By Capricor Therapeutics, who are providing a community update on their phase III trial, HOPE-3, which was evaluating their investigational product, Deramiocel, for treatment of Duchenne muscular dystrophy. I'm Eric Camino, PPMD's Vice President of Research and Clinical Innovation. I'm also joined on the call today by one of our regulatory consultants, Dave Zook, who's a Chair at Faegre Drinker Consulting. Also on the line, we have Dr. Craig McDonald from UC Davis and Dr. Jonathan Soslow from Vanderbilt Children's Hospital. And then from the Capricor team, we are joined by their CEO, Linda Marbán, their Chief Medical Officer, Michael Binks, and their Chief Development Officer, Mark Awadalla. As we go through the presentation, if you have any questions, we will have an open Q&A at the end. So there is a chat function at the bottom of your screen. You can submit questions to that.
We also had some questions submitted ahead of the webinar. We'll try to get to as many of those as we can during that portion. We are also recording this webinar, so if you have to step away or if there's someone who this would be relevant to, it will be posted to PPMD's websites. You can always come back and take another look or share it with someone who this might be relevant to. But I think with that, we can get started. So I'm going to hand it over to Linda to start the presentation.
Thank you. Thank you so much, Eric. You know, this is, I don't know, I think this might be the sixth time we've done a webinar with PPMD. We started our clinical journey a full, I don't know, 10 years ago with the HOPE-Duchenne study, which I'll talk about in a few minutes. I just want to give a minute shout-out to Pat Furlong, who has been a mentor and a guide to Capricor from before 2016, where we met in a small room at Cedars-Sinai Medical Center and reviewed MDX mouse data. And she shared the story of her boys and her hope of using cell therapy to make them better. And I'm really proud, Pat, this is dedicated to you and your efforts and to all those boys and young men that have come before and after. Next slide, please. We're a public company.
I won't read this forward-looking statement, but our filings are up to date with the SEC, and if you have any questions, please feel free to reach out to our legal team or to any of us. Next question. Next slide. Eric just went through the attendees, so we can skip to the next slide. Thank you, so today I'm going to provide data that has previously been presented primarily as our top-line data of the HOPE-3 clinical study. First, I'm going to go through Deramiocel and talk a little bit about how it works, why it works, and the previous clinical experience. We're going to talk a little bit about the overview of HOPE-3, who the patients were and how they came in.
Of course, the most important concern of every person with Duchenne, the safety of the trial, and then who the patients were in the trial. Finally, we'll get to the part that many of you are so interested in and curious about, which is the efficacy, which will be co-presented by Dr. McDonald, who will present the skeletal muscle and performance of the upper limb data. Dr. Jon Soslow will follow up with the cardiac data. Finally, I will come and talk to you about our next steps with the regulatory filings and bring you up to date. This is a very proud day for us, and you are the community that I most want to talk to. I'm excited to share with you. With that, let's start the program. Next slide, please.
So I just confirmed about five minutes ago, and I stated in my intro remarks that our clinical journey with Duchenne muscular dystrophy started literally 10 years ago in January of 2016 with the HOPE-Duchenne clinical study. It was a study done primarily at Cincinnati Children's Hospital, where we looked at potentially reducing the amount of scar in the heart, as well as looking for cardiac functional improvements in a patient population that had a significant amount of cardiac scar already in their heart. This was our first foray into Duchenne muscular dystrophy treatment, especially the cardiomyopathy. 13 patients were in the treated group, and 12 were followed as natural history. And what that study showed was that we had a reduction in scarring in the heart just with 75 million cells given once over the course of 12 months.
And we also saw improvements in skeletal muscle function primarily in the first quarter. Why am I spending time on HOPE-Duchenne, which was 10 years ago? Because the data that I'm going to share with you today shows the connection of all of the clinical development that Deramiocel has undergone in those 10 years with consistent clinical data across the time frame. We saw a reduction in scar. Therefore, now in HOPE-3, we saw a reduction in scar. We went ahead with HOPE-Duchenne, the open label extension, to show that multiple dosing was safe. We had never considered multiple dosing before. Those patients allowed us to test that, and that was very safe. So we were able to then go forward with HOPE-2. As you know, HOPE-2 was published in The Lancet.
We showed significant improvements in skeletal muscle function, as well as preservation and cardiac function across multiple endpoints. You guys have all seen this data over time, or it's available for your perusal by looking at The Lancet article or any of our slide decks. Again, let's just go on the journey, so reduction in scar and trends in function, improvement in cardiac function, skeletal muscle function in HOPE-Duchenne, multiple dosing, and the open label extension of HOPE-Duchenne. Significant improvements once we've gone to multiple dosing in HOPE-2 four times a year, 150 million cells intravenous. Now we're seeing improvements in skeletal muscle function, extension of functional ability that is literally double what would be expected, and then preservation of cardiac structure and function as well, and generally, it was well tolerated.
The open label extension of HOPE-2 has probably been the most important study that we have ever been able to be part of in Duchenne. We've treated these 13 young men for over four years, some of them going into their fifth year. We've shown the data at your conference, as well as at multiple other conferences, where we show sustained reduction in skeletal muscle dysfunction. Sustained reduction in cardiac muscle dysfunction is measured by ejection fraction and a very favorable long-term safety profile. Talk to the guys in open label extension, and they will tell you that they show up literally on the day that their infusion is allowed to be scheduled next because they have already started to feel a decline in their function, and they want to come back and get that boost again. So very safe and very effective.
