All right. Welcome back. My name is Sylvain Turkan. I'm a senior analyst at Citizens covering precision medicines. Now it's my pleasure to host Solid Biosciences. Bo Cumbo, thanks so much. You're the CEO and President of Solid Biosciences. Thanks so much for joining us today.
Thank you, Sylvain. Thank you, Citizens, for inviting us. Thank you.
Maybe can you give us a little bit of background today about the Solid Biosciences post-merger with Avanti, where you came from, and kind of what technology are you bringing to the table for those that are not familiar with the Solid Biosciences of today?
Yeah, Solid Bio has changed a lot in the last two and a half years or so, two years. It's actually Solid's been around for a while, focused mainly on Duchenne. But two years ago, it underwent a transformation when two companies merged together, Solid and Avanti Bio. Avanti was run by myself. And I'd been building that company for a while to really transform gene therapy. I think everything revolves around delivery and gene therapy. Even if you look at all the comments, and I'm sure we're going to get into it, all the comments that Prasad and others have made about gene therapy recently, it all talks about first-generation companies. I believe that many years ago that we need to change gene therapy forever. You really need to change delivery. Delivery comes in three flavors. It comes in capsids, promoters, manufacturing, whether it's purity, et cetera.
We started working on that with Avanti. That really helped transform Solid at the merger because we work very, very hard on next-generation therapies that I think are going to play into this administration's hands when you think about what they want. They want better gene therapies. They want clinical endpoints. They want true value. I think that's where next-gen programs, next-gen delivery come into play. As we sit here today, we have what I believe is the best gene therapy for Duchenne coming to the market in clinical trials now, eventually coming to market. It's a next-generation drug. It has next-gen capsid, next-gen manufacturing, and the best construct design. You follow that with FA, and you follow that with CPVT and other programs. We also have 19 different partnerships working on using our delivery tools, our next-generation capsids, promoters, manufacturing.
We believe that if you're going to, and this is no pun intended, but if you believe if you're going to make gene therapy great again, it starts through Solid. Every construct should have Solid inside. We're working on that. You're going to see that play out over the next couple of years. We believe every program will eventually have a Solid component to it: capsid, promoters, plasmids, et cetera.
Great. No, that sounds great. Can you maybe talk us or walk us through the construct of SGT-003 and kind of how is it exactly differentiated from ELEVIDYS or from REGENXBIO's program?
Yeah, yeah. It comes down to really a couple of different components. One, we believe we have a novel transgene. That transgene was one of the last ever made from Jeff Chamberlain as he iterated from the earliest constructs all the way to the last one, which is ours, where you have removed the middle hinges. You create a mini protein that's very flexible in nature. It still binds to the terminal ends, but you do not have this rigid, tight protein. As the muscle is moving, the protein can move with it. Because remember, all of us are taking a very long protein, and it has four hinges. You need those middle hinges for strength and rigidity because you have such a long protein. When you are shrinking it down, you create a much tighter protein. We have removed the hinges in the middle.
You see that makes a difference in flexibility. Ultimately, we believe that will increase durability, long-term durability, so the protein does not break or the muscle does not tear. The next is the in-os binding domain. You have to have R16, repeat 16, repeat 17, so you can recruit for a protein called alpha-syntrophin. Once you have alpha-syntrophin, that has to bind specifically in that region of R16, R17, then you get in-os. Once you have in-os, then a whole cascade event happens. We are the first program that has ever been able to show enzyme in-os activity in human subjects. That is the data that we presented most recently. We believe in-os increases vasodilation, blood flow, decreases inflammation, decreases fibrosis, and creates a whole different outlet of benefit that other programs cannot have.
We believe that the cardiac benefit that we are seeing in our kids is a direct response due to in-os activity in the blood as well as at the muscle fibers.
Great. Yeah. Obviously, we already had a chance to see a little bit of some of those potential design choices translate into outcomes. Can you maybe summarize the outcomes that we've seen in the first couple of patients in the INSPIRE trial?
Yeah. Look, I think I don't know how close you guys follow Duchenne. I'm sure it's pretty close. I've been in Duchenne for a very long time. There was a lot of questions around microdystrophin. Does microdystrophin work? We wanted to be able to answer that question as early as possible. As we run longer clinical trials, we have a lot of confidence internally that we're going to hit that p-value. We take a sort of a waterfall cascade approach view on understanding at the very beginning of how you can dose, transduce, express all the way down to activity to give us confidence. When you take a look at what we were able to generate, it all starts with binding capacity and speed. This comes back to the capsid, right? This capsid is called AAV-SLB101.
