Morning, everyone. Welcome to our next session. I'm Brian Skorney. I'm one of the senior biotech analysts here at Baird. Very happy to have with me presenting in a fireside chat format, the management team from REGENXBIO. This is a name that I cover. They are focused in the gene therapy, really one of the major innovators in gene therapy therapeutics over the last decade or so. With us, we have the President and CEO, Curran Simpson, and Ram Palanki. Guys, thanks for joining today. I guess to start, maybe Curran, can you tell us a little bit about what the company does, the technology that you're focused on, and sort of the history of AAV development at REGENXBIO?
Sure. Go into the slide. So we've been in business for roughly fifteen years. One of the early originators of AAV technology, in collaboration in the old days with Jim Wilson. And over that time we were, for the maybe first five or so years, mainly out licensing technology to other companies. So you've seen products developed out of that early, those early days, like Zolgensma, as an example of our technology base. Around eight or nine years ago, we decided to internalize a lot of our development, and I'm really pleased to show our pipeline today because what you'll see are four different assets that are moving into late stage development, or actually all the way towards a BLA filing starting this year. We think about it in terms of two franchises, a retinal and rare disease franchise.
We'll talk today about RGX-202, a program we're super excited about for Duchenne, which we expect to initiate pivotal trials late this year, and I brought Ram with me to help out on RGX-314, the ocular programs. We have a program with a subretinal delivery that's in late stage pivotal trials, large studies being enrolled as we speak for wet AMD, and then we're really pleased this year to start moving forward with our partner, AbbVie, on diabetic retinopathy, using a different mode of delivery, the suprachoroidal route, and then we're imminently getting ready to file our first module for RGX-121, indication for Hunter syndrome. That'll be our first BLA, so it's a huge event for a small company to go down that path.
I don't think I need to reiterate the pipeline, but really thrilled to see all of these different bars in either phase III or heading to it. As I showed the Duchenne program over the last year, we've put out really exciting data that we can talk about today, and then as well, a huge franchise in place with our partner, AbbVie, focused on wet AMD and diabetic retinopathy.
Great. So maybe to start with 314 and the ophthalmology program, I just kind of tell us what is the concept behind what you're trying to do with gene therapy here for these patients, and how did the AbbVie partnership come about?
In general, the concept here is we're trying to create a biofactory of therapeutic protein in the eye, and we use our vector to actually install a transgene that can produce it for your lifetime. That's the concept. As you know, anti-VEGF is a standard of care in treating all of the retinal diseases, not just wet AMD, so we're in phase III right now with our subretinal program, and we plan to file our BLA both in the U.S. and EMA in first half 2026, and we'll be the first ones coming to the market, so those are the basic concepts, and what we're trying to solve is really, there are three big unmet needs in wet AMD today. I think one is durability, two is efficacy, and three is actually disease progression.
We're trying to solve for all the three. I think what people are trying to talk about every day today is durability, but durability also has to account for both efficacy and the progression of the disease over time. Because we have this consistent expression of protein, we believe we have a foundational way of establishing anti-VEGF that could actually modify the disease and give better outcomes to patients on a functional and anatomical basis.
Great, so you mentioned sort of the timeline for the phase III studies. Can you just talk about the design of those phase IIIs, how you're sort of comparing 314 to any standard of care or control arm?
So, as you know, we forged a partnership with AbbVie, and these two programs now, one is ATMOSPHERE and ASCENT. ATMOSPHERE is actually a head-to-head trial in a non-inferiority design with Lucentis every month dosing. And ASCENT is actually head-to-head with Eylea, every two-month dosing. Both of those are standard of care, as you know, and are reimbursed across the world. So we've designed two trials that could actually account for the two different standard of cares and what we believe is the best regimen that actually shows the type of outcomes you're looking for. Both of those are designed on a global basis. As I said, first half 2026, we'll be filing both in EMA and the U.S.
Got it, and one of the big questions I get a lot on sort of gene therapy in wet AMD is, you know, we're seeing the standard of care kind of evolve from, you know, it was monthly dosing to sort of PRN-ish dosing, and now longer and longer intervals without dosing, obviously, high-dose Eylea, Vabysmo having longer intervals. I mean, how do you kind of think about 314 's role and, you know, comparing and contrasting when you have the phase III data versus the sort of longer interval injections?
