REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Thank you, everyone, for joining us at the UBS Healthcare Conference. I'm Ellie Merle. I'm one of the biotech analysts here at UBS. Very happy to be with you all in person. And very happy to have REGENXBIO here with us for a fireside chat for the next 39 minutes and 25 seconds joining us from REGENX is CEO, Ken Mills; and Chief Medical Officer, Steve Pakola. Thank you guys so much for joining us.

Maybe before we get into the juicy questions around what AMD and DME, I'll just -- a broader high-level question. Can you tell us the history a bit about REGENX and the expertise that you guys have as well as IP in the gene therapy front?

Yes. Thanks, Ellie, to you and the team for hosting us and having this in person. We're happy to be here. And had some great interactions already this morning. So looking to use the fireside and afternoon meetings to kind of extend upon that. REGENXBIO is an AAV gene therapy company. We were formed in 2009, principally on the basis of discoveries that were made in the lab of Jim Wilson at the University of Pennsylvania, where he had with his team, isolated novel variants of AAVs. And that became, I think, a chapter in the history of the company and frankly, in the history of AAV that expanded the platform and the utility of AAV in a significant way. It sort of took things from being reasonably safe to safe and effective, and that was due to a lot of properties of these naturally occurring variants that were different than things that have been isolated in the past, higher levels of expression, more durability, manufacturability and even aspects of safety that were improved as well. Also some really interesting findings in terms of tissue targeting, biology associated with specific tissues. Second chapter of the company after sort of partnering up with UPenn was one of partnership and licensing. We helped foreign companies, we helped foreign programs for years up until probably about 2013, 2014. We became the basis of a lot of new AAV programs, things that entered the clinic ultimately, things including Zolgensma that became commercially approved products or late-stage programs. And it was at or about that sort of inflection point of 2014, 2015, where the principles, the founders of REGENXBIO decided we wanted to be participants in the development of drugs using AAV technology. We have seen the benefits of it through the lens of these partnerships and company formations, but we wanted more. So we set out to build our own team, which we've done and kind of the current chapter and you talk about capabilities is standing on top of that intellectual property partnership with UPenn, the partnerships with a number of companies who have delivered on, I think, the promise of the new technology. We now have 400 people at REGENXBIO mostly in Rockville, Maryland, but some sort of spread out around the world that are focused on the development of AAV therapeutics. We make AAV therapeutics at REGENXBIO, we manufacture them. We deliver them to patients through our ongoing clinical studies. We work on new research and development and continue to expand the utility of the platform and the science that stands behind it, but also sort of look at frontiers of new science. And we continue to have partnerships and work with partners. More recently, though I think our partnership has been focused on clinical candidate assets that we've advanced and extending those to future opportunities for commercialization. So I think it's a long history. It's an important history. It's really well founded in science, a good plan, great people. And we've always found a way to capitalize ourselves with the sort of right amount of cash to keep the expansion going in a meaningful way for all stakeholders and certainly shareholders. But ultimately, today, I think we have some of the best end-to-end capabilities as a pure-play AAV gene therapy company as can be seen across the landscape, and I'm really proud of that fact.

Yes, absolutely. I mean I think if -- and if I editorialize a bit, if there's anything we've learned about the gene therapy space in the past couple of years is that it's maybe not as easy as we might have thought. And so certainly, the expertise there is very important, both on the manufacturing side as well, which I'm sure we'll get to. Turning now to some of your maybe internally developed programs like I guess partnered with AbbVie now as well, 314. In the wet AMD DME space, some people might say, "Hey, we already have VEGF injections. Now we have faricimab, extending the duration even further. What's your perspective on the unmet need still an opportunity for gene therapy in the VEGF space?

