All right. Good afternoon, everyone. Welcome to our Piper Sandler Healthcare Conference. My name is Yas Rahimi. I'm a biotech analyst here at Piper Sandler. Thrilled to have the team from Edgewise Therapeutics on with us. What an awesome year. I think your stock has been up like, I don't know, 500%. Yeah, we like that. Yeah, we like that too. Yes. I remember having breakfast with you guys last year at the conference before we launched coverage. So it's been, honestly. Yeah, everything's gone as planned. An incredible journey, and you guys have done a terrific job. Thank you. Keep going. Well, we have data coming out very shortly. So I think hopefully we'll keep it going. Yeah, so I assume, you know, obviously let's spend some time on CANYON, which is pretty imminent in December. You're here, which makes me think that right after this conference, you guys are going to enter a quiet period and start hunkering down. As of 7:00 P.M. tonight. 7:00 P.M. tonight. Oh, 7:00 P.M. tonight. No, you can't be. We have dinner with you. Make it 8:00 P.M., please. We'll make it 8:00. Yes. No, that's great. And obviously, with being in a quiet period, there's not a reason to believe that you want to push the data into JP Morgan, right? Like we still have a couple more weeks left to. No, we're locked and loaded now. OK. As usual, we always bother you before you read out data. What do you want to see? What's the bar that you want to achieve? You guys do a very good job articulating it. We just want to see that you're not giving us another answer. No, we're not going to give you another answer. No, the base case is we think that so this is CANYON trial. Just the groundwork. CANYON trial is a 40-patient placebo-controlled trial, 3-to-1 randomization. The drug is an oral dose of 10 mg for one year, still controlled. The primary endpoint is creatine kinase. It was powered on creatine kinase that was based on the data from ARCH. And key secondary endpoints that we are looking at are North Star, NSAD, 10-meter walk. We've incorporated MRI. We're looking at two major endpoints of fat fraction and T2, which is edema. We also have included patient-reported outcomes, PROMIS-57. And so that data set, and we'll have additional biomarkers beyond CK, which will include troponin I2, which is TNNI2, which is an on-target biomarker for fast muscle. We'll look at things like myoglobin, which I think can be actually really a pathologic biomarker, which the agency might find attractive as something to look at. All of those will be reported in the next couple of weeks. The goal here is to see statistical significance on the primary. I think our base case is that we would like to see about a point change in North Star relative treatment from placebo. We do not think that will not be statistically significant, but I think it will show a trend. Why we think that point is really important is that one point on the North Star over a one-year period is deemed clinically meaningful to the patient. I think if we were to see that clinically meaningful level of efficacy and the other secondaries trended in the same direction, I think we would go to the agency, have a discussion with them that we provided benefit to the patients. Of course, we'd have to have the safety profile to show that this is beneficial. We would have supportive data from the biomarkers that preventing muscle damage is likely to have clinically meaningful benefit to the patient. We would have completely enrolled our follow-on study, our pivotal study, GRAND CANYON. We would have a combined safety of the drug, and we would have a confirmatory study that would support whatever basis of the CANYON study. All those things together, I think, would be advantageous to have a conversation with the agency. Now, if we had as much as a two-point change, we probably would hit statistical significance. And that, obviously, we believe that that would be approval based on that. So that is the time frame. But I do think hitting two points would be a challenge. So we put that as kind of a 20%-30% opportunity. The base case is really, I think, probably 60% chance of someplace in the base. And there's always that worry. You want one, and you end up with like 0.85, right? I know. I don't want that either. Yeah. It's like we call it. Look at all these. We call it the periphery. Yeah. Right? Yeah. Right? Yeah. You don't know. It really depends on I think what we want to. I think if the one is the minimum to go with the agency, that's what I mean. What do we want to be able to as it gets further and further from one? It starts becoming, can I actually power the GRAND CANYON study? How many Becker patients do I really need? And then is it clinically meaningful? So hitting stat sig at a level that isn't clinically meaningful isn't helpful either. Right? So I think there, and it depends on the, then you're down picking through, did we have an outlier? I mean, it becomes it's a small study. Small study. It's a small study. OK. I think that at the time you're going to report out any change in terms of I think you've communicated CK change should be 40% placebo-adjusted. TNNI2 should be about 80%, myoglobin about 40%. Like you're expecting that those biomarkers are going to be within that framework. OK. I think that's consistent. If you look at DUNE, which was the first set of controlled data, that's exactly what we saw in the biomarkers. 