All right. Good afternoon, everybody. Welcome to this final session of day one of the Morgan Stanley Global Healthcare Conference. We are very excited to have the team from 4D here. Let me just start with a quick disclosure statement. For important disclosures, please see the Morgan Stanley Research Disclosure website at www.morganstanley.com/researchdisclosures. With that, we have David, Kristian, and Chris with us. It has been an exciting time for 4D with pivotal wet AMD data less than a year away now. Before we dive in, maybe give the audience a quick intro to the company and your gene therapy platform for those who may be less familiar. Sure. David Kirn, Founder and CEO. It is good to see you. Thanks for having us. Yeah, we are bringing next-generation gene therapy to large markets. We think that makes us pioneers in the gene therapy space, and we can do that because we have used directed evolution to invent highly optimized vectors, which allow us to overcome the hurdles with traditional gene therapy, and that is bring down the doses, lower cost of goods, better safety profile, better efficacy profile. Our lead product is 4D-150. It is for neovascular diseases of the retina, starting with wet AMD and moving on to diabetic macular edema and ultimately to diabetic retinopathy. Then we have a pipeline of products behind that in both retina and lung. Okay, great. We will probably spend most of the time on 4D-150, just given the stage of development and the potential opportunity here. But maybe a bit more background on the asset, why you decided to go into these indications with this molecule. Chris, you want to speak to that? Yeah. As David referenced, 4D-150 is the lead asset of looking at wet AMD as the first indication. I think the history of this space, retinal disease of wet AMD and DME in particular, has been driven by bolus anti-VEGF therapeutics, which have been highly efficacious, at least in terms of providing initial vision benefit. The challenge has been historically that these therapies are delivered intravitreal, so a needle in the eye at some rate or frequency dependent upon the patient. And that, of course, creates treatment burden. It's hard for patients to stay on therapy despite gaining vision on these therapies. So what a lot of companies have endeavored to do is to increase the durability of their medicines so that they can therefore reduce that treatment burden need on patients, physicians, and their caregivers. And that durability quest, if you will, has been met by incremental benefit— Okay. —I mean, incremental changes. You see drugs like EYLEA HD or VABYSMO, where they can extend that durability by a number of weeks. Maybe it results in one less injection per year. That's been meaningful. Those medicines have become very successful from a commercial perspective. However, we think the ultimate goal here would be could you not just extend durability by a couple of weeks, but could you actually push it by months or years, or maybe even the lifetime— Right. —for a patient. We think a gene therapy modality, provided that it's safe- has the potential to do that. I think the unique thing about the science from 4DMT is that we have shown the ability to produce very selective vectors which we think have a connection to the safety of the medicine. We think that underpins why R100, which is the vector for 4D-150, is very unique. It gave us great interest in going into mass market retinal disease with 4D-150 to accomplish just that. We think we have the possibility of not just affecting durability by a number of weeks but maybe doing it by orders of magnitude, months, years. In addition, potentially in doing so, also allow a patient to maintain their vision for years to come. That, we think, is paradigm shifting for patients and for the overall therapy area. Okay, great. You've entered into a license agreement with Otsuka for 4D-150. Maybe can you talk about the terms of the agreement, how it came together, and what you saw as the mutual benefits there? Yeah, absolutely. I think importantly, first of all, as a part of the Otsuka relationship, they have commercial rights for Asia-Pacific for 4D-150 across all retinal indications. We roughly model the value of that around 10%, maybe 15% of the total global value. Then by definition, 4DMT, we retain the global commercial rights for the balance, call it 85% or so of what we think is the total commercial potential of 4D-150. Otsuka's been a great partner. They have a very strong presence globally, but especially in Asia-Pacific. In return for that out-licensing, I think we received upfront payments north of $110 million. I forget the exact number, but in that range. That gave us some great non-dilutive financing. Which actually allowed us and given us the flexibility to accelerate our plans to go into diabetic eye disease. Yep. We have announced publicly that here shortly, we will start our global phase III trial for diabetic macular edema, which we will actually do in partnership with Otsuka. It is a global trial, one single trial required for potential regulatory approval. We have agreement to that from both the FDA and EMA, so we are excited to