REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Good afternoon, and welcome to REGENXBIO conference call to provide updates from the AAVIATE trial. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to turn the call over to Mr. Patrick Christmas, Chief Legal Officer of REGENXBIO. You may begin.

Good afternoon, and thank you for joining us today. Earlier today, REGENXBIO issued a press release announcing initial data and updates from our Phase II AAVIATE trial of RGX-314 for the treatment of wet AMD using in-office suprachoroidal delivery. The press release is available on our website at www.regenxbio.com. We will also be reviewing slides during this call, which you can access via the Investors section of our website. Today's conference call will include forward-looking statements regarding REGENXBIO's future operations and clinical trials. These forward-looking statements are subject to risks and uncertainties that may cause actual results to differ from those forecasted. And can be identified by words such as believe, may, will, estimate, continue, anticipate, assume, design, intend, expect, could, plan, potential, predict, seek, should, would, and other words of similar meaning. Any such forward-looking statements are not guarantees of future performance and involve certain risks and uncertainties. These risks are described in the Risk Factors and the Management's Discussion and Analysis sections of REGENXBIO's annual report on Form 10-K for the full year ended December 31, 2020, and comparable risk factors sections of REGENXBIO's annual reports on Form 10-Q, which are on file with the Securities and Exchange Commission and available on the SEC's website. Any information we provide on this conference call is provided only as of the date of this call, October 1, 2021, and we undertake no obligation to update any forward-looking statements we may make on this call on account of new information, future events or otherwise. Please be advised that today's call is being recorded and webcast. I would now like to turn the call over to Ken Mills, President and Chief Executive Officer of REGENXBIO. Ken?

Thank you, Patrick. Good afternoon, everyone, and thanks for joining us on today's call. We're pleased to welcome 2 well-respected retinal physicians to join us on this call. Dr. Nikolas London from Retina Consultants of San Diego and Chief of Ophthalmology at Scripps Memorial Hospital, and Dr. Peter Campochiaro from the Retinal Cell and Molecular Laboratory and Professor of Ophthalmology at The Wilmer Eye Institute. On today's call, Dr. London will walk us through the 6-month data from our Phase II AAVIATE trial, which he presented earlier at the Retina Society 54th Annual Scientific Meeting this afternoon. Both, Dr. London and Dr. Campochiaro, will join us for a Q&A session. Dr. Campochiaro is the principal investigator of the Phase II AAVIATE trial and was a lead investigator of the Phase I/IIa trial for RGX-314 for the treatment of wet AMD using subretinal delivery. He has also conducted multiple preclinical studies in the suprachoroidal delivery of RGX-314. We're pleased to share today's initial data from the Phase II AAVIATE trial of RGX-314 for the treatment of wet AMD. RGX-314 is a potential best-in-class, onetime gene therapy and AAVIATE is the first study designed to evaluate the effects of gene therapy using suprachoroidal delivery approach with the SCS Microinjector. This targeted in-office delivery approach could provide access to gene therapy treatment in all settings of patient care. We're encouraged by the emerging clinical profile of RGX-314 that was announced today, which has been shown to be well tolerated. At 6 months, a treatment effect was observed at the first dose level. Patients had stable visual acuity and retinal thickness along with a meaningful reduction in anti-VEGF treatment burden. Beyond today's data update, we also announced the expansion of the trial. As previously announced, we have completed enrollment in 3 cohorts of patients at 2 dose levels, and now we plan to enroll patients in 2 additional cohorts to evaluate RGX-314 at a third dose level of 1x10 of the 12th genome copies per eye. And so now I'll turn it over to Dr. Steve Pakola, our Chief Medical Officer, to give a quick overview of RGX-314 in the ongoing study. Steve?

