Hello, ladies and gentlemen. Thank you for standing by, and welcome to 4D Molecular Therapeutics webcast presentation of interim data from the 4D-150 phase 2 PRISM dose expansion cohort in wet AMD patients with severe disease activity and high treatment burden. At this time, all participants are in listen-only mode. Later, we will conduct a question and answer session, and instructions will follow at that time. As a reminder, today's call is being recorded. 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 welcome to our webcast. We issued a press release describing the 4D-150 PRISM clinical trial interim results on Saturday, February 3rd, and a recording of this webcast will be accessible in the investors section of the 4DMT website after the completion of this call today. With me today are Dr. David Kirn, our Co-founder and Chief Executive Officer, Dr. Bob Kim, our Chief Medical Officer, and Dr. Arshad Khanani from Sierra Eye Associates and the principal investigator on the 4D-150 PRISM clinical trial, who will discuss the data. Dr. Khanani presented the PRISM interim data on Saturday, February 3rd, at the Angiogenesis, Exudation, and Degeneration conference. We remind you here, we may be making forward-looking statements. For further details, you can visit our website. With that, I would like to turn the call over to our CEO, David Kirn. David? Thank you, Uneek, and thank you everyone for being here with us today to discuss these exciting results from the 4D-150 phase 2 PRISM clinical trial. Our focus today is wet AMD, which is the leading cause of vision loss in the elderly in the U.S. and Europe, and drives an $18 billion retinal diseases opportunity. 4D-150, our lead product candidate for retinal diseases, is the first intravitreal genetic medicine with a dual transgene payload targeting four VEGF family members. This gene therapy utilizes our modular R100 vector, which we have invented at 4D, to deliver transgene payloads to the retina with a single, routine, low-dose intravitreal injection. We shared positive interim data over the weekend from the 4D-150 phase 2 PRISM clinical trial in patients with severe disease activity and a high treatment burden. The results met all of our study objectives. 4D-150 demonstrated a favorable safety profile with no significant or recurrent intraocular inflammation. Stable vision and improved retinal anatomical control were demonstrated. Finally, robust reduction in anti-VEGF treatment burden was demonstrated, especially at the 3E10 dose level. We demonstrated an 89% overall reduction in treatment burden, and 84% of patients received zero or one injection, and 63% remained completely injection-free. We believe 4D-150 is the first investigational ophthalmology drug to receive both FDA RMAT and EMA PRIME designations. These designations, along with these positive data, enable us to rapidly advance our pivotal trial program with a phase 3 clinical trial expected to initiate in Q1 2025. Our balance sheet is strong, with approximately $300 million in cash as of the end of December 2023, which is expected to fund operations into the first half of 2026. I'd now like to walk you through a comprehensive overview of our 4D-150 clinical programs. In wet AMD, we have the phase 1/2 PRISM trial. We are pleased to report that we have completed enrollment for all three cohorts in two distinct patient populations. I'd like to note that our phase 1 and our phase 2 cohort enrolled patients with severe disease activity and a high treatment burden. This patient population has not been adequately studied in previous phase 2 wet AMD trials, including those that have been recently reported. In contrast to this dose expansion cohort, the population extension cohort has a broad range of baseline disease activity and treatment burden patients. We also have the ongoing phase 2 SPECTRA trial in a broad population of patients with diabetic macular edema. We're pleased to report that we've completed enrollment of 22 patients in the dose confirmation cohort ahead of schedule, due to high patient and physician interest. We're very encouraged with the safety profile of 4D-150 to date, including the lack of any significant inflammation reported from the 110 total patients treated as of the January 19th data cutoff. Now, let's dive into how 4D-150 addresses important unmet needs. On this slide, we review three major limitations with standard of care treatments, all three of which could contribute to vision loss over time. First, current anti-VEGF treatments are not durable. Recurrent, lifelong intravitreal injection regimens, even with recently approved anti-VEGF agents, are a significant burden on patients, on their families, on physicians, and on the healthcare system.... These burdensome regimens also lead to chronic undertreatment, often due to logistical challenges for patients and their caregivers. Second, the standard of care, even again with recently approved bolus intravitreal injection agents, results in oscillating peak-trough anti-VEGF concentrations that lead to variability in retinal subfield, central subfield thickness, or CST. This CST variability can contribute to vision loss over time. Third, VEGF-C is an important 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. In summary, all three of these limitations with standard of care, repeated intravitreal anti-VEGF therapies, can contribute to vision loss over time. We designed 4D-150 to overcome all three of these limitations, thus addressing patients' unmet medical needs with the potential to preserve vision over many years. First, invented the proprietary AAV vector R100 here at 4DMT using directed evolution. R100 was designed for efficient penetration from the vitreous through the inner limiting membrane barrier, which blocks other AAVs, to transduce all layers throughout the macula following intravitreal injection. We believe that this efficient delivery at lower doses than our competitors should translate into a highly favorable safety and efficacy profile. We then designed and inserted a dual transgene payload that expresses both the aflibercept protein and an RNAi molecule to inhibit VEGF-C. Thus, 4D-150 is able to target and inhibit four VEGF family members: VEGF-A, B, C, and placental growth factor. With 4D-150, we address the durability limitations of the current standard of care, frequently cited as the greatest unmet need in wet AMD. 4D-150 has the potential for multi-year durability by driving continuous, local, and