REGENXBIO Inc. (RGNX) Earnings Call Transcript & Summary

Good morning, and welcome to the REGENXBIO conference call to review additional positive long-term interim Phase I/IIa trial update for RGX-314 for the treatment of wet AMD. [Operator Instructions] As a reminder, this conference call is being recorded. I would now like to turn the call over to Mr. Patrick Christmas, Senior Vice President and General Counsel for REGENXBIO. You may begin.

Good morning, and thank you for joining us today. With us are Ken Mills, REGENXBIO's President and Chief Executive Officer; Dr. Steve Pakola, our Chief Medical Officer; and several esteemed retinal physicians and key opinion leaders. Dr. Allen Ho, Director of Retina Research at Wills Eye Hospital and Mid-Atlantic Retina; Dr. Robert Avery, Founder of California Retina Consultants and Research Foundation; and Dr. Peter Campochiaro, Director of the Retinal Cell and Molecular Laboratory at Johns Hopkins Wilmer Eye Institute. Earlier this morning, REGENXBIO provided an update via press release, which 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 our clinical development of RGX-314, in addition to regulatory and product development plans. 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 expect, plan, will, may, anticipate, believe, should, intend 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, 2019, which is 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, April 22, 2020, 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 morning, everyone, and thanks for joining us. Hope you're all healthy and staying safe as we make our way through these challenging times. At REGENXBIO, for the past several weeks, our focus has been on the health and safety of our people and our communities and the important work we need to continue in order to help patients. On today's conference call, we look forward to a review of the data announced this morning from our Phase I/IIa study of RGX-314 for the treatment of wet AMD. I'm pleased to say that the data continues to support what we've previously reported for this study: RGX-314 has been well tolerated in 42 patients and has demonstrated long-lasting durable anti-VEGF effects in the eye over 2 years after a onetime administration in severe wet AMD patients in Cohort 3. These patients in Cohort 3, which have reached the 2-year time point, have demonstrated improved visual acuity and stable retinal thickness. This is on top of the significantly reduced anti-VEGF treatment burden. We've also provided an interim update from later cohorts. The previously reported 73% of patients in Cohort 5, who had not received anti-VEG injections -- anti-VEGF injections as of 6 months, have remained injection-free now up to 9 months. And we now also have 6-month protein data for Cohort 4 and 5, which support the dose-dependent protein expression that we've noted previously at 1 month. We're honored and grateful to have several leaders from the retina community that we work with joining us today. Dr. Allen Ho will walk you through the data. As Patrick mentioned, we also have on the call with us Dr. Bob Avery; Dr. Peter Campochiaro, who are both investigators in the trial. Each of these physicians have worked with wet AMD patients for many years and can provide perspective from their experience in our study of RGX-314 and from treating patients with other wet AMD options. Additionally, Peter and his colleagues at Johns Hopkins have been part of the team of world-renowned gene therapy and ophthalmology experts involved with us in the early development of RGX-314 candidate. So we'll invite you to ask questions of them following the data review. And please feel free to ask more general questions as well. But first, I want to turn it over to Dr. Steve Pakola, our Chief Medical Officer, to give a review of the data that we announced this morning and an overview of RGX-314 in the ongoing study. Steve?

