Summary of main points

1. The PI3K/AKT/mTOR (PAM) signaling pathway is dysregulated in approximately 50% of tumors. PIKTOR is a combination of a PI3Kα inhibitor, serabelisib, and a dual mTORC1/mTORC2 inhibitor, sapanisertib. This multi-node inhibition (MNI) has demonstrated significantly stronger pre-clinical pathway suppression in various endometrial and breast cancer cell lines (slide 11) compared to single-node inhibitors like inavolisib (Itovebi) which only targets PI3Kα.

2. Faeth’s phase 1b clinical data, which investigated PIKTOR + paclitaxel in various solid tumors, is promising. In the phase 1b study of 19 patients, there were only 5 patients with endometrial cancer (EN) and 4 of them responded. Three of these EN patients achieved a complete response (60% CR rate), one achieved a partial response (PR) and one had progressive disease (PD). A major near-term catalyst for the stock is the phase 2 topline readout in endometrial cancer in 2H ‘26.

3. In contrast to Celcuity’s Gedatolisib, Faeth’s PIKTOR has two advantages. First, it targets only PI3Kα whereas Gedatolisib is characterized as a pan-PI3K inhibitor which inhibits all PI3K class I isoforms: α, β, δ, and γ. Inhibition of only PI3Kα is predicted to impart a cleaner safety profile in patients. For example, PI3Kδ is expressed on immune cells, therefore its inhibition can predispose patients to serious infections. A second advantage is that Faeth’s PIKTOR is an all-oral regimen, providing patients with added convenience, whereas Gedatolisib is an IV drug.

Key Point #1: Multi-node inhibition and the PAM pathway

PI3Ks come in three classes, and the Class I enzyme has four isoforms (α, β, γ, δ), of which PI3Kα is frequently over-expressed in cancer cells. When PI3K is active, it switches on Akt, which then acts on downstream targets, including mTOR, to drive cancer progression. This PI3K/Akt/mTOR axis is hyperactivated across a wide range of human cancers, and its members are frequently mutated.

The FDA has already approved several PI3K inhibitors, most recently Genentech’s inavolisib (a PI3Kα inhibitor). Faeth’s approach targets not only PI3K signaling, but also the mTOR pathway. PIKTOR is a combination of a PI3Kα inhibitor, serabelisib, and a dual mTORC1/mTORC2 inhibitor, sapanisertib. Preclinically, PIKTOR has demonstrated significantly improved potency vs various single node inhibitors with IC₅₀ values (slide 11) in the low nanomolar range.

Key Point #2: The endometrial cancer data so far sets up a near-term catalyst

Serabelisib, formerly TAK-117, and sapanisertib, formerly TAK-228, originated from Takeda’s acquisition of Intellikine. The combination now known as PIKTOR was previously not efficacious in patients with advanced renal cell carcinoma (RCC) after VEGF-targeted therapy. Similarly, in an endometrial cancer study investigating Sapanisertib + TAK-117 (PIKTOR), the overall response rate (ORR) was 0%. However, both these studies did not include paclitaxel in the combination (in the endometrial cancer study mentioned above, the ORR with paclitaxel monotherapy was 18%).

To this point, Faeth recently conducted a phase 1b dose escalation study of PIKTOR plus paclitaxel in patients with solid tumors. Patients had comprehensive molecular profiling to understand the extent of aberrations in the PI3K/AKT/mTOR pathway. Although this was a small study (slide 19) of 19 patients, the results were promising: an overall response rate of 47%, 3 complete responses all in endometrial cancer patients, and 4 partial responses. There were only 5 patients with endometrial cancer in the study, 3 of whom achieved a complete response.

The excellent response in endometrial cancer patients in the phase 1b is why the setup for PIK-201, Faeth’s ongoing Phase 2 study of PIKTOR + paclitaxel, appears favorable. This study is restricted entirely to advanced or recurrent endometrial cancer patients with a PI3K/AKT/mTOR pathway gene alteration who have failed prior systemic therapies, including a platinum-based therapy and an immune checkpoint inhibitor, either separately or together. Treatment options for recurrent or persistent endometrial cancer after platinum-based chemotherapy dwindle rapidly, and the response rate for single agents such as paclitaxel used in second line treatment is between 4 and 27%. A more recent study evaluating lenvatinib plus pembrolizumab had an ORR around 34%. Antibody drug conjugates (ADCs) however have shown ORRs as high as 67% (though these are dosed IV).

