Hello everyone, welcome back. I'm Brian Skorney. If you don't know me, I'm one of Baird's senior biotech analysts. Next management team we have participating in our fireside chat is the management team from REGENXBIO. Ken Mills, Ram Palanki to my right. This is a name that we cover, recently initiated on, very exciting name in the AAV space, I would say, certainly one of the leaders in AAV drug development. I'm very happy to have them here today to discuss what's going on. So maybe, Ken, just to kind of, like, give everyone a high-level overview, it'd be great if you could just kind of share some of the history of REGENXBIO, the expertise that you guys have built and maintained in the AAV space, and what kind of programs you're currently working on. Yeah. Thanks, Brian. Thanks for the invite, the participation in this conference, our first time, and look forward to the discussion right now. So, we'll move past. We may make some forward-looking statements, maybe not too much in this presentation, but in our discussion. So REGENXBIO was founded in 2009 based on AAV intellectual property that we licensed from Jim Wilson Lab at the University of Pennsylvania. And early chapter of the company was a lot about technology aggregation and partnering. So, it turns out, from maybe 2010 to 2015, which was the year that we went public, we entered into a lot of what we consider to be NAV technology platform licensing deals. NAV technology is what we call the intellectual property that underpins all of our AAV therapeutics, our one-time in vivo adeno-associated viral-based therapeutics. While we have a pipeline that we're developing, and I'm going to get to that shortly, we also have a pipeline of over 20 partner programs that span the whole spectrum of still early preclinical research in certain diseases, all the way through to one of the first AAV products that was approved, a drug called Zolgensma, that is now marketed by Novartis worldwide for the treatment of spinal muscular atrophy. We receive royalties, and in many of the cases, in the licenses, we've gotten upfront revenues in the form of license fees or development milestones and commercial milestones. So strategic partnership has been in our blood since we went public in 2015. As I mentioned, we started to focus, though, on the development of our own pipeline of AAV therapeutics. I'm going to walk through where we are there, but I want to point out a couple of things before we do that. One is our infrastructure. We're largely based and headquartered in Rockville, Maryland, just outside of Washington, D.C. We have about 400 employees, and we have what I consider to be the most well-integrated AAV therapeutic development capability that exists, everything from basic research and fundamental technology, all the way through preclinical development, clinical development and execution, including late stage, and most recently, about a year ago, in our headquarters building, we opened up a GMP manufacturing capability, which will cover us not only for late-stage development, but also commercialization. We have a partnership with one of the leading pharma companies, AbbVie, to help commercialize our AAV therapeutics in retinal diseases. About a year and a half ago, we introduced a new corporate strategy whereby we plan to have 5 of our AAV therapeutic programs in late stages of development or commercialized by 2025. So, where's that going to come from? Well, we have 8 ongoing clinical programs, and 7 of those 8 programs we've reported clinical data on, on an interim basis or on a final basis. We have 2 programs that are in pivotal phase. One, a wet AMD subretinal program, again, partnered with AbbVie, that is enrolling up to 1,200 patients in 2 separate pivotal clinical trials for a one-time treatment for wet age-related macular degeneration. another pivotal stage program in a rare genetic disease called Hunter syndrome, or MPS II, where we just recently announced that we enrolled our full pivotal plan of 10 boys, this is an X-linked disease, to support our first BLA filing in 2024. So, there's kind of the 2 leading tips of the spear, if you will, for us in our Five by 2025 strategy. But we're also developing programs in diabetic retinopathy, Duchenne muscular dystrophy, and other neurodegenerative diseases that are close cousins to Hunter syndrome. So, as I said, overall, this is a snapshot of our 8 programs. I think we're going to get into some of the depth of it with Brian here in a minute. And finally, on a sort of, you know, corporate summary basis, I wanted to touch on 2 things. One is, you know, I, I always focus on the fact that as a company, we need to balance kind of 4 important strategic elements for our growth: people, plan, science, and capital. So, happy to say that we ended the Q2 of this year with over $400 million in cash. That gives us the opportunity to continue to execute on our pipeline plan, strategy, and growth into 2025. And with respect to our pipeline internally, we are excited