Hi everyone, I'm Ellie Merle, one of the biotech analysts here at UBS. Very happy to have REGENXBIO here with us as part of the UBS CNS Day. Joining us from REGENXBIO for a fireside chat is Steve Pakola, the Chief Medical Officer. Steve, thank you so much for making time on what I'm sure is a busy morning for you ahead of flying to Dallas for MDA. With that, maybe I'll kick it off. Can you give us a broad overview of REGENXBIO? I know you guys have a lot of different programs in development and also a pretty hefty amount of cash milestones that you could be receiving in the next 12 to 18 months from some of your partners. Maybe just a high-level overview of your programs and then we can jump right in. Sure. First, thanks for having me, Ellie. Glad to participate. Yeah, so REGENXBIO. We're leaders in the gene therapy space, and we have been for over a decade now. This is on the back of our proprietary platform of AAVs, which have become, several of them, the most characterized and evident gold standard, really, as of today in terms of actual clinical data and long-term data in terms of safe and durable gene therapy expression. This has been across a broad range of therapeutic areas and also external partners and out-licensees. Probably the most notable one is Zolgensma for treatment of SMA. We get royalties from that. That has helped our cash position that you referred to. Now, we are a sponsor, and we pivoted some years ago to developing our own products given the innovation that we had in-house. That's led to us now being a company that has three late-stage programs that are on the cusp of potential commercialization. We've made a lot of advances, and we have a lot of near-medium-term milestones and inflection points for the company based on the late-stage status. The, I guess, nearest term that we're very proud of is our RGX-121 program for treatment of MPS II, Hunter syndrome. Just last week, we announced submission of our company's first-ever BLA, where we completed the rolling submission. This is a program that is on track to potentially have approval late this year. This is a program we also recently announced a global partnership with Nippon Shinyaku. Really exciting advance for the company. We also have a program, Duchenne Muscular Dystrophy treatment with experimental therapy RGX-202. This program is currently in pivotal development for potential accelerated approval based on an established biomarker that's considered reasonably likely to predict clinical benefit. There are a lot of differentiating aspects of this that I'm sure we can get into. Timeline-wise, enrollment's going very, very well, and we target completion of pivotal enrollment in the second half of this year, which would put us on track to have top-line pivotal results early next year and advancement to potential approval in the second half of 2026. Rounding out these three programs, we have RGX-202 in our ophthalmology retina franchise, which is in global pivotal development via subretinal delivery for treatment of wet AMD. We also have a phase two program that's moving into pivotal using in-office suprachoroidal delivery for treatment of diabetic retinopathy, which is a massive, almost completely untapped market potential. Here we have another global partner for our overall 314 franchise, and that's AbbVie. We struck that deal a few years ago, and that's allowed us to go global and really have the validation of such a recognized entity that obviously has a global expertise and also expertise in retina. We have not only the validation, but the oomph as we advance in late-stage development. As you said, a lot going on. Glad to talk about any of it. All right. Great. Maybe just starting with the MD since we're getting data Wednesday morning. Yeah, what are we getting at MDA in terms of age, number of patients? Sure. Stage again here is we're in pivotal, but we have the ability from our phase two trial to continue to put out more and more data on more patients and also critically more long-term results and show durability. We previously, in November, had our first results presented on this program where we have seen exactly what we want to see. I'll first say a little about the phase one two program. We're enrolling or we enrolled in this study patients four to eleven with Duchenne ambulatory population. The goal was dose ranging to pick an optimal dose for pivotal and also, of course, show evidence of some effect both on the biomarker microdystrophin in the muscle, the standard biomarker endpoint, and also some other biomarkers. Obviously, to show potential benefit in terms of function via the standard functional measures that I can highlight. Already, we've shown positive results in November where at dose level one, we enrolled three patients. In dose level two, we'd enrolled a handful of patients as of then where we had clinical data. We saw very robust and consistent microdystrophin expression levels as high as others have seen. I think the consistency was very striking. I think what has garnered the most interest from the community and really is differentiating when we look at the clinical results is that we saw robust microdystrophin expression even in the older age range, that is, patients eight and older. This is something that no one else has reported or been able to demonstrate. That includes both approved gene therapy and experimental gene therapy. This is a major advance for the field, actually, because there's always been the theoretical belief that the older the muscle gets, the