RARE Daily

A Cell Therapy to Control Heart-Damaging Inflammation in Duchenne

November 2, 2023

Duchenne muscular dystrophy is a rare neuromuscular disease that causes muscle degeneration and premature death. As the condition progresses, heart muscle cells die and are replaced with scar tissue. This leads to heart failure, which is currently the leading cause of death among people with Duchenne. Capricor Therapeutics is developing a therapy that uses caridosphere-derived cells from healthy human hearts to slow progression of the condition though their anti-inflammatory effects. We spoke to Linda Marban, CEO of Capricor Therapeutics, about Duchenne muscular dystrophy, the damage the condition does to the heart, and how the company’s experimental cell therapy modulates the immune system to control chronic inflammation caused by the disease.

Daniel Levine: Linda, thanks for joining us.

Linda Marban: Thank you for having me. I’m looking forward to the conversation.

Daniel Levine: We’re going to talk about Duchenne muscular dystrophy, Capricor, and its efforts to develop cell and exosome therapies to treat the condition. Let’s start with Duchenne. For listeners not familiar with it, what is it?

Linda Marban: Duchenne muscular dystrophy is a genetic disease. It is X-linked, which means it comes from the mother primarily and is expressed most frequently in males. So typically, it’s diagnosed, for instance, in boys around three years of age. What the genetic mutation does in Duchenne, which is the most severe form of the muscular dystrophies, is it prevents the appropriate production of a protein called appropriately dystrophin, which acts as sort of a cushion and a glue to protect cells. So the way that I sometimes describe it colloquially is it’s like the bumper of your car. It prevents day-to-day damage. If you ever go to get into a tight parking spot, you don’t worry so much if you slowly hit the car in front of you with your bumper because it’s going to protect you, no damage. If you took that off, you have a whole different set of headaches and you probably would start damaging the frame of your car pretty soon. So that’s what happens in Duchenne muscular dystrophy. The muscle cells without the protection of dystrophin get damaged in day-to-day use, and they die much more rapidly than your muscle cells or mine. And as a result of that, they’re constantly in a repair mode. Ultimately, the muscle runs out of cells to repair with, and then that muscle group dies and is replaced by scar tissue, which we call fibrosis. Once the muscle cell becomes fibrotic and no longer can move, and so ultimately the person in this case, the young man with Duchenne, will lose that muscle group. And that’s why you see them getting worse and worse from large muscle groups like the legs all the way down to their fingers later in life. Then ultimately they’ll lack the ability to breathe appropriately. Their hearts don’t contract appropriately and they typically die somewhere between 20 and 30 years of age. To put sort of the frosting on the cake there, it’s one of the most tragic diseases because parents see their children decline all through their lives. So, they never get to revel in those moments because they know that whether they’re picking up a soccer ball today, tomorrow they may not be able to do that anymore. And so it’s very painful both to the patient as well as to their family.

Daniel Levine: We’ve seen new therapies emerge for Duchenne. What’s the prognosis today for patients and how have these therapies changed the Duchenne landscape?

Linda Marban: Yeah, so the prognosis at this point is still fairly draconian in terms of the fact that they typically, as I mentioned, are now dying between 20 and 30 years of age. Now, 10 years ago it was between 15 and 20 years of age. And so they’ve had a tremendous add to their lifespans, primarily by the use of steroids, which primarily address the inflammatory consequences of the disease as well as better ventilation techniques that allows them to keep breathing normally for a much longer time.

Daniel Levine: Most people wouldn’t think of Duchenne as an inflammatory disease, but what role does inflammation play in the condition?

Linda Marban: So, there are two aspects to the disease, which is the lack of dystrophin, meaning that you have a constant and persistent damage to the muscle, and then you have the inflammation that occurs because of the constant breakdown of muscle products. So, most people focused on therapeutic development for Duchenne think about fixing the dystrophin mutation. But until we can go into the germline or into very, very tiny babies and fix the mutation, what you really are going to be looking at is a balance between enough cells that can make dystrophin, maybe with a gene therapy or an exon skipper, and then controlling the inflammation and the inflammatory component of the Duchenne disease in order to help new muscle take root, last a little bit longer, and function a little bit better.

Daniel Levine: Before we talk about your lead experimental therapy, I did want to talk a little bit about your platform technology. I think it would be useful to explain a little biology to listeners. What are exosomes and what role do they play?

Linda Marban: So, exosomes are nanometer-sized lipid bilayer vesicles. What that basically means is that they’re little tiny fat bubbles, but the membrane on the outside is the cell membrane. So it’s exactly the same as every cell in your body. Exosomes are made by all biologic fluids. So beer has exosomes, milk has exosomes, obviously there’s billions and trillions circulating in our blood right now, but they are nature’s communication device. They are essentially the words of cells. And it’s funny because up until really recently, 10, 15 years ago, they were considered to be the trash cans of cells. So, there’s also these types of membranous testicles that are released from cells that are like the cells putting out their trash. And so it was just assumed that these were just smaller trash cans. But ultimately in the early 2000s, a group of scientists got together and they were able to determine that the exosomes, in fact, were not carrying trash but carrying messages in the forms of nucleic acids as well as proteins. And so exosomes themselves are probably one of the most efficient drug delivery vehicles that we could conceive of. This is nature’s way of delivering contents, and we’re taking advantage of that as well.

