Hi, good afternoon. So thanks for holding out for the last session with REGENXBIO. Happy to have Ram Palanki here, Chief Commercial Officer, and Nina Hunter, VP of Corporate and Business Development, as well as Regulatory Affairs, with us today. So I guess in the past year, I guess even six months, I'd argue you've made some pretty big leaps and bounds across all of your programs, and I'd love for you to just give us a quick run-through of where you are. And then we can dig into some of the details of the exciting programs that everyone seems to be focused on.
So, Ram, why don't you go ahead and give us a quick overview of REGENXBIO, and, you know, sort of what makes you stand apart in the gene therapy space, and some of the programs, all of your programs, frankly?
Thanks, Annabel. It's always good to talk to you. I think 2024 and 2025 are transformative for us at REGENXBIO. I think coming into the last earnings call, you probably heard our CEO speak to it. By the end of this year, we would be pretty much every program that's in the clinic would be in pivotal stage or would have filed a BLA. So if you look across the programs, 314 wet AMD program is in the midst of phase III today. The subretinal pivotal program, which is a global program that's been getting executed in the U.S., Europe, and Japan. And we would be pretty much tracking towards finishing enrollment in the pivotal program. We would be starting a phase III for DMD and would have filed a BLA for 121.
That really sets the stage for us to transform to being a commercial stage company going into 2025. I think that's the most exciting part, and when you look across these three programs, you know, one is actually addressing public health priorities in wet AMD and DR. The other one is, you know, coming behind the competitors within DMD. We have a best-in-class construct, and the data to date suggests our beliefs on the best-in-class construct are getting confirmed. And 121, obviously, is a rare disease, and there's a huge unmet need there, and it has surpassed our own initial target product profile estimates we had. And we can speak more about that as we go through this conversation.
Sure, sure. Well, why don't we actually start with wet AMD and DR, because those are some of the bigger programs, and you just essentially stated it's a public health concern. So I guess what gets you excited about the wet AMD, and I guess especially in light, you know, in the context of other gene therapy programs underway, and even in the context of some of the other longer-acting development stage programs that are, you know, advancing also in clinical development. So maybe we can start with that really quickly.
Yeah, it's... I mean, when you think about retinal diseases and wet AMD, DR, these are all very close to my heart. I think you and I have spoke about this a few times. I started my life with the launch of Lucentis back in the day at Genentech, and from there to the journey to REGENXBIO, what Lucentis started as a product that was addressing an unmet need, that was a game changer in how the retinal diseases have been treated for the past couple of decades. I feel like REGENXBIO is on the same type of transformative stage right now, with the pivotal studies being in the midst of getting enrolled.
I see this as, when you talk about gene therapies, obviously we are far ahead against other gene therapies that haven't actually entered into a pivotal stage program. We're on track to finish enrollment and go into global regulatory submissions coming into first half of 2026. We're starting a second pivotal, potentially coming into the first half of 2025 in diabetic retinopathy. The concept of one-time treatment in these diseases that are chronic and tend to be lifelong, I think totally changes the way you have to think about patient disease management, where you're laying these foundations of a therapeutic in the eye that pretty much helps every single patient over the long term.
We have presented data up to four years now from our earliest stage phase I/IIs that shows in previously treated patients that have very severe disease, most patients have gone treatment-free and are gaining almost two lines of vision over four years. That's really the unmet need that exists today in the marketplace is two components. We talk a lot about durability of treatment and cutting down the number of treatments, but the most important concept there is you cannot compromise the patient's vision in the process. I think gene therapies, generally speaking, have this ability to sustain these long-term visual outcomes, which again, we've kind of shown that in our phase IIs and hope to continue to do that as we you know, come into 2026.
Is the field ready for subretinal?
Yeah, it's... I mean, remember, Lucentis got launched in 2006. Before that, retina was 100% surgical field. And pretty much, over 80% of retina surgeons, retina specialists are trained as retina surgeons. They all have to learn the basics of the surgery, which is vitrectomy. And then on top of vitrectomy, a lot of retina specialists do complicated surgeries like membrane peels and lot more complicated procedures like macular holes and such. And when you look at the volume and the competency that exists in the marketplace today, the numbers are pretty much telling the facts. There are about 500,000 procedures that are done today that involve vitrectomy on an annual basis in the US alone.
