Hello, ladies and gentlemen. Thank you for standing by, and welcome to 4D Molecular Therapeutics' 4D-150 Wet AMD Development Day. 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 all for joining us for our 4D-150 Wet AMD Development Day webcast this afternoon. We have an exciting day ahead of us, so thank you again for your attention and support. 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 or our SEC filings. With that, it is my pleasure to hand it over to Dr. David Kirn, our Co-founder and Chief Executive Officer. David? Thanks, Uneek. Good afternoon, and thank you for joining us today. Our team is thrilled to share long-term safety and efficacy data from all patient cohorts in the PRISM trial and our plans for the phase III development program. We also have a world-class group of retina specialists here to discuss the data phase III plans and to answer your questions. Here's our agenda, which should take about ninety minutes to get through items one through nine, and the remainder of the time is for your questions and answers. Genetic medicines have historically been focused on patients with severe and rare diseases. At 4DMT, we believe that our genetic medicines can be transformative for large market diseases, including for all patients with wet AMD. The results we'll share with you today have validated this vision. Here are the key takeaways for today. First, we've observed robust and durable clinical activity in all wet AMD populations studied to date. Second, safety and tolerability data continues to be outstanding, with the profile to date in line with approved anti-VEGF agents on the market. Finally, our phase III trial is designed to maximize the probability of clinical, regulatory, and commercial success. Now, to our first key efficacy takeaway, I will now share top-line efficacy in three wet AMD populations. First, the most severe and long disease duration patients in Phase I/II- A. Second, a broad wet AMD population typical of busy retina clinics in our phase II- B, and finishing with relatively recently diagnosed patients from phase II- B, in which anti-VEGF agents are typically most effective. In wet AMD, the impact of anti-VEGF agents depends on the population studied, which is typically newly diagnosed phase III, and we've confirmed a similar profile with 4D-150. For our first patient group, PRISM phase I, II-A, enrolled one of the most severe and long disease duration patient populations ever tested in wet AMD. We were nevertheless able to show an 83% reduction in annualized injections. Since these patients had received roughly 10 injections on average in the preceding year, an 83% reduction translates to a decrease of eight injections down to only two over the entire year. So patient burden was clearly significantly reduced. Importantly for proof of concept, a strong dose response was evident in favor of the high dose of 3E10. In addition, 44% of these highest-need patients were injection-free after a year. Now, let's put this into context in the real world. Beovu is a blockbuster therapy. In a treatment-naïve and newly diagnosed population, Beovu was only able to get the same percentage of patients to every 16-week dosing versus 52 weeks in our population of much more severe patients. If these data were replicated in the real world, 4D-150 would be a transformative and paradigm-shifting therapy for severe wet AMD patients. In addition, in this population, we've shown that the patients with the most intact retinal function and integrity, as evidenced by retained visual acuity, had an injection-free rate of 64% at 52 weeks. This finding is consisten with 4D-150's mechanism of action. Finally, our 3 longest-term phase I patients remain injection-free over roughly two and a half to 3 years after 4D-150, and their aqueous humor aflibercept levels remained detectable and stable at all time points over 2 years of measurements. In summary, 4D-150 has clear and compelling clinical activity in the most severe patients ever tested in this field. Together with a compelling tolerability phase II-b testing was warranted in a broad population of wet AMD patients. phase II-b, we enrolled such a broad wet AMD population, including recently diagnosed and severe disease patients. As expected, the injection-free rate increased when we moved to this broad population. 70% of patients were injection-free through 52 weeks based on Kaplan-Meier estimates, with an additional 10% who needed only one injection through 52 weeks. Finally, as expected, when we focus on the 50% of patients in phase II-b who were diagnosed within the preceding six months, we see an injection-free rate of 87% through 52 weeks, based on Kaplan-Meier estimates. The other two patients each received only a single injection to date. In summary, we showed clear clinical activity in all wet AMD population studies to date, and as predicted, the injection- free rate correlates strongly with disease severity and duration. Now to discuss the safety profile of 4D-150. The efficacy we've shown would be irrelevant without a compelling safety profile. To date, our investigators have been pleased with the tolerability of 4D-150 to date, with an intraocular inflammation rate that's numerically similar to what's been reported with Eylea itself, plus other approved anti-VEGF products. So based on these findings, we're moving phase III development. Phase III design has been informed by multiple inputs, including our outstanding data from PRISM and our collaboration with both the FDA and EMA, afforded by our RMAT and PRIME designations. Key design features will be reviewed today, including the enrollment of newly diagnosed and treatment-naïve patients. Now, successful development of novel retina therapeutics requires close collaboration with global experts in the field, and we're pleased to have recently announced the formation of our Ophthalmology Advisory Board, comprised of world-renowned retina specialists and thought leaders. As we scale 4DMT, we've successfully established ourselves as a platform and a product company with a diverse portfolio of product candidates. In this next phase, we believe we can become the global leader in genetic medicines for large market ophthalmology. Towards this goal, we've recently expanded our internal team as phase III and plan for com mercialization. I'm deeply gratified to have hired four biopharmaceutical leaders with deep retina expertise in all phases of the product life cycle, including clinical development, medical affairs, and commercialization. Now, in addition to our CMO, Bob Kim, we have a team that has been directly involved with, and in most cases, led the development and approval of every recent major retina product in AMD, with the exception of EYLEA. This team has also been involved in the commercialization of five major products, including Lucentis, Beovu, Izervay, Vabysmo, and Susvimo. Our most recent hires are Dhaval Desai, our Chief Development Officer, Chris Sims, our Chief Commercial Officer, and Carlos Quezada-Ruiz, our SVP and Therapeutic Area Head for Ophthalmology. Our ability to recruit these talented and experienced executives is a testament to what we've built at 4DMT and to our clinical data with 4D-150. Today, you'll hear from both our internal team and our world-class retina specialists, Dr. Arshad Khanani from Sierra Eye Associates in Reno, Nevada, Dr. Carl Regillo from Wills Eye Hospital in Philadelphia, and Dr. Dante Pieramici from California Retina Consultants in Santa Barbara, California. I'd like to thank each of them for taking time to be here with us today. Now, I'd like to introduce Carlos Quezada-Ruiz, who will speak to unmet needs in wet AMD and to how 4D-150 is designed to address these unmet patient needs. Carlos? Thank you, David, and good day, everyone. Despite the introduction and availability of anti-VEGF agents, age-related macular degeneration is still a leading cause of visual impairment. The issue remains that real-world patients are not clinical trial patients. Life happens to them, and it is unlikely to receive treatment in the frequency and consistency required to achieve and sustain the visual gains seen in clinical trials, like MARINA for Lucentis, shown here. The real-world ORBIT study shows us that the patients don't get treated as frequently and consistently in the real world, and subsequently lose vision over time due to the inconsistency, infreq uency, and therefore, the low number of injections that patients receive in the real world. In SHORE, currently available treatment options have limitations, and patients are not able to keep up with th eir injections. Based on the gap between pivotal trials and the real-world data that we see, it is clear that extended durabilit y is the major unmet need for our patients, and therefore, it's imperative to preserve the initial vision gains with a therapy that can potentially solve for those adherence challenges. The American Society of Retina Specialists Preference and Trend Survey, also known as the PAT Survey, is conducted annually and assesses the preference of its members on a variety of medical, surgical, and socioeconomic topics around the world and in the U.S. This survey has been conducted since nineteen ninety-nine, and in two thousand and eighteen, this survey showed results that long-acting, sustained delivery and/or reduced treatment burden were the greatest unmet need in the management of wet AMD. A lot has happened between then and now, including the approvals for longer duration, second-generation anti-VEGF agents. Despite that, in this year's PAT Survey, we see that the safe and durable therapies that reduce treatment burden again rank as the top unmet need for retina specialists, and patients also prefer getting fewer injections, by the way. So it is clear that from the patient and physician perspective, the ideal therapy to bridge the gap between the visual outcomes seen in clinical trials versus those seen in the real world, has to have at least three characteristics: First and foremost, it must align with one of our maxims in medicine, primum non nocere [foreign language], which means first, do no harm. This therapy has to have a favorable safety profile and comparable to, or even better to those of our current standard of care. Secondly, we would like to see visual outcomes that are equal to or better than those achieved by our current standard of care, with robust reductions in the treatment burden and long-term durability. And we believe all of this in a therapy would result in the potential for extended vision preservation. And finally, the ability to be delivered through a simple, safe, and reliable route of administration, such as that intravitreal injections offer, would make it ideal. And based on the totality of the data to date, the proven mechanism of action of aflibercept, and the ease of administration, we believe that 4D-150 has the potential to be this ideal therapeutic, bridging the gap between clinical trials and the real world, effectively improving and maintaining vision long-term for all wet AMD patients. 4D-150 was designed to deliver a dual transgene to the retina to continuously express aflibercept, a very well-known and established anti-VEGF agent with more than a decade of clinical experience across multiple retinal diseases. In addition, the transgene payload also has an inhibitory RNA molecule that prevents retinal cell production of VEGF-C, another known pro-angiogenic factor. This product candidate is our lead asset and forms the foundation of our ophthalmology franchise. Here you see our ophthalmology pipeline tackling the most common retinal diseases impacting patients around the world. We're working diligently to advance phase III with a 4FRONT global development program in wet AMD, which will begin in the Q1 of 2025. This will then be followed by our diabetic eye disease program, currently in diabetic macular edema, with our SPECTRA study shown here. Finally, we're really excited to keep expanding the R100 platform to benefit patients with retinal diseases with our 4D-175 program entering clinic later this year for the treatment of Geographic Atrophy. With that, I will hand it over to my dear colleague, mentor, and one of the best ophthalmology drug development experts of our time, Dr. Robert Kim, our Chief Medical Officer. Thank you, Carlos. I'd like to start by reminding everyone that anti-VEGF treatment needs in the wet AMD population are very heterogeneous. This is illustrated by the Lucentis HARBOR study, in which wet AMD patients were followed for two years with criteria-driven PRN treatment following three monthly loading doses. Patients on the right had high anti-VEGF needs, requiring up to twenty-four injections in twenty-four months, while patients on the left had lower needs, requiring as few as three injections over twenty-four months. Since 4D-150 is a novel genetic medicine, phase I and IIa development began in the high-need population to adequately balance benefit-risk. In terms of outcome, we were anticipating effective maintenance of disease control, as these patients had received an average of ten injections in the year prior to enrollment in PRISM. The reason for the maintenance