I'm Joy Stafford with the Healthcare Partnerships Team at MDA. Thank you for joining us today for the MDA Industry Update Webinar, The Evolving Therapeutic Landscape for Becker Muscular Dystrophy, an Update Part One. And thank you for all you do for MDA and the neuromuscular community. MDA's Clinical 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, biotechnology, and medical equipment companies. These webinars are just a part of MDA's medical education resources. We encourage you to visit the medical education pages of mda.org. You'll find resources such as Considerations for Care case studies, recorded Grand Rounds webinars, research grants, and so much more. At the end of this webinar, you will receive a survey link. Please take the time to complete this short survey so your voice is heard, and you can help us create more impactful programming for the future events. Now, I would like to turn it over to John Wing from Edgewise Therapeutics for today's webinar. Hi. Thank you. Thank you, Joy. Thank you, everyone, for joining us today. Again, my name is John Wing. I'm the head of Medical Affairs at Edgewise Therapeutics, and we're happy to bring you this industry update. As mentioned, the title of today's talk is The Evolving Therapeutic Landscape for Becker Muscular Dystrophy, an Update. This is part one of a three-part series, so you'll be hearing more from us later in the summer and then sometime into the fall so we can bring some good educational programming and awareness to Becker muscular dystrophy. Next slide, please. So for a program overview, as most of you might know, Becker muscular dystrophy, or BMD, is a serious dystrophinopathy. Declining function can begin at different ages, but once it begins, Becker patients are on an irreversible path to losing muscle and then consequently losing function. To bring awareness to this disease to the community, we will discuss the following today with our panelists. The clinical course and natural history of Becker muscular dystrophy. We'll look at defining the disease, the pathophysiology, and clinical consequences. Then we'll follow up with the patient advocate who will tell us about his personal experience of living with Becker muscular dystrophy. And then to close, we'll look at the emerging clinical trial landscape. And I think we should ask ourselves this question as a community: Are we ready? What's next? What's available for patients with Becker muscular dystrophy coming up? Next slide, please. So the panelists today, I've introduced myself, but we also have Dr. Barry Byrne, Associate Chair of Pediatrics and Director of the Powell Gene Therapy Center at the University of Florida. And he'll talk about the clinical course of Becker muscular dystrophy. We'll have Nevin Steiner, a patient advocate, telling us about his story as he's living with Becker muscular dystrophy. And then to close it out, we'll have Joanne Donovan, Chief Medical Officer of Edgewise, and she'll talk about the opportunities for the Becker community. So next slide, and I'll hand it off to Barry. Thank you. Thanks. Thanks very much, John, and I appreciate you all attending today's seminar on Becker muscular dystrophy. I'm going to start off by providing some background, which I hope provides the context to understand the spectrum of disease in Becker. To begin, just to understand the causative mutations that lead to Becker muscular dystrophy in the dystrophin gene, which is shared with those mutations in Duchenne muscular dystrophy, you can see the large transcript of the dystrophin gene in the top panel from unaffected individuals leads to a full-length dystrophin protein. In Duchenne muscular dystrophy, either mutations that are caused by frameshift or stop codons lead to truncation of the protein and very little, if any, dystrophin production other than what's made through revertant fibers. But in Becker muscular dystrophy, shown in the bottom panel, these mutations or changes in the gene are in frame and therefore allow some of the protein to be made, but with diminished function. This helps us then to understand the global prevalence of Becker dystrophy at about 1.6 per 100,000 people. That translates to about 5,000 affected individuals in the U.S. The next slide. What are the consequences then of those mutations? Certainly, if we think about the mutation severity leading to a spectrum of disease, there's a very close relationship between Becker and Duchenne muscular dystrophy because they are both in this family of conditions known as dystrophinopathies. And on the left side, when there is an unaffected level of functional dystrophin, there are no clinical findings. But with less and less dystrophin present, you can develop muscle damage, which ultimately leads to the clinical findings of global weakness and cardiomyopathy in both Becker patients and those with earlier onset weakness with Duchenne dystrophy. But it really is important to emphasize that this functional loss of dystrophin and the genetics of the individual that carries that mutation in dystrophin results in varying levels of protein expression and a spectrum of disease severity. Next slide. So how does muscle breakdown happen in the context of a Duchenne or Becker mutation? When the protein is present, as shown in these green arrows, that