So every retina surgeon goes into the operating room on a weekly basis, and most surgeons do perform at least a handful of surgeries every week. So that kind of translates into, you know, the competency that already exists and the volume that already exists, and the access to the operating room already being in place. We believe a treatment that can sustain on a long-term basis the type of visual acuity outcomes we're hoping to accomplish, it is easily adaptable within the OR. Yes, we do agree that the breadth of that adoption would be a lot broader if it is an in-office procedure, and hence we are pursuing the suprachoroidal routes.
As we go through the process of dose escalation and find a dose to take forward, that would be the next step in the development of 314. But I think the first step is what we have as a risk-benefit profile and what we've shown on a dose basis, and the outcomes that we've seen on a long-term basis. The competencies exist, the access to the site of care exists, and there are a lot of patients that want to go and get their problem fixed, and so do a lot of physicians.
What part of the market do you think would be readily eligible for you to tap into for a subretinal procedure?
I mean, think about this way, right? Wet AMD is a chronic disease that is lifelong, so there's just a prevalent pool of patients that have been going through the process of cadence and fatigue in the clinics today that have been receiving long-term treatment. And that's hundreds of thousands of patients. I mean, on an annual basis, there are close to 800,000 patients in the clinics today that are getting treated with anti-VEGFs. Out of that, you know, even when you take 20%-30% of patient population that is going through-- that has already gone through the process of long-term treatment, and is ready for a long-term solution, that represents a significant opportunity, and it's a multi-billion dollar opportunity.
Yeah. I wanna touch on the SCS delivery. Obviously, that's gonna be one that is much more readily available to patients and even physicians, and they can incorporate into their practice patterns a lot easier. But I guess in, for the SCS administration, it doesn't look at this point that you're completely eliminating the need for anti-VEGF with only a 50% injection-free rate. So how should we think about this in light of the TKIs in development that could go for six or 12 months? You know, is gene therapy gonna be, you know, a treatment that is administered and then doesn't really eliminate the need for return injections?
Yeah, I think it's the wrong way to measure efficacy based on percent of patients going injection-free or retreatment-free. When you look at the data sets from TKIs through all of the gene therapies that have been coming out with early data, as well as you know, some of these incremental durability aspects of products like Vabysmo, even high-dose Eylea, all of these only offer that type of extended durability in a percentage of patients, which has been pretty consistent across all data sets. It's about 50%-60%. That just shows how the disease actually presents itself on a phenotype basis.
There are just certain group of patients that require a lot more anti-VEGF than, than others, and I think that portion of the patients actually benefit from long-term treatments like gene therapy because you're actually decreasing the need of that anti-VEGF levels in those patients with a baseline foundational biofactory of anti-VEGF, that now, when it needs some supplementation over time, will still be much less than other treatments. So I think that is really the biggest advantage you have with gene therapies, is by sustaining and establishing this baseline level of therapeutic agent in the eye that is sustained over a long term. I think it benefits every single patient, independent of the phenotype you're dealing with.
Certain patients are gonna go injection-free, and certain patients are gonna require some top-ups here and there, which would be lower than if they would have not received gene therapy or did not have a long-term solution as a base foundation for their treatment.
Mm-hmm. And, how do you see TKIs fitting into this?
I mean, my view on TKIs is, you know, maybe some of the measurements you can take from the DR data that has come through from these trials shows a drug effect. I'm not sure how that translates into pivotal data.
Mm-hmm.
We'll just have to wait and see. And I also... You know, the trial designs, the type of patients you're picking, and the criteria that are going into these trials are starting to take a different shape between different programs. And all of that is going to have an impact, not just on the regulatory approval, but when you come on the other side, reimbursement... I think payers, and not just in the US, but when you step ex-US especially, the health technology assessment agencies are going to look at these study designs very closely. I think it's going to happen in the US, too, as we get more and more agents into the commercial sphere.
Decisions are going to be made on a reimbursement basis for products that can sustain the type of due diligence from the people that actually want to pay for these.
Okay. And at this point, for SC delivery, what are the limitations to exploring a higher dose?
I mean, you've seen. I mean, we've publicly presented this, right? So we've gone through three dose levels of escalation in diabetic retinopathy. The first two dose levels that we've looked at, we feel like we have established a target product profile that is giving us the confidence to take it forward into a pivotal stage program. I think in wet AMD, we continue to explore the data, and as we get more data into view, coming into second half this year, we'll make a decision that will be in line with, you know, what type of target product profile we are trying to accomplish in wet AMD. I think the TPPs in wet AMD and DR are very different.
