REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Good morning, everyone, and thank you for joining us at the UBS Virtual Healthcare Conference Day 2. I'm excited to have the REGENX management team here with us for a fireside chat, and we're joined by REGENX Chief Medical Officer, Steve Pakola; and Chief Scientific Officer, Olivier Danos. Gentlemen, welcome, and thank you for making time for us.

Good morning Esther. Thanks for the invitation. We're glad to be with -- here with you.

Good morning.

And I apologize for not being on camera. We've had some technical difficulty. But perhaps, Steve, maybe you can start us off with what's on tap for the rest of the year and give us an overview of where things stand with REGENX and what we should be expecting as the year progresses?

Great. Yes, I'd be glad to give you a snapshot of REGENXBIO and what's on tap for the year. For the listeners upfront, REGENXBIO has been a leader in gene therapy for more than a decade and have really been a pivotal force in advancing the curative potential of gene therapy. And we've done this in part by advancing our own broad pipeline of gene therapy programs with multiple ongoing clinical studies, that I'm sure we'll hit on in the Q&A. And these include a pivotal trial for our lead program, RGX-314 for the treatment of wet AMD and also a planned clinical development to start with RGX-202 for the treatment of Duchenne muscular dystrophy with an IND submission planned for mid this year. our NAV technology platform has enabled the development of commercialized therapies and numerous gene therapies in clinical development. And these programs are both ours as well as some others from our partners across a range of therapeutic areas and happens to include Zolgensma for the treatment of SMA, which is with Novartis now. We're also leaders in gene therapy production expertise and capabilities with a new cGMP production facility coming online and this is expected to allow us to scale up to 2,000 liters using our platform suspension cell culture process. So quickly just to run through our own internal program as a backdrop to the Q&A. Again, our lead program is RGX-314. We believe RGX-314 has the potential to profoundly impact all aspects of clinical management for patients with wet AMD and diabetic retinopathy and could be a one-time gene therapy treatment option for a broad range of patients who currently rely on repeated anti-VEGF injection therapy. We're currently completing a Phase I/II trial on wet AMD with patients now out up to 3 years since dosing and these patients have shown stable and improved visual acuity as well as anatomic response and importantly these outcomes have been achieved with a meaningful reduction in anti-VEGF injections. We also recently initiated our first pivotal trial for treatment of wet AMD, the Atmosphere study, and we look forward to moving towards a potential BLA filing in 2024. In addition to the lead program with subretinal delivery of RGX-314, we're also evaluating a novel route of administration to the suprachoroidal space, which allows for an in-office procedure where we use the SCS Microinjector and we're currently enrolling patients in a Phase II trial for treatment of wet AMD using this route of administration and this is going to allow us to have data -- initial interim data from the first 2 dose cohorts from this trial later this year. We have another study looking at suprachoroidal delivery of RGX-314 in a Phase II study for treatment of diabetic retinopathy. And this is important because we know anti-VEGF repeated injections do work for treatment of diabetic retinopathy and there's actually on label for Lucentis and Eylea, but the treatments are simply not being given doctors and -- their patients are not signing up for this treatment because of the unsustainability and the significant treatment burden of repeated injections. So that's our lead program for retinal indications. We're also leaders in CNS delivery of gene therapy. And in this platform, we have RGX-121 for treatment of MPS II and RGX-111 for treatment of MPS I, 2 lysosomal storage disorders that have significant neurocognitive, neurodevelopment complications that are not addressed with existing enzyme replacement therapy. And we've reported interim data from the RGX-121 trial, which has shown biomarkers and measures of neurodevelopmental function up to 2 years after dosing, which indicates CNS activity of RGX-121, may be more -- at least one of the really intriguing things we've seen, Esther, is signs of systemic enzyme expression and biomarker activity even from our CNS delivery platform. So that's some of the data that we'll look to mature further out. We also recently announced development of RGX-202, a potential single administration gene therapy for the treatment of Duchenne muscular dystrophy. And so we're glad to have Olivier here with us today who is a -- I can say this, he wouldn't say this humbly, but he's really one of world experts in research and development around Duchenne muscular dystrophy. And through his leadership over the years, we've advanced development of a novel advanced microdystrophin construct that we're working diligently towards an expected IND submission mid this year. So a lot of stuff, Esther, we can talk about. So Olivier and I are at your disposal.

