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 two-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 also 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 Advisor 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 risk 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. Appreciate joining the call today. Next slide. Edgewise Therapeutics is a 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-in-class therapeutics. EDG-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 disease.
EDG-7500, currently in phase one 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 muscular dystrophy is a severe, underappreciated condition with a significant medical need.
These patients typically are diagnosed in their adolescence. 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 are muscular dystrophies, and there are many different varieties of muscular dystrophy. It often starts with a mutation in the sarcomeric unit, which is essentially the part of the muscle fiber involved in contraction. In certain muscular dystrophies, there is an 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. 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 hypercontract, where you get mechanical stress, and you damage that individual muscle fiber. Go to the next slide. Here you can see a denotation depiction in the fiber of the 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 contractures. 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 does Sevasemten actually do? So in muscle disease, excessive contraction-induced muscle damage leads to damage to the muscle, which leads to an aberrant 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.
And now I'd like to introduce Barry Byrne to provide some understanding and 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 the next slide, please. So just to understand how important it is to define the tools used to measure 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 for example, standing on your heels is a prerequisite to be able to walk, particularly when there's an uneven surface. This assessment of 17 different tests can be used to assess progression in Becker dystrophy and potential therapeutic effects of a drug like 5506. Next slide. Several natural history studies have been conducted, which help define the rate of decline in Becker.
The three studies listed here, De Wel, Bello, and Niks, all show that over a four-year to five-year period, there is a loss of about 1.2-2.4 North Star points per year. I'll show you the consequences of that in terms of form and function that patients experience as this disease progresses. This, of course, causes significant morbidity and ultimately, as it relates to the cardiac findings, also mortality in this patient population. 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 Stars 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 an ability 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 four groups. You can see in the most high-functioning group with baseline North Star 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 in function with the North Star score in that domain of 0. So next slide.
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, a 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, they're often using compensation like pulling themselves up the stairs on the handrail. 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 10m walk-run test.
In Group 4, where there's 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 a huge impact on quality of life and is 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 a further decline and rapid loss of function, and one of the goals in maintaining function in this patient population is to change even just one point on the North Star, which would have a significant impact on quality of life.
A nd 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 was 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 100m timed test. We enrolled 12 patients, and we stepped up the dose over time.
As you'll see, we identified a 10mg 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. These data today are focused on 24 months of exposure in these patients. On the next slide, we have just kind of an aside here. This was a single-center study. So an interesting trivia is that people traveled 190,000 mi to participate in this study.
We started out with relatively frequent visits, so they were going back and forth a lot. 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. These patients were significantly functionally impaired.
As you saw, what is a North Star in the mid-teens, 15, so they have lost significant function. Only half of them could rise from the floor. Eight seconds is a long time to be able to traverse 10 m, and we could see that they had decreased muscle mass, as evidenced by a decrease in serum creatinine and also a decrease on the DEXA 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, 4-31, 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. There are no unusual side effects that we've noticed. We've not had any dose reductions or adjustments. No treatment discontinuations because of AEs, no SAEs. We have had patients withdraw. Actually, two of them are coming back in the open-label extension that we are now moving patients into the ARCH study. One for travel reasons.
The next slide shows function. That's what we really want to see here. 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. 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 one patient who had a meniscal 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, basically during their rehab, and all of the other patients at 24 months showed basically an improvement compared to the natural history, with several of them showing an absolute improvement there, so you can see that 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. We saw rapid and sustained decreases with Sevasemten, the creatine kinase, fast skeletal muscle troponin, and myoglobin, indicating target engagement and also providing support for identification of the 10mg dose as our target dose here.
On the next slide, we also looked at other measures. We've shown here the 100m timed test velocity, which is stable over 24 months, and maximum grip strength, again, stable over 24 months. 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. 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 an essentially maximal biomarker response at the 10mg dose.
And that supports our pivotal cohort, 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 five and 32, so very much mirroring the population that you just saw, not on corticosteroids.
And they are getting a dose of 10 mg. 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 the fourth quarter of this year. 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.
We're also looking positively that positive data from CANYON could support a pathway to explore earlier approval of Sevasemten for Becker. 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. 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.
That's what's coming up later this year. 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 five and 32, not on corticosteroids. Our target enrollment is 120 patients.
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. We are also looking at additional measures, including time function tests, biomarkers, MRI, patient-reported outcomes. It's a very robust study. 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 adolescence. 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 three major markets of the US, EU, and Japan. Interestingly, 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 don't treat these patients. They often treat them 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.