It is the only capsid of the kind I feel very confident to say I have the best skeletal muscle cardiac tropic capsid that has ever been dosed in humans, period. You can see it in our data. We saw it in the preclinical data. It has translated now over to data, into human data. You see it in liver targeting. You see it in binding capacity, speed of transduction. That is what translated down into VGs, the vector genome copies per nucleus. Highest level out there, vector genome copies per nucleus. That is the start. That is like, OK, it is getting into the cell. Now you look at, does it produce protein? Everyone thinks that is really where you should stop: Western blot, mass spec, et cetera. Really, that is just the beginning of all this. We have 110% on Western blot, 108% on mass spec.
You take it a step further. OK, you have high protein. What does the fiber count look like? Your muscle, what's the muscle content look like? 80% of all, 80% average of muscle fibers were positive at the intermediate biopsy. Why do I think that's important at the intermediate biopsy? Your muscle fibers go up from a positivity standpoint over time. At a 12-week point, you have 80% saturation, means you're at a really good place. Personally, I believe you have to get to that sort of 40%-50% fiber count to really see a true clinical benefit. How many fibers are you changing in the body? You get the more, the better. That's not where you stop. You go, OK, I got 80% positive muscle fibers. What's happening to the dystrophin sarcoglycan complex? Is it coming together?
At a 70% range, and it's the first time any company has ever shown 70% of the entire complex coming together, that it's a high watermark for any company in Duchenne. You see in-os activity. OK, you have the complex coming together. Are you making the protein? Is it producing a benefit? For the first time ever, you see in-os activity at 40-something %, a 62-fold increase over baseline of in-os activity, 42% of all muscle fibers had in-os activity. Now we get into muscle integrity. We can make fibers. I mean, we can make protein. We can produce positive fibers. We see in-os activity. What gives you confidence you're going to hit a p-value in a clinical trial? Duchenne is a muscle integrity disease. You understand that over time, the muscles break down, tear down, turn into fibrotic tissue.
Can you do anything for muscle integrity that's going to give you confidence that you can hit a clinical endpoint? There are three types of biomarkers you can look at for muscle. One is the acute phase of muscle injury. Second is chronic phase. Third is sort of this muscle maturation phase. We can look at seven different biomarkers and say we're having a major impact on the acute phase: ALT, AST, lactate dehydrogenase, CK. The chronic phase would be more of troponin or other biomarkers. The muscle maturation or titin for the chronic phase. The muscle maturation, embryonic myosin heavy chain. For the first time ever, we can show a reduction in embryonic myosin heavy chain. Why is that important? Your satellite cells are having to repair muscle fiber, and they turn into the embryonic myosin heavy chain.
Basically, you're seeing these cells try to repair the muscles as they're being torn down. It depletes the satellite cells altogether. That's not what you want in DMD. If you can reduce that and muscles can mature for the first time ever, your satellite cells, your pool of satellite cells will stay there. We can show like over a 40% reduction. That gives me a lot of confidence that we're going to hit clinical endpoint. It's just now about setting up the right clinical trial design, patients, endpoints, time. We feel very confident that we have the drug to do it now.
Great. Thanks for the summary. One thing, when I looked at the data that struck me on maybe the early biomarkers is your relatively tight number in vector copy numbers that you have in the cells and your dystrophin expression levels compared to some of your peers who on patient is very low, very high. Does that speak to the quality of your vector, or did we just get lucky?
I don't think it's luck, but you never know until the end. I don't think it's luck. I think it all came because we could see it in our preclinical studies. Remember this capsid, I talked about binding capacity. It's really due to the integrin receptor. We put over 60 integrin receptors, our RGD peptide. We put over 60 RGD peptide insertions for integrin receptors on the capsid. Two different integrin receptors we target. We never disclosed the integrin receptors. Some people have been very smart and picked out one of them. There are technically two that we target. You see these upregulated in fibrotic tissue, inflamed tissue, dystrophic tissue. We had a hint. You could see it in preclinical studies that we were human cardiomyocytes 20 times the level of AAV9.
We also saw it in both mouse and monkey compared to RH74 or AAV9 on distribution, vector copy numbers, et cetera. We had a hint. It turned out it played out just like we thought it would in the human subjects that we dosed. We also knew it was very tropic to the heart. We were getting 75% expression at day four, which is unheard of in the mice. We think that this is why we are seeing a change in the heart because getting to the heart is creating in-os activity across skeletal and cardiac muscles and then showing an impact.
Great. Yeah. Obviously, the cardiac aspect of your data is important because maybe you can just talk about the disease, DMD, what the implications are for cardiac problems in that disease and what your biomarkers point to.
