4D Molecular Therapeutics Inc Aktie

Thank you. All right, good afternoon, everybody. Welcome to this final session of day one of the Morgan Stanley Global Healthcare Conference. We're very excited to have the team from 4DMT 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/research disclosures. So with that, we have David Kirn and Chris Simms with us. It's been an exciting time for 4DMT 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. So Dave Kirn, founder and CEO. It's good to see you. Thanks for having us. Yeah, we're 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've 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.

So our lead product, 4D-150, is for neovascular diseases of the retina, starting with wet AMD and moving on to diabetic macular edema, and ultimately to diabetic retinopathy. And then we have a pipeline of products behind that in both retina and lung.

Okay, great. So 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?

Yes, so, as David referenced, 4D-150 is our lead asset, looking at wet AMD as the first indication. I think the history of this space, retinal disease, and 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 of 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, 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.

And 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 for a patient. And we think a gene therapy modality provided that it's safe has the potential to do that.

And 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, and we think that underpins why R100, which is the vector for 4D-150, is very unique and it gave us great interest in going into mass market retinal disease with 4D-150 to accomplish just that.

So we think we have the possibility of not affecting durability by a number of weeks, but maybe doing it by orders of magnitude, months, years. And in addition, potentially in doing so, also allow a patient to maintain their vision for years to come and that we think is paradigm shifting for patients and for the overall therapy area.

Okay, great. And 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 kind of what you saw as the mutual benefits there?

Yes, absolutely. So 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. So then by definition for 4DMT, we retain the global commercial rights for the balance, call it 85% or so, what we think is a total commercial potential of 4D-150. Otsuka's been a great partner. They have a very strong presence globally, but especially in Asia Pacific and in the 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. It's actually allowed us and given us the flexibility to accelerate our plans to go into diabetic eye disease. We've announced publicly that here shortly we'll start our global Phase 3 trial for diabetic macular edema, which we'll actually do in partnership with Otsuka.

It's a global trial, one single trial required for potential regulatory approval. We have agreement to that from both the FDA and EMA. So we're excited to get that program underway and the Otsuka partnership has allowed for us to do that and do it in a way where we didn't have to raise dilutive financing.

Certainly makes sense. And 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 kind of those early to mid-stage trials?

Yes, so we had a pretty robust Phase 1-2 program in PRISM, so we looked at very severe patients, who were getting 9, 10 injections in the prior year, who'd had the disease for four or five years or more, and then a broader population in 2B, and then ultimately a subset of those who'd been diagnosed in the last six months. So we have a very broad experience. In all of those, we did a dose response, assessment of 1E10 versus 3E10 vgs per eye. And in each one of those we saw a really nice dose response in terms of the reduction in treatment burden, and then safety was consistent. This was well tolerated across both those sub-vials.

And then, given the encouraging Phase 2 data that we've seen, we're now heading into Phase 3 data, I believe it's second quarter and second half of next year. So can you tell us a little bit about the design of the 4FRONT Program and what aspects of the PRISM Program inform 4FRONT?

Yes, absolutely. So as I said, I think having that robust Phase 1-2 experience, over 70 patients at the Phase 3 dose, gave us a really nice understanding of which patients we wanted to enroll in Phase 3. So we elected to move all the way to treatment-naive patients in 4FRONT-1 and 60-plus percent 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 either 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. So 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. So that's #1. And then patients they get the three standard loading doses. They get either 4D-150 or a sham injection. And then they, 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. The supplemental criteria, the baselines based on kind of where their CST and BCVA are, the on average between week 4 and week 8. It's sort of at the maximal treatment benefit of both the loading doses plus 4D-150's ramping up.

Yep. It was a pretty stringent starting point, which we like because it means we're going to protect BCVA, protect that primary endpoint by doing that. And so patients get a supplement if they worsen by either 10 letters alone or 100 microns on CST, or if they hit 5 letters and 50 microns. So we think that's pretty tight, should protect the BCVA. And then primary endpoint at 52 weeks is BCVA non-inferiority. We think we're robustly powered for that. Right. And then secondary endpoints will be treatment burden reduction and the percent of patients who are injection-free at 1 year and so on.

Okay. 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 powering assumptions for the studies?

Sure. Yes, so ultimately we were -- because we saw such rapid enrollment and we were able to, we were in a robust financial position, we could upsize those and really up the power particularly not only for us at 4.5 letters of non-inferiority but at 3.9 for global, including in Japan for our partner that Otsuka there. So ultimately, we randomized on the order of 525 to 530 patients on both studies. And so we think that, that puts us at 90 plus percent power, not only in the U.S. but globally.

Okay, excellent. And then 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 and then our data was really compelling. But go ahead. You've had a lot of those conversations with doctors and patients.

Yes, 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, and sometimes a good data set to help hopefully validate that is how does clinical trial enrollment proceed.

I'll be honest with you, when I joined 4DMT, we had this debate, did we go into frontline patients or not, or do we have more examples? Or do we have more experience, the question I had was what's going to be the receptivity with patients to a frontline, you've been just recently diagnosed, and your physician is going to offer you the potential for a gene therapy, which may give you freedom from injections for the rest of your life, or you may need supplementations, but how likely is it for a naive patient to be excited about that.

We always think, assume that someone that's been on bolus anti-VEGF for a number of years, they understand and appreciate 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. 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've generated so far. And I think one of the very unique things about our program and what we've shown thus far is that while our efficacy is very compelling, I think it's very similar to other programs, our safety data really has stood apart.

And 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. And 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 don't like getting needles in the eye. 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 would absolutely pursue those options, and I think that ultimately drove the speed of enrollment. Okay.

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 therapy how have those changed and is it just time passing?

Yes, let me, I'm going to start by just setting the stage and then Chris can speak specifically. But the stage here is it's really truly remarkable is that we started this development in patients four and a half years ago. And four and a half years ago at Adverum, I just had some blinding episodes in DME. There's a real fear.

People say, 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. It's really remarkable. And so Chris has had a lot of those discussions kind of speak to how that perception's really changed.

Yes, I think all throughout that time period, like the unequivocal recognition of the need for significant treatment burden reduction has remained inconsistent.

Right.

You talk to doctors, there's 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's over 40%. And that continues to grow.

So not only is this patient on the right, but it's also on the left. At need, but there's this the offices quite often have a capacity issue. I launched IZERVAY, so geographic atrophy medicine, and you would hear from doctors all the times like they have a lot of GA patients but they would struggle with how do you fit GA patients into an already super busy injection clinic.

So 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? And I think, 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 with their members, and they ask the question, in essence, was which program or drug in development are you most excited about?

And they gave them a list of options, from gene therapy to TKIs to other bolus things, and more than 2x the level of interest, like 60% I think on average said gene therapy was what they were most excited about. And 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 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 2-year PRISM data. I guess just kind of reaction to the data, excitement around gene therapy, even more generally beyond just the data.

I would imagine. Yes, very much so. I mean, I think the big takeaway is it's consistent right prior to what we shared at ASRS was a 2-year update and we had previously shared an 18-month update so it was an incremental six months and now we've shared 2 years of data across all those Phase 2 populations that we reference, some more severe patients that were getting in 10 injections a year to patients that were broad or more recently diagnosed.

And I think what we see is largely throughout those different time periods, now out to 2 years, a very consistent safety profile, and 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. We see those numbers in the 70, 80, 90% range, and we've seen that continuously now out to 2 years. So that's very validating.

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? And the more we can show data out to 2, 3 years, maybe potentially even more, potentially, it gives them increased confidence of how they think about it when they consider this in a commercial setting for their patients.

Okay. And 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's the feedback you get whether it's 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'd like to see?

Yes, so I'll tell you, when we share the PRISM data that I just referenced, that 2 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%. 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. They still have a very compelling profile.

And keep in mind, Vabysmo has been a pretty significant commercial success with reducing treatment burden by, we model like 20%. We don't think we're going to be anywhere in that range. So we think that's highly compelling across all of all of those stakeholders to have a very, very strong target product profile in the commercial setting and we have we haven't officially engaged with payers, but we have done a lot of market research with payers, sharing their profile, getting their reaction.

