharmacology from the University of Delhi, I knew I wanted to pursue graduate school, so I took the Indian entrance examinations and pharmacy board exams. I got into the National Institutes of Pharmaceutical Education and Research (NIPER), which is one of the elite programs near Delhi. At the same time, I was admitted to the Ohio State University. I knew that in India, you could still get a great education and great ideas, but the frontier science often arrived with a lag. In the U.S., you were closer to where things were being invented. I knew I wanted to be at the cutting edge, and I chose Ohio State for that simple reason.

At Ohio State, I worked on small-molecule inhibitors of tau aggregation. That experience widened my horizons. I could take the pharmacology and medicinal chemistry I’d learned at the University of Delhi and apply it to cutting-edge molecules nobody had seen before — compounds that were invented in the lab. Looking back, it really was the right decision.

2. What were some of the highs and lows of PhD training, and lessons learned along the way?

PhD training had the usual highs and lows, but my first four years were mostly one thing: failure. I was chasing moonshots, and almost everything failed. But I chose that lab because I was fascinated by genetic medicine. Pharmacology was my foundation, and once I took a genetics course, I couldn’t stop thinking about biology as code. DNA is the operating system, RNA is the working program and proteins are the executed output. When a mutation inserts a bug into that system, such as a repeat expansion or a stop codon, the whole program can break and cause disease.

This type of thinking pulled me into Maurice Swanson’s lab. I became focused on RNA splicing, polyadenylation, and RNA editing — the machinery that determines which message is actually made. I wanted to “hack” that message. For example, if you can skip an exon in Duchenne, you’re not making the full protein anymore, but you can make a functional “near full-length” version. You’re effectively commenting out a problematic line of code and restoring a working program. That principle became the throughline of my PhD: build molecules, whether delivered through gene therapy or other approaches, that modulate RNA in a way that produces functional improvement.

The reality was that the biology was compelling, the tools were meaningful, but delivery kept failing. And in many ways, that delivery problem has been the long arc of my career. During those early years, my mentor helped me stay sane by reframing the work as a series of puzzle pieces. If one piece isn’t moving, focus on another piece where you can make progress, publish, and sharpen your judgment, and then come back. Biotech is slow, and in neurology in particular, the biggest successes are often 20-30 year stories. People who built drugs like Spinraza and Leqvio didn’t get there in a straight line. You stay at it. You keep chasing. That perspective is a big reason I stayed in the field long enough, and now at Dyne, I finally see delivery start to unlock. It takes a long time, but I’m truly happy to be part of something that will bring functional improvement to patients.

3. When you were in training, what was the “dream”? Did you know you wanted to eventually enter industry?

Honestly, I didn’t have a single “dream” job. The obvious path in a strong academic lab is academia, and I did consider it. I chose a postdoc because I thought I might start my own lab, and I had opportunities along the way — I was close to starting faculty roles, including nearly starting at places like Houston Methodist, Case Western and Boston Children’s-Harvard. But ultimately, I didn’t choose a direction based on career factors. Instead, I chose based on the problem I want to solve and the impact I want to make.

That’s the same reason I went to Verily, Google Life Sciences at the time. They were trying to address a key problem: using emerging approaches, including early forms of what we’d now recognize as generative AI methods, to predict responders versus non-responders and to understand disease subtypes in ways that could actually change how drugs are developed. It connected to techniques I’d already used in the ALS clinic at UCSD. The career moves might look nonlinear, but I’ve always been chasing the problem and the impact that functional improvement can have for patients with high unmet need.

4. As you moved from academic research into your position at Verily, what parts of that transition surprised you the most? What shifted for you in how you approached science?

Moving from academia into Verily surprised me in a few ways. The first was psychological: you’re trained to believe the only real scientific currency is the high-impact academic paper. I went in with the misgiving that I might lose something by leaving academia. I couldn’t have been more wrong. In industry, including at Google, we produced strong, high-impact work at a steady pace. The idea that industry science can’t be rigorous is just not true.

The biggest shift for me was focusing on human impact through product. When you look at projects through a product lens, you quickly see what has a path and what doesn’t. I learned to run crux experiments quickly across multiple approaches and make decisions about where to focus. This philosophy of being fast to fail is something I learned early and highlights the high impact projects deserving of my focus. The other thing that stood out was collaboration and team spirit. It exists in academia, but is precise in drug development, which needs a multi-disciplinary team — research, clinical, regulatory. Without all of those, you don’t get to something meaningful for patients.

[On leaving Google to start LocanaBio]

When I left Google to start Locana, it came from the same push: impact. How do I create the most impact? I thought building a company with top-tier VCs, Vida Ventures being one of them, and focusing capital and resources on a problem could move faster than spreading effort across fifty moonshots. I wanted depth around a particular human problem to successfully “debug the program” and create impact.

Subscribe now

5. What were the highs and lows of the LocanaBio journey? How did that experience change how you looked at what problems are worth building companies around?

When Locana was founded around 2016, it started as a diagnostics company based on platform work coming out of research in Gene Yeo’s lab (https://yeolab.com/ ) where I did my postdoc. The shift to therapeutics really happened in 2018, based on my postdoctoral work published in Cell (DOI: 10.1016/j.cell.2017.07.010), when I came back from Google Life Sciences to Locana and focus on the therapeutics angle.

Around that time, we had been talking with ARCH Venture Partners and Lightstone, who were interested in building a therapeutics company in neurology. We raised a seed round, followed by Series A and Series B with venture firms that included Vida ventures & Cure Duchenne ventures. In total, over roughly three to five years, we raised ~$160 million and built genetic medicine programs for DM1, DMD, and genetic epilepsies. From the beginning, we wanted Locana to be a true platform company. ARCH was very supportive of that approach. Coming out of a lab that focused heavily on RNA biology, it made sense to systematically test a wide range of RNA-targeting strategies. We looked at many different platforms that were emerging at the time.

We started early with RNA-targeting CRISPR, but it ran into immunogenicity and delivery issues pretty quickly, which limited its viability. From there, we explored other approaches and eventually focused on what we called small nuclear RNAs or snRNAs. These were essentially ASOs, but encoded and delivered by AAV. One advantage was localization — they sit in the splicing zone and can drive very high levels of exon skipping.

But AAVs have real limitations. One limitation is the inability to redose patients. If a patient has already received a gene therapy, they may not be eligible for another AAV-based treatment. That alone excludes a meaningful subset of patients. Another issue is distribution. Even with natural AAV serotypes, you may see a gradient of transduction of target cells. That can cap effect sizes and sometimes result in marginal efficacy. Lastly, safety can be an issue with AAV mediated gene delivery, especially at doses above 1E14 vg/kg in especially in older patients when the total dose is higher.

In contrast, with transferrin receptor–mediated delivery (TfR1) because the receptor is expressed broadly across cells, you get a much more homogeneous delivery. You can redose, and you can keep adding drugs to cells that didn’t get treated the first time. That allows for a more holistic treatment of an indication, rather than relying on a one-time delivery event. Over time, it became clear to me that delivery was the core bottleneck, and that’s the problem I kept chasing.

When people ask about the highs and lows of Locana, I mostly think about learning. It was my first venture-creation experience. Every stage felt different, and each stage forced you to learn something new. You had to wear many hats — science, business development, working across disciplines. We worked with a C-suite with deep Big Pharma experience, and I learned a lot from them. I learned about competition, about how the venture process actually works, about partnerships and asset acquisition, and about building towards a real market. Those were the periods where the most learning happened, and I don’t really think about them as lows. Without that accumulation of experiences, the next step in my career wouldn’t have been possible.

[On the move to Lexeo therapeutics]

After Locana, I started a discovery unit in San Diego at Lexeo Therapeutics. Lexeo was about applying genetic medicines to cardiac disease, and they have a very strong cardiology team. Even though my time there was relatively short, I learned about cardiac drug development, including cardiac endpoints and regulatory strategy.

That experience mattered because the diseases we work on at Dyne are multisystemic. They’re not just skeletal muscle diseases. There’s a cardiac component, a CNS component, and a smooth muscle component. Understanding how to think about cardiac biology, clinical development, and regulatory strategy made me better prepared for that complexity.

6. What were the early conversations like to become Dyne’s CSO as Oxana Beskrovnaya transitioned to a CIO role?

Oxana Beskrovnaya, then CSO at Dyne, and I had been in overlapping networks for a long time. Genetic medicines, and really biotech, is a small world. Many people at Locana already knew Oxana through prior connections. Because of those ties, I already knew 15 or 20 people at Dyne before I arrived, which made the early conversations feel very organic.

Where we aligned very clearly was on the issue of delivery. We both recognized that delivery was the central unsolved problem, and that Dyne was a real pioneer in this space. During the interview process, it became clear that John Cox, our CEO, had a very specific vision for the CSO role. The role was meant to drive the research engine in close alignment with late-stage development. The focus was on getting drugs into patients for DMD and DM1, and then advancing additional programs like FSHD and Pompe.

My role was to oversee day-to-day research strategy and pipeline development. Meanwhile, Oxana’s transition to CIO allowed her to focus on broadening the long-term platform potential, including how best to leverage the platform to deliver therapeutics across the blood-brain barrier to the CNS. The division of responsibility was both clear and complementary.

[What drew you to Dyne’s science?]

Transferrin receptor–mediated delivery in the AAV space was already gaining attention when Dyne was getting started. Companies like Apertura from Ben Deverman’s lab, Avidity, and PepGen were emerging, and the biology around transferrin receptor targeting was well understood. But what stood out to me was that not all TfR1-targeting approaches are equivalent.

The differences come down to affinity, epitope selection, and binding behavior. Dyne’s Fab was designed very deliberately. I spent time reading the papers they had published and studying the underlying data. The fact that the Fab does not interfere with red blood cell production is critical. Its size and epitope choice matter, the smaller size improves tissue penetration. At the same time, it avoids the rapid renal clearance you see with smaller peptides. The PK and PD properties are very strategic and intentional for holistic treatment of the disease.

Beyond the data, there was also alignment in scientific thinking. I’ve worked on DM1 and DMD since my PhD, and DM1 was the focus of my thesis. The mutation in DM1 is a CUG repeat expansion at the RNA level, and these repeats accumulate in the nucleus as RNA foci. From a mechanistic perspective, using a chemically modified siRNA to target a nuclear-localized RNA never fully made sense to me, given that the RISC complex is largely cytoplasmic. That doesn’t mean siRNA can’t work, but it’s not the most natural fit. ASOs, which act through RNase H1 in the nucleus, align much more cleanly with the cell biology. That scientific coherence mattered to me.

[On designing transferrin receptor binders, and what leads to differentiation]

Differentiation in transferrin receptor targeting ultimately comes down to a few core principles. Circulation and half-life of the molecule matters. Productivity after binding to TfR1 and how effectively payloads are delivered across tissues also matters. Affinity also plays a role.

What distinguishes FORCE^TM, in my view, is how well it delivers across muscle, heart, smooth muscle, and CNS. It occupies a very specific sweet spot, and it is truly modular. We use PMOs in DMD, ASOs in DM1, siRNA in FSHD, and enzyme replacement in Pompe, all delivered by the same Fab. Many other platforms require reengineering the platform or transport vehicle for each payload. FORCE does not. Lastly, FORCE does not interfere with the endogenous TfR1 function and therefore avoids persistent related anemia.

That modularity creates enormous opportunity. In some ways, it is an embarrassment of riches. The real challenge becomes prioritization—deciding where the scientific readiness aligns most closely with the urgency of the patient community. But the flexibility of the platform itself is a major advantage.

Share

7. Looking ahead, what directions or questions within Dyne’s platform feel most exciting or high potential to you? What was differentiating about the recent clinical trial results?

Looking ahead, the work at Dyne is incredibly exciting. We recently announced topline data from the registrational expansion cohort of our DELIVER Phase 1/2 trial, and this really represents a defining moment for the program. The drug is zeleciment-rostudirsen (z-rostudirsen) which was previously called Dyne-251. We started with a MAD cohort and chose the 20 mg/kg dose Q4W as registrational. We then dosed 32 patients, with 3:1 randomization, in the registrational expansion cohort (REC) powered on dystrophin protein expression as the primary end-point for accelerated approval.

We met that primary endpoint with statistical significance and a p-value of less than 0.0001 at just six months, which is a very strong result. The study was not powered to demonstrate statistical significance on functional endpoints, but even so, with only 24 patients on drug at six months, we reached nominal p-values below 0.05 in two of the six functional endpoints (time to rise velocity and 10 MWRT velocity), with all six trending in the right direction. Importantly, we have also shown sustained safety and tolerability out to 36 months. From the perspective of someone who has worked in the DMD field for a long time, this functional data is unprecedented, and extremely exciting to see.

We’ve also been encouraged by data from our ACHIEVE trial, where we presented long-term results at World Muscle Society. In that study, we showed not only knockdown of DMPK and correction of splicing, both of which are biomarkers of target engagement, but also improvements in functional measures such as myotonia (vHOT), muscle strength (QMT), timed function tests such as 10-meter walk run (10MWR), 5X Sit-to-stand (a measure of truncal and core strength) and CNS related PROs (MDHI subscale). One aspect of the data that stands out is the patient and clinician perspective. We incorporated PGIC and CGIC questionnaires, asking patients and clinicians whether they believed patients were improving on treatment. Patients reported that their daily activities and quality of life were improving, and clinicians independently reached the same conclusion. That kind of concordance, especially over longer follow-up, is very meaningful to us and is what makes the long-term data particularly exciting. We are now enrolling a registration expansion cohort at 6.8 mg/kg dose with vHOT at 6 months as an intermediate clinical endpoint.

[On why the microdystrophin approach has struggled]

When it comes to microdystrophin, I can only speak based on published data and what we’ve seen in the field. The approach originally gained momentum after a paper describing an individual in their 60s who retained ~54% of dystrophin (England, S., Nicholson, L., Johnson, M. et al. Very mild muscular dystrophy associated with the deletion of 46% of dystrophin. Nature 343, 180–182 (1990). https://doi.org/10.1038/343180a0) and remained largely ambulant. That observation helped catalyze the field.

The challenge is that dystrophin is a very large protein, and you can’t fit 54% of it into a single AAV vector. As a result, the protein had to be truncated, leading to microdystrophin constructs that retain less than 35% of the original protein. But there are no Becker patients with less than roughly 40% dystrophin who are asymptomatic. The evidence is supported by the Pfizer study. Pfizer studied a minidystrophin candidate which failed its primary end-point (change in NSAA from baseline) at 1 year in the phase 3 CIFFREO study despite high minidystrophin expression.

Beyond protein size, there are delivery challenges. Microdystrophin is still delivered via AAV, which brings issues with patchy distribution. If you don’t transduce satellite cells, you don’t correct early regeneration deficits. In pediatric patients, muscle growth over time leads to dilution of vector genomes, and because you can’t redose AAV, that loss can’t be corrected. Taken together, these factors make it very difficult to achieve durable and meaningful efficacy especially at limiting doses due to high dose-AAV related toxicity.

8. With Avidity’s acquisition changing investor sentiment around DMD/DM1, how – if at all – has that external landscape influenced how you think about advancing Dyne’s pipeline?

The acquisition of Avidity hasn’t really changed how we think about advancing Dyne’s pipeline. We remain focused on what we’re doing. What it does do is validate the unmet need in these indications and validate transferrin receptor–mediated delivery more broadly. Pharma is taking notice because these are real drugs addressing real diseases.

There is a very high unmet need in DMD, DM1, and FSHD. In DMD in particular, the need is immediate. We need to get therapies to patients as quickly as possible. DM1 and FSHD are larger markets, and as awareness and diagnosis improve, those markets will continue to open up, increasing both clinical and commercial opportunity. There is room for multiple players, and overall, we remain excited and focused on our mission.

[On advancing the pipeline]

Our approach is fundamentally data-driven. We know the platform is clinically validated, safe, and capable of delivering meaningful benefits to patients. Right now, the priority is execution and continuing to advance the platform and deliver therapies to patients across our pipeline.

At Dyne, the work isn’t done simply because a drug is in the clinic. Nonclinical strategy continues alongside development. Radiolabeled studies, genotoxicity work, carcinogenicity assessments, and other regulatory-mandated studies all have to be completed to get programs across the finish line.

That work applies not only to DM1 and DMD, but also to the broader pipeline, including FSHD and Pompe. Over the next three to five years, I believe many of these problems can be addressed. Beyond that, we begin to think more deeply about patient experience and other opportunities that can be unlocked through the FORCE platform—which is also why the CIO role exists.

9. You’ve worked on neuromuscular diseases from so many vantage points — mechanism, tools, delivery, and leadership. What’s kept you committed to this space, and how do you think about the “right modality” today?

I started in this field because of the unmet need – I was really interested in solving those problems. That commitment hasn’t changed, and over time, it’s become more personal. Now, I have friends in the DM1 community and friends with children who have DMD who don’t have therapeutic solutions. Delivery has been the missing piece, and we’re finally making progress with our RNA targeted platform. Delivery systems like ours are highly promising in treating these multi-systemic disorders where tissues such as skeletal muscle, cardiac muscle and CNS are affected. Overall, I’m just motivated to bring improvement to these patients.

10. For someone early in their career who wants to work at the intersection of science and human impact, what mindset or habits have mattered most in your own journey? Advice for leadership?

Collaborative work and team spirit matter more than anything else. It’s always about quality over quantity. I’ve always believed in working with good people—people who are empathetic, who are kind, and who genuinely care about working as part of a team. I’m a big soccer fan, and I think about it that way: if the team is moving left and right together, back and forth together, you’re going to win.

For me, that really comes down to working with people and understanding them. First and foremost, you have to trust the people you work with, and that trust comes from empathy and from being genuinely aligned around a common goal. In my case, that goal has always been patients, and most of the people I work with are aligned around that as well. Everyone is human, and over time, if you approach people with that mindset, you start building trust across the organization, regardless of role or seniority.

Once that trust is there, the next step is alignment. You have to align your goals with the organization’s scientific strategy and its financial strategy, because this is biotech and everything ultimately comes back to product. That alignment isn’t easy. It takes careful thinking. But when it’s done well, it makes your work easier, and it makes it easier for others to support what you’re trying to do.

From there, you identify key stakeholders, mentors, and decision-makers and bring them along with your ideas. They trust you at that point. They understand that you’re aligned with the organization’s thinking. You take advantage of every learning opportunity, because learning never really stops. And in the end, while ideas matter, execution matters more. If you follow those principles, they help resolve personal challenges, organizational challenges, and ultimately help you get the work done.

11. Which mentors have had the greatest impact on your journey?

There are many mentors who have made a transformational impact on my journey. At the University of Delhi, I had a teacher (https://in.linkedin.com/in/prof-dipak-k-majumdar-32392011), an Eli Lilly alum, and taught physical pharmacy and pharmaceutics. He’s the reason I still remember certain chemical equations to this day. He was very practical in how he taught drug development, and he changed the trajectory of many careers. A lot of my classmates ended up in pharma roles in the Northeast and in Boston, and he was a big reason people became motivated in those directions.

During my PhD, my mentor Maurice Swanson (https://neuroscience.ufl.edu/profile/swanson-maurice/) taught me essentially everything I know about RNA. He brought both breadth and depth and was instrumental in shaping how I think scientifically. Later on, mentors like Gene Yeo, Eric Adler in cardiology, and John Ravits in neurology were incredibly influential.

Now at Dyne, learning from leaders like John Cox, our CEO, Doug, our Chief Medical Officer, and Oxana, our CIO, has been invaluable. I’ve been very fortunate with the quality of people I’ve been surrounded by. But you also have to recognize that learning opportunities are always there. Most days, I feel like a sponge.

12. What’s a question you wish younger scientists would bring to mentors more often, but rarely do?

The question I wish younger scientists would ask more often is about the end goal. Not a two-year plan, and not just whether they want to start a company or move into a specific role, but what they think they would genuinely be happy doing in ten or twenty years. That requires careful introspection. What really motivates you? What makes you happy day to day? It’s about the journey. If someone can think carefully about that and feel confident that the path they’re choosing truly brings them happiness, that matters a lot.

I think about Dylan as an example. He’s a neurology resident, working all the time, and he still finds time to work on Biomarker. He does it because it makes him happy. For me, it’s always been about impact. Early on, that meant impact in the lab. Then it was impact through Verily, Locana, and Lexeo. Now it is impact through the FORCE platform, which has the potential to work across many indications and treat many diseases. Looking ahead ten years, my impact might stem from different roles, whether that’s Dyne, a board position, or even venture capital, but the goal remains constant: to look beyond a single organization and drive progress across multiple channels.

Yet there are some in our industry who take more circuitous paths: individuals with experience that cuts across a range of disciplines. Samantha Singer is one of these unique talents—a “bridge builder” within organizations, fluent in both science and business. She left a PhD program at Rockefeller after realizing she loved communicating ideas more than bench work. She walked away from a fully funded Harvard MBA and a job at BCG to build an independent consulting practice. She moved from consulting to Biogen, where she ran organizational effectiveness, product operations and was Chief of Staff to the CEO. Crossing into academia, she became COO of the Broad Institute where she helped foster a unique “Broadie” culture and vision. After building expertise across a wide range of disciplines (science, operation, finance) she pursued CEO roles: first as an EIR at TRV where she led Abata Therapeutics, and now as head of a stealth biotech incubated at Atlas Ventures. In navigating this career journey, Samantha follows her North Star: “pursue what you’re genuinely curious about, go where you can learn the most, and do it with people you respect.”

In 2006, Samantha was diagnosed with relapsing remitting multiple sclerosis. “During the worst parts of the disease, many of the traits I thought were core to who I was simply weren’t available to me anymore,” she explains. The turnaround came with a transformational therapy [Tysabri]. Samantha is clear that without this drug, her life today would look very different. Her experience with MS sharpened her focus at work: “I want to take on problems where there is real risk and the possibility of genuine transformation. That’s when I feel my leadership is most well spent.”

As an EIR at Third Rock, Samantha split her time across several ventures: a project focused on somatic mutations in the brain, operating roles at Celsius, Thrive, and eventually as CEO of Abata. That period required “real comfort with ambiguity and the willingness to pour energy into projects that might never see the light of day.” It also shaped her leadership approach—one rooted in transparency and fostering a culture that doesn’t stigmatize failure. Navigating a brutal funding environment as head of Abata, sharpened her current approach to company building: “focused, capital-efficient, and oriented toward getting human data on a lead asset on Series A dollars.”

In our interview, Samantha discusses her discovery of genetics in the eighth grade, career advice from Nobel laureate and Rockefeller President Torsten Wiesel, learnings on how large pharmas really make decisions, the highs and lows of company creation and her experience across different biotech funding cycles. She closes with tactical advice for people early in their careers, advocating for a simple habit: “meet one person you don’t work with every week, and keep doing it for the rest of your career.” Biomarker readers, meet Samantha Singer.

1. You have had such a varied career. What guided you at different points along the way?

My background and training do not resemble a linear path. Throughout my career, I’ve tried to follow what I’m interested in and be where I can learn the most and make a difference. I’ve also tried to prioritize working with exceptional people. As a result, few of my moves were “planned” in the traditional sense. I would talk to people about what I wanted to do and learn, and in almost every career move, someone spotted or suggested a next opportunity. These weren’t roles I would necessarily have identified on my own. Only in the last few moves has my path been more deliberately shaped towards CEO roles. Everything in my career before that – from consulting to the Broad Institute – was driven by what I wanted to do and learn, not by a particular title I wanted to hold.

Share

2. How did your diagnosis and battle with MS influence the way you define success – personally and as a leader?

MS profoundly changed my relationship with my self-definition of who I was and what I could or couldn’t do. Before I was diagnosed, I saw myself as someone with very high capacity: articulate, energetic, confident in how I showed up in the world. During the worst parts of the disease, a lot of that was taken away. I had trouble speaking. I struggled with fatigue and brain fog. Many of the traits I thought were “core” to who I was simply weren’t available to me anymore.

I had to adjust my path. I took a role where I wasn’t presenting, where I could still contribute without relying on the capacities I’d lost. That’s how I ended up as a Senior Director in Organizational Effectiveness at Biogen, restructuring a dozen parts of the organization and building deep relationships with leaders across the company. Those relationships later helped me find my next steps as I recovered.

Coming out of that experience, once I got effective treatment [for MS], my identity again shifted. I started to see myself not as a fixed set of traits, but as “a lot of things I’ve yet become.” That sounds philosophical, but it’s really where I landed—we are not just who we are today, but rather a set of possibilities. I believe that’s true for everyone. Embracing that gives you courage to try things you might never have pictured yourself doing.

By the time I was diagnosed [with MS], I already had some comfort with risk earlier in my career—particularly leaving my PhD for consulting and then not going back to BCG [consulting] after finishing my MBA. When I was at HBS, BCG was paying for my MBA, and the plan was to return. But I started working over the summer with a former BCG colleague, Jill Altshuler, on her independent consulting work and realized I enjoyed that model more. I decided to partner with her instead of returning to BCG. That was a big decision because I had to pay BCG back for the degree.

I remember going to a Professor at HBS and asking, “Should I do this?” He helped me be concrete about the risks and benefits. Once we did that exercise together, the decision to leave BCG became clear. This reframing reinforced something I’d already started to practice: a lot of regret comes from not making those leaps sooner. Diagnosis with MS then layered on another dimension to this problem. Having to completely re-evaluate what I was capable of freed me from a rigid sense of “this is who I am.” As a leader, that’s been hugely important. It’s made me more willing to experiment, more empathetic when others are navigating change, and more focused on growth over fixed identity.

[On taking career risks]

I do think risk-taking is easier at certain stages—earlier in your life, before you have a mortgage, kids, or financial obligations where a six-month gap in income could harm other people. Conversely, taking risks later when you’ve built up a financial cushion is also easier. When I talk to people about taking risks, I always anchor it in their personal and financial situation: What buffer do you have—mentally, emotionally, time-wise, financially—if the downside actually happens? Not everyone can take the same level of risk. But I do think more people can take thoughtful risks than actually do.

3. For people living with chronic, progressive autoimmune diseases like MS, uncertainty becomes a daily reality. How does that lived understanding shape the way you see biotech and drug development?

For me, Tysabri (natalizumab) was a transformational therapy. I can honestly say that without Tysabri, I would not be doing any of the things I value most about my life today. I would not be able to serve as a CEO. I wouldn’t be doing CrossFit and boxing. My relationship with my daughter—being able to be fully present and active in her life—would look entirely different. There would still be a life, but not this life that I have now. I deeply appreciate, in a very personal way, what transformational therapies can do. I had some appreciation before, from seeing family members benefit from treatments for other conditions, but MS made that understanding far more visceral.

I know what it means when a therapy changes the trajectory of a life. It also reinforces that, for me, the only work I truly want to commit to is one with the potential for transformational impact. I’m not particularly energized by helping a company expand its portfolio from sixteen to seventeen drugs in a crowded space. There’s nothing wrong with incremental improvements—in dosing schedules, formulations, or product features—they do matter. But for my own time and energy, I want to take on problems where there is real risk and the possibility of genuine transformation. That’s when I feel my leadership is most well spent.

4. You’ve spoken about discovering biology early and carrying that passion to Rockefeller — only to face the “hard truth” midway that bench science wasn’t your path. What initially drew you into molecular biology, and what realization ultimately convinced you to step away from the lab?

I’ve appreciated science for as long as I can remember, but the defining moment was in eighth grade, when my science teacher introduced genetics. Sometimes you encounter an idea that completely changes how you see the world. For me, genetics was one of those ideas. I remember thinking, “Oh my God, that’s how biology works.” It was a complete frame shift, and I saw an incredible beauty in it.

I grew up in Kansas, so there was a particular irony in that sequence. They taught genetics one week, and the next week they had to teach evolution [intelligent design]. I opted out of that segment and went to the library instead, but genetics had already hooked me. That’s what committed me to a life in science: that moment of realizing how elegantly the system works.

From there, the path followed a familiar pattern. I did lab work as an undergraduate, and the “next logical step” was to apply for PhD programs. That’s what you did if you were doing undergraduate research. I applied, got in, and ended up at Rockefeller doing yeast molecular genetics—formally “yeast cell cycle” work. It was very specific, very beautiful science.

The problem was that I was simply bad at the lab work. I probably should have seen it coming. People would ask me in interviews if I liked to cook, and I’d say “absolutely not,” which in retrospect was a red flag. Lab work is somewhat like cooking: recipes, precise measurements, timing, temperatures, and a lot of patience. I didn’t have good dexterity. I didn’t have the patience. I routinely ruined experiments, including other people’s. I dropped things every day. I spent hours in cold rooms running columns and hated it. The combination of being bad and not enjoying the lab work fed on itself.

What I did love, and what my advisor increasingly steered me toward, was the conceptual and communication side: thinking about ideas, reviewing work, and figuring out how to clearly and concisely pitch a scientific concept. I loved evaluating ideas and shaping how they were communicated.

Eventually, I went to see Torsten Wiesel, who was then the President of Rockefeller. He was tasked with convincing me to stay in the program, when others had already failed. I walked into his office, a bit intimidated, and laid out my pitch: “I love science, I love ideas, I love working in teams with smart people. I just don’t think the lab is for me. There must be something else I can do.” He was the first person there who actually agreed with me. He said: “You’re absolutely right. If you don’t love being in the lab, you shouldn’t do science. It’s too hard to do if you don’t love it.” Then he asked, “Who can I introduce you to so you can learn about other paths?”

He introduced me to lawyers, consultants, and people in publishing, just for informational interviews. That was my first exposure to using conversations to map out alternative careers. I’ve used that process repeatedly ever since: telling people what I love to do, what I want to learn, and asking where that might fit. That’s ultimately what led me to consulting.

Torsten also said, “I’ve been working with the board to create a master’s degree pathway. I think you should be the first example.” He didn’t want me to leave with no ongoing connection to Rockefeller. He literally wrote a memo at his desk stating that I would receive a master’s degree. I walked out with what I jokingly call a “proto–master’s degree,” which was formally granted about nine months later when the board approved the program.

Looking back, that was also a leadership lesson: he reframed what “success” looked like. He didn’t see it as a failure that a student was leaving the PhD track. He saw an unhappy young scientist who could be happier and just as successful elsewhere, and wanted to ensure Rockefeller remained part of her story.

5. As a consultant and then at Biogen, what surprised you most about how large pharmas actually make decisions?

One of the most striking realizations, both as a consultant and later from inside a company, is just how much distance there is inside large organizations. There is distance between the people making big strategic decisions and the people executing them. There is distance between key functions like research, regulatory and commercial. They are in different buildings, different reporting lines, different life trajectories. Every possible dimension of distance is present. Yet, to make truly outstanding decisions, all of those perspectives need to come together. The people who are most effective in big pharmas are the ones who build bridges across that distance. That became a big focus of my work: creating communication and relationships across functions.

The good news is that anyone at any level can do that. You don’t have to be senior to create value by connecting people. Communication is fundamentally about humans, and organizational success depends on that humanity and those interactions.

A very concrete example: we once launched a product with packaging that technically met the requirement of being childproof—but in practice, you had to push so hard to open it that it broke the capsule in half when it finally gave way. The connection between “childproof” and “usable” had been missed. We had effectively no viable packaging within months of the launch. Fixing this issue was my responsibility.

I went to John Cox, who was head of pharma operations and technology. I explained the situation. His first reaction was…colorful. But then he said, “What are you going to do now?” That was the leadership lesson: don’t wallow in failure; focus on the next move. So I went to the commercial lead and asked, “What packaging do you actually need? We’ve been focused entirely on childproofing and blister pack designs. Have you collected any data on what patients actually want?” I said, “If we can move to a bottle instead of a blister pack, I can get you childproof bottles that don’t damage the capsules almost immediately.” He admitted they hadn’t done any market research on packaging preferences. Because we already had a relationship, he agreed to fund a quick study. The results were clear: patients didn’t want blister packs; they wanted bottles. That allowed us to pivot quickly and avoid a months-long, multimillion-dollar mistake.

The root issue wasn’t intelligence or effort. It was a lack of connection between functions. Once we built that connection, the solution was obvious.

[On working in pharma first]

One thing I often tell people—which may be an unpopular opinion—is that early in your career, it’s incredibly valuable to work in Big Pharma rather than going straight to a small biotech. Small companies generally need either very junior people at the bench or senior, highly experienced execs. Pharmas, by contrast, hire broadly and offer a tremendous training ground. At Biogen, I worked in HR, supply chain, and strategy—all within one company. You learn how large organizations really function: that you can’t just convince the BD lead to love your asset; you also need buy-in from research, clinical, and commercial—who may barely know each other.

You also build a network [in large pharma]. Your colleagues will move on to other companies, and that diaspora becomes a powerful professional web. These organizations also invest heavily in leadership development—programs and training that small biotechs simply can’t afford. I encourage people early on to consider Big Pharma a place to build their foundation in skills, relationships, and understanding of how the ecosystem actually works.

6. What motivated you to take on operational responsibility at the Broad, and what did you learn about how academia and industry can work together? Where do incentives collide most often?

My move to the Broad Institute stemmed from my experience as Chief of Staff to George Scangos at Biogen. In that role, I helped him manage his C-suite team and facilitated executive meetings. It gave me a front-row seat to what it really means to operate at the C-level and confirmed something I’d started to think about during my MBA: that I wanted to ultimately be a CEO.

I didn’t see myself as a future CFO or CCO as I hadn’t fallen in love with a single function. What appealed to me was building effective teams, setting strategy, and aligning people around it. Being Chief of Staff validated that those were the problems I wanted to own.

So as that role [at Biogen] was winding down, I started asking, “What’s the next thing I need to learn to prepare for a CEO role?” The answer was general management: owning a P&L and being responsible for core operations. I explored options within Biogen, including country-level leadership roles.

Around that time, I was at a dinner with David Altshuler [then at the Broad] and my former business partner Jill Altshuler. I gave my usual spiel: “Here’s what I know I can do—organizational change, execution, leadership. Here’s what I want to learn—general management and P&L responsibility.” David said, “We’re interviewing for a Chief Operating Officer at the Broad. What do you think about that?” It hadn’t occurred to me, but I took the idea seriously, went through the process and it turned out to be a great fit.

The Broad was approaching its tenth anniversary and asking, “What does a sustainable Broad look like beyond our founders? How do we think about leadership development for a future where the founding academics won’t always be there?” Those are exactly the kinds of organizational questions I’m good at. As COO, I had an organization of about 280 people across all G&A functions and responsibility for the associated spend and that gave me the general management experience I wanted.

There was another dimension that appealed to me. I wanted to learn how to “motivate from the heart” more effectively. Coming from science, I was strong on facts and logical persuasion but less adept at inspirational communication and emotional connection. At the Broad, people like Eric Lander are extraordinary at that—he’s a gifted storyteller and motivator. Working alongside leaders like him was a master class in how to connect with people in a different way.

I also had a deep prior connection to the Broad. As an independent consultant with Jill, we had helped write the original business plan that was taken to Eli Broad to secure the founding gift. I like to say I was a “midwife” at the birth of the Broad. Coming back ten years later and seeing how that very novel organizational design had actually played out, and then helping shepherd it into its next phase, was incredibly meaningful.

[On structuring incentives]

One of the most fascinating aspects of the Broad is that it is almost entirely culture-driven. Unlike a company, it had no corporate strategy documents, no annual goals, no formal performance reviews, no bonuses—none of the conventional alignment mechanisms. And yet it functioned as a cohesive organization. When you walked into the Broad, you knew what it meant to be a “Brodie.” There was a shared sense of purpose and a recognizable way of behaving. That culture was more than any formal system and kept people aligned.

Comparing that to industry is instructive. At the Broad, the time horizon is long. You can propose a big idea without knowing how to get there; you’ll figure it out over the course of a career. Guardrails are intentionally minimal so that people can wander into uncharted territory.

In biotech companies, the time horizon is much shorter. Runway is finite, usually six months to a few years, and you are accountable to shareholders who’ve given you money for a specific purpose. In that environment, guardrails are essential. You need focus, clear objectives, and discipline about what you will and won’t do with the capital you’ve raised.

So the main tension between academia and industry often comes down to time horizons and guardrails. Academia thrives on open-ended exploration; companies must balance innovation with fiduciary responsibility. Bridging those differences so that truly novel science can translate into focused, executable programs is where collaborations either work beautifully, or fall apart.

7. As an EIR at TRV starting in 2018, what were some of the first things you worked on? How is that approach different today with your stealth company in the Atlas ecosystem?

My path into Third Rock started with the same kind of conversation pattern as many of my transitions. I was talking to people and saying, “I’d really like to be a CEO—but I also need to learn how to be one.” Third Rock’s response was, “We don’t have a CEO role for you right now. Why don’t you join us as an EIR? You’ll see what it’s like to build companies and learn more about what CEO-ship looks like in practice. We’d rather you do that with us than with another venture firm.”

Third Rock’s culture is similar in some ways to the Broad’s. They believe innovation takes time, and they put a lot of emphasis on “group genius”—bringing people together, letting ideas flow organically, and allowing concepts to evolve until they’re ready to become companies. There are few timelines and not many guardrails. Reporting structures can feel amorphous. It’s highly unstructured by design. When I joined, there was one project I was immediately drawn to, but otherwise, the guidance was essentially, “Do what you want. Here’s a list of ideas and teams, go talk to people, wander around, see what resonates.”

I got interested in Celsius and ended up spending half my time as COO there and half on a project we called Tembo, focused on somatic mutations in the brain that drive dementia. The science was fascinating, but we eventually concluded there was no way to make the economics work within a five-year investment horizon. There simply wasn’t a viable business case for investors.

I later became deeply involved in Thrive Earlier Detection, an early cancer diagnostics company. I basically invited myself in: “Can I help? Can I join this effort?” They said yes, and I became the COO there after rolling off Celsius. When the pandemic hit, I stepped back from the COO role, spent a period focused mainly on Tembo, and then became involved in what ultimately became Abata Therapeutics. We killed Tembo, kept iterating on Abata, and eventually launched the company. Throughout this entire period, I was an EIR at Third Rock, not an employee of any single company, until Abata formally launched. It was an extremely organic model.

[On those who would succeed at a firm like TRV]

The people who thrive in that environment are comfortable with radical ambiguity. They’re self-directed, clear about what they’re interested in, and able to define success for themselves without a lot of external validation. When people ask me whether they should be an EIR at a place like Third Rock, I warn them: it may be the highest level of ambiguity you’ve ever experienced. You’ll have to find your own projects, live with uncertainty about whether anything will ever launch, and accept that feedback is often indirect and emergent.

My current work with an Atlas stealth company operates within a tighter set of constraints shaped by the current market environment. Yet, the common thread is still comfort with ambiguity and a strong internal compass.

8. Looking back on the Abata journey, what felt like the true highs and lows? And did your personal connection to the disease area shape how you made decisions along the way?

My personal connection to MS influenced one decision very directly: I was adamant that relapsing–remitting MS was not the place to focus. I don’t think there is meaningful unmet need in RRMS that justifies building a new company around it. The real unmet need, and place where you can truly create new value, is progressive MS. That conviction came both from my personal experience and my understanding of the landscape.

In another sense, having MS helped me articulate the mission. I could say, very personally, “I would love to bring to others the kind of transformation I experienced, and I know progressive MS patients don’t have that.” That narrative mattered. But on the other hand, it also almost kept me from joining. I had to ask myself, “Do I really want to spend every day thinking about how hard life is for MS patients? I’ve already done that in my own life.” I ultimately decided yes, but it wasn’t an automatic decision.

Once we committed, the decisions themselves were driven by the data and by business realities. We also had type 1 diabetes as an indication and, initially, inclusion body myositis. I believe the Treg platform we were developing could have been remarkable in those contexts as well.

The low [of this journey] is very clear: shutting the company down. We had two cleared INDs. Sites were up and ready. Progressive MS patients were signed up and waiting to be dosed. However, we simply could not raise the capital needed to run the trial. The environment was such that new investors were unwilling to fund anything without substantial clinical de-risking. Our existing investors were supportive, but not at the level required to finance an expensive cell-therapy program. We were at the intersection of a capital-intensive modality and a market with very low risk appetite. It just wasn’t possible.

We tried everything: a Series B, an IPO (we had a cleared S-1), private rounds, debt, reverse mergers, outright sale, even consolidation (“What if we merged multiple Treg cell therapy players into one, regardless of who’s CEO?”). We turned over every rock. I’m confident there was no path to fully fund Abata in that environment. It simply wasn’t the right time for that company.

The highs, for me, were watching the team navigate really tough scientific and technical challenges with resilience. For example, we weren’t able to discover a novel TCR for our MS program despite intensive effort. At some point, we had to admit, “It’s not there, at least not in a way we can practically access.” So we changed the rules of the game and used a well-characterized “tool,” the TCR, that others had already published. The novelty was in putting it into Tregs, not in the TCR sequence itself. We had already used the TCR for other work and knew it was effective.

Another example: our first attempt at manufacturing with progressive MS patient samples failed. The process worked beautifully in healthy donors, but not in the population we actually needed to treat. That could have been demoralizing and massively derailing. Instead, the team treated it as a problem to solve. They retooled the manufacturing process based on what they were seeing and fixed it quickly enough that we stayed largely on track.

Those moments, when the team could say “we have a problem” without internalizing it as personal failure or trying to hide it, and then solve it together, are what I’m most proud of. That level of resilience is essential if you’re going to do truly transformative work in biotech.

9. What are the toughest cultural or operational challenges during periods where capital is difficult to access? How do you keep teams aligned through uncertainty?

My bias is toward more transparency, not less during difficult times. I think effective leadership requires both caring and courage: caring about people as human beings, and having the courage to tell them hard truths. Uncertainty about funding is frightening, especially when people’s livelihoods and families are at stake. But people are not naïve. They know there is a finite amount of cash in the bank. Pretending otherwise doesn’t protect them, it just erodes trust.

At Abata, I committed to updating the entire company at our monthly all-hands meeting. I told them what we were trying to do—Series B, reverse merger, various strategic options—and what feedback we were getting. I also told them what I couldn’t share and why. We were honest: “We do not currently have enough money to run our trial. Here’s what we’re doing about it. Here’s what we’re hearing from investors: the science is fantastic, the team is outstanding…and the risk appetite just isn’t there.”

Crucially, we always gave people something actionable to focus on. Sometimes that meant, “We need more data on ‘X or Y’ to tell the story effectively.” Sometimes it was, “Question every expense: do we need this now, or can it wait three months?” Often it was simply, “Execute, execute, execute. If we do get funding, we need to be ready to enter the clinic quickly and deliver data.”

As we got within a few months of running out of cash, we went further. We told people, “Please update your resumes. Start talking to your networks. This is not being disloyal, it is being responsible. If we don’t close this funding, we will all be looking for jobs, and we don’t want you starting that process late.” We asked them to be transparent with us if they were deep in other interview processes and told them we would support that. Some people did get offers before we officially wound down. Many others were far enough along in their search that they landed quickly once the shutdown was announced. That was the right thing to do for them, and it wasn’t actually that risky for the company. If we had secured funding, people could have always turned down offers elsewhere and stayed.

10. Given the explosion of new modalities such as cell and gene therapy, RNA, and AI-based design, where do you think the next major wave of therapeutics will come from in the next five to ten years?

You always need to build companies that are appropriate to the current context. When we launched Abata, autologous cell therapies were very much in favor, and investors were excited about platform stories that could span many indications. We built a company that fit that moment. That is not what is getting funded today. Investors are far less willing to underwrite complex, capital-intensive platforms without near-term data.

I care deeply about patients, but on a day-to-day basis I’m also accountable to investors. They’ve entrusted us with capital, and there’s a real obligation to build companies that can deliver on their expectations in the prevailing environment. That means being very selective about modalities and business models. For cell and gene therapy right now, I have a very high scientific and financial bar. I want to know that a company has enough runway that by the time it needs new capital, it will have the data and relationships to make that possible.

