Hi, everyone. Welcome. This is the Fireside Chat with REGENXBIO. My name is Vikram Purohit. I'm one of the biotech analysts with the research team. Before we get started, just need to read a brief disclosure statement. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. With that, happy to have with me Ken and Steve from the REGENXBIO team. Thanks for joining. Appreciate it.
Thanks for having us.
We have roughly a half hour to get through quite a few different topics. Ken, I was thinking first, we could just start with some opening remarks from your side on just kind of key inflection points that you feel the business has had throughout the year. And then I'm sure there's interest in hearing about progress with 202, 314, and additional pipeline programs, but I'll let you kick it off.
Yeah. 2023 has been an exciting year of, I think, growth and development for the company. We have, we're marking this somewhere, just out in the hallway, I mean, eight ongoing clinical trials, or at least programs, probably more than that, in truth, in terms of literal numerical number of trials, but eight different diseases that we're focusing on as a company. We have some exciting data coming up this coming quarter and through the beginning of next year from our Duchenne and diabetic retinopathy and wet AMD study. We're running two pivotal trials, right? You know, basically in wet AMD with our subretinal approach, and we're in a pivotal phase. We fully enrolled our pivotal phase of development for RGX-121, our lead neurodegenerative program for Hunter syndrome.
You know, we have expanded the capabilities of the company in both research and manufacturing this year. Really finished the first full year of use of our GMP facility in Rockville. We're now supporting all of our clinical trials with bulk drug and soon to be our fill finish line in Rockville later this year. And in research, we continue to believe that, you know, it's kind of a limited platform, AAV, for addressing a lot of different diseases in unique ways with one-time treatments, whether they're, you know, more bespoke indications and sort of rare, you know, genetic diseases, or in very, very large indications, like in wet AMD or diabetic retinopathy.
So, you know, we're just a few weeks away from our first measures of secondary endpoints, efficacy endpoints in our Duchenne trial. The beginning of November will be our AAO update. I'm sure Steve will touch on this for diabetic retinopathy. So a great time to be kind of touching base on everything that is REGENXBIO right now.
Great. Maybe let's go to DMD first, just because it's been a topical area people have been digging into recently. Before we get into any specifics on what you're going to be presenting next month, like, at a high level, how long have you been thinking about DMD and kind of what line of work led you to DMD as an area of focus? Because you now have two programs nominated there, so what was the path to getting there?
Yeah, REGENXBIO's entry into DMD is just a few years old, but it's because of our Chief Scientific Officer, Olivier Danos, who's been thinking about it across probably three or four decades. You know, in his research, both in industry and in academia, or sort of at NGOs. Olivier has done a lot to kind of contribute to the field when it comes to muscle wasting diseases and Duchenne in particular. He came to REGENXBIO with a notion that there was beginning to be scientific evidence that microdystrophin-based constructs using AAV were showing evidence of benefit in important models of disease, and that was emerging even in early clinical evidence.
But there were still limitations that a lot of the reagents that were being used in the clinic had been designed in, like, the 1990s or early 2000s. So we're talking about things that were, like, two decades old. So Olivier and his team spent time. We had some really good molecular biologists internally, people that really understood modeling in Duchenne preclinically, to develop a new optimized candidate. We added some science that had never been included in a reagent candidate before, into the clinic. We focused a lot on manufacturability. You know, it's a intravenous one-time administration for these class of products. Microdystrophins are at the higher end of the range in terms of doses, so, having good product quality but also good product yields to be, appropriate on how you think about cost of goods was a major focus of ours.
Lined up really well with us investing in our own manufacturing and process capabilities as well. So, you know, we launched our clinical trial, I think, with, you know, the most recent science that was available to focus on microdystrophin candidate. There's obviously others. There's now an approved, an accelerated-approval product in the U.S. based on class of products that are microdystrophins. We think we're a meaningful improvement to that, and we're looking forward to clinical data that continue to support that thesis.
Got it. And on that point, could you just recap for everyone the early clinical data you presented so far and what we can learn in October, and how that October update could, I guess, kind of de-risk the thesis you have with the construct of 202?
