Hi, everyone. My name is Maury Raycroft, and I'm one of the biotech analysts at Jefferies. Thanks for joining us today. I'd like to welcome our guest today, Bo Cumbo, the President and CEO of Solid Biosciences. Bo's going to provide an intro to Solid, and do a couple slides, and then we'll turn it over to fireside chat. But Bo, I'll let you come up and talk about the slides, and thanks for joining us today.
Yeah, thank you very much, Maury, and, thank you, Jefferies, for the invitation. So I'm just gonna go through about eight slides and chat a little bit, and then take some questions. So before I get into it, I'm gonna obviously make some forward-looking statements. Please take time to look at it. There's gonna be a number of forward-looking statements, and obviously results could differ from what I state, and many of which could be out of my control. So, you know, please take the time to look at this. It's on our website. So what I'm gonna cover a little bit today in the Fireside Chat is the people, the management team that is running Solid.
Our pipeline is very diversified now, but we're very excited today to talk about our IND that cleared. We put that press release out for our next generation Duchenne drug called SGT-003. That IND was approved, and the press release went out last night. Very excited about that, and we'll talk, I'm sure, a lot about that program, but I also will spend a lot of time on our cardiac programs that are moving forward, as well as our capsid library. We'll talk a little bit about manufacturing. We've made a lot of progress in manufacturing, and really changed up the way we do manufacturing.
While we're not utilizing this in our Duchenne program right now, we believe that we can lower COGS greater than 50% from what's currently being utilized as far as triple transfection, and that's gonna change a lot of things in the way we think about the programs going forward. We also are working on novel capsids. Obviously, our first novel capsid will be going into Duchenne early next year into patients, but we also have multiple other capsids that we're working on to build a capsid library, not only for our pipeline, but for non-dilutive financing. Now, the management team is great. I'm very, very pleased with everyone that you see on the screen here.
We have a very deep and experienced team, and you can see it's not just deep within biotech, but more specifically within precision genetic medicine, and even more specifically, within gene therapy. Many of us came from Sarepta Therapeutics or bluebird bio, Pfizer, et cetera, so you see a lot of the same logos. What you do see is you see also a lot of individuals that came from AavantiBio. For those of you who don't know, I was building AavantiBio. I'd left Sarepta to build AavantiBio, which was a cardiomyopathy gene therapy company, and that company was purchased by Solid Bio about a year, well, about a year and a half ago, and the management team took over from that point, once the merger closed. So very excited about the team.
Now, when we were building our pipeline, and as we're thinking through things, we put them in a very strategic manner, and why do I have manufacturing platform and capsid delivery or capsid programs at the top? Because when you think about gene therapy, delivery is everything, and delivery can take really three sort of flavors. One is CMC. You're looking at your empty to full, you're looking at your yields and your purity. The other is capsids. How can we drive the program, the gene of interest, right to the muscle?
And third is promoters, and really, we have two platforms out of the three that we've been working on for many years, and as I mentioned before, our manufacturing platform, as we've made a lot of modifications, we've even been moving away from triple transfection to dual plasmids, and we're increasing the yields pretty dramatically, where we believe that our future generation drugs will COGS will go down roughly 50% or greater. So it's really gonna change the way we, we think about gene therapy, because that is the biggest hurdle, is CMC manufacturing, and a lot of times. And then novel capsids. We have been working on novel capsids for two years, multiple different ways, inserting peptides, point mutations, as well as other modifications.
And we, our parental capsids were based off either AAV9 or rh74, so we mixed them all up. We are gonna be dosing humans soon in our DMD program with a novel capsid called SLB101. This will be the first time this capsid goes into humans. Very excited about that. I'm sure Maury is gonna ask a lot of questions about our DMD program, and I'll get into some of the animal studies as we talk about it, because it's different than AAV9. And then what you see is everything that flows up under it, and we're gonna spend a lot of time today on DMD, so I won't get into it on this slide, but if you look at our cardiac programs, well, we have FA, we have DMD, we have BAG3, and we have our arrhythmogenic CPVT.