The company I’m leading now is antibody-based. It’s well-funded with several years of runway, highly focused, and very lean—about 10 people, no internal labs, everything run through CROs. We expect to be in the clinic next year and to be generating data quickly. In many ways, it’s tailor-made for this environment: focused, capital-efficient, and oriented toward getting human data on a lead asset on Series A dollars.

Right now, that’s what investors need to see: clinical data as quickly as possible on the initial capital. Any modality or company design I consider has to pass that test.

[On today’s investing environment versus past cycles]

It’s hard to make clean comparisons across cycles because I occupied such different roles in each. In 2008, I was at Biogen seeing the financial crisis from a large-company vantage point. At the Broad, I was much more focused on academic funding dynamics—like what happened when stimulus dollars temporarily boosted NIH budgets and then receded—than on biotech capital markets per se.

What feels different now is the breadth of uncertainty. In past periods, you might have had stress in one part of the system—say, public markets—but other parts (NIH funding, VC, pharma BD) would be relatively stable and able to compensate. Over the last few years, it has felt at times as though every gear in the system has been under strain: NIH budgets, venture funding, IPO windows, follow-on offerings, pharma M&A, all of them. These gears are interdependent, and when too many of them seize up at once, it becomes hard to know where to turn.

Things are improving. As you noted earlier, the $XBI and M&A are up, and that will help. But the feeling over the past couple of years has been that a larger portion of the ecosystem was “locked up” at the same time than in prior cycles. That has been distinctive and challenging.

11. What defines an effective leader? Examples or mentors from your career that come to mind?

One of the most important traits I’ve seen in great leaders, especially at places like the Broad, is the ability to see possibilities and commit to them even when the path is unclear. They can pull people off a default trajectory and rally them around something bigger and more challenging.

I’ve also talked about the combination of caring and courage. Leadership is deeply human. It’s about listening, understanding where people are coming from, and recognizing that people behave exactly as they think they should, given how they perceive the context around them. If you want to change behavior, you have to change how the situation occurs to them through communication, clarity, and genuine care.

At the same time, leaders must hold a high bar. Your job is to motivate people to reach beyond what they think is possible. But you can’t do that if failure is stigmatized. High standards must coexist with psychological safety. If people are stretching, it’s inevitable that they’ll fall short sometimes. How you respond to that is culture-defining.

If someone comes to you and says, “I screwed this up,” and your reaction is anger or humiliation, you’ve just taught them and everyone watching that honesty is unsafe. They will not bring you problems early again, and the culture shifts toward fear. If instead you respond with empathy and forward motion, for example, “That must feel awful. I know you cared about this. What are we going to do next?” you normalize learning from failure and trying again.

I often tell people, especially in women’s leadership or parenting contexts, that being a parent can make you a better leader. Parenting isn’t a prerequisite for leadership of course, but there are parallels: seeing the possibilities in people, investing in their growth, and balancing high expectations with unconditional support.

12. For someone early in their career who wants to work at the intersection of science and human impact, what mindset or habits have mattered most in your own journey?

The single most important habit I recommend is deliberately building your network. You’ll gain experience wherever you work, but your network is what will open up unexpected opportunities, support you when you’re stuck, and give you perspective you didn’t know you needed.

Your network is more than your mentors; it should also be peers, former colleagues, and even people you’ve mentored. Some of the most important career doors open sideways, not upward.

A very practical rule I set for myself at Biogen, and that I still follow, is: once a week, have breakfast, lunch, dinner, coffee, or a walk with one person you don’t work with day to day. That’s it. One person a week. That’s more than 50 people a year. For me, that quickly became two people a week, and now it’s closer to one a day. I rarely regret those meetings. They generate opportunities I never would have scripted, they become sounding boards when I’m stuck, and they provide emotional support in tough stretches.

If you work with someone you like, stay in touch. It doesn’t have to be constant, but keep the relationship alive. Over time, that web of relationships becomes one of the most valuable assets you have.

As a firm, RTW has had a busy year: writing a history of neuropsych innovation, thinking deeply about healthcare policy and affordability, supporting over 70 portfolio companies, and managing over $8B in assets. Yet fundamentally, Rod Wong and his team are laser-focused on one activity: turning over rocks. “When an investment stands out, it usually reflects a blend of both fundamental and non-fundamental dimensions. You have to build the skills and team that can evaluate these factors,” explains Rod Wong, Managing Partner and Chief Investment Officer of RTW.

From an MD/MBA student with an interest in economics, to a sell-side equity analyst at Cowen, to an investor at Sigma and Davidson Kempner, Rod proved adept at finding these “little anomalies” in healthcare: “I’m wired to look for bargains—Munger or Buffett would say this is an innate characteristic...but I attribute it to my training: I studied medicine, economics, and went to business school. I had a grounding in NPV, discounted cash flow, and fundamental valuation.” In 2008, Rod faced his first real setback as an investor. “Leading up to the Great Financial Crisis, we had lived through one of the most blissful periods of sustained low volatility in biotech. Mentally, I wasn’t prepared for things to change so drastically.”

Faced with an existential threat to his investing career, Rod doubled down and did his homework: “During that time, I read around 30 books on financial crises. Now it would have been more helpful to read these before…but I did end up getting that education.” When founding RTW in 2009, Rod took these lessons with him, encouraging his team “to lean in and capture opportunity when fear is highest.” The strategy has paid dividends.

The firm has invested in companies across the development life cycle: from Madrigal and Akero that are changing the game in MASH, to ArgenX, PTC Therapeutics, and Insmed that have commercialized products, to M&A targets like the recently acquired Avidity (Novartis) and private companies like the obesity start-up Kailera. In our interview, Rod outlines what factors he looks for in “stand out” opportunities and the models he uses for company valuation. He touches on contrarian views in biotech and how he built conviction in names like Akero and Avidity. Ultimately, however, Rod emphasizes that “turning over rocks” is a team sport: “individual excellence only takes you so far. If you want to do something truly impactful…everything great is accomplished through teams. Everything.”

Below is an interview with Roderick Wong, Managing Partner and CIO of RTW from December 2025:

1. You originally pursued medicine. What drew you into that initially, and what was the first moment you felt a pull toward investing?

When you approach this question from a genuine love of science, medicine, and innovation—then it [biotech investing] becomes a very natural way to spend a career. Money or success isn’t the primary driver. I grew up in the Midwest, and both of my parents were professors. My mom wasn’t in science, but my dad was a physicist, and so I gravitated toward the sciences from a young age. When I realized I wasn’t going to win a Nobel Prize in Physics, I had to ask myself where else I could contribute…and what else interested me. This [desire to contribute] is how I joined the “pre-med” track at Duke. In college, I also majored in economics. I remember being fascinated—not so much by business, but by the analytical structure of microeconomics. Fast-forward to medical school, and I discovered that I loved scientific and medical innovation. I considered a PhD, but what I really enjoyed was looking broadly across science. To me, doing a PhD was more about depth within a narrower focus. So I went to business school, like many others. During [MBA], I interviewed for every type of job — corporate, equity research, consulting, etc. Towards the end of that process, I interviewed at Cowen with their equity research team. The moment I walked in—these teams are small—I met them, and it felt like looking in a mirror. The feeling was instantaneous. People often describe going on a first date, meeting the love of your life, and knowing right away you’ll get married; it was that kind of career moment. Fortunately, they offered me a job, and from there my career followed a somewhat linear path.

[On mentors from sell-side]

I had one sell-side job before my first buy-side role, and Eric Schmidt was my first boss. He’s still on the Street today, though he did spend some time as the CFO of a biotech company [Allogene] . He and Josh Schimmer—who was one of my classmates in business school and also an MD—are now back together building healthcare research at Cantor [and host the Biotech Hangout]. But back in the day, it was a small highly regarded biotech equity research group at Cowen. Eric was an exceptional boss. Mentors influence your life in different ways and make different kinds of impressions. In Eric’s case the two defining marks he left on me were: first, showing what it means to be a genuinely good person and leader, and second teaching me the foundational principles of how to conduct high-quality, deep research. Those were the two lessons I carry with me today. It’s hard to say which of those lessons is more important, but I really do believe that having a first boss who was an outstanding human being set me on the right path. In finance, you can encounter a lot of tough personalities—not bad people necessarily, but people for whom money is the top priority. Eric was not that type of person. He provided a terrific foundation.

[On finding a career niche in industry]

When I advise students, I emphasize that there are huge differences across different jobs in biotech — in the same way that medical students recognize the differences between being a surgeon, an internist, and a pathologist are really significant. So there’s a real “What Color Is Your Parachute?” element to finding your path. I knew I loved innovation, but I didn’t want to work in a lab. I enjoyed patient care but did not want to be a full-time clinician. For people that decide on equity research like I did, the next most important realization is that our business is still very much an “apprenticeship” model. Consulting or banking, by contrast, are far more developed and institutionalized paths; when someone joins a place like McKinsey, their manager does matter, but they rotate onto a new engagement every few weeks. So your experience is shaped less by any single boss and more by the firm’s training systems and overall culture. That isn’t the case—at least not yet—in biotech investing. You join a small team, and it shapes your entire working life. The team itself will matter far more than the institution’s name on the door. Once you’re in this business, the people matter more than anything else.

2. What were some early lessons learned in your days in equity research and then investing? What frameworks, if any, transferred from your medical training?

In my first buy side job at Sigma, I didn’t have a moment of real difficulty; I was still in a blissful naïveté about the hard parts of the biotech business. I had another terrific mentor there, and he [Wayne Holman] left me with the deep impression of just how much rigor and depth great work requires. That also stayed with me for the rest of my career. The first real setbacks I experienced were at DK. There I had several extremely formative experiences, one of which was building a team for the first time. Another was learning to operate within an organization that was—and still is—a larger institution. DKCM was a mature partnership, with all the organization structure you would expect — I had to learn to navigate those dynamics. Lastly, I also had to learn to fail for the first time. I was at DK during the financial crisis—something that, many people in our industry today probably barely remember—the GFC in 2008. Leading up to it, we had lived through what in our business was considered one of the most blissful periods of sustained low volatility. I hadn’t prepared for things to change so drastically. It ended up being a really important learning experience. In 2009, I read something like thirty books on financial crises—ten on the Great Depression alone. Now it would have been more helpful if I had read those before [2008], but I did get that education afterward. Since then, the world has been far more volatile and I’m personally grateful that my career evolved in that sequence. For my first few years [in industry] I could focus purely on the micro—the individual drugs, the specific companies, all the detailed skills that are hard to develop and revisit if you’ve skipped them. Some people enter the business from the opposite direction, thinking top-down first, and I personally think it’s much harder to do it that way.

3. Since starting as an investor, you have seen a couple boom/bust cycles in biotech. For the companies that survive, are there a set of features in common (apart from solid science)? How do you actually assess the quality of a team and their ability to execute?

When I think back to the 2009–2010 period—and then compare that [market landscape] to the hindsight we all gained by 2020—what stands out most clearly is how stark some of the market dislocations were. At the time, many businesses were trading at valuations that made absolutely no sense.

One example I always return to is the cosmetic laser industry. These devices—used for skin resurfacing, tattoo removal, and related procedures—represented a global business with roughly $500 million in annual revenue. Even though the U.S. was in recession, global revenues were essentially flat, and the industry was operating close to breakeven—even at the depths of the downturn. Yet the entire sector traded as if it were on the brink of bankruptcy; collectively, the public companies in that space were valued at zero enterprise value.

You didn’t need to be a healthcare specialist to recognize the disconnect. Any investor would have told you this made no fundamental sense. So I invested aggressively, and that inefficiency started to unwind within months—one of the companies was acquired before the summer of 2009.

I think part of why I acted decisively is that I’m wired to look for bargains—some investors have that instinct, and some don’t, as people like Charlie Munger or Warren Buffett would say. But part of it came from training: I had studied economics, gone to business school, and had a grounding in NPV, discounted cash flow, ie fundamental valuation. Those frameworks made the opportunity impossible to ignore.

With reflection, I now see this through a more historical, top-down lens. In any financial crisis, you get pockets of valuation dislocation that have nothing to do with fundamentals. They’re driven by capital flows, forced selling, and broad system-wide fear. Recognizing that pattern helps in two ways: first, it prevents you from hiding under the covers during periods of extreme volatility; and second, in the ideal case, it allows you to do the opposite—to lean in and capture opportunity when fear is highest.

4. You’ve previously noted that mid- and late-stage biotechs may drive the next phase of sector growth. At the same time, we’ve seen several notable acquisitions of early clinical companies—Halda, Metsera, Capstan, Aliada, Orbital. How do you read pharma’s appetite as we emerge from a “nuclear winter”?

When you look across pharma, there aren’t that many big players, so you can analyze them company by company. Viewed holistically my takeaway is that roughly half of major pharmas are now focused on the post-2030 period. Because of where they are in their product life cycles [and patent cliffs], they are increasingly prioritizing early-stage deals—the types you’ve referenced.

But the other half are still very focused on clinical stage assets and validated modalities through the end of this decade. These companies are entering high patent-expiration cycles and must mitigate the impact of looming losses of exclusivity. For them, late-stage and commercial deals will dominate.

Over the next 6 years, I expect a healthy mix of both early- and late-stage transactions.

But the deeper context goes beyond M&A. Over the last decade, we saw a massive expansion in new modalities and innovation across a wide range of disease areas. The winners of that era were the people who could identify and participate in early scientific breakthroughs.

The future rarely resembles the past. Much of that early-stage science has now matured. The next 10 years will be shaped far more by late-stage and commercial stories—how they perform, how they scale, and how they generate durable clinical and financial outcomes.

Innovation in early stage science will certainly continue, but investors shouldn’t miss the fact that late-stage opportunities will become more abundant and more financially consequential. Commercial-stage companies operate at a different scale: the dollar values are larger, the markets are larger—everything is larger. Missing that shift is like focusing on the tail rather than the dog.

[How do you orient yourself towards commercial stage opportunities as a firm?]

It’s important to remember that commercial vs development-stage analysis requires fundamentally different skill sets. With a development-stage biotech, aside from the CEO, the people you most want to speak with are the Chief Medical Officer and the Chief Scientific Officer.

But once a company is selling an approved drug, the key person becomes the Chief Commercial Officer. For some reason, investors don’t always internalize that parallel.

If your investment universe increasingly consists of commercial-stage companies, then you need the capability to evaluate them. And those capabilities are different—you’re not hiring the same people, and you’re not relying on the same frameworks.

People sometimes assume that if you can evaluate a biotech company, you can evaluate it at any stage. But that simply isn’t true. A CMO is not a CCO, and the evaluation of development-stage risk has almost nothing to do with the evaluation of commercial execution. Investors must recognize that distinction as the sector continues to mature.

5. You have taught financial analysis in healthcare at NYU. From an investor’s standpoint, what aspects of valuation are truly unique to biotech—especially when traditional tools like DCFs or NPVs often break down?

When I was in business school, the risk-free rate was 7%, and that was treated as gospel. But the reality is that if you take a dogmatic approach to something like the cost of capital, your framework will break down in certain environments.

That doesn’t mean the core valuation frameworks we all learn—whether in business school or on the job—aren’t the right ones. It simply means you can’t be overly rigid about how you apply them.

In my view, all three core valuation frameworks – DCF / NPV-based analysis, Comparables-based analysis, and M&A-driven strategic value analysis – matter. They matter because the market you operate in uses them. Sometimes the market leans heavily on comps; sometimes strategic value dominates; sometimes discounted cash flow is the only sensible anchor. These frameworks are interrelated but often operate independently, and if you ignore any one of the three, there will be times when you fail.

But valuation frameworks aren’t the whole picture. Markets reflect human behavior, and humans also operate through non-valuation based frameworks: momentum, sentiment, technicals. Academics dislike the mention of technicals, but a sizable portion of practitioners trade on them.

As a practitioner, you have to incorporate these as well and acknowledge that pricing at any moment is the amalgamation of all these human-driven approaches. Anything more dogmatic than that is, frankly, misguided.

6. Can you walk through a time when RTW held a contrarian view on one of your portcos while the Street modeled differently? What allowed you to hold that conviction?

Building from the valuation frameworks we discussed, the question really becomes: What does it mean for something to “stand out” as an opportunity? When an investment stands out, it usually reflects a blend of both fundamental and non-fundamental dimensions. You have to build the skills and team that can evaluate these factors.

To make that concrete, consider a setup where an upcoming event is approaching, the name is heavily shorted, and most long-only institutions have exited. In that case, the stock may be positioned to move powerfully—if the event is positive—even though that setup is entirely non-fundamental.

The most compelling opportunities are the ones that stand out across multiple dimensions simultaneously.

Now, there are also cases—like the cosmetic laser example during the financial crisis—where one dimension alone is so extreme that it overwhelms the others. Fundamentally, those names were trading at valuations that made no sense. In situations like that, you may be willing to ignore every other bucket: no clear catalyst, no interest from strategics, nothing in the near term. But the fundamental mispricing is so obvious that you are willing to take the duration risk—two, three, four, even five years—because the one signal is so strong.

You only need to be intentional and aware of the trade-offs. You might tell yourself: “This scores poorly everywhere else, but it’s trading at zero enterprise value; it’s a cash-flow-positive business; eventually deep-value investors will rediscover it.”

The key is intentionality—knowing exactly why the opportunity is compelling, which dimensions matter most, and what you are consciously choosing to ignore.

7. Avidity and Akero are two recent wins for RTW and shareholders. Both companies had points where they really struggled. Can you speak to what you saw initially in these companies that drove conviction? What lessons can other management teams or investors learn?

Those​​ [Avidity and Akero] are both good examples of how you actually underwrite a development-stage company. And that brings you to the framework that Adam Koppel already discussed with you [on Biomarker], especially the first and last components—namely, will it work, and if it does, what is it worth [valuation/price]? And for both of those companies, the central emphasis was answering those two questions with confidence, especially the first one because of where they were in development. And for both, the very short conclusion is that they scored extremely well; we believed the odds of success in their development programs were high. And then, on the second question [will it sell], both were addressing blockbuster unmet needs, where we had high confidence that success would translate into a significant commercial opportunity.

Once those two boxes were checked, the rest became a matter of valuation—what the companies were worth under different market environments, and how to manage the path between now and those outcomes.

In Akero’s case, we had actually missed much of the early company lifecycle—the private period and the early public phase. Our interest was piqued only after a major setback in Phase 2. We discussed this in depth on a podcast with the CEO, Andrew [podcast linked here]. The valuation setup following that setback created an extraordinarily asymmetric risk–reward heading into the long-term follow-up from the same Phase 2 study. Our assessment was that the odds of success remained high.

With Avidity, we had been involved since it was a private company. This year the key question was the path to market for one of its two key drug programs. We had confidence that their proposed registration trials would be acceptable and had high odds of success—though we don’t know the definitive outcome yet, since the company was acquired before the trials finished [data are expected to be released Spring of 2026]

Avidity did experience a major setback early after it became a public company: a serious safety event in its muscular dystrophy program during Phase 1. That required a deep scientific exercise: Does this safety signal make biological sense? Is there a plausible mechanistic rationale? Our conclusion was that the signal was likely spurious—though we couldn’t know for sure. Our conviction increased as the sample size grew without it happening again.

Experience also played a role. After many years in this business, you see plenty of frightening early safety findings—even in drugs we now consider “as safe as water.” Something alarming happens in an animal or a single patient, and in the end, in large, well-run trials, the signal disappears. So experience teaches you to keep a level head with these situations. But that part—specifically in Avidity’s case with the safety event—is sometimes a very difficult exercise, because you can never say with 90% probability that everything is fine.

8. With the complexity of neuropsychiatry trials (placebo effects, effect-size challenges, heterogeneous patients), how do you think about constructing a neuropsych portfolio? Do you see room for true platform companies here, or is the opportunity set better expressed through selective single-asset exposure?

It’s an interesting question. I haven’t thought specifically about the portfolio-construction question you’re asking, but I can offer a broader historical perspective.

In fact, our new RTW Think Tank have just written a book on policy, which should be released right before JPM. We devote a chapter to the history of innovation in neuropsychiatry.

Right before I entered the industry [ of biotech investing], neuropsych was experiencing a significant wave of innovation driven by two major categories - antidepressants and antipsychotics. At that time, several major pharmas had meaningful neuropsychiatric businesses. But what followed was a prolonged 20-year fallow period. Why? Because the innovations of 25 years ago were priced as frontline therapies: cost-effective, relatively safe (at least compared to predecessors), and used broadly. Once those drugs went generic, the associated price points no longer incentivized innovation for the refractory populations that emerged after frontline agents became standard of care.

As a result, major players—Eli Lilly being the most notable—exited neuropsych entirely.

Then something unexpected happened. Antipsychotics began to be tested as adjunctive therapies and as second- and third-line treatments for depression. Because antipsychotics had always addressed smaller populations, they were priced at 3–4× the level of frontline antidepressants. And because payers accepted that price, it created a return-to-innovation signal for the field. That shift catalyzed where we are now—psychedelics, new mechanisms, and a renaissance in neuropsych, particularly in depression.

[On catalyst for neuropsych]

Ketamine is an old medicine [dissociative anesthetic], but for depression, it was new mechanism. And when you think about psychedelics—they are the most extreme manifestation of how innovation has been re-incentivised for depression. Their treatment paradigm is operationally intense. These are not once-daily pills taken at home. A session might require hours in a monitored clinical setting. It’s logistically complicated and expensive. What ketamine did was test the hypothesis that society and payers would accept such a paradigm. And because ketamine and J&J achieved commercial success, it paved the way for psychedelics.

Now, what’s exciting is that psychedelic antidepressant trials—using traditional endpoints like MADRS or HAM-D—are producing some of the largest effect sizes ever seen, in some cases after a single treatment session. These are durable, one-time or few-time therapies with the potential to transform depression. They are part of a broader innovation arc—one that is only now beginning to realize its full potential. At this point, I think the biggest opportunity is in single asset companies in neuropsych rather than platform companies.

9. How will AI be integrated in healthcare and biotech? Who will the near-term winners be?

Obviously AI is going to reinvent workflows of every kind, and the investment industry is no exception. We—as with everyone else—need to adapt.

But perhaps the more interesting question is where the investable opportunities are today. Some of the hype is, of course, just hype. But there are areas where the opportunities are tangible—even through a very traditional Buffett-style lens. And many of those opportunities are not in therapeutics.

There are healthcare businesses that have already introduced AI-based products and are generating new revenue streams today. One example we like to highlight is RadNet, a portfolio company of ours. They are the largest imaging chain in the United States, and they have already introduced AI-driven adjunctive screening tools for radiologists. That is real, commercial adoption—now, not in five years.

On the drug-development side, the impact will be powerful, but I think it will disproportionately benefit companies with proprietary datasets. And “dataset” can mean many things: genetic data, deep historical experience in small-molecule design, 3D structural data, or other proprietary knowledge.

AI amplifies whatever “superpower” you already have. If you add AI on top of an existing advantage, it can make that advantage stronger. But I’m more skeptical of the idea that a drug company can start with nothing but an “AI-first” identity and expect that alone to confer defensibility. Some companies will succeed from that starting point, but it’s hard—they lack unique data or experience.

[Will big pharmas, with the largest proprietary datasets, benefit the most in the near term?]

The short answer is yes—large pharmas and biotechs will benefit the most. For the large organizations that overcome the inertia that comes with their size and embrace AI, effective implementation will be transformative.

10. What do you want RTW to be known for in 20 years that it is not known for today?

Our journey since inception has been to build something from nothing—to become, I believe, one of the leaders in the business we operate in. I’m proud of that. So part of my vantage point now is simply: How do we remain a leader? Remaining a leader is hard.

But there’s also a broader aspiration. Our industry [biomedical innovation] has done a remarkably poor job of communicating the value of what we do, compared to the technology industry. We have not convinced society that innovation in this field is important, valuable, and worthy of celebration rather than suspicion. I think we have a responsibility, as leaders in the industry, to contribute to that conversation.

Now, a lot of skepticism is grounded in real issues. There is an affordability crisis in U.S. healthcare. Anyone who denies that is delusional. But the fundamental challenge is recognizing that two things can be true at the same time. First, that innovation is extraordinarily valuable and should be celebrated, and second, that the system is failing many people on affordability and access. If you fail to hold both truths simultaneously, you will misdiagnose the policy problem and therefore the policy solution. The book we’ve written is our first step toward contributing to this broader dialogue.

In twenty years, I hope RTW is known not only for investment excellence, but also for helping elevate public understanding of why innovation matters.

The person who has probably done the best job of this is the physician–comedian on TikTok—Dr. Glaucomflecken. Through comedy, he’s helping people realize that the healthcare system is far more complex and ridiculous than they assumed.

Without diving into the entire policy discussion, I think it’s incredibly important for people to understand cause and effect in healthcare: why innovation is, at a societal level, such a bargain, yet why individual patients can still face financial crisis due to access barriers, co-pays, and insurance structures. Both truths matter. And if we don’t improve public understanding, the consequence is that we risk future innovation. Many countries have experienced exactly that: underappreciation of biomedical innovation leading to underinvestment, leading to worse outcomes. We should learn from those examples.

11. Across your career, what is the belief you’ve changed your mind about the most?

It’s a great question. The belief that has changed most for me isn’t about macroeconomics or the healthcare industry. It’s about myself.

I began my career as an individual athlete, like many people in this business. I was good at something—the analogy is shooting hoops—and that skill carried me early on.

But the big learning lesson is that individual excellence only takes you so far. If you want to do something truly impactful, or even if you simply want to achieve a higher level of success, everything great is accomplished through teams. Everything.

So I had to learn that. I went through my management and leadership journey, and all the classes I didn’t pay enough attention to in business school came rushing back. Suddenly, [after this realization] they all made sense.

The impact, importance, and the satisfaction of being a coach, a manager, and a leader—that has defined the last ten years of my career. It’s the belief that changed me the most.

Yet sometimes these molecular or genetic backups fail: a single allele may be too crucial to compensate for. “In haploinsufficient conditions like Dravet Syndrome, loss of a single copy is enough to drive disease,” explains Barry Ticho, MD PhD and CMO of Stoke Therapeutics, “in this case, a single SCN1A allele is unable to produce enough sodium ion channel…what ensues is an epilepsy and neurodevelopmental syndrome,” he says. In situations like these, a therapeutic approach that can augment gene expression is needed – yet there is nuance: “by using an anti-sense oligonucleotide (ASO) that can ‘stoke’ translation of endogenous RNA, we avoid overexpression of RNA in the wrong cell type,” Ticho emphasizes. Unlike an AAV vector that will expresses RNA in a range of cells, Stoke’s ASOs binds endogenous RNA, blocks non-productive exon inclusion and thereby boosts production in the correct cell type. Built from research done by Adrian Krainer’s group, Stoke’s TANGO platform yields ASOs that bind mRNA to augment production of proteins like SCN1A (Dravet) or OPA1 (ADOA). ASOs are a validated therapeutic modality, with approvals in conditions like spinal muscular atrophy (Spinraza), ATTR amyloidosis (Tegsedi) and DMD (Exondys).

With completed Phase1/2 trials for Dravet Syndrome, Stoke’s ASO zorevunersen has generated compelling data thus far: “we are hearing incredible stories from our OLE program…children previously unable to go outside without having seizures are now having birthday parties and playing with the neighbor’s children.” In upcoming phase 3 studies in Dravet, Ticho and his team hope to see improvement in cognition/development, alongside seizure reductions: “this would be the first disease modifying therapy in epilepsy…and we believe a huge breakthrough for these children and their families.” In parallel, Stoke is running phase1/2 trials for its autosomal dominant optic atrophy (ADOA) program: an ASO aimed at bolstering OPA1 production. The goal is to prevent retinal degeneration and halt vision loss in patients with this haploinsufficient OPA1 mutations—for this program Ticho and his team are armed with a robust PD imaging biomarker that can supplement hard clinical endpoints like vision loss [see Q#7]. “It [ADOA] is the exact type of pathology that genetic medicine is best suited for,” states Ticho, “in our early clinical trials we hope to demonstrate convincing change in our target engagement biomarker…and then ultimately in stopping vision loss.”

Ticho has spent decades developing genetic medicines. An MD-PhD from UChicago, he worked with Murray Rabinowitz on the intricacies of mitochondrial RNA: “Murray was a tremendous scientist with a vision,” reflects Ticho, “he was also personally struggling with muscular dystrophy and was an exceptional example of resilience.” Then as a pediatric cardiology fellow at Boston Children’s Hospital and on staff at MGH, Ticho was exposed to both basic science research (via Mark Fishman) and clinical studies of a Merck-made statin, in familial hypertriglyceridemia patients. This initial exposure to industry, led him to later join the translational medicine group at Merck: “I always advise trainees to spend some time at a big company…you see how things are done at the highest level and also are able to gain mentors,” he says. From there, Ticho ran cardiometabolic and genetic programs at Merck, Biogen and Moderna, before co-founding and helping launch Verve Therapeutics. In our interview, Ticho reflects on the unique Boston ecosystem that enabled founding (and funding) of a company like Verve. In his current role as CMO at Stoke, Ticho and team remain laser focused on treating rare haploinsufficient disease: “we believe that our first two programs [Dravet and ADOA] will be PoC for out platform…ultimately our ambition is to treat 1000s of such conditions, enabled by our platform [TANGO].”

A seasoned clinician with decades of big pharma experience, Ticho’s greatest piece of advice is not about technical know-how, but rather soft skills: “recognize that there are many ways to make a difference,” he reflects, “but ultimately your network and mentors will help guide you towards that path...it is never too early to meet these people.” In the fast-paced, competitive biotech industry, Ticho has served as one of these rare mentors for countless trainees. He has transitioning from counseling patient families to nurturing fledgling biotech companies: “my goal is to make a difference in science and medicine,” he says, “there are many ways to do this, but I feel extremely well-positioned in my current role.”

Below is an interview with Dr. Barry Ticho, Chief Medical Officer of Stoke Therapeutics, from October 2025

1. What initially got you interested in science and medicine? Briefly, what did you work on for your PhD at U Chicago?

Growing up I had a “biology fun kit” at home: there was a microscope included, and I would take pieces of grass, leaves, grasshopper legs and just observe them under the microscope for hours. I remember trying to just see how all the cells were connected. It brought me a lot of joy—those tiny discoveries and observations. When I got to high school and beyond, I just continued that. I became fascinated with how the human body forms, and how we’re able to talk to each other, move and think.

My father was an ophthalmologist, and he took me occasionally on his rounds. Sometimes he would have me sit and read children’s stories to some of the pediatric patients he had operated on. Back then, they kept these patients in the hospitals much longer than they do these days. I remember one boy with strabismus who had both his eyes bandaged, and I would read to him every night. One day, my father brought me to the clinic when he was taking off the bandages for this boy’s surgery—just as the last bandage came off and the boy opened his eyes, I saw this look of utter amazement that he could see again. I remember another case of a child who had retinoblastoma and needed tumor excised from his eye. These experiences made an early impression on me.

[On his MD-PhD training]

First, given the current circumstances I must thank the NIH for sponsoring my MD-PhD program and for recognizing the value that physician scientists bring to human health. I hope these types of programs that you and I graduated from will continue to be funded and supported. The realization that we need physician-scientists who can span what’s going on in the lab and going on in the clinic is important and is what drove me into the MD-PhD program.

As an MD-PhD student, my thesis was on mitochondrial function in a cardiology lab. In part this was because the heart muscle has one of the highest concentrations of mitochondria, and mitochondrial diseases have a disproportionate effect on the heart. My advisor was Dr. Murray Rabinowitz, an elected member of the NAS, who himself had muscular dystrophy. Ultimately, he passed away at age 55 and was quite debilitated by his condition—he ended up being on sort of a handheld respirator for many years of his life. He was an inspiration—both for his scientific vision and his courage dealing with his own health issues.

I was focused on studying an RNA polymerase that is mitochondria specific and untangling how it worked. So, this was my first real introduction to RNA, and I’ve sort of been working on RNA, on and off since then. Now with my work at Stoke, I think I’ve certainly come full circle.

2. After your MD-PhD and pediatrics residency, you pursued a fellowship in cardiology at Boston Children’s Hospital. What drew you to pediatric cardiology?

In terms of my decision to go into pediatrics and cardiology—I was fascinated with how the heart forms. The heart forms from just four embryonic cells, and those four cells coalesce into a polarized tube. That oriented tube will fold on itself and form four chambers, and only then form valves, and connections with both the lungs and the rest of the body. I found it amazing that all of this was specified in four pre-programmed cells. So, my interests in developmental biology and molecular cardiology were really what drove me into this area. I was fortunate to also be able to train at Boston Children’s Hospital, where I started using Zebrafish to study development. I started basic science work with Roger Brietbart, Len Zon and then ultimately Mark Fishman. Another clinical inspiration I had was Jane Newberger, who was doing a lot of preventive cardiology in familial hypercholesterolemia patients—this was a purely clinical area, but led to my first collaboration with industry [Merck].

I was ultimately part of a clinical trial that was being done by Merck—using statins to treat pediatric patients with hypercholesterolemia. They had already approved this statin in adults but wanted to go after this specific pediatric population as well. This ended up being a terrific early experience in clinical trials for me.

3. When did you decide to enter industry? What were some of your motivations at the time?

For me, the motivation to join industry full-time was a feeling of dichotomy. I was doing work in the wet lab that, although important, had a somewhat tenuous connection to patients. It [lab and clinic] felt like two very different worlds. Ultimately, I wanted a role where I could do all that at the same time—where there would be a unified purpose. I found that in biotech there’s this real feeling of translational medicine—everyone working together to directly take what’s being done in the lab and apply it to human disease…asking questions like: how do we design the Phase 1 trials to test what’s been demonstrated in the lab? Working in this area requires a good understanding of the animal studies, the ability to communicate with scientists, and the technical knowledge to design experiments that are relevant to patients.

The other motivation for me [to go into biotech] was having a greater impact. I found the one-on-one patient interactions rewarding: seeing a patient overcoming whatever illness they have. But for me, I wanted broader impact that could touch hundreds or thousands—because that is certainly what making a new medicine will do.

4. Coming from Harvard Medical School/MGH, what initially surprised you about working at places like Merck, Biogen and Pfizer

My first job was at Merck, and it brings up a piece of advice I have [for readers]. After I made the decision to go into industry I talked to others who had made the jump before me. I asked them: what’s the best way to learn? The first piece of advice I got was to go to a big pharma—companies like Merck have the resources and expertise to mentor and train. One also gets a sense of what the “gold-standard” is for running a clinical trial. I was fortunate that I found a place in the company’s clinical pharmacology group, which was jargon for translational medicine. In this group I helped design/run phase 1-2 proof of concept studies. My co-workers were all physician-scientists, and we just spent all our time trying to figure out how to get early PoC in patients. I learned how to design trials, run them rigorously and follow “good clinical practice.” One thing that is often a “surprise” for physicians coming from academia to industry is the level of rigor: preclinical experiments need to be done much more thoroughly…the data gets sent to FDA and will impact human beings after all.

Another thing I realized during this time is that learning how to ask the right questions is the most important skill to have—how do you learn this? It really comes down to mentorship, which I received in academia but also at Merck. After a couple years, a position at Biogen opened up, and I joined to help start their cardiovascular franchise.

5. At Biogen you worked on multiple programs and at Pfizer you were head of external R&D innovation. What did you learn about constructing a portfolio at these two pharmas?

When thinking about a pharma portfolio, and adding to that with partnerships, it really requires a couple things. The first is to understand the field well enough to predict what it will look like in 5 to 10 years. Especially true of drugs still in preclinical or phase 1 testing, we are really designing medicines for a treatment landscape 10 or 15 years from now. Putting together a portfolio means having that forward looking approach: trying to imagine the gaps in treatment that we might be able to fill with a very early-stage program: convenience, tolerability, efficacy or combination strategies in the context of an evolving standard of care.

At Biogen, I was mainly focused on helping build heart failure programs. Specifically, we were looking at cardiorenal syndrome and disease—there is so much cross talk between these two organs. I was also focused on genetic cardiomyopathies, though these programs didn’t ultimately end up getting pursued. Lastly, I also had the chance to work on Tysabri for MS and anti-amyloid therapies for Alzheimer’s. So, I benefited tremendously from my experience in Biogen, in part because not all of it was cardiology related. The experienced forced me to learn a whole new field and have a big impact in terms of the treatment landscape for MS and AD.

[On how large pharma thinks about M&A]

After Biogen, I went to Pfizer where we really focused on programs with grounding in human genetics. Here I was much more focused on portfolio development. So how does Pfizer, or big pharma in general, make some of these decisions [about bringing in external innovation]? It depends partially on the expertise in the company. Obviously, if a company has deep expertise in the therapeutic area or certain technology, they’re less likely to go outside. However, if there’s a realization that there is an evolving disease area or technology that’s going to be up and coming, they are of course more likely to partner or acquire from outside. Sometimes there is a term thrown around for such programs: NIH, or “Not Invented Here.” This can be a little bit hubristic: the idea that “big pharma knows best,” or an outside perspective is not needed. It can be a detrimental attitude, which can handcuff a company to internal programs for political or financial reasons, and at worst lead to an inferior product.

[Has this “NIH” attitude changed over time? M&A in the past few years has been pretty robust]

Yeah, I think so. There has been a realization, especially in the past few years, that large pharma is very good at running large phase three trials or commercializing successful products. On the other hand, there can be a risk aversion on the innovation side and large company bureaucracy can hamper internal R&D. But over the past few years the attitude to outside innovation has changed: Pfizer and many other pharmas have dedicated external innovation groups, and many also have their own venture arms that are largely strategic. I think the increase in M&A is driven by the realization that innovation happens faster in smaller companies like Verve and Stoke. At a smaller biotech there is a focus on a more limited number of products or platforms that allows for faster decision making.

6. What led you to co-found and lead Verve? What were the initial conversations and vision for the company?

Verve is a product of the environment that’s set up here in Boston. Initially, Sek Kathiresan had a brave idea for preventive cardiology: to make a one and done gene editing solution for cardiovascular disease. Ultimately, there was a group of seven of us founders, each brining a different expertise. We started meeting every Friday morning over coffee, just talking about the idea, and ensuring we had all the pieces in place. Eventually we started having these meetings in the Google Ventures office, where there was the additional benefit of free food. We put together a pitch deck, took the idea to a few firms and had a positive response. To speak briefly about the relevant expertise, we had Sek of course in terms of cardiology and I was brining LNP knowledge from Moderna. We also had Burt Adelman who was an expert in R&D, Kiran Musunuru and Keith Joung who are gene editing gurus as well as Issi Rozen and Anthony Philippakis.

[Advice about company building]

A word of advice: network early. It’s never too early to go out and start building a network, even during your training. Talk to as many people as you can and try to gain contacts and knowledge in different areas. Forming a network is never easy, but in Boston it is possible because of the proximity of science, medicine and finance.

7. How do you view the future of gene editing?

I’m somewhat biased of course, but gene editing is going to be the way we treat many diseases in the not-too-distant future—especially with increasing levels of whole genome and exome sequencing [due to cost reductions]. When you take a gene editing technology into the clinic, it is critical to choose an extremely validated target. That is what we did at Verve with PCSK9…this validated target can serve as human PoC to then build on later. Moderna had done something like this…they tried to show that they could get EPO production from mRNA [prior to COVID]. However, this product [EPO] was not commercially viable, which was not ideal—since the PoC took a lot of time and money. I feel very strongly that going into proof of concept, you need to have something that is an established target but also is commercially viable. Do not pair a new technology with a new target in an unproven commercial indication. There are just too many unknowns in that scenario.

8. What led you to join Stoke as CMO, and what is most exciting to you about the company’s technology and vision?

The modality is incredibly exciting. The company is called “Stoke” because we can stoke protein expression for treatment of halpoinsufficient disease—a difficult problem at present. A huge advantage here is that the RNA we are targeting must already be expressed in a given cell for our drug to have an effect. This limits off target expression compared to delivering an exogenous mRNA molecule or viral expression [AAV]. We have also found that by giving different amounts of ASO, we can accurately titrate or adjust the amount of protein produced. This is critical because in halpoinsufficient disease, too little protein product causes disease, but too much may cause a separate and equally devastating condition.

The MECP2 gene gives a clear example. Haploinsufficiency in this gene causes Rett syndrome, but gene duplication also causes a severe neurodevelopmental disorder. In cases like this it is important to restore normal MECP2 expression, without overdoing it. In this scenario one may also not want a permanent approach like gene therapy, which cannot be titrated.

The other aspect that attracted me to Stoke was that RNA modulation as a field has really come into its own. This is the perfect time to be designing RNA-based therapies. Gene therapy using AAV vectors has a lot of promise, but right now it has been hampered by off target toxicity and indication selection. On the other hand, you have companies like Alnylam and Ionis that are approving dozens of RNA-based therapies. Delivery to the brain is still an issue, but Alnylam, Biogen and Ionis and others have shown that local intrathecal delivery can drive meaningful CNS uptake. This is a key point in our Dravet Syndrome program.

[On early-stage clinical trial design]

We are now running a phase 3 trial for our program in Dravet Syndrome—a pediatric epilepsy and neurodevelopmental disorder caused by haploinsufficiency of the ion channel SCN1A. Our lead program, an ASO called zorevunersen [STK-001] aims to increase expression of SCN1A to drive therapeutic benefit.

In terms of clinical development, we pursued a standard approach: initially a single ascending dose trial, followed by a multiple ascending dose trial to evaluate safety and PK. In our case, we didn’t have a direct target engagement biomarker, so we are estimating biological effect based on our preclinical data and drug concentration in the CSF [from SAD/MAD studies]. We have very strong preclinical data in rodents and monkeys where we directly measured brain expression of SCN1A after administration of our ASO. From these studies, we built a pharmacodynamic model to predict the correlation between ASO concentration and protein expression in the CNS. This data—the NHP in particular—gave us a lot of confidence that our treatment/modality was behaving as expected. The strength of this program really comes down to genetics—we know the causative gene [SCN1A] in Dravet Syndrome. Ultimately, our PK-PD models have been validated in the clinic with results from our phase 1/2 study. However in general I am a huge fan of having a direct target engagement biomarker

9. What are you most proud of from a development standpoint in terms of your recent data and programs at Stoke?

For the Dravet program [zorevunersen] one of the key things that we were able to show was modification of a hard clinical biomarker: seizure frequency. We saw a dose related effect in our phase 1/2 and extension studies, now out to over three years. Dravet Syndrome, as I mentioned is a disease caused by deficit of a sodium channel called SCN1A. It is a haploinsufficient disease, meaning only one mutated copy can produce disease because there is only half of the normal sodium channel expression in the brain. These children have severe seizures, but also substantial developmental delay. Current control of Dravet is with anti-seizure medications, but these do not alter progression, nor do they prevent developmental delay. Many patients may end up with the cognitive function of a two-year-old.

In our phase 2 trial, we were able to show in children who are on anti-seizure medication that we could have 89% reduction in the number of seizures. In addition, using measures of cognition and behavior we showed that with treatment, children improved their scores compared to natural history controls.

We believe this early data is telling us that that we are having a disease modifying effect, which has never been shown in Dravet or any form of epilepsy. In our open label extension arm, we have some patients who have been on drug for four years and are now having sustained benefit.

[What are the major results and upcoming milestones from the Dravet program?]

We are deep into our phase 3 program [EMPEROR Study]. We talked to regulators around the world and reached an agreement on trial design prior to initiation. Now we are enrolling US patients and have had a tremendous amount of interest from clinicians and families of children with Dravet. I’ll tell you the story of a boy with Dravet who every time he would go outside the sunlight would trigger a seizure. This family had to keep their whole house dark to prevent him from seizing. After treatment, this boy could now go outside and play with the neighbors. This family has even been able to take the shades down in their house and let the sunlight in. We have also had several stories of children with Dravet who are non-verbal, and after treatment gain the ability to speak and even sing happy birthday. Part of our ability to move quickly comes from a strong clinical advisory board, who are the leading experts in Dravet Syndrome. Even prior to meeting with regulators, we had a strong clinical plan that closely resembled the phase1/2 studies. When you have endpoints and enrollment criteria that match earlier trials, it de-risks the phase 3, to an extent.