more damaged it gets, the more fibrotic it gets. The muscle fibers are basically not healthy enough to get transduction and really pump out the protein, so to speak. We also see, in part because of this, the lower microdystrophin expression levels that other programs have seen, and also the lack of translation of those programs, gene therapy, into any kind of clear functional benefit on the traditional measures. That's why it's also important that in the phase I/II data, we're seeing these microdystrophin levels translate into benefit in terms of the time function tests. Things like time to stand, 10-meter walk, run, time to climb, and also the traditional NSAA measure, the North Star. Traditionally, the North Star has been a little pooh-poohed recently because of the crudeness of it and the lack of sensitivity that has perhaps in part led to less than stellar results and some modest results in some other programs in gene therapy. We are seeing very good results across the board when we compare our results to external matched controls that carefully match based on age and baseline function, where you get to see, you know, how would these boys do if they were not getting treatment? In each of the children, we are seeing clearly patients are doing better than what you would anticipate based on their age and their function. The community is excited, of course, early days, you want to see more patients and you want to see longer follow-up. That is why we're very excited about this half of the year and this coming Wednesday morning at MDA where one of our investigators, Dr. Carolina Tetsurosha, is going to be presenting an update on the microdystrophin biomarker results where we're going to have a couple more patients that she can report on. Importantly, one of those patients is in the one to three age group. This is an age group where there's no approved gene therapies available in the U.S. We are seeking a broad label, one and above age, ambulatory boys. That is actually what we're including in our pivotal study. It is a good early read to see how we're doing on expression in that younger age group. We're excited about that, but we're also excited about later this half of the year coming out with functional data. That's going to include a couple of things: longer-term follow-up on the patients that we've already reported on. For dose level one, we reported in the past on 12-month data functional. We'll have the opportunity to report out to 18 months on some of those boys. In dose level two, we reported on nine-month data and we'll have the chance to report on 12-month data for those boys. Also, some more patients who've reached the nine-month time point at dose level two to provide some data there. Nice trifecta of additional functional data we look forward to reporting on. All right. right. Great. How should we think about what would be differentiated in terms of the functional data? I mean, we'll look at the NSAA. We'll look at the 10-meter walk. I guess how or 10-meter walk, how should we think about when you compare in the context of what we've seen from Elevidys, what would be differentiating? Sure. I think there's the aspect of comparing by age range. We know with Elevidys from the regulatory submissions and additional reports in the public domain from other data that's come out that we know the efficacy has been shown and the approvals are based on that four to seven age range. Even within that age range, there's that aspect in terms of functional benefit where it's clearer in the lower end of the four to seven, and there's a paucity of data in terms of what would happen at eight and above. I think there's probably the clearest place to look to see, is there some differentiation on the fact that we have differentiation in our in theory and what we've shown preclinically, the inclusion of the C-terminal domain is one of the clear differentiators. Are we seeing that translate in the clinic? I think those tougher-to-treat patients in terms of not only microdystrophin expression, but also showing functional data, a clear place to look is that eight and above population. That's where we've already seen the nice functional data that I'd mentioned. I think there's looking to see, can we show consistency there in that older age group with more patients being shown and with consistency over time when we look at not just nine months, but 12 months and eventually 18 months. I think that's one aspect as well as just the overall consistency that we see across both those levels and across biomarkers that we look at. Mentioning biomarkers and not just microdystrophin we're looking at, we're also looking at VCN or vector genome copies per nucleus, which is important because the more vectors you have, the more protection you have from any potential loss of effect over time. Because of the greater number of vectors, there's more room for dilution effect while keeping enough transduction and expression and also percent positive fibers. One biomarker advance we've seen that's a differentiator is we're seeing much higher genome copies per nucleus. In the four to seven age range at dose level two, we're seeing 50; we saw over 50% in the patient that we reported in dose level two, sorry, 50 genome copies per nucleus in that age range. Even in the older boys, we're seeing on average 18 genome copies per nucleus. These are quite impressive values. Excited about microdystrophin expression and also other biomarkers. Importantly, that's translating into the functional