Now, finally, I'm not going to waste any more time. I'm going to talk to you about the HOPE-3 clinical study. As I said, many of these data slides have been shown before, but I wanted to make them very specific for this community. And with that, we'll go to the next slide. So I'll just take one more second to tell you how does Deramiocel work. It is a multimodal mechanism of action. Our potency assay, which is designed to measure lot-to-lot consistency, batch-to-batch ability to induce the same biology over and over again. So it'd be the same as you expect the same dose of ibuprofen and Motrin. We want to give you the same dose of bioactivity in Deramiocel. The active ingredient is called the CDC, the cardiosphere-derived c ell.
The three studies that are highlighted here are ones that are also reflected in our mechanism of action, which is anti-fibrotic, immunomodulatory, and anti-inflammatory. Today, we're primarily talking about clinical data, but if you're interested in digging more deeply into our mechanism of action on the Capricor website, our Chief Operating and Scientific Officer, Dr. Kristi Elliott, has done a really nice YouTube video discussing how the mechanism of action was determined and how it's measured and how it impacts clinical function and performance. And that's available for your perusal at any time, as I said, on our website. Next slide, please. The HOPE-3 pivotal trial design is a randomized, double-blind, placebo-controlled trial. We randomized 106 patients. 105 patients were part of the ITT. The one patient withdrew consent prior to his first infusion.
It was a one-to-one randomization, which, as you know, means half the patients got Deramiocel and half the patients got placebo, and they did not know what they were getting. We measured baseline function as far as the performance of the upper limb, which is the primary efficacy endpoint. We did a screening measurement using cardiac MRI of our secondary endpoints so we could measure left ventricular ejection fraction. And then, in addition to that, what we did is measure certain other types of ways of sort of belt and suspend where you're being careful to understand that the data is very consistent. So it's not just the performance of the upper limb as the primary. A Type I error-controlled secondary is the mid-level PUL, the Global Statistical Test, which encompasses cardiac, skeletal, and a patient-reported outcome, LGE, which is a measurement of cardiac scar.
Taken together, what we have seen is that when you look for statistical significance or how likely the data that you are seeing is due to chance, what you're seeing in HOPE-3 is unequivocal clinical benefit for those patients that receive Deramiocel compared to placebo. Next slide, please. So I'm going to ask Mark Awadalla, our Chief Development Officer, to run through the demographics with you briefly and talk a little bit about the patients who were in the HOPE-3 clinical study. Mark.
Thank you, Linda.
Can you hear us?
Yeah.
I think we can hear you.
Thank you, Linda. As Linda said, we randomized 106 patients into the HOPE-3 trial. 105 patients of the trial were dosed with investigational product. The study was well-balanced across factors such as age, PUL entry item score, and the baseline PUL score. We had 83 patients that were part of the key secondary endpoints that had evaluable MRIs, and it was also well-balanced with starting LVEF. Out of those 83 patients, 65 of those patients had documented cardiomyopathy. The majority of the patients that were enrolled in the trial were non-ambulatory, and the majority of patients are currently on study.
Yeah. So thank you, Mark. Now, I would like to ask Dr. Michael Binks, our Chief Medical Officer, to discuss perhaps the most important aspect of Deramiocel for long-term utilization, and that is a safety profile. Dr. Binks?
Thanks, Linda. Yeah, so this is the largest study that's been conducted with Deramiocel. So it's a good opportunity to see what the safety profile is likely to look like in broader use, and of course, it's in a blinded setting, so we can see the adverse event rates with placebo. It's clear that with Deramiocel, there are more adverse events that the investigator thought were due to the infusion. These were mostly mild in grade or moderate, and almost all occurred within hours of the infusion and resolved spontaneously or with the use of antihistamines, and there was complete resolution at 24 hours in by far the majority of cases. Now, the symptoms were things like headache, fever, an increased heart rate in some, some nausea, a little bit of vomiting in some. That's the sort of picture of the symptoms that we saw.
There was only one serious adverse event relative to five in the placebo arm, and this was of a severe infusion reaction, but again, resolved within 24 hours with no sequelae, no long-term consequence, so overall, we're pleased to see that there was no new safety observation, and of course, that's in the context of the previous HOPE-2 study data, but importantly, the HOPE-2 open label extension data following patients out for four years of treatment, and in that time, we saw no new safety finding, so overall, we believe this is really a safe and well-tolerated drug.
Thank you.
Thanks, Linda.
Thank you. So with that, I'm going to take one minute and introduce Dr. Craig McDonald to present the skeletal muscle data. None of you need a real introduction to Dr. McDonald. He's probably one of the most visible proponents of developing therapeutics for Duchenne muscular dystrophy and has therefore been on many of these webinars, as well as in front of the FDA multiple times to try and make life better and longer for those with Duchenne. Dr. McDonald?
