Edgewise Therapeutics, Inc. (EWTX) Earnings Call Transcript & Summary

Hello, and welcome to Edgewise Therapeutics Investor Event. My name is Mike, and I'll be the operator for today's call. I'd like to pass the call over to Mike Carruthers. Please go ahead when you're ready.

Thank you, and good morning. This is Mike Carruthers, Chief Financial Officer at Edgewise Therapeutics. Welcome to our call to discuss our positive 2-year results from the ARCH open-label study of sevasemten in individuals with Becker muscular dystrophy. You can join this conference call on the Edgewise website at edgewisetx.com. We're using slides to accompany our remarks today, which can be downloaded from the Investor Relations section of our website, and a replay of the conference call will all be available as a webcast on our website. I'd like to introduce Edgewise President and Chief Executive Officer, Dr. Kevin Koch; and our Chief Medical Officer, Dr. Joanne Donovan, who will lead our call today. Dr. Alan Russell, our Chief Scientific Officer, Dr. Behrad Derakhshan, our Chief Business Officer, and I will be available to answer questions as needed. As a special guest, we have Dr. Barry Byrne joining us today. Dr. Byrne is the Director of the Powell Gene Therapy Center at the University of Florida and the Chief Medical Adviser for the Muscular Dystrophy Association. Before I turn the call over to Kevin, we want to remind everyone of the following safe harbor statement. The matters we're discussing today include projections and other forward-looking statements about the future results and research and development goals of Edgewise. These statements are estimates, based on management's current expectations and involve risks and uncertainties, which could cause them to differ materially from actual results. We refer you to risk factors discussed in our filings with the SEC, including our annual report filed on Form 10-K on February 22, 2024, and other Edgewise filings with the SEC. These filings identify important risk factors that could cause actual results to differ materially from those in our projections or forward-looking statements. Edgewise specifically disclaims any obligation to update any forward-looking statements, except as required by law. I'll now turn the call over to Edgewise CEO, Dr. Kevin Koch.

Hi, Mike. Thanks a lot, and thank you all for joining. I appreciate joining the call today. Next slide. Edgewise Therapeutics is the leading muscle disease biopharmaceutical company developing novel therapeutics for the treatment of muscular dystrophies and serious cardiac conditions. The company's deep expertise in muscle physiology is driving a new generation of first-line class therapeutics. Edgewise-5506, now called sevasemten, is an orally administered skeletal myosin inhibitor in clinical trials for the treatment of Becker muscular dystrophy, Duchenne, limb-girdle muscular dystrophies as well as McArdle's disease. Edgewise-7500, currently in Phase I trial, is a novel cardiac sarcomere modulator for the treatment of hypertrophic cardiomyopathy and other disorders of cardiac systolic dysfunction. The entire team at Edgewise is dedicated to our mission, changing the lives of patients and families affected by serious muscle disorders. Next slide. Becker muscle dystrophy is a severe underappreciated condition with a significant unmet medical need. These patients typically are diagnosed in their adolescents. They tend to have functional deficits early in their 20s and ultimately lose motor function and ambulation in their 40s, and have a shortened lifespan because of cardiovascular comorbidities. No therapy has ever been approved specifically for Becker. It's a relentless march of progressive muscle disorders where people have built lives, have families and that independence is taken away from the prime of their lives. So it's a devastating disease. Next slide. Let me tell you a little bit how our drug works and there -- muscular dystrophies, and there is many different varieties of muscular dystrophy. It often starts with a mutation in the sarcomeric unit, which is essentially the part of the fiber -- muscle fiber involved in contraction. In certain muscular dystrophies, there is a aberrant genetic mutation in a key structural protein called dystrophin. Denoted on the left side, you can see that these dystrophin molecules in the blue are involved in cross-linking the muscle fiber. And when that muscle fiber contracts, that dystrophin keeps the muscle fiber together, spreads the stress across the muscle fiber and prevents damage to the muscle fiber. In diseases like Becker muscular dystrophy, some of those dystrophins are missing, thus, the fiber is not fully cross-linked and certain fibers within that muscle hyper-contract where you get mechanical stress and you damage that individual muscle fiber. Go to next slide. Here, you can see the notion -- a depiction in the fiber of a lumbrical muscle of a Duchenne mouse with a genetic lesion similar to Duchenne. On the left, you can see that as the muscle fiber contracts, you see damage to the membrane with leakage of calcium into the fiber that turns on apoptotic mechanisms, which cleave the Z-disc of the fiber and form these contractors. On the right side, what you see is that treatment with a small amount of 5506 leads to complete blockade of that muscle breakdown. Next slide. So what is -- what does Sevasemten actually do? So in muscle disease, excessive contraction-induced muscle damage leads to damage to the muscle, which leads to an aberrate response of trying to repair the muscle and replacement of healthy muscle with fat and fibrotic tissue. That leads ultimately to the loss of function. What Sevasemten does is to block that aberrant muscle contraction, protect the muscle and prevents the contraction-induced injury and, ultimately, the progression of the disease. Let's go to the next slide. I'd now like to introduce Barry Byrne to provide some understanding contextualizing of the Becker muscular dystrophy, and how we measure a progression of the disease in this indication. Barry?

