All right, good morning, everyone. Thanks for joining us for our eighth annual Genetic Medicines Conference. It is my pleasure to introduce our next presenting guest. We have Curran Simpson from REGENXBIO. Curran, welcome. Thank you. Thanks for having me. So the format for this session is the fireside chat about a 25-minute fireside chat. And as always, we welcome the audience to please ask questions. With that, I think we'll go ahead and get started. So Curran, if you... To start us off, if you could spend a few minutes to introduce REGENXBIO, and maybe talk about some of the key clinical programs. Sure, happy to do so. REGENXBIO is roughly 15 years old. We started out the first five or so years doing a lot of out-licensing of the NAV technology, that's the AAV gene therapy programs. You've heard of programs like Zolgensma, for example, came from that original technology. So a long history in gene therapy. I joined the company roughly nine years ago when we decided to do our own internal development of programs. And over the years, we've gone from 20 people or so to 350 now, covering, I'd say, two main franchises. One that we're really excited about is our rare disease franchise, which is got a program called RGX-202 for the Duchenne indication. That's really exciting this year in terms of upcoming milestones. And then, along the years, we've had a very big partnership with AbbVie for our retinal franchise, for a program called RGX-314, that's in a variety of clinical trials for two different delivery methodologies. One is a subretinal administration, which is in the back of the eye, and that's in two very large pivotal studies that are still enrolling globally. And then, real excited about the suprachoroidal indication for diabetic retinopathy, in which we are planning an end-of-phase 2 meeting later this year. And that all of these are partnered with AbbVie, and expecting to move into pivotal next year. I think just to summarize our pipeline and what makes us so excited about the next six months, and then all of next year and beyond, is four programs that'll be in late-stage development, many of which have large commercial opportunities. I think on the execution side, we're knocking it out of the park. We're really kind of hitting on all cylinders as we get into late-stage development. Got it. Got it. Thank you. So, I wanted to spend some time first on RGX-202. That's your DMD or Duchenne muscular dystrophy program. Obviously, there has been quite a bit of development in the DMD space, both gene therapy and non-gene therapy approaches. Can you talk about 202, and from your perspective, what makes that program unique or what makes it differentiated from other approaches out there? Sure. Yeah, and I can remember three or four years ago, with our Chief Scientific Officer, Olivier Danos, who has many, many years of experience in Duchenne, thinking about the type of product that we wanted to develop for this indication. And it struck us that sort of a me-too to what else was out there, trying to play on some cost of goods advantage, what have you, would not be really where we wanted to go. So we decided to develop a construct that was differentiated from the Elevidys program. And specifically, it's differentiated in the C-terminus that's part of that construct, which effectively makes microdystrophin more human-like, more like full-length human dystrophin. Why is that important? It's important because we think it increases the half-life of the microdystrophin, and we also think that functional difference, which also gives us the eligibility for accelerated approval, because it's a differentiated product, could lead to improved repair of the muscle once the force is exerted, whereas other constructs can't do that. So, really excited, and we've checked a lot of boxes in the program this year: safety, dose escalation, no SAEs to date, with a number of patients treated at both dose level one and dose level two, and now, microdystrophin levels in older patients, especially the eight and older category, which are almost three times what we've seen published for other studies. and, you know, that we think is going to lead to another differentiation of the product that gives older patients who are trying to maintain muscle function, potential for long-term good functional outcomes. Okay. Got it. Makes sense. And in terms of safety, so you mentioned, so far, in a few patients, you know, it's been well-tolerated. Can you talk about the possible effect of that C-terminal domain on safety, if any expected at all? Well, I think that, you know, this is something that if you actually go back to the AdCom for Elevidys, the FDA reviewer was commenting that the more that microdystrophin, which is ultimately a synthetic construct made to look like dystrophin, the more it looks human-like, the more it should be compatible with your immune system and with constant expression. And so ultimately, we don't know specifically how much will that C-terminus contribute to safety profile, but what we do know is, to date, our safety profile is really a positive aspect. As a parent of a recently... Parents that we meet with recently diagnosed children that are thinking about therapy options, safety is the first start for their thought process, and we're able to show them data now, that's very compelling in that aspect. So feel good. The construct, not just the construct, but the serotype, which is based on AAV8, has a long history of being well-tolerated as well, so it's the full package, I think. Got it. Excellent. Another question in terms of the target population, too. So you're looking at patients who are younger, as well as the subpopulation of patients who are actually older and heavier. Can you talk about that differentiating factor as well? Yeah, I think, our view is that we won't restrict ourselves to a specific age group as we recruit next year our pivotal study. So we did just open a cohort, midyear, for patients aged one to three, and that's really important for two reasons: one, that's not an element of the current label for Elevidys, so it's an area where there's an unmet need, and I think the second part is, long term, with therapies emerging for Duchenne, newborn screening is likely to become much more prevalent, and so tying in the desire to treat younger patients with the emergence of newborn screening will help us maximize the opportunity. Okay. Got it and in terms of your interactions with the FDA to date, what is your confidence level in the accelerated approval path for RGX-202? I think we're very confident. We've had an