In breast cancer, it is worth recalling Celcuity’s positive market response upon release of their data in July 2025-this was in wild type patients, defined as patients lacking a PIK3CA mutation. Below is Faeth’s discussed endometrial cancer data with mutation details. All patients who would be considered wild type (in other words lacking a PIK3CA mutation) according to Celcuity’s VIKTORIA-1 criteria are indicated on the y-axis. Of note, there is one patient with endometrial cancer and a PIK3CA mutation among other mutations who achieved a CR (their progression-free survival, PFS, is low presumably since that patient died from COVID). It should be noted that Celcuity’s positive market response was from data in breast, rather than endometrial, cancer.

The table below summarizes Faeth’s completed, ongoing, and future trials. Hyperglycemia, or high blood sugar, is the most common adverse event within the PI3K inhibitor class of drugs. The metric to measure this is HbA1c. Faeth’s phase 2 study, PIK-201, has an exclusion criteria of HbA1c ≥ 8.0%. In other words, patients with a HbA1c level above this are not allowed in the study. Celcuity’s VIKTORIA-1 phase 3 study had a more stringent exclusion criteria of HbA1c ≥ 6.4%. Despite this, Faeth is reporting (slide 23) relatively low rates of hyperglycemia in their ongoing phase 2 study, although in a small group of patients (9% grade 1-2 and 5% grade 3-4).

Key point #3: PIKTOR, compared to Gedatolisib, is more selective and is dosed orally

Celcuity’s compound, gedatolisib, simultaneously inhibits all four Class I PI3K isoforms (α, β, γ, and δ) along with mTORC1 and mTORC2 whereas PIKTOR inhibits only PI3Kα and mTORC1/2. As noted above, this might impart a cleaner safety profile for PIKTOR. While it is still early, Faeth has shown some data that supports this theory: for their ongoing endometrial cancer phase 2 study (PIK-201), Faeth is reporting only 14% grade 1-2 stomatitis (mouth inflammation) for PIKTOR + paclitaxel (slide 24) vs Gedatolisib’s >50% stomatitis adverse events (AEs) observed in various combinations in breast cancer trials.

Gedatolisib is given by IV-infusion whereas Faeth’s PIKTOR is an all-oral regimen, providing patients with added convenience (though it should be noted that paclitaxel is given intravenously and fulvestrant is given intramuscularly). Because it combines two separate drugs rather than one single molecule, each component’s dose in PIKTOR can be titrated independently.

Faeth recently published a pharmacokinetics poster in which one of the aspects studied was the stomatitis dose/exposure relationship. This adverse event was most strongly correlated with the daily discrete dose of sapanisertib and the Cmax of sapanisertib. In this poster, Faeth included some data from a previous unpublished study of PIKTOR in patients with advanced nonhematologic malignancies. In that study, grade 3 stomatitis was observed (one case) in the higher 4 mg sapanisertib + 200 mg serabelisib dose. In the ongoing endometrial cancer trial for which data will be released later this year, the dose is lower at 3 mg sapanisertib + 200 mg serabelisib. This should overall have lower rates of stomatitis and other AEs (as supported by a snapshot of 14% grade 1-2 stomatitis discussed above).

Insider buying

Both the CEO, Anand Parikh, and the CFO, Brian Stephenson (indirect purchases made by the Brian Stephenson Revocable Trust) have made noteworthy open market buys.

Risks

1. A common bear case argument is that a competitor could add everolimus (Afinitor), an approved mTORC1 inhibitor, onto their own PI3Kα drug regimen to recreate PIKTOR

On a recent call, an analyst asked the following question: what’s stopping a competitor from adding everolimus (approved mTORC1 inhibitor) to their existing PI3Kα regimen? Faeth’s CEO noted that sapanisertib is unique since it inhibits both mTORC1 and mTORC2 whereas FDA approved everolimus inhibits only mTORC1. Faeth has previously demonstrated that to get full blockade of the pathway, one needs to inhibit both mTORC1 and mTORC2 rather than mTORC1 alone. Other dual mTORC1/2 inhibitors exist, however, none of them are FDA approved to my knowledge which makes this risk a minor one.