stabilizes the membrane across the muscle bundles, contraction of the muscle leads to uniform force exerted across the muscle fibers and the entire muscle tissue. In this example, for example, a fast-twitch muscle fiber that is more responsive to acute shortening can bear that load across the muscle tissue and not be damaged. But when the dystrophin is absent, there is no anchoring structure for the membrane to withstand those shear forces, and the muscle can become injured. And that cycle of injury and regeneration is ultimately characteristic of both Becker and Duchenne. And the injury leads to muscle cell loss or myofiber loss and contributes to the weakness that is progressive over the lifespan of both patients with Becker and Duchenne. And so one of the goals ultimately of therapies is to create a greater degree of homogeneity within the muscle so that these forces don't disrupt the muscle membrane and preserve muscle function. So next slide. We can see some of these ultrastructural differences in this micrograph of a slow-twitch muscle fiber shown in the left panel surrounded in the pink outline versus this fast-twitch fiber, which has a distinct characteristic of these Z-disc elements. And those fast fibers are more likely to be disrupted because of the forces that are distributed across the muscle during contraction. This is particularly exacerbated in eccentric exercise where the muscle is lengthening and contracting at the same time, like happens when going downstairs, for example. And you can see the preferential disruption of the fast-twitch fibers over slow-twitch fibers. And this is an important therapeutic target for treatment of Becker and Duchenne patients. Next slide. So characterizing the symptom onset is one important way to establish the degree of disease manifestation and how this ultimately results in weakness. In Becker muscular dystrophy, we know that symptoms can, depending on the assessments that are done early on, can be identified even as young as five years old. Some patients with more functional dystrophin can be as late as their sixth decade. Typically, the onset of symptoms is between 8 to 13 years old. The majority of patients over 20 have findings of weakness. This manifests itself as walking difficulty in the late teens, and this progresses ultimately with disability and loss of ambulation. Partly because patients remain ambulant throughout this period of early adolescence and adulthood, they have a greater effect on their heart function. The primary cause of death in this patient population is heart failure. One way to assess the degree of muscle damage is through an imaging strategy to assess the amount of fat replacement that can occur in the muscle. And so using MRI, you can see that in Duchenne dystrophy, around ten years of age, only about half the patients are ambulant because of this increasing fat fraction in the musculature. Normally, this might be in the single-digit percentages, but by this age, you can see that a good portion of the various muscle groups have certainly greater than 25%, up to 50% of the muscle volume is replaced by fat. And that's shown in the A panel with the brighter areas of imaging that represent intramuscular fat. In Becker dystrophy, you can see that by age 41, even in an ambulant patient, there's also a significant portion of the muscle that is replaced by fat. And that distribution of fat accumulation within musculatures does differ between Becker and Duchenne, and this impacts their functional status. To evaluate individuals with Becker, much like is done commonly in Duchenne, there is a scale used called the North Star Ambulatory Assessment, or NSAA. The NSAA uses 17 different criteria and activities to assess function and determine their functional level, with a maximum score, which you can achieve without compensation. Every one of these 17 activities leads to a maximum score of 34. This measure is used to track the disease severity over lifespan and is an important indicator of symptom onset and disease severity. When we correlate the North Star with the amount of fat infiltration, this really outstanding study used imaging to assess fat fraction, which is shown between the baseline and 12-month time point. That a third, almost a third, of the patients had very high functional scores near the maximum, or at least 32 or above. They had the lowest amount of fatty replacement. As fat infiltration increases, you can see that there is a diminished North Star score. This, on average, declined by 1.2 points annually over a five-year period that was assessed in this study. This is a very helpful metric for disease severity and tracking disease progression. Another imaging technique that's used to assess patients long-term is the cardiac MRI. Since we know cardiac involvement is almost uniformly found in Becker patients, it's important to understand the severity of the cardiomyopathy and how that might influence treatment decisions. In this study, 15 patients from a neuromuscular clinic were evaluated by MRI. You can see that the ejection fraction, the LVEF, was greater than 60 in five of those individuals who were younger. In the ten individuals that were followed longitudinally with an average age of 42, there was a diminished ejection fraction. Anything less than 55, shown