Welcome, everyone. 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 two presented by Edgewise Therapeutics. 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 will find resources such as Considerations for Care case studies, recorded Grand Rounds webinars, research grants, and so much more. Now, I would like to turn it over to John Wang from Edgewise Therapeutics for today's webinar.
Hello, everyone. Again, my name is John Wang. I'm the Executive Director of Medical Affairs at Edgewise Therapeutics. Thank you again for taking your time to listen to us today as we have our second part of our series on Becker muscular dystrophy to bring education and awareness to the community. Today's presentation is entitled The Evolving Therapeutic Landscape for Becker Muscular Dystrophy: An Update. I just want to share some forward-looking statements and to note that EDG-5506 is an investigational molecule and is not FDA approved. I just want to take a quick moment to do a brief overview of our program today. As you may 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 consequently function.
For this second part of our series on Becker muscular dystrophy, we will discuss the following: the rationale for targeting fast muscle fibers in Becker, the use of blood biomarkers of muscle damage to give some perspective of muscle health in Becker, and the recent 12-month data from ARCH and open-label phase 1b of EDG-5506 in adults with Becker muscular dystrophy. So you've already met myself, but I want to introduce my two panelists today. Speaking first will be Alan Russell, our Chief Scientific Officer, and he'll cover the topic of the rationale for targeting fast muscle fibers and the use of biomarkers. And then followed up by Joanne Donovan, our Chief Medical Officer, who will do our overview of the ARCH 12-month data. So Alan, I'll hand it over to you.
Thank you very much, John. I just have a very short introduction to talk about science, and then Joanne will get to the meat and potatoes of the presentation, so if you go on to the next slide, John, so the first thing to do is just to introduce the kind of structural function of dystrophin. Quite often, you see these types of graphics on the left-hand side to show where dystrophin is. It doesn't necessarily tell you what it does, though, so dystrophin is a long protein that anchors the sarcomere, the contractile units of muscle, to the membrane and then to the extracellular matrix. But what does that really mean, and on the right-hand side, oops, go back one, on the right-hand side, you have a little graphic of structurally what that represents.
Those dystroglycan elements, so the whole complex there on the bottom left, are represented as these green stripes on the muscle. They actually insert into the Z-disc of the muscle, and they connect the fibers together via the extracellular matrix such that when one fiber is contracting in that middle panel, right, because each fiber is individually innervated, the cross-sectional structures help support the contraction of that fiber by transmitting some of that force in the transverse direction. Those elements provide support in a direction you don't often think about, right, because we often think about muscle fibers as these kind of longitudinal force-developing elements. Now, of course, if you don't have the dystrophin element, the whole complex falls apart, or if the complex is dysfunctional. Then you can see that those muscle fibers, when they contract, are largely unsupported.
All of the stress is now resolved along the fiber instead of along and across. And that really is bad news for muscle fibers in the context of Becker and Duchenne muscular dystrophy. Next slide. You can see this in action. Now, this is an MDX muscle, so this is from the dystrophin null mouse, and these are very small muscles from the fingers of these mice, and it allows you to see right through them under phase microscopy. And as you can see, about now when this muscle fiber is contracting, you start seeing the muscle fiber moving when it should not be. There we go. And that is because the lack of dystrophin causes longitudinal stress. That causes membrane stress. And when the membrane is stressed, it allows the entrance of calcium. Calcium turns on all sorts of bad stuff.
It causes hypercontraction, and that's why you're seeing the muscle fiber kind of slithering around now, and then it also activates proteolytic, apoptotic, and necrotic machinery, and you can see proteolysis in action here on the top of this muscle with these kind of very sharp lines suddenly appearing and then retracting, so that's essentially proteolysis occurring at the Z-disc, chopping up the sarcomeres and the whole muscle retracting as it is unanchored. Now, this happens in you and I if we go to the gym and do a vigorous workout, and it's part of the adaptive process in order to get stronger, but of course, if you have Becker, for instance, then what happens is the amplitude of that breakdown is way too much. You get too much breakdown. The body can't keep up in terms of repair. You get chronic inflammation, fibrosis, and muscle replacement.