steady state expression of our two transgene products following a single routine intravitreal injection. This is in marked contrast to the incremental durability improvements of several weeks demonstrated by new agents such as faricimab, Eylea HD, and many other investigational agents. We believe that 4D-150 is potentially highly disruptive and could dramatically reduce the overall treatment burden in these patients. Here we share published data showing the detrimental effects of oscillating peak-trough anti-VEGF concentrations, which can lead to variability in central retinal thickness. On the left, we illustrate both high variability from poorly controlled disease and low variability from well-controlled disease. Extreme oscillations in retinal thickness and anatomical instability may contribute to long-term vision loss, as shown on the right, where higher variability in the first year of treatment predicted for greater permanent vision loss for patients. The goal of 4D-150 is to provide continuous, local, and steady state expression of anti-VEGF molecules to maintain stability of the retina. This stability should drive long-term vision preservation. A third limitation with current standard of care is that they do not inhibit VEGF-C, which is also a potential driver of wet AMD and increases in response to VEGF-A inhibition. To address this, we added a second payload component within 4D-150 to express an RNAi molecule to inhibit expression of VEGF-C. In summary, we believe 4D-150 is well-positioned to be a market leader for VEGF-driven retinal diseases because it is designed to overcome all three of the major limitations with current therapeutic regimens, and this has the potential to preserve vision over the long term with a safe, routine, one-time intravitreal injection. I'd now like to hand the presentation over to Dr. Bob Kim to go over the trial design and baseline characteristics of the trial. Bob? Thank you, David. I'd like to start by discussing how to think about wet AMD patient populations, since AMD is a heterogeneous disease comprised of different populations, which in turn is important to understand when designing clinical trials and interpreting results. First, you can see here on the X-axis, we have retinal CST, which reflects disease activity. Higher numbers mean thicker, more swollen retina, and more active or severe disease. Normal CST is about 280 microns. On the Y-axis, we have the actual number of injections a patient received in the preceding twelve months, as opposed to an annualized rate, which indicates their treatment burden and reflects how difficult their disease is to control. Now, when we look at baseline characteristics of other phase 2 wet AMD trials involving treatment-experienced patients, we note that they had mean CSTs in the normal range, which is evidence of well-controlled disease at baseline. Average actual injections in the preceding 12 months was reported to be roughly 4-5 in some of these trials. Now, let's look at the patients enrolled in our Phase 2 Dose Expansion, who had a mean CST of around 440 microns and required about 10 actual injections in the prior 12 months. We consider these as patients with severe disease activity and high treatment burden, who are among the most challenging-to-treat patients. We enrolled these patients by design in this phase 2 PRISM cohort. Since these patients have the highest unmet need despite standard of care injections, we believe 4D-150 has the potential to be transformative for these patients. In addition, strong clinical activity in these hardest-to-treat patients should be predictive of strong activity in the broader patient population. As David mentioned earlier, we have recently completed an enrollment of our population extension cohort to evaluate 4D-150 in a broader patient population as well. Here, we show the design of the Phase 2 PRISM dose expansion cohort, which is a multicenter, randomized, clinical trial evaluating safety and clinical activity of 4D-150. We designed the inclusion criteria to focus on the highest unmet need patients based on disease activity measured by CST greater than or equal to 325 microns, and presence of subretinal or intraretinal fluid, as well as an anti-VEGF injection treatment burden of 6 or more actual injections in the prior 12 months. In addition, patients also required best corrected visual acuity at screening of 34-83 letters. After enrollment, patients were then randomized 2 to 2 to 1 to receive 4D-150 at a high dose of 3E10, a low dose of 1E10, or aflibercept 2 milligrams Q8 weeks control. This slide shows the clinical trial design. All patients received aflibercept on day -7. Patients in the 4D-150 arms initiated a 20-week prophylactic topical corticosteroid taper on day -1. Patients and sites knew if treatment was 4D-150 or aflibercept, but they were masked to the dose of 4D-150. Study endpoints include safety and tolerability, change from baseline in BCVA and CST, and proportion of patients requiring supplemental aflibercept. The criteria for supplemental aflibercept are listed on the left. All arms were eligible to receive supplemental aflibercept if the criteria were met. Today, we'll be sharing a landmark analysis at 24 weeks for all patients based on a data cutoff of January 19th, 2024. This table summarizes the key baseline characteristics of the 51 patients enrolled in our Phase 2 Dose Expansion cohort. Overall, the arms were well-balanced, but of note, patients enrolled in the 3E10 arm had more chronic disease. I would like to point out that patients had a mean CST of 442 microns, highlighting severe disease activity. This was despite receiving an actual number of nearly 10 anti-VEGF injections in the prior 12 months, reflecting unambiguously highly active disease. These baseline characteristics are much higher than in other phase II studies studying extended delivery of anti-VEGF agents. I'd like now to hand the presentation over to Dr. Arshad Khanani, a lead investigator of the PRISM clinical trial, to present the data. Arshad? Thank you, Bob. I'm pleased to report today that 4D-150 met all objectives we set out to achieve in this severe and difficult-to-treat patient population. As a single routine intravitreal injection, 4D-150 achieved a favorable safety profile with no significant or recurrent inflammation. We saw an 89% overall reduction in anti-VEGF treatment burden, 84% of patients receiving zero or one injection, and 63% of patients remaining injection-free in the 3E10 dose arm. In the aflibercept control arm, we saw substantial CST fluctuations on OCT, while in the 4D-150 arms, we saw minimal fluctuations, showing the potential of sustained expression from a single injection of 4D-150 in patients with severe disease activity and high treatment burden. In addition, phase I data shows the potential of long-term disease control with 4D-150 through up to two years of follow-up. Now, let's review the recent data I presented at Angiogenesis. For any new treatment, safety is a priority. In terms of safety, 4D-150 demonstrated a favorable safety profile with no significant or recurrent intraocular inflammation. Notably, high-dose 3E10 group had no grade 1 or higher inflammation. 