Okay, hi, good afternoon, everybody. This is Kristin Kloska at Cantor. Thank you so much for being here. Very happy to be hosting our first fireside chat together. We have Bo Cumbo, the President and CEO of Solid Biosciences. Thanks for being here.
Yeah, thank you, Kristen. Thank you, Cantor.
Awesome. To start, may I just please ask for a brief overview of the company, and we'll get right into the good stuff?
Yeah, so Solid Biosciences is a precision genetic medicine company, primarily in gene therapy. We focus on high unmet needs in the neuromuscular and cardiac space. We focus on four programs right now: Duchenne muscular dystrophy, Fragile Cachexia, CPVT, which is Catecholaminergic Polymorphic Ventricular Tachycardia, and TNNT2 is our next cardiac program after that.
Okay, thanks. Bo, you've spent a lot of time in the gene therapy space. Now, on safety, what are some of the better known factors that companies need to be taking into consideration? Beyond this, what do you think are some of the less obvious safety factors that Solid Bio is utilizing?
Yeah, you know, we constantly think about safety in every one of the programs that we build. A lot of safety events we think about can be mitigated from a delivery standpoint. Delivery comes in three flavors, which is the capsids, promoters, the manufacturing from a purity standpoint. We spend a lot of time on that to try to mitigate gene therapy because we know that gene therapy can come with risk. We know the benefits can be great as well for these kids. We spend a lot of time looking for new capsids that have better biodistribution, can transduce a little bit better so you can lower the dose, promoters that can drive to very specific tissue, and then purity so you don't have to dose as much virion matter because of high full-to-empty capsid ratios. That's where we're at right now.
So far to date, we've dosed 15 boys in our Duchenne program. We're going to be dosing relatively soon NFA and CPVT in Q4. We're spending a lot of time looking at safety. To date, knock on wood, it looks like we have a pretty safe drug.
Okay, would love to go through each of those components in a little bit more detail. Unfortunately, we are seeing some setbacks with the Levitus. I think it's really important to, again, take the step by step to understand the differences with SGT-003. First, on the capsid, why is it both critical for safety and efficacy to target the integrin receptors?
Yeah, so the integrin receptors are upregulated in skeletal and cardiac muscle. There's a lot of publications out there that show they're even more upregulated in dystrophic or inflamed, damaged tissue. We use RGD peptides in this variable region that I don't believe we disclosed. I don't believe we disclose the integrin receptors we target, but we use RGD peptides. We insert about 50- 60 in each capsid in this one region to target these receptors. What that does is it increases the binding capacity to the skeletal cardiac muscle. Because we're able to do that, because we'll be able to see in preclinical models, we felt very comfortable that we could have a lower dose. We actually have the lowest dose in Duchenne. We dose at 1E14. Other companies dose anywhere from 1.33E14 all the way up to 3E14, depending on the company.
We believe that that really does matter. It seems to have mattered in our preclinical, I mean, in our clinical data. It looks like we're getting high vector genome copies per nucleus. It really starts with that VG to nucleus basis. To date, it looks like it's paying off for us.
Okay, in general, why do you believe that next generation capsids are better than the ones where we have more familiarity? What risks come with having less clinical evidence around their profile?
Yeah, yeah, that is the trade-off. I think all of us in gene therapy, if we want gene therapy to be truly investable again and take it to better heights, we've got to move into second and third generation delivery tools. That is capsids, promoters, and manufacturing purity from a purity standpoint. The capsids, we're working on multiple capsids right now. I think I have 20 more going into non-human primates in the next month or two. These capsids, you try to bypass the liver. SGT-101, for example, is 1-2x liver de-targeting. Depending on the animal species, you saw it in the mouse, you saw it in the monkey, you can get higher in certain and other capsids. You want higher distribution, better distribution. You want faster binding capacity to the integrin receptors. All that will eliminate antibody response. It can eliminate complement activation.
