RGNX - NASDAQ

Hello and thank you for standing by. Welcome to the Q3 2022 REGENXBIO Inc. Earnings Call and Update on ALTITUDE. [Operator Instructions] 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 meeting. 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 at 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 this preliminary and does not purport to project financial positions or operating results of the company. Actual results may differ materially. I would now like to turn the call over to Ken Mills, CEO of REGENXBIO. Ken?

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 as 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 to review and discussion of these data in greater detail shortly. We've been working diligently to prepare on 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 was the potential one-time gene therapy for the treatment of Duchenne and 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, domain found naturally occurring -- 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 dosing patients in this pivotal program. Most recent positive interim data update from this -- study of this candidate reported that RGX-121 was well tolerated across all cohorts study. 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 continued with plans to enroll additional patients in Cohort 2 expansion arm. Our manufacturing innovation center and GMP capacity -- capability remains a key differentiator for REGENXBIO and a key element of our strategy. Our in-house facility is cutting edge 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 and 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 REGENX-314 development cost 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 314 development costs are shared with AbbVie. Beginning in 2023, AbbVie will be responsible for funding the majority of all REGENX-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 the 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 is proven to reduce the risk of developing vision threatening complications. However, due to the unsustainable treatment burden using anti-VEGF therapies, primarily the 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 2.5x1011 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 5x1011 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 133. Five serious adverse events were reported, none of which were considered drug related. For the total group of Cohorts 133 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 the which were mild and resolved on topical corticosteroids. There were no meaningful differences in safety outcomes observed for patients who are 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 or DRSS. Specifically, 20% of patients representing 40% of patients in dose 1 and 11% of patients in dose 2 achieve 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. And 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 both of it who is sitting next to me in lovely Pasadena. We're laid out, Lejla we're really excited to hear your presentation yesterday at the Retina Society meeting here itself now, it's really a great opportunity for us to hear your clinical perspective as Lead Investigator in the trial on the interim results that you presented.

Great. Thank you, Steve. It's a pleasure to be here today. And I'm very excited about interim data that was presented yesterday in discussing this morning. Primarily as Steve nicely highlight diabetic retinopathy is a tremendous problem a huge public health problem globally and that release to be very busy clinics diabetic retinopathy patients who unfortunately because of their status and working age cannot keep up with the treatment burden a frequent injections. So, that results typically my clinic about 90% of my patients are being watched and non-treated. And also not even coming for the appointment. But clearly there is a tremendous need for better treatment more unsustainable treatment. And having a onetime treatment in office me provide solution. So, I'm excited to see the interim data result. First of all, the efficacy looks very promising with improvements in all cohorts include -- including in the Diabetic Retinopathy Severity score. And no disease worsening that we saw in the data results. But even more importantly the safety result looks promising as well. The fact that we're seeing good results with minimal evidence of inflammation, which was encouraging to me. So overall, this translates to me for hopefully when they having a treatment option for 90% of those patient are currently being observed, who are potentially going to we have disease affecting visual decline in the future and 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 in 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 at third dose level of 112 GC/eye. And Lejla outline in that as well yesterday at the presentation. The trial is currently enrolling two new cohorts. Cohorts 4 and 5 at this third dose level. cohort 4 and 5 are enrolling patients stratified by drss levels with patients in cohort 4 having moderately severe to severe NPDR which is DRSS levels of 47 to 53 and patients in cohort 5 have mild to moderate PDR which is DRSS levels of 61 to 65. So, excited at that ability to evaluate in 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 a setting of no prophylactic steroid's patients will be enrolled in these cohorts regardless of baseline AAV8 NAbs status. So, now 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 experts across the retina space is also a very experienced central reading center greater an expert in overseer including assessment of diabetic retinopathy and use the standard DRSS scale. So, Peter really a perfect opportunity to really blend your expertise both clinically, but also how you think of endpoints when it comes to diabetic retinopathy and use of the DRSS scale so, we'd love to hear your key takeaways from this interim data updates.