Thanks, Ken. RGX-314 is a novel onetime gene therapy, which includes the NAV AAVIATE vector containing a gene encoding for a monoclonal antibody fragment, which is designed to enable sustained production of anti-VEGF protein, modifying the pathway for formation of new leaky blood vessels and retinal fluid accumulation. For patients with wet AMD, the current standard of care requires frequent and burdensome anti-VEGF injections. Real-world evidence has shown that patients commonly lose vision, because injection frequency drops off over time. We believe that this onetime treatment option could potentially provide long-term anti-VEGF expression after a single injection. This slide shares our objectives for the study, safety and efficacy endpoints, including visual acuity, retinal thickness and anti-VEGF retreatment injections, and our retreatment criteria are per our investigators to follow based on worsening visual acuity and/or fluid. The study design is shown here. We have completed enrollment of 60 wet AMD patients across 3 cohorts. And as Ken mentioned, we have expanded the trial to include a third dose level. So we have the opportunity to evaluate doses ranging from 2.5x10 11 to 1x10 12 GC per eye. Patients in cohort 1 were randomized to receive RGX-314 at a dose level of 2.5x10 11 GC per eye versus monthly 0.5-milligram ranibizumab intravitreal injection at a 3:1 ratio. And similarly, patients in Cohort 2 were randomized to receive RGX-314 at an increased dose level of 5x10 11 GC per eye versus ranibizumab. Cohort 3 is evaluating RGX-314 at the same dose level in Cohort 2, but in patients who are neutralizing antibody or NAb positive. We now plan to enroll patients in cohorts 4 and 5 with similar design. 15 patients in Cohort 4 will receive RGX-314 at a dose level of 1x10 12 GC per eye. And Cohort 5 is designed to evaluate RGX-314 at the same dose level in 20 patients who are NAb positive. In the study, patients receive an anti-VEGF injection on day 1 to evaluate their response to anti-VEGF via OCT scan at week 1. After response is confirmed by change in retinal thickness in the cohorts with the control arm, they would randomize to receive either RGX-314 or ranibizumab monthly injections. RGX-314 was administered at week 2 in office using the SCS Microinjector. Patients did not receive prophylactic immunosuppressive corticosteroid therapy before or after the administration of RGX-314. Now for an overview of the data, I'd like to turn the call over to Dr. Nikolas London. Nik?

Great. Well, thank you, Steve. It is really a privilege to be here, and I just can't thank you guys enough for allowing me to present at the Retina Society to a group of my various teams -- colleagues. So looking at the slide here, these are the first data ever reported from a gene therapy trial that's been delivered into the suprachoroidal space of the eye. I'm very encouraged with what I've seen so far. I believe the data from the patients in cohort 1 at 6 months after RGX-314 administration demonstrates the potential benefit of a onetime RGX-314 administration to the suprachoroidal space for the treatment of wet AMD. I'm personally very excited about the data that I was able to present today. I'd like to start the data review with some background on the patients coming into the trial. Across all 3 cohorts of the study, the baseline best corrected visual acuity and rental thickness were relatively similar and what you'd expect from well-treated wet AMD patients that we see in our clinic. All patients were already receiving frequent anti-VEGF injections before enrolling into the trial with a mean of 9 annualized injections in the past year. Looking at the safety profile of RGX-314 when delivered suprachoroidal, as of September 13, 2021, the data cutoff date for this analysis, RGX-314 was reported to be well tolerated across 50 patients dosed in cohorts 1 through 3. There were 4 serious adverse events reported in patients, all of which were not considered to be related to treatment with RGX-314. If we look at cohort 1, at the treatment emergent adverse events in those 15 patients, they were all generally mild and none of them were severe. There were mild cases of intraocular inflammation reported in 4 patients based on a very detailed slit lamp exam that you typically only do in a clinical trial and not in a real-world setting. Onset of inflammation was approximately 2 to 6 weeks following dosing with RGX-314 and all cases resolved with topical corticosteroids with no patients on corticosteroids as of the data cutoff date earlier this month. It is important to remember that these patients were not receiving prophylactic corticosteroids before or after administration of our RGX-314, which is unique to this trial. No serious safety concerns were noted. There were no cases of retinal pigmentary changes observed on exam or imaging. No cases of choroidoretinal vasculitis or occlusion and no cases of hypotony were observed. The next few slides relay efficacy data from Cohort 1 at 6 months. This slide shows the mean central retinal thickness from day 1 to month 6. You can see that the patients treated with RGX-314 demonstrated a stable central retinal thickness over the course of the 6 months, as did patients who were receiving monthly ranibizumab, as expected. This is on the backdrop of a mean of 1.2 anti-VEGF injections over 6 months in the treatment arm, compared to the control patients, who were receiving monthly injections for a total of 7 injections over the 6 months. Also, when looking at relative change from baseline, the central retinal thickness remained stable across both groups over 6 months. This slide shows the best corrected visual acuity results of functional results over 6 months. We can see here that the visual acuity over time is stable when measured from day 1 after anti-VEGF screening injection. Again, this is in the context of reduced anti-VEGF injections. This is the outcome we would hope for in previously treated wet AMD patients. If we can address the underlying disease and reduce or eliminate their need for frequent anti-VEGF injections, while stabilizing their vision gains, that is really very meaningful for our patients. But we can also note that there was an interesting difference in how patients in the monthly ranibizumab group responded to that initial anti-VEGF injection, prior to treatment of any of the patients with RGX-314 compared to the RGX-314 arm. The week 1 randomization day visit, best corrected visual acuities taken just prior to randomization, which provides an opportunity to assess change at 6 months from the week 1 visit as well as to check for consistency in terms of stability of vision. As such, when we measured the change from week 1, when the patients had shown response to the anti-VEGF injection and had been randomized, the stable levels of best corrected visual acuity are more apparent in the RGX-314 group with the difference of only 0.5 letter -- negative half-a-letter at 6 months. So the changes in best corrected visual acuity is similar in the 2 arms of the cohort, both showing stable visual acuity. It is important to remember that the stable visual acuity and retinal thickness observed in patients dosed with RGX-314 are accompanied by a reduction in the anti-VEGF injections for patients that needed frequent anti-VEGF injections to control their disease in the prior year. To the left, we see the injections for each patient in the year prior to enrolling in the study. After dosing with RGX-314, there is a meaningful change in the annualized anti-VEGF injections over 6 months with a 76% reduction in injection rate compared to the 1 year prior to RGX-314 treatment. Four out of the 14 patients received no anti-VEGF injections following study treatment. In these patients, visual acuity and central retinal thickness was observed to be stable from day 1 over 6 months with a mean change of BCVA of plus 1.3 letters and a mean change of central retinal thickness of minus 6 microns. Just to recap, suprachoroidal delivery of RGX-314 was well tolerated in 50 patients in cohorts 1 through 3 with no drug-related serious adverse events. In Cohort 1, 6 months after dosing with RGX-314, a treatment effect was observed at its lowest dose level. Patients demonstrated stable visual acuity and retinal thickness along with a meaningful reduction in anti-VEGF treatment burden, in the context of no patients receiving prophylactic corticosteroids before or after administration of RGX-314. There were 4 patients with mild inflammation, which was essentially asymptomatic and resolved within days to weeks with a short course of corticosteroids. I look forward to seeing additional data from the AAVIATE trial as we continue to follow Cohort 1 patients and await data from the higher dose cohorts. I will now turn it back to Steve.