Yeah, I mean, you know, the evolution, we went from Lucentis to Eylea, Eylea to Beovu, Beovu to faricimab and Eylea HD recently. I think the market is clearly saying any incremental durability is what clinicians are looking for, and you went from one month to two months to now faricimab being somewhere between three to four months. And it still only addresses the type of incremental durability in about 50% of the patients, right? The other 50% are still depending on their phenotype and where they fall on the heterogeneity of the disease, they all still need a lot more treatments. But I think the concept here being this is a lifelong disease, it needs lifelong treatment, no matter what type of incremental durability you get to.
If you're able to solve for it on a much longer term basis, I think there is a lot of value in actually retaining the function in patients and better outcomes.
Great.
I think, if you look at the bioreactor data, so we did a bridging study when we changed our manufacturing process to bioreactor-based. We've got patients that are out three and a half to four years now, so it's just so much different than some of these iterative improvements that, you know, we're really excited that patients will benefit from it.
Right. And you've recently announced plans to pursue phase III in diabetic retinopathy with the suprachoroidal administration. I guess maybe to kind of bring things high level, you know, there's sort of three different modalities of treatment here: subretinal, which is your 314, phase III program, suprachoroidal, which is the DR program; and of course, you talked about sort of intravitreal injections. Can you just kind of like walk through what are these three different types of procedure/injections, and how do you see kind of the space evolving with gene therapy, and how important it is?
Yeah, I mean, listen, route of administration is everything with gene therapy. I think, the safety aspects, the efficacy aspects, they're all based on where you're actually administering the drug, how compartmentalized it is, and what type of transductions you're achieving. So, you know, all the work we have done to date really suggests that subretinal space and the suprachoroidal space are... If you have to rank them, subretinal space is the most immune privileged space, and then the suprachoroidal space is the next most immune privileged space, and once you go into the intravitreal space, the fact is when you put the drug in the vitreous, you're exposing the entire anterior segment to it. I think Adverum data is pretty classic.
You've seen what the safety outcomes of it, our competitors that we speak to, like for DMD, have limitations on dose escalation, right? You've seen their profiles in terms of, you know, what they're able to accomplish on efficacy, but they're not able to dose escalate. And even in the context of using steroids for six months, I think with the suprachoroidal space, the fact that we're using such a short period of steroids for about seven weeks also suggests that it's such an immune privileged space. So you take all those concepts and you look back at our phase I/II data that Curran mentioned, with four years of, you know, follow-up, patients are gaining almost two lines of vision, majority are staying injection free.
That concept, you know, when it got confirmed for us on a dose basis and safety basis, we moved the phase III program with the subretinal route of administration. I think people don't understand that the subretinal injection is something that clinicians are trained. They come out of their fellowships knowing how to do it, and we actually do the subretinal injection with a routine surgical procedure, right? Which is vitrectomy. There are about 500,000 vitrectomies done today on an annual basis. That's their bread-and-butter surgery. So there's no competency issues here. There's existing infrastructure. So for us to install something into the marketplace with an existing procedure, that's how people are comfortable, we see that as a leeway to enter the market, establish an infrastructure on a global basis.
We are still, you know, dose escalating in the suprachoroidal program with wet AMD, and when we find the dose, it's probably a few years away. We would be walking in with a broader spectrum of life cycle management when that route of administration moves into phase III. We've already found a dose that can move forward in diabetic retinopathy. I mean, if you look at historical data in diabetic retinopathy, a lower dose is efficacious versus what you need for wet AMD. As it stands today, you know, we presented our dose level two data in suprachoroidal at one year, and we saw that administering 314 in the suprachoroidal space actually halted the disease in its tracks. We had almost close to 90% of patients on a risk reduction basis for vision-threatening complications.
What you're trying to do there is treat early Diabetic Retinopathy and actually avoid the disease progression, so patients never develop complications that are irreversible, and you have to treat them for life.
Right. So, I mean, I think, you know, investors, we have a tendency to kind of like anchor to things that we know, right? Wet AMD is a huge market, diabetic macular edema, more progressed state, obviously a big market. DR has not been a successful market for intravitreal injections, despite very good efficacy. I guess, how do you kind of think about why that sort of failed to really have commercial liftoff? And how does 314 as a suprachoroidal administered gene therapy, how does it potentially kind of flip that experience on its head?