Thanks very much, Kevin. I'm glad to join you and the Edgewise team to give you some context regarding the clinical assessment of patients with Becker that has been used in the Edgewise studies to date, if you can advance to the next slide, please. So just to understand how important it is to define the tools used to management of function in Becker and Duchenne muscular dystrophy. The North Star Ambulatory Assessment has really come to the forefront of the most comprehensive and useful approaches to assessing function. And this slide is meant to just give you an idea of what real-world implications are, for patients with Becker, when they lose the ability to run or to stand and rise from the floor. And for example, standing on your heels is a prerequisite to be able to walk particularly when there's an uneven surface. And this assessment of 14 -- 17 different tests can be used to assess progression in Becker dystrophy and potential therapeutic effects of a drug like 5506. So next slide. And several natural history studies have been conducted, which helped define the rate of decline in Becker. The 3 studies listed here; De Wel, Bello and Niks, all showed that over a 4-year to 5-year period, that there is a loss of about 1.2 to 2.4 North Star points per year. And this is -- I'll show you the consequences of that in terms of form and function that patients experience as this disease progresses. And this, of course, causes significant morbidity and ultimately, as it relates to the cardiac findings also, mortality in this patient population. So in next slide, if we group Becker patients as they were enrolled into the Edgewise study between North Star scores between 30 and 34, which are the highest functioning Group 1 patients versus those in Group 2 with North Star Assessments at baseline between 20 and 29. And then over time, those same group of patients would progress to a North Star of between 10 and 19. And the least functional assessment is in this Group 4 with North Star between 0 and 9. And so we're really hoping to demonstrate the importance of even modest changes in North Star and what happens when a compensated effect becomes inability to do that particular function. So in the next slide, you'll see as we break out the function over the 17 items in these 4 groups. You can see in the most high-functioning group with baseline North Stars between 30 and 34, the key adaptations are rising from the floor and standing on heels, and we'll show in more detail on the next slide what proportion of patients ultimately lose this function and then lose the ability to walk or stand. And you can see as the compensation is lost, as you move towards Group 4 over these many years, you can see that each of these domains is completely lost and function would be a North Star score in that domain of 0. So next slide. So just focusing on Group 1 patients with the higher functioning North Stars of 30 to 34. The principal effect on rising from the floor is compensated for in about half of patients, and then a small portion, about 10%, are unable to stand on their heels and would have impaired walking. And then a greater percent, 70% actually compensate for that dysfunction and ultimately leads to loss of walking ability. Next slide. In the Group 2 patients, which have now, you see, lost the ability to stand only on their heels, they also now proportion start to lose the ability to hop or to climb or descend stairs. And you see that this climbing or descending stairs now represents a significant loss of function in this group. And if we go to the next slide, you'll see in Group 3 patients now focusing on that stair climbing activity. When you ask patients in retrospect, when they start to develop difficulty climbing stairs are often using compensation like pulling themselves up the stairs on the hand rail. Now you can see that almost 90% of patients have lost the ability to stand on their heels and also hopping on one or the other leg. And now that results in a loss of function in terms of walking ability and ability to perform the 10-meter walk/run test. In Group 4, where there is a lower functioning patients, in the next slide, you can see now compensation has given way to loss of function in almost all domains. And this has this huge impact on quality of life and it's representative of the inexorable progression of this disease. Next slide. So just to summarize really that in terms of care of this patient population, it's important to recognize that even nominal changes in North Star have a huge impact on daily living. The disease is progressive, and once compensation begins and there are some domains where function is lost, this results in further decline and rapid loss of function. And one of the goals in maintaining function in this patient population is to change even just 1 point on the North Star, which would have a significant impact on quality of life. And so that's what I think we'll see as we progress through the information to be presented today, if you can go on to the next slide. And next, Joanne Donovan, who's the Chief Medical Officer of Edgewise, will talk about the effects of 5506 on function.