Thanks again, Nik, for providing your perspective on these results. We're certainly all very pleased to have reached milestone and actually be able to share interim results from AAVIATE. Before we turn the call over to the operator for questions from the audience, I'm going to start things off.

So maybe first for you, Peter, on the phone. Here we are with initial clinical results with suprachoroidal gene therapy approach. And I hope you don't mind me saying to the audience that it's really your -- a lot of your seminal preclinical work on suprachoroidal delivery of gene therapy, including RGX-314, as well as other factors that has paved the way for us and I think the field in general for recognizing the potential for this space. So I think with everything you've seen preclinically, how is that translating so far into what you see here clinically?

Well, Steve, I think that it's very encouraging. What we saw in rats and in primates was that we could deliver a vector into the suprachoroidal space and get widespread transduction throughout the posterior part of the retina and the RPE. And histologic studies showed no evidence of inflammation in the rats and as you know, REGENXBIO performed a study in primates, which showed really no inflammation. So it's really encouraging to see that, that -- those observations are translating into the clinic. Now we also saw in rats very strong anti-VEGF effect. And I think these initial data in -- with the lowest dose level suggests that there definitely is an anti-VEGF effect. The ability to significantly reduce the number of injections and maintain stable vision and stable retinal thickness really indicates that even at this low dose level, there is an anti-VEGF effect. So I think it's very encouraging, and I have to congratulate REGENXBIO, because this is not only useful in terms of development of a treatment for neovascular AMD, but it's providing critical information that can be used in the future for gene therapy for inherited retinal degenerations.

