Ladies and gentlemen, thank you for standing by, and welcome to 4D Molecular Therapeutics webcast presentation of interim data for the 4D-150 24-week landmark analysis from PRISM Phase II population extension cohort in broad wet AMD. As a reminder, today's call is being recorded. With that, I will hand the call over to Uneek Mehra, Chief Financial and Business Officer, who will make introductory comments. Thank you, operator, and thank you everyone for joining our webcast this morning. We issued a press release describing the 4D-150 PRISM interim results for our population extension cohort earlier today, and the recording of this webcast will be accessible in the investors section of the 4DMT website after the completion of this call. We remind you here, we may be making forward-looking statements. For further details, you can visit our website. With me today are Dr. David Kirn, our Co-founder and Chief Executive Officer, who will provide introductory remarks. Dr. Bob Kim, our Chief Medical Officer, who will review the program summary and next steps. And Dr. Arshad Khanani from Sierra Eye Associates and our lead principal investigator on the 4D-150 PRISM clinical trial, who will discuss the data. The PRISM interim data for the population extension cohort was presented earlier this morning by Dr. Raj Maturi, a principal investigator in the PRISM study at the ASRS Annual Scientific Meeting in Stockholm, Sweden. With that, I would like to turn the call over to our CEO, David Kirn. David? Thank you, Uneek, and thank you everyone for joining us. This is an exciting moment today for 4DMT, for ophthalmologists, and for their patients with wet AMD. The data we'll be reviewing today confirms and expands 4D-150's potential as a pipeline and a product, with multiple potential multi-billion-dollar ophthalmology market opportunities, including wet AMD, DME, and diabetic retinopathy. This data also confirms our strong conviction in the 4D-150 phase III program in wet AMD. Thank you to all the patients, clinicians, and the entire 4DMT team for your efforts to get us where we are today. Here are the key highlights for today for 4D-150. First, we're delighted to report that 4D-150 continues to be safe and well-tolerated in both wet AMD and DME, a key strength for this program and testament to our powerful platform technology and product development. Second, 4D-150 demonstrated strong clinical activity in a broad wet AMD disease activity population, which is representative of our planned phase III and commercial populations. Third, 4D-150 has demonstrated durable clinical activity from phase I long-term follow-up. Finally, the results we'll share today confirm our conviction in our planned wet AMD phase III program, commencing in Q1 2025. I'll now review the key takeaways of the PRISM phase II population extension 24-week landmark data. In population extension, we enrolled a total of 45 patients with wet AMD, including 30 at the high dose of 3 × 10^{10} vg, which is our planned phase III dose, + 15 at the low 1 × 10^{10} vg dose. 4D-150 was safe and well-tolerated overall. At the high dose specifically, none of the 30 patients experienced inflammation in the anterior chamber of the eye, and none had significant inflammation in the vitreous. All patients completed their local prophylactic steroid regimen on schedule and remained off steroids. These safety results are consistent with what we previously reported in the severe disease population in our dose expansion cohort. Strong clinical activity was demonstrated, and a dose response in favor of the high dose versus the low dose was evident. We demonstrated a robust reduction in patients' anti-VEGF injection treatment burden. Overall, high-dose patients had an 89% overall reduction in annualized injection frequency. 93% of patients received either zero or one injection, and 77% were injection-free. BCVA improved by 4.2 letters relative to baseline at week 24 in the high-dose arm, and this was 5.7 letters higher than in the low-dose control arm. CST results showed sustained anatomic control that was greater than the low-dose and without fluctuations overall. We believe these positive results reinforce the potential of our planned phase III program. We have now more than doubled the patient safety database at the planned phase III dose level, and we've confirmed robust clinical activity with key efficacy endpoints in our planned phase III population. We're now finalizing the few remaining details of our phase III study design, which we plan to share in September, and we remain on track to initiate the first study in Q1 2025. We show here that standard of care bolus anti-VEGF therapies unfortunately do not preserve long-term vision in the real world. You can see there is a consistent loss of vision each year, demonstrating the remaining high unmet medical need in these patients. So why do patients still lose vision with standard of care treatment? Here we describe three major limitations, all of which can contribute to vision loss over time. First, current anti-VEGF treatments have limited durability, which leads to suboptimal compliance and under-treatment. Second, bolus intravitreal injection agents result in oscillating peak-trough anti-VEGF concentrations that lead to damaging fluctuations in CST. Third, VEGF-C is a driver of wet AMD and can lead to persistent disease activity in patients treated with VEGF-A inhibitors, and this target is not addressed by any of the currently approved agents. As shown here, 4D-150 was designed to address all three of these limitations. Our approach is to deliver a single intravitreal injection, resulting in durable, steady-state anti-VEGF levels within the retina and choroid and to inhibit all four VEGF family members that drive the disease. Thus, 4D-150 has the potential to transform the treatment paradigm and to preserve vision over many years. Innovation in treatment of wet AMD has been incremental, with durability improvements of several weeks over standard dose Eylea, demonstrated by new agents such as Vabysmo and high-dose Eylea. The resulting reduction in injection burden is approximately 20%-30%. With these relatively modest improvements, these second-generation products are predicted to reach peak worldwide annual sales of over $11 billion across all retinal disease indications. Susvimo is designed to reduce injection burden over the course of roughly six months after