And payers in the U.S. is largely Medicare Advantage providers, plans, being in a heavy 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're talking about we'll go into with more detail and share some of our internal work and research to help the broader investor community give 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 it what it looks like.

You want me to take that one, David? I guess I can take that one and give you a little break. Yeah, so when we when you think about the trial design, it's all about what patients go in. We thought we'd optimize that, then kind of the treatment, and then the endpoints. And in terms of the supplemental injection criteria, we wanted to make sure that we really protected that BCVA primary endpoint.

And so we tightened them up a little bit from what we've been doing in Phase 1, 2. At the same time, we'd refine 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 to 85% range that we've been in and all the other studies. And so we feel really good about the fact that we have, we believe, protected the BCVA primary endpoint, but also we'll have a robust treatment burden reduction.

Okay. Great. And we talked about it a bit earlier, but safety, obviously, a particular focus in wet AMD and other retina studies as well. But 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 summary? sense of how that's been received in the Phase 3 program? And 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?

Yes, certainly. So the regimen is a 20-week taper of Durezol, so it starts out I think four times per day and then it graduates down a drop a day every month thereafter. So to your point, we think 20 weeks is probably way more than enough. It's designed out of an abundance of caution. But 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.

And it's a good question. We would there be, in the clinical trial setting, some patients that were hesitant and what patients told us loud and clear is taking a topical drop, which many of, which are very used to doing themselves, right, 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.

So we have picked up on literally zero concern through our Phase 3 program on a patient having any hesitancy because of a topical steroid taper at the beginning of the being put on 4D-150.

Okay, great. And then we're not asking you to front run your own commercial day five weeks from now, but assuming success in Phase 3 and commercialization, I guess, can you give us kind of 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. So I'm glad to go into it now, even if it preempts the conversation on the 21st. It's always good to say it is a few times. My background, by the way, is I've been in retina and the commercial side for nearly 14 years now, and I've 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've done it in a small company setting and a large company setting. The commercial footprint in both of those scenarios is largely the same. And that's roughly 2,500 to 3,000 injecting ophthalmologists. The vast majority of those are retina specialists in the U.S.

Interestingly, about 1,200 to 1,300 of those, so roughly half, account for north of 85% of all those treatments. So there's a big bolus at the beginning, and there's a long tail. 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 scale an audience of that size. And the reality is you probably need 60 to 80 or so field-based employees in both clinical sales and reimbursement support and a total commercial footprint 100 to 120 or so.

That I think is a common size regardless of the size whether you're commercializing a large company setting or a small company. So that's very scalable and doable for us. 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 are, we can be competitive against much larger companies or established players, even though we're a smaller organization. So we plan and are likely to prepare accordingly to that.

Okay. And you touched on it a little bit earlier, but I guess it's kind of 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?

Yes, very important, I think, as many of your audience members, I'm sure, are aware. You're aware that retina clinics today largely fit within a Medicare buy-and-bill model. So these medicines that they inject today are purchased from a distributor. The clinic then and assumes the responsibility for claiming reimbursement once they inject these patients.

And they've, I think, largely built pretty robust practices around that, and they make a gross profit as a part of that treatment paradigm. So I think it's important to understand for 4D-150 is, actually, the answer is somewhat embedded in your question in that we do fit into that pretty seamlessly. 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. So 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 those things are pretty consistent. And so from that standpoint, I think we seamlessly integrate into the product acquisition, storage, administration pieces of the process.

Then 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%? And I think what we remind folks is that today the economics of a practice is driven by the price of the medicine, right? Practices get a percentage of that price as reimbursement. So while we it's premature to say what our price will be, clearly it's going to be higher than a single IVT injection of bolus anti-VEGF.

So you'll get reimbursement of a higher price point. You'll also get that reimbursement up front. And 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.

But if we were to price for multi-years worth of value, generally we often think about at least five years, then you would capture the value of that patient or those patients that otherwise would have been lost to follow up. So 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? Like, different routes of administration, I guess. How are you thinking about -- 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 REGENX program, it has shown, I think, very compelling data so far, certainly from an efficacy and safety standpoint. It does 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 don't 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. therapy program that uh, it's 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's been a history there with safety concerns that we you alluded to earlier. So how that profile looks through its development program, I think we're going 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'll get to your SPECTRA data, and then we should start thinking about design of Phase 3. What would you tell us to focus on as DME moves forward?

Sure, so on DME it's an excellent market as Chris can tell you. It's probably two-thirds the size of the wet AMD market and maybe even higher on that need there and those patient populations tend to be less compliant. So Phase 3 design will look a lot like the wet AMD study in terms of primary endpoint BCVA, well-powered. Details shortly on the study design but again, run in with five bolus injections, which is typical of DME studies, reloading, five loading doses, and then response to Aflibercept during that phase.

So it's going to look a lot like the other, the wet AMD study. We do have approval in Europe, 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 and then the data the 2-year data will be essentially similar data to what we've shown before which is basically it's only nine patients at the high dose so it's a which is important in this, so we hope to show ongoing safety of 2 years and injection burden reduction with very strict injection criteria in that, which will be different in Phase 3. So stay tuned there, but we expect to announce initiation of that study this quarter.

Okay. Great. And then just quickly, I want to make sure we touch on 710 and in CF, status of the program. We're going to get a program update back after this year. What should we be looking for there as well?

Yes, so it'll be a program update in terms of expectations around total patients to be enrolled in different patient populations and dose levels. Again, we're moving into patients who are on modulators as well as patients who have no modulators available. Optimizing the dose, optimizing the endpoints. We'll then have a conversation with FDA.

So I think in Q4, we'll simply be updating the program operationally and saying here's what you can expect in '27 in terms of timing and nature of those decisions of those data and regulatory updates next year.

Okay, great. And just rounding out the questions, cash runway, what's funded, what we've spoken about, for what we consider funding, for what we consider funded.

Thank you for giving me a couple of minutes.

We have $431 million in cash, in cash equivalents as of June 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 or do post 4FRONT-1. That's something that's gated post due date of the 4FRONT-1 data that we expect in Q2.

Alright. Super helpful.

I think we will shut it down there, but thank you for being here. Thank you for listening, guys. It's great to have you. Thank you.

Thanks very much. I'm Josh Schimmer from the Cantor Biotech Equity Research team. I'm very pleased to introduce from 4D Molecular Therapeutics. We have Kristian Humer, Chief Financial Officer; and Chris Simms, Chief Commercial Officer.

Kristian, why don't we get things started? Give us a quick snapshot of where 4D is today and where the company is headed.

Perfect. First of all, thank you, Josh, for having us. Really, really appreciate it. So 4D in terms of pipeline, we have our lead program, 4D-150 is in Phase III for Wet AMD. Our two Phase III trials are fully enrolled. We're guiding to the first Phase III trial to read out in Q2 of next year and the second Phase III trial to read out in the second half of next year.

We will announce towards the end of the month, the initiation of a Phase III trial in DME, the next indication for 4D-150. We have a kind of lung program in 4D-710, where we'll provide an operational update towards the end of the year. That's a program in CF. From a cash perspective, we've got around $458 million in cash as of 6/30 this year with cash runway into the second half of 2028.

Okay. Excellent. So as we gear up for the 4FRONT clinical trial readouts, maybe not the ideal individuals, finance and commercial to ask a clinical data question.

We'll give it a shot.

We'll do our best.

We'll give it a shot.

It feels like Wet AMD clinical trials of late have been full of surprises between the AXPAXLI data for Ocular Therapeutix and the DURAVYU data for EyePoint. As you kind of look at those readouts, any lessons or takeaways as we think about 4D-150 and the 4FRONT trials?