Thank you, Barry. I'm really pleased to be able to share these data with you today on how Sevasemten is affecting function and biomarkers of muscle damage in these adults with Becker. And on the next slide, the overall design of the study is shown. Now the ARCH study is an open-label, single-center study to assess Sevasemten safety and pharmacokinetics in Becker. The primary objective was safety and tolerability. Remember, we brought patients over from the Phase I study and continued them in this study and added additional patients. They were ambulatory males aged 18 to 55 with a dystrophy mutation and a phenotype of Becker. They were not taking corticosteroids. And the only functional criteria was that they could complete a 100-meter timed test. We enrolled 12 patients, and we stepped up the dose over time. And as you'll see, we identified a 10-milligram dose as the dose going forward in our studies. In addition to safety and tolerability, of course, we looked at safety and multiple functional measures, as I will show you. And so these data today are focused on 24 months of exposure in these patients. In the next slide, we have just kind of an -- a sight here, this was a single-center study. So an interesting trivia is that people traveled 190,000 miles to participate in this study. We started out with relatively frequent visits, so they were going back and forth a lot, and we are enormously grateful to these patients for continuing in this study and sharing their time to be able to understand more about Sevasemten. On the next slide, we have what they looked like at baseline, and these patients were significantly functionally impaired. As you saw what is North Star in the mid- and the mid-teens, 15. So they have lost significant function. Only half of them could rise from the floor. 8 seconds is a long time to be able to traverse 10 meters. And we could see that they had decreased muscle mass as evidenced by a decrease in serum creatinine and also a decrease on the DXA evaluation of the muscle mass. So all in all, these patients with Becker are at a more advanced stage than typical ambulatory studies with Duchenne. And you would expect adults with these similar baseline scores 4 to 31 to be expected to decrease, as Barry showed, by 1.2 points per year. So they would be expected to be in the decline phase of their disease. On the next slide, shows safety. And paramount, of course, is safety. Sevasemten remains well tolerated at all of the doses we studied. And there are not unusual new side effects that we've noticed. We've not had any dose reductions or adjustments, no treatment discontinues because of AEs, no SAEs. And we have had patients withdraw. There are actually 2 of them are coming back in open-label extension that we are now moving patients into the [ NSAA ] study and 1 for travel reasons. On the next slide shows function. That's what we really want to see here. And we saw that the North Star stabilized and continued to diverge from natural history now at 24 months. This is the full data set, all North Star evaluations, all patients. And whether they started at -- on the left is the individual ones. Whether they started at 31, whether they started at 4, you can see a consistent stabilization and improvement in some cases in North Star, which is not what you would expect in these patients. On the right shows the average with a 0.2 mean decrease in North Star over 24 months, and the overall best fit shows an increase in stabilization, a slight increase in stabilization over 24 months. And that's compared, of course, to the 2.4 decrease that you would have expected to see in patients like this. On the next slide is analysis, if we use last observation carry forward similar. So basically, no matter we've shown you all of the data, however, we look at it, we are still seeing a consistent theme of stabilization. And in fact, there is 1 patient who had a meniscus tear and surgery that showed some decline afterwards they were still rehabbing. And on the next slide shows the individual responses, and that person did have a decline over time during -- basically during their rehab. And all of the other patients at 24 months showed a -- basically a improvement compared to the natural history, with several of them showing an absolute improvement there. So you can see that is we've got a very good estimate of what we see in time. I'd also point out, these are the 95% confidence intervals. These are not SEMs. So the reproducibility of this measure is quite good, and it does not include a decrease of 2.4. So on the next slide, we also looked at biomarkers as we've shown you before. And we saw rapid and sustained decreases with Sevasemten of the creatine kinase of fast skeletal muscle troponin and myoglobin, indicating target engagement and also providing support for identification of the 10-milligram dose as our target dose here. In the next slide, we also looked at other measures, and we've shown here the 100-meter time test velocity, which is stable over 24 months, and maximum group strength, again, stable over 24 months. So this is very reassuring and really exciting for this patient population to be able to show maintenance of function, maintenance of muscle strength over this extended period. So we're really pleased with these data. On the next slide, these data then support our future clinical development plans. We've been able to see safety. It's well tolerated at all doses. Sevasemten demonstrated rapid, sustained and significant decreases in multiple biomarkers of muscle damage. We've seen stabilization of functional assessments with trends towards improvement in some. The pivotal dose was identified with a essentially maximal biomarker response at the 10-milligram dose, and that supports our pivotal cohort and the -- which is in GRAND CANYON design. Now on the next slide shows our current study that is ongoing. CANYON is fully enrolled. It's actually the largest interventional Becker study to date. And we have top line data anticipated in Q4. The primary endpoint is biomarker. And the key inclusion is adult individuals with North Stars between 5 and 32, so very much mirroring the population that you just saw, not on corticosteroids. And they are getting a dose of 10 milligrams. We are looking at that at the end of 12 months, and we will be reading that out as shown on the next slide later in fourth quarter of this year. And we really think this could be transformative in terms of showing placebo-controlled data. It's important in that it gives us additional information to be able to refine the statistical analysis plan of the GRAND CANYON pivotal cohort to improve, to optimize the chances of trial success. And we're also looking positively that positive data from CANYON could support a pathway to explore earlier approval of Sevasemten for Becker. And we'll be looking at, hopefully, statistically significant changes in biomarkers of muscle damage. These are not something that one sees with the natural history of the disease, the abrupt decrease and stabilization. And as we look at trends and potentially statistically meaningful changes in secondary endpoints, this is something that we think that we could, in the best of all possible worlds, move towards an earlier approval on. So that's what's coming up later this year, and ongoing on the next slide is the GRAND CANYON study, global, multi-center, placebo-controlled pivotal cohort assessing efficacy and safety of Sevasemten in Becker. The primary endpoint will be North Star at 18 months. We are also looking at the same population here, adults with North Stars between 5 and 32, not on corticosteroids. Our target enrollment is 120 patients. And based on the emerging data from ARCH, we are powered at well over 90% to observe a difference corresponding to the natural history decline of 1.2 points per year. And we are also looking at additional measures, including time function tests, biomarkers, MRI, patient reported outcomes. So it's a very robust study. And on the next slide, I will turn it over back to Kevin.

