Edgewise Therapeutics Inc Aktie

Good morning, and welcome to the Edgewise Therapeutics Research Update. [Operator Instructions] As a reminder, this call is being recorded, and a replay will be made available on the Edgewise website following the conclusion of the event.

I'd now like to turn the call over to Michael Nofi, Edgewise's Chief Financial Officer. Please go ahead, Michael.

Thank you, and good morning. Welcome to the Edgewise Therapeutics conference call to discuss the differentiated mechanism of action of our cardiac sarcomere modulator, EDG-7500. This morning, we issued a press release announcing these findings, along with the presentation slides for this call, is available in 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. Alan Russell, Chief Scientific Officer; and Dr. Michael Ayers, a cardiologist and Executive Director, Clinical Development and EDG-7500 Program Lead.

Before we begin, I would like to remind you that some of the statements made today during the call 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 undue reliance on these forward-looking statements, and Edgewise disclaims any obligation to update the statements.

I will now turn the call over to Kevin.

Michael, thank you. So I want to provide some historical perspective on the company and where we're going as a company and our new focus on the cardiovascular pipeline. We'll spend most of the day discussing the Mechanism of Action of 7500 and how that fits in the therapeutic portfolio for the treatment of cardiovascular disease.

And then I'll end up with some near-term milestones for the company.

As you all know, we started back in 2017 as a muscle platform company looking to invent and develop drugs for the treatment of orphan and rare muscle disorders with a high-unmet-medical-need. We started our program working on identifying a drug for the treatment of muscular dystrophies -- that target of interest there was a type 2 skeletal muscle myosin inhibitor that was really a novel concept at the time. We ran a high-throughput screen, identified some leads, produced thousands of molecules, and ultimately selected sevasemten as the clinical candidate and filed the IND in 2020.

Very rapidly, we were able to mechanistically validate the hypothesis that we would prevent muscle damage in muscular dystrophies and move that forward into Phase III. That Phase III will be reading out in -- by the end of the year. Along the way, though, a company, Servier, found our data really compelling and made us an offer that really changed the nature of the company, actually acquired sevasemten for $2.65 billion last July with the deal closing last July, $1.55 billion upfront and $1.1 billion in milestones.

So it was a great milestone for the company and provided us significant cash to be able to propel and fund our cardiovascular programs. Great work by that team. So I want to turn back to the cardiovascular portfolio because really, the initiation of the cardiovascular portfolio came out of a counter-screen for the skeletal muscle program.

So when you run a high-throughput screen, you'll get a number of hits, we ran through about 2 million molecules. We found dozens of lead series. And then we ran a counter-screen to make sure that we had selective skeletal muscle inhibitors. During that time, we found a set of leads that were actually more potent on cardiac tissue than skeletal muscle tissue.

And so we found molecules that were quite similar to what were found previously, which were type 1 cardiac myosin inhibitors, very similar to the drugs, aficamten and mavacamten. But we chose not to just follow that path and make a third-generation type 1 myosin inhibitor. We found another lead series that was quite unique. And what was unique about them, they were pharmacologically active, partial inhibitors and when tested in vivo, they did not lower fractional shortening or ejection fraction in the rat.

And so they had a unique profile -- and then we started -- after we completed the IND of sevasemten, we started to really focus in on the cardiovascular program and that particular lead series. We made several thousand molecules in that space and ultimately chose EDG-7500 for development in 2023, where we filed the IND.

Just in the past couple of months in June, we reported on the 12-week Part D data and showed really in a lot of ways, validation of much of what we've seen preclinically with the drug. We'll be talking extensively about that in the coming 45 minutes. And so turning to the next slide, 7500 is poised to go into Phase III by the end of the year.

We found a second-generation molecule that has a somewhat different metabolic profile optimized for HFpEF, which is now you probably saw on ClinicalTrials.gov, has been -- enrollment is open for the HFpEF study. And we won't say too much about 003, but we do feel like we have a lead series and are in the candidate selection mode.

So we're very excited about the portfolio in cardiovascular disease and look forward to talking to you about how we discovered the drug and some of the key biologic nuances of this value proposition. Next slide. So, I just want to give you a quick executive summary of what you're going to hear today. 7500 regulates the cardiac cycle.

So essentially, we are controlling the rate in which the cardiac cycle moves throughout different parts of the cardiac cycle through control of the lever arm, which is -- of the drug binding to the regulatory light chain. This targeting of the regulatory light chain can produce really diverse phenotypes and pharmacologic profiles.

There are RLCs that look virtually identical to CMIs, and there are regulatory light chain modulators that have very strong diastolic effects and a completely sparing of systolic effects, which is exemplified by EDG-7500. Preclinically, EDG-7500 slows early systolic pressure, speeds up mid- to late-diastolic, enhances early diastolic relaxation, which is the key pathology in HCM and HFpEF.

Clinical findings have been consistent with these preclinical observations, whereas EDG-7500 has reduced gradients, preserved net systolic function and improved diastolic relaxation; and we'll be showing some of that data today. More interesting, we'll show you a bit of data on the biophysical arrangement of the heads associated with the lever arm and that by maintaining availability of the heads to reengage the actin filament.

During exercise, we believe that we'll be having a strong effect on endpoints like peak VO2 and KCCQ when a patient exercises or exerts themselves, and we'll show you data to support that position. So with that, I'm going to hand it off to Michael Ayers and allow him to discuss some of the details of the story.

Thank you, Kevin. When I went from running a full-time HCM practice to part-time, I did so because I find this narrative and story so compelling for our HCM patients, and I am just over the moon excited to talk to you today about this mechanism. So when we go around and we talk to investors, cardiologists, knowledge leaders, or just anyone about this drug, 4 questions come up with some constancy.

One, how exactly does this thing alleviate gradients? And two, how does it do so? How does it modify contractility without ultimately suppressing ejection fraction, previously thought of as the holy grail for obstructive HCM treatment. How does it improve diastolic dysfunction? And is it doing so in a unique way relative to other agents? And lastly, is there something in this secret sauce that allows for meaningful symptom and functional improvements relative to other things in the class.

So I'm really excited to go through those 4 questions with you today. Let's start on the next slide with a little bit of a disease-state background to make sure we're all on the same page. HCM is the most common inherited heart condition affecting around 1 in 500 people. It's dramatically underdiagnosed, misdiagnosed, and there are delays in diagnosis that impact care. It's defined as having a heart muscle thicker than 1.5 centimeters in absence of some cause.

