Our next presenting company is 4D Molecular Therapeutics. With me are David Kirn, CEO, founder, and co-founder of the company, and Uneek Mehra, Chief Financial Officer and Chief Business Officer. I think you guys have some slides you want to run through first, so we can start with that and then we'll jump straight into Q&A. Absolutely. Well, thanks for having us. I'll just show a few slides just to introduce the company, and then we can just get into Q&A. Sounds good. So, at 4DMT, we're harnessing the power of directed evolution for targeted next-generation genetic medicines. So, we're a leading clinical stage next-generation AAV company. Our platform is directed evolution, which is a Nobel Prize-winning technology in which we start with 1 billion synthetic capsids that are proprietary to the company, and then we do serial selections in non-human primates to identify vectors that are highly customized for any tissue in the body. So, it's an incredibly robust platform. We do also have a robust product engine. We have strong clinical proof of concept across three different therapeutic areas, including large-market ophthalmology, lung, and cardiology. These products all use three different routes of administration, so we've shown that directed evolution can allow us to invent vectors that we use by either intravitreal injection, aerosol delivery, or intravenously for the heart. Our pipeline is robust: five clinical candidates in seven patient populations, including four large-market ophthalmology opportunities, each of which is a multibillion-dollar opportunity for us. We also have two IND candidates, one of which will have the IND filed this quarter, and that's for geographic atrophy. We have made great progress with FDA and EMA on our lead program in 4D-150, so we have both RMAT and PRIME designation for 4D-150 in wet AMD, which we think is the only product in ophthalmology that's ever had that dual designation. We have strong in-house capabilities for everything from GMP manufacturing to next-generation vector discovery, payload design, product engineering, and we have a very strong balance sheet with close to $600 million in the bank as of end of Q1, and Uneek can speak to our cash position later in the presentation. We have a robust and broad product portfolio, and the vast majority of these, we've retained 100% of the rights as well. In ophthalmology, we have 4D-150 for wet AMD, DME, and eventually, we believe, DR. We also have several rare disease opportunities with 4D-125 and 4D-110, and then 4D-175 is our geographic atrophy asset. Importantly, these all leverage the same R100 vector that we invented for low-dose, safe, non-inflammatory delivery with intravitreal injection. Pulmonary leverages our aerosol vector A101. The lead product there is 4D-710 for cystic fibrosis, lung disease, and currently in a phase 1/2 with strong proof of concept for safe delivery and gene expression. And then 4D-725 is for alpha-1 antitrypsin lung disease. And then finally, cardiology, C102 is the vector for low-dose IV delivery to the heart, and the lead product there is 4D-310 for Fabry disease cardiomyopathy. 4D-150 is, again, our lead product. It's in wet AMD and DME currently and soon to be, we believe, will move eventually into DR. We believe we're poised to be the market leader here for a number of reasons. First of all, therapeutic durability and the need to continually redose with bolus therapy is a problem in wet AMD for these patients, and we believe with a single injection, we can dramatically reduce the need for injections in patients and, in some cases, completely prevent patients from needing further injections over time. The second real issue in wet AMD is that with the bolus therapeutics, standard anti-VEGFs, what we can see in some patients is oscillation in the thickness of the retina. So, retina becomes very edematous, and then it shrinks down, and then it swells again and shrinks down. That oscillation over time is strongly correlated with loss of BCVA, loss of visual acuity over time. So we believe that giving nice, continuous, steady state expression right in the retina, right where we need the therapeutic to be, is just a better fundamental way to deliver an aflibercept than these boluses. And again, in our product, we also have an anti-VEGF-C mechanism, so we're targeting four different mediators of wet AMD, which we think we're the only product that can do that. We have recently, several months ago, presented data from the PRISM phase 2 clinical trial. In this case, we were focused on what was called the dose expansion in the highest need patients in terms of anti-VEGF need and the highest disease burden in terms of the thickness and presence of fluid in the retina by OCT. So very high need, difficult-to-treat population, starting the most difficult, which we thought from a development standpoint makes sense. It's hard and the hardest to treat patients with the highest unmet need. And what we showed is with a single safe, routine intravitreal injection, we had outstanding safety, as you can see in that second column, with no significant or recurrent inflammation. Patients are on topical eye drops and get off those on time over the course of about five months and then stay off of the eye drops. So, it's very well tolerated and easy to administer. We saw an 89%, almost 90%, overall reduction in the need for anti-VEGF injections. So, if you think about Vabysmo, it is a blockbuster, and they've probably taken maybe 30% of the injections out of the system by their greater durability. We're not going 30%. We're going 90% with a single administration. 