Welcome, everyone. My pleasure to start this fireside chat with Solid Biosciences. I'm Joe Schwartz from the Leerink Partners Biotech Equity Research team. It's my pleasure to be joined by Bo Cumbo, CEO of the company. We really appreciate the opportunity to get an update. Maybe we can have you start us off by just giving us a quick level set. You've had some really exciting data. It seems like you're advancing the science quite nicely with your next generation microdystrophin gene therapy for Duchenne. Can you summarize that data for us and how you're pushing the envelope here?
Yeah, no, we're very excited about the data we released. Obviously, released, I think, it was like the 17th or so of February. We've dosed seven boys, but we released six patients' worth of safety data and three patients' worth of dystrophin, as well as some cardiac data and biomarker data. I feel very good about where we are. We have a long way to go. The dystrophin data is, I think, best in class from what we've seen in the past. We looked at a whole to give us confidence in where we're going, we wanted to make sure that we walked all the way through the different steps of just the raw protein down to biomarkers of muscle integrity.
Once you understand that the muscle is shoring up, that should give you a lot of confidence that clinical trial design, if it's strategic and thought, patient baseline, time, endpoints, then it should give you a lot of confidence that we can hit that endpoint. We had about 110% protein expression in Western blot, 108% mass spec, 78% was the mean positive fibers, 70% the whole sarcoglycan complex coming together. We finally see NOS activity for the first time. NOS activity can help with a lot of different functions in the muscle, oxidative stress, help break down inflammation. We saw a host of biomarkers that gave us comfort that we're having shoring up the muscle. We looked at three different types of biomarkers. We have the acute muscle damage biomarkers. That can be like CK, ALT, AST, lactate dehydrogenase.
We tie that to chronic biomarkers like Titin or Troponin I. Once we understand that we're shoring up the muscle with these two acute and chronic biomarkers, we look at muscle maturation with using embryonic myosin and heavy chain. All of that leads us to believe that something is going on in a positive way with these little boys. That should lead to clinical benefit over time.
Okay. Super interesting. Your phase III confirmatory trial seems like it's pretty well designed to give you a good shot at showing a benefit based on controlling the types of patients who are enrolled and having some different sensitive endpoints. Can you talk about what you've done there?
Yeah. We've always felt, even before we had the data to know how good the drug seems to be, we always felt that the clinical trial design needed to be enhanced, that there are a couple of different things that you really needed to modify from what other clinical trials had had. Age is very important. And four, five, and six-year-old boys, these little boys, while they're not "normal" from a milestone development standpoint, they're still increasing. They're still doing pretty well, increasing different scores. So it's very hard to tease out change in a four, five, or six-year-old boy. We made sure that we're now enrolling kids from age four up to less than 12, but we're only looking at functional endpoints in seven, eight, nine, ten, eleven-year-olds. That way, these kids are either plateauing or declining.
That way, you get away from the noise of the four, five, and six. We can use the four, five, and six-year-olds as dystrophin, safety, help augment that. The other thing is endpoint. Endpoint, you have a four, five, and six-year-old that's actually increasing development, but then you're using a composite score like NSAA. It's a blunt instrument. It's not very specific. Actually, it makes it even more challenging to show an endpoint when you're four, five, and six with a composite score. We use stride velocity or rise time, 10-meter run/walk, secondary endpoints that are very specific. The last is time. Time is 18 months. It's interesting. We've always thought time was important, but we're always rushed in this industry to get an endpoint in 52 weeks.
In these rare diseases, it can be Duchenne, it can be Rett, it can be FA, it can be a host of different diseases. Fifty-two weeks is very challenging to get an endpoint. Now we actually can even look back. We have data in hand, and we can look at the Pfizer trial. We can look at REGENXBIO. You can look at Solid's original study back in the day, 2001. Positive fibers increase over time. Typically, all these companies have a baseline biopsy, an intermediate biopsy at week 8 or week 12, and then a 52-week biopsy. If you look at the week 12 biopsy compared to the week 52 biopsy, your positive fiber count goes up over time. If you think about a 52-week trial, the kids are not even at steady state of positive fibers, and your trial's over.
