BioWorld Insider: Capricor’s CEO pursues a BLA and talks rare disease

Speaker 1: The BioWorld Insider podcast.

Lynn Yoffee: This is the BioWorld Insider podcast. I’m Lynn Yoffee, BioWorld’s publisher. Our guest today is Linda Marbán. She has been in the biopharma space for more than 20 years and is a co-founder and the CEO of Capricor Therapeutics. Capricor just said that it plans to file a BLA in October seeking full approval of deramiocel for treating Duchenne muscular dystrophy cardiomyopathy.

The company also just expanded its commercialization and distribution deal with Japan’s Nippon Shinyaku for Capricor’s lead asset in treating Duchenne muscular dystrophy. Dr. Marbán has been working on the treatment for Duchenne for many years. She has some insights into how to tackle a rare disease development program and how the FDA has changed its ways over time to help out.

Welcome, Dr. Marbán.

Dr. Linda Marbán: Thank you so much, Lynn, for having me. I’m very excited to be here.

Lynn: Awesome. She’s talking today with Lee Landenberger, a BioWorld staff writer and the BioWorld Insider podcast host. Lee, over to you.

Lee Landenberger: Thanks, Lynn, and thanks, Linda, for joining us today. First off, would you tell me a little bit about Capricor and your upcoming BLA?

Dr. Marbán: Thank you so much for having me today. It’s a momentous time for the company. As Lynn said in her opening remarks, I’m a co-founder of the company. I sort of took a step back for, oh, seven or eight years to let the technology build, and then once it was ready to jump into the clinic, I took over as its CEO, gosh, more than a decade ago now, almost 13 years.

My little anecdote is that when I founded the company, I was reading BioWorld. It was back in the day when everybody read actually print articles. I remember thinking, one day I’m going to be in BioWorld, and here I am. This is a big time for us, for our company, for our baby company, and we’re excited to be a part of the BioWorld podcast.

Capricor was founded out of technology from Johns Hopkins University based on a cell therapy that was discovered there called cardiosphere-derived cells. These are cells that are taken from ex-planted hearts that could be transplanted but are not for technical reasons, and don’t think that that’s going to be a supply chain issue because it happens about 40% of the time. For instance, we got 50 heart offers just in the last month nationally.

What we do is we take these cells and we put them through proprietary methods. We grow them up. We turn them into doses of 150 million cells, and then they’re infused using intravenous delivery into, in their current status, boys and young men with Duchenne muscular dystrophy, and primarily those currently with cardiomyopathy or late-stage upper limb loss of function.

Lee: OK. Thanks. Tell me about your medical background, which I think is in cardiology, and also toss in there about your assets mechanism of action. I’m really curious about how it works.

Dr. Marbán: Yes. I’m a PhD in cardiac physiology, and my team still makes fun of the fact that when I talk about cardiac function, I still get excited, so it is the heart of the matter for me. Basically, our mechanism of action of our product is that it works by immunomodulation, so controlling bad inflammation and encouraging repair, because remember, our bodies, while they’re breaking things down, they’re building things up, and so it works hand in glove.

There’s additional anti-inflammatory components. There’s pro-angiogenic, which is a neovascularization, so if healthy muscle is built, whether it be cardiac or skeletal, it allows the blood to get there and for the tissue to be adequately perfused, and it’s anti-fibrotic. This is the way repair would flow, right? You break down inflammation, you allow healthy new tissue to grow, and therefore you have less generation of scar tissue, which in science language, as you know, is called fibrosis. Anti-fibrotic, anti-inflammatory, immunomodulatory, and pro-angiogenic are the main mechanisms of actions of our product.

Lee: OK, so you’ve been working on a Duchenne treatment for a long time. Why did you that was the indication that you wanted to pursue?

Dr. Marbán: We started working on Duchenne muscular dystrophy in 2015, really, when the idea was presented to our co-founder, Eduardo Marbán, in a science meeting, that the idea that the cardiomyopathy associated with Duchenne muscular dystrophy would be an interesting target. We had already been looking at adult heart disease, the heart disease that happens if you’ve had a heart attack and you have damage to your heart.

