Welcome everyone to the 42nd annual JP Morgan Healthcare Conference. My name is Tessa Romero, and I'm the Senior Biotech Analyst at J.P. Morgan, or one of them. Our next presenting company is Edgewise Therapeutics, and presenting on behalf of the company, we have CEO Kevin Koch. Kevin? Okay. Well, thank you all for coming, and thank you, Tess, for the invitation. It's been a great year at 2023 and even better year for 2024 for Edgewise Therapeutics. Here's my forward-looking statements. Okay. So Edgewise Therapeutics is a research and development biotech company targeting muscle for the treatment of rare unmet medical need diseases. We've had rapidly advanced our drug for muscular dystrophy, now in pivotal studies, Edgewise 5506 in Becker muscular dystrophy, and additional data coming this year in Duchenne muscular dystrophy. We've also moved into clinical development Edgewise 7500, which is a novel mechanism for the treatment of hypertrophic cardiomyopathy. And again, we are committed to treatment of our patients that have high unmet medical need. We've been very productive in 2023. We completed the enrollment of our first phase II clinical trial in Becker muscular dystrophy, controlled 1-year study. Completed that as of October 2023, and we'll read that out in the end year of next year. We've also initiated a pivotal study called Grand CANYON in Becker muscular dystrophy. That started in the November timeframe. I'll talk a little bit more about that later in the presentation. We've advanced our Duchenne studies LYNX extensively. We've dosed over 50 patients now with Duchenne muscular dystrophy, and the first trial ever in gene therapy-treated Duchenne patients, FOX, where we're adding 5506 to see additional benefit in that patient population. And then finally, we initiated 7500 in a normal healthy volunteer study in the September timeframe, and we are now initiating the MAD studies, multiple ascending dose of normal healthy volunteers, as we speak this week. So great year, great progress. So what are the milestones for 2024? So we anticipate reading out LYNX, our Duchenne data, being able to pick a phase III dose and initiating a phase III trial, in the second half of 2024. We'll report on ARCH, which is our open label Becker study, 24-month data on the initial 12 patients. I'll talk a little bit more about that design. We'll talk about that in the second quarter. DUNE which is a study expanding the market opportunity into limb-girdle disease, will be discussed sometime in the first half, and we expect that phase II control data from CANYON by the end of the year. Sometime in the third quarter, we anticipate having initial data in phase I for our cardiovascular asset, 7500, normal healthy volunteer data, SAD, MAD, and patients with obstructive HCM, single dose. So let me tell you a little bit about 5506 and muscular dystrophy as a disease. So muscular dystrophy, and I categorize those two major categories, are Duchenne and Becker muscular dystrophy. In these two diseases, there's a key structural protein that's missing or mutant. So in Duchenne muscular dystrophy, this protein, dystrophin is completely missing. It has a very rapid progression. In Becker muscular dystrophy, dystrophin is mutated and has in lesser amounts and is a slow progressing disease, but patients still lose ambulation in their thirties and forties. Not a great disease. What is key about this structural protein? It holds the muscle together as it contracts, and so that eliminates stress and allows the muscle to function effectively and is not damaged. Now, if you exercise extensively and the next day you feel sore, that's because your fast muscle has been damaged, and now that fast muscle needs to be repaired, and there's edema associated with that. So that's why that muscle makes you, gives you, makes you sore that next day. Now, in muscular dystrophy, every day, these patients are having these hypercontracted fibers damaging that muscle, and over time, the body senses that continuous damage and replaces that normal muscle with fatty and fibrotic tissue. And then, and only then, do you lose function. This is why Duchenne muscular dystrophy is not diagnosed until the patients are four years of age, because the muscle damage is ongoing prior to the loss of function. So what we want to look at is muscle damage is the driver of loss of function ultimately, and we want to stop that in its tracks. So let's talk a little bit about Becker muscular dystrophy. Now, Becker is a disease of patients who have minimal dystrophin and truncated forms of dystrophin. It's a high unmet medical need disease. There are no standard of care, and there are no therapies approved for this disease. So this is. We have fast track designation for Becker and a substantial market opportunity and a high unmet medical need, disease. We first tested our drug in Becker patients. We can do a lot of manipulations, get a lot of PK/PD in adults. And we started a study with 12 patients, started them for two months at 10 mg, four months at 15 mg, and six months at 20 mg. So really a dose escalation study for safety and tolerability of the drug. Now, people think about Becker of not being severe. Now, these patients, six of the 12 could not get up off the floor by