Sure. Yes, and thanks for inviting me. Lejla really outlined at great, which is, we have two products that are FDA approved for treatment diabetic retinopathy and the regulatory endpoint that we use is Diabetic Retinopathy Severity score, which really is something that we do with reading center level in general at a clinical level Lejla and I won't be counting my grinders, and looking at it as closely as we do with a clinical study. It's important to understand that the DRSS was developed a long covered almost 30, 35 years ago now for the early treatment diabetic retinopathy study is one of the first randomized studies done across medicine. And the importance of a two\-step change, is that a very significant change in the level of retinopathy and that's why the FDA the EMA use that for regulatory approval. However, in clinical practice, what we want to see is overall our patients getting better and as Lejla correctly pointed out, the reason we don't use the FDA approved products both Lejla and Lucentis that often you know, there are few patients we do use it out. But in general, we don't is because it requires very frequent injections in these working age patients simply can take the time off from work not to get these injections are there for now. You know, maybe they just don't want to do it. Most of these patients actually have very little changes in patients that don't really see proof that with these injections but as physicians we can see the improvement and that really brings up the point of RGX-314. This is to me is a killer app for gene therapy, the idea of doing it in office procedure to allow these patients to have an improvement in the Diabetic Retinopathy Severity scores, which we saw very nicely with the presentation 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?

[Operator Instructions] 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 the inflammation. So the inflammation rate at, 5E11 dose cohort seem to be pretty similar to the wet AMD at the same dose. Could you give more colors on the like the onsite - onset duration and how long inflammation was resolved like what's – steroid and how long if used and how long does it take to resolve? Then I have a follow-up question on - new pro cohort. So can you give more colors on the short course steroid is it similar or same as AAVIATE for wet AMD such as administration like do you potential both topical and one-time subretinal injection. And what was steroids have used and what will be the dose regimen? Thank you very much.

Thanks, Xian as this is can Steve, I think those questions are best directed to you and experts there.

Great, hi Xian, thanks for the questions, I'll give the initial comment and pass it over to Lejla [ph] to give her perspective of what she experienced within the trial first hand. So in terms of inflammation you're exactly right. We saw, we didn't see anything unanticipated. So we were quite pleased with the low rates of mild intraocular inflammation in the characteristics were what we've seen previously nothing concerning in that. We see it, come on in generally within two to six weeks of RGX-314 and very easily managed with short course of topical corticosteroids. Our investigators and we will hear Lejla perspective, very happy with the profile that we're seeing. That's consistent with what we've seen previously. But we also have this great opportunity to evaluate and further characterize in setting of prophylactic steroids where that allows the clinicians to assess. How these patients do and potentially mitigate even further. The risk of inflammation and 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 paper over weeks which are investigators and our thought leaders are very comfortable with that type of profile prophylactic regimen. But we have Lejla here who actually dose patients in the trial and is very aware of the data, we saw across the trial. What was your perspective as you think of your own experience and your colleagues experience in the trial as far as inflammation.

Thank you, Steve. Yes exactly what you highlighted we haven't had patients in this trial in watching them very carefully for any evidence inflammation. I would say it was really mild if it this present presented exactly two to four weeks after the injection potentially after six and really very rare to, maybe more presented that anterior segment itself. So what that actually translates really is symptomatic for the patients. This was something because these patients are in clinical trial setting. We're closely watching and noting and if we see any hints of it, because of our sensitivity to inflammation gene therapy trial, we were proactive in treating them. So I think the treatment, like you mentioned is very reasonable very active as well in topical steroids format and it was a short sequel that was used as well for patients who did. And I'll point out in this cohort is about 6% of patients overall across actually all three cohorts that had inflammation very manageable with topical steroids, I think what that translates to my clinical setting I think the 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 for Vikram. We have two questions. So the question is when doctors treat patients with DR how are they measured progress are they generally looking at a two-step improvement in DRSS or for any level of improvement and then also to know how do you believe the addition of a dose of prophylactic steroid will impact the commercial opportunity for RGX-314 in DR if at all? Thanks.

Steve again right at you.

