Solid Biosciences Inc. (SLDB) Earnings Call Transcript & Summary

Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. It's with great pleasure that I'd like to welcome the Solid Bio team. We've got Bo Cumbo and Gabe Brooks joining us today. And we're going to do a fireside chat format. So for those who are new to the story, maybe give a brief intro to Solid, your key programs and platform.

Yes. Thank you, Maury. I appreciate the invitation. Solid Biosciences, we're a precision genetic medicine company. We have 3 drugs we're primarily focused on at the moment: one, Duchenne muscular dystrophy; second is Friedreich's ataxia; and third is CPVT, catecholaminergic polymorphic ventricular tachycardia. We should -- we're very hopeful that we will have 3 drugs in the clinic by year-end. We've already have, obviously, one drug, our 003 drug. for Duchenne muscular dystrophy, we've been dosing for about a year now. And our FA program, we'll be dosing our first patient in Q4. And we'll be filing CPVT IND this quarter and on track for that. So we also have Capsid Library that we work on, but we also make more than capsids. We plan on trying to change delivery for not just solid, but for all small companies and academics that are doing gene therapy. So we create capsids, promoters, buffers, dual plasmids, all second-generation-third-generation delivery tools to enhance gene therapy for a host of different programs. And our goal is to have 40 different academic labs or small companies in our network by year-end. We're already at 19, and we have a handful more that we're working on now. And the goal is increase -- put solid inside in all the constructs in the near future. So very excited about it.

Got it. Yes, it's a great intro. And you mentioned your DMD program that's been ongoing for about a year now. Patient demand for that has been high for the study. Maybe talk about enrollment strategy, where you want to be by the end of this year with enrollment and bookend scenarios for closing the time line gap with one of your competitors, REGENX.

Yes. I'll start, and I'll kick it over to Gabriel, Dr. Brooks. Demand is high, and we've been very fortunate to have a lot of people want to get into the trial, not only pre-data, but post data and very excited. We haven't announced how many patients we've dosed. The last public statement was 7, and we've continued to dose additional patients. Public statements, we would dose 20 patients by year-end. We're well on track to do that and 30 patients by the end of Q1 next year. But very excited about the program. REGENX is, I think, the program you're talking about catching up to competitor. They had about 1.5 years on us. I think the IND approval, I think, in January '23, somewhere right around there. And -- but we're catching up very quickly because Dr. Brooks and the operational excellence that we have. So Gabriel?

Yes, Maury, and I'll take that in a slightly different direction, which as you said, I believe you asked about what our strategy was for recruitment and enrollment. And as Bo is indicating, we are in a good position to be kind of overwhelmed with demand. And that allow -- as we are thinking about that cohort of 20 participants, we want to be able to have the most informative data set to inform our successful BLA with the FDA. And so we have been students of DMD and the first-generation therapies that have gone forth, the fordadistrogene and ELEVIDYS that -- as we know in the Phase III clinical trials were negative. We've learned from that, and we've tailored our inclusion/exclusion criteria to try to maximize our probability of success by showing where we're going to be able to see discriminate functional benefit. So what that means is when we think about the demand we're facing in those 20 participants, we are favoring certain age groups so that we can have the best probability of ultimate success in terms of being able to demonstrate functional improvement for the BLA submission next year.

Got it. That's helpful. And we'll definitely talk more about just the types of patients you're enrolling. I wanted to also touch on just the regulatory path where there's been debate on whether your DMD program can still get alignment with FDA for accelerated approval in the U.S. based on a single-arm study with natural history data as a comparator. Wondering what feedback you've gotten from FDA, especially with new leadership there on the pivotal path?

I'll just start at the beginning, and then I'll kick it over to Dr. Brooks. Well, one, we were meeting with the FDA in the fall. So we have not aligned with the FDA yet because we have not met with them. I think the public information that we've provided that we will be requesting a meeting with the FDA in late summer, early fall. It's a 60-day time from request to time to meeting. And then it's 30 days after time of meeting to time of minutes in hand. So that's about a quarter. Yes, it is a quarter. And so that's going to be Q4. So your interaction question is going to happen in Q4. We do have a lot of other meetings on CMC and et cetera, and Dr. Brooks can talk about that. They've been very responsive. And so I don't know, anything else to add?

