REGENXBIO Inc. Q3 FY2022 Earnings Call

Hello and thank you for being here. Welcome to the Q3 2022 REGENXBIO Inc. Earnings Call and Update on ALTITUDE. It is now my pleasure to introduce Chief Legal Officer, Patrick Christmas.

Good morning, and thank you for joining us today. Earlier this morning REGENXBIO released financial and operating results for the third quarter ended September 30, 2022, as well as new data from our ALTITUDE trial. The press releases and data presentation are available on our website at www.REGENXBIO.com. Today's conference call will include forward-looking statements regarding our financial outlook and our 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 Management's Discussion and Analysis sections of REGENXBIO's Annual Report on Form 10-K for the full year ended December 31, 2021, and comparable risk factors section of REGENXBIO's quarterly 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, November 3, 2022, 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. In addition, any unaudited or pro forma financial information that may be provided is preliminary and does not purport to project financial positions or operating results of the company. Actual results may differ materially.

Thank you, Patrick. Good morning, everyone. Thanks for joining us. I'm pleased to begin today's call with a recap of the recent business highlights, as well as an update on our corporate goals. Vit Vasista, our Chief Financial Officer will provide an overview of financial results for the third quarter ended September 30, 2022. We're bicoastal today; Steve Pakola, our Chief Medical Officer on the West Coast recently attended Retina Society. He will provide an in-depth overview of the data that was presented yesterday at the Retina Society Meeting from our Phase 2 ALTITUDE trial evaluating RGX-314 for the treatment of diabetic retinopathy or DR using suprachoroidal delivery. Towards the end of the call, we'll be joined by ALTITUDE Investigator Lejla Vajzovic from Duke University and Independent Retina Expert, Dr. Peter Kaiser from the Cleveland Clinic. Lejla and Peter will stay on with us as we open up the line for questions. At REGENXBIO, our mission is to improve lives through the curative potential of gene therapy focused on developing therapies for diseases that have significant unmet need. We continue to be a leader in gene therapy. There are thousands of patients who have been dosed with AAV Therapeutics derived from our NAV technology platform and hundreds more receiving treatment every quarter. I'm very proud of how our company has been advancing our internal pipeline, and I believe our fundamentals have never been stronger. We put into place our 5x'25 strategy to progress five AAV Therapeutics from our internal pipeline and license programs into pivotal stage or commercial products by 2025. I'm now going to summarize some of the program highlights and operational updates from our announcement this morning. Our global eye care collaboration with AbbVie to develop and commercialize RGX-314 for retinal disease continues to advance and is on track for our first BLA filing in 2024. Progress in trial enrollments and emerging clinical trial data also supports excellent progress in our suprachoroidal delivery programs. At AAO, RGX-314 subretinal delivery for the treatment of Wet AMD was reported to be well tolerated with long-term durable treatment effects now observed up to four years. We expect this trial along with the two ongoing pivotal trials ATMOSPHERE and ASCENT to support our planned BLA submission in 2024. In October, we also announced positive interim data from the Phase 2 AVA trial of RGX-314 for the treatment of Wet AMD using suprachoroidal delivery. These data show that RGX-314 was well tolerated with stable BCVA