With all this information, I think we've created a better clinical trial. Now with the drug showing the benefits or showing the early results that we see, it gives us a lot of confidence that we should have a better mousetrap, so to speak, on the clinical trial design. Hopefully, that's going to give us a P-value.
Excellent. I want to dive in a little bit more into the drug itself. It seems like it's had a lot of optimization over the years, decades. Can you help us understand how it's been optimized? We found the suite of muscle integrity biomarkers really interesting. Can you help us tie what you've been observing in the patients treated with the drug together with the potential mechanism? Dystrophin is a big protein, and there's a lot of different functions, some known, some unknown. This could take up a lot of time, but I just want to make sure we touch on what you're actually developing here.
Yeah. I'll start by just the modification of the capsid and the manufacturing, and then we'll get into sort of the proteins and the biomarkers. We've modified a lot. Obviously, we have a very unique construct itself. It's the only construct that has R16, R17, which creates a landing spot for a protein called Alpha-syntrophin. When you have Alpha-syntrophin, it will bind to this R16, R17 repeat domains. You can recruit NOS. We think that NOS is very important. There are publications out there that look at patients that have mutations with and without NOS. Actually, the patients that have NOS, they tend to do better. They tend to walk better. These are Becker patients. We have the only domain that does that. We have two hinges on our protein because, remember, we're shrinking down a very large protein that all of us have.
We all have four hinges. You have the two on the domains that bind the two ends, and then you have two other hinges. We've removed those hinges to create ultimate flexibility of the protein as we shrink it down. Hopefully, this will increase durability over time. The capsid is very unique. We have modified the capsid with RGD peptides. These peptides, we knew in fibrotic tissue, inflamed tissue, dystrophic tissue, that these integrin receptors that we're targeting are upregulated. There are two of them that we target. We hoped that that played out, and it did play out in our data. We see rapid transduction. We knew in the preclinical models that this capsid was acting very different. We could show that in mice, we could get up to 75% expression at day four. That's unheard of.
No one's ever shown expression at day four, and we're getting 50-75% depending on the muscle. We hope that that translated into humans. We think it did. You can look at the vector genome copies, and it's a very high number, vector genome copies. Our manufacturing process completely revamped. We use a process that we created ourselves. We create our own equipment, so it's all automated. That gives you a very high full-to-empty ratio. We think that that really does matter. We think it matters from safety. When you have a high number of full capsids, you're not having to dose as high from a VG to KG standpoint. Hopefully, that helps with safety, helps definitely with COGS. More importantly, it also helps with efficacy because these capsids, they don't know that they're empty or full. They're just doing their thing.
They're just looking for these receptors to bind to. If you have a ton of empties or partials, they're binding to the receptor, and they're blocking the fulls. In our lab, we can see that as you increase your full capsids to empties, you increase efficacy as well, or at least transduction and expression. All of this mattered, and I think it plays out in the biomarkers that we're seeing now. I don't know where else you want me to go, but that's.
Yeah, that's perfect for my next question, actually. Just wondering if this data will continue to mature when we can expect the next update from these patients in the next batch.
Yeah, yeah. We dose seven. I want to go into the FDA with 90 days' worth of data for about 10-12 boys. We've already dosed seven as of February 17, 18, somewhere in there. That was released when we did the raise and we released the data. I told you I dosed the number seven, patient number seven, on that Monday. We have five additional boys that are scheduled to be dosed in the month of April.
You can quickly do the math and say, "Okay, sometime over late summer, early fall, we can request a meeting with the FDA, have a very good discussion, have at least 90 days' worth of data for 10-12 boys, depending on how many we actually want to have to go in." We'll release the data once we come out of the meeting, get the feedback from the FDA, understand what we have, what we don't have. We'll share that with the street, and we'll share the data with the street. We're looking sometime in the fall.
