REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Good morning, everyone, and thank you for joining us today on a weekend. I am Ram Palanki, Executive Vice President of Commercial Strategy and Operations at REGENXBIO. Earlier this morning, Dr. Charlie Wykoff from the Retina Consultants of Texas presented the interim data from our Phase II bridging study of onetime RGX-314 for wet AMD using subretinal delivery. These slides are available on our website on the Publications page at www.regenxbio.com. They're joining from remote locations today, Steve Pakola, our Chief Medical Officer from New York. He will provide a quick overview of the bridging study. He will then be joined by the bridging study investigator Dr. Charlie Wykoff from Texas and Independent Retina Expert, Dr. Peter Kaiser from the Cleveland Clinic. Steve will lead the discussion about the data with these retina surgeons. And at the end, we will have some time for questions and answers. Steve?

Thank you, Ram. We're very excited today to have data from our RGX-314 studies presented at Angiogenesis and in particular to have initial interim data from the Phase II bridging study presented by Charlie for the first time ever earlier this morning. This study is evaluating RGX-314 manufactured using the initial adherent cell culture process compared to RGX-314 manufactured using our proprietary NAVXpress platform process. This is the scalable process that is expected to support commercialization. Importantly, this process uses the same materials and steps, but with the suspension-based bioreactor process, allows for high yield at large scale. We're well equipped to use our NAVXpress platform process to produce cGMP material in our Manufacturing Innovation Center that scales up to 2,000 liters. This is a unique capability for us, which we expect to use across all our clinical trials, including for RGX-314. Before we jump into Q&A, Charlie, first of all, as always, that was a really excellent presentation you gave this morning virtually for the retina community. Could you summarize for those on this call, the new interim results that you presented earlier today.

Yes. Thanks. Good morning, good afternoon to everyone. Ram, Steve. Great to be with both of you and Peter, great to join you for this discussion. To me, this is quite meaningful data and important for a lot of reasons. If I take the 2 top reasons, first of all, it's clear validation now that the hyperstack and bioreactor process associated RGX-314 production appear clinically identical and indistinguishable, which is really important as clinical trialist. And then maybe more important as we look forward is that this is a sort of a sneak peek in my perspective about what the data from the Phase III program and Phase IIb -- Phase II/III program could look like, right? The pivotal trials that are ongoing, there is has very similar enrollment and retreatment criteria being used in those 2 pivotal trials. And so it's sort of a sneak peek on what that data might look like, which is quite promising to be able to talk about what that could look like from a commercialization perspective for us as clinicians seeing these patients on a daily basis. So if we talk briefly about the outcomes, first of all, the trial design, this was, patients had to have active disease at baseline. I can't overemphasize that enough. They had to have fluid when they came into the trial, quite different than some other programs out there, and they had to show responsiveness in the prospective component of this trial. They were all treated with a bolus injection of ranibizumab and then when they showed responsiveness, they were given subretinal RGX-314 during vitrectomy at day one. All patients were then retreated with a bolus ranibizumab injections 2 weeks later and then they were followed very carefully every month through 6 months and retreated as needed if they needed retreatment according to prespecified criteria. With that sort of core background, there were 2 doses that were studied. There was a lower dose at 6.4x10 of the 10th and a higher dose at 1.3x10 of the 11. And these doses were specifically picked on based on data from the long-term Phase I/II data that we've seen now for a couple of years. And then the outcome is, I believe 3 major points. First of all, safety. Safety looked good. There were 5 serious adverse events, none of them drug related. The most common adverse events were similar between the hyperstack and the bioreactor-produced cohorts. And then the 3 most common adverse events were your typical postoperative experience with subconjunctival hemorrhage; postoperative intraocular inflammation, which was observed in 9 eyes, 8 of which were mild, 1 of which was moderate, all began in sort of the typical postoperative period 1 to 2 weeks after surgery and all resolved with a sort of standard steroid topical drop treatment. There were no systemic steroids that used in this trial and no prophylactic steroids. And then third, we expected to see retinal pigmentary changes in the periphery inferiorly and we've seen that now about 13% of both arms. And then from a vision and anatomy perspective, you saw what you would hope to see in this trial, which was improving vision over time on average and a stable central rental thickness. And you'd expect stable central rental thickness here because, again, these are patients that have been previously treated and they've also received 2 bolus ranibizumab injections at the beginning of this trial before they're observed and retreated as needed. And then finally, from a treatment burden perspective, we're seeing a meaningful reduction in the treatment burden for these patients. It's always a little challenging to compare redosing to post-dosing frequency because you're using different criteria. We see that problem in every single one of these trials, looking at reducing treatment burden. But to me, the most meaningful number is the portion of patients receiving no re-treatments afterward and that being a substantial majority of the patients is quite meaningful to me. That's through 6 months. So quite promising. And I think it's really important to begin to digest this data as we think about the ongoing pivotal trials.