Daniel Levine: Capricor has developed what it calls its StealthX technology. This can be used to develop both precision therapeutics and vaccines. How does the platform work?

Linda Marban: So, we decided that while we understood that the mechanism of action of CAP-1002 are the exosomes and they certainly would be a good opportunity for a product, what we realized is that the cells were doing a fine job of going into the body, releasing the exosomes, and causing those downstream biologic effects that are ameliorating the progression of Duchenne muscular dystrophy. But what we also realized in the series of ‘aha’ moments was that we wanted to take advantage of the exosomes’ ability to deliver contents past the cell membrane, and they are coded essentially with the cell membrane itself. So, the body sees them as familiar, not foreign, no immune responses raised, and then they fuse to the cell membrane and can deliver content safely inside—so avoiding detection by the immune system and destruction by those parts of innate immunity that are always circling around in the body. And so, what we decided to do is instead of using the exosomes made by CAP-1002, we take a standard cell line, it’s a 293F cell line, we isolate out the exosomes, and you can think of them as empty or blank envelopes. So, we isolate them out. We have developed technology to grow them up in vast numbers, and then what we can do is custom load them or decorate them with something on the outside called a molecular moiety, which tells the exosome what type of cell to go towards. And we’ve seen some really exciting data with muscle targeting using that exact strategy at this point.

Daniel Levine: I take it that’s important because that’s been one of the big challenges in terms of treating Duchenne, is to target the cells that need to be targeted in this condition.

Linda Marban: That’s exactly right. And it’s not just in Duchenne, right? This opens up the door to such a vast array of diseases. It’s kind of staggering, and I was talking to a colleague on Wall Street just the other day who had mentioned that this would be like monoclonal antibodies or some other type of technology that first seemed rarefied and only for the most draconian of diseases. But in reality, it’s now used for almost all types of diseases, especially inflammatory diseases. We see exosomes in the same light, delivering contents past the cell membrane and into the nucleus to alter gene expression. Protein translation or post-translational modifications has been a dream of scientists and doctors since the idea of a cell and a nucleus was discovered. And the rudimentary way of doing that right now is to use lipid nanoparticles. But we all know from getting those vaccines and from some of the mandates, for instance, from some of the Scandinavian countries, that lipid nanoparticles not only can bring about some nasty side effects, even in a vaccine, it’s unlikely that you could use them in any type of a repeat delivery paradigm because the toxicity would ultimately be too much for the liver and the kidneys and maybe even the heart. So, exosomes deliver the opportunity of a lipid nanoparticle, but with no toxicity, [and] ability to target directly to the tissue of interest, whether it be muscle or brain or lung or liver. And then it also allows for the specific delivery of protected cargo. So a really great opportunity,

Daniel Levine: Well, you can engineer exosomes to carry different payloads. What’s the range of things they can carry?

Linda Marban: So, put your thinking cap on and let’s talk about that because it could be a small molecule, like for instance a chemotherapeutic agent that is what they would call hydrophobic—so very hard to get into the blood and to where you need that chemotherapy to go. Put it in an exosome, it’s protected in there, and you can use a much lower dose, get it to the site of injury, probably far fewer side effects. You can put any kind of small molecule in there if you want to get it to a specific place, and then put something to target it on the outside. So it becomes one of those kinds of dreams we have as scientists, which is that you can target your therapy and not have to worry about dosing the whole body if you want to get a medicine to an ankle or a knee. So it’s a really great opportunity to use that targeting technology. You can use nucleic acids, gene therapies, viruses, you name it, we can put it in an exosome and it’ll get where it’s going in a much safer, more usable fashion.

Daniel Levine: I mean, it seems like this could address a major problem with both gene editing and gene therapies.

Linda Marban: That’s what we’re thinking. We’re working on that as well as others. We’re obviously not the only ones doing exosome-based therapeutic development, but we think that we’re one of the farthest along in terms of manufacturing large numbers of exosomes, as well as this loading and targeting. So yeah, there’s a tremendous number of wonderful opportunities ahead.

Daniel Levine: Your lead experimental therapy is CAP-1002, which is an allogeneic cell therapy. What are these cells, how are they derived, and what do you do to prepare them as a therapy.

Linda Marban: In terms of what CAP-1002 does: CAP-1002 is a cell-based therapy. It’s an off-the-shelf product. It means we actually make it, we make from donor human hearts that are transplant qualified but can’t be used for technical reasons. We isolate out a rare population of cells, and then we put them through proprietary methods to grow them up to become our product, which is called CAP-1002. The mechanism of action of CAP-1002, which has been published and discussed in about 200 academic peer reviewed papers, is that they work by controlling inflammation. And the word there, which is most important, is this immunomodulatory. That means that there’s a certain kind of inflammation, which helps repair your body normally. And the cells, our cells, help do that as well as reduce the amount of fibrosis—so scar generation. Now, CAP-1002 is not a stem cell. It does not go in, it doesn’t stick around. It doesn’t replicate or make new muscle itself. What CAP-1002 does is it goes in and it stimulates a pretty bold response by releasing exosomes. Exosomes are nature’s communication device and exosomes track to the sites of injuries in the body and then stimulate natural repair mechanisms. So basically CAP-1002 is sort of the delivery device for the exosomes that allow natural repair to occur.

