Good morning. I'm Geulah Livshits, a biotech analyst at Chardan, and it's now my pleasure to introduce our next guest. We have Bo Cumbo, our President and CEO, and Dr. Gabriel Brooks, CMO of Solid Biosciences. Thank you both for joining us today. The format for this session is a fireside chat, and this audience is likely somewhat familiar, at least with Solid, but to bring us to the same page, can you maybe give us a snapshot of where Solid is as a company now and flag the recent key milestones and upcoming catalysts, and then we'll dive in more?
Yeah. First, thank you, Gula, and thank you, Chardan, for the invitation. Solid Biosciences is a precision genetic medicine company focused really on neuromuscular and cardiac diseases. We are primarily focused on gene therapy at the moment, and our main lead programs, our top lead programs are our next generation Duchenne muscular dystrophy program, as well as CPVT, catecholaminergic polymorphic ventricular tachycardia program. That'll be IND first half of next year, which is coming up relatively quick, followed by multiple other programs, mainly the cardiac or neuromuscular space, TNNT2, both dilated hypertrophic cardiomyopathies, as well as BAG3, as, and then FA. So that's where we are at now.
We've focused a lot of time and effort on delivery, and delivery for us really means, you know, sort of three flavors, capsids, promoters, and actually the manufacturing, the full-to-empty ratio specifically on our manufacturing process. We spend a lot of time on capsids as well as our manufacturing platform. We have our own capsid library for our internal programs, and then we spend a heavy amount of time on our process and even make our own equipment to create what we believe is the highest full-to-empty ratio of any gene therapy company out there.
Mm-hmm. Great. So you've guided to reporting some initial data on SGT-003 in Duchenne later this year. I believe so, to maybe frame expectations for the readout, can you first walk us through how that trial is designed, and talk about, for example, the patient eligibility, the regimens that you're using, etc.?
Yeah, I'm gonna touch on some few points at the beginning, and then I'm gonna turn over to Dr. Brooks on the clinical trial design eligibility, but first, you know, we've already guided that we will be dosing this year. We dosed our first patient in Q2 as and we hit guidance. Second patient was on Q3, and it went very well. We were very pleased from a safety standpoint of how the dosing went. No SAEs, no thrombocytopenia of any grade, no GGT elevations, bilirubin, no troponin elevation.
So we're very pleased. First child was 20 kilos, second child was 26 kilos. You saw nausea, vomiting, which you typically do with gene therapy, but outside of that, they did very, very well. We announced that we'll be dosing our third patient by the end of this month. We're gonna hit that target. I'm not saying whether we dosed or not, but we're definitely gonna hit that target. We hit guidance there. You asked about timelines of data rollout. We've made it clear that our guidance currently is we will announce data at the end of the year, but most of the investors want us to wait for that third patient.
If you just do rough math, obviously, we dosed, we're gonna dose in September, based on our guidance, and if you just do math on a 90-day biopsy, and then about four to six weeks to actually get the data from the tissue, that puts it into early Q1. Most of the investors want us to wait for that third patient, and so we have not changed our guidance. If we want two patients, it'll be the end of the year. If we want three, it'll be early Q1. So that's more to come on that. But I'll turn it over to Dr. Brooks on the clinical trial design and what we're gonna release at the end of the day, you know, when we've released two to three patients.
Yeah, absolutely. So in brief, you know, our initial study design was really focused on safety. And so we had two cohorts of boys, four and five and six and seven-year-olds, which we've launched, and, you know, as Beau has alluded, we're really grateful or gratified to see that the very benign safety profile that we saw in our non-human primate for our GLP toxicology seems to be recapitulated in the clinical experience with a very benign safety profile so far, which is fantastic, not only for SGT-003, but also for this novel muscle-tropic capsid that had never really been in man before, so that de-risks, you know, we hope that that's very promising not only for the Duchenne program, but also for the other programs that can leverage that capsid.
Having seen the changing regulatory landscape and the opportunities that provides, we've actually gone ahead, and we've altered our study design now for a more meaningful study from a clinical standpoint, and as you can see, if you look at our clinicaltrials.gov posting, we're now opening up a much larger study, leveraging now this current study to look at boys that are a little older, more predictably in the declining phase of the ambulation, looking a little longer, but ultimately, what the message is being conveyed is that we are now aggressively moving from initial safety, which we're accruing, to a more meaningful clinical design, which I think will be the best way to accelerate getting this drug into the armamentarium of the physicians who so desperately need it.
I mean, we've expanded pretty dramatically. We have three additional sites coming on in the US and in Q3. I say Q3, actually, one of the sites came online last week, Craig McDonald at UC Davis. And he's already quarantined off drug for, you know, because he's signing up patients. And then we have CTA filed in the Canada and approved. Site opening up Q4 in Canada. We filed the CTA in both U.K. as well as Italy. So Francesco Muntoni and Eugenio Mercuri come online first half of next year. We just did an ad board two or three weeks ago, 12 or so physicians, all from Europe, Germany, France, Nordics, Spain, so we'll build out all of that. All that's part of the clinical trial design.
