Good morning, everybody. It's great to be here. I'm Dave Kirn, co-founder and CEO of 4D Molecular Therapeutics. Looking forward to some brief introductory conversation up front here, and then we'll launch into our Q&A. It's great to be here. First of all, 4D is now a hase 3 company. We've initiated our first Phase 3, the 4FRONT-1 program, for wet AMD with 4D-150. It's a huge milestone for the company, and we're excited to accelerate the enrollment on this program. This is what we're going to cover today: these value propositions. You can see, number one, we're addressing multiple multi-billion dollar blockbuster opportunities with wet AMD and DME, initially with 4D-150. 4D-150 addresses the primary unmet medical needs in wet AMD and DME, which is treatment burden reduction. In every survey you look at, physicians and patients, the number one thing they want is treatment burden reduction. They do not want needles in the eye. We address that head-on in a very transformative way, as you will see in a minute. We have a very favorable safety profile, so we have not seen any of the issues that have plagued gene therapy historically, such as inflammation, including in the eye. We have a very favorable safety profile, as you will see in a minute. We also leverage the fact that we are expressing aflibercept, which has been in over 60 million eyes safely over a decade. We believe the ability to fit seamlessly into the clinic flow, so this adoption commercially should be very straightforward. No special handling, no special injections. This is a routine intravitreal 10-second procedure to inject. We believe there will be seamless integration into the practice flow with very low cost of goods and pricing flexibility. Finally, we expect top-line data on both 4FRONT-1 and 4FRONT-2 in the second half of 2027. Let's hit each of these head-on. We talked about a large market. You can see the branded anti-VEGF market is $17 billion. We expect in our launch window it will be up to about $20 billion annually. This is a gene therapy for a high-incidence disease, which means ongoing revenue. Again, you can see the market leader in the light blue is Eylea, which is what we express. Now, when we think about commercial launches in the space, we see when we go from Lucentis to Eylea to Vabysmo, the launches get more and more efficient, more rapid. What's fascinating about this is these are really incremental improvements. As we go from the left to the right, each new therapy with Eylea and then Vabysmo is adding two weeks between injections for patients. Just a two-week delay to your next injection translates to a blockbuster. Think about that. Thirty percent treatment burden reduction. What we're talking about with our agent in the phase 3 population is over 90% injection burden reduction. You think about how transformative that could be. If you can have these kind of launches and this kind of economics with these incremental improvements with our approach, it should be quite dramatic. Primary unmet medical need is patients don't want an injection in the eyes. We'll show you that here. As patients, as they come back for more and more injections, their CST, their retinal thickness is going up and down, up and down, as you can see. That translates to vision loss. Because they can't stay on these regimens, about 40% will fall off of therapy, meaning they're now untreated and they're going to go blind. The patients and their caregivers hate the recurring injections, and it results in loss of vision over time. We can hit that head-on. With a sustained backbone therapy, we can control the disease. Many patients will never get another injection. Patients who do get an injection may get a top-up a couple of times a year, one or two times a year, still marked reduction from what they're getting currently. Physicians strongly believe that we talk to that this will translate into better vision outcomes over time. What kind of treatment burden injection are we talking about? We talk about Vabysmo reducing the treatment burden by about 30% versus Eylea. We are looking at 83% in the highest-need patients, an 83% reduction from what they were getting previously. That is a massive impact on a patient's life, where they have gone from 10 injections a year to essentially two—transformative. As we move from left to right, we see an earlier, broad population here with an 83% reduction and an earlier-stage patient population where it is a 94% reduction. On the left is probably where we will launch the product. We have excellent data showing that these highest-need patients do very well on our therapy. The far right is what we are going to be focused on in phase 3, where you can see why we believe that phase 3 is set up for success. We believe from a commercialization standpoint, we can address all these, and we should have a very broad label. Okay, safety profile. None of this matters without great safety. I said aflibercept is known to be very, very safe in the eye. Again, 64 million eyes injected to date. We're seeing an excellent safety profile. You can see in green there, those are patients who had zero inflammation. We had about 2%–3% one-plus, which is very mild inflammation that resolves. And 99% of the patients got off their topical steroid drops on time. Patients are essentially trading a few drops for a couple of months for a markedly reduced number of injections