Thanks, Ken. The clinical profile of RGX-314 is very promising as we continue to learn about the consistent and durable effects of anti-VEGF gene therapy in wet AMD patients. The onetime administration of an AAV-mediated anti-VEGF antibody fragment is designed to enable sustained production of anti-VEGF protein. And we have now demonstrated consistent results across 2 years in Cohort 3. We believe this is the longest time line of continuous therapeutic effects from a single administration of a therapeutic as demonstrated in patients. The data from Cohort 3, which Dr. Ho will walk us through, are summarize briefly here on this slide. Patients in Cohort 3 demonstrated markedly improved visual acuity and stable retinal thickness as well as significantly reduced need for anti-VEGF intraocular injection over 2 years' time and stable protein expression. In this cohort, 50% of patients did not get any anti-VEGF injections over the full 2 years. And interestingly, one additional patient did not get any injections between 9 months and 2 years. We saw an impressive improvement in visual acuity with an increase of 14 letters in both the full cohort as well as the 4 patients who did not receive injections in the second year of the study. As Dr. Ho will show, this indicates that the increase in BCVA was not driven by the patients who did receive anti-VEGF injections. This improved vision and durability of anti-VEGF activity is particularly meaningful for the patients who did not receive injections in the second year of the study as real-world evidence has shown us that patients commonly lose vision over time, even with the current standard of care. Additionally, patients in Cohort 3 showed a stable anatomical response over time. I'd like to point out that these clinical measurements were in the setting of a dramatic reduction in anti-VEGF injections. Across the full cohort, there was a greater than 60% reduction of treatment burden with an average of 2.8 injections per year. And importantly, again, 4 out of 6 patients were injection-free after 9 months. And finally, the protein expression levels over 2 years in Cohort 3 show consistent protein production. This gives us confidence that the transduced cells in the retina are producing RGX-314 protein at a steady rate throughout the study. Now I'd like to take a quick step back and remind us of the basic background information of the study, where we are using a subretinal procedure to deliver our gene therapy to the retina. RGX-314 is designed to deliver a gene encoding an anti-VEGF antibody fragment into retina cells using our proprietary NAV AAV8 vector. Previous preclinical studies have shown that our proprietary vector AAV8 provides more efficient gene delivery to the retina compared to other AAV vectors. Now a quick overview of the ongoing Phase I/IIa study. We have dosed 42 severe wet AMD patients in 5 dose cohorts. These patients received an anti-VEGF injection at study entry to evaluate their response to anti-VEGF via OCT scan. After response was confirmed, RGX-314 was administered via subretinal procedure, including a vitrectomy and subretinal injection. Patients did not receive any prophylactic steroids beyond those normally administered post-op after routine vitrectomy. Patients are then evaluated for safety and efficacy endpoints over the course of 2 years with safety at week 26 as the primary endpoint and secondary efficacy endpoints of visual acuity, retinal thickness and anti-VEGF rescue injections are measured every 4 weeks for 2 years. As reported today, patients in Cohorts 1, 2 and 3 have completed the 2-year study. These patients have moved into a separate long-term follow-up study to collect additional safety data. Cohorts 4 and 5 continue to have monthly study visits, and we will provide further efficacy data at the 1-year time point in the next few months. I wanted to provide here a snapshot of the protocol specified anti-VEGF retreatment criteria that we have instructed our investigators to follow. The criteria listed here are specific and provide a very low bar or threshold for physicians to retreat. As this was a first-in-human study for RGX-314, we wanted to allow physicians to have broad discretion for retreatment for any sign of disease. And finally, this slide provides a snapshot of the demographics of the patients coming into the trial. The demographics are very typical of severe wet AMD patients. As you can see across all 5 cohorts, the ages, baseline BCVA and baseline retinal thickness measures were relatively similar. Patients were enrolled regardless of whether they had AAV neutralizing antibodies. This is actually a benefit of using the subretinal administration as the subretinal space is immune privileged. As you can see, these were patients who needed frequent anti-VEGF injections. They have been treated for an average of over 4 years in almost all the cohorts. And in the year prior to study entry, they had received anti-VEGF injections every 1 to 2 months. This provides some background on how severe these patients' wet AMD was prior to entry into the study. I'd now like to turn over to Dr. Allen Ho, one of the investigators in the study, who will walk us through the safety and efficacy data from the third cohort of patients as well as updates on Cohorts 4 and 5. Dr. Ho?