So Steve has expertise and skills that I do not in that regard. But I want to give a little bit of a window and I'll hand off to Steve about some of that about the history of why gene therapy for wet AMD, even as a starting point because this -- in our history, it originated probably around in 2010, 2011, we actually received as we were still a private company and kind of sourcing ideas for how to apply onetime treatments that had curative potential to different diseases. We received some brands from the National Eye Institute in partnership with basically retinal surgeons like Peter Campochiaro and Szilard Kiss at Cornell. And they were really interested in focusing on taking more existing mechanisms in biologics. At that time, it was mostly Lucentis and Avastin and finally, is to deliver them with onetime treatment to sort of convey the benefits of the pharmacology of these treatments, but change the pharmacodynamics of the repeat injections. I just fascinated by that because it kind of turned everything I thought that was going to be a win for gene therapy on its year a little bit. It went from low-hanging fruit of rare diseases to almost like a biosimilar play with sort of a onetime administration. And we generated a lot of data over that period of time. We looked at different AAV vector capsids to use. We looked at different routes of administration, we looked at different treatment models. We looked at different molecules. We looked at things even outside of the anti-VEGF pathway. And what theme kept coming back was over and over again like existing treatments, existing standard of care, paired up with pretty well-characterized AAV capsids delivered in a sort of tried-and-true pretty established way, eventually, one of the first drug approvals, as we know, in AAV history was LUXTURNA. It was delivered via the subretinal injection. We actually extended the research work we were doing and partnered with Al Maguire and his wife, Jean Bennett, who basically were the motive force behind LUXTURNA to help think about how to extend AAV into the treatment of wet AMD with their surgical approach. That were the origin of RGX-314. And end-to-end, we entered the clinic, and that's what we have in pivotal face today with all that thinking, all that initial research. It's coming on 10 years. And I think the thing about it is the one thing that hasn't changed over that period of time are how you follow with your team, the retinal market very closely and carefully across all modalities. A lot of new things have come forward as there continues to be asked for sort of longer duration treatments, extended treatments. There's not a onetime treatment out there. There's nothing that are really even close to it. Except, I think, the potential of gene therapy in our late-stage development of subretinal and fast follower suprachoroidal. And so I've been impressed and surprised that over a 10-year period, the unmet need and the demand for something like that has still existed and yet with all the great science and all the great new technology coming forward. Frankly, we're still using something in development 10 years later that I think has the right target product profile, but it's based on AAV. Steve comes to it a little bit more recently. So I think has some fresh perspectives, though, as well, and I'd love to hear from him. That's my handoff.

Yes. It's fascinating that over those 10 years, as you advanced on our hope for a onetime treatment option. We've had a lot of great innovation happen in the retina space that you've seen, Ellie. And we've had various programs fail and other programs succeed and you mentioned faricimab, for example. And there's also the port delivery system, both Roche and Genentech. So I think that those programs are great advances for the field, frankly, I think it's great. They are incremental benefits. So you're still going to need repeated injections so you can extend that out in the case of faricimab to in a lot of patients queue every 12 to 16 weeks, which is great. And I think that's going to do very well in the marketplace from all our discussions with thought leaders and retina specialists in the space. But the reason it's going to do well is because of how important this durability is and how much of an unmet need exists because of the unsustainability the noncompliance that is inherent even when you get out to every 3- or 4-month kind of dosing. So if anything, this just validates the need to keep going even further. And the biggest potential would be if you could at least in a sizable proportion of patients achieve sustained anti-VEGF activity with a single injection. So all these advances only shine a brighter light on the unmet need that continues to exist. So exciting for the overall field at a macro level, how much innovation is going on. But again, it only further highlights what Ken has been working at for at least a dozen years now. And I think it's not surprising that this kind of rose to the top as far as moving away from or adding to our rare focus where you're replacing a missing gene to complex disorders where as Ken mentioned, this is a, yes, multi-genetic environmental factors, but we know anti-VEGFs work. So the mechanism is extremely well validated over and over again. We just know that the ways that we have of treating this just don't get us there as far as in the real world, translating that. So the benefit is not just that you increase compliance and you decrease treatment burden and visit burden. But ultimately, what matters is that translates into better visual outcomes in the real world and fewer patients going blind. So that's why this resonates so well with thought leaders in the space, investigators and their patients when they describe this overall proposition of this onetime treatment.

