Thank you for standing by, and welcome to the REGENXBIO Interim Data Update from Phase II AVA trial of ABBV-RGX-314 for treatment of wet AMD using suprachoroidal delivery, Hawaiian Eye and Retina 2024 conference call. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. To ask a question during this session, you'll need to press star one one on your telephone. If you'd like to remove yourself from the queue, simply press star one one again. As a reminder, today's program is being recorded. Now I'd like to introduce your host for today's program, Mr. Ken Mills, President and CEO of REGENXBIO. Please go ahead, sir. Welcome, everyone, to our Hawaiian Eye and Retina event. I am Ken Mills, CEO of REGENXBIO, and I'm pleased to introduce our agenda and make some opening remarks. In November, REGENXBIO announced the pipeline prioritization and corporate restructuring plan that will enable us to focus our capabilities and resources on large commercial opportunities where our product candidates are differentiated, can be expedited, and support meaningful value generation soon and for the long term. Our highest priority programs are ABBV-RGX-314 for the treatment of retinal diseases, RGX-202 for the treatment of Duchenne, and RGX-121 for the treatment of Hunter syndrome. Today's event is designed to review and discuss the new interim data from our AVA trial of ABBV-RGX-314, henceforth referred to as 314, for wet age-related macular degeneration or wet AMD. The slides for this event are available on the webcast and later on our website on the Presentation section at regenxbio.com. We'll move forward. On the second slide of our presentation, you will see that today's event may include forward-looking statements. Please see here a full slide of our forward-looking statements disclosure, which can be reviewed at any time. Please be advised that today's call is also being recorded and webcast. On slide three here is our agenda, and today we're happy to be joined by REGENXBIO Chief Medical Officer, Dr. Steve Pakola; and Dr. John Pitcher from Eye Associates of New Mexico; and Dr. Allen Ho of Wills Eye Hospital. Today, at the Hawaiian Eye and Retina Meeting in Maui, Dr. Pitcher presented positive six-month data from the AVA trial of 314 for wet AMD, using one time in-office suprachoroidal delivery. The slides from his presentation are available on our website on the Publications page, again, at REGENXBIO.com. Steve will provide a quick review of the update and then lead a discussion about the data with these two retina specialists. At the end, we should have some time for some question and answers. Before I hand it over to Steve, I want to remind everyone that RGX-314 is designed for the treatment not only of wet AMD, but also diabetic retinopathy and other chronic retinal diseases. Moving on to slide four, we believe that there is a multibillion-dollar potential for RGX-314 as a single injection treatment to become a first-in-class gene therapy for wet AMD and the standard of care to treat and prevent the progression of diabetic retinopathy. You can see here the market for treating retinal diseases is estimated to grow to approximately $17 billion globally within the next five years. Now, we want to point out on slide five, we know that there is a gap between the vision outcomes observed in clinical trials of current anti-VEGF treatment options and what doctors are facing in the real-world clinical management of a disease like wet AMD. Patients on average, lose vision over time with current treatment regimens due to unsustainable compliance and non-adherence. A single treatment with 314 has the potential to close this gap between the clinical trials and the real-world outcomes. In our study of subretinal 314, long-term data through 4 years shows a durable treatment effect and the potential of one-time treatment to maintain vision, vision that may normally be lost in the real-world setting. Treatment with one-time gene therapy, with the potential to prevent disease progression long term, could be the key to preventing vision loss for millions of patients. Now I'll turn it over to Steve to take us through the data and the conversation with the specialists. Thank you, Ken. To start off, slide six shows the basic design of the AVA trial. This is a phase II randomized active control dose escalation trial, evaluating one-time in-office 314 administration for the treatment of patients with previously treated wet AMD. Enrollment is complete for the latest cohort, in which patients received dose level 3 and were given short-course topical or periocular steroids before or after dosing. Today, we'll discuss the latest safety and efficacy results from all dose levels up to six months, which Dr. Pitcher presented at the Hawaiian Eye Conference earlier today. Before diving into the results, a quick scientific refresher on slide seven. 