benefit. Absolutely. I guess an interesting aspect of your protocol is you're using eculizumab, a complement inhibitor, as part of the pretreatment. I guess what prompted this? Was there sort of any concern on AEs that sort of pushed you to include that as a component, or is it just a precaution? I guess, have you seen preclinically that complement inhibition could help vector transduction into the target cells since you mentioned sort of having that high rate? Sure. We're proud as a company to have taken the path of proactively prophylacting to really decrease any risks of complement activation in the clinical setting. What prompted that? There certainly was nothing in our preclinical package or anything about our vector AAV8. It was really what's been seen in the field where with some other vectors, there's clearly been shown to be complement activation and some of this leading to pretty dire responses and bad sequelae, such as thrombotic microangiopathy as really the most common downstream sequelae that's been seen. Our view was, why take any risk on this, especially in a first-in-human study? Even over the long haul, our view from talking to patient advocacy, patient families, investigators, thought leaders was the risk-benefit was quite clear in favor of adding this. I think that's because it's really not a nuisance for investigators and investigational sites and patients because it's really a matter of weeks, not months we're talking about. In fact, just roughly two weeks where you start a few days before dosing to really dampen down any baseline complement activity, and then you continue for about a week after, which is the highest period of risk for complement activation. Then you're off it, and you feel comfortable and less concerned about this potential risk that's clearly been seen with AAVs in general. There's probably some component of this that's a class effect. The feedback we've gotten from the investigators is very positive that it's not an issue A and B. Even psychologically, they feel much more comfortable with this approach. Interesting. That makes sense. I'll add, because of it, at least in part, it's a little conjecture how much is the immune suppression, transient immune suppression, and other optimizations we have like higher purity, but we're not seeing complement activation. In fact, we're not seeing SAEs or any AEs of special interest, not even LFT elevations, which a high proportion of patients have with approved gene therapy. That's further support for the complement inhibition approach. Yeah, that makes sense. On the topic of your regulatory conversations, I mean, we get a lot of investor questions about this. I know there's some debate around what amount of data would be needed to get an approval in light of Elevidys already being on the market. I guess, how confident are you in being able to receive accelerated approval based on microdystrophin alone? I guess, what do you think that you need to show from a functional perspective in this sort of single-arm pivotal trial for the FDA to be comfortable with using microdystrophin as a surrogate? Sure. Yeah, we get that question a lot as well. We feel it's, frankly, pretty straightforward because the proof is in the pudding with your actual discussions with the FDA. There's not conjecture as far as actual discussions that we've had at the review division. There's really a broad discussion that we've had end-of-phase two meeting, after which we finalized our protocol, which really only involves some tweaks. Certainly, nothing on this major issue of, is accelerated approval open to us and exactly how to show that. Consistent with that, after submitting the final protocol, after the end-of-phase two meeting, there continue to be no significant issues in terms of the stability to move forward with accelerated approval. The aspect that I think is key is even with an approved treatment via gene therapy with this approach is differentiation. That is where things like our C-terminal domain inclusion and the functional elements there, which is the most close to natural dystrophin of any of the gene therapies out there, either approved or being experimentally tested, and also state-of-the-art production, which has allowed us to have the highest purity with the highest full-to-empty capsid ratio. This opens up the door to being able to show some differentiation-like things in the older age group. There is also the reality that there is nothing available gene therapy-wise in that one to three age range. That is a particularly low bar for the accelerated approval pathway. I'll say one additional practical real-world reality is existing gene therapy, it's just not going to be able to address how many boys are out there that need this treatment, need some form of gene therapy that families are clamoring for. I think there's multiple layers where we went in being confident of accelerated approval and where we basically had confirmation of that. Nothing's changed since that end-of-phase two meeting. The other potential differentiator is safety, including with our overall regimen with immune suppression, where I've mentioned one clear differentiator that we can actually show, I think even statistically in the long haul, is our liver safety, seeing no LFT elevations when existing therapy, I think it's upwards of 40%, have some level of LFT elevation, some of those quite striking. That's sort of a precursor or a suggestion of how much immune response is happening that you actually have the sensitivity to look at