Yeah. So, just back in July, we had an internal R&D day that we hosted. We talked about the fact that in our first-ever clinical trial for our candidate, we had dosed 2 patients. We had safety data on those patients out as far as about 90 days, and we were seeing, importantly, a safe profile at the first dose level, which is actually below what the, you know, equivalent approved product is and below even where another company, Pfizer, is with its pivotal development.
But nonetheless, in our hands, pre-clinically, it was a dose that was showing meaningful response in the animal models, and we thought would have not only a safe profile, which I think we all but confirmed early on here in the development, but also would begin to show potential evidence of clinical benefit in boys as well. And so that's what's coming next, Vikram, is just in a few weeks, we'll have the first thing that we're able to measure, again, at early time points, just about three months, which is the gene therapy not only safe and has it sort of traveled through kind of after a one-time delivery, the period of time where, you know, you can be certain that you're kind of dealing with a safe medical product candidate?
But also, has the gene therapy itself done what it was designed to do? Has it turned on in terms of expression? And in our case, what we're able to do is we're gonna measure the protein that's being expressed from the candidate, this new novel truncated form of dystrophin with our special science designed into it, and see levels of protein for the first time. Others have already shown that they've done that with other candidates. I think we show that we can do that with our candidate, then, you know, we're absolutely in the game of being able to then show that the benefit of the science we designed in could have even more improvements longer term. But the first step is to show that we're expressing that protein at reasonable levels. And this is our first dose as well.
So we have a trial that's designed to go up a factor of 2, even, beyond what this first dose is, which means, you know, what you might see from us initially, could be improved upon, both in terms of expression, and I think the evidence, too, is that, you know, the long-term outcomes can be improved.
Got it. Then the natural question then is, how much microdystrophin expression from this first dose level is going to be enough? How do you respond to that question? Like, what's the benchmark in your mind.
Yeah. So, you know, it's in my mind, I've been saying, you know, that we'd like to see evidence of expression based on the assays that we're using and how we're sort of characterizing our microdystrophin, and it's somewhere between 20%-40%. But this is. You know, I'm kind of drawing on other data to support what's been seen. It's from other companies and other constructs and other methods for development, but I think it's something that is, you know, a reasonable approximation. This is our first dose, as I said. I think, you know, we achieve that or something that approximates that with the first dose. You know, in principle, the second dose is twice that. So, you know, we, if there's a linear correlation, we could see a doubling of that through dose escalation.
Got it. Got it. And, maybe going back to the fundamentals of how 202 is, you know, different structurally. So you talked about a unique promoter. You talked about the extended CT domain.
Mm-hmm.
That's on the construct of this gene therapy.
Yeah.
From a real-world perspective, what benefits do those two pieces of the construct provide versus a gene therapy that doesn't have those items? Or what could they provide?
I mean, the big differentiator is the C-terminal elements of dystrophin that the team has been able to design into RGX-202. The simplest way I can describe it is it potentially makes the drug itself, and the drug here is, well, this is a one-time AAV gene therapy treatment. But ultimately, what it's doing, what the sort of, you know, continuing pharmacodynamics are, are expressing dystrophin protein, you know, in cell walls, for as long as possible, as long as the vector lives. And on a per protein molecule basis, we think that our microdystrophin could be more potent, more effective than other microdystrophins that are part of regimens that others have designed. That means, you know, less protein could give more of a response.
The same amount of protein could give a better response long term, and it's because the C terminus is importantly complicit in stabilizing the cell walls of muscle and recruiting other species, other proteins, to the walls of cells or the membranes of cells, to be able to reinforce the structure of those cells. And without that C terminus, we've shown preclinically that the microdystrophins are a little bit less effective.
Mm-hmm.
With that C-terminus, again, they're more effective or, you know, to me, more potent.
Sure, sure. I guess pivoting, but staying on, staying on DMD, but pivoting to a different topic. Understanding it's early days right now for the 202 program, but thinking forward, what do you think is the path to a potential pivotal study and the potential approval, given everything else that's going on in this space right now?