surgical implantation. In contrast, 4D-150 has the potential for multi-year durability and even greater reductions in overall injection burden versus second-generation agents. Our target reduction in patients' injection burden is at least 80%, with sustained benefit over at least 3-5 years. We believe this represents a compelling target product profile for both patients and caregivers. Wet AMD is a multi-billion dollar revenue opportunity. By 2035, we expect wet AMD to be an approximately $10 billion market annually in the US alone. We estimate that each 1% of market share for 4D-150 could translate into $300-$500 million in revenue, assuming we price with at least 3-5 years of benefit. Thus, we believe 4D-150 clearly has blockbuster potential in this indication alone in the U.S. We predict market adoption of 4D-150 in parallel across three key patient segments. First, the high treatment burden patients, representing approximately 20% of the overall population. Second, logistically and/or compliance-challenged patients who have difficulty getting to the clinic for repeated injections, representing another 20%. And finally, the remaining 60% of the overall wet AMD population. So wet AMD is only the beginning. We believe our promising wet AMD clinical results to date have clear read-through to our ongoing 4D-150 clinical trial in DME, or diabetic macular edema. These markets encompass approximately 3.4 million patients in the U.S. alone. In addition, future opportunities with 4D-150 include moderate to severe non-proliferative diabetic retinopathy, or NPDR. Finally, we're leveraging the same proprietary R100 vector and manufacturing platform used in 4D-150 for the 4D-175 product candidate for geographic atrophy patients. These two markets encompass an additional 4.2 million addressable patients in the U.S. The promising safety and efficacy data generated with 4D-150 to date, with a single intravitreal injection, has driven significant momentum in both investigator and patient interest. Enrollment rates have accelerated between sequential cohorts in our PRISM and SPECTRA clinical trials. We believe that this momentum will continue into Phase III enrollment and commercial uptake with this compelling product profile. Here we show the breakdown of patient numbers treated with 4D-150 to date in all four wet AMD cohorts in PRISM and a fifth cohort of DME patients in SPECTRA. 139 patients have been treated in total to date, and 80 have been treated at the highest dose of 3e10 VGs per eye, our planned Phase III and commercial dose. We started development in the wet AMD patients with the highest disease severity and treatment burden in both phase I and the phase II dose expansion cohort. As planned, following safety and efficacy data in this population, we then moved into a broad patient population that is representative of our planned phase III population. Finally, based on this wet AMD data, we initiated clinical development in DME patients with broad disease activity. In parallel, to maximize our steroid prophylaxis options for potential commercialization, we have enrolled wet AMD patients with both severe and broad disease activity into an alternate ocular steroid regimens cohort. Of note, no oral or systemic steroids were included in any regimen. We plan to use our current topical Durezol eye drop regimen in phase III. I'd now like to hand the presentation over to Bob Kim to summarize the PRISM clinical trial design and baseline characteristics for the population extension cohort. Bob? Thank you, David. Today, we'll be sharing a 24-week landmark analysis for all 45 patients from the population extension cohort, based on a data cutoff date of June 24th, 2024. This is the design of the phase II portion of the PRISM clinical trial, evaluating safety and clinical activity of 4D-150 at the 3E10 and 1E10 dose levels, with the dose expansion cohort shown on the left, as we reported in February, and the population extension cohort shown on the right. As discussed, the population extension cohort includes patients with broader disease activity than in dose expansion, which focused on the most severe and highest treatment burden patients. The inclusion criteria for population extension are shown on the bottom right. Patients must have received 1-6 prior anti-VEGF injections in the past 12 months, with at least one injection in the last 12 weeks. Screening BCVA had to be between 34 and 83 letters. Here, we show a figure that compares the population extension and dose expansion cohorts. Retinal CST is shown on the X-axis, reflecting disease severity, and the actual number of injections a patient received in the last 12 months is on the Y-axis, which reflects patient's treatment burden. In February, we reported phase II dose expansion cohort data. These patients had a mean CST of 440 microns and 10 actual injections in the prior 12 months, as shown in the upper right. These patients had severe disease activity and a high treatment burden. In contrast, the population extension cohort enrolled patients with broad disease severity and treatment burden, with a mean CST of 330 microns and an average of 4.4 actual injections in the prior 12 months. The patients in this cohort are representative of the planned phase III population. This is the clinical trial design for the population extension cohort. All patients received aflibercept on week -1 before receiving 4D-150 on day zero. Patients then received intravitreal 4D-150 at either the high dose of 3 × 10^{10} or the low dose of 1 × 10^{10}. As is done in some other gene therapy studies, another aflibercept injection was given on week 4 to ensure anti-VEGF coverage during the 4D-150 transgene expression ramp-up phase of approximately 8-12 weeks. Consistent with other pivotal gene therapy studies in wet AMD, this week 4 dose will also be used in our phase III trials. Patients initiated a prophylactic ocular steroid regimen involving only local administration. Study endpoints included safety and tolerability, annualized anti-VEGF injection rate, proportion of patients requiring supplemental aflibercept injections, and change from baseline in BCVA and CST. The criteria for supplemental aflibercept injections are shown on the right and are the same as were used in the dose expansion cohort. This table outlines the key baseline characteristics of the 45 patients enrolled, with 30 in the 3E10 arm and 15 in the 1E10 arm. All patients