2. Toxicity in larger trials

Data to date suggests a favorable safety profile. In the failed study in RCC where the doublet (serabelisib + sapanisertib) had 31 patients, however, the discontinuation rate due to treatment-emergent adverse events was 29%. For larger trials, this will have to be monitored closely, however it should be noted that this RCC study investigated a higher dose of PIKTOR than what is currently used (4 mg of sapanisertib vs 3 mg of sapanisertib used in ongoing trials).

3. Success in earlier, smaller trials could anchor investors to a higher clinical bar for success, increasing expectations for future data releases

As was observed with Celcuity (slide 3), in PIK3CA mutant patients, in a small phase 1b study of 30 patients, the median progression free survival was an impressive 14.6 months in the gedatolisib + fulvestrant + ibrance (palbociclib) triplet. In June of this year, Celcuity released (slide 21) phase 3 data in a larger number of patients for the same triplet regimen also in PIK3CA mutant patients. The PFS was 11.1 months (vs 5.6 months in the control arm) and Celcuity’s stock fell by more than 20% despite being an overall impressive result.

Acknowledgement: Cheers to the smart for bringing Faeth Therapeutics to my attention a couple of months ago.

Key points:

1. Nurix Therapeutics recently announced a major licensing and collaboration agreement with Roche for bexobrutideg (NX-5948 aka bexdeg), a BTK degrader. While this deal included a $700M upfront payment, it also included a 50:50 split of U.S. profits and a 40:60 (Nurix: Roche) split of development costs. In the short term, while this decreases likelihood of an acquisition by players other than Roche, the partnership is a major de-risking event given the backing and validation of a large pharma partner.

2. In preclinical data that was generated by Nurix therapeutics, bexdeg addressed several mutations that traditional BTK inhibitors can’t address. Bexdeg also showed a high degree of selectivity pre-clinically against BTK vs BeOne’s BGB-16673 (tacabrutideg) and one of AbbVie’s BTK degraders: out of 8,700 proteins, bexdeg only degraded BTK whereas competitor compounds degraded at least 2 other targets, albeit at different levels.

3. Clinical data thus far suggests that bexdeg has roughly similar efficacy but improved safety compared to BeOne’s BGB-16673, the BTK PROTAC furthest along in clinical development. Nurix management has also indicated plans to expand (slide 15) bexdeg into several indications with large market sizes.

Key point # 1.

The deal with Roche was announced before the market opened on June 8th, 2026. The initial market reaction was a spike in share price to ~$23. As details behind the deal were digested the stock was closer to $17.

This deal with Roche means that NRIX is unlikely to be acquired by anyone else over the next several months. In April, Nurix reported a cash position of approximately $540.7 million. With the recent Roche deal however, their cash position now is ~$1.2 billion, de-risking their ability to achieve various milestones and providing run-way well into 2028.

Key point # 2.

Chronic lymphocytic leukemia (CLL) is a slow-growing blood cancer where there is overgrowth of a type of white blood cell called B-lymphocytes. The standard of care includes targeted oral therapies like BTK inhibitors (both covalent, cBTKi, and non-covalent, ncBTKi) and the BCL-2 inhibitor venetoclax. The most recently approved non-covalent BTK inhibitor is pirtobrutinib which can address the common C481S mutation. But, it does not effectively target all BTK mutations. A recent study found that the most common acquired BTK mutations detected at PD (progressive disease) during pirtobrutinib treatment were T474X and L528W, the latter which has been successfully targeted pre-clinically (slide 3) with bexdeg.

In a proteomics study, bexdeg had the cleanest profile compared to BGB-16673 and an AbbVie BTK degrader and only the desired target, BTK, was degraded to an appreciable extent. In a call last year, during the Q&A session, the Nurix team noted that this selectivity was the reason why they believe fungal infections are low in their clinical data to date.

The structures of the 3 compounds tested above by proteomics are shown below. A fourth structure on the far right was in a recent publication by authors from AbbVie.

Key point # 3.