Great. Thank you very much, Linda. It's really my pleasure to participate here and present the skeletal muscle data. I want to just really focus on the target population here that was included in the HOPE-3 trial. Much of this was really based on our key learnings from the HOPE-2 trial. If you look in that upper diagram, this gives you the performance of upper limb entry score. Historically, a very similar evaluation called the Brooke score has been done for decades in Duchenne patients. This was really adapted from the Brooke score. Patients that have actually complete really overhead reach without any type of compensation are considered a PUL entry score of six. That's shown in the upper right. Those that can get their hands above their scalp with compensation would be a PUL entry score of five.
Those that get their hand up to the shoulder height level and above a PUL entry score of four. Those that can get a weighted object to the mouth. What we do essentially in the Brooke score, it was an eight-ounce glass of water, which is about 240 g of weight. The clinical evaluators here actually put a weight, a cooking weight in the cup, and we get the patient to get the cup up to the mouth. Then a PUL entry score of two is an unweighted hand up to the mouth level. So it was really these PUL entry scores of two to six that comprised the target population for the HOPE-3 trial. From our previous learnings, we know that most of the progression in the total PUL score typically occurs in those patients that have PUL entry scores of two to five.
But those that have some initial decrement in the upper limb, even with a PUL entry score of six, also were included. We also included some patients who were in the late ambulatory phase of the disease because what we've learned in natural history study, and these are two graphs that have actually been developed from our published natural history study with the cTAP group. This was based on natural history data provided by Cure Duchenne and had been derived from patients in the Prosensa Duchenne natural history study. But the data on the left actually shows that patients that have a 10-meter walk/run test time of greater than 10 seconds, actually, if you follow those patients over time, this is a Kaplan-Meier survival curve, essentially 100% of those patients will lose ambulation over the next two-year period of time.
We've actually defined that 10-second, 10-meter time as approaching loss of ambulation. What we learned, importantly, in the data shown on the right, is that if you take patients in that late ambulatory phase defined as 10-meter walk/run time greater than 10 seconds, essentially 100% of them will actually lose upper limb function over the next two years. 100% will actually transition from a PUL entry score of six to a PUL entry score of five or lower. That natural history data really informed the inclusion criteria for this trial. We included actually ambulatory patients that were destined to lose upper limb function that had a 10-meter walk/run time of 10 seconds or greater.
And these patients, as many of you know, with Duchenne patients, these are patients that are historically never included in ambulatory clinical trials because they're felt to be at too great a risk to lose ambulation. And they're really sort of in no-man's land as far as being able to participate in a clinical trial. So we purposely included those late ambulatory patients as well as the non-ambulatory patients with PUL entry scores of two to six in this trial. Next slide. So this is, again, the data on the primary endpoint, the total PUL score. The most up-to-date version of the PUL was utilized, the version 2.0. And I think what is important that the FDA really hones in on is what's the primary pre-specified clinical endpoint in a clinical trial and does the trial meet that clinical endpoint with statistical significance.
And this actually shows data in terms of the mean percent change from baseline in the Deramiocel treated patients shown in the blue versus the placebo patients shown in the gray. And what you can see there is there was much greater decline in the total PUL score in the placebo-treated patients versus the patients receiving cell therapy and essentially a 54% slowing of progression of upper limb deterioration. This was highly statistically significant with a p-value of 0.029. And so, again, this was pre-specified. The statistical analysis plan was sent to the FDA several months prior to the unblinding of the data. I think we have perhaps an either next slide or next window on this slide if you advance here. If we could, yeah. So with that, I'm going to turn the discussion over to the key secondary endpoint, which was cardiac function and measures of structure.
Dr. Jon Soslow from Vanderbilt is going to go over the objective measure of cardiac MRI. Jon?
Thanks, Craig. So I'm going to talk about cardiac MRI as an outcome measure. And as many of you probably know already, cardiac MRIs really are a best outcome measure in patients with Duchenne muscular dystrophy when we're looking at the effect on cardiomyopathy. And this is because there's no concerns with acoustic windows. It's the gold standard for measurement of ventricular ejection fraction and volumes in adults and children. And it has significantly improved reproducibility compared with echocardiography, which means that we get a much tighter evaluation of function. And that means that we can enroll less patients and really detect a smaller change using cardiac MRI. If you go to the next slide, we and others have shown that left ventricular ejection fraction, left ventricular end-diastolic volume, and then systolic volume all associate strongly with mortality.
So at the top here, LVEF for every 3% decrease, there's a significant increase in the association with mortality. So the idea of preserving or stopping or slowing that left ventricular ejection fraction progression is really the most important thing that we can do in these patients when we're talking about treating their cardiomyopathy. If you go to the next slide, this is the data from the secondary endpoint, LVEF in all patients. And this is on the left, the mean change from baseline in left ventricular ejection fraction at month 12. And you can see that there's a significant difference between those on Deramiocel in blue and those on placebo in gray. So that the Deramiocel patients had a 91% slowing of their progression of disease. And I think this is really well illustrated in the figure on the right, which is the raw mean change from baseline.
As you can see, between baseline and month 12, these patients had almost a complete arrest of their cardiomyopathy progression. They really stabilized. There was a significant difference between the patients on Deramiocel and the placebo patients of almost 2.5 percentage points, which is about what we see in terms of progression of disease, which is 2%-3% per year in almost every study that has been published. If you go to the next slide, so I'm going to talk a little bit about the pathogenesis of disease, so the underlying cause of what causes cardiomyopathy. On the left, you see an old autopsy specimen of a patient with Duchenne muscular dystrophy. Those arrowheads are pointing to white areas, which are scar and fibrofatty infiltration of the heart.