When they've reached out to them, they've been enthusiastic about joining our trial. 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. We have 93 million shares outstanding. With that, we'll take any questions from the callers.
Thank you. If you'd like to ask a question, please click the raise hand button at the bottom of your screen at this time. If you're dialed in via phone audio, star nine will raise your hand, and star six will unmute your line when prompted. Our first question today comes from the line of Joe Schwartz from SVB Securities. Please go ahead. Your line is now open. Please unmute. Joe, your line should be open now. I'm going to have you unmute. And if we don't hear from you, there you go.
Sorry about that. It's Joe Schwartz from Leerink Partners. So it's super interesting that the patients in ARCH traveled an aggregate of 190,000 mi for the assessments during the study. So I was wondering if you have any information on the patients' motor activity and how well Sevasemten suppressed their CK spikes in those who were more active.
That'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 reflective in their 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, 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 the FDA looks at it and says, "Really? 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. That is the key here. And the ARCH study is, I think, a significant part of that supportive evidence in terms of showing 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, why don't you follow up on that?
Sure. So I think the data have been very consistent that once patients start to decline, they continue to decline. We have five-year data. We have now three studies. You look at the cross-sectional data. We have it. We've shown it. Others have shown it. 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. They're down, representing that third group of patients having lost functions that Barry showed. We know they're getting from one place to another. They are continuing to decline. That is in the more data that came out. One of those papers came out. It came out earlier this year.
So I think that we are seeing this very consistently with more data emerging from that. I think two 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 we didn't see that bump. We saw it at two months. They were stable. And then moving down, they were stable. And in many cases, trended up.
Yep. That makes sense. Thanks for taking my questions.
Thanks, Joe. Hey, 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 biomarkers are not as variable as one might think over a one-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 assuage the agency that this is too variable to measure and that ultimately blocking muscle damage would predict at some level a 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.
Very helpful. Thanks for taking all my questions.
All right. Thank you. And the next question today comes from the line of Laura Chico from Wedbush. Please go ahead. Your line is now open.
Good morning. Thank you very much for taking the question. 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 stat-sig improvement on the biomarkers, a numeric benefit on North Star, can you just walk through the timeline 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?
Yeah. I think what we are doing is being forward-looking. And 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 to follow up, I mean, we've invested in some of the CMC requirements for a launch of the 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. Excuse me. Then maybe a quick follow-up. In the individual breakdown of NSAA's responses at 24 months, there were a couple of patients that had between plus two and plus four point improvements on North Star. 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 two to four point gain on North Star mean for some of your patients right now? Thank you.
Yeah. 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.
All right. Thank you. And the next question today comes from the line of Yasmeen Rahimi from Piper Sandler. Please go ahead. Your line is now open. And just a reminder, it is star 6 to unmute on a phone.
Good morning, team, and congrats for the 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 and grip tests as well as the biomarkers, do you see sort of uniformity, especially in patients who exhibit a greater benefit?
Guess what I'm trying to figure out is like is there a directional magnitude that all tracks the same with the patient has the greatest change in the North Star also gets the greatest change in the biomarkers as well as functional? That's question one, and then question two 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 one, two, three, and four in North Star, is there a group that you would, I guess, if you had to enrich a population with the least POS of a placebo response, is there a placebo response that a group four is going to be different than if you end up at group one or group two? Would love to get your color on that and appreciate you taking my question.
Yeah. Barry, could you take the functional question first, and then we'll handle it?
Sure. Sure. Yeah. Happy to, Kevin, so yeah, I think to your point, it's where is there more likely to be a clinically meaningful benefit in these groups with early changes like in group one or 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 there becomes orthopedic disability when one has prolonged seating as opposed to walking, and so it's more likely to be meaningful in group one and group two than it is certainly in those more advanced patients in group four.
Yeah. And Yasmeen, I think just taking your question on the direct correlations of biomarkers with functional outcomes, I think it's first off, there's small n's. 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 turnover in their muscle.
So I would say that part of what you're seeing is an effect on the muscle in a way that'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 would allow them to function more effectively and would be a higher score on the North Star.
I think also the patients traveling across the country for two years. They're 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 could say that all patients that have an improvement also have responses in their biomarkers.
So yeah, I think 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.
All right.
Thank you so much, and congrats again.
