Welcome, everyone, to the Piper Sandler Healthcare Conference. My name is Biren Amin. I'm the Managing Director here at Piper Sandler. I'd like to welcome our next company. We have Solid Biosciences, and I'd like to introduce Kevin Tan, their Chief Financial Officer, as well as Gabriel Brooks, their Chief Medical Officer. So welcome, gentlemen. Thank you, Biren. Great to be here. Yeah. And so I guess maybe just start us off with, provide us an overview of Solid's pipeline. You're clearly working on SGT-003 as your lead asset, but then you've got a number of opportunities earlier stage, so maybe talk about the focus there as well. Sure. We're a precision molecular genetic company focused on neuromuscular and cardiovascular diseases. And as you've mentioned, we're in the clinic with next-generation gene therapy for Duchenne muscular dystrophy and really gratified to see so far a very safe story. We're continuing to dose on the back of that, and we're looking to actually come to share some of the early biomarker data of the muscle biopsies and some of the markers of muscle integrity in kind of mid-Q1 next year. And then we're still also interested, and we have a long and enduring interest in Friedreich's ataxia, and we continue to have a lot of interest there. So that's certainly in our pipeline. And then on the cardiovascular side, it's really an exciting time for us. We believe a really novel approach to catecholaminergic polymorphic ventricular tachycardia, an inherited arrhythmia syndrome that really, its manifestations are lethal arrhythmias starting at age seven. A fairly large patient population we believe is heavily underdiagnosed, and current standard of care therapy still leaves patients with the threat of life-threatening ventricular arrhythmia and burdened with a lot of side effects from the current medicines. Behind that, we have a really robust and dynamic pipeline, including thin filament disease, TNNT2, BAG3, RBM20, and really pleased to share, yesterday we announced the definitive license agreement with the Mayo Clinic. They have a platform technology Sup-Rep to be able to go after diseases that heretofore we couldn't drug with gene therapy, and they have a proven track record of being able to bring this technology forward from a scientific standpoint. So this is really a beautiful collaboration between really leading science and translational and clinical execution. So I mean, congratulations on that collaboration with Mayo. I guess maybe just on that, what attracted you to that platform as a Sup-Rep platform? Can you talk a little bit about that and what you're hoping to achieve with that? Absolutely. So if we think of AAV gene therapy being able to deliver and transduce with proteins that are only effective if there's an absence of that protein, that does limit the technology. And with the idea of Sup-Rep, we can then think about gain of function mutations and other mutations where really we need to silence the pathogenic protein and then replace it with what would be fit for purpose for that biology. So that really does open the door for a whole host of cardiac indications that, as I mentioned, heretofore until now, we haven't really been able to propose a therapy, and this is what we believe we can do. Great. And then as far as the lead pipeline program, SGT-003, this gene therapy for Duchenne muscular dystrophy, there are also other gene therapy programs either in development or that have been approved. How does SGT-003 compare to some of those programs? Absolutely. So with Solid Biosciences' first foray into this space, we really learned about a lot of limitations of first-generation gene therapy. And that is we learned that we really need to be potent in the transduction of the target tissue. And so that really led us to the proposition of, can we develop more tropic vectors? The other issue is that we believe that we need very pure products, so a very high full-to-empty ratio, why, because not only does that reduce the exposure to excess antigens, but we actually have seen that if you increase the full-to-empty ratio, you actually are able to more potently transduce the muscle. You're not blocking those receptors. And so those are the critical components, in addition to what we believe is the best construct, because it avoids some of the liabilities of product out there and the inclusion of the Hinge 2 region, which we think can lead to muscle takedown, teardown. The last thing you want to do when you transduce a muscle cell is to actually promote that muscle cell's teardown. We want to preserve that muscle cell that we've worked so hard to transduce. And so avoidance of that liability of that Hinge 2 region is really critical. And the construct that we're using does avoid that. And then compensatory vasodilation is a really important just normal pathophysiology or normal biology of muscle. When we use our muscles, we need those muscle cells need more oxygen. They need more glucose. So you need to have a compensatory vasodilation. This is a critical component of dystrophin. This is a piece that we have in our construct, and we're able to show that, yes, when we transduce cells, we can localize nNOS, which makes the nitric oxide to the appropriate place in the cell, and it is active. So we're very confident that we're proposing to these boys, to their families, a biology that more recapitulates dystrophin than other options out there. So from a construct design standpoint, something that's potentially more effective and safer as well compared to at least ELEVIDYS, and then we'll see what REGENXBIO shows, I guess. And I think another