97% of patients completed the 20-week topical corticosteroid taper on schedule. At the low dose, only a single patient had 1+ mixed anterior chamber cells at week 16, which resolved by the next visit. The patient completed their steroid taper by week 26. All patients are currently off steroids through up to 48 weeks of follow-up, with no patients having to resume steroids after their taper was completed. There were no 4D-150-related SAEs or study eye SAEs. There were no cases of hypotony, endophthalmitis, retinal vasculitis, retinal effusions, or retinal artery occlusions. Comprehensive ophthalmic examinations were done at every visit to look for anterior chamber cells or vitreous cells. Each row represents a patient, each column represents a visit, and each box represents the SUN score for that visit. Again, no clinically significant or recurring intraocular inflammation was observed in this trial. Looking at BCVA, stable visual acuity was observed through week 24 in this wet AMD population with severe disease activity and high treatment burden. Because patients are eligible to receive supplemental aflibercept at any time point, and patients receiving aflibercept received an injection every eight weeks, the difference versus aflibercept was averaged at week 20 and 24, consistent with many other studies. Looking at those results, a mean change compared to aflibercept was -1.8 and +1.8 letters for the high and low-dose arms, showing that the visual acuity was stable in all groups, with 95% confidence intervals overlapping at every time point. Let's look at CST to evaluate for disease activity as measured by OCT. Patients on the aflibercept arm showed high variability and fluctuations of up to 100 microns in their CST. This variability is more than that has been described in other wet AMD trials, highlighting that this trial enrolled patients with very severe disease activity. Now, looking at the CST in the 4D-150 treated patients, in contrast to the fluctuations in retinal thickness observed in the aflibercept arm, CST remained relatively stable through the 24-week period in both dose levels of 4D-150. At the 3E10 arm, the overall magnitude of change from baseline to week 24 was similar to that in participants receiving bimonthly injections of aflibercept. Also, it appears that the CST in the 3E10 dose at all time points was lower than aflibercept control, very close to the trough in the CST seen four weeks after aflibercept injection, highlighting the benefit of sustained expression with 4D-150. Here, we show the robust reduction in treatment burden for these patients. At the high dose level, we observe an 89% reduction in mean annualized anti-VEGF injections. At the low dose level, we observe an 85% reduction. Here are the swim lane plots for individual patients, showing 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 high-dose group was reduced by 89%. 84% received no injection or only one injection, and 63% of patients remained injection-free. The low dose also demonstrated similarly strong reduction in treatment burden. Now, I would like to share some specific patient examples to highlight the benefit of 3E10 dose of 4D-150 in these chronically treated patients. First patient is the one who was on monthly ranibizumab injections. Second one is a patient who received monthly aflibercept injections, and the third patient, who was receiving bimonthly faricimab. As you recall, these patients were required to have fluid at screening, which indicates that they were not well controlled on these treatment regimens. After 4D-150, all of these patients have been injection-free. As a busy retina specialist, I am excited to see these results. These data highlight the benefit of a single intravitreal injection of 4D-150 in these highest treatment burden patients with wet AMD. Finally, we would like to provide an update from the phase I dose exploration cohort of PRISM, and specifically, durability in our injection-free patients at the high dose level. Safety continues to be maintained in all 15 patients, with no new inflammation since the last update. In terms of durability, the three patients in the high-dose arm that were injection-free beyond 1 year remain injection-free through week 80 to 104, highlighting the emerging long-term sustained benefit of 4D-150. We come back here to the summary slide. 4D-150 achieved all of our objectives in this clinical trial, including safety, efficacy, and long-term durability. I am excited to work with the team at 4DMT on the phase III planning for this promising one-time dual transgene intravitreal therapy. I'll now hand it back over to David to discuss the next steps. Thanks, Dr. Khanani. The excellent results we showed today validate our belief in the potential of 4D-150 to be a highly disruptive product in the neovascular retinal diseases market and paves the way for phase III development. Given the robust clinical data and ongoing discussions with the FDA and EMA, we have decided to run a phase III non-inferiority trial based on BCVA, evaluating 4D-150 versus a control arm of aflibercept 2 milligrams every eight weeks. The non-inferiority margin for FDA and EMA is 4.5 and 4 letters, respectively. Based on the totality of the results to date, we have selected 3E10 VG per eye as our pivotal trial dose. We expect to enroll approximately 225 patients per arm. We expect to enroll a broad population of wet AMD patients, including patients with severe disease activity and a high treatment burden. We're also thrilled to 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're the only ophthalmology product candidate to ever receive both designations. We expect additional regulatory interactions in Q2 this year, and we plan to provide an update