84% of patients had either 0 or 1 supplemental injection, and 63% were completely injection-free, which is just, again, evidence of a high degree of activity. Retinal anatomical control, we said, was important to kind of stabilize that retina and get rid of these oscillations. When we compared to an aflibercept control arm, we saw exactly that, that the retina CST thickness was really stabilized on 4D-150, whereas in the aflibercept group, we could see it oscillate up and down, which leads to vision loss over time. We did update long-term durability from our phase 1 study. We had three patients in the 3E10 dose level, which were injection-free at one year, and all three of those patients continue injection-free with up to two years of durability now. So similar to other AVV retinal programs, we're now showing that this is a very durable way to deliver drugs to the eye. The phase 1/2 clinical trial, PRISM, the next update from this study will be a separate cohort of patients on PRISM that have actually more broad wet AMD disease activity. So, in contrast, the last data update, which was a cohort that was the highest need patients, that was a 50-patient randomized control study. This will be 32 patients, same two dose levels of 4D-150, but more broad, some newly diagnosed, some diagnosed, and high need, and more of a blended population to just extend the activity and the safety to a broader patient population, which will be similar to phase 3. In parallel with that, we're designing and planning for phase 3 as well. 4D-175 is, again, leveraging the same R100 vector, but for geographic atrophy, going after a well-genetically validated target complement factor H. In this case, we have a short-form complement factor H, which is shortened but retains all the functional activity of full-size complement factor H in a way that allows us to get it into the AAV capsid but also have better penetration into the retina, which we think could translate into even better efficacy than full-length complement factor H. In this program, we'll be filing the IND this quarter and starting the trial in the second half of the year. Do you want to speak to cash balance? Yeah. I mean, maybe just to reiterate on the key milestones coming up, I think David has already spoken about the population extension that's coming up in July 2024, so at ASRS. We also have publicly announced an update on our phase 3 clinical trial design, which is in Q3, right around the same time. And then for 4D-150 for DME, we have a 24-week analysis on 22 patients coming up in Q4. So, these are two material and quite significant data catalysts for us at the second half of the year. Spoke about 4D-175 for GA. Our next update on CF is on June at ECFS, where we'll have more data on our patients further to what we announced last year at the NACFC, which is the North America Cystic Fibrosis Conference. Overall, strong cash balance, $589 million. That takes us into second half of 2027 and includes both accounts for two phase 3 studies on wet AMD. So, we feel pretty good where we are positioned right now with a number of catalysts coming in the remainder of the year. And with that, we can give you back, and you can tell us. Cool. Yeah. And thanks for that. That was pretty comprehensive, and clearly, there's a lot going on with the company this year. Maybe we can start with 150. So, I guess a question we get asked a lot is so we had updates from you guys and also updates from competitors around the same time. Can you maybe tell us how you're thinking about your competitive positioning in wet AMD for gene therapy? And maybe we also have these other products coming into the pipeline, the sort of long-term inserts in the eye. How are you thinking about how your product would be differentiated from other gene therapy products as well as other potential long-term therapies? Sure. So, 4D-150, we think we're very well differentiated from each of these other approaches, and I'll get to that in a minute as to why. We think we have an amazing opportunity in front of us in wet AMD, DME, and eventually DR. Each of these is a multibillion-dollar opportunity, even with small-market penetration, which we think we can do better than that. In terms of other gene therapies, what people have really been looking for, physicians and patients, is a simple single intravitreal injection with great safety because large market, you're just not going to tolerate chronic inflammation. That's what we've been able to show uniquely, is that we can get high degree of activity, great safety, patients get off their steroids. It's a simple steroid regimen of topical eye drops, and it's all done with a simple intravitreal injection that basically takes 10 seconds in the clinic, just like an Eylea injection. That's a game changer. That's a fundamental. Nobody else can say that they have that, not REGENXBIO or Adverum. No one. That's a massive opportunity for us right there. If you think about DME, none of the gene therapies are in there. We're all aware of the history of Adverum in that population where that chronic inflammation in the front of the eye may have translated into that hypotony. We don't see that inflammation in the front of the eye, so we don't think we're going to see that. Again, assuming we can demonstrate safety in the second half of this year, then DME is a massive opportunity for us, large, growing population. We're the only game in town there as well. And then anything that works in wet AMD typically has efficacy in DME, which then translates to diabetic retinopathy. So, that is all wide open for us, and we're highly differentiated versus other gene