Great. Thanks so much for that, Peter. Yes, I think it's 1 of the areas we're very excited about, especially now that we've moved into completion of a second dose level and now expanding into a third dose level, and also being able to look at NAb positive patients as well as NAb negative patients. So I think a lot of interesting learnings that are going to come from these different cohorts. And that segues into my question for Nik really that, you've just given the first presentation on these initial results. So you don't have so much time in that window, obviously, at the actual conference. So this is an opportunity to step back and hear how you look at these type of data when thinking of a onetime suprachoroidal delivery of the gene therapy. How do you look at that? And what are the key factors that -- for our audience, how you think of this kind of data in terms of yourself as a practicing retina specialist and also an investigator?

Yes. Thank you, Steve. So I think I might have been telling you this earlier today, but as I was doing some prep work for the slides, I was really set and focused on the last slide, where we're summarizing things. And I kind of found myself going on for a while about sort of what am I excited about with these data. And I could probably talk forever about it, but this is really -- I kind of see it as a bit of a revolution and I really am excited about what we might get in the future for both the clinicians and our patients. So you guys are enabling us to do a safe and effective and essentially painless suprachoroidal injection in the office as opposed to the operating room. Surgical procedures are always barriers for patients. And so having something that could apply to patients across all levels to me is very exciting. We are enrolling in this study phakic patients as opposed to only pseudophakic patients in some of the other clinical trials looking at gene therapy. There are no topical corticosteroids or corticosteroids prophylactically given of any sort throughout the study, which really takes away a little bit of a headache for treating physicians, which I just love. The safety profile was excellent. Of the 4 patients that I know of with inflammation, they were all extremely mild. These are cases of inflammation that were found on a study exam, which -- these aren't patients coming in complaining of symptoms. They were asymptomatic and they were found to have sort of mild inflammation. I know at least my -- 1 patient had no clue that she had any inflammation and within a week, it resolved on a topical drop. So that just makes us very comfortable when we're treating our patients. And as you alluded to, the fact that we're getting an efficacy response at the lowest of three-dose levels. You're going to double that and then you're going to double it yet again for the highest dose level. So I'm just excited to see sort of where we go from here and what's going to come out and you give me a reason to want to go to meetings now to see what the results are.

That's great. And it's great to see everybody here in Chicago and to have these results presented. So thanks again to you, Nik, and you, Peter. So now I'd like to turn it over to the operator, so we can take questions from the audience.

[Operator Instructions] Our first question comes from the line of Gena Wang of Barclays.

I have several. Maybe I'll first start with inflammation, for both Dr. London and Dr. Campochiaro. So inflammation for the first cohort, we saw from 4 out of 15 patients, even though all inflammation resolved as of now. What could be the reason causing the inflammation? And do you expect the inflammation come back later on? And with a higher dose, do you expect higher rate of inflammation? My second question is related to -- if we're looking at the Slide 14. So how does the protein level correlate with the rescue injection? My third question, sorry, my last question is the -- in this population, the CRT seems smaller, 264 versus some retinal trials gets 400. So how should we interpret the data when we try to see comparing the other trials in terms of the patient population baseline characteristics?

I can start with the first question. The virus is, of course, foreign. And when it's injected in the subretinal space, there is a lot of immune privilege that reduces the amount of exposure to the immune system and reduces the likelihood of inflammation. In the suprachoroidal space, there's not as much immune privilege, and we're just learning about exactly what that space is like in terms of its exposure to the immune system. So there -- it's very likely that the virus may in some individuals induce an innate immune response, which is a relatively acute reaction, occurs within weeks. And it often is -- it can be a very mild inflammation. We don't expect that this is any predictor of later inflammation. Later inflammation is often due to antigen presentation by transduced cells, and that's a different thing. So we can't, from these data, indicate that there's likely to be inflammation down the road. As far as a dose response, certainly, we're learning with other spaces, there is a dose response for inflammation with intravitreous injections. And we don't know yet with suprachoroidal, but we will learn a lot from these additional cohorts, but we really can't say at this point. So I think the only thing we can say is this inflammation is very mild. It's likely due to an innate immune response. And it's -- it occurred without any steroids on board and responded extremely well to the steroids, and it's not predictive of future problems with inflammation.

