Solid Biosciences Inc. ($SLDB)

All right. Thank you very much. My name is Bo Cumbo, representing Solid Biosciences, and thank you, Goldman Sachs for the invitation. So we're going to be making a few forward-looking statements. Please take time to look at the cautionary note regarding forward-looking statements and take the time to read through it. As you know, this is science, and it's hard to predict sometimes, but I'll be doing my best to look forward. So here's the pipeline of Solid Biosciences. It's a very robust pipeline. We're going to be up top Duchenne and FA, followed by a maturing cardiac pipeline that is one of the deepest cardiac pipelines in the gene therapy space. Today, I'm going to be really focused in on Duchenne and FA, and I'll touch a little bit on our platform. As mentioning before, we have 2 programs that are already in the clinic as well as our Capsid platform and manufacturing platform. Our program, our novel next-generation program for Duchenne called 003 is currently in Phase III clinical trials as well as we're continuing to enroll in our Phase I/II INSPIRE program, which we've already dosed 51 patients as of this week. We also have the first-in-class dual route administration for Friedreich's ataxia targeting not only the cardiac but CNS manifestations of disease is another program, just like the 003 program for Duchenne that we're extremely excited about. And our Capsid library is becoming very robust. We do have Polaris out there. We have 50-plus agreements with academic labs as well as small companies. But by the end of the year, we should have multiple other capsids that we can license out that are going through nonhuman primate studies currently. So let's spend a little time on 003. We believe at solid, when we think about Duchenne, we take a -- we look at the disease from a muscle integrity standpoint. And realistically, we look at both acute and chronic biomarkers of muscle integrity. And that gives us a lot of confidence to understand the long-term clinical benefit of this drug as we enter in the Phase III double-blind study. So we'll take a little look at in a second of all the data that we've accumulated to date and why we feel so confident that we are providing these young boys clinical benefit long term. Our next-generation program consists of really 3 important factors. Realistically, there's a fourth factor that's not up here, and that's the manufacturing. But we look at our program in 3 buckets right now, a novel microdystrophin transgene. This is a unique transgene compared to all the other programs that are currently out there, and that's because of the inclusion of this repeats of 16 and 17, repeats 16 and 17, which is this in nNOS binding domain. And when you have nNOS, you could increase blood flow, decrease inflammation, decreased induced ischemia as well as muscle injury. And we believe this is one of the benefiting factors of our program. We use the CKA promoter. It's highly active in both cardiac and skeletal muscle. And then we have this next-generation capsid called SLB-101 now named POLARIS-101. Just for background, why did we rename POLARIS is because we're -- as I mentioned before, we're talking about our capsid platform. By the end of the year, we plan on having multiple other capsids available. And so we want to make sure that we brand them, distinguish them from the others. But this capsid that we're using in our Duchenne program, in preclinical studies, it was really quite amazing. It was liver detargeting in both the mouse as well as the nonhuman primate. We got better distribution depending on the muscle group. We could get the diaphragm up to 10x better distribution than AAV9. You can get 3 to 4x better distribution in the quad or the gastroc. In the -- as far as cardiac goes, when we compared it to AAV9 and looked at actually expression in human cardiomyocytes, we saw about 20x better expression in the heart. And that's due to this RGD peptides that are scattered across this capsid, really binding to endocrine receptors and driving quick and rapid expression. So it has an increased binding capacity over all other capsids that binds, transduces and expresses very quickly. Of note, we've also learned that this capsid clears the human body very, very fast. And we are seeing it in our human subjects, our current patients in the INSPIRE trial. It's 90% cleared out of the whole blood by day 4. We think that, that's really going to make a difference when you think about safety, especially from like an aHUS or TMA standpoint. As the body is looking to clear the antigen, it has already left circulation. And I think that, that's going to play an important role down the road. So we take a look at our human data in multiple different ways, not only from an expression standpoint, but also from a muscle integrity biomarker standpoint from the acute phase to the chronic phase and then toward this satellite cell preservation phase, which is embryonic myosin heavy chain. But it all starts with [ Transduction ] & Expression. Some