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 the 7500 series 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.
Yeah. So maybe take a step back and why we're disclosing, what we're disclosing in December, and then the subsequent disclosure in the first half of 2026. So what we've noticed is the run rate for Mavacamten and HCM is now above $1 billion. So remember, there's been a question about, is there an HCM market? How big is that HCM market? So now with a run rate north of $1 billion and additional agents probably coming into the area, it's a substantial market. Now, so what has limited the market for Mavacamten? It's that it's well utilized within the centers of excellence. We have academic centers that can do the echoes, 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 echoes 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 mg level for 28 days to show that we still do not have effects on ejection fraction, 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 developing. 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 contraction 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%, 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 two liabilities. One is you have to monitor them, and you have to do multiple echoes 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 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 of our mechanism. And then later in the first half of 2026, we'll have additional data to support the efficacy of our drugs at 12 weeks.
Just for this data, there will be a quantitative readout for the 25 mg dose group, right? It will include both the obstructive cohort and the non-obstructive cohort.
Correct.
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?
Yep. So all of the 20.
So they're going to be called longer than four weeks, right?
No. So the first 25 mg will be four-week data on entirely new patients.
I see. Got it.
So I think the reason to look at the 25 mg is, remember, we saw efficacy at 50 mg. 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 mg? What do we start at 50 mg? There's pros and cons to starting with either dose. So I think this 25 mg will give us some understanding of that.
How large is that? Like 10 patients per cohort or how big?
We haven't given the numbers, but it's sufficient.
It's a meaningful number.
A meaningful number of patients, right? And it'll add to this database that we have a very tight exposure response or lack of exposure response to EF.
Okay. I'm assuming since this is my assumption between reading the tea leaves. It's the lowest dose you're going to give an update that there will be, and even if your lowest dose, you're effective enough to show it. I don't know. That's me extrapolating.
Or may or may not observe that.
Yes. 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. Just tell us 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 with the clinical data?
Yeah. 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 of the wall thickness of the ventricle. Second, we noticed that even though we required the patients to have an ejection fraction above 60, some of those patients were actually, I think four of them, were below 60. And what we noticed was a disparity between the core lab, which is a single lab reading all the echoes, and the individual investigators' read of the echoes. 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.
We essentially have a group of people deciding who goes on the study and who does not. So the 25 mg 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 six 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 two weeks. We go to 50 for two weeks. We go to 100 for four weeks, and then 150 for the next four weeks. That's a 12-week cycle. And then those patients roll into an open label extension after the 12-week.
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 2026 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. The core lab is a single lab that reads all the echoes. It takes about four to six 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. 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.
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 that.
On the 25 mg efficacy.
On the 25 mg dose, correct?
Correct.
Yeah. So then.
On the Part D, we'll largely just be safe.
Okay. Got it. I think one of the things that I think investors have, obviously, they understood the patient selection is really critical in assessing AFib, right, because it's a high comorbidity. Could you maybe talk about you talked about the sick heart valves that should have never been in the study. What is the requirement in the 12-week study as well as the low-dose study? If you have a history of AFib, will you completely rule it out? What is sort of the process?
No. We'll have, generally, the CMIs have capped the prior AFib in and around 15%. We'll be roughly in the same place. We've not put a formal cap in, but I think that that's realistic to believe that. We incorporated having a six-month lookback. 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 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 two parameters. One is the left atrial size. The second is left atrial reservoir strain. If you go in 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 three of the four 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 AFib on a much higher level. So we 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 mg is as effective as 50 mg, 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 zero effect. But it is important to understand what is a minimal effect and the starting point.
Then a lot of investors are also starting to kind of visualize the 12-week time point. 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 four weeks, your effect sizes were as good as the CMIs at.
At a fixed dose.
At a fixed dose, and that wasn't even optimized, right? So people are trying to figure out now you're going nine 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 four weeks and 12 weeks. That's important to see, in particular, in non-obstructive. So in obstructive, what you normally see is the gradient reduction occurs very quickly. And that translation doesn't deepen necessarily over time. At least from our data, from seven 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 in a non-obstructive patient from, say, four 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, this is what type of things we'll try to figure out.