So we're gonna have a very broad group of physicians, the best physicians, to fill these sites, to fill these trials. So, we're pretty excited about all that.
Mm-hmm, so maybe staying on that theme, can you share how that has been going with respect to demand and screening and site activation?
Yeah. Absolutely. So, you know, we're until this point, heretofore, we've really been in this sequential enrollment period during sentinel dosing, as really mandated by the by the agency for understandable reasons. We're, we're thrilled to be emerging from that so that we can dose in parallel. But to answer your to address the question that you had is, what are you experiencing from the community? Is we're experiencing a lot of enthusiasm in terms of families coming to us wanting to, you know, be considered for potential participation in this study. We're also seeing that as Beau is alluding from a lot of interest for from sites. And so why is that? I think that, you know, the microdystrophin that we have has been recognized within the community as really being advantageous.
So finally, we're kind of coming to the clinic with this, the what promises to be the best-in-class microdystrophin, which is what we want for these boys. That we're already seeing safety, I think, you know, and we hope to see that accrue over time. We have to be cautious, of course. But that's really exciting for the community. And then, I think, you know, the community has seen, you know, what the clinical trials have shown for the currently marketed therapy, and I think there's a desire for something better.
It's interesting when you think about the age groups that we were initially dosing, sort of the four to five, six to seven. I mean, that was right in the heart of the other company that I used to work for. You know, that was the heart of their approvals, right? You would think it would be hard to recruit. I mean, those are the spots that we filled fastest, was the four to fives.
Interesting.
At this point, it's very hard to say, while we're in the sentinel dosing, to say no, which unfortunately, we've really had to hold off. But now that we can do parallel dosing, we can accept those very brave boys for participating in a clinical study.
Well, that's great. So maybe coming back to the planned readout that you'll have, either at the end of the year, Q1, or whenever it ends up being, can you expand a little bit on the type of metrics that you'll plan to be reporting and how we should think about that?
Absolutely. So you know, we're investigating the biochemical effect of this drug. Obviously, the microdystrophin expression is really critical, so we're looking at how many percentage of fibers are positive, of course. We're looking at measuring the protein levels in multiple orthogonal methods, so certainly Western blot, but also the tandem mass spec as well. Yes, we'll have biochemical markers of disease modification in terms of hopefully, you know, we'll see that the CK is coming down and other markers of muscle integrity, so we'll be looking at that as well.
If we think about functional measures, and we wanna see, you know, what are you gonna see in the first twelve weeks in terms of functional measures, this particular patient population is probably the most difficult to look at that because they're boys that are gaining skills at the same time as the disease is having an effect on them. So with three patients, you know, I think we have to just, you know, we'll see what we see, but in terms of really making any clear judgments about efficacy, it's way too early. This is why we are so aggressive in pivoting, even now, into looking at a more meaningful study, a larger patient population in an older age group, where we believe the ability to discern a treatment effect is gonna be far more, it's a far more tractable task.
Yeah, when you think about Duchenne, just now, we're just getting down into, like, natural history, you think about Duchenne, fours and fives are increasing, the six is no man's land. You don't know what's gonna happen to six, seven, you start to plateau, but it's a and decline, but it's a rolling hill of decline. It's not like a complete drop-off. And so what we wanna do, and these kids have been ravaged with this disease from day one, so we want to give them time. We want to get to the population that's sort of plateauing to declining. That's gonna be the seven to elevens.
We want to go out eighteen months because you're asking a drug to overcome a disease that's been ravaging the body since birth, in twelve months. We're extending it to eighteen months to increase the power. Our rise time, our baseline criteria, if you select for five seconds or less, like other companies have, you're only selecting for the best and the most healthy patients, and already in a very challenging timeframe and disease state and age.
So we've modified that to get, you know, a little bit, a better population, you know, more on the decline so we can show a benefit. And then we got rid of the primary endpoint of this, you know, NSAA, where people are really subjectively guessing at zero, one, two. You throw that on top of everything I also just mentioned. Our endpoints will not only be safety and expression, but then also endpoints like rise time, stride velocity, 18-month trial with a patient population that's declining. It's a really strategic trial. We listened to the KOLs, all the KOLs, the real thought leaders, Dr. Eugenio Mercuri, Dr. Francesco Muntoni, Craig McDonald, helped us design this trial in a very strategic manner, and I think that's going to play out for us in the long run.
Yeah. I mean, not only do these boys need, deserve a next generation gene therapy, but also they deserve a more thoughtful clinical study design and so we've really, you know, looked at the negative studies so far, studied them, and talked to, as Beau has alluded the key experts here.
