Good afternoon, everyone, and welcome to this afternoon session of the 2026 Leerink Partners Global Healthcare Conference here in Miami, Florida. I'm Mani Foroohar, Senior Analyst at Leerink Partners, and I'm hosting from 4D Molecular Therapeutics, Kristian Humer; David Kirn; and Chris Simms. I've got virtually the whole C-suite here. Absolutely. Well, thanks for having us. Well, let's dive in. There's a lot of focus for you guys on the speed and completion of enrollment for the 4FRONT program, both in terms of your expansion and the size of those studies and what that implies about statistical power, potential label on a positive study. Also, people are reading across to what does this imply about unmet need, demand, patient attitudes. Can we start with a quick overview of where we are and the sort of speed and acceleration of enrollment, U.S. and EU, respectively? Sure. I can kick it off, and then Chris and Kristian can weigh in. I'm David Kirn, Founder and CEO of 4D. 4D-150 is our lead asset in Wet AMD and DME. It's a product that we invented through directed evolution to basically invent a vector that's very low dose, low inflammatory potential, highly effective, and we express aflibercept. That's a product that's currently in phase III. Two different phase III programs, 4FRONT-1 and 4FRONT-2. 4FRONT-1, we've completed enrollment. That was a U.S. study. We're thrilled with the pace at which that enrolled, and I'll get to that in a minute. 4FRONT-2 is a global study. This is very much positioned as a global program. In terms of the enrollment rate, you know, we'd projected roughly 18 months to enroll. We hit 11, and that's despite upsizing the study because we raised some additional capital and did a partnership in the second half of last year. You know, roughly 500 patients and a really lights out enrollment, which we think reflects the high unmet need in the eyes of the patient, plus the physicians' excitement about our data. Then maybe, Chris, you can speak to the PAT survey and other interactions you've had. Yeah, happy to. Mani, it's great to be here. You know, Chris Simms, Chief Commercial and Business Officer, as David alluded to. You know, going into our 4FRONT-1 phase III program, we knew there was physician enthusiasm. We heard it anecdotally, but you never know until you get it out there as to what the traction and the uptake is gonna be, particularly in 4FRONT-1. We studied a completely treatment-naive patient population. To see an 11-month completion of enrollment with an upsized trial, we think is highly encouraging and we think also reflective of what ultimately will be commercial interest and demand. As David alluded to, it's consistent with the feedback we've heard from the retina community in terms of the unmet need, notably around, you know, paradigm changes in durability. The data point we reference quite often is the American Society of Retina Specialists does an annual survey with their members. They call it the ASRS PAT Survey. One of the questions they asked last year was, of all the assets in development, what do the retina physician community find to be most exciting? By far, the number one selected option was gene therapy, to the tune of 54% of respondents said that gene therapy is what they found most exciting. Second behind that was TKIs at about 17%, so 3x in terms of the physician enthusiasm. We think that certainly carried over in terms of the pace of enrollment. Let's talk a little bit about patient population. It's obviously a vast indication, a lot of nuance around, you know, intensity of treatment, you know, what will be in your study, rescue therapy medications. You know, treat and extend in the case of a commercial model for patient. Talk about the patient populations enrolled across the 4FRONT studies and how those will translate to commercialization against the label. Sure. I can start, and then Chris can speak to commercialization. You know, we start with the PRISM study where we treated really three distinct populations there. You know, roughly 100 patients plus on those studies, so very robust phase I/II exploration where we looked at the most severe patients who are getting 10 injections per year, highly refractory. We saw great reduction in treatment burden in those patients of roughly 80%. We then went to a broad population where we again saw roughly 80% treatment burden reduction. In the patients who were diagnosed within the last six months, we saw roughly 90% treatment burden reduction, with about 70% of those patients injection-free. We're thrilled with the fact that we see efficacy across all these patient populations. We think they're all on the table for commercialization. For strategic reasons, for the phase III, 4FRONT-1 and 4FRONT-2, we went into patients diagnosed within the last six months, where we're seeing the best results. We exclude patients with extreme CSTs of over 500, and we confirm responsiveness to aflibercept, so we kind of enrich that population to do well. In 4FRONT-1, that's 4FRONT-1, and then 4FRONT-2 is a blend of those patients, plus patients who