Edgewise Therapeutics Inc Aktie

Hello, and welcome to the Edgewise Therapeutics Update Call. [Operator Instructions] As a reminder, this conference is being recorded today. If you have any objections, please disconnect at this time. I would now like to pass the call over to Michael Nofi, Edgewise CFO. Please proceed.

Thank you, and good morning. Welcome to the Edgewise Therapeutics conference call to discuss our top line data of EDGE-7500 from the Phase II CIRRUS-HCM Part D 12-week trial in individuals with obstructive and nonobstructive hypertrophic cardiomyopathy. This morning, we issued a press release, which outlines these results. 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 www.edgewisetx.com. A replay of the event will also be available as a webcast on our website.

Joining me today are Dr. Kevin Koch, Chief Executive Officer; Dr. Behrad Derakhshan, Chief Operating Officer; Dr. Aylin Tugcu, Senior Vice President, Cardiovascular Clinical Development and Medical Affairs; Dr. Michael Ayers, Director of the HCM Center of Excellence at the University of Virginia and EDGE-7500 Clinical Program Lead; and Dr. Chris Duton, Senior Vice President, Cardiovascular Clinical Research and Operations. At the special guests, we have Dr. Anjali Owens joining us, a CIRRUS-HCM Investigator and Medical Director at the Center of Inherited Cardiac Disease, and Associate Professor of Medicine at the University of Pennsylvania.

Before we begin, I would 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 these statements. I will now turn the call over to Kevin.

Thanks, Michael. Thank you all for joining today. Edgewise is a leading muscle disease biopharmaceutical company developing novel therapeutics for muscular dystrophies and serious cardiac conditions. The company's deep expertise in muscle physiology is driving a new generation of novel therapeutics. Sevasemten is an orally administered first-in-class skeletal myosin inhibitor now in Phase III studies for Becker, which will read out in the fourth quarter and in Phase II studies in Duchenne muscular dystrophy. In our cardiovascular pipeline, we have EDG-7500, which is a novel cardiac sarcomeric modulator for the treatment of symptomatic hypertrophic cardiomyopathy currently in Phase II, which will be the subject of our disclosure today.

And as a second novel molecule, EDG-15400 is a novel cardiac sarcomeric modulator for the treatment of heart failure, currently in Phase I, which we're moving into Phase II in the third quarter. We've really had a company-changing event as of June 1. I'd like to describe it a bit for you. So Edgewise Therapeutics entered into a definitive agreement under which Servier, an independent international pharmaceutical group governed by our foundation, will acquire Sevasemten and Edgewise's muscular dystrophy platform, which will conclude all IP, know-how and additional key personnel. These milestone payments of up to $1.1 billion and a cash infusion of $1.55 billion make for a very important event for Edgewise and the ability to independently move forward and become a true cardiovascular company.

We think Servier is an excellent partner with the global scale, patient commitment and commercial reach to maximize the full potential of the drug for the treatment of patients with Becker and Duchenne. We expect this event to close sometime in the third quarter, subject to regulatory clearance. With that, I'd like to pass it over to Michael Ayers to discuss the unmet medical need in Hypertrophic Cardiomyopathy.

Thank you, Kevin. Hypertrophic cardiomyopathy is the most common inherited cardiomyopathy affecting around 1 in 300 people. It is underdiagnosed, misdiagnosed and even patients who are correctly labeled suffer from significant delays in diagnosis before the shortness of breath, chest tightness, fatigue, passing out or ultimately recognized as HCM. There are 2 subtypes, obstructive and nonobstructed, and we'll get into that on one of the upcoming slides. But suffice it to say, current treatments have significant limitations for both subsets in obstructive patients, but particularly nonobstructive hypertrophic cardiomyopathy, an area breth of any real approved evidence-based therapies. As we zoom out and look at the heart models on the next slide, you'll notice the healthy heart in the center, where all of the segments are around 1 centimeter thick.

Now the first thing I'm going to point out on the heart of the left and the heart on the right, the obstructed and nonobstructed heart is actually a similarity at a cellular level. Both of these hearts are virtually indistinguishable on a cellular level, both have abnormalities in how they contract and both, more importantly, have abnormalities in how they relax. So now let's zoom out and think a little bit about the differences. The difference in an obstructive and nonobstructive heart is not the heart muscle itself, it's actually a location problem. The heart on the left will suffer from a blockage of blood flow when the thicken heart muscle is positioned in just the wrong spot. And now in order to achieve 120 millimeters of mercury of systolic blood pressure, the ventricle has to create 170 millimeters of mercury or more of pressure.

There's an uncoupling of that work and now the heart is essentially working harder than it needs to. The heart on the right doesn't suffer from the location issue, but still has those same cellular problems, abnormal contraction and more importantly, just like the heart on the left, abnormal relaxation. Segueing out of that and beginning to take a 30,000-foot view as a state of modern therapies, I'll be quite candid. The obstructive population on a population level has some relatively good options. Modern therapies make patients feel better, they can exercise further. Their blood work looks better.

But on an individual level, we're going to see a much less rosy picture. Only 2 out of every 3 patients in modern trials in obstructive hypertrophic cardiomyopathy will achieve full gradient relief or full symptom relief. And only 1 out of every 3 patients will achieve both full gradient relief and full symptom relief. Now there's really 2 hypotheses in the field why that might be. The first hypothesis is that these drugs reduce obstruction by reducing systolic function. That is how they work. And while that might alleviate obstruction, that might have some undue consequences when it comes to exerting yourself and your ability to muster up some of that cardiac reserve.

And it certainly has some more pragmatic implications in introducing an echo-dependent dosing strategy. Now the second hypothesis as to why there's so much residual symptomatology despite effective gradient relief is that these drugs are actually mild or modest at most in improving diastolic function. Moreover, the way in which they improve diastolic function comes at direct systolic liability. We have coupled the diastolic improvement with systolic cost. And that's why when you zoom out and you look at both disease states, the real unmet need here is a drug that can alleviate obstruction without introducing systolic cost and potentially improve diastolic function directly.

We now can see kind of a granular build of that unmet need, the residual symptoms, the fact that there's no approved therapies whatsoever that are evidence-based and nonobstruction. And on our top 2 bullets, we have that echo-dependent strategy, that test nisnance for providers who are having to migrate through the REMS and for patients who are having to return for echoes on weekly to monthly cadences. And that's not to mention the elephant in the room, the black box warning for systolic heart failure, which is directly tied and linked to the way these drugs work. It's in that light that 7500 steps into play with a novel mechanism of action. This drug reduces obstruction, not by diminishing overall systolic performance, but by reducing early systolic pressure generation.

It also directly changes myocardial mechanics in a way that improves diastolic performance and hopefully introduces us to an era that I think you might think is quite possible of an echo independent dosing strategy moving forward that not only divorces itself from echoes, but also begins to address that large unmet need of diastolic dysfunction. And with that, I'm going to turn it over to Dr. Aylin, who can hopefully convey some of what makes us so excited this morning.

Thank you, Michael. CIRRUS-HCM Part D is our 12-week open-label goal-directed dose escalation study of EDG-7500 in both obstructive and nonobstructive HCM. The primary endpoint is safety. We enrolled 53 patients, 20 with obstructive and 33 with nonobstructive HCM. All patients started at a 25-milligram dose and were up titrated every 2 to 4 weeks with the goal of optimizing efficacy and tolerability. The escalation criteria were subtype specific. For oHCM, dose titration was guided by left ventricular allow tract gradients resting below 30, Valsalva below 50-millimeter mercury. For nonobstructive HCM, titration was guided by NT-proBNP targeting below 200 picograms per milliliter or greater than 50% reduction from baseline.

After week 12, patients transition into a long-term extension on their optimized stable dose with physician flexibility to use up to 200 milligram. Next slide, please. Here are the baseline characteristics for our 53 participants. This population is directly comparable to what was enrolled in pivotal CMI trials. For our obstructive cohort, mean aged about 59, 45% female, 70% NYJ Class II, 30% NYJ Class III, atriibrillation history of 10%. Baseline KCCQ scores in the low 60s, confirming meaningful symptom burden. Left ventricular ejection fraction was preserved at 66.6%, resting LVOT gradient was 40-millimeter mercury, Valsalva 85-millimeter mercury. The nonobstructive cohort was younger at mean age 49, with longer disease duration, higher NT-proBNP at 781 picograms per milliliter and higher atrial fibrillation history at 21%. KCCQ scores were comparable across both subtypes, around 61 to 66 confirming similar symptom burden.

The populations are representative, symptomatic and directly benchmarkable against published CMI data. Next slide, please. We screened 107 individuals, 53 were enrolled, a screen failure rate of 50.5%, consistent with pivotal CMI trials. Now let me walk you through the dose distributions because the 2 subtypes landed in different places, and that's a direct result of different escalation criteria we use. For obstructive HCM, where titration was guided by LVOT gradient, 65% of patients reached 100 milligram or higher by week 12, with 35% on 100 milligram and 30% on 150 milligram. About 1/3 of patients met the gradient target at lower doses, so the protocol held them there.

For nonobstructive HCM where titration was guided by NT-proBNP, the distribution shifts to the right. 84% reached 100 milligram or higher with a full 50% at 150 milligram. The NT-proBNP target required more dose to achieve and the escalation design allowed patients to get there. So the difference in dose distributions between the 2 subtypes is driven by the escalation criteria, left ventricular outflow track gradient for obstructive HCM, NT-proBNP for nonobstructive HCM, not by differences in tolerability. I'd also note that our Valsalva gradient target for obstructive HCM was below 50-millimeter mercury, whereas pivotal CMI trials used below 30-millimeter mercury. Despite that, the efficacy results are robust across every domain, and we see that as a meaningful optimization opportunity as we move into dose selection for our Phase III trial.

With that, I will turn it over to Dr. Anjali Owens to walk us through the left ventricular ejection fraction and efficacy data of Part D.

Thank you so much, Aylin, and good morning to everyone. It's really my pleasure to be here today to present the top line results of the 12-week Part D data. I'm going to present the results in 3 sections, starting with safety by a deep dive into all ways of assessing systolic function, then we'll focus on efficacy in the obstructive population followed by efficacy in the nonobstructive population. We have not observed any detrimental effect on systolic function with 7500 to date. Here, the first slide shows data from our Part A single-dose study and you can see on the left, resting gradients, which are responsive to Cmax versus Ctrough with the maximal gradient response observed at Cmax.

But what you'll observe on EF on the right-sided graph is no sensitivity to the concentration of drug, a very flat line for EF despite the concentration and when it is taken. Next slide. Next, I have core read echo data in the obstructive group and the nonobstructive group. You can see there on the left, looking at LVEF at baseline and over 12 weeks of treatment. And on the right, the absolute change from baseline. These are extremely flat lines with very little variability, and we saw no participants with a drop in LVEF to less than 50%. Next slide. Here's another way of looking at the LVEF change. This is looking at LVEF absolute change from baseline versus EDG-7500 plasma concentration. I have dots in gray that represent the healthy volunteer placebo group, and you can see the range of LVEF on the left for them and then the obstructive group and the nonobstructive group in the triangles and the squares.

And again, what you can see here is no relationship between LVEF and plasma concentration. There is no decline in LVEF as concentration goes higher. There is also no unexpected drops at low concentration. Next slide. This is another way of looking at systolic function. This is global longitudinal strain complementary to left ventricular ejection fraction. And you'll see the absolute change in GLS from baseline on the left. You got your healthy volunteer placebo group, again in gray and their range, followed by the obstructive and nonobstructive groups, looking at a far range of concentration. Again, you see no change, no decline in global longitudinal strain despite the concentration of 7500, very flat, very reassuring that we're not affecting systolic function with this drug.

Next slide. Yet another way of looking at systolic function. This is global circumferential strain. Again, another way of looking at how the heart is functioning from a contractile state, healthy volunteers, placebo in gray, followed by the obstructive and nonobstructive group. And again, a very flat line right near 0, showing that despite even very high concentrations of 7500, we are not seeing a decline in systolic function as measured by global circumferential strain. Next slide. Here, we have all of the patients to date that have been dosed with 7500. So you have the single and multiple ascending dose population, Parts A and B, obstructive HCM, Part C, nonobstructive HCM and all of our Part D participants versus the EDG Plasma Concentration.

And what you can see here is a very, very flat line. We are not seeing declines in ejection fraction that are dose dependent nor are we seeing outliers with unpredictable drops in ejection fraction. This to me is very good data that's accumulating over time, supporting that we may be able to move away from dosing based on echo because we don't have to worry that the ejection fraction is going to drop at higher dose levels with 7500. Next slide. So to summarize that data across all studies, we now have greater than 240 individuals who've been exposed to 7,500 with more than 700 echos now performed assessed by the core lab and over 420 of those echoes were in patients who have HCM. We've seen, one, no clinically significant changes in LVEF; two, no reductions in LVEF to less than 50% and very importantly, no heart failure events, no hospitalizations due to drop in LVEF.

And this is with doses spanning from a very low dose at 25 milligrams all the way up to a high dose of 300 milligrams. This observed lack of systolic liability does support moving toward an echo-independent dosing strategy. This would uncouple dosing from safety echos and allow us to dose based on symptomatic improvement. And finally, this preservation of global circumferential strain, which is a very highly sensitive marker of systolic mechanics, really separates the mechanism of action of this drug from CMIs and the published data on CMIs. Next slide. Next, let's move to efficacy. We're going to start with the obstructive population where we saw robust gradient and feel and function improvements, again, with no impact detrimentally on LVEF.