on these discussions to finalize the phase III design in Q3 2024. We expect to initiate our phase III clinical trial program in Q1 2025. Now, looking ahead to phase III, we applied our preliminary phase III eligibility criteria for CST and BCVA to the phase II dose expansion cohort. The criteria focused on patients with CST less than 500 microns and BCVA of 40-78 letters. This excluded 4 outlier patients from the aflibercept arm and 4 outlier patients from the high-dose arm, but still represented overall a high disease severity and high treatment burden population. Of note, the patients on aflibercept every eight weeks were still not well-controlled on this study in this population. When we compare both arms, we see BCVA for the high dose, 4D-150, was 3.3 letters higher than aflibercept. We also see a near 100-micron benefit in the high-dose arm versus aflibercept on CST. The mean CST over time is stabilized in the high-dose arm versus the oscillating CST in aflibercept control arm. This data once again highlights promising sustained disease control with high-dose 4D-150. We also continue to see excellent reductions in anti-VEGF injections, as shown on the right, with a 90% overall reduction in annualized injection rates, 88% of patients receiving zero or one injection. We believe these data are highly supportive of our advancement of 4D-150 into phase III trials. I'd now like to conclude by highlighting the upcoming milestones for our ophthalmology program. As you can see on this slide, we have many important upcoming milestones in 2024. Before I open up the call to questions, I wanna take a moment to thank the entire 4DMT 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 up to questions. Operator? We will now begin the question and answer session. If you have joined via Zoom, to ask a question, please use the Raise Hand feature, which can be found at the bottom of the Zoom application. If you've dialed in by phone, you may activate the Raise Hand by dialing star nine on your keypad, and star six will allow you to unmute. Once called upon, you may unmute and ask your question. I will now pause a moment to assemble the queue. Our first question comes from Josh Schimmer from Cantor Fitzgerald. Good. Thanks so much for taking the questions, and congrats on the really exciting data. Three quick questions. First, what are the gating steps to starting the phase III trial? Second, which manufacturing are you going to be using? Do you expect this will, for the wet AMD indication, be in-house, or will you be using a CDMO, and where are you in terms of scaling up for clinical and commercial supply? And then the third question is, for those patients who did need additional injections of anti-VEGF therapies, is there any way to discern whether it was an issue with maybe the original transduction in those patients just not being as robust, or whether the treatment effect was wearing off, or whether they just had too active a disease process for the therapy to really impact this meaningfully? Thank you. Thanks, Josh, for the question. I'll answer the CMC question first, and then turn it over to our CMO, Bob Kim, for the phase III gating question and the response question. On CMC, I think one of the great strengths of this company is we have an incredible CMC team. We manufacture all of our, ... clinical trial material in-house in our own manufacturing facilities. For this study, we'll be manufacturing the material in-house at commercial scale and with a commercial process, such that we'll have a seamless transition to a CDMO in the future down the road for commercial supply using the exact same process and at commercial scale. So we, we feel really good about that, and that won't be gating for phase III initiation. I'll now turn the questions- other questions over to Bob regarding phase III gating and responses. Yes, so regarding steps towards phase III, we've had some very productive initial interactions with both the FDA and EMA. And as we've shared, we have a general alignment on the initial study design of a non-inferiority study. There are some details that we are going to be working out with these agencies, and this will be facilitated by the RMAT and PRIME designation that we've attained. So basically, at this level, we're just sorting out details. Regarding your question about rescues, I think we're not worried that there's differences in transduction. We think that wet AMD is a heterogeneous disease, and that some of these patients just have disease, as you put it, that's just too active to overcome. Thank you very much. Our next question comes from Kelly Shi from Jefferies. Hi, good morning. Congratulations on the results, and thank you very much for taking my question. For DME, previously, you stated that the starting dose in phase II was going to be 5e9 VG per eye, and now it looks like you're evaluating 1e10 and 3e10. Could you please talk us through that decision? Is it a reflection of good safety profile or maybe insufficient efficacy seen in DME so far at 5e9? Or perhaps is this an attempt to go at a higher dose for potentially increased durability to avoid redosing? Thank you. Thanks, Kelly, for the question. I'll answer that quickly. It's all about safety. You know, we've seen great safety at 3e10. We're thrilled that there were no grade one plus or higher episodes of inflammation of the high dose in this study. And we've now treated 110 patients across all of our studies with varying degrees of follow-up, and we've seen no significant inflammation across the 110 patients. So we're thrilled with the safety, and that allowed us to very quickly go to the 1e10 and 3e10 doses in DME. As a follow-up, second question, could you please talk us through your statistical assumptions for phase 3 with 225 patients per arm? What is that accounting for? Is it gonna be 4.5% or 4% for EMA guideline? Thank you. Sure. Good question. So you've pointed out the different non-inferiority margins that the different regulatory agencies have required, and the 4.0 margin is more challenging than the 4.5. So the 225 patients per arm should provide adequate power to cover the tighter 4.0 non-inferiority margin. Thank you very much. Our next question comes from Salveen Richter from Goldman Sachs. Salveen, star six will allow you to unmute your keypad. I will return to Salveen, and we'll take a question from Jonathan Miller from Evercore ISI. Hi, guys. Congrats on the data. Thanks for taking the questions. I wanted to ask