Thank you, Steve, and good morning, everyone. I'm very pleased to present the Phase I/IIa study update today and to be joined by my colleagues, Bob Avery and Peter Campochiaro to answer any questions you may have. On this slide showing overall safety of the program to date, I'm very impressed with the overall safety. REGENX-314 continues to be well tolerated across all doses with no drug-related SAEs reported. Common ocular SAEs have been noted in this trial for patients that received surgery to develop -- to deliver gene therapy. Many were transient and related to the procedure, including conjunctival hemorrhage, inflammation, irritation and pain are also all expected post procedure. And a minor reduction in vision is also expected due to an air fluid exchange at the end of surgery. As you can see in this slide, many of these SAEs resolved on their own within days to weeks after the procedure. Changes in RPE, or retinal pigmentation, were observed in a number of patients, but there have been no associated clinical symptoms or visual acuity changes. We've also seen this in retinal pigmentation in other gene therapy studies. Retinal hemorrhages are an anticipated event in severe wet AMD patients as their disease progresses, and the majority of these occurred in the early cohorts of the study. Very importantly, for the subjects in this study, there were no clinically determined immune responses or drug-related information beyond what is expected, following routine vitrectomy surgery. Let's go to the next slide, looking at efficacy endpoints. This slide shows mean change in visual acuity and CRT, which stands for central retinal thickness, and average injections over 2 years in Cohorts 1 through 3. The top bars show -- that's corrected visual acuity. And across the middle, you'll see central retinal thickness. And then on the bottom, you'll see the number of annualized injections required in those cohorts, in Cohorts 1, 2 and 3 as you go across from left to right. Across all 6 patients in Cohort 3, visual acuity improved over the 2 years, with the mean best corrected visual acuity increase of plus 14 letters over baseline and mean retinal thickness, which was stable over time. It's important to note here, as Steve laid out earlier in the conversation, in Cohort 3, 3 out of 6 or 50% of patients from Cohort 3 received 0 anti-VEGF injections over 2 years following administration of RGX-314. One additional patient from Cohort 3 who received 4 injections between RGX-314 surgical administration in month 9 was then injection free from month 9 through year 2. So in total, 4 of 6 or 67% of Cohort 3 patients needed no injections from months 9 through the end of the 2-year study. These results are impressive considering these Cohort 3 patients had chronic wet AMD. Recall that these are most needy patients that we enrolled in this study and had previously required frequent injections for greater than 5 years on average prior to entering the study, and his vision would typically deteriorate over time even while on standard of care anti-VEGF injection treatment. Going to the next slide. Drilling down a bit into changes of vision, we wanted to show you changes in vision over the 2 years of the study. Here, you can clearly see the difference between Cohort 3 and Cohorts 1 and 2. In the 2 lowest dose cohorts, we see there is no improvement in vision. And if anything, a trend towards decreasing vision for Cohort 1 despite treatment, which is pretty consistent with the course of vision change over time in chronic wet AMD patients under standard of care injections. In sharp contrast, in Cohort 3, we see visual acuity improving across the 2-year period. Next slide. The next slide is a graph of the 4 out of 6 patients who did not receive any injections after 9 months, not at all different than the curve for the entire Cohort 3 at plus 14 letters. So not only is vision improving, this is being achieved in these patients without rescue injections in the second year of the study. Next slide. This slide shows individual best corrected visual acuity at 2 years for Cohorts 1 through 3, individual patient data that is. Patients in Cohorts 1 and 2 were continuing to require frequent anti-VEGF injections throughout 2 years in the study. But you can see here clearly that there are changes in vision decline in Cohort 1, and patients in Cohort 2 are relatively stable despite regular injections as we would do in our office clinics. In Cohort 3, however, we see a dramatic improvement in vision over 2 years. 5 out of 6 patients in the cohort had improvements in vision ranging from plus 6 to 32 letters. This shows that the vision gain we saw on average over 2 years was not driven by 1 or 2 patients in this third cohort. Each patient in this cohort had either maintained or improved visual acuity at 2 years. We also see that 4 patients with vision improvement did not have any rescue injections after 9 months. Let's look at the 1 patient that's footnoted with minus 3 letters at 2 years, and this was -- this subject had a procedure that was -- resulted in an incomplete dose of RGX-314. In this case, the physician had an initial unsuccessful attempt at making a bleb in the subretinal space, causing a small hole in the retina. The physician then moved the needle a bit to create a bleb next to the first hole. When the bleb was developed, it was observed that the majority of the study drug leaked into the vitreous from the first attempted site. This occurred in just 1 study patient in the entire study, not just in this Cohort 3, so the denominator is out of 42 subjects across 5 cohorts. It occurred early on in the study, and we learned a lot from this with regard to procedure. To emphasize, it has not occurred in any subsequent cases. We spent some time talking about improvements in stabilization in vision and retinal thickness, but I do want to be sure to highlight that these clinical results are in the backdrop of reduced treatment burden. On this look at individual injections, we can see that the anti-VEGF injections that the patients received prior to study entry to the left. Look at this graph, and you can see individual patients in these swim lanes and the vertical bar in the middle is RGX-314 administration. On the left, you can see the injections prior -- in the real-world prior to administration of RGX-314. And to the right of that bar, you can see the notable decrease in the anti-VEGF injections. For 4 out of 6 patients, we see the decrease in injections, and 3 patients at the bottom have received no injections over 2 years, and the 1 patient who had received 4 injections in the first 9 months of the study and then no injections after that. Note that the patient with the inadequate dose is in the top swim lane, and you can see that the majority of the injections in Cohort 3 were from this single patient. Next slide. This slide provides a good overview of the reduced treatment burden across the first 3 cohorts at 6 months and 2 years following the administration of RGX-314. The gray bars represent the injections received in the year prior to the study, prior to administration of RGX-314. We can see for Cohort 3, there was a meaningful decrease of greater than 60% in injection burden at month 6, that is now updated and maintained at 2 years updated in this presentation. Turning to Slide 16, and I think this is a very important slide. We have evidence of consistent biologic activity, which is aqueous RGX-314 protein detection in the eye over the 2 years after administration of RGX-314 for Cohort 3. Protein expression levels were consistent and sustained over 2 years, ranging from 180 to 230 nanograms per milliliter. This level of durability in protein production gives me confidence that the gene therapy has appropriately encoded retinal cells for long-term production of the anti-VEGF protein. Said simply, it looks very strongly like the gene therapy is working. Next slide. Turning to the update on Cohort 5. As previously reported at the end of last year, 8 of 11 patients had reached the 6-month mark without requiring anti-VEGF injections. The patients in this cohort have now reached 9 months in the study and hence the update, and we can share that the data remain consistent. The same patients are still injection free. It is very encouraging to see patients remain injection free, and we look forward to additional data from these patients in the coming months. Finally, we also now have protein expression data at 6 months. Recall that we were showing protein data expression from 1 month in the past. Now this is 6 months from all 5 cohorts. This slide underscores the dose-dependent increase in protein expression, similar to what was reported previously for the 1-month time point across all 5 cohorts. Again, very strong evidence that the science is working. Next slide. Just to recap and summarize. I do believe that RGX-314 is the most advanced and clinically validated gene therapy program for the treatment of a major retinal disease. In the past, we do have a commercially approved gene therapy for retinal disease, LCA RPE65. But that is a niche inherited retinal disease. We're talking about a major retinal disease and I'm very impressed by the overall outcomes that we have seen so far. I believe that this gene therapy could be an important onetime treatment option for patients who require frequent and burdensome anti-VEGF injections. Now I'll turn the call back to Steve. Steve?

