Hello, ladies and gentlemen. Thank you for standing by, and welcome to the Adverum's webcast to discuss the 26-week interim analysis of the ongoing LUNA phase II trial that was presented earlier today at the 2024 ASRS annual meeting. At this time, all participants are in a 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 26-week interim analysis of the ongoing LUNA phase II 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'll be joined by Dr. Star Seyedkazemi, Chief Development Officer, Peter Soparkar, Chief Operating Officer, and Linda Rubinstein, Chief Financial Officer. In addition, it is our pleasure to welcome Dr. Charles Wykoff, Director of Research of the Retina Consultants of Texas and Professor of Clinical Ophthalmology at the Blanton Eye Institute of Houston Methodist Hospital. Dr. Wykoff is a principal investigator on the LUNA clinical study and has more than five years of hands-on clinical experience with Ixo-vec. As a reminder, we may be making forward-looking statements, including statements related to the potential of Ixo-vec and plans and milestones regarding Ixo-vec, 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, which are described under the caption of Risk Factors in Adverum's filings with the Securities and Exchange Commission. For further details, please visit our website. At this time, it is my pleasure to turn the call over to Adverum's President and Chief Executive Officer, Dr. Laurent Fischer. Laurent? Thank you, Mike, and thank you everyone for joining us today to discuss these very exciting results of the LUNA 26-week interim analysis with our pioneering intravitreal gene therapy product candidate, Ixo-vec. It is my pleasure to welcome an esteemed retina specialist to the call, Dr. Charles Wykoff. Earlier today, Dr. Wykoff presented the LUNA 26-week interim analysis at the ASRS annual meeting, currently held in Stockholm, Sweden. To kick things off, I would like to remind you of the goals of the LUNA study, which were to select a dose and a prophylactic regimen to enable pivotal phase III trials, which we plan to initiate in the first half of next year. The results at the 26-week landmark interim analysis substantiates the preliminary data we presented earlier this year at Macula Society and continue to demonstrate that we're on track to achieve the specific goals of LUNA. We have replicated the potential best-in-class clinical activity from the OPTIC first-in-human study, where the patients with the longest follow-up received Ixo-vec over five years ago. In addition, LUNA continues to demonstrate that with enhanced prophylaxis and our lower doses, we can optimize the target product profile of Ixo-vec. Taking the efficacy and safety data together, today's results reinforce the potential best-in-class product profile of Ixo-vec. As background, given the likely initial target population for gene therapy, which are patients with relatively high treatment burden, as well as the profound clinical activity seen in OPTIC, our clinical development strategy has been to enroll a broad patient population in LUNA, including hard-to-treat patients. Patients in LUNA required a mean of more than 10 [aflibercept injections] in the year prior to receiving a single Ixo-vec injection. In LUNA, we continue to demonstrate greater than 90% reduction in treatment burden, with 76% of patients remaining injection-free at the 6 x 10^10 and 83% at the 2 x 10^11 dose at six months. Importantly, visual acuity, as measured by BCVA, was maintained at both doses, and central subfield thickness, or CST, a measure of macular thickness and an indirect measure of fluid, was stable in the LUNA study population. Notably, in a subgroup of LUNA patients with high fluid at baseline, that is a CST greater than 300 microns, we confirm what we saw in OPTIC, with Ixo-vec significantly reducing their CSTs, and this reduction was maintained through six months. Moving to safety, Ixo-vec was well- tolerated, with no Ixo-vec-related SAEs. In LUNA, Ixo-vec demonstrated an improved safety profile as compared to OPTIC. In the small minority of patients for whom inflammation was observed, all inflammation was responsive to locally administered corticosteroids. Importantly, local corticosteroid prophylaxis continues to effectively minimize inflammation, with greater than 90% of participants in these arms having no or minimal inflammation through week 26. Of note, no patient in the 6E10 difluprednate alone cohort needed additional corticosteroids beyond the scheduled prophylaxis to manage anterior chamber or vitreous inflammatory cells. Last but not least, and we'll dive into this more later, in our ASRS presentation, we shared for the first time the results of a specified patient preference survey. The survey is designed to understand patient preferences after receiving Ixo-vec over prior treatment with standard of care... and whether patients would like to receive Ixo-vec in their other eye if they had wet AMD in both eyes. Importantly, these questions are asked in the context of a patient's prior standard of care with regular intravitreal injection, as compared to Ixo-vec, which incorporates their experience on the different prophylactic regimen we tested. Notably, but perhaps not surprisingly, the vast majority of patients responded that they would indeed prefer Ixo-vec over the prior treatments they had received, and that they would want to receive Ixo-vec in the fellow eye. In the 6E10 difluprednate alone cohort, 100% of patients said they would prefer Ixo-vec therapy over the prior treatment they received, and that they would want to receive Ixo-vec in the fellow eye. As we know, all of all ocular gene therapy have some degree of dose-dependent, vector-related inflammation and endothelial changes. This data, together with the patient preference survey, supports what we have long believed, that for viral gene therapy products, which have a potential lifelong benefit and for which patients have only one shot on goal, it is critical to provide patients with the best possible efficacy and the greatest potential to be free of injections for life. We now know that it is what patients need and want. We believe the data from Ixo-vec shows a favorable benefit risk for patients, with 6E10 emerging as the dose we intend to take into clinical studies with a favorable safety profile and the potential that best-in-class efficacy for the treatment of wet AMD. 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 four to 16 weeks per label, and the market is actually ripe for innovation. Moving along some of the real-world data, the first challenge with wet AMD is the treatment burden, which is significant and has a real impact on patients and their families, as well as cost to the broader healthcare system. As a result, patients are often undertreated, whether due to missed visits, limited access, or treatment paradox, treatment extent, all of which ultimately lead to poor outcomes in the real world. As demonstrated in this slide, while vision initially improves with anti-VEGF, these gains are ultimately lost, with vision deteriorating over time. These trends are even seen in clinical trials. For example, in the pooled TENAYA and LUCERNE trials, patients in the faricimab arms failed to maintain the vision gains in the second year. In addition, Dr. Wykoff recently published in Ophthalmology Science a six-year analysis of AAO's IRIS Registry, highlighting the challenges with the high treatment burden associated with today's standard of care and the need for new agents that have the potential to better control wet AMD for years or for life. From this publication, we now know that patients lose vision as a result of undertreatment, and for those patients who are treated regularly, the vision gain is 0.68 letter with each incremental anti-VEGF injection. Now, imagine if this vision benefit could be realized with a one-time injection, delivering lifelong aflibercept levels and preserving vision. On the next slide, we'll 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 the implantable TKIs and the recently reintroduced port delivery system. As discussed, even the latest approved treatments do not extend therapy beyond 16 weeks, and those in development, such as TKIs, have only demonstrated with a single implant the potential to extend treatment, but they appear to require an implant every six months. Gene therapy holds the promise of a single injection, providing potentially lifelong therapeutic benefit. Thus far, data presented on Ixo-vec have demonstrated promising activity beyond three years, with levels of anti-VEGF up to 4.5 years. Before handing the call over to Dr. Wykoff, I'd like to give a brief recap of our OPTIC data. These data were published in a peer-reviewed journal, The Lancet eClinicalMedicine, in January. OPTIC demonstrated robust and sustained therapeutic levels of aflibercept beyond four years. Data are unmatched by any other gene therapy program in the field. In