All right. Thanks, Peter, for that. So Gena, you had 2 other questions. One was regarding the swimmer lane clot with the demonstration of the reduction in treatment burden and any potential relation with protein level. So we haven't presented protein results in this presentation. For us, the key aspect is what we see on this slide, particularly in the context of stable visual acuity and stable CRT. As far as the baseline CRT, you did pick up on a key aspect, Gena, that the retinal thickness is certainly less than what we had in our Phase I/II study. And that's actually by design, because you'll recall that, that was a true first-in-human study where we had very difficult-to-treat patients, who not only were receiving very frequent injections, but still -- many of the patients still had thick retinas at entry. So for this study as well as our pivotal subretinal delivery program, we require that we exclude the patients who are not under some level of reasonable control at entry. So that gets rid of some of the high retinal thickness levels, and we wind up with a lower baseline level and what you saw presented by Dr. London.

Our next question -- I'm sorry.

I was just going to say -- this is Nikolas London, I'm not surprised at all about the low central retinal thickness given how well controlled these patients were. They were 20/25 to 20/40 on enrollment, and they had been followed fairly closely by their physicians. In my experience in my patients, I think I have 7 or 8 patients in the study. They tend to be very compliant patients that want to engage in clinical trials and at least in this one, people were very excited about it. And so well-controlled patients have thin retinas and good vision. So that doesn't surprise me.

Our next question comes from Alec Stranahan of Bank of America.

Two from me. My first is on selection of the 10x -- or 1x10 to the 12 dose level. Could you help expand on your thought process behind selecting this dose in particular? And do you think there may be room to add additional dose levels beyond this, if necessary, given the relatively good tolerability seen to date? And then secondly, for Ken, on the AbbVie collaboration. I guess, as much as you can say, how much of the discussion focused around the more mature subretinal data versus the data from these suprachoroidal studies in terms of driving AbbVie's interest? Or was it maybe a more holistic view on the program?

Thanks, Alec. I'll start off with your first question before we hand it over to Ken. So as we've announced, we've not only completed dosing at the second dose level, which is twice the dose of the first level, and now we've started with the expansion in Cohort 4 and 5 with another doubling of the dose. Really basic drug development here at this key juncture where we have the opportunity to learn about dose range with this route of administration. So our ability to go to this level is based on what we see and our overall package being able to go to this dose. So we're happy to do that. Maybe I'll ask Peter, though, if he has any other thoughts in terms of thinking of dose ranging.

Yes. So I think that these doses are very rational in terms of the way that you dose elevate in a clinical trial. And I think that Alec's question is a very good one, is this the third cohort dose or the fourth and fifth cohort dose, the highest that could be given. And I think that is really to be determined by the data that we obtain in this clinical trial. I think that the primate, the nonhuman primate, data certainly supports higher doses. So based upon that and then based upon what observations are made in the fourth and fifth cohort, that always could be a consideration. And of course, the other consideration is the level of efficacy. If at all the efficacy were such that where really something that didn't require anything else, then, of course, going to an additional dose probably wouldn't be a consideration.

Great. Thanks, Peter. Ken, do you want to take the second question?

Sure. Alec, thanks. As we talked about a few weeks ago, the -- AbbVie is a true worldwide strategic partner in the potential future development of RGX-314. We're in the middle of a regulatory review period. So when we expect that to close before the end of the year, we'll be working on this together and they completed full diligence of RGX-314 program work that was ongoing during our discussions that led to the collaboration and partnership. So more to come when we get to the other side of that regulatory review period, but thanks for the question.

Our next question comes from Dane Leone of Raymond James.

Congrats on data. I'll limit questions to 2 since it's Friday and probably everyone's attention span's waning here. So 1 for the team and then 1 for maybe the investigators. The first 1 for the team, since you guys did comment in terms of serious AEs across the 50 patients treated within the first 3 cohorts, I think it's probably a fair game to ask you for any commentary you can give regarding rates of inflammation within Cohorts 2 and 3. Essentially, the conversation off of the presentation today has centered around whether you're going to experience a dose response in inflammation, as you step up the dosing into cohorts 2 and 3 versus cohort 1. So anything or any color around potential dose response in inflammation would be appreciated. Secondly, for the investigators, one thing that I think hasn't been discussed here, but was also updated today, is actually the long-term subretinal data. Maybe put into context for us what you think the clinical hurdle of adoption for these therapies would be and what you need to see on clinical outcomes that would make you consider this a good treatment option for your patients? For example, in Cohort 5, I think roughly 1/3 of the patients at 2 years are actually free of standard of care. What would your hurdle be for something that could be applied in office via the suprachoroidal microinjector?