How soon could you expect the 12-week data? Is it going to come out in 1 Q? How soon can you engage with the agency to think about phase III development?
On phase III?
Yeah.
Yeah. So we've already started thinking about what kind of trial we're going to run. We've got two 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 2026. That hasn't changed. And so I think that's really the key. And I think the idea is to have a discussion with the agency sometime in the second quarter of 2026 and just align on endpoints, trial duration. We've got some really interesting ideas that we're exploring that would be 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 Arens?
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. The feedback we got was somewhere in the 80-100 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 REMS, right? Plus, we're a different mechanism. So you've got a couple of things that we can rely on. And I think the strategy is put the data package together, go to the FDA and say, look, here it is. Don't ask, do we need 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 zero echoes because you don't need an echo other than baseline in the study to look at, say, diastolic parameters. But can you eliminate echoes and you can replace them with other measures? So the two 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 % 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 can 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.
That goes back to your question around why we are exploring the dose over 12 weeks. It's that 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 that are on the market, you're seeing patients who are not responding. You're seeing patients not realizing efficacy. And part of that issue is either you're dropping an ejection fraction or the physician is dosing to the minimally efficacious dose because they're concerned around ejection fraction. If you don't have an ejection fraction problem, it's pretty easy to continue to dose an individual.
Right. So now, in obstructive, I think it's very, and we talk across these two 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 non-obstructive, you probably have to drive a level of remodeling to feel the full benefit. And what we saw was with Mavacamten and 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 four spots. So clearly, there's a narrow TI in the non-obstructive patients.
And what we would want to try to understand is what is the time relationship and what is the depth of the response you can see in non-obstructive.
And I think also one of the things you said, you have a drug that works on the diastolic space, and non-obstructive 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 series study, you're just including all kinds of patients from non-obstructive. You're not trying to stay in like a.
We have a relatively broad spectrum of patients in the non-obstructive. 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? Are they really HCM patients? How fibrotic are they? How sick? Are you going beyond the threshold? At the same time, you want to be able to recruit your study with the patients in the middle. So this is kind of a fine line, I think.
I know there's like two and a half minutes, and then you have many more inflection points in 2026, but maybe I think a lot of investors are also very excited about 15,400, 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 and HFpEF?
I think 15,400 has some unique characteristics that are different to 7,500 that make it a little bit more amenable to the HFpEF population. So I think honestly, the bar we've set for ourselves from the healthy volunteers is to see pretty much the same thing that we saw with 7,500. So no LVEF, the plasma concentration. And I think we're in the middle of the MAD right now. Healthy Volunteer MAD will have that data in the first half of 2026, 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 2026.
It's pretty clear endpoints too for a relatively small 2A and where we would want to see changes of 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 changes the same as 7500. So I think all those things would bode well, and you could measure all those things in a 2A study in those patients.
Great. And then team, I know we have like 48 seconds. Also, another big milestone is going to be the pivotal Grand Canyon study reading out in Q4. 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 NSAA score. It's blinded. We don't know who's on there, but how is it tracking with your assumptions, I guess? Sorry, I could only ask one question. I feel like that was the important one.
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 and the open label extension, and perhaps some analysis of what we have in the Grand Canyon. But of course, blinded data, sometimes there's a fool there and they go hunting for that. We have built, I should say, a very robust model based on the Leiden data of natural history and built a model of how you would look at North Star relative to the expected response over time. We've validated that model with two other natural history data sets.
And I think quite importantly, we published this in a poster at World Muscle, 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 sig on North Star and whatever secondary endpoint we describe.
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 their covering analyst from very early on can say what a tremendous job Chris and his team has 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, so.
Yeah, we've made very selective early investments in a 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 CMIs. 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.
Boards can, I mean, the 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 have to 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 of working with him, and I've had the pleasure of working with you guys. So it is between your personality fits and the way you work, it's like a perfect relationship, honestly. And I'm very excited for you guys to work together. So let's thank the Edgewise team. We are super excited for December in 2026. So.