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

Good morning, everyone. My name is Gena Wang. I'm senior biotech analyst at Barclays. Welcome to our second virtual Global Healthcare Conference. First, I wish everyone is staying healthy. And I would like to thank all the participants, investors, companies and especially our event team and corporate access team who made this virtual healthcare conference possible. With that, I would like to introduce our next presenting company, Solid. With us, we have Joel Schneider, Chief Operating Officer. We also have Cathryn Clary, chief Medical Officer. Joel, I will hand over to be you to begin you presentation.

Thank you, Gena, and good morning, and I'll just share my slides very quickly. Let's go to the beginning now. So good morning, Gena. Thank you for hosting us this morning. Just a quick recap for Solid and where we are before we dive into the fireside chat. 2021 is kicking off as an exciting year for us. Really kicking off with activities and preindications that we're be providing next week. That comes in the form of a presentation by our clinical trial PI, Dr. Barry Byrne, at the Muscular Dystrophy Association Conference, where he'll be sharing 12-month safety and efficacy data from the IGNITE DMD ongoing trial, which is a Phase I/II study, in which we're testing our microdystrophin candidate that we call SGT-001. We'll also be hosting a conference call this coming Monday, March 15 at 4:30, where we'll go through a detailed -- really a deep dive into the data that Barry will be summarizing on Thursday, and again, sharing more details around the safety and efficacy that we've seen in the IGNITE DMD trial to date. And so I thought the best way to provide a snapshot and a recap for you would be a quick recap of the science as well as the IGNITE DMD clinical study in which we're testing our microdystrophin gene therapy candidate called SGT-001. These are my forward-looking statements. So as a reminder, the vector that we call SGT-001 is comprised of 3 distinct components: a differentiated gene of interest or microdystrophin candidate, which is differentiated in its function, and I'll touch on that in just a moment. It's also differentiated by the promoter that we're using, which is a muscle-specific promoter that we call CK8. And we're also using the capsid called AAV9, which is classically -- a classical derived capsid, which has been used extensively in the indications that require high trophism for skeletal muscles, cardiac muscles or the respiratory muscles of the diaphragm. And I want to stress that each component of SGT-001 has been carefully selected based off of comparative analyses. Dystrophin is a large protein. It's made up of many highly similar components, as highlighted on the top portion of this slide, and because of that and because of the limitations in packaging size, we've had to carefully select the components of full length dystrophin to include it in our microdystrophin candidate, which is illustrated in the bottom. Now dystrophin's primary role is to stable the muscle against contractions in skin injury, and it does so by acting as a molecular shock absorber. Really, it tethers the external components of the muscle membrane to the intracellular contractile component and prevents muscle damage upon expression. And secondarily, it also recruits these district and associated proteins to the muscle membrane as well. And collectively, they're known as the DGC or dystrophin glycoprotein complex. For years, collaborators that we've been working with and the many that make up our scientific advisory board have been developing these highly rationally designed, yet truncated versions of dystrophin called microdystrophins. And while many of them have shown promising protection against injury in the form of contraction induced injury, for the longest period of time, researchers couldn't identify the regions that are necessary for the secondary function of dystrophin, this restoration and localization of these dystrophin associated proteins. Now that all change around 2010 when Dongsheng Duan, who's one of our closest KOL and SAB members, found the region within dystrophin that is critical for the restoration of a very specific dystrophin associated protein called neuronal nitric oxide synthase, which as the name suggests, when successfully localized and recruited to the muscle membrane, produces nitric oxide, and nitric oxide is critical during periods of high energetic need. It leads to vasodilation, and therefore, improved blood flow and proper oxygenation of the muscle band. SGT-001's microdystrophin candidate uniquely include the nNOS binding domain. We've demonstrated that in preclinical models as well as in our clinic biopsies that our microdystrophin can restore the expression of nitric oxide synthase. And in preclinical models, this incorporation of this domain leads to unique functional benefits. So while many microdystrophins can protect the muscles against contraction induced injury preclinically, ours is the only one that's been able to demonstrate