Hello, ladies and gentlemen. Thank you for standing by, and welcome to Adverum's webcast to discuss preliminary efficacy and safety data from the ongoing LUNA clinical trial. At this time, all participants are in listen-only mode. Later, we will conduct a question-and-answer session, and instructions will follow at that time. As a reminder, today's call is being recorded. It is now my pleasure to turn the floor over to Mike Zanoni, Adverum's Head of Investor Relations, who will make introductory comments. Thank you, operator. Good morning, and welcome, everyone. Adverum recently issued a press release providing the details of the company's preliminary efficacy and safety results from the ongoing LUNA clinical trial. The press release is available in the investor relations section of the company's website at investors.adverum.com. Today's call will be led by Dr. Laurent Fischer, President and Chief Executive Officer, who will be joined by Dr. Setareh Seyedkazemi, Chief Development Officer, Peter Soparkar, Chief Operating Officer, and Linda Rubinstein, Chief Financial Officer. In addition, it is our pleasure to welcome our clinical advisor, Dr. Szilárd Kiss, distinguished professor of ophthalmology and a practicing retina specialist with over 20 years of ocular gene therapy experience. Dr. Kiss will provide his perspective on the potential of Ixo-vec and will be available for the question and answer session of today's conference call. As a reminder, we may be making forward-looking statements, including statements related to the potential of ixoberogene soroparvovec and plans and milestones regarding ixoberogene soroparvovec, which are based on certain assumptions made by Adverum based on current conditions and expected future developments. Actual results and the timing of events could differ materially from those anticipated in such forward-looking statements as a result of various risks and uncertainties. These are described under the caption Risk Factors in Adverum's filings with the Securities and Exchange Commission. For further details, please visit our website. This presentation also contains cross-trial comparisons. Cross-trial comparisons are not head-to-head clinical trials and are inherently limited and may suggest misleading similarities or differences in outcomes. Results of head-to-head comparisons may differ significantly from those described herein. At this time, it's my pleasure to turn the call over to Adverum's President and Chief Executive Officer, Dr. Laurent Fischer. Thank you, Mike, and thank you everyone for joining us today to discuss these very exciting preliminary results from the LUNA Phase 2 study with our pioneering intravitreal gene therapy product candidate, ixoberogene soroparvovec. Later this morning, we are pleased to have Dr. Arshad Khanani from Sierra Eye Associates present these results at the 47th annual meeting of the Macula Society at La Quinta in the beautiful Coachella Valley. As all of you know, wet AMD is the leading cause of vision loss in people over the age of 65 and requires lifelong injections with anti-VEGF. To kick things off, I'd like to provide a high-level summary of the results we announced in our press release earlier this morning. The preliminary data suggest that we are on track to achieve the goals of LUNA, which are, one, to replicate the potential best-in-class activity from the OPTIC first-in-human study we initiated over five years ago, and two, to demonstrate that with enhanced prophylaxis, we can improve the tolerability profile of Ixo-vec. Today's results demonstrated the continued potential best-in-class clinical activity of Ixo-vec in hard-to-treat patients requiring more than a mean of 9 anti-VEGF annualized injections in the year prior to receiving the 1 Ixo-vec injection. We have demonstrated a greater than 90% reduction in treatment burden, with 85% and 68% of patients remaining free of injection at the 2e11 and 6e10 doses at 6 months. Importantly, visual acuity, as measured by BCVA, was maintained at both those levels. In addition, central subfield thickness, or CST, a measure of macular thickness, improved and remained stable in the LUNA study population. Notably, in a subgroup of LUNA patients with high baseline CST, Ixo-vec significantly reduced their CST, with this reduction maintained through six months. Moving to safety, Ixo-vec was well-tolerated, with no Ixo-vec-related SAE. In LUNA, Ixo-vec demonstrated an improved safety profile as compared to OPTIC. In the small minority of patients where inflammation was observed, all inflammation was responsive to per-protocol, locally administered corticosteroids. Importantly, we have identified a promising local prophylactic regimen that demonstrates the potential to be our go-forward regimen for pivotal studies. This prophylactic regimen, Ozurdex plus difluprednate drops, led to greater than 90% of patients having no or minimal inflammation, 0 or 0.5 AC cells. For gene therapy products, which have a potential lifelong benefit, but which all have some degree of viral vector-related immune response, we believe it is critical to provide patients with the greatest potential to be free of injections for life. We believe data from Ixo-vec so far shows a favorable benefit-risk profile for patients, positioning Ixo-vec as a potential best-in-class therapy. Now, taking a step back to the landscape beyond intravitreal gene therapy, obviously, wet AMD is a large and growing market, with standard of care anti-VEGF treatments given anywhere from every 4 to every 16 weeks per label. If we look at some of the real-world data, the first challenge with wet AMD is the treatment burden, which is significant and has real impact on patients and their families, as well as cost to the broader healthcare system. As a result, patients are often undertreated, either due to missed visits, limited access, or a paradigm of treat and extend, all of which ultimately leads to poor outcomes in the real world. As demonstrated in this slide, while vision initially improves, these vision gains