On to this session of the Morgan Stanley Global Healthcare Conference. I'm excited to welcome the team from 4D Molecular Therapeutics. Let me just get through a quick disclosure before we get started. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. If you have any questions, please reach out to your Morgan Stanley sales representative. We have Dave and Chris here representing the company. Maybe we can just start out with, for those less familiar with 4D, could you provide a brief intro to the company and the gene therapy platform? Sure thing. Thanks for having us. It's great to be here. At 4D, we're a next-generation genetic medicines and gene therapy company. Our fundamental platform underlying our products is the use of directed evolution and Nobel Prize-winning technology to invent customized vectors for any tissue we want to target, which we believe then gives us better safety, lower cost of goods, and allows us to go into large markets. Our lead product, 4D-150, is basically a gene therapy AAV-based medicine that expresses aflibercept in a sustained fashion for, we believe, multi-year durability for wet AMD and diabetic eye disease. We're currently in phase III, two phase III trials that are rolling very, very well. I think there's a huge commercial opportunity here. We also have a cystic fibrosis program with an inhaled agent that expresses the CFTR transgene. We've shown very high-level expression and early signs of clinical activity there. That's currently moving into phase two II. Okay, great. If we start with wet AMD and diabetic macular edema, from a high level, how would you describe unmet need in these conditions? We often hear about injection burden reduction or injection freedom, but what are patients and physicians looking for versus what maybe we're hearing from investors? Yeah, that's a great question. Chris, you want to take that? Yeah, I can start on that for sure. It's a great question, Judah. I think the unmet need, there's two levels of unmet need when you think about it. The first is what you just referenced. It's extended durability so that you lessen the burden of injections or needles in the eye. That's pretty obvious. I think every asset that's been in development recently that's come to market or in development, they're all pursuing this additional durability without sacrificing efficacy. Of course, ensuring that safety is consistent with what we see in standard of care today. The other unmet need that's probably less talked about, but I think is every bit important, is with these incredibly efficacious anti-VEGF agents today, you gain vision largely. Most patients will gain five, six, up to eight to 10 letters of vision upon initiation of therapy. Sadly, a lot of those patients, by the time you get to year one, if not a little bit further out, have lost that vision gain. The other important unmet need is to holding onto that vision gain for the life of the patient, if you can. That requires an agent we believe that has years of durability and sustained expression so that you keep that disease in control for years as opposed to months or weeks. Okay. You've shared a good amount of data across both indications. Maybe just from a high level, can you share what the data look like on the most important metrics that you would say resonate with physicians and with patients for 4D-150 in terms of both safety and efficacy? Yeah, so at a high level, we've treated well over 100 patients with 4D-150 safely. For a large market indication like this and like diabetic eye disease, safety is paramount. At the phase III dose, we have 80 patients who've received the phase III regimen. There, we've had more than 97% of patients with zero inflammation or toxicity. That's really a remarkable safety profile. A couple of patients who did have some cells detected in the eye, it was mild and very, very transient and resolved. No patients had to remain on steroids for inflammation. Very well tolerated. That's job one. I think that gets a lot of physicians excited because they weren't sure that was going to be the case with the gene therapy. In terms of injection burden reduction, we've looked really at three distinct populations. One is the kind of highest need treatment, recalcitrant patients with fibrosis, atrophy, sort of the most difficult to treat. We started there for safety purposes. It's good drug development. You start with patients with highest need. We showed really nice reduction there from their prior year of therapies. Patients were getting 10 injections. We brought that down to less than two on average. It was about, you know, roughly 80%, 85% reduction there. 50% of those patients went from 10 injections down to zero or one. That was pretty exciting. In the broad population, we saw a very similar reduction, 83% reduction in treatment burden versus on-label aflibercept. There we had roughly 80% of patients either had zero or one injection. I think 57% had zero injections. What's interesting is we moved into the patient population of that broad population. We looked at the patients who've been diagnosed in the last six months, where perhaps their retina was healthier, less fibrosis, atrophy. What we saw there was really remarkable. 