It's catecholaminergic polymorphic ventricular tachycardia. It's a mouthful. You might not think you know the disease, but you do, if you've ever heard of kids unfortunately passing away while they're playing soccer or basketball or any other sport, this is it, and it's a rare disease. It's very fatal, it's young, and we believe that we have a way to transform this disease once and for all. So when you look at our overall pipeline, this is what it looks like. We're gonna talk today about Duchenne, but we have FA, we have BAG3, we have two indications in CPVT, many of which will be heading into IND in the next, you know, what's. A couple of which we're gonna head into IND in the next year to year and a half, followed obviously by Duchenne.
So when you think about Duchenne, and I talked about us having the IND open, we will be working on IRB approvals very shortly, started already. Then once we get IRB approvals, that takes about 6 weeks on average, and then we'll start working on screening patients. We already have patients lined up who want in the trial. I have not screened them, so I don't know if they'll hit the baseline criteria or have antibodies to the capsids, but we have patients lined up, and then we'll start dosing patients. When we think about timing of readouts, you know, you're going to get safety readouts this year.
You're going to get expression readouts and CK readouts this year, and then by the time those readouts are happened, you should be roughly two quarters away from another IND in the CPVT indication that I talked about. So really transforming the way you think of Solid going forward. So our near-term milestones, I think this is my last slide. Obviously, I completed the GLP tox because I did get the IND open, and we will be looking for patients and, you know, working with the sites. We're working with U.S., UCLA, and Nationwide Children's Hospital as our phase one, and that's in the United States. And then we'll be dosing patients shortly after. Our capsid library, we're already through two rounds of non-human primates, pigs, mice, heading into the third round of early next year.
We also have other capsids that are headed in non-human primates. We have a capsid called SL-3134, and this capsid bypasses the liver almost altogether, in mice, and so now we wanna see what it looks like in, in non-human primates. If that capsid holds up in a non-human primate, similar to what it did in the mouse, then we will have a capsid that, could once again, transform AAV because it bypasses the liver. So when you think about complement activation and other things, very exciting times. And then BAG3. That's just AVB-401. We're doing dose range finding studies. We're doing some non-human primate studies right now. We'll do some more in January, and then, head into IND proof of concept studies, later next year.
CPVT is actually, caught up relatively fast to all the other programs, because we have a lot of preclinical data from our, partner, Dr. Priori, out of Italy, who's the world's leading expert in CPVT, especially for gene therapy. I'm very excited about this program, and it's one of a kind. There are no-- there is no competition, for... that I know of, for the gene therapy space in this, in this, program. We have $142.9 million of cash. Our market cap has changed a little bit today, but I think it's roughly $50 million or so. So a negative enterprise value with a lot of assets, great management team, and very exciting time ahead. And with that, I'll turn it over to Maury, and we'll start chatting.
Sounds good. I'll sit with you. Yeah, so congrats on the milestone and getting the IND filed and cleared. I guess starting off, you disclosed the dose in the press release. Maybe talk about how you decided to pick that dose.
Yeah. No, it's a great question. We spent a lot of time on it, and it was harder than you think, but also some of the readouts, the most recent readouts of other drugs helped shift us into different thinking. So remember, we're using this capsid called SLB101. It's never been utilized before. We inserted peptides that bind to integrin receptors and skeletal muscle and should drive expression, and we did a lot of preclinical work, obviously in the mouse, MDX mouse, and then obviously in the non-human primate. We were getting roughly 100% expression at multiple doses in the mouse, right? So you know, we were very pleased with it, and we thought to ourselves we could go lower than where we started, where we ended up at 1E14.
When we also dosed our non-human primates, we started looking at the different tissues, and we're comparing it to our old program, which was on AAV9, and you're seeing just really robust biodistribution compared to AAV9, especially at the higher doses. Like the quad was three to five times higher. The gastroc was three to five times higher. The diaphragm, which is very hard to drug, and when you think about these older children in Duchenne, where they've already lost ambulation and really, you're just trying to support the heart and the diaphragm, intercostal muscles, the diaphragm was five-10 times greater, and that was a surprise for us. We did not expect that. And so, you know, when you're dosing these boys, you do not want to treat them as guinea pigs.
You want to give them the best shot possible, and we felt, "Go, go big," especially with the recent results, see if we can surpass everybody else in the market with expression and then ultimately, clinical endpoints. We also, from a safety standpoint, we had already studied three times higher than that dose in non-human primates. All the animals did very, very well. No unscheduled sacrifices to talk about. There were liver enzyme increases, ALT, AST, modestly from day eight to day 14, very transient in nature, and so we felt we had a wide, comfortable margin. So give the kids the best shot. I think we- there's a window open now. Let's see if we can create a better program.