here, 42 was the average number. This represents an injury to myocardial striated muscle. One way that that's detected by imaging is use of a dye called gadolinium. And you can see in the lower panel, this one individual who's 41 years old had extensive areas of myocardial fibrosis and injury detectable by gadolinium, late gadolinium enhancement. So these are important tests along with the functional tests to track progression of Becker muscular dystrophy. And ultimately, we know that there is an effect on ambulation and how patients can compensate for that by use of assistive devices. So this questionnaire really reflects also on the quality of life that people experience by the need to use assistive devices and have difficulty walking. But you can see that on average, adult respondents to this questionnaire found at least half of them used assistive devices by the time they were adults. So if we go on to the next slide, how do we use these findings and others to understand the disease severity? And one self-reported outcome is related to pain. And you can see this mapping of pain points that either in control subjects were very limited, common orthopedic pain points, knees, ankles, shoulders. But in Becker muscular dystrophy, you can see there was diffuse pain over a wide area in the majority of patients with Becker dystrophy. And this diffuse pain certainly impacts quality of life. And the next slide gives us the opportunity now to hear from Nevin Steiner about his journey with Becker muscular dystrophy. Thank you, Barry. I'm going to tell you about my journey with Becker muscular dystrophy. I'm 39 years old, married, and have two kids. Luckily, my son, he loves playing sports. I wasn't very good at them, so he's taken that passion. I'm a producer at ESPN and now a part-time advocate for Becker muscular dystrophy. I was diagnosed at the young age of six, so it was roughly 1989, 1990. So as Barry mentioned, that's definitely a young age to be diagnosed. One of my first memories of struggling with Becker, I was in nursery school, and the nursery school was probably about a mile away from a fire station. And we walked to that fire station, and I couldn't walk back. There were a variety of incidents like this as a little kid where my parents noticed we would be walking somewhere, and about five minutes in, nope, they would have to carry me. So I always like to say my parents, but I really need to give the credit to my mother who never stopped trying to figure out what was going on. And by the time I was six years old at Albert Einstein in New York City, I was diagnosed with Becker muscular dystrophy. For the most part, growing up, I did live a fairly normal life. It's interesting as you get older, you actually have the ability to get stronger because your muscles start to develop, even though at a certain point in time they are going to weaken again. I played every sport, baseball, basketball, a little bit of soccer. I wasn't allowed to play hockey. I think that's the reason why my seven-year-old son is an ice hockey player. I even somehow managed to make it to the varsity tennis team in high school. So despite any of the challenges I had, I actually developed a love for sports, developed the ability to play sports even if I wasn't that good. When I was older, about 25 years old, I became interested in bike riding. I was able to participate in the Trans New Hampshire Bike Ride to raise money for muscular dystrophy, and it was one of the highlights of my life. I still don't know why and how I was able to ride 70-plus miles. It wasn't just one day of riding. It was two days of riding. And I don't know if it helped progress the disease a little bit more than it would have. As I talked to everyone, it was important that I live my life and that I was happy doing it. It was a great opportunity. Actually, this year, in a couple of weeks, I am going to be the director of that ride. Everything has come full circle. What my parents did growing up, I don't think is normal for someone with Becker. I see a lot of people that have Becker that, "Oh, the symptoms are not that severe. I don't need the care that someone with Duchenne needs." I didn't think about what it was that I was going through. I went to physical therapy. I went to occupational therapy. I went to the cardiologist. I went to the neurologist. I went to the regular doctor. It was just normal. But I also didn't see, for the most part, I didn't think there was anything wrong with me. And that's continued into my adulthood. It was about 35 when I started to progress. But even prior to that, I've been my own advocate for most of my life since I graduated high school. And even without symptoms, I continued to go to the cardiologist, the neurologist, the pulmonologist, seeing if I can do physical therapy, occupational therapy. I've put myself out there for everything. And that's the credit to my parents, especially my mother, for telling me, "This is just what you have to do. This is the normal." So I think there's a stigma around Becker. When I was growing up, I wasn't that involved. And I wish I knew what life would be like at the age of 39 because I didn't know at 17, 22 that this was going to happen. So I wish I was more involved. But at the same time, when you're younger and you're meeting