Okay. Very helpful. I think you said that you aim to have 20 patients treated by the end of the year.
If I had drug right now, enough drug, I could treat all 30 patients by May. I mean, we could not manufacture at risk until I knew the data in hand. I know the data in hand now. We have signed all the manufacturing contracts to make material. I am telling you, we said 20 patients by the end of the year, 30 patients by the end of Q1 because we assume we are going to be treated similar to what REGENXBIO received from the FDA. Their guidance was 30 patients. They came out of the meeting with the FDA, guidance of 30 patients at 10% microdystrophin expression. I am very hopeful that is how we will be treated, but I have to wait and see. If we had drug right now, I could dose all 30 patients by end of May. The demand is insane.
I just need more drug, and then we can fill the trial.
Makes sense. Can you spend a minute on just some perspective for us around the manufacturing?
Yeah. Yeah. We use Forge, and the only limitation was I just needed to know what I had in my hand and that I felt like I had confidence that I had a drug to push forward. We have signed the agreements with Forge now to run multiple, multiple, multiple runs with Forge. All the material will be coming in over the course of the year, and we will have plenty of material. We will go to the FDA. Our process was very clean to the beginning, so we think the FDA is going to appreciate it. We already had, as I mentioned, 80% true-fulls. Batch to batch, 77 was the low, and 81 is the high. It is very consistent from a full-to-empty ratio. I think the manufacturing process is very clean. We will talk to the FDA about it in the fall.
I've signed all the contracts to do so many different runs to make sure I have the material. I just needed to know what I had and what I didn't have.
Great. How are you guys thinking about functional endpoints, which have been challenging based on NSAA? How open-minded are you guys to using other endpoints that might be?
Yeah, we're not using NSAA.
A little bit more sensitive.
Yeah. We're using stride velocity 95, rise time, 10-meter run/walk. These would be the endpoints that we're using. We also now know that we have at least an early signal in cardiac function as well with the ejection fraction as well as troponin reduction in two boys. We will be looking at that as well. That adds a whole new wrinkle into this microdystrophin program that we'll be looking at and talking to the FDA about. To your point, we're not using NSAA. I mean, we'll have it, but that's not going to be our primary endpoint. It'll be stride velocity, rise time, 10-meter run/walk, and then cardiac endpoints.
How good is the understanding of how those behave with natural history?
I think pretty good. Stride velocity is actually a really interesting one because it's all automated. EMA uses it now. I think the FDA is starting to lean into it. I think there was even some comments yesterday on the Senate floor about using common sense and using automation. I think all this leans into a very positive outcome for us long-term.
Interesting. Great. On these potential cardiomyopathy benefits, how do you demonstrate these kinds of things robustly? Is there any way to get them on the label? How do you think about what you actually, in the statistical hierarchy, what you elevate in order to potentially differentiate?
Yeah. Yeah. Look, it's early data. We showed three patients, two patients at 180 days, one patient at 90 days. He was out to like 140 days at the time we released the data. I think it's an interesting early signal that we're going to continue to monitor and look at this. We knew our drug preclinical, we knew that I told you about the mouse. We were getting expression in the heart about 75% day four. I think that's quite interesting, especially when you start thinking about redosing, by the way.
That was my next question.
Yeah. You have to have, we'll talk about redosing. You have to have two things that actually happen in redosing. One of them is you have to transduce very quickly. This capsid data. We also saw in human cardiomyocytes about 21-fold difference of expression in cell data compared to AAV9. We knew we had a shot at doing some. When you look at Duchenne, 25%-26% of kids age 6 have some form of underlying cardiomyopathy or the beginnings of cardiomyopathy. By age 10, it's like 60%. It's quite sad. You see either lower ejection fraction or sometimes troponin I peaking up. We started to take a look at it. I think it's early signals. We're going to lean into it.
As long as it holds up, I mean, this is something obviously that the FDA will be very interested about. We're just going to have to wait and see if more data and more continue down this path. I think there's more and more natural history that we can lean into. I think we're working with different groups that are working with Capricor and other companies that are focused on this. More to come on that.