get that program underway. The Otsuka partnership has allowed for us to do that, and do it in a way where we did not have to raise dilutive financing. Okay. Certainly makes sense. Maybe just getting a bit more into wet AMD, you have evaluated different doses of 4D-150 in different subpopulations of wet AMD patients. I guess broadly how would you characterize efficacy and safety across those early to mid-stage trials? Yeah. We had a pretty robust phase I/II program in PRISM. We looked at very severe patients who were getting nine, 10 injections in the prior year, who had had disease for four or five years or more, and then a broader population in 2B, and then ultimately a subset of those who had been diagnosed in the last six months. We have a very broad experience. In all of those, we did a dose response assessment of 1E10 versus 3E10 vg per eye. In each one of those, we saw a really nice dose response in terms of the reduction in treatment burden. Safety was consistent, and this was well-tolerated across both those levels. Given the encouraging phase II data that we have seen, we are now heading into phase III data. I believe it is second quarter and second half of next year. Can you tell us a little bit about the design of the 4FRONT program and what aspects of the PRISM program inform 4FRONT? Yeah, absolutely. As I said, I think having that robust phase I/II experience over 70 patients at the phase III dose gave us a really nice understanding of which patients we wanted to enroll in phase III. We elected to move all the way to treatment-naive patients in 4FRONT-1 and 60%+ in 4FRONT-2. We do, in the 4FRONT-2, based on European requests, we do include some of those patients who've been diagnosed in the preceding six months, so still recently diagnosed. The reason is we see even better results in those patients than the broad population, so newly diagnosed. We also select for patients who respond to aflibercept on study. So we have a run-in phase where only if you show a 15% reduction or clearance of all fluid based on the CST do you get randomized. Got it. That, we think by choosing newly diagnosed patients who also respond well to aflibercept and then capping the CST at 500 to remove anatomical abnormalities, which can be problematic, we think we've really identified a patient population who's most likely to respond well to this therapy. That's number one, and then patients, they get the three standard loading doses. They get either 4D-150 or a sham injection, and then on the 4D-150 arm, they only receive supplemental injection if they hit the criteria. On the aflibercept arm, they get standard Q8 aflibercept. Plus, they can also get the supplemental injections if needed. Okay. The supplemental criteria, the baseline's based on where their CST and BCVA are on average between week four and week eight. It's at the maximal treatment benefit of both the loading doses plus 4D-150 is ramping up. Yep. It is a pretty stringent starting point, which we like because it means we are going to protect BCVA, protect that primary endpoint by doing that. Patients get a supplement if they worsen by either 10 letters alone or 100 microns on CST, or if they hit five letters and 50 micron. Got it. We think that is pretty tight, should protect the BCVA. Primary endpoint at 52 weeks is BCVA non-inferiority. We think we are robustly powered for that. Right. Secondary endpoints will be treatment burden reduction and the percent of patients who are injection-free at one year and so on. Okay. Yeah. And since we saw you here last year, both 4FRONT studies finished enrollment ahead of expectations and actually over enrolled. So maybe just remind us of how many patients were ultimately randomized, and how did that impact power and assumptions for the studies? Yeah. So ultimately, because we saw such rapid enrollment and we were in a robust financial position, we could upsize those and really crank up the power, particularly not only for U.S. at 4.5 letters of non-inferiority, but at 3.9 for global— Yep. —including in Japan for our partner, Otsuka, there. So ultimately, we randomized on the order of 525 to 530 patients on both studies. Okay. So we think that that puts us at 90%-plus power, not only in the U.S. but globally. Okay. Excellent. Just related to that pace of enrollment, I guess from a high level, I don't know if there's one specific factor you could point to, but what drove interest amongst investigators and patients? Well, Chris can speak to it. It starts with high unmet need. Yeah. Our data was really compelling. But go ahead. You've had a lot of those conversations with doctors and patients. Yeah. As the commercial person, you look for good evidence pre-commercial to be like, is the unmet need, is the demand what we often hear from physicians and pick up on in market research? Sometimes a good data set to help hopefully validate that is how does clinical trial enrollment proceed. I will be honest with you, though, when I joined 4DMT, we had this debate, do we go into frontline patients or not, or do we have more experience? The question I had was, what is going to be the receptivity with patients to a frontline? You have been