therapies. If we think about the TKIs, the implants every 6 months or so, well, first of all, that's a 6-month play. It's not a multiyear play like ours. And secondarily, they've really positioned those as a product that's more of a niche in patients who have had a great response to therapy already. Some of the data that was presented around the time of ours had patients where their retinal thickness was normal. They weren't even swollen at all, let alone had fluid like our patients. I think that's been more positioned as a niche therapy to extend the duration of treatment in patients who are going to respond well anyway. Now, we're all aware of the recent data they've had in DR, which maybe opens up the question of how much disease activity is there currently, and we'll just have to see how that emerges over time. But I think we're very well differentiated in terms of being active in the highest need patients. We should be able to easily treat earlier stage and less active disease patients given our safety profile and simple intravitreal injection. It's really a massive opportunity for us. Then leveraging the same vector in geographic atrophy with a great target just gives us a fourth large-market opportunity. Got it. And Daniel, just to add on that, that is the reason we also think we have both the RMAT and PRIME designation. There's no other therapy that has that. So that eases our regulatory discussions as well. So, I just wanted to throw that in as well as a different. Really good point. Good point. As we think about long-term efficacy, so we have 24-week data. That looks pretty compelling, but then I guess the biggest question is what's that going to look like at 12 months, 24 months? You're talking about a one-time treatment. What are physicians looking for in terms of when you think about injection rate reduction as well as injection freedom? So, we've seen almost 90% in injection reduction so far, and 63% of patients remain injection-free at 24 weeks. But what are you looking to show long-term that would be sort of clinically irrelevant? Yeah. I think there's two things to look at. Number one is based on our data that we presented to date, our enrollment is off the charts. So, what we've seen is we have aggressive enrollment targets, and we've done. Patients have for this sort of therapy and for what we've shown to date. So I think that's differentiating. And then let's look at the Vabysmo launch. They're literally going from 8-12 weeks in most patients. A few patients can get up to 16 weeks, but it's basically 8-12. So, they're taking about a third of the population a third of the injections out of the system, and yet it's a blockbuster. So, that tells you if you can stretch out therapeutic benefit beyond that, which we can do, and hit something anywhere close to 90%, you're going to have a blockbuster on your hands. There's no doubt about that. If you then add in this potential to say, "Hey, long-term, this is just a fundamentally better way to deliver the biologic, to have it there continually 24 hours a day, steady state, so you don't get those oscillations," that's going to translate into long-term visual outcome benefits. Well, again, that's another huge reason for patients to want to use this and for physicians to want to use it. So we'd love to continue to have a high degree of injection reductions. Some number of patients will be injection-free. Some will need one a year. Some might need two. But everybody's going to benefit, we think, across the entire range of wet AMD patients. Got it. And then similarly, in terms of safety, how do we get comfortable with the long-term safety profile? So far, safety has been pretty good, but admittedly, patients are just coming off of the steroid treatment for the time point we have at this point. How do we get comfortable with safety after that, after patients are not receiving steroid treatment? Yeah. Safety is always critical, and we're always looking to build the database, and we'll continue to report out new patient populations such as this population extension, 32 patients at ASRS in July. So we're always building on that, and we're also giving longer-term follow-up on our phase 1 patients. Again, as we said before, some of those patients are out at 2 years now, and we haven't seen any late toxicity crop up. With AV gene therapy, typically, if you're going to see inflammation, which is typically if you're going to see toxicity, it's related to inflammation, you see it early on. You're going to see it in the first month, maybe 2 months. But the number of patients where you just suddenly have it pop up at a late date where there was nothing early, it's incredibly rare, if not a case report. We feel really good about the safety because, again, we think we've had patients off of steroids for a long period of time. We just haven't seen anything on steroids or after steroids. I think the history of the field suggests that we're in really good shape. Can you help us frame expectations for the upcoming data at NACFC and maybe elaborate a little more on why it's important to study this population extension cohort? What's different about these patients from the patients you've dosed so far? From what you know at this point, what are your expectations for efficacy? Yeah. So, I think just starting from good drug development, we thought it was important after phase 1, after we sorted out what dose range we wanted to be in, to start with the highest need patients, prove safety and activity there, and then move into a broader population, which is what we're doing here. So, we had these really blockbuster results from the