Hi. Good afternoon, everyone. Welcome to the UBS Healthcare Conference. I'm Ellie Murrell, one of the Biotech Analysts here at UBS. Very happy to have REGENXBIO here with us for a fireside chat. And joining us from REGENXBIO is Ram Palanki, EVP, Commercial Strategy and Operations. Well, thank you so much for joining us.
Thanks for having me, Ellie.
Maybe before we go into specifics on your many programs, can you provide a high-level overview of REGENXBIO, some backstory on the company, and yeah, the programs that you have ongoing?
Yeah. Just going back into the history, we were founded in 2009. And the whole basis back then was we acquired a technology out of the University of Pennsylvania that was a byproduct of the discovery from Jim Wilson. And the idea there was he discovered a slew of vectors that could actually have this selective tropism to different tissue types in the body. So you can bring in more efficiencies and deliver gene therapy that's safer and more effective. Since then, we've been technology leaders in the AAV space, pretty much large caps, mid caps, small caps. Everybody's licensed our technology over the years. And our technology has been probably validated in thousands of patients, both on a research basis and commercial basis. And the diversity of the footprint that it represents, too, really brings forward the type of leadership we've played in AAV technology, generally speaking.
I think the most exciting part sitting here with you right now is actually that we're moving to be business leaders in the AAV space within the next 12 months, and a lot of exciting things that are going on in the organization that I'll speak to as we go through the process.
Yeah. Maybe can you give us an overview of the pipeline and key milestones expected over the next year or so?
Yeah. And the reason I was saying that we are about to transform ourselves into business leaders is it's actually the mature late-stage pipeline we have. And I think I'll probably walk through each one of them. I'll start with RGX-202, which is our best-in-class next-generation product for DMD. To date, we have been able to bring forward some of the data on a biomarker basis that clearly shows that the rational design we've used and the thoughtful process we went through to design the vector and the asset itself on the basis of transgene, codon optimization through muscle-specific promoter that we have installed into the construct is all translating into potentially a best-in-class outcome based on the data we've shown to date. But the most exciting part of that whole evolution today is coming into these earnings.
We've announced that this month we'll actually be bringing forward the functional data on the patients we've already shared on a microdystrophin basis. And we came out of a very successful end-of-phase two meeting with the FDA, confirming the fact that we have access to the accelerated approval pathway. And the main constructs and pillars of the foundations for having access to the accelerated approval pathway is safety, efficacy. And bottom line, safety is where everything starts. You have to have a product that's safe. And then on the basis of that, if you show even better safety, better efficacy, that's really where the entire accelerated approval pathway is meant for. So we feel really, really excited about coming out of that meeting, having that alignment, and coming into this month, providing the functional data.
We'll also be announcing the details of the pivotal trial very much in the near future. So you will know everything about the program as we're moving forward. Then stepping into the diabetic retinopathy program, which is our suprachoroidal program that we've been talking about in the context of that program maturing into going into a pivotal stage, along with our partner, we've been able to accelerate the entire end-of-phase two program from our original guidance of in 2025 to now fourth quarter 2024. Once we complete that end-of-phase two meeting, we'll be able to provide details of that program as well in terms of the design and the plans moving forward along with our partner in the near future, in the very near future. We also give guidance around our program in MPS II, Hunter Syndrome, RGX-121.
We've started a rolling BLA submission, and we plan to finish it off by first quarter 2025, and that puts us on a path to potential BLA approval, so when you take all these exciting milestones that are coming through on a late-stage basis, we really have an opportunity to turn into a business leader in the world of AAV very soon.
Yeah. A lot going on. Starting with DMD, where we're expecting some news near term. Just starting with the construct and where you see this potentially improving on Elevidys, tell us more about this.
Yeah. We've been very thoughtful, and we used a rational design to come up with RGX-202 as a best-in-class construct. And when we say it's next generation, it really takes all of those concepts into account. Starting with the transgene itself, we are the only construct that has the CT domain. And if you go back into history and even look at the process that Elevidys went through with the FDA, one of the objections that the FDA brought forward was the lack of the CT domain and its role in conferring function in these patients. So we've been able to think through all of these things very proactively. And that's a big differentiator in the construct.
