Yeah. All right. Good afternoon, everyone. Glad I wasn't still talking about the mentalist. Good afternoon, everyone. My name is Cory Kasimov. I'm one of the senior biotech analysts here at Evercore, and it's my pleasure to host our next discussion with Edgewise Therapeutics. And you can see we're fortunate enough to have both Kevin and Behrad with us. So thank you guys for being here in Miami.
Thanks, Cory.
And so, kind of to kick things off, as we're in the sort of twilight of 2025, I think a good place to level set this conversation is to ask you to look back on the year and talk about what you'd highlight as the company's main accomplishments.
We've had a lot of accomplishments. It was really started off, and I'll pick the December, like a full year of CANYON readout for the Becker patients. It was really the first controlled study in the Becker muscular dystrophy population. There's no therapy for these patients. We hit our primary endpoint of our biomarker of creatine kinase. We also had statistical significance on the on-target biomarker of TNNI2, which is a muscle damage biomarker for fast muscle. We're very close, even though we weren't powered for StatSig in the North Star endpoint. What we saw was we came close, obviously. We also showed that for the first time that the natural history, which has been projected from that study, actually matched with the natural history in a controlled study. I think all that data really supports our efforts to run a fully controlled phase three trial.
That phase three trial completed enrollment last February, and it's an 18-month study, 175 patients, 98% power to see a 1.7-point change in North Star, which is a key endpoint for Becker, and North Star has been blessed as a primary endpoint by the FDA for almost all the main muscular dystrophies, so that result, and then the upcoming trial by the end of the year, we should have the phase three readout sometime November, December of 2026, so this time next year, we should be up here talking about perhaps a successful trial for the first treatment for Becker patients.
Awesome. Awesome. Okay. So where I want to start this conversation is, not surprisingly, with EDG 7500 for HCM, giving the pending update there. You go back to the April data, and I think we characterized it as a home run relative to expectations with the one big caveat, the safety signal with atrial fibrillation. So putting AF to the side for just a moment, believe me, we'll get there. How would you characterize those results at that time versus your own internal expectations? What aspects of the data set stood out to you?
Yeah. So a key aspect of working in the HCM space is how do you expand the market? So Mavocamten is obviously a highly effective drug. It now has a run rate north of $1 billion, but it's taken a long time and hasn't fully penetrated the market. So why is that? You know, it has this REMS, which requires extensive echo monitoring for ejection fraction decreases. And of course, we all know that you're trying to avoid having ejection fraction decreases below 50% in that patient population. But the problem is the CMIs, their mechanism of action to drive efficacy is to lower ejection fraction. So you have competing essentially mechanisms for both efficacy and also drive your safety problem.
So what was most exciting for us to be able to re-establish and point out again, in September of 2024, we put out that we had seen no changes in ejection fraction relative to concentration of the drug. We reconfirmed that in April, that in a 28-day study at multiple different concentration levels, we saw no relationship between the concentration of the drug and the ejection fraction and saw no change in ejection fraction in those patients. So what that does for us is really demonstrate a highly differentiated mechanism where you can drive efficacy without the safety problems of the CMIs and then also allows us to access the larger market of the community cardiologists who are now not using the CMIs because of the cardiovascular and the ejection fraction issue. So that was really an important aspect of the April release.
The second aspect is how robust the efficacy data was. So if we looked at the KCCQ scores, we were up in the mid-20s, which is unheard of, even in an open-label study for the obstructive HCM patients. For the non-obstructive patients, even at a low dose, we were seeing a 16-point change in KCCQ. This was accompanied across these populations of deep changes in NT-proBNP, which are a predictor of diastolic effects. We demonstrated rapid effects on E-prime, which is a key diastolic parameter. So across the board, the efficacy and the safety of the drug was really exciting. I think that was a highlight of the April disclosure.
Okay. So now, as it relates to AFib, can you speak to the specific changes you've made to the trial protocol to reduce this risk?
Yeah. So I think just consider that there's now been four large phase 3 studies run in non-obstructive and obstructive in the U.S. over the past four years, and we use pretty much the same investigators. Those trials all had about a 40% screen failure rate. So there's a lot of patients who want to be on a trial, but unfortunately, I've been screen failed out for the MyoKardia and the Cytokinetics molecules. Those are the patients that are left. So the doctors really want to put their patient on a drug. So we allowed the PIs to select who would go on the study, and we didn't have enough guardrails to actually evaluate the patients in a way that would say, is there a risk to this particular patient for a particular reason?
When we saw the four AFs, we went back and looked at the original echo evaluation, and what we found was we looked at what's called a core lab. The core lab is a single lab that reads all the echoes, and there were significant differences between the investigator lab echoes and the core lab echoes. That was a red flag because we needed to know the kind of patients we were going to treat. Second is, did we have a high enough bar for the risk of AFib in that patient population? What we did was incorporate a multi-pronged approach. One was we'd have the PI read the original echo. We then would have an internal person at Edgewise who is an expert in echo evaluation read the echo.
