Capricor Therapeutics, Inc. (CAPR) Earnings Call Transcript & Summary

Good morning, ladies and gentlemen, and welcome to the Capricor Therapeutics HOPE-3 Phase III top line data call. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to turn the conference over to our host, Mr. A.J. Bergmann, Capricor's Chief Financial Officer. Please go ahead.

Thank you, and good morning, everyone. Before we start, I would like to state that we will be making certain forward-looking statements during today's presentation. Statements may include statements regarding, among other things, the efficacy, safety and intended utilization of our product candidates, our future R&D plans, including our anticipated conduct and timing of preclinical and clinical studies, our enrollment in patients in our clinical studies, our plans to present or report additional data, our plans regarding regulatory filings, potential regulatory developments involving our product candidates, potential regulatory inspections, revenue and reimbursement estimates, projected terms of definitive agreements, manufacturing capabilities, potential milestone payments, our financial position and our possible uses of existing cash and investment resources. These forward-looking statements are based on current information, assumptions and expectations that are subject to change and involve a number of risks and uncertainties that may cause actual results to differ materially from those contained in the forward-looking statements. These and other risks are described in our periodic filings made with the Securities and Exchange Commission, including our quarterly and annual reports. You are cautioned not to place undue reliance on these forward-looking statements, and we disclaim any obligation to update such statements. With that, I'll turn the call over to Linda Marban, CEO.

