From the Cantor Fitzgerald Biotech Equity Research Team. Very pleased to welcome the team from 4D Molecular Therapeutics. We have David Kirn, Chief Executive Officer, Chris Simms, Chief Commercial Officer, Dhaval Desai, Chief Development Officer. Gentlemen, welcome. David, I think you've got some slides to run through, and then we'll head into Q&A. Sounds good. Thanks for having us, Josh. So we'll start out with a few slides just to orient you all based on our Development Day of 4D-150 yesterday. So I think I can control these from here. Let's hope. Okay, that's good. Very good. Thank you. Okay, so these are the key takeaways from the 4D-150 wet AMD development day. So first of all, we've shown that 4D-150 has robust and durable clinical activity across all wet AMD populations studied. We'll get into that in a minute. Tolerability has been excellent, with a safety profile and inflammation profile that's in line with approved anti-VEGF agents to date. And we also shared the 4FRONT-1 phase III design, which is designed to maximize the probability of clinical, regulatory, and commercial success. So as we get into the efficacy data, we know that population matters in wet AMD. This is a very heterogeneous disease, and so we have three interesting different populations that we studied 4D-150 in. First of all, the phase I and II- A was very much a an end stage, heavily pretreated population, the most severe disease and very long disease duration out to beyond 10 years and up to, on the average, about 10 injections in a prior year. So a very severe population that we're really not used to studying in wet AMD, but it was appropriate to start there in phase I for safety purposes. Phase II- B was more of a broad population that one would see in a busy retina practice with some severe patients, but also some recently diagnosed patients, so a nice blend. Phase II-B, the population extension part, where we looked at the 50% of patients who were recently diagnosed in the preceding six months, moving more towards a typical phase III population, still more severe, but moving in that direction, we studied those patients as well. So we have a really nice data set that looks at 4D-150 clinical activity across all these 3 distinct patient populations. So when we start with the severe patient population, again, these patients were getting on the order of 10 injections in the preceding year. After one year of therapy, what we saw is a 44% injection-free rate. So to think about this, these patients had disease for anywhere from 5 to 10+ years. We're getting 10, almost monthly injections in the preceding year. Patients came on with very active disease, elevated CST, and yet 44% of those patients were retained, remained injection-free at the end of the year, and 50% got either zero or one injection. Treatment burden reduction was 83%, so going from 10 injections in the course of a year to two. This is something that our key opinion leaders and experts in the field think would be very, very attractive to these patients. Now, as we said, population matters. When we get into a more broad population, what we saw was a 70% injection-free rate, so consistent with most anti-VEGF agents seem to work better in earlier stage or less advanced patients. We see 70% injection-free and a treatment burden reduction of 89%. 80% of patients either had zero or one injection. Now, what gets really interesting is we get into the broad population who's more recently diagnosed, say, in the last six months. That was half of these patients. What we see is the injection-free rate going up again. So 87%, based on Kaplan-Meier estimates at 52 weeks, with a treatment burden reduction that's difficult to measure in this population because some patients only had a single injection, so it's very difficult to calculate that, but nevertheless, a reduction in treatment burden. Safety to date, this is critical for large market opportunities. So at 4D, we believe with our technology, move into large market diseases, but to do that, you need to have a reasonable cost of goods, and you have to have an excellent safety profile. We're thrilled to date with the safety profile of 4D-150 in both wet AMD and DME, where we're really not seeing significant inflammation. We've seen no vasculitis, no hypotony, none of, none of the other things that people worry about to date. And so to date, our IOI profile is in line with standard Eylea, which is not surprising since that's what we're producing from the 4D-150. So we need to keep an eye on this. Obviously, we're not out of the woods, but we're thrilled with the safety to date. So the 4FRONT phase III program will be starting this first phase III in Q1 next year with 4FRONT-1 and then 4FRONT-2. The second large study would be on the heels of that soon thereafter. The design is attempting to maximize our likelihood of clinical success, regulatory, and commercial