From a safety perspective, we’ve now given over 700 doses of our drug to 81 patients. In terms of both efficacy and safety, regulators were very convinced by what we had [prior to phase 3].

[What about your ADOA program?]

The rest of our pipeline is also focused on haploinsufficiency, using clear human genetics as a guide. The next most advanced product is treating autosomal dominant optic atrophy [ADOA]. ADOA is the most common genetic optic nerve disease driven by loss of a protein called Opa-1. We are using our oligos to upregulate OPA1 protein levels to restore mitochondrial function in the optic nerve. We now have data in several animal models that show that we can increase these protein levels in the retina, especially in the retinal ganglion cells that are affected in ADOA. In this case [unlike Dravet] we do have a biomarker that indirectly measures target engagement: we can look at mitochondrial function and oxidative stress in the retina directly by imaging flavoprotein fluorescence [FPF] using a machine called the BEACON. We’ve run a two-year natural history study in patients with ADOA showing that FPF increases over time. Our hope is that when we start treatment, we can see stabilization and then reduction in FPF in our treated group compared to controls. We believe that this early type of biomarker change will eventually translate to improvement in visual acuity.

10. What are the challenges with working on rare disease as a public company in today’s macroenvironment? How will success in rare disease enable development for more prevalent diseases?

We have a platform that has utility for many diseases, and ultimately, we would like to be able to use this platform across many genetic diseases. Our hope is that once safety and efficacy have been established for conditions like Dravet Syndrome and ADOA, we could work with FDA to more quickly apply our platform to other genetic disorders. Ideally this application would be without the time delays caused by rigorous preclinical toxicology studies for each new disorder. We have several other programs in development now, and we are staying focused on haploinsufficiency. Eventually we hope to bring our products to as many patients as we can. However right now it is important to stay focused and use company funds wisely to prove out our concept in the two lead programs. As a relatively small company we cannot afford to dilute our efforts. Public market reactions [around indication selection or early clinical data] can be distracting and discouraging. In my role, I am trying to help maintain that discipline around our two leading programs and move those forward effectively. With two successes under our belt, we can then expand to other, more common diseases. I do think we have a platform that can be of benefit patients in hundreds or thousands of different disorders.

11. Advice to physicians/scientists who want to eventually enter drug development?

The first piece of advice is to always seek joy and pursue what gives you a sense of fulfillment. From the time I first looked in a microscope, all the way to what I’m doing today, I get joy from science and the prospect of helping people. I am a curious person, and I feel that I am learning constantly in my current job. In terms of specific career moves, one must recognize that there isn’t always a fixed path. I went through pediatric residency, cardiology fellowship, post doc and faculty positions intending to stay in academia. All of a sudden, I then decided to choose a different role in industry. My second piece of advice is to just be open to new paths. Realize that there isn’t one set way you have to do things…it is OK to defy expectations at certain points.

Lastly, networking is important. What can be useful is starting your career at a larger company where you can meet terrific mentors who have the time to teach you. These mentors can show you the “right way” to do things, like running clinical trials. Once you go into a smaller biotech, there is an expectation to hit the ground running. In industry, there is a whole new language to learn, which can feel daunting. Having good mentors helps make this transition feel manageable.

Natural catastrophes create “ecological opportunity.” With reduced competition, well-adapted species can colonize niches quickly – often to the detriment of other inhabitants.

With a touch of melodrama characteristic of the biotech industry, many have dubbed the past several years a “nuclear winter.” Rising rates, reduced risk appetite, a narrow IPO window, and anti-pharma policies (e.g., IRA) sent the $XBI tumbling, with late-stage companies trading at deep discounts. The number of publicly traded biotechs dropped by 20% over the past 40 months—a culling (of negative EV companies) that some would argue is a positive for the industry.

On both the public and private side, companies with mature clinical assets and data were the first “species” to repopulate during the downturn: there were nearly 100 private mega rounds (>$100M) in 2024, making it harder for smaller, preclinical competitors to access capital. While some of these mega rounds did fund preclinical platforms or mechanisms, a large proportion were allocated to ventures with assets in Phase 2 or 3 clinical trials. On the public side, the average preclinical biotech was worth $511 million in 2021—in 2025 this figure stands at $16 million.

Biotech is now emerging from its “nuclear winter”: the $XBI is above $100 (for the first time since 2021), and we are on track for strong M&A to close out 2025. Much of the excitement (and financing) in the industry centers around private and public companies with mature clinical datasets—rightly so, as these companies are closest to helping patients. The recent multi-billion-dollar acquisitions of Metsera (Pfizer), Akero (Novo), 89 Bio (Roche), Verona (Merck), and Intracellular (JnJ) are a testament to strong clinical data, experienced management teams, and savvy investors. However, these events also have the potential to create a crowding of clinical-stage NewCos around validated mechanisms.

As the biotech niche continues to “repopulate,” one must acknowledge that preclinical and phase 1 companies play a pivotal role in the ecosystem. Without investment in platform technologies or early-stage assets, innovation will stagnate—the apex predators (large pharma) will inevitably suffer. More importantly, truly novel drugs may not get to patients.

Share

Are early-stage companies showing signs of surviving this “nuclear winter”? Can they access non-dilutive capital, secure pharma deals, and thrive in 2025? Acquisitions of companies like Orbital, Aliada and Capstan, along with platform deals inked by companies such as Monte Rosa and Arrowhead, suggest that certain preclinical datasets and approaches are highly valued by strategics. What themes unite these desirable technologies or mechanisms? How are pharma partners selecting this early-stage science, and how do deal structures differ by indication space?

In this series, we highlight early-stage biotech-pharma deals (preclinical or phase 1) in neuroscience, oncology, cardiometabolic, and I&I. Within each indication, we identify “microtrends”: the types of platforms, mechanisms, or assets (preclinical or in phase I) that have been most successful in attracting M&A or partnerships over the past 4 years. For each early-stage “microtrend,” we highlight the pharmas that have participated, those with internal programs, and those that have yet to enter the space. Lastly, we identify early-stage companies (without deals) working within these thematic areas: companies that we believe are poised for future deals or M&A. Our intent is to identify the early-stage science that has weathered the storm, and will hopefully advance to the clinic in the next 5-10 years.

For Part I of our series, we begin with the brain: discussing over 60 early stage (preclinical or phase I) deals (M&A or partnerships) since 2021. Often considered the most difficult area of drug development, neuroscience has the highest unmet need for innovative therapeutics. These “microtrends” showcase areas of early-stage neuroscience that are relatively attractive to pharmas, and may drive the next-generation of clinical stage breakthroughs.

Subscribe now

Neuroscience: think location

When considering the nervous system, think “location, location, location,” advises Rob Baloh, Head of Neuroscience at Novartis [Biomarker interview, 2025]. Genetic and biochemical studies have revealed promising therapeutic targets within neuroinflammation, cell death, and metabolism: the challenge now is to drive deep inhibition of these pathways in CNS or muscle. “How do you hit the right target, with the right level of inhibition in the right part of the brain?” emphasizes Baloh.

Later stage dealmaking in neuroscience has renewed interest in early-stage science and platforms. The past couple years have seen acquisitions of clinical-stage companies like Intracellular, Reata, Longboard, and Decibel, and promising phase 2 and 3 datasets from companies like Denali and Avidity. Although a somewhat controversial win (both clinically and commercially), the approval of anti-amyloid therapies like lecanemab and donanemab has shown that the FDA will accept surrogate endpoints for approval. Within neuropsychiatry (a relative black box regarding mechanisms), acquisitions of companies like Karuna, Cerevel, and Intracellular have renewed interest in target discovery efforts. In genetically defined epilepsy, companies like Stoke, GRIN, Encoded and Praxis will have mature (phase 2/3) datasets as soon as 2027.

We examine over 60 early-stage M&A events or partnerships within neuroscience over the past 4 years: deals that were driven by assets / platforms in the preclinical or phase 1 stage. From this dataset, we identify 6 “microtrends”: 1) BBB-shuttle technologies, 2) precision RNAi, 3) neuroinflammation and homeostasis modulators, 4) AAV-driven gene and cell therapy, 5) AI-driven target discovery platforms 6) neuropsychiatry and 7) epilepsy. Within each microtrend, we identify common deal structures, pharma participants, and early-stage companies poised for future deals. We also discuss competitive headwinds and barriers to these approaches. This list is not exhaustive; rather it is intended to provide selected case studies for how the industry is viewing early stage neuroscience.

“Neurology patients are among the most vulnerable, with the highest unmet need,” comments Al Sandrock, CEO of Voyager Therapeutics [Biomarker Interview]. “We have an increasing understanding of the science and genetics of these diseases…now we need to refine how we deliver these targets,” he says. Non-dilutive funding via partnerships and M&A will drive interest in private and public equity investment in this space. In turn, continued support of early stage neuroscience companies—from both pharma and investors—is crucial for getting novel therapies to patients.

Subscribe now

Microtrend 1: BBB-shuttled therapeutics

The Science: Encasing our nervous system is an ancient defense system honed by evolution--one largely impenetrable to many man-made therapeutics. The blood brain barrier (BBB) refers to several adaptations of the vasculature supplying our central nervous system: endothelial cells with fortified tight junctions, low rates of transcytosis, specialized receptors that efflux drug-like molecules, and a layer of pericytes/astrocytes that provide additional support and protection. Early work in the 1980s - 1990s showed that the BBB, while formidable, is not unassailable. Certain receptors, like transferrin-1 (TrfR1), are enriched on the endothelium, and when agonized can deliver cargoes into the CNS. Companies like Roche/Genentech and Denali were among the first to clinically develop “brain shuttles” that exploit this transferrin receptor. Roche is currently pursuing trontinemab: a TrfR1 shuttled mAb targeting amyloid-beta that is in phase 3 clinical trials for AD. Denali has coupled TrfR1 targeted mAbs to recombinant enzymes missing in diseases like Hunter syndrome, in order to more effectively provide replacement therapy (and has several additional shuttled assets in its pipeline). Monoclonal and protein therapeutics are a cornerstone of biotechnology. Brain shuttles may facilitate the delivery of these large molecules to deep brain structures, spinal cord or muscle. There has been an uptick in dealmaking in the space—strategics are searching for both optimized TrfR1 shuttles to “get in the game,” and next-gen transcytosis receptors (distinct from TrfR1, CD98, IGFR1) to design the neurotherapeutics of tomorrow.

Notable early-stage deals: there has been a recent uptick in BBB-shuttle interest. The most striking event was AbbVie’s recent acquisition of Aliada Therapeutics: a JnJ backed biotech developing a shuttled anti-amyloid beta asset that was initiating phase 1 trials. Strong NHP data showing high CSF/brain penetrance from this shuttle likely drove the $1.4B acquisition, along with some innovation regarding the specific anti-amyloid moiety. Novartis has inked two partnership deals with Sironax and Bioarctic to utilize their BBB transport vehicles in neurologic indications (like AbbVie, Novartis has a commitment to neuroscience and counts the SMA gene therapy Zolgensma in its commercial pipeline). ABL Bio, a Korea-based biotech, has had success in partnering with both Sanofi (shuttled aSyn program, $75M upfront) and recently GSK ($50M upfront) for access to its preclinical IGFR1-based brain shuttle. Partnership deals in this space typically provide upfronts of $30- 100M and biobucks/milestones of >$1B. However, as late stage clinical data from Roche and Denali readout in 2026 and beyond, the structure of these deals could shift significantly.

Pharma Interest: With its acquisition of Aliada, AbbVie joins Roche and Denali in the battle for the best TfR1 shuttle. Though no data is yet public, Lundbeck also reports internal TfR1 programs in its R&D day investor materials: citing a 2017 deal with Ossianix as key to establishing its shuttle platform. In partnerships with ABL Bio, GSK (2025), and Sanofi (2022) are pursuing a different approach: an IGFR1-mediated BBB transport vehicle, which, along with targets like CD98, has shown preclinical promise as a brain shuttle. Novartis has pursued two partnerships with Eisai and Sironax for access to their BBB tech (undisclosed targets), and had previously inked a 2022 deal with Voyager for a BBB-penetrant AAV. Eli Lilly and BMS do not appear to have any publicly disclosed shuttles in the pipeline, though in 2021, they formed a research partnership with the Wyss Institute to discover next-gen BBB transport technologies. Eli Lilly also has an undisclosed research agreement with Qinotto to develop their BBB platform. Merck, Bayer, and AstraZeneca do not seem to have ongoing research agreements, internal programs, or partnerships in the BBB-space. JnJ had an undisclosed 2022 deal with the now defunct Bioasis Therapeutics for its LRP1 brain shuttle, though it is unlikely that the large pharma is now pursuing this asset.

Early stage companies poised for deals: Early stage companies with preclinical BBB platforms need to demonstrate strong non-human primate (NHP) data showing robust brain and CSF penetration (high CSF/serum ratios) in order to garner pharma interest. The Trf1 shuttle space is increasingly competitive—Roche and Denali will have late stage clinical data in 2026. If these readouts are positive, large pharmas or investors may continue to converge around “validated” mechanisms (i.e. Trf1 or IGFR1). Of particular interest is whether shuttled anti-Abeta mAbs (Roche’s trontinemab) have reduced risk of ARIA compared to naked amyloid antibodies.

Next-gen companies may try to focus on identifying novel transcytosis receptors on the BBB, with lower levels of expression on peripheral tissues (for example, TfR1 is present on muscle and hematopoietic cells). Some early-stage companies working on next-gen (better Trf1 or novel target) CNS transport vehicles include: Aerska, Cenos Therapeutics, Manifold, Gate2Brain, Qinotto (R&D collab 2024 with Lilly), and Ossianix (2017 collaboration with Lundbeck). Manifold and Aerska are particularly compelling. Manifold’s mShuttle platform allows screening of hundreds (and potentially thousands) of constructs in vivo. So far, they have used their platform to identify TfR1 antibodies with favorable properties, and novel (undisclosed) BBB receptors. Aerska is a blend of microtrends #1 (BBB) and #2 (RNA modulation): they are tagging RNAi molecules with TfR1 binders to “shuttle” these molecules into the CSF. This would avoid intrathecal or intracerebral injections of RNAi for precision neurology applications. Both companies are early-stage (seed/Series A) and poised for deals with large pharmas strategics. Recently, the biotech Souffle also launched with $200M in funding — the company is searching for receptors that will facilitate drug delivery to a range of tissues (likely CNS), and their first applications are neuromuscular disease and cardiomyopathies.

Competitive headwinds: There are other ways to access the CNS. AAVs or exosomes that can traverse the BBB offer an alternate route to transcytosis receptors. Recently, the AAV space has suffered significant setbacks in the wake of patient deaths in the muscular dystrophy space (Capsida and Sarepta). There are several notable early-stage deals focused on AAV or exosome approaches, ones that offer a “competitive” strategy to BBB-shuttles. These are fully discussed in microtrend #5, but include Voyager’s deals with Novartis (2022) and Pfizer (2024), Caspida-Abbvie (2024) and Sangamo-Eli Lilly (2025).

Share

Microtrend 2: Precision RNA modulation

The Science: For precision neurology, RNA has become an increasingly attractive intervention point. RNA modulation offers the potential to precisely silence, repair, or fine-tune pathogenic messages without altering the underlying genome or delivering bulky proteins/DNA constructs across the BBB.

The best established modalities are siRNAs and antisense oligonucleotides (ASOs), pioneered by biotech success stories like Alnylam and Ionis. siRNAs load into the RNA-induced silencing complex (RISC), guiding it to cleave disease-causing transcripts, while ASOs can either degrade RNA directly or redirect splicing to boost transcript production. Clinical precedent exists: Biogen’s Spinraza, an ASO that corrects the splicing of SMN2, transformed outcomes in spinal muscular atrophy (SMA). Building on this early work, biotechs like Dyne, Avidity, Arrowhead, DTx, City, and Aerska are advancing siRNAs engineered for uptake into neurons, muscle, and Schwann cells. Companies like QurAlis and Trace Neuro are taking a different approach: developing splice-switching ASOs that restore UNC13A function in ALS to correct pathogenic “cryptic splicing” events. Beyond silencing/splicing modulators, newer approaches attempt RNA rewriting. Ascidian is designing large RNA constructs that replace faulty exons, offering a strategy to correct broad classes of mutations in one step. Another novel approach involves small-molecule modulators of RNA processing. Skyhawk and Anima are identifying compounds that influence how spliceosomes or ribosomes handle transcripts, enabling oral, brain-penetrant drugs that act upstream of protein production.

The central challenge remains delivery into the nervous system (see microtrend #1), but as companies refine targeting chemistry and uptake strategies, RNA modulation is emerging as one of the most dynamic frontiers in neuro drug development. As expected, big pharmas are taking advantage of this exciting new science.

Notable early-stage deals: In 2024, the Sarepta-Arrowhead alliance reset expectations for RNA in neuro: more than $1B upfront and up to $10B in milestones, structured through cash, equity, and deferred payments. That scale dwarfs most neuro licensing deals, where upfronts rarely exceed $100M, and positioned siRNA delivery as a strategic priority. A year earlier, Novartis’ $500M upfront acquisition of DTx Pharma underscored the same theme: differentiated delivery into Schwann cells was worth a full buyout.

From there, momentum spread into other RNA modalities. Roche’s $42M upfront, $1.8B bio partnership with Ascidian extended RNA rewriting into the CNS, while Lilly made a suite of bets from Scribe’s in vivo CRISPR editors (DNA) to QurAlis’s UNC13A splice-switching ASOs to two successive ProQR RNA editing alliances worth over $5B in milestones (but with little upfront $). Meanwhile, Merck and Takeda placed complementary wagers on small-molecule modulation, with Skyhawk and Anima, respectively. These transactions reveal big pharma’s deal strategy in this space: high upfronts for differentiated delivery, milestone-heavy partnerships for earlier-stage platforms, and a concentration of interest among pharmas with established neuro portfolios.

Pharma Interest: The largest upfronts have gravitated towards siRNA delivery in neuromuscular and neuronal disorders, where disease biology is genetically validated and delivery breakthroughs are unlocking new tissues. Sarepta’s alliance with Arrowhead, Novartis’s acquisition of DTx, and Biogen’s partnership with City Therapeutics collectively show pharma confidence that RNAi is ready for broader CNS and neuromuscular applications. At the same time, pharmas are diversifying into splicing correction, drawn by the strong genetic validation of targets like UNC13A and mHTT. Merck’s deal with Skyhawk represents a commitment to small-molecule splicing modulators that could offer oral convenience over ASOs. Lilly on the other hand is positioning itself as one of the few pharmas building a multi-modal broad RNA franchise. In terms of riskier bets, Roche’s partnership with Ascidian and Takeda’s alliance with Anima highlight pharma’ willingness to take selective bets on less proven technologies.

We see a tiered pattern of engagement. Novartis and Lilly are assembling broad RNA toolkits that span silencing, splicing, and editing, while Roche and Merck are making more concentrated bets. Deal economics mirror a maturity gradient: billion-dollar upfronts are reserved for validated siRNA platforms with tractable delivery, mid-sized commitments flow to splicing programs with clear disease biology, and milestone-heavy deals cover high-risk repair or translation mechanisms.

There are several pharmas still without high-profile neuro-RNA deals or partnerships. First, modality leaders constrained by delivery, such as Moderna, BioNTech, and Pfizer, have the RNA chemistry and scale but lack BBB-penetrant vectors. This is the most volatile group: once a systemic or shuttle-enabled RNA delivery platform shows human proof, these companies are likely to pivot quickly and become aggressive acquirers. Second, RNA incumbents with existing alliances, such as Alnylam and AstraZeneca, are quieter because they are effectively covered. Alnylam’s CNS RNAi pipeline is largely embedded in its Regeneron partnership, while AstraZeneca channels RNA collaborations through Ionis in non-CNS disease. Third, shuttle-first pharmas such as Sanofi and GSK may be betting that validated BBB shuttles for antibodies can later be repurposed for RNA payloads. They are positioned to transition quickly once RNA-compatible shuttle data emerges. Of the two, GSK may move faster, as it has already partnered broadly across neurology biologics.

Early-stage companies poised for deals: This past month saw the announcement of two high-profile private financings in the RNAi space. Aerska (led by Alnylam and Ochre Bio vets) launched with $21M in financing to develop Trf1r shuttles coupled with RNAi to enhance CNS delivery. The recently announced Soufflé is using its platform to discover and develop cell-specific RNA molecules, with a focus on genetic neuromuscular disease and cardiomyopathies—though it is hard to imagine they won’t turn their attention to the CNS eventually.

Microtrend 3: Neuroinflammation and homeostasis

The Science: Neuroinflammation is a hallmark of pathology in a range of neurologic indications. Proliferation and activation of microglia and astrocytes (gliosis) occurs in Alzheimer’s, Parkinson’s, ALS, and even neuropsychiatric disorders like schizophrenia. Preclinical experiments have revealed that genetically defined targets like GBA1 and LRRK2 (PD), C9ORF72 (ALS), TREM2 (AD) and progranulin (ALS), play central roles in modulating inflammation and cellular homeostasis--strengthening the hypothesis that dampening chronic neuroinflammation may have therapeutic benefit. Recent work has shown that lysosomal and mitochondrial biology are intricately tied to neuroinflammation--mutation of targets like PINK1 and GBA1 promote gliosis, and activate downstream inflammatory pathways like cGAS-STING. Post-mortem studies from patients with progressive MS have shown that iron-laden microglia contribute to chronic neuroinflammation and neurodegeneration behind a closed BBB: prompting some to target these cells directly (e.g. via BTK inhibition). Despite excitement around the biology of neuroinflammation, clinical setbacks—surrounding high profile targets like TREM2 and complement— have dampened enthusiasm for this approach in neurology. Emerging targets heading into clinical trials (e.g. NLRP3, TYK2, BTK) will be pivotal in restoring faith in this approach.

Notable deals: The allure of targeting neuroinflammation or cellular homeostasis rests in its broad applicability. Targets like complement, TREM2, NLRP3 may be leveraged across several diseases, with pipeline in product potential. In the last several years, NLRP3 has been the dominant target for early stage dealmaking: Roche’s 2020 acquisition of Inflazome and Novartis’ buy out of IFM Tre established the value of preclinical companies in this space around $300-450M with significant milestones. Several companies with NLRP3 inhibitors (Roche/Inflazome, Ventyx and Nodthera NLRP3i) are in phase 2b trials for conditions like PD — these results will be critical in understanding the role of the inflammasome in neurodegeneration. TREM2, a target genetically linked to development of AD, has similarly garnered interest for its ability to impact microglial function, clear protein aggregates and dampen inflammation. Alector and Abvvie recently stopped the open label extension of their TREM2 agonist (AL002) after its phase 2 study (INVOKE) missed on key primary and secondary endpoints. Concerns about the ratio of soluble to membrane bound TREM2 have been offered as explanations around disappointing trial results. Nonetheless, Novartis has a planned Ph2 for its internal TREM2 agonist in AD, and Sanofi acquired Vigil Neuro’s TREM2 agonists (mAb and small molecule) for $470M. Eli Lilly made a relatively small acquisition of Disarm therapeutics in 2020 (out of scope) for $135M upfront. A newer target, SARM1 mediates wallerian degeneration in preclinical models, and may contribute more broadly to axonopathy and inflammation seen in a range of neurologic disorders (though Lilly has not publicly announced planned trials).

There has been a score of early-stage deals focused on assets targeting lysosomal function (and downstream neuroinflammation) in Parkinson’s disease (PD). LRRK2, a kinase/GTPase genetically implicated in PD, has profound effects on the function of innate immune cells like monocytes and macroglia. Several companies (public and private) are pursuing development of LRRK2 inhibitors, including Biogen, which acquired Denali’s LRRK2i when it was in phase 1 testing for ~560M upfront. The preclinical biotech Caraway, which was acquired for $650M by Merck (2023), was developing small molecule activators of the TRPML1 and TMEM175 to promote lysosomal function, restore GBA1 activity, and reduce inflammation in PD. Lastly, Abbvie acquired Mitokinin for $110M upfront in order to access its PINK1 activators to restore mitophagy (and dampen activation of downstream pathways like cGAS-STING) in neurons and glia.

Pharma interest: Sanofi (via Vigil) and Novartis both have active TREM2 programs in development, while Novartis and Roche have NRLP3 inhibitors in their respective pipelines. Sanofi and Roche are also both developing CNS penetrant BTK inhibitors for progressive MS--with some phase 3 data suggesting this approach may slow progression of secondary PMS. Whether BTK (which modulates microglial function in addition to B cells) will be pursued in neurodegeneration remains to be seen. Sanofi has also shown interest in genetically validated neuroinflammation targets like RIPK1 (2018 deal with Denali for its phase 2 ready inhibitor) for treatment of conditions like ALS. However, negative phase 2 trials (HIMALAYA) in ALS and MS halted development of this asset. Overall Sanofi appears most committed to neuroinflammation, (TREM2, BTKi and RIPK programs), with Novartis and Roche following close behind. Though not directly impacting neuroinflammation, Abbvie’s acquisition of Mitokinin (PINK1) and Merck’s deal with Caraway (GBA1 via TRPML1) seek to restore homeostasis and thereby reduce downstream activation of inflammatory pathways like cGAS-STING. The Abbvie and Merck approach may be more indicative of the overall pharma sentiment in 2025: modulate genetically validated targets and thereby impact downstream chronic neuroinflammation.

*** After publication (10/21/25), Vanqua Bio inked a $70M upfront partnership with Biogen (10/24/25) for development of their preclinical C5aR1 inhibitor for a “range of inflammatory disorders (now reflected in the section graphic).

Early stage companies poised for deals: There are several early stage companies with preclinical and phase 1 assets in the neuroinflammation space. SUDO Biosciences is developing an oral brain-penetrant TYK2 inhibitor for neurologic disease (preclinical), while Neuron23 is pursuing the same target for MS (phase 1). Ventus Therapeutics is developing small molecule inhibitors of both NRLP3 and cGAS-STING for neurology, whereas Tenvie Therapeutics is pursuing SARM1 and NLRP3 inhibitors (preclinical) for undisclosed neuro indications. Sironax (BBB partnership with Novartis) is in phase 1 testing for its SARM1 and RIPK1 inhibitors for neurodegenerative disease. Vanqua Bio (launched in 2019) is more specific with respect to their indications: they are developing small molecule activators of GBA1 (PD and lewy body dementia) and C5aR1 complement inhibitors (AD and MS). Vanqua recently released phase 1b data showing strong GCase activation in the CSF (PD) for its lead GBA1 activator (VQ-101) in healthy volunteers. Arvinas, a protein degrader company that secured an early stage oncology deal with Pfizer, is also developing a brain-penetrant LRRK2 degrader that will soon have phase 1 healthy volunteer data. Provided PK/PD results are favorable, both Vanqua and Arvinas could garner interest from pharma partners interested in making a move in Parkinson’s. Lastly, CAMP4 has a GBA1 ASO (to boost mRNA production) in discovery stage for genetic and sporadic PD, though it is too early to assess how this modality will compare to small molecule modulation of this target (e.g. Caraway and Vanqua).

Microtrend 4: Target Discovery Platforms

The Science: Every new medicine begins with the same fundamental question: what should we target? Modern discovery platforms are designed to give systematic answers, replacing intuition and trial-and-error with scaled biology and computation. These novel systems bring together human genetics, pooled CRISPR perturbations, and iPSC-derived models of neurons, glia, or immune cells to surface causal drivers of disease. AI models trained on cell-painting assays, spatial omics, and population-scale genetic datasets can (in theory) distinguish true disease suppressors from bystanders, generating ranked target lists complete with mechanistic context. Importantly, the output is not a single drug candidate but rather a stream of tractable targets that can seed pipelines. Big pharma sees (some) value: collaborations now span functional-genomics “disease suppressor” maps, AI-based phenotypic discovery engines, and neuroplastogen screens designed to expedite processes throughout the neurotherapeutics industry. Yet, until these approaches start to deliver cold hard drugs, much of the industry still views this work as unproven (reflected by relatively meagre upfronts).

Notable early-stage deals: Recent early-stage deals show pharmas paying for the ability to generate novel targets rather than for single molecules. Roche and Genentech’s $150M upfront alliance with Recursion exemplified this shift: their bet was on AI-driven phenomics capable of surfacing causal nodes across CNS and oncology, not on a defined asset. GSK’s earlier partnership with Adrestia leaned into functional genomics, systematically identifying disease suppressors and modifiers that could rewire pathogenic pathways - an approach now mirrored in Insmed’s acquisition of the company. AbbVie’s collaboration with Gilgamesh is a newer twist on the same story, positioning neuroplastogen biology as a discovery platform for psychiatric disorders rather than a one-drug pipeline. BMS’s tie-ups with Evotec reinforce the point: pharma increasingly values externalized phenotypic screening and genetic target-validation engines as renewable sources of insight.

Upfronts remain modest compared to asset acquisitions, but milestones are structured to reward platforms that repeatedly generate validated targets with mechanistic depth and translational evidence. Scientifically, the common denominator is a multi-layered approach: perturbation biology in disease-relevant cells, phenotypic profiling across imaging and omics, and computational frameworks to integrate those signals with human genetics. Strategic activity is concentrated in neuroscience and immunology - areas where causal maps are incomplete and high-throughput discovery platforms can perhaps be most useful.

Pharma interest: Most major pharmas now see CNS target discovery as a capability rather than a one-off deal, but their approaches differ. Roche and Genentech have been the most public, leaning on Recursion’s AI phenomics to industrialize causal target identification across neurology. GSK has taken a genetics-heavy approach, betting on Adrestia’s synthetic-rescue maps to reveal protective modifiers and suppressors in neurodegeneration. AbbVie’s partnership with Gilgamesh reflects a biology-first pivot toward synaptic plasticity and psychiatric disease (aligning with their historical interest), while BMS has expanded its Evotec alliance to add CNS discovery capacity through PanOmics and molecular glue programs. Merck is validating its external human-tissue strategy with Cerevance, where NETSseq milestones show it is comfortable buying into platforms that start from post-mortem brain samples.

The quieter players are instructive as well . Amgen’s deCODE unit, Regeneron’s Genetics Center, Novartis’s NIBR informatics and phenotypic screens, and Sanofi’s enterprise-scale AI discovery group already give these companies powerful internal target engines, making them less reliant on external CNS platforms - at least for now. By contrast, Pfizer and Bayer look primed to be next movers. Pfizer has poured resources into AI-driven disease modeling (CytoReason, primarily in immunology, not neuro) but lacks an external discovery partner. Bayer, meanwhile, has already partnered with Recursion in oncology and fibrosis. Extending that relationship into CNS may be a logical step as the company seeks to refresh its neuroscience strategy.

Early-stage companies poised for deals: Several early-stage biotechs have robust CNS target discovery platforms without yet having headline partnerships. Cajal Neuroscience is a “target-first” platform in neurodegeneration, combining human genetics, pooled CRISPR perturbations, and high-resolution microscopy to systematically identify causal drivers of neuronal loss. With a $96M Series A and no major partnerships, it is well positioned for its first strategic deal. MapLight Therapeutics, which is pursuing a “better Cobenfy” in SCZ, takes a circuit-level approach for its target discovery platform. They are using optogenetics and spatial transcriptomics (STARmap) to link brain network dysfunction directly to molecular targets. System1 Biosciences is scaling phenotypic screening across neuronal and glial models, generating functional “fingerprints” of perturbations that can uncover targets outside of well-mapped genetic pathways. Quiver Bioscience is developing a “Brain GPS,” layering 3D human brain organoid models with ML to nominate network-level intervention points - particularly relevant for complex psychiatric and seizure disorders.

The timing is critical: with Roche and Denali’s BBB shuttle data approaching, delivery into the brain may soon be less of a bottleneck. Strategics will then need fresh, differentiated targets—and these platforms offer exactly that: novel biology in patient-relevant models.

Competitive Headwinds: Two dynamics are pulling investment away from pure CNS discovery platforms. The first is the surge of modality-driven bets that promise near-term clinical catalysts: Lilly is advancing Prevail’s gene therapies in Parkinson’s and FTD, while Roche has committed to exon-editing in the CNS through Ascidian. These programs may compete directly for attention, tilting spend toward translation over upstream discovery. The second headwind is the gravitational pull of large, cross-therapeutic AI/phenomics alliances, with Recursion’s multi-disease partnerships being the clearest example. CNS groups may struggle to win incremental resources against these enterprise-scale deals unless a platform is firmly rooted in human brain tissue (hard to get) and comes bundled with biomarkers that can be measured for target engagement in clinical PoC studies.

Microtrend 5: Gene and cell therapy

The Science: Gene therapy (GTx) platforms have increasingly converged with Adeno-Associated Virus (AAV) engineering and BBB biology, aiming to deliver genetic payloads safely and efficiently into the central nervous system. Traditional AAV serotypes such as AAV9 and AAVrh10 show some natural CNS tropism, but only at high systemic doses, which can trigger dose-limiting toxicities in the liver and dorsal root ganglia. The past year has seen toxicity from such modified vectors (e.g., Sarepta and Capsida). To overcome this issue, companies are developing engineered AAV capsids with improved ability to cross the BBB and target specific neuronal or glial populations at much lower doses. AAV-BBB constructs optimize capsids for transcytosis across brain endothelial cells, while maintaining manufacturability and minimizing immune neutralization. For neurodegenerative and neuromuscular diseases, where gene delivery to neurons, astrocytes, or Schwann cells is critical, these vectors could make one-time interventions clinically viable. Pharma interest has therefore shifted from traditional single-asset gene therapies toward platform deals, where the delivery vector itself is the differentiator.

Cell therapy remains the holy grail of neurology. By the time of diagnosis in PD, over 75% of dopaminergic neurons have been lost. “Regrowing” neurons entails injecting patient-derived stem cells capable of re-integrating into basal ganglia circuitry (synapse formation), producing the correct neurotransmitters (e.g. dopamine) and persisting over time (durability). This approach could theoretically be applied to most neurologic conditions like AD, ALS, MS, spinal cord injury and even intractable epilepsy (e.g. Neurona).

Notable early-stage deals: Early transactions, such as AbbVie-Capsida and Pfizer-Voyager, both in 2021, were primarily option-based collaborations, reflecting cautious optimism about the novel capsid’s performance. By 2023–25, however, deal sizes expanded sharply as validation grew: Neurocrine-Voyager in 2023, Novartis’s repeat deals with Voyager, and Lilly-Sangamo in 2025 all signaled that engineered BBB-penetrant AAVs were gaining traction. In parallel, targeted GTx plays, such as AviadoBio-Astellas and Novartis-Kate Therapeutics (both announced in 2024) demonstrate a continued appetite for rare neuromuscular indications that can benefit from improved AAV tropism.

These deals show pharma converging towards BBB-optimized AAVs as a unifying delivery backbone for neuro and neuromuscular GTx, mirroring the pattern earlier seen in RNAi and shuttle technologies: high-upfront buyouts for proven tissue delivery (Prevail, DTx, Kate) and milestone-heavy partnerships for capsid platforms still in validation (Voyager, Sangamo, Capsida). Yet, true M&A remains rare, with Lilly-Prevail and Novartis-Kate Therapeutics being among the few outright early-stage buyouts in the space. Recent safety events, including a reported patient death in a Capsida trial and lingering AAV toxicity concerns, have tempered both investor and pharma enthusiasm. Deal valuations will likely plateau until human data from next-generation capsids establishes a clearer safety margin and durable CNS transduction profile. The nearest term readout in CNS is Capsida’s Phase 1/2 trial results, expected by late 2025 or early 2026. These results carry enhanced scrutiny after a patient death a few days into the CAP-002 trial. Voyager Therapeutics also expects preliminary safety data in early 2026.

Deals in cell therapy largely fall outside the scope of this article, predating the 2021 cut off. In 2019 Bayer acquired BlueRock therapeutics for their allogeneic dopaminergic cell therapy for PD ($240M upfront); the company is currently enrolling a phase 3 trial in PD patients, with an earlier phase 1 study demonstrating promising functional integration of cells into the substantia nigra (Biomarker interview from 2022). Aspen neuro is another biotech pursuing allo cell therapy for PD, currently in phase 1/2a trials (with interim analysis showing clean safety profile). Aspen has yet to announce any large pharma partnerships or deals as of 2025, but could be a target pending internal trial data and BlueRock (Bayer) readouts . Neurona, developing human MGE-derived inhibitory interneurons for treatment resistant temporal lobe epilepsy, is currently enrolling in phase 3 testing (funded by a $102M private financing in April 2025). If BlueRock, Aspen and Neurona data look promising, expect to see more activity and deals in early stage cell therapy. Companies pursuing Treg approaches in MS (e.g. Tr1x and Abata Tx) or CAR-T in GBM or CNS lymphoma were not included in this analysis.

Pharma Interest: Promising recent data from clinical stage companies pursuing local delivery of AAVs Uniqure (HD/caudate injection), Taysha (Rett syndrome/intrathecal injection), and Neurogene (Rett) may increase interest in approaches utilizing BBB-penetrant AAVs (not requiring burdensome local delivery).

Companies pursuing early-stage GTx approaches, including Lilly, Novartis, Pfizer, and AbbVie, have each positioned BBB-penetrant AAV vectors as foundational infrastructure for their neurology portfolios (even according to public statements). Lilly’s Prevail acquisition anchored its CNS entry and has since been followed by the Sangamo deal. Novartis stands out as the most aggressive consolidator, balancing platforms through Voyager and single-asset acquisitions, such as the Kate Therapeutics acquisition. Pfizer and AbbVie, through earlier deals with Voyager and Capsida, respectively, established exploratory capsid collaborations but have yet to translate them into late-stage CNS programs. Astellas’s 2024 partnership with AviadoBio underscores continued interest in single-asset AAV programs for rare neurodegenerative diseases, particularly where proprietary BBB-penetrant capsids provide first-mover differentiation.

Conversely, Roche, Biogen, and Takeda remain on the sidelines despite deep neuro experience. Roche has channeled capital into BBB-shuttle, RNA, and antisense strategies, while Biogen has deprioritized high-risk vector work after several setbacks in neurology. Takeda is focusing on RNA and ribosome modulation, while GSK and Sanofi are more active in antibody BBB shuttles and small molecule neuroinflammation, respectively. The landscape reflects a space in transition equilibrium: pharma is testing AAV-BBB modalities through discrete programs while keeping full-scale platform acquisitions on hold pending human capsid data. Should Voyager’s next-generation TRACER-AAV programs, such as the VY1706 tau-silencing candidate entering IND in 2025, and Sangamo’s ST-503 neuropathy trial (Phase 1/2, mid-2025) or forthcoming ST-506 prion CTA (2026) demonstrate durable, safe CNS transduction in humans, the next wave of consolidation is likely to converge on a handful of clinically validated capsid families ( and define the industry’s preferred BBB-penetrant vectors).

Early-stage companies poised for deals: Aera, founded out of the Broad Institute, launched with $193M to build capsid-free protein nanoparticles and engineered LNPs for extrahepatic delivery. SonoThera has a $60.75M Series A and an ultrasound-guided, non-viral, redosable platform. It has also secured exclusive licenses to GE HealthCare’s Optison and Sonazoid microbubbles - useful, partner-friendly clarity around the device/agent stack. Ring Therapeutics (Flagship Pioneering) is advancing Anellovector™ redosable gene therapy and while it has announced research partnerships with A*STAR/SERI in Singapore, it has not announced big-pharma BD, keeping optionality open for platform access deals.

Why these three now? Each maps to a different path around AAV’s re-dosing and payload constraints while showing the kinds of de-riskers that matter to strategics. Aera’s endogenous-protein carriers suggest broad payload compatibility and a clean regulatory narrative for systemic delivery. SonoThera’s co-admin (ultrasound + microbubbles + payload) gives partners a practical way to pilot CNS delivery without encumbering whole portfolios. Ring’s anellovirus-based vectors directly address redosability—a top diligence question in CNS. Collectively, they offer clear mechanisms, substantial financing, and near-term translational milestones that fit option-heavy, milestone-weighted deal structures.

Competitive Headwinds: Two dynamics are pulling investment and attention away from pure AAV-BBB platform discovery. First, capital is rotating toward translational programs with imminent human data. Pharmas are prioritizing assets that can generate clinical readouts within 18–24 months, such as Prevail’s Parkinson’s trial or Neurocrine–Voyager’s GBA1 program, over exploratory vector engineering. Safety incidents, notably the Capsida trial death, have heightened scrutiny, leading to smaller upfronts and milestone-heavy deal structures until clear safety margins emerge.

Second, alternative delivery technologies are gaining ground (microtrend #1). Roche and Denali’s TfR1- and IGF1R-based BBB antibody shuttles are demonstrating consistent brain uptake without viral load toxicity, while Ionis, Alnylam, and Lilly/Scribe are advancing in-vivo RNA and DNA editors that reduce reliance on viral capsids altogether. These programs compete directly for CNS budgets. Beyond competition, systemic challenges persist, including manufacturing scalability across new capsid variants, population-level neutralizing antibody prevalence, and regulatory concerns over dorsal root ganglia toxicity. Until these are mitigated through standardized production and validated human safety datasets, most pharmas will likely treat AAV-BBB deals as options on future validation rather than full platform acquisitions.

Microtrend 6: Neuropsych

The Science: Neuropsychiatry has shifted from symptom-suppressing monoaminergic drugs toward neuroplasticity-modulating agents (“psychoplastogens”), precision biomarker selection (EEG, digital phenotypes), and assisted-therapy paradigms. Two assets now anchor the clinical narrative: MM120 (LSD-ODT, MindMed) with Phase 2b superiority in GAD and FDA Breakthrough Therapy status, now in multiple Phase 3 programs; and COMP360 (psilocybin, COMPASS), which hit the primary endpoint in the first positive Phase 3 trial in TRD. Meanwhile, large-cap validation is rising at the commercial end of the spectrum via Johnson & Johnson’s acquisition of Intra-Cellular Therapies (Caplyta/lumateperone), signaling durable appetite for CNS revenue and late-stage pipelines alongside earlier neuroplastogen bets. The Karuna and Cereval acquisitions, along with MapLight’s recent IPO signal continued interest in improved muscarinic drugs with enhanced efficacy/safety profiles.

Notable early-stage deals: The preclinical and early-clinical deals in neuropsych are anchored by option-heavy collaborations and select tuck-in acquisitions of preclinical platforms. On the option side, AbbVie-Gilgamesh (May 2024) opened with $65M upfront and up to $1.95B in option+milestones to co-develop next-gen neuroplastogens. In schizophrenia, Boehringer Ingelheim - Sosei Heptares (Mar 2024) set a clear Phase-1/1b path: €25M upfront, €60M option exercise, and up to €670M in milestones around GPR52 agonists with option timing after Sosei’s ongoing Phase 1/1b and Phase-2-enabling work on HTL0048149. Neurocrine–Sosei Heptares (Nov 2021) established a muscarinic (M4/M1) neuropsychiatry collaboration at $100M upfront and up to $2.6B in milestones. On the acquisition front, Otsuka-Mindset (2023) brought Mindset’s preclinical psychedelic chemistries in-house for ~C$80M (~US$59–60M), following an earlier joint development pact via MSRD. A broader signal of strategic appetite for precision neuropsychiatry at the discovery/early-clinical edge is Amgen–Neumora (Oct 2021), pairing deCODE genetics with Neumora’s platform ($100M equity at FMV, plus licenses) across neuropsychiatric and neurodegenerative programs.

Pharma Interest: Early option-heavy bets will convert to selective asset M&A once de-risked. AbbVie’s 2024 option deal with Gilgamesh ($65M upfront, up to $1.95B) is the archetype; its 2025 purchase of GM-2505 (bretisilocin) for up to $1.2B shows how encouraging early signals can flip to outright acquisition. Mechanistically, buyers are pragmatic: GPCR plays (muscarinic/GPR52) get attention because they’re familiar to regulators and operationally simpler than therapy-intensive psychedelics (e.g., Boehringer’s GPR52 schizophrenia program with Sosei Heptares). There is also regulatory drag on psychedelic-assisted models after the FDA’s negative decision on MDMA-therapy ( Lykos therapeutics), pushing interest toward non-hallucinogenic drugs, or designs that minimize unblinding. Finally, capital is concentrating: after high-profile setbacks (e.g., emraclidine from Cerevel), diligence expectations around placebo control, blinding safeguards, and patient recruitment have tightened.