Good morning, everyone. This call this morning represents the culmination of 20 years of work. This technology was originally conceptualized on a poster that was handwritten in Capri, Italy more than 20 years ago. And through all the years of understanding the mechanism of action trying to find the perfect way to deploy the powers of what was once CAP-1002 and is now Deramiocel, we are now proud to be able to present today the data that was released in a press release this morning that shows that the HOPE-3 pivotal clinical trial of deramiocel to treat Duchenne Muscular Dystrophy has shown statistically significant improvement in both skeletal and cardiomyopathy. Today, in order to update you not only on the data from the trial, but also talk about our future plans and then to contextualize the relevance of this data for the Duchenne community, I am joined by my esteemed colleagues, A.J. Bergmann, who you just heard from; Dr. Michael Binks, our Chief Medical Officer; Mr. Mark Awadalla, our Chief Development Officer; Dr. Kati Maharry and Nathan Hogan, our statisticians here at Capricor; Dr. Craig McDonald, a physician that needs no introduction in the Duchenne community because of his prominence in the clinical developments understanding of and treatment of Duchenne Muscular Dystrophy and other neuromuscular disorders; and Dr. Jonathan Soslow, by far considered the leader in the world of understanding Duchenne cardiomyopathy and has published extensively on the natural history of this disease process in order to contextualize this important data for you. Next slide, please, A.J. You can see in this very simple agenda that I'm going to be walking through some of the very basics of the trial, the trial design, how we did it, how we conducted it. The rigor by which this data was collected. The fact that we have now an adequate and well-controlled study, which has been asked for by the FDA, and I will give you all of those details, and we look forward to your questions at the end. Mostly what I'd like to say before I begin this call is my e-mail, my phone, my text messages this morning has exploded in the last few minutes since the release of the press release by the most important people in this whole experimental design that we've built, and that is those of Duchenne Muscular Dystrophy and their families. These boys and young men and their families have hoped this is the first clinical trial that I am aware of, where there are statistical significance, clinical significance and also anecdotal support for the fact that deramiocel changes the life course of these boys and young men. Next slide, please, A.J. I think most of you on this call know about Duchenne Muscular Dystrophy is an x-linked disease. It mean it's primarily expressed in boys and young men, although there is a growing body of evidence that the mothers of these boys as well as the sisters of these boys have manifestations of the disease as well. And we look forward to being able to be providing therapeutics for them in the future. Deramiocel is the largest protein in the human body. It acts as a cushion and a glue, so it protects cells from damage and it also helps it holds its structure. The pathogenesis of Duchenne Muscular Dystrophy is the worst of the muscular dystrophy because those with this disease do not have any dystrophin that is naturally made by their body. Therefore, all of their cells are always undergoing decline ultimately breakdown and early cell death, leading to the loss of progressive muscle groups. Duchenne takes typically between 25 and 30 years to take the life of a boy or a young man. And every day during that progression of the disease, they are losing some aspects of their ability to function. We hope to be able to attenuate the course of this disease with deramiocel moving forward. I'd also like to highlight that one of the most important aspects of deramiocel and [indiscernible] of Duchenne Muscular Dystrophy is the inflammation. Inflammation is caused by the constant breakdown of muscle. The immune system is put on alert that there is something going on that is bad. And as the immune system is activated at least to greater cellular breakout. So if you can find a therapeutic where you can attenuate inflammation and fibrosis, you have a potential success. And I think that is what we have seen here today. Next slide, please. Deramiocel has been under clinical development for over 10 years in the treatment of Duchenne Muscular Dystrophy. We started with the HOPE-Duchenne study that was published in the Journal of Neurology, where we showed a reduction in the amount of scar in the heart and trends for improvements in cardiac function. We then show that we could multi-dose switching to an intravenous paradigm in the HOPE-Duchenne open-label extension, which rapidly led to the conduction of the HOPE-2 and the HOPE-2 OLE clinical studies. The HOPE-2 and HOPE-2 OLE clinical studies have shown not only that we can reduce the amount of damage done to the muscle that we improve cardiac function, but we improve skeletal muscle function, that we are addressing an unmet need that nobody else has been able to address, and that is primarily nonambulant patient population and that we see long term, multiple years, 4 years coming into 5 years of safety as tolerability as well as efficacy. As you know, we filed a biologics license application based on the hope to the HOPE-2 open-label extension data as well as the natural history data collected by Dr. Jonathan Soslow and published in circulation heart failure. And what we are talking about today is the data that was asked for by the Food and Drug Administration to supplement that BLA in order to prove the fact that deramiocel works in treating Duchenne Muscular Dystrophy. What's most exciting to me and what I want to highlight on this relatively busy slide, the culmination of this work is HOPE-3, the data that we have put out this morning, and we will continue to discuss now. And moving forward, it has been predicted by each one of our clinical studies. In HOPE-Duchenne, we showed a reduction in cardiac cars measured by LGE. You'll hear in the next few minutes that, that was substantiated in this randomized, double-blind, placebo-controlled trial. The improvement in upper limb function shown in every one of our clinical trial continues to be supported and now shows statistical significance in a 106-patient randomized, double-blind, placebo-controlled trial and the improvement in cardiac function is again substantiated from the HOPE-2 and the HOPE-2 OLE study. Now how does Deramiocel work? Let me remind you of that. So on the next slide is the multimodal mechanism of action of Deramiocel. We've recently published work in a peer-reviewed journal. The measurement of the mechanism of action has been ongoing in our lab and others over the past 20 years, but what has been most important in the development of Deramiocel as a drug product is the development of a potency assay that is directly related to the biologic mechanism of action of Deramiocel. And that's shown in this relatively simple graph, which shows that we have antifibrotic activity, immunomodulatory activity reminding you that inflammation is equally damaging to patients muscles with Duchenne Muscular Dystrophy and other neuromuscular diseases, by the way, as well as anti-inflammatory itself, just slowing down that inflammatory response. So allowing inflammation to be reduced, allowing healing to begin and then ultimately preventing the development of scar, which leads to the loss of muscle function. All of this has been validated, approved by the Food and Drug Administration as the potency assay moving forward, which allows lots and lot of consistency, allows us to scale up our manufacturing, allowed us to pass our pre-licensing inspection for our San Diego manufacturing facility. And with this data, we believe we are prepared to launch deramiocel to treat Duchenne Muscular Dystrophy. Let me talk to you for a minute about HOPE-3, our pivotal Phase III trial. This trial has been conducted at 20 sites across the United States. It is a randomized, double-blind, placebo-controlled trial of 106 patients. The primary efficacy endpoint is the performance of the upper limb version 2.0. The key secondary endpoint is left ventricular ejection fraction, and we have other Type 1 error controlled secondary endpoints, the mid-level performance of the upper limb, that is the ability to move essentially your elbow or your arm and analogous pass by which could be improved by preserving mid-level function is eating, fresh in your hair, drinking water, hugging your mom as Pat Furlong would say. A global statistical test, which is a [ field ] function and survive type of endpoint. It combines looking at the relationship between the performance of the upper limb, left ventricular ejection fraction and a patient-reported outcome called the PGI. We have left -- late gadolinium enhancement that is a die that is used to examine the heart using MRI and allows you to determine the amount of scar in the heart, and we see that as well statistically significantly, and I'll talk about that in the next few minutes. As I mentioned, it was a 1:1 randomization. Patients received 150 million cells via intravenous infusion 4 times a year. And as you'll hear in the next few minutes, it was safe and well tolerated. Next slide. Inclusion criteria were primarily based on performance of the upper limb criteria. That means that patients have to have upper limb function with a PUL entry score between 2 and 6 primarily between 2 and 5, where we took in several of those patients that were still in late ambulation at risk of losing angulation and still maintaining a significant amount of upper limb function. The purpose of this was to provide the opportunity for those that are at the edge of losing ambulation to get deramiocel and also potentially for label opportunities. What you can see shown here in this slide, which can be also elaborated on by Dr. Craig McDonald, who, as I mentioned, has joined me today, the ability to feed yourself or lift your arms, raise your arms above your head are all the criteria by which patients are randomized into this trial, and we are then able to measure their functional developments as a result of the performance of the upper limb, which is a 21-item scale. Next slide, please. So shown here is the demographics of the study. HOPE-3, as I mentioned, was 106 patients, randomized double-blind, placebo-controlled. The mean age was in the placebo group, slightly younger, 14.6 years and the deramiocel group 5.4 years. The overall in the trial, the average was 15 years of age. We had a slight difference in left ventricular ejection fraction at baseline with the placebo group being slightly healthier with an entry ejection fraction of 59% and a deramiocel entry -- left-ventricular ejection fraction of 55%. A total of 91 patients had left ventricular ejection fraction measured and you can see that the average baseline criteria for ventricular fraction was 57%. There was no difference in baseline in the performance of the upper limb and the placebo versus the deramiocel group of any measurable difference. But the overall PUL entry score for the close with entry scores of 2 to 3 at 48 or 4, 5 and 6 PUL entry scores and overall entry store of 58. All considered well within the standard expectations of this particular patient population. Most of our patients were nonambulatory. Let me highlight at this moment, the incredible relevance of this therapy in the Duchenne community. There is nothing approved actually for this patient group. And we are the one therapeutic that can be given across the life course of Duchenne Muscular Dystrophy to attenuate the progression of the disease. Many of the boys and young men receiving deramiocel are in their early '20s and feel and function better than they ever thought they could at this point in their life. Next slide are the safety results of the HOPE-3 clinical study. The safety of deramiocel is one of the aspects of this clinical development program that we are most proud of. And that is because, of course, the one thing you want to be able to do in drug development is provide a therapeutic that not only works but doesn't impact the quantity or quality of life of a patient. The reason our patients in our deramiocel clinical trial, HOPE-2, HOPE-2 open-label extension, HOPE-3 and HOPE-3 open-label extension have