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

All right. Welcome everyone to the 42nd Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the Senior Biotech Analysts here at JPMorgan. I'm joined by my squad, [ Lorea Hall ], Priyanka Grover and Malcolm Kuno. Our next presenting company is Solid Bio. Presenting on behalf of the company, we have CEO, Bo Cumbo. Bo?

Yes. Thank you very much, Anupam, and thank you JPMorgan for the invitation. I really do appreciate it. I'm going to be making a number of forward-looking statements today. Please take time to look at the forward-looking statements on the deck. We also filed on the 8-K. Obviously, results may vary. So, please take a moment to read this. So today, we're going to be talking about Solid and really the transformative changes that we've made over the last year is really leading platform, partners, pipeline management and a very strong balance sheet. Our management team, we just recently added our new Chief Medical Officer, Dr. Gabriel Brooks' team. He really rounds out the entire team now. He's a cardiologist by training, most recently came from Pfizer gene therapy programs and joined the team in October. So now we have a full team of very experienced professionals in the biotech world. Our pipeline was put together very thoughtfully and strategically, where each and every program builds upon each other, high large populations, high unmet need and significant mortality that we're going to try to correct. We have collaborators around the world now. So it's no longer solid on its own. It's UCLA, Nationwide Children's Hospital, University of Missouri, Duke, Wisconsin, Iowa, all of these universities and thought leaders are supporting us and helping us with our program. So, we really do have depth and breadth outside of Solid to transform lives. We have platform capabilities that we believe are unmatched, not only from a cardiac and skeletal capsid library, but also our manufacturing capabilities, and we'll talk a little bit about that, focusing on not only yields, but also the full-to-empty ratios that really do matter when you're thinking about delivering gene therapies. And we'll spend a lot of time today on our first IND that's now open for 003, our next-generation Duchenne Muscular Dystrophy drug. So this is our pipeline that we'll talk about. Obviously, I'll spend most of the time today talking about Duchenne at the top, but then I'm going to skip down and focus in on CPVT, the RYR2 and CASQ2 mediated CPVT, which we will have an IND roughly 12 to 15 months from today. So we're very excited about that program. Then I'll spend time on BAG3, dilated cardiomyopathy, and I'll also talk about our platform technologies, capsids and manufacturing. So we'll dive into our lead program. Everyone knows what Duchenne is. It's top of mind of a lot of different companies. And rightfully so, because it's a high unmet need and where we need to make dramatic changes to these kids' lives. We have what we believe is truly a next-generation program, and it really starts with 3 aspects of the program, the transgene, the capsid and the manufacturing process. From the transgene, we have a very unique transgene, one that has domains that other companies do not have. It starts with the repeat domains of R16 and R17. When you have R16 and R17, you're able to recruit for a couple of different proteins, alpha-syntrophin and others, and then that creates a binding spot for nNOS. In preclinical models, when you have nNOS, you have Vasodilation, ultimately increased blood flow, and that creates healthier, heavier muscles. Now we think that this is going to play a role in the longevity to children. When we look at mouse models, when we look at fast-twitch muscle recovery in the EDL, you see come right back to normal. And this, we believe, is due to the Vasodilation ultimately to the blood flow. We also have removed a couple of the hinges to create a very flexible microdystrophin in nature. So as the muscles are contracting, the microdystrophin that we've created, it has enough flexibility to move with the muscle. Therefore, you try not to have breakdown of muscle, and you do see some [ ring ] fibers in preclinical models when you have different hinges. And so we've removed those hinges to make sure that we have a very flexible construct. And really, what's the most important is not just the transgene, but can we get that transgene into the nucleus into the muscle, and it really starts with the capsid. And we have a very unique capsid never been used before first-in-human studies. And we both preclinically, we have a lot of data that shows that this capsid is significantly different than the parental capsid AAV9 and I'll talk a little bit about that. It all starts with delivery, how fast and how robust can you get this transgene in? And at day 4, we're getting 50% to 75% microdystrophin expression into the heart, into the diaphragm and the quadriceps. It's really unheard of. You don't see transduction and expression within a week. But this capsid has increased binding capacity. We've actually put this capsid in the face of IVIG at 0.5, 1 and 2 grams per kg, looking at can we bind and transduce and express in the face of antibodies. And the answer is yes, and we have significant expression even in the face of IVIG. Now, one of the things we wanted to understand is, now that we have expression at day 4, what does expression look like at peak at day 29 or day 30? And we are going to take biopsies in our children at day 90. So, does that expression hold to day 90? And the answer is yes. As we are looking at different muscle groups, this is 6 on the screen today, you can see, once again, day 4 expression which is unheard of, very robust peaks at day 29, and it holds all