Twenty twenty six Emerging Outlook Biotech Summit. I am Debjit. I'm one of the therapeutic analysts, and my privilege to welcome our next presenting company, Solid Biosciences. Joining from Solid is Bo Cumbo, President and CEO. Thank you so much for your time, Bo.
Yeah, thank you, Debjit, and thank you, Guggenheim, for the invitation.
Let's do a very quick introduction to Solid. Obviously, the company has changed dramatically since you've, you know, taken over.
The company, it's a great little company. We have about 120 employees. We market ourselves as a, you know, precision genetic medicine company, but primarily, we focus on gene therapies. Our first three 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, like, an entire capsid library and platform that we built on delivery, because to make gene therapy investable again, really investable, broadly speaking, we have to change delivery, and delivery is, you know, 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?
Yeah, look, I think that press release on Monday was a huge first step. I don't know if people realize the importance of it. You know, this is a very unique time. I think a lot of you know, I've 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, you know, the INSPIRE trial is an open-label study trial, but we're seeking accelerated approval in the United States and we're gonna be you know, asking that question of the FDA real soon.
But we think from, you know, a, you know, 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 purist point of view, even though it's an open label trial, and that's what we're doing. So number one, we're gonna have a very large safety database. You know, we already dosed 36 patients. We will meet with the FDA shortly. We should be over 40 patients by the time we meet with FDA. That's gonna help the discussion, because currently, right now, there's no, you know, drug-induced liver injury, no myocarditis, no aHUS, TMA. I'm not saying it's not gonna happen down the road, but as we sit here, you know, on the stage today, it's zero of 36.
We haven't looked at the data, at 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 gonna do it. And we 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 kid screened out, so we're lining up the second patient now. And, you know, 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 wanna lean into, why wouldn't it be this one? You have a large number of patients already dosed. It's gonna get bigger. We're gonna be dosing 50 patients, and then by the next, you know, let's call it quarter or two, we're already at 36. It looks like a very clean safety profile. We're not using anything other than steroids, so nothing's 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 gonna lean into one, this is where you lean into. So I think we're doing everything right as a company, but we're gonna find out. We're gonna have that meeting. Second meeting is already scheduled. Obviously, we have not held it, but it has been scheduled, and it'll, you know, let's, 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, you know, do what you're doing with corticosteroid, et cetera. Can you sort of outline those key differences and how that plays into the planned registration study in boys 7 to 11 years of age?
Yeah, I think the great news, as we were thinking about 003 many years ago, you know, 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 gonna look like. This was before ELEVIDYS failed. It was after they failed the phase II, but before they failed the phase III, 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 one. And so what did it have to look like? And that's why we started from scratch. So it starts with the capsid, it starts with delivery.
You have to have a capsid that beats rh74, AAV8, AAV9 in every muscle fiber. And so, you know, 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 to primarily, that you see upregulated in skeletal and cardiac muscle. We knew that it would transduce and express very quickly. Within four days in certain muscle groups, like the heart, it was at 50%-75% expression at day four. That is dramatically different than rh74, AAV8, AAV9. You just don't see it. And then, by the way, then it clears in day four, 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 is gonna make a difference from a safety standpoint. We knew that this capsid also got to human cardiomyocytes and expressed about 20 times greater than AAV9. So that was sort of the distribution. We knew it was liver retargeting. It was liver retargeting in the mouse. It was liver retargeting 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 GGT just stays flat, and so we're not seeing what others are seeing.
So we feel confident that what we saw in the monkey, what we saw in the mouse is, you know, happening in the human subjects, at least, to date, with N of 36. 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. 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've also add, you know, other proteins, alpha-syntrophin, caveolin-4 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, you know, and should not be least, is our manufacturing process. Process is really clean. You have about 75%, you know, 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 gonna give the Heisman to the full receptor, and you're not gonna be able to—you're gonna see in a very uniform approach in cell data, that when you have a lot of fulls, it decreases expression. As you increase your fulls, you increase your expression in a very uniform manner. Obviously, it's gonna be different in human subject, but at least you know, you know what to look for. But safety is a big deal. You know, you're dosing these little boys at VG/kg standpoint. If I'm dosing you at 1E14 VG/kg, and I have 50% full ratio, I'm literally having to double the dose to give you the true fulls. That's gonna put pressure on the complement system.
That's gonna put pressure on the liver. These are the things you want to avoid if you're gonna build a next-generation program. We took all this into consideration. We, we came from Duchenne companies. We know what we're trying to beat. You know, if you're gonna innovate, if you're gonna innovate. If you're gonna 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, Dyne, us, et cetera, you know, building next gen programs. I hope the FDA realizes this. This is. You know, I came from back in the day, in mid-1990s of HIV. As you know, I know I look young and spry, but, you know, I was. I started in 1995, and, it's pretty amazing.
By the way, I'm clearly not gonna 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 disease state, you have to have multiple companies trying to innovate. And I think that that's what the FDA is gonna see here, and I'm very hopeful. You know what the funny thing is? I'm just gonna 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 gonna end up taking this market is ease of use. Ease of use, it's so simple.
