Good morning, and welcome to the Edgewise Therapeutics research update. At this time, all attendees are in a listen-only mode, and a question and answer session will follow the formal presentations. 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, it's 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 of 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 these statements. I will now turn the call over to Kevin.
Hi, Michael. Thank you. I wanted 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 EDG-7500 and how that fits in the therapeutic portfolio for the treatment of cardiovascular disease.
I'll end up with some near-term milestones for the company. As you all know, we started back 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 two 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 by the end of the year. Along the way, though, 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.
$1.5 billion upfront and $1.1 billion in milestones. 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. 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. When you run a high-throughput screen, you will 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.
We found molecules that were quite similar to what were found previously, which were type one 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 one myosin inhibitor. We found another lead series that was quite unique.
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. They had a unique profile, and then after we had 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 this 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 have seen pre-clinically with the drug. We will be talking extensively about that in the coming 45 minutes. Turning to the next slide, EDG-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. You probably saw on ClinicalTrials.gov, enrollment is open for the HFpEF study. We will not say too much about EDG-003, but we do feel like we have a lead series and are in the candidate selection mode.
We are very excited about the portfolio in cardiovascular disease, and look forward to talking to you about how we discover the drug and some of the key biologic nuances of this value proposition. Next slide. I just wanted to give you a quick executive summary of what you are going to hear today. EDG-7500 regulates the cardiac cycle. 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 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 are completely sparing of systolic effects, which is exemplified by EDG-7500.
Preclinically, EDG-7500 slows early systolic pressure, speeds up mid to late systole, 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. We will be showing some of that data today.
More interesting, we will 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 will be having a strong effect on endpoints like pVO2 and KCCQ when a patient exercises or exerts themself. We will show you data to support that position. With that, I am 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. When we go around and we talk to investors, cardiologists, knowledge leaders, or just anyone about this drug, four questions come up with some constancy. One, how exactly does this thing alleviate gradients?
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?
Lastly, is there something in this secret sauce that allows for meaningful symptom and functional improvements relative to other things in the class? I am really excited to go through those four questions with you today. Let us start on the next slide with a little bit of a disease state background to make sure we are all on the same page.
HCM is the most common inherited heart condition, affecting around one in 500 people. It is dramatically underdiagnosed, misdiagnosed, and there are delays in diagnoses that impact care. It is defined as having a heart muscle thicker than 1.5 cm in absence of some cause, and broadly speaking, we like to classify it into two buckets or phenotypes. While both of these patients have thickened heart muscles, they have slightly different pathologies or problems. The first is your obstructed group.
This group has a thickened heart muscle right at the outflow tract, which results in a divorcing of the pressure inside the ventricles relative to the aorta. There is a pressure difference, so now to generate your 120 mm of mercury systolic blood pressure, you might have to do 170 mm of mercury of work. The second subtype is the non-obstructed subtype, which also has thickened heart muscle, but doesn't have that misplaced thickened heart muscle right at the outflow tract.
Though I'll point out, both the obstructed and non-obstructed 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 a third of patients with obstructive hypertrophic cardiomyopathy have residual symptoms despite gradient relief, and we think that's from the diastolic dysfunction. 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. 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%-60% of these myosins that are participating in a given heartbeat while the other 40%-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%-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 two-thirds of patients, it results in that obstructive physiology we described on the previous slide.
What it also results in is diastolic dysfunction, really from two 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. 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 be 5 L 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 beat 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, at first glance, looks like a normalized state where you've moved back to that 40%-60% of myosin availability, the inhibited myosin heads become semi-permanently off, such that when you need to recruit those myosin heads, you can't. This is really a pseudo-normalized state.
Let's talk about what issues come from this pseudo-normalized state throughout the cardiac cycle. The cardiac cycle is made up of two 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, if 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 dissociation. 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's moving into the outflow tract.
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 shortens 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. 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.
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. 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. Let me just orient you to what you're looking at here. As Michael showed, there's these three 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 two 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. A 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. The regulatory light chain can be controlled through phosphorylation, and it has two main functions. The first function is to adjust the stiffness of the lever arm to modify the efficiency of force development and relaxation.