such low dropouts even with many of our patients staying on for years and the open-label extension program is because of the safety. Primary safety concerns, if you can call them that, are extremely simple. They're mild flu-like symptoms reported in some types -- some of the patients, 25% to 35% of the patients have some version of a pyrexia, which is fever, cough, some get itchy, a significant proportion get headache. Physicians manage this easily with antihistamines and Tylenol. And as is evident from the lack of serious adverse events as well as the reliability by which patients come back for new treatment is evidence of the safety as well as tolerability profile of Deramiocel. This is something we stand behind, years of data supported Data Safety and Monitoring Board has been following our patients for years, and the FDA has received all safety data and timely filings. So we continue to be proud of the safety impacts of deramiocel. So now let's get into what you guys really came to hear today, which is the efficacy of deramiocel because we've been talking about some of these other features for quite some time. So as shown here in this bar chart is the pictorial representation of our primary efficacy endpoint. That is the performance of the Upper Limb, 2.0 at month 12 shown with the green arrow is actually the difference of means, which is a 54% slowing of disease, a 1.2 point change on an absolute scale. And what we can see here is that, that statistical significance to the likelihood that this is due to chance is less than 3% at the p-value of 0.029. The difference is shown on the Y-axis as a percent change from baseline. Although as I mentioned, the absolute change was 1.2 points, both can be represented. This happens to be the way that the statistical analysis plan was drafted, submitted to the Food and Drug Administration. We received no comments on the statistical analysis plan and patients as well as regulators as well as statisticians find this a very easy way to quantify performance of the upper limit. Let me just explain that to you, so you understand the importance of percent change. If I have a PUL score of 20 and I lose 2 points and my colleague, Mark has a PUL score of and he loses 2 points, that is a very different amount of functional loss for me versus Mark. So this percent change allows us to actually quantify the loss on a per patient basis and its relevance. So again, this was something that was submitted to the Food and Drug Administration was decided by us and multiple statisticians that we have worked with over the course of the last year is the best way to represent functional improvements, changes declines in this patient population. And our staff team is happy to take questions on that, should you have any. In the next slide, we show our secondary endpoint, which is left ventricular ejection fraction. Shown here is a 91% slowing of disease, again, measured by the green arrow showing the difference of means and the percent change from baseline. We are using a rent change with a p-value of [ 0.041041 ], those zeroes are mighty important right now. This data is also important, a 91% slowing of disease. We saw stabilization across the board in patients treated with deramiocel, and we saw a decline in those that were placebo treated. I want to point out, and this is something I've been thinking a lot about, and I think our KOLs can provide context here. The disease, Duchenne Muscular Dystrophy is one that takes somewhere between 25 to 30 years to take the life of a boy or young man with Duchenne. As I said at the beginning, it is a slow and slightly steady decline towards that inevitable and terrible outcome, the primary cause of which is loss of cardiac function. In order to do a cross-sectional analysis of looking at these guys for one year and to see this kind of data is unprecedented. If you can delay the progression of this disease by 91% in terms of preservation of heart function, where 65 of the 83 documented patients with cardiomyopathy at baseline have stabilization, we have a tremendous opportunity to potentially extend not only the quality of life of these boys and young men but potentially the quantity of life of these boys and young men. And I wanted to highlight that here, the importance of treating this aspect of the disease. Shown here is a fourth plot. A fourth plot is a special type of way of representing data. It is a way of showing that data either goes positively, which is to the right of the zero showing that the treatment is having an impact in one way or another. And to the left of the zero would be showing favoring placebo in one way or another. What has shown in this very beautiful plot is the fact that we not only hit the primary efficacy endpoint of the [ POL 2.0 ], the total score. We hit the key secondary endpoint of left ventricular ejection fraction with a p-value of 0.04, as I just mentioned on the previous slide. We hit the -- all Type 1 error controls, secondary endpoints. What does that mean? What it means is that sometimes in a clinical trial, when you sort of laundry basket a lot of secondary endpoints, you can kind of lose statistical value by this concept called multiplicity. When you type one error, control a secondary endpoint, you're controlling for multiplicity, you're saying, "Yes, we really do think that there is statistical validity here, and we're going to test it using traditional means." So the three secondary endpoints that you see here are the mid-level dimension of the performance of the upper limb, statistically significant improvement was a p-value of 0.008. The total global statistical test, the one that I mentioned a few moments ago, that measures, deals, functions and survives as a secondary endpoint with the T statistic, a p-value of 0.01. And then finally, one that was additive part of the cohort B of the clinical trial at the request of our cardiology colleagues, is late gadolinium enhancement. Gadolinium is a die that is used in MRI. You've probably seen it if you've heard me speak before, when we talked about HOPE-Duchenne, where you see the tissue differentially stained with healthy tissue stained black and scar tissue stained white, people who are experts in reading these types of images and then quantify the number of segments of the heart that is impacted by scarring or other ways of looking at is the percent of the heart that is affected by scarring, and it's a very efficient means of looking at the damage in the heart. In all heart disease, this is an important measure. But in Duchenne Muscular Dystrophy, it is extraordinarily important, but because what Dr. Soslow, Dr. Chet Villa, [ Dr. Larry Marca ], many of these physicians that have studied this very different cardiomyopathy for the course of their careers has shown this [ fibrofatty ] replacement, as the slow an insidious killer of these boys and young men. They develop scar slowly. They don't know what's happening. Many of them are off their feet. Their hearts are not working as hard as they could if they were playing basketball or soccer. So they're kind of oblivious and then ultimately, there's so much car that the heart actually can no longer compensate. They develop a [indiscernible] heart failure and ultimately, nothing that clinicians can do can pull them back from the edge. So the fact that we see a reduction in a statistically significant reduction in the amount of scar with a p-value of 0.02 is probably one of the most amazing aspects of this trial. We are attacking this disease at where it is causing the most potential damage. And we are looking forward to following the boys and young men that are prescribed deramiocel to see that they have extension, not only of quality of life but also length of life. Next slide, please. So many of you who have heard me speak before, have seen this particular slide. I like it. I call it the good player on the Sandbox slide. Deramiocel can be used with any therapeutics that are currently approved, currently available or under clinical development that we know of, whether it's an [indiscernible] or a gene therapy that is trying to attack the disease at its source, which is the lack of dystrophin or some other types of antifibrotic or corticosteroids. In fact, we required every patient in every trial to be on standard doses of corticosteroids because we believe that, that is the standard of care that has been most efficient at extending life in these boys and young men, deramiocel goes well with all of them. There are no negative impacts, and we actually believe that we're going to see synergies over time in this type of polypharmacy because if you can reduce inflation and you can reduce fibrosis and you can drive repair and then you have these other therapeutics that are in there that could be adding dystrophin or repairing the gene, we then have an opportunity to really attack the disease at both sides of its mechanism of destruction, both the lack of dystrophin and inflammation and fibrosis. Next slide, please. So where are we going from here? This is obviously probably the most important day in the history of Capricor and our history in the development of Deramiocel. The name of the company, as I mentioned, comes from the Little Island on Italy in which we first discovered the seminal work that has led to this point. We have met the Phase III primary efficacy end point of the [ POL 2.0 ]. The key secondary endpoint of left ventricular ejection fraction, both achieving statistical significance of p equals 0.03 and 0.04, respectively. As I said earlier, statistical significance was achieved in all type 1 error controlled secondary end points. Deramiocel is a first-in-class therapy designed to treat not only Duchenne cardiomyopathy but also the skeletal muscle myopathy, and we made those seminal discoveries now multiple years ago in our preclinical studies and now has been validated in multiple clinical studies, culminating and what I consider to be probably one of the very best clinical trials that's been done in the understanding of Duchenne muscular dystrophy, randomized, double-blind, placebo-controlled, 106 patients, highly overpowered at greater than 90%. We really have measured all of the bells and whistles here and done a stellar job of taking this to this end point. Safety and tolerability, one of the most important aspects of treating any type of disease because you push a bunch of patients to feel and function better with consistent clinical experience supporting the safety and tolerability of deramiocel. Obviously, the whole world knows that we received a complete response letter. We thought we were on track to PDUFA last year based on the HOPE-2, the HOPE-2 open-label extension data as well as comparing the cardiac data to Dr. Jonathan Soslow's cardiomyopathy natural history study. The FDA had felt that, that was adequate data for a label. The administration upon review of the data decided that there was not adequate data, they issued a CRL. We have now answered their concerns by offering them data that is randomized, double-blind, placebo-controlled, an adequate and well-controlled clinical study. We're going to submit this data in response to the CRL. We're hoping to get a relatively rapid PDUFA date right now or until our Type A meeting in August, they were telling us it would be a Class II resubmission which is about 6 months, so look for sort of the conservative estimate of a PDUFA in July. But because we now believe that this data substantiates all of their concerns, we've passed prelicensing infection. Our commercial manufacturing facility is ready to go Cohort B, which is the aspect of the trial that was done or made -- was done using a drug made at our San Diego commercial facility shows independent statistical significance. We are ready to go and our patients, their families and all of the people in the Duchenne world that have been following this therapeutic for years. I think today, we should raise the glass and celebrate that perhaps we are first time providing an opportunity for these boys and young men, especially those that are nonambulant with no other options in front of them to have an opportunity to extend their lives. And with that, I will again offer my thanks. I'm joined here by my colleagues who can answer specific medical scientific or statistical questions. And I look forward to continuing to work with you as we take this towards launch and commercialization. Thank you.