So, you know, you think about the physicians: Why are physicians only dosing 40 patients, roughly a quarter 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, 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 gonna end up taking this entire market. I can sit up here and talk about why my drug is gonna be the best drug out there from a scientific standpoint. Physician's time is gonna end up being the, the major role in market share.
All right, we're done. 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.
Yeah.
Anything you can share from that and how that's changed over the...?
Yeah. Yeah, it really was about how we use steroids. We filed some method to use patents. And so we dosed our first 10 boys. We noticed some variability in the children. And most companies would say: "Oh, it's variability, you know, due to, you know, heterogeneity disease." We didn't, 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, you know, we'll, 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, you know, how important that first 24-48 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 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 one of dosing. So if I dose you today with SGT-003, I'm also increasing your steroids on the same day.
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 three , all the signals change. We think it goes back to how unique this capsid is. We see it in the animal studies that it's you know, we're seeing transduction, and we're 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, you know, 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.
We believe it's gonna 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, you know, we have 50+ academic labs and partnerships with small companies already in place. My guess is it's gonna be 100 in another year. And why? Because the physicians and the researchers are voting with their feet. They're gonna move away from first gen therapies. In three years, you're not gonna see new programs come out with rh74 or AAV8. And why? Because there's better delivery, and SLB101 is gonna end up being the workhorse for gene therapy, period. You can see it, how these physicians are moving. So this is where the world is going.
We wanted to file those method of use patents, because I think, on how you use steroids with this SLB 101, because I believe, and this is just my beliefs, is that it's gonna change whatever disease state they're in. So if we have a company that we're, we know we're working with, that they're in FSHD. I fundamentally believe how you dose this, these steroids with SLB 101 in that program for FSHD is gonna change their course. So you know, that's why we filed the patents, because we believe we, 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, you know, personally, I would have gone 24 months. I couldn't convince physicians and families to go out 24 months. You know, you're dealing with a disease state that's been ravaging the body for extended period of time, since the womb. You know, by age 12, that's typically when people, the children, lose ambulation. The fat fraction is 80%. That means, you know, 80% of the body is fat. So, like, when you're at, like, age 7, 8, 9, 10, you know, 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 gonna, unfortunately, pass away due to the disease for 2 years.
Eighteen months is a really good start. You know, you will see change. The, I think we made a lot of mistakes in our early trials. We used for ages 4, 5, and 6 kids. While they're they're not normal, but they are increasing in development over time. You used a clinical endpoint as NSAA, a very blunt instrument, that's subjective in nature. The physicians only got zero, one, two, three. 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's over at 52 weeks, adjust to the new protein. We've solved for all this. We're using ages for phase III double-blind trial, 7, 8, 9, 10, 11 years of age. Why?
Because they're either plateauing or declining. We're using time to rise at a very specific endpoint, and the FDA agreed to the time to rise as the endpoint. To get into the trial, it's gonna 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 gonna 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 this... I personally believe it's got the best drug, and right now, 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 two different things. Can you just walk us through-
Yeah
... strategy there?
I will tell you, I should be, 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 gonna 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, the heart is important, and all of three of those areas, you know, become in difference of importance or different weight of importance as you age, as you mature, because, you know, you know, 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 a MRI-guided enhanced imaging into the dentate nucleus. It's a stereotactic, MRI-guided. 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 are able to accomplish. You start with the neurosurgery. You hit both sides of the dentate nucleus. We wanted to cover 15%. We believed that was gonna be meaningful for these patients, as you think about it diffusing in the dentate nucleus. We blew that out of the water. You wanna talk about precision genetic medicine, we were trying for the center of the dentate nucleus. We were 0.3 millimeters off of the center of the dentate nucleus.
That's how guided it was. So you're not gonna have capsid going all over the brain. Anyone who's gonna try with the neurotropic capsid or try to push the dose up to get to the dentate nucleus, you're just gonna have capsid going everywhere, or you're gonna 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 and the heart. It takes about two 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.
You know, 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 gonna wait 15 years to understand if they're gonna have dilated cardiomyopathy before I dose, or am I gonna try to help this, my child right now? And the answer is, I'm gonna 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 gonna do that. That's this. We've dosed our first patient. He was 27 years old. He was very, very sick. mFARS capsid, 93. He was 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 tell you, I'm personally very excited. Yeah, we're about... I don't know what the date is right now, but I think we're about 40 days out from dosing. He's doing great. He had a headache, resolved with Tylenol, and we haven't seen anything else, and we're already hearing things, but it's we don't have proof yet, that the gentleman's 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 a 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 gonna flock to this program if you have FA.
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, you know?
Yeah, we're gonna dose, you know, 3 to 6 patients over the course of the year. Three patients, and then I'll probably read out second half of the year on the first three, but we'll continue to dose cohort two. We call it cohort two. So we'll dose cohort one, cohort two, but cohort one will probably read out the 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.
Yeah, it's 2.14. I mean, that, that's a 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 for us.
Thank you, Debjit. Appreciate it. Thank you very much.