94% reduction on average. Patients had 0.3 injections over the course of a whole year. We had 80% injection-free at one year, and 87% of patients had zero or one. It's interesting. We've shown this broad activity across this very diverse patient population. We see pretty very consistent safety and activity. The exact percent who are injection-free or get zero to one injections is going to depend on the exact population you're looking at. It's broadly active in a very reproducible way. Last thing I'll add is we saw a very strong, clear dose response in every population we've looked at, both in wet AMD and in DME. Again, a consistent dose response is what you want to see as part of good drug development. Okay, great. Maybe just in terms of 4D-150's mechanism, can you tell us a little bit more about the contribution of the VEGF-C siRNA? We've seen some data from a VEGF-C trap. There's some literature out there on these targets, but can you help us understand what role this component might be playing in the design? Yeah, so when we thought about the design of 4D-150, we said, what's the market-leading anti-VEGF? It was clear it's aflibercept. Let's take an agent that's been in over 60 million eyes safely and effectively. That was an easy decision. We had more room, and we asked the question, are there any other targets that are emerging that seem to play a role in resistance over time? VEGF-C sort of percolated to the top, and we elected to put in an siRNA to knock out VEGF-C as well. There's no good model to prove that that is improving efficacy. We just can't do that. What was interesting is when we did that, the way we engineered it, it actually boosted aflibercept expression by two or three fold based on how we did the genetic construct. At a minimum, that's adding aflibercept expression, and there may be some patients out there where VEGF-C is an important target. Okay, great. You touched on it earlier, but the safety profile, I would say, regardless of modality, is highly important for a retina specialist. There's some precedent in the space in gene therapy, but I would say even in GA, right? It's just an area that these specialists are highly focused on. Like you said, so far, the 4D-150 safety profile has looked encouraging even after the prophylactic steroid regimen. I guess how has that safety conversation evolved with practitioners? Are they waiting for more data? Do we have enough at this point? What are they looking for on the safety front? Yeah, I think the short answer is they're there. They support and believe in the safety. I think that's reflected in two ways. One is the enrollment rate. What's remarkable to me is how quickly we went from a situation where Avalanche, Adverum program, had had some real concerning safety issues, particularly in DME. Partially corrected when they dropped the dose. Coming into this, that's one reason we started in the most severe recalcitrant patients. In the span of four to five years, we're now in a position where FDA, our advisory board, and the community at large said, yeah, you can not only go into wet AMD in a large 400 patient, two 400 patient trials. You can go front line. Think about that. This is a gene therapy for not only a large market, but front line large market. It's enrolling like gangbusters. If you look at that, you say, yeah, they believe in the safety profile. Maybe just on that topic, you guys were at ASRS earlier this year. It seems like the tone changed on gene therapy for VEGF-driven disease. Was that your sense this year? Yeah, and I mean, Chris is the expert. He talks to hundreds of these guys. Why don't you answer that question? Yeah, I think you're spot on, Judah. We definitely believe the tone has changed. We actually believe we've been a big part of helping that shift as well, to be honest. What you may be alluding to is the ASRS every year conducts a survey. They call it the PAT survey, their preference and trend survey. I think about 900+ of U.S. retina specialists respond to that, so a pretty representative sample size out of roughly 3,000 doctors in the U.S. They ask them a wide variety of questions. Of course, two areas that we paid particular attention to. One was what continues to be the unmet need. For this year, and I think every year since it's been done, durability, extended durability still comes up as the one unmet need that's still the greatest. That's consistent. There's another interesting question that says, of all the new modalities and novel treatments that are in development, what are you most excited about? I think that was a new question. They listed all the options you could choose from. Roughly 50% of them selected gene therapy as their first choice, as what they're most excited about. The other agents, the second choice was TKIs, just two that I think are widely known as being in development. About 17% chose TKI. We think that is certainly a very relevant data point that validates the excitement around our program and gene therapy at large. Okay, great. Just getting into a little bit of kind of retina specialist practice dynamics, when we talk to those that are in high volume practices, it seems that there's certainly interest in greater patient capacity, kind of freeing up work time. They also seem to prefer a predictable workflow. I guess how does 4D-150, if approved, fit into that mentality? It seems like there could be sort of a paradigm shift in terms of workflow. How are you communicating with practitioners on that front? Yeah, it's a great question. You touched on a lot of really important points there. First of all, when we talk about treatment burden reduction, that clearly has a benefit for the patient and their caregiver. It has the similar benefit for a practice in theory, right? It's like you have fewer injections that you need to administer to maintain the disease. Most retina practices are high throughput. They're seeing 50, 60, 80 patients a day per doctor in some cases, and they have capacity constraints. All evidence would