And what happens in DMD, and so this circle right here is the left ventricle. And what happens is that the myocytes, so the muscle cells in the heart, undergo chronic inflammation and then resolution of that inflammation and healing. And then eventually, that inflammation leads to cell death. And the cells die and are replaced by scar and by fat. And so we see that fibrofatty infiltration. And that happens in the left ventricle in what we call the free wall, and then it progresses to the rest of the heart. And we can image that using cardiac MRI. And so that's what Linda was talking about earlier, looking at late gadolinium enhancement. And so this image on the right is an example of a late gadolinium enhancement image where you see that bright area pointed out with the arrow. And that bright area is that fibrofatty infiltration.
So it's essentially an illustration of the replacement of the normal cells of the heart with scar and fat. And if you go to the next slide, there's been some really nice work done by Aashoo Tandon out of Cincinnati that showed that when they looked at all the cardiac MRIs in their DMD patients, that the patients without LGE, so without that late gadolinium enhancement or the fibrofatty infiltration, are shown here in green, they had a very stable left ventricular ejection fraction. They really didn't have progression of their cardiomyopathy or of their disease. Once these patients had identifiable late gadolinium enhancement, so once we were able to see scar in their hearts, that's when their hearts began to progress. And they started to see progression of left ventricular dysfunction. So that really is the onset of cardiomyopathy.
So that's the first point, is that when you have LGE or cardiomyopathy in general, that's when you start to see progression of left ventricular dysfunction. The second point is that we really think that this fibrofatty infiltration is the primary cause or at least the best way we can image the cause of progression of cardiomyopathy. So if we could stop the progression of scar, that would have a huge impact in the disease. So if you go to the next slide, this is a secondary analysis of LVEF in just the patients with a diagnosis of cardiomyopathy. So these patients either had known late gadolinium enhancement, already had LV dysfunction, or had a diagnosis of cardiomyopathy at their primary center. And these are the patients that we would expect to have a more rapid progression of cardiomyopathy because they already have scar, like we talked about.
In this subgroup analysis, Deramiocel performed even better. That means that the patients with placebo had significant progression of disease. Again, the Deramiocel patients had stabilization such that there was over a 3 percentage point difference between the two. I'd like to, next slide, I'd like to turn this back over to Dr. Marbán.
Thank you, Jon, and thank you, Craig. So I'm going to talk about this graph, and then I'm going to make a few comments in general about the data. So what this is called is a forest plot. And you guys probably have seen me present one similar to this from the HOPE-2 study before, but just to remind you that it basically shows the propensity of multiple endpoints to be either due to a treatment effect of the drug that you're giving or whether or not it's driving towards placebo or basically no clinical efficacy. And what we can see here in the Performance of the Upper Limb 2.0, our primary efficacy endpoint, it's trending, in fact, statistically significant towards Deramiocel being effective in treating the skeletal muscle myopathy. We saw the key secondary endpoint.
A key secondary endpoint is very important nomenclature because it allows for labeling opportunities. We saw improvement and statistical significance in cardiac function in the patients that were treated with Deramiocel compared to placebo. Digging down a little deeper, we saw that we had even more statistical significance in the mid-level dimension of the PUL 2.0. Dr. McDonald did a great job of describing that, but I'll just remind you that's arm function, so it might be correlated with the ability to feed yourself or take a drink of water or, as Pat used to say, to hug your mother. The total global statistical test was also statistically significant in terms of PUL function and survival metrics, so skeletal muscle function, cardiac improvement of the left ventricular ejection fraction, and finally, a patient reported outcome measure called the PGI.
And then finally, as Jon just talked about, late gadolinium enhancement, which is the amount of scar in the heart, and we see that that was statistically significant too. All of these are what statisticians call Type I error controlled. That means that you put very, very tight regulation around them mathematically as to whether what you're seeing can be due to chance or whether, in fact, it is actually due to treatment by your therapeutic. So taken together, we are going to present this data to the FDA. We believe that this should answer all the questions raised in their Complete Response Letter on the BLA that was submitted last December. And we're hoping to move rapidly towards an approval for Deramiocel in DMD, not only now cardiomyopathy, but also skeletal muscle dysfunction. Next slide, please. I'd like to close with several very important points.
First of all, Deramiocel is. I would call it a colloquial good player in a sandbox or can be used in combination with existing therapeutics. Theoretically and practically, because of the mechanism of action of immunomodulation and anti-fibrosis, Deramiocel may over time be shown to even improve the impact of gene therapies and exon-skipping therapeutics because you want to keep the inflammation down as you allow new muscle to be created. And Deramiocel drives the repair processes in and of itself. So whether you are a patient that receives a gene therapy, an exon-skipper, or whether you're on stable med regimens like corticosteroids or standard cardiac meds, which were required in our trial, corticosteroids, and then most of our patients, in fact, almost all of them were on cardiac medications, Deramiocel can be additive.
It's very important to understand that it's safe, effective, and can be used along with other therapies, as I just said. Next slide, please. What are the takeaways from today? The phase III HOPE-3 study met its primary efficacy endpoint of the Performance of the Upper Limb 2.0 and the key secondary endpoints of left ventricular ejection fraction or how the heart meets the needs of the body, both achieving statistical significance. To remind you, for those of you that are not statisticians, statistical significance is really benchmarked against the idea of how likely the data that you're seeing is due to chance or luck versus likely a treatment effect. Sort of the gold standard cutoff is 5%.
