REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Good afternoon, everyone. My name is Gena Wang. It's my great pleasure to introduce our last but not least presenting company today, REGENXBIO. With us today, we have Steve Pakola, Chief Medical Officer.

Steve, so maybe I'll start with the big picture question. So how do you plan to achieve the new strategic goal of 5x25?

Great. First, thanks, Gena, for having us. It's always great to be down in Miami and get a chance to chat and meet others. Yes, so our 5x25 plan. So this is a plan that our CEO, Ken Mills, announced last year, where we target having 5 programs, either our own or licensed programs advance to pivotal or commercial stage by 2025. And we as a leading AAV gene therapy company, from a scientific standpoint, clinical development standpoint and also manufacturing and CMC expertise, feel we're very well positioned to achieve that. It's going to take a lot of execution though. So that's the key part, particularly in my house in terms of development. We're already a good chunk of the way there in terms of getting into pivotal development. As you know, our lead program, RGX-314, an anti-VEGF gene therapy for treatment of VEGF-driven retinopathies like wet AMD and DR. We are over a year into our global strategic collaboration with AbbVie, and that's going extremely well. And our lead program subretinal delivery for treatment of wet AMD is advancing nicely, in pivotal development already with 2 ongoing Phase III studies, non-inferiority design studies against on-label anti-VEGF agents. And within the RGX-314 overall franchise, we and AbbVie are very excited to be advancing suprachoroidal delivery, which is a nonsurgical approach to delivering onetime treatment, and we have Phase II trials ongoing in collaboration with AbbVie for treatment of wet AMD and also treatment of diabetic retinopathy. Last year, we had several updates where we showed good safety and tolerability and also, importantly, clinical proof of concept based on validated endpoints that are important even from a regulatory standpoint. And given those results, we and AbbVie decided to expand both studies and add additional cohorts to both of those, and we initiated those in the second half of last year. And screening has been going really well, so well that we updated our guidance to say completion of enrollment in the first half of this year, which gave us the confidence to also guide to initial interim results from the expanded cohorts in both of those studies in the second half of this year. So I think those could be 1 or 2 more on the checklist of the 5x25, depending on how the results that we and AbbVie see at the end of this year, considering how we might move forward. And then we have another big update in the last 6 months on our rare side, our MPS II program, RGX-121, for treatment of Hunter syndrome or MPS II, where based on the results that we have to date and a lot of very good, constructive, collaborative regulatory discussions with the FDA, have advanced that program into pivotal stage already. And execution there is really getting 10 patients treated with the dose level 3, the dose that we've completed a cohort on previously, and where, importantly, we're now using the commercial-ready process, the bioreactor suspension process, that is really a great advance for us using our NAVXpress platform, which we can produce at scale up to 2,000 liter. And we control our own destiny, as Ken and Vit like to say, in that we have built up -- we have 18,000 square foot manufacturing and analytics and lab space where we can produce GMP material ourselves for later-stage development in DMD. And on one other thing, in terms of milestones for this year, is because we've advanced to initiating the first-in-human study in Duchenne with RGX-202 and also announced that we'll start dosing this half of this year. We also will have initial interim data from that trial as well in the second half of this year. So a lot of execution to deliver on that 5x25 plant.

That's clear. Before I dive into specific program, I just wanted to ask about cash. Question, I think you did guided previously, [ cash one way ] into 2025. And I assume that will be taking into consideration of a 5x25 plan, right?

That's correct.

And then maybe a related question. Any SVB exposure?

Yes. We do not, on the Part B. And then Part A, we, yes, continue that guidance. And I think in terms of our cash and...

The Silicon Valley...

Yes. So there, we're clean.

You are all clean.

I know that's -- I guess that's a mandatory question here. [indiscernible] any meaning. But on Part A the cash and -- so yes, so that guidance hasn't changed. And there's also the factor of certain milestones that we could get from our global collaboration and other sources as well.

Okay. Very helpful. So I wanted to ask you about the DMD, because this is a new program. And actually, we did get quite a lot of the inbound questions, especially given current competitive landscape. So maybe starting with the key differentiation from your construct compared to, say, Sarepta, Pfizer and Solid construct. And what is the -- why the functional -- like CT domain is so important?