to have 3 clinical updates on an interim basis that are coming in the next 3 to 4 months. The beginning of October, we're going to have a first efficacy update on an interim basis on our Duchenne study. The beginning of November, we're going to have a new update on an interim basis for our Phase II diabetic retinopathy study, both of these at medical conferences. And then we've also announced early in January 2024, we're going to have a new update on our in-office device, wet age-related macular degeneration phase II study. So, three interim program updates for some of the most important parts of our pipeline in the next three to four months. And overall, I think we're excited to maybe get in a little bit of the details here. Yeah, great. Thanks. So going into those details, maybe we could start on 314 and talk a little bit about the opportunity there. Obviously, wet AMD, a lot of people are very familiar with that space and sort of the injectables. How do you kind of think about the opportunity for a one-time gene therapy here, to sort of take market share, and what sort of data do you really need to generate in phase III, to sort of build a big commercial market? How about it, Ram? I think, Brian, you've been covering this space for a very long time. I, the main components really come down to this: every treatment you have out there, over time, patients lose vision. And the reasons are none of them are sustainable. Even as we start talking about, components like Vabysmo, high-dose Eylea, there's only a percentage of patients that actually get to, like, that incremental durability concept. But still, over time, all these patients end up losing vision because you can't sustain it. I think, what we are trying to do is really change that whole equation, right? To date, we've been talking about durability and durability, and durability, but we need to start switching the conversation to: how do you sustain the vision in these patients on a long-term basis? I think that's where we really kick in. It's not just durability, but it's actually changing the patient's ability to retain vision, and over time, actually be functional, right? And if you can do that with one-time treatment in majority of patients, and you actually, on a post-treatment basis, can take away a lot of the burden in another percentage of patients, I think that's a game changer. So, there's a lot of debates in towards in terms of the different approaches for treating patients from subretinal to suprachoroidal to intravitreal. And maybe you could just kind of review the three different methodologies for providing treatment to patients in the gene therapy space and you know what the benefits of subretinal, which is your current phase III program, are. Yeah, so I mean, when we talk about route of administrations, we should go back historically and look at where retina started. If you go back to, like, 2006 and before, before Lucentis launched, this was predominantly a surgical field. I mean, the concept of doing 4 million injections now in the U.S. last year alone, wasn't even, like, sustainable concept when Lucentis trials were going on, right? So I think on an identity basis, every retina specialist is a surgeon. They get trained as a surgeon, they come out, and they do surgeries every day. Even today, about 500,000 surgeries are done in the U.S. alone, in their ASCs through HOPDs. I think the concept of surgery to injection really happened with the introduction of Lucentis. Yes, that's what they do on an everyday basis, but they also do surgeries on an everyday basis. Then, if you start thinking about route of administrations for a biologic, I think intravitreal. It makes all the sense. So, once you switch to gene therapy, you really have to think about, you know, the concept of the vector and the serotype of the vector and its ability to transduce the tissue that you're trying to transduce on a cellular basis, right? That's a retinal tissue. So, the best ways to do it is two ways: either subretinal or you go through the suprachoroidal space, which are very close to the tissue that- ... you're trying to transduce versus intravitreally. You're putting the vector into the space where it could transduce many other anterior segment, so segments of the ocular space. So, I think those are really the big differences. And to date, you know, if you look at the data from preclinical days through clinically, it's been consistently shown that the intravitreal space is the most inflammatory space. And you've seen our data to date. We're in the phase III program right now with subretinal. There hasn't been any inflammation detected from our phase II through as we are executing through phase III program. And in our suprachoroidal program, even before we ever installed steroids, we saw this mild inflammation- ... that kind of came and went away with topical steroids. So, coming into the latest cohorts, we installed prophylactic steroids for about 7 weeks. And you compare that to a lot