At EHA this year, Nurix reported bexdeg Phase 1a dose escalation data in 48 patients with relapsed/refractory CLL/SLL at doses ranging from 50-600 mg daily. Only 16/48 patients were on the RP2D of 600 mg yet the overall objective response rate (ORR) was 83 %. Patients were heavily pretreated with a median of 4 prior lines of therapy which included prior BTKi therapy (98 %). Around 10 % of these patients had CNS involvement. The median PFS, progression free survival, was 22.1 months with a follow-up of 22.4 months. In a similar cohort of patients (N = 67) also with 4 prior lines of therapy, BGB-16673 achieved an ORR of 85 % and median PFS of 24.4 months with a follow-up of 25.4 months. The differentiator for Nurix was safety: Grade 3+ TEAEs were observed in 51 % of all patients (N = 142) vs 63 % of patients for BGB-16673 (N = 67). The treatment discontinuation rate was higher for Beone (18 %) vs Nurix (6 %). For BGB-16673, serious adverse events leading to death occurred in 5 patients (7.5 %). Interestingly, BeOne reported that none of these were treatment related. Bexdeg data for the phase 1b dose expansion looked promising as well: for patients who received prior BTKi but no prior BCL2i (cohort 5, N = 14), the ORR on 600 mg of bexdeg was 92.9 % despite a high rate of BTK mutations at baseline (53 % BTK mutations). No head-to-head studies of bexdeg vs BGB-16673 have been conducted so it is hard to comprehensively compare them clinically.

The table below shows some of the trials for bexdeg. Not included below is an additional planned phase 1b/2 of bexdeg in CLL combinations including venetoclax (NCT07520006) and planned phase 2 studies for Chronic Spontaneous Urticaria and Multiple Sclerosis.

Some of the bexdeg’s expansion (slide 12) opportunities include I&I disease CSU (Chronic Spontaneous Urticaria) and MS (Multiple Sclerosis). CSU is an inflammatory skin condition characterized by itchy hives and swelling of the skin. BTK inhibitors have shown some promise in targeting CSU but a degrader of BTK might have more profound impacts since degradation abolishes not only the kinase function of BTK, but its scaffolding function too. In a recent presentation in Chicago (!) at the Society for Investigative Dermatology Annual Meeting, bexdeg showed deep BTK degradation in the skin of healthy volunteers (slide 10). An IND is expected later this year for CSU.

In multiple sclerosis, BTK is an emerging target and bexdeg’s CNS penetrating ability might address some of the limitations of existing BTK inhibitors. Nurix also has an IRAK4 degrader in collaboration with Gilead which might have phase 1 data later this year, and a STAT6 degrader (NX-3911) in collaboration with Sanofi. Both of these programs have a similar 50:50 U.S. profit share and data releases for these programs might be catalysts for NRIX beyond bexdeg over the next year. Today, Kymera announced faster than anticipated enrollment in their atopic dermatitis (AD) trial with a STAT6 degrader, KT-621. Nurix’s NX-3911 (SAR448272) in collaboration with Sanofi is earlier in development for AD and NRIX’s 16 % gain today could, in part, be driven by Kymera’s announcement.

There are two relevant developments worth noting. The first is AbbVie’s law suit against BeOne regarding BeOne’s BTK program, including BGB-16673. At the least, it is clear that several big pharma players see the value of a BTK degrader asset. AbbVie’s trade secret claims against BeOne are proceeding as of May 2026 (BeOne listed this as a risk in their 2025 10-k; page 81). To make matters more interesting, it appears that AbbVie’s BTK degrader ABBV-101 has been discontinued. An article from Biospace confirmed discontinuation and the status for one of ABBV-101’s clinical trials is listed as “active, not recruiting.” As further confirmation, AbbVie’s pipeline in Feb 2026 listed ABBV-101 in Phase 1 but the April 2026 pipeline does not list ABBV-101 anywhere. With this likely discontinuation of AbbVie’s BTK degrader, it will be interesting to see how the case with BeOne evolves. Roche has not publicly disclosed their rationale for choosing Nurix over other BTK degraders, but this ongoing case, along with bexdeg’s selectivity, might be part of it.

Perhaps relatedly, Derek Lowe’s recent blog post describes unexpected toxicity from unknown AbbVie degrader “compound X.” In the referenced paper from authors from AbbVie, this particular degrader showed normal liver enzymes but degeneration in bile ducts in a dog study. To be clear, neither compound X’s structure nor biological target is disclosed in the cited paper (but interestingly, its molecular weight does match that of the structure on the far right of the image of structures above-the “AbbVie compound 1”). It is possible that this problematic safety profile was observed with AbbVie’s BTK program, but nothing has been confirmed publicly or in the paper.