Yes, Maury, I think -- outside of that, having that direct interaction with the FDA and coming back to you to sharing with you our learnings, which we're looking forward to doing in Q4. What can we say? We can say that this is probably the most propitious time for this drug to come to the FDA. Why? Because the guidance had changed on confirmatory trials in January. So now instead of having to have a fully enrolled Phase III, you have to just have started your Phase III. Guess what? We're on our way to doing that. Then the public statements...

Before, right?

And public statements we've been -- we've seen from Makary and Prasad actually are even leaning in what we see is that they're leaning in even more to saying it's important to approve drugs to allow patients to have choices, especially if you're seeing incremental benefit. This is what we hope the direction the agency would go and what we're seeing just from the public statements is aligned with that.

There's still a high unmet need in Duchenne. I mean the kids are still declining [indiscernible] that's curing everything. There's a lot of unmet need in Duchenne. And as long as there's unmet need, I think the agency is going to look to find choices for families, not just in gene therapy, but exon skipping and everywhere else. And so I fundamentally believe that I think the -- you can hear the agency even yesterday, the statements that they made at [indiscernible] about incremental changes, should get approved to help people make a choice -- have choices. I think that's fundamentally what's going to happen in Duchenne until it's cured. And until then, there's an unmet need, and we've got to keep pushing as an industry to try to make second-generation, third-generation, fourth-generation drugs that keep moving that needle to help these kids.

And not only is there unmet need, I think the current -- we're seeing now the limitations of the currently approved drugs in terms of the toxicity that we've seen commercially, which I think we knew from the label that there was hepatotoxicity, but I think having choices for medicines that may be able to avoid these liabilities are going to be really important for the agency.

Got it. And for this meeting, you mentioned you want to have about 10 to 12 patients with sufficient follow-up data to go into the meeting. Was that specifically requested by FDA? Or do you think it's going to be -- this is going to be a sufficient look at the data and allow you to align?

I think it's the latter, and I'll turn it to Dr. Brooks. I think it's the latter. We picked the 10 to 12 because we wanted 90 days' worth of data for a minimum of 10 to 12 patients. And that way, we can have a robust discussion. Actually, we'll have more data than that because he's going to continue to dose patients, but that will fall in the safety bucket. So there will be additional safety data, but -- as we get to the meeting. But we feel 10 to 12 patients, and it's just -- we haven't disclosed how many patients we've dosed, but we're just ticking away time.

I'll go on a limb here. Look, when we saw the first cohort of boys, that first 3 patients, and the data was so extraordinary and so differentiated than anybody had ever seen from an expression, a consistency and now safety standpoint. There was a question, should we just go to the agency now? But we knew that to have the most informative discussion, we would need to show consistency, show a larger database. And so our decision was, let's wait until we have around a dozen patients so that we can go -- participants so that we can go to the agency and have a more informative discussion. I think that will be more fruitful for everybody, for them and for us.

Got it. And with REGENX, they are helpful in the situation because they've got an alignment on a pivotal study showing greater than 10% microdystrophin at 12 weeks in 30 patients. Do you still think this alignment is a reasonable expectation for your pivotal design? Any additional perspective there?

I think, look, I would find it shocking if they treated one company different than they treated the other. They've made public statements as well that they're not going to go back and change guidance for other companies. I don't think that they're going to also change guidance for another Duchenne company. So that's a long-winded way of saying I believe it's going to be consistent.

Got it. And Dr. Brooks?

Yes. Look, far be it from us to speak for the agency. They're going to have their opinion. We're going to speak with them. I don't want to get out ahead of that. But I think that what they had agreed or what REGENX had shared was the alignment was reasonable.