The most active in early-stage neuropsych BD include AbbVie (platform option at Gilgamesh in 2024, then the GM-2505 buy in 2025; plus Cerevel for late-stage scale), Boehringer Ingelheim (option-to-license with Sosei Heptares on GPR52: €25M upfront, €60M option, up to €670M milestones), Neurocrine (long-running muscarinic collaboration with Sosei Heptares - $100M upfront, up to $2.6B), Otsuka (tuck-in of Mindset to internalize preclinical psychedelic chemistry), and Amgen (not prolific but repeatedly adjacent to precision-neuro at the early stage).

Players active in neuropsych but skewed to late-stage or internal include Bristol Myers Squibb (Karuna/KarXT - late-stage consolidation), Johnson & Johnson (Spravato plus Intra-Cellular), and Lundbeck (with Otsuka, deep internal/co-dev bench; less reliant on preclinical in-licensing). Those largely not doing early-stage psych BD but rationally poised to move: GSK (re-engaging in CNS via neurodegeneration platform work; BBB know-how could spill into psych), Sanofi (CNS build via Vigil; capacity to add psych options), Bayer (broader CNS capabilities growing, potential to extend to psych), and Pfizer (quiet in psych BD lately, but a plausible re-entry candidate if high-quality early data emerge).

Early-stage companies poised for deals: Delix Therapeutics has first-in-human data for non-hallucinogenic psychoplastogens that demonstrate CNS engagement without psychedelic effects, positioning the platform as an “adjacent-to-psychedelics” neuroplasticity bet that avoids therapy-intensive care models. However Delix’s underlying thesis (psychedelic-like efficacy without the trip) remains a risky bet. Lusaris Therapeutics is developing an ultra-short-acting, sublingual 5-MeO-DMT program backed by a top-tier syndicate (RA Capital/Venrock), with a profile that designed to minimize clinic time while preserving rapid-acting antidepressant potential. Lastly, Karuna veterans (Daphne Zohar and Steve Paul) have launched Seaport Therapeutics, have developed a “Glyph” platform that aims to bypass the liver and increase CNS bioavailability--they have neurosteroids, muscarinic agonists and psychedelics in their pipeline with no deals announced yet.

Microtrend 7: Genetic and focal epilepsy

The Science: Epilepsy is a disorder of neuronal network hyperexcitability and hypersynchrony, arising from an imbalance between excitatory and inhibitory signaling in the brain. This “imbalance” has been hard to define and treat. Current therapies are not disease modifying, instead working by inhibiting excitatory ion channels or potentiating inhibitory ones. While epilepsy is often acquired (secondary to trauma, infection, tumors or strokes) a significant proportion of early onset cases are genetic. Human studies have revealed causal mutations that drive pediatric epilepsy and neurodevelopmental syndromes: Dravet syndrome (SCN1A mutations), KCNT1-related epileptic encephalopathies, KCNQ2/KCNQ3 (Kv7.2/7.3) epilepsies, DEPDC5-related focal epilepsies, GRIN syndrome and CDKL5 deficiency disorder are several among many such disorders. These conditions are particularly amenable to precision approaches: either restoring normal protein expression (via AAV-driven gene expression or ASOs), suppressing mutant alleles (via RNAi or ASOs), or rebalancing excitability through cell-type–targeted modulation (e.g. Rapport therapeutics). There has been increasing interest in these genetic syndromes, as proving grounds for ASO, AAV or even cell therapy approaches in neurology and rare disease.

Most early-stage epilepsy therapeutics are small molecules targeting ion channels or genetic medicines aimed to address pediatric epilepsies. In terms of early-stage deals, pharma partners prioritize clean chemotypes with validated targets, quantitative PD markers (CSF), and a credible path to human proof-of-concept. The Lundbeck-Longboard acquisition ($2.6B) for a late stage drug (bexicaserin) in Developmental and Epileptic Encephalopathies (DEE) shows the potential for early-stage epilepsy assets once they have human PoC.

Notable early-stage deals: On the small molecule ion channel side, Biohaven’s 2022 acquisition of a preclinical Kv7 platform (Channel) to build BHV-7000 is the largest upfront ($100M) and total deal value. Ovid’s licensing of small molecule KCC2 activators from AstraZeneca exploits chloride homeostasis to restore inhibitory tone - with a planned indication in epilepsy, but with potential expansion into neurodegeneration (which is also characterized by hyperexcitability). UCB’s collaboration with Praxis around KCNT1 channelopathies shows big-cap appetite for a small molecule target refined by precision genetics in rare disease, while Jazz’s upfront for a preclinical epilepsy asset (selective Kv7.2/Kv7.3 inhibitor from Sanioa) signals renewed comfort with ion-channel risk when the target is validated. Lundbeck’s purchase of Longboard, though later-stage, is an equally loud signal: strategic buyers will pay for differentiated, clean seizure mechanisms, and once a commercial beachhead exists, earlier bolt-ons become easier to justify. Not every bet lands. Spark’s terminated gene-therapy tie-up with CombiGene is a reminder that durable translational signals (ideally NHP plus robust early clinical biomarkers) are the price of admission.

Pharma Interest: Pfizer already owns a sizable U.S. neurology commercial machine via its 2022 Biohaven CGRP acquisition (Nurtec ODT portfolio); yet has no disclosed epilepsy pipeline save for historic collaborations (via Cervel spinout). Roche dabbled via Spark’s CG01 gene-therapy deal (focal epilepsy) but exited and later papered an IP/data license so CombiGene could reuse Spark data. Novartis has neuro scale (and a global rare-disease footprint) but no visible epilepsy R&D. Given its access-to-health initiatives and prior neuro investments, it’s a natural BD fast-follower once clearer human PoC stacks up in genetically validated targets such as KCNT1, Kv7 or KCC2. BMS shows essentially no epilepsy interest and remains oncology-centric and is the least likely near-term entrant absent a platform-synergy rationale. By contrast, Takeda was active internally: soticlestat (TAK-935) missed primary endpoints in Phase 3 Dravet/LGS leading to program discontinuation in June 2025. Given its interest in neuroscience, Takeda may keep scouting preclinical/phase 1 assets. Biogen’s later stage deal with Stoke Therapeutics (Phase 3 ready asset, $165M upfront) for their ASO targeting SNCA1 in Dravet Syndrome is compelling: validation of Stoke’s asset in phase 3 (potentially the first-ever disease modifying therapy for epilepsy) will likely increase appetite for other biotechs developing assets for genetic epilepsies/neurodevelopmental disorders (e.g. GRIN therapeutics).

Early-stage companies poised for deals: Against that backdrop, several up-and-coming platforms look primed for deals. Tevard’s tRNA-based approach, further catalyzed by Stoke-Biogen’s ASO in Dravet (now in phase 3), validates the thesis that genetic medicines can modulate channel biology and be disease modifying. Rapport’s precision small-molecule platform has already shown human PoC in focal epilepsy (phase 2), increasing confidence that its discovery engine can generate intriguing assets. Actio is the clearest “own-the-gene” bet in seizures: a KCNT1 small-molecule inhibitor aimed at a well-defined, gain-of-function channelopathy with an obvious orphan disease regulatory path. Quiver is developing ASOs for several genetic epilepsy targets (UBE3A, DEE13, DEE4 and SYNGAP) and has an interesting AI-guided ASO design platform: it can generate sequence candidates, prioritize tractable loci (up- or down-regulation), and align them with genotype-enriched cohorts. Bloom exploits the clinical observation that ketosis has anti-seizure properties: creating a live microbial drug that impacts gut-brain signaling to promote ketosis in the gut, and hopefully reduce seizure frequency. Bloom completed a phase 1 study in healthy volunteers in 2023, and is planning to move into phase 2 trials. QurAlis brings hyperexcitability know-how from motor-neuron disease into epilepsy via validated Kv7.2/7.3 precision modulators and quantitative electrophysiology readouts. Interest in Kv7.2/7.3 modulators may skyrocket if success is shown by BioHaven and Xenon in upcoming readouts. Lastly, CAMP4 just raised $100M and has a SYNGAP1 ASO in GLP tox studies (boosting mRNA production) with clinical studies slated for 2026.

Competitive Headwinds: Unfortunately, early epilepsy PoC is still noisy. Seizure diaries have regression-to-mean and placebo effects, while objective target engagement or PD biomarkers aren’t standardized or available across sites. This uncertainty forces larger N and/or longer run-ins, inflating costs and timeline, and lowering BD confidence in pre-IND option deals - even when the biology is mechanistically sound.

Summary Graphics (M&A and Deals in Neuro)

Good ideas are commonplace—much rarer are the individuals who work for years to force them into reality. During the genomic renaissance of the 1990s and early 2000s disease-causing genes for conditions like Huntington’s, Parkinson’s and Alzheimer’s were identified. Many neurologists had the same great idea: leverage genetics to make novel drugs for their patients. How to evaluate these new therapies in humans was less clear: “When I was training in neurology, there was not a formal clinical trials program at MGH,” remembers Dr. Merit Cudkowicz, Professor of Neurology at Harvard Medical School and the inaugural Executive Director of the Mass General Brigham Neuroscience Institute, “I had to learn from other departments [like infectious disease] how to run and analyze trials.”

Subscribe now

A clinical trial, like any good experiment, requires careful preparation. It takes years to draft protocols, identify appropriate biomarkers, perfect statistical plans, recruit patients and then generate the data. “In neurology we are often limited by a lack of relevant biomarkers or robust endpoints,” describes Cudkowicz, “those looking for quick wins are often disappointed.” Following the initial optimism of the genomics bubble, neuroscience drug development faltered. Complicated biology stymied therapeutic efforts, even for patients with clear genetic drivers of disease. An example is the SOD1 mutation in amyotrophic lateral sclerosis [ALS]: “When I was working with Dr. Bob Brown as a resident, we didn’t yet know that this was a toxic gain of function mutation,” says Cudkowicz, “we tried replacing SOD1,but this didn’t work.” In the early 2000s modalities like anti-sense oligonucleotides [ASO] and siRNA were in their infancy—it was often unclear how to durably hit targets in the brain or spinal cord. “Over thirty years after SOD1 mutations were identified as causing ALS, we are now seeing the approval of what we believe to be a truly effective drug [Tofersen],” she says.

Cudkowicz’s career has focused on developing the protocols and infrastructure to allow for evaluation of drugs like Tofersen. After being mentored by renowned neurologists like Bob Brown, Walter Koroshetz and Anne B. Young, she established the first formal clinical trials unit in neurology at MGH (NCRI) in 1994, and the national Northeast ALS consortium in 1995. “I was trying to replicate what had been done in oncology…and even conditions like multiple sclerosis, where there was robust collaboration and resources to run trials,” she remembers. Cudkowicz and her team at NCRI have streamlined protocols, innovated in trial design (HEALEY ALS Platform Trial), identified novel biomarkers and started global collaborations for ALS and other neurologic conditions. In her role as an ALS patient advocate, she has raised crucial funding for research and given patient voices a platform: “our success is only possible because patients make us better clinicians and researchers,” she states.

In 2025 there remains a lack of disease modifying therapies for most people with ALS, and for those suffering from conditions like Parkinson’s and Alzheimer’s. Yet the tide is beginning to turn: “with the emergence of new therapeutic modalities…there is more interest, excitement and novel agents to test than ever before,” states Cudkowicz, “our focus now is on removing the traditional barriers of clinical trials and fostering collaboration.” With Cudkowicz at the helm, the newly minted MGB Neuroscience Institute will bring together patients, basic scientists, trialists and industry: “My goal is that in five years, I want patients to feel like the MGB neuroscience institute is “the place” to go—with the best, novel diagnostics, coordinated care, clinical trials and basic research.”

Clinical trials in neurology—a good idea that is easier said than done. Yet Cudkowicz and the team at NCRI have been working for decades to put the pieces in place to formally test novel drugs. After such careful preparation, I am deeply excited to see what the next few years of work brings for patients with neurologic disease.

Below is an interview with Merit Cudkowicz MD MSc, Julieanne Dorn Professor of Neurology at Harvard Medical School, Director of the Healey & AMG Center for ALS and Director of the MGB Neuroscience Institute, from May 2025:

Subscribe now

1. What got you interested in science and medicine initially? Who were some mentors that inspired you?

I wrote in my high school yearbook that I wanted to be a neurologist, believe it or not. I always had a fascination with the brain and medicine. My father was an immunologist at the University of Buffalo—he always had students in our home and was always working on papers. My mother had worked as a research technician…so we were a “science household.” I studied engineering in college but came back to medicine towards the end and enrolled in the HST program at Harvard Medical School. In HST, my mentor Michael Moskowitz taught our second-year neurology course—he is a fantastic headache neurologist and neuroscientists who inspired many physician scientists.. He was such a great teacher and got me even more excited about neurology

2. Early on in your academic career, how did you decide on neurology? Any memorable patients during your training?

I loved my neurology rotation in medical school. Back then everyone was always in the hospital—now I am not saying this is a “good thing,” but I remember seeing attendings rounding until nine or ten in the evening. There was constant teaching on the neurologic exam and in thinking through pathology. I had a lot of memorable patients—one who had a stroke flying in from London and presented with a transcortical aphasia: he was unable to produce language, but he couldunderstand communication. I spent a lot of time with this patient and even saw him recover, gradually. I felt that neurology is a field where you could spend a lot of time with patients and really think through pathology in a deep way. Part of this was that at the time, we didn’t have many treatments to offer, so the field emphasized a lot on thinking and teaching.

[How did you decide on clinical trials as a focus of research?]

At the time, there were not many formal neurology fellowships available. I decided to make my own in neurotherapeutics. In the 90s, the genes for Alzheimer’s and Huntington’s disease were cloned. The genomics boom had previously ushered in a new age in oncology, and there was hope that the same could be done for neuroscience. To be honest the thinking was a little naïve back then: we didn’t have the modalities or understanding we now have. Nonetheless, I wanted to develop a way to test treatments for these diseases. At MGH neurology every faculty member was a researcher with their own lab; so, there was a lot of enthusiasm for this type of idea. There was not a formal clinical trials program at MGH, so I looked around for a way to get training. I asked my residency director, Walter Koroshetz, what to do: he advised that I go to Rochester NY, where they had a clinical trials program run by Dr. Ira Shoulson, a movement disorder specialist focused on Parkinson’s. I went out to meet Ira—long story but he was actually good friends with Anne Young, the chair at MGH. When I was back in Boston, Anne called me into her office and “yelled” at me. She said she would be more than happy to support a program in experimental therapeutics at MGH, and hired me to build that program. Generally as a short piece of advice: when you try to do something new, always run it by the chair first! So, I ended up receiving mentorship from Ira, started working with Bob Brown on the genetics of ALS, and took courses in statistics at the school of public health. Initially our group started trials in a variety of neurodegenerative diseases—AD, HD and PD—but eventually I decided to focus on ALS.

3. Neurology drug development is hard. What are some of the biggest wins that you have witnessed in the field?

Multiple sclerosis has a lot of great examples of breakthrough therapies. Their breakthroughs came from a combination of planned research and good luck. The planning was in developing tools to measure the disease—T1 and T2 MRI techniques—that were predictive of functional outcome. Anytime there is a surrogate marker, gadolinium enhancing lesions in this case, it accelerates therapy development. The “chance” part was the discovery of beta interferon as a treatment, which was somewhat serendipitous. However, after this first big win in MS drug development, the MS community, academia and industry worked very well together to develop many follow-on therapies, which were even more effective. I would say that many fields in neurology have “MS envy,” because of how well drug development has gone for that indication. We have wanted to do a similar thing for patients with ALS—we want to have 10 to 15 therapeutic options. However, although we have neurofilament light as a marker of disease, it is not specific. Developing a sensitive and specific surrogate marker is one of the hardest parts of therapeutics research.

4. Briefly, what do you see as the biggest technical barriers to neuroscience drug development today?

One barrier is having biomarkers that reliably predict clinical response. In ALS, we are finding that neurofilament light [NfL] is good for genetic forms of the disease, like SOD1, but may not be as robust for sporadic cases. We will need to use a combination of fluid biomarkers for complex illnesses like ALS. We are also looking to combine fluid biomarkers with readouts like electrophysiology and advanced imaging. We are trying to learn from some of the good PET imaging studies done in Alzheimer’s, but these can be difficult to implement in large scale trials.

Diagnostic delay is another barrier across neurodegenerative disease: we diagnose people relatively late in disease course. In ALS, for example, it is on average one year from when patients notice their first symptom to when they're diagnosed—if the course is only on average three years, we are missing a huge chunk of prodromal and early disease: ideally we’d like to identify and one day treat patients before they are symptomatic. We need to learn from some of the biofluid and imaging studies being done in AD and PD, as well as other areas like heart disease—you want to modify risk and intervene before a heart attack occurs. In many neurologic conditions, another barrier is disease heterogeneity. In conditions like frontotemporal dementia and ALS, we often lump all patients into one bucket. In other conditions, like breast cancer for example, there are different tools to stratify patients based on hormone receptor and HER2 positivity. We don’t yet have those tools yet for most neurologic conditions. I worry that trials sometimes miss or discount small responder cohorts, because they are lost in the noise.

5. When selecting a new agent to test in ALS, or more broadly in neurology trials, what are the key things you look for?

Number one is a solid mechanism: do we know how the drug works, and is it linked to ALS by genetics or biochemistry? We can get some of this information from preclinical models of disease: transgenic animal models and also iPSC derived motor neurons. We can also look for biochemical evidence in post-mortem tissue or patient blood. We set the bar high for pre-clinical work, before going into patients. We have a Northeast ALS Consortium, which has a science advisory board. We have most companies present to that board, and we give them advice on their pre-clinical models and the strength of the data. We also give them a sense as to if they are ready for human trials and help design early studies. We do this because we want folks to learn from prior experiencesand keep improving.

[What mistakes do you see investigators or companies often making in thinking about running and designing early Ph1/2 studies?]

Often there are many mistakes: especially when someone is new to the field, or they want the “quick win.” We frequently see underpowered studies with endpoints that are too short in duration. ALS is a condition with lots of variability, so that must be accounted for in study design. Small companies often do not have access to a lot of funding, so they have “one shot” to see if their drug works. These companies can be tempted to skip preliminary human work that verifies target engagement and dose finding; then they go to the “pivotal” study and the drug fails. In this scenario it is hard to tell if the mechanism is incorrect or the dose was simply not correct. We try hard to get companies to run the right target engagement studies, but acknowledge it is hard for them to access capital. Part of what I do as an ALS advocate is to raise money for these studies from foundations, the NIH, or other philanthropies.

6. Especially in the current environment, what challenges do companies face in getting drugs with new biology or mechanisms to patients? What can we as physicians do to help?

There is a lot we can do. We can try to lower the costs of clinical trials and make them easier to run. For example, a lot of the clinical trial assessments are done in the hospital presently. Are there ways to develop digital tools that can be used at home? I think running more distributed trials has a lot of promise, and we would like to pioneer that for ALS. I have also tried to get rid of the things that slow down progress. These can be simple changes like making sure we are all using the same IRB, so we don't have to duplicate unnecessary work. We have also started running platform trials that share a placebo group: this saves costs and lowers the number of patients that are started on placebo. We are also initiating earlier biomarker driven studies, in which data will be shared, and researchers or companies can learn from the collective experience.

I think we also need to lower barriers for patient enrollment into trials. I was just in China for an ALS meeting, and they move into patients sooner: albeit in small trials, dedicated solely to target engagement. I think we could do this more in the US and it would help both patients and drug developers.

7. The MGB neuroscience institute seems like an incredibly collaborative and exciting endeavor. What is the larger vision of this center?

Across the neurosciences we want to delivery seamless integrated care for patients. We want a patient—whether in the community or the MGH main campus—to have access to high quality care, clinical trials and have great communication with providers. Right now for example, a patient with Alzheimer’s can enter our system from many different ways—geriatrics, psychiatry, neurology, primary care—and there is not enoughcoordination of care between these disciplines. The idea of the institute is to create this center of excellence where patients can receive coordinated care and have immediate access to clinical trials or participating in research. I also want to eliminate the friction or silos between our scientists to enhance collaboration. Ultimately we want to connect basic scientists with clinical researchers to help translate their work. My goal is that in five years, I want patients to feel like the MGB neuroscience institute is “the place” to go—with the best diagnostics, coordinated care, clinical trials and basic research. It will also be a great place to train students and residents, as they will have a ton of exposure to the cutting edge. Hopefully we can also reduce some of the barriers for companies running trials that I mentioned, as well as promote the formation of new companies based on MGB research.

8. You have mentored many trainees over the course of your career, what advice would you give about establishing a successful academic career?

First—follow your passions and do the things you love. If you don’t know what exactly to focus on, talk to lots of people. Do not feel intimidated to approach people.

Another piece of advice I got from one of my mentors, Dr. Anne Young, is to work with people you like—who you feel are easy to get along with and are kind. I have always stuck to that notion, and it makes collaboration so much more fun. It is crucial to also create teams that work well together. Anne Young would also always say to not forget to have a personal life. She always made sure to have dinner with her family and leave work at the hospital or in the lab. I try to remember this because we all feel the pressure to work late, and there seem to be endless things to do. Spend some time with friends, family and on your hobbies. The last thing is to have many types of mentors. You should always have one primary mentor who is invested in your success: someone who is passionate about helping you. For me, Bob Brown was my primary mentor, even though he was a basic scientist. However, once I settled on running clinical trials, he connected me with others who became mentors as well. Go find the people that have what you need, and you can learn a lot from them…but don't forget to have one person who is your primary advocate.

Share

Yet localization is not simply a didactic exercise, it is central to the history of neuroscience. A grisly construction accident damaging the frontal lobe of Phineas Gage, demonstrated this region’s role in personality and executive function. A misguided hippocampal lobotomy of “patient H.M.” set the stage for the study of memory formation.

Understanding “where” often points to “what” process (or pathology) may be the culprit. For example, weakness that localizes to both upper and lower motor neurons, with sparing of other pathways (like sensation), could suggest the terrible diagnosis of amyotrophic lateral sclerosis (ALS).

Yet the art of clinical localization has its limits: it does not explain why a particular pathology (like ALS) develops or suggest what to do about it. For this task, a subcellular localization is required. “When the Huntington disease gene was cloned, it was a turning point for me,” describes Dr. Robert Baloh, Head of Neuroscience at Novartis Biomedical Research: “molecular neuroscience had the potential to make drugs that could help patients.” A genetic localization can identify targets and pathways that if manipulated may alter disease progression.

As a budding academic neurologist in the early 2000s, Baloh appreciated the complexity and “uncertainty” of clinical neurology. Yet he yearned for a deeper understanding of molecular neuroscience. With mentors like Bob Brown, David Holtzman and Jeff Milbrandt for support, he started a research group investigating the genetics of neuromuscular conditions like ALS and Charcot Marie Tooth. Initially at Wash U in St. Louis (before moving to Cedars-Sinai with a joint appointment at UCLA), Baloh’s lab mapped how mutations in genes like TDP43 and C9ORF72 drive neuronal injury and neuroinflammation.

As Vice Chair of Neurology Research at Cedars-Sinai, he saw how genetic insights could be leveraged across different areas: “I was able to dive into Parkinson's, Alzheimer's, psychiatry and a bunch of other disease areas…I found it fascinating.” Around this time Baloh also witnessed drugs like Zolgensma, Spinraza and Risdiplam transform the lives of children with spinal muscular atrophy (SMA): “I took care of kids with SMA…but I did not think in my career I would see such an effective treatment…the sudden approval of these medicines had a huge influence on the course of my career.” Resolving to focus on drug development, Baloh accepted a position at Roche in 2020, and then at Novartis in 2021, as Global Head of Neuroscience: “I’m someone who loves delving into a variety of different areas of neuroscience, and thinking about where the science is closest to becoming a medicines and making a difference for patients.” At Novartis, Baloh takes a human-centered approach, relying on genetics and biomarkers to gain conviction about a particular program.

Today, “localization” in neurology goes beyond neuroanatomy, to include specific genes, pathways or processes within a cell that are disrupted. The challenge now is to deliver targeted therapies to the correct location, in sufficient quantities, at the right time: “for many conditions we have very good therapeutic targets…but we have only recently seen technologies that can address these targets in key areas, like behind the blood brain barrier and in the deep brain structures, which are much more difficult to access,” Baloh says.

With his team at Novartis, Baloh is laser focused on leveraging clinical neurology, genetics and emerging modalities (like gene and cell therapy) to hit the right targets in the right spots. “This is just the start,” Baloh emphasizes, “ultimately we will have assets that impact multiple nodes of disease biology and can provide tremendous benefit to patients.”

Below is an interview with Robert Baloh, MD PhD, Global Head of Neuroscience at Novartis Biomedical Research:

Subscribe now

1. What got you interested in science and medicine initially? Who were some mentors that inspired you?

This is an easy one for me—my father is also an academic neurologist. He clearly had a huge impact on my career. I often tell people however that he did not directly encourage me to go into medicine—not because he wasn’t happy with it, but just because he didn’t want to “interfere” with my life. At the same time, I could see he was extremely passionate about the field; he continues to write about neurology and neuroscience even after he retired. Just seeing his excitement had a big impact on me.

When I went to college, at Brown University, I majored in neuroscience—which is pretty specific for an undergraduate major. I got to learn from Mark Bear who is a well-known synaptic physiologist and neuroscientist who since moved to MIT. Spending time with him pushed me even further towards studying the brain. How does the brain work? It was, and remains, the biggest question out there. As an undergrad I participated in some fMRI studies mapping movement representation in the cortex—and to be frank I was disappointed. I didn’t think studies like these were going to move the needle for patients back then [1990s]—now imaging has advanced considerably, and a lot of the fMRI studies today are quite remarkable in what they can demonstrate about the brain. But around the same time when I was an undergrad, the Huntington gene was cloned. This was a turning point for me…and I switched my focus to molecular neuroscience. Then I went to the MD-PhD program at WashU in St. Louis and joined Jeff Milbrandt’s lab—after that I was hooked. Jeff and his lab had so much energy, and it was such an exciting time to be a scientist.

Jeff [Milbrandt] was an interesting mentor, because at the time even though he was a somewhat young PI, he already had a “biotech” type of mindset. We were working on cloning genes before the genome was sequenced and were looking at the translational relevance of a variety of neurotrophic factors. We wanted to use these factors in neurodegenerative disease—Regeneron, Amgen and other companies were exploring this as well. I remember actually resenting some of these biotechs—because as a PhD student I was competing with them and had fewer resources. That said, I enjoyed the translational angle a lot. I even thought about going to Biogen to do a post-doc, because we had a collaborator there. I was lucky to get this early experience—both in academic science and in biotech. It definitely planted some seeds that led to my current role.

Share

2. Early on in your academic career, how did you decide on neurology? Any memorable patients during your training?

I loved graduate school [PhD]…but I felt that I should still get clinical training. Part of that feeling was a curiosity about clinical medicine, and part was the security—research is risky and doesn’t always work out! It was a no-brainer for me to choose neurology given my interest in neuroscience, and I decided on the Mass General Brigham combined neurology program for residency—where you will be starting in a few weeks! I had an amazing experience. Marty Samuels was the chair of neurology at the time, and you could not ask for a better teacher or mentor. He knew everything and was one of the pillars of “old school” neurology: along with C.Miller Fisher, Raymond D. Adams, Rick Tyler, Lou Caplan and others. He [Samuels] was hilarious—his morning report or grand rounds would be like watching The Tonight Show, combined with a masterclass in clinical neurology. From him I learned what it was like to be brilliant at something—not to say I ever reached his level of clinical ability…but I saw what true excellence looked like. It is helpful to aspire to this level in whatever you do.

[On how clinical neurology is different than science]

Clinical medicine is not a deductive science. I think one of the things that being a clinician teaches you is to deal with uncertainty--it's very helpful for the rest of your life. In medicine you often have to make important decisions and communicate these decisions, without all of the data at hand. Even in biopharma, I observe physicians often have an easier time with this than others, making decisions on probabilities and accepting that we will often be wrong. One really has to embrace uncertainty in clinical medicine, and see that there is something intuitive about it that at times seems more akin to art than science —this is something that Marty [Samuels] was so brilliant at. Sometimes people are really good at both [science and clinical medicine], but more often being a good scientist does not directly translate to clinical ability, and vice versa. They end up being two separate skills.

3. How did you decide on neuromuscular medicine for your fellowship? What did you work on as a post-doc and early career faculty member at WashU?

I became interested in neuromuscular disease primarily from Bob Brown and Tony Amato, when I was a resident at Mass General Brigham. After residency though, I was looking for a fellowship where I could learn about neuromuscular disease and also do research, and at the time these types of opportunities were difficult to find. I chose WashU in St Louis—where I did my MD-PhD training.

Dave Holtzman at WashU is another major mentor of mine. When I was starting my PhD at WashU he was a junior faculty member, and he was on my thesis committee. By the time I ended up returning for fellowship, he was chair of the department and very supportive of my returning. He worked with me to find a creative way to design a fellowship where I could apply human genetics to neuromuscular medicine—at that time [early 2000’s] SOD1 was the only ALS gene that had been discovered. I was excited about neuromuscular disease because you can leverage genetics to make cellular and animal models—you can also biopsy tissue [peripheral nerve and muscle] and perform nerve conduction and EMG to assess function.

For my post-doctoral work, I was jointly mentored by Dave [Holtzman], Jeff [Milbrandt] and Alan Pestronk who ran the clinical neuromuscular program and was willing to let myself and another MD/PhD neurologist split the clinical work so we could get into the lab. I was lucky to have such strong support for fellowship. I ended up working on Charcot Marie Tooth disease initially, because the genetics were abundant, and the field was less crowded around one gene as in ALS. However, even back then I sensed that I didn’t want to study one disease or process for the rest of my life. I felt that all science was cool, and was a bit like a “dog chasing squirrels.” From an academic research perspective it is likely better to stick with one problem or area and become known as “the expert,” and really be the leader in that particular area. However, this ability to look step back from complete focus, and to learn both things outside my area of expertise and even neurology, is really what I embraced when I first went to industry, and in my current role at Novartis.

[What were some exciting stories you pursued in your lab?]

In ALS, we first explored TDP-43 pathophysiology, which was distinct from that of SOD1 and surprising in many ways. We later started working on C9ORF72 and in particular how loss of function in this protein drives neuroinflammation in glial cells—but of course can also produce toxic gain of function manifestations like dipeptide repeat proteins that damage neurons. I enjoyed this work a lot—but I also really enjoyed taking a leadership role in a department [at Cedars-Sinai]. As Vice Chair for research and in starting a basic research center, I was exposed to clinical and basic research across a range of areas—Alzheimer’s, Parkinson’s, multiple sclerosis and others—and learned how genetics and tools like imaging and biomarker analysis were being leveraged.

As a rule, I generally don’t have regrets when it comes to my career. Certain things may have been optimized, but of course I’m not sure I would have gotten to where I am if I had changed anything along the way, and I feel very fortunate to be here. I have learned that the way I like to do science—exploring a range of different topics—is more satisfied for me in industry than in academics. To make a successful career in academia you have to be somewhat more focused in your thinking and research activity—to publish papers and earn a reputation in a particular field. I learned that if you find that difficult, then there are other options [like industry], though admittedly somewhat later in my career.

4. What were some drug development stories that you were most excited about in neurology?

When I was a neuromuscular fellow at WashU, I did a camp for children with muscular dystrophy and related diseases like spinal muscular atrophy [SMA] every year. It was super fun. I took care of a bunch of kids with this disease, and learned a lot. At that time, we knew the genetics, but I did not necessarily think that in my career I would see an effective treatment for SMA. Years later as a faculty member, I followed the Nusinersen story closely as we had collaborators at Ionis—but to see it in action was astounding. The same goes for Zolgensma and Risdiplam, which followed shortly afterwards. The approval of these medicines changed the course of disease for those patients and had a huge influence on the course of my career. At the time [of the SMA approvals] I was building a research department at Cedars-Sinai and really enjoyed establishing the neuromuscular division as well. I had some great collaborators working on therapeutic development—Clive Svendsen for example—but we were not able to bring to bear the same resources as biopharma. I found that I was most passionate about making new therapies for patients. A lot of my mentors had run academic departments, but to me, the prospect of developing the next Zolgensma was too exciting to resist. Thinking back as I said, even during my PhD I had the urge to enter biopharma as a way to turn science into new medicines.

5. What do you see as the biggest technical barriers to neuroscience drug development today? [Briefly what are you doing at Novartis to address some of these barriers?

There are different challenges facing different fields within neuroscience. For example, psychiatry is very different from say, genetic neuromuscular disease. In the case of conditions where we have strong genetics—like muscular dystrophies, SMA, Huntington’s, some types of ALS—the challenge is really biodistribution of the right modality, and when to treat. Getting the therapy to the right location at the right time is the key, because we have validated targets and biology. I believe that many past failures in this space were in part due to insufficient delivery mechanisms—AAV or ASO biodistribution to the muscle or nervous system is difficult, especially in adults. In SMA, where we have had great success with gene therapies like Zolgensma, it is likely that biodistribution to lower motor neurons and the rest of the central nervous system is better in an infants [than in adults]. Therefore on the AAV side, we have been very focused on looking at “evolved” capsids with improved CNS or muscle delivery: higher tissue transduction from a lower systemic dose, and de-targeting of peripheral organs. Naturally occurring viruses won’t have these properties—so we have spent a lot of energy thinking about engineered delivery mechanisms for neurologic and neuromuscular diseases.

6. At Novartis, you view the neuroscience portfolio on three levels—neuromuscular/genetics, neurodegeneration and neuroinflammation. Can you give some examples of how you are thinking about each category?

With genetically defined targets one has some sense of causality—for example you don’t need to understand the precise function of the SMN gene to know that its correction will greatly benefit SMA patients. With other conditions where we don’t have such clear genetics, we really look to human tissue, biofluids combined with natural history data to build conviction around a target. We believe multimodal data, including genetics whenever possible, is crucial for target selection.

I am less convinced that for a given [sporadic] neurologic disease there is a “perfect” target out there. Take Alzheimer’s disease for example: we have evidence that modulating pathways like TREM2, ApoE—along with amyloid and tau—could potentially impact disease progression. These are all core pathophysiologies that have been studied for a long time. Ultimately, combination approaches targeting multiple disease nodes is most likely to give patients benefit—rather than hitting just one “magic” target.

[Neuropsych appears to be limited by a lack of mechanistic understanding. Even once “clear cut” wins such as Karuna’s (BMS) and Cerevel’s (AbbVie) M1/4 agonists are now less compelling in the light of late-stage trials. At Novartis, how do you think about entering such a challenging area?]

Psychiatry has not been easily amenable to the approach of identifying genetic loci that influence disease progression and targeting these pathways. Historically [psych drug development] has essentially been phenotypic screening in humans and then rodents. I've gotten to work at two great neuroscience companies, Roche and Novartis—the companies that discovered benzodiazepines and LSD. The history of these discoveries involves medicinal chemists ingesting the compounds they synthesize and qualitatively describing their experience. Needless to say, this is not a scalable approach—for the safety of medicinal chemists alone!

We subsequently moved into model systems for psychiatry drug development—however these rodent models of depression or psychosis are very far from representative of human disease. So, what does one do? I think we [as a field] need to invest in biomarker development for “precision psychiatry” and move into human testing as early as possible. We need some way to measure target engagement, along with imaging or behavioral biomarkers that can give early signs of efficacy—like in other fields. Now if you look at the M1/M4 [Karuna/Cerevel] story, the discovery of that target in psychosis was still “by accident”, and is what I mean by human phenotypic screening. There was a theory that increasing acetylcholine signaling in Alzheimer’s disease would be beneficial for cognition; trials in the 1990s also showed that xanomeline decreased AD-associated psychosis. This observation led to trials in schizophrenia, and subsequent engineering of more specific M4 agonists and modulators to decrease peripheral side effects, in addition to combining with a peripheral blocker. It is very hard to reproduce this type of story for future therapeutics, given its serendipity.

Psychedelics are interesting--Albert Hofmann wanted to study LSD in psychiatric disease from early after discovery. There is a very long discussion to have here around these molecules and potential mechanisms. A fundamental question to me is whether one can separate the euphoric and dissociative effects from beneficial effects on depression, PTSD or other psychiatric diseases, or rather the two are intrinsically linked. However, given the lack of good preclinical psychiatry models and scarcity of precision biomarkers, clinical development continues to be challenging.

7. Early drug development efforts (in any area) often start with testing in preclinical models. How do you evaluate internal preclinical data? Are there certain models that you find to be the most robust?

We internally debate this question often. Initially there was a lot of excitement about rodent transgenic models of neurologic disease—like the SOD1 mouse in ALS. What we realized was that these models don’t have good translatability in terms of discovering new targets or pathways. Similar genetic lesions often manifest differently in other species, so for target discover it is much better to use human data where possible. However transgenic models can be very useful to measure target engagement: to show that a drug is having its intended effect. We still rely on these models in ALS, AD and other conditions for pharmacokinetic and pharmacodynamics.

We do not try to do a 1:1 correlation between a mouse model and human disease for prediction of clinical benefit, rather we use preclinical models to gain confidence that we can alter biology in a predictable way in the right compartment of the target tissue, i.e. the CNS. From here, we try to move into humans as quickly as possible and leverage biomarkers to assess impact on neuroinflammation and neurologic function. Even this can be risky, because not all biomarkers are clinically validated or predictive of approvable clinical outcomes by the FDA.

Share

8. Which biomarkers across neurology do you find most exciting? Besides neurofilament light [NfL], are there markers of neuronal injury or neuroinflammation that you feel are becoming more robust?

All biomarkers are very context dependent—even neurofilament light [NfL], which is among the most “validated” to date. For example, elevations in NfL just mean that there is axonal injury: it needs to be combined with imaging, CSF biomarkers or functional endpoints to truly have meaning. NfL is really just like a troponin or CK of the nervous system—it could be elevated for a variety of causes that are not directly relevant to disease pathology [trauma for example]. Similarly, neuroinflammatory and glial markers like GFAP need to be taken in context: we are trying to develop panels or a cadre of such markers that can accurately assess the functional astrocytic and microglial state in the brain. Looking at just a single biomarker will never be that useful.

Advanced imaging can also be very powerful—MRI revolutionized the relapsing MS field and has been incredibly impactful for therapeutic development. However, implementing imaging in large scale trials can be costly and complicated; fluid biomarkers are often more convenient from a trial perspective. For small early studies you can do more complicated imaging and biomarker collection—but you have to be much more focused as you bring this forward to a large phase 3.

[Are we limiting ourselves in neurology by testing single agents in isolation? Perhaps multiple nodes need to be impacted to show functional benefit]

One would love to be able to go directly into clinical development with multiple different nodes being targeted in a neurologic disease. It's just not realistic given the current way we conduct clinical trials, and the difficulty of dealing with multiple unknowns simultaneously in both efficacy and safety. We need to first show benefit from single agents, before we start combining mechanisms and modalities. I agree that perhaps it is the case that both amyloid and tau need to be targeted in Alzheimer’s—hopefully in 10 years neurologists will be able to combine multiple agents as disease progresses. However, for now we need to prove that just one therapy will be of benefit. My hope is that as soon as we show these agents to be effective in isolation, physicians will start to study them together to hit multiple nodes of disease pathology. First this will be done in small studies using biomarker profiling, and then in larger efforts. Ultimately, I think this type of work, done by enterprising physicians and scientists, will move the needle most for patients.

9. What advice do you have for trainees who want to play a role in drug development, and really deliver for patients? Is there any advice you wished you had received earlier in your career?

Throughout my early career I was always focused on getting to the next step as quickly as possible. I was always very driven…to learn, to get a job to pay my bills, to start a lab, to get the next grant. But rushing through isn’t necessarily the “right way” to approach this type of career—which is long and full of opportunity. What I would say is most important is to find mentors that can really give you support and help you through the tough times. I found that in Jeff Milbrandt and Dave Holtzman at Wash U, which was the best reason for me to go there for fellowship and stay as an early career faculty member. So, if I have a piece of advice for physician-scientist trainees it would be to really find these mentors that you can rely on…because you will really need that support as you start your independent career!

Precision separates health from disease. Each second, thousands of tiny vesicles are released from a given motor neuron: allowing them to communicate with other neurons and muscle fibers. This complex coordination between nerve and muscle depends on the fidelity of synapses—the physical touch points neurons make with each other, and with innervated muscles. Synaptic dysfunction is an early hallmark of many neurodegenerative diseases. In amyotrophic lateral sclerosis (ALS), upper and lower motor neurons are damaged, leading to aberrant communication with muscle fibers: “altered synaptic transmission is at the heart of ALS pathology,” describes Dr. Eric Green, co-founder and CEO of Trace Neuroscience, “early in the disease you see dysfunction in the synapse that precedes loss of the motor neuron [cell body].” Without precise communication between nerve and muscle, these patients gradually lose the ability to move, speak, swallow and breathe.

But what drives early synaptic dysfunction in disorders like ALS? “In 2022 there were two breakthrough papers from the labs of Aaron Gitler [Stanford] and Pietro Fratta [UCL], which linked TDP-43 pathology to the loss of UNC13A” says Green. TDP-43 is a nuclear protein that contributes to RNA processing. When abnormal aggregates of TDP-43 trap this protein in the cytosol, it is unable to perform its normal role in (nuclear) RNA splicing. Ninety seven percent of ALS patients have TDP-43 inclusions in their motor neurons, effectively leaving these neurons “deficient” in nuclear TDP-43. Gitler and Fratta showed that loss of nuclear TDP-43 impacts downstream splicing of UNC13A—a protein that primes synaptic vesicles for release. “UNC13A disruption blocks a key step in the chain of events in nerve and muscle function,” states Green, “it is just one node in a complex pathology…but genetic evidence highlights its importance.” Mutations that impair UNC13A splicing are independently associated with increased risk and faster progression in ALS and FTD, strengthening the notion that UNC13A deficiency is central to pathology.

Trace Neuroscience is developing an anti-sense oligonucleotide (ASO) that aims to correct aberrant UNC13A splicing—by restoring functional UNC13A to motor neurons they hope to slow disease progression. “My career [in biotech] has focused on developing therapies that leverage human genetics,” says Green. A cardiologist by training, he cut his teeth at MyoKardia before co-founding Maze Therapeutics and joining as their CSO: “the genetic platform at Maze laid the groundwork for the approach we took when founding Trace,” describes Green.

Precision separates expert from novice, health from disease, and success from failure in drug development. Green and his team hope that by developing a targeted therapy—correcting just a single mis-spliced RNA—they can restore synaptic precision to a dysfunctional nervous system. “It is impossible not to feel bonded to patients suffering from ALS,” emphasizes Green, “though there are promising genetic therapies [e.g., Tofersen] available for a small subset…the majority are in need of a breakthrough.” As Trace pushes their work into humans early next year, Green hopes to provide precisely that.

Below is an interview with Dr. Eric Green co-founder and CEO of Trace Neuroscience from May 2025:

1. What initially got you interested in science and medicine? Who were some early mentors that pushed you in this direction?

My father was an oncologist, who retired just last year. There were always medical textbooks in our house, and I was always curious—especially about the molecular and genetic contributions to disease. For example, when I was in 6^th grade I did a project on schizophrenia and its causes. I remember feeling like there was so much mystery in this area [neuroscience]. What is going on in the brain to cause this disease? Unlike a broken bone, there is no clear cause or solution. These types of problems have always appealed to me.