I'll start with the gradient data pictured on the left, resting data in the blue line, Valsalva data in the light green. This is baseline over 12 weeks of dosing. And at baseline gradients were 40 dropped to 18, which represents over 50% reduction versus baseline. Valsalva gradients were quite high in this population with a baseline of 85 dropping to 40 after 12 weeks, which again represents greater than 50% reduction. And you can see that in aggregate, this cohort reached our levels of obstruction that are below the threshold that we think is important. So below 50 for Valsalva and below 30 for resting. Overall, in this population, we saw 90% demonstrated clinically meaningful improvement in their gradients, either at rest or with Valsalva.

Next slide. What happened to our biomarkers. So we know from studies of other drugs that modulate contractility that when you decrease the gradient, you typically see improvements in NT-proBNP and troponin. And that's exactly what we saw here after 12 weeks in the obstructive population. So you can see on the left, about a 60% reduction in NT-proBNP baseline to 12 weeks. And on the right, about a 40% decrease in troponin baseline to week 12. That's summarized with 74% of our obstructive patients who achieved either a normal level of NT-proBNP or a reduction of greater than 50% from baseline. And I'll just call your attention to the time line. We are seeing those drops quite early at the 4-week visit.

Next slide. What about how patients feel and markers of disease state and stated quality of life. So for that, we're looking at the KCCQ score. And this is the KCCQ-OSS pictured in the graph on the left, where you can see from baseline to week 2, a pretty strong improvement even within the first 2 weeks that continues to improve. At week 12, we're up to a 24-point improvement in the OSS score. The CSS score also improved by about 20 points from baseline to week 12. Again, these are open-label studies, and we know that from other work, placebo accounts for at least 5- to 7-point increase. So we'll take this with a grain of salt, but very favorable data.

And in comparison to an open-label COLLIGO study of mavacamten, this is real-world data for mava, about an 11-point increase by week 12. Next slide. What about a responder analysis? How do we get a sense of how many patients are going to improve, which is really what we want to know when we move into Phase III and ultimately, if the drug is approved. So this responder analysis looked at the percent of obstructive patients who achieved what we think of as a clinically meaningful change in the KCCQ-OSS defined as a greater than or equal to 5-point change. And we saw that 85% of patients in this cohort achieved that with 75% achieving greater than or equal to 10 points.

And I'll just call your attention to the last bar where there's a very large improvement of over 20 points in over 30%, almost 40% of this cohort. So robust clinical improvement. Next slide. Let's look at that in another way. This is looking at field by NYHA functional class, where one is asymptomatic. And you can see here that 55% of patients are over half achieved an asymptomatic status by 12 weeks of treatment with 70% improving by at least 1 class. Next slide. This is an analysis that looks at the transition from 3 to 2 or 1 or 2 up to 1 and also includes patients who may have stayed unchanged. Now it is quite hard to go from Class III with the symptoms with very minimal exertion to asymptomatic. And so I just want to call your attention to 50% of the patients who went from Class III to asymptomatic at Class I.

Next slide. What do we think is maybe the cause of this improvement in symptoms, what's happening at the level of the myocardium? And we'll get into more of this at the end of the presentation today with some high frame echo data. But what we know from transthoracic echo is that we're seeing rapid improvements in the mean E-prime lateral velocity. And that is a signal that tells us that diastolic function is likely the driver of improvement here is that we are affecting lucotrophy, ventricular relaxation and improvement in diastolic function. And you can see the gains that were here by 12 weeks. Next. Okay. Let's move into nonobstructive data, and I will show you here early observations at 12 weeks.

And I'll just caveat this by saying that in my clinical experience, it often takes longer to affect patients with nonobstructive HCM than it does obstructive HCM where you don't have that gradient release and after load reduction as an early marker of benefit. You can move to the first slide. So let's start with biomarkers since we don't have a gradient in nonobstructive HCM, we focus our attention really on biomarkers, how patients are feeling and then evidence of diastolic function. So let's start with the biomarkers. And you can see here, baseline biomarkers were in the 700s for the NT-proBNP, and we saw a 65% reduction in NT-proBNP levels from baseline to week 12, and we saw a 33% reduction in troponin from baseline to week 12.

And we don't know what will happen in the long-term extension, but I would submit to you that these curves to me look like they are still moving down and have not yet plateaued. So I am not sure that we've reached the maximal effect that we will ultimately see in long-term extension. We did see that 88% of these patients achieved either a normal level of NT-proBNP or a reduction of greater than 50% from baseline. Next slide. Let's look at KCCQ. And for simplicity's sake, we stuck with the OSS, which was also shown for the obstructive population. And we saw a 13-point improvement in KCCQ-OSS from baseline to week 12. And for the CSS, we saw a very similar 12-point improvement. Now again, if you take a look at that curve, it is still rising.

I do not think we've yet seen the plateau at week 12, which is not surprising in a nonobstructive population, and we'll get additional data from long-term extension to see when that plateau will occur. This is a similar responder analysis. And again, this helps us to understand what percent of patients do we think will be helping with a therapy such as 7500. And we saw in this analysis that 73% of patients had what we would consider to be clinically meaningful levels of KCCQ improvement defined as greater than or equal to 5-point improvement. And again, I'll call your attention to that very large improvement group, which is pretty impressive over just 12 weeks.

Next slide. This improvement, to put it into context, this is, of course, not a head-to-head study. These were 2 separate studies, one of aficamten, which was open-label Cohort 4 and 7500 on the left, again, open label. And we saw a 73% of patients with clinical improvement at week 12 compared to about 56% with aficamten from the REDWOOD study. Next slide. Let's look at KCCQ improvement as it relates to NYHA improvement. Again, these are our markers of how patients feel on a therapy. And we found that 52% of patients or just over half achieved Class 1 by 12 weeks. And again, Class I is elusive and really means that you've become asymptomatic. And we saw a larger percent, 64%, who had at least 1 class improvement. And on the next slide, I'll walk you through what those changes were.

And you can see here that 58% of patients went from Class II to Class I and a smaller percent went from Class III to Class I, which is much harder to do. Next slide. What do we think is happening at the level of the heart and driving these improvements. Again, it takes us back to diastolic function in this disease in nonobstructive HCM, we know the heart is stiff. We know it is noncompliant and that drives up filling pressures that drives up the NT-proBNP and drives symptoms, particularly exertional symptoms. So what we've seen in the echo data is an improvement in the E-prime lateral of 1.6 centimeters per second that starts as early as week 4 out through week 12, and this represents a 37% improvement from baseline. Next, we'll transition back over to Dr. Ayers to talk about some preliminary data from our high frame rate echo study.

Thank you, Dr. Owens. It's crystal clear as always. We appreciate your expertise. We're very motivated to continue to marry our preclinical data to clinical data that helps with this differentiation of mechanism that makes it clear. One of those studies is a high frame rate echo study, which is going to help us understand how clinically this drug has these novel lucotropic or diastolic benefits as well as some novel benefits on right ventricular function and the way in which it's alleviating obstruction. As a teaser to some of that data to come, some of that high fidelity data set, what we have here are the E/e prime ratios for our obstructive and nonobstructive cohorts. E/e prime is considered one of our best, if not the best, stands for how high the pressure is inside the ventricle at the end of diastole.

And what we see here are remarkably robust decreases in E/e prime in both the obstructed and non-obstructed cohorts that are not only directionally consistent, but consistent in magnitude of reduction. As a comparator, if you were to look at the E/e prime literature for, say, odyssey, you're going to see around a 1 to 1.3 point reduction in E/e prime. So these are significantly more improved than what's been published prior. We think that this is reflective of the tissue level myocardial relaxation that we are embarking upon our myocardium with this drug. With that, I'm going to segue into the safety data. This has been a generally very well-tolerated drug. To move through that data on a granular level, we'll see that no participants in our trial have experienced a left ventricular ejection fraction of less than 50% or heart failure due to drops in left ventricular ejection fraction.

When we start moving through our treatment-emergent adverse events, or TEAEs, the most common that we have seen is in obstruction, we had 3 patients with fatigue. And in non-obstruction, we had 3 patients with an upper respiratory tract infection, the cost of doing business in the winter and 3 patients with a rash. We had 2 participants with new onset atrial fibrillation, both were in our obstructive cohort and both were ultimately deemed unrelated to study drug given very high background risk of atrial fibrillation in those 2 individuals. We had 5 participants with serious treatment-emergent adverse events, all of which were considered unrelated to drug that we won't go into detail on this slide. With that, I'm going to turn it back to the boss.

Thank you, Michael. So what we hope to have demonstrated here to you all is that EDG-7500 is a novel mechanism with a differentiated safety profile relative to standard of care, which is the CMIs. There are a couple of things about the CMIs, I think I should state that describe their mode of action. They are complete inhibitors of cardiac contraction. So at some point, you can completely eliminate cardiac contraction. We are a modulator of cardiac contraction. We only can inhibit less than 50%, and we are a partial inhibitor. That means that we can never drive the ejection fraction down in the dangerous levels.

We think that this partial inhibition is reflected in the mechanism of action is that we are always poised to reengage the active filament and when a patient exercises or a patient has some level of activity, we have a greater level of cardiac reserve, which allows us to actually come back and fully perform functions. This translates in the clinic into better effects on feel and function measures and deep responses in NT-proBNP, like we've shown in this presentation. A third piece of data that we showed preclinically is that we have stronger effects on the diastolic portion of cardiac activity. I think this data clearly shows direct lusitropic effects based on the high frame rate data and the core data for echocardiographic data.

Finally, I think the lack of systolic liability supports the potential of having an echo-independent dosing paradigm without any risk of drug-induced systolic heart failure. We have provided an initial synopsis of a draft Phase III protocol that does not include echo-based titration. The agency has directly told us that the trial design was reasonable for this class of agent. And that they would like to see additional Phase II data to support our desire to have a trial where we do not need to have multiple echos to actually get patients to the appropriate dose and do not have a drug mechanism that drives drug-induced systolic heart failure. And we're on track for Phase III initiation in the fourth quarter of 2026.

Next slide. So why is this really important? The CMIs, because of the black box warning and the need for ejection fraction monitoring require multiple echos and highly trained, sophisticated physicians to monitor the drug. And in fact, that reality caps the number of physicians that can prescribe this drug. And that the real opportunity in hypertrophic cardiomyopathy is to move our drug, 7500 into the community cardiologists who do not want to do multiple echos. This would expand utilization of the drug and expand the market outside of the center of excellences dramatically. We think this is the real opportunity for our drug mechanism and the profile we've shown. So finally, I'd like to finish up that given the Servier deal, we are in a really strong position with a runway into the early 2030s.

We currently have pre-deal $500 million on the balance sheet, no debt and 105 million shares outstanding. Next slide. So here are the milestones for the next year or 1.5 years. We anticipate having a Phase III initiation of 7500 in obstructive and nonobstructive HCM later in the year, probably fourth quarter. We intend to -- now that we have the final data set for Phase II, have an end of Phase II meeting with the agency early next quarter. We should have design feedback by the fourth quarter. And we would expect to be able to provide 48-week long-term extension data of 7500 in the first half of '27.

We have another really exciting drug for the treatment of HFpEF, which is 15400. We will initiate and dose our first patient in the first quarter or the third quarter of 2026. We anticipate being able to release the first cut of data sometime in the first half of '27 and initiate a Phase III in the second half of '27. We have the finances to be able to do all of that and more based on our Servier deal. Next slide. With that, I'd like to thank you all for your attention and happy to take any questions.

[Operator Instructions] Our first question comes from Jenny Gonzalez-Armenta with Leerink Partners.

It's Jenny on for Joe. Can you just walk us through why the 2 new onset AF events were deemed unrelated to Edgewise EDG-7500 and whether there are any apparent relationships to dose exposure or timing of dose escalation? And was that assessment investigator determined or independently reviewed?

Michael, do you want to take that?

Yes. So when we communicate with our PIs, what we do is we allow them to use their clinical judgment and relatedness. In these particular instances, the patients had Afib risk calculators that were performed as part of standard of care that were both high to very high. And given the fact that they had very robust improvements in treatment, the PIs thought that the overall background disease rate was more likely driving this than our drug. That said, our second question is an excellent one. We've done extensive work looking at dose exposure relationships, temporal relationships, et cetera, and we've been unable to find any convincing connection between our drug and risk of atrial fibrillation. We're pretty happy that we've put a lot of this narrative to bed and are ready to move forward in a randomized fashion in Phase III.

And maybe just as a follow-up, if we can ask the clinician, like what are her thoughts on this rate and how she would see this if the Phase III confirms efficacy and maintains the profile, how she would view that in clinical practice?

I think, Anjali, how would you -- looking at this profile, how would you think about how competitive this molecule would be if these were the same results after Phase III, I guess?

Yes, happy to answer that. AFib is part of this disease. Up to 30% of patients with HCM have Afib. We see it more in the highly obstructed patients who've been obstructed for a long time. So it's certainly part of this disease. And I think the way to answer the question is the way that you answer any question, a randomized placebo-controlled trial. And I think that's what we need. We saw rates of Afib in all of the CMI trials to date, and you really need to answer the question with a randomized trial where you have a placebo arm.

Our next question comes from Tessa Romero with JPMorgan.

Congratulations, Kevin and team on these data. I think the most critical question here from us is what do these results here mean for the design of your Phase III program? Even if it's just initial thoughts, can you provide some perspectives on how you think about the right endpoint or endpoints in treatment duration here for each of these populations to optimize the chance of success? And Dr. Owens, perhaps you can just share how you think about this as well.

Just -- I'll just take this on the high level on the clinical trial design. I think based on our mechanistic evaluation, we think that we would have a strong effect on things like peak VO2. From a design aspect, I think it's been clear from the EMA and from the FDA that peak VO2 is an important measure or at least a CPET life measure, coupled with a KCCQ. So I think that's pretty clear of what the primary endpoints ultimately will be. There are some nuances to those primary endpoints. I think we're still under discussion with the agency on the trial designs that include 2 different trials for each population or combined study.

