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

All right. Welcome, everybody, to the fourth day of the 41st Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by Malcolm Kuno and priyanka grover from the team. Our next presenting company is Solid Biosciences and presenting on behalf of the company, we have CEO, Bo Cumbo. Bo?

Thank you Anupam and thank you JPMorgan team for the invite. I really do appreciate the opportunity to present. Before we go into presentation, let me take a moment to talk about forward looking statements, these statements involve risk and uncertainties, many of which will be out of solid control. Actual results could And please take a look at the slide deck. It's posted on our website as well as the 8-K this past week. Now with that said, 2023 is going to be a transformational year and very meaningful advancements for the Solid Biosciences. We just completed a merger with Avanti Bio, and I'm going to talk a little bit about that. And that merger has really helped us think about our strategic pipeline of programs that are going to continue to evolve over the course with anticipated '24. So let's just take a look at Solid Biosciences at a glance right now, and I'm going to go to in-depth on each one of these topics through the presentation. As I mentioned, we completed the merger of Avanti at December 2, 2022, roughly about 1 month, 1.5 months ago. Headquarters are now in Charleston, Massachusetts. And now we've already combined the 2 companies together from a pipeline, novel capsid development that I'm going to go into as well as the expertise and the personnel for both companies. Now our pipeline that we'll talk about today starts with SGT-003. This is going to be our next-generation Duchenne program that's utilizing a novel capsid called SLB-101. And we expect our IND second half of the year and first patient dosing in the second half of this year as well. Our second program And we're using -- this is ABB-202. And we're trying to work on both cardiac as well as neuromuscular CNS manifestations from this disease. And we're doing this by a dual route expression increase, but also the distribution of expression over time. Third program is BAG3. This is one -- our first program that's going to be coming out of our cardiac pipeline. We have multiple programs are going to be working on 2023. BAG3 was the first one we announced. We're using Rh74 capsid with a specific cardiac promoter that we have not disclosed -- and all of our programs, by the way, the 003, FA, cardiac are on Both companies were working on capsid libraries was the next-generation programs. I'll start with delivery and not going to go into depth about them, but we're developing these next-generation capsid libraries with 2 different strategies. And we're very excited about the results that will continue to come through in '23 as well as '24. We're well positioned for success in the next couple of years. We have additional programs that will be announced in mainly from the cardiac side that we've been working on. We have December 31. This will take us into 2025. Now the teams, as we've merged the 2 companies together, the team, the executive team is really well known in the industry, not just in biotech, but more in rare disease, precision genetic medicine or in gene therapy. just highlight a couple of the names here that in the audience today. But as you can see, the executive team from top to bottom is really well done. We announced this week. to coming to Solid, he was the CFO of Selecta Biosciences and before that, he was the Treasurer at Sarepta Therapeutics, along with Ty Howton and myself who came from Sarepta before up here at the panel as well. Dr. Carl Morris is a neuromuscular specialist. It's a at Solid for about 7 or 8 years. But before that, he was at Pfizer working on a lot of their programs. But as you can see, we are really stacked across the board. Of note, we have a regulatory Chief Regulatory Officer on the executive team. I think that's extremely important in a complex environment that we're working in a gene therapy to have. Our Head of Tech Ops, who's also on this slide, Paul Herzich, is a gene therapy manufacturing specialist. He, prior to AavantiBio, he came from BridgeBio. He was the CMC -- the Vice President of CMC for BridgeBio and before that, Logic and Novartis. So we have a very well routed executive team. But it doesn't just start at the executive -- it doesn't just stop at the executive, you really need multiple layers throughout the team to really build a true platform company. A lot of people say, you have a platform company, but this merger is put all the pieces together to do that. We have the ability to make constructs new gene therapy constructs for new diseases, optimize those -- that transgene. We're working on promoters. You're going to hear us talk a lot about capsids where we're building our own capsids for next-generation delivery. We have vector cores as well as PD labs that we can make small scale material on our own. We do not have to go a CDMO. We have the ability to go up all the way to 500 liters in-house. So we really do have a platform. And you're seeing that platform come together now when you look at our pipeline. Our pipeline starts with our Duchenne program, our next-generation Duchenne program, followed by FA and BAG3 that I'm going to go into today, but you can also see we are working on multiple cardiac programs have not been disclosed. A few of those will be disclosed first half of this year. One