That muscle replacement is really the key driver of disease. You can track these early contractile problems all the way down to the fibrosis and really the long-term disability that results as a result of this condition. Next slide. It's been known for many, many years that fast muscle fibers are more susceptible to this type of injury than slow muscle fibers. This data is actually from healthy individuals all the way back from 1983. These folks did 30 minutes of controlled lengthening eccentric exercise, which is specifically designed to injure your muscles. Then a muscle biopsy was taken out immediately after. What they look for is the incidence of Z-disc streaming. I've shown that marked by the red arrows there. That's where the Z-disc has been torn apart.
You can see it represented as a fuzzy line instead of a clean line. On the right-hand side, they've identified a fast fiber. On the left-hand side, a slow fiber. You can just see on a very simplistic level, the Z-discs of those slow fibers are about twice as thick as those on the right and are presumably more resistant to this kind of transverse stress. It's about a three-to-one injury rate under these scientific conditions, fast fibers being much more likely to become injured than the slow ones. Now, this is in healthy people, but it turns out that that's also the case in these muscular dystrophies, and I'll show you that in a sec. Now, as you probably know, when muscle is injured, muscle fibers release injury biomarkers. I'm just introducing this because Joanne's going to give you a lot more information on this.
We often, of course, focus on CK because it's a standard assay. It's often the beginning of the route for diagnosis of someone with Becker muscular dystrophy. But of course, CK is only one protein of many when the muscle degrades that is released. You know, think of these things as a big bag of very specific proteins. And we have three examples here: myoglobin, CK, and Troponin I 2. We really like Troponin I 2 because it's a protein that's specific to fast muscle fibers, and that is our target. And I'll get to that in a second. But when you see CK, you should also see all of these other proteins. So if a compound or an intervention is meaningfully changing the relationship between muscle contraction and muscle injury, you should see a change in a whole bunch of these proteins and not just a single one.
Now, another reminder is we often focus on fibrosis as a mediator of disability. But of course, when you do injurious exercise, there's also acute impacts too. Now, this is again in healthy people, but presumably a person with Becker muscular dystrophy suffers a version of this every day too. So when you do injurious exercise, you get acute decreases in muscle strength. You get increases in muscle soreness, and you also get increases in muscle hardness. So essentially, how much fluid is present in that muscle in the form of edema. And the combined effect of those three things is that your muscles don't work as well. So there's something to just bear in mind that you have both acute and you have chronic impacts of this type of muscle injury.
And if you could arrest the injury, you might have effects on both of those, which could potentially lead to improvements of function, not just stasis as a result of decreasing fibrosis. Okay, so here's the strategy. Contraction causes excess injury and degeneration. The fast fibers are more likely to be injured. So what we're going to do is apply a small molecule that decreases contraction selectively in fast fibers. And by doing so, we hope to stop these very susceptible muscle fibers from going through these cycles of injury and damage. Okay, so it's a very, very simple concept that we're going to modulate how much those fast fibers contract. We're not going to touch the slow fibers or the cardiac muscle fibers. And in doing so, we'll change that relationship between contraction and injury, okay, with a goal towards not doing it enough to yield a functional deficit.
Now, this is just another reminder of something that we take for granted, but often forget in the context of muscle function and therapeutics, that there's a difference between strength and function. I think we often conflate these two things, but I've got two examples there of different individuals. One is clearly a lot more stronger than the other. But is that person more functional? Can that person do a larger variety of things? And the answer is no. We take this for granted that you see people of all shapes and sizes, but you're not worried about their overall physical function because muscle is so plastic, right? So it turns out in the context of our therapeutic that you can modulate strength and not see any functional changes whatsoever. We have a lot of built-in reserve capacity.