So we have not come to a conclusion on that. So I think it's pretty much all we can provide today. I do believe ultimately that we will not have an echo-based titration. And that's all of the information we've gotten back from the agency that, that will be a clear differentiator for our drug. I know, Anjali, do you want to provide some thoughts on the Phase III design at a high level?

Sure. Yes, I think there is a drug that we have that has not shown any safety events with systolic function. So that really opens up the possibility of designing a trial in a way that's very distinct from what we've seen for CMI trials. I think that's a good thing in general to move beyond that and really focus on symptom benefit and function benefit. And I agree, the endpoints are similar to what we've seen in other trials that should be considered, but with the broad possibility of changing dosing strategies, et cetera.

With regard to the time line for endpoints, I think that's a harder discussion, and there may be some nuance between what you see in an obstructive population and what you see in a nonobstructive population in terms of time that it takes to realize the full benefit of the drug. And so I think you might have to split the difference a little and perhaps look at the nonobstructive patients a bit longer.

Yes. And I think just to add to that, with the open-label extension, we'll be looking at patients beyond this 12-week study and that data will be important in making a decision of the duration of the trial and are there significant differences between the 2 populations.

Our next question comes from Yasmeen Rahimi with Piper Sandler.

Congrats on the outstanding data. One of the key objectives of the CIRRUS study was also to really explore dose titration, which you really did very well. Give us a glimpse of additional work that's needed? Or do you think this is the titration that you would propose in the Phase III study? And if that's -- or if there's a couple more dose PK/PD analysis that needs to be completed?

I think there's still additional analysis that we clearly need to do. And that's partly the open-label extension. But as you noted or as we noted, we had stopping rules for increasing dose that included gradient, which we would not use in Phase III. So we have -- are now analyzing and looking at the data of feel and function relative to the gradient response. As you can see in our initial single-dose data, there is a significant difference between a Cmax measure of gradient and a Ctrough measure of gradient. And what we've noticed preliminarily is that the gradient is not as good a predictor for feel and function with this mechanism likely because of PK.

But the NT-proBNP continues to be a very strong correlate with feel and function measures. So I think that all combined, we don't have that fully crunched yet, but I think there's still much to be said about where we would start in dosing, where we would end up and the duration of those doses.

And then maybe one last question. Given with the strong balance sheet, would you consider also running a head-to-head against a beta blocker or even a CMI trials.

Certainly under consideration, but there are a number of -- Anjali certainly could opine on her view of the beta blocker versus novel mechanism approach. I think in some respects, that's a second trial as opposed to the initial trial. But it's still under the discussion and possible. So maybe that's the most complete answer I can give you.

Our next question comes from Joshua Yan with Raymond James.

This is Josh on for Marty. We just had a quick question on specifically the KCCQ. We were just wondering if you can maybe describe to us like how KCCQ responses improve over time specifically and as well as like for the dosing in Phase III, do you -- I see that I think 50% of patients are on 150 mgs in NHCM portion of the trial. Do you expect to push doses even higher? -- congratulations again on the data.

Aylin, let me speak to maybe what's known in nonobstructive HCM and the duration. And maybe Anjali can weigh in on that as well.

Yes. But we have seen in prior CMI trials with nonobstructive HCM, then the trials have been longer in duration that it takes longer effect to get a KCCQ to plateau. What we have seen in our trial is that at week 12, the KCCQ was still in an uptrend, and we have not seen a plateau effect. So the KCCQ seems to improve over longer treatment duration. And I think that's consistent with prior CMI trials as well for the nonobstructive HCM. And I'll turn it to Anjali, who can also chime in here.

Yes. I think the real concept here is to titrate the dose in a way that is commensurate with the half-life of the drug, its mechanism of action, get a patient to a stable dose for some period of time prior to your primary endpoint, right? So that's really what we think about when we're designing the trial in terms of timing and dose. And I do think that if you have no liability in terms of systolic function and no other adverse event that has cropped up yet as a limiting feature, then you do want to maximize the dose so that you get maximal benefit on your feel and function endpoints.

And if that takes 8 weeks or 12 weeks, then you probably want to have a patient at a stable dose, whether it's 150, maybe there are patients who will need 200, we'll see in the open-label long-term extension if that's the case. get them to that stable dose and then give it a few weeks, give it probably 3 months so that they then have the primary endpoint at a point where they can maximize benefit.

Our next question comes from Adithya with Evercore.

This is Adi on for Cory. I had a question for the doc on the titration limits set, especially for the HCM patients, the NT-proBNP target. Could you maybe describe to us details about this target set? And if these -- how would this play out in the clinic in terms of tactical aspects?

Yes, Anjali, I think he's asking in regards to how you might utilize an NT-proBNP in a Phase III and the pros and cons of that measure.

Yes. So it's certainly a marker of stretch. And we know from the obstructive CMI trials that the response on NT-proBNP early in dosing was a very strong predictor of the ultimate improvement in peak VO2, for example. Again, this is the obstructive population. So I think that's the ballpark that you're aiming for is an early and robust decrease at least by 50%. And where we come up with that number, it's a little bit made up, and it's a little bit looking retrospectively at CMI data, but you want to get at least 50% down from baseline, I would say. And that's where these targets have sort of come from loosely. I am not a strong proponent of using that in terms of Phase III titration or anything like that.

I think Phase II is the time to really explore what those changes are, what you can expect from a dose, a certain dose of your drug and then make your best guess in terms of titration and dosing to get maximal benefit. But the reason we do it is that at least in the obstructive population, it's a predictor of what you're going to get for peak VO2 change. The nonobstructive group is a bit harder, and we don't really understand yet what the best targets are in terms of surrogates that will tell us that we'll get an impact on peak VO2. That is still a little bit of an open question, and I think it probably is because that the nonobstructive group is much more heterogeneous. And there are other factors at play that impact change in peak VO2 for that group.

Got it. So just from a clinician perspective, if we do think to titrate based on feel and function, what sort of markers would you use if proBNP is still not cemented?

In the real world, we do use NT-proBNP, and we use just a basic interview that we conduct regularly when patients come in to see how they're feeling relative to baseline. Again, these are very simple questions. Are you better than you were? Are you the same? Are you worse? And then we couple that with biomarkers. And there are some programs in HCM centers that utilize NT-proBNP. There are others that do not. There's recent data from the HCMR study showing that NT-proBNP can be an important prognostic marker in this disease. And so I think you'll find over time that more of us in the clinical world, real world are using NT-proBNP.

So we use it in conjunction with the interview with our patient and what their heart looks like to get an overall sense of whether they're moving in the right direction. And if the NT-proBNP remains high, for example, once they've been optimized on a CMI in the real world commercial drug, and they still have symptoms, then we may be targeting other things. We can put them on the treadmill and see if they're still obstructed and go up on the dose. We may add something like an MRA or an SGLT2 inhibitor. We may address their obesity with the GLP-1. So it kind of gives us a ballpark sense of where the patient is in the trajectory.

If I may just add to that, and I'm going to turn it to Michael as well. I think with our Phase II data, we have a good understanding what our target dose is for both obstructive and nonobstructive patient population. What is really wonderful about 7500 is we do not have to up-titrate against ejection fraction, which gives us a lot of flexibility. And with that target dose, we have an additional option to up-titrate based on symptom or based on how the patient feels and functions. So that is very different than what has been done until now where ejection fraction was a liability or something to uptitrate against, which will not be the case in 7500. Michael, do you have anything else to add?

In some ways, I'm taking my edge-wise hat off and putting my clinician hat on when I answer this. What our Phase II data has done is it has established a good understanding of a dose and efficacy relationship that we can use to design a successful Phase III trial. And it's done so without revealing some dose safety concern that should limit our titration scheme in Phase III, which leads us to be really optimistic headed into Phase III. But the clinician component of this is that ultimately, what we hope to provide exiting Phase III is a situation where you as a clinician get to use your favorite marker question study to titrate to your patient in the room.

We want to remove this echo-dependent strategy that has led to medications not being given to the right patients in the right time course, right? We're not utilizing the current class of medications like we could. You're being tied to these other arbitrary rules of how to go up and down. And it could just be the doctor in the room with the patient deciding how they're going to use this drug to effectively make their patient feel.

Our next question comes from Laura Chico with Wedbush.

I have 2. On the first one, this relates actually to the extension study. Do you have a sense as to how many patients or what proportion are actually increasing towards the 200-milligram dose in the extension trial? And if you could just elaborate a little bit more on what those drivers would be to titrate higher in the extension study, that might be helpful. And then second, I guess, I'm sorry if I missed this. For Phase III, I'm trying to understand what's the specific echo schedule you are proposing to FDA for your design? I guess I'm assuming REMS placement would be a review issue, but I'd love to know if I'm wrong there.

So we haven't given a number of patients. I would say there are a number of patients that have gone up to 200. And I think it's been a combination of giving the physician flexibility. So some have moved up based on NT-proBNP. Others have moved for feel and function. If they were Class II, they would get additional drug and look to see if you could drive the Class I in the open-label extension. But that's all we can provide today on that note. What was the second question?

REMS.

REMS. Yes. So what we have proposed to the agency is no echoes during the titration, 0. And the agency directly in minutes told us that design looked reasonable, pending additional Phase II data.

Our next question comes from Debjit Chattopadhyay with Guggenheim.

Can you hear me?

Yes. Hi debjit.

Congrats on the data. I have a couple of follow-ups here. On the nonobstructive side, given the impact on diastolic function, why is the KCCQ somewhat lagging the CMIs? And then for the physicians on the call, once approved, how would you use 7,500 over the other CMIs? Or is there sort of a subset of patients who are automatic candidates for 7500 as opposed to a CMI?

That's completely false that we are lagging CMIs. I don't know where you get that data. Please provide it to me.

We're just looking at the ROC ACCQ numbers, right, in the teens versus given your prior Phase Part Ab data where it was much higher.

Well, that was an end of 2. I don't know what to say. Perhaps that's a level of interpretation. Anjali, when you're interpreting some of this KCCQ, can you walk us through how you think about it from a -- from a clinician standpoint?

Sure. The KCCQ is granular in a way that perhaps is different than what we do as clinicians in the real world. We don't use the KCCQ at our center. We follow about 2,000 patients with HCM. And so we're really benchmarking how they are relative to baseline. And that roughly correlates with the KCCQ score and an improvement of greater than 5 points is what's been shown to be clinically significant and a meaningful improvement. So when you look at improvements in the teens, that is significant improvement from a clinician standpoint and usually map back to a patient that says they feel much better.

Got it. And in terms of prioritizing 3,500 over the CMIs?

Sure. So I can give you our experience here. We follow about 300 or so patients on commercially available CMI, and we have a wait list of probably 20 patients right now waiting to get in to start a CMI. And the reason they're waiting is because of the backlog in echos and visits that are required for the REMS program. So we have reached a point at a large center of excellence with over 2,000 patients where it's difficult to start additional patients.

So there is a burden from a REMS standpoint for the echo lab, for the clinicians, for the pharmacy team. If there was a drug that did not require safety echoes to be performed and could be dosed based on clinical judgment alone, that would really open up the avenues to provide the drug to an increasing number of patients. If you have similar efficacy to a CMI without the safety constraints, that would really open up your ability to prescribe.

[Operator Instructions] Our next question comes from Kripa Devarakonda from Truist Securities.

Congratulations on the data. For KCCQ, just a follow-up question. Did the CFS trajectory follow the same pattern as the OSS data that you showed? And just based on -- there's been concern from the KCCQ values because of the lack of a placebo arm. Dr. Owens, can you just help us understand a little bit more? I know you talked about it a little bit, but how you interpret these KCCQ values? And if there's anything we need to take away from the delta that you see between the nHCM and the oHCM patients?

Anjali?

Yes, sure. I'm happy to. So nHCM, in my experience, just takes longer, a little longer for them to feel the same benefit, again, because the acute relief of obstruction and the after load that goes with it is often an impetus for a more rapid change in symptoms. So I think it's a little easier to target the obstructive group because you've got that target of a gradient when it comes down, feel better. It takes a little bit longer if you're looking at diastolic function and remodeling to improve filling pressures with the nonobstructive group. That would be my shalt on that.

I take KCCQ with a grain of salt always. And in particular, we know that there's a placebo effect in all studies with HCM that we've looked at, open-label and even our Phase III studies, we see a pretty strong effect even in the placebo groups for KCCQ. So I think you do have to take that with a grain of salt. That being said, the best we can do is look at other open-label design cohorts of CMI, and that's what we provided in this data set, not as a direct comparison, of course, 2 different drugs, 2 different trials, but as a ballpark framework for how to interpret the KCCQ changes. And I think if you look at the data that we showed, it's favorable.

Our next question comes from Lander Egana-Gorrono from H.C. Wainwright.

So based on the data, were you able to identify which efficacy endpoint, either biomarker or echo data correlates best with symptom improvement in KCCQ and NYHA?

I think that's -- I'll take that. I think that's still under evaluation and would be also subject to looking at longer-term data to see how that evolves over time since the trial will be at least 24 weeks. So I think that's part of the discussion.

Awesome. Awesome. And maybe one more. Just even if there were no ejection fraction reductions below 50%, did any of the patients experience a significant decline in ejection fraction that remained above 50%?

Well, no. So what we showed was all of the data that we have, and it's all within the range of the placebo group from the normal healthy volunteers, which is plus or minus 10%, which is the variability in the measure of the ejection fraction. So no, we did not see any patients outside of that placebo range.

We have shown you other markers that measure systolic function such as global longitudinal strain and global circumancial strain, which are more sensitive markers of systolic reduction. And as you have seen, we have not seen any dose exposure relationship with those markers as well, which is different than what has been shown with the CMIs.