As a college student, I fell in love with chemistry and started working in Greg Verdine’s group at Harvard. I came to really appreciate curiosity-based discovery and considered myself more of a budding scientist—however, I was always drawn to practical applications to health and disease. So, given that I loved science but wanted to impact human health, I decided to pursue MD-PhD training at Stanford.

2. You started iLabs (acquired by Agilent) while still an MD-PhD student. What did this early experience teach you about innovation?

I never considered starting a company while an undergrad at Harvard. At the time [my advisor] Greg Verdine was starting some companies, but it was not common practice—and still somewhat “taboo” to do so as an academic. Then I went to Stanford [MD-PhD program] in the 2000s—this was in the early days of Google, and it was a totally different environment than Boston. A lot of my friends during grad school were in the computer science or electrical engineering departments. They aspired to work in Silicon Valley and start companies. Being at Stanford just opened my mind to entrepreneurship.

My college roommate and I co-founded iLabs (together with a few other classmates)—he had been a consultant at McKinsey, and we had been discussing inefficiency in scientific research. We realized that while the operating budgets were large for these research organizations, the systems that scheduled and managed research were primitive. We founded iLabs, and the company went through a number of pivots. Ultimately, we focused on making scheduling software for core facilities—where we felt there was the most opportunity. I loved the process of starting a company, and how interdisciplinary it was. The venture ended up being quite successful and got a lot of traction amongst research facilities. This experience, and being at Stanford and Silicon Valley, made me eager to work on another startup in the future. However, I felt that what I really wanted to do [as an entrepreneur] was contribute my deep knowledge in science and medicine to building companies. I finished at Stanford and started as a resident at Brigham and Women’s Hospital, with the intent of establishing myself in academia and then moving into biotech.

3. After finishing your medical training, how did you come to be involved with MyoKardia?

As a cardiology fellow, one of the questions on my mind was how we could leverage the emerging genetics of heart failure to make new therapies for patients. Unlike some genetic diseases where you could draw a straight line between the genetic defect and clinical presentation, in heart failure it was more complex. Often families could have the same mutation but very different disease manifestations. In thinking about this issue, I learned about the work going on at Third Rock Ventures (TRV)—this was in 2012, so just a couple of years after the firm was founded. TRV was taking an unconventional approach in creating and financing companies, which is now more common today. Their mission was to build companies that really took advantage of an emerging area of basic science that could help patients. I got to know the group at TRV, and they happened to be creating MyoKardia at the time. It felt like a great fit, because I could leverage my clinical knowledge [in cardiology] and deep interest in human genetics.

[What initially drew you to TRV?]

I had done some work in venture previously and felt it to be interesting and energizing. However, I did not want to be a traditional investor—I wanted to help build and operate companies as an entrepreneur. At the time (2012) Third Rock was itself a startup, so I felt there was a ton of energy to be creative in building impactful companies. The culture was terrific, and I was learning a lot from experienced entrepreneurs and investors. It was exactly what I wanted, and set out to find, when came to Boston.

[Mavacamten was approved, and MyoKardia was acquired for $13B – a win for patients and investors. What were some of the key lessons about biotech you learned from this experience?]

There are some general lessons from MyoKardia, many of which really came from Charles Homcy. Charles is a cardiologist, partner at Third Rock and one of my most important mentors in biotech. He really was the guiding force behind MyoKardia. Some general lessons I learned were to really look to genetics to guide drug development, which is an orientation I have taken to Maze and now Trace. Advances in sequencing and genomic profiling have made this easier over time and enabled a lot our current work [at Trace]. Another lesson is to remain close to patients. At MyoKardia all of us, even those of us who were not clinicians, got to spend time with people who had hypertrophic cardiomyopathy. Especially in genetic diseases, it is important to have a strong connection to patient families. This is another lesson I have brought with me to Trace: every person who works here has met somebody with ALS. Every one of our investors has met somebody with ALS. The patient experience really helps to keep everybody focused on our one shared goal. Organizations that have a strong shared purpose are powerful and can accomplish great things—this was a lesson I learned from Mark Levin, one of the founders at Third Rock.

Subscribe now

4. What was the founding vision of Trace, and how did your experiences at MyoKardia and Maze influence this vision?

The experience at MyoKardia taught me that rooting drug discovery in human genetics is a powerful approach. In 2017 we were starting to see a huge explosion in the availability of genetic data and biobanks, so it was a moment where it was possible to think about a platform to generalize these discoveries. That was the core problem statement that we had when I went back to Third Rock to start Maze. We spent the next several years building an engine to characterize genetic insights and develop precision drugs based on these learnings. We wanted to identify several areas to focus our efforts, which were mature enough in terms of the science and could impact patients significantly. ALS was an area we identified early on at Maze, and we started working with Aaron Gitler at Stanford, whose lab was focused on this disease. Over my five years at Maze, we had success in several rare diseases, which validated our approach—Pompe and genetic [APOL1] kidney disease for example. In 2020, working together with Aaron Gitler we made an important scientific breakthrough that unlocked UNC13A as a therapeutic target for ALS. After some exploratory work, we felt we could move on this target quickly and it could have a huge impact. By this point I had developed a strong connection to the ALS patient community and felt a calling to do everything I could to bring these patients and families a meaningful treatment. As I reflected on how best to do this, it became clear to me that we needed the specialized expertise, resources and focus of a dedicated company.

5. What do we know about the biology of UNC13A?

The discovery we made together with the Gitler and Fratta labs was that UNC13A, which is an essential gene for synaptic transmission, is lost in nearly everyone with ALS by a very specific mechanism. When TDP-43 accumulates in the cytosol (an early hallmark of disease), UNC13A RNA becomes improperly spliced leading to its degradation and loss of the protein. We already knew from human genetics that variants in UNC13A increased the risk for developing ALS and accelerated disease progression. However, until these discoveries we didn’t understand how this was working and so couldn’t effectively design a medicine. This was one of the rare basic discoveries that both sheds light on disease mechanisms and immediately points the way to a therapeutic approach. We hypothesized that if we could find a way to prevent improper splicing and restore UNC13A, we could preserve synaptic transmission and motor function. Based on previous groundbreaking work in spinal muscular atrophy (SMA) with nusinersen, we thought that an ASO could be developed as a medicine that would bind the UNC13A RNA and ensure its correct splicing.

I vividly remember discussing this discovery with Aaron [Gitler] in 2020, and we both came back to the point that the combination of human genetics and mechanistic understanding gave us enormous conviction—UNC13A mutations increase propensity for mis-splicing of this molecule and also lead to more severe disease. Thus, we felt that out of the hundreds of mis-spliced genes in ALS, restoring this target could substantially alter disease progression. Over time, we have reinforced that confidence by showing that correcting UNC13A mis-splicing in cellular models of ALS is sufficient to rescue defects in synaptic transmission.

As a cardiologist, I see some parallels between ALS and diseases like heart failure—indications where we have multiple effective drugs that impact different nodes of disease biology. We think UNC13A and synaptic function is one very important pathway in this disease, and we are trying to correct it with an ASO. We have confidence based on human genetics that it will have an outsized impact on disease progression. I hope that one day it can be part of a toolkit of complementary mechanisms for treating this disease.

6. What are the main challenges to developing an ASO in neurology? What has Trace learned from past failures in ALS and other conditions?

There are a lot of issues, including delivery of drugs to the right cells, clinical trial design and biomarkers that are particularly challenging in neurology. At Trace we have worked hard to build this expertise in house and through our network of advisers, as we develop an UNC13A ASO. We have learned a lot from the experience at Biogen with Nusinersen [SMA ASO] and Tofersen [SOD1 ASO], which is tremendously helpful. Finding good biomarkers of target engagement and early clinical benefit are important, and we are investing in developing some of these ourselves. We are fortunate that in ALS we are a little further along in terms of biomarkers than a space like psychiatry, for example. Ultimately at Trace, what we have learned from some of the successes in neurology is the importance of having the triad of genetic target validation, clear mechanistic understanding and a specific modality [ASO] to hit our target. When those pieces are in place, you have the greatest chance of being successful. The number of programs across neurology that have these three components is not that large.

[How do you measure UNC13A target engagement?]

There were no preexisting assays for doing that. We are having some good initial success at building assays, but it's been a tour de force trying to get these to work from cerebrospinal fluid (CSF) samples. We have to build extremely sensitive assays, since there is not much UNC13A normally present in the CSF.

7. What are some of the milestones and catalysts you feel will be important for Trace over the next year

The moment we’ve circled on our calendar from day one is when we will enter human trials. We continue to be on track to do this in the early part of next year [2026]. Right now, this occupies the vast majority of our attention.

8. What are some approved (or late stage) drugs in neurology, or companies that help provide Trace with a roadmap for success?

In many cases, the nervous system is a harder place to go than other areas. We are now starting to see good success with ASOs in neurology: in ALS and other neuromuscular disorders like SMA. In terms of other programs, I am excited about what Stoke Therapeutics is doing for Dravet Syndrome—applying targeted ASOs to correct a mutation [SCN1A] that causes a form of pediatric epilepsy. As I mentioned before, they have a triad of genetic validation, mechanistic understanding and the correct modality. We are hoping to be part of this lineage at Trace, and we believe that we have the correct target and molecule to make a difference for patients.

9. On a more macro level how do you keep your team motivated given the current environment?

There is no doubt that it's a very challenging moment for biotech…a moment that is lasting quite a while now. I think you must be a bit of an irrational optimist in this business, given everything we know about the rates of failure across the industry. But I do continue to have an abiding faith there are a lot of areas of medicine where there are important unmet needs. ALS is only one example. If drug development is successful for these conditions, there are going to be viable businesses. Private and public markets will reflect that [eventually]. I think the environment will improve and we will see more companies rewarded for pursuing novel biology with a laser focus on patients’ unmet need. At Trace, I just try to always remind our team of the mission and the patients we serve.

10. Any advice for trainees hoping to have a career in biotech or drug development? What is a piece of advice that you wish you had received earlier in your career?

My dad was a practicing oncologist for his entire career. My mom was a teacher for 40 years. Growing up, I thought this is what a “profession” or career looked like. Now, I think there are multiple ways to go about having a career: one with multiple chapters, especially in biotech. Some are in academia for decades before entering industry, and others go into biotech even earlier than I did. I think there is a lot of opportunity with new paths opening all the time due to advances in science and evolution in company creation models. My main advice is to be flexible and open to that serendipity. Be bold, have confidence in yourself and take those chances when they present themselves.

Al Sandrock MD PhD, CEO of Voyager Therapeutics and son of a merchant marine captain, adds a more concrete link: “when you are at sea, people also come to the captain with their medical problems. When [my father] was able to help someone with their problem, he felt so great.”

With his father’s impromptu medical experiences buoying his interests, Sandrock decided to become a physician. Of all the disciplines, neurology and psychiatry most resemble the “uncharted sea.” Mapmaking is laborious—with billions of neurons to explore, recent work has shown that just a cubic millimeter of human brain contains 150 million synapses or connections (1.4 petabytes of data).

As an undergraduate at Stanford, Sandrock was exposed to the expansive mystery of neuroscience and disease: “I remember a lecture by the psychiatrist Jack Barchus…where he discussed the biological basis of schizophrenia and depression. I was blown away that you could explain such complex diseases by imbalances in chemicals in the brain.”

Determined to create new therapies for patients suffering from neurologic disease, Sandrock pursued MD-PhD training from Harvard medical school. With scientific pillars like Paul Patterson, Story Landis, Ed Furshpan, and David Potter for support, he studied axon guidance and regeneration in the context of nerve injury: “Why can peripheral nerves regenerate [to an extent] whereas central neurons do not? Even my PhD was geared towards addressing clinical problems. I had this early desire to help advance new therapies,” he describes.

As a resident neurologist at Mass General Hospital [MGH], Sandrock witnessed how better “compasses” helped neurologists navigate disease: “Even in the 1990s we started to have some tools at our disposal.” Specifically, he witnessed how gadolinium enhanced MRIs could help distinguish new vs residual lesions in multiple sclerosis (MS). Learning from experts like Steve Hauser and (his co-resident) Tim Vartanian, Sandrock saw how MRI lesions could be used as a surrogate marker for disease activity—crucial to evaluating new therapies like beta-interferon: “The effect of beta-interferon on reducing new or enlarging lesions was really what made many of us really believe in its effect. Here was objective surrogate evidence that correlated with the clinical results.”

Share

Seeing the betaseron story unfold inspired the young neurologist to learn professional drug development. Leaning on his former co-resident Nancy Simonian for support, Sandrock left his prestigious NIH grants and Harvard tenure track job to join Biogen. The decision was an agonizing one: “I initially declined the offer and kept my grants active…but Nancy really went to bat for me, and I was able to get the job [offer] back. I started in February of 1998.”

What followed was arguably one of the most prolific drug development careers in biotech—certainly within the field of neuroscience. Under Sandrock’s captainship, the crew at Biogen developed drugs like Tysabri, Tecfidera, Plegridy, Spinraza and Aduhelm.  Despite the successes, Sandrock speaks first to his shortcomings: “I have failed at certain points in my career and been at times even been dragged through the mud for it…failure is the nature of our industry.” He goes on to say: “all it takes to keep going is to remember the patients you serve…I have met children who would not be alive today without Spinraza. I know MS patients who [with the help of our treatments] could become moms and enjoy their children…I still feel like a neurologist, but my ‘practice’ now serves a larger population.”

This desire to serve a larger population, and again captain the ship, led Sandrock to the CEO position at Voyager Therapeutics in 2022. Put simply, Voyager seeks to build better boats for neurology drug development. The hull of the company is Voyager’s brain penetrant AAV capsid technology. One family of Voyager’s novel capsids utilizes the ALPL receptor to cross the BBB into the CNS—this technology is designed to allow gene therapies to access difficult to reach areas of the CNS (e.g. deep brain structures) without the steep concentration gradients of intrathecally injected oligonucleotide treatments. In our interview, Sandrock describes how the Voyager scientists discovered the capsids (TRACER platform), identified ALPL and other receptors, and the suite of medicines and modalities they are pursuing. Their pipeline includes monoclonal antibodies (Tau/AD), AAV-delivered vectorized siRNA (SOD1/ALS, Tau/AD), vectorized antibodies (Aβ/AD), and gene-replacement therapies (FXN and GBA1 in partnership with Neurocrine).

In our discussion, Sandrock highlights his guiding principles for navigating clinical development (the Sandrock Shamrock Q#6) and underscores the obstacles that can sink neurology drugs before they get to patients. Eager to give credit to his crew, Sandrock stresses the team-based nature of drug development: “It takes so much expertise to build a drug that teamwork is a necessity—it cannot be “all about you,” and credits Voyager scientists with persisting in identifying the ALPL receptor (Q#8).

Voyager is pushing the boundaries of neurogenetic medicines. They are sailing into the wind: it is a high-risk, high-reward journey. With Sandrock at the helm, and recent hires expert in neuro drug development (Toby Ferguson/CMO and Nate Jorgenson/CFO), they stand a good chance of calming the choppy waters. My hope is that they can (finally) ferry neurology patients in the right direction.

Below is an interview with Al Sandrock, CEO of Voyager Therapeutics from August 2024:

Subscribe now

1. What initially made you interested in science and medicine, and led you to the HMS MD-PhD program? Any early mentors you want to highlight?

My parents were a big influence on my decision to pursue medicine. My father joined the merchant marines when he was 16 years old, so he did not finish high school. My mother grew up in Japan, and in many ways was trained to be a wife and mother. But my parents both revered physicians…just revered them. My father eventually became captain of a ship and would always tell me: “when you are out at sea, people come to the captain with their medical issues.” He would pull out the Merck Manual and do his best. When he was able to help someone with their problem, he told me that he felt so great. This had a big impression on me as a child.

In high school, I remember seeing a film where a scientist dissected a frog leg and made a muscle prep. The idea that electricity could stimulate muscle contraction was amazing. I found it unbelievable that science could help understand this process. This cemented a dual love of both biology and medicine. When I was in college, my father’s brother died in his 40s from heart disease. I remember realizing that there is so much left to be done in terms of making new medicines. Even when I was just starting medical school, I had a desire to help make new drugs.

In college [at Stanford], Donald Kennedy was the head of the human biology department. He was one of the pillars of neuroscience in the United States in the early days, who ended up becoming President of Stanford. He gave lectures on the nervous system that were just beautiful. He would invite physicians to lecture—I remember a lecture by the psychiatrist Jack Barchas, where he discussed the biological basis of schizophrenia and depression. I was blown away that you could explain such complex diseases by imbalances in chemicals in the brain. Scientists and clinicians like these really inspired me.

2. What did you work on during graduate school for your PhD work?

As an undergraduate at Stanford I worked with Roland Ciaranello, who was a psychiatrist and scientist. He didn’t have a PhD but encouraged me to pursue one—[Roland] felt it would have helped him in retrospect.  When I got to Harvard Medical School, I started working on dopamine receptor signaling in the gut. At that point I got the feeling that if I didn’t do a PhD I would just be “winging it” with respect to basic science—and that the more rigorous training would be a good idea.

I was intrigued by developmental neurobiology, in particular the work being led by Paul Patterson, Story Landis, Ed Furshpan, and David Potter. I initially worked for Story Landis but then switched to work with Bill Matthew who had trained with Patterson as a post-doc. I studied axonal regeneration. Back then, we were identifying nerve growth promoting factors via monoclonal antibodies. Specifically, I researched how extracellular matrix factors promoted peripheral nerve regeneration. I was asking the question: why can peripheral nerves regenerate pretty well whereas nerve fibers in the CNS do not? So even my PhD was geared towards the clinic, and I had this early desire to help advance new therapies.

3. What attracted you to neurology for residency?

I was relatively open minded but given my interests in neuroscience I knew it had to be psychiatry, neurology or neurosurgery. To be honest, prior to my rotation I wasn’t even sure what a neurologist did—I had a better idea about psychiatry given my undergrad mentor at Stanford. I found that I did not enjoy the practice of psychiatry as much, despite finding the content fascinating. Neurology was amazing: Walter Koroshetz [now NINDS head] was my attending, and he took me under his wing. I also met the well-known neurologist Allan Ropper.  I learned from great teachers such as Raymond Adams and C. Miller Fisher.   I was mentored by people like Steve Hauser and Bob Brown…and I saw the most interesting patients, and really felt that I was a medical “detective.”  Back then, we didn’t have MRIs…we really had to rely on the history and neurologic examination to figure out what was going on.

Another striking thing about neurology: I felt that the level of suffering for these patients was so immense. When the brain is diseased it often prevents the individual from adequately seeking help, caring for oneself or even bonding/communicating with family members. It struck me that it is a double tragedy: being sick and then having the organ responsible for processing and dealing with things [the brain] be dysfunctional. In many ways, I had the most empathy for neurology and psychiatric patients. The biggest drawback [of choosing neurology] was that we had relatively few treatments. However, even in the 1990s we did have some tools: L-DOPA for Parkinson’s, acetylcholinesterase inhibitors for myasthenia gravis, IVIG for Guillain Barre Syndrome [GBS], among other options.

There are also a lot of specialties that have no idea about the brain. In the old days we would spend a lot of time in the ER and admit patients directly from the street. Often, we would be the first physicians to see them after triage. This doesn’t seem to happen as much anymore, but it was certainly a terrific learning experience. Though I hated the hours in the ER, I loved working up totally new patients from scratch. I really felt like a detective at times. In my opinion, this is more fun that just being a consultant to the primary team.

[What were some advances in neurology taking place during your training?]

Towards the tail end of my residency [1990s], the beta-interferon and MS story started to crystallize.  A good friend, and fellow MD-PhD [Tim Vartanian], told me about how patients were responding to interferon treatments and that it appeared to be disease modifying. Within MS, we also saw the advent of MRI biomarkers to assess disease progression. I remember seeing a patient at MGH with Steve Hauser, where we were trying to figure out if a patient had a new MS lesion or an exacerbation of a previously existing lesion. When we did an MRI, we saw a new gadolinium enhancing lesion that could explain the patient’s symptoms. This prompted us to treat with high dose steroids, which we may not have done if it was a previously existing lesion.

The effect of beta-interferon on reducing Gadolinium-enhanced T1 lesions as well as new or enlarging T2 lesions is really what made us [neurologists] believe in its effect. Here was objective surrogate [imaging] evidence that correlated with the clinical picture. After seeing this story play out, it really strengthened my interest in going to a place like Biogen.

4. Shortly after becoming an attending neurologist at MGH, you joined Biogen as a Medical Director. What motivated this move?

I was not the brave one: some friends from residency, including Nancy Simonian, made the move first. Nancy went to Biogen two years before I joined. In 1996, I had just become an assistant professor at Harvard with NIH funding (the R29, the so-called FIRST award) for 5 years (along with some smaller grants). Around this time, I saw an ad in the New England Journal for a medical director position at Biogen.  The ad specifically called for a neurologist with research experience. I called Nancy Simonian to get more information: she, and others, made it clear that people in industry were incredibly bright and really cared about making drugs for patients—coming from academia I had sometimes heard otherwise. I ended up applying for the medical director job, and Irving Fox was the one who recruited me.

[The transition to industry] proved to be a gradual and somewhat heart wrenching process.  I was offered the job at Biogen and declined it at first. During the recruitment process they even sat me at the table with the current CEO during the company holiday party. However shortly afterwards, I had a change of heart and called them to decline the offer. Understandably, they were a bit upset. About a month later [in January], I was at home on the weekend working on a grant. My son came up to me and asked if I wanted to play. I told him I could not because the grant was due soon. He said: “Daddy I don’t want to be a doctor because I’d have to write grants.” I realized that he was really saying: “you are choosing to work rather than be with me.” I felt that just because I wanted to do this “crazy” academic neurology thing, my kid should not have to pay the price. In talking to Nancy [Simonian] about industry, she mentioned that she did not have to work every weekend [if she didn’t want to]. I called Biogen and asked for the job back. They asked: “are you always this indecisive?” Nancy really went to bat for me, and stressed it was a tough decision for me to leave academia. They gave me the job and I started in February of 1998.

5. What were some early lessons learned at Biogen about drug development?

In a company what you work on is not strictly your decision and depends on company strategy and long-term vision. Until you get to be very senior, it is hard to change the direction of the company. I chose Biogen because they had already entered MS and neuroscience with the development of beta-interferon. I trained as a neuromuscular specialist, but always kept an interest in neuroimmunology and MS.

The other major difference is the level of teamwork. In academia you are very focused on your individual output, whereas in industry it is much more about the team. It takes so much expertise to build a drug that teamwork is a necessity—it cannot be “all about you.”

[What was the focus of Biogen when you joined in the 1990s?]

When I joined, Biogen was regarded as an immunology company. They were debating moving into the cardiovascular space. The pipeline featured an anti-CD40 ligand mAb for autoimmune disease, an LFA3 fusion protein for psoriasis and an adenosine A1 receptor antagonist for heart failure. Ironically, there was nothing dedicated to neurology when I started. Richard Flavell had been the head of R&D, so he really shaped the adaptive and innate immunology focus of the pipeline.

6. You became famous for developing medicines such as Tysabri, Tecfidera and Spinraza. Using these medicines as case studies, what are some checklist items for pushing forward drug development programs?

Sarah Sheikh [now at Takeda] once dubbed my checklist the “Sandrock Shamrock.” When talking about drug development, the first principle is unmet need. This is for several reasons: first, I have to be able to get my team out of bed to work on an important problem. Motivation is a huge factor in drug development.

Further, in diseases of high unmet need, there is often a more flexible regulatory path along with easier patient enrollment. If you are the 15^th drug addressing an indication, it becomes harder on all of these fronts. Ultimately (post-approval) there is also less commercial risk if the unmet need is high. The second principle is to find a validated drug target. When we were developing drugs for MS, there was a lot of focus on preclinical animal models—the EAE mouse model for example. Back then (in the 1990s) we didn’t have easy access to human genetics, but now I prioritize human genetic data over animal models. The goal is to find causal biological targets, which is a lot more reliable with human genetic evidence. The third element is path to proof of concept. When you are the head of R&D at a company you do two things: choose [targets/programs] and execute. Even with the right target, if the clinical path to proof of concept is too difficult, the program will languish and the opportunity cost is very high. In neuroscience especially, this can be challenging and is often a huge source of wasted capital for companies. For example, there were so many stroke trials that failed in phase 3 with thousands of patients enrolled. When I first got the job at Biogen, I was lucky to work with Larry Jacobs and Henry McFarland at NIH on MS drug development. NIH was able to do monthly MRIs on patients, and we were able to track how interferon greatly reduced the number of gadolinium enhancing lesions. We also saw that if the patients stopped interferon treatments, these lesions came back.  We realized that this imaging biomarker would allow us to run small PoC trials in MS with approximately 50 patients per arm, which could read out in 6 months.  We had a path to quickly determining if an agent was promising enough to advance to phase 3 trials.

The fourth element is competency. Do you have the expertise in your company to be able to choose and execute on programs? If you aren’t doing the work in a particular therapeutic area, everything looks good on the surface.  And you are prone to make mistakes?  The key question is: do you have the competency to evaluate the data and assess if it is interesting, i.e., to choose correctly? Second, do you have the clinical development expertise to execute to de-risk drug candidates efficiently, and ultimately to get the drug approved?  

[On other drug development principles]

There are also 3 known unknowns when developing any program, answers to which will be crucial if the program is going to be successful. The first relates to the relationship between drug and biology, i.e., the relationship between pharmacokinetics (PK) and pharmacodynamics [PD].   This is where you start to get an idea of the therapeutic window.  How much biology can the drug safely produce in vivo?   This is determined for each drug first in animals and then in early human studies.  If you are unable to answer this question in animal pharmacology and in early clinical trials, you have not significantly de-risked the program.

The second unknown relates to the relationship between biology and disease.  Even though you have chosen to perturb a biological process that is validated by human genetics to be in the causal path to disease, you don’t know how much biological change is necessary to achieve a clinically meaningful treatment effect?   For example, how much do we need to lower mutant SOD1 protein to alter disease progression in ALS?  This can be learned from other programs with other drugs—this may be where it is an advantage to be a fast follower rather the first in the clinic.  The relationship between biology and disease is frequently not linear; there is often a threshold effect, below which biological changes do not produce a discernable clinically relevant treatment effect. 

The last known unknown relates to how early treatment should begin.  The search for genes that affect the risk of disease may identify biological pathways that are responsible for disease initiation.   After disease initiation, other pathways that propagate disease may become more important.  In neurology, symptoms often manifest long after disease initiation by which time many cells may have been irreversibly lost.  Thus, by the time the patients are diagnosed, disease initiation biology may have given way to other biologic mechanisms that underlie disease progression.  For example, by the time patients start anti-amyloid treatment they have had AD pathology for 15 - 20 years or so—I believe this limits the efficacy of such a drug. The same could apply to SOD1 ALS.   If we can start treatment in patients before clinical manifestation of disease, we may see larger treatment effect sizes.  Early treatment will require novel clinical trial designs and diagnostic biomarkers. 

Share

7.  What do you see as the biggest barriers to successful neuroscience drug development today?

At the macro level, the biggest current threat to our industry is the concern over drug pricing and reimbursement. In high-risk therapeutic areas like neurology, [R&D and clinical development] is incredibly costly. For an investor, they must see a good return on these high-risk assets, otherwise they will invest elsewhere. In the US, drug prices drive only 11% of health expenditure, but there is disproportionate political focus on regulating prices—in the form of legislation like the IRA.  A great primer on this topic is Peter Kolchinsky’s Biotech Social Contract. He makes the point that once drugs go generic, they go generic forever—it is a way to fulfill the social contract after a period of pricing flexibility where the cost and risk of drug development are paid back to investors who took the risk in the first place.

In terms of science, delivery across the BBB has been the biggest obstacle for neurology drug development. ASOs and siRNAs must be injected intrathecally with steep concentration gradients, and relatively poor distribution to deep brain structures. Intraparenchymal injection into the brain also has a ton of safety issues, and similarly poor CNS-wide distribution. I joined Voyager to help make gene therapies more accessible to neurology patients: we are developing key genetic tools for treating neurologic disease.

8. What led you to join Voyager? What about the company mission or internal data was so appealing to you?

While the preclinical data looked promising, I ultimately took a leap in joining Voyager and betting on the company’s capsid technology.  Faith and optimism are always part of the equation in biotech…and in many areas of life.

The idea of BBB-penetrant capsids came from the scientist Ben Deverman, originally at Caltech—he named the first of these capsids “PHP,” the initials of his research mentor Paul H. Patterson. Paul was also the scientist that pushed me to pursue an MD-PhD at Harvard and was a cherished mentor for us both. Unfortunately, when Ben did this work Paul was already sick with glioblastoma. Ben told me recently that, tragically, Paul may not have been able to grasp the implications of the novel capsids due to his illness.  Ben and I have talked a lot about Paul, because he was both of our inspirations.  I told Ben that I know that Paul would have been very proud of his breakthrough research.

But the fact is that the early Ben Deverman capsids worked beautifully in mice, but they only worked in mice and only in certain strains of mice.  We now know that the receptor these initial capsids utilized to cross the BBB [Ly6A] was expressed only in rodents. When I saw the Voyager data in non-human primates, I felt that it could be a game changer for patients. Now it could have well been the case that these capsids were using a cynomolgous monkey-specific receptor not found in humans. However, soon after I joined we started seeing cross-species brain penetrance [indicating that the putative receptor was conserved through evolution].   And the Voyager scientists were in hot pursuit of the receptors that mediate BBB crossing. The first such receptor was called Receptor X.  

[On finding the “Receptor X” utilized by Voyager capsids]

When I joined the company, I felt that we may not be able to identify receptor X.  At Biogen, we ha experience trying, and failing, to identify the receptor that the JC virus (which replicated in the kidney) highjacked to get into the brain to cause PML.  However, our scientists [at Voyager] are so good—they were not deterred by my pessimism and ended up finding the receptor. This has been very enabling for the company.

[What does identifying ALPL as one of the capsid receptors do for Voyager?]

Finding that one of our capsid families utilizes ALPL allows us to perform more targeted optimization to develop second and third generation ALPL binding capsids. We can also potentially develop other modalities—antibodies or peptides—that engage this receptor to shuttle cargo (e.g. mAbs or oligonucleotides) into the brain more effectively.

9.  Can you discuss some exciting developments in the wholly owned programs? What makes you excited about targeting Tau and AB in AD?

[On Voyager’s anti-amyloid asset in early preclinical development, and Tau mAb]

There are now 3 FDA-approved anti amyloid drugs given intravenously [IV], and hopefully subcutaneous versions of these agents will be coming soon. To develop another IV administered anti-amyloid therapy does not make sense commercially, so this was not our approach. However, under current treatment regimes, AD patients must go every other week or every four weeks for antibody infusions. This can be a huge burden for cognitively impaired individuals.  On a personal note, I had to receive IV rituximab for treatment of my non-Hodgkin’s lymphoma. I observed that the IV infusion suites were always packed. The idea of expanding IV mAb infusions to AD patients represents a huge logistical challenge to the healthcare system. Our solution is to vectorize the antibody—use our AAV to enable durable gene expression of an anti-amyloid therapy in the CNS. This would lower the burden on infusion centers and on cognitively impaired patients: We also are working to make a regulatable gene expression platform that could be utilized with our vectorized antibodies—if the patient starts to experience unfavorable symptoms, we want to be able to modulate gene expression to address those symptoms. This is a way to develop a more feasible therapy for patients, while also working on totally new technology.

As we now know, anti-amyloid treatments are not a cure, at least not when used after patients are diagnosed with mild cognitive impairment or early dementia.   As such, many of us in the field believe the next best hope is in tau-targeting treatments.  Our anti-tau antibody, targeting a C-terminal epitope, is the furthest ahead in development among Voyager’s product candidates.  Whereas N-terminal anti-tau antibodies failed to show efficacy in the clinic, there are several companies pursuing mid-domain, MTBR, and C-terminal epitopes.  We chose our C-terminal directed antibody because it robustly blocked the spread of human pathological tau in an animal model in which the N-terminal antibodies fail to block the spread.    Our goal is to obtain human proof of biology with an IV anti-Tau mAb using tau PET imaging.   If that is successful, we then have the option of moving the antibody further in development, vectorizing the antibody with AAV gene therapy, or both.   We also have another approach targeting tau in late-stage research utilizing an AAV gene therapy approach whereby we vectorize an siRNA that decreases the expression of tau.  We expect this program to enter the clinic in 2026.

We also have a program directed against ALS caused by gain-of-function mutations in SOD1.   We anticipate that this will be our first wholly owned gene therapy entering the clinic. We are also advancing two other Neurocrine partnered gene therapy programs.  All three programs will employ a novel, BBB-penetrant AAV capsid discovered at Voyager, and we expect INDs in 2025.  There is an efficient path in SOD1-ALS to proof of biology (CSF SOD1 levels). as well as proof of concept (plasma neurofilament light).  Last year, FDA granted toferseron, an SOD1 lowering anti-sense oligonucleotide, accelerated approval based on plasma NfL, which was deemed a surrogate marker reasonably likely to predict clinical efficacy. Though SOD1 ALS is rare, it validates our gene therapy platform, so has very high strategic value. In our preclinical data, we find that 80% of spinal motor neurons are transduced by our capsids and we can achieve 80-90% SOD1 reduction. So, for our clinical PoC we plan to measure CSF SOD1 levels for target engagement, along with plasma neurofilament as a surrogate.  Tofersen has already shed light on the relationship between CSF SOD1 reduction and plasma nFl. 

10. What enables IV antibodies to be effective in clearing plaque and target engagement in the CNS, given low CNS distribution?

It's an interesting point. Generally, monoclonal antibodies are very poor are getting across the blood brain brain:  the brain to plasma ratio is typically in the 0.1 to 0.5% range.  For this reason, one has to give very high doses of peripheral [IV] antibody. The reason why these mAbs can effectively clear plaque is due to the fact that they are incredibly potent. Often these mAbs have picomolar binding affinity.  Moreover, they are typically very specific for the intended target. Thus, high concentrations in blood allow for a tiny fraction to gain entry into the CNS is enough to enable target engagement and biological effects.   Aducanumab was one of the first pieces of convincing evidence in humans, as evidenced by the robust, dose- and time-dependent clearance of amyloid plaques seen with PET imaging.  

11. What makes you most excited about Voyager and its mission over the next 5 years? What are the biggest milestones you hope that the company will achieve? 

We want to build a multi-modality neurotherapeutics company going after genetically validated targets. We want it to be heavily focused on neurogenetic medicines, but not just gene therapy [also oligonucleotides targeting RNA]. Even in sporadic disease [science] will eventually identify genetic targets by modern [bioinformatic] methods. We are also collecting some of the best operators to aid our mission. We just hired Toby Ferguson as CMO—he is an MD PhD neurologist with a decade of clinical development experience at Biogen.  He led the development of tofersen for ALS, as well as multiple other programs.  As CFO, we appointed Nate Jorgensen. Nate is a PhD neuroscientist by training, but garnered extensive experience as a buy side and sell side analyst, and former CFO at a publicly traded company. Voyager aims to collect the best talent and become a leader in neurotherapeutics discovery and development.

12. Any advice for a budding physician-scientist interested in getting involved with drug development or biotech?

Drug development is not taught well, if even taught at all. I was just having this conversation with a colleague in the industry. We agreed that students in medicine and science might benefit from more formal training in drug development.

Right now, my advice would be to “just do it.”  Learn by completing internships as a student, and then getting into the industry when you are comfortable taking the leap.  I waited until I did a post-doctoral research fellowship, completed residency and clinical fellowship training, and beginning my career as an independent academic neurologist.  I feel that I use all of my training every day.   But I was 40 years old before I took the leap!  My path is not for everybody, but I don’t regret what I did.  You should move to industry when you are comfortable, but I would say that there is no substitute for actually joining a team that is trying to make a new treatment for patients suffering from bad diseases.  The more innovative the approach, the riskier it is.  There is a lot to learn and it can be daunting at times.  On the wall behind me, I have a printed out copy of Teddy Roosevelt’s Man in the Arena speech. Do not be afraid to get into the arena and fail if need be. The higher the unmet need, the riskier the program, with greater chance for failure.

I have failed at certain points in my career and even been dragged through the mud for it. I’m likely to fail again: this is the nature of our industry.   At certain points, you may feel like giving up. However, all it takes is to meet one patient who has benefited from a drug that you helped to develop. I have met children who would not be alive today without Spinraza. I have danced with MS patients at advocacy events, who would be totally disabled if not for the medicines that we pioneered at Biogen. I still feel like a physician, but my “practice” serves a much larger population than when I was a practicing neurologist.

Subscribe now

Share

Using engineered T-lymphocytes to battle cancer has already yielded results for patients: “Initially, we saw CAR-Ts used in patients with literally kilograms of tumor burden. After [CAR-T] therapy it was melting away,” describes Dr. Jennifer Brogdon, Head of Cell and Gene Therapies at Novartis.

The first demonstration that T cells taken from patients [autologous] could be engineered to target B cell malignancies came from Carl June’s group at UPenn: “There were two papers published in the summer of 2011, detailing the experience of three CLL patients who were treated with a CD19 targeting chimeric antigen receptor T-cell [CAR-T]. Within a month of the publication, Novartis was already talking to the researchers at UPenn,” explains Brogdon, who was on the internal diligence team at Novartis.

A trained immunologist, who studied antigen presentation for her doctoral work, Brogdon had been spearheading cancer immunotherapies within Novartis prior to 2012. Yet when she saw the early CAR-T data, she was in awe: “I was at Penn the day that Carl [June] announced the news that Emily Whitehead's bone marrow was in remission. This was a solidifying moment where I felt like this modality would be bigger than we could have imagined.”

Brogdon and a growing team at Novartis quickly pivoted, entering the race to develop the first FDA-approved CAR T-cell therapy for cancer patients: “To see this large organization [Novartis] so swiftly pivot to develop CTL019—it was incredible,” she remembers. In 2016, Novartis was able to replicate early UPenn results in larger clinical trials: showing an 83% remission rate in children with B-ALL at 3 months. A year later the CD19 targeting CAR-T, Kymriah (CTL-019), became the first FDA-approved cell therapy for patients with B-ALL. “There were definitely several company parties afterwards,” says Brogdon with a chuckle. “Across the different campuses they also had big Kymriah posters so that everyone felt like they were sharing in the achievement.”

In the 8 years following Kymriah’s approval, the cell therapy space has exploded. There are six FDA-approved products for cancer patients with hematologic malignancies, all of which target antigens on B-cells [BCMA or CD19].  Many earlier-stage companies developing CD19/BCMA CAR-Ts are now shifting their focus to address B-cell driven autoimmune diseases like lupus erythematosus.

While there is a rich (many would say overcrowded) pipeline of autologous therapies for B-cell driven cancers, solid tumors remain elusive for this modality. Durable allogeneic (off the shelf) therapies have been similarly difficult to produce.

In our interview, Brogdon discusses the challenges facing the cell therapy field and the progress made in manufacturing autologous products (including Novartis’ T-Charge approach). She also describes opportunities for “next-gen” therapies: durable allogeneic cells, in vivo T-cell engineering, logic gating, NK or Treg therapies, and novel solid tumor targets.

Subscribe now

At the forefront of one of the most cutting-edge sectors in biopharma, Brogdon reflects that her career in science started at the bottom of a lake: “I initially got interested in biology in high school…I was able to do a longitudinal science project focused on the biology of zooplankton,” she remembers. Imbued with a love of tiny organisms, she went on to study microbiology in college and earn a PhD in immunobiology from Duke. During our interview she shares high and low points during training, strategic moves she made to land a job in industry, and tips for operating in a large organization like Novartis. The complexity of her work aside, her motivation is simple: “I came from a family of caregivers. My dad was a pastor and carpenter, and my mom was a nurse… from the very beginning, I viewed science as my way to have an impact on patients.” 

With one cell therapy approval under her belt already, and several clinical stage development candidates in the pipeline, Brogdon has succeeded in her childhood ambition to help patients. Yet the work is not done: “It is up to us to build on early signals of efficacy and tackle different components of what is currently limiting in the cell therapy field.”

Below is an interview with Jennifer Brogdon, Head of Cell and Gene Therapies at Novartis:

Share

1. What initially made you interested in science? Were there any early mentors that pushed you towards becoming a scientist?

I became interested in biology during my freshman year of high school. I was able to do a longitudinal science project focused on zooplankton. Each year I got to build on that science project and present the results at a science fair. For example, there was a power plant on a lake nearby to where I lived…I asked: how does efflux from the plant affect the ecosystem [pH, temperature] of the lake and the function of the zooplankton? I ended up getting a Navy Science Award for this project during my senior year. My biology teacher, Mr. Robinson, really fostered my curiosity about how things work and function. I got grounded in curiosity driven science at a young age, which was super cool.

When I went off to college to get my Bachelor of Science degree, I started studying microbiology and was fascinated by these tiny organisms. I was looking for some part time work to offset the cost of college, and funny enough there was a lab studying the same zooplankton that I had done experiments on [in high school]. So, I spent a semester or two working there. I loved it!

2. What did you study in your PhD, and then post-doc years? Did you plan to have a career in academia?

As I’m taking college classes [University of Illinois], I realized quickly that I enjoyed every lab course: biology, chemistry, organic chemistry, microbiology. I really fell in love when I took an immunology lab class. I felt I was witnessing “crazy” things on the bench, such as B cells producing antibodies to different antigens. At that point, I decided I wanted to get a PhD; intuitively I felt that science was something I should build upon. I also had some great teaching fellows during my college science courses. In fact, the TA for my immunobiology course went to Duke for her post-doc and I [unintentionally] followed her there for my PhD training.

[Did your family encourage you towards science specifically?]

I came from a family of caregivers. My dad was a pastor and carpenter, and my mom was a nurse. My older sister also went to nursing school, so I grew up surrounded by people who cared for their community. I did not like blood, so medicine was out of the question for me! However, I really felt I wanted to use science to help people. From the beginning, I viewed science as a way to have an impact on patients.

[What were some high and low points during your scientific training]

I set out to get a PhD in microbiology and immunology, which was a combined department at the time. I began studying human T cell biology, and structural interactions between CD4 and MHC class II molecules. My thesis work investigated how these interactions changed T cell function. One high point was just that we had a great community of people in the lab who were a lot of fun. We worked hard and played hard. Often people would be in lab till 11 o'clock at night; however, we would also play volleyball as a work break in between experiments.

A low point was trying to get my thesis work started. My thesis advisor thought she was giving me a project that was going to be straightforward and easy, as it was a natural evolution of her postdoc work at Harvard. It was not. I was tasked with making 50 different point mutations in the HLA DR beta chain and re-expressing them in different cell lines. This was a time when plasmid production, cloning and transfection were not straightforward. There was definitely a period of time when I kept coming up against a wall—trying to just figure out the tools I could use to actually do interesting science. Ultimately, there was a bit of serendipity: I went to a lab in Wisconsin to learn how to grow human T cell clones with antigen specificity, which was a technique that moved the needle on my specific project.

[On tools in immunology]

My PhD was in the early 90s, so the tools were limited. We were still using gel-based sequencing methods and had to read out the sequences manually. There were some good HLA-specific antibodies, but antibodies for other targets were not readily available. At this time, some professors at Duke were even using HLA-specific antibodies that came from immunizing themselves with cells from other faculty members—pretty crazy to imagine now! Even mini-preps were laborious, and I had to use hundreds of cesium chloride gradients to purify DNA of the different HLA mutations I was studying. Immunology has evolved so much over the past couple decades.

3. What factors led to Novartis in 2004/2005? What were some initial things that you were working on?

When I was doing my PhD [early 1990s] leaving academia to go to industry was taboo. It was frowned upon. I think we are in a different world now. Academia now does so much translational work, which is often a collaboration with industry. In my opinion, this has been a rather sizable change in the past 30 years. I went to Yale for my post-doc with the intention of transitioning to industry. Yale even had some resources for post-docs who were considering transitioning to industry or biotech. However, in the early 2000s there were not a huge number of companies hiring in immunology. I was also trying to stay in the New England area for personal reasons, which made the job search even more restricted.

