Edgewise Therapeutics, Inc. (EWTX) Earnings Call Transcript & Summary

Hello, and welcome to Edgewise Therapeutics Investor Event. My name is Sarah, and I'll be the operator for today's call. I would now like to pass the call over to Edgewise Chief Financial Officer, Mike Carruthers. So please go ahead when you're ready.

Thank you, Sarah, and good morning, everyone. Welcome to Edgewise Therapeutics Conference Call to discuss our sevasemten update for our Becker and Duchenne muscular dystrophy programs. This morning, we issued a press release, which outlines these updates. You can access the press release as well as the slides that we will be presenting today by going to the Investors and News section of our website at edgewisetx.com. A replay of the event will also be available as a webcast on our website. Joining me today are Dr. Kevin Koch, President and Chief Executive Officer; Dr. Joanne Donovan, Chief Medical Officer; Dr. Behrad Derakhshan, Chief Operating Officer; and Dr. Alan Russell, Chief Scientific Officer. As a special guest, we have leading neuromuscular expert, Dr. Barry Byrne, Professor and Associate Chair of Pediatrics and Director of the Powell Gene Therapy Center at the University of Florida. Before we begin, I'd like to remind you that some of the statements made during the call today are forward-looking statements that are subject to a number of risks and uncertainties. These may cause our actual results to differ materially including those described in our reports filed with the SEC. You are cautioned not to place any undue reliance on these forward-looking statements and Edgewise disclaims any obligation to update the statements. I'll now turn the call over to Kevin.

Thanks, Mike. And for the introduction. I'd like to thank you all for joining today. I'm happy to be able to report that sevasemten continues to show significant promise for the treatment of Duchenne and Becker muscular dystrophy. We reported a new positive observations in our open-label extension study, MESA, and new 3-year data from our 12-patient ARCH MESA trial. We had a positive interaction with the FDA, which provided clear path to approval for sevasemten and are on track to deliver top line data on our confirmatory pivotal GRAND CANYON study in the fourth quarter of 2026. On the Duchenne front, I'm happy to be able to report that we observed a clinically meaningful decrease in functional decline in a broad population of Duchenne patients when compared to natural history and have identified a target dose for Phase III. We will discuss with the FDA timing and study designs for the pivotal studies in the second half of this year. Turning back to the details of the unmet medical need in Becker muscular dystrophy. Becker is a devastating disease affecting over 12,000 adolescent boys and men in the prime of their life, which is no approved treatment options today. Over a multiyear period, these patients can completely lose their ability to lead independent lives, often leading to a complete loss of ambulation and a shortened lifespan. Sevasemten is a drug with an entirely novel mode of action, and we believe this mode of action can address these unmet medical needs. And again, the FDA has provided us fast-track designation for sevasemten because of the severity of Becker muscular dystrophy. I'd like to turn our attention to some of the details of what we'll discuss today in the Becker program. Sevasemten continues to demonstrate a favorable safety profile for up to 3 years of treatment from the ARCH studies. In the new open-label data in both the ARCH and CANYON studies we see sustained disease stabilization in a population that would expect to lose function significantly over time over this time frame. We've built a prognostic model of natural history using a database of academic modeling of Becker patients and being able to demonstrate that we are significantly altering the disease trajectory in these patients. We had a positive Type C meeting with the FDA that provided a clear path to sevasemten registration with the potential to accelerate timing to the Becker launch. And then finally, we're on track to provide top line data in the fourth quarter of '26. We've enrolled over 175 patients. We have that powered a greater 95% -- 98% to deliver a statistically significant difference in North Star versus placebo. I'd like to now hand over to Joanne Donovan to discuss the details of the program.

