#313 Becker Muscular Dystrophy Clinical Trials with Edgewise Therapeutics
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Dr. Joanne Donovan has served as the chief medical officer at Swise Therapeutics since 2021. She's a double doctor, having earned both her MD and PhD. So obviously, she has an impressive resume holding an appointment at Harvard Medical School for over 30 years and has held leadership roles at multiple pharmaceutical and biotech companies. She's been deeply involved in clinical research in the muscular dystrophy field for over a decade. So now,

So naturally in this episode, we're learning about muscular dystrophies and focusing specifically on Becker muscular dystrophy. We also recommend if you're interested in muscular dystrophies to check out the show notes. We have other episodes of DNA Today about muscular dystrophies, including episode 156 and 202. But Dr. Donovan, thank you so much for joining me in this episode. I am really excited to dive into your expertise and learn along with the audience.

Great. Well, I'm delighted to be here and share some of the exciting things that we've been doing here at Edgewise. Yeah, there's so much to learn. And before we get into all of that, I wanted to mention to the listeners to please note that Seva Sempton is an investigational agent that is not approved for use by any regulatory authority in any territory. All information shared in this podcast episode is intended for healthcare providers only, which is the majority of our audience.

This episode is for informational purposes only and should not be considered for any professional medical advice. Always consult your doctor or qualified medical professional for any questions you have regarding a medical condition, procedure, treatment, or trial. And that goes for pretty much all episodes of DNA Today.

Dr. Donovan, let me learn a little bit more about your role and about Edgewise as a company, because I'm somewhat familiar, but I want to, you know, learn a little bit more and fill the listeners in as well. Great. Thanks.

So we have been around since 2017 at Edgewise, and we are a muscle-focused company. We are very much focused on muscle biology. That is our area of expertise. And in particular, on how we can protect muscle from the damage that occurs in Becker and Duchenne muscular dystrophy. We also have a cardiac program that is similarly focused on muscle tissue.

We are currently working on Sevaceptin, which is a fast myosin inhibitor in our clinical program. And we are looking at that in both studies in Becker and Duchenne. One of the things I'm particularly proud of the way we are at Edgewise is we are deeply committed to patients. And we have been listening to patients and trying to understand the patient voice.

particularly in Becker muscular dystrophy, which is a disease that has been somewhat in the shadows. It hasn't been a disease that has been at the forefront and it is often compared to Duchenne muscular dystrophy. Oh, you're lucky you don't have the more severe form. It's a bad disease for these patients. It's something that has really been very...

enlightening to see over the last several years. And we've done quite a bit in terms of trying to reach out to the community, to listen to the community, and to educate the community about the disease. So that's a real area of focus for Edgewise, in addition to doing our clinical trials.

Yeah, there certainly is a lot more information out there about Duchenne DMD. And I think oftentimes it does overshadow in some ways Becker and Becker can kind of be an afterthought or like it's a sub bullet on a slide. So it's encouraging that at Edgewise, you guys are focused on Becker and that there is this clinical studies going on in terms of that sense. And

You know, as we said, we're going to focus more on Becker today. So hopefully we can remedy that a little bit by having this episode be focused on Becker. And a lot of people, as you said, do learn about this in school and CMEs and all of that in the context of DMD. But in terms of Becker, can you give us a little bit more of an overview of what this condition is, like symptoms, when onset usually begins of those symptoms and maybe the

how it is different from DMD, because you kind of alluded to the fact that it can be seen as milder than DMD, which I think is a correct statement, right? But fill me in a little bit more on the details of Becker. Yes. So the basic defect in the genetic defect is that the dystrophin protein is present, but it is dysfunctional in some way. It doesn't do...

fully what it's supposed to do. And what the dystrophin protein does is not to create power in the muscle, but to protect the muscle from damage. So when we contract our muscles in an extreme fashion, we damage them. You know, you do CrossFit and you're really sore the next day and it can even be worse than that. You can look and see biomarkers of muscle damage that are circulating.

Well, folks that have Becker have damage because of this contraction-induced injury, but it happens every day. It happens with daily activity because that dystrophin protein isn't there to protect the muscle.

And ultimately what happens is that ongoing inflammation, that ongoing damage leads to loss of muscle tissue. And that is reflected in a loss of muscle function so that the disease is often diagnosed somewhere in the middle childhood, nine years old on average, but it can be a wide range

range. It's often not diagnosed if the symptoms start earlier. So in retrospect, we hear these men saying, you know, I was always slow. I didn't know why it was happening. But now I understand what was happening even then. I was symptomatic years before I really got a formal diagnosis.