And we've also installed a lot of other components on the basis of muscle-specific promoter, as well as codon optimization for the entire construct to ensure we have a construct that can move forward on the basis of efficiencies for transduction, localization of the transgene itself, and the expression of the transgene. So ultimately, it all translates into potentially better function in these patients. All of that to say, not just the construct and its benefits, but also we've been very thoughtful about leveraging our in-house capabilities on a manufacturing basis to actually scale up a commercial process that can actually supply, as it stands today, almost 2,000 doses when we get to market. So I think the fact that we're carrying a process that's already been commercially scaled up, and there are no process differences going into the clinical program, it also avoids any regulatory risk for the asset.
To date, the product has been very safe, and that's a very important component of the accelerated approval pathway. I think all of these observations to date and our meeting with the FDA on an end-of-phase two basis really gives us a lot of comfort and confidence that as we're moving this program, we can bring a best-in-class product to patients very soon.
In terms of the phase one two design, walk us through what efficacy metrics you've been tracking, what efficacy data we've seen so far, at what doses, and in how many patients?
Yeah. To date, we've presented the microdystrophin data at three months in about seven patients. So we have two dose levels we are investigating, dose level one and dose level two, obviously, dose level two being the higher dose, which is at 2E14 level. We've shown microdystrophin data in a spectrum of patients, and the majority of those patients have been in the older age group and consistently, we've shown we were able to observe double-digit consistent expression and a magnitude of expression that when you compare to benchmarks and what's been already shown with other products, we're magnitudes higher. I think that is the beginning of an observation that has given us the confidence on this program.
As I said, we've announced that we're going to be presenting the functional data from some of these patients that we've already declared the microdystrophin data in that have enough of a follow-up. Yeah.
Yeah. Can you be more specific on sort of the length of follow-up, number of patients, what type of functional data that we'll be getting?
Yeah. All the functional data you're talking about are time function tests that you've traditionally seen that have been brought forward from other products and from the approved product that's in the market today, along with NSAA. The time points that tend to be meaningful to bring forward are somewhere between nine to 12 months.
Got it. And you recently had discussions with the FDA. Can you talk a little bit about how you're thinking about the development strategy in broad strokes? I know you haven't been specific on the details of the design, but you have characterized it and how you're thinking about it. Maybe just share any feedback from these FDA discussions and how you're thinking high level about your ability to access the accelerated approval pathway.
Yeah. The basics for accessing the accelerated approval pathway is really about a product in the context of what's already been approved. The product that's coming to market has to be safe. And that's the first criteria. The other component of that evaluation is efficacy. And better efficacy is helpful. But the basis of approval is based on either better safety or better efficacy. I think in both of those scenarios, you have to be safe first. So the bar in terms of getting accelerated approval is really about making sure that first you have a very safe product. And then if you're also able to show that on an efficacy basis, that makes the whole argument more compelling.
I think we, to date, with the microdystrophin data have been able to show, especially when you match the age groups, that the expression levels we're seeing with microdystrophin are consistently in double digits and high enough when you compare it to the benchmarks that exist today. And the general thinking in the clinical community on a directional basis is around 10% is what is supposed to be meaningful to see an effect in patients.
Thinking longer term, what data do you think you need to show to differentiate yourself from Elevidys?
It comes down to the concepts that we just discussed, right? The basis for approval is being able to show that you're safe and you have an efficacy that is consistent across patients and probably even better than what's out there. So the way to think about the differentiation comes from a totality of evidence on the basis of PK/PD data and all of that translating into that consistency and magnitude of effect. So that will be the basis for approval and differentiation. Again, to date, when we compare the age groups and cohort of patients where there's a rapid decline of function in patients and a rapid progression of the disease, we were able to show that we're getting to meaningful levels of microdystrophin expression. And as I said, this month, we'll come forward with functional data. I think that will all provide a pretty good perspective to the community.
Yeah. Maybe can you just be a little bit more specific in terms of the functional data? How specifically should we compare this? And what would you view? I know it's going to be a small handful of patients, but what would you view as an initial signal that this could provide differentiated efficacy or even at the very least comparable efficacy?
Yeah. Given the fact it's a handful of patients, what we're really trying to accomplish here as an organization right now is directionally understanding that the totality of evidence supports our belief that this is a best-in-class product and could go through the accelerated approval pathway. You will see all of the time function tests along with NSAA and all of those against how patients with natural history behave in the context of the age group and their trajectory of the disease. I think that will give you a really good perspective on the efficacy and the drug effect of RGX-202 because those databases on a natural history basis have been very well established.
In terms of the update on the pivotal program coming up very soon, what exactly will you tell us at that point in terms of size of the study, anything else that we can expect to learn from this update?
Yeah. We've given guidance already that very soon we'll be providing all the details of the pivotal program now that we have alignment with the FDA. So you will see them.
How should we think about the timelines for how long this study will take and when you could potentially have this data and file and come to market?
I think when we come out with providing details around the pivotal program, that will also provide clarity on timelines and when we'll be able to get to the other side.
Great. Well, we're looking forward to the update soon. Maybe turning to 314, your anti-VEGF gene therapy for wet AMD and diabetic retinopathy. I think there's a lot of investor debate around the place for a gene therapy in the wet AMD or DR space. What's your perspective? What do you see as the unmet need and the commercial opportunity there?
Yeah. Let's start with wet AMD first, and then we'll go into DR. Obviously, with wet AMD, we've been executing to our pivotal programs with SR. And if you look at the entire landscape and the competitive world today, everybody's been trying to solve for durability, right? The problem with the disease is when you go into the real world, the existing regimens are not sustainable. Hence, everybody's been trying to accomplish a real-world regimen that can actually help sustain vision over the long term. I think gene therapy has the best opportunity to do that on a long-term basis versus every other innovation that's happening out there.
The foundations of a clinical management spectrum that requires chronic treatment that could be started with a single treatment that will establish therapeutic protein for your lifetime, I think really has a transformative approach to how you look at managing wet AMD patients. Most patients could just end up never needing any other treatment. And some patients will have a huge shift in their treatment burden period. To be able to do that and have the flexibility in managing patients over time with a single foundational treatment of gene therapy anti-VEGF is transformative in the marketplace. I think that's where gene therapy fits in terms of managing wet AMD.
No matter what treatments are being developed in the competitive landscape, to date, we've been able to show almost four years of durability with our subretinal approach where patients continue to sustain their vision and gain vision and at minimum maintain vision. So I think those concepts on a long-term basis that can modify the disease and sustain function in patients is the most important concept that I think only gene therapy can address on the longest-term basis. And then when you shift to DR, the people to date understand DME, which is a complication of diabetic retinopathy. I think it's really important to understand that diabetic retinopathy is the underlying cause for diabetic eye disease that continues to be there. It keeps progressing over time. And depending on the progression rate and severity of progression, it turns into these complications like diabetic macular edema, proliferative diabetic retinopathy.
All of those are only addressed when you actually get there. So you've already lost a lot of the vision and things that you just can't recover. So the concept of being able to manage DR progression on a preventive basis and avoid these complications with a single in-office injection is transformative how you manage a public health priority. I think that's where the DR program fits. And as I said, we, along with our partner, have been very excited about the program. And hence, we've accelerated this whole end-of-phase two meeting into fourth quarter this year. And once we know all of the details, we'll announce that in the near future.
Great, and so you have the ongoing subretinal phase three programs as well as moving forward with the suprachoroidal programs. Where do you see the strategy between subretinal and suprachoroidal?
I mean, let's talk about DR for a second. We only have a suprachoroidal program. And the reasons there are these patients tend to be asymptomatic in early disease. And your goal is to actually keep them asymptomatic so they don't ever develop these complications. In that context, I think an in-office procedure that could be easily done in an office with minimal any procedure-related AEs is a very critical piece of the whole puzzle. So the product profile we have there, it's very much independent to suprachoroidal. As you shift into wet AMD, it's a very different story because this is a disease that has major implications in terms of how the disease progresses. And the subretinal approach has been shown to be the most efficacious and safe.
We don't do any prophylactic steroids in the subretinal program other than the routine steroids that are given for managing the post-surgical complications. That itself tells you that it's probably the most immune-privileged space, and over the long term, I think that's going to become a very important concept because these patients are older patients, and adding any type of long-term steroid prophylactic use just creates an entire new spectrum of complexity to clinical management, and the fact that we are actually in the midst of phase three programs that will be declared not too far into coming to the market. Our guidance today is BLA submission is in 2026, right, so as we think about the competitive environment, the subretinal program has the opportunity on a global basis with our partner AbbVie to be approved and coming to market years ahead of anybody else.
The type of maturity the program has on a long-term basis, both for efficacy and safety, it's a great place to bring the concept of gene therapy to the market and establish that type of affinity and competency with gene therapy. Then suprachoroidal coming behind it can actually expand that opportunity into the office and create access to more patients in the earlier forms of the disease. That's how we see the whole lifecycle management where between subretinal and suprachoroidal, we're giving options to patients, to physicians. We have an opportunity to go and establish gene therapy in the treatment of retinal vascular diseases much earlier than anybody.
Yeah, you have a pretty large-scale phase III program going on with the ATMOSPHERE and ASCENT pivotal trials, which we are coming up on data if you're guiding for a BLA filing in 2026. Can you give us an overview of the design of these programs as well as the timelines?
Yes. I mean, the timelines, we've given the guidance. That's kind of where we are. As for the programs itself, we have two phase three programs, ATMOSPHERE and ASCENT. ATMOSPHERE is actually a trial that's been designed to test 314 against Lucentis monthly dosing regimen, and ASCENT has been designed to test 314 against the bi-monthly dosing regimen of Eylea. Both of those are non-inferiority trials. Both of those are global trials, and both of those are meant to get approval in all of the major geographies across the world around about the same timing, so the idea with these two programs is to introduce gene therapy in multiple geographies across the world so millions of patients can have access to it.
From a commercial perspective, how do we think about the different profiles, particularly on some of these secondary endpoints beyond just showing, say, non-inferiority on BCVA, but on the proportion that can go, say, injection-free, other components like that? How are you looking at what would be competitive data?
I think for gene therapies and that concept of one-time therapy over a long term, what you're really trying to shoot for is that 70%-80% reduction in total treatment burden, which I think translates into about 50% of patients going injection-free over the long term, and we've been able to demonstrate that from our early data, even on a long-term basis for up to four years. I think those concepts really become important, not just from an injection burden standpoint. It's really about sustainability of vision over the long term. That's the reason that you want to have this extended therapeutic protein in the eye so you're not dealing with these cyclic troughs and peaks that ultimately lead to disease progression and patients ending up losing vision.
Makes sense. And now pivoting back to the suprachoroidal program, can you walk us through the timelines there both in DR in terms of moving into the pivotals, but then also in wet AMD and the latest there?
So I mean, DR, we just talked about it. From our original guidance to going into end-of-phase two next year, it's all been accelerated to fourth quarter this year. So once we actually finish off the end-of-phase two meeting with the FDA, very soon after that, we will be able to provide all the details around the program and the timelines. So that's kind of where things are. And that's an exciting component of the fact that the program got accelerated. The reasons are because we and our partner are excited about it.
I guess what data updates can we expect over the next 12 months specifically from the suprachoroidal program?
I think we have announced this. We have actually expanded the ALTITUDE program with a new cohort of patients that have DME. So we'll be going into dose level four to treat patients that actually have diabetic macular edema. And we have also announced that we've expanded our wet AMD suprachoroidal program into dose level four. So once those trials, those cohorts get recruited with dose level four and we have enough of a follow-up, then we'll be bringing forward the data.
Can you provide an overview of the collaboration structure that you have with AbbVie, in particular as we're entering a period where we're going to get a lot of major updates from the programs, some of the potential near-term milestones that you could be receiving?
So the totality of the relationship here is, I'd say, global strategic relationship. AbbVie participates in terms of development, majority of the cost. And we actually are responsible for the minority of the cost as we think about the totality of the program itself. And then when it comes to commercialization, we are responsible. The construct in the U.S. is everything is shared 50/50, both on a profit and loss basis, I mean, cost and profit basis. And then ex-U.S., we receive double-digit royalties. And they're 100% responsible for commercializing the product. That's the totality of the construct. And we have milestones that come through in the form of development milestones and commercialization milestones. That totality of that number is around $1.3 billion. We've announced this in the past. So those milestones come through at different stages of us hitting different parts of the development milestones. For the suprachoroidal program, specifically as we talk about DR, it's up to $200 million.
Great. And pivoting to MPS II, where you are on your way to filing a BLA, can you provide an overview of what you see as the unmet need here and the potential near-term opportunity?
For the, sorry, which program?
MPS II.
MPS II. So very exciting for us because we're actually transforming from, as I said, technology leader into a business leader. And RGX-121 is the first product that actually gives us the opportunity to carry forward our science into patients on a commercial basis. We have announced that we've actually started the rolling submission as we speak. And we plan to wrap it up by first quarter 2025. That puts us on a path towards, say, BLA submission and approval. And I think as we started the RGX-121 program, one of the most exciting things we were trying to do was solve for the unmet need that exists in the neurocognitive decline. And as the program matured and we came to the other side of the pivotal data, what we're observing is the product has exceeded our original expectations.