314 utilizes a novel AAV8 vector, encoding a gene for an anti-VEGF monoclonal antibody fragment with the goal of sustained protein production by the patient's retinal cells, resulting in long-term VEGF suppression. We and our global development partner, AbbVie, Allergan, are advancing 314 via two routes of administration: subretinal, which is currently in phase II global development, and also in-office 314 suprachoroidal delivery, which is in phase II development for treatment of diabetic retinopathy in the ALTITUDE study and also in the AVA study for treatment of wet AMD that we are discussing today. On slide eight, we see the patient demographics are well-balanced across treatment groups. Of note, there is a high treatment burden in all groups, with an average annualized rate of nine anti-VEGF injections. Moving to slide nine, safety. Across dose levels in over 100 patients, 314 treatment has been well tolerated, with no drug-related or ocular serious adverse events, including in dose level 3. Importantly, there were zero cases of intraocular inflammation in patients who received short-course prophylactic steroid eye drops. Slide 10 further illustrates that the lone two cases of intraocular inflammation on slit lamp exam in the periocular steroid prophylaxis group were very mild and resolved by the next visit without recurrence, while again, no cases of IOI were seen in the topical steroid group. This is actually consistent with what we've seen in the separate ALTITUDE study in patients with diabetic retinopathy, where zero out of 20 patients who received short-course prophylactic eye drops developed intraocular inflammation. Now, on slide 11, we move to efficacy. In the three dose levels, including dose level 3, stable BCVA and disease control, as measured by central retinal thickness, was achieved. On slide 12, we see this stability of function and anatomy was achieved in the setting of a dramatic reduction in anti-VEGF injection burden, ranging from 68%-80% annualized injection rate reduction, with the highest reduction observed at dose level 3. Slide 13 shows the swim lane plots for all the dose level 3 patients at each visit, with the colored dots denoting visits where an anti-VEGF injection was given. To the left is single-dose 314 treatment, that is prior to 314 treatment. We see visually the high injection burden in these patients, while after 314 treatment, it's clear that these patients received fewer injections, including 50% of the patients needing no eye injections. In those patients who received no supplemental anti-VEGF injections, on slide 14, we see these patients still were able to maintain stable vision and disease control. So in conclusion, 314 suprachoroidal administration has been well tolerated, and in dose level 3, with short-course prophylactic topical steroids, there were zero cases of intraocular inflammation. One time in-office 314 administration also continues to demonstrate stable vision and disease control, with a meaningful reduction in treatment burden, with the highest reduction observed in dose level 3, where there was an 80% injection burden reduction, with half of these patients injection-free. We are encouraged by these positive interim results as part of our global program for the treatment of wet AMD. As we mentioned, these results were presented at Hawaii Eye today by Dr. John Pitcher, who we are pleased to have on the line with us today. So John, let's start the Q&A session with you. Looking at this data set that you presented in Hawaii today, what are your take-home messages? Thanks a lot, Steve. Well, it's pretty clear that this data was well received by the retina specialists in attendance. It's also very clear to the retina community and our patients that we're in need of more durable and potentially curable treatments for neovascular AMD. Many of my patients are receiving 12 or 13 injections per year and still at risk of vision loss. So in order to create a paradigm shift or revolutionize the standard of care, new therapeutics need a combination of efficacy and safety. And we see that in the AVA study, with no evidence of ocular or drug-related SAEs over six months. With topical steroids, which these patients used in cohort six, topical drops, there were no evidence of intraocular inflammation, which I think is really a big point of this study, and again, very positively received today at the meeting. In addition, we saw a dose response with each dose level, up to 50% of patients with dose level 3 not requiring rescue injections in the 6 months of the study. Thanks, John. As Ken mentioned, we also have the benefit of having Dr. Allen Ho from Wills Eye in Philadelphia on the line. Allen, we won't talk about the Eagles today, so we'll talk about something more positive, these interim results. So you're obviously an extremely experienced investigator with a lot of experience across many wet AMD programs and trials. What are your key takeaways when you look at this data set? The data sets support very strong interim safety and efficacy data for a gene therapy platform that can be performed in the office for our most frequently needed injection patients, that is wet AMD. The safety issues is something to pause upon and reflect because we've seen a number of new products in the retina space that have suffered from safety issues, some of which have taken the post-approval out to essentially commercially