All right, thanks very much. It's my pleasure to be hosting Edgewise Therapeutics. We're gonna have Kevin and Behrad give a presentation of the company for about 15 or so minutes, and then we'll just do some Q&A. Please take it away, and thanks very much.
Hey, Paul. Thanks. Great to be here, and here's my forward-looking statements. So Edgewise been around about 6 years now. We started off as a muscle physiology company with experts in the role of muscle in human disease. We built a high-throughput screening platform using phenotypic screens to identify our own novel targets. We then added to that platform a group of genetically engineered animal models of muscular dystrophy and ultimately cardiovascular disease. And then brought in a group of scientists with a lot of experience in drug discovery and expertise in clinical development. So very rapid results from our platform. From a standing start, from a novel target without a lead, we identified the lead series, optimized it, moved it into clinical development, and are now in phase III, in about 6 years.
So, very successful and rapid progress. That first phase III study is now in Becker Muscular Dystrophy. It is a fast Type II myosin inhibitor, which is an ATPase. We've also initiated studies in Duchenne Muscular Dystrophy in phase II, and Limb-Girdle, and McArdle's Disease. Out of that initial screening campaign, came a set of really novel cardiovascular molecules. We had sort of a choice of things that were cardiac myosin inhibitors, as we target the sarcomere, which is the muscle fiber fragment that you can run these assays in. So instead of going after a best-in-class cardiac myosin inhibitor like mavacamten and aficamten, we decided to go our own way, find another novel target in the sarcomere to regulate cardiac function, and that molecule, EDG-7500, just went into the clinic in September.
Third program is our cardiac metabolic program. As you might imagine, modulating muscle is become really exciting, today. In fact, interest in the GLP-1 space and the loss of fast muscle has driven us to think hard about how we could use muscle and target muscle for metabolic disease and obesity. So that's 7500. So let's talk about 5506, and give people kind of how we view muscular dystrophy in that space. So muscular dystrophy, which includes Duchenne muscular dystrophy and Becker muscular dystrophy, is a disease where a key structural component of the muscle, dystrophin, is either missing in Duchenne or mutated or at a lesser amounts in Becker. But realistically, these are a continuum of one disease. There are Duchenne patients that look like Becker patients, and there are Becker patients that look like Duchenne patients.
The real question is, why is that, and what is the true role of Dystrophin? So what Dystrophin does is not provide function, and we are all currently aware of how, the more recent, therapies have not shown benefits in function to the patients. What the Dystrophin really does is when the muscle contracts, it ties the fibers together so that they all work in unison. When you're missing the Dystrophin, you're missing the Dystrophin, individual fibers in that bundle hypercontract, and that hypercontraction leads ultimately to how you lose function. So this slide gives you kind of the choreographs, the set of events. You have muscle contraction, damage to the muscle, that leads to an inflammatory response and ultimately regenerative response.
But in a Duchenne patient and a Becker patient, that regenerative response fails over time, and instead of replacing the muscle with normal muscle, you replace the muscle with fibrotic and fatty tissue, and then you lose function. So what is the proof of that? In young Duchenne patients, their biomarkers of muscle damage are highest when they're 1-2 years of age, before they ever lose function. So muscle damage precedes loss of muscle function. Okay? So how can you measure that? And this got me excited when I first foresaw this program. It's always good to look at the clinic and work backwards. So what can we measure in the plasma compartment? Well, when these muscle fibers break apart, they spew their contents and components of the muscle into the plasma compartment, and you can measure them.
So interestingly, the one that everybody knows about, which is creatine kinase, is actually used to diagnose the disease, and that's how they actually end up doing the genetic testing to determine whether a child has Becker Muscular Dystrophy or Duchenne Muscular Dystrophy. The next one that we're most focused on is TNNI2. Why are we most focused on that? Because TNNI2 is found exclusively in fast muscle. So what I said before is we are a Type II fast myosin inhibitor, so that is the on-target biomarker measuring fast muscle damage. So that's one of the things we'll be talking about today in our clinical trials. So why do we care about Becker? We went initially into Becker because first, it's adults.
