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

Good afternoon. Thank you for joining us today for this webinar with Capricor Therapeutics. So we wanted to hold this webinar to talk with the community about Capricor's investigational product, deramiocel, talk a little bit about cardiomyopathy in Duchenne, discuss what a complete response letter is, what it means and touch on the HOPE-3 trial and Capricor's plans moving forward. So we have a number of panelists with us today for this webinar. So from PPMD, we have Pat Furlong and Lauren Stanford, who's our Senior Director of Advocacy as well as myself. We have Dr. Tim Franson, who's Principal at Faegre Drinker. We have 2 pediatric cardiologists, Dr. Chet Villa from Cincinnati Children's and Dr. Jon Soslow from Vanderbilt Children's. And then from the Capricor team, we have Mark Awadalla, Chief Development Officer; Dr. Micheal Binks, their Chief Medical Officer; and Dr. Linda Marbán, their CEO. So this webinar is being recorded. So if you have friends or family who this will be relevant to, it should be up on PPMD's website within the next week. And then after we get through all of the material today, we are going to have an open Q&A portion. So if you have questions, there's a chat function at the bottom of your screen. Go ahead and put your questions in there while we're going through the webinar, and then we'll try to get to as many of those as we can. We also have a large number submitted before the webinar. So we're going to try to tackle those as well. But we're just going to get started because we have a lot to cover today. So I'm going to hand it over to Lauren, who's going to begin by having a conversation with Dr. Tim Franson kind of around complete response letters, what those are and what they mean.

Hi, everyone. Good afternoon or good morning if you're with us from the West Coast. It's great to be here with you. And I have Tim -- Dr. Tim Franson here with me. We're just going to have a brief discussion about complete response letters and CRLs. And Tim is a Principal at Faegre Drinker, but I'd like to call him our regulatory and FDA expert. So we have the right person on the line. So Tim, I don't know if you wanted to introduce yourself briefly before we get into our Q&A.

No, that's fine. I'm a physician and pharmacist by training and have consulted with PPMD for almost 15 years.

Thank you. Okay. So like Eric said, we have a lot to get to, so let's get right into it.

Tim, would you mind explaining in plain everyday language what a complete response letter or CRL is and how it differs from other traditional letters a company might receive from the FDA?

Absolutely. So it's best to frame this as part of the overall FDA review process. When a company, also called a sponsor, is preparing to register a new product for approval consideration, they submit a large dossier of information. And FDA then makes a determination whether that can be reviewed, that's called a filing decision. And if it passes the filing decision, then there is a set amount of time, either 6 or 10 months for FDA to review that document. There are frequent interactions during that process. So a company has some indications of questions that may arise. And then comes that magic moment at the end of the overall review process when FDA registers a decision about next steps, whether there may be a full approval and a product is prepared for marketing, and that is just a traditional approval letter or whether there are still some points that need to be clarified for -- before a product is labeled and approved. And that's the complete response letter. A complete response letter is not uncommon. In fact, between 2018 and 2023, over 30% of new drug and new biologic applications were complete response letters. What these usually indicate are that FDA has some remaining questions about what is in the application or what has been assessed. Frequently, it may be as simple as agreeing on appropriate labeling statements so that practitioners and patients have a full understanding of all the implications from the application summary. So there are actually several subtypes of these complete response letters and that they can be for safety or effectiveness, manufacturing issues or bioequivalence if there's a comparison with a prior approved product. And each of those may be handled uniquely. If it's a simple thing, a sponsor may be able to respond such as with labeling and it only takes after that a 2-month review process or FDA may request additional analysis of previously submitted material, which is pretty straightforward or that additional studies may be necessary, which may be brief for long term. So there's a number of flavors to complete response.

And you touched on this a little bit, but would you mind giving a little more detail on what the most common reasons a company might receive a CRL from the FDA?

Sure. First of all, it would not receive a rejection that is a filing decision made early. So the parts of the application are there. And frequently, when there are different groups at FDA, the chemistry people, the clinical people and so forth that are involved, they may raise questions about additional details, perhaps when a drug is studied in a larger population, whether there are particular subgroups such as ambulatory or non-ambulatory where additional assessments need to be made. And so those are the kind of questions that frequently arise. Mostly, it's benefit-risk type determinations, although it can be manufacturing processes and so forth.

That's very helpful. And what are the regulatory implications of receiving a CRL? For example, does it affect eligibility for future priority review or anything else like that?

Well, the decisions on priority or standard review are typically made on the quality of data and not on whether there is a complete response or not. A complete response is just a pause, if you will, to gather what may be additional information required to answer questions that the regulator has raised. And sometimes, these things arise earlier in a process and a company may have the opportunity to respond during the initial review cycle or sometimes it comes in near the end, and that may be when new parties who get involved near the end of processes, as always happens with any application that senior management becomes involved, there may be additional comments, questions that hadn't been previously raised that trigger a request for more information. So it does not impede a reconsideration. It does impact the time line for those things.

Okay. You know our patient community pretty well. You know we're really active, and we want to be doing all the things and helping. Are there ways patient communities can be supportive or involved during the CRL response process to help ensure the progress continues? Or is it a time when we should step back? Just what do you think is best for the community to do?

Well, in the formal process, there is no patient voice that is mandated or invited because usually, it is technical questions and not related to issues of patient preference or the kind of data that is involved there. On occasion, a sponsor may call upon a patient community to provide input on particular technical aspects. And we've certainly seen that with patient preference analyses where that have been helpful in clarifying questions. But overall, writing cards and letters at this stage maybe boosting the spirits of the company, but would not necessarily influence the proceedings because it's an FDA and sponsor type interaction and is technical and not the same kind of interpreted thing that we may be able to engage our patient communities and family communities in.

Understood. And the last question I have for you is, how should the patient community interpret the CRL, especially when this is a very highly anticipated therapy, a lot of people were like waiting on the edge and nervous and all these things? So how would you say the community should interpret this?

Well, as with most complete response letters, it indicates a pause to answer some questions that were outstanding, but is not casting a pall upon the probability of approval. Overall, it just means things need to be sorted through in one area or another in order to answer the FDA's questions to allow them to have the information they need for labeling. So while it's a frustration to the community because it involves more time, it is certainly not atypical in the overall drug development and review process. So just hang on, hang tight and await this next step.

Okay. Great. And hopefully, we are able to provide all of you with some background on CRLs and what they mean. And if you have any other questions for Tim or I regarding the overarching CRLs and how they work, please feel free to drop them in the chat, and I will try to respond. But with that, we will pass it over to Linda to talk in more detail about what's going on with Capricor.