All right. Thank you. And the next question today comes from the line of Tess Romero from JP Morgan. Please go ahead. Your line is now open. And Tess, I've sent you a prompt to unmute your line.
Oh.
Awesome.
Good morning. Good morning, Kevin and team. 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 two 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? Thanks.
Barry, I think that's yours.
Yeah. Tess, I'm happy to answer. So obviously, as you saw, this patient population are young adults and middle-aged adult patients who've 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-derived weakness benefits also from movement and rehabilitation.
And so as patients begin to take more chances in a way, they become very cautious with your 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 experienced 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.
It may take more than a year, though. 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?
Yeah. 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-twitch muscle fibers actually will have an effect to, as has been shown, an effect 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, then there may be a natural tendency towards minor increases in CK that are 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.
Just to follow up, Tess, I mean, activity is good for muscle. It's 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. 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. 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. I think as we get out to one- and two-year studies, you'll see that play out in stabilization or benefit to the patient on their functional capacity.
Thank you.
Thank you. The next question today comes from the line of Leonid Timashev from RBC Capital Markets. Please go ahead. Your line is now open, and please unmute.
Hey, guys. Congrats on the data. I had 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 in 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 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 four to begin with, you saw a similar stabilization, and to go to your question, yes, we are seeing a similar group of patients. We have had very few, for example, with screen fail 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, "Yeah, I'm just going to hang out here at a 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.
Got it. That's really helpful. And then I know we've been focusing on Becker, but just wanted to sneak one in on Duchenne. Obviously, these have been pretty severe Becker patients. But given the strength of the two-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 the Duchenne patients are having much higher levels of biomarkers. And 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 four- to nine-year-olds. And so one might suspect that the four- to six-year-olds are improving and that the seven- to nine-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 we'll be able to identify a phase three 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.
Anything in and around a decrease in CK is probably relevant to the Duchenne patients. I would suspect that we will attain those levels of modulation of the muscle damage, and that would be beneficial to the patient ultimately.
Very helpful. Thank you.
Thank you. And the next question today comes from the line of Alexander Xenakis from Truist Securities. Please go ahead. Your line is now open. And please unmute.
Hello. Congrats on the data. Thanks for taking my question. With the individual patients and NSAA data that you presented, I think aside from the meniscal tear patient, there were two patients, I believe, that showed a little bit of a decline. Were there any standout characteristics with those patients? Were they also in the more advanced stages, group four patients? Maybe some correlation there. And then can you remind us of. Oh.
Yeah. I think maybe answer that one first. I think 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?
Yeah. No.
You can actually see that.
Yeah. Those were the same patients from the one-year data. They were essentially stable going from 20 mg to 10 mg.
Yeah, and you can see the guys on the bottom, the guys who started out at four and five, both had an improvement.
Yeah. Yeah. So perhaps in light of what you thought that the patients that were on the lower end actually improved perhaps somewhat more because they felt better and could perform more functions.
Maybe.
Maybe.
Yeah. 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 as four points a year down. I would suspect that you might see a robust response in these older Duchenne patients with the drug.
On that note, for the natural history data that we have, is there a breakdown of natural history for group one, group two? 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 the best that has been shown is the Becker data, the five-year data showing individual patients. And you see that the decline over 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.
Gotcha. And maybe one more from me. Can you remind us how much, I guess I'll use the word subjectivity or objectivity, there is in the North Star endpoint? 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 NSAA assessment?
I'll just take that quickly and join and add a little bit. There are some specific optimization of the measure of the North Star. We have physical therapists who are specially trained by a single group that provides homogeneous training and training on how to observe and score the North Star. This group is called ATOM.
That's used across the industry. That's one particular piece of the puzzle to have a highly reproducible North Star. I think, the North Star across populations, the accuracy of the North Star can be different. Obviously, if you're trying to get a four or five or six-year-old to perform 17 activities in a reproducible way, that might be challenging for a 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 have anticipated using it in Becker adults and adolescents. I think certain populations of Duchenne might also be amenable to the North Star measure to measure a progression of the disease. Joanne, maybe talk about what your thoughts are 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 three studies that are ongoing, and it's quite a bit less than the. It's a fraction of the variability in Duchenne's, 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 more you can decrease the noise, the power of the study increases dramatically.
Thanks so much for the color. Congrats on the data.
Thank you. 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.
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 their 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. Take any additional questions offline. Thank you.
That concludes today's webinar. Thank you all for your participation.