they're going to get. This is very simple to administer and very well tolerated. This is the DME data. That was Wet AMD that I just showed you. This is DME. And remember, diabetic macular edema—this is where another interventional product from Adverum caused significant toxicity and actually hypotony and some significant vision loss. We've seen no inflammation whatsoever. I think this is a testament to our innovation as a company. Our platform of directed evolution generated a vector that has this kind of safety profile. We are very excited about Wet AMD and DME. Now, what about adoption into the clinic? We have seen some commercial challenges with gene therapy. Why is that? With hemophilia, people have been worried about safety issues. They've been worried about the high cost of goods—a $3 million dose, right? In some cases, such as subretinal injection for the eye, an unusual injection technique. That has really been what the headwinds have been against gene therapy. Now, why are we different? First of all, this is a routine intravitreal injection. It fits seamlessly into the clinic flow. There is no special storage or shipping. Routine. In terms of practice economics, physicians in the US use a buy-and-bill model where they buy the product, use it, and then bill insurance. In our case, since we will be getting the equivalent of multi-years—three to five years—of income upfront, think about what that does to their cash flow. It is a big advantage. It is not just neutral; it is a cash advantage to them. As I said, 40% of patients will fall off therapy completely, and they will never see them again. They will never capture that revenue. With 4D-150, they are going to get it in everybody that they treat. We think physicians are going to love this in their clinic. It's going to fit in seamlessly, and it should really augment their economics and free them up to do other procedures that also generate revenue. I should say, again, low cost of goods. We're not talking about a million-dollar therapy. Our cost of goods is less than $1,000. We have great pricing flexibility. Again, with the kind of patient numbers we're discussing, it's a blockbuster opportunity, and pricing should not be an issue. Top-down data is expected in the second half of 2027. This involves two randomized phase 3 trials in wet AMD with the primary endpoint being BCVA non-inferiority. When we think about enrolling, we will enroll those patients who are on the far right of the injection burden reduction curve. We're going to take patients who have excellent retinas—retinas in great shape, expected to transduce well, and where we anticipate our best possible efficacy. We're also mandating that patients respond adequately to aflibercept. This further enriches the population compared to what we did in our Phase 2b, targeting patients most likely to respond and do well on therapy. We have supplemental injection criteria set by some of the world’s leading experts in this field. Our team has developed and/or launched six of the seven major retina products currently available. They know what they're doing when setting these criteria, aiming to succeed both on BCVA and injection burden reduction. These are the timelines. Again, we're thrilled to have initiated multiple sites and treated multiple patients already. We expect to have top-line data in the second half of 2027 for both Forefront One and Forefront Two, which would position us for a BLA filing in 2028. This is the pipeline. We also have an exciting program in cystic fibrosis, where we anticipate important data readouts in the second half of the year and, hopefully, some phase 3 regulatory guidance. All right, thank you for your attention. All right. Thank you. If you want to join us, welcome everyone to the Leerink Global Healthcare Conference 2025. Thank you for the presentation. I guess we're going to go into maybe a little bit of a discussion. In addition, we also have Uneek Mehra who is the CFO, as well as Chris Simms, the CCO. Before we dive into the phase 3 study, as you mentioned, 4D is now a phase 3 company. You have initiated enrollment in the study for wet AMD. Obviously, the phase 3 study was informed by the phase 2. In the phase 2 study, you've seen that the patient that were newly diagnosed did a little better than the general patient population. Can you walk us a little bit through the potential underlying mechanism for that and how it has informed the design of the phase 3 studies? That's a great point. Just a little historical context: retinal therapies for wet AMD and DME are typically approved based on frontline studies where patients have no prior therapy. Once those studies are completed and approval is granted, the label is usually very broad—covering all comers. The commercial launch typically starts with more severe patients, and then moves toward the more recently diagnosed. That's kind of the history. What we've done is conduct very broad-ranging clinical development. We have data on the most severe patients—those who had 10 injections in the preceding year and still had very thickened CST. Essentially, we started with the worst 10%–15% first We have shown great efficacy there, 83% treatment burden reduction from previously and a significant number of injection-free. On the other end of the spectrum, we went into 2B broad and then 2B recently diagnosed. Those recently diagnosed