addition, Ixo-vec demonstrated 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. It's potentially lifelong and transformational solution for wet AMD patients and their caregivers. As seen in OPTIC, Ixo-vec's long-term profile is further established at time points beyond six months, where most patients who are free of injection at one year continue to be free of injection at three years, with maintained vision and maintained anatomic outcomes. Looking ahead to the next few quarters, we're excited to further establish Ixo-vec's long-term product profile through nine months and 52-week landmark analysis. Now, I would like to pass the microphone to Dr. Charles Wykoff, who has more than five years of clinical experience as an investigator studying Ixo-vec. Dr. Wykoff will provide an overview of the 26-week landmark data from our interim analysis. Charlie? Thank you, Laurent. That was an excellent summary of the LUNA data and the context of where we are today in the management of wet AMD. You know, as we look forward at the LUNA data over the next few slides, I'm gonna unpack this from a design perspective, then an efficacy perspective, and then we'll look at the safety, all of these in detail. So first, looking at design. We've seen from OPTIC that strong efficacy, consistent efficacy has been demonstrated through years of follow-up. And we've also noted levels of intraocular inflammation that were clinically relevant, and therefore, LUNA was meant to fill that void, to understand better different prophylactic regimens, to see if we could do better with reducing IOI rates, and also evaluate lower doses of Ixo-vec itself. That was the context of LUNA. Patients were randomized to four different steroid prophylactic regimens with that objective in mind, and all patients had previously treated wet AMD. You'll see their baseline characteristics in a couple slides, but they were all heavily pretreated, very consistent with OPTIC. All patients were then given one of two doses in a double-masked, randomized fashion of Ixo-vec, either 6E10 or 2E11. This data today represents the 26-week interim analysis that was pre-specified. Ultimately, the primary endpoint of LUNA is at one year, and this is going to be a two-year trial in total. Supplemental anti-VEGF injection criteria, always important to consider, and these were fairly standard, I would say, in LUNA. Three different characteristics. One, an increase in CST of greater than 70 microns from baseline, confirmed by the Central Reading Center, or a loss of 10 letters or more of visual acuity from baseline due to new or worsening fluid-associated wet AMD or new vision-threatening hemorrhage, again, due to wet AMD. So again, this represents the pre-specified interim analysis at week 26, and 58 of the 60 patients randomized completed the week 26 visits. Two patients did not complete that visit. One patient passed away, unfortunately, and one patient developed dementia and came out of the study. Neither of these were related to the study drug. Here you can see the anti-VEGF agents that patients were receiving prior to enrollment in LUNA. You can see the large majority had received aflibercept, and 17% had received faricimab, but also bevacizumab and ranibizumab were being used frequently in these patients. This slide illustrates the baseline demographics and ocular characteristics for these patients, and importantly, here, we've compared this to the OPTIC trial baseline data on the far right. You'll see the age is very consistent for this population of patients in their mid to late 70s. You can see that about half or a slight majority are female, and the majority here are Caucasian descent. You can see that on average, across both OPTIC and LUNA, patients have had a diagnosis of wet AMD for approximately three years, with 10 mean annualized anti-VEGF injections. Critical to point this out, this is a heavily pretreated population of patients. Now, there is a spectrum of need of anti-VEGF injections among patients in clinical practice, and it's important to understand that this represents one end of that bell curve, our most difficult to treat patients. 10 injections in a year is quite meaningful. Baseline visual acuity in LUNA was about [20/40]. This was slightly better than the 20/50, approximately, in OPTIC, and that was related to baseline enrollment criteria. Then CST, about 340-360 microns in LUNA, again, significant fluid at baseline, not quite as much fluid as the OPTIC program at 397. And you can see that a minority of patients were phakic at baseline. So with that context of who these patients are on the side of the trial, let's now dive into the efficacy results. This first slide compares the treatment frequency before and after Ixo-vec, with OPTIC on the right and then the two different doses for LUNA, 6 × 10^10 in purple and 2 × 10^11 in blue, or dark purple in the middle. You can see a meaningful, I'd say, fairly dramatic reduction in treatment frequency, from 9.9-10.2 injections in annualized fashion before Ixo-vec dosing to 0.5-1.4 injections on an annualized basis following Ixo-vec treatment. Again, substantial reduction, very consistent across both of these doses and also consistent across trial programs here, OPTIC to LUNA. If we look at the specific percentage of patients who remain injection-free, again, you see consistency here from OPTIC into LUNA. OPTIC was 73%, and here in LUNA, we're seeing 76% and 83% being injection-free through week 26 in the 6E10 and 2E11 population of patients to date. This next slide shows the swimmer's lane plot. You know, we've seen this a lot from many different programs. I think it helps visualize the clinical course for each of these patients individually. Right on the left of that, a vertical black line where patients receive Ixo-vec, you see many dots, and those each represent an intravitreal injection of an anti-VEGF agent. Again, you see many colors here. You see that all of the anti-VEGF agents that are available clinically, essentially, are being used in these patients. That represents, again, these patients being a difficult to treat population of patients. In clinical practice, we often see trying to switch between these agents to try to get better outcomes for patients, and that's exactly what you're seeing in this heavily pretreated population of patients. Following Ixo-vec, you then again see those same percentages we reviewed on the previous slide. In the 6E10 population, 76% of patients remain injection-free through week 26, and that percentage is 83% for the 2E11 population of patients. Combining these, that overall percentage then is 79% remaining supplemental injection-free through week 26. If you dive in a little more detail into the patients that have required and have received supplemental injections at the bottom, you'll see that the majority of those received a single injection, or seven of those patients, and five have received more than one injection through week 26. So looking now at a more granular level of both visual acuity and CST outcomes among these patients. Again, for reference, we're including the OPTIC data here. I think it's a nice place to anchor yourself as we're so familiar with that data that's now been published since the beginning of the year. So on the top graph here, we're looking at best-corrected visual acuity, and the key finding here is stability. You're seeing stability through week 26 in the LUNA populations, both doses with minor fluctuations and no apparent dose response. You'll notice that the blue dotted line, the OPTIC line, is slightly lower, and that's simply, again, related to the baseline difference in visual acuity that we reviewed before. On the bottom graph, you're seeing change in CST over time. Importantly, CST can be defined in different ways, and in this case, it includes the pigment epithelial detachment, which is, I think, the best reflection of true state of disease activity. In this context, you're seeing very strong stability, again, minor fluctuation through week 26 from the LUNA data, and similarly with the OPTIC data through week 28 showing stability of CST. Again, at baseline, you see a slight separation there of the blue dotted line, and that only represents the difference that OPTIC was slightly thicker at baseline. The next two slides dive into a little bit of some subpopulations here within LUNA that I think are quite clinically meaningful. The first is a look at patients that were injection-free on both doses here, the 6E10, again, in purple and the 2E11 in the darker blue. And these are patients, again, that have not received any supplemental injections through week 26. And again, showing really the same finding that we saw on the previous slide, which is stability with minor fluctuations in visual acuity at the top, and again, stability in CST at the bottom. This next slide to me is quite meaningful. I think this really emphasizes the anatomic control that we are seeing in this difficult to treat population