Let's go ahead and get started. Thanks for coming everyone to the Piper Sandler Healthcare Conference. I'm Allie Bratzel, one of the senior biotech analysts here. It's my pleasure to be introducing Solid Bio. Joining us today from Solid, we have the CEO, Bo Cumbo. Yeah, thanks for joining us.
Thank you.
So, you know, just to start things off, so maybe just to level set for investors, could you give us a quick overview of Solid, you know, the progress you made over the last year since the AavantiBio merger, and then the setup into 2024?
Yeah. I think we're very pleased with what we accomplished post-merger. The merger has actually took place, as you know, in December of 2022 between AavantiBio and Solid . We incorporated the two companies together, restructured the pipeline, as well as the personnel and executive team, and made progress. Our goal was to first get. You know, we're a genetic medicine company, primarily in gene transfer, mainly neuromuscular and cardiac.
We have a couple of different neuromuscular programs in DMD and FA, and then we have four or five cardiac programs, dilated cardiomyopathy, arrhythmogenic cardiomyopathies, as well as, you know, hypertrophic cardiomyopathy. So, overall, it's been a great year. Very excited about it. We've got our DMD IND open, and we'll be moving forward dosing patients next year. Hopefully have another IND shortly after we have a DMD readout in the fall of next year.
Perfect. So obviously, we have, we have a ton of questions on, on your, you know, lead asset, SGT-003. Maybe before jumping into that, though, maybe just a question for you on the, on the DMD competitive landscape. You know, based on the recent news, in the space with, the EMBARK trial from Sarepta, you know, failing to hit stat sig on their primary endpoint, can you frame for us, you know, how, how is the opportunity for SGT-003, to deliver benefit to the DMD patient community, you know, changed as a result of that?
Yeah. I think first and foremost, all of us in the space were sad, because we wanted these drugs we wanted, you know, Sarepta's drug to show benefit for the children. So, you know, it was, it was a sad day, for the kids. I think for, for us, it really doesn't change how we go about our business.
We always believed that we had a, a better construct and a next-generation drug because of our capsid, which creates a much better biodistribution in certain tissues like the diaphragm, the quad, the gastroc, compared to Solid's original program, so which was using AAV9. And we also changed up the manufacturing platform. As you know, we moved away from Solid's original program, which was HSV. Now we're triple transfection, you know, HEK293 triple transfection, and suspension-based.
And we have a very, very high full-to-empty ratio, and so, and a clean product. And so we believed at all times that we were creating a next-generation drug, and therefore, we had our plans in place on what we're gonna do in the U.S., how we're gonna go at ex-U.S. And yeah, I mean, realistically, the only thing that has changed is now we feel that the market is wide open, that a floor has been set on data.
There's been a lot of lessons learned, from Sarepta and the community on their program, and now we're gonna try to take those learnings and create a better, a better outcome. And so nothing's really changed. We're gonna dose cohort 1, which is three to four patients, and we're gonna look at safety first.
Safety is the primary endpoint for this trial, followed by microdystrophin expression and dystrophin-positive fibers. We'll also look at CK and some other items and then and really make a determination on next steps. I think one thing it has changed, you know, is how do we view the next trial? You know, the approach that we were gonna take was a cohort 1, cohort 2, and just a stepwise approach, really create a robust data set and and you know come in behind Sarepta. I think that that's changed. Now we can think about, can we go registrational quicker?
Mm-hmm.
Where do we go, and how do we tackle ex-U.S.? Because ex-U.S., you know, that's, commercially speaking, it's a very different animal than the U.S. And with the failed phase III, it's gonna make it very challenging, reimbursement-wise. So, you know, can we, can we, can we find some leverage there, some opportunity there, ex-U.S.? I think we can.
Excellent.
So...
And then, you know, some of the big news out of Solid earlier this month was achieving IND clearance for-
Yeah
... SGT-003. So to the extent you're able, can you give us a sense of the, you know, FDA feedback on the IND submission, you know, especially on, on the safety side? Any questions, anything that gave them pause?
Yeah.
You know, just asking based on the 001 experience.
Yeah.
Just, you know, any color there would be helpful.
Yeah, I'll give you some color on especially on the safety side. No questions were asked. All right, so let's just... From the safety side, no questions were asked. We actually had a very good GLP tox study. That study concluded March of this year, 2023, and all the animals did very, very well.
And we dosed so we've announced our dose now. So we're gonna dose in humans at 1 E14, we dosed in the non-human primates up to 3 E14. All the animals did very well. We had one animal that had ALT, AST increases about three times the upper limit of normal, from day eight to day 14. No changes after that, just came straight back down. Just blip down, blip down. No questions were asked on safety.