Thanks, Dane, for the 2 questions. I'll take the 1 you addressed to the team. So as you mentioned, we summarized the overall safety across the 3 cohorts in terms of no drug-related SAEs and well tolerated. And then we -- as we've always signaled even from the beginning of the year when we completed dosing of cohort 1, that that's what allowed us to believe we'd have a fulsome 6 months at least data package to present initial results for Cohort 1. So it was always our plan and always what we communicated to focus on Cohort 1, but we've also had a precedent to also update more broadly in terms of the overall safety in terms of SAEs and any drug-related SAEs across other cohorts in ongoing studies. So we're excited that we completed dosing in those cohorts. We're not going to discuss any specific results of cohort 2 and 3, because those are at earlier stages. They completed enrollment and patients are earlier in their course. But we can say what we announced that we're excited that based on the ongoing data that we're able to advance beyond dose level 2 into dose level 3 in both NAb negative and NAb positive patients in cohorts 4 and 5. So I'll now hand it over, but let's start with you, Nick, on Gena's (sic) [Dane's] excellent question of it's great to be seeing this treatment burden reduction in the setting of stable visual acuity and anatomy. What's down the road when you think about this? What's the bar for treatment burden reduction that will make you say, "Hey, I really want to provide this for my patients"?

Yes. That's -- I mean it's a great question. It's something that comes up all the time, is that -- I don't know if the caller is still on the line. Yes. So was that exactly what the question was? Or was it how I decide between suprachoroidal injections and subretinal injections?

No. I mean, very simply, the question is we do have some evidence in terms of RGX-314 as a vector in the subretinal delivery route of administration. Getting to roughly 7 out of 11 patients being free of standard of care at 2 years. Is that the right hurdle for what you're looking for with a suprachoroidal injection if they can get the dosage in effect to kind of match what they did with subretinal? Or is there a different hurdle that you would state for the clinical community?

Yes. So you mean 7 out of the number of treated patients. So yes, I think the hurdle is going to be a little bit lower for a suprachorodal injection, because it's an easier conversation to have with patients. Patients are often inherently reluctant to go to the operating room. And so if you can offer them an in-office procedure that's going to reduce their injection burden even less than what we saw in subretinal, it's going to be a very attractive option for patients, who are elderly. They've got caregivers, that come to the office with them. If you said you can come in every 3 months instead of 2 months or something along those lines, I think it's going to be a lower bar than what we've seen in the subretinal study.

And I'll correct myself, Dane, that -- Gena had excellent questions, too, but so did you here. So these were from you. So Peter, what's your bar in terms of treatment burden reduction? Or how do you think of that whole question of what would make this a treatment that you'd be excited about for your patients?

Yes. I agree very much with Nik. I think that we look at things in terms of risk benefit. And it appears that the potential risk from the injection itself is minimal. I mean there's really essentially no risk. We haven't really deciphered yet if there is any risk and what the level of that risk is from the delivery of the vector into the suprachoroidal space. And so we'll learn a lot from these trials about that. But based upon what we know at this point, it seems like it's likely to be a very favorable benefit risk ratio. And -- yes, so I agree with Nik, that I think the likelihood is that patients will be very accepting of this sort of approach. And naturally, the more we can reduce injections, the better.

Thanks, Peter.

Our next question comes from Mani Foroohar of SVB Leerink.

So first of all, I would like to pull together a couple of threads from Gena and Dane, respectively, around the possibility or plausibility of a dose response on the inflammation side. Appears subclinical based on your description, but at potentially higher doses, it could be clinically relevant. Given how responsive -- the response has been to short brief course of steroids, what would your bar be to add a brief prophylactic course of topical steroids upfront to avoid a potential more severe inflammatory reaction given how responsive this is?

Mani, one important reminder here is that we're doing this dose escalation that we've already completed the dosing for dose level 2 and now expanding into dose level 3. Just as we started the study in the initial cohorts, we've continued without prophylactic steroids. So as Nik and Peter have alluded to, it's really a great opportunity for us to learn an overall risk characterized based on looking at data from patients who have not had prophylactic steroids. And as Nik and Peter have discussed, the profile that we see here is favorable. So it gives us that chance to look and you really do the studies to really evaluate whether you will see a dose response or not. But all we can really say is that based on the data that we have to date, we were comfortable to proceed to first dose level 2 and now dose level 3 without prophylactic steroids. Nik or Peter, do you want to highlight anything?