were previously treated. Overall, the arms were well-balanced. Mean BCVA was 72 letters at baseline, or roughly 20-40 Snellen equivalent. Patients had a mean CST of 329 microns, indicating active disease. As mentioned earlier, the mean number of actual anti-VEGF injections in the prior 12 months was 4.4. I'd now like to hand the presentation over to Dr. Arshad Khanani, lead investigator of the PRISM clinical trial, to present the data. Arshad? Thanks, Bob. I would like to start by summarizing the safety profile from 4D-150 in this cohort. Safety is a priority for any new treatment in wet AMD. 4D-150 was safe and well-tolerated, with no 4D-150-related serious adverse events. There were no cases of hypotony, endophthalmitis, vasculitis, pleural effusions, or retinal artery occlusions. In 30 patients treated with 3E10, no significant inflammation was reported. All 30 patients completed the prophylactic steroid regimen on schedule, and none resumed steroid treatment. This slide summarizes the safety results from comprehensive ophthalmic examinations completed at every visit to look for cells in the anterior chamber and vitreous. Cells were graded according to the standard SUN and NEI scores. Each row represents a patient, each column represents a visit, and each box represents the SUN and NEI score from that visit. As seen with all of the dark green boxes, 4D-150 was very well-tolerated. At the 3E10 dose level planned for phase III, no clinically significant or recurring intraocular inflammation was observed in any of the 30 patients. Specifically, no inflammation was detected in the anterior chamber in all 30 patients, and none was detected in vitreous in 29 of 30 patients. A single patient had trace cells detected that did not require treatment. At the lower 1E10 dose, 14 of 15 patients had no inflammation. A single case of mild to moderate inflammatory cells was noted in a patient. This patient also had trace cells in the vitreous of the non-injected eye as well. This patient improved rapidly on a topical Durezol taper. This outlier case represents approximately 2% of all patients in this study, whereas 98% of study patients had no significant inflammation. Here are the swim lane plots for individual patients from both dose groups, showing both the pre-enrollment anti-VEGF injections on the left and the supplemental anti-VEGF injections on the right for both treatment arms. At week 24, the annualized anti-VEGF injection rate in the 3E10 dose arm was reduced by 89%. 93% of patients received either no injection or only a single supplemental injection. Finally, 77% of these 30 patients remained completely injection-free. The low dose demonstrated clear biological activity as well, with a similarly strong reduction in overall treatment burden. A dose response was suggested when looking at the injection-free rate of 77% at the high dose versus 60% at the low dose. These data highlight the efficacy potential of a single intravitreal injection of 4D-150 in wet AMD patients, representative of the planned phase III population. Here are the BCVA results. As seen in the dark blue solid line, for all patients on the 3e10 dose, mean visual acuity improved by 4.2 letters from baseline. The dashed blue line shows BCVA results from the subgroup of 3e10 patients who were supplemental injection-free. The BCVA in these patients improved by 4.7 letters from baseline. A dose response was observed between the high dose of 3e10 and the low dose of 1e10. The mean change in BCVA from baseline was 5.7 letters higher in the 3e10 arm versus the 1e10 arm. As a reminder, these are previously anti-VEGF treated patients with broad disease activity. This slide shows the CST as measured by OCT, a measure of disease activity and response to treatment in wet AMD. As shown with the dark blue line, the 3E10 dose level was associated with sustained and greater anatomic control versus the low dose, with the CST reduction of 9.2 microns from baseline. As shown with the dashed blue line, the CST results from the 77% of patients who remain injection-free on the 3E10 dose, their CSTs improved by 32 microns from baseline. No CST fluctuations were observed. Consistent and sustained disease control was demonstrated without supplemental aflibercept injections in these patients. Summarizes the reduction in treatment burden at the 3E10 dose across the severe patient population from dose expansion and the broad disease population from population expansion described today. The data show a consistent anti-VEGF treatment reduction across both patient populations. An 89% reduction in mean annualized injection rate was achieved in both populations. 93% of patients achieved zero or one supplemental injection in the broad population, versus 84% in the severe population. Finally, 77% of patients in the broad population were supplemental injection-free, versus 63% in the severe population. This consistent and reproducible data across two study cohorts confirms 4D-150's potential to significantly decrease treatment burden regardless of disease activity. Here we have a case study from the population extension cohort of a patient treated with the 3E10 dose, who has been supplemental injection-free through 24 weeks. This patient received four anti-VEGF injections in the prior six months and missed the day 28 per protocol injection. As shown in the lower left, this patient's BCVA was consistently improved throughout 24 weeks, and by week 24, their BCVA was improved by 6 letters. OCT images of the patient are displayed at the top of the slide, and associated CST results are shown in the lower right. Sustained CST control and improvement can be seen through week 24. These BCVA and CST results confirm strong and sustained disease control after a single injection of 4D-150 without any supplemental anti-VEGF injections. Here we have an update from the phase I stage of PRISM, which is now in long-term follow-up. We previously presented three heavily pretreated patients in the 3E10 dose who were injection-free through 1.5- 2 years. Of note, these patients received 11-12 injections in 12 months prior to receiving 4D-150, and all three patients remained injection-free for 2- 2.5 years. Mean BCVA has remained stable, and mean CST was improved and sustained without fluctuations. This highlights the emerging long-term sustained benefits of 4D-150 at the phase III dose. Importantly, 4D-150 continues to be safe and well-tolerated across all 139 patients dosed to date in both PRISM and SPECTRA clinical trials. This includes follow-up in 22 DME patients through up to 36 weeks, and there has been no inflammation observed. All patients have completed their topical prophylactic Durezol regimen on schedule and did not resume. 