piece here is coming to the clinic with a novel capsid. We made a very important choice, which was to we know that we need to address the immune system coming in with virus. And this is a novel capsid. We're actually here as a company really the only company to have dosed at a high dose a novel capsid and thus far seen safety. And this is a huge achievement. And we've done this with steroids alone. And that's important because if we committed early to use and we had no reason to use other immunomodulatory agents based on our preclinical package. The GLP toxicology package was very reassuring. And so we came to the clinic with steroids alone. If we had to use rituximab or Soliris or other things like that, that would expose the boys to more immune suppression. And certainly using things that have a REMS means that it's very difficult to actually organize the sites around getting the appropriately trained personnel. And from a commercialization standpoint, having a REMS as part of your package, needing to use Soliris, we feel would have limited the availability of the drug to patients. And what we all want in this community is for all of these boys to have the best possible chance of stabilization of their muscle. So the program's currently in a phase I trial, right, called INSPIRE Duchenne trial. So currently, I think as of last update, you've had three patients, correct, that have been safely dosed. When should we expect the next update? That's right. So we dosed our third brave young boy at the end of September. The normal time of the biopsy would be at the end of December, but just because of the calendar, we're likely going to have that biopsy a little later, and then in terms of the timing of processing and everything, puts it again kind of in that early Q1 period. Got it. And then, so that in the early Q1 period, we would have efficacy data from the three patients. That's right. And that package of efficacy data is really biomarker data. And I think that's important. I'm just going to dwell on that for a second, because what we're going to be able to see or what we're really looking forward to seeing is, have we gotten the virus there? Are we seeing the microdystrophin? We're expecting to see robust microdystrophin, percent positive fibers, microdystrophin expression, and NOS. And then biomarkers of muscle integrity. So we want to look at the blood and say, are we seeing less muscle breakdown? And that's not just CK, but there are other biomarkers that we can look at to say, is the metabolism of the muscle improved? Is the integrity of the muscle shoring up? This is something that we are going to be looking for as reassurance as we continue. Things that are really not going to be that informative are things like functional tests, like time to rise and other things at three months, especially when the boys have been on a boost of steroids, very, very hard to interpret. So I just want to make sure that we set the expectation appropriately. We're really looking at, are we hitting our target, and are we seeing the pharmacodynamic effect that we would expect would be reassuring? Right. And then I think on dystrophin expression, it's a pretty well-accepted biomarker across the field as well as among the investor community. What should we be looking at as far as improvement? I mean, there is, I think, patient to patient, there's some variability that we see. What's considered to be, from a company standpoint, an encouraging outcome where you know, okay, directionally, you're heading in the right path? So one way to think about this is if we see 20%-30% microdystrophin fiber positivity, that's really saying that you're supporting that muscle because you're able, there is an effect of the neighboring cell. And so that would be, I think, the minimum that we would want to see. And percent positive fibers, I think, are probably the most informative. And the reason why I say that is we've seen a lot of variability from company to company in terms of what baselines look like, whether or not you're using tandem MS or Western blot. These are all they give data, but the comparability, even Western blot to Western blot of data, is tough to understand when you don't really understand exactly what those methods are. Percent positive fibers are really our north star, and that's what we'll be looking to. Again, to answer your question, that kind of minimally acceptable, we're thinking around a third. Got it. And then I guess from a functional data standpoint, I know it's not going to be Q1. You need longer follow-up. What does that look like? How much follow-up would you need before you'd start to disclose some of that data? Is it like 12 months, or is it longer than that? So there's two questions there, if I could. Oh, of course. One question is, how much time would we want to see? What we've learned, again, in this field from, I think, those first-generation programs, CIFFREO, EMBARK, is that you start to see microdystrophin expression plateau at 52 weeks, sometime between three months and 52 weeks. We're not exactly sure when it plateaus. We have a drug, and we want to see what is the clinical effect of that drug. You really need to see that full pharmacodynamic expression, right? 