You can go fast, you can take a lot of blood, you can work out all these metrics in Becker patients, and there's a significant unmet medical need. There are 12,000 Becker patients across the E.U., U.S., and Japan. There is no standard of care. They do not use steroids. In fact, oftentimes, they don't even go to a neurologist over time. They end up going to a cardiovascular doc because there's nothing to give a Becker patient. So we think this is a huge unmet medical need. We have Fast Track Designation from the agency, and we believe that the clinicians, if we had a treatment, would treat most of the Becker patients. So is this a bad disease? People say it's heterogeneous and not a big deal.
People even say, companies say: "I'm gonna turn my Duchenne patients into Beckers." But this is not a great disease. If you look at this, half the patients are in a wheelchair in their twenties, thirties, and forties. And you can imagine, you were kind of a normal guy up until your twenties. All of a sudden, you lose function. You might be married, you have a job, you have a career, and all of a sudden, "Man, I can't walk anymore, and I can't get up off a chair, or I can't get off the floor. I can't step on a sidewalk." This is a bad disease. This is not good to have Becker. So why has it been so hard to run clinical trials here? So this is also viewed as a highly heterogeneous disease, but it really isn't.
You have to look at the patients carefully to understand how to select patients. So we will be the first company to do a selective, targeted trial in Becker Muscular Dystrophy. So about 70% of the ambulatory patients are in decline. When a set of patients are in decline, they continuously decline about 1-1.2 points on the North Star. So the North Star is what the FDA has said they view as the relevant endpoint for a Becker trial, and there is a homogeneous, consistent decline when you select patients with a North Star of 5-32 over a 1-year period. So we believe we can run a targeted trial in this population and see benefit in this patient group. So what's our evidence? So we started off with a Becker trial.
We started off at 10 mg, it went for 2 months, then went to 15 mg for 4 months, then went to 20 mg for 6 months. Now, we felt this was really a safety study, but we were able to gain and glean a lot of really useful information out of this open label study. So as we might represent, the patients are in a bad shape. Half these patients cannot get off the floor by themselves. So this is a pretty severe population. Their median North Star is about 15. So here are the results. At 12 months, we saw a 40% decrease in creatine kinase, and at 12 months, we saw a 79% decrease in TNNI2, the on-target biomarker for muscle damage in fast muscle.
In fact, half these patients were in the normal range. So we think this is strong evidence that we are affecting the muscle damage response in these patients. So how does that translate into a functional endpoint we care about? So in this patient population, one would've expected that you would've lost 1.2 points in the North Star. We increased 0.4 points of the North Star. So you might say, this is... "You're preventing muscle damage. How would-- How can you increase the North Star?" Well, you can increase the North Star because you're making the muscle healthier. Healthier muscle functions better, and remember, when you work out too hard, the next day you feel sore, that's the fast muscle being damaged. So if you normalize that fast muscle, you feel better and can perform the function more efficiently, which is why we believe you see an improvement in function.
So the compound is very well tolerated. We've seen changes in these biomarkers that I would think would be important representation of what we'll see, and add benefit to the patient. We've seen improvements in functions and a change from what we think the natural history would go, and we've selected a dose of 10 mg based on TNNI2 in our preclinical models, associated with the target concentration of the drug. So what's the opportunities for this drug? So this drug does not care about how much dystrophin you have, which mutation you have. It's agnostic to the mutation. It's an orthogonal mechanism that can work with any therapy.
So we think it has opportunities as a single agent, we think it'd be used in combination with steroid, and we believe it can be used in combinations with gene therapy and exon skippers, which is both very large populations in both Becker and Duchenne. Here's the clinical trials, just to give you a highlights. We have an extensive program. In EDG-5506, we've completed the CANYON phase II enrollment. So this is a 40-patient trial, 3-to-1 randomized, 1-year placebo-controlled trial in Becker with North Star patients between 5 and 32. That'll read out in about a year. We've initiated the pivotal study in GRAND CANYON about the same time. That will be an 18-month study, should be about a year to recruit. We also have LYNX, which are Duchenne studies.
I'll talk about that a little bit about that later, and we've initiated FOX, which is a gene therapy study. We've had a tremendous number of parents of patients who have received gene therapy ask us: "We need something else. Our kids are declining." So we thought we would get ahead of what's out there and demonstrate that our drug can be used in combination with gene therapy and show the same benefit.
Can I ask maybe a few muscle questions?
Sure.
Before we talk about HCM? So, how are you thinking about the powering of the GRAND CANYON study?