Yeah, I mean, if you look at DR, you have to think about the type of patients that actually affects the disease, right? So these are working age group, non-compliant patients. We all know how notorious diabetic retinopathy patients are, and just diabetic patients are in terms of compliance. There's a lot of data to suggest that most of these patients, when they walk into the ophthalmologist's office, about 50% are lost to follow-up. Almost majority of them never actually follow up on their appointments. So the concept of actually taking early diabetic retinopathy patients that mostly tend to be asymptomatic, and convincing them to get on a lifelong treatment of intravitreal injections is just not possible or sustainable.
I think what we're trying to do here is a single injection, stop the disease progression, so you can actually stop them from ever developing those complications. I think when we get to market, the process is going to be patients that have already developed those complications in one eye, because this is a bilateral disease, are going to sign up immediately because they know the impact of that.
when they actually develop the disease. And over time, that concept will be administered to, on an adoption basis to patients, on a monocular basis.
Great, and then you mentioned that you're planning to initiate a phase III. What are sort of the hurdles to getting to a phase III start? What else needs to be done now that you have DL2 dose information?
Yeah, we've been evaluating the entirety of the data with our partner, AbbVie. Obviously, every decision we make now on a global basis, we do it with them. I think you know the construct. You know, we pretty much. They share two thirds of the development costs, and we pay for one third, and in the U.S., we share everything fifty-fifty on a commercial basis, but the development cost is still two thirds. So we've been evaluating all of that, and coming into, you know, this year, I think we're getting comfortable with where all that lands, and we've already said that, you know, we're looking towards starting pivotal program going into next year.
Great, and I think there's a milestone associated with that as well, right?
Yes.
Yeah. So this year, we'll look forward to an end of phase II meeting that AbbVie actually will be driving, the meeting itself, and then next year, we are eligible for a milestone off the first patient dosed.
Great. And then moving on to DMD, can you describe RGX-202, how it's sort of different than the approved gene therapy, Elevidys from Sarepta, and how you think that could potentially benefit patients greater than sort of the first shot we've seen here?
Yeah, I think there's multiple points of differentiation. First off, the serotype AAV8 is different and sort of well understood in terms of its safety profile. I think the most intriguing aspect of differentiation is the C- terminus. So if you went back to the AdCom that was held for Elevidys, you can see the FDA reviewers commenting that microdystrophin is quite different from full-length dystrophin because it's also devoid of the C- terminus, and so our construct includes that, which might, we hope, in the clinic, demonstrate better functional outcomes. Also, you know, our early data, back to the serotype, is showing incredibly good biodistribution, so we look at things like vector copy per cell.
We see very high numbers in terms of the biopsy numbers that we're recording, and that's corresponding to really high levels of microdystrophin as well, especially in terms of differentiation, patients that are eight and older, we're seeing almost three times the levels that we're seeing or published by Sarepta in the past. So we think there's a lot of differentiating factors. The last one I would mention is we have a large-scale manufacturing process that is capable and has demonstrated purities up around 80% in terms of full capsid, so that's at least thirty-some percent higher than Sarepta's. And I think I don't underestimate it. We've had discussions with patient advocacy groups. That's a big difference for people who are thinking about treating their son for this disease. So we couldn't be more excited as to how the last year's gone on this program.
I think, Brian, it's also the data is being very consistent for us, right? If especially when you start looking at the older age group patients.
Yep.
I mean, you probably have dug pretty deep into the entire data set for Elevidys, but there were patients actually in the trial that actually didn't even have any expression of microdystrophin. As you get into the older patients, the type of consistency we're seeing and the magnitude of consistency we're seeing should all hopefully translate into functional outcomes.
Great. Yeah, maybe you could just kind of talk through the data that you've shown so far in the few patients that you've treated, and how that sort of is different from the experience that we've seen with Sarepta, certainly in larger studies.
Yeah, I think if, if you go all the way back to the preclinical data, we were pretty convinced from looking at that, that we wanted to be at 2 E14 per kilo. And that's because in the MDX mouse model, which is what pretty much everyone uses for Duchenne, we saw almost restoration to wild-type levels of functional benefit at that dose. So the only question really in the clinic was: Could we get there safely? And so we started out early in the year, last year actually, with dose level one, and we quickly dose escalated to dose level two, which is our pivotal dose. And at that dose, we're seeing very, as I said earlier, microdystrophin levels that are sort of averaging in the 50% range of normal.