Okay. Great. What about the potential for redosing? It's a big challenge, but you and others are going about it stepwise in order to see if you can chip away at the hurdle there.
I think it's something that we all need to work on. Some of these kids get great benefits. Others do not. You don't want to leave them behind. There are also children that have naturally occurring, they've been exposed somewhere in life, and they have naturally occurring antibodies to these capsids. You have to have two things. You have to do two things to really get redosing to reality. One, you obviously have to get the antibodies to a certain threshold. You can use an IdeS, plasmapheresis, FcRn, combination of two or three of those to get it down to a certain threshold. Remember, these antibodies are going to come roaring back. Your window, you have to have two pieces of the puzzle. You have to, one, use a third agent or plasmapheresis to get down to a certain threshold.
You have to then dose, transduce, and express in that window before antibodies come roaring back, which means you need a capsid that can transduce very quickly. This is why when we talk about binding capacity, I used to talk about it all the time, binding capacity, transduction speed of a capsid. You have to have these RGD peptides for integrin receptors. It latches on super quick, super tight, transduces and expresses in a window. I think we're the only capsid that's ever shown transduction at this level within seven days. We're at day four, 50-75% expression. I think we have the best shot of anybody to make this happen. Now I need a third agent to lower antibodies. We're working on that with multiple groups right now, as well as plasmapheresis. You can do a combination of the two.
They're ongoing with studies that are doing this. It's not out of the realm. Why would other companies be doing this if they didn't believe that it could be potential as well? We're going to lean into it.
Okay. Great. You have a lot of other things going on. Let's switch gears and talk about FA.
Very excited about FA.
Yeah. Now that this IND has been cleared, what do you need to do before you can dose the first patient in the second half of the year?
Sign contracts with the universities, the IRB approvals, get the Neurosurgeons and the Physicians lined up. Patients are not going to be a problem finding the patients. It's a good/bad situation, meaning good because we have families that are begging to get into the trials. It's sad because there's so many families trying to get into trials. Realistically, it's just IRB approvals, getting everything squared away. We already have the drug on hand. We'll dose second half of the year, more on the late Q3, early Q4. We're getting two to three different sites up and running now. We have a ton of patients that want to get into the trial. It's the only trial of its kind, dual route of dosing so we can hit all the different manifestations of the disease.
What was real important to us when we started working on this drug, we started working on multiple drugs. We ended up licensing this drug through University of Pennsylvania. I started working on FA in 2020. Our goal in 2020 was it did not matter where you are in the course of the disease, we can get to the tissues that are needed. You have a child that's four years of age. She or he doesn't know if they're going to have cardiac manifestations. The DRGs in the spinal column are still intact. The cerebellum is still intact. You want to be able to dose that kid. You also want to be able to dose a 20-year-old. Maybe the spinal column, the DRGs are no longer functional, but the cerebellum needs to be treated.
Maybe with cardiomyopathy, without cardiomyopathy, you need to treat that person. Or a 40-year-old, 40-year-old that has cardiomyopathy, has no DRGs left in the spinal column and needs to go to the cerebellum. You want to make sure you can get to all the kids, all the patients. I think this is the only drug that can. It is very specific. We are going to be able to show day one that we are getting right to the dentate, the cerebellum. We are using gadolinium, a pressurized catheter with gadolinium. You are going to be able to show on an MRI that we are getting right to the area. There will be no guessing. You will know. I think that is going to be real important for you guys from investors to say they hit the target.
You use another capsid that you just think, "Oh, it's neurotropic." It's going to go everywhere into the brain. It's not going to get right to the dentate. That is where you have to get. You have to get to the Purkinje cells. You have to get to the dentate, the cerebellum. We are the only company of a kind that is going to be able to show that day one, day one.
Yep. Very interesting. Given the range of clinical symptoms that these patients have and so much demand, how are you going to design the study? Are you going to focus on any particular subsets of patients in order to give yourself the best chance of isolating meaningful clinical improvements?
