REGENXBIO, Inc. Aktie

Good morning, everyone. Welcome to day 3 of the Morgan Stanley Global Healthcare Conference. We're very excited to kick off with the REGENX team. We have Curran, Mitch and Steve with us.

Just before we get started, I'm going to read a quick disclosure. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures.

With that, I'm Judah Frommer, one of the SMID biotech analysts. Like I said, we have REGENX, and it's been an eventful year for REGENX. The coming 12 months will certainly be exciting, but maybe before we dive into the program, maybe give the audience a quick intro to the company, your gene therapy platform for those who may be a bit less familiar.

We've been in AAV gene therapy for 15 plus years at this point. Our base technology is based on AAV8 and AAV9 as the capsids that we've put into clinical studies over time. And I think in the first few years, mainly did a lot of out-licensing of the technology, and that's one of the programs that came from that was Zolgensma, so long lineage of success in scaling these technologies up.

About 12 years ago, we decided to internalize programs and develop our own, and now we sit here today with a retina franchise that's got a significant partner with AbbVie and some late-stage data coming soon. And then the rare disease side, which I think our primary asset is the Duchenne program, RGX-202, alongside the Hunter program as well. So a lot going on, and I feel like we're just at the last edge of late-stage development, hopefully heading into commercialization next year.

Okay. Great. So maybe let's start with 202, the gene therapy for DMD. You're currently working on a BLA submission, so can you tell us how your gene therapy differs from others that are approved or in development in this space?

Yes, I think there's some significant differences. We went into the program several years back with the idea of a different differentiated product. I think the primary, from a molecule standpoint, it's the addition of the C-terminus to the microdystrophin. And the C-terminus all the way back to ELEVIDYS's AdCom, you can see FDA referencing that addition as making microdystrophin more like natural dystrophin.

Our preclinical studies show a differentiation in basically muscle repair because of that C-terminus. And so that was incorporated. I think also two other key elements of it are a very modern manufacturing process. We can make very significant quantities of the product with a future low cost of goods, and most importantly, 80% full capsids, so very high purity as well. And then the last piece that Steve can certainly speak to later is the immune suppression regimen. So that's what allows us to deliver the maximum dose safely and gives patients, we think, the best opportunity for benefit.

Great. And the BLA submission would be for accelerated approval supported by data from AFFINITY DUCHENNE. You reported top line results from that study earlier this year. What did we see on the surrogate endpoint in that study and how consistent was microdystrophin expression across patients?

Yes, I think we're showing a couple of areas of significant differentiation. Certainly in patients that are, I'd say, 7 and older, we're seeing levels of microdystrophin 4 to 5 times greater than what was shown previously on ELEVIDYS. And then I think on the consistency side, 80% of the patients have been measured to have 40% or more microdystrophin as a percentage of normal. And so we feel like the delivery and the methodology we're using is giving people the maximum chance and significant levels of biomarker.

One other aspect of that is very high vector copy numbers. And what do we think that's important for is long-term durability. And, of course, that takes time to adjudicate and see if that manifests in the clinic, but we're really hoping that, that leads to the ability to treat young patients and sustain that benefit longer.

And maybe just remind us of the range of ages that were enrolled in AFFINITY?

Yes, we're enrolling 1 and older. We've dosed patients that were 12 at the time of dosing, so we've got a really broad range. And interestingly, in the recruitment of the pivotal study, a pretty balanced level at each age group, so 1 to 4, 4 to 7, and 7 and older, a nice balance across all three, so we can see -- because there is an age dependency to the manifestation of the disease, we can see the clinical benefit more pronounced in the older children.

Okay. Great. And you reported a statistically significant correlation between microdystrophin expression and changes in NSAA. So, maybe just walk us through that analysis and its significance we can get into the various analyses used such as cTAP?

I'll let Steve cover that.

Sure. Thanks. So as some backdrop, correlation of a surrogate biomarker to an actual benefit or a functional outcome measure is one of the key central tenets that you can think of for accelerated approval. And there's a historical reference point, if you think of ELEVIDYS, where we know from the AdCom, the briefing book, and the discussion that, that was one of the aspects that was an issue for the review team in that, yes, with certain types of cuts, there was some potential correlation, but it was a very weak correlation. And the FDA really called that out actually, in the label that was finally approved, it specifically points out the lack of demonstration of correlation.

So one of our goals, of course, from all of the differentiation that Curran mentioned was to have translation into functional benefit. And then also the stronger benefit you have, the more likely you can actually show that correlation. So we've always had that in our analysis plan right from end of Phase II meeting both, of course, the primary endpoint and the key secondaries, but also a correlation.

So at top line, since that was the top line time point with the N of 9 subjects, we did the correlation analysis with NSAA and, in fact, saw a highly statistically significant correlation. But I think what was particularly telling was how strong that correlation was. The correlation coefficient was about 0.9, which is quite remarkable, I think, for any surrogate. So for us, we feel like we're ticking all the boxes for what you would want to do to go in with a package for accelerated approval.

Okay. Great. And maybe just walk us through the observed correlation utilizing the cTAP predicted values. Could cTAP provide support from a regulatory perspective, or is FDA more focused on external controls with propensity score weighting that seems to be a topic of conversation in this space?

Yes, so our pre-specified from the beginning has been propensity score weighting, consistent with precedent. We have thought that totality of evidence is very important to add more confidence in the robustness of any finding. So, cTAP is also something we look at. And it's actually one of the things we raised with the FDA not to change anything as far as the primary and the key secondary, but really to have an additional way of assessing the actual change from baselines that we see on an NSAA since cTAP is really a recognized way to actually evaluate that.

Okay. Great.

And we've seen, as hoped for, very consistent findings across propensity score weighting and cTAP.

Okay. Perfect. And we've seen safety become a significant overhang for the approved gene therapy, certainly. But maybe just walk us through safety comparison for 202 versus the approved therapy or others, and maybe, you know, we can talk about the immune modulation regimen at the same time?

Sure. So I think a lot of what Curran mentioned was not just differentiation on efficacy, but also safety. And you mentioned that's been a very big overhang in the space, given the unfortunate deaths that have occurred. And one of the historical aspects of those is that there were those severe fatal liver failure cases but those really were presaged by very high liver injury rates, approximately 40%. So from our standpoint, one aspect was, well, let's have higher purity. So much higher purity in terms of full capsid and Curran mentioned the preclinical data where we saw definitely a dose response going from 1E14 to 2E14.

So I think we and really the field have always wanted to get to that optimal dose but you got to be able to do it safely. And we know the community, they have 1 shot at gene therapy for their child. So they wanted to take the best swing at that shot. So for us, safety and being able to get to that optimal dose preclinically, so the higher purity, and also we implemented a proactive immune regimen, which included steroid, sirolimus, and eculizumab. And that's important because we're specifically targeting the key safety issues that exist in the space, so complement activation, and of course, liver injury.

And importantly, we've had that from the very beginning. So all our patients have had that now, over 60 patients between our pivotal and confirmatory. So I think that allows the FDA and the clinical community to really consider that whole data package, not just for efficacy, but for safety. And we're seeing that safety benefit translated in the clinic where we have less than a tenth, literally, of the liver injury rate that's been seen with existing therapy. So that combined with the functional results that we're seeing that Curran mentioned is showing that translation of theoretical preclinical differentiation into the clinic.

Maybe just to follow up on that, maybe a year or two ago, we sensed some hesitation around sirolimus specifically in that modulation regimen. But clearly, there's more comfort with that product today? I mean, maybe just talk about the evolution and maybe how others have adopted a similar regimen?

Yes, so we were ahead of the field in thinking about it this way and wanting to make sure we had the best safety and the best benefit risk. We've seen others follow, so I think that gives a lot of validation both within this therapeutic area and others. And at the beginning, I have to say, centers hadn't done this, so it was an open question. But the nice thing about doing a trial and expanding to 20-plus centers is, you actually get to see how it works. And most importantly, the clinicians and their practice setting and the patient families get to see how it's working.

And what we saw is first patient would be treated at a center, and they'd see there was no issue, and then they'd actually pick up. So we'd see on an individual center a pickup. The other interesting thing is going through this experience, not only is there the potential benefit -- risk-benefit, to having this immune modulation standpoint, but interestingly, the overall feasibility, if you look at the net effect, it actually can be better because, yes, up front you're giving these short-term events. But if you're preventing liver injury and complement mediated activity, without that, you're having patients who need extra blood draws when they have abnormalities that are complement activation, or if they have LFT increases, you've got to see them more frequently, and they're going to have to stay around the center longer. So it's actually a very favorable tradeoff once investigators actually see that balance.

Got it. Okay.

I think one thing on safety as well, when we last showed FDA our data, it was in 2024 in our end of Phase II meeting. We're planning a pre-BLA meeting at the end of this year, and in that case we'll have 63 patients safety. So a much larger data set that will support, we think, a broad perspective on safety and just a much higher end, we're excited about that.

Okay. Great. So maybe just touching on that, so like you said, expecting to submit the BLA early next year, I believe. So how many patients' worth of data does FDA want to see, like you said, 60-ish patients for safety? How many patients might have 12-month functional data for the filing?

Yes, so we have roughly 63 patients on safety. We've got the 30 that were in the pivotal study with biomarker data. And then on function, I'd say roughly half of those patients will be at 12 months assessment, give or take a few. And I think that's the key on the timing is the CMC module is the one that will be ready last, but we can take advantage of that with our clinical data and literally give the most recent data cut as part of the filing. So we think that will enhance the ability for FDA to review that.

Okay, great. And there's been some regulatory surprises and pivots in rare disease under the current administration. So maybe just talk about your level of confidence in the accelerated approval pathway, 202's profile in your FDA interactions. I guess within those, what makes you optimistic about the potential here?

Well, I think just our experience with the Hunter program really shows that we received a CRL earlier this year, suggesting we run a different style trial with an RCT-based study, and then appealed that and ended up being asked to file off the existing data set. So I think that's a very concrete example of a single-arm study being accepted by FDA for review. We see other examples recently as well. So -- and we see direct quotes from Karim Mikhail supporting regulatory flexibility. So I'm super optimistic that we're on the right path, both our data supporting it and the FDA moving towards that. They know that there's a huge unmet need still in Duchenne, and I think that will drive it.

Okay, excellent. And you completed enrollment in the confirmatory study, which should help give the agency a little more comfort. Maybe just remind us the design of that study and when we can see a readout from the confirmatory?

So, importantly, that is a confirmatory study, and it's always been in there in our protocol and what we had in there from the time of the end of Phase II meeting. So really not intended for any kind of statistical assessment at the time of AA since we know longer follow-up and more patients are needed for that. So 30 patients enrolled in open-label approach with the typical functional assessments of NSAA and the 3 main timed function tests with a look at function over time, but with a primary endpoint of 2 years.

Great.

And I think the other aspect is we have greater than 60 for safety, but we do know that if you're going to get those typical safety events, right, gene therapy here, you tend to see it with complement activation in the first month or so and with liver injury in the first several months. So that's really an advantage because with all of our greater than 60 patients, we'll be far enough out to be assessing that even at the time of the AA submission.

I think with an AA approval in 2027, we dosed our last confirmatory study patient in April of this year, so go out 2 years, there won't be a big lag between the two and then I think that will be helpful for the FDA discussions.

Okay, great. And then you're also planning on initiating a placebo-controlled study in the first half of the year intended to support global submission. So has FDA expressed any interest in this kind of study? I figure it will be some time before we see data from that, but could that come into play with the U.S. submission, do you think?

We haven't, I think, therefore, pretty much in any communication with FDA, we've had a mention of an RCT-based study. I think that the difficulty of that in Duchenne is known with product on the market. This is really more targeting EMA and their requirements. I'm sure it will be a consideration as part of the total regulatory plan and a positive one. And we're looking forward to starting the study up. It'll be in recruitment by the time we're sort of at a mid-cycle review. So I think that will help.

Okay, great. And maybe just last one on 202 before moving to retina. But you've guided to a potential U.S. launch, right? With AA, you could be on the market in the back half of '27. So how many patients do you think could be addressable with 202 at that time and maybe just remind us from a manufacturing standpoint, how many doses you could have ready at time of approval?

Yes, I can work backwards. So we can produce 2,500 doses per year in Rockville in our in-house manufacturing capability. We think the prevalent market is actually growing. ELEVIDYS is being dosed below the level of incidence. So I think if you look at the ambulatory population, I've heard estimates in the range of 5,000 patients. A subset of that would be eligible for RGX-202, and I think a very significant subset of them. So we expect to have hundreds of doses available at launch. And we're actually, in fact, already building that inventory now.

Okay, excellent. So maybe just switching to 314, the anti-VEGF gene therapy for retinal diseases. So you have top line data, Phase III data coming in, in the fourth quarter for subretinal 314 and wet AMD. So before we get to that readout, maybe just talk about the opportunity for a gene therapy in VEGF-mediated retinal disease.

You want to speak to that?

Sure, so retina's been a great field to be in over the last couple of decades, lots of advances. Really the majority of those have been with anti-VEGF. And I think the advances show where the unmet need is, which is yes, anti-VEGF works, but if you have to give it a lot in the real world, patients simply aren't getting what they need. And that's why we've seen even with incremental benefits, like going from Lucentis to Eylea, going from Eylea now to Vabysmo and Eylea HD where these are being rewarded with blockbuster status so the retina community and patients are showing how important even a few weeks to a month or two of extension of the durability is.

So right from the beginning for us, you know, if that's a single or a double, a real home run would be a 1-time treatment that can dramatically reduce injection burden and even in a proportion of patients prevent the need for injection. So I think the marketplace is bearing out validating why this is such an opportunity for us and AbbVie, and why they're excited about this space.

We're planning ahead of data later this year, October 20th, a day dedicated to sura-vec. And you won't have to listen only to us. There will be KOLs there that have years of experience with the program that will talk to, where does this sit in the current standard of care? We're super excited. It's been a long road to get here, but we were just out at AbbVie, 1.5 weeks ago talking to their commercial team, and they're getting the tools ready for the launch and beyond. So it's a very exciting time.

Excellent. Maybe just on, you know, the Phase III, just walk us quickly through design of the program and maybe a bit on powering and what are the non-inferiority margins? Are they the same in the U.S. and ex-U.S.?

Sure. So to start, these are -- this is the largest gene therapy program that's ever been executed. So that right off the bat gives us a lot of confidence relative to other programs that are looking to address durability in wet AMD. So we definitely wanted to power these studies very well. And AbbVie, of course, did as well for their interest in a global opportunity. So that allowed us to go with very big studies and also go globally, which was important to AbbVie and I think also the generalizability of the results.

So a lot of de-risking in the design of these studies because there's a long history of treatment of wet AMD and non-inferiority design. So that's exactly the approach that we have. Two pivotal studies, both non-inferiority designs to on-label repeat anti-VEGF in 1 study, Lucentis, and the other Eylea, and Eylea being the global program. So this is non-inferiority on change from baseline and best-corrected visual acuity. The key on that is what non-inferiority margin delta you go with. So in both studies, that's 4.5 letters and that's recognized in the space.

And we've met with EMA previously, so we have general alignment on this. I think they'll also look at 4.0 in the reality. So I think there'll be some sense of the totality and the consistency of the studies. So, I think very de-risked when you think of the size of these studies and the traditional ways of powering the study.

Okay. And maybe just as we get closer to that top line readout, just a sense of kind of what success could look like? Is it being statistically significant on that BCVA? And maybe just remind us how safety is trended in this study. Obviously a big focus in retinal gene therapy, given what we've seen from other programs.

So on the first question, of course, hitting the primary endpoint with statistical significance is key. But that's really only part of the goal and the value proposition. It's to do that even with a reduction in injection burden. And that bar, the minimal bar we find and AbbVie finds in each of our independent assessments with the community and working together on this is you want to see over 50% reduction in injection burden. So that's sort of, frankly, the bar. But our goal, of course, we hope to see greater than that.

One of the benefits we have is that we've done a lot of -- not only do we have these large pivotals, but we've done various studies, even beyond the first in-human study, which in that study, we saw very good durability, but we have other studies like pharmacodynamic bridging study that allowed us to get to the commercial-ready product. We also have bilateral dosing studies, which is one of the benefits of compartmentalized delivery. And in those studies, we see 70% plus reduction. So you can kind of think somewhere in that range as a success plus hitting the primary endpoint.

Okay. And that's then just on safety that we've seen thus far, Adverum comes up less today than it did previously, but what have we seen on the inflammation front?

Yes. And that's one of the -- on top of efficacy, that's one of the other bigger reasons we chose subretinal given the historical issues with non-local administration where you can have off-target potentially very significant safety issues. And we have not seen immune-mediated responses or inflammatory responses. And that's also important because that's in a setting where we don't have to give additional supplemental immune suppression, which in these indications, retina specialists and 80-plus-year-old patients, you don't want to add that burden on where if you're compliant, then you're going to have side effects of the steroids. And if you're not compliant, then you're going to potentially have the inflammatory response in the real world. And we've gone through the pivotal study, of course, approaching all the patients, reaching the final 1-year time point and DSMB independent DMC, as you'd expect, and no issues.

Okay. And maybe just walk us through the commercial aspects of subretinal versus going intravitreally, which some other gene therapies are doing. I guess what has been kind of provider and market response to subretinal as the delivery?

Yes. We think there's a meaningful place. The vitrectomy, the procedure itself, there's 500...

Over 500 surgeons that we've trained on this.

So we've got broad coverage and ability to dose. We own the bulk manufacturing responsibility for the program, and AbbVie is managing the fill-finish aspect of that under their umbrella. So I think we are now just starting up the joint commercial team. We think payer response to this will be very positive. One thing that was really remarkable was the uptake in Europe when we started opening sites there. So I think this is not just the U.S. only, although that's obviously a huge market, but a global opportunity. So we're excited, and I think one thing that will play into commercial viability is data we just released that shows 5-year durability of the program. That's beyond what we might have expected and obviously very welcome..

Got it. Okay. And you mentioned the excitement from your partner. You recently initiated your study in DR, NAAVIGATE, which I believe unlocked a milestone as well. So maybe just talk a bit about the opportunity in diabetic retinopathy relative to wet AMD, and maybe loop in the decision to administer suprachoroidally there?

Yes. So I think in this case, right from the beginning, we knew that patients wouldn't adopt a subretinal approach. They're asymptomatic. And the history with approved products with little uptake is that people don't want monthly injections. So I think it is a perfect fit for gene therapy and our suprachoroidal program advanced a couple of years behind the subretinal program, but the first indication that we've seen proof of concept in was DR. And -- so we were able to get that study up and running. It generated a $100 million milestone, and I would say just early signs on recruitment are extremely robust. There's a lot of patients out there. You may want to talk about just what type of patients we're going after in the treatment.

Yes, so these are moderately severe to severe NPDR patients before they develop the sight-threatening complications of DME or PDR. And that's really the big unmet need for the reasons Curran mentioned, that we know anti-VEGFs work there, and they're even on label, but nobody is -- virtually nobody is signing up for this given the status of the patients at that time. But if you had an in-office one-time treatment for this set of patients, just to give some context, if you look at the severe and PDR patients, they have a 50% chance in a year of advancing here.

So the ophthalmologists and retina specialists can literally show them the picture showing their disease and tell them the risk that they're at. And I think we talked about the competitive advantages in wet AMD. Here it's just wide open, right? Because you really need a one-time injection. People aren't going to sign up for repeat injections.

And in this case, we're showing data out 2.5 coming up on 3 years. So again, good durability in a different compartment of the eye.

Okay, excellent. And I want to make sure we touch on Hunters and 121. So I guess maybe recent feedback from KOLs or elsewhere regarding the MRI findings and what the path forward could look like here?

Yes, this one is quite perplexing in the sense that as part of the clinical hold on 121 and 111, we are doing imaging of all the patients that were treated in the study and some of these patients were treated 6 years ago. So we've been working to find them that some of them live ex-U.S. and that's been a bit of a challenge. We imaged both the brain and the spine, and in the spine we have findings that when we talk to KOLs, they say, "I haven't seen these, but I haven't looked for it." But -- so it's very unusual to have a contrast MRI on the spine of these patients. So we're in the process now of looking at the long-term data that we have in hand, which is pretty limited right now and we need to image all of the patients.

But I think we can see from FDA's communications about the hold that I think they're taking a very logical step towards us, working with us on resolving this. This could turn out to be a natural history and a finding that is common when you image in that manner. That all needs to be figured out. It's probably going to take us 6 to 9 months to get to a point where we have the full data set to evaluate. But I think really importantly, the kids are doing very well. They're asymptomatic. And if you think about the difficulty of that disease and the morbidity that's with it, then I still think that this is something that in a few months, we might have a different answer and a better outlook on moving forward.

Okay, great. And maybe we just round out with -- remind us of cash runway, what's funded with the cash you have on hand, but I think there are also additional sources of potential non-dilutive capital that we could expect, maybe some additional milestones. So maybe if we could just walk through those aspects?

Yes, absolutely. So our cash runway right now will get us to Q4 of 2027, which is very important. It's well past the key catalyst for both 314 as well as 202, and well past the regulatory fronts. As you mentioned, it does not include additional non-dilutive financing. Upon regulatory success and milestones on 314, that will come with additional AbbVie payments for us. That will certainly get us into 2028. So with all that in mind, that's funding all our pre-commercial effort for both 314 as well as 202 as we speak. And once we get into 2028, we could actually have 2 potential commercial products. So commercial revenue will promote -- certainly replenish our balance sheet.

Okay, excellent. With that, we're just about out of time. So thank you very much for the time today, guys.

Thanks for having me.

Yes, thank you.

[Audio Gap] I'm one of Baird's senior biotech analysts. I have with us for the -- my first fireside chat of the session. REGENXBIO is a company that I do cover, a big fan of. They're working on a number of gene therapies. I would say they're more or less like the preeminent gene therapy company out there as far as AAV gene therapy goes. So we're going to walk through the story. They have a number of clinical programs, very late-stage at this point, a couple of potential approvals over the next 2 years, more than a couple. So maybe just to, kind of, get things kicked off, it would be great if you could just, kind of, give us a very high-level overview of what's REGENX? What do you guys do? What's, sort of like, the core competency? And what's the value of, sort of like, your AAV platform?

Yes. Glad to be here, and thanks for the invite. We've been in business for roughly 15 years, working on AAV, primarily AAV8 and AAV9 as the base capsids that we've been innovating on. The company is really divided into 2 different areas. One is the retina programs that we've got Steve here, who is expert in retina that can speak to that. And then the other is the rare disease programs, which is primarily near term, the Duchenne program, which we started a few years back. And then behind that, we have the Hunter program that we're still working on an active BLA. So we have a broad set of indications, broad set of ways to deliver AAV. And probably, I think, the lead on how to deliver safely, which has always been a concern around AAV over the years. I think we've really leveraged all of the institutional knowledge gained over those years and really applied it to our programs.

Great. So maybe we'll start with the Duchenne muscular dystrophy to kick things off. I mean this has been a hot and cold area for the entire time I've been covering, which I think goes back almost 15 years at this point. There's been a number of therapies approved. There's been a number of disappointments in terms of clinical trial data. Talk to us about RGX-202, your DMD gene therapy. When you, kind of, compare and contrast it to the other gene therapy on the market, ELEVIDYS, what do you see as, sort of, the key advantages here? And in terms of the design of the dystrophin itself in terms of the vector and the CT domain and what that could potentially mean in terms of functional benefits?

Yes. I think there are several pillars in the design that differentiate our product. One is the core design of the construct that includes the C-terminus, which is naturally present in full-length dystrophin. It's been incorporated into our microdystrophin. And early on in preclinical studies, we could see it behaving differently and able to affect, actually repair the muscle as opposed to just enabling the muscle to show force. So that's a huge differentiator. I think also the purity level of the product. So we have been working on AAV manufacturing for over 10 years. We're probably the only company to be able to make high-dose AAV at 80% full capsid, which I think is extremely appealing to FDA.

And particular to Duchenne, Steve's team really looked at other, I think, technologies that evolved in transplant, for example, where we used a modified immune suppression regimen to enable us to deliver safely this high-dose AAV and give patients the best possible chance at functional benefit. So early on in the program, we could see right out of the gate that our SAE rates were much lower than the currently approved program. And then over time, as we've accrued additional functional data, we've started to see this really large magnitude of effect from patients versus their baseline levels that really is differentiating on function as well.

And alongside of that, more at the biomarker level, very high levels of microdystrophin, very high vector copy numbers per cell, which we hope will translate to long-term durability of effect as well. So we really -- we love the data that has been created. The top line data, we think, was really compelling. Everyone that we've shown it to, investigators, patient groups, all really are supportive of it. And so our sole focus now is to move that towards the BLA submission and potential approval next year.

Great. So one of the things that we've, sort of, been very impressed about on the dystrophin expression side of things is not just the depth of microdystrophin expression that you're getting, but just the consistency compared to ELEVIDYS. I know in the FDA review, they had slides showing a fairly large percentage of patients are at like very low levels of expression. You guys have shown some interesting data. Can you talk a little bit about how you have presented, sort of, the expression correlation with functional benefit out of the patients they've treated so far?

Yes, absolutely. Maybe I'll let Steve take that one.

Sure. And I think that's one of the numerous differentiators that we see from our data package. And I think one of the key aspects is, just to presage that, is all of those safety benefits are what allow us to get to an optimal dose. And we believe that's key for differentiation, not just on safety but also the efficacy. And it may be where it actually makes sense. And if you only have a modest efficacy benefit, you may not be able to show correlation.

So for us, the consistency of the microdystrophin and also translation of that into consistency on functional benefit has been a key story. And related to that, particularly for accelerated approval, that translating into actual correlation. So that's always been in our statistical analysis plan, and we've actually shown that. So based on looking at NSAA correlation to microdystrophin, we've seen not only a high statistical significant correlation, but what's important is it's a very strong correlation. So if you look at the correlation coefficient, it's roughly 90% or 0.9, I should say. And that's much stronger than what's been seen previously. With some cuts with ELEVIDYS, there's a very small correlation...

The Peter Marks [ study ].

Yes. Peter Marks showed that. And it shows there's an interest in that from a regulatory standpoint, but that wasn't viewed as compelling because of how weak that correlation was. And that's why in the label, it's very clear that -- clearly stated that there's not a correlation. The other thing is we see that consistently across the different ways of looking at NSAA, whether it's propensity score weighting, which is the key primary, but also external control matching or cTAP approach. So that's based on the top line cut that we did -- that we presented earlier this year, and we look forward to having that data with a larger data set as we advance and have the full data set for the pivotal studies.

Great. So we just touched on Peter Marks, but the DMD space has been, like, one of the hot button topics in regulatory overall. We've seen a lot of leadership interventions in DMD reviews over the last 10 years. We have, sort of, new leadership in CBER right now, and you guys are in the process of submitting or planning to submit in the very near term, a BLA for 202. So maybe just walk through us where regulatory discussions are and like what stage you're at in terms of planning for BLA submission and what those next steps are and relative level of confidence in how the regulators are looking at your package?

Yes. And this is where I think the Hunter program is a little bit intertwined with 202 in that we just submitted a BLA for Hunter. And so from an organizational standpoint, we know how to do that again for Duchenne. We have the nonclinical section of the BLA already complete and ready to go. CMC and clinical are going as planned. So we expect to do a Q1 submission. What's a little bit new is we've had back and forth discussions with leadership at FDA. They want to see the data. And so we're very eager to bring the data to them. So we'll do a pre-BLA meeting late this year with FDA to go through it.

And if you think about the last time FDA saw our data was in the end-of-Phase II meeting. We have about 10x that amount of data. We had 5 or 6 patients back then. We have 63 treated now. So this will give us an opportunity to show FDA basically from the most recent data cut, what will be filed in the next quarter. So we're really excited to see that. And I think we see, to your question about new leadership, strong support for accelerated approval and understanding of the unmet need in Duchenne because the prevalent market continues to grow. There's a pretty narrow administration of the approved program -- approved product. And so we see a great fit for our program as we move forward and the urgency for it.

Great. So maybe that's a nice segue into the confirmatory study that you're running, AFFINITY. Can you talk about the design of that study, when you expect data from that study? And to what extent do you believe FDA is going to take confirmatory study into consideration as it begins to come through the BLA?

Yes. I think certainly, the confirmatory study, and I'll let Steve talk a little bit about the design, was actually part of the original protocol that FDA reviewed. So both the pivotal and the subsequent confirmatory study were outlined and the approach was outlined in that protocol. I think importantly, when we finished enrollment of pivotal, we went straight to enrolling the confirmatory. So we've completed enrollment on the confirmatory study. And I think that will be favorably viewed in the review process. I don't know if you want to talk through the design a little bit, Steve?

Sure. So a key aspect is this was from the beginning, always part of the accelerated approval pathway aspect. So as Curran mentioned, I think it's important to note that was always part of the overall protocol that was discussed at the end of Phase II meeting. So we got to incorporate any feedback and proceed with finalization of that protocol submitted in advance with the study. So that's always been in there, the pivotal and the confirmatory. The analysis plans for the primary endpoint and the key secondary endpoints has been consistent throughout. And we've also been consistent with the immune regimen that Curran mentioned throughout our early-stage pivotal and confirmatory.

We wanted to have a broad population. So we have 1-plus years of age in there and also a relatively broad population in terms of mutation status. So we only exclude the 8, 9, 10 deletions and otherwise, it's wide open. So very comprehensive 30 patients and looking at function out to 2 years as a means to confirm the reasonably likely to predict clinical benefit from the pivotal study. We haven't given specific guidance on when we have results from that. And I think it's also important to note that, that's really confirmatory. We've always said with the FDA, we'd provide data from those patients that we would have as far as safety, for example, which is as far out as you'd expect for these patients.

And I think another important point is we started enrolling this right after we finished enrollment of the pivotal, and we completed enrollment very, very quickly. So the benefit of that is we're not just going to have some follow-up for safety. We're going to have follow-up beyond that initial 3 months window when you expect to see safety issues. So we think that's a pretty compelling safety package to come in along with microdystrophin and the functional data that we'll have from the pivotal.

Okay. Great. And then maybe a similar question just for the AFFINITY RISE study, which is, sort of, the confirmatory study that I think the FDA also wants you to do, but is structured for maybe European approval, which so far has required RCTs. Just with the design and...

Yes, sure. And our approach there all along has been for global regulatory purposes since we know for Europe, as you mentioned, that we need a randomized controlled trial. So that's always been part of the plan, and we're happy that we're at a stage where we can advance with that. We've gotten feedback from Europe. So we're confident to proceed with this. So it would be a standard randomized controlled trial. We haven't given a lot of details on this as we make the final touches on the protocol. But I think you can expect it's not going to be dramatically different from the precedent that fortunately is out there for thinking about randomized controlled trials.

And the plan for that will be that it is actively enrolling during the period of review for the accelerated approval. So in sequence as well.

Okay. Great. So maybe we can move on to sura-vec in the not-too-distant future, very soon, we're going to see the first Phase III data for a gene therapy to express VEGF in an ophthalmology indication, wet AMD. So maybe you could just kind of, like, walk through what sura-vec is doing and what, sort of, the goals of the studies that are enrolling with AbbVie are?

Yes. We just had a meeting with AbbVie last week really to plan for top line data, which is they've already got the shell of the PR written, which is exciting. So that will be a joint release. And as people know, hopefully, the studies are significant, 2 large pivotal studies with over 600 patients per study moving forward. So we'll have top line data coming out in Q4. And Steve, maybe you can talk a little bit about what we expect to see with those.

Sure. And not only are they large, these are actually the largest gene therapy trials ever conducted in gene therapy. So this is really a milestone, not just for our company, but really for the whole space. And they're also very comprehensive and global. And this has always been the goal of having AbbVie that we could really take sura-vec globally. And that's really been a benefit for this pivotal program, and it really gives us confidence to the question that you're raising about what we hope to see. So the primary endpoint is derisked in the standpoint that it's a standard approach that's used when you're doing an active control. So it's non-inferiority to on-label anti-VEGF repeat injections that are available, LUCENTIS and EYLEA. And so that's obviously number one, you got to hit your primary endpoint to show similarity to existing therapy.

But the ultimate goal is really to achieve that with a dramatic reduction in injection burden. And in our case, also having a proportion of patients that not only have a reduction, but don't need any anti-VEGF and all the while keeping disease activity at bay. So non-inferiority, but with dramatic reduction. What's the quantification of that? AbbVie and we have always been consistent with this based on a lot of canvassing of retina specialists. So a minimal bar for us is over 50% reduction in injection burden.