And broadly speaking, we like to classify it into 2 buckets or phenotypes -- while both of these patients have thickened heart muscles, they have slightly different pathologies or problems. The first is your obstructive group. This group has a thickened heart muscle right at the outflow tract, which results in a divorcing of the pressure inside the ventricle relative to the aorta. There's a pressure difference.

So now, to generate your 120 millimeters of mercury systolic blood pressure, you might have to do 170 millimeters of mercury work. The second subtype is the non-obstructive subtype, which also has thickened heart muscle, but doesn't have that misplaced, thickened heart muscle right at the outflow tract.

But I'll point out, both the obstructive and non-obstructive groups suffer from diastolic dysfunction or abnormal relaxation. When it comes to current therapies in this area, to be honest, there are some effective agents at relieving outflow tract obstruction, but they do so directly via negative inotropy. They decrease how hard the heart is squeezing and they keep that highway out of the heart open.

What is less well treated at present is the diastolic dysfunction that is shared in both of these groups. We know that around 1/3 of patients with obstructive hypertrophic cardiomyopathy have residual symptoms despite gradient relief, and we think that's from the diastolic dysfunction. And we know that current therapies have some diastolic benefit, but that benefit is coming directly at systolic cost that's ultimately tied up to echo monitoring for ejection fraction excursions.

Let's talk a little more about HCM pathology on the next slide. So no matter your shape, of the HCM, no matter where your thickness is, there's kind of a shared pathogenesis at the sarcomere or muscle cell level. Let's start with what a healthy cell looks like. In a healthy cell, there are myosin that are available to bind with actin. And at any given moment, you might have 40% to 60% of these myosin that are participating in a given heartbeat, while the other 40% to 60% are in an off or relaxed state.

When you exercise, that number goes up. When you take a nap, that number goes down. And in everyday life, you modulate myosin availability based on need. In HCM, this system is dysregulated. And now you have a myosin overavailability such that basically all the time, around 80% to 90% of your myosin are engaged in activities with actin. What that results in is a hyperdynamic EF, it results in thickening of the heart muscle and in about 2/3 of patients, it results in that obstructive physiology we described on the previous slide.

What it also resulted is diastolic dysfunction really from 2 things. One, too many myosin heads are on at the end of the heart squeeze. And so it takes longer to pull them off and each myosin head is a little stickier than normal. And two, because the heart muscle is thick, when you get to the end of diastolic filling, the pressure is higher than it would have been in a normal heart. Lastly, myosin overactivation impairs what's called the cardiac reserve.

Now the cardiac reserve says, at rest, I might need 5 liters a minute of blood flow, but with activity, that number might go up to 10. So I need to be able to change blood flow based on need. That thickened heart when asked to be faster, can't fill well and the cardiac reserve gets diminished. In this environment, the approach from cardiac myosin inhibitors makes some sense. If too many myosin heads are on, why don't we turn them off?

The issue is that while this adverse glance looks like a normalized state where you've moved back to that 40% to 60% of myosin availability, the inhibited myosin heads become semipermanently off such that when you need to recruit those myosin heads, you can't. This is really a pseudonormalized state. And let's talk about what issues come from this pseudonormalized state throughout the cardiac cycle.

The cardiac cycle is made up of 2 components, the squeezing and the relaxation of each heartbeat. The squeezing is known as systole, when actin is bound to myosin and the sarcomere is shortening, pushing blood out of the heart. Diastole is when myosin is popping off of actin and the heart is relaxing. The cardiac myosin inhibitor is going to turn off myosin heads, decreasing contractility, keeping that outflow tract open, but the benefit is coming not just because of, but due to myosin turning off.

There is a systolic liability directly tied to the benefit of gradient relief. In diastole, cardiac myosin inhibitors don't actually speed up the release of those sticky myosin heads to allow the heart to fill. What myosin inhibitors do is they just say, well, at the end of systole, fewer myosin heads are on, it's going to take less time to pull them off.

There is no direct speeding up of that association. It's kind of diastolic benefit by happenstance. Moreover, that diastolic benefit, again, is handcuffed to systolic cost. When we think about HCM, it's not a wholesale problem of systole or diastole. And that's why this broad approach of just turning myosin heads off becomes further problematic.

We think of obstruction as a systolic phenomenon, and that's true, but it turns out that obstruction is initiating in early systole when the mitral valve is moving into the outflow tract. And you have to have that moment in order for obstruction to then propagate through mid- to late systole. But it's early systole that is the most important moment to target potentially therapeutically.

When it comes to diastole, again, there's abnormal relaxation. But as the heart rate speeds up, mid- to late diastole shorten and early diastole becomes more and more important. Said another way, when it's time to vacuum and your heart rate picks up, you lose some of mid- to late diastole and early diastole becomes the sweet spot for cardiac filling. This is particularly true in HCM.

So as we take a step back and say, with that in mind, what would the ideal HCM medication look like, we can come up with some conclusions. It would obviate or alleviate obstruction, but it would do so by targeting the initiation of obstruction in early systole. And by decreasing pressure generation in early systole, obstruction would never initiate and therefore, it wouldn't propagate in mid- to late systole.

You could then utilize mid- to late systole to catch up on that myocardial work. You could have a form of systolic procrastination where you're just doing the ejection fraction towards the end. In this scenario, there's no gradient and EF is preserved, potentially helping you escape things like echo monitoring for titration. In diastole, I've emphasized for you that it's early diastole that is really important for those myosin heads to come off.

And the ideal therapy would directly speed up this process, and it would do so without handcuffing your benefit to systolic liability. Again, this idea that you could have your cake and eat it, too. Lastly, the ideal therapy would save your cardiac reserve. So that when it was time to bring in the trash from the curb, you could pick up your cardiac output. You could tolerate those faster heart rates.

And when needed, you could increase how much blood was squeezing out with each beat. To do this, you have to maintain myosin availability. So the ideal therapy would do that, too. This kind of fine-tuning, I'm really excited to tell you, we think is possible, and I'm going to turn it over to Alan to tell you a little bit more about that.

Thank you very much, Michael. What you can see on this slide is a more detailed exploration of the sarcomere. And let me just orient you to what you're looking at here. As Michael showed, there's these 3 different states of myosin, the off, the ready to bind, and the bound states of myosin. What I want to show you now is a walk down the rod domain of myosin. So what you can see just south of those myosin molecules is 2 units. It's the essential light chain and the regulatory light chain.

They're bound to the hinge region of that rod domain, and they essentially control the compliance of the lever arm that's responsible for generating the shortening force once myosin attaches to actin. So regulatory light chain is an adjuster of force. It doesn't turn it on or off, but it modifies the efficiency of the way that myosin binds to actin and develops force. Now the regulatory light chain can be controlled through phosphorylation, and it has 2 main functions.