Yeah. So we used a standard deviation that came out of the two sites that ran, so CINRG and Bello, that came out of the longitudinal studies. We also used our baseline or screening to baseline standard deviation of measurement of the North Star, and it turns out that the North Star is much more reproducible in an adult. So what we ended up with a 120-patient trial, 2-to-1 randomization, we end up with greater than 90% power to see about a 1.2-point change. So,
1.2?
Yeah.
Okay.
Yeah, and we think, we think 1 point is clinically meaningful.
Right.
We've talked to many people about that. We're very well powered for that study based on, I think, a very rational-
Okay
... As you probably know, the Duchenne studies have a higher deviation because it's much more difficult to get kids.
Of course
... to reproducibly do this. So I think North Star is the right measure-
Yeah
... for a Becker trial.
Yep.
And a right, right measure for our drug.
Okay, and when we think about the data you have so far, so it's, it's obviously really encouraging. You're seeing stabilization, even this trend towards improvement. Do you think there's any placebo effect embedded in that? Like, what do we know about placebo effect of a test that is somewhat effort dependent in this condition?
Yeah, you know, what's interesting about... So ATOM, which is the, a physical therapy group that is trained to make these measures of North Star, they're actually pushing the patients to do their best response right from baseline-
Mm-hmm
...through. So there, there's less subjectivity-
Right
... with this strategy, when you push them in that way.
Yeah.
I think it's a little more reflective-
Okay
... than, say, a six-minute walk.
Okay. Okay, interesting. And then I guess just more broadly, right, you talked a lot about the biology and stuff, but, like, who do you think are, you know, who do you think is the actual right age range to benefit from this mechanism? I mean, do you think it really could have benefit up into adulthood when someone's already in a wheelchair? Or like, you know, based on your biological understanding of these conditions, like, is there a, is there a threshold where suddenly, like, it shifts? Like, how did you guys think about that in the program and overall?
Yeah, it's interesting. We, you know, we think of troponin I being elevated as a surrogate for they still have turnover of fast muscle. So in these later stage Becker patients, their median troponin I was up in the 10s and 20s, and you could bring it down to virtually zero. So I think that they still have fast muscle turnover, and if you look at the histology across populations, they all still have fast muscle. It's just all the muscle is depleting over time.
Right.
Now, I think how I view the, so how can you just affect fast muscle and the... The slow muscle is degrading as well, but the fast muscle is what turns over, and that turnover and that constant burn of the fast muscle creates a change in the microenvironment that leads to this ultimate change of fatty tissue deposition. Now, what we saw preclinically was even though we had no direct effects on heart tissue, we actually prevented the fibrosis in the heart.
Hmm.
So what we're and what we showed
How is that?
Well, what we showed both preclinically and clinically is we block systemic inflammation. As you might know from, just from basic cardiology, if you have high CRP, so you have, like, that's the measure of-
Yep
... an era of high levels of inflammation, all of your outcomes are worse in cardiovascular. So we think the effect on the heart is twofold. One is you're protecting the diaphragm, so you're decreasing the load on the heart from breathing, and then you're directly blocking the inflammatory response systemically, which also protects the heart.
Interesting. Okay, makes sense.
I really do like the inflammation work in patients was really-
Right
... exciting.
Yeah.
It takes about six months to see that.
Yeah.
... from the, based on the SomaScan.
Yeah.
I think as to your point around wheelchair-bound patients, I think you're looking at a different trial, right?
Right.
'Cause your endpoints are gonna be a little different-
Yeah, of course.
You're looking at-
You're looking at the pole, yeah.
Full point out.
But they still have the upper body.
Right.
Right? And for them, retention of anything, even being able to use a computer, is a big deal.
Yep, makes sense. Lastly, before we move on, so what is the data flow gonna look like from you guys at BMD in terms of catalysts and... Yeah.
Yeah, so two things. One, we'd like to see. So as we developed the Becker story, we were thinking about selecting dose for phase III, and we felt like over time, the way to feel confident you've gotten to the maximal dose without overdosing the patient is to see two consecutive cohorts of drug having the same biomarker response. Then you would go to the lower response, because... And that would be the TNNI2 endpoint. So I've maximally inhibited the damage biomarker for the on-target mechanism. Second thing that's quite interesting is the agency has been interested in us finding the highest tolerated dose and to actually move patients to that dose when you have the opportunity to. This is specifically in Duchenne.