Got it. And was there any specific feedback from FDA related to?
No.
The study then?
No, it was good.
Got it.
It was really good. I, it was, you know, don't want to comment. We would have said something if it was material.
Right.
But we were very pleased with the IND.
Okay. For the study in the press release, it mentions two cohorts. What's going to be the difference between the two cohorts? And it also mentions potential to expand. Maybe talk about that as well.
Yeah, the two cohort thing, we're starting with cohort one. That, and I stated in the press release, a minimum of three patients. Most likely it will be three to four patients, and then we're going to take a look at expression and CK, and we'll release that data in aggregate, but we're not going to do patient by patient. You know, we're going to wait until we see some of the patients together. And truthfully, I'm just going to, at that point, if we have really good data, then I'm going to potentially go to the FDA, depending on the outcome of what happens in the field.
T o see where the strategic opportunity is and go for that. If I feel that we need to go to a different cohort, what we'll do is we'll either go in a lower age group or a higher age group, but we won't change the dose. We feel that the dose is the right dose based on the animal studies.
Got it. Anything else that investors should know about the trial design and, yeah, any enrollment criteria?
We will be using steroids only, as immunosuppression regimen, and they'll be on a steroid dose for at least three months prior to the study. We are dosing relatively, I said before, four to five-year-old, so these are going to be relatively young children, small children, weight-wise, less than 20 kilos. We will expand from there as we need to expand. You know, I think. And, and we, we want to be a global trial. Our first two sites are UCLA, Nationwide Children's Hospital. After we get through this trial or phase I-II, we will, we're going global. Because the opportunity now, unfortunately, for these children, because I wanted the, the other companies to knock it out of the park for the children.
But unfortunately now, there's about 300,000 kids, ex-U.S., that are going to be very challenged to get reimbursement if they get reimbursement at all. And so we are going to be a global company. We're going to do trials ex-U.S., and we're going to try to get this drug approved, ex-U.S. as well.
Got it. And to clarify for the two cohorts, so you'll get results from the first cohort, and if you repeat that in the second cohort.
It'll either be older children or younger children.
Okay
D epending on what we see.
And then if everything looks good there, and depending on the external environment as well, you'd have a conversation with FDA, basically?
Yeah. Yeah, I want to see what happens, and then I'll, I'll piggyback off that strategically.
Got it. And, just for investors who may be new to the story, too, maybe talk about, some of the differences between how 003 works from an expression level versus the competitors out there, too. Some of the key-
Well, competitors, we've never done head-to-head, so I can't tell you, right? But what I can tell you is our internal, you know, the old original 001 program versus. Which was an AAV9 program, and it was an HSV manufacturing platform, versus this new program, which is a SLB101 capsid that has, you know, the peptide insertions, and it's on a triple transfection manufacturing platform. Very, very different, by the way, manufacturing platform, and I'll, I'll specify this so you understand. It's like very pleased with the manufacturing platform. You know, we're talking high 70% true fulls capsids. That's true fulls, that's not partials. If we added in the partials, like a lot of people, you know, sort of lump them together.
W e'd be in the high 90s. So from a purity standpoint of true fulls, very pleased, in the high 70s, 77, 78. And then where, you know, partials are roughly 18, 19, and then empties were 1%. So we're ecstatic with this because compared to the original program, you're talking 40%-50% for their phase 1 trial, and then, I mean, the first group of kids in the phase 1, and then they made some modifications, and it was higher, but it was nowhere near this.
40%-50% true fulls.
True fulls. Yeah. Yeah, it's a, it's a big difference. And then, the capsid is going to be different. So what did we see? Well, we saw, you know, three to five times greater biodistribution, depending on the muscle. In the diaphragm, we saw five-10 times greater distribution. You see higher expression in the muscles. You saw some liver detargeting, depending on the animal. You saw much more liver detargeting in the mouse than the non-human primate, but you still saw it. And then from a CK reduction, which is great in a short period of time snapshot, because, you know, you're taking down the animals, unfortunately, you see a huge reduction in CK compared to AAV9.