success. It's been informed by our PRISM data, as well as the phase III designs of other programs. As you'll see in a minute, our team has led the development of six different products in large market ophthalmology, so they really understand how to design and run these studies. We have had extensive discussions with FDA and EMA, and we're very much aligned with FDA on the 4FRONT phase III design. Goals again is to hit primary endpoint of BCVA non-inferiority. This is sort of non-negotiable with the FDA. This is what they want, and this is what we have to deliver, but we also want a secondary endpoint of reducing treatment burden for patients, in terms of what patients want and what we'd want to have commercially, and then the design features here, we will be taking treatment-naive patients into the study. Treatment-naive and newly diagnosed, this, I think, is probably a first for a genetic gene therapy like this in a large market. This is very much supported by investigators and by the FDA. We also will require patients to demonstrate responsiveness to aflibercept on study, so we'll try to weed out those bad actors who might put the primary endpoint at risk, so I think it's a study design that's set up to win. We'll be focused on the 3E10 dose. We'll be using our standard Durezol drops for the steroid prophylaxis. We will use three monthly loading doses, as is typical on these phase III studies on both arms, and then the comparator arm will be aflibercept Q8 weeks, 2 mg, which is the standard comparator for non-inferiority studies, and those patients will not be allowed to get rescue injections. So thrilled with our ophthalmology team. We've really evolved. You know, we've known Josh for over a decade, and we started with a platform, broad, diversified product portfolio. Now we're laser focused on ophthalmology. We have, again, four leaders, two of which are here today, and they've been really instrumental in getting six different large market products approved and through phase III and several launches. This is the design. You can see the schema here, where patients will get their three loading doses. If patients respond anatomically and by BCVA criteria, they'll be randomized into the study, and they'll either get 4D-150, followed by sham injections or supplemental injections as needed every four weeks, whereas the aflibercept arm will get alternating aflibercept and sham injections throughout. Again, the primary endpoint is BCVA. Key secondary endpoint will be treatment burden reduction on the 4D-150 arm. So with that, thank you, and Josh, we'll look forward to taking the questions. All right. Super. Thanks for the overview. So one of the slides you showed yesterday kind of compared PRISM to some of the other trials, and you made the point that those patients are most like the ARCHWAY trial patients. For the phase III program, which do you think is the right benchmark, you know, in terms of the baseline-type patients you'll be enrolling? Or do you think you'll have major differences compared to, like, the high-dose Eylea trials or the Vabysmo trials? Yeah. Probably Dhaval's the best to speak to that. Yeah, so great question, Josh, and part of the reason that we went into the treatment-naive population for phase 3 is that we know what these patients do. After three injections of Eylea, Eylea HD, Vabysmo, whatever it is, doesn't matter the dose, doesn't matter the agent, doesn't matter the frequency you give it on, we know that those patients, at the end of the year, wind up getting about six or eight letters. They wind up getting about 130-140 micron decrease. And the reason we went into that population is if you look at the data from the 2B and even the data from the most recently diagnosed, what you see is those CST lines and those visual acuity lines are almost rock solid. They stay down, and they go up in terms of visual acuity, and they stay up. CST goes down, and it stays down. The reason for giving three injections is we know we get the initial benefit that you see, and then we expect 4D-150 to be able to hold them for the rest of the year. So we expect our results to be very much in line with the treatment-naive studies that are out there. Got it. And in terms of the baseline patient criteria, though, I think you did kind of answer it, indicating that you'd expect that sharp CST decline. Now, you're selecting for responders. I don't think to Eylea. You didn't give kind of the specific responder criteria, but I assume it's kind of a threshold effect in CST reduction? Mm-hmm. Yeah. Anything, anything below that? Yeah, so maybe just going back to the baseline piece. So the baseline criteria for almost all of these studies in newly diagnosed wet AMD are pretty much the same. They're roughly, you know, 70 years old, 65 letters, about 350 microns. Yeah. So that's what we expect to be enrolled into this program. Got it. When it comes to response