Absolutely. And maybe if we can talk a little bit more about the data that we've seen so far, maybe starting with the subretinal program and what you're looking at in terms of durability? And from that data, how you're thinking about what the ultimate product profile would look like commercially?

Sure. So we have the benefit of a Phase I/II study where we dosed 42 patients with subretinal delivery across 5 different doses of onetime subretinal delivery of RGX-314, and we have some of those patients out well beyond 3 years, and we presented results after 3 years with Cohort 3, where we've seen excellent long-term results where we see very good stability. And what we see good stability on is efficacy that we've seen in the higher 3 dose cohorts, where we see good control of disease, which we measured noninvasively by thickness of the retina or central retinal thickness as we call it, in the space, best-corrected visual acuity. We see very good stable to even improve visual acuity in Cohort 3, and we see those good outcomes in the setting of dramatically reduced treatment burden, including a high proportion of patients who don't need any injections. So that's really the profile. That's what we want to be able to see. And that's what gave us confidence to move into pivotal development. And we now have 2 Phase III studies ongoing for subretinal delivery, and it's also what AbbVie is very excited about that we're able to go into pivotal development with subretinal delivery with 2 different doses against a standard of care treatment regimen if we use in one study, Lucentis monthly injection and the other study, EYLEA or aflibercept, really the 2 most respected and understood controls that you could go for in a noninferiority design approach on the typical -- the standard best-corrected visual acuity outcome at 1 year. And what's exciting is that's the bar for regulatory approval, if we can show noninferiority with the benefit of dramatically reduced treatment burden in the RGX-314 treatment arms that translates into the real world into real superiority because we know patients in the real world aren't getting anything close to the number of injections that they need with available treatments.

And how should we think about the time frame and where you are with enrollment and when we could see some data?

So we're excited that both studies are off and running. So the second of the 2 pivotal studies. The first is ATMOSPHERE. The second is ASCENT. The second of the 2 pivotal studies started at the beginning of this year. So we're rocking and rolling with both of these studies, and it's great to have AbbVie on board. One of the things we're excited about is we continue to execute and be the ones running the existing studies. So it's personally, professionally exciting for our team to continue to leverage our expertise in this space. So as Ken mentioned, we have a lot of different areas in gene therapy that we've developed real core competency and expertise. So to keep going with that is exciting. What we've said and we continue to be on track for as we want to get these studies done in time for a BLA submission in 2024. So we're excited about that.

Awesome. And I know we were speaking a little bit about this before this fireside. But how do you kind of make sure you're not pushing it too far in terms of durability? And how are you thinking about any kind of rescue VEGF and your expectations there?

Sure. So any study where you're looking for increased durability, you still need to have an option for patients if they get worse clinically or particularly clinically on best corrected visual acuity, but even anatomically where they may need a rescue injection. And this is something that exists in the field for any of these increased durability plays. Interestingly, if you have a onetime treatment where you have sustained anti-VEGF, the -- it sort of takes the guesswork out of the treatment regimen that you would propose. So we were talking about Kodiak, for example, where for that treatment or any of these incremental increased durability-type plays. You still have to decide, well, how often am I going to have a retreatment? And I think you're right in those cases, you have a balance that you have to play, where you want to have it be as extended as possible but you don't want to go too far, you may sacrifice on best-corrected visual acuity and how many times patients need retreatment. In our case, this is a onetime where instead of having a longer peak and trough here, it's a steady state of anti-VEGF. And then it's in what subset of patients may they need a top off, for example. So that's the first point that there isn't that issue of trying to figure out retreatment because there is no -- with anti, there isn't with the gene therapy itself. The retreatment criteria we use in our study are quite standard very close to what's been used in other programs like port delivery system, for example, where we quantify, and we look for a specific amount of increased thickening of the retina, so the anatomic endpoint and/or a certain amount of decrease in letters read on the best corrected visual acuity measure. One important aspect is that our Phase I/II was the first-in-human study where we didn't have clinical proof of concept yet. So there, not only did we have a tougher to treat patients, but the investigators really could reinject at the slightest issue, even with just residual fluid even if it was improving. So even in that setting, we had a dramatic reduction in treatment burden. So we're enthused by the opportunity to go from that setting to pivotal where directionally we have more controlled patients going into the study, and we have more standard criteria for retreatment to help keep the retreatment rate to what we would anticipate would be needed in the real world.