Operator, I think you can open the line for questions, please.

[Operator Instructions] with that, the first question comes from Leland Gershell with Oppenheimer.

My congratulations on these very strong data from HOPE-3. I wanted to ask, and I know you had discussed this a bit during the prepared remarks, Linda. But with respect to the primary and secondary endpoints, percent slowing versus, I think, what was on clinical trial [indiscernible] mean change. If you could just walk us through a bit further in your discussions with FDA and perhaps part of your how that will be handled versus mean change and if there may be any differences or further discussion that's needed with respect to the agency regarding those as registrational.

Yes. Thanks, Leland. So obviously, there's been a lot of discussion, a lot of planning that went into the statistical analysis plan. We work with multiple outside statisticians, James [indiscernible] of the analysis group, who's done a lot of work in Duchenne. And then with the patients and advocacy groups, PPMD and some of the groups that also have worked on patient-reported outcome measures, clinical relevant outcome measures. And the determination of using percent change as a way of measuring the change using the performance of the upper limb. I personally think was one of the greatest steps that Capricor was able to make. So we even worked with Adam International, the group that develop the performance of the [ upper limb ] and presented the idea to them before we wrote it in our [indiscernible], they also like it. The PUL is still a relatively new measure. We're still understanding it. And as I said in my remarks, a PUL score of 20 and a guy who loses 2 points on that has a very different outlook on those 2 points lost than a guy who starts at 40 points and loses 2 points. So percent change allows you on a patient-by-patient basis to assess the loss for that particular patient. And for more clarity on that, [ Anna Mahu ] actually, again, one of the developers of the performance of the [indiscernible] just published a really lovely paper that was made available peer reviewed in September, discussing this exact issue, and that's actually where a lot of these ideas came from. In terms of absolute change, we saw that as well. So the FDA had said that the clinically meaningful change in the performance of the upper limb would be 1 point. We see 1.2 points many of that change attributed to mid-level pool, which is their arm, which is also validated in video assessments that we actually have in front of us, we just can't show today. So look forward to the future of being able to see on video what is actually happening to the arm function on these guys that are on deramiocel. The good news is, is we see statistical significance in the absolute change as well. It's a p-value of 0.05 so just making the cutoff, but that's all you've got to do. So whichever way the agency wants to look at it, we hit it. And we look forward to having that conversation with them. We really don't think this is going to be an issue that's going to roadblock us at all.

Great, and one follow-up. As the results that were presented were across the entire HOPE-3 population, just wanted to ask with respect to cohort B versus A, obviously, B from San Diego which is the facility that's been fully inspected in past and all that versus from L.A., just plan to hear of any concerns or any possible items that may come up with respect to [ procurability ] of deramiocel given the data set across both A and B.

Yes. So we were delighted. We had built a statistical analysis plan, which allowed us to look at A plus B and then drive that primary towards Cohort B should we not achieve significance with A plus B. We hit the primary at A plus C. So that's great. But be it is even better than A. We think that's largely because we put really stringent quality assurance, quality control measures in place. our potency assay was approved and now it's done in every lot. And so every batch of drug that comes out of San Diego goes through a much more rigorous type of evaluation than from our Los Angeles facility just because we are developing it for commercial use. So the p-value for Cohort B was really quite extraordinary and this will do several things in our minds. Number one, it shows the efficacy of deramiocel produced by our San Diego facility. Number two, and perhaps even more importantly, it shows that an efficacious product can be made by a manufacturing expansion. So this allows us to have a significant opportunity for expanding our manufacturing capabilities and treating any and all of those worldwide that ultimately can benefit deramiocel, whether with Duchenne or other indications. And the other issue, of course, is that it really closes a lot of holes, we believe that FDA could raise any concerns about manufacturing or CMC because of the efficacy of this product as well [ us passing POI ] already in preparation for approval. So I think this is one of the best findings of the study is how well Cohort B did, and I'm very proud of the data from this aspect of the trial.

And the next question comes from Ted Tenthoff with Piper Sandler.

Great. Thank you very much on this glorious day. Congratulations. I know how much hard work is going into this and really how meaningful this is going to be to boys who suffer from this terrible disease. I wanted to get a sense for the response to the BLA. What really goes into that to the reply -- I'm sorry, to the CRL? Is it just the submission of this new data set, are there any other components or anything else that needs to be included in that submission? And you mentioned the potential to accelerate their review. Can you maybe tell us a little bit about that strategy?

Yes. So in response to the CRL, we are going to be submitting this data. We submit all of the data and we will address all of the issues that were directly raised. So obviously, everybody has seen it because the administration put it out, but we would be happy to share. And so they addressed concerns regarding whether we had an adequate cardiomyopathy patient population for cardiac label, we do. So we have 65 out of 83 of our patients, as I mentioned, were diagnosed with cardiomyopathy at baseline. 92% of the patients in the trial were on cardiac [indiscernible] baseline. That was another concern race in the CRL. So we feel really great about our cardiac opportunity, the LGE and we have very good indication that we're going to be able to answer all of their concerns regarding the clinical data with this very stellar data set. We had already answered the CMC, the chemistry manufacturing control issues that have been raised in the CRL. So we're very confident in that. we've had some time to think and our teams are never quiet. We're also going to be submitting additional mechanism of action data where we will be able to support further with further analysis, the actual mechanism of action, which we've been talking about, I showed a very simple slide. There's hundreds of pages of scientific work that is gone into understanding how this works. Sorry, the final aspect of your question, Ted, which is acceleration of the PDUFA date, we didn't think that the CRL was issued fairly originally, but we understood it. Okay, it was a small data set. There were a lot of questions. None of the questions raised in the CRL were ones that we hadn't heard from the agency before. We were glad that we had, had the opportunity to file the BLA under the previous administration. We were glad that they could see through the small trial and some of its warts and bruises to the potential efficacy. But now with this absolute manifestation of efficacy, hitting statistical clinical significance, doing a clinical trial that is how clinical trials should theoretically and practically be done, we're going to be asking the agency for a rapid review, and we will hopefully use some of the political capital as well as the families and advocacy groups to help us work with the FDA to get that accelerated.

And the next question comes from Joe Pantginis with H.C. Wainwright.

Congratulations as well. This is really fantastic after the path you followed building this case here. I know it's been difficult, but it's very rewarding now. So two questions to start. First, can you give a little perspective with regard to the LVEF percentage increases and how this reflects clinically to the patients? And then number two, you just spent a bunch of time describing the responses to the CRL components. What would you consider, if any, the worst or the most demanding case that might be still outstanding?

Yes. So I'll take the last part of that first. I don't think we have any. I think that this addresses every single one of them. Like I said, I felt like we -- if we didn't have this data set coming, I would have thought to the end to get a BLA approved based on the data that we have. I believe in that data. It's been published in the [indiscernible], published in the Journal of Neurology, patients have long term over 4 years of efficacy, you can't turn your head to that. So I believe strongly in what we had. This [indiscernible] icing on the cake. It's like the wedding case, like this is it. This is the best that she possibly can have. And so we don't feel like there were any issues. In terms of clinical relevance, one of the greatest pleasures of my career has been getting to know Dr. John Soslow, who is a caring physician, but also an incredible [indiscernible]. John, I hate to put you on the spot, but could you possibly tell everybody a little bit about the clinical significance of this data, what it means to you, to your patients and sort of to the field?

