Regenxbio Inc (RGNX) 2022 Q3 法說會逐字稿

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 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, 2021.

In 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. 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. Vasista, our Chief Financial Officer, will provide an overview of financial results for the third quarter ended September 30, 2022. The -- we're by coastal today, Steve Pakola, our Chief Medical Officer, on the West Coast, recently attending Retina Society, where he'll provide an in-depth overview of the data that was presented yesterday at the Retina Society meeting from our Phase II ALTA 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 Leilasvich from Duke University, an independent retina expert, Dr. Peter Kaiser from the Cleveland Clinic. Leila 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 525 strategy to progress 5 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 retina disease continues to advance and is on track for our first BLA filing in 2024. Progress in trial enrollment and emerging clinical trial data also supports excellent progress in our suprachoroidal delivery program. 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 4 years. We expect this trial along with the 2 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 II 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 6 months. We announced the expansion of this trial to further explore the third dose level in a sixth 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 II altitude trial of RGX-314 for the treatment of DR using suprachoroidal delivery, and Steve will lead a 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 is a potential onetime 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 domains found naturally occurring in naturally occurring dystrophin. RGX-202 is designed to support the delivery and targeted of 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 2, also known as Hunter syndrome. This is currently being evaluated in an expanded pivotal phase program called Campsite. We are 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 3 cohorts indicated encouraging dose-dependent reductions of cerebral spinal fluid GAGs following onetime administration of RGX-121 Improvements in neurodevelopmental function and caregiver reported outcomes demonstrated CNS activity up to 2 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 I/II 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 capacity 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 onetime 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 at this point in the year, I'm very proud of the progress we've made to advance our 5x25 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 9 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 costs, reimbursed 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, Ebby 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 ALT2 data.

Thank you, Pat. 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 II altitude trial of 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. Leila Vosevi, 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 Coal Eye Institute at the Cleveland Clinic. DR is a complication of diabetes and 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 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 multicenter open-label randomized controlled dose escalation Phase II 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 nonproliferative diabetic retinopathy NPDR or mild proliferative diabetic retinopathy, PDR. Patients in Cohort 1 received RGX-314 at a dose level of 2.5E11 genome copies per eye, which we refer to as dose on while patients in cohorts 2 and 3 received RGX-314 at an increased dose level of 511 GC pre, which we refer to as dose 2. Patients in cohorts 1 through 3 did not receive prophylactic corticosteroid therapy before or after our JK314 administration. As of October 17, 2022, RGX-314 was reported to be well tolerated in cohorts 1 through 3. 5 serious adverse events were reported, none of which were considered drug related. For the total group of cohorts 1 through 3 receiving RGX-314, 50 patients in total, common ocular adverse events in the study through 6 months were predominantly mild and included contractile hemorrhage, consentible hyperemia and episcleritis. In addition, 3 patients experienced intraocular inflammation, II, all of which were filed and resolved on topical corticosteroids. There were no meaningful differences in safety outcomes observed for patients who were now positive.

Best Corrected Visual Acuity remained stable in cohorts 1 through 3 through 6 months. At 6 months, patients treated with RGX-314 demonstrated clinically meaningful improvements in disease severity versus observational control as measured by the diabetic retinopathy severity scale or DRSS, SPSS 1 and 11% of patients in dose 2 achieved 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 0 out of 50 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. Leila Both of who is sitting next to me in lovely Pasadena, Leila, we were really excited to hear your presentation yesterday at the Retina Society meeting here. So now it's really a great opportunity for us to hear your clinical perspective as a lead investigator in the trial on the interim results that you presented.

Thank you Steve. It's a pleasure to be here today. I'm very excited about interim data that was presented yesterday and discussing this morning. Primarily, as Steve nicely highlights embedicornopathy is a tremendous problem, a huge public health problem globally. And that relates to think very -- 2 very busy clinics with diabetic ryopathy patients who, unfortunately, because of their status and working age cannot keep up with the treatment burden of frequent injection. So that results typically in my clinic, about 90% of inpatients are being watched and not treated and also not even coming for the appointment. So clearly, there is a tremendous need for better treatment, more sustainable treatment. And having a onetime treatment in office may provide that solution. So I'm excited to see the interim data results.