The dose exposure curves are not only flat, but there's minimal excursion. And so as you spend some time looking through those, I would focus on both of those features.

Our last question comes from Paul Choi with Goldman Sachs.

Congratulations on all the progress. My question for Dr. Owens is if you take the totality of the data here in both the oHCM and nHCM subgroups, particularly the gradient changes as well as the biomarker changes, if you were to project to the best of your ability, what the peak VO2 changes might be in a randomized population for the next study, how would you guess this might potentially compare versus the data we have on hand from the pivotal studies for the CMI inhibitors?

That's a tough one, but I'll do my -- nothing like predicting a peak VO2. We can't do that on a good day, by the way, even on patients not on CMI. So I would say, let's separate the populations in the obstructive group, I think it's easier to predict that if you have a robust effect on gradient and NT-proBNP, that you will have a robust response in peak VO2. So what extent that will be may depend on the comparator arm and whether or not you've included patients on beta blockers, what the doses of those AV nodal blockers are. We know that can affect your exercisability, your heart rate reserve, et cetera.

And with the mechanism of action that's different than CMI and may preserve that cardiac reserve, I think we may see a real benefit, in particular, in patients who are not on beta blockers. So that's one question. For the nonobstructive group, I think it's a little bit harder to predict from what we know on CMI, we're looking at a 0.4 to 0.6 change in peak VO2 despite a very robust reduction in NT-proBNP. And it may be that we need to look at a slightly different assessment of CPET, something that's a submax marker in order to really understand and maybe that it's harder to move the needle on peak VO2 in nonobstructive HCM. It may be that you need a subset of patients who are poised to respond.

And again, that goes back to background therapy, whether you're suppressing their heart rate response, whether you're suppressing their ability to have cardiac reserve. And with the mechanism of action that, one, targets lusitropy; two, does not prevent cardiac reserve, I am optimistic that we'll see favorable changes in peak VO2.

I think that's the end of the questions. So really, I'd like to thank everybody involved in this program. Certainly, Dr. Owens, really, thank you very much for providing your insights today. Certainly, I would like to thank all the employees of Edgewise who participated and made this happen. I'd like to really thank all the clinical trial investigators that execute on this trial and then most importantly, the patient community who participate in these trials. And then ultimately, in the end, the shareholders who have our continued confidence and support.

So it's been a really exciting time to be here at Edgewise. I believe we're on the cusp of demonstrating the potential of novel therapeutics that could fundamentally improve the lives of patients who need more effective therapies, and thank you for joining the call.

Thank you for attending the Edgewise Therapeutics Update call. This concludes today's conference call. You may now disconnect.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Tessa Romero, and I'm one of the senior biotech analysts here at JPMorgan. Our next presenting company is Edgewise Therapeutics. And presenting on behalf of the company, we have President and CEO, Kevin Koch. Kevin, over to you.

Okay. Thanks, Tessa. Always great to thanks for joining today. Let me get organized here. These are the forward-looking statements. Edgewise Therapeutics is a leading muscle disease-focused biopharmaceutical company developing novel orally active drugs for the treatment of muscular dystrophy, serious cardiac conditions and metabolic disease. The company's deep expertise in muscle physiology and is driving a new generation of first-in-class agents.

Additionally, our mission is to change the lives of our patients and their families. We've had a very productive year in 2025. We completed with sevasemten, our drug for muscular dystrophy, completed enrollment in our Becker pivotal study of last February and expect a readout of that data in the end of this year.

We also disclosed and discussed our Duchenne program extensively. The Duchenne's program showed in LYNX where patients who have previously been treated with steroid or in FOX where patients have been previously treated with gene therapy. We showed a decrease in the rate of decline of those patients and still have a number of patients as many as 60 on study. We'll be collecting data later this year on that subset of patients.

We had positive data with 7500, our cardiovascular asset. This is a cardiac sarcomere modulator, a novel mechanism. What we showed was our 28-day data where we showed robust changes in feel and function measures like KCCQ and New York Heart Association, really astounding data. We initiated our Part D 12-week study over the summer. We reported data in December, where we had a very strong safety profile and in particular, no changes in left ventricular ejection fraction relative to the concentration of drug or drug dose, which is a really important differentiator for the product.

In another cardiovascular asset, 15400, we filed the IND over the summer. We moved it into normal healthy volunteer studies, and that drug is now positioned to go into HFpEF studies in the second half of this year. And finally, we were able to raise based on that data, $200 million, which gives us a strong runway through '28. So really an exciting year.

Today, I'm going to focus on 2 key programs. The Becker program with sevasemten, where, as I've said, we will have a pivotal study reading out at the end of the year and EDG-7500 for the treatment of hypertrophic cardiomyopathy, both obstructive and nonobstructive where I'll talk about some of the observations we had at the end of the year.

So what's really exciting for me is we started the company in 2017. And from an idea from our founder, Dr. Russell here, we went all the way to Phase III and we'll have a readout in 9 years. Pretty amazing result, I think. And we're at the cusp of becoming a commercial organization. I'm going to tell you a little bit about why we think this product will be successful and how it will impact the patient community.

So Becker is a rare genetic life-shortening, debilitating disease of adults, and this is a disease where these patients are missing a key structural protein called dystrophin. And these patients into the adult forms, they have a dysfunctional dystrophin. These patients are typically diagnosed in adolescents. They progress slowly over time, but ultimately die of cardiovascular comorbidities and lose ambulation in their 40s and 50s. So a debilitating disease.

Our mechanism addresses the core underlying disease driver in that muscle damage whenever a patient moves of contraction-induced injury drives the loss of muscle and that loss of muscle leads ultimately to the loss of function. That loss of function ultimately drives how the FDA views you would measure this to actually show the benefit of the drug.

So -- we have a unique mode of action. We've done extensive studies, and we're one of the first to identify that certain kinds of skeletal muscle called fast skeletal muscle are degraded before the slow skeletal muscle. And if you could block that skeletal muscle degradation, you would be protective of the disease progression in these patients.

So we invented a fast myosin inhibitor of type 2 fast skeletal muscle, where we showed extensively that this affected the disease rate preclinically. In the clinic, we've seen decreases in biomarkers associated with muscle damage. And we think this particular mechanism will completely aggregate the progression of the disease.

I'll show you data that I think supports that. So we've run a number of studies in the Becker population. ARCH was our first study. This was an open-label 12-patient study. We've now treated these patients out to almost 4 years. Really exciting. I think 11 of the 12 patients are still on study. We also ran a biomarker-based study, essentially a proof-of concept mechanistically in DUNE.

So DUNE was we challenge a patient with exercise. That would drive their biomarkers up of muscle damage, and we were able to aggregate that with the drug. So exciting result actually validating the mechanism of action. We were the first company to run a controlled Phase II in CANYON in Becker population, that was a very successful study, 40 patients, we showed in a statistically significant manner decreases in biomarkers of creatine kinase and TNNI2, which is an on-target biomarker of disease progression.

And then finally, GRAND CANYON was completed in 2024 -- 2025 in February, and I'll show you a little bit about that study. What's -- I think is the most astounding thing about this particular -- these trials is that 99% of the patients who have ever taken the drug and are eligible to go into the open-label extension are still on study, meaning that there's a durable response based on ARCH -- there is benefit, I think, to the patient because why would a patient go around and go and be part of a clinical trial, the drug wasn't providing benefit.

And I think a very strong safety profile. So really excited about these results. Now how do we develop this drug? And how do you measure a functional capacity? So the FDA has guided to a key endpoint called the North Star. Now what is the North Star? The North Star is a 17 activity measure where you measure each activity at 0, 1 or 2 or can't do it, partially can do it, can do it like a normal person.

So the total score is 34. So the question is we're powered for a 1 to 2-point change in North Star. So what does that really mean to a patient? So if you're walking across the street, and you get to the curb and you can't lift your leg. That's one point. If you're on the toilet and you're a 35-year-old guy, and you have to call your wife or your kids, I can't get up. That's a point.

These guys fall very often, and they fall and they can't get up. It is a horrible disease, yet there is no treatments for any of these patients. And we're really the first to exploit and drive a new medicine for these guys. So here's the data. I think it's really exciting. On the bottom of this slide, you can look at the gray line.

And we have expertise and have done a lot of work on the natural history of the Becker patient population and which patients lead to a homogeneous decline and that over a 3-year period, we would expect a decline of 4.4 North Star points. Interestingly, in the blue line, you see no change or no progression of the patient. This is an astounding result if you think about it. This has never been seen for these studies.

So I think this really points to a durable effect and clear benefit to the patients. Here's the CANYON study. So the CANYON study is the first placebo-controlled study associated with Becker. There were about 3:1 randomization. As you see on the bottom line, we would -- this is a 12-month study, just to be clear. So on the bottom line, at the 12-month time point, the predicted value would be about 1.2 to 1.5 North Star points decline based on natural history.

Our placebo virtually completely matched that results in the natural history. So how we're thinking about our natural history was predicted by the first placebo-controlled study and the decline of those placebos. Now again, what you can see with the treated patients is that we completely aggregated the progression of the disease.

And then when we go out to 12 months to 18 months, what we saw that the patients now, all patients going on drug in MESA continue to benefit. So I think it's a really exciting result. So as you think about how we're going to develop this drug and what is going to be the supportive evidence beyond the primary endpoint and the secondary endpoints of time function tests.

Can you build a model based on the natural history? So there are about 4 or 5 studies out there that have looked at the natural history over a 2- to 5-year period. So we took one of those studies and we built a model. And that model is built on things like age, North Star, 10-meter walk, time of onset, a host of different parameters.

And what we did was we took each individual patient who was treated, and we predicted what they would be, how they would progress based on the background phenotype of the patient. And then we zeroed that, placed that at 0 and then asked the question, how did the drug affect those patients. As you can see on this slide in this waterfall plot, 21 of 27 patients had benefit from this drug outside of what you would have predicted from the natural history.

So really interesting point can be used for supportive evidence with the FDA when we get our positive North Star response. So here's our Phase III study. We overenrolled the study. We were supposed to enroll about 120, 125 patients. There was such enthusiasm for the drug that we actually got 175 patients. We are keeping people away at that point.

So this is now 98% powered or greater than 98% powered for an 18-month study at 10-milligram dose oral and to see a 1.7 point change in North Star. The tipping point of this particular study is about 0.7 points -- so anything above 0.7 points, we have a better than 50% chance of hitting. So very well-powered study, done extensive work in how do we decrease the variability of the measure of the North Star and how do we run a really ideal world-class study.

So with all of this in mind, we're very bullish on the potential of this asset. And we truly believe this will be a successful program, be positive readout in December. And so that we've gone off and built and started to build our commercial program. And we've hired the senior leadership in marketing, market access, med affairs, our own patient advocacy group, which we've built and our sales force.

So we're poised to be able to -- with a successful trial at the end of the year, be able to jump right to the NDA filing and the launch of the product. So how big is this market? I mean it's got tremendous potential. There are 6,000 Becker patients in the U.S., 12,000 in the major markets. This is for the ambulatory patients, which is about 70% or 80% of the patients.

We would anticipate we could perhaps get all the patients, whether ambulatory or non-ambulatory because of the mechanism of action of this drug. That's a regulatory negotiation with the FDA. But this is potentially a $5 billion market based on the sales of other products in this type of space, rare disease drugs. So really important drug, really important for the patients, important for the shareholders and the staff.

So -- turning the page on to the cardiovascular program. So people always talk about actually my Board says, we're running 2 biotech companies, which we are running 2 distinct biotech companies. But there -- interestingly, there is quite a bit of overlap. So we've taken our second drug, 7500 and shown this is a highly differentiated mode of action with strong efficacy in the original trials.

So what is hypertrophic cardiomyopathy? This is a severe inherited disease of the heart. They have progressive disease. This is something -- if you go back and you think about this, there is these athletes who die suddenly in their 20s. They often have an enlarged heart, and that's the -- trademark is that the ventricle thickens and that thicken ventricle leads to dysfunction in the heart, and you can have acute coronary events because of this.

This particular disease is carved up into 2 major types: obstructive HCM and nonobstructive HCM. Obstructive HCM is that you have a thicken wall of the ventricle, but the mitral valve actually comes over and closes down that path out to the aorta, which generates what's called a gradient. So that group of patients are called obstructive HCM patients.

Patients with just a thicken wall, but don't have the obstruction are called nonobstructive HCM patients. There have been some new current therapies specifically designed for obstructive and nonobstructive HCM, and they are approved for obstructive HCM. But there are some issues. And I think these challenges have led to a decrease in the ability of these drugs to actually attain the market potential they could attain.

What is that issue? Well, the mechanism of action leads to decreases in the contraction of the heart. That's called left ventricular ejection fraction. For both of the CMIs, that has led to a black box warning of heart failure. Now I don't know about you, but if I'm a heart failure patient, I'm an HCM patient, I have heart failure and you tell me, I'm going to give you a drug that has heart failure as a side effect. That may not be the best marketing strategy.

In fact, I think what we've heard from our research is that patients are concerned about both the potential of heart failure, but also that they have to go back to the doctor over and over and over again to titrate their dose to get them to the right dose. What this has always often also done is that it's driven utilization of the drug entirely into the academic centers.

So 80% of the patients in HCM actually reside with the community doctors, not at the center of excellences. So if you could find a drug that didn't cause heart failure, meaning you had no changes in ejection fraction, that drug would open up a multibillion-dollar market. Well, that's what we have. We have a drug mechanism where we do not see ejection fraction changes where we still see strong efficacy.

And you can measure this by the dose of the drug or the concentration of the drug. I'm going to show you some evidence of this in the next couple of slides, but it's a very important differentiating factor for our mechanism. Second key aspect of this mechanism is how it affects that benefits the patient, but doesn't affect the ejection fraction is we slow the rate of contraction, not the actual contractual site.