non-viable. These safety data to date are very, very positive for this, this program and, you know, really support the idea of potentially suprachoroidal in-office gene therapy going forward for other conditions like diabetic retinopathy. We'll need to look at those data carefully as we go forward. I think from a larger, zooming out to maybe 30,000 feet, you know, retina has led in gene therapy with the first-in-human gene therapy approved in 2017 for a very rare disease, Leber congenital amaurosis, Spark Therapeutics. Just three weeks ago, we had gene therapy, a different type of gene therapy, CRISPR gene therapy, gene modification approved for sickle cell disease. This biofactory gene therapy, the data sets here today that Dr. Pitcher presented and that we have to date in the subretinal and also the other suprachoroidal program for diabetic retinopathy from REGENXBIO, have the support, really the viability of a gene therapy biofactory approach to common retinal diseases. I'm excited about it, and I think the colleagues were as well today here in Maui. Thanks, Allen. So you both touched on the importance of safety in the, the gene therapy space, historically. And of course, here, this data, we see what we were hoping to see in terms of mitigating inflammatory risk, fortunately, with just a 7-week taper topical drop regimen. So I think it would be helpful for our audience to hear your perspective when you think of one-time in-office treatment along with this type of regimen. Is that something that you find feasible, or any significant problems when you think of potential treatment for your patients? John, why don't we start with you again on this one? Yeah, I think that the topical approach with steroid drops is very palatable to patients and retina specialists. You know, we've seen other products require much more intense immune suppression. And in this case, the ability to achieve both mitigation of topical inflammation and potentially elimination of intraocular inflammation just with drops is potentially a game changer in the risk-benefit discussion with patients. Great. Allen, anything to add to that? I would agree with Dr. Pitcher that short course topical steroids are a completely acceptable way to control. And note that there were no recurrences of the inflammation, that these inflammatory events were mild. Yes, very acceptable. You have to. You know, if you contrast this with other spaces in which gene therapy is delivered, this is very much acceptable. Specifically, no oral steroids, no long-term topical steroids for more than several months, and no evidence of recurrent inflammation after short course topical steroids in this, our 314 AVA presentation. Okay, so let's switch on over to the efficacy side of the coin. Ken, in his introductory remarks, pointed out the challenge that we have translating clinical trials with repeated injection approaches, where when you then go into the real world, we see actually a continued loss of visual acuity over the years, at least in part, due to the unsustainable treatment burden. And I'd like to hear both of your real-world perspectives. So, you know, moving away from the clinical trial setting and into your practices, what do you actually see in the real world in terms of patient adherence to the available chronic treatment regimens, and how you see that translate into actual visual outcomes for your patients? Why don't we switch it up this time, Allen, if you could give us your perspective. Yeah. There are efficacy metrics that, of course, include visual acuity, how the patients are doing on the chart. There are efficacy metrics in terms of burden of treatment, how often the adult 40-year-old daughter has to take off a half day of work to come in and bring their mother in for an injection. So, certainly, gene therapy addresses burden of treatment from the standpoint of potentially less visits. In terms of vision, what I find most interesting and promising scientifically is that if we can achieve a steady state production with this biofactory approach. With the in-office suprachoroidal injection that maybe over time we'll see less decline in vision that we see in years 2, 3, 4, 5 in the real world, and also in some of the previous injection clinical trials that were long-term follow-ups of, for example, ranibizumab or aflibercept. Maybe the pharmacokinetics of a steady state production would be permissive of maintaining stable vision over time. We're getting senses of this in long-term follow-up in the subretinal 314 program. We're getting senses of this in, for example, other platform deliveries, like a port delivery over time. Maybe we'll see less atrophy, maybe we'll hold on to vision. That's really important. Very important. Obviously, that's the key issue for patients with neovascular AMD that are being treated over time. Thanks, Allen. And John, how about your experience with your patients over time? Yeah, it's still I frequently will see patients experience setbacks or vision loss due to inadequate treatment with current standard of care. And it's not always easy to avoid. Patients may travel from far distances to receive