of the intravitreal programs. They all go up to 20+ weeks and different types of regimens of steroids on top of it. And that kind of took away even the minor risk we had for any incidents of intraocular inflammation. Right. So that really gets us comfortable where we are now, is even on a dose escalation basis. Now we're operating with a prophylactic regimen, even on a competitive basis, is very short- ... and has took away that risk today. Got it. And when we talk about inflammation, I think there's a lot of confusion in the street between sort of the different types of inflammation, what qualifies as IOI and, you know, different levels of severity. Can you just talk about the spectrum of what we've seen, you know, from kind of even the Bayview side to other, intravitreal, gene therapies, to what you guys have actually seen on a minimal basis in, suprachoroidal, and how those adverse events sort of differ? Yeah, it's, I mean, I think the word inflammation really took a hit with two, two parts of the recent development activity, right? Maybe three. With Abicipar, they received a CRL, and- Yeah ... and that's because they had actually vision-threatening intraocular inflammation. Then you kind of follow that Verum story, and they actually had hypotony and which led to vision loss. And then you step into the Bayview story, was a good drug, great launch, and then they had this permanent vision loss concept due to retinal vasculitis, right? So those inflammatory components that lead to vision-threatening or permanent vision loss type of AEs versus general intraocular inflammation that's observed even with just an injection. I mean, if you go back to the label for Lucentis through Eylea, through every drug that has come into the space- ... there has been incidents of IOI, no matter which drug you take into account. So I think that's really the difference. It's the profile and the severity of the inflammation, the manageability of the inflammation, and the sequelae of the inflammation leading to permanent vision loss are the differences. Great. And then when we think about your phase III design, you made some protocol changes earlier this year. Can you just walk through the phase III, the decision to upsize the phase IIIs, and, you know, what sort of data we need to see, both for sort of regulatory success and what you kind of view as the commercial success bar? Yeah, maybe I'll talk about the phase III program that's ongoing right now, and it's probably the best way to compare what we're doing in that study on a probability of success basis would be our phase two pharmacodynamic study that we presented at Angiogenesis. That study actually takes into account pretty much the same doses and the same type of patient profile that's been actually on an inclusion basis coming into the phase III trial. That study has shown now, we have presented up to six months data, majority of patients going injection free and all of them gaining vision on the basis of their baseline being at different places. So I think that's a pretty good indicator of what to expect out of our phase III program, given it's the same exact type of patient population, same exact doses, same exact retreatment criteria. That should give you and the rest of the world a little bit of a perspective on what could be the probability of success and what type of data we should expect coming out of the phase III program. Great. And then you've, in parallel, been moving forward with the suprachoroidal programs. We're gonna see some updated phase II data there. Talk to us a little bit about you knows where you think you move forward here. What, what sort of data points are you looking for in phase II to move forward in phase III? And, you know, I know we've talked a lot about diabetic retinopathies. Is there sort of a segmentation of 314 as a subretinal approach in wet AMD and in suprachoroidal for diabetic retinopathy? Or do you think you can move forward in suprachoroidal across a broader set of indications? I mean, historically, the program started with subretinal, right? And our approach has always been really thinking about the risk-benefit of these route of administrations. We've always stayed away from intravitreal for one reason, because, again, consistently the data shows from the preclinical stage into the clinical stage, it's the most inflammatory space to operate in. So where we started with subretinal, kind of, had that evolution and maturity on data coming into the phase III before we ever started suprachoroidal. The concept here is we had all the data we needed to get the drug to patients as quickly as possible. We believe that market is significant, and it's worth $multi-billion. Just because of the one-time treatment concept and the fact that you can price it in $tens of thousands of dollars- I think even a market share around 15%-20% represents a very large opportunity there. The idea is to get that product out there into the marketplace and set up the infrastructure for