I'm Ellie Merle, very happy to have REGENXBIO here with us today to talk all things their neuro pipeline. Joining us from REGENX is Steve Pakola, Chief Medical Officer, and Olivier Danos, Chief Scientific Officer. Thank you guys so much for making the time. Just a quick disclaimer before we start: as research analysts, we are required to provide certain disclosures relating to the nature of our own relationships at UBS with any company on which we express a view on this call today. You can find these disclosures at ubs.com/disclosures or reach out to us and we can provide them to you. With that being said, maybe just to kick off, Steve, can you provide us a high-level overview of your pipeline? Sure. First, Ellie, thanks for having me and Olivier here. Great to participate in the meeting. So as a quick intro, REGENXBIO is a leading gene therapy company, and we're particularly focused on gene therapy delivery to three main organs. So the retina, so in the ophthalmology space, CNS, brain and other CNS tissue, and muscle. So these are the three areas where we also have advanced clinical stage programs. And I'll start with our lead program, RGX-314, for the treatment of wet AMD and also diabetic retinopathy. You mentioned this is a neuro conference. We like to think of the retina as really an extension of the brain and neuro tissue, so sort of ties in somewhat. So this is an advanced stage program that's actually in pivotal development for subretinal delivery for treatment of wet AMD. And this is in collaboration with our global partner, AbbVie. So we're currently running a 1,200-patient pivotal program for treatment of wet AMD. And this is the largest ever in vivo gene therapy pivotal program ever run. So really just an example of how we're leading in this space. And we can talk more about this program later if you wish. Two other programs are our program in the CNS space is RGX-121 for the treatment of MPS II or Hunter syndrome. This program is actually also in pivotal stage development. And we actually completed the pivotal trial enrollment last year. And based on this, we're actually in the process of getting ready for a BLA submission later this year where we're going to submit under the accelerated approval pathway with a reasonably likely to predict biomarker for this program. Third but not least, or last but not least, is our RGX-202 program for the treatment of Duchenne muscular dystrophy, which is in Phase II dose ranging assessments. We've already, over the last few months, given several updates on the initial patients treated in this program where we've seen excellent safety and also very robust microdystrophin muscle expression values, which is an accepted surrogate marker for an accelerated approval pathway based on precedent. We've seen this at two dose levels. We've also seen it even in older patients being able to have robust microdystrophin expression. So that program, we're planning to make final formal pivotal dose selection and actually start the pivotal program for Duchenne later this year. So later this year, we'll actually have three programs in pivotal or later stage development. So a lot we can talk about, Ellie. Awesome. Maybe starting with DMD, just because you recently had data and we're getting quite a number of investor questions here. Maybe for Olivier, can you walk us through your construct and in particular how it's differentiated from Sarepta? Sure. So what we're doing in this trial is that we are transferring to patients' muscle a mini version, a short version of the dystrophin protein, of the gene that causes dystrophin protein. We have to come up with a short version because this is the only way we can use AAV vectors. We're limited by the capacity of these vectors. And the dystrophin is a huge protein, naturally. But it turns out that there are many evidences showing that you can reduce the size of dystrophin and still get smaller proteins which have the essential functions that allow for maintenance of muscle integrity upon muscle contraction, right? So those are called microdystrophins, sometimes mini dystrophin, but more currently, usually microdystrophins. And Sarepta has reported and has got recently approval using one type of microdystrophin which has been developed. We've come up with another version, our own version of the microdystrophin, which we believe brings a number of advantages. The way we do that is that we actually include additional pieces of the protein that we know are actually very useful not only in maintaining the essential muscle integrity, but also in allowing for enhanced muscle resilience and enhanced muscle recovery from all the stress caused by contraction. So there's a lot of data, preclinical data, showing that in particular, adding what we call the C-terminal domain to our construct can be beneficial. Of course, it's never been proven in patients, and that's what we hope to show eventually in the clinic. But there are data at the biochemical level. There are data in animal models that show that this extended version of the microdystrophin is better. To do that, we had to tweak a little bit our initial construct and make room to add