are ultimately lost, and vision deteriorates. These trends are even seen in the clinical trial setting. For example, in the pooled TENAYA and LUCERNE studies in the active faricimab arms, patients failed to maintain the peak vision gains in the second year. Secondly, gene therapy offers the potential to deliver constant levels of anti-VEGF in the eye for life. In contrast with current bolus therapy, anti-VEGF levels wane between injections over a period of weeks, and fluctuations in CST are seen as a result. These fluctuations in CST are known to negatively impact long-term visual outcomes. For example, in the same TENAYA and LUCERNE studies, fluctuations in CST were seen in the Eylea-every-8-week control arm, further highlighting the current challenges of current anti-VEGF. On the next slide, we will show you how we believe gene therapy has the potential to advance wet AMD treatment beyond the current standard of care, as well as some agents in development, such as implantable TKIs, for which we've recently seen updated data. As discussed, the latest approved treatments do not extend therapy beyond 6 weeks per label, and even those in development, such as TKIs, only have the potential to extend treatment to 6 months, though this requires upfront booster injections of anti-VEGF and regular implants. The two most advanced gene therapy programs, including RGX-314, a subretinal gene therapy program, and Ixo-vec, have demonstrated promising activity beyond three years, with levels of anti-VEGF out to four and a half years with Ixo-vec. On the next slide is a recap of our OPTIC first-in-human data. These data were recently published in the Lancet's eClinical Medicine in January of this year, and here we show a strong efficacy profile and what we believe is the longest duration of treatment burden reduction seen with any intravitreal anti-VEGF therapy in development. The% of patients free of injection is not only the highest out of any anti-VEGF therapy currently approved or in development at the 6-month time point, but also at the one year, two year, and three year time points. We believe this is important for patients and caregivers and arguably for all stakeholders, a potentially lifelong solution. Now, I would like to pass the microphone to Dr. Star Seyedkazemi, our Chief Development Officer, who will provide an overview of the data. Star? Thank you, Laurent. Good morning, everyone. As a reminder, I'll also be referring to the OPTIC data that Laurent introduced throughout this presentation. LUNA is our ongoing phase 2 trial in previously treated patients with wet AMD. It is a multicenter, double-masked, parallel group study in patients receiving active treatment and who have demonstrated response to anti-VEGF. Importantly, investigators and study participants are masked to the dose of Ixo-vec, and we believe that maintaining the masking of the LUNA study through the one year primary endpoint, as recommended by the FDA, underscores the robustness of this study. Patients in LUNA were randomized 1:1 to receive a single intravitreal injection of either the 6E10 or 2E11 doses of Ixo-vec. Patients in the study received one of four prophylaxis regimens, including two local options, namely a 22-week course of difluprednate eye drops and a single administration of Ozurdex, a bioerodible intravitreal implant of dexamethasone. Both options were evaluated with and without a 10-week course of oral prednisone. Early in the study, we identified that after 6 patients received Ozurdex alone or with prednisone, that this regimen did not provide adequate prophylaxis. We decided to amend the protocol to add a course of difluprednate to the Ozurdex regimen to improve the duration of prophylaxis coverage. Patients in LUNA may receive supplemental injections according to the criteria in the table at the bottom right of the slide, which are relatively standard for wet AMD clinical trials. These are an increase in CST of 75 microns, confirmed by Central Reading Center, or a decline in vision of at least 10 letters due to worsening of IRF or SRF, or new vision-threatening hemorrhage. We will conduct an interim analysis at 26 weeks, which we intend to leverage for an end-of-phase-two meeting with FDA. The primary endpoint analysis will be conducted at 52 weeks. Here on this slide is the study disposition as of the primary data cutoff of November 15, 2023. Supplemental injection data is as of January 2, 2024.... Notably, this preliminary data set contains certain data at 14 and 26 weeks, and other data for all patients through the most recent visit before our data cutoff date. 60 patients were randomized, with 54 and 26 completing week 14 and week 26 visits, respectively. Two patients discontinued early, one patient passed away due to complications unrelated to study drug, and another discontinued as a result of an AE of dementia unrelated to study drug. Here is a breakdown of prior anti-VEGF therapy. Of note, 10 patients had been treated with aflibercept a year prior to entering LUNA. Moving along, here is an overview of demographics and baseline characteristics in LUNA overall and broken out by dose. This study is being conducted in patients who received a mean of more than nine annualized anti-VEGF injections in the year before Ixo-vec. For comparison, the OPTIC characteristics are provided, with notably consistent prior annualized anti-VEGF treatment. Also notably, patients in LUNA had slightly higher BCVA and slightly lower CST relative to OPTIC, which is representative of a patient population more consistent with the real world. Overall, this was a difficult to treat and highly treatment-experienced patient population. Now moving into the exciting clinical data from the LUNA study. First, we'll look at aggregate treatment burden reduction data by dose before moving into the swim lane plot. Per the disposition we showed you earlier, the time points for this analysis were at both week 14 and week 26. Across both dose levels at these time points, patients saw greater than 90% reduction on average in annualized