Yes, absolutely. Thank you for asking me. So as they mentioned, the 2.4% difference in LVEF, that's striking because we see pretty much in study after study that there's a 2% to 3% decline in LVEF in these patients once they develop cardiomyopathy. And we and others have shown that LVEF is a very strong predictor of mortality. And in fact, he's shown that a 3% decrease has a hazard ratio of over 1.3 for association with mortality in those patients. So they have a 32% increase chance of having a mortality event for every time their LVEF drops by 3%. So this is clinically extremely meaningful for these patients. And what I'll say is that we treat these patients with cardiac meds that are adopted from the adult literature. There are no approved cardiac medications. It's an unrelenting progressive disease. And honestly, those developed meds really don't work very well. So where -- we and others have honestly grown tired of going to these patients funerals like we're not making enough of a difference with the drugs we have and so a drug that can slow or stop cardiomyopathy progression is really a game changer in this field.

The next question comes from Kristen Kluska with Cantor.

Let me also add my congratulations, and you should be proud of all the young men and boys that you've been able to help with this therapy. So I had a few questions. Just first on the SAP change, I understand the rationale especially as patients come in at different baselines. But can you just help contextualize for us? Did you bring this idea to the FDA in the meeting prior to the database lock. And then did they echo that they were supportive of it? Just to understand that because I think there's a lot of focus on that this morning.

So explain baseline differences, is that what you're asking, Kristen? I understand the question, sorry.

No. I'm saying I understand the rationale for why the percent of disease slowing makes more sense. But if you can just help us understand when this change happened in terms of your FDA dialogue and again, just reinforce that they were supportive of using that.

Yes. Thank you so much. Sorry for whatever reason, the webcast is a little funky for everybody including us today. Yes. So as I said, this is sort of iterative thinking that develops with us with our statistician colleagues with talking to the Adam group that developed the performance of the [indiscernible] newspaper in September, I mentioned kind of blue. The field wide open as to what's really important in how do you quantify and qualify progression as well as working with some of the advocacy families and learning what really matters to them and how to measure their function, either decline or stabilization. We've submitted the percent change opportunity to the FDA as part of our statistic analysis plan. it's now been several months since we submitted it, but we definitely long ago past any 30-day review period. We have put it in all of our documents that was in our final [indiscernible] that was submitted prior to database lock. So we don't expect any concerns from that. But in sort of the beautiful belt-and-suspenders way, we also see statistical significance in the performance of the upper limb in terms of absolute change which is going to be -- whichever way you want to look at this, it's a win. We won, according to Hamilton, the musical. So we don't really anticipate that there's going to be problems in dealing with whether absolute or percent change. I'll use this moment to sort of talk about the heterogeneity of Duchenne Muscular Dystrophy. And I think there's kind of a misnomer in genetic diseases, especially in diseases where there is a mutation that affects one protein. It should be so easy to fix. And I think that's sort of the kind of the cool aid we all drink when we go into this as our careers is that this got to be easy to fix. But what you realize is that anything that happens in the human body is very complicated. And so the fact that we can see statistically, which is obviously mathematically how likely is this data due to chance, improvements in this patient population using this measure of functional performance and cardiac improvement is really quite game changing, both for the world of drug development, but also for the families and the boys themselves that are impacted.

Assume that the endpoint on the mean absolute change as well, I think that's important this morning. And then I know you had previously talked about that the agency would be willing to exercise regulatory flexibility. I think the way Wall Street initially interpreted that is if you missed on PUL and maybe hit on LVEF up, there would be a chance there. But obviously, in this scenario, you hit on both. So I'm curious how you're thinking about the actual addressable patient population will be cardiomyopathy is about 80%. But then since you hit on the skeletal endpoints, one can argue that supports essentially everybody. So I'm curious how you're now thinking about the patients that would be eligible for this therapy.

Yes. So obviously, we now have changed our optics a little bit, achieving both statistical significance as well as clinical significance in the skeletal muscle myopathy, as we have been instructed by FDA to study over the past 10 years, we always considered ourselves a therapeutic for cardiac. And so the skeletal muscle is something that they felt that they could measure and therefore, decide efficacy on. So we have that. We also have improvement in cardiac function, long-term stabilization. As I said, even in this 1-year study and 91% slowing of disease and Dr. Soslow and his colleagues are working tirelessly to try and find therapeutics and now they finally will have something in their toolbox should we achieve approval with which to offer these boys and young men. The most important thing, and getting to the heart of your question, no pun intended, who are we going to try and market this to? What's the label going to say. We have over 40% of the patients in a correlation analysis that was done had improvements in both cardiac and skeletal muscle function with over 70% of the patients having a response in either cardiac or skeletal. So we're going to go back in, in response to CRL to keep our cardiomyopathy indication open. We don't want to submit a supplemental or new BLA or anything like that. And then when we have our labeling discussions, and we talked about the data, we will certainly ask also for a label for the skeletal muscle myopathy, based on the strength of this data. All of this will be determined in our meetings with the FDA after we present this data to them. But even almost anybody, even the high school students can look at this data, look at the CRL and think that there's a wonderful opportunity for approval here.

And if I may ask the physicians on the line, I would love to hear how they're potentially considering using this in their practice now that they've seen this data.

So Linda, do you want me to take that? This is Craig.

Yes, please, Craig, if you could answer that question. And then maybe, John, could...

Yes. So Craig McDonald, [indiscernible] PI on the HOPE-3 trial and have been involved in the HOPE-2 trial as well as the HOPE-2 OLE. So I have probably the greatest long-term experience using deramiocel clinically in an open-label context, so in terms of really being able to see patients who I know were on therapy. And so I think the question really pertains to who I would want to use this therapy. And I think it's clearly quite reassuring from my perspective, to see really the consistency of results across the placebo-controlled trials of HOPE-2 and HOPE-3 and the long-term HOPE-2 open-label extension. And I find that to be really compelling. But as far as who I would want to use this therapy. And I think, first of all, the trial itself was conducted in patients that were 10 years of age. There were late ambulatory patients with 10-meter walk run times greater than seconds. We know those patients will -- 100% of those patients will lose ambulation over the next 24 months. So we refer to those patients as sort of approaching loss of ambulation or the late ambulatory population. And in addition, we -- a large portion of the patients were nonambulatory patients that had at least hand-to-mouth function PUL entry scores of two or greater. But I think it's important to keep in mind that patients in the -- who entered the open-label extension have also had PUL scores -- PUL entry scores of 1, and there's been demonstration of stabilization of the PUL even in those more severely affected patients. So I would say, first of all, I would want to treat nonambulatory patients, any patient with any deficit of 1 point or more on their total pole score. I think that would be kind of at the ceiling range. And I think in terms of the floor value, I think if you've got a PUL entry score of greater than or equal to one, and you've got meaningful upper limb function that you could still preserve. I think that would be a patient that you would that you would want to treat. I think if somebody has completely lost upper limb function in terms of preservation of upper rim function, I think payers and clinicians may be consider that a population that would be less responsive to upper limb function. But in addition to that, I think any patient, irregardless of their upper limb function that's got left ventricular ejection fraction that's in the abnormal range of less than 55% or if they have presence of late [indiscernible] enhancement on a cardiac MRI even before the age of 10, so a 7- or 8-year-old patient that has like [indiscernible] enhancement, that would be a patient that I would want to treat as well. So I think that's a pretty broad population of Duchenne patients, but I think it's really -- that's really informed based on the data that we have available to us in terms of efficacy and safety. So I think really, for the most part, I think we're probably talking late ambulatory patients and a large portion of the nonambulatory population with some deficit in upper limb function at the outset, but at least some upper limb function that you can still preserve or even if they've got quite profound loss of upper limb function, if they've got cardiomyopathy and late [indiscernible] enhancement, I think those patients could benefit from the therapy as well. Jon, maybe you could weigh in just in terms of the cardiomyopathy aspects of it in terms of who you'd want to treat?