of patients. So these are patients with a baseline CST of greater than 300 microns at baseline. So they had a meaningful amount of fluid at baseline, and in that light green population, importantly, you're seeing CST stability over time through week 26, with actually a reduction of 30 microns of CST at week 26. So to avoid the fluctuation between bolus injections, which this population of patients would often experience in clinical practice, I think is a meaningful step forward for the management of these patients. And then this next slide sort of grounds the clinical data that we just saw in the aflibercept production data inside of the eye. So this is the aqueous aflibercept levels, both in OPTIC and in the LUNA patients. Let's walk through this slide. So the blue lines represent individual patients from the OPTIC trial. And we've shown this data before at different time points, and this shows stability of intraocular aflibercept production through many years of follow-up, quite meaningful data. And then layered on top of that, you have the dots on the far left here at week 12, and these represent the week 12 aflibercept aqueous production levels within LUNA. Again, in the 2 E11, excuse me, population in darker blue, and the 6 E10 population in lighter purple there. Again, showing very consistent levels of aflibercept production with what we saw in OPTIC. And remember that in OPTIC, all of these patients received therapeutic benefit, and this is showing the LUNA population of patients as production of aqueous aflibercept in the exact same range. With that background on the efficacy data from LUNA, let's now pivot and look very squarely at the safety data. Again, that was one of the main reasons why LUNA was performed. And LUNA has been, I think a really important trial to inform the development, of course, of Ixo-vec, but also quite meaningfully for gene therapy across, you know, retina and ophthalmology in general, right? We've learned a lot from these different prophylactic regimens, and important that we go through that today. So this first slide summarizes this at a high level, and then we'll dive into detail. So Ixo-vec was overall well- tolerated at both doses. There were no Ixo-vec-related serious adverse events, and all Ixo-vec-related adverse events were either mild or moderate. There were no episcleritis cases, no vasculitis, no retinitis, no choroiditis, no vascular occlusion, and no hypotony. It is important to go through each of these. That sounds like a long list, but we've seen all of these with different agents in development over the years. So it's really critical to actually think about all these potential bad outcomes and state when they're not present. The most common Ixo-vec-related adverse event was dose-dependent anterior cellular inflammation that was responsive to local corticosteroids and anterior pigmentary changes that have not had an impact on visual acuity. Both local prophylactic regimens appear promising to date and are being considered. Overall, I believe that the enhanced prophylaxis here in LUNA with topical diclofenac, in particular, has been quite meaningful. And then two key learnings, I think, for the field in general, are that oral prednisone did not appear to add additional benefit. And secondly, an intravitreal dexamethasone implant known as OZURDEX without topical diclofenac did not provide adequate prophylaxis, and again, we'll look at that data in detail. Then finally, summarizing the safety data here, 91% of patients in the local corticosteroid prophylaxis arms had no or minimal inflammation, not only at week 26, but at every single visit, up through week 26, and again, we'll show you that data in detail. So this slide, again, I think is obviously quite meaningful for Ixo-vec, but also broadly for the field. So this slide highlights two of the key learnings that we took away from these four prophylactic regimens that we've studied here. So the first, on the left side of the slide, is that the intravitreal dexamethasone implant or OZURDEX did not provide adequate prophylaxis, and therefore, there was a protocol amendment early in the clinical trial. I think this speaks to the strength of the team running this trial, that they were able to sort of in real- time see when changes need to be made and then implement those for the benefit of the field and for patients. That protocol amendment specifically added topical difluprednate eye drops after week four for the patients randomized to the dexamethasone implant. What we saw based on that change was, I think, a quite meaningful shift in the proportion of patients with inflammation to a much improved safety profile with the addition of topical difluprednate. Then secondly, on the right part of the slide here, we did not observe a benefit of oral prednisone. I think this is actually kind of different than what most people would have predicted before seeing this. But again, now we have prospective high-quality data showing oral prednisone did not add benefit beyond local topical steroids, or local corticosteroids alone. So then moving forward now, building on those insights, here we show the data related to the baseline steroid prophylactic regimens that are being considered for future clinical trials. And that is difluprednate eye drops alone at the bottom there, in blue, and then difluprednate eye drops plus the intravitreal dexamethasone implant in that cream color, at the top. And this is showing anterior chamber cellular activity on the left and vitreous cellular activity on the right. Very granular analysis, looking at all of these outcomes at each of the visits. I think the first takeaway is that most patients at most visits did not have any cellular inflammation. There were four patients in each of these groups that had at least one clinical visit with cellular activity. And of note, there does appear to be a potential increase in the number of patients with anterior pigmentary changes toward the end of the 26-week period. Then importantly, diving even to these prophylactic regimens to see what we can learn here at week 26, this slide really unpacks the patients with receiving topical difluprednate. And the reason this is important is that the 26 weeks was pre-specified initially, because that's when all the patients would be off of their baseline prophylactic regimens. But again, because of the need to pivot, because the intravitreal dexamethasone implant did not provide adequate prophylaxis, and we needed to change the protocol because of that, many of the patients that have received the intravitreal dexamethasone implant, as well as topical difluprednate, are not off of their prophylactic regimen yet at week 26. And therefore, the cleanest analysis that we can make about what do these patients look like when they're off of their prophylactic regimens, is to really focus on that, on those 20 patients there in light blue on the left of the slide, that were on the topical difluprednate alone. And when we look at those 20 patients, now on the right side of the slide, we see that anterior chamber cellular activity and pigmentary-related adverse events do appear to be dose-dependent. A few other points to make here is that all of these cases of inflammation have been responsive to local, in particular, topical corticosteroids, and these pigmentary-related adverse events have had no impact on visual acuity. Okay, the last slide here now comparing the safety outcomes that we just showed you with the OPTIC data, I think really sort of bring the concept of LUNA, at least through 26 weeks, full circle. Right, we talked about the one of the objectives of LUNA was to really study these enhanced prophylactic regimens, and this slide, I think, I think, shows us that, that we've succeeded in, in finding one and potentially two regimens that are quite capable of controlling inflammation here at a, at a very clinically reasonable level. That's because at the bottom of the slide on the left, again, you see the anterior chamber cell inflammation in OPTIC, and then you see that same color-coding pattern in LUNA above that. You see meaningfully less inflammatory events within LUNA, again, with these enhanced prophylactic steroid regimens. In particular, that it's that local steroid prophylaxis population of patients in which 91% of those patients have had no or minimal inflammation at any of their study visits through week 26 in LUNA. So with that summary, I'd love to pass it back to Laurent. Excellent. Thank you, Charlie. So going back to the swimlane plot that Charlie presented earlier with the overall population, I would like to focus on a group of patients who received multiple anti-VEGF agents in the year prior to receiving Ixo-vec, including VABYSMO, which is the latest bispecific antibody approved for the AMD, which is on its way to becoming a $4 billion product. As you can see, this group of 10 patients who received VABYSMO the year before Ixo-vec, were similarly hard to treat