suggest, even from the AAO, they've shown evidence that the growing prevalence and incidence rate of AMD based on the aging population versus the supply of retina specialties, that divide is going to get greater over the next 10 years. You need innovation to help solve for that. We think 4D-150 could solve for that in a really meaningful way as opposed to a couple of weeks. The other important part is these practices are kind of like well-oiled machines right now with how they run injection data. If you introduce a therapeutic into that that is disruptive to their flow, it's going to, I believe, result in adoption barriers. What's nice about our profile is how it's stored, how it's shipped, how it's inventoried. All of that is pretty much the exact same as an anti-VEGF is today. There's no disruption to that practice flow. The mode of distribution, how you inventory it in the fridges, all very consistent. We think we can tuck seamlessly into that process that's so important to them. Okay. Can you touch on kind of learnings from the steroid regimen that you've implemented thus far? You've got studies where there is a shorter regimen in place. What have you been able to take from, I guess, across all studies, both kind of patient preference and practice, along with how practitioners are thinking about implementing the steroid regimen? Yeah, I can speak to the data and Chris can kind of speak to uptake in the clinics. Safety is paramount. With a gene therapy, you really need to cover patients for the first four to eight weeks or so while that capsid is being degraded and the protein goes away. Just to be safe, we started with a 20-week taper where it's four drops a day for a month and then three, two, one. That was very well tolerated and accepted from patients. In DME, we asked the question, could we drop that to 16 weeks? That was successful. There was no evidence of, no incidence of inflammation whatsoever in that population. In the future, once we're on the market, we can play around with shorter regimens. For now, we just don't want to rock the boat. That safety profile is so important for the age. We just keep it as is. Okay. You want to speak to uptake of? Yeah, the steroids are widely available, relatively inexpensive, covered pretty much on every insurance plan that you could imagine. We don't think there's a limit in terms of access and certainly not availability. It's as simple as writing a prescription for the patient and having it sent to your local pharmacy. These patients, unfortunately, they're older and they have a lot of other things happening. That's not an uncommon thing for them to have to administer. A lot of them have taken drops for other conditions in the past. We think that's a fairly seamless thing to integrate. As important, I think when you ask patients around, hey, what is your openness to taking a steroid regimen prophylactically for the benefit of treatment burden reduction? We have yet to have a patient say that wasn't a very worthwhile trade-off. Is there anything in the trial protocol that ensures drops are taken as needed that might not translate to the real world? Is that kind of real-world barrier lower than maybe people perceive? I think certainly on the trial, good drug development would say you put in whatever you can to make sure everyone's consistently taking their drops. Patients are taking drops actually on both arms just to make sure that's easy. If you want to speak to the real world? Yeah, I mean, I think part of the design is, and David's alluded to this before, I think that the breadth of steroid coverage probably is more than you probably need. Part of the design is to have buffer there against, I think, patients sometimes that may lapse occasionally in terms of the frequency of taking the drop. In the real world, if you get to, we will obviously suggest to replicate what you do in their clinical study and what's in our label. If that's not followed precisely, we still believe that patients would have some pretty healthy coverage from a steroid perspective. Okay, great. You touched on here, but 4D-150 is tracking ahead of expectations on enrollment. What can we look forward to in terms of enrollment updates? I guess what would be the cadence of providing those updates? Yeah, we haven't given formal guidance on that, but we do expect to give updates. What we've been doing to date is just sort of giving guidance on timing of data. We brought it from the second half of 2027 into the first half. Now we've given an update to say not only that, but we'll have enrollment completed in Q1 of 2026. The next step would be to update the timing of data when we're comfortable with that. We do expect to give periodic updates, but we haven't formally signaled a specific number or time point for that yet. Okay, that makes sense. In terms of trial design and registrational path for Forefront, it seems like it's fairly similar to other trials we've seen in the wet AMD space. I think investors are just always concerned that changes at the FDA could be impacting regulatory pathways for anybody in this space. What would you say are some of the important considerations in terms of trial design and how confident you are in U.S. and maybe also ex-U.S. regulatory pathways? Yeah, it's something we take very seriously. First of all, we work with a large number of world-class advisors who've been there and done that for EYLEA, high-dose EYLEA, VABYSMO, Brolucizumab. We have a great network who helped to design this study, plus our internal expertise. We also have the RMAT kind of breakthrough designation with the U.S. FDA, and we