Good morning, everybody. First, I'm going to discuss the CANYON study. Like, Kevin said, that is moving into the MESA study. The CANYON study was a Phase II multicenter study to look at sevasemten safety and effects on biomarkers in adults with Becker. The primary endpoint was prespecified and was change from baseline in CK averaged over 6 -- on 6, 9 and 12. It was not powered for North Star. The key inclusion criteria was we were looking at ambulatory mails from 12 to 50 with a dystrophin mutation and Becker phenotype, not on corticosteroids and with a North Star between 5 and 32. And that's because natural history told us that, that was the group of patients with Becker who are in the decline phase and have a reproducible natural history. We enrolled 40 adults and 29 adolescents and studied them for 12 months. Adults were on 10 milligrams of sevasemten and adolescents were on 1 of 2 doses. On the next slide, we show the primary endpoint. CK was decreased from baseline by 28%, which was statistically significant and TNNI2, which is specific for fast myosin decreased by 77%, again, statistically significant. But importantly, the functional data shows that the North Star over 12 months in these participants was stable. The placebo group decreased approximately what you would expect from natural history. The point estimates from natural history studies show mean annual decreases between 1 and 1.7, and that's shown by the green triangle. The placebo was consistent with that. The difference between placebo and active treated was 1.12 north star points. That was -- had a p-value of 0.16. Now these patients moved into the MESA study, the open-label extension. And in fact, the patients from all of our Becker studies are moving into the MESA study. 99% of eligible participants are currently enrolled. And that is of the March '25, we gave you that because that's the data cut corresponding to the data when everyone in CANYON has reached 6 months, a full 6 months of MESA. And what happened to them when they continued on sevasemten in MESA. And what we see is that the active treatment group continue to be stabilized and in fact, increased by a North Star difference of 0.8 versus baseline 18 months before. The placebo group that had declined was increased by 0.2 points since the initiation of sevasemten at the 12-month point. And looking at this duration is particularly important because 18 months is also the duration of the GRAND CANYON study. So we're showing stability over that time point. We have developed a predictive model to look at North Star changes and use that to contextualize what we've seen compared to natural history. We work with investigators at the University of Leiden. This was presented at MDA in March. And we looked at their natural history over up to 5 years to develop a predictive model based on age, functional measures that explained most of the variance in North Star, and we validated this against publications showing other natural history data in patients with Becker. And what this gives us the ability to do is look at each individual and predict their North Star trajectory, and we'll do this for our patients in ARCH as well as in CANYON. So in CANYON, after 18 months, these participants were predicted to decrease a North Star of 2.2 points. So we were enrolling patients that were predicted to decline consistent with the natural district. That's the actual patients that we enrolled. And in fact, they increased by 0.8. So that's a very meaningful difference for patients to change over that period upon. Now you heard before about our ARCH study, that was 2 years open-label study. Those patients have also continued in MESA and 11 of 12 are dosing now out at 36 months and they are stable over time. The North Star change at 3 years is 0.2 points, and the predicted decrease is over 4 points. So again, the treatment group with sevasemten is continuing to diverge from natural history. So what I'd like to do is actually ask Dr. Byrne to comment on what kind -- what's the meaning of those kind of changes for men who are living with Becker?

Thanks, Joanne. Certainly, the evidence that you've just shown about stabilization is really important and what is in the next, I believe, progressive disease that has important consequences for the quality of life in patients living with Becker. And just as is shown on this slide, even moving 1 point from unable to compensated performance of the scale of the North Star can enable someone to become a committed ambulator, get up off of a chair or live without direct assistance even in something like independent personal care. So I think we've seen this even in feedback from patients that these are important changes. So I'm really delighted to see the data thus far and now this large number of men with Becker dystrophy?

Thank you. So we took this to the FDA and had a successful Type C meeting. The FDA reviewed the data for consideration of an accelerated approval and thought really that the CANYON data alone was insufficient for an accelerated approval, actually, they said North Star is a clinically meaningful endpoint for traditional approval. And they encouraged us to continue to share the natural history prospective modeling, the MESA data ahead of the completion of GRAND CANYON. So we'll be working with them on that. They emphasize their support for GRAND CANYON for the design of GRAND CANYON so that it has potential as a single adequate well-controlled trial to support marketing authorization. And we are quite interested in the recent developments that are positioned to potentially shorten approval time. We already have fast track with rolling submission as well as exploring other options to accelerate the path to approval in this -- in a potential first therapy for this disease that has no approved therapies. We have fully enrolled GRAND CANYON with 175 patients based on the data from CANYON in many of the same centers, we're able to look at the powering again, and the study is powered at over 98% to get a significant difference, a statistically significant difference, assuming the mean difference of 1.7 extrapolated from the CANYON finding over placebo at 18 months. So that study is ongoing and moving towards having top line data in fourth quarter of next year.