Yes. Great question. We know there's a lot of interest in this space, and certainly Sarepta, in the near future. We're very positive also from a regulatory standpoint of the direction that things are going in terms of consideration of accelerated approval, et cetera. I think one thing I'd say even separate from the individual treatment approaches and constructs and vectors is the reality of how many boys are out there needing treatment. So we've always viewed that this is an opportunity to fill an unmet need that is going to take more than 1 player. And certainly, with those advances on commercial scale manufacturing and our expertise in that, at 2,000 liter suspension, we also think that we have the ability to efficiently produce at large scale to supply a pretty high vector load requirement that is generally for muscle-directed diseases. Now into the individual programs after that. Another, I guess, easy component even before the differentiation of the transgenes is the different serotypes. So out there is Rh74 and AAV9. Ours is AAV8. Obviously, we have a lot of experience with AAV9 in our CNS programs. But there's an automatic differentiator right there in terms of serotype immunogenic status of patients, where there's always going to be some subset of patients who may be seropositive for the vector that's used in the Sarepta program, and therefore they won't be able to be treated with that product and vice versa, when patients who will be in the minority of patients who have seropositivity to AAV8 in our case and down the road, AAV9 for Pfizer, depending on where that program would go. So those are the kind of broad aspects that there's definitely going to be room for more than 1 player. As far as differentiators and why we're excited and the community is excited, traditionally the existing microdystrophin transgenes, because of the size limitation in terms of cargo packaging that's inherent with AAVs have not included the C-terminal domain in the key components of that. And our CSO, Olivier Danos, who's worked in Duchenne for I think over 3 decades now, this has been something he has been our working on ever since joining REGENXBIO, taking his expertise on that and combining it with gene therapy expertise and his lab of finding a way to include that key component the C-terminal domain. And the reason that's so important is we know the C-terminal domain is key for recruitment of key intracellular proteins that are important for the optimal function of dystrophin, native dystrophin, or in this case, microdystrophin, in terms of anchoring to the cytoskeletal structure in terms of actin and microtubules but also in preventing contraction-induced stress. And that, in part, was theory, but we've since confirmed that and Olivier Danos has confirmed that in preclinical results with the mdx mouse model, where with the C-terminal domain included in a construct, we were able to have those key dystrophin-associated proteins demonstrated immunohistochemistry-wise present at the cell membrane. So that's dystrobrevin and NAS, so the key components that lead to better functioning. There's also other advantages that we have in terms of the benefit of learning from gene therapy best practices over time that we're able to incorporate that wouldn't have been possible with earlier generation products such as CpG deletion, getting rid of those, to decrease immunogenicity and other codon optimization approaches. So it's really that constellation of molecular advances, both transgene and outside the transgene plus those broader considerations that have us excited about differentiation.

So you mentioned AAV8 and Rh74. And if I recall, actually these 2 has close to 90% homologous sequence. And that trigger early days sort of IT dispute between Sarepta and REGENX. So maybe 2 questions. One is since they have a high overlapping sequence, like in the real world, how much we know in terms of -- I think we know less Rh74 other than Sarepta. Everyone else using AAV8. So what is the -- how much overlap in the real-world patient population that -- in terms of existing neutralizing antibody? What is the overlap there? And the second question is any update on the IP part.

Yes. So great question on the cross reactivity potential. Given the immuno acid sequence similarity, it's an appropriate question. Our aspect -- as you referred, we know a lot more about AAV8, and we know even in older population, where there's more time to have been exposed to AAV8, that only 30% to 40% or so -- about, let's say, 40% of patients have neutralizing antibodies to AAV8. We know that from external data, but also from our own wet AMD and DR data. Neutralizing antibodies don't matter for subretinal, and we're still evaluating whether they matter for suprachoroidal. But anyway, we've learned from that experience that it's a minority of patients. We don't -- long story short, we don't have a clear answer on exactly what that Venn diagram will look like. Presumably, there's going to be a component of that where a patient who is seropositive for one will wind up being seropositive for the other. I think that's the kind of thing we're going to learn more as we ramp up. One nice thing we're doing in addition to the Duchenne, the AFFINITY DUCHENNE, the intervention study is we also have a screening protocol where it will be really a nice theater into the intervention study but also will allow us to screen a lot more patients to know the rate of NAV positivity in this specific patient population. On the IP, as Chief Medical Officer, I don't stay as close to the IP, and I don't think we've had any additional guidance on that. That's my easy out.

Understood. So maybe -- okay. I'll ask you more clinical questions. So why are you using prophy SOLIRIS?

Yes. So SOLIRIS, eculizumab, a complement inhibitor, we did decide to include a short course of that as prophylaxis in our first-in-human study in RGX-202. Historically, complement activation has really been seen almost predominantly with AAV9 at this level of dosing. And I know other non-AAV9 programs, therefore, may not be using or deciding to prophylax. Our view was abundance of caution. This is the first time we're dosing in the clinic. It's easy enough to evaluate and then later decide to get rid of that component of prophylaxis. And I think one of the nice things is we have a lot of ways to, with laboratory assessments, look for subclinical very early, very sensitive ways of even small amounts of suggestion of complement activation, where if in a setting of short course SOLIRIS prophylaxis, we do not see complement activation. That combined with the lower probability, since it's not AAV9, we later and later develop and would always have the opportunity to take that out.

Okay. So can you walk us through how long is the prophy regimen of SOLIRIS? It's from which day to which day?

