As a reminder, this conference call is being recorded. I would now like to turn the conference over to our host, Mr. AJ 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're 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 showed that the HOPE-3 phase III 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, AJ Bergmann, who you just heard from, Dr. Michael Binks, our Chief Medical Officer, Mr. Mark Awadallah, our Chief Development Officer, Doctors Kati Meghdari 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, AJ.
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 email, my phone, my text messages this morning have 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 with Duchenne muscular dystrophy and their families. These boys and young men and their families have hope.
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, AJ. I think most of you on this call know about Duchenne muscular dystrophy. It is an X-linked disease. It means it is 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 provide therapeutics for them in the future. Titin 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 hold its structure.
The pathogenesis of Duchenne muscular dystrophy is the worst of the muscular dystrophies 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 aspect 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 the quality 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, it leads to greater cellular breakdown. 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 toward improvements in cardiac function. We then showed that we could multi-dose, switching to an intravenous paradigm in the HOPE-Duchenne open-label extension, which rapidly led to the conduct of the HOPE-2 and the HOPE-2 OLE clinical studies.
The HOPE-2 and the 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, that we improve skeletal muscle function, that we are addressing an unmet need that nobody else has been able to address, and that is the primarily non-ambulant patient population, and that we see long-term, multiple years, four years coming into five years of safety and tolerability as well as efficacy. As you know, we filed a biologics license application based on the HOPE-2, 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.
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 scars 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 trials 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. Shown on the next slide is the multimodal mechanism of action of deramiocel. We've recently published this 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 anti-fibrotic 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, 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 lot-to-lot 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. New slide.
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 I error-controlled secondary endpoints in the mid-level Performance of the Upper Limb. That is the ability to move essentially your elbow or your arm. An analogous task by which it could be improved by preserving mid-level function is eating, brushing your hair, drinking water, hugging your mom, as Pat Furlong would say.
A global statistical test, which is a full function and survival 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 had late gadolinium enhancement. That is a dye 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 one-to-one randomization. Patients received 150 million cells via intravenous infusion four 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 had 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 ambulation 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 development 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 15.4 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 ejection fraction was 57%. There was no difference in baseline in the Performance of the Upper Limb in the placebo versus the deramiocel group of any measurable difference, with the overall PUL entry score for those with entry scores of 2 to 3 at 48 or 4, 5, and 6 PUL entry scores, an overall entry score of 58, all considered well within the standard expectations of this particular patient population. Most of our patients were non-ambulatory. Let me highlight at this moment the incredible relevance of this therapy in the Duchenne community. There is nothing that is 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 trials, 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 in 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 of the patients. 25%-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 in 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. 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, 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 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 Limb
, and 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 two points, and my colleague Mark has a PUL score of 40 and he loses two 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.
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. 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 rank change with a p-value of 0.041. 0.041, those zeros 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 25-30 years to take the life of a boy or young man with Duchenne. As I said at the beginning, it is a slow and steady, 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 for these boys and young men, and I wanted to highlight that here, the importance of treating this aspect of the disease. Next slide, please. Shown here is a forest plot. A forest 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 is shown in this very beautiful plot is the fact that we not only hit the primary efficacy endpoint of the PUL 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 all the Type 1 error controlled secondary endpoints. What does that mean? What it means is that sometimes in a clinical trial, when you sort of laundry list a lot of secondary endpoints, you can kind of lose statistical value by this concept called multiplicity. When you Type 1 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 with a p-value of 0.008. The total global statistical test, the one that I mentioned a few moments ago that measures feels, functions, and survives as a secondary endpoint with the t-statistic, a p-value of 0.01. And then finally, one that was added as part of the cohort B of the clinical trial at the request of our cardiology colleagues is late gadolinium enhancement. Gadolinium is a dye that is used in MRI.