expectation is that significant visual acuity gains and CST reductions are typically seen after the first three injections of anti-VEGF treatment, but these patients were all well past that point. As we gained experience and increased confidence in the safety and efficacy profile of 4D-150, we moved into a broader population, more representative of the typical patient mix seen in retina clinics. phase II-b of PRISM, we expected more recently diagnosed patients to show improvements in both BCVA and CST reduction, depending on how many prior anti-VEGF injections they had received, which could be as few as just one injection. This brings us to where we are today, on the brink phase III, about three years since the first patient was dosed with 4D-150 at the end of 2021. Over the course of 2024, we've shared landmark analyses from different phases of the PRISM study and are excited to share extended follow-up data with you today. At this point, I'd like to hand things over to Dhaval, who will share with you extended follow-up data from the PRISM study. Dhaval? Thanks, Bob, and good afternoon, everyone. You've heard from David and Bob around the methodology for PRISM. To quickly recap, in the phase I/II-A program, our aim was to establish an initial safety profile for 4D-150, obtain any signals of efficacy, and determine doses for the next phase of study. Once these had been established, we wanted to take the opportunity to further define the efficacy and safety profile in a broader wet AMD population, which included more recently diagnosed patients. Additionally, we wanted to determine dose and refine the patient population for our registrational program. Secondary to the strongest dose response seen between 1E10 and 3E10, we have confirmed 3E10 as the dose to phase III. as such, the focus of the data presentation will be on 3E 10. The 1E10 data can be found in the appendix of the deck, which we have released on our investor website. Before we get into the specifics of the data, I wanted to take a moment and level set on response to anti-VEGF therapy in wet AMD. Here, you see CST curves from three registrational studies in treatment-naïve wet AMD that utilize aflibercept 2Q8 as one of the study arms. In all three studies, the initial anti-VEGF injection provides a majority of the anatomic benefit seen over the course of fifty-two weeks, highlighted here by the red circles. All subsequent injections provide nominal additional benefit and serve to primarily maintain the gains seen with the initial injection. This is reinforced phase III ARCHWAY trial that studied Susvimo, which is designed to provide continuous delivery of anti-VEGF in previously treated patients with wet AMD. The results show that maintenance of retinal anatomy is the clinically relevant anatomic outcome for this pretreated wet AMD patient population, showing no change in CST from baseline. You've heard already that population matters when it comes to wet AMD studies. This slide provides an overview of the difference between the populations enrolled in PRISM and those enrolled phase III wet amd studies. Patients in the early phases of PRISM are even more advanced and have seen more pretreatment than ARCHWAY, the largest treatment experience study in wet AMD. In contrast, phase II-b patient population, while less severe than the phase I/II- A, is still more in line with ARCHWAY as compared to any of the treatment-naïve programs. Based on pretreatment history of all patients in the PRISM study, we would expect a response that more closely mirrors ARCHWAY for the maintenance phase of treatment in naïve wet AMD studies. Moving on to results from the PRISM program, the phase I/II-A analysis will provide all available data points for patients enrolled in the 3E10 and aflibercept arms. The data becomes more variable towards the end of the BCVA and CST curves, secondary to variable follow-up, as some patients have yet to reach these milestone visits. This is indicated by the gray box, and the number of patients evaluable at those corresponding time points are provided. Here are the swim lane plots for the phase I/II-A patients for PRISM for 3E10 and aflibercept 2Q8, both of whom were eligible to receive supplemental injections based on pre-specified criteria. Patients in the 3E10 group received an average of 10 injections in the year prior to enrolling in PRISM, as compared to the aflibercept comparator, which received nine. In this heavily pretreated population, we saw a reduction in annualized injections of 83% in the 3E10 group, which translates to a reduction of eight injections per year. In contrast, the aflibercept group showed only a 28% reduction. In addition, 44% of these patients at 52 weeks required no injection after receiving 4D-150. Over half of all patients needed zero or one injection, and three quarters needed only up to two injections in the 52 weeks after receiving 4D-150. CST data from all patients at all time points show sustained anatomic control, with 4D-150 equivalent to aflibercept dosed every eight weeks, with fewer 50-micron or greater fluctuations over the longest follow-up available. This degree of variability in CST has been shown in published papers to result in worse long-term visual acuity outcomes. At week 56, the last time point where data is available for all patients, the CST curves have converged at roughly minus 55 microns from baseline. As previously mentioned, the aflibercept arm was allowed to and did receive supplemental injection. This is in contrast phase III amd studies, which did not allow for any supplemental injections in the 2Q8 aflibercept control arms. Visual acuity data from all patients at all time points with 4D-150 is comparable to aflibercept 2Q8 over the longest follow-up available. In these hardest to treat patients, we see a clinically significant annualized reduction of 83% in the number of injections needed to control disease. In addition, half of these patients needed at maximum one injection over the course of 52 weeks, and 44% needed no injection over that same time period. phase II-b clinical analysis will provide all available data points for patients enrolled in the 3E10 arm. Similar to the phase I/II-A, the data becomes more variable towards the end of the BCVA and CST curves, secondary to variable follow-up, as some patients have yet to reach these milestone visits. Again, this time frame is indicated by the gray box, and the number of evaluable patients at the corresponding time points are provided. Here is the swim lane plots for phase II-b patients from PRISM. As previously stated, patients in the 3E10 group received an average of four injections in the year prior to enrolling in PRISM, with roughly one-third having only received one injection prior to enrollment. Additionally, half of the patients were diagnosed within six months of screening. In this broader population, at week 32, where data was available for all patients, 73% of these patients remained injection-free, with 93% needing at maximum one supplemental injection. Kaplan-Meier estimates for these outcomes at one year are 70% injection-free and 80% needing at maximum one injection. CST data from all patients at all available time points shows sustained anatomic control, with 41/50 starting week 24 with minimal fluctuation. The slight inflection of the CST curve at week 36 is driven in part by three injection-free patients that have not reached or missed the week 36 visit, as well as three patients which received supplemental injection. Visual acuity data from all patients at all available time points shows stable visual acuity through week 32. Additionally, the shape of the visual acuity curve up to week 32 is more similar to what we would expect in phase III population. As noted in the previous slide, variability exists towards the end of the visual acuity curve with one patient at week 52. This patient shows anatomic stability as compared to week one, with no notable ocular adverse events. As would be expected, patient population matters. In this broad population that is less heavily pretreated and closer to the time of diagnosis, the proportion of patients requiring a maximum of one injection is 80%, and the proportion that needed no supplemental injections over the 52-week time period following 4D-150 administration is 70% by Kaplan-Meier estimate. In an effort to further characterize the impact of time since diagnosis of disease on 4D-150 efficacy, we analyzed patients who were within six months of their wet AMD diagnosis. 50% of patients in the phase IIb met this criteria. The subset of patients who met the criteria are shown in this swim lane plot, two-thirds of which had only received one injection prior to enrollment in PRISM. What you can see in this data is a continuation of the concept that population matters. The injection-free rate in these patients with recently diagnosed disease is 87% at week 32, where data is available for all patients. None of these patients needed more than one injection to control disease over a follow-up of up to 52 weeks. One of the subjects that received supplemental injections did not meet the supplemental criteria and has not received a subsequent supplemental injection out to the latest follow-up at week 44. As expected, the CST curves in these patients remain stable throughout the course of follow-up. The same is true with the BCVA curve in these patients, which remained stable throughout the course of follow-up. The patient at week 52 is the same patient previously mentioned who had stable CST. Finally, in the dark bar, we see that as more recently diagnosed disease is treated, the proportion of patients that need minimal to no supplemental injections through week fifty-two increases. We know that efficacy is only enabled by safety in wet AMD. We'll now present the safety data for both 3E10 and 1E10 in wet AMD, with follow-up through up to one hundred and thirty weeks. On this slide, we see every patient enrolled in the 3E10 dose in wet AMD, including the phase I, II-A, phase II-b, and alternate steroid cohort. On the left-hand side of the slide, you will see anterior chamber results, and on the right-hand side of the slide, you will see vitreous chamber results. The two 4D-150-related IOI events in the 3E10 dose can be seen on the right-hand side as light green boxes that represent mild, transient, one plus vitreous cell. Additionally, there are two cases of non-4D-150-related findings. The first can be found in the top row of the left-hand side, representing three plus AC cell, which occurred post-cataract surgery and is a known complication. The second is a red box on the left-hand side, representing four plus AC cell associated with a suspected bacterial endophthalmitis post-supplemental aflibercept injection. In conjunction, this patient also had two plus vitreous cell, as seen on the right-hand side. Neither event is related to 4D-150. The patient was treated as a suspected bacterial endophthalmitis with tap and inject, resolved quickly, and at last follow-up at 104 weeks is plus 12 letters in BCVA from baseline. Here, we provide the 1E10 dose. On the left-hand side, in addition to the previously reported one plus AC cell, there is one new case of one plus AC cell post-cataract surgery, which resolved the following visit without treatment. On the right-hand side, follow-up is provided from a previously reported patient with two to three plus cell, according to the investigator, and a complex past medical history, including a positive medical history for multiple infections that can cause uveitis. The patient continues to be monitored and was treated empirically for presumptive bacterial and viral causes of uveitis, as well as additional corticosteroids. In conclusion, 4D-150 remains well-tolerated across all populations, with no 4D-150-related serious adverse events. 