And I think that's, that's exciting, and as Ram pointed out, it isn't zero and 130%. It's consistently, I would say, somewhere in the 20%-50% range. And that's meaningful for patients that are older because it... Before all of this, that, that age group was considered more difficult to treat with gene therapy, and the benefit was, was questionable, and I think we're hoping to sort of check that box as we go forward.
Great, and then so we get a lot of questions about sort of the regulatory path for 202. You know, Elevidys, surprisingly, unsurprisingly, received full approval for ambulatory patients four years and up, accelerated approval for non-ambulatory patients. you know, there's a lot of language around how FDA considers accelerated approval applications if there's a standard of care in a certain indication. From your discussions on the FDA, what do you think the pathway here is for 202? Where can you see an accelerated approval pathway, if there's an accelerated approval pathway, and how do you intend to kind of exploit that in a pivotal?
Yeah, we're coming off an end of phase II meeting with FDA, and I think we found that meeting to be very positive. I think the word we keep using is regulatory flexibility. And ultimately, there's multiple ways for us to demonstrate differentiation, which is what's really required to pursue the accelerated approval pathway, and that can be a number of ways. So we're now treating patients in the one to three age category. That's not in Sarepta's label, so that's an avenue. We show differentiated microdystrophin in older patients, giving them more promise for functional benefit. That's another avenue, and actually, during the meeting, FDA brought up safety as a potential differentiator. So I wouldn't say there's only one way to achieve accelerated approval.
I think it comes down to really the data set that we'll provide, consistency of benefit, and the risk-benefit equation that FDA will make, and we plan to be extremely aggressive with our approach, and are looking towards starting pivotal late this year.
And then I guess. Would the endpoint for approval be microdystrophin expression, in your view? And is there any way to do actual clinical efficacy studies in a placebo-controlled or head-to-head manner?
Yeah, it's a great question. Our primary endpoint will be microdystrophin production versus their baseline levels. I think we're still discussing with FDA the final construct of that, and I think what you should expect is exactly what you saw in the AdCom for Sarepta, that there'll be a desire for FDA and the review team to look at the microdystrophin levels that we're showing and indications of functional benefit, so we're measuring NSAA, time to rise, some of the walk/run indices, and so as long as we can show correlation, let's say, versus baseline levels of functional performance, and we show improvement commensurate with microdystrophin, and it. You literally can see what Peter Marks did in the AdCom and made his own graphs.
Right.
That's what we call regulatory flexibility. The FDA wants these treatments to be available to patients, but what they really want is definition that there's proof that there's efficacy associated with it. Our expectation is that our functional data will be limited this year, but directionally very positive, and so we're excited-
And then-
- to move that forward.
So I guess I feel like the question gets asked a lot about the regulatory framework, but most people kind of believe in the flexibility that FDA has here. I guess the bigger question is from a commercial perspective, what sort of data points do you need to sort of have a competitive edge versus Elevidys? Obviously, some of the data's been pretty disappointing, but it has a pretty big head start in terms of patient numbers and a safety database. What sort of, y ou know, when you talk to parents, what sort of markers really need to be shown by 202 to kind of convince people this is definitely the better option for your child?
I mean, if you look at the totality of data, right? You take the Elevidys label and Sarepta trials, there's eight and over seven patients, right? We've already treated close to that many number of patients, so. And then you go into, you know, the whole stratification of the patient population itself. You take the ambulatory patient population, about 30% of the population is about one to three, right? One to four.
So you take, you take all of those concepts, we are actually the first ones that are going into that, you know, early population from a one to four concept, and then you think about the older patient population and the type of data we have observed to date and what they have, we think by the time we get to market, given the supply constraints that exist, that there will be a significant amount of prevalent pool left. And on an incident basis, the type of trial design we have and potentially the type of data we might end up showing, I think we will have the ability to dominate the incident population, especially from that, you know, zero to four group.
Right.
We believe there's a very large market opportunity there. I think this is a blockbuster opportunity, and the type of manufacturing efficiencies we have actually accomplished gives us a lot of flexibility on a COGS basis, and depending on where the data lands, we will be able to supply most of the market when we get there. I think we can even compete on a price basis, and we'll be responsible about it, given the best-in-class construct we have and the data that's consistently showing that we might have a better product.