The other thing we do, which I think is really novel and important is that a hallmark of heart failure in general is that the left ventricle becomes very stiff. So what you want is a mechanism that relaxes the ventricle. This is called the diastolic effect when it's filling. So you fill the ventricle with more oxygenated blood to be pumped out.

And what we're able to show in our studies is that we had a diastolic effect, meaning that we could enhance the relaxation of the ventricle, fill it with more blood, pump out more oxygenated blood, and that makes the patient feel better. So the profile of this mechanism is that we don't lower ejection fraction. So there's no risk of heart failure, yet the patients feel much better.

And some of our data is probably some of the best data on feel and function you've seen in the industry. So excited about this clinical profile. Here's just some quick tidbits of what we showed last April. We were able to -- 89% of the patients, you could relieve their gradient down below a threshold of normal. You could -- 56% of the patients actually were in the normal range or driven to the normal range on a biomarker called NT-proBNP.

This is a surrogate marker for diastolic effect. and 56% getting the normal, normal is normal. That's what you want to do with a cardiac patient. We were able to show directly the diastolic effect via echo parameters. And most excitingly, what we saw were 89% of the patients benefited greater than 10 points on KCCQ, an open-label study, but profound benefit to the patients as well as the measure of New York Heart Association changes where they -- 78% went to normal type 1, astounding data.

Also saw the same type of activity in nonobstructive HCM. We saw an 88% benefit to patients, 10 points or more in nonobstructive HCM, deep responses on NT-proBNP and our diastolic effect that occurs very rapidly. So this is, I think, some of the most robust data ever seen in nonobstructive HCM. So we're really enthusiastic about this result.

So -- we then moved on to -- that was a 28-day study. Now we've moved on to 3-month studies, 12-week studies. This is the Part D of the CIRRUS program. We're dosing patients up and trying to get each patient to their optimal dose. And at each dose range, we measure every parameter, ejection fraction, KCCQ, New York Heart Association, NT-proBNP.

And what we want to do is we're not planning to run multiple echoes in the Phase III. We're planning to look at the profile of the drug and ask how do I use perhaps just feel and function to get patients up to the right dose. So AHA guidelines are not driving a dose to a gradient reduction or an NT-proBNP. It's largely driven by how does the patient feel.

So if we can do that, we would fit ourselves into current standard practice in the community doctor, which is the goal of the drug. So here's the data in the ejection fraction. The new data are the green diamonds across the study. As anyone can really see here, there is no relationship to the concentration of the drug and the effect on ejection fraction.

In fact, as you look at the above the line out at 600, 700, 800 nanograms per milliliter, we actually see people with increases of ejection fraction. So this is dead flat. So really exciting result. We talked about this in December. So how does that affect the commercial opportunity for this mechanism, this drug?

Right now, the CMIs are largely utilized in the academic centers and the HCM-focused clinics. What we can do with our mechanism is address the 80% that the CMIs can't address. That's provided in the community to the cardiologists. They don't have the echo capability with the academic centers too. They don't have the organization to monitor the REMS, and we can move this product from perhaps a $2 billion opportunity to a much larger opportunity.

So how large is that opportunity? 165,000 patients have symptomatic HCM, and that group is growing. It's a growing number. We think this is a $10 billion opportunity. And back in the day, when Bristol acquired MyoKardia, they thought that it was a $6-plus billion market opportunity. Now mavacamten is making $1 billion, a very successful agent, but they're only accessing 20% of the docs who can prescribe this drug.

Our mechanism can open that up. So all this, you need cash, and we were able to raise $200 million last year. We're very well financed. We have $563 million in the bank, no debt and runway through '28. So in a really good financial position to drive the organization to hit all our milestones. So what are our milestones for the next year?

So obviously, GRAND CANYON is going to read out. We're on track for readout in the fourth quarter of this year and NDA submissions in '27. We'll make a decision on the Duchenne studies. We have a readout in the second quarter of an additional year of data to try to understand, can we block the progression of disease even in a much more aggressive group of patients in the Duchenne population.

We'll -- in the 7,500 space, we expect to report data on the 12-week Part D complete study in the second quarter of this year. We expect to initiate our Phase IIIs, and we're already in discussions with our advisers and looking forward to an interaction with the FDA in regard to the trial design for Phase III in obstructive and nonobstructive HCM.

We also have taken our 15400 molecule, second-generation molecule, the same mechanism in the healthy volunteers. We expect to be able to report data in the second quarter on that program, initiate a trial in HFpEF in -- over the summer and read out data in the first half of '27. So exciting times, tremendous progress. It's going to be an eventful year, so to speak.

And so I look back and we were developing this slide presentation, I thought to myself, wow, we have 2 multibillion-dollar differentiated assets. How many companies have that? This is really going to be an amazing year for the company. So thank you for your attention. Look forward to presenting the data in the future, and I'll take any questions.

Thanks, Kevin, so much for that presentation. We covered a lot of ground, and I have 13 minutes of Q&A here. So let's see what I can accomplish in that time. So let's just dig right in. So as we think about your upcoming -- let's start with the HCM side of the business first. As we think about your upcoming Phase II CIRRUS-HCM update, can you maybe characterize in a little bit more detail the size and the scope of data that you will be providing at that time?

Yes. So we promised 20 patients, and we got 20 patients by the end of the year. And actually, we had overenrolled that study. There was a lot of enthusiasm with the investigators. I think they're seeing things they've not seen with the CMIs. We had recruited by the end of the year about 40. We had -- we stopped screening.

As remember, we have a screening process for a month, then we enroll and we have about another month to get the data for the core lab. So we've stopped screening. A few more patients will go on the study. We think somewhere between 50 and 60 ultimately will be read out by the end of the second quarter.

Okay. And key efficacy measures, safety, everything that we would -- we should normally be think about...

Everything we provided in the Part B and C in the 28-day study would exactly be the same thing.

Okay. And if you had to think about the scenario outcomes here and those like scenario boxes that we like to do, like how would you characterize what a win looks like in 2Q versus what might be a home run versus what might fall a little bit short?

I think our base case is that we will continue to see no changes in ejection fraction even as we continue to go up. I think with increased length of dosing, we'll see a deepening of the response. I don't know how far that goes. But in my personal opinion, I think a drug that doesn't lower ejection fraction, the ejection fraction lowering has an effect on the total feel and function measures.

So one of the deficits of the CMIs is that by lowering ejection fraction, you're decreasing your efficacy broadly. So I think we could see deepening and more robust efficacy. And then clearly, everything else we've seen, we feel the drug is well tolerated.

Always a lot of discussion around atrial fibrillation. What we've showed with our last presentation was we're in the noise of the placebo. Single-digit AF is part of the phenotype. Nothing to worry about. Every KOL has said exactly the same thing. They have to deal with this all the time. Not a big deal.

Okay. And at 12 weeks, do you think you'll be able to ascertain whether or not 7500 is looking different than the cardiac myosin inhibitors? And in what ways do you believe there may be differences at 12 week in terms of clinical benefit? Are you able to get a little bit more granular on what efficacy biomarkers...

I think the feel and function, as I just have said, I think there's the potential of having deeper responses on NT-proBNP. That's really important because NT-proBNP has provided the strongest correlate for peak VO2. And peak VO2 is the approvable endpoint, both in obstructive and nonobstructive HCM.

So I think that measure is highly predictive of the potential of how big the response on peak VO2 and that peak VO2 response sizes how big of a trial you need to run and what the actual benefit of the patient is. So I think that's an important parameter to be able to monitor.

Okay. And any like numbers, benchmarks that you want to put out there?

No. No.

Why?

Well, we know what good looks like. So we can talk about what that might be, but it's really in the context of the entire trial.

Yes. Okay. And just to put a little bit of a finer point on the statement you made on AFib. Kevin, set the record straight here. What causes nuance at AFib in patients with HCM? Does your drug cause it or not? And is there any ways to mitigate these events in a broader Phase III?

Well, there's nothing mechanistically that would say that this mechanism has any effect on the AF rate. What we've consistently seen across every study, not just our studies, are patients who are at high risk of AFib get spontaneous AFib. I'll give you a tidbit that is a little bit new is that we had a patch, a Zio patch to look at the event rate of a whole variety of tachycardias and atrial fibrillation.

And we -- that was provided before we dosed the patients, so the screening period. During that screening period, we found 3 patients who were asymptomatic AFib, who did not have AFib in a prior study, meaning that those patients had new onset during the screening period. That means that's a 10% rate of new onset in the population of the patients we're treating. So it just happens to be, people will have to get used to single-digit events of AFib, which is exactly what you've seen with the CMIs, nothing different. So it's not a story.

Okay. And another question we just get is, are there any potential risks over time to decoupling LVOT gradient reduction from LVEF in patients with HCM?

Risk of...

Like is there any adverse risk to not seeing those reductions?

The depth of the gradient response and how important that is.

Yes.

The gradient response, I think, is it's not an approvable endpoint. The gradient response is something that some of the physicians use. But again, the physicians -- the guidance is to go to feel and function. So gradient is a guidepost for potential benefit, but the real benefit is measured in the KCCQ and the peak VO2. So the depth of the -- and I think from all of our data, we have astounding effects on gradient. So I think it's kind of a mute point again.

Okay. Okay. And so maybe any -- I know you've talked a little bit about your Phase III program before here. Obviously, we have a fairly large Phase III nonobstructive HCM study reading out for aficamten in 2Q. Can you talk a little bit more about the internal and competitive data points that might influence how you design the study?

There's a couple of variables here. You can run 2 studies, 1 in obstructive, 1 in nonobstructive HCM, and you can run them very similar to the EXPLORER, SEQUOIA relative to ODYSSEY and ACACIA. That's easy, perhaps the right thing to do. But I think there's a couple of other parameters. One is, would you utilize an active comparator?

Second might be, would you want to run one large study because if you don't need to measure ejection fraction, because of the safety of the mechanism, perhaps you can just use feel and function and look at both populations simultaneously, which would streamline the trial and accelerate the rate in which you could recruit patients and read out the trial.

So those are all different kind of parameters that we're evaluating. We've not made any decisions yet. We will be discussing with the FDA some of these options in the coming months. And obviously, the Part D data will inform some of the decisions we make to run the most efficient, effective and differentiating trial in Phase III.

Okay. And maybe I have -- let's see here. I have like 4 more minutes. Let's see, where do we go next? Maybe we could just talk briefly on GRAND CANYON here. Like Kevin, you talked a little bit about your powering here and the size of the study, patient population, et cetera. But like how are you optimizing the conduct of this study to optimize the chance that you have for success?

Yes. So there's a few things. You have to get down into the weeds of running these trials. So you have a physical therapist actually trained to measure the North Star and the other parameters. So it's key to have a well-trained PT. That means that we have to know who the PTs are. We need to make sure there's homogeneous training.

This is done through a group called ATOM that actually trains these folks. But we do see differences between a different PT with a measurement later on. So what we try to do is we want the same physical therapists to read out the baseline as well as the primary endpoint. So by having that, you remove the essentially user variability of the PT on one case.

We also look at measures, for instance, the difference between the screening North Star and the baseline North Star. And if you see big differences, that's unlikely to be a patient effect because we generally do not see wide swings in North Star. If you see a point or 2, that's typically in the range. If you see 5 points, there's something wrong. We go back.

And what we do is we video the patients and actually had a third party say, okay, what is the right answer here? And then we go back and retrain again. So this has been a point of concern for everybody in the Duchenne space in North Star because Duchenne patients have very wide ranges of North Star, a lot of variability.

But we've cut down that standard deviation because of our efforts in training the PTs and because adults generally can perform the North Star better than 4- and 5-year-old kids. You think about it, if you're a 4- or 5-year-old kid and you tell them I have to -- you have to do 17 different activities and do them as hard as you can.

We all have had 4-year-olds. They don't perform like that. So I think for the adults, we have a much higher level of certainty that we'll get very high-quality data and that will result in the success of the trial or at least make this trial much more likely to be successful.

All right. Last question for me is just you do kind of have 2 businesses and 1 here, 2 different verticals. How do you think about where you direct your resources across these 2 verticals of the company? Like -- and if you could talk a little bit about your cash on hand and just how you're thinking about overall investments.

Yes. So I think the front of mind at the moment is to build the commercial backbone to be able to launch sevasemten. So I think we need to find room to do that. We're not going to go crazy. We'll gate it for the Becker release. But at the same time, I want the expertise. I want to have a deep understanding of this disease state and be able to launch the product.

The second is you look at the opportunities for each of these indications. I think clearly, we can execute on obstructive and nonobstructive HCM ourselves. We can clearly launch a product in Becker and continue to run the Duchenne studies. I think about HFpEF. HFpEF is an interesting area, perhaps the largest opportunity, but inherently, there have been very large trials run.

So the question becomes, do I really need to run a Phase III that's 3,000 or 4,000 patients in 3 years? Or is there a targeted group within that HFpEF population where you may be able to run a smaller study that's more focused where you see a very large effect size, that is part of the design strategy right now for what we're going to run in Phase II.

I think for HFpEF, really interesting turn of events in HFpEF with GLP-1s coming into play. We're talking extensively about how many patients will be taking a GLP-1, perhaps on a backbone of SGLT2 inhibitors in HFpEF 3 or 4 years from now. And what we've noticed, which is really important is in those studies, they did not see a true diastolic benefit.

And that is the fundamental basis of our mechanistic advantage is that being able to relax the ventricle. So I think that's a really prime opportunity. We certainly want to recruit patients into our HFpEF study who are on that background and see if we can move the diastolic effects.

Kevin, I want to thank you so much and the entire Edgewise team for being here and everyone for joining. Thank you.

