Welcome everyone. My name is Pat Cusick. I'm the Account Director with the Health Partnerships Team here at the Muscular Dystrophy Association. I want to thank you all for joining us today for the MDA Industry Update webinar sponsored by Edgewise Therapeutics, titled "A Novel Approach Designed to Protect Muscle in Becker Muscular Dystrophy." On behalf of MDA, we'd like to also thank you for all you do for MDA and the neuromuscular community. MDA's Industry Update webinars are programs which provide an opportunity for the medical community to receive information and updates impacting care and treatment directly from pharmaceutical and biotechnology companies. These webinars are just part of MDA's medical education resources. We encourage you to visit the medical education pages at mda.org, and you'll find resources such as considerations for care, case studies, recorded Grand Rounds webinars, research grants, and so much more. Now, I'd like to introduce our presenters for today's webinar. First, we have Alan Russell, the Chief Scientific Officer with Edgewise Therapeutics, and Joanne Donovan, Chief Medical Officer with Edgewise Therapeutics. All right, and without any further ado, I will go ahead and turn it over to Alan. Alan, go ahead. Good morning, if it is your morning. Good afternoon, if it is your afternoon. And I guess we have a few evenings as well. If you go to the next slide, I'm going to do the science introduction, and then Joanne will take it off with the admittedly more interesting clinical section. So this is just our forward-looking statement. We're a public company, so we're obliged to put this up just to make really one observation that, of course, Sevasemten EDG-5506 is not approved in any jurisdiction. This is an experimental therapy, and as such, you know these results that we'll show you are provisional. If you go on to the next slide. So I'll do the introduction, as I mentioned. I'm going to talk to you about the mechanism of Sevasemten 5506 and how it relates to Becker muscular dystrophy. And then Joanne will take it up with data from our ARCH open- label study, which has now hit the two-year mark. And then we'll take some questions and answers. Hopefully, it'll be educational and you have some interesting questions. Okay, so I'm going to talk to you about contraction-induced injury. So Becker muscular dystrophy, as you all know, is caused by mutation of the dystrophin protein. So it's generally present but mutated. This is an in-frame deletion. There's no therapies for Becker muscular dystrophy. And as such, this is an adult myopathy that's often termed as mild, but really only mild in the context of how terrible Duchenne is. In and of itself, it's an unrelenting progressive neuromuscular disease that never improves, only really ever gets worse. Once you're starting to decline, that decline is irrevocable, and Joanne will tell you a little bit about that. That affects all aspects of these patients' lives, particularly independence and mobility, and health outcomes. Okay. What the problem is in Becker muscular dystrophy is when their muscles contract, they get injured. Okay, so what we have here on the left-hand side in the blue is a healthy muscle contracting. And what we've done here is illustrate the dystroglycan complexes. So these are the large complexes of protein that include dystrophin, but also a lot of other proteins. And the end product of that aggregate of proteins is it connects fibers together, and that's marked here in those blue connections. And the reason that connecting fibers together in muscle is important is that when one contracts, it's supported by the other ones. So not all muscles in, and not all fibers in muscles contract at the same time or to the same level. So we have a scenario here where that central fiber is contracting more than the other ones. And you can see how those blue connections help bring all those fibers together and support that contraction. Okay, now, when we do exercise, when we go to the gym, when we do any kind of activity, we have wear and tear of our muscles, and it's in fact how our muscle fibers adapt. You know, when we go to the gym, we're actually giving ourselves controlled injury, and that's how we improve our strength and overall muscle function. That's a totally normal part of physiology, and that repair process brings you back to a normal state. Now, in case of Becker, that contraction, unfortunately, is amplified. Those contractions, the blue links, are dysfunctional so that when a single muscle fiber contracts, it's less supported by the ones around it. That leads to this amplified contraction-induced injury response, so instead of a small subset of fibers being injured when you're active, a larger subset of fibers are injured, and that creates a problem with repair and adaptation. Right, so instead of you adapting in a positive way, you now adapt in a negative way, and the negative adaptation is inflammation and fibrosis, largely, and particularly in Becker, focal loss of the calf muscles in particular, your quads really get pounded in Becker, and they're replaced by fat and fibrosis, and that really limits ambulatory function, generally starting in the 20s to 30s. Go on to the next slide, so what's the goal of 5506? 5506 is a small molecule, once-a-day therapy, designed to inhibit fast skeletal muscle myosin, and that's illustrated there in that middle frame with the green circles. Right, so why would we want to do that? What we want to do is adjust the contraction of muscle fibers to a range that they can be accommodated rather than in the normal setting where they cannot be accommodated. So as you take sevasemten, what happens is it dials down the contraction of your fast muscle fibers, which are the ones that are really most susceptible to injury through this mechanism. And in doing so, when you have the compound on board and the muscles contract, now when they contract, they're not injured as much. Okay, so it's really just correcting that imbalance between how much the muscles can contract and how much they get injured, with our goal of dialing down that contraction so we minimize the injury associated with activity. And I have one data slide to illustrate that on the next one, I think. So what you're looking at here is actually a dystrophic muscle, an mdx muscle. On the left-hand side, this is contracting in a dish without the compound, and on the right-hand side, with a small concentration of the compound. And you can see on the left-hand side, as that muscle is contracting, it's getting stressed. Those individual