Then we'd have a core lab who would also read the echo, and we'd get together, look at all the results and say, are they the same? Do we agree we should put this patient on? What is their risk? That allowed us to reinitiate the studies. We dosed a number of patients at 25 mg in a 28-day study, extension of the part D to identify the minimally efficacious dose. That paradigm allowed us to get the study started, evaluate our processes, get our triage in order as we got the part D portion of the study in place. Now we think we have a very effective way of looking at patients. The key parameters we look at is first, are they an HCM patient? The wall thickness has to be a certain wall thickness for them to be diagnosed as an HCM patient.
It turned out that two of our patients with AF were not HCM patients. Second key parameter is atrial function. That can be measured in two ways. One is the size of the atria. So patients who have a very large atria have a very high risk for AFib. Also, a third parameter is left atrial reservoir strain. That parameter is the best predictor for future AF. So those parameters are how we look at and triage the patients. Those patients were not included in the phase threes of the CMIs, and then so we actually, unfortunately, have to exclude those patients as well because they have a very high risk of AF.
Okay.
And I think, Cory, the important point in what Kevin is highlighting on the adjustments that we've made in part D, as you and I have discussed before, is it's not like we're disproportionately selecting or cherry-picking patients. We're now finally leveling the playing field and matching like-for-like to the SEQUOIA and EXPLORER phase three clinical studies. So we're looking at the same types of patients that they looked at in their phase threes.
Right. Right, right, right. Makes sense. Okay. So then how many extra patients did you enroll in parts B and C, and how many in total in part D, like relative to your April update?
Yeah. So we enrolled 29 patients in the April update. We haven't disclosed the number of patients, but we will disclose that in a couple of weeks in December, the next disclosure at the 25 mg level. And we will have at least 20 patients of data from the part D, the 12-week portion for the disclosure this month. And for the disclosure of the efficacy in the first half of 2026, we'll have a total of at least 40 patients. And in this month and the next couple of weeks, we'll provide a lot more detail in regards to the number of patients, their profile, and when we expect to have data.
And so the update we get this month, will it exclusively be focused on safety, or will we see any efficacy readout?
Part D will be exclusively focused on safety. Where you'll see efficacy is that the 25 mg, 28-day patients, so from part B and C, will provide pretty much the same data we provided in the 50 and 100 mg.
Okay. I wanted to ask about the dosing. Why are parts B and C being run at 25? Is it to find the minimally efficacious dose?
Yeah. So we had about 30% of the patients at 50 mg had a full gradient response to the obstructive patients and had robust changes in NT-proBNP. So I think classically, the FDA would like you to see what is the minimally effective dose. And so we enrolled a cohort at 25 to get that additional data. It also informs where we should start the dosing in the phase three. So should we start at a low dose and go higher? Can we start at a 50 dose? Can we start even at a higher dose?
Okay. And then.
The other thing that it allows us to do, Cory, is obviously we want to continue to build the body of evidence that we've dissociated the plasma concentration to the LVEF. And so if you look at some of the CMI data, even at very low doses and low plasma concentrations, there was a ton of variability in the LVEF. You could see as much as a 20%-25% drop. So we wanted to make sure that we had ample coverage both at the low exposure and at the high exposure ranges to completely kind of get into the discussion that, look, we've explored the dose range and we just don't see this LVEF to plasma concentration. So one of the key mechanistic aspects of our mechanism is we are a partial inhibitor. So we can never fully block the contraction biochemically.
Where if you take a CMI, you can completely inhibit contraction. Now, we don't know the origin of the variability of the ejection fraction measures in patients, but it might be that because we're only a partial inhibitor, it's saturable, whereas for a CMI, for certain patients, you can drive their contraction down to zero. And that leads to these high levels of change in ejection fraction even at relatively low doses. Now, the problem for the CMIs and how it relates to the REMS is if you cannot predict who will have an ejection fraction below 50%, you have to monitor that in the patients. You can't avoid it. So this is a key aspect.
If we can continue to show no relationship in the concentration of the drug relative to ejection fraction, and we do not see the variability you see with the CMIs, that gives stronger support that we may not need to have an echo at all within the studies.
So that goes into my next question. And well, kind of two parts here. In part D, if I understand right, the current titration schedule is 25 up to 200. Is that right?
Right. Up to 150, and then in the open label, we can go to 200.
Okay, and this schedule will help inform what you take into phase three.
Right. Correct.
Let's assume for a second that 7500 successfully navigates clinical development, is ultimately approved. Is it your expectation at this time, given this lack of a relationship between concentration and LVEF, that you'd be out there without the need to use echoes to guide the titration? It'd be based on feel.
