Solid Biosciences Inc. Aktie

Welcome back, everyone on day 2 of Citi's Biopharma Back-to-School Summit. Yigal Nochomovitz, senior biotech analyst here at Citi. And so this is one of the final sessions of the day, but certainly a super important one for sure. My pleasure to have with me Solid Biosciences and the President and CEO, Bo Cumbo. So welcome, Bo. Thank you very much for doing this.

So you have a lot going on, obviously. Maybe just to set the scene, if you could kind of give us a high-level overview of the pipeline, what you're doing in DMD. Of course, Friedreich's Aaxia is super important as well. And you have a very important set of updates coming up in the fourth quarter, both in terms of regulatory and data. So I'd love to hear more about it.

Yes. Thank you, Yigal. Thank you, Citi, for the invitation. Great to be here. We're very excited. I think for those who don't know, Solid Biosciences is a precision genetic medicine company. We focus primarily with AAV at the moment. 2 disease states, we put most of our -- almost all of our resources and personnel to is DMD and FA, Friedreich's Ataxia and Duchenne muscular dystrophy. We are heading into a very interesting time over the next, let's call it, half a year for Solid Biosciences.

We have multiple inflection points. The first one in the next couple of months is we're going to be holding a meeting with the FDA to talk about accelerated approval to actually show them some of our clinical data. It would be the first time that actually we have shared and actually looked at as well as analyzed and then shared our clinical data, and we'll be doing that in the fall with the FDA and talk to them about a pathway for accelerated approval.

And then after we have that meeting with the FDA, which should happen in Q4, then we will update the Street and provide them -- the Street, not only our clinical data that we shared with the FDA, but also the sort of regulatory discussion on what is our path forward if we have one and how we're going to move based off the information that we have.

We also have Friedreich's Ataxia. We've already dosed our third patient, planning patient #4 in September, patient #5 in October. That's currently scheduled. That means you guys -- the Street will have at least 3 patients of mFARS data in Q1 or really first half of next year, but most likely Q1 of next year. And then you'll have some extra safety data from a couple of patients as well as long as we can dose patient 4 and 5. So very excited about that. I think it's an exciting couple of months for Solid.

Okay. Well, I know you can't speak to too much detail in terms of the actual data, but can you give us a sense for the types of data and sort of the magnitude of data in terms of how many patients you might expect to learn about for DMD in the fourth quarter? And also, I know you still haven't had the conversation with the FDA, but what are the -- if you can kind of enumerate what you might see as like the differential scenarios there in terms of how things could go forward with the feedback from them?

Yes. Yes. Let me backtrack and give you -- let's start with the end of '25, so we can get here so you can figure out how we got here and then where we're going to go going forward. So in the end of 2025, at the very end of '25, we submitted a statistical plan, a SAP plan on how we were going to -- basically the rules of how we were going to look at natural history data and do our data comparison for our INSPIRE trial when we actually had our clinical data.

We also, at the end of '25, early '26, talked to the FDA about how we were going to set up our Phase III clinical trial design. That's called the IMPACT trial as well as our endpoints that we were going to look at. And I think that's critically important because that's what we're going to be -- those endpoints are going to be the ones that we're going to talk to the FDA about in the fall.

In March, we had another meeting with the FDA. We established that there's still a high unmet need in Duchenne. This sounds trivial, but realistically, when there's an AAV gene therapy that's got full approval, you need to make sure that the FDA acknowledges that Duchenne still has a high unmet need. They did. And they also acknowledge that our drug is novel.

That's also important when you think about just making sure that they don't view all the gene therapies as a me-too. And so our drug, our proteins are novel. But during that meeting with the FDA, we talked -- we started talking about a hypothetical situation of how we're going to look at our data -- and also Duchenne videos. We got back and forth with the FDA on that. They gave us a couple of ideas. So we had to go back and modify our statistical plan, our SAP plan. based off that conversation. And that means how we were thinking about taking -- selecting the data and being able to analyze the data going forward. That SAP plan was submitted in late July.

Now we are pulling all our natural history data in. We will be using how the SAP plan of how we are going to analyze the data and select the data that's going to be used in the clinical analysis. We're pulling our clinical data in. We will be creating a dossier, a briefing book for the meeting. We'll be requesting the meeting very soon and then meeting with the FDA in the fall.

What are we going to talk to them about the endpoints to your question? It's the ones that were already listed in the IMPACT trial for the Phase III, Time to Rise, Stride Velocity 95. And then we have a couple of other endpoints like 4-stair climb, 10-meter run walk, and we'll utilize those to create the data package.

How many patients will we have? Well, it's -- first, you have to understand, we've dosed 53 patients, all safe all the way down to age 6 months, all the way up to age 10. And those patients are ongoing. We are only looking at patients that have at least hit 365 days, 1-year period of time. And we have to -- basically, when you have the meeting with the FDA, you have to cut your data about 5 months ahead of time.

So when you -- when we cut the data at day 365, we're going to have a little over 12 patients of data for the FDA to review that has at least 1 year. A couple of patients who actually have up to 18 months, but at least 12 patients, slightly more to discuss with the FDA. And more data continues to roll in at the course of -- over the course of this year, but it won't -- we won't be able to import that into the briefing book.

Okay. So the goal there, I gather is with those 12 patients, as you point out, to be able to make a statement around functional benefit that would support, in your view, assuming you show that a pathway for accelerated approval. Is that correct?

Yes. What you want to do is you want to look for clinical benefit. Like remember, these -- what's the FDA have to do here? The FDA has to make a judgment call. They actually wrote that in our meeting minutes. The last time, accelerated approval is based off the judgment call of the totality of all the data. And we have a whole bunch, as you know, a ton of biological correlate data looking at anything from western blot all the way down to muscle integrity biomarkers such as embryonic myosin heavy chain, titin, et cetera, but they want to see clinical data.

And so now we need to show that the drug is actually doing something in the patients that have been -- had biological correlate data. And so it's not just -- it can be western blot, it can be mass spec, but it also can be some of the biological correlate data or a whole host of data set looking at patients that are moving in a manner that's different than natural history. And you don't need to -- you just have to make a judgment call. It has to be directional in nature because one -- for one, our trial is 18 months. The INSPIRE trial is an 18-month, but we're taking an interim look at 12 months to give the FDA some data.

So directional in nature, clinical benefit based off biomarkers, including western blot, mass spec, et cetera. All of that data in totality, along with our Phase III that is up and running, that is a double-blind, placebo-controlled multicountry study, that should give the FDA a lot of confidence that they can make a good judgment call that maybe we can have a pathway for accelerated approval, and that's we're hoping for as we move forward.

Okay. So it doesn't necessarily have to be -- since it's a small sample size to be statistically significantly different versus natural history necessarily, just you have to be able to show some valuable -- clinically valuable separation that sort of meets the like overall litmus test across all these different...

Yes, they have to make a judgment call and they have to have confidence in the data set that gives them enough data to make this judgment call. And it's also great, by the way, that the new CBER head's in place because I think when you're having to make a judgment call, you definitely want leadership in place, so you can actually bounce ideas off them and sort of get their support. And having the CBER head now in place, I think, it is beneficial for us as well as we head into the meeting.

And just so everyone understands, at the moment, you're in the active process of doing this analysis. So you don't necessarily have all the answers...

No, no. Yes. No, no, no. We were in the process, but we don't have all the answers yet. So we're pulling all the natural history data in. You have to run -- you have QC all the data for natural history. You have to run through the statistical plan and sort of requirements because a lot of the natural history data won't be utilized because it doesn't meet the requirements that were placed in the SAP. Then you have to get your data to come into the in-house.

You have to QC the data, then you have to do the comparisons. You run a bunch of different comparisons. And then you put your briefing book together. So yes, and we haven't even scheduled the meeting yet. We're getting ready to schedule the meeting in about a month. And then you have to submit your briefing book 45 days in advance of the meeting. So we still have a little bit of time to do this work.

I know I appreciate you're in the middle of it, but qualitatively, can you give sort of a sense as to, for example, with time to rise, like what might be a good result relative to natural history? Is there a way to...

There's not a way for me to actually qualitatively or quantitatively give you an answer on that because I don't know exactly what natural history is going to say.

You don't know that...

You're trying to be natural history, and I don't know exactly what natural history is going to say for the subset of patients that actually made at 12 months. We've dosed anywhere from ages 6 months to 10 years of age. So there's a whole...

But you're trying to do like age math...

You are, and that's why it takes a little bit of time. That's why I don't -- i couldn't give you an answer.

Understood. Understood. Okay. So that's obviously an important. And that meeting with the FDA is in the fourth quarter.

Yes, it will be in the fourth quarter, and we plan on hitting that time line.

And then so somewhere, I gather like...

30 days later, we'll get the meeting minutes. As soon as we get the meeting minutes, I go to the Board of Directors to make sure that they're cool with it. And then we're going to release all the data and sort of the regulatory update to the Street.

Okay. So it sounds like back half of 4Q '26 is a more likely time. Is that...

I would say, back half of '26 to very, very early '27.

Okay. Okay. Got it. All right. Very good. And then as far as the study -- the confirmational study, confirmatory trial, the IMPACT trial, where does that stand in terms of its rollout today?

Yes. So we're still waiting on Europe. We don't have Europe up and running yet. Right now, the only 2 sites that we have, Australia and Canada. And so enrollment really won't pick up until we have all the European sites. We have -- so we have Belgium, Italy, I think France, U.K., Spain. There's a whole host of countries that need to get up and running. That should happen at the end of the year to early next year. And then we have a couple of sites in the United States for kids that are traveling from abroad. They do this sort of health care tourism. They obviously cannot get reimbursed for ELEVIDYS.

And so -- because they're from overseas, but they would like to participate in clinical trials. They come to the United States for health care. And so these tend to be a sort of kids coming from families that can afford it. And so we'll set up some sites in the United States. We'll set -- that that will happen at the end of the year to early next year. We'll set up all the European sites and then enrollment really enhances after that. It's also important that we're going to meet with the FDA in Q4. And if something comes out of that, then we can also modify the trial if needed based off the discussion with the FDA.

And there, obviously, as you said many times before, they're already aware that you've initiated that study and...

So we met with them, as I said, like December-ish of last year, '25, talked to them about the Phase III. We sent them the press release when we enrolled the first patient, and that was somewhere like May of this year, something like that. So they're aware.

Yes. Any -- do you want to offer any thoughts in terms of what happened with Capricor and how that shook out with the FDA? Does that -- what lessons did you learn or not learn there in terms of what the FDA is looking for in the DMD package?