themselves, so I would call that a severe disease. Half of their muscle, as measured by serum creatinine, is available, so they've lost over half their muscle. Yet they still have turnover of the muscle, as measured by serum creatine kinase, so there's still active disease going on in the muscle they have left, okay? Looking at the North Star, the North Star is a measure of functional capacity in these patients. They have a North Star of 15. That is a more severe disease than most of the Duchenne patients in any of the trials you've seen, previously, or recently. So severe population. Now, the compound was very well tolerated, no significant or serious adverse events. All the adverse events are typically spontaneously resolving and very mild. So it was a highly well-tolerated drug over a 12-month period. So the key thing, I told you that muscle, muscle damage is really important to monitor as you look at the progression of the disease, and so you can measure these muscle damage biomarkers in the plasma compartment. So when the muscle's damaged, it leaks these muscle plasma biomarkers leak out into the plasma. You can measure them, and then you can get a feel for how much damage is going on. So creatine kinase is a well-known biomarker that actually is used to diagnose Duchenne and Becker patients. We saw a 37% decrease in creatine kinase at the one-year time point, and we even saw decreases in creatine kinase after one month of dosing. Even more important, what we saw was a 79% decrease in TNNI2. So what is TNNI2? TNNI2 is a troponin. There are three different kinds of troponins: one for slow muscle, one for fast muscle, and one that most people know called cardiac muscle. We saw. This is a measure of target engagement because we are interacting specifically with the fast muscle fiber. Now, 79% is a great response in these patients. We took five of those patients all the way down to normal. So we're demonstrating that we have very strong levels of inhibition of our on-target biomarkers. So how does that translate into function? One of the impediments of doing research in the Becker population has been the lack of natural history studies. There's been two great natural history studies that have come out in the past six to eight years. Both of them have given precisely the same data result. Over a multi-year period, you see about a 1.2-point change in North Star. As you remember, reminder, North Star is a 34-point scale of 17 different activities measuring zero, one, or two, okay? And 1 point is actually clinically meaningful. So you think about it, if you walk across the road and you step up on the curb, 1- point is I can't step up on that curb, or 1- point is I can't get up off the chair. So that's a meaningful endpoint. So, as you see here, the median set of patients we treated had a North Star of 15, and in this subset of patients that we're treating with Becker, all of these patients are declining. And so you can see this by this spaghetti plot. In two separate studies at two separate universities came up with exactly the same data over a multi-year period of over 100 patients. So we think this is really strong validation of our trial design to move this into phase II and in phase III. So what do we see in our open-label study of ARCH? We saw a 0.4 North Star point increase in function. So we didn't just block the decrease in function, we increased the function with this drug in a patient population expected to decrease by 1.2-2 points. We also have 75% of the patients showed a stable disease or an improvement in North Star. This is really unprecedented for anything in the Becker field, so we're really excited about this result. When we talked about this in last June, the patient community was ecstatic. The recruitment increased dramatically, even in the Duchenne studies. Everything really was... People were excited. We were actually paying attention to a set of patients who really have a high unmet medical need, and I anticipate great success in this Becker population. So, what do we do in the Becker population? So we had started with a phase II study that was dose ranging, but we were so excited about what we saw in ARCH, we decided to convert that phase II study into a controlled phase II study and a pivotal study so that we could seek approval sometime in 2025 and 2026. So, let me just tell you about CANYON. CANYON is a 40-patient trial, three-to-one randomization at 10 mg over a period of one year.... They have multiple endpoints, biomarkers being the primary, functional endpoints in North Star, as well as number of timed function tests, PROs, MRI. We will be reading that out at the end of the year, and we believe that if we hit the primary endpoint of biomarker changes, and additionally, have a good trend towards other secondary endpoints, that we should speak with the agency and talk to them about how this patient population with a high unmet medical need should deserve this drug because of the safety profile and the potential benefit. To add to that, what the agency has asked in the last couple of years is if you really want accelerated approval, you should have your pivotal study actually fully enrolled, and that fully enrolled study should be enrolled before you file that data. So we initiated