But presumably also high enough that you would make sure that you would have success in...

That's right.

Okay. Makes sense. And certainly having the underlying gene therapy, which is durable. And so it's not like a complete lack of treatment. It might be a top off, as you say.

And then that's an important point that our investigators bring back to us, for example, Peter Campochiaro had set on podium at different retina congresses that a onetime gene therapy changes the way the field should even think about the need for retreatment because in a traditional world, if with an experimental agent that, say, has a longer half-life or some added mechanisms that allow you to go longer. You still are worried or you may be worried if you see them coming to your clinic at 3 months, and it's starting to go up, you're thinking, well, if I don't treat now, is it going to be worse in a month. Because the drug is going to be lower from here, whereas if you believe there's a sustained level, then you think about that differently in that patient that they may be under better control.

Yes, absolutely. And I want to talk about suprachoroidal and maybe just in thinking subretinal, what the importance of suprachoroidal is in thinking about the opportunity long term? I mean these are compelling data that we talked about if replicated in larger studies. How does suprachoroidal expand the opportunity? What happens if we're just talking subretinal?

Well, I think, as I described in the history, from a target product profile perspective, it was incredibly important, I think, to embrace gene therapy and sort of in a lock and key mechanism with the retina community. Talk about the target product profile what it could mean, not apologize or rationalized about the technology and don't create any shortcuts through that rationalization. So we went with known AAV capsids, known standard of care type of biologics and known and well-characterized surgical approaches to ensure that there was going to be something there for patients. When you step back and you talk about a surgery versus an office procedure, it raises questions for everyone. Well, I would hope to get into the office-based environment to be able to deliver this the way -- that the intravitreals are today. But the truth and the reality of the technology that was available and continues to be available, there's no shortcut to that. So we invested heavily to optimize the use of the capsids, the use of the biology of gene therapy with subretinal. And then we decided we're going to build off that foundation. We weren't going to shortcut through that. That in my belief is the way to go here from a sort of investment thesis perspective. Once we build that foundation and started to say, okay, now we're going to move on to a relatively secure pivotal phase with subretinal, we started to think about the hope of a new target product profile. How do we get into the office? And because of work we have done and because of what others had done, we eliminated a lot of other routes of administration because one of the things we weren't willing to sacrifice was safety. And we were seeing over and over again, almost like a class effect with some of the other routes of administration that you'd see preclinical evidence of a safety profile that we didn't think we wanted to migrate. Keep in mind, subretinal from a safety and tolerability perspective, I think was one of the cleanest signals we have seen in first-in-human work in AAV gene therapy. And that's particularly important when you're taking it towards a patient population that's hundreds of thousands, maybe millions of patients. Any signal, it's only going to get larger. It's not going to get smaller when you make that. So we went searching, and we literally spent a better part of a year or 2 looking for alternatives that were comparable or something that we could again, not rationalized, but show scientifically, preclinically, had sort of similarities. It wasn't things that were already proven and available clinically to us. Those things are eliminated. Suprachoroidal, we ferried it out on our own. We worked through the science preclinical, and we're the first ones ever exploring it in human clinical studies. Simply put, it's an in-office-based procedure that we're hoping and thinking can translate the pharmacology of what we have in late-stage development with subretinal into an even bigger opportunity because it presents stakeholders like the patients themselves, the caregivers, well, there -- a different proposition overall. It's earlier stage. We've reported out some data on the first doses. We're seeing the types of signals that we saw preclinically in terms of we're in sort of measurable ranges of efficacy. We're seeing safety and tolerability like what we produce in the animals. And my view overall is -- and I think this is really where the resonance with the timing and the sort of approach of the partnership with a group like AbbVie, we are entering the phase of something where we needed expansion geographically. And then we potentially needed a partner to expand something at a scale like we couldn't even imagine. And that's both where AbbVie has played a role as a partner. And we are working, as Steve suggested, we're continuing to steer. If the market opportunity in my mind for subretinal is a blockbuster application then suprachoroidal is blockbuster on steroids. I mean it's got the potential to sort of grow the market of wet AMD by 5 or 10x, and it's got adjacent applications like in diabetic retinopathy, like the things that aren't even going to be accessible to us with subretinal. But none of that happens, none of that works if we sort of rationalize that we needed to rush ourselves into an alternative and office procedure. We've seen how that has worked out. And again, I would suggest there's no shortcuts. I think this is the way to have done it. And it's the way that we're going to get revenue generated the fastest, the way that we're going to get a profitability and a sustainable business, the fastest.