criteria, I think folks are familiar with the data from the VIEW 1, VIEW 2 studies, which is the aflibercept registrational program. What that basically shows you is that that response up front predicts for fluid variability over the next 52 weeks. What we're looking to do is really optimize, as we said, protect the primary endpoint, but optimize for the secondary, which is treatment reductions in the following 52 weeks. Okay. What do you think you need to show? Um... Yeah, I think, you know, we want to show BCVA non-inferiority. We, we hope over time that by flattening that CST curve, we may actually improve vision outcomes, but that's going to take a number of years to prove, because we know that up and down oscillation of the CST does lead to vision loss over time in the control arm. But BCVA non-inferiority, we want to show a significant treatment burden reduction versus the control arm. You know, FDA probably sets a very low bar for that. We think we can beat that. And, yeah, that's primarily it. You know, if we hit on those two endpoints, I think we're in really good shape. So what do you think a significant reduction in treatment burden looks like, either in terms of injection free or just the absolute reduction? Yeah, I think for patients, you know, we heard loud and clear from the KOLs yesterday that they think that treatment burden reduction is huge, and then the icing on the cake is really the opportunity to potentially be injection-free for a whole year or many years. So they're both important, I think, to patients. I think, you know, FDA would likely want something on the order of 50%, and in our studies to date, we've been in more of the 80%-90% range, so we think we could definitely overcome that hurdle. And then, you know, we're thrilled with the injection-free rate, you know, of anywhere from 70% to mid-80s with the broad population, plus looking at the more recently diagnosed, giving a higher level. If we came anywhere close to that in a phase III, we'd be thrilled. We do think it's possible that we do even better than this recently diagnosed phase II-B population, because again, we are going to the treatment-naive, and then we're mandating that response to weed out resistant patients. So if anything, we hope those results could even get better. Okay, so you think treatment-naive are even easier to treat than the ones who've been evaluated, like, across the totality? I think so. The trials Especially if you select for those who are, you know, responding to aflibercept. In terms of the reinjection criteria, which we talk a lot about, what are they going to be here? So, we haven't disclosed this entirely. What we have said is the reference point will be after three loading doses of aflibercept. So, you know, we're gonna get people really well controlled and then measure from there. That's more, kind of later, reference point than we've done before, so it's kind of starting at a lower CST. At the same time, however, you know, we are going to adjust the supplemental injection criteria based on CST and BCVA or both, to optimize for protection of the primary endpoint BCVA, but also allowing us to show a significant reduction in treatment burden. So that's how we think about it. We do have a team now that has very intimate knowledge, and in as many cases, led these other phase III programs, where they've defined these sorts of disease progression endpoints and have deep knowledge of that. What is there to adjust? I mean, there's CST, there's BCVA. We did see Regeneron go for an " and" criteria. Would you go to that extent, or you're thinking more about, you know, just where that CST cutoff would need to be or where the BCVA I think it could be both. You know, I think we want to protect BCVA, but as you know, you know, CST usually progresses before BCVA, so you have to have a CST-only criteria, but you could also think about criteria that also would say an " and" as well. So that's really how we think about it. Okay, got it. It seemed like significant enthusiasm to enroll the trial. When do you expect it to start? What are the gating steps for initiating it, and any thoughts in terms of how long it might take to enroll? So Q1 to start, we're still on track for that. You know, we've got a great team already, and now we've added some significant firepower with these guys coming on board, and a number of people they've worked with before have executed these trials. So we feel really good about our ability to recruit it. You know, you never know what the enrollment rate's gonna be until you start a study, but we feel very positive in terms of the investigator interest, and also, we just hear from investigators that their patients really want something like this. Especially since they're gonna get standard of care loading doses anyway, we hope that that barrier to enroll in the study is relatively low, and we can enroll it briskly. We're not giving formal guidance, obviously, at this time, you know, until we get started in terms of the timing to enroll, but it is a 500-patient study. So, you know, we think we can enroll it as briskly as anybody does these studies. Would you pursue an SPA with the FDA? Do you see any need for that? And then beyond the FDA, how are you thinking of aligning with European or other regulatory groups? Yeah, so for the FDA, we report into CBER, not CDER, and then Wiley Chambers, who was a big voice, had retired, and now obviously has no influence over CBER. So we had direct conversations with them under the RMAT designation, so we had multiple, very productive interactions with the FDA, and we just didn't need an SPA. We are very much, you know, following the tried and true approach of, say, Vabysmo and other major drugs, where it's non-inferior to BCVA standard comparator arm, and so we just found we didn't need it, and we're well aligned with them. EMA, you know, again, we're designing these studies to lead to approval globally, and we're very close with EMA, where we have PRIME designation there. We've aligned on the high level, primary endpoints and structure of the study, and now we're just ironing out some details with EMA. As the market shifts away from 2 mg Eylea to either high dose or Vabysmo, how do you think about, you know, evaluating 4D-150 either relative to or kind of using them as either induction or rescue agents? Yeah, I'll speak to the trial design and regulatory aspects, and maybe Chris could speak to the commercial aspects. But, FDA made it very clear that you have to compare to the 2 mg Eylea because that's been the comparator for Vabysmo and high-dose Eylea. And so what they fear is that if you have non-inferiority, and then you start comparing to the non-inferior agent, and you keep doing that, you might have this creep away. So they want you to stick with 2 mg Eylea for the study, but do you want to speak to the commercial aspects of that? Yeah, I mean, excuse me. It's interesting for the reasons David mentioned that phase III is designed the way it is with, you know, the original Eylea. What we, what we've noted with both of those assets as they've been launched from both Genentech and Regeneron is, and both of them obviously perform well. They have a good efficacy and safety profile, but the true incremental benefit from both of them is measured in weeks, maybe, relative to what the patients would have been getting previously. And then when you compare that to what we're seeing in our phase II data, you know, the corollary is what 45% of patients on the Vabysmo can get out to week 16 in a patient-naive population, and then compared to what we see in phase II, we've got roughly the same percentage that are at 52 weeks in a much harder, more severe-to-treat population. So I think commercially, that data continues to play out in phase III. It's a very compelling commercial proposition. During the event yesterday, David, you alluded to aflibercept level expressions being durable, but I don't think you showed any of that data. Maybe you can help quantify and then also let us know, like, when might we see more about that? Yeah, so we put it in the appendix. Okay. It was already a very extensive slide deck, so we figured that didn't make the cut, but it is in the appendix. But what you'll see is, you know, the in phase I, we got those levels over the course of two years. As you know, the aqueous humor is sort of the tip of the iceberg for what you're actually producing in the retina. And so we've seen a strong dose response at 12 weeks with the aflibercept levels. That having been said, we do have patients who have very low levels in the aqueous, or even negative, who have long-term responses. And we showed in primates that, you know, again, the amount we think we need in the retina, based on standard, aflibercept, is such that, levels can be very low or even undetectable in the aqueous. So it's a very crude measure of what's going on in the retina, but we do see a dose response. And for the three patients at the high dose who are now out, two and a half to three years, we did see nice, stable levels at whatever the set point for that patient was. But the levels between patients vary quite a bit. When might we see a data publication outside of a medical conference? Yeah, we haven't given guidance on that. I mean, we're moving so fast and focused on phase III, but we'd love to get a publication out, certainly within the next year, for sure. You're evaluating compared to a regimen that really isn't necessarily reflective of standard of care in terms of the regular. Yeah Every two-month Eylea. You're gonna show a benefit relative to something that is not the standard of care- Right. Right? Right. How do you, certainly in terms of injection frequency- Yeah How do you think about that adjustment when it comes to pricing? Yeah, Chris? I'm sorry, was the last part relative to pricing? I didn't get the last. Yeah The last piece. Yeah, so pricing is an interesting conversation, right? Whenever you go into this space, or any space for that matter. Ultimately, any pricing decisions are gonna, I think, reflect the value that we show in our, excuse me, our phase III data. At this point, though, I think it's important for a couple of things, it's important to understand. One, as David mentioned, the cost of goods profile we think is very conducive to going to a large market. We don't think of this as a product that's niched to a small subset of AMD patients. We truly believe it's a product with a profile that can appeal to all of them. We think that allows for great pricing flexibility. Where that ultimately sits is gonna be a function of, you know, what we see in our data and what we think the value and the true treatment reduction burden is, that'll be delivered. But we think we can be competitive, we think we can show value to patients and physicians, and also, importantly, to payers. All right, maybe we can turn to the CF program. There's a lot more to forty than the wet AMD and ocular indications. Maybe give us some of the latest updates for 4D-710, and what we should be looking for from that program over the next 12 to 18 months. Yeah. So we're really excited about that program, Josh. I think, as you know, we've really seen remarkable delivery and transduction in these patients who are not amenable to CFTR modulators, with over 90% of cells on multiple biopsies and brushings staining positively for the transgene. We've seen data on quality of life and on FEV1 improvements in some patients, not all patients, certainly at this point, but we've seen promising improvements there. As you know, we dose de-escalated because of with the directed evolution, we found that our vector was so efficient, we had to drop the dose. We were actually overexpressing, and that might have led to some reduced, transiently reduced FEV1s at the highest dose. So we've walked that back, and now I think we're really excited to see the results from this lowest dose cohort there to decide on the dose to take into advanced development together with the CF Foundation. Would that next step be a pivotal trial, and? That would be the plan. Yeah To get to a pivotal trial as quickly as possible. I mean, the FDA has made it very clear, as you know, in these rare diseases, they don't want you to play around in uncontrolled phase II's. They want to get right to a study that answers the key questions. I think, last year we talked about the potential to have, like, mucociliary clearance studies to the evaluation and the protocols. Is that something you've been able to incorporate? Not yet. We looked carefully at that. We would love to have a functional marker, because what we're getting is this very high-level expression. But in this patient population, we're not just seeing clear, consistent, you know, 10+ improvements in FEV1 in everybody, so we'd really love to have a functional readout. Unfortunately, just that mucociliary clearance, the more we looked into it, it looked like you'd have to have probably a 100-patient study to really tease that out. And we've looked at some other endpoints. But to date, we know the transgene is very functional in vitro. The same transgene has been functional in the pig model of CF, but we just don't have a good functional marker in humans, unfortunately. Early thoughts on trial design and primary endpoint or endpoints? Yeah, I think FDA has made it clear to us that some combination of FEV1 and quality of life would be sufficient. I think most investigators want to see a consistent FEV1 effect. Certainly, in this case, since there's no available therapy for these patients, it could be a small randomized study or could even be a single-arm accelerated approval study. But those would be the endpoints, and you know, we've talked about you know, sort of 50 to 100 patients for a study like that. Feels like we've kind of gone back and forth a little, whether this might be a monotherapy or a placebo-controlled trial. What's kind of guiding that, and what. I think you know, our ability to do a single-arm, uncontrolled study. We would have to see very significant change from baseline in patients where you wouldn't really need that control arm. Certainly for the quality of life, we'd need a control arm regardless. So I think if at this lower dose levels, we feel like we're seeing consistent enough, major enough FEV1 improvements, we could go back to the FDA and say, hey, maybe this is a single-arm study initially, and then a randomized phase III. But I think if it's more in the range that we've seen to date, and we want to rely on quality of life as well, then it would need to be randomized, obviously. Got it. What in your mind is a meaningful FEV1 signal? You know, it's very interesting. If