REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Ladies and gentlemen, thank you for standing by, and welcome to the REGENXBIO Update Call on RGX-314 for the Treatment of wet AMD. [Operator Instructions] I would now like to turn the call over to your host, Ken Mills, Chief Executive Officer. You may begin.

Good morning, everyone. Thanks for joining us so early. We're pleased this morning to be sharing new interim data from our Phase II AAVIATE trial of RGX-314 for the treatment of patients with wet AMD using suprachoroidal delivery. Here on the call this morning to discuss the data are Dr. Steve Pakola, our Chief Medical Officer; Dr. Arshad Khanani, who will be joining us to share his thoughts and for Q&A. Dr. Khanani is an undisputed leader in the retina community and a strong advocate for patients. He's the Director of Clinical Research at Sierra Eye Associates, preeminent retinal surgeons and one of the clinical investigators involved in our RGX-314 clinical program. Throughout the call, you can follow along with the slides available on our website or in the webcast. Now I'd like to turn the call over to Steve to talk through in greater detail about the new interim Phase II AAVIATE data.

Thank you, Ken. Both we and our global strategic partner, AbbVie, are excited about the continued progress advancing RGX-314 for the treatment of wet AMD, including the 2 ongoing pivotal trials evaluating onetime subretinal delivery of RGX-314 as well as the AAVIATE trial evaluating RGX-314 suprachoroidal delivery in wet AMD for which we are presenting new data this morning. I will be using slides that are available under the Media Presentations and Publications section of our website. Please take note of our forward-looking statements, Slide 3. Today's conference call will include forward-looking statements regarding our regulatory and product development plans. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from these forecasts. Now before we jump into the data, just a quick reminder on routes of administration on Slide 4. There are 3 main approaches to deliver gene therapy to the back of the eye. For RGX-314, we are assessing onetime administration via the subretinal route in our pivotal program for the treatment of wet AMD and are also investigating delivery into the suprachoroidal space, using the in-office SCS microinjector in Phase II trials for the treatment of wet AMD and diabetic retinopathy. This suprachoroidal approach can potentially expand patient access to RGX-314 into the in-office setting. And today, we are pleased to provide interim data from the ongoing AAVIATE trial in patients with wet AMD and announced the expansion of this trial. Moving to Slide 5. RGX-314 utilizes a novel AAV8 vector encoding a gene for an anti-VEGF monoclonal antibody fragment with the goal of sustained protein production by the patient's retinal cells, which may result in effective long-term VEGF suppression. Moving to Slide 6. The AAVIATE trial is a multicenter, open-label, randomized, active controlled, dose-escalation study evaluating the efficacy, safety and tolerability of suprachoroidal delivery of RGX-314 in patients with wet AMD. Patients in Cohorts 1 through 5 did not receive prophylactic steroids. On Slide 7, the primary end point of the trial is mean change from baseline in best corrected visual acuity, or BCVA, at week 40. Other end points include mean change in central retinal thickness and number of anti-VEGF intravitreal injections received following RGX-314. In terms of where we are today, earlier this year, we announced the completion of dosing in all 5 cohorts across 3 dose levels, including cohorts of patients who are NAb- as well as NAb+ at entry into the study. The update we are providing today is the interim 6-month results for the first 4 cohorts and overall safety analysis for all enrolled subjects in Cohorts 1 through 5. The next slide, Slide 8, highlights the baseline characteristics for all patients in Cohorts 1 through 5, which continue to be well balanced across cohorts. Of note, patients across cohorts had a high anti-VEGF treatment burden on entry into the study. Turning to the updated safety data on Slide 9. Based on the data cutoff of August 1, interim data shows that RGX-314 continues to be well tolerated across Cohorts 1 through 5 at all 3 escalating dose levels in a setting of no prophylactic steroids. There were no drug-related ocular or systemic SAEs and no cases of chorioretinal vasculitis or occlusion or hypotony. For the total group of Cohorts 1 through 4, the cohorts with 6-month results available, common treatment-emergent adverse events through 6 months in the study eye were conjunctival hemorrhage, increased intraocular pressure, episcleritis and conjunctival hyperemia. A higher rate of mild to moderate intraocular pressure or IOI was