That makes sense, and I guess the expectation is that that type of trial design will be appropriate for all the different age groups that you'll be looking at.
We'll have safety. we'll have fours and fives. We'll have six and sevens added for the safety a nd then, we're also looking at both the younger and older populations, so we can build that safety database, but the clinical endpoints will be based on a population and a time frame and the endpoints that are appropriate.
Any other thoughts regarding how you're approaching the regulatory path here, again, in the context of the evolving regulatory landscape here?
We believe that accelerated approval is on the table. I think Dr. Marks has actually stated this publicly as well, and we do speak with the agency one way, shape, or form. But you know, we believe that accelerated approval is gonna be on the table as long as you can show safety database with significant amount of microdystrophin expression, whether it's dystrophin-positive fibers, etc., and then directional benefit compared to natural history in the United States. Ironically, ex-US coming from a commercial individual, ex-US is a very different animal. You can get accelerated, you can get a conditional approval or approval, but if you don't have a p-value in your secondary trial or your or your registrational trial, it's very challenging to get reimbursement. You know, the reimbursement authorities are very different in the U.S.
They give you a rating, and based on that rating, you get reimbursement. You know, you really have to hit your phase II and phase III to get reimbursement. There's two hundred and eighty thousand kids, ex-U.S., that are going to decline, if not worse, unless we get something to them. So we are building a trial appropriate for ex-U.S. as well. That'll be double-blind placebo-controlled trial, the same design as the U.S., except ex-U.S. will be placebo-controlled. United States for accelerated approval will be based off of natural history and and microdystrophin expression. So when the agency in the United States hopefully gives us accelerated approval based on our data, that I'm hoping happens then we can say also we have a double-blind placebo-controlled trial going ex-U.S.
For ex-US authorities, the EMA, etc., we're gonna do what's right. I believe that we will hit the endpoint of over time because of the trial design, and we'll go from there. And that's how, you know, hundreds of thousands of kids that need a drug.
Mm-hmm. Great. So, I mean, on the topic of endpoints, so we did see pivotal phase III trials missing the endpoints in this space, although we've seen some promising data from other companies such as REGENXBIO. Again, what are you hearing from KOLs? And we kind of touched on this earlier regarding the demand for this new wave of gene therapies, yourselves and others included in this space, including a number of non-viral approaches that have been emerging.
I'm going to turn it over to Dr. Brooks next. I think it's very interesting when you watch what's happening in Duchenne. Now we're able to fill our trial. We had about three times the demand than we actually had drug for our trial. REGENXBIO is clearly filling their trial. Avidity, Wave, Dyne, they're all filling their trials. I think a lot of families and KOLs are wanting that next-generation drug. I think we all are striving for the day that we can truly change the disease dramatically, and we haven't done so yet. We're all working. I think the families are very educated. The KOLs are very educated. They're looking for these drugs. That's why we have the demand that we have, but I'll turn it over to you.
Yeah. So I think maybe just touching on an earlier topic, which is, you know, the landscape, the regulatory landscape and the overlap of what that means in the clinic. You know, my hat's off to Sarepta in terms of, you know, really pushing the agency to go to a place that we all needed them to go to, which is a little bit more flexibility in terms of how they are thinking about the totality of the data set that they're being faced with. However, that's in the setting of two negative trials.
You know, I think that those negative trials we all see that. I think the parents and the patients see that, and to be able to come to the community with a more thoughtful study design that will deliver a more clinically meaningful benefit for the drug is going to be compelling, again, and not only to the regulators, but also to the community.
And on the topic of kind of the differentiation from the oligotherapies, obviously, a one-time gene therapy is going to be a one-time approach. Or, you know, how do you think about kind of the competitive landscape in that dimension?
Yeah, well, one. I personally, this is just, you know, my personal thought. I don't think a gene therapy is going to end up being one and done. I think it is one and done right now. But the technologies are moving relatively quick for the degraders, right? The FcRns, IdeS, plasmapheresis combination. You know, you're already seeing some companies look at antibody positive kids that have not been dosed on gene therapy and have a lower antibodies. And there's not even primary data out there. It looks pretty good. So I think, you know, ironically, Duchenne in five, seven years is gonna open completely back up.
But in the next five to seven years, you know, we're stuck with this one and done. But realistically, you look at SMA, you look at Duchenne, there's a lot of combination therapy that's going on. Right now, it's really, really on exon 51, 45, 53 in combination with gene therapies. But a lot of the KOLs see this because of the nature of the drugs right now, they see it as combination therapy. Until we can truly, quote-unquote, cure the disease, you're gonna see combination therapy play out. And the payers are gonna have to reckon with this, but I think that is gonna be a reality where the KOLs go. And then the world is gonna catch up to how you can redose gene therapy, and then that opens up the disease state all again, so for gene therapies, but.