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

Yes, so I'll handle the second question first. So when you look at any new treatment as retinal specialists been heightened sensitivity to intraocular inflammation and 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 to me that that's not a big deal. So I'm not concerned about that. Certainly, we have to see more patients, but so far none of that data concerns me in any way. In terms of the first part of your question DRSS, we do that at a reading center level. This requires really carefully counting macro-aneurysms speeding et cetera in clinical practice, the average so retinal specialists is absolutely not going to do that but what we are going to do is look at these patients over time to make sure that they are improving. So in other words, if they have early neovascularization so like levels 61 which was enrolled in this clinical study, we're going to be watching that neovascularization very closely with any of our treatments for that matter to make sure that that area is resolving So in other words we would expect with our treatment that neovascularization would disappear because that neovascularization is what leads to future vision problems attachments switchers hemorrhage and that's what causes have actually blindness untreated. So that's what we're most worried about. Over time we would watch to make sure they disappear, but we also like to see the hemorrhages the microdystrophin disappear also. This is something we could very easily deal with the clinical exam so most retinal specialists are not doing a formal DRSS evaluation we're just looking at the patient with dilated fundus exam.

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, maybe you can 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, 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? And then 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 so in terms of rationale for the higher dose. These are both AAV8 study in ALTITUDE, these are the first two studies ever evaluating suprachoroidal delivery of gene therapy for these indications. So this is really an exciting time for the field and for us to really characterize RGX-314 via this route of administration. And we actually have - interim data that we presented with dose level three in the wet AMD setting from the AAV8 study. So we can affect have a head start of evaluating this. So it made perfect sense for us in our strategic partner AbbVie to continue to evaluate in the study. Regarding dose level one and dose level two, as Peter mentioned, there are various cuts and ways to look at change in DRSS. And the reality is, when we look at the totality of this data, we see what we want to see in terms of both dose level one and dose level two. That aspect as far as what we would need to do in a pivotal study there we are very confident in an observation control for the reasons that Lejla and Peter both nicely elucidated that even though we know available repeated injections "work" in terms of improving DRSS and improving DR and preventing vision threatening complications. Those treatments are simply not used only a rare proportionate patients as Lejla mentioned. So standard of care is really still watchful waiting so an observation control is ideal for this setting and one of the nice things about DR development and it's nice that we have the concurrent control in this trial, where we see what you'd expect to see and I think either Lejla or Peter would be great deal [ph]. When you look at our observation control and you think of precedents controls - in the literature and your own clinical experience what do you expect to see if you don't treat patients.

I think it's CPI no exactly what you've highlighted, I would expect to see progression overtime to vision we're sitting in complications for diabetic retinopathy and as soon as we were [indiscernible] observational arm if they are accessible because that is the real world that in currently. We are observing these patients not - treatment with frequent injections, and so from my personal opinion and really experienced into clinical across the board it's quite accessible.

Yes, fully agree the current clinical standard from a regulatory standpoint it 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 It's also a very doable study my patients is the opposite if you put anti-VEGF is to control will be very hard for me to get a patient into the study. So it's the opposite of what you were thinking, but from a regulatory standpoint absolutely totally fine to do I think sham control. In terms of numbers, I think the beauty of this data set is that there is a control group. So you can kind of see what happens over time and what's happening to the control group at a six-month interim data is sort of what we would expect 20% or so having pretty significant worsening. A few patients get better and if you look at the control groups say exhibit miss Ride/Rise et cetera some Panorama some of these other studies that have been done it's about 10% to 15% will actually improve a little bit, and largely that's not due to the fact that the disease is getting better in general what that - is that the patient in that study is suddenly realize oh, wait a minute. I actually do better control my sugars better control my blood pressure because in this study and that's what leads to that improvement. It's going to be with like in general as Lejla said these patients are going to go downhill they don't improve, but if you do improve sugars and blood pressure that will improve and we've seen that in the U.K. PDs and the DCT studies in the past.

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

Hi, this is Sarah on Ellie. Thank you so much for taking our question. I guess looking at the change in DRSS score that you see at month six, differences across cohorts between sort of no worsening or no change on a greater than two-step or even one step improvement, I guess 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. And then I guess the second question as any detail or color that you can provide on the five SAEs that occurred during treatment would be great? Thanks so much.