Now we hope to get higher than that, and we have confidence in that. You never know until you have the readout. But one of the benefits we have is we've done several studies here beyond the first-in-human study. We did a bioreactor pharmacodynamic study, where we got to see a much higher reduction in anti-VEGF injection. We also did a fellow eye study, which is an important advantage of subretinal and even suprachoroidal delivery that gives you more confidence to inject in the fellow eye. And if you look at the totality of that data, we see more like 70% plus reduction in injection burden. So that really gives us as much confidence as you can hope for, never any guarantees, but that's what gives us and AbbVie confidence going into the pivotal readout.

And so you said that you guys had just had a call to kind of draft up a blank PR. I guess what -- can you give us any guidance in terms of like what the thought is on what will be released in the first PR? Would it just be, like, a simple achieved non-inferiority, didn't achieve non-inferiority? And because I think to your point, right, a lot of us want to kind of understand not just the success of the trial, which may be you may succeed, but not necessarily be something that is commercially super attractive, but, like, you showed 100% reduction in injection burden, that would be very meaningful. So will we see more than sort of the up down on success of the study in the initial PR?

Yes. I think you'll see, obviously, the top line results and the non-inferiority, but key secondary endpoints as well. As we know people are looking for things like supplemental injection levels and disease burden reduction. So I would expect to see that even though, obviously, we're still in draft form. One thing I think really important to point out is we just recently published 5-year data on patients that were treated in some of the early studies. And so one of the key questions around the overall commercial viability is durability of effect, and we're really seeing fantastic 5 years. It was beyond what we might have anticipated in the target product profile.

Great. So that kind of is a segue into my next question, which is, sort of, right, we've seen a little bit of an evolution with injections. We've gone from, sort of, the first day -- early days of Avastin and Lucentis monthly to twice monthly or PRN EYLEA to now EYLEA HD and VABYSMO. How do you kind of -- as you scope together all the data and the hypothesis around sura-vec, how do you make the case to ophthalmologists to, kind of, switch from VABYSMO, which seems to be the market leader in new initiations right now to gene therapy? And is there -- are there different patients? How do you, kind of, think of the bucket of patients? Is it patients who are very uncontrolled regardless of injections? Is that sort of the low-hanging fruit? Or do you think AbbVie and you are, like, just targeting really all of the wet AMD patients out there?

I'll let Steve comment, but I think it's going to be a mix. I think there are patients who, for example, only reside in a certain area half a year and go to Florida for the other half, and therefore, don't get their regular injections. So we've heard anecdotes of those being ideal patients for a gene therapy approach. We definitely, I think, and Steve can speak in more detail, have treated patients with a high disease burden. So I firmly believe that when we see the data, we won't have to say, "Oh, you've got to treat early," or, "You've got to find patients that have a low disease burden to be included in your thought process of who to treat." But maybe you can share some of the anecdotes you've heard from KOLs, Steve?

Yes. And I think your last point is important to accent with some additional color that we hear and we actually see when you look at the data is -- and this goes to our pivotal as well as our prior data, you can't just look at injection burden reduction and visual acuity effect without taking into account how hard to treat are those patients that you let in.

And this is important as you think about pivotal data, including TKIs and other therapies that are reading out where we have the confidence to look at a broader population, not just the so-called easy-to-treat patients based on the data that we've seen. And to your point, and we get this a lot, not surprisingly, and we always have, how do you see this fitting in as incremental benefits occur like EYLEA HD and importantly, VABYSMO? And the way we look at it is those are actually validations of what we're trying to do because these are really incremental benefits initially going from every month injection to every other month being a blockbuster. Now going from every other month to in some patients, not all patients being able to get to every 3 months, 4 months, 6 months.

So if anything, that only supports that the more reduction that you can get, especially if it's a much bigger reduction such as even preventing patients from needing any injection that's really transformative. And that's what we hear from the community that distinction. And they've really voted with their feet in how they've actually adopted advances like VABYSMO. And that is one of the reasons for sure, as Curran mentioned, that we wouldn't just come out with the primary endpoint. We'd also come out with how tough to treat were these patients, and how much of an effect did you have on injection burden?

That's helpful. And then you and AbbVie are also driving forward. You started dosing a patient in Phase IIb in your suprachoroidal administration with -- in diabetic retinopathy. Can you just, kind of, outline the differences in terms of the procedure between wet AMD and DR and why there's differences for those 2 indications?

Sure. So DR is a very different indication other than the ultimate goal is to dampen VEGF activity. And the reason -- one of the key differences is the goal is not to treat the vision-threatening complication like in wet AMD. It's actually to prevent advancement to these blinding complications. And that's really been a significant unmet need. We know that repeat injections actually work, but it's just not really tenable to take a patient who's currently asymptomatic and tell them, "Oh, what I see in your eyes, I can treat with repeat injections to prevent you from needing injections in the future." It's just not really a value proposition that plays.

But if you have an in-office injection procedure like suprachoroidal, that's one time, and you can show the kind of results that we've seen in the ALTITUDE study before AbbVie and we advanced into the Phase IIb NAAVIGATE study, that's a value proposition that makes a lot of sense. And we already have 2.5-year data where we see very consistent strong effect at preventing patients from actually developing vision-threatening complications, 70% reduction. So we picked suprachoroidal because for us, we wanted to preserve the key benefit of subretinal, which is not administering in any cavity where you get spread to all types of ocular tissues. So with suprachoroidal, you get compartmentalized injection into that space with a simple procedure to optimize efficacy and safety by preventing off-target tissue aspects, which has really been a big problem in gene therapy for ocular indications.

Okay. And then in the last few minutes, I'd love you to touch on NAVSUNLI. This is your gene therapy for Hunter syndrome. This has always seemed like the most straightforward type of gene therapy and should just easily be approved, but it's hit some roadblocks there. So can you just, kind of, talk through where we're at right now with the clinical hold that occurred and then trying to get that resolved and then subsequently refiling?

Yes. We're -- we have clarity now on from all the way back to the CRL that was obtained to a Type A meeting that we held subsequent to that, where we had, I thought, very strong support from FDA leadership. Basically, we had to commit to 2-year data for both biomarker and clinical data, neurocog data for the study. And that is, at the time was the basis for resubmission. Alongside of that, we had committed to imaging these patients based on events that occurred on 111, which we think are likely unrelated. And in that imaging, we were imaging not just the brain, but the spine as well.

And we had findings that we discussed with FDA in some of the spine MRIs that we really can't, at this point in time, decipher if these are part of natural history or if these are potentially product related. And it's going to take us I think more time to do the complete imaging on all patients and then also the time course on several of these patients because some of them were treated 3 to 5 years ago and try to definitively outline, is this something that we would have normally seen in natural history. And again, we don't have MRIs with contrast in patients that are untreated. This is a single-arm study. So I think really, we're still planning to proceed with the program. We just need more time to get this evolution of imaging completed, and then we'll make a call on resubmission at that point.

Okay. Great. And then I see you down there. So you had pro forma cash of $313 million last quarter. Just walk us through -- and that you state that you got you to 4Q '27. Help us think through that cash burn up against the combination of milestones, potential PRV sales, and just outline what are the cash needs going to be? And what are, sort of, the levers for non-dilutive capital to come in?

Yes, absolutely. So the cash at hand right now, as you said, will get us into Q4 of 2027. That's very important because the expected PDUFA date for 202 is around that time frame. What's not included in that is, if we do get regulatory approval and submission for 314, that will come with additional milestones. We have not disclosed it. It's not to the same magnitude as the DR milestone, which is the $100 million we received a few months ago. So it's not in the same degree, but that would modestly get us further into possibly even 2028.

I think it was very important to actually get into '28 because we'll have potentially 2 product launches. So commercial revenue will actually get us even further beyond that. So that's not included. Likewise, the PRV, we have not included that into the cash runway at this moment in time. But I know we're flashing red here. But nonetheless, I would say the critical components for the commercial launch is in place as we speak. That was the reason why we did a raise a few months ago when we did because we want to make sure that the ex-U.S. RCT for 202, as an example, will get started. Commercial readiness is starting as we speak. So we'll be well prepared as we get into 2027.

Yes. All right. Well, exciting times ahead. Thanks so much for being here. Always a pleasure. Thanks for everyone in the audience.

3, 2, 1. Welcome everyone to the second quarter of 2026 Regenexx Bio Earnings Conference call. My name is Elaine and I will be your conference operator today. All lines have been placed on mute to prevent any background noise. And after the speaker's remarks, there will be a question and answer session. If you would like to ask a question during this time, simply press star then 1. one on your telephone key. To withdraw your question press star one again. At this time, I'd like to turn the conference over to Patrick Christmas, Chief Legal Officer of Region X-PIO.

Please go ahead.

Good morning and thank you for joining us today. Earlier this morning Regenexx Bio released financial and operating results for the second quarter ended June 30th, 2026. The press release is available on our website at www.regenexxbio.com. Today's conference call will include forward-looking statements regarding our financial outlook in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend, and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties. These risks are described in the risk factors and the management's discussion and analysis sections of Regenexx BIO's annual report on Form 10-K for the full year ended December 31st, 2025, and comparable risk factor sections of Regenexx BIO's quarterly reports on Form 10-Q, which will be on with the Securities and Exchange Commission available on the SEC's website.

Any information we provide on this conference call is provided only as the date of this call, August 6, 2026, and we undertake no obligations to update any forward-looking statements we may make on this call on account of new information, future events, or otherwise. Please be advised that today's call is being recorded and webcast. In addition, any unaudited or pro forma financial information that may be provided as preliminary and does not purport to project financial positions or operating results of the company. Actual results may differ materially. I'll now turn the call to Curran Simpson, President and CEO of Regenexx Bio.

Thank you, Patrick, and good morning, everyone. Thank you for joining us today. The second quarter was another period of positive momentum for Regenexx Bio, achieving key milestones across our late stage pipeline of gene therapies. During the quarter, we announced that we completed enrollment in the confirmatory study for RGX202, reached alignment with FDA on the path to resubmit the BLA for RGX121, and dosed the first patient in the NAVIGATE trial of Cirovec in diabetic retinopathy, achieving a $100 million milestone payment from AbbVie. We have substantially strengthened our financial position through receipt of over $200 million total, inclusive of the ADVI milestone payment and new capital, ending the quarter pro forma with more than $310 million. This extends our runway into Q4 2027, which includes the expected PDUFA date for RGX-202 and brings us closer to our goal of delivering new, needed medicines to patients and generating our first product revenues. Before I turn the call over to Dr.

Steve Bacola, our Chief Medical Officer, and Mitch Chan, our Chief Financial Officer, to provide updates on our clinical and financial progress, respectively, I'd I'd like to highlight a few key program updates. Let's start with RGX202, our wholly owned potential best in class therapy for Duchenne muscular dystrophy. We believe the top-line pivotal data shared in May further establish RGX2 as a differentiated gene therapy candidate. RGX-202 has uniquely demonstrated a large magnitude of effect relative to baseline and strong correlation between microdystrophin expression and functional improvement at one year. This is a comprehensive body of evidence that we believe will support potential accelerated approval. We recently reported that we had fully enrolled and completed dosing in the confirmatory study of RGX202 ahead of schedule. We have enrolled over 60 patients in the pivotal and confirmatory trials to support a robust safety data set in the planned VLA filing.

Momentum for RGX202 remains strong. strengthened cash position enables continued investment in our strategic priorities. including preparing for the U.S. commercial launch of RJX-202. We will soon initiate a randomized placebo-controlled study in Duchenne named Affinity Rise outside the U.S. to support future global regulatory submissions. We also continue to manufacture intended commercial supply at our FDA-inspected, commercial-ready manufacturing facility located in Rockville, Maryland. We remain committed to bringing RGX202 to patients as soon as possible through multiple key milestones, including initiating the XUS-RCT in the first half of 2027 and submitting the first module of the BLA to FDA in Q3 2021. with potential U.S. approval in the second half of 2027. Moving to RGX 121, following our collaborative discussion with FDA in June, we aligned on a path forward, we have since held a productive Type A meeting with the agency in July. During the meeting, the FDA confirmed that our available data is sufficient for review under the accelerated approval pathway. And no additional studies, including an RCT, will be required for BLA resubmission.

The resubmission will include longer-term efficacy and safety data, including participant imaging that we have submitted and continue to compile and analyze as part of our ongoing monitoring requirements. and we are working to resubmit the BLA in Q3. Beyond our rare programs, we continue to make meaningful progress across our retinal franchise through our strategic collaboration with AbbVie. Along with dosing the first patient in the Phase 2b-3 Navigate study for diabetic retinopathy, we and Abby recently presented long-term data in both wet AMD and diabetic retinopathy. These studies highlight the durable safety and efficacy profile that underscores our confidence in the potential commercial success of CERAVEC. With the NAVIGATE study now underway in diabetic retinopathy, near-term focus of the partnership has shifted to the upcoming pivotal readout for CERAVEC in subretinal wet AMD, a milestone that is highly anticipated in the field. We are pleased with the continued momentum across the collaboration and look forward to sharing top-line data from the Atmosphere and Ascent Studies in the fourth quarter. Our focus is clear for the remainder of 2026. execute against our key milestones, and bring hope for transformative gene therapies closer to patients in need.

With that, I'll turn it over to Steve. Thank you, Kern. I'll start with the RGX202 program for the treatment of Duchenne. As the current referenced, we are incredibly excited by the continued momentum we have seen in the Affinity Duchenne clinical program and look forward to initiating BLA submission this quarter. As a reminder, RGX202 is the most advanced clinical stage gene therapy program in Duchenne, And both the pivotal and confirmatory studies enrolled ambulatory patients aged one and older As reported in May, top line results from our pivotal study demonstrated a highly compelling combination of robust microdystrophin expression, encouraging functional improvement, including in older boys, and a favorable safety profile. These positive results, together with the statistically significant strong correlation observed between microdistripan expression and NSAA improvement, will serve as a key component of our upcoming BLA submission. As Curran shared, we are also progressing plans to expand the clinical development of 202 to support future regulatory submissions outside the US through the XUS Affinity Rise study. This global double-mass placebo-controlled randomized trial is designed to enroll approximately 100 patients with a 2-to-1 active-to-placebo randomization.

With enrollment now complete in the confirmatory study, we are excited to initiate this study in the first half of next year. We look forward to sharing more as we progress. Turning now to our retina franchise, we continue to be encouraged by the growing body of evidence supporting Cirevec as a differentiated potential one-time gene therapy for retinal disease. Last month at ASRS, we presented multiple datasets that further reinforced the durability, efficacy, and safety profile of the program across both WET-AMD and DR. In subretinal wet AMD, we reported long-term follow-up data from our Phase 1-2 study. Results demonstrated CERV-EVK maintained or improved visual acuity with a meaningful reduction in treatment burden through five years. These results are even more impressive as they reflect a wet AMD population that faced a high burden of chronic anti-VEGF injections prior to receiving one-time gene therapy.

We're very encouraged by these results as we approach top-line data later this year. In DR, we presented new two and a half year follow up data from the altitude study. These results demonstrated CERVEC maintained durable improvements in disease severity, continued prevention of vision-threatening complications, and a favorable long-term safety profile following a single administration. While chronic anti-VEGF injections are approved for DR, real-world data shows that there is a staggeringly low use due to the high treatment burden. We believe the potential to prevent vision-threatening complications with a one-time in-office administration represents represents an important option for these patients. Finally, this summer, we've had the privilege of joining both the Duchenne and Hunter Syndrome communities at family and advocacy conferences. These families and advocates inspire us and power our mission every day.

Every interaction we have at these events underscore how urgently families are waiting for new treatment options that can can meaningfully change the course of these diseases. We're deeply grateful for the community's partnership, support and enthusiasm for our programs. With that, I'll turn the call over to Mitch to review our financial results. Mitch?.

Thank you, Steve, and good morning, everyone. Regenexx Bell ended the second quarter of 2026 with cash, cash equivalent, and marketable securities of $106 million. Research and development and general administrative expenses are generally consistent with the same period in 2025, reflecting the continued advancement of our late-stage clinical programs and our operational capabilities to support our planned transition to a commercial-stage organization. Subsequent to the quarter, we strengthened our financial position through two important financing events. First, we received the $100 million milestone payment from Abby following our first patient dose in the Phase 2b-3 Navigate study for DR, reflecting the continued progress within our strategic retinal collaboration. In addition, we successfully completed a follow-on public offering of approximately $108 million in net proceeds. We end the quarter pro forma with more than $310 million.

These additional resources support both near and long-term strategic priorities, including advancing commercial readiness activity across our late stage programs, specific near-term investment to prepare for the potential RGX 202 commercial launch in the United States and planned initiation of RGX 202 XCUS RCT study to support future regulatory opportunities outside the United States. Including these proceeds, Regenexx BIOS cash runway is into the fourth quarter of 2027, which enables us to complete multiple milestones including the top line data in wet AMD and expected PDUFA day for RGX202. This cash runway guidance does not include any potential receipt of proceeds associated with additional potential non-dilutive sources of funding, including healthcare royalty agreement, milestone payment associated with our partner programs or any proceeds from the potential sale of RGX 121 PRV. We find ourselves well positioned to leverage these and other funding options as we advance towards multiple product launches. With that, I turn the call back to Curran to provide final thoughts.

Thank you, Mitch. We leave today's call with confidence in our strategy, our execution, and our financial position. With the capital to deliver against multiple catalysts, we remain sharply focused on executing and advancing potentially transformative gene therapies to patients. We believe the next 18 months will be a defining period for Regenexx Bio, and we look forward to sharing our progress.

With that, I'll turn over the call for questions. Operator? Operator 1 Thank you. We will now begin the question and answer session. If you have dialed in and would like to ask a question, please press star 1 on your telephone keypad to raise your hand and enter the queue. If you would like to withdraw your question, simply press star 1 again. We will pause for just a moment to compile the Q&A roster. Your question comes from the line of Judah Frommer from MS. Your line is now open.

Good morning, guys. Congrats on the progress and thanks for taking the questions. Two from us. Maybe first, could you just give us a little more color on enrollment for the affinity confirmatory study, what demand looked like from patients and investigators there? It does seem like that enrolled relatively quickly. And then maybe just feedback from ASRS, kind of general excitement for gene therapy versus alternative modalities that extend treatment, any particular feedback on subretinol and superchoroidal delivery versus intravitreal gene therapies and relative unmet need in wet AMD.

D versus DR for gene therapy. Thanks. And just to clarify, Judah, the Affinity Confirmatory is speaking to Affinity Rise, the new program, or a different one?.

The confirmatory that I believe will, I think it's set up as the phase three portion of Affinity to Duchenne, is that right?.

Okay. Yes. That completed in June. The enrollment that completed in June. Yes. I think when we think forward to the global study that we just announced today, We certainly think enrollment just at 100,000 foot level will be very positive. We enrolled the 30 patients in our confirmatory study post the pivotal. ahead of schedule. I think that's an indicator of overall patient demand. And globally as well, you see significant uptake of gene therapy, XEUS, so I think we feel that.

enrollment in that study is positive. I'll turn it to Steve for thoughts. Sure, so, Kern, you gave the 100,000 foot view. I can sort of give the ground level view. And as you mentioned, Judah, enrollment was really good. And I think the more data we gathered, the more enthusiastic enthusiasm there has been. And as some of the other sites would treat a patient, they would get more excited as well.

So I think a lot of that is obviously the differentiation of 202 that we've talked about in terms of the product itself and the safety profile, as well as the encouraging functional results we're already seeing. So yes, I think that really gives us a lot of momentum going into Affinity Rise. The other question you had was on 314 and ASRS last week, and I think the one word key message. or what was absorbed was durability. So in both wet AMD and DR, we presented longer term follow up. So five year results from wet AMD and two and a half year results from DR. And we're seeing great durability and excellent safety with longer term. follow-up. And, you know, I think to the follow-up or the additional question on that as far as unmet need that we're seeing compared to some of the other nice advances that have happened in the space in terms of durability, One of the nice things with the greater durability is that we're seeing more and more interest on the one-time option.

So big advance or unmet need if you can have that in sustained anti-bed job. And DR, the unmet need and the differentiation is even clearer because in that disease with an asymptomatic nature, you really need a one-time treatment, not repeated injections over time.

Thanks. Your next question comes from Lily and Sun Goh from Learing. Your line is now open.

Hi, good morning and thank you for the update. So maybe just a question regarding the patent portfolio. How should we think about the potential impact of patent expiry on Zogersma royalty stream in the coming years? And also we think about potential revenue stream or royalty rate for IDBESMA compared to Zolgesma? Sure. This is Patrick Christmas. I can start.

As we've announced, our U.S. patent on Zolgensma has expired, but we do have coverage in about 20 countries outside the United States where we'll continue to see revenue and royalties on Zolgensma. In addition, we have coverage on Avisma both in the US and worldwide on that product. I think I think Novartis has announced that they could reach up to $2 billion in sales, and so we expect to see continued significant royalties there as well.

Thank you. Your next question comes from the line of Annabel Samimi from Stifo. Your line is now open.

Hi, thanks for taking my question. A couple here. So for what AMD is you approach data? I know most of these physicians are retinal surgeons and perform vitrectomies, but how many physicians would you say have already been trained on your procedures specifically? And can you remind us how many patients have opted for bilateral treatment? And then secondly on DMD, I guess for the timing of the RCT, I think it's going to be in full swing as you are going through review. So given that you could potentially file in 1H27, I guess suggest that you'll have some of the data and any expectations that FDA is going to wait for the biomarker outcome of that study to to make any decisions on your own program. Thanks. Or we'll require the data. Thank you.

I'll take the second one and then we'll have Steve speak to the first question. I think on the RCT and the timing, the goal here is obviously to have it up and in active enrollment at the time of review. We think that's important in terms of the overall regulatory strategy. I don't think that there would be an expectation. of data being available or, you know, specific data from that study playing onto the data the active review that would be for accelerated approval and i think one of the reasons for that is that We'll have over 60 patients dosed at the time of filing, so our safety database will be pretty extensive from the pivotal study and the confirmatory study that we completed enrollment on. And we also, in terms of the timing, will also have roughly half the patients through 12 months of their functional assessment. So we think we'll have a very strong data package underpinned by the really positive data we show with our top-line release earlier this year. I think one thing that we are seeing, though, that I think is really important to our global study is, I believe, in terms of... obtaining accelerated approval, having a reasonable timeline for completion of a confirmatory study is an element of that. don't think it has to be in proximity to the approval of an AA pathway.

Steve, I'll let you talk through the... Sure. Hi, Annabelle. Thanks for the question. For wet AMD, we've trained quite a lot of surgeons globally now. So over 500 surgeons have actually been trained. And I think this speaks the actual... evidence of what we've been discussing over time, the scalability of this is really straightforward, not surprising given these are retina specialists who are used to doing much more complicated procedures. So we're really excited about that as far as moving forward. We in AbbVie of course, and the bilateral question.

We're seeing great interest. One issue is technically, so to enroll in the bilateral study, you have to meet all of the study requirements. So that already will cut out a certain proportion of patients. And although it's a bilateral disease, exactly when patients will meet the criteria in terms of disease activity will change over time. So given those aspects, we're really encouraging. We hear a lot of anecdotal cases from surgeons of... asking, you know, can they have their fellow eye treated if they are already getting repeated injections in both eyes before they saw whatever response they had in the 314 Cerevec treated eye. So we haven't given any specific numbers on this. We are at the, but.

certainly we're encouraged. Great, thank you. Your next question comes from the line of Brian Scorney from Baird. Your line is now open.

Hey, good morning, guys. Thanks for taking the question. My question is on affinity rise, actually. I was hoping you could go over some more details around the study design. I sort of heard the highlights of it at the beginning of the call. But how long is the placebo-controlled period? And can you just review the primary and key secondary endpoints and the enrollment criteria in terms of the ages of patients, and what ex-US regions do you anticipate enrolling in this study?.

Yes, thanks. Thanks, Brian. So what we've provided that you see in the press release or the high level aspects of the design. So, for ex-US requirements, including Europe, not surprising, placebo-controlled. Importantly, we've chosen a two-to-one randomization with active, so we think that's a nice positive for families. their children as far as odds of getting treatment. As far as the other questions that you asked, we haven't disclosed those in terms of the regions that we're going to go. And also some of the other aspects that you've mentioned, but we certainly look forward to getting into more details about the design as we get closer. to the initiation of the trial in the first half.

Your next question comes from Alex from Bank of America. Your line is now open.

Hey, guys. Thanks for taking my questions. I guess one on MPS II and then one follow-up on Affinity RISE. So, on the resubmission MPS II, I guess, what specific question from the FDA is the longer-term follow-up and imaging answering? Like, do you expect this will meaningfully shift the known clinical profile for one-to-one in this setting? And do you expect this to On affinity rise, I guess, how should we think about crossover from placebo? In the study, I guess, just thinking about the ethics of keeping patients on placebo for a progressive disease like COVID. And just to clarify, will this study enroll any U.S. patients? Thank you.

Sure, I'll take the first question and Steve can walk through the second. On MPS II, If you think about sort of where we started with the program, the initial data provided was six-month data for biomarker. And over the course of the ongoing review, we've now expanded that to two-year biomarker data and two-year neurocog data as we've updated the filing. So what was requested in the Type A was really just a consolidation of that and the safety requirements. update that would go along with that in terms of extending out the time. So I think the really positive, if you focus back to the CRL, there were a couple of components of the CRL that was issued in February that that were really challenging to overcome, which were really the trial design and the inclusion of a control arm. The Type A meeting, we feel, reset that to a more now basically an ongoing review of the data that we've provided. So we were not asked to provide additional patient. patients being dosed or additional patient data beyond the two-year horizon.

So now I believe we'll see something closer to, you know, an evaluation of the benefit-risk at that point, with all of that data consolidated into one data. one resubmission. I'll let Steve talk through Affinity Rise.

Yes, Alex, great question in terms of crossover. One aspect is even how we want to get access for these patients in need and certainly patients who commit to getting into a clinical trial. That's one of the reasons we wanted the two-to-one randomization. But that still leaves the other third of patients that you're referring to. So, you know, I think it's reasonable. to expect that we would give those boys a chance in a crossover, and then we also get to learn more with more exposures in the trial.

Your next question comes from Luca Eze from RBC Capital Markets. Your line is now open.

Oh, great. Hi, team. This is Shelby on for Luca, and thanks for taking our question. Maybe on DMD, I believe you said the BLA will include a combined safety data set for over 60 patients and then 12-month functional data for at least half of the pivotal cohort. So, can you quantify how many patients will have that 12-month functional data at the time of BLA initiation this quarter versus that completion in the first quarter of 27? And does the FDA require kind of a pre-specified minimum for accelerated approval?.

So any color there, much appreciated. Sure. Yes, I can take the last part of the last question there. There's no pre-specified level of functional data that's required for submission. And to your question around the number of patients, if you roll back to our top line data, we presented data for nine patients at 12 months. And so by the time the clinical module is submitted, which is, the critical path is really defined by the CMC module, as we've talked about before. But that does give us the advantage to add additional patients to the clinical clinical module, we're estimating out of the 30 that were treated in the pivotal, uh, portion of the study, roughly half of those would be through 12 months. So, we're not super precise whether it's 14 or 15, and that depends a lot on visits and assessment and QC of the data, but we obviously feel that we want to present the strongest package at that time, and that's one element of this.

Your next question comes from the line of Ellie Merle from Merkleys. Please go ahead.

Hi, this is Joseph for LE and thank you for taking our questions. So for RGX 314, what is your latest perspective on the commercial outlook in the evolving landscape? And in terms of launch preparation, could you characterize your site qualification efforts so far and provide any color on commercial sites you plan to qualify initially. Thank you. I'm sorry, just to clarify, that's for subretinal wet AMD?.

That's correct. Okay. Yes, I think one aspect, just to step back a bit, is ultimately on the commercialization effort for subretinol, Abby will have the primary leadership in that role. It will not be surprising that many of our clinical sites, which, Steve, correct me if I'm wrong, were well above 100 sites used for enrollment in the US, would be, some of those sites would be obvious for also commercialization of the product. We're just starting now joint development of the commercial plan with AbbVie, given that we expect a 12-month review cycle subretinal BLA filing. So that work is just beginning now. It's a bit early to be specific about it, but we have no doubt that the strength of AbbVie's commercial team and their familiarity now with the program over the last three and a half years will get a running start on commercialization. the prospects of the product, we look at WET-AMD and we look forward to a launch date in which which the wet AMD market could be in the range of $10 billion. And I think historically, we've seen think subretinal has a meaningful place in that market. And as Steve mentioned with treatment of the fallow eye, that raises the potential commercial prospects even further.

So I would suggest that whenever we speak to doctors who are very experienced with this program. They can easily identify out of 10 patients, two or three that are obvious candidates for the subretinal administration because of various factors, availability for monthly injections, disease burden, et cetera. So again, we feel like there's a very meaningful market here.

potentially one of the largest opportunities in gene therapy. Your next question comes from Sean McCutcheon from Raymond James. Your line is now open.

Hi, guys. Thanks for the question. And speaking to the wet AMD readouts in the fourth quarter, can you speak to the expected non-inferiority margin and atmosphere and descent? Would you anticipate it to be significantly narrower than the standard four and a half letters due to the partially masked nature of the studies? And any commentary on the powering of the study plan would be helpful. Thanks.

Great. I'll defer that one to Steve. Sure. So, Sean, you named the non-inferiority margin 4.5 letters, and that has been standard in recent history, and the FDA has reiterated that. We've never had that challenge by the FDA based on the design and that masking approach has been in there throughout the study. Working with AbbVie, we have very large sample sizes. These are the largest gene therapy programs ever executed. We have 90% power in these studies.

Your next question comes from the line of Paul Choi from Goldman Sachs.

Go ahead. Hi. Good morning, and thanks for taking our questions, and congrats on all the progress. I have two questions, first on 202. you update us on what the potential cadence of additional data updates might be as you proceed to your BLA filing and just what additional longer-term updates you plan to provide from the pivotal portion there? And my second question is on 121. And with the recent approval and launch of Denali's Avaya. Can you maybe just update us on, you know, what you're hearing in the field in terms of receptivity to new therapies here for hunters and how, you know, the market might potentially be primed for your and your partner's launch in the future? Thank you.

Yes, I'll comment first on the 121 question. And I don't have any specific information regarding Denali's launch progress, but I think from our frequent interactions with the patient advocacy groups, we see a very high level of of interest in their program. I think it's well over 20 years before a new therapy has been available to patients and so I think I think there's excitement. And I think thinking about RGX 121, uh, But our goal is to provide potential options for patients to choose their therapy beyond what's already available. So I do think indications of strong uptake, which I think is positive for the field, and and indications that patients still want choices in the therapy that they choose. And I think the obvious benefit of gene therapy, in this case being the one-time treatment potential. In terms of additional data updates on 202, we haven't disclosed any specific updates and probably won't until the BLA filing is complete in Q1 of next year.

I think around that time, once the data has been submitted, we'll obviously consider an update at that point. But in the meantime, right now we don't have a specific update planned other than certainly notifying the field and the market regarding submission of the modules and timing around that to confirm. that we're on track. Okay, great. Thank you.

Thanks. Your next question comes from the line of Yi-Chet from H.C. Winwright. Your line is now open.

Hey, good morning. This is Katie on for you. Just a couple quick clarification questions. For atmosphere and ascent, it looks like you're looking for top line in the fourth quarter of this year. Will you disclose both trials together with the full non-inferiority margin and injection burden data or is that something that's mostly AbbVie's call? And is there a milestone tied to the top line versus the 2027 submissions? Yes, I can cover that.

The studies will be disclosed together. They're pretty much right on top of each other in terms of timing. We haven't given specific guidance regarding the data that will be disclosed at that point. That is a joint... effort between Abby and ourselves regarding the ultimate release of But certainly, you would expect to see primary endpoint disclosure for both studies. And we'll be more specific as we get closer around secondaries as well. There is not a milestone associated with top line data, but there are milestones that we haven't disclosed the specific amounts around. for BLA acceptance and then BLA approval. And those are elements that Mitch mentioned in his update, you know, additional non-dilutive financing options that can move forward. our cash runway even further out.

Great. Thank you, guys.

Ladies and gentlemen, that concludes our Q&A session and today's call. Thank you all for joining Human Now Disconnect.

This live transcript is auto-generated without human intervention or review.

[Call has ended.]

Let's maybe go back to last week. Again, data was a landmark as you described it. However, there's a lot of debate among the investment community around kind of regulatory and why waiting. You guys have been pretty clear that you'd like to wait to submit that data set until the new leadership team at the FDA is in place. However, there's maybe a counterargument to be made that like kind of control the control of world in life, and that's something you can't control.