and a meaningful reduction in anti-VEGF treatment burden at all dose levels out to six months. We announced the expansion of this trial to further explore the third dose level in our six cohort, with a short course of prophylactic ocular steroid following RGX-314 administration in order to potentially prevent the observed incidence of mild to moderate intraocular inflammation. Yesterday, as I mentioned at the Retina Society meeting, new positive interim data was presented from our Phase 2 ALTITUDE trial of RGX-314 for the treatment of DR using suprachoroidal delivery and Steve will lead the review and discussion of these data in greater detail shortly. We've been working diligently to prepare for the initiation of our first in human trial of RGX-202 for the treatment of Duchenne and continue to expect to dose the first patient in the affinity Duchenne trial in the first half of 2023. RGX-202 is a potential one-time gene therapy for the treatment of Duchenne and is being developed as a highly differentiated product, designed to deliver a transgene for a novel microdystrophin that includes the functional elements of the C-Terminal domain found in naturally occurring dystrophin. RGX-202 is designed to support the delivery and targeted expression of genes throughout the skeletal and heart muscle using our NAV AAV8 vector. RGX-121 is our candidate for the treatment of Mucopolysaccharidosis Type II, also known as Hunter Syndrome. This is currently being evaluated in an expanded pivotal phase program called CAMPSIITE. We have been dosing patients in this pivotal program. The most recent positive interim data update from this study reported that RGX-121 was well tolerated across all cohorts studied. Biomarker data from the patients in all three cohorts indicated encouraging dose-dependent reductions of cerebral spinal fluid GAGs following one-time administration of RGX-121. Improvements in neurodevelopmental function and caregiver-reported outcomes demonstrated CNS activity up to two years after RGX-121 administration. The expanded pivotal phase of this program is expected to enroll up to 10 MPS II patients, using commercial scale GMP material to support a BLA filing in 2024, using the accelerated approval pathway, with the potential to enroll additional patients. This is our second active pivotal program and another opportunity for a BLA filing by 2024. Our ongoing Phase 1/2 trial of RGX-111 for the treatment of severe MPS I or Hurler syndrome continues with plans to enroll additional patients in Cohort 2 expansion arm. Our manufacturing innovation center and GMP capability remains a key differentiator for REGENXBIO and a key element of our strategy. Our in-house facility is cutting edge and allows us to move quickly from candidate selection to production of clinical-grade material, which supports accelerating the early development of AAV Therapeutics. Additionally, we believe our approach focuses early on product quality and process control, which lessens the need for changes during clinical development to enable efficient transition from clinical trials to commercial readiness. I would now just like to take this time to thank our entire REGENXBIO team, all of our investigators and their site support staff and the patient communities for their commitment to the continued development of our AAV Therapeutics. We certainly believe that one-time gene therapy can address a whole range of unmet needs in both chronic and rare diseases, and we remain dedicated to these patients and their families. Overall, reflecting on this quarter and at this point in the year, I'm very proud of the progress we've made to advance our 5x'25 strategy. And with that, I will now turn the call over to Vit for a review of our third quarter results and financial guidance.