might have had one to three prior injections in the preceding six months. We're really focused in on that population that's relatively recently diagnosed, most of them treatment naive. You know, despite that, we see phenomenal enrollment. It's really been a remarkable uptake, and Chris can speak to kind of our thoughts on commercialization in different populations. Yeah. It's, you know, by definition, we are anchoring to more of a treatment-naive population, an entirely treatment-naive population for 4FRONT-1, but by definition, that includes a broad population because some of those treatment-naive patients, to your point, are gonna have a higher treatment need, and others are gonna be less. We think we'll have a broad population within within that patient grouping. However, historically, a couple things. One, the FDA usually looks for pivotal trials to show a vision benefit. If you have majority of your patients that are on an existing therapy, typically they've reached a ceiling in terms of their vision gain, so it's hard to show an incremental vision benefit. Therefore, a naive patient population is how most of the pivotal studies are designed. To that point, when you look at the pivotal programs from any of the anti-VEGFs that have been approved, be it bevacizumab or an EYLEA HD or, you know, going back to the Lucentis or Eylea days, all of those pivotal programs were included treatment-naive patients similar to how we've designed our trial. In a commercial setting, that does not preclude you from treating patients that have preexisting disease. We don't expect our label would be restrictive to a patient type based upon time of diagnosis. Let's talk a little bit about differences in competitive dynamic between the U.S. and E.U. and where you think you fit in upon approval in each of those markets, where physician practice and economics are a little bit different in each place. Yeah. You wanna speak to that? Yeah, happy to. Let me start with the U.S. first, right? First of all, regardless of the market from a physician and a patient standpoint, the unmet need continues to be the need to alleviate treatment burden and show better durability. The ASRS PAT survey that I referenced earlier, they actually did include in that survey European and non-U.S. retina docs and similar responses in terms of interest in gene therapy, as well as the unmet need for increments of durability. The unmet need is universal. When we look at where we think 4D-150 would fit into a clinic, the U.S. model is clearly different from a reimbursement standpoint. The buy and bill model in the U.S., you know, it's heavily been driven by bolus treatments. However, we think that a 4D-150 profile from an economic standpoint can actually be more beneficial than the current model for a couple of reasons. One, you know, from a pricing standpoint, we will reflect most likely three to five years of benefit, so the price point would be higher, and therefore, you get upfront reimbursement, and we think that's meaningful for a clinic as well. We also help with things like practice capacity, where a lot of retina clinics need something to help alleviate the capacity constraints that many of them have today because of the growing need for retinal care. So that's how we think about the U.S. opportunity and how it fits into the clinic. Europe is different to your point. It's less driven from the economics related to the treatment itself usually price points and reimbursement is more government controlled, and it varies by country. What I'll tell you, though, as we've modeled out the potential of 4D-150 in our value proposition, we think the reimbursement would be there for our profile based upon two factors. One, the potential to significantly alleviate treatment burden on a large scale. also really important is we think we'll be able to show in our profile the potential to preserve vision over time that current bolus therapeutics can't do. you see this in the real world data, where a lot of these therapies, while they're highly efficacious and patients gain 5, 10 letters of vision upon initiation of therapy, often related to undertreatment, a lot of those patients have lost that vision as early as a year, if not sooner, on current standard of care. A 4D-150-like profile that's providing constant, you know, treatment and expression of aflibercept, we think we'll be able to show that vision that a patient gains, you can hold on to it for years. We think the value of that for all payers, but I think particularly gonna be important for European payers is gonna be very significant. Let's talk about where you are in your engagement with physicians around MSL efforts and around raising awareness. Obviously, this is a little bit of a different model than where anti-VEGF therapies, which have reshaped retinal surgical practice since when I was in medical school, obviously. How are practices gonna have to change how they approach patients, given that this is a very different model than what essentially every retina practice has been built around in terms of high volume, repeat