The first function is to adjust the stiffness of the lever arm to modify the efficiency of force development and relaxation. And the second function of myosin is to adjust that position of myosin relative to actin from these off states to these ready to bind states. If you go on to the next slide. 7500 essentially modifies both of these functions of the RLC.

So what I'll tell you over the next few slides is a story that kind of adds some flesh to the bones of these simple facts associated with 7500 mechanism. Firstly, 7500 reduces the stiffness of the lever arm and there's consequences to that reduction in stiffness, primarily slowing that early contractile process that Michael told you about and also speeding relaxation.

The second function that 7500 carries is it actually moves those myosin towards actin, moving them away from this off state to this ready-to-bind state. So in many ways, in that context, it looks more like an activator than it does an inhibitor. We go on to the next slide. In the discovery of EDG-7500, we synthesized more than 1,000 analogs and subjected them to detailed mechanistic profiling.

During this process, we recorded surprising mechanistic diversity in this class of compounds. EDG-7500 was selected to maximize effects on early contraction and relaxation without carrying a systolic liability, but these properties are unusual. A good contrast would be other RLC modulators that have been described in the literature and have often been labeled as myosin inhibitors.

By that, we mean that there are strong negative inotropes and inhibit contraction under most conditions. They also exhibit a narrow therapeutic index in vivo with strong inhibition of cardiac contractility and an increased liability of systolic heart failure.

One of the nice elements of the JCI paper story is that we highlight this diversity by describing the enantiomer, the mirror image of EDG-7500, a compound called EDG-7499, which also behaves in most respects like a cardiac myosin inhibitor. Next slide. Okay. So what I'm going to do now is just walk you through some basic target identification, and then we'll get on to the nuts and bolts of the mechanism.

So first, I'd like you to focus on the left-hand side of this image. What we have here is isolated myosin subunits. They exist in a dimer here. You can see that rod domain, the RLC, ELC and the myosin, and we're measuring ATP consumption in the preparation of these proteins. You'll notice a couple of things here. One is that the slope of the inhibition with 7500 full-length protein is very gradual.

The second thing you'll notice is that it's not complete. So the most that you can inhibit this system is approximately 50%. Next, what we do is we strip off the RLC subunits with a detergent. It's relatively easy to do this and then you can replace those subunits subsequently. Once we remove those RLC subunits in the middle figure, you can see that the compound is inactive. It is no longer modulating the ATPase function of this preparation. If we then put RLC back again, in this context, it's a recombinant human version of the RLC, you see that activity return.

So the activity is completely dependent upon the presence of that RLC subunit. Next slide. A second element of the target identification is to take that full-length myosin and use an enzyme to clip off the lever arm of myosin and just leave the myosin head itself and those 2 RLC, ELC subunits. What you can see is in the full-length version, that's the dark blue dots.

The compound is inhibitory as we showed before, with that 50% maximum effect. Once you chop off the lever arm, you render that preparation inactive to 7500. 7500 no longer has any effect. So what that's telling you is that the meat and potatoes of the inhibitory effect of 7500 is that lever arm region and not the enzymatic function of the myosin itself.

Next slide. Okay. What I'm going to do now is break you through the various questions that Michael proposed that we've received multiple times about how 7500 works. So the first question, how does it reduce gradients without suppressing contraction? The first thing we're going to do is use a pictorial trick so that you can visualize the nature of the inhibition from EDG-7500. This is actually not in the paper, and it's some beautiful work done in our in-house labs downstairs.

So what you're looking at here are glass cover slips coated in those full-length myosin molecules. Then what we do is we add fluorescent actin to that preparation, and you can actually see the myosin moving that actin around on the cover slip by visualizing that fluorescent actin. And you can see on the left-hand side, those little actin filaments are creeping around quite efficiently.

If we add a high concentration of 7500 in the middle, what you see is these actin filaments are still moving around, but that is -- it's much more slowed, approximately 50% compared to the left-hand figure. The right-hand figure is a video, but it's hard to see because when you add a high concentration of a cardiac myosin inhibitor, you've essentially arrested those filaments completely. You've removed all of the actin enzymatic function and those actin filaments are now unable to move. They're just frozen in time. And you can see that represented by the figure on the right-hand side.

So 7500 slows, but does not stop the motion of myosin. Next slide. You can also see this slowing in other simple preparations that we use in the lab. In this case, what you're looking at is fiber bundles isolated from pig cardiac ventricle. Now these fiber bundles are then treated with a detergent that removes the membranes, and you can actually activate contraction in these fiber bundles directly by just adding calcium.

In this experiment, what we do is we rapidly add calcium and we look at the speed of force development. So on the left-hand side, we've added calcium at that 0 time point. And then what you see is the contraction increasing up to a plateau, then we remove the calcium and then that contraction goes down. What you can see in the blue line there is addition of 7500 slows that force development.

Now there's a concentration response. The Kcat is just the rate of that contraction. And you can see very much like the ATP consumption figures earlier, a partial inhibition of this system with a concentration response. So the more 7500 that you add, the more you slow force development. Next slide. Just to add a little bit of extra complexity, and this is really important for 7500, that slowing effect is contingent upon how much calcium is in the system.

As you stimulate the heart, calcium is released into the muscle fiber and directly interacts with the active filament or elements on the active filament to initiate contraction. The more calcium you add, the more contraction that you get. What we found with 7500 is at high levels of calcium, the slowing effect is very, very modest. That would be the dark blue triangles there. Whereas at low calcium, you see much more slowing, okay? And that will give you open triangles.

So as you go through this calcium cycle, you exhibit more slowing at low calcium and less slowing at high calcium. Next slide. So the theory here would be in early contraction in early systole, EDG-7500 should slow that contraction and then it should have a lesser effect in the mid- to late parts of systole. We've actually measured this early contraction using a high-frame rate echocardiogram measure of pre-injection time.

Now pre-injection time is that period of the systolic cycle where injection is not occurring and pressure is increasing. It's the period between electrical stimulation of the ventricle and opening of the aortic valve. So what you see in these cases is a 17.3% increase in that pre-ejection time with 7500.

So you're essentially increasing that -- the time that, that pressure increases and you're delaying the early pressure that leads to gradients in obstructive hypertrophic cardiomyopathy. It's a very selective way of relieving gradients with this medicine.

Next slide, and next question. How might 7500 modulate hypercontractility without suppressing LVEF? This is a big question. We received this all the time. How can you turn down contraction and not see decreases in LVEF and this comes on the next slide to the other function of the regulatory light chain.