So we feel that the agency is hopefully satisfied, clearly, because they opened the IND. I mean, the IND, you know, I'm skittish by nature, and I will tell you that the day before we actually got the IND, which we got early, by the way, we didn't have to wait the full 30 days.
Okay.
We got the IND the day before. I was actually like: "Something's wrong. We're not getting enough questions." You know, I was thinking to myself, "This is spiraling downward," and it turns out, no, everything was fine. So, you know-
Okay.
It went very smooth, and we're very pleased.
Excellent. And then, in conjunction with the IND clearance, you also provided us with some details on the planned clinical trial that's gonna start dosing next year. Can you walk us through the key details on that?
Ages four to five, lower weights. We're, you know, shooting for right around 20 kilos. This is important because fat fraction matters and, you know, when you're taking these biopsies.
Mm-hmm.
Unfortunately, just, you know, for your knowledge, like, when these kids lose ambulation right around age 12, their fat fraction's 80%.
Yeah.
By 10, it's, like, 60. So realistically, you know, you want to get as younger, as healthier as possible, so your muscle is more intact. We're looking at four to five years of age, less than 20 kilos. You know, we set floors and ceilings for the NSAA, even though it really won't matter because it's only, you know, a minimum of three patients, up to four patients in this cohort. So it's... We'll get NSAA data, but you're not gonna... It's gonna be, you know, there's an asterisk there, that it's not gonna be robust. We'll look for CK, and stuff like that. So the kids are gonna be young, healthy. We set a rise time limit, so less than five seconds. NSAA, floors and ceilings. That's pretty much it. Obviously, antibody negative-
Yeah
to the capsid.
Yeah, and then I think you already talked about the, you know, the starting dose you're looking at. And I think you've been pretty clear you expect that to be, you know, therapeutic. Can you kinda elaborate on that? What, you know, what gives you confidence that this is gonna, you know, lead to robust expression? And what do you need to see to be, you know, comfortable that you don't need to evaluate higher doses?
Yeah. So we dosed our preclinical studies at on multiple doses. And even at 5E13, we were getting 100% microdystrophin expression across the board. Obviously, 1E14 was still at 100% or higher, and this was different tissues that we looked at across the board. We've wanted. You know, when we were picking the dose and we were doing this, we were assuming at that time, Sarepta was gonna be approved and on the market with the p-value and EMBARK, et cetera. So the goal was to beat them and to bring a better drug to market. Our safety profile looked good. I told you before, you know, we didn't really see anything in the non-human primates, and we dosed up to 3E14.
And so we want to put our best foot forward. We want to quietly and thoughtfully make progress and then have the best drug on the market. And that's why we selected the dose 1E14, 'cause our data suggest we should have great expression in these kids. I hope so.
Yeah, perfect. So thinking about next year, and kind of the cadence for updates that we should be expecting. You know, I know we're not gonna be looking for, you know, a blow-by-blow or day-by-day update every time a patient's dosed. So I think, you know, you said that would change, you know, if an SAE or, you know, some, some safety signal arises. So I... You know, kind of frame for us what we should be looking for, you know, next spring. Should we assume no news is good news until you announce, you know, that you've completed dosing in the first cohort?
Yes.
How should we-
No news will be good news. We're not gonna be announcing... So as I mentioned before, cohort one is minimum of three patients to four, to three to four patients. We do not plan on announcing anything as we go patient by patient. So if you don't hear anything from us, that is a good thing. And we will get through the cohort. We will let you know, you know, you guys know when we're through with the cohort. And that'll be our first... Hope, let's hope that's our first announcement that we are, we're completely dosed. And then, so that will be, you know, based on time, and the FDA wants you to dose 30 days, wait 30 days in between patients. So right now, what are we doing?
Just so you can sort of understand the timing of when is that first patient in. Got IND approval, then we start IRB approvals with the hospitals. We're working with two hospitals, Nationwide Children's Hospital and UCLA. Their IRB approval process typically takes four to six weeks once you start that meeting, you know, their meeting. They don't schedule meetings on a daily basis. They have them typically scheduled, you know, staggered either by two weeks or a month. So, you know, we have to wait for the next meeting. Then that kicks off our process. It's about four to six weeks when you don't have Christmas involved. Obviously, we do, so add a week for Christmas. Once that's done, obviously, that pushes it into the January timeframe.
You start screening your patients, screening them for antibodies and baseline criteria, then schedule your patients, then dose. That, you know, three weeks, four weeks right there, the screening, scheduling, dose. So, you know, Q1, we are gonna be dosing patients. Then we wait 30 days in between patients, per FDA, three to four patients. This puts us hopefully telling you that we are completed the cohort, you know, late spring, early summer, and then we will announce our data. We take biopsies, by the way, baseline, biopsies at day 90. Obviously, biopsy at the year-end as well, one year later. So, 90 days post 4th patient puts the timeframe of all the data being released late Q3, early Q4, if everything goes well. So we're excited about that.