this additional information. We've been able to do that. We came up with a protein with a mini dystrophin, a microdystrophin that we're very happy with. We changed a few more minor things, which are I mean, they seem minor, but they're actually very important, which are inside the microdystrophin, there are certain sequences which are very important for the stability of the protein, right? And we optimized all that. At the end of the day, we came up with something that we think is certainly advantageous. What's the function of the C-terminal domain and how we should think about maybe the degree of clinical benefit from this? So the function I think you can see the function as an aggregator and something that helps forming a whole hub of proteins around dystrophin. So there's an essential minimal hub that's been known as the dystrophin-associated complex. Those are proteins which are absolutely essential for function. But the complex is actually much larger than that. It brings in other proteins that are very important for signaling, for ion homeostasis, for NO synthase binding to the so I mean, I could go on and on with the list of things that are happening and that are being organized by the Dystrophin protein. Adding the C-terminal domain allows a better, quicker, more stable formation of this complex. So we believe that it means that pharmacologically, we're going to have something that is likely to have a different behavior, right? And again, this is the inference from what we see in the animal models. Understood. And in terms of what we should look for in data disclosures from here this year, what should we expect in terms of data from the second patient dose with dose Level 2? And when you'll release this, will you release this patient on its own, or will you wait to combine it with a later update such as when you determine the pivotal dose and the pivotal study start? Sure. So as you mentioned, the second patient dosed with dose Level 2, we did announce initial safety with that updated MDA where the patient has been doing well. So that completes our main dose Level 2 cohort of two patients, after which we can go into expansion phase and dose more patients. So this year will be certainly big for further disclosures on safety, microdystrophin expression levels, and also in the second half of the year, more functional results we've guided towards. The specifics of when we would disclose the second patient's microdystrophin levels, which we don't have yet, it's a 12-week time point. We haven't given that. But you mentioned the other key milestone that we have coming up, which we have guided towards, is with these multiple dosings at both dose levels, actually making a pivotal dose selection at mid-year. I think it's reasonable to infer it wouldn't be too long before we'd be disclosing additional microdystrophin levels. Again, with expansion of the cohort, the ability to have more not only microdystrophin measures, but also particularly with the earlier stage patients, functional data later this year. Understood. Maybe if you could walk us through some of the microdystrophin data that we've seen so far and put it in the context of what we've seen from some of the other gene therapies in the space and how you think about what this could mean for the strength and functional data that we're getting later this year. Sure. So I think one important context for the trial that we're running is that we're including patients at screening age four to 11. So that's a broader age range to really assess safety and also pharmacodynamic effect, including the microdystrophin expression. And you mentioned in the context of other programs, there's really a dearth of information about microdystrophin expression and efficacy beyond the 45 and the 47 age group. And part of that is probably tougher to treat. And also as greater disease muscle pathology advances, there's a general belief that that sicker, more advanced muscle tissue may be very tough to get the same type of expression levels that you can achieve before the disease has advanced to the stage that you see in the boys over, let's say, seven years of age. Now, given that, we've also enrolled a broad range of kids. So at dose level one, we dosed a four-year-old, a 6.5-year-old, and a 10.5-year-old. And we saw very good, robust microdystrophin expression in the kind of range that you would want to see with what's been reported previously with Elevidys. Of course, there's an extremely wide range of microdystrophin levels that's been reported previously from other programs like Elevidys. So there's an extremely wide confidence interval for any mean or median that might be reported. But certainly, the values that we're seeing are very good. And we and others in the field were particularly excited to see that even the 10.5-year-old had 11% microdystrophin compared to control, which again, given the age, that we were quite excited about. And what was new at MDA was the microdystrophin level expression for the first patient in dose Level 2. And this patient actually turned 12 right around the time of dosing. Even at that age, when we used the second dose level of 