40% on CK relative to placebo, as well as 85% of those on TNNI2. OK. At the time that you report the data, I assume you will not be able to communicate unless it's a two-point difference, non-stat sig, that we could be more. Will we know at the top line what the regulatory path will be on this data set unless it's a stat sig difference? Yeah. I think it will be a discussion with the agency either way. We've had some prior discussions with them. We understand how they view the biomarkers. We understand how they view the North Star and NSAD. I think we did discuss with them, if you remember, how we came to CANYON and GRAND CANYON. We converted a dose-ranging study that was going to be done over a year. And we talked to the agency. And what they really wanted us to do is if we wanted to jump directly to a pivotal strategy, they wanted two discrete placebo-controlled studies, and they wanted one dose for both of those studies. And so we converted what was a dose-ranging study that would take an extra two years. We converted that to CANYON, which was the 40-patient placebo-controlled study, and GRAND CANYON, which is the 120-patient placebo-controlled study with North Star as its primary. That was the agreement. So we already have a level of agreement on what they think would be relevant. Then, of course, I think they've given us clear guidance on CK of, is that a surrogate? We do not believe that will be a surrogate. But we do think they gave us clear guidelines on why they don't like CK as a surrogate. One is these biomarkers of muscle damage go down with disease progression because the patients have less muscle. So what we've shown, or what we believe we will show in the placebo, is that the CK will be very flat. It will not change dramatically. We had a poster at The World Muscle Society supporting that with historical data, longitudinal data from the Leiden group, that CK only goes down about 5% over a one-year period. And then, second, we will show a steep decline in CK and other biomarkers within the treated group. So what the agency doesn't like about the biomarker is they're too variable. They're associated with activity, and they go down with disease progression. What I'd like to be able to show them is that over a year in Becker populations, these biomarkers are not variable, and that we have a true drug effect, and turn the conversation into something more along the lines of we believe preventing muscle damage is potentially clinically meaningful to the patient. The KOLs would support that effect. And we're seeing a true drug effect of sevasemten. So therefore, if I prevent damage, shouldn't that be good for the patient? And we'll see where they go with that. Behrad, how big is the Becker opportunity in the U.S.? Yeah. There's about 5,000-6,000 diagnosed prevalent patients. So typically, these individuals are diagnosed in early adolescence. It's kids who are not keeping up with their peers. Mom takes them to the doctor. They do a blood test. They see the CK is elevated. They do a genetic test that diagnosed with Becker. So we don't see a lot of underdiagnosis on this diagnosis. A lot of these patients are actually the prevalent pool. And then you think about, OK, what percentage of the ambulatory, which would be the indication that we would be going after, it's ambulatory Becker patients in the first instance. And that's about 70% of them. But that doesn't mean that the non-ambulatory couldn't potentially benefit. And we've seen some flexibility with regulators around a broader label than the study population when looking at rare, ultra-rare diseases, of which Becker is one. So I think we think it's a very attractive market. I think the peak potential here is somewhere between $2-$3 billion a peak. And so we're pretty enthusiastic about it. And like Kevin alluded, there's no background standard of care. These individuals have basically nothing. And imagine being a guy between 20 and 40, starting a family, and then all of a sudden, within a year to two years, you've gone from being very active to wheelchair-bound, mobility devices. You can't play with your kids. That's what you're talking about. So I think another thing about CANYON, which we don't talk about, is that we do have an arm of the study, which is adolescents. So since those adolescents are diagnosed, they don't generally have rapid changes in things like North Star that are measurable over a one-and-a-half-year period. They do have relatively high creatine kinase and other biomarkers. That population from a standpoint of a safety is important. Seeing biomarker responses in that adolescent group is important because that's when the patients are diagnosed. I could envision the label looking like all ambulatory patients. Ultimately, you would start a patient typically when they're 14, 15, 16, and you treat them for the rest of your life. We've had really good, I think, uptake and durability on study. Meaning in ARCH, we had, if you remember the data, we had two patients drop off because of family planning. We needed to have the reproductive toxicology coverage to actually continue the dose. So they wanted to come off. But interestingly, they came back on, meaning that they were willing to travel across the country to Atlanta to come back on the study because they thought the drug actually was providing benefit. So I think it's not only just, I'm not going to lose function, but actually, I probably feel better when I'm on the drug. And we've heard that on multiple occasions, that they actually feel better on the drug. They have either less pain or they feel better. And perhaps I don't think that's a placebo effect. I think that's a real activity of the drug. And remember when we talked preclinically, when we were in some of the preclinical models, the preclinical species were more active, and they felt better. So I think this is part of the translating to humans. OK. Perfect. Team, let's now transition to HCM, right? So past Becker, we're going to be back into the HCM cohort and getting ready for the MAD data, right? So I assume you're