This [time] was before CTLA4 and PD-1 monoclonal antibodies were developed, so immunologists were not yet in high demand. However, I was able to get an interview at Novartis for a job working on Th1 and Th2 cells—the area of focus for my doctoral work. Before my interview I remember discussing Novartis with my mom, who was a nurse in Illinois supporting some clinical trial work. She had interacted with folks from Novartis as part of a heart failure trial and had a very high opinion of the company—its employees and their level of scientific rigor.

When I interviewed [at Novartis] I also met an immunologist from Laurie Glimcher’s lab, and we were like two peas in a pod. We totally geeked out on science. Any fears about “missing out” on cool science by going to industry were totally allayed. I had a really fun interview meeting with the entire team—I was even working on some unpublished work [as a post-doc] that an interviewer at Novartis had spent some time pursuing [at another company]. It was a great experience.

[When you first got to Novartis, what were some initial lessons?]

There were a lot of lessons to learn right away. But I was energized because immediately I took my primary T cell expertise and designed a high throughput screening [HTS] assay where we screened a million compounds against primary T cells.

In academia I went from working in 96 well plates to using 1536 well plates on robotic machines based in the Novartis San Diego facility. We completed this screen in the first 1.5 years I was at the company. It was amazing and I loved it. But there were other struggles. For example, in industry we use acronyms like crazy—there was a language learning curve to even understand what people were talking about in meetings. We now have an internal cheat sheet for acronyms in drug discovery at the company. There is also a much higher level of scientific rigor. We are developing things that will go into patients: so, I had to become an even better scientist.

[What were some early successes?]

In the large T cell screen, we found some interesting hits and partnered with an external chemo-proteomics company for target identification. I then moved into immuno-oncology at a time when Novartis was not focused on this area—but I wanted to try to push the boundaries and it indeed led to some interesting publications. For example, we had a nice JEM paper on GITR-agonist antibodies and redefining the role of the Fc component. This was work we published back-to-back with a similar story from Jim Allison’s lab.

4. What were your early interests and exposure to cell therapy?

There were two papers published on the in the summer of 2011, detailing the experience of three CLL patients who were treated with a CD19 CAR-T at the University of Pennsylvania.  Within a month of the publication, Novartis was already talking to these researchers and clinicians, and had started internal diligence. By the end of 2011 I was on the diligence team, and we signed the deal with Penn in August of 2012. Because I trained as a T cell immunologist and had been working in IO for several years at this point, Novartis felt I had the expertise to get involved. Personally, I felt like this was a project made in heaven for me.  I was lucky enough to end up on the team that brought CTL019 [Kymriah] forward to the ODAC [Oncologic Drugs Advisory Committee of the U.S. Food & Drug Administration], and later to approval. In parallel, we were developing a research collaboration with Carl June and his team at UPenn. The rest is history, and it has been amazing to see the impact on patients.

[What about that initial data made the biggest impression on you?]

Initially we saw patients with literally kilograms of tumor burden. After [CD19 CAR-T] therapy it was melting away! By this time, I'd been at Novartis for about 8 years. I had developed a sense for the speed at which we moved, which until this point was not that fast. To then see the organization so swiftly pivot [to diligence for this cell therapy]—it was incredible. I was at Penn the day that Carl [June] announced the news that Emily Whitehead's cancer was in remission. This was a solidifying moment where I felt like this modality would be bigger than we could have imagined. Again, it was fascinating to see people from all parts of the organization come together. There is no script or playbook for this scenario--but we felt that we were defining a new landscape of medicine. It was an incredible time.

[On the competitive nature of industry]

As soon as other companies started coming on board, there was an internal drive to win the race. There was so much to focus on, but we had some good luck and things fell into place. For example, we were able to [acquire] a Dendreon facility for cell manufacturing. There was a lot of pressure to map out all the logistics, capabilities needed, supply chain, chain of identity, regulatory requirements, clinical plans, etc., to define the path towards registration, but also a lot of excitement for patients. We kept hearing amazing clinical stories that literally brought tears to peoples’ eyes. Penn was reporting 94% CR rates in its pediatric populations, and we were getting over 80 percent responses as well. This was crucial because often smaller academic trials don’t replicate in larger industry-led studies.  We went to the ODAC in 2016, and the prep work we did for that was phenomenal. It was very stressful because there wasn’t a playbook, and we were trying to prepare for every question possible. The actual ODAC experience was overwhelming, and the unanimous 10-0 vote spoke volumes about this innovative breakthrough.  Tim Cripe, [member of the FDA advisory panel and Chief of Hematology & Oncology at Ohio State], said “This is probably the most exciting thing I have seen in my lifetime”.

[What was it like to be working at Novartis during the approval of Kymriah in 2017?]

It was so exhilarating! The energy level at the company was palpable, even after the ODAC [prior to approval]. When we got the actual approval, it was global news—Forbes, New York Times and every outlet was reporting it. I feel lucky to have gotten that experience and more importantly, to truly be making a difference for patients.  As a team, we felt like we could conquer anything as we started changing the practice of medicine. Looking back, it still feels surreal at times. There were definitely several company parties afterwards! Across the different campuses they also had big Kymriah stickers and posters put up everywhere so that everyone felt like they were sharing in the achievement. It was such an inspiring time.

5. With respect to oncology, where are we now in terms of cell therapy? What were the biggest milestones in the past few years and landmark approvals?

There have been a  number of approvals for B cell malignancies with CD19 and BCMA targeted therapies, with six approved products. Because B cells naturally interact with T cells, destroying [B cells] with CARTs can be quite effective. What we also learned from the target profile of CD19 and BCMA, is that B cells are dispensable. You can manage B cell deficiency with intravenous immunoglobulins [IVIG] and other treatments—this has helped pave the way for multiple products across multiple indications and we’re now exploring development in autoimmunity as well.

[What are the different factors you look for in these cell therapies?]

In oncology indications, you need to examine the depth of depletion and the persistence or durability of the CAR-T. Persistence and durability [of the CAR-T] really matter in terms of achieving responses and lasting remissions for patients. There are differences in responses from indication to indication, and how quickly those occur. For example, in the multiple myeloma space, targeting BCMA can lead to responses that evolve over the course of 3 to 9 months. However, with CD19 as a target, deep clinical responses can happen more quickly, within 1 to 3 months.

Considering the target product profile is essential: when you move into the allogeneic space, durability can be affected—the modified T cells don’t persist. The big question in oncology is how we maintain that durability as we create new products? For autoimmune indications, where we want to use CAR-Ts to achieve an “immune reset,” there are even more unanswered questions. What level of durability and B cell depletion is needed? How long do you need to promote B cell aplasia before you get a normal repertoire returning? Will allogeneic or even other approaches like bispecifics [antibodies] be useful? We've learned from oncology, that we do get longer lasting responses with CAR-Ts compared to bispecifics. In autoimmunity there may be additional benefits in not having a persistent CAR-T around [which may favor alternative approaches] though we don’t know all the rules yet in the factors required for transformative benefit.

6. What are the biggest scientific barriers for cell therapies? What are some broad strategies Novartis is taking to overcome these?

With the first approval of Kymriah, we realized that autologous cell therapy can really have curative potential. To make these treatments available to as many patients as possible, we had to make that process [leukapheresis, engineering, expansion, delivery] more scalable.

One big area of focus for us was to innovate around the cell manufacturing: faster turnaround times while retaining all the best aspects of the T cell biology. This is how we evolved the T-Charge platform: we now have two assets in the clinic using this technology, including the CD19 product YTB323. What we have done [with T-Charge] is to have the cell expansion occur in the patient, as opposed to ex vivo in the lab. We have found that this increases our response rates dramatically and improves response durability.

What we are focused on now is continuing to leverage this [T-Charge] platform as we move to solid tumors, which is another big area of focus for us. We did a partnership with Legend Biotech last year to develop a CAR-T for small cell lung cancer. We are going after DLL-3, which is a clinically validated solid tumor target. Our hope is that combining the T-charge platform with this novel CART will provide more benefit to SCLC patients.

The area of solid tumors is really interesting, because that's where the CAR-T field actually started back in the early 2000s. These initial attempts suffered from a lot of on-target, off-tumor toxicity. But we have now come full circle and are again attempting to tackle these diseases. The field is starting to see signals of activity, though it is still early. It is up to all of us to build on those early signals and tackle different components of what might be limiting as we strive to make more impact on the lives of patients battling these terrible diseases.

7. In 25 years, what will the field of cell and gene therapy look like?

Cell and gene is a fast-changing field with new developments in synthetic biology, delivery systems, and gene editing.  A key challenge is how to make safe and effective therapies that are easy to deliver to patients, even in the community setting. I hope that in 25 years, personalized medicine helps us match patients with the right therapies, and the therapies are available when needed, either through radically simplified ex vivo delivery or new in vivo methods. I'm also optimistic about the prospects for patients who have no other options, and hope we can overcome the historical obstacles of solid tumors and extend to non-oncology areas where curative potential is possible.

8. What are some broad areas of science outside of your work at Novartis in C&GT that you are excited about?

Definitely neuroscience and neuroinflammation. We continue to uncover unique ways in which the immune system impacts disease and the complex relationship between the brain, inflammation and various neurological disorders is truly fascinating. As the field continues to evolve with better tools, deeper mechanistic insights and potential therapeutic strategies, I’m excited to see where these might lead to transformative benefit for patients.

9. Any pieces of advice for a trainee in science and medicine looking to make an impact in industry?

Think about what you love, what brings you joy. Then reflect on your natural talents—what you’re really good at and what energizes you. Use these strengths to guide you in a direction that inspires you every day. Notice what sparks your interest and use this to find your path and your North Star. It may be a winding path with challenges and setbacks. But if you follow your passion, you stay true to yourself and will overcome the obstacles.

Within our bodies, microscopic “soldiers” fight a winner takes all battle between host and pathogen. When these “troops” are missing in action, chaos ensues: “During my rotation in pediatrics, I was exposed to children with primary immunodeficiencies. We didn't have any therapeutic options for these families,” remembers Dr. Maria Grazia Roncarolo, the George D. Smith Professor of Stem Cell and Regenerative Medicine at Stanford, and co-founder and President/Head of R&D at Tr1X.

Decades of careful research have shown that our immune soldiers are highly specialized. Some can attack and engulf pathogens directly, whereas others kill cells invaded by virus, or produce soluble factors that can protect against future assaults. Patients with rare genetic mutations can lack entire regiments of their immune army. For example, patients with ADA-severe combined immunodeficiency disease (SCID) are deficient in lymphocyte populations like B-, T- and NK cells. Over nearly two decades (working across France, Italy and the US), Roncarolo pioneered therapies for those with devastating rare diseases like ADA-SCID and Wiskott Aldrich Syndrome: “I helped create a relatively small institute in Italy, which then developed a huge pipeline for rare genetic diseases. This work led to two drugs now on the market [Strimvelis and Libmeldy] …this was a major milestone for gene therapy,” she says.

In addition to developing gene therapies for patients with immunodeficiencies, Roncarolo has made fundamental contributions to the field of immune tolerance. Intense immune battles can lead to collateral damage when healthy tissues are inadvertently exposed to toxic cytokines or destructive cells.  In cases of transplant rejection or autoimmune disease, white blood cells attack healthy tissues directly. “[In autoimmunity] the immune system is totally dysregulated…multiple cell types are causing damage,” says Roncarolo. “What is needed is a system reset.”

Enter regulatory T cells (Tregs); peripheral emissaries whose job is to quiet the troops or kill unruly effector cells that refuse to stop fighting. Increased Treg activity is associated with immune tolerance, whereas loss of these cells can induce autoimmunity.

“We noticed that in some patients, despite mismatched stem cell transplants, there was tolerance [of the graft],” describes Roncarolo. In the 1980s, her group showed that in patients with mismatched grafts—transplants that the immune systems should attack—some individuals evaded rejection. Roncarolo isolated cells from these patients and hypothesized that they might drive tolerance. Working at DNAX in the 1990s, Roncarolo’s group showed that the cells from her patients were CD4+ T cells and produced extremely high levels of IL-10. Thus, they were the first to characterize type 1 regulatory T (Tr1) cells—a Treg subset that lacks expression of the classical FOXP3 marker.

Since their initial description, Tr1s and other Tregs have held therapeutic promise for conditions where the immune system targets healthy tissues. While Tregs have been effective in animal models of inflammatory bowel disease (IBD), type 1 diabetes (T1D) and graft versus host disease (GvHD), isolation and persistence of these cells after adoptive transfer in humans has been challenging in clinical trials.

Enter Tr1X (pr: “Trix”), a venture seeking to harness the power of Tr1 cells to combat GvHD, IBD and other autoimmune diseases. “Tr1 cells suppress immune activation through IL-10, which has pleiotropic functions…in theory these cells can reset the immune system in a way that other Tregs cannot,” describes Roncarolo. Co-founded by Roncarolo, David de Vries, Jan de Vries and Jonathan Perrin, Tr1x has developed a proprietary method to create high purity allogeneic Tr1 and CAR-Tr1 cells. These “off the shelf” solutions aim to provide enhanced durability and immune modulation, compared to classical Tregs. Importantly, their scalable production may (one day) expand patient reach: “current autologous Tregs, CD19 or BCMA effector cell therapies require a huge effort to collect and manufacture…we think we can modulate both B and T cells with our products and eventually provide access to more patients,” says Roncarolo. In April of this year, Tr1X announced IND clearance to test its lead Treg asset (TRX103) in Ph1 trials of patients with GvHD. The company also completed a $75M series A financing led by The Column Group in 2023, which will enable further development of their Treg pipeline. This includes an IND for TRX103 in Crohn’s (H2 2024) and a CAR-Tr1 asset (TRX319) for B-cell driven autoimmune disease.

Roncarolo has already changed the game for patients suffering from rare genetic disorders. With the team at Tr1X, she is building upon decades of work in immune tolerance to expand the reach of cell therapy to patients suffering from autoimmune attack. Yet battling a dysregulated immune system isn’t easy.  Roncarolo knows from experience that only human testing will reveal whether they are winning the war: “The goal is to show that our cells can truly work from within: that they can reset the patient's immune system, activate endogenous regulatory cells and secure long-term remission or cure.”

Below is an interview with Dr. Maria Grazia Roncarolo from May of 2024:

Share

1. What got you interested in science and medicine initially?

Despite coming from a family of businesspeople, I always knew I wanted to be a doctor. I can't explain why, but it was a dream I carried with me from a young age. When I was in junior high school, I started volunteering on an ambulance crew, which deepened my desire to pursue a career in medicine. I never shared this dream with my father because he had already charted out clear paths for each of his three daughters. My destiny, according to him, was to become a chemical engineer. He envisioned me working in our family-owned business, which produced industrial paints. For the longest time, I respected his wishes and kept my medical aspirations to myself. During my last year of high school, my father passed away unexpectedly. After his passing, amidst the grief and turmoil within the family, I was also torn between honoring my father's plan for me and following my own dream. In the end, it was my mother and sisters who gave me the courage to pursue medicine. They told me to follow my calling and enroll in medical school, reassuring me that they would manage the family business. In Europe, you can go straight to medical school after high school, which means six years of study plus one year of internship. Thus, while my sisters took on roles in the company, I embarked on my medical journey at the age of 18.

2. What was medical school training like in Europe?

The initial years of medical school in Europe were quite basic: physics, chemistry, and mathematics—foundational topics that are comparable to what you would study in [a US] college. By the end of the second year, we started to learn physiology and biochemistry. By the fourth year, we started studying pathology. I remember at the time, pathology came as a shock to me. The approach was highly empirical, lacking a lot of the precision and clarity we have today because of tools such as genomics, precision medicine, or biomarkers. Diagnoses were based on patterns and correlations that could fit multiple diseases, making the process feel more like guesswork than science. I found this deeply disappointing. I realized I wanted evidence-based medicine, not medicine based on empirical observations and correlations. The experience inspired me to pursue research. I began working in a lab at the start of my fifth year of medical school. It was during my pediatrics rotation that I found my true calling and research focus. I encountered children with primary immunodeficiency, often referred to as "bubble boys." These children suffered from severe combined immunodeficiency (SCID), a condition we now know encompasses over 37 different diseases under a single clinical phenotype. At that time, treatment options were extremely limited. Bone marrow transplants were just beginning to be explored, and my medical school had not yet adopted this practice. Seeing these children, and the lack of therapeutic options available to them, was heart-wrenching. We had to tell parents that we did not have any curative solutions. This experience solidified my decision to focus on pediatric immunology. I wanted to find solutions, not just manage symptoms. Thus, at this point in my training, I decided to pursue research in pediatric immunology and complete my residency in pediatrics, followed by a fellowship in clinical immunology. This path into pediatric immunology was serendipitous, yet it felt like the perfect fit. The desire to help those children and find solutions to their conditions guided me through my career, shaping my work in cell and gene therapy.

[During your medical training did you get exposure to research?]

During my first year of residency in pediatrics, I was fortunate enough to win a prestigious grant that allowed me to spend a year doing research abroad. Initially, I considered going to New York's Memorial Sloan Kettering Cancer Center, but ultimately decided to go to France. This grant not only supported my salary but also covered some of my research expenses. With special permission, I went to Lyon, France, for what was supposed to be a 1-year research stint. That one year turned into 15 months, during which I immersed myself in groundbreaking research. It was a period of intense learning and growth, both professionally and personally. Upon completing my residency, I faced an exciting yet challenging decision. I had enrolled in a fellowship program in Clinical Immunology at the University of Milan, but at the same time, my French mentor offered me an assistant professor position in Lyon. Determined to take advantage of both opportunities, I received special permission to pursue both simultaneously. This arrangement meant that I would spend most of my time in Lyon, working as what was then called a "Maître de conférences" or assistant professor at the university, and travel to Milan one week each month to fulfill my fellowship requirements. It was a demanding schedule, but the experience was incredibly enriching. Balancing these dual roles was not easy, but it allowed me to broaden my expertise and strengthen my connections in the medical and research communities across two countries. This period laid the foundation for my future career, blending clinical practice with cutting-edge research, and reinforced my commitment to advancing the field of pediatric immunology.

3. A lot of your early work was in the field of cell and gene therapy – leading the first stem cell-based gene therapy for ADA-SCID What was it like to be part of these clinical trials, and how did it inform your future research?

One of the main reasons I chose to go to Lyon instead of MSKCC was because of their innovative fetal stem cell transplant program for patients with SCID. In cases where patients didn't have an HLA-matched sibling donor, Lyon was experimenting with fetal liver stem cell transplants. I was very interested to explore this as a curative option for SCID and other monogenic diseases like metachromatic leukodystrophy and thalassemia. During my investigations, I made two key observations. First, I found that some patients succeeded with transplants despite a complete donor-host mismatch--indicating an active process of tolerance. This sparked my interest in understanding this tolerance mechanism. Secondly, we attempted fetal stem cell transplants in utero to avoid the high GVHD risk associated with post-birth transplants. However, we soon realized that even in utero transplants could result in GVHD and rejection. These insights led me to shift from allogeneic fetal transplants to an autologous stem cell gene therapy approach: using the patient's own engineered cells to reduce GVHD risk and harness the immune system more effectively.

It was in one of these patients that exhibited active tolerance where the first observation of Tr1 regulatory cells was made. Despite the limited tools to detect these regulatory cells, we published evidence of this mechanism in the late 1980s. My journey toward uncovering the function of these Tr1 cells continued at DNAX, a Bay area-based biotech company founded by three Stanford professors Arthur Kornberg, Paul Berg and Charles Yanofsky. The timing of my arrival at DNAX was somewhat fortuitous. DNAX had just cloned the mouse IL-10 gene, and wanted to clone the human IL-10 gene. By this time, I had found these regulatory cells in my patients but had not yet figured out how they function. After joining DNAX, I gave some of these patient-derived cells to Kevin Moore, one of my colleagues at DNAX. His postdoc came back to me after five days saying that the cells I had given him produced copious amounts of IL-10 and that he had cloned the human IL-10 gene! Thus, if I had to look back, being part of those early clinical trials in monogenic inherited immunological diseases is what led to the discovery of the Tr1 cells and took me down the research path of trying to understand how these cells function.

Subscribe now

4. Can you walk us through the tools available at the time in immunology that helped in your research?

When I reflect on the tools available during my early research in immunology, I can identify three significant steps that marked the evolution of the field and profoundly impacted my work. The first step occurred during my time in medical school with the advent of monoclonal antibodies which enabled the advancement of immunofluorescence techniques to investigate the immune system. Of course, the process was still quite labor intensive and time-consuming since we examined slides under a microscope and had to manually count the positive cells. The second pivotal moment came when I returned to Lyon in 1986. I had joined an immunology lab supported by Schering-Plough, which had incredible resources, including advanced technology such as the fluorescence-activated cell sorter (FACS). This lab attracted top talent, including a researcher who would later become my husband. They introduced me to single-cell cloning, allowing us to characterize biological cells at the single-cell level. This technology enabled us to investigate different cells from our patients more precisely, providing deeper insights into their immune functions. The third major advancement happened when I moved to the DNAX in the Bay Area. DNAX was at the forefront of DNA recombination technology, enabling us to clone cytokines and their receptors, which is what allowed us to clone human IL-10 and obtain the necessary reagents to study cytokine production and expression in cells. These advancements were crucial as they also coincided with the sequencing of the human genome in the late 1990s. At Stanford and DNAX, we focused on interpreting the newly sequenced genes and generating biomarkers to identify them, which was transformative for our understanding of immunology.

5. Can you walk us through some of your early discoveries about Tr1 cells and how you balanced this with your work in gene therapy?

Reflecting on my early discoveries about Tr1 cells, I consider it one of my major scientific achievements even though (to date) my clinical impact has been more pronounced in treating monogenic diseases through gene therapy. In the early days after discovering the Tr1 cells, we determined that these cells were distinct from Th1 and Th2 cells based on their cytokine production profile and receptor expression. We demonstrated their suppressive function and found that these cells exist not only in transplant patients but also in the general population. We submitted our findings to Nature, but the paper's publication was delayed by almost a year because we had to show that Tr1 cells also existed in mice and were relevant in a mouse model of disease. We eventually demonstrated this using a model of IBD/Crohn’s disease.

Around the same time, I returned to Milan to establish a research institute for gene therapy. Although I continued my work on Tr1 cells, my primary focus shifted towards building the San Raffaele-Telethon Institute for Gene therapy (TIGET) and developing a pipeline of stem cell gene therapy products. This effort culminated in the approval of Strimvelis for ADA-SCID and Libmeldy for metachromatic leukodystrophy: both significant milestones for the field and for the institute, which went on to grow substantially in size and capability. It was also during my time in Milan that I developed some initial technology to generate Tr1 cells in vitro for patients undergoing allogeneic stem cell transplantation. We even managed to treat patients and demonstrate safety and efficacy, but the process was not yet optimized for broader clinical trials. When I joined Stanford in 2014, my primary goal was to build the Center for Definitive and Curative Medicine (CDCM), which included setting up a GMP facility and establishing a robust clinical trial office. Despite these major responsibilities in setting up these new institutions, I balanced my time and continued to work on Tr1 cells within my lab. We optimized a Tr1-based cellular product and then went on to conduct two promising clinical trials. These trials involved using a product derived from the donor of the allogeneic stem cell transplant, which contained approximately 10% Tr1 cells. These trials showed promising data, demonstrating both safety and initial signs of efficacy but also highlighted several challenges. The challenges we uncovered is what ultimately led to the creation of Tr1X later on.

6. What were some of the initial obstacles in thinking about translating these findings about Tr1 cells to the clinic?

Broadly speaking, there are overarching challenges in the cell therapy space. For instance, some of the advanced therapies like CAR-T cells that have become commercial products and gone on to save lives have a very high price tag. While the high cost of CAR-T therapy is justified by its life-saving potential, it does limit accessibility as not all patients can benefit from it. In addition, the need to use patient’s derived cells to engineer the CAR-T limit the feasibility. For instance, patients who are immunosuppressed or have undergone extensive chemotherapy might not have viable cells to extract for CAR-T production. Even when cells can be extracted, manufacturing them successfully can be a challenge. Another major obstacle is the logistics involved. The process of leukapheresis (extracting the patient’s white blood cells), manufacturing the CAR-T cells, and then shipping them to the clinical site on time, is complex and fraught with delays and complications. These logistical hurdles can prevent timely treatment and reduce the therapy’s overall effectiveness. Despite the promise of cell therapy, the number of patients treated with CAR-T is still a fraction of those treated with biologics like anti-PD-1 and anti-CTLA-4 antibodies or small molecule therapies. Biologics are more scalable and accessible, partly because they don't face the same manufacturing and logistical challenges. Thus, as we were thinking about translating our research findings surrounding Tr1 cells, we understood that for cell therapy to truly compete with biologics [cost and patient accessibility] these practical issues need to be addressed. Developing more efficient manufacturing processes, improving logistical frameworks, and finding ways to make these therapies more broadly available to patients in need was on the top of our mind.

Our experience with the initial Tr1-based clinical trials had revealed several challenges in generating autologous Tr1 cells. The feasibility of producing these cells at a clinical scale was difficult, and the cost of goods was prohibitively high. Given these challenges, it became evident that the most viable path forward was to develop an off-the-shelf product that did not rely on the limitations inherent to natural regulatory T cells. Unlike effector cells, natural regulatory T cells, including Tr1 and FOXP3+ Tregs, have intrinsic limitations when it comes to commercial viability, such as poor growth and expansion capabilities. These limitations made it clear to us that a new strategy was needed. This ultimately led to the creation of Tr1X, which engineers CD4+ T cells to become Tr1-like cells through genetic modifications, allowing them to mimic the natural Tr1 cells' regulatory functions without their limitations. By starting with cells from allogeneic sources rather than the patient’s own cells and using lentiviral vectors to introduce specific genes, we can reprogram these CD4+ T cells into Tr1-like cells, which have better growth and expansion properties, offering a more feasible and scalable solution for therapeutic use.

7. At what point did you start to consider translating the years of research on Tr1 cells that you had done until that point into a private venture? What is the founding story of Tr1X?

I'm a strong believer in academia's ability to translate research into real-world applications. The freedom to operate and make clinical trial decisions independently of business or financial pressures is invaluable in my opinion. This belief is what drove me to Stanford, where I went on to build the CDCM. The aim was to create a research center that brings together high-impact research investigators across therapeutic areas with best-in-class translational capabilities and proven leadership to accelerate the development process from the bench to the bedside, particularly in cell and gene therapy. The CDCM's success to date really demonstrates the value of such infrastructure with over 30 Phase I clinical trials in the pipeline currently, all representing potentially transformative treatments.

Having said that, there are obvious limitations within academia as well. Developing off-the-shelf technologies, for example, is nearly impossible within an academic setting due to resource constraints. Significant funding is often required to bring a product to the clinic—far beyond typical academic grants. I have always believed that there are two main factors that should drive the formation of a company: 1. The need for substantial capital and 2. The speed of development. In a biotech environment, with adequate capital and the right team, progress can be rapid. In academia, you are part of a larger system with broader priorities, which can slow things down. In our case, it became clear that while Tr1 cells could be developed within an academic setting, advancing our engineered Tr1 cells and making “off the shelf” products, required forming a company. This transition allowed us to leverage the capital, speed, and focused resources necessary to advance our work on Tr1 cells and bring these life-saving therapies to the clinic.

8. Briefly, how does the Tr1X platform work? How is this platform differentiated from peers isolating FOXP3+ Tregs for therapeutic intent (e.g. in RA, MS, transplants)? [Can speak to unmet need/efficacy, scalability/cost, feasibility etc.]

In parallel with the biological characterization of Tr1 cells (1997), our team worked extensively with FOXP3+ Tregs (2001). In fact, we were among the first to describe human FOXP3+ Tregs. However, over the years, we found that Tr1 cells offer broader and more flexible modes of action compared to FOXP3+ Tregs. Tr1 cells suppress effector T cells mainly through IL-10, a pleiotropic cytokine that not only drives their differentiation but also inhibits inflammation, downregulates antigen-presenting cells, and creates a tolerogenic microenvironment. This broad action suggests that Tr1 cells could potentially reset the immune system, offering a curative approach rather than just suppression. Moreover, Tr1 cells are induced in the periphery, making them easier to generate through genetic engineering.

At its core, the Tr1X platform is quite simple. It leverages the natural properties of CD4+ T cells, reprogramming them into Tr1-like cells (TRX cells) through genetic engineering. This process begins with the isolation of normal CD4+ T cells from peripheral blood, which are then transduced with a lentiviral vector encoding two critical components: human IL-10 and a truncated NGF receptor (tNGFR). The IL-10 cytokine is essential for the differentiation and function of Tr1 cells, while the tNGFR serves a dual purpose, allowing for the selection and purification of successfully engineered cells during the manufacturing process. It also enables the tracking of these cells in patients’ blood post-infusion using monoclonal antibodies specific to the NGF receptor (CD271). Through a proprietary reprogramming process, the CD4+ T cells are then transformed into Tr1-like cells, mimicking the functions of natural Tr1 cells by producing IL-10 and exerting regulatory functions. The initial product from this platform, TRX103, targets disease prevention but also active disease treatment, particularly conditions related to allogeneic stem cell transplantation and Inflammatory Bowel Disease. These TRX103 cells are very pure regulatory T cells designed to modulate immune responses and prevent graft-versus-host disease (GVHD) and other immune-mediated complications. We also have a second, more advanced platform where the TRX cells are further engineered to express a chimeric antigen receptor (CAR), enabling them to target specific antigens associated with B- and T-cell mediated autoimmune diseases. For example, our second product, TRX319, is designed to target B cells in autoimmune diseases where B cell activity is a significant component of the pathology, such as certain forms of lupus and other B cell-mediated autoimmune conditions.

[On additional indications for CARTr1 platform]

As you know, there's incredible excitement surrounding the use of CAR-T therapies, particularly targeting CD19, for conditions like myasthenia gravis and lupus. I believe our product TRX319 has a distinct advantage because it not only targets B cells but also modulates T cell responses and reduces inflammation. This dual action could give us an edge in terms of mode of action and safety. One of the significant challenges with current CAR-T therapies is the need for extensive lymphodepletion, typically achieved with high doses of cyclophosphamide and fludarabine. For those of us in the field of stem cell transplantation, we know these drugs are far from benign and can be tough on patients. If our product can achieve effective results with less or no lymphodepletion, it would be a major advantage. Having said that, the field of CD19-targeted CAR-T therapies has become quite crowded, particularly for an indication like lupus. Thus, even though we believe our product might be superior in lupus, we are also actively considering other autoimmune diseases for our initial indications. Our goal is to identify the conditions where our therapy can make the most significant impact while navigating the competitive landscape effectively. The final indication selection will be made soon as we continue to scale up the process and produce the clinical-grade vector.

[On the biggest challenges Tr1X needs to solve going forward]

Our overarching goal is to show that Tr1 cells can offer a comprehensive solution for autoimmune diseases and transplant-related conditions, paving the way for broader applications and ultimately transforming patient outcomes. The primary challenge will be to prove the efficacy of engineered Tr1 cells. While early trials with FOXP3+ Tregs have shown safety, their efficacy to date has been limited. We need to demonstrate that Tr1X’s engineered Tr1 cells can not only provide symptomatic relief but also potentially cure underlying conditions by resetting the immune system and thus achieve long term remissions.

Subscribe now

Share

The tale of radiotherapy begins in 1895. While studying cathode tubes, German physicist Wilhelm Conrad Röntgen observed the power of X-rays to visualize materials of different densities. Starting with his wife’s hand, Rontgen and colleagues soon exploited radiation to study human anatomy—sowing the seeds of “diagnostic medicine.” 

The initial observations that radiation could be used therapeutically soon followed: in 1896, Emil Grubbe used x-rays to treat breast cancers and lymphoma. Marie Curie, Pierre Curie, and Henri Bequerel also observed that tumor forming cells were quickly destroyed when exposed to Radium-226. A century of advances in nuclear medicine have yielded powerful therapeutic modalities, like external beam radiation therapy (EBRT) and brachytherapy, which are pillars of modern cancer treatment. 

The first “Roentgenogram”, Curie’s treatment of cancer cells with radium, or modern EBRT and brachytherapy are all conceptually similar: expose healthy and diseased tissue alike to radiation. In the 1940s Saul Hertz had a different idea: biochemically target radiation to a particular site in the body. Hertz’s radioactive iodine (I-131), which is selectively taken up by the thyroid tissue, is still used for diagnosis and treatment of thyroid lesions. Thus targeted radionuclide therapies (TRT)—atomic isotopes that emit beta or alpha particles—have in fact been used for several decades. 

II. On the road to success 

While there have been historical successes in medical applications of radionuclides, there have also been massive setbacks—particularly with respect to targeted radiotherapeutics. The commercial failures of Zevalin (yttrium-90-labeled anti-CD20 mAb) and Bexxar (Iodine-131-labeled anti-CD20 mAb) deterred many seeking to develop such therapies. Both of these drugs were highly anticipated for the treatment of refractory or relapsed non-Hodgkin lymphoma using a validated cancer target, CD20. 

Zevalin, developed by IDEC Pharmaceuticals (now part of Biogen), was approved by the FDA in 2002 and EMA in 2004. Commercial expectations were high: Wall Street analysts expected sales of $100 million in the first full year of sales with peak sales reaching $500 million. Zevalin’s peak sales of $30 million was a setback for Biogen/IDEC and the entire radiopharmaceutical space. 

Bexxar, approved by the FDA in 2003, suffered a similar fate. At the time of product launch, Bexxar boasted compelling clinical data: 63% of patients experienced tumor shrinkage with benefits lasting for 2 years and 29% of patients experienced complete response. Similarly, analysts again expected sales to reach $350 million by 2005. Those expectations never materialized, and despite strong clinical data Bexxar was discontinued in 2014. 

²²³Ra-dichloride (later marketed as Xofigo) was the first alpha-emitting therapy (see section IV) to enter the market when it was approved by the FDA in 2013 for the treatment of bone metastases in mCRPC. Radium-223 mimics calcium and selectively targets bone due to natural tropism, with high specificity for areas of bone metastases. It was acquired by Bayer in late 2013 with high hopes and analyst estimates that annual sales could peak at around $1.5 billion by 2020. Although Xofigo was more successful than Zevalin and Bexxar with sales reaching $300-400M, it was still well short of expectations.

III. A turning point

Previous commercial failures handicapped investment in the field of targeted radioligands for the better part of a decade. Barriers to manufacturing and commercialization were thought to be insurmountable (discussed in Section V).

In 2018 Novartis made a bet that they could deliver on the promise of TRT: they acquired Endocyte to further the development of Lu-177-PSMA-617 (now called Pluvicto). Their successful execution on clinical trials and commercial development of both Pluvicto and another radionuclide therapy for neuroendocrine tumors (Lutathera; Lu-177-DOTATATE), has turned radiopharmaceuticals into one of the hottest areas in biotech. There are now dozens of venture-backed biotechs developing radioligand therapies (RLTs) (Table 1). 

In subsequent sections, we delve into technical considerations for next-gen radioligand therapies (RLTs): isotope selection, half-life and targeting moiety. Using Pluvicto and Lutathera as case studies, we highlight the characteristics that enabled clinical and commercial success. Lastly, we touch on key obstacles for the radiopharmaceutical field, and how earlier stage biotechs are rising to the challenge. 

IV. Finding alpha…or beta

The vast majority of new ‘targeted’ medication seeks to manipulate and disrupt specific biologic pathways driving oncogenesis. While targeted therapies can result in remarkable tumor regressions, often with validated biomarkers to guide patient selection, a central problem has been the development of therapeutic resistance. Resistance mechanisms are multifaceted and while advances in chemistry can prophylactically target some emergent mutations, and combination regimens can reduce the probability of drug resistant clones, these strategies have limitations. 

Radionuclide based therapeutics take a different approach. Unlike tumor specific therapeutics, radiation is cellularly agnostic. It is highly efficient at destroying DNA, regardless of cell type. The goal of the new class radioligand therapies is to find ways to harness this nuclear weapon: limit its cytotoxicity on healthy tissue and unleash it on cancerous cells. Targeted radionuclide therapies are typically made up of a targeting ligand (e.g. antibody, peptide, or small molecule) conjugated to a chelator that holds a radiation emitting isotope that damages DNA following cellular internalization.

There are 2 current major classes of radionuclide therapies: beta emitters and alpha emitters. Beta emissions are the release of excess electrons from a radioactive isotope (e.g. Lu-177 in Lutathera). These emitted electrons typically travel 1-5mm, causing single-stranded breaks in DNA. In contrast, alpha-emitters release a larger helium atom that travels 50-100 µm in tissue and deliver 1500x more energy deposited per path length traveled vs beta-emitters and  chemotherapy. Alpha emissions readily cause double-stranded DNA breaks, which are more deadly to cancer cells than single-stranded breaks. Many believe that with the proper targeting mechanism, alpha-emitting radiotherapies (ARTs) can more readily destroy cancer cells while sparing adjacent, healthy tissue. 

Alpha emitters and their properties: Currently, there are a limited number of alpha-emitting radionuclides being investigated. The three major alpha emitters under investigation are Astatine-211, Lead-212, and Actinium-225. Xofigo (RaCl₂-223; Bayer) was the first alpha-emitting radionuclide drug to be approved by the FDA due to strong clinical data in treating late stage prostate cancer, but ran into commercial issues (in part due to difficulty manufacturing the active radioisotope). Recent interest in Astatine-211, Lead-212, and Actinium-225 is partly driven by isotope availability, in addition to stability properties outlined below.

• Astatine-211 has a half-life of 7.2 hours. Current production methods of Astatine-211 allow for reasonable yields and high purity using an alpha-particle beam to bombard bismuth. However, despite the reliability of its production methods and the widespread availability of bismuth, there are currently not enough accelerators capable of creating Astatine-211 in quantities large enough for clinical use.   

• Lead-212 (Pb-212) has a half-life of 10.64 hours. It is produced from its parent isotope of radium-224. There are 2 main challenges associated with the use of Pb-212. First, generators producing Pb-212 must be replaced within 1-2 weeks due to the short half-life of radium-224 (~3.6 days). Second, because of its short half life, Pb-212 faces distribution challenges since the isotope must be distributed soon after its production. Currently, several new biotechnology companies, such as ARTBio are developing new approaches for creating Pb-212 in more sustainable, scalable ways. Some of these new production methods use thorium-228, a radioactive isotope that is present with good availability and a half of 1.92 years. Even so, as the production methods for Pb-212 continue to evolve, improved distribution methods will be needed to facilitate wide-scale clinical use. 

• Actinium-225 (Ac-225) has one of the longest half-lives at 9.92 days. The current supply of Ac-225 used in clinical trials have come from the US Department of Energy’s Oak Ridge National Laboratory (ORNL) and the Institute of Transuranium Elements in Karlsburg, Germany. This is because Ac-225 can only be extracted by the natural decay of thorium-229 obtained from waste stockpiles containing uranium-233 (from past reactions for nuclear energy or nuclear weapons. There are several new methods under production for creating Ac-225 that show some promise, but none that have been used at scale.    

ART excitement aside, we believe there is a role for both beta and alpha emitters in the market. Alpha emitters will shine in indications where the tumor target is confined to a more limited area with a more obvious target due to a greater degree of cytotoxicity and limited range of emission. Lutathera and Pluvicto (discussed in section VI) both employ the beta emitter Lu-177 as their therapeutic radioligand of choice. Beta emitters are better equipped to tackle disease with greater target site heterogeneity or lower target expression where you can take advantage of its greater range to damage and effect a larger degree of tumor tissue. As of September 2021, of the 161 ongoing registered radionuclide therapy clinical trials, ~80% focused on beta-emitters while the remaining 20% were focused on alpha-emitters [Ostuni, E., & Taylor, M. R. G. (2023). Commercial and business aspects of alpha radioligand therapeutics]. We expect this dynamic to change as more companies embrace and develop alpha based radioligand therapies.

V. Nuts and bolts of radioligand therapies 

Radioligand therapies are difficult to engineer and manufacture. As this modality is still emerging, the principles for optimizing potency while minimizing toxicity are continuously evolving. 

Radionuclide half-life 

The half life of a given radionuclide influences several considerations ranging from clinical dosing and toxicity to supply chain constraints. Theoretically, to reduce the off-target toxicity of TRT, the half-life of a radioactive isotope should match the half-life of its targeting ligand. This is so that as the targeting mechanism leaves circulation, the drug is less toxic and can be excreted with minimal side-effects on the healthy tissues like the kidney. Identifying isotopes or changing the targeting antibodies to achieve symmetry in half-lives will be a potential avenue to create safer, more-effective radioligand therapies. 

The half-life of the radioisotope also influences its commercialization and distribution strategy, a non-trivial design criteria whose importance has arisen from previous commercial failures. As the half-life of a radioisotope decreases, the necessity for production closer to the patient for distribution increases. Radioligands with shorter half-lives will require more distributed production facility footprints to ensure administration to patients. 

Pharmacokinetics and dosimetry

An attractive feature of radionuclide therapeutics is the ability to ‘see’ what you are treating and borrow established concepts from dosimetry studies in beam based radiation oncology. Dosimetry refers to the science by which radiation dose is determined by measurement and calculation. Imaging of drug uptake into tumor or normal tissues can be used to calculate pharmacokinetic distribution directly, versus other therapeutic modalities where tissue distribution is calculated based upon blood concentration and animal modeling. Radionuclide therapeutics typically have fast clearance to minimize systemic normal tissue toxicity and specifically in the kidney where the concentration of drug naturally is higher during excretion. Fast clearance rates allow clinicians to readily titrate dosing regimens with imaging to optimize dosing. This represents a major advantage versus other systemic therapies where the tissue distribution and tumor uptake can be variable from patient to patient and hard to adjust until dose limiting toxicities arise.

Theranostic Potential

Approved late stage clinical stage radioligand-based therapies have been used to target mature antigens (PSMA & SSTR) with well validate overexpression in metastatic prostate cancer and somatostatin receptor positive neuroendocrine tumors. Though the hunt for novel targets is underway, true validation of these new markers may need to occur in early human trials. This highlights an important advantage of radioligand therapy: the dual therapeutic and diagnostic (“theranostic”) potential. Because one is able to detect and localize levels of radiation, developers of radioligand therapies can dose the medication and observe its localization in real-time, calculating the radiation burden on both tumor and non-tumor tissues. This serves as a mechanism to quickly and more cheaply identify winning targets and indications, early in human testing. The quick switch between therapeutic and diagnostic phases also enables combined clinical adoption of the complementary TRT products, like Lutathera paired with Netspot, creating synergistic effect in their commercial sales and marketing strategies. The expanding availability of PET (Positron Emission Tomography) and SPECT (Single Photon Emission Computed Tomography) imaging has facilitated adoption of these products.

Dose Limiting Toxicities

The broader public fear of radiation has ironically resulted in radionuclide based therapies having clean safety profiles relative to other systemic therapies. Dosimetry literature from external beam radiation has been applied to motivate dosing regimens for radionuclide therapies but due to the more specific accumulation of radiation in tumor tissue with radioisotope conjugates, the toxicity in clinical practice has been lower than expected from calculations based upon external beam dosimetry. As a result, radionuclide therapeutics almost never reach dose limiting toxicity in clinical trials. Dosimetry studies specific for radionuclide conjugates may enable more aggressive dosing in the future, potentially resulting in improved efficacy. 

The clinically observed toxicities have commonly been in the kidney (off-target), where radionuclide particles may be reabsorbed and have higher concentration prior to excretion, and in the salivary gland (on-target) which expresses low levels of PSMA and may be targeted by PSMA directed therapies such as Pluvicto. Renal toxicity has a long latency period before presentation and is usually cumulative, chronic, and progressive. Minimizing renal exposure through chemical modifications such as cleavable linkers, excretion promoting moieties and modifying albumin binding are areas of research and development. For example, At AACR 2024, Bayer disclosed their PSMA targeting alpha particle radionuclide conjugate, actinium-225 (225Ac)-PSMA-Trillium, with a customized albumin-binding moiety designed to improve therapeutic efficacy and reduce side effects in normal organs, such as salivary glands.