Look, I think our safety database is holding up. The kids look great. We do track some biomarkers. The biomarkers are still heading in the right direction on all fronts. We look at things like troponin, troponin continues to go down because a lot of these kids have elevated troponin at baseline. Even the little ones, even 5 years of age, you see spikes in troponin; 10 years of age, most of the kids, half the kids have some underlying cardiomyopathy. We're seeing all the signals that we saw early are continuing. And I think that's going to play out. Hopefully, when the FDA -- when we have the conversation with the FDA that they're going to see that there's benefit and it looks very safe.

Got it. And so the wheels are in motion for the study and for enrollment, especially potentially getting to 30 patients by the end of first quarter of next year. And so -- but if everything aligns with the conversation with FDA, theoretically, you could be -- could have pivotal data by the middle of next year and could potentially be filing by second half of next year. Is that the right way to think about the time lines there?

We're not going to set time lines, but I think directionally, you are correct.

Okay. Got it. Helpful. And how important is the early biochemical data for CK, LDH and also the liver enzymes to the regulators since there's no guidance around these biomarkers, but they could translate to future functional benefit?

So I think -- so this clearly paints a very full picture because we are looking comprehensively at muscle injury and muscle integrity when we talk about titin and muscle preservation when we talk about embryonic myosin heavy chain. And in terms of if you want to say a validated surrogate endpoint, there isn't. I mean, for a biomarker besides renal failure and creatinine, there isn't a lot out there. But this is a comprehensive picture of muscle integrity, muscle -- reduction of muscle injury and muscle preservation. And so I think that in their entirety, they paint a very compelling picture. I think embryonic myosin heavy chain, frankly, has an enhanced value because it's really showing very objectively muscle preservation, and we're very interested in that biomarker. We're also very interested in titin, which shows muscle integrity. And so we are working hard to try to figure out how we can elevate those biomarkers to be able to help demonstrate again this holistic picture of how SGT-003 is impacting these muscles and leading to muscle preservation.

Yes, I'll take another approach. Look, we showed a very comprehensive data set, not just for you guys, but also for us. There was a big question about microdystrophin. Does it work because of the past trials? And so if we're going to go on this journey with children, we want to know, do we have a shot for this drug to work. So we looked at it from the beginning of dosing all the way to activity. And so we started with vector genome copies, and we have the highest vector genome copies per nucleus. That's a great start, but can you produce expression in dystrophin. So we looked at dystrophin from not only Western blot, but mass spec. Some people like Western blot, some people like mass spec. So we gave you both, and it's the highest expression. But that's just expression. What happens at the fiber count? So we need to look at the fibers. We fundamentally believe you've got to get to at least 50% of the fibers to where you're going to show clinical benefit long term. We're at 80%. And that's at the intermediate biopsy. But we know the fiber count goes up over time. All right. We didn't stop there. We said, okay, now is the entire complex coming together. And I believe we're the only ones that ever showed like positive fiber count for the complex coming together for [indiscernible] and that was 70%. Next step, iNOS activity. iNOS activity should be able to increase blood flow, decrease inflammation and hopefully help in multiple other ways. We could show that. Then that led to, okay, are you seeing activity for the muscles because we have all this expression, but is the muscle integrity shoring up because this is a muscle disease. We looked at acute biomarkers. We looked at chronic biomarkers. The acute ones fluctuate a lot, chronic ones don't. So you can look at titin. It doesn't bounce around like that, and you can tie them back together. Both were decreasing. Then you look at muscle fiber maturation, which Dr. Brooks is talking about the embryonic myosin heavy chain. And then you have titin, troponin, you have ejection fraction. All of this said, we are showing activity in the muscle down to the muscle fiber and it's shoring up. So now it's about clinical trial design and the strategic -- how we can strategically think about that and what do we change? Well, we changed the age. So we're not looking at 4-, 5- and 6-year olds that are increasing in development. We're looking at a little bit older patient population. We'll have all these other patients in there for safety and expression, but we're focused in. Rise time, we changed the rise time. So it's not healthy kids, less than [ 5 seconds ], a little bit sicker. We changed up NSAA. So it's not a blunt instrument. It's very specific, stride velocity, time to rise, et cetera. And then we're going out 18 months. All of this, we believe, gives us the best possible chance for victory long term, and it's going to give the best chance for these kids.