injections in all of our clinics, or they may become sick or have unreliable transportation options. And we're, I'm sure Allen would agree, always getting questions from patients about how many more injections do I need? And patients being able to switch that discussion from a chronic treatable condition to a potentially curable condition, I think a one-time in-office gene therapy option could help and obviously eliminate a lot of the obstacles we currently face in standard of care. Great. Thanks again to both of you, John and Allen, for your expert perspectives on these interim results and how you see that translating potentially into a potential new treatment approach for treatment of your patients with wet AMD. So now we're going to turn it over to the operator to take questions from the audience. Operator? Certainly. Ladies and gentlemen, once again, if you do have a question at this time, please press star one one on your telephone. If you'd like to remove yourself from the queue, simply press star one one again, and we'd please like to limit yourselves to one question. You may get back in the queue as time allows. Our first question comes from the line of Gena Wang from Barclays. Your question, please. Thank you. I think I will ask maybe two questions, very quick one. The first one is, dose level 3, you grouped 3 cohorts together. Any differences among cohorts 4 and 5 and 6 regarding injection-free rate and the injection reduction? And the second question is, more for the two doctors. I think on slide 11, if we look at it, BCVA and the CRT, there was not a clear dose response. You know, any thoughts there regarding the both measurements? Hi, Gena. I'll take the first question on dose level three and the grouping of the different cohorts. Really, the only meaningful difference was this elimination of intraocular inflammation that we saw in the cohort with topical short course prophylaxis. Otherwise, the efficacy measures were fairly similar across the groups, and that's why we chose to combine them. I don't know if either John or Allen, you want to comment on Gena's second question. Gena, could you repeat the second part of your question? Second question. Yeah, sure. So on slide 11, I think that there is a three different doses, dose level 1, 2, 3, and then there was a measurement of a BCVA and a CRT. When we look at the three dose levels and look at the change of a CRT or BCVA, there is not a clear dose response. I wanted to ask the doctor's thoughts there. Yeah, so John, why don't we hand that one over to you? Your perspective on what we see in terms of disease control, in terms of the stability of central retinal thickness across the three dose levels. Yeah. I think the point here is that the CRT and vision levels are remaining stable across the doses. I don't think there's necessarily an expected delineation there between the different dose levels. The key is that they're remaining within a range that we would expect with treatment. Thank you. One moment for our next question. Our next question comes from the line of Alec Stranahan from Bank of America. Your question, please. Hey, guys. Thanks for taking our questions. Two quick ones from me as well. Maybe just expanding on that last line of thought. You added a third dose to the study. Given the 9A profile and now the IOI is under control at the highest dose, is there a possibility or room to add an even higher dose to the study, or are you satisfied with the performance so far? And then in terms of next steps, I know follow-up on the primary is out to nine months. I think safety is 12 months, so we'll get another update from the phase II. But .In terms of gating around planning a pivotal, what does that sort of look like? And who ultimately decides whether that study begins, you or AbbVie? Thanks. Thanks, Alec. As you ended your questions with the aspect of our partner, AbbVie, and really, that's an important context for both parts of your question. This is a global collaboration, so as these new cuts of data come out, we review this together, and we make assessments on what additional data we want to see in follow-up in any future development decisions. So given that, we're really not in a position to give any specific guidance on dose selection, for example, other than the fact that we're very pleased to have three different dose levels where we're seeing efficacy and seeing good safety and tolerability, as well as having learned about the ability of topical that is less invasive than in short course prophylactic steroids to mitigate risk. So I think that puts us and AbbVie in a good position to assess how do we transition, as we look at these data packages into later-stage development. And I think also in terms of any specifics on future updates, same basic type of answer. Sorry, we can't give you more specifics, but that's really going to come down to further discussions with us and our global partner. Operator? Thank you. One moment for our next question. Our next question comes from the line of Ellie Merle from UBS. Your question please. Thank you, guys. Thanks for taking the question. Just in terms of the phase III planning, maybe just a little bit more color on the last question asked. Would you theoretically, I guess, wait for the subretinal phase III to read out before you would start a phase III or pivotal on suprachoroidal, and just, like, how you're thinking about that? And then I guess, what can we expect in terms of timing for when we could get some of this long-term efficacy data? And just any color in terms of how that's trending beyond six months in terms of durability. Thanks. Hey, Ellie. Ken. We don't have any interrelationship between the subretinal work that's going on, and we initiated those two pivotal trials, the first of them almost a year and a half ago, and they continue to progress well and be on track for the guidance for the subretinal BLA that we've given in late 2025 and through early 2026. So you know, the suprachoroidal data today is our first opportunity to see this 50-patient data set at six months, to kind of digest it with the community, bring it out there publicly. And I think, you know, the AbbVie and the REGENXBIO teams are going to have opportunities to now sort of interact and consider more what the longer-term data is going to look like across the course of this year. I think we've said, since the end of last year, we updated our strategic plans that, you know, coming into 2024 was going to be a data-rich year, and I think the maturity of the suprachoroidal data, both for wet AMD and diabetic retinopathy, is something that we're excited about to have this first data set, with this, you know, really, I think, full cohort of dose level 3, is heading in the direction that we're encouraged about. It's January. We're going to keep focused on the work we need to do to make those decisions, but I think this is a year where we see a lot of data being able to inform important decisions for this program. But again, not related to subretinal. That's well on track for the BLA filing that we've guided you already. Great. Thanks. Thank you. One moment for our next question. Our next question comes from the line of Luca Issi from RBC. Your question please. Oh, great. Thanks for taking our questions. This is Lisa on for Luca. Maybe another question on a potential pivotal. Just wondering how you are thinking about a phase III trial design. Would the study be similar to the subretinal study, comparing a single dose of gene therapy to on-label anti-VEGF, or would you consider a protocol with equal injection rates? Any color there would be helpful. Thanks. Hey, Lisa. Thanks for the question. Again, not a point in time today where we're giving specific guidance on any transition to pivotal or plans around pivotal. I do think that, you know, the work that went into the decisions and the trial designs for subretinal have been very consistent with what the regulatory agencies have required for assessment. And then last year, we updated further that both ATMOSPHERE and ASCENT have been strongly impacted by our worldwide partnership with AbbVie to take into consideration how ex US, not just regulators, but also commercial decision-makers, are influenced by clinical data at pivotal phase. And I expect that those types of features and attributes will find their way into the suprachoroidal design, both for wet AMD as well as for indications like diabetic retinopathy going forward. So I, you know, I think you can learn some from things that we've done and, and what the industry has done in terms of how to, use comparators and how to, assess design. But, you know, as of today, we're just excited about the six-month update that, Dr. Pitcher talked about and that, Allen and the rest of the community are getting to see for the first time here. Thank you. One moment for our next question. Our next question comes from the line of Brian Skorney from Baird. Your question, please. Hi, guys. Thanks for taking the question. This is Charlie Moore on for Brian. We were just wondering what your thoughts are on the decrease in the injection freedom percentage from 67% to 50% at dose three. And you know, what do you have any thoughts on how that might compare to competitive programs, particularly in the TKI space? Thank you. Hi, Charlie. So I'll take a first general response, and then I think I'll hand it to Allen to give his perspective on injection burden reduction over the long haul with a one-time treatment in the context of some of the other treatment programs and development that are out there. So you know, you mentioned some nominal differences in injection-free rates. Those are really nominal differences that with these sample sizes, I don't think you have as much power or sensitivity when you're looking at something like a binary endpoint of no injections versus some injections. So I think if you look at the totality of not just injection-free, but how many patients are having a partial response, that's where you get at the injection burden reduction. So with that greater sensitivity, that's where we're really glad to see that with dose level three, we have a 80% reduction in injection burden. So Allen, how about your perspective on the type of results that we're seeing in