prevention of fatigue induced by fatigue inducing assays. And so we incorporated that binding domain into SGT-001, and it's the SGT-001 microdystrophin transgene that we are currently testing in our IGNITE DMD clinical trial. Now the data that we'll be highlighting at the Muscular Dystrophy Association, and that we'll be recapping that on Monday call, is the collection of functional assessments performed on 2 different dose levels tested in IGNITE DMD: 3 Patients dosed at 5E13; and 3 patients following a dose escalation at a 2E14. We've been collecting the primary endpoints of safety as well as microdystrophin expression, but IGNITE DMD was originally designed to treat all patients; all patients regardless of age, weight or status of ambulation. And so to better inform continued development of the program, it's a historically collected many secondary endpoints, some of which are highlighted on this slide. Now Monday's presentation will include a snapshot of the secondary functional assessment that we think are very relevant, and that we're going to continue to come black as we continue enrollment throughout this coming year. But importantly, these functional endpoints will help us really design continued development of the microdystrophin gene therapy clinical design as we think about a Phase III program and beyond. And so in summer, we've collected data from 6 patients dosed, 3 at the low-dose of 5E13, 3 at 2E14. We're going to be sharing a snapshot of functional data collected at a 12-month time point across all patients and are looking forward to doing so this coming Monday, and then again on Thursday. What we've shown from a biomarker demonstration in terms of efficacy in IGNITE DMD trial is widespread in microdystrophin expression across all patients dosed with a high-dose of SGT-001, the 2E14 dose. Alongside that widespread expression of microdystrophin in 50% to 70% of muscle fibers, we've also shown the restoration of these critical dystrophin associated proteins, a couple of which are highlighted here, and show the unique capability of our microdystrophin to restore the localization of the neuronal nitric oxide synthase or nNOS, leading to proper nitric oxide production in the bed -- in the muscle bed. We've also highlighted using our Western blot, which is a qualify the method that we've carefully designed over the years that patients in the high-dose cohort are expressing approximately 10% of normal dystrophin levels, ranging from 5% to 17.5%. Patients that are enrolled in IGNITE DMD moving forward are using a second-generation version of our manufacturing process, which is a really important part of our clinical strategy as we move forward/importantly, the second-generation process includes improvements to the purification method that results in a significantly enriched full capsid population. In our first-generation process, where there was a mix in every gene therapy manufacturing process, produces a mix of full empty capsids. In that first-generation process, we were at a mix of approximately 1:1 or 50% full capsids containing our microdystrophin and approximately 50% empty. And now in our second-generation process, we're actually over 90% full. And what that means as we move forward and all patients will be dosed with this process moving forward, is that at any given dose and patients enrolled this year are being dosed at the 2E14 dose level, but that at any given dose, the effective total viral load or total capsid load is actually half of what it was with the first-generation process. We think this is a meaningful part of our clinical strategy as we move forward. And hopefully, will lead to improved safety of SGT-001 as we move forward. So critical part of our manufacturing evolution as we enroll patients in the Phase I/II study throughout the duration of the year. So as I mentioned, the end of 2020 and beginning of 2021 are very busy for Solid. As we've highlighted, we would be resuming dosing in IGNITE DMD this quarter. And as I've also highlighted, this -- next week, we'll be sharing 12-month safety and efficacy data for the 6 patients that have been dosed with IGNITE DMD: 3 at the low-dose of 5E13; and 3 at the high-dose of 2E14. Looking forward towards anticipated milestones throughout the rest of the year, we plan out sharing biopsy data, efficacy data from patients that are being dosed, as of this quarter, with our second-generation manufacturing process; and we look forward to doing so. We also plan to share more information about our path towards commercial readiness, as we think about locking down our manufacturing processes for Phase III study as well as the preparations and plans for registration study coming out of continued analysis of functional data coming out of IGNITE DMD. We also plan on sharing in the second half of the year some of the work that we're doing on next-generation vector biology through the form of continued evolution of our pipeline and pipeline expansion beyond the promising collaboration we have with Ultragenyx. So I'll stop there, Gena and hand it back to you now. Thank you.