The target level of modulation for 5506 is very modest, and it really doesn't yield functional deficits at all. In fact, we see modest functional improvements in the context of Becker, and Joanne will tell you about that. Here's everything all at once. So we're returning to these lumbrical muscles. All right, the left-hand video is the one you already saw where the muscle degrades as it's contracting. Now, what we've done is we've added in the right-hand panel where we've added our compound 5506 for one hour before the intervention. I think it's contracting. Maybe not. Yes, there you go. So one hour of 5506 at 0.3 micromolar, that should be not millimolar. Don't get too scared. That should be micromolar, is enough to limit that muscle fiber to contracting at 85% of normal. So you've taken 15% of the contractile reserve of that muscle.
It's really very modest in terms of the range of muscle fiber contraction, but it's enough to stop the stress. So by doing this, you've essentially normalized the stress inside the muscle to something it can deal with, right? So that fiber contracting at 100% is broken down and looking pretty shabby. And on the right-hand side, the thing just steams up. You haven't changed the dystrophin elements. You haven't changed the kind of molecular defect within the muscle. But what you have done is normalize the stress such that these stress channels aren't opened and the calcium doesn't enter. So by doing so, we hope to change the relationship between muscle contraction and muscle injury such that when an individual with Becker, for instance, takes the compound, they shouldn't notice any difference. But when they move their muscles, those muscles should now not respond in an unhealthy way.
They should respond in a healthy way. Okay. At this point, I'm going to hand you over to Joanne and talk to you later.
Great. Next slide. Very nice to speak with you all today. And we are going to have an opportunity for questions later. So I believe you can do it in the chat box if you want to store that thought. And we'll be happy to chat later. Basically, what we've done is we've taken EDG-5506 into the clinic. And we have started with a phase one study and included adults with Becker. That led to an open label extension in those patients. And I'll show you information from that, the ARCH study. And that formed the foundation for a phase two study in Becker as well as a phase two study in Duchenne muscular dystrophy because, after all, the same contraction-induced injury that we see in Becker is seen in Duchenne and vice versa.
And then I'll tell you a little bit at the end of how we're expanding CANYON actually to a pivotal cohort based on what we've seen so far. So the next slide, basically, you see patients with Becker. It's a progressive muscle disorder. It is a mutation in the Dystrophin gene. It does produce a protein. Unlike Duchenne, where there's no protein at all, this produces a protein with decreased function. But still, there is this contraction-induced injury. It's X-linked recessive. We know that people present at all ages with this. And so the impression is this is a very heterogeneous disease. But what I'm going to show you from natural history data is that once it starts, it continues. Once patients start to develop weakness, they progress. And importantly, for the clinic, the most common cause of death is heart failure from cardiomyopathy.
So it's really important to, we're not going to talk about that today, but it's important, as you know, to keep people in the medical system and to keep them hooked up with cardiologists for the appropriate preventative care there. And one of the things that we hear from patients, we were talking about it a little bit before we started, is that the Becker community wants to be seen by themselves. They don't want to hear that, "Oh, it's milder. You're lucky." It's still a devastating disease. Any of us would feel devastated if we could not do the functional things that are lost in the progression of Becker. So on the next slide, this shows briefly, I mean, this is a boy basically with Becker. Yes, he can get up off the ground, but he displays the particular Gowers sign.
And I don't think that video is working, but basically, the area, if we click on that, that when you talk about folks retaining ambulation, it's still a significant disability. And when you see folks walking around, they have considerable impairment, even if they can transfer and walk limited distances. So on the next slide, one of the measures that we are using to look at, to quantify function in Becker is the North Star Ambulatory Assessment. Now, that has been used and validated in Duchenne muscular dystrophy. And one of the good things about using it in a natural history or clinical study is that it measures things that are important in daily life. You talk about things like the impact. And the 17 measures in order of difficulty are shown on the left. But when you think of these, they translate very clearly into daily life.