Mm-hmm.
In diabetic retinopathy, you are treating the disease that's more peripheral, and also more within the spectrum of the periphery than the rest of the eye. That's pretty clear with the type of data we've observed. At dose level 2, coming into AAO last year, we saw almost close to 90% reduction in the risk of developing, you know, major vision-threatening complications, like PDR, DME, neovascular glaucoma. And these are all diseases once you do develop, your choices are you have to treat them lifetime, or you can confer the patients the same outcomes that they would've gotten if there was a preventive therapy. I think that's where the most exciting part is for DR, as a treatment that can stop these events from happening, on the basis of progression.
Yeah, so I do want to move over to DR because that is one area of the market that's, you know, despite having a number of therapies, is pretty much untapped as far as therapies go. So just can you give us a quick review of the data, you know, especially in terms of the VTCs? You said 90% reduction, about 89, 90% reduction. What are some of the other things that stand out to you as far as your program and what it looks like as far as the competitive landscape out there?
Yeah, obviously, the competitive landscape is validating the market potential for diabetic retinopathy, right? It's every program out there has been exploring the potential of a durable treatment in diabetic retinopathy. I think one of the things that you have to remember is diabetic retinopathy is an underlying disease throughout the life of a diabetic patient. It's never going away. It's this diabetic retinopathy is always there. How it translates and where it goes in the context of the progression varies depending on the baseline severity. So every patient goes through the progression, and when you take patients that have already progressed to that moderate to severe component, within a year to a couple of years, we know they will end up developing PDR and all of these other diabetic complications that then require lifetime intervention.
So then, you know, you think about the concept and go, "Why hasn't any product that's already been approved for diabetic retinopathy been used?" The question becomes, because today, most of the anti-VEGFs there, either you treat patients once they develop these complications for a lifetime, or you have to make a choice that you start treating them for lifetime before they develop those complications.
So the value there is very different, because you're making a choice to treat asymptomatic patients for their lifetime and telling them, "You know, this will prevent you from getting there," versus the conversation would be, "I can start you when you get there, and then I still have to treat you for lifetime." But I think when you convert that narrative to a one-time treatment that can actually stop the progression of this disease, especially when you start talking about even patients that have already had experience that in one eye, and the bilateral component is really huge, it's a pretty simple equation for those patients.
You tell them, "I can do a single procedure for you in the office, and you will never experience what you had with your other eye, or we can wait till then, and your choice is lifetime treatment." So it's, I think, the target product profile you have with the one-time treatment in a disease like DR, during the asymptomatic phase—when I say asymptomatic, it's not the disease progression, but it's the visual progression, that patients don't see in the early stages.
Mm-hmm.
But if you can explain to them that, you know, it will stop them from ever getting there, and I think where the whole adoption will start is probably patients that had bilateral disease and have already experienced the complications that progress in one eye, is a good place to start. And with millions of patients in the clinic, I personally believe this market is much larger than even wet AMD.
Sounds very much like the geographic atrophy dynamic, but these are patients who started 30, 40, 50 years old.
Exactly, and that's what's happening in the geographic atrophy market today, is most physicians are able to convince patients that have already lost one eye-
Mm-hmm
... because they know that their choice is if they don't get treated, they're losing that second eye, right? So once you've gone through the process, I think, in asymptomatic patient population, like geographic atrophy and dry and diabetic retinopathy, it's a pretty easy conversation to have.
Yeah. So I guess help us understand the significance of AbbVie actually announcing that it's moving forward in phase three. What were the boxes that they had to check to move forward from their perspective? Obviously, it's- they're the ones controlling the, the decisions here. You know, they, they have the ultimate say on those decisions, but maybe you can sort of give us a sense of what you had to discuss with them to get to that level, to that decision.
Yeah, I mean, you know, our collaboration, the general construct is, they take on two-thirds of the development expenses, and we take on one-third of it. For the U.S. and ex-U.S., they take on 100% of the development expenses. In the U.S., we share everything 50/50 on a cost and profit basis. And ex-U.S., it's high teens to low twenties in royalties for us. So you take that construct, and then there are other milestones that come as part of a development decision making. So the DR development decision comes with a $200 million milestone when the first patient gets treated.