Great. That's quite a bit to cover, but we'll do some fast talking here.

Yes.

So let's start with the anti-VEGF agent and maybe a big picture question. This is a -- this is a rapidly evolving therapeutic landscape, and there's some degree of controversy surrounding single administration, vector-based approaches, such as yours. But can you talk about where you think 314 could fit into the treatment paradigm moving approval? And if you can talk about the different patient groups, wet AMD versus and PDR and where you are targeting your attention as you're developing these -- this agent, that would be very helpful.

Sure. So big picture, as you said, it's a dynamic space and really some great advances in retina that over the last more than a decade has centered mainly around anti-VEGF treatment. So that has certainly been a major breakthrough in the treatment of VEGF-driven retinopathies, like wet AMD, diabetic retinopathy complications and Retinal Vein Occlusion, RVO. And what we know is repeated anti-VEGF injections definitely work. And if given on-label or even anything close to on-label, have a tremendous benefit for patients in terms of preventing vision loss, what is the most important outcome that we want for these patients. What this has also taught us, though, is that repeated injections indefinitely is a tremendous treatment burden that no matter what we see in the pivotal trials where there's very strict follow-up of those patients and very strict following of repeated injection dose regimens that in the real world, patients are simply not getting the treatment that they need to preserve vision. So over and over again, we see follow-up of the pivotal studies and also real-world data registry outcomes where patients are continuing to lose vision and continuing to go blind in some cases because of under treatment. The validation really of how much of an unmet need this is, is really what we see going on, where there continues to be advances in development of other approaches to extend the durability of anti-VEGF treatment approaches and we're seeing some successes in this regard, like Beovu other than what's more recently held that back in terms of the occlusive vasculitis. But other approaches like Kodiak and also repeat, refill approaches like Roche/Genentech PDS. And these are all nice incremental advances that show the value that exists for making a more tolerable or sustainable way to deliver anti-VEGF treatment. So for us, the ultimate way to achieve this would be a onetime sustained foundational delivery of anti-VEGF. So that's why we're excited about onetime gene therapy as a potential to address this unmet need and potentially also have a better treatment approach by having a steady level of anti-VEGF on board as opposed to the traditional peak and trough and variability that is associated with that, which many studies are now showing is also an independent predictor of bad visual outcome for these patients is the variability of the control of the disease because of the peak and trough, repeat dosing type of approach. And then also, of course, noncompliance. So that's why we're going after wet AMD and that's also why we're going specifically after initially on the DR side of things after advanced DR patients, but before they've developed the blinding complications of either DME or advanced proliferative disease and its complications because this, again, is a population where we know that repeated anti-VEGF injections improve diabetic retinopathy severity and thereby prevent patients from developing blinding complications. But doctors and their patients are just not signing up for it. So the doctors and the patients need a more sustained delivery treatment approach that will allow these patients to get the treatment they need to prevent advancement to the blinding complications of diabetic retinopathy.

Understood. That's helpful. So I think if I can -- I don't want to put words in on your mouth, but what I heard you saying is that it's really sort of the sustainability of the drug level in the eye and reducing that variability patient to patient and even over time period is what makes your approach more attractive than even what's in the clinic right now with some of the novel agents that are promising to increase durability?

Yes. I think that's true for most of what's out there is that most of it is trying to either pack more molecules in or have a more sustained delivery approach of anti-VEGF. So there's also faricimab, which is a nice incremental advance via using an additional mechanism. But either way, they generally involve still a peak and trough kind of concept and also still require repeat dosing. So it's certainly valuable to get from existing every month, every other month, occasionally, every 3 month dosing in the traditional treatment extend approach that's used in the real world, getting from there to having more patients with potentially every 4 months or 5 month or even every 6-month treatment regimens with some of these incremental advances, but they still involve the continued repeat injection plus, in many cases, this peak and trough concept.