Good afternoon, everyone. Welcome to our Piper Sandler Healthcare Conference. My name is Yas Rahimi. I'm a senior biotech analyst at Piper Sandler. So thrilled to have the team from Edgewise Therapeutics here and lots to cover, and I don't even know where to start in 25 minutes. So the team, I think probably the best place is to start with the near-term disclosure that you're going to provide across 7500, the CIRRUS study.

So I'm sure the first question from everyone throughout your meetings has been, are you on track to provide a disclosure this month? And what will the disclosure entail? So maybe help us understand that.

Yes. So maybe take a step back and what -- why we're disclosing what we're disclosing in December and then the subsequent disclosure in the first half of '26. So what we've noticed is the run rate for mavacamten in HCM is now above $1 billion. So remember, there's been a question, is about is there an HCM market? How big is that HCM market. So now with a run rate of north of $1 billion and additional agents probably coming into the area, it's a substantial market. So what has limited the market for mavacamten. It's that it's well utilized within the center of excellences. We have academic centers that can do the echos, work through the REMS and treat the patients with the safety liabilities. What's holding up that market is the ability to get into the community cardiologists.

So why isn't it being utilized with the community cardiologists. It's simply because there are too many echos and the complexity of the REMS. And why would a community cardiologist use a CMI. So in the end, what we want to try and point out is that we have a fundamentally different mechanism where we do not see changes in ejection fraction to drive efficacy and therefore, will be utilized within the community docs, which expands the market exponentially for drugs in HCM. So what are we going to disclose in December? December will be additional data at the 25-milligram level for 28 days to show that we would -- we still do not have effects on ejection fraction -- with regardless of the concentration of the drug. That's the key differentiating factor for our mechanism.

And if you notice with the CMIs, there's a high level of variability of the concentration of the drug relative to how much they lower the ejection fraction. That inherent variability of the CMIs limits the market opportunity for the CMI class relative to the sarcomere class that we're developed. Very important point. So why is that biochemically. Because we are a partial inhibitor, so you cannot fully inhibit the contraction of the heart. If you look at the CMIs, you can completely ablate contractions biochemically. And we believe how that translates is that you have an inherent variability in the ejection fraction measure.

So the second piece to this ejection fraction, this is why we want to focus on the ejection fraction is you have an inherent safety liability of patients being driven below 50% in ejection fraction, which drives the REMS. The second, I think, important piece that's underappreciated on ejection fraction is if you lower ejection fraction by 10% or 15% or 20%, you're essentially lowering cardiac output. I'd like to pose the question, why would a patient feel better if you lower their ejection fraction by 15% or 20%, there's no reason to believe they should feel better. So the ejection fraction issue with CMIs drives 2 liabilities.

One is you have to monitor them and you have to do multiple echos to get them to the optimal dose, and it limits the efficacy of the drug. And this is what we showed in April that we had outsized effects on KCCQ, large effects on your New York Heart Association changes and robust effects on NT-proBNP. So what we're going to show in December will support that hypothesis and that -- of our mechanism. And then later in the first half of '26, we'll have additional data to support the efficacy of our drug at 12 weeks.

So just to -- for this data, there will be -- it will be a quantitative readout for the 25 mg dose group, right? And it will include both obstructive cohorts and the nonobstructive cohort. Is that just the patients for which we saw data on in April that are followed longer? Or no, it's a complete new set of patients that are going to be, call it longer than 4 weeks, right?

No. So these -- the first 25-milligram will be 4-week data on entirely new patients. So what we -- I think the reason to look at the 25 milligrams is remember, we saw efficacy at 50. The agency would like us to look at what is the minimally effective dose. And then from our dose escalation strategy to optimize the dose for each individual patient, where do we start? Do we start at 25 or do we start at 50. There's pros and cons to starting with either dose. So I think this 25-milligram will give us some understanding of that.

And how large -- is that like 10 patients per cohort or like what.

We haven't given the number, but -- it's a meaningful number of patients, right. And it will add to this database that we have a very tight exposure response or lack of exposure response to AF.

Okay. I'm assuming since you're -- this is my assumption between reading [ materials ], it's the lowest dose. You're going to give an update that there will be -- even at your lowest dose, you're effective enough to show it like I don't know that that's me extrapolating.

You may or may not observe that.

And then I think the next question that people will have is, since April, you guys went back and optimized the patient selection, making sure that they had no sick heart valves, made sure that their AF history was 180 days or no, like just tell us like what is the protocol. Is the protocol of this low-dose group the same as in the 12-week study? Or is it the same protocol as the April data study.

So you remember in April, what we did was we noticed in that original disclosure that some of the patients we recruited were not HCM patients because the wall thick was symmetrical. Second, we noticed that even though we required the patients to be -- have an ejection fraction above 60, some of those patients were actually, I think 4 of them were below 60. And what we noticed was a disparity between the core lab which is a single lab reading all the echos and the individual investigators read of the echos.

So what we did, and we did this quite quickly within weeks was to institute a different paradigm. One was to add additional restrictions on the inclusion criteria. The second was to have an individual at Edgewise read the echo and then had an additional core lab to read the echo. So we essentially have a group of people deciding who goes on the study and who does not. So we -- the 25 milligrams allowed us to work through that bug very quickly to optimize that. And then we started developing the Part D strategy.

We rebuilt the database because we were going to do a drug optimization that took about 6 weeks, talked to the FDA, talked to the IRBs and started screening in June with Part D. Now remember, the Part D is a 12-week study. And to be precise about how we're dosing that 12-week study, we start at 25 for 2 weeks. We go to 50 for 2 weeks. We go to 100 for 4 weeks and then 150 the next 4 weeks. That's a 12-week cycle, and then those patients roll into an open-label extension after the 12 week.

So we have completed some patients through 12 weeks. We'll give you an update this month about how many patients, where we are, what we've promised is at least 20 patients' worth of safety data in Part D and with at least 40 patients of data at the total in the first half of '26 when we have the efficacy. The reason why we can't just put out all the data that we have right now is that we want to wait for what people call the core lab data.

So the core lab is a single lab that reads all the echos. It takes about 4 to 6 weeks to get that data after you've completed the 12-week, partly because you're batching all that data and it's one individual reading it. So we're measuring baselines at the core, and we get the 12-week at the core. That data is the most reproducible and actually the most accurate. And think of it as in cancer studies, an unconfirmed partial response versus a partial response. So we want to only report partial responses or complete accurate data as opposed to muddling up a mix of PI data and core lab data.

And I assume the type of disclosure in December is very similar to what you had in April, sort of the breakdown across efficacy, right, and safety, right? I assume...

On the 25 mg efficacy. And on the Part D will largely just be safe.

Okay. Got it. I think one of the things that I think investors have -- obviously, they understood that patient selection is really critical in assessing AFib, right, because it's a high comorbidity. Could you maybe talk about -- you talked about the thick hard walls that should have never been in the study. What is the requirement in the 12-week study as well as the low-dose study? Is it -- if you have a history of AFib or you completely ruled out? What is sort of the process.

No. We'll have the -- generally, the CMIs have capped the prior AFib in and around 15%. We will be roughly in the same place. We've not put a formal cap in, but I think that's realistic to believe that. We incorporated having a 6-month look back. You could argue you could go back further or not have any AF at all, but I think it's representative of the Phase III populations observed in EXPLORER and SEQUOIA. So that's important. And then one of the other -- the couple of things that we need to look at are the ventricle diameter, which is important. If you notice from the patient demographics, it's up at 20.

When you get below, say, 15, you start running into patients who have no mutation and below 15, they start looking like HFpEF patients. The other thing is that they start becoming more fibrotic, depending on which population you look at and how many comorbidities they have, you're really testing a different hypothesis than the HCM. So you really want to recruit HCM patients. On the atria, one of the most important things is 2 parameters. One is the left atrial size. The second is left atrial reservoir strain. If you go into the literature and you look up left atrial reservoir strain, you'll find that's the highest predictor for future AF. So you don't want to be too low.

And it turns out 3 of the 4 patients that we dosed had very low left atrial reservoir strain. So it doesn't occur in all patients. You don't expect to see AF just because you have a certain reservoir strain. What it does is put you in a position where you will have random AF on a much higher level. So we've incorporated all those things for the study.

One of the questions that will come up also as you're -- going back to the December disclosure of the lowest dose. If 25 is as effective as 50, like it seems like you haven't achieved your lowest ineffective dose, do you still have to do more dose exploration on the low-end side for regulatory agency. Or is that really not necessary to keep going.

I don't think we have to get to 0 effect. And it is important to understand what is a minimal effect and the starting point.

And then a lot of investors are also starting to kind of visualize the 12-week time point. And now with the dose optimization and being able to go up to even 200 mg, often, they're asking us what do you hope to gain by driving the effect because you're already in 4 weeks, your effect sizes were as good as the CMIs at a fixed dose, and that wasn't even optimized, right? So people are trying to figure out now you're going like 9 weeks longer plus you're exploring a higher dose? What do you hope to find.

I think it's important to think about the depth of the response between 4 weeks and 12 weeks. That's important to see, in particular, in nonobstructive. So in obstructive, what you normally see is the gradient reduction occurs very quickly, and that translate doesn't deepen necessarily over time from -- at least from our data, from 7 days to 28 days, it didn't deepen. It's kind of -- I think it's a little bit unknown how the response would deepen between in a non-obstructive patient from, say, 4 weeks to 12 weeks. That's a very important piece of this. So can you go low and long.

We noticed in the original data disclosure that our diastolic effect occurred very quickly, which we don't know how that translates from early to late in each population, right? So either one of those things. I think from what we originally looked at, even at the low dose got up to the higher dose levels if you went longer. So all these things were -- this is the type of things we'll try to figure out.

And how soon could you -- post the 12-week data is going to come out in 1Q, how soon can you engage with the agency to think about Phase III development?

Go ahead.

On Phase III?

Yes.

So we've already started thinking about what kind of trial we're going to run. We've got 2 options that we're exploring right now. I think we're just waiting for some of the efficacy data from Part D to finalize it. But I think we're still on track to kick off the Phase III fourth quarter of '26. That hasn't changed. And I think that's really the key. I think the idea is to have a discussion with the agency sometime in the second quarter of '26 and just align on endpoints, trial duration.

We've got some like really interesting ideas that we're exploring that will be really, really good to bring up to the agency. The other thing that we've spent a lot of time on is the question we often get is what is the bar to walk away from the REMS, right, because that's clearly the impediment for broader adoption of the CMIs. And I think we've spoken to a number of folks who used to head up the cardiorenal at the FDA. And the feedback we got was somewhere in the 80 to 100 individuals, so healthy volunteers and subjects dosed. If you don't see a concentration to LVEF relationship, there's no reason for the FDA to look at that data set and say, you need a REMS, right?

Plus we're a different mechanism. So you've got a couple of things that we -- and to rely on. And I think the strategy is put the data package together and go to the FDA and say, "Look, here it is. Don't ask, do we need a REMS. Let them tell you if you actually need one." And I think that's the philosophy.

So the goal here is the Phase II, we will measure everything at every time point. And then the goal will be to have 0 echos because you don't need an echo other than baseline in the study to look at, say, diastolic parameters. But can you eliminate echos and can you replace them with other measures. So the 2 main measures we're looking at right now are New York Heart Association changes and NT-proBNP. So what we noticed in the original disclosure what we provided was that it's not the percent decrease of NT-proBNP, but it's the depth of the response. So if you can drive people to normal in NT-proBNP, you've probably dosed them high enough.

If you could drive someone from NYHA Class III or Class II and drive them to one where they're asymptomatic, that's probably enough, right? So you don't have to continue to dose patients if they're normal.

And that goes back to your question around why are we exploring the dose over 12 weeks is we're trying to drive a philosophy of let's get as many people to normal as possible. And I think the value there is really we know that at least some of the CMIs are on the market, you're seeing patients who are not responding. You're seeing patients not reaching efficacy. And part of that issue is either you're dropping ejection fraction or the physician is dosing to the minimally efficacious dose because they're concern around ejection fraction. If you don't have an ejection fraction problem, it's pretty easy to continue to like dose an individual.

All right. So now in obstructive, I think it's very -- and we talk across these 2 different populations like they're one, but they are a little bit different, meaning when you remove the obstruction, you have a very rapid benefit to the patient. They feel it immediate. In nonobstructive, you probably have to drive a level of remodeling to feel the full benefit. And what we saw was with mavacamten in the ODYSSEY study, they had 21% of the patients had an ejection fraction below 50%. We know from some of the data they've put out, they haven't given us all of the data, but that patients who started with low ejection fraction and patients who went down too far did not benefit as much from the forest plots. So clearly, there's a narrow TI in the nonobstructive patients. And what we would try to -- try to understand is what is the time relationship? And what is the depth of the response you can see in nonobstructive?

And I think also one of the things is that you have a drug that works on the diastolic phase and nonobstructive is diastolic disease. And so you have a much larger therapeutic window where you're not really have to handpick a very moderate population to hand select to see a clinical benefit. And I'm making, therefore, the assumption that both in this 25 mg dose group as well as the 12-week CIRRUS study, you're just including all kinds of patients from nonobstructive. You're not trying to stay and like a broad spectrum.

We have reasonable -- we have a relatively broad spectrum of patients in the nonobstructive. I think it's clear that you will have a ceiling effect. So if you pick people with a KCCQ score of 85, well, you can only go up so much. If you pick people that are, say, below 20, right, how -- are they really HCM patients? Are they -- how fibrotic are they, how sick or have you gone beyond the threshold. At the same time, you want to be able to recruit your study with the patients in the middle. Well, it's kind of a fine line, I think.