Got it. All helpful. And probably not entirely relevant to your strategy as it stands now. But when REGENX has their pivotal data second quarter of next year, I guess, how will that inform what you're doing? And maybe talk a little bit more about the different patient populations between your study and REGENX study?

Well, we don't know what their data is going to look like. I'm rooting for them, rooting for the children. We'll see. I think they're releasing data tomorrow. It will be good to see. So I don't know how to answer that because I don't know what they're going to show.

Ultimately, I think -- there's 2 innovators here. So I think we had Sarepta, ELEVIDYS and fordadistrogene first-generation capsids, they had the microdystrophin transgene that it had and modest effect. So the innovation, I think, REGENX and our hats off to them again, is to say, well, we need a higher dose to get better transduction. And using that first-generation wild-type capsids, we need to have more profound immune suppression. And so that's the innovation as the immune suppression, which thus far, we see has been tolerated, which is good news for those boys. We took an entirely different approach, and we said, look, we need to, yes, use the best microdystrophin that is able to reconstitute the dystrophin-associated protein complex. So that's that microdystrophin-5. But our innovation was to how can we make a capsid target where it needs to go, skeletal and cardiac muscle and avoid the liver using just prednisone. So we don't have to use eculizumab and Soliris and expose kids to that immune suppression. And so that's exactly what we've done, and we've been so grateful by the data, which has demonstrated really a delivery on the hypothesis. GGT, a measure of hepatic injury, completely flat. AST-ALT, we're not talking about, "Oh, there's spikes in AST and ALT and that's liver injury." We're actually seeing AST and ALT coming down because that's a muscle -- that's actually released from muscle when it's injured. And because we believe we're showing up the muscle, we're seeing it coming down. And so with REGENX, let's say they get approved, there's still a lot of need left. One is a potent delivery, a potent gene therapy that doesn't require Soliris or sirolimus. And so that's a safety advantage if we can provide that for these boys, plus we'll see how there -- as Bo says, we'll see how the data pans out, and we're looking forward to seeing that.

Got it. And in your first 3 patients, you showed great data there, and you're going to have data fourth quarter of this year. How are you setting expectations for how the data is going to look in the fourth quarter?

Yes. We're not discussing the expectation. Look, we were very pleased with the data. It was consistent. I think directionally, it was consistent. We're going to continue to look for a directional consistent change in all the different -- from expression to vector genome copies to dystrophin-sarcoglycan complex coming together to biomarkers. If we just can see consistency, that's what's important because we know there's going to be fluctuation in patients. The consistency of the data is really important to us.

Maury, we have been cranking away dosing patients. I think -- negative news is really good news. We're sitting here saying steroids alone, just fine for this gene therapy. We're getting into now a number of patients where we can feel more confident that we haven't seen those adverse events of special interest like myocarditis or TMA, aHUS or anything like that. You would expect by now, if you've dosed so many patients, you would see a signal. So we're feeling more confident. I mean, anything can happen, of course, but we're feeling more confident about from a safety standpoint. And I think the biomarkers, I would love to share with what we're seeing, the biomarkers, but we're encouraged that when we flip the card on that microdystrophin expression, we're -- that it will be -- continue to be consistent.

Got it. And just to clarify, when you have the data update, will you also have the regulatory update around it?

Yes, that's exactly right.

Yes. And that's why we're not going to disclose anything until we have the meeting with the FDA. And that's why I was telling you it's basically a quarter because it's 60 days between time of request to time of meeting, 30 days from time of meeting to time of minutes. I'll talk to the Board after that, and then we'll share the data and the message.