2.8% of patients receiving the 3E10 dose in AMD experienced mild, transient 4D-150-related IOI events, a rate that is numerically phase III results of standard of care anti-VEGF agents. Importantly, 99% of patients were able to complete their steroid taper on time, with 97% not needing to resume. No patient had 4D-150-related hypotony, endophthalmitis, vasculitis, choroidal effusions, or retinal artery occlusion. And finally, no DME patients have experienced IOI events to date. In summary, we believe with the longest follow-up available, through 130 weeks across multiple populations, that 4D-150 has shown a robust and durable treatment burden reduction, strong and sustained anatomic control of CST with fewer fluctuations of greater than 50 microns, commonly seen with standard of care anti-VEGF. BCVA remained stable or even improved, dependent on the population treated. All of this when maintaining a well-tolerated and favorable IOI profile, which is numerically phase III results from approved anti-VEGF. Based on all of the collective data, we are excited to be rapidly moving forty-one phase III development. i'd now like to welcome our panel of retinal experts for a discussion of the data from the PRISM study. Thank you for joining us today, gentlemen. It's a pleasure to have all of you with us. Carl, Dante, Arshad, welcome to the 4D-150 Wet AMD Development Day. Before we get into the data, I'd like to maybe just get your thoughts on this concept of the pretreated AMD population and the types of response one would expect. Arshad, maybe I'll give you that one first. Yeah, Dhaval thanks for having me here. I think we know that patients who receive frequent injections and still have fluid, those are the hardest one to treat in our clinic. And I think the main thing is that these are the patients who are desperate to decrease their treatment burden, whether it means one injection, two injection, three injections. And as we know, with the newest agent, based on our TRUCKEE study, also, when we switched those patients to faricimab, they added a week or so after switching to faricimab. So these are the highest-need patients, and about 15% to 20% of our patients in our clinic. Going into gene therapy for that patient population, well, the reason was that we had some setbacks with other programs, and we wanted to make sure that we take the severest of the patient population to get a biological activity signal and, of course, establish safety. So I think these are the worst of the worst patients, highest need, and I think seeing the results you showed today is very promising, confirming the activity of 4D-150 in these tough-to-treat patients. Yeah. Thanks, Arshad. Carl, you're actually the senior author on the ARCHWAY paper, which is kind of the biggest study we've seen in pretreated patients. Thoughts just around kind of treating these patients that have been heavily pretreated or even mildly pretreated, seeing four to five injections like they did in ARCHWAY? Yeah. ARCHWAY is the port phase III study, and it was very different pretreated patient population. It was recently diagnosed, and in fact, all the studies with PDS, phase II LADDER phase III ARCHWAY, honed in on recently diagnosed, previously treated within a nine-month timeframe. So those patients had just gone beyond their typical loading, three, four injections, to get them dry and get their visual acuity to the best it's going to be. And PDS did a very good job over refilling every six months, maintaining that disease control and the visual acuity at baseline. That's very different than the patient population that Arshad just described, and that's the types of patients enrolled in actually all the gene therapy and all the TKI programs to date at the phase I, II level, which is heavily pretreated over typically years. And so you're going to get the worst of the worst with that. You're going to get high-need patients, that is, needing high levels of drug to maintain control or even potentially suboptimal responders and maybe even some severe cases that could be even classified as burnt out. Now, that's not usually the case, but as Arshad mentioned, the patients that are selected to be enrolled in your Phase I/II-A, for example, are those motivated to reduce the treatment burden, even just a little bit because they're getting frequently treated they're getting treatment so frequently every four, five, six weeks, which is really tough for patients to do in the real world. So, that degree of reduction was really good, and I thought it was very impressive. Again, with Archway, the point was made, that's more of an all-comers patient population, so that has that, as Arshad said, 15% to 20% of high need mixed in there, but the majority is not high need, and so they don't need as high of a level to maintain control. Yeah, thanks, bud. Dante, anything additional from you on that? My colleagues have said it very well. Again, this is a chronic high-need population of patients that you selected, and you were able to really maintain visual acuity, maintain the OCTs in these patients, so that's the goal at this point. I mean, people seem to be under the impression at times that we need to show some visual improvement and reduction in OCT, but we've really pretty much squeezed all that out of these patients already. The goal really is to maintain these indices, particularly the visual acuity, and I think you showed that very well, even in this really difficult-to-treat population. Had we not treated this population with 4D-150 or an intravitreal injection, they would have lost vision. They would have gained OCT thickness over time. You know, the results that you've shown, particularly in this patient population, are remarkable, in my opinion. Yeah. Thanks, Dante. Maybe I'll just stay with you there as we turn to the data. You know, there's this belief out there that, like, at least 50% of patients in the phase I/II-A needed to be injection-free for this to be viable. You know, can you just give me your thoughts on the data that was presented, specifically, you know, the 44% injection-free rate, the 83% reduction in injection burden, what that means to you as a clinician for this population, and maybe even what that means for your patients that kind of fit that profile? Yeah, I think these are excellent outcomes. I mean, again, had we stopped treating these patients, they would have very shortly needed additional treatment. And in this population of patients, get 44% who didn't need any further supplemental therapy over the course of the follow-up is really a home run. That's remarkable. I mean, you know, these are very, again, very frequently injected patients, and to get that many patients at a one-and-done. You know, I think we all always think of gene therapy as one and done, and that may be because of inherited retinal diseases, we're going to fix the patient, but this is gene therapy for drug delivery. So getting these home-run cases in this difficult-to-treat population is really pretty remarkable, in my opinion. But even more importantly, again, the goal here is a significant reduction in the treatment burden, and you have 80-plus% of patients, or 80-plus% reduction in treatment burden in these patients with, you know, half needing only one injection. So again, this is, I think, very much speaks for the power of this agent in even the worst or most difficult, most anti-VEGF-needing patient population. So, yeah, I think this is impressive results in this population, and it even looks better as we go to the more naive patients. Yeah, thanks, Dante. Additional thoughts, Carl? No, I agree entirely. The higher the need, the more frequent the injection frequency is to maintain disease control. I don't expect many of those patients to go injection-free. We're delivering a drug level that's going to be adequate for most patients in the all-comers group, but, you know, I think you're lucky, and 30, 40, 50% all-comers is in a very acceptable range for to be injection-free. That is one and done, which is very impressive. It's very attractive for patients, of course, and everyone's going to want to be that one and done, but the reality is, most people are not, if you're selecting only the very highest need. Of course, as you get into an all-comers, you expect that percentage to rise, and it will, because you're going to deliver an adequate drug level that will potentially control, with a one and done for many patients, so maybe as you expand the patient population, such as in your II-B, and you showed that. I may be jumping ahead, but you showed it. Yeah, and Arshad, maybe, can I ask you to comment, not necessarily from the retina physician perspective, but for your patients in clinic that are like this, that kind of look like these patients, can you talk about the acceptance rate of any agent that has this sort of profile? I think, you know, the main thing, just as you said, that population matters, and you know, we dosed the first patient with 4D-150 in the phase 1 study, and I'll tell you that these patients would do anything to get less injections, as I said, and I think there's a disconnect in that sense, where there is this idea of one and done and cure, which is an additive bonus. We're still going to monitor these patients, even if they don't go injection-free. I think in my clinic, there's about 15% to 20%, as I said, of patients that are super high need, and I think every single one. We actually screened a lot more than we recruited, and the reason for that was they didn't qualify because we were looking not only for worst of the worst, but the worst of the worst with certain CST criteria. So many screen failed, even if they were getting significant number of injections. I think this discussion about one and done has to be delivered with gene therapy. Well, I think it's an additive bonus, but we are still going to monitor these patients. I think every single patient that is coming in our clinic and getting of Vabysmo or even EYLEA HD, very frequently will be interested in this therapy. I think the key here is that it's all about safety with sustained delivery approaches, and if the safety is comparable to intravitreal routine injection, I think that's a huge benefit because that expands the patient population from not, not just the high-need patient population, but to broader patient population. I think if the gene therapy is not safe, then you're gonna leave it for the toughest of the toughest patients because they rather have the risk-benefit profile of, "Well, I'd rather not come in, get an injection every month, but be on drops for a long time. But here, that's not the case. So I think this data actually is very relevant because obviously it's a safety data set with good efficacy profile, which moves that patient population to a much broader patient in my clinic. Yeah, that's great. Thanks, guys, we appreciate it. Moving maybe quickly to phase II-b, can I just maybe get your thoughts on the data in this broader population, and what type of result would you expect here to be considered compelling in terms of injection-free, in terms of patients needing zero and one injection? Carl, maybe I'll hand it to you to lead us off here. Yeah, in fact, you said it in your presentation. This is a broader patient population of a heterogeneous disease, and so you've got a mix of high need and a mix of moderate need, and maybe even a few low needs because you had some patients that just had one prior injection. You don't know where those ultimately would lie in practice, right? So you would expect much better results, much higher rate of reducing the treatment burden, but in particular, a much higher rate in injection-free, and that's exactly what you got. You know, the burden wasn't as high, so you can only reduce that so much, but the injection-free rate went way up and is exactly what I would have predicted, and I'm sure everyone is not surprised to see how much better the drug or the therapy shines in this broader patient population. In fact, I think it was said in the talk that it is more in line with what we, the types of patients we enrolled in LADDER and ARCHWAY with the Port Delivery System, because it's a shorter timeframe of patients being treated and your analysis of six months, diagnosed within six months, is really tremendous, exactly as you would expect. That's in all comers if you enroll treatment-naive patients at this point. And then, Dante, maybe, like, again, same question: What would you find compelling here? Is it, is it kind of what we've seen? Do you want to see more? Is it not necessarily that high? No, no, I mean, I think the results you have as they stand are very compelling. And I agree, as we're migrating from the chronic patients to the more naive-like patients, we're getting even better results. You know, 70% of the patients injection-free over the follow-up period, with higher percentage, with lower needs. And you know, this is pretty typical, too, migrating the populations. I think that, you know, in the LADDER trial, they did have more naive patients, but they were less naive than in the ARCHWAY trial, and so there's been a migration in a number of the clinical trials for other gene therapies as well. And again, you start with a more difficult population because you want to make sure that it's safe, and as it appears to be safe, then I think we feel more comfortable moving towards the more naive patients. And I think that's exactly what we're doing here, and we've seen that with the tyrosine kinase inhibitors. We've seen that with other gene therapies and even the Port Delivery System. Again, the LADDER patients were more chronic than the ARCHWAY patients. And moving the ball towards the more naive patients, we would expect even better results with better durability and hopefully maintaining the safety, which is what we've seen here so far. Yeah, and we'll get to safety in just a moment, Arshad. But before we do, maybe I'll just give you a chance to comment on kind of what you expect and what you would consider a compelling result in this sort of population. I think, you know, as said by Carl and Dante, I mean, this is a very powerful result where you can say, on average, every patient that comes in, in your clinic with new wet AMD, you can tell them that, you know, if this pans phase III, you know, a significant reduction in treatment burden and majority of the patients being injection-free, I think that makes this product utilized in essentially, you know, a large number of patients in our clinic. And as I said, as long as the safety continues to look