Yes. Thanks, Craig. I agree with you completely. So we define cardiomyopathy is either less in trigger dysfunction or presence of [indiscernible] enhancement and I think those are the patients that would benefit. And I do want to point out, I mean, so this LVEF improvement goes that they showed here goes along with that [indiscernible] enhancement improvement. So what I mean by that is we're not just seeing an [ LVS ] improvement because of improved contractility or decrease in [indiscernible] blood pressure. It seems like there are structural changes that they are preventing the progression of disease and they're slowing the progression of [indiscernible] enhancement and for that really critical data that suggest that [indiscernible] an underlying cause of the LVEF dysfunction and also really critical data to suggest that if you started in someone who [indiscernible] enhancement or has just started to see it that you can help slow or prevent that progression. So completely agree with what you said from a [ cardiomyopathy ] standpoint, Craig.

And then just -- that's great, John. And then just to give an overall context, about 55% to 60% of all Duchenne patients that I see are actually non-ambulatory. And I think certainly, survival has been enhanced by the use of noninvasive ventilation, but many of these patients are still dying from their cardiomyopathy, even if they're aggressively provided with a nighttime noninvasive ventilation. And so forth. So I think that we're really talking about a fairly substantial proportion of the Duchenne population would potentially benefit from this therapy. Now whether the FDA provides an even broader label to treat younger ambulatory patients, I'm not sure that [indiscernible] would necessarily have the appetite for that, but we certainly do have data in the ambulatory patients that risk for a loss of upper limb function where we're seeing evidence of efficacy. And I would be excited to begin to design studies to treat even younger patients with Duchenne. We certainly have patients that are antibody positive that aren't eligible for gene therapy. And so I think that's another population that perhaps we could develop some clinical experience and maybe in an open-label context or maybe in placebo-controlled setting. But Linda, does that answer your question? What you're looking for from the clinicians?

Yes. That was fantastic, actually, really fantastic, and I learned myself still. So the clinical contact here, I think, is incredibly important. And now that we have clinical trials really completed in this program. We now are obviously going to be focused on treating large numbers of these patients and sort of who is going to come in and benefit from deramiocel, which Dr. Soslow and Dr. McDonald provided nice overviews on so thank you both.

And the next question comes from Madison El-Saadi with B. Riley Securities.

Congrats on the results much needed for the Duchenne patient community. And this is my [ hand ] for Madison. On the significance of 85% nonambulatory patients enrolled, I appreciate the context that was given earlier. Did you see any treatment effect differences between ambulatory and nonambulatory. Sorry if I missed that [indiscernible] that was -- I think that's when the webcast rows. And also, if you could comment on reasons for MRI data, sample size is different in LVEF versus what we see for [indiscernible]. Maybe just comment on why is that? And then lastly, if you could touch on any cardiac outcomes [indiscernible] data you are seeing or will become available as you get ready for this next print towards the BLA submission and possibly looking at maybe a PDUFA date.

So there so many questions there. So I think the first question was on ejection fraction as it compared to HOPE-2 and was -- what was I concerned about it? No, I wasn't concerned about it at all. We continue to see statistically significant stabilization improvement injection fraction. A lot of our open-label extension data over many years and compared to natural history. This is actually placebo-controlled. He's on 91% slowing disease over the course of one year with absolute stabilization in nearly every one treated with deramiocel and so we feel that this is a great representation and as Dr. Soslow eloquently said, over time, we should be able to see whether these translate into extension of quantity of life. And I certainly -- I'm looking forward to sticking around and seeing these guys live well longer than natural history would predict. In terms of other cardiac outcomes, we've obviously measured a lot of things in the HOPE-3 trial. This is call to introduce the top line data. Our plan is to submit the full data set not only to the Food & Drug Administration, but we are in late-stage processing of submitting a peer-reviewed publication of this data, which will further expound on the other measures that were collected and recorded on. What I can say is that there is a cohesion of end points and cardiac function that are suggesting that this data could have long-term implications for preservation of cardiac function and stability. The one that's the most important to us, and I believe, to our physician colleagues is the late [indiscernible] enhancement, the reduction in the amount of Star. As I mentioned in my earlier remarks, the fibrofatty accumulation that occurs as the pathogenesis of this cardiomyopathy is very unique and therefore, is even more relevant to look at scar over time, and we look forward to continuing that journey with these patients as we roll forward. And by the way, I would like to add there that most of the HOPE-3 patients have rolled into open-label extension. So we'll continue to have data coming from them over the course of the second and maybe even a third year of open-label treatment until they roll into commercial products, which is our intention. I got lost, and I'm so sorry, your first question, I don't remember what that was. Can you remind us?

Yes. Linda. Thank you, Yes. The ambulatory versus non-ambulatory, if you've done any ForEx -- if that was included in the ForEx plot, sorry if I missed that. What does the treatment magnitude difference for ambulatory versus nonambulatory?

Yes. So we haven't built into our actual modeling, the ambulation versus nonambulatory patient population, although we did build it in as a covariate in one of our models to look at the difference in the trajectory of those that can still walk or have our flow decliners versus sort of a normal progressor of Duchenne but we didn't actually slice it that's in as most of our patients are nonambulant or as Dr. McDonald said earlier on the verge of becoming nonambulant. So the idea is to stabilize and continue to observe them. This is -- Again, I want to emphasize, this is one of the learnings in clinical trial conduction and development is -- we were looking at a cross-section of one year in the life of a boy or young man that's anticipated to live 30 years. And if you look at the average age of 15, they're actually sadly quite frighteningly halfway through their life span. So we're looking at a very small section of time. So what we want to do is be sitting around, chatting about our patients when they are 40, 50 years old. I'd just like to add that only 15% were ambulant at baseline, which is too small of a sample size on which to do any independent statistics.

Yes. And your sample size for [indiscernible] endpoint versus the LVF, those ends are different? That was my clarifying question, like for VF, there were some assessments for MRI that may have been missed. Just can you clarify the explanation for that?