Got it. Okay. And maybe quickly just talk about the plan for the ex U.S. randomized double-blind controlled study. When do you plan to start that? And what could be the size and scope of that?

I'm going to kick it to him in a second, but it's Q4, and we'll have that up and running. Ironically, this is going to help us a great deal in the United States. Our goal -- Dr. Brooks and my goal is to get this drug to every child available globally, which means that we had -- in some countries, we had to do a double-blind placebo-controlled trial, hit a p-value so we can get reimbursement in France, Spain, et cetera. Ironically, we started working on that trial a while back. We'll have that trial up and running at the end of the year. However, it is going to help us dramatically with the FDA, especially with the change of guidance that Dr. Brooks talked about. So as Dr. Brooks is talking to the FDA about accelerated approval in the United States, he can look at them in the eyes and say, we'll be dosing patients in a confirmatory study, double-blind, placebo-controlled ex U.S. study in a month or 2. And so it's really going to help us out a great deal. And I think that that's a big positive for us. Dr. Brooks?

When we look at the learnings from the first-generation therapies, and we talked about how we needed to go back and innovate. REGENX innovated with their immune regimen. We're innovating with a new innovative capsid and new product. That's the biologic innovation. When we look at Cifirio from Pfizer and EMBARK from Sarepta, and we look at those Phase III study designs, we learned a lot. They were both negative trials. There was no benefit for either therapy. But there were hypotheses that were generated that were consistent. And when we went back and we looked at the large natural history databases with our partnerships with those investigators, those were confirmed. That means when you ask about what about the Phase III study design, what does it look like? We have refined the patient populations to find where we believe we're going to be able to see to discriminate -- to discern a difference in placebo versus treatment, looking at the right length of time of follow-up in the right number of patients with better endpoints. So not NSAA, but time to rise, looking at a longer time point, 18 months as opposed to 12. The end, I'm not going to share. But all of those things, Maury, I honestly believe if we took fordadistrogene movaparvovec, I think it's modestly effective. I think ELEVIDYS is modestly effective. I think if we use that in the correct refined study design, we would have wins. Now we have a much more potent product. By every measure, we believe that our probability of success for the Phase III is very high.

Got it. And maybe just clarifying for that ex U.S. study, do you have buy-in from ex U.S. regulators at this point? Or is that something you still have to do?

We still have to work on that, yes.

We're working.

Got it. And maybe talk about -- you talked a little bit about safety already for the program. And maybe just talk about that and how you think that could help differentiate versus some of the other players?

Yes. Look, we look at safety very carefully. Everything that we have seen that we shared with you guys on the first 6 patients, we're seeing it's very consistent, looks great. And Dr. Brooks already talked about ALT, AST, GGT, it's all going down. GGT is flat, ALT, AST goes down. And so it looks very clean. I need to knock on wood and hope it continues. We're going to be continuing to dose patients for the rest of the year. So everything looks good right now.

Yes. And from a differentiation standpoint, coming to the FDA, I think we have a remarkable story here to share that for another product for accelerated approval, you need to see either safety or efficacy improvements. And here, we can come and say, this is differentiated from -- frankly, any AAV gene therapy at a high dose where we're not seeing any liver impact at all. Right now, patients and families are struggling with having to go back into the hospital after being dosed. We know that there's liver enzyme elevations that's in the label. So I think this is -- this prospect is very positive to be able to come back to the agency to say, here is another drug that physicians can have in their armamentarium that may liberate them from this safety concern. And then also that requires prednisone, doesn't require a REMS, doesn't require involving other people outside of the neurologists in terms of the treatment team.

Got it. And one of the things you've shown a little bit of data on is potential for redosing. Wondering if you could just talk a little bit about that and how you could potentially proactively address redosing strategies?

