All right, afternoon, everyone. Welcome back again. I'm Brian Skorney. I'm one of Baird's Senior Biotech Analysts. I'm really excited to have joining me to my right, Bo Cumbo, the President and CEO of Solid Biosciences. Bo and I go way back through a couple of companies that he's been at. Bo, maybe can you start by just giving us a brief introduction to the company, what technology you're focused on at Solid, and the current status of your key programs?
Yeah, first, thank you, Brian, and thank you, Baird, for the invitation. Yeah, Solid Biosciences is a precision genetic medicine company. We currently are in gene therapy. It doesn't mean that we'll always be just in gene therapy, but we focus primarily on neuromuscular and cardiac programs with a slight twist in the Friedreich’s ataxia program with some CNS. Most of our lead programs are with Duchenne muscular dystrophy, that's called SGT-003, followed by a Friedreich’s ataxia program, and then SGT-401, which is catecholaminergic polymorphic ventricular tachycardia. We also have SGT-601, a TNNT2 dilated cardiomyopathy that we're working on that is going through GLP toxicology right now.
Great. Maybe starting with DMD, which is your lead, there's been a lot of progress here, but also we were just talking before this is coming up here, a lot of controversy, especially over the past year in the therapeutic space. I mean, kind of review what this disease is, the current therapeutic options out there, and where you see SGT-003 trying to fit in.
Yeah, it's unfortunate that it's such a fatal and terrible disease. There's not a lot of choice. Kids either have, you know, some of the kids have excellent skipping therapies they can choose or steroids, and then there's one gene therapy program. We're trying to bring another next generation for Solid gene therapy program to the clinic. We're in the clinic too, but to the market and provide choice for the patients. So far today, we've dosed 15 young men, little boys, and all of them are doing very, very well. We're very happy about that. We have a lot more work to do, but we're just plugging away.
Great. Maybe talk a little bit about the structure of SGT-003, how you've sort of designed this to differentiate versus, you know, not only the approved gene therapy product, Elevidys, but some of the historical ones, Solid's old program, Pfizer's program, and what sort of makes this so unique and different?
Yeah, so we tore it apart from the beginning, and we changed up the capsid. The capsid is called this SLB-101 capsid. It is a modified version of AB9, has RGD peptides in a specific region of the capsid. Those RGD peptides really bind to integrin receptors on skeletal and cardiac muscle. In animal models, whether it's the mouse or the monkey, depending on what you're looking at, it can be delivered to targeting in both models. It can also change the biodistribution as well as expression in the diaphragm, the quad, the gastroc, et cetera. That capsid is quite unique. The construct itself, we pulled this Dr. Chamberlain's construct that has the R16, R17 binding domain, repeat domains. Those repeat domains actually recruit for a couple of different proteins that are unique to Solid, one of those of which are NNOS.
NNOS in combination with some of the beta sarx and delta sarx that we can upregulate really can help beneficial for the heart as well as skeletal muscle endurance, anti-inflammatory effects, et cetera. Very excited about that program. The CMC, we've changed up the CMC completely. The CMC platform that we use, suspension-based HEC-293, is light years away from the old program. We have a very high full-to-empty ratio. We think that the full-to-empty ratios really do matter. We try to stay very consistent in between 75% and 80% and have so to date. We're trying to get better. Our additional program, CPVT, is higher than that. It's in the high mid-80%. Our TNNT2 program is in the mid-90% or low 90%. We're trying to make enhancements on all the CMC. All of this combination, we talk a lot about internally, we talk about little levers making a big impact.
If you can make a big impact on or a little impact on biodistribution, a little impact on liver detargeting, a little impact on full-to-empty ratios, the combination is where we believe truly turns this into a very good program.
Great. We have clinical data now. There's a number of patients that you've treated. Walk through that clinical data. How much of that clinical data is really supporting sort of the thesis here? What would you kind of point to in terms of the biomarkers to reinforce?
Yeah, so we've dosed 15 patients to date. The data, when we released the data, we had had six patients of safety, and we had three patients of efficacy, expression, and some cardiac biomarkers. I'll focus in on that data because we have not released any additional data to date. We will down the road. The first three patients, we had to also not only convince investors, but we had to convince ourselves. We knew that there was a drug already on the market, and we had to make sure that we felt comfortable that we could, you know, at least meet or beat expectations with our drug and invest money. It started with expression. It really started with VG per nucleus. How many copies are we getting to the nucleus? We were shooting for three. We felt that three was a threshold that we really did want.