just recently diagnosed. Yeah. Your physician is going to offer you the potential for a gene therapy. Right. Which may give you freedom from injections for the rest of your life, or you may need some limitations, but how likely is it for a naive patient to be excited about that? We always assume that someone that has been on bolus anti-VEGF for a number of years, they understand and appreciate— Right. —the burden that comes with that, but would a naive patient have the same level of enthusiasm? I think we were blown away with the enthusiasm. Yeah. It starts with doctors. I think one of the things that helped us a lot is we were intentionally about making sure as much as we can with the clinical trial sites to make sure they were aware of the PRISM data that we have generated so far. I think one of the very unique things about our program and what we have shown thus far is that while our efficacy is very compelling, I think it is very similar to other programs, our safety data really has stood apart. I think when it comes to a gene therapy, that data, combined with, as David referenced, the high unmet need we think was critical to driving the pace of enrollment. Listen, we have a great team. We intentionally built a team that was very focused, that knew retina, that had those relationships and were able to get out and advocate for our medicine and make sure the data was appropriately shared. I think the collection of all those things and combined with patients do not like getting needles in the eye. Yeah. Yeah. But they would do that in the interest of saving their vision. But if they can reduce that, while not risking the loss of vision, they will absolutely pursue those options, and I think that ultimately drove the speed of enrollment. Okay. We've talked about this in the past, but we've certainly detected hesitancy amongst retina specialists around anti-VEGF gene therapies. I think part of that did come from the Adverum episode years back. But that does seem to be changing over the last call it year or so. So maybe just help us with updated perceptions around gene therapy. How have those changed and is it just time passing? Yeah, I am going to start by just setting the stage, and then Chris can— Please, yeah. But the stage here is it is really truly remarkable is that we started this development in patients four and a half years ago. And four and a half years ago, Adverum had just had some blinding episodes in DME. There was a real fear. People saying, "Well, okay, you can go in, but go in carefully and slowly." And in four and a half years, we went from that— Right. —to lights out enrollment in frontline patients globally. Yeah. It is really remarkable, and so as Chris has had a lot of those discussions, speak to how that perception is really changed. Yeah, for sure. I think all throughout that time period, the unequivocal recognition of the need for significant treatment burden reduction has remained consistent. Right. You talk to doctors, listen, there is over 600,000 patients in the U.S. today that are on some sort of regular anti-VEGF therapy. That equates to well over 800,000 eyes because the bilateral rate of disease is quite high. It is over 40%, and that continues to grow. Not only is this patient unmet need, but offices quite often have a capacity issue. I launched IZERVAY, so geographic atrophy medicine, and you would hear from doctors all the time. They have a lot of GA patients but they would struggle with how do you fit GA patients into an already super busy— Yeah. —injection clinic? The enthusiasm for gene therapy to make a real dent in that has always been there. But to your point, there's been this question around, can you do this safely? Right. As David mentioned, as time has evolved, as our program has evolved, and there's been more of an abundance of data that goes out and says, "Hey, we think there is a way to do this. It starts with the science and do it safely," I think that enthusiasm has really come back. We just saw evidence of this, in 2025, the American Society of Retina Specialists, they do their own survey every year— Sure. —with their members. Sure. They ask the question, in essence, which program or drug in development are you most excited about? They gave them a list of options from gene therapy to TKIs to other bolus things. More than 2x the level of interest, 60%, I think, on average, said gene therapy was what they were most excited about. Then by comparison, TKIs were a distant second to that. So we think it's real. We think it shows up, and as you mentioned earlier, the pace of clinical trial enrollment is certainly is evident when we talk to physicians and survey them as well. Okay. Maybe just speaking of ASRS, you guys had a presence there over the summer. You presented your two-year PRISM data. I guess, just reaction to the data, excitement around gene therapy, even more generally beyond just the data. Palpable, I would imagine. Yeah, very much so. I think the big takeaway is it's consistent. Yeah. Right? Prior to what we shared at ASRS was a two-year update. We had previously shared an 18-month update, so it was an incremental six months. Yeah. Now we've shared