end-of-phase 2 meeting with FDA. We've also done more informal workshops with FDA, really because we feel open transparency of data, both with FDA and with the field for Duchenne, is a critical aspect of developing in this field. We've identified several areas of differentiation with FDA that will enable us to file via the accelerated approval pathway. I think we all have to remember, though, accelerated approval is an action that happens during the review, so we obviously will have a full review of the pivotal protocol with FDA and full alignment with that, but ultimately, these are review issues, and so we're patterning our study and designing our study for an accelerated approval filing. Okay, got it. A couple more questions on 202, and then we can move on to 314. Mm-hmm. With Sarepta obviously having a head start in DMD, what gives you confidence or what do you think is your advantage in terms of capturing the market share once or if 202 is approved? I think it's safe to say that there's a lot of room for improved efficacy to prevail in terms of future market share, especially in the older population. So we're seeing much higher microdystrophin levels in older patients that we've treated and hoping that translates to better level of functional benefit for those patients, and I think that's a big gap in the commercial programs that are approved that we can fill. I think the other element that we should think about is our facility in Rockville can produce well over 2,000 doses a year at a very attractive cost of goods, and we feel like that's a competitive advantage that no one else in the Duchenne space has. So I think there's just a lot of optimism on our side and a lot of drive to get into the pivotal program late this year and recruit that next year. Okay. Got it. And just to kind of close it out, so can you summarize the upcoming milestones for 202? Yeah. So we'll have more descriptive updates on, you know, the specifics of the pivotal program. I'm assuming along with that, a little bit more guidance on timeline to BLA. And then, by year-end, we should also have our first functional data, which will be largely data from patients treated at our first dose level, which is still a level that, in preclinical data, we saw benefit conveyed in the mdx mouse model. And then we'll also see the first data from our dose level 2 patients, some of which will be out 12 months and a few at nine months. So a little bit more limited data set, and then I would assume we'll be updating that early next year as more patients cross the... We think about post six months is when you can get a good read on functional benefit. And so as we accrue more patients that are, passing that timeline, then we'll be able to give more functional data. Got it. Okay. All right, let's move on to your 314 program. So that's the program that's partnered with AbbVie. You have two approaches in development, subretinal, as you mentioned, and suprachoroidal. For 314, in general, can you give us a brief overview on why do you think that approach, either subretinal or suprachoroidal, is an appropriate one for wet AMD and DR? It's a great question. I'll start with wet AMD for subretinal. I call it internally, maybe people are tired of me saying it the same way, but I think it's the gold standard for clinical data from ocular study in wet AMD. We've got patients out four to five years now, several of which have never had another injection or a rescue injection. We have really excellent safety record demonstrated, and durability of effect on vision, and I don't see any other program out there that can show that level of data. We do know that, you know, for subretinal, because it's a vitrectomy, there will be, down the road, a desire to have life cycle improvement on that to widen the market, even though we think subretinal itself is a large market. And so that's where we have also a suprachoroidal approach to wet AMD, that's in development with AbbVie, in which we've just decided to dose escalate to a DL4 to get a complete safety database and dose escalation ahead of a pivotal decision. For diabetic retinopathy, again, I was joking a little bit internally, our one benefit of our therapy is it's for people that don't want to go to the doctor. Mm. So why do people... If there's an approved product like Lucentis for diabetic retinopathy, then why don't people use it? It's because you have a lot of people that are in their forties or fifties that have been diagnosed, they don't, and their prescribers don't want to put them onto a monthly injection at that point in their life. And so people don't comply or they don't enter treatment, and because of that, over time, their vision decays. So gene therapy is absolutely an ideal approach for this. People can go in with a one-time in-office visit. And our phase 1/2 data supports the fact that, rather than two-step worsening or having a lot of vision-threatening complications, we can give these patients sustained disease prevention and feel that this is just gonna be a huge market down the road because it's wide open for gene therapy. There's not much else being developed in that space. Got it. Okay. So for your subretinal program, you have two phase 3 studies ongoing, ATMOSPHERE and ASCEND. Can you tell us the key differences between those two studies? And overall, how does the program position the company for commercial success in wet AMD? Yeah, so the, the main difference between... So ATMOSPHERE is enrolling only in the U.S. It's comparator non-inferiority study against Lucentis. And it's a large study. Both studies are in the range of 600 patients each. And then ASCEND is also a non-inferiority study that's being conducted. When AbbVie opted in on 314 with us, they wanted... It was very important to them to globalize the study, and so ASCEND is now being recruited, not just in the U.S., but ex-U.S., again. So the two different comparators and the decision process behind that was just having, you know, the best possible data at filing and approval against two of the main and well-understood compounds that are in the market. Got it. Okay. And moving on to the suprachoroidal program, the ongoing phase 2 AVIATE study. Can you give us, you know, a one-minute overview of the study and a high-level summary of results to date? for the DR or for- For Wet AMD. Wet AMD. Okay, so wet AMD, if you think back to the dose levels of Lucentis that are used in diabetic retinopathy and in wet AMD, it's always been known that a higher level of Lucentis was required to treat wet AMD. And so, at our earnings midyear, we decided to explore a