people that have Duchenne and they're telling you, "Oh, my son's most likely going to die in a couple of years," or, "Oh, my son's already died," and you feel like, "Oh, I just have Becker. I'm not as important." Well, that's not true. I was probably about 34, 35 when I started to progress. We lived in a condo, my wife and I, and there were stairs. And one day it was like, "We're not going up these stairs anymore. This isn't going to work. This isn't safe. We can't do this. I'm afraid of falling down." It was the same thing about riding my bike. At that same time, I was on a bike trail with my dad, and I got to the end of one road and I said, "I have no balance. I can't do this anymore. This has to stop." So we stopped. So my wife and I went through the process of finding a house that was a ranch. When you look at 35 homes, you've seen everything. And so many say they're a ranch, but they're not really the proper setup for you. So eventually, we found the right one, and we were able to make sure everything was on one level that I needed. There is a basement, which I don't have to go down to very often. If I do, my wife helps me down there. We went through the process of installing the proper ramps, the rails outside so it's easy for me to maneuver the stairs. We did our bathrooms. We put in higher toilets. We put in showers that are walk-in. We put in railings everywhere. We basically prepared for the worst because then it probably wasn't that bad, and I would still say I'm pretty optimistic that it's not that bad now, but it's no joke. I might be at the age of 39 where someone with Duchenne is at 10 years old, and I don't want anyone with Becker to ever have to go through this, but this is what we have to go through. I can't safely go up and down stairs, getting out of a chair and getting into a chair. If it's a couch, it's even worse. It's hard. It's not easy. Falling down, I don't like to talk about this, but I recently tripped over a rug, and I went down, and how do you get back up, well, I have no hip strength, so someone had to come and help me up, and when you're out in public, I'm way more cautious because I don't know my surroundings, and you don't know who's going to be there to help you. Even falling in public recently, was anyone there to help? One person came over. A bunch of people just walked by and asked if I was okay, thinking that I'm just an average adult and I'll be able to get up on my own, but no, I'm not able to get up on my own. Recently, we did some traveling. You can tell from these pictures, we love going to the beach, Yankee Stadium. So I was in Dallas, Texas, and then we went to Florida to visit my father. And airplanes, they're not made for people with disabilities. And I don't even have a wheelchair. I just have a walking stick, which for the longest time, I hid my disease from everyone. I didn't want people to know. I didn't want people to worry about me. And then I became involved in advocacy. And I said to myself, "I'm done. I'm going to be out there. I'm going to tell people what I have. I'm going to make this the most important part of my life. I'm going to tell my story. I'm going to help other people because the goal is not about what you can't do, but what you can do and living your life." So when that happened, I turned the disease, which went from being invisible to it's visible. People know I have it. People will ask. And it's funny when you see little kids, especially at my son's school, and they're like, they want to know what it is. And I'm like, just ask me. I'll tell you what it is. I'll speak your ear off for a long time and let you know what it is because I'm not hiding behind it anymore. And I'm not afraid to ask for help. I work at ESPN, as I said, and I complained about the parking. I've said I need an automatic door in the bathroom because doors are heavy. I have trouble opening and closing doors. Who would have thought you go somewhere and you can't open the doors easily anymore? Well, that's me. So I got an automatic door put in. I needed a higher chair. I got a higher chair. So they were able to accommodate me. One of the things that also happened is I don't walk in the parking lot by myself. I don't carry anything. So people that I work with, they know they're going to come out, and they're going to help me carry my stuff into the office and make sure that I don't fall. Because if I fall, especially I work at night because sports happen at night, and I need to cut the highlights. So if I fall, I don't want to be alone, especially in the dark. Because think about you fall in your own house. Okay, you're going to get up. You're going to find the couch where you can get up. You fall in the street, and someone doesn't see you. Forget it. So along with my walking stick, I'm also going to get a scooter because going long distance, why be stressed out when I can be more relaxed sitting down and not worry about someone running me over? It's not worth it. It does take a while to get a device like that, especially if you're going to go through insurance because insurance companies, they're not the easiest to work with because they don't see this as something that's urgent, like a broken leg. Well, do you want me to have a broken leg? And then it's going to be more expensive. I'd rather have the