observed in Cohort 4 than in Cohorts 1 through 3. Across cohorts, IOI predominantly presented as anterior cells on slit lamp examination, and all cases of IOI resolved on topical steroids. The incidence and severity of episcleritis in Cohort 4 was consistent with the previous cohorts, and all cases were mild and resolved on topical steroids or NSAID treatment. Of note, at dose level 2, looking at NAb- and NAb+ Cohorts 2 and 3, there does not appear to be a meaningful difference based on pre-existing NAb status. On Slide 10, this graph shows that subjects treated with a single injection of RGX-314 and those dosed with ranibizumab every month demonstrated stable BCVA over 6 months. Both the mean BCVA from day 1 to month 6 and from week 1 pre-RGX-314 treatment to month 6 as shown in the upper and lower figures, respectively, had overlapping confidence intervals. On Slide 11, this graph shows the mean central retinal thickness from screening through 6 months. Subjects treated with a single RGX-314 injection and subjects dosed with ranibizumab every month demonstrated stable central retinal thickness at 6 months. The next 3 slides are swimmer plots that show the frequency of injection for each patient across cohorts both before and after RGX-314 and looks at the percent change in annualized injection rate after RGX-314 compared to the annualized injection rate prior to receiving the RGX-314 onetime treatment. On Slide 12, as previously reported with dose level 1 in Cohort 1, we see a 76% reduction in injection burden and some patients not receiving any injections over 6 months. On Slide 13, for dose level 2, we see a similar reduction in injection burden of 72% in NAb- Cohort 2 and 64% in NAb+ Cohort 3, and more than 1/3 of the patients are injection-free in both cohorts through 6 months. Notice that there does not appear to be a meaningful difference based on pre-existing NAb status. And now on Slide 14, our first cohort in dose level 3, Cohort 4 NAb- patients, we see an impressive 85% reduction in treatment burden at 6 months with 2/3 of patients injection free. Slide 15 presents the annualized injection rates, both pre- and post-RGX-314 administration across cohorts. We're pleased to see there is a dramatic decrease in injection burden across cohorts with the highest reduction to date achieved at dose level 3 in Cohort 4. On Slide 16, looking at the subgroup of patients who are injection-free through 6 months, a single RGX-314 injection demonstrated stable BCVA and central retinal thickness in these patients. Given the outcomes observed for visual acuity and retinal thickness, as well as the clinically meaningful reduction in treatment burden with the highest reduction in dose level 3, we have expanded the AAVIATE trial to include a new Cohort 6 at the same third dose level as Cohorts 4 and 5 with a short course of prophylactic ocular steroids following our RGX-314 administration to potentially prevent the observed incidence of mild to moderate IOI. This cohort will be inclusive of patients independent of preexisting NAb status. Subjects will also be receiving an additional anti-VEGF injection before and after RGX-314 treatment, similar to our ongoing subretinal RGX-314 pivotal wet AMD program. So on Slide 18, to summarize the interim update today. RGX-314 treated patients across all cohorts continue to demonstrate stable vision and retinal thickness at 6 months with a reduction in treatment burden across all dose levels, regardless of whether patients entered the trial with preexisting AAV8 NAb. We are very encouraged to see the meaningful reductions in treatment burden at 6 months across all dose levels with the highest reduction seen at the third dose level. These interim results have added to our knowledge of the emerging clinical profile of a single injection of RGX-314 administered suprachoroidally for the treatment of wet AMD. We look forward to applying these learnings to the newly expanded Cohort 6 that will allow us to further evaluate dose level 3 with a short course of prophylactic ocular steroids intended to potentially prevent the observed mild to moderate IOI. I take this opportunity to acknowledge the study patients, the investigators, the REGENXBIO and AbbVie teams for all their efforts to advance this first-ever evaluation of gene therapy via the suprachoroidal route of administration. I'd now like to turn to Dr. Khanani to hear his perspectives on this update of interim results. Arshad is an investigator in the trial and also an expert clinician and experienced clinical trialist across all of the retina experimental agents out there. I think it would be great for us to hear your perspective on this interim data and particularly what you think is most noteworthy as you evaluate this in the context of how you think of treating your patients with wet AMD.