patients, requiring about 10 mean annual injections prior to receiving Ixo-vec. And as you can see, in these 10 patients, half of them who received 2E11, the other half received 6E10. Every single one of them are free of injections at the time of the six-month analysis. I would like to show you now the impact on treatment burden from LUNA at six months and in OPTIC out to 3+ years. First, let's compare on the left-hand side, the reduction in annualized injections across other gene therapy agents. As you can see, Ixo-vec is superior reduction in annual supplemental injections at six months and also the longest available data set up to three years. Now, let's look at the differences in injection-free rates, which is a higher bar to achieve and where the differences are even more profound. Remember, as we discussed earlier, the importance of delivering lifelong benefits to gene therapy. Considering these injection-free rates across studies and in hard-to-treat patients, you can see that Ixo-vec has demonstrated 76%-83% injection-free rate at six months in LUNA at 6E10 and 2E11, which is unmatched by any other program. These are tracking well with OPTIC, where the clinical benefit was sustained, with 53% of the patients entirely free of injection through at least three years. This is truly game-changing and shows the potentially transformative impact of a gene therapy program like Ixo-vec. Now moving to exciting results from the pre-specified patient preference survey. With any novel therapy product, it is critical to understand how the burden of therapy impacts patient preferences. For wet AMD gene therapy, the burden of treatment of the standard of care encompasses financial costs, fear of needles, caregiver burden, opportunity costs, and discomfort after treatment, among other issues. For our LUNA interim analysis, we prospectively incorporated a patient preference survey to understand patient preferences at multiple time points after receiving Ixo-vec. At week 26, we asked the following questions: Would you prefer Ixo-vec therapy over the prior treatment you received to treat your wet AMD? And would you want to receive Ixo-vec therapy in your other eye if you had wet AMD in both eyes? Remarkably, when analyzing the survey results for all LUNA subjects on both doses, including those receiving oral corticosteroids and those who received suboptimal prophylaxis prior to the protocol amendment, you can see that 88% of the patients responded that they would prefer Ixo-vec therapy over the prior treatment they had received, and 93% responded they would want to receive Ixo-vec in the fellow eye if they had bilateral disease. Double-clicking on the difluprednate alone cohorts, 100% of participants responded they would prefer Ixo-vec therapy over the prior treatment they received, and that they would want to receive Ixo-vec in their other eye. This patient testimony and experience supports Ixo-vec's favorable benefit-risk profile relative to the standard of care. We look forward to continuing our patient-focused development of a potentially lifelong treatment for wet AMD and to present patient preferences over time. In conclusion, we believe that our early LUNA data supports a favorable benefit-risk profile for Ixo-vec, with 6 × 10^10 emerging as our dose for pivotal studies with favorable safety profile and the potential to be best in class. This is important for a one-time gene therapy, where you have only one chance to dose patients, and we're therefore looking to optimize the therapeutic profile, matching the unparalleled efficacy with a safety profile that is acceptable and manageable for the patients and retina specialists. Looking ahead, we expect to present LUNA nine-month landmark data in the fourth quarter of 2024, to present our LUNA 52-week primary analysis in the first quarter of next year, and to initiate a pivotal trial in the first half of 2025. We continue to conduct both formal and informal interactions with FDA, EMA, and other agencies, and look forward to updating you with details of our pivotal trials in the fourth quarter of this year. Okay, I believe it's time for us to transition to the Q&A part of the call. Operator? Thank you. We will now begin the question-and-answer session. If you would like to ask a question, please press star one on your telephone keypad to raise your hand and join the queue. If you would like to withdraw your question, simply press star one again. Your first question comes from the line of Joon Lee from Truist Securities. Your line is open. Hey, guys. Congrats on the impressive data, and thanks for taking our question. I have a question for Dr. Wykoff. Dr. Wykoff, in a trace at 1+, 2+ AC or VC cells, these are all very confusing for us, but, you know, we have to understand clinical terms like minimal, mild, moderate, and severe. So how would you characterize, in clinically more relevant terms, the safety profile you're seeing with Ixo-vec, using the proper prophylaxis? And, you know, related to that, were investigators counting cells in the Beovu, VABYSMO, or EYLEA HD trials? And if so, what were they seeing, and how does safety and tolerability of Ixo-vec compare, Ixo-vec so far compare to those, other therapeutics, in a trial setting? Thank you. And I have a quick follow-up after that. Hey, Joon. Thanks for the question. Just before I pass on to Dr. Wykoff, we're very pleased to present today that 100% of the patients at 6E10 in the difluprednate alone regimen had no or minimal inflammation at week 26, and that none required to be on steroids to treat inflammation beyond the scheduled prophylaxis. So I think this bodes well for the dose we're selecting for the phase III trial. And you asked specifically about the relevance of minimal trace cells in the clinic, and I'll let Dr. Wykoff answer this question. Yeah, great, great question. A lot to dive into there. I think the backstory here is important and relevant that you're aware of, but just to review it for everyone, you know, when we first started studying intravitreal gene therapy for anti-VEGF and management, at the very first trial in retina was with OPTIC. And we started that trial without any baseline steroid prophylaxis. And I remember seeing some of the first patients with inflammation, and we actually observed them when there was trace and mild, moderate cell even.... and then things got worse, and we realized pretty quickly in the trial that we needed to treat these patients prophylactically. So we have evolved a long way since then. That was 5+ years ago, to be very clear, and I still have those patients actually doing extremely well five years out, not receiving any injections, with no active inflammation. So we've come a long way, and the original patients actually are doing quite well overall, the ones that I'm managing. You know, but now, today in LUNA, you asked a question about the numbers versus the clinical terms, and, and I think that there, that there's no necessarily distinct number at which mild turns to moderate, and mild-- moderate turns to severe. It's sort of more, you know, 0.5 and, and 1+ cell, I think are both clinically relevant. So the, the most important takeaway is that, that if you're using gene therapy, you want to be exceptionally aware of small levels of inflammation. That's why we're being so detailed here, because you want to treat it and make sure that it goes away and does not escalate. That's what we've learned with gene therapy over time. And so I think overall, though, if I was pinned down, I would say 0.5 is trace level, and then 1+ is mild, and beyond that, 2+ is sort of the moderate range, if I had to give you exact numbers, but some people might, you know, disagree with those numbers slightly. And then your last point about comparing this to other therapeutics is an interesting one and sort of hard to answer, you know, definitively in a short period of time. I would say it depends on the therapy that's being used. Gene therapy is a very different, you know, benefit to risk ratio for patients versus a bolus anti-VEGF injection that would need to be given dozens, maybe hundreds of times for this population of patient over the course of their lifetime. And so I think that there's a trade-off there. You can do a single intravitreal injection of a gene therapy, and avoid repeated bolus injections. That's a huge advantage. I think there's a lot of patients that would be willing to take a risk of expected mild inflammation that is controllable with local steroids for that, benefit trade-off. And so, you know, to look specifically at one of those parts of the calculation and compare it drug to drug, I think is missing sort of the bigger picture. But to answer it very clearly, I think, you know, you know, if you look at the trials of pegcetacoplan and aflibercept over time, you know, the non-severe inflammatory events are often in the single digits in the other anti-VEGF and anti-complement trials. And so I think what we're seeing here