51 patients have been treated at the planned wet AMD phase III dose, and topical Durezol prophylactic regimen had no significant inflammation, hypotony, retinal vasculitis, choroidal effusions, retinal artery occlusions, with up to 2.5 years of follow-up, and no recurrent inflammation post-steroid taper has been observed. This safety profile is highly promising for phase III development and our patients in the real world. We are pleased to report that we have seen no 4D-150-related hypotony, endophthalmitis, vasculitis, choroidal effusions, or retinal artery occlusions across all patients. I will now hand it back over to David to discuss next steps. Thanks, Arshad. The exciting results we shared today validate the potential of 4D-150 to be a highly disruptive product in the broad population of wet AMD and the overall retinal diseases market. Here, we review our phase III pivotal trial design and registrational planning in wet AMD. We will be running two phase III non-inferiority trials based on BCVA, evaluating 4D-150 at the 3E10 VG per eye dose level versus a control arm of aflibercept 2 milligrams every 8 weeks. The non-inferiority margin for FDA and EMA is 4.5 and 4 letters, respectively. We expect each study to enroll approximately 450 patients or approximately 225 patients per arm. The population extension cohort characteristics and treatment regimen discussed today are representative of our planned phase III design. We have received both RMAT designation from the FDA and PRIME designation from the EMA for 4D-150 in wet AMD. These designations enable increased collaboration between the two agencies and an opportunity for expedited product development. To our knowledge, we are the only ophthalmology product candidate to ever receive both designations, which differentiates us from our competitors in this market and enables us for global commercial readiness. We plan to provide an update on our finalized phase III pivotal study protocols this September. We remain on track to initiate our first phase III pivotal trial in Q1 2025. In summary, 4D-150 achieved all of our objectives in this population extension cohort and program update, including safety, efficacy, and long-term durability. These results confirm our conviction in our planned wet AMD phase III program. In addition to phase III plans, we also look forward to sharing 52-week wet AMD data from both PRISM dose expansion and population extension cohorts in February 2025, and 24-week DME data from part one of SPECTRA in Q4 of 2024. Our balance sheet remains strong to fund the phase III program, with $589 million of cash as of the end of Q1 2024, and with runway into the first half of 2027. Before I open up the call to questions, I'd like to take a moment to thank the entire 4D MT team for their remarkable innovation, execution, and dedication. I'd also like to deeply thank our investigators, clinical trial staff, patients, and their families. Thank you, and I'm happy to now open the call to questions. Operator? In today's session, we will be utilizing the Raise Hand feature. If you would like to ask a question, simply click on the Raise Hand button at the bottom of the screen. Once you've been called upon, please unmute yourself and begin with your question. Our first question today comes from Salveen Richter. Good morning. Congratulations on the data. A couple of questions from us here. One is, were there any baseline characteristics associated with achieving injection-free status versus not? Could you give us a little bit more clarity here on the CST side as well? And then just speak to, for the phase III study, what items are left to gain alignment on, and could you confirm that you'll evaluate one, not two, 4D-150 dose levels, and whether there's any ongoing work on dosing fellow eye or evaluating higher doses? Thank you. Thank you, Salveen. This is David Kirn, CEO of 4D. So, you had a question about baseline pre, predictive factors for injection-free status. So again, 77% at the high dose were injection-free. Yeah, we've been thrilled that a broad range of patients, even very severe patients in terms of CST and prior number of prior injections, have been able to respond and achieve long-term injection-free status. So as of today, here's nothing that predicts for, you know, patients who won't be able to achieve injection-free status, but that's something we'll continue to study over time. In terms of the CST details, you know, we're thrilled again with these results. So as we said in the introduction, patients still lose vision with wet AMD on standard of care, and we believe that's due to this oscillation or fluctuation in the, retina that comes from that intermittent bolus therapy. What we've been able to show in the prior study cohort dose expansion, and now in this population today, was a rock solid, CST, particularly in those 77% of patients who are injection-free. We really don't see any change from 12 weeks after any sort of bolus, if aflibercept loading dose is gone and out to 24. So on 4D-150 alone, that CST is rock stable, and there's no evidence of fluctuations. We think that's going to translate into BCVA benefit, and in fact, on this study, we saw a pretty remarkable 4.7 letter improvement in the injection-free patients in terms of their BCVA. With regards to phase III, you know, we've made great progress there with the FDA and EMA under these special designations that we have of PRIME and RMAT. And we're getting down to the final details, and we will release the final study design in September. I would say the open details there around, you know, the precise enrollment criteria, things like that. But, you know, the primary endpoint of BCVA, the secondary endpoints, the overall patient population, the dosing regimen, the steroid regimen, all of that is locked in. So we're, you know, this data today really increases our conviction in that plan and that program. And then you had a question about confirming a single dose level, and we can confirm that in both of these cohorts, in PRISM, we saw a nice dose response favoring the 3E10 dose level. So, we are now confirming that we're