Thank you, Joel. That's very helpful overview. And maybe I wanted to start with the data that you will present next week. So what kind of functional endpoint data from the first 6 patients can we expect, or what type of data you will share with us?

Let me hand it to Cathryn to walk you through that.

Thank you, Gena, for the question. As Joel highlighted on the slide, we've actually collected a number of secondary and exploratory endpoints in IGNITE DMD because we really wanted to understand sort of the totality of the effect that gene therapy could have in a complex disease like Duchenne. We are collecting the typical functional endpoints, such as North Star Ambulatory Assessment, 6-minute walk test and timed function tests. We're also looking at biomarkers, such as creatine kinase. We have skeletal MRI in the study, cardiac and pulmonary tests. And importantly, we're also looking at the patient and parent reported outcomes on functioning at a year. So what we're planning to present next week is a snapshot of some of what we think is the most relevant data from that sort of list of outcome measures. And we're really -- I think you should save the date. And we're really asking people to sort of focus on the totality of the data, both -- and there's actually 3 groups. We are going to be presenting data from a controlled group of subjects who were initially randomized into the trial when the 5E13 dose was being developed. And then we stopped randomizing the 2E14 or in the open-label fashion, but we have 3 patients that are controlled patients as well as 3 at the low-dose and 3 at the high-dose. And so you'll see 1-year data from all of these patients.

Okay. And with all those functional measurement, like just wondering how frequent they would collect it or its just the one data point at the 12 months?

Yes, with the functional, we -- actually, the patients are followed pretty closely, as you can imagine, in the first year of a gene therapy trial. So they are collected every 3 months. We'll be focusing mainly on our prespecified time point of 1-year, which is our efficacy time point. As you know, in gene therapy trials, because of higher doses of steroids given in the first few months, you tend to see -- you can see a lot of variability if you look at the time course of these assessments over time. So we're focused more on the 1-year time point at this stage.

Okay. Very helpful. And then the other part is, you do have a wide range of the patient age population, like from 5 to 14. So how should we interpret the data from that?

Yes. It's a great question. And you're absolutely right, we have a wide range of ages in the trial, from 5 to 14 because when IGNITE DMD was originally designed, the intention was to actually evaluate a larger group of ages. And we started -- actually, our first patient dose was a 14-year-old patient. And as you know, the natural history of Duchenne is quite variable. There's different trajectories of deterioration. And in the younger boys, ages 4 to 5, we often will see a 1 to 2 point improvement in, say, on the North Star Ambulatory Assessment, whereas after that age, starting around 6 or 7, we begin to see a decline, although again, it's variable. So in analyzing our data, we really felt it was important to put it into the context of natural history, particularly because it is a small data set, just 6 patients dosed at 2 different doses. And so what you'll see next week is we will be putting the results of the test into the context of natural history, given the age of the patients.

Okay. Okay. Very helpful. And then, certainly, they all have the other baseline numbers, right? So you have [indiscernible] levels, but in short, patient comparable [indiscernible].

Yes. Yes. If you're talking about the baseline of the different assessment scales that we'll use, absolutely. It will be baselined to 1-year, is what you'll see. Yes.

Okay. Yes. And I think older patient will be relatively straightforward to look at and the younger patient will be a little bit noise depend on the natural history. Okay. So you also mentioned -- I think, Joel, you mentioned, the next 2 patients will be still receiving the 2E14 doses. So like what is the plan? What is the bar that you think this is supply dose or you need to actually follow those values?

Yes. So at this point, for the next 2 patients dosed were, obviously, quite focused on safety and also evaluating the efficacy at 2E14, along with the data we've already generated with the first manufacturing process at 2E14. We haven't ruled out increasing the dose, but it's really not in our current plan.

Okay. So then, what will a bar for the protein level in terms -- in order to be competitive versus other products out there?

So Joel, maybe I'll let you take that one.

Sure. Gena, I think fundamentally, what we're focused on at this point is really next week's highlights of how we see functional data playing out, both in terms of the control cohort that's part of the study, and then also, in the context of natural history. And there's a very well scrutinized and analyzed history to leverage. So I think as we move forward, and we've begun to share our functional data, I think there's still a very -- there's a large unanswered question based on all of us developing these promising candidates about the effective dose response. What sort of levels of expression you need to lead to a meaningful benefit? And I think as we mature in clinical development, we're clearly going to be focused on demonstrating functional benefit are we seeing improvements or changes from the trajectory of natural history that is suggested across a totality of endpoints or a variety of different endpoints that can be explored on what benefit looks like. So for us, we want to continue to see demonstrations of widespread microdystrophin across the muscle bed. We're satisfied with the levels that we're seeing. And really, what we're going to be focused on is how that translates to dual functional benefit for patients, which is ultimately how these drugs are going to be approved in either case.