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. EDG-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 the EDG-7500 mechanism.
Firstly, EDG-7500 reduces the stiffness of the lever arm, and there are 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 EDG-7500 carries is it actually moves those myosins towards actin, moving them away from this off state to this ready-to-bind state. In many ways, in that context, it looks more like an activator than it does an inhibitor.
If you 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 they're 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 onto the nuts and bolts of the mechanism. 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 EDG-7500 full-length protein is very gradual. The second that 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 returning. 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 two 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% maximal effect. Once you chop off the lever arm, you render that preparation inactive to EDG-7500. EDG-7500 no longer has any effect.
What that is telling you is that the meat and potatoes of the inhibitory effect of EDG-7500 is that lever arm region and not the enzymatic function of the myosin itself. Next slide. What I am going to do now is break you through the various questions that Michael proposed that we have received multiple times about how EDG-7500 works.
The first question, how does it reduce gradients without suppressing contraction? The first thing we are 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 is some beautiful work done in our in-house labs downstairs. What you are looking at here are glass coverslips 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 coverslip by visualizing that fluorescent actin. You can see on the left-hand side, those little actin filaments are creeping around quite efficiently. If we add a high concentration of EDG-7500 in the middle, what you see is these actin filaments are still moving around, but it is much more slowed, approximately 50%, compared to the left-hand figure.
The right-hand figure is a video, but it is hard to see because when you add a high concentration of a cardiac myosin inhibitor, you have essentially arrested those filaments completely. You have removed all of the actin enzymatic function, and those actin filaments are now unable to move. They are just frozen in time. You can see that represented by the figure on the right-hand side.
EDG-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 are looking at is fiber bundles isolated from pig cardiac ventricle. 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. On the left-hand side, we have added calcium at that zero time point.
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 EDG-7500 slows that force development.
There is a concentration response. The k_act 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. The more EDG-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 EDG-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 actin filament or elements on the actin filament to initiate contraction. The more calcium you add, the more contraction that you get. What we found with EDG-7500 is at high levels of calcium, the slowing effect is very modest. That would be the dark blue triangles there.
Whereas at low calcium, you see much more slowing. That would be the open triangles. As you go through this calcium cycle, you exhibit more slowing at low calcium and less slowing at high calcium. Next slide. 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-ejection time. Pre-ejection time is that period of the systolic cycle where ejection is not occurring and pressure is increasing. It's the period between electrical stimulation of the ventricle and opening of the aortic valve. What you see in these cases is a 17.3% increase in that pre-ejection time with EDG-7500.
You're essentially increasing 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 EDG-7500 modulate hypercontractility without suppressing LVEF?
This is a big question. We receive this all the time. How can you turn down contraction and not see decreases in LVEF? This comes on the next slide to the other function of the regulatory light chain. As I mentioned before, EDG-7500 moves myosin towards actin instead of away. 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 EDG-7500 can intervene in this process. On to the next slide.
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. 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. What you're doing is at rest, you're measuring whereabouts 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.
If I added mavacamten, for instance, that number would go down as you move those myosin heads away from actin and towards the thick filament. Interestingly, when you add EDG-7500 without adding any calcium, you're not activating this system. You move those heads away from the thick filament and into this pre-activated state.
EDG-7500 is influencing the position of myosin, bringing it closer to actin. Next slide. 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 contracting. 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 re-lengthen 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 EDG-7500 treatment under these conditions accelerates that force redevelopment. Not only does it accelerate it overshoots.
So treatment with EDG-7500 and this positional change of myosin actually preloads these myosins 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 EDG-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 for why you don't see LVEF changes at pretty much any concentration you look at with EDG-7500. You get that slowing of contraction that's very important for obstruction relief and 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 EDG-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 this 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 EDG-7500 accelerates that relaxation process.