taking one dose level into Phase III, and that will be the 3E10 dose level. Before we move on, I'd just like to turn to Arshad and see if you have anything to add to your Selvi's questions. Yeah. Thanks, David. Thanks, Selvi. So I think for me, this data set is super important because of your question about CST. If you remember in the dose expansion, we were looking at patients who are super high-need, difficult to treat, to establish biological activity. So, you know, as a clinician, we want to make sure that obviously, gene therapy, number one, is safe, and number two, is efficacious. And in, in that cohort, we had patients with significant fluid over 6 injections in 12 months, CST greater than 325, and a lot of fluid with a very high actual treatment burden history. And there we saw great efficacy in terms of injection-free and, and minimizing the number of injections and stable anatomy, as David was saying. So this data on broad patient population, which, by the way, includes some high-need patients also. So this is not a patient population that's completely dry with a very low CST. This is around 320 to 330, you know, in terms of CST to your question. So these are also active patients, but some of them, you know, were relatively fresh, and others were longer. Because what happens when you go from phase II to phase III is you get a broad patient population. And for me, you know, as the lead investigator, always goal is to de-risk the pivotal program. So adding this cohort gives us the confidence that you have patients who are high-need, patients who are lower-need, patients who are chronic, patients who are fresh. If we can have activity in those patients, then it essentially de-risks the phase III program, and, and I think this data set really highlights that. And of course, you're going to get patients who are, you know, not all super high-need, you're going to be able to have better numbers in terms of injection-free and others. So I think this kind of confirms that there's great biological activity, there's maintenance of CST, there is minimization or no fluctuations. And of course, for me, as a clinician, the biggest thing is safety, and the safety profile here we are seeing is very consistent with what we have seen in the past. So I think this kind of makes a really good pathway for having this in phase III program in the near future and hopefully available for our patients. Thank you, Arshad. Thank you. Selvi, you also asked about fellow eye study. So that is something that we intend to study as part of a phase III package. That's something FDA will want to see. We do expect in the commercial setting to treat the control, you know, the fellow eye. A significant percent of these patients, I think it's up to 40%, will develop the disease in the other eye, so we want to be able to treat those. So we do intend to do that. We have treated the fellow eye in our rare disease program with the same exact vector and manufacturing platform for that product, and it was safe and well tolerated. We've also done the same in non-human primates. We expect to do that, and we expect it to be safe and well tolerated and effective. Thank you. Our next question comes in from Tazeen Ahmad. Please unmute yourself and ask your question, Tazeen. To do so via phone, it's star six. Hi. Good morning. Can you guys hear me? Yes. Okay, great. Perfect. Thanks for the, for the chance to ask questions, and congrats on the positive data. David, I just wanted to get some color on that one patient that you described as having the case of inflammation in the lower dose. Obviously, it's a low percentage in the relative scheme of things. Can you just provide additional color on the profile of that patient and what might have potentially caused the case of inflammation and when that case occurred? And can you just compare general rates of inflammation of this sort to what you see with Eylea and Lucentis? And then I have a follow-up. Well, thank you, Tazeen. I'll kick it off and then turn it over to Arshad. So first of all, you know, this is incredibly rare as a single patient out of 139, so less than 1%. You mentioned the Eylea. The label for Eylea, I think, has about 2%-4% of patients can have some inflammation. So again, our profile of 98% having no significant inflammation compares very favorably to Eylea. This particular patient, this two plus popped up at week 24, and the patient was put on a Durezol taper at that point and responded very quickly and is now asymptomatic and doing very well. So incredibly rare, and responded well. You know, to reiterate, we had 51 patients to date on the 3E10 plus Durezol regimen, which we're taking into Phase III, and there we had no significant toxicities. You know, no grade 1, no grade 2, just 1 patient with trace cells that were not treated, so very favorable safety profile. In terms of the patient and maybe why this happened, the patient has a complex medical history and background. You know, untreated syphilis in the past and also some missed his week 4 loading dose and had a little bit of a bleed from missing that dose. So it's a complex patient background, and we'll continue to study it and, you know, see if we can predict this in the future. I think the bottom line is, this is less than 1% of our overall patients, very consistent with the Eylea label, and the safety profile has been incredibly compelling to date. Arshad, would you like to add anything on this patient? Yeah, no, I think, you know, as a clinician, safety is a priority. We have, you know, intravitreal injections, obviously, that work really well, and we have this treatment burden that patients have poor outcomes in the real world. So anything that's gonna be adopted broadly in terms of a sustained delivery needs to be very, very safe. So I actually, you know, as a clinician, I'm always interested in safety, and obviously, it's super important. So this patient, as David said, you know, looking into more history, has complex history. And remember, these patients, you know, have to be on topical drops also for 20 weeks, and if they miss one appointment for their follow-up, I am questioning if they also took their drops as instructed. But I think, you know, these things happen in terms of, patients can miss appointments. And so I think for me, it's the overall data package and, and data that I'm looking at as a clinician. I just presented the first-time results for the