Okay. But on the other hand, I'm kind of thinking that because it is a gene therapy and it should be -- if whatever the hypothesis is correct that among the protein you express should correlate to the functional or better functioning improvement, so from that perspective, do you have -- do you think the others, I think of Pfizer, will need to be seen? And Sarepta showed like 30-something percent, like Pfizer, based on a small number patient, also in the 30% range. So if you are in the 10%, would that be a disadvantage to begin with to show the similar magnitude of functional improvement? Do you have a goal to achieve at least, let's say, 30% -- 20%, 30%?

Gena, it's a good question. And I think back to even our preclinical data sets, we're recessing functional benefit in mice, and then we did a comprehensive analysis in dystrophic dog, which is really a large animal model that more complexly -- or a more complex way resembles Duchenne. And from our perspective, even in our preclinical data sets, the difference between 10% to 20%, 15% to 30%, in terms of expression and ultimately functional benefit, was very hard to parse out. I don't think it's very straightforward. If it's complicated by the heterogeneity of the disease, as Cathryn highlighted, is a progressive, heterogeneous disease with multiple paths of progression. So we're really understanding what level is we need to achieve to demonstrate clear on unambiguous benefit or what we're focused on. I wouldn't say that we're focused on matching anyone else's specific protein levels. I think, given the complexities, we spent a lot of time developing very well-qualified methods for quantifying our dystrophin just like everyone else has. And unfortunately, we all do that in our own way. So we all have our own natural -- our own healthy controls revenues as a percentage of -- as a percentage to measure things depending on my healthy levels versus somebody else because that can range dramatically. So for us, the focus is on unambiguous detection of expression and how that meaningfully translates to functional benefit. Cathryn highlighted that for us, the focus is on a 12-month time point because we think that will be the first evidence of sustained durability potentially of benefit, whether improvements or function or separation from the natural history. So I think for us, we're doing the work that we can. We also have -- are building our differentiated microdystrophin to differentiate the program. And so it's very hard to do an apples-to-apples comparison. I think it's going to be a focus for on the benefit observed and how that benefit can meaningfully be translated into usable endpoints for continued clinical development.

Okay. Okay. I think that's fair. So regarding the safety part you did propose, one part is the manufacturing part. Any other flaws and giving also we see a complement activation not just happening with your program, and we also saw it with Pfizer. So any most updated understanding what could be the cause and then what could be manageable. I think Pfizer also mentioned additional -- how many patients they treated, actually 6 saw more -- they did not see any complement activation, but they put a proactive monitoring system. So like from your end, what is your latest [indiscernible] on this complement activation?

Well, as -- yes, sure. As we've previously disclosed, in our new protocol and with the new manufacturing process, we also decided to put in a clinical risk mitigation strategy, which involves the use of 2 complement inhibitors before we give the gene therapy infusion. So they're given that the day in order to decrease the complement reaction. The complement system is part of the innate immune system. It's always an alert. And we're giving a huge viral load to these kids. So it makes sense. It actually is the right immune response that they have some complement activation. What we wanted to do and what we've really analyzed in our own data as we did last year, looking at all of their laboratory data, all of the clinical data, we recognized that there was a correlation between the total viral load that was received, the degree of complement-related AEs and SAEs, and then -- and the SAEs that we saw and the complement activation in the blood. And so that's why, in consultation with a number of complement biologists and experts in gene therapy, we did decide that -- given that this is a reaction you see in the first 2 to 3 weeks, and then it's over that it did make sense to just prevent it from the very beginning. What's interesting is when we first started with this, we thought, well, we'll try it and then maybe we'll be able to back off. We've come to believe it's actually -- could potentially be a real advantage to be able to provide that safety assurance, if we're able to demonstrate that, and would potentially allow us to treat higher weight patients. So that's the strategy that we're using. It's the 2 complement inhibitors. So -- and we're also limiting the weight of the next 2 patients dosed at 18 kilograms. But of course, over time, we'd like to be able to increase that, if we can do that.

Okay. So it sounds like you don't have any plan to withdraw potential proceeds.

Well, again, we're going to learn from our patients. Right now, we're really focused on dosing the next few patients safely, and then we'll evaluate. We continue to consult with experts about this. And we're going to -- we'll proceed cautiously, but we want to do what's actually best in terms of the program and being able to have the boys get the benefit of the gene transfer therapy that they're receiving.