Thanks, Joanne. Exciting data set. So there are no approved therapies for Becker muscular dystrophy. As you might imagine, these patients are diagnosed typically in their adolescents. And so the prevalence builds over many years as these patients often live into their 50s and 60s, but it's a slow progressive disease, and there are over 12,000 patients in the 3 major markets of the U.S., EU and Japan. Interestingly, we -- it's hard to find these patients. We go out and we've built a broad outreach package to find these patients, and physicians have looked at our data set, and in the past, they have -- they don't treat these patients, they often treat them with their -- for their cardiovascular disorder not for their muscular dystrophy. And we think many of these patients -- these physicians would go out and reach out to these patients. And when they reached out to them, they've been enthusiastic about joining our trial. So we think this is a disease of high unmet medical need with a high prevalence where a new therapeutic would have a tremendous impact on the patients. Next slide. The company is very well financed. We raised money. In January, we have $550 million in the bank. This will take us through 2027 with all of our projected studies in both muscular dystrophy and cardiovascular disease. We have zero debt, and we have 93 million shares outstanding. With that, we'll take any questions from the callers.

[Operator Instructions] And our first question today comes from the line of Joe Schwartz from SVB Securities.

It's Joe Schwartz from Leerink Partners. So it's super interesting that the patients in ARCH traveled in aggregate of 190,000 miles for the assessments during the study. So I was wondering if you have any information on the patient's motor activity and how well Sevasemten suppressed their CK spikes in those who are more active?