Risks

1. Competition from other BTK degraders in development. BeOne’s BGB-16673 is further ahead in development. While bexdeg clearly has better selectivity pre-clinically, BGB-16673 might be first to market. Overall, I see BeOne’s position as a minor risk since the drugs seem to have different profiles and I believe there is room for more than one BTK degrader in the market. A good long-term safety profile, which usually goes hand-in-hand with minimal off-target effects, of a new BTK agent is important given how long patients are on therapy and bexdeg is highly selective. BeOne is dosing at 200 mg but Nurix is able to dose as high as 600 mg in their phase 2, highlighting the tolerability profile of bexdeg.

2. ABBV-101’s discontinuation might be viewed by some as a clinical risk for BTK degradation or a safety risk. With ABBV-101’s likely discontinuation, the focus is now on bexdeg and BGB-16673. Even if the discussed paper of concern above is from AbbVie’s BTK degrader program, the paper makes it clear that toxicity is not due to on-target or off-target degradation but rather the physiochemical properties of that particular degrader. I view ABBV-101’s discontinuation as a minor risk. One would expect major bexdeg toxicity to have emerged by now, 4 years after the first patient was dosed, and Roche likely did deep diligence on bexdeg’s safety profile (pre-clinically and clinically) before the $700M deal.

3. There is at least one BTK mutation, BTK-A428D, that is resistant to both BTK inhibitors and degraders including bexdeg. However, this is thought to be a rare mutation that can be addressed with combination regimens so it is not a major risk.

In summary, NRIX is pursuing biologically validated targets and their lead degrader against BTK, bexdeg, has an impressive balance of safety and efficacy. Updates from the rest of Nurix’s pipeline, including the IRAK4 and STAT6 programs, might be additional catalysts in the next few months. Having Roche as a partner to help execute ongoing and future clinical trials will be invaluable and I look forward to more data releases over the next 12-24 months.

Amphista’s main pipeline

-BRD9 degrader for AML (Acute Myeloid Leukemia), AMX-883

-SMARCA2 degrader for Non-Small Cell Lung Cancer (NSCLC).

AMX-883, BRD9 Molecular Glue Degrader

The rationale for degrading BRD9 for AML is described here and one of the main takeaways is that BRD9 degradation in AML cells more strongly inhibited cell proliferation as compared to inhibition alone. Many small molecule degraders in the clinic are PROTACs which are bivalent compounds with a POI (protein of interest) ligand connected to an E3 Ligase ligand via a linker. The result is formation of a ternary complex in which one end of the PROTAC binds to the POI (in the image below, the green part of the PROTAC binds POI BRD9) and the other end of the PROTAC binds the E3 Ligase (in the image below, the red part of the PROTAC binds the E3 Ligase CRBN). The result is ubiquitination of the POI and its eventual degradation. For several POIs, inhibition is insufficient to fully abrogate downstream signaling whereas degradation is (another example: IRAK4).

AMX-883, unlike most BRD9 degraders to date, is a molecular glue (MG). Molecular glues are monovalent compounds that also degrade a POI but they are usually smaller in molecular weight and have a slightly different mechanism of action. PROTACs show binding affinity to both the POI and E3 ligase whereas MGs generally either bind to the E3 ligase or to the target protein which results in recruitment of the other protein and formation of a ternary complex similar to what is shown above. Derek Lowe’s blog post from 2021 describes both PROTACs and MGs very well.

There are a few hundred E3 Ligases in the human genome, though the majority of PROTACs reported to date recruit VHL or CRBN. C4 Therapeutics’ PROTAC CFT8634 for Synovial Sarcoma is a CRBN-based PROTAC and so is Foghorn Therapeutics’ FHD-609 for the same disease. CFT8634 was discontinued since monotherapy didn’t result in sufficient efficacy. Foghorn paused development of FHD-609 for safety reasons (grade 4 QTc prolongation).

One of Amphista’s initial MG for BRD9, AMPTX-1, is a unique compound since it is a reversibly covalent molecular glue which recruits an entirely different E3 Ligase, DCAF16. This was the first reported molecular glue degrader of BRD9. AMX-883, which was recently nominated as Amphista’s clinical BRD9 degrader candidate for AML, is a slightly modified version of AMPTX-1 (see image below). Given the discontinuation of both C4 Therapeutics’ and Foghorn Therapeutics’ BRD9 degraders, I find AMX-883 fascinating. The compound is differentiated in two ways: it is a molecular glue rather than a PROTAC and it recruits an entirely different E3 Ligase, DCAF16.

