Great. We're going to get started here, so thank you very much. Hi, everyone. We're going to get started here for the REGENXBIO presentation. Thank you for joining us today. We have Curran Simpson, CEO of REGENXBIO, Mitchell Chan, who is now the new CFO, as well, Steve Pakola, who is CMO. So REGENXBIO has an exciting platform of gene therapies, and Curran, I'll let you give the quick overview on your platforms, and then we'll get into Q&A.
Sure. We started out almost 15 years ago with what's called the NAV platform, and that's developed today into most of our programs being based on AAV8 and AAV9. I would classify where we are as a company. We refocused the company last November on, I think, two key franchise areas. One is the programs that are in retina, which is most of which is partnered with AbbVie, so a really significant collaboration there.
Then the other franchise is focused on muscle, which is the Duchenne program that we reported data on yesterday, and also includes the rare disease area for the Hunter program that we've just filed our first BLA module in the last month or two. So we're really excited as to how this year has really materialized in terms of progression. And next year, we'll have four programs in late-stage development, one of which we're hoping to get an approval on. So it's an exciting time.
Excellent. So let's go straight to the topic du jour, which is RGX-202. Before we get into the data, can you just describe to us why you believe this is a best-in-class program and what differentiates it?
Yeah, I think there's multiple aspects of how we think about this as the next generation of gene therapies that are available for Duchenne. I think the underpinning of it, and one of the most critical elements, is the existence of the CT domain within the construct. And I actually have been trying to figure out why others didn't necessarily include that in constructs that were developed many years back. There's an element within AAV of packaging that's very difficult. And so the more you add to your construct, the more difficult it is to actually produce the product. And we figured out how to package efficiently the base microdystrophin with the CT domain included in it, and now we have a really, really high-yielding process that's associated with it.
But that CT domain is really critical because we not only, through the microdystrophin itself, can allow the muscle to create force, but the CT domain is really essential to the repair of the muscle once the force is exerted. And so we think that kind of completes the cycle of how the muscle functions. And I think, you know, from the beginning of if you look at the program results of initially demonstrating really good safety at Dose Level 1, quickly dose escalating to Dose Level 2, and then the really high levels of microdystrophin we're seeing, particularly in the older boys, the only piece remaining to understand relative to wanting to go into a pivotal program was, does that all translate into functional benefit?
And that's been a really key question in Duchenne with a microdystrophin approach. And I feel like the data that we put out yesterday begins that process of. I think Mike Kelly said it beautifully yesterday, sort of resetting the expectations for microdystrophin-based gene therapy.
Okay, great. So just maybe you can help us understand. So obviously, you had the functional data out yesterday in five patients, though. So when we think about functional data in this heterogeneous population, five patients seems like a lot. So why don't you help us understand the weight of that, of the importance of this functional data?
Sure.
What we would have expected and what we actually saw.
Yeah, and I'll start, and then I'll let Steve comment further. We reported data for our first dose level, Dose Level 1, we call it, for three patients. And then we had two patients at what's Dose Level 2, now our pivotal dose, out to nine months. And a majority of the patients that we've dosed in the phase I/II study are patients that were eight and older. We have dosed across all ages now. But interestingly, those patients tend to be in the decline phase of their disease progression. And when you think about it from a functional data perspective, that actually makes the data we've shown yesterday even more striking, that all of the patients have stabilization of their disease progression, but at least three of them have really significant improvement, which wouldn't be expected normally.
What we've done in the release is compared them to external controls that I'll let Steve describe, where we match patients from a large database, and we analyze how those patients would have progressed, and we compare that to the result we've gotten. I think fundamentally, at a top level, what we're showing, there's no way that could have happened by chance. There has to be a drug effect. Interestingly, we see that clearly at Dose Level 1, and then we see it very pronounced in particularly one patient at Dose Level 2. If we can just simply reproduce that in a pivotal setting, the probability of success of the study, I believe, is very high. I don't know, Steve, if you want to step in on.