The green line is going down faster than the black line. And you can measure a concentration response for that. So k_rel is our rate of relaxation, and you can see as you elevate the concentrations of EDG-7500, you increase that speed of relaxation. One of the super interesting things about EDG-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 at slowing the contraction, right?
So it's quite possible to engineer an exposure of EDG-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 six 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 six-month study, we treated the pig. You can see on the left-hand side, there's no change in LVEF.
So much the same as 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 two very clear phenotypes here. The first in the middle is that end-diastolic pressure is decreased in the presence of EDG-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 is the measure of ventricular compliance, the end-diastolic pressure-volume relationship, and you can see that that's also decreased. You've improved ventricular compliance and the ability of that tissue to relax. Two great signs that you're directly affecting relaxation with this compound without cost on LVEF. At this point, I'm going to hand it back to Michael to describe clinical effects, then talk about exercise capacity and cardiac reserve.
Thanks, Alan. 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 dissociation, and that is manifest clinically. What we see here is what's called an e' measurement. 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 ventricles. Systolic pressures are dramatically changing, and that actually influences some of our e' 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. 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-HCM Cohort 4 or what kind of e' changes you're seeing with myosin inhibition, that's going to give you e' augmentation, speeding up of relaxation of around 16%-24%.
What you see here is the proof in the pudding of the lusitropic benefit of this medicine with a 37% increase in e'. This goes hand in hand with robust improvements we saw with another filling metric, E/e', 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, in 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 mg, and you can see at week one, the gradient hadn't yet moved. You hadn't lowered early systolic pressure enough that you had initiated gradient release.
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 mg of this compound, you are getting a lusitropic benefit that is showing up in blood work prior to the gradient being released.
Lastly, let us go through why we think that moving into a phase III trial, EDG-7500 might translate into really noteworthy, meaningful improvements in symptoms as well as functional capacity like those seen in a cardiopulmonary exercise test. 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 two things together and you get your resting output.
However, when we are not at rest, when we are living our everyday lives, you are changing cardiac output based on demand, and you are doing that with those two features. You are 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 are 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. 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 will not. But if your myosin heads are closer to active and available for business, when it is time for you to augment cardiac output, stroke volume will go up, and we think that will be meaningful for patients. You will 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 us use more myosin heads. Let us augment ejection fraction. We think that this is going to be differentiating, particularly in the non-obstructive space, where you are 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 will start with the normal rat on the left. This rat was given a normal dose of a cardiac myosin inhibitor and a supraphysiologic, 10 15 fold higher than what we would use clinically, dose of EDG-7500 in order to induce some systolic dysfunction at baseline.
We then took these three different groups and gave them dobutamine, which is a compound that will speed up heart rate and increase ejection fraction or try to 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.
Your EDG-7500 sees a much larger augmentation of stroke volume, where you are 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, an MYH7 R403Q pig, that was treated chronically with EDG-7500. What you will see first is that the blue triangles moved closer in resting stroke volume to the wild-type controls.
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 is 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. 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 are very excited to tell you about in the future. So let us take a step back and revisit those four questions. How exactly does this thing get rid of the gradient?
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? 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 EDG-7500.
You can alleviate gradient without reducing net systolic function. How do you improve diastolic dysfunction? 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 actin-myosin 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 in exercise, as seen with our BNPs and KCCQs.
Lastly, is maintaining myosin availability important? What are you going to do for functional status? 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 am going to hand it back to Alan to bring us home.
This is just a little bit of fun here, a little history of how people have described factors that control the heart. About 130 years ago, back in 1897, an academic in Germany, Theodor Wilhelm Engelmann, described four 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 will notice, though, is that relaxation was not defined by Engelmann at that point.
That was largely because for an 85-year period, people assumed that relaxation was a passive process that could not be intervened in. 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.