Yeah. It's a great question. What is benefit? The range of what is benefit in these FA patients can vary pretty dramatically. We're treating the underlying cause of the disease by replacing frataxin. Some patients have 5% frataxin. Others have 35% frataxin. You're trying to get them to that phenotype, get to that level where they wouldn't have a phenotype or at least closer to that level. It all starts with Mitochondrial Health and how you think about restoring function to the mitochondria. There's going to be a lot of biomarkers we can use. There's also going to be biopsies we can look at. Eventually, you'll get to the clinical endpoint. I mean, you can look at what I'm doing in Duchenne from muscle integrity. You can sort of translate that to mitochondrial recovery.
We're going to follow that path. Common sense. This is going to be a common sense trial of how we can treat patients and help them recover wherever they are in their course of the disease. You see the playbook we've already mapped out with Duchenne. That's how we're going to play FA.
Okay. Great. The CPVT program is progressing?
It's progressing, yeah. Everything's on track to file the IND first half of this year, in the next couple of months. The FDA wanted a six-month non-human primate study that ended about three weeks ago or so. We took down the animals. Now they're being analyzed. All the animals did great. We're on track to file first half. We'll be dosing patients second half of the year. I mean, ironically, you think about Solid now. I mean, when you and I started talking a couple of years ago, we were a preclinical company.
By the end of this year, if everything goes well with CPVT, we should have three drugs in the clinic coming out of the FDA meeting with hopefully some good guidance upon Duchenne, heading into a confirmation study with Duchenne ex-US, enrolling all 30 patients or so, 20 patients by year-end in Duchenne, dosing FA, dosing CPVT. We also have TNNT2. That's another dilated and hypertrophic cardiomyopathy that will be ready for IND in 2026. I'm trying to actually slow that one down because I don't have the staff to do all of everything. This capsid, SLB 101, we have it in 19 different groups right now. Academic labs or companies are using the capsid. The goal is in five years to have 50% of every cardiac or skeletal muscle program coming out of academia using our capsid.
This company, it's dramatically changing before your eyes.
Yep. That's clear. Maybe a little bit more on CPVT before we have to conclude for time. You have some really interesting preclinical data here. How are you thinking of getting this to potentially translate into the clinic for all these patients who need something?
Yeah. It's a real interesting disease state. They haven't had anything other than beta-blockers and flecainide since like the 1990s. They have ICDs. They have flecainide. They have beta-blockers. There's about 5-10% breakthrough every single year. Of course, they end up, unfortunately, passing a lot of times due to these ventricular arrhythmias and heart failure. We're going into RYR2 population. We chose that population because it's large. I mean, the CaSQ2 population is great population too and will be in that population. RYR2, from a commercial standpoint, it's big. It's 15-20 times the size of Danon and very fatal. No other companies doing what we're doing. We have the chance to change the course of this disease and rewrite how you treat it. We'll start with patients that break through. As we build a database, then we'll move forward.
It's like a cancer trial. You're using it like third line at first, really build up the safety database, get physicians comfortable that this can sort of provide protection, cardiac protection, and then move up into the treatment regimen.
Pretty cool.
Only company I've ever seen doing it. You have really unique drugs along the way.
Yeah. Yeah. We look forward to learning more about that trial design. It seems like you would know it when you see it if there's a treatment effect.
It will. I mean, hopefully, they don't have arrhythmias. You put them on a treadmill, and arrhythmias are what you would see. If you can protect them, if you can protect the child and they get dosed age somewhere between 7 and 12, that's when you would typically diagnose. We will start with older patients and we will work down. If you can protect them from arrhythmias, it can be huge. It can be huge. It is the only treatment of its kind. Once again, the only treatment of its kind, CPVT, the only treatment of its kind for FA, a very unique next-generation drug for Duchenne. I think all three make a pretty cool little company.
Yep. Absolutely. Thank you so much for the update, Bo. Really appreciate it.
You bet. Thank you, Joe. Thanks.