So I would say that prophylactic steroids -- I don't get to tell REGENXBIO what to do in terms of designing their studies, so my input maybe not that impactful. But from a clinician's standpoint, I would want to have enough inflammation or whatever disease process to either threaten permanent damage to the eye or cause significant symptoms, but neither of those we were even close to. And corticosteroids, while they're very widely prescribed and we use them very frequently for patients with uveitis or post surgical, they're not completely benign medications. They can cause ocular hypertension and it causes cataract inflammation if they are used for prolonged usage. So I would -- what we saw in the Cohort 1 to me, was almost a nothing burger in terms of inflammation, and I would have to see something way more significant than that.

Our next question comes from Esther Rajavelu of UBS.

Congrats on the data. I guess, Dr. London or Dr. Campochiaro, you mentioned the IOI test is typically not done in the real-world setting. And I was wondering if these had not been tested for specifically, would these inflammation events have self resolved? Or do you think the -- do you think they would have become symptomatic? And then sort of following up on that is the NHP data that I think that was mentioned in response to another trial supporting higher doses, is that based on suprachoroidal administration in these animals?

Yes. So I can take the last question first. Yes, it was a nonhuman primate study in which there was suprachoroidal injection of RGX-314. And they're really -- so even higher doses than what are going to be used in this trial were tested, and there was really no sign of inflammation. And that's based upon clinical examinations as well as histology. As far as -- let's see, what was the other question?

The other question was the inflammation that was seen in the 4 patients. The doctor had referred to these as not -- they -- essentially, they were nonsymptomatic inflammations and wouldn't have been [indiscernible] in the real-world setting. So just trying to understand if they would have self-resolved in a real world setting or if they would have gotten worse?

I got it. Nik, here. Yes. I mean I would expect them to self resolve to be honest. I've even had patients with the level of inflammation that I've seen that go away on their own within a few weeks. I think in a clinical trial, we often have a little bit of a shorter trigger to treat patients like this. We don't want to really see anything and we just don't know. So we kind of are ultra cautious, but I've had patients with -- my 1 patient of the 4 that I had, I've watched and sat on plenty of patients like that in the clinic, and they did great. So I doubt they would have gotten worse.

Yes. And I would just add to that, that what Nik was referring to is that this is based upon a slit lamp examination, which is a magnified view of the front of the eye and the vitreous looking for cells. And so it's quite a sensitive test. And anything that -- even an injection can cause a little bit of cellular reaction. After essentially all procedures that we do, there usually -- if you look hard enough, you can find some cells. And so I think Nik was referring to the fact that in the clinical trial, we're looking hard to find any evidence of any cellular reaction. And it's a pretty sensitive evaluation. And so normally, when you have a patient who has uveitis or a significant amount of ocular inflammation, it's very obvious. It's -- they're symptomatic. They have pain and discomfort. And then when you look at the slit lamp, you see very many cells. So I think it just indicates that this was a very mild cellular reaction.

Your next question comes from Matthew Harrison of Morgan Stanley.

This is Vikram on for Matthew. So just 2 questions from our side. So first, staying on the topic of the inflammation. So I know you mentioned at the start of the call that the inflammation set in roughly 2 to 6 weeks, I believe you said, following administration of 314. But I was wondering if you could provide a bit more detail on how the inflammation presented across patients? And how long were patients on topical corticosteroids prior to your seeing resolution of the inflammation? And then secondly, on efficacy. So for the patients that did not need retreatment, were there any similarities across baseline disease or baseline characteristics that could help you explain why these patients had a stronger initial response to 314 versus those that did need retreatment through the first 6 months?

Vikram, so on your first question on the intraocular inflammation, yes, as you said, the onset was 2 to 6 weeks post dosing. And these were -- so as far as the presentation, just as Nik has summarized and Peter as well, these were picked up on that magnified view as slit-lamp where you see cells, and that's where you can make an assessment based on that. And those patients were all treated with topical corticosteroids. And as per our September 13 cut that this analysis is based on, all patients were off steroids and no inflammation. The second question, I think, was on those patients who did not need any injection during the 6-month time period, if there were any predictors for those patients. This is our first cut of the data and going through this. So we can look more over time. I'd say on first cut, nothing clearly differentiates those patients. But I think it's important to note, we have those patients who needed no injections. And then overall across the whole cohort, the 76% reduction in treatment burden.