is more IOI than you would see with bolus injections. But again, we expect that, I think overall, with gene therapy at these doses of the virus. Well, thanks for that clarification and, you know, expounding on the profile. Okay, a follow-up question, if you had 100 patients who require, on average, four injections, and then another group that require 10 injections a year on average, which group do you think has a higher chance of achieving injection freedom? So this is a, a really good question because I think we've seen that, you know, in OPTIC, we took in that first-in-human study, the absolute hardest to treat patients. In LUNA, we have actually a broader patient population, including a pretty significant number, about 29 patients, that had six or less injections a year prior. So if you look at that subgroup, which people have looked at with other program, we see that overall, actually 90% of the patients are free of injection at 26 weeks. So and this is actually just to confirm that, you know, with Ixo-vec, we actually give Ixo-vec. There's no booster injection of aflibercept needed at week four, and actually, we measure the treatment effect 26 weeks after the last injection. So in that rigorous analysis, we see 90% benefit. But to kind of—that's just to give the number from our own trial, but Charlie may want to add to that in easier-to-treat patients, whether gene therapy is likely to work better or not. Yeah, thanks. I think that's a great question. And, you know, I think like most human diseases, there's a spectrum of phenotypes, right? And so as you're implying, yeah, there's all sorts of variety of how many injections some people need. And if you really go back to the CATT, the HARBOR trials from a decade ago, or more, we saw that there are a subpopulation of patients that might only need a few injections and not require injections long- term. And so it is important to be clear that where gene therapy benefit here would not be for those patients, obviously. If you can treat once or twice and never give a shot again, that's ideal. But that's not most wet AMD patients. Most AMD patients need chronic therapy to achieve optimal outcomes, and we're not there in the real world. There's multiple data sets showing we're not there because we're underdosing long- term. So the benefit profile opportunity here for patients is tremendous. But then, yes, I think the higher need patients overall probably have a higher level of VEGF, pathologic VEGF-A inside of the eye. And so, sure, you know, I think lower frequency need patients probably have a lower overall VEGF-A level in the eye steady state. Now, is that production, is that d urability of VEGF-A in the eye, outflow related? There's a lot of things that would determine steady state VEGF-A levels in the pathologic state. But overall, yeah, I think for an intravitreal gene therapy, you know, it's gonna be probably easier to achieve optimal control among patients with lower need injections before enrollment. That's not an absolute, but overall, that probably makes sense biologically. I think- Last question. You know, what's important for us... Yeah. No, sorry, sorry. Go ahead. What's important for us is to demonstrate that durable long-term expression of aflibercept that we've actually shown through 4.5 years in our OPTIC trial, and these very robust level we've shown in every single patient in whom we actually tested these levels in OPTIC with an overlap between the two doses, which is now confirmed by the efficacy we see with that, great percent of patients being free of injections at week 26, in the overall population, and even higher in the patients, in the broad patient population are the ones that have actually a lower treatment burden. Great. And then, and I promise, last question, and this is for Dr. Wykoff. You know, assuming a price tag of $30,000-$60,000 for one AAV gene therapy, which is kind of where we model these, how do you think payers, your insurance, you know, companies, would respond when you prescribe a gene therapy for, you know, a, a patient with maybe, anywhere between one to four injection requirement per year? So maybe before I pass it on to Dr. Wykoff, I think it's important to know that the vast majority of these patients are actually over the age of 65 and therefore covered by Medicare. So it's a unique patient population that's covered by the same payer for life. The life expectancy is roughly 10-12 years based on actuarial tables. And so if you think about getting a vast majority of patients free of injections, potentially for life, you can imagine that a potential cost of three to five years of the actual treatment would save a lot of money for the payers. With 76% free of injection, there's real benefit. Now, the question is, what if patients, as you asked, needed only four or less? And I'll pass it on to Dr. Wykoff. Yeah, I think it's an important question, and I certainly respect the broader concept of cost and that balance at a societal level. You know, I think the first thing I think of, though, when you bring that up is it's my job as a physician in a doctor-patient relationship to provide the optimal treatment and the choices for that patient. And so to me, it really comes down to risk-benefit ratio, first and foremost. What's going to be best? And then typically, that's how I practice, and then from there, I figure out the finances. I would just add to... You know, we're very pleased to see that even in the patient that received VABYSMO, requiring up to 10 annualized injection of VABYSMO two year prior, all of them are free of injection, showing that there's a clear benefit here in being able to get patients off their current, even the latest anti-VEGF, which is a very significant market opportunity that we believe we can, take on. Your next question comes from the line of Joe Thome from TD Cowen. Your line is open. Hi there. Good morning. Congratulations on the update, and thank you for taking our questions. Maybe the first one is a little bit more of a checkbox, but did you measure the intraocular pressure in the patients? And, you know, while we don't necessarily know the go-forward prophylactic dose, maybe specifically in the OZURDEX patients, and maybe what did you see there? And then second is a little bit of a follow-on from Joon's second question, maybe for the company and for Dr. Wykoff. But when you look at a pivotal study, what is sort of the ideal severity of patients to study, maybe to best to emphasize the competitive profile of Ixo-vec versus some other gene therapies in the field? Obviously, some others have looked at patients with a little bit less disease severity. How do you best capture the patients that might necessarily see this in the field versus, you know, kind of while establishing that competitive profile? Thank you. Thank you, Joe. Great question. So first of all, in a four-minute presentation, we did not include the slide on IOP that we presented at Macular Society, but we'll add this to our corporate deck, and these patients were well controlled. I'll pass it on to Dr. Wykoff to answer that question. He answered that from the podium as well today. Yeah, thanks. You know, I'm so glad you brought this question up, actually. This is actually kind of personal for me, truthfully, and I think the story here is positive. But you know, I think I had the first patient that hit a dose-limiting toxicity in INFINITY in DME and had meaningful surgical hypotony. So you know, we have seen significant hypotony in the past with a meaningfully higher dose of Ixo-vec. And so I think that's something that needs to be followed, and I think the team has done a tremendous job of mining the OPTIC data originally and now being extremely thorough with the LUNA data, looking for IOP issues. You know, when I had that effect, I thought to myself, I thought, "Man, I, I don't know if I can do this gene therapy stuff anymore. The risk here is too meaningful." But that thought died pretty quickly when you talk to patients because this need for long-term, repeated injection in this population of patients, this very high need to maintain their vision, is quite real. It's not just a slide finding. Patients have significant issues receiving long-term adequate therapy. And so I'm a believer in gene therapy and the value here, and of course, there's risk with everything we do in life. I think we need to follow IOP very carefully. And so in that context, the slides we're on just reference, I think they're public now, show really stability of IOP, and we looked at that not only between the two doses here, but also importantly, as a fellow eye comparison. And really no indication of patients having any meaningful fluctuation in IOP post-dosing, which I think is also consistent with the OPTIC data at the 2E11 dose, especially also. So I think quite positive in that regard, but something that does continue to be, need to be followed because we have seen an adverse event, again, at higher levels in