Well, good morning, good afternoon, wherever you are. Thank you so much for joining us. Doing PPMD webinar is kind of like coming home. We've been doing these for a long time. We've been updating the community with the progress of deramiocel, started off as CAP-1002. And we have spent many years uncovering the mechanism of action and working with FDA to get this across the line. Today, I am really pleased to be joined by my colleagues, people that I hold in the highest of esteem, Dr. Chet Villa, who has been my muse for years now in understanding the cardiomyopathy associated with Duchenne, the patient experience and sort of the unmet need. Dr. Micheal Binks, who has recently joined us as our Chief Medical Officer, I consider it one of the great achievements of my leadership team in the last 2 years because Dr. Binks has such a presence, and I heard him present. I met him at a PPMD conference and was able to understand the incredible depth of understanding he has for the patients, but also the medicine and the science. And then finally, Jon Soslow, who I also met at a PPMD conference, and I became so encouraged by his ability to take on tough issues and fight for what he believes in and really address the understanding of using imaging to predict the outcomes for cardiomyopathy. And I think if I could say that there is one person that has put the blue dots on the trees of this hiking trail to the top of this mountain. It's Dr. Soslow for helping us understand the progression of the cardiomyopathy. So these amazing people are here today, and I don't want to take much more of my time or your time with me presenting, so I'll go on with my rest of my presentation. Next slide, please. Deramiocel. So many of you know us right now. We are an allogeneic cell therapy. It's an off-the-shelf product that is not a stem cell. It does not go in and become part of a functional muscle group. What does deramiocel do? Deramiocel, and I'll talk about the mechanism in detail in a little bit, actually has the ability to calm down the immune system. So there's probably less death of muscle cells. It's anti-fibrotic, our actual potency assay, which has been approved by FDA demonstrates its antifibrotic property. That means it slows down the aggregation of scar and allows healthy muscle. Weather it's been treated by a gene therapy or an exon-skipper to thrive. We have positioned deramiocel as a good player in the sandbox in the sense that it should be used in combination with any of these other therapies because the more that we can calm down the immune system, the secondary implications of Duchenne muscular dystrophy and other neuromuscular disorders, the greater opportunities for these other therapies to work well. So keep in mind, all of the people that are on deramiocel and that will receive it in the future have the opportunity for every standard of care medicine, whether it'd be a gene therapy, an exon-skipper, a steroid or heart medications, that are available for them to use. So with that in mind, I want to talk to you a little bit about our path with the Food and Drug Administration. I think many of you have been following our journey and perhaps I can get the next slide now. I think many of you have been following our journey. We have been working on deramiocel, formally CAP-1002, for the treatment of DMD cardiomyopathy really for about almost 10 years now. It came to our attention that the type of pathophysiology that is associated with Duchenne cardiomyopathy would exactly fit the mechanism of action of our product. And so we started the journey first in mdx mice, that's when I had the opportunity to meet Pat and learn about her journey. Then we did a clinical trial called HOPE-1, which we then took to the FDA and talked to them about our path to approval. And you'll see our clinical trial journey in a few minutes. But suffice it to say, I want to identify that we did HOPE-1, HOPE-2, HOPE-2 open-label extension and HOPE-3. And finally, in our meetings with FDA last year in August of 2024, we had this incredible pivotal meeting in which they were willing to take the cardiac data from HOPE-2, as published in The Lancet, the HOPE-2 open-label extension data compared to Dr. Soslow's external comparator control, which also really was collected by the whole cardiac consortium of -- funded by the Office of Orphan Products of FDA and National Heart, Lung, and Blood Institute and asked us to submit on the cardiomyopathy label. This happened in an amazing interaction with 38 reviewers in White Oak, Maryland just about 1 year ago. And of course, this is an incredibly important indication because while there are other therapeutics evolving or approved for the skeletal muscle myopathy, there's currently nothing specifically for Duchenne cardiomyopathy, but deramiocel. So we proceeded, and we proceeded in our interaction with the agency. We submitted the BLA at the end of 2024 as we had been requested to do. We submitted individual patient data propensity match, which means that it looks like you're taking a natural history population and using it as a control group. It's very well accepted statistically. They accepted -- the FDA accepted our BLA. We had 50, 5-0, information requests that we answered from the agency between January and June of 2025. We passed our pre-licensing inspection of our new and ready-to-go commercial facility here in San Diego, California, where we were told that it was unexpected how well for a small company we have built our manufacturing paradigm. We have approval of our potency assay. We have approval of most of our CMC requirements. All of them can be met by the original PDUFA date as assigned of August 31, 2025. We had a mid-cycle meeting in which 10 minutes of the 60 minutes were used because there were really no issues that were raised. So you can imagine that as we were preparing for our late-stage meeting, as we were preparing for our advisory committee meeting, as we were preparing for PDUFA, we were very surprised by some turn of events. So first, our advisory committee meeting was canceled. It was canceled in the public forum before the company was even told. We didn't even know officially for an entire week after it was published that our advisory committee meeting was canceled. Then we thought, okay, maybe they have enough data. That's fantastic. We'll prepare for the late-stage meeting. We were on par for our late-stage meeting. It was scheduled for the middle of July. And then all of a sudden, a few days before a late-cycle meeting was literally supposed to happen, we received a complete response letter. Next slide, please. So let's talk about what was in the complete response letter. The complete response letter came to us as a surprise. And in there was information that could easily have been either asked for or garnered through the mid-cycle meeting or earlier in the review process or even perhaps not accepting the BLA for approval because all of the data that was cited not meeting the statutory requirement for substantial evidence of effectiveness was submitted in the BLA at the end of the calendar year. Now -- this took us as a great surprise. We've been working with the agency. We have a very collaborative relationship with them. We thought that everything was going well. Prior to reaching -- receiving the complete response letter, we've reached out to the agency multiple times to try and work with them once the advisory committee meeting was canceled. Dr. Craig McDonald, Dr. Villa, Dr. Soslow, along with Pat Furlong as well as some of our statisticians that work with us externally sent a letter to the FDA, explaining why deramiocel should be looked at favorably at least in terms of an advisory committee, if not for direct approval, based on the data that has been collected and presented to which there was no reply. Finally, in the CRL, they gave us an opportunity for something called a Type A meeting to determine the path forward for potential approval. So this is where Capricor is luckier than some of the other companies that are receiving CRLs right now. And let me just take a minute to explain this to you. In the background, we had done a clinical trial. Some of you were probably participants in it called HOPE-3. HOPE-3 is a randomized, double-blind, placebo-controlled trial evaluating deramiocel in Duchenne muscular dystrophy. Now originally, the primary efficacy endpoint of HOPE-3 is and has been the Performance of the Upper Limb 2.0. Now as we had been developing deramiocel, originally CAP-1002, for the treatment of the heart disease, that's what we invented it for. We have been working with the agency. The entire time trying to get them to understand that what we needed was a primary efficacy endpoint that would allow us a cardiac label because the work had not been done by Dr. Soslow on the cardiac consortium. Identifying the risk for morbidity and mortality, the agency kept coming back to us and saying, "Look, you have skeletal muscle efficacy. Why don't you use that?" We understand the pathogenesis of that part. We don't understand the cardiac part. What happened last year in August was so game changing because not only did we show that there's unequivocal proof that deramiocel seems to perform better than a natural history study in terms of feeding the cardiac disease, but now the FDA has something to hang their hat on their own funded study, identifying the pathogenesis and morbidity and mortality of DMD cardiomyopathy. Originally, in that meeting, the purpose of that meeting was for us to change the primary efficacy endpoint of the HOPE-3 clinical trial to cardiac. And at that point, the agency said, "Don't do that. Expand your label with the skeletal muscle disease. Now just go in with the data that you have." But because we have this fully enrolled, fully treated last patient, last visit in June clinical trial, if the current administration does not think that the current BLA meets the standard for statutory requirement for substantial evidence of effectiveness, let us do what Sarepta has done and other companies have done and read through the primary efficacy endpoint of PUL and either change it to ejection fraction or allow us to take that and use it for the substantiation of the regulatory requirements for approval. That data is still blinded. We haven't looked at it. It is completely pure data that can be used to support the substantial evidence of efficacy. And look, many of you know and have heard me say many times, I'm a scientist. I started in this field because I had the desire to make life better for human beings that were sick. If for some reason, we don't have evidence of effectiveness in cardiac disease in HOPE-3, I don't want you to get that either. So we are willing to put ourselves on the line. We are just asking FDA for the regulatory flexibility that they have so loudly talked about in all of their public presentations. Now you probably saw that there were some CMC issues that were raised in the CRL. All of those were either addressed in information requests that had already been submitted and they had not reviewed it based on the CRL or have been addressed currently, and we plan to be able to submit full responses to the CMC items as recently as next week, the first week of August. So we're ready to go. We're hoping that FDA exercises some regulatory flexibility. That's an update on the regulatory piece. I know you all are going to have questions. I'm going to roll forward and just remind you, on the next slide, please, that CDCs are from healthy human hearts. They are not stem cells. I already talked about that, talk about manufacturing after you hear from our key opinion leaders. There's over 300 peer-reviewed scientific publications, substantiating the mechanism of action and the efficacy of deramiocel that we have been treating patients across multiple trials. We have over 250 patients and over 700 infusions. So this is a very safe product, very safe once a quarter infusion is nice and easy. Finally, last slide just to remind you that the indication that we are going after is the treatment of deramiocel with treatment of cardiomyopathy, I've spoken too much, in patients with DMD, and it's 150 million cells, IV infusion every 3 months. And with that, I will turn the floor over to my esteemed colleague, Dr. Chet Villa.