An 85-year gap between defining most of the functions of the heart and then the ability to relax. That is really through understanding that you could accelerate this process. Another gap occurs as pharmacologists try and intervene in this relaxation process. In many ways, directly identifying and optimizing positive lusitrops has been the holy grail of pharmaceutical research for the last 40 years or so. Between 2015 and 2025, the community made 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 effects, 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 are the first people who have actually nailed this one down to directly cause lusitropic benefit. It has been a long journey if you look at that timeline, but we believe in both EDG-7500 and EDG-15400, you have compounds that selectively and directly accelerate relaxation of the heart. We think this will have great therapeutic potential. I am going to hand this back to Kevin just to wrap it up.
Thanks, Alan. Thanks, Michael. Really great presentation. Obviously, we have made great progress in the program, and this is one of the milestones of talking about the mechanistic aspects of EDG-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 2026 based on both the trial design and all aspects of moving EDG-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. That would be an important milestone for the company to create an ease of use for EDG-7500 among the community cardiologists. As for 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.
Also, we just saw on ClinicalTrials.gov that we have initiated the trial of EDG-15400 in HFpEF, and that is open for screening today. Milestones for 2027 are we plan to provide 48-week data, the open label extension of the CIRRUS-HCM 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 2027. A little bit longer than we thought because the KOLs have essentially said you need to have a large enough data set to be really able to interpret the data, and this is a placebo-controlled study.
I think we have moved that to more realistic second half of 2027. Then we have made great progress on EDG-003. We have chosen a therapeutic indication of heart failure. This molecule will be showing in future scientific meetings some of the unique profile of this molecule. With that, I think we can take some questions, and I will look forward to hearing your thoughts.
Great. Thank you to all our speakers. Yes, at this time, we will be conducting a live question and answer session. To our covering analysts, please use the raise hand feature to be added to the queue. When it is your turn, you will receive a message on your screen, and then you will hear your name called. Please accept, unmute your audio and ask your question. We kindly ask that you please limit yourself to one question this morning. Kindly hold for a brief moment while we pull for questions. Our first question comes from Joe Schwartz at Leerink. Joe, you may unmute your audio and ask your question.
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. 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 EDG-15400, that we have an ejection fraction cutoff of 50, which is typically normal for the typical HFpEF population. I think they've looked at the EDG-7500 data and the EDG-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.
I think that remains to be validated through the agency providing us feedback on the phase III clinical trial design and moving forward. 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. I think they have all the data now and they'll make a decision.
Okay, great. Thanks for that color. If I could just ask a follow-up on the isoform selectivity. Does EDG-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-
Yes.
-any AF is just background risk.
Thanks for the question, Joe. It is an obvious one. Just the same as the myosin inhibitors, EDG-7500 has biochemical activity against both atrial and ventricular forms. In many ways, the pharmacology that we describe for the ventricle, this kind of slow and speeding type of thing, is intact in the atria. As such, there is no direct correlation between those effects and atrial fibrillation. We see it as important in HCM that you affect both chambers of the heart to relieve stress. That was our goal going in. That looks like what we have got.
Just to be clear, though, the CMIs have exactly the same effect on both compartments, both the atria and the ventricle.
Makes sense. Thank you.
Thanks for the question, Joe. Our next question comes from Yasmeen Rahimi at Piper Sandler. Please go ahead, Yas.
Good morning, team. Thank you for the excellent presentation. We have been asking you many questions, and it was really great to put into context the MOA and combine it to the clinical product profile that you are 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. How important is this publication for enrollment of your phase III and of course, strategic discussions?
I will take the second question. We do think that it is important to provide the mechanism because I think it just provides context for recruitment. I will ask the question of Michael, how the key opinion leaders have reacted to the mechanism and their understanding of the differentiation from the CMIs.
Yeah, thank you for the question. KOLs are just very excited about this because the two 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? Two, can we provide diastolic benefits to people that do not have supernormal ejection fractions of 70 or higher to begin with? KOLs feel like we addressed both of those issues head-on, so they are quite excited.
I should point out that Sherrid proposed this effect on early systole back in the mid-2000s. This is actually something people learned in textbooks, but were never able to demonstrate this, either pre-clinically or clinically. 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.
Thank you so much.