And this ongoing process of muscle damage leads to first compensating. They're not able to get out of a chair without pushing on the arms. They're unable to get off the floor without a lot of assistance if they fell. And ultimately, it leads to real inability to even to walk.

30, 40% by the late 40s may be in a wheelchair. And that's not a mild disease. So...

That's kind of what the disease progression looks like. So they're losing functions like being able to get up a chair. Well, that also extends into, well, are you able to get off the toilet? I mean, are you able to take a step up and down curbs? So that really limits your mobility. People think of, well, these people can walk, they're ambulatory, but that's

There's a lot of disability there that affects them in their daily lives. And these are guys with families, with jobs, and having a real impact on their activities of daily living. So that's what we're trying to address. We're trying to protect the muscle from this ongoing damage and preserve and even improve muscle function.

And like you said, for people that don't have Becker or DMD, when we go and exercise, like a few days ago, I was playing pickleball and I went a little hard because I was going against my cousins that are really athletic. I'm like, all right, I got to bring it up my all. And, you know, the next day I'm sore. The day after that, I'm fine because my muscles are able to recover because I don't have a muscle condition.

From what I'm understanding, people with a muscular dystrophy, their body is not able to have those muscles recover the way that maybe my body is able to. Am I getting that right? They get more damaged. So you would see circulating proteins like creatine kinase.

And so if you think about it with CrossFit or something like that, well, if you were playing pickleball actually against somebody who wasn't quite as good as they were, you were taking 10% off of that and just not going to the extreme. Well, your muscles wouldn't hurt the next day. And so that's actually what Sevacemtin does. It limits the contraction by a very small amount, but enough to protect the muscle.

So it's a little bit counterintuitive that if you inhibit myosin contraction just a little, what you do is you prevent that extreme damage to the muscle. So you're preventing the person from really testing and pushing that muscle. You're like, nope, let's bring it down a little bit so that we don't end up having that

contraction-induced muscle injury. Am I getting the phrase correctly? That's exactly right. Yes. Okay. And so that's what this investigational drug is doing is being able to limit that part. So what we're looking at then is like the skeletal muscle fiber and specifically that part, because there's lots of different muscles and tissue types that many of us learn in anatomy classes, but it's really focused on

on that part? In particular, it's focused on the fast muscle fibers. It turns out that about half of our muscle fibers are the kind that get damaged more easily. And those are the ones that Sevacemtin affects. It's very specifically targeted to those. It's not targeted to cardiac muscle or smooth muscle, only the fast muscle fibers that get damaged with contraction-induced injury in the muscular dystrophies.

Interesting. Okay. So then tell me a little bit more about how Edgewise is investigating this potential therapy. Where are you in the process? Like how close are we to having this potentially be on the market? Because it takes for people that are not aware in the pharmaceutical industry, it takes a very long time to go from

the R&D, the research and development, like all of those phases to finally people can actually be prescribed this medication. So where is Edgewise at in that long, long, arduous process? So we are currently enrolling in a pivotal trial, essentially a phase three trial that we intend to be able to bring to the FDA to say, yes, we think this is something that you should approve.

And the way we got there is we did a study, an open-label study, so everybody got drug in a dozen men who were in our original phase one study and some others. And what we did was we looked at how they reacted to the drug. We looked at safety. We looked at pharmacokinetics. We also looked at function. And they were treated for two years.

So this disease progresses over a year, over two years, and you would expect that they would start to decline in function. We use something called the North Star Ambulatory Assessment, which is 17 different measures of daily living. It's going up a stair, down a stair. Can you pick up speed when you run? Can you get up from a chair? These kind of activities, they're all scored by a physical therapist.

And they would have gone down about two and a half points over two years. And they didn't. They were stable. And in any kind of a neurological progressive disease, hanging on to what you have is really important. In fact, at least half of them actually got better. So that is amazing to see.