So, we have not formally done that, so we would expect in the first half of 2024, we would have the Duchenne data. But we're trying to, you know, do as the agency has asked-
Right
... and also choose our phase III dose in the most appropriate way.
Okay. Okay, all right. Makes sense. Great! Do you wanna switch to cardiology?
Sure. How much time we got?
You've got 12 minutes.
Oh, there it is. Okay, cool. Oh, lots of time. Okay, so 7,500. So this came out of a screen. We were looking initially for a skeletal selective molecule that led to the lead, that led to 5,506. We ran a counter screen, which was a cardiac myofibril, to look at the selectivity between skeletal and cardiac. What we found was a very novel mechanism, that even within our initial filings in the S-1, we talked about having a broader therapeutic window between the concentration of the drug and the change of ejection fraction relative to the cardiac myosin inhibitors. So you guys all know the cardiac myosin inhibitors, they have a black box and a REMS.
They have very steep declines in ejection fraction relative to their concentration, which requires them to use echo-guided titration of the drug to get to a target exposure. So what we wanted is a drug that would not require echo-guided titration, would have a different mechanism, perhaps having deeper responses, and that's EDG-7500. We do all the things that the myosin inhibitors do, except we change the kinetics of the interaction. So we have a slower effect on contraction, which spreads out the concentration relationship on the Cmax, and we have a faster release of the myosin heads, providing a larger left ventricular volume and some other aspects, which I think are very beneficial. And the diastolic dysfunction is the key underlying issue with non-obstructive HCM in certain populations of HFpEF. Here are the heart.
I won't go through that, we save some time for questions, but as you can see, you have a thickened wall. You have a decreased size in the left ventricle and an increased left atrium. So the hypothesis here is that you interact... And this is what the cardiomyopathy inhibitors do, is they interact with the bright blue heads, and you have too many of those, which leads to hypercontraction, which leads to the deficit and the ultimate cardiomyopathy in HCM patients. And so what a cardiac myosin inhibitor does is bind directly to that blue head. So it's a direct interaction with the force generation piece of the mechanism, and this is a depiction of the sarcomere. Now, let's get down in the weeds. Here are the weeds. The weeds are what the sarcomere really looks like.
There are a dozen targets within the sarcomere. So what we're doing is we have a target that is distal from the ATPase. By having that target that's distal, we get differential biology. So, it was a little bit empirical, but we saw this in some of the preclinical models, and we're very excited about this result. So there is efficacy to be left on the table with the cardiac myosin inhibitors. We see about 40% of the patients do not have a clinically significant decrease in gradient in an obstructive HCM population, and we see about 30% of the patients not have an effect on the New York Heart Association 1-point change.
Should this mechanism, I know you haven't disclosed everything about it, but should this mechanism, as you understand it, work in these mavacamten patients that are suboptimal responders?
It's a really interesting question.
Okay.
and how you include them in the studies.
Yep.
and you see if this is
Right.
This is due to perhaps the therapeutic window.
Mm-hmm.
or is it due to the biology?
Right.
I should point out that only 40% of HCM patients have a mutation that's been identified, so it's still quite a bit happening in this space. But there have been some newer data now about the particular mutations and particular outcomes. So obviously, we're looking at that very carefully.
Your point is a good one 'cause some of these patients are getting cardiac myosin inhibitors. The issue is you can't push the dose too much because you lead to a steep drop in ejection fraction.
Right.
Probably a proportion of these, no matter-
Yeah
... you know, you've got dose-limiting toxicity that's preventing you from pushing.
Makes sense.
So, we've extensively studied this molecule. We've put out all the preclinical data. We'll have additional preclinical data, chronic data at ACC, coming up. We looked in the cat model of obstructive HCM, and we looked in the pig model of non-obstructive HCM. What we found was quite profound. With a single dose, we saw a 60% gradient reduction in the cat model of obstructive HCM, with only a 2% response in the ejection fraction. This would be 20% with Mava. We also saw some really interesting things in the pig model. In the pig model, you have an increased ejection fraction because of the hypertrophy. We could normalize that ejection fraction in the pig.
We could increase the relaxation of the left ventricle, we could decrease the wall thickness of the left ventricle, and we decreased the atrial volume. All these things are in line to having a profound effect on the kinetics of contraction in the ventricle on the diastolic end. And as you know, this is certainly an important population, the non-obstructive HCM patients, and we should be able to hopefully see this in in our studies in the future, and that will translate into being a jump into some of the larger HFpEF populations.