Thank you, Allen, for that presentation, and thank you as well for your perspective on the trial results that we've seen to date. To finish up the presentation section of the call, I'd like to take everyone back to the route of administration, as we've discussed. This study was conducted using a subretinal delivery. As most of you are aware, we are also working with a new delivery device, the Clearside SCS Microinjector, which is intended to be used in an in-office nonsurgical approach to deliver the gene therapy into the suprachoroidal space. The images shown here are from a preclinical study published by Dr. Campochiaro and show encouraging transduction in the retina using the routed delivery. We are finalizing our plans and look forward to starting clinical trials with this device in 2020. I'll finish up here with our upcoming milestones for 2020. We have been really pleased with the data thus far from the RGX-314 Phase I/IIa study and look forward to getting the 1-year data from Cohorts 4 and 5 in mid-2020. We will use that data to finalize the design of the pivotal program of RGX-314 subretinal delivery for the treatment of wet AMD, and we expect to initiate a pivotal trial in the second half of 2020. In addition, we expect to initiate a Phase II trial of RGX-314 using suprachoroidal delivery for treatment of wet AMD in the first half of 2020 and plan to have an interim update from the first cohort by the end of 2020. We also plan to initiate an additional Phase II trial of RGX-314 suprachoroidal delivery for the treatment of diabetic retinopathy in the second half of 2020. Thanks, again, to you, Allen Ho, for providing your perspective on these results. Now we move on to the Q&A section of the call.

And I can't help but take advantage of this great opportunity where we have Allen as well as 2 of your colleagues who are not only as well as you, great investigators, but also, of course, great thought leaders in retina in general and also, of course, in the treatment of wet AMD patients. So Allen, Bob and Peter, we often have discussed over time the results that we have here, and we think of the clinical outcome for patients and generally looking at functional outcome in terms of visual acuity, anatomic outcome in terms of retinal thickness or presence of fluid in the retina and also very importantly treatment burden, which, of course, is a big unmet need. I'd really like to ask each of you to give your general perspective of when you see results like what you presented, Allen, how do you translate that? And how do you weigh that when you think of a patient sitting in your exam room with wet AMD? So why don't we start with you, Allen, since you gave the presentation.

Sure. I'm happy to discuss this, and we'll be interested in Peter and Bob's perspectives. Let me pull back a little bit into the context of current events and just explain what's going on in retina clinics now. We are, of course, taking care of patients with emergent and urgent needs in the COVID-19 pandemic and medically essential patients as well. We have these senior patients, 70-year olds, 80 years olds, 90-year olds coming into our clinics, where we're trying to create a safe environment. And they come in knowing that they are the most vulnerable to have severe illness if infected by COVID-19, and it speaks to the importance of visual acuity. So in terms of efficacy endpoints, vision is important and treatment burden is particularly important for these seniors. I had a lady yesterday who came in from a nursing home. She said, Dr. Ho, I came in to see you for my injections for wet AMD. And I know that when I return, I'm going to have to be isolated for 2 weeks in my unit at the nursing home because I left the nursing home. I think it speaks to the importance of reducing burden of treatment for these patients. It's literally, and not to be overly dramatic, a potentially life and death situation in the context of COVID-19. But vision and quality of life, I guess -- I would incorporate the vision and treatment burden into quality of life. It's really important for quality of life. Having a onetime treatment now is even more important for these patients.

Thanks, Allen. That's an interesting perspective with COVID-19. That's something we and all other sponsors are dealing with from a sponsor perspective with ongoing studies. And we've heard that anecdotally, this concept that a onetime treatment actually could have a certain benefit when you think of this reality of the burdens and the potential risk that might exist with needing very frequent follow-up. Bob, how about your perspective on how you think of these different endpoints in terms of real-life and how you treat your wet AMD patients?