So when, you know, when you're making major decisions like that on a global basis, not just for the US market, you have to go through a whole process of research and evaluation on the probability of success, for the, for the overall program, not just on a regulatory basis, but also on a reimbursement, pricing, ultimate commercial success for the program. So I think having a partner like AbbVie that has an infrastructure in 170+ countries, that puts a very detailed convex lens on all components of that evaluation, is the reason it took us this long to even to kind of come through a process of, how do you, how do you develop this product? But more importantly, how is this product applicable in majority of the global markets?
Mm-hmm.
That's really translated into some of the confidence that we brought forward in the last earnings call that we are both getting to a place where this needs to move forward. You know, we've been very thoughtful about how we will examine this data, even on a long-term basis, because we presented the one-year data at AAO, and as you've seen, a lot of the competitive data hasn't even brought forward the concept of vision-threatening events and vision-threatening complications. Because ultimately, it's not the DRSS score that matters. It really comes down to, are you able to really take down that risk of developing these vision-threatening events when you modify these patients on a DRSS basis?
We have consistently shown that effect seems to be 70%+ on the basis of improvement for us. And then on the basis of worsening in the control arm, you know, we saw about 40% of patients worsening, with 0% in that have been treated with 314, and that continues to be the case.
Mm-hmm. And when do we see the next update on dose level three, the next data set?
Yeah, we've announced coming into second half, we'll be giving all those updates on just the DR program, getting a lot more details around what the whole execution plan is.
Okay. Just one other question. Looks like you have the most efficacy in the NPDR population. I think that's where you showed some of the best data and the best reductions in the VTCs. Does that limit you primarily to the NPDR population, or you still have an opportunity in the PDR patient-
Yes-
Moving forward into phase 3?
I think, moving into phase three, the plans right now are all NPDR patients, Annabel, and that's actually-
NPDR or PDR? Sorry, just-
NPDR.
PDR.
NPDR.
Oh, NPDR. Sorry, I just want to make sure everyone hears that properly.
Um-
'Cause I didn't hear it.
Nope, nope. You got it.
It isn't NPDR. Got it.
Non-proliferative diabetic retinopathy.
Yeah.
I mean, that's where the highest value is, because you want to actually prevent these patients from developing PDR.
Mm-hmm.
That's the majority of the population in the clinics today. When you actually stratify the patient population with diabetic retinopathy, the largest number of patients that are sitting in the clinics, both in retina and also in primary care ophthalmology setting, are patients that have this non-proliferative diabetic retinopathy, which is a ticking time bomb for them to get to those stages of PDR and other vision-threatening complications. So that's where we find the highest value, is if we can stop the progression in those patients, that's really a game changer.
You have selected, is it dose level two you're moving forward, or you have dose level three that you'll be taking on?
Yeah, I mean, it's, you know, we continue to evaluate this. But, you know, we know we have a dose that we can carry forward right now. Then it really becomes a view coming into second half on which dose will be going forward. Just given the data set we have in our hands already, we feel very confident.
Okay, great. I want to move on to the other programs of top of mind for many investors. Obviously, DMD 202, and I'm sorry, RGX-202 and DMD, rather. One of the key questions we get, obviously, with the landscape as it is right now, is how to think about your opportunity, the population, given Sarepta's potential for final approval, how their expansion might turn out. Where do you see how do you see this impact? What are the scenarios, and how do you see this impacting your commercial opportunity, your opportunity in general, for this population?
... Maybe I'll give some broad strokes, and, and if you have any questions on regulatory, I'm gonna bring Nina in because she-
Mm-hmm
speaks to the agency every day.
Sure.
So let's just kind of think about the big picture here. Our construct itself is based on the fact that we have something that looks and feels like natural dystrophin, and the idea there is that should translate into better outcomes for patients, generally speaking. We have a muscle-specific promoter, which also makes the entire asset a lot more in terms of transduction and such. The data continues to show that what we have invested into is translating into those type of outcomes. When you think about the DMD market, you know, about 50% is ambulatory, and other 50% is non-ambulatory. And the 50% of the ambulatory, pretty much 50% of that population is eight years and above.
Mm-hmm.
And another, you know, 10%-12% is less than 4, and, and then about 20% is at 4-7. So you take those age groups, and you kind of stratify, you know, how, how that could potentially impact, coming on the other side of the competitor's label. There's just a ton of lots of, patients that are, that are just eligible on a treatment basis that won't be, met both on a age and supply basis, just given where things are today with, with the, with the competitive environment. And there is also a serotype exclusivity, as it, as it relates to the, competitor serotypes versus what we have. So that itself, we believe, is about a 15% exclusivity, on, on the basis of, sero- pre-existing immunity and such.