Great, thanks Sarah. So on your first question about the different cohorts in the different dose levels and the Nab status. Very similar to what we see in AAV8 study, 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 that you would anticipate. And also thinking of baseline DRSS how severe you are at baseline is a variable that can impact whether you can improve two steps or not. I think that's actually a good question. So I'll turn it over to Peter to talk about that nuance of creating and how to think of data based on baseline characteristics. But certainly, if you take that into account, we find and again looking at the totality of the data is that in each of the dose levels in each of the cohorts that patients are moving in the right direction unlike the control arm. If you really take into account all the variables of not worsening biologics like a couple of the control subjects and having improvements on average in the other. So then again we and AbbVie guess not only look at these results, but also our AAV8 study to really assess how do matter or not. And that's why we chose and the expansion to enroll patients independent of their NAV status will still measure it and will still be able to assess that to see if we continue to see no impact there. I think before I go to the next question I'll -- I think Peter you're -- I think it's a nice question to really get your sense when you get into the data, how do you look across cohorts based on the baseline characteristics for example --

Yes, I think, whenever you look at interim data, especially in Phase 2 relatively small numbers of patients, who don't want to read too much into. You want to look at the totality of that data and to me, if you look at all the cohorts, they are trending in the right direction. There's right shifts in every single cohort, whereas in the control group, you don't see a shift at all, which is sort of expect maybe even a slight less shift, which eventually untreated you'd expect to occur over time. But if you look at say, Cohort 1 versus 2 and 3, there is actually a very large balance at baseline the DRFS scores and it is a very important balance. So in Cohort 1, there's more patients in but early PDR so level of 61 and level 61 is really minimal amount of neovascularization that fits. So to move that two steps forward is actually very easy with just a little bit of anti-VEGF like any anti-VEGF given to a patient with mild NVD. That NVD is going to disappear. They quickly go to 57 and then drop even further. Thereafter, whereas you take somebody who's say severe and NPDR and try to improve them two steps. That's a much bigger change in terms of what needs to be done to the eye. So if you have a lot of PDRs or early PDR, it's going be easier to show a two-step change, but that's not what we care about. We care about the overall population of patients and to me that's what I said at the beginning that the right shift of all these patients is what's more exciting. They're really looking granularly at a few patients who just kind of went one way or the other way, right at six-month time point

Great. And Sarah your other question on SAEs. So here none of the five SAEs were considered drug related. And really the types of things that happened to patients -- diabetic patients who on average are older, not quite as old as the Wet AMD patients. But just to give you an example, broken femur other unrelated aspects and in fact the only ocular SAE happened in the fellow eye for the patients who had worsening vitreous hemorrhage. So overall, very, very clean from a safety standpoint

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. Wondering if you can elaborate more on the decision to include prophylactic steroids. Was this due to the diabetic retinopathy alone or the totality of the data between the diabetic retinopathy and Wet AMD program. And as well on the baseline characteristics I noticed that the Cohort 2 and 3 patients had no prior anti-VEGF injections, but the Cohort 1 patients did and they appear to respond a little bit better. So was just wondering going forward for the high dose cohorts will you enroll patients who are anti-VEGF experience versus anti-VEGF naïve. Thanks.

Thanks, Lisa. So to elaborate more on the decision to expand. Again we take advantage of all the data we have, so that's one of the nice aspects of having both a Wet AMD AAV8 study ongoing, as well as this ALTITUDE study in DR patients. So it really gives us a chance to look at safety and tolerability and also biologic effect for these VEGF driven retinopathies and we're very pleased with our partner AbbVie and we look in concert at these interim data, and I think it was a very natural high decision to go up on dose to dose level 3 as we did with the same exact dose in AAV8. The second question Lisa on previous treatment. Yes, as you mentioned there were some patients in one of the cohorts who had previous treatment. What we do in these types of studies is we make sure there is a certain washout window. So even if that patient is not "treatment-naïve" they at least have not had any anti-VEGF injection in at least six months to minimize the risk of a confounding factor there. There were actually some interesting presentations yesterday, getting into and from other programs, thinking about treatment-naive versus not. So we'll follow with that same approach going forward. So we haven't amended that part of the protocol where a patient can have had prior anti-VEGF but not within a recent timeframe.