Okay. Thanks, Joanne. So I think there's been tremendous excitement from the physicians and patients around this data set and really the potential of sevasemten, the first therapy to treat Becker patients. We've demonstrated over the past couple of years, long-term safety and reduced biomarker responses in the ARCH study and trends towards improvement in function over a 24-month period. In CANYON, the first placebo-controlled study in the Becker population, we met our primary endpoint of CK lowering. We showed stabilization of the North Star with trend towards improvement versus placebo over 12 months and the placebo acted just as predicted from natural history. So the first time we've seen that in a placebo-controlled study. The ARCH and MESA data, CANYON MESA data, a long-term extension continues to show positive trends in North Star, demonstrating sustained disease stabilization, continued slowing of progression. And finally, GRAND CANYON is highly powered, shows a statistically significant difference in North Star versus placebo over 18-month period. We've had good progress with that program. Very few dropouts moving along very quickly and well. So the regulatory path is clear. There are no approved therapies. It's a rare disease population over 12,000 patients in the major markets. and we've completed what we believe is a successful Type C meeting where the FDA provided us a clear path to approval. I'd like to turn our attention now to the Duchenne population. And Duchenne continues to be a devastating disease of young boys and adolescents. Despite recent approvals, there remains a significant unmet medical need with over 35,000 patients in the 3 major markets. What's really unique about the sevasemten mechanism that is mutation agnostic, meaning it can treat all Duchenne patients, and in fact, we believe because of the foundational nature of this mechanism, it can be used in combination with things like exon skippers with steroids. And we're the first company to evaluate this novel mechanism or any novel mechanism in combination and on top of gene therapy-treated patients. So it's a very exciting time. I just want to remind you about how Duchenne muscular dystrophy progresses and what's the origin of the disease. Now Duchenne muscular dystrophy is a disease, is a genetic disease where patients are missing a key structural protein called dystrophin from their skeletal muscle. And when a patient with Duchenne actually contracts their muscles, they hypercontract certain fibers and those fibers are then damaged. Go to the next slide. Those fibers turn on a set of remodeling and mechanisms that look to replace that fiber. And what first happens is that these little dots on the left or contractures, which are the broken down fiber. And then you need to have an immune response to actually clean up that fibrotic damage and then replace that fiber. And what happens in Duchenne muscular dystrophy as that the regenerative processes are overcome by this damage process and you replace the normal fibers with fat and fibrotic tissue, which leads default loss of function in muscular dystrophy. On the right, you see that sevasemten, which can decrease the contraction of the muscle by a very small extent to completely block the muscle damage response in the muscular tissue -- muscular dystrophy, skeletal muscle tissue, and this leads to the potential benefit of sevasemten in patients. So how do you develop the drug in this space? And how do you get to the right parameters to run a Phase III trial in muscular dystrophy? So in Phase II, what we really want to do is explore a range of doses to assess the safety and identify potential beneficial dose for patients in Phase III. A couple of really important thing is to determine. One is what's the target patient population. So what is the age range, what is the severity range of the patients you want to treat to create a homogeneous patient population to increase the odds of seeing statistical significance? We want to understand what's the background therapy of these patients, and we've studied extensively patients on a background of steroid, a background of patients who have been on exon skippers and a background of patients who have been on gene therapy. And we also want to try to understand at the same time what might be the primary and secondary endpoints for a Phase III design. We'd also like us to understand, can we do this quickly? And how do we dose range as rapidly as possible? We took a tack to have a 3-month placebo-controlled period to evaluate biomarkers from dose selection followed by an open-label period. As you remember from the Becker study, the biomarker responses occurred very rapidly, and we thought we could understand the biomarker response and then translate that into the functional benefit in the patient and understand how we would dose the drug. Finally, an added complexity to this particular trial is that the FDA recommended that we transitioned all subjects to the highest tolerated dose in the open-label extension after an additive safety review. So what we did in both LYNX and FOX is to an intrapatient dose escalation going up to a maximum tolerated dose and then going back down to what we think was the target dose to study that in greater depth. And so what we'll be talking about today is 18-month data in the LYNX study in patients on a background with steroid and exon skippers and 12-month data from patients who have been treated with gene therapy. With that, I'll hand it over to Dr. Donovan and talk about the details of the study.