Well, one, I find it great that they're actually continuing to communicate and review the data. I think that shows a lot of flexibility. Obviously, you had the AdCom, you had all the debate around it, yet the FDA is still communicating and working with the FDA. I actually think that, that is a good sign, not just for Capricor, actually just for rare disease, having the flexibility or having the willingness to actually communicate and talk through the data because some of these rare disease packages are very challenging, especially in kids, young kids, Duchenne kids, cardiomyopathy or young looking at pull.

I think these are very hard diseases, and it takes good communication. I'm actually pleased to see that they're still talking. I think we did learn some lessons on how you think about setting up your Phase III, how you think about -- and we didn't just learn it from Capricor. We actually watch all the trials, all the trials that are ongoing and the lessons learned, not just in Duchenne, but all the rare disease trials and how the FDA communicates around them as well.

So we try to always do the best thing we can. We know that this is an open-label study. We know that the FDA doesn't like some of these endpoints because they can be effort-based in an open-label study, and you worry about bias or coaching or training and anything, all this stuff. By the way, that's one of the reasons we love Stride Velocity 95. It gets away from all of that. Stride Velocity 95 is a great endpoint when you want to tie it back to another endpoint like a functional endpoint and say, hey, look, here's 2 endpoints, one functional in nature, one effort-based in nature, one that has no human touch whatsoever in Stride Velocity 95, and you can show sort of comparison.

If you have those 2 approach, I think that really helps with the FDA. And hopefully, we're going to try to do that, all of this and create the best package we can, knowing there are limitations to the data.

Okay. So presuming you get good feedback and they say, we agree, we think you should file for accelerated approval. How quickly can you get that filing together?

Yes. So all right. In that scenario, and that's the A scenario, right? So in that scenario where they high-five us and they say, you're good to go, which the FDA never does that. But if they do say that, then we're in the middle of PPQs. Probably, it's CMC, that's the last to file. We're in the middle of our PPQs. We've on our PPQ1, PPQ2 is done. PPQ3 is underway. We'll probably have all that data in by end of year. That means we need to meet with the CMC part of the FDA early next year to go over that data with them. And then once -- if the FDA is good with our 3 PPQs and everything looks good, then we'll start making the CMC module.

And we could potentially have the CMC module completed over mid-summer. And then once we do that, that would be the time that we could file the modules.

But -- so interestingly, like, for example, if they say, great, go ahead, high-5, they don't do that, but anyway. Let's say they say, okay, well, 12 look good, but we want to see 24, for example, which is not inconceivable. So -- but then you could accrue that while you're doing this, right? I mean, it could it be...

That's the great news. We dosed 53 kids. And like they're already dosed. And so every single day is another day that they are just gathering data. So in a scenario where the FDA says, hey, listen, we really like your data. However, we really want 25 patients for the data. The great news is those 25 have already been dosed. And you guys, all the investors, we were pretty transparent, actually very transparent on all our safety last year and this year. And we updated our press releases, I mean, our presentations pretty much on a monthly basis, and you could see the ends.

And so basically, you guys can pretty much track exactly when we dosed 25 to 30 patients. I will just go on and give you a heads up that we actually released a press release very early in 2026, and we basically said 25 patients had been dosed by the year-end of '25 -- '25 to '28, something like that. And so if they kick it out to 25 patients, yes, that's like 3 months -- 3, 4 months. So it's not bad at all. That's the great news of dosing 53. It's just sort of like there the data is going to be rolling in over the course of the next couple of months.

And I guess it's hard to really have a lot of insight into that number, right? What they...

You got to have the meeting. You have to have the meeting. You have to talk to the people. You have to understand what they're going to -- how they feel about the data. Duchenne is tricky. And obviously, you can see it from all the other companies. And so we don't want to get ahead from the -- ahead of the FDA. Let's just have the meeting with them, hear them out. We're going to push. We are going to push. If our data looks good, then we're going to push. And so let's see what happens.

Okay. All right. Let's talk about another important rare disease, Friedreich's Ataxia. So obviously, it's good to see there's been some progress in that field and where there is an approved drug, as we all know. But your approach is potentially more on pathway in terms of restoring the missing protein. So yes, tell us about the -- first of all, just tell us about 212 and how it works in terms of the dual mode of administration.

Yes. So we're very excited about this. We want to make a drug that we can meet the patient wherever they are in the course of their disease. And so as you think about different types of patients, different phenotypes, that's 40 years old, very severe, needs help in the heart, needs help in the spinal cord and cerebellum. We'll have a drug for them. Hopefully, then we go down to like a 20-year-old, maybe they have plus or minus cardiomyopathy, spinal column is somewhat intact, cerebellum is intact. We have a drug for them or a 6-year-old. 6-year-old, they're definitely not going to have any cardiac symptoms yet.

You really have no idea of the course of her disease, and we will have a drug for her. That's the goal long term for this study. Right now, what we're doing is we're studying really the sickest patients. And we're studying the non-ambulatory patients that are pretty well advanced. I mean our first 2 patients were mFARS of 80. To put in perspective, 93 is the worst of the worst. Third patient was dosed in August, and she was mFARS in the 50s, low 50s. So a little less severe, but still pretty severe.

And we have 2 additional patients that are coming up. What we're trying to do is dual route of administration. What does that mean? That means that we first go right to the heart of the problem, which is the dente nucleus of the cerebellum. We dose that patient using an IDN stereotactic approach. It's an MRI-guided approach so we can actually see the coverage of the dente nucleus in real time as we're dosing the patient. We use an enhancement agent, so we can see through the MRI exactly how much we're covering.

We want to cover roughly 15% to 20% of the dente nucleus. We're covering a lot more than 15%, 20% of the dente nucleus. We've never disclosed that number for our first 3 patients, but it's significant. And then we let the patient rest. That procedure, just to let you know how that procedure works. From the time that they walk in to the time that they finish, it's about 4 hours. Realistically, the surgery itself because you're only going 3 millimeters in, you're really only going -- you're only doing about 2 hours of surgery.

So it's in and out. It is done -- that 2 hours of surgery means from the time the needle goes into the time the sutures are all sutured up, you're done. They rest for about an hour, and then we give them the IV dose. Eventually, this is going to be outpatient dosing. We'll have multiple clinics across the country that will be doing this. We already have 3, which is Ohio State, UCLA and CHOP or Penn. And then we're going to basically open it up to additional sites. And so additional sites for our Phase III trial.

So what are our goals just so you understand. We've dosed 3. We're getting ready to dose, hopefully, knock on wood, patient #4 in September, patient #5 in October. We're hoping for 2 additional patients by year-end to give us 7 total. That means we can meet with the FDA sometime in the first half of 2027, and we can provide them the data and start talking about a registrational trial.

If we have a path forward for a registrational trial, this will be a real placebo-controlled trial. And why? We want to make sure that we not only get approval in the United States, but we also get approval ex U.S., and we get reimbursement ex U.S. Friedreich's Ataxia founders effect is out of Europe. It's a huge population. It's bigger than the United States. And we want to make sure we can get this to all the patients that are needed.

So we would hope to start that trial end of next year and into '27 and get it up and running. So we have -- sometime next year, if everything goes well, we'll have a Phase III in Duchenne and the Phase III in MA.

So how big a Phase III would you need? That's depending on what the FDA says, but it doesn't sound like it's going to be a very big trial.

Yes. So realistically, it all comes down to the powering, right? So the powering, if you think about mFARS just natural history, you always go up into the right. You always move unfortunately, they always progress. The mFARS never stops. So depending on your average mFARS baseline, you can sort of pick and project how many points they should increase over the course of a year to 1.5 years. And then with the first 7 to 10 patients that we dose, we'll understand what are mFARS, whether it's a pause, whether it's a reduction, whether it's just a slowdown, understand that trajectory, and then we'll be able to power the study.

My guess, my rough guess is no more than 50 patients in a double-blind placebo-controlled trial. That's guessing without actually having any data. I have no data that tells me right now of the impact of our drug on the first 10 kids or 10 patients because we've only dosed 3 and they've only been out for a short period of time. But we'll be able to power this and power it against natural history, and then we'll figure out how to -- how many patients we can have.

So for the initial 7, what's the time point where you're going to measure mFARS for the first point?

90 days.

90 days. So some of those 3 are just getting there now or not...

Well, patient #1 was dosed in January. Patient #2 was dosed in March. Patient #3 was dosed in August. There was a gap in between March and August because we had 3 back-to-back-to-back screenouts due to heart issues. And so they didn't make the background. They didn't make the criteria to get into the trial. So that delayed us about 2 or 3 months. So we have 3 patients, different time points. So we actually have some decent -- we're going to have some decent data for you guys in Q1.

So you have -- so for those first 2, you have some initial clues, I gather.

We do.

Okay. And then for the placebo, what is it going to be? Because it's going to be like a sham procedure. How are you going to do that?

It's a placebo/sham. It's a placebo in the arm, obviously, for the IV portion of the dose and a little sham and you don't do a burr hole. You don't do any -- you don't -- it's just a little nick on the back because actually, when the patients actually do to the surgery, all they have is -- if you cut yourself shaving, you have the little round Band-Aid. That's all you actually have here in the trial. They don't really feel it and it heals very quickly. And so you wouldn't have to do a burr hole or anything like that. It's really just a sham cut with a little Band-Aid.

Another important question is when you -- I mean, it's a small study, so it could potentially be sensitive to the splitting in terms of who gets the severity on both arms. Is there a correlation between the rate of progression of mFARS and the absolute value of mFARS, meaning do you want to make sure that the average is kind of similar...

Yes. No, no, 100% because you -- depending on where you start if you start lower, you actually have more -- you lose more points per year. So if you start at like a 20 or 30, you can lose 4 to 6 points in a year. If you start at like a 40, you might lose 3 to 4 points a year. You start at 60, you might lose 2 points a year. You start at 80, you're going to lose about 0.5 to 1 point a year. And so where you start absolutely depends on sort of like the -- how many points you're going to lose over the course of the year. It is -- this disease is -- while it's heterogeneous, it's very relentless. It always marches up to the right. And so to your point, it's very important to get the baseline correct.

And as far as I understand, and we've talked about this in prior sessions, even if you see a slowing of the progression, that would basically be a positive...

Look, let's just take mFARS of 80, right? The most severe person possible. 80 to 90, it's very hard to actually even tell a difference between 80 and 90. 93 is the most severe, but at 80, they're in really bad shape. So they lose about 0.5 a year. And that's on the conservative route. You could actually say they lose a point, let's just say 0.5. If you can just pause for 1 year, you delayed 1 full year of progression. If you decrease even a point, you sort of reverted back 2 years. You sort of moved them and gave them basically 2 years of mFARS decline back or increase back.

So yes, so no, it really does matter. And if we can just slow this disease down or pause it or or change the course of mFARS directionally, it could be huge. It could be huge for the community.