patients, that's where injection burden reduction jumped to 94% reduction and 70% injection-free in a year. Why might we see that? I think one thing is probably with any novel therapy, we know they typically do better in more recently diagnosed patients who have less severe disease. That is not surprising. I think for 4D-150, it may be, again, this is a gene therapy where we transduce the retina. If you think if the retina is less fibrotic, less atrophy, healthier, you are going to get better transduction, better gene expression, better efficacy. We think it makes sense. I think what's important is to remember is the breadth of that activity. We're unique in having a lot of data in the most severe patients where the launch will occur initially, and we still have fantastic results there. Again, thinking about the learnings from phase 2 into phase 3, there was a large portion of the patient population that was injection-free at one year, but some patients did not reach that outcome. Regarding the patients who required additional injections, are there any commonalities among them, any baseline characteristics that could explain the lack of response, or any correlations you have observed with baseline characteristics? I’d like to first point out that we are seeing efficacy across the board. It is not a lack of response, but rather a lack of being perfectly injection-free or functionally cured. This is a minor point, but an important one. We observe activity across all patients at a level that could be considered a landmark for this field. It has the potential to revolutionize treatment in a multi-blockbuster market, including wet AMD and DME. In terms of where we see the greatest injection-free rate, this appears linked to factors such as BCVA. For patients who have been treated for a long period, BCVA can serve as a surrogate indicator for the presence of fibrosis or atrophy, which in turn may help predict outcomes in the most severe patients. In the more recent patients, I think we just have such a high injection-free rate of 70% at one year. The numbers are too small to kind of pick out any predictive factors there. It's just the efficacy is too high. Great. You provided an overview during the presentation of the phase 3 studies. Both the Forefront One and Two studies are aiming to enroll treatment-naive patients, with the first one being 100% and the second one having 60%. I know there is also the Forefront Two that is focusing on those diagnosed within six months. How should we think about what portion of the overall patient population that represents? Yeah, I think, again, it's going to be essentially the entire incident population ultimately. From a prevalence standpoint, I think that will still be the majority of patients. If you look at Forefront One, all patients will be previously untreated, with six months or less disease duration. Forefront Two will be a blend of approximately 60% no prior treatment and 40% who can have a few prior injections, but all within that six-month window where we saw the best results. We expect to see excellent results in both. These studies were designed with FDA and EMA input through the PRIME and RMET designations that we have. Yeah, and maybe just to add, the incident population, at least in wet AMD, is quite large in this space. I think roughly 30-35% of the overall population is incident in any given year. Important though, to David's earlier point, we would not expect that you would have a label that is restricted to a newly diagnosed or a recently diagnosed. There is every, I believe, Vabysmo, there is precedent that would support that. From a commercial perspective, I would not expect that we would have restrictions around reimbursement or anything of that nature that would be tied to the patient's time to diagnosis or status. You've initiated enrollment in Forefront One. As you showed in the presentation, enrollment is expected to complete, and then we'll have that in 2027, right? Correct. How should we think about cadence of enrollment comparing Forefront One to Forefront Two, knowing that there is a six-months newly diagnosed component to Forefront Two? Yeah, both of them have the six-months component, but the Forefront Two allows for patients who've had one to four prior injections. In theory, that could be a little bit faster than Forefront One, but we are very excited about Forefront One and the investigator enthusiasm we've seen. We think they'll both enroll briskly. Chris, do you want to speak to kind of your interactions with physicians and how that's going to translate to enrollment? Yeah, for sure. I joined September of last year. I think between then and now, probably interacted with nearly over 200 US retina specialists. We've also surveyed them. One of the key questions we've asked is about their motivation to enroll a naive patient population in a phase 3 trial like this. As importantly, what they believe their patient's motivation would be to go into a trial like this. Thus far, the enthusiasm has been off the charts, honestly. They're incredibly excited. We started last week, so right out of the gate and early on, where again, the enthusiasm continues to be high. I think it just reflects on what is a significant unmet need in this space. If you're a patient and you have the potential to go months or not years without needing another injection, the promise of that and