Thank you for the questions, Yasmeen. Our next question comes from Laura Chico at Wedbush. Please go ahead, Laura.
Thank you very much for taking the question. I think this might be directed towards Alan, I guess, and apologies if I miss this. Have you run EDG-7500 head-to-head versus CK-586 in some of these assays, ATPase, motility, fiber assays? I guess I am just trying to understand in the context of slide 16, where there is that continuum, where do CK-586 and EDG-7500 sit relative to each other? 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? Thank you.
Do I do my bit first, or do you want to do your bit?
You do it first.
Okay.
I'll catch up.
Laura, it's a great question. What does CK-586 look like? We take that compound and run it through the full ringer to see how it compares. What I would say is that these things have complicated profiles, but in many ways, CK-586 exhibits profiles on that spectrum towards the CMI end.
You can see that in action in the rat data, the Cytokinetics are 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. I think that's probably what's going on with CK-586.
Yeah, I think the JCI paper was very clear where, actually, probably as closely related as you get the enantiomer of EDG-7500 and EDG-7499 has a very distinct profile. 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 bias versus a 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 EDG-7500 that we could drive benefit for the patient without systolic liability, and that was a hypothesis we made when we selected EDG-7500.
Now, in regards to what we have provided to the agency in regards to the phase III protocol and essentially echo monitoring, we have provided a baseline echo of a 12-week echo that is not read by the PI. It is taken by the PI, sent to a core lab and stored, and a 24-week echo at the end of study. We are using tolerability, essentially to get patients to a target dose. We will tell you about the target dose we have 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.
Thanks very much.
Thanks for the question, Laura. Our next question comes from Tessa Romero at JPMorgan. You may now unmute your audio and ask your question.
Hi, guys. 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? What specifically underpins your confidence that in larger studies with the molecule, that you will continue to be safe and well-tolerated, and if you think about EDG-7500 as a chronic medicine for HCM? Thanks.
You want me to-
Yeah, go ahead, Alan.
I can start. The liabilities of RLC, if you look in the literature, if you mutate RLC, much the same as if you mutate any sarcomeric component, you will get HCM. 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 a small molecule. 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.
Yeah, I think, if you go into the literature, you'll find knockouts or even human mutations. All of that information goes back to- it can be recapitulated in rat and mouse models. We've, of course, treated in our tox studies, we've taken multiple measures either via ECG or overt structural changes, and we do not see any of these effects in the rat models on long-term dosing.
Remember, we did the six-month health R403Q pig model of non-obstructive HCM, and we actually see, I would say, a benefit on the atria in that model at six months where we see a decreased atrial size. One of the comments in one of the papers is that you see hypophosphorylation or decreases in phosphorylation of the RLC. In our pig studies, we see either neutral or increased levels of phosphorylation after six months of dosing.
Benefits to the atria. I think that all fits together that there is really no tie to the mechanism. I think, again, like all things in HCM, whether you decrease the contraction or increase the contraction, hemodynamic change in the heart leads to increased rates of atrial fibrillation. I think the whole AFib thing is not tied to this mechanism in any way.
Thank you.
Great. Thanks for the question, Tessa. Our next question comes from Leo Timashev from RBC Capital Markets. You may now unmute your audio and ask your question.
Hey, guys. Thanks for taking my question and a really interesting mechanism, and appreciate the clear presentation here. I wanted to ask a multiparter on calcium, if you can help disentangle some of what we are seeing there. I guess given the impact and the sensitivity of the drug's effects to calcium, do HCM patients have normal calcium levels in the heart?
Calcium blockers are also fairly common drugs in the cardiac space. I guess, do you anticipate any impacts of calcium blockers on how EDG-7500 would work? If I can squeeze in one last one, just given the impact of EDG-7500 moving myosin closer to actin, can that also increase heart rate? Thanks.
I will address the first two, and then I'll hand it over to Michael to talk about physiological stuff. Calcium and HCM is, well, the dysfunction in HCM, of course, is sarcomeric largely, right? Calcium will make attempts to overcome the dysfunction there. So you may get changes in calcium transients, but still you'll have systolic and diastolic levels of calcium.