We achieved that and went much higher. Once we got to past VG per nucleus, we looked at expression, both mass spec and Western blot. Those numbers were decent numbers, which gave us confidence to take a look at the positive fibers. The positive fibers, we were always trying to shoot for right around that 40%. Why? Because we, you know, when we talk to some of the researchers, the researchers that really do the DMD research, one out of every two fibers, if you can get to one out of two fibers, it'll protect the adjacent fiber. That's what we were trying to shoot for. Once we understood our fiber count, we said, what does beta sarc look like? Beta sarc is highly localized in the heart. We knew that we were getting to the heart. We wanted to look at positive fiber count of beta sarc.
That was really, you know, enhanced as well. We looked at NNOS production. Finally, once we had all these ducks in a row, we wanted to look at muscle integrity. There's three different types of biomarkers we were looking at. The acute phase, ALT, AST, lactate dehydrogenase, CK, they can be highly variable. You tie those to chronic phase, like TITAN. TITAN only is in the blood or in the urine after the muscle's, you know, really torn apart and degenerating. You can combine those two and get a better picture. Finally, muscle maturation with embryonic myosin heavy chain. You really only see embryonic myosin heavy chain when the muscle is trying to repair. It's in a constant state of repair and depleting the satellite cells. We felt very good.
What we saw at the end is we saw what we had hoped to see, some slight signals in the heart. We saw ejection fraction changing. It was early days. It was only three patients. We saw troponin decreasing. We are actively enrolling patients that have elevated troponin. All these little boys have spikes of troponin, even at five, six, seven, because they're having the beginning stages of underlying cardiomyopathy. We also look for ejection fraction that's either in the hyperdynamic range, above 70%, 75%, 79%. If you can get a couple of those kids, can you bring them back down to normal? Kids that are slightly below normal, can you get them back up into the normal range? Hopefully we can see that over time. All of that gave us confidence to move forward with the trial. We dosed 15 kids.
We actually dosed more, but we haven't disclosed all the boys to date. Knock on wood, doing great. No SAEs, never used sirolimus, never used aclamazumab, never used IVIG, no rhabdo, no myocarditis, no AHAS, no TMA. To date, as I sit here with you, things are good.
Great. One of the things that really kind of brought out a lot of controversy is a couple of the liver-related deaths that have occurred in Elevidys on the commercial setting. Maybe help contextualize, and you did mention very clean safety profile, but how do you think about sort of the vector copy number, empty capsids, how much of an impact that can have on ALT, AST, overall dosing, and immunosuppression, and how you think this program could kind of fit in and avoid these safety issues?
Yeah, you know, we think about this a lot. Like I said, small levers can make a big difference. This is where just total virion load in the body can matter. You can decrease, relatively easy by a couple of different levers, one product to another, just by looking at viral load or virion load in the body over a quadrillion different virions. I think that will matter. This is why we focus on full-to-empty capsid ratios. This is why our dose is the lowest dose in gene therapy, 1E14. We don't plan on upping the dose. We believe we have the right dose. We'll have the lowest dose. We'll have one of the highest, if not the highest, full-to-empty capsid ratios in CMC. It was liver detargeting. The capsid was already liver detargeting in the preclinical models.
Obviously, we're not going to be doing liver biopsies, but we do look at ALT, AST right from the start. We look at, and we published our GGT data at a couple of different conferences, including the MDA and I think PPMD. All of this matters. To date, we had one boy that had a grade 1 liver enzyme bump. He was tapering. We taper very quickly our steroids. I don't know if many people know this. At day 30 post-dose of gene therapy, we start tapering. By day 60, all the kids are off. We've backed down to the normal range of Duchenne steroids. We've had 94% success to get down to just the DMD steroid base at day 60. The only case that we had was this little boy. He was in between the taper. He was at summer camp. He had a grade 1 liver enzyme spike.
They put him back up to the 2 mg/kg. Liver enzymes normalized. He stayed in camp the entire time. That's the only thing we've seen. To date, we hope that continues. We do know that this is AAV and that anything is possible. We feel, from a statistic standpoint, after dosing 15, you would see something. We haven't yet. It is AAV.