We're in the middle of a classical SAD MAD normal healthy volunteer study with echo guidance to look at the difference between the concentration and the echo values, and then we'll be going into obstructive HCM patients second quarter of next year, as soon as we get the sites up and running. Now, the exciting part of this is that with a single dose, we think we can differentiate from mavacamten based on our cat data. And so the package that we'll put together for probably third quarter of next year will be safety in normal healthy volunteers, SAD MAD, and differentiation and obstructive HCM with a single dose, and demonstration of the diastolic relaxation effect that should be differential relative to the cardiac myosin inhibitors.
How quickly and in how many people, either healthies or patients, can you show differentiation on this ejection fraction issue?
It's a good question. I mean, we're, we'll see. You probably have to get through the MAD-
Okay.
I think, to actually see it, to get enough data points.
Is healthy enough there?
Boy, I hope so. But I think we're-
You'd have to de-risk that based on precedent.
Yeah, we should have precedent. There is data that has, that is published on the MAD in the normal, healthy volunteers. So I would think we can show that there.
Okay. Okay, very good.
Okay, so, deliverables for the 2024, it's gonna be a very active 2024. We'll have the 3-month control data in Duchenne, which will be a biomarker as well as some functional endpoints. We'll have the ARCH 24-month data, which I think, going back to your point about placebo, over 24 months, it'll be clear.
Yeah.
If it's still flat or up-
Yeah
... it'll be clear, these patients, unless the natural history is completely wrong.
Right.
That'll be clear. We have an exercise challenge study, which supports this link between activity and biomarker response-
Mm-hmm
... which is quite interesting, and put it in front of the FDA to get some level of quantitation associated with that. We'll initiate the phase III DMD study, the phase II CANYON controlled study with 40 patients will read out by the end of the year, and then we should have data on EDG-7500 in healthy volunteers and obstructive HCM.
Great. Can I ask one more Becker question, actually?
Sure.
I was thinking about this natural history question, and I was looking at that chart you have and some of the bars, right, like the lines are, they're diagonal, which I think denotes, right, that there's, like, not a ton of patients at certain age ranges, right, in this natural history.
Oh, in that-
Yeah
... in that the ambulant.
Yeah.
Yeah.
So I was like wondering, like, you know, Becker, you lose a lot of these people to follow up. Is it possible at all that the natural history data is overestimating the progression because so many patients are lost, and only the more severe ones are caught up in these kinda databases and studies?
Um-
Or is that kinda ruled out in your trial demographics?
It's kinda. I would say that it probably, that set is overlapping.
Okay.
I think your question is maybe different, is there a set of people who are lost?
Right.
But I also would think that the set of people that wanna participate in our trial-
Are the same as the natural-
... also the same people within that subset.
Yeah, yeah, yeah. Okay.
Right?
From a clinical risk perspective, it's like, probably fine.
Yeah. But it's a good question, though, because-
Yeah
... are they just lost?
Well, the answer, the Italian natural history study, if you look at it, Bello followed cohorts for up to five years. There's actually people who don't progress within that natural history. So about, I think 30%-40% of his patient cohort don't progress, and they have certain mutations.
Mm-hmm
... that by selecting with the, North Star thresholds that we've selected-
Right
... we automatically exclude them anyway. So you could argue that actually, in his practice, you actually see the majority of the real-world representation of Becker patients.
Yeah. Okay. Makes sense. Sorry, interrupted. Please.
No, it's great.
Wrap up.
I've gotta say that since we put the data out in June, there's been a groundswell of enthusiasm from multiple different populations, and our recruitment has been brisk.
Yeah.
So there has been, hasn't been an effect with the gene therapies and other things that are out there. People believe in this mechanism. This makes sense to the parents of the patients, and it's kind of exciting-
Yeah
... to see the enthusiasm. So we have $290 million in the bank. That is, cash runway through 2025. Very good position to be in with multiple milestones coming this year.
Okay, great. Well, thank you guys very much. It's always a pleasure. Appreciate it.
Thank you.
We've one minute of time, so... I don't know how much else we can really cover.
Yeah. Okay, that's good.
Okay.
Thank you.
Thanks, Paul.