REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Thank you. There's no clock. It's all 31. Okay. You've got to read. All good. All right. Thank you. Good morning, everyone. Welcome to day three of the Morgan Stanley Global Healthcare Conference. We're very excited to kick off with the REGENXBIO team. Connor, 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 REGENXBIO, and it's been an eventful year for REGENXBIO. The coming 12 months will certainly be exciting, but maybe before we dive into the program, 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, uh, mainly did a lot of out-licensing of the technology, and that's one of the programs that came from that was Zolgensma, so uh, long lineage of 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. Cool. Great, so maybe let's start with RGX-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 11th 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 you know 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 it, that is very high vector copy numbers. And what do we think that's important for is long-term durability. 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... We're 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.

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.

You know, we can get into this.

The various analyses you use, such as CTAP. That's great. 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. And 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 2 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 value. You know, could CTAP provide support from a regulatory perspective, or is FDA more focused on external controls with propensity score weighting? This 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 uh precedent. Uh, we have thought that uh totality of evidence is 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 uh raised with the FDA not to change anything 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. And we've seen, as hoped for, very consistent findings across propensity score weighting and CTAP.

Okay. All right. Perfect. And we've seen safety become a significant overhang for the approved gene therapy, certainly. But maybe just walk us through safety comparison techniques. RGX-202 versus the approved therapy or others, and maybe, you know, we can talk about the immune modulation measurement 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 that is the fact that the ability to get a handle on this for people has been difficult. 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. 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 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, but we sense some hesitation around sirolimus specifically in that modulation regimen. But clearly, there's more comfort with that with that product today? I mean, maybe just talk about the evolution and maybe how others have adopted.

Similar regimen. Yeah, 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 then I think 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 a 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 could be better because, yes, up front you're giving these short-term 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 1 thing on safety as well, when we we last showed FDA our data, it was in 2024 in our end of Phase 2 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.

Broad perspective on safety and just a much higher N. We're excited about that. Okay, great. So maybe just touching on that, so like you said, expect them to submit to BLA in Q3 2026, 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?

On safety, a pivotal study data function will be at 12. So we have roughly 63 patients on safety. We've got the 30 that were in the pivotal study, the 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 -- the CMC module is the 1 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, you know, RGX-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, excuse me, 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. And we see direct quotes from Kareem McHale 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. 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 2 meeting. 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. Patients enrolled in open label approach with the typical functional assessments of NSAA and the 3 main time 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, 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. Month. So that's really a 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 AAA submission. Nice.

I think with an AA approval in 2027, we dosed our last confirmatory study patient in April of this year's go.

Go out 2 years, there won't be a big lag between the two. And 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?