the way to day 90. That gives us a lot of confidence as we're taking our biopsies at day 90 in our children that we're going to get robust expression. Now one thing that we didn't really notice in the original study is a dose curve because at 3E13, 1E14 and 3E14, we're all getting to 100% expression. So where is this dose curve? So we went down. We went all the way down to 2 each well. This capsid is acting different than other capsids. And you can see very robust expression in all the muscles, however we found the dose curve. You also see that nNOS expression, which we believe is ultimately very important, especially when blood phone, you're thinking of endurance in these children. Blood nNOS is 100% at 3E13. Keep in mind, we are dosing our children at 1E14. Even though we're getting significant amount of expression at 3E13, we're going higher. One, we have the safety window to do so, and I'll talk about that in a second. But two, we really want to put our best foot forward and really try to help these children and deliver as much microdystrophin expression as possible. Now how does it compare to Solid's original program, we're using AAV9. Well, in biodistribution, expression or disease progression looking at CK is significantly different than Solid's original program using AAV9. Of note, in the nonhuman primate study when we did our GLP TOX in the diaphragm, we were getting 5x to 10x greater biodistribution in the diaphragm, which is a very hard muscle to drug, 5x to 10x greater in diaphragm. Think about all the children that have pulmonary function decline. We don't know yet if that's going to make a difference. But our hypothesis is the increased biodistribution will increase expression in the diaphragm. We already know it's going to the heart very well. And this will help a lot of the nonambulatory children. Now, we looked at Grip Strength. I already mentioned, we looked at fast-twitch muscle and the EDL can recover. We also looked at Grip Strength, treadmill exhaustion and mass spec. Now, take a look at the doses. This is 3E13 once again at the high dose, we're dosing in our human subjects to 1E14. And I showed you before, we're already at 100%. Now we're looking at a mass spec percent normal dystrophin, we're getting to 100% at very low doses. And we already know that we can change Grip Strength, change treadmill exhaustion, change recovery of the EDL. So we're very excited about that. It looked the same in the nonhuman primates. When you look at biodistribution, the skeletal muscle, cardiac muscle, and it was also liver detargeting, very similar to what we saw in the mouse. Now, I'll be very clear on GLP TOX, because Solid of old had issues when they were dosing their children. This, we did not receive one single question from the FDA in our IND on safety, not one. It was well tolerated in both groups throughout the study. There were no mortality events. There were no unscheduled takedowns. We didn't have to intervene at all in the study. There were no pathology findings, no organ weight changes. The liver enzymes were comparable to vehicle at the target clinical dose, and we dosed up to 3E14. So we feel very comfortable in the study. Now what is our primary objective? Well, let me start by saying that we are actually trying to get IRB approvals right now. We should have that approval by the end of this month, maybe early in February. We will be dosing patients' mid-quarter to the end of the quarter. That will start our first patient dosing. We have to wait 30 days in between patients. Our primary objective is obviously safety. Our second is going to be looking at efficacy and focus on microdystrophin expression and some other clinical endpoints. Our first trial, our first cohort is going to be aged 4 to 5 years of age, low weight. And we're going to be dosing, as I mentioned, minimum of 3, most likely 4 patients in this cohort over the course of the next couple of months. Now we have here Cohort 2. However, if Cohort 1 looks really well, microdystrophin expression, as well as safety, we will speak with regulators and think about amending to go into a double-blind, placebo-controlled trial as fast as possible. So as I mentioned before, the primary endpoint, looking at safety and then looking at expression, timing. Well, if everything goes well, we'll be dosing patients over the next couple of months. We should finish dosing right around summer. So over the summer months, we should be able to announce that safety and that we're through our Cohort 1. If that timing holds up, that means late Q3, early Q4, we'll have all the microdystrophin expression for everyone to see, as well as patient videos, baseline and day 90 and some clinical endpoints, albeit 90 days after you the start of the dose. Now, as I mentioned before, we're going to give all that readout in Duchenne late Q3, early Q4 if our timing holds up. At that point, we're 5 to 6 months from our next IND, which is another fatal young disease. We talked about Duchenne. Everyone's focused on Duchenne because it's such a horrific disease in children. If you don't know this disease, you should get to know it, Catecholaminergic Polymorphic Ventricular Tachycardia get diagnosed age 7 to 12, sometimes as low as 5. Mortality is 40% in 10 years. Your quality of life is severely impacted. And you could have a spontaneous arrhythmia at any time and die. There is no drug on the market to treat the underlying cause of this disease, and we believe that we have a solution. What we're trying to do is soak up the excess calcium that you see in the sarcoplasmic reticulum that you can see here that causes these arrhythmias. Once you overexpress calsequestrin, the normal rhythm should come back to these children. When we look at animal models, this is