One of the biotech analysts at Jefferies. I'd like to welcome the CEO of Solid Biosciences, Bo Cumbo, and Gabe Brooks, the CMO of Solid. Thank you b oth for joining us today.
Yeah, thank you for the invite.
And we're going to do fireside chat format. So maybe to start off, Bo, if you want to give a one-minute intro to Solid for those who may not be familiar with the company.
Yeah, very exciting little precision genetic medicine company. We focus on neuromuscular and cardiac health. We have a couple of drugs that are progressing through our pipeline very nicely. One that's in the clinic already, next-generation Duchenne drug, microdystrophin called SGT-003. That drug is already in the clinic. We've already dosed three patients safely and very excited about that. Our next therapeutic that's coming up is for CPVT, Catecholaminergic Polymorphic Ventricular Tachycardia, a mouthful, but a fatal disease that definitely needs some attention, and we should have an IND submitted in the first half of 2025, and then we have three other programs that are sort of neck and neck, working its way through BAG3, TNNT2, mainly focused on cardiomyopathies, as well as capsid pipeline, capsid library that's ongoing as well, so exciting little company and more to come.
Got it. Yeah, it's a great intro. And you mentioned the three patients dosed and the safety disclosure there where everything looks good. Maybe talk about your approach with 003, including the AAV capsid manufacturing process and product and anything notable you're doing with risk mitigation relative to your prior 001 study and other competitor gene therapy programs out there.
Yeah, I'll tell you what, I'll give a quick overview on the program itself, and then I'll turn it over to Dr. Brooks to talk about the clinical trial design and to cover it all. So we're very excited about the next-gen programs called 003. It uses a novel capsid called SLB101. It has a peptide insertion in AAV for integrating receptors and skeletal muscle. It's supposed to get greater distribution as well as hopefully better expression long term as well. We do see very fast transduction speed, which is going to help not only in the early days as we're dosing patients, but as we think further down the road when we think about redosing or dosing patients that are antibody positive.
We also have a very unique manufacturing process where we have a very high full-to-empty ratio, 80% to greater than 80% true fulls, and we're very excited about that. Currently, we use a triple transfection, but we're moving toward dual plasmid down the road for some of our other programs. We spend a lot of time on this, and the trial's been ongoing. We've already dosed three patients, and I'll turn it over to Gabe to talk a little bit about the next clinical trial.
Absolutely. And thanks again for having us. So in terms of one of your questions, I think embedded in one of your questions is about risk mitigation in terms of a novel capsid. So I think something not to be missed here is this is a real landmark in the field in that we're really this is the first high-dose novel capsid that's shown thus far tolerability, three patients, so we need to be modest. But this is a completely novel capsid that thus far is showing tolerability. In terms of risk mitigation, this is in the setting of steroids alone. So this is a standard of care therapy as you would think for Zolgensma or ELEVIDYS in terms of just giving prednisone. This is the immunomodulation that we're providing for this therapy, and thus far that seems to be sufficient.
We don't have to use eculizumab or sirolimus or rituximab upfront, even at a dose of 1 times 10 to the 14th VGs per kilogram. In terms of the clinical trial, as you can see, if you go to clinicaltrials.gov, we have really pivoted already to be thinking about registration, to be thinking about how can we develop a dataset that's going to be compelling to demonstrate, one, a compelling level of microdystrophin expression, and two, clinical confirmation. So with that said, we have adjusted our inclusion-exclusion criteria to target a patient population that we believe is more predictably in the declining phase of ambulation. That gives us an ability to better discriminate a treatment effect. So really lessons learned having been students of the first-generation microdystrophin gene therapy trials, CIFFREO from Pfizer and EMBARK from Sarepta.
We are also really honing those clinical endpoints to those where we think we can that really are best for clinical trials. That's not the NSAA. NSAA is a great epidemiologic tool when you're looking at a large, diverse patient population of ambulant boys, but we're looking at other endpoints like Time to Rise where it's better calibrated and much more predictable, and therefore seeing it a treatment benefit, we should be much better placed.