Thank you. So this is the design of the LYNX study. Primary endpoint was safety, and the goal was to look at biomarkers and function over the longer term and to select a dose for Phase III. We enrolled boys aged 4 to 9 ambulatory on stable dose steroids largely and with certain functional criteria. And that was the case for cohorts 1 through 5 with increasing doses. We also enrolled a cohort that were not on steroids, that were steroid naive, and they were dosed at a dose of 5 milligrams. And as Kevin said, in the open-label extension part of the study, we dose escalated. We were -- with the DMC, we were changing doses and then moved to the target dose. On the next slide, we have the baseline demographics of the participants enrolled in LYNX. Now interestingly, although the enrollment range was 4 to 9, the age was shifted towards the upper end. Overall, the age was 7.5 and I'm going to particularly focus on cohorts 2 and 3, which were the cohorts that were largely dosed with the 10-milligram dose. And for about half of that 18 months, that Kevin talked about, have been on the 10-milligram dose. So that gives us the most information about that. The functional measures are shown here and about 15% were on an approved exon skipper. So we, on the next slide, here is the safety. And this is the safety in the placebo-controlled period, where you can compare across. And it was -- well, it was benign basically. It was well tolerated in the placebo-controlled period at all doses. We did see the most common adverse events have been dizziness and somnolence that we saw more at the higher doses, again, transient and mild. And in the open-label period, the safety profile was similar. Now, I'd point out this is a data cut from May, from last month, and this is interim data. So it will continue to evolve. Now we looked at biomarkers. And again, based on our experience in Becker and initially focused on that. And what we did see at CK. With CK, we didn't see changes even up to the 30-milligram dose, and we moved up to see if we could see more biomarker changes since it was well tolerated in the placebo period. TNNI2, we did see a profound decrease at the higher dose and a tendency towards a decrease of the 15-milligram dose. And what was quite interesting on the next slide was that in the group that was not with steroid naive and only on 5 milligrams, we still saw a 52% decrease in CK and a 65% decrease in TNNI2. Now this is relatively small numbers, but it does raise the possibility that steroid use is actually masking sevasemten's effect on biomarkers. And I would call your attention to that with the Becker participants, we observed significant decreases in CK and TNNI2. And these folks were not on steroids. So we were basically in the position to shift to functional measures to look at dose selection basically. And on the next slide, what are we going to use is functional measures? We're trying to look at small numbers of patients. And we, of course, included the North Star Ambulatory assessment that you're quite familiar with. And we also included the strive velocity 95th centile which is becoming more prominent. You've heard about this from -- in other Duchenne studies as well. And in contrast to looking at the North Star at a single point in time when the patient -- they are at the clinic site, this is looking over 3 weeks and basically looking at peak ambulatory performance over 100 hours of typical activity of daily living. And EMA, in fact, has approved this as a primary endpoint in Duchenne studies. And importantly, it's more sensitive, so you can look with smaller numbers and over shorter time to avoid single variability. And what we saw then in the cohorts is shown here. SV95, that's the change from baseline in the meters per second, the 95th percentile of velocity -- strive velocity in these boys. And in the doses between -- well, between 2.5 and 10, we see stability. It was even up a hair at the 10 milligrams at 3 months. And these are small numbers. You can see single digits basically. But what we did see in the 15 and 30 milligram grew was what was ultimately shown to be reversible decline in the SV95. And when we saw this, we decided that we would move all of the cohorts into either the 5 or the 10 milligrams for further study. And as I mentioned, Cohorts 2 and 3 were on 10 milligrams for the majority of the time. Some of them started out at 5. And you can see on the bottom of each graph. And because we were stepping up in dose, all of the cohorts were exposed to higher doses of the sevasemten in the red area, either at a 15-milligram or in cohort 5 at 30 milligrams. And when looking at cohort 2 and 3, I think it capitulates the whole story that we saw stability with 15 milligrams, we see a jog down. But then with the move to 10 milligrams, they're improving. And in fact, at the end of 18 months, they are basically stable compared to their baseline. The gray line indicates the natural history, and this is from the EMA approval document. And it is quite meaningfully different. Those are the 95% confidence intervals on the SV95. This is the 23 patients in cohorts 2 and 3. And you can see at Cohort 1, they didn't do quite as well. But again, they did better when they moved to 10, cohorts 4 and 5 saw an initial decrease and an improvement to better than natural history once they were back on the 10-milligram dose. So this is a very powerful dose selection tool to be able to identify that 10 milligrams would be appropriate dose moving forward. So what about other measures? The North Star, we, of course, the is open-label. We don't have a placebo group. We compared it with the multivariate regression model that was published in 2022, again, based on individual baseline functional measures, age, height and weight. The boys on sevasemten in cohorts 2 and 3 decreased a North Star by 1.5 points over the 18 months. So that's about 1 point per year. Again, this is in boys that are almost 8 at the start, so an average of over 9 -- towards at the end of the 18 months. And one would have predicted that they would have declined by about 3.5 points over that 18 months. And again, we are seeing that be observed with sevasemten was better than predicted, Much as we saw the observed with sevasemten for SV95C was better than the predicted or the natural history. We also saw the 4-stair climb remained stable with less than a second increase over the 18 months for these almost 8-year-old boys. We also did further analysis to look at sensitivity of the North Star basically. And we looked at boys with different data cuts evolve and below North Stars of 25, above and below age 7. And we found that consistently the difference between the observations with sevasemten versus the predicted favorites sevasemten by more than a couple of North Star points over that period of time. So we're going to move on to the FOX study. And looking at boys that were previously treated with gene therapy, I should say, in adolescents as well. Primary endpoint was safety. We enrolled ambulatory individuals between ages 6 and 14 that were previously treated with gene therapy for -- with an interval of more than 2 years after study drug administration. And that was to look at with a point where the biomarkers are stable, and they were relatively far out from the doses of steroids. So here, they're on the dose -- stable dose of steroids. We enrolled 32. Again, we looked at the same endpoints as within the LYNX study. And about 2/3 of the patients had been on the ELEVIDYS in clinical trials previously with a quarter in the Pfizer clinical trial and 9% in solid clinical trials. And their baseline data, as shown here, of course, they're older. These boys are 10 on average. So we're looking at 10- and 11-year-old boys starting from a North Star in the low to mid-20 and with those functional measures that are somewhat decreased compared to those in the LYNX study. So how do we, first of all, safety, and what we saw was that in the -- we had seen in LYNX that there was a slowing down in the highest dose cohort. And we saw this more profoundly in the boys in the FOX study. There was, as I mentioned before, dizziness and somnolence and slowing down. And we moved those individuals down to the 10-milligram dose within 6 months and actually within 3 months for the 30-milligram group. So we are looking now at 12-month data and trying to put that in context, which is admittedly difficult because there isn't data in the natural -- or the "natural history" after gene therapy. And so what we could find after 2 years is on boys that had been previously treated with ELEVIDYS. And there were a couple of posters that have been disclosed in boys that following 2 years after treatment and 3 years after treatment. Now those are the same groups, but they are relatively robust, 53 in 1 and 50 in the other. And in fact, the boys in FOX are likely to have been included because they were mostly from those studies. And between baseline and year 2, there was improvement between baseline and year 3. There was a decline. So the net change appears to be down. Again, not a perfect comparison, but just trying to get a sense of what's happening to the boys who is at past year 2. And in fact, our -- the boys in the FOX are now looking at the period 4 to 5 years post gene therapy, rise from floor appear to have an increase 10-meter walk run. And that's consistent with -- as you get older in the natural history, there's more decline. That's not a surprise in nongene-treated therapy. And what we did see in the boys in the FOX study was over the year, and that was a year that included that period when they were on the higher doses a net decrease of North Star of 2.4 points. The change in rise from floor and 10-meter walk run, the change was less than a second on those. So they appear to be relatively stable. But it's -- again, this is not a perfect comparison. And on the next slide, what we are weighing here is our functional observations in the LYNX and the FOX study that do support that 10-milligram dose what our plans going forward are to continue open-label dosing with the voids and adolescents that are currently in the study. We are looking to design the Phase III in the best way possible. We are doing -- completing a population PK model to look whether 10-milligram dose is exactly correct for the youngest boys and whether we need to do waste dosing in very young boys. We are going to explore the primary and secondary endpoints with regulatory agencies and if we continue to look at this against the evolving therapeutic landscape in Duchenne. And our plan is to go to the FDA in the fourth quarter for a meeting to discuss the Duchenne Phase III design and move on from there. So with that, I'd like to ask Dr. Byrne to comment on kind of where this all fits in the Duchenne's landscape.