good, which we have seen to date. But I wanted to make one more point, Dhaval, is we're talking a lot about the port delivery system, right? Dante, Carl, and I are very closely involved because we believe that sustained delivery leads to better anatomic control, less CST fluctuations, and we know the data from many different trials showing the CST fluctuations greater than fifty microns actually end up damaging vision long term. So, you know, I was curious to compare this. You know, look at what, you know, the ARCHWAY and LADDER trials have shown. So as you remember, CST was used in ARCHWAY, which is center point thickness, which excludes the PEDs. If you look at the LADDER phase II paper by Campochiaro, and, you know, I published the end of the result paper. If you look at the LADDER paper, there were two CST graphs that you have seen, and one is with PEDs and one without PEDs. And if you look at the one with PEDs, the CST essentially looks similar to what we have seen. Of course, the comparator there was, you know, ranibizumab. So what I'm saying is that I think the control that we have seen in the data set to date is very comparable to sustained delivery that we have seen in the Port Delivery System. And obviously, this is an intravitreal injection, but of course, this needs to be studied more in phase III. But again, I cannot emphasize the fact that patients are looking for decrease in treatment burden, and that's why we are using a lot of Vabysmo and Eylea HD for that reason, and that burden, even if it's just one or two weeks longer than standard of care, this will shift that much more for those patients. I think as physicians, we're in the you know, business of preventing vision loss and maintaining vision over time, and I think if you have less CST fluctuation, that's where sustained delivery shines, and hopefully, we'll see better outcomes for our patients. That's where our goal is with this kind of treatment. Yeah, and you know, I think all of you kind of made a point on this, and it's a good time to move to that section, that's safety. As we all know, and we kind of lived through the launches of new products and development of new agents, efficacy is only enabled by a good safety profile. And so maybe just one quick comment from all of you on safety, and we know safety is kind of done and measured by two sticks. One is frequency, and the other is severity. And so just high-level thoughts on what you've seen through the program so far, and kind of what you would expect moving forward. Maybe Carl, I'll give you that one first. Sure. You know, I can give you my overall impression is safety looks very good, and it's already been mentioned. Safety is. It's gonna be really important because we have therapies now that work really well, that are very safe. They're just not very durable. And Arshad brought up the great point that sustained delivery is the only thing that's shown good long-term vision outcomes, port delivery four or five years, and visual acuity is maintained beautifully. Fluctuation is not good, and sustained delivery of any type minimizes that, but it's got to be safe, or else we won't use it. Look, case in point, Beovu, you all know it well. Worked better, lasted longer than all the biologics we had before that, but had IOI rates that were over 2x that of; they were about 2x that of Eylea, the control arm, and we never used it. I mean, it was just deemed unacceptable. In gene therapy, as such, we're dealing with here, there is a relatively narrow therapeutic index. You could boost that dose, but you're gonna get more IOI, intraocular inflammation. Right now, I think it's at a very acceptable level. So we wouldn't wanna go higher. Then it's gonna curb utilization in practice and the perception of the product as being unsafe if it goes much higher. I think of IOI in three basic categories. You sort of already mentioned or alluded to. One, severity. We didn't see any severe cases. Severe i n the sense that it needs management, that's intensive, or it can damage the retina and damage the vision, have long-term visual consequences. We don't wanna see that at all, any lingering effects on vision from an IOI event. So that we haven't seen. And the other thing is high frequency, of course. So even mild to moderate, if it's happening at 4%, 5%, 6%, that's probably not gonna be acceptable, 'cause it becomes a nuisance, a management problem that patients and doctors have to deal with. And then, of course, chronic recurrent inflammation is the other problem, potentially with any product at hand. So if you find yourself needing to go back on steroid drops to control inflammation, or you can't taper it off, that becomes an issue that you're gonna get a lot of pushback if that happens in clinical trials, push back in terms of acceptance commercially. Yeah. Great, thanks. Dante, thoughts? Yeah, I mean, Carl, you said it all very nicely, as usual. And yeah, of course, safety is important. And I think that if we look at the data today, 'cause safety is really a long game, too. I mean, it requires thousands and tens of thousands and hundreds of thousands of patients, sometimes before we find something. But if we look at the data to date, I think particularly comparing it to other similar type of therapies, you're doing very well here. There's very low frequency, as Carl mentioned, of anything happening, and the cases that do happen are very easily managed with topical steroids. Of course, everyone's put on a prophylactic steroid, but most, the vast, vast majority of are successfully weaned off this without any rebound or chronic safety event. You know, I'm optimistic, cautiously optimistic, always as a clinician, that as we move forward. But to date, I'd say you look good, and there's nothing holding us back from moving along further based on the safety that we've seen so far. Great. Arshad, last comment on safety? Yeah, I would say that, you know, I see 90-plus patients a day, and I don't have time to manage these patients up and down, and for a long time. So physicians want predictable prophylactic regimen, they want predictable IOI profile, and they want no recurrences or irreversible vision loss. So all the points that Carl and Dante made. And, you know, the reason is this is not any retinal disease with no treatment option where you can, you know, use drops for a long time because patients are desperate. Here, we have great agents, and I think that's where the bar has to be set, is that you have to go low dose, you have to have a vector that's retinotropic, and you need to have a good prophylactic regimen. And then that way, you end up with a very predictable clinical profile that physicians can tell the patients that if you take your drops for 20 weeks or so with this way, you're gonna be fine. And I think we don't wanna be. You know, remember, there's a decrease in treatment burden, there's also visit burden. So even if you are decreasing the treatment burden, which is injections. If you have to monitor a lot of these patients for a really long time, that becomes also not very attractive from busy clinicians like Carl, Dante, and I, so we are really in a situation where we have so many patients, and we just don't have time to deal with, you know, safety events, and that goes with any drug that comes to the market or any platform or any gene therapy. Maybe, Arshad, I'll stay with you in the closing five minutes here to lead us off with one comment. So as you think about 4D-150, what are the key attributes that come to your mind in terms of a potential future option to treat wet AMD? Listen, you know, I've been in the gene therapy space, like Carl and Dante, with all, essentially all programs, and I think gene therapy really is a paradigm shift, and I'm talking about overall gene therapy, not just specifically 4D-150, but gene therapy has had issues in the past, and that's what everybody is concerned about, and it's safety. And so with the safety profile to date, with the efficacy profile that we have seen, where majority of the patients who are, you know, diagnosed recently are essentially injection-free or requiring minimal injection, this profile becomes very attractive. You know, we are getting inundated by GA injections and other things, and having a treatment that's delivered in clinic and that can give efficacy and sustained delivery and disease control over time, I think it becomes very attractive for a large number of patients, in my clinical practice. Dante, maybe you next. Like, key attributes of 4D-150 that you think maybe would set it apart as a future treatment option? Yeah. It's certainly for a gene therapy, I think it's an intravitreal approach, as Arshad's mentioned, so it's an in-office treatment. We're not gonna have to go to the operating room or do a more difficult injection thing. I think, you know, second of all, I think the molecule or the gene therapy, the dual transgene is interesting, and I think it permits the use of lower vector doses, and this is gonna mean safer and less inflammation. And that's maybe why we're seeing that. We're using lower dosages than have been used in some other trials for intravitreal approach, and so we're seeing less inflammation. And maybe it's we're getting the same efficacy or even better efficacy because of this dual transgene, you know, or blocking A, B, and C and D, potentially, in these patients. So I think that that's very intriguing to me. You know, the durability data and the one-and-done data that you've shown so far in these populations, I is very compelling. Okay. Thank you. And then, Carl, maybe just last comment on attributes that you find attractive for potential therapy. Yeah, I think we've honed in on probably the best balance of efficacy and safety here, and others have mentioned it too. Safety is really important, and so going forward, and even jumping ahead phase III into the commercial setting, as long as safety holds up well, you're gonna get an expanded use over time, so we'll start with the frequent flyers. We kind of all talked about that as the most attractive option for patients, but even patients getting current anti-VEGF biologics every eight, ten weeks would be potentially also very interested in this, or any sustained delivery approach, right? We may start with that, as Arshad put it, and he's absolutely right. 15% to 20% of the patients are the, quote, "frequent flyers," but even the middle group, even other patients, you know, you could see it expanding potentially over time. That, that's how we see this playing out, as long as both efficacy and safety hold up as they are, right as we're seeing right now. Excellent. Thank you. Well, gentlemen, I'd like to thank you for being on this panel. We'll talk in just a minute after we've moved on to the next session. Thanks very much, and we'll talk to you soon. I'll now hand the presentation over to Carlos, who will review the phase III program. Thank you, Dhaval. As it was just seen in the data from PRISM, forty-one fifty has shown positive interim data, showing the robust efficacy and safety data for forty-one fifty with extended follow-up. These encouraging results form the foundation of our confidence to be rapidly moving into phase III. Our team brings solid experience in late-stage development, filing, approval, and launch for most of the major anti-VEGF products currently commercially available worldwide, and we've used our collective knowledge, experience, and the totality of the anti-VEGF data to design this trial in partnership with our Ophthalmology Advisory Board and in alignment with the global regulatory guidance for success, building upon our RMAT and PRIME designations. The first study, 4FRONT-1, in our global development program, will initially focus on North America, and our design features, as I'll review in the next slides, have been optimized to first and foremost maximize the probability of meeting the primary endpoint while maintaining a robust reduction in treatment burden and meeting the unmet need. 4FRONT-1 is a non-inferiority trial with the objective of evaluating safety, efficacy, and durability of forty-one fifty, and the primary endpoint will be measured as the mean change in BCVA fro m baseline to week fifty-two. We will enroll treatment-naive wet AMD patients, and patients who show response to aflibercept after the week minus five injection in the loading phase will be randomized to one of the two treatment arms. By requiring a response to aflibercept in the study based on functional and anatomical parameters, this will help us optimize the patient population, maximize the chances of success. 