the potential for that is, I think, quite compelling. We are optimistic. We'll see as we get into the next couple of months and see how enrollment is going. At this point in time, we're pretty enthusiastic about, I think, what we believe could be a brisk enrollment period. We do believe that there's a real commercial opportunity here from what we're hearing from all the retina specialists. I think there's good data to say that enrollment is predictive of commercial success in many diseases, and we expect it to be the same here. Certainly. Anti-VEGF response is a key inclusion criteria. Could you walk us through how it's going to be assessed? Yeah, it's a CST endpoint, so easily measured. We've just set a bar where we think probably 85%-90% of the patients will clear it. We just want to make sure that we weed out any patients who are going to be really resistant to therapy. We saw that in the 2B. 40% of the injections were in two patients who were just refractory to aflibercept. If we can weed those out, it's just going to enrich for an even better, more compelling result in phase 3. You expect a small percent of. A small%, but an important% because those patients really don't respond at all to aflibercept. They're rare, but they're important to weed out. Weeding out those patients, can you tell us about the study power and the magnitude of effect that you would want to capture? It's a non-inferiority study. The margin of non-inferiority on the letters is 4.5 letters in the U.S., and we're powered at 90% to hit that. Right. Still with study design, could you tell us a little more about the supplemental injection criteria? Yeah, I would say without getting into all the details on exactly how they're calculated, they're very, very strategically designed based on our results from PRISM and based on other phase 3 programs to give us the best chance to make sure we protect that primary endpoint, but that we also have a very robust 80+% injection burden reduction. We think they've really been optimized for that based on changes in BCVA and changes in CST. We think it really positions us for strong success. If we think about, in both arms, if you think about potential supplemental injection and the fact that the primary endpoint is a non-inferiority, how will you account for those patients that require supplemental injection after treatment? How do you see that impacting power? Patients certainly can get these supplemental injections on both arms as needed. We know that if you look at Q4 week versus Q8 week, Lucentis and Eylea, it never made a difference in terms of BCVA. We do not expect that is going to put the primary endpoint at risk in any way. Patients can get injected, but again, we expect to see a very significant reduction in the Eylea supplementation on the 4D-150 arm versus the control arm. Our target would be, we think anything over 70% would be commercially a blockbuster, and we expect to be 80% or higher based on our PRISM data. All right. Now maybe broadening up and looking into the commercial opportunity. Can you maybe talk a little bit about how you see gene therapy positioned within this space and then how you see your approach differentiated from other genetic medicines? Yeah, it's a great question. I think there's been lots of activity and evolution in gene therapy, certainly in this space as well. Right now, I think the leading asset in terms of timelines is likely going to be a subretinal treatment based on their program. We would suspect there is a market for that, although on the lower end because of the complexities of that type of administration. I think the ultimate product profile here is one like ours where you can administer a gene therapy through a simple intravitreal injection, which retina practices do 80-90 times a day. We think our profile, one, it's intravitreal. We think our product profile allows for it to be seamlessly integrated into the clinic that exists today. It would fit within a buy-and-bill reimbursement model. There's an economic component to that that's important to a retina clinic. We think we can optimize within that as well. Product stability allows for that. Ultimately, we think if we can hit that profile, we have the potential, in our view, to be a backbone therapy. In other words, the therapy that you would go to to maintain the majority of your patients, and then you use the other bolus type of injections as needed for patients that may need a top-up. That is the vision. We think that also supports what the unmet need is that we hear from physicians and from patients. I would say just in terms of gene therapy in that landscape, we've seen surveys where gene therapy is by far and away the most exciting modality for these retina physicians. They're highly technically interested. They're early adopters of new technologies. This is something that gets them very excited. We think we have significant advantages in terms of excitement from these physicians versus things like TKIs or other approaches. All right. Again, thinking of commercial positioning and potential labels. Obviously, the data from the phase 1 patient and phase 2 patient is maturing. You're getting more duration data, right? How do you expect potential duration of effect to impact potential labels, and how would that impact potential pricing? Yeah, I'll speak to AAV first, and then Chris can speak to the commercial