So like just maybe walk us through what are the primary advantages of actually waiting to submit this data set?

Yes. I actually would probably want to clarify, the waiting aspect of that is further discussions with FDA. So what we're looking to do is see FDA stabilize in terms of new leadership, additional changes last week, as everybody saw. And I think we look at all the changes as really, really positive in the sense of -- particularly in rare disease where the patient advocacy groups and patients are in great need for alternative therapies to come to market. So as it relates to the Duchenne data, we think the top line data checks every box that you need for accelerated approval. Our plan is to begin initiate filing the BLA in Q3 this year, and that rolling BLA process will complete in Q1 of '27. So that gives us plenty of time in '27 to secure an approval. So I think that part got co-mingled with when would we meet with FDA leadership. We obviously want things to settle down there, let the new leaders in FDA get assimilated into the organization and then get their support for what we're trying to achieve.

Got you. Got you. That's helpful. I'll probably -- bouncing back a little bit between the data and the regulatory piece. I think there was some confusion last week around -- you show expression for 30 patients or so, but then you saw the functional data only for 9 patients. Is that simply a function of timing, meaning the patient -- because if I recall it correctly, expression was an earlier time point versus the functional data, I think it was, I think, 12 weeks versus 52 weeks. So is the fact that we haven't seen the remainder of the functional data just simply a function of timing because those patients have yet to reach that landmark? Or is that more complex than that?

Absolutely. So we, in real time, continue to get patients through their 12-month assessment. So what you saw in the data set was safety on all 30 patients, or 31 actually in the study. You saw microdystrophin levels for all of those patients. And then the functional assessments, keep in mind, we finished enrollment late October, early November of last year. Those patients' 12-month data point won't occur until later this year. And so as we also -- as time goes on and as we initiate our BLA filing process, the 9 patients that we saw in our top line data release will grow to maybe double that over time.

And are you committed to continue to show that data as they accrue in terms of function? I mean there was a very -- was a fantastic correlation between function and expression. Are you committed to ultimately show kind of the same data set with all 30 patients? Or is it a little too early to comment on that?

I mean, over time, we will certainly show that. There's no commitment, if you think about from a protocol perspective, there was no prespecified number of patients that had to be correlated to microdystrophin level. So that's flexible. But we think the strength of the data, the p-value of -- associated with the microdystrophin result and then the correlation of function to microdystrophin, those are very, very strong tenets of the accelerated approval approach. Keep in mind, for ELEVIDYS, correlation of microdystrophin to functional outcomes was nowhere near as strong as what we're seeing. And I think that was an element of the review process that concerned the review team. We feel this data will be convincing of the role of the surrogate biomarker.

Got you. Got you. That's helpful. Maybe just sticking to the data, let's comment quickly around safety, the broader field of DMD gene therapy has had some tragedies and setbacks. Can you just maybe comment on your safety? I know you have a differentiated approach in terms of your prophylactic regimens and whatnot. However, last week, I think we saw, for the very first time, TWO SAEs. Like how should we think about all that?

Yes. I think we were pretty detailed about the TWO SAEs out of the 30 patients that we've treated. And in both cases, one was liver injury and the other was myocarditis. Those were resolved without sequelae, so fairly easily managed. And I think if you think about contextualizing those results, you can compare them to the what's on label for ELEVIDYS. We're about 1/10 of that liver injury level. And this is a result we think of both the construct, the purity of the product, and the IS regimen that we're using. The other, I think, contextualization is the levels of SAEs that we've seen in the end of 30 is below what has been seen historically on Zolgensma. And I think that is an important comparative to think about as we think about safety and the benefit to risk ratio that we feel is very positive for our product.

I'm glad you brought up Zolgensma. I'm not sure if that was a [ compliment ], I fully appreciate it. Maybe bouncing back again to regulatory. It feels to me that there is a little bit of hesitation in kind of fully committed to a confirmatory trial that is placebo-controlled randomized. And I appreciate that running that trial will come with a meaningful number of operational challenges and there's some ethical considerations and whatnot. But wouldn't like being more forthcoming about that going to give you more leverage with the FDA, meaning you go to the FDA and say, I'm going to get approved on accelerated approval, but at the same time, I'm fully committed to get to the bottom of this. So I will run a randomized clinical trial to actually show that there's a tangible benefit to make for these patients. Like how should we think about like not being so forthcoming about a randomized clinical trial for confirmatory?

I think there's probably two answers to that. One is that -- number one, we're very comfortable with the magnitude of effect that we're seeing in our current study. And keep in mind, we also have a confirmatory study running behind it that's almost fully enrolled at this point. So that will be an end of 60 patients data worth. And as these patients move out to 2 years, it will be impossible for an 8-year-old to continue showing the functional benefit relative to natural history. And so we think we have a very clear and significant magnitude of effect that supports the AA approach. Second part answer, though, is all the way back to JPMorgan, we disclosed that we plan to run an ex-U.S. study, which will be an RCT-based design. And so we will have that in place at the time of review. We've already gotten feedback from EMEA on the design of the study. And so we do plan to move forward with that. So it's not an either/or. We're doing actually all of these. And should -- I think it's speculative, but should having that study in place help with an accelerated approval pathway, we'll be in a good position to support that.

Got you. Got you. That's helpful. And again, we already kind of talked about this, but I think in the press release last week at some point, there was a language around FDA has recommended a randomized controlled trial. Was that in the context of accelerated approval or is that in the context of the confirmatory trial?

I think the context isn't fully known. I think that is a statement you'll see just about on any response in a discussion around trial design. And even in the Duchenne trial design guidance, you'll see a recommendation for an RCT-based study. Having said that, within that same guidance, there's an allowance for an accelerated approval pathway. So both are valid. We have had good discussions with the review teams about the nature of our study and what we would need to bring to a BLA to support accelerated approval. And I think we -- when we look at the data now that we have in hand, I keep saying the same thing. It checks all the boxes in terms of the magnitude of effect overcoming any potential bias associated with an external control strategy, NSAA values that are 4.5x or 4.5 NSAA units better than control or baseline. Those are levels well beyond the variation in natural history that you could see.

And keep in mind, the controls that we're using are based on data from hundreds of patients, not one or two, but databases that we've been able to access for modern studies that are up to the current standard of care. So I feel like that -- and FDA in that same meeting indicated a willingness to look at the data in the guides of how accelerated approval review should be done. So we feel confident we're in good shape. But again, we're trying to cover all bases. I think we always have to keep in mind, number one, the unmet need is huge. The prevalent market is growing in Duchenne. And if everyone is required to do an RCT-based study, there will not be a new gene therapy approved based on what I see in development until 2030. And I think that's completely untenable.

And I think the data that we have would be supportive to meet that unmet need. And I know from a lot of discussions in the last 2 weeks with patient advocacy groups, they're going to be pushing very hard on regulatory agencies to make these therapies available, not just ours, but in general. So I think that's an important aspect of this. Speed counts and time is muscle, is what we hear from the patients.

Time is muscle is pretty powerful. Maybe just quickly on -- I think you already touched upon it, I want to kind of double-click on it. You showed some very impressive functional benefit last week, and I appreciate there's a large natural history cohort at this point, which is not something we have in every rare disease that is available out there, I guess. But can you speak about whether any of those benefits were not only compared to natural history, but also just compared to baseline? Or like any of these endpoints, any of those kids actually getting functionally better than baseline? Just maybe talk a little bit about that part.

We have comparisons to the external control databases that we access. We compare it to incoming baseline characteristics. And then we also use the CTAP model, which is a predictive model, which accesses the same data in some ways. And in all cases, we see benefit. And I do think the surprise for us, especially when treating patients 8 years and older, is going in, stabilization would have been a great outcome that their baseline level of function is maintained. In several of the patients that we've reported, they're actually improving. And I think that's really, really interesting. And I think that -- we think it's a basis of the design of the construct, which includes the C-terminus. So it's a differentiated product. And I think interestingly, FDA has recognized our product as differentiated from ELEVIDYS, for example. And I think that's important, that they'll look at our program as a unique construct in Duchenne that provides this type of benefit. And that goes all the way back to our preclinical data where we saw restoration of function in the mdx mice to wild-type levels.

Got you. That's helpful. Maybe let's talk about the prophy regimen. Obviously, you use different prophy regimens that include steroids, eculizumab, and sirolimus, which is obviously different versus some of your competitor out there. How -- obviously, the data, so far, is in the context of the clinical trial, how practical is to actually use the prophy regimen in the real world, if you will? And maybe if you could comment on the dose of steroids that you use? Like is the fact that using eculizumab and sirolimus allow you to use lower doses of steroids versus your competitor? Or how should we think about all that?

The steroid levels are doubled during the 3 months of IS, where we increase and then we taper down. So by 3 months, the IS regimen is complete. And I think -- what I would say is as we've expanded sites, which was our main goal in the confirmatory study, was to access new sites with new investigators, it was to get a read on exactly what you've asked about, which is how widely will this be accepted. And so now we have tens of investigators instead of single-digit investigator level, giving feedback on our program. And to a tee, I think every one of them is saying this is very manageable. And the reason they like it is the level of post-treatment surveillance is less because you're treating upfront. So we're not sweating over every lab result hoping the patient is doing okay and knowing -- not knowing if they can intervene in time. In our case, by intervening ahead of time, the lab values stay stable, and they don't have to worry as much about patients post treatment. So I think in general, we don't see any obstacles to this in a commercial setting.

Got you. Got you. Maybe last one on DMD before I pivot. Maybe what's your view on kind of the competitive landscape? Obviously, Sarepta has had some setbacks, but there's still a commercial product available out there. There's solid also in the mix here that has, obviously, construct that has a different -- there's different molecular biology, if you will, behind it. They have the C-terminus domain versus they have the nitric oxide domain and whatnot. What's your view on the broader field? And maybe just kind of remind us differentiation for your product versus some of the others.

Yes. I think if we look at where we are roughly 2-plus years post launch of ELEVIDYS, the prevalent market is larger than it was 2 years ago. The uptake is less than people had planned for. And I think there are concerns. One of the things that we hear from patient advocacy groups is when people are considering a gene therapy is safety. Is this -- am I going to get the benefit for the risk that I'm taking? And I think that's the answer that we're trying to give with our program, is we are likely to deliver the intended level of microdystrophin. We see that in our data in a safe manner.

And then that gives you the best possible chance for functional benefit. I think underpinning what differentiates us in some ways, and I think in a major way from our competitors, all U.S.-based manufacturing in-house under our control, high product purity and a really attractive cost of goods, which is not important to a patient, but important to access. And so I think we're positioned very well to, for example, move quickly on a BLA process. Our CMC approach on the Hunter program, we had no observations in our manufacturing facility. The CMC package was complete and without any delays that you see in other CRLs. And so we're leveraging that in this program, I think, in a very strong way.

Got you. Got you. That's helpful. All right. Maybe pivoting to wet AMD. Obviously, we're all waiting for the pivotal data here, ATMOSPHERE and ASCENT. Maybe what's your latest thinking on probably the success and confidence around it? And then maybe remind us, I believe both trials were upsized, this is years ago, quite meaningfully versus what was the original plan. What was the driver behind that decision?

I think that occurred around the time that the partnership with AbbVie was consummated. They have, I think, a philosophy of powering a study even on secondary endpoints to 80% or greater, and that was one of the reasons the size of the study was expanded. The other reason, which is very important, is adding additional sites in Europe was a priority for a global submission. We actually got tremendous recruitment in Europe faster than expected. So there's a great unmet need there as well. I think it has a high probability of success based on that powering, based on the way the studies have been conducted. There's two doses, don't forget. So two ways to win. And our data from the Phase I/II is very compelling. We would expect -- if we think about the target product profile, greater than 50% or greater of the patients, hopefully, rescue-free.

The 50% or greater injection-free patients, is that the time point they're 1 year?

Correct. And then what we've seen in our Phase I/II data historically is that roughly an 80% reduction overall in treatment burden, so less injections. If we're near those values in our pivotal setting, then we feel like we've met our target product profile, and this is on its way to hopefully a commercialization effort.

Got you. Got you. Okay. That's actually very helpful. I know we're already almost at time, believe it or not, here. Maybe just a quick update on Hunter, the MPS II program. Obviously, we've seen standard of care making progress. We've seen obviously the approval of Denali. Maybe what's your take on that approval? And maybe just give us an update on your program and where you stand in the context of obviously the clinical hold recently been lifted.

So we think the Denali approval was significant in terms of evaluating our CRL. We feel strongly that our submission met many of the -- if you read the approval letter for Denali, we met many, if not all, of the criteria on which that program was judged. So we've been having good discussions with FDA. We filed an appeal to the CRL itself. And I believe we have fresh eyes looking at this in FDA, and we're optimistic that this can move forward. We know for sure that the Hunter patients out there are looking for alternative therapies. The burden of treatment, even with the really great approval for Denali to give patients options, it's a weekly infusion for a young child and a one-time gene therapy, we think, has substantial benefit in terms of burden of treatment. So we feel very strongly that, that program should be approved, and we're working collaboratively with FDA to move that forward, hopefully.

Sure. Got you. That's helpful. I know we're almost at time here. Maybe let's close with an open-ended question. Curran, what do you think is the most underappreciated aspect of the REGENXBIO story today?

I think the thoroughness of the science that we conduct -- I think we hold a high standard in terms of protecting patient safety. The way we approach even where we deliver programs like the retina programs, they're immune-privileged. So we don't see a lot of things that affect safety like intraocular inflammation. So I think we think about the way we design our programs, starting with the patient, and what their experience will be and obviously, trying to ensure that they get a meaningful benefit from the therapies that we provide. And I think that permeates all of our programs in the way we approach things. And I think these are turbulent times. Occasionally, I meet with investors and say, you're the boring company. Nothing ever goes sideways on things. And well, it's a little more turbulent now than we'd all like it. But we're sort of pushing through this in a very linear fashion, and I'm very optimistic we're going to have a good outcome at the end of it all.

Got you. We are out of time. Curran, I appreciate you joining us. Thanks, everyone, for joining us for the conference here, and we'll talk soon. All the best.

Thanks.

Welcome, everyone, to the REGENXBIO RGX-202 Top line Pivotal Data Webcast. At this time, I'd like to turn the conference over to Patrick Christmas, Chief Legal Officer of REGENXBIO. Please go ahead.

Good morning, and thank you for joining us today. Earlier this morning, REGENXBIO released pivotal top line data from the AFFINITY DUCHENNE trial of RGX-202 as well as financial and operating results for the first quarter ended March 31, 2026.

The press releases are available on our website at www.regenxbio.com. Today's webcast will include forward-looking statements regarding our financial outlook in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend, and other words of similar meaning.

Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties. These risks are described in the Risk Factors and the Management's Discussion and Analysis sections of REGENXBIO's annual report on Form 10-K for the full year ended December 31, 2025, and comparable Risk Factors sections of REGENXBIO's quarterly reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the SEC's website.

Any information we provide on this conference call is provided only as of the date of this call, May 14, 2026, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events or otherwise. Please be advised that today's call is being recorded and webcast. In addition, any unaudited or pro forma financial information that may be provided is preliminary and does not purport to project financial positions or operating results of the company. Actual results may differ materially.

I'll now turn the call to Curran Simpson, President and CEO of REGENXBIO. Curran?

Thank you, Patrick, and good morning, everyone. Thank you for joining us. Earlier this morning, we announced positive top line data from the pivotal trial of RGX-202, our potential best-in-class investigational gene therapy for Duchenne muscular dystrophy.

This data is highly meaningful for us and for patients, and we are excited to share it with you today. We have shared very encouraging Phase I/II results for RGX-202 previously. And today, I'm very pleased to have a group of experts with us to reflect on the first Phase III results from our AFFINITY DUCHENNE trial.

Our Chief Medical Officer, Dr. Steve Pakola, will present the data before opening the call to Dr. Aravindhan Veerapandiyan, also known by his patients as Dr. Panda, Dr. Carolina Tesi-Rocha and Dr. Diana Castro to share their perspectives. We're also very pleased that Dr. Panda will share videos from his patients treated with RGX-202 to give you a sense of what this positive data looks like for families in a real-world setting.

Before jumping into the data, I'll provide a quick recap of the first quarter 2026 earnings, which we also reported this morning. REGENXBIO continues executing against our mission to deliver multiple first and best-in-class gene therapies. As you'll hear today, the positive data and momentum continue for RGX-202. Across the pivotal and confirmatory studies, we have dosed more than 50 patients with line of sight to dosing 60 patients by midyear.

Supported by today's updates, we are planning for a potential approval in 2027. In retinal disease, we are on track to dose the first patient in the Phase IIb trial for diabetic retinopathy in the second quarter, which would provide a $100 million milestone payment from our partner, AbbVie. Additionally, preparations continue to report top line data from the subretinal pivotal studies in the fourth quarter.

I'm also very pleased to share the partial clinical hold placed on RGX-121 for the treatment of Hunter syndrome has been fully lifted. We recently filed an appeal of the 121 CRL and are continuing to engage the agency regarding a path forward for the program. Overall, I am happy to share that we remain well positioned to have 3 approvals over the next couple of years, including 2 blockbuster opportunities.

Turning back to our main event, the RGX-202 pivotal top line results. Today's positive data update is especially meaningful as we look at the impact of this progressive devastating disease. High unmet need remains for Duchenne patients as current options face limitations related to efficacy, safety and access. The untreated Duchenne population continues to grow in the U.S. and globally. Physicians and patients need new next-generation options.

Our Duchenne gene therapy program is differentiated from other gene therapies in multiple ways. Our novel construct with the C-terminal domain enables us to deliver a microdystrophin with more key elements of the full-length dystrophin that's missing in boys with Duchenne. With the CT domain, RGX-202 is uniquely designed to better preserve and protect the muscle as demonstrated in preclinical studies.

This novel construct, combined with our proactive short-course immune suppression regimen and leading product purity levels allows us to maximize the potential for therapeutic benefit while maintaining an impressive safety profile. I'll now turn the call over to Steve to walk us through the exciting data that reinforces our confidence in RGX-202 as a potential best-in-class therapy for patients. Steve?

Thank you, Curran. Before we dive into the details, let's start with the results. I'm thrilled to share that the pivotal Phase III portion of the AFFINITY DUCHENNE trial of RGX-202 met its primary endpoint with high statistical significance. Patients' functional outcomes exceeded expected disease trajectory across age groups and RGX-202 was well tolerated.

Additionally, RGX-202 demonstrated highly statistically significant correlation between microdystrophin expression and functional improvement on NSAA change from baseline and NSAA versus cTAP predicted value. This is a landmark distinction in Duchenne gene therapy, where a correlation of this strength has never been seen.

Today's data set includes microdystrophin biomarker data from 30 patients, interim safety from 31 patients and interim 12-month functional data from 9 patients aged 4 and older. I'll note that the microdystrophin data is shown for 30 patients, not 31, as 1 patient refused the 12-week biopsy.

Our pivotal study included 31 ambulatory boys aged 1 year or older with any DMD Duchenne mutation except deletions or point mutations in exons 8, 9 or 10. This is a wide enrollment criteria, allowing us to impact both the incident and prevalent populations at potential launch. As we go through the data set, keep in mind that we have treated a very balanced age range of patients in our pivotal study as displayed here.

Turning to our microdystrophin data. The primary endpoint of the pivotal study was the proportion of patients with microdystrophin expression above 10% at week 12. The pivotal trial met the primary endpoint with high statistical significance with 93% or 28 of 30 patients exceeding this threshold. Notably, 80% of patients exceeded 40% microdystrophin expression.

We saw a 71.1% average microdystrophin expression across all patients and a 41.6% expression in patients aged 8 and older. This is the highest average microdystrophin expression reported for this age group across gene therapy programs. We believe this robust expression supports the potential for improved outcomes. And as you'll see, this is supported by the strong correlation to function.

Biomarker data supported consistent robust expression, transduction and sarcolemal localization of microdystrophin with a high level of vector copies and percent positive fibers. These are among the highest vector copy numbers seen in the field, supporting the potential long-term durability of 202.

Turning to interim safety. RGX-202 safety profile is supported by a novel immune suppression regimen designed to proactively mitigate safety events that can occur with high-dose gene therapy. We implemented this short course regimen from the start of the program. Unlike others in the field, it remains unchanged. We believe this targeted proactive approach has been a significant success factor for our program.

RGX-202 was well tolerated in line with the Phase I/II data. Of the 31 patients dosed, there were 2 treatment-related SAEs. Both were easily managed and resolved within weeks without sequelae. One was a case of subacute myocarditis, which was reported in an 8-year-old participant. At 33 days after dosing, he presented with mild chest and abdominal pain, normal troponin and mild elevation of high-sensitivity troponin. This event fully resolved without sequelae. The participant's most recent cardiac MRI confirmed no heart muscle fibrosis and no change in ejection fraction.

The second case was a case of asymptomatic liver injury reported in a 10-year-old participant and diagnosed via labs 43 days after dosing. This patient's GGT peak elevation was 123 units per liter and his abdominal ultrasound and bilirubin levels were normal. This event also fully resolved without sequelae.

The common drug-related adverse events are those typically anticipated with gene therapy and all were considered mild or moderate and resolved without sequelae. Notably, no drug-related thrombocytopenia, myositis or neurotoxicity were reported. We believe this is an impressive safety profile and an important differentiator for the physicians and families making decisions about their gene therapy options.

Also supporting our differentiated liver safety profile, mean GGT and total bilirubin, measures of liver injury remain stable and well below upper limit of normal throughout the 12 months.

Turning to our exciting interim 12-month functional data. The disease trajectory for Duchenne is well established, allowing use of multiple validated methods with large external data to evaluate our functional outcomes. The primary method in our SAP is propensity score weighting, which mimics a randomization setting.

At 12 months, patients are demonstrating functional improvement compared to external controls on NSAA and all time function tests. Across all 4 domains, we see a favorable profile for RGX-202 compared with external controls. This remains true for the subset of patients aged 8 and older. These favorable functional outcomes are even more notable in this population where patients are expected to be in the decline phase.

At 12 months, caregivers are also reporting improved function on key dimensions of the POD C that are most relevant to Duchenne. We are pleased to see how these boys are performing in day-to-day activities. These 12-month functional outcomes are incredibly impressive, and we believe are rooted in the novel RGX-202 construct.

In a landmark update for Duchenne gene therapy, there is a strong statistically significant correlation between RGX-202 microdystrophin and functional improvement. The correlation is observed for both NSAA change from baseline and change from baseline compared to expected disease trajectory using cTAP. Notably, the correlation coefficient is greater than 0.9 in both analyses.

Additionally, correlation between microdystrophin and the time function tests showed directional trends, and we expect to expand this data set as more patients reach the 1-year mark. This strong correlation supports RGX-202 microdystrophin expression as a surrogate endpoint likely to predict clinical benefit.

Now that we've shared these impressive results, let's hear from our expert Duchenne physicians. Dr. Panda, Dr. Tesi Rocha and Dr. Castro. First, thank you for joining us today. And let's start off at a high level and hear what each of your overall impressions are on these top line pivotal data that we presented this morning. And let's start with our investigators and you specifically, Aravindhan, what's your take on these results?

I'm quite impressed by the microdystrophin expression as well as function and most importantly, the functional data of the older boys that are older than 8. I think it's impressive. And as I've shared in the videos of the patients, those are impactful for me. I think it just gives us confidence in RGX-202 in altering the disease progression in these patients.

Thank you for that, Aravindhan. And let's turn to you, Diana, seeing these results for the first time. What's your take?

I think I agree with Dr. Panda. We have been doing this for many, many years. We have heard a lot of other products talking about dystrophin. But my question always is what does dystrophin means by itself if there is not function associated to the dystrophy level.

And I think that this is not only impressive in terms of the amount of dystrophin that we're seeing in these cases, but also that there is correlation with function because at the end, this is what it matters for these patients, right, is that how do we prolong their life and how do we keep quality of life as they get older. And the only way we're going to achieve that is it's getting obviously better function as they go.

And so turning to you, Carolina. You've treated patients with 202 in the trial as well. And now that you've seen the top line results, what are your key takeaways?

Well, overall, my impression is that the data, it's encouraging. The safety profile presented appears favorable, which is critically important, right, in the current DMD gene therapy landscape. And while the functional data set is still limited in terms of the patient number, it's reassuring to see patients showing favorable trajectories, particularly when viewed in the context of the cTAP modeling and historical controls.

So that type of comparison is clinically meaningful because it helps frame in a way whether the observed changes are moving in the direction that we all hope as we were in the clinical trial to see beyond the expected disease progression.

Great. So you've all hit on the importance of not just biomarker, but of course, that translating into function. And you've mentioned, Diana, that importance of correlation to really see what does microdystrophin of a particular construct actually mean.

So given these results and how you look at it, can you put that in any kind of context as far as the existing unmet needs you see in terms of the patients you treat today and what these results might mean as far as RGX-202 as a potential therapeutic option going forward?

Sure. I think that, like I said, we definitely need to concentrate in function. And what is -- what we're seeing unmet needs, 2 things. One, we're not treating patients early enough. And I think this is something that you guys are addressing, which -- because we're going to move into newborn screening. And if we're going to end up in that area, we're going to need therapies that are going to address the situation as early as we can. That is one.

The other one is that what we have right now, the products we have and what's coming, we talk about the young population 4 and above, but we have to also think how much are we going to get for the patients that are older, the 8- and 10-year-old patients that are obviously getting weaker as the condition progress. So I think that, that area, it's a big area of unmet need and something that we hopefully can address with this type of product if we're getting that function in those older patients as well.

Thank you for that. It's interesting that there is really an unmet need for various reasons across that age range. And how about you, Carolina? Anything to add on unmet needs for your patients and families?

Well, I think that the families are -- remain very interested in the gene therapy, right? But there is increasingly -- they are becoming increasingly sophisticated on how they think about it. They want to understand not only the potential benefit, but also the durability, safety, immune suppression regimens, eligibility and how the treatment might affect future options.

So I think that many families and patients view the gene therapy as an important opportunity, but they are looking for transparent discussion on what is known, what remains uncertain and how we can monitor and mitigate risk.

So there are like certainly a lot of unmet needs in terms of eligibility. So there are some programs that are currently in investigation, and they have more cuts in terms of what could be acceptable in terms of the mutations that the patients have. Some of the families deal with positivity of some of the AAV vectors that might not make them candidates. So is the unmet need for those patients that cannot get commercial access to treatment.

And certainly, the 2 I would say, age groups, those that are very young and those that are very old, how these therapies will be useful for them in these different type of age ranges. So I think that there are still a lot of unmet needs, but we hope that at least having more opportunities and different gene therapies with different constructs might help them make their decision in the future.

Aravindhan, what's your view when you think of potential unmet need for your patients as well?

Yes, Steve, I think the therapies that we have in the pipeline as well as that we are using right now, I mean we used to say that none of them are cure. They're trying to change the disease progression. And like Diana was saying, there are those older patients or late ambulatory patients and also younger patients, which we don't have a lot of data available to show their function.

And I think the data that's presented here today kind of addresses that point. So it gives us confidence to use RGX-202 in that population. And also second, the -- with Diana's comment on correlation between the function and the microdystrophin expression, which is unique, and it was reassuring to see that the microdystrophin that is being expressed actually translates into function.

And I would love to continue to explore that as we get into more -- looking at more patients data from the trial to see how this pans out, not just with the NorthStar Ambulatory Assessment score, but also with the other functional assessments. And I think that is a unique analysis and unique results that we should share to show the impact of this microdystrophin construct.

Great. Thanks, Aravindhan. So as a follow-up to these perspectives, can you say a few words about how you think about the overall benefit risk profile that you're seeing for RGX-202 when you hear these results?

Sure. I mean as this field becomes more complex, this landscape keeps changing. I think as physicians and families, patients, we're looking for something that -- therapies that can be stronger, therapies that can be safer and hopefully more predictable for the patients. We already are dealing with a complex condition. So when it comes to have to deal with a therapy like gene therapy, we, as physicians, we want to feel that we know where we're going.

So what you're showing is hopefully a more predictable response in terms of safety. For example, liver. Liver is one of the biggest complications that we have and one of the causes of more really long-term complications in terms of gaining weight and so on with the fact that we have to increase prednisone to really high levels. So with the use of different immunosuppressors in this case, with your therapy, hopefully, we're going to avoid those complications as we treat more patients.

But again, I think it's just about how do we find a therapy that it will last longer, that will stay -- that will be more safe and also more predictable for different stages of the disease.

Thanks, Diana. How about you, Aravindhan? What are you seeing here when you think about the overall benefit risk profile for RGX-202?

No. Thanks, Steve. I agree with Diana. I know the -- from a safety standpoint, like I've always said, I feel more confident using more comprehensive immunosuppressive regimen. Now as you know, now the field is evolving and people are using sirolimus as a standard of care, whereas REGENX was thoughtful that we implemented this early on as part of the trial.

And I think that that additional layer of protectiveness against these -- to prevent these immune-related side effects, I think that gives us a little bit more confidence to dose more patients with RGX-202. And I think that is definitely a differentiating factor that I would say from a safety standpoint.

So last but not least, Carolina, any thoughts on overall benefit risk considerations having seen these results?

Right. So again, they know that when they make the decision to get gene therapy, there's a lot of potential risk. And again, it's good and encouraging to see the safety profile presented continues to appear favorable despite these 2 cases that presented with both the cardiac and liver toxicity complication.

I think that this is one of the elements that the families are looking at. Nowadays, we have for the commercial use of gene therapy, the add-on -- the potential add-on of more immunosuppression, but seeing that immunosuppression in this particular protocol was started from the get-go. So then we have the information about the potential safety, right?

So many of us, we could be using different type of immunosuppression initially not suggested by the commercial products and currently under investigation. But it's nice for me to see as a clinician that here in the protocol, we design it in a way that makes sense for the potential complications. And we are also during the clinical trial, not only see the safety profile that appears favorably, but how our patients are able to tolerate this stronger immunosuppression that pertains to the particular gene therapy trial. So I think that, that is -- it's very important for me as a clinician, but I think it's very important for the families, too.

Well, that brings us to the end of the panel discussion. So thanks to all of you for your insightful perspectives this morning. Before I turn the call back to Curran, Dr. Panda is actually going to share a video to give us a glimpse into what the data we've shared today looks like for patients he's treated with RGX-202 with videos both in the clinic and in the real world.

I am pleased to share videos from 2 of my patients who received RGX-202. These first 2 videos are of a 6-year-old boy. At baseline, he can walk up 4 stairs, placing 1 foot on each step and touching the handrails. One year later, he performs the task more quickly. At home, he races up a long sterile with his sibling without using his hands. He makes it clear he's won the race to the top.

This same boy at 1 year post dosing is jumping, clearing both feet off the ground multiple times in a row. He's able to run over leaves and grass in a park and makes his family smile with his dancing.

These next videos are of a different boy who was 5 years old at dosing. At baseline, he jumps clearing both feet just off the ground surface. One year after dosing, he jumps higher without placing his hands on his body. The same boy's family recently shared with me how much he enjoys playing on the trampoline. At 2 years post dosing, he is jumping, rolling and galloping on the trampoline. His parent shared that. He played on the trampoline for 16 straight minutes this day.

What's impressive about this activity is the muscle strength not only to jump, but to continuously get back up from a bouncy surface. I'm always grateful when the families share their progress and a look at how the changes in muscle strength and endurance are impacting their day-to-day life.

Wow, Dr. Panda, this is incredibly moving. Thank you for sharing these videos, and thank you to all of our esteemed physicians for joining us today. It is so heartwarming to see how well these boys are doing in a real-world setting. It's amazing to see them look happy, strong and having fun with their families 1 and 2 years after RGX-202 treatment.

It's an incredible reminder of why everyone at REGENXBIO is committed to bringing new next-generation therapies to patients. To sum up what we shared today, RGX-202 demonstrates evidence of positive functional outcomes with an encouraging safety profile supporting potential FDA approval via the accelerated approval pathway in 2027.

RGX-202 achieved its primary endpoint with high statistical significance. Interim functional data demonstrate improvement across all functional measures compared to external controls, with highly statistically significant correlation between our novel microdystrophin and function.

In our discussions with the FDA, the agency noted whether RGX-202 microdystrophin protein expression can serve as a surrogate endpoint reasonably likely to predict clinical benefit. With our emerging data set, we are demonstrating strong correlation between the 2 and look forward to discussing this with the FDA at a future meeting.

Today's top line data is highly exciting and an encouraging step on our path to deliver RGX-202 as a potential best-in-class therapy for patients and is highly supportive of our plans for potential accelerated approval next year. On behalf of everyone at REGENXBIO, I want to say thank you to the patients, families, physicians, study sites and advocates who have partnered with us on this mission.