of the best parts about putting the 2 companies together is this next-generation capsid delivery platform that were both building independently, and now we've merged them together. And there are 2 very different approaches, but we're going to be able to combine the capsid library together course of '23 and into '24 on one side of the screen, you'll see the cardiac capsid library that we're working on looking at multiple libraries using unique barcodes and artificial intelligence. And then with these barcodes, we have 3 different animal species that we'll work on in 2023, 2024. That will be mice, nonhuman primates and pigs, and we will look for RNA-positive cardiac selection and the DNA for negative liver selection. Now on the -- that's for cardiac. On the other side, for skeletal muscles, we're taking a very ground-up approach where we're doing point mutations within capsids as well as peptide insertions. And we're looking for speed of delivery and speed of delivery in the next phase of Duchenne is going to be extremely important. I'm going to about that. How fast can we deliver the transgene and express proteins as quick as possible. And this is where our capsid came out of for our next-generation Duchenne program. It came out of the library that Carl has been working on using peptides and point mutations and I'm going to talk about that. Combined, this is going to be a very powerful platform that's going to continue to evolve of the course of 2023 and into 2024. We will use this platform not only for internal programs, but out-licensing for nondilutive financing once we have all the animal data in hands. Manufacturing capabilities. We took the best pieces of both Aavanti and solid and put them together, and we have every aspect of manufacturing that you really need to think about when you want to be a platform based company. We have process development teams, analytical development teams, and we're very very fortunate that we have gene therapy CMC regulatory teams embedded in each one Of our programs right from the very beginning. Because in this complex world, dealing with regulatory agencies and gene therapies, you need to have a sight on regulatory for the beginning from a CMC standpoint, and we have those teams in place. We also have our CDMO partners across the board for FA for Duchenne, for BAG3, but it's one thing to have CMC partners -- CDMO partners. It's another thing to make sure that when you hand it off to them after your process development that you have very established MS&T, manufacturing science and technology teams embedded into those CDMOs, and we have that in place. We also have a vector core that can produce small-scale material for our research teams, 2 to 3 different constructs per week can be made. In that way, our R&D teams get the material they need for mouse models, but our PD, AD and MS&T teams get to focus on the big picture of Duchenne, FA and BAG3. It's already paying benefits to our first program, and I'm going to talk a little bit about this. We have switched Solid's old first-generation 001 program, and we have moved it into 003, which have moved into triple transfection and optimizing a capsid. And as you can see here, we have already -- could show multiple fold difference compared to AAV9 and our first-generation program by tweaking the process development as well as changing the capsid. So we're very, very pleased about the process changes and how this could affect our microdystrophin program or FA or any other program that we're working on. Now I want to let you know that we're well positioned for strategic pipeline growth and we have an eye on BD, not only internally -- for bringing programs internally, but also looking at opportunities externally as well. We take a very hard look at the different indications that we into our pipeline. And we have a commercial lens right from the beginning, making sure that once we think about all the indications and the reimbursement that we have a significant amount of population within our indications for once we hit milestones that they should have major inflection points for our investors. We have all the internal capabilities. We're continuing to build our network and then we have the strategic manufacturing in place. And you already see that within our pipeline. First program is going to be our next-generation Duchenne program that i'll talk a little bit about followed by FA and then our third program, BAG3 dilated cardiomyopathy. But as you can see, we have 2 other cardiomyopathies that are listed here that will be announced sometime this year, one for dilated cardiomyopathy, another for Hypertrophic cardiomyopathy. Now let me go into Duchenne. This is going to be our next-generation program, and I know many of you know Duchenne so I won't spend a lot of time on it, but it's caused by this mutation in the dystrophin gene, which leads to the absence of dystrophin protein. And once you have this absence, the child, unfortunately, lose their ability to walk in their early teens and then succumb to respiratory and heart failure in the 30s. Now there's roughly 10,000 patients in the United States, but more importantly, this is say 10,000 patients is the subset of patients that's below that number, the early children, 3 to 7 that are naive, the children that have antibodies right from the beginning to all the programs that are out there. It's the older patients, and there's subsets of older patients that are non-ambulatory with low ejection fraction or respiratory