Thanks, Joanne. Great job in reviewing a complex set of studies. And the rigor of FOX and LYNX is helped establish a dose across a wide dose range, which has not been commonly done in Duchenne studies to be economical with the study complexity. And so these studies covered that entire range, which I think helped find the strike zone for sevasemten that establishes what is the rest best balance between target engagement and the effect on fast-twitch fiber contraction. So knowing the dose now enables a Phase III study to go forward with also what's been learned in more high-resolution assessment of clinical outcomes that are clinically meaningful and the SV95C seems to really emerged as the best way to collect more meaningful data in a real-world setting than single assessments done at a study site for the North Star. This collective data is really providing insight into what boys can do when they're in their home environment. So I think it's really well positioned to develop sevasemten as an early option for patients with Duchenne. And that I think also the data regarding the concomitant use of glucocorticoids, it may become preferable in early diagnosis to begin treatment with sevasemten as opposed to the significant impacts on growth in bone health of the early use of glucocorticoids. Certainly, it's now 4 states initiating newborn screening for Duchenne, this is another opportunity to understand better how to manage Duchenne diagnosis in early age. And I think we're seeing a paradigm evolved in SMA that it makes a lot of sense that there will be combination therapies like sevasemten offers has been shown in the FOX study to have an adjunctive effect in the context of an additional disease-modifying therapy. So I'm quite excited about how this will proceed. I know it's been a complex area in Duchenne compared to the more homogeneous minings and dose selection in Becker, but I think it's really well positioned to move forward quickly now and to -- and get the benefit of sevasemten in this patient population that continues to have significant unmet need.

Thank you, Dr. Byrne. That's really a great overview of the opportunity here. I really appreciate it. So we had a great first 6 months and deliver on everything we're expecting to. We provided data on FOX and LYNX. We've gotten FDA feedback on the approval path for sevasemten and our GRAND CANYON study recruitment is complete and we're progressing effectively for -- and with the readout in the end of '26. We reported on our CIRRUS data, a 28-day readout in April. We're on track file an IND for our second cardiovascular candidate. We positioned in HFpEF and other heart failure syndromes. In the second half of 2025, we have a couple of key milestones. So we'll be providing an update on 12-week data, Part D of the 7500 program in obstructive and nonobstructive HCM. This is an update. We have been treating patients at 25 milligrams for the past 1.5 month-or-so and have just started screening in the Part D aspect of the CIRRUS study. And we expect to file the IND and initiate clinical trials with our cardiovascular candidate. We finally -- we expect to be able to deliver on a Phase III and initiative Phase III 2026 obstructive and nonobstructive for 7500 and also a Phase II trial in HFpEF with our cardiovascular second-generation molecule. And of course, we hope to be able to initiate a Phase III in Duchenne in 2026. And at the end of '26, we're on track to provide GRAND CANYON results in the Becker program. So an exciting year upcoming, looking forward to the presentations of the data. We are very well capitalized to execute on all these important milestones. We have $624 million in cash and cash equivalents. We have no debt and 105 million shares outstanding. We have cash runway through 2028, which would include 2 Phase IIIs in HCM, the launch of the sevasemten program in Becker and completion of the Phase III in Duchenne. And additionally, a Phase II study in HFpEF with our cardiovascular second-generation molecules. So very well financed for a number of milestones through '28. So it will be an exciting time for the company. And I'd like to thank you for your attention. And I'll now turn it over to the moderator for questions.

[Operator Instructions] Our first question today comes from the line of Joe Schwartz with Leerink Partners.

This is Will on for Joe. Congrats on the progress here. So one for us, I guess, just on the FDA's decision regarding the potential for accelerated approval. could you please provide any additional color on why they may have decided the CANYON data were insufficient? Was there any one specific hangup for the agency such as the sample size or the duration of follow-up? Or was this more multifactorial? I guess from our end, considering the favorable safety profile, the fact that the pivotal data are about 1.5 years away, combined with the unmet need, we were cautiously optimistic that the FDA would be amenable here. So any additional color would be helpful.