One particular challenge with alpha particle radionuclides with multiple alpha-emitting ‘daughters’ in their decay chain. Longer half-life radionuclides including radium and actinium can prematurely release alpha particles, causing damage to healthy tissue when not retained at the tumor site.

Enhancing potency

Similar to antibody drug conjugates (ADCs) the potency of radionuclide conjugates is a function of tumor penetration and pharmacokinetics. Alpha particle conjugates in particular are highly toxic once internalized the therapeutic window for these therapies is dependent on the proportion of uptake in the tumor versus in normal tissue. As a result, the approach for enhancing potency is simply to dose higher without dose limiting toxicity.

Radionuclide conjugates can also take advantage of bystander effect killing, the concept that radiation emitted from the radioactive isotope often affects cells adjacent to the targeted cells. In cases where tumor specific antigens are expressed on only a subset of cancer cells within a tumor, the bystander effect could allow non-expressing adjacent cells to be affected and die from local radionuclide molecules. In a more extreme scenario where there may not be cancer specific antigens but instead there may be tumor specific antigens expressed by cancer associated fibroblasts or other cell types nearby cancer cells, the bystander effect may enable tumor targeting using non-cancer associated antigens such as FAP.

VI. Pluvicto & Lutathera: a Novartis case study

Novartis’ Pluvicto has witnessed a remarkable surge in sales since its FDA approval in March 2022 for treating PSMA-positive metastatic castration-resistant prostate cancer (mCRPC). Though 2023 is only the first full calendar year of its commercialization, as a later-line, post-taxane therapy, it has scored 980 million USD in global revenue. The demand exploded, and according to company executives, the sales growth would have been even greater if not restricted by the supply challenges in 2023. To expand the supply capacity, Novartis has earned FDA approval for its Millburn supply site with two additional lines and further submitted for approval its Indianapolis site. The company has alleged that the supply is now “fully unconstrained” and expects the sales of Pluvicto to ride over 1 billion USD for 2024 ($980M for 2023). “What obviously unlocked the field was the wonderful clinical data coupled with the fantastic first year of sales of Pluvicto,” says Alex Pasteur, a biotech investor at F-Prime. 

Pluvicto has undeniably captured significant attention since 2022, igniting a heightened interest and investment among MNCs in the realm of radiopharmaceuticals. Yet, it was the landmark approval of Lutathera in 2018 that truly ushered in the era of RLTs. Approved for the treatment of somatostatin receptor (SSTR)-positive gastroenteropancreatic neuroendocrine tumors (GEP-NETs), Lutathera addresses a far less common type of tumor than does Pluvicto. Though targeting a smaller patient demographic, which naturally limits the market potential, Lutathera still demonstrated an impressive initial growth in sales. It soon brought in over 400 million USD revenue in 2019, the first full year of Lutathera’s commercialization, underscoring the unmet need in this condition. 

Five years after the approval in adults, Lutathera was approved for pediatric patients in April 2024, and is now advancing towards first-line therapy for GEP-NETs. In September 2023, Lutathera met primary and key secondary endpoints in the phase 3 NETTER-2 trial. In patients with Grade 2 and 3 GEP-NETs, the use of Lutathera in combination with long-acting octreotide has obtained significant improvements in progression-free survival (PFS) and objective response rate (ORR), compared to receiving high-dose long-acting octreotide alone. This positive readout makes Lutathera the first radioligand therapy to demonstrate clinically meaningful benefit as a first-line treatment. 

Pluvicto is similarly pushing into earlier-lines of treatment, with its Phase III PSMAfore trial. This Ph3 trial is designed for mCRPC patients who have received treatment with androgen receptor pathway inhibitor (ARPI) therapy, but not taxane-based chemotherapy. However, the most recent data from the PSMAfore trial, published in October 2023 provided a complex answer to this question of whether or not Pluvicto can push into the second line treatment market. Pluvicto met its primary endpoint of radiographic progression-free survival (rPFS) with a HR of 0.41, cutting the risk of radiographic progress by 51% compared to the treatment with simply a change in ARPI. It also demonstrated a more than doubled median rPFS to 12.0 months compared to the 5.6 months in the control arm.

Importantly, both Lutathera and Pluvicto have yet to show convincing overall survival (OS) benefits in randomized clinical trials. Mature OS data from the phase 3 NETTER-1 trial showed a numerically superior (48.0 vs 36.3 months) but not statistically significant (p = 0.30) improvement in OS. Potentially, this result could be due to a high rate (36%) of patient crossover in the control arm to radioligand therapy after progression. Similarly, the overall survival (OS) data readout of Pluvicto at the second interim analysis of PSMAfore was potentially confounded by an 84% crossover rate, producing an HR of 1.16 for Pluvicto (indicating increased mortality). This led Novartis to postpone FDA filing pending additional followup data from the trial. Recent more mature trial data may suggest an OS hazard ratio < 1, which will be presented at ASCO 2024. Large effect size improvements in PFS and response rate in conjunction with high rates of crossover have troubled other anti-cancer therapies including CAR-T products like Abecma. While the activity of such agents are promising (as measured by PFS and ORR), marginal OS readouts in crossover settings may limit progression into earlier lines of therapy. This is an issue the FDA acknowledges: with top officials agreeing that PFS and other surrogate endpoints may suffice until later trials confirm OS benefits. Recently, 12 members of an FDA advisory committee voted unanimously to support the use of minimal residual disease (MRD) as a surrogate endpoint to enable accelerated approvals in multiple myeloma—suggesting that over the coming years, regulatory endpoint innovation may become a major theme in oncology.

Beyond SSTR and PSMA, additional targets including FAP-α, IGF-1R, NTSR1, HER2, hK2, CD33, MCR1, and GRPR1 are entering preclinical and clinical development. Novartis recently extended a deal with PeptiDream to develop novel macrocycle ligands for next-gen RLTs. Novartis is continuing to push the envelope in the radiopharmaceutical space: striking additional deals with 3B Pharma, Bicycle Therapeutics and iTheranostics to help develop new targeting ligands. 

VII. Recent Investment and M&A in RLTs

The recent surge in M&A and investment activity in radioligand therapies has been driven by positive commercial and clinical readouts, and intense interest in alpha-emitting isotopes.

The potential of alpha emitters to deliver a more concentrated dose of radiation to the targeted tumors while minimizing damage to the surrounding healthy tissue, has initiated a wave of new drug development. Notably,  Fusion Pharmaceuticals (acquired by AstraZeneca), Point Biopharma and RayzeBio (acquired by Bristol Myers Squibb), have all invested R&D efforts in developing alpha-emitting TRT pipelines. Ac-225 is perhaps the most advanced of the emerging alpha-emitting radioisotope assets: it has high linear energy transfer (LET), allowing for a strong but controlled delivery of radiation localized to the tumor site. It also has a half-life slightly longer than Lu-177, which makes it a suitable choice for transport and delivery to hospitals from the centralized production site. However, Ac-225 is one of the rarest radioisotopes in the world. Its annual global production is currently only 63 GBq (1.7 Ci), an amount that could treat less than 1000 patients per year, which may limit its clinical development. 

Continued interest in antibody drug conjugates (ADCs)—a conceptually similar therapeutic concept—has also likely played a role. Dealmaking trends highlight the value of in house manufacturing and established commercial scale supply agreements. 

VIII. Next-gen radiopharmaceuticals 

Amidst investor and market excitement, it remains crucial not to overlook the challenges inherent in the upstream supply chain of RLTs. 

The production, distribution, and waste disposal of radionuclides demand specialized infrastructure, as well as the expertise of professionally trained staff, operating under rigorous and refined workflows. To the pharma players in the radiopharmaceutical industry, setting up and sustaining an efficient radionuclide production facility not only requires substantial upfront investment but also a deep understanding of and compliance with regulatory frameworks. Swift and safe delivery of radionuclide therapies to the mass patient population across the country and even the world necessitates well-developed models and seamless cooperation of the transport and storage systems. These systems and manufacturing facilities can cost hundreds of millions of dollars and several years to build. Last but not least, the scarce availability of the source materials, along with the nascent stage of development for alternative production techniques, have substantially hindered both research and clinical applications of certain radioisotopes, mostly alpha-emitters like Ac-225. 

Many of the obstacles that limited the commercial success of Zevalin and Bexxar still challenge the field today:

Commercial penetration

The growth of the radiopharmaceutical industry is limited by the complexity and regulation of drug administration. The Nuclear Regulatory Commission (NRC) requires that providers distributing radioligand therapies have completed 700 hours of training and experience. These are typically radiation oncologists, who are the same individuals who administer other radioactive compounds and therapies (i.e., SBRT, EBRT, radioactive contrast, etc…).  Another important challenge hindering the clinical use of radioligand therapies is the division of labor across medical oncologists who typically prescribe systemic therapy, and radiation oncologists, who administer nuclear medicine. Currently, medical oncologists refer eligible patients to nuclear medicine to receive radioligand therapies, but are paid and reimbursed for delivering competitive therapies including chemotherapy and other systemic targeted therapies. To refer patients out for care by their nuclear medicine colleagues, oncologists stand to lose a source of revenue. These complexities in care coordination and competition led to <10% of eligible patients from receiving Bexxar and Zevalin. Novartis’ Pluvicto has soothed concerns around commercial penetration, becoming a blockbuster in 2023 and already reaching +47% YoY growth in Q1 2024. However, to truly unlock the full potential of radioligand therapies, regulation must be aligned to support the distribution of therapy and coordination between oncologists and nuclear medicine practitioners. 

Supply Chain  

Creating a sustainable supply of radionuclides for clinical use poses challenges. Currently, the projected demand for radionuclide therapy far exceeds the projected supply given current production methods. The Department of Energy’s (DOE) national laboratories remain the primary source of less commonly used or exotic radionuclides, produced from their large reactor and accelerator facilities. These facilities include the High Flux Isotope Reactor (HFIR) at ORNL, Brookhaven Linac Isotope Producer (BLIP) at BNL, the Isotope Production Facility at Los Alamos Nuclear Science Center (LANSCE) at Los Alamos National Laboratory (LANL), and the Advanced Test Reactor (ATR) at Idaho National Laboratory (INL).

These facilities were all built 50+ years ago, have upcoming retirement dates in the coming decades, and do not have plans for replacement. Research collaborations between university institutions have been one stopgap solution to ensure adequate supply of therapeutic radionuclides. For example, Fusion Pharmaceuticals executed a 15-year lease agreement with Hamilton, Ontario-based McMaster University to build a 27,000 square foot current Good Manufacturing Practice (GMP) compliant radiopharmaceutical manufacturing facility. 

Two major problems also exist with the distribution of TRT. First, distance from the clinical care center is limited by the half-life of a given radionuclide. For isotopes, like actinium-225, with longer half lives, it is less of a concern. However, an isotope like Pb-212 (half-life of 10 hours), would need to be created a la carte near the site of distribution. Second, as was seen with Novartis’ Pluvicto, supply chain resiliency is imperative to maintain a stable supply of drug for patients.  In early 2023, Novartis paused all new patient starts and delayed doses to patients for weeks because of supply constraints. In response to this, the FDA approved a new facility to ramp up production of Pluvicto. 

These factors have made it clear that sustainable radiopharmaceutical businesses will need to find creative ways to ensure both manufacturing resiliency and supply of source isotopes in the coming decades. 

Limited Optionality and Target Risk 

While the radiopharmaceutical industry has entered into a period of resurgence, there are both cultural and structural factors that limit explosive clinical trial growth as observed in other maturing modalities. There are a limited number of heavily studied radioisotopes to build products from that clinicians understand and have experience with. Given the limitations with manufacturing and procurement of GMP radioisotopes, switching isotopes is difficult and in a sense a company may be ‘locked in’ to a payload in a market where the optimal isotopes have not yet been comprehensively determined. Identifying ways to differentiate a therapy from other competitors in the same indication may thus be dependent on innovations in linker/chelator technology and the target/targeting mechanism. These clinical development and binder decisions are critical. Understanding that few sources of differentiation exist in TRT, we view the field as “winner takes all” in a specific indication. This also poses large commercialization risk within a given indication. 

IX. Conclusion

TRT has the potential to revolutionize radiation oncology, providing microscale and specific delivery of radiation where external beam delivery has had limitations. While early clinical data are exciting and a wave of biopharma investment has flushed the field with resources, clinicians and scientists alike have a lot to learn from upcoming clinical trial readouts. Radionuclide therapeutics, due to their distinct mechanism of action, also hold significant promise as part of combination therapies with other targeted treatments.

We see four key levers of differentiation within radioligand therapeutic companies:

1. Choice of radioisotope: Alpha-emitters provide increased cytotoxicity at shorter ranges while beta-emitters provide less cytotoxic potential across longer distances. Due to intrinsic supply chain and production constraints, identifying a consistent source of isotope whose availability is minimally affected by geopolitical or manufacturing issues can be an important differentiator. While potency differences across radioisotopes are still being worked out in clinical trials, the optimal isotope for a given antigen or indication may need to be empirically determined. Consideration around half-life will also greatly affect commercialization and distribution efforts. Longer half-lives afford more supply chain flexibility but alongside costs in terms of potential toxicity. 

2. Targeting mechanism: The targeting mechanism of a TRT plays an important role in its target specificity and its off-target cytotoxicity profile. Different mechanisms have been used to date including small molecules (i.e. Lutathera), peptides (i.e. Pluvicto), and monoclonal antibodies (i.e. Bexxar, Zevalin). New TRT are being researched using Fabs and nanobodies for targeting. Each of these different compounds exhibit different selectivities, binding characteristics, and half-lives that will ultimately affect the success and efficacy of their given TRT platform. Unlike ADCs or other antibody conjugate based therapeutics, long half life is not a critical design criteria, and should match the choice of isotope. In contrast, tumor specific localization can be a more important design criteria and may be better serviced by peptide, Fab/nanobody, small-molecule, and other target binding moieties with improved tumor penetration.
   
   

3. Engineering out toxicity: Binding based delivery of toxic compounds such as in ADCs or in radiopharmaceuticals are limited by a narrow therapeutic window. Engineering improvements including tumor specific cleavable linkers, excretion promoting moieties, albumin binding moieties that can reduce accumulation and toxicity in normal tissues will enable higher dosing and increased tumor clearance. Platform technologies that can address this engineering challenge can be broadly applicable to different antigens and therapeutic indications.

4. Production and Distribution Capabilities: Seeing the failures of Bexxar and Zevalin and most recently with the production and distribution issues plaguing Novartis, it will be important for future TRT companies to harmonize their production and distribution capabilities to create a resilient supply chain that can provide all patients access to medication. For example, ARTBio is developing benchtop format Pb-212 generators the size of a large thermos that provide flexibility to the production of their radioligand and the ability for onsite drug elution. This technology, termed AlphaDirect, can be operated in conventional radiopharma GMP facilities and uses an accessible source isotope with a use-life of months. Creative approaches like these will facilitate clinical adoption of alpha-emitter therapies. 

“When I started in the 1970s, I was naïve enough to think that if I wrote papers people would use them, but that didn’t happen…if they were going to lead to therapies for patients you have to form companies,” says Professor Bob Langer.

Yet biotech company formation is a risky proposition. Fledgling and mature companies alike, need skilled shepherds to provide expertise, connections and capital. “Some of the most extraordinary scientists in my lab in the last few years have wanted to take their discovery and impact human health. They realized that by working with the venture community, they could tackle major problems and have the resources to do so,” describes Professor Stuart Schreiber.

Who are these shepherds of scientific discovery, and what skills do they bring to the table? Many trainees now seek to fuse science, medicine and finance as investors. “One way to succeed [in investing] is to be good in a couple different areas and find the intersection of these strengths. In other words, be one the few that knows how several variables are moving and uniquely position yourself to find the intersection,” says Adam Koppel of Bain Capital Life Sciences.

One thing is clear: biotech investing requires hard work, and a high tolerance for risk. “Biotech is an industry of incredibly high risk…It's not easy, and there are less stressful ways to make money,” says Arjun Goyal of Vida Ventures. Often, successful investors find gold where others see only a pile of rubble: “When you go to a conference, you’ll often see two biotech companies, one on the left, with investors flooding around it, and one on the right, totally neglected. Go right. That is where you find something that might be irrationally unappreciated,” describes Rajeev Shah of RA Capital. On some level, pattern recognition and gut instinct are essential: “there's definitely an element of this business based on intuition and gut instincts. You have to learn to trust that…intuition and judgment is what separates the highest quality investors from the rest of the pack,” states Simeon George of SROne. 

How does one develop this instinct as an investor or company creator? When considering a career path, it helps to hear first-hand from those in the trenches—folks actively learning how to build and identify successful early-stage biotechs, or back public companies poised to change the way medicine is practiced.

To this end, Biomarker interviewed 24 rising stars in biotech investing and creation in 2024. Those with enough experience to provide sound counsel, yet early enough in their careers to render any advice actionable. We start with how these folks, many coming from an academic background, first got involved in investing: “I’ve always found investing to be an exciting career path – it’s analytical, involves constantly learning, and, over the long run, is extremely meritocratic…the fact that venture perfectly marries [science and finance], drew me in,” describes Alim Ladha of MPM. Others came to investing after first working at a company: “I worked at a biotech before grad school and loved my experience. I knew I wanted to dedicate my career to developing novel therapies to treat patients with devastating disease after grad school,” says Linda Vo of Third Rock Ventures. 

We discuss what it was like to first close a deal, and lessons learned along the way. “Venture is definitely a career where the best way to learn is by doing. Sprinting on a fast-paced deal facilitated a huge amount of learnings in a very short timeframe,” says Harry Won of OUP. “The biggest lesson I learned in my first deal was how important it is to quickly establish a solid investment thesis as your North Star. You then need to be disciplined about triaging new information in the context of this thesis during diligence,” asserts Amanda Chen of Vertex Ventures HC. Others, like Kevin Li of Frazier Life Sciences, speak to starting their public investing careers in a bear market: “Macro is an important short-term consideration when considering investments in both public and private companies. However, this experience illustrated the necessity of maintaining a long-term view of the fundamentals, especially in highly dynamic market conditions.”

In 2024, what gets these rising stars excited about an investment or creation opportunity? Some walk us through their mental model: are the right team members and investors at the table to maximize success? Will the [asset] truly make a difference to patients?” describes Aniqa Tasnim of 5AM Ventures. Others boil it down even further: “Just do good work and don’t speak in circles! Combining these traits with an exciting translational biology hypothesis, which can improve upon patient need, gets me really excited,” says Artie Arumov of Qiming. Others are somewhat circumspect about what motivates them initially: “I don’t think it’s always possible…to boil down why I start to gain conviction. I’ve become a bigger believer in ‘the prepared mind’ – that is to say the more you understand and think about an emerging modality or interesting piece of biology the more likely you’ll be able to quickly and appropriately become excited,” says James Buxton of NEA.  

Lastly, we touch on advice for aspiring venture investors and creators. How does one break into the exclusive (and perhaps intimidating) world of biotech investing? Danjuma Quarless from Abbvie Ventures speaks to the relationship-based nature of the industry: “each person wishing to join venture must intentionally build strong relationships, which takes time. I’d recommend attending as many ecosystem and investor events as possible and ensure that you understand the market and current state of investing.” Others emphasize the importance of “testing out” the job before you buy: “VC fellowships can be a good entry point into venture if you can spare the time, so be on the lookout for those opportunities,” urges Nil Gural of Polaris. Noelle Hutchins of Omega says to use your strengths to your advantage: “I would recommend that you stay true to your authentic self, as these characteristics can be used to your advantage…the key to this job is that you must stay quick on your feet, organized, and always on the hunt.  Bring the best catch back to the pack, don’t bring sticks and bones.”

Developing drugs is one of the most difficult endeavors we undertake as a species, and there are many requisite skillsets for success. We hope that this article serves as a resource for those interested in investing or creation—disciplines necessary to support our ecosystem and get new treatments to patients.  

The article below includes selected responses from the 24 rising stars. An appendix containing all responses is attached at the end of the piece

Share

What is one of your favorite science papers you have read in the past year? What excites you about this work, or the area more broadly?  

David Baker put out a paper on computational design of passively permeable macrocyclic peptides that I found interesting (link). Macrocycles are a bit of a “tweener” between small molecules and large biomolecules. In certain cases, you can get macrocycles that engage a target akin to a biologic but are also sufficiently small molecule-like to enable oral delivery (e.g., MK-0616). Peptide chemists can only churn through so much chemical space, so accelerating that process with a computational approach could be super interesting, and might practically help drug developers generate more of these types of therapies down the road. - Alex Loftis, Vida 

Building upon elegant work out of the Sanger Institute a couple of years ago, Wang and colleagues elegantly showcased translational utility for the emerging concept of somatic mosaicism – clonal remodeling of cells via postzygotic mutations – as a driver of pathology in NAFLD. The researchers introduced somatic mutations into mouse livers and proceeded to study the clonal competition and downstream fitness effects these clones conferred, observing that a protective phenotype was attributed in certain scenarios of increased genetic somatic mutation carrying clones. We’ve classically thought of somatic mutations as genetic drivers in cancer but have yet to thoroughly look at the opportunity outside of oncology, and thus this work suggests there is a new opportunity ahead for elucidating the genetic predisposition of non-cancer diseases (I&I, metabolic, neurodegenerative), potentially offering a new frontier of genetic-led precision medicine.   - Artie Arumov, Qiming 

Li et al., 2023 is a notable example of the intersection of next-generation biology with cutting-edge chemistry. My background is in computational biology, but the fundamental basis of drug discovery is chemistry by nature, so the transition to venture has help me appreciate this spectrum. Examples like this highlight instances where both fields contribute to accessing the non-druggable space to positively impact patients. - Danjuma Quarless, Abbvie Ventures

I like outliers. So I get excited when I read something that is very different from anything I’ve seen in the past. A recent example is this preprint from Andrew Fire’s group where they discover RNA “Obelisks”. These obelisks are circular RNAs ~1kb in size, predicted to form rod-like secondary structures, and even have ORFs coding for a novel protein superfamily they term “Oblins”. From a biotech perspective a few things come to mind of potential interest: (1) the mechanism of circularization for such a large circRNA molecule (could it compete with other RNA circularization methods?), (2) the stability of the molecule, and (3) translation efficiency. The science here is obviously very early (too early for a company), but nonetheless gives an example of the types of science I like to track. - Patrick Lundgren, Hummingbird VC 

“Glioblastoma remodeling of human neural circuits decreases survival” Nature 2023. This is beautiful work at the intersection of neuroscience and tumor biology. Here, Michelle Monje and Shawn Hervey-Jumper explore the role of functional connectivity between glioma cells and neurons and how these connections influence cognition and drive disease progression. They go on to show that disrupting communication between neurons and glioma cells inhibits proliferative and migratory potential of GBM, leading to improved survival. One of my take-aways is a call to broaden our aperture to include non-cell-autonomous aspects of tumor biology to think about ways of deliberately identifying and targeting tumor-parenchymal interactions in high-grade gliomas and beyond. - Travis Hughes, Digitalis 

One of the papers that took me down many rabbit holes in the past year was “Emergent autonomous scientific research capabilities of large language models” by Boiko et al, which was also recently published in Nature. Currently, lab automation enables scientists to regain time that can be redirected toward higher risk/reward experiments that do not require industrialization (exploration), in addition to enhancing the reliability and replicability of workflows that are repeated often (exploitation). This paper, FutureHouse’s mission statement and several other papers like this one, highlight how an AI copilot can enhance scientists’ productivity even further by shortening the experimental cycle. It aids in the design of experiments, accelerates execution of experiments and semi-autonomously analyzes results to propose improvements for the subsequent cycle. - Pablo Lubroth, Hummingbird VC

Share

How did you get involved in venture? What initial misconceptions did you have about biotech venture investing or creation? 

My journey to venture began in college when I enrolled in a biomedical engineering intro course at University of Rochester. With a curriculum focused on experiential learning and projects that frequently interfaced with the medical center, I was immediately intrigued by the potential to have a transformative impact in healthcare. A standout memory was from a final project in Biosystems & Circuits, in which we designed and built a communication platform for patients with Locked-in Syndrome, a rare disorder that causes total body paralysis except for eye movement. With this excitement, I did a speedrun toward any opportunity that would support my pursuit of a career as a tenured professor, which was (at the time) my end-all be-all. While working on my PhD thesis at MIT, located in the heart of the Kendall Square life science innovation cluster, I started to understand the diversity of opportunities within biotech/biopharma that stretch beyond academia. I tried on different hats, including in venture creation (Flagship Pioneering), healthcare investing (RA Capital), biopharma (Novartis), and boutique consulting (Clarion). After graduating, I joined Satellite Bio, a start-up spun out of my thesis lab. As one of the first employees, I focused primarily on operational excellence for our R&D and TechOps teams, but felt disconnected from strategic discussions that helped set the broader company timelines and milestones. I leveraged my network for warm intros to new potential roles to help fill this knowledge gap. I ultimately became most excited about a venture capital fund called Vertex Ventures HC (VVHC), and was fortunate to join the investment team in September 2022. - Amanda Chen, Vertex Ventures HC

After starting my career as a research scientist, my contributions over time earned me opportunities to join leadership and governance sessions at AbbVie. These were my first experiences with our BD and strategy groups, which led me to join a 2-year development program. AbbVie Ventures was one of the four rotations I completed, and I found the work incredibly engaging and exciting- it didn’t feel like work. What drew me in were 1) the ability to engage the entrepreneurial ecosystem at large, which is vibrant and exciting, and 2) the opportunity to review and have exposure to many scientific disciplines and technologies. An early misconception I had was that venture investing and company creation were solely about science and research. However, I quickly learned that relationships and the quality of a leadership team are broadly considered most important. - Danjuma Quarrless, AbbVie Ventures 

When I was in my second year of medical school, the treatment paradigm for hepatitis C completely changed. It suddenly went from a largely incurable disease to a highly treatable infection with a 96% cure rate after only three months of taking a benign pill. I explored how the standard of care changed so quickly and discovered the entrepreneurs, scientists, and investors who helped make that change possible, including researchers at the University of Alabama. What surprised me was that transformative innovations can happen outside of the universities with the highest research dollars. According to the National Science Foundation database the University of Alabama ranks 143 in research spending in recent years. Innovation can be found in many places, and it’s important to maintain academic relationships to come across these interesting opportunities. - Jason Wang, Frazier Life Sciences 

I joined venture from operating roles at both large companies (Davita) and startups (Synthego). Venture initially drew me in with it being one of the few places a background in both kidney care and gene editing could possibly be useful! Initially I had the laudable but naive perspective that simply selecting strong companies through diligence made for a good investment portfolio. Particularly in venture, so much more goes into the success of a fund - the access to investments you may have, how you operate on boards, timing of your investments, and more. The success of the investment really only begins with making the investment. - Shoman Kasbekar, Foresite Capital

I joined RA as an associate on TechAtlas (our internal research and diligence team who serve as subject matter experts and work closely with our investment team evaluating opportunities ranging from newco ideas to commercial-stage public companies) because I wanted to be exposed to everything I might want to do in biotech. Working in TechAtlas is like working at a hedge fund, a venture fund, and a consulting firm (where your only clients are RA’s portfolio companies) simultaneously.  Of all the cool things I got to do within TechAtlas, some of my favorites were helping our newcos make strategic decisions and diligencing early-stage companies. I love the challenge of spotting something awesome before anyone else sees its potential. I love the creativity needed to find the perfect application for a new technology, the rigor needed to evaluate new science, the clarity needed to shape an idea into a story that can inspire others. I even love the pressure of working on early-stage investments. I think there should be a certain level of anxiety that comes with the responsibility to help make big-impact decisions like selecting indications and targets to pursue, designing make-or-break experiments, and hiring the people who’ll drive the company forward. But sharing that pressure with a team, all of whom are committed to realizing the same vision, is such a privilege. - Rebecca Silberman, RA Capital 

What was the first deal you worked on that resulted in an investment? What are the biggest lessons you learned from this experience? 

My first deal was Dren Bio’s Series A, where I had the opportunity to partner with CEO Nenad Tomasevic and team. I was excited about the lead asset, the CEO’s past work, and the possible upside on their platform. The company has since exceeded expectations in every axis I could imagine. I think this comes from Nenad and team’s absolute clarity on what needs to get done, which results in the speed and capital efficiency that the company has enjoyed thus far. It has become a trait I look for in founders. - David Yang, Lux Capital

BioAge Labs was the first deal I worked on that resulted in an investment. OUP participated in BioAge’s $170M Series D financing announced in February 2024, and I worked on this deal supporting Mitra Miri, a principal on our team, as well as Matt Cohen, one of OUP’s managing partners. BioAge is a clinical stage company developing an oral apelin receptor agonist in combination with incretin therapies for the treatment of obesity. Venture is definitely a career where the best way to learn is by doing, and sprinting on this fast-paced deal facilitated a huge amount of learnings in a very short timeframe. This includes the diligence, of course, but also all the dynamics that come into play after you build the conviction to get to a “yes” internally. A critical element, especially in fast-paced deals, is to run a rigorous process you can be proud of, and working on this deal with Mitra and Matt was an opportunity to learn that in action. - Harry Won, OUP

After almost 10 years in various venture internships and roles, I can definitively say that I’ve learned twice as much from of the deals that failed than the deals that resulted in an investment. So, sharing some lessons from the so-called “failures”: (1) Always replicate key experiments in an independent lab, this is never money or time wasted. (2) You will spend tons of hours working on ideas and diligence with founders, only to have them turn down your term sheet and go in another direction. This is not a loss. The fraction of time spent during ideation and diligence pales in comparison to the hours that would be required from Seed to exit. You’ve spent some time ‘dating’ the founder to figure out that you’re not on the same page for ‘marriage’ and learning that is hugely valuable. (3) Just because a deal falls apart doesn’t mean you have to stop rooting for the science/team that you were excited about. Careers are long and people remember when you are in their corner, especially when you don’t have to be.   - Lauren Mifflin, Frazier Life Sciences 

The first deal I worked on that resulted in an investment was Crossbow Therapeutics; a company developing TCR mimetic antibodies against intracellular targets. At the time we met the company, we were already forming a hypothesis around opportunity areas in cell therapy at Polaris and Crossbow was a wonderful fit in terms of what we considered the next frontier in cell therapy. Meeting the stellar team only strengthened our conviction.  Crossbow is a company pursuing an ambitious idea, and fittingly has an amazing team behind it that is able to balance innovation with execution. We look forward to sharing some of the exciting developments later this year! - Nil Gural, Polaris 

The first deal I worked on that resulted in an investment was Boundless Bio. What drew is to the investment was strong biology coupled with an exceptional CEO. What I learned, particularly in early-stage venture investing, is that while you can't precisely forecast how the science will evolve post-investment, betting on the team pays off. Luckily, that bet paid dividends with Boundless Bio! - Sahil Chopra, Vertex Ventures HC 

For me, any biotech company that is bringing forward new technology or pipeline projects that will result in truly differentiated products for patients is exciting. Gaining conviction that the company and science is ready to do this with reasonable resources, both time and capital, is often the biggest hurdle in an investment. ‘Reasonable’ is obviously almost completely dependent on both a firm’s investment strategy and the company specific investment thesis.  To clarify – At MPM BioImpact, it’s absolutely not an issue if early-stage companies haven’t figured out their product development path – it’s often exciting to partner with companies to put this path together. - Alim Ladha, MPM 

What are some factors that get you excited about a company or company build? Is there a mental checklist or model that you construct during diligence?

For a therapeutics company (where 5AM spends most time), I get excited when I can articulate how a company’s technology or novel insight enables them to uniquely address a high unmet need area. While every opportunity is totally different, being able to answer the differentiation/”why now” questions unlocks some high-level “checklist” items for a platform or asset company: 1) Balanced biological vs. technical risk?, 2) Does the development plan create meaningful value for the next financing?, 3) Compelling exit path?, 4) Are the right team members and investors at the table to maximize success?, and 5) If the product is approved, does it make a difference to the lives of patients? - Aniqa Tasnim, 5AM Ventures 

The exciting factors are a technology's or application's raw potential, especially in novel therapeutic drug platforms. New company builds are challenging in the beginning because the team doesn't have the resources, corporate structure, or maturity of an advanced company, which means investors and board members must contribute heavily to their development in the beginning. However, a much higher degree of aspiration, optimism, and excitement exists as the company attempts to succeed on a grand scale. A red flag would be a founder or executive team that signals a diminished ability to rely on their investment syndicate or scientific advisory members for insights. Capital inefficient companies would be a massive red-flag in this market. - Danjuma Quarless, AbbVie Ventures 

We anchor to the exit (whether pharma M&A or going public) and what we think this company could be worth in success (for us, focusing on the lead program(s), not the platform). For therapeutics, this tracks well with magnitude of potential clinical impact, which is the source of my passion for this work, as it is for most biotech investors. A non-exhaustive list of considerations: 1) How validated is the target and the proposed MOA, and is the modality the best approach for a given indication (instead of having a promising technology and looking for a problem)?  2) How compelling is the preclinical data, how developed is the chemistry/PK/potency? 3) Does the clinical trial design make sense, is it possible to demonstrate PoC in a short time? 4) What is the competitive landscape, are there regulatory challenges or tailwinds? How easy is the drug to manufacture? 5) What are the value creating milestones this financing purchases, are they enough to get investors excited the next go around? Is there enough runway to get that raise done? These points are especially important in tough financing environments. 6) Last and most importantly, team is critical. Are there experienced drug developers around the table, whether at the helm or deeply involved as advisors? - Harry Won, OUP

I don’t think it’s always possible, nor fair to the companies, to boil down why I start to gain conviction in a particular company. I’ve become a bigger believer in ‘the prepared mind’ – that is to say the more you understand and think about an emerging modality or interesting piece of biology the more likely you’ll be able to quickly and appropriately become excited when the right opportunity presents itself. More recently the companies I’ve become excited about have tended to be tangentially related to ones that we’re very recently interacted with. Time will only tell is that’s a prepared mind or recency bias, but there are interesting subsections of biology which can helpful inform others. - James Buxton, NEA 

Every project is different - a compelling therapeutic seed build can start from a clinical stage asset or from a technology idea on paper. There is no fixed starting point or universal data package & diligence recipe. What is critical for me is to ‘see the drug opportunity’ that a platform or asset could uniquely unlock, supported by a compelling data rationale of ‘why it will work’. In therapeutic discovery we are always chasing the intersection of the right drug, for the right target, for the right patient, with the right clinical trial. - Maurizio Fazio, Atlas 

Things to get excited about:  Does the company have a technology/product that is differentiated? Will their product or drug be a gamechanger in a particular disease and/or target indication?  Is the overall science/ biology validated?  Does the company have a mgmt. team that can execute?  Do the timelines make sense, and what are the overall projected budgets and costs with the current fundraising?  And, of course, does the company have a viable exit path? Is there a growing investor sentiment, i.e. how hot is this deal?   Red flags:  Technical risks (foreseen toxicity, difficult to reproduce academic laboratory results), regulatory risks (unclear efficacy endpts), clinical developmental path is not well defined  - Noelle Hutchins, Omega Funds 

During diligence, I try to remember that making an investment is as much a decision of “when to” as it is “whether to.” I ask the usual questions on biological rationale, market opportunity, and valuation. But I also focus on the key milestones achieved by this raise and whether this is the right time to invest, or if it would be more prudent to revisit at the next raise, even if that would mean investing at a higher valuation. I map the company’s development milestones onto the upcoming catalysts and trends in their field to try to understand what headwinds/tailwinds exist outside the company’s control. I try to put each company’s approach into the context of the history of their field to understand what technical/scientific breakthrough unlocked their solution (and whether another breakthrough is on the horizon which will totally change the competitive landscape). When I find a company at the right stage of development for us to invest and poised to capitalize on an opportune moment in the evolution of their field, I feel like I’ve found something special. - Rebecca Silberman, RA Capital 

My focus is on therapeutics, and I ask myself the question "If this company were to succeed in developing this drug candidate into an approved product, why would a doctor prescribe it?" Asking this question early on in my diligence process helps me contextualize the investment opportunity and identify key questions I need to dig into. - Suan Tuang, TCG Crossover

Subscribe now

Using your mentors as examples, are there any traits or skills that you have tried to develop to become a better investor or creator? 

Balance is important to success in investing and company building. I continue to learn from Bruce Beutel about the importance of the day-to-day activities needed for success within a biotech company, and the constantly evolving scientific planning & scenario mapping happening, as one example, and certainly one that I leverage in both our company build efforts as well as in supporting portfolio companies as a board observer. The plan will inevitably change multiple times over (if it’s not, then you’ve got another problem!), based on experiments and emerging data, and being able to continue handing off the baton from one scenario to the next without losing momentum is critical. Anna French has taught me to not be afraid of thinking outside the box and in fact owning a personal brand of scientific creativity, but importantly never at a high level and always with an appreciation and understanding for the scientific nuance within the field of interest. There’s a lot of crowd sourcing for the same sets of drug targets and therapeutic approaches, yet often the best discoveries and inventions require a small subset of people to have taken the initial risk and pushed ahead. Handing off the creative baton while keeping the pace is key to success!   - Artie Arumov, Qiming 

I’ve learnt a huge amount from Ali Behbahani and Ed Mathers who have invested through multiple economic cycles. While they each have their individual investing styles, they’re both fantastic at understanding (and communicating) how time, risk and reward are intertwined when assessing a new opportunity. Specifically, I’ve tried to spend more time thinking about how risk can quickly compound when a company is addressing several unanswered questions – mechanism, delivery, patient population, clinical development plan for example. - James Buxton, NEA 

I have to give a shout out to my high school biology teacher and one of my longest standing mentors, Jim Johnston, who deserves full credit for putting me on the science path in the first place and continuing to support me ever since. Jim has taught me the value of being humble and curious, staying hungry, and having people and ideals in my life that I would gladly run through a brick wall for. I’ll also give a nod to Howard Marks, who I don’t know personally, but his suggestion to be mindful of others being greedy vs fearful has been continuously applicable. - Roman Camarda, Novo Holdings US 

If someone decides that VC is for them, any advice on finding a job in this environment? What are 1-2 things you would recommend doing to be proactive? 

Do a fellowship! You won’t know until you try it. Also remember there are other career paths that give you exposure to what you do as an associate in VC. I think it’s really important to talk to as many people as you can before deciding what you might pursue after grad school – use those alumni networks. - Alex Loftis, Vida 

Certain investing strategies will speak more to some people than others. If you are looking for a job, try to learn about firms’ investing strategies. See which strategies best match how you view the world. Alignment there will often make you successful in the hiring process and on the job. - Alim Ladha, MPM 

There is no substitute for doing the job. There are now several venture firms that offer summer internships that provide exposure to the day-to-day activities in this world to current students. Equally important, you can get a sense of whether you really “like it” which is important to long term career success in venture capital. - Jason Wang, Frazier Life Sciences 

Unlike banking and consulting, investment firms may hire irregularly and often on an as-needed basis. Finding the right role can require being in the right place at the right time. For those considering a career in investing, I encourage seeking conversations with people of different personal and professional backgrounds and at varying career stages. When I was starting out, this helped me identify and vet potential opportunities, as well as solicit career advice, which was invaluable to me as I was considering a future in clinical medicine vs. Investing. - Kevin Li, Frazier Life Sciences 

Take advantage of any opportunities to gain relevant experience beyond your scientific skills. If you’re still in grad school, join the biotech club, look for internships/fellowships or consult for a company. Also, don’t be shy about emailing and networking. Often times, opportunities arise without ever being advertised so having a strong network is helpful. - Linda Vo, Third Rock Ventures

Offer to introduce investors to companies, scientists, future founders, or generally great people that haven’t already met. From my perspective, this is a better way to get your foot in the door than sending your CV or even a warm introduction. We have also found and hired investors all over the world through their writing. - Pablo Lubroth, Hummingbird 

My two pieces of advice are knock on as many doors as you can find, and do your best to stay positive when invariably not all of them open. No one can tell you how long and winding that road will be. As far as I can tell, the only things you can control are how prepared you are when you do approach a door to knock on it, and how you feel after the process has gone positively/negatively/anything in between.  - Roman Camarda, Novo Holdings US 

Share

Advice to prospective or first-time entrepreneurs in 2024, as they bravely pitch to VCs in the new year? 

Take time to understand your audience (VCs) and communicate your pitch accordingly. It pays (pun intended?) to understand what governs the drug development industry. Many life science entrepreneurs come from academia, an ecosystem in which incentives will favor pursuit of novelty for the sake of knowledge advancement and scholarly discourse. While drug development certainly also rewards innovation, there are several other considerations for developing a new drug. Non-exhaustively: a new drug should serve an unmet need, be efficacious, be safe, be manufactured reproducibly, be produced/sold/reimbursed in a way that allows profit, address a patient population that is identifiable and understood, etc. There are risks associated with all the above, and the job of a VC is to understand the opportunities and risks associated with investing in a company, while also balancing their portfolio. Understanding this vantage point will help you tailor your pitch. - Amanda Chen, Vertex Ventures HC

The last couple of years have not been easy for entrepreneurs. Clearly articulating the “why now?”, your technology’s differentiation, and the bar for success in your field is important as ever. In the current environment, ensure that the financing plan efficiently drives to the next major value-creation milestone for your company. If a platform, clarity and discipline on defining the 1-2 key products/applications for the technology – that create value in themselves, and also de-risk the underlying technology – are particularly important right now. Finally, it’s never too early to build relationships with early-stage investors and gather feedback whenever possible.  - Aniqa Tasnim, 5AM Ventures 

It all comes down to effective storytelling – who are the cast of characters, what is the conflict, what is the resolution, and how do you get there? For biotech startups, telling the story in a clear and crisp, data-supported way is the best way to capture attention and get investors to understand what exactly you’re building.  It’s worth remembering that investors have dozens of companies competing for their attention at any given time. Therefore, the extent to which you can compellingly answer both “why” and “why now” in a logical and transparent way, often determines whether your company gains traction internally at a given firm. - Harry Won, OUP

The first time you meet a VC should never be a pitch. For prospective entrepreneurs, this means that you should be spending a significant amount of time trying to meet investors and learn about them and their interests. Cold intros are generally very low yield, so build slowly from your existing network (e.g., your academic network) asking for 1-2 warm intros. This is not a sprint but a marathon. Set clear and actionable goals for yourself on building out your network, whether that be attending “X” networking events per month, new coffee chats, or even spending a certain number of hours engaging with your school’s tech transfer group. When I was at Chicago, I kept a very large Excel sheet where I had mapped the top 100 healthcare funds across the Penn and Chicago alumni networks, my LinkedIn network, and then mapped out key “nodes” of secondary connections. I’m not sure I would recommend this approach for everyone, but take building and maintaining relationships seriously. When you finally get to a pitch, it’s such a relief to see a friendly face and often that’s the person who can intro you to the rest of their group as someone that they know and respect. - Lauren Mifflin, Frazier Life Sciences 

I can’t stress this enough: first, articulate clearly your target & product thesis. Second, in your early VC interactions ask for help and feedback to navigate the landscape of likely investor fit for your project. Lastly, remember that rejection is often about the idea/project, but just as often about fit/externalities (Fund cycle, portfolio strategy, timing etc.) - Maurizio Fazio, Atlas 

A good first pitch is meaningful – prepare well, ask “friendly” investors to give you feedback before you get on the road, make sure you are delivering a crisp and clear message, take the time to cater your pitch to your audience Today, more than ever, efficient use of capital matters – make sure that you have a solid development plan and the capital you are asking for can take you to meaningful milestones Be resilient - there may be many “no”s along the way but you are your best advocate and all you need is a few “yes”s - Nil Gural, Polaris 

Milestones, milestones, milestones. Exactly what will you accomplish with the capital, how can we be confident you will accomplish these milestones, and why will these accomplishments drive a value inflection for your company? We’re in an environment that highly scrutinizes fundamentals. While storytelling remains as key as ever, also drawing a logical bridge to derisking milestones is critical. - Shoman Kasbekar, Foresite Capital

Subscribe now

Any predictions for what biotech will look like at the end of 2024?  