Thank you, Ken. REGENXBIO ended the quarter on September 30, 2022 with cash, cash equivalents and marketable securities totaling $617 million compared to $849.3 million as of December 31, 2021. The decrease was primarily the result of cash used to fund operating activities and capital expenditures, as well as temporary unrealized losses on marketable debt securities during the nine months ended September 30, 2022. R&D expenses were $63.3 million for the quarter ended September 30, 2022 compared to $47.9 million for the quarter ended September 30, 2021. The increase was primarily attributable to personnel costs and expenses associated with the clinical trials and manufacturing-related activities for our lead product candidates and was partially offset by REGENXBIO-314 development costs reimbursable by AbbVie under our eye care collaboration. In accordance with the collaboration agreement, REGENXBIO will continue to fund certain ongoing clinical trials for RGX-314 through the end of 2022, while other RGX-314 development costs are shared with AbbVie. Beginning in 2023, AbbVie will be responsible for funding the majority of all REGENXBIO-314 development expenses. Based on our current operating plan, we expect the balance in cash, cash equivalents, and marketable securities of $617 million as of September 30, 2022 to fund our operations into 2025. And now, we would like to return the call over to Steve for an in-depth discussion of the recently announced ALTITUDE data.

Thank you, Vit. As Ken shared, we recently presented interim data updates for RGX-314 trials for the treatment of Wet AMD using subretinal and suprachoroidal delivery. RGX-314 is also being developed for the treatment of DR, and we're pleased to be sharing new interim data from our Phase 2 ALTITUDE trial of our RGX-314 using suprachoroidal delivery that was presented yesterday at the Retina Society meeting. Slides from that presentation can be found in the media presentations and publications section on our website. Joining me this morning we have Dr. Lejla Vajzovic, Associate Professor of Ophthalmology and Director of the Duke Vitreoretinal Fellowship Program and the Lead Investigator who presented the ALTITUDE data yesterday. We're also joined by Dr. Peter Kaiser, Director of the Center for Ocular Research and Evaluation at the Cole Eye Institute at the Cleveland Clinic. DR is a complication of diabetes, and it is the leading cause of blindness in adults between the ages of 24 and 75. An estimated 27 million patients are affected by this debilitating disease worldwide. DR is a slowly progressing disease that can lead to vision-threatening complications including diabetic macular edema or DME and neovascularization that can lead to blindness. Like in Wet AMD, patients with DR are treated with anti-VEGF therapy, which has proven to reduce the risk of developing vision-threatening complications. However, due to the unsustainable treatment burden using anti-VEGF therapies, primarily as a result of the frequent intraocular injections required, many patients with this condition put off receiving any treatment until symptoms become unavoidable. We believe that gene therapy like RGX-314 could potentially overcome this hurdle and provide an important therapy for DR patients to significantly alter their disease progression. ALTITUDE is a multi-center open-label randomized controlled dose escalation Phase-2 trial evaluating the efficacy, safety, and tolerability of suprachoroidal delivery of RGX-314 using the SCS Microinjector in patients with a DR diagnosis of moderately severe or severe non-proliferative diabetic retinopathy NPDR or mild proliferated diabetic retinopathy PDR. Patients in Cohort 1 received RGX-314 at a dose level of 2.5x10^11 genomic copies per eye, which we refer to as dose 1. While Patients in Cohorts 2 and 3 received RGX-314 at an increased dose level of 5x10^11 GC/eye, which we refer to as dose 2. Patients in Cohorts 1 through 3 did not receive prophylactic corticosteroid therapy before or after RGX-314 administration. As of October 17, 2022, RGX-314 was reported to be well tolerated in Cohorts 1, 3. Five serious adverse events were reported, none of which were considered drug-related. For the total group of Cohorts 1, 3 receiving RGX-314, 50 patients in total, common ocular adverse events in the study eye through six months were predominantly mild and included conjunctival hemorrhage, conjunctival hyperemia, and episcleritis. In addition, 3 patients experienced intraocular inflammation (IOI), all of which were mild and resolved on topical corticosteroids. There were no meaningful differences in safety outcomes observed for patients who were NAb positive. Best Corrected Visual Acuity remained stable in Cohorts 1 through 3 through six months. At six months, patients treated with RGX-314 demonstrated clinically meaningful improvements in disease severity versus observation control as measured by the Diabetic Retinopathy Severity Scale (DRSS). Specifically, 20% of patients representing 40% of patients in dose 1 and 11% of patients in dose 2 achieved a 2-step or greater improvement in DRSS score versus 10% in observation control. Additionally, 54% of patients, representing 60% of patients in dose level 1 and 51% of patients in dose level 2, achieved any level of DRSS improvement versus 20% in control. It's important to note that zero out of 15 RGX-314 treated patients had at least a 2-step worsening in DRSS score, while 20% of patients in the control arm experienced at least a 2-step worsening. So with that I will now turn the call over to Dr. Lejla, who is sitting next to me in lovely Pasadena. Lejla, we're really excited to hear your presentation yesterday at the Retina Society meeting, and it's a great opportunity for us to hear your clinical perspective as Lead Investigator in the trial regarding the interim results that you presented.

Great. Thank you, Steve. It's a pleasure to be here today, and I'm very excited about the interim data that was presented yesterday and discussing this morning. Primarily, as Steve nicely highlighted, diabetic retinopathy is a tremendous public health problem globally, leading to very busy clinics with diabetic retinopathy patients who unfortunately, because of their status and working age, cannot keep up with the treatment burden of frequent injections. This typically translates to about 90% of my patients being watched and non-treated, and many are not even coming for their appointments. There is a tremendous need for better treatments; more sustainable treatment options. Having a one-time treatment in office may provide a solution. I'm excited to see the interim data results. First of all, the efficacy looks very promising with improvements in all cohorts, including the Diabetic Retinopathy Severity score, and no disease worsening that we observed in the data results. More importantly, the safety results look promising as well. The fact that we're seeing good results with minimal evidence of inflammation is encouraging to me. So, overall, this translates to hopefully having a treatment option for the 90% of those patients who are currently being observed, and who are potentially going to have disease affecting visual decline in the future. This option may provide a solution to the vision worsening.