You know, you can say second half of the year, but it's really later Q3, early Q4, that we would be in that sort of timeframe.
Thinking about that initial, you know, two-month, you know, biopsy update, I guess, what should we be looking for, you know, as a successful read out there?
Yeah.
What specifically will we?
We'll be looking at dystrophin, you know, dystrophin as a percent normal, microdystrophin as a percent normal. We're using mass spec. So you're not gonna be really able to go apples to apples. Well, you wouldn't be able to, if our competitors were using, you know, mass spec, they're using Western Blot. But even if you were doing that, methodologies would be different for different companies, so you can't really look at it. But, you know, if we're in the 20% range of just microdystrophin expression and then dystrophin-positive fibers in the 40% range, we're gonna be very pleased, especially with these early patients, these three and four patients. So we are using Flagship as our third party.
Both Pfizer and Sarepta use Flagship as the same third-party to look at dystrophin-positive fibers, so we're using the same group.
Okay, perfect. And then in terms of just, you know, development plans post, you know, cohort one, I guess, you know, do you have a sense of, you know, kind of the number of patients you need to dose and duration of follow-up that you need to give you and regulators confidence that, you know, SGT-003 is ready to go into a pivotal trial? Or I guess, kind of, at what point is the agency going to be willing to have, you know, start having that conversation with you?
I think if I can prove safety and microdystrophin expression, good, robust microdystrophin expression, then we're gonna have we can start having conversations about registrational type trials. You know, with the registrational trials, you need to have potency assay in place.
Mm-hmm.
We don't have that in place yet, you know. We also would have to do a commercial manufacturing process. So there'd be work that we would need to do. But if we're starting to dose patients and we get through safety, then we'll start leaning into those next aspects of what we need to accomplish for registrational trials because the market, I think, is gonna be open. And so if I can start working with the agency sooner rather than later, once I understand safety and expression, the better. And let's not forget, there's 300,000 kids ex-US. And you know, reimbursement ex-U.S. is very different than reimbursement U.S. And they take you know, these rating agencies, as you know, like French, the ASMR ratings, really dictate a lot, and so they look at data.
And so I think the ex-U.S . is wide open for us to, potentially, you know, leverage and take advantage of.
And then maybe just kind of more of a general question, but you know I guess how and when would you expect SGT-003, you know, differentiated profile, you know the transgene, including the nNOS domain, and then with the muscle-tropic capsid? Like, when would you expect that, like, best-in-class profile to be validated in the clinic? Like, is that something you would see in, you know, the three-month update or, you know, that wouldn't really emerge until-
Yeah
... you know, the 12-month, you know, clinical update? Or, or how, how should we think about that?
Yeah. I think really, realistically, that's long-term data, long-term follow-up. You're not gonna see, you know... We have R16 and R17 domains that it recruits for alpha-syntrophin and then ultimately recruits for nNOS. When you have nNOS, you know, blood flow is increased. In preclinical models, you see healthier, heavier muscles that are intact. So we would think that this would help with endurance, long-term endurance. So you might be able to parse out what happens in 10 m-100 m.
Mm-hmm.
Hopefully, you would see that we'd hit p-values in both, and because that will show that the endurance is there even in the face of the disease.
Mm-hmm.
So you'll see that data play out over time. I think then there's other aspects of our construct that are different, that adds more flexibility to the construct itself with the removal of hinge 2. When you have hinge 2, you know, you can see a very, very rigid, very strong construct, but that also creates myotendinous. It creates ring fibers around the myotendinous junction in preclinical studies. So durability could be an issue, and so we want to make sure that we have durability. So I think there's a couple different aspects of the construct that could play out over time.
Mm-hmm.
But right now, I just want to focus on safety.
Yeah.
If I, you know, Solid's original program back in the day, the one that doesn't exist anymore, it was actually really quite good. I mean, if you look at the data-
Mm-hmm.
Dystrophin-positive fibers were in the 40%. I mean, it was good. And SAA data at one year and two years looked really, really good. The problem is that it was safety. You couldn't, they couldn't get past safety. So, you know, while it's very interesting what's going on with the market and competitors, truthfully, I'm just focused on getting through these next three or four patients safely because I believe I have a great construct. I believe I have the right dose, and once I get through safety, then, you know, guns blazing, and let's see what happens.