two years of data across all those phase II populations that we referenced, from more severe patients that were getting 10 injections a year to patients that were broad or more recently diagnosed. I think what we see is largely throughout those different time periods, now out to two years, a very consistent safety profile. Importantly, a very consistent level of efficacy as measured by the retention of vision, which is super important, obviously, but also the continued treatment burden reduction rate. We see those numbers in the 70%, 80%, 90% range. We've seen that continuously now out to two years. So that's very validating. I think a question that often comes up from retina docs when they think about a gene therapy modality, to no surprise, is what will this look like long term? Yeah. The more we can show data out to two, three years,— Right. —maybe potentially, it gives them increased confidence of how they think about it when they consider this in a commercial setting for their patients. Okay. I guess speaking of the potential commercial opportunity for 4D-150, we touched on the powering for 4FRONT, but beyond success from a regulatory perspective, I guess, what is the feedback you get, whether it is from payers, prescribers, patients of what is a compelling profile for 4D-150? Is it a stat sig benefit in 4FRONT? Is there more to the profile they would like to see? Yeah. I will tell you, when we share the PRISM data that I just referenced, that two years of data, you're seeing the maintenance of vision, you're seeing safety that's very consistent, and you're seeing overall treatment burden reduction rates, again, between 70% and 90%. Right. That profile is immensely compelling to all of the stakeholders that you just referenced. In fact, doctors will tell you that it doesn't need to be the treatment burden reduction rates in that range— Yeah. —to still have a very compelling profile. Keep in mind, VABYSMO has been a pretty significant commercial success with reducing treatment burden by, we model at 20%. Yeah. We don't think we're going to be anywhere in that range. We think that's highly compelling across all of those stakeholders to have a very strong target product profile in the commercial setting. We haven't officially engaged with payers, but we have done a lot of market research with payers. Right. Sharing their profile, getting their reaction. Payers in the U.S. is largely Medicare Advantage plans. Sure. Being a heavily Medicare patient population. A quick plug, we will have an Investor Day focused on a lot of commercial topics on the 21st of October. Oh, great. Where a lot of this commercial content that we are talking about will go into with more detail and share some of our internal work and research to help the broader investor community get hopefully a better appreciation for the commercial opportunity. Okay, great. Maybe just a bit deeper on treatment burden, and I think this is something that investors maybe struggle with from time to time in terms of cross-trial comparisons. Just remind us of the rescue criteria in 4FRONT. We tend to see some variability across trials in that regard. So what informed your decision on the rescue criteria here, and again, just remind of what it looks like. You want me to take that one, David? Well, I guess I can take that one. Give you a little break. Oh, good. When you think about the trial design, it's all about what patients go in. We thought we'd optimize that, then the treatment, and then the endpoints. In terms of the supplemental injection criteria, we wanted to make sure that we really protected that BCVA primary endpoint, so we tightened them up a little bit from what we've been doing in phase I/II. At the same time, we'd refined the patient population, so we think at the end of the day, it's a wash, and we'll probably end up back in that same kind of 80%-85% range that we've been in in all the other studies. We feel really good about the fact that we believe protected the BCVA primary endpoint. We'll also have a robust treatment burden reduction. Okay, great. We talked about it a bit earlier, but safety obviously a particular focus in wet AMD and other retina studies as well. I guess just on the prophylactic steroid regimen, it seems like you are controlling inflammation risk fairly well. Just remind us of that regimen. Can you give us a sense of how that's been received in the phase III program? Is there any cushion embedded within that regimen to the point where, in the real world, if that's the regimen you're using, if a patient misses a dose, would you have raised concerns of IOI? Yeah, certainly. The regimen is a 20-week taper of DUREZOL. It starts out, I think, four times per day, and then it graduates down a drop a day every month thereafter. To your point, we think 20 weeks is probably way more than enough. Yeah. It's designed out of an abundance of caution. Should, in the real world, patients not be precise in their adherence to that 20-week taper, we think there's room built within that to still provide, I think, a cushion around safety for sure. It's a good question. Would there be, in the clinical trial setting, some patients that were