about that look at the phase II data, when cut by the phase III inclusion criteria. Now, the, the phase III obviously includes a broader population than this phase 2. Is it fair to assume that among patients with less severe disease at baseline and were included in this phase II, maybe some of that lessening of the sawtooth or the benefit on BCVA might be less apparent in those patients where there was less disease at baseline? Is that the right way to think about it? How do you expect the various endpoints to change as you look at a broader, less severe at baseline population? Thanks, Jonathan. I think we'll have our CMO, Bob Kim, answer that question. Right. So, I think, regarding the sawtooth pattern, it was quite dramatic. The magnitude of the swings was, it approached 100 microns, and that's kind of unprecedented, regarding, you know, the swings that have been described in other anti-VEGF studies. I think as we and it reflects the extremely, I think, refractory disease in these patients. As we broaden the population, I think we would expect the swings perhaps to be a bit smaller on average. But nevertheless, we expect the stabilizing effect on fluctuations to persist in the 4D-150 treatment. Great. And on maybe some of the other endpoints, would you expect VEGF injection freedom to be higher? Would you expect VEGF induction burden to be... You know, how would you expect those other key endpoints to change? So regarding injections, it's kind of hard to improve on a 90% reduction in the annualized injection rate. We're hopeful that we might see an improvement in the injection-free rate, but you know, we'll be exploring that in our population extension cohort, and hopefully we'll be able to share that with you later this year. Our next question comes from Matthew Caufield from H.C. Wainwright. Great. Hi, good morning. Thanks for taking our question, and obviously a very exciting update. So with a minority of patients not injection-free through 24 weeks, what are your thoughts around prospective redosing down the line? And is this something at all that you're potentially thinking about for Phase III? Thank you. Thanks, Matthew. Not sure the injection-free rate is 63%, so that's well over 50% injection-free, and 84% of the patients had either 0 or 1 injections. But perhaps Arshad Khanani would like to comment further on that point. Yeah, absolutely, David. Good morning, everyone. So I think, we know that it's a very variable heterogeneous disease, and in this highly severe patient population with a very high treatment burden, that's why I highlighted those patients, that these were worst of the worst patients in our clinic. And I think, you know, as it goes into broader patient population, we expect those numbers, that David just gave to actually improve, in my opinion, 'cause I've seen that, in other studies with sustained delivery as we participate in all the clinical trials that are happening. In terms of redosing, I'll pass it to Bob. I don't expect to redose gene therapy. I think as long as I am helping the patient either completely resolve their disease or decrease their treatment burden significantly, I think this treatment has the potential to be broadly utilized in a busy retina practice. But Bob can comment on redosing of 4D-150. Right. At this time, the benefit that we're seeing in this severe population is actually very exciting. The fact that we're seeing any supplemental injection-free patients, we regard as a big success, and those patients who are receiving rescues, for the most part, seem to be doing much better than they were beforehand. So, we're in this population, we're delighted with the activity that we're seeing. Something that we will be exploring at some point, it's something both the regulatory agents have asked, is since wet AMD can affect the fellow eye, is if we will be coming up with a plan to address second eye treatment. Very helpful. Thank you very much. Our next question comes from Salveen Richter from Goldman Sachs. Good morning. Can you hear me? Yes. Yes. Oh, perfect. Thank you. Congratulations on the data here. Just three quick questions for me. One is, you know, whether there's any efficacy data beyond week 24 that you can provide to help us better understand the longer-term outlook here. And then, could you comment on physician feedback at the medical meeting? And then finally, how you're thinking about positioning the drug going forward here in the treatment paradigm. Thank you. I'll take the first one quickly and then turn it over to Arshad for the next question. So in terms of safety and efficacy, this is a 24-week landmark analysis, but this is obviously an open study, and we feel very good about what we're seeing beyond 24 weeks and feel like the durability's been excellent overall with 4D-150, including in our phase I patients out now 1.5 to 2 years with a stable CST and BCVA, and those patients remain injection free, those three patients from phase I. In terms of safety, we've given high-level safety update through week 48, which is the most follow-up that we have on these patients. And again, there's been no significant inflammation or recurrent inflammation, and all patients remain off of steroids, which is really a, a remarkable safety profile. I'll now turn it over to Arshad Khanani for the other to answer the other questions. Thanks, David. So when I presented the data, I got numerous messages right away after the data was presented, and I think the number one thing, as I said, for our field is safety is a priority. And the reason is, we have agents that work great and have a good safety profile. So any sustained delivery product that is gonna be widely adapted has to have a very favorable safety profile. And looking at the data we have seen with phase I and phase II patient population gives me quite confidence that the safety profile we have seen is very, very good. And the reason is not just that patients receive 20 weeks of steroids and we saw, you know, only one patient with mixed cell in the low dose, but rather that there was no reinitiation. And that's something that's key for the field because you don't want to have a gene therapy that will decrease intravitreal injection burden, but you stay on steroids for several years. So I think that's the key. So I think the safety data was very, very exciting. And then piggyback to that, looking at the efficacy in these severe patients, we have these patients in our clinic on a daily basis, and no matter