introducing gene therapy into a public health priority, right? Nobody has done this before. We're the first ones that are coming out and introducing a product that actually helps millions of patients versus hundreds and thousands of patients today. So, I think setting up that infrastructure, both on a provider basis with CMS, and just the whole process flows and product flows that need to be in place to make this successful, really is the pillar for the subretinal program. And the suprachoroidal programs have been maturing, and the data, as it evolves, we'll make the right decisions to move it into the phase III program. To your point, the DR program is very exciting for us. You know, the concept of, in fact, preventing the progression of the disease from patients actually getting to a place where now what you've lost, you can't actually bring it back, right? So, these patients are all in the clinic today, and they don't get treated because of only one reason, the current sustainability of these intravitreal injections in a diabetic patient that is very non-compliant and committing them to their life. The question that physicians go through is: do I actually start treating these patients when they develop vision-threatening complications, or do I start it before? Because no matter where I start, I have to treat them for life. Right. Right. But with us, it's a whole different story. It's, you know, you start early, you stop the disease from progressing with one-time treatment. That is an absolute game changer in the minds of providers, patients. I mean, we've been talking to them for a while as we thought about designing this program, and that concept of being able to stabilize the disease and stop the disease in its tracks is a great concept with a single injection. I could use our entire time to clearly just keep going on 3 on 4, but I do wanna touch on some of your other programs, which is equally—which are equally exciting. So maybe moving on to DMD, I think a lot of us are familiar with the first approved DMD therapy in the gene therapy space, Elevidys. So maybe you could just kind of review in the context of that product, how your construct is potentially differentiated and where you see the gene therapy opportunity for REGENXBIO. Yeah, so our product candidate, RGX-202 is of the same class as the approved product, which we're very excited about. I mean, this is the fourth AAV, third AAV approved, but the first accelerated approval of any AAV product, which is really meaningful from a U.S. regulatory perspective and something that we're strongly supportive of, especially for these rare diseases with high unmet need. Here's the thing. A lot of the reagents that were in the clinic a few years ago, just when they were starting out to originate with clinical data at places like Sarepta and Pfizer, were based on science that was developed in academic labs, like 20 years ago. And, you know, at that time, what was known about the molecular biology of AAV, and it had constraints. People were trying to work with certain tools that 20 years later had completely changed. Our Chief Scientific Officer, Olivier Danos, had been working in AAV gene therapy and Duchenne research for about many decades. I won't age him out here. But he came to us from Biogen. He had reflected on a lot of the work that was going on, and he said: "I want to start a program with new science in Duchenne. I want to add features to these expression cassettes that are happening with AAV that don't exist, because there are elements of full-length dystrophin that can be put into these new product candidates." And he focused on one end of dystrophin, the C-terminal end of the full-length protein. He said, "This area in particular..." He had a partnership with someone named George Dickson in the UK, who had established already in vivo models, that if you included these additional domains of the C-terminal end of dystrophin, you got more potency, you got more function in animal models of disease. And so, we wanted to reproduce this in an AAV. Took us a few years. I mean, the tools were there, but this is not a layup. But ultimately, we engineered RGX-202 to be the first product candidate for a microdystrophin, a truncated form of full-length dystrophin, with this new domain from the C-terminal end of full-length dystrophin. And we're going to be the first ones to explore it clinically. We have data coming in a few weeks that'll show our first evidence of expression in a couple of patients that we dosed in our initial first-in-human study here. What we're really going to be interested in is following the journey of these patients out to later time points, when the functional, the motor function, the muscle function of these patients can be established. It might be at 6 months or 9 months. We certainly assume by 12 months or 2 years in the sort of natural history of this disease, that, that RGX-202 may have the opportunity to become something that's new science, that could be best in