hesitant? What patients told us loud and clear is taking a topical drop, which many of which are very used— Right. —to doing themselves— Right. —already for different other conditions, was a very small price to pay for the potential benefit of saving significant amount of potential future needles in the eye and the possibility of preserving vision. We have picked up on literally zero concern through our phase III program on a patient having any hesitancy because of a topical— Okay. —steroid taper at the beginning of the being put on 4D-150. Okay, great. We are not asking you to front-run your own commercial day five weeks from now, but assuming success in phase III and commercialization, I guess, can you give us some initial thoughts on what a launch could look like, what a commercial build-out could look like in terms of a field force? Are there particular areas of the market you might initially focus on? Yeah, for sure. I am glad to go into it now, even if it pre-empts the conversation on the 21st. It is always good to— It is easier. —say this a few times. Exactly. My background, by the way, is I have been in retina and the commercial side for nearly 14 years now, and I have done commercial leadership roles in large pharma companies like Genentech Roche. I was on LUCENTIS for a while. I was at Novartis. I launched a drug called BEOVU and built the team there from scratch. But I was also at Iveric, and I built the retina team to commercialize IZERVAY. So I have done it in a small company setting and a large company setting. The commercial footprint in both of those scenarios is largely the same. Yeah. That is the beauty about retina. There are roughly 2,500 - 3,000 injecting ophthalmologists. The vast majority of those are retina specialists in the U.S. Yeah. Interestingly, about 1,200-1,300 of those, so roughly half, account for north of 85% of all those treatments. There's a big bolus at the beginning, and there's a long tail. Yeah. The reason that's important to share for your audience is that that has a direct connection to what type of commercial footprint do you need to— Sure. —scale an audience of that size. The reality is, you probably need 60- 80 or so field-based employees in both— Yeah. —clinical sales and reimbursement support, and a total commercial footprint, 100 - 120 or so. That, I think, is a common size regardless of whether you're commercializing in a large company setting or a small company. Yeah. That's very scalable and doable for us. Sure. We know the approach there. I've done it a couple of times and we don't need a partner to do that and do it in a way where we can be competitive against much larger established players, even though we're a smaller organization. We plan and are likely to prepare accordingly to that. Okay. You touched on it a little bit earlier, but I guess just the economic model of some of these high-volume retina specialist practices, I guess, how could a gene therapy fit into a typical or maybe fairly established workflow? What are the considerations for retina specialists as you start talking to them about that? Yeah, very important. I think as many as your audience members, I'm sure, are aware that retina clinics today largely fit within a Medicare buy and bill model. These medicines that they inject today are purchased from a distributor. The clinic then assumes the responsibility for claiming reimbursement once they inject these patients. They've, I think, largely built pretty robust practices around that. They make a gross profit as a part of that treatment paradigm. I think it's important to understand for our 4D-150 is actually the answer is somewhat embedded in your question in that we do fit into that pretty seamlessly. Yeah. We're intravitreal administered, so it's a needle in the eye. It's just the same as EYLEA, VABYSMO, and all the other established anti-VEGFs are administered. We're not a surgical procedure. We think everything about the distribution system is likely to mirror what clinics use today for anti-VEGF therapy. The storage requirements, all of those things are pretty consistent. From that standpoint, I think we seamlessly integrate into the product acquisition, storage, administration pieces of the process. The other side of this is, well, they make money today, and if we reduce treatments by, call it 80%, the knee-jerk reaction is, are you not therefore reducing the economics of a clinic by 80%? I think what we remind folks is that today, the economics of a practice is driven by the price of the medicine, right? Right. Practices get a percentage of that price as reimbursement. While it's premature to say what our price will be, clearly it's going to be higher than a single— Yeah. —IVT injection of bolus anti-VEGF. You'll get reimbursement of a higher price point. You'll also get that reimbursement up front. The other component where economically we think we can make a positive impact for practices is today, a lot of patients are lost to follow-up, right? We've seen data that as early as 18 months, 40% of patients that started on anti-VEGF therapy have fallen off for a variety of reasons. Clearly, when that happens, the clinic is not capturing