[Operator Instructions] Now we'll open the line for Q&A. Our first question comes from the line of Judah Frommer from Morgan Stanley.

Thanks for the presentation today, all the incremental data and for providing us with this panel. It was really helpful. Maybe one just on the liver SAE. GGT of 123 didn't look all that high. I think you said it was 2x upper bound by reviewer. So maybe just some color on the adjudication of that SAE. And then I have a separate follow-up.

Great. Thanks, Judah. Good to hear from you. I'll start that question off with Steve. He can comment and work with the panel if needed.

Sure. Thanks for the question, Judah. Yes, so out of 31 patients, we had the liver injury. We had no other cases of liver injury. Yes, as you mentioned, it wasn't a particularly high liver enzyme elevation. But I think -- in this field, there's a desire to really stay on top of these patients. And in a clinical trial, there's a lot of frequent assessments.

So as far as the adjudication, the way SAEs work is whether you meet any of the criteria. And one of the criteria is hospitalization. So there's various reasons why a patient would be hospitalized. Sometimes it can even be for administrative reasons depending on availability of outpatient infusion, for example.

So -- and actually, in this case, this patient was one of your patients, Carolina. So since we have the benefit of you here, I'll turn it over to you as well to give your perspective on how the patient did and how the patient is doing and also circumstances around determination that it was an SAE.

Yes. Thank you, Steve. That is absolutely right. The reason why this was determined to be an SAE was exactly because of administrative issues in terms of the inability of us to use the infusion center over the weekend. The complication happened on a Friday. And so we decided to do pulse Solu-Medrol, and we were not able to do that in the outpatient infusion center.

So that was the only reason. The patient was always asymptomatic. This was just laboratory finding with abnormalities as they were mentioned before. GLDH was also elevated. So we already have plans to pulse this patient with Solu-Medrol. However, based on the GGT, AST and ALT elevation that were not -- they were trending up despite the CK trending down, indicating the increase in the liver enzymes were not attributable to the increase in CK.

So that is what motivated us to think about the Solu-Medrol even before getting the GLDH from the central lab. But these results came back around the same time and showing a level of 5x of the upper limit of normal. So consequently, we decided to give the patients 5 pulses of Solu-Medrol at the 30 milligrams per kilogram, which he tolerated well.

And we also have the opportunity to run other tests to rule out other potential reasons for him to have this elevation on the liver enzymes. And both viral tests came back negative as well as other metabolic laboratories that were done at the time.

Thanks, Carolina. I'll also add that not only were there no other liver injury cases in the other patients, but even looking at a very granular level at the liver enzymes in all the patients, even with this patient included on a mean basis, no suggestion at all of liver injury subclinically. So this really does round out a very nice picture for liver safety as a differentiator from existing therapy where there's a recognized 40% rate of liver injury. So we're very happy with these safety findings.

Okay. Great. And then just on the regulatory path from here. In the press release, you mentioned recent discussions with FDA and recommendation for a randomized controlled trial, but it seems like there's openness to interpretation of biomarker correlation to functional benefit. So anything you could elaborate on how these 9 patients and how many additional patients will need to potentially avoid a randomized controlled trial?

And then if I could just sneak one more in for the panel. Just curious on that comment about sophistication of patients and families. How many do you sense are waiting for next-gen therapies beyond gene therapy? Or is there still a desire to kind of get therapy to patients as quickly as possible?

Thanks, Judah. I'll take the first one, and then I'll send over to Steve for the patient perspective. I think on the FDA interactions that we've had, none of them have really been in a situation where we've actually reviewed this data. Of course, we just unblinded it recently.

I think the magnitude of effect that we're seeing here is directly applicable to the accelerated approval pathway. So the concern with the review team is more bias that could be introduced using external control strategies. But I think when you consider that and the experts that we've worked with, the bias that would exist is dramatically overcome by the magnitude of effect we're seeing in functional benefit.

There's no specific request from FDA to show x number of patients functional data as part of AA. But what was specifically requested was to show the correlation. And given the strength of the correlation that we've shown, I think we have what we need to show that.

I think it's the first time any gene therapy study has shown this level of correlation between the surrogate biomarker and functional outcome. So I think our data is going to be very strong in supporting that. Now I'll kick it over to Steve.

Sure. Yes, it's a good point that the Duchenne patient families are often very sophisticated. And we, for example, hear feedback from patient advocacy that some families are even raising their comfort level with the product purity with over 80% full capsids, which is pretty sophisticated for a patient family.

And Diana, raising that aspect that you obviously have a lot of experience treating these patients and families. You're raising this aspect. Can you say a few more words about that and how that really impacts how you talk to the patients, families about different treatments and treatments in the pipeline that can give greater comfort to these families.

Of course. Good morning, everybody. I have the privilege of -- we have a nonprofit clinic. So we take people with insurance, without insurance, private and so on. And it's very interesting how it really people are learning so much about these therapies. And I think, obviously, social media, right? Families talk to each other. They are doing their own research.

And it's important for us also to be prepared to answer their questions. And I think when I start mentioning things about as we learn because we don't know everything. I don't know everything for sure. And as we learn, I think one of the more impactful points to me when I heard about the capsids and when you transmit that knowledge to the families, I think that makes a big difference because they are already taking a risk -- they're already making a big decision in their families with their sons.

But now they are hearing, well, we're making this risk, but then hopefully, we're going to make -- we're going to get more medication. Hopefully, that's going to translate into more microdystrophin and hopefully into more functions. So it's never going to be an easy decision for these families. But we're making them, like I was saying before, more predictable, hopefully, and with a better safety profile, we are playing in a completely different -- it's a completely different game, I will say.

So it's just -- the knowledge is coming up. We have to keep learning. We have to keep being open about everything that is coming, but knowing that families are more educated right now and they know what's going on.

Our next question comes from the line of Mani Farhar, Leerink Partners.

I wanted to touch base on timing of FDA engagement. I know it's something we've talked about on and off. We talked about in the call in light of some commentary that you made with a reported stat news and an article that came out. How do you think about timing of the engagement, timing of filing, maintaining a sense of urgency around the unmet need to support accelerated approval?

Well, certainly, the sense of urgency is extremely high. Right now, the treatment level for the approved gene therapy is lower than the incidence level for new patients that need treatment. So I think that is a really important factor in our time line.

We want to go as quickly as we can with filing. We have options to file as a rolling BLA or as the full BLA depending on when we submit. I think our timing on further discussions with FDA, we do want to -- obviously, FDA is going through a leadership transition, which is significant. We do want to let that settle in.

We expect that the new leadership will, I hope, have a mandate on rare disease flexibility. I think those are the indications that we're hearing that will be, I think, more uniformly adopted. And with that environment, we're in great shape with our data to push for accelerated approval.

So I think what we're absolutely pinning on is the ability to have an approval in 2027. That would mean we have to file sometime in the first half -- early first half of 2027 to achieve that, and we're on track to do so.

Great. And as a quick follow-up, could you give me a sense of where we are in terms of the potential outcomes of that engagement? Obviously, you have a confirmatory study ongoing, exactly what the FDA might want post the conversation is not exactly to have the meeting with them. Talk about the range of outcomes of that upcoming discussion, how to think about the path forward to accelerated approval? Any potential changes to the confirmatory trial that might be needed depending upon the FDA's attitude towards the necessity for a randomized trial?

Yes. I think that's a great question. And I think on the subject of a randomized trial, given that there has been guidance over the last couple of years from FDA that the accelerated approval pathway is open to start an RCT study from scratch, which we see some entrants doing that, even the commercial product doing that, you wouldn't see an approval based on time line estimates until 2030.

So I can't imagine an environment where the Duchenne community is willing to wait 4 years for an approval of an RCT study base. And so what I think will help us will help -- the unmet need will be clear. Our data is really clear and very significantly different from what we see with natural history analyses that we're doing.

And I think the discussion on our end will be very flexible. If the confirmatory study were nearly completed or needs to shift to an RCT study as part of accelerated approval, we would consider that. I think that's something that we'd have to determine if that has to be run ex U.S. because I think it's challenging to run such a study in the U.S. But that, I think, is the heart of the conversation that we'll have with FDA second half of this year.

Our next question comes from Alex Stranahan of Bank of America.

Congrats on the progress you're making across the pipeline. Two questions from me, both on 202. I guess, first, how do you expect the picture of functional benefit to evolve as you move towards the full 60-patient data set? Anything in terms of balance of patient age or other factors that could differ from the 9 patients you shared? And when might we see this data?

Great question. I think on the age distribution for the first 30 in our pivotal, we've seen a pretty even distribution of patients in the 1 to 4, 4 to 7 and 8 and older. And I'll let Steve comment on enrollment for the confirmatory study and what we're thinking about in terms of additional data updates.

Yes. Alex, thanks for the questions. Yes, it's a great point you raised that we've shown 9 patients worth of data that was based on everything we could get in there as far as how many patients in the 4 and older age group had reached the 12-month time point by the time of the top line data coming in.

So an issue is how much confidence do we have going forward of that replicating when we have more patients. We didn't have time or to have slides that really break down demographics of the different patients. But we have had time to look at that. And fortunately, the demographics of these 9 patients match very well with the overall data set.

So that gives us a lot of confidence as we go forward that the very impressive results we're seeing here are not driven by any fluke of the type of patients that are in this 9 out of 31.

Okay. And then maybe just one quick follow-up to a question that was asked earlier, but maybe I'll ask it in a slightly different way. I guess, do you expect the review team or the framing of the conversations you're having, like did this change at all once the FDA heads turned over a couple of years ago? And do you expect that to change given the recent departures as well?

That's a great question. I think that the review team has been consistent over the years regardless of leadership that was in place at the time of the different meetings. But I think, again, I'd caution that the meetings that we've had other than our end of Phase II, where we had some limited data to share have all been devoid of the data that we're showing you today.

And I think once we have that conversation, with FDA where this data is on the table for discussion, I think it will be more productive on both ends to look at what we've got to look at the magnitude of effect that we're seeing.

As I've said recently, I think we have everything -- if you read the accelerated approval regulation, all of the elements that we are providing check those boxes. So I think that's where we're looking to meet with the review team and actually have a data-driven discussion rather than hypothetical of just general assumptions.

Our next question is from Annabel Samimy from Stifel. Is your line on mute?

It is. I'm sorry. Okay. Sorry about that. So I'm just on the question of the correlation analysis, if you're filing by the first half of '27, do you have a sense of how many patients will have completed the 12-month functional assessment? And could you actually have a very, very significant data set to provide to them on your initial BLA? So that's the first question. I have some follow-up.

Yes. I think the expectation would be early '27 filing, we would have, importantly, on safety, at least 50 patients available based on the enrollment rate that we had for the confirmatory study. So on the safety database, significantly more than what we're showing here, which is great.

On function, if you look at the proportion of patients in these age categories, as I said, fairly evenly balanced. If you think about functional assessments, then it's the 4 and olders that contribute most to the assays that we're describing. And we would have -- I would just give a range, 15 to 20 of them through their 12-month time point at that point. Is that helpful?

Yes, that's helpful. That's great. And just as another separate follow-up. So in terms of the microdystrophin expression, I know some have demonstrated microdystrophin expression increasing over time. Of the patients that did not show greater than 10%, is there -- have you been measuring their microdystrophin expression over time? And do you think there is an opportunity for them to actually have that sufficient dystrophin expression post that 3-month time point of measurement. I'm just curious how these patients might evolve.

Yes, we don't -- I think the data you're referring to was data early in the Pfizer study where at 12 months, there definitely was an increase -- we only have the one biopsy that's taken at 12 weeks to measure microdystrophin. We don't have additional biopsies in the protocol for measurement at a later time point.

But I think it's important in the data set to note that 80% of the patients treated had greater than 40% microdystrophin. So if there's a threshold effect, I think we're well beyond that for the vast majority of patients on microdystrophin. So I think we're really pleased with that data set. Steve, I don't know if you want to follow on with that.

Yes, that's exactly right. We have in the trial open biopsy to really have the most robust ability to assess. But that also means you really want to limit how many of these you do for these patients and the families to go through the biopsy.

And we're really helped by the data that you've mentioned, Annabel, that we know historically, if anything, it's going to go up. So I think 3 months is a conservative estimate. Of course, we don't know for sure with any given program, but this is really impressive for where there's the most data.

And of course, the biggest thing is, is this translating to functional benefit? And can we even show a correlation with this data. So we're really happy to have ticked both those key boxes.

Our next question is from Luca Issi from RBC Capital Markets.

Let's move on. Our next question comes from Brian Skorney, Robert W. Baird.

On the data. My question is, what would the hurdles be to running an entirely separate randomized controlled study, even separate from your ongoing confirmatory study, just seems like having an RCT running would address a lot of potential issues down the road, whether it be FDA recommendation for accelerated approval based on the recommendation for an RCT to establishing ex U.S. approvals to giving payers and stakeholders better data to work with.

It seems like there isn't an available gene therapy across most of the world. So it seems like having a placebo arm could be something viable. Do you think this would be an IRB ethics issue? And in that vein of questioning for Dr. Panda, Tesi-Rocha and Castro, do you think this data breaks the equipoise for running RCT?

Thanks, Brian. That's a great question. I think in general, running RCT-based study with gene therapy is highly challenging, and I'll let the experts comment more on that because I think very quickly, patients typically know whether they've gotten a gene therapy or not based on the administration of gene therapy.

So being able to fully blind a study of that type is a challenge. I do agree that there are countries where standard of care does not exist in terms of an available gene therapy. And those are logical places that we would consider as we are considering a study for ex U.S. licensure of that nature.

So yes, I think it can be done more likely ex U.S. than within the U.S. But Steve, maybe you could address this with the panel.

Sure. Carolina, why don't we pass this on to you the question of Equipoise given these results and at least from a U.S. perspective, how you think of an RCT.

Yes. I agree with the comments that access is an issue. And when we look at this globally, it's a problem for other countries that don't have the possibilities. But that also opens the opportunities for us in this particular case with when we have an already approved commercial drug, it becomes very challenging to be able to do a randomized placebo control in the U.S.

So I agree with others that if we do this, it will have to be counting on international sites. And certainly, there are like different places in the world that have very good groups that have participated in other clinical trials. So I think it's doable. And it will also allow access to these patients that sometimes they have to travel internationally to our sites to be able to participate. So I would like to see that.

Our next question comes from Sean McCutchen of Raymond James.

Can you speak to the number of patients from this analysis that were previously included in the Phase I/II assessments and what you're seeing on the trend in both microdystrophin expression and particularly in functional outcomes for the newly disclosed patients? And then maybe one for the docs on the panel.

If you could please speak to your comfort with the prophylaxis regimen as well as maybe speak to whether you see the added eculizumab as providing additional safety benefit relative to your experience with other microdystrophin gene therapy programs?

Sean, thank you for the question. I'll let Steve comment on the study design and the number of patients from Phase I/II...

Sure. Thanks, Sean. So we have the 9 functional data patients who are all the patients that we had available for and above. 5 of those 8 are from the Phase I/II data that we've shared previously.

Basically, the patients -- and this is all prospectively defined in our Phase I/II/III protocol, patients who were in the Phase I/II who meet the pivotal enrollment criteria are then carried over into the pivotal data set. So we were really excited to be able to add to that 5 an additional 4 subjects.

And you can see that with those 4 additional patients, we have high magnitude of effect and significant difference from external control by all the different ways that we look at that. So we're very encouraged. We'll continue to accrue additional data, which with more we anticipate, as raised earlier, this 9 patients demographically is very similar to all the other patients. So we're excited to keep going.

Our next question comes from Ellie Merrill from Barclays.

So just to clarify on the FDA conversation. So when exactly did the FDA recommend a randomized controlled trial to you? I guess, was this in the recent meeting? Or I guess, is your press release referring to just general guidance from the FDA? If you could just clarify, I guess, when that was said, if it was said and kind of the context around that?

And then just a follow-up question. I know this was touched on a bit earlier. But I guess if the FDA recommends running a randomized controlled trial before filing when you do meet with them, what would your strategy then be with respect to filing in that scenario? Do you go ahead and file? Or do you work on the design for the randomized control trial?

Thanks, Ellie. Yes, I think we have a pretty advanced design for an RCT-based study, which is intended for ex U.S., and we're planning to put that trial in action over the course of this year as we take a global approach to the program.

So I think on a design standpoint, it's pretty straightforward. We have a great data set to pull from in terms of how we would design the study. I think the trigger to do so will be dependent on the conversations we have with FDA.

But I do want to caution again that completing an RCT study as a precursor to filing or a precursor to approval means that it's very unlikely that any new gene therapy would be approved until 2030. And I think that scenario is really untenable for the community and for -- it's the opposite of regulatory flexibility.

So I think what we're saying is that our data using this external control strategy, which has been reviewed by FDA as well is going to meet the requirements associated with accelerated approval. And yes, if an RCT study is a requirement for a confirmatory study associated with that, we could always pivot our confirmatory study to meet that need. That's not something that we would shy away from.

So I think it's just a matter of going through the data with FDA. And then I believe that there will be sufficient opportunity for us to collaboratively solve that with FDA based on the conversations we've had recently with them.

And Steve here, I want to circle back as well to Sean, your other question of our IS regimen that is very targeted and which we believe our results are validating what we chose to do from the beginning. And fortunately, we haven't had to change this throughout the entire program.

But since we have a panel with a couple of investigators who've used this immune regimen within the trial. So I can ask Dr. Panda and also Carolina to comment on your experience using this regimen. So let's start with you, Panda.

Sure. Thanks, Steve.

I think from a -- like I answered before from an immunosuppressive regimen standpoint, especially, I think eculizumab, we haven't seen any clinically complemented -- complement-mediated things like TMA or other issues related to complement. I think that speaks to probably due to eculizumab, immunosuppression or prophylaxis.

Now from a comfort level standpoint, initially, when I first started, I had some reservations, but I think mainly because of -- can they have additional side effects because of all these agents that we are using. But we have dosed several patients who have used these eculizumab as well as sirolimus now, and this has been generally well tolerated by these patients. So again, this experience gives us confidence to use this immunosuppressive regimen to prevent some of the side effects.

Carolina, anything to add?

Yes. I fully agree with Panda. I initially felt the same concerns that the experience has been positive, both from me and my team handling this strong immunosuppressive regimen, but also from the families being able to cope with all the extra visits that they have for particularly the eculizumab infusions.

So overall, quite positive and seeing the safety profile that is also encouraging to keep going.

Our next question comes from Daniel [indiscernible].

Congrats on the progress on the data. Just a quick one for me for microdystrophin expression. Maybe I missed it, but what are the age of participants who did not achieve the 10% microdystrophin expression? And were there any underlying characteristics that you believe prevented them from achieving that?

Thanks, Daniel. Steve, I'll send that one your way.

Sure. So this patient was in the 4 to 7 age range. There really wasn't anything demographically unique about this patient. I think it's just the reality that occasionally, unfortunately, it's rare that a patient and a family will choose not to get the biopsy based on their experience, for example, with the baseline one.

So we, of course, get a baseline biopsy and measure. So again, all in all, missing one, we still have really impressive results in the 30 patients, about as good as we could hope for.

Our next question is from Paul Choi, Goldman Sachs.

Can you hear me now?

Yes.

My first question is for the panelists. With regard to the correlation that has been presented so far on the patients who are through 1 year and the relationship between microdystrophin and the functional results, the data are largely clustered in the middle here. And do you feel like 40% is sort of the minimum threshold you would need to see in terms of microdystrophin likely to result in a functional improvement?

That's my first question. And my second question is just with regard to the FDA and just sort of any updated interim data that you might present. Can you clarify if you'll present any additional 1-year data cuts over the course of 2026?

Thanks, Paul. I'll take the second one, and then I'll ask Steve to work with the panel on your first question. Yes, I would expect that as the data set matures on function and patients cross the 12-month time point that we'll have updates on function. We don't have a specific time frame identified for that yet, but it will likely be sometime this fall. I'll move that over to Steve for the discussion on microdystrophin.

Sure. So the question of correlation and the particular clustering. One way to look at this is that the clustering is actually a good sign. It shows that the vast proportion of patients are having very good expression levels, which perhaps is really what's translating to the functional benefit -- so I'll turn this to Dr. Panda since a lot of these patients were yours in the overall trial.

How do you think of the correlation data and what this means for you when you think of what's the percent of microdystrophin that could lead to benefit?

Thanks, Steve. I think I was quite impressed and surprised to see this direct correlation because I wasn't, to be honest, expecting this from our experience in general with gene therapy or other -- even other dystrophin restoration therapies. I think this is quite impressive to show the function correlating with the dystrophin expression, though the n is small.

I think from a cutoff standpoint, it's really hard to kind of say, I mean you have to have 40% because we have had -- we came up with, I think, the -- from an endpoint standpoint, 10% because we have seen that functional improvement with that 10% of microdystrophin expression. So I wouldn't conclude from this analysis that you have to have 40% or 50% of microdystrophin expression to have function.

And our final question will come from Yi Chen, H.C. Wainwright.

Could you comment on whether the FDA has indicated how many patients would be needed for the safety profile of the drug if accelerated approval is being pursued? And particularly, is there such a requirement for patients less than 4 years old?

Good to hear from you. In terms of the protocol, the pivotal protocol prespecified 30 patients for the pivotal program, and that was reviewed by FDA without comment. So we feel like from a safety standpoint, we have what we need to enact a filing.

Having said that, we'll have more than that. We'll have closer to 50 by the time of filing based on immediately beginning to enroll and now rapidly enrolling the confirmatory study. So we feel and all of the benchmarks that we've been able to access support that, that should be a very adequate safety sample size, particularly given the low frequency of SAEs that we're seeing.

So I think that potential risk is very low in terms of submission strategy.

That concludes our question-and-answer session. As a reminder, a webcast replay will be made available on the REGENXBIO corporate website. Thank you for joining.

Everyone, welcome back to the next session of this first morning of the Global Healthcare Conference here in Miami. I'm still Mani Foroohar, Senior Analyst at Genetic Medicines. I have Curran Simpson joining us as CEO of REGENXBIO. And Curran, there's absolutely nothing going on in the space. It's very boring. No news whatsoever, obviously.

Yes, I made the mistake a couple of months ago about saying we were the boring company. All we do is execute to plan and put up data when we say we will. And a lot has changed in the last couple of months, and this is a huge year for us. We've got some big catalysts coming up, really excited to take those forward.

That is awesome. I think the universe has a sense of humor when we start saying things, it listens. Let's start with the most topical news, which is -- where are we in terms of your FDA conversations? Who your FDA counterparties are in that conversation -- DMD specifically. And does the recent announced change in leadership at CBER influence that and how?

Yes. I think if I kind of work through the 202 program and planned regulatory interactions, if I work from the back end of that, we're planning a pre-BLA meeting mid this year, which will be, I think, primarily a discussion around what we've thought about on the program for years, which is the relationship between microdystrophin and functional benefit. And I think this is where our initial data looks extremely promising. So that's the pre-BLA meeting, and that's the last step before we initiate filing of the BLA.

Ahead of that, we have an interaction with FDA. One of the things that's changed in the last, I'd say, 6 months or so is our access to data, natural history data, new ways to compare the data using CTAP method, for example, which we've recently published. And so we have a targeted meeting with FDA to talk through that because some of that is, I would call, in addition to what we already prospectively put in our protocol in 2024. So we've got a fuller data set and more ways to measure functional benefit versus natural history. And we want to make sure going into the pre-BLA meeting, that's as aligned as it can be. And -- so that's the sequence of interaction with FDA.

How does the news of last week change that? I think there was a general worry around accelerated approval in terms of the track record. I don't have to speak to any instance of a program, but I think people were getting concerned about whether the AA pathway was still open, which is what we intend to file under. And I think that what we're looking for in this change is that what we hear from Dr. McCary around accelerated approval is uniformly adopted through the agency and hopefully applied to our program should our data warrant it. So I think that's what we're looking forward to.

I think what we can do in that is continue to move the program forward, dose more patients, build our database of functional data. And what we did after we recruited the pivotal in October was we continued to add patients to the program as part of the confirmatory study. So at the time of filing, we'll have roughly 50 patients' worth of safety exposures at that point, which I think only puts us in a better position for a positive discussion with FDA.

Let's talk a little bit about manufacturing as part of this process, both as part of the data package where it has a much larger role than it does in traditional small molecule antibodies. And then -- we'll start with that, and then I'll go on to the commercial side. I don't want to turn this into a 20-part question.

Sure. Yes, manufacturing, we invested 10 years ago, early on in process development and analytical with people that were experienced in biologics, new large-scale production. And we applied a lot of the principles to large-scale biologics production to AAV production. And so interestingly, that came to fruition in terms of all those early process development initiatives translating right into the Duchenne program. So we have very high yields with very high purity. We didn't have to give up one for the other. And so 80% full capsid in our final product profile. I think interestingly, when you think about Duchenne and you think about clinical development, that product profile hasn't changed throughout, from the first patient we dosed into the last patient we've dosed in the pivotal study, the product profiles remain the same, which helps a lot with interpreting the clinical results.

And then in terms of scale up, we can produce 2,500 doses per year in our Rockville plant. We have full control of manufacturing, both on the bulk process and fill/finish. And having that control is enabling us now to build launch quantities throughout this year for potential approval in 2027. And we expect the cost of goods to be very attractive there.

So let's talk about the commercial dynamic. Obviously, in DME has been volatile. Some of that has been because of safety signals, label changes, label [indiscernible] changes for existing commercial competitor. Should we think about pricing as in line with existing commercial competitor? Or is that asset so different in terms of profile that that's not really an anchor? I was thinking about [indiscernible], obviously.

Yes. I think it's early days. We haven't really worked through on our side, the pricing strategy. But I think given that we're seeing the safety profile that we're seeing, you'll see more data this week at MDA, and then you'll see a larger data set with our top line data in early Q2. Given the safety profile and the early functional benefit, I think to expect that we would be in line with the commercial product is a reasonable starting point.

Great. And you talked a little bit, I guess, on the manufacturing side and what the margin profile means. Talk to us about how -- presuming that we see the data to MDA that's reflective of what you expect and the pivotal data shows functional benefit, the safety profile that we've seen thus far, et cetera, is filed and launched on time line contemplating the accelerated approval conversations that we've had. How much build-out on the OpEx side would you need between now and that launch to support commercialization?

Well, I think the starting point is all the capital that's required to meet commercial demand is already in place. So that's part of our ongoing burn rate, if you will, is the manufacturing is already in place and ready to go. So the cost of building launch inventory, as an example, is really the variable cost of production. And given the high yields that we experience, then the cost to be ready at launch with hundreds of doses is relatively small compared to what you've seen previously in gene therapy. So we feel like we're in a great position to really make a huge dent. The prevalent market is larger than it was 2 years ago based on the dosing levels that have occurred with the commercial product. And so the opportunity has actually gotten larger in our thinking. And our capability to meet that has, because of the investments we've made, put us right on the edge of being able to quickly take a significant position in the market.

Let's talk about the global opportunity. So time line to accessing OUS markets, how you think about infrastructure, partnership, that obviously is a meaningful pool of patients, [indiscernible] commercial competitor has made, I think, a partnership approach. Like how do you think strategically about that?

Yes. I think this is where being a fast follower helps tremendously. And what we see is from an accelerated approval, you're able to penetrate rest of world pretty quickly. You see, I think, strong sales from Roche in areas where not many have thought about it. I think Zolgensma paved the way for that in some ways. And then Elevidys has done well ex U.S. So our view would be to access markets of the AA approval internationally under named patient sales, for example, that could do that. We also have plans longer term to run a more standard placebo-controlled study because we know for some countries, EMEA, that's really a requirement that hasn't changed. If it does, we'll take advantage of it, but I don't see it changing near term. So I think it's -- and that's where I think having a partner in place ex U.S. would make a lot of sense to help do that. We don't have, obviously, a sales force in Europe to leverage whereas a potential partner might.

We'll always talk about partnership and what that means for your financial dynamics. Let's touch base on your partner on the ophthalmology side. We're expecting a $100 million milestone from them this year from Allergan. [indiscernible] you want to think about it for early dosing in diabetic eye disease. That's triggered by the first patient dosed. Talk to us a little bit about what the further path of cash flows from that partnership looks like and how you do or don't bake that into the guidance you gave at the recent earnings call in terms of cash runway?

Okay. Yes. So the cost of development is in our cash runway for both the remaining spend on the subretinal program and the starting spend, if you will, on diabetic retinopathy. And that was why the original milestone for $200 million with AbbVie was devised as first patient dosed in a pivotal. We didn't contemplate a IIb study. So when that became an element of the development plan where there's an interim read and then we would go quickly into a pivotal off that data. We redid the milestones so that we get $100 million off dosing first patient in the Phase IIb study, and that helps dramatically with the spend on diabetic retinopathy. So in a way, the milestones are paying for our portion of the study going out. We've pointed to having cash going into 2027 that does not include this milestone. So that will be supportive along the way.

And then I think the other really significant event that will drive value for us is in the fall when we unblind the subretinal studies with AbbVie, two 600-plus patient studies, the largest gene therapy studies ever run. And we really, really like the product profile that we see meeting our TPP, if you will, in subretinal. So safety looks great. The efficacy, we're out 4 years on some patients now. So I think that's a little bit of an untapped value add for the company that, quite frankly, has been quiet because we've been enrolling for a long time, but that time has ended, and we're looking forward to the top line data. We feel like it has a high probability of success.

While less of a focus than DMD and the debates on the regulatory and manufacturing safety debates on MPS, the commercial side of the story in ophthalmology has been one where investors have been more reticent to give credit. It's a big market. We haven't seen a gene therapy work there. The existing standard of care is, at least for wet AMD, pretty effective if applied as on the label. It is very literally a needle in the eye frequently. So there are some challenges for the patients to put it mildly. Talk to us how you and your partners think about the commercial opportunity for subretinal, suprachoroidal.

Yes. Subretinal, I'll start there. I think a couple of years ago, people were saying for subretinal that the standard of care was formidable and that an approach to extend out and in the case of gene therapy, maybe indefinitely the treatment would barely make a dent in that market. And now you've seen EYLEA HD, et cetera, come in and take significant portions. And any of the new entries to wet AMD extending out the treatment being adopted. So gene therapy to me is the next big step in that. It's not going out 4 months, 6 months, it's going out 3 years, potentially more.

So I think that on what we hear from KOLs, if you keep in mind, the wet AMD business is expected to grow to over $10 billion in the next few years, there is a significant place for the subretinal approach. And interestingly, I think differentiating our program for patients who are really hard to treat, people that have had monthly injections for years that are difficult to maintain, where if they become noncompliant, their vision deteriorates quickly. And we've treated patients like that when you look at our previous data. So I think put that all together and the fact that vitrectomies are common operations that are done by a retinal surgeon, it's not unrealistic to think of we could take 10% of the market. We could take 20% of the market if you consider fellow eye. That's a lot. There's no other gene therapy that has that kind of potential in ocular that's this close to an approval. So we feel great about that.

I think diabetic retinopathy from the beginning, we knew that a subretinal approach would not be likely adopted by patients who already won't take Lucentis and so -- because they're asymptomatic, they don't see the need and the drive to have such a "severe treatment." That's where the suprachoroidal delivery of RGX-314 is incredibly attractive. It's an in-office treatment, one time. And we've got patients out now 2.5 years where we're seeing 2-step improvement on many of those patients. And I think people are now seeing DR as big of a potential opportunity, if not bigger than what we see in wet AMD because of the unmet need. So I think all of those together, we'll hear AbbVie, I think, speaking about our program a lot more now that we're in late stage. They have responsibility for the filing for the subretinal program once it reads out, and they're very quick to -- from data to filing, they've got a powerhouse in terms of regulatory and clinical support there.

I'm going to pivot over to MPS if I may. Another kind of regulatory conversation with the nuance and obviously, 2 different programs. Presumably, you're actively in conversation with a Japanese partner. Talk to us about the state of that conversation with the FDA, when we should expect to hear more? And what are the underlying issues to resolve based on what we know thus far, which is maybe incomplete?

Yes. So I think there's 2 elements to it. There's the clinical hold that occurred on 111 and 121 and then there's the CRL that was issued on 121. The clinical hold, we've received the hold letter. And I think everything that we were already proactively working on is in the letter. So we feel that, that is a resolvable issue within months, not years. There's no new preclinical work that's been asked for, nothing of that nature. So we're following up on that. So I would expect to see us working towards getting off hold first, and then we will have the Type A meeting post that to address the CRL.