I will just provide my opinion there. I think the biggest point they made was there was a very strict interpretation of wanting to see statistical significance in a controlled study on a functional endpoint and hitting 0.0 or 0.2 or 0.16 was not sufficient. And I don't know if this is absolutely true, but perhaps having the readout of the Phase III so close to the accelerated approval as they get closer and closer together, perhaps was not interpreted in our favor. As opposed to our thought was we had -- we're primed for a confirmatory study. Given the place where the FDA is today on the risk tolerance, perhaps they thought they would just wait and not put themselves in a position where they would have to withdraw support for the program if they gave it and accelerated. So perhaps a different environment at the FDA than we had anticipated perhaps 4 months ago. That's probably the best color I can provide.

The next question comes from Laura Chico with Wedbush Securities.

This is Dennis on for Laura. So just on DMD, like as you evaluate the LYNX and FOX data, could you expand further on how you see the target population for a pivotal study? Like what are the key inclusion and exclusion criteria to implement to ensure that you identify the population most likely to realize the benefit?

Joanne, why don't you provide that feedback? And maybe Barry can also provide what he's seeing.

I think we're -- the general consensus is moving is that to get a more homogeneous population probably needs a bit older boys that have been enrolled. And that including the youngest group is somewhat problematic because you have the mixture of kids going up in North Star and indeed in SV95 and then going down. So it makes it harder to pull out the signal. And of course, it's all about signal to noise, so that noise of people going in 2 different directions becomes problematic. So I think that, that is the way that we are moving towards. We are looking at a broad population in terms of background therapy, such as dystrophin-targeted therapies as well. And that is what we are thinking. We're going to include the endpoints, of course, that we have seen. We are impressed with the performance of SV95 even in very small groups here to be able to distinguish changes, and we need to discuss that with regulators certainly.

Dr. Byrne, do you have any additional comments?

Yes. And I can add some color to that. So I agree with Joanne that sort of having more homogeneity will add to the level of confidence in the outcomes. But there is a counterbalancing factor that I think 1 of the reasons we've not seen the magnitude of effect of some of the therapies that have been applied in late school age in a 6-, 7-, 8-year-old group is because there is probably some degree of irreversibility in Duchenne that's not been appreciated previously because this was assumed that regeneration muscle would have sufficient plasticity that could overcome any fibrosis or fab conversion that happened even earlier than the time of diagnosis. So there may be a benefit to having both populations, those that are more homogeneous and then an early intervention group. And certainly, this might be an opportunity coming from the program, the states where newborn screening is being initiated. Obviously, those younger patients are not going to -- may not the -- have the same reliability in terms of the clinical outcome measures, but the functional outcome measures like SV95C ultimately in a preschool population would be very interesting data set.

Yes. I think also certainly with discussions with the EMA and the FDA in regards to the role of SV95, as you know, as Joanne described, the SV95 is considered a primary endpoint in the EU, but it's under evaluation within the FDA. So I think that's a very direct question to the FDA that we'd like to hear their commentary on in the coming months when we get feedback from them.

The next question comes from Tessa Romero with JPMorgan.

Kevin, maybe you can walk us through really, what were the key pushes and pulls that ultimately got you over the line to say that a pivotal trial in DMD is the right next step for Edgewise, what was that key finding or observation that ultimately drove the decision here?

I think what -- from our perspective, we've achieved a threshold of seeing a 2-point change versus natural history across populations in the DMD space, and we saw a level of consistency between functional endpoints that would make us believe that we could design a trial. The question does become perhaps the timing of this, which we haven't really addressed the timing of when should we start the study? We think it's a worthy study to run. The question is, when will we start it? And is it better as a life cycle management aspect for this drug? Or is it something we should invest in earlier? So I still think that we believe the investment would make sense. In Duchenne, the question is when. And we still need to hear from the regulatory agencies what's the bar from the regulatory agencies? And also what is the competitive landscape over the coming year or 2? I think it's a tough call with some of the changes that are incurring perhaps additional demands. We're seeing functional benefit as opposed to simply certain marker benefit for approval that may be coming. It's a big question mark for what the environment is going to look like a year or 2 from now. So I think that this is what we're weighing over the next couple of quarters, and we need additional feedback from regulatory agencies about how they view the space, what's the bar.

And what I would add, though, is that this company was founded on the commitment to muscle therapies and to developing something in the Duchenne space. So what we want to do is make sure that we run the right study and have the right information to go ahead and that's what we are -- that's what we've been doing. As Barry said, this is -- this was a complex study, and we're going to continue to gain information, and we're going to continue to figure out a way to do to design hopefully, what will be a positive Phase III study. And that's our goal.

The next question comes from Leonid Timashev with RBC Capital Markets.

It's Anish on for Leo. Just a couple of quick ones from us. Given that you saw some dose dependence on biomarkers like CK and TNNI2, how does steroid use to play in here? Would it truly have a masking effect or a synergistic effect with seva? And then as we think about patient cohort stability longer term with NSAA benefit, how can we be sure it's due to seva and the mechanism over typical patient heterogeneity playing in your favor?

I don't think we have a lot to say about the mechanism for the biomarker. What I would say, and as Alan can comment, we are looking at a number of other biomarkers and other proteins that move in the right direction even at the lower doses as well. So it's more complex than we had anticipated.