So we're very pleased with the results of that. And that gave us the information to design this pivotal study that is currently enrolling in the United States, in Europe, and beyond. And we are looking to enroll about 120 patients. This study is called the Grand Canyon Study.

our pivotal study. Dr. Donovan, tell me more about the details of some of these improvements. What are the types of responses that you've seen from some of the participants in this trial, especially that earlier one that you were referring to? And this is the earlier one. And we have to also acknowledge that this is an open-label study, that people know that they're on drug. But we have heard that some of the symptoms like cramps,

are decreased in these patients. And also in terms of endurance. So in the North Star scores, some of the patients did have some improvement as well. On average, it was the same. So that's encouraging in a disease that has progression over time. Because holding on to those

functions that you can do, you know, that's really important. You just don't, when you talk to people with whatever stage of disease, if I could just keep where I am, that would be great. Wow. All right. So tell me more about Grand Canyon then, because that's the current study that you're, you're enrolling patients in. And from my understanding,

This is going to be like 18 months that people will be part of this study and it's double blinded, randomized, placebo controlled. Can you break down a little bit what all of that means and why it's important to do it this way? It is important to have a placebo control. Of course, people don't want to have a placebo. They want to be on active drugs.

It does progress over time, so we do need to have about 18 months to be able to see a clear difference between not being on drug and being on drug. That's how we powered the study. We're looking at biomarkers in the bloodstream, but we're also looking at functional measures like the North Star Ambulatory Assessment. And we're looking at MRI because that's a very promising method of looking at

the progression that happens in the muscle. Actually, the muscle is replaced by fat and fibrosis, and you can see that very clearly on MRI. So we are enrolling men, adult men between the ages of 18 and 50 who have Becker, who have a mutation in the dystrophin gene. And we are looking at men who are

have a North Star score within a certain range that allows us to power the study. Of course, you always want to be able to

show a difference. And so that's why we have looked at certain limits basically in North Star. So they're not about to go off their feet. And Becker is somewhat heterogeneous. So some mutations don't deteriorate over time. So if they're at the top of that scale, we're not including them. It's not to say that they wouldn't ultimately benefit, but in a clinical trial, you want to concentrate on

the people who you can see a difference in a reasonable amount of time.

Yeah, that's really important just to say, okay, they need to be at kind of this point in the disease progression so that you can see, are they stable? Are they improving? Are they declining? Especially when you have that placebo aspect that you hope to see that the people that are on the investigational drug are stable or improving compared to the portion of the participants that are on the placebo. So you explain what that inclusion criteria is. So the box is

that a patient would need to check for that healthcare provider to then say, okay, patients of mine are checking these boxes. Are there any exclusion criteria? So if they have a feature where it's like, okay, well, this makes them not eligible to potentially enroll in the trial. Yeah. So we are excluding men who have low ejection fractions. Becker has very commonly folks have cardiomyopathy. So it's a

ejection fraction below 40%. So that's like how the heart is functioning? Is that what that means? Exactly. So we want to have them at a reasonable stage there. They can't be on other investigational agents, of course. They have to have good pulmonary function. And that's pretty common. It's unusual to have that pulmonary function at this stage of the disease.

And we have a lot of sites across the United States that are enrolling. We listen. These are our guys who've got families. They're busy. They don't want to be going to the clinic all the time. We were able, because of the safety that we have seen, we were able to cut down the visits to once they get started between three and six months.

I should touch on the safety. The most common side effects that we've seen are dizziness and sleepiness. So we actually give the drug at night. It's a pill once a day. And we've also found that those side effects in particular tend to disappear as you've been on the drug for a bit. So they're most common in the first couple of weeks, say.

and then tend to diminish. So the drug has been very well tolerated. A lot of clinical trials like this will...

help and have, I don't know what the right term would be, but stipends or something to help financially assist with travel and figuring out what site is most appropriate. Is that something that Edgewise is offering so that it's easier for patients to enroll and stay participating? Yeah, exactly. We have a concierge travel service that supports travel prepaid as much as possible.

and any other costs that are associated. This should be cost neutral. It's a small stipend, but in general, we aim to make it cost neutral, child care, whatever else needs to happen for the individual and supporting person to come. They can get in touch with us at studies at edgewisetx.com. And there's also a

The patients can do that. No, this isn't oriented towards patients. There's also a website, beckergcstudy.com for healthcare providers. And that's beckergrandcanyonstudy.com. That's why it's got those initials. And so that's what we are. We're trying to reach out to the community. In fact, we had last month, we had

a community education and engagement day at six sites across the country. We had several hundred people that are affected by Becker. Their families come and in the not too distant future, there will be videos posted on educating on what's the role of exercise, what's good or what's bad, cardiac disease, what do you need to know about that, physical therapy,

And just living with Becker, what are clinical trial opportunities out there? So that will be posted and it will be linked to on our website. That will be out in the near future. That was not just us. It was a number of academic institutions as well and advocacy organizations that helped support that and pull that together.