by now, since September, actively in the MAD portion of the study enrolling obstructive and non-obstructive. Maybe help us understand in September, before the data, you continue to go to Gilead to believe you have an easy, non-titratable, no-echo based drug of a novel mechanism. What is your view now? What do you have as you look at your product profile as the MAD study is enrolling? Yeah. I think really nothing has changed. We still believe that we will have a fixed dose. This dose would probably treat 70% of the patients, 80% of the patients. We would have a dose adjustment to maximize efficacy for the patients. And we would have to decide what is the deficit. So you can do it a bunch of different ways. A standard gradient would be a measure, a single gradient measure. And that could be anywhere between, say, one month and 12 weeks. So maybe four to 12 weeks, you come in whenever you'd like. It could be simply as, do I feel good or not? To titrate up. To titrate up, right? So if I feel like I have a slight deficit in my exercise endurance, I could titrate up. We've thought about things even like a patient you can measure by stethoscope, the murmur. The doctor can do that. Or maybe you'd look at the proBNP. So we've had deep responses in proBNP. Would you want to see it essentially, could I go further? Maybe I would drive a patient to normal proBNP. That would be an interesting endpoint. So we're still pondering how you would get every patient to a maximal efficacy. But I think the base case still exists that we would select a dose to start most patients on. To you, that have eligibility. And then get them down, yeah. Right. What about the echoes? Do we feel still like you have a product profile that warrants no echo monitoring associated because you don't or still need LVEF? We still believe that ultimately this drug will not be sensitive to the drug concentration of ejection fraction, and we'll see how as we get longer and higher exposures with these patients, we'll see where that ends up, but I do think we've shown initial data that we can dissociate the concentration of the drug relative to the ejection fraction. At some point, we ultimately may see that, but I would expect to have very limited folks below 50. I don't know if we will ever see anybody below 50. If you look at the preclinical models, it kind of just flattens out, so we never really drive the ejection fraction below a threshold, so we don't know when we'll get there, but we'll continue to dose until we find that. Yeah. I think ideally, you get into a commercial situation where individuals get started on a dose. And then when they come in for the normal six-month echo, you do an echo, and you're like, oh, your resting gradient looks great. Maybe your Valsalva is at like 55 or 50. And then you can dose adjust them. And then when they come back again after six months, you're like, yeah, great, everything looks good, right? That has not changed. That has not changed. That's within what the standard of care is for these individuals. And we've always said that we want to insert this drug like any other drug, cardiovascular. If you take a blood pressure drug, you'll get a dose. We'll measure your blood pressure. Yeah, because it's a part of standard of care. It becomes standard of care, yeah. What struck us from the single-dose data is how quickly patients reported feeling better. Yeah. Right? It Right? It wasn't like they took the drug and they were like, I wonder if it's doing something. There were a number of cases where the individual was like, oh, I feel it doing something. And that's actually a really good thing because that obviously impacts compliance and adherence. And it's also good for the doc to know, OK, this dose is working in my patient. Do you and I know that once Becker comes out, a lot of clients are going to ask around what is their expectation in the MAD readout? To simplify, let's just focus on obstructive for right now, right? Because we saw SAD for obstructive, let's just focus on what do we want to see on obstructive MAD data, right? You guys said you want to see deepening of an effect. I think the CMIs at 28 days do about 70%, right? And then you have said. We would, again, I think would not see a change in ejection fraction relative to concentration. We'd have somewhere around a 60%-70% change in gradient that would be exposure related. We'd want to see a deepening of the response to the proBNP, which is important, and we want to start to see the diastolic effects that is really attributable to this novel mechanism that we saw in the preclinical models. Because that is, for the KOLs and for, in particular, the strategics, the Holy Grail of heart failure is, can you affect the relaxation of the ventricle within the diastolic filling parameters, and will that ultimately lead to greater levels of benefit to the patient? Can you measure that in the MAD studies? Yeah, we can measure that in both the obstructive and the non-obstructive patients. We think the question is there's never been a drug that has done this. So how does that translate to feel and function and/or the primary endpoints for the approval of these trials? So I think what we have talked about less is that what do you do with the after the 28-day data, what happens? So those patients will be washed out of their drug for 30 days. We'll then get a CPET, so an exercise challenge. We'll then start them on a 12-week study, and we'll have some interim measures along the way, and at the 12-week time point, we can get a peak VO2. So what we'd like to triangulate to is the effect on gradient, the effect on diastolic endpoints, the durability of that response, and how that translates to the phase III approval endpoint for these