Right. You see, basically, one grade one. How well do you think that ultimately correlates with any sort of liver-related outcomes? Obviously, your call is part of Elevidys's selling point over other earlier generation ones, where we really didn't see major safety events until the commercial setting, where we started seeing deaths. Obviously, ALT, ASTs were on the rise.
Yeah, you know, you can look back. I look at all the studies. I look at all the clinical trials. I look at the package inserts and what's been published with the FDA and try to figure out how our program is matching up. You're never going to have apples to apples. I feel very comfortable right now dosing 15. I've never had a drug-induced liver injury, and that's defined by the 2009 FDA guidance. It's pretty black and white. As we sit here today, we're at zero, and we've dosed 15. You know, we can look back at other trials. We can look back at other data, see the % that are in those clinical trials. While it's not head-to-head, it gives us comfort to say, seems like this drug is pretty clean. Now, do we have to keep dosing? Of course.
I'm going to dose 30 to 40 patients. Goal is dose 20 by year end, 30 by end of Q1. I'm well on my way, if maybe slightly ahead of schedule there. We've dosed a pretty decent range of kids. Most of them are in the 5 to 10 range. I've probably dosed, we believe we've dosed one of the youngest, if not the youngest kid in microdiscipline. We haven't disclosed his age, but he's sub two. We have a decent range of patients. Every day, I'm getting more and more confident that I have a clean drug.
With all the data that you're generating, it seems very convincing that the next steps would be to sit down with the FDA and discuss a pivotal path forward. I guess, what design are you proposing? What metrics do you think you need to show to put forward a convincing pivotal package, particularly in the context of all the controversy of Elevidys's approval and the words that the current CBER director has had?
Yeah, I think it's a great question. At the beginning of the year, I wanted to, I believe that we could just go in with 10 patients and go in with 10 patients and show the difference and show our drug and then hopefully get a path to accelerated approval. I still hope that that is the case. Everything that's happened over the last year does give you a little bit of pause to say, do you need more? Do you need more patients? Do you need more time? That's OK because we've been dosing a lot of patients. We're thinking through that. Right now, we want to have the meeting in Q4 with the FDA.
One of the key things that we wanted internally, and you might have seen yesterday, is that before we had the meeting with the FDA, before I was going to sit down with the division, I wanted to be dosing, needle in the arm, dosing our double-blind, placebo-controlled trial that's going to be run in XUS. That was really important for us to get the trial up, but more importantly, to dose before we meet with the FDA. I haven't done that yet. Why is it important? I'm asking for, I'm going to be going in asking for accelerated approval. I believe that we should, there should be drug choices out there for the kids, for the families, for the KOLs. I understand that the FDA is going to want a confirmation study.
If I already have the double-blind, placebo-controlled trial up and running with kids dosed, they know that they're going to get that data. They know that it's well underway. I wanted to have that study underway. I've got it posted. We're working on the countries. That's given me a little bit of pause.
Yeah, so I did see that post. As we talked about before, I'm a big advocate for doing an RCT, particularly given some of the questions on Elevidys. Can you walk us through the design? How, you know, sort of went through the period with eteplirsen where a six-minute walk was the endpoint, then NSAA for the gene therapies? What are the important endpoints to look at here? How long of a follow-up period do you think you need to really demonstrate effects?
Yeah, so it's going to be obviously a multi-country, multi-site trial, double-blind, one-to-one, 80 patients. Time to rise will be the endpoint, basically looking at clinical, the 7, 8, 9, 10, 11-year-olds for the clinical endpoint of time to rise. Secondary endpoints, drive velocity, cardiac output, like ejection fraction. We'll also be looking at troponin levels over time because I do believe we're going to see a difference there based on what I'm seeing currently. That trial should be underway, should be dosing this quarter. Actually, sorry, I still think I'm in Q4. So Q4. I don't know, was there another part of the question there? Time to rise. I think we made a lot of, oh, it's 18 months. It's an 18-month endpoint. I think that all that really does matter because when you look at history, I think we selected the wrong age group, four, five, and six.
These kids are not normal, but they're developing at a pretty good clip. You only enrolled healthy kids because the baseline criteria to get off the floor was less than five seconds. So it was five, you know, really healthy five-year-olds. You chose an endpoint of NSAA, composite score. We got away from that. We're doing time to rise. Your fiber count, you really haven't even adjusted to the drug yet. Your trial's over 12 months. We extended it to 18 months. I think all of this increases the power or the chances of having a positive outcome. I want to get the drug everywhere. I don't want to just get the drug to the kids in the U.S. I really want to get this drug. I think it's very safe. It looks like it's going to be effective from what I can see.