That's wonderful. Yeah. Once those are released, we will update the episode show notes and our website, dnhda.com. So people can have direct access to that. So if you're listening to this a little bit later, check to see if it's already there. And I wanted to repeat the URL that you shared, beckergc, Grand Canyon, study.com, and then forward slash HCP, healthcare providers that will get you right where you need to. And we're going to put that link in the show notes as well. And so for those healthcare providers listening that are like, okay,

okay, I have some patients in mind that meet the inclusion criteria. There's nothing in the exclusion criteria that would rule them out in terms of having that patient being enrolled. So they have some patients in mind at this point. Obviously, a good way to start is going to that website and we'll include the email address you shared as well. Is there any other advice you have in terms of what healthcare providers should know about

especially just thinking about those next steps of helping introduce their patients to this and connecting them with you guys. And certainly with that email studies at eduaztx.com,

We're happy to chat. That's kind of the central lead-in to us. But if somebody wants to hear more, get more information, the publications, the recent posters and presentations are also posted on our website for people's information.

Yeah, amazing. Well, anything that you wanted to leave our listeners with, especially, you know, it's mostly if not all health care providers listening at this point. Anything else that I didn't ask you about that you're like, oh, this is a good thing to mention? I mean, we have such fabulous information about Becker in this episode. And I really appreciate, especially with how much experience you have, particularly in this area. It's just really great that you were the guest on this episode to explain this all to me.

Yeah, I think that there is an increasing amount of information on Becker, which is really exciting to see the community, the academic community, the docs that are generating more information on this disease. And it's really important to the community. So proud to be a part of it. It takes a village, not just our company, but a village out there to help improve the lives of these patients.

And it's just so exciting to see that in the rare disease space in general, we just have so much promise, I think, with so many investigational drugs and different ones that there really is, I think, more energy and hope in that sense of how well things have been going the last few years in general. And I think just Edgewise being a part of that progress.

is just really exciting. It's an exciting time to be working in genetics and helping patients that have some of these disorders. So, Dr. Donovan, thank you so much for coming on. And listeners, again, that URL is beckergcstudy.com forward slash hcp for healthcare providers, obviously. And healthcare providers, if you have a patient that you're telling about this study and they want to learn more, you can do that.

you can personally direct them to beckergcstudy.com. So that's just the URL without the forward slash. And all of those links along with the email address studies at edgewisetx.com

Everything is available in the show notes for this episode if you're listening to it in a podcast app. So you can just swipe and see that or you can go directly to DNAtoday.com and click on this episode for all of the information. Thank you so much, Dr. Donovan. This was just really interesting and enlightening. And I appreciate you taking the time to educate myself and the listeners. Well, thank you so much. This was great. Great questions. And I'm happy to share more with the community if possible.

in healthcare providers if they are interested.

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Looking to jumpstart your career as a genetic assistant? These essential roles involve patient communication, data management, genetic testing coordination, and admin tasks, making proper training a must. The Genetic Assistant Online Training Program at Johns Hopkins University School of Medicine is a top choice. DNA Today listeners rave about how this course boosted their genetic counseling skills and prepared them for grad school.

The spring cohort starts soon on January 27th, so apply now before it's too late. The program includes two 10-week instructor-led courses. Armed with a basic science background, you'll earn a certificate from the Johns Hopkins School of Medicine upon completion. You'll also gain practical skills and insights from leading instructors that will give you a competitive edge in genetic counseling and related fields.

Learn more at dnapodcast.com slash sponsors or simply search Genetic Assistant Online Training Program Johns Hopkins.

When it comes to your health, knowledge is power. I've always believed that the more we understand about our bodies, the better decisions we can make, whether it's about the food we eat, the exercise we choose, or how we plan for the future. But traditional healthcare often feels reactive and not proactive. That's why I'm so excited about 23andMe Plus Total Health, a longevity platform that puts you in the driver's seat of your health journey.

With 23andMe plus Total Health, you get advanced genetic screening, giving you insights into your potential future risks, and comprehensive blood testing throughout the year to track how your health is changing. It's a level of personalized care that goes far beyond the one-size-fits-all healthcare system that unfortunately we're used to. Advocate for your health today. Go to 23andMe.com slash DNA Today to receive 10% off your Total Health membership.

Again, that's 23andMe.com slash DNA Today. You can also find this link at DNAToday.com. Take charge of your future health with 23andMe Plus Total Health because your health deserves a personalized approach.