I think we had a great amount of understanding and clarity in the U.S. applied by FDA's evaluation of the first-ever accelerated approval of an AAV gene therapy in Duchenne. It told us as a company, it told you know a lot of stakeholders, especially you know families that you know FDA was supportive of surrogate biomarkers like measures of you know protein in cell membranes as you know predictive indicators of clinical benefit. And you know with that as kind of a roadmap, we've also seen that that was established looking at the labeling of the product with relatively small number of patients. And on a program that also was only ever examined at one dose level, right?
There was never even necessarily any kind of dose ranging that was done, just kind of a constant, dosing at the same dose throughout the entirety of a clinical program. It's pretty unique. For us, you know, we expect, to finish our 3 + 3 design that we have for, you know, 1E14, which is our current dose, 2E14, which would be dose escalation. And with data in hand from that trial, be able to make a decision about moving into pivotal phase and sort of reproduce with a small number of patients, the potential for an accelerated approval based on microdystrophin expression as a surrogate endpoint for approval.
That's something that we believe from where we started and what we reported on July, what we'll update on in World Muscle Society, something that we believe we can transition into coming into 2024. And be a company that's... So we're in pivotal phase already with our wet AMD subretinal. We fully enrolled pivotal phase with respect to our Hunter program. So this would be our third program that we'd be in pivotal phase with at REGENXBIO, Duchenne muscular dystrophy as early as 2024.
Got it. Okay. I'll ask you one more question on DMD, and then we should pivot to ophthalmology. At your investor day earlier this year, you also talked about an exon 53 targeted product candidate. Could you kind of talk us through the thesis for that program and where it stands right now?
Yeah, I think, you know, another reflection on the part of Olivier and the scientific team when he arrived at REGENXBIO was that while these microdystrophin constructs are improvements to what exists, which is nearly nothing, and that our science is an improvement, even on those reagents that I alluded to already had been designed years ago. Really, what we need for, you know, full correction of Duchenne muscular dystrophy is full length dystrophin to be expressed or near full length dystrophin to be expressed. Unfortunately, AAV is not big enough to be able to package the full length genome of the dystrophin. But a lot of technology has been developed to be able to use different types of moieties to change kind of the transcription and translation of genes.
We think that we've designed something that can allow us to express near full-length dystrophin using technologies that others have used and delivered on a kind of chronic repeat basis, but do this with a one-time treatment in AAV. We're starting that work. We have IND-enabling work going on. We think that there are INDs that we're targeting for as early as 2025. That could be the first clinical candidates where we're using a one-time treatment with AAV to take people's existing DNA, boys' existing DNA, and turn that into something that is a productive full near full-length dystrophin expression. I think that that for us needs to be done at a level of efficiency that hasn't been demonstrated with any other types of technologies before, but we think preclinically, we've seen that.
Got it. Okay, great. Any questions on DMD before we go to ophthalmology?
Yeah. With respect to our Duchenne program, we're using immune suppression in short course based on a number of recommendations from physicians who've had experience with different types of microdystrophin products that sort of predated us in the clinic. There's actually a working group that's been assembled by some academicians that have sort of looked at certain types of responses that have occurred in other trials. And so, we're using short course of steroid, things that are on the order of days. We're actually using some other immune suppressive agents, as well as something like a week or two of an anticomplement medicine as part of the prophylactic regimen in the early investigation of RGX-202. And it's been very supportive, I think, of the evidence and the safety profiles that we've seen.
Anyone else? Okay, let's pivot to ophthalmology then. So 314, Ken, you've got subcutaneous as well as a suprachoroidal,
Subret-
Subretinal, sorry. Subretinal and suprachoroidal, routes of administration for 314. Let's touch on subretinal first. You've got two studies enrolling there, AATMOSPHERE and ASCENT. You, a little while back, announced that you're increasing the enrollment targets for both studies. Just talk us through what the intent was there. And I think you mentioned that a larger patient database could afford you some flexibility with labeling considerations. So just talk us through what those could be.
Can you talk about this?
Great. Thanks, Ken.
Sure.