drugs. And then be able to understand how do I get each individual patient up to the right dose for that individual. But do that in a very physician and patient-friendly way, which would, I think, for all intents and purposes, say we would not ultimately have a random and a black box. Because you'd want to be able to show that you did not lower ejection fraction dramatically. Yeah. I think the underestimated value of 7500 is really in the non-obstructive. I think, as you know well, right, the percentage of patients is typically being like 66% is obstructive, 33% is non-obstructive. I think we're seeing that shift a little bit. We're seeing more non-obstructive feeding into the pool of symptomatic patients, and so it's going to get closer to 50/50, maybe 55/45. I think if you show that diastolic benefit with this molecule, I think you take the whole HCM market. Because if you're a doc and you have one drug that does two things versus one drug that does one thing, and you're managing both patients, you're going to go for the drug that does both things. I think that's the real kind of value proposition. I know that when we spoke earlier in this month about in November around sort of seeing the data. Because the MAD study is enrolling obstructive and non-obstructive. The obstructive population is already advancing well. You were thinking to maybe you were at that time thinking, should we wait for both data sets? Should we release one? Where are you in your thinking? Because I think people are trying to wonder, like, we're going to get one data disclosure or two. Right now, the base cases will disclose both populations, obstructive and non-obstructive. I think it's probably obvious that we already had recruited 11 obstructive patients. So that's ahead. Yeah. So I think depending on what the data teaches, is it? We were very successful with the last presentation because we were very focused on a couple of clear endpoints. Do we want to muddle together obstructive and non-obstructive strategies? I think it'll be at the time of the data, we'll see. Maybe it's mostly obstructive in an early data on this non-obstructive. We haven't decided yet, really. We haven't really decided yet. I think let's say it's separate instead of together. We have a good idea of what we want to see in the obstructive. What do we want to see in non-obstructive, right? Like it's a little tougher in a SAD study, I think, getting some of these diastolic measures correct. Can you see something in 28 days on feel and function, and is it even meaningful because there's a significant placebo effect? I think you can look at the depth of the BNP response, and that could be meaningful. I think it's quite meaningful for the KOLs, and then the diastolic benefit. Is there a clear differentiation from the CMIs where you see the diastolic effect but no changes in ejection fraction? So that would be a level of disclosure, which I think would be valuable, but you wouldn't really know how that all translates until you get out the 12 weeks, right? Then maybe, team, I think it's very clear that strategic interest in EDG-7500 is high, given that there are a million HCM patients. The MAD data is upcoming in 1Q. Do you think the MAD data, let's say obstructive and non-obstructive, both are available, are taking quite a lot of risk out of for potential strategic? Or do you think you really need to go to a 12-week study and more time points and more data? I think the conversations we've had, I think that becomes a real kind of inflection point for the company. And I think just to kind of emphasize, I think the strategic interest has been across both programs. I think a lot of people have been waiting for CANYON to read out. Because the setup there is really nice. It's either you've got a path to an early approval, or you fundamentally de-risk the phase III trial that's fully recruited, right? So if you're strategic, you're taking a bet on what would essentially be a successful program. And then on the cardiac side, I think it's a little bit more data than single-dose data. And then that diastolic piece becomes a really important piece for the story, particularly for strategics, as they think about the next-gen molecule that we have going into heart failure. Yeah. So there's a read-through, I think, for the second-generation molecule on the diastolic effect, which ultimately is for the second molecule a real value proposition. And we're starting GLP toxicology on the second molecule. And we expect to have an IND second quarter of 2025. So everything will line up into the second quarter of 2025. Last question, when would you start potentially, based on your math now, to start pivotal studies for 7500? Right now, we're planning for first half of 2026. Yeah. And the base case is to run a more parallel approach in non-obstructive and obstructive. And it really will be we've upped the number of patients we plan to recruit in CIRRUS-HCM, I think, up to 75 now on ClinicalTrials.gov. So we will have substantial data sets in both populations. We're still discussing the trial designs. There's multiple ways to skin the cat. But we'll have more data on that later. Yeah. I think for the non-obstructive, right, given that it is a competitive landscape, what are you going to learn in a phase II that you wouldn't learn running a formal phase III? Why take a year and a half out of the development timeline and go straight to phase III? And KOLs are like, guys, you should do that. Yeah, no, that makes sense. Well, team, I can't believe the 25 minutes flew by, and thank you for all of your guys for an awesome year. Can't wait for 2025. Looking forward to continuing. Yes, continuation. Yes, thank you. Let's say thanks to the team for. Thank you.