Sure. Yeah, sounds good. Thanks, Annabel, for having us, as always. Yeah, I think Curran hit on a good summary comment of, is this real? Is this something that could have happened by chance? And that's where the external controls come in so valuably. So you can actually think of each individual patient and actually match based on natural history database. And that's what we've done. And it's critical to do that within Duchenne because there is variability, and it's driven by age and also how well the boys are functioning when they enter the study. So fortunately, we can use these natural history databases to match on not only age, but the underlying function. So we use the traditional measures like time to stand, 10-meter walk/run, four-stair climb.
That really gives us confidence that with that matching, we can know what would happen in this boy if they weren't getting a treatment that was helping them. And across the board, we're seeing much better outcomes for these boys at nine months for Dose Level 2, and at 12 months already for Dose Level 1. And the thing that I think has gotten the most interest in the community, and you heard a little bit of this if you listened to the KOL call, that what really separates is those older boys that Curran mentioned. So there, we know, even with variability, these boys are in the rapid decline stage. So these are the toughest to treat and the ones who unfortunately are really falling off a cliff, unfortunately, in terms of function.
So too even in that age group have not only stability, but seeing these boys do better. And Dr. Panda, one of the investigators, showed a video of a Duchenne boy, 12 years old, who a year after is riding a bike for extended duration. So that is really quite striking, and it really supports what Curran mentioned on the differentiation of the C-terminal domain. So it fits with this concept that by having a construct that is much closer to full-length dystrophin, there's the potential to really differentiate not only on microdystrophin levels, which, by the way, we saw much higher in these older boys as well, compared to any other gene therapy. Seeing that translate into the clinic, that gives us a lot of confidence going forward.
I'll just add that it was riding a bike in New York City, which I won't even do. So all right, so maybe you can talk to us about the time frame that you looked at. It was 12 months and nine months for Dose Level 2. When would you expect to start seeing separation? When did you see separation, and how much of that is from the steroid use initially as you're prescribing or as you're giving them the gene therapy?
Sure. So our immune suppression regimen is just three months, and it has a taper to it. But still, there could be some confounding factor for some time period. So that's one of the reasons that nine months is a nice time point where you've waited long enough, not just to have the separation, but to make sure that you don't have an effect of any underlying confounding factors. So that's in a nutshell why we thought of nine months, even prospectively, as an important time point. So basically, we wanted to have whatever data we had available for Dose Level 2, and that's why we have the two patients there. We, fortunately, for the first three patients at Dose Level 2, had one-year data.
And the one-year data is interesting because we know there's a recognized minimal clinically important difference in Duchenne for these different functional outcome measures that the FDA, Dr. Peter Marks, has actually referenced and used as part of approval for Elevidys. And so we have the opportunity in Dose Level 1 with 12-month data to show that we actually exceeded those benchmarks quite easily. Dose Level 2, we're exceeding those as well, but technically, the MCID is based on 12 months. So we look forward to hopefully confirming clear separation from those MCIDs when we get to 12 months.
Was there a speed of onset that you saw that was notable and different from Elevidys?
You mean over the one-year time frame?
Yeah.
Small sample size, so it's hard to really glean trajectory when you think of that aspect, but there's nothing surprising in the evolution that we've seen.
So one thing that I thought was interesting is that we've heard from KOLs that as you look at different age groups, the endpoints that you need to measure are very different. In a younger population, it's more ambulatory. It's the 10-meter walk/run, et cetera. And then in the older populations, you're getting more to function. And so I guess for those older patients, how remarkable is it that they were actually able to show a difference on some of these more ambulatory measurements that may have completely deteriorated by the time they were 8, 12, 10, whatever it may be?