GRAND CANYON last November. This is an 18-month study, Northstar as the primary endpoint, same secondary endpoints, 120 patients. We can see a change in Northstar of about 1 point with 90% power. So very well-powered to actually see this benefit in this patient population. So what is the potential opportunity here? There are 12,000 patients in the EU, in the U.S., and in Japan that have Becker muscular dystrophy. It typically afflicts patients that are greater than 16 years of age. They often lose ambulation in their thirties and forties. So we think this is a significant market opportunity. If put it into kind of context, the Friedreich's ataxia market is about the same number of patients, the same demographics, 30- and 40-year-olds, same issue of losing ambulation, same issue of having a cardiomyopathy as its primary morbidity. So we think this is a really exciting potential therapeutic indication above and beyond the Duchenne indication. So let's talk about Duchenne. There's been a tremendous amount of research and effort going into Duchenne therapies. Unfortunately, I believe that none of them ultimately will be enough for these Duchenne kids. So we have moved our molecule into Duchenne studies. We've treated over 50 Duchenne patients now from 4-9 years of age in multiple cohorts, each cohort with an increasing dose. The first three months of that cohort will be a placebo-controlled study looking at biomarkers, and because the biomarkers change so rapidly in this particular indication and in Becker's, we think we can use the biomarkers to help select dose for our phase III. Additionally, because of patient outreach, the patient advocacy groups, we know that a number of patients who have been previously treated with gene therapy have a significant unmet medical need. Their patients and their kids are progressing, and so we decided to initiate FOX, which is patients who have been treated with gene therapy two years out. We now will treat them with 5506 and look for biomarker changes, as well as functional benefit in patients who are declining. Very exciting study, first of its kind. So in the Duchenne space, we are treating all of the patients who are ambulatory, and with all known therapies, and can add or act as a single agent in these these populations. So we're treating patients who are on a steroid background only, which is standard of care in Duchenne, treating patients who are on steroid and other, things like exon skippers and other drugs that are used for Duchenne, patients who are not treated on steroids. So we have a cohort of steroid-naive patients to see the single agent activity of the drug, and treat patients treated previously with gene therapy. So the entire gamut of ambulatory patients are treatable with 5506 because we are mutation agnostic. So obviously, the market here is quite substantial, $1.1 billion currently, growing to $5 billion by all estimates over the next 3-5 years, and then additional upside into additional therapeutic indications, as I've described, with 35 patients in Europe, U.S., and Japan. So let's talk about a new drug that we've discovered. So when we initially ran our screens for skeletal muscle modulators, we had a counter screen to actually say: How selective were my skeletal muscle molecules? This came out of that counter screen, and initially, we saw that these molecules coming out of the screen were highly selective, highly potent on cardiac tissue, and had a wide therapeutic index, even with the initial 50 molecules that we had made. So that's EDG-7500. So hypertrophic cardiomyopathy is the target disease that we're going after, is a disease that's the most common inherited heart disease in the world. It's found in 1 in 200-500 people. Many patients are asymptomatic, but they often progress later in their lifespan to a true symptomatic disease. So what's going on in hypertrophic cardiomyopathy? As you can see, the ventricle wall on the right side is enlarged and enhanced, and in obstructive HCM, that bulge you see actually leads to a gradient across that individual channel, and that leads to a loss of oxygenation of the body because the flow is actually impeded... and ultimately that leads to a patient having fatigue, loss of endurance, it's you know really a poor quality of life. Now, in non-obstructive HCM, what you see is, and this is a hallmark of the disease, is that the left ventricle is very stiff and cannot relax sufficiently to fill the left ventricle and allow the oxygenated blood to flow through the body. So two different diseases, two different endpoints, but really one underlying mechanism of the relaxation of the ventricle and the increased thickness of the heart leads to poor function in the heart. So there's a new drug out on the market called mavacamten, that has been highly effective and is approved for hypertrophic cardiomyopathy, obstructive form of it, but there is still efficacy left on the table. 