We're seeing patients now coming off of ERT or never initiating ERT. That's happening in the majority of the patients. That really transforms 121's product profile into being a true one-time product, one-time treatment for these patients with Hunter syndrome. I think that puts us really squarely in the concept of gene therapy in these patients where now they can just go on one-time treatment and avoid the treatment burden that comes with ERTs because they have to go for weekly infusions. I think we'll be able to really transform patients' lives and caregivers' lives and ultimately have an impact on the healthcare system just being able to be a one-time therapy.
How should we think about the population size of MPS II and in particular any specific segments of the population, like the CNS involvement that you're targeting and the sizing there?
Yeah. I think the way to think about this is there are probably about 100 patients in the U.S., and then when you step into the major geographies, European five represent about the same magnitude and number of patients, then you kind of go into Japan and other territories on a global basis. It's a sizable opportunity, and the way to think about it is majority of those patients are neuro- they have neurocognitive issues, which are referred to as neuronopathic patients, so the treatment is meant for majority of the patients that are diagnosed with MPS II, and we are the only ones that are actually treating patients in that six-month-old and above, so even from a label standpoint, we will have the opportunity to bring the treatment on a one-time basis and avoid this over-the-time decline by treating patients very early on in the disease process.
And with newborn screening coming into play for MPS II, it's already been installed in many of the states in the U.S. And by the time we get to market, it'll be available probably in the majority of the states, which will actually accelerate the patient identification and being able to bring the treatment forward where I think it will be the most effective because you're able to preserve most of the function in the patients if you go early in the treatment. And these patients on a distribution basis across the U.S. as a geography, mostly majority of the patients are distributed across less than 10 centers of excellence. So it's a very prescriptive opportunity where we don't need a big infrastructure to bring the product to these patients.
So we see this as a substantial opportunity that will lay the ground for other products that are coming behind, right? So 202 and other products that we're developing even in retina and in the entire space. And we do in the future. This really helps us to install an infrastructure that we can leverage and operationalize on an expansion basis to make our future launches efficient.
Great. Maybe turning to manufacturing, manufacturing with gene therapy is fairly complex. Walk us through where you stand with that, maybe starting with 314.
Yeah. I mean, as you know, we have our own GMP facility that's an in-house facility, and we have developed our own processes that are industry-leading. I think more than with 314, with 202, the complexities in DMD manufacturing are very well known and supply constraints with being able to meet the demand. We have been very thoughtful about it, and we have a suspension-based process that's a next-generation process. We call it NAV Express for all the right reasons. As I said, we have already developed a commercial process that can supply 2,000 doses for DMD patients. With 314, the levels of dose you need to treat the disease just gives you a lot of advantages on the basis of scalability. We'll be able to supply pretty much the entire market on a global basis with the type of process we have today.
And I guess just in terms of the phase three studies, I guess what were the processes used there? And what's the intended sort of commercial process that you would use?
Yeah. We have carried forward the commercial process into our phase three. So the idea has always been both for 314 and DMD that we've been thoughtful about process changes never impacting the time to commercialization and the overall regulatory risk. So we feel very comfortable where we are having carried the commercial process into these pivotal programs.
Great, and maybe just to recap, you have a lot of programs going on. Can you summarize sort of the major milestones coming up in the next 12 months as well as your cash runway?
Yeah, so I think in totality, if you start thinking about DMD, as I said, the most exciting thing that you'll hear this month is the functional data, and then, as I said, we've already had the end-of-phase two meeting with the FDA, and we know we have access to the accelerated approval pathway, and we'll also come forward in the very near future with details of that pivotal study. We've accelerated the DR program, end-of-phase two, along with our partner into fourth quarter this year, so we will have clarity on coming out of that meeting and confirmation on how that program is going to look like, and in the near future, we'll also provide details on that program. Obviously, RGX-121, we've started the filing, and going into next year, we'll finish it off in the first quarter 2025, which puts us on a path towards BLA approval.
I think across all of our late-stage programs right now, we are really transitioning REGENXBIO to become a business leader from technology leader over the next 12 months.
Great. And in terms of cash runway?
Cash runway, we've given this guidance. Our cash runway is into 2026, and that doesn't include any of these potential development milestones from AbbVie. It doesn't include a potential PRV that we could get once 121 is approved, so all of these are non-dilutive options for us that could actually support the company's cash strength over time.
Great. Well, I think we're at time. But, Ram, thank you so much.
Thank you.
Yeah. Appreciate it.