I think one element of the 121 discussion, there were 2, I think, main issues. One is the biomarker. So D2S6 is a little different in perception to heparan sulfate. It's less published in terms of people's awareness of that. But D2S6 is just a subunit of heparan sulfate. So to the extent that other programs that are dependent on heparan sulfate as a biomarker get approved, I think that precedent is really, really important for 121 because we've measured in addition to D2S6, heparan sulfate in the same data set that we've already shown and feel really confident that we have a really meaningful effect on reducing it.

And then the second part was, did we dose patients who were neuronopathic in the study. And we have Dr. Joe Muenzer, who's world expert on MPS disease, has independently looked at our data and confirmed that the patients we treated were -- because of their mutation status and other baseline characteristics, clearly neuronopathic patients. So I think we're just looking forward to a Type A meeting where we can get into that in a lot more depth with FDA. We're willing to pivot to heparan sulfate, if that's what it takes to obtain an approval. Bottom line is we love our data. We haven't had any outside group that's reviewed our data, say, this is not compelling or patients wouldn't benefit from this. And I think we've had really strong support from the patient advocacy groups in that. So by all -- as it relates to NS Pharma, we've confirmed to them that we're convinced that we can manage this to an approval.

So I want to dig in on that dynamic around neuropathic patients. So the review of your patients to find them more neuronopathic is one side of the date. There will be those more conservative, skeptical, bearish, whatever phrase you want to use, investors who will argue, well, isn't the debate more how you determine if patients out in the world are neuronopathic and who to give it to as opposed to are your patients in the study qualified. How do you answer that conversation around, well, the real debate is how do we find out who is neuronopathic in the community?

Yes. I think that -- yes, the criteria can be pretty straightforward. Patients of newborn screening will be diagnosed with MPS disease. That doesn't necessarily mean they're neuronopathic. So the second level of diagnosis is their mutation status. Some mutations are clearly -- sort of 66% or more of patients diagnosed with MPS disease are neuronopathic from all the available literature. And that next layer of how to get to that is a few things. If they've had a sibling that's neuronopathic, they will be neuronopathic. If they have a mutation that is known to cause a neuronopathic decline, that will qualify. And then the last one is if they've actually started to deviate from normal cognitive development, and this will be a discussion with FDA, by x units, make up a number, then clearly, they're on a decline phase. That one, I think, you should be pretty liberal with how early you intervene because you can't reverse the damage. So we've always felt that long term, this has to be something that's dosed early on if you want to fully prevent the worsening of the disease. But I think there are very clear criteria that we could agree with FDA on, and we had this discussion with them that we'll continue to have it with the Type A meeting as well. But I think it's something we can sort out.

And hopping back from there to the related balance sheet question. Can you remind us which of the programs that you're currently in discussion with the FDA or will be filing in the next year would be eligible for PRV?

In terms of the PRV, the interesting thing on 121 is originally, there was a September deadline. So if we were not approved ahead of that, the PRV would have expired, but that legislation was renewed. So 121 will remain eligible for a PRV. 111 would be eligible for a PRV, but we haven't started the pivotal. And then actually, the 202 program as well will be eligible. So 3 of them.

And obviously, there's a debate that now that time limitation is lifted, there's an open discussion in the market around what is the PRV worth? Obviously, we can't put a number on it. But when you think about where the demand for these assets is, I'm not sure if you guys have already started those conversations or tested those waters. I would presume you have given what we thought would be the timing of the PRV for MPS. Talk about how you think about those assets as a source of financing that is nondilutive to ownership.

Yes. I think they're incredibly valuable. And I think particularly in the risk/reward of developing a rare disease, they are an important factor. So we were pleased to see the legislation renewed. There has been a PRV sale post renewal that is in the $200 million range. So people might have speculated that, that was going to drop to $125 million to $150 million, and it hasn't. And I think part of it is -- it's like old baseball cards. There's a scarcity of PRVs available. Over time, that will probably normalize. And so I would imagine the pricing of a PRV will normalize over time as well. But it's still significant value to a company like ours. Every PRV would be at least half a year's worth of burn. So that's why we're wanting to continue to develop in this area, mostly because we care about the patients and everything they've done for us over the years being part of our studies, but as well, you have to pay the bills. And I think these are a very nondilutive strong way of doing so.

I want to go from that sort of broadly handling of the balance sheet side of the house to the operational and strategic side of the conversation. Obviously, you guys are tremendously focused on a near-term potential launch in DMD. Your partner, AbbVie Allergan are obviously quite busy on the opto side. MPS is TBD, although as far as partner there. How do you think about the pipeline earlier in DMD? And are there like opportunities for expansion? Is that even the right strategy? Or is the company so fully busy across all these programs does it make sense? Like how do you think about what the right answer is? Because I'm presuming success over the course of all these programs in the next couple of years?

Yes. I think that's a great question. 95% of our spend is targeted towards these late-stage programs. But the 5% that isn't is incredibly productive. We have new capsid technology that we're developing, liver detargeting capsids and also capsids, which are customized for suprachoroidal administration. And we are doing preclinical work in dry AMD as well using that new capsid. So I think we'll be in a good position once people hopefully see positive catalysts on these main programs to say what's next? I think we'll have good answers for what's next.

Well, we'll be looking forward to that. We're winding down to the end of our time. Thank you, and I look forward to continuing the conversation.

All right. Thanks for having us.

Thank you for standing by, and welcome to REGENXBIO's Fourth Quarter and Year-end 2025 Earnings Conference Call. [Operator Instructions]

I would now like to hand the call over to Patrick Christmas, Chief Legal Officer of REGENXBIO. Please go ahead.

Good morning, and thank you for joining us today. Earlier this morning, REGENXBIO released financial and operating results for the fourth quarter and year ending December 31, 2025, The press release is available on our website at www.regenxbio.com. Today's conference call will include forward-looking statements regarding our financial outlook in addition to regulatory and product development plans. .

These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties.

These risks are described in the Risk Factors and the Management's Discussion and Analysis section of REGENXBIO's annual report on Form 10-K for the full year ended December 31, 2025, and comparable Risk Factors section of REGENXBIO's quarterly report on Form 10-Q, which will be on file with the Securities and Exchange Commission and available on the SEC's website. Any information we provide on this conference call is provided only as of the date of this call, March 5, 2026, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events or otherwise.

Please be advised that today's call is being recorded and webcast. In addition, any unaudited or pro forma financial information that may be provided is preliminary and does not purport to project financial positions or operating results of the company. Actual results may differ materially.

I'll now turn the call to Curran Simpson, President and CEO of REGENXBIO.

Curran?

Thank you, Patrick. Good morning, everyone, and thank you for joining our call today. 2 is set to be a pivotal year for REGENXBIO with great focus on advancing our late-stage pipeline in 2025, we entered the year with near-term top line Phase III readouts and ongoing commercial readiness activities in Duchenne muscular dystrophy and wet AMD. Last but not least, we are also entering the pivotal Phase IIb/III program named Navigate for diabetic retinopathy being developed in collaboration with our eye care partner, AbbVie.

Our clear focus on execution in 2025 has led to a robust set of important catalysts to transform REGENXBIO from a late-stage development organization to a commercial entity. Today, I am joined by Dr. Steve Pakola, our Chief Medical Officer, who will walk through the ongoing clinical advancement of our programs; and Mitch Chan, our Chief Financial Officer, to provide our financial updates. With that, let me start with RGX-202 our late-stage Duchenne program. I'm pleased to report that momentum for RGX-202 our potential best-in-class gene therapy for Duchenne remains strong.

We completed dosing in our pivotal study last fall and are seeing robust enrollment in our confirmatory trial, reflecting continued enthusiasm from the Duchenne community. Our growing clinical data set, including the 18-month Phase I/II NSAA results shared in January demonstrate meaningful differentiation from the known natural history of Duchenne across multiple validated measures. Combined with a favorable safety and biomarker profile to date, we believe RGX-202 has the potential to deliver durable, clinically meaningful benefit.

With less than 1% of the global Duchenne population having received an approved gene therapy and no approved option for patients ages 1 to 3, the unmet need remains significant. We look forward to sharing additional Phase I/II data next week at the Muscular Dystrophy Association's Annual Meeting and top line data from our pivotal study early in the second quarter as we advance towards a BLA submission.

We look forward to engaging with FDA midyear to discuss our planned BLA submission using the accelerated approval pathway. We have FDA engagement planned ahead of the pre-BLA meeting and intend to support our primary microdystrophin endpoint with significant functional data, both in the pre-BLA meeting and at the time of submission. By the fall of 2026 we will have 12 months functional data on the majority of pivotal trial patients. In addition, with the enrollment momentum in our confirmatory study, our safety database continues to expand.

In our retinal disease programs, our partnership with AbbVie continues to progress. Top line data for subretinal cerovec in wet AMD are expected in Q4 this year. Atmosphere and Ascent represent the largest global gene therapy program in this indication. And if approved, CERovEK would be the first gene therapy for wet AMD. I'm also pleased to share that site activation plans are also underway in the NAVIGATE pivotal study in diabetic retinopathy with first patient dosing expected next quarter. triggering a $100 million milestone from AbbVie.

Finally, turning to our MPS programs. Since receiving the CRL for RGX-121 two weeks ago, we have also received the clinical hold letters for both RGX-111 and RGX-121. We believe that the requirements to remove the holds are addressable. And in fact, had already been in the process of addressing them. We continue to work on the CRL response and working towards a type A meeting with the goal of resubmitting the BLA. We remain committed to the MPS community and the Hunter syndrome patients waiting for a treatment for this devastating disease.

As we enter 2026, our focus is clear. execute against our key milestones and bring the hope for transformative gene therapies closer to patients in need.

With that, I'll turn it over to Steve.

Thank you, Curran.

I'll start with the RGX-202 program for the treatment of Duchenne. As Karen mentioned, we are incredibly excited that enrollment in the Affinity Duchenne pivotal trial completed in October 2025 and -- as a reminder, this study enrolled ambulatory patients aged 1 and older and is the most advanced clinical stage gene therapy program for Duchenne RGX-202 has demonstrated a highly differentiated safety and efficacy profile with consistent robust microdystrophin expression in the Phase I/II study. This includes the positive NSAA data we disclosed in January.

As Karen referenced, the 7.4% average improvement compared to the recognized CTAP model observed that 18 months is striking. These results are generally consistent with the October 2025 data, showing all patients exceeded their expected functional outcomes when compared to cTAP as well as match external controls at 12 months. It's important to note the majority of these patients were 8 years and older at dosing an age when functional decline is expected, making these functional outcomes even more impressive.

The Duchenne patient and physician communities continue to recognize the excellent safety profile of RGX-202 to date. As reported in the Phase I/II study, we have seen no SAEs or AESIs, including no thrombocytopenia or liver injury. We attribute this to our proactive immune suppression regimen, our novel construct and our field-leading product purity with more than 80% full capsids. We are very pleased with how these differentiated elements enable us to deliver [indiscernible] at a 2e14 dose and maximize the potential for efficacy without compromising safety.

Next week at MDA, we are thrilled to share additional new Phase I/II data on podium, including functional and safety outcomes. With this momentum in our pivotal study, and results to date in the Phase I/II study, we look forward to sharing top line data from the pivotal study in early second quarter this year. Turning now to our CureVac franchise, which is advancing onetime treatment for wet AMD and diabetic retinopathy or DR.

Enrollment is complete in atmosphere in Ascent are 2 large pivotal studies intended to support global regulatory submissions for subretinal wet AMD starting next year. The data from the subretinal program have been excellent with durable outcomes reported through 4 years in the Phase I/II trial. Additionally, SERIVEC recipients in the felloweye bilateral dosing study demonstrated a 93% reduction in annualized anti-VEGF injection need at 12 months with 60% of recipients remaining injection-free through that time frame.

We look forward to sharing top line results from Atmosphere and Ascent with AbbVie in Q4. We are very excited to be advancing CERIVEK into pivotal stage for DR using in-office suprachoroidal delivery with AbbVie. This progressive vision-threatening disease is a public health priority globally. It remains a leading cause of vision loss among working-age adults in the U.S. and a onetime treatment could change the way this disease is treated for millions of people. Site activation activities are underway in the Phase IIb/III NAVIGATE trial. This is a double-masked sham injection control trial evaluating CeraVe at [indiscernible] which is the same as dose level 3 in the Phase II ALTITUDE trial.

The Phase IIb portion of the study will enroll 136 patients with nonproliferative DR or NPDR. The primary endpoint is 2-step or greater improvement on the diabetic retinopathy severity scale or DRSS, at 1 year. As a reminder, in the Phase II [indiscernible] trial at 2 years post treatment with dose level 3 and short course prophylactic topical steroids, no intraocular inflammation was observed. The majority of subjects achieved DRSS improvement with 50% achieving at least a 2-step improvement without any additional DR treatment. [indiscernible] at Dose Level 3 also reduced the risk of disease progression, demonstrating a greater than 70% risk reduction in vision-threatening complications compared to historical control.

As Curran mentioned, we are working towards addressing the clinical holds for 111 and 121. And in the interim, we have received the final genetic analysis from the SAE in the RGX-111 study. The analysis of the resected tumor was conducted by an independent third-party lab and as we reported, detected an AAV vector genome integration event associated with overexpression of a proto-oncogene [indiscernible].

Clonal integration of AAV vector elements into the Plage 1 gene was detected in the tumor tissue. Analyses supported classification as a plug-on family neuroepithelial tumor and are consistent with the hypothesis that AAV vector integration at the [indiscernible] site contributed to tumor formation. Of note, this participant had a background of factors that could have contributed to risk of oncogenic transformation.

This child underwent an unsuccessful stem cell transplant at 4 months of age with loss of donor chimerism and he received chemotherapeutics that may have contributed to DNA damage. Notably, the report concludes based on formal neuropsychological testing and developmental pediatrician assessment that the patient's neurocognitive development is above average, which indicates mitigation of MPS I disease. We anticipate the analysis will be published in a peer-review journal this year, and we are pleased that the patient continues to do well.

Finally, I'd like to express my sincere gratitude to all the patients, families, clinicians, site staff and patient advocacy representatives who have supported these trials.

With that, I'll turn the call over to Mitch to review our financial guidance.

Mitch?

Thank you, Steve, and good morning, everyone. REGENXBIO ended the quarter on December 31 and with cash equivalent and marketable securities of $241 million compared to $245 million as of December 31, 2024. This year end figure reflects the $110 million upfront payment from the PanchenYaku in the first quarter of 2025 and the $145 million in net proceeds received from the royalty monetization with Healthcare Royalty Partners in the second quarter of 2025 and offset by cash used to fund operating activities through the year.

We continue to invest in derisking our late-stage program in 2025. R&D expenses were $228 million for the year ended December 31, 2025, compared to $209 million in 2024 with much of this cost going to pivotal trial execution and manufacturing of RGX-202 [indiscernible]. We also continue to bring meaningful revenue to ReGenXBOu in 2025 with total annual revenue being $170 million. This includes the upfront license revenue under our [indiscernible] collaboration as well as an increase in royalty revenue for Zolgensma and Visma, both of which are included in our royalty monetization agreement with Healthcare Royalty.

We expect the December 31 cash balance reported today to fund our operations into early 2027. This cash runway guidance does not include the $100 million development milestone we expect to receive from AbbVie upon first patient dose in the NAVIGATE study or any additional funds from the May 2025 Healthcare Royalty agreement, which together could extend our runway into the second half of 2027. This guidance also does not include any future revenue from our MPS programs.

In all, we find ourselves in a strong position to leverage multiple funding options as we advance towards multiple product launches. With that, I will turn the call back to Curran to provide final thoughts.

Thank you, Mitch. As you heard today, our strong execution has positioned us for an exciting and transformational year ahead as we share pivotal readouts and look to enhance the treatment landscape in Duchenne, wet AMD and diabetic retinopathy, representing large indications and commercial opportunities. Our investment in in-house manufacturing and co-development with world-class partners keep us in a strong position as we approach commercialization. .

Last week, we joined the rare disease community in recognizing Rare Disease Day, and I'd like to take a moment to acknowledge these patients, families and community leaders. We know they are counting on us to deliver innovative new medicines, and we greatly appreciate the support they've shown us, particularly on our rare programs recently. Their needs are significant and urgent and we are inspired by their commitment to raise awareness and give voice to the critical need for new therapies.

With that, I'll turn the call over for questions.

Operator?

[Operator Instructions] Our first question comes from the line of Mani Foroohar, Leerink Partners. Please go ahead, Manny.

So as we get closer to data and regulatory clarity in terms of submission around DMD, obviously, there's a lot of debate and concern around whether a controlled trial or an appropriate control arm could be, obviously, there are both Sarepta and solid seat in the confirmatory and pivotal studies, respectively. What gives you confidence on your past flow rating approval and on the design of your confirmatory study was a little bit different than both of those competitors. .

Thanks, Mani. I think there's a number of aspects to that, that give us confidence. I think number one, the fact that the protocol was prospectively reviewed by FDA. We received comments on the design of the study and the stats plan around comparison to external controls -- so we feel like we have -- and none of that's changed. We haven't altered the pivotal protocol through execution. I think the second pillar of that is there's not a narrow difference between the results we're seeing on functional outcomes versus natural history comparatives, and this is matching many patients against the patient treated. So I think that the fact that we have such compelling data, specifically in the older patients where they're typically in a decline says, I feel will sort of trump the concept of a placebo arm, which we don't think is ethical.

And I think the other aspects of how that relates to the confirmatory study -- the confirmatory study was included in the original protocol as in addition to the pivotal design. So again, that was reviewed by FDA we're really pleased with how the enrollment is going there. And 1 thing that's enrolling as quickly as we have on the confirmatory study does in a positive way, increases the number of safety exposures that we have at the time of filing. We're talking about roughly 50 total rather than the 30 that were in the pivotal group. So a broader safety database at the time of review, which will be very helpful because in our end of Phase II meeting, 1 of the things that we heard as a ticket to accelerated approval was similar efficacy but improved safety. And that was pre black box warning for elevates.

So I think we are in an even stronger position now around our data set, and we look forward to discussing that with FDA in our pre-BLA meeting.

That's helpful. And as a clarifying question. when you talked about reaching alignment, submitting the protocol, including the confirm risk date for the call, can you give us teloft when that happened? And if those interactions were with FDA and CBER under the current leadership or under the prior leadership for seeding soda Mary? .

Yes, I can comment on the latter part of the question. It was just -- it was under the prior leadership. This was roughly 2024 that these discussions took place. But I would say the review team that we spoke to when this was reviewed by pretty largely intact from what we can tell to date. Steve, if you want to discuss just the prospective nature of the data plan.

Sure. Thanks for the questions, Mani. So highlighting what Curran mentioned, the importance of prospective design. So this was all set as of those discussions that Curran met. So for example, the primary, this is accelerated approval. So we were very clear in our design of the primary being microdystrophin. We were also very clear in the secondary functional endpoints that we were looking at in the methodology for assessing that. So this is in a case where midstream we change something or we looked at data and adjusted how we were looking at the data. .

And Mani, 1 thing I would add in general is we understand the environment and where people are trying to assess FDA's position from the very beginning of the study, we knew about the controversy around micro dystrophin as a biomarker reasonably capable of predicting clinical benefit or functional benefit. And I think that's why in the way we've designed the study and then the way we're approaching FDA, we're maximizing the functional data that we bring to the review. And I think that's an incredibly important aspect of how we're approaching this because we feel like the functional data really supports the improved biomarker data that we have over current therapy.

Our next question comes from the line of Judah Frommer of Morgan Stanley.

Maybe just a follow-up on 202 to start. If does end up wanting potentially longer duration follow-up, specifically for safety and you go down the path of a traditional approval. What would that entail? What would the confirmatory trials will be in that scenario? And then just on the hunters program, there's an approval decision coming up for Denali. What would you hope to learn from that program as you go back to FDA to discuss once along with them.

Sure. Judy, I think on -- if FDA expects longer-term functional data, the time points I would keep in mind is we completed enrollment of the pivotal study end of October last year. So at that point, this year, we'll have 12-month data on the full pivotal data set. And then, of course, there's time for QC of the data and then incorporating that into a filing. But it's a near-term event that we would have functional event -- functional data on the full pivotal data set.

And then if you consider that maybe there's a larger sample size required. The fact that we immediately went into enrollment of the confirmatory study, just keeps working towards more data as we go through the year. So I feel like there's no discontinuity between our pivotal and our confirmatory data set. But we feel like the data we've seen in the Phase I/II is already strikingly different from natural history. And so more is not always better in that case, given the unmet need that we're seeing, the prevalent market continuing to grow.

So we feel like we're in a good place, notwithstanding as well the safety profile that we're showing. We have investigators clamoring for something where they don't have to worry post treatment of these events that have been seen in high-dose [indiscernible]. On the outcomes for 121, we certainly will pay a lot of attention to Denali's PDUFA decision. And in particular, the fact that part of that submission and significant element of that submission is heparan sulfate based biomarker.

If you go on chat GPT and pull up D2 S6, it clearly says that it's a subcomponent of heparan sulfate. So we see them as the same, but in the event that FDA continues to not necessarily see them the same, but endorses heparan sulfate, we'll be in a great position with our data to pivot to that, if that's what's necessary. But we feel really strongly that our data set using D26 shows really good biomarker reduction, very consistent across patients who we know are neuronopathic from external reviews.

And so we look forward to the Type A. But I think -- to your point, it will be helpful to see decisions on Ultragenyx' program and Denalis program to see how that may or may not affect ours.

Do you have those hopper and sulfate assays if it's a relatively simple addition to the submission?

We do.

Our next question comes from the line of Annabel Samimy of Stifel.

I'm going to be original and ask about 314. So I noticed that you test you were moving forward with dose level 3. And I know also that you had agreed with AbbVie to conduct a Phase II trial to test the higher dose, but you are going with dose level 3. So I guess the question is why -- is it not going straight into a Phase III? Does Phase II/III also count as part of that pivotal -- and just curious about what you found with the L4 that made you go with the L-3 and what does this mean for wet AMD.

Great.

Thanks, Annabel, and I'll comment a bit on the trial and what's coming, and Steve can comment a little bit on the dose selection. Keep in mind, for the Phase II studies on diabetic retinopathies. -- relatively small sample size, but strikingly good results in terms of what we were seeing on 2-step improvement, et cetera, that we've published. The goal really of the Phase IIb as it stands now is just to expand that data set to a higher number of patients and confirm that result. But it's sequenced to be often interim look and then directly into a larger pivotal study.

And I think that's just prudent risk management as we develop the program and move forward. The patients that are treated in the Phase IIb will certainly contribute to the safety database that will be created for DR, so they are helpful in some ways, managing the size of the pivotals that we have to run. Now I'll let Steve talk a little bit about the dose selection.

Sure. First, Annabel, thanks for raising certainly 1 of our big priorities, which is DR, given what a massive unmet need that is where we certainly believe a onetime treatment is really what's needed for this disease to make the ultimate impact. And the other thing I'd say is on the dose selection and the Phase IIb/III concept is it's a real validation of not only our commitment but also AbbVies to embark on a Phase IIb/III program.

So as any program, we do the dose escalation to really look at safety and efficacy. I think 1 of the aspects was with the time that we took to evaluate dose level 1, dose level 2, dose level 3, the longer we look, the more compelling dose level 3 became and it really reached a point of pretty remarkable results where we were definitely hitting our target product profile where the durability to actually see 50% of patients not only be stable, but actually have at least a 2-step improvement in diabetic retinopathy was really quite compelling.

And I think clinically, even more meaningful for clinicians is the fact that there was a dramatic reduction in vision-threatening complications over 70% compared to what you'd anticipate without treatment based on natural history data. So I think this constellation was really what drove the decision for us and AbbVie if you're already at your target product profile and meaningfully with short course topical steroids, 0 cases of IOI, which is really the big sensitivity in the retina community when it comes to safety. We really had what we needed to go forward.

And once you hit your target product profile and you're really frankly, plateauing in terms of the results that you'd anticipate and you're seeing durability that made it a clear decision for us and [indiscernible] to move forward.

Just a follow-up, like I know that you're exploring deals for and what AMD are you not going to move forward with that 1 given the profile for DLL3? I guess I'm just trying to understand if there's any safety question with the L4.

Yes. So wet AMD is just a trickier indication in terms of reading the tea leaves and looking for a signal in terms of efficacy compared to DR where there's no other treatment and you're really looking at a pretty binary assessment of things like actual improvement in DR. So I think it's just more straightforward to make a decision on DR as compared to wet AMD. So we in Ai are continuing to evaluate the data. .

Our next question comes from the line of Alec Stranahan of Bank of America. .

Two for me as well. I guess first is on the functional data. Could you just remind us how much of this you'll be providing the top line? I guess how many patients you expect you'll have at that point for the 12-month functional data? And then -- just on MPS I, curious how the neoplasm in the MPS I patient maybe shifts the benefit risk discussion with the FDA and guess what kind of mitigation measures you're considering here given it sounds to be AAV-related.

Thanks, Alec. I could speak a bit on the top line data plans. So I think as we've previously discussed, we will have, obviously, a safety data update on the full cohort, which is -- we'll have biomarker top line data for the primary endpoint for the full pivotal data set as well. In terms of functional data, we haven't set a specific time for the release of the top line data. So it's a little bit in flux, but I'd set an expectation of roughly 7 or so patients at 12 months for functional data.

And then, of course, throughout the remainder of the year, we'll consider updating that as additional data comes in. Historically, we did report some 9-month data early in the Phase I/II studies, and I think we're going to try to avoid that because that really doesn't work well with most of our natural history comparisons that we would like to make. And I think on top of it, we just feel 9 months is too early to judge sort of stability of effect on function. But as we go past 12 months, then I think we get to a meaningful level of functional data, and they're well past the removal of mean suppression agents.

And I can jump in as well, AleC, on the MPS I neoplasm. So you, of course, hit the nail on the head of, what does this mean in terms of the overall benefit risk. And our view and what we hear from clinicians as well is that -- on 1 hand, you have the risk of a rare event such as tumor, which isn't completely unanticipated, given the fact that -- we know that integration can happen with AAVs. And in fact, it's even included in AAV gene therapy labels for that reason the potential risk. So Fortunately, it does seem to be a very rare event. We have over 6,000 patients treated with AVs of different sorts by different sponsors and here's a case where integration happened at a proto-oncogene.

So the clinical community, if we raise this with investigators and KOLs in the space, almost instinctively their first response is, okay, there is a rare risk of a tumor versus 100% risk of inexorable decline and irreversible brain damage. So it really comes down to that context for this devastating disease with such unmet need that the clinicians, it hasn't changed their view of the favorable benefit risk. So from our view, going forward, as far as mitigations that you raised, just as in this patient, we can look at MRI -- periodic MRI.

We've already looked at that and the other patients, not only in the 111 program, but also 121 and not seeing any other evidence. And of course, full disclosure and investigator brochure and informed consent. And with that knowledge, clinicians and the patient families are able to make that assessment about benefit risk.

Our next question comes from the line of Paul Choi of Goldman Sachs.

I have 2 on RGX-202 please. First, with regard to the data you'll have next week at MDA. Can you just clarify what patient numbers you'll have an additional duration of follow-up? Or should we just think of -- or will it just be additional details on the 18-month data that you previously presented? And my second question is, you've -- in your press release talk about the functional data to date in the context of a cTAP analysis. Can you comment on whether the -- in terms of your FDA interactions, there's alignment on using these kinds of analyses versus sort of conventional North Star analysis? Any clarity there on the FDA's acceptance of those -- that evaluation framework would be helpful. .

Thanks, Paul. I think because the MDA manuscript is in deep editing mode with Steve, I'll let Steve cover the expectations for MDA next week. But it will be, I think, a pretty substantial update, maybe the last update, if you will, in terms of Phase I/II data as we transfer over to our pivotal program. But Steve, maybe you want to comment on what to expect?

Sure. So all patients with the primary endpoint, I think, is obviously a key aspect for what we anticipate. We're almost there actually in what we've disclosed before. I think function, the key thing is more patients and longer follow-up. We're really excited about the fact that we've already disclosed previously last year and early this year, several different cuts of functional data, we're really happy with what we've seen in dose level 1 and dose level to even out to 18 months with dose level 2 for the cTAP.

So it's just really a great chance to keep building on that base of functional data. The consideration on the different ways of looking at function and what to compare to, CTAP, I think it's important to note that the program doesn't hinge on CTAP. It's really a supportive analysis. So our view is the totality of the data is important that in looking at control data from external databases. It's very comforting and very validating of different ways of looking at it. You see very consistent results. and that's what we've seen to date. But certainly, our primary approach from a functional basis, and this is what we've prespecified as well is the traditional approach separate from cTAP where that includes as well the propensity score weighting.

So I think that's going to give audiences, also a sense to see how the results are looking compared to what 1 would anticipate based on a prior analysis. So we're going to be looking at all this, and I think you can anticipate seeing several different ways of looking at comparison to expected trajectory without treatment.

I think 1 thing I'd add on MDA as we have a poster that will accompany the podium presentation. We haven't talked a lot about benefit to cardiac in Duchenne. And part of the reason for that is that we expect those type of outcomes to be much more long term in terms of seeing that in the clinical setting. So what we're providing at MDA is a preclinical model of specifically showing the differentiation of our construct using the C terminus in potentially preventing cardiac deterioration, if you will.

So just something to have a look at as part of the total data set, some additional preclinical data that we think really supports what we've known from our preclinical work where we saw good biodistribution in the MDX model in cardiac muscle. So stay tuned there.

And the other key thing is continued safety. So the earlier question about how much long-term safety. So each update is not just the functional but a chance to show continued differentiation on safety.

Our next question comes from the line of Luca Issi of RBC. Luca.

Great. Maybe, Steve, any update on safety for DMD? You obviously have a very strong scientific hypothesis around sirolimus and eculizumab and ratio, et cetera. But we've seen obviously more setbacks for the field on the safety side from Pfizer and rep that we would have liked. So I guess what percentage of your patients have ALT and AST elevations at this point? And how are the kinetics of those curves in terms of both like peak and area under curve compared to Sarepta and Pfizer. I don't think we've seen those curves before. So I need context there would be much appreciated.

And maybe quickly, Steve, also on the CRL for MPS II, the Napoli -- why did you measure heparin sulfate and baseline versus after therapy using 2 different routes of access I think the CRL notes that you used ICV of baseline versus final tap asset therapy, which obviously created some variability. So I'm just curious for why you decided to do that .

Sure. So on the safety aspect, there are several reasons why we anticipated having a differentiated safety profile, the higher purity the specific construct and our immune modulation regimen. And I think a key factor is we haven't changed our immune modulation at all. since the beginning of the study. So I think that gives comfort in how to analyze the type of safety data that we're seeing. Phase I/II, we continue to see no cases of the liver injury. So it's 13 patients, but 0 out of 13 is clearly different from existing therapy where that rate is 40%.

So we look forward to showing some more details on that from the Phase I/II study at MDA as well. Also on thrombocytopenia, no cases of thrombocytopenia as well, which is 1 of the key complement mediated signals of complement activation that could signal a potential risk for other more serious events. So we continue to see the differentiation that we'd like to see and look forward to showing more data going forward. And of course, we'll have the top line results in the first half of the second quarter, which will be another cut for you to get more comfort on the data.

So on to the CRL, there was, yes, some comment about the potential impact of route of taking the sample. There was consistency actually in the vast majority of patients utilizing the same approach. We actually have the benefit of screening and baseline measurement where we have total consistency of ability to match like-for-like or apples-to-apples in terms of the same method of sampling and we see really the same results in terms of change from baseline. So that will be part of our response of doing -- showing that analysis more clearly and more upfront so that they can get comfort around that difference.

Our next question comes from the line of Brian Skorney of Baird. Brian.

A couple of questions for me. Maybe going back to some of the questions around the adult 2 subunit discussion on Hunter applications. There's a lot of talk about it in CRO and I think references -- this as a discussion point in the mid-cycle review meetings. I guess at any point where measures of regular heparan sulfate discussed and submitted in the application process. It seems like something that could have been addressed. -- during the review? And can you share what the SH data look like in the CS app and the other organs with us?

And then on DMD, given what you've been through in the Hunter review, what sort of dynamics and questions are you looking to have answered in the pre-BLA meeting with the agency. And I guess, the bottom line is, does anything coming out of your BLA meeting matter if it isn't coming directly from an ipraside.

Thanks for the question. I'll take the DMD 1 and then I'll maybe have Steve talk through the heparin sulfate data, which we did provide limited Hepinsulfate data during the review, but it was quite late in the review cycle. But I think in terms of what are the outcomes we're looking for in the pre-BLA meeting, I think that's the point at which, if you recall all the way back to the original protocol and our end of Phase II meeting, 1 of the things that we discussed with the FDA was correlation of the microdystrophin results to functional outcomes was something that was an expectation of FDA.