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

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

Sure. So in patients with this disease of course, we look for complications and the investigators look for complications and at the end of the day the investigator and we of course sponsor agree if it's indicated to treat a patient that they should proceed with treatment and it's 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. So we have the one patient in the control group, who did need treatment that we elaborate on in the footnote who given with treatment wound up with 4-steps versus at the end. And we had a alone patient in the 50 RGX-314 treated eyes that had a single anti-VEGF injection early in the course and you see how that patient did. So if you look at the totality of this data also directionally, it goes in the same shift in terms of outcomes that Peter discussed in terms of how we look also at the imaging basis of how severe the diabetic retinopathy is. Lejla as you presented this data, you have a perspective on thinking of retreatment and the realities of that aspect. What you think of this kind of patient population that goes up to 61 and then 65 where we're including those patients because they're at very high risk of advancing. How do you think of that in terms of the risk of going to DME and high-risk PDR and needing treatment.

Seamlessly you pointed out historic diabetic retinopathy trials have not typically included mild PDR or moderate PDR and you are doing that in this trial. And with that, with that inclusion, or there may be significant gains to have there's also a risk of progression especially early on in the treatment protocol. So as you pointed out, the one patient did receive anti-VEGF injections was really quite soon after enrollment. The one wonders whether there was any response to the treatment that early enrollment period and it was also higher diabetic retinopathy severities for mild PDR patients. So we are right there set up for unfortunately already progressing to complication and so I think that could be very well explained by that.

Okay, great. And then you might have touched on this a bit in the previous questions here, but just. So thinking about observing the decrease in greater than 2-step improvement observed from Cohort 1 to Cohort 2 and Cohort 3. How are you thinking about, or what are your expectations for the, for the higher dose. Thank you.

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

Thank you. [Operator Instructions] Our next question comes from the line of [indiscernible].

Good morning. Thank you for taking the question. One on potential improvement from 6 to 12 months. So you have previously shared the data on improvement from three to six months and compare that to the standard-of-care said news about wanted to see -- if you can basically know how that continues to progress beyond six months and what would be your expectations for 314?

So in the existing cohorts and then going forward, we care about these time points that we have presented to date and we certainly look forward to compiling and cleaning and being able to report in the future on longer term follow-up time points for these cohorts, including the one-year time. As far as expectations, I think one aspect is illustrative reasons, one can think of what's been done before. How repeat injection with existing therapies impacts diabetic retinopathy severity and the realities of as treatment frequency decreases in patients fall off use that the diabetic retinopathy severity returns. And I think as our guests have highlighted, we know without treatment which would be the observation control in future study that patients in general, do not get better. And it's just that small percentage of patients that get better, due to other factors that Peter highlighted. So, it really puts us in a good position in terms of a regulatory standpoint, we think a bigger studies that are powered and take out the risk of imbalances in terms of hitting a regulatory bar while also hitting what ultimately matters to the investigators and the patients which is shifting the severity to the right, into the favorable direction and keeping patients from getting worse and developing the blinding complications that Peter highlighted.

Thank you. And I'm showing no further questions. So with that, I'll hand the call back over to CEO, Ken Mills for any closing remarks.

Thanks, operator. I appreciate that. Steve thanks for walking us through that overview and really grateful to Dr. Vajzovic which and Kaiser for both their time early this morning, their perspectives on treatment paradigms in DR and perspectives in weighing in 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 one that's dedicated to expanding the understanding and the applications of AAV vectors, developing and generating new innovative AAV therapeutics that have the potential to significantly impact patients' lives. We've had several data 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 capital over 600 million to fund our mission and operations into 2025 and through multiple filings and other anticipated data milestones, so truly believe we have a clear and definable path to achieve our 5x'25 vision to advanced five AAV Therapeutics, from our internal pipeline and license programs into pivotal stage or commercial products by 2025. We look forward to keeping you all updated on our progress as we finish the year. Begin to look ahead at 2023. Again thanks very much to our guests and the entire team and have a great rest of the day.