six months? And in the long haul, as you mentioned, if you have a sustained anti-VEGF activity potential with a one-time treatment, how that might compare to what you're seeing when you think of repeat injections with longer durability, TKIs or other programs? Yeah, so long-term delivery platforms include, of course, this gene therapy program, suprachoroidal and subretinal. We think about devices that are releasing over time, like a port delivery. We're thinking about pharmacologic approaches like TKIs in combination with anti-VEGF. The program here is impressive. I mean, if you look at dose three, 50% are injection-free. These are frequent flyer patients that were enrolled in this program. There is a, you know, 70%-80% reduction in terms of the need for injections after intervention with this gene therapy program. You have to be a little bit careful for fair balance on what the criteria are for reinjection. Some of the criteria, actually, that have been established by the FDA for programs going forward are a little bit problematic in the sense that they require you can't rescue until you have three lines vision loss, significant fluid, things that are not so comfortable to the retina community. We talked about this here in Maui. So the devil is a little bit in the details, but the results here are impressive. If you look at 80% reduction in dose level 3 and 50%, a shutout, essentially, no need for injections. That's impressive, no matter what you compare it to. Thanks, Allen. Thank you. One moment for our next question. Our next question comes from the line of Annabel Samimy from Stifel. Your question, please. Hi, thanks for taking my question. Just want to go back, and I know you're not really answering any questions about the design of the phase III or dose selection. But when you are looking at BCVA and CRT and not really seeing the dose response, is the factor that will drive dose selection going to end up being injection freedom in the end? Is that the determining factor that you think would be ideal to select the dose for phase III? And I guess secondly, this is more for the physicians. I guess I'm wondering, what do you think is the ideal patient population here? Obviously, these were heavily pretreated patients, and it doesn't seem like they are ever going to get dry, you know, as far as when you look at the anatomy. So, how do you feel about that, and what can be done to push these patients, I guess, further from an anatomical perspective? Thanks. Thanks, Annabel. So, before handing it over to the experts on the design development standpoint, you know, certainly we're very excited about the injection burden reduction. As John or Allen would highlight, that only matters if you can keep the disease and the VA stable. So we really look at the totality of it. There's somewhat of a ceiling effect that can exist in terms of the BCVA and the CRT benefits. So that's one aspect where you may not see as clear a dose response there, but that's where the injection burden can come in and really help. But in short, we really look at all of these measures together. John, why don't we start with you, and what do you think of as an ideal patient population when you think of one time in-office gene therapy? Well, these patients had to have fluid to be eligible for the enrollment, and they were frequent flyers. They. You can see on the swim lanes, I believe it's slide 13, how many injections these patients had prior to dosing. So I think we look at these patients, and I had patients in the trial who were able to get dry in the trial and stay dry. So, there are anatomic and vision retreatment criteria for these patients. And so it is encouraging to see patients who are receiving every 6 weeks, you know, 4 weeks-6 weeks, 8 weeks, injections on standard of care, be able to go long term with either less or no injections. So those are the patients I'm looking at in my clinic that would benefit. Okay. And now- If I could just, sorry, go ahead. Yeah, I was gonna ask Allen, from his perspective, who would, who would be the patients at the front of the line? I would agree with John, and thinking about the differences in his practice versus my practice as a suburban, urban practice with offices in three states and patients, we try to get close to the patients. You know, we still have patients who would want to who travel less distance than, for example, John's practice in New Mexico, where they're coming across maybe a couple hundred miles every six weeks. We want to offer them something that reduces treatment burden. But for John's practice, where the distance and the burden is greater in a sense, I would think it would be particularly appealing. Patients will kind of self-select, you know, what kind of treatment they want, what kind of clinical trial they're going to come into. It depends on their education, their sophistication. There's a lot of education that's going along, just in general, watching television with wet AMD products and advanced dry AMD products on TV. So, there's a large proportion of patients for which this would appeal. Yeah. And on that large proportion, would you put a