anti-VEGF injections, which compares well to the 2 E 11 dose results from OPTIC at similar time points. Now, looking at injection-free rates, we see 68% of patients injection-free at 6 E 10 and 85% of patients injection-free at 2 E 11 through week 26, consistent with the 73% injection-free rate we observed in OPTIC. Ixo-vec has achieved the best injection-free rate ever reported in wet AMD therapy. On the next slide, here is the swim lane plot for the entire study population across both doses, with treatment history of these patients on the left side of the graph and on the right side, any supplemental injections administered after a single dose of Ixo-vec. This slide includes all data through the supplemental injection data cutoff date of January 2, 2024. Overall, we saw a dramatic reduction in treatment burden across both dose levels, including a 93% reduction in annualized injections, with 75% of patients remaining free of injections. Let's now review vision and anatomy results from LUNA. As you can see on the graph, mean BCVA is maintained over time at both dose levels, and these results are similar to our observations in the OPTIC study. The boxes on the right summarize mean change in BCVA from baseline to the last visit for all patients with available data through the data cutoff, confirming maintenance of vision. The CST results show reductions from baseline that are maintained at both dose levels over time. In OPTIC, patients had higher CST levels at baseline, leading to greater reductions in CST from baseline. More importantly is the maintenance of stable CST over time in LUNA, and as we presented earlier in OPTIC, out to three years. We also evaluated BCVA and CST in patients who received no supplemental injections. Here we look at mean change in BCVA and CST from baseline. We can see in this subgroup of patients, vision and CST results are similar to our overall observation, with maintenance of vision and stable CST over time across both doses. These clinical outcomes are supported by our data on the next slide, showing levels of aflibercept measured in the aqueous humor at week 14. In LUNA, aflibercept levels delivered with both 6E10 and 2E11 doses fall within the range seen in OPTIC, in which all patients whose aflibercept levels are shown received clinical benefit. Also critical is that our exclusive and leading data sets confirm that with Ixo-vec, the early aflibercept levels were predictive of stable aflibercept out to four and a half years. We look forward to continuing to share these data with you as data reach five years landmark analyses and beyond. Taken together with OPTIC, these LUNA results suggest patients may receive a lifelong benefit from a single injection of Ixo-vec. Moving to the safety portion of the presentation. In summary, Ixo-vec was well tolerated, with inflammation that was responsive to protocol-defined local corticosteroids. There were no Ixo-vec-related SAEs. No cases of episcleritis, vasculitis, retinitis, choroiditis, vascular occlusion, or hypotony were observed. The most common Ixo-vec-related AEs were dose-related anterior inflammation and anterior chamber pigmentary changes, consistent with the published data from OPTIC at two-eleven. Notably, the Ozurdex plus difluprednate regimen resulted in over 90% of patients having no or minimal inflammation. This optimized prophylaxis resulted in an improved inflammatory profile versus OPTIC two-eleven. We are pleased to identify a promising go-forward regimen that has the potential to be used in pivotal studies. A key learning from the study was that oral prednisone did not provide meaningful benefits. While studying this was an important contribution to the field, we are pleased with the outcome, given the complexities of oral prednisone in this setting. In this heat map of the anterior chamber and vitreous, we see particularly good coverage during the period of peak inflammatory response with Ozurdex plus difluprednate and minimal inflammation, with a few instances of trace or only 0.5+ cells in the AC or the vitreous. Patients who received difluprednate eye drops alone also had effective coverage of the anticipated period of peak inflammatory response, with a few patients with cells at the time of the data cut, all subsequently responding to local steroids. On this slide, we have summarized additional key learnings from LUNA about corticosteroid prophylaxis for our program, which led to the identification of our potential go-forward regimen and also advances our understanding in the field. As seen on the bar graph to the left, we learned very early in our study that a single Ozurdex implant did not provide adequate prophylaxis. We amended the protocol early to add difluprednate eye drops after the week 4 visit, which significantly improved the effectiveness of the regimen, as you can see in the graphic to the right of the arrow. In addition, the bar chart on the right side of the slide compares local only versus local plus oral prednisone, showing no meaningful benefit of adding oral prednisone to our local steroid regimen. On the next slide, we consider these data in the context of what we've seen in OPTIC with Ixo-vec at 2e11. These results compare favorably to OPTIC, where in the OPTIC study, patients received significantly less prophylaxis. These data show a significant improvement and underscore the potential of Ozurdex plus difluprednate as the prophylaxis of choice, with greater than 90% of patients having no or minimal inflammation. The improved safety results in LUNA, combined with efficacy data that are on track with long-term outcomes in OPTIC, highlight the potentially favorable benefit-risk profile of Ixo-vec gene therapy for wet AMD in this heavily pretreated patient population. The last safety slide shows mean IOP over time, which was stable throughout the period of follow-up across both doses, with no cases of hypotony. Now turning back to Laurent to put these data in the context of the landscape. Thank you, Star. I'm excited by the data you just presented from LUNA. I