40% of the patients do not have a significant gradient relief that is clinically meaningful, and 35% of the patients do not have a one-point change in New York Heart Association, both of which means that there are patients who are untreated. Now, the other really significant consideration here is that mavacamten has what's called a REMS. Now, a REMS is a defined strategy for dosing to eliminate a significant side effect of cardiac myosin inhibitors, which is called essentially decreased ejection fraction below a threshold, and that will have a negative effect on the patients. So that REMS impedes the ability of patients to dose up and impedes the efficacy of the drugs, ultimately. So what does EDG-7500 do? 7500 slows the rate of contraction velocity, it accelerates the rate of relaxation, and normalizes the impaired cardiac relaxation observed in hypertrophic cardiomyopathy. So what does that mean? We are projecting that we'll have a higher therapeutic index, and instead of needing to do a titration with echo, which is long and arduous, we can use fixed-dose treatment of these patients and provide the same benefit. Now, because of our mechanism, I think we can drive higher concentrations, higher levels of target engagement, and see better efficacy than the CMIs. So both the effect on relaxation, driving to greater efficacy in a broader population, and eliminating the REMS would be our goal for 7500. So how does this work? Really cool video. You have the lever arm crawling along the actin filament, which is the yellow part on the top. You can see that in normal patients, you have a certain number of these ATPases, the little blue head, bound to the actin filament as the muscle is contracting. In HCM, you have too many of these heads associated with that, with that actin filament, and what the CMIs do is that they move the heads off the actin filament and block that contraction. Now, with CMIs, though, this is really an on/off switch, so there's no toggle at all. It's just on or it's off. That means when you lower gradient, you lower ejection fraction, which means you have a direct link and a very narrow TI, mechanistically, because of the, of the drug. What do we do? We affect the rate in which the actin filament, is interacted with the ATPase. That rate constant change allows us to have better control of the contraction, and that improved control leads to a better TI. So how have we tested this preclinically? We've looked biochemically, we've looked in dog models to look at the compliance within normal dogs. We've also tested the drug in multiple disease models of obstructive and non-obstructive HCM. What we saw in the cat model of obstructive HCM was a 66% decline in gradient, while we saw virtually no change in ejection fraction. As a comparator with a CMI, you'd see a 20% or 30% or 40% change of ejection fraction. This is just a single dose. And in the non-obstructive HCM studies, we saw a decrease from an abnormally high ejection fraction of 11%. We saw an increase in the relaxation rate, and relaxation is improved in the heart of the non-obstructive pig. This is a genetic model of non-obstructive HCM. We see a wall thickness decrease, pointing to the role in remodeling of the heart, and we see the left atrium, which is also often enhanced in the heart of these pigs, decrease in size. So exciting data. This all occurs with a single dose of the drug. So we are in a phase I study. We've completed the single ascending dose portion of the study. We're moving into multiple ascending dose portion of the study. We'll have data sometime in the third quarter, which will include the SAD, MAD, normal healthy volunteers and three cohorts, so three different doses in of three patients in obstructive HCM, where we should see changes in gradient relative to changes in concentration and the effect on ejection fraction. And we would hope to see that we would see minimal effect on ejection fraction and dramatic effects on gradients. Follow that with a 28-day study and ultimately in non-obstructive and obstructive patients, and ultimately an open label where we can treat patients indefinitely through 25. So we think that, you know, just having a novel mechanism in this space is important. Now, we think we can compete directly with the CMIs, but having a novel mechanism, you know the progression. In a new therapeutic indication, you have the first generation, you have the second generation, and then you have novel mechanisms that are improvements over the original mechanisms in a growing market, of, you know, perhaps several hundred thousand patients. So we're really excited about this opportunity and this drug. So we are very well-financed, $290 million in the bank. We have money through 2026 to execute on all the milestones I've described. And again, just to reiterate, and I wanna give Tessa some time to ask for some questions, we'll have data, LYNX Duchenne data in the first half. We'll be able to use that data to design a phase III trial, talk to the agency, get that rolling. We have ARCH data and phase II DUNE data the first half, and we'll have this key pivotal data in CANYON, which is the first controlled Becker data that has ever been done. And we'll have the phase I data from 7500 showing differentiation from the CMIs. With that, thank you all, and appreciate your time. Great. Thank you, Kevin, for the presentation. So I thought I would start the conversation here on LYNX. What learnings would you like to ultimately come away with at the conclusion of LYNX in anticipation of a possible phase III trial here? And are you able to give us a