Thank you, Linda. And thanks to PPMD as well for hosting this. Next slide. So as everyone, I think, is aware, muscle injury is detectable immediately after birth in patients who have DMD. This leads to progressive skeletal, respiratory and cardiac dysfunction, which ultimately leads to mortality. Through research funded by PPMD and others, life expectancy has grown quite a bit over the last 3 decades, so that patients are now living into their late 20s or 30s if they receive standard of care therapy. And in fact, the neuromuscular and respiratory improvements have significantly delayed the onset of respiratory failure, and that has unmasked the significance of DMD cardiomyopathy, which generally shows up later than skeletal and respiratory muscle weakness, the point where cardiac disease is not a leading cause of death in DMD. Next slide. So when you look around the world, we can see that about 40% to 50% of mortality in DMD is due to cardiac disease, and that is independent of the population and independent of geography. Next slide. And so what have we learned about DMD cardiomyopathy over the last decade? As you heard from Dr. Marbán, we have learned quite a bit, so when you were looking even in the mid-2010s, a lot of what we were learning was coming from cardiac MRI. So in the 1950s through the '70s, the way that we had to be able to look at the heart was mostly by under the microscope. And there, we could see that there was evidence of cardiac fibrosis in people who had passed away in their late teens and early 20s. In the 2000s and 2010, cardiac MRI had improved to the point where we were able to image these tissue changes, and you started hearing us use the term fibrosis. What that is? We were looking at what we call late gadolinium enhancement. And in areas where we saw fibrosis on the old histology, we could see these changes. And so we started using the term fibrosis, fibrosis, fibrosis to characterize these changes that happen in the heart. Next slide. And why this mattered is there were a number of studies that came out in the early 2000s and mid-2010s that basically said when we are able to detect this late gadolinium enhancement or what we used to call fibrosis, is that, in fact, seminal. So here on this slide, you can see in green the way that heart function stays stable over time prior to the onset of this late gadolinium enhancement. Then once that develops, again, what we used to call just fibrosis alone, we start to see heart functions start to decline. Next slide. Now over the last 5 or so years, we have gained further understanding of this, and it has really started to underscore why we need early therapies that change the long-term trajectory of DMD cardiomyopathy. So first, we started to learn quite a bit from what was happening in the skeletal muscle disease, especially from studies that were coming out of imaging DMD where they were able to use MRI to show fatty replacement of the muscles, especially in the leg and also now in the arms and in the respiratory muscles as well. And we started to ask the question, well, if this is what's happening in the skeletal muscle disease, is the same thing happening in the heart? Is that old paradigm of fibrosis alone really correct in the new era with current outcome? Next slide. And in fact, what we found is the same sort of things that were happening in the skeletal muscle were happening in the heart. And just later, like everything else about heart disease in general. So on the screen left, you can see the heart muscle from somebody who is a preteen. At the bottom of the screen, you can see the kind of dark pink stuff, which looks like more typical muscle. In the in between, you see light pink that is kind of interspersed between that dark pink, and that's the areas of fibrosis for that scarring that we used to think was the dominant theme. And then at the top, what you can actually see in very light white is actually we're getting the very beginnings of fatty replacement of the heart. And why this matters is that means that you're getting irreversible replacement of the heart even in early stages of disease. And in fact, when we started to look at adults or even late teens, we started to see quite profound replacement of the heart in a number of our patients. So again, on screen right, you see a similar area of tissue, but what is the dominant picture is one of fatty replacement. So there's large areas of white. There are very few areas of that dark pink and there are scattered areas of fibrosis. So this really started to beg the question, should we be starting therapies early? Can we preserve that muscle? And how do we go about doing that? Next slide. Furthermore, when we started to look at other areas of the heart, not just the left ventricle, which had been the historic way that we looked at it, we saw similar things. So in the right ventricle, the chamber that comes to the lung, we actually saw more profound muscle loss and in fact, there were areas where there was almost no muscle in the right ventricle. And similar things were happening in the upper chamber of the heart or atrium. And so this really started to change the paradigm and say we need new therapies that preserve cardiac muscle now rather than kind of using the old paradigm for non-DMD cardiomyopathy. Next slide. And so where we are at now is that we understand that late gadolinium enhancement, the stuff that we used to call just fibrosis is really fibro-fatty and that you can get that disease very early. The late stages of disease are characterized by almost complete replacement of the myocardium in areas. So you've lost whatever muscle that was there. So really, we need early therapies that can preserve cardiac muscle in every way that's possible. And finally that, that fibro-fatty replacement or fatty replacement occurs in all of the chambers of the heart. So we really need good ways to modify this to really get the best outcomes that we can. Next slide. This matters especially in patients with DMD or in anybody who's nonambulant because what we know is in neuromuscular cardiology that disease progression is often asymptomatic. So in the patients that I take care of who don't have DMD or don't have neuromuscular disease, we do things like exercise testing, stress testing, as you may hear it called. And we ask them about, are you able to go up steps? How fast can you go up steps, all of those things. For patients who have DMD or skeletal myopathy, confuses that picture? Or if you're already nonambulatory, we miss that all together. So patients go effectively from not symptomatic to symptomatic and we miss those in between stages. We can use cardiac MRI to track those changes and that has really become fundamental to our understanding of how the disease progresses and where we might be able to intervene and you'll hear more from Dr. Soslow about that. Next slide. So where does that leave us? Right now, there are no DMD-specific cardiac therapies. We have generic therapies that are used in other cardiomyopathies that may help. Guideline-directed medical therapy, what we typically use to treat heart failure and non-DMD cardiomyopathy is really focused on the late stages of disease. It's not focused on disease modifying and it's not DMD specific. We are working to improve access to things like ventricular assist device and heart transplant, but those things remain exceedingly rare in the current era. And we've only found 6 heart transplants to date. So we really need to be able to modify that early stage of disease while we continue to work on continued access to the late stages of disease and advanced therapy. And really, we need these new therapies to stop people from DMD from passing away prematurely due to cardiac disease. The promise of skeletal muscle therapies is there. And now we need to start to focus on the cardiac impact of the disease as well. Thank you.