I can start with that. I think the first, maybe overstating the obvious that I would point to is 4D-150 in our program scientifically couldn't be more different than I think the programs you referenced -- where gene therapy that expresses aflibercept. I think a key takeaway again, stating the obvious most likely is that EYLEA is a really good drug. It performs well. The efficacy has been proven. It's the standard of care for over a decade now. And I think the bar for success when you have a comparator of EYLEA's is pretty high. We feel good about our chances.

I mean, in essence, we express aflibercept. So that is EYLEA. It's the reason why we chose that as a protein to express with 4D-150. And we believe the data we've shown so far has shown strong progress certainly as it relates to treatment burden reduction versus on-label EYLEA and the ability to preserve vision long term. So that may not be a total surprise, but I think it's becoming evident as you see the data come through from some of these other programs that the bar for efficacy and safety is high and as it should be.

Okay. As we think about interpreting the forward results, I guess the goal -- primary goal is to show non-inferiority versus Q2 months EYLEA on BCVA. And I think based on the data we've seen from other programs, that seems like an achievable hurdle unless there's something weird that happens. And then as we move to the key secondary endpoint of reduction of EYLEA supplement injections.

So I guess on that metric, first, given some of the design changes from Phase II to Phase III, do you have kind of a general sense of what you'd like to see in terms of that reduction? And at what point does it become clinically meaningful for specialists?

Yes, great question. So our Phase III program is 4FRONT-1 and 4FRONT-2, right? 4FRONT-1 is the first trial that is North America, so U.S. primarily with some sites in Canada as well. And before I get to, I think, the core of your question, maybe take a little bit of a step back and just remind the audience a little bit around just the history of this space and what's driven kind of the evolution of the space.

As many of you likely know, treating Wet AMD has been done through bolus needles in the eye or intravitreal injections. Years ago, that started with Lucentis being a 4-week drug, at least per label and then EYLEA comes out and says it's an 8-week drug and extends that durability a little bit further. And what we've seen since then is largely an attempt to increase that durability and increments. You saw VABYSMO, which we think extended durability maybe by a couple of weeks, reduce maybe an average of an injection per year and similar with EYLEA HD.

So what we endeavor to do is to not extend that durability or reduce that treatment burden by an increment of 15%, 20% is to do more of a paradigm change through a modality like an always-on continuous backbone therapy like 4D-150. So as you referenced, Josh, what we've shown in our PRISM data, at least in Wet AMD so far is we've shown across a broad range of patients, so patients that historically were getting over 10 injections per year. So a pretty severe largely patient population to patients that were more recently diagnosed that we've shown treatment burden reduction rates in that 80-plus or so percent range.

A little bit of variability in that depending on the patient population, but generally, that's what we've demonstrated with the ability to preserve vision in concert with that significant reduction in treatment burden. So we certainly believe that if we show that in our Phase III program, we have a huge opportunity to change the treatment paradigm, and we think that translates to commercial success.

To your question about how we've adapted the Phase III program, so we've looked at some of the results from the Phase II program. And what we saw as patients were more recently diagnosed, the patients diagnosed in the last 6 months, that treatment burden effect that I referenced was more pronounced with those patients. So patients that were on therapy 4 or 5 years, we showed up to 2 years a treatment burden reduction rate in like the mid-70s or so range.

But when you look at patients that were diagnosed within the prior 6 months, and then they went on to 4D-150, we've now shown data up to 2 years in that patient population. And you see treatment burden reduction rates as measured by what you would have gotten on label EYLEA, full disclosure, in the mid-80s range. So a more pronounced effect. So when we went into our Phase III program, we said how do we enhance for a patient population that's likely to have a higher level of response. And we think more recently, our newly diagnosed patient population is likely to do that for us.

So our 4FRONT-1 trial is entirely treatment naive. 4FRONT-2 has a blend of treatment naive in some patients that were previously treated, and that satisfies a European regulatory requirement. So that's an important change. Important, though, to recognize all of the Phase III pivotal programs for retina disease, AMD, primarily, you look at any of the approved medicines, they've all been studied in a naive patient population.

So we're not breaking precedent with our design. While there are some nuanced changes to retreatment criteria and enrollment criteria that I can certainly go into. Largely, we think our design for our 4FRONT program resembles the traditional design that you've seen of trials in this space, the control arm versus standard of care being EYLEA, which is being treated on label with the possibility of supplementation and importantly, the primary endpoint being non-inferiority in vision at week 52. So largely consistent with history with a couple of adaptations that I just referenced.

I guess in the real-world practice, is there a standard approach for those patients who are being watched for PRN EYLEA? Is there a standard reinjection criteria? Is there an array of practice? And how does that align with the criteria that you've selected in 4Front?

Yes, that's a great question. For those that know retina, it's probably not a lot that's standard, right? What is standard is, I think most physicians when it comes to treating patients in the real world with bolus therapies that exist today use a treat-and-extend approach.

So they start out and say, "Hey, I'm going to start treating you probably on label probably every month for the first couple of injections. And then their approach is to say, I'm going to try and extend you to the maximum interval possible without undertreating you with preserving vision and controlling anatomy. What a doctor will use to determine how long that interval is or how soon they will retreat can be highly varied. Some doctors say any retinal fluid whatsoever, regardless of what's going on with vision is going to get a reinjection.

Others will say, "Hey, there's some fluid. If it's been stable, it hasn't been a change in fluid for a while and your vision has been stable. I'm okay with the contingency let you go without a retreatment. So there is some variability. There's an art and a science to that. So how do we approach that from a clinical trial because you can't just leave it out there and say, you decide physicians, especially in a Phase III program. So you want to control that.

So we basically designed criteria in consultation with thought leaders and KOLs in the space that says, hey, we're going to need something to guide when a patient gets a supplemental treatment that's on 4D-150, what should that be? So we talk to the physicians. We have an expert panel that guides us on that. We look at what other programs in the space have done, and we try and come up with things that certainly help us ensure that we have maximum chances of success in our Phase III program. But at the same time, we've got to balance whether those criteria are relevant in the real world. So we think our criteria that we designed for our Phase III retreatment or supplemental criteria accomplishes that.

So I mean, in the real world, naturally, the PRN criteria will require fewer injections than Q2 month EYLEA. So as you think about the hurdle rate for 4FRONT and what you need to show, not just have a positive trial, but to convince the specialists that you really are reducing injection burden not against Q2 month EYLEA, but what they're currently practicing. How do you think about the type of data you need to be generating to make that case?

Yes. So I think a couple of things. So -- and I'll push back a little bit on the statement that in the real world, you actually get dosed less than Q2 week EYLEA. That's true for some patients. It's not true for all patients. In fact, what the data shows is that half of patients on EYLEA, and we actually just ran this data recently, we have an Investor Day planned that largely focused on commercial topics on the 21st of October. Quick plug, everyone should -- we'll go into this in more detail.

But what that data would show as we looked at it is that half the patients actually get treated more frequently than the Q8 EYLEA. So there's a good portion of patients that are on a Q4, Q6. And by the way, the reduction in that as newer agents like VABYSMO, Eylea HD have come out has been incremental. It hasn't been massive. In fact, our data would suggest that at most, those newer agents have reduced the average number of bolus injections a year by about one.

So the aggregate is like 6 or 7 over the course of the year if you're on standard therapy, if you're in the maintenance phase. Half of those patients are getting more frequent than Q8 and then a portion are certainly getting less than Q8. So they are patients that have less severe disease, they're likely at Q10, Q12, some patients get up to Q16. But the general belief that, hey, patients don't need Q8 is actually not true in the real world, and it largely is driven by -- there's a high degree of variability in patient types.

We even see this in our data. Like we see patients that were getting 10 injections in the prior year in our PRISM data that up to 9, 10 months were supplement free and all of a sudden, they needed a couple of injections, and then they go back on a period of time when they're supplement free again. And we think that speaks to the high variability of the disease.

And again, I think -- so if we can, over a longer period of time, reduce that regardless of what interval you're on by orders of magnitude, 70%, 80%, 90%, which we think we have a chance of doing, that's highly significant regardless of whether you're a patient that was on Q8 exactly or getting it every 6 weeks or getting every 12 weeks.