So I can't speak to the other programs out there, because, you know, I've never measured it, but I can talk to you about 001, the original Solid program.
Got it. Yeah, I guess, so with the biodistribution, it sounds like you're getting good results there.
Yeah.
That could translate to better efficacy in patients. And then you also have the nNOS domain. You mentioned the peptide insertions, too.
Yeah.
How does that differentiate? Because your construct could potentially be better than some of the competitors as well.
Yeah, you know, the nNOS is. I mean, you heard the FDA even talk about it at the AdCom this past year. They really leaned into it. I think, you know, the R16, R17, it recruits for proteins that called alpha syntrophin, and alpha syntrophin are you see a lot within the the muscle fiber, and that recruits for nNOS. And when you have nNOS, you see some of the preclinical studies, you see healthier, thicker muscles. You hope that this is gonna translate to endurance. So like, you know, you've seen some readouts. If you have a 10-meter run/walk, and you hit a, a p-value, you would hope that that would translate into longer endurance, into the 100-meter, but we're gonna have to do the studies to find out.
Got it. And, I think you mentioned you could potentially have efficacy from this or so, not efficacy, but some sort of a data update from the clinical study next year. Is that?
Yeah, we should have roughly two, right? So we'll lump. You know, we're gonna do IRB approval, and then we're gonna do patient screening, then we will start dosing patients. There's 30 days in between patients that we have to wait, which is standard, you know, a lot of the gene therapy companies. We will wait for a minimum of three, potentially four patients to group together, and then we'll let you know at that point when we completed enrollment in the cohort. No news will be good news. I'm not gonna tout one patient at a time because who knows what happens on the second patient. Then we will take biopsies of these patients 90 days post their first dose or their only dose, and then we'll lump that together.
That, if everything goes smoothly, we dose, you know, on a consistent basis, you're talking late summer, early fall will be expression and CK, as well as follow-up safety.
Got it. That's helpful.
There's two readouts hopefully this year. And I'm excited. I know everyone's focused on Duchenne. At that time, when we have these readouts, I'll be on the cusp of another IND within two quarters for CPVT, that's the catecholaminergic polymorphic ventricular tachycardia, and that's two indications. It's RYR2, 20,000 patients in the United States, and it's CASQ2, which is 2,000 patients in the United States. Obviously, tens of hundreds of thousands more ex-U.S., and this will be a global study as well. I think it's Italy, the United States, and one other country.
For CPVT, this is different capsid, which is pretty far along in the process, and this is also.
It's a different capsid. It's pretty far along. It's a capsid that Dr. Priori, who started this program out of, in Italy, she's been working on this for a while, and there's just a lot too much data, so we don't want to change the capsid and go back. There's too much data. And the, the arrhythmias, at the low dose in both RYR2 as well as CASQ2 are, are nonexistent in the, the mouse models, at the low dose. Well, at all doses, but at the low dose more specifically.
Got it. I guess while we're on CPVT, maybe talk about study design there and how that could look.
Yeah, too early to talk about study design. So what we're gonna do is we're gonna do the GLP talks and then once I do that, I'll start talking about study design.
Okay.
You know, you know, we're, we're excited that we're already now a clinical stage company again, and by this time next year, we will be on the cusp of having three different types of indications.
Got it. And, going back to DMD, wanted to get your thoughts on NSAA as a measure for DMD. Is it sensitive enough to detect changes in milder patients? And, what did you learn from Sarepta's EMBARK study failing to demonstrate a statistical benefit on NSAA? Does that diminish enthusiasm for the approach?
Well, NSAA is a good, it is a good predictor of decline. You know, I, I'm not gonna get into really dissecting their results. It is a good predictor of decline. It is relatively sensitive. You see one point change, it does matter to patients, and it matters to every single patient. You know, you're losing an ability if you lose a point, and so it does matter to kids. I think, this time is also, you know, relatively predictive of decline. You know, as the kids rise, if they get above five seconds, you typically see decline in non-ambulatory and ambulatory. I mean, and from ambulatory to non-ambulatory over a period of time. So I think that that's predictive as well.