patients, perhaps treat and extend? Yeah, it's a really good question. So as you mentioned, right? The approach to treatment today with bolus therapies is some version of treat and extend. I think physicians try and tailor and customize that to what they think is the right frequency for that patient. Unfortunately, I think in the real world, that does lead to a level of undertreatment which then corresponds to the loss of vision over time. We actually see a model where 4D-150 as a backbone therapy would actually shift it from a treat and extend approach to more of a treat and monitor approach, where a patient upon initiation of 4D-150 is likely gonna be observed by the physician at some frequency in the early phase, call it the first four to six months at a higher frequency. Maybe in the first month or two, the doctor will wanna see them back monthly for observation. Getting them through that prophylactic steroid period. What we hear from physicians when we ask them this question is they see the model evolving where once the patient is doing well and they've observed that for maybe three or four months, then they start to feel more comfortable extending that patient out for an observation period. Most of the physicians will tell us that they'll be comfortable getting the patient settled into like a four to six month type of observation where you just come back in for a quick checkup, maybe it's a quick OCT, and then based upon that, if they need a supplement, they'll provide that, but if they don't, then they'll have them come back again for, you know, on that interval. I think the model will change, and I think the clinic will, you know, adjust their operations to accommodate for that. But in fairness, I think we have work to do and work with the retina community to help educate them on how the profile of 4D-150 will be different and help them start thinking about how they would adjust their approach to treatment. We also have some time to do that, which ties into, you know, how we think about building out a medical team and so on to allow us to go and do that work. Well, if you're just gonna hand me the question, how do you think about building a medical team and doing that work? I think as early as possible. It's like there's a balance there, but I think generally I've launched a couple of medicines in the retina field, and if you have market-shaping work to do, and I think there is some market-shaping work to do in this space with a modality that is as potentially as disruptive as 4D-150, you look to do that in advance of your potential approval. I think the exact timing I think is up for consideration, but I think certainly well before that, you know, T minus 12 months, you start to think about putting a team out there. In fact, we shared this publicly. We actually already have a team within our medical affairs group that engages with a good portion of the retina community. Today, they're mostly oriented to helping support our phase III program, but that team is already in place, and it wouldn't be surprising for us to, you know, look at redeploying that team once phase III is complete in both studies to help with some of this work. How do you think about the opportunity in places like Japan and other markets where they have large populations, substantial Wet AMD populations, real markets, but maybe not places where 4D is gonna be launching at scale. Talk to us about economics and how you think about partner economics, how that flows through to your income statement to your balance sheet, and how that goes through your planning as you approach commercialization. Yes, I could speak. I mean, we have a partner for Asia Pac now for 4D-150. Japan is the largest market there today. We'll see how that evolves. There's reason to believe that other markets like China could also be of more significance further into the future. The construct of that deal is, you know, we receive, I think, very healthy upfront and cost-sharing arrangements as we go through our development program, and then there'll be milestones and royalty payments back to us based upon sales into that market once we get to that point of commercialization. We like that model. We particularly like that model for markets where we don't have the commercial scale and ability to kind of commercialize ourselves today. I think it remains to be seen whether we'll follow that model for like Europe, for example. U.S. is what we'll continue to prioritize and hold on to. You know, once we have phase III data, would we be open to a European partner similar to the construct for Asia Pac? Of course, we would. That's something that I think we'll spend more time on once we actually have phase III data. I think the timing for that is probably more related to having that data in hand before we go down that road. While we're on the topic of Europe, a conversation I've had with a couple of other companies throughout this conference before over the course of this presidential administration is a discussion of MFN, especially for mass market sensitive Medicare reimbursed, public