52 weeks is likely not the right time. Even if we look at a corollary, if we look at the remarkable success of givinostat in terms of from a regulatory standpoint, if they had looked at 12 months, it would have been a failure. You need time for the biology to sort itself out so that you can start to see a discrimination between not dosed and dosed. For givinostat, now we have something like microdystrophin. Maybe we'll see if it has more efficacy. We'll just have to see that. But certainly, 52 weeks is likely not enough time. 18 months, I think, for seeing the full effect is what we would like to see. Now, the question about when we feel we have a package that's reassuring, we're going to have microdystrophin at one year, for sure. We're going to have microdystrophin at three months. When we feel we're going to have a package that in totality is enough to come to regulators, that's something that we're working through. We're certainly interested in engaging the agency, and thus far, they've been very amenable to having discussions with us. So the phase I trial, you recently expanded the trial protocol where expansion of sites as well as age cohorts. Talk a little bit about the rationale there. So that's first question. And second is, when do you go to FDA? Is it after you have a substantial number of patients in the phase I trial, maybe some timelines around that as well? Absolutely. So we're thrilled to really be ramping up this study. Thus far, we've really been in sentinel dosing where we've had to dose, wait for safety, talk to the DSMB. Each of those conversations have gone very well to proceed without any really major modifications of the protocol. So that's great. So we're emerging from sentinel dosing. At the same time, we've gotten a lot of interest in partner sites. We now have six active sites in the United States. Sorry, six active sites, one in Canada. The rest in the United States, very highly engaged sites with lots of patients that are very interested in our study. And so we're, and the reason why is really twofold. One, we're, of course, very interested in working with these sites, but we've been really seeing a lot of demand to be part of this story. So that's really the site expansion. We have, as you noted on clinical trials, said that we're expanding this trial to 40 patients and have increased the age range to less than 12. And that's because we're dedicated to looking at this SGT-003 in patients that are a little older, maybe more predictable in the declining phase of ambulation, which is important to look at signals. In terms of when we're going to go to the FDA to discuss, it's really helpful for them if we're coming to them with data. And so what I hopefully am laying the groundwork is we've been methodical dosing these first three patients. We're expecting to see an acceleration of the dosing. And then that will need to have enough time, three months, certainly biopsy data, safety data. We would like to see some efficacy data before we come to the agency to really have a fulsome discussion about the pathway forward. The discussions that REGENXBIO has had with the agency, I think, are really important and helpful and really, I think, validate our opinion and that of Peter Marks explicitly, that accelerated approval is definitely on the table for microdystrophin and that having clinical data that one can correlate with that microdystrophin data is important. That's exactly what we're looking for as well. And so this is in the ambulatory setting. What are your thoughts on potentially testing in non-ambulatory? Do you want more patient experience in the ambulatory before you go to older patients? So we want to meet these boys where they are because there are lots of non-ambulatory boys that have not had access to these studies. And so we absolutely are dedicated to looking at the safety and efficacy of SGT-003 in older boys greater than 12, ambulatory and non-ambulatory, as well as younger than four. Why are we so focused on ambulatory? Because as a steward of this biology of this drug, we really need to look to see where we're going to have the richest data set. And right now, the signal of ambulation is the one that is the richest in terms of looking for an effect. And so that's why we're focused on that group. And we are very much focused on looking at the younger boys. We have some thoughts about promising technology that can help us look at functional changes in those younger boys. And then certainly, there are established markers in the older boys that are important in terms of upper limb function and pulmonary. One piece that's really important is cardiac. As we know, as we said, there's another side of the house here of Solid Biosciences, which is emerging as a nexus of cardiac development. Sorry, development in the cardiac space. Don't forget that Duchenne has a cardiomyopathy. We are very focused on that. We're looking at cardiac safety all the time here. We're really eager to see, does the expression of microdystrophin lead to potential benefit? We don't know, but this is something that we're very focused on. Got it. And then I guess on the capsid that's being used with this program, it's an engineered novel capsid. How does it compare to some of the other standard capsids, like AAV9, for example? Yeah. So it's engineered. It's a rationally designed capsid to actually bind to specific integrins, which we haven't disclosed, on muscle to transduce. And we see at least fivefold increase in transduction of muscle cells. And those are skeletal muscle cells. What's really also quite compelling is that we're able to hit the diaphragm and see robust expression in the diaphragm. And again, these fold changes are, in comparison to AAV9, a capsid that is already somewhat muscle-tropic and certainly cardiac-tropic. So we're seeing much more robust expression, transduction and expression in skeletal muscle, including the diaphragm, the heart. And then we do see about a twofold decrease in liver targeting. So it is somewhat