failure, how are we going to dose these children because they are all not getting to follow the same disease progression. And our plan is to drive functional microdystrophin expression as fast as possible and then we're going to deliver what we believe will be the best-in-class transgene. Now how are we thinking about this when we create our next-generation program. We took the best pieces of what we thought across the board, and we put them together. We started with our transgene. And this is the same transgene that Solid was using in their first generation program. Why did we keep this transgene? You're going to see publications and presentations come out in this first half of this year, where we're going to be presenting data for those patients that they dosed in the 001 program, their first generation program out to 3 years. So we have patients that are going to have 3 years' worth of data, 2 years' worth of data and 1 year worth of data. And what you are going to see in that presentation, in that publication is that compared to natural history, 6-minute walk test, pulmonary function in SAA across the board, these children are acting very, very different than natural history would tell you otherwise. And so we're going to take that transgene because we know it works, and we're going to put it in our next-generation program. We've switched to a new capsid, moving away from AAV9 into this SLB-101. This peptide insertion with point mutations because it drives expression very, very quickly, and that's extremely important when you're thinking about the world where you might have to redose. And I'll talk a little bit about that. And then we've changed to triple transfection manufacturing process. And with these changes of capsid as well as triple transfection manufacturing process, you can see that we're increases in the microdystrophin compared to their original program. Now why is it important that we drive expression very, very quick. Think of a world where we have to work on redosing or children that already have antibodies to these drugs or older children who have low ejection fraction than pulmonary function, how do we think about giving them different doses and coming back over and over again to make sure that we can drive expression. It all starts with can you transduce in a very short window. Can you transduce and start to express in a very narrow time frame so you can drive down these antibodies. And we can show now with our new capsid in 4 days, that's the top bar, in 4 days, we can drive transduction has already occured because this is expression. And we're getting almost 75% to 80% or some of the mice 100% dystrophin positive fibers by 4 days. I've never seen this data before in Duchenne. And I think it's pretty significant because it gives you the flexibility to start thinking about how we can get into redosing down the road. And at 30, 29 days across the board minus a couple of mice, across the board, we can drive expression very, very quickly. This is dystrophin positive fibers. So this is not Western Blot or anything like this, just how many fibers are positive. We also can see this capsid is acting very, very differently than our first-generation program. On the left-hand side is biodistribution, in the middle is expression and on the right-hand side is disease progression looking at CK. Now in children CK fluctuate up and down because they're running around like crazy because they're feeling good after they get dosed. In a mouse model at 29 days, it is a very good point to where you look at disease progression. And you can see pretty dramatically that our SLB-101 or our 003 program is acting different than our first generation program. From biodistribution, full change above AAV9 across the board in the quad and hard is different. However, it is deliberately targeting compared to AAV9 as well, and then microdystrophin expression in the middle, you can see, now this also translated over to nonhuman primates. This is a reporter transgene but you can see in frontal skeletal muscle, cardiac muscle and liver compared to AAV9, significant increases in biodistribution, the skeletal muscle and cardiac, however, liver detargeting as well. We have dosed our GLP Tox non human primates where it's a 3-month study. We're not halfway through, but we're close to being halfway through. As of this morning, all the animals are alive and well, doing well for this GLP Tox. And we're using this capsid, this transgene, et cetera. And we'll have additional data that will be coming out later this year. Now FA, if you don't know FA, it is a serious disease, monogenic disease caused by the loss of frataxin, when you have this loss of frataxin, you have -- 1 of the most important things to understand about the disease is a multisystem disease. Both the CNS and neuro manifestations as well as the cardiac manifestations are very severe. It's roughly 8,000 patients. And our approach is to make sure that we tackle the entire disease population, all the patients from the CNS and neuro side as well as the cardiac side and we're doing this by dual route of administration trying to increase frataxin across the board because it's not just the amount of frataxin that is needed but it's also the distribution of frataxin to the affected areas. And I'll show you some of the data. This is the cardiac mouse model, and we feel very comfortable frataxin, if you overexpress you can get to toxic levels. And so what you want to do is you want to push the dose as high as possible