have PRIME in Europe. I think we're probably the first gene therapy to have that, certainly in a large market. We've used a study design that's just straight down the middle, same study design that's used for all these other blockbuster agents in the field. Randomized control trial, BCVA, non-inferiority, and frontline patients. These other studies, although commercially, they get used in the more severe patients initially, the approval studies have historically been frontline. Our safety profile allowed us to do that. We think we're about as conservative and straight down the middle as we possibly could be. We wouldn't expect changes at the FDA to impact us, and so far they certainly haven't. Anything to add on that? No, I think that's fair. I mean, the only other regulatory comment I would make is based upon the data we've shown so far from our wet AMD program, both the FDA and EMA said, hey, when you're ready to go into DME, we think you just need one phase III confirmatory trial. We see that as strong support for the data we've generated. Okay, that's great. Maybe just circling back on enrollment that we get, like you said, there's a lot of active development in kind of extending duration of treatment in wet AMD. You've got the EKIs, you've got other gene therapies. I think folks would have thought that maybe everybody would be competing for patients. How much emphasis would you put on demand specifically for your program and what might be differentiating for you in terms of enrollment versus just to focus on the entire space and investigators looking to enroll patients in any trial they can? I think, look, for clinical trial enrollment, we're thrilled with the enrollment rate. Other novel agents have enrolled well as well, if that's what you're getting at. I think what's uniquely differentiated here is, we have quite a robust database of, again, over 100 patients total, 80 at the phase III dose, across a broad range of populations. Some of the TKIs, they focus more on kind of the patients with much lower treatment necessity, much less severe disease. That's a smart strategic move for them. I think for us, we have robust data across the most severe all the way to the more recently diagnosed. I think the incremental benefits, whether it's VABYSMO or a TKI of a few weeks, maybe a few months, it's just fundamentally different from something that has multi-year probably expression for the rest of the patient's life. It's just fundamentally a different category. We feel we're kind of complementary to these short-acting bolus or even long-acting bolus therapeutics. I mean, I think we're fortunate, I think we all are in this space to develop medicines with a retina community that's highly engaged. Right? I think that's, and just for sure, the sites, our top sites are also the top sites for, I would suspect, the other programs as well. That helps tremendously. That plays into it. I think what is also very true is that if those physicians and their patients didn't believe in the potential and the profile of your medicine, it doesn't matter that the ecosystem is conducive. You have to believe that what you have is something that could be super meaningful for a patient. We hear that for sure. Honestly, going into it, the question I had was, naive patients' gene therapy, how does that kind of play out? We've been thrilled. It reflects what we heard from physicians anecdotally before we started 4FRONT-1 because they said, yeah, no, their patient demand is certainly there. It's really good to see it in the enrollment numbers that we're seeing come through. I guess as you continue to prove out a safety profile like you did with updated DME data, is that resonating in the AMD trial? Do you get a sense that that data is appreciated by investigators in 4FRONT? If you're asking, does the DME safety help to give people even more confidence in one of the, I think given the history of gene therapy with the, you know, the Adverum Avalanche intravitreal product, it does resonate because they had chronic inflammation in wet AMD, but when they went to DME, they had some pretty big kind of patient disasters. For us to come in there, we went in very cautiously. We thought, okay, DME, we got to be careful. There's maybe something different about this disease. To come out of that study, albeit it's a small, you know, it's a phase I, II it's small, but zero toxicity, zero inflammation, zero front of the eye issues. I think that's really compelling to the physicians. That's what we saw at ASRS this year. Got it. I think in Q4, you'll be giving us some more data from the PRISM wet AMD study. Can you just remind us of what's coming on that update and what you'll be looking for? Yeah, we'll be showing all three wet AMD populations. The broad population will have a year and a half. The subset of that, those patients that had kind of six months or less, which is half of those patients, we'll have a subset analysis around that. We'll also update out to two years, the recalcitrant most severe population. Okay, great. I just want to make sure we touch on 4D-710 in CF. What are the latest developments in that program? What should we be looking for in terms of updates there? Where are you directing investor attention on CF? Yeah, sure. Just to remind folks, 4D-710 is an aerosol-delivered product that delivers a copy of the CFTR transgene to airway cells. Historically, that had been the holy grail for cystic fibrosis to replace the missing gene, but nobody could get gene expression in the lungs, and they failed repeatedly. We used directed evolution to invent an aerosol-delivered customized