It can, or at least reduce complement activation, reduce some of the liver injury cases that we see. All of this can be handled with delivery. It takes a lot of time and effort. To your point, to your final point, you go through all the animal studies and still unknown in humans. This is why in our Duchenne program, for example, we contemplated because we knew other companies were using triple immunosuppression. When you're using a new capsid, you think about it at the very beginning, like what's it going to look like? That's why we didn't use anything other than steroids at the beginning. Now we know that we don't need anything other than steroids, at least it looks like it. I was afraid if we use triple immunosuppression at the beginning, we would be like, oh, our drug is very safe.
Investors and analysts could say, is it the drug or is it the immunosuppression? I wouldn't be able to tell you. We feel very good now. We've dosed 15 boys with steroids only. I think we know what we see. It's been all released to date. That is the catch-22. We need better delivery tools. However, it does have to go in humans and you don't know what you have until you do it.
Okay, thank you. Moving on to the transgene part of the equation, dystrophin is obviously very complex and we're seeing several different approaches by companies. Can you discuss your particular approach with the NNOS binding domain and the hinges for protein flexibility?
Yeah, so you know your construct matters. I mean, we're taking a full-length dystrophin and we're shrinking it down to an engineered, you know, mini dystrophin variant. What you put in this variant really does matter. It's not full-length. You obviously want a flexible protein that can move and adjust as the body is, as the skeletal muscles are moving. You think about the hinges and making sure that you either remove hinges or only have the hinges that don't cause damage. We actually only have two hinges at the end, at the two actin binding domain C terminal. It just binds and the construct itself can move and adjust and be flexible with the skeletal muscle. There are other proteins that are very important.
We have R16, R17, and it turns out we believe that this is becoming more and more important as we do additional research on other proteins that actually recruit for even outside of NNOS. NNOS is very important when you think about oxidative stress. You know, all of us have it and it increases blood flow, decreases inflammation, decreases oxidative stress and fibrosis. In combination, it turns out in combination with other proteins like beta sarcoglycan, delta sarcoglycan, it can really have a profound impact on the heart and other muscles. The combination of all of this, where you have recruitment for alpha syntrophin, recruitment for NNOS, recruitment for CAVIN4, as well as increased production of full-length beta sarcoglycan, delta sarcoglycan, all of this tends to matter. What you put in your construct matters. We believe that we have the best protein.
One thing I've really appreciated from our conversations, Bo, is your belief that for manufacturing, you can't just look at yields, but you really need to appreciate the purity aspect. How does this ultimately impact both the safety and the efficacy of our candidate?
Yeah, so fundamentally, we believe purity trumps yields. I don't think a lot of companies look at it that way. They look at yields because COGS, you know, manufacturing is very expensive in gene therapy. Realistically, purity matters more. We take a very hard line at Solid to make sure that we have the best and the highest full-to-empty ratios out there. Why does it matter? For example, if I'm dosing you at VG- KG, if I'm dosing you at a 1E14 dose, but my full-to-empty capsids are really 50% full, realistically, I'm dosing you at 2E14. I'm putting a lot of pressure on your liver. I'm putting a lot of pressure on complement activation. I'm also probably decreasing efficacy. Why? Because the capsids don't know if they're full or empty. They're binding to the receptors. They're just looking for the targets.
If they get there first, then they can potentially block. We can show that in cell data. You can't really show it, it's going to be too hard to show it in human data, but in cell data, we can see that the full-to-empty ratio matters on expression. COGS should be the least of the concern when it comes to safety and efficacy. COGS matter because you're doubling up the dose as well. The total virion amount in the human body is important when you're thinking of gene therapy. Full-to-empty ratios really can drive a major difference. It's a bunch of little levers that we try to pull to create this sort of big impact. It's a better capsid with better distribution, a lower dose, and then a better promoter for specific tissues, and then a higher full-to-empty ratio so you can lower the overall virion dose in the body.
All of that, we believe, matters. This is how we need to think about gene therapy in general.
Okay, now that we have all this background information that we can appreciate, let's put it into context relative to what you've reported for your DMD candidate. First, on the safety aspect, what are you seeing? Knowing what we know about the construct, why do you think that's the case?