in these clinical trials. The other aspect, though, is how many patients do you need from a safety standpoint and duration of follow-up. That's where we have buy-in for the approximately 30 patients that we're going to look at. That's the population that we're targeting to complete enrollment in by the second half of this year. Great. Makes sense. Do you have alignment or have you discussed with the FDA who or how the method for the match control group would be? Yeah, we included that in our end-of-phase two package and have that in our protocol. I think it's not surprising that we need some type of external match control. I think a big outcome of the end-of-phase two meeting was no need for an actual placebo control. We never wanted to go that way, even ethically. We just didn't feel that was appropriate to have boys and families endure any kind of long stretch that you would need for that. First and foremost, we have the buy-in for that, but we also had the buy-in based on an approach. Right now, we're looking at individual patient matched controls where we control based on age, but also function, use of all of the time function tests. We use the same basic approach with the propensity matching analysis. That's more or less akin to what was used for Elevidys. We won't reinvent the wheel in terms of that. That also allows for some comparisons, although cross-study comparisons, there's always that usual caveat. We've been very explicit on that approach in our end-of-phase two meeting because we didn't want to just get buy-in on no placebo control and the basic approach of external matching, but actually agreement on how we would do that. Understood. Quickly on MPS II, I guess, how should we think about sort of the opportunity from a is there maybe a group of patients at centers waiting for therapy, or could it take time to, say, identify the appropriate patients? I know that you've done the licensing deal in the U.S. and Asia. I guess we'll see what your plans are in Europe. Just in thinking about the opportunity, sort of how centralized or not is the treatment? Yeah, here we have the benefit of the fact that the vast majority of patients are on current standard of care, which is enzyme replacement, which unfortunately requires weekly dosing, which is quite a burden for the boys and the family, where you have to take a whole week to be thinking of the next time you're going to have to come into the clinic, and that's a whole day, and the stresses of being in the clinic for the child. The other downside of current existing ERT is it doesn't address the CNS complications and the inevitable neurocognitive decline. There is a clear value to be added here in both those fronts in terms of a one-time therapy that can address the CNS manifestations. Practically, to your specific question, there's the reality that these patients are known. They're in the system. So are they lined up? They're inherently lined up and known to the treating clinicians. The other aspect is we obviously can have access to that through the investigators. We have Nippon Shinyaku there as well, who has experience in rare disease. I think that sets us up quite well to move in and be able to have initial uptick quite impressively. The other aspect is newborn screening, where I think as that continues to ramp up, that's going to also help in terms of having children have an opportunity to be treated earlier. We have actual clinical results down to the lower end of our inclusion criteria, six months. I think that also opens up the opportunity of not only existing patients and families in the system, but also newborn screening identified patients. Great. With one minute left, I just want to quickly touch on 314. I mean, I know you have the phase three reading out with the subretinal next year. Also, you could be getting $500 million in milestones from AbbVie just from dosing in the pivotals in DR and wet AMD. I know you've said that you expect the initial dosing in DR to be later this year. How should we think about the likelihood that you'll move forward into pivotal with suprachoroidal and wet AMD? Yeah, we're still in the dose ranging side of wet AMD, where we're currently looking at dose level 4, whereas dose level 3 from our dose ranging is where we'd already seen not only proof of concept, but hitting our target product profile in DR, where we had an 89% reduction in treatment burden risk. That is 89% reduction in vision-threatening complications, the ultimate goal there. That's why we in AbbVie are so excited to move forward with planning for pivotal for diabetic retinopathy. Wet AMD and DME are indications where it's known that there's a higher VEGF drive in patients once they reach those symptomatic stages. It's not surprising you may need a higher dose. That's why we in AbbVie decided to go higher with a fourth dose. We have enrollment ongoing in both evaluation of DME in the ALTITUDE study and wet AMD in the ABBV-RGX-314 study with DL4. We look forward to having more data as we move towards completing those cohorts. That will take a little time. DR is such a massive opportunity where it is really only a one-time in-office treatment that has the opportunity to address that massive market. That is the near-term one, but we will continue to see if we can move to in-office suprachoroidal with wet AMD at this higher dose. All right. right. Great. Steve, thank you so much for joining us today and, yeah, sharing all the color on your ongoing programs. Always a pleasure to talk, Ellie. Thank you.