That's great, Charlie. Thanks for that nice summary of the presentation that you gave this morning. I'd like to now turn it over to you, Peter, as Ram introduced you, you are not an investigator in this particular study. But of course, as much as anyone in the field, you stay very close to not only all the approved treatments, but all the various experimental treatments that are being evaluated to fill the unmet need that exists within treatment of wet AMD. So as you look at these initial data, what are your main takeaways?

Yes. There are several things. First of all, congratulations, Charlie and REGENX. This is really very nice results. And as a clinical trial, as the bridging study, sometimes can be very scary, right? Because you're moving from sort of a small-scale clinical research processes that were in the past to a Phase III clinical trial-ready process and a commercial-ready process. And we've seen examples in the past where that jumped from clinical trial grade to commercial grade, things change. More inflammation, for instance, was seen in the past with other drugs. In this case, this bridging study really gives us a lot of confidence about this process, right? So first of all, you have now 30 more patients who've received at least the high dose. We haven't seen the low-dose results, but the high dose with minimal safety issues and excellent results in terms of producing the ranibizumab protein as well as reducing central subfield thickness and even in this case, showing an improvement in vision. So to me, that shows that moving from clinical grade or clinical trial grade to commercial grade, which is in the Phase III, should work, we hope. Obviously needs to be proven, but as a clinical trial, this was as good of a bridge study as you could have hoped for.

Great. And it's interesting. You're hitting on something Charlie mentioned the phrase, a sneak peek in a way since intentionally, we do have the same 2 doses, the low dose and the high dose, same exact dose in our pivotal program with our two ongoing pivotal studies atmosphere in ascent. So Charlie, you used that phrase. Maybe you can elaborate on how you would think about the relevance of the initial results in this overall study as to how you would be thinking about the ongoing pivotal program?

Yes. I think it's quite important, right, because we have now up to 4-year data from the Phase I/II program. We learned a tremendous amount with that program. That program with subretinal RGX-314 really was a first for many reasons in our field. And we saw that with cohorts 3, 4 and 5, all those patients had meaningful reductions in their treatment burden because of the production of an anti-VEGF protein inside the eye with this gene therapy. And then to be able to use that data to inform this bridging study and the pivotal trials was meaningful, but there were a couple of leaps of faith. For example, the doses of RGX-314 used in this program were different than any of the exact cohort concentrations used in the Phase I/II program. It was 2 doses of straddling, I think, between cohorts 3 and 4. So quite meaningful doses. We would expect good protein production, but again, different doses, you're not totally sure. So here and now to have this Phase II data showing meaningful protein production in the range that you would expect based on the Phase I/II data and also seeing very strong clinical outcomes for these patients with 60% to 73% of patients receiving no supplemental treatment after RGX-314 dosing with critically stable to improved vision and anatomy, I think it's quite meaningful. It shows that the doses that have been taken forward in the pivotal trials are going to be clinically useful and clinically meaningful. So it allows us to now begin to think about how we would potentially use this therapeutic if and when, of course, the pivotal trials show the same data. I think it's a reasonable step to conclude that these will probably be very similar patients. The inclusion criteria were almost identical between this program and the pivotal trials and again, the retreatment criteria, again, very, very similar, I think, actually completely identical. So I think it allows us to begin to have a discussion about how we could use this with the caveat, of course, that it has to be reproduced in the pivotal trials.

And we've spent the last few minutes talking about these results and the interpretation and the implications in a way of how we assess the ongoing pivotals. If I may, if we can kind of maybe step back and give our audience a broader perspective since we have the benefit of both of you as leading retina specialist surgeons, clinicians on top of being experienced clinical trialist. If we step back and look at the overall landscape of treatment of wet AMD patients and different treatment options in various stages of development. Maybe you could give our audience of a sense of how you evaluate and think about risk benefit and the overall profile that you're looking for when you think of treatments for your own patients in your clinical practice, that can allow us to gauge how we can think about different treatment approaches that will be coming forward. Why don't we start with you, Charlie?