Yes. This capsid is different, and we noticed it early. And it gives us a lot of hope that redosing in Duchenne is going to happen eventually. I think the easier bar is the antibody positive kids first and then you go for the redosing. We're already speaking with multiple firms on IdeS and FcRns to combine with our approach. This capsid is unique. We saw it in mice. We're like, "Oh, that's interesting." You're not seeing neutralizing antibodies. So you dose with rh74, you wait 30 days, you look at the neutralizing antibodies, you didn't see in the mice. You go, "Oh, it's just a mouse." So then we did it in nonhuman primates, same thing. You dose with rh74, you wait 30 days, you look for neutralizing antibodies to the capsid, you didn't see it. So we took human serum samples from patients, 3 patients that had been dosed with ELEVIDYS and different time points from 6 months to multiple years. And you saw the titer levels in the 5,000 to 7,000 range, which is great because that means that you can use an IdeS or an FcRn or plasmapheresis or a combination, get to a certain threshold, dose, transduce, express. This capsid is also very unique because you're going to be lowering antibodies down to a threshold, but you're going to have a window to dose and transduce. We can dose and transduce at 4 days and get 50% to 75% expression in the mouse. This capsid because of the RGD peptides, it's binding capacity and its transduction speed is so quick that you don't need a long window to dose, transduce and express. So now we're working with multiple firms on this approach. We're doing all the animal work this year. We'll do the animal work next year. We'll speak to the FDA sometime next year on this approach. And in the meantime, we're going to be filing -- going to talk to the FDA this year on accelerated approval, start the confirmatory trial. Everybody is going to be focused on that. Meanwhile, in the back, we're like that duck in the water, where you can't see your feet moving on redosing, but it's going pretty quick, and we're going to have multiple firms supporting us. A lot of KOLs want to help us, too. So I can't promise anything, but this capsid does look like it's the only one that could potentially redose.

Got it. Interesting. And you've got unique capabilities with capsid development that's in-house. Maybe talk about some of the potential there and whether something on the BD front could come up with your capsids over the next couple of years?

Yes. Look, we're building all the tools. So it's not just capsids. We have capsids, promoters, dual plasmids. The dual plasmid, by the way, changes a drug dramatically from a full [indiscernible] ratio. I mean our TNNT2 program, when this dual plasmid is incorporated, it goes all the way up to like 92%, 93% full. It's amazing, yields through the roof. We also have buffers. And we're getting these capsids out to all the academic labs, all the small companies. It's a running joke, make gene therapy great again and you start with delivery tools. And for all the investors, I want you guys to be able to invest in company X, company Y, and they cannot -- we don't want them using first-generation capsids. We don't want them using rh74, AAV9, AAV8. You want them using new capsids, new promoters, new plasmids. So we're giving them out to a lot of academic labs. We have 19 now. I think we have 14 in the works. Our goal is 40 to 50 by the year-end. And then in a couple of years, we want the majority of skeletal and cardiac muscle programs to have solid inside. And that way, we're getting long-term royalties. All the companies are getting new tools, second generation, third generation. You guys can invest in multiple gene therapy companies who feel better about expression, better about safety, et cetera.

Absolutely. Yes, Maury, just -- I know we're over, but it's -- when these tragedies occur with the -- in Danon or with ELEVIDYS, it's bad for the entire -- it's bad for all of us. So if we can get away from first-generation capsids to the -- to a safer, highly potent muscle capsid, that benefits everybody. Nobody should be using rh74, AAV8, AAV9 in this day and age when SLB-101 is more potent and seems to have a safer [indiscernible].

But it's going to take time to get all these capsids out there.

Got it. All really helpful. And we're pretty much out of time. Maybe -- and we didn't talk about Friedreich's ataxia or CPVT. Maybe just comment on like the key points investors need to know there and...

Okay. Really quick. The Friedreich's ataxia program, so getting into the clinic this year, precision guidance to the exact substructure and the cerebellum that we need to sub-millimeter targeting. So very compelling and then CPVT also in the clinic this year with endpoints that can be, we believe, a pathway to registration from the beginning. So these are very exciting programs and look forward to discussing with you later.

Great. Bo, Gabe, thanks so much for joining us today.

Thank you. Bye-bye.

Thank you.