Now importantly, there was no specified number of patients of data that had to be provided to make that correlation. I think that was something that everyone considered would be a review issue at the time I think as we've seen in our Phase I/II data, there's a very strong correlation that we're seeing to date, all of our patients above the 10% threshold, and we're seeing the majority of patients having not just sustained function or lack of disease progression, but improvement in age groups where you wouldn't expect it.

So I think we have really compelling data, which at the time of the BLA discussion -- pre-BLA discussion, I think, will be very helpful, hopefully, to encourage we're ready to file the BLA. The timing of the pre-BLA meeting is optimized now to provide sort of maximum functional data at the time of discussion. So we have moved it out slightly, but it doesn't really alter I think the overall speed at which we can file, which we could file immediately after that meeting.

Typically, a pre-BLA meeting will incorporate feedback from FDA leadership -- so I think that's why that's an important event for us. And obviously, ahead of that, we're going to do as much as we can informally outside of that process to assure ourselves of a positive outcome. It's helpful. And then I'll let Steve talk about heparan sulfate a bit.

[indiscernible] .

Yes. Thanks for the question, Brian. So -- to start off, D2 S6, it's important to note that biologically, it's the substrate that directly would link to the enzyme that we're reconstituting with treatment. So that's why prospectively, that's what we put forward throughout the program. We do measure heparan sulfate. And likewise, we see not surprisingly a dramatic reduction in heparan sulfate. And I guess, similar to the earlier question about different routes of sampling in our response to the CRL will certainly lay out in greater detail our heparan sulfate results.

The other thing is we really have an opportunity to clarify a lot of the factors, not just the biomarker and function is another area where our clinicians are very positive about what they're seeing. And as you'd expect, the longer the follow-up, the greater clarity, you can anticipate seeing. So we can certainly show longer-term follow-up, which is 1 of the pathways that the FDA listed as a way to deal with the CRL.

Our next question comes from Eliana Merle of Barclays.

This is Tejus on for Elliot. You mentioned you expect 12 months functional data from the majority, if not all of the pivotal patients in the fall of this year. So how should we think of those data in context of the regulatory strategy? Could those be submitted as a supplement -- and could that extend the review time line.

That's a good question. I think that it will likely be a result of the discussion that we have at the pre-BLA meeting in terms of what level of functional data is required to submit -- there's no point to submit early if we're going to get additional data requests. So I think getting clarity on that with FDA will be very helpful. we'll be in a position, and we've already obviously completed our nonclinical work and that module is well along. We've completed substantially the in manufacturing work related to the BLA and that module will be ready quickly.

So I think the -- to answer your question, the timing of the full filing for the BLA will be dependent on the clinical data and the functional data that we incorporate into it. The chance to add it is a 120-day safety update that's part of a BLA submission. That has historically been very difficult to include additional clinical data beyond safety as part of it. So I'm not confident that we would be able to add at that point more functional data. So I think when we file, we want to be confident that, that's acceptable with FDA.

Okay. And just quickly on what the base case is think you refined requesting a pre-BLA in mid-'26. So how quickly after that should we expect an update? And the actual BLA submission, is that still expected mid-26.

Yes. The BLA submission could happen directly after the pre-BLA. One of the topics in the pre-BLA meeting will be the timing of submission with FDA. So I think post that meeting, we'll be in a good position to update on the overall filing time line. But yes, it's possible that we can still file within 2026. That's really dependent on these ongoing discussions.

Our next question comes from the line of Daniil Gataulin of Chardan.

On TM2, you mentioned pre-BLA meeting in mid-26 but also additional plant interactions in the first half. What is the agenda for those meetings? And secondly, what do you expect the regulatory path and the time lines to look like for European approval.

In terms of the regulatory interactions, we have planned meetings with FDA ahead of the pre-BLA meeting to get at some of the questions we've had today around our data analysis methods, some of which are new because we've been able to access additional natural history databases. And as Steve mentioned, and we've published additional cTAP data. So just trying to ensure that when we deliver our pre-BLA package, it's in line with FDA expectations. We haven't discussed the timing of those meetings, but they will be interspersed with things like top line data and our pre-BLA meeting as we go forward.

So the whole idea here is to de-risk the pre-BLA meeting with ongoing dialogue with FDA and ensure that we're fully aligned so that we have a high probability submission in terms of FDA acceptance. And I think, again, that's why we continue to publish our functional data because -- that's what we think is the most compelling aspect of this on top of safety is there's a huge unmet need in Duchenne, and we see the prevalent population actually growing. We see a pretty narrow payer band in terms of patient ages that are being reimbursed. And so we expect there to be a lot of energy around additional therapies being made available. And with our data, we think we have a compelling case to do that quickly.

Is that helpful? .

It is. And with respect to the regulatory path and time lines for European approval?

For European approval, right now, we're getting feedback on designs that include a placebo arm, which are feasible to run ex U.S. We don't have a specific time line that we've put out in terms of when that study would start, but we'll be more specific about that post that official feedback from EMEA.

Our next question comes from the line of Bill Man of Clear Street. -- it seems that there's kind of a broad.

To read the 121 CRL and extrapolate that to 202. So I was just hoping that you could point out specific points within the 12 RL that you don't expect to -- you expect to differ in 202 and not keep it from approval?

Yes, it's a great question. I think there are some real clear differences between 121 and some of it goes back to the history of development for both programs, the 121 program really was based on biomarker premise, meaning D26 being reasonably likely to predict clinical benefit. And we felt like we had closed that loop in terms of the RMAT designation, we got on the program in 2023.

In the case of 12 sometimes you need several years of post-treatment follow-up for those patients to clearly state that they're deviating from natural acquisition of skills and cognitive improvement. And so going into that filing, we didn't have the extent of clinical data supporting the biomarker that we do on 202. So in Duchenne, thinking ahead on that and knowing that there was controversy around microdystrophin within FDA. We leaned in heavily on recruiting as quickly as we possibly could and also putting together the functional data to correspond directly with the biomarker data. And so we know going into the review process that will need both -- so that wasn't the case on 121.

We were really relying on the biomarker premise and that's supporting data, but we only had at the time of filing 6 months of clinical data. In this case, for Duchenne, even going back to dose level, one, we'll have beyond 2 years' worth of data. showing durability of effect. And then for DL2, as we mentioned, several of our patients, maybe half the cohort out past 12 months.

So a much different discussion with FDA that will be armed with clinical data showing correlation to we think are very positive biomarker results that show the benefit. So I think that's probably the main difference between how those programs will go and why we think will be more successful in providing that kind of data.

And from the actual results, we also have the benefit of the safety differentiation again, -- and I think also the greater your data is the clear you can believe that there's an actual difference. So I think the 8 and older data, in particular, that Erin mentioned earlier, where patients are not just stable, they're actually improving. So I think that goes into the delineation here as well, where that is definitely not something 1 would anticipate without treatment and even with existing therapy to have an actual improvement in those tough to treat older boys. .

And I know, Steve, you mentioned that 6,000 patients have now been treated with AAV in 1 form or another. Is there a difference in the rate of AAV associated neoplasms across different tissue types or serotypes or disease states?

Yes. From preclinical data and clinical data, there doesn't appear to be any particular difference between different serotypes in terms of the rate of integration. So I think that's why across different programs that issue is raised that there's the possibility that given that there is rare integration, that at some point, you could have the integration basically go where you don't want it to go. But no, there's no real strong evidence of a particular predilection -- of course, you look at other factors like where do you give the drug, what is the promoter different?

What's the target tissue. And those are the aspects that give us a lot of comfort in terms of how this has really walled off from our other bigger opportunities of 314 and 202.

Our next question comes from the line of Sean McCutcheon of Raymond James. Sean.

Now you've announced the Navigate with the Phase IIb focus on 2-step DRSS improvement, how are you thinking about, if at all, the flexibility on that endpoint on binary or ordinal DRSS going into the Phase III, particularly as it relates to pulling out a benefit at 1 year versus the 2-year time frame where you saw the clearance benefit on 2 improvement at Dose Level 3 and altitude.

I think I'll let Steve shot at that.

Thanks, Sean. Yes, we're very pleased with the FDA's openness to looking at different types of endpoints and not just the traditional binary 2-step improvement or 2-step worsening and the precedent that's now out there. We and AbbVie decided to stick with the traditional 2-step change that's traditionally been used. But I think you raise a great point, and it's 1 of the positives of the Phase IIb design that we have. Yes, we are starting with at least 2 steps improvement, but we have the flexibility to take into account that data to assess?

Is it more sensitive or in another way, more power per number of patients that you have if you use an ordinal end point, and I think it is reasonable to think that, that may be the case because we're seeing benefit on both ends, we're seeing not only a higher rate of patients improving but also critically a higher percent of patients who are not getting worse. So an ordinal endpoint, when we look at things with AbbVie, may -- is certainly an option.

Our next question comes from the line of Yi Chen of H.C. Wainwright.

This is Eduardo on for you.

I guess a quick question going back to 2002. I'm curious if you've used the cTAP method to apply towards placebo arms in the elevates study. Obviously, 1 of the big gripes with the historical competitors that to see borrowers don't necessarily track with them. So I'm curious if you've actually used that method to see if you predict the placebo arms in these other randomized trials.

Yes. So there's different studies out there, of course. And there is always the caveat you have to mention about cross comparisons and specifics that might be different Certainly, when we look at what's out there with elevates in terms of cTAP or other models, particularly in the older boys, again, we do not see this evidence of older boys getting better versus just stabilization.

So a lot of the differentiation tends to be driven by the control data and approach. But again, I guess I'd circle back to, it's important to look at cTAP external matched control and also the propensity score weighting. So I think when we have our next data update is going to be easier for the clinicians and the broader community to try to compare what's been seen previously. But again, what we're seeing so far, if we continue to see that, we feel very confident about the differentiation by whichever method that we'll be presenting.

Thank you. Ladies and gentlemen, that does end the Q&A portion of our call and conclude today's conference call. Thank you for participating. You may now disconnect.

Good morning, everyone. Thanks for being here today. My name is Ranveer Gathwala. I'm a Vice President in the Healthcare Investment Banking Group at JPMorgan. It is a great pleasure that we have REGENXBIO today here with us. We're joined by Curran Simpson, CEO; Mitch Chan, CFO; and Dr. Steve Pakola, CMO of the company. I will hand it over to Curran shortly to run through the presentation, and afterwards, I'll moderate a Q&A session with some questions. With that, I will hand it over to Curran.

Okay. I got a little bit of buzz there. Okay. Well, thanks for spending a little bit of your Wednesday morning with me. Really pleased to present the company overview, to start by having a look at the forward-looking statement slide. I will not read it to you, I'll spare you with that. This is a really transformational year for the company. For those of you that may not know us well, we've been in AAV gene therapy for roughly 15 years. So a long legacy, first is out-licensing company, if you will, products like Zolgensma emanating from our original IP and technology. And then in the last 8 to 10 years, really taking new programs internal and developing them ourselves.

In NAV technology, there's 100-plus vectors that are within that NAV family. And we have five licensees, primarily via AAV8 and AAV9. And I'm proud to say that our technology, we've got over 5,000 patients dosed over the years.

We're going to mic you up so that [indiscernible] audio issues.

Okay. Thank you. This is a really pivotal year for us. No pun intended. We have a BLA under review for our Hunter program. I'll go through the pipeline and show you that. And we have top line readouts for two late-stage programs. One is the Duchenne program first half of this year. and then a very large wet AMD program readout with AbbVie late this year. So it's a real exciting time.

And as a result of that advancement, we're gearing up, you'll hear about manufacturing today. for commercial readiness, developing that some on our own and some in collaboration with our partners.

I'll just touch at the end of the conversation about new capsid development. So we have AAV8 and 9, those have been our base platform for years and years that our current programs are based on. But within our research team, we've been developing new capsids as well because we want to continue to evolve our technology and in effect, widen the therapeutic window for products.

You'll hear a lot from AAV companies. I thought I'd start with what makes us different. As I mentioned, we have a capsid discovery and engineering team based on originally AAV8 and 9, we now have new capsids that we're working on preclinical that could be used in the suprachoroidal space, liver-detargeting, capsids, all of these really to be more tissue-specific and again, widen the therapeutic window for AAV create better efficacy, better safety and that's the long-term vision.

We have a clinical development engine. Steve Pakola's team this year enrolled the two largest gene therapy trials ever run. And we're looking -- that's the top line data for the wet AMD study. And so we can scale significantly in our clinical development team and run very large trials very effectively.

Last but not least, close to my heart being an ex chemical engineer. I'm just a paper pusher, but we have industry-leading manufacturing. So we adopted a lot of the advancements that were made in biologics and brought that into gene therapy.

You've heard for years, FDA talking about how gene therapy manufacturing needs to mature beyond an academic setting. And we're definitely, I think, on the cutting edge of that scalable processes, high-purity capsid and great cost of goods in the future. just walk quickly through our pipeline. We have a rare disease overview. We also have a retinal disease overview.

In rare disease, we get a lot of attention because of our Duchenne program. I'll show a little bit of new data later on that program, which is advanced. We've been fully enrolled our pivotal for RGX-202. And from a milestone perspective, we're pointing to top line data for RGX-202 in Q2 2026 and also pointing towards a BLA submission mid-2026.

And it's not just the clinical aspects that we're getting ready. We're getting the CMC piece and the nonclinical sections ready. We have experience now filing our first BLA with the Hunter program, which is next and that program is in the late stages of a review with a PDUFA date of February 8 this year.

I'll skip ahead to Sura-vec, which is the anti-VEGF program partnered with AbbVie. As I mentioned, fully enrolled pivotal studies, 600-plus patients in each study. And those patients, that top line data will read out late this year for both studies. So look forward to that outcome. And that's going to kick off pre-commercial planning in a much more significant depth with AbbVie than we've done before. And we feel super confident that us together with AbbVie in terms of commercialization readiness, this is going to be something to watch. It would potentially be the first non-rare gene therapy approved. So we're really excited about this indication.

Equally exciting is a late-stage study will start a Phase IIb/III study for diabetic retinopathy first half of this year. That's going to a different space. So the wet AMD study is a subretinal injection, the diabetic retinopathy indication is into the choroid region of the eyes. So suprachoroidal administration. And then -- so -- and then we'll start that. And that, interestingly also has with it upon dosing the first patient in the Phase IIb study, a $100 million milestone associated with it.

So a very comprehensive portfolio, a lot of late-stage catalysts for this year, a lot going on for a company of only 400 people. We're really proud of the progress we've made this year.

I'll start with the Duchenne program. Most of you know that the long-term goal in Duchenne is very simple. We want to provide functional benefit to children who usually around 5 or 6 years old experienced a pretty significant decline in function. And so what we've been able to do with the program, and I'll talk a little bit about the specifics of RGX-202 is develop a novel construct.

So our construct, if you go all the way back to the Elevidys AdCom, one of the reviewers spoke pretty candidly about microdystrophin containing a C-terminus makes it much more like natural full-length dystrophin. So that was one of the clues we had in development to say we should include the C-terminus. It's important in muscle repair, and we think that would potentially deliver a better functional outcome for patients than microdystrophin devoid of that. And that's what we aim to prove in our clinical studies.

This week, we reported an extension of the 12-month data that we had already reported for our Phase I/II study, showing durability of effect, in fact, improvement of effect out to 18 months. So getting closer to a 2-year time point for some of these patients. And we'll have continued updates through the year on long-term durability as our functional data evolves.

What's different about 202? I mentioned the construct. So it's based on AAV8, it's well known. We have a lot of experience with that vector, we can make a lot of it in manufacturing, which is important for cost of goods, and it includes the C-terminal domain, which differentiates in performance, particularly in our preclinical studies, mdx mouse studies, we saw a huge difference in functional benefit at the 2E14 dose, and that's what we've carried forward into our pivotal program.

We get a lot of questions about our immune suppression regimen that's been consistent from the first patient dosed. We called it DL2, now we call it our pivotal dose. And we've had a proactive approach to immune suppression implemented from the very beginning of our study. And that has been one of the main factors in the safety profile that's evolving from our Phase I/II data. So we'll get into a little bit more detail on that, but that's definitely a differentiating aspect in which other companies in the Duchenne space have migrated closer to what we're doing in the clinic.

Manufacturing, we talk about, we specifically targeted 202. It's a very high vector requirement because it's systemically delivered. And so focusing on high yields suspension bioreactor process, and importantly, high purity was the target of that program. And we're happy to have a process with really positive cost of goods outlook but most importantly, an 80% full capsid level in the batches we produce.

It's one of the areas for our future BLA filing we pulled forward. We've already completed our process validation lots that would be part of the submission. And so we're really excited and very prepared to be a commercial player in this area.

So the new data on the next slide I'll show is that, number one, all participants demonstrated microdystrophin levels above 10%. That's our primary endpoint. And so in Phase I/II, we got a good indication that we have a high probability of success in our pivotal program.

We've -- to date on our Phase I/II patients had no SAEs or SAEs or AESIs observed. And I think what we're seeing as well we do patient reported or caregiver reported outcomes. It gets lost sometimes in numbers and data, but what we're seeing are children able to do sports, ride bikes, as you see here that never could before.

That's an absolutely critical element of this. So we don't want to lose the human aspect of this. We're really thrilled that the kids are able to do all kinds of things that they never could before. And we're recording and logging those activities as part of the program. So just something that we're very excited about.

We're recruiting ambulatory patients aged 1 and older. So very broad age inclusion criteria. We've completed, as I said, the pivotal trial enrollment. We immediately went over to enroll another 30 patients for the confirmatory study, and we're pointing towards having substantially all of those patients recruited by the time we file. So we'll have roughly 50 to 60 patients dosed by midyear. So it's really exciting. We're seeing a lot of growing interest in the program as we report more data.

So to get to data, this is what we reported at the World Muscle Society at 12 months. So you see four patients here. And you can see that -- in each case, at least three out of the four cases, we have a substantial improvement in NSAA versus the natural history control analysis and also CTAP, which is a new analysis that we're starting to utilize. And so we were really excited about that.

The overall change is 6.6%. And I think important, we get asked the question, what's clinically meaningful? A change of about 2.5% is considered clinically -- minimally clinically meaningful. So at 6.6%, we're well above that. And here's the exciting new data at 18 months.

Now we're looking at a larger change. So patients continue to improve in function on NSAA above where they were at 12 months, now at 18 months. And you see even more separation now in the fourth patient as well.

So first indications, and this is something we're very interested in because early data, we reported really high vector copy numbers from our initial biomarker data. And that gave us a clue that maybe this could actually contribute well to durability of effect. And so this data is starting to support that. We need to go further, but at 18 months, we're seeing continued improvements. So now we're at a delta of 7.4% in aggregate, which is roughly 3x what's minimally clinically important.

And so NSAA is one where, I think in the Duchenne community, people had walked away from that as saying it's unreliable. It's not as specific. We like time to rise better because it's more easily performed. But I think the fact that we're seeing big differences in NSAA in our patients tells you that the drug effect is very pronounced. And I think that's super important.

So when I look at the program and I think about where we are, and I think about future conversations with the FDA, I think safety is incredibly important. We're seeing really, really good safety outcomes in our patients. But just as importantly, we're seeing the functional benefit as well. So the benefit to risk ratio we feel of our product is really something that is going to move this program forward quickly.

I love fireman's thermometers. So I requested the team build me one of these, I don't know, maybe I'm too old to know what a fireman's thermometer is. But just to check off some things that we've done and things that will be coming. So we've already manufactured batches that are eligible for commercial supply.

As I said, we completed enrollment of 30 patients and we're continuing to enroll. We pointed to, again, a substantial number of those patients being recruited ahead of our filing date.

In March, we'll have an additional data update on our Phase I/II data at MDA. Early Q2, we'll have top line pivotal data. Along the way, we'll have additional FDA and EMEA interactions. And then all pointing towards a BLA submission midyear.

And I would say that one reason that I feel great about this is we did roughly this level of execution in 2025 and delivered on every one of targets that we had set. So I feel like operationally, and as a company, when we say we're going to do something, we deliver. And I think that's been demonstrated and set up as well for this year.

What are we doing in terms of demand? We're obviously thinking about broad ambulatory access. We've been treating patients, as I said, from 1 to 11, might have had a 12-year old in the study to date. So a broad inclusion criteria. We have full control of our drug supply. So we can produce up to 2,500 doses per year in our Rockville facility and we can also fill drug in our Rockville facilities. So both bulk production and fill finish.

We're activating additional sites, not just for clinical development, but also seeing that when our investigators get experience with our program, they become champions for it. So we want to expand sites that we're at to get that experience and continue to let investigators see for themselves how the patients are doing. And then we also are looking at expanding globally. So plans for ex U.S. studies as well. So a lot going on, but a lot of energy moving this program forward.

As I mentioned, for the Hunter program, we're in the middle of a BLA review now. So I won't speak to a lot of specifics about that, but it's a very active review. Hunter, I don't think there has been a new treatment in Hunter for 20 years. And so there's a huge unmet need here. We deliver directly to the CNS. And there's roughly 500 patients in the prevalent market per se for the U.S. And on an incident basis, it's ultrarare, so it's roughly 50 new patients per year.

There's been a lot of advance in newborn screening for MPS and we want to come in synergistically with that with a treatment that we feel our data demonstrates, number one, really good reduction of biomarkers. So I'll show here that the reduction of D2S6 which is similar to heparan sulfate, is roughly 80% after treatment at week 16 and then all the way out to a year.

And that's commensurate with improvements that we see in neurocognitive development for younger patients. We see normal neurocognitive development or more normal. And then for patients that are older who have already experience neurocognitive decline we're seeing stabilization or slight improvement. And that was really what we were targeting.

Over time, I would expect this will move to treating younger patients. We want -- we don't want to treat patients later because you can't reverse the degradation that's happened. So I would expect over time, and that's why in our study, we included some very young patients as well.

So we're really excited about this data. We're, as I said, in an active review. We have a PDUFA date, February 8, and we have really exceptional clinical data. We published in September additional full year data on the program as well for you to see. So looking forward to kicking off the year with a positive outcome.

Sura-vec. So back to the retina franchise, as I mentioned, the first potential gene therapy for chronic retinal disease. Wet AMD is the program that will read out later this year. There's a lot of excitement in AbbVie. They pay 2/3 of the development cost. So you imagine 1,200 patients. These are big studies. And it's wonderful to have AbbVie with us on that because it takes a lot to stand that up. But now we're in the data collection mode with the patients and as I mentioned, pointing to top line data.

We think there's a really meaningful place in the market for subretinal injection. I think there's been skepticism about that. I understand the skepticism. But what we see is a real strong adoption of programs that extend intervals between treatment. And you can't get, as shown by this data, better extension of treatment than some patients here that are 4 years out without supplemental injections.

So we have long-term durability already demonstrated from our Phase I/II studies via the subretinal injection. And very importantly, for retina, we also have really incredible safety demonstrated because of the -- we're going to an immune privileged section of the eye.

And so we're really looking forward to this data. I think there's a lot of excitement growing in the field for this. And we see very high interest of the retinal specialists in a gene therapy coming to market. So all eyes on this.

And then last, I'll talk just a little bit about diabetic retinopathy. You can see here, again, trying to treat diabetic retinopathy early to avoid these vision-threatening complications is the real goal here there's a proven -- we know Lucentis works in this, but we know the adoption is very low. And why is there very little adoption because people don't want to get a monthly injection at 45 years old, to control it or maybe they don't even have symptoms at that point.

And so again, this is a perfect solution for gene therapy. We have already 2-year data showing dramatic reductions in [indiscernible] and also lack of events occurring. So we've prevented disease progression. So we think that this is a case where gene therapy is an ideal fit for a market that really has never experienced much penetration. Because already going into a Phase IIb/III study, we've established 2- to 3-year durability. And so that's well within the target product profile we've described before.

Last, I'll follow up with manufacturing. We have beautiful anybody that's in the room that wants to come to Rockville, you have an invite to see our manufacturing facility. I didn't -- I'll tell my manufacturing head later, I said that. But we're really, really proud of it. It's a beautiful facility. It goes up to 2,000 liters in capacity, and we can dose -- we can create 2,500 doses per year of RGX-202. We have a second side of the facility that can produce up to 350,000 doses for Sura-vec.

So we have -- this is for Sura-vec, that was one of the real strong basis of the AbbVie relationship was our ability to manufacture. So we're really excited about that. This facility was inspected in the summer by FDA for the first time, no observations. And I'm really proud of that as well, the ability to put this together, put it together a gene therapy platform that's scalable and then have FDA come in and say you're doing it the right way was really gratifying for the team and for the industry, I think.

Productivity is important. I think there was a statement years back by FDA that said, if you don't have above 50% full capsid, you really shouldn't be going into the clinic with that product. And we took that to heart. As I said earlier, we're up to about 80% full capsid, in particular, on the high-dose Duchenne program. And I think that contributes positively to the safety profile.

And this is actually the last slide, sorry. I just wanted to mention, we have a couple of new additions to our pipeline diagram, and they are based on -- in this particular case, new capsids that we've developed that are specifically developed for suprachoroidal. And what has that enabled us to do. We're able to get either the same amount of transgene expression with a much lower dose. Or we're able to get to the same dose and basically produce maybe 8 to 10-fold higher transgene levels.

And that's really important for the eye because, again, it widens the therapeutic window that you have to work in without getting to a high dose where you start to see inflammation and things like that. So this is a case of our research team being really smart with development, knowing what to look for, what to manipulate on our existing vector platform to improve performance.

So unmatched in-house end-to-end capabilities, leadership in gene therapy. We've been doing this a long time. We've gained a lot of experience not always the best experience, and we've corrected that. And this is the culmination of years of learning that we want to bring really great therapies to patients that are safe.

Exciting near-term catalysts. This is a big year for us, pivotal readouts. And obviously, the main goal here is creating long-term value for patients. So letting patients get off of weekly infusions of enzymes, for example, letting patients get out of going to the doctor every month to get an injection in their eye. So these are really meaningful outcomes that we hope to bring to the market. And with that, I'll stop.

Thanks so much, Curran. That was fascinating presentation. I think it's amazing that there's so many shots on goal in different areas, too. So that's what makes it very exciting.

Maybe I'll kick it off with some questions focused on each part of the pipeline, starting off with 202, and thanks for joining us, Steve. Thinking about 202, when you first started the program, you must have been fourth or fifth to market. And since then, a lot has changed. So maybe could you speak to how the competitive landscape has evolved, how you're thinking about what role 202 could play for patients and how that ended up happening.

Yes, I think -- can you hear me okay?

Let's try again.

Test 1, 2. Yes. That's okay. Yes. Great. Thanks. It's a great question. Yes. When we started, there were other entrants ahead of us. And that was, I think, a driving force for why we chose differentiation. It's not making something that was the same as that was out there, but actually trying to look forward and say, what are things that we see in the field that we could do differently to end up with a differentiated product that might take a larger place in the future commercial market.

And as you said, a lot has happened. Programs have gone away that were intended late-stage programs. And our program has accelerated. We completed pivotal enrollment 3 months ahead of when we had planned. And we're on the cusp of top line data.

I do think that no one could have predicted some of the things like the safety issues that have been found, liver enzyme elevation, things like that. And that's where the proactive approach we've taken to immune suppression has really helped with that. The main goal with Duchenne is to deliver as much product as you can to maximize the chance of functional benefit. But in trying to do that, you take risk, right? And what we're finding is that the combination of the high purity and the immunosuppression regimen allows us to deliver at a high dose. And that's where we're starting to see these really remarkable functional outcome.

So I think, ultimately, I think we have a really meaningful place in the future commercial market as a result of that, not the least of which is we can make enough doses in 2 years to cover almost the whole prevalent market.

That was the immunosuppression regimen that you started off with, maybe if you can comment on that in a little bit more detail. We've seen when that first happened, people were questioning it. There were a lot of how is this going to work? And now we're seeing competitors or other folks kind of adopting a similar strategy. So could you maybe walk through what that suppression regimen looks like and maybe why that's so important to the success of the program?

Sure. Thanks for having us, first of all. Curran really hit on the aspect of early on what we did not just with the immune regimen but high purity. And that's really based on our expertise in this area and really having been leaders in the gene therapy space overall.

So we did a lot of investment upfront and really thinking about how do we get to an optimal dose safely. And A lot of people don't realize this, but though I think they're realizing it more and more that a key part of efficacy is the safety because if you don't have the safety, you're not going to be able to get to the right dose.

So the triple regimen. So we have the increased steroids that is traditionally used. We've also included two other agents that importantly are very targeted to what's been seen with other programs. So this is our learning from other programs, not something we've seen with ours, but safety first for the reason we mentioned getting to an optimal dose that -- and a dose level that others have not been able to do.

And this is before some of the unfortunate effects for the community that have been seen for other programs. So one aspect, obviously, liver injury that you mentioned that with existing therapy can be quite extensive. So we have Sirolimus and we also have Soliris or eculizumab. So another category that's been an issue is complement activation, which can lead to thrombocytopenia, but also more serious TMA. And what we've seen as clinicians have taken this up.

It's sort of a paradox because -- but that actually makes sense when you think about it is that by having a little more effort upfront, you actually decrease the monitoring and reactive steps that are needed. So if you don't have 40% liver injury because of your regimen, you're not having to have more treatment and more visits, more blood draws.

So we're really set up to not need things like relocation of patients for 3 months with excess levels of monitoring to have to retreat reactively.

Amazing. And looking ahead for top line data coming up in the second quarter, what types of data should we be expecting as far as disclosures? And what would the benchmark for success look like from your lens?

Yes. So for top line data, we expect to have obviously, an update on safety for the pivotal group. We'll have full microdystrophin data on all 30 patients. And we'll have functional data for a subset of them that have gotten out to months is where we tend to first look at this in a pivotal setting. So I would expect to see those as the key elements of the top line data.

And you mentioned in the presentation that you're going to have a discussion with the EMA as well. Maybe if you could talk about your strategy for outside the U.S. and how you're thinking about the program globally?

Yes. I think globally, there's still a need in EMEA to have a placebo-controlled study as part of your overall approach. We have some designs that we've worked through that we want to get feedback on and then start to implement. So it is part of a longer-term strategy to go beyond just U.S.-based development.

Great. I'm going to switch gears to -- just to make sure we have time to cover all programs to 121. You mentioned that we're getting closer to the PDUFA date. To the extent you can comment on how that process is going? And any additional insights? Is there anything that you have to do between now and when you expect approval?

Yes. I think we've had the customary information requests along the way. We've had nicely face-to-face meeting in White Oak with the team, review team, which I think was very productive. It's the first face-to-face. I think we've had in 2 to 3 years now. So I think that was very helpful.

If you think about the sequence of review, we had nonclinical review quite early. CMC with the facility inspection was midyear. The last submission was the clinical module as part of the rolling BLA. So most of the recent dialogue has been around the review of the clinical module. Again, we showed some of our data here. We think it's extremely compelling. And I would characterize is we haven't gotten an information request. We didn't feel like we could really adequately respond to with our data set.

Amazing. And I think people are also looking at Denali's MPS II program as well with, I think, a PDUFA set for April of this year. So maybe could you comment on how none compares and if there's any overlap or competitive positioning?

Sure. I think they're both using accelerated approval approach using a surrogate biomarker. So that's similar. And both, I think, of us have shown really substantial reductions of that biomarker. I think in a commercial setting, something that's a true differentiator is it's a onetime gene therapy. So you have a choice between a weekly infusion which seems very effective from what I've seen or a onetime gene therapy treatment.

That's why we're really bullish about our prospects that even if people go on to enzyme replacement therapy, for example, over time, because of the burden of treatment, they're going to want to consider gene therapy, and we think we have a really strong value proposition.

And that program is partnered with Nippon Shinyaku. Maybe if you could comment on the terms of the partnership and what each -- what role each party plays as part of that partnership?

Yes. So they are in charge of the overall commercialization. They already have an existing rare disease sales force in place, and we're in charge of the manufacturing and supply chain aspect of it. And then we have -- in terms of the financials, I would say, meaningful double-digit royalties that come to us as a result of sales.

And they do -- there could be an option to expand other countries beyond what they initially partnered with us on. So opportunity for growth in the program.

Amazing. I want to have some time for 314 as well. So for the wet AMD program, I feel like the slide largely under the radar for the most part, but it's kind of coming into the spot right now. Can we maybe chat about what the clinical hypotheses were and how the partnership with AbbVie came in place and why you ended up pursuing this so far.