Yes. I think it's a complex situation with steroids and perhaps they are masking the pharmacological effects of the compound, which is definitely apparent when you look at the functional endpoints. And it's something that we're digging into right now. Certainly, what we're seeing in longer-term data that we'll give you updates on later is movement in these biomarkers, they just take on -- so the stories are having a complicated effect, perhaps it remember.

Yes. I think that we had plans of -- we've collected things like proteomics platform, the SomaScan platform. as well as longer-term biomarker data, and it does appear that over time, some of the biomarkers deepen and in particular, the SomaScan fingerprint over time seems to move the patients towards a more normal phenotype and from the Duchenne phenotype. I should also point out that the fingerprint of a gene therapy-treated patients is somewhat different than the gene therapy for -- than the proteomic fingerprint of a nongene therapy steroid background patients. So there's a level of complexity of what these drugs do, but in all cases, it appears over time that we moved the fingerprint of the patient population we're looking at to a more normal phenotype, which I think is reassuring, but it takes some level of time to see that fully for. And so this is partly one of the reasons why we continue to dose the open-label extension, and we want to either receive those biomarker response deepen and also see continued stabilization. And of course, as you go out in the Duchenne populations for longer and longer time periods, the delta of what you anticipate their decline should be -- should increase, which gives us much greater confidence in running a Phase III study in one of these patient populations. Also in thinking about the design, we're also contemplating probably need at least 18 months, which was the duration of the givinostat study of the older boys. So these are all considerations for the Phase III design, which these types of things and continued dosing of the current patient population will give us additional information.

The next question comes from Srikripa Devarakonda with Truist Securities.

I have 1 question on the accelerated approval feedback that you got from the FDA for BMD. I wanted to dig a little deeper into the comment in the PR, where it says that the FDA is encouraging at once you continue to share data from the open-label extension and the modeling data from natural history. Does that mean there is a potential to revisit the accelerated approval even ahead of GRAND CANYON data? And at what frequency would you be able to show the FDA these data? And I have a follow-up.

Well, the cadence of the data cuts, the next data cut will be in probably the beginning of the fourth quarter. And so we can have that ready for a discussion with the agency of the first quarter of '26. I think they gave us some really clear guidance that they wanted to participate in building -- helping us build the model that would be most supportive of both the MESA and GRAND CANYON data from a standpoint of natural history. So the view on the model that we've built as one where they would like to have participation in building that model and how it would support both of the potential filings. With fast track designation and also with the newly announced, although a little bit undetermined voucher program, where the FDA will look at data early to speed up approvals, we think that we'll be able to provide them portions of the MDA for the portions of the filing earlier and then be able to jump off from a positive GRAND CANYON result, ultimately getting us to market in a more rapid way. So I think this is really under -- I think it's a moving target at the moment exactly how the FDA might work with sponsors to accelerate marketing approvals. But I think it's -- they seem quite open and interested in driving this kind of interaction. So we'll set to be determined.

Okay. That's very helpful. And I have a follow-up question for Dr. Byrne. You mentioned the potential for sevasemten to be used in early age instead of steroids. What would you need to see to be able to do that? Would you need to see a head-to-head study?

Joanne can comment and then I can chime in.

I think that there is -- yes -- so in order to -- we talked about and thought about younger boys for sure. And whether there's interesting data that something like SV95 can actually look at changes even in a young as 1.5 year olds, which is, of course, very exciting to be able to try to intervene and preserve muscle early. So I think those are all things that we are thinking about. We needed certainly to understand the dose and the PK modeling to be able to go down to lower ages. And it's something we'll certainly be talking about with experts like Dr. Byrne.

Yes. I agree that there's -- this is an exciting area to expand into. It's probably not on the immediate horizon because of the complexity of understanding the PK at that age and the proper dose, but it's an area where there certainly is an exciting opportunity.

The next question comes from Yas Rahimi with Piper Sandler.

This is Liam on for Yas. Congrats on the data. Just to bring it back to the Type C meeting, we're just wondering if the FDA specified if they need to see a specific delta on the NSA change in order to support approval in BMD and whether they mentioned any key secondary endpoints you'd be looking for as well?

I think that they were looking for statistical significance in a functional endpoint and that North Star was an appropriate endpoint for a full approval. Beyond that, they were, I feel, reasonably confident that even a 1-point change would be meaningful because I think we brought along a better patient to speak to the FDA. And I think they were compelled by that conversation of the -- what a 1-point change means to a Becker patient. And so I don't think the magnitude was in question. It was the demonstration in a well-controlled, placebo-controlled trial that you would see a statistical significance. So I think we've designed that into Phase III.

I think, you have to look at this disease as the decline occurring over a decade over 2 decades. And if you can alter that slope of decline, you know that the adolescents are starting in their third -- in the 30s in North Star, you know that the guys in their 40s are down in the single digits predominantly. So if you can decrease that decline, that has a clear meaningful effect on that. And I don't think that we've been questioned about that by the FDA.

The next question comes from Cory Kasimov with Evercore.