fibers that are not getting supported are getting stressed, and that actually causes the initiation of a degradation pathway. And you can see that propagating by the emergence of these kind of dense blobs, which is really just snipped-up fibers. They've become stressed. It's activated proteolytic enzymes, and the poor thing is just degrading in real time as the muscle fiber is contracting. On the right-hand side, we've dialed that contraction down by 15%. So we've just really taken the top end of the contraction of that muscle and now adjusted the contractile performance of that muscle to a place that it can be accommodated. So this fiber is now contracting as if it had dystrophin. It doesn't get that stress response, and there's no breakdown of the fibers. So if we could achieve that in the limbs of a Becker person, right, you would change the relationship between how active they are and how much they're injured. And we believe that that would have long-term positive health benefits to these guys with Becker. Okay, now at this point, I'm going to hand it over to Joanne, and she'll tell you where we are in the clinic and where we're going. Great. Thanks, Alan. And so you're familiar with the North Star, because the real question, how do we measure disease progression in the clinic? It's really easy under the microscope to watch that muscle, but how are we going to do it in the clinic? And one of the measures that has been used in natural history studies is the North Star Ambulatory Assessment, of course, used classically in Duchenne. But this is a dystrophinopathy. The same type of measures of real-world activity are assessed. And the 17 measures that you look at and are scored, whether they can perform normally, get two points with compensation, or with one point or not at all, they really translate on the right to real-world events. Can you climb a stair? Can you stand on one leg to get dressed? Can you get to sitting? Those kinds of things that are important in daily life, and it spans a wide range of levels of function, so on the next slide, this shows the North Star Ambulatory Assessment in natural history of Becker. There have been three studies published in the last several years that look at how much of the North Star is lost per year, and you can see that whether the interval of observation has been a year, nine months, up to five years, you see that for those that have at least started to lose function, so our 32, so they've lost a couple of points in North Star. Once they start to do that, they continue to lose additional functions, and so we are looking at that group of patients in our clinical studies to look at the patients that are already progressing, and we quantitated that on the next slide. We looked at the baseline function in patients that were in our studies. We had 80 patients, and we looked at them by baseline scores. We know from that kind of progress that I showed you on the previous slide that it takes five to eight years to go from the 30s to the 20s to the 10s to the teens in terms of your North Star score. So what does that mean for an individual? And I think that's one thing that your patients sometimes have a hard time understanding. What is the progress of the disease? What is the future, frankly? And can I just stay at this level? And that's not what we see in the natural history. So on the next slide, it shows you some of the different what patients look at at different levels. If they have a North Star in the 30s, the dark blue are functions that are lost. The light blue are compensated for, so they start to have trouble rising from the floor with a North Star in their 30s. When it falls to the 20s, then they're compensating in a lot of different functions, rising from a chair, pushing up with arms, being able to climb a step. Everybody is having trouble rising from the floor, and they're having trouble running, being able to clear both feet. After another eight years or so, now you're starting to go from compensating to losing function, so they're starting to lose those functions that they were compensating for when their North Star was 10 points higher. Climbing a stair, being able to get up if they fall, hopping, less important, but at the same time, it goes to being able to stand on one leg, for example. And then with a North Star in the single digits, a lot of the functions have been lost, unfortunately. So in our clinical development program in ARCH, and the next slide, we looked at what happened over time. This is an open label study, single center, looking over 24 months to assess sevasemten safety and pharmacokinetics. We looked at ambulatory adults aged 18 to 55 with a Becker phenotype and a mutation consistent with that, not on corticosteroids, and they could complete a 100-meter timed test. We looked at safety as well as functional measures, but the trial was really designed to look at safety and tolerability in a dozen patients. We started out with a dose of 10 mg. This was the first trial in patients out in the world. We gradually went up, and as you'll see, we identified 10 mg was the dose that we would go forward with, so we dropped people back to 10 mg, and the next slide shows you what these patients looked like. These were generally men in their 30s. Half of them couldn't rise from the floor, so relatively advanced disease, North Star 15, so fairly have already lost a number of functions, and their creatinine was low. Their DEXA showed a decrease in lean muscle mass, but they had ongoing contraction-induced damage with the serum creatinine, with the serum CK being elevated, so on the next slide, it shows safety. We had basically, this is over one to two years that we basically saw things that were not unremarkable, basically. These are things that happen in daily life, basically. The falls were not atypical for Becker patients. There were no SAEs, no treatment discontinuations, and no dose reductions. On the next slide, we have what happened to the individual patients with the North Star. So over two years, whether their North Star started 31 or started down at two, literally, for the screening, they remained stable over the 24 months. There's some variation, but relatively stable. On the next slide shows the average of the North Star in these patients. So in comparison to the natural history, where we would have expected patients like this to have decreased by about 2.4 points, we saw that they were stable over 24 months, and actually, the average is stable, and this takes into account all of the data available over the period of the trial. We