And as I mentioned before, 7500 moves myosin towards actin instead of away. So I'll show you a little bit of data over the next couple of slides that just illustrates how the RLC can modify the position of myosin and 7500 can intervene in this process. On to the next slide. Now one of the wonderful things about muscle is it's so organized, you can actually use X-ray diffraction and scattering patterns from that diffraction to be able to tell where those myosin heads are in relation to actin.

So you can actually tell whether you have a red head, a green head or a dark green head essentially. On the left-hand side is this measure put into graph form. And we have a resting muscle. These are, again, pig ventricular tissues. And what you're doing is at rest, you're measuring where about are those myosins relative to the actins. Are they close to the actin or are they further away? If that number increases, they get close to actin and if it goes down, they get further away.

So if I added mavacamten, for instance, that number will go down as you move those myosin heads away from actin and towards the thick filament. Interestingly, when you add 7500 without adding any calcium, you're not activating this system, you move those heads away from the thick filament and into this preactivated state. So 7500 is influencing the position of myosin, bringing it closer to actin.

Next slide. So this is a physiological trick that you can use in these pig fibers that you can activate with calcium. But instead of looking at force development from rest, now what we're looking at is force redevelopment once these fibers are maximally contracted. So you add calcium, the fiber contracts fully and then you rapidly shorten that fiber, which causes the myosin heads to disengage. They pop off transiently.

And then what you do is you relengthen the fiber and you measure how long it takes for that force to redevelop. So this is a surrogate for how efficient those myosins are in the fully activated state. And what you can see is 7500 treatment under these conditions accelerates that force redevelopment. Not only does it accelerate it, it overshoots.

So treatment with 7500 and this positional change of myosin actually preloads these myosin once calcium is present to develop more force faster. So if you go on to the next slide, you can kind of see this all at once. So instead of just early contraction slowing with 7500, you actually have this continuum where slowing turns into speeding. So as you progress through early systole into late mid systole, now you have a catch-up phenotype in which that early slowing is overridden by that speeding phenotype.

And we believe that's the secret sauce why you don't see LVEF changes at pretty much any concentration you look at with 7500. You get that slowing of contraction. That's very important for obstruction relief in obstructive hypertrophic cardiomyopathy, but it doesn't lead to any transient decreases in LVEF because of this catch-up phenotype.

Next slide. So the third question, how might 7500 improve relaxation? I'm returning now to these fiber bundles that we have from the pig ventricle that we've removed the membranes and we can activate directly with calcium. You add the calcium, the fibers contract. And now we're looking at the other side of the spectrum. We're going to rapidly remove calcium. We're going to look at how fast these fibers relax.

Top left-hand figure, you can see that addition of 7500 accelerates that relaxation process. The green line is going down faster than the black line. And you can measure a concentration response to that. So Krel is our rate of relaxation. And you can see as you elevate the concentrations of 7500, you increase that speed of relaxation. One of the super interesting things about 7500 that's very defining is that if you look at that concentration response for relaxation, it's actually more potent at doing this than it is slowing the contraction, right?

So it's quite possible to engineer an exposure of 7500 that accelerates relaxation without touching systole at all. You can kind of see this in action on the next slide. So I'm going to use a preclinical story, and then I'm going to hand it over to Michael to tell you a clinical one. So in this case, what we did is 12 -- is 6 months of treatment with EDG-7500 in the pig model of non-obstructive hypertrophic cardiomyopathy.

So this pig has a mutation in the myosin molecule itself, MYH7 that leads to a non-obstructive phenotype. There's no obstruction in this pig, but they get hypertrophy and they get diastolic dysfunction. In this 6-month study, we treated the pig you can see on the left-hand side, there's no change in LVEF. So much the same is in the humans.

We haven't decreased contraction of the heart. At the end of this study, we instrumented these pigs so that we could actually measure pressure volume relationships in the heart.

And you can see 2 very clear phenotypes here. The first in the middle is that end diastolic pressure is decreased in the presence of 7500. It's elevated in the untreated pigs because they have diastolic dysfunction and residual end diastolic pressure that's relieved with the compound. On the right-hand side, this is a measure of ventricular compliance, the end diastolic pressure volume relationship.

And you can see that, that's also decreased. So you've improved ventricular compliance and the ability of that tissue to relax, 2 great signs that you're directly affecting relaxation with this compound without cost on LVEF. So at this point, I'm going to hand it back to Michael to describe clinical effects and then talk about exercise capacity in cardiac reserve.

Thanks, Alan. So rather than speeding up relaxations by merely having fewer myosin heads on board attached to actin at the end of systole, we think we're directly speeding up that association. And that is manifest clinically. What we see here is what's called an e-prime measurement. So your heart is shaped somewhat like a bullet with the apex or tip and the flat part at the top of the bullet being the mitral valve. When the heart squeezes that bullet shortens.

And then when the heart relaxes, that bullet is going to lengthen as the mitral valve moves away from the tip. We actually directly measure the speed of this mitral valve movement in early diastole, and it's a way for us to capture how much of a suction cup effect you're seeing in early diastole. How much is the ventricle actively pulling blood down through the mitral valve to fill for the next beat.

In obstructive physiology, there are many changes occurring within the ventricle. Systolic pressures are dramatically changing, and that actually influences some of our e-prime changes. As such, as a clinician, I think the purest place to look for the lusitropic benefit of an HCM med would be in a non-obstructive cohort. So I'm going to draw your attention to the right side of this slide.

As a point of reference, if you were to look at, say, REDWOOD Cohort 4 or what kind of e-prime changes you're seeing with myosin inhibition, that's going to give you e-prime augmentation speeding up of relaxation of around 16% to 24%.

What you see here is the proof in the pudding of the lusitropic benefit of this medicine with a 37% increase in e-prime. This goes hand-in-hand with robust improvements we saw with another filling metric, e over e-prime in this same cohort. Now keep in mind that Alan showed you that the lusitropic or relaxation benefit of this medicine is more potent earlier than the changes in systolic contractility and changing how the ventricle squeezes. You get the relaxation benefit first.

We think that this is manifest on this graph, where we have an obstructive patient who was given a low dose of 25 milligrams. And you can see at Week 1, the gradient hadn't yet moved. You hadn't lowered early systolic pressure enough that you had initiated gradient relief. But despite the gradient still being present, the BNP, which is a measurement of wall tension, is going down.

We think this is reflective of the fact that even at 25 milligrams of this compound, you're getting a lusitropic benefit that is showing up in blood work prior to the gradient being relieved. So lastly, let's go through why we think that moving into a Phase III trial, 7500 might translate into really noteworthy meaningful improvements in symptoms as well as functional capacity like those seen in a cardiopulmonary exercise test.