2E14, we saw a very high microdystrophin expression of 75.7%. Of course, safety first, very good safety across both dose levels. But we see very good expression across the board. To see this high-level expression with dose Level 2, even in a 12-year-old, has us very encouraged and very much looking forward to the second dose Level 2 patient values. As far as how that could translate to potential function without drawing too direct a line and it's still early days, but Dr. Veerapandiyan, the investigator who presented this at MDA, showed some pretty striking videos of some of his patients with both clinic videos and also some videos that the family took at home to show Dr. Veerapandiyan of a patient doing things that their son had not done before, like swimming and running and riding a bike, etc. Just anecdotal at this stage, but certainly has us encouraged to provide more data in the second half of this year. I think we can think of in terms of translation of this to functional benefit, one is actual microdystrophin expression. And the other is what's the potency GC per GC of what we're delivering? And I think that's where everything that Olivier described comes in, where having the functional elements of the CT domain could potentially have an opportunity of doing better in the long run in terms of potential functional outcomes. Realistically, that's not the kind of thing you would see in short follow-up, but the longer and longer we follow these patients, the greater the opportunity there is to see benefit and potential differentiation. I guess more specifically, what should we think about what we'll be getting in terms of the range of follow-up and number of patients later this year? Do you expect to dose any more patients ahead of moving into the pivotal trial? Yeah. Taking the second one first, it's certainly not gating. So we've guided towards mid-year for pivotal dose selection and then starting the pivotal in the second half of the year. We have the potential to keep dosing at dose Level 2 in the existing protocol. Technically, at the point we start pivotal and then we dose those patients. O ne of the benefits of the accelerated approval pathway with a biomarker like microdystrophin is there's really the opportunity to look at the totality of the data, especially since we're using the commercial-ready process already in the ongoing study. So certainly nothing gating and nothing as far as starting a pivotal. And it's certainly nice if we can continue to help treat these boys at the sites that we have open. So I think it's reasonable to think we would continue to advance. Makes sense. That's a. Yeah. I remember the other part of your question, Ellie. Since the longer the follow-up, the greater sensitivity there is to see something. Certainly, the first three treated patients have had longer-term follow-up. So you can envision the opportunity to look at six months and longer follow-up in that cohort of patients. The second dose level patients will have had shorter time frame hitting six-month results at least, though, by mid or a little later than mid-year where there's the opportunity to look at that duration. Makes sense. Yeah. It'll be an interesting update. Maybe you alluded to the pivotal trial start and potential for accelerated approval. I guess how are you thinking about the pivotal trial design? And specifically, how many patients do you think you'll need to enroll? Sure. So one aspect is dose that we've already talked about. I think given the dose response and good safety and going back to our preclinical, the work Olivier has done and his group, we see a nice dose response between dose Level 1 and dose Level 2. So given good safety, we continue to see good safety, I think we'd be comfortable with dose Level 2. The reasonably likely to predict biomarker microdystrophin will be key on that aspect. Looking at precedents for demonstrating efficacy on the biomarker, we're really in the range of dozens of patients, dozen or two, that if you look at precedent, what's been needed from an efficacy standpoint, I think that gives you a rough standpoint of where we're at. We haven't given any specific guidance on exactly what numbers, but certainly something very manageable, especially with how big of a patient population that exists. The other factor we're frankly thinking about is broader opportunities and bigger unmet needs. I mentioned the dearth of information out there and knowledge about older patients. There's also not much information on some of the different mutations, exon mutations on the C-terminal domain that have traditionally been excluded because of risks related to immune response based on neoepitope-type considerations and also weight. So given the broader range of patients that we're including in our Phase II study, it really gives us an opportunity to think of not only the traditional age range looking at microdystrophin, but also looking at safety and biomarker response in different age segments that could potentially help the field learn more about the broader age range of patients that we know. Patient advocacy groups and all the patient families are very urgently looking for