If you have something less than 5%, which we have 3% and 4% here, then it's very likely that what you're seeing is almost exclusively due to a treatment effect and not some type of chance, and that's why the FDA likes adequate, well-controlled studies so that they can make these determinations between chance and efficacy. Statistical significance, they just described it, was achieved in all Type I error controlled secondary endpoints. Type I error is a statistical term, and that means that you are assuming that something, the error would be that you assume that it works when it really doesn't. These are controlling for that. Deramiocel is a potential first-in-class therapy designed to treat DMD skeletal and cardiomyopathy. I do not believe that there is anything else approved. There is no medically directed guideline therapy specifically for the cardiomyopathy associated with Duchenne.
Therefore, Deramiocel can be the first in class for that. A very safe and tolerability profile consistent with prior clinical experience. Most importantly, the HOPE-2 open-label extension guys have received over 16 doses each at this point. They are pleased to report both in documents and also in anecdotes that they are doing very well on Deramiocel from a safety and tolerability as well as efficacy perspective. We are planning, oops, I guess the slide just retired. Planning to submit our response to the Complete Response Letter incorporating the HOPE-3 data following alignment with the FDA in our Type A meeting. I can answer questions on that if anybody has them. I'm sure you do.
Next slide, I just want to thank everybody, the patients that have participated over these 10 years, the Parent Project Muscular Dystrophy who have been our allies and friends for more than 10 years with, as I mentioned, Pat, sort of coming to an initial meeting to discuss the potential therapy over 11 years ago. I can't say enough thanks to Dr. McDonald, who is probably one of the most caring physicians and thoughtful leaders I've had the pleasure of working with in my long career in cardiac physiology. He always has something important to share and has really got the patients in mind with everything that he does. Dr. Jonathan Soslow, Jon and I met at a PPMD meeting.
I liked his attitude, and I liked the fact that he really was able to coalesce the ideas of using MRI to really be able to drill down into what is causing the pathogenesis of cardiomyopathy in Duchenne. I approached Jon, and Jon, I can't say thank you enough for working with us, and Chet Villa, who's not on our call today, but I think most of you know Dr. Villa from Cincinnati Children's. He is my muse and my mentor in the fibrofatty replacement and some of the other types of pathology associated with Duchenne cardiomyopathy, and I look forward to continuing to work with Dr. McDonald, Soslow, Villa, and all of the HOPE-3 investigators as we get this product across the line to commercialization. I think that's the end for us. Eric, I don't know if you want to make some comments and take some questions.
Well, thank you all for the presentation. I think we're just going to hop in. I've seen a bunch of questions come in. We had a handful that were submitted before. I think what we'll probably start with is some of just the regulatory kind of process questions, and then we can dive into some of the HOPE-3 data. And I'll probably, when we get to those, go back to specific slides that were relevant. But we did have a handful of questions kind of come in around timing and things like that. So I think just first question here would be, how soon do you anticipate having a formal submission for this HOPE-3 data to the FDA for filing and review?
Yeah. So our goal is to send in a response to the CRL with this top-line data and some other data before the end of this calendar year. And then we should have some feedback from FDA by the end of January to the path forward. We're sincerely hoping that with the strength of this data, they will realize that the data that we presented in our BLA was, in fact, reflective of the efficacy of Deramiocel. And we hopefully will be able to move relatively quickly to approval.
Yeah. Great. Thank you. And then the other piece with this that I think is always a little bit tough is we're learning more as we continue to have more approvals and what this process looks like as a community, but it's always a little bit challenging. And so given that there was the previous BLA and the CRL, do you maintain your kind of priority review status as you go through this process? Does any of that change at this time?
Yeah, so right now, the FDA has told us in response to our Type A meeting, which happened in August, that they would consider this a Class 2 resubmission, which allows them six months to review the file. We are hopeful because there are so many patients that are waiting in the wings to get Deramiocel that perhaps couldn't qualify into a clinical trial, but feel like the time is ticking in terms of their cardiac function as well as their skeletal muscle function, and that hopefully will be able to go faster, but right now we do not have a priority review status.
Okay. And then you also said that you have some of those responses to the CRL. Is there any other kind of pending responses that need to be addressed aside from this new phase III data?
No. So there were also CMC Chemistry, M anufacturing, and Controls issues raised in the CRL. But luckily, we have already addressed all of those and received confirmation from the FDA that they have received those answers. So we don't expect to have CMC issues. And I can remind the community that we will be proud to announce last year that we passed a pre-licensing inspection of our commercial manufacturing plant here in San Diego. And so we are ready to go commercially as soon as we can get this across the line.
Thank you. And then that was all obviously very FDA specific. We did have a question. We have a lot of international families as well and who are on. And so I think a question of, will you be making submissions to globally? Kind of what's the plan for outside the U.S.?
We're just gearing up on that now. We had a planning meeting this week internally to sort of think about our OUS plans. Obviously, we would like to take this worldwide. We do have a relationship with Nippon Shinyaku to sell, market, and distribute both in the U.S. and in Japan. So Japan is on the radar. In terms of the European countries, EMA and MHRA in the U.K., we have had conversations with them and will prepare data packages as the opportunity becomes likely and available.