So you know, you kind of translate all of those, and then ultimately, these markets will become incident markets, too. And with a potential best-in-class asset, we have an opportunity to carve out majority of those incident population, on the basis of treatment eligibility, as well as, you know, the thoughtful investments we've made into, DMD, generally speaking, on a manufacturing basis, and having a, suspension process that has been scaled up to 2,000 liters, at our internal GMP manufacturing facility. Just gives us advantages on the basis of, having cost-effective, manufacturing process that supports high doses, in the world of gene therapy.
Right. So just going back to, I guess, the potential outcomes, Nina, maybe you wanna pipe in. How do you see the FDA looking at the landscape right now, and how—what are some of the considerations they are taking when they consider an approval for a competitor that has some clear limitations as far as with the population they can target, as well as some limitations for supply? You know, I would think the FDA is considering all of these aspects, so what's your thought on this?
Yeah, I agree, and I obviously can't speak for the agency, but some of the topics that have been discussed include all of those that you just noted. Obviously, Elevidys right now is currently limited to only those patients without pre-existing antibodies and corresponding label restrictions that they have, right, to ambulatory patients, ages four to five. And while we all wait for the determination whether or not the data submitted supports traditional approval and broadening of the label, we continue to hear from patients and their families of the need to have treatment options, and FDA's hearing this as well. Families are enthusiastic about additional AAV gene therapies, and they share that they are willing and eager to participate in the development of potential next-generation therapies.
The community has requested transparency around data for safety and efficacy around all these age groups, and we are the only ones that have dosed a wide age range of 4 to 12 with no SAEs, where we've shown data, and especially with double-digit data in terms of micro dystrophin expression. So I think the agency will have to consider all of this, the continued unmet need in the field, and setting precedents for what it means for accelerated approval in gene therapy.
So it's surprising that time flies very quickly, but what's the next pathway that we should expect for DMD? You've got some data coming up in second half. How should we see the next few steps, as well as remind people what you're waiting for on the MPS II filing?
Yeah, so for DMD, we're excited to, for later this year, end a phase II meeting with the agency, where we'll have clarity on the pathway and the timeline. And then, we've said that by the end of the year, that we would be initiating pivotal studies for DMD.
With functional data in hand?
Um, yes.
available to you?
Yes. Yes, with patients that we've dosed, especially the earlier ones, right? In dose level I, we will have more data.
Okay. And then for MPS II, not to be forgotten—to file your BLA, which we seem to have completely, like, ignored here, but-
Yeah
... you do have a big filing coming up. So how, how do you see that proceeding? When is that on track for second half, and how does your infrastructure develop from there?
Yeah. So from regulatory perspective, we feel very confident about that BLA being submitted this year. We have initiated all those activities to support a successful submission. I turn it over to Ram for the infrastructure in terms of the commercial piece.
Yeah, Annabel, on a commercial basis, you know, these patients are all at a very concentrated number of centers of excellence. You know, we're talking most of these patients on the basis of a diagnosis and an early treatment or managed maybe in 5-6 centers in the country. And even on an expansion basis, it's about 10 centers. So it's a very prescriptive commercial opportunity, where the patients are very clearly identified and available. And the other part that's happening right now in the marketplace is newborn screening for MPS II.
It's already been implemented in about 50% of the states, and by the time we come to market, we think almost it would be adopted on an 80% basis, which, again, makes the identification of patients through that journey to getting treatment a lot more efficient. And we are the only trial that have actually recruited patients less than 5 years, and a strong portion of those patients in our pivotal are actually less than 2. So we, we have data to support, on the basis of newborn screening, that we could treat these patients early on, and, and the long-term data on a neurocog trajectory basis is suggesting that earlier treatment is better. I think we have value in every single patient, but, you know, the more you can preserve, the better the outcomes.
You know, on the other side, what's come through for us at a pivotal dose in our pivotal trial is that patients are discontinuing ERT, so which truly translates 121 into a one-time treatment. I think it really sets us apart, even on a competitive basis, that we are solving for the burden of treatment that exists with ERT today-
Yeah
... single treatment.
All right. Well, that's great, and unfortunately, we're over time. But thank you for that run-through. There's a lot going on here, so, for anyone who is interested, you've got three or four programs that you can sink your teeth into there. Thank you all for participating. Thank you, Ram and Nina, and we'll talk soon.
Thank you.
Take care.
Bye.