liver de-targeting. So those critical pieces mean that when we are dosing those boys, we're getting more of what we put into their bodies to the target organ, the skeletal muscle. That's great, so potentially, again, leading to a superior clinical profile. Absolutely. And from an efficacy standpoint, and we hope, and we have to always look to see what the data tells us. But by having less of this virus in the system, especially being exposed to the liver, where certainly the liver is hugely important in immunology, that we hope to see less of an immune response. Another really important piece of this virus, which we discovered, is through these modifications, we see expression happen early. So we start to see expression happening at two to four days. And I come from a platform AAV background at 4D Molecular Therapeutics. And certainly, I've been in this space for a number of years. And it's really compelling to see the expression so, so early. Now, what does that mean? I have to say, we're not exactly sure, but it's tantalizing that potentially transducing and expressing so early means that those viruses aren't available to neutralizing antibodies that the body's going to make in the first place, and then also, when we think about coming into patients that have natural immunity or redosing, and we know we're going to have to immunosuppress them. The quicker that we can transduce and express means the less we need to have that profound immune suppression when we do these more difficult tasks of trying to go after patients that have natural immunity or have been exposed to viruses. This is something that we're focused on. I think the field is focused on it, and we think this is a huge opportunity, and this could be a tool. The fact that we can get in there and express so quickly, this could be a tool that's important for solving that riddle. That's great. I guess I also want to pivot maybe to the second pipeline program, SGT-501. This is gene therapy for a cardiac condition called CPVT. I think there's plans to file IND next year. Talk about that program and the potential there. I think the potential is enormous, so SGT-501 is targeting catecholaminergic polymorphic ventricular tachycardia and inherited arrhythmia syndrome, and the entire disease is in the name, and catechols just mean adrenaline, and VT, ventricular tachycardia, in these folks, it's a bidirectional VT, which is inherently unstable and really leads to sudden cardiac death, and we know that the natural history of CPVT is 50% mortality in 10 years. Clearly, the medicines that are being used today have suppressed that, and those are high-dose beta-blockers, nonspecific beta-blockers, as well as a sodium channel blocker called flecainide. But those patients still face an unacceptably high level of breakthroughs, and those breakthroughs are life-threatening ventricular arrhythmias, so starting at age seven, these folks are walking down the street, and then they will just go down, and hopefully, they'll be revived, but that could be a fatal event. And so with the prospect of a durable protection that we hope to bring with 501, this can really liberate those patients from the specter of those life-threatening ventricular arrhythmia events, also liberate them from some of the side effects of the high-dose beta-blockers that can have a pretty severe impact on their lives. And also, some of these folks have implantable cardioverter defibrillators that can have what's called VT storm, which is when you have an event, the device does its job. It delivers a shock, which every patient. I'm a cardiologist, they all say the same thing. It's like they read the book. It feels like I got kicked in the chest by a horse. And when that happens, you have more adrenaline. That causes your heart to go into the rhythm again. You have a shock. And you have what's called VT storm, where you have a shock, shock, shock until hopefully you get out of it. Or sometimes what happens is the battery dies, and you're left in VT. And so this is unacceptable that anybody has to face this. And so this type of therapy, we hope, will liberate the patients from these events, liberate these patients from these medicines, and liberate these patients from the liability of potentially having that horrific event. And it's a very different concept for a cardiomyopathy as opposed to we've seen, I think, remarkable progress with Rocket and Danon. This disease, Danon is a fatal disease. And they have made a lot of progress in terms of thinking about and negotiating with the agency for reduction in mass and improvement of symptoms. But this pathway is one where we can look at arrhythmia using an exercise stress test in a matter of months, something that we believe is going to be directly translatable into a surrogate of survival. Also, liberating patients from these medicines will make them feel better, make them perform better on the stress test. So the regulatory pathway here is really, I think, quite compelling. And we're looking forward to getting into patients. And just one important thing to note is when you think about Danon and CPVT, I mean, CPVT is 10 to 15 times the population of Danon. It's just a much, much it's an incredible opportunity that hasn't seen medical innovation in decades, really. So we're really excited about this program. So phase I next year. And then we'll see data maybe by year-end or into 2026. So exciting progress. I know we're out of time, but we'd like to thank you gentlemen for coming to Piper Sandler Healthcare Conference. And looking forward to more interactions. Thank you so much. Thanks for having us. Thanks.