500 patients will be randomized in a one-to-one fashion to either a single dose of 4D-150, or to the comparator arm that will be receiving aflibercept 2 milligrams every eight-week dosing. Once randomized, all patients will then complete their third and final loading dose, and the steroid prophylaxis regimen we're using in 4FRONT will mirror the regimen used in PRISM. Patients randomized in the aflibercept arm will receive sham injections on alternating visits, but will not be eligible to receive supplemental injections. After week 4, patients in the 4D-150 arm will receive sham injections at every visit and will be eligible to receive supplemental aflibercept based on pre-specified criteria. We look forward to study initiation in Q1 of 2025. I will now hand the presentation back to Dhaval for a discussion on our 4FRONT clinical trial design. Thank you very much. Dhaval? Thank you, Carlos, and welcome back, gentlemen. Dante, since I see you first, maybe I'll give you the first question. Can you maybe just talk about your thoughts on using 4D-150 phase III 4front program, treating treatment-naive patients? Yeah, I think the most important thing in migrating towards a more naive population or a completely naive population is that the safety data looks good for this. I mean, you know, we are talking about. Again, when we start these trials, we start in the more difficult patients partly because we want to make sure that it's safe, and it seems to be safe, so I think migrating to this population is very reasonable. The data you've shown us so far, when we go from these very high-need patients to these the more naive patients, as one would expect for reasons that Carl mentioned, we're going to get a better outcome as far as durability. We're going to have a higher percentage, as we've seen, of patients that are one and done or need one or two injections of supplementation over time, and it's just based on the nature of the population of patients. You're going to have a run-in phase here with intravitreal injections, and so I think that this is going to more mimic how things will go down in the real world if the drug becomes commercially available, 'cause people probably aren't going to jump right into a gene therapy. They're going to do some injections, and then offer this to patients. So I think that approach is very reasonable as well. So yeah, I think migrating towards a cleaner population of patients is going to de-risk this study as far as durability. I think the safety makes it reasonable to do this, and we should see visual improvements over the course of the study as these naive patients are given intravitreal injections, and then maintenance, hopefully, of this vision and anatomy in the long run with the 4D-150 kicking in. Yeah, Arshad, to that end, right, maybe one of the things as we were planning this study we thought about is moving to this population, perhaps at the end, will give the numbers that, and the shapes of curves that people are more used to. Any concerns from you in going to the treatment-naive population? No, I think this is the best population to study because, you know, the non-inferiority margin that's required, that the aflibercept has always been studied in the naive patient population. ARCHWAY, remember, the comparator was ranibizumab, and it was a different patient population. And now, based on the regulatory guidance and the potential of these treatment, you know, in a broad patient population, I think this is the right way to go. We expect what we are going to... We can predict what we are going to see. As Dante said, we're going to see visual acuity improvement and maintenance in anatomy and visual acuity with forty-one fifty, hopefully, and with aflibercept, you'll see the CST fluctuations that you usually see with every eight-week aflibercept, and the visual acuity should be, um, you know, comparable. One thing I really like what Dante mentioned was the role of VEGF-C, right? And that data from the COAST and SHORT study will come out next year in terms of, like, how much better it is to block VEGF-C and D on top of, you know, aflibercept and ranibizumab, so I'm looking forward to that. But I think that may play a role here. We just have to wait and see, but this is the best population. The other thing is that, you know, when patients come in, and you offer a treatment that can result in minimum burden or no burden in terms of injection, in a clinical trial setting, obviously, you know, these patients are followed for five years in gene therapy trial. I think they really like the idea of being watched carefully while they're also minimizing the number of injections if they get the 4D-150, and then loading them gives us time to have, you know, transfection and protein production to the steady state. The way this is designed, I think is ideal in my opinion, and I think it meets all the clinical trial criteria I look into when I'm helping companies design clinical trials. Yeah, and Carl, I mean, you know, having seen a number of these studies, right, six to eight letters at the end of 52 weeks, roughly 130 to 140 microns reduction in the treatment-naive population, is that still the standard? Or if you have, you know, a significant proportion of patients that are not getting injections, is there some, you know, kind of leeway afforded there? How do you think about that in a treatment-naive patient population? There's some fluctuation and some differences that may occur in a treatment-naive patient population, but this, again, is what virtually all studies other than ARCHWAY utilized. Right. And so I think it actually affords us great predictability. It's already been mentioned in terms of the types of patients and how they're gonna respond, so I think it's amazing how similar all the curves look really, when you look back at all the trials going back to the original ranibizumab studies, so you have confidence that your control arm will behave the way it does, and you have confidence that the treatment arm is gonna behave well based on your previous studies, including your II-B, because the II-B is most likely the types of patients that you're gonna be enrolling here. They're most akin to that, so I think you've got it. It's gonna put the product in its best possible light, and you've got a very high chance of success, because you have to minimize the amounts of rescue, right? If the vast majority of patients are getting lots of rescue, then it effectively becomes dual therapy, and a non-inferiority trial design is then not valid. So, you know you're gonna shine based on all your previous experience with this drug, particularly the II-B, which is the types of patients we're likely to see in phase III study. Yeah, Dante, maybe can I ask you to comment? You know, every study that we've seen since you know, kind of the first aflibercept studies, you know, kind of now use these loading regimens before kind of moving to whatever regimen we move on to. Can you talk about the concept of that, based on some of the data that we've seen on response to initial load and how that may potentially enrich for a patient population on the back end, the following fifty-two weeks? Yeah, I think it's important to make sure that we're enrolling VEGF-responsive patients to begin with. So, you know, it's not something else going on here. And so having a loading period where you can evaluate the patient, maybe after the first injection, to demonstrate that there's a response is very important. Second of all, if the patient has some sort of, you know, RPE rip after an injection or something like that, that's a patient potentially you could eliminate from the trial as well very early on. So kind of de-risking the trial in that way. And again, I think that this is probably what the real world's gonna be like anyhow. I mean, Carl mentioned earlier that, like most things, when a new drug comes out, even though it was studied in naive patients, we tend to use it in the more difficult-to-treat patients, first of all, and then go to the naive patients. So I think that we're you know, people are gonna be more comfortable seeing the 4D-150 being at, you know, used after a small, you know, initial injection period on a weekly or monthly basis. Yeah. Thanks. Arshad, and then maybe I'll send one to you. You know, one of the things that we know is that patients that respond really well, the papers have been written on it, to the initial loading dose, tend to have less fluctuations on the back end. Does that make you more or less, or you don't really think about it at all, comfortable in terms of using a sustained delivery approach on the back end when you've selected for these patients up front? I think, as Dante said, clinical trials are designed for regulatory approval and putting the drug that's being studied for success, right? But real-world usage is all patients. So yes, you are having some criteria of response, which is important because it's a one-time gene therapy, right? It's not reversible. So you're gonna make sure that patients who actually respond to it are getting the treatment. But no, it doesn't bother me because if it's approved and it's available, then you're gonna use it in all patients, as Dante and Carl emphasized many times. You know, I'll give you the Vabysmo example from our TRUCKEE study, which has studied several thousand patients. Pretty much everybody was high-need and very active patient population. And then once physicians got comfortable within the first six to 12 months, they start switching patients who are on aflibercept eight weeks or 10 weeks or even, you know, like, 12 weeks to go, even like 16 weeks and 20 weeks. Physicians started using it because they realized that this is better than what we had. So I think here we have an in-clinic intravitreal single-dose gene therapy that can really control anatomy. So even for that high-need patient, as I said earlier, you are seeing so much fluctuation with frequent anti-VEGF. You can minimize that, and they may not be injection-free. That's fine. You have the baseline, you know, production of anti-VEGF. I think what people don't understand completely at times is it's a very heterogeneous disease, and you are gonna produce a certain level of aflibercept and, you know, interference, the mRNA for VEGF-C in each patient. And if that is higher than what they need, they're gonna be needing no injection, and if it's lower than what they need, they're still gonna get benefit from it. So, so again, you know, clinical trials optimize for regulatory approval and success. Real world, we'll generate as much data as we can, but I see it being utilized in a broad patient population. Carl, maybe just the last point on loading regimens here. We're moving to a standard three-injection load, as we've seen in a lot of the wet AMD studies. Previously, we've used one, then we've used two. Thoughts around kind of the right number: Is three it? Where do you kind of fall out on that? Oh, yeah, this is very standard. Three is the standard for treatment-naive. The one or two that you referred to, of course, were previously treated patients, but when you're dealing with a treatment-naive patient population, you need no less than three. Three is the standard. That's the way phase III studies have been designed to date. It's three, and then every other month, EYLEA, so you know, this is a good study design, very solid, poised for success, no doubt about it. Even if you didn't have the response, I think you'd be very, very likely to be very successful, but that just increases the chances of success because you weed out a few of those poor responders. They're not gonna be great, though. In a phase III study. They're gonna be a very minor proportion of your patients. But this looks like it meets all the regulatory criteria, and, like I said, it's a very predictable types of patient population that we're gonna study here, and it's a very familiar study design. It's what we've been doing pretty much all along, and I think it's the way most studies going forward are gonna be designed. Keep in mind, we're in the sustained delivery phase of our research with wet AMD, even DR/DME potentially, too. In other words, there aren't a lot of new biologics, injectables, that we're gonna be exploring. A lot phase III studies in the coming years are all gonna be sustained delivery approaches just like this. Yeah, and maybe that's a great place to segue into our last question for the session. And so how do you talk about-I mean, all of you are enrolled or participating in multiple wet AMD studies, leading multiple wet AMD studies. How do you talk about a study like 4FRONT- 1 in the context of phase III studies that are currently enrolling in wet AMD? And how do patients go about kind of selecting one or the other? Carl, maybe I'll just start and stay with you where we were for a comment on that. Yeah, I think there's good choices for patients here. I think it's gonna be an easy recruit. You know, you tell the patient, "Look, you're gonna get standard of care treatment upfront, whether you're randomized to gene therapy or not. You could get the gene therapy," and that's super attractive, and you've got good rescue criteria set forth to make sure patients will have successful, good outcomes across the board, and you know, I think there's gonna be other types of studies and other products very similar to this, but not a lot, and I think we're gonna have good choices for patients. I think this is an easy recruit. I don't see a lot of competition. We certainly don't have a lot of novel, new biologics that I see we're gonna be testing in the coming years soon. Not a lot, you know, just one or two here or there. Yeah. I think this is gonna be a fast recruit, very attractive, and good data that stands behind it at the phase I, II