We were really looking around for other types of cardiomyopathies with which to build the therapeutic, and when we heard about Duchenne muscular dystrophy, that it was primarily a cardiomyopathy fostered by the development of scar, leading to the pathophysiology of loss of function, ultimately heart failure, and at that point was just being considered the number one cause of death in Duchenne. We realized that this would be a wonderful opportunity to make a difference in the lives of young people, boys and young men, with Duchenne muscular dystrophy.

We started along the typical clinical development path. We did some animal studies where we showed in the mdx mouse, which is the gold standard animal model, that the cells actually improved cardiac and skeletal muscle function. We published that work in Stem Cell Reports, now in 2018, and then we were able to continue that work and show that the exosomes released by the cells mitigate the mechanism of action or mediate the mechanism of action. We published that also in Stem Cell Reports, and so that was when we were really off to the races.

Our first clinical trial was called HOPE-Duchenne. It was a 25-patient clinical study done at Cincinnati Children’s Hospital Medical Center. We did a one-time infusion of 75 million cells into the coronary arteries of these boys with Duchenne muscular dystrophy, and we found that we saw a reduction in scar, trends towards improvement in cardiac function, and skeletal muscle attenuation of disease. That really launched our whole program.

Lee: When we recently talked about Capricor’s deal expansion, we got to talking about rare disease drug development, and you’ve mentioned that the FDA’s strong efforts in laying the groundwork for your company’s Duchenne treatment have been really helpful, and I was curious about some of the details. Would you give me some behind-the-scenes on the agency’s willingness to make changes that help you in the development of this drug?

Dr. Marbán: Yes, so this has been a game changer for us and a lot of people have been asking in the past, really, 24 hours since we broke the news that we’re going in for the biologics license application for the cardiomyopathy, and that seems like it’s a change of pace. We had been talking about the performance of the upper limb, upper limb function, for the past many years, and the reason that we are finally able to go after the indication, the cardiomyopathy, that we originally started in the business to look to attenuate was primarily because of the flexibility of the FDA.

As I mentioned to you, Lee, and thanks so much for chatting with me the other day, FDA realized that you can’t do rare disease drug development the same way that you do large normal indications like congestive heart failure or something like that, because those studies require a lot of people, a long time, and sort of adjudication of the mathematical algorithmic assessment of statistical relevance to, and relating that to benefit, right? To clinical benefit.

Oh, I have a p-value of .01, that means there’s a 99% chance that what I’m seeing here is not due to chance, therefore it’s a treatment effect, therefore it’s going to help people. That model works, right? You’d feel very comfortable with that model, but the problem with a heterogeneous disease process like Duchenne muscular dystrophy, which is a rare disease, so there’s just not a lot of people out there with it to study, is you may actually miss the opportunity to really have a therapeutic benefit by laser focusing on one thing. I think the agency is recognizing that.

CBER, Center for Biologics, is the one that we work with directly, led by Peter Marks, who really has been game changing in his willingness to hear the full story. Let’s hear real-world evidence, let’s see what’s happening to human beings, let’s look at their videos, let’s hear what their families are saying. Let’s look at the math and the statistics as well, and let’s take the totality of this evidence, put it together with the most important component of, is this safe, will it actually not hurt a person, and then let’s get things to people that can make them better, live longer, better, and more fulfilling lives.

Lee: Linda, do you know why the FDA’s Peter Marks, who you’ve called a visionary, has decided to be so flexible in this development process?

Dr. Marbán: I don’t know. I haven’t spent a lot of one-on-one time with Peter. We work a lot with Nicole Verdun, who is the super-office head of the Office of Therapeutic Products, and she has been an extraordinary partner. I really say partner, in moving this therapeutic forward. I know that she’s under the guidance of Peter, so I’m guessing it’s coming from him as well.

I think the idea of totality of evidence was already swelling behind, probably mostly pushed forward by what happened during the pandemic, where big regulatory decisions had to be made very quickly, with not typical amounts of time or data. Look at the benefit that was derived. We slowed down the pandemic in such a way that lives that were being lost are no longer being lost. An incredible success.