a different patient population. So the second part of your question was related- Right ... to the phase III population and what patient we're planning to enroll. Obviously, we'll provide more data on the specific details for the phase III in the fourth quarter. But suffice to say that when we went from OPTIC to LUNA, we did expand that patient population, including about half of the patients that had up to six injections the year prior. Still a high annualized number, but some patients with significantly less injection. So at six to 10, while we saw 76% free of injection in the hard-to-treat population, in that broad population, it was 100%. So we want to actually include in the phase III a broad patient population of patients that are responsive to anti-VEGF. That's the most important thing. We'll treat them with Ixo-vec. There's no need with Ixo-vec to add a booster, aflibercept, like other individual gene therapy programs, and then want to measure the benefits. I think what was particularly exciting in this release is the fact that these patients that are the hardest to treat, that receive Ixo-vec, 88% of all say they prefer that, including that prophylactic regimen, compared to the prior standard of care. We think given that very positive, you know, patient preference and focusing on what the 21st Century Cures Act says, that we need to refocus on patient preference and patient choice. We want to make sure that we actually enable as many patients to benefit from Ixo-vec as possible, given the benefit risk that we see. Great. Thank you very much. Your next question comes from the line of François Brisebois from Oppenheimer. Your line is open. Hi, thanks for taking the question, and congrats on the data. I was just wondering if you could just discuss a little bit more about the impact. Maybe this is for the team and Dr. Wykoff, but the impact of OZURDEX, just not having all patients, because of the amendment that was pre-specified, not having all patients complete prophylaxis. Is this, does this has have any impact on efficacy here or, we don't see an impact here? So thanks, thanks for the question, François. We've seen no impact of the prophylactic regimen that we used on efficacy, and we looked carefully as whether there was an impact of either, neutralizing antibodies or prophylaxis, which in the past has been historically something that people have published on. So I'm glad you're asking the question. We've seen no impact. Because the amendments we did, mandated patients on OZURDEX alone, had to add the appropriate drops. So these patients, about 36% are still in the taper, so we don't want to give a definitive answer on whether that regimen can move forward in the phase III or not. But what we do see today is that difluprednate alone, that, 22 weeks prophylaxis we used in LUNA, is a regimen that control inflammation very well. In fact, 100% of the patients in 6E10 had zero trace cells, and we would have to show a meaningful benefit of OZURDEX in order to select something that is a more intensive prophylaxis versus the drops. I will pass it on also to Dr. Wykoff to add any comments to my answer. Yeah, I agree with those comments. I think going into LUNA, right, that was the key question for me, and I think most of us investigators doing this was, you know, what can we do to optimize, sort of minimize, if you will, the rates of inflammation? I think this is one of the values of this trial. You know, it's rare actually to see a program pause and then do a quite scientifically meaningful phase II trial, right? This could have gone straight into pivotal with a, you know, a best guess on what the prophylaxis could have been, and that might have succeeded. But I think this was the scientifically prudent choice, and it was made, and it was, I think, very valuable for the field because, I think many of us would have predicted a different outcome than what we've seen prophylactically, right? There was very good logic of why to use OZURDEX and very good logic about why to use oral prednisone, and the answer has been pretty clear to me, which was, unfortunately, neither of them added benefit, right? It'd be great to say that some other combination was, you know, a whole lot better, you know, zero inflammation completely and no pigment and all that, but we haven't seen that. But I think what we can say is that OZURDEX did not add benefit, did not add adequate prophylaxis by itself, and that oral prednisone did not add benefit beyond local steroids. The topical difluprednate alone was quite effective and achieved what we need to achieve to make this clinically, clinically viable. Okay, great. Thank you, François. Thank you. And then, yeah, maybe just one last one here. In terms of the stability of the CST here, is this something... How important is that to the medical community? Thank you. Yeah. I'll pass that on to Dr. Wykoff. Yeah, thanks. I think this is a really important question and gets into the weeds, which is a great place to be. You know, it's interesting, right? Because if you look at efficacy, two major ways that we're looking at this, with this and other gene therapy programs, right? You look at retreatment rates, and that's important and quite relevant, but not exactly, you know, apples to apples, if you look at pre-gene therapy frequency of dosing to post-gene therapy frequency of treatment, because now you have very specific supplemental criteria. And that's a challenge and a limitation of all of these programs. And I think, so the clearest way to get at the biology and the clinical effect, I do think, is to take a deep dive into the OCT. And there's quite higher order analyses that can and will be done, but the simplest way and the most consistent way across programs is to look at CST, which is a measure of the thickness of the most important part of the macula, really in the foveal region. And to see stability there, I think is really meaningful and not a trend upward over time. And then, you know, to break it down even further and to look at that subpopulation of patients as we broke out with a CST of greater than 300 microns at baseline, that really suggests that there is clinically relevant fluid at baseline. And again, to see stability there and actually a lower CST at week 26 than at enrollment, I think is clinically meaningful. Because remember, these patients are coming in receiving bolus injections. Their OCT is fluctuating every time they get an injection, and now you're seeing stability lower than their baseline. And that suggests, based on the work of Usha Chakravarthy and many others, that if you can minimize the CST bouncing over time and create a stable plateau, even if you're not completely dry, right? Some of these patients probably still do have a little bit of residual fluid, but it's the fluctuation, we think, that long- term drives worse outcomes. So to see stability here, to me, is clinically relevant. So we're very pleased to see that in our trial. We haven't seen any kind of trends of a regression to the mean in the CST, particularly the one with a lot, a lot of fluid. We published also already that we show pretty significant reduction in CST fluctuation, and also a high percent of patients that have dry maculas with more percent IRF and SRF fluid free from the OPTIC study. We'll continue to publish this data and analyze it, obviously, but we're very pleased with showing these level of CST that are dropped and completely maintained, and no trend to a regression to baseline or late rises that you know have been seen. Your next question comes from a line of Graig Suvannavejh from Mizuho Securities. Your line is open. Yeah, good morning. Hey, Graig. Thanks for taking my questions. Graig, I think we lost you. Can you hear me okay? Yeah, we can hear you now. Hi, Graig. Okay. So sorry about that. Good morning. Thanks for taking my questions, and congratulations on the data. I had two questions, if I could. One was about the patients, where you did see maybe higher inflammation. I was wondering if there was any analysis that you've done to look at those patients more closely to see if there was any kind of patient characteristics about them that in particular might have led to, you know, 1+ or 2+ cells versus, you know, 0.5. And then maybe a question for Dr. Wykoff, which is really a bigger picture question. The question is, if you think about the totality of the wet AMD patient population, I'd love to get your thoughts on what segment or what segments of the market or the patient population do you think gene therapy is most appropriate for, and whether that's on a percentage basis of your totality of wet AMD patients. And then a follow-up would be, you know, there are multiple companies obviously developing a gene therapy product and, you know, without any phase III data yet for these more mature data, at least across the board, how do you think your retinal specialists as a whole will go about thinking about which products might be more