And you pointed out that VABYSMO was an incremental improvement over EYLEA. So you kind of rerun the math from the VABYSMO lens, is it kind of roughly similar? Do you feel like the burden of evidence is a little higher because the duration of activity of VABYSMO is also a little higher?

Yes, a touch, but again, on the margins. So it's like what we've seen so far in our data that we've run is there's still, I think, north of 40% of patients on VABYSMO that are not getting a Q8 frequency in terms of the retreatment criteria.

And admittedly, I think in aggregate, there's a lot of patients that are getting Q12 or Q16, which is amazing for those patients. I think it's also important to know because sometimes we get this question saying, and I get this a lot from a commercial lens, which is, hey, Chris, what patients would a doctor not consider 4D-150 for?

And my knee-jerk is, I don't think anyone should not be considered for 4D-150 if you can preserve vision for the life of the patient. But I think practically, what some doctors may look at is if you have some patients that do fine on 1, 2, 3 bolus injections a year, which is relatively a lower treatment burden for those patients, they may be least considered for a long-acting therapy like ours.

However, the data that we've seen in the category would suggest that probably less than 20% of the patients and maybe even less than 15% fall into that category where 2 or 3 injections per year seems to be adequate for their ongoing maintenance of disease.

Since 4FRONT is being studied with a lead-in EYLEA, how would it be used in the real world? Would specialists -- would you expect them to have flexibility to use VABYSMO or EYLEA for high dose.

Yes, exactly. We don't -- we think -- listen, if a patient responds to Anti-VEGF therapy, I think the biggest thing for before you get introduced to a gene therapy that's lifelong is that you are responsive to Anti-VEGF therapy. And I think what the science would suggest, and we think regulators would agree is that if you respond to EYLEA, you're likely to respond to VABYSMO and vice versa as well.

So we don't anticipate a criteria where because we use EYLEA in our clinical trial setting that, that's the drug that you have to show response to. We think there's flexibility there, and we think that's reflected in what happens in the real world today. There's still like a fair amount of switching as well that occurs in this space today. Patients often stay on the maintenance therapy, but there is evidence that patients will get switched from one brand to another for a variety of reasons.

Wet AMD practice is primarily a Part B buy-and-bill type landscape. So that obviously introduces a number of commercial considerations, both from the payer perspective, and they're willing to pay for 4D-150 depending on how you think about pricing it, which maybe we can talk about and then also, obviously, practice economics themselves. So maybe you can kind of address those two angles around access and reimbursement.

Yes, absolutely. So let me first start with -- before we get too deep into the reimbursement mechanics, I think it's important for the audience to be reminded that at least for Wet AMD, over 90% of patients are Medicare, right? An older patient population presents in the elderly. So no surprise, the vast majority of patients are -- their insurance is via Medicare. Of that 90%, 92% that's on Medicare, for simple modeling, half of them are on a Medicare Advantage plan of some sort and the other half fall on a Medicare fee -- direct reimbursement from CMS or the Medicare fee-for-service.

And the importance of understanding that payer mix, if you will, is because of what you just suggested. It's a buy-and-bill model, which means that physicians acquire the medicine, they take on the responsibility for getting reimbursed for the medicine, and they administer it in their office, right? So Medicare Part B buy-and-bill.

So the thing that helps us as 4D-150 is that we think we tuck into that process pretty seamlessly. The method we think of distribution for 4D-150 would be the same as Anti-VEGF therapy today. The storage requirements would be the same. The injection itself in terms of doctors can use whatever gauge needle, the volume of the medicine, all of that would resemble what they would be use to today for any of Anti-VEGFs use.

And that -- it's in the weeds a little bit, but it's really important because in these busy retina clinics, of course, they're seeing sometimes 60, 70, 80 patients a day. So if you can minimally disrupt your practice flow, that's important. So operationally, we think we fit in really well there.

From a reimbursement standpoint, there's two big pieces that are important to reimbursement that you just touched on. One is how are payers going to look at it, right? And as important in a buy-and-bill model is how do physicians get reimbursed and how does it affect their practice economics. Because retina clinics today, they make a profit, they make a margin on the drugs, the drugs that they inject. And if you have a therapy that says we can reduce your treatment amount by 80%, the knee-jerk reaction is what's that going to do to my practice economics.

So we think we have a good story on both of those elements. First of all, what we've heard from payers as we've done research is that payers recognize a few things that are really important. And the caveat, Medicare Advantage payers. We don't go talk to CMS at this point in time, but Medicare Advantage payers who manage Medicare lives on behalf of CMS.

Those payers will tell us a few things. 80% in recent research suggests that the importance of long-term vision preservation is -- 80% would say that's really, really important. 100% said there's a need for new advanced therapies to treat Wet AMD. 93% in our most recent survey suggested that there's a -- they have a concern about patients losing vision over time because of persistence to therapy. Which is things we also see in our real-world data.

So we think the payer enthusiasm for a therapy like 4D-150 that could potentially reduce treatment burden by 80-plus percent and preserve vision long term is really high. Of course, how favorable they will be will also be a function of what we'll be priced at, and that's to be determined. We think we have massive pricing flexibility. We don't think this is a $1 million therapy. We don't even think it's a $100,000 therapy at this point in time. But exactly where pricing will fall will be determined at a different point in time.

So we think we're in a good position to provide value from a payer perspective, notably the Med Advantage plans. And then from a physician standpoint, how it affects their practice economics is a really important dynamic as well. And a couple of things that we highlight that is important.

First of all, today, when you make money on these current bolus injections, it's a function of the price, right? So you get reimbursed as a percentage of the list price. So just for illustration, if your reimbursement is 5% of a $2,000 drug, your net gross margin is $100. While we don't know our price, it certainly won't be equivalent to bolus injection, right? So it will be a higher price point. So the value of getting reimbursed upfront, not having to wait for increments over time, plus the value of reimbursement on a higher price point is favorable, we think, for a physician from an economics perspective. What it exactly looks like will ultimately be determined by what the price point is. So that's one.

The other point is we think at this point that we'll have the ability to price to capture multi years of value. Again, this gene therapy is always on board. We think it's going to be helping preserve vision for years to come. So again, for your audience, just to illustrate this, if the pricing ultimately reflects, again, just for illustration, 5 years of value, it's important to recognize today, patients getting bolus treatment are not on therapy for 5 years.

In fact, 40% fall off therapy for a host of reasons by the time they get to 18 months and it continues to drop off over that continued -- those years. So if you have a therapy that economically, you can capture the value of a patient that otherwise would have had to stay on therapy for 5 years, it's easy to recognize the incremental value to a practice of a therapy that can deliver that. So those are a couple of things that we point to when we talk to doctors around how this could certainly affect their practice from an economics and an operational standpoint, but we think it could affect it in a positive way.

So capturing multi years of value for an elderly patient population, I could envision a payer maybe having or pushing back a little bit if they don't necessarily feel a patient may live 5 more years. that would potentially be a little contentious.

A little morbid.

And that may not even be legal. I don't know how you kind of think about navigating that particular dynamic.

I'm not sure if that would be a particular dynamic we would have to navigate to your point. However, should we have to, I think there's a couple of other things that need to be considered in that conversation.

First of all, today, unfortunately, yes, it's an older patient population. But we hear a lot of stories. We do a lot of research with payers. We're going to highlight some of that at our Commercial Investor Day in October. And I think we could all appreciate the impact that losing your vision would have on anybody, but particularly an older patient. At this stage in their life, vision is a source of independence. It's often a source of identity.

So while, yes, you may be injecting a therapy that would last for longer than the patient may actually unfortunately stay alive, we think that's an exception to the norm. And as well, we think we can say, hey, while the patient is on therapy, we can help preserve their vision. So what's the value of keeping healthy vision for the duration of that patient's life. I think that's immense. I think that's game changing. Patients think it's game changing as well and what's the follow-on benefits of being able to maintain your independence and so on.