class. So excited about the first step for the field, but, you know, we've got to keep improving here, too. Right. And then just to dig in a little bit more on your construct, I know following Sarepta for so many years- Yeah. And as you pointed out, they've basically been working with both the construct and the manufacturing process that originally came from an academic lab, versus REGENXBIO, who has, you know, arguably one of the most modern manufacturing capabilities of AAV. When you saw the slides that were presented at the AdCom, I mean, just any thoughts in terms of the ability for a REGENXBIO construct to be more consistent in terms of its ability to transduce cells? Yeah, I mean, the AdCom was fascinating to kind of get some more views of how the FDA review office was thinking about what they want to see in Duchenne. You know, we, of course, all the individual sponsors are having discussions with them about their own programs, but it's great to see kind of the reflection. The, you know, one of the things that I saw the, you know, the advisory committee itself reflect on, and the office, was, you know, what can microdystrophin be, and what is known about the natural history of the disease and the biological plausibility of AAV gene therapy? One of the things that came up was basically, what has clinically been characterized as an attenuated form of Duchenne, right? Becker. Yeah. Right? And they had multiple slides, Brian, right, if you remember? Yeah ... that showed, "Oh, here are genomes and protein sequences that have been published since the early 1990s of Becker patients, and let us show you those compared to the candidate that we're evaluating here today." And what was the difference? It was the C-terminal end. All of these Becker patients actually had the domain that we've engineered into RGX-202. So I thought, "That's nice, because we're seeing evidence of, you know, FDA reviewers and the advisory committee sort of nodding their heads that, 'Oh, yeah, a candidate that might have things that are more reflective of things in nature might be more biologically plausible.'" And, you know, I mean, that, that was definitely a thesis that Olivier had. You know, on, on the manufacturing side, since you touched on it, I mean, we absolutely... You know, our whole field has needed to modernize manufacturing since the first products were approved. You know, I mean, it just... FDA led the way with the approval of Luxturna and Zolgensma, but that was 2017, 20-- We're in 2023 now. Wow! The whole field has capabilities to be able to, you know, use the bioprocessing that's done for traditional biologics and antibodies and proteins and so forth, and apply it to AAV. We just needed to make the investment. Right. You know, we hired our whole staff from Human Genome Sciences, MedImmune, you know, Glaxo, AZ, and it wasn't AAV people, it was industrial process people for GMP manufacturing, set them loose on AAV technology. And now I think we're manufacturing as efficiently and as of high quality as anyone in the field. Importantly, you know, that, that's really necessary in a disease like Duchenne, because our doses, in terms of the amount of virus we're administering with these IV administrations, you look at our pipeline, that's probably a factor of 100-1,000 higher, you know, dose, if you will, on a per individual basis than what we do in the CNS, what we do in the retina. So the manufacturing quality and the efficiency and the yields to get, importantly, you know, reasonable cost of goods and quality product is important. Then you also have a number of programs in sort of a classified as sort of a rare neuro field, and maybe even referring back to the updates in regulatory with DMD. How does sort of the decision for the FDA and on the CBER side, in particular, to grant a Subpart H approval, how does that sort of change your view of rare neuro and the opportunities here? Does it open up more surrogate endpoint studies? And has that manifested in your current pivotal program, and potential pathway there? It's been incredibly important for us for years to bring together stakeholders to talk about accelerated approval for AAV therapeutics. Because plausibly, everyone agrees on the science and the sort of clinical path in most of these diseases, right? Right. There, there's a gene that's missing, and as opposed to Duchenne, that I alluded to, where we're at this stage not able to put back the full-length functioning protein, in most of the other retinal, rather, rare genetic diseases that we're all working in, we are putting back the full-length endogenous proteins and genes that are missing in the right cells and tissues. And so, you know, that’s very unique. I mean, it’s something that hasn't been done before. And so again, from a plausibility perspective, once you establish proof of concept, and especially where there is high unmet need, no additional treatments, it should really get there as soon as possible. That's everyone's reflexive