So you mentioned the placebo-controlled trial, which would support the global approvals. Is there a scenario where even with the 7, if the data look really good, that there's an accelerated approval pathway? Or that's kind of too much of a stretch?

We're not going to go into the FDA and ask right now. I think -- actually, I don't think it gains us any time. I think if we can go into a really well thought through placebo-controlled trial sometime next year and dose relatively quickly, just thinking through the bureaucratic process of working with the regulatory agencies, especially in Europe, it would be more beneficial just to do the trial the way we were thinking about it. We'll bounce the idea off the regulators. If we see something that is just remarkable in nature, then we'll talk to them. We're not there yet, clearly. And so we'll have to wait. But right now, our thought process is we're going for full approval.

And the Europeans in particular, I mean, they should be okay with the placebo because I know over there, they know there's some questions around that.

That's correct. That's why we're going to do the trial in the United States.

Oh, you're only going to do U.S. Okay. All right. Do you want to speak a little bit about the platform very briefly because you do have the capsid platform and you have a lot of licensing agreements for the technology. That doesn't get a lot of airtime. So...

Yes. No, we're very fortunate. I think we have a great capsid in what's called POLARIS now. It used to be called SLB101. it is called POLARIS. We have 50 different agreements, whether academic labs or small companies wanting not only our capsid, but a dual plasmid, sometimes talking to us about a promoter and manufacturing capabilities. Long term, we believe this POLARIS capsid will be the dominant capsid in any of the cardiac or skeletal muscle diseases that are using AAVs.

We're already seeing universities shift away from first-generation AAVs and move toward POLARIS. We're open for business because we want to actually change the course of gene therapy, make it investable again, get a lot of companies that are out there that are smaller that can't afford the $10 million capsids and you should not go back to the AAV8s, rh74s, AAV9s, first-gen capsids because we know what you're going to get, and we know what to expect there. So why not try POLARIS? And so we're working with multiple companies. We're working with multiple academic labs.

We have other capsids, too. We create all our capsids in-house. We create them with either AI on one side or we hand make them on the other using RGD peptides and inserting peptides and making small mutations. So we have 2 different type of capsid platforms all coming together. Our next capsid looks like it's called 282. We'll name it soon. And we're going to license that capsid out as well as well. I think we have like 4 or 5 other capsids that are going through nonhuman primate work right now. We'll have all that hopefully, by year-end. We're going to present some of that data very early next year. And hopefully, it will change the trajectory.

No one's -- to your point, Yigal, no one's paying attention to it. What's going to happen in 3 to 5 years, while everyone is focused on Duchenne, everyone's focused on FA, all of a sudden, you're going to see 100 -- I'm making the number up, 100 to 200 programs coming out of academic labs using Solid inside, Solid technology inside. And then the great thing is that royalty stream will be coming down the road. And so long tail. And while everyone is going to get the big inflection points, hopefully on Duchenne and FA, then all of a sudden, the capsid platform really kicks in, in year 3, 4, 5, 6.

Okay. One more. You already touched on it. You mentioned AI being used to design some of the capsids. So is that the primary usage of the AI tools at Solid? Or are you using it for other things like preparing filings, analyzing data, summarizing....

We have -- so we're building it internally for ourselves. We have a third party that's helping us build it. What we want to do is we want to analyze all our preclinical data, all our CMC data for every single batch, all of our clinical data compared to natural history and be able to run this for each and every program. We're also allowing some of our customers that I just mentioned on our capsid platform to pull their data into our networks and help them analyze their data. And then the AI platform actually writes -- helps write all the regulatory documents.

So anybody that uses our capsids, right, they can leverage our nonhuman primate data. They can leverage our mouse data. They can -- all the GLP tox data. They can help them get through regulatory process quicker. If they use our platform, our AI platform, insert their data into our platform, then actually they can leverage other people's data as well. It's is all anonymized. So they get to keep their data, but they also get to leverage all the data that we're building. And so we're going to be doing that for all our customers that are using our capsids.

All right. Very good. Well, thank you very much, and a lot to look forward to for the balance of the year and beyond.

Yes. Thank you, Yigal.

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.

Hi, guys. Good afternoon. I'm Ellie Merle, one of the biotech analysts here at Barclays. Joining me from Barclays is my colleague, Tejas Wein. We're very happy to have Solid Biosciences here with us today. A lot to talk about after a data update yesterday. Joining us from Solid is Bo Cumbo, President and Chief Executive Officer; and Gabriel Brooks, Chief Medical Officer. Thank you both so much for making the time.

Maybe to begin, can you give an overview of your program and where you see it in the DMD landscape?

Yes. First, thank you very much for the invitation. Thank you, Ellie. Yes, Solid is a precision genetic medicine company. We focus on our lead programs, Duchenne muscular dystrophy called 003, followed by a Friedreich's ataxia program. We also have multiple cardiac programs, CPVT, TNNT2. And we make a host of delivery technologies such as capsids, promoters, dual plasmids for gene therapy delivery as well. And do you want to go in the DMD program?

Yes. Yes, let's go for it. I mean, there's a bunch of DMD gene therapy programs. So, let's talk through your program and how you think it compares to the others.

Yes. Obviously, they're not head-to-head comparison trials going on. But I think 003 is really one of the most comprehensive datasets that's out there. We take a very different look than most companies; we not only look at transduction and expression, but then we take the next step and really focus in on muscle integrity, satellite pool preservation. Cardiac ejection fraction, troponin increases or decreases. And so I think overall, what we're so proud of is that we have generated a pretty large dataset that is growing pretty rapidly. And that's what I think we're most proud about right now.

Well, let's talk about the data update from yesterday. Yes, what was new from the dataset?

Yes. I'll tell you what, I'll start, and then I'll kick it over to Dr. Brooks, who's our Chief Medical Officer. I think what I'll just say is we're through 20 patients right now. And we have 40 patients dosed, all safe, 20 patients that we have expression data on. I think what I'm most proud of is that it's very stable. There's not a lot of fluctuations. Everything looks -- it's very comprehensive. Everything points in the same direction. It's the lowest dose, it's the highest expression, and it's the easiest regimen. And from a commercial person, that's going to resonate in the market.

But I'll turn it over to Dr. Brooks to go over the data and the clinical data, et cetera.

Great. Thanks, Bo. So right now, the data that we've been showing is our Phase I/II INSPIRE DUCHENNE study of SGT-003 in boys that are ambulatory, where, as Bo alluded, we're really grateful to have 40 young participants in this trial. And then we have the IMPACT study, our double-blind, randomized, placebo-controlled trial that's already enrolling in the rest of the world. And when we -- what we showed in Orlando just yesterday was that we have, as Bo alluded, really outstanding expression: 60% mean normal microdystrophin and 63% of the fibers, as well as really compelling downstream markers that show muscle protection by CK, all of the markers that we look at are coming down nicely, which is really important to show that this microdystrophin is being effective in protecting muscle and preserving muscle.

We uniquely are looking at the need for muscle to regenerate. And what we're seeing is that need come down with -- after the drug has been administered. Solid Biosciences was founded by a family that was touched by Duchenne muscular dystrophy. And so we've been really careful to listen to the needs of the patients and the families. And one thing we hear about is we need safer drugs. And so we designed this drug to avoid the liver, and that's what we're seeing. We're seeing actually AST/ALT coming down because that's released from the muscle.

But in that week 9 period where we know the experience with the currently approved drug is that there can be a lot of incidence of liver toxicity leading, in fact, to hospitalization and unfortunately, some fatalities, we don't see any increase in the liver biomarkers at that time period. And that's really important. Another piece that's important to families is, as Bo alluded, how easy is it to tolerate this drug, meaning, do you have to have long, high-dose steroids for a long period of time, which can lead to weight gain, can lead to behavioral problems. The families can really have a hard time when you need to have long, high-dose corticosteroids for the 60 and-plus days of other products.

So, we've actually reduced the time of high-dose steroids to only 30 days and then taper those down to their normal regimen. And we've been effective at doing that without seeing any of these liver abnormalities. That's really important, I think, for the families; it's important for the boys. And also, we've been able to do this -- to conduct this study with this drug with steroids alone, meaning that those families aren't having to worry about: Is my kid going to get sick because they're on high doses of much stronger immunomodulatory regimens like eculizumab, sirolimus, where these boys could unfortunately get sick from an opportunistic infection. Here, we've been grateful to see that all of this hard work we've been doing to try to make a safer product seems to be showing in the clinical trial to do just that.

I guess very impressive dataset so far, but one thing that might be unique is you guys have kind of held back some of the functional data. Maybe could you talk us through that decision and your overall like data disclosure strategy?

Yes. And we've actually stated this very -- I thought very clearly; I saw some people on Twitter saying, where is the data? But we've been -- we've consistently said what we're about to say today. A lot of the issues that companies that have an open-label trial get into is they look at the data and then they find a natural history database and they do the comparison. They do so after they've looked at the data and the FDA sort of frowns upon that because they think that they're snooping the data a little bit on and picking the natural history compared to the dataset they have. We've made it pretty clear that we want to align with the FDA prior to analyzing any functional data.

So we give you all the updated safety database, which is in 40. We provided that yesterday, all the dystrophin data, all the muscle integrity data, the cardiac data, et cetera. But we have held off on the functional data on analyzing the functional data that's actually in the third party. The FDA, if they wanted to come audit us and see if we've ever looked at the data, they could see that we haven't. And that way, when we're having a conversation with them on how to look at natural history literature and create a comparison, so we can go forward for accelerated approval.

They can feel very comfortable that we're being upfront and honest about that what we have, what we don't have, and we can select natural history together. We're going to meet with the FDA this quarter, and that's only a couple more weeks away before it's ends. So, we're going to meet with the FDA, start having that conversation with them. I think it's going to take 1 to 2 meetings, hopefully, to align on path forward for accelerated approval, how we can use natural history, how we can analyze our data to the stat plan that's already been submitted by Dr. Brooks. And then we can -- then we'll analyze the data, and then we'll share it with the world. But I think it's a very thoughtful plan, whether it's the -- whether whoever is in the FDA, I think they'd appreciate how we're being very thoughtful about the data.

And if I could, though, one other piece there is, as hopefully has conveyed, we have been really rigorous about how we've looked at all of the data, whether that be biomarker data or functional data. Here, we're preserving the integrity of the time function test data. And we're also doing other measurements of function of these boys, including the Duchenne Video Assessments. And so what is that? That's a way for the family to capture activities that these boys do at home. It's analyzed by a third party. And what they're looking for isn't speed. They're not saying, is he getting up a couple of stairs faster? Is he getting up from the floor faster, but how he's getting up from the floor, how he's walking up the stairs, what kind of compensations he's using.