Yeah, so we've dosed 15 boys. We've announced we've dosed 15 boys. We're continuing to dose, and we're doing so very safely. To date, we've had zero SAEs, zero hospitalizations. We've never had to use eculizumab or sirolimus, IVIG. None of that's ever been used, just steroids. We do look for myocarditis. We look for drug-induced liver injury, and we haven't seen it to date. We have zero drug-induced liver injury, zero myocarditis, zero rhabdo, zero TMA, AHAS. We had one boy on a steroid taper. We put in our press release, had a grade one increase in liver enzymes on the taper. We start tapering our steroids at day 30, and by day 60, all the kids are off and back down to baseline steroids. He's the only one. One out of 15, it's about 93% have all been able to taper by day 60.
We think that matters because it's the overall steroid dose. It was a grade one. By the way, the kid was in camp the whole time, summer camp, having a good time. We disclosed it. That's all we've seen. We see nausea, vomiting, thrombocytopenia. The thrombocytopenia is immune-mediated thrombocytopenia. It lasts about four or five days from day six to day eight nadir, and by day 10, it's on the way back up. By day 14, it's over. We haven't seen any clinical manifestations of any of this. To date, it looks safe. I've dosed 15. Need to dose more, but it looks good right now.
Thank you. Switching gears to efficacy, I think the field has really debated microdystrophin expression based on mixed data we've seen from other gene therapies. You've always emphasized that the % of positive fibers may be even a more critical tool for understanding. Why is that?
Yeah, yeah. When you talk to a lot of the researchers, like Jeff Chamberlain and others, they'll talk about the importance of one fiber protecting the other. If you have a fiber that is positive, then it should provide some support and protection to the adjacent fiber. That gives you a guidepost of trying to get to close to one out of every two fibers, you have 40% or so. We believe that will confer clinical benefit over time. When we did our study, we took a very different approach of looking at muscle integrity and all the different biomarkers, not just for you guys, but really for us as well. This has been trying times in biotech, and you don't know where to put your money.
On our first three to six patients, I wanted to see the biological correlates to say something's going on inside the kid's body that cannot be coming from steroids alone. We took a holistic approach. We started with the vector genome copies per nucleus. We believe that if you can get above 2-3 , it's beneficial. 7-8 , even better. That really sets the stage for the next leg, which is your Western blot or mass spec. I don't really lean into the Western blot and mass spec as much as everybody else does. I think it's a good tool directionally. I think positive fibers are very important, looking at what's the positive fiber count. Then you need to quantify, okay, if you get dystrophin positive fibers, what is the percent positive for like beta sarc, delta sarc, alpha and gamma?
That tells you that the complex is coming together. Then you see NNOS production. You can look at biochemical correlates of muscle integrity. The acute phase is like ALT, AST, CK, lactate dehydrogenase. They're highly variable, but you can tie them to some of the chronic biomarkers such as TITAN or troponin in the heart. You get to this sort of muscle maturation phase where it's like embryonic mice and heavy chain. You want to see a slight decrease, so you know that the muscle is not undergoing constant repair. At that point, it gives you a lot of confidence when you see this cascade of events to say something's going on. You're definitely making an impact internally. Now it's about clinical trial design, making sure you have the right patient, the right endpoints, the right baseline criteria.
You go out far enough to get this benefit, and that's what we're doing now.
Okay. As we think about your next efficacy update, which will include more patients, are these the same key endpoints and measurements that you think we should carry the most weight at when assessing the?
Yeah, I think it's the totality of all the data. You know, back in the day, we always, you know, Western blot this, Western blot that. Realistically, I think it's all the data sort of pointing in a direction. You know, you are going to have variability in these measures. Instead of just saying, you know, oh, you didn't hit this, but you have seven other measures over here, but this one's low, it's really the totality of all of this. That's why we didn't just look at one. I think we looked at seven or eight different biomarkers and then three or four different histological data points. It's all of that combined that gives you a very robust picture of are you doing something, and hopefully that pans out. I mean, we're dosing a decent amount of kids, and by this time next year, yeah, we're in September.