for RYR2. By the way, 20,000 patients in the United States have this specific mutation here, RYR2 in 3 different doses at 12 weeks, all arrhythmias are eliminated. For CASQ2, which is a much smaller population, roughly 1,000 to 2,000 patients in the United States, once again, at all the doses, at all the time points, all the arrhythmias have been eliminated. We're very, very excited about this program, and we will be in the clinic roughly about 15 months from today and about 5 to 6 months after we read out our Duchenne program. So a lot of inflection points for investors to get behind. Now, what we're going to do, this will be a global trial. We'll start in the United States, but we'll have multiple sites. We already have orphan drug designation. We will be seeking rare pediatric disease designation. We're very hopeful to get it. We don't have it yet, but this is a childhood disease, and we believe that we can get it. We're also going to plan to apply for the innovative licensing and access pathway. So we can start talking to payers about reimbursement for this deadly disease. As I mentioned, it's 20,000 to 22,000 patients in the United States, it's larger population ex-US. Now, as we're going into this IND for CPVT in Q1, we'll be dosing patients in the first half of the year, 2 to 3 quarters later, another IND for another fatal dilated cardiomyopathy called BAG3, codes for this BCL-2- associated athanogene 3 protein. And once you have these reduction in proteins, you end up cardiomyopathy ultimately end up at heart failure. We're taking rh74 with this very specific promoter, and we're applying to this. We're working with Dr. Eric Adler at our UC San Diego. We're very happy to have his lab supporting us on this. And this is a big population in the United States, greater than 20,000 patients. Now, our drug specifically goes right where you need it. You needed to go to the heart. You don't want it to go other muscles. And you can see that we're not going to the gastro. We're not going to the liver. We're going to straight to the heart. We use a very specific cardiac promoter with rh74. We get to 80% of the cardiomyocytes, and it's positive for BAG3, so we're very excited, and we actually don't believe that we need 80%, so we can pull this dose, hopefully back down to lower levels. When you look at the mouse model on the left, we wait until we see a phenotype, and that's when we dose. And on the right-hand side, we can eliminate cardiac dysfunction, right back to wild-type vehicle, so rescues cardiac function at week 24 at a very low dose 2E13. Now our platform technologies, I believe we have some of the best, not only manufacturing, but capsids. This is our next capsid. It's called SLB134. Kevin likes to call it snow leopard, because it sneaks up on you. It gets right to the heart, but it bypasses the liver. And it's a 1,000-fold liver detargeting compared to what the parental capsid was. So, this is a mouse. We want to see if it's going to be the same in the monkey. We're going in nonhuman primates this quarter. If the nonhuman primate holds up to what we see in the mouse, this can change the way we think about gene therapy and all the events that you could have by overwhelming the liver. It's a 1,000-fold liver detargeting. However, it still is cardiac tropic as you can see, the parental capsid. Now our manufacturing platform, we believe is one of the best, not only from yields, which we've increased yields about 20x. We've also moved away from triple plasmids to dual plasmids. And you can see when we move to dual plasmid, you can see increase in yields, it obviously lowers COGS, and we're significantly proud of our achievements there. But we're also proud of what we're seeing in our full-to-empty ratio. Compared to other CMOs and other companies that we know about, we have the highest full-to-empty ratio with the exception of one company that I know of in the space. Now when we talk folds, we talk two-folds. We're not talking partials, partials, we lump into empties. Some companies want partials in with folds. If we did that, we would be saying 97%, 98%. However, if you want to talk from a purest point of view, two-folds batch-to-batch somewhere between 77% and 81% two-folds. It really does matter. When you think about how you're dosing children, you're dosing BG to KG. And so you're going to have to increase your viral capacity for that child and also increase your COGS to get to that true dose. So when you start at a very high full-to-empty ratio like we have, one, hopefully, it should help on safety, 2 on COGS. So, a lot of achievements that we have, a lot of milestones that we're going to have this year. One, we're going to be dosing our first patient hopefully this quarter. We're going to read out safety over the summer. That will put us in time frame of late this year to also read out our microdystrophin expression late Q3, early Q4. We're also going to be filing CTAs. If we have great data, why not go global and why not go into a double-blind placebo-controlled trial. There's going to be a lot of patients not only in the US, but especially ex-US that are going to need a drug. So we're going to file our CTAs. We're going to wait and see what we have and then we'll quickly move into another trial. At that time, we're only 5 or 6 months away from CPVT IND. I told you before, highly fatal, very young and life altering. And we believe that we have a way that we can solve this. A couple of quarters after that, BAG3, IND, our capsids are going to go through multiple rounds of nonhuman primates as well as [ pace ]. And our platform technology from manufacturing is going to continue to advance. So with that, I'll say thank you very much. I appreciate your time. And once again, thank you, Anupam.