Thank you, Chet. I really appreciate that background, and we all continue to learn from you. I'm going to spend the next few minutes going through, first of all, how deramiocel works, how we make it and then just briefly sharing with you an overview of the data. Many of you have seen this data sort of in piecemeal and over time, but I think it's worth taking a look not only at the data that is currently out in the public purview, but also the data that made up our biologics license application. But first, one of the strengths of deramiocel at the cell therapy is that we have spent literally 20 years developing an understanding of what the cells are, how they work, how they work to repair cardiac dysfunction, how they actually work to manage skeletal muscle deterioration. So we have done years' earth of preclinical studies, identifying, first, the mechanism of action of reduction in inflammation, reduction in fibrosis, improvement in skeletal muscle function and improvement in cardiac function. We then moved this program into the clinic, first doing studies of intracoronary infusion thinking that the cells needed to get close to the site of injury, learning that we could actually back out to intravenous infusions and also be able to increase our dosing, not only in terms of number of cells and frequency, where we showed improvement in skeletal muscle function and cardiac structure and function. And then finally, the gold standard of any therapeutic development is the development of potency assays that directly and absolutely measure the efficacy of a product before it goes into a patient so that lot-to-lot consistency can be maintained. And in this slide, we sort of show that path to how we got to this point. Now how do we actually make deramiocel? Let's look at that on the next slide. We start with transplant qualified donor human hearts. That means these are hearts that could potentially go into another person, but cannot go in for technical reasons usually. And what we first do is along with the organ procurement organization is make sure that these donor hearts are very, very safe. They don't have viral pathogens, they don't have antibodies and then they don't have anything that could possibly be transferred to another human being. That is, first and foremost, what we do. Then we bring it back into our labs and we select specific regions of the heart that we have learned over these years, where there is high likelihood to find the cells of interest, which we know become deramiocel. But there's very few of them in the heart. It's why the heart can't usually fix itself. So we use proprietary methods to get those cells out, and we call those explant-derived cells. They become the foundation of our master cell bank or what is called here the drug substance. Once we get the drug substance, we go through all kinds of testing to make sure that the cells are what we think they are, to make sure that they're living, to make sure that they can divide, to make sure they have extracellular markers that identify them as what we now know as deramiocel. And of course, we put them through a lot of sterility testing to make sure that they are not carrying anything forward that could possibly get into a person and harm them in any way. And this is one of the reasons why this product is so very safe. Then this is where the magic starts, where we actually put it into a production, where we put it into a type of cell culture, it's a suspension culture that synergistically allows expansion of the cells to many, many, many more than would naturally be available. And then that once it is done, is frozen down and put into vials where it ultimately will come to you. Now again, we put them through all the testing that went through with the drug substance. We look at viability, cell number. We make sure that they express exactly what we think they do. We make sure that they do not carry any risk for any pathogen development or passing on pathogenesis and then, of course, again, the most important aspect once we make sure that it is clean and safe is we put it through the potency assay so that lot-to-lot variability is extremely low, if not nonexistent, in terms of providing you with the highest quality deramiocel product that we can. We've worked many years to develop this program, and I'm very pleased to say it's been looked at and scrupulously examined by FDA through our chemistry, manufacturing and controls program. We passed pre-licensing inspection, as I mentioned, and we now are geared towards commercial manufacturing in much higher numbers. Now I'm going to switch gears on the next slide and start talking about our clinical experience. I alluded to this in my introductory remarks. We have been working on treating patients with Duchenne muscular dystrophy cardiomyopathy for multiple clinical trials. First HOPE-Duchenne, we were able to show reduction in the scar in the heart measured by late gadolinium enhancement and improvements in cardiac and skeletal muscle function. This trial actually had formed our dosing and treatment paradigm in terms of numbers of cells. We treated patients in an open-label extension of the original HOPE study, and we were able to identify that it was safe to increase the number of cells that these patients were getting. And also the frequency of dosing, and we were able to infuse intravenously based on preclinical studies. This was the game-changing study. We then did the HOPE-2 clinical trial. I'll show you a little bit of data from that, although most of you are aware of it. It was published in The Lancet. This was our game-changing study, which we were able to show significant improvements in cardiac structure and function as well as skeletal muscle structure and function and was very well tolerated, very safe, and again, as I mentioned, published in The Lancet. The HOPE-2 open-label extension study is the one that we're so proud of here at Capricor. We continue to treat these boys and young men. They're growing older with us, which is really exciting, 4 years coming into their fifth. Some have gone out to college, some have gone on to careers, some of them have reported that they've had no change in skeletal muscle function as measured not only by measures of the Performance of the Upper Limb, but also functional assessments that they do on themselves. Their cardiac function has stabilized, and we have a long-term safety profile. These guys are coming in. Some of them have had 16 infusions at this point and continue to show up every quarter because of the safety and efficacy of this product. And then finally, the HOPE-3 clinical trial, the one that I've spoken about, which is blinded, we haven't unblind it. Let me remind you that the original primary efficacy endpoint was the Performance of the Upper Limb 2.0. We have now asked the Food and Drug Administration to change that primary efficacy endpoint to left ventricular ejection fraction to reflect our long-term history of treating the cardiac disease associated with Duchenne and to lead to the first approved therapy for cardiac disease in Duchenne muscular dystrophy as opposed to standard of care medication. I'm going to quickly now walk you through our clinical experience and give you snippets of the data. Obviously, there's much more of it. With that, I'll ask for the next slide. In HOPE-2, it was a randomized double-blind placebo-controlled trial. It was the first trial in which we did intravenous infusion of 150 million cells 4 times a year. We brought the subjects in every quarter to measure the Performance of the Upper Limb. They got 3 MRIs of their hearts at baseline at month 6 and at month 12, where the primary analysis was done and the data from that study was really quite extraordinary. Many of you know that, that study was stopped early due to primarily resource reasons, but also because we wanted to see if the therapy was going to be potentially efficacious and the data speaks for itself. Next slide, please. So shown