Daniel Levine: What’s the regulatory path forward?

Linda Marban: So, we are in a phase 3 clinical trial. Now that’s the last stage before applying for a biologics license application or BLA. We are doing a primary group from our pivotal trial out of our Los Angeles facility. It was our original clinical plant. And because we have had so much feedback from the advocacy groups in the community that they want to see CAP-1002 get approved as quickly as possible, FDA has worked with us to come up with a plan where our initial approval will be out of this Los Angeles facility. And then we will come in almost immediately after the final patient is enrolled in what we’re now calling cohort A, the Los Angeles group, and we start cohort B. And cohort B will be from our GMP manufacturing plant in San Diego, which is better able to meet commercial supply as well as meet full GMP requirements, both in the United States and outside. And so, we anticipate our first pivotal data to be top-lined by the end of 2024, and then the BLA to follow in 2025.

Daniel Levine: And does this have the potential to treat other conditions that involve damage to the heart?

Linda Marban: Yeah, so it’s not just damage to the heart, it’s damage to the skeletal muscle as well. So, our therapeutic works both in the heart and in skeletal muscle, and absolutely we are exploring, as we speak, opportunities. We spent years learning about these cells, developing them, figuring out, as I just elucidated, their mechanism of action. We are actively interested in treating other diseases of inflammation and fibrosis, which as you can imagine, there are many.

Daniel Levine: How are you going about prioritizing potential indications to pursue?

Linda Marban: Yeah, I think everybody goes through that sort of analysis and develops an algorithm based on an unmet medical need, the strike zone, so to speak, of the mechanism of action of, in this case, CAP-1002, and the disease of choice. And then things like market, other opportunities on the market, and competitive landscape, as well as how willing and able the patient community is to enroll clinical trials and a variety of other questions like that. And we have a few that we’re actively looking at right now that are really within our strike zone of neuromuscular rare disease, and hopefully the audience will stay tuned and find out what that is over time.

Daniel Levine: And what’s the plan for marketing the therapy? Are you going to build a commercial organization or would you pursue a partnership?

Linda Marban: Yeah, so we have a partnership and that was really exciting for us. So, we wanted to find a partnership or partner that had commercial abilities in the United States, and the perfect partner for us was a Japanese company called NS Pharma, which is a subsidiary of Nippon Shinyaku, a pharmaceutical company based in Kyoto. And they took the rights for marketing and distribution. So we take the cells through the regulatory process, we negotiate reimbursement, we manufacture them, NS buys them from us, they sell them, they have a Med Affairs team in place and all of the salesforce for an already approved exon skipping therapy called Viltepso that they have within their wheelhouse. And so they’ve got everything set for us, and then we sell them the product and take a step back and collect royalties on the backside. So, it’s a really wonderful opportunity for us and for them, for us because it allows us to take our product all the way through—we know it better than anybody and it would take a while for somebody else to learn it, and it’s a win for them because they have all of the tools in place for marketing and distribution, and this gives them another product in their pipeline.

Daniel Levine: You recently completed a $23 million registered direct offering. How far will existing cash take you and what’s the plan for raising additional capital?

Linda Marban: So, the money that we’ve just raised will take us through top-line data from the cohort A that I mentioned a little bit ago. And obviously that will trigger some milestones for us, from our potential fundraising opportunities through that, including potentially through our partner and NS Pharma. And we have good strong balance sheet going into data. That’s what we wanted and we’ll evaluate as we go along, of course.

Daniel Levine: Like a lot of companies in the sector, your stock has been depressed, it’s near a 52-week low, it continues to be a difficult financing environment. What was the conversation like with investors?

Linda Marban: I think you’re exactly right. It’s a difficult time, especially in biotech. The XBI has significant pullback and they’re anticipating more. Biotech investments are high risk, and an economy that is struggling and trying to find its place, as well as some of the global activities, biotech is a tough space to be raising money in right now. Having said that, with our strong data from the open label extension studies, our phase 2 studies, the understanding and description of our mechanism of action, and our path forward with FDA, we were lucky enough to get our partner Nippon Shinyaku to make an equity investment of $10 million, as well as Highbridge Capital come in. And that represents a really strong institutional investor to help support us all the way through data. So we feel really good about the deal that we did. Of course, everybody takes a little bit of a haircut in a fundraise these days, but the most important thing is a strong balance sheet and the ability to deploy and meet our goals, and that’s what we’re going to do.

Daniel Levine: Linda Maran, CEO of Capricor Therapeutics. Linda, thanks so much for your time today.

Linda Marban: Thank you so much. Have a wonderful day.

This transcript has been edited for clarity and readability.


Stay Connected

Sign up for updates straight to your inbox.