Thanks, Vikram, for-
Sure
-having us. Yeah, I think an important concept for this is this is a decision not just by us, but by our global partner, AbbVie.
Mm-hmm.
It in fact is one of the key reasons why we wanted a global partnership with somebody who has the great experience of AbbVie. So, not surprisingly, there is the opportunity to improve the global reach of RGX-314, and that's always been a goal of ours.
Looks like your mic might be off.
So with AbbVie, this is a great opportunity not just to expand patient numbers, but also actually get experience outside the US. So we expanded to include Europe, Israel, and Japan... and sort of a double whammy in a good way, that with that expansion, we can enroll more patients, and we can have more power for key secondary endpoints. And certainly the more endpoints you can hit on, that really helps you, particularly ex-US, when you think of Europe and health technology assessment organizations. So for us in AbbVie, there's the chance to show more value by hitting on some of these secondary endpoints. And a lot of them fit in the category of part of the big value proposition, which is dramatic reduction in treatment burden.
So we can not only look at some of the key ones, like % reduction in injection burden compared to what patients were needing before one-time gene therapy, but also look at certain binary cuts, like how many patients don't need any injections, and also other cuts along the spectrum, like maybe a patient only needed a top off, or maybe even though patients needed treatment, it was under a certain cutoff. So we can really achieve great power with the increased patient numbers to hit on some of these.
Got it. Okay. Taking a step back, subretinal, suprachoroidal, where do you see both of these options, assuming they're eventually approved, fitting versus each other, and then the other anti-VEGF agents that are out there currently in the market?
Yeah, certainly in either case, the other agents that are out there in the market and that are coming all fit in this category of extending durability, which is great. Those are good incremental benefits, and we're clearly seeing that the marketplace values those incremental benefits from greater proportion of patients getting from 8-12 weeks and from 12-16 weeks, et cetera. But it's really a paradigm shift to think of a one-time treatment where a majority of patients may not need any injections. So we think both really have a place. Now, with subretinal, that's the most tried and true. That's really the gold standard when thinking of getting safe and effective transduction and expression at the target tissue. But it does involve surgery.
It's still the benefits outweigh the risks of a simple surgical procedure, but suprachoroidal brings in the opportunity to not only have a one-time treatment, but an in-office non-surgical treatment. So we really see that as an opportunity to expand the optionality, really, in terms of the spectrum of patients that the doctor and the patient and the treating physician think is a great opportunity.
Got it. Got it. Now, in terms of the path to a pivotal program for the suprachoroidal option, do you have any updated thoughts there? And do you think there's the potential to use any data points from the ongoing subretinal pivotal program to kind of bridge the path towards approval for suprachoroidal?
Sure. So starting with wet AMD, where that question in part relates, particularly what we can learn from the ongoing subretinal, it's too early to say, and conservatively, you know, we're not going to come out and say that we can do less, but certainly it helps inform the same, same drug, little different route of administration. So I think it certainly will give us more confidence. The other thing it gives us is really de-risking from a regulatory standpoint, because we know the route to approval, and there's at least the comfort level of the subretinal experience, and it's a tried-and-true route, not administration, but tried-and-true regulatory clinical development path. Treatment of diabetic retinopathy, there's a lot of benefits there as well. We do have a pathway there.
We know from the repeat injection anti-VEGF, where there's the opportunity to go against a negative control. That's a really big positive in terms of powering and probability of success, because we know that without treatment, patients with moderately severe to severe NPDR don't get better magically, and in fact, they generally get worse and significantly worse. Again, a nice case of de-risking, where there's the opportunity to demonstrate adequate safety and efficacy in hundreds of patients, not thousands of patients. The other key aspect that's less regulatory, but more the true value and the unmet need is, we know anti-VEGFs work to prevent patients from developing blinding eye disease, but the problem is the repeat injections. It's just too much of a burden. Really, a one-time in-office injection can really step in and potentially fill that unmet need.
Got it. Got it. Now, your two studies ongoing right now with suprachoroidal, AAVIATE, ALTITUDE, you've mentioned that we could see some updated data there later this year, early next year. Just walk us through what those updates could be and what's the incremental information we're going to get from those updates versus what we've already seen?