highest need patients. We'd expect to see something similar in the broader patient population that we report out in July. If anything, they may be less treatment high need. There'll be less high disease activity. So, we think it'll be more like a phase 3 population that we're going to treat. So, it's going to extend that efficacy. It's going to extend that safety to 32 patients, same two dose levels, 1E10, 3E10. We would expect to see similar results in a similar series of areas of interest, which would be safety, BCVA over time, CST over time, and then reduction in injection frequencies over time. Then we'll look at how many patients are injection-free or got 0 to 1, just like we did in this population. Do you have a sense of what% of patients fall under the criteria for the population extension versus the more severe patients you've dosed so far? You mean the upcoming data, how many will be the most severe? I guess, in general, what% of patients fall under that? Oh, I'm just saying. Yeah. We think it's probably about 20%-25% of patients would fall into that most severe category, whereas this broader one would encompass, I think, probably 95% of all patients. Okay. Cool. I think you've shared some details on your phase 3 plans in terms of the dose you're planning to use, size of the patients. What additional updates should we expect seeing in 3Q? What else is there to finalize with FDA in terms of discussions for the phase 3 trial? Yeah. Do you want to kind of speak to the update in Q3? Yeah. I mean, I think the regulatory update we've so far provided is about the size of the arm. First of all, we believe it's going to be a non-inferiority in BCVA. We've said the control or the competitor is 8-week Eylea. We've said, based on the powering, it's about 225 patients per study. Now, what is left is, I think, the finer details around the protocol in terms of we know the primary endpoints. We also want to make sure we are aligned on the secondary endpoint because that will be important to the payers in terms of annualized reductions, other metrics that need to be there. And then the whole sort of details about the protocol in terms of loading doses versus rescue criteria across the arms, those are still discussions. We know FDA has a 4.5-letter threshold. EMA has a 4-letter threshold. Daniel, it's really trying to just get, I think we feel, almost 80%-90% of the plan we've already sort of aligned. Now, it's just finalizing those. That's what we have indicated we will point out in the Q3 update. Got it. Why did you decide Eylea was the right competitor? Why not compared to Vabysmo? Like you mentioned, it's taking a lot of the market share. Wouldn't it be better commercially to show sort of benefit over that? I mean, it's certainly something we could do over time. And we certainly have patients both on the phase 1 and phase 2 who are heavy Vabysmo users and where we've gotten them injection-free or very, very few injections. So we have shown efficacy in patients who are getting recurrent Vabysmo very frequently. But I think FDA just feels like aflibercept just has much more experience in the population. It's much more of the standard of care, if you will. And so that's why we do it. Yeah. To David's point, I mean, I think it was either Lucentis or Eylea because, again, when you're doing non-inferiority, FDA would want something that has been studied. So high-dose Eylea or the newer agents were not in the real-world discussion. Got it. You also have an update for DME later this year in Q4. What should we expect to see there? And then after that, what are development plans in that indication? Well, historically, agents that work in wet AMD work in DME, right? It's the same pathogenesis, the same molecular targets. So, we'd expect we would be looking at 22 patients, same dose levels, 1E10, 3E10 range generally, and looking at safety, CST, BCVA. Reduction in injection frequency is a little bit more difficult in DME because patients come in; there are very few patients who would have been on for a year or two the way they were on wet AMD where we can compare to prior. There will be some. So, yeah. So, it'll basically be the same dataset in 22 patients with DME at that time. And again, we would predict that we should see pretty similar safety and activity in DME. There's no reason to believe we wouldn't. Got it. You also talked about your GA program. Can you maybe elaborate a little more on why complement factor H is the right target? We have two approved agents targeting C3 and C5. So why do you think this would be differentiated from what's currently available? Yeah. It's a really important question. So when we think about designing these products, once we have a vector like R100 that can just deliver whatever we want, the world is open to us. We can go after almost any target. We can knock things down. We can overexpress things. And so when we thought about geographic atrophy, we felt we could either go after a validated therapeutic target or a genetically validated target. And so that's how we usually think to de-risk our products. We either express something that's either an aflibercept, which is actually an approved protein, or at least a target that's validated genetically or therapeutically. So we looked at C3, C5, targeting those with nanobodies. And we do have products in our pipeline that have those nanobodies where we could target either one of those or both. And then we looked at the complement factor H opportunity. And this short form complement factor H was designed and tested at University of Pennsylvania with a complement expert who really engineered this beautiful