Why is that important? Well, number one, it's -- these boys don't live in the clinic. They live at home. And so really, how are they functioning at home is the most important thing to that boy in their life. So we're assessing these a third party is scoring them. But the beautiful thing is we actually get the opportunity to look at these videos. And what we're seeing is really remarkable in these boys cutting out to a year, where you see that they're doing these activities like getting into a car or walking up the stairs, and what we're noticing are less compensation. That's really exciting for us.

The videos were presented at the MDA conference this week.

Yes. And maybe to talk about your Phase III design, which, again, rather uniquely, you're running a placebo-controlled and you recently announced FDA alignment on that design. Could you walk us through that conversation and how you arrived on the endpoints, and maybe the overall plan for that trial?

Yes, I'll start it off, and then I'll kick it over to Gabriel. Realistically, it's extremely important to run a double-blind, placebo-controlled trial for 2 reasons. The first and foremost is we know that we have a drug; we absolutely want to get this drug to every child that has Duchenne, not just in the United States, but the rest of the world. If you look at how the HTA assessments for reimbursement work ex-U.S., we have to hit a p-value, and we have to hit a p-value and do a rigorous trial. And we're very focused on making sure that we get this drug to all the little boys. And that's one of the reasons we're going to use this double-blind, placebo-controlled trial for registrational purposes ex-U.S., hit the p-value, hopefully, and then get reimbursement.

However, we can also use this trial for confirmatory study with the United States with the FDA. And so they're going to feel very comfortable that when we go forward and ask for accelerated approval based on the dataset that we have for INSPIRE that they know that they are going to get the confirmation study from the double-blind, placebo control. I think that's going to give them a lot of confidence as Dr. Brooks and others are speaking to the FDA. It's the right thing to do, and that's where we're at.

Now I'll turn it over to Dr. Brooks to talk about the trial design.

Yes. Thanks, Bo. And to your question of how did we find alignment with the FDA, we approached this from the perspective of rigor. We wanted to make sure that drug development 101, we're picking the right patient population, we're picking the right endpoint, and we're picking the right follow-up time. And so we are in a perfect position because there have been folks that have gone before us, the EMBARK study, the CIFFREO study, though they were both negative studies, we got the -- we have the opportunity to learn from them, and we did.

So we learned what patient population to select. And this is what we spoke with the Agency about -- that we want to take those patients that are more in the predictably declining phase, which means that it's a more homogeneous patient population, which is much easier to see a signal, drug development 101. Also, we need to have a more calibrated, sensitive marker of function and certainly, the NSAA is a great epidemiologic tool. It's not great for drug development. So we're using Time to Rise, which is more sensitive and more calibrated.

And then finally, we know and Gevinistat can tell us this, that if you just wait 1 year in these boys, they decline, but their decline is gradual. And so, being able to say, are you stabilizing? And, we hope to say, and I really believe this, that we might actually see improvement. But at least if we see stabilization, 1 year can be very tricky to see that stabilization. You need to go a little longer. So we went to 18 months. So for those kind of 3 pillars of drug development, we had a really great advantage of having these studies go before us. So, when we came to the FDA, and we submitted our study design, the alignment was pretty rapid.

And I think it's important for the FDA to know that we're doing this trial prior to us coming in for the second meeting to talk about accelerated approval. So, they know we're not taking shortcuts; we're going to give them the trial that they want. And so hopefully, as we go speak to them in the next couple of weeks, it gives them a lot of confidence that we're doing the right thing.

Yes. I think one other thing you guys have made cardiac as kind of a centerpiece of your dataset as well. Could you maybe talk us through why that's so important in Duchenne and what you could show there?

I'll start and kick it over to the cardiologists on the stage. I think it's -- I've been in Duchenne for a very long time. And I think it's extremely important when you think about cardiac disease to understand that these little boys are -- unfortunately, they're going to die from cardiac and respiratory disorders. It's interesting, though, when you think about it, because there's 2 camps. There's the camp that really understands what we're trying to do, and there's the other camp that says, you don't have cardiomyopathy or low ejection fraction at such an early age. And for the some part, they are correct. Others, there's a lot of heterogeneity in the disease.

You do see lower-than-normal ejection fraction. Every one of these boys, every couple of months, will have a spike in troponin. They leak troponin constantly. And I find it very interesting when the families of these little boys go to see their doctors somewhere 10, 11, 12 and are shocked that their son gets told -- the physician tells them, you have ejection fraction in the 50s, and your son has cardiomyopathy. And they're just blown away.

Realistically, it didn't happen overnight. It happens actually unfortunately, over 4, 5, 6 years, starting at age 4 or 5, just micro-tears, troponin spikes, ejection fraction drift. And then all of a sudden, you end up with the diagnosis. But -- so, we spend a lot of time on this because we know you really have to get to it early. You really need to start thinking about this of 4, 5, 6, 7 years age. And then, hopefully, you can extend the child's life long-term by increasing ejection fraction high and keeping troponin down.

So I'll turn it over to Dr. Brooks to talk about our results, but I think it's critically important that we do this.

And just to follow on the background there that Bo gave so well. These families, this is a diagnosis-stage reality. They're already dealing with so much and coming into these appointments with their neurologists. And when they get the news that now the cardiomyopathy has started, I mean, this is something that is inexorable. It's going to just be a progressive decline. Our drug has unique properties in terms of the nNOS binding domain that make it a prospect for actually addressing the cardiomyopathy. Well, that's great. On the other hand, we know that this capsid, POLARIS-101, targets cardiomyocytes 21x higher than AAV9, already a potent AAV for cardiac targeting.

So, when we looked at the INSPIRE Phase I/II study, we really looked at the cardiomyopathy from the standpoint of safety. Why? We're potently targeting the heart. Could there be the potential of cardiac injury with this capsid. And that's what we looked at. And as Bo is alluding to, in fact, instead of seeing safety signals, we have never seen myocarditis. We haven't seen declines in cardiac function. Very, I think, exciting news is what we see instead is in those boys that have an EF that is on the lower side, we're actually seeing an improvement of ejection fraction, the way that the heart is pumping, the amount of blood that it pumps actually looks like it's coming into the normal range if they started and they were abnormally low.

And as Bo is alluding to, a marker of myocardial injury called cardiac troponin seems to be coming down. We know these boys. They don't have ripping troponins that myself as a cardiologist would necessarily care about if I was seeing somebody in the emergency room. But the fact is that they have slow, smoldering cardiomyopathy every single boy until it becomes evident, and then that's when the family knows they're in trouble.

Here, what we are seeing is we're putting out that fire. It seems to be that we're putting out that fire with the troponin coming down and very excitingly, in those boys that have manifestly lower function of their heart, it actually seems to be improving after therapy. These are early days. This is really motivating us to focus on the potential cardiac efficacy signal. So we want to change and pivot to say, instead of just looking at safety, we'll continue to do that, but now we have the opportunity to look at efficacy.

Maybe just in the last few minutes, could you just remind us kind of the cadence of the regulatory strategy maybe as a base case over this year? And maybe just with how things are evolving in the landscape that could potentially change?

Yes. So I mean, we laid it out earlier this year that we wanted to have 3 -- at least 3 meetings. The first one was going to be talk about the double-blind, placebo-controlled trial, get that out of the way. That's done. The second meeting is coming up this quarter, obviously, that means a couple of weeks. We have not held the meeting as of today. We have submitted the briefing book. We'll talk there about the pathway forward for accelerated approval. Is there a high unmet need? Is there a path for us? And then talk about how we can use our data and analyze our data.

I think third meeting, then, if we can align somewhat on the first 3 objectives in this meeting, the third meeting would be to talk about, okay, how much data do you want -- and that way, we can generate it. We have -- we've dosed 40 patients. Dr. Brooks is continuing to dose additional patients. So we're going to have a tsunami of data coming in over the next couple of quarters. How much data do they really want? We'll align there. We have some CMC meetings we're working on. We've already had a CMC meeting that we squared away the potency assay.

Now we'll start working on the PPQs, and we'll do that as well. And hopefully, by the -- if everything goes as planned, and hopefully, by the end of the year, we can get alignment on a pre-BLA meeting and then actually start filing either very late this year or early next year as a rolling submission. That's if everything goes to plan, and we're taking a pretty conservative approach, but we're moving really fast actually, from not only the amount of data that Dr. Brooks is generating on the INSPIRE trial but already starting our double-blind, placebo-controlled trial as well. So, we'll see. Do you have anything else to add?

Maybe just in terms of your plans for commercialization and your latest cash runway, how you're thinking about the strategy?

Yes. So cash runway, we were very fortunate. We just raised $240 million. It puts us cash in the first half of '28. So we have a significant runway, and we can just focus on doing the job. Commercialization, I plan on commercializing this myself, both U.S. and ex-U.S. and definitely in select countries ex-U.S. In U.S., we've done this many times. And looking forward to competing against whether it's Sarepta or REGENXBIO and seeing what this -- I think this drug is, from a commercial standpoint, best-in-class. Why? It's the lowest dose. It's the easiest to use, but the highest expression. It's pretty simple. It's outpatient, a couple of hours in the clinic, kid goes home. And ease of use is going to really help this market itself.

What's the latest with your interactions with the ex-U.S. regulators?

We speak with them, and we also have ILAP designation in the U.K., which is really setting us up for potentially first-in-class there. And we are -- we just hired -- we're working on hiring a Head of Commercialization, ex-U.S. as well to start working on all of the HTA assessments and a Head of Regulatory ex-U.S. We're going to spend a lot of time in select countries the larger countries in EU, and we're going to commercialize there, hopefully, in the next couple of years.

Well, thank you both for joining us and sharing all the updates. Appreciate the time.

Yes. Thank you. Thank you.

Thank you.

Good morning, and thank you for joining Guggenheim's 2026 Emerging Outlook Biotech Summit. I am Debjit, one of the therapeutic analysts, and my privilege to welcome our next presenting company Solid Biosciences and joining from Solid is Bo Cumbo, President and CEO. Thank you so much for your time, Bo.

Yes. Thank you, Debjit, and thank you, Guggenheim for invitation.

So let's do a very quick introduction to Solid. Obviously, the company has changed dramatically since you've taken over?

The company, it's a great little company. We have about 120 employees. We market ourselves as a precision genetic medicine company. But primarily, we focus on gene therapies. Our first 3 drugs are one for Duchenne. We'll talk a lot about that today. Our second therapy is for Friedreich�s Ataxia and our third therapy is for CPVT, which is catecholaminergic polymorphic ventricular tachycardia.