So we mentioned earlier, at rest, your output is made up of how many times the heart is beating and how much is being pushed out with each beat. Add those 2 things together and you get your resting output. However, when we're not at rest, when we're living our everyday lives, you're changing cardiac output based on demand. And you're doing that with those 2 features.

You're increasing heart rate, which requires normal filling of an HCM heart, which is more difficult at higher heart rates, again, why early diastole is so important. But you're also increasing stroke volume so that the amount of blood being delivered each beat goes up. This is particularly important in early exercise. While the first metric, heart rate is going to be dependent on diastolic reserve on how well your heart can fill at faster heart rates, the second component, augmenting your stroke volume is of equal importance, if not greater importance in early exercise.

And this component requires that same concept of myosin recruitability. If your myosin heads are crammed into a permanently off state, when you ask your stroke volume to pick up, it won't. But if your myosin heads are closer to actin and available for business, when it's time for you to augment cardiac output, stroke volume will go up, and we think that will be meaningful for patients. You'll see a pictorial representation of that on this slide.

With a cardiac myosin inhibitor, heart rate starts to go up, but stroke volume remains relatively stagnant, a finding that you can pull out of cardiopulmonary exercise data in various HCM CMI trials. Compare and contrast that with the left-hand panel where you see, well, I need more cardiac output. Let's use more myosin heads, let's augment ejection fraction. We think that this is going to be differentiating, particularly in the non-obstructive space where you're not also benefiting from alleviation of obstruction.

Myosin availability is normal and natural, and we think that the regulatory light chain is a way to fine-tune this system. We have preclinical data that does support this supposition. I'll start with the normal rat on the left. This rat was given a normal dose of a cardiac myosin inhibitor and a supraphysiologic 10- to 15-fold higher than what we would use clinically dose of 7500 in order to induce some systolic dysfunction at baseline.

We then took these 3 different groups and gave them dobutamine, which is a compound that will speed up heart rate and increase ejection fraction, or TR2, a state that really mimics exercise. What you see in red is that the CMI rat did see some increases with dobutamine, likely driven predominantly through heart rate changes. But your EDG-7500 sees a much larger augmentation of stroke volume, where you're starting to approach what the normal rat control did with respect to fractional shortening changes.

On the right, we have a different model. This is a non-obstructive pig, MYH7 R403Q pig, that was treated chronically with 7500. What you'll see first is that the blue triangles moved closer in resting stroke volume to the wild-type control. So you already started to resemble more of a normal or non-affected pig. When you gave dobutamine, again, you see the same result. There's myosin availability and recruitability with this compound.

So when you ask the heart to do more, it does. Ejection fraction picks up and stroke volume increases. Again, we think this is going to be differentiating in a Phase III trial and in everyday life with this compound. You can see that reflected with our KCCQ, albeit this was non-placebo-controlled Part D data, where you see really robust improvements in KCCQ. And on the right, I want to draw your attention to the shape of that non-obstructive curve. It continues to uptrend through week 12, a result we're very excited to tell you about in the future.

So let's take a step back and revisit those 4 questions. How exactly does this thing get rid of the gradient? Well, by changing lever arm stiffness, you decrease early systolic pressure, you prevent obstruction from happening, from initiating, and gradients go down.

Can you do it without changing the EF? Well, by moving myosin closer to actin, by speeding up force development in mid- to late systole, you see ejection fraction, global longitudinal strain, and global circumferential strain all remain static throughout treatment with 7500. -- you can alleviate gradient without reducing net systolic function.

How do you improve diastolic dysfunction? Well, rather than being diastolically beneficial by happenstance by just turning off myosin heads, directly linking your mechanism of diastolic benefit to systolic liability, we directly at low doses, potently speed up actomyosin disengagement, creating a suction cup ventricle in early diastole that is going to be meaningful, not just at rest, but when you ask the heart rate to pick up and exercise, as seen with our BNPs and KCCQs.

Lastly, is maintaining myosin availability important? What are you going to do for functional status? Well, we think it is, and we think that the ability to increase stroke volume when you exercise is going to be pivotal for how our patients feel and how they ultimately perform in a cardiopulmonary exercise stress test in Phase III.

With that, I'm going to hand it back to Alan to bring us on.

So I'm just -- this is just a little bit of fun here, a little history of how people have described factors that control the heart. So about 130 years ago back in 1897, an academic in Germany, Theodor Wilhelm Engelmann, described 4 physiological properties that define cardiac function. You can use these in a pub quiz, if you like, they describe contractility, heart rate, conduction velocity, and excitability. What you'll notice though is that relaxation was not defined by Engelman at that point.

And that was largely because for an 85-year period, people assume that relaxation was a passive process that could not be intervened in. Now in 1982, a group led by Dirk Brutsaert in the Netherlands changed that thinking about relaxation and lusitropy, largely through examination of adrenergic agonists and their effect on accelerating relaxation. So an 85-year gap between defining most of the functions of the heart and then the ability to relax.

And that's really through understanding that you could accelerate this process. Now another gap occurs as pharmacologists try and intervene in this relaxation process. In many ways, directly identifying and optimizing positive lusitropes has been the holy grail of pharmaceutical research for the last 40 years or so. So between 2015 and 2025, the community makes some breakthroughs there. We have SERCA gene therapies.

We have pharmaceutical companies trying to identify direct activators of SERCA. This is the channel that sucks calcium away from the muscle and should accelerate calcium removal and relaxation. The CMIs, of course, have their own lusitropic effect, but these are coupled to systolic deficits and all of the heart failure syndromes that you can get with large concentrations of those compounds.

We believe we're the first people who have actually nailed this one down to directly cause lusitropic benefit. It's been a long journey if you look at that time line, but we believe in both 7500 and 15400, you have compounds that selectively and directly accelerate relaxation of the heart. We think this will have great therapeutic potential.

I'm going to hand this back to Kevin just to wrap it up.

Thanks, Alan. Thanks, Michael. Really great presentation. Obviously, we've made great progress in the program, and this is one of the milestones of talking about the mechanistic aspect of 7500. Just to give you some milestones for the rest of the year and 2027. We expect to have regulatory feedback in the first half of '26 based on both the trial design and all aspects of moving 7500 into Phase III. I think this is quite important because we plan on having a Phase III profile where we would not use echo monitoring to get people to their target dose.

And so that would be an important milestone for the company to create an ease of use for 7500 among the community cardiologists. EDG-7500 Phase III initiation is probably by the end of the year. We already have CROs in place and are talking to sites as we speak. And also, we just saw on clinicaltrials.gov that we've initiated the trial of 15400 in HFpEF, and that is open for screening today.