Yeah, I think that this space and how these patients are managed is really variable depending on the physician that you speak with. Some folks are talking about, you know, using exon skippers to temporize while you get to what you know could be a more definitive gene therapy. I, you know, can it be combination therapy? I think we're in a bit of a data-free zone. I think we need to learn. We're not quite there yet.
Great. And then to jump to something entirely different, where are you guys with manufacturing for this expanded trial and the expanded kind of view that you have now in this space?
Yeah, so because of the confidence I had on the first two young men, we pulled forward our manufacturing. Thousands of liters are being produced as we speak. We're at a 1,000 scale of manufacturing capability now. We could easily go to 2,000, but there's really no need. We can just do multiple 1,000 runs. We're pulling them all forward so we can fill the trial. We announced, I think last week or two weeks ago, it hit clinicaltrials.gov, the new clinical trial, and it's 43 patients. So we're making all the material for those patients, and we're also gonna be making the material for the double-blind placebo control trial that's gonna happen ex-U.S.
And so all that is taking place, and, in our runway, which we already have runway into 2026, and all that's built in, so I'm very excited. It's a very pure drug, too. I think that's important. You know, I don't know what other companies state from a full-to-empty ratio, but you know, batch to batch, 77% is the lowest, 81% is the highest. Those are true full capsids, and that's important for three different reasons. One, from a safety standpoint, I dose you at a vg/kg standpoint, right? But if I'm at 1E14 vg/kg , dosing you 1E14 vg/kg , 50% true full, realistically, I got to dose you at 2E14 vg/kg . I'm gonna potentially impact the liver, potentially complement activation or safety issues. I've also doubled my COGS.
The other thing that we don't really talk about in gene therapy is these capsids don't know whether they're full, empty, partial. They're just doing their job, and they hit these receptor sites, and they block. And so if you get a partial or an empty and it blocks a full, your efficacy go down. We can show you, and it's actually on my slide deck, it's cell data, but it shows you in a very linear fashion, as you increase your fulls, your full ratio, your efficacy goes up, your transduction goes up.
Makes sense.
And it makes sense, right? 'Cause they're just attacking the receptor site. So Duchenne, 77%-81% true fulls. Our CPVT program, we've even made bigger advancements, we're 90+% true full. I think it's industry leading on both accounts, ironically. I, but no one will tell me because everyone, no one talks about full to empty ratios. I think it's the most important thing in gene therapy, period.
Great. So you brought up CPVT. I did want to touch on it briefly. Can you give us the highlights?
I'm gonna let him speak. He's the, he's the expert in the space. It's unbelievable opportunity, though. Let me talk, it's unbelievable, the commercial guy's coming out me. CPVT, seven to 12 years of age, you get diagnosed, 40% mortality. There hasn't been a change in this disease state since 2009, which was flecainide. Before that was the 1990s with beta blockers. This is the only precision genetic medicine drug that I know of that can really change the course of the disease if the KOLs are static.
So, CPVT, catecholaminergic polymorphic ventricular tachycardia. Basically, it's adrenaline-mediated, arrhythmia that presents as, life-threatening ventricular events. So, with exercise or emotion, we usually find it's when patients are faced with bidirectional VT that can deteriorate into, a non-pulsatile rhythm. And, as Bo alludes, there are medicines that are used. Unfortunately, the breakthrough rate is fairly high, you know even patients that are on dual therapies. And so really the prospect for patients of a gene therapy is to provide durable, a durable protection of those patients, so that, you know, noncompliance is not an issue, you know, or just the ineffectivity of their oral medicines.
And, you know, what we see in our preclinical models, this is very very reassuring and very encouraging in terms of a potential approach that can really eliminate the incidence of these arrhythmias. In the preclinical models, we use extremely strong stimulants of the adrenergic receptor. So really a promising drug, and from a clinical standpoint, a clinical development standpoint, very promising because our endpoints are arrhythmia, which are provocable by exercise stress tests which is how we manage patients in the clinic. So we can look to see, you know, the effect of this medicine really through a quite elegant test, which is a standard Bruce protocol.
No competition in the space for what we are trying to accomplish. There's, you know, 20,000 patients in the United States for RYR2 and CASQ2, and you know, even commercially speaking, once you do all the cuts, you're talking the size of Duchenne.
Great. So in the last 20 seconds, what are folks missing about Solid?
I don't know, because there's a lot of really good things out there. I think, you know, Solid had a tough past, but we've turned the page on that, and I think it's a bright future, looking not only at Duchenne, but at all the different pipeline programs, very strategically placed. I think, take another look at it and you know, decide for yourself.
Sounds good. All right, well, that brings us to the end of this session. I'd like to thank you both for the great discussion.