level. Yeah, thanks. Dante? Yeah, I mean, I think Carl's right. This is a pretty straightforward trial. I think it's designed in a way that people know they're gonna get treatment. It's very alluring based on the data that you have. It's easy to discuss with the patient that this, you know, the preliminary data and the phase I and II trial looks real safe. I mean, that's always very important. The patients wanna know what's the downside of this, and that's the potential downside, looks good. There's a big upside based on the preliminary data that we've shown, and I think that, you know, as I compare and try to think of, like, how is this study gonna compete with the other studies, I think that, you know, I'll give you guys a pat on the back a little bit, Dhaval and Carlos and Chris and Bob Kim, the people that that Dave Kirn put together, is a great team that's well-respected in the retina community. You have a lot of experience with anti-VEGFs, with durable therapies, like the Port Delivery System. So I think you guys are gonna know how to get this thing recruited. That's just my inclination, but that's your pat on the back for the team. As always, you're too kind, Dante. Thanks very much. And Arshad, maybe I'll give you the last word here. Yeah, as I said earlier, I think, you know, five-year follow-up for gene therapy patients and potential for the control arm to roll over, and I don't know if that's decided or not. You know, there's always patients who sign up for these studies. You say, "You will likely get gene therapy, and if you don't, you get standard of care every eight-week injections for two years." And then, you know, if there is hope that we can provide and do a crossover for those patients, that really helps from a busy clinical site perspective and recruitment from patient motivation. You know, I think majority of the patients that we talk to are interested. Obviously, they wanna know the data, and I think having that safety data set with long-term follow-up for these patients from, you know, phase I and II-A, and even future, even longer for II-B, I think will be very meaningful for patients and clinicians. And listen, there are patients who don't wanna get gene therapy, then we have other options, like TKIs. And so I think, you know, I think we have the patient population, and we can easily manage multiple naive wet AMD trials, at least in my clinic, being top recruiters in many of the wet AMD trials. Just saying that, Dante, to make you smile. Not showing off, just saying that. So I think, you know, we have to discuss what we have for patients, standard of care and multiple clinical trials, and then share the data with them, and then, you know, discuss the risk and benefits and burden, and then the follow-up, and then I think patients make the decision they want. But I agree, I think having the potential of not having treatments down the road, right? Because they're still gonna be randomized and masked, so they won't know what they're getting. But I think having that hope for a disease that is a lifetime of treatment, getting this in a trial setting will be attractive. Yeah. Well, gentlemen, thank you very much again, once again, for being part of this panel discussion. We'll see you on the tail end for the open Q&A. But for right now, I'd like to turn the session back over and welcome Chris Sims to the stage. I'll now hand it over to Chris Sims, our Chief Commercial Officer, to walk you through preliminary commercial consideration. Chris? Thank you, Dhaval. Good afternoon, everyone. It's great to be here. As we know, the anti-VEGF market is large and growing, globally forecasted to exceed $15 billion in 2024 and projected to continue to grow annually by approximately 3% as the population ages. The wet AMD market in the U.S. alone has a projected value of $6 billion and exceeding over $9 billion in the U.S. for all indications. So it's a large market that's growing. However, and importantly, unique to this market is the ability to scale and commercialize, driven by an injecting retina specialist audience of about 2,500 to 3,000 physicians in the U.S., which is a very scalable audience, often requiring a commercial or medical field force footprint in the range of 150 employees or so. Further, we are building manufacturing capacity to produce commercialized product at scale, and we believe that will provide a cost of goods that will allow for pricing for the large market indications that are being pursued. Of course, while pricing decisions will ultimately be driven by the final product profile phase III results, at this stage, we think we have the potential for pricing that reflects the value of an efficacy and durability product profile that will significantly reduce treatment burden, while also supporting broad adoption for all patient types, if approved. As shown earlier by Carlos, the 2024 PAT survey shows that despite advances in traditional anti-VEGF therapies, the top unmet need areas, as reported by both U.S. and international retina specialists, is for agents that improve durability to reduce treatment burden with treatments that are safe. As we know, anti-VEGF has been established as the standard of care, and incremental advancements in anti-VEGF treatments have yielded blockbuster opportunities. And yet, as shown on the last slide, a significant unmet need remains to address treatment burden with treatments that are safe, efficacious, and more durable. The breakthrough opportunity with forty-one fifty is not measured in weeks, but the potential for months or even years of alleviating treatment burden across all patient types, thus presenting a major next-generation opportunity. To realize this opportunity, we believe our target product profile is designed to have safety comparable to leading anti-VEGF brands, deliver efficacy that maximizes visual outcomes with meaningful advances in durability, and importantly, be administered in-office as an intravitreal injection. On that last point, we believe the in-office administration is further enabled by a product that is stable and can be stored in-office refrigerators, much like anti-VEGF therapies are today. And as mentioned, we believe we have the potential for a final cost of goods profile that would allow for pricing that's appropriate for large markets like wet AMD, if approved. Ultimately, we believe this target product profile can address key needs across three critical stakeholder groups, namely patients, physicians and their offices, and payers. With that, I'd like to turn the call back to David to make closing remarks. Thanks, Chris. Here are the key takeaways from our presentation today. First, we've observed robust and durable clinical activity in all wet AMD populations studied to date. Second, safety and tolerability data continues to be outstanding, with a profile to date in line with approved anti-VEGF agents on the market. Finally, phase III clinical trial is designed to maximize the probability of clinical, regulatory, and commercial success. Here are the upcoming milestones for our ophthalmology pipeline. We'll now move on to Q&A. Before I open up the call to questions, I do want to take a moment to thank our investigators, our clinical trial staff, patients and their families, and of course, the entire 4DMT team for getting us to this point today. I'll now open the call to questions, and we're all here to answer your questions. Operator? Hello. We will now begin Q&A. For today's session, we will be utilizing the Raise Hand feature. If you'd like to ask a question, simply click on the Raise Hand button at the bottom of your screen, or if you've called in, dial star nine on your phone's dial pad. Once you've been called on, please unmute yourself and begin to ask your question. Please limit to one question and one follow-up before jumping back in the queue. Thank you. Our first question comes from Mani Foroohar with Leerink. Please unmute and ask your question. Thanks for taking the question. A quick one about the one patient that, I don't know if I heard this correctly, received a supplemental injection when they didn't necessarily meet criteria. Can you give us a little more detail on sort of how that happened, and actions that may or may not need to be taken in terms of tightening up, sort of trial conduct to make sure that there is a little closer, following of that, of the criteria? And I have a follow-up. Okay, Dhaval? Yeah, Manny, thanks for the question. So as part of the PRISM program, in addition to the pre-specified supplemental criteria, there was an option for physician discretion to provide a supplemental injection. And that's what was utilized here. So it did not meet the CST criteria, it did not meet the vision criterion, nor the hemorrhage criteria. And that was just allowed as part of the protocol. Moving forward phase III, as is pretty standard with most registrational programs, we'll make sure that supplemental criteria are based on central reading, center confirmation, and things of that nature. Okay, and separately, I think as everyone would expect, the percentage of patients that are injection-free at 52 weeks or lower than 24 weeks, I don't think that's surprising to anybody, given the underlying biology, but I guess this might be for the physicians on the call. Given that there's going to be a meaningful number of patients in real-world use, post a pivotal trial, who will require supplemental injections, how frequently would you be bringing patients back, either in the severe or broad population, in real-world practice? i.e., how much of the visit burden is going to be taken off themselves, off of the patient in your office, given that you're still going to have to track them on some kind of semi-ongoing basis? Yeah. Thanks, Mani. Carl, maybe I'll send that to you first. Sure. I think if we're dealing with a patient that was a high-frequency need type patient, it's definitely going to reduce office visit burden. As we expand, I mentioned earlier, I think there's going to be an expansion. Maybe my patients that are getting drug every eight, 10 weeks might consider this, too. I do think that just because, one, we want to monitor the eye we're treating, and they have a fellow eye that has AMD, dry or wet, we can only decrease the follow-up burden so much here. However, that being said, at least the way we currently practice, we are looking forward to remote monitoring capability, and I think that's really nicely suited to these types of patients. Unlike PDS, where you have a device, and you have to watch that, too, here, there's no device. Once you get beyond a few months beyond the tapering of the steroid, if they haven't had an IOI, they probably won't. So it's really just disease monitoring, and you could do that with office-based visits, maybe once every three months, I would say, is probably going to be how I see this playing out over time. Again, part of that's also monitoring the fellow eye and so forth, and/or incorporating some of the new remote capabilities that are going to start to come into our practices, like home OCT. Dante, anything additional from you? Yeah, no, I think it's a very good question, you know, because there's the burden of the injections, and there's the burden of the follow-up, and how's that going to be reduced? But we've seen this a little bit with the port delivery system as well. I think that in the first year, we're probably not going to reduce the visits that much because we're going to be tapering steroids, and we're going to want to watch the patients as they taper off the s teroids with the gene therapy. But as we get comfortable that this patient really isn't the anatomy is staying very stable, maybe they're the one-and-done patient, I think we're going to be. It'll be instead of treat and extend, it'll be just extend follow-up, and then we monitor, and if things look good, then extend the follow-up a little bit more in these patients, so it'll be just extend, examine and extend, and as Carlos mentioned, I think there really is going to be monitoring at home. I think the physicians can have, like, a brief evaluations, where the patient maybe just comes in and has an OCT and maybe a color picture and is expedited through the practice, doesn't need to be dilated and things to monitor, but we'll figure that out. That's, you know, if we have something that works, can increase the durability. I think that we'll figure the monitoring part of it out in the future. All right. Thanks, Mani. Next question? Thanks, guys. Our next question comes from Salveen Richter with Goldman Sachs. Please unmute your line and ask your question. Good afternoon. Thanks for taking my questions. Two questions from me. One is just given the non-inferiority trial is against two milligram aflibercept and not the high dose, and given that aflibercept arm isn't allowed supplemental injections, how do you think about the relevance of this study design to clinical practice? And then secondly, what is now your level of confidence on the safety profile, including the risk of developing cataracts at this point with the sample size and follow-up? Thank you. Dhaval, you want to take that? Yeah, so, Salveen, in terms of the non-inferiority bar, I think, you