Helpful. Yes. Okay. So if I'm paraphrasing and please correct me if I'm wrong, subretinal on its own large opportunity. And I like your term blockbuster on steroids and suprachoroidal as well. You're able to do successfully and in a safe manner. Maybe in terms of the suprachoroidal, can you walk us through maybe where you are in the dose escalation in the various trials, your confidence in the safety, particularly? And I know that we can't talk timing, I guess AbbVie will probably make some decisions about which medical meetings. And I guess, not -- in my words not yours, but about which medical meetings we might get updates at? But what should we look for kind of high level over the next 6 to 12 months in terms of these dose escalation trials?

Sure. As Ken mentioned, these are the first-ever clinical studies evaluating gene therapy delivery to the suprachoroidal space. So it's really a nice advance for the company, but also the field with large -- so we have 2 separate studies ongoing now: one, looking at suprachoroidal delivery for treatment of wet AMD. So same patient population like we're looking at in the subretinal study. That's the AAV8 study, and we have a separate study looking at suprachoroidal delivery for treatment of diabetic retinopathy. And that's the ALTITUDE study. So these are dose escalation design studies. I'll start with the AAV8 study. So there, we have done a -- we started that study earlier, so we're further advanced. And based on our preclinical package, where we did not see inflammation, which fit with the concept of delivering locally compartmentalized as opposed to what Ken referred to with the intravitreal routes or other routes of administration. Given that we did not see inflammation preclinically, we were able to proceed into our first-in-human studies without need for prophylactic steroids. So we're excited about that as well. So the AAV8 study, we looked at a dose level 1, where we saw good safety and tolerability and good proof of concept in terms of what we wanted to see which is good visual acuity outcome, anatomy and a significant reduction in treatment burden. So we saw over 70% reduction in the treatment burden that is a number of injections that the patients needed. So that allowed us to go up to dose level 2, double the dose. And we -- there looked at a Cohort 2 with -- in patients who did not have preexisting neutralizing antibodies. And Cohort 3 at dose level 2 in patients who do have preexisting systemic neutralizing antibodies to the AAV8 vector. So it just is a little segue or explanation here. One of the benefits with subretinal is not only is that the most validated, including with an approved product but we also know because of the compartmentalized delivery into the subretinal space, which is relatively immune privilege, you don't have to exclude patients who have preexisting neutralizing antibodies. That's very different from intravitreal administration. In any of those trials, you exclude patients who have preexisting neutralizing antibodies because it gets in the way of what you're trying to treat. And we know that with intravitreal delivery. We don't know that yet for suprachoroidal delivery. We expect less immune response just based on our preclinical package. But these being the first-ever clinical studies. We're looking at it very methodically, looking at patients with and without preexisting neutralizing