people really enjoy Western Blot, others like to talk about Mass Spec. I personally like to talk about positive fibers. We provide it all that way. Every single person can get what they want from this. I think I get asked all the time, what is my favorite point about our data. And truthfully, it's the consistency of it. It does not matter what you want to look at. It's very consistent across the board and very linear. And so I think that should give you a lot of comfort that no one is cherry picking data here. It's all our data, and it all looks roughly the same. And so Western blot, mass spec positive fibers look good, but we don't stop there. We take a look at this -- the dystrophin sarcoglycan complex, which is critically important to these young boys. And if you look at the individual proteins that will make up the complex, whether it's beta-sarc, delta-sarc, gamma-sarc, alpha-sarc, et cetera. Each one of these proteins provide a benefit for these little boys. And so we quantify that data. And as you can see here, very consistent with the expression data for dystrophin, beta-sarcoglycan is in the 60% range in day 90 and 69% at day 360. But we also look at nNOS. And as I mentioned before, this is -- nNOS is very important for blood flow, decrease inflammation, decrease oxidative stress. And this is an activity assay. So it's not like a Western blot. This is actually activity at the sarcolemma level. And you can see a 35% activity of this very unique protein. But then we take it a step further. We know that we're producing protein. And so what happens on the next phase, and this is the muscle integrity part. Remember, this Duchenne is a muscle integrity disease. It's -- and we look at acute as well as chronic biomarkers, and it does not matter what you want to look at CK, ALT, AST, lactate dehydrogenase go in chronic phase sort of Titin. Now some will say ALT, AST is a liver enzyme, not in Duchenne. In Duchenne, the entire skeletal muscle is breaking down. And so these boys, and I'll show you in a little bit, these boys baselines are 300, 400, 500 depending on the ALT or AST. And when you bypass the liver, when you have liver detargeting like our capsid does, you can actually take a look at how the muscles are reacting to our drug. And you see a decrease in ALT and AST as well as lactate dehydrogenase and then ultimately Titin. This leads us to what we believe is one of the most important biomarkers is embryonic myosin heavy chain. Now remember, it's a disease of regeneration degeneration, and that is what is going on in Duchenne. And when your muscles are breaking down in the degeneration phase, satellite cells are activated and proliferate and then they're trying to repair or generate new muscle fibers. And that's where embryonic myosin heavy chain comes in. And in Duchenne, you have a lot, and that's the baseline up top, you have a lot of this embryonic positive fibers that are activated. Now you don't want that. Normal healthy subjects should not have embryonic myosin heavy chain at baseline, and we're trying to drive that down. And we are seeing a decrease of roughly 44% in our little boys. And that gives us a lot of confidence at Solid that ultimately, we are going to see a clinical benefit in these young children. And that's when we -- how we design our clinical trial. We also take a look at cardiac care. When you look at how these little boys unfortunately pass away, it's due to mainly cardiac failure -- cardiac and respiratory failure. And so it's very important to look at cardiac benefit right from the beginning. Now some of the naysayers will tell you, hey, you don't have dilated cardiomyopathy or low ejection fraction at this early age. One thing is very important to know. You also don't wake up at 12 years of age and end up with an ejection fraction of 50% or 55% with a diagnosis of dilated cardiomyopathy. That happens over time. There is a drift that happens, and a lot of the physicians have become numb to it. And so they don't really talk about it all the time to the parents. One day, the child will come in, it's ejection fraction of 65%. The next year, it could be 63%, the following year, 61%. But that is significant over time, that drift that happens. And so we're tracking all our little boys. And what you see is you see while the vast majority of them will have normal ejection fraction at this age, you do see a subset of patients that are at least one standard deviation below normality, and that's somewhere right around the 58%. And we have 12 boys, 12 little subjects that have an ejection fraction in the high 50s. And of those 12 boys, each and every one of these little boys got right back to a normal level or had increases. And I think that's very important. We believe we have hypothesis on why, and there'll be more to come as we release more data. But it all comes back to the unique construct design that we have, the proteins that we can recruit for and the amount of protein we can recruit for. And that sort of combination, we think is