Well, I agree with what Allen has just said completely. I'm also very impressed with the visual acuity improvement in this third cohort at 2 years. I think all of the factors we look at, not just vision, thickness, treatment burden, all these things are important. But I'm really quite enthusiastic about this improvement of 14 letters in a really difficult-to-treat population, who had had an average 30-some-odd treatments in the past to see this sort of improvement in the opposite of a naive population but a well-treated or difficult-to-treat population is beyond what I expected. And so my initial reaction is one of excitement over this level of improvement and we could think that it might be due to the constant treatment that these patients are getting. We've proven it with the protein measurements, but it may be that continuous treatment may have some benefit. There have been some suggestions about other studies looking at the fluctuation in the vision -- I'm sorry, fluctuation in the swelling and vision maybe a bad indicator long term. But this is very encouraging. Of course, anatomic improvement goes hand-in-hand with the swelling -- I mean with the visual improvement over time. And the treatment burden can't be underestimated, as Allen pointed out. But I'm most impressed with this visual improvement at 2 years.

Great. Thanks, Bob. So before we hand it back to the operator to open up for general questions. Peter, how about your perspective and any key take-home messages you might have from this data?

I think one thing that particularly impresses me about these data are how much sense they make scientifically as well as clinically because one of the real values of this trial is the measurement of transgene levels. And you can see in the first 2 cohorts that the levels obtained were quite modest. And the results were not particularly good. We still had to do a lot of injections. And even despite those injections, particularly in Cohort 1, the visions didn't do great. Then you get to Cohort 3, and now you see that there is a substantial constant production of the anti-VEGF protein and you see that the majority of patients no longer require injections. And despite this, without any injections, they're doing extremely well because there's this constant production of the anti-VEGF. You can look at Cohort 3 as who're sort of right at the threshold. And there's -- most of the patients -- we know that our patients with wet AMD have different needs. They're not all the patients are not exactly the same. Some require more than others. And Cohort 3 is sort of a picture of right at that threshold. Then you go to the next 2 cohorts, you see further increase and now you see even more patients who don't require any injections, but despite not having any injections, continue to improve in visual acuity. And it tells us that this is something that with sustained delivery of an anti-VEGF agent, that the vast majority of patients are going to do extremely well. Now there are a couple of patients in those last 2 cohorts who still require injections. And that is -- it tells us about the fact that there may be some patients who even with sustained suppression of VEGF, need more. And in this trial, we had a very low bar for trying to identify, as was pointed out by Allen, these are some of the most difficult patients. These are patients who required frequent injections for years. And there are some patients who, despite frequent injections, don't have an optimal outcome. The way that we tried to identify patients who were more likely to be very responsive to anti-VEGF is to take patients who had at least a 30% reduction in the excess thickening 1 week after injection of ranibizumab. That actually is a pretty low bar. So what you can see is that there were a couple of patients who, despite that 30% reduction after -- a week after ranibizumab, they are not patients who are fully responsive to just anti-VEGF. And so going forward, with patient populations who are not as difficult as this, we anticipate that there may be some -- maybe a little bit more rigid test that will better identify the patients who are very responsive to anti-VEGF. And then we anticipate that there's going to be very, very few patients who require injections once they have this high level sustained suppression of anti-VEGF.

Well, Peter, that's extremely helpful. Thanks for that perspective. And I think it also gets across all the learnings that we can get from this data on this Phase IIa study, and we can think forward in terms of that learnings into development. So thanks again, Allen, Bob and Peter, for your insights and your perspective on these results. We want to make sure to leave time for others who are lining up in the queue to ask questions of all of you. So I'd now like to open up the call for questions from those on the phone. Operator?

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

I have 2 questions for 3 doctors. The first one is regarding efficacy and second question is regarding safety. So when we look at the -- over 2-year update, we do see the letter improvement compared to a 1.5-year update. However, we do see the retinal thickness actually increase as well. When we look at 1.5 years, a single with 40-micron reduction for all 6 patients and a 21-micron reduction for 3 patients -- for Cohort 3. And -- but now we do see Cohort 3 from all 3 -- all 6 patients, the retinal thickness actually increased to 2-micron. However, the letter visual acuity continues to improve. So 2 questions regarding efficacy. First, what is the retinal thickness for these 3 patients? And then second, why we did not see the correlation between retinal thickness versus the visual acuity? And I will have one follow-up regarding safety.

Gena, thanks for your questions. Yes, I think this is a great question. That's worth having all 3 of our expert investigators chime in on. One thing I'd clarify is when we look at CRT from a sponsor perspective and going into the study, our goal, taking into account how chronic and how tough to treat these patients are that were enrolled in the study, the goal is to have at least contained CRT and even at least maintain visual acuity, any improvements are really a bonus over that if we're able to maintain those markers of activity with a dramatic reduction in treatment burden. But let's hear from the treating physicians. Allen, your take?