We have multiple other programs as well, our next program, dilated cardiomyopathies, TNNT2. And then we have an entire capsid library and platform that we build on delivery because to make gene therapy investable, again, really investable broadly speaking, we have to change delivery and delivery is focused on capsids, promoters, dual plasmids, manufacturing purity. So we spend time in all those areas as a company and hopefully lift everybody up.

Perfect. So on Monday, I believe you put out a press release aligning with the FDA on a registration study.

Yes.

How important is that in the context of everything that's happening with the FDA and any potential accelerated approval?

Yes. Look, I think that press release on Monday was a huge first step. I don't know if people realize the importance of it. This is a very unique time. I think a lot of -- I read all the press with different companies and what's going on. And so we're trying to do everything right here the best we can. We're obviously in rare disease. We have -- the INSPIRE trial is an open-label study trial, but we're seeking accelerated approval in the United States, and we're going to be asking that question of the FDA real soon.

But we think from a psychological standpoint of just understanding what the FDA wants by reading all the language that other companies have received, try to do everything you can from a purest point of view, even though it's an open-label trial, and that's what we're doing.

So number one, we're going to have a very large safety database. We already dosed 36 patients. We will meet with the FDA shortly. We should be over 40 patients by the time when we meet with FDA. That's going to help the discussion because currently, right now, there's no drug-induced liver injury, no myocarditis, no aHUS, TMA.

I'm not saying it's not going to happen down the road, but as we sit here on the stage today, it's 0-36. We haven't looked at the data, the functional data. And I think that that's extremely important because as we talk to this FDA, we can guarantee that we've not snooped any of the data. So as you're talking to them about a stat plan or you're talking to them about natural history or external controls and how you can use it, one of the issues that they would have is how did you select this natural history? Well, we can select it with them hand-in-hand in partnership here because we don't know what the functional data looks like in our 36 patients. and we can have that discussion with them. But last but not least, going to your question, the double-blind, placebo-controlled trial.

The FDA wants some kind of certainty. And I think it's very challenging in a lot of cases to do double-blind trial. But here, in Europe, Australia, Canada, you can do a double-blind placebo-controlled trial for Duchenne, and we're going to do it. And we've got the guidance from the FDA. We had a really good discussion with them. They've made some changes in how we think about the trial design and secondary endpoints. They said that the trial is reasonable, and we're moving forward.

We should have actually dosed our first patient next week. But unfortunately, the little boy was really sick. And so we won't be dosing him, but we're already scheduling our next patient, should be dosing our first child in the double-blind placebo-controlled trial in the next 90 days or so, first get screened out. So we're lining up the second patient now.

And I think this discussion helps with the FDA. There's clearly a lot of chaos that's going on. But if there's one drug company that you want to lean into, why wouldn't it be this one? You have a large number of patients already dosed. It's going to get bigger. We're going to be dosing 50 patients by the next, let's call it, quarter or 2. We're already at 36. It looks like a very clean safety profile. We're not using anything other than steroids. So nothing is being masked. You actually know what you got.

We've started the double-blind placebo-controlled trial. We haven't looked at any functional data, so we can actually spend time with the FDA and talk about how to use things, and they know we're not snooping anything. If you're going to lean into one, this is where you lean into. So I think we're doing everything right as a company, but we're going to find out. We're going to have that meeting. Second meeting is already scheduled. Obviously, we have not held it, but it has been scheduled and let's call it the next quarter.

So ELEVIDYS has both, at least from my perspective, advanced the field and set the field back. SGT-003 has multiple discerning features, which allows you to do what you're doing with corticosteroids, et cetera. Can you sort of outline those key differences and how that plays into the planned registration study with in boys 7 to 11 years of age?

Yes. I think the great news as we were thinking about 003 many, many years ago is many of us within the company either came from Sarepta or came from Pfizer or came from other Duchenne companies. And so we really understood 3 years ago, what we thought the field was going to look like. What we -- this was before ELEVIDYS failed. It was after they failed the Phase II, but before they failed the Phase III and before, obviously, all the safety events that have plagued the drug.

So we built a TPP to beat that drug, and we built it from day 1. And so what did it have to look like? And that's why we started from scratch. So it starts with the capsid, starts with delivery. You have to have a capsid that beats rh74, AAV8, AAV9 and every muscle of fiber. And so regardless of how you look at it, we call it binding capacity. It binds very quick to these integrin receptors.

We have RGD peptides inserted into this capsid. It binds on integrin receptors, 2 primarily that you see upregulated in skeletal and cardiac muscle. We knew that it would transduce and express very quickly. Within 4 days in certain muscle groups like the heart, it was at 50% to 75% expression at day 4. That is dramatically different than rh74, AAV8, AAV9. You just don't see it. And then by the way, then it clears in day 4. So it's out of the blood, the capsid, and this is human subjects.

In the human subjects at day 4, it's 90% cleared out of the blood, and that's going to make a difference from a safety standpoint. We knew that this capsid also got to human cardiomyocytes and expressed about 20x greater than AAV9. So that was sort of the distribution. We knew it was liver detargeting. It was liver detargeting in the mouse. It was liver detargeting in the monkey. Obviously, we can't do liver biopsies in humans, but what we can do is look at their ALT and AST and they go down. And so we're not seeing the spikes or in GGT just stays flat. And so we're not seeing what others are seeing.

And so we feel confident that what we saw in the monkey, what we saw in the mouse is happening in the human subjects, at least to date with N036. Then we talked about the construct, the actual transgene itself. We know that there's other proteins that are critically important. We know that you need to have a flexible protein because you're taking a long protein, you're shrinking it down. And you want that protein to be as flexible as it can be in the human subject.

And then we want nNOS created. Why is nitric oxide important? Well, it increases coronary perfusion, decreases oxidative stress and decreases fibrosis and inflammation over time. There's lots of publications out there that show the importance of nNOS in human subjects. And so we add that aspect in. We also -- other proteins, alpha-syntrophin, Cavin4 to help with the ERK phosphorylation of the heart. This construct is different than any other construct that's out there. You tie that with the capsid, you've got a really good program. But the last and not -- and should not be least is our manufacturing process.

Process is really clean. You have about 75% full to empty ratio. Why does that matter? Well, these capsids don't know that they're full or empty. They're just looking for the receptors to bind. And when you actually have an empty capsid that binds to a receptor, it's basically going to give the [ Hizman ] to the full receptor. And you're not going to be able -- you're going to see in a very uniform approach in cell data that when you have a lot of falls, it decreases expression.

As you increase your pools, you increase your expression in a very uniform manner. Obviously, it's going to be different than a human subject, but at least you know what to look for. But safety is a big deal. You're dosing these little boys at VG to KG standpoint. If I'm dosing you at 1E14 vg/kg and I have a 50% full ratio, I'm literally having to double the dose to give you the true falls. That's going to put pressure on the complement system. It's going to put pressure on the liver.

These are the things you want to avoid if you're going to build the next-generation program. We took all this into consideration. We came from Duchenne companies. We know what we're trying to beat. If you're going to innovate -- if you're going to cure a disease, you need to continue to innovate. You can't have one company dominate the landscape. You have to have multiple companies, whether it's Avidity, Wave, Dine, us, et cetera, building next-gen programs. I hope the FDA realizes this. This is -- I came from back in the day in mid-'90s of HIV. I know I look young and sprite, but I was -- I started in 1995. And it's pretty amazing.

By the way, I'm clearly not going to let you get to the second question. But it's pretty amazing when we think about how important innovation is in this industry and how if you really want to cure a drug -- a disease state, you have to have multiple companies trying to innovate. And I think that that's what the FDA is going to see here, and I'm very hopeful. The funny thing is I'm just going to keep going. The funny thing is we sit here and we talk about the reasons why I believe this program is the best program out there.

We'll talk about nNOS, you'll talk about the capsid. We'll talk about everything I just mentioned. Ironically, what's going to end up taking this market is ease of use. Ease of use is so simple. And so you think about physicians, why are physicians only dosing 40 patients, roughly 1/4 of ELEVIDYS. It's not because the drug doesn't work. It's because it's challenging to dose. You have to monitor it.

The biggest thing for these physicians is their time. It's not about anything else. They're treating SMA, CPVT, I mean, Charcot-Marie-Tooth, limb-girdle, FSHD, all these diseases, then you get to Duchenne. What do you end up with? You end up with 40% liver injury, somewhere between 10% and 15% hospitalizations. Cardiomyopathies that you're seeing, then you're having to use sirolimus or eculizumab. Different physician has to dose sirolimus. Different physician has to dose eculizumab.

You have to monitor levels for the kidney. You can get gut necrosis in the little children. All of this takes time. And then when you start pulling sirolimus off, what do you do? You have to make sure you monitor because you don't know what's up underneath the waves. Ease of use is going to end up taking this entire market. I can sit up here and talk about why my drug is going to be the best drug out there from a scientific standpoint. Physicians' time is going to end up being the major role in market share.

All right. There was probably an interesting learning for you guys during your clinical trial process in terms of infusion rates, especially given the binding and the very rapid uptake. Anything you could share from that and how that's to get?

Yes. It really was about how we use steroids. We filed some method of use patents. And so we dosed our first 10 boys. We noticed some variability in the children. Most companies would say, "oh, it's variability" due to heterogeneity disease. We didn't believe that. So we looked for any markers. Is it weight? Is it age? Why do you have variability? We did find a marker and that marker -- and we'll talk about that marker at the MDA conference.

But realistically, it all came down to the first couple of days and how you dose and how your body reacts to the AAV and how it gets -- how important that first 24 to 48 hours is for the drug to get into the nucleus and then transcribe and ultimately express. And we noticed that there is a signal that certain children had and that decreased expression. And we're trying to solve it with how we dose with steroids.

We were dosing this program, and we were using increased steroids on day 1 of dosing. So if I dose you today with 003, I'm also increasing your steroids on the same day. And we found that there is a signal that if we move the steroids back 3 days and just bring the steroids back, so you start your increased steroids day minus 3, all the signals change. And we think it goes back to how unique this capsid is.

We see it in the animal studies that it's -- we're seeing transduction and we were seeing expression at day 2 in mice. And so we know something is going on with this capsid that's very unique compared to all the other capsids. You're seeing massive -- massively increased time to transduction and expression. And so we have to think differently. We can't just treat this like a typical AAV.

So we just moved the steroids back. And we believe it's going to change everything. And that's why we filed method of use patents on how you use steroids. Because if you look at what the world is doing right now, we have 50-plus academic labs and partnerships with small companies already in place. My guess is it's going to be 100 in another year. And why? Because the physicians and the researchers are voting with their feet. They're going to move away from first-gen therapies.