Climbing a step, even a single step. Can you do curbs? Much less stairs. Can you stand on one leg and dress yourself? Can you stand from a chair so they can toilet themselves? So these translate very clearly into measures of everyday life. And actually, the FDA views them as important for that reason and has encouraged the use of them in Becker as well. Now, in natural history studies, on the next slide, the North Star has been looked at over time. The scale goes from zero to 34. Zero is basically non-ambulatory. 34 is non-ambulatory. And it's very interesting in that there is a ceiling effect so that at 34, there's a variety of strengths, to Alan's point.
But once they start to fall before 34, once they start to have to compensate, and I didn't mention, each of those 17 tasks is scored as not zero, not able to do, one, able to do, but with compensation. So the Gowers, they have to push themselves up off. And two, can do without compensation, can do as an unaffected person can do. So once they start to lose even a couple of points, it's downhill. This is a study of 100 patients or more in Padua, Italy. And they were followed over five years. So when they're still at the top, they haven't shown any degree of compensation. They're not starting to get weak. They're good. They continue to be up there. But once they start to go, and that could be at any age, they have a progressive course over the next five to 10 years.
And that's captured in, we looked at some of the patients actually in our study at baseline on the next slide. And we said, "Well, what kinds of activities does this translate to in different North Star scores?" Because I think it's important to also give people a picture of what their life is going to be like in five years, in 10 years, and to be able to make compensations. When we've talked to patients, "What kind of a house do I live in? What should I be planning for?" So if you translate that natural history of about 1.2 points per year translates to about 10 points over eight years, what does that look like? And the next slide shows, and this is a complicated slide, I appreciate, what we did was we divided the patients who scored from zero to 34 on the North Star, the blue boxes.
And so what are the folks who are over 30? They're not really changing very much. And on the right are our bars for individual functions. And there's some of them pointed out here. So one of the first that they lose is the ability to rise from the floor unassisted, not using the Gower's. Standing from heels actually is something that's early. But in the 30s of North Star, they can complete all functions. When you go down 10 points, so that's seven years later, five years later, they can complete most functions, and that is the lighter green bars. But weakness in those functions is evident. So you're starting to see they're having trouble getting up from a chair. They're having trouble climbing a step. They can do it, but they're having trouble. They have trouble from rising from the floor.
They can't get up speed when they run. And then eight years later, on average, where are they with North Star in their teens? And now they've started to lose many of those functions. Things are really going badly. And when you get down another most of a decade, they've lost many of those with the dark green. So minimal activity to complete typical ambulatory activities. So as John said at the beginning, it's a serious disease. And they have life expectancies in their 60s and 70s if cardiac disease is not an issue. So they are looking forward if once they start to get weakness, they are looking towards having significant disability. So what have we done to try to help this community? The ARCH study is the open label study that we looked at in the patients who completed the phase one. There were 12 patients.
Looked at safety and tolerability, of course. This is an open-label study and we dosed them with different doses of EDG-5506 over a year, actually, so major target is safety tolerability, so in the next slide, we saw that the drug was safe. Actually, one more slide. These folks that came into the trial were significantly impaired. They had a mean North Star of 15, so they are starting to lose many of the functions. They're clearly in the decline phase and they're actually very different. They're more advanced than the boys who are typically in Duchenne studies. They've lost muscle mass. Their serum creatinine is low. Their DEXA shows decreased muscle mass, so in terms of safety, we saw that mostly typical things that would happen over 12 months, the most common adverse events that appear to be associated are dizziness and somnolence.