So all of this will become a core part of our economic story because, again, we think we will be able to show data that in contrast to all the other bolus therapies that exist where vision in the real world is lost, what's the value of actually preserving the patient's vision for multiple years? We think that's quite significant. And I think that becomes a part of the story to illustrate to payers why we can have that effect.

Going back to the reinjection criteria that are used currently in the real world -- with the launch of 4D-150, do you expect to push practice towards the reinjection criteria that was used in 4FRONT? Or is the approach more, let's say, fair, whatever you're doing, fine, keep doing that and you can layer 4D-150 on top?

Yes. Well, I've worked in retina since 2013 now.

I know what you're going to say.

You know what I'm going to say. And I think commercially, we always remind physicians, this is what the label says. This is what we can share promotionally. This is the evidence that exists. And I think a lot of doctors say, this is -- that's great information, Chris, thank you very much, and this is what I'm going to do.

Exactly, I knew that's where you'd go.

Yes, exactly. So our role is to certainly educate. We think the criteria are super relevant. And I think some physicians will look to that and say that's -- I'll use that as an input to how I'll decide. But let's be real and pragmatic, right?

In the real world, doctors approach this, how they decide to retreat the criteria they use their revisit monitoring schedule. I think most retina physicians will approach that using their own expertise and make the decision that we think is right.

Is it possible for 4D-150 to be provided as a prefilled syringe? We hear a lot about how that -- how important that is amongst the current treatment options. Is it relevant? Is it feasible?

I think interesting, we think possibly feasible in full disclosure, not something that's on the top of our priority list right now. And again, I had the good fortune of launching the first prefilled syringe for Lucentis at Genentech many years ago, and that was materially beneficial to a busy retina clinic because as you can appreciate, if you're injecting 50, 60, upwards of 80 patients a day, if you can save 3 minutes for each injection in the steps required, it matters.

The significance of that is different for a gene therapy that you're probably not going to be treating 50 times a day, certainly not in the first several years. So the time savings, the convenience benefit, is not the same in our context as I think it is in a bolus therapy context.

There are some major players in this space currently who may perceive 4D as a threat to their existing businesses. How might you consider entering the market cognizant of that dynamic as a small company? And do you feel like you benefit from a strategic partner to really go toe-to-toe with the big players in this space?

I love that question for several reasons. I've launched medicines in retina in both large company settings. I did it at -- I worked at Genentech, I worked at Novartis -- and I've launched medicines in a small company. I worked at Iveric Bio and built and led the team that launched IZERVAY prior to the acquisition to Astellas.

I actually -- both context, you can be super successful and it can be a lot of fun and you can have a good impact for patients. I love the opportunity to launch in a small nimble biotech like 4D-150 and like we did at Iveric Bio, it gives you speed, gives you flexibility. I think it gives you better proximity and closeness to your physician and patient base that sometimes is harder to capture in a large company environment, not impossible. And I like that dynamic.

The other important thing is, listen, in the U.S., there's about 2,500 to 3,000 retina docs. 2,500 to 2,600 account for probably about 95% of all VEGF treatments today. So we don't -- you don't need a 500-person or 1,000-person commercial team to scale a market of that size. I've done it several times. So largely the commercial footprint is, I don't know, 100 to 150 people somewhere in there. Small biotechs like 4D-150 can certainly take that on. We did it at Iveric in a similar situation, and we'll plan to do it here.

So long answer, but short is we don't need a strategic partner to commercialize, I think, either U.S. or Europe, and our plans would suggest we're going to do it ourselves.

All right. Kristian, maybe frame for us what we should be looking for, kind of, beyond what we've talked about for 4D in the coming months and years.

Sure. Again like, the key things to look for is the 4D-150 -- the 4FRONT-1 data readouts in Q2 of next year and 4FRONT-2 second half of next year, all eyes on that. I think in closing, what I would like to say and something that's still miss, kind of not understood enough is that we really do fundamentally believe we have the potential to really change the treatment paradigm here for Wet AMD patients and DME patients.

This is not going to be a niche opportunity if we continue to see the activity that we're seeing as of right now. And so it matters. It matters to incumbents, and it will matter to us.

Do you have adequate manufacturing capacity for what could be very, very meaningful early demand?

We do, yes. We've switched to a third-party manufacturer, and we're preparing exactly for that and fully prepared.

Excellent. Terrific discussion. Thank you, Kristian and Chris, for joining. Thanks everyone, for tuning in, and very much looking forward to the event upcoming in New York.

Thank you.

Thank you.

Okay. Well, thank you, everyone, for joining us. We are here with FDMT. Kristian Humer, CFO; and Chris Simms, CCO and CBO.

Maybe you could start with an overview of your directed evolution gene therapy platform, your pipeline progress and your 12-month catalyst path.

Yes. It's great to be here. Thanks for the opportunity. I'm happy to start with that, and Kristian can fill the details on our catalysts that are coming up over the next 12 months. So first of all, 4DMT, we're a next-generation gene therapy company, platform company. We have a number of programs in development, but the program that's taken the majority of our focus right now is a program, we call it 4D-150, and that's a gene therapy that we're studying for the treatment of wet AMD. So our wet AMD 4FRONT-1 and 4FRONT-2 Phase III trials are underway right now. So that's our leading program. We hope to start our trial for DME, so diabetic macular edema, the second largest indication in retinal disease later this year with 4D-150 as well. And we have other programs in cystic fibrosis, but that the 4D-150 is the primary focus for us right now, considering where we are with Phase III.

And with that, Kristian, do you want to speak more to the catalysts that are coming up?

In terms of catalysts, the big catalysts are next year, kind of first half of next year, there'll be Phase III, 4FRONT-1 data. And second half of next year will be 4FRONT-2 data. This year, we'll have kind of by the middle of the year, we'll have a 2-year duration update for our PRISM trial, kind of our Phase I/II trial in wet AMD and 2-year duration data for our DME Phase II sometime second half of this year. And we endeavor to provide an update on our cystic fibrosis program, 710 by the end of the year.

Okay. So multiple leadership changes at the FDA. You guys as a gene therapy company go through [indiscernible]. How are you thinking of your positioning in this current environment?

Yes. So no doubt, there's been a lot of change. I'll tell you that our interactions with the FDA have been pretty standard. We've been very productive. So nothing that's come up in any of those interactions that would cause us to have any view that's different than what we've been operating with. We also think the fact that our Phase III program, our Phase III trial designs are fairly standard in their design. If you look at how we've designed 4FRONT-1 and 4FRONT-2, it's very a similar design to how other new agents in this space have been studied and approved. So the Vabysmo design, the EYLEA HD design and even other pivotal programs going back many years ago, we follow a very similar type of trial design as that. And we think that design is conducive to a very productive regulatory path forward with the FDA and the European regulators as well.

Yes. So starting with wet AMD, you enrolled faster than expected and upsized your North American Phase III trial. Maybe speak to the expectations for enrollment for your global trial and whether this could be upsized as well. And overall, what this says about the physician enthusiasm for gene therapy in the eye?

Yes. I love that question for a couple of reasons, actually. So first of all, yes, to your point, we started out just over a year ago with initiating our first Phase III trial, so 4FRONT-1. And at that time, we estimated that it would take about 18 months to enroll at the time a n-size of 400. What happened instead is we actually ended up rolling over 500 patients and enrollment finished in 4FRONT-1 in just under 12 months. So we finished enrollment in March of this year. So faster enrollment and as well as with an increased n-size. And we've already said publicly 4FRONT-2, we think is enrolling at a similar pace as 4FRONT-1. And the difference is that it's a global trial. And the n-size, we also will increase that as well. So we expect that to -- the official n-size is 480, and we're likely to overenroll that similar to what we did with 4FRONT-1.

As the commercial guy who's launched a couple of drugs in the space, when you get -- you're trying to prepare for commercialization and you hear all the feedback and you do the modeling and what the opportunity is, and we think it's certainly very significant. One of the things that can be a good proxy, we believe, is pace and enthusiasm for a Phase III program. So for me to see that level of physician and patient enthusiasm that helped drive that 4FRONT-1 enrollment time period, it's very encouraging. We think it points to -- it's a good proxy for what we think the unmet need is and how we can possibly solve for it.