First of all, the efficacy looks very promising, with improvements in all cohorts, including improvements in babaticcardinosoty severity scores and no disease worsening that we saw in the data results. But even more importantly, the safety got looks promising as well. The fact that we're seeing good results with minimal evidence of inflammation was encouraging to me. So overall, this translates to me for, hopefully, one day having a treatment option for 90% of last patients that are currently being observed, who are potentially going to be have a disease affecting visual decline in the future, and this option may provide a solution to the vision worsening.

Great. Thanks so much, Leila, for that perspective. As the audience can hear, we're very excited about this interim data that Leila presented and the potential of RGX-314 for patients with DR. As we continue to build upon the drug profile of our JF314 in DR, we've made the decision to expand the altitude trial to include a higher third dose level of 1e12 GC per eye, and Leila outlined that as well yesterday at the presentation. The trial is currently enrolling 2 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 and PDR, 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 we're excited at that ability to evaluate in an expanded DRSS 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 steroids. Patients will be enrolled in these cohorts regardless of baseline AAV NAV 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 has been expert across the retina space is also a very experienced central reading center, greater and expert in over Sear, including assessment of diabetic retinopathy and use of the standard DRSS scale. So Peter, really a perfect opportunity to really blend your expertise both clinically but also how you think of end points 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 update.

Sure. Yes. And thanks for it. Leila really outlined it great, which is we have 2 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 at a reading center level, in general, at a clinical level, Leland I won't be counting microns and looking at as closely as we do in a clinical study. And it's important to understand that the DRSS was developed a long time of almost 30, 35 years ago now for the early treatment diabetic lanopathy study was one of the first randomized studies done across medicine. And the importance of a 2-step change is that's a very significant change level of retinopathy. And that's why the FDA and the EMA use that for regulatory approval. However, in clinical practice, what we want to see is overall, our patients getting better. And as Leila correctly pointed out, the reason we don't use the FDA-approved products, both EYLEA and we expect this that often.

There are a few patients we do use it on. But in general, we doll is because it requires very frequent injections and these working age patients simply can't take the time off from work to get these injections or they are burnout. They just don't want to do it. Most of these patients actually have very little changes in vision. They don't really see an improvement with these injections, but as physicians, we can see the improvement. And that really brings out the point of RGX-314. This is, to me, is a killer app for gene therapy, the idea of doing an 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 Leila yesterday of 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?

Thank you. (Operator Instructions). And our first question comes from the line of Gena Wang with Barclays. Hello.

Thank you very much. This is Xiaobin Gao for Gina. I have 2 questions. The first question is about the inflammation. So the inflammation rate at 511 dose cohorts seem to be pretty similar to the wet AMD at the same dose. Could you give more colors on the like on-site unset duration? And how the inflammation was resolved, like what steroid and how long is used and how long does it take to resolve? Then I have a follow-up question on the new profit cohort. So can you give more color on the short course still rod? Is it similar or same as Aviat for wet AMD such as administration? Like do you plan to close topical and onetime sustainer injection? And what steroid will be used? And what will be the dose regimen.

Steve. I think those questions are best directed to you and the experts there.

Great. Shia, thanks for the questions. I'll give initial comments and pass it over to Leila to give her perspective of what she experienced within the trial firsthand. 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 and in the characteristics where what we've seen previously, nothing concerning in that we see it come on in the -- generally within 2 to 6 weeks of RGX-314 and very easily managed with a short course of topical corticosteroids. Our investigators, and we'll hear Lalit 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 a 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 taper over weeks, which are investigators and our thought leaders are very comfortable with that type of prophylactic regimen. But we have Leila who actually dosed 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. Having had patients in this trial and watching them very careful for any evidence information, I would say, it was really mild. It did present it presented exactly 2 to 4 weeks after the injection, potentially up to 6 and really very rare to maybe a little more frequent than that anterior segment sells. So whether that translates really asymptomatic for the patient. This is something because these patients are in clinical trial setting, we're closely watching and noting. And if we did see any oftentimes because of our sensitivity to inflammation gene therapy trials, we were proactive in treating them. So I think the treatment, like you mentioned, is very reasonable, very effective as well in topical steroid format, and it was a short paper 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 3 courts that had the inflammation very manageable with topical tar. And I think what that translates to my clinical setting, I think the safety profile is promising and very manageable by a retina specialists.

Great. Thanks, Leila. Next question.

And our next question comes from the line of Vikram Pariet with Morgan Stanley.