In 3 years, you're not going to see new programs come out with rh74 or AAV8. And why? Because there's better delivery. And SLB101 is going to end up being the workhorse for gene therapy period. You can see it how those physicians are moving. So this is where the world is going. We wanted to follow those method of use patents because I think on how you use steroids with this SLB101 because I believe, and this is just my belief, is that it's going to change whatever disease state they're in. So we have a company that we know we're working with that they're in FSHD.

I fundamentally believe how you dose these steroids with SLB101 in that program for FSHD is going to change their course. So I -- that's why we filed the patents because we believe we have a tiger by the tail here with 101 and with our 003 program.

With respect to your registration study, do you think 18 months is the right time point to do the final assessment?

Well, personally, I would have gone 24 months. I couldn't convince physicians and families to go out 24 months. You're dealing with the disease state that's been ravaging the body for extended period of time since the wound. By age 12, that's typically when people -- the children lose ambulation. The fat fraction is 80%. That means 80% of the body is fat. So like when you're at like age 7, 8, 9, 10, you're 40%, 50%, 60% fat fraction depending on the age.

I would have preferred to go 12 months, but you can't convince families to do a double-blind placebo-controlled trial in a kid that's ultimately going to unfortunately pass away due to the disease for 2 years. 18 months is a really good start. You will see change. I think we made a lot of mistakes in our early trials. We used ages 4, 5 and 6 kids.

While they're not normal, but they are increasing in development over time. You use a clinical endpoint as NSAA, a very blunt instrument that's subjective in nature. The physicians only got 0, 1, 2, 3. You get into the trial, rise time was less than 5 seconds. So you only selected the healthiest 4-, 5- and 6-year olds for the trial.

And then you didn't even give the body time to adjust and your trial is over 52 weeks, adjust to the new protein. We've solved for all this. We're using ages for Phase III double-blind trials, 7, 8, 9, 10, 11 years of age. Why? Because they're either plateauing or declining. We're using time to rise as a very specific endpoint and the FDA agreed to the time to rise as the endpoint.

We're -- to get into the trial, it's going to be higher than 5 seconds and lower than 10 seconds. It's right in that sort of sweet spot where the kids are either plateauing or slightly declining. And then we're going out 18 months. We're going to let the body adjust to the new protein for 6 months, and then we'll have 12 months of time for us to see benefit.

I think from a probability of success to hit the endpoint, this trial has all the aspects of it. And then I personally believe it's got the best drug and right now, it seems pretty clean as well.

Let's pause on DMD for a second and then talk about the FA program. You've sort of taken a very different approach to it, dual vector targeting 2 different things. Can you just walk us through the strategy there?

I would tell you, I should be more excited about Duchenne than I am FA, but truthfully, my heart is in FA. I think this is going to be an AveXis-like moment in FA. That's my personal belief. We're going to have to wait and see how things play out. We believe, fundamentally, you got to get to the dentate nucleus of the cerebellum. Of course, the spinal column is important and the heart is important. And all 3 of those areas become difference of importance or different weight of importance as you age, as you mature because the disease continues to ravage the body.

We're the only company that's doing what we're doing, dual route of administration. So we start with an MRI-guided enhanced imaging into the dentate nucleus. It's a stereotactic MRI guided. You should -- Dr. Lonser, out of the Ohio State University, he's our neurosurgeon, and he is ecstatic about what we tried to do and what we're able to accomplish. You start with the neurosurgery. You hit both sides of the dentate nucleus. We wanted to cover 15%. We believe that, that was going to be meaningful for these patients as you think about diffusing in the dentate nucleus.

We blew that out of the water. The -- you want to talk about precision genetic medicine and we were trying for the center of the dentate nucleus, we're 0.3 millimeters off of the center of the dentate nucleus. That's how guided it was. So you're not going to have capsid going all over the brain. Anyone who's going to try with a neurotropic capsid or try to push the dose up to get to the dentate nucleus, you're just going to have capsid going everywhere or you're going to cause a tox.

Because we can do this and we're at the E9 doses -- dose in the brain, and that's total VG. We can actually then lower the dose for the spinal column in heart. It takes about 2 hours or so for the neurosurgery. We let the patient rest an hour, then we dose IV. IV can be a lower dose as well, E12, gets to the heart, gets to the spinal column.

And I think about this when we thought about programs and how we develop a program, I thought about what would I do if I'm a father of a little girl with FA that's 5 or 6. Am I going to wait 15 years to understand if they're going to have dilated cardiomyopathy before I dose? Or am I going to try to help this -- my child right now? And the answer is I'm going to do everything I can to help the child right where the heart of the matter, and that's getting to the dentate nucleus and then protecting the heart and the spinal column over time.

There's only one company, one drug that's going to do that. That's this. We've dosed our first patient who was 27 years old. He was very, very sick. And FARS capsid 93. He is in the high 80s. If we see any signal from this guy, it's a miracle. And I will be screaming from the rooftops. I'll tell you, I'm personally very excited. We're about I don't know what the data is right now, but I think we're about 40 days out from dosing. It's doing great. He had a headache, resolve with Tylenol, and we haven't seen anything else. And we're already hearing things, but we don't have proof yet that the gentleman is doing very, very well from an efficacy standpoint, we have to wait.

I think this could be one of these AveXis type moments. Obviously, SMA is so different than FA from a mortality standpoint, but I think this is one of these that can change the disease state overnight. We already have 50 patients trying to get into the trial at Ohio State. That's one site, 50 patients. If we see benefits in this drug, if we see safety, the entire world is going to flock to this program if you have FA.

And when do you expect to put out data on this one? Do you have a preset number of patients you want to treat before you...

Yes. We're going to dose 3, 6 patients over the course of the year, 3 patients, and then I'll probably read out second half of the year on the first 3, but we'll continue to dose Cohort 2, we call it Cohort 2. So we'll dose Cohort 1, Cohort 2, but Cohort 1 will probably read out second half of the year. And if it's anything great. I think this is a very unique little company.

Last few seconds. What do you think should be the right bar for mFARS here because current standard of care, the bar is...

2.14.

Exactly. So...

Yes, it's 2.14. And that's the regulatory approval for SKYCLARYS. So it's 2.1.

Well, awesome. Looking forward to all the data updates this year and especially on the regulatory side. Thank you for making time Bo.

Thank you, Debjit. Appreciate it. Thank you very much.

Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I am one of the senior biotech analysts here at JPMorgan.

I'm joined by my squad, Rati Pinge, Priyanka Grover, Joyce Zhou. Our next presenting company is Solid Biosciences. And presenting on behalf of the company, we have CEO, Bo Cumbo.

Yes. Thank you, Anupam. Thank you JPMorgan for the invitation. It's good to see all the friendly faces in the audience today and those who are attending. Before I start, the forward-looking statements, I'll give you -- I'm going to pause on the forward-looking statements and tell you a little story.

Before we actually started the presentation, 2 of our attorneys come up to me and talk about, are you excited about JPMorgan?

And I'm like, "Oh, great. What are you going to say?" Well, I'm going to tell you about everything that's going on. We've dosed 33 patients, all safe, no drug-induced liver injury, no myocarditis, no aHUS.

We've already enrolled our first patient and scheduled our first patient in the double-blind, placebo controlled. We dosed our first patient in FA. This has been -- this is the best year that we've ever had as a company.

Our capsids -- we've had 50 different agreements for our capsids. People are starting to come to us as a platform technology company and using all our delivery vehicles inside for a Solid inside for next-generation therapies.

We have TNNT2 that's on its way. We're getting ready to dose our first patient in CPVT. And I'm going to tell everyone around how we plan on taking the majority of the market share in our Duchenne space over time and how we believe that we're going to change patients' lives in FA.

The 2 attorneys looked at themselves, they walked off. And the next thing you know, I get the note, cautionary note regarding forward-looking statements. So that's how we get this slide.

And I've never seen a headline like that before, but you might want to read it because I'm going to say a lot of things, as you can tell.

I'm very pleased and happy to report -- to show you this pipeline. 3 years ago, when I was with Anupam, this was a vision. And when I was at this conference, we spoke on Thursday.

And everything that you see on this slide was really a vision of what could become. But we actually had hopes and dreams, and we finally got here. And I do want to thank all our investors that really helped us with this journey over the last 3 years.

And I think you can see now that we are poised, hopefully, to do great things for families and patients in the years to come. We have dosed, as I mentioned before, 33 patients in our Phase I/II Duchenne trial called INSPIRE.

We're about ready to dose our first patient in the double-blind placebo-controlled trial. He just screened, negative for antibodies, which is a good thing, and he'll be enrolled very shortly or dosed very shortly in the next couple of months.

We have dosed our first patient in Friedreich's ataxia, and this is a milestone that I want to scream from the rooftops first ever time -- first ever that anyone's dosed dual route administration.

You do an IV dosing for the heart and the spinal column, you do intradentate nucleus dosing for the cerebellum. The patient is doing very well right now. It's early days. We have ways to go, but we're very pleased. We're close to -- we had to prioritize. We're a little firm.

We only have 119 employees and a small medical team. So we had to prioritize FA over CPVT, but we have over 30 patients that are trying to get into the trial for CPVT, 3 different sites, and we should be dosing this quarter.

We've now moved TNNT2 forward as well through GLP tox, and we're close to submitting an IND. I don't know if we can actually do it as a company because we're a little company, but this is another dilated cardiomyopathy. And then we have our capsid platform and our other programs, and I'll talk a little bit about that.

Last year was an unbelievable year for execution of this company. We did things that Solid has never done before. And we dosed, as I mentioned, over 30 patients in our first trial. We've had 30 different partnerships.

I think it was right around 30 or 23 in Q1 of last year, and now we've exceeded over 50 different partnerships with our capsid program.

FA, we received IND clearance at this time last year in the same meeting, and now we've dosed our first patient. And CPVT, we had our IND last year as well. And now we're all poised for an unbelievable potentially transformative year for Solid.

For our capsid library, we just announced over 50 different partnerships, and I'll talk a little bit about that in the next couple of slides.

For Duchenne, as I mentioned before, we're going to actually -- we're fully enrolled for our trial. If you look on clinicaltrials.gov for the INSPIRE trial, we had -- we were planning on scheduling 50 to 60 patients in the study. As you know, we've dosed 33. However, we are fully enrolled, and we're -- we have more than enough patients for every single slot, and we're going to be notifying the sites, hopefully, in the next month or 2 that we're basically not going to take any more recruitment because we filled every slot that's possible.

So now it's just about scheduling, doing the antibody test, scheduling, doing the biopsies and getting them dosed. We are dosing our first patient with -- in the double-blind, placebo-controlled trial.

Our first patient will either be in Australia or Canada. We will also open up European sites. We believe they will take about 18 months or so before we completely and fully enroll the double-blind, placebo-controlled trial. We're very excited about this trial because we want to bring this drug to every patient across the world.