know, it's been established, and 2q8 has been the comparator arm for forever. I think it's a little bit early to kind of start thinking about high dose of aflibercept in terms of becoming the new standard for clinical trials, and so I think we're very comfortable with where we're at in the design and the ability to achieve the primary endpoint. In terms of the development of cataract and one arm versus the other, maybe I'll turn it over to Carlos to just comment on cataract rate and our concerns on phase III setting. Thank you, Dhaval. And thank you for the questions. You know, what I would add to what Dhaval mentioned regarding the non-inferiority, I think Dr. Khanani addressed it very nicely before. And the truth is that the non-inferiority margin has been established against two milligrams of aflibercept in the pivotal trials there. Eight milligrams, you know, was compared against the two milligram aflibercept, and therefore, there's a potential risk of type I error if we were to compare only to eight milligrams. So I definitely agree with Dhaval's perspective around that. It would be, you know, probably premature to compare against the eight-milligram arm solely. And when it comes to the risk of cataract, we're going to be using, as I mentioned, phase III, Durezol, that, you know, has a well-known safety profile. And we think that the risk of cataract for these patients is going to be actually low. And in addition to this, both of the arms are going to be receiving Durezol as well. So I think that if cataract is developed over time, we probably are going to be expecting to see a very similar rate across the two arms as well. Excellent. Thank you. Next question? Our next question comes from Tazeen Ahmad with Bank of America. Please unmute your line and ask your question. Tazeen Ahmad, can you please unmute your line and ask your question? Operator, let's take the next question. We'll come back to Tazeen when she sorts that out. Just let us know when she's back. Sounds good. The next question comes from Jon Miller with Evercore ISI. Please unmute your line and ask your question. Hi, guys. Thanks so much for giving us the update and taking my question. I'd like to start with a follow-up to Mani's question. Looking closely at those Swimmer's plots, it looks like there were actually a fair number of patients that got supplemental injections solely based on investigator discretion that did not appear to meet the central criteria. I noticed you gave a little color about why those patients got those injections, but do you guys think that those weren't fair injections? It would seem to materially change the rate of rescue needed if you, for instance, didn't include those patients. phase III, where central reads are gonna be standard for determining eligibility for supplemental injection, do you anticipate to see different rates there versus what you saw in phase II-b? and I've got a follow-up as well. All right. Thanks, Jonn, for the question. I'll turn it over to Dhaval, and then maybe he'll hand it to some other folks. Yeah, Jon, thanks very much. You know, in clinical trials, in early phases, and specifically with the patient population that we were enrolling, higher need, we wanted to allow for some flexibility for physician discretion. As you move into registrational programs, as is typical across the board, you take less of that... more and more of that variability out of the equation by sending those calls to a central reading center. Visual acuity is pretty straightforward, you can, you measure it on the chart. But, in terms of, you know, being fair, unfair, or whether or not, we have a position on that, we haven't really adjudicated all of these. I think the purpose for using physician discretion is to be exactly that in the early phase, to allow the physicians to have the ability to treat their patients appropriately, and kind of make those calls. Carl, I see your hand up. Maybe do you want to make a comment on that? Yeah, you're absolutely right. It's pretty standard to have investigator discretion at the early stages like this. And I'm gonna say, based on experience, especially with port delivery, it's not uncommon that investigators sort of jump the gun, so they see some fluid coming back. But we've learned a lot through PDS. In sustained delivery of all types, you're likely to see some fluctuation. Keep in mind, we're dealing with a product here, a therapy that's not gonna just suddenly wear off like a bolus injection. So in practice, sure, we jump on new fluid all the time, and that there's a tendency to want to do that in the trials. I can tell you, during port delivery, I can't tell you how many times I had one of my co-investigators say, "I'd like to give a supplement, but they don't meet criteria yet," and I would say, "Hold off." I'd see the patient two, four weeks later, and lo and behold, it's actually better, and we have a publication on that, how you can see fluctuating fluid. S o the nice thing about this forever treatment, in essence, is you've got that safety net, and so we just have to change the mindset of clinicians, and that includes investigators, especially if they're not well-versed in sustained delivery, that they don't have to jump when they see fluid. We expect to see little amounts of fluid that come and go, and that's okay. That's very, very well-tolerated, and it will not affect vision, and that's been shown in many, many studies. Thanks, Carl. Next question? Our next question comes from Tazeen Ahmad with Bank of America. Please unmute your line and ask your question. Can you guys hear me? Yes, we can. Yes. Okay. So thanks for the presentation today. A couple of my conversations recently with investors seem to revolve around how they think efficacy should be defined for gene therapy versus how you, as a company and also the doctors on the call, define efficacy. So specifically, how do you talk about the importance of injection freedom, meaning not needing any rescue injection, versus having a reduction in injection rate? And I know that the doctors talked about this earlier in the presentation, but it seems to be a sticky point, so I thought I would ask again. Thanks, Tazeen. I'll kick it off, and then we'll turn it over to the experts, but I, I do think that if you look at the history of gene therapy, particularly in the eye, you can see why people got this idea it had to be one and done. I think they were assuming, you know, very high cost, they were assuming it's gonna be toxic, you know, that based on, you know, prior programs, or that it was gonna require a surgical intervention to do the subretinal injection. I think what we're seeing here now is that with a safe, simple intravitreal injection, that changes the game completely, and now we can be held to kind of more standard, criteria for other agents in the field, and when you look at it from that standpoint, this is a home run across all efficacy endpoints. But let's turn it over to Dhaval, and you can kind of have our experts weigh in. Yeah, you know, in place of me opining it more than what you have, maybe I'll turn it over to our expert panel. Dante, I see you're off mute. Maybe I'll give it to you, and then Arshad after. Yeah, I mean, I think our thinking, Carl really said it in the last presentation. It's this continuous delivery of anti-VEGF at some level, right? I mean, this is what we see with the port delivery system. You know, our mindset really is that we have something on board for these patients, and, you know, for some of the patients, that's gonna be enough. They may never need another therapy. But for the vast majority of these patients, the success is gonna be a few injections a year, or maybe one injection a year, and needing to come in less at the end of the day. But getting the same visual outcome, the same anatomical outcome that we would get with, you know, frequent, either monthly ranibizumab or every other month of aflibercept-type injections. So yeah, I think that we just need to think about this a little bit different when we talk about continuous delivery of VEGF suppression. Arshad? Dr. Khan- Yeah, I'll add, too. [crosstalk] Sorry, I wanted to- Yeah, go ahead. Sorry. I just wanted to maybe on the thought of injection freedom, how long would injection freedom need to last? Is it forever, or is there a minimal amount, if you could say the importance of injection freedom in this instance? Arshad, you want to take that? Yeah, I can take that. I think this is the key. Great question, by the way. I think I see the biggest disconnect between physicians and investment community, and I think partly is what David said earlier about people think this is gonna be like Luxturna, right? And that's not the case. And we are not curing patients because we are fixing a gene. We are making a biofactory approach in the eye to release anti-VEGF. I mean, the injection freedom, as Carl and Dante said, we'll be monitoring these patients with even if they are injection-free, maybe twice a year, like we do for dry AMD patient or even home monitoring. And you know, I've seen that, you know, sometimes you give an intravitreal injection to a patient, a week later, they have worse activity, or they get a bleed. So patients are very heterogeneous. Sometimes the disease goes up and down, and that's why, you know, with sustained delivery, we are more confident that we're gonna have better outcomes because we have anti-VEGF on board. But to directly answer your question, obviously, the longer, the better. But if somebody needs an injection to top off, you know, once a year or six months, or they needed one because they had more activity, I think we can do that, and I don't think patients mind that. I think the biggest frustration I have as a clinician is I see these patients, and I know exactly what they need. They need less burden. They need the best outcomes, and it doesn't matter if they needed one additional injection compared to getting one every month for the past year. I think that's a huge win. So I think there's clearly a disconnect, and I think from a clinician's perspective, I think gene therapy is a paradigm shift for me because of the outcomes and also decreasing treatment burden, and bonus, they get injection-free. That's a home run. Dante, I see your hand up. You wanna, you wanna jump in? Yeah, I mean, you use the word freedom from injection, but, but if you're getting intravitreal injections on a regular basis, you don't have much freedom. I mean, if the patient gets sick, if they can't make it to an appointment, that's very likely that they'll miss a month or two or three or more, and they'll lose visual acuity, they'll gain a lot of anatomy, and the benefits will have been lost. With the continuous suppression here, I think that we're going to put a floor on this so that hopefully the patients, even if they missed an appointment or two or three, they're still gonna be doing f airly well. Remember, at the end of the day, the efficacy that we see in the clinical trials, we don't get in the real world, and it's because these patients don't maintain these intravitreal injections over time. So we're hoping that therapies like this, with continuous suppression, if the patient misses here and there, they actually have some freedom from injections, freedom from coming in. They have some wiggle room, that they're not gonna have this disastrous results in between these periods because the VEGF suppression, at some level, is still there. So, you know, I think we need to think about it that way, and hopefully, we can look at efficacy data in the real world down the road, and we'll see that we're doing a better job. We're not having these, you know, these hills, where things get better and then get worse over time because patients can't maintain this non-freedom, intravitreal injections. I agree with all you guys. I don't think being injection-free is all that important or necessary, and that means forever. So I think that what's most important is great disease control with minimal numbers of injections on an annual basis, and that we can't do with anything right now. So that's what makes this so attractive. I'll tell patients, "You know, you can expect a supplement here and there," and that's probably the best way to do it, the way to phrase it, is supplement now and then. You might need a higher dose here and there. But I think it's good. People have been emphasizing, they're absolutely right. My colleagues talking about long-term visual outcomes is really the big bonus. Now, in a registration study, we're not gonna demonstrate that, but we know, and if you get continuous treatment, two, three, four, five years, you're gonna, you're gonna have better outcomes than with intermittent biologic injections. Thanks, Carl. All right, next question. Our next question comes from Gena Wang with Barclays. Please unmute your line and ask your question. Thank you for taking my questions. I have several parts of questions, but phase III study design. So maybe first question is, how do you impute the BCVA data when patient, the drug arm that requires rescue injection? And the second is that how do you define response to aflibercept? And then third question is, you know, just want to