RHONE-X study, which is the four-year follow-up Vabysmo study, extension study with over 1,400 patients, treated with Vabysmo, and the inflammation rate in that trial was between 1%-2%. So I think if you have a rate that is 1%-2%, I think that is very reassuring at this stage that this gene therapy is very, very safe. Obviously, you want to make sure that you're looking for those signals, and that's why very detailed examinations were done in this study, looking at anterior chamber, looking at vitreous, and grading the cells. So I think the bottom line for me is that you know, in this large data set of 139 patients, the rate is less than 1%, and this is very reassuring. These are very large numbers that now we have accumulated. And as a clinician, the other thing is that you don't want to restart treatment after tapering off if you have patients having inflammation because you don't want patients on long-term eye drops. So that's the other reassuring thing here, is that when you look at the 3 Tendo, all patients completed their prophylaxis on steroids and did not resume. So I think that profile is very meaningful in terms of predictability and adoption in a clinical setting for practicing physicians. Okay, perfect. Thanks for all of that color. And then I just wanted to get a sense from how you're thinking longer term. You've got a really high percentage of patients that have remained rescue injection-free. Our doctor checks indicate that if you can hit a year without needing a rescue injection, that would be impressive, and clearly, you're, you're on track to be past that. But in a blue-sky scenario, how are you thinking about the need for potential rescue injections from anti-VEGF? And what is your view about looking into the potential of redosing, if redosing is needed several years down the line with your therapy? So I'll kick it off and then turn it to Arshad. But you know, in terms of the durability, you know, we know that AAV gene therapy in the retina is highly durable. We know that for rare disease studies out to 10 years and other subretinal programs, for example, out to 4 years and beyond. So we know it's going to be durable. We updated the durability data from our phase I injection-free patients, showing that all 3 of the patients who were injection-free at 1 year are now still injection-free at 2-2.5 years. So we think if a patient declares himself as injection-free through, you know, kind of that 6-9 months phase, they're probably gonna remain injection-free for a long time. You know, if you look at the CST and BCVA curves, the means for the injection-free patients that we showed today, those are rock stable and steady, well, improved from baseline, so it's no evidence that those patients are gonna be rescued any time soon. And then briefly, in terms of redosing, as I said, we have redosed. We haven't redosed the patient in the contralateral eye. And then in the future, I can imagine, as part of, say, life cycle management, we could even do this in parallel with phase III. We do expect to study, you know, another injection in the same eye, in that small percent of patients who might need a little bit more. That's not part of the phase III program, but that is something we could certainly study over time. Maybe I'll turn it over to Arshad now. Yeah, thanks, David. So I think as a clinician, we see patients on very different spectrum of disease. So we have patients that are on, let's say Vabysmo or Eylea, 8 milligram, you know, every 4-8 weeks. Of course, Eylea 8 mg, you can't do every 4 weeks after the injection initial, a nd then, we have patients that are on 2 or 3 months of dosing. So I think the key is that when I am, you know, recruiting for gene therapy trials, I'm never promising that patients are cured. Rather, I'm saying that we have this innovative treatment that is a paradigm shift in terms of controlling disease activity, minimizing CST fluctuations, which actually leads to long-term vision loss and decreasing treatment burden. Obviously, if a patient is on monthly for tocilizumab, there's a good chance that they will need supplemental, but they may go from getting an injection every month to maybe 2 or 3 injections over 1 year, versus a patient that's on treatment every 2 months, and they have a higher chance of going injection-free. So I think we need to kind of think about management of wet AMD very differently because every patient is different, and our goal as clinicians is to optimize the visual acuity outcomes long term. And with that, we can add supplemental injection once in a while for a patient that is super high need because we will be able to maintain that anatomy and disease control and maximize their outcome. So I think the focus should be on, of course, a reduction in treatment burden for these patients, and also the number of patients needing zero or one injection. But yeah, of course, if you get injection-free, that is something that patients also like. In terms of gene therapy working long term, you know, the first patient that was ever dosed with 4D-150 was my patient, and she has stable anatomy without any fluid now, as David said, over two and a half years of follow-up. So this doesn't happen without a treatment that is actually working in a patient. We have a biofactory approach with steady levels of anti-VEGF. And as a reminder, we have dual transgenes here. Not only the aflibercept transgene, but also interference mRNA for VEGF-C, which is elevated in patients who get treated chronically. I think having those two mechanisms, combined with the lower dose, we're able to achieve disease control that actually can benefit patients long-term. So, so very exciting to see the data and having patients in this trial, especially the long-term first patient ever got treated with 4D-150. Okay, perfect. Thanks for all of that, Colin. This question comes from Jon Miller. If you'd like to unmute and ask your question. Thanks so much for taking the question, guys, and congrats again on really good data. One quick clarifying question. On the phase III BCVA endpoint, obviously, non-inferiority makes sense. Do you know what the primary analysis time point is likely to be, and if there are going to be secondary analysis time points beyond that? And then maybe switching gears to talk a little bit about the CST results, which do look really strong in injection-free patients, but I'd like to focus on the patients who are not