Milestones for '27 are we plan to provide 48-week data in the open-label extension of the CIRRUS study of the 50-some-odd patients that we produced back in June. We plan on having Phase II data probably in the second half of '27, a little bit longer than we thought because the KOLs have essentially said you need to have a large enough dataset to be really able to interpret the data. And this is a placebo-controlled study.

So I think we've moved that to more realistic second half of '27. And then we've made great progress on 003. We've chosen a therapeutic indication of heart failure. And this molecule will be showing in future scientific meetings some of the unique profile of this molecule.

So with that, I think we can take some questions and look forward to hearing your thoughts.

[Operator Instructions] So our first question comes from Joe Schwartz at Leerink.

Great. Thanks for hosting this enlightening event and congrats on the publication. My first question is a regulatory one. I think the FDA has wanted to go through all of the latest Phase II data to support dosing without routine echo monitoring. So does today's mechanistic package and the publication contribute to that conversation? Or do you think the agency only gives way to clinical exposure response data here?

I think that they've recognized that this is a differential mechanism. I should point to 15400 that we have an ejection fraction cutoff of 50%, which is typically normal for the typical HFpEF population. So I think they've looked at the 7500 data and the 15400 data and with an understanding that it's a novel mechanism, and perhaps have drawn the conclusion that we will not see excursions below 50% or at least outside of the range of normal variability of the ejection fraction measures.

But I think that remains to be, I think, validated through the agency providing us feedback on the Phase III clinical trial design and moving forward. So stay tuned. I think it's important, but I think we have -- at least from our initial feedback in January, February that our trial design seems reasonable. And I think they have all the data now and they'll make a decision.

Okay. Great. And then if I could just ask a follow-up on the isoform selectivity. Does 7500 engage the atrial light chain isoform as well as the ventricular one? I'm just asking because of the atrial fibrillation question some have raised and whether there's any direct atrial pharmacology at all or whether any that's just background risk.

Thanks for the question, Joe. It's an obvious one. Just the same as the myosin inhibitors, 7500 has biochemical activity against both atrial and ventricular forms. And in many ways, the pharmacology that we've described for the ventricle is kind of slowing and speeding type of thing -- is intact in the atria. As such, there's no direct correlation between those specs and atrial fibrillation. We see it as important in HCM that you affect both chambers of the heart to release stress. So that was our goal going in, and that looks like what we've got.

Just to be clear, though, the CMIs have exactly the same effect on both compartments, both the atrium and the ventricle.

Our next question comes from Yasmeen Rahimi at Piper Sandler.

Thank you for the excellent presentation and we have been asking many, many questions, and it was really great to put into context the MOA and combine it to the clinical product profile that you're seeing. I guess the question that I have for you is you have before this publication became available, started to share this mechanism with key opinion leaders. Maybe you could talk about the sentiment and the perception that they have versus the differentiation that they see versus the CMIs. And how important is this publication for enrollment of your Phase III and, of course, strategic discussions?

I'll take the second question is that we do think that it's important to provide the mechanism because I think it just provides context for recruitment. But I'll ask the question of Michael, how the key opinion leaders have reacted to the mechanism and their understanding of the differentiation from the CMIs.

Thank you for the question. KOLs are just very excited about this because the 2 major problems right now or unmet needs are, one, how can we do this without laborious echo monitoring, which means how do we remove systolic liability from the equation? And two, can we provide diastolic benefits to people that don't have super normal ejection fractions of 70% or higher to begin with.

And KOLs feel like we address both of those issues head on. And so they're quite excited. I should point out that Sherrid proposed this effect on early systole back in the mid-2000s. And this is actually something people learned in textbooks, but we're never able to demonstrate this either preclinically or clinically. And that actually -- I think we have validated those original hypotheses, the origin of the gradient in HCM. That paper is in a footnote on one of the slides.

Our next question comes from Laura Chico at Wedbush.

I think this might be directed towards Alan. I guess -- and apologies if I missed this. Have you run 7500 head-to-head versus CK-586 in some of these assays, ATPase, motility fiber assays? I guess I'm just trying to understand in the context of Slide 16, where there's that continuum, where do 586 and 7500 sit relative to each other?

And I guess just one quick clarification. Kevin, on the base case assumption for Phase III, it sounds like not using it to get to a target dose, but what would be the expectation on echo scheduling?

Do you want my bit first? Or do you want to do your bit?

Laura, great question. What does 586 look like? And of course, we take that compound and run it through the full ringer to see how it compares. And what I would say is that these things have complicated profiles, but in many ways, 586 exhibits profiles on that spectrum towards the CMI end.

And you could see that in action in the rat data that Cytokinetics have published and indeed in the clinical data showing LVEF PK/PD relationships pretty much indistinguishable from aficamten, it's clearly possible to make RLC inhibitors that probably slow that early contraction so much that you start eating into LVEF. And I think that's probably what's going on with 586.

Yes. I think the JCI paper will be very clear where actually probably as closely related as you get the enantiomer of 7500 and 7499 has a very, very distinct profile. And we wanted to point that out is that this becomes based on our mechanistic hypothesis in our preclinical screening, a choice, a choice of a molecule that does not affect systole and is diastolic biased, versus the choice of a molecule that has a systolic liability if you believe that you need to have systolic decreases to have efficacy.

We obviously had a different belief when we chose 7500 that we could drive benefit for the patient without systolic liability. And that was a hypothesis we made when we selected 7500. Now in regard to what we have provided to the agency in regard to the Phase III protocol and essentially echo monitoring, we've provided a baseline echo, a 12-week echo that is not read by the PI.

It's taken by the PI, sent to a core lab and stored and a 24-week echo at the end of study. So -- and we're using tolerability essentially to get patients to a target dose. We'll tell you about the target dose we've chosen later on. But essentially, an echo in the beginning and an echo at the end and no utilization of a PI read echo throughout the dose escalation process.

Our next question comes from Tessa Romero at JPMorgan.

Exciting day for Edgewise and thank you for all this detail. Kevin, Alan, Michael, if we think about the RLC as a target, are there any liabilities based on your understanding of how the drug works in the heart and its impact on the cardiac cycle? And what specifically underpins your confidence that in larger studies with the molecule that you will continue to be safe and well tolerated. And as you think about 7500 as a chronic medicine for HCM?