Great. Thanks so much, Lejla, for that perspective. As the audience can hear, we're very excited about this interim data that Lejla presented and the potential of RGX-314 for patients with DR. As we continue to build upon the drug profile of RGX-314 in DR, we've made the decision to expand the ALTITUDE trial to include a higher, third dose level of 112 GC/eye, as Lejla outlined in that presentation yesterday. The trial is currently enrolling two new cohorts. Cohorts 4 and 5 at this third dose level. Cohorts 4 and 5 are enrolling patients stratified by DRSS levels, with patients in Cohort 4 having moderately severe to severe NPDR, which has DRSS levels of 47 to 53, and patients in Cohort 5 having mild to moderate PDR, which has DRSS levels of 61 to 65. We're excited about that ability to evaluate in an expanded range. Patients in these cohorts will receive a short course of prophylactic ocular steroids following RGX-314 to evaluate the ability to prevent or reduce the incidence of the mild intraocular inflammation seen to date in the setting of no prophylactic steroids. Patients will be enrolled in these cohorts regardless of baseline AAV8 NAbs status. We also have sitting here with us in Pasadena this morning, Dr. Peter Kaiser, who, in addition to being an expert clinician and clinical trial expert across the retina space, is also a very experienced central reading center grader and expert in overseeing assessments of diabetic retinopathy and the use of the standard DRSS scale. So, Peter, this is a perfect opportunity to blend your expertise both clinically and how you think of endpoints when it comes to diabetic retinopathy and the use of the DRSS scale.

Sure. Yes, and thanks for inviting me. Lejla really outlined it great, which is that we have two products that are FDA-approved for the treatment of diabetic retinopathy, and the regulatory endpoint that we use is the Diabetic Retinopathy Severity score, which is something that we do with reading center level in general at a clinical level. Lejla and I don't count my grinders and look at it as closely as we do with a clinical study. It's important to understand that the DRSS was developed a long time ago, almost 30 to 35 years ago now, for the early treatment diabetic retinopathy study; it was one of the first randomized studies done across medicine. The significance of a two-step change is that it represents a very significant change in the level of retinopathy, which is why the FDA and the EMA use it for regulatory approval. However, in clinical practice, what we want to see is whether our patients are improving overall. As Lejla correctly pointed out, the reason we don't use the FDA-approved products, both Lejla and Lucentis, as often is that very few patients do. Most of these patients actually have very little changes, and those who don't see proof that with these injections, but as physicians, we can see the improvement. This really brings up the point of RGX-314: this is, to me, a killer app for gene therapy, allowing these patients to have an improvement in the Diabetic Retinopathy Severity scores, which was nicely presented by Lejla yesterday at the ALTITUDE interim study results. This is very exciting for all of us in the retina field.

Wonderful, thanks so much, Peter. And with that, we are ready to turn the call over for questions. Operator?

And our first question comes from the line of Gena Wang with Barclays.

Hello, thank you very much for taking our questions. This is Xian for Gena. I have two questions. The first question is about inflammation. The inflammation rate at the 5E11 dose cohort seems to be quite similar to that of wet AMD at the same dose. Could you provide more detail on the onset duration and how long it took for the inflammation to resolve, including the duration of steroid usage and the time required for resolution? My follow-up question is regarding the new pro cohort. Can you elaborate on the short course steroid? Is it similar to or the same as AAVIATE for wet AMD? Specifically, what is the administration plan? Will you use both topical and a one-time subretinal injection? What steroids have been utilized and what will be the dosing regimen? Thank you very much.

Thanks, Xian. This is can Steve; I think those questions are best directed to you and the experts there.

Great, hi Xian, thanks for the questions. I'll give the initial comment and pass it over to Lejla to give her perspective on what she experienced within the trial firsthand. So in terms of inflammation, you're exactly right. We didn't see anything unanticipated and were quite pleased with the low rates of mild intraocular inflammation. The characteristics were what we saw previously and nothing concerning. We see it, come on in generally within two to six weeks of RGX-314 and it's very easily managed with a short course of topical corticosteroids. Our investigators and we will hear Lejla's perspective, were very happy with the profile that we're seeing. That’s consistent with what we've seen previously. We have this great opportunity to evaluate further characterizing the setting of prophylactic steroids, which allows the clinicians to assess how these patients do and potentially mitigate even further the risk of inflammation. We're doing that with topical ocular steroids in the expansion of the ALTITUDE study, and it will just be a standard short course with typical taper over weeks, which our investigators and our thought leaders are very comfortable with that type of prophylactic regimen. Lejla, as you actually dosed patients in the trial and is quite aware of the data we saw across the trial, what was your perspective in your experience and also your colleagues' experience regarding inflammation?