percentage on it, on those patients who may have that high level of burden coming into the office and being frequent flyers, and that this would be an ideal treatment for them? Yeah, that's a little tougher. Let's forecast a little bit down the road, and if I saw this kind of vision stability over years two, three, and four, instead of getting injections, if we establish that on a pivotal trial, that would be obviously bringing a lot of patients in. So I think it's probably a little too early to estimate percentage, but I can say that things are looking promising, especially if it holds up in this in-office procedure, like we're seeing in the subretinal program as well. Okay, got it. Thank you. Thank you. As a reminder, ladies and gentlemen, if you do have a question at this time, please press star one, one on your telephone. One moment for our next question. Our next question comes from the line of Andreas Argyrides from Wedbush Securities. Your question please. Great, thanks for taking our questions. And this is for the physicians. Maybe you guys could provide a little bit more color on the dose level 3 results and how you might think that the cohort six, which had patients getting two extra injections, might have impacted the results. Any thoughts around that? And then, building off that last question as well, as far as identifying patients who would be best responders, and then also, what would you ideally look for a gene therapy in terms of extended duration? How far out would you really feel like the value proposition justifies the higher price point? Thank you. Thanks, Andreas. John, why don't you take this one? So if I understood correctly, the question was regarding dose level 3 and some patients receiving extra injection before and after dosing. You know, we know that in gene therapy, that the time to create protein does take some time. So I think that that's not an unreasonable ask in this trial to have that support these patients through that time period. The second question, I kind of missed. It may need to be repeated. Sorry. So from the previous analyst question about the best responders, how would you. How are you thinking about identifying those patients? And then also, when it comes to gene therapy, what would be an ideal, you know, a long-term duration that you'd like to see? Well, I think any, you know, any patient with fluid is a potential candidate, so that's the reason that we get stuck on injections with these patients at certain intervals is because of the presence of fluid. So even adding this as a supplement to injections is not unreasonable, but I mean, it's obviously impressive to be able to achieve an 80% reduction in dose level three. And I think the consensus, what the discussion at the meeting was that, you know, even a two-thirds reduction in the amount of injections was mentioned by a retina specialist at the meeting today would be acceptable and actually be really a home run. So I think this exceeds that. Thank you. One moment for our next question. Our next question comes from the line of Mani Foroohar from Leerink. Your question, please. Hi, good afternoon. This is Leerink, on for Mani. Thank you for taking our question. So let me just a quick question regarding the central retinal thickness. So we have a range here between the doses. So ranges from -6 micron in dose level 1, to about a +2 micron at the level 2, and then +16 at dose level 3. So how should we interpret the data? What would be a difference that would be considered clinically meaningful? And would you expect to continue to see the central retinal thickness go up, should you explore a higher dose? And as a separate question, I may be kind of tagging along a few of the questions that were asked, were there any commonality between patients that reached the injection-free status versus those who didn't? Thank you. Thanks for the question. On the retinal thickness aspect, it's important to recognize that while this is an objective measure of retinal thickness based on OCT, there is inherent variability both with the measure and over time, that's generally accepted as, you know, anywhere from 20 microns-25 microns. So those differences that you mentioned are all within the random chance. So really seeing the same level of stability and certainly within the range of zero, in other words, stable. On. I want to maybe I'll have Allen comment on that as well, after I just quickly say there wasn't really a strong commonality. These are small samples, so it's hard to slice and dice them. So I think we were encouraged that patients had meaningful reduction in injection burden and also these cases of injection-free status, generally across the board, with no clear differentiation, but again, based on small numbers. Allen, you see a lot of OCTs and follow-up in your clinic and also in a clinical trial setting. Do you see anything of note when you compare across groups, these stable retinal thicknesses? Thanks for the question. That's a good one. Central retinal thickness drives a lot of our treatment decisions, in addition to vision, of course. We're privileged to have the OCT, quick access