It was a coalescence of multiple factors. So some patients actually couldn't go on the magnet. They had some money contractors or spinal fractures that they just couldn't lay down and get in the magnet. Some of the patients didn't -- we're missing an image along the journey, either a baseline or 6 months or 12 months, so we couldn't do the analysis. And then we used the core lab. So I want everybody to know that every MRI was collected by the site it was immediately uploaded to a core lab. The core lab took those images in the quality assess them, quality control them, and then they were the ones that decided whether the images and it had to be all three3 images were readable and accessible. Once that was done, they were then put into a pool where they were read by a third-party reader and the data collected. So this is a very rigorous collection and evaluation process. And I can be noted by anybody that's ever looked at an MRI from a kid with Duchenne muscular dystrophy, it's like looking at a snowstorm. They're very hard to read. So sometimes the quality of these images just make it impossible to really use the type of rigor that one has needed to measure for a clinical trial. So that's a difference in the number of patients I've reported out for cardiac function.

And the next question comes from Aydin Huseynov with Ladenburg.

My sincere congratulations. It's a great day for Duchenne patients and parents A couple of questions on my end. So I wanted to ask you about other cardiac points that we'll describe in HOPE-2, [indiscernible] wall thickening and others. I think there were about 20 card deck measures in HOPE-2. And whether those measures were statistically significant in HOPE-3.

Yes. So this morning's focus is the release of an analysis of the top line data, primarily focusing on the primary efficacy endpoint, the key secondary and the [indiscernible] error controlled secondary endpoints. There's a lot of data, I think my team tells me there's 150 pages of tables of data that we have. And so we're just starting to go through those, look at the relevance do some correlations. And we'll be providing more data either in scientific meetings and publications or future calls.

Appreciate that. And just a follow-up question. So given the effect not only on cardiac muscle but also in scale. So what do you think could be other applications of deramiocel on [ scale muscle ] marketing in terms of other indications? And what are your plans as it comes to other indications?

Yes. So you and I have been talking about other indications for a long time. I think the next shot on goal will be [ Becker's ] cardiomyopathy and skeletal muscle biopsy. We'll be working with the agency on that. My goal is to begin conversations with them on what the requirements might be for U.S. approval in vectors in the first half of 2026 once I get this launched across the line. Obviously, I think as broad as one's imagination can be. We now understand -- and the good news is in the development of the understanding of the mechanism of action of immunomodulatory anti-inflammatory antifibrotic is going to be used in a lot of different disease states, a lot of different manifestations and such. And so we have to kind of decide on the plethora of opportunity where we will take the program. Right now, we are gearing up for market entry for DMD. That's going to take a lot of our time. Manufacturing is [indiscernible] probably as we speak, making doses in San Diego. And so we have a great market opportunity with [ CMG ]. We're going to think about [indiscernible] and we're just starting to think about pipeline development above and beyond where we are. It's actually a long time about the development of antibody therapeutics and how that happened and how [indiscernible] changed the world. And we really think that deramiocel has the opportunity to do something similar and we're going to continue to work on that.

And the next question comes from Catherine Novack with Jones.

I think some of the questions we're seeing are how this is going to be handled when FDA stats team looks at the raw data themselves. And I just wanted to ask in one more -- I know you've gotten this a bunch, but one more confirmatory question on the percent change versus the absolute change. It sounded like that was more of a tacit approval rather than specific feedback that you got. So is there -- does there seem like a possibility that they would run the absolute change as the primary endpoint in their analysis?

Well, first of all, FDA typically works under a tacit approval mechanism of action, right? When you submit even the most simplest of documents like investigational new drug application, you know you can do your trial when you don't get feedback. So in that situation [indiscernible] silence as a set, or no news is good news and using two co-local expression. So we don't have any problems there. We don't think they're going to raise any problems. They do get the raw data. The good news is, as I've said now a few times, is we even see statistical significance with absolute change. So whichever way they look at it, they can look at the heads or the tails and they're going to get the same answer. I don't anticipate there's going to be any problems in their statisticians assessing the data, one of the things I'm very proud of is the rigorousness by which this protocol was developed by which the statistical analysis plan was developed by the statisticians that work for and next to and around Capricor in order to make sure that every [indiscernible] study was adequately controlled, well designed, blinded randomization was done in the most rigorous fashion. And so I don't think they're going to be able to poke holes on anything specific. Should they send us information requests for questions as to why we did something in the way that we did. We have the math and we have the rationale and we have the team to explain it. And your questions have been the same as mine over the past period of time, which is, is there anything they can poke holes in and I think my [indiscernible] team sitting next to me here, I feel very confident in the quality of our data.

Linda, this is Craig, if I could just comment briefly on this concept. I think it's important to note the performance of upper limb is -- there's really three key dimensions to it, there is an off-shoulder dimension. There's a mid-level dimension, which is sort of focused on elbow function. And then there's a [indiscernible] dimension, which is focused on hand function. And if you look at the natural history data, the upper shoulder dimension is really quite dynamic. Patients really plunge with regard to their function, and they'll lose 5 or 6 points in a single year. And whereas the mid-level dimension actually is much more linear is much more predictable. The distal dimension moves much more slowly. But in terms of quality of life and in terms of importance to the patient, it's -- the items are really quite important and quite essential. And I think it's important to point out here that even with the -- looking at the total score of the [indiscernible], there was [indiscernible] significance that was achieved. If you look at the [ Pole 2.0 ] mid-level dimension, which was shown in [indiscernible] slide 14, the forest plot, there was still a 1-point treatment difference and the p-value there was 0.008 and that was the same primary endpoint that was actually used in HOPE-2 that the FDA had signed off on. And so I think this concept of percent change, if you look at percent change in -- with a higher score at baseline where patients are going to perhaps lose more items and lose more function. I think the percent change makes a lot more to look at really across the entire spectrum of Duchenne patients. And I think importantly, the prespecified endpoint in terms of the PUL 2.0 total score, it really doesn't matter whether you look at it in terms of percent change or absolute value, you still get statistical significance. And I think with the data coming out from me, I may knew who is one of the key developers of the PUL along with the [indiscernible] our group and others. I think this concept of percent change really make sense from a methologic and statistical point of view. But I think we will be armed and ready to justify this with the regulatory authorities.

Great. And then just going back to thoughts on possible differences in statistical analysis. Is there any difference potentially, let's say, in terms of handling of missing data, where they could have a more rigorous approach that might change the statistical significance of the end point?

Yes. So I'm going to have Dr. Nathaniel Hogan, our Director of biostats here [indiscernible] answer that question, Nathan?

Yes, that's a great question. So in the [ pole ], we have -- we don't have a lot of missing data in the [ pole ] but on top of that, we have run many sensitivity analysis on different methods for imputing the missing data, and all of them show a consistent and robust treatment effect and a similar result to the primary analysis.

Linda, this is Craig again. Yes. Just really quickly, I think I've been involved in clinical development of Duchenne Therapeutics for many years in terms of the multiple approved drugs in the U.S. as well as the EMA. I think this nonambulatory population has huge unmet burden. And oftentimes, we've sort of relied on accelerated approvals or extrapolation of data to try to get them access to therapeutics. But here, we actually have hard data in terms of two placebo-controlled trials, long-term open-label extension. And I think of the 8 or 9 approved therapeutics for DMD. I don't think I've seen as rigorous a data set or as compelling a data set as this particular data set, particularly in the non-ambulatory patient population. So I think that's just important context in terms of addressing these concerns that the regulatory authorities may be concerned about the prespecified submitted statistical analysis plan, I think we're -- I'm glad we're talking about this that we actually met the primary endpoint. And actually, you look at that forest plot and the consistency across all the key secondary endpoints, it's really just amazing and compelling to me. So that's just provide a little additional context of the discussion.