vector for the lung airways. We use a nebulizer device that's commercially used called the AeroEclipse II. This creates a particle mist of droplets that distribute from the largest airways all the way down to the alveoli. That part of the delivery, we didn't fix. That was kind of inherent on the delivery device and the nebulization. With that product, we went into the clinic at a dose that we thought could have some transduction. We did biopsies within a month or two after dosing. We found really kind of off-the-charts expression. We were up at sort of 500x, 500% of normal protein levels, and we were targeting over 90% of the cells. We were super physiologic. It was safe and well tolerated at the first dose level. Ultimately, we elected to dose de-escalate. Now we have nine patients at the lower doses, three at dose level three, and six at dose level four, which is 2.5E14. That's the data we're going to be, is the most important data to update at the end of this year, is those patients more in the therapeutic range. We're still super physiologic, but not nearly as much. We're going to be looking at continued safety. It's been incredibly well tolerated. No evidence of toxicity or inflammation on these lung biopsies at one to two months out. We'll also be looking at lung airway function, and there's a couple of ways to do that. One is with FEV1, which is quite crude and difficult to reproduce in small numbers of patients, but it kind of looks more at the large airways. There's something called lung clearance index, which is much more reproducible, less effort dependent. This has been used for product approvals now in pediatrics. We'll be looking at that to look at kind of smaller airway function. We'll be using high-resolution CT scanning to look at lung architecture. We'll continue to look at quality of life, where we've seen some pretty dramatic improvements. That'll be the totality of that data. The other thing we'll be sharing is the first data on late biopsies. Anywhere from a year to three years out, are we still expressing the transgene? What's the expression duration in lung? Going into this, we thought we would probably have gene expression out to at least a year and a half to two years, at least based on animal modeling. That would allow us to re-dose every year to two years. We'll be sharing that long-term follow-up data as well. Okay, great. Maybe just to wrap up on the company's specific questions before we do kind of a mini survey that we're doing with all management. Okay, can you remind us of cash runway and the development milestones that are supported by the runway? Yeah, we're thrilled to have a cash balance of $417 million at the end of last quarter. This funds both Forefront One and Forefront Two and all of the company operations all the way out into 2028. With data coming in the first half of Forefront One, we think we have the ability to run the company without bringing in additional capital until that reads out. If we do bring in capital, it will be to fund the DME study. We'd be very opportunistic with that. We're well capitalized and we can get out beyond the 4FRONT-1 and 4FRONT-2 data. The cystic fibrosis program historically has been funded by the Cystic Fibrosis Foundation. We'd be looking to continue that. Okay, great. Now just transitioning, like I said, to kind of three questions we're asking everybody. No pressure here. Biotech seems to be more exposed to external and macro factors of late. We're asking each management team three questions. The first is on China's rise in biotech innovation. How are you, or are you thinking about competitive position here? Will this influence R&D or business development strategy? Take that one. You're allowed to pet. Yeah, you want to use the right. It's not lost on us for sure. We are watching developments in that market for a number of potential opportunities. We talk a lot about 4D-150 and 4D-710, but we have other assets that we look at developing as well. I think we're open to multiple scenarios, be it partnership for that market or looking at could that market be used for development purposes. Got it. Maybe a little closer to home. AI, does 4D Molecular leverage AI in any way in, you know, whether it's drug discovery or clinical processes or something else? We use it for the vector discovery platform. As you might imagine, we have a billion vectors. We put them into animals by different routes of administration, identify customized vectors for any tissue in the body. You might imagine that's a very rich database to have AI go in there and ask the question, you know, what features of capsids make them go this direction or that direction, this tissue versus that tissue. That's where we apply it. Okay, great. Maybe a little bit closer to home, just on the regulatory side of things. What's been most impactful to your business on the regulatory side? Changes at FDA, pricing debates, I don't know if we're there yet for you guys, tariffs, something else that I didn't call out, just regulatory consternation if there is any. I guess we have consternation that everyone else has. Right. You know, we haven't seen it. Yeah. We're thrilled that we have the RMAT and PRIME designations for our lead assets, and nothing has changed there. Our interactions on both the wet AMD and the cystic fibrosis program have not changed. We haven't seen it. It hasn't been evidenced to us, and I think it hasn't changed our development plans at this time. Okay, great. All right. I think we will leave it there, and thank you very much for the thoughtful insights here. Thanks for having us. Yeah, appreciate it.