Yes. It's interesting. We did not have a device to measure that activity in this part of the trial. I presume it would have been -- in some respects, the biomarker could have been more variable. But as you saw in our presentation, there is a durable decrease in all the biomarkers. So even though some of these patients clearly would be more active coming into the unit, that was not necessarily reflected in the biomarkers and in particular, in their functional benefit from the drug.

Okay. Interesting. And then how should we view the merit of CK as a surrogate biomarker and BMD? And what do you think you need to see from CANYON in order to lead you to approach the FDA to discuss the potential for accelerated approval?

Joanne, do you want to take that?

So -- thanks, Joe, for the question. So CK is a very variable biomarker on an individual basis, which is why FDA looks at it as really is that -- that's quite variable. What we're also doing is supporting that with longitudinal data and trying to understand that in other data sets, both for CK and for fast muscle troponin, which is very specific to this drug and shows a profound decrease as well. So we are working to support that. But of course, it needs to be supported by functional measures. And that is the key here. And the ARCH study is, I think, a significant part of that supportive evidence in terms of showing a long-term benefit in terms of stabilization.

Okay. That's very helpful. And then as a follow-up, how well do you think the natural history data we have in BMD predicts what we could see in the placebo arm of CANYON and GRAND CANYON studies, which are obviously interventional? And we all live in fear of placebo effects, and so I was just wondering, have you been able to take that into account in your thinking?

Joanne, do you want to follow up on that?

Sure. So I think that data has been very consistent that once patients start to decline, they continue to decline. So we have 5-year data, we have, with now 3 studies. And you look at the cross-sectional data, we have it, we've shown it, others have shown it. And what you see is that the young men in their late teens, early 20s, are often right at the top of the spectrum, right at the top of the North Star. Then you look at what's going on in those in their 40s. And they're down, representing that third group of patients having lost functions that Barry showed. So we know they're getting from one place to another. They are continuing to decline. So that is -- and the more data that came out, one of those papers came out, still -- it came out earlier this year. So I think that we are seeing this very consistently with more data emerging from that. I think 2 years is a long time to see as a placebo effect as well. And we are seeing these are reproducible. We didn't see -- if you look back at that, we didn't see an initial placebo bump. What we saw was, if we didn't see that bump, we saw at 2 months, they were stable and then moving down, they were stable and, in many cases, trended up.

Joe, I'd like to just follow up a little bit is that the FDA views these biomarkers as somewhat variable. And I think what will come out of CANYON is that CANYON and the placebo group will probably show a pretty flat biomarker response over a period of a year. And that will actually point to the agency that this is a -- these biomarkers are not as variables one might think over a 1-year period. And that our deep response early after the beginning of treatment and that durability of that biomarker response and ultimately, hopefully, statistical significance relative to placebo will suade the agency that this is too variable to measure and that ultimately, blocking muscle damage would predict, at some level, providing clinical benefit to the patient. So that is the narrative we're building for CANYON in our discussion with the agency at that point.

And the next question today comes from the line of Laura Chico from Wedbush.

I guess one question for Edgewise and then one for Dr. Byrne, if he's still available. Just with respect to CANYON, if the data were positive, and you showed a static improvement on the biomarkers, a numeric benefit on North Star, can you just walk through the time line or sequence of events thereafter? I guess I just want to make sure I'm understanding. I presume you would be approaching FDA, but what would timing to a potential NDA submission look like?

Joanne, you might project the timing. I don't know how much detail we can really provide, but it depends -- but Joanne, why don't you take a crack at it?

Yes. I think what we are doing is being forward-looking, and we are -- of course, we are powering a pivotal study, and that's based at 90% plus powering. But we're also making sure that we're prepared to be able to go to FDA, to be able to file in an expedient fashion and not get surprised by good data. So we are doing the things we need to do to be prepared for that.

Just as a follow-up, I mean we've invested in some of the CMC requirements for a [indiscernible] product as well as building our quality group. So that would be entirely ready to move as rapidly as we could to the agency for that discussion.