This is Gospel on for Vikram. We have 2 questions. So the first one is when doctors treat patients with DR, how are they measuring progress? Are they generally looking at a 2-step improvement in DRSS or for any level of improvement? And then also, two, 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?

Steve again right at you.

Great. Thanks, Gospel. I'm going to direct it right away to Peter because I think both these questions fit 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 around the specialist, we've been heightened sensitivity to interact that inflammation in that 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 a safety review committee for Novartis. And this is not the same thing. There's no red inclusions, revalve occlusion, rental vasculitis. In this is very mild intraocular inflammation that's treated with a short course of steroids. To me, that's not a big deal. So I'm not concerned about that. Certainly, we have to see more patients. But so far, not the 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 microaneurism speeding, et cetera. In clinical practice, the average geared specialist 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're improving.

So in other words, if they have early neopterization, so like Level 61, which was enrolled in this clinical study, we're going to be watching that neovasculat 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 at neovascularization would disappear because that novatiation is what leads to future vision problems, traction attachments, sites hemorrhage, and that's what causes eventually blindness untreated. So that's what we are most worried about. Over time, we would watch to make sure they disappear. But we also like to see the hemorrhages and the microassdisappear all. So this is something we could very easily do with the clinical exams. So most retospecialists are not doing a formal DRSS evaluation. We're just looking at the patients who have dilated funds.

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

Just a couple from us also on DR. First, maybe you could 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'd 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 to dose 2, but maybe there's a bolus of one step in proves in Cohort 3. And secondly, could you talk about the observational control in the study? Is this an appropriate comparator arm to your discussions with the SBA? I guess looking at a pivotal study, do you think you would need to run a head-to-head similar to what you're doing in the wet AMD program...

Thanks, Alex. So in terms of rationale for the higher dose, these are both the AVA study and altitude. These are the first 2 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 3 in the wet AMD setting from the AAV8 study. So we, in effect, have a head start of evaluating this. So it made perfect sense for us and our strategic partner, AbbVie to continue to evaluate in this study regarding dose level 1 and dose level 2. 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 1 and dose level 2. 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 Leila 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 in a rare proportion of patients, as Leila 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 Leila or Peter, it would be great. When you look at our operation 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?

Yes. Now exactly what you've highlighted. I would expect to see progression over time to vision worsening and complication from digiconopathy. And a similar echo, I think observational arm is very acceptable because that is the real world setting currently. We are observing these patients not treatment with frequent injections. So from my personal opinion and really experienced in the clinical across the board, it's quite acceptable.

Yes. totally 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. It's also a very doable study. My patients. The opposite is if you put an anti-VEGF as a control, it would be very hard for me to get a patient into the study. So it's the opposite of what you would think. But from a regulatory standpoint, absolutely totally fine to do HSAMcontrol. And in terms of numbers, I think this -- 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 this control group in a 6-month interim that is sort of what we'd expect about 20% or so are having a pretty significant worsening A few patients get better. And if you look at the control groups, say Vivid Vista, Rod ride, 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, is that the patient in that study suddenly realized, so wait a minute, I actually need to do better control my sugars, better control my blood pressure because I'm in this study. And that's what leads to that improvement. It has nothing to do with like in general, as Lena said, these patients are going to go downhill. -- they don't improve. But if you do improve the sugars and blood pressure, that will improve things. And we've seen that in the U.K. PDS and the DCCT studies in the past.

Thank you. And our next question comes from the line of Eli Merrell with UBS.

This is Sarah on for Eli. I guess looking at the change in DRSS score that you see at month 6, differences across cohorts between sort of no worsening or no change on a greater than 2-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 a second question is any detail or color that you can provide on the 5 SAEs that occurred during treatment would be great.

Great. Thanks Sarah. So on your first question about the different cohorts and the different dose levels and the NAV status. -- very similar to what we see in the 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 2 steps or not. I think this actually would be a good question, but I'll turn it over to Peter to talk about that nuance of grading 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 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 by a lot, like a couple of the control subjects and having improvements on average in the others, and again, we and Abbiato not only look at these results, but also our APA study to really assess how do maps matter or not. And that's why we chose in the expansion to enroll patients independent of their NAP status. We'll still measure it, and we'll 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, think it's a nice question to really get your sense when you into the data. How do you look across cohorts based on the baseline characteristics, for example...