Yes, that makes sense. So you have a noninferiority margin that you have to hit at these studies. But based off of your discussions with physicians, what do you really need to show in this data set for this to become practice-changing as a foundational therapy?

Yes. So I mean, first things first, right? You have to hit your primary endpoint. So for us, that's non-inferiority on vision at week 52. And you also have to have a profile that's safe, which makes perfect sense when you consider that this therapy area has lots of efficacious and fairly safe agents available today. So you need to show safety and efficacy in that regard. From a paradigm-shifting perspective, what we think we can deliver is what we've seen through our Phase II program, which is treatment-free rates in the 50% range depending upon the population of patients at week 52 and overall treatment burden reduction rates, 80-plus percent.

And we think that's highly meaningful for a couple of reasons. So first of all, when you look at how this entire anti-VEGF space has evolved over the last 20 years, we started out with Lucentis back in 2006 and EYLEA launched and Lucentis was a on-label 4-week drug. EYLEA was approved for use every 8 weeks. And advances since then have come in incremental advances in durability measured by a week or 2. So Vabysmo is a 16-week medicine, but not all patients are at 16 weeks. So you get a sense that these incremental advances in duration have yielded significant commercial value at both medicines like Vabysmo are worth over $4 billion, I think, in the current year.

But the benefit from a treatment burden reduction standpoint was a week or 2. We think we can affect that by orders of magnitude in the 50% of patients being treatment-free or over 80% of treatment burden reduction that patients will benefit from. So that treatment effect is definitely a paradigm shift versus what everything that's been done before. So that's what we aspire to. We think with a backbone for retina approach, which is how we coin it, we are uniquely positioned in the space that's highly competitive, but also has still a very high unmet need in terms of reducing treatment burden.

Yes. And when you think about executing on the operational aspects of the trial, especially around managing sorts of confounding factors such as cataracts or the potential for investigators' discretion on supplemental injections. How are you making sure that you have kind of those aspects in check?

Yes. So on the cataract question first, first of all, you would expect that any incidence of cataracts would be observed in both arms, assuming both treatment arms are balanced. And just as a reminder for your audience, our trial design has half of patients being randomized to 4D-150 and the other half of patients being randomized to on-label EYLEA. And both arms will get a prophylactic steroid regimen. So if a patient develops a cataract, we would -- we have a protocol that allows for that cataract to get removed and then the patient should stay in the trial.

As far as supplemental treatments are concerned, we have very well defined and we think very reasonable criteria that would trigger a supplemental treatment. Those criteria were developed with world experts in retina. And there is no physician discretion. So if there is a flag for a supplemental injection, that would get elevated to a -- we have a committee that would look at that and verify that it meets the criteria, but there is no option for a physician to exercise their own discretion. It has to meet the criteria and go through that process.

In terms of commercial positioning, there are also TKI programs that have reported data and are emerging in this space. How would you characterize the positioning of those agents versus the gene therapy? And what do you expect their durability will be in real-world practice?

Yes. So like I mentioned earlier, the entire space has evolved by incremental advances in durability. And that's meaningful, which that's actually been a good thing for patients. And you can understand it, right? If you tell a patient that you're getting 6 or 7 needles in the eye on a given year and you can reduce that by 1 or 2, most patients would be very attracted to that. We think of TKIs and other bolus type of therapies in development as trying to advance an incremental benefit in that regard. So there's interesting science beyond the TKIs that are in development, but all of them are trying to squeeze out another increment of durability. That's not our positioning. We're not trying to advance incrementally. We're trying to set a whole new treatment paradigm, which is why we call it a backbone for retina.

We actually think of a treatment paradigm where we think the majority of patients could be considered to have an onboard 4D-150 that's constantly managing and controlling the disease for the rest of that patient's life. And for some patients, because it is a very dynamic disease that may need occasional supplementation, there is a wide number of different options that a doctor can choose from and TKIs and other things in development could fill that need for supplementation when and if needed. But our positioning, we think, is very clear. It's a backbone type of approach. We're not a bolus therapy like those other agents. And we think that has very significant clinical meaning, both for our practice and certainly for patients.

Yes. And noting that TKI did recently report data from a superiority trial, maybe could you remind us of the rationale and why you chose noninferiority and how that reads through to payer dynamics if launched?

Well, we chose the -- our approach because we think the data that would get generated from our approach is most meaningful to physicians and their patients. It's how drugs have been developed in the space. It's how the data that comes out of these programs, physicians use to translate to how they would incorporate it into their clinic and some other designs, I think are interesting, certainly from a headline perspective, but may not be as applicable to the clinical setting.

So that's what drove our design. We wanted to make sure that we generate a data set that one, obviously allowed us to have a shot at approval, show that the medicine worked in a meaningful way and solve an unmet need and show that the data that would come from our pivotal program could be translated by a physician to their clinic for application to their patients. And in addition to that, as you just referenced, we will need to show that we can generate value for payers, right? There's multiple stakeholders in this space. And it's a complicated set of variables, but you have to think through all the stakeholders that are ultimately going to be important for the success of your medicine. So payers are a big part of that, both U.S. payers and ex U.S. payers, which is one of the other reasons why our 4FRONT-1 and 2 program is we think of it as a global program. 4FRONT-2 is being run around the world. We have sites in the U.S., in Europe, and South America and Asia because we think the unmet need that we're solving for or trying to solve for around significant reduction in treatment burden, it's a global issue.

In fact, if you look at other countries around the world where access to retinal care may not be as accessible as it might be in the U.S. or in the Western world, what we could solve for with an always-on constant gene therapy could actually be more significant in countries where that access to care is more limited. So our design was done with keeping all of those variables in mind.

The last thing I'll mention, which I think could be really interesting in terms of what we can show in a future state is the ability to preserve vision. So it's really interesting in this space. These therapies, these bolus therapies that exist today, are highly efficacious, right? You get diagnosed, and it's very common. You see this in data that patients within the first couple of treatments will gain 5 to 10 letters of vision. And for that patient, that's incredibly actually life-changing in many respects.

Unfortunately, if you look at a lot of data in the real world, despite gaining that vision initially, a lot of those patients, if not the majority, over time, will lose that vision even if they're staying on therapy. And one of the big reasons for that is for a variety of factors, patients tend to get undertreated in the real world. So that vision gain happens, they hold on to it for a while and then you get out a year or maybe beyond that for some patients and a lot of those patients have lost that vision. In fact, a lot of those patients, their vision will eventually go below where they started.

But there's also really good data that shows that if you have constant VEGF suppression, you see this in the data set from Susvimo, the port delivery system from Genentech or even other studies where like Lucentis was dosed monthly regardless of disease activity, you actually see that vision gain be maintained for years. We think based on our modality, we have the potential to show that as well, which is very exciting. So you can imagine telling the patient that, hey, you have the potential that this might be the last injection you'll ever need. And in addition to that, there's a potential that vision that you care the most about, not only can you -- we give some of that vision back to you, but there's a high likelihood that you can hold on to that for years to come. We think the combination of those 2 elements is incredibly compelling for all stakeholders, payers and physicians. And back to the first part of your question, we designed our trial. Hope to show that.

So at launch, do you expect a dynamic where you'll have advanced patients as the early adopters and then shift over time to earlier stage? And maybe can you characterize what the treatment goals are for each of these populations?

Yes. It's a great question. Wet AMD patients, DME patients are highly variable, right? You get a distribution curve like you do in many diseases. So you get some patients that may only need 2 or 3 injections per year to manage their disease. You get some that almost need monthly injections. And then you get the standard distribution curve in the middle where the average is 6 or 7 or so per year. But your point is spot on. Upon launch of new medicines in this space, I saw this when I launched a drug called Beovu at Novartis several years ago, and I think we said this with new launches from Vabysmo and EYLEA HD that the patients that are treated first are the patients with the highest need, which makes sense. Those are the patients that are most interested and motivated by trying something new.