Understood. Thank you. So talking about subretinal, perhaps. Can you talk about what particular patient profile is ideal for the subretinal treatment?

Yes. So one of the nice things right off the bat was subretinal delivery is that we know that, that space, where we're delivering the drug is relatively immune privileged. And that has a couple of important implications. One is, to your point, about the population is, we don't have to exclude patients who have pre-existing neutralizing antibodies or NAVs to our vector AAV8, which fortunately, in the population, it's just 30% to 40% of patients who are positive for preexisting neutralizing antibodies. But still, we don't have to worry about excluding those patients from treatment, unlike with other approaches that go with, for example, intravitreal administration. In our trials, we include pseudophakic patients. In other words, patients who've already had cataract surgery. In a Wet AMD population, it turns out these older patients, often 80 years and older have already had cataract extraction. We believe gene therapy with subretinal or suprachoroidal delivery would work just as well in patients who haven't had their native lens taken out. The only reason we exclude them in our clinical trial is because of the confounding impact of any cataract development would have on our primary endpoint at 1 year after treatment. So generally, it would be a pretty broad swath of the wet AMD population. Key factors would be since the mechanism is anti-VEGF, we would, in our trials and in the real world, it would be patients who are responsive to anti VEGF treatment. So for example, in our pivotal study that we started we require that a patient has a screening Lucentis injection and has at least some response anatomically, based on OCT measurement to that screening injection. Fortunately, most patients do have a response to anti-VEGF, but there is a minority of patients who have very minimal or recalcitrant to anti-VEGF. And those wouldn't be patients who would be ideal candidates for our trial. Otherwise, it's a pretty broad population. If your question is directed more to what would be kind of a sweet spot, who would be maybe the patient's first in line, so to speak. No, it would be that broad range of patients who, yes, they're responsive to anti-VEGF, but they still need reinjection every month, every 2 months, every 3 months, and in cases where patient by patient, there's a particular sensitivity to the treatment burden even patients who need less frequent injections. So those would be patients where the alternative of a onetime treatment would be particularly compelling.

Got it. Okay. Maybe switching gears here a little bit to the suprachoroidal administration. You have 2 important readouts. One, in the third quarter, it's an interim for the Phase II wet AMD and later in the year for the Phase II for NPDR. Can you help set expectations for what we should expect to see and where the bar is in your mind for what is acceptable and what is great?