injection-free, where obviously you're selecting here in that group patients that have some increase in CST that leads to their getting a supplemental injection. But can you maybe contrast the rate of that injection that you see here with what might be expected in this less severe patient population? How rapidly do you expect to see the loading dose of aflibercept effects wearing off and CST rising over the rest of that six-month period? Thanks, Jonathan. I'll kick it off and then turn it over to Arshad. Your first question was related to BCVA primary endpoint in phase III. That's gonna be at approximately 52 weeks, so one year. We do intend to file on that, and then we would continue to follow the patients for up to 2 years for BCVA, but we would file on a primary endpoint of BCVA non-inferiority at approximately 52 weeks. In terms of the CST, you correctly point out, you know, that the overall CST, we saw a nice dose response in favor of the high dose. The injection-free patients, 77% of all patients at high dose, were essentially flat. And, you know, if you look at, say, 12 weeks, where you're really sure that any of that upfront. The loading doses of aflibercept should completely be gone. Now you're looking at 4D-150 alone in isolation. You know, from 12- 24 weeks, that CST curve couldn't be more stable. So then you look at the overall curve, and you can see some patients that, you know, roughly 20%, who are not injection free, are driving that gradual uptick. And I think that's where, you know, Arshad was saying, you know, this is a heterogeneous disease, and there's just gonna be some patients who you don't get 100% injection free. You're certainly probably benefiting those patients that are having less injections than they would have. They're benefiting there. They're almost certainly benefiting in terms of BCVA, you know, because those patients are benefiting from BCVA on this study as well. But they may need an occasional injection. So maybe I'll turn it over to Arshad now to comment on those questions. You know, I think disease control is super important when you have a new treatment. What you don't wanna do is fool yourself into thinking a treatment is working while the disease activity is getting worse. So that's why it's important to look at the baseline characteristics as well as the follow-up in the study. For example, you know, I've been involved with the Port Delivery System for over 8 years, and the pivotal Archway study showed stabilization or maintenance of CST over time, and that led to the approval, obviously, based on non-inferiority on patients. So here we have patients, on average, about 320 microns of CST, so there's not too much to improve here. Obviously, this study also included patients that have advanced disease and, you know, in some of the patients, because a broad patient population. So this patient population, not just all patients with CST of 220, it's an average, right? So I look at this curve in two different ways. First curve I look at is improvement in CST after the aflibercept injection and maintenance of that in the supplement-free cohort, which is 77%. So there's 23/ 30 patients that were treated have improvement in CST that's maintained. To me, that is an evidence of true biological activity and not supplement-free because of retreatment criteria. Because this question comes a lot, like, if you make retreatment criteria very relaxed, you may look like you're working, but you are not. But here, what we see is that, you know, an aflibercept injection, you know, leads to about 50 microns or so of improvement, and then within the range of error, at 24 weeks, you are still, you know, around 30 or so per CST reduction of 30 microns. So that kind of truly shows that this is actually true biological activity. And then there's some outliers, right? CST also includes patients with pigment epithelial detachment, which is PED, and that doesn't require treatment in all cases in clinical practice. We actually chase fluid, we don't chase PED. So in a broad patient population, there are 7 patients who are likely driving the CST average up. But my interest is for establishing true biological activity to get that benefit of gene therapy, right? Sustained delivery, no fluctuations, no treatment burden or minimal treatment burden, you are getting that percent to 77%, and I think that's the exciting part, that the patients, you know, are having this disease control that is sustained. And then the last point is the fact that if I had a patient that needed supplemental, as I said earlier, even after doing gene therapy, I know that the supplemental injection rate will be much lower than if I did not treat them with gene therapy, because we're getting baseline levels of, Anti-VEGF, suppression. So I think that patient is also pleased with it. So I think having broad patient population here kind of shows the value that as clinicians, we are able to treat a much broader patient population in our clinical practice than just a subset of super high-need patients. Makes sense. Thanks. Maybe one more from me. The BCVA benefit that you see, this, this dose response BCVA benefit, why are you seeing it here in these, in this broader population, but we didn't see really any hint of it in the more severe patient population, where you might expect there to be a, a better opportunity to improve, baseline? And why is there, likewise, then, a, a dose response here where there wasn't a, a BCVA dose response anywhere else? I'm just trying to get a sense for how this difference in population is driving the difference in the BCVA data that we're seeing. Yeah, so I think that's a good question. I think we know, treating wet AMD, that patients who have very advanced disease, high treatment burden, a longer duration, and persistent fluid, over time, when you treat and control the disease, the patients don't improve visual acuity. So I think in terms of dose response in disease control, we look at anatomy, and obviously, if you get visual acuity benefit, which is very strong by the way, here, is a result of the fact that your treatment is controlling disease very well. So in the past, we didn't see that visual acuity improvement, which we did not expect, because these were much more advanced patients with very chronic disease, even longer duration than what we are studying here. Here, we have patients who are relatively fresher. Of course, we have a