So maybe I'll address the first part of the question about thickness and the disconnect between thickness changes and improvement in visual acuity. We -- so when we measure thickness with the OCT machine at different points in the study, it's kind of giving us snapshots at monthly intervals. And what's happening in between those snapshots is a continuous variable that we don't capture of fluid, either in the subretinal space or within the macula. There were a couple of observations that have come out of recent trials and just basically clinical experience over time, where investigators are looking at where fluid is making a difference and how much fluctuation in fluid there is, as being a difference. Those changes are not really captured when we do OCT images at monthly intervals. So for example, let me be a little more specific. If you have fluctuations in fluid over time, like you might see with intermittent intravitreal injections, you're not going to have the same kind of visual acuity function that you would if you can drive the macula more consistently with an approach that's biologic and scientific, like we're seeing with gene therapy. That may account for why the macula is staying relatively stable at specific times of OCT measurements, but the vision may improving -- may be improving in Cohort 3.

Thanks, Allen. I think in the interest of time, since you really addressed that question to make sure we have time for the other questions. Gena, why don't you go ahead with your second question?

Sure. So regarding the safety, we do see -- I think Allen, you also mentioned at the call, the mild-to-moderate retinal pigmentary changes, they're not concerning. I was just wondering if you can give additional color, how long did it last? And how it was resolved?

So pigmentary changes are color changes in the back of the eye that we have seen. And I'll be interested in the perspectives of the other surgeons as well. To be honest, it's something that is initially subtle and then over time, we can see it in the areas where we deliver the gene therapy and sometimes some change inferiorly as well -- inferiorly in the back of the eye. This is something that has been observed in preclinical gene therapy evaluation, that is animal models, it's something that's seen in the LUXTURNA commercially approved gene therapy. We've seen cases of it. I've talked to the surgeon who's done the most commercial LUXTURNA changes -- surgeries, and they've seen it across many of the surgeons that do that. The good thing is that visual function, visual acuity, specifically, has been very stable, both in the LUXTURNA patients and in this cohort, something worth following. And in terms of resolution, it's not something that resolutions -- resolved, but it does change over time. You might see a little bit of increasing pigmentation and then decreasing pigmentation over time.

Our next question comes from...

Comment on the first question again because I'm not sure whether it came through. I previously mentioned that in the design of this trial, patients got an anti-VEGF injection right at baseline. And then within a couple of weeks, they had the gene therapy treatment. And they had many, many prior injections. So the goal was not to decrease thickening. We expected very little change in thickening because they didn't have a lot to begin with and a change of plus 2 microns is not an increase. This is essentially stability, and this is exactly what one would expect with sustained suppression of VEGF when you have patients who have previously been getting injections and got one just within weeks of the gene therapy treatment. So this is exactly what one would predict.

Great. Thanks, Peter, for that clarification.

If I can just ask -- like following Peter's answer. So the -- even though the retina, I think, maintain the same level, so the retreatment criteria still remain very stringent. Any fluid buildup, the requirement -- basically any fluid built up, you will give rescue injection. If that maintain the same, and you do not need to give patient rescue injection, right? Just wanted to make it clear, my understanding is correct.

Yes, that's correct. So the rescue injections were at the investigator's discretion, but they were as shown in that slide, very, very liberal in terms of any fluid and you have the ability to give an injection so that even a little bit of return of fluid, patients tended to get injections.

Our next question comes from Dane Leone with Raymond James.

Thank you for the presentation and the insight, and thanks to all the docs joining us on the call. I wanted to clarify something that was said during the commentary and with the cadence of the clinical effort here. For the docs here, we've heard that in the month of April, retinal clinic visits are down a lot. I was just curious what -- how -- from your respective institutions have -- what's been the decrease in visits and I just want to clarify, you were talking about that there are still patients that are clearly medically necessary to be getting these interventions, and they might still be showing up to the clinic. Is that what we're kind of thinking if we're going to start maybe the suprachoroidal approach during this time period right now, that you still have patients that would be able to come in and get this. But is there a disruption in terms of handling a clinical study of understanding regular follow-up and visits for these patients if obviously, people are not actually coming to the clinic? And then I have one follow-up.

Great. Thanks, Dane. Since Bob, let's give you a chance to chime in on this one.

Sure. In our clinic, our patient volume has dropped about 60%, but that 40% is almost entirely injection patients. And a few retinal detachment suspects or people who have just had surgery for something urgent like retinal detachment. So we have had a big drop in overall volume of patients, but almost very little change in the patients who are getting injections because they do know that they help. And so from a practice standpoint, we're still seeing the vast majority of our people who need injections. With respect to the trials, our patients are still coming in for trials in general. There are some trials that -- other trials that aren't as urgent that they're not coming in for. Interestingly, the patients who've had this treatment and had been injection-free for a year, don't feel quite the same urgency to come in because they feel almost as though they've been cured. And so it is interesting that I've had to get on the phone and talk some of them in because they're no longer getting injections so much. And so it's just testimony to the benefit of this particular treatment on the treatment burden that they've had for years. That being said, I do think a trial will be possible for the suprachoroidal delivery because people are still coming in who need injections. And so I think we could still enroll such a trial.

Great, Bob.

Great. I've one follow-up if I can. Sorry.