Yes, I could start and then maybe Steve can talk a little bit about the studies themselves. I mean the partnership for AbbVie, I think, materialized roughly 3.5 years ago. And I think the upfront view that we had was REGENXBIO wasn't going to build a sales force for retina. And so this is where AbbVie came in as an obvious candidate that they have an existing large sales force. They have a franchise in ophthalmology.

And so it was a very good partnership. It's been a good partnership in terms of our relationship with them over the years and -- but they do think big. And so the reason these are big studies is they're developed for global purposes. We've recruited roughly 100-plus patients in Europe as part of the ASCENT study. And so they're powered for broad submissions and filings that would support a global program. So I think we're really excited for next year. I think those watching gene therapy, looking at the first non-rare indication coming to top line data will be exciting to see how does that fit in a commercial setting. And I'm really optimistic that AbbVie can really exceed people's expectations on subretinal administration.

Sure. So over the last few years, it's really been great to work with AbbVie. The really allow us to do what we've always wanted to do, which is to get 314 to as many patients as we can. So -- and also what a great validation to have a company with the experience and expertise globally also in eye care. So it's really worked out the way we've hoped. And it's not just for wet AMD, but of course, for DR, we both see the unbelievable untapped potential for a onetime treatment to address that really massive unmet need.

Thank you so much. I think we just came up on time, but a great presentation. Thank you for the Q&A. Thanks so much.

Thanks for having us.

Good morning, everyone. Welcome to day 1 of our Piper Sandler Healthcare Conference. My name is Yas Rahimi. I'm a biotech analyst here at Piper Sandler. Really thrilled to have the team from REGENX here. 2026 is a big year for REGENX. You guys have been the pioneers in gene therapy.

Would love to kind of start off the role that sort of your views into 2026 and how you're thinking about some of the key inflection points, and then we'll go through each program one by one.

Sure, yes. Really big year for us in terms of -- we have really solid dates in mind for some really key milestones. The first is, first quarter February PDUFA date for our Hunter program. I've been with that program for 9 years now. So it's exciting to see it getting to this point of review and we've had good success over the summer with the inspections. But next on the list is in early Q2, we've guided to top line data for our Duchenne program. So we completed enrollment last October and look forward to the results there. I can talk about more in depth on that. And then in September this year, we announced completion of enrollment. I think they're the largest gene therapy trials ever conducted with AbbVie. So we are now pointing to top line data for the subretinal program for wet AMD late next year.

Wonderful.

Lots to look forward.

Lots to look for, lots of rich catalysts that are here upcoming. You guys have made a tremendous amount of investment and work and hard work went into building a manufacturing facility. So help us understand sort of the capabilities that the facility has as one of the leaders in the gene therapy space.

Sure. Yes. So we started probably around 10 years ago when I joined building up the CMC approach. And I think historically, FDA and others have been pretty critical of gene therapy manufacturing, saying it needed to be modernized and that's exactly what we set out to do. So if you walk into our manufacturing facility located in Rockville, it will look like a biologics plant, suspension bioreactor with HEK293 cell line that we use. And we've really sort of cracked the code on gene therapy expression levels for vector. We've published some of that at ASGCT. And I think importantly, having control of manufacturing, particularly for the Duchenne program, where there's a really high vector requirement is a huge asset to us and a differentiator.

Wonderful. Maybe let's talk about RGX-121, which is upcoming here with PDUFA date in February. I think recently, you noted that the inspections have been completed. PDUFA date is on track. Just kind of help us understand sort of what is left to do between now and PDUFA and what your disclosures are going to look like between now and then?

Well, we'll certainly give a disclosure around February when the PDUFA date comes. The BLA was submitted as a rolling BLA. So we submitted nonclinical and CMC and then the clinical module last. So as you could expect, most of the review at this point is down to the clinical module. We published data in September with full 12-month data on all of the patients in the pivotal, which looked really exciting. And so yes, we're looking forward to proceeding to a PDUFA date, hopefully, a positive decision. I think the manufacturing plays into that as well. The facility was inspected as part of that in the summer, and we got out of that with no observations, which is pretty rare. So we feel like we've derisked one key aspect of the gene therapy world in terms of CMC and nonclinical looking really positive.

And maybe it would be also great to think about sort of how you envision commercialization, we transition to become a commercial company with manufacturing and scalability on hand, which will be maybe a question that comes up is like finding patients, warehousing them, what work has been done hires in terms of building the commercial team?

Yes. We signed a deal early this year with NS Pharma. So we are in a partnership in which NS Pharma will handle the commercialization aspect. We felt it's a bit too early for us to build out a sales team for an ultra-rare indication. But the benefit we have is we do control the manufacturing supply chain. We'll have a lot of input, obviously, into the commercialization because many of the sites we're going to will be the same as what we used in the clinic as well.

MPS is ultra-rare disease and finding patients is actually pretty straightforward. There's emerging, I think I heard 40% of the States in the next 1.5 years will be doing newborn screening. And so that will be an automatic funnel to find patients. They're very aware of our program. We've had a 10-year relationship with the MPS society that will help us greatly with that. So we're looking forward to it. And I think we have all the elements for a successful launch.

How do you think 121 will play into the market?

I think onetime gene therapy is really truly differentiating. So if you think about the burden of care, which currently, there aren't any treatments available for the CNS manifestation. But for things like enzyme replacement therapy, patients have to come in many times weekly for infusions and imagine the burden of having a child. So a onetime gene therapy, I think, will be a very powerful alternative for patients, and we expect really strong adoption.

Wonderful. As many investors are also aware, first of all, you will be the first gene therapy to enter the ERT market, which would be another key milestone for the space. Investors who follow the program understand that DNL310 also has an upcoming PDUFA date on April '26. So maybe help us understand sort of the evolving landscape when it comes to the space with multiple gene therapy programs available and the differentiations of them?

Sure. I just talked to a couple of people within patient advocacy groups. It's been 20 years since they've had anything new approved. So having 2 programs potentially approved is great for patients. Again, I like our position in the sense of a onetime gene therapy. I think our data -- particularly, we have data in younger patients. So I think in terms of who are the right patients to dose and coming off newborn screening, once the damage is done, it can't be undone. So early treatment is going to be important. And I think the strength of our data is in that younger patient population.

Great. Team, would love to talk about 202 and DMD. Maybe start off with helping us understand what is the strategic interest in 202 for DMD?

Yes. I think it plays out a lot of strengths within the company. Number one, it's in rare disease, which we just talked about the Hunter program. That's a key element of our portfolio. Number two, our Chief Science Officer, Olivier Danos, has been working in Duchenne for 25 years or so. And so he had a lot of input, obviously and drove the design of the construct, which includes the C-terminus. And if you go all the way back to the Elevidys AdComm, you'll see FDA reviewers talking about the value of making microdystrophin more like natural dystrophin. And that automatically includes, if you do that, the C-terminus, which we were able to accomplish.

So what that does is it helps with restoring function once the muscle has been damaged through exercise. So that gave us promise of delivering better functional benefit. But then I think the last piece of the puzzle -- well, maybe there's 2 more, but one is the immune suppression regimen that we're using. So far, we've had no SAEs in our Phase I/II study. We'll be happy to roll out our safety update in the Q2 top line data. We feel very positive about that. And then playing into that is the manufacturing process. We're at 80% full capsid. So the majority of the product is the intended product and that's what allows us to maximize the dose and give the best possibility for functional benefit.

And how do you think it differentiates versus other gene therapy programs in DMD?

I think that when we -- if we look at our Phase I/II data and we look at the benefit to risk profile, I think we have the best product in development. And I say that because we're seeing improvement in patients that are 7 and older, where automatically, those patients are normally in a decline phase of their disease. We're seeing those children improving in function, not just stabilized. And we're also, as I mentioned, not seeing safety events. So you put the 2 together, I think we have a compelling case.

The data is on track for 2Q of next year. Maybe just housekeeping items. What type of data will you have on hand at the time of the disclosure? And what is sort of the bar for success or the expectation going into the readout?

Yes. So we'll have in Q2, we'll have for all 30 patients, overall safety update and we'll also have data around the primary endpoint, which is microdystrophin with proportion of patients at 10% and above for microdystrophin. We'll also have functional data, I would say, on roughly 1/3 of those patients, it depends on visits and timing, et cetera. And key is at 12 months. We don't believe data earlier than that because it could be subject to immune suppression, et cetera. And more importantly, that's what allows us to match to the external controls because most of the NSAA data for external controls is a 12-month data point.

So what success looks like is we want to see differentiation on time to rise, but even more importantly, I think, on NSAA, which we haven't seen in other programs. And that's what we're seeing in our early Phase I/II data at the pivotal dose. So same safety, same -- if we can just replicate what we've done in Phase I/II with 30 patients in the pivotal, we'll be in great shape, I think, in terms of the application.

And team, obviously, the data readout is critically important, but what is your planned path that data? Obviously, you'll be getting ready to file. Is this something you want to embark on commercializing on your own? Or are you actually actively looking to partner in this program? What are some of the key factors that you're going to be making that decision, obviously, post the data?

Yes. No, I think we love having the program on our own within our full control. And the program to date has been largely U.S.-based. So moving as fast as we can to an approval in the largest market. We're definitely open to a partnership that could broaden the scope of the program to a global enterprise, but I think that's not our current near-term focus. And we have everything we need to do it. We've got the manufacturing capability. We've got a sales team that's being brought online as we speak. So we'll be ready, and we're pointing towards an initial BLA filing in mid-2026.

Perfect. And Curran, you alluded to sort of the commercial capability. So the advantage of getting ready for 121 and then for the DMD program, sort of the learnings and the capability of scaling up, like what is -- if you could just touch even though these are different programs, different constructs, but there's a lot of read-through when it comes to scalability of manufacturing.

Yes. I think there's a couple of things. Number one, having a facility that's been inspected with no observations, that will be the same facility that's used for the 202 program. So we feel that element is derisked. And the process looks almost identical, just a couple of changes there. Interestingly, the -- as well, the partnership with NS Pharma will help us on the supply chain aspect, delivering to patients. But don't forget, we also were the initiator early on of Zolgensma. It's our IP. And many of the dosing sites for Duchenne are also the same for SMA. So there's a synergy there that we're learning from as well.

That's great. Another big readout will be actually the 314 readout in 4Q, the pivotal study, which is in wet AMD. Maybe before we go there, just give us sort of a recap of where we stand currently in the current wet AMD market. I think the market is driven by anti-VEGF and TKI therapies. So maybe help us understand the rationale for subretinal delivery and the importance of it and what would that mean in the market?

Yes. I think certainly, wet AMD, I think the last estimates I saw were between $6 billion and $8 billion, and it's growing. By the time we would launch, it could be above $10 billion. And so probably the largest market that a gene therapy is being developed in. We went with subretinal because that's really a validated method of applying a gene therapy. It's also very free of safety events. And so as a first entry into gene therapy, we decided to start with subretinal, even though people think it's awkward because it's surgery. There's actually tons of vitrectomies done every year. Retinal surgeons want to do surgeries. So we think there's a meaningful space for a subretinal gene therapy. We did a study in the course of developing 314. We call it the bioreactor study. And it was basically a crossover to the commercial process. And if you just look at that data and that replicates in our pivotal data, which we think it will, we're going to have a really exciting product.

And are there -- your partner, AbbVie, what are some of the financial obligations for AbbVie on a successful study that's going to be reading out?

I'm going to get Mitch in the game.

Yes. Yes.

Once approved, there is some regulatory milestones associated with it. But when it comes to profit sharing, it's 50-50 in the U.S. And ex U.S. will be a sales royalty. We have not disclosed the exact figures there, but it is a pretty lucrative market. And just to add on a little bit more, the procedure itself is not very tedious. Meaning these doctors takes about, 20, 25 minutes at most. Wow. So it's actually not as cumbersome as some may believe.

Wow. What is your partner and what you guys are thinking? I think you alluded to the market is right now $8 billion, it could grow to $10 billion. So assuming this could be a $2 billion product like -- and what is the size of the population that could be eligible that you would think would opt out?

I think at any given time, there's roughly 100,000 patients with wet AMD. That is also growing over time. So these retina centers are overrun. They don't want to take on a lot more patients. Gene therapy is a great solution for that. One administration, we've got patients out almost 4 years now with no additional treatment required.

I think AbbVie sees it as a huge. They will carry the commercialization of the product. We'll certainly have input given the development history we have. But think about their sales force and muscle. They've got 7,000 MSLs. There's a lot there and they're investing deeply into this program over the years. So I think they're -- now that we have a solid top line data late next year, I think you're going to start to see them getting more involved with commercialization activities.

And for investors who are revisiting REGENX and looking for the Catalyst, what was the study powered to show? What enabled to?

Both studies are non-inferiority studies. One is against Lucentis and the other is against Eylea. And there's also 2 dose -- 2 active doses in each study. So they're highly powered, 600 patients each study. So we feel like our probability of success is positive here.

Great. Let's maybe a few more minutes to talk about RGX-318, which is in diabetic nephropathy, a very high unmet need. Maybe with -- you guys are very active in kicking off the study. So maybe help us understand sort of what -- where are you in the process? What is left to do?

So we're in the process now of finalizing site selection, finalizing the start-up of those sites. We'll dose the patient next year and we'll be open to public about that event as well. We think there's a really positive outlook on enrollment here because of the unmet need. It's an in-office procedure and so that will facilitate getting patients through quickly. The study is designed to have a Phase IIb where we in the Phase IIa, we dosed maybe 15 to 20 patients per arm. Now we're talking about 2 or 3x that will be more detailed about the design as we go forward. But that will roll directly into a pivotal of an interim analysis and that will also kick off a second pivotal at the same time.

So there will be a readout and then these patients will automatically roll into the pivotal and concurrently. Is that the way you're thinking?

Yes, the patients will be part of the pivotal data set ultimately, yes.

And at what point can you come back and start actually communicating with investors and analysts around what that transitional studies look like.

Yes, we haven't specified a date for that yet, but we'll be more -- once we get the study up and running and we see the enrollment trends, we'll be giving more guidance on expected dates for expansion into the pivotal, et cetera. I do want to remind that there's a $100 million milestone for dosing the first patient in the IIb study. So that's really critical in terms of cash runway.

We're expecting that to be early next year. And that's for the first part of the study. Once we have the second part into the pivotal -- second pivotal, there's another $100 million associated with that as well.

That's great. And team, how much read-through will there be from the wet AMD subretinal program to the diabetic nephropathy program?

I think they're a bit different in the type of disease, the severity of the disease. The dose is higher, for example, in the wet AMD study. But I think in general, they're using the same base product, but in a very different way, both dosing in immune-privileged areas. So we've put safety as the top requirement for any retina study and then efficacy has to come with them, which we've got both, we think.

Okay. Very helpful. And team, what is sort of the cash position of the company? And what does it entail to sort of fund a very big year ahead?

With the cash balance that we have at hand, it will get us to the early part of 2027. What's not included in that figure is additional non-dilutive financing, which includes a potential monetization of a PRV that's associated with 121's approval. That's been going for north of $150 million recently. And the $100 million for the DR first patient dose, which is to receive early next year as well, too. So all in all, that could get us deep into late '27, if not even early 2028.

Great. And I think also these big catalysts are going to be key inflection points of the stock that is generating a lot of interest because I think if you look, it's been up over the last quarter over 100%. What are maybe -- I know since we have like 3 minutes left, and you guys did a great job like covering all the questions. Clearly, investors listening to the fireside chat or in this room, everybody is looking for next big year. That's very clear with an approval and 2 pivotal studies reading out. This is the time to own REGENX, right, and do work on the name. What are maybe some of -- you guys have been the pioneers in this space. What are some things that you guys do feel like investors haven't given you credit that really is going to come to fruition in 2026?

Well, I think just like biologics, gene therapy has had its ups and downs as it's emerged and a lot of the downs have been around safety. So we've been working for years and years on immune suppression regimens and applied what we learned to the Duchenne program. And it's enabled us to now maximize the dose as opposed to having to hold back and maybe not give the full benefit to a patient. So I think it's that institutional core business that what we do is gene therapy and that's all we've been doing for 15 years. Early on, we did it through licensing, but then we took on our own development. And so the core knowledge of how to make, how to dose safely and how to design a program to maximize benefit for patients all resides within our walls, which I think is exciting.

And I think that we've always been, I think, very transparent about our data, and that's something we will continue as we become a commercial entity to talk to people about how the products work, how they're designed and how we make sure that safety is top of mind.

Great. Well, team, it's wonderful to kick off the conference with you this morning as my first fireside chat. Really looking forward to a great year ahead of us. So thank you again for being part of our day. I must give a big applause to the team.

Good afternoon, everyone, and thanks for joining the REGENXBIO session. Our pleasure always to have Curran Simpson, CEO; Steve Pakola, CMO; and now Mitchell Chan, CFO.

And I think we come at a time when gene therapy seems to have come back to a certain degree in favor, although the FDA is certainly throwing a wrench in the works for some people. But still, I think there's some increasing optimism, let's just say, for gene therapy. And I guess in that vein, I think it's fair to ask you the question what sets REGENX apart from, I would say, some of the other companies in the space who've seen a little bit more volatility and hits and misses. And maybe you can just talk about how you stand in this -- your standing in the space.

Yes. I think there's a benefit to being -- we've been doing this for 15 years. And so gene therapy as a field, I think, has continued to evolve. I think the area I would highlight is immune suppression. And I can remember only 7 or 8 years ago, we weren't anywhere near as advanced as we are now in terms of how to manage delivery of AAV. So with the near-term focus on safety for gene therapy, I think we've spent a lot of time doing really methodical, careful Phase I/II studies that allowed us to learn and benefit. And now we're applying what we learned into the pivotal programs. And I just think the probability of success, we feel is very high because of that homework that we did early.

And you also have quite a manufacturing capacity already well established. So maybe talk about how that sets you apart from the others.

Sure. Yes. We are well through BLA review for the Hunter program. And as part of that, in the summer, we had an FDA inspection, 5 inspectors, 5 days, the normal routine. But I think for a brand-new facility and effectively a brand-new technology, which is, I think, a more modern manufacturing capability, suspension bioreactor process, we got out of the audit with no observations, which not many companies can boast about, which we do a little bit. But more importantly, that's the anchor for these late-stage readouts that we have. We've already got drug manufactured and in vials for the Hunter program ready to hopefully get a label on them.

And it's the core of, I think, our Duchenne program as well to have really high-yielding processes. And the process for Duchenne looks very similar to what we just were audited on in Hunter. So in a way, it derisks any CMC issues from those programs. So that was a decision we took 4 years ago. And I think you never know how early you should build that capability. It seems either too early sometimes or too late. In other cases, I think we got it just about right in terms of where it fits in our development.

And then, can you just review the capacity that you have? Is this for all the programs or just the rare disease programs at this point?

Yes, we can manufacture for all of our programs. So we are the primary supplier for the retina program with AbbVie for bulk drug and then for Duchenne and for the Hunter program, all are made in Rockville. And we actually have an identical second train that we can activate to expand our capacity further if we need to, 2,500 doses a year for Duchenne. And I think something closer to 100,000 doses a year for the retina program, obviously, much lower vector concentration. AbbVie manages the fill/finish at a site that they control for the retina program. But long story short, capacity is absolutely in hand, I would say, for the next 4 to 5 years, and we can obviously expand that if we choose to.

And just for everyone, to be clear, you're in 3 Phase III programs, if not filed for 1 program and all of those programs were studied with the commercial drug that you're going to be using?

Yes. Yes. So we were able to move quickly enough in all 3 programs to a commercial level process that in each of the pivotals that material has been used. So product profile in our pivotal programs will be identical to what is seen in the commercial setting, which reduces, again, our goal has been to reduce risk associated with CMC from day 1. I think about half the CRLs that were issued are due to CMC, and that looks like something that so far, we've navigated well.

That's great. So speaking of reducing risk, let's talk about the biggest risk component right now, which is a little bit out of your control, but I guess maybe you have a little bit of more of a front row seat to how the FDA is handling gene therapy, given some of the developments in the space, it's been a bit of a roller coaster comparing or approving drugs on natural history. Presumably, you can do it for these very rare conditions, but we're seeing that perhaps in some cases, you can't. So if you could go into that with us a little bit and tell us why you think your situation is different.

Sure. I'll let Steve comment a bit on the protocol design for Duchenne. I think what we're seeing in real time with the Hunter program is a pretty straightforward review. And as you know, that study as well does not include a placebo arm. We haven't had any questions regarding the design of the study. We are -- one thing that I think has changed that we were prepared for from the beginning, we've always known for a program that uses a surrogate biomarker that clinical data supporting that would be required, not a full data set or else you're doing a traditional approval. And so by planning ahead for that, we've been able to supply FDA to show the correlation between the 2. Maybe specifically on the Duchenne program, you want to talk about the natural history control scheme?

So I think one of the key things writ large even outside this particular indication, of course, is what you prospectively say you're going to do. So I think that's an important aspect when you think of the different programs. So for both 121 for Hunter and also 202 for Duchenne, the plans that we put forward have stayed the same. So Curran described the 121 aspect. On 202, we're utilizing external match controls. And I think this is something there's a benefit within the Duchenne space of recognizing that baseline age and baseline function are critical predictors of how patients are going to do. So you can really get a better sense of, well, is treatment having an effect if you can match very closely based on age and function from large databases.

So that's what we've accumulated, and it also gives us the perspective or context of what's been seen previously with ELEVIDYS, for example, using that approach. There's also the ability to do sensitivity analyses with different ways of doing that type of exact matching and a totally different approach is using this recognized CTAP modeling to compare to what you're seeing with the boys that you treat with your product. And we've presented data from our Phase I/II study, where at both the lower dose and also the higher pivotal dose, we're seeing real improvements on all these different ways of looking at how the boys are doing and we've seen this across the age range. And I think what's been most notable is in the older boys so the 8 and older, where traditionally, we know with ELEVIDYS and other gene therapies in ambulatory boys that age, you don't get very good or consistent microdystrophin expression.

And then maybe not surprisingly, you don't see functional benefits. And what we're seeing is not only stabilization in those older boys, but actual improvements. So then the separation from natural history is even more dramatic. So going forward, how is this all going to be looked at? I think part of the aspect is what is the magnitude and consistency of what you're actually seeing compared to a methodical prospectively defined approach. And so we're excited at the fact that we just completed our pivotal enrollment in the Duchenne program in 1 and above boys where we're going to have the primary endpoint microdystrophin 3-month readout in early Q2 of next year and also have available whatever patients we have available with clean data with 12-month functional data. So we feel we're in a strong position to hit our primary endpoint, but also have additional functional data to show that correlation that we'll need.

Okay. Before we get too much in the weeds on DMD, I just want to go back to MPS. This is going to be the first gene therapy for Hunter's disease. And it's in a market that is completely served by enzyme replacement therapy. Even though there's an enzyme replacement therapy that's presumably in development that could cross the blood-brain barrier, you have a potential to potentially go in there and disrupt it. Though Denali is sitting at a $3 billion valuation, you guys are sitting around $500 million or $600 million valuation. So I guess, how should we think about this disconnect, number one? And number two, how do you think this market evolves with some of the development products that are coming in and how gene therapy can disrupt that? I know that DMD, there is a high desire for gene therapy. What is the Hunter market like? It's much smaller, but clearly it's still meaningful as far as a size of market for a product.

Yes, there's roughly 500 patients in the prevalent pool. And on incidence, it's roughly 50 per year. So it is ultrarare, but I think the one area that will be distinctly different with a gene therapy being offered is it's a one-and-done treatment. So we have patients that are out several years now showing very durable effect. The burden of treatment with enzyme replacement therapy is going to an infusion center once a week for several hours. And as a parent, that is a huge toll for the caregivers to manage. And so I think that we will make a significant inroad into the market based upon dramatically reducing the burden of care.

And more importantly, the element that we didn't necessarily know would occur. We were always convinced the CNS manifestation of the disease would be addressed by the treatment. But in addition to that, oddly, because we treated patients in Brazil where ERT was not available, we also saw they were getting a systemic benefit. So 80% of the patients treated in the pivotal are able to stay off of ERT. So I think we really have something that's going to be very compelling. This is what we hear from the patient advocacy groups. They've just been waiting. So there's an urgency on their end to get us through the finish line and to have options available. And we're happy to see multiple options come into the market, but we feel like we have a good proposition.

And how strong is that advocacy group?

Really strong. I think probably...

Not DMD strong maybe, but...

Yes. No, the MPS society, there are -- where are the patients, that's one of the first questions. There's very strong patient registries available for MPS. So it's actually including now newborn screening coming into play and helping identify them early, which is when we really want to treat. So I think locating the patients and having centers available to do the treatment, which is a sophisticated methodology, we know what those centers are. We've already done our clinical work there, and they've handled commercial product before. So this is, I think, going to be a great first program to launch. And I think we know where the patients are, and we have the support of the advocacy groups.

Is there a warehouse of patients waiting for treatment?

Oh, yes, absolutely.

And as far as the age range for that you study, you studied very young populations below the 5 years, which was typically seen with ERT. So you're up to 2 years old, I think.

Yes.

So once they have the newborn screening, that pool of patients should be pretty readily available.

Yes.

All right. Great. So okay, back to the DMD program. So obviously, you've completed enrollment. That's excellent. And right now, what are some of the characteristics, clinical characteristics about your program that gives you the greatest confidence at this stage?

Sure. So I kind of harken back to what Curran mentioned about all the careful work we did upfront that ultimately is leading to what we're seeing in terms of clinical characterization. So we really methodically from all the 15 years of leadership in this space, took into account optimizing the construct, number one. So it was very important for us to make this as close to naturally occurring dystrophin as possible. And the key aspect there is inclusion of the C-terminal domain. And we showed preclinically that, that makes a difference that constructs with the C-terminal domain have better outcomes in DMD animal models than constructs that don't. So that was number one.

Number two, it's not just the molecule, it's the actual overall product. So under Curran's leadership from a very early stage, we wanted to have state-of-the-art production suspension cell not only high yield, but high purity, importantly, particularly in a space like systemic gene therapy where there's such a high viral load. So we have an optimized construct, but also highest purity in the field with over 80% full capsid. And lastly, as Curran mentioned as well, careful immune suppression regimen. So we started out with what others are learning over time, unfortunately, given some of the events that have happened in the space to really right from the beginning, target what are the really detrimental side effects that can happen.

And the 2 main buckets are complement activation, and the later adaptive immunity T cell B-cell response leading to such adverse outcomes like liver injury and unfortunately, liver failure. So to address those in a targeted fashion, right from the initial protocol, we included eculizumab, a complement inhibitor for just a couple of weeks and sirolimus for 2 months with a 1-month taper in addition to the standard steroid regimen that's used in these gene therapy trials. And what we're seeing with this constellation in our Phase I/II study is excellent safety. So we have no SAEs, no adverse events of special interest.

And most notably, that is 0 liver injury. And although it's just Phase I/II, it's 13 patients with existing gene therapy, we know that, that rate is 40% liver injury. So there's already differentiation in terms of that with ELEVIDYS, for example, which also gives us more confidence about preventing other more serious events. We also see 0 thrombocytopenia, which we think is potentially due to the constellation of the 3-legged stool of characteristics that I described, which is a finding that's seen with other programs. And given these good results and the feasibility of applying this regimen, the investigators are very happy with this approach. So I've talked about safety, but safety directly links to efficacy in that it's because we pulled all these things together that allowed us to go to what is generally thought of as a target dose to get to 2E14 vector genome per kilogram.

And we're the only ones who've been able to get to that. And we think a big component of that is all these safety aspects where we really took that into account right from the beginning. So the construct aspect and some of these other aspects are translating into efficacy signals already in the Phase I/II. First, the whole goal is you want to get a functioning microdystrophin and you want that expressed. And what we see very good and robust and consistent expression across the age range. So starting with that biomarker aspect. You have to take age into account when you think of microdystrophin expression since the younger boys, not surprisingly, can have higher microdystrophin expression because of the healthier muscle. And then over older ages, 8 and above, it's much harder to get a good gene expression. So for example, in 8 and above ambulatory boys treated with ELEVIDYS, it's low double digits, 11%, 12%, I think, on average.

We're seeing consistently higher microdystrophin levels, most notably in the 8 and above, we see on average 40% microdystrophin. So on that aspect, we're very happy. What really matters is that translating into functional benefit. And that's where we're seeing -- we've shown results in the dose level 1 and also in the pivotal study with 4 boys. And across the board, we're seeing the patients are doing better on the functional assessment. So on the different ways of comparing to external natural history that I described, the boys are doing better than you would have expected them to do based on these comparisons. And they're also doing better based on different ways of measuring function.

So the NSAA and also the time function test. We went in expecting NSAA crude test. It's not as sensitive. Maybe that won't show as much. But actually, we're seeing very good response on NSAA, including in those 8 and above boys that are the hardest to treat. So all in all, we're -- this just has us very excited to go into having pivotal top line results in early Q2.

That's great. Just one more question on the point of safety. The prophylaxis that you use is for a set period of time. When some of these safety issues come up? Obviously, it's a one-and-done thing. So does it usually show up within months? A year, 2 years? Like what -- how do you get comfortable with that safety issue?

Yes, that's a great point. And we know a lot about that also based on what the mechanism of the side effects are. So for example, complement-mediated adverse events tend to occur in the first couple of weeks. So you kind of have a peak in complement activation generally with gene therapy as early as 5 days. But if you get through those first couple of weeks without any issues, you pass that stage. The liver injury and some of the other adaptive cellular-based responses tend to occur more in the 6-week to 8-week to up to 3-month period. So the nice thing as far as monitoring and characterizing safety, if you get through that time window, you have a very good sense that you've mitigated against those 2 categories of events.

So that also has us excited about the top line data because we'll have at least 3-month follow-up for all the boys in the pivotal study because the primary endpoint is 3-month microdystrophin. But by definition, we'll also have the safety data of at least that long for all the boys, which we'll be able to disclose at that time.

Yes. And I guess, despite the drama that occurred with ELEVIDYS, it seems that the interest in DMD for gene therapy has not waned given that you pretty rapidly or enrolled your study ahead of schedule. So would you say that, that's characterizes correctly?

Yes. I think just as you said, we earlier were projecting out to late this year, and we brought it in. So the enrollment did ramp up. The interest ramped up and in part because of various reasons we did this, but certainly, the ability to keep treating patients with open centers. We just continued enrolling into our confirmatory study, right as soon as we completed enrollment in the pivotal. So we are seeing that increased interest. And I think the more data we come out with on safety and efficacy is just helping the community recognize potential differentiation that may exist here.

Yes. Some of the sites that we're dosing at clinically now haven't previously or have discontinued dosing the commercial product. So I do think that speaks to interest in our program and potential for differentiation.

That's interesting to know that. So speaking of interest, I want to move to 314 for wet AMD really quickly because gene therapy for wet AMD has suddenly gained a little bit more interest from larger strategics. Obviously, we saw the Adverum takeout. We saw 4DMT in the Otsuka licensing. You obviously had a very big partner or have a very big partner in AbbVie, yet the investor community still doesn't believe wet AMD is a market. So what do they know? What do you know? And what do we all have wrong? So maybe you can just characterize it like that, set the stage here.

Well, I think I have to start with thanking everyone for their patience. We ran the 2 largest gene therapy trials that have ever been conducted, but that was something that we felt strong about powering the study the way we did having 2 doses, which helps derisk the outcome, I think. And AbbVie has been investing for the last 3 to 4 years heavily in this so it does take a long time to enroll those type of studies. But here we are, we finally have a stake in the ground, finished enrollment in September, and we're really excited that we'll have top line data on the program at the end of next year.

And I think AbbVie is continuing to invest not just in subretinal, but in suprachoroidal. I think what we're differentiated on and why there's enthusiasm around our program is the demonstrated safety of subretinal administration and efficacy. So we have a nice therapeutic window to operate in where we're continuing to show long-term results that are really what people want is to not go and get their eye injected every month or 2 months, whatever the new interval is. And I think on top of it, people are seeing new developments in ocular therapy changing the -- what's considered current practice. And I think people felt like for years, the current practice or the prior practice with Eylea and Lucentis was impenetrable. Well, now we're seeing new components come into the market. And so there's, I think, more receptiveness that gene therapy could disrupt even further that.

And you're obviously speaking to Vabysmo and the port and all of those different developments.

Yes.

Okay. So maybe we can just talk on one component that investors have had a hard time wrapping their heads around is the subretinal versus intravitreal. And I would say the Street sees it as a big stumbling block to commercializability. How do you see it? How do retinal specialists see it? Maybe you can just give us a little color there.

Yes. Steve, you might want to reflect on ASRS.