You know, 10-meter run walk is interesting to me, but you also have to have the endurance to keep up with the 100-meter, in my mind. And then stride velocity, I love stride velocity. I don't know if you know what stride velocity is, but basically these kids wear a little, basically a tag around their ankle. Some wear one, some wear two. They have to wear it four weeks. I don't know Sarepta's study design, but typically you have to wear it four weeks ahead of a readout. So four weeks before baseline, four weeks before six months, four weeks before one year, and they take. You have to have 50 hours of time at a minimum, up to 150, and they take just that 5% of each kid's daily action.
So they strip out, if, you know, one kid is playing video games a lot, another's very active, they strip all that noise out. They only take 5% of your day, the highest 5%. And I think, and the EMA loves it. I think you're gonna see the FDA pay attention to it eventually, and maybe they already are. And I think that's a sensitive readout as well. So, you know, we are going to learn. That's the. I guess, the great news of being behind, is we're gonna learn from others on how do we, how do we create a better trial design? And I'll do that, but I'm not gonna talk about it right now.
Fair enough. Fair enough. But it sounds like for NSAA, you view it as an important endpoint. It sounds like you know a lot about it as well.
I do view it as important. I mean, that's why a lot of companies use it as a primary. And that's why the FDA, I mean, if you recall, Duchenne, the controversy around six-minute walk tests in the day, and now they wanted to move to NSAA because it is relatively robust and there is, you know, it is measurable.
Got it. And, let's see, for biopsy data, when you get that and expression data, what are your expectations there? What do you want to see when you do those biopsy results?
Yeah, I want to see at least, you know, I'm highly focused on dystrophin positive fibers. You know, we're going to talk about Western blot, we're going to talk about mass spec. However, really, methodology by any company can change those numbers relatively easy. Dystrophin positive fibers are done by a third party. They're done by Flagship, typically. I know two other companies in the Duchenne space use that company, so I do think it'll be as close to apples to apples as possible. I'm shooting for 40% dystrophin positive fibers. That's what I'm shooting for, and if I get higher, then I think we've got a game changer.
Got it. And, for the capsid SLB101, any thoughts on how immunoreactive that could be, and could you potentially. Do you have a strategy for redosing patients?
Yeah, I mean, well, let's take the last part. I think redosing is the future. I've said this a thousand times. I think there are now companies, all the companies are looking at how we can redose, how we can dampen down the immune system, when we can do it using IDeS, FcRn, plasmapheresis, combinations. I think the future is going to be redosing. Unfortunately, there's going to be a lot of children, as we've seen in some of the AdComs in other areas, that did not get the response that they need, and they deserve, and so we're going to have to find a way to redose. And these older kids, by the way, they're heavy. They've got a lot of fat because they've been on steroids their whole life. They've lost a lot of muscle. Fat soaks up this virus.
Odds are good that we're going to have to redose these older kids more. So let's, let's find a way to do that. I think that is going to be the future, that's going to open up Duchenne. However, you know, as far as our capsid goes, I think, it's looking a lot better than AAV9. It was liver de-targeting in the animals. Don't know if, you know, we'll see that in... We won't be taking liver biopsies, so we won't know in the humans, but it was in the animals, and so we're also at half the dose that Solid's original program was, because they were at 2 × 10^14, in oh one. We're 1 × 10^14 here. So let's see. Let's see how it plays out.
Yep. I think we're almost out of time. Maybe last question for DMD. Sounds like you're not going to comment on potential regulatory path right now, but how would you see Solid positioning versus Sarepta and Pfizer? Is there any more perspective you can provide on that?
Look, you know, sometimes it's good to be second. I'm going to be watching and learning and paying close attention. I think the globe is open to us now, and there's a lot of kids ex-U.S. I don't know how the U.S. is going to play out, but I will strategize around it as I see, as I see this. I'm going to be in constant communication with the FDA, as we move forward. We're going to dose these three or four patients. If I have a good drug, if I have a safe drug, I'm going to lean heavy, see what we can do.
Sounds good. Maybe to close out, highlight key events ahead investors should be focused on.
JP Morgan will provide guidance on the IND timelines for CPVT and potentially for BAG3. We should disclose. We'll start talking more about a manufacturing platform because I believe that we can lower COGS roughly 50% for future programs. That's going to change the way we do gene therapy in general, and we'll see. We won't be dosing patients, I doubt, by then, but and I wouldn't announce it anyway, so that'll probably be it.
Got it.
All right.
Okay, thanks for joining us, Bo.
Thank you, Maury. Thank you, guys.