would now like to show you Ixo-vec's impact on treatment burden from LUNA at 6 months and in OPTIC out to three years. On the left, we compare the reduction in annualized injection across both intravitreal and suprachoroidal gene therapy agents, which are delivered in the clinic in an outpatient setting, similar to today's standard of care. As you see, Ixo-vec not only has superior reduction in annualized injection reduction at 6 months, but also the longest available data set out to three years. On the right, the difference is even more profound. Remember, as we discussed earlier, the importance of delivering lifelong benefits with gene therapy. Looking now at the injection-free rates across studies, you can see that Ixo-vec has demonstrated 68%-85% injection-free rates at 6 months at 6x10^11 and 2x10^11, better than any other program, and those were sustained in OPTIC, with 53% of patients entirely free of injections through three years. This is truly game-changing and shows the potentially transformative impact of a gene therapy program like Ixo-vec. One question we get is: What type of wet AMD patients are most likely to benefit most from Ixo-vec? As you will recall from both LUNA and OPTIC, we enrolled hard-to-treat patients who required significant treatment with more than 9 annual injections in the year prior to Ixo-vec. On average, compared to OPTIC, LUNA patients had slightly better vision and slightly drier eyes at baseline. Here you can see the BCVA maintenance and CST reduction for the entire LUNA population, which Star showed you earlier. On the next slide, we ask: How do patients with higher CST at baseline do on Ixo-vec? If you look at the subgroups based on baseline CST above or below 300 microns, we see effective anatomic control maintained across both groups... with greater CST reduction among patients with baseline CST above 300 microns, maintained through 6 months. We've also done the comparison between LUNA and OPTIC, where we know that patients had sustained reduction through three years, which we will show you on the next slide. Here you can see the CST reduction comparing the high baseline CST patients in both the OPTIC and the LUNA studies, showing that patients with high CST at baseline show improved CST through approximately six months, with benefit demonstrated in OPTIC the past two years. Moving to the next slide, we know that LUNA patients received multiple anti-VEGF agents in the year prior to Ixo-vec, including the latest bispecific antibody faricimab, approved for wet AMD. Here's a reminder from the earlier data where star showed us the entire swim lane plots for the total population in LUNA. Now focusing on a subgroup of 10 patients who received Vabysmo in the year before Ixo-vec. These were hard-to-treat patients who required, on average, of over nine annual injections before receiving one-time Ixo-vec. You can see that in this subgroup of 10 patients, 50% of whom received 2e11, the other 50% of whom received 6e10, 100% are supplemental injection-free as of the January data cutoff. In conclusion, we believe that our early LUNA data supports a favorable benefit-risk profile for Ixo-vec, and also one that is potentially best in class. This is important for a one-time gene therapy, where you only have one opportunity to those patients and therefore are looking to maximize efficacy with a safety profile that is both acceptable and manageable. We believe these efficacy and safety data from LUNA suggest that Ixo-vec has the potential to strike this balance. Looking ahead, we expect to present our LUNA 26 interim analysis mid-2024, to have continued FDA and EMA both formal and informal interactions over the course of the year, with a focus to finalize our phase 3 design and to initiate our phase 3 in the first half of 2025. Okay, I believe it's time for us to transition to the questions and answer portion of the call. As a reminder, we are joined today by Dr. Szilárd Kiss, who is available to answer questions. Operator? We would now like to open the line for questions. If you have a question, please press star one one at this time. Given time constraints, we ask that each analyst limit their questions to two per analyst. If there are questions we don't get to during today's webcast, management is happy to follow up with folks individually after the conclusion of the webcast. So thank you very much. To kick off this part of the webcast, I'd like to, and prior to opening it up for our analysts, ask the first question to Dr. Szilárd Kiss, who is Distinguished Professor of Ophthalmology, a Professor of Genetic Medicine, and a practicing retina specialist. Szilárd, can you give us your general impression of the challenges you see for your patients with the current standard of care, as well as your thoughts on intravitreal gene therapy for wet AMD, based on the benefit risk that we presented so far with Ixo-vec? Thank you so much, Laurent. It's a pleasure to be here this morning. You know, the current state requires repeated bolus injections. Although we are looking at somewhat improved intervals, we're still talking about extending by weeks, and those injections really need to be given for the lifetime of the patient. The challenge is, one is for the patient. You know, there continue to be decrease in visual acuity over the long term. There's a treatment burden, not only in my clinic, but after the patient goes home, after they've had the injection. Oftentimes, they're sort of out of commission, you know, with their activities of daily living for a day or two. There's inevitably a suboptimal injection frequency. You know, trying to get patients in every month or every two months is still a challenge, even in New York. You know, I think that's where gene therapy comes in. Given the fact that now we're talking about a potential one-time treatment, and we're talking about suppressing VEGF and AMD over years, that potentially represents a paradigm shift, where not only you have the treatment burden decreased, but there's some evidence, you know, in the LUNA