That's a really great point because the scales break down if many of the children are not able to even walk. So you go from having a continuous variable to they're either walking or not, unfortunately, once you're getting to the 12-year-old age range, and I think that gets back to the trajectory of these boys, unfortunately, at eight and above, where if they're already going down very steeply, how do you really improve upon that? How do you really stop the train from going down, so that becomes more of an issue, and maybe it's an issue with other gene therapies. If you don't have a clear effect, are you changing the trajectory just by having it be less steep, or are you actually able to have a more significant impact where you actually can show improvement?
Small numbers so far acknowledged, but there's clearly something happening for these boys where they're actually getting better, which for the investigator and the other thought leader we had yesterday, as well as our other thought leaders that we speak to in the community, that is just not something you'd expect, in part because of how crude some of these measures can be once you get to that older age range.
Okay.
We've had comments as well from the investigators that feel like the functional measures we're making don't adequately describe the progress that they're seeing. And I think one thing that's going to be very interesting in the pivotal study is implementing the stride velocity measurement, which is more a continuous measurement. Because when you look at our video, you can see not just the ability to stand up X number of seconds faster, it's the intensity of the movement they're able to generate that's also quite striking. And that stride velocity measure will pick that up more readily. So we're excited to implement that as part of the pivotal study as well.
Right. I guess one of the things that had people surprised, I don't want to say concerned about your program, just surprised in general, was the breadth of the Elevidys label. It was ambulatory. It was non-ambulatory with confirmation later on down the road. It was in age groups from four all the way up. So give us some of the things that you're trying to bake into your phase III program to separate from that because you just laid out your phase III program yesterday.
Yeah, I think we're approaching the pivotal study as the first step towards a broad approval, so not sort of a narrow age-related approval. So we'll enroll children across one plus, so not four to seven or 8- 12 or anything like that. And we want to have kind of a balanced representation in the study across those age groups. I think what we see in the prior approval is a lot of regulatory flexibility was applied. And I feel like our End of phase II meeting, where we talked with the very same review team, the same thing, that there was a lot of discretion given to us as the sponsor from the agency. There was a lot of support, in particular for our safety profile, which we previewed to them at the time. And that database has only gotten richer over time.
And what they said around accelerated approval, which I think was really important, is it's ultimately the risk-benefit that they're looking at. So if you couple the safety profile that we've been able to show with the functional benefit we released yesterday, there's no doubt in our mind that we have a good case to make for accelerated approval based on differentiation of performance and risk-benefit improvement. And that's basically the way the accelerated approval regulations are written. So we feel like the data is supporting our ambition perfectly right now.
Okay. A couple of things that I took from yesterday's call. I was surprised at how much the KOLs focused on safety. That was like the first thing they said, aside from functional improvement, the first thing they said was safety. So I guess in your phase III, you are, well, at least in the phase I/II , you've already added a cohort of ages one to three, which has never been studied before yet in DMD. How does that factor into the phase III? How much of that population could be counted in the phase III? And what kind of population might you have of that one to three-year-old? And just maybe speak to the safety in general also.
Sure. Maybe that first, since it is paramount.
Yeah. It was surprising how that's exactly what they focused on.
Yeah. And that, by the way, is what we hear in general. And I think the consideration is the history in this space, where though gene therapy has been safe in the majority of boys, there have been some very bad outcomes in a handful of boys, let's say, that have been immune-mediated. So I think that's led to understandable sensitivity here. That's one of the reasons why we've taken a proactive stance in terms of immunosuppression, where we're really limiting risk of bad outcomes from immune-mediated outcomes. And not only is safety paramount, but that's, of course, then what they look at in data.
And I think one of the, aside from the excellent results we're seeing, the fact that we're not seeing safety-related issues, not even some of the things that are more common, like liver-directed injury, for example, where we've seen no transaminitis, which you almost might think of as a leading indicator of the type of immune response you're getting. So that certainly is very encouraging. I apologize. I forgot the non-safety-related.
I mean, it allowed you to start exploring this three-year-old population.