PROTACs are known to have a Hook effect (Figure 3 in link) which is a phenomenon where high concentrations of PROTAC molecules can result in lower degradation. This is caused by unproductive formation of binary complexes (one part of the PROTAC molecule either binds either the POI or the E3 ligase to from a binary complex rather than forming the desired ternary complex required for degradation). Molecular glues are advantageous since they generally do not suffer from the Hook effect. Interestingly though, AMPTX-1 showed a Hook effect in cells at high concentration and authors concluded that the compound has a hybrid MOA (mostly acting like a molecular glue, but Hook effects were observed).

SMARCA2 degrader for Non-Small Cell Lung Cancer (NSCLC)

Including brief notes on Prelude Therapeutics, Foghorn Therapeutics, and Plexium Inc.

The brief rationale for targeting SMARCA2 is that mutagenic loss of SMARCA4 results in dependence on its paralog, SMARCA2, to support cancer cell growth. Selectivity of SMARCA2 degradation over SMARCA4 is important given that SMARCA4 ablation in mice leads to embryonic lethality. Unfortunately, the chemical structure of Amphista’s SMARCA2 degrader has not yet been disclosed, but it appears that it would also be a DCAF16 targeted molecular glue. Once again, Amphista is in a space where at least one other company has already stepped back from development-Prelude Therapeutics (PRLD).

On November 3rd ‘25, Prelude announced pre-clinical abstracts for a new, JAK2 inhibitor program. That day, PRLD surged approximately 152%. On November 4th 2025, at 7:01 AM, Prelude announced a $35M upfront Incyte deal for their JAK2 inhibitor program. Four minutes later, at 7:05 AM ET, they announced a pause in their SMARCA2 program and nearly all gains were erased by market open on November 4th. Prelude's VHL-based IV PROTAC (PRT3789) and oral CRBN-based PROTAC (PRT7732) were both paused given the “complex biology and aggressiveness of disease in patients with SMARCA4 deletions.” Since then, the stock has appreciated quite well and Prelude recently closed a $90M stock offering.

Foghorn Therapeutics, , on the other hand is pursuing SMARCA2 inhibition strategy, rather than degradation. Their lead compound, FHD-909, also known as LY4050784 (collaboration with Eli Lilly) is an allosteric compound that inhibits the ATPase activity of SMARCA2 with greater than 30-fold selectivity for SMARCA2 over SMARCA4. So far, it is hard to say if SMARCA2 inhibition would result in better efficacy than SMARCA2 degradation in the clinic.

Plexium, Inc., a private biotech company, is pursuing a molecular glue strategy with PLX-61639 (unknown structure) to degrade SMARCA2. This compound appears to also recruit DCAF16 in a covalent fashion, similar to Amphista’s strategy. The table below briefly summarizes the discussed approaches towards targeting SMARCA2. As an interesting side note, I found an abstract where researchers took one of Prelude’s SMARCA2 selective PROTACs (the same compound shown in the table below assumed to be PRT7732) and tested it alongside their SMARCA2 degrader in rats by IV dosing. Despite in vitro selectivity for SMARCA2 degradation over SMARCA4, both compounds degraded SMARCA4 as well in vivo, a discrepancy to in vitro observations.

How could Amphista’s approach of recruiting DCAF16 for degradation be beneficial rather than CRBN or VHL?

A paper from 2019 by Xiaoyu Zhang and co-authors from the Ben Cravatt lab described a set of electrophilic PROTACs that engage DCAF16 to degrade different POIs. They found that DCAF16 was capable of promoting ligand-induced protein degradation at rather low covalent engagement/binding of the molecular glue (10-40 %). Furthermore, since DCAF16 mediated degradation involves formation of a covalent adduct between the compound and DCAF16, the durability of protein degradation is thought to be greater. Similar observations were seen for Amphista’s AMPTX-1: in an in-vivo study in mice subcutaneously implanted with MV4-11 xenografts, BRD9 degradation was maintained at 16 h post last dose (78 % BRD9 degradation for the more active enantiomer). By this point, the concentration of AMPTX-1 was 3x lower than it was at 2 h post last dose, supporting extended target engagement.