Okay. Okay. And then, you mentioned that you will be totality of the data. Can you give a little bit more color on what kind of totality data will make you decide that's the Phase III dose?

Yes. So, I mean, again, we're still really evaluating all the different assessments that we have in the trial. I mean, there's some that we're still really evaluating that we won't be sharing next week. So we're -- I think the whole feel, Gena, is thinking about what really is the best way to move forward in registration trials. The North Star Ambulatory Assessment is a good functional outcome measured, but there is a fair amount of subjectivity in the effort of the buoy in a sort of a clinic setting to do it, and there's a lot of variability in that, plus the heterogeneity of the disease makes it sort of a difficult primary assessment measures. So I think a lot of us are thinking about how do we think about the variety of different outcome measures? Perhaps, a composite outcome measure there might be preferable. So I think that's what the field is really thinking about, how do we move forward, and certainly, it's solid. We're doing a lot of thinking and discussing with experts on this matter.

Okay. So then, regarding -- actually, regarding North Star, that's actually very interesting, I think, not just you, I think a few others also made comments. And then, our feedback actually from experts, the leading -- actually most people quoting their papers, most leading DMD experts made comments that steroids is -- can easily be -- show clinical benefit using North Star, if the gene therapy cannot -- like if North Star is not sensitive to use as a metric to -- for the gene therapy, then the gene therapy clinical benefit may not be enough because they are using the steroids you can easily detect by North Star measurement. So that was the expert, and that was actually very interesting feedback to me. But on the other hand, I think in the near term, most people will still be focusing on North Star. And I think DMD also still focusing on North Star. So for next week -- or maybe not next week, what kind of the magnitude of the North Star improvement that you will be looking for that you think that, that's the right dose for me to move to Phase III?

Yes. So I don't want to give a definitive answer on that. But what I will say is that we're going to be looking at the natural history and looking at what we see versus natural history. That really is, I think, the important thing. That's why we've decided to put every measure that we talk about next week will be in the context of natural history because, again, when you've got a 10-year-old, say, or an 11-year-old, the expectation is or -- they have a mean decline in North Star of around 3 to 4 points a year. So we have to put it into that context. Of course, overlaid on that is the variability within individual voice. They have different trajectories of decline. The baseline scores also have to be looked at. If there's a lower baseline score, there's more of an opportunity for potential improvement. So there's a lot of factors that we're going to try to put in context to help interpret the scores you'll see next week.

Okay.

Gena, one thing that I add to that, and going back to the overview that I gave is, we have had a very significant ambition to treat all patients that have DMD. It's always been a goal. It's evidenced by the first patient dose. And because of our knowledge of the DMD landscape, because of the progression of the disease, one example as Cathryn just highlighted, in which North Star expectations are different in different age revenues, we've included all these additional meaningful functional endpoints to explore as well. What is more relevant is a functional outcome for 11-year olds might be very different than what's relevant for a 4-year olds. So when we talk about totality, we want to highlight that yes, we have a wide age ranges that have been dosed so far at both dose levels. And we've included all these endpoints to understand efficacy, not just for potentially 4- to 5-year olds or 4- to 7-year olds, but what looks positive for patients beyond different end-range. So while North Star, of course, will be a part of it, we actually are eager to kind of talk and expand our conversation to what other meaningful functional endpoints can also be used to demonstrate benefit, and hopefully, now as we think more forward-looking, to really tackle all the patients beyond that age range, it also desperately need a promising therapy. That's the vision and that's always been the motivation behind it.

Yes, I agree. I totally agree. And on the other hand, we do need to align with FDA.

Of course.

I know it's difficult for them to change. Like they already changed from 6 minutes walk test to 9 minutes walk. It will be difficult for them to change to the new endpoint.

Absolutely.

So now, we went over time. Just one last question. So I understand as compared to the natural history, but what kind delta, because I understand like 13 maybe declined by 3 scores, so for the delta compared to the microdystrophin history, what delta do you think it will be clinically meaningful in your -- like with be your bar you think that's the right dose?

Yes. I mean, again, we haven't set that bar because, again, it's -- that's one particular assessment. I mean, we really are looking at the totality of the different assessments. And all I can say is, tune in next week and you'll have a better understanding of what we're talking about.

Okay. Well, looking forward to the data. And thank you very much for participating.

Thank you, Gena.

Thank you for having us, Gena. Have a good day.

Okay. Bye-bye.

Bye.