Sure. So what we've already seen and presented in both programs is good safety and proof of concept across a range of doses, actually. And at the Investor Day that Ken mentioned, we not only talked about DMD, we also gave an update on recent cohorts in both studies where we added short course, topical and non-invasive forms of prophylactic steroids, where early follow-up, but long enough follow-up, that we could demonstrate that with topical steroids, short course, we could actually mitigate and actually eliminate in the patients treated in both studies, any IOI. So for us, that's a very big step from a safety and tolerability standpoint. So moving forward, a key focus for us is also durability.
So, at AAO in early November, we'll be presenting an update on ALTITUDE, where we'll present longer term follow-up, one year follow-up. Previously we presented six months, so this is really a great opportunity to see, can we see durability in terms of not only safety and efficacy, but also effect on actual diabetic retinopathy severity?
Okay, great. We have 2.5 minutes left. And Steve, maybe we can touch on some of the other pipeline programs. 121, for MPS II, you've mentioned that a BLA filing is on track there for next year. You've also mentioned that we could see some campsite data ahead of that filing. So just frame for us what we could expect to learn, and just any updates on where regulatory interactions stand with that program.
So we talked about earlier that we got, you know, Regenerative Medicine Advanced Therapy designation from FDA, which is a designation that only comes with FDA evaluating clinical data from a program, in this case, in our Hunter syndrome program. I think the supportive evidence is there that we're showing biochemical changes in the cerebrospinal fluid of these kids, and that correlates with intracellular changes that are known to have correlation to improved cognition and neurocognitive outcomes in kids. You know, we've enrolled, you know, tens of boys in this study. This is not gonna be a 100-patient study. In fact, even in our sort of pivotal phase, we targeted 10 boys to enroll over, you know, 5 or 6 months.
That's about the evidence that you can generate in sort of incidence prevalent populations like this. But I think really strong endorsement with that RMAT designation, that the use of a surrogate biomarker, looking at changes, in this case, reductions of the native substrate of the enzyme that's missing in these boys, is predictive of good clinical outcomes. So that's gonna be the basis of our regulatory approach here. So we'll be able to show those biochemical changes in the pivotal phase boys that were enrolled sometime in the beginning of next year and plan to file the BLA after that. What I'm really excited about with that event is after, you know, Hunter syndrome, we have Hurler syndrome lined up right behind it, and it is as close a cousin to the disease as you could possibly have.
And we'll rely on, if not identically, something very similar in terms of the surrogate endpoint for approval. So, you know, the same type of barrier that I think has been, you know, broken through with the first AAV approval, based on accelerated approval pathway for Duchenne, I think we're encouraged will happen for neurodegenerative diseases like Hunter syndrome and then Hurler syndrome. And then another fast follower on that is our work that we've been doing in CLN2 form of Batten, where we just had our first clinical data presented by investigators just a couple of weeks ago, that showed, again, expression of protein, but also changes in clinical measures in these kids who have regular seizures. With Batten, we saw an 86% reduction in the seizures, pre- and post-administration of drug in terms of that delta.
So, you know, here's three programs that are very similar in terms of clinical approach. I think, clinical implementation, regulatory pathway, and commercial potential in terms of their size, that we view are all very potential rapid, accelerated approval development programs. And it fits in nicely, and I talked about at the beginning, we're running eight clinical trials, you know, in different diseases. Three of them I mentioned, could possibly. Two are already in pivotal phase. If we bring Duchenne into the clinic in pivotal form in 2024, that'll be three. Said publicly at the beginning of last year, that we have a goal to have five programs in late-stage pivotal development or commercial by 2025. So I feel like we're well on our way to achieve that.
I think it's with a broad spectrum of focus and a great deal of strong capability scientifically, clinically, and from a manufacturing perspective. I just, there's no one in AAV gene therapy that's like that, except for REGENXBIO.
Great, and with that, we're actually at time, so it's a good, good spot to end out at.
Thank you.
Thanks for your time.
Appreciate it.
Enjoy the rest of the conference.