I can start, liabilities of RLC, I mean, if you look in the literature, if you mutate RLC, much of the same as if you mutate any sarcomeric component, you will get HCM. So I guess that's a liability if you did that. Now of course, what we're doing here isn't doing that. We're just modulating the RLC with the small molecule. So as such, we're not aware of any hypothetical problems that could occur as a result of modulating RLC. It's a pretty subtle effect that we're looking at that hopefully you got a feel for in the data that we presented.

Yes. I think if you could go into the literature, you'll find knockouts or even human mutations. And all of that information goes back to -- can be recapitulated in rat and mouse models. And we've, of course, treated in our tox studies, we've taken multiple measures either via ECG or structural changes. And we do not see any of these effects in the rat models on long-term dosing. And we -- remember, we did the 6-month R403Q pig model of non-obstructive HCM.

And we actually see, I would say, a benefit on the atria in that model at 6 months where we see a decrease in atrial size -- and one of the comments in one of the papers is that you see hypophosphorylation or decreases in phosphorylation of the RLC. In our case studies, we see either neutral or increased levels of phosphorylation after 6 months of dosing. So benefits to the atria.

So I think that all fits together that there's really no tie to the mechanism. I think, again, like all things in HCM, whether you decrease the contraction or increase the contraction, hyperdynamic change in the heart leads to increased rates of atrial fibrillation. And so I think it's kind of a -- I think the whole AFib thing is not tied to this mechanism in any way.

Our next question comes from Leo Timashev from RBC Capital Markets.

Really interesting mechanism and appreciate the clear presentation here. I wanted to ask kind of a multiparter on calcium, if you can help just tangle some of what we're seeing there. I guess given the impact and the sensitivity of the drug's effect to calcium, do HCM patients have normal calcium levels in the heart? And then calcium blockers are also fairly common drugs in the cardiac space. I guess, do you anticipate any impacts of calcium blockers on how 7500 would work? And then if I can squeeze in one last one. Just given the impact of 7500 moving myosin closer to actin, can that also increase heart rate?

I will address the first 2, and then I'll hand it over to Michael to talk about kind of physiological stuff. So calcium and HCM is -- well, the dysfunction in HCM, of course, is sarcomeric largely, right? And calcium will make attempts to kind of overcome the dysfunction there. So you may get changes in calcium transient, but still you will have systolic and diastolic levels of calcium.

I don't anticipate the compound being modified particularly in an HCM patient in regard to calcium concentrations. At diastole, you still have very low levels of calcium and at systole, you have these maximal levels of calcium. Calcium channel blockers don't affect calcium transients per se.

They affect the influx of calcium, but those calcium stores that I'm talking about coming from the SERCA, the big bag of calcium within the muscle -- and that largely is unaffected by those types of therapies. So our calcium effects that we described at this kind of low-to-high calcium should be impacted irrespective of whether you're on a calcium channel blocker or whether you're on HCM.

And I will pass the other question.

Maybe just preclinically, we've examined exhaustively in myocytes and other systems that we've not seen any effect on the calcium channel.

Yes, that's a good one. Not a direct one.

The third one is relatively simple. Actomyosin distance when not bound should have no impact whatsoever on heart rate. Heart rate is going to be determined by electrical signaling, which is going to be largely mediated by needs of cardiac output. And so that's pretty uncoupled or divorced from actomyosin distance.

Great. Thanks for the questions, Leo. Our next question comes from Kripa Devarakonda at Truist Securities.

I have a question on nHCM program. So based on the data you've seen so far, do you expect higher dose requirements for nHCM? And why do you think that might be the case? And do you, in general, think that nHCM is a harder population to treat? And with this mechanism that you talked about today, does that provide a higher safety ceiling for these patients these patients lacking a gradient?

I think we are looking at the data from longer-term dosing. We're looking at data whether there is any real effect on the length of time. We haven't discussed that at this point, but we feel that 24 weeks at this point seems sufficient for the non-obstructive patients because we have early diastolic effects, which are the main driver of the pathology of non-obstructive HCM.

I think from our discussion of the cardiac reserve, I think ultimately that these patients when they are -- they need to exercise like you might exercise or increase activity like in a peak VO2 measure for the trial would actually be enhanced because of the positioning of the heads to be reengaged during activity. We want to design a Phase III trial that optimizes efficacy.

And so we're going to make sure that we do that. And once we do that and we are still absent of systolic liability, we're hopeful to move forward to a world of HCM treatment where the provider can dose the medicine, how the provider thinks it's appropriate. And when you need higher doses, you can go higher doses. But those are sort of 2 separate questions.

And remember, in our SABER study in Part D, we had stopping rules when a patient with non-obstructive got the 200 picograms per milliliter of NT-proBNP and stopping rules in obstructive when they got below 50 mmHg on Valsalva gradient. We will not have those stopping rules in the Phase III, and we will look to get everyone to a target dose. So we would try to suspect that we will get everyone to a higher dose in the Phase III with a target dose that we'll define a little bit later.

And you have one question about whether non-obstructive HCM people would need higher doses. If you kind of take a look through the presentation, what you'll see is that the diastolic benefits of the compound generally occur at lower exposure. So we don't think this is the case. We think the doses required for non-obstructive and obstructive will largely be the same.

And I think it's really important to keep in mind that when you look at who benefits from cardiac myosin inhibitor in non-obstructive world, it's very high EF. Why is that? That mechanism requires systolic dysfunction to achieve diastolic benefit. We've uncoupled those 2 problems so that you can tackle lusitropy and diastolic benefit head-on, absent systolic concern, and that is the differentiating feature in the non-obstructive space.

Our next question comes from Adhi Sikand at Evercore.

I wanted to ask, particularly Slide 33 was very interesting where it shows at 25-milligram, the BNP improves before the gradient moves across the broader dataset, have you looked at whether other efficacy changes show similar benefit at 25-milligram dose that early like at week 1 and week 2?

I think it's -- the quantitation of some of these measures, I think, is -- I don't want to say yes or no. I think that anecdotally, physicians have told us that patients feel better immediately, including non-obstructive patients. But I don't know if we have -- I would say, absolutely, we have a correlate that's as clean as the NT-proBNP, which is -- when people saw our data on the NT-proBNP, they pointed at that directly as that looks like an immediate diastolic effect. So I don't want to be absolute about this, but I think trending that, yes, you see people feeling better virtually immediately at a relatively low dose.

Our next question comes from Moritz Reiterer at Guggenheim.

For the great insight into the mechanism. My question is specifically about the KCCQ response in non-obstructive patients based on the data that you've shown, and you've also alluded this during today's presentation. You're not seeing any plateauing of the KCCQ improvement by week 12 yet, whereas in CMIs, by this time, the effect is sort of already starting to level off. So is there anything in your mechanism that you think might explain this kind of delayed persistent improvement in KCCQ that you've been seeing in the nHCM patients?

In obstruction, there's an immediate hemodynamic change with gradient relief, and you get a lot of bang for your buck with respect to benefit upfront. We think there's continued diastolic benefit even in that group, but alleviation of obstruction is a pretty monumental event. In non-obstructive cohorts, you get improvements in lusitropy. You get changes in how the heart is filling.

But what we're also seeing and continuing to explore and are excited to talk about in the future is the remodeling that's going on for the non-obstructive heart through time. So we think that the absence of plateau isn't reflective of the fact that the molecule is not active early. We think the molecule is very active early. We think that the continued benefit is because as these patients marinate in the medicine, they continue to get beneficial structural changes.

Our next question comes from Mazahir Alimohamed at Oppenheimer.

Comprehensive presentation this morning. So I guess the first one is non-obstructive HCM. As we know, it's quite a heterogeneous disease with phenotypic variants, patients with significant fibrosis, et cetera, and patients with even near-normal relaxation, but symptoms from other causes. So I guess with that, I guess, the big question is which phenotype do you think responds best?

And will Phase III enrich for objective diastolic dysfunction rather than enrolling on symptoms alone? And maybe a clarifying add-on is kind of with RLC phosphorylation, it's quite often reduced in HCM and failing myocardium. So does 7500's effect depend on baseline phospho-RLC status?

So we do that one first?

Take that one first.

Yes. So we did experiments where we phosphorylated the light chain with the kinase, and it doesn't affect the activity of the compound. So the compound is kind of inert to the phosphorylation status of the first and I will hand it back to...

Restate the first one for me. The question is really --...

I'm lost.

Can you repeat the first question?

Yes, sure. The question is so which phenotype for non-obstructive...

So I have good news on that one, we don't think there's a preferential phenotype. So we're very used to cardiac myosin inhibitors where the benefit is all being derived by very high ejection fraction and potentially by men, if you look at the ACACIA dataset carefully. We think that our mechanism is agnostic to starting ejection fraction, and we think it's probably agnostic to even myosin overactivation, which is quite variable in non-obstruction. So we think we're going to have a very broad benefit across non-obstructive phenotypes, which, as you put it, is a very heterogeneous group.

Our next question comes from Paul Choi at Goldman Sachs.

Thank you for this elegant overview. My question relates to Slide 32, where you show the e-prime lateral data for both the oHCM and nHCM populations. I'm curious, since HCM frequently involves septal hypertrophy, I was wondering if the septal e-prime data aligns directionally with what you've shown here for the lateral e-prime data. And similarly, was the magnitude of changes for the oHCM and nHCM population same for the septal e-prime? Any clarification you could provide on that would be great.

Great question. It's been variably reported in cardiac myosin inhibitor and other HCM literature, lateral versus septal. So that's a very well-formulated question. We see similar, but slightly less magnitude improvements in the septal, which is pretty common when you look at e-prime. The septum tends to be a little more tethered in the lateral wall, which has more room to slide around the pericardium. And we see similar magnitude of benefit in both o and n cohorts, but great question.

Our last question comes from Mark Hitrik at Stifel.

Ours was kind of related to 586, Cytokinetics' next-gen CMI. So that one was described at least to some degree is hitting the regulatory light chain. I'm curious kind of if you could offer some color how that drug specifically differs from yours. And from a regulatory perspective, could you also maybe share whether the FDA would really appreciate the nuance like mechanistic differences and really if there's any risk to this profile, particularly as it relates to obtaining a no-echo titration?

Yes. We talked about 586 earlier. It is indeed an RLC modulator and the data is very clear about it. We think it's more inhibitory than 7500, and you see that reflected in LVEF and fractional shortening dose responses, both in rodents and in humans. So it's probably largely doing the same things that we described, just more on the systolic slowing side.

In terms of regulatory, the regulatory authorities are going to look at the data on hand. They're not really going to focus so much on mechanism. Of course, that's an influencer, but they're going to look at the data presented to them. So, it's really up to them how they view the Cytokinetics versus 7500, 15400 data.

Yes. I mean we think with our dataset, the 7500, we've shown it to electrophysiologists. We've shown it to prior FDA authorities who are now consulting. Now they all have said we have a compelling dataset that we do not see an ejection fraction change with our data and not concentration or dose related, whereas you do see that relationship of concentration of dose association with 586.

And this is why we put out the JCI paper to describe how selection of the drug that binds to RLC has a lot to do with what kind of clinical profile you would obtain. And so looking forward to having folks reading that paper quite enlightening about the diversity of pharmacology you can see by interacting with the RLC.

And as you might suggest just for the medicinal chemist type folks in the audience, if there are any, these are allosteric modulators interacting with a complex group of proteins and small changes in chemical structure will drive significant changes in pharmacology based on binding site and how that might interact within essentially a moving complex of multiple proteins.

Yes. I mean this is the nature of allosteric modulators, and it's something I've been working at for 25 years now. So it wasn't a surprise to me that small changes in RLC modulators make big changes mechanistically. And you can see that illustrated in the enantiomer of 7500, which we described in the protein. So it's really just a mirror image. It's exactly the same structure outside of that. And yet that compound is way more potent. It is a full inhibitor of the system under all conditions. It doesn't have a calcium shift to it at all, and it has very steep PK/PD in -- et cetera. So hopefully, you'll enjoy that story in JCI Insight.

And its clinical evidence in support of what you guys are saying, look no further than how the trial is designed for 586. It's a HFpEF trial enriched with hypercontractile patients. And that's because you have to start hypercontractile to weather the systolic storm of decreased ejection fraction with that compound.

Great. Thanks for the question, Mark. So this concludes our Q&A session for today. I will now turn it back over to Kevin for some quick closing remarks.

Thank you all. Thanks all for joining. As we mentioned, the mechanism of action of 7500 will be published later today in JCI Insight and a link to the paper will also be available on Posters and Publications page of our corporate website. I want to thank everyone who has contributed to this program, including the many Edgewise employees whose dedication and hard work helped make this milestone possible.

I also want to express our gratitude to the medical and patient communities participating in our clinical trials as well as our shareholders for their continued confidence and support. This is an exciting time for Edgewise. Today's update highlights the strength of our cardiovascular pipeline and the momentum behind our approach to fine-tuning the cardiac cycle in symptomatic heart failure.

We believe we are on the cusp of demonstrating the potential of novel therapeutics that could meaningfully improve the lives of patients who need more effective treatments options. Thank you all for the call -- joining the call today, and have a good day.

This concludes today's conference call. You may now disconnect.

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.