antibodies. So we've completed dosing in dose level 2 which is double the dose of level 1 in both NAV negative and NAV positive. And we then move to dose level 3, double that second dose, also still without any prophylactic steroids in a Cohort 4 NAV negative patients and Cohort 5 NAV positive patients. And we've completed dosing in Cohort 4, and we plan to complete dosing in Cohort 5 this half of the year. So we're rapidly approaching that. So a lot of advance so to have gotten through 3 dose levels in a dose response curve, we're excited, especially given that we've already presented results out to 6 months showing again, what we were hoping to see with dose level 1. ALTITUDE, which started after AAV8, this is a very exciting opportunity because these are patients that we know if you treat with anti-VEGFs repeatedly, you can improve the underlying diabetic retinopathy as measured by the diabetic retinopathy severity scale. And we know that, that translates into decreasing the rate of patients developing site threatening complications. In spite of that proof, in spite of Lucentis and EYLEA having label expansion that includes that doctors and their patients are not signing up for this because it requires repeated injections into the eye. So this is really a unique opportunity for suprachoroidal, in particular, where with an in-office onetime treatment, if you can replicate those findings of improving diabetic retinopathy severity that could really open up a tremendous opportunity that can't be achieved by any repeated administration approach or any kind of surgical approach, which is one of the added reasons we focused on suprachoroidal for diabetic retinopathy. So there, we completed dose level 1, the same dose level as dose level 1 in the ADH study in Cohort 1. And we also are excited to have completed dosing in dose level 2 in a Cohort 2 NAV negative and Cohort 3 NAV positive and having completed that dosing. Here again, in dose level 1, we show proof of concept. So it's exciting to have that efficiency where we have proof of concept that we can explore any dose response from there, that's particularly meaningful in this indication because our signal detection here looking at diabetic retinopathy response as measured by the DRSS that's actually not only signal detection, that's actually the pivotal endpoint. If you can show that at 1 year, that is an approvable endpoint because it's such a validated scale and 2-step improvements considered clinically meaningful. And we know that, that prevents patients from going on to develop the site threatening complications. And we're seeing a response rate that clinically meaningful 2-step improvement. We're seeing a response rate in the first Cohort at 6 months, that was 47%. And it turns out nominally, that's very -- lines up very well if you look at the subset of patients in terms of severity of baseline to what you see with very frequent injection, Lucentis or EYLEA at that time point.

Interesting. I'm excited to see further updates from those programs. We only have a couple of minutes left, so I want to make sure we touch on some other interesting programs like MPS I and MPS II. Maybe if you could tell us a bit about where these programs are and what we can expect to learn over the next year or so, both from a data perspective from each of these programs as well as around next steps in terms of thinking about the path to market.