I think that was sort of the wake-up moment of, OK, the way we’ve been doing this may not necessarily be the only way to evaluate the efficacy of a potential product. I guess Peter is just riding that.
In terms of within the agency, I don’t know. I don’t work in the agency. I’m sure there are people that would prefer it to be the way it used to be, but I also think that there’s a lot of people there that really believe in the opportunity to get drugs on the market that can really accelerate the treatment of disease.

I’ll just say, I’ll just add here, and it’s a little bit of a postscript, I think the FDA’s job is ridiculously hard. I know that when I get emails and phone calls and texts from moms and dads and even young men themselves begging me for a therapeutic because they’re concerned about losing function or their life and how it pulls on my heartstrings, I can only imagine what it feels like to be a regulator and have to be in that position of potentially saying no to somebody who really thinks something might make them better.

Lee: OK. Great. Do you think the change has been made quickly enough for Capricor?

Dr. Marbán: I think the changes for us have been fast enough. I know that there are organizations out there that may not feel that they’ve had the type of experience that we’ve had with FDA. I can tell you that it was a sea change for us when we first were working with the agency as we did phase I and phase II of our work. The phase II clinical trial, HOPE, it was called HOPE-2, was resoundingly positive. We published those results in The Lancet, which is a major publication in the space. We hit our primary.
At that point, under sort of the old administration, the agency was not willing to consider moving us forward, even towards accelerated approval, despite the power of the data. When the administration changed, we really felt that difference.

From where I sit today, from where we are working in Capricor right now, I don’t think we can ask for anything more. I can say this is incumbent upon me and my team to deliver now. We have to make sure we get this across the line. We have every plans on doing that. We will submit our full BLA by the end of this calendar year. We’re on track to do that. We continue to move it forward.

I guess if I had anything to add, there’s a lot of requirements that go on behind the scenes and what they call chemistry manufacturing and controls or CMC, and that’s manufacturing. The way that drug development is done these days in biotech is that mostly the most developed products or the most product development, not developed products but product development, is coming from small companies that don’t have a lot of money.

We, for instance, couldn’t really do the manufacturing scale-up that we needed to do until very recently. I guess the only thing I could potentially ask, and this is small, is that the agency give a little bit more swath to those companies that are coming from behind from a capitalization perspective, and of course, make sure that it meets the demands, but understand that it’s been more of a challenge to get there from a CMC perspective, but that’s a small thing.

Lynn: Lee, thanks so much. I had one additional question for Linda. Everyone in our industry understands that it takes years and years to develop a human therapeutic, and they’re often interested in the backstory. I heard you mention earlier in this episode that Dr. Eduardo Marbán was the person who initially identified in an academic lab this technology. Can you tell us who Eduardo is and what the connection is and how it led to your involvement with Capricor?

Dr. Marbán: Thanks for asking me that. Eduardo Marbán is the director of the Cedars-Sinai heart medical center and was the co-founder of the company, which was founded, as I mentioned, back at Johns Hopkins University, where he was chief of cardiology. All of the groundbreaking work was done in his academic lab and then licensed to the company. Eduardo, similar last name or same last name, is my ex-husband, and we worked to start the company together. While he has less of a role in the company now, no longer on the board, he still serves in a scientific advisory capacity.

Lynn: Interesting. Thanks for sharing that. Thank you so much for your time and insight today.

Dr. Marbán: Thank you so much.

Lynn: That’s our show.

As always, BioWorld will continue to keep you informed of all the most important scientific, clinical, regulatory, and business updates. We’re a daily news service covering the development of the most innovative human therapeutics designed to improve the human condition. If you need to track the development of drugs, turn to bioworld.com. You can follow us on LinkedIn or X, and if you want to share news with us, drop us an email at newsdesk@bioworld.com.

Also, if you’re enjoying this podcast, don’t forget to subscribe via your favorite platform.

Thanks for joining us today.

Speaker 1: BioWorld, published by Clarivate, is a subscription-based news service that delivers actionable intelligence on the most innovative therapeutics and medical technologies in development.