the value of those patients. Right. But if we were to price for multi years' worth of value,— Yeah. —generally, we often think about at least five years, then you would capture the value of that patient or those patients that otherwise would've been lost to follow-up. All that put together, we actually think, to summarize, we fit seamlessly into the current process, and we think the economics of a 4D-150 gene therapy could actually be better than what they currently have today, albeit it's calculated a little bit differently. Okay. Great. And maybe just specifically on competition within wet AMD gene therapy, right? Different routes of administration, I guess. How are you thinking about it? It seems like there's just a huge TAM available to kind of everybody that might be pursuing a new modality here, but just how you're thinking about learnings from the competitive landscape. Yeah, for sure. I think, listen, there's a huge market. The unmet need is real, so I think there's room for lots of different players. We think we're uniquely positioned against, I think, anything else in development. I think our positioning versus bolus therapeutics that are in development, be it a TKI or other anti-VEGF type of modalities, is clear. We're a continuous backbone therapy. And versus other gene therapies, the REGENXBIO program has shown, I think, very compelling data so far, certainly from an efficacy and safety standpoint. It does though require a subretinal surgery to deliver that medicine. And we think that in a commercial setting could have significant barriers to adoption just because that will take time and will be disruptive to a practice flow. And of course, if you do not have to do a surgery to deliver your medicine because you have a safe intravitreal therapy available, then we think we would be the preferred choice in that situation for sure. Then the other gene therapy program that has been advanced by Adverum, which was acquired by Lilly, intravitreal as well expresses aflibercept like we do. But I think many of your audience would know there has been a history there with— Yeah. —safety concerns that you alluded to earlier. So how that profile looks through its development program, I think, remains a big question of interest for the community. Okay. Just in the last couple of minutes, I want to make sure we touch on DME. What should we be looking for in terms of, I think we will get two-year SPECTRA data, and then we should start thinking about design of phase III. What would you tell us to focus on as DME moves forward? Sure. So on DME, it is an excellent market, as Chris can tell you. It is probably 2/3 the size of the wet AMD market and maybe even higher unmet need there, and those patient populations tend to be less compliant. So phase III design will look a lot like the wet AMD study in terms of primary endpoint BCVA, well-powered. We will give details shortly on the study design. But again, running with five bolus injections, which is typical of what DME studies five loading doses, and then response to aflibercept during that phase. It is going to look a lot like the wet AMD study. We do have approval in U.S., Europe, and Japan for a single study there given the robustness of our data. We do have PRIME designation for that in the U.S.. RMAT, excuse me, PRIME is in Europe. Then the two-year data will be essentially similar data to what we have shown before, which is basically it is only nine patients at the high dose— Yeah. —so it is safety, which is important in this. We hope to show ongoing safety at two years and injection burden reduction with very strict injection criteria in that, which will be different in phase III. So stay tuned there, but we expect to announce initiation of that study this quarter. Okay, great. Then just quickly, I want to make sure we touch on 4D-710 in CF, status of the program. We are going to get a program update back after this year. What should we be looking for there as well? Yeah. So it will be a program update in terms of expectations around total patients to be enrolled in different patient populations and dose levels. Again, we are moving into patients who are on modulators as well as patients who have no modulators available, optimizing the dose, optimizing the endpoints. We will then have a conversation with FDA. So I think in Q4, we will simply be updating the program operationally and saying, "Here is what you can expect in 2027 in terms of timing and nature of those data and regulatory updates next year." Okay, great. Just rounding out the questions, cash runway, what is funded, what we have spoken about thus far. Yeah What we consider funded. Thank you for giving me a couple of minutes. We have $431 million in cash and cash equivalents as of 6/30, with cash runway into the second half of 2028. In terms of what the cash runway includes, it does not include commitments that are due post-4FRONT-1. That is something that is gated post due date, 4FRONT-1 data that we expect in Q2. Okay. All right. Super helpful. I think we will shut it down there, but thank you for being here. Thank you for listening, guys. It is great to have you. Thank you. Thanks for having us.