You've probably seen it if you've heard me speak before when we talk about HOPE-2, then 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 can then quantify the number of segments of the heart that is impacted by scarring, or other ways of looking at it 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 Markham, many of these physicians that have studied this very different cardiomyopathy for the course of their careers have shown that this fibrofatty replacement is a slow and insidious killer of these boys and young men. They develop scars 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 scar that the heart actually can no longer compensate. They develop a fulminant heart failure, and ultimately nothing the clinicians can do can pull them back from the edge. So the fact that we see a reduction and 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 length of life, but 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 in 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 exon skipping 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 spending 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 inflammation 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 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 three primary efficacy endpoint of the PUL 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 endpoints. deramiocel is a first-in-class therapy designed to treat not only Duchenne cardiomyopathy but also the skeletal muscle myopathy.
We made those seminal discoveries now multiple years ago in our preclinical studies, and now it has been validated in multiple clinical studies culminating in 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 endpoint. Safety and tolerability, one of the most important aspects of treating any type of disease because, of course, you want your 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, adequate and well-controlled clinical study. We're going to submit this data in response to the CRL. We are hoping to get a relatively rapid PDUFA date right now or up until our Type A meeting in August. They were telling us it would be a Class 2 resubmission, which is about six 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 pre-license inspection. Our commercial manufacturing facility is ready to go. Cohort B, which is the aspect of the trial that 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 a glass and celebrate that perhaps we are first time providing an opportunity for these boys and young men, especially those that are non-ambulant 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.
Thank you. Ladies and gentlemen, we will now begin the question and answer session. To ask a question, you may press the star followed by the number one on your telephone keypad. To withdraw your question, please press the star followed by the number two. With that, our first question comes from Leland Gershell with Oppenheimer. Please go ahead.
Good morning, Linda and team, and my congratulations on these very strong data from HOPE-3.
I wanted to ask, and I know you had discussed this a bit during prepared remarks, Linda, but with respect to the primary and secondary endpoints, percent slowing versus I think what was on ClinicalTrials.gov of mean change, if you could just walk us through maybe a bit further in your discussions with FDA and perhaps part of your SAP, 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. Thanks.
Yeah, thanks, Leland. So obviously, there's been a lot of discussion, a lot of planning that went into the statistical analysis plan.
We worked with multiple outside statisticians, James Signorovitch 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, clinically 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 an international, the group that developed the Performance of the Upper Limb and presented the idea to them before we wrote it in our SAP. They also like it. The PUL is still a relatively new measure. We're still understanding it.
As I said in my remarks, a PUL score of 20 and a guy who loses two points on that has a very different outlook on those two points lost than a guy who starts with 40 points and loses two points. Percent change allows you on a patient-by-patient basis to assess the loss for that particular patient. For more clarity on that, Anna Mayhew, actually, again, one of the developers of the Performance of the Upper Limb, 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. The FDA has said that the clinically meaningful change in the Performance of the Upper Limb would be one point.
We see one point, two points. Many of that change attributed to mid-level PUL, 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 in these guys that are on deramiocel. The good news 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.
Thanks. Just 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 and passed and all that, versus A from LA. Just wanted to hear of any concerns or any possible items that may come up with respect to the probability of deramiocel given the data set across both A and B. Thanks.
Yeah. 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 B, so that's great. But B did 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 were 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 significant opportunity for expanding our manufacturing capabilities and treating any and all of those worldwide that ultimately can benefit from 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 as us passing PLI 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.
Thanks very much, and again, my congratulations.
Oh, thanks, Leland. You've been great to work with.
And the next question comes from Ted Tenthoff with Piper Sandler. Please go ahead.
Great. Thank you very much. On this glorious day, congratulations. I know how much hard work has gone 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 the review. Maybe tell us a little bit about that strategy. Thanks.
Yeah. 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's 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 a cardiac label. We do. So we saw 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 meds at baseline. That was another concern raised 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 controls issues that had been raised in the CRL, so we're very confident in that. Because 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 analyses 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 has gone into understanding how this works.
Excellent.
And then, 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 a clinical trial 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 FDA to get that accelerated.
Great. Excellent. Well, congratulations and best on these next steps.
Thank you so much, Ted, and thank you for standing by me for all these years.
My pleasure.