here, we've shown this many, many times, but I'll just reiterate, in blue are the subjects treated with deramiocel and gray are the placebo-treated patients. What we saw is the primary efficacy endpoint was met. That's the Performance of the Upper Limb, 1.2 is mid-level. That was the arm that was recommended by the agency at the time because it was the one that would be most easy to be quantified. We hit a p-value of 0.01, which means there is an extremely small chance that the data that you see is due to chance. More importantly, sort of on a day-to-day basis for those of you that are receiving deramiocel or want to, it was a 71% slowing of the disease process over the first 12 months of treatment and that has continued. Again, game-changing, ejection fractions shown on the right blue is treated deramiocel patients, gray are the placebo patients. This was the first study that showed stabilization and in fact, improvement in ejection fraction in Duchenne muscular dystrophy. Let me remind you, our patients at a later stage nonambulatory one, those of you that are like that, you know that your hearts are highly at risk for declining in this very, very fragile time in your bodies. Those of you with young kids, you don't have it now, but it's very, very likely that your sons will -- or you yourselves will experience a reduction in cardiac function that ultimately is the #1 cause of death now in Duchenne muscular dystrophy. So having a therapy that is safe that can be started young and that can reduce the ramifications of the heart disease cannot be overemphasized. Next slide, please. This is the most important slide in my presentation today. This is the slide that we showed to the Food and Drug Administration. And this is thanks to Dr. Jon Soslow and his colleagues that actually gathered the data, did the imaging study and looked at the risk factors for morbidity and mortality in DMD. In The Lancet that's shown on the left, what we published in The Lancet is shown on the left, it's called a forest plot. And what you basically do in a forest plot is you show many, many measures that can either go to the left, which has had no treatment effect or to the right of the midline, which means that there's likely a treatment effect. And what we see is in 21 of 22 cardiac measures, deramiocel was better than placebo in 21 of 22 cardiac measures. The ones that are called out on the right are the ones that are most important is how the heart meets the needs of the body ejection fraction, volumes global statistical test of all the cardiac measures. And as you can see here, what we see is a very strong indication that deramiocel is actually addressing the very measures that the cardiac consortium calls out in their reasons for Duchenne cardiomyopathy to be the #1 cause of death. Reduction in ejection fraction over time leads to them falling off a cliff and ultimately losing their lives. We believe that we can actually attenuate this disease process, slow it down in addition to the current standard of care cardiac medications. Next slide, please. So just to summarize, we saw a significant stabilization in HOPE-2 of upper limb and cardiac function. We met the primary efficacy endpoint with a 71% slowing of disease in mid-level pool, 1.2 with a p-value of 0.014. We saw statistically significant effects in several critical cardiac parameters, including ejection fraction, which is now what we're asking for the primary efficacy endpoint in HOPE-3. Again, almost a nonexistent cost that this would be considered to be chance. Next slide, please. Now the open-label extension study is a really important study. As I mentioned a minute ago, it's actually the clinical study that I feel most proud of because it's just long-term safety and efficacy of deramiocel, but we also have the advantage of working with our colleagues to gather natural history studies. So in an open-label extension, everybody is getting your drug. So you can't really have a placebo group to bank on. But in Duchenne, because, unfortunately, it's a chronic disease in which decline is usually the only way to go, you are able then to be able to use external controls. So in the next slide, I want to highlight what I think is one of the most important slides that I can show you today, which is that over 3 years of treatment with deramiocel, those treated had a 99%, 99% slowing with a chance that it was due to a chance of good luck, almost nonexistence again, a P-value of 0.008 compared to the external comparator control, the Dr. Soslow data. This means that there is a very good chance, almost an incontrovertible chance that deramiocel is making those patients with ejection fraction -- with DMD cardiomyopathy, their ejection fraction better. Take this home. This is a safety -- a safe therapeutic that is improving the heart in conjunction to all the cardiac medication. Next slide. Additionally, we're showing improvement in skeletal muscle function. And those are the guys that are in the long-term open-label extension study of HOPE-2 will tell you, they will actually feel when their dose is wearing off. Some of our guys will tell us that they have measures that they kind of measure their own function with at home. They can push open a door, they can transfer themselves. They can move around in bed. All of a sudden, they start to feel weaker. They start to feel that they're losing it. And that's why most of the guys that are coming in for the open-label extension infusions, come in on literally the day that they are eligible for their next infusion because they want to make sure that they can maintain the strength that they've achieved. This is another external control group. This one is coming from Cincinnati Children's Hospital Medical Center. Thank you to Dr. Villa and his colleagues for allowing us access to this data, which shows that over time, those that are treated with deramiocel have a 52% slowing of disease over this 3-year time period. Next slide, please. The most important aspect is how an individual does. We all know that Duchenne muscular dystrophy is a heterogeneous disease. One of the reasons why clinical trials in this space are so hard, one of the reasons why it's so difficult is that you always have variability and so there's some people that just don't respond or don't respond as well or may have some other physical indication that doesn't allow them to perform well in a lab. That's why people are starting to work on, measuring things at home or outside of a clinic, but I wanted to introduce you to one of our open-label extension and actually HOPE-2 patients. He's an incredible guy. Many of you might know him. And what you can see on the right is as his scores over the course of time, he is rock stable in his Performance of the Upper Limb. And what we can tell you is that at his current age, which is in his early 20s, not typical that they're not losing skeletal muscle function. They're losing skeletal muscle function. But what's more important to him, what is more important to his family, what's more important to those that love him is that his heart function is stable. And you can see this is over a long stretch of time that his ejection fraction has really stayed stable. So we continue to be committed to him to all of the patients that are in the open-label extension. We have over 100 patients now that are in open-label extension. We are supporting these patients. We are a small biotechnology company, but we are so committed to this space that we are providing deramiocel to them until we get it across the line, until we get approval, until we have the opportunity to have -- everybody have access to deramiocel. We believe in our patients, and we're grateful to them for first offering themselves to us and now to see the benefits along with us. Now I'm going to turn over the podium to Dr. Binks, our Chief Medical Officer. He's going to talk about perhaps what is the most important aspect of deramiocel, which is its safety profile. Dr. Binks?