And I know there's like 2.5 minutes, and you have many more inflection points in 2026. But maybe I think a lot of investors are also very excited about 15400, which is in heart failure, the healthy volunteer data set is going to come out in the first half. So I guess, I think a lot of investors understand because you could -- what do you want to see to want to move forward to a small Phase II study in HFpEF.

I think 15400 has some unique characteristics that are different to 7500 that make it a little bit more amenable to the HFpEF population. So I think, honestly, like the bar we've set for ourselves from the healthy volunteers is to see pretty much the same thing that we saw with 7500. So no LVEF or plasma concentration. And I think we're in the middle of the MAD right now. We have a healthy volunteer MAD. We'll have that data in the first half of '26. And we've already got a plan on what kind of Phase II we want to run, and that's going to kick off in the second half of '26.

It's pretty clear endpoints too for a relatively small IIa and where we would want to see changes in NT-proBNP, about 20%. That's kind of the rule of thumb in heart failure. Second, we'd like to see a very nice profile from a standpoint of the variability of dosing with the drug. And of course, we don't want to see the ejection fraction change is the same as 7500. So I think all those things would bode well, and you can measure all those things in a IIa study in those patients.

Yes. Great. And then team, I know we have like 48 seconds. Also another big milestone that's going to be the pivotal GRAND CANYON study reading out in 4Q. I think it's very clear, any statistical separation would warrant moving forward and filing in a big opportunity in this orphan indication. Help us understand sort of what do you see on a blinded basis. And sorry, on the [ NAF ] -- it's blinded, we don't know who's on there, but how is it tracking with your assumptions, I guess? Sorry I can only ask one question.

We haven't disclosed that particular aspect of that. Obviously, we are looking very carefully. I think there's probably a good time in maybe perhaps next year to provide both the demographics of who we enrolled and perhaps an update on MESA, which is the CANYON data in the open-label extension and perhaps some analysis of what we have in the -- what we have in GRAND CANYON.

But of course, blinded data sometimes is a fool to go hunting for that. We have built -- I should say, we have built a very robust model based on the [ Leiden ] data of natural history and built a model how you would look at North Star relative to the expected response over time. We've validated that model with 2 other natural history data sets. And I think quite importantly, we published this in a poster at World Muscle is that, that model correlated very well with our placebo in CANYON. So I think that's an important piece of the supportive data for the NDA filing once we hit [ stat stake ] on North Star and whatever secondary endpoint we described.

Perfect. And recently announced adding Chris Martin, who many of you know, was the Chief Commercial Officer of Verona. And many of you who watched the story and I was the covering analysts from very early on can say what a tremendous job Chris and his team have done. Maybe help us understand now that he joined Edgewise, obviously, he's going to be a great asset as the company potentially will be getting ready for Becker and also in preparation for HCM.

Yes. We've made very selective early investments in the commercial buildup. We have a really experienced team at Edgewise, who's done this before in rare disease. And Chris sitting on the Board is just an added benefit. He's just gone through one of the most successful launches in a very competitive space. And we're in a space with Becker where we have no competition, and then we're going into a space where we're going to be competing with the CMI. So his insights have already been invaluable to kind of our strategy. He's gone through our whole launch plan. I've spent a lot of time with him, and he's adding value already. And I think...

Board's -- I mean, a very astute aspect to our Board was we could have gotten someone who's kind of sitting atop of the vision of something at a big pharma or we hire someone who's actually built a group that was highly successful hands on. And I think that's an important differentiator as we build out our group.

No, that's amazing. I've had the pleasure working with him, and I have the pleasure of working with you guys. So it is between your personality fits and the way we work, it's like a perfect relationship, like honestly, and I'm very excited for you guys for you guys to work together. So let's thank the Edgewise team. We are super excited for December in 2026.

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.

Okay. We'll continue with the next session, which is Edgewise Therapeutics. Good afternoon, everyone. I'm Paul Choi, and I cover biotechnology here at the firm. It's my pleasure to welcome to my immediate left, Kevin, CEO; and Behrad, COO. What we'll do is kick it off -- let Kevin kick it off with some maybe high-level overview of the company, sort of where the lead programs are and then we'll get into Q&A.

Yes. So thank you all, and thank you for joining us today. Edgewise Therapeutics is really a muscle platform company, developing targeted agents for genetically-driven muscle diseases of high unmet medical need. Really founded by Alan Russell working in the muscular dystrophy space. That drug ultimately has come to fruition.

Much of what we designed -- this is really starting from scratch. This target has never been worked on. Went through the -- identified the lead molecules, went through the preclinical work, went through clinical work, which validated our preclinical approach. And now the drug is in Phase II and Phase III studies in Becker muscular dystrophy and in Duchenne muscular dystrophy. We had a very exciting readout in December of GRAND CANYON, which was the first controlled study in Becker muscular dystrophy, where we hit our primary endpoint of decreasing muscle damage biomarkers.

And also, we're quite close on hitting the functional endpoint of North Star in that Phase II study. Underpowered for the functional endpoints but a 40-patient study but a strong safety profile, hit its biomarkers in a statistically significant manner and had a nice trend for function. We announced in the first quarter that we had completed enrollment of the Phase III confirmatory study in Becker. And so that is an 18-month study. We overenrolled the study up to 175 patients, greater than 96% power to hit a 1.6-point change in North Star. And we'll be reporting data in June, this, in the next couple of weeks on our interactions with the FDA, their evaluation of the GRAND CANYON package and some additional data from our open-label MESA study.

We also, in parallel with that program, are working in the Duchenne space. So Duchenne is obviously a space with a very high unmet medical need. There has been some results of some agents in the past year or 2. Unfortunately, this continues to be an unmet medical need in this space. We'll report on our Phase II data, open label in Duchenne, roughly 80 patients with endpoints over a 6- to 18-month period at multiple different doses.

The goal here is to show that we've been able to see a change relative to propensity-matched patients of about 2 points. It also -- hopefully, we can convince you that we've identified a dose for a Phase III study, perhaps a patient population. And then we'll be discussing the functional endpoints and the primary endpoint for a Phase III design, which will ultimately be to go to the FDA and the EMA for some conversations on what's appropriate for that part of the discussion in Duchenne.

On the HCM side, so as you remember, we, again, defined a novel target for the treatment of hypertrophic cardiomyopathy that came out of our skeletal muscle program. That drug, we showed really positive data in normal healthy volunteers in single-dose data in September. What's highly unusual and significant about this program is that the drug shows that has no concentration relationship with the change in ejection fraction. So as you know, the competitor drugs in this space are the cardiac myosin inhibitors, so changes in ejection fraction, which is associated with efficacy.

We've been able to decouple that efficacy from the change of ejection fraction so that provides differentiation for the product. We've also shown an outside sized result on certain feel and function measures, which are part of the primary endpoint for cardiovascular drugs called things like the KCCQ score and New York Heart Association changes. And really great importance is that we're the first drug to show very rapid changes in a measure called e-prime, which is the diastolic relaxation of the ventricle. That's predicted based on our mechanism and preclinical models. We think that translates not only to benefit in the HCM space but also potentially benefit in heart failure in general and HFpEF in particular.

And then as 1 more milestone, sometime in the next probably a month or 2, we'll be announcing the entry of -- into Phase I of a second-generation cardiac molecule that will be targeting HFpEF as its primary indication.

So a lot going on this year. Just to give you one more flavor of the rest of the year, we are currently dosing patients for 28 days at 25 milligrams in the Part B and C of CIRRUS. We've also completed the protocol for Part D, which is a 12-week study in patients with HCM, both obstructive and nonobstructive. That protocol now is with the FDA and also through the IRBs. So we anticipate in the next month or 2, we'll be dosing patients in Part D with a readout by the end of the year.

Okay. You've definitely framed out a busy remainder of 2025, Kevin. But maybe sticking with your last point on the 7500 program in HCM. I think maybe just to help people understand the program a little better, can you maybe walk us through, first, the MOA and then maybe just remind us what you showed with your 28-day data recently to help set the stage for your Part D data later this year?

Yes. So this drug was designed to eliminate this relationship between the concentration of the drug and the ejection fraction change because the ejection fraction lowering of the CMIs below 50 drives a REMS and a black box. You want to...

From a risk of heart failure?

From a risk of heart failure. So we want to eliminate that particular aspect. And so how did we do that? We identified a mechanism where we optimize the drugs in preclinical models and animal models to eliminate that liability. We also wanted to have a greater effect on the diastolic activity. So we are more potent at low calcium levels biochemically, so we have a greater effect on the relaxation of the ventricle when it's filling with blood before it pumps out.

And then the third critical differentiation of the mechanism is we're a partial inhibitor. So we cannot maximally inhibit contraction in the heart tissue. And that combination of being a partial inhibitor having greater effects on the diastolic portion leads to the profile we've seen in the clinic. The 28-day data came out in April. We showed dramatic changes in things like KCCQ and New York Heart Association changes over a 28-day period. We had scores up to 24-point improvement of 5 points is considered clinically meaningful.

We also saw deep changes in NT-proBNP, which is a measure of diastolic function. We had deep changes in gradient in the obstructive HCM patients. So we're very pleased with the profile. And the drug is moving forward and I think will be very successful.

Right. So to continue on the last part, you said there now you're continuing with dose escalation at this point. But you're also talking about -- thinking about working through starting off Part D of your study, which will include both obstructive and nonobstructive patients. And so maybe, I guess as you think about the landscape at this stage, how are you thinking about what is considered, I guess, clinically meaningful for Part D of your study? And how does that potentially differ for your obstructive patients versus your nonobstructive patients?

Yes. It's interesting the profile we've seen so far. I think what's -- one of the goals is to minimize things like the number of echoes you need, and to demonstrate that in a broader group of patients, you continue not to see the ejection fraction changes. So that's a goal of the Part D. The second goal of the Part D is that we had a signal of atrial fibrillation in some of the patients. And there's a couple of things that we've done to change that.

So now the CMIs, if you look at the Phase II studies, there was a relatively high rate of atrial fibrillation. And patients with HCM in general as a background have high rates of atrial fibrillation. So what we've done is thought through very carefully. First, we need to dose patients who are truly HCM patients. Second, we need to look at patients who do not have a high risk for atrial fibrillation. And so this is important so that we really are following now the guidelines that the CMI set up in their Phase IIIs as opposed to trying to treat all the patients.

That's important for the safety profile as well as the efficacy profile of the drug. So I think what we'll do in the Part D is demonstrate really 0 effect on atrial fibrillation and show exactly the same benefits on feel and function, proBNP, gradient.

Right. It seems to me that at least some of the patients who experienced AF events had predispositions to it and various risk factors. And so...

The other thing you have to factor is -- so think about the treatment setting, right? We went to largely the same sites where the CMIs have been doing their Phase IIIs and where you see most of the commercial, which is a center of excellence. So the patients that we were treating were maybe skewed towards, if you look at the baseline demographics, to being more severe. If you look at their baseline gradients, if you look at baseline rates of hypertension, if you look at where the LVEF was, in aggregate, those patients were a little bit sicker.

And so that doesn't mean that you can't treat those patients, right? That means that you might want to take a different approach to a more severe group of HCM patients. And you probably don't want to do it in an open label, you want to do it in a controlled setting where your placebo helps you out. And I think that's the lesson learned here was that those patients were not eligible patients for CMIs.

A lot of the sick ones were not eligible for CMI. And a physician looked at the patient and said, "I need a therapeutic. Edgewise's profile, particularly on LVEF is really, really attractive." And so I think that's one of the things that we've learned is like you -- those patients are in dire need for a therapy, and we'll continue to study them but probably not in an open label.

Right. And then maybe just returning to thinking about what is considered a good outcome for your obstructive patients versus nonobstructive patients. Any sort of ballparks or just sort of how you're thinking about it?

Yes, what we noticed, which is really important is that the patients -- we think of getting people to normal as being a positive thing, normal meaning ejection fraction of 60. When you come from 70 or 50, we seem to converge on normal. We saw that when we normalize biomarkers like NT-proBNP, we are able to drive the New York Heart Association measure down to asymptomatic from Class II or Class III, which is really exciting.

And then with the KCCQ scores, we saw patients go from the 60s and 70s up to 90-plus, which is essentially normal. So in both populations, we saw the ability to take a patient from a disease state to essentially a normal state. And what we heard from many of the patients that their feel, how they felt about the drug was they felt spectacular when they're on the drug. So we want to try to replicate that.

Now from question of obstructive versus nonobstructive, I think we all saw the data that the ODYSSEY study with mavacamten did not hit their primary endpoint of KCCQ and peak VO2. We don't have all the data. We don't know why that occurred...

Or the magnitude of the miss.

Or the magnitude of the miss and we'll probably get that data later on in the late summer. But that's -- it really provides an opportunity for Edgewise in that space. The Cytokinetics drug, aficamten is also being studied in the nonobstructive area. And I think that data have been reported, I think first quarter of '26, that will probably come out. So obviously, we're looking very closely at that. But I view that as a really clear opportunity because if you look at our data on ejection fraction, we're absolutely 0 effect.

In fact, the ejection fraction when you look at, we started patients who are 52, 54, 56, instead of going down like the CMIs have seen with the nonobstructive patients, our ejection fraction actually went up, which is really highly differentiated in the nonobstructive space. So I think we're very excited about the opportunity in nonobstructive. Again, in obstructive, seeing these KCCQ scores north of 20 is highly differentiated and almost double what we observed with the CMIs. So we're excited in both populations. But certainly, the hope would be that we might be the first agent to have an approval in nonobstructive.

I think where you're going as well, Paul, particularly on the differentiation, in obstructive is like what is the TPP ultimately going to be, right? And I think we're trying to shift from a paradigm where today, the class of molecules were going to -- they have a pre-prescribed REMS that is set up to monitor for safety. The REMS is there to look for patients with dropping LVEF.