and the OPTIC trials, that maybe anatomy and visual function can also be maintained or even improved over the long term. It's something that we really haven't seen with the current anti-VEGF bolus therapies. Thank you, Szilárd. Do we have questions from our analysts? Our first question comes from the line of Joon Lee with Truist Securities. Your line is now open. Hi, Joon. Oh, hey, thanks for taking our question, and congrats for the strong data. Yeah, I do have two questions. So the first question is, so had you included an aflibercept comparator arm in the phase 2 LUNA trial, which you would need to do for a non-inferior registration trial, would your BCVA and CST data have looked even better? I mean, so doesn't 2 mg Eylea every two months show a declining BCVA and CST over time, or am I not thinking about this correctly? And I have a follow-up. So thanks for asking these questions. I think what is very clear in these severe patients population with high treatment burden is that they require over nine injections. In fact, the subgroup on Vabysmo was over 10 injections, annualizing the year prior. Some people and other companies recently present data where they do a withdrawal of the aflibercept in the control group, that in patients that had actually nine injections, so one every 6.5 weeks, and they waited 9 weeks for the first injections and gave 2 injections with 6 months. And you can see actually that there's more fluctuation in CST and a difference between the treatment. We think that for this very treatment-experienced population, for phase 2, it actually allows all patients to benefit from the gene therapy, and they can reserve as their own control. We have enough information to be able to power a study for phase 3 based on the data we have. We're very pleased to see that not only we maintain vision, but we can actually reduce CST and maintain that CST, which is a marker of disease activity, out to six months in all patients at both doses. All right. And, you know, I'm really pleasantly surprised that the phase 2 LUNA data looks numerically better than phase 1 OPTIC data. Trying to figure out why that may be. I mean, do you think the better prophylaxis may have contributed to the clinical efficacy, given the—I mean, is it possible that the further reduction in inflammation could have contributed to the better transduction of the gene therapy? Thank you. Thank you for that question. I will start by answering the question, then I'll ask Dr. Szilárd Kiss. So we have seen no correlation in OPTIC or in LUNA between any of the minimal inflammation we've seen and efficacy to date and it sits right there. We're very pleased with the go-forward regimen, with the Ozurdex plus difluprednate, which, as you can see, shows only traces in a couple of patients at a couple of time points, and is very promising. And that's obviously compared to the OPTIC study, where we're actually the first to actually try to use steroid eye drops, but for a period of time that was too short. We see that despite that, the patient at 211 did very well, with no patients required any steroids after the end of the study, while having this great benefit of more than 53% free of injections and overall over 80% annual reduction in anti-VEGF. So the combination of a very, effective Ozurdex implant that takes away the risk of non-compliance initial period, we think is actually very promising. It's also available globally, and the addition in the tapering phase of the eye drops gives us, so far in what we've seen in our LUNA study, an excellent prophylactic, go-forward regimen. Szilárd, would you like to address, further the question that, June asked? Laurent, yeah, thank you. You know, I don't have any great insight. I think what I'm looking for is consistency of results. You know, when you look at how Ixo-vec is functioning across 2 trials, there seems to be some differentiation that's emerging early, right? But that differentiation is in terms of the injection-free over the first 6 months compared to other gene therapy programs. And so, you know, that's what I'm looking at. The actual numbers, you know, may fluctuate a little bit, just the law of small numbers, but the fact that Ixo-vec, given intravitreally, continues to provide an injection-free interval at 6 months for more patients compared to the other programs, is really what I'm looking at, you know, in these early studies. Great. And just a quick follow-up. At this juncture, what do you favor in terms of dose, 60/10 or 2/11? Or are you gonna reserve that for, you get more data? Thank you. Thanks, June. Excellent questions. As we have identified a go-forward regimen that is very promising, we see that both doses give us very promising efficacy as well, with the highest rate of injection-free patients of any study, of any program, at any dose, including the lowest dose. You can also see that in the go-forward regimen, there's no difference, or we haven't seen a difference so far in the AC cells, and we see great control of immune response. So given what we discussed earlier, is the potential to have patients free of injection for life, that's, you know, potential 18%-20% difference at the 2/11 dose may be worth a, you know, more aggressive or longer steroid prophylaxis. But obviously, we think that the totality of the data at 26 weeks will be, what will give us the answer, and at that time, we'll have the option to select one dose. Also, potentially, as been done with other studies, take both doses into phase 3. But right now, we like the fact that for gene therapy with a one-time opportunity, giving the highest chance of being free of injection for life is really what we should be looking at. This is regenerative medicine, gene therapy. We see cures with rare diseases. This is gene augmentation with an aflibercept-encoding vector. Slightly different, but still the same concept of a potentially lifelong benefit. And so the benefit risk today looks good at both doses, but we're looking at the benefit risk over time, and we're thinking one year, two years, three