I want to get it to everybody across the world. Reimbursement-wise, ex-U.S. is very important that I have a double-blind placebo control. I hit an endpoint so I can get reimbursement. I can also use that trial as a confirmation study for the United States and give the FDA confidence that you can lean in on accelerated approval, based off the surrogate market for clinical benefit. The safety is there. You're going to get the results from this phase three. That's why we did it.
Great. Before you took over as CEO of Solid Biosciences, you were CEO of a company called Avanti, which actually merged into Solid Biosciences. I remember we talked at that point. You guys were working on gene therapy with the Friedreich’s ataxia, which I'm really excited to see is now actually coming into the clinic finally. Walk us through a little bit about the FA program and how Solid Biosciences is trying to address this underlying disease with gene therapy.
Yeah, we felt we worked on this for a long time. We went through a lot of different animal models, unfortunately, a lot of non-human primate work as well. We wanted to make sure that when we brought a drug to the clinic and ultimately, hopefully, to the market one day, that we can address patients where they are in the disease. Meaning, if you have a 40-year-old that has just CNS or just cardiac manifestations, you have a drug for them. If you have a 20-year-old that has cardiac and CNS manifestations, we have a drug for them. If you have a four-year-old that's just diagnosed and you have no idea what her journey or his journey is going to be, we have a drug for them. We felt like it was very important to get to the heart, the spinal column, and the cerebellum.
We did a lot of work. We did a lot of animal work to understand levels that you need to get to the cerebellum. We couldn't make that work just via IV or IT or even dual-route administration there. We are doing dual-route administration direct to the dentate. It's a pressurized catheter approach with using gadolinium. We can really see in real time exactly how much we're covering of the dentate nucleus. We want to get to about 20% or 30%. We let the patient rest about a couple of hours, and then we do IV. The IV will get to the heart and the spinal column. We believe by this elegant design of dual-route administration, we can combat all the different manifestations of the disease and hopefully help patients out. Should be dosing Q4. Right now, we have two IRBs open, which I believe are UCLA and Ohio State.
Penn will be hopefully open soon. Those would be our three sites. We did a family event the other day. 300 families came. Really high, a lot of people want to get in the trial. We'll be dosing three patients at first, 18 and older, because that's what the FDA wanted, get safety. Then we'll move down into the age groups that we want to get to.
How do you think about solving for the right dose here? Since you're sort of doing two different doses, obviously, you're taking real-time gadolinium measurements of drug exposure. Ultimately, the goal is to produce for taxine, right? Are you taking measurements in different tissues?
You're just taking measurements in the heart, heart biopsy. We can dose, you know, upregulate the dose in the heart. In the cerebellum, it's not about pushing the dose. It's about the coverage of the dentate nucleus. We believe it's only needed 20% to 30%. You can increase the volume without increasing VGs, without increasing the viral load, just increase the volume for the coverage of the dentate nucleus. We don't believe you're going to have to do that based off the animal models because you don't need a lot. I think that's one thing that's quite surprising that when you're in FA, it's unlike Duchenne. You don't need a lot of for taxine before you start seeing a benefit. We can look at the dose in the heart, and in the cerebellum, it's more about volume and coverage.
OK. It's a small amount, but do you have a target profile in mind for cardiac biopsies? How much expression you want to see?
Yeah, you don't need much. You know, 15% to 30%, somewhere in there.
OK. Above normal or increase?
Increase.
OK.
Yeah.
You have a number of other programs moving into the clinic in the cardiovascular space that you've been talking about for a while, notably CPVT and dilated cardiomyopathy. Can you talk a little bit about the opportunities for these two and how the programs each seek to address the disease?
Yeah, CPVT, catecholaminergic polymorphic ventricular tachycardia. It's a mouthful, but basically, it's just arrhythmias. The great news about this disease state, I don't have to change the structure of the heart. It's just a signaling, it's due to excess calcium in the sarcoplasmic reticulum. As these kids have an adrenaline surge, their heart goes into, you know, this sort of arrhythmic state. You end up, you know, either they pass out or, unfortunately, they pass away. We're just trying to shut off that signal. We shut off that signal by increasing calsequestrin. By upregulating calsequestrin, you actually can turn off the signal. Once again, you actually don't need a lot. At least you don't in the animal models. Somewhere in that 20% to 30% range of excess calsequestrin will soak up enough calcium. When they do get this adrenaline surge, they don't go into VT.