Thank you, Steve. It's happy to be -- I'm happy to be here. It's a pleasure. So I think a few things you highlighted that are very promising. The first thing, obviously, this is the first trial for suprachoroidal delivery of gene therapy in the clinic. So that is very meaningful for me as a clinician. If I can deliver gene therapy in a safe and effective setting in clinic, I can help a large number of my patients who are suffering from neovascular AMD. The other thing is the fact that we are dose escalating to make sure that we look at efficacy as well as safety and finding the dose in the dose level 3 with 85% reduction in annualized injection rate and 67% of my patients or the patients in the trial injection free, that is very meaningful as a clinician for an approach in clinic. And then obviously, gene therapy is a paradigm shift. It's a new way to treat this chronic disease where we know that patients lose vision over time due to undertreatment. But at the same time, safety has to be balanced. And it's good to see that the inflammation we are seeing with suprachoroidal delivery is a short onset. It's not chronic, and it resolves quickly and doesn't stay for a long time. So I think that safety profile is very meaningful for us as clinicians because we don't want to have inflammation that stays for a long time, requires up and down treatment, on and off treatment. Here, we know that the inflammation happened between 2 to 6 weeks and resolved a short course of days or weeks of ocular steroids. So overall, I'm really excited to see that we are seeing an efficacy level that is very meaningful and a safety profile that is very acceptable for retina specialists treating patients with neovascular AMD.

Great. Thanks so much, Arshad, for those perspectives. And now I'm going to turn the call back over to Ken.

Thanks, Steve and Dr. Khanani, for your perspective, and we'll hear more both of you soon in our Q&A, but let me just provide a quick summary of all of our updates today that we shared and also share a few final thoughts before moving on. We continue to be encouraged about the potential impact of RGX-314 and what it could have for millions of patients facing vision loss from wet AMD. Over the weekend at AAO, we were pleased to share new positive interim long-term follow-up data from the Phase I/IIa trial of RGX-314 for the treatment of wet AMD using our subretinal delivery method, where RGX-314 continues to be well tolerated and demonstrates durable treatment effect now reported out to 4 years. Remember, this Phase I/IIa trial preceded our 2 ongoing pivotal studies, atmosphere and a sense that support our plans for a BLA filing in 2024 and we expect this evidence of 4-year durability to provide valuable support for our planned BLA submission. The interim updates from our AAVIATE trial this morning are exciting. We continue to evaluate the profile of RGX-314 in this Phase II study and consider its potential for transition into pivotal phase. Overall, we're looking forward to continuing to drive the RGX-314 program as a key part of our 5x25 strategy. And finally, as Steve acknowledged, we're nearing the 1-year point in our strategic partnership with AbbVie to develop and commercialize RGX-314. And for me, the past year really reinforces that they are a strong and complementary partner for REGENXBIO and that the teams together continue to leverage REGENX's and AbbVie's leading capabilities in gene therapy and global development and commercial infrastructure within eye care. Together, we aim to make remarkable impact for millions of patients suffering from vision loss associated with retinal disease. So at this point, we're going to turn the call over, operator, for questions.

[Operator Instructions] Our first question comes from Dane Leone of Raymond James.

Thank you for updating the data with RGX-314 and the commentary around the ongoing clinical development. Two questions from me. One, a strategy question and then one a fairly simple data question that I know is everyone -- on everyone's mind. So the first strategy question was with Cohort 4 and now that the planned additional cohort with the prophylactic ocular steroid use. What -- where do you think the end goal of this study is? So you've built up -- you've added cohorts as you've gone along to investigate what the profile of the drug is, what the dose intensity needs to be. But maybe just remind us of where you think you need to get to clinically on an efficacy standpoint and safety standpoint to then begin a pivotal study and how that pivotal study could potentially be designed and on what end points? And then just a very specific question. For those patients that did experience intraocular inflammation in Cohort 4, can you just confirm what the longest period of inflammation was and whether that's been resolved at this point and whether all patients are now off any support of ocular steroids?

Great. Steve, do you want to take those?

Sure. Thanks for the question. So starting with what are we looking for, what's our target as we go forward, as Arshad mentioned, we learn with each cohort in this escalating design. And this being the first ever study in this route of administration, it's really a great opportunity. And that is why we started without prophylactic steroids to really conservatively fully evaluate both safety and efficacy. And we're already seeing really excellent results from our perspective. Cohort 6 is a great opportunity for us to get more exposures in both NAb- and NAb+ patients now that we haven't seen a real impact based on NAbs. And I think the other aspect I'd say is with our global partner, we look at and get excited about this interim data, and we plan with AbbVie. So this is a partnership where we consider learning as we go in this first-ever study. And I think our target hasn't really changed. And certainly, the meaningful reductions that we're seeing, I think, are very encouraging but certainly to evaluate what will we see in a setting of prophylactic steroids and also directionally, the fact that we're including additional anti-VEGF run-in injection that is exactly how we are utilizing upfront anti-VEGF injections in our subretinal pivotal studies. So we think directionally that can also further inform what type of efficacy we can see to then consider how we go into pivotal. On your second part of that first question, pivotal really -- we have a long history in the space. We evaluated subretinal. We're in pivotal with subretinal. A lot of the same considerations are at play just with a different in-office route of administration. So I think the regulatory path would not be too different and, again, something that we would be advancing in discussions with AbbVie. On your second question about the IOI in Cohort 4, I confirm that, yes, all those cases were fit with the time course and the easily responding to topical steroids and resolving, or all resolved on topical steroids.