Got it. Yeah, I think that's a great insight around 003 and the clinical program. And you mentioned identifying these patients that are predictably declining. Maybe talk a little bit more about that. What criteria are you looking for and what gives you some insights there?
Yeah, so again, if we think about the first-generation programs and we look at the patients that they chose, these boys were between four, five, and six years of age. In retrospect, I think they did their best job at the time, but in retrospect, if you look, this is a very tough age to start to discern a difference in ambulatory function because the boys are gaining skills because they're growing. At the same time, it's intersecting with the exact time that they're losing muscle. And so just the natural history, if you look at the natural history, the variance is the highest in this age group. So we are, let me be very clear, we are committed to treating boys across the age spectrum and ambulant and non-ambulant. This is where we want to go.
However, if we want to look for efficacy, which we are obliged to do in the cleanest way possible, we want to look at an older age group of patients, and this is exactly what we're doing for ambulatory function. And then we want to make sure that we can use markers that can predict that those boys will be stably ambulant, but we can see a decline in ambulatory function. So that goes a little bit to our inclusion-exclusion criteria. We've focused on that bracket, if you will.
Got it. And there are some competitor DMD programs in the space where we continue to learn from those, and I assume you guys take that information in as well and adapt based on that. And so Pfizer's DMD phase III, their data showed microdystrophin levels higher than those achieved by Sarepta, but they missed on all the endpoints. How do you reconcile the paradoxical data there, and what are you doing differently in your studies to get more consistent results across all the measures?
You know, first, I think on the endpoints, they both failed the primary endpoint, NSAA, and realistically, Pfizer didn't do a deep dive into the secondary endpoints that Sarepta did. So we don't actually know what Pfizer hit or didn't hit from a secondary or tertiary endpoint because they didn't do the deep dive digging for data. The second thing you're talking about expression, I think, and you and I have had conversations about this in the past, Western blots, whether it's Jess system, Western blot, mass spec, a lot of it relies on methodology, standard curves, et cetera. So numbers can be all over the board. I really look at dystrophin-positive fibers to understand what's going on within the body. I think actually REGENXBIO has some pretty good data.
But one thing that we've noticed across the different trials is that you really need to look at dystrophin-positive fibers over time and make sure that you're getting that pharmacodynamic effect where you're getting enough positive fibers producing microdystrophin, and then you watch the clinical benefit over time. So I think there's some good learnings there. The REGENXBIO data is encouraging for patients. I don't put any weight on Pfizer's failure, especially when it comes to expression because they didn't really do a deep dive and they didn't go out long enough. I think Dr. Brooks mentions time. Time is very important in these clinical trials, especially in these disease states such as Duchenne or myotonic dystrophy or Rett or limb- girdle, et cetera. The body's been ravaged by these diseases from day one.
You also have this dynamic effect of producing a protein that's never been in the body, and it does take time. I think 12-month clinical trial is too short of time. That's why we're going 18 months in our clinical trial. As we dose the kids, they start producing microdystrophin. We give them some time to produce significant microdystrophin looking at it from a dystrophin-positive fiber standpoint and then following them out for 18 months. I think that's going to give us benefit over the other clinical trials.
Got it. Yeah, that makes sense. And just with the positive fiber potential there, have you had conversations with FDA on that, and have they commented on just the Pfizer data at all? I guess, have they given you some guidance on what to look for in these studies?
We've had private conversations with the FDA that's been informal, and we'll keep those conversations private. I think Dr. Marks, though, last week publicly spoke at the Broad Institute and clearly stated that accelerated approval is on the table, not only for potentially REGENXBIO, but us as well because they're viewing every individual program as a different program. Have we talked to the FDA specifically about positive fibers? No, but we will. We're going to gather data. We're already dosing patients, and Dr. Brooks is going to continue to dose patients. And then we'll gather enough data and have that conversation with the FDA. But they're highly aware of the different methodologies that are used by different companies and how that can change results from a protein expression standpoint. They also are clearly aware that dystrophin-positive fibers probably matter, and you can look at other metrics as well.