what you do, you give them monthly anti-VEGF injections of potent drugs like, you know, bevacizumab and Eylea, and they still have fluid, and they fluctuate throughout. They will have less fluid a week later, but at one month, they have severe amount of fluid. And seeing that stability of OCT is very exciting because in clinical practice, that's how we treat disease. So overall, very, very positive feedback from my fellow retina docs that attended the angiogenesis meeting virtually. So I'm really thrilled to be a part of this, and you know, together, we are going to hopefully change the course of treatment for our patients by taking this program in later-phase studies. And I'm excited to be a part of the phase III trials that's going to launch Q1 of next year. Our next question comes from Geulah Livshits from Chardan. Hello. Congrats on the data, and thanks for taking the question. So you mentioned the safety that you've seen so far across the 110 patients. I think the FDA has some recommendations regarding the size of the safety database of the relevant dose. This draft guidance, I think, is around 400 or so. So can you talk about how your current set of programs will let you get there at the 3E10 level? Thanks, Geulah, for the question. We'll turn that over to Arshad Khanani and then Dr. Bob Kim. Arshad? Yeah, I mean, I think, you know, you have to look at the totality of data, and I think what we have seen in gene therapy program is that if there is a safety issue, it will show up within the first year, if not earlier. What usually happens is that as patients are tapering steroids to, you know, over time- Right ... if there is a safety issue, the disease, the inflammation will recur. So in this case, we have not seen that, and I think that's why I feel confident in the safety data set we have so far, because, you know, gene therapy, the safety is dependent on vector, and this vector is retinotropic. We are not seeing too much transfection in the front of the eye. This vector, again, you know, is dual transgene, and we are using very good doses, and that really helps also. The prophylaxis regimen with topical steroid appears to be working very, very well. So if we had any safety issues, it will show up during the tapering or right after the tapering, and we have not seen that so far. So I think that is, to me, shows that, you know, the safety we have seen so far gives us confidence to move forward. And I'll pass it to Bob for the other answers. Thanks, Arshad. From a regulatory point of view, generally, I say guidelines are that you, you need at least 400 treated patients and 300 patients treated at or above the to-be-marketed dose for, in the case of wet AMD, at least, 12 months. So we mentioned, a phase III, sample size of about 225 patients per arm, and if you were to have two studies, you'd have 450 patients. So that's well above the requirement, and all the patients that we've treated in our phase 1/2 PRISM study will count as well. And for safety, also, the patients in DME will be relevant, so no problem covering the safety requirement. So, thanks for the question, and just to reiterate, I think for phase III, really, at this point, it's about aligning EMA and FDA on final details of the protocol, and then it's all about operational start-up, which will take about 5-6 months once that protocol is finalized. Thanks for the question, Geulah. Our next question comes from Mani Foroohar from Leerink Partners. Hey, guys. A little more an operational question. What AMD studies, the pivotal setting can be quite broad, and obviously, this is the sizable global market. How do you think about the geographical footprint wherein you'd study patients? And how do you think about the puts and takes around whether or not sort of a global commercialization partner in at least some geographies make sense? Thanks, Mani, for the question. So I'll answer the operational question quickly, and then we can speak to opportunities for business development outside of that. You know, we have the opportunity to run either global studies or U.S. only, followed by global study. There are two studies. I think right now we're believing that our program will be global and that that would support global regulatory filings. We're committed as a company to commercializing 4D-150 and our other large market ophthalmology products in the U.S. on our own. That's core to our business plan, but outside of the U.S., you know, we see opportunities for potential partnerships. And I'll turn it over now to Uneek Mehra, our CFO, to comment on that. Yeah, thanks, Mani. I think, we've indicated earlier publicly that we have an interest in finding the right partner ex-US, both from a capabilities perspective, on the development and, more importantly, on the commercial side. As you've rightly noted, ex-US market is a pretty big market. It's a large market disease, even in those geographies. So Europe, Japan, and some of the Asian continents present a great opportunity. We have received significant interest in terms of partnership interest, and we are prosecuting those, both on the dimensions of those capabilities, the ex-US. Thank you. Great. And as one quick follow-up, we're going to be—you're going to be accumulating a fairly substantial database of patient experience here in this market, which obviously reflects applications of this, of your vector across other ophthalmology indications. Beyond those places where current anti-VEGF therapies are used, how do you think—how should we think about indication expansion, into other areas of ophthalmology? Well, we think the R100 vector showed great safety and activity across a range of different disease indications, including not only wet AMD but also in rare monogenic diseases. And we're also excited about 4D-175, which is our geographic atrophy agent for that will be entering clinical trials in the second half of this year. So we think that this should be great read-through with the R100 vector in terms of safety and activity, and also just speed of development. The manufacturing process for each of these products is identical, and it's, this is a very modular platform that we can leverage for efficient development. Great. Thanks. I'll hop back in the queue. I know you've got a lot of questions. Our next question comes from Kostas Biliouris from BMO. Hello, good morning, everyone. Thanks for taking our question, and congratulations on the great data. Maybe a couple of questions from us. One on