I think precision oncology will return into the biotech spotlight, catalyzed by promising clinical readouts within emerging target classes and with novel drug modalities finally making value-accretive pushes! We’ll see investments and data readouts for therapies against novel targets, and learnings from the last ~4 years of antibody and cell therapy technology will finally begin to show themselves with exciting opportunities both entering and reading out in the clinic. The current sentiment is incredibly asset focused (show me a DC through clinical asset) and these are certainly getting financed – by the end of 2024 I think we’ll see an increase in more Seed investments, as the bullpen of high-value asset investments begins to empty out. - Artie Arumov, Qiming 

While the PIPE activity in the public markets is certainly a recent positive trend the uncertainty surrounding what the Fed will do with rates in subsequent months and the upcoming US election doesn’t fill me with hope for the number of IPOs in the second half of the year. History tells us that M&A activity drops up in the months ahead of an election and I don’t see why that shouldn’t be the case this cycle. Finally, the XBI has been so tightly and inversely correlated with interest rates that we should expect to see private deal activity roughly follow activity in the public markets, all be it a few months behind. - James Buxton, NEA 

After a very upbeat start to 2024, I foresee the biotech markets ending the year on a rather volatile note, especially with it being an election year. We can expect ongoing M&A or dealmaking frenzy among major pharmaceutical players, particularly in hot sectors such as cardiometabolic diseases, antibody drug conjugates and radiopharma in oncology. Additionally, I anticipate significant consolidation within crowded fields like cell and gene therapy. Biotech companies that prioritize strong science, data, and have the potential to improve patient care are best positioned to make a lasting impact, regardless of market fluctuations.- Sahil Chopra, Vertex Ventures HC 

Starting at JPM this year, much of the uncertainty and anxiety of the past year has given way to a cautious optimism if not excitement. As I write this, the XBI turn-around appears to be well underway along with a re-opening of the IPO window. Despite an uptick in deal flow and numerous green shoots, I think investors are still approaching new opportunities with the increased scrutiny of the past year. Biotech investors are looking to reward high-quality clinical data (Series B+), while looking for promising new opportunities for early-stage investments (Seed/Series A). However, this leaves many great companies stuck somewhere in the middle. The biggest challenge of 2024 will be the pre-clinical Series B, as companies and investors alike search for ways to attract outside investors to transition promising programs into the clinic. - Travis Hughes, Digitalis 

Share

Appendix Attachments

Investor Bios

Bios 24 In 24

3.62MB ∙ PDF file

Download

Download

All responses from 24 selected investors

All Responses Biomarker

446KB ∙ PDF file

Download

Download

Subscribe now

The offer was quite something: “when I became the Chief of Endocrinology at MGH, I had just turned 31. It was my dream job,” recounts Rosenblatt, now a senior advisor at Flagship Pioneering, Ascenta Capital and Bain Capital Life Sciences. After all, this was the department that first used parathyroid hormone to treat osteoporosis, developed radioactive iodine to combat hyperthyroidism and conducted early studies pointing to the use of GLP-1 in diabetes. Working with Dr. John T. Potts,Jr., Rosenblatt had already helped uncover the structural basis by which parathyroid hormone (PTH) activated its receptor. The newly minted chief of endocrinology figured that he, his wife and their recently unpacked boxes would never leave Boston or MGH.  

But just 3 years later (1984), Rosenblatt found himself leading the colossal Merck, Sharp & Dohme Research Laboratories. The career change was motivated by several factors, including science and clinical impact. Chief amongst them was his own mother’s example: “What enabled me to make that change [to industry] was the model of my mother. When I was eight years old, my father died. My mother took over his business…I saw her learning something new, challenging herself and doing good work.” Because of her influence, Rosenblatt didn’t reflexively see industry as a negative.  Rather, he saw the power of industry to help patients by inventing new therapies for unmet medical needs.

It was at Merck that he learned drug invention and development from the likes of Roy Vagelos, and pioneered the clinical development of alendronate (FOSAMAX) for treatment of osteoporosis. Rosenblatt found that impacting drug development entails both external and internal challenges: “we had to convince Merck to take this gamble [to develop FOSAMAX], against great skepticism.”  It paid off: the drug became a blockbuster and is still the most widely prescribed drug for osteoporosis.  After then going back to academia (to Harvard and then as Dean of Tufts University School of Medicine), Rosenblatt returned for his “second tour of duty” at Merck (2009-2016): “it was a bit different this time, because I was the chief medical officer…my job was to be the voice of the mission. To remind people that even when there are commercial pressures, we're here for patients.” Since 2016, Rosenblatt has been at Flagship Pioneering—first as its CMO and now as senior advisor. In addition to advising many companies in the Flagship ecosystem, he played a pivotal role in helping Moderna navigate clinical development of its mRNA-based vaccine during the COVID-19 pandemic (Q#9).

Harvard medical school graduate, 31-year-old chief at MGH, Professor at Harvard, Dean at Tufts, Chief Medical Officer of Merck and then CMO of Flagship Pioneering. Rosenblatt’s CV reads as if he has waltzed from one success to the next.

The man himself is somewhat more circumspect about his career. The first in his family to go to college, Rosenblatt at one point thought he should resign from his post-doctoral lab position after a series of failed peptide syntheses (Q#3). As a medical intern, when he missed a diagnosis of tetanus, he tendered his resignation to the chief of medicine. Fortunately, in both cases, his mentors encouraged him to keep going.

When asked about his success, Rosenblatt replies: “People were willing to take a gamble on me… I actively sought out mentorship and as a result they felt a sense of ownership.” He gives similar advice to trainees looking to succeed in academia or industry: “surround yourself with people you really admire…and from whom you can learn a great deal.”

Above all else, Rosenblatt suggests that the only part of a career one can truly plan is its guiding force: “careers often encounter a lot of challenges or stresses. I think you need to have a North Star…you need to know what is going to guide you through a crisis.”

Whether re-designing healthcare systems, uncovering the innerworkings of the cell, synthesizing drugs, or designing novel algorithms, following one’s North Star is key: “I believe health can be improved most through new therapeutics…the biggest breakthroughs are discoveries that wipe away disease,” says Rosenblatt. In closing, he poses the question to those just starting out: “What do you believe in? Which principles guide you?”

Below is an interview with Dr. Michael Rosenblatt, from February 2024:

Share

1. What was your first taste of science and medicine? Briefly, what about this initial experience drew you in?  

In high school I liked the sciences, but also enjoyed the humanities and literature. I thought I was headed towards chemistry or engineering, but one of my high school teachers said: “if you want to combine the humanistic element with science, you should think about medicine.” Nobody in my family was a physician—actually I was the first person in my family to go to college, let alone medical school.

When I got to Columbia for undergrad, I had a transformative experience in science. I was pre-med, so I was taking organic chemistry. There was a famous chemistry professor at the time named Gilbert Stork. He asked the graduate students who ran the laboratory course to find him one or two students who could work in his lab.

I got nominated, so instead of taking the actual organic chemistry lab course, I worked in the Stork lab.

What was special about this situation was that Professor Stork felt his grad students and postdocs should be independent and figure things out things for themselves. If they needed him, they would call him. But he loved being in the laboratory and working at the bench. So, he used us college students as assistants to help run his own experiments. We would come into the lab and get to work shoulder-to-shoulder with one of the giants of organic chemistry. So I did that for two years, including summers, and I just couldn't get enough. It was just so much fun and so challenging. The only downside perhaps was that he [Stork] was brilliant—at the time, I didn't have the perspective to realize that not everybody was a Gilbert Stork. I honestly felt that compared to him, I could not make it as a chemist. So I decided to pursue medicine instead. But I just loved the whole discovery process of research. I loved the fact that I could do something new in the lab. I loved that there were all these instruments I could use to tell me what was going on with molecules—or eventually with cells, as my research became more translational.

2.  What was medical school like for you?

Going into medical school, I thought I would likely wind up being a doctor in Northern New Jersey. While growing up, I loved our family doctor. He was my “model” of a physician. I had no knowledge of a career in academic medicine—I didn’t know such careers existed. When I got to Harvard Medical School, I met physician-scientists for the first time, and a light bulb went off.

I’ve had several mentors who have really helped my career. My advisor in medical school was a man named George Cahill, who was a famous endocrinologist based at the Joslin Clinic. I really like reasoning out signaling pathways, so had an interest in endocrinology. It was also a specialty where I felt there was not as much memorization: you either have too much or too little [hormone], and there are only 10 glands that are truly important. I went to Dr. Cahill and asked to do research in his laboratory. He was not taking students at the time, but recommended working with Dr. John Potts at MGH. Potts was using peptide and protein chemistry—this was long before recombinant DNA technology—to study parathyroid hormone. I was initially reluctant—I didn’t find the medical school lectures on calcium and bone to be that interesting. But after I met with Dr. Potts, I became fascinated with his work. The problem I went on to study during my fourth year of medical school was: how does parathyroid hormone [PTH] bind its receptor?  Where does it specifically bind, and how does this lead to receptor activation? Over the next decade, I then went on to design inhibitors of this interaction based on structural characterization of PTH and its receptor. It was painstaking work—we didn’t have the same NMR or crystallography techniques available—but I loved it.

3. What were some of the highpoints and lowpoints during your training as a physician-scientist?

Research entails long stretches of working on a question without any positive feedback. Then one day, you get an answer to the question. This answer either depresses you, or makes you ecstatic. If you are hooked on the process, no matter the answer, you go on to do it again. It’s a manic-depressive exercise! I'll share one high point and one low moment.

One of the “highs” was when I was studying how hormones bind and activate G-protein coupled receptors (GPCRs). This is a general problem of potential clinical significance. I finally figured out and mapped the activation domain of parathyroid hormone after it bound its receptor. I reasoned that if we chopped off the activation domain, the modified PTH could still bind its receptor but block the function of endogenous hormone. In other words, by removing the activation domain we would create a hormone inhibitor. I’ll never forget looking at the data from our scintillation counter—seeing that we could block binding of endogenous PTH with our inhibitor. A related success was that in order to figure out the touch points between the hormone and the receptor, I had inserted photo-activatable moieties in place of certain amino acids. These moieties allowed us to use light to crosslink PTH to its receptor, and then shear the protein to find the actual points of contact between the hormone and the receptor.

A very low point occurred when I was working for John Potts at MGH. He had a team in the lab doing peptide synthesis and sequencing. These key team members were Australian, and decided to go back to Australia for family reasons. The lab was disrupted. Dr. Potts thought that I should travel to Australia and learn the peptide synthesis and sequencing techniques from these two former lab members. It was a great opportunity, and I took it very seriously. I went to Australia for several months to learn how to chemically synthesize PTH analogs—or at least the 34-amino acid long active fragment. I came back to MGH with my “chest all puffed out,” confident in my skills. When I got back into the lab, the first synthesis failed. The second did as well. I was crestfallen, but my mentor told me to try again: “these things happen.” I tried for the third time, and again it was a complete failure: the material was totally dead.

At this point, I felt I had no choice. I thought I better go resign. I went to Dr. Potts and said: “you've invested in the wrong guy, and I can't make this work. I don't know what's going on.” Fortunately, he didn't give up on me. We eventually worked it out and made good products. I had a similar low moment when I was an intern at MGH.

I was medical intern at MGH. In the first two weeks, I saw these cases that I had never learned about in medical school: for instance, I saw someone with leprosy and another with transposition of the great vessels. I also saw a patient with tetanus—actual tetanus—and I missed the diagnosis. I went to the Chief of Medicine and said: “either I have to quit this residency, or I need to come back next year after learning what I somehow missed in medical school.” He paused and then asked me: “what did you do when these cases came in?” I replied that I was unsure, so I called in the specialists from each field. He replied: “Well then I think you're going to be okay Mike.” I learned that it’s good to know what you don’t know and a good consult goes a long way in clinical medicine.

Subscribe now

4.  You graduated from Harvard medical school in 1973 and eight years later were chief of Endocrinology at MGH. What allowed you to ascend so quickly?

I have always had great enthusiasm for what I am doing. I actively sought out mentorship The connection that you make with a mentor gives him or her a sense of ownership in you. They start supporting you. I really needed this support because I had no knowledge of how careers work in academia. Perhaps this “ownership” is what led Dr. Potts to put his faith in me. Potts was the chief of the endocrine unit, and I was just one member of a very large integrated division. He then became chairman of medicine and had to choose his successor. He chose me—the youngest guy in the whole group. Part of it was a successful research trajectory, but I also helped fix the administration for the endocrinology outpatient clinic, which was a mess. So, he felt that I had administrative talents and the potential for leadership.

But your question points out the ethos of the time. People were willing to take a gamble on young people who had not “completed every step,” or climbed the career ladder in a conventional step-by-step. Higher ups were willing to promote based on the notion of raw talent. MGH was at one time famous for this ethos. The former chief of medicine—a man named Walter Bauer—made an endocrinologist the head of arthritis. The longtime head of cardiology was an immunologist, whereas the head of endocrinology was a nephrologist at the start of his career. These folks were all young and Bauer was just betting on the best athletes. There was a desire to keep really talented folks within the institution.

5.  Who were some of your early clinical or scientific mentors?

I mentioned Gilbert Stork and John Potts. Later on in my career, Dan Tosteson became a close mentor. He helped me figure out how to navigate administrative responsibilities vs. research vs. clinical work, and how to innovate in education. Dan was an intellectual giant.  He inspired me.  I really am grateful to him for doing that. He pushed me when I was mid-career to take on new challenges outside my comfort zone.   

6.  What led you to transition from academia to industry?

When I got the offer to be the Chief of Endocrinology, I was 31 years old. It was my dream job, and it was arguably one of the historic seats in US or global endocrinology. I remember coming home and telling my wife: “We can unpack all of the boxes in the basement because we won’t ever leave Boston.” But over the next three years, I started to meet the folks at Merck. At that time, they had several drug discovery programs in endocrinology, and I started to consult for them. I would go down to their headquarters three or four times a year to meet with various researchers at the company. For me, a whole bunch of myths got blown away. One myth was that the only smart people were in academia, and the people in industry were intellectually “second class.” When I was talking to the folks at Merck, they were every bit as smart as the people at Harvard and MGH. The second myth was that: “folks in industry are only motivated by money.” Not true—they were motivated to create drugs that made a difference to patients. I started to realize that in all of my grant applications, the “preamble” was always the same: if my research is successful, it will provide insights to pathways that will enable us to make drugs.

I began to feel that the people at Merck were doing what I had been claiming to do in my grant applications:  make new medicines. By happenstance, during this time a major position at Merck opened up. They offered me the job because they didn’t have an internal successor. I was tasked with converting a chemistry-oriented organization into one more focused on biology and medicine.

What enabled me to make that change was the model of my mother. When I was eight years old, my father died. My mother had to take over his business with no technical experience. When I was growing up, my mother would discuss business challenges with my younger sister and me. I always thought these challenges were interesting—and I certainly never viewed “business” as evil. My mother was learning something new, challenging herself and doing good work. When I was thinking about going to Merck, I had lots of people tell me that I was “crazy” and that my career would be “over.” Many said I would become “totally forgotten.” I felt that the model of my mother gave me the confidence to make this change. In addition, I had already gotten to the place I dreamed about in academia—chief of endocrinology. At this point I felt open to anything—especially once I saw the exciting science going on at Merck.

7. What were some early lessons about how operating in industry was different from your positions in academia? What series of events led to the development of FOSAMAX?

Joining Merck was a huge learning curve. To be honest that is part of the reason I did it. My prior training did not teach me anything about making a drug: there are whole scientific disciplines inside pharmaceutical companies that aren't represented at all within academia…areas like safety assessment, drug metabolism, formulation. Compare this breadth with my previous work, which was being an expert on parathyroid hormone. At Merck, I was suddenly in charge of an integrated unit that covered areas like cardiology, GI and nephrology. At the time there were no endocrinology programs in the division that I was recruited to lead.  uI had to learn about therapeutic areas that were new to me, in addition to learning how to make drugs. In many respects, it was terrifying. However, I had very experienced people helping me. By the end of the first year, I started to feel comfortable. But it was an illusion--by the end of year two, I again realized I knew nothing!

I was lucky that the Head of Research at the time was Roy Vagelos. During my annual reviews, he would always say: “Mike, you're an expert in bone and calcium. There must be opportunities in osteoporosis…why aren't we working on that?” At the time, we didn’t have any clear targets. But by the third year I was at Merck, I felt the science had matured a bit. Around this time, we tried to license the drug that became FOSAMAX. The drug [alendronate] was the chemical discovery of a little Italian company, Gentili—but as Vagelos liked to say: “it was a biological and medical discovery of Merck.”

[On the development of FOSAMAX]

The Italian company that developed the drug was looking at an important medical application: the hypercalcemia of malignancy. Breast and prostate cancer metastasize to bone and cause massive amounts of calcium release. This bisphosphonate compound looked like it would work there. But we understood the biology—that if you blocked osteoclast function and halted osteoclast resorption, you could give bone a chance to recover. Osteoporosis is a disease of too much bone resorption. When we saw the early data for alendronate, we knew it had the potential to be applied in this larger indication. Ultimately it was a roll of the dice that this molecule would work. A small group of us had to convince Merck to take this gamble, against great skepticism—it paid off and the drug became a blockbuster.

8.  What advice do you have for physicians and scientists who also want to jump to industry to develop drugs? When is the “right” time do you feel?

In academia, individual contributions are very much the coin of the realm. The roster and order of authors on a publication is very important, as well as where you publish. In industry, it is much more of a team effort. There is an understanding that to take a drug all the way from the laboratory to approval is a campaign, often involving hundreds of people. You need to be a team player.

Another point is that in industry, you always have a boss. I don't care what level you are—you answer to someone in a way that is quite different than the relative independence of academia. 

In industry, the company makes strategic decisions to focus on some areas that are hot--the way oncology, rare disease and immunology are now. That means stopping other programs.  If you are unwilling to “reboot” and learn new things, then you are going to have a problem in industry.

There are many potential jumping off points from academia to industry and many good reasons to make that transition. However, if you want to enter industry at a level where you immediately help decide the direction of where a company goes, it is better first to remain in academia for long enough to become an expert in a field.  It gives you credibility in science and medicine. I tend to advise young people to wait a little bit [before going to industry]. If a student really wants to become an investor or work in biotech immediately, and can’t picture going through additional years of training, the I encourage them to make the switch earlier. But making the MD “real” by finishing residency is valuable in my view. Learning how to write grants and do science well is also a valuable.

9. Leading some of Merck’s clinical development programs you must have gained a broader perspective on drug development and the biotech ecosystem. What were some of these learnings?

After my “first round” at Merck, I went back to academia for nearly two decades. I then returned to Merck for a second “tour of duty.” This time it was a bit different because I was the chief medical officer. I realized that the big pharma companies—Merck, Novartis, J&J, GSK—are mission-driven and have a deep commitment to patients and shareholders alike.

When I came back as CMO, my job was to be the voice of that mission—remind people that even when there are commercial pressures, we exist for patients. We are here to create new medicines. Ironically, I thought being CMO would entail mostly being the person who “blows the whistle” and says that a drug is not safe; to be a voice of extreme caution above all else.  It turned out to be quite. Merck [and other large pharma companies] are so conservative that sometimes they lose sight of the reason a drug is being developed.  Often I had to remind them that: “diseases also cause problems and adverse effects.” You've got to hold up the adverse events of the untreated disease versus the potential adverse effects of a drug. in a drug trial. I learned that being the voice of patients often entailed pushing the development of certain programs forward when the benfit:risk ratio is appropriate, rather than holding the drug back.

10.  What led you to Flagship Pioneering in 2016? What excited you about that move? What excites you about your current work?

After about 10 years working at Merck, I began to feel like I wanted to learn something new.  What was attractive about Flagship Pioneering is that they have a distinctive methodology: they're not a traditional venture capital firm. Unlike VC’s, they are an organization that creates new companies: with their own scientists, discoveries, and methodologies in its own labs. They are always pushing the boundary, and on the edge of science. Flagship begins the creation of all their companies with a simple question: “what if?…” The creation of Moderna was based on: “what if?” we could make the body into a molecular factory? What if we could use mRNA to make peptides and proteins that the body could use to fight disease. Coming from big pharma, I was intrigued by that methodology. For me, this involved unlearning some of the “de-risking” strategies I used in the past. If you are at big pharma or even academia, you have to point to existing data, otherwise taking a risk with no preliminary data would lead people woto think you are crazy. At Flagship, you create a supposition and you start the project without data or existining publications, with little justification for taking on risk other than if you guess right, you wil have a breakthrough.  

[On Moderna]

In the second week of January 2020, I called the Chief Medical Officer of Moderna—Tal Zaks.

I said: “I am looking at this report from Wuhan, China. There is this virus there. I wonder if our mRNA technology could be applied to making a vaccine.” He replied: “Mike you are about a week late. We've gotten the sequence, and already started.” Tal was a first time CMO and asked me to help him navigate calls from the CDC, FDA and other regulatory issues. Moderna went all in—they put other projects on hold and “bet the farm” on their technology. By the way, mRNA was highly doubted by 90% of those in academia—almost everyone I spoke to in early 2020 said that RNA is too short-lived and inflammatory to be used be useful in humans. Of course, when it worked, they said it was “obvious” from the start!  The company took a huge risk, and their leadership is to be commended. It was a intense, once-in-a-lifetime experience for. To me, it really illustrated how exciting platform technologies that can be applied to multiple areas can truly be.

11.  Any parting advice for trainees in science or medicine?

A couple parting words of advice. It is important to know who you are, and who you are not. Be honest with yourself about that. What do you really like to do? Second, careers often encounter challenges or stresses. You need to have a North Star: you need to know what is going to guide you through a crisis. My North Star is patient impact, and it has guided me through several career crises. More than that, I believe health can be improved most through research that leads to new inventions, new therapeutics. I think making health systems more efficient is terrific. But the biggest breakthroughs in health come from discoveries that wipe away disease. I'm a great believer in research as the tool to change health. Ask yourself: what do you believe, and which principles guide you?

Another point is that I didn't plan any part of my career. There is just too much that is up to chance, and things aren't going to work out the exact way you want. I advise people early in their careers to just take it one step at a time. A final piece of advice applies to when you are assuming a new role or job. The three things that I looked for always are: one, how can I contribute? Do I feel that I can help with the mission? Second, will I learn new things? Third, what is the quality of the people involved? What is their reputation? Are these people I will enjoy being with? Ask yourself these three questions whenever you are making a career decision.  

Share

Subscribe now

Yet occasionally, events remind us that the stakes in biotech are far higher—especially for those of us trained as physicians: “I came to UPenn’s shortly after Jesse Gelsinger died,” remembers Simeon George (MD MBA), CEO of SR One.

Gelsinger was a rising high school senior with OTC deficiency, a rare disease in which ammonia builds up to lethal levels in the blood. Scientists at UPenn recruited Gelsinger into one of the first gene therapy trials, which used a viral (Ad5) vector to deliver the missing OTC enzyme to his liver cells. Gelsinger developed a lethal immune reaction to the adenovirus vector—within four days of receiving the experimental therapy he was dead. “His death reinforced the gravity of the work that our sector does. When we bring these amazing new therapies to bear, we need to be humble and cautious…it really underscored the challenging nature of trying to develop new therapies,” reflects George. 

As we sat down for this interview, nearly 25 years after Gelsinger’s death, Simeon George’s firm SR One has just announced a registered direct offering in CRISPR Therapeutics. CRSP recently developed the first FDA-approved gene editing therapy to cure sickle cell disease and beta thalassemia. “This is a brand-new modality that didn't exist a decade ago, and now has a first product on the market with a rich pipeline of other applications,” comments George, who is on the CRSP board of directors.  For someone who helped treat sickle cell patients at UPenn, the moment is surreal: “Meeting some of the patients that have been on this therapy and hearing their story, is the reason I get out of bed with a smile on my face. It is so incredible just to have even the smallest level of involvement in a story like this.”

The son of physicians, George was motivated by the Gelsinger tragedy to help safely develop new therapies for patients in need. After a brief stint as a life sciences consultant at Bain and Co, George joined SR One (GSK’s former venture arm) where he has been for over 15 years. He led SR One’s investments in CRISPR Therapeutics (CRSP), Principia Biopharma (acquired by Sanofi for $3.7bn), Turning Point Therapeutics (TPTX), Progyny (PGNY), Arcellx (ACLX) and Nkarta Therapeutics (NKTX), both of which he co-founded. In 2020 George led SR One’s spinout from GSK—opening the firm to outside capital.

In our interview, George talks us through his early interest in medicine and lessons learned in nearly two decades of investing. He discusses why areas like gene-editing, cell therapy in autoimmune disease and artificial intelligence are exciting, and the importance of investing in teams: “I bet on teams that understand how to execute, and how to do all of the critical pieces of drug discovery and development.”

For those wishing to make an impact in biotech, his advice is short and sweet: “You must follow your passion. I can't stress that enough. You have to feel fired up about what you're doing.”

Below is an interview with Simeon George, MD MBA, CEO of SR One from February 2024:

Subscribe now

1. What was your first taste of science and medicine? Briefly, what about these initial experiences drew you in? 

Honestly, it's been the only thing that I've been passionate about since I can remember. My earliest memories have all been around medicine and science—I grew up in that kind of household. My parents were both physicians. I just loved the idea of training in this craft, using all of your skills and your experience to solve someone’s most pressing problems.

My Dad was an OBGYN and my mom also initially trained in that field. It's such an intense experience–delivering babies, dealing with malignancies, but also benign gynecologic conditions in healthy patients. I remember [growing up] feeling like my parents were in an episode of a soap opera–there was medical drama daily. I came to appreciate the problem solving part of medicine– I love this about biotech, too: the concept of figuring something out that isn't necessarily obvious. It’s such a high impact way to spend your time.

If you can help people at critical points of their life, you also directly impact their loved ones, their livelihoods and society. This is the first thought I have in my mind every morning and honestly, I wake up with a smile on my face ready to tackle whatever challenges lie ahead. How I have impact now (investing) is much different from my wife who is a pediatric ophthalmologist. I see what she experiences with patients directly, and how incredibly rewarding it is for her to use her skills and experience. In my career, the thing that I love the most is the idea of working with incredible founders and entrepreneurs. We’re trying to rewrite the medical textbooks: I genuinely believe in that and it's so inspiring to work with people who have the same ambitions. In our sector, regardless of your motivations, success is defined by helping patients and bringing new medicines into the market. It’s such an empowering way to spend your time. It is hard for sure, but it has always been my driving force.

[Did you have experiences early on that piqued your interest in biotech or drug discovery?]

The most vivid memory I have about biotech early on, was when I was at Penn for medical school. Shortly before I arrived there was this tremendously unfortunate death from a gene therapy–the patient’s name was Jesse Gelsinger. Jesse had a rare metabolic disorder and unfortunately succumbed due to an immune reaction to his AAV gene therapy treatment. A lot of the amazing work in gene therapy, cell therapy and mRNA has all come out from Penn which is amazing! But Jesse’s death was this really dark moment for the field.

I remember being on campus and everyone talking about what happened. At that moment, the gravity of the work that the biotech sector does was really apparent. When you're bringing these amazing new therapies to bear, the upside sounds incredible. But human biology is unpredictable and we need to be cautious and humble. This tragedy left an immediate impact on me, underscoring the challenging nature of trying to develop new therapies.

Share

2. What led you towards the MD-MBA path, and what was graduate school like for you?

On my CV it looks like I did a lot of things with a “plan” in mind. The reality is that I did not have a clear plan or career objective in mind while I was in graduate school. I wanted to do something in medicine and have patient impact–but I didn't exactly know what this would look like.

I came to Penn to pursue the dual degree in part to explore various paths and in part to follow my fiancée (and then wife) who was already at Penn Med. My wife is my role model for someone who should pursue medicine. If there is anyone you would want taking care of your child or your loved one, it is my wife. She’s got this service orientation and a drive to pursue excellence in her clinical domain. She’s had [this quality] ever since I’ve known her.

For myself, while I loved medicine, I was exploring different ways that I could express my creativity. After finishing the basic sciences portion, I took a gap year and worked at an agricultural bio startup, which ultimately didn’t pan out, but it was an incredible first business experience.

The MD/MBA tract is this amazing program at Penn and while I was there, every waking moment was spent either in the clinic or learning about business. I did several internships across consulting, banking, and at SR One. I loved my clinical rotations too, as I was really drawn to putting my skills to work to have maximum patient impact. But my intuition was that I wanted to be closer to biotech in some capacity, even though it wasn’t exactly clear where that would lead me. Upon graduating from Penn, I pursued consulting because it felt like doing a “residency” in business. However, I was in consulting for less than a year when SR One reached back out because they wanted to hire an investment professional.

It all just worked out! My wife was at CHOP training as a pediatric ophthalmologist, and SR One at that time was based in Philadelphia, so it made sense personally to make the move. I honestly didn't know much about the venture career path, but I liked the team and thought it could be an interesting area to dip my toes in and see what happened!

3. What was it like making the transition to GSK/SROne?

At that time, SR One was a really interesting setup as the corporate venture arm with GSK as its sole LP. The fund was largely left to its own devices and everything from sourcing, to diligence to decision making, to board management, to investment management through to exit was done in house [at SROne]. For me, it was a great training ground. I got to work with some really high quality people who really understood pharma, since a lot of them had come from GSK R&D and BD. They understood how value is created through medicines and how everything that we do is in service of how we identify and develop these medicines. The SR One team was an understated group of people who produced a lot of high quality work with not a lot of hubris or ego around them.

A colleague of mine, who unfortunately, passed away, Ken Gossett, just had a nose for founders and companies with a vision for how they were going to develop medicines. He focused primarily on small molecules like antivirals or cancer agents but also worked with Algeta, one of the first big successes in the radio pharma world. His track record was honestly one of the best that I've seen. Just to be able to spend time with him, and observe the way that he worked was great mentorship for me.

After a few years in Philadelphia, I moved to the Bay Area which was a formative period for me as I had to really learn by doing. I got to build my network, and led my first deal. Principia is one of the early deals that I did–SR One co-led Series A. When I think back on that period post global financial crisis, there are so many lessons learned including the level of resilience that the entrepreneurs had to build and run start-ups. It was so hard to raise money at the time, the Principia round took over a year to raise a 36 million series A. A lot of foundational experiences came from those first five to six years, between learning from my team and then figuring stuff out by myself.

Over the years we developed an incredible track record at SR One, and with GSK’s support in 2020 we spun out and raised third party capital. Since that time we have now raised multiple funds investing across company creation through to public market investing.

4.  What were some of the lessons you learned on notable and successful deals like Principia? Generally, what were the key things that went right, in companies like these?

I'm a big believer in this idea of learning from good and bad experiences. Sometimes you learn more from things that don't go well than you do from the successes. If you've read the book by Daniel Kahneman, Thinking Fast and Slow, there's definitely an element of this business based on intuition and gut instincts. You have to learn to trust that. I think this intuition and judgment is what separates the highest quality investors from the rest of the pack. With Principia, honestly, the first meeting with those scientists, David Goldstein and Ken Brameld, you could just tell these are truly world class chemists. Their understanding and insight was profound. They knew just how to design these reversible covalent binders and how they were going to pursue these first sets of targets, including BTK. At that time, everyone was focused on BTK for oncology, and it was really exciting to see how with “just a chemistry tweak”, Principia could go into the autoimmune disease space. They laid out their capabilities and experiences from Roche so clearly. I vividly remember coming out of that first meeting with their team on University Ave, Palo Alto. I wanted to invest in the company right after meeting them. But of course I had to then do the work to back up that initial hunch. We did the work on markets and technical and chemistry and IP. We didn't have a CEO yet, and had to also figure out how to build the investment syndicate. There’s all this work that you have to do, but I go back to that first principle on how you have to have an intuition around the quality of the founders. During the early stages, I think that's critically important. That has been true of every deal that I've done that has been successful. And frankly, I didn’t trust my intuition on a lot of the deals that turned out to have not been successful. The deals that I should have done but missed were also instances where I didn’t trust my intuition.

The best example I can give you [of a miss] was when we were thinking about investing in Chinese biotechs, and so I spent quite a bit of time there. When I met John Oyler, I just knew he was extraordinary. I came close to investing in his company [BeiGene] but ultimately, we chose not to. My intuition was telling me that there is something special about this individual and the company he is building. I wanted to be close to him and invest, but I couldn't get over my own hang ups around all the risks associated with investing in China. We missed that. I saw [John Oyler] last year and told him I wish I had a time machine to go back and invest. He was incredibly gracious, and I hope that we find another way to work together in the future. I'm drawn to compelling founders and entrepreneurs, and I feel like I've got a pretty good sense of what that looks like. So that’s a skill set I’ve always tried to lean into, and I hope that it gives me an edge.

5.  Does today’s venture ecosystem—feel like previous cycles you have lived through? What are the similarities in terms of venture funding and creation to previous post-bubble times? 

I’ve been pretty clear on this, with myself and with my team: there's no time to moan or complain about what's happening with inflation and the stuff you can't control. There's just no point spending time to predict it. History doesn't repeat itself, but it rhymes. From the day I started at SR One through to today, the one thing that has held true is that if you have a line of sight towards a medicine, all options are open. You can raise private money, public money, venture debt, royalty…you can do partnering deals with biotechs or pharma. There are so many ways to continue to build your business, if you are singularly focused on creating a medicine that has true patient impact.

As a fund, we exist to raise and deploy capital. For us, it's all around executing on a plan to develop the medicine. This strategy worked in 2008, in the aftermath of the global financial crisis. It also worked during COVID. Everything that we need to do has to be focused on identifying the next crop of startups, founders and entrepreneurs who are building companies that will bring new products to the market. This is where we spend all of our time. The cost of capital can go up or down, the quantum of capital can be constrained and can be relaxed. However, our job is to be appropriately balanced in terms of risk and reward and focus on one question, “where is the medicine?”

The beauty of being a venture capitalist is that we have time to be able to build these companies to hit their critical milestones. So thinking about building a business that is fit for February 2024 is not going to do us any good when we're in 2030. A practical example would be when we are thinking about an early-stage company during its series A round. I'm certainly focused on and have a heightened sensitivity around what are the key deliverables for this round of financing. I also think about how much conviction we have if the company hits a portion of their deliverables. Is there an ability for this company to keep raising money to continue to be a viable startup? And the nuance of that question is understanding where [SR One] and our co-investors are going to be at that point in time. Are they aligned in supporting this fragile startup that is usually at a very nascent stage of development? It's like locking hands with the partners around the table, and trusting that as the company progresses and achieves its goals, those already involved will keep up the support.

We have more modalities than we know what to do with them at this point. The CRISPR Therapeutics approval is so incredibly formative because we got involved when it was the proverbial “two guys in a garage” with questionable IP, to where it is today: a multi-billion dollar company with one approved product and a deep pipeline across oncology, cardiovascular, auto-immune disease and regenerative medicine. CRSP also has a team that has proven it can out-execute any other company in gene editing. These were the ingredients that got us excited to invest once again, even at this later stage.

6.  Casgevy was approved in December 2023 for treatment of SSD and recently for beta thal, representing an enormous milestone for the CRISPR/gene editing field. What does this mean for you personally, and for the field?

It was such a surreal moment. As the data was being generated, we became aware of the jaw dropping concept that [Casgevy] was curing these patients. Thinking back, while I was in medical school, we had patients who were suffering from sickle cell crisis coming into the hospital. There was not much that you could do for them- oxygen and pain relief. For those who can even find a bone marrow donor, often the body rejects the graft later on.

The ability of a therapy to transform the lives of sickle cell patients is incredible to me. Meeting some of the patients that have been on this therapy and hearing their story, it's the reason I get out of bed and have a smile on my face. It is so incredible just to have the smallest level of involvement in a story like this. I wish my father was alive so I could tell him about it, because it's definitely the proudest moment in my career.

For the field, it sets the bar for what the technology needs to deliver to impact patient care across the next crop of medicines. There are so many logistical challenges around a product like this: from the supply chain, to the way it's delivered. Ultimately, the patient receives the care so if you're going to go down that path, the drug needs to be the best thing that has ever existed for them. One of the things the last few years have helped clarify in my mind is that you can't come up with a “me too” product for a new modality. The data needs to be truly differentiated.

I believe it’s beneficial to consider the landscape where revolutionary technologies like CRISPR/Cas9 can be applied to understand the genetic causes of diseases. We should focus on executing plans to develop products with positive outcomes. Although challenges remain regarding their delivery, I’m confident they are going to get solved. We have challenges around bone marrow preconditioning, which I’m confident will be solved. This is going to take time. However we have got to capitalize these companies and be there to support them in finding the answers. This approval is the tip of the iceberg for what it means for the field. It's possible! We have the regulatory prowess to get through it, and there is receptivity. Thinking back to Jesse Gelsinger, we must remember that there is always a risk-reward trade off with these approaches. However, the narrative is pretty clear on what needs to happen next for gene and gene editing therapies.

[Please discuss the recent registered direct offering. What does it give the company?]

After spinning out from GSK in 2020, and having a new fund now set up, we have wanted to continue to support CRISPR. It's been a personal ambition and a great testament for our continued support and belief in this incredible company.  We wanted to supercharge the incredible activities that are happening on the in vivo gene-editing side, as well in the cardiovascular, oncology and auto-immune CAR-T programs.  Over the next couple of years we expect to have line of sight towards more medicines to come from the CRISPR engine.

[Many challenges remain in gene editing: ex-vivo approaches, cost, access, scalability, harsh bone marrow conditioning regimens. What do you see as the major obstacles for the next-gen therapies?]

At SR One, we've been focused on looking at ways to do whole gene insertion with small and large stretches of DNA. We also need to deliver these editors in a way that has optimal editing efficiency in the right tissues. This is one of the largest bottlenecks. We need to solve this in order for the field to evolve to in vivo therapies. Preconditioning is another problem that we are now focused on solving to help increase both the patient access and commercial opportunity for Casgevy and other medicines. If we can make it easier for patients to go through bone marrow preconditioning, it could potentially unlock even more patients that would be able to benefit from this therapy. Beyond DNA editing, we've made an investment in a company ADARx that's working on RNA editing. There's also epigenome editing, base editing, amongst many editing approaches in development. Going back to first principles, focus on medicine, the optimal indications, and then just start executing. We know that the CRISPR/Cas9 system works incredibly well. You can't just pick another technology to be different, or to simply try to get around existing IP. The rationale should ideally be driven by why your approach makes sense for the disease you’re going after.

7.  There has been a shift from using CD19 or BCMA CAR-T in autoimmune diseases. Companies like Arcellx (co-founder), Kyverna, Cabaletta, Gracell (AZ), NKarta are pursuing this strategy. What gets you most excited about this area?

This is certainly an area that we're following very closely across both our existing investment portfolio and the new deals we are evaluating. Both cell therapy companies that we have co-founded (Nkarta and Arcellx) have generated exciting clinical data in the oncology setting and are now looking to potentially expand their scope into autoimmune disease.

[To harken back to the Principia story where BTK inhibitors were applied to autoimmune disease after cancer, it seems like there is a similar theme with CAR-T therapies]

Yes, you are right. I honestly feel like we should have thought of this idea sooner! The Principia example is perfect. We knew how Rituxan (anti-CD20 mAb) worked mechanistically and the impact it had on B cells. You see the great treatment effect on cancer, so it made sense that you could have profound benefits in a wider set of diseases. The same thing could be said when we think about the B-cell resetting via CAR-T therapies for autoimmune diseases. When we saw the data presented last year in 15 patients, well the pictures are worth 1000 words. There were amazing responses. Though a small study, it certainly got the field excited. Kyverna also just had incredible success with their IPO.

In part, I think it is because there is a strong mechanistic rationale for why these treatments work, in particular for CD19 B cell depletion therapies. There are questions around which indications to go after and which subset of patients to target? How severe do they need to be to go through a therapy like this? For autologous therapies, the regulatory considerations will need to be worked through carefully. I'm optimistic, but I also think these companies need to be thoughtful about the way they develop this product. We ideally want to invest behind teams that understand how to execute and navigate through these critical pieces of drug discovery and development.

8.  Alphabet’s Isomorphic labs just entered into agreements with Novartis and Eli Lily to use their AI tools, including a next-gen alpha fold, for small molecule and therapeutic discovery. What has you excited about AI in early-stage companies?

It's a good question- we're still grappling with it. We come from the mindset that medicine is the product from which value is ultimately derived. Despite this product centric approach, I think the power of computation is going to transform every industry including biotechnology. The Nimbus example is a great one; they've been using their computational capabilities from Schrodinger over the last 15 years now and have had immense success moving programs forward and creating shareholder value. Odyssey (where SR One co-led the Series A) has benefited from the computational approaches to advance their product pipeline in short order. The company has moved its lead program from the research setting to clinical testing in less than 3 years.

I'm excited to see how our start-ups now use AI and ML to tease out the signal from the noise in clinical development. As a physician, what I am most excited to see if we can new medicines forward for patients in needs by better designed clinical trials. AI might even obviate the need for a certain amount of testing, either preclinical or clinical- because of the quality of the data it can produce, its reproducibility and the separation of signal to noise across massive data sets.

We led an investment last year in Rezo based on founding technology out of Nevan Krogan’s lab at UCSF/QBI. He is truly one of the pioneers of using quantitative biological approaches across disparate data sets (including human tissue samples / genetics / proteomics) to create protein protein interaction maps of different diseases. You’re then able to see things that you wouldn't see if you're only looking at one data set. We've hired an ex-Google scientist to come and really focus on the AI aspects of this approach. It’s early days, but I’m encouraged by the level of pharma engagement around what Nevan and Rezo are doing. I am hopeful that [AI] will have a profound effect on biotech in the coming years.

9. Any advice for trainees interested in biotech or investing? Particularly, career advice you wish you had known when coming up?

You just have to follow your passion, I can't stress that enough. You have to feel super fired up about what you're doing. You have to have a learning approach and mindset, and you have to look at every situation, no matter how challenging, from the perspective of what can you learn from this. Ultimately, if you survive it, you should also think about what you can do better or differently. The mindset around what you're doing is so important! You should leverage the power of networks and be curious as well to meet people who inspire you. For me, none of this has been planned. I had no idea what I was going to do in my career. It's all about being open and being curious: working hard, talking to interesting people and following your intuition. That’s critical! As you hone in on where you want to spend your time, then I think you really need to build expertise. You really need to have a point of view and you need to be informed. That thought, and that passion should come out when you're interacting with people. When I meet someone new and they leave an impression, it means something. For those working and living in Boston or the Bay Area, take advantage of the fact that you are in the hotbed for biopharma innovation. I like the idea of being well rounded too. Have some interests outside of science and try to get a holistic view. Don't just think about drug discovery and development, but think about all the other issues that ultimately impact our sector. Start to think about the IRA, about pricing, reimbursement, access, all the different parts of the value chain. As it actually turns out, they are important for our businesses. Maintain that broad approach to understand ultimately what creates value in biotech, which is bringing transformative new medicines to patients.

The last thing I'll say: I spend time between the Bay Area and London. What is interesting to see is in Silicon Valley you’ve got young adults (and sometimes kids!) with an aspiration to transform the world. This is usually done most effectively through technology start-ups but there is no reason that we can’t inspire young adults in biotech to do exactly the same thing.

In biotech there is more of an expectation that you have to work your way up and have grey hair before taking on the establishment. I just don't think that's right. If you look at the CEOs we have backed, it has been more first time CEOs than experienced CEOs. While I love experienced CEOs, there is something about the pure hunger, ambition, desire, chip-on-your-shoulder attitude that the first-time entrepreneurs have. I think young people that are reading this should be inspired to go out and build the next crop of great biotechs bringing new medicines to patients. This is your time! It's not like the older people have figured everything out–we're all learning as we go. The onus is on the next generation to push hard now and change the world!

Subscribe now

Share