Thank you, Steve. Yes, exactly what you highlighted. We have had patients in this trial, and I've been watching them very carefully for any evidence of inflammation. I would say it was really mild, if it presented, exactly two to four weeks after the injection and resolved on its own. Rarely did any patient show any signs of severe inflammation. This, because these patients are in a clinical trial setting, we were closely monitoring and noting any symptoms, and if we saw any hints of it due to our sensitivity to inflammation in gene therapy trials, we were proactive in treating them. The treatment, as you mentioned, is very reasonable and active as well in topical steroids format. It was a short dose sequence that was used for the patients who did experience inflammation. I think the overall safety profile is promising and very manageable by specialists.

Thank you. And our next question comes from the line of Vikram Purohit with Morgan Stanley.

Good morning. This is Gospel on behalf of Vikram. We have two questions. First, when doctors treat patients with diabetic retinopathy, how do they assess progress? Are they usually looking for a two-step improvement in the Diabetic Retinopathy Severity Scale, or any level of improvement? Additionally, how do you think the introduction of a preventive steroid will affect the commercial potential for RGX-314 in diabetic retinopathy, if at all? Thank you.

Steve, again, right at you.

Great, so thanks Gospel. I'm going to direct it right away to Peter because I think both of these questions fit very well for getting a clinical perspective on how DR patients are managed and also how to think about topical steroids.

Yes, so I'll handle the second question first. When you look at any new treatment as retinal specialists, we have heightened sensitivity to intraocular inflammation, and the term is a catch-all phrase. Obviously, it includes anything that we could possibly see. When I look at the results of the suprachoroidal treatment both in AMD and diabetic retinopathy of RGX-314, this is mild IOI. I served on the safety review committee for Novartis, and this is not the same thing. There's no retinal artery occlusions, retinal vein occlusion or retinal vasculitis. This is very mild intraocular inflammation that's treated with a short course of steroids, so to me, that's not a big deal. I'm not concerned about that. Certainly, we have to see more patients, but so far none of the data concerns me in any way. In terms of the first part of your question about DRSS, we do that at a reading center level. This requires really carefully counting macro-aneurysms and other visual factors. In clinical practice, the average retinal specialist is not going to do that, but we will look at patients over time to make sure that they are improving. In other words, if they have early neovascularization, levels 61, it's enrolled in this clinical study; we will be watching that very closely with any of our treatments to ensure that area is resolving. In general, we expect improvement, but patients typically require frequent injections for type of diseases as well.

Thank you. And our next question comes from the line of Alex with Bank of America.

Hi guys, thanks for taking our questions. A couple from us also on DR. First, could you talk about the rationale for adding the higher dose level in ALTITUDE? Is there a certain bar on DRSS or some other metrics that you would ideally like to hit that you're not already? Just trying to understand how you're thinking of the data thus far, given that it looks like there was actually a step down in DRSS improvement from dose one to dose two. But maybe there's a bolus of one-step improvers in cohort three? Secondly, could you talk about the observational control in the study? Is this an appropriate comparator arm through your discussions with the FDA? I guess, looking at a pivotal study, do you think you need to run a head-to-head similar to what you're doing in the wet AMD program? Thanks.

Thanks, Alex. In terms of rationale for the higher dose, these are both AAV8 studies in ALTITUDE. These are the first two studies ever evaluating suprachoroidal delivery of gene therapy for these indications. So this is an exciting time for the field and for us to characterize RGX-314 via this route of administration. We actually have interim data that we presented with dose level three in the wet AMD setting from the AAV8 study. So we have a head start in evaluating this. It made perfect sense for us and our strategic partner AbbVie to continue to evaluate in the study. As for dose levels one and two, as Peter mentioned, there are various ways to look at change in DRSS. The reality is when we look at the totality of this data, we see what we want to see in terms of both dose levels' outcomes as well. In terms of what we would need to do in a pivotal study, we are very confident about an observational control for the reasons that Lejla and Peter elucidated nicely. Even though we know available repeated injections work in terms of improving DRSS and improving DR, the treatments are simply not used; only a small proportion of patients, as Lejla mentioned. So standard care is still watchful waiting. An observational control is ideal for this setting, and one of the nice things about DR development is that we have the concurrent control in this trial where we see what you'd expect to see. I think either Lejla or Peter could address this, and when you look at our observation control and think of precedents in the literature and your own clinical experience, what do you expect to see if you don't treat patients?