I don't anticipate the compound being modified, particularly in an HCM patient in regards 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 are coming from the sarco, the big bag of calcium within the muscle. That largely is unaffected by those types of therapies.
Our calcium effects that we've described as this low to high calcium should be intact irrespective of whether you're on a calcium channel blocker or whether you have HCM. I will pass the other question over.
Maybe just preclinically. We've examined exhaustively in myocytes and other systems that we've not seen any effect on a calcium channel.
Yeah, that's a good one.
Not a direct one.
Okay.
is relatively simple. Actomyosin distance when not bound should have no impart 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. So that's pretty uncoupled or divorced from actin-myosin distance.
Great. Thanks for the questions, Leo. Our next question comes from Kripa Devarakonda at Truist Securities. You may now unmute your audio and ask your question. Kripa, you may be on mute.
Hey, guys. Can you hear me now?
Yes.
Yes.
Thank you. Thank you so much for taking my question, and thanks for the very detailed presentation. I have a question on nHCM program. Based on the data you have seen so far, do you expect higher dose requirements for nHCM? Why do you think that might be the case? Do you, in general, think that nHCM is a harder population to treat? With this mechanism that you talked about today, does that provide a higher safety ceiling for these patients lacking a gradient? Thank you.
I think we are looking at the data from longer-term dosing. We are looking at data whether there is any real effect on the length of time. We have not 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 need to exercise, like you might exercise or increase activity, like in a pVO2 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, so we are going to make sure that we do that.
Once we do that and we are still absent systolic liability, we are hopeful to move forward to a world of HCM treatment where the provider can dose the medicine how the provider thinks it is appropriate. When you need higher doses, you can go higher doses. Those are sort of two separate questions.
Remember, in our CIRRUS-HCM study, in the Part D, we had stopping rules when a patient with non-obstructive got to 200 pg a milliliter of NT-proBNP and stopping rules and obstructive when they got below 50 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 and suspect that we will get everyone to a higher dose in the phase III with a target dose that we will define a little bit later.
You had one question about whether non-obstructive HCM people would need higher doses. If you take a look through the presentation, what you will see is that the diastolic benefits of the compound generally occur at lower exposure. So we do not think this is the case. We think the doses required for non-obstructive and obstructive will largely be the same.
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 two problems so that you can tackle lusitropic diastolic benefit head on, absent systolic concern, and that is the differentiating feature in the non-obstructive space.
Great. Thank you so much.
Thanks for the question, Kripa. Our next question comes from Adhi Sikand at Evercore. You may now unmute your line and ask your question.
Hi. Thanks for taking the question. I wanted to ask you, particularly slide 23 was very interesting, where it shows at 25 mg, the BNP improves before the gradient moves. Across the broader data set, have you looked at whether other efficacy changes show similar benefit at 25 mg dose that early, like at week one and week two? Thank you.
I think 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. 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.
Okay. Thank you.
Thanks for the question, Adhi. Our next question comes from Moritz Reiterer at Guggenheim. You may now unmute your audio and ask your question.
Hi. Thanks so much for taking my question, and thanks for the great insights 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 already starting to level off. 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? Thank you.
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 hearts through time. We think that the absence of plateau isn't reflective of the fact that the molecule's 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.
Thank you.
Thanks for the questions, Moritz. Our next question comes from Mazahir Alimohamed at Oppenheimer. You may now unmute your audio and ask your question.
Thank you. Thank you guys for the comprehensive presentation this morning. I guess the first one is, non-obstructive HCM, as we know, it's quite a heterogenetic disease with apical variants, patient significant fibrosis, et cetera, and patients with even near normal relaxation, but symptoms from other causes.
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? Maybe a clarifying add-on is in, kind of with RLC phosphorylation, it's quite often reduced in HCM and failing myocardium. Does EDG-7500's effect depend on baseline phospho-RLC status?
Should we do that one first?
Take that one first.