In summary, Amphista is pursuing at least two targets that public biotechs have discontinued. Their approach is differentiated since they leverage molecular glues through a reversible covalent mechanism. The durability of DCAF16-mediated degradation in an animal model is compelling, and if this company ever goes public, I will be watching closely.

Acknowledgement: I thank my friend Patrick Rivers for bringing Amphista Therapeutics to my attention a while back.

-Their EGFR PROTAC degrader for non-small cell lung cancer, CFT8919 (in collaboration with Betta Pharmaceuticals), was discontinued based on clinical data to date and capital priorities. This is not too surprising given BeOne’s discontinuation of BG-60366 last month, also an EGFR degrader. Interestingly, investors did not react negatively to this news yesterday.

-A new phase 1b trial for Cemsidomide is planned for 2027 with 2 arms: Cemsidomide + dexamethasone + PI (proteasome inhibitor) and Cemsidomide + dexamethasone + a CD38 antibody.

-I noticed a change in how they frame their opportunity. In the April 2026 deck (slide 14), the estimated peak revenue for the initial Cemsidomide opportunity is listed as $2.5-$4B. In the May 2026 deck, this slide is gone and instead (slide 12), possibly because of the additional trial planned above, an overall estimated revenue is given for relapsed refractory multiple myeloma (~$25.5B) without a specific number for Cemsidomide.

-Cash of $268.3 million, compared to $297.1 million in December 2025. Earnings per share of -$0.20 which beat the estimate of -$0.25.

The stock was steady yesterday and up today . The exact reason for today’s increase is unclear but it might be tied to the points above and/or updated sell side analyst ratings. Either way, the next real data releases I am looking forward to:

-June 12th 2026: a presentation (poster, rather than an oral presentation) of updated results of their phase 1 study with Cemsidomide + dexamethasone at the EHA 2026 congress. My first post included data from this trial but data cut off at that time was Sept 2025.

-2H 2026: an update on the dose escalation progress from the Phase 1b trial of cemsidomide + dexamethasone + elranatamab.

Thanks for reading; looking forward to those readouts!

Key Points

1. Biochemically, cemsidomide shows the strongest binding affinity to CRBN, a substrate receptor of the E3 ubiquitin ligase, among other degraders in its class like BMS compounds iberdomide and mezigdomide.

2. In a mouse model of multiple myeloma, cemsidomide was dosed at 1/100th of the dose of mezigdomide yet achieved similar tumor regression, an outcome driven by superior pharmacokinetics and potency.

3. In the clinic, cemsidomide’s 48 hour half life, compared to iberdomide’s 9-13 h half life and mezigdomide’s 14-20 h half life, enables a unique 14 day on and 14 day off dosing schedule which results in lower rates of neutropenia than mezigdomide, the next most potent compound in the class. Furthermore, cemsidomide achieved an ORR of 50 % in a highly refractory multiple myeloma patient population.

4. Although there are risks related to the competitive landscape and safety concerns in larger trials, they don’t affect the underlying case.

Scientific background and ongoing trials

The IMiDs, lenalidomide and pomalidomide, are amongst the earliest known molecular glue degraders of IKZF1/3. They “glue” target proteins IKZF1/3 to CRBN which results in their degradation through the ubiquitin proteasome system. CELMoDs, Cereblon E3 Ligase Modulatory Drugs, are a newer class of drugs which do the same thing but with much greater potency.

Below is a snapshot of C4T’s ongoing trials for cemsidomide in multiple myeloma. In the phase 1b trial, cemsidomide is given in combination with dexamethasone, a steroid which reduces side effects and provides an anti-myeloma effect, and elranatamab, a T-cell engager (BiTE) supplied by Pfizer. CELMoDs have a unique T-cell activating property hence the rationale for the combination with elranatamab. In multiple myeloma, CAR-T therapy is best in class. Carvykti was approved in 2022 but data demonstrates that 2/3 of patients still relapse within a 5-year period, signifying the need for novel treatment options.

Key point #1.

Pre-clinically, amongst various CELMoDs and IMiDs, in work by authors from BMS, cemsidomide showed the strongest binding to CRBN in a binding assay.

Key point #2.