I think it's important to point out that in the observational arm, if patients are accessible, the expected progression is typical for diabetic retinopathy, which generally leads to complications. As soon as we put patients into the observational arm, it reflects the current reality, where we are observing these patients and not treating them with frequent injections. From my clinical experience, that's quite typical.

Yes, fully agree. The current clinical standard from a regulatory standpoint is not to do a head-to-head study against intravitreal anti-VEGF injections. That would not be required; a sham control in this disease is not only regulatory reasonable, but it's also a very doable study for my patients. If you put anti-VEGF as a control, it would be hard for me to get a patient into the study. It's the opposite of what you may think, but from a regulatory standpoint, it is totally fine to do a sham control. In terms of numbers, I think the beauty of this data set is that there is a control group, so you can see what happens over time. The control group has shown is what we would expect: about 20% or so having significant worsening. A few patients get better; look at the control group's experience in reduced variability in such studies.

Thank you. And our next question comes from the line of Ellie Merle with UBS.

Hi, this is Sarah for Ellie. Thank you so much for taking our question. Looking at the change in DRSS score that you see at month six, differences across cohorts between no worsening or no change or greater than two-step improvement, do you look at this as an effect of the neutralizing antibody status and thoughts about that moving forward into a potential Phase III or labeling? Secondly, could you provide any detail or color on the five SAEs that occurred during treatment? Thanks so much.

Great, thanks Sarah. So on your first question about the different cohorts and the different dose levels in the NAb status, very similar to what we see in AAV8 studies. We've not seen an impact as we look at this data. Of course, with 15 to 20 patients per cohort, you're going to have some variability. Also, considering baseline DRSS and how severe you were at baseline is a variable that can impact whether you can improve by two steps or not. I think that's actually an insightful question. So I’ll turn it over to Peter to discuss the nuances of the data based on baseline characteristics. But certainly, if you take that into account, we find the totality of the data shows that in each of the dose levels, the cohorts are moving in the right direction unlike the control arm. If you really consider all the variables, such as not worsening, biologics, and how multiple control subjects behave as well.

Yes, I think whenever you look at interim data, especially in Phase 2 trials with relatively small patient sizes, you don't want to read too much into results. You want to look at the totality of that data, and if you look at all the cohorts, they are trending in the right direction. There's a right shift in every cohort, whereas in the control group, you don't see that shift at all. If you look at Cohort 1 versus Cohorts 2 and 3, there are lots of patients in both and they were balanced regarding baseline characteristics. However, in Cohort 1, there were more patients with early PDR, so the level 61 patients had minimal neovascularization at the start. Therefore, achieving a two-step improvement is much easier with just a small amount of anti-VEGF treatment. In contrast, if you take someone with severe NPDR and try to improve two steps, that's a bigger change. This means having a lot of PDRs or early PDR, makes it easier to show significant results. Ultimately though, we care about the entire patient population as well as overall trends.

Great. And Sarah, your other question on SAEs: none of the five SAEs were considered drug-related. The types of SAEs that happened were typical for diabetic patients who are generally older. To give you an example, a broken femur and other unrelated aspects occurred. The only ocular SAE happened in the fellow eye for the patients, which had worsening vitreous hemorrhage. Overall, our safety profile appears very clean.

Thank you. And our next question comes from the line of Luca with RBC Capital Markets.

Great, thanks for taking our questions. This is Lisa on for Luca. Just two questions from us. Can you elaborate more on the decision to include prophylactic steroids? Was this due to the diabetic retinopathy alone, or is it based on the total data between the diabetic retinopathy and Wet AMD programs? Also, I noticed that the Cohort 2 and 3 patients had no prior anti-VEGF injections, but Cohort 1 patients did and they appear to respond a little bit better. So I was wondering if for the high dose cohorts, will you enroll patients who are anti-VEGF experienced versus anti-VEGF naïve? Thanks.

Thanks, Lisa. To elaborate more on the decision to expand: again, we take advantage of all the data that we have. It's one of the nice aspects of having both a Wet AMD AAV8 study ongoing as well as this ALTITUDE study in DR patients. It gives us a chance to look at safety, tolerability, and also the biological effect for these VEGF-driven retinopathies. We are very pleased with our partner AbbVie, and we looked in concert at these interim data, and I think it was a very natural decision to go up on dose for dose level three as we did with the same exact dose in AAV8. The second question, yes: as you mentioned, some patients in one of the cohorts had prior treatment. What we do in these types of studies is ensure there is a certain washout window, so even if that patient is not "treatment-naïve," they have not had any anti-VEGF injection in at least six months to minimize confounding factors. There have been interesting presentations on this, and we’ll follow that same approach moving forward. We haven't amended that part of the protocol where a patient can have had a prior anti-VEGF treatment but not within a recent time frame.