what's driving some of this. Now this is the liver data that we look at. There's been a lot of emphasis on liver. This is 24 subjects, but if you ask me what all 50, 51 of the boys look like, it's going to look the same and we'll update this slide pretty soon. Now on the right-hand side, I think it's important to understand, as I mentioned before, we look at ALT and AST as liver -- I mean, muscle integrity biomarkers. And that's because look at how high they are at baseline. You're looking at 400, 500 at baseline depending on the biomarker, and these decline relatively fast. So that tells you that you are doing something, not only you're bypassing the liver, but you're also shoring up the muscle. Now GGT is flat, and that's exactly what GGT should look like. It should not look like an EKG, should be very flat. And you can see the whisker numbers, the whisker bars in there, and you can feel confident that to date, knock on wood, this drug has been safe. We've had no drug-induced liver injury. No aHUS, no TMA, no myocarditis as I stand here today. This is our overall safety profile. As you can see, as I just mentioned, it's looking very good. Of note, we did have a little boy that had to be admitted to the hospital and for a lab abnormality, and he was given 2 different types of doses of antibiotics, only antibiotics and was discharged and he's in the database here. But overall, our safety profile continues to look better and better as we accrue more patients. This is the overall results that I just went over. It does not matter what you look at or which biomarker you like the best. They're all extremely consistent, whether it's expression, whether it's muscle integrity, embryonic myosin heavy chain, CK, ALT, AST, et cetera, all the way down to troponin, which troponin decreases over time and the ejection fraction increases or stays stable. Now I'll switch gears [indiscernible]. This is our Friedreich's ataxia program, extremely excited. This is another high unmet need, not only in the U.S. but also in the EU. There's 5,000 to 7,000 patients in the United States. It's a big founder effect out of Europe. So you see a much larger population in Europe of about 25,000. And that also incorporates the Middle East as well. I think what's important when you think about FA is that you not only have cardiac manifestations, but you have CNS manifestations of the disease as well. And when you talk to families, they'll say, it's wonderful if you can treat the heart, but if you can't walk, see, speak, swallow, cough, et cetera, quality of life really does take over. And so we want to make sure that we create a drug that meets the patient where they are and that can treat both manifestations, both the CNS and cardiac manifestations. And so we take a very unique approach to this. Now before I go into our approach, I just want to talk about mFARS. And I think this is critically important to understand what we can look at and what we can't based on the patient population we're currently dosing. mFARS is really broken down into 4 groups, and you can see the actual maximum scores in the second column. The first column in blue. And basically, you look at lower limb coordination, upper limb coordination, upright stability, bulbar function. And this is how they're measured. I think one thing that's critically important to think about mFARS is as you progress with this disease, mFARS always goes up. It always moves to the up and to the right. And that is not a good thing, and it's very progressive in nature. Even when you're in the most severe patient population, which we are, and that's sort of we dose all these patients in the sort of dark orange to bright red where they've already lost most, if not all, of the lower limb and upper limb coordination and most of the stability. You continue to progress over time until unfortunately, you pass away. And we're going to be taking a hard look at mFARS over the course of our program. And what we're trying to do is solve for this by treating both aspects of the disease that I mentioned before, but without pushing the dose up. And we're doing this by this very elegant way of dual route administration. And by doing dual route administration, you can get to the heart of the matter of the disease, which is really the dentate nucleus of cerebellum, the spinal column and the heart. By separating the route of administration, you're able to give a much lower dose. Our dose -- total dose for the dentate administration, intra dentate administration is in the E9 range, and that's total dose that's not done by weight. Of course, the dentate nucleus is very small. By doing that, we can actually give a lower dose in the IV and get to the spinal column and the heart. And that is a VG to kg dose, and that is in the E12 range or the low E12 range. Now why is this important? As I mentioned before, you want to get to the patient wherever they are in the disease. And so I want you to think about 3 different types of patients. You can have a 30-year-old patient who has already