double-check, did the baseline BCVA, was that defined at the week minus five, and is that common practice? Okay, thanks for the questions. Bob Kim, do you want to start us off, and then we'll turn it to Carlos? So the first question was how are we going to impute visual acuity in the context of an aflibercept injection? That'll be part of our statistical analysis plan. So we'll, I mean, we've given deep thought to that and are currently interacting with the agency on that. But there's a path forward. We can regard some of these as intercurrent events, but I think it's... we won't go into the details at this point. Regarding the response to an aflibercept, I'm not sure I understand the question. Are you talking about- It's- In what context? Yeah, no, so more the screening stage. Like, you have two loading doses- Oh, right. Or one loading dose, and you define the patient will be- Right respond to aflibercept. Okay. How do you define that? Okay, in very early stage. So we have an anatomic and a functional assessment, but we haven't disclosed the specific, you know, thresholds. Yeah, and if I may add, you know, I can tell you that, you know, for the criteria of response, we're basically, you know, as Bob was mentioning, we're not disclosing any specifics right now, but we definitely have included all of the cumulative evidence and experience in assessing response at the different trials of anti-VEGF, and we've adapting this to maximize the 4D-150 chances of success. So, I believe that, you know, this is gonna help us. I think Dante or Carl mentioned this before, we basically want to maximize the population that are included to maximize the chances of meeting the primary endpoint for 4D-150. Mm-hmm. All right. Thank you. Next question. There was a third question, and that was why are we- Baseline -the baseline at week minus five? That is an expectation of FDA, that the baseline be set prior to any you know, the first study intervention pharmacologically. So, that's why it's week minus five. Thank you. All right. Thank you, Gena. Thanks, Bob. Next question. Our next question comes from Kostas Biliouris with BMO. Please unmute your line and ask your question. Hello, thanks for taking our question, and congrats on the progress. Two questions from us. Can you talk a little bit about the patient who experienced a retinal macular hemorrhage in phase I/II? Any color you can provide around that would be helpful, and I have a follow-up. Sure thing. You want to speak to that, Dhaval, or? Yeah, I think, Bob, I'll pass that one to you. Oh, yes. That was a patient in the dose exploration cohort, the high dose, that was doing actually quite well, rescue-free, and to everyone's surprise, developed a submacular hemorrhage that was, I guess, a moderate size. It did impact visual acuity, so at that time, the investigator elected to treat with a series of monthly anti-VEGF injections for about five injections while the hemorrhage resolved. So after about five injections, the hemorrhage was gone, the visual acuity had recovered. But that investigator elected just to prophylactically just continue dosing every eight weeks, and the patient is doing quite well. Thanks, Bob. Next question. Very, very helpful. Thank you. The next question is phase III design. the reference point phase III appears to be after three loading doses, whereas in phase I and phase II, the reference point was after one or two loading doses. Given that we have two different reference points here, and potentially differences also in the rest of criteria, how should we be thinking about comparing your result in phase I, II phase III? thank you. Thanks, Kostas. Great question. I'll turn that over to Carlos. Thank you, David, and thanks for the question. I think that, you know, we've we're basically building upon the data that we've seen in PRISM, and as it was emphasized today, in PRISM, we had a very broad population that range from very long-standing, long duration of since disease diagnosis to more recent patients, but definitely not the treatment, i.e., patients that we're gonna be enrolling phase III program. so I think that overall, the objectives of the phase one study were accomplished, showing safety and efficacy in the broad population. And given that the expression of the aflibercept that we know very well is well established with regards to efficacy and profile, and we know how patients who are treatment naive respond to this, we have a very high degree of confidence in the fact that these changes are actually going to maximize not only the BCVA gains, but also the durability potential. So to summarize, you know, the population that we're phase III, it's going to help us maximize the BCVA gain and the potential for extended durability. And in addition, we've taken all of the learnings that we've had from the disease activity criteria that we've built upon, you know, some of the phase III trials, but also historically, to maximize the chances of this program to be successful. Thanks, Carlos. Next question. Our next question comes from Kelly Shi with Jefferies. Please unmute your line and ask your question. Thank you for taking my questions. First question to our doctors. So if you present the current profile of 4D-150 to patients, what would be your best guess on the proportion of patients would be willing to switch to a gene therapy who are currently on high-dose EYLEA or Vabysmo? And I also have a follow-up. Thank you. Yeah, Arshad, why don't I give that to you first, and then Carl and Dante, we'll have you both weigh in. Yeah, that's a great question. I think, you know, we have to understand that, based on our work in the TRUCKEE study and other real-world studies, you know, majority of the patients on faricimab as well as EYLEA HD are not going to 16 weeks, right? And I think most of them are going two to three weeks more than aflibercept two milligrams. So I think this gives us an opportunity, and I can share this experience as an enroller, one of the highest enroller in the PRISM, all stages, phase one and phase II A and phase II B. I think when you give patients an option of having minimal burden or no burden, I think the majority of them want to sign up for it, as long as they are comfortable with the data to date. And of course, we have excellent long-term data to date, but by the time this product is available, we're going to have phase III dataset that will confirm the efficacy and safety. So I think, you know, at that time, it will be even much more extensive dataset that will be very important to utilize to give it to the patients. I would say, you know, patients who are going four months, you know, on Vabysmo or EYLEA HD, maybe not the treatment for them, but I think anywhere, anybody sitting at four weeks, eight weeks, even ten weeks, I think those patients are going to sign up. So I would say, you know, I don't know what Carl and Dante think, but 50% plus, you know, eventually. But as we said, that we will start with the higher-need patients, which is 15%-20%, and try to move it to less-needing patients over time as we establish our real-world experience. Dante? Yeah, I mean, I, you know, if I look at, say, patients who are getting just EYLEA or Lucentis now or a biosimilar or something, now that these better agents have come out, you know, assuming insurance is okay with it, most of them want to switch to it if they're every four to eight weeks. So it's very, there's a very high percentage of patients that are going to want to have something that lasts longer. Now, again, we're going to assume that the safety is going to be similar. We're going to have to assume that the outcomes that we've seen in the phase II trial are similar. But I think a lot of people would jump to this, granted that we have those indications of safety and efficacy, and patients are ready to. Some patients, not a majority, of actually a minority in my practice, I'll tell them I have something that lasts longer, and they'll say, "Oh, I'm just happy to stick with what I got, even though I'm coming in every eight weeks or four weeks," or something like that, so yeah, there's a big market for this in patients who are chronically treated, I think, switching them over. And Carl? I totally agree, and as said earlier, I do expect as long as the safety holds up, phase III results look like phase II-b and the experience thus far with both safety and efficacy, I easily see this expanding more and more gradually over time. We're all a little risk-averse, so you know, with something truly very new and different, even the second-generation biologics, as we call it, EYLEA HD and Vabysmo, you know, we just didn't just convert everybody right out of the gate. It's a process that's gradual over time, and I see this within a few years growing more and more as we get comfortable with it, as mentioned earlier. All right. Perfect. Thank you so much. Very much. I also have a follow-up- Yeah -if I may. Okay. Yeah. So the 4D-150 shows the sustainable control of CST in patients with different severity. But when you take a closer look, you can see some, like, up and down over time. So it's kind of, like, challenging to draw a trend line from any time point, which actually sometimes the investors question at a previous, like, a data cut. Curious, what is the biology behind this type of shape of curve, given that gene therapy is supposed to give stable inhibition of VEGF, not like a repeated injection regimen EYLEA leads to, like, a fluctuation on CST? Thank you. Yeah, so it's a great question. I think a couple of things as it relates to that, and then I'll pass it to our KOLs as well to kind of address. But right out of the gates, I think one of the things that we have to kind of understand is the datasets we almost knee-jerk try to compare these two are these treatment naives, where the lines are straight, and the patients are very homogeneous. If you look at the phase I, II- A, and even the phase II- B, there is a mix of different patient types in there, and what we're really looking for is control. And what we call control, roughly, is 50 microns on either side, maybe a little bit more, maybe a little bit less, depending upon the physician that you're at. But the important thing to remember on these things is both studies, the phase I/II-A, as well as the II-B, enrolled active wet AMD. If you are not controlling these patients, giving them an active therapeutic, what's going to happen with those curves is they're not gonna kind of stay in that same place. They're gonna start running away from one another, because this is active disease. Then the second thing around just kind of where the curves go, the other thing of importance is that you'll notice that whether it's the I/II-B or the II-B, the curves have less bounce. Clinical studies have shown us that if you bounce more than 50 microns, that is not a good predictor for bad visual acuity outcomes. And so maybe I'll kick it to Carl for the first comment on, you know, variability on OCT and kind of what that means, and then just what you're seeing in this, and what do you interpret out of that in terms of control or not? Yeah, there's lots of reasons for variability and sometimes just natural, of course, and we got small studies, small numbers, so we expect to see these curves fluctuate a little bit. First of all, there's fluctuation based on when we do a bolus injection, the medicine wearing off, right? That's one reason why you see a change in CST and potentially even vision. But what I mentioned before, with sustained delivery, we can see slight fluctuations, but it's not necessarily wearing off, so we'll see that happen too. As Dante mentioned, as long as the fluctuation is small, 25, 30 microns or so is very well tolerated, it's been shown time and time again, then we're gonna have a great result, and that's very acceptable, and including the way we handle that in practice too, not just the clinical trial. So I think there's very different reasons why you may have fluctuations, some big, some small. You just don't want to see big ones, and you just don't want to see it as a reflection of the effect wearing off, and it doesn't seem to be the case here, which is really good. Thanks, Carl. All right, it looks like we're out of time now, so I just want to end by saying thank you once again to our patients, our investigators, the experts we've had on this call. You've been fantastic and very insightful. Also love to thank the 4DMT team. This was a huge effort to get all this data together so quickly with short timelines. Phenomenal effort there. We look forward to having conversations with many of you. Please feel free to reach out to Julian Pei, our head of IR, to set up a meeting. We look forward to having those discussions. So to end, I'd like to summarize once again, 4D-150 has shown a compelling target product profile that sets us up for success in phase III. We've shown robust, durable efficacy in all populations studied to date with wet AMD. We've shown a compelling safety profile that's in line with current approved anti-VEGF agents, and phase III is designed to maximize the likelihood of clinical, regulatory, and commercial success. So thank you once again, and have a great evening.