Okay. Great. And then if we could go back to slide 6. So as questions were coming in, I was trying to mark them and match them up to maybe the content that would be most relevant. So just to start again, we did have a question, I think essentially asking, how does this differ from maybe other approved therapies? I think sometimes families see anti-inflammatory and they go, "Okay, well, I'm already on a steroid." So can you just maybe talk through a little bit of the mechanism? And then just a reminder, you said that someone from the company has made a mechanism of action video that the families can view as well.
Yeah, so this is one of the aspects of the development of Deramiocel that I am most proud of. It is a cell therapy with a defined mechanism of action. I want to reiterate for those of you that may be joining or interested for the first time, it is not a stem cell. These cells do not go into the body. They do not become part of injured tissues and replicate themselves. What they do is they're infused in by intravenous delivery. They typically are stored in the microvasculature of the lungs for some sort of amount of time, days to weeks primarily. Don't worry, there's no respiratory consequences. We even treated ARDS patients during the COVID pandemic and did not see any changes in oxygen saturation, so don't worry about that. From there, exosomes are released.
Exosomes are typically taken up by the macrophage, which is one of the major cell types in the immune system. The macrophages themselves go then through a clonal expansion, releasing exosomes that drive what we would primarily call immunomodulation, which is driving sort of the immune system from angry and inflamed because there's all these protein pieces floating around as the body is desperately trying to make dystrophin to healing and repair mode, which is evidenced in this immunomodulatory bar graph shown in the middle here and as Dr. Elliott of our team spends a significant amount of time on discussing in the YouTube segment on our website. And all of that tamping down the immune system then allows the cells to be anti-fibrotic, actually reducing the amount of fibrous tissue that is created, allowing for healthy muscles to heal and be repaired.
Therefore, that is likely the reason for the improvement in skeletal as well as cardiac muscle function.
Thank you. And it'll be helpful, I think, too, yeah, families have additional, they can go kind of watch that video, which should also be helpful. On slide 9, when you were talking about, I guess this is twofold. So one just general question around kind of what's the for the procedure, kind of how long does a typical infusion take? And then there was also just a question with this of, I think, Mike, you noted that there was use of antihistamines to kind of help deal with some of the AEs that were seen. Was that implemented into the protocol as kind of prophylactic? Is that something that you anticipate? Or is this more just kind of by decision of the treating physician?
So the.
I'll ask Dr. McDonald to take that question.
Sure. Yeah. So actually, due to some early experience with some allergic reactions to the cells, we implemented a pretreatment protocol where patients get a high dose of oral steroids sort of in addition to their usual steroid regimen, and then antihistamines, essentially H1 and H2 blockers, and that, fortunately, has helped prevent serious infusion-related reactions, and we've been really quite pleased with how that has worked in terms of preventing these more significant infusion-related reactions. The infusion itself usually takes just about an hour and usually very well tolerated. Sometimes patients get a metallic taste in their mouth. That's from one of the excipients or the preservatives. Patients actually on placebo similarly get the same metallic taste just because they receive the same preservative in the placebo preparation, but all in all, this has been, I think, extremely well tolerated, and the pretreatment protocol has really worked beautifully.
I don't see this ever being used in a home infusion setting because I think it would be far too risky to have a patient have an infusion-related reaction without a medical team present that can urgently and emergently deal with such a reaction. So I see this really being done at an infusion center, at a medical center that patients go to. I don't see this really being done on a home infusion basis. So.
Thank you.
That's helpful. Thank you. And then I think on the, we had a question related to both, so both the PUL and some kind of ambulatory. So maybe on the next, maybe that was slide 10 where you started to talk about some of the prognostic factors and looking at some of the late ambulatory patients. So there's a question of basically, is this something that could also benefit ambulatory boys, not just the non-ambulatory? And so knowing that you enrolled some late ambulatory patients, do you two parts, I guess. One, do you have any functional data from kind of lower limb functional outcomes? And the other piece of that would be, do you anticipate this being something that could be used in younger ambulatory patients?
So in terms of lower muscle function data, except for two patients in HOPE-Duchenne 10 years ago, we do not. For the rest of that question, I'm actually going to ask Craig again to take it because I think the issue of the younger kids and sort of the opportunity for treating is far more relevant from the physician. Dr. McDonald?
Yeah. I think by all means, this would potentially benefit younger ambulatory patients with Duchenne. I think realistically, the FDA is likely to look predominantly at the patient population that was actually studied, which included these late ambulatory patients and non-ambulatory patients. And I can't say whether they would consider a broader label. But I think with a biologic like this, I think the FDA has oftentimes provided approvals that are more consistent with the patient population that has actually been studied. I think there will be emerging data. I think we are in the process of discussing and planning potential clinical trials that might target some younger ambulatory patients.
I think there's some emerging preclinical data that if you treat mice with essentially Duchenne muscular dystrophy and you treat them very early in the course of their disease, you can actually have quite nice prevention of disease progression and fibrosis and so forth. So now that we have, it's exciting news in terms of newborn screening on the horizon. I think we're going to be looking at potential protocols where we can offer this to younger children. I think I know there were questions about potential synergistic effects with other therapies. There's really no reason to believe that this would not be of benefit to a patient who was treated with AAV gene therapy or exon skipping therapy or another therapeutic.