Maybe I'll turn it over to Dr. Brooks to touch on some of the other biochemical measures that we look at.
Sure. Yeah.
So yeah, and just very clearly, I'm a former Pfizer employee, and so I have no inside information and nothing is disparaging. I think one thing I just want to touch on is that if you look at CIFFREO, the phase III, and if you look at EMBARK and you look at the clinical data, they're really the same in terms of the clinical endpoints that we're seeing. Both CIFFREO showed a modest improvement in those boys that were older, just as EMBARK did, and they both missed on all of their endpoints, and they both had a modest impact on CK, so that shows that the drug had some biologic effect.
And so they're very, very, so it's a modestly effective drug that had really a very modest effect in probably the worst patient population to look for ambulatory function, as kind of we've discussed before, if that makes sense.
I've forgotten why you handed me the microphone.
Oh, right.
So thank you. So yeah, so one of the things that we're going to be looking for, and we're really excited to share this data, is we have these three boys so far. We're enrolling more boys into this study. We're looking forward to sharing in the early spring the biopsy data, and along with that biopsy data, that'll be 90-day biopsy data for that first cohort of boys and safety data for the entire cohort of those boys. We'll be also showing muscle integrity, markers of muscle integrity, which I think really speak to, can we get to the right cell? Those are our vector genomes. Can we express the protein? And that's the microdystrophin. We're looking at multiple different ways of showing microdystrophin. Yes, tandem mass spec, yes, Western blot, and dystrophin-positive fibers as well.
Also we're looking at measures of muscle integrity, so that's CK, LDH, ALT. We're looking at all of those factors to show that we are protecting the muscle, and that should give us more confidence as we continue to move forward.
Got it. Yeah, I think that's a great segue for the next question, just how to think about your data update, first quarter 2025, and what you're going to be showing for positive dystrophin fibers, level of microdystrophin expression, and what should we expect for these biomarkers as well? Should CK be the primary focus for comparing and contrasting?
Yeah, I'll start, and then I'll turn it over to Dr. Brooks. I think, look, this is three-month data, and I think Dr. Brooks summed it up nicely. What you want to see in three months is you want to see signs that the muscle is shoring up, the muscle integrity is increasing. Because this is why we're going out to 18 months. We believe that at the very beginning, microdystrophin is being produced. You're seeing some benefits, whether it's CK, AST, lactate dehydrogenase, other markers as well, and you're watching to see if the muscle is reacting to the microdystrophin. That's going to give us a lot of confidence that over time, as more and more positive fibers should be increasing.
By the way, if you go back and look at all the clinical trials, you can look at Pfizer's phase I, where they start at eight weeks versus where they go to 52 weeks, it increases. Pfizer's phase III, same. Solid's original 001 study, absolutely the same, where they started at 12 weeks, where they ended at 52 weeks and even 18 months, always increasing. So as we're looking at this first three-month early data, we're looking at muscle integrity signs that the muscle is shoring up. It's going to give us a lot of confidence that these kids are moving forward. So when you think about what are we going to show, we're not going to be screaming from the rooftop about NSAA or six-minute walk test because we don't believe that the three-month will show anything.
If you try to compare it to others, they're looking at nine months or 12 months. Even now, REGENXBIO showed longer-term data so we're going to be looking at CK, AST, lactate dehydrogenase, some other markers, see if children have any other biomarkers that could be a sign, and that's where we're going to go, and I'll turn it over to Dr. Brooks to see if you have anything else.
For specific measures there, is there anything that you're saying just as far as what you want to see on CK, what you want to see on LDH at three months? Because we'll be able to extrapolate.
Yeah, sure, I can touch on it. I don't think it's one marker. I think it's the sum of multiple parts, right? Because CK bounces. So you could, for example, you can see CK quickly drop 30-40%, and you're going to be ecstatic at 30%. A 30% decline in CK very quickly is a good marker. But then the kid goes running around, and it spikes back up, and you see that all the time. However, you see CK going in one direction, lactate dehydrogenase going in another direction, in the same direction, AST going in the same direction. Then the totality of the evidence starts adding up. So I think if you're seeing 20-30% declines of these biomarkers all heading in the same direction, you can feel really good that something's going on.
Yeah, no, that's absolutely right. You need to look at orthogonal measures. That's exactly what we need. For the blood biomarkers, how often are you guys looking at those in the first three months?
In the first three months? I have to open up my protocol. Fairly often. I think initially for safety, it's pretty dense, but then we have to balance asking of these boys to undergo blood draws and then the data that we're looking at. But I think we have—I'd have to guess—I think we have four or five blood draws for CK in the first three months.
Got it. Okay. Okay, all helpful. And for next steps for DMD, you've amended the protocol in hand to rapidly expand the study. How quickly can you ramp up dosing, and do you feel there could be headwinds to enrolling the study in the U.S. just with Sarepta broad label?
Sure, so I'll take that in order, so we are emerging from our sentinel dosing, which is a mandate that we have to follow from the agency, so we're emerging from that because we have a nice safety data set, early safety data set, and so that's great, so now we're looking for parallel dosing. We're really gratified to see the interest in the community about participation, and that comes from families as well as the sites. So we have multiple new centers that are coming on board. We just onboarded Craig McDonald out at UC Davis. We have Jim Dowling in Toronto at SickKids, who's active in screening boys, and then we're looking at a couple of other ones, and I'm not exactly sure, so I'll pause on naming that, calling them out, but we have a number of other sites in the U.S.
By the end of this year, we're going to have around six sites in the U.S. that are open and many more in the beginning quarter. We're not only looking at U.S. and Canada, but we're also expanding into the U.K. and to Italy as well. I think that speaks to the enthusiasm within the community. Just to touch on for one second, in terms of what are the challenges, and yes, of course, there's a challenge with the ELEVIDYS being on the market. A lot of families, we can look at the data, and we can have some ideas about, is there room for a best-in-class therapy? We think that there is a lot of room, and that's why we're dedicated to this. These families face really tough choices.
You have a boy who you're watching lose functional capability, and there is a drug that's approved that you can get your insurance to pay for if you can battle it, and some of them choose to go on to ELEVIDYS. Some of them are interested in looking at REGENXBIO, which is great, and some of them are interested in looking at us. This is a very tough choice for these families, and it's important just to acknowledge that there is that reality.
Yeah, I just want to make one comment. Realistically, we're not having trouble recruiting at all, and if anything, we just didn't have enough drug, and we only had two sites open, and you can look at REGENXBIO as well. They filled their trial relatively easy. I think the other important thing is the first three children that we dosed were all five years of age, and why do I bring that up? Because four to fives were the group that actually was approved first with Sarepta, so you would think that that'd be the hardest group to recruit for, and it was not. All three of our children are five years of age. If there's anything that holds us back, it's because we're being very thoughtful about our clinical trial design and who gets into the trial, and we're making sure that we don't just accept anybody.
We are screening out children. If there's any issue in recruitment, it's actually from our end of saying, you know what, we want to be tight and try to keep as tight of a homogeneous population as possible. That's what we're doing.
Got it. Makes sense. And how many patients do you need to dose in the phase I/II before you can have discussions on a pivotal plan with the regulators?
Yeah, how many do we need? We don't know. We're going to talk amongst ourselves. If we can end up with 10 to 12, 15 patients of decent long-term follow-up data, then maybe we'll knock on the FDA's door sometime next year and say, we'd like to have a meeting. We haven't really decided on how many patients we feel that we need before we knock on the door and say, let's have a meeting. But it's definitely not going to be the full study. It's going to be somewhere in between 10, 15 patients.
Got it. Okay. Let's talk briefly about REGENXBIO. They had an update earlier this week where they disclosed their clinical pivotal plans and also some functional data as well. Just wanted to get your perspective on that, how that informs you guys, especially the pivotal plan.
Well, actually, it lined up pretty nice compared to what we were thinking. We didn't know what their pivotal plan was. And I mean, obviously, our trial is slightly different in a different age group, but primary endpoint was exactly what we were thinking, safety and microdystrophin expression. And I think that that's what we're going to have to show. And the FDA's made comments that, and he made comments, Dr. Marks made comments last week at the Broad Institute. All these drugs, including REGENXBIO, including ours, should be open for accelerated approval. But really, we need three things. We need safety, we need expression, and we need directional benefit compared to natural history. We'll have all those things in our clinical trial. We're going to be looking at safety and microdystrophin expression as our primary endpoints. And so I think it aligns, and I'm encouraged what they showed.
I'm encouraged for the families because I do think these kids need choices.
Right. Do you have comments?
Yeah. I think just to reiterate strongly Bo's point there that what they disclosed in terms of their discussions and their thoughts about registrational path comports very much with the conversations that we've had and discussions in our thoughts in terms of, as has been discussed by Dr. Marks as late as last week, that accelerated approval pathway is certainly open for and must be considered individual for each individual microdystrophin that comes to them.
Got it. All makes sense. And I wanted to spend some time on the CPVT program as well. You mentioned IND submission first half of next year. There's a lot of white space with this opportunity since there's no targeted therapy available. For this setting, we're wondering how much gene expression is necessary to meaningfully reduce or eliminate arrhythmias, and is there potential for any off-target risk there?
That's a great question, so taking those in order, there is a lot of white space in terms of that this is, we're offering the promise here, and we hope we can deliver on this promise as a durable continuous therapy, and these patients have a mortality rate of 4%-5% per year. Sorry, excuse me. Life-threatening ventricular arrhythmic events, 4%-5% per year in the context of maximal medical therapy, which is high-dose beta-blockers and flecainide, as well as having ICDs and the sympathectomies, so it's important that that's addressed because that's an unacceptable burden of disease. In terms of how much of the myocardium does one need to transduce and what percentage of how much calcium sequestration overexpression do you need in order to stabilize the RYR2 receptor in order to abolish the arrhythmia, what we've been really, it's been really interesting.
We're seeing an effect in our non-clinical models at low doses as well as a dose response, which allows us to really dial in, we believe, the dose that's sufficient. That dose does not need to be 100%. It doesn't need to be a cell autonomous therapy. So we don't need to hit every cell. There's mathematical modeling that has demonstrated that you only need about 30% of the myocardium to completely abolish the arrhythmia. There's a lot of theories about what that is. If it's a source-sink relationship, we're not sure, but phenomenologically, you don't need the entire myocardium. We can get by, we believe, with a modest dose and be profoundly effective.
Got it.
Yeah, and just IND first half of 2025, everything's on track. Drug is in the freezer. Preclinical model, as Dr. Brooks mentioned, is already done, showed dose effect. And we're just taking down different cohorts right now of the non-human primate GLP tox, so all the animals have been dosed, with good data to date, but we have to take them down and look at them, so we're doing that right now.
Got it. And we're pretty much out of time, but you mentioned the capsid development earlier too. So you kind of have a platform potential there, and we've seen a couple of capsid deals in the space as well. I don't know, maybe in closing, if you want to just comment on BD potential and just key catalysts to add investors should be focused on.
Yeah. I mean, I think we've had a couple of companies. We definitely have a lot of academic labs that want our capsids, and we've already provided to 13. I think we've got another six or so that are knocking on our door to get our capsids. We have 10 more capsids that are in development right now for cardiac-specific indications, liver de-targeting. We'll take a look at them. They've already gone through three different species: mice, non-human primates, pigs. And we'll have those capsids hopefully by the end of next year ready to either license out as well as give to academics. And I think we have companies that are interested in our programs right now as well. We have a lot of different cardiac programs coming on: TNNT2, BAG3, FA, CPVT. So we have companies that are looking at BD opportunities, but they're just discussions.
Got it. Okay.
Yeah. Thank you, Mark.
Bo and Gabe, thank you very much for joining us.