Yeah. We did experiments where we phosphorylated the light chain, with a kinase, and it does not affect the activity of the compound. The compound is kind of inert to the phosphorylation status of the protein. I will hand it back to Michael.
Can you restate the first one for me?
Oh, we should, I'm lost.
Sorry. Can you repeat the first question?
Yeah, sure. The question is, so which phenotype for non-obstructive-
Oh, yeah.
Which phenotype?
I have good news on that one. We don't think there's a preferential phenotype. 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-HCM dataset carefully. We think that our mechanism's agnostic to starting ejection fraction, and we think it's probably agnostic to even myosin overactivation, which is quite variable in non-obstruction. 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.
Got it. Thank you.
Great. Thanks for the questions, Mazahir. Our next question comes from Paul Choi at Goldman Sachs. You may now unmute your audio and ask your question.
Hi. Good morning, and thank you for this elegant overview. My question relates to slide 32, where you show the e', lateral data for both the oHCM and nHCM populations. I am curious, since HCM frequently involves septal hypertrophy, I was wondering if the septal e' data aligns directionally with what you have shown here for the lateral e' data. Similarly, was the magnitude of changes for the oHCM and nHCM population the same for the septal e'? Any clarification you could provide on that would be great. Thank you.
Great question. It has been variably reported in cardiac myosin inhibitor and other HCM literature, lateral versus septal. That is 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'. The septum tends to be a little more tethered in the lateral wall, which has more room to slide around the pericardium. We see similar magnitude of benefit in both oHCM and nHCM cohorts. But great question.
Great. Thank you.
Thanks for the question, Paul. Our last question comes from Mark Hitrik at Stifel. You may now unmute your audio and ask your question.
Thanks for taking our question. Ours was kind of related to CK-586, Cytokinetics' next-gen CMI. That one was described at least to some degree as hitting the regulatory light chain. We are curious 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 these nuanced mechanistic differences and really if there is any risk to this profile, particularly as it relates to obtaining a no echo-based titration. Thanks.
Yeah. We talked about CK-586 earlier. It is indeed an RLC modulator, and their data is very clear about it. We think it is more inhibitory than EDG-7500, and you see that reflected in LVEF and fractional shortening dose responses both in rodents and in humans. So it is probably largely doing the same things that we described, just more on the systolic slowing side.
In terms of regulatory authorities are going to look at the data on hand. They are not really going to focus so much on mechanism. Of course, that is an influencer, but they are going to look at the data presented to them. So it is really up to them how they view the Cytokinetics versus EDG-7500, EDG-15400 data.
Yeah. I mean, we think with our data set to EDG-7500, we have shown it to electrophysiologists, we have shown it to prior FDA Authorities who we are now consulting. They all have said we have a compelling data set that we do not see an ejection fraction change with our data. It is not concentration or dose-related.
Whereas you do see that relationship of concentration of dose association with CK-586. 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. So looking forward to having folks reading that paper. This was quite enlightening about the diversity of pharmacology you can see by interacting with the RLC.
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.
Yeah. This is the nature of allosteric modulation, and it is something I have been working at for 25 years now, so it was not a surprise to me that small changes in RLC modulators make big changes mechanistically. You can see that illustrated in the enantiomer of EDG-7500, which we describe in the protein.
So it is really just a mirror image. It is exactly the same structure outside of that. Yet that compound is way more potent. It is a full inhibitor of the system under all conditions. It does not have a calcium shifter in it at all, and it has very steep PK/PD in rodents, et cetera. Hopefully you will enjoy that story in JCI Insight.
As clinical evidence in support of what you guys are saying, look no further than how the trial is designed for CK-586. It is a HFpEF trial enriched with hypercontractile patients, and that is because you have to start hypercontractile to weather the systolic storm of decreased ejection fraction with that compound.
Great. Thanks for the question, Mark. 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 for all for joining. As we mentioned, the mechanism of action of EDG-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.
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 treatment options. Thank you all for joining the call today, and have a good day.
This concludes today's conference call. You may now disconnect.