little sense of how you might present these data to everyone? Yeah ... in the first half year, and- Yeah, so it's, I think it's we have placebo patients, so every cohort has its own three placebos. Yeah. Certainly, we could take a cohort relative to the placebos. Now, the complexity here is we're treating 4-9-year-olds. Yeah. I think what it'll do is provide a broad swath of the biomarkers- Yeah ... in a placebo group relative to a dose of our drug, a concentration of the drug, and the effect on the biomarker. So this study is really driven to find the right dose for phase III. And what do we believe is the right dose? The right dose is where we have high levels of target engagement- Mm-hmm ... meaning we're looking for TNNI2 to decrease dramatically. Mm-hmm. We think we should be able to drive it down to 80% decrease, because we saw that in Becker, and that would be that knowledge would give us that we have fully saturated fast muscle in a way that has completely blocked the damage due to the fast muscle. Mm-hmm. Now, CK is a rather nonspecific muscle damage biomarker. It's highly variable. We would expect some change. We would expect at least 40%. Mm-hmm. I don't know how much lower you might go, but I think that's how we've always think of as the base case. Okay. That dose where we see an 80% change with two consecutive doses- Mm ... would mean that we've fully saturated that target. Kevin, sometimes we get the question on LYNX. You've evolved the trial design a little bit since it started. Maybe you could just orient the listeners to why that happened. Yeah. So we first, two things: One, we started low because we went into a pediatric population. Yeah. And second, we were asked by the agency to find a highest tolerated dose, in fact, twice. So we tended to like to do what the FDA asks, and so they wanted us to continue to dose up until we identify some adverse event. Yeah ... that would keep us from continuing to dose. We did not do that in the Becker patients. We wanted to get rolling and fast, and we had already knocked that biomarker. So we used the biomarker to decide when to turn into phase II and phase III. The agency asked us, "Continue to dose. I wanna see what happens. I wanna see what the therapeutic window is in a peds population," which, perhaps, is expected or could be expected. Okay. And then you can get an understanding of the minimally effective dose in a more granular way. Okay. And what underpinned your decision now to initiate the FOX trial in children and adolescents previously treated with gene therapy? I have to say that the outpouring from the patient advocacy groups and the parents of the patients, they recognized that their child was progressing, and there was no treatment for these patients. Our KOLs and our SAB allowed us to interact with many of these patients, ultimately, and we felt that it was really our role to be able to test our drug in this population. It was a very well-tolerated drug. Mm-hmm. I think it could provide benefit. We knew that the biomarkers were elevated- Mm-hmm ... in many of these gene therapy patients, and we thought we could help these patients, and I think that, I think it's the right thing to do. I was hoping we could turn the conversation and talk a little bit about Becker's. You know, you talked a little bit about the CANYON design. Can we, can we just review how CANYON is powered around CK, which I think is the primary endpoint?... for the phase II portion of the study. And is it possible that you could hit stat sig on NSAA over 12 months, or do you think you really need that longer treatment duration? So one of the key points of NSAA, and it's been a lot very controversial in the Duchenne population. Now, getting 4- to 7-year-olds to follow a, you know, instructions for the NSAA is challenging. Yeah. The NSAA in Becker, actually, adults are quite good at doing the NSAA. So it turns out that the variability of the Becker measurement and the NSAA in Becker is much smaller. Mm-hmm. So I think a key aspect of that is that we think that it is possible to hit if we had, say, a 1.5-2-point change in North Star in Becker, we could hit stat sig, right? But the trial was not designed for that. It was designed around the CK endpoint. And from our previous data of baselines relative to the rapid change in CK we see, we believe that we can hit statistical significance with CK and even at a greater level with the TNNI2. So So I think there's a strong possibility that we'll have statistical significant benefit on the biomarker endpoints, and I think we have a shot at statistical significance on things like North Star and other time function tests. Mm-hmm. But that's not the base case. We think a strong trend coupled with things like MRI, and we've already seen effects on pain in these patients, so the patients literally tell us they feel better. So we've actually put in an exit interview sort of apparatus to say: "How did you feel on your drug? Did this make you feel better? Do you have pain?" All of these things that are really quality-of-life measures to go along with a discussion with the FDA of, you know, why shouldn't these patients get this drug? Because it's safe, there's a high unmet medical need. And the bar, as you know, moves around in that