to data. If you look carefully at the curves of the doses, they start similarly. The error bars for each of the doses overlap, and if you go over time, the curves are very much sitting on top of each other, and the error bars continue to overlap. I think, the sample sizes that Steve alluded to are not super large. I think they're significant to make some conclusions that all three of the doses seem to be working to maintain central retinal thickness from time of randomization to administration of our three fourteen. Thank you. One moment for our next question. And our next question comes from the line of Daniil Gataulin from Chardan. Your question, please. Oh, hi, guys. Thank you for taking the questions. A couple from me. One on slide 10, I believe, for cohort six. One of the patients did not get a full 314 dose. So wanted to ask what happened there, and if there are any problems with the injector, why did that patient not get a full dose? And second, for the physicians, in interacting with the patients, if you could provide any comment on their interest, or difference in their interest in subretinal versus suprachoroidal program. Thank you. Hi, Daniil. Thanks, thanks for the question. So the incomplete dose that we highlighted there for full disclosure was actually a straight administrative aspect in terms of the prior dosing manual with the lower dose was followed instead of the updated manual for the dose level three. We chose to include this patient in this group, even though they got a lower dose, because they still got the prophylactic ocular steroid approach. And since this was looking at really the impact of short-course steroids. So that was the reason we included in that. But it certainly had nothing to do with ease of administration or problems with the injection. I think John and Allen, you guys have enrolled multiple patients. Any perspective on how your patients, when you're screening, have considered the subretinal program, or, you know, compared to the suprachoroidal, recognizing, as Allen, you mentioned, it's really a case by case, but maybe there's some general pearls you can give? Yeah. You know, the biggest difference here with the vitrectomy and the subretinal studies is pseudophakic patients. So the suprachoroidal approach has the advantage of being able to be done in both phakic and pseudophakic patients. So that's, that's a big plus. And the injection itself is not technically challenging. I think retinal specialists are getting much better at administering suprachoroidal injections. And there's even special code now for administration in the office for the procedure code. So I think we're getting more comfortable with it, and it's a great option for these patients. Allen, I would also mention that the limitation on subretinal injection to pseudophakics is just a study design, inclusion, exclusion criteria. If this were to be approved and commercialized, we can use it in phakic, those that have not had cataract surgery or in those that have had cataract surgery, pseudophakic. The reason why it was not included in the subretinal program was because when you do a vitrectomy, you progress the cataract, so the cataract will be cloudier, and that was going to potentially confound visual acuity results. Of course, you can have a cataract surgery after having a subretinal surgery. Just having a cataract itself does not preclude that particular aspect of the program. We just limited it in the clinical trials. Thank you. This does conclude the question and answer session of today's program. I'd like to hand the program back to Ken Mills for any further remarks. Yeah. Thanks, everyone, for joining us today. We are excited about this data and what it means for patients, especially in the real-world setting. The value of the 314 program overall is expanding. We're excited about that and excited about our eye care partnership, of course, with AbbVie. We believe that this is a multibillion-dollar potential for 314 to become first in class for wet AMD and the standard of care, as we alluded to, for other treatment options in diabetic retinopathy, for instance. 2024, we're focused on executing on this updated strategic plan I talked about to create value quickly, efficiently, making progress on our pipeline, starting off with this data this year to a number of key inflection points. Upcoming milestones include completing enrollment of first pivotal trials for 314 in subretinal, potential to initiate pivotal trials for 314 using suprachoroidal delivery, potential to initiate and enroll pivotal trials for RGX-202 in Duchenne, and the filing of a BLA in 121 for MPS II. As I'm reflecting on this potential, I think it signifies transformative value over the course of this year, that by the end of 2024, it's possible that all the key platforms of our prioritized pipeline could be initiating pivotal stage development, have fully enrolled pivotal trials, or filed BLAs. So we look forward to sharing more updates across our pipeline with you at the upcoming events soon and across the entirety of this year. Thanks, everyone. Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.