Great. Well, thank you. And yeah, we also had a question come in basically, I think, around the newborn screening thing with news of the Duchenne being added to the RUSP yesterday about how early of intervention can we think about for something like Deramiocel. I think that's always the thought of earlier intervention potentially being beneficial. And of course, conducting studies to identify safety and efficacy is also important. On the next slide, I think there was just a question. And I think you did show this data in the forest plot of just. So this is showing some of the mean change. And I think there was just a question about kind of what was the actual change in kind of points between the two groups.
But I also thought it might be helpful just to talk through, for those who aren't familiar with the PUL, how is the performance of upper limb kind of scored?
Yeah. So there are an upper dimension or shoulder dimension to the PUL and elbow dimension, and then a distal dimension that really focuses more on hand function. And so the items that are administered to a patient really are determined by that PUL entry score that you actually have. So a patient that actually has more limited arm function, they don't necessarily administer those shoulder tasks. But the shoulder dimension items really focus more on overhead reaching and outward reaching levels of function. And then the elbow dimension functions would be focused more on the functions of the biceps and triceps and elbow flexion, elbow extension. It really is important in terms of self-feeding and really getting your arm into functional positions. And then the distal items would focus more on distal hand function.
The reason we went with percent change and it's really more robust statistical approach to the PUL, we vetted this with Anna Mayhew, who is one of the co-inventors of the PUL, is a research physiotherapist. The patients with Duchenne will typically, when they have PUL scores in the upper 30s or low 40 range that have a lot of preserved shoulder dimension items, they typically will have a very rapid loss of those shoulder items. And they'll have big point swings in the PUL, whereas patients that have already lost those shoulder items that you actually do the mid-level PUL items or the elbow dimension items, those actually are lost in a more predictable linear function. Hence, that's why the mid-level PUL was a key secondary endpoint. Then those hand function items end up being lost over a much slower period of time.
But nonetheless, they're extremely functionally relevant to a patient. So as you can imagine, if you rapidly lost a higher number of points and patients started out with a higher number of points, it really makes sense to actually look at this concept of percentage change in PUL because the patients who are starting with those lower values that have really important distal hand function and some elbow function left to try to preserve even one or two points to that patient is extremely important in terms of clinical meaningfulness. So it was really, I think, a more statistically robust way to actually look at the PUL data.
That's a really helpful explanation. Thank you. And then we had a series of kind of cardiac-related questions come in. So maybe we move to slide 12. First, maybe we can go to slide 13. There we go. But for the patients enrolled in the study, knowing that there's kind of variants in kind of cardiac meds that patients get started on, were patients in both the placebo and the treated group on similar stable cardiac kind of regimens throughout the study?
Yeah. So Mark on my team, I think he reported that in the clinical trial, over 92% of patients were on stable cardiac meds throughout the course of the trial. And that was in all patients.
And then we had a question come in about a similar idea to some of what we're talking about to the skeletal muscle function, which is, should we be thinking about this from an earlier intervention standpoint? And would there be benefit from starting something like this therapy before we see cardiac involvement? And so, Jon, I don't know if you wanted to speak a little bit to just the care aspect of how we generally think about maybe initiating cardiac meds in Duchenne and then how that might relate to something like Deramiocel.
Yeah, absolutely. So as most people here probably know, we start medications prophylactically around eight to 10 years of age with ACE inhibitors and then mineralocorticoid antagonists. And we start the MRAs either around 10 to 12 or when we see late gadolinium enhancement. And then after that, most of our med decisions are based on cardiomyopathy progression of disease. Where if we see someone who's progressing more rapidly or has left ventricular dysfunction, we'll start beta blockers and then SGLT2 inhibitors. And that's designed because, as you pointed out, we know that these patients are going to get LV dysfunction down the road. And we know that if we do something earlier, as the people who asked the question implied, that we will have preservation of function. And that preservation of function will hopefully last a little bit longer.
In terms of Deramiocel, I think the initial sort of sweet spot for this would probably be with onset of late gadolinium enhancement or in patients with left ventricular dysfunction just because we know that they're starting that cardiomyopathy process. I certainly agree that moving that over time to an earlier, more prophylactic therapy could be beneficial in these patients. I just don't think we have data right now to say what that ideal time would be. I think that I would lean towards the presence of cardiomyopathy or LGE. I imagine that the FDA will do the same.
Thanks, Jon. And then I think on slide 15, where you kind of talked a little bit about that late gadolinium enhancement piece, there was another question that came in just around kind of, I think, a similar thought of differences in terms of LVEF, or was a patient starting at a certain LVEF better responder? And I think maybe it's helpful to just talk again about kind of this late gadolinium enhancement and what the response was in these patients.
Yeah, that's a great question. So presumably, the people who are most likely going to respond, like I said, are patients who have cardiomyopathy. And the reason that that's actually the ideal group is less for the Deramiocel response and more for the placebo responses. Those are the patients that we most expect to have progression of disease. So you're more likely to show a difference. And those are the patients from Deramiocel who are most likely to show a benefit in that we know they're already progressing. We know that they're already moving forward with disease. On the flip side, if you have significant late gadolinium enhancement and you have much less muscle left, we would anticipate there's probably going to be less of a response.