Sure. Great. I want to spend a few minutes on 121. It probably gets less of the press than your other two programs, but it's technically the lead program. You're up for filing an approval hopefully next year. Can you walk us through some of the key enzymatic biomarker data in MPS II, and, you know, what you see as sort of the commercial opportunity here?
Yeah. I'll let Ram cover the commercial side, but the pivotal data we've already shared with FDA in our pre-BLA meeting last summer, and I think everyone finds it very compelling. It's measuring D2S6, which is basically similar to the heparan sulfate approach. I think that one of the big surprises, really, out of the data set is initially, I've worked on the program for almost eight years now, and we're thrilled that accelerated approval is being made open, if you will, by FDA. But the interesting piece is we're seeing systemic benefit from a treatment to the CNS.
80% of our patients that have been dosed have been able to either not go on enzyme replacement therapy, or if they were previously on it, taper off of it, and that's measured by urinary GAG levels to demonstrate that the systemic levels are decreased as well. So that really changes the whole value proposition, I think, for the program, which was already exciting, but now potentially a full systemic capability of the program to, you know, basically, we've talked to patients, parents who have had children doing enzyme replacement therapy for much of their lives.
One parent told me that his son has been in an infusion center for three years over this time. So think about the potential benefit that patients could receive from this. It's really awesome.
Yeah.
Yeah, I think, you know, to Curran's point, when we actually started this program, our whole intent was to solve for the neurocognitive unmet need. And as the program evolved and the pivotal dose data came out, we were pleasantly surprised with the type of product profile we have now is it's truly a one-time therapy. Patients do not need any other, you know, supplemental therapy with ERT. So I think, on a value basis and a cost-effectiveness basis, we have a therapy in our hands that could be, again, priced responsibly, but that represents the value of the asset. And then if you think about the patient distribution, we're talking really about less than 10 centers in the country.
So on a infrastructure basis, what you need is very prescriptive, very small, so you can get to a break-even on profitability very, very fast with this product. So we see it as a sustainable opportunity that can set the stage as we go into 202 , in the future, and I think from a 202 perspective, we'll be literally walking into an existing gene therapy infrastructure, potentially with a best-in-class product, that has better outcomes, and that really helps us to take the efficiencies we're putting into 121 and the existing infrastructure to make the launch process seamless for us.
Great, so I guess pulling things back high level, can you kind of talk about, with all the things that you have going on, the sort of cadence of catalysts that we're gonna see from your various programs over the next 12-18 months?
Yeah. So it begins. I think you'll see, towards the fall, sort of two major outcomes. One would be coming off the end of phase II meeting for diabetic retinopathy. We'll talk about the results of that and confirm the pivotal trial starting the next year. And then I think there will be a lot of attention and focus on the 202 program functional data, the first data that'll be released, and that'll largely consist of data for dose level one for roughly three patients, and also data for dose level two for about two or three of those patients. So I think those are the major catalysts. The diabetic retinopathy, as you mentioned, next year would generate a significant milestone.
One thing we didn't mention, I think, on RGX-121 is that's eligible for a PRV upon approval, so that we would expect that sometime late next year as well.
Okay, great. And then I guess in the last couple of minutes here, is there any other questions that I haven't asked that you would want to point investors to in terms of what's going on at REGENXBIO?
No, I think it's an exciting time for us. We're evolving from a, you know, early clinical stage company to a late clinical stage and commercial stage company now going into 2025 . So it's a time of transition to build a lot of value, and, you know, we're probably the only company that are operating in public health priorities like wet AMD and DR, and then two very large rare disease programs like Duchenne and then sustainable opportunities like MPS II. So, you know, with all of these now maturing and getting to a place where, we can potentially have three products in the next, two to three years being on the market, I think that's a very exciting time for us.
Yeah, great. And I guess there was a little bit of a restructuring last year. A number of programs were cut, so you could focus on these programs. Are you guys still continuing to look at anything in sort of the discovery earlier phase?
Yeah.
Are we maybe gonna see any INDs then?
It's a great question. Yeah, we definitely retained within the research team really strong focus on ocular new product development and then on muscle. So those are the, you know, framing the core rare and ophthalmology programs. So I would expect next year we'll be talking a little bit about some new programs, especially on the ocular side. But right now, we're 350 people trying to manage four late-stage assets. We're focused on that 100%, but we continue to develop new compounds, new capsids that we're excited about. So stay tuned early.