By this time next year, I mean, we'll have a ton of data, a ton of data.
Okay. You've got to meet with the FDA next quarter. What data do you anticipate having on hand to share with them? What are your requests going to be on the regulatory path forward?
Yeah, we want to meet with the FDA in next quarter, and we want to share the data with them. We've been pretty quiet about the data. I actually don't have it, and we'll have it in the next quarter to give to the FDA. We want to just talk about the accelerated approval process and, you know, what is the path for accelerated approval? Realistically, we'll do what the FDA wants us to do. We have plenty of, we have 25 patients in the queue right now that are trying to get into the trial. They're in some phase of screening. I've already dosed 15. We have plenty of patients that we can enroll. If the FDA wants us to enroll 30, 40, 50 patients, it is not going to be a problem.
We have 25 in some form of screening right now, and on top of the 15 I've dosed. Just tell us the path that you want. We're asking for approval, accelerated approval path, similar to what RegenXx received, which is, you know, 30- 40 patients safety database, 10% median expression, you know, via Western blot or mass spec, whatever they choose, or dystrophin positive fibers, and directional clinical benefit compared to natural history. That natural history can be, we can look at, you know, very time-sensitive measures such as rise time, stride velocity, forced air climb, or we can look at cardiac function, ejection fraction. We can look at troponin. There's a lot of different things we can work with the FDA on. We just want a path. We think that this drug seems, as it today seems safe, looks like we're having a biochemical change.
Now we have to see if we can show clinical differences as well.
Okay, thank you. Switching gears now, I want to talk about CPVT, excuse me, and would encourage people to watch a short video on your website. It details the program. We get to hear from a family that has experienced this. First, this is an indication that most probably can't pronounce, let alone are familiar with. Could you please share with us a little bit about this disease, calcium's role in the heart muscles?
Yeah, yeah, it's called Catecholaminergic Polymorphic Ventricular Tachycardia. It's a very fatal disease that not many people know about. It gets misdiagnosed a lot. In epilepsy, HIV, a lot of kids end up dying because they get misdiagnosed. Average age of diagnosis is 7-12 . It's fatal for many. There's about 20,000 patients that should have this disease based off of the mutations that we're going after. We're going after RYR2 and CASQ2 mutations. Diagnosed, it's probably about 8,000- 9,000. When you take the cut of antibodies on top of that, it's about 7,000- 8,000 total patients that we'll be able to dose, like, you know, that are active, that are identified. Highly fatal. If there's one great thing about this disease, it's that we don't need to remodel the heart. This is arrhythmia, and it's all due to excess calcium and due to these mutations.
The excess calcium in the sarcoplasmic reticulum causes an arrhythmia when you have this shock and this adrenaline surge. That is what ultimately causes the arrhythmias. You're just trying to break the cycle. You don't even need a lot of this calcium question. You really need to soak up about 20%- 30% in our preclinical models to actually get to a level where you can dose and hopefully break the cycle.
Why don't you think there's been any success for this indication? It seems quite large for orphan.
No one's done what we're doing. There are other drugs that are, you know, small molecules that are coming at it from a different direction. We are the only company that is looking at absorbing the excess calcium during diastole. That should break. You don't, like I said, you don't, cardiomyocytes, you don't even have to get above 30% to sort of break the channel or the arrhythmia, at least in preclinical models. That's what we're shooting for. We'll just be looking for arrhythmias. I don't know. It's hard. The last drug was beta blockers and flecainide, 1990s. There's really no other drug out there for it. It's a huge opportunity. The KOLs are excited. The families are excited because this might be the first true disease-modifying drug.
Thank you. I will stick to saying CPVT for the time being.
It's hard. You should watch the video. If you have a chance, go to the website. Kids don't realize that they have it. Families are destroyed. The child that's on the website, his brother died at eight. He was like 15 or 16, the older brother, and he was rock climbing. He got to the top of it, looked down, had an adrenaline surge, went into arrhythmia, died, got revived, then got genetically tested and realized that his mother had it, his younger brother who died had it, and he died but was revived. This is what's happening. This is a big disease state that no one really knows about. It's very hard to say. You guys probably know this disease. There are a lot of kids that play soccer, basketball, etc., and they die on the pitch or on the court. It could be Catecholaminergic Polymorphic Ventricular Tachycardia.