Oh, yes. Yeah. So that gave us more confidence on age range. And certainly, the results we're getting made investigators and others in patient advocacy say we'd really like to see this broaden and have more boys have an option here, especially since that one to three, there are no available gene therapies. So a lot is going in the direction of evaluating this. And our safety profile further, I think, differentiates in our willingness and excitement to go after the one to three. As Curran mentioned, our pivotal is one and over. So certainly, the safety and even any efficacy we show with long-term follow-up in these boys will be important in the overall BLA assessment. To your question of whether these can count in really any of our Dose Level 2 patients, we've had very good discussions with the FDA on that.
And I think because of how much progress we made on our commercial production in the process that Curran is better able to speak to, but we're already using the process that we would use on the market. So I think we have reasonable confidence that we can show the type of analytic comparability that potentially could allow us to utilize the 12 patients that would already be dosed at Dose Level 2 in the phase I/ II.
Yeah. I guess another, I guess, a little bit bigger picture question, because you're looking at the one- to three-year-old population, as a physician says, they need to reset their expectations around what to expect from a treatment. So now, are we rethinking our expectations around when you can actually start treating these patients? Because obviously, there's newborn screening now. There's a way to capture these patients a lot earlier before they start deteriorating, and do you envision that, like in MPS II, where newborn screening is going to be very important, is this going to be translating also into DMD?
Yeah, I think that you see that from a number of the sponsors that are involved in gene therapy, that they're all thinking long-term early treatment is going to be the way the field moves to, as you said, prevent the progression of the disease as early as possible. And I think that was why we, one of the reasons we wanted to open the cohort of the one to three ahead of the pivotal was to get a start on that so when, at the time of filing, we'd have some long-term safety and durability results at that point to show in the review process. So I think they all go together, including over time, newborn screening emerging as that early signal that we might pick up early diagnosis with.
Okay. Great. And I guess what kind of impact this may have on phase III interest? So as a physician, they need to make a choice between an approved product, an approved exon skipper, or a clinical trial. So how do they sit there and decide what are we going to offer to our patients? And so maybe you can speak to that.
Sure. So we got some good perspective yesterday from a clinical trialist and also patient advocacy expert who works with CureDuchenne in either setting, as you mentioned, all of the available options would be explained. So approved therapy, at least in the four and older, and also any next-generation therapies. And that's where the differentiation is so important, both the theoretical CT domain, the actual microdystrophin values that we're seeing, and now the functional data, plus, as we mentioned, paramount safety. So from a clinical trial standpoint, Dr. Panda, who was on our call yesterday, who's enrolled the most patients in our study, gives us very real anecdotal experience about how he describes this. And what is always brought up to us by patient advocacy and actual families and investigators is the reality that this is a one-shot opportunity. Once you pick one gene therapy, that's it.
You can't get a separate one. So you want to pick the one that you think is potentially going to have the best outcome for your boy when you think of a family. And these are very well-educated families, by the way, compared to other disease areas, I think in part because of the great work that patient advocacy does in this space. So they come back with very specific questions. They care about quality of product. They'll come and say, well, what's the empty-full ratio with different therapies, if you can believe it? So they're extremely educated. And that's one of the other differentiators we haven't even talked about is quality of product. So this is why I think Dr. Panda has gotten so much interest and why we heard yesterday so much interest from the patient advocacy side. As Dr.
Kelly mentioned, the expert Chief Scientific Officer at CureDuchenne, he anecdotally described there's many patients who are sitting on the sideline really evaluating what next-generation gene therapy could come along. And they see the potential differentiation and actual clinical data now that's come out. And he said literally patients were waiting for this data to be able to weigh the opportunity. So of course, each family is different, and there are different considerations, and they may weigh the risk-benefit differently of these different variables we're talking about. But certainly, we feel very favorable from hearing from our investigators and patient advocacy of many patient families being excited about next-generation gene therapy.
Right. So just for context, the phase III trial is only 30 patients. And all these patients are sitting on the sidelines. So how rapidly do you think we can start getting an answer on this phase III trial? You just dosed your first patient, we learned yesterday. So when do we think we'll see data here?