Thank you. And the next question comes from Joseph Pantginis with H.C. Wainwright. Please go ahead.
Hey, everybody. Good morning and 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? Thanks a lot.
Yeah, 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 if we didn't have this data set coming, I would have fought to the end to get a BLA approved based on the data that we had. I believed in that data. It's been published in The Lancet, published in the Journal of Neurology. Patients have long-term, over four years of efficacy.
You can't turn your head to that. So I believe strongly in what we had. This is not even icing on the cake. It's like the wedding cake. This is it. This is the best that you possibly can have. And so we don't feel like there are any issues. In terms of clinical relevance, one of the greatest pleasures of my career has been getting to know Dr. Jonathan Soslow, who is a caring physician but also an incredible academician. 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?
Yeah. 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%-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, it'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% increased 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 adult meds really don't work very well.
So we and others have honestly grown tired of going to these patients' funerals. 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.
That's fantastic. Thank you very much for that, and looking forward to a potential positive FDA outcome. I think you have the data to show that. So congratulations again.
Thank you. And thank you, John. That even brought tears to my eyes. Thank you.
The next question comes from Kristen Kluska with Cantor. Please go ahead.
Hi. Good morning, everybody. 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 meetings prior to the database lock? And then did they echo that they were supportive of it? Just trying 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 didn't understand the question. I'm 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.
Yeah. Thank you so much. Sorry.
For whatever reason, the webcast is a little funky for everybody, including us today. Yeah. So as I said, this was sort of iterative thinking that developed with us, with our statistician colleagues, with talking to the Analysis Group that developed the Performance of the Upper Limb. Anna Mayhew's paper in September, as I mentioned, kind of blew the field wide open as to what's really important and how do you quantify and qualify progression, as well as working with some of the advocacy families in 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 statistical analysis plan. It's now been several months since we submitted it, but we definitely long ago passed any 30-day review period. We have put it in all of our documents.
It was in our final SAP 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, we won, 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.
I think that's sort of the kind of Kool-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. 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.
As we met the endpoint on the mean absolute changes, well, I think that's important this morning. 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, there would be a chance there. But obviously, in this scenario, you hit on both. So I'm curious how you're thinking about what 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.
Yeah. 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 had been instructed by FDA to study over the past 10 years, we always considered ourselves a therapeutic for cardiac.
The skeletal muscle was 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 one-year study and 91% slowing of disease, and Dr. Soslow and his colleagues are working tirelessly to try and find therapeutics. 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 in getting to the heart of your question, no pun intended, was 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 and respond 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 talk 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 a high school student, can look at this data, look at the CRL, and think that there's a wonderful opportunity for approval here.
Thank you so much. 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. Thank you so much, everyone.
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 provide.
Yeah. So Craig McDonald, I have been national 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 are on therapy. And so I think the question really pertains to who I would want to use this therapy in.
I think it's really 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 in, I think, first of all, the trial itself was conducted in patients that were 10 years of age. There were late ambulatory patients who had 10-meter walk-run times greater than 10 seconds. We know 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, a large portion of the patients were non-ambulatory patients that had at least hand-to-mouth function, PUL entry scores of 2 or greater.
But I think it's important to keep in mind that patients who entered the open-label extension have also had PUL entry scores of one. And there's been demonstration of relative stabilization of the PUL, even in those more severely affected patients. So I would say, first of all, I would want to treat non-ambulatory patients, any patient with any deficit of one point or more on their total PUL 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 want to treat.
I think if somebody has completely lost upper limb function in terms of preservation of upper limb function, I think payers and clinicians maybe consider that a population that would be less responsive in terms of upper limb function. But in addition to that, I think any patient, regardless of their upper limb function, that's got a left ventricular ejection fraction that's in the abnormal range of less than 55%, or if they have presence of late gadolinium enhancement on a cardiac MRI even before the age of 10, so a seven or eight-year-old patient that has late gadolinium 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 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 non-ambulatory 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 gadolinium enhancement, I think those patients could benefit from the therapy as well. John, maybe you could weigh in just in terms of the cardiomyopathy aspects of it in terms of who you'd want to treat.