The goal is we're going to dose Q4. We have sites open. We're going to have sites open in Canada as well as the U.S. and eventually, Europe. We're going to dose three patients. These are going to be adults. We're going to wait about six months, let the calsequestrin increase over time. Then we're going to put them on a treadmill and look for arrhythmias. This is how they get diagnosed. They get diagnosed by this Bruce stress test. We're going to do that to see the efficacy of the drug. Over time, we'll continue to go down in age. We'll also start taking medications off that they're on. They're either on, you know, beta blockers and flecainide with an ICD. Maybe we'll take off flecainide and see if we can continue to decrease arrhythmias.
If so, then this will be the first drug of its kind in this disease state in almost 30 years. I think the flecainide was in the 1990s as well as beta blockers. The community is really excited about it because there has not been a true precision genetic medicine company or drug that's in the space. Pretty excited about that too. When you think about like these three drugs that I have, you know, Duchenne is, I believe, is going to be a really next generation drug. FA is going to be a very unique drug, dual route of administration, treat all the manifestations of the disease. CPVT, only drug of its kind. We have another drug for TNNT2. It's in GLP tox right now as we speak. For TNNT2 dilated cardiomyopathy, there's about 27,000 patients there. Not a single drug on the market for that.
We are sitting here in a very unique spot with Solid. We have three, by the end of this year, we'll be dosing three different disease states, going into a phase three XUS for Duchenne. We are trying to figure out if we have enough cash for the dilated cardiomyopathy with TNNT2. It's probably one of the best cardiac programs we have, but we might need a partner for that one.
Which is a good segue into the last question, which is, can you kind of review the current balance sheet and the burn and any thoughts on, you know, public financing as the next step versus partnerships or non-dilutive financing?
Yeah, I think as of Q3, we had about $268 million that we announced. That takes us into the first half of 2027. We're not stumbling into 2027. That's fully loaded, and that's all the trials and everything included. Partnerships, yeah, you know, partnerships are beneficial. I also think that we can make this on our own right now. The drugs that we were working on are becoming more and more valuable. As I get more and more human data, I'll be in two other, you know, disease states very soon. The goal will be, if I have a partnership, it'll have to be the right partner. We do talk to companies all the time and to be determined on that.
Great. In the last couple of minutes here, is there anything that I didn't ask or we didn't discuss that you think investors in Solid or potential investors in Solid should know?
You know, I think what we're trying to accomplish at Solid is a little unique. We're not just creating therapies for ourselves that you see in the clinic. We fundamentally believe that to change gene therapy, you need to change delivery. What does that mean? I think it's three flavors. It's capsids, it's promoters, and it's manufacturing. We need to get away from first-generation tools. If we can generate new capsids, novel capsids that are liver detargeting or very specialized for skeletal or cardiac muscle or other targets, new promoters that really drive expression right to the target, and manufacturing purity. I know yields are very important, but if you can get to that 90% level, I think all of this will make gene therapy investable again. What we're doing is we're getting all these drugs, all these tools out to companies all over the place.
Any small company that wants novel tools, capsids, promoters, help with manufacturing purity, we're pretty much giving it to them in many cases with royalties on the back end. Otherwise, they can't afford these new capsids. Therefore, what do they end up with? They end up with RH74, AAV9, et cetera, AAV8. You guys don't want to invest in them because they're using old technology. We're trying to lift the entire market up. We are actively creating new tools for our own programs. I don't want them just to sit on the shelf. We have 26 different collaborations right now. I think it's actually more now, but as of the last press release, it was like 26. Our goal is to get to 100. I believe at that point, then the majority of programs, gene therapy programs will have Solid inside, meaning promoters, capsids, manufacturing.
Hopefully, it can lift the entire gene therapy space over time. That will make you guys want to invest in these little companies because I don't think we should just give up on gene therapy.
I agree 100%. I hope you do it. Thanks for the time today, Bo.
Thank you.
It was a pleasure.
Thank you.