Yes. So even before these recent deals in this space, as you know, the annual ASRS PAT survey of, I think it's close to 1,000 retina specialists now ask a lot of intriguing questions each year. And one of them this year was of all the different pipeline approaches out there, what are you most excited about? And half of the respondents way more than any other category said gene therapy.

Was it specific to you or specific to gene therapy?

Gene therapy in general, with the other categories being tyrosine kinase inhibitors and some other aspects. So I think that speaks to this concept of the onetime treatment option that is more than an incremental benefit which while important and the market has proved, it's important with things like Vabysmo and high-dose Eylea. And hopefully, tyrosine kinase inhibitors will be another, but they're still incremental and they still mean injections for the rest of your life. So I think that's why there's so much interest in gene therapy. Now for us, and I think why AbbVie came in on this and is bullish and advancing both subretinal and suprachoroidal, of course, with suprachoroidal diabetic retinopathy as even going into pivotal first half of next year is both of these have the advantage of being compartmentalized local delivery so you don't have the same safety issues that have plagued other programs, specifically immune-mediated inflammation.

And the retina specialists, these are surgeons who like doing surgery and do a lot more complicated things than a subretinal bleb or in-office suprachoroidal injection. So we -- and we've been able to scale this with the largest studies ever done in terms of subretinal and suprachoroidal with a lot of experience in the community giving that injection. So we are not seeing any barrier in terms of being able to go into these areas. And obviously, neither is AbbVie.

Okay. Mitchell, I didn't forget you. But I keep hearing the largest gene therapy studies ever conducted. So why don't you tell us about how this is being paid for? And maybe you can talk about some of the sources of cash that are coming in that are almost as sizable as your market cap.

Great question. So these studies are fully enrolled as we speak, and we're very fortunate to have a great partner with AbbVie. Our balance sheet will get us into the early parts of 2027, but that's not including any nondilutive financing optionalities, which includes the monetization of the PRV, for example, as well as DR milestone, which we're expecting to receive $100 million from AbbVie as well. But just those 2 as an example, that will get us into the early parts of 2028, which is well past data readout and well into commercial launch for some of these products.

And the milestones that you get from an approval in MPS are also.

Yes, we haven't disclosed publicly the exact amount, but we are eligible to receive incremental regulatory milestones from NS Pharma for our MPS program as well.

So just to be clear, market cap of $600 million, about $350 million in nondilutive financing coming, you still have your cash and you have other milestones coming. So I just thought I'd level set that for you guys for anyone who's interested in a good value play with lots of catalysts. This is it. So we're totally out of time. And I thought -- I think that's a good place to end it.

Excellent. Thank you.

Thank you.

Welcome, everyone, to the Third Quarter 2025 REGENXBIO Earnings Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded.

At this time, I'd like to turn the conference over to Patrick Christmas, Chief Legal Officer of REGENXBIO. Please go ahead.

Good morning, and thank you for joining us today. Earlier this morning, REGENXBIO released financial and operating results for the third quarter ended September 30, 2025. The press release is available on our website at www.regenxbio.com. Today's conference call will include forward-looking statements regarding our financial outlook in addition to regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted and can be identified by words such as expect, plan, will, may, anticipate, believe, should, intend, and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties. These risks are described in the Risk Factors and the Management's Discussion and Analysis section of REGENXBIO's annual report on Form 10-K for the full year ended December 31, 2024, and comparable Risk Factors sections of REGENXBIO's quarterly reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the SEC's website.

Any information we provide on this conference call is provided only as of the date of this call, November 6, 2025, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events, or otherwise. Please be advised that today's call is being recorded and webcast. In addition, any unaudited or pro forma financial information that may be provided is preliminary and does not purport to project financial positions or operating results of the company. Actual results may differ materially.

I'll now turn the call to Curran Simpson, President and CEO of REGENXBIO. Curran?

Thank you, Patrick, and thank you, everyone, for joining us today. I am pleased to share the strong momentum across our late-stage pipeline of gene therapies with the potential to deliver the best outcomes in devastating diseases. Our progress is anchored in our leading end-to-end capabilities, including in-house commercial-ready manufacturing and innovative science, all driven by our commitment to bring new medicines to patients in need.

Today, I am joined by Dr. Steve Pakola, our Chief Medical Officer, to discuss the exciting clinical development across our rare and retinal franchises, and Mitch Chan, our Chief Financial Officer, to provide financial updates. Let's dive in and start with RGX-202, our wholly owned program for Duchenne muscular dystrophy. We are very encouraged by our progress in this program and are moving rapidly to deliver a much-needed differentiated treatment to Duchenne patients. Our comprehensive therapeutic approach behind RGX-202 includes a novel construct. RGX-202 is the only microdystrophin that includes the CT domain, making it closest to naturally occurring dystrophin. A novel immune suppression regimen designed to enable high-dose delivery and proactively counter issues seen in other AAV programs and commercial-ready manufacturing that is delivering the highest purity levels in Duchenne gene therapies.

Boys with Duchenne have one chance of gene therapy. That's why we specifically designed RGX-202 with these elements to maximize opportunity for functional benefit. We are very pleased to see that this approach is resulting in the favorable safety and efficacy profile seen in Phase I/II. We're also very excited to announce that we completed enrollment in the AFFINITY DUCHENNE pivotal trial, putting us on track to share top-line pivotal data in early Q2 2026 and submit a BLA using the accelerated approval pathway in mid-2026.

To meet demand from the patient community and support accelerated approval plans, the confirmatory trial is open and continues to enroll patients. As a reminder, we were able to complete enrollment ahead of our original year-end guidance, underscoring the community's enthusiasm for RGX-202 and strong need for new treatment options. We have more than enough supply of RGX-202 ready and available for the entire confirmatory study. Delivering on the commercial readiness plans we shared last quarter, we have produced the first batches of RGX-202 intended for commercial supply at our manufacturing innovation center here in Rockville and expect to imminently complete our PPQ or process performance qualification campaign.

There is a significant commercial opportunity for RGX-202 due to our novel construct, immune suppression regimen, and our manufacturing capabilities, including our ability to produce 2,500 doses per year, which make us uniquely prepared for clinical and commercial success. We continue to invest in preparations for a commercial launch in 2027 when the vast majority of the prevalent population will remain available.

Now to RGX-121, also known as chlamidiginelamparvovec, the potential first gene therapy and one-time treatment for MPS II. Our recent FDA interactions regarding the ongoing BLA have been highly productive, and we remain confident in RGX-121 approval by early next year. We delivered positive 12-month data to FDA, which Steve will discuss in more detail. And the FDA completed inspections of our clinical sites and in-house manufacturing facility with no observations, a rare and significant achievement. These developments have further strengthened our confidence in the ongoing BLA review.

With our commercial MPS partner, Nippon Shinyaku, we look forward to the February 8 PDUFA date and delivering the first commercial doses of RGX-121 by early next year. Let's turn our focus to our retinal disease franchise and our ongoing partnership with AbbVie to develop Surabgene lomparvovec or sura-vec for wet AMD and diabetic retinopathy. These programs have the strength of AbbVie's leading clinical and commercial global eye care infrastructure behind them.

In subretinal wet AMD, we recently announced that the last patient was enrolled in our 2 global Phase III studies. This is a tremendous accomplishment. Together, ATMOSPHERE and ASCENT represent the largest global gene therapy program ever conducted, with over 1,200 patients enrolled across 200 sites. If approved, subretinal sura-vec would not only be the first gene therapy for wet AMD, a disease that impacts millions worldwide, but also the first gene therapy for a non-rare indication. We look forward to sharing top-line data in the fourth quarter of 2026.

As a reminder, we manufacture all clinical and future commercial sura-vec at our facility here in Rockville. Like wet AMD, our diabetic retinopathy program is designed to deliver sura-vec to patients that rely on frequent lifelong injections to halt degeneration and vision loss, and we look forward to initiating the Phase IIb/III pivotal program. Across our pipeline, these achievements reflect the strength of focused execution and a differentiated approach to developing and delivering best-in-class therapeutics.

With that, I would like to now turn the call over to Steve for more in-depth updates on our clinical programs. Steve?

Thank you, Korin. I'll start with the RGX-202 program for the treatment of Duchenne. As Curran mentioned, we are incredibly excited that enrollment has completed in the AFFINITY DUCHENNE pivotal trial. As a reminder, this study is designed to enroll ambulatory patients aged 1 and older and is the most advanced clinical-stage gene therapy program for Duchenne. RGX-202 has demonstrated a highly differentiated safety and efficacy profile with consistent, robust microdystrophin expression in the Phase I/II study. Last month, at the International Congress of the World Muscle Society, we presented individual NSAA data on the first 4 patients who received the pivotal dose. All 4 patients 1 year after dosing exceeded expected disease trajectory across multiple methods of assessment. Specifically, each patient exceeded their expected functional outcomes when compared to matched external controls and the well-established CTAP disease progression model.

These data, combined with the June 2025 data showing all patients demonstrated improvement on time function tests, reinforce our belief that 202 is driving meaningful functional benefits for patients with this degenerative disease. It's important to note the majority of these patients were 8 years and older at dosing an age when functional decline is expected, making these results particularly impressive. The Duchenne patient and physician communities continue to recognize the excellent safety profile 202 has demonstrated to date.

As reported in the Phase I/II study, we have seen no SAEs or adverse events of special interest, including no thrombocytopenia or liver injury. We attribute this to our proactive immune suppression regimen, our novel construct using the NAV AAV8 vector, and our field-leading product purity with more than 80% full capsids. We are very pleased with how these differentiated elements enable us to deliver 202 at the 2E14 vector genome per kilogram dose. We believe this dose gives patients and families the best shot at efficacy without compromising safety. In the Phase I/II study, this approach has translated into a favorable safety and efficacy profile for patients.

With this momentum in our pivotal study and results to date in Phase I/II, we intend to expand the RGX-202 program outside of the U.S. and are actively exploring opportunities to do so, starting in Europe. Shifting focus to RGX-121. The positive 12-month pivotal data delivered to the FDA and presented at ICIM in September were consistent with the previous findings and demonstrated the long-term potential of RGX-121 to change the course of MPS II.

Further, we saw a continued favorable safety profile and a strong correlation between biomarker level and neurodevelopmental improvement. If approved, RGX-121 would become the first and only gene therapy for MPS II and potentially the only one-time treatment option to address the neurodevelopmental decline for this devastating disease. The hunter and MPS communities have been fierce advocates for the need to deliver new treatment options to their children as quickly as possible. We look forward to continuing to advance our BLA and potentially bringing this much-needed therapy to boys living with Hunter syndrome in the coming months.

Turning to our retina sura-vec franchise for wet AMD and diabetic retinopathy or DR. Completing enrollment in our pivotal wet AMD studies is a major milestone in our and AbbVie's continued effort to serve the millions of patients worldwide suffering retinal diseases. The data from our subretinal wet AMD program have been excellent, with durable outcomes reported through 4 years. Additionally, in the fellow eye study, SurtVc has demonstrated comparable safety and efficacy when dosed in the second eye. These results, along with patient enthusiasm to return and receive treatment in their second eye, underscore the robust interest we're seeing among patients and physicians.

Finally, I'll speak to sura-vec for DR using in-office suprachoroidal delivery. We continue to make progress towards initiating a global pivotal program. Site selection is in progress for the Phase IIb/III double-masked sham injection-controlled trial for patients with nonproliferative DR or NPDR. In the Phase II ALTITUDE trial, a single in-office injection of surVc was well tolerated. In patients with NPDR, surVc demonstrated durable long-term efficacy, including meaningful DRSS improvement and an over 70% reduction in the risk of vision-threatening events.

Finally, I'd like to express my sincere gratitude to all the patients, families, clinicians, site staff, and patient advocacy representatives who have supported all these trials. With that, I'll turn the call over to Mitch to review our financial guidance. Mitch? Thank you, Steve, and good morning, everyone. REGENXBIO ended the quarter on September 30, 2025, with cash, cash equivalents, and marketable securities of $302 million compared to $245 million as of December 31, 2024. The increase was primarily driven by the $110 million upfront payment from

Nippon Shinyaku in the first quarter of 2025 and $145 million in net proceeds received from the royalty monetization with Healthcare Royalty Partners in the second quarter of 2025 and was partially offset by the cash used to fund operating activities in the first 3 quarters of 2025. Revenues were $30 million for the quarter ended September 30, 2025, compared to $24 million for the quarter ended September 30, 2024. The increase was primarily due to the development service revenue under the Nippon Shinyaku partnership in the third quarter of 2025. We expect the September 30 cash balance reported today to fund our operations into early 2027.

Note, this cash runway guidance does not include multiple nondilutive financing opportunities that could further extend our cash runway. These include the sale of our anticipated priority review voucher for RGX-121, development or sales milestone for our MPS programs, development milestone associated with our diabetic retinopathy program per the AbbVie collaboration, and potential additional funds from the May 2025 healthcare royalty agreement. Together, these nondilutive opportunities could further extend our cash runway well beyond 2027. In all, we find ourselves in a strong financial position as we advance towards multiple product launches.

With that, I turn the call back to Curran to provide final thoughts.

Thank you, Mitch. As you've heard today, our strong execution throughout 2025 has positioned us for an exciting and transformational year ahead, including the anticipated approval of RGX-121 by February and top-line readouts in Duchenne and wet AMD, both large indications and large commercial opportunities. Each of these potential best-in-class gene therapies address a significant unmet need for patients and are built upon our 15-year history of pioneering AAV gene therapy with a commitment to scientific excellence and disciplined execution. I want to thank our REGENXBIO team, partners, and the patients and families who participate in our trials. Your partnership is key to advancing our mission to improve lives through gene therapy.

With that, I'll turn the call over for questions. Operator?

[Operator Instructions] And our first question is going to come from Judah Frommer with Morgan Stanley.

On the progress here. Maybe first just on 202. Can you help us with when next interactions with FDA will be? And can we get your thoughts on clearly news coming out of FDA that impacts the DMD community with arguably higher unmet need in DMD, but also just on external controls and other gene therapy programs, how are you thinking about the potential for the accelerated pathway for 202 at this point?

Thanks, Judah. Yes, I mean, if you think about the progress next year, we'll have top-line data that we pointed to in early Q2. And then we've also guided to a mid-2026 BLA submission. So absolutely, we'll have potentially several FDA interactions. Of course, the key one is the pre-BLA meeting. And based on that timing, we haven't got a specific date set for it, but it would happen somewhere around the vicinity of top line data and preparing to file the BLA. I think in general, we are watching carefully other programs going through FDA and the debate around external controls. We've continued to update our access to some of the same databases, for example, that were used in the ELEVIDYS approval.

And I think that when we look at it, one of the things that's striking to me is, especially in our older patients, we're not looking at a marginal stabilization of patient functional outcomes. We're looking at a really significant difference from natural history in which we're matching that patient to, say, 12 up to 20 patients. And so I don't think we're going to be going into FDA with sort of a modest benefit approach. I think what we're seeing in our data is a significant benefit and even improvement in patients that you would expect maybe the best case at their age would be stabilization. So I think that's the strength at which we think we're eligible for accelerated approval. And I won't leave out to date the safety profile of the program. So you think about benefit to risk ratio, and I think we can provide a significant advantage over the product on the market to date.

Great. And then maybe just a quick one for Mitch. On cash runway, I guess, kind of when you internally probability weight potential for these nondilutive financings that you listed, can you give us a sense of where those could potentially get you through without kind of bringing in external capital, or how you're thinking about the potential for cash runway if we do layer in some of those nondilutive options?

Yes, absolutely. So if you factor in the nondilutive financing options, inclusive of the PRV as an example, and for modeling purposes, if you use the market price, as you're probably well aware of what the prices are for these PRVs, it could significantly get us into -- well into 2027, if not even early parts of 2028. But again, this is all contingent on what the market price of some of these items can go for. Other nondilutive financing, for example, the milestone associated with the DR first patient dose, that we already disclosed is $100 million. So that in itself, you can factor into the cash runway.

And the next question will come from Manny Freuhar with Leerink.

This is Lili Nsongo on for Mani. Just a quick question regarding the confirmatory trial for DMD. Maybe could you provide an update in terms of the tempo of enrollment? And where do you see enrollment be at the time of filing?

Good question. So we've begun enrolling the confirmatory study actually right at the end of October when we completed the pivotal enrollment. And it's hard to predict at this point where we'll be, let's say, mid-2026 at the point of filing, but I would expect us to be substantially through enrollment of the confirmatory study given that, that's prespecified in our protocol as an additional 30 patients. So we'll have to monitor that as we go, and we'll definitely give updates throughout the first half of next year regarding progress. Steve, maybe you just want to comment quickly on high-level design for confirmatory.

Sure. So the basic concept is very similar to what we've already done. So we're looking for a broad patient population of ambulatory patients 1 year old and above. So very broad. And this is really based on the data that we've seen to date, whereas Curran mentioned, we're seeing very good differentiation, not just on safety, but also in terms of functional benefit for these boys. And that's particularly striking in the older boys, and we're seeing results that have never been seen by any program when you look at function in those 8 and older boys. And no placebo control. So that's stayed consistent. And we're looking to enroll an additional 30 patients. And it's key what Curran mentioned, we're just continuing to roll along with all the sites that we've got up and going that we're enrolling in the pivotal. They're energized. And one of the things we're seeing is with each new update that we give that's showing more and more differentiation, we're getting more and more enthusiasm from the investigators and the patient families that they see. So we're very excited about the pace of enrollment.

And the next question will come from Gena Wang with Barclays.

So I would just ask one regarding the regulatory part. I know you have 2 programs like DMD and MPS II, you need to talk to the FDA. Just wondering, so for the DMD, when will you have a pre-BLA meeting with FDA? And then also regarding the MPS II, I know PDUFA is February 8. Any additional meetings set up before approval? Maybe any update color you can have in terms of interacting with the FDA, especially after Nicovodon's departure? And any concern regarding agreed upon the accelerated approval path?

Sure. Gena, I'll take the second question first and then circle back to Duchenne. For the Hunter program, we're far along with the BLA review. As you know, the PDUFA date was moved to February 8 from the initial date. We expect between now and that decision point to have a late-cycle meeting with FDA and that we're getting messages from the project leader to schedule that. So that's moving along as what I would call business usual. I think it's important to point out on the Hunter program, we're already past our facility inspection, no observations. Our clinical sites have been inspected as well. with no observations as well. And so some of the things that have held up other programs were derisked, if you will, in that process. And the other, I think, area that we interact as we undergo this review is in the information request that we get from FDA.

And I think I would characterize those as well as typical requests, some of which in an encouraging way are questions related to commercial aspects of a program, specifications, pharmacovigilance. So the color of the interactions we're having is positive, and we feel positive about the data we provided for that program. And therefore, our confidence is high that this program, and we think patients support that has a really, really important place in therapies. For Duchenne, the pre-BLA meeting will happen between our top-line data, which we pointed to early Q2 of 2026, and the filing of the BLA. We haven't got a specific date for it yet, but somewhere in that time frame is when we would expect to have it.

And our next question will come from Luca Issi with RBC Capital Markets.

This is Katy on for Luca. Congrats on the progress this quarter. Maybe a question on your manufacturing capacity, if you can talk about your in-house capacity. The Rockville site is obviously up and running and already produced first commercial batch. So I'm wondering what is the scale of production volume that the site is designed to deliver today? And what percentage of domestic patients are you planning on capturing with that site, maybe for both the MPS II and DMD, if you could speak to that?

Sure. Yes, the manufacturing facility is -- contains a 2,000-liter bioreactor. It's the largest bioreactor that we know of utilized in gene therapy, and we've already scaled the program up to that level. We've been public about being able to produce up to 2,500 doses of RGX-202 per year. And I think keeping in mind that just is what we can do on an ongoing basis. We can certainly inventory, which we're doing presently more quantities than that to have a significant number of doses available at launch. The Hunter program, being an ultra-rare program, I would characterize it uses less than 5% of our overall capacity. So it's not -- we have good yields, good expression, and we have our own internal fill/finish capability. So we can run very efficiently, but it doesn't take up a significant amount of our overall capacity.

And our next question will come from Annabel Samimy with Stifel.

Great progress on all the programs. Just on the issue of using FDA natural history as a control in DMD, I guess it's clear that you have both propensity match comparisons and now the CTAP disease progression model. Is that something designed into AFFINITY prospectively? And could that then further support? And is it a measurement that's accepted not only in the DMD community, but also considered as a valid metric from FDA? That's the first question.

Okay. Great. Annabel, I think that's a great one for Steve to address.

Sure. Annabel, great question. I think right off the back, it's important to recognize each program and indication is different. So starting with VMD, external natural history matching can be done in different ways, and you mentioned a couple of them. That's why we're excited about our data. We're seeing clear response across the dose range that's very consistent when we look at a traditional external natural history matching by baseline characteristics and also the CTAP model. There is also the propensity score matching approach that's been accepted by the FDA, and that's actually prospectively specified in our protocol as an accepted approach for 202.

On the 121 program, Importantly, we've had numerous interactions with the FDA, of course, and there hasn't been an issue of how we've prospectively looked at our individual data. And the only thing that's been asked for from an efficacy standpoint was what we provided in terms of the encouraging 1-year data. And since then, we discussed with the FDA, was there any other data that would be needed? And the answer was no, that this would allow them to complete their review. So I think this reality of what type of feedback we've gotten from the current regime puts us in a good place for both these indications.

And I'm going to be different and ask a wet AMD question. I guess, can you opine on the recent M&A and licensing activity for gene therapy and wet AMD? Obviously, we had Lilly Fredberm and 4DMT licensing, and of course, your licensing. So does the Street have it wrong on the level of interest from retina specialists? And where is your program rank as far as level of engagement with these retinal specialists?

Sure. It might be good, Steve, to reflect on what we just heard out of AAO regarding gene therapy in general and specifically our program.

Sure. So I think there's tremendous excitement about one-time treatment. And the way to do that is gene therapy. And one strong piece of evidence is what we're hearing actually from retina specialists -- and this is coming from the PA ASRS survey of close to 1,000 retina specialists, where every year, a number of questions are asked of these experts in the field, the actual treating clinicians. An important one is exactly what you're asking, how -- what pipeline approaches are you most interested in asked to retina specialists across all the different approaches and half the respondents say, gene therapy because of the onetime potential here that isn't the case for any of the other treatment approaches like TKIs or any other durability approaches because no matter how long you extend that durability, you're still going to need injections indefinitely for any of the indications that we're looking at.

I think we're seeing that in terms of interest in the field and some of the licensing deals or M&A deals that you mentioned, Annabel. And of course, we have a major global partnership with AbbVie, who has quite a lot of experience globally, including quite a reputation when it comes to ophthalmology and experience there. So their continued advancement with our program, including paying $2 of every $3 for the advancements, both in diabetic retinopathy and other areas, I think, really speaks to the validation of not just gene therapy, but specifically our program with the muscle of AbbVie behind it globally.

And the next question will come from Alec Stranahan with Bank of America.

This is Matthew on for Alex. Given a recent expectation for a box warning for a competitor product and the removal of the non-ambulatory indication, just curious whether your expectation is for something similar on your label or other AAV gene therapy labels and how you're thinking about long-term development in the non-ambulatory population in general?

Thanks for the question. I think in terms of expectations, I mean, I think our track record in Phase I/II on safety has been exemplary. And I wouldn't expect a black box warning of that nature, given that we've shown clearly the incidence rate of any sort of liver injury for us is virtually nonexistent in terms of the data, whereas we're seeing on the label for ELEVIDYS or in their filing that they have upwards of 40% liver injury in the approved product. So I think we don't expect that. In fact, we expect to leverage safety as part of the accelerated approval pathway that we're pursuing.

And I think accompanying that is strong conviction that the differentiation of the product with the immune suppression regimen we utilize and the construct and manufacturing purity. Put those all together, I think we have something very different and very exciting to the patient community to date.

And our next question will come from Brian Skorney with Baird.

I'd actually like to tack to regulatory questions on the EMA side of things. I know EMA has granted 121 the ATMP designation. But I was just wondering the status of any plans for it at the EMA. And also, any thoughts on the potential sufficiency of the AFFINITY Duchenne study for EMA review? Or what else do you think you need to do there? Is your FDA confirmatory sufficient for EMA filing?

Yes. We've had some interactions with EMA regarding RGX-121. And I think that what we're typically seeing there is the requirement for a control arm, placebo control arm still seems to be the predominant feedback that we get. Having said that, there's a significant opportunity in named patient sales that would potentially exist of an accelerated approval. So I think that's something that we are carefully evaluating and could be part of our commercialization approach. Steve, do you want to address the Duchenne question?

Sure. Brian, so based on all the discussions we've had stateside, so to speak, we're very confident on our approach here. Not having had the discussions outside the U.S., we don't want to project what will be the case. Certainly, historically, there has been a need for a placebo control there. We recognize the problems of that as well as with the patient advocacy community. There is increased data that keeps growing with different ways of assessing function that are becoming accepted in different regulatory regions, like the SV95C, just to give one example. So it's something that's an evolving field, but it's really going to take actual discussion. And we keep coming back to differentiation because it matters. So the functional data, if we continue to see what we're seeing, including in the older boys, not just stabilization but improvement, we think we're in a stronger position for being able to come up with an approach that would be acceptable ex U.S.

And the next question will come from Sean McCutcheon with Raymond James.

Just one for me on diabetic retinopathy. A competitor was able to get an agreement with FDA for an ordinal 2-step DRSS change primary endpoint for the pivotal studies in NPDR. Can you speak to how that's informing your discussions with AbbVie on your pivotal NPDR program and ability to adjust that study plan to potentially improve probability of success relative to a 2-step DRSS improvement at 1 year?

Yes, thanks for the question. Yes, I think one item off the bat is that the ordinal approach is something people have thought about over time. The prior lead or director of the ophthalmic division had always required a meaningful change in DRSS, with meaningful defined as either 2-step improvement change or in either direction of worse or improvement. So the advance of being able to get more information out of each patient's DRSS change by looking in an ordinal way now with the new regime has come on the table. So it is definitely something we've been looking at, both us and AbbVie in close collaboration. So I think it gives us more options.

Fortunately, what we've seen is we look good in both respects, 2-step improvement, a greater proportion of patients achieving that and also 2-step worsening a greater proportion of patients showing that in a placebo-controlled setting, as well as what you expect without treatment in the real world and other controlled negative control arms. So we think we're really well-positioned to really take advantage of what looks best in our discussions with the FDA.

And the next question will come from Daniil Gataulin with Chardan.

A quick one on suprachoroidal wet AMD. First, can you remind us how many patients you're looking to enroll at dose level 4 for that study? And now with the subretinal program fully enrolled, do you expect the speed of enrollment for suprachoroidal program to pick up a little bit now with the shifted focus to that program?

Thanks for the question, Dan. So SCS wet AMD is advancing. We're looking to enroll 20 patients in that arm. As you mentioned, we reached the quite significant milestone of completing enrollment in the SR wet AMD pivotal studies, the largest gene therapy program ever conducted across any indication. It's a great point that now, with that trial completed enrollment, a lot of the overlapping sites can now focus on the suprachoroidal delivery route. So yes, indeed, we're seeing a pickup in enrollment in that study.

And a quick follow-up for subretinal program, do you expect Abbott to file in the U.S. and EU roughly at about the same time?

Yes, I think that's a safe assumption. We haven't got a specific timeline for the filing mapped out. We're primarily focused on top-line data next year, but we would expect a global filing, and we'll be more specific as we get closer about the interval between U.S. and ex-U.S. filings. But they're recruiting not -- the basis of the ASCENT study being recruited in Europe was to enable that to be a smooth process.

And the next question will come from Bill Man with Clear Street.

So I just wanted to look again at the functional endpoints on 202 and just ask about the powering around those and whether or not you believe there's a certain threshold or, I guess, outcome that you need to see as a bar for success to really kind of put together a definitive answer in front of the FDA that kind of can't be denied.

Sure. Thanks for the question. So we are seeing a nice response, both in terms of change from baseline with improvement, even in the older boys, where you might expect just stabilization or worsening, and with improvement, just stabilization. So I think we're in a good position where if we continue to see what we're seeing and what we report on in early Q2 next year, with not only the primary endpoint for accelerated approval, but also the microdystrophin, I think we're going to be very well set up. And that's based on, to your question, looking at the traditional endpoints. So certainly, NSAA, where marginal effect, if any, depending on the age of the patients has been seen previously, and also the time function tests. So the traditional time to stand, 10-meter walk run, time to climb as the traditional ones where there's a lot of data out there, and we have the opportunity to look with propensity matching. So how good of a data do we have to see?

Again, if we continue to see what we're seeing, we're going to pass that bar because of the differentiation that we're seeing. And some bars you can look at are not only against natural history, but also there's data and published interpretations of the data on minimally important clinical difference that we're surpassing. And we can also look by age and by baseline status, what's been seen with approved therapy. And that allows us to feel that we're in a good position to have power based on the data that we're seeing, again, if we continue to see what we're seeing. The overall package is important as well. So the benefit-risk relative to that functional improvement, then we go to the safety where, again, we're seeing very good differentiation.

And on your suprachoroidal program, where are you on your understanding of how closely that can recapitulate the amount of vector delivery of your subretinal delivery?

So, are you asking if the protein levels match in terms of transgene expression between the 2?

Yes.

Yes. I think because -- Steve can comment further, but because they're delivered to different compartments of the eye, it's very difficult to do direct comparison. So ultimately, what we look at is sustained vision and safety. But Steve, maybe you want to comment further on the differences we see.

Sure. So geographically, there are different spaces. They're both close to the target tissue, and they're both in compartmentalized spaces. So that's why we selected them so that they greatly limit off-target tissue potential side effects in terms of immunogenicity. That also changes, as Curran mentioned, the reality that you really can't compare the apples and oranges. But fortunately, what really matters is what do you see clinically, which shows that you have the transgene product at the target tissue where you need it. And that's where the diabetic retinopathy data is so compelling for us in AbbVie that you're seeing what you want to see. And that's why we're advancing with suprachoroidal already and actually accelerated development so that we can -- we and AbbVie can actually start Phase IIb/III next year.

And our next question will come from Yi Chen with H.C. Wainwright.

Could you comment on your current thinking regarding the pricing strategy for RGX-121 versus 202? And also, how large a sales team do you think you need for 121 versus 202?

Yes. So if you recall, earlier in the year, we signed an agreement with NS Pharma for commercialization in the U.S. And so the pricing decisions will be made by NS Pharma as we move through the approval process. And Mitch can comment, we certainly will enjoy a nice royalty from sales, but the actual price determination will be made by them. We would eventually make the price decisions since we wholly own the Duchenne asset. And I'd say at this point, it's very preliminary for us to state any sort of thinking on pricing until we get closer to commercialization.

Yes. So as you recall from the Ennis Pharma partnership, we are eligible to receive meaningful double digits in sales royalty. So as Curran kind of mentioned, pricing decisions will be made by Enn Pharma at a later time.

And the next question will come from Paul Choi with Goldman Sachs.

With regard to 202, could you please comment on where you think you might see the potentially greatest demand initially as you start to commercialize in 2027? Do you think about it in particular exon skipper experienced patients or just thinking primarily about newly diagnosed patients? Any color there would be helpful. And then second, on -- with regard to your collaboration with AbbVie and 314, how are you thinking about sort of rough timelines for potential Medicare coverage of 314 post approval? And just sort of what are sort of the block steps there involved for gene therapy coverage in this particular Medicare population?

Yes, I'll take the first one. I think, obviously, if you look at the inclusion criteria for the study, we're dosing patients and older. So we'll have data at the time of review for potentially a broad label. One thing that we see based upon the public announcements on sales is that the prevalent market really isn't changing in terms of Duchenne. So by 2027, the prevalent market will be something like 14,000 patients. And if you think about eligible for gene therapy, it's probably closer to 3,000 patients when you subtract out non-ambulatory. So at the time of launch, our aim is to have a broad label and really be able to address patients of all ages. But to your point, we do expect that over time, as the prevalent market diminishes, which could be past 2030, is that at that point, we would be in a great position to address the incident market. Most KOLs think early treatment is ultimately the answer for gene therapy, and we'll have the data in hand to support that age group based on the fact that we're already dosing kids right after diagnosis in some cases.

I think on the Medicare coverage for 314, that's a question that I'll defer out a bit. We haven't had those discussions with AbbVie. AbbVie will obviously be leading the significant element of the commercialization. But we do believe broad access for gene therapy is fairly easily achieved. It's just too early in terms of our conversations with AbbVie to be specific there.

This does conclude today's question-and-answer session and conference call. Thank you for participating, and you may now disconnect. Have a good day.