division. Yes. Yeah. Are there any questions from the audience? I'd love to ask a market dynamics question here, and how you might compare and contrast potential commercial dynamics for 5506 in Becker's and then DMD. It seems like we have kind of two different landscapes here. How would you kind of characterize those? Well, you know, I think Becker is an under appreciated market, and I, I spoke a little bit about the Friedreich's ataxia market and how the uptake of those drugs has been dramatic. Yeah. It's literally the same market, same number of patients. Yeah. Becker in itself, in some respects, the regulatory bar is lower because there is no treatment. So I think every Becker patient could benefit from our drug. Mm. So even though the population is smaller, more patients can benefit, and they will be on it longer. So from our calculations and our research, the Becker market could be as large as the Duchenne market. Mm-hmm. Great. In the epidemiology there, Kevin, it's pretty well known, right? Particularly in the U.S., but maybe you could just orient us to how you're thinking about BMD epi. Across the world? So it really is, there's no difference from different parts of the world, but certainly in Japan, it's a significant unmet medical need, and there is no therapy across the world in Becker. So we believe that an approval in Becker would be very advantageous. And, you know, there is, I mean, I guess you could argue also, and this is maybe a little more speculative, that every Duchenne patient treated with a gene therapy is a Becker patient. Yeah. So that's a little more speculative as to whether, you know, you could, you could convince the regulatory agencies that these are now merging into a new population of Becker, but that could be an entry point. Mm-hmm. coupled with, say, our data from FOX. Mm-hmm. So if we had benefit in FOX, we had benefit in Becker, I think we should be able to treat all those patients. But again, all these things are negotiations. Does it make sense maybe to talk a little bit about EDG-7500? And you framed out really nicely the mechanism for us in your presentation and also the trial design. But maybe you can just frame what the key objectives you think you might be able to accomplish in that 3Q, it seems like, readout, versus 2025, if I'm not mistaken. Mm-hmm, mm-hmm. Like, how you see the cadence of data flow for that program, because I think that investors may be a little bit newer- Mm. to that part of the story. Yeah. Yeah. Yeah. So, we'll use the SAD/MAD to look at the safety parameters in the AE profile. That'll give us an idea of where to start within the obstructive HCM patients. So, what we did a lot of research on was that, mavacamten ran a single-dose study in HCM patients. Mm-hmm. Two of those patients had obstructive HCM. What they saw with a single dose was a decrease in gradient, 40%-60%, but at the same time, they saw a decrease in the ejection fraction of greater than 20%. Now, as you saw with our preclinical data, you saw that we had a 60%+ decrease and essentially zero effect on ejection fraction. So the data set of the safety of the drug over 100 patients in normal, healthy volunteers, plus nine patients' dose range and obstruction, should it was really the fastest way we could show differentiation in the obstructive HCM market. And then within that same protocol, we've added a 28-day study, which is, we're restricted by the amount of tox coverage we have for the moment, a 28-day study in obstructive patients and a 28-day study in non-obstructive patients. So how we thought through this is that once we get a solid dosage form so the patients can take their drug home, we'll provide the drug for 28 days. They'll flip onto an open label, and now, not only can you get data at steady state with the drug, but now you can start looking at the biomarker data, a proBNP, other biomarkers, and also looking at changes in New York Heart Association over an eight-12-week period. So we'll have, I think, essentially a constant data flow- Mm. of 10-20 patients in two different populations of HCM, looking at de-risking the drug over and over again in these populations. So 2025 will also be a really exciting year for data flow as we get the phase II s rolling sometime probably the second quarter of 2025. So there's a long-term kind of vision of how to rapidly move this molecule forward in the HCM population. Now, a key exciting, really exciting point about that molecule is the diastolic effect. So this relaxation effect of the drug is unique to the drug. Mm-hmm. There are multiple indications where the diastolic dysfunction is driving the disease. Yeah. This is particularly in non-obstructive HCM, but also certain populations of heart failure, like HFpEF. So being able to demonstrate that relaxation effect of the drug would take us into many other directions, which may expand our trial strategy, because some of these therapeutic indications are much larger- Yeah ... than the HCM market. Yep. Yeah. But stay tuned. That, something is probably gonna come out of the non-obstructive data. Okay. I think we might need to leave it there. Thank you so much, Kevin, and the Edgewise team for being here. We really appreciate it, and thank you for everyone for joining. Thank you.