Yeah, it's interesting. I mean, I hear critics talk a little bit about, you're not going to see cardiac manifestations that early. Why do you see troponin? Why do you see troponin everywhere? You shouldn't have elevated troponin. You shouldn't have low ejection fraction. Many kids, 25% or so are at around age 6. Start having declines or start having early manifestations of cardiac disease, whether it's a rise in troponin here or there, or whether it's a decrease of cardiac output, ejection fraction, you start to see it. At 10 years of age, about 50% of the kids have it. You can even look in different databases, and you can see elevation of troponin. You do see it. What we're showing, we dosed two boys that had elevated troponin at baseline. We took three different measurements pre-dose of gene therapy looking at troponin.
We see it's elevated, and we dose, and we can return it right back to baseline and actually go below baseline back to normal. We also are seeing ejection fraction changes in two of the three boys that were presented. Hopefully, that plays out in multiple other boys. We'll see. That's positive because one of the kids was actually at a low level compared to where he should be at natural history. It's not low, like 40%, 45%. At his age, for a normal child to be at like 60%, that's low. To be able to show an increase up to, I think it was like 70% or 72%, that's important.
Great. Obviously, the trial is now enrolling. You had some initial data. Can you maybe tell us where we are at with the trial? Does the initial data kind of accelerate enrollment? Also, we had the patient death on ELEVIDYS. Maybe that shuns more patients to the trial as well.
It did.
When do we get the next update? And what will it be?
All right. I'll answer your last one first, and I'll come back. The next update, look, we're going to meet with the FDA in the fall. We're going to request a meeting late summer, early fall. We have to wait 60 days before you grant that meeting. You can assume that the meeting will be Q4. Whether it's early or late, this Prasad might come into play. I might want to strategize around that. Everything's on track to have that meeting because we're continuing to dose patients. Patients are doing great. Safety is holding. We'll be on track to have that meeting in the fall. When we want to have that meeting, strategically, we need to think through it. Did the patient death with Sarepta have an impact? Yeah, 100%. I think that I listened, I read the transcripts to the call yesterday.
It clearly had an impact for them. It had an impact for us. We had a major influx of patients wanting to get into trial. Not only did we have a major influx of patients, we had physicians that wanted to get into the trial, that wanted to be a trial site. I think that's important for us. We'll continue to plug away. We have no need to need more patients because we have more patients than we have drug right now. We have plenty of drug, but there's a number of patients. It actually helped us because we had four or five screenouts. We had one boy that we were planning on dosing. He unfortunately fell and broke his femur. We had to replace him. We had another one who had the flu. We had another one that screened out for antibodies.
When you have a backlog of 20-plus patients, you end up with about a three-week delay. I mean, delay. You are able to replace patients very quickly. We have plenty of patients that want to get into the trial. We have the trial going on in the U.S. We also have a double-blind placebo-controlled trial that starts in the fall, ex-U.S. That is going to be up and running. Ironically, with everything, all the chaos that went on yesterday, it turns out that that trial that is going to be in the fall is very strategically important for Solid. Very important, whether you want to think about it. No matter how it plays out, the chaos that is going on right now in the field, that double-blind placebo-controlled trial will be up and running and dosing by year-end, ex-U.S.
Meanwhile, we're going to be plowing ahead, dosing patients in the U.S., looking for accelerated approval in the U.S. We're hitting on all cylinders. All patients seem to be doing great. We're going to continue to dose.
Yeah. Maybe talking about Prasad's appointment here, right? Obviously, your stock was down significantly yesterday. All DMD stocks, in particular, because of his comments around Sarepta. It seems it's a lot more targeted at Sarepta versus gene therapy in DMDs in general. I mean, we won't know until the fall. Do you think the accelerated approval pathway is still something that is possible in the U.S.?
Yes, I do. But we're going to watch what plays out. But I think no agency, look, the FDA is about helping patients get efficacious drugs for their diseases. You have a whole host of thousands, I think, what, 7,000 orphan diseases, many of them very fatal. You don't want that on your hands. So accelerated approval is a very needed mechanism to get drugs to patients that are in high unmet need, that don't have a drug like Cybaldi, which can cure you. Perhaps you don't have that many places in rare orphan diseases. And so accelerated approval has got to play a path. How does it change? I'm sure there'll be change. But this is where next-generation drugs come into play. This is why we built this drug. When I first started, I had many investors and analysts say, why are you doing what you're doing?