And the next question comes from Boobalan Pachaiyappan with ROTH Capital Partners.

All right. Okay. All right. So congratulations on today's data. A couple of questions, mostly for the KOLs. So let's just say like hypothetically, deramiocel will get [ accrued ] by tomorrow. So I wanted to speak to you or I wanted to get your thoughts on your comfort level in prescribing deramiocel on top of patients who are getting [indiscernible] therapy. Do you feel there will be any payer pushback? Or how are you thinking about it?

Craig, please go ahead. And then, Jon, if you want to provide some color, that would be great.

No, I don't think there'd be -- I think this really has the potential to work synergistically with both [ exon ] skipping products as well as gene therapy products. I don't think I would use deramiocel within the first 6 months after a patient has been treated with the [ AAV ] gene therapy just in terms of immunologic responses and the close safety monitoring that's required for gene therapy. But I think by all means, I think deramiocel can be used synergistically with [ exon ] skipping therapies with gene therapy with [indiscernible] inhibitors against that and with steroid medications. These patients in this trial were all treated with stable doses of steroids. So I think that my discussion with third-party payers in terms of the patient that was perhaps treated with one of these other therapies would be really probably focused in large part also on the really compelling cardiomyopathy data that we see in cardiac MRI and the really compelling data that we have, that deramiocel could actually stabilize the progression of the cardiomyopathy, which I don't think we didn't necessarily have data in terms of the other approved Duchenne therapeutics on. So that would be really my thoughts on that question.

Yes, I agree. I mean, we really look at this as we need to layer therapies on with different mechanisms of action in order to really improve the quality and duration of [indiscernible] these patients. And I think deramiocel has a really nice place in that layering because it's different -- a different mechanism and I think it really should be synergistic. In terms of the approval, the -- we have spent a lot of time on approvals for a lot of drugs, and I'll say that the more data we have, the easier it is. And I think that the fact that every endpoint hit in this study will make our lives significantly easier. And I think Craig's point about this being really if they get the cardiomyopathy label, it would be the only cardiomyopathy drug for DMD. I think that really will make our lives significantly easier to layer this on after someone receives gene therapy or while they're on [ ] skipping or something along those lines.

Great. And then very quickly, with respect to the particular response that we saw today, I was wondering if you could comment on whether this was what was expected? And was it in line with what is known from the nature of the [indiscernible] studies?

In terms of the placebo effect, we believe that it's in line with what we've seen in natural history. It's certainly in line with what Dr. Soslow has published in terms of the cardiomyopathy in line with the performance of the upper limb. Of course, let me remind you that the placebo group and the treated group were well matched in terms of baseline characteristics and appropriately stratified. So we believe the placebo group is well represented in terms of the natural history progression of the disease.

Thanks, Linda. Maybe one final question to you. So after submitting the CRL response to the FDA, I was wondering how you're thinking about the pathway to approval in ex U.S. region, particularly in the U.K. and European Union. Do you think today's data will facilitate that process? Or how are you thinking over the timelines? Any thought?

Yes. So the EMA is laser focusing on Cohort B. As I mentioned in my earlier remarks, we saw statistical significance independently in Cohort B. They like to see data from the commercial manufacturing facility. Once we're ready, and once we understand most favored nations and once we decide how we're going to proceed outside the U.S. and once we've launched in the U.S., we'll take the ex U.S. territories on. We have an agreement in place with [indiscernible] for rights -- for sales and marketing distribution in Japan. We'll be working very closely with the Japanese PMDA in order to move that program forward, and we'll continue to update the as well as the markets on how we intend to proceed. Right now, I think like almost every other drug developer, especially small companies such as Capricor, we're focusing on the United States. We manufacture our products in the United States, our teams are all based here in the United States. And so that's our focus for right now.

And the next question comes from [ Yanan Zhu ] with Wells Fargo.

Great. And I wanted to add my congrats on the [indiscernible] the results here. Just wondering whether there is any correlation between the [ PUL ] endpoints and the LVEF endpoint, especially between the absolute change of the [ PUL ] endpoint and LVEF endpoint given that there's some questions this morning, but I understand that as an absolute endpoint change in PUL also hit p-value. But if there's any correlation, I think that might further reassure the results.

Thanks, Yanan. So our brands must work similarly because that was the first question I asked our stats team after I saw the preliminary top line data now finalized top line data. And we're very delighted to say that over 40% of patients had improvements in both left ventricular ejection fraction and the performance of the upper wound. And as I stated earlier, 70% or a little bit more patients had improvement in either skeletal muscle or cardiac muscle function. And this, of course, is then also validated in the global statistical test, our Type 1 error controlled secondary endpoint where we looked at the relationship of performance of the upper limb, left ventricular ejection fraction and the patient-reported measure of PGI, which shows statistical significance. So overall, we believe that there is a nice correlation and a good improvement. And as [indiscernible] left were one of our Duchenne moms, so eloquently said, people ask me, do I want my son's heart to improve or his skeletal muscle to improve, I'll take either or both, and that's how we're approaching deramiocel.

Wonderful. Linda, I was also wondering about Cohort B specifically, given that you mentioned that the EMA -- more of a EMA focus. And also, you mentioned Cohort B data actually looks even better than Cohort A. So on the absolute change in PUL end point, could you comment on whether Cohort B alone also reached that stake? And whether that p-value is a little -- any different than the overall?

Yes. So yes, Cohort B did reach the [ cyclical ] significance, very statistically significant in the PUL and yes, we are going to use that data to help support primarily manufacturing that the product that is made in our San Diego commercial facility is actually as good or better than anything we've ever made. And as I said earlier, but I want to emphasize it also shows that you can do a manufacturing expansion of deramiocel very successfully in that our potency assays predict bioactivity. So this is a giant win showing the Cohort B has done so well.

And I'm showing no further questions at this time. I would like to turn it back to the Capricor's management for closing remarks.

Thank you so much for taking your time. I do know there were problems with this webcast. It's a first-world problem because there were so many of you that tried to call in and just overloaded the lines. We will be posting this webcast. The transcript will be available. And of course, if you have continued questions, please feel free to reach out to me and my team. I'm going to take this final moment to say thank you, everybody says thank you to the families that participate in the clinical trials. But what I can say is the Duchenne families have become my family. I feel them every day. I hear from them regularly. I watch them as they're growing older. And just like our own children, I celebrate when they have something really positive happen to them. And what we're hearing around is that those that are long-term treatment with deramiocel are living better, healthier lives. And now we have mathematical support to be able to go into the regulators and get this for everyone. Thank you for our investors. Thank you for believing in us all this time. And thank you for joining us this morning. We look forward to continuing the journey with you in a successful approval and ultimate launch of deramiocel for DMD.

Thank you, presenters. And ladies and gentlemen, this concludes today's conference call. Thank you all for joining. You may now disconnect.