[Operator Instructions] Our next from Alec Stranahan with Bank of America.

This is [ John ], and I'm on for Alec. So I guess, the first question, kind of, I want to ask for Dr. Khanani. So as compared to subretinal or just for suprachoroidal in general, as an administration pathway. You did mention that it does have acceptable safety profile. So I guess my question would be, what kind of safe drug would be considered acceptable? And if you could put that in perspective of the current landscape as compared to Lucentis, EYLEA, that would be really appreciated, if you have the experience using those drugs. So that's my first question. I think second question is for the management. I think if we're looking at the current wet AMD and neovascular AMD landscape, we do see kind of the 3 players in the market having shifted a lot in the past year or so. So I guess the question would be, how do you think the 3 or 4 would be able to position against the current landscape?

Thanks for the question. So I think, first, to just kind of answer how do we -- how do we utilize current available agents. A majority of our patients with neovascular AMD to the first-generation agents like Lucentis and EYLEA need injections 4 to 8 weeks. And that's where most of the patients sit, and that's what causes a high treatment burden leading to missed appointments, long-term vision loss as time goes due to undertreatment, CST fluctuation. In terms of the newer agents that we have available Vabysmo and then we saw the data at AAO with high-dose EYLEA. We are just increasing incrementally the treatment interval by 1 week or 2 weeks or 3 weeks or 4 weeks on patients. So -- so the current patients that are sitting between 4 to 8 weeks, may go, 10 weeks, they go 12 weeks. So it is in advance for the field, obviously, to decrease treatment burden. But at the same time, we know that patients, even with less frequent injections eventually get the fatigue and then they drop off. So the excitement about onetime gene therapy that's delivered in clinic, obviously, is from both from patient’s as well as clinician’s perspective. From a patient perspective, if you have a safe and effective treatment in clinic, that means that can be given to a majority of the patients that have this disease. And if they need supplemental injections, we can obviously give the supplemental injections on top of it. But if we can keep majority of our patients injection-free with an in-clinic injection approach. That goes as close to be considered very early in the treatment course. And so it's more coming close to an early option than a late option that people consider gene therapy as a secondary option. But now if you have an efficacy profile, that is excellent and majority of the patients are injection-free and the safety profile that only utilizes a short course of ocular steroids. And if we continue to see the positive vision and OCT data. And if you continue to see a favorable safety profile, this approach in clinic can be very meaningful compared to frequent injections that are given in clinic.

Thanks, Arshad. And [ John ], to address your second question, I mean, I think I'm just going to build off of what Arshad was talking about, what we're seeing in terms of the potential opportunity for gene therapy in general and certainly RGX-314, we view as the sort of latest stage of development of any gene therapy today is that the unique profile of a onetime treatment. We reported over the weekend, Dr. Campochiaro presented from some of the first patients that ever received RGX-314 showing durable response out to 4 years in some of those patients continuing to be injection 3. We're seeing -- making decisions on moving things forward into pivotal phase with subretinal or with respect to our suprachoroidal assessments of a minimum baseline interest of 50% of patients injection free measurable time points as part of our studies. And -- now we're seeing that durability as well. We just don't see a target product profile out there that's like that. And we continue to hear from the clinics and do assessments commercially with the AbbVie team and the REGENX team that while these new incremental treatments that are coming to the market are addressing some patients, they're not addressing all. And in fact, there still continues to be a large population of patients in the spectrum of wet AMD that continue to have high treatment burden no matter what they're offered as first-line therapy. And we consider that to be an important and meaningful commercial market for AAV gene therapy and RGX-314 in wet AMD and another indication.

[Operator Instructions] Our next question comes from Vikram Purohit with Morgan Stanley.

This is Gospel on for Vikram. We have one question. And my question is -- what is your current thinking as to why the intraocular inflammation has been observed with the suprachoroidal delivery?