also saw on the next slide that the biomarkers of muscle damage, so things like CK that you measure diagnostically, but also very specifically targeting the fast skeletal muscle fibers, and this biomarker troponin is different than the cardiac troponin you hear about. There's a different troponin for fast skeletal muscle fibers and for slow skeletal muscle fibers, so that is profoundly decreased, statistically significant, and it is at the 10-mg dose, and it's stable over time, as is myoglobin, which is released from necrotic skeletal muscle fibers as well. So we're seeing consistent decreases that are sustained over the 24 months, and this allowed us to then pick a dose of the 10 mg. On the next slide, we also saw that the 100-meter timed test continued to be maintained over that time period. And Alan showed you, yes, we're taking a little bit of the function of the fast myosin, but that's different than looking at actual strength measures, and because of the recruiting of additional muscle fibers. So strength is maintained over the 24 months, basically. So we are able to maintain strength. We're able to maintain function over that period, which is really important to these patients so that they don't progress in the disease. That would be a huge win. So to summarize, what we saw in the ARCH study is that the drug was well tolerated at all doses. We saw rapid, sustained, and significant decreases in multiple biomarkers of muscle damage. There's more that we haven't shown, a whole panel, a proteomic panel, that showed changes. We showed that functional assessments were stabilized, and a number of patients actually trended towards improvement as well. And that we were able to identify a dose for a pivotal study with the 10-mg dose based on safety, biomarkers, and function, and to bring that forward to what we are now doing, which is a registrational trial, essentially a phase III trial. So the Grand Canyon study is an ongoing pivotal study in Becker. The key inclusion criteria are men between the ages of 18 and 50. They need to have a genetic identification of a mutation in the dystrophin gene with a Becker phenotype that is ambulatory with a North Star between 5 and 32. So that group that are declining and are ambulatory. We are aiming to enroll 120 patients. And as you'll see on the next slide, we have a number of sites across the country. We're very much aware that men in this age range, they're working, they have families. We really want to make it as convenient as possible to participate in the study. In addition to the United States, we're enrolling across Europe as well as Israel. We are focused on a number of sites in the United States and will also provide any travel assistance. We have a concierge travel agency to help patients attend clinic visits, which are relatively infrequent. There's seven visits over an 18-month period in the study. That, given the safety of what we've seen so far, we're able to space out the visits like that. That's where we are for Becker muscular dystrophy. We also have trials ongoing in Duchenne. In Becker, we have an open label extension to follow after the Grand Canyon study. That's the MASA study. That is enrolling now. We're enrolling in a natural history study, the GRASP study that is being run out of the Virginia Commonwealth. And as I said, the LYNX and the FOX trials are enrolling boys with Duchenne muscular dystrophy because the mechanism is potentially useful not just in Becker, but also in Duchenne and potentially other muscular dystrophies as well. So with that, thank you for joining today. We are happy to answer any questions you have now or also to be able to get in touch with us to ask questions about the study or find out more about where sites are actively enrolling right now. So with that, I will thank you for your attention and ask if there are questions. I don't see any right now in the webinar. Now, if you have any questions, you can go ahead and chat those in. All right. I don't see anything coming in. So Joanne, Alan, thank you very much for that insightful presentation today. We appreciate your time. And thank you to everyone who was able to attend today. Make sure you go to mda.org, and you can rewatch this if you like, if you missed any of that important information. Otherwise, make sure to keep your eyes out for future industry update webinars. Otherwise, everyone have a wonderful day. Thank you for joining us. We did. Yeah, we did. There's a question in the Q&A. I'm sorry. I missed that one. It just popped in. All right. If you are in the current Grand Canyon study, will we automatically continue or the current Canyon study, will you automatically continue into Grand Canyon? So the current Canyon study is a one-year trial, and that was expanded to the Grand Canyon study. Patients who are currently in the Canyon study, which is 12 months, will move into MASA, the open-label extension study at the end of the 12-month period. The Canyon study will give us important information on being able to better analyze the Grand Canyon study. That is going to read out at the end of this year and will give us more information and, importantly, give us information on analyzing the registrational endpoints for Grand Canyon. All right. Thank you. We have one other question. What are the criteria for participating in the MASA study? For the MASA study, participants that were in either any of the studies, Edgewise studies, looking at sevasemten, either the ARCH, the DUNE study, which is a pilot study being conducted in Denmark, or the Canyon or Grand Canyon. All of those patients can move into the MASA study. The criteria is that they have completed the parent study, and there are no safety concerns that would preclude them from continuing on the drug. Okay. And then we have one more question. Let's see. My son's 12 months ends next month. Will he continue with 5506 until the next study begins? Thanks. He's finishing the Canyon study. We had adolescents in the Canyon study. And yes, they will continue in the MASA study on sevasemten. And while in the Canyon, they would have been on placebo or active. It's two to one. Two-thirds of the patients are on sevasemten, one-third on placebo. And all of those will continue on sevasemten in the MASA open label extension. Terrific. Excellent. Well, that looks like all the questions in the chat. Unless I missed no. That looks like everything. All right. Well, once again, thank you, everyone, for your time today and attending. And have a wonderful day. We'll see you next time. Thank you. Thanks. Thank you, guys. Bye.