to understand what those frataxin expression limits are and then drive the dose down. And we started in the E14 and we're already down to the E12 each well. This -- the lowest -- the best dose on this is 6 each valve via IV. We can increase ejection fraction, we can increase survival. However, we also think that we can actually go a little bit lower and we're going to continue to tweak this as well. One thing of note, we want to make sure that we are -- when we're restoring frataxin that we're restoring the health of the mitochondria. And that's what you see on the right-hand side of the screen. Succinate hydrogenate in patients who have FA when you do autopsies and you look at the mitochondria and the DRGs and the heart succinate hydrogenate is completely depleted. So we want to know can we restore the health of the mitochondria. And by increasing frataxin, we can restore the health and mitochondria in store ejection fraction and survival. We think it's extremely important, as I mentioned before, that we look at long lease up for tax in expression over a broad range of targets because it's not just the amount of frataxin, but it's the distribution of frataxin. This is a 6-month nonhuman primate study. So it's a long study. It's a lot of animals. And what we did is we took multiple doses -- but we also dosed them 3 different ways, IT only, IV only and dual route of administration. So we could understand if we can get to a nice therapeutic level, therapeutic range within the cardiac as well as the DRGs by doing this elegant distribution of dual route administration. And we feel very comfortable that we have tackled the cardiac side, we're still going to continue to work on the CNS side in 2023 as we move forward into our IND-enabling studies. But this was a big study, and this helped solidify that dual route administration can provide for tax in expression to a broad range of targets without increasing toxicity. Our third program is BAG3. This will be our first cardiac program coming out of our pipeline with others to follow. If you don't know BaG3,BAG3 codes for this BCL2 associated enthanagene3 protein or BAG3. When you have reduction in BAG3, you end up with cardiomyopathy and you ultimately have heart failure. This is a very large population, 29,000 patients in the United States, high incident population per year as well. If you have reduction in BAG3, your life is severely impacted. Eventually, heart failure sets in. Once you're symptomatic, 25% mortality in the first year, 50% in 5. If you are a patient, you are seeking treatment for this disease state. Now we are taking an approach using RH74 as our capsid with a cardiac-specific promoter and as I mentioned before, all our programs are triple transfection across the board. And we looked at multiple different aspects of this. We looked at how does -- multiple different capsids, multiple different promoters and how do they all compare. This is just a subset of that data because we had a program that was using AAV9 with a specific promoter. We also had the program using RH74 with that same promoter. And you can see on the left-hand side is biodistribution -- on the right-hand side is expression. First 2 columns are Second 2 columns are AAV9, both using the same manufacturing process, and you can see significant differences. So we think we're well on our way with this program. We're going to continue to evolve this program and tweak this program. We're working with an expert in the field, Dr. Eric Alder Adler and out of UC San Diego with his lab and that program is ongoing as well. Of note, on the right-hand side, you can see that our program is liver-targeting compared to AAV9 as well. We think that, that will help us drive the doses lower. Driving to the future. Last slide, what are our milestones this year. We are going to complete our GLP Tox. I just told you a couple of minutes ago. We're not halfway through, but we're close to halfway through our GLP Tox. All the animals are doing well. That should be completed in the next couple of months. We are going to report functional data from the first-generation program that has been paused. And remember why. We're using that transgene from the first-generation program for our next generation. program. And this publication is going to show you that these children that have been dosed out to 3 years are acting very, very differently in natural -- compared to natural history, 6-minute walk test, pulmonary function, NSA across the board. So from a durability standpoint and from an efficacy standpoint, you can feel very confident. We're going to have an IND submission second half of the year and hopefully first patient dose at the end of the year as well. We're going to continue to tweak and evolve our FA program on the CNS side. We feel very confident we've nailed the cardiac side. We're going to continue to evolve the C&S to make sure we get into therapeutic ranges, continue to transition from HSV to triple transfection Candidate selection for this and move into IND-enabling studies as -- and then we're going to be very thoughtful, but aggressive on BD and how we continue to enhance our pipeline, how we think about in-licensing assets that will continue to evolve solid and also out-licensing the cardiac capsids, the skeletal capsids for nondilutive financing in the future. Of note, as I mentioned before, we have $214 million of cash that is unaudited. That is on December 31, and we expect that to take us into 2025. With that, thank you very much.