opportunities to help their boys beyond that younger age range. Absolutely. Makes sense. We very much look forward to hearing more about the pivotal trial design at the update mid-year. Maybe with the time we have left, I wanted to talk about MPS II. So maybe you guys are filing a BLA this year. You've reported pivotal data. Can you tell us a bit more about MPS II and where the unmet need is in your view and how RGX-121 addresses that? So MPS II, also known as Hunter syndrome, is a rare X-linked monogenic disorder. It affects predominantly boys as well. And it's caused by a missing or malfunctioning gene that encodes for a lysosomal enzyme, IDS. That's critical for breakdown of cellular products, specifically glycosaminoglycans or GAGs as they're abbreviated. And without this enzyme, the key aspect is you have a major buildup of GAGs in this type of lysosomal storage disease where you have such a buildup of these that you start to have malfunctioning cells, degradation of cells and tissue and organs, including the brain. And this leads to pathology at a very young age in these children where you have not only overall slowed development and patients not hitting their milestones, but as early as the second year of life, you see not hitting neurocognitive and neurodevelopmental milestones. And ultimately, these children have actual regression of even what they were able to hit as early as six to seven years of age. Now, fortunately, there is enzyme replacement therapy that's given systemically that is onerous because it takes multiple treatments over time indefinitely. But fortunately, this allows the systemic components to be addressed. So on your question of what are the biggest unmet needs, the biggest clearly is something that can address the CNS manifestations that I just described because this is really what's leading to the significant morbidity at a very young age for these children. And once you have this progression, it's really very difficult to do anything about it. So you really want to treat as early as you can. So our goal is with CNS delivery of RGX-121 to actually address this main unmet need of CNS inexorable decline in these children. So that's why we're excited that with CNS delivery, with a one-time treatment, we've been able to clearly have an effect on CSF levels of the GAGs, the heparan sulfate specifically, that is what builds up in MPS II disease that we've been able to significantly decrease those levels in the CSF. This is what has allowed us to advance to a stage where we can submit a BLA later this year under the accelerated approval pathway with heparan sulfate CSF-specific biomarker related to what actually builds up when you're missing this enzyme. The reason this is reasonably likely to predict clinical benefit is not only are we measuring the specific substrate that builds up, but we know from the disease population itself that there is a clear correlation between CSF levels of heparan sulfate and the specific breakdown or substrate that is what exists for IDS, this enzyme. There's a clear correlation between the levels in patients who have neuronopathic MPS II and those who have non-neuronopathic or attenuated disease and also normal. So the story really fits together well for a biomarker to be considered reasonably likely to predict clinical benefit to allow for our BLA later this year. Absolutely. Makes sense. Just last question to close it out. Since this theoretically could be the first product that you're launching from your pipeline, can you help us understand maybe how many patients would be amenable to treatment with 121, specifically the proportion of patients that have this CNS involvement and maybe higher level, how you're thinking about the overall commercial opportunity here? It is a rare disease in the U.S. incidence-wise, anywhere from 50-100 children born each year. There's significant advance in newborn screening where this has been added to the panel that's recommended, and states are now starting to take this up and add this to their newborn screening panel. So we expect good diagnosis earlier, which will allow for better prognosis for these kids. About close to 75% of MPS II patients have the neuronopathic type. So most of these patients would be amenable. So you get some sense of the population that we'd be going at with a one-time gene therapy treatment where that makes it a reasonable market opportunity from a rare disease-type program. Not massive, of course, but still something that can help a lot of children who otherwise would not have benefit or not really address this unmet need. The other thing I'd point out is that this is sort of the leading tip of the spear where this gives us a chance with a first approval and a first launch to really then, as a fast follower from a company standpoint in rare disease, then move forward with the much bigger opportunity of Duchenne with RGX-202. Makes sense. Well, thank you both so much for making the time and walking us through DMD and MPS II. I know we didn't get to touch on 314, but we'll stay tuned for updates on all those programs. And thank you both so much for your time. Thank you. Thanks, Ellie.