you have a big enough population, there have been modulator approvals for specific mutations where you have 3%. So the physicians would say in this population, where there's nothing available, if you could stabilize the FEV1 over a long period of time, that would be a win. Obviously, for a phase III, that's not, you know, it would take too long and be too large a study. So I think if you hit 5%, every 4% or 5%, everyone would be very happy with that. Got it. And how durable would that need to be? FDA is talking about nine months, but obviously, we'd hope that this would be out for, you know, perhaps a year and a half or more. We do believe that we can redose in the lung specifically. We have shown that in primates. Other people have shown it in primates, ferret models, so we're pretty confident that we can do that, but we don't yet know whether is that, whether that's gonna be at a year and a half, or three years, or later. What criteria are you looking for to trigger a redose? The criteria? Well, two things. One would be. So you'd love to get repeat biopsies of these patients, so we have amended the protocol to go beyond this initial biopsy that we do between four and eight weeks. We'd love to get later biopsies to say, h ow much is that? How rapidly is that signal dropping? You know, it started at 90%, 95%. You know, a year later, is it still at 90%? Is it 50%? You know, that would help guide us in terms of the turnover rate. The other thing we could look at is in patients who have a nice FEV1 response, does that degrade over time? And so we're looking at both of those things. But as you know, in a small population like this, and it's difficult. You know, we're very fortunate that the patients and the CF Foundation supported these biopsies in the first place. It's very difficult to get multiple lung biopsies in these patients, just ethically. Now turning to 4D-310 and the Fabry program, you're off clinical hold. Yeah. What's your latest thinking in terms of advancing this program? I think at one point you were talking more about potentially outlicense or finding a partner. Is that still a priority, or is this something that you think you'll advance further on your own at this point? You know, I think. So we're excited about the data to date. It's only six patients. It's been a slow one to enroll, but the results are compelling. I mean, you've seen them. You know, we see improvements in echo, GLS. We see improvement in cardiopulmonary exercise testing and quality of life, so it's exciting. And it's a high unmet need in Fabry disease, leading cause of death. You know, that having been said, you know, we have our hands full with large market ophthalmology. So I think as a business, we'd love to get back in the clinic and validate that rituximab sirolimus regimen blocks the hemolytic uremic syndrome, as others have shown. We just need to confirm that in a few patients here. Maybe three to six patients is all it would take, and then, really, I think at that point, we could either. If it looks like it's a very accelerated approval, and it. That's certainly possible in this disease. The improvements we're seeing, it's clear from the FDA that that would be an opportunity as an accelerated approval, maybe even single arm. If it really is a straight shot on goal and we're getting great enrollment, we might keep it ourselves, you know, or the alternative is lock down the regulatory plan, lock down the safety, and then partner it out, or even start a new company around it. So we're looking at a lot of different corporate structures for that, but we want to see that advance because I think patients need that, and it's looking very promising. Then for the wet AMD and CF programs, are those ones that you can do globally on your own, or at some point, might you consider strategic or regional partners? I think we definitely can get the approvals on our own. You know, we built the team to do that. I think Chris will have to speak to the commercialization, but we do think we can do. We could do it. I think the pharmaceutical interest, particularly on the wet AMD side, has been very high. But we know it's a big value driver for our company, so we wouldn't want to do a value degrading partnership. It'd have to be the right partnership, ex- U.S. only. But we certainly think we can execute on the phase III's on our own. And Chris, do you want to speak to commercialization? What would be required? Yeah, for sure. I mean, globally more complex once you get ex- U.S., but commercializing in the U.S. within retina, it's not a, y ou know, small companies have done it, and we just recently did it at Iveric. You know, your footprint to scale a 2,500 to 3,000 retina specialist audience is not that large. So, we could certainly, I think, commercialize in the U.S. on our, on our own, with even being a smaller company. Yeah. All right. Well, looks like we're out of time.