And Steve, the only thing I'd add to the duration of corticosteroids, I think it's for the inflammation. I think it's just -- since there is no protocol in terms of how we would treat patients with inflammation, it's sort of just based on the investigator and sort of how they feel about treating it. Some people are, again, ultra conscious and they'll say, "Okay, I'll see you back in a couple of days, or I'll see you back in a week", and some would be very comfortable with the low level of inflammation saying, "Okay, I'll see you back at your next scheduled visit in 2 weeks." So there's going to be -- especially in the small number of patients, quite a bit of variability there that may not be very meaningful.

Our next question comes with Luca -- our next question comes from Luca Issi of RBC.

Great. I have 3, but it should be all pretty quick. The first is on efficacy. The second is on the device and the third 1 is on strategy. So on efficacy, just circling back on the prior conversation. And again, I know early days, and we only have data for the low dose. But how would you compare the efficacy so far to subretinally? It looks to me that the reduction in annualized injection is somewhat comparable between the 2 routes of administration. However, the percentage of patients that are actually injection-free is worse. Wondering if you would agree with that? The second on the device, I think the PDUFA day for ClearSight is in 30 days. Hopefully, that product gets approved, but should that not be the case, are there any implications for REGENX that we should think about it? And then third one, on strategy, you seem obviously pretty excited about this data. So wondering if you can elaborate on why you think it is still the right strategy to continue to invest capital in the subretinal delivery?

Thanks, Luca. So we'll hit your 3 questions starting from efficacy. Yes, as you noted, we had good meaningful annualized injection rate reduction and across our 3 highest cohorts in the subretinal study, and I think it was great to hear Dr. London and Dr. Campochiaro talk about how they think of treatment burden. And so you raised -- the 2 ways you could look at is the overall injection burden reduction and then also a proportion of patients that don't need any injections. And I guess to paraphrase, Peter, the more dose -- either dose that you can get, the better. I think it's too early to try to compare across studies, because we did see from the subretinal study that a lot depends on the underlying disease and how severe or refractory or not the patient population is that you enroll. So I think what's exciting for us is we have not only this initial data readout, but we're going to have longer-term readout from this cohort and also all these other cohorts that we talked about to really assess potential dose response and effect. And on the ClearSight device. Yes. Right from the start, we picked the ClearSight device as the best and most clinically validated approach to deliver our RGX-314 to the subretinal space. Yes, it's great that they're moving along with Bausch, and that certainly would be great to have that approval. With or without that, we feel in a very good place to keep advancing with ClearSight. After all, there's over 1,400 eyes that have been injected, most with triamcinolone, but also other products with good safety, tolerability and feasibility. And so the last question since you said the word strategy, I'm going to hand that over to Ken.

Thanks, Steve. I think, Luca, you know us, and we've got the benefit of having Dr. Campochiaro and Dr. London here that our level of engagement with the community and talking with physicians about the types of benefits that a range of gene therapy options can bring is kind of -- embodies the innovation that we're trying to bring forward with AAV gene therapy. The subretinal approach, unequivocally for us the procedure itself, the data that we've generated over many years, the durability, the long-term safety and understanding, is such a solid foundation that our continued investment in our pivotal phase programs to support that getting to physicians and patients as quickly as possible is very important. And I think we continue to view that, that product has a meaningful place for many patients in terms of unmet need in wet AMD spectrum. While this initial data is very encouraging, we want to continue to pursue the suprachoroidal approach, leveraging the understanding that we've shared today, the data that we've talked about historically preclinically and connecting that to -- more to the story that's going to come forward on durability, long-term understanding of safety, and complete that profile the way that we did, I think, intelligently and cooperatively with all stakeholders in subretinal. That's our approach. It's a big commitment, but it's an important one. I think there's a lot of value to be brought forward to help doctors like Dr. Campochiaro, Dr. London and all of our investigators in the community, who support us, get something new for patients that is really special.

At this time, I'd like to turn the call back over to Ken Mills for closing remarks.

Those probably were my closing remarks, but I want to again thank -- thank you, Peter, and thank you, Nik, for talking with us today, talking with our friends in the investment community, and I know the stakeholders at the conference are very excited to hear the presentation and to hear your perspective on it. So thanks to both of you. Thanks for moderating, Steve, and it is late on a Friday. So everyone, have a great weekend. Thanks for joining us.

All right. Thank you, Ken.

This concludes today's conference call. Thank you for participating. You may now disconnect.