the BCVA, sorry, on the CST trajectory. I'm wondering, what do you think the steady state of CST will end up being, given what you see there? And would it be ideal to be at zero, given that you have a loading Eylea dose at the beginning? And any comments around the steady state of CST that you would like to see here would be helpful. And then I have a follow-up. Thank you, Kostas, for the question. Arshad, would you like to take that question? Yeah, absolutely. You know, as clinicians, we are, you know, our goal is to stabilize CST, and as you saw, the fluctuations are significant in the control arm. So you know that these patients are the most severe and have very high treatment burden. So when I look at the CST curve, I'm looking for relative comparison to aflibercept and where the CST of 4D-150, 4D-310 is landing. So if you look at those graphs, you see that the CST achieved at 4D-150 is actually close to the trough that's seen four weeks after the aflibercept injection. So that tells me that you're having steady state of anti-VEGF that is, you know, controlling the disease. We all know as clinicians, that peak and trough in CST shows, of course, uncontrolled disease, but also can lead to, you know, visual acuity decline over time. So when I'm looking at the trends, I'm actually looking at the comparison, and then if you look at the Phase III population by, you know, excluding the outliers, you see a huge difference between the groups. So, so I think that's what I'm comparing with, because this is the patient population that is so severe that sometimes you can't even control them. You know, many of us even try every two-week injections in this kind of patient population, and they're not controlled. So, so overall, looking at that, I think we are getting a very steady state and very good disease control, and I think that's why I'm excited that in patient population that is going to be broad, we'll be able to do even better than aflibercept than what we have seen in the phase III subset analysis. Thank you. Very helpful. And maybe a follow-up, and sorry if I missed that, but have you looked at aflibercept levels in patients who received gene therapy? And if so, have you observed any differences among patients who needed a rescue injection versus those who are rescue injection-free? Thank you. Thanks, Kostas. The answer in phase I, we looked at that, and we reported out data at 12 weeks of aflibercept expression. We saw a really nice dose response there and levels that were consistent with preclinical modeling for a high degree of efficacy at those levels. Now, what's important about this therapy is what we are achieving is sustained, continuous, steady-state, local concentrations in the retina, which is really a game changer as compared to this bolus anti-VEGF therapy with the peaks and troughs. So as Dr. Khanani mentioned, that should translate into long-term vision preservation that we're very excited about. And, you know, I think a lot of this data has led to excitement and a high speed of enrollment in these phase IIs. Maybe, Arshad, I don't know if you'd like to comment on speed of enrollment in these phase IIs and how that might translate to phase III. Yeah, absolutely, David. I think there was so much excitement about this program that we had many patients who were waiting, you know, in the back of queue to enroll at a record time. You know, if I have a patient that is getting anti-VEGF injections, their first question is: "Is this a lifetime disease? Do I need to come every month or every other month?" Even with, you know, second-generation treatments like faricimab, we have a good subset of patients that require frequent injections, you know, monthly or every other month. And I think as we plan phase III and recruit, we will actually start planning in advance because I know that it's going to recruit really fast. Because these are previously treated patients, they know what injection burden looks like, and having a treatment that can eliminate the need for any future injections in more than, you know, 50% of the patients and decrease the treatment burden significantly. And this is an in-clinic treatment, so I think this is going to enroll very fast as we launch it. And I think just looking at, you know, even your DME program, you know, we had patients waiting because it enrolled the initial cohort so fast. So I am excited, you know, about that fact that physicians are excited because we all have these patients that have a very high treatment burden, and they want to do anything to eliminate that. Great. Thank you, and congrats again on the data. Thank you. Our next question comes from Lisa Walter from RBC. Oh, great. Thanks for taking our questions, and, congrats again on, on the data. So, first one, we have seen one of your competitors at Barclays this morning doing a PIPE, and their data is obviously coming on, on Thursday. Just wondering, what are your expectations for that data, and how are you thinking about, differentiation versus them? Any color on, on that much appreciated. Thanks, Lisa. You know, we're confident that our therapy has shown a high degree of safety with a very clean safety profile. We think that's why we're getting such great high rates of enrollment, and why we achieved both RMAT and PRIME designation. We believe we're the only ophthalmology asset to ever have those two designations. So we're very excited about the future and operationalizing phase III. We don't worry so much about our competition here. We think our product speaks for itself. We think we're the only product that's shown this kind of activity in this patient population with very severe disease activity and a high treatment burden, and we think it's highly differentiated product profile. Thank you for the question. Oh, got it. I have 1 follow-up. Just on your phase III, I know you've already flagged that 2 mg aflibercept once every 8 weeks is a possible control arm, which is in line with the FDA's guidance document. But given how standard of care is evolving, I'm wondering if you are also considering Vabysmo or Eylea HD as the control as well? Yeah, we're comfortable with the standard Eylea. It's very clear from FDA feedback and EMA feedback that that's an acceptable and appropriate regimen. And I'll turn it over to Bob Kim, our CMO. Yeah. So the non-inferiority margin, it's like the antibiotic problem. You need a reference drug, and so the agency has designated, you know, ranibizumab and aflibercept as