Okay. Great. So I'll start with the AAVIATE study, which is our SCS delivery for wet AMD. That one to set expectations, it fits very much with how we look at looking for a treatment response with sustained anti-VEGF that we looked for and showed in our prior subretinal Phase I/II study of our 42 patient study where even during that study, we always talked about with this disease, looking for 6 months data as really the initial interim time point to be assessing the key readouts that we would care about. So a lot of that is the same here. So first, though, before I get into the efficacy pharmacodynamic side, this is the first study ever looking at suprachoroidal delivery of gene therapy. So first, safety, tolerability. So one aspect is that, of course, and that would be the typical readout that you can look at our precedent there for what we show. On the pharmacodynamic efficacy side just as again how we're used to looking at in our subretinal program as we've given these readouts now out to 3 years for cohort 3 in that study. It's a lot of the same -- the usual suspects. So is it working anatomically? So we have the benefit of looking at retinal thickness and fluid on OCT, how is that translating to visual acuity, are we showing stable to improved visual acuity and importantly are we able to achieve good anatomic and functional outcomes with decreased treatment burden? So we'll look at what the treatment burden was in terms of anti-VEGF need for these patients before they entered the study and also be able to look at whether they've needed anti-VEGF supplemental injections during that 6-month time period or not and if they have needed it how frequent was that, was it more, same or less than what they needed before. We also have aqueous humor samples that we get during the trial. That tends to lag the real-time clinical and imaging results that we can turn around very quickly because we do batch analyses, and the time to do the analyses, do the QC, et cetera. So that sometimes can lag. But certainly, all the clinical safety, tolerability and efficacy measures that we've shown in the past are a good road map for what to expect there. The DR, this is the second study ever done with suprachoroidal gene therapy, which kicked off just a couple of months after we started the wet AMD study. Here, this is a different disease with different ways of looking at treatment response than wet AMD. And it's also a treatment setting where we have the benefit of a true control arm that doesn't involve giving any anti-VEGF because of what I mentioned earlier that in these advanced DR patients without the blinded complications yet, although it's on-label to treat these patients with either Lucentis or Eylea repeatedly and definitely as soon as you stop giving those injections, the diabetic retinopathy severity starts to come back. So it's still standard of care to watch these patients given weighing everything about the option of watching versus proceeding with repeated injections indefinitely. So that gives us the benefit of a control arm and one of the benefits there is that we know historically from other control arms in prior studies like PANORAMA and RISE and RIDE and other studies that have been done in a diabetic populations that if the natural history of diabetic retinopathy, patients do not get better magically or spontaneously if you are not treating them, so the placebo response rate in other words patients who get meaningful improvement in diabetic retinopathy severity. In other words, an improvement of at least 2 steps on the DRSS scale, that happens in a small fraction of patients. So for example, 5% or less if you look at 6 months of follow up in patients who are not getting treated. Whereas if you are getting repeated anti-VEGF injections, we know in this particular range of diabetic retinopathy severity patients that a sizeable percentage of these patients do improve by 2 steps. So for DR, we're -- and that's one of the reasons as we chose going into DR and this indication as opposed to for example DME, or a PDR is that the odds of -- the probability of success is high and the understanding or the risk of having uncertain results because, for example, a control arm response rate is less likely, given what we know about the natural history of this disease. Now I say probability of success high if we have sustained anti-VEGF. So that's really what's exciting about the study to really test suprachoroidal delivery of RGX-314 to provide that and see if that translates into -- with a onetime treatment, really an effect on diabetic retinopathy severity.

Understood. So maybe even just taking a step back a little bit for suprachoroidal administration. Can you walk us through your thought process on, like you said, it's a novel approach of administering gene therapy. So why is that important for vector-based therapy specifically and some of the pros and cons versus the approaches that attempted to deliver AAV using intravitreal injections?

Yes. So over the years, we've followed and also evaluated with our own vectors and Olivier has led a lot of this work for us. And very early on, it became clear to us that a subretinal delivery for some of the reasons that I mentioned is really the gold standard. However, it does involve a surgical procedure. So to expand the optionality of gene therapy, anti-VEGF delivery, the potential, if we could evaluate an in-office nonsurgical treatment option that could open the door to other indications like diabetic retinopathy, for example, where, although these patients are at a very high-risk of advancing the blinding complications for right now, they're still asymptomatic. So the option of a onetime in-office approach is a stronger risk-benefit profile to consider for that particular treatment scenario, just to give one example. Also very early on though and looking at potential in-office approaches, we evaluated suprachoroidal as a better option than intravitreal for a couple of reasons. One, like subretinal, it's local delivery. So you're delivering the payload, very close to the target retinal tissue. And number two, you do not have the risk of the inflammatory response that in part seems to be related to the expected anterior efflux of intravitreal payload into the anterior chamber and outflow system through Schlemm's canal, trabecular meshwork, but then going through anterior chamber, eye structures like iris, ciliary body, et cetera. And perhaps associated with that aspect or others as well in our hands and in others like Peter Campochiaro's in small animal models and large animal models with AAV8 and including RGX-314, in preclinical studies, we have not seen inflammation in these models, even at doses higher than what we can go with in the clinic. And we've seen good expression in a broad area of the retina. And that's what's held back suprachoroidal delivery previously with first generation AAV vectors like AAV2 and AAV5, but again, the advance has really been with our NAV vectors, particularly AAV8 and AAV9. We have not seen the inflammation and maybe in part, because of that, we've seen good transduction and expression.

Got it. That's very helpful. I'm going to switch gears here a little bit and touch on your earliest stage asset, the DMB program a little bit. So with regards to 202, what -- can you help us understand what differentiates your DMB approach from several others that are perhaps more advanced in the clinic?