It doesn't mean there's not going to be a response, but we think that patients probably with a better LVEF and less LGE are probably going to respond better because there's more muscle left. And so when you stop the inflammation, when you stop the progression of fibrosis, you'll probably get more bang for your buck. Does that mean it won't work for someone with worse function? Absolutely not. But it just means that some of that enthusiasm is going to have to be a little tempered in someone with more severe disease because there may be less muscle to sort of preserve.
Thank you, Jon. And then another question on the same lines, and I think probably a little bit thinking of some of the approved therapies where we do have maybe recommendations around minimum ejection fraction. So there was a question of, would there be a minimum ejection fraction needed to receive Deramiocel? And this also might be too premature, but.
Yeah. The short answer is I'm not sure. The long answer is what I would say is, as a cardiologist, if someone has bad function, I would like to get them on all the therapy that I can safely put them on. And so the only concern that I would have in that situation is whether there's what the margin for them would be and whether their function is good enough to handle coming in to the hospital, getting an infusion, getting that volume load from the infusion, getting all the premeds and everything else. And if there's any concern that their function will be bad enough that that might put them at risk, then I would say this may not be a patient who should be getting it.
But if just a specific LVEF, I don't know that I would have a cutoff for where too low to administer because, as I said, I'd like to get everybody with low LVEF on as many meds as I can. But I think we'd have to take that on a patient-by-patient basis and make sure that we're doing something that's safe for that individual patient.
Thanks. And then I know Craig already touched on, I think, on slide 17, and Linda, you did as well, that this should work in combination with other approved therapies. I think a question was, were there any patients that were on approved therapies enrolled in the study? And if so, kind of what those therapies were?
Can you answer that?
Sure, Linda. Yes. We had approximately 20 patients that have been taking exon skipping therapy along the way. Everybody was on corticosteroids as background therapy in addition to where the majority of patients were taking background cardiac therapy. So yes, so far, we have not seen any safety trends with combinations of therapies.
But I think what people are asking about is how many patients were in HOPE-3 that were on exon skippers and/or gene therapies in the past?
I believe it's about 18 to 20.
Great. Thank you. And then we had another question just asking about kind of timeline of this would be a therapy. How frequently would this be administered? And would it be continually administered throughout the lifetime of a patient if approved?
Yeah. So right now, we're doing quarterly infusions. I think that's working out very well. And in terms of length of time, we have not hit a wall yet with open-label extension of HOPE-2. So our current plan is lifetime. It's pretty impressive, actually, that we have over four years of data in these same boys and young men. And the trajectory of their disease is very significantly attenuated compared to anybody in a natural history cohort that we've looked at. So in general, we feel pretty bullish about this being as long as they want to get it, it's available for them to get.
And Linda, maybe I could just provide a little help on that because I think I've treated more patients and treated patients for longer. I mean, we have patients in the open-label extension that have been on this therapy for over five years. I can just comment on two patients in that open-label extension I saw this week. One was a 22-year-old that had lost the ambulation at age 11, fairly typical pattern of progression. And that patient has been on therapy for over five years, still has maintained hand-to-mouth function, a PUL entry score of three. But remarkably, this patient is actually able to lean forward to pick up a low item or an item nearly off the floor with a reacher and then actually regains his posture back up to a sitting posture. The other patient actually is in their 20s. He's attending graduate school.
He has actually recently traveled to South America independently, and he has continued on this therapy long term, so I really see this as being a therapy that can be continued for a very long time in patients. I can't comment on for the entire lifespan, but certainly for a long period of time, and I think used also synergistically with some of our other exciting therapeutics that are on the horizon.
Great. Thank you. And then kind of a final question was around, we also see a lot of cardiac involvement in our Becker population. And so I think there's curiosity to, would this potentially be a suitable approach for that population? And are there any plans to expand and look at that?
Yeah. So whoever asked that question is reading my mind because I almost put a slide on Becker in this deck. So especially working with Dr. Soslow and Dr. Villa and sort of reading some of the literature, the cardiomyopathy of Becker is literally identical to the cardiomyopathy of Duchenne. And so our plan at Capricor is to approach the FDA in the first half of 2026 to discuss the path forward for Becker. And we certainly hope we can move relatively rapidly because we understand that there really is nothing to treat their cardiomyopathy either.
Great. Well, we've kind of come to time. So I did want to just say that, first of all, thank you all for joining us, walking through the data, taking questions from the community. And then as you move forward in your engagement with the FDA, as you have the announcements to share, we'll make sure to share that with the community as well so everyone can be as up to date as possible. Again, if you have additional questions, please feel free to send them along to us, and we'll make sure we get in contact with the team at Capricor. And again, this was recorded, so this will be online. So feel free to share with friends and family who might find this relevant. But again, I'd like to thank everyone for taking time to speak with the community today.
Thank you so much, Eric. And thank you, PPMD. And like I said, I want to end where I began, which is this began really with Duchenne families coming to the academic lab and asking us to pursue this as a potential indication. Pat was in the room in some of those very early mouse study days. And I think this is evidence that when people really put their mind to treating disease, great things can happen. So thank you, everybody. I hope you have the happiest of holidays, and my team are available for questions if you have any. Thank you so much.
Thanks everyone.