Thanks so much, Bo, [Operator Instructions] Bo, I wanted to start out, just actually on a quick comment that you just made on business development. When you think about that in terms of your pipeline -- early stage pipeline today, would you consider clinical stage or mid-stage candidates versus, say, additional preclinical assets?

Yes. That's actually one of our goals this year, and we've already kicked off multiple processes and looking at opportunities to where we can augment our pipeline, get value inflection points early on. I think when you're building a precision genetic medicine company, you need to stagger your different programs, especially from a gene therapy standpoint because of the CMC. So we're moving our gene therapy programs. They're staggered by about 1.5 years a piece, and then we're going to look for BD opportunities to augment our pipeline in clinical stage or very close to clinical stage where we can get multiple inflection points over the year. We're going to stay within this precision genetic medicine realm, and we're highly focused on neuromuscular and cardiac indications. However, we -- if it's something great comes across the board, we really won't shy away.

And then on 003 in DMD, given the competitive landscape of Sarepta, Pfizer and those products potentially coming to market as soon as this year, where do you see the pockets of unmet need in the microdystrophin gene therapy...

Yes. I think, one, we're going to let the data play out for Sarepta. One, I think anyone who's in New chais rooting for therapies to hit the market and change the patient lives forever. And that's our goal. And we're going to continue to evolve programs, whether Sarepta's program or Pfizer's program gets on the market, continue to evolve and try to make best generation and better programs that can help patient lives. And we're going to take a look at the data. Once we understand where the gaps are, where there's opportunities, that's what we'll target. Right now, for our program, it's more important that we establish safety. We dose the next 10 patients in Phase I, it could be 10, could be 12 in Phase I. We establish safety. We look at microdystrophin expression. We're very confident that it's going to be different than our 001 program based on what we're seeing in preclinical models. And then we're going to strategize on where is the unmet need based on the data that's out there based on the landscape, and we'll continue to adapt.

Questions from the audience... What are the gating factors right now to that IND submission in the back half of the year?

Carl?

So we're in the midst of the GLP tox studies and also the GMP manufacturing campaign is sort of kicking off. And so we're just going to guide -- we just need to get the clinical material.

And where is that clinical material coming from? And how should we think about the progress to getting like commercial...

We've announced previously that we're with Forge Biologics as our CDMO. And we've scaled up to 1,000 liters. And so we're just looking to that to continue to process material and release it.

Questions from the audience? Malcolm...

Maybe it's too early but given that.. various muscle tissues behave differently, and we're probably going to see various degrees of duration. How should we think about redosing there?

I think redosing is going to play a very big role down the road in Duchenne, whether we don't know the time frame. But there's a large population that are going to need some type of approach right from the beginning that already have antibodies to the different capsids that are out there. So you're already going to have to start thinking about a type of redosing strategy where you can knock down the antibodies as well. And I'll turn it over to Karl for a second, but we're looking at multiple different ways to think about redosing. We're already in talks of different partners of how we can think about this. And -- but it starts with our program to understand can we transduce and express within that first week because when you knock down the antibodies, you don't want to do it for an extended period of time, especially with patients that are steroids and have compromised immune system. So what we needed to understand is with this next-generation program, can we transduce within the next first couple of days and start expressing. We were completely surprised that we're seeing the expression that we're seeing within 4 days. That means transaction occur very early and an expression. So it gives us the opportunity and the flexibility to now find multiple paths. But maybe, Carl, do you want to talk a little bit about?