Yeah. Okay. On Friedreich’s ataxia, why do we need therapies that target the root cause of the disease? How might that, coupled with the fact that you have a dual targeting approach, help with the differentiated clinical phenotypes that tend to present with this condition?
Yeah, we thought it was real important to treat all the manifestations of the disease. We could have actually had an IND open for the cardiac part of it years ago. When you talk to families, they'll say, "Listen, it's wonderful if you can fix the heart, but if you can't swallow or speak or have the ability to move, quality of life really does matter." We started working years ago on trying to get to the brain. It's very challenging without causing a tox event in the heart. You can go IV and push the dose up. You can get to the cerebellum, 5% of the non-human primates, but no more. You push the dose up and you're going to have frataxin overexpression. Same with IT. No matter how hard you try, you really can't get to the cerebellum.
The dual route administration allows you to elegantly get to the heart, the spinal column, and the cerebellum without causing frataxin overexpression. The doses are super, super low. You're talking E8, E9 in the brain. You're talking E11, E12 in the heart and spinal column. Your overall dose, because you're breaking up the route of administration and going right to where you need to go without trying to push the dose up, works great. We also believe that we, based on the preclinical models, the only, and because of the nature of the phenotype of FA, you don't have to get to, you don't have to push the dose up like, or frataxin expression up like Duchenne, like a dystrophin in Duchenne, 30% could be easily enough. Get to the cerebellum, change the progression of the disease, change the progression of the disease in the heart.
That's what we're shooting for. We're doing this MRI guided with utilizing gadolinium so we can see in real time if we're going to cover dentate nucleus and then IV immediately after. The whole procedure is a couple hours. It's about an hour. The prep is a little bit longer than the procedure for the CNS and to the dentate is about an hour. You rest the patient and then they do the IV. All within the same day. Same drug, different doses, same day.
Okay, thank you. What is your short and midterm goals as it relates to licensing your capsids, and how do you benefit from these deals
Yeah, so I'm taking a little bit different approach than others. Yes, we started off this entire conversation saying, you know, how do we make gene therapy investable again? I think it comes back to delivery, changing delivery for everybody. Why do little companies that enter in gene therapy with great ideas use AAV9 and AAV8, RH74? Because you have to. They can't afford the license for other new novel technologies. Therefore, we're never going to break the cycle of turning gene therapy into what I believe it can become. We provide our capsids to a lot of small companies for a nominal fee, but we do get royalty streams. We give it to academic labs. I think I'm looking at Nicole; she's my Head of IR because I can't remember what it was in the press release. It was like 25, 26 different licenses out there.
Our goal is to have somewhere between 30% and 50% of all cardiac and neuromuscular programs using a piece of our technology across the world in the next three to five years. If we do that, then we can elevate everybody. We can elevate all the small companies. We're going to elevate the academic labs. Those programs will make it into bigger hands. It all comes back to us, whether it's a royalty stream, milestones. I'm not focused on the upfront like some of the other companies are because I want to change all gene therapy. I understand the innovator's dilemma that we have when it comes to the cycle of how you have to make these tough decisions on whether to move a program forward or not. I'm adamant on giving our capsids and promoters and dual plasmids to as many people as possible.
Okay, thank you. To close, we'd love to know your financial situation and also if you have any other takeaways for our audience today.
We have cash into mid-2027. I think we announced somewhere right around $268 million, somewhere right around there at the last press release. We're not trying to raise money anytime soon, but we just want to head down. I think the company is a great little company. We're trying to do things that are unique, either build next-generation programs or unique programs like our FA and CPVT and TNNT2 programs. We have a lot of work to do. We know that and we're humble, but we're proud. It's 110 employees. We're doing a lot with what we have. Thank you very much for your attendance.
Thank you, Bo.
Yeah, thank you.
We're rooting for you.
Thank you.