And we also plan on using this trial as a confirmatory study for accelerated approval in the United States. So it's critically important that we do start dosing this trial soon.

For FA, as I mentioned, we've already dosed our first patient. We already got our second patient lined up. We have not scheduled him yet, but he's lined up. We'll wait until we're cleared on safety from our first patient. We have a few more weeks to go.

And then we'll start dosing those -- the second patient and then ultimately third. And CPVT, as I mentioned before, we should be dosing this quarter. We'll talk a little bit about 003 and how we have differentiated profile, and then we'll also talk about the capsid and sort of intertwine the 2 together.

So we believe that 003 has a significant potential and significant upside. It's a compelling clinical profile demonstrated in the Phase I/II trial. We've dosed 33 patients.

We have about -- in the patients that we've had microdystrophin, which are N of 10, the mean expression is 58%. It's the highest of any of the microdystrophins that are out there to date.

We also at the lowest dose, and I think that's critically important when you think about it, we're at 1E14. So we're a lower dose than all the drugs you at a higher expression. We can show the dystrophin-associated protein complex at high levels.

We actually quantify ourselves beta-sarcoglycan, so we can look at how well we're putting together the entire complex. And we have early cardiac data. Now we look at cardiac data from a safety standpoint, but we're seeing observed troponin declines, and we're also seeing ejection fraction increases in patients that are low or low normal.

Safety-wise, it's very well tolerated to date. And we do know this is gene therapy that could change. But as we sit here today, we have 0% drug-induced liver injury. We have 0 TMA, 0 aHUS, 0 myocarditis.

And hopefully, that will continue. We're very humble in this space knowing that this is gene therapy and it can change. But to date, our safety profile looks very, very good.

And that's N of 33. And we'll talk a little bit about the potential significant commercial opportunity in a little bit. I think the landscape has changed dramatically of what the future will look like.

And I think there's a major opportunity for this drug to have an impact in the market. Now our program 003 leverages our next-generation technology to deliver this therapy.

And what we use is we use a capsid called SLB-101. This is the first time that this capsid has actually been in humans. It is -- the capsid is designed to bind to endocrine receptors on skeletal and cardiac muscle.

And that's why we get such enhanced and quick binding capacity and enhanced distribution as well as liver detargeting. We'll talk a little bit about this.

The construct that's within the capsid is uniquely designed. It contains R16 and R17 binding domain, which localizes nNOS to the muscle membrane. And nNOS is critically important, as you guys know, to help improve muscle perfusion.

It increases blood flow, reduces pathology, fibrosis and increases cardiac protection. And we believe that this is why we're seeing some of the benefits we are.

We only use steroids, and that really separates us from the rest of the pack, and it's outpatient dosing. And so it's generally well tolerated.

As mentioned before, currently, we have not seen any drug-induced liver injury, TMA, aHUS, myocarditis. We use steroids alone. We also only use steroids for -- increased steroids for 30 days.

And that is the shortest course of any of the companies that are in this gene therapy space. So from day 30 -- day 0 to day 30, we have an enhanced steroid regimen like the other companies do, but we taper at day 30.

So by day 60, all the patients, except for one, have been down to their standard steroid regimen. And I think that's critically important. It also helps you when you look at day 9, 8, responses.

It makes you feel comfortable that those responses that you're seeing are not caused by steroids. They're actually caused by 003. And I think that's important.

We talked a little bit about the expression, and we -- and I think it is important to understand that we have the lowest viral dose, viral load for the body.

We're 1E14, Elevidys, the drug that's approved for Duchenne's 1.33E14. And then we have another therapy that's in clinical trials that's 2E14. So when you think about the impact of the body from a viral load standpoint, we are the lowest.

Now what you're watching here is you're watching the footsteps of all the academics and all the small companies transition away from old gen technology to rh74, AAV9 capsids, AAV8 capsids and move to the next-generation capsids.

And I think this signals a wave that you should pay attention to because all the researchers are starting to realize that if you really want to change gene therapy and make gene therapy investable again as well as hopefully get the clinical results, you need to change delivery and delivery is critical.

And we're seeing it in masses right now, 50-plus different groups we have agreements with. Some are academic labs, some are small companies, some are larger companies. And I think I'm speaking to right now, any investor that's out there that wants to invest in a small company, a gene therapy company or a small gene therapy company or an academic, don't use the old technology.

There's a lot of really good technology that we have that will give you and we'll work with you to make sure that you can create next-generation programs, so you can get money and investors into your platform.

So if you are thinking about creating a new construct, call us. The e-mail is at the bottom, and we'll make sure that we give you next-generation tools. By the way, it's not just our capsids. It's our dual plasmids. Companies are used in our dual plasmids that helps right now -- increase our full-to-empty ratios.

We have promoters across the board. We have buffers. We can really help all the small companies and as well as the academic labs, create better gene therapies for the future. And hopefully, we can make gene therapy really investable again.

Now what creates this new capsid and what turns this into such a novel delivery mechanism is not just onefold. And when you think about like Formula 1 racing cars and you think about what makes a car so special, it's not just -- it's not the engine, it's not the airflow.

It's not the driver, it's not the pit crew, it's all these pieces. And basically, that's what happened here with this capsid. You see 2 to 3x liver -- better liver detargeting in this capsid. You see -- depending on the muscle, you can see anywhere from 3 to 5x up to 10x better distribution with this capsid.

It clears out of the blood within 4 days of the -- from -- in humans, which is very different than AAV9, AAV8, et cetera. So it's already cleared. You have -- you can have a really high full-to-empty ratio.

And it's all these little things that add up to turn this capsid into truly what's differentiated and turning this program into something special.

But here's some of the data and the preclinical data that I'll go through, and then we'll actually get into the clinical data.

Whether you're looking at luciferase activity, you look at low doses in the mouse compared to AAV9 or rh74, there really is no comparison. And what is so shocking, and I think it translated so well is the expression, the binding capacity, ultimately transduction and expression at day 2 and day 4 because we found out after the fact, once we dosed humans that by day 4, it's completely cleared.

And so really, you're getting all this expression out of the first 2 days of this dosing, and it matched exactly what we saw in the mouse. We also -- when you compare it to AAV9 or rh74 and you look at the heart and the heart and quadriceps, there is really no comparison when you look at the fold change in luciferase.

And we're -- hopefully, we're seeing that exactly play out in our program, our Duchenne program. We know what's liver detargeting. We knew what was liver detargeting in the mice that's the top left-hand corner. And what we saw in the monkeys down the bottom left was GGT levels. However, we didn't realize it was going to really translate that well into human. And so this is the liver biomarkers, and it's like driving a flat road in the state of Florida. It's very clean. It's very flat. There's not a lot of bumps. You don't have -- your liver enzymes look like an EKG. It's just -- it makes you feel really comfortable.

And by the way, this is N of 14 because we're trying to keep the data clean and show you. But really, if I showed you N of 33, it's the exact same slide.

All patients are doing very well. ALT, AST actually go down over time, GGT stays flat. Now we made this slide, believe it or not, not for investors, not for the FDA.

We've gathered all this data because when we first started doing this study, we were a $38 million company. We knew that there was competition on the way. We wanted to make sure that we felt that once you dose our therapy that we had confidence internally to put the $100-plus million into the program and drive a program to the clinic.

And what happened was quite shocked us because we have 11 or 12 different measures here that all point in the same direction. It is almost impossible for you to argue that the drug is not doing something in the human body to shore up muscle. And so we have different biomarkers here. Some are for the chronic phase, the acute phase of muscle integrity. Others are the chronic phase of muscle integrity.

Others are for sort of this muscle maturation when you think about embryonic myosin heavy chain, all of them point in the same direction. Many of them get stronger over time.

And it makes us feel really confident that our drug, 003 is doing something for these children. And long term, you're going to get that clinical benefit. Now our microdystrophin expression, it doesn't matter whether you look at Western blot or mass spec, we have the highest expression that's out there. It's 58% for Western blot, 58% for mass spec.

For kids that have gone out longer, it's even higher expression. immunofluorescence, which is positive fiber count, roughly 51% to 67% depending on the time.

This is the highest in the industry, and we feel very confident that this is long term is going to provide benefit for these kids. When you look at microdystrophin positive fibers and you do a comparison, with either beta-sarcoglycan or nNOS positive fibers, you get a very positive response. And I believe that the Pearson correlation is 0.95% when you look at the 2.

And so we're the only company that's ever quantified beta-sarcoglycan, the actual DAPC and looked at the fiber count, and we're in the high 50% to 70% positive fiber count for beta-sarc.

And then nNOS, the only company that can produce nNOS, which will obviously increase blood flow, decrease fibrosis, hopefully give cardiac benefit, and we can produce this 26% to 36%.

I want you to pause on this slide. Anyone who wants to talk about muscle pathology and whether this drug is actually doing something in the muscle needs to take a picture of this slide, go back and read what about -- what is embryonic myosin heavy chain because this is going to truly give you the confidence that this drug is doing something in the body and shoring up the muscle.

After this presentation, I would hope someone would ask Dr. Brooks, who's our Medical Officer, why embryonic myosin heavy chain is so critically important. I'll give a quick overview. And this -- I will tell you that when we showed this to our KOLs, one of them called them up the next day, Dr. Brooks, and said I couldn't sleep all night because this is a game changer.

Muscle stem cells or satellite cells are activated to repair and replace damaged muscle and fibers. And in Duchenne, what you see is you see high levels of embryonic myosin heavy chain. You also ultimately deplete your satellite cell pool because of this.

During this process, these newly formed dystrophic muscle fibers express embryonic myosin heavy chain. When you have a drug that creates microdystrophin and you're shoring up the muscle, if you're doing something, you should see a decline.

And we're seeing a decline of roughly 49%. I believe that this is the one signal out of all our signals that should give everyone pause and say this drug is doing something to shore up muscle integrity.

And ultimately, that's going to lead to clinical benefit for these boys. Whether we look at the chronic phase or the acute phase of muscle integrity, looking at serum CK, ALT, AST, titin, LDH, they all head in the right direction, whether it's day 90 or day 360.

And keep in mind what I said earlier, at day 30, we start tapering our steroids. So by day 60, patients are already back down to where the kids started in Duchenne. So when you look at day 90 -- day 90 declines like this, you can feel very confident, it's actually coming from the drug, not coming from steroids. We also measure troponin over time. Why do we measure troponin overtime? Well, all these little boys in Duchenne, they have spikes in troponin. The physicians don't really do anything about it, but they're getting these little micro tears.

Every 2 months or so, you'll see a spike in troponin in these little boys. Now you'll have the naysayers say, well, you don't have cardiomyopathy at ages 5, 6, 7, 8, correct.

