Edgewise's Sevasemten program meets the FDA's guidance for Accelerated Approval - and has a good chance of working in Phase 3.

If the Food and Drug Administration is serious about giving "expedited approval for serious conditions" they should encourage Edgewise Therapeutics to submit for approval in Becker Muscular Dystrophy.

Word Count: 3,453 words, Reading Time: 16 minutes

Edgewise Therapeutics EWTX 0.00%↑ reported placebo-controlled Phase 2 data in December 2024 for their drug candidate sevasemten in the treatment of Becker Musclar Dystrophy (BMD). The data was, for the most part, exactly what the company expected and close to the best case scenario investors could have hoped for. During recent investor conference presentations the company has said they intend to go to the FDA for clarity on their ability to submit for Accelerated Approval ahead of their Phase 3 data readout in late 2026. Accelerated approval is not the biggest factor in determing the NPV of this program - that would be the probability of success in the Phase 3 trial - but accelerated approval could allow the company to be on market in early 2026 versus early 2028. Two additional years of sales and the associated cash flow would help fund their pipeline, specifically their cardiology assets, and could make a big difference in how investors perceive the company and the possibility of future dilution. Recently, when Chimerix CMRX 0.00%↑ unexpectedly received clearance from the FDA to submit for accelerated approval the stock rallied from $0.87 to eventually a buyout offer at $8.50, even before the confirmatory trial results which are in no way guaranteed to succeed. I do not believe investors are currently placing high expectations that Edgewise will be able to file for accelerated approval.

In this article I intend to lay out why the agency - based on their own guidance - should specifically give conditional approval to sevasemten pending the confirmatory readout and why I also think the confirmatory readout has a good chance of succeeding when the Phase 3 data is released in Q4 2026.

Note #1: I know that maybe by the time you read this Edgewise might have released a data update on their cardiovascular program in hypertrophic cardiomyopathy. That side of the pipeline represents the bulk of the current valuation for the company and, depending on the quality of the data, has the potential to move the stock +/- >50%. With this article I hope to establish that Edgewise has more value backstopping it than just that cardiomyopathy program and that value is not being appreciated by investors. The Hypertrophic Cardiomyopathy program is obviously quite interesting and may warrant a future article, depending on the next data update.

Note #2: This email has a lot of slides and pictures so might be best viewed in browser or on the Substack app due to length. If you don’t see my signature at the end, your email client cut off the bottom of the post.

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Why Accelerated Approval Makes Sense

You can read the FDA’s December 2024 draft guidance here. Draft guidance is often made final so while nothing the FDA writes is ever truly binding it does give good insight into their current thinking about rapidly delivering approvals to the public in serious conditions.

While they organize their document differently, I will boil down the document into four parts:

1. Unmet Need

2. Efficacy

3. Safety

4. Fully Enrolled Confirmatory Trial

Through each of the four parts I will attempt to demonstrate why I believe Edgewise has met or exceeded the standards necessary for Accelerated Approval.

When it comes to regulatory actions, decisions may not always seem logical. In the end, despite everything I lay out here, the FDA simply might just say no for reasons that will never be revealed or make sense to investors.

But through these sections I will also attempt to justify why I think the company’s GRAND CANYON Phase 3 trial has at least a 50% chance of succeeding. I will also take some lessons from the failure of Fulcrum Therapeutics’ Phase 3 in FSHD, what I learned from that trial’s complete lack of efficacy, and why those lessons I do not believe are relevant to Edgewise Therapeutics based on what they have shown so far.

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Unmet Need

The above slide makes an excellent, well argued case for the unmet need in BMD. Now I am not arguing this rises to the level of Duchenne Muscular Dystrophy. That is a condition that progresses faster, affects younger patients, and has a more established and aggressive advocacy arm to articulate the voice of the patient. But the FDA has shown a tendancy in the past to want to approve new musuclar dystrophy drugs. They have shown they are willing to use novel endpoints determined by the community and KOLs (Reachable Workspace in FSHD), willing to rely on one placebo-controlled trial, and willing to consider surrogate biomarkers in the totality of the evidence. I think it will be easier to summarize what Edgewise has already shown in their three BMD studies thus far and we can weave the unmet need from there, especially in the confirmatory trial section where I think I can make a valid analogy to the accommodations the FDA gave Amylyx AMLX 0.00%↑ in Amyotrophic Lateral Sclerosis knowing their confirmatory trial was fully enrolled and was going to read out shortly after an approval decision.

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Efficacy

The disease progression of Becker is marked by a uniform and persistent loss of function in motor abilities. It is a cruel disease striking patients in the prime of their life and taking away their independence in a grinding fashion year after year. The above graph charts the decline of motor abilities via three natural history studies using the North Star Ambulatory Assesment score, a 34 point scale of function measured across 17 rating items (2 - Normal, 1 - Modified, 0 - Unable To Achieve). The scale being so simple makes it have a good degree of inter-prescriber consistency. I think it’s rational to say that three physicians could see one patient independently and arrive at NSAA scores that are very close if not the same.

Once a patient starts to decline (goes below a score of 32 on the NSAA) the three studies above helped Edgewise arrive at the theory that patients decline uniformly at about 1.2 to 1.8 total points on the NSAA yearly. So if a patient starts at 30, this theory posits that a decade later they will be around a 15. This is an unbelieveably brutal diagnosis to give a patient. I used the word “theory” above because there is very little placebo-controlled data in this disease. Edgewise is running the first ever Phase 3 trial in BMD. So predicting the behavior of the control arm is a bit of a wild card but we do have some evidence to guide us.

Let’s recap the efficacy of the first of Edgewise’s studies:

ARCH was a single-arm, open label study to be compared to the natural history data. Over a two year period, 9 patients gained nearly one point in NSAA score compared to the natural history expectation that they would lose 2.4 total points on the NSAA. This delta was obviously hugely encouraging news for patients. Something to note in that +0.75 above is I believe it excludes one patient who had a meniscal tear, confounding that patient’s last few measurements. But even if they were included in the average, the nine patients who made it out to two years were, on average, able to halt their disease progression for two whole years. That’s incredible news! Also encouraging was the responder analysis that showed 66% of the two year patients either were stable or improved. Three patients started the study but didn’t make it to two years, but two of those three transferred to other open label studies with the drug. For open label data this was a remarkably encouraging starting point regarding the NSAA endpoint which comprises the primary endpoint for the Phase 3.

The company also looked at two specific biomarkers and had biomarker-based endpoints as the primary endpoint in all of their Phase 2 studies, perhaps not expecting to see such a clear separation on NSAA.

Creatine Kinase (CK), an enzyme released from damaged muscle, is a logical biomarker to use in muscular dystrophies but it can be confounded by increased activity levels of the patient. CK levels were consistently reduced in ARCH patients by roughly 35% out to the two year mark at every intermediate and final measurement.

The study also looked at troponin I protein from the TNNI2 gene, which is a measure of “fast twitch” skeletal muscle. Sevasemtem’s mechanism of action is to inhibit contraction-induced damage that causes excessive degeneration. Therefore, troponin I protein (TNNI2) could act at a surrogate for muscle damage that has occured. Sevasemtem caused a large, immediate, and consistent drop in this protein. That’s a great sign that muscle damage was potentially being reduced.