We've guided to the BLA filing in 2026, so we'd expect to see.
So we have to work backwards. You're not going to do math for us. Okay.
I actually think we're saying 2026. There's a lot of opportunity to pull that in, and I can guarantee it will do everything we can. I think enrollment, the interest in the program is, since yesterday and since even prior to that, super high. I think they were waiting for this initial functional data to sort of cross that last T, if you will, so I feel real optimistic. Drug's all made. We're ready to go, and we're going to go as fast as we can next year, and as soon as we complete enrollment, we'll be happy to talk about the rest of the timelines in more detail.
Okay. And just to clarify, the primary endpoint is percent of patients who reach greater than 10% microdystrophin at three months.
Correct.
Okay. And just to maybe you can share that specific endpoint that's a little bit different than what Elevidys has, which was just microdystrophin expression.
Yeah. Do you want to talk through a stage?
Sure. We'll look at that as well. And we feel very confident on both measures. We felt it would be more clinically meaningful to actually see patients who are getting above a threshold that's recognized in the field as an important threshold for translating into a functional benefit. The truth is we're very well-powered in both ways of looking or cutting the data. So that'll be relevant, I think, when people actually look at the data. But it's as much important to have that number of patients from a safety database even. And certainly, with the results we're seeing so far, we saw all of our patients above that particular threshold.
And the magnitude of effect, and I think also critically the consistency of the effect, where we certainly didn't have any patients with zero, and we had all patients with at least 10. And the only one close to that threshold was a Dose Level 1 patient. So all of these factors make us very confident in the selected primary endpoint, but also these different secondary endpoints like quantification.
There is a clear dose-response between Dose Level 1 and Dose Level 2 on top of being an older patient population for Dose Level 2. So, okay.
Yeah. You can see that in the published data we put out for vector copy number. You can see that bumping up about 2x, and then the microdystrophin levels subsequent to that were in the same ballpark.
Okay, so we're coming down to the wire, but I do want to ask you: we get a lot of questions on commercialization, what the low-hanging fruit is for you, and just where you think you're going to be positioned within the options here.
I think I would summarize it that the data we have in hand gives us a path to a broad approval. The design of the study is four and older. I think that's our ambition as well, is to not see a narrow approval in a certain age range. But I think what we're seeing in the eight and older patients is probably more evident because, as Steve mentioned, they're in the decline phase. But all patients should get benefit from this, and so our philosophy around the pivotal is to go for a broad approval, and I think on a commercial setting, we've talked about the prevalent, or we've heard about the prevalent population being available till 2030, then our expectation would be to be on the market and address a significant proportion of the prevalent market.
Okay. Great. So not just the ones with neutralizing antibodies, but the whole prevalent market.
Correct.
Okay. Great. And just in the 30 seconds, I want to touch on this MPS II because I think it's important as a pathway to DMD. But maybe you can speak about MPS II and what that offers to you. I know it's a smaller population, but you filed a BLA or you're finishing a BLA right now.
Yeah, we're midway through filing our rolling BLA for Hunter. I look at it, it's the gift that keeps on giving. The data initially was targeting CNS manifestation, but we're also seeing the systemic benefit, which is really significant. 80% of the patients that were treated have not had to go on to enzyme replacement therapy. So I think we've got a lot of support. I think you see a lot of accelerated approval, positive outcomes at FDA right now, and we're right in line for that. So we're expecting potential approval third quarter, early fourth quarter next year. And that does come with a PRV as well, which is very meaningful for us.
It also comes with, I guess, approval of the manufacturing process.
Absolutely. Yeah. So the commercialization of the facility, having an approved facility ahead of Duchenne being right behind it, is a perfect setting for us.
With capacity for a DMD population.
2,500 doses a year can be produced at our facility.
Great. I've got zero flashing at me. So I think that's all we have.