lost lower limb mobility, upper limb mobility, most of his or her stability, can barely speak, can't read, can hardly swallow. And realistically, you're probably not going to do that much in the spinal column, the dorsal root ganglia. I'm sure you can help in the heart. But it's very important to get to the dentate nucleus and try to restore that individual that -- some of the ability for that individual or at least slow down the disease. And so that's why we do this dual route. You also have a 20-year-old patient. This 20-year-old could have the ability to walk, maybe not. Might have cardiomyopathy, maybe not -- you don't exactly know where they are. But by doing this dual route administration, you can treat that patient. And then you think of a 6-year-old little girl, 6 year age, she just got diagnosed. She just got diagnosed. She really doesn't know what her future is going to be. You want to make sure that you can treat them that little girl as well before the disease really takes over and slows her down. So dual route administration will get to the heart, spinal column and the dentate nucleus for that little girl as well. This is the only drug I know of its kind that can treat different all different populations of the disease wherever they are within their disorder. Now this is -- this is the dentate nucleus, what we're trying to do on the right hand -- on the left-hand side is coat about 15% to 20% of the dentate nucleus. That's what we believe you need for coverage before you can start really seeing meaningful clinical benefit. On the right-hand side is our dose. And you can see we use this enhancement agent. It's a dual -- it's MRI-guided dual route administration right to both dentate nucleus with an enhancement agent. And we were shooting for 15% to 20% coverage. And you can see here, while we didn't quantify it -- we did quantify it internally, we just haven't disclosed it. It's significantly more than 15% to 20%. This is patient 1. By the way, patient 2 was even higher coverage of the dentate nucleus. Now what we're going to do the rest of the year, we're hoping to dose somewhere in the range of 5 or 6 patients by the end of the year. And then we can hopefully have a readout early next year and provide all the clinical as well as safety data. Now I don't have a safety slide in here, but I'll tell you, both patients did extremely well. Second patient had no AE at all, like no headache, no nausea, no vomiting, no fever. The first patient only had a headache that were resolved with Tylenol. And so both patients did extremely well. We've never had an SAE, knock on wood. And the only AE that we've had was a headache, as I mentioned. Later on this year, we're going to continue to dose. Eventually, we're going to go down to ambulatory and then we'll do some ambulatory, non-ambulatory study if we want to. Anticipated milestones. This is going to be a pretty exciting year for the company. This year and next year could be transformative and really with multiple inflection points this year, either through regulatory interactions as well as data readouts. Now we've already met with the FDA twice in the last 6, 7 months, once on the Phase III clinical trial design, the double-blind placebo-controlled trial for Duchenne. And obviously, that trial is underway. We got approval from the FDA. We're still working on approval with European countries, and that should happen relatively soon. Currently, Australia as well as Canada is open, and we'll have more sites open later up this year -- later on this year. We also met with the FDA to establish whether there was an unmet need in the disease state and to talk about a couple of other things. Even with a commercial approved microdystrophin gene therapy, the FDA still states that there is a high unmet need in Duchenne. They also have acknowledged that our program is unique. We create a unique protein. We also have a unique capsid that has these RGT peptides on it for better expression and distribution or at least better distribution. So they do acknowledge that our program is unique as well as there is a high unmet need. Now one thing we talked about is, is our trial -- do we have enough data for a surrogate marker for clinical benefit? And the answer was no because we've actually never shared clinical data with them. It turns out you need clinical data to get that clinical benefit, and we have not even looked at it. We're going to look at this July and August, start doing all the analysis internally. So currently, what we're doing right now, we're updating the stat plan. We're going to submit their stat plan this month in June. We are -- once we do that, Dr. Brooks and his clinical team are going to start looking at all our data and doing the analysis over July and August. And then we'll request a meeting to go over the data for the first time with the FDA later this year. I do think it's important to understand that the FDA has told us in the past at this last meeting, they're really not that fond of open-label studies with