Yeah, and I think that's the key to really unlock the value of this market. Because I think what we're seeing from the research that we've done, my team's done a lot of market research, and what we've learned is you've pretty much saturated the MAVA users at the centers of excellence because I think you've run into a capacity issue in the ability to put patients on MAVA because of echo restrictions and because of the continuous monitoring of the REMS, but they've got 10,600 patients on MAVA, which is actually pretty good, but the opportunity is actually sitting in the community. The community guys don't have the resources, nor do they want to be forced into an echo regimen that's dictated by REMS.
So in order to get to those community guys, the simplest thing is to say, "Hey, here's a drug you don't have to monitor using echo," and that's going to resonate with them, so then the part D becomes an exercise of, we'll measure everything, so we'll measure at 25, 50, 100, 150. We'll look at how the echo safety parameters look. We'll look at what correlates with New York Heart Association, how NT-proBNP might be correlated with the biomarkers, and by doing that, you can now create a paradigm that, for instance, a doctor asks their patient, "How do you feel? Have you gone from a class two to a class one?" and if you now go into a class one, you ask the question, "Well, perhaps I still have more to go, but now I'm asymptomatic, but my NT-proBNP is, say, 300." Normal is 150.
So do I want to take you now another step towards being normal?" So the goal of the titration is to eliminate echoes and ultimately make the patient asymptomatic. So I'd like to almost coin the concept of a complete responder. So if you have someone who's the normal range of NT-proBNP in the normal range of New York Heart Association and in the normal range of KCCQ, that's a complete responder. Do I need to treat them anymore?
Right.
Yeah. And philosophically speaking, right, think about it like a non-obstructive. You don't really have a gradient to measure. So if you treated an obstructive patient in the same way that you manage a non-obstructive patient without having to rely on echo. I mean, the echo is an artifact of the fact that you're monitoring for LVEF, so therefore I get a gradient measure at the same time. But if you don't have to do that, then you can really rely on traditional measures be it NT-proBNP or NYHA.
Right.
When you're looking at, for instance, a beta-blocker, you're saying, "How do you feel? What's your blood pressure? What's your heart rate?" It's a qualitative measure of how I feel, and it's a quantitative measure of something you think is relevant to the particular patient.
Right. Okay. All right. Two quick questions on HCM, and then hopefully I can sneak one in on Becker. Just to go back to AFib and to tie a bow on this, what would an acceptable rate of AFib be in this update we get in the coming weeks? Is it 0%? Is it low single digits? Is it anything better than?
Actually, we always try for zero. Zero is always a good one. But the reality is, I think the best data you can look at is the placebo rate in controlled phase 3s. So you now have three studies. You have Odyssey, you have Explorer, and you have Sequoia. And the rates go from 2%-8%. So anything we've heard for most of the investors, anything in the single digits is clearly acceptable because if you run a controlled phase 3 study, that's the background rate for these studies.
Okay. And once you get to the more complete kind of part D update next year, when could you start phase three after that?
We're on schedule for phase 3 start probably the fourth quarter of 2026. We've got a good idea, and we've got some creative ideas of how we want to do the phase 3, which would potentially allow us to abbreviate the timelines a little bit. We'll probably provide some color on that, if not at the end of the year, certainly when we put out the full efficacy data for part D.
Okay. And then one question on Becker in our last minute here. With the phase three data coming up second half of next year, what do you need to show in that trial to give this product the best chance at commercial success?
The tipping point on that trial is 0.75 to hit stat-sig. Right? I think everything we've seen from the open label data in MESA from patients who've been on the drug for as long as three years is that you see continued stability. The way to think about it is it's an 18-month study with power 98% to show a 1.7-point difference. But you don't look at it in an isolated way. You have to look at, well, what does one point of maintaining a function on an annual basis mean? And right now, we've gone with our ARCH patients up to three years, and they're net positive, and the predicted natural history would have predicted they declined 4.8 points. So one point is really, really good, and we're powered for 1.7 over that time.
So I think if we see anything in the one-point range, we'll be able to.
So, one point you think about it: you're walking across the street, you're trying to lift your leg to get on the curb. That's one point I can't do that. I'm sitting in a chair or I'm in the bathroom. I need to get off the toilet, just to be blunt, and I can't get up by myself,
and you're a 30-year-old guy.
That's devastating. Now think about it, five points over three years. Five points is, I'm walking normally. I may have a gait change, but I can still walk. Five points is, I need to have a scooter to get around. Five more points, I'm in a wheelchair.
Yeah. The best way to think about it is let's say you're an adolescent, you get diagnosed, and you basically keep them at the level they were throughout their natural history as opposed to declining. So what does it mean to lose a point a year? Right? That's essentially the best way to think about it.
Okay. That's very helpful. We're unfortunately out of time. Thank you guys very much, and good luck with the upcoming data.
Thanks, Cory.
Thank you all for your attention. Thank you.