As noted above, in a multiple myeloma mouse model, cemsidomide (CFT7455) dosed at 10 μg/kg shrinks tumors to a similar extent as mezigdomide (CC-92480) dosed at 1000 μg/kg. This enhanced efficacy likely stems from superior pharmacokinetics: cemsidomide was detectable for up to 48 h in tumors but mezigdomide was not detectable beyond 4 h in the same model. One caveat is that this data was generated by C4T.

Key point #3.

In multiple myeloma, the depth of response, measured by a complete response (CR) rate or MRD negativity, is important. Despite an ORR > 95 %, BMS’s iberdomide + elranatamab combination achieved a CR rate of 45 %, a number that can likely be improved upon with a more potent degrader like cemsidomide. Also, BMS’s trial did not include dexamethasone, but C4T’s does (this is easy to miss from company slide decks and press releases) which should help both from a safety and efficacy standpoint.

Safety: In C4T’s Phase 1 study of cemsidomide + dexamethasone in relapsed refractory multiple myeloma with 72 patients, 6 % had TEAEs resulting in dose reductions whereas in the mezi/dex trial, this rate was 25 %. In C4T’s trial, 33 % of patients experienced grade 4 neutropenia (low levels of neutrophils, a type of white blood cell), a known class effect of these drugs. For the mezi/dex trial, this rate was 48 %. As noted above, cemsidomide’s long half life enables a two week on and two week off dosing schedule which is difficult to replicate by competitor drugs with shorter half lives.

Efficacy: In the same C4T study, in the 100 μg arm (14 patients), the ORR was 50 %. The Phase 1/2 study of mezigdomide + dexamethasone conducted by BMS had a similar ORR for the 1 mg dose of mezigdomide: 55 % (N=11). Importantly, C4T’s patient population was heavily pre-treated: 75 % of patients had prior CAR-T or T-cell engager therapy and 75 % had prior BCMA therapy compared to 12 % of patients in the mezi/dex study (dose-escalation cohort). Many of these patients didn’t exist at the time BMS conducted their study.

C4T reported a median PFS of 3.7 months and median DOR of 9.3 months for all doses. In the mezi/dex trial, the median PFS was 4.4 months and the DOR was 7.6 months. On a recent call by C4T, an analyst asked about the discrepancy in C4T’s durability of response (the PFS appears worse than mezigdomide’s but the DOR appears better) and management noted at the time that it is premature to conclude final estimates of PFS and DOR given later enrollment of the two higher dose levels (75 μg and 100 μg). Lastly, it should be noted that no head-to-head clinical trials of cemsidomide vs mezigdomide have been conducted to date.

Risks:

1. A new treatment for multiple myeloma was recently approved by the FDA and this combination of teclistamab and daratumumab demonstrated unprecedented efficacy (hazard ratio of 0.17). This risk is minor given the high rates of infections (96.5 % of patients had any-grade infections) and neutropenia (75.6 % grade 3/4 neutropenia) in the active arm.

2. Emergence of overlapping toxicity in the cemsidomide + elranatamab trial, namely neutropenia. In 2022, when cemsidomide was dosed on a 21 day on and 7 day off schedule, a few (2) patients underwent dose reductions due to neutropenia. The market reaction was a 50 % decline in the stock price. This is also a minor risk as C4T now administers cemsidomide on a 14/14 schedule and will explore 3 doses: they will start at 75 μg and will titrate up to 100 μg or down to 50 μg (in the phase 1 study, cemsidomide achieved a 40 % ORR at 75 μg, not far off from 50 % ORR at 100 μg).

3. One other catalyst is C4T’s collaboration with Betta pharmaceuticals for an EGFR degrader for NSCLC, CFT8919. An update at the end of Q1'26 was expected, though there are no updates as of April'26. This is a minor concern as CFT8919 is not C4T’s main asset in the pipeline. Additionally, C4T has other ongoing collaborations with Roche, Biogen, and Merck.

In summary, the market’s impatience misses the fact that CELMoDs are truly differentiated from IMiDs. CCCC currently trades at just below ~1x cash ($250M market cap vs $297M cash) while comparable TPD peer NRIX trades at ~3x cash. This valuation discount appears to reflect some of the risks described above. However, if data updates for both the phase 1b and phase 2 trials continue to demonstrate lower rates of neutropenia and durable responses, CCCC could close the gap in valuation over the next 12-24 months. Thanks for reading my first post!

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