preventative care. One thing that happened to me a couple of years ago is my cardiologist retired. And I will say this. I have no problem with pediatrics, even at the age of 39, because they're the ones that know Becker and Duchenne the most because most Becker and Duchenne patients are kids. A lot of them don't get to adults. And now we're getting to adulthood. So I went to a new cardiologist, and he asked me, "Why are you here?" And I said, "If you don't understand why I'm here, then I'm going to go back to the old cardiologist where he had someone lined up for me who understands why it's important to see someone with Becker and Duchenne." I take heart medications to prevent anything from happening. I want preventative care. I want to continue to do everything that I do. Go to the neurologist twice a year. Go to the pulmonologist. Go to the regular doctor. I see more doctors than my entire family combined in the span of one year, and I don't want that to change because it's really important to help me live my life, and it's important for doctors to understand why we're there. If anything goes wrong, we want to be in front of it. We don't want to be behind it and, "Oh, wait, it's too late." Could I be in a wheelchair 5-10 years from now? I could. Did I think 10 years ago that was a possibility? No, I didn't, but it is a possibility. I'm going through the same progression, I would say, as someone who's probably 10 years old with Duchenne, and we don't know where this is going to go 5-10 years down the road, but we're prepared for it. Other things that I struggle with, hamstring. As I said, opening doors are hard. Opening jars are hard. I have two cars. One's push-start, and one I got to turn the key. And in the winter, when it's freezing outside, turning that key might take some extra effort. Everything I do takes extra effort and planning. I can't just go into it and just be like, "Oh, it's going to be fine." You have to prepare for where you're going to walk, where you're going to sit, what the crowd's going to be like. So the mental toll that something like this can have on you can sometimes be more extreme than the physical toll because the preparing, the worrying about what other people are going to think, even though it doesn't matter what they think, you always have to be 10 steps ahead. What I want for Becker patients, and there's not a lot of them that I know, and I want more of them to come out and get the care that they need and be open about their disease. I want to make sure that people are able to live their lives. And the drugs that Edgewise are coming up with are definitely things that are going to help us do that. Raising awareness with the patients, with the families, with the doctors is really important. Just transparent. I can't be in the Edgewise trial. I'm already too far advanced. So hopefully, the drug becomes available for real, and I can be a part of it. But I want everyone to take away that it's not a joke. Living with Becker, it's serious. It's not just the stepbrother of Duchenne. I know Duchenne is very serious and sometimes more serious. But to be honest, this is scary what we're going through. But I'm going to continue doing it with a smile. And my goal is to be there for my family as long as possible. And that's the goal for everyone else. Now I'm going to turn it over to Joanne. Okay. Thank you, Nevin. That is so important for providers to hear from people who are living it, and because that's something that in the office, you don't hear the whole story, so it's very much appreciated. I'm just going to sum up very briefly that this is what you heard, that Becker is serious, and we see that contraction-induced injury is a key aspect of that, and we heard about some of the things that are most important in terms of maintaining skeletal muscle function, mobility, and independence, as well as a healthy heart is incredibly important, and there's a lot of challenges out there, and we're trying to work to improve that. I'm not going to talk to you today about the trial that we have. It's Canyon, a Phase 2 study of EDG-5506. But to say there are multiple opportunities in Becker now in the United States. This wasn't the case a couple of years ago. We're going to go into more detail on this with the subsequent webinars. But there's four trials enrolling: two natural history studies, which is critically important to be able to design best and to compare data from active treatment, the GRASP study, looking at endpoints at a number of academic centers, ImagingDMD, looking at MRI at a couple of centers as well, both very important studies. And additionally, Vamorolone, which is a steroid with less side effects, is also at a single site looking to enroll patients. And Canyon is enrolling at about 14 sites over the U.S. and Europe right now. So you'll hear more about those. And we want to extend the conversation. Happy to answer questions if there are questions in the chat for us all. Thank you. I am not seeing anything right now in the chat. You can find us all. You can actually contact us at Edgewise through studies@edgewisetx.com, and we'd be happy to answer more, but it was great. I appreciate Dr. Byrne in going over the actual history of the disease, so. Okay. Thank you, everybody. Have a great day. Thank you. Thank.