appropriate versus another? Thanks. So, thanks, thanks for this question. Obviously, you know, we're very pleased to see that the 6E10 dose cohorts that received aflibercept, we had only, all patients had zero trace cells. In fact, with one, only one patient with 20 trace cells, one patient in the 2E11 that had 2+ cells. But, we feel that these are, you know, very acceptable levels that you'd anticipate. We've seen, as you recall, in OPTIC, some patients with less prophylaxis having some blebs that were easily managed, and, none of them were clinically meaningful. We haven't seen any baseline demographics, but we start seeing with more patients treated in all programs, some patients that have actually cells, even late, some even 3+ cells presented, today. You know, you expect that immune response is gonna be somewhat different, and you need to monitor these patients for a while. I think the goal is to get them eventually safely off prophylaxis, so they are set for the aflibercept levels that we know with Ixo-vec are gonna be stable for life. Then we will talk about the different type of patients, and we went from OPTIC to LUNA with a broader patient population. We presented the overall patient results with 76% of patients free of injection, with the 6E10 and even 100% of the patients that had six or less injections. But obviously, how that gets taken up into the real world, that's something that I think would be a good question for Dr. Wykoff. I think one of the questions we heard today is, what does that look like long- term? And I think we have patients past five years, including some of Dr. Wykoff's patients, that are free of injection with no inflammation, doing great, and we have that patient preference. So I think a combination of more long-term data that we are presenting, you know, nine months data on LUNA and 12 months, that we committed to present, is gonna be important to show that sustained benefit. Yeah, I agree with all those points. And the key point is long-term follow-up, and I think that, you know, a potentially one-and-done therapy, it's all about the long-term follow-up, safety, efficacy, balance there. And, you know, to have the data now published with OPTIC through two years, and to also have, you know, 3+ years presented, and then patients well beyond five years in my clinic and others doing well is quite meaningful. And so then you asked specifically about the proportions of patients. I think the key there from a clinical perspective is that that will change over time as we become more familiar with it, right? When something is newly introduced into the market, yeah, the most tiny patients are the ones that are gonna be most interested in early adopting that. And I could see that being a preference for many of those patients, because those patients ask all the time: "Doc, what's next? I really still need to get these shots. Is there anything different? Can we, can we stop?" And the answer could be yes, with a gene therapy that's commercially available, which is quite exciting for patients to hear about, and they're aware that these are being studied out there and ask regularly about them. And then your last question about the different products. You know, I would say all of us as investigators are supportive of all these programs, right? It's good for the space, it's good for patients to have choice.... And I think, you know, the REGENXBIO program being in phase III trials is quite exciting. It's exciting for patients, it's exciting for the space. It's a surgical approach. It's been shown to be safe and well-tolerated and effective. I look forward to that trial hopefully being, or those trial program, trial program being, successful. And sort of exactly how that plays out in the marketplace and what patients want to go to surgery and what might, whom might want an intravitreal injection, I think is yet to be determined. Thank you. If I could have one follow-up, and this is again for Dr. Wykoff. Just on the prophylactic regimens, I'm in particular curious about the IVT dexamethasone and difluprednate. The question is, in your experience, how troublesome or not is such a prophylactic treatment? What I'm trying to get at is, you know, could it serve potentially as a deterrent in any way? I'm not suggesting it is, but I'm just curious as to your thoughts on that as a way to manage inflammation. Thanks. Thanks. Thanks for that question, Graig. Before I pass it on to Dr. Wykoff, just, as a reminder, we feel that difluprednate alone is sufficient to actually very adequately control the immune response that you instigate to the capsid at 6E10, with 100% of patients having zero trace cells and nobody requiring additional steroids after the prophylaxis for inflammation. So, that is, you know, consideration. We'd have to show a benefit of the OZURDEX implant in addition to the drops to warrant taking that forward. We're still evaluating both, obviously, and I think we're very pleased to see early on that OZURDEX worked very well and removed any potential compliance issues or ability to put the drops. And I think that's, it'd be great to get your perspective. There are obviously a lot of implants in phase III that'd be required to be given every six months with TKI. So how are implants, I guess, you know, adopted or accepted by your patients? Yeah, I think those are all good points. You know, and specifically about the prophylactic regimens, you know, again, looking back, there was great logic for all four of these arms. And so in a theoretical world, right, let's say when you had one injection inside of the eye of a dexamethasone implant, if that had done perfect control, that would've been a nice option, right? Because then you don't have to worry about the patients using the drops at home and the compliance issues. We know from glaucoma that there are compliance issues. So sure, there are like, you know, parallel universes that may have been nice to see. But with this data, I think the positive, you know, benefit I see here is, first of all, a clear answer, which is nice. It's nice to know that the dexamethasone, dexamethasone implant alone was not sufficient and the oral prednisone did not add benefit. And so in that context, to see quite a meaningful control of inflammation with topical difluprednate alone is reassuring. And secondly, to see compliance of these patients utilizing the drops is quite reassuring. Remember, this isn't happening in a vacuum. These patients are coming in because they're high-need patients, and they need repeated injections. And so in that context, these patients are quite motivated. They're motivated to maintain their vision. That's why they're coming back for the injections, and they're also motivated to get away from the repeated bolus injections every one to two or three months. So I think in that context, yes, topical difluprednate is quite possible, and I think that the patient surveys really echo that, and that's been my experience in talking with the patients directly. I would just go back to that patient survey, which really is a measure of effectiveness that includes efficacy, safety, and that includes the compliance. Even in the n=10 population, with 20 patients that were on oral steroids that we know fully tolerated, 88% say they would prefer Ixo-vec with that prophylactic regimen over the standard of care, 93% with one in the other eye. And that was 100% when you look at 6E10 with difluprednate alone, which is the dose that we're moving forward into phase III trial. So pretty exciting to see how patients think about it, and obviously, the context matters of this injection, the treatment burden, the fact that, you know, up to 40% of them stopped taking the injection by three years. There's still a lot of unmet medical need that we're hoping to address with respect to that. Thanks so much, everyone. Your next question- Thank you, Graig. Your next question comes from the line of Luca Issi from RBC Capital Markets. Your line is open. Oh, great. Thanks so much for taking my question. Congrats on the data. Maybe two quick ones. Just circling back on prior question, maybe ask a little bit more directly here. It feels to me that you're considering either OZURDEX plus topical or topical alone as the prophy for phase III. One, is that correct? And two, if so, how are you picking one versus the other? And then maybe second, maybe Laurent stepping back, bigger picture. Again, the competitive landscape continues to evolve here. We're seeing data this morning from 4D Molecular Therapeutics. When you look at the totality of your data, including efficacy, safety, prophylactic regimen used, how do you think your data stacks up versus them? Any thoughts there? Much appreciated. Thanks so much. Right. So let me go first on which one of the two local prophylactic regimens are the ones we want to take into phase III. Well, we know that difluprednate alone works very well. I mentioned that 100% of the patients in that 6E10 difluprednate