If we can shift that practice where the decision on performing an echo to look at whether it's gradient or LVEF is at the discretion of the physician in order to optimize efficacy. That's a fundamental switch to really unlock the value, which is not really sitting at the centers of excellence exclusively. It's at a group of physicians that we call Community Plus that are the community cardiologists that have these patients but are hesitant to push them on to a center of excellence right now and can't handle the burden of putting them on a CMI because of the echo titration required.

So I think it's a fundamental shift in the thinking. If you think about it, if you were a CMI company, you would want to avoid performing echoes. The fact is they have to do it because of the safety liability. Nonobstructive is a good example. Why would you need to do an echo in the nonobstructive patients when there's no gradient to relieve, right? So I think they've been forced to have to do that. And we're trying to say, imagine you treated obstructive patients like a nonobstructive patient where you don't require a safety echo. That's a very different proposition.

Great. Maybe just continuing on that thread as you think about 7500 potentially coming onto the market in a few years. You talked about the REMS being a key point of differentiation and 7500 potentially being the first nonobstructive drug as well. But just in terms of market development and market identification, I guess, with theoretically 2 CMIs being out on the market ahead of you, where do you see sort of the key areas that you would focus on in terms of commercialization or focusing in terms of your marketing and launch efforts down the road, a little bit further down the road?

Yes, I think as Behrad has said, I think the opportunity is really in the more of the community practices. And one of the impediments is that these community docs, they have their own -- is running their own business for all intents and purposes. They need to have a highly qualified echo reader. They're responsible for that echo result and monitoring that patient and they need to put in place the -- essentially the infrastructure to monitor those patients, to do the paperwork and to make sure those patients in a relatively rigorous way are monitored across the continuum forever for all intents and purposes, and especially when they're getting to the right dose, which is echo-intensive.

So the question is for those groups of doctors, it's easier for them to actually send that patient off to a center of excellence. But the center of excellence have a saturation point as well. They can't continually add echo facilities or people. So even though there are some groups that may have 1,000 HCM patients, they can only put 100 of those HCM patients on a CMI because of the requirements. So now we'll see what the REMS turns out to be for aficamten, but we don't know how it is but we know they will have REMS at some point.

The other thing to think about is like the nonobstructive is really interesting because if you look at the dynamics, and Cytokinetics have talked about this as well, and we've seen the same thing from our market research is as a proportion, the nonobstructive patients are constituting a larger proportion of diagnosed HCM patients. So the general thought has always been it's 1/3 of the market is nonobstructive, 2/3 is obstructive. We're seeing a bit of a shift. It's getting closer to 50-50, not quite there.

And so if you have a drug that can treat the nonobstructive population, because remember, we have a unique benefit which is driven by this diastolic effect. So we're a lusitropic agent. And so I think that aspect plays out really positively in the nonobstructive. And you saw the data, right? The 50-milligram, our lowest dose, we saw 16-point changes in KCCQ, which was almost double what you've seen with the CMIs. So I think that, to me, is like one of the most interesting ways to capitalize on the market is to go out through the nonobstructive.

We already know what we do in obstructive. You saw the data. With almost a single dose, you're driving a pretty dramatic effect on gradient, on feel and function, on NYHA, and on old diastolic parameters, whether it's NT-proBNP or you're looking at e-prime and e over e-prime and other end disease.

So AHA guidelines don't say treat to a gradient reduction. They say treat to...

Symptomatic relief.

Symptomatic relief, correct. So that's what we're really shooting for.

Great. Maybe 1 more on HCM before we talk about sevasemten, which is one of the interesting developments recently in the space has been the Cytokinetics MAPLE study, which hit -- we don't know the details yet, but it hit on the primary endpoint and beat standard of care beta blockers in the head-to-head study.

So my first question there is do you think this will drive broader adoption of CMIs in the frontline setting, whether it's aficamten or Bristol's CAMZYOS? And second, given that a competitor in the space has successfully run a head-to-head study, do you feel like this is necessary for your 7500 program for utilization in the frontline setting?

Yes. Beta blockers can be effective in some patients for obstructive HCM. So I think in the obstructive space, I think it's a bit more of a challenge to say that I won't go through a beta blocker first before I move to a CMI. This probably would help, but then you're back to, do I need to do extensive echoes to get people to their maintenance and to their target exposure? So how much of an effect that could be is an open question, I think.

I view the nonobstructive opportunity as being even greater for a MAPLE-like study because I think it's kind of well-conceived today by the physicians that the beta blockers don't work at all in nonobstructive. It's just kind of you try it, I hope it works. And there is no standard of care in the nonobstructive. So in fact, I think a MAPLE-like structure in nonobstructive might be a more feasible and commercially viable strategy to be the first drug for treatment of nonobstructive as opposed to trying to push it into the obstructive population. But I think we have to do a lot more work on that space to see if that's the appropriate study.

For 7500?

For 7500, yes.

Great. I want to shift gears to sevasemten and maybe talk a little bit about the DMD space and -- which is one of the most notable market developments this year in the DMD space has been unfortunately a patient death on Sarepta's ELEVIDYS. And so I'm just sort of curious what has the downstream impact been on Edgewise in terms of either patient-inbound interest or clinician-inbound interest in your DMD program. Can you maybe comment on that a little bit?

Yes. I don't know if I've seen a lot of changes from that. There is the rate in which they can get patients lined up for the Sarepta gene therapy, and that hasn't changed, I think. I don't know if there's been a lot of change in the ambulatory patients. I think within the nonambulatory patients, I think there's been a bit of a pause in the thought process because there's just simply less data there.

But from my standpoint, people still believe there is some benefit in the gene therapies. Now there has been some data published both last year at MDA on the 2-year ELEVIDYS data and then this year, a 3-year ELEVIDYS data. And there was a fairly substantial decline in the North Star from 2 years to 3 years. So that's starting to become more well known. And the question is, what is the durability of the response and how does that affect the market uptake? And does it affect us or does it affect the enthusiasm for getting some of the second-generation gene therapies?

Now from our standpoint, we're a bit agnostic to that, so we have studied the patients who have previously been given a gene therapy. So 2 years out, these are both Sarepta patients, SOLA patients, Pfizer patients. And so we do have an understanding of what the rate of decline is out by 2, 3, 4 years. We'll be reporting on that data later on this month. Also, I think -- I don't think we've seen a dramatic change in retention of patients. I think some patients have gone off the gene therapy. But I don't think it's like a flood to the gene therapy programs.

Do you feel like you'll be in a position in the near term to talk possibly about your Phase III design and just kind of what a post-gene DMD population looks like? Is it ambulatory, nonambulatory? Is it limited maybe to a certain age range of patients or certain North Star baselines? Maybe just at a high level, how are you guys thinking?

At a high level, I think there's good evidence to say that if you can develop a protocol and demonstrate benefit in any population of Duchenne patients, you'll -- the label would essentially read like, for instance, all ambulatory patients, right? So you've seen that with givinostat. You've seen that with the Sarepta drug. So I think that's true. So then it's identifying the right patients.

The question for us becomes, is there an age group? Is there a functional baseline that you would use? Is there a dose that you would use? And we should be able to provide that update of, do we have the right parameters to be able to develop that Phase III? Now one of the key aspects of this is what is the primary endpoint. We're quite inclined and we're quite interested in a measure called the SV95, which is a wearable device. That endpoint is approved as a primary endpoint in Europe. It's under evaluation in the U.S., but we don't know how long that will take. So that's 1 -- we think it's a highly quantitative endpoint that's highly objective because...

For extreme populations, yes?

That's right. But of course, we have the North Star, which is the standard and we have things like Time to Rise and 4-stair climb. So we will discuss and disclose multiple functional endpoints. The goal here is that do we have a window in which we can work? And what would be the primary endpoint? Which is probably going to end up being a discussion with both the FDA and the EMA of what's appropriate for this population and talk about the trial design.

And the balance of like how many gene therapy-naive versus gene therapy-experienced patients to include in the study, right? Because what's clear for us and just looking at the process is there's still a tremendous unmet need post-gene therapy as early as 2 years post getting dosed. So if you're seeing a rate of decline that's aligned with natural history based on the data that Sarepta put out at MDA, that tells you that, yes, you provided an initial bump but now they continue to decline at that -- at the same rate as predicted by natural history. So you need something for those individuals.

You bring up an interesting point, which is that these patients post whatever initial therapy they may be getting will still probably have a chronic need for treatment here. So I guess as you think about the landscape of rare and orphan diseases and drug pricing in those categories for what may be a potentially chronic treatment here, what does, I guess, your work or market data work sort of suggest...

Well, you look at risdiplam on top of ZOLGENSMA. We've seen other molecules. SPINRAZA gets used on top of gene therapy. We've even seen in the U.S. some patients who received gene therapy but then have gone on to receive the HDAC inhibitor, givinostat, right? So that flexibility is there. And I think the interesting dynamic for Edgewise is, from a cadence standpoint, we would be launching in Becker sometime in Q1 2028 if we go through the full approval based on GRAND CANYON.

We would be selling our price in Becker. And as you know, there's nothing approved in Becker. It's completely a blank slate for us. And so the question is, can we take that value and that price associated with that value and translate it to the Duchenne population? Based on our market research, there's flexibility because, again, it's not -- you're not talking about 30,000 patients. You're talking about a very discrete number of patients, about 12,000 to 12,500 ambulatory Duchenne boys, maybe 15,000 in Europe. So you're not having a tremendous impact on overall budget, even with the advent of the gene therapy at 3 million-plus.

Right. I think the other interesting aspect is for years, people are saying that I'd like to turn my Duchenne patients into Becker patients. Now we have a treatment for Becker. What does that mean to the market now people think about the drug? Because if we can demonstrate effects in Becker, does that translate over to some view of, if I provide a gene therapy to a Duchenne, that's now formally a Becker? They have expression of a microdystrophin.

And how does that play through with the regulatory agencies because it will take a while to really understand the natural history of the gene therapy-treated patients to run a trial and there's really no drug for them to take. So what do you do with them?

Right. Behrad, earlier, you just mentioned GRAND CANYON potentially forming the basis for a future Becker's approval. But can you maybe help us bridge the gap between your CANYON data, what the agency has said and how has that informed your thinking on where GRAND CANYON might fit into the regulatory package?

Yes. So as you know, we had some really interesting data from CANYON, right? We hit our primary endpoint, which was CK. We hit TNNI2, which is our on-target biomarker. And we had a 1.1-point difference in North Star, which didn't quite hit stat sig, but what was really interesting about the CANYON data is the first study, placebo-controlled study in Becker patients, and actually, the placebo behaved exactly as predicted by natural history. Very seldom do you see that play out.

So I think you look at that data package and you look at the data that we generated in ARCH, which was the open-label study, and obviously, we've captured some data in MESA, which is our open-label study. So we put together a pretty interesting package that we put in front of the FDA. And the question is, hey, is this data the basis for some sort of accelerated path to an approval? Because we've talked about this before. Generally, the FDA hasn't been open to CK as an accelerated endpoint because it's so variable and noisy. We even saw that in our CANYON data in the placebo arm, right?

It's tough to measure.

It's tough to measure. So I think the question is like what's going on at Cedar at the macro level without leadership in place and then really balancing the quality of the data that we put in front of them and what's the flexibility in terms of an abbreviated path to an approval that is beyond the line purely on GRAND CANYON? Is there some flexibility to come in with additional data somewhat in a rolling submission type strategy to really work with the FDA? So that's what we've been exploring with.

And obviously, with the date of a readout in the fourth quarter of '26, so there is kind of -- the timing there is by the time we get the data, if we can get some of the data signed off on, you essentially cut off 6 months off the back end after the GRAND CANYON data. So either way, you win as long as you can move faster.

Yes. With GRAND CANYON, maybe can you remind us, is there anything -- given that it's about roughly 1.5 years out, should we expect any potential interim updates from that program between either in the back half of '25?

No, like many studies, I think we were kind of a little bit back-end loaded for the recruitment of the patients because Europe opened up a little bit later than the U.S. And so getting an interim analysis is not going to be highly productive, I'd say, a 1-year cut. And we're pretty satisfied with the statistical analysis plan right now. Of course, that is not settled and confirmed at the moment, but we'll develop that in collaboration with the agency and different areas of supportive data.

We certainly want to shore up natural history studies and do that in a prospective way to augment the placebo groups. So that is another piece of secondary information that's important to the agency in these rare diseases.

Also, I just wanted to point out, we've had a pretty remarkable retention rate at MESA from all the patients who have enrolled. We've had a 99% enrollment. So clearly, something -- these patients are experiencing something and they're continuing to want to be involved with the studies.

Great. We're coming up on time here so maybe just 1 quick 1 which is just on your HFpEF program. Just remind us how you're thinking about this particular patient population here. Who will be included in the treatment experience, just newly diagnosed? And just sort of what time lines for the initial data might be?

Yes. So we initiate the Phase I studies in, say, third quarter of this year. We'll be positioned to run a HFpEF study probably based on the tox coverage, about a 3-month study. The readout is likely to be something along the lines of NT-proBNP. Our bogey for that, as you can see, a 20% decrease in NT-proBNP in a broad HFpEF population that has generally led to, in heart failure, a clinical benefit for those patients. So that's pretty straightforward.

I think it would be likely we would run a placebo-controlled study. HFpEF requires larger studies. They have a number of background meds that you need to account for. And then the big question for us, are there 1 or 2 targeted populations where we run a fairly generic basket study and try to use the Phase II study to identify the right population for this drug?

Great. Unfortunately, we've run over so we'll have to end it on that note. My thanks to Kevin and Behrad and Edgewise for joining us.

Thank you, Paul.

Thank you, Paul.