Yes. I'm part of a large group here in Houston, 20 docs and then a large group across the United States. And there's no doubt that treatment burden is a very real problem. It's a problem from a patient perspective, in my opinion, most importantly. It's a struggle for these patients to come in as frequently as they need to. And we've certainly gotten better from the first time we were using anti-VEGF injections. Our current agents are more durable than our original agents in my opinion. But we need something that truly is more durable and not just more durable in my opinion, but something that can achieve truly the same outcomes as frequent bolus injections. And that's what this drug looks like, RGX-314 for a meaningful majority of patients that are eligible for this trial. They're receiving no retreatment after they get dosed. So if this were commercially available with this exact same data after a Phase III program, I would talk about this drug with most of my wet AMD patients or the large majority because they all ask every single visit on those docs, is this my last injection, even though you sort of described the paradigm repeatedly in the past. They all want something that's less frequent and potentially a one and done or a very infrequent retreatment. So patients are very interested in asking for this. There's no doubt. And then if I think forward, okay, well, who exactly among all those many, many patients could potentially be eligible, I think that answer is going to evolve over time, right? When this first comes out, I could see 1 in 5, 1 and 4, my patients being very interested in using this, right? Pseudophakic patients that have persistent fluid that are needing monthly dosing, that's a large percentage of patients. But then, of course, once you get good outcomes with those, I could see that number expanding meaningfully over time. I think we've learned a lot about the risk-benefit ratio here, and I think that this is going to be a quite meaningful addition to our armamentarium.

Great. How about you, Peter, anything to add to Charlie's view?

Yes. I mean I think we -- when we look at the anti-VEGF landscape, we have medications that appear to be, say, "4-month medications." We have faricimab that is approved up to 4 months. We'll see what the high-dose EYLEA gets approved for, but they had pretty good results up to 4 months. But there's two sides to this bell curve, right? So there are patients who do really great in both Charlie and I's practice, they probably could be 4 months, maybe even longer with some of these medications. And those are the patients who probably don't need this, but that's the one side what is being ignored in those clinical studies. And we saw that really most acutely in the Kodiak studies was there's a population of patients, 25% to 30% that are on the opposite end of the spectrum that require very frequent treatments even with our best medications, even when they're receiving EYLEA or faricimab, they're still at 4- to 6-week intervals. So there is very high need for an anti-VEGF agent. Giving something like this, we've now seen this in Charlie's work as well as in the Phase I/II, in a large population of patients, subretinal injections of the vector appear to be safe, a lot of the learnings from Phase I/II are put into the Phase III as well as this bridge study. And you can see the sort of things that we worried about were reduced in this, and we'd hope to see a similar reduction in the Phase III safety. But to me, this is not a difficult procedure. We are part of this study at the Cleveland Clinic. I am not an investigator in it, but it is not -- we're all used to doing subretinal injections. This is not a difficult procedure to learn for most retina specialists. So I agree with Charlie, this is going to be used. There's a large population of patients who would want it. But it's not everyone. I don't want people to think we're going to use this on everyone because there are patients who are doing well with our current medications.

Excellent. So although we zoomed out more broadly, both of you are hitting on some of the potential advantages of a onetime treatment where we have the benefit of the initial results that were presented from the bridging study and also Allen Ho presented some data that's been presented previously from the Phase I/II subretinal delivery trial where we see very good safety and tolerability out to 5 years and out to 4 years, the longest duration that we have efficacy data for, we see very good durability. Maybe you both could accent more how that particular aspect, the onetime treatment option would impact how you think of this treatment option compared to although greater durability, different treatment approaches that would still inherently require repeated injections. Peter, why don't we start this time with you?

Sure. It's interesting. When you think about this, most patients, and if you think about yourself, most patients don't like intravitreal injections. This is something that they do because it's a necessary evil. And they know absent treatment, they're going to lose vision. If you look at any of the real-world studies, especially real-world studies in other countries, where the number of injections are dramatically lower than what we use here in the United States. The results in the real world is a steady decline over time. Anti-VEGF works great at the beginning, but all of us, the physicians and the patients get burned out, so to speak, and then they try to push the interval, they try to push the visits. And this we are acutely aware that turned to pandemic. And we saw very nicely, so the patients who sort of were on sustained delivery or gene therapy studies. So we have patients in the Phase I/II at the clinic. These are the patients who did well because, in fact, they had onboard something that's producing a -- factory producing ranibizumab, which prevented any worsening. And so sort of the idea of getting that nice improvement with anti-VEGF injections and maintaining sort of the improvement over time that's the idea that really gets me excited because whenever I look at the real-world outcomes, and I see that decline back down, it always disappoints means as a clinical trialist. I wish they would stay in the clinical trial, but retina specialists don't listen to the clinical trial results, and they certainly don't list the labels. So having something that's much easier. You do it and then you follow and occasionally, you may need to rescue, which is no big deal, but it keeps the patient basically maintained for a very long period of time, maybe for life.