years, five years, and hopefully life. Thank you. Our next question comes from the line of Joseph Thome with TD Cowen. Your line is now open. Hi, Joseph. Hi there. Hi there, good morning. Congratulations on the data update, and thank you for taking our questions. Maybe just the first one, for Dr. Kiss. Can you just comment a little bit on your impression of the inflammation seen at the potential difluprednate Ozurdex? ... regimen, are you comfortable with this? And maybe just overall, what level of inflammation are you comfortable with in your, in your patients in general? Obviously, it looks like it's going in the right direction. And then, second, for the company, now that you've dosed, you know, quite a few patients across LUNA and OPTIC, obviously, the efficacy data is very strong. There are still some patients that do need rescue injections. I guess, do we know enough about the patients that require rescue injections? Is there anything specific about their disease course? And, if so, how would you incorporate that into a pivotal program? Thank you very much. Yes. I'll start maybe with the latter part of the question, and then I'll ask Szilárd to comment. So first of all, what we're presenting is the data in all patients that are actually including in this trial. So we haven't excluded the go-forward patients based on baseline criteria. We are looking at whether there are factors that could contribute, that has been seen in small samples in other studies that would be incorporated in phase III. We think that these are the hardest to treat patients with a high disease burden, and they obviously are doing very well. So far, I think the kind of most common factor predicting the need for injections is the treatment burden, but that's with the current treatment of standard of care. We haven't seen really any clear trend to date. So we're very pleased with that, as well as the go-forward regimen with the combination of Ozurdex and steroid eye drops, giving us what I think is a very robust, effective, and kind of compliance-resistant patients. But I'll ask actually Szilárd to comment on his thoughts about Ozurdex versus steroid eye drops for prophylaxis for gene therapy. Sure. Thank you, Laurent. You know, it's a great question, and I think we have to put it into context, both of gene therapy and both to the benefit to risk ratio, right? So, inflammation is seen with all gene therapy, right? Whether that's systemic or intraocular. And so the question is: Can you control that inflammation, and what are you getting on the upside, on the other end of giving that gene therapy? And I think it's nice to see, very nice to see that local control of ocular inflammation is achievable here, right? And it's achievable with Ozurdex plus minus difluprednate drops. And, you know, Ozurdex gives you the benefit that it's out of the patient's hands, right, so to speak, right? So you give the steroid, you cover the inflammation, and you don't have to worry about any you know compliance challenges. And so that's sort of the risk of ocular gene therapy. And I think when you look at the 4D data and other data, even the suprachoroidal data from you know other company from REGENXBIO, you see that there is inflammation that needs to be treated. So then what I really look at is, what am I getting out of it? And if I'm getting an injection-free you know patient population of 85% at 6 months, and I'm getting injection-free at four and a half years, an Ozurdex and a little drop at the beginning is really no big deal. You know, I can tell you that, you know, 10 out of 10 of my patients would take that if I give them these numbers that we see in this preliminary analysis. You know, and then ultimately, we'll see what, you know, further analysis comes. But I think that it's nice to see that we are able to control ocular inflammation with the efficacy that Ixo-vec gives us, you know, in this preliminary analysis. Our next question comes from the line of Gregg Moskowitz with Mizuho Securities. Your line is now open. Greg, thanks for joining us. Yeah, thanks, Laurent. Congrats on the data. Thanks for taking the question. I had a question, just for initially, our doctor on the line. Doctor, it seems as if we're almost like in a golden age of innovation in wet AMD in terms of having gene therapy approaches and sustained-release implant, you know, based approaches as well as bispecific. So, in your opinion, like, how is everything going to fit? Will these all end up being like, you know, a very fragmented market and because patients are heterogeneous, it's just gonna, you know, we in the investment community will just have to make some judgments as to like, you know, what patients will get what? So just trying to make sense of all of this, and then maybe back for Laurent and the team, just in terms of the next steps on the forward and your thoughts on the phase III program. Is it going to be one dose and one prophylactic regimen going forward? You know, and you know, what are your thoughts on the differences between the high dose and the low dose that were tested in LUNA or are being tested in LUNA? Thanks. Right. So maybe I'll let Szilárd kind of start with answering the question about... I think really what you're asking is, what patients are the ideal patients to be treated with gene therapy, and how does that compare to the current landscape, including the ones that are in development, like the TKI implants? I'll start with Szilárd, and then I'll answer the rest. So it's great to be a retina specialist. You know, when I was training, wet AMD patients went blind, and then we got these injections where we had to give them every month or every six weeks. And we really have entered a new era of FDA-approved treatments that are appreciably better, right? So Vabysmo being one of them. So you know, we're able to stretch out some patients, we're able to decrease that treatment burden with Vabysmo. I was surprised, honestly, to see that there were so many Vabysmo patients that entered, you know, the Ixo-vec LUNA