We actually give the drug at night. It's something that tends to happen transiently at the beginning of dosing and then goes away. First few days is typical in a minority of patients. So what do we see in terms of the biomarkers that Alan talked about, the biomarkers of damage to muscles? CK, you're familiar with. That went down by 37%. Went down pretty consistently. And we looked at fast skeletal muscle troponin, which is specifically in the fast muscle fibers. And that went down by 80%. We looked at other markers on the next slide. They went down early on. Within a month, they stayed down. And this allowed us to actually look at to select a dose for what is going to become our pivotal study, potentially registrational study in Becker. And excuse me, in the next slide, importantly, well, what's going on with function?
And that natural history data of similar patients with similar North Star on average would suggest in the purple that they should be declining. They should be going down 1.2 points per year. Not much, but steady. And what we saw was these folks looked the same or actually, on average, improved, which is not what you would expect in patients with this degree of disease. So three-quarters remained the same or improved as opposed to going down. So that's very encouraging. And the next slide, these folks were in the middle here. You wouldn't have expected them to change. And they stayed the same or trend up. So that isn't consistent with what we've seen with natural history. Now, it's 12 patients, open label. We need to do a larger study. And that's exactly what we're doing. So we looked at other functional measures. Those are stable.
And to Alan's point, grip strength. We're seeing good strength measures. The patients do not feel any pain. But what they do feel in the next slide is the pain is somewhat better. So pain is not uncommon in Becker and other limb-girdle muscular dystrophies. We did see a positive trend in. And we've heard anecdotally from people that the muscle cramps are better. Taking the edge off that contraction in fast muscle fiber seems to help. So we've learned a lot from this study. We've learned in terms of safety. We've seen biomarkers go down. We've seen function trend up. And we're seeing a dose to be able to start a larger study, which is where we are on the next slide.
We're starting an 18-month study GRAND CANYON that is looking at a dose of 10 milligrams a day, two to one active to placebo, looking at adult Becker patients that have started to decline, but are still ambulatory, basically. We are planning to enroll at many centers across the United States as well as in Europe. This is going to be an 18-month study that we're kicking off in the very near future. There are relatively few studies that have been done in the Becker population. We've got a lot of interest from people and are encouraged. There are some natural history studies in the United States. If patients aren't interested in an interventional study, we'd encourage them to also consider participating in a natural history study because that's so important in neuromuscular disease to being able to develop potential treatments.
With that, I'll turn it over to folks if they have questions. Thank you for your attention. Joy, if you can, there are any questions from the audience, you can type them into the chat box. Joy, I don't see any. I don't know if you have any questions.
I don't have any questions in the chat right now. We'll wait another minute if anyone wants to chime in on that. We'll monitor the chat box.
Yeah, and if not, we also should say that on our website, there are links to where you can find us and ask questions at trials@edgewisetx.com, and let us know if you have questions or if patients have questions and would be interested in learning more.
Wonderful. Well, thank you so much for all the great information that you shared today, and thank you to Edgewise Therapeutics for the insightful presentation and to our medical professionals for attending today's program. We hope that you'll join us in the future for industry update webinars.
One question.
On cardiac muscle.
Alan.
Thank you so much. Is that Gyula? So it doesn't directly affect cardiac muscle. So the compound EDG-5506 is highly selective to fast fibers and as such, does not really affect slow fibers. That's the other half of skeletal muscle and cardiac muscle fibers, although it does hit embryonic myosin, which is present in regenerating skeletal muscle fibers. So we protect those regenerating fibers too. We have done preclinical studies in an MDX model called the DBA/2J-mdx mouse. Now, these mice really don't have any muscle regeneration, and they get a lot worse cardiac fibrosis. And we actually, in two separate studies, have seen nice decreases in cardiac fibrosis with this intervention too. So while not directly affecting the heart, what we believe is going on, but positive effects on the skeletal muscle knock onto that compartment.
If, of course, we could get that in Becker, that would be just terrific, but no direct effects on the heart.
No problem.
Okay. Thank you.
Yeah.
Everybody.
Thank you, everyone. We hope that you have a wonderful day. Thank you, Joanne, Alan, and John, and Edgewise Therapeutics for being a part of today's industry update webinar.