I want to also ask again on the approval pathway for Becker and this new voucher program that you mentioned is a potential way to accelerate a review now post GRAND CANYON. Did the FDA specifically mention this program, this opportunity to you? And if so, is there any sense on what you would have to do to implement it and when you would start submitting other aspects of an application package prior to the readout of GRAND CANYON, if this is indeed a viable program for sevasemten?

Yes. This has actually came out after we had actually spoken to the FDA. So this is not offered up as an option. And I think it was -- it's not it's unclear at the moment what that program will look like ultimately. But we're certainly in the throes of thinking through how we would approach the FDA for discussions with this -- with new program, but there's very little information. This needs -- this came out I think about a week of sale, but it is in congruence with the idea that the commissioner has seeking ways to accelerate approvals. So from that standpoint, it's reassuring that we should be in a position to have data early and provide modules of the filing to them to review more quickly. And so that may take off time off the back end of the GRAND CANYON results.

Okay. I guess at this point, though then, would you prefer the default position that investors take which is what we're taking already, but the default position kind of across the border is that the GRAND CANYON study will be the pivotal study to enable a full approval and just assume a normal time line off of that, that has the potential to be accelerated.

Yes. I would suspect, I think that's the base case that we're looking at.

The next question comes from Paul Choi with Goldman Sachs.

This is [ Cleo ] calling in for Paul. I kind of want to like circle back on that in terms of like the BMD filing strategy. You mentioned earlier in the call that you're looking at other options for accelerating it even if it is a full approval. Are we sort of correct in assuming that, that is not going to include any kind of statistical amendment to the study but rather potentially exploring options like acquiring a prior-to-review voucher or something like that. Just a little more color would be helpful for us as we think about this time line going forward.

I think that while we are in a position where we are moving ahead with our CMC package to make sure that, that's available well before any potential filing as well as the rest of our package, and we're looking at ways of exploring getting the statistics ready for the FDA to accelerate once we have the GRAND CANYON study. They are interested in engaging on the natural history study. So that always gives us an opportunity to discuss more accelerated pathways. And as you know, fast track is the presumption that when you file with fast track, you get the priority review.

Fast track in and of itself, provides the opportunity for a priority review and additional conversations on a regular basis with the agency, and they've been open to having these conversations.

The next question comes from Moritz Reiterer with Guggenheim Securities.

This is Moritz from Debjit's team. I would like to come back to the steroid-naive cohort on the BMD side. Do you have functional data from that cohort as well? If so, do you see a sort of a similar delay on the efficacy, the functional efficacy of sevasemten in steroid-treated versus steroid-naive patients? And if so, what might that mean for the Phase III design as well as the overall role of sevasemten in BMD?

Yes. These patients who are not on steroids that are relatively flat in SV95 over a 3-month period. It was a very small group, and those patients. Some of those patients moved on to take steroid post 3-month period. So I think the ends are quite small. So we would need to add additional patients in this nonsteroid cohort to get additional information. I think we are capable of running a trial in steroid-naive patients. I think there's places in Europe as well as alternate patients in other parts of the world where steroids aren't utilized to the same extent as they are in the U.S. But that's to be determined. And as you might imagine, it's a relatively complex regulatory path within the U.S. to actually move forward with the nonsteroid treat population, but it is intriguing the magnitude of the biomarker response and what we've seen very early studies in small ends.

Yes. The original design, they were -- what we were asking ethics committees was basically to delay the treatment with steroids for 16 weeks, and that was deemed appropriate. So they did have the option that was written into the protocol. It's starting at 16 weeks. So a couple of bids. So the numbers become very, very small. But as Kevin said, they're stable. They seem to be very stable over time.

The next question comes from James Condulis with Stifel.

Just another on Becker. Just curious, in your discussions with regulators, did the baseline imbalances on North Star and CANYON come up at all? And kind of along those lines, I guess, as you think about the Phase III, should that imbalance color our view at all of the 12-month effect size? Or is it really not all that important? Just curious for any color. I'm curious if the KOLs, any thoughts also.

It actually didn't come up with FDA. I would say that remember, the CANYON study was 40 patients 3:1 randomization and 2 cohorts. So that was -- that's where randomization doesn't always operate perfectly with small numbers like that. And the GRAND CANYON study, we have 175 patients, 2:1 randomization. So 120 randomized to 1 group and approximately 160 to the other. So that should not happen with that large number of enrollees.

There are no further questions at this time. So I'd like to pass the call back over to Kevin Koch for closing remarks. Please go ahead.

Well, thank you for your attention. Great questions. And I think we have a really exciting set of programs here at Edgewise, making great progress and look forward to speaking with you in the future. I really like to thank all our supporters of our shareholders, but in particular and the employees that actually work for Edgewise and their families and the hard work. There was to provide all this information you all today. I think even more importantly, it's the patients and their families that took the time to participate in our studies and the physicians who manage these studies to bring these new therapies to patients with high unmet medical needs. So I'd like to thank you all for your attention. We look forward to speaking to you in the future. Thank you.

That concludes today's webinar. Thank you for your participation. You may now disconnect.