That's all right. Go ahead, Dane. Follow-up.

Okay. Yes. So we now have 2-year data from Cohort 3 -- which actually when I have spoken to some of you in other instances, has been kind of a milestone for the clinical community and understanding the durability of these gene therapies and really kind of the mental hurdle to say, yes, this is something that is going to have clinical utility given all things considered with what it might cost and the procedure and the unknowns involved. Supposing that we have this Cohort 3 data and Cohort 5 is extrapolated correctly for the dose level, the protein expression that we're getting and say it looks good at a 2-year mark, the question really continues to come back, the debate within kind of our community and what we're constantly asking you guys about is what percentage of your patients in your mind with this dataset would qualify for this therapy that you would use this therapy for, assuming that it is going to be a subretinal delivery?

So let's steer this one to you, Allen.

That's a really good question. And I think it's a little bit of a moving target. For example -- and I highlighted the change in the environment for the management of wet AMD in light of a pandemic. We expect, of course, or hopefully, the pandemic to reduce its intensity and its threat to this particular demographic of patients with this common disease that is wet macular degeneration. I think how do you put this in to play in a real world, let's say, post approval? It's hard to really say, but there is going to be increasing demand for something that is more durable. Initially, we might have thought about using this in our most difficult-to-treat patients. And that's reflected in the study population here. I mean think about it. These were patients that were called from very mature retina practices across the country with very experienced clinical investigators, talking to patients about using this new science, having a surgery when they were just getting injections in the office, and the patients went for it because the burden of coming into the office, the burden of having their adult child take a day off of work to bring them there, the burden of being waiting in our waiting rooms for 2 hours, for example, with each visit is very significant. So I don't want to give you a specific percentage of patients, but it applies to the most difficult-to-treat patients. And in the context of trying to avoid office visits, I think the opportunity is increasing.

Great. Thanks, Allen. We have a bit of an embarrassment of riches here with 3 great experts who can address all of these questions, but I know we have a queue of questions.

Our next question comes from Gbolahan Amusa with Chardan.

Congrats on the 2-year result. I had a question about your hypothesis on the 4 responders, let's call them, out of 6. I think you showed something like 292 mgs per mL in terms of transgene or protein produced. And so I'm calculating 92 for the other 2 patients. So isn't this more an issue with response to the procedure as opposed to anti-VEGF, i.e., the efficacy results? And therefore, do you have a hypothesis on how to pick who's going to respond to the procedure? And then I have a quick follow-up after that.

Thanks, Gbola. Yes, we've often talked about it in the past. So just quickly chime in from the sponsor perspective. We've always thought of the protein expression is very key and sustained protein expression is very key to show that we have durable expression. But we've always cautioned against trying to get too quantitative about a specific threshold because that's going to vary from patient to patient. But I think our clinicians can talk about that based on their experience with the underlying variability that exists with their wet AMD patients. Bob, why don't we have you take this one?

Well, there is clearly the variability from patient to patient. Also, a confounder in this case would be the one patient that got an incomplete dose and I don't know his exact protein level, but I would anticipate it being low. So that may be biasing some of it. But we do see quite a bit of variability in the VEGF demand -- the anti-VEGF demand from patient to patient. And I think we expect that is more likely to cause. But it does seem with this increasing production in the Cohorts 4 and 5 that we're going to be able to get around much of the concern about protein production. It seems like the higher doses that we're seeing in the higher cohorts are correlating with even fewer patients needing injection -- needing injections long term. So the Cohort 5 population looks really good with respect to the need for reinjection, and that may be due to the higher protein production. But I don't have the individual breakdown of patients, but I do think, in general, the more protein, the less likely for reinjection, but there's an awful lot of individual patient variability that has to be factored in, and these numbers are very small with 6 and the cohort here and there.

Thank you, Bob. And very quickly because we have other questions, but I can't help but ask you, Peter, given your decades experience thinking about protein expression and that translation into efficacy. Any quick other thoughts on that topic?

I think Bob answered it very well. And I previously commented on it that in Cohort 3, the levels of expression are probably right at that threshold where there are going to be some patients that really -- the patients who need particularly high levels of anti-VEGF, who may not -- it may not be satisfied. I think in the Cohort 4 and 5, we're at a level that, that's going to really take care of most of the variability. So I anticipate that those -- that sort of dose is going to be particularly good for the vast majority of wet AMD patients.

Great. And just a quick clarification question on Slide 17 for Cohort 5, the first 2 patients at the top had injections, and then the rest didn't. Is that sequential? And therefore, does that imply you learn something about the procedure after the first 2 patients?

No, I can quickly address that. This is -- these were not how they were chronologically enrolled in the study. We simply sequence them on the slide for easier visibility.

Our next question comes from Mani Foroohar with SVB Leerink.