Yeah. Thanks, Craig. I agree with you completely. So we define cardiomyopathy as either left ventricular dysfunction or presence of late gadolinium enhancement. And I think those are the patients that would benefit.
I do want to point out. I mean, so this LVEF improvement that they showed here goes along with that late gadolinium enhancement improvement. What I mean by that is we're not just seeing an LVEF improvement because of improved contractility or decreased systolic blood pressure. It seems like there are structural changes that they are preventing the progression of disease, and they're slowing the progression of late gadolinium enhancement. That's really critical data that suggests that they're getting at the underlying cause of the LV dysfunction. Also, really critical data to suggest that if you started in someone who's got late gadolinium enhancement or has just started to see it, that you can help slow or prevent that progression. Completely agree with what you said from a cardiomyopathy standpoint, Craig.
And then just to say that's great, John.
Then just to give an overall context about 55%-60% of all Duchenne patients that I see are actually non-ambulatory. I think certainly survival has been enhanced by the use of non-invasive ventilation. But many of these patients are still dying from their cardiomyopathy, even if they're aggressively provided with nighttime non-invasive 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 CBER would necessarily have the appetite for that. But we certainly do have data in ambulatory patients that are at risk for loss of upper limb function where we're seeing evidence of efficacy. 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 in, maybe in an open-label context or maybe in a placebo-controlled setting. But Linda, does that answer your question, what you were looking for from the clinicians?
Yeah. That was fantastic, actually. Really fantastic. And I learned myself still. The clinical context here, I think, is incredibly important. 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. Thank you.
Thank you. The next question comes from Madison El-Saadi with B. Riley Securities. Please go ahead.
Good morning, team. Congrats on the results. Much needed for the Duchenne patient community. And this is [Maanasa] for Madison. On the significance of 85% non-ambulatory patients enrolled, I appreciate the context that was given earlier. Did you see any treatment effect differences between ambulatory and non-ambulatory? Sorry if I missed that forest plot. I think that's when the webcast rolls. And also, if you could comment on reasons for MRI data, sample size is different in LVEF versus what we see for PUL 2.0. Maybe just comment on why is that. And then lastly, if you could touch on any cardiac outcomes in interim data you are seeing or will become available as you get ready for this next sprint towards the BLA resubmission and possibly looking at a mid-year PDUFA date. Thanks for taking our questions.
So sorry, there were so many questions here.
I think the first question was on ejection fraction as it compared to HOPE-2 and was, "Was I concerned about it?" No, I wasn't concerned about it at all. We continue to see statistically significant stabilization improvement in ejection fraction. A lot of our open-label extension data is over many years and compared to natural history, this is actually placebo-controlled. We saw a 91% slowing of disease over the course of one year with absolute stabilization in nearly everyone treated with deramiocel. And so we feel that this is a great representation. And as Dr. Soslow so eloquently said, over time, we should be able to see whether these translate into extension of quantity of life. And I certainly am 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 a call to introduce the top-line data. Our plan is to submit the full data set not only to the Food and 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 endpoints in 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 gadolinium enhancement, the reduction in the amount of scar.
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 product, 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 me?
Yeah. Yeah. Linda, yes. Thank you.
The ambulatory versus non-ambulatory, if you've done any forest, if that was included in your forest plot, sorry if I missed that. What was the treatment magnitude difference for ambulatory versus non-ambulatory?
Yeah. So we haven't built into our actual modeling the ambulation versus non-ambulatory 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 slow decliners versus sort of a normal progressor in Duchenne. But we didn't actually slice it that thin as most of our patients are non-ambulant, or as Dr. McDonald said earlier, on the verge of becoming non-ambulant. So the idea is to stabilize and continue to observe them.
Again, I want to emphasize, and 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 a young man that's anticipated to live 30 years. And if you look at the average age at 15, they're actually, sadly and quite frighteningly, halfway through their lifespan. 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 in which to do any independent statistics.