I think whenever you look at interim data, especially in Phase II with relatively small numbers of patients, you don't want to read too much into it. You want to look at the totality of the data. And to me, if you look at all the cohorts, they're 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 what you expect and maybe even a slight left shift, which eventually untreated you'd expect to occur over time. But if you look at, say, cohort 1 versus 2 and 3, there's actually a very large imbalance at baseline the DRSS scores, and it is a very important balance. So in Cohort 1, there's more patients but early PDR. So Level 61. And Level 61 is a really minimal amount of neovasculatat the disk.

So to move that 2 steps forward is actually very easy with just a little bit of TEG like any anti-VEGF given to a patient with mild NBD, that NBD is going to disappear, they quickly go to 57 and then drop even further thereafter, whereas you take somebody who say severe NPDR and try to improve them 2 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, early PDRs, it's going to be easier to show a 2-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, the right shift of all these patients is what's more exciting than really looking gradually at a few patients who just kind of went one way or the other way right at a 6-month time point.

Great. And Sarah, your other question on SAEs. So here, none of the 5 SAEs were considered drug-related. And they are really the types of things that happen 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 AE happened in the fellow eye for the patient who had worsening vitreous hemorrhage. So overall, very clean from a safety standpoint.

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

Great. This is Lisa on for Luka. Just 2 questions from us. Wondering if you can elaborate more on the decision to include prophylactic steroids. Was this due to the diabetic retinopathy data alone or the totality of the data between the diabatic retinopathy and wet AMD programs. 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 appeared to respond a little bit better. So just wondering going forward for the high-dose cohort, where will you enroll patients who our anti-VEGF experience versus anti-VEGF-six

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 PR 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 decision to go up on dose to dose level 3 as we did with the same exact dose in AV -- the second question, Lisa, on previous treatment. Yes, there -- as you mentioned, there were some patients in one of the cohort who had previous treatment. What we do in these types of studies is we make sure there's a certain washout window. So even if a patient is not "treatment naive, they at least have not had an anti-VEGF injection in at least 6 months to minimize the risk of a confounding factor there. And there were actually some interesting presentations yesterday getting into -- 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 time frame.

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

2 questions 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 is the term in of patients received standard of count? 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, the sponsor agree if -- it's indicated to treat a patient that they should proceed with treatment. And it certainly, with the longer we follow these patients, that's one of the key potential benefits of a 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 even with treatment wound up with 4-step worsening at the end and we had a lone 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, that also directionally 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 Leila as you presented this data, you have a perspective on thinking of retreatment and the realities of that aspect when 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.

Steve, you pointed out are the historic diabetic retinopathy trials have not typically included mild PDR moderate PDR and you are doing that in this trial. And with that inclusion, there may be significant gains to have, there's also risk of progression, especially early on in the treatment protocol. So as you point out, the one patient that did receive anti-VEGF injection 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 batterinopathy severity for the mild PVR patients. So we are right there set up for, unfortunately, already progressing to complication. So I think that could be very well explained by that.

Okay. Great. And then you may have touched on this a bit in the previous questions here. But just -- so thinking about the -- or observing the decrease in greater than 2-step improvement observed from cohort 1 to cohort 2 and 3, how are you thinking about -- or what are your expectations for the higher dose. Thank you.

Andres, we'll have to see, of course. So that's why we do the trial, we are encouraged that with dose level 1 and dose level 2, we're seeing what we want to see and now to have this opportunity to look at a higher dose level. And as Leila mentioned, we're also expanding to include not only the mild PDR, but also the moderate PDR. -- and stratifying based on that. So we're 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 learned from both.

Thank you. (Operator Instructions). Next question comes from the line of Daniil Gataulin with Charden.

I have one on potential improvement from 6 to 12 months. So you previously shared the data on improvement from 3 to 6 months and compare that to the standard of care liberated renmisabel. I wanted to see if you know how that continues to progress beyond 6 months and what would be your expectations for (inaudible)?

So in the existing cohorts and then going forward, we care about these time points that we've presented today, 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 1-year time point. As far as expectations, I think one aspect is for 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 and 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 a 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, if we think of 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.

And I'm sure 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. Fisch and Kaiser for both their time early this morning, their perspectives on treatment paradigms in DR and perspectives and weighing in on the new interim data from the altitude trial. 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 I truly believe we have a clear and definable path to achieve our 5x25 vision to advance 5 AAV therapeutics from our internal pipeline and license programs into pivotal stage or commercial products by 2025. And -- 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.

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