Yes. Maybe I can take this question. Can you hear me?

Yes.

Yes, we can hear you. Yes.

All right, great. Yes, thank you, Esther, for the question. So it's true that we're not coming first in this race and collective endeavor to meet the problem with Duchenne muscular dystrophy. Duchenne muscular dystrophy is due to deficiency in a very, very large protein that comes from a very large gene that doesn't fit into AAV and there's been a lot of activity over the past 20 years, trying to reduce the size of this protein. And fortunately, it is actually possible. And people have come with so-called microdystrophin, which are the therapeutic [ tail order ] that you can put into AAV. So the name of the game up till recently has been to eliminate as much as possible from the protein to be able to have a small transgene with tissue specific promoters, everything in there. That fits into the 5 kilobase of the AAV payload. And for this reason, people have concentrated on the primary function of dystrophin, which you hear about everywhere, which is this is actually a shock absorber that transmits the force from the contractile apparatus in the muscle cell to the extracellular matrix and actually in each [indiscernible] will then contract and transmit to the organ the contraction. So this is the molecule that really does the link that allows for contraction to occur. So obviously, if you don't have this molecule, the muscle is weak. It degenerates, it cannot withstand the stress of the contraction. And all the preclinical studies available now for many years, as I was saying, shows that those microdystrophin can fix this part of the problem. Now dystrophin is not only that. Dystrophin is also a very complicated protein that acts as a hub, an organizer at the cell membrane, which is called the sarcolemma and myocyte. So at the sarcolemma, dystrophin organizes a pretty sophisticated protein complex that has many functions and has many functions in signal transduction, in repair of the membrane after contraction, in recovery of the calcium homeostasis, in the physiological level of NO synthase then act on vasodilation and brings the needed blood flow to the muscle when it works. So all kinds of things that also are central to dystrophin function. And the current microdystrophin obviously retained part of it because otherwise, it would be totally nonfunctional, but they've left out a lot of them. And they left out a lot of them for the sake of saving space, right, and being able to put it into AAV. So we looked again into the problem, and we found that by doing a number of adjustments here and there, we would be able to fit more of the part of the dystrophin that actually organizes this protein hub. And this part is in the C-Terminal domain at the extremity of the -- at the C-Terminal extremity of the protein. And we've added an additional 150 amino acid protein domain there that actually is able to promote additional formation of those complexes. That happens through, again, let's not get into the details, which the whole thing is not fully understood. But what's clear is that they are very important proteins called alpha synuclein that binds there and recruit all kinds of protein that will then interact and fulfill their functions. Okay. So we believe that this would be a differentiator. It would be -- sorry -- and that's what we -- I mean, our choice was based on data from the [ George Dickson ] Group in London who had initially shown that by including this extra domain, you were able to have muscle that can recover from contraction stress much more efficiently than without this domain. So based on that, we made our construct, we've now finishing the IND-enabling study package and I'm very excited to get -- go into to start the trial hopefully before the end of this.

Got it. Okay. So a quick question on the ASGCT poster that you shared earlier this month. It appears the CT domain of the dystrophin, it's known to bind to 2 proteins, alpha-syntrophin and alpha-dystrobrevin. What are the roles of these 2 proteins that make interaction with dystrophin important?

Okay. So the alpha-dystrobrevin binds the [indiscernible] C-Terminal domain, it also binds the sarcoglycan, and therefore, through the sarcoglycan, it is already recruited, but not with full efficiency to the complex by the current microdystrophins. What we add here is an extra interaction with the C-Terminal and make a complex that's actually more efficient. That's what dystrobrevin is. For the syntrophin, for -- the syntrophins are proteins that actually act out as recruiters. They stick to the C-Terminal domain, and then they have themselves domain that will attract a number of protein, including nNOS, but not only nNOS. And what the -- sorry, nNOS being the neuronal NO synthase, that's important for vasodilation. So synuclein brings nNOS, but synuclein also interact with calcium channels and a number of things that are -- believed to be important.