were at zero or trace cells, so we know that works, and they all have completed their prophylaxis. Only 60% of the patients in the OZURDEX plus drops have completed the prophylaxis. Once all of them have, we would have to show a meaningful improvement of the OZURDEX over what we've seen in difluprednate to pick the OZURDEX, and that's what we plan to report with data and choice of prophylactic regimen in the fourth quarter. Now, looking at the totality of the data, obviously, we see that we can very effectively manage the immune response where the difluprednate drops. And when we look at the overall efficacy, and if we take at six months the freedom of injection, which I think is the highest bar, we show 76% in the hard-to-treat patients that are free of injection at the 26 weeks date. If you compare that to the data that was presented this morning, where patients received actually a booster, aflibercept, after the 4D-150 injection at week four, and they report the 24-week data, so 20 weeks after last injection, they actually show 76% in that patients who receive less than six injections. If we look at the same patient population without the booster, with aflibercept, overall, 90% of the subjects are completely free of injections, and actually, 100% of the 6E10 are free. So if you look at the totality of the data, we think that from a benefit risk and a target product profile, both obviously are exciting products and advancements for the field. But I believe that given that with gene therapy, you have a one chance to be free of injection, the management inflammation with maybe slightly longer topical steroid will warrant a 20% increase in chance of being free of injections for life, with data out to 4.5 years with aflibercept level and three years clinically. And as Dr. Wykoff mentioned, some of his patients passed five years free of injections. So this is a marathon, not a sprint, and gene therapy is a long-term solution to a lifelong disease, and that's how we think about, you know, moving this program forward with actually a patient-focused drug development, kind of you know, embracing the 21st Century Cures Act and focusing on these patient preference. And it's very clear what patient wants and needs. They want to be free of injections and preserve their vision. And we're very happy to report that this is the first time data was presented in the field with preference from patients for these novel therapies that do require some prophylactic. Your next question comes from the line of Daniil Gataulin from Chardan. Your line is open. Hey, guys. Thank you for taking the question and the stress on the data. First one, for Dr. Wykoff. How big of an interest would you say in gene therapy treatment do you see in treatment-naive patients? And for the team, what are your plans at this time for including that patient population in the pivotal studies? So thanks for the excellent question. It's interesting to see that, you know, as we make progress understanding the benefit of gene therapy, there are more naive patients that are coming to this trial. So they're probably not necessarily the initial target for these groundbreaking, you know, regenerative medicine therapies, but obviously, they're doing very well. And I'll pass it on to Dr. Wykoff to give his perspective on patient asking about it. I don't know how much awareness there is in the general public about gene therapy beyond the retina specialist to date. But certainly, I think based on that patient preference, I would assume that, you know, their friends and family would probably have similar feedback or interest in those type of medicines. Yeah, yeah, it's a good question, and there's a lot of awareness and interest, of course, in gene therapies and cell therapies out there. Patients ask all the time. This stuff is in the lay press, and it's online everywhere. And so patients ask about this all the time, not only for wet AMD, but all the retinal diseases that we manage. And so these are conversations we're having regularly, and I think that target population is evolving and will continue to evolve. And we have to remember here that we're looking at phase II data, and long-term phase I data. And ultimately, we'll need pivotal data before we're talking about exactly what patients to treat. That, that's still, you know, a meaningful amount of time away, and I think the goalpost will continue to change. I think now, commercially, if this were available right now, I think the target patient profile would be the enrollment, you know, demographics you saw here, patients receiving multiple injections over the previous 3+ months. And those patients, they, they genuinely ask all the time, "What's new? What's different? What can I do that's, that's moving me beyond these regular bolus injections?" And I think there, there really is a need here, and I think there's a potential clinical role, as we've talked about, to achieve better outcomes, for these patients long-term that's meaningful. So your second question was about, you know, what kind of patient we want to enroll in a phase III trial. I think given what we see from both the patient preference as well as the 100% of patients who receive VABYSMO for free injection after six months, we think there's a real important answer here as to what patient will benefit, and we want to include the broadest possible population for phase III. We're having very productive conversation with FDA and EMA about specific population, and we'll be glad to report on that. I think the most important aspect of those, obviously, is that we want to include patients that respond to anti-VEGF, so that they clearly show potential for lifelong benefit of an anti-VEGF, and that is the most important criteria for enrollment. We've seen that we showed benefit in both patient population in our LUNA study, beyond what we've seen in OPTIC long-term. And, you know, there's a potential to include even patients who relatively fresh or recently diagnosed, that's where you don't really necessarily know how many injections they'll need. But having that disease and signing up for lifelong injections may be very motivated to have the potential to be, free of injection for life. Got it. Thank you. One more question on the data. I saw a couple of patients received a couple of supplemental injections out of protocol. Can you comment on these patients? ... I'll pass it on to Dr. Wykoff. Yeah, it's a good question. I think there's two things to say about that. First of all, you know, in any prospective trial, you want to regulate exactly who's getting treated and why, so you can interpret the data at an aggregate level. But the second level of data is, again, that, that critical, you know, doctor-patient relationship, and it's, and it's the investigator's responsibility in every case to do what's right for the patient, even if it's not consistent with the protocol. I think that's what you're saying, what you're seeing. Now, this is still very fresh data. I have not seen the granularity of exactly why patients were treated, but that would be my expectation, that there would be patients with possibly a little bit of fluid that's increasing, that doesn't hit the criteria for supplemental treatment, and the physician's doing what they believe is right in the best interest of the patients, and I support that. That's something that we've always taken to heart in these trials. And what's interesting is that we've also adapted over time. So early on in, you know, the PDS trial, the gene therapy trials, the TKI trials, we really jumped at any bit of fluid. But I think we have learned that if you have chronic VEGF suppression inside of the eye, that possibly a little bit of fluid can be tolerated. Exactly how much fluid, where that fluid can be, I think, has yet to be defined. There's that point. There's also the point that there can be minor fluctuations on fluid over time, that sort of wax and wane in a way that we don't understand biologically yet. But we've seen that in a lot of these long-term or extended durability trials, and we need to better understand those fluid dynamics. And that concludes our question- and- answer session. I will now turn the call back over to President and CEO, Laurent Fischer, for some final closing remarks. Thank you, operator. I'd like to thank all the patients who participated in this trial, as well as their families and caregivers. I'd like to thank all the investigators who support our LUNA and OPTIC trial, as well as the clinical site teams, and Dr. Charles Wykoff for joining us today, and of course, my entire team at Adverum that's been working tirelessly to make this happen. I'd like to thank everybody for taking the time to join us on this call today. We really appreciate the support and look forward to updating you on the LUNA study later this year. Operator, you may now disconnect the call. This concludes today's conference call. Thank you for your participation. You may now disconnect.