Thanks, Linda. So I'd like to just give you an overview of safety that was observed in the HOPE-2 and HOPE-2 OLE studies, first of all. As in many studies, and you might expect, most patients did report an adverse event. In the case of deramiocel, 50% or 60% were thought to be related to the study drug. Overall, these were mild and well balanced between the deramiocel and placebo group and resolved within 24 hours following infusion. There were 2 serious adverse events reported to -- in the deramiocel group, and I'll tell you a bit more about those in a moment. There were some milder hypersensitivity responses, reasonably well balanced between the HOPE-2 deramiocel and placebo group. There were no deaths in either study. The particular focus of our safety monitoring around respiratory decompensation, immune or HLA sensitization or arrhythmias basically drew a blank in terms of detecting events. Next slide, please. So in terms of the serious adverse events that have been related to deramiocel, there are 2 in the HOPE-2 study, and 2 have been reported in the still-blinded HOPE-3 study. All of these resolved without sequelae and share some fairly similar characteristics. Although they're all described slightly differently here in the reporting term, there are essentially severe allergic responses, we think, to deramiocel. They tended to present with tingling around the lips, a tickly cough, tightness in the throat, a bit of flushing, sometimes swelling with a fast heart rate and in some cases, reduced blood pressure. And they were all managed in the infusion units with additional steroids or antihistamines resolved within 24 hours and had no long-term sequelae. In 2 of these instances, epinephrine was used, so there were obviously fairly major events. Each event started during the infusion itself. After the first event occurred, we instituted a mitigation regime, on the next slide, that involves pre-administration of high-dose oral steroids and histamine receptor antagonist. And in addition, we limited the rate of infusion for the first 20 minutes or so just to allow minimization of exposure to -- in those who may have an allergic reaction. And I should also just mention that these allergic-type reactions occurred either on the first or most commonly on the second infusion with deramiocel and have not -- there have not been any such events in the HOPE-2 open-label extension study. So clearly, the first couple of infusions need to be watched fairly carefully, but the drug is administered in an infusion center that are well equipped to deal with these types of allergic responses. So that's it on safety. It's a short part of the presentation because there's not a lot to report.