dose level four, number one, because we had demonstrated really exceptional safety at dose level three, and we increased the dose level and are now recruiting at dose level four. We get asked a few different times, what are we looking for in dose level four for both wet AMD and DME, which is another indication we're looking at for dose level four. It's really, we've seen a trend through the data as we've dose escalated of reduced supplemental injections. We'd like to see that go further, and we'd like to see even better levels of vision, BCVA, being improved in that administration. So we'll be recruiting those studies probably for the next six months or so, and then we'll be able to update on data next year. ... Got it. Okay, so, so you mentioned the one aspect that allowed you to dose up was safety. Mm-hmm. Can you talk about the key safety findings from the program to date? And talk about the prophylactic regimen used at, I think, dose level three and four, and how does that prophylactic regimen differ from the competitor programs? I think the prophylactic, we implemented that going into dose level three, and we haven't seen significant numbers of cases of intraocular inflammation, so a good safety profile, and the steroid regimen is tapered quite early, so I think importantly, the data that you're seeing, you know, within six weeks, a little bit further out for some patients, we're able to taper steroids, and the tolerability has been excellent for that dose level, and that's the same trend we would expect to see in dose level four, and that's the basis of the new study. Okay. Got it. And to spend a few minutes on the DR program, so as you mentioned in your earlier remarks, there are effective treatments available, right? For DR. Mm-hmm. People are not using them. So what gives you confidence that they will be using, you know 314 once it is approved? So I think this is really one of the big benefits of having AbbVie as a partner. We've done extensive market research to look at our target product profile, and have seen really positive response from KOLs, from every aspect of the program. So we have a really high level of confidence that if we develop in diabetic retinopathy with this in-office one-time administration, that the uptake would be significant in the field, and that's been verified externally, again, with the joint development team that we work with at AbbVie. So it's really exciting for us. And that target product profile was constructed from the actual data from the study. It wasn't a model or anything like that, so we're really pleased with it. Got it. Okay. And I think what I would add on the end of phase two meeting, that's originally was scheduled for Q1 of next year, and I think the excitement internally and the excitement with AbbVie had us expedite that meeting into Q4 this year. Running a DR study, the endpoints are well vetted from a regulatory standpoint, and so we don't expect any surprises in the end of phase two meeting. It'll be confirming things like the sample size associated with the study, inclusion criteria, things like that. But the precedent has been set for a two-steps improvement or two steps worsening as regulatory endpoint-accepted endpoints has already been set. So we feel like it's a fairly low risk meeting coming up. Got it. Makes sense. I see there's a few minutes left, so I wanted to pause and see if there are any questions from the audience. Please. For the- One second. For the DMD program expansion into the age one to three-year-olds, was there any pushback or additional non-clinical work that was needed to go younger? From FDA? Yeah. No, actually, we were encouraged to get into that age group. So, no, we weren't asked for any additional data. We had, going into that amendment, you know, treated a number of patients, mostly older, obviously, four to 10, or as old as 11. But yeah, there wasn't really a request for additional data, and we are doing this at dose level two. Thank you. Any other questions? Please. So... To state the obvious, little kids get bigger. What's your thinking about durability over time, and are you considering exploring an immunosuppressive regimen that would redose these kids, you know, five or six years after the initial dose, if you're getting them at one, two, three years old? Yeah. So a couple of thoughts on that. I think in terms of durability, that is an area where we know the half-life of the C-terminus based microdystrophin is longer than without it, and so that can help. And I also think that by being roughly two or three times higher in microdystrophin level than the waning of the treatment over time would be less severe, perhaps. All to be confirmed with real data down the road. But yes, I think we are going to explore immune modulation as an element of this for potential redosing down the road, and we're also gonna be exploring globalization of the program. The most of the focus right now is on U.S. and accelerated approval, but, with the data we have in hand and expect to get, we're gonna, think a little bigger with that over the next few months. Thank you. I guess in a couple minutes that we have left, another program, RGX-121, the most advanced program clinically, but probably least talked about program at the same time. Can you talk about MPS II and what does RGX-121 allow you to achieve in MPS II patients? Yeah. So, incredibly exciting data. This started nine years ago when I began, and the hope there was just to reduce the GAG levels or D2S6 levels in the CNS, and we've achieved that reproducibly, if you've seen the pivotal data that we released. As exciting as that, or maybe even more, is we're also getting a systemic benefit, meaning the enzyme is getting into the periphery, and patients are having very low urinary GAGs. And so that 80% of our patients that were treated in the study have either gone off of ERT or never had to go on to it, which is a huge improvement in our overall target product profile. So we're in the process imminently ready to file our BLA. We're planning on a potential approval next year. And yeah, it's an ultra-rare disease, but it will set up our manufacturing and supply chain for commercial readiness for RGX-202, so it gives us a rolling start into becoming a commercial company. So it has a lot of strategic value. Excellent. But most importantly, a lot of value for MPS II patients that have been waiting for years. Got it. Excellent. I think that brings us to the end of this session. Curran, I appreciate you- Thank you ... coming to our conference. Thank you, everyone. Enjoy the rest of your day. Thanks.