functional endpoints. And I don't think that's a surprise to anybody, which is why we wanted to do -- in the same breath, by the way, they acknowledge, hey, thank you for starting our double-blind, placebo-controlled trial, and we've already dosed our first patient. And so we're working very hard to try to eliminate any bias that's in the INSPIRE trial, and we're going to provide data to them later on this year. I'll also give an update on the enrollment for the placebo, double-blind placebo-controlled trial and hopefully find a path forward with the FDA. And we're very excited about the discussions with them. Of note, safety never came up in our discussion, and we did provide them somewhere between 30 and 38 patients worth of safety data at the time of the meeting and no discussion around safety whatsoever. So for FA, we are going to dose somewhere right around 5 patients, hopefully by the end of the year. And then if everything goes well with safety and potentially efficacy in these patients, we'll reach out. We'll set up a meeting with the FDA at the end of the year to early next year and talk about a path forward, whether it's either with the natural history study or some kind of other study where we can gather additional data and think about how we can move our program into future studies down the road. For CPVT, we have multiple patients that are trying to get into the trial. We have been going slower with CPVT, and we've been doing it on purpose. We're only 130 full-time employees, and we have 2 programs in the clinic with 3 different trials with INSPIRE and -- Duchenne. So we are going a little slow, receiving patient later this year. We also have another program called TNNT2 dilated cardiomyopathy, and that will be ready for an IND later this year as well. So with that said, I will say thank you very much to Goldman Sachs. I appreciate your time, and thank you for letting me present.

So you mentioned that the...

Yes. So one of the discussion points that came up for anyone who's online, the question was around the unique transgene and any discussion points around it. So the transgene has this repeat domain called R16/R17. And when you have R16/R17, you can actually recruit for a protein called alpha-syntrophin. And when you have alpha-syntrophin, that actually is a binding spot for another protein called nNOS. And nNOS is needed, and you actually -- there's studies out there that show that patients with nNOS and without nNOS. Patients with nNOS actually walk longer. They do better in life. And this protein has been shown to increase blood flow, decrease fibrosis, decrease oxidative stress, decrease inflammation. And we're the only program that has this repeat domain of R16/R17, and that gives us the ability to discuss this with the FDA. This protein, combined with the sarcoglycans, especially beta-sarc and delta-sarc can really provide a lot of benefit, especially on the cardiac side. And I think that that's one of the reasons that we are seeing a difference in some of the cardiac output that right around that.

Can you talk about the commercial landscape...

The commercial landscape has continued to evolve. Unfortunately, there's a lot of patients that need help. And I think it was important that the FDA did state that there is a high unmet need for Duchenne, even with the products that are currently on the market. Unfortunately, I say unfortunately because I don't -- I wish the disease it didn't exist, but the market is actually the gene therapy naive market is unfortunately getting bigger. And why do I say that? Every single year, there's about 400 patients that are born with Duchenne. So roughly 100 patients are born with it a quarter. Currently, with the gene therapy that's on the market, of course, this is my guesstimation -- is the majority of patients are being dosed in the 340B clinics, and that puts the net price, my math, not anyone else's somewhere right around $2.8 million. When you really break it down, that's about 40 to 44 treatment regimens per quarter. That means there's -- each quarter, there's about 60 little boys that are born that are not being treated. So the actual incidence population or the prevalent population is increasing because the rate of therapy is actually slowing down. And so this -- I hate to put in these type of terms, but unfortunately, there's about $1 billion to $1.2 billion that annualized that is born in Duchenne each year. And if you're treating with the microdystrophin type of program. And so the market is getting bigger. And that's an opportunity for us to come in with the next-generation gene therapy. As I mentioned in the presentation, we've dosed somewhere right around 51 patients, more to come very soon. And the drug looks relatively safe with safety profile with some of the highest expression out there. And so I think that this long term is going to provide a clinical benefit. And hopefully, we can take the majority, if not all, the market share in the disease state. Thank you very much. I appreciate your time.