reimbursed in the U.S., therapies for which Wet AMD obviously fits the bill. Yeah. How do you think about that opportunity, U.S. versus EU pricing and MFN impacts? Does it influence your willingness or interest in partnering OUS or wanting to control pricing in both places yourself? Yeah, it's something you have to keep in mind, for sure. I think there's still lots of things that are evolving, so we'll see where we are in kind of our launch window of, you know, late 2028-2029 and how those things are playing out. It's certainly things that I think you have to consider and it brings up things like what would be are there would you look at all markets in Europe equally, or would you prioritize one country versus another based upon some of those dynamics. I think all of those things are possible. I think the important thing that we want to continue to reiterate is, at the end of the day, this is a pricing conversation in terms of what can you get and I think pricing for us is a function of what's the value that you are providing. We remind people that we think our profile would be disruptive. We think we can provide value unlike any other bolus therapy that's been introduced or is trying to be introduced into this space solely because of the factors we mentioned earlier, paradigm-shifting alleviation of treatment burden. Even more importantly, notably for some European countries, is the possibility that you could hold on to that vision gain for patients. There's a lot of countries, by the way, in Europe today where they cap how many anti-VEGF injections a patient can get. Some patients are only getting two, maybe four injections. What you see when that happens is that those patients lose vision quite rapidly, and it begs the question as to what was the utility of those treatments initially. If you can show a value prop that says, "Hey, those patients can get the vision gain, and because of our always there profile with our medicine, you could hold on to that vision." That has to be of significance and value to a payer. The other side is that will then reflect on what we think we can command in terms of pricing. We'll remind people as well as we do have a pricing or a cost of goods profile that gives us significant pricing flexibility. That always has to be in balance. Certainly, you have to think about MFN when you make those decisions. You know, we have a cost of goods profile that's less than $1,000. This is not a therapy where you have to price it in that, you know, six, five plus figure range to have a viable business model regardless of the country. I think one of the counterpoint points to that in the U.S. is there are somewhat price-dependent incentives. Yes...for physicians. I think that's part of the challenging balance where you don't wanna price too aggressively, so you can access Europe. I'm expressing what investors have told me. Yeah. You don't wanna price too aggressively in Europe, but you also don't wanna follow MFN. There's incentives to price high in the U.S. From a physician perspective, although maybe those don't translate to you as a company. Like, how do you think about navigating those things? Is it just a function of Goldilocks, and you kind of have to, you know, you kind of have to ride those rapids or is there a more structured way to think about it? It's an art and a science, right? You try and place a structured approach to it. You prioritize the markets that you think where the value is the greatest. At the end of the day, you try and find that sweet spot for sure, where you optimize access for patients regardless of the country they're in. We don't have a simple formula that says this is exactly how it's gonna play out because those that may have that, I would suggest we would scrutinize that 'cause there's so many unknowns. At the end of the day, you're gonna try and weigh all those variables together and find that right price point where you try as much as you can to balance those different stakeholders. You're spot on. Some of those are diametrically opposed to each other. By the way, even in the U.S., you could find that. You'll find some clinics that are more economically maybe driven and savvy, where based on how the reimbursement model works here, they may desire a higher price point because that translates to a higher reimbursement rate. There's other clinics that may not operate that way that wouldn't think about it the same way. Our challenge, which is not unique to us, anyone that launches new therapies in this space have to figure out the same thing, is finding that right balance. Not just for the launch window, but how does that play out over the life of the product? Coming back to data and patient populations. Sure Obviously, Wet AMD is not the only indication where an injectable anti-VEGF therapy is standard of care. Talk about the development path and sort of commercial opportunity and differences between the two, between Wet AMD and diabetic eye disease. Yeah. I think we think about, you know, Wet AMD is a massive opportunity. It's the largest market for anti-VEGFs today. DME is also