Yes. It's days to a couple of weeks before and similar on the back end. The reason there's a range there is it's dependent on weight of the child, of the boy. So very light subjects need less of a ramp-up and then heavier boys will need longer. So we're in the days to a couple of weeks kind of range. which is also why we have comfort around it. It's not a long-term consideration. And again, later in development, we can always reassess.

So at what point you would be able to detect the complement, like be able to make a decision? Like if your patient on SOLIRIS had the ramping up and then weaning off, at what phase you would be able to detect the cells can tell you that you do not need this?

One of the things the field has learned is through the complement activation cascade. You start to see signs of that, for example, in the AAV9 setting across different programs relatively early, even in the first few days, around day 5. So we have lab draws in those early time frames that are really going to allow us to see do we have any suggestion of complement activation or not pretty early on and across the first few patients to really reassess based on that.

Okay. And then for the first data update second half this year, 3 months [indiscernible] data, like any thoughts, the benchmark there and also your starting dose, 1E14, giving -- if we look across different competitive landscape, that should lead you to the -- within the therapeutic window. And then do you have any benchmark in terms of the initial data you'd be looking for?

Yes. So we'd started dosing first half of the year and a 3-month time point for the muscle biopsy, microdystrophin protein expression. Our goal is, by the end of the year, to get as many patients as we can with that endpoint. We do have staggered dosing initially, given a first-in-human study. So that will limit how many patients we can have 3-month data for it. But we'll still shoot to have as much as we can. As you mentioned, 1E14, historically, we would expect to see signal at that dose. And even ethically, from a regulatory standpoint with a onetime gene therapy, you should be starting at a dose where you have apropos to believe that you can have benefit for the children, in this case, the Duchenne boys. So we do have a belief that we should see signal here. And our second cohort will double the dose. We'll go up to 2E14. So we think we're in that range where we should be seeing something. As far as what to see on that, it's challenging to cross compare, as we know, from different programs with different assays and the different endpoints. But we'll be looking at all of those in terms of percent of cells with microdystrophin and percent expression. And from the literature, you see all kinds of ranges of what's been seen. So we'll take advantage of that breadth of experience. And we think, pound for pound, so to speak, with the differentiating aspects that we have that are independent of the level of -- the molar level of protein that you express that relative functioning and stress-resistant level that is imparted by that. If we're in that range, I think that will give us even more confidence.

Okay. I know we only have a few minutes left. I do want to ask one of more advanced program, wet AMD program, especially on the suprachoroidal. So the Cohort 6 data, which we likely will see later this year, so we know that you started with the prophy steroids. So what is the benchmark you think it will be competitive clinical profile with suprachoroidal delivery? And then with Cohort 6, what you are looking for?

Yes. So Cohort 6 is the same third dose level as used in the prior 2 cohorts. But as you mentioned, with short course local prophylactic steroids, the goal here is twofold: gather more data at this dose; and also see how immune modulation with a short course of steroids might impact safety and also maybe even efficacy. From the safety standpoint, which is really the key aspect, we do know without prophylactic steroids from the prior 5 cohorts that -- there is some, albeit small, risk of intraocular inflammation that fortunately has been easily controlled with short course steroids and disappears within days to weeks with standard steroids. So very different from characteristics that have been seen with other routes of administration like intravitreal. So we were already encouraged by that. Now we and AbbVie still think that's great, but lower would be better. And since all other programs have used some form of prophylactic steroids, it seems an easy enough thing for us to consider evaluating. And now is the time, while we're in Phase II development, and these initial studies actually assess that. And I'd say the bar is lowering intraocular inflammation rates and seeing if we can even prevent intraocular inflammation. I don't think preventing is a requirement at all because any time you inject into the eyeball, even with approved therapies, anti-VEGF agents, there's some risk of intraocular inflammation. And it's just a matter of how closely you look for it. So we know even in the label for ranibizumab, for example, there's one study that was like 18% intraocular inflammation because it was an early study, and they were looking very closely. So I think that's the -- the bar is lowering it, which would be good. And ideally, we'd have it closer to 0, the intraocular inflammation.

And what about the efficacy part?

Yes. So we've conservatively had a target profile from a minimal target of what would be required to have a value proposition that's compelling for the treating physician and the payers and the overall community. And we've, in the past, talked conservatively about greater than 50% of patients who are injection free. And that should translate into an even higher percent reduction in treatment burden overall, because there's not only those patients who are injection free, but the others who still need some top-off injections from our experience, have a lower rate of injection than they used to. From the data we have, we'd like to shoot for even higher, but we talk about that from a conservative level. But the data we have in suprachoroidal delivery looking at dose level 3 and in a setting of prophylaxis, we can -- we've achieved higher than that. We can look to replicate that in Cohort 6.

Great. I know we are running out of time, but thank you for the update, and we look forward to the data update later this year.

Great. Thank you.

Thank you. Thank you, everyone.