Yep. And your sample size for PUL 2.0 endpoint versus the LVEF, those ends are different? That was my clarifying question.
For LVEF, there were some assessments for MRI that may have been missed. Just can you clarify the explanation for that? Thank you.
It was a coalescence of multiple factors. So some patients actually couldn't go on the magnet. They had so many contractures or spinal fractures that they just couldn't lay down and get in the magnet. Some of the patients were missing an image along the journey, either a baseline or 6-month or 12-month, so we couldn't do the analysis. And then we used a 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. They quality assessed them, quality controlled them. And then they were the ones that decided whether the images, and it had to be all three 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 was a very rigorous collection and evaluation process. And as 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 is needed to measure for a clinical trial. So that's the difference in the number of patients reported out for cardiac function.
Understood. Thank you and congrats again.
Thank you so very much. Thank you. We're delighted as well.
And the next question comes from Aydin Huseynov with Ladenburg. Please go ahead.
Good morning, Linda, team. 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 endpoints that were described in HOPE-2: LVDS, LVES volume, wall thickening, and others. I think there were about 20 cardiac measures in HOPE-2. And whether those measures were statistically significant in HOPE-3.
Yeah. This morning's focus is the release of an analysis of the top-line data, primarily focusing on the primary efficacy endpoints, the key secondary, and the type 1 alpha or 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. We're just starting to go through those to look at the relevance, do some correlations. We'll be providing more data either in scientific meetings, in publications, or in future calls.
Yeah. Thank you. Appreciate that.
And just a follow-up question. So given the effect not only on cardiac muscle myopathy but also skeletal muscle myopathy, so what do you think could be other applications of deramyocel on skeletal muscle myopathy in terms of other indications? And what are your plans as it comes to other indications?
Yeah. 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 myopathy. 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 Becker's in the first half of 2026 once I get this launched across the line. Obviously, I think it's 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, anti-fibrotic. This can be used in a lot of different disease states, a lot of different manifestations of 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 busily, probably as we speak, making doses in San Diego. And so we have a great market opportunity with DMD. We're going to think about Becker's, and we're just starting to think about pipeline development above and beyond where we are. We've talked for a long time about the development of antibody therapeutics and how that happened and how Avastin 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.
Thanks so much. Congratulations again.
Thanks.
And the next question comes from Catherine Novack with Jones. Please go ahead.
Hi. Morning, Linda and team. Congrats on the results. 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 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 does there seem like a possibility that they would run the absolute change as the primary endpoint in their analysis?
First of all, FDA typically works under a tacit approval mechanism of action, right? When you submit even the most simplest of documents like an investigational new drug application, you know you can do your trial when you don't get feedback. So that situation's silence is consent. No news is good news, to use a colloquial 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 worked for and next to and around Capricor in order to make sure that every aspect of the study was adequately controlled, well-designed, blinded randomization was done in the most rigorous of fashions. And so I don't think they're going to be able to poke holes in anything specific. Should they send us information requests for questions as to why we did something the way that we did, we have the math, and we have the rationales, 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?
I think my stats team sitting next to me here feel very confident in the quality of our data.
Linda, this is Craig. If I could just comment briefly on this concept. Yeah, on this concept. I think it's important to note the Performance of the Upper Limb is there's really three key dimensions to it. There's an upper shoulder dimension. There's a mid-level dimension, which is sort of focused on elbow function. And then there's a distal 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. They'll lose five or six 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, those distal 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 PUL, there was statistical significance that was achieved. If you look at the PUL 2.0 mid-level dimension, which was shown in, I think it was slide 14, the forest plot, there was still a one-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.
I think this concept of percent change, if you're looking at percent change 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 sense to look at really across the entire spectrum of Duchenne patients. I think importantly, the pre-specified 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. I think with the data coming out from Anna Mayhew, who is one of the key developers of the PUL along with Eugenio Mercuri in our group and others, I think this concept of percent change really makes sense from a methodological 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 endpoint?
Yeah. So I'm going to have Dr. Nathan Hogan, our director of biostats here at Capricor, answer that question. Nathan?