So assuming, you know, you demonstrate, you know, safety, I'm gonna ask kind of a cart before the horse question on how you're thinking about, you know, pivotal trial design, specifically on, you know, endpoints. You know, I think we're all aware of shortcomings on NSAA and see the rationale for something like, you know, SV95C to be a primary endpoint. So I guess, you know, at this stage, what are your thoughts on that? And then-
Yeah
... and also, what's your sense on FDA's openness to some of these other, you know, endpoints to serve as-
Well-
Approvable?
I'll answer that one first. I think they're wide open. I don't think FDA really demanded NSAA or six-minute walk test or anything. I think they're open for other endpoints as long as you can improve, you know, and explain why you're using that endpoint and why it would be a marker for clinical success. I think there are markers for clinical success. I think you touched on one, SV95 is a very interesting aspect. I think rise time can be interesting. There's other milestones, depending on the age of the child, that you can really go after, too.
Mm-hmm.
Instead of a composite score that looks at a broad range, you can be very specific, and I think that that's what we're gonna do, and that's one of the lessons that has been learned. Fortunately, we haven't, we haven't had the opportunity to fail yet, so therefore, I can just learn-
Okay
... from mistakes that have been made, you know, in the market. And so, that's what we're gonna do. And I don't know when we'll have that discussion with the agency, but as soon as I understand the safety, I will.
Okay. And then, you know, we're kinda coming up on time here, so I'm gonna shift over to the, you know, the capsid library. I think maybe something that isn't as well understood about the SGT-003 readout next year, that it should provide validation for, you know, your rationally designed capsid. So can you just kinda expand on that and just also maybe more broadly talk about your efforts on the, on the capsid library-
Yeah
... and the kinda like optionality you have there?
Yeah. So we have a whole capsid library. And our first capsid that came out of the library is called SLB101. That is the capsid that's being used in the Duchenne program. It... We've inserted peptides that are specific for antigen receptors on skeletal muscle, and we see very, very different. So the parental capsid for this one was AAV9, and we see increased biodistribution 5-10 times greater than AAV9 in the diaphragm. Huge for Duchenne, especially pulmonary function for these kids. So, 2-3, 2-5 times higher in the gastroc and the quad compared to AAV9. So we're very excited about this. A little bit of liver detargeting in this capsid.
We have another capsid that's going in non-human primates in Q1 of next year. We call it 134, and this capsid is the parental capsid of Rh74, and it's a 1,000-fold liver detargeting compared to the parental Rh74. It is shocking. And so it's in mice, so we wanted to throw it in a monkey to see if it validates in the monkey, because if we see what happened in the mouse compared to the monkey, then we might have something pretty extraordinary there for gene therapy. So we have a whole different capsid library. CMC is another big difference in the new Solid.
Our yields are, we've made multiple process changes throughout the course of the year to where we are increasing the yields, about 15 times greater than we were at the beginning of the year. We also have an empty-to-full ratio, a true full ratio of roughly high 70s, high 70%, 77%-78%, depending on the batch. That's true fulls. That's not partials. If I lump partials in with that, then I'm in the 90s, 98%-99%, 'cause I only have 1%-2% empties. A lot of companies lump partials and fulls together. We don't. So high 70s for true fulls. If you lump them together, high 90s.
That our COGS for our future programs will be able to decline about 70%, and that changes the way we think about gene therapy forever, 'cause COGS are always been the barrier, and this is gonna eliminate that. So very excited. And one point, I know we're gonna run out of time. I think one point that's very, you know, everything is about the clinic. You know, can you get to the clinic? Can you get data? Obviously, we're gonna be in the clinic in Duchenne. We're gonna have a readout, you know, or we're gonna get through safety, and we'll announce that we got through safety by getting through the cohort. We'll announce the data in the fall, right into Q3, early Q4.
At that time, I will be roughly two quarters away from another IND in what's called catecholaminergic polymorphic ventricular tachycardia, or CPVT. If you don't know this disease, take a moment to look at it. This is a highly fatal young disease. You actually do know this disease because these are the kids that you hear about. They're playing soccer, playing basketball, football, and they just die on the field. They have a mutation. We're going after this RYR2 and CASQ2 mutation. Our preclinical studies in all of our doses eliminate the arrhythmias completely. And we will be hopefully in the clinic, you know, into Q1 of next year. So we're gonna be reading out Duchenne, and five or six months later, we're gonna be on the cusp of this other IND that's highly fatal in children.
At that point, I think this Solid is a, is a very, very different company. So exciting times.
Excellent. Yeah, and, and we've barely even touched on the cardiac pipeline, but-
Yes.
Huge-
Huge cardiac pipeline. You know, four or five programs. They're all young, but, the CPVT is next in line.
Excellent. Well, we're out of time, but, Bo, thanks for-
Yeah, thank you.
... dropping by and telling us the Solid story.
Yeah. Thank you.