So you get tested on patients that are often getting 9, 10-plus injections per year, almost on a monthly cadence. We feel really good about that challenge that we anticipate getting in the commercial setting because we've generated pretty robust data on patients that look just like that. In fact, if you look at our severe patient population from our Phase II PRISM trial, which is data that we've shared now out to 2 years, you will see that those patients were historically getting on average 10.2 injections in the year prior to going on to 4D-150. And after 2 years, we've shown a treatment burden reduction where they were on pace to get just over 20 if you take that 10 and assume 2 years of treatment. And on 4D-150, the average number of supplemental injections was 4.

So over -- about an 80% treatment burden reduction after 2 years on a patient population that was getting injected almost monthly. So if that's the type of patients that we get tested on in the commercial setting, we think we can show a very significant treatment burden impact on patients that are arguably the hardest to treat. That's a test that we think all new agents launched in this space are going to get tested with, regardless of whether you're a TKI or other bolus therapy that's in development, that's the patients that doctors are going to be most motivated to try your new drug on out of the gate. And I think how you do with that patient population is going to be pretty informative as to how the rest of your commercial launch goes.

Yes. On pricing, a high price naturally is attractive for buy-and-bill purposes, but also may have some payer dynamics to watch. How are you thinking of balancing between those 2 aspects?

Yes, it's kind of like Goldilocks, right? Not too hot, not too cold. There are a lot of variables you have to think about. So very familiar with all the dynamics that go into pricing. There's a practice economics piece, which you alluded to based on the price of the drug that physicians make profit. There's also the consideration of there's a societal consideration, there's a payer consideration. There's a patient out-of-pocket consideration. So there's lots of things that go into the mix. And I mean, as we sit today, we have no idea what the pricing will be. We'll make those decisions when we're further along in our development program. But what I will tell you is that philosophically, because part of pricing as well, it's a math exercise, but it's also a bit of a philosophy exercise as to what you think you're trying to do.

We truly believe that 4D-150 can be a backbone therapy for retina disease -- patients with retinal disease. It's hard to have the aspiration and vision there and then price it in a way where you limit access to the 10% or 12% of patients that can truly afford it. So that's going to be important to us when we make those decisions. Practice economics will certainly be important to us as well. And we'll make those decisions when we have Phase III data and we have a better view of the landscape.

The good thing that I'm excited about is that we don't -- despite being a gene therapy, sometimes that comes with the assumption or the connotation that your pricing must be well in the 6 figures, your cost of goods must be exorbitantly high, which is often the case for other gene therapies and sometimes in more systemic settings. Our cost of goods is less than $1,000. So when we have to make that pricing decision, we have a lot of pricing flexibility. And at the end of the day, I think we'll price it in a way where we consider all of those variables and make the best decision that hopefully satisfies the needs of all the stakeholders and patients to physicians and payers and of course, for investors and owners of the company.

And in this population, we have Medicare Part B fee-for-service and Medicare Advantage. Maybe if you can discuss the split between those 2 and how coverage and out-of-pocket differs.

Yes. It's -- so absolutely right. wet AMD, we think 90% to 95% of patients are covered on some sort of a Medicare arrangement and then 5% or so are still on the commercial plan. In the Medicare population for rough estimates, it's kind of half fee-for-service, half Medicare Advantage. Medicare Advantage portion could have a variety of different constructs and designs. The patient out-of-pocket can vary. Sometimes it's more driven by having a deductible upfront that they have to kind of burn through before their out-of-pocket goes down, but it can often depend upon how that individual Medicare Advantage plan has constructed the design for that particular patient.

And what you typically find in the Med Advantage space is you have -- as opposed to being on or off formulary, that's not really how it works. It's more of you have a step through or other types of things that you have to get over -- get through in order to get access to sometimes more expensive medicine that exists today. I would expect some version of that to exist for us as well. All of that's manageable. All of those are things that you would normally expect to see.

Medicare fee-for-service is very different. It's direct reimbursement from CMS through one of their MACs. And typically, the design of the plan there is the drug is covered by -- 80% of the cost of the medicine is covered. And most patients have supplemental insurance for that out-of-pocket 20%. So their out-of-pocket would be very minimal. So that's usually a fairly more accessible payer segment for a patient to be in. For patients that don't have the supplemental insurance for that 20% out-of-pocket, it can be more limited in terms of what they can afford. It varies by patient, of course. But I think you hear even evidence of that today, if a patient wants to go on a branded anti-VEGF drug and they don't have supplemental insurance for that 20%. 20% of a $2,000 anti-VEGF today is about $400. So for some patients, that's tolerable for some, it's not. So that's something that we'll certainly have to consider.

And do you factor dosing the second eye into your projections?

We certainly do. Yes. We estimate about 40% of patients with wet AMD have bilateral disease. So our development program, we have a planned contralateral eye study that we'll run to provide hopefully a label that supports dosing in the fellow eye.

So turning to DME. You have alignment on a single Phase III trial. Any experience that you can leverage from your wet AMD trials here?

Yes, a lot. So we're very excited about starting our DME trial. We hope to initiate that in the back half of this year. I actually think DME is the second largest indication, as you know, in this space today after wet AMD. But it's largely underpenetrated in terms of the market potential for a bunch of reasons, younger patients, patients aren't necessarily as adherent to therapy as you would see with the wet AMD population. So I actually think that a gene therapy like 4D-150 that solves the adherence challenge by design, right? Once it's there, it's always there and helping to treat the disease, could actually unlock the diabetic macular edema market in a way that is even more significant than it exists today. So we're thrilled about the opportunity in DME.

As you mentioned, we have regulatory alignment from both the FDA and EMA for a single global trial. We're planning to start that trial in the back half of this year in partnership with our -- with Otsuka, which we have an Asia-Pac relationship with. And yes, I think a super, super exciting opportunity and exciting follow-on development for us after wet AMD. And we've learned a lot to your question about how we could execute against that. In fact, the fact that we have pretty wide awareness right now within the retina community at the 4D-150 profile. We have a really strong network of clinical trial sites. I think all those things that we can do fairly quickly. And hopefully, we would see enrollment that's similar to what we've seen with AMD. We think the physician enthusiasm certainly is as high there as it is in AMD.

How much of an issue really is capacity constraints within these clinics? And does this come up as a reason for prescribing gene therapy versus other reasons such as economics?

It's -- I love that question. So it does. Listen, the reality is there's more demand for the services of retina specialists today than there's often retina specialists available to meet that demand. That can vary by geography. Some geographical areas that's more pronounced than others. But it's also projected that divergence of supply versus demand is projected to increase over time. We have a continuing aging patient population and the number of new retina specialists that are being trained and put into practice is not keeping up with that. So we think the timing of 4D-150 could really be interesting in that regard, where you could significantly not just alleviate treatment burden for the patient, but you can help create capacity room for the clinic as well.

And listen, the clinics are becoming more competitive and more complex, right? I was on Lucentis years ago when it was Lucentis, EYLEA and off-label Avastin. That's largely the drugs that physicians had to choose from. And today, you have biosimilars, you have new agents, you have GA drugs that launch IZERVAY. So there's lots of other things that have created complexity in these retina clinics. So anything that can offer a simplifying solution the way we think 4D-150 can, can help solve, we think, be a big part of the solution around capacity.

And most doctors recognize that. And for doctors that don't seem to recognize that because they may not be paying attention or measuring that, I would encourage your audience to talk to a practice manager in that clinic because those are the folks that are often managing the back office [indiscernible] so on, and they would tell you pretty quickly that there's definitely [indiscernible] looking for real innovation to help solve for that. An incremental durability of a week or 2 from a bolus new therapy doesn't really solve for that unmet need. We think we can.

And are there any other indications that you're interested in pursuing with 4D-150? And in that context, how are you thinking of phasing spend as you go into these large market opportunities?