Okay. And then maybe a quick follow-up. So in the individual breakdown of NSA's responses at 24 months, there were a couple of patients to have between 2 -- plus 2 and plus 4-point improvements on North Star. And Dr. Byrne, I was just wondering, you gave a lot of context in terms of kind of what the loss of North Star scores imply for your patients, but what would a 2- to 4-point gain on North Star mean for some of your patients right now?

Yes. Thanks for the question, Laura. It can be enormously significant because of the impact on daily living. So patients being able to ambulate just even within their home, being able to get to work, rising from the seated position, obviously, necessary also for driving just to get to work and live their life. So I think it's really encouraging to see that in some individuals where they have been compensating that, that could restore function or it's less likely we'll see a function that's lost come back completely. But certainly, reversing compensation is one of the things that we could hope for and expect.

And the next question today comes from the line of Yasmeen Rahimi from Piper Sandler. [Operator Instructions].

Congrats on that outstanding data. I guess the first question I had is, if you look -- I mean, the individual patient data across North Star is very impressive. If you overlay that individual data with the individual data in CRISPR as well as the biomarkers, do you see sort of uniformity, especially in patients who exhibited greater benefit? I guess what I'm trying to figure out is like is there a directional magnitude that all track that the patient has the greatest change and the North Star also got the greatest change in the biomarker as well as functioning. That's question one. And then question 2 is for our physician who provided wonderful insight on what is really clinically meaningful for these patients. I guess, given, if you look across Group 1, 2, 3 and 4 in North Star, is there a group that you would, I guess, if you had to enrich a population with the lease POS of a placebo response, is there -- like is there a placebo response at a Group 4 is going to be different than if you end up at Group 1 or Group 2? I would love to get your color on that, and I appreciate you taking my question.

Barry, could you take the functional question first, and then we'll handle...

Sure. Sure. Yes. happy to, Kevin. So yes, I think to your point, it's where is there more likely to be a clinically meaningful benefit in this group with early changes like in Group 1 for those with more severe changes. And it tends to be that when there's a complete loss of function, and then that disability really helps cement that function because they've become orthopedic disability when one has prolonged seating as opposed to walking. And so it's more likely to be meaningful in Group 1 and Group 2 than it is certainly in those more advanced patients in Group 4.

Yes. And Yasmeen, I think just taking your question on the direct correlations of biomarkers with functional outcomes, I think it's -- first off, they're small ends. Second, I would argue that there's a component of this where the patient feels better when they have, I would say, decreased muscle damage or churn in their muscle. So I would say that part of what you're seeing is an effect on the muscle in a way that it's preventing progression of the disease, but at the same time, you're also -- the patients have reported that they feel better. In some instances, there's less pain in the patients, and that will allow them to function more effectively and would be a higher score on the North Star. I think also the patients probably across the country for 2 years, there just anecdotally needs to be -- they must feel there's benefit to being on the drug. And so while I think exact correlations of percent decreases in biomarkers don't entirely match up with improvements in North Star, I think you can say that all patients that have an improvement also have responses in their biomarkers. So yes, I think that's -- it's difficult to have a one-to-one correlation, but I do think there's a broad sweeping observation that decreases in biomarkers and muscle damage is a positive thing for the patient.

And the next question today comes from the line of Tess Romero from JPMorgan.

Congratulations on the data here. Dr. Byrne, thank you for being here as well. We'd be very interested to hear how your impressions of the program have evolved over time as this data has unfolded? And for the Phase II CANYON trial, we wanted to also ask you specifically, doctor, about the Edgewise team made some comments about how they think about CK performing over a 12-month period. Do you agree with this stability view? And what is your level of comfort that there will be a statistically significant separation here? And to put a little bit of a finer point on it, what are you looking for in function over 12 months?

Barry, I think that's yours.

Yes, I'm happy to answer. So obviously, as you saw this patient population or young adults and middle-aged adult patients who have been living to this point with some level of disability. And so the fact that, that progression can be arrested and, in some cases, there are reasonable gains in function, I think as you -- over time, certainly, every patient with muscle -- weakness benefits also from movement and rehabilitation. And so as patients begin to take more chances in a way, they become very cautious with the walking ability as it declines. So as patients improve their physical functioning, and especially as Kevin mentioned, there may be a lessening of the chronic pain experience and also significant in every patient population with neuromuscular disease is fatigue. So those will impact significantly the quality of life. And ultimately, I think as they can potentially gain new skills over time. So it may take more than a year though, and that's not surprising given the duration of the disability at the time they've initiated this therapy.