Thank you. I'm going to turn it now over to Dr. Jon Soslow to talk about the clinical perspective. And it is always a pleasure to hear you speak, Jon. So I'll be quiet.

Thank you, Linda, and thank you, PPMD, for hosting the webinar. So as Linda said, I'll be talking about the clinical perspective. And if you go to the next slide, we're going to start with what do we see in the clinic, what do we see in our patients. And so next slide, this is a paper from way back when in 1992, looking at the progression of cardiac function in patients with Duchenne muscular dystrophy. It was the first one I could find published. And they looked at something called left ventricular ejection fraction, which is the most common measure that we use to evaluate heart function. And this is done on echocardiography. And what you can see from these points is that patients started in various different spots, but for the most part, everybody declined. And this is what we see clinically that this is a disease that leads to an unremitting progression of left ventricular dysfunction. Now if you go to the next slide, since that time, there have been many, many guideline papers, many, many changes in the way that we routinely treat patients. These are from our most recent guideline paper. And we now give ACE inhibitors or ARBs with the presence of LV dysfunction or start prophylactically around 10 years of age. We give mineralocorticoid antagonist with the presence of late gadolinium enhancement or fibro-fatty changes, as Chet described earlier, or with any LV dysfunction. And we give beta-blockers with any tachycardia or with patients who have left ventricular dysfunction. In addition, we've adopted a lot of more advanced medications from adult medicine, including SGLT2 inhibitors and angiotensin receptor-neprilysin inhibitors. And we use these usually for ejection fractions around 40% or less. This is a significant change in the therapy that we give compared to where we were in 1992. We're much, much more aggressive, and we're much more focused on prophylaxis where we start medications before we see cardiomyopathy. If you go to the next slide, this is a look at left ventricular ejection fraction progression from our natural history study. It started a little later in age because these patients were all getting cardiac MRIs instead of echos. But what you can see is that there's still that unremitting progression of disease. These medications work, but they don't work that well and they're not preventing progression. This line right here is an LVF of 55%, and that's what we consider normal for an ejection fraction. So once the line goes below that, we're considering that abnormal function. Next slide, please. So what does this mean if we look at it over time? Well, this is from a similar study, one of our studies where we looked at ventricular function and looked at outcomes and this looked at the LVEF change at 1 year and 2 years. And as you can see, we saw about a 3% change at 1 year and about a 5% change at 2 years. So it's really a 2.5% to 3% change per year. And when you look at other studies in the literature, they all come out around the same place, whether you're looking at a clinical trial or a natural history study, it's somewhere in that 2% to 3% change per year for that progression of disease that we end up seeing in our patients. Next slide, please. So what does this dysfunction mean? And that's a big part of this for us. What do we do with that information? So this is, again, an older study. This is an echo study done in 2002, where they looked at what's called a survival plot. So this is time down here, and then this is the percent that survived. And as you can see from this study, those who had left ventricular dysfunction, low LVEF at the time of entering the study had a worse outcome or a worse survival than those who didn't. So it associates with mortality. If you go to the next slide, this is our more recent paper looking at cardiac MRI, which is a more sensitive and accurate way to evaluate cardiac function. And in this study, we showed that for every 3% decrease. And again, that's the expected decrease over 1-year period. So for every 3% decrease, we see a significant increase in the risk of death. This is also true for the diastolic and systolic volumes and for measures of function called strain. But the LVF was really one of the more sort of notable and remarkable in that study. Next slide, please. We've also shown that the time that you develop heart dysfunction matters. And same with the time that you develop that late gadolinium enhancement or fibro-fatty infiltration that Dr. Villa was talking about. So the earlier you get LV dysfunction or the earlier you get that delayed enhancement, the more likely you are to have a bad outcome or to have a mortality event. And so if we can delay that onset of left ventricular dysfunction, then we know that we can keep that patient or these patients alive longer. Next slide, please. The other really big thing that we and others have shown is that the rate of progression of heart dysfunction matters. So it's not just where you're starting, but it's also how quickly you're progressing. And this is a very intuitive thing. So the more rapidly you progress, the more likely you are to have decreased survival. But it's important because this suggests that if we can affect this progression, if we can slow down or stop the progression of left ventricular dysfunction, that, that could have a direct impact on survival and keep patients alive for longer. Next slide, please. So a summary of that, the start of cardiomyopathy and heart dysfunction varies in each patient with DMD. As Dr. Villa pointed out, a lot of times, it really seems like once you get late gadolinium enhancement, that's when that starts. However, once it begins, there's really an unremitting progression of dysfunction. It just keeps going down year after year. Current medications help, but they're not enough. They're not everything that we need. We need better meds. Severe dysfunction and dilation is for boating. Earlier heart dysfunction is more likely to lead to early death. And if we can slow down or stop the progression of heart dysfunction, we can delay mortality from heart disease. Next slide. So when I go to look at my clinical perspective of this medication and this therapy, I think this slide and the next slide really encapsulate everything that I've seen and sort of bring it all together for me. And this is that HOPE-2 data that they've shown before. And you can see here that the LVF is stable in the patients on deramiocel. And in the placebo, the LVF goes down. And importantly, the placebo matched perfectly with the matched patients from our natural history study, and they matched 2 different cohorts. And that suggests to me that the placebo patients really were behaving as we would have expected. That they were declining at the same rates that we see in natural history studies. But these deramiocel patients remained stable. And if you go to the next slide, this is really what I find striking. So these patients over a 3-year period remained stable. They had no progression of their left ventricular dysfunction. And when you compare that again to our natural history study, that's just not what we see in patients. We see that, that progression of disease that we spoke about. And right now, I have no medical therapies that I can give that I feel will effectively stop the progression of disease, that I feel will effectively stabilize left ventricular ejection fraction. So I think this is really what's the most striking about deramiocel to me. Next slide, please. So in summary, heart dysfunction associates with mortality. Earlier age of onset of heart dysfunction associates with mortality. So if we can delay that onset of left ventricular dysfunction, we think or we know that these boys should live longer. And the rate of progression associates with mortality, so we can slow down or stop that progression that should lead directly to an improved mortality. Despite increasingly the aggressive medications, the outcomes in DMD cardiomyopathy have really only minimally improved, and we know that patients are still dying from cardiomyopathy and stabilization of progressive heart dysfunction would significantly improve outcomes. Thank you.

Thank you, Jon. As usual, that was great. As I said earlier, but I can't say enough, I am a tremendous fan of the work that you've done. I just want to finalize before we open the floor for questions, and I promise I won't take long. What are the takeaways from this meeting? The takeaways from this meeting is that we believe that we can combat this complete response letter with data from the HOPE-3 clinical study. We stand behind the data that was presented. It's strong. It's good. It shows statistical and clinical significance, but we have in our back pocket, the HOPE-3 data. We've asked the Food and Drug Administration to switch the primary efficacy endpoint, the left ventricular ejection fraction. We have already submitted a protocol amendment to that and this is actually something that there is precedent for in regulatory history, and we look forward to working with the FDA to get this therapy to you as quickly as possible. And thank you for your support, thanks to PPMD for the years of support. Thank you for the families and for the people that believe in us and also who open their bodies to try out new medications to try and stem the progression of Duchenne. Eric?

Thanks, Linda, and thanks, everyone, for a really informative presentation. So we're obviously running over time, but I do want to make sure that we get to some of these key questions that we saw come in from the community. So some of this was touched on during the webinar. And I know folks will be able to see the recording of this later within a week's time up on the website. But I think, ultimately, what we're seeing come through in some of the questions, our family is just trying to understand where it is deramiocel sit with the FDA and kind of time lines to an approval decision. So I think that the very first question we're kind of going to start with is just what is Capricor's next step kind of in the near term?

So our next step in the near term is to work with the FDA. We've already submitted the protocol amendment to switch the primary of HOPE-3. We've drafted an e-mail, which we sent into the agency combating what they stated was inadequate data from the CRL. We are looking forward to a Type A meeting, which should happen hopefully very soon imminently. We haven't gotten a date, but we're waiting on it, where we'll be able to go in and talk with them to make sure we're all on the right path to approval. We believe that there is definitely precedence for this type of thing.

And then on the HOPE-3 trial data, when can we expect a potential readout?

That's going to be dependent on response from the agency. So because we want to preserve the blind and we want to preserve the independent aspect of the data and make sure the statistical analysis plan is exactly what the agency will take as reason to approve the drug, we will maintain the blind until we hear from the agency.

Okay. And then this probably shifts a bit depending on kind of what you're able to do with the HOPE-3 trial. But then can you just talk a little bit of potential time line and then process from that to getting to kind of an approval decision?

Yes. So as soon as we have guidance from the agency, we can submit the statistical analysis plan, finally called the SAP. And then it's dependent upon the imaging cores to make sure that the images are read and processed appropriately. We expect that to be done and analyzed. And so we're hoping that it will be relatively quick. It will be all dependent on FDA on what they want in terms of the documentation for how long it will take from then to the next PDUFA and to approval.

Great. Thanks, Linda. And then, Lauren, I'm going to kind of direct this one at you. We've had a few questions come in from the community of, is there anything that we can do from kind of a community voice, patient advocacy standpoint?

Yes. No, I think that's a really good question. And Tim and I got into in the beginning that right now during the CRL process, that it's very much more data focused than community input, unfortunately, at this moment. But if the time comes, when it's time for us to share stories or do things like that with the FDA, we will be sure to let you guys know. I feel like we try really hard to make sure that those opportunities are presented. But I think right now, unfortunately, there really isn't much for us as patient advocates to do. And it sounds like our friends at Capricor are doing all the things and sending all the data that they need to be doing. So I don't know, Tim, if you had anything to add on to that either.