molecule to be highly potent, smaller, so it could penetrate through Bruch's membrane and get down deeper into the retina and have better efficacy. It also allows us to fit in AV. And he had years and years of publications and preclinical data showing this was a highly active molecule. So we looked at the totality of the data. We said we could move probably 18 months faster with this because the data already there. And we felt that it's the best validated genetic target. So about 75% of patients with GA will have a polymorphism in complement factor H that significantly reduces the activity. We felt that in those 75% of all GA patients, which is millions of individuals, we could be targeting the exact driver of the disease. That's why we picked this first. We do have C3 and C5 inhibitors in the pipeline. Okay. As you think about development in GA, so I think a big point of debate in that indication has been sort of the demonstration of functional benefit versus anatomical benefit, which is what we've seen with the approved therapies. How are you thinking about focusing on BCVA or lesion rate reduction when you think of endpoints for your initial trials? Yeah. So endpoints, in addition, is safety, which should hold because, again, the vector's the same. It should be same dose levels, same biodistribution, same lack of immunogenicity of the vector. We'll look at CFH levels in the aqueous. So we'll tap the eye and confirm that we're getting physiological levels. And then in terms of activity, I do think that at least initially, it will be about lesion growth and slowing that or halting it entirely. We only get about a 20%-25% reduction with the current C3, C5 inhibitors. And then we think over time, that can translate into BCVA maintenance, basically, depending on where those lesions are and the nature of those lesions. So we do think the initial signal will be in lesion growth, but then over time, show a BCVA benefit. Okay. Perfect. So now we can switch gears to 710. So you recently provided an update on sort of your conversations with FDA on the path forward for this program. I think some people were expecting accelerated approval to be sort of the update. You've mentioned that's still on the table. So maybe you can give us sort of a brief summary of what the update was and how you're thinking about the path forward for accelerated approval. Yeah. Sure. So, I think I can kind of kick it off and then hand it over to Uneek. But if we think about development strategy, accelerated approval can be, if it's a single-arm study, can be extremely attractive. You get to the market early. But FDA has clearly said you have to have written rolled your phase 3 in the background. So do you save that much time? We'll see. The randomized controlled study would only be about 60-80 patients. So again, not a huge study. We're working in the TDN with the Cystic Fibrosis Foundation. That's something we think we could efficiently enroll. The chicken-in-the-egg thing is FDA says, "Well, for a surrogate marker, a biomarker like CFTR expression in lung, to be validated as a surrogate for accelerated approval, it has to correlate with clinical benefit." Well, we're the first to ever show this. No one's ever achieved this. So, by definition, it's never been shown. So we have to be the ones to show that correlation. And by the time you show that correlation, are you better off just going and doing the definitive randomized trial and getting it fully approved? So, that's where we are, and that's where we've left our options open. But do you want to speak to the development plan there? Yeah. So, I mean, the idea is to do a good, solid development plan as we've already done with all the other products, right? So now we've indicated 6-9 more patients to really understand the correlation between the high expression that we continue to see across all the doses to a functional or a clinical benefit like FEV1. So assuming that's the staging that we have now alluded to, we think that will take us into 2025. So yes. I mean, I think you call it a disappointment, but for us, it's always been, "Let's just follow the science and follow good development practices. Okay. Perfect. Just a comment on the FEV1 is we've been treating these patients who have had very high FEV1s in phase 1 just because safety is paramount. We're now going to be looking to get patients on board where they're somewhere between 40-80 at baseline, where you can actually see that improvement in FEV1 more reproducibly and more robustly, so. Cool. Maybe last question. So, if you have a lot going on, how are you thinking about accessing capital as interest rates? It seems like cut rates are being pushed to the end of the year. People might be thinking it was going to be easier to access capital this year, and that might be changing. So, how are you thinking about sort of the macro environment as you think about raising funds? Yeah. I think we are sort of data-driven, catalyst-driven. I think, as I said, we are very good from a balance sheet perspective for Wet AMD, which is our sort of lead indication. As DME data unfolds, we will then decide in terms of access to capital. There are various routes. We're also, from a prioritization perspective, looking at alternative options for CF and for Fabry, given that we have four large Ophtho indications, which we want to totally own and take forward. So, I think it's a portfolio choice that we'll make appropriately. Okay. Perfect. I think with that, we're at time. So, thanks again for joining us, guys, and hope everyone enjoys the rest of their day. Thank you so much. Thanks for having us. Thank you.