broad range of patients, but there's a good number of patients here that they don't have seven years of disease. You know what I mean? So I think the earlier you intervene, there's more potential to gain vision. But seeing a dose response with this excellent visual acuity gains shows us and confirms that biological activity. Our goal is to have a sustained delivery to maintain visual acuity in our patients, but if we can improve the outcomes by controlling disease and not having CST fluctuations, that would be a big plus for the field. And I think that's why sustained delivery is exciting, that we hope that we are able to have outcomes that are better than current standard of care because of controlling of disease activity and not CST fluctuations. So I think bottom line is, it's the patient profile in my conclusion, but both confirm the control of disease, and I think the visual acuity gains are very exciting. And I think for me, I need to see a dose response, and in both cohorts we have seen that, which confirms the biological activity. Thanks, Arshad, and thanks, Jonathan. Let's try to get some more questions in here. It's from Gena Wang. Please unmute and ask your question. Thank you for taking my questions. I have three questions. First, and actually mostly is for Dr. Khanani. I think you give a lot of additional color. So maybe first question is, you know, regarding. You did mention you have a broad, you know, they enroll more broad patient population in this cohort. When we look at the data, you do see quite some patient has only one injection or two injections historically. We understand those are the relatively newly diagnosed patient. So, like, you know, for commercial opportunity, is there a real-world opportunity for gene therapy in this patient population? And also for the clinical trial perspective, since we understand less about those patient historically, is there any actually risk for the Phase III study to enroll those patient population? My second question, sorry, I will be trying to be very quick. Second question also, what is the best practice regarding timeline for baseline measurements relative to Eylea dosings? And then quickly, on the 1E10, you did not show the data from supplemental injection-free patient. Sorry, the supplemented injection-free patient. What are the data look like for the 1E10 cohort? So I'll answer that last question quickly, and then pivot to Arshad to answer the rest of your question. So that looked exactly what you'd expect, a little bit better than 1E10 overall, but still not nearly as good as the 3E10 on in terms of both BCVA and CST. So over to you, Arshad. Yes. Hi, Gena. Great, great questions as usual. So I think for me, you know, gene therapy that is safe has the potential to be utilized in a broad patient population. You know, I see patients every day, they come in with new wet AMD, and they have seen their family members go blind. They have had friends that actually get injections for the rest of their life. So the first question they ask is, you know, "How many injections am I gonna get?" And the answer is, "You're gonna need treatment for the rest of your life." So it's a lifetime of treatment for these patients, and, you know, these patients are scared that they need to come in forever. So we wanna give hope to patients who have new disease and not just, you know, have a treatment for chronically treated patients, but rather somebody coming in, we treat them with one injection or two injections, then say, "Hey, after we control the disease, we'll be able to give you a treatment that can be more durable, that can minimize the number of injections you're gonna need or stop the disease." So I think that patient population is super important to study, and that's why we have, you know, these patients who are relatively fresh in terms of disease. And I think studying the patient population also helps for clinical adoption and also phase III planning. To your second question, I think we need to look at the maintenance of anatomy. So the question about what are the baseline characteristics or rescue criteria? And then, you know, we have the average here, but I think studies do it differently. But I think for me, it's more about maintenance of the anatomic benefit that you get after introducing gene therapy. Back to David. Thanks, Arshad. And Gena, just to be clear, we do share in the appendix the 1E10 injection-free patient slide, so you can look at that in the appendix of the deck. Let's try to sneak in one final question. I think it's coming from Mani. Is that right? Our final question that we have is from Clara Ding, if you'd like to unmute and ask your question. Hi, good morning. This is Clara Ding for Kelly, and thanks for taking my question, and really congrats on the data. Just wanted to get more clarity on the second dose administered at week 4. Do you see any pattern of injection-free BCVA and CST stabilization differences between those patients who received both doses and those who got one dose? And how do you plan to implement the second dose in the pivotal trial to make sure patients are not missing it, in the pivotal trial? Thank you. Yeah, I think in the pivotal trial, we'll hire the right CRO, and we'll be all over the sites to make sure patients come in for that dose. And we did have 5 patients who missed that week 4 dose. 80% of those patients, 4 out of 5, were injection-free long-term at 6 months. So not every patient is gonna need that, but we still think it makes sense biologically, scientifically, to cover patients with that week 4 dose of aflibercept during transient ramp up. We think ramp up probably peaks at between 8 - 12 weeks, so it's, you know, some patients may benefit from a dose covering them during that ramp-up phase. So, but overall, patients who missed that did very, very well in terms of injection-free status and outcome. Thank you. Thank you. Okay. Should we wrap it up? Okay, great. Well, let's summarize. Thank you all for attending today. Really appreciate the insightful questions that we received. In summary, we're thrilled with the safety and efficacy of 4D-150 in this broad wet AMD population. And again, this increases our conviction in the importance of this product for patients long-term, commercially, and also in our phase III design and likelihood of success. So thank you everyone today for your time, and we look forward to speaking with you in the future.