Understood. And some of the feedback that we've heard from researchers in this space suggests that the cardiomyopathy aspect of the disease remains unaddressed with the ongoing clinical trials. So just curious, is that something that you think is relevant to explore at this stage, given where the treatment landscape is and the life expectancy for these patients now?

Yes. Very much, but a question here. The cardiomyopathy is a major outcome. Yes?

We lost you there for a second, sorry.

Sorry, I was saying that. Can you hear me now?

Yes.

Can you hear me? Yes. Okay. The cardiomyopathy is actually what those patients are nowadays mostly dying from. I mean the -- but this is a late onset, this is something that happens in adult patients. It's progressive, if you can detect it early on, but the disease, the cardiomyopathy disease actually appears very late. And this is true of patients, and this is true also of any animal models of Duchenne muscular dystrophy. So in the context of our trial -- of all the current trials including ours where we are targeting young patients, this is not -- we're not using the cardiomyopathy as an endpoint, right. Now obviously, we believe that some of this extra protein that will form the complex due to the presence of the C-Terminal, could have an interest in their parts. But this is also something -- this is something that's still being investigated. Up to now, the animal models for the cardiomyopathy were pretty much irrelevant, but people are now coming up with more interesting models and we're very actively looking into that using our construct. So you're right. This is definitely of interest. This is something that needs to be done. I wouldn't say that this is not [indiscernible] addressed by current trials. It's not built into trial to look at the heart, but these patients will be followed, hopefully for many years. And the jury is still out on the activity of the current microdystrophins for cardiomyopathy.

Got it. Okay. We're almost -- we're actually out of time here. But just one other quick question on the MPS II asset. So Steve, I think when we started out, you sort of talked about both potential for peripheral and cognitive symptoms of the disease. What -- I mean what is -- what type of dialogue do you expect to have with the regulatory agency on the pivotal trial design to sort of demonstrate efficacy in both?

Yes. It's a great question, Esther, where -- we've been assessing our encouraging biomarker data on the CNS side, so the CSF, where we are showing an effect on the specific GAG specific heparan sulfate that is mechanistically considered the best predictor for neurocognitive involvement in MPS II, for example. But also now that we're seeing evidence of effects systemically, this really opens the door to regulatory discussions in terms of both of those. So we're evaluating the biomarker data, the predictive value of that as we look for other functional outcome markers as that data matures. Of course, the difficulty is it just takes longer and more patients to show the functional aspects. Given the lack of treatment options for the CNS complications, we think there is a strong case as we build more data. The systemic aspect, yes, there's enzyme replacement therapy option there and other approaches that are being looked at. But these all still involve repeated treatment as opposed to a onetime treatment that certainly for the CNS aspect allows for what we call an inside out approach where you are actually having the cells create their own native enzymes and having local cross correction within the CNS tissue itself, which may have more efficient effect than outside in where you are putting enzyme into the system and even with these newer agents where you get -- you are trying to get across the blood-brain barrier from the systemic. So on the regulatory side, these are all the things that we now feel now that we have advanced and have biomarker proven concept and functional measures as well in the CNS and now biomarker results systemically, these are the aspects that we want to by the end of the year have flushed out and discuss with the FDA how we move from the existing dosings that we have into a pivotal plan.

Understood. and have you -- can you see a role for an NfL in the MPS patients?

Yes. That's a marker that some are looking at. We think the most direct marker for activity is what the enzyme does and which GAGs its breaking down and heparan sulfate in particular. It's still as far as some of the other more indirect ways to assess the more downstream aspects. I think the jury is still out on that. Olivier, you also are a expert in CNS aspects and...

No, I agree with you. The most relevant biomarker is the measure of GAG, although there are subtleties attached. We had to actually design bio assets for very specific subtypes of GAGs that are relevant to the activity of the enzyme that's missing in MPS II and that what we're replacing in these patients. But that's really the target for us.

Got it. Okay. Well, we are well over time right now. But this is a very interesting discussion, and I hope one of many. So thank you for your time. I really appreciate it. And now we look forward to staying connected.

Thank you. Esther.

Thank you, Esther. Thank you very much. Bye-bye.

Bye-bye.

Bye-bye.