No, I think that's very reasonable. Obviously, if there's a particular matter where patient advice -- family advice is needed, I'm sure the company or FDA would request that. At this point, that's hard to predict. But I'm presuming we'll hear more after that Type A meeting, which is critical.

So I'm going to jump in here really quick. I'm not sure patient letters to FDA will do that much. But where patient letters will really make a difference to your Congressmen, to your senators. I've never had the opportunity to really be up on Capitol Hill. And I guess most other companies have government relations. But being a scientist, I just sort of thought the process would be naturally driven by data. But the elected officials definitely need to hear from you, please let them know. Especially if you have a specific story, they are really interested in hearing the stories they are really interested in seeing how the new FDA is functioning. And it's going to be important that our voices are heard. FDA makes the decisions based on data, but patients and their lives have to come into that decision process.

Thanks, Linda. And then I think just in terms of maybe continued kind of clarity. So Dr. Binks touched on some of the safety data there. Linda, both you and Jon kind of touched on some of the data from HOPE-2. So some of the questions were just kind of specifics around where was maybe the FDA's concern? Is it more of the small numbers? Is it a lack of placebo in terms of trying to understand kind of, again, where we're at today, where we're looking with them to potentially the HOPE-3 trial results?

I'm going to geek out for just 1 minute here. The issue with HOPE-2 predates the submission of the BLA. In fact, we've been debating the HOPE-2 data with the FDA for a good 5 years now. The issue is that the model or the original statistical design was based on the assumption of something called normality. And if you can sort of see like a hill in your head, that means that half of the people will be on one side of the hill, half of the people will be on the other side of the hill in terms of their averages. And so you can do your statistics based on the fact that the data is sort of normally distributed, is what I call. That happens in larger sample size. That's why big pharma do big trials because the more people you have, the more they fall within a normal distribution. By stopping HOPE-2 early, which we had to do for many reasons, then when you look at the actual data, it violated the assumption of normality. Now once you violate the assumption of normality, you then have to use different kinds of statistical measures, which are called nonparametric measures, which means they look at the likelihood that your data is due to chance based on not taking into the fact that you have a normally distributed population. If you do this test correctly, you end up in a nonparametric way, looking at HOPE-2 was statistically significant, and I showed you that data, and that's why The Lancet took it. Because that hits on the canonical way the statistical analyses are done. If you violate normality, you have to go to nonparametric measures. What the FDA is contending and I really do think that maybe they just need to look at the data a little more carefully is that they say that, no, no, no, you missed your original primary efficacy endpoint, which relied on this assumption of normality and, therefore, nothing that happened below that statistically is relevant. And I'll leave that with one point, even if you go with the original model, which you have already violated from PREMISE-1. The data was very close. The p-value was less than 0.1. So no matter how you look at this, this definitely looks like there's a reasonable, in fact, robust treatment effect.

Okay. Thanks for that, Linda. That's complex, obviously, but we do appreciate you taking the time to kind of...

I do love my stat.

And then so when the HOPE-3 readout does occur? Would you be able to come back and present that data to the community?

Oh, yes, we will be very excited to do that.

And then just some general, I think, kind of questions that we have any time talking about potential therapies. So just around deramiocel itself, there were a few questions of just is this something of more of a potentially replacing other cardiac therapies or more beneficial be used in combination? And then there was, again, a question kind of around the age limit from the trials versus kind of maybe when we could think about like earlier intervention with cardiac meds?

Yes. So our goal is that deramiocel would be in addition to cardiac meds. Dr. Soslow, Dr. Villa, all of their colleagues in the world of cardiac treatment for Duchenne will say that they've already got their guys on standard of care meds and they are addressing them all the time. So this will be in addition to cardiac medication. Now is it possible over time if you get in early enough that there could be a reduction in the need for some? Perhaps we will be able to watch that sort of in part of post-marketing observational studies, and we're excited for that opportunity. In terms of the age limits, the way that we are trying to build the label is the presence of scar, which already is suggesting that not good things are going on in the hearts of those guys could happen when they're pretty young or -- and cardiac dysfunction is measured by MRI or echo or whatever measurement of choice where the ejection fraction begins to drop. Although let me just say sort of in addendum to that, some of our best data comes in those guys that still have really good preservation of cardiac function. So we're looking to stabilize them. And hopefully, they won't dip below and need treatment for cardiac dysfunction, but for stabilization of their hearts.

Great. Thanks, Linda. Pat, I don't know if you have any kind of other questions you're seeing come in. I mean those are some of the big -- I wanted to get some of those big thematic ones since we did run over quite a bit, but I appreciate everyone staying on for that. I just want to make sure I didn't miss any kind of key points from the community standpoint.

No, thank you for that. I'll just add one last question. I think just because we know -- you know that heart failure is part and parcel of Duchenne. And we've asked the question the muscle too more times than I can count over the last 31 years. So would you -- Dr. Binks, Dr. Villa, Dr. Soslow, if you had a child with Duchenne, is this preventative? So at age X when we typically see that there is scar present and then you know what's going to happen following, is it an idea to -- or would you have to do a study to promote a very early intervention? I'll just arbitrarily say, 8 years old as you typically see significant stain at that time.

Go ahead, Jon.

Sorry, I think that's a great question. And I think the way I look at this is that the strongest data really seems to be preservation of left ventricular ejection fraction. And so from my standpoint, I would say this is probably a preventative therapy. Now I do agree with what Linda said earlier though that the presence of LGE, I think, would be an important thing for me in the beginning, just so that I know that I'm giving someone a therapy when I know that their cardiomyopathy has started. Now whether this moves down the road to being something that is preventative for everybody, I think that would probably require other trials or at least a lot more clinical experience. But in the beginning, I would look at this as a preventative for patients with delayed enhancement.

Thank you so much. I think we've gone over now. So this has been a wonderful webinar. Thank you to all of the team from Capricor. And thank you to Jon and Chet, who are always present and thankful for you protecting our heart, all these little children and some women that we still care for. And so maybe one day soon, Linda, you'll consider a trial in carrier females that are at risk. So I can't thank you enough. Thank you, Tim. Thank you, Lauren, Pat. Thank you, Eric. And thank you for the background, Emily. Otherwise, we wouldn't be online. So thank you all for joining us. I think this is a very wonderful opportunity to protect the heart and keep in mind that the heart of the muscle, too. So thanks for joining us. We'll see you again soon with HOPE-3 data.

Thank you so much. We really appreciate everything PPM does for us and for the world. Be well. Thank you all.

Good bye.