Sure. These are 2 lysosomal storage diseases that are pretty well known and characterized because they have existing enzyme replacement therapy treatments from groups like Sanofi Genzyme and Shire, Takeda. What's missing here for the children that are diagnosed with MPS I and MPS II is that those ERTs are not crossing the blood-brain barrier when they're delivered intravenously. And so the development of complications and ultimately death from the CNS manifestations of the disease in many of the boys, usually, it's 60% to 70% of the diagnosis is fatal. So we're going direct into the CSF with a onetime gene therapy treatment that includes the gene that's missing for the enzyme. It's taken up by all the cells. It's kind of -- uses the hydrodynamics of CSF to sort of circulate the AAV capsids, which really, in essence, are small particles. And then biologically, they're taken up by all different types of cells throughout the CNS. And we're seeing impressive changes in biochemistry and biology. And recently, just a few months ago at a world symposium on lysosomal storage disorders, we showed some of the first data ever on the correlation between some of those early biochemical measures and longer-term clinical outcomes. So that was a big goal of this program. We probably needed to get there, we needed many children about over 20 at multiple dose levels, and we needed time in the past to be able to show sort of the longer-term effects of the clinical outcomes out to 1 year to 2 years. In one case, I think we have a child that was dosed almost out to 4 years. So we're sort of locked in now on the logic of the science was there, but here's the correlation between biochemical evidence and the clinical evidence that's gotten us excited about thinking about what the regulatory pathway here is from an acceleration perspective. And as a company and with others, we've been really focused on the use of accelerated "approval pathways" kind of because those are things that are afforded to rare disease programs. Programs with high unmet need, particularly benefited programs, I think, that have a well-understood natural history, which MPS I and MPS II do, as I alluded to. Things that have existing drugs tend to have better natural history profiles than others. So what we said is that with this data that we thought was exciting a couple of months ago, we've been sort of ruminating internally and having dialogue with a lot of different stakeholders about what the pathway is going to be, update on that in the second half of the year. But to have achieved that kind of correlation that proof-of-concept evidence in boys and girls in MPS I and MPS II was an incredibly meaningful event and more soon.

Okay. All right. So no guidance on that. One will learn about the...

Not today, Ellie.

But I -- we'll stay tuned. Maybe just on thinking about the commercial opportunity in both of those as well as the emerging landscape, I know others in development as well for those, but particularly potentially also going after the CNS manifestations. Maybe just separating it out between MPS I and II, how you think about the prevalence as well as the unmet need and competitive landscape in each.

No, I think a safe onetime treatment using AAV is a unique profile. I mean depending on the jurisdiction, you will find things like bone marrow transplant, stem cell transplantation available to some of the kids when they're diagnosed, especially with severe genotypes. We all know that, that -- those have serious side effect profiles, including anywhere from a 10% to 30% mortality rate, engraftment is a challenge. There's delays that occur in the time between when the procedures occur and when full engraftment can occur, which can take up to a year. That's why we've been really happy that one of the most sort of focused elements of our procedure has been safety and again, just getting to that number of sort of double digits of boys with a strong safety and tolerability profile has been important. I think we've -- as I think I alluded to with respect to the wet AMD approach, there's no shortcuts for these kids either. You need to go with what is really best available in terms of the science. So I think that we established, and we looked at a lot of different route of delivery mechanisms. And we found -- frankly, there were 2 that were sort of best characterized in a number of large animal models, monkeys, pigs, and canine models of the disease that told us that this is where you're going to get the most change histopathologically. And so we brought that into the clinic. Again, another thing we pioneered sort of like suprachoroidal basically, for the first time, we have surgeons, interventional radiologists doing surgeries in kids with a procedure that they've never used before, and it's having these types of profound effects. And I think that -- so -- when I look at the landscape of other things going on, I feel like we're way ahead. I feel like we have a path forward with respect to overall acceleration. We've got a great safety profile, and we're seeing the types of changes in these kids and the responses from the caregivers and the families that we want to see. So I feel really good about where we are.

Yes. It's an exciting program. Well, we'll stay tuned for more on that. And then, I guess, lastly, on DMD. I know you provided an update of the quarter. Maybe just from here, what are the next steps before you can enter the clinic and dose the first patient?

Yes. So we got our R&D safe to proceed back in January, and we were working on site selection, standing up sites and sort of finishing our work to dose. We had a little bit of a footfall to our manufacturing, what you do after a footfall is you grab the ball from the ball person, step back to the line. Throw the ball up and hit it again. And that's what we're doing right now. We're just bringing our clinical supply back online. We've reguided to when we're going to reinitiate our clinical trial, and that is in the first half of next year.

Got it. Well, I'm being told that we're out of time. So thank you guys, so much for joining us, and I appreciate all the color and insights.

Thanks a lot.

Thank you.

Thank you.