Congratulations on the sustained durability data. That was quite interesting. I want to follow-up on a couple of Gbola's questions regarding procedure process. Regarding the patient -- the one patient that had a 3 letter loss because of leakage of the drug product into the vitreous. Do we see any inflammation of the consequence? I know there's been a discussion around inflammatory response to virus in the vitreous for another program being developed for wet AMD? And then as a second question also around procedure process. You've talked a little bit about continuing to improve the procedure, the administration in pursuit of a better response rate, as Gbola put it. What are the additional learnings that you picked up regarding improving procedure administration, consistency of the surgery between surgeons? And how are you integrating that into your pivotal study going forward?

Thanks, Mani. To reiterate, something that's been discussed before, we saw no evidence of any inflammatory response related to any potential response to the vector in any of the patients, including this patient. Keep in mind that at the end of the procedure, there's an air fluid exchange. So any of the leak of -- through the retinotomy back into the vitreous would have been removed during the air-fluid exchange. Allen, do you have any thoughts on Mani's question?

Sure. We think of the eye as having some kind of relative immune privilege. Think about what we've all learned in the -- I'll come back to COVID again about, what happens in lung alveoli when there's a viral infection, what happens with inflammation. When you inject and consider the number of virus particles, we're talking about 3 billion, 10 billion, 100 billion, more than 100 billion viral gene copies that are going in. We're -- it's incredible how quiet these eyes have been. So to get right at your question about the one patient that had had the leak with gene copies that wound up in the -- and viruses in the vitreous, every eye was very, very quiet. I mean we had a little bit of inflammation that I described in the -- that you would expect after any vitrectomy surgery but the eyes are amazingly stone-cold quiet. It's incredible, in contradistinction to other ways of delivering the virus that we've seen in other wet AMD programs. Now that particular surgeon, and that was, I think, surgery #14, you asked about the process and you're speaking to variability in surgeons and delivery. After that, we had 0 events of leaks from bleb -- inability to raise a bleb or leaks from bleb from another bleb created next to a bleb. So I think we've gotten much better. I think one of the training processes that we do, as we go back and look at the video tape and kind of look at the film, Monday Night football, review of game film. We edit our surgical film. We train. We learn from each other and the processes and the hardware and really, the industry in the ecosystem of retinal hardware, for example, the cannula that is now surgeon controlled with a foot pedal. All these things contribute to incremental safety and consistency in dosing. We had none of these events after that one shared event that we showed all the other surgeons. And I'm very confident that this particular method of delivering something in the subretinal space will be achievable in the broad commercial setting should it get there.

I'm sorry, but I'm going to have to run because I got injection patients waiting for me.

Well, thank you so much, Peter, for your insights and answering the questions that we had.

All right. Bye-bye.

Bye-bye.

Our next question comes from Matthew Harrison with Morgan Stanley.

This is Kostas on for Matthew. 2 quick questions from me. The first one is about the intra-patient variability in BCVA. You addressed the intra patient variability, and I was wondering given that what we see monthly is a snapshot, as you said. What do you think about the intra-patient variability over time? And how important this is for you? And the second question is about the long-term effect of the drug. After how long post-injection could we tell that what we see in the 2 endpoints is the final or the total effect of the drug? Is it 6 months out, 1 year or later?

Great. Thanks for the questions. Bob, do you want to take this one?

Sure. The second question about the time point, what you see, when it ends, I think I can answer that most easily with the protein data being stable out to 2 years and the visual acuity just increasing out to 2 years makes me feel comfortable in saying that this seems to be effective for 2 years. And maybe beyond that, I would certainly hope. With respect to the intra-patient variability, I find that's a tricky question, and one has to look at that in all of the similar trials because when you're looking at small patients -- I mean small trials like this with a handful of patients, just a few really needy patients can sort of bias the results. So I don't think we have a lightweight group here. These are all patients who had 30-some-odd injections on average with 9 on average in the previous year. And so these are -- this is a very needy lot to start with. But still, even within that subgroup, there are some, as Peter mentioned earlier, that just may not completely respond to all the anti-VEGF you throw at them. And we've seen that in the clinics as the "nonresponders." It's a small percentage in our general population, but probably a larger percentage in this study than on average, whereas most studies as they go towards Phase III and beyond, try to find easier patients to show efficacy. And I'm particularly impressed with these results in a difficult population of patients rather than the less demanding patients who may see and some later stage trials, you may be looking to compare this to in the future.

I'm showing no further questions in the queue at this time. I'd like to turn the call back to Ken Mills for any closing remarks.

Thanks, operator, and thanks very much, Allen, Bob and Peter for joining and sharing your valuable time and views today. We appreciate everyone on the call joining us. Look forward to providing further updates. Maybe to Allen's point, look forward to some sports coming back online sometime soon. I hope everyone stays safe and well, and have a great rest of the day and week.

Ladies and gentlemen, thank you for your participation on today's conference. This does conclude your program, and you may now disconnect.