Thanks, Bo. [Operator Instructions]. So on SGT-003, you talked about enrolling that first set of patients. Have you identified these patients? Have you map them to a site?

Well, yes and no. I mean, we need to get IRB approvals first. Obviously, so our sites, Nationwide Children's Hospital and UCLA, Dr. Perry Shieh, Kevin Flanigan are very well-known experts in the field. We have a number of families that are trying to get into the clinical trial. They have been calling. They're even changing their children's steroid regimen, because you have to be on a 3-month stable steroid regimen prior to getting into a study. So they're already calling and asking and thinking a trial. Of course, as I mentioned before, it's only 4 patients. So there's not a lot of room. We really can't screen until we get IRB approval. So we're going to get IRB approval hopefully this month, maybe early next month, but then we'll have multiple patients to screen at that time, and then we can say, we've enrolled or not.

Can you comment a little bit about the age of the patients that are going to be enrolling in the first couple?

Yes. It's 4 to 5, and this cohort is 4 to 5 years of age. And we're not going to have trouble enrolling, if that's the question.

How are you thinking about scenarios around the [ Levites ] label expansion and how that will either impact your near-term or long-term development of SGT-003, whether it's from a clinical or enrollment perspective?

Yes, that's a great question.

I know little something about that.

Yes. And look, I think everybody at Sarepta, Solid, Pfizer, we all shooting for the same thing to try to help these kids. So let's start there. I think what we're doing is, we're going to go into the United States. We're going to go into ex-US. It's going to be a global trial. There's a lot of demand. All the families are always looking for things that are going to provide a true clinical benefit for their child. So whatever happens with [ Levites ] here in the United States really doesn't impact our plans. We know that we have significant demand in the states already for our clinical trial. We're going to be filing CTAs as I mentioned, throughout this year in multiple countries. Obviously, [ Levites ] will not be outside of the United States immediately, if at all, we just don't know. And there will be plenty of patients. So, it really doesn't affect us. We've got our game plan, double-blind, placebo-controlled trial will be coming. We'll pick a different endpoint. We'll focus in, and we'll be ready.

Questions from the audience?

Hello. Thank you for the nice talks. So you mentioned that you use the dual plasmids system for the production. So, 90% for ratio is really high. I mean that's really clear. So can you disclose your productivity? We know that dystrophin is pretty big. So usually, we have very low yield. So do you have data for like the productivity?

Yes. So that's a great question. So let's start with the manufacturing process. We've made about 5 changes over the course of the last 12 to 15 months. They've really dramatically changed not only the yield, but the purity of the drug. Now for Duchenne, what you don't want to do is you don't want to change your manufacturing process in the middle of trials, especially when you're trying to go straight into a double-bonded placebo controlled trial after this cohort. So you want to hold your process type. We already had a pretty robust process, especially from a full-to-empty ratio. We were using triple plasmids prior. And so the Duchenne program was using triple plasmids, we were getting significant yields and high full-to-empty. We won't be altering that process. Now everything I mentioned before about changes moving to dual plasmids, that will be implemented in our cardiac programs right from the start and as well as the high full ratio. As Duchenne, we'll wait to post marketing to implement the changes in manufacturing. If you're talking about yields, obviously, you have to scale up. And so everything that we're doing in our PD labs, if it's scalable to 1,000 liter, you're talking high E17, low E18s at that level. So it's significant. From a COGS standpoint, I would have to think it's one of the lowest COGS out there, some of the lowest COGS out there.

You mean that you use a triple plasmid transfection for the DMD?

For DMD, we're using triple transfection, triple plasmids until post marketing, and then we'll do a bridging set, so cardiac will use dual plasmids.

How about the dual plasmid system? What's your recovery?

65%.

65%. Great. Thank you.

Additional questions?