action, right? The FDA had never done it before, and how did they do it? So we formed a consortium. FDA participated in, a lot of sponsors did. I think we actually talked about two areas of focus. One was Duchenne, and the use of microdystrophin as a surrogate endpoint to support approval, and the other was rare CNS disorders that have basically enzymes that are deficient and substrates that can be measured in serum or plasma, or in our case, cerebrospinal fluid, and that those changes are also surrogates. So, now's the time. I mean, you're seeing this shift, and there's also new leadership, there's been new reorganization at the FDA. I think that there is a real, vocal level of support for accelerating technologies that are here today, that are in the clinic today. One of our partners, literally overnight, announced that they had come to agreement or alignment with FDA on basically an accelerated approval pathway in a rare cardio- you know, myopathy muscle disease, Danon and Rocket, and they've been a licensee of ours for several years using our technology. And they're part of a consortium in discussions that we have with FDA as well. So, you know, on our Hunter program, we had guided at the end of last year that we've engaged with the FDA, we've talked about using the accelerated approval pathway, and that means using a biomarker, a substrate in the CSF, as an early indicator of the prospect of direct benefit that will support a BLA we'll file next year. But for me, that's the first of many. That's, you know... And that's why our 5 by 25 strategy is so important. If we have guidance on a BLA for Hunter syndrome next year, the AbbVie partnership for subretinal is talking about late 2025 for a BLA, and then by 2025, 2026, we want our Hurler syndrome, our Batten disease programs, and even our Duchenne programs to be on tracks for BLAs. So, you know, this, this strategy is realizable. I think the regulatory environment is very supportive. The science is there. I mean, as I alluded to upfront, we've reported data on seven of our eight programs, right? The only one that we just started to dose recently is our ocular manifestations of Batten disease, and I'm sure we'll have, you know, updates on that next year. We just started dosing it, but every single one of our programs is working. Then when we think about that 5 by 25 strategy, how do you think about sort of the next programs? Like, what sort of constitutes an attractive both development pathway and commercial opportunity? I mean, they're pretty disparate in terms of your wet AMD opportunity versus Hunter, Hurler. They are, and we love that. I mean, we wanna build a sustainable business. We want to be unique, and we wanna do important things. And I think, you know, there's a group of people in the company, Ram included, that are so passionate and knowledgeable about retina and about the history of retina. And, you know, you talk to him a lot about this, and I've shared a lot of that journey with him. And so we're looking at more things that we can do in retina for large populations as well, right? I mean, we have to leverage that infrastructure and capability and not through the AbbVie partnership per se, things that we have always done on our own. And Duchenne, you know, look, I brought it up, I sort of dangled it out there. As a field, we need full-length or near full-length Dystrophin to really be the type of game changer for these kids. No one's been able to achieve it yet, but, you know, Olivier came to us, and he had a lot of ideas several years ago, and one of them was to get this, you know, new improvement into the existing reagents, and the other was to chip away at how to do full-length Dystrophin. So we started to report on some of that research just in the last few months, and we'll have an IND that's, you know, basically accelerating through preclinical development and looking to file something in 2025, where we'll use AAV and certain modalities to take existing genes from kids and stitch them together, rather than putting something new in there, use what already is there as machinery to try to express near full-length Dystrophin. And that's a theory that people have talked about for a while, just no one's been able to do it with great efficiency. Some of our data is showing some of the best efficiency that we've ever seen preclinically. So, you know, we're still committed to rare, we're very committed to retina. I think we also are committed to things that are important and that are sustainable from a business perspective. Great! Well, I think it's an exciting story. We're thrilled to have you here today. I don't know if you have any other things that I didn't ask that you think are important to tell investors, but, love to hear those now. What do you think, Ram? What did we miss? I don't think we missed anything. We're so-- We're so good. We covered it all. Got it all. There's There's one minute to go. Perfect. All right. Thank you so much. Thanks, Ram. Appreciate it. Thanks, Ram.