Thank you. And our next question comes from the line of Andreas with Wedbush.

Good morning and thanks for taking the question. So for us, on the bottom of Slide 9, it says that a couple of patients received anti-VEGF therapy. Could you tell us how we determine if patients receive standard-of-care, and what the criteria were? I have a follow-up.

Sure. In patients with this disease, we look for complications and the investigators look for complications. At the end of the day, the investigator and we as sponsors agree if it's indicated to treat a patient that they should proceed with treatment. Certainly, with the longer we follow these patients, that's one of the key potential benefits of sustained anti-VEGF treatment is the ability to prevent patients from developing vision-threatening complications. We had one patient in the control group who did need treatment, and we elaborated on that who, given with treatment, progressed rather than declined. We also had a lone patient in the 50 RGX-314 treated eyes that had a single anti-VEGF injection early on. If you look at the totality of the data, directionally, it also goes in the same shift in terms of outcomes. Lejla, as you presented this data, how do you think of retreatment in that population?

Yes, you pointed out that historic trials have not typically included mild or moderate PDR patients; we are doing that here. That inclusion carries significant potential gains, but there's a risk of progression, especially early on in the treatment protocol. To your observation, one patient did receive anti-VEGF injections relatively soon after enrollment. One wonders if that was indicative of the progression that early on, rather than the treatment having any bearing on the enrollment period, which indicates risk associated with advance.

Okay, great. You might have touched on this in previous questions, but just regarding the decrease in greater than two-step improvement observed from Cohort 1 to Cohort 2 and Cohort 3. How are you thinking about or what are your expectations for the higher dose? Thank you.

Andreas, we will have to see of course, that’s why we do the trial. We are encouraged that with dose level one and two, we are seeing what we wanted. Now we have the opportunity to look at a higher dose level, and as Lejla mentioned, we're also expanding to include not only mild PDR but also moderate PDR while stratifying based on that. We will have a lot more patients and a lot more data to assess dose response here, as well as how we can assess it in Wet AMD.

Thank you. Our next question comes from the line of an unidentified caller.

Good morning. Thank you for taking my question. One on potential improvement from six to twelve months. You have previously shared the data on improvement from three to six months and compared that to standard-of-care; I wanted to know if you can share any expectations for RGX-314 continuing progress beyond six months?

So, in the existing cohorts and moving forward, we care about the time points presented to date, and we certainly look forward to compiling the data for future reporting on longer-term follow-up time points for these cohorts, including the one-year time. As for expectations, one illustrative way to contemplate this is to see what has been done with repeat injections with existing therapies impacting diabetic retinopathy severity. As treatment frequency decreases, patients may drop from treatment, and that diabetic retinopathy severity tends to return. What we believe about our safety profile is that we do track well from the regulatory standpoint and that provides a larger study that hits the necessary regulatory bar while also prioritizing what is ultimately important to the investigators and the patients: shifting severity to the right and preventing patients from worsening and developing blinding complications. Thank you, operator. I appreciate that. Steve, thanks for walking us through that overview. I'm really grateful to Dr. Vajzovic and Dr. Kaiser for both their time early this morning and for their perspectives on treatment paradigms in DR and insights on the new interim data from the ALTITUDE trial. I just want to reiterate that REGENXBIO continues to perform at a very high level. We have an amazing team that is dedicated to expanding understanding and applying AAV vectors, and innovating effective AAV therapeutics that have the potential to significantly impact patients' lives. We've had several updates over the past months from both our eye care collaboration with AbbVie as well as our rare disease portfolio. We have a foundation of over $600 million to fund our mission and operations into 2025 through multiple filings and other anticipated data milestones. I truly believe we have a clear and definable path to achieve our 5x'25 vision to advance five AAV Therapeutics from our internal pipeline and licensing programs into pivotal stage or commercial products by 2025. We look forward to keeping you all updated on our progress as we finish this year and begin to look ahead at 2023. Again, thanks very much to our guests and the entire team. Have a great rest of the day.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect.