Good afternoon, everybody. This is Kristen Kluska from the Cantor Biotech team. I'm joined with my colleagues Josh Schimmer and Rick Miller, and we're very happy to be hosting Edgewise Therapeutics for the next session. I'm joined by Kevin Koch, the President and CEO, and Behrad Derakhshan, the Chief Business Officer. Thank you both so much for joining us today. Thank you, guys. Thanks for having us. Thanks for talking to us. Yep. So as part of our Cantor Muscular Dystrophy Symposium, we've asked each team to address the key theme in their discussion. And for the Edgewise team, the theme is the DMD space seems focused on replacing dystrophin. So why should the focus be preventing contraction-induced muscle injury? That's key in Becker and DMD. So to get started with that theme, maybe we can just talk about some background information. I think first it would be helpful to understand what specifically happens in a muscle fiber that allows for contraction. It really does seem like such a simple process on the surface, but what does it really look like from inside the cell to achieve muscle contraction, and how do motor proteins such as myosin help with the process? Okay, great. No, I love to take that question. I mean, it's really an innovative approach to how we might treat muscular dystrophy. You have to go back to the basics of what is driving the damage in muscular dystrophy and the loss of muscle. So people think in muscular dystrophy, dystrophin is a key structural protein that cross-links to the muscle. If you're missing that protein, you have Duchenne muscular dystrophy, which is a much more aggressive form of the disease. You have Becker muscular dystrophy. You have some amount of truncated dystrophin that also helps with the disease progression. So they tend to lose ambulation in their 30s and 40s. A key aspect of what dystrophin does is dystrophin cross-links the bundle of fibers, the muscle fibers, and as it moves, it moves in unison. And in that way, the muscle is protected when you have a contraction. Now, when a normal person overworks their muscle, you'll hyper-contract certain fibers within that muscle. And what that will cause is damage to the muscle, even if you have dystrophin. Now, that you feel that the next day as soreness in your muscle. So when you wake up the next day, you've worked out too hard and you're sore, that's from fast muscle fibers being damaged. So let's dig into the actual biology of what's going on. So that hyper-contracted muscle and the contractile process is one where you have ATPases, the myosin heavy chain, interacting with the actin filament. And the more ATPases you have attached to the actin filament, the greater the level of contraction. And so how does the muscle actually contract? That ATPase binds ATP, turns over ATP to ADP, generates energy, causes the contraction, which drives that effect. So we're interacting with that ATPase and blocking that effect. So we fundamentally block the contraction. Now, you only really want to block the contraction in the hyper-contracted fibers. The hyper-contracted fibers are the ones that break, not after normal contraction. But there are more ATPase heads on that hyper-contracted target. So our drug selectively interacts with those hyper-contracted fibers, protects those fibers, and blocks the damage. So why is that important? As you probably know, a muscle damage precedes loss of muscle fibers and loss of function. So maybe thinking about the disease etiology in Duchenne, patients are typically not diagnosed until they're 3 or 4 years of age, yet they have 0 dystrophin. So if dystrophin was important for the function of the muscle, how can a child walk if they have no dystrophin? So the dystrophin is not important for the function of the muscle. It's important to keep the muscle from being damaged. So what we should be measuring when you replace dystrophin is not. You should be measuring the muscle damage that occurs, and are you inhibiting the muscle damage? Because the muscle damage leads to an aberrant regenerative response, which ultimately replaces the normal muscle with fibrotic and fatty tissue. Then the patient loses function. So if you target muscle damage as we're targeting with our myosin type II ATPase inhibitor, that is fundamentally blocking the disease driver and ultimately going to be disease-modifying in the progression of the disease. Kevin, can I ask a quick clarifying question about that dynamic? You kind of described the difference between healthy individuals who exercise and patients with muscular dystrophy and the fiber damage. But in one context, the muscle stem cells help give rise to more muscle fibers, stronger muscles, and bulk in the healthy situation. Whereas in the Duchenne situation, when those muscle cells are dying, are the muscle stem cells just not doing the same job? Are they being overwhelmed? Why is there a difference in the end result? I think it's an interesting question because some amount of activity, so to speak, and exercise, even in a Duchenne population or a Becker population, has been shown to have some benefit. But I think it has to do with the rate of damage relative to the rate of the regenerative response. Now, you can see that if you do and we've done this already in the Becker population. You can see this by looking at a proteomic profile of a patient. And the patients have a change in their metabolic processes that both are inflammatory but also are related to fibrotic responses and essentially fat responses. So you're changing the nature of the regenerative response. And I think it's very similar to if you think about other fibrotic diseases. So if you think of IPF, you think of constant insults and a flaw in the regenerative response to generate fibrotic tissue in IPF. The same is for scleroderma. You might argue the same is for NASH and some other diseases. Here, you have a genetic defect that constantly drives a damage response. And that genetic defect is what's the driver. But the response to that genetic damage is almost identical. And you get the same biological process coming out the other end. So essentially, we're fibrosis of the muscle for all intents and purposes. Got it. Thank it. Thank you. Well, thanks for that interesting background. I guess, can we talk a little bit more specifically when you think about the different forms with DMD and Becker muscular dystrophy, specifically at the difference of the level of the muscle fiber and contraction? And how does that correspond to the differences in the different muscle injury between the two forms of the diseases? Yeah. So the muscle fiber is segmented into different, call them, substructures separated by the Z disk. And you can have populations of small dystrophins, truncated dystrophins, spread out between these muscle fibers. And that provides a partial protection. And so in Becker muscular dystrophy, that partial protection leads to a slower damage response, less intense damage. And ultimately, the counterresponse to regenerate the muscle is not overcome as quickly. And so you can measure this preclinically or clinically by looking at biomarkers like creatine kinase, TNNI2, myoglobin, myosin basic protein. The actual turnover of the muscle is lower in a Becker patient. In a Duchenne patient, since they have no dystrophin, that turnover of the muscle is more aggressive. That leads to these biomarkers being higher. So the best known of these biomarkers is creatine kinase. That's the first biomarker that often diagnoses a patient. So what you might see in a patient is that the parent might notice that they're walking when they're 16 months instead of 12 months. They'll go to the doctor, and they'll say. They'll do a test, and they'll see very high creatine kinases. That leads to a genetic test. Now, many parents never even notice that the kid is doing anything different. Oftentimes, the doctor says, "You know, they'll grow out of it." That's a very common theme because of the wide range of ambulation in children. Sometimes they wait then to 3 and 4 years of age. Now you end up with what's called Gower syndrome, which is a noticeable diminishment of the ability to walk. That's when they'll go in and get another CK and another test. So it's really the muscle turnover is driving the rate of the disease. Really interesting concept here. So, creatine kinase that it's highest at one or two years of age, that's when a child begins to walk, and they're putting stress on their quadriceps, which is the first muscle that is actually decreased in a Duchenne patient. Now, a Becker patient is typically diagnosed in their adolescence, typically 14 to 15 years of age. They can't perform at the same level as their peers. They go in for testing. They'll have CKs kind of 4,000. At one or two years of age with a Duchenne, they have CKs of 20,000. So it's a substantial difference. Interestingly, the younger patients with Becker who are diagnosed between five and 10 years of age, they have an intermediate level of these biomarkers. So their biomarkers are in the 10,000-15,000 range. Interestingly, those patients with Becker will lose ambulation in their late 20s. So the damage to the muscle precedes the ultimate loss of muscle and the ultimate progression and the rate of the progression of the disease. Now, looking at this on a year-by-year basis, it's very difficult to ascertain the exact biomarker level relative to an exact disease progression. But you can see when you group them, you can see the rate is very consistent, that more muscle damage leads to more loss of function. I think there's an important piece to your question, Kristen, which really kind of and I know we're going to get to this is around what is the therapeutic goal of some of the options that are out there right now, right? I think the point that Kevin makes around a Becker patient having a truncated form of dystrophin consistently across all of their muscle fibers is very important from a therapeutic standpoint as you think about what some of the gene therapies are trying to achieve with a microdystrophin, right? So ideally, what a perfect microdystrophin is aiming to do is create a new population of Becker patients because a lot of the constructs one of the more prominent constructs was based on a mutation that was found in a Becker patient that lived into their 60s. Now, if you ideally express 100% microdystrophin in every single fiber, you might be able to revert the phenotype to a Becker. But that's not what's happening. And I think what you see from some of the data that's out there, as recently as last year's MDA, you're not getting uniform expression. You're getting chimeric muscles that have different levels of dystrophin expressed at different points. And that's actually a problem because over time, you're not getting that consistency. You're getting a muscle that's under stress at different points along the fiber. So that's an interesting point as you think about the therapeutic landscape and what they're trying to achieve. Okay. Thank you for all of that background. I think this is a good opportunity to second to some of your programs and how you're looking to address some of these items. So first on EDG-5506, it's a myosin type II inhibitor. How does this molecule fit into the damage that is constantly occurring with muscle contraction in these patients? And how does it prevent it? Well, so it's highly selective. So going back to the basics, there's two major types of skeletal muscle: fast skeletal muscle and slow skeletal muscle. And the designation for which one is driven by the primary sequence of the myosin heavy chain of the ATPase. And so the fast myosin fibers are bucketed by themselves based on the myosin heavy chain primary sequence. So the architecture of the fast skeletal muscle versus the slow skeletal muscle is interesting. The fast skeletal muscle is, I would call it, your adaptive response to an environmental challenge. The Z disk, which is the disk that holds these fibers together, is actually more narrow in a fast skeletal fiber. And that tends to disrupt faster where the slow skeletal muscle is more resilient. So what we saw from the original papers and actually the original idea to go out and try and develop a drug against this target was that in patients with Duchenne, you could look at biopsies of these patients, this is data back from the 1980s, that the biopsies, the embryonic form of myosin heavy chain, which is associated with regeneration of the fiber, is associated with the fast muscle fiber and not the slow muscle fiber. We then actually published our own work, among other people that published the same thing, that you could see a differential effect in biomarkers like troponin I2 that are associated with the damage in the fast muscle is preceding and much more aggressive than the damage in the slow muscle fibers. And so by targeting the fast muscle myosin, you selectively interact with the part of the fiber that's degenerating more aggressively. By protecting that fiber, you would protect the entire microenvironment and the overall damage to the muscle. Okay. Thank you. There's a lot of variability in the Becker muscular dystrophy population. Some patients can even walk late into adulthood. What specific population did you look at in the open-label ARCH trial? And what would expected outcomes look like over the study period in natural history? Rod, why don't you take that one? Can't do it? Okay. I'll take it. Yeah. So there's been now actually a third natural history study that has come out. So the first two, the first one came out from Bello in 2016 in Nature Communications. And then a second came out from Niks more recently. And then a third, a Belgian group, just published another paper on this. And Bello, obviously, is the first one. It's longer. They have now 5 and 6 and 7-year data. Niks has, I think, 3 and 4-year data now. And this last paper was 2-year data in Becker patients. Overall, though, the same theme came out of each one of these natural history papers is that patients end up they'll go along for a period of time, and they won't decline aggressively. But there'll be a certain level of muscle damage that they get to, and they're no longer able to compensate with their other muscles. At that point, the patients begin a rather homogeneous decline in measures like North Star over a period of time. Now, that across the three studies is now more than it's actually the last study showed even a greater decline. But let's just put it in perspective that across these three studies, it's been at least a 1.2-point decline in North Star across these three studies from three separate studies from three different academic centers, all using North Star. Now, the key to this historical data is that you look at Duchenne data back from 15 and 20 years ago. There was not a standardized way of measuring things like the North Star. There's now a group called ATOM, which actually trains the people specifically to objectively measure the North Star. So that is some of the work that our work is based on, I would call it, higher quality data because the data has been controlled in a much more specific way because of the training of the physical therapists who are doing this. The other thing that's very important about the North Star to think about, North Star is an effective measure of function, but you have to apply it to the right population. Now, North Star, just to give a highlight of what it looks like as a way of measuring functional response, is 17 separate activities measuring 0, 1, or 2. 0, I can't do it. 1, I can partially do it. 2, I can completely do it like a normal person. Now, as you might imagine, taking a 4 or 5 or 6 year-old and getting them to repetitively do 17 activities at one setting is probably a challenging thing to do. Now, if you take that same measure and you ask an adult to do that measure, they would be much more reproducible. And what we found is that we have a much smaller standard deviation of the measurement of the North Star within the adult population. You also can see in Duchenne that patients that were measured between 7 and 15, Elevidys was recently approved, they also had a statistically significant effect on North Star. So North Star is a very good measure for adults in certain populations in Duchenne. And I think we've chosen that as our primary endpoint for our further trials in Becker. We think we have very strong natural history to support that the patients who begin to decline, and we've selected patients with a North Star between 5 and 32 based on the historical data, we think they will decline in an essentially homogeneous way of 1.2 points per year. When we put out ARCH data, which will be our 24-month data coming out this quarter in our Open Label Becker study, you should note those patients should have declined by 2.4 points over a 2-year time frame. So a couple of points now that I'm able to unmute. One is that Kevin's absolutely right. I think one of the things that was quite staggering to us when we kind of embarked on this journey with 5506 was just there was no one really developing drugs in Becker. And so we wondered, what's going on? Why hasn't anyone looked at Becker before? Because if you want to draw a parallel to another kind of muscle or rare disease, it's very comparable to Friedreich's ataxia: age of onset, time to loss of ambulation, ultimate cause of morbidity, mortality. And so the reason was because of what Kevin pointed out is the lack of natural history. And that's really enriched over the last three years, which has allowed us to capture that data and really power a study to show a benefit in North Star. As it relates to kind of North Star and Duchenne, just to add something to Kevin's point is there's no approved therapies in Becker. So the data you get isn't confounded by a background of medications that these individuals would be on otherwise. Duchenne kids, as you know, they receive steroids from a very young age, as early as three years old, four years old. So when you're looking at the natural history of Duchenne kids and you're thinking about why is North Star so noisy in that Duchenne population from some of the recent readouts, it's because you've got a bunch of kids, as Kevin pointed out, are naturally improving in their North Star anyway. And then you've thrown a steroid at different doses, different regimens, and different durations, which further confounds kind of the measurement of a North Star in a child. I think that's why we feel like Becker is just a cleaner population in order to measure North Star when you're looking for a therapeutic such as ours in that space. We just should add academic centers. Isn't there always this question of single-site data, and is that really the highest quality data? What really gave us a lot of confidence is now we've measured. We do a baseline and a screening for each one of the North Star measures for our Becker patients, both adolescents and adults. And what we found is we confirmed that this standard deviation of the measure of the North Star is very consistent to what was reported in the academic papers. So we're confident that this is relevant. And of course, that allows you to power the study very effectively and then knowing the standard deviation. Given the mechanism, would you expect a reduction in contractile force? And if so, is that even something that would manifest on the North Star assessment? It probably wouldn't manifest in the North Star. The most sensitive test is probably at grip strength. The grip strengths, the patient actually can't it doesn't actually notice the change in small changes in grip strength. So it's a quantitative measure, yet there's very little noticed by the patient. Part of this is that you have so much muscle, you're only using 40% or 50% of your muscle even during a level of exertion because full utilization of muscle is a cramp. So you have a wide range of utilization of muscle. When you want to increase force in your muscle, you increase the stimulation. So you can compensate for that loss. So what you're really trying to do is even out these hypercontracted fibers, which tend to have more target engagement. And then by targeting that myosin on these hypercontracted fibers, you can affect the damage response without affecting the actual function of the muscle. Thank you. To follow up from there, how did the biomarker changes you saw in the ARCH trial give you some confidence that you were actually seeing reduced muscle damage? Yeah. So we focus a lot on TNNI2 because TNNI2 is very, very low, below the limit of our assay's detection in a normal patient. And it's elevated in the Becker patients. And we saw half the patients, half of the 12, go down below normal, so essentially below the limit of detection. And the overall decrease in TNNI2 was 80%. Now, why do we think that's important? During the ARCH study, we studied doses of 10 mg, 15 mg, and 20 mg. And the first dose was 10, which was based on some of the normal healthy volunteer data we had. And we looked across the entire year. And that first two-month interval, the 10 mg drove the biomarkers down to the same extent as it had driven it down at 20 mg. So we felt like even the initial dose was enough to get full target engagement. Now, we don't need to have additional target engagement because we really want to block that response without additionally blocking the muscle contraction. So we felt that was enough drug to actually test the therapeutic hypothesis. Great. And based on the ARCH data, you ended up moving into the Grand Canyon trial, which has undergone some amendments to be potentially pivotal. What is the rationale with the Grand Canyon trial, and what endpoints will you be looking at that could potentially support filing? Yeah. So it's a little complicated. So what we did was we spoke with the agency. What we had going last year was a phase 2 dose ranging study called Canyon. What we did in conversations with the agency was to split that study into two studies. One was Canyon, which is a phase 2, 40 patients, 3:1 randomization for 1 year with biomarkers as the primary endpoint. The second study was Grand Canyon, which is essentially replicating the phase 2 Canyon in Grand Canyon. That study is 120 patients, 2:1 randomization with North Star as the primary. So a couple of things that the agency really was keen on. One was to have 2 controlled studies. Second was to have a single dose. So we chose selected 10 mgs because we thought we had had maximal target engagement with that dose. Then a key aspect of this is to try to complete Grand Canyon, which would be the confirmatory study, at the same time as completing Canyon. Canyon itself, the 40-patient randomized controlled study for a year, will read out at the end of this year. What we anticipate is being able to fully recruit Grand Canyon by the end of this year. By the time we would be interested in filing Canyon as a study, we would be fully recruited in Grand Canyon. I think there was even a recent discussion point on someone else's drug where they hadn't completely recruited their confirmatory study. I think it is becoming perhaps a hard-and-fast rule at the FDA that please get this confirmatory study up and running before you file for an accelerated approval. Now, what we would do with Canyon is we expect to see statistical significance on the biomarker. We expect to see a trend towards functional benefit in these patients and a trend in the PROs and by MRI. So the trial is not powered for North Star. But obviously, if it hit on North Star, we think it would be a fully approvable study. We think that the preponderance of evidence and the lacking of any therapy within the Becker population might give us an opportunity to go to the agency and have a discussion with them about this study because we have the Grand Canyon already fully enrolled. So I mean, it's an aggressive approach. There's no harm in going to the agency with having that discussion. The Canyon study should allow us to perhaps more precisely with the analysis set of Grand Canyon, perhaps there's a certain group within Canyon that responds more effectively or some other aspect of Grand Canyon that we can modify to actually make it a more successful trial. There's lots of things we can do. I think a big readout by the end of the year will be Canyon because it'll really dictate and directionally show us we're on the right track for an approval. Yeah. As a base case, it fundamentally de-risks 5506 and Becker coming out of Grand Canyon. So you're going to get a readout that will really have direct read-through into what Grand Canyon might show. So to Kevin's point, you might look at that data and say, "Man, if they'd have had a higher end or run that trial for 18 months instead of 12 months, they would have knocked it out the park in terms of stats." So I think that's the beauty of the way we've kind of structured the Canyon-Grand Canyon duo. Okay. I know we just have a couple of minutes left, so I do want to make sure we can talk about some of your efforts in DMD as well. You have the Lynx trial, which is including patients on steroids, non-steroids, and different dystrophin therapies. So how do you believe that the 5506 mechanism fits into the different backgrounds? And how might you expect to see differences amongst these different subsets as well? So thinking about our mechanism, we're independent of dystrophin level. We're independent of individual mutations. So we're agnostic of that. We interact with a target that's found in all fast muscle. So I think what we wanted to do was set ourselves up to be in a position to say that Duchenne and Becker are a continuum. And even the companies with dystrophin therapies are saying they're turning their patients into Becker. So if we were to have a Becker approval and you've treated your Duchenne patient with a gene therapy, well, now they're a Becker. Why wouldn't our label say, "Patients who have been treated with gene therapy are now Becker patients. We should treat them"? And oh, by the way, there is no other treatment. So I think you could argue with a straight face that exon skippers and gene therapies create Becker patients, and we should treat those patients with our drug because it doesn't matter how much dystrophin they have. They all could benefit. So we wanted to be able to make that case. We will have started FOX, which is our gene therapy previously treated patients. It's always great to treat patients who are naive to steroid, which is standard of care because single-agent data always isolates the effect of your drug. So I'd like to see the same biomarker response in patients who are steroid naive. And of course, we would study the patients who are on a background of steroid and exon skippers because that's really standard of care today. We've hit all three buckets of patients that exist in Duchenne, and we want to show benefit in all three of those patient populations. Okay. Thanks. I just have one question left. But Josh, Rick wanted to see if you had anything first. Nope. Go ahead. This is very helpful. Okay. Yeah. So I think, look, it's clearly a big year for the company. So maybe can you help frame for us what you're looking forward to the most this year? And then again, this is a muscular dystrophy symposium, and I know you're starting to think about the mid to long-term projections as well. So would love to also hear kind of how you're using this platform to think beyond the current pipeline, for example, the cardiomyopathy space as well. Thank you. Yeah. No. So it's a big year. The second quarter, certainly the ARCH data, the 24-month data will be exciting to see, and the initial Lynx data because people would like to see the translation of the Becker data into a DMD population. I think at the end of the year, obviously, with the Becker phase 2 readouts, controlled studies always drive a lot of enthusiasm. And now, a very exciting program that came out of our original high-throughput screens in skeletal muscle biology turned out to be our cardiovascular asset. And this asset is a sarcomere modulator that would affect disease populations like hypertrophic cardiomyopathy, but because of the biology we've seen, also could be expanded into other diseases of diastolic dysfunction. And so that will read out in the third quarter. I think there's a lot of enthusiasm for that asset. We've shown some really exciting data pre-clinically to date. We'll have additional very exciting chronic pig data coming out at ACC. And so that's another thing to map on the calendar or something that would be value-creating for the company. Awesome. Well, thank you so much. Lots to look forward to here, and we really appreciate all of your insights. Thank you, guys. It's been a great discussion. Really appreciate it.