Okay. And on CK, Dr. Byrne, any comments?

Yes. The challenging part of CK is even, in unaffected individuals, there can be changes in response activity. So I think the stabilization effect on the membrane of the fast skeletal muscle fibers actually will have an effect to -- as has been shown, in fact, to lower CK, but also when one increases activity level, strength is improved by progressive injury and repair and so -- in all of us. So when patients begin to do more and exercise more and more active than there may be a natural tendency towards minor increases in CK that they're potentially offset by the direct mechanism of action of the drug. So it's hard to separate those entirely. And I think we just have to see over time how that and the more sensitive assessments of troponin help to support the functional outcomes that are observed so far.

And just a follow-up, activity is good for muscle. And sets an opposing response of perhaps CK not being down to normal. In fact, moving muscle is good for the muscle, and therefore, creates a healthier muscle. So there is a bit of a competing factor here about how much exercise and activity is good for the patient. Certainly, inactivity is not good for the patient, which will lead to atrophy of the muscle. So there's a balance, I think, that you need to look at in regards to the muscle damage biomarkers and the depth of the response. And I think as we get out to 1- and 2-year studies, you'll see that play out in stabilization or benefit to the patient on their functional capacity.

The next question today comes from the line of Leonid Timashev from RBC Capital Markets.

Congrats on the data. I have a question on some of the baseline characteristics and how that's translatable, and maybe I'll have a follow-up. So given that you enrolled fairly severe Becker patients here, as you're watching the enrollment in CANYON and GRAND CANYON as well, I guess, how similar are the patients that are being enrolled there? Are they generally as severe, are they somewhat less severe? I guess I'm just trying to gauge how they might respond relative to these 12 patients at ARCH.

Joanne, why don't you take that one?

Yes. So we have an upper bound on enrollment at 32. And I think one of the things that we have seen in clinical trials in muscular dystrophy is, as we learn whether -- what the most likely group is to benefit, then we can look at the statistical analysis plan for the GRAND CANYON and potentially modify that. That being said, I think one of the striking things that you saw on the individual data is that despite whether they were at 32 or 31 or 4 to begin with, you saw a similar stabilization. So -- and to go to your question, yes, we are seeing a similar group of patients. We have had very few, for example, with [indiscernible] because they were above 32. So we're seeing a typical population. And they are motivated to be in clinical trials. I think that some of the message that we have -- that we are also just working to reach out to the community is that once one has had a decline in function, it's not enough to say, yes, I'm just going to hang out here at the North Star of 20 for the next 10 years because that isn't what happens. People tend to decline. Once you've started the decline, then the individual slopes in the natural history study are that they do continue to decline. And so that is an understanding of the disease that really wasn't there a half dozen years ago even. So we are seeing people that are motivated to get into the trial who are in that decline phase. And we're really encouraged by the data to be able to make a difference for this community.

That's really helpful. And then I know we've been focusing on Becker, but just wanted to sneak one in on Duchenne. And obviously, there has been pretty severe Becker patients. But given the strength of the 2-year data here and the robust biomarker decreases, I guess, how do you think about what we should expect from LYNX and sort of the Duchenne population just given what we've seen here?

Well, certainly, certainly, the Duchenne patients are having a much higher levels of biomarkers. And they're -- depending on the age, let's call it, a different and variable level of decline in these patients. So with LYNX, as you remember, we're dosing 4- to 9-year olds. And so one might suspect that the 4- to 6-year olds are improving and if the 7- to 9-year olds are declining. So I think how we would interpret this, and we're still in the throes of enrolling and analyzing data from the fifth cohort is that we ultimately have seen biomarker changes with increasing exposure. And we hope to be able to identify a Phase III dose for these Duchenne patients. Now you might also say that the depth of the response on CK of 40% seems to be sufficient to provide significant benefit on functional endpoints in North Star for a Becker population. So anything in and around a decrease in CK is probably relevant to the Duchenne patients. And so I would suspect that we will attain those levels of modulation of the muscle damage and that would be beneficial to the patient ultimately.