But they don't wake up overnight and just have cardiomyopathy at age 10, age 11, age 12. It starts early, and it starts with these little micro tears and that's where you see these little spikes of troponin. So we've been measuring it over time.

And then what we're seeing is a decline of 70% of troponin. Now we're also measuring this in our double-blind placebo-controlled trial. Why? We're thinking about the future. We're thinking about the time 10 years from now when we can show that we can change the structure of the heart, we can hopefully even change mortality and change the label because by measuring this from day 1 and tracking troponin and tracking ejection fraction, which we have here, we hope that we can show a benefit and ultimately work this into the label.

Ejection fractions are very unique. People will say, at this age, you don't have low ejection fraction. That's not technically true. Duchenne is a very heterogeneous disease. You have a lot of kids that are "normal ejection fraction right around 65."

You have other kids that are in this low normal phase, one standard deviation below 65. And you have a few that are even further than that. And so we've been tracking all these boys and looking at ejection fraction.

And what's very interesting is if you were normal at right around 65, you stay normal. If you're low normal, you go up. And if you're low, you go up as well.

And that's what you see on the right-hand side. And we've been tracking this now over -- for some patients over a year, and we're seeing the increases, and they're staying consistent.

And this gives us a lot of hope for the future for long-term mortality, we have to do the work. and we have to do the studies.

And we're going to be tracking this in our double-blind, placebo-controlled trial, and we're going to be tracking those kids for 5 years.

Now our safety, our safety is actually getting better. And our thrombocytopenia is lower than it was. And it's because of how we tweaked and modified dosing of this capsid in this drug. And we feel really good about where the safety profile is.

As I mentioned before, no drug-induced liver injury, no myocarditis, no aHUS, no TMA and the safety profile is actually getting better. The dosing has been intense. Some weeks, we go -- we've dosed 5 patients in 1 week.

We actually didn't dose for the entire Christmas holidays. We stopped dosing right around December 10, I think, December 11. We did not dose Thanksgiving.

And you can see from November to basically January, we increased the number of participants a great deal. As I mentioned before earlier in the presentation, clinicaltrials.gov were scheduled to dose somewhere between 50 and 60 patients in this trial.

We have filled every slot. And so we are going to shut down recruitment pretty soon on this trial. I feel terrible for the little boys there trying to get in, but there's just too much demand for. But we have the IMPACT DUCHENNE trial that's going to be opening up. That's going to be in Europe, Canada and Australia. That's going to be our double-blind, placebo-controlled trial.

My eyes are so bad, by the way. I contacted our Head of IR. I said, I think the fonts are wrong. She goes, "no, this is from Minecraft." And I was like, "Oh," so I had to quickly learn that this is Minecraft and I thought my eyes were even getting worse.

I don't even know what Minecraft is.

Yes. Well, we're trying to save kids. I don't understand them, but we're trying to save them. And it's -- I guess it's a game that they really like. So -- but this trial is going to be active and it's underway.

And I think it's really important for you to know that when we meet with the FDA later -- either this quarter or early next, that we're going to already be dosing.

And I think that's going to be important when we talk to the FDA that they know that we're not cutting corners that we're actually trying to do what is right and give them a true double-blind placebo-controlled confirmation study.

Now what are we going to do this year? We're going to have 3 meetings, hopefully, by midyear with the FDA. The first one is already scheduled. That's the Phase III placebo-controlled discussion with the FDA.

We have scheduled that. We've submitted the briefing book. We've not held the meeting. We don't have any minutes, obviously, but that's coming.

And our second meeting will be somewhere late Q1 to mid-Q2. There's about a 3-month window there that we're aiming. That's going to be a very important meeting for us where we can start talking about external control benchmark data like publication benchmark data, our stat plan and really good alignment with the FDA.

I think it's really important for everyone to know that we have not looked at any of our functional data, 0 functional data. So when you look at all our data, our patient data, you have safety data, you have the expression data, you have the blood work, the biological muscle integrity data, but then you have your functional data.

That will be like rise time, NSAA, Stride velocity, none of that data has been reviewed. And why? Because when we actually talk to the FDA, we want to give them the confidence that we've not snooped the data.

When we're talking to them about external control, what external control to use, what publications to use, we have no idea what our data looks like. That will give them confidence they can even audit us. That will give them a lot of confidence that when we set the stat plan, set the external control, set the publication review, now it can be -- no one snoop the data and they can be -- they can feel confident in that.

And I think that's really important for you. And then later this year, we'll have a meeting to talk about the accelerated approval pathway and how much data you want. In U.K., there's a couple of things here, but we've got the ILAP, which is the Innovation Passport.

I think that's very important for you to know that, it's like fast track breakthrough orphan drug, all wrapped up in one. There's only 3 companies that receive this, and we're one of them. We could be U.K.'s first gene therapy to market.

The opportunity is huge. The opportunity is huge, all right? And I won't take too much time to say other than to say, I listened to our colleagues at Sarepta yesterday on how many -- how much they sold last quarter. And when I think about this, I think it's roughly about 40 -- my guess without knowing is roughly, they sold about 40 patients worth of therapy.

Now every single quarter in the United States, unfortunately, there's 100 boys born with this disease. So they are not even -- in my guess, not even close to 40% to 50% of the actual birth rate per quarter. This market is actually getting bigger.

There is a high need for new therapies. And hopefully, we can generate that. Last 2 slides. I'm very proud to say we did the first ever dual route administration in Friedreich's ataxia. We use a capsid called HU68.

It's a CNS tropic capsid because we need to get to the brain. We did a lot of work, and we know that you have to get to the cerebellum if you really want to make a difference.

And I want to tell you, I'm so proud to say that we really got to the cerebellum right where we wanted. And Dr. Brooks can talk about the pinpoint accuracy of this. But we delivered our therapeutics right to the area.

We were hoping to cover 15% to 20% of the dentate nucleus. We blew away our targeted -- our internal target on delivery here, and we're very pleased to know that the patient is doing well.

The patient is resting at home. It's too early to say all clear because we have a couple more weeks to do that. But right now, everything is good. We're going to dose 3 boys -- 3 FA subjects participants in the nonambulatory phase. The first patient was in his late 20s. He was very severe from a CNS standpoint.

If we actually see anything from this patient, it will be a miracle and we will screen from the rooftops. But we -- this is a safety study, and that is what it is designed to do. We will then -- once we go from non-ambulatory, we'll go to ambulatory and then we'll work into even lower kids.

This year could be transformational for us. We have a lot of different milestones to hit. We've got a lot of inflection points for investors, and we have a lot of data points or great studies for patients that are in need. So with that said, I'll turn it over to questions. Thank you very much.

Thanks, Bo. So I'll ask the first couple of questions, and I'll open it up to the audience as well.

So I guess my first question is, if you had to boil it down to where -- in the community in 2025 in the DMD community, there was a lot of talk about safety profile. And you presented 33 patients worth of safety that looked very differentiated. Where is this differentiation coming from in terms of viral load or where is...

Yes. No, it's a great question. Actually, it goes back to the capsid. It goes back to my Formula 1. It's not one thing that actually made it great.

It's -- the capsid was liver detargeting in the preclinical models two to threefold. It was also better distribution depending on the muscle group, somewhere between 3, 5, 6, sevenfold depending on the muscle group.

We also knew that the purity was much better. So we were getting in the 75% to 80% [ true fold ] ratio. We knew the blood is clearing out of the blood at 4 days. And so it's out of the blood. And when you think about like a complement activation or aHUS/TMA and it's looking to clear the virus, it's not there.

All of these little pieces, I believe, is what has turned this program into something that hopefully can be great one day. So I don't believe it's one smoking gun. I believe it's a lot of little pieces that made a big impact overall.

And then I think you're going to give us an actual SGT-003 data update. I think the slide said midyear. What's going to be the size and scope of that data? How much duration are we going to get? And kind of how do you think about, not just on safety, but maybe differentiating on the expression and efficacy side?

That's a great question. I'm going to -- hopefully Gab heard the question, but I'm going to turn it over to Dr. Brooks.

Yes. So I think that what we're -- I think what Bo is sharing -- is that -- shared before is that from a functional endpoint standpoint, this is all of the patients' data, we want to make sure that, that contributes to the registration.

And so we're holding that back as we shared. But this is, I think, an intensely rich data set that we will be able to share as we proceed midyear with our discussions and alignment with the agency, and then we know the street is really interested in understanding that, and we're thrilled to share that we then gives us the ability, I think, to then share all of the data in terms of what we can in terms of the biopsy data, the biomarker data, the progression of the biomarker data.

And then there are also some really interesting data that we're looking at in terms of how these boys are doing functionally at home. So we actually are capturing that. It's very exciting data to look at seeing how they're doing. And so we'll be excited to share that as well.

So I think the cadence we talk to as it relates to our interactions and collaboration with the FDA. So that's that midyear time point. And then the content, I think, is we want to share as much good news as we're seeing, which is the entirety of the data set minus what we need to safeguard, which is that registrational data.

And then also, to your point on the midyear regulatory update, right, what are the series of scenarios that we should be thinking about based on the regulatory environment we are today in DMD?

Well, we're -- I mean, we're hopeful that we have a pathway for accelerated approval. And I think that we've done everything -- I think we've done everything that we can to ensure that we have a good pathway.

We've done -- we're going to have a very large safety database, hopefully right around 50 patients in the next couple of quarters.

We're going to start our double-blind placebo-controlled trial. We have not snooped any of the data, so we can actually have a great conversation with the FDA around external control and as well as the stat plan.

And I think the scenario will be we will have a path forward for accelerated approval sometime this year. And that means that we will -- if that is the case, if we're fortunate enough to have those conversations and get that path, we should start a rolling BLA at the end of the year and finish up by mid next year.

That is our game plan right now. We are also, as I mentioned, going to be enrolling a double-blind, placebo-controlled trial ex U.S. That will take about 18 months to enroll.

And our game plan is to use that trial for confirmation study for the United States as well as full registrational approval ex U.S. So I think those are the scenarios, Dr. Brooks?

Yes, absolutely. My CEO is very, very humble in the sense that I think that we are engaging with the agency and meeting them where they are. We want to be able -- we are in a position to show them, we take seriously your guidance. And so we're holding safe this functional data.

We are dedicated and are -- have already started our double-blind, randomized, placebo-controlled trial as part of your guidance. So when we come to them, we're coming to them from a position of we respect the guidance, we respect what you need to do to get to an approval. And I think that, that means that I feel quite confident that, that gives us every opportunity for a pathway for accelerated approval and again, with news on that midyear this year.

Any final questions from the audience? Thank you, Bo and team.

All right. Thank you.

Thank you.