implications. We know that AAV therapy in the retina is highly durable. We know that. It's been shown with Luxturna out to 10 years. Regenxbio, with their subretinal injection, has great data showing stable expression efficacy out through four and a half years and counting. Adverum, despite all the inflammation they've seen, they see very stable, beautiful expression and efficacy data out through four and a half years. We know it's durable. We'll check that box, and we'll follow our patients and show that. There's no mystery here. AAV in the retina, it's a very stable, non-inviting tissue. It's highly durable. Do you want to speak to the commercial implications? Yeah, absolutely. A couple of thoughts. First of all, we talk a lot about efficacy for good reason, but in this space, like all the other therapies, safety has to be there, right? I have been in the space for 12 years, Lucentis with Genentech, then I launched Vabysmo at Novartis, and recently Eylea. I have a good set of experiences as to what a foundation of safety is going to be. We assume, based upon our data, that we have an advantage from a safety profile. To your question, I think you're right. Pricing and other factors are going to be hinged upon to a degree upon long-term data. I think the advantage we have there as well, by the time we get to a commercialization window, we'll have long-term PRISM data to show what we think would be a significant treatment burden reduction, again, across a very diverse patient population, from those that had severe disease to those that were more recently diagnosed. We think that data will be really helpful when it comes to helping price our product. We think that'll be helpful and informative for payers, particularly ex-U.S. payers. As David mentioned in his presentation, pricing is hard to predict when you're three or four years away from a launch window. However, with what we believe is a relatively low cost of goods profile, regardless of what the market dynamics are at that point in time, I think we can be adaptable and be very competitive, and at the same time, maintain a very, I think, lucrative commercial opportunity. All right. I want to take maybe a minute or two to talk also about the Cystic Fibrosis Program. Obviously, we saw data last June on the program. You are going to be sharing data this year as well. Can you remind us of what you will be sharing and what the expectations are there? Sure. That's essentially a Phase 1/2 study for 4D-710, which is an aerosolized delivery vehicle and therapy for cystic fibrosis lung disease. It expresses the CFTR transgene throughout the lung airways. Historically, there had never been a vector that could deliver to the airways. Through directed evolution, we invented a novel AAV that's very, very efficient at expressing throughout the airways after a simple aerosol administration with no evidence of inflammation. In the clinic, we'll be reporting out approximately 12-14 patients with data at four different dose levels. We'll be showing safety profile, which has been excellent to date. We expect that to continue. We'll be looking at biopsy data at four to eight weeks to show gene expression, what percent of cells are expressing. We've been hitting well over 80%, over 90% of cells expressing. We will also be looking at clinical endpoints such as FEV1, lung clearance index, quality of life. As we have been learning and evolving that study, we have been really focusing now on patients with lower baseline FEV1, so we can show that kind of improvement we want to show in phase 3. We have also been optimizing the dose. We have realized we can actually come down on the dose and decrease our cost of goods further and give FDA what they usually want, which is to know what the lowest effective dose is. We have come down on the dose very significantly, about four-fold, and still see very high-level gene expression. We look forward to giving longer duration durability data and some new patients at these lower doses. We'd like to give a regulatory update as well in terms of a pivotal trial design and plan. We look forward to it. In the meantime, there are also other programs using different modalities, specifically mRNA that are currently in development with readout expected in the first half of this year. Can you help us think about maybe the benefits and challenges of each approaches, and how do you see potential for gene therapy there? Yeah. First of all, to my knowledge, no one else has shown this kind of gene delivery. I mean, basically, all of the vectors that I'm aware of had failed to show any gene expression, and we're hitting over 90% of the cells. First of all, you got to have a delivery vehicle no matter what you want to express. You need a delivery vehicle. To my knowledge, we have the only validated delivery vehicle with that kind of delivery and gene expression and safety. In terms of RNA, that could have potential, but again, very short-lived molecule. You're going to be looking at very frequent dosing. It could be weekly or even daily at some point. Whereas with gene therapy with an AAV, we would expect gene expression out for anywhere from a year and a half to two years, and then maybe we periodically re-dose. We would just have much longer duration of expression. All right. That is all the time we have for today. Thank you for your time, and thank you, everyone. Thank you.