reference drugs, where there's a non-inferiority margin established of four point- you know, about 4.5 letters. The problem is, drugs that follow are non-inferior to one of those drugs, and what the agency tries to avoid is non-inferiority to non-inferiority, stacking non-inferiority. So at the moment, we're not aware that there's any non-inferiority margin established, for example, for Vabysmo or high-dose Eylea, so we have to work with one of those reference drugs at the moment. Got it. Thanks for taking our questions. Our next question comes from Josh Schimmer from Cantor Fitzgerald. Hey, thanks for taking the follow-up. So, during the conference session, a couple of times, the idea of home OCT monitoring came up. Just curious, to better understand what would be involved with home OCT monitoring and how feasible you think that will ultimately prove to be, and what timelines there might be for that becoming an option for patients? Thanks, Josh. Arshad, you want to take that one? Yeah, absolutely. So, you know, in a prospective clinical phase III study, you want to see those patients, you know, on a routine monthly basis in most cases. I think home OCT, OCT is exciting, but I think, you know, that's something that can be done in long-term follow-up studies or as a sub-study in the phase III. So, you know, we still need the OCT data. We still need to do the examination of the patient. So home OCT is exciting, but it's not, you know, something that is utilized in pivotal studies as a primary modality to monitor fluid, but rather more in the extension phase or as a sub-study to look at utility. And as you know, a large DRCR trial is happening, looking at the use of home OCT. Now, once this product is commercialized, absolutely. I think the goal would be that we know that patients, majority of them will not need injections, so if a patient gets one treatment and is doing well, they can monitor themselves with home OCT, and as soon as if there's any activity, we can call them back in clinic. So that's going to reduce the treatment burden even more, and that's why sustained delivery and gene therapy is very exciting because you can use home OCT to kind of even decrease the burden even more, and I think that will lead to better and stable visual outcomes in the real world for our patients. So very exciting idea. So would there be expensive equipment that patients need to have at home? How would they be trained to use the device appropriately? ... Yeah, so those are questions that are out of the context for this, but we are doing those in sub-studies and other programs where the company that makes that OCT trains and sends the equipment. So not part of, you know, this discussion, and I think they have their own validating studies going on to get home OCT approved. So that would be some discussion that will be more geared towards that company's planning. But here, I think, you know, we see a sustained delivery effect, which will decrease treatment burden, and any technology we can use to decrease treatment burden in combination of gene therapy is very exciting. Thank you. For our final question, we'll return to Mani Foroohar from Leerink. Thanks, guys. I think there's been a lot of debate around, as mentioned, some of the ways this market could evolve with home OCT. Can we talk about presuming that it, that does not result in a broad shift in the market, and practice patterns continue to look kind of like what they look like now, how frequently would patients be brought back into the clinic, based upon this product profile? Arshad? Yeah, absolutely. So I think, you know, home OCT is not going to change, you know, the number of anti-VEGF injections that we are giving with Vabysmo or high-dose Eylea. It is going to help patients who have already received gene therapy or sustained delivery to even come less often to our clinic. So I think in terms of, you know, utilization of gene therapy is not going to change. Remember, home OCT is just showing fluid accumulation at a nanoliter level, and then you can bring those patients in. So I don't expect clinical decision-making changing because of home OCT, but rather decreasing treatment burden for our patients who are utilizing sustained delivery. But if a patient needs to come in every month or every two months to get their bolus anti-VEGF injections, home OCT is not going to change it. In terms of, like, how often I'm going to follow these patients, obviously, I'd like to follow them during their steroid taper stage, and then at that time, we'll be collecting OCT data and then seeing how the disease is stabilized. I'm very confident that once the disease is stable in the first 4-6 months after getting 4D-150, then I think you can kind of you know, find which patients need to come to clinic or, or not, and majority of them will not require to come in clinic. And at that time, we can launch home OCT to kind of, you know, let the patient monitor and then, you know, bring them in when the fluid accumulates. So, I think this will really help patients come in very minimally to our clinic because of the sustained delivery that we are seeing and sustained disease control. And then, you know, I think physicians will independently, you know, based on their specific patient, individualize the follow-up. But I do see significant decrease in treatment burden utilizing home OCT once the patient is stable and well-controlled with 4D-150. Great. That's really helpful. Congrats again, guys. Thank you. There are no more questions in the queue. I would like to hand the call back over to Dr. David Kirn for closing remarks. Thank you, operator, and thank you to all of our analysts for the excellent questions today and really stimulating discussion. Thank you to the audience and also to our 4DMT team for participating today. In summary, we're very excited about 4D-150 and its ability to potentially disrupt and transform the wet AMD market. We see clean safety and now approximately 110 patients treated to date, a high degree of efficacy in severe disease activity and high treatment burden patients, and we're excited to be operationalizing the phase 3 clinical trial for initiation in Q1 2025. Our goal has been to disrupt and transform the treatment of wet AMD, and we think that this 4D-150 data to date gives us confidence that we're on that track, and we'll make that a reality for patients. Thank you all for your time, and again, thank you, Dr. Khanani, for your support today in this call.