a great opportunity for us, as Chris will tell you in a minute. There's probably a significant under-treatment of that population, so if we can increase the compliance on treatment, we could actually grow that market. Then diabetic retinopathy is wide open for us. Again, bolus anti-VEGFs really aren't used there even though they're effective. We think those are all viable markets. There's now. You know, we already have alignment with FDA and EMA on this filing on a single DME study. Now with Wet AMD, the new guidance from FDA would seem to apply to us in Wet AMD as well, so we're gonna be looking at that, whether we could file off a single study there and then, you know, again, we'd like to get at some point into diabetic retinopathy as well. There's a tremendous amount of value on the table for us and I don't know if there's anything you wanna add to that. I would just probably repeat things you just said. I mean, I actually believe from a commercial perspective that with time, for our profile, you could see DME actually being as large, if not larger, of a commercial opportunity as AMD for a couple of reasons. One, the prevalence of patient need is actually higher than AMD, and patients are historically vastly undertreated. The average number of injections that a DME patient gets versus what they need to get is also very much understated versus the unmet need. If you talk to physicians and you ask them about the unmet need, you'll hear quite consistently that DME patients where adherence to therapy is a challenge. The effects of that over time on a younger patient population is a challenge, it's something they worry about. Nothing happens, as you know, in this space unless there's belief in the safety profile, which is, I think, a key differentiator for us. If they believe in the safety, and you have a product that provides continuous disease suppression and, you know, expression of aflibercept, they actually see the attractiveness of that for a DME patient population even be higher than AMD. We actually think that it's our second indication. It's the second largest market opportunity today. I could see a scenario where it becomes, you know, as big if not bigger of a commercial opportunity for us. That, by the way, does not include what potentially could be the opportunity for diabetic retinopathy, as David alluded to. We're excited about the potential to go into DME, and we're hoping to get that trial started in the third quarter of this year. I know we spent the majority of our time talking about the alpha side of the house. I don't wanna totally ignore the rest of the company, obviously. Talk to me a little bit how we think about CF, where we are, and what the next update's gonna be there. Sure. The CF product 4D-710 again uses a vector that we invented through directed evolution, this Nobel Prize-winning technology, and allows for a low-dose, safe inhalation therapy. We've shown in the phase I study a high degree of highly reproducible and robust transgene expression throughout the airways, both large airways and smaller airways. We've shown a nice dose response. We had too much expression early on, so we've actually had to decrease the dose to get in the right dose range that's more physiologic. At this dose level, we've had great safety, very durable expression. We've now followed patients anywhere from one to three years out and gotten repeat biopsies and showed ongoing expression. We solved the big problem for the field. We got a high level expression and high durability, particularly compared to things like RNA or herpesviruses that are much more transient. We're thrilled with that. Now that we're in the right dose range, we need to run a phase II in the right patient population where we can maximize our ability to see benefits on airway function, and that would be things like FEV1 or a Lung Clearance Index, which is a new, more sophisticated and precise measurement, as well as quality of life. We're enrolling the phase II. We're gonna give a program update in the second half of this year, and we'd love to get you know, a robust data set and then have a conversation with FDA about a phase III study design. Great. With that, we're running now to the end of our time. One quick update. I wanna talk about where you guys are in terms of balance sheet and how far your runway runs versus where these critical events are gonna play out, especially for the 4FRONT studies. Yeah, sure. Over to you, Kristian. From a cash perspective, as of December 31st, we had a little bit over $510 million in cash, and are guiding to cash runway into the second half of 2028, which gives us plenty of cash runway to get past 4FRONT-1 data in the first half of 2027, as well as 4FRONT-2 data in the second half of 2027. The DME trial that we're going to initiate in the third quarter of this year is fully funded. What is not funded would be the commercial ramp-up that we should expect post 4FRONT-1 data. Perfect. With that, we're winding down just on time. All right. Thanks for having us. Thank you. Pleasure as always. Thanks, Mani. Appreciate it.