trial, right? And it really told me three things, right? There's still an unmet need, right? So this, this chapter in anti-VEGF therapy for AMD is not written. There's unmet need on the doctor's part, unmet need on the patient's part. The second thing it told me was, you know, there's confidence in the investigators to put patients in an Ixo-vec trial, right? So you know, it-- there's confidence that, you know, the efficacy and safety profile can be managed, and especially the efficacy that we've seen previously. It was amazing for me to see that Ixo-vec outperformed Vabysmo, right? So you had these patients, you know, that were pushing, you know, an annualized injection rate of about 10 with Vabysmo, which many of us consider to be the latest and greatest. And yet, you know, you give them an Ixo-vec and enrolled in LUNA, and they're injection-free, you know, supplemental injection-free after Ixo-vec. And so I think that, you know, it's nice to be a retina specialist because we have options, but I think the next chapter is really gonna be over years of treatment. Now, of course, TKIs are in the mix, and, but those also require, you know, many injections, right? So, you know, what do I mean by many? I think anything more than three or four a year could potentially qualify for a gene therapy, right? I mean, if I tell my patients, "You have an 85% chance of not needing one in, you know, six months, you have a very good chance of not needing another one for four years, four and a half years," that's a very different conversation than, "Oh, you've got to come in every six months for a repeated injection." And so, you know, it. I'm very lucky to be practicing now, rather than, you know, 20 or 25 years ago. I think, you know, with these intravitreal gene therapies, specifically Ixo-vec, we are going to enter the next world of, "Listen, you may not need another injection. There's a very good chance you may not need another injection. And so thank you so much for this answer. To address the second part of your study, what are our phase III plans, doses, prophylactic, timing? As we clarified when we made this data release, and is the fact this is a preliminary data. So the 26-week interim analysis is coming mid-year. That will be the foundation to decide and finalize the prophylactic and the dose, and have the, you know, final conversation with this end of phase II, at an end of phase II meeting with the FDA. Our feeling and our thoughts today is that our go-forward prophylactic regimen will be Ozurdex plus steroid eye drops, and we see good control with eye drops alone. I think it's worth noting that compliance can be an issue. We've seen that in patients in OPTIC and also in LUNA. So we like the lack of compliance-related issues with the Ozurdex implant, putting the control of immune response in the hands of the retina specialist. So we believe that we have selected the prophylactic regimen. There'll be only one for phase 3. Dose, I think, is still premature. We like to preserve the efficacy that we see at 2 × 10^11, for which we have longer-term benefit risk from OPTIC. But we think that even the 6 × 10^10 looks better than our competitors at their highest dose, and so that's also encouraging. And if there was a difference in the benefit risk or the ability to mitigate inflammation, immune responses, that would be a very acceptable dose and still best in class. So we have the option to select the dose at the interim analysis. As I mentioned earlier, potentially a lot of non-inferiority studies, which is what we're contemplating, are using two doses, and that's also a possibility. So, more to come. We would like to use data to really make decisions, and that's what we'll be doing and sharing with you in the upcoming weeks and months. Thank you. Our next question comes from the line of Aydin Huseynov with Ladenburg. Your line is now open. Good morning- Hi, Aiden. Everyone. Hi, Laurent. Thank you for taking questions, and congratulations with the nice data- Thank you. Positive data. So a lot of questions were asked by colleagues, but I want to just dive in a couple of questions that I have here. So regarding the phase III trial design, could you a little bit elaborate on how do you think this may look like? I know you don't want to talk much about it, maybe haven't discussed that, but just talking in general, non-inferiority versus superiority. We saw that the 4D Molecular Therapeutics announced that non-inferiority to 25 per arm. But just wanted to get your thoughts on how this may look like and how many actually trials are expected to be, one phase III or two phase IIIs? Great. Thank you, Aiden, for asking this question. We believe that the non-inferiority trial that had been used to get the most recently approved Vabysmo on the market provide the best design as far as its ability to compare to the standard of care, as well as a label that would make it clear for physicians to understand the benefits compared to the current standard of care. So, the trial design of a non-inferiority, looking at approximately 225 patients per arm, seems like an appropriate design and power to look at a 4.5-letter non-inferiority versus the standard of care. But those are still assumptions that we're using to actually, engage with the FDA in our conversation to, look at that. It's a, it's a non-inferiority confidence interval of 4 letters for EMA. But we have PRIME at EMA and ILAP in the UK and Fast Track in the US. That allows us to have a number of both formal and informal conversations. For gene therapy, the primary endpoint is at 12 months, not 9, like others, or earlier. That's mandated by the agency in the US, and it does require 2 clinical trials, showing non-inferiority. So that is what we're looking at, and we look forward to, once we've had these, confirmation in writing by the agencies, share that with the investment community. Thank you. Our next question comes from the line of Daniil Gataulin with Chardan. Your line is now open. Hi, Daniil. Great to see you. Yeah. Hey, good morning, guys. Congrats on