And the next question today comes from the line of Alexander Xenakis from Truist Securities.

Congrats on the data. With the individual patient's NSAA data that you presented, I think aside from the meniscus tear patient, there were 2 patients, I believe, that showed a little bit of a decline. Were there any standout characteristics of that with those patients? Were they also in the more advanced stages, Group 4 patients, maybe some correlation there? And then can you remind us...

Yes. I think -- let me answer that one first. I think the -- there's no correlation where they started. Joanne, correct me if I'm wrong on that. There's no real correlation on where they started. And what was the other part of the question?

Were they the more severe patients?

You can actually see that.

Yes, those were the same -- those are the same patients from the 1-year data. They were essentially stable going from 20 milligrams to 10 milligrams.

And you can see the guys on the bottom, the guys who started out at 4 and 5, both having improvement.

Yes. So perhaps an input on what you thought that the patients that were on the lower end actually improved perhaps somewhat more because they felt -- perhaps they felt better and can perform more functions.

Maybe.

Maybe.

Yes, I think it's great that it seems to improve across baseline.

I think it does bode well for older Duchenne patients who are nearing loss of ambulation, which I think their expected delta in an older Duchenne patient might be from recent studies as many 4 points a year down. And I would suspect that you might see a robust response in these older Duchenne patients with this drug.

On that note, for the natural history data that we have, is there a breakdown of natural history for Group 1 and Group 2? And should we be thinking about that to compare it more granularly when we look at the eventual data from the larger studies?

Joanne, maybe add a little bit of color on the natural history in Becker.

So they are the best that has been shown, is the Bello data, the 5-year data showing individual patients. And do you see that the decline over the -- that range, he did actually 10 to 32, is very, very tight, actually. So you see -- it's not -- as you look at that, and we can share that, that above 15, say, is not any different than below 15.

Got you. And maybe one more for me. Can you remind us how much, I guess I'll use the word subjectivity or objectivity there is in the North Star end point? And as you are doing larger trials that are now going through multiple centers with multiple assessors, are there any safeguards or measures to ensure the consistency of the NSA Assessment?

I'll just take that quickly and Joanne can add a little bit. Well, so there are some specific optimization of the measure of the North Star. We have a physical therapy -- therapists are specially trained by a single group that provides homogeneous training and training on how to observe and score. The North Star's Group is [indiscernible], and that's used across the industry. So that's one particular piece of the puzzle to have a highly reproducible North Star. I think the North Star across populations, the ability -- the accuracy of the North Star can be different. Obviously, if you're trying to get a 4- or 5- or 6-year olds perform 17 activities in a reproducible way that might be challenging for North Star. But when you get to older children or adults, the North Star becomes probably a much more reproducible measure of function. And I think that's why we would anticipate using it certainly and haven't just been using it in Becker adults and adolescents. I think certain populations of Duchenne might also be amenable to the North Star measure, to measure progression of the disease. Joanne, maybe talk about what are your thoughts on that?

They're very well trained. Last month at MDA, we also looked at the reproducibility characteristics of NSAA and NSAD actually, and showed that the standard deviation was quite tight, which you could appreciate just by looking at those 12 ARCH patients, but then we extended that to all of the patients at screening and baseline in all 3 studies that are ongoing. And it's quite a bit less than the -- it's a fraction of the variability in Duchenne set and -- which is not surprising, but that has a really big impact on the power of your study to be able to see -- it grows exponentially, the signal to noise. The better you can -- the more you can decrease the noise, the power of the study increases dramatically.

There are no further questions at this time. So I'd like to pass the call back over to Kevin Koch for closing remarks. Please go ahead.

Well, thank you all for calling in and joining the presentation. In conclusion, I'd like to personally thank everyone who has chosen to support our mission, particularly the talented and dedicated employees and their families. Really most importantly, though, I'd like to thank our patient community, the clinical trial investigators, all the trial participants as well as the shareholders for the continued confidence and support. It's been really an exciting time here at Edgewise, and I truly believe that we're at the cusp of demonstrating the potential of a novel therapeutic that could fundamentally improve the lives in need of more effective therapies. Thank you for joining the call and take any additional questions offline. Thank you.

That concludes today's webinar. Thank you all for your participation.