Yeah. That's a great question. So in the PUL, we don't have a lot of missing data in the PUL. But on top of that, we have run many sensitivity analyses on different methods for imputing the missing data. And all of them show consistent and robust treatment effect and a similar result to the primary analysis.
Got it.
Thanks for taking the questions, and congrats again on the data.
Thanks, Catherine.
And once again,
Linda, if I could just, Linda, this is Craig again.
Yep, please. Always.
Yeah. 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 non-ambulatory 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 and long-term open-label extension. And I think of the eight or nine approved therapeutics for DMD, I don't think I've seen as rigorous a dataset or as compelling a dataset as this particular dataset, particularly in the non-ambulatory patient population.
I think that's just important context in terms of addressing these concerns that the regulatory authorities may be concerned about, the pre-specified submitted statistical analysis plan. I think I'm glad we're talking about this, that we actually met the primary endpoint. 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. That's just to provide a little additional context of the discussion.
Thanks, Craig. You always teach me something every time we talk.
All right. Thank you. And once again, if you would like to ask a question, simply press star one on your telephone keypad. The next question comes from Boobalan Pachaiyappan with ROTH Capital Partners. Please go ahead.
Sorry.
Hi. Good morning. Can you hear me okay?
I think I can hear you now. Yes.
All right. Okay. All right.
Congratulations on today's data. A couple of questions, mostly for the KOLs. Let's just say hypothetically, deramiocel gets approved by tomorrow. 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 exon-skipping therapy. Do you feel there will be any payer pushback, or how are you thinking about it?
Craig, please go ahead. And then John, if you want to provide some color, that'd 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 six months after a patient has been treated with 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 HDAC inhibitors, givinostat, 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 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 necessarily have data in terms of the other approved Duchenne therapeutics on. So that would be really my thoughts on that question.
Yeah, 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 life in these patients. And I think deramyocel has a really nice place in that layering because it's a different mechanism, and I think it really should be synergistic. In terms of the approval, 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 it gets a 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 exon skipping or something along those lines.
Great. And then really quickly, with respect to the placebo 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 natural history 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 and 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. regions, particularly in the U.K. and European Union. Do you think today's data will facilitate that process, or how are you thinking about the timelines? Any thoughts? Thank you.
Yeah. 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 launch in the U.S., we'll take the ex-U.S. territories on.
We have an agreement in place with Nippon Shinyaku for rights for sales, marketing, and 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 EMA 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 product in the United States. Our teams are all based here in the United States, and so that's our focus for right now.
Thank you very much, and congratulations again,
and the next question comes from Yanan Zhu with Wells Fargo. Please go ahead.
Oh, great. Thanks for taking our questions, and I wanted to add my congrats on the splendid result 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 question this morning? But I understand that the absolute endpoint changing PUL also hit P-value. But if there's any correlation, I think that might further reassure the results. Yeah.
Thanks, Yanan. And so our brains must work similarly because that was the first question I asked our staff 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 Limb. And as I stated earlier, 70% or a little bit more patients had improvement in either skeletal muscle or cardiac muscle function.
This, of course, is then also validated in the global statistical test, our Type I 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 showed statistical significance. So overall, we believe that there is a nice correlation and a good improvement. As Mindy Leffler, 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." That's how we're approaching deramiocel.
Wonderful. Linda, I was also wondering about cohort B specifically, given that you mentioned that's more of an EMA focus. Also, you mentioned cohort B data actually look even better than cohort A.
So on the absolute change in PUL endpoint, could you comment on whether cohort B alone also reached that state and whether that P-value is a little any different than the overall?
Yeah. So yes, cohort B did reach statistical 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 and that our potency assays predict bioactivity. So this is a giant win showing that cohort B has done so well.
Wonderful. Thanks for taking all the questions and congrats on the results.
Thank you so much, Yanan .
I'm sure you have no further questions at this time. I would like to turn it back to the Capricor 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. It just overloaded the lines. We will be posting this webcast. The transcripts 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. 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 on 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, 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 and 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.