the data, and thanks for taking the question. I have one on the baseline characteristics. So having seen the data from OPTIC, that had more severe baseline population and now from LUNA, with less severe characteristics, how are you thinking in terms of baseline characteristics for the pivotal trial? Thank you, Daniel. That's a great question. As we've shown in actually this dataset earlier today, we see actually, patients that have, that have a severe disease that requires frequent injections. The number of injections across OPTIC and LUNA is the same, about 9.9 annualized in the year prior to receiving Ixo-vec. There is slightly better vision and slightly drier eyes, which is actually closer to the real world, where patients are well controlled in these patients, in, in these settings. I think this is a perfect population to evaluate in phase 3 trials. We also have actually some patients that you can see in the streamline plots that only had treatments for a few months. They needed to have at least two injections in the last four months, I believe, to enter the trial. These patients also do very well. So I think there's a broad range of patients we can include, and we will look at the interim analysis to inform whether there's a more specific population that we would like to enroll in phase 3 with a high probability of success versus a subset. But I think that we're very excited about the data we see. And what we showed you also today is that even the patients with the highest CST across both trials see that very nice reduction in fluid, and that reduction in fluid, the CST, is actually maintained through six months. It's been, of course, maintained through three years in our OPTIC trial at 2e11 with Ixo-vec. I think this gives us a lot of opportunity to look at whether there are even ways to optimize for what we see as potentially best-in-class data with Ixo-vec at the two doses that we're considering, 2 × 10^11 and 6 × 10^10. Thank you. Our next question comes from the line of Lisa Walter with RBC. Your line is now open. Oh, great. Hi, Laurent. Hi, thanks for taking our questions, and congrats on the data. Just a couple- Thank you. From me. On the prophy regimen, just wondering if you can comment on what percentage of patients completed the pre-specified course of treatment with the go-forward regimen versus those who required additional prophy beyond what was outlined? And, second, you know, given the impressive data today on both safety and efficacy, are there any plans to revisit diabetic macular edema patients? Thank you. Great. Thanks, Lisa, for these excellent questions. So as we mentioned, this is not the 26-week interim analysis. This is still a snapshot. You've seen the dispositions that Star presented earlier. So we still have patients progressing across multiple time points, and we'll be able to actually be more affirmative at the 26 weeks interim analysis. So it's a little premature to say that. When we are where the fulsome analysis will be able to really compare the different prophylactic regimens. Anecdotally, you know that, we know that the sites that enroll the first patients, that is three patients, one beyond 15 months, all three patients are free of injections, are post their prophylaxis with no inflammation. That is not representative of what we've shown today, but just an example that this can be controlled, and we feel that this optimized regimen gives us a really excellent path forward as far as controlling the inflammation while preserving the incredible efficacy that we've seen in both LUNA and OPTIC, now out to three years in OPTIC, and this six months look in the early analysis, preliminary analysis in efficacy and safety from LUNA. So we're very excited about that. I forgot about... What was your second question? Oh, DME. Yes, that's right. So, you know, DME, diabetic retinopathy, is obviously a clear unmet medical need as well. And you know, I think we'll be very excited to see whether other programs show us promising data. We know this is a significantly smaller part of the market that's covered by different payers, probably a more challenging patient population. Also, it's first compliance, so compliance with the prophylactic may be a challenge. So I think this is something we'll be continuing to evaluate down the road. And we believe that right now, the focus on wet AMD is what we're gonna be doing, but always a potential to revisit based on our understanding of the field. We've been doing that for more than five years. As pioneers in the field, we've learned and taught others how to use a steroid eye drops as prophylactic. And now we are hopefully keep advancing the field by demonstrating that orals are not necessary to contain the immune response after an intravitreal gene therapy vector. And that maybe an Ozurdex implant or something similar could be the optimal way to think about, minimizing any of the risk related to non-compliant patients forgetting their drops or being hospitalized without their drops, which we've seen. And so we actually really try to understand how we think about this for patients who may get a benefit for life, and to minimize the risk in not only this trial, but phase 3 and once these agents are on the market. I'm showing no further questions at this time. I will now turn the call back over to Adverum's CEO, Laurent Fischer, for closing remarks. Thank you very much, everybody, for joining us today. We're very, very pleased to be able to present the preliminary data from our LUNA trial. I would like to thank all the patients, families, caregivers that supported LUNA and OPTIC, as well as the clinical site team, and of course, Dr. Szilárd Kiss for joining us today, and of course, my entire team at Adverum. I'd like to thank everyone for taking the time to join us on this call today. We really appreciate your support and look forward to updating you on the LUNA trial later this year. Operator, you may now disconnect this call. This concludes today's conference call. 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