There's already a drug that's in Duchenne. I said, because this isn't a cure. It's not ELEVIDYS. It's where the market is going to end. You have to continue to build next-generation therapies. I think we have one. I think we have the best capsid. We have the best transgene. We have the best manufacturing. I have the best fiber count. This is all going to play out. Hopefully, it translates over. That is why you do what you do. You need to continue to build better drugs. I think I'm going to have the best drug on the market.
All right. Great. I think that's a wonderful way to wrap up the DMD discussion here because I was going to ask you what your pitch is being a third-gen gene therapy to the market and excellent skippers. I think you summed it up perfectly here.
Look, we're a $200 million, I don't know, $200-something million dollar company. We're building a company. We were always building a company where we could be a highly profitable little enterprise off X% of just the U.S. incident population. Everything else is upside. All the prevalent population that's going to be in place now, especially with all the delays that you heard of yesterday, that population is going to hopefully continue to be there for gene therapy. You have, unfortunately, about 400 new patients born each and every year in the U.S. You have thousands that are born, 800 or so born in the EU each and every year. You have over 200,000 patients ex-U.S. that are going to need therapies. All of that is upside for the company that we're building right now. It's a great place to be. It's a great little place.
Great. Friedreich's ataxia, can you just talk about your work there with SGT-212? And you've moved it in a clinic. Maybe give us an update where you are.
Yeah. We'll be dosing patients. We should be dosing patients in Q4. Obviously, we're a tiny little company. We didn't put a lot of resources pre-IND that a big company would, having got the sites up and ready and running. IRB approvals have to wait until you get the IND open. We are doing all that work right now, working with three different sites, have the trial up and running, IRB approvals, second half of the year, sites up and running, the surgery suite ready. We should be dosing patients in Q4. Very excited. The community is ecstatic about this drug. We just held a community forum about two, three weeks ago. We had 300 attendees. We get letters all the time of people wanting to get into the trial. This is the only drug of its kind. We have been working on FA for five years.
We know that you can get to the heart via IV. You can get to the DRGs in the spinal column, whether it's IV or IT. You can't get to the cerebellum. You can't really get to the dente of the cerebellum unless you go direct. We are doing a dual route of administration to make sure that we get to every single patient, wherever they are in the course of this disease. It's the only drug of its kind that actually can treat a 40-year-old with both cardiac or CNS disease, treat a 20-year-old that has CNS disease with or without cardiac, or treat a 4-year-old that has no clue what her diagnosis, her journey is going to be.
The only drug of its kind to get to the spinal column, the DRGs, the heart, and the dentate of the cerebellum, the McKinsey cells, right where you need to go. Big population, 5,000 patients, 7,000 patients in the United States, 15,000-20,000 ex-U.S. and Europe, and high unmet need. I think this is the only drug of its kind that's going to be able to get to the source and the heart of the matter.
Maybe with respect to some of the other gene therapies out there, for example, ELEVIDYS, you're trying to address all the aspects of the disease here, right?
Yeah. I mean, look, you can talk to the families. I mean, it makes sense. Think about if you had the disease. Would you want me to fix your heart, but you're unable to speak, see, hear, walk, swallow? The answer is quality of life will really matter. The only way you're going to do that is get to the heart of the problem, which is the cerebellum. Then protect the DRGs if you're in your teens or your younger life as much as possible. The only drug of its kind that can do that is this one. I have a lot of respect for my friends at Lexeo. They're doing a lot of good work. They're helping us because I'm watching their path.
We're the only drug that's going to treat every patient, regardless of their journey, where they are in life, and whatever their manifestations of disease will be.
Great. Lastly, obviously, even we've talked many years before. When we were still at Avanti, you had a large pipeline based on cardiovascular diseases. You obviously brought that over. Can you maybe talk about the most advanced one in CVDs?
CPVT. CPVT, catecholaminergic polymorphic ventricular tachycardia.
I didn't attempt that word.
Yeah. Just say CPVT. Highly fatal arrhythmogenic ventricular tachycardia following an IND in the first half of this year. We should be dosing patients the second half of the year. It's a one-of-a-kind drug. Hopefully, get diagnosed 7-12 years of age. It's highly fatal, 40% fatal within the first 20 years of life. It's the only drug of its kind. Hopefully, we can show what we're going to do in the mice and restore normal rhythm and be able to take kids and people off some of the drugs that they're on and remove some of the fear that they have just each and every day from adrenaline. Adrenaline surge, that's all they need. It could kill them. I mean, hell, think about yesterday's market. That's all you need is one adrenaline surge, and you can die. That's our first drug. We have TNNT2. We have the Mayo collaboration. We have four or five drugs there.