Thanks for the question. We -- in our preclinical study didn't see intraocular inflammation or inflammation. But of course, preclinical studies don't always translate and often don't completely translate into the clinic, and that's why we do the studies. And that's why we started with a very clean, conservative approach without just including prophylactic steroids because we wanted to see what type of characteristics we would see if there was inflammation that would occur. So why? Historically, we know with subretinal we have an immune privileged space or relatively immune privileged space, and that's been very helpful for the subretinal program where we don't need to have prophylactic steroids. And we also already knew we didn't need to worry about preexisting neutralizing antibodies. Suprachoroidal space is a different space, fortunately, it's a compartmentalized space and you can deliver treatment locally, which are the reasons why we chose suprachoroidal because we felt directionally that, that should help both in terms of efficacy and also safety to prevent migration of product the way that can occur with intravitreal administration. So all those factors, I think, are very supportive in our way, although intraocular inflammation has been seen as Arshad summarized from his perspective and how we and AbbVie see it, this is easily manageable. And we now have a great opportunity to see if we can even mitigate that further with short-course prophylactic steroids.

[Operator Instructions] Our next question comes from Gena Wang with Barclays.

I have 2 questions. The first one is on Slide 9. So the safety summary, I did not see Cohort 5 data there. I'm just wondering -- since it's already dosed, wondering what is the inflammation rate for Cohort 5? And what is the longest you use for the steroid on patients to mitigate the inflammation? And the second question is for Dr. Khanani. If we look at Slide 14, so the Cohort 4, we show efficacy data, 67% injection free, we also have 85% injection reduction. So are these -- which numbers is more important to you? And do you see gene therapy already reaching the minimum clinical benefit using these numbers?

Maybe Arshad, do you want to take Gena's question first, then we can circle back on her other questions?

Yes, absolutely. So Gena, that's a great question. As clinicians, we want to have a treatment where we can reduce treatment burden significantly. And if we can eliminate the need for injections, that's a big bonus. So if you look at 67% injection free for an in-clinic approach that is very promising as a clinician because I can tell these patients who were receiving frequent injections in the past that there's a good chance that they may not need injection. And if they need injection, then the number of injections you need will be much less. So overall, this dose level is giving us efficacy data that is really meaningful as a clinician practicing. As you know, the landscape is changing with treatment of geographic atrophy and other things that may come in the future, as well as my prior point, patients losing vision due to under treatment. If we can treat majority of our patients with this single onetime in-clinic approach and then give supplemental treatment for those who need additional treatment or top of injections, this can really change our long-term outcomes, in my opinion, where patients may be able to preserve vision longer and under treatment will become less with gene therapy being utilized in clinic.

Gena, back to your first question on Cohort 5. So as you know, this is an ongoing study. And when we do these interim updates, we basically have to go based on the data that we have as of the time point that we're proceeding with. And in spite of that, though, we always do take into account overall safety in terms of SAEs and any significant findings across all the cohorts even for ones who don't have the full duration of follow-up that we're looking at, at a given time point. When we look at common AEs, and this is how we've always done it based on just the scientific validity of comparing apples-to-apples, having the same duration of follow-up so that we know with Cohorts 1 through 4, we have the same duration of follow-up so that we can really compare and think about the rates that we're seeing and the characteristics that we're seeing of the common AE. So we basically follow the same approach. We did complete enrollment of Cohort 5, as you know as well earlier in the year. We just didn't have the 6-month follow-up. I can say that, of course, we are announcing that we're expanding to Cohort 6 with that same dose and that we are including patients whether they're NAb+ or negative. And on your question about the steroid treatment in patients. So again, the IOI resolves in days to weeks, the standard approach taken by clinicians is they then taper the steroids over multiple weeks since you never just take patients rapidly off steroids. So then the actual duration of the steroids, topical steroids can extend a few more weeks than that.

[Operator Instructions] Our next question comes from Ellie Merle with UBS.

Can you just elaborate a little bit more on the use of topical steroids like how long they were used as well as with the intraocular inflammation, just what the average duration was of the inflammation? And then was there any relationship between the intraocular inflammation with the efficacy reported weather between BCBA of the patients or in terms of the number of VEGF injections received? And then I know this was touched on earlier, but just can you kind of elaborate a little bit in terms of like any more specifics around the time lines where you might consider moving into pivotal trials that suprachoroidal delivery, would you potentially dose higher beyond those Level 3, I guess, if you're -- like depending on how the [ prophy ] steroids look? Or what sort of the dose level 3 be the dose level that you would use in a pivotal trial?

Thanks, Ellie.