Yes. I mean there's -- we've talked about whether it makes sense to consider diabetic retinopathy after diabetic macular edema. We haven't made a final decision on that, but I think there's lots of physician feedback that would suggest that, that's something we should consider. And as far as thinking about prioritizing the phasing spend, maybe, Kristian, do you want to speak to that?

Look, I think there, it's very clear. We're laser-focused on the execution of wet AMD and DME. That's kind of the Phase III trials that are ongoing. But we're acutely aware kind of the potential value of our platform. I think at these current share prices, probably investment in our platform is going to be moderate. But over the medium to long term, we believe there's significant value there in our platform.

Touching on cystic fibrosis, you plan to provide an update in the second half of this year? What could that contain? And how are you thinking of a forward path to accelerated approval versus Phase III?

Look, we reported in last December kind of what we believe is super interesting kind of early signal of our vector in cystic fibrosis with our 710 program. What we want to do kind of with the next update is really provide the kind of 12 patients' worth of data with 9 to 12 months of duration. I think that's what we'll guide to in the update that's coming kind of second half of this year.

Maybe in our last few minutes, you can touch on the cash runway, assumptions factored into that. And on partnership strategy, clearly, your platform has broad utility. How are you thinking about out-licensing on the forward?

Absolutely. So from a cash perspective, as of the end of Q1, we had $458 million in cash and cash equivalents and they're guiding to a cash runway into the second half of 2028. What that doesn't include is the ramp-up in commercial spend that would happen post 4FRONT-1 data. That's something that we can commit to kind of once we have that data. In terms of partnership, look, I think, as Chris mentioned, here, I mean, we require kind of an 80 to 100-person sales force to execute commercially here in the U.S. on any of our retina programs. We think we can do that by ourselves. We want to make sure we maximize value for our shareholders.

In terms of ex U.S. I think those rights for us are strategically and economically important. I think we're going to be really careful kind of how we approach that from a partnership perspective. And if need be, we can go it alive for sure.

Okay. And just in our last minute, you touched on this a bit with COGS and pricing of gene therapy, but is there anything else that you would want investors to understand about your story and your strategy?

Look, I think we covered a lot. To summarize, again, I think this is a -- we're doing something that's never been done with a gene therapy before. We're going after a very large market with wet AMD and DME that we can execute on by ourselves. And I think if touch on wood, if we're right in what we want to do, it has the potential to really change the treatment paradigm of these patients and how these patients are being treated today.

Okay. Well, with that, thank you very much for joining us, and we look forward to seeing all the progress.

Thank you so much. Thank you for having us.

Thank you.

All right. Good afternoon, everyone. Thank you to those of you in the room and those dialed in on the webcast. My name is Faisal Khurshid. I'm one of the Senior Biotech Analysts here at Jefferies. Really pleased to have with us the management team of 4D Molecular Therapeutics. 4D is a super interesting company working on gene therapies for the masses with a lead-program and approach in wet AMD. So we have with us today David Kirn, CEO; Kristian Humer, CFO; and Chris Simms, Chief Commercial and Chief Business Officer. So with that, David, could I ask you to please start by introducing the company?

Yes. Thanks for having us. It's a pleasure to be here. I think we're going without slides today. Is that correct?

Yes.

Great. So, we're a next-generation AAV gene therapy company with a lead product, 4D-150 for wet AMD and diabetic eye disease. Our underlying technology is directed evolution, which is a Nobel Prize-winning technology that allows us to invent best-in-class vectors that have the features that we want for large-market products like 4D-150. So, it's been a powerful platform for us. It's allowed us to invent and develop 4D-150, which expresses the industry-leading anti-VEGF aflibercept, but does it in a continuous fashion, 24 hours a day, 7 days a week. It right in the back of the retina, right on site where it's needed.

So we think this is fundamentally a backbone therapy for neovascular diseases of the retina, which can continuously suppress the disease activity and lead to better patient quality of life, treatment burden reduction and vision improvements over standard bolus therapies. We have 2 Phase IIIs, 4FRONT-1, 4FRONT-2 in wet AMD and 4FRONT-1 is completed enrollment at a very high rate, which is thrilling to see. It's been completed now in Q1 and will read out in the first half of next year.

We think that high enrollment rate was driven by the unmet need that patients have and by the physicians' excitement about gene therapy and the results we're showing. We have a second product -- second Phase III, 4FRONT-1, which is a global study and that we expect to complete enrollment in the second half of this year with readout in the second half of next year. And we'll be starting a diabetic macular edema Phase III in the second half of this year.

Got it. Excellent. So maybe starting with that, you mentioned the unmet need and the rapidity of the enrollment that you saw in the pivotal studies. Can we start just high level conceptually, what is the point of 4D-150, why do we need this when there are a few drugs that are approved for this disease?

Yes, I'll kick it off and then turn it over to Chris, who's been in retina for nearly 14 years of commercializing products. So people think of wet AMD and DME is having effective therapies, and that is true. There are bolus anti-VEGF therapies that can transiently inhibit the VEGF signaling, which then calms down the blood vessels, reduces edema and allows vision to improve. However, that's transient. And so what the result is, is patients -- most patients are going to need injections roughly every 8 weeks.

It could be anywhere from every 4 to every 12 weeks on average. But that's just -- most patients can't sustain that. So what happens is they get undertreated and they end up losing vision. And it's a huge impact on their quality of life, having to go to the clinic and getting a needle in the eye, which they absolutely hate. You can imagine the needle in the eye.

So there's a real unmet need for a product that can actually sustain the anti-VEGF effects consistently and constantly without going up and down, up and down, up and down, and where patient compliance is not necessary for therapeutic benefit and therefore, preserve vision. So that's why there's a huge unmet need. We think that's why patients are flocking to it. And Chris has done a lot of thinking about this and analysis of various surveys on this that he can share with you to say that physicians believe the same thing.

Yes, I can add a little bit of color. Thanks, David. So as David mentioned, the current standard of care is bolus anti-VEGF treatment. And that modality has existed for about 20 years now, actually. I think the initial anti-VEGF therapy was launched in 2006 and highly efficacious initially LUCENTIS and then follow-on medicines like EYLEA and more recently, VABYSMO and EYLEA HD. What's important to recognize is that all the innovation that's come from follow-on, more next-gen bolus therapies have largely extended the durability interval a little bit.

So every new entrant has kind of stretched the durability by a week or 2. And when you talk to physicians, that's super important for the obvious reasons that David just mentioned, right, needles in the eye, the frequency of that is burdensome for the patient and for the clinic. But despite that incremental advancement in innovation, we've seen large commercial success. You've got a medicine like VABYSMO, I think, which, again, added an extra benefit of a couple of weeks of durability. And I think it's on pace to be nearly a $4 billion to $5 billion in sales medicine for Roche/Genentech.

So we know that incremental advances in durability are highly important and they translate to commercial value. We've seen that historically. And our simple proposition is we're not trying to advance the incrementality by a week or 2. We think we can make a paradigm shift in an incrementality measured in months, if not years and not for the rest of the life for many patients, and that's a completely different treatment paradigm, and we think the commercial opportunities would be consistent with that shift in treatment paradigm as well.

Got it. And then from a clinical and commercial value proposition perspective, can you explain like your view on how -- like should investors think that this has to be curative to have a real value proposition? Or what does kind of extending durability look like? And what's kind of the benchmark that would really reframe expectations in the disease?

Yes. it's a good question. It comes up a lot, especially when people hear gene therapy. I think sometimes the natural reaction, gene therapy must be one, highly expensive and it must be curative. And I think that's true for other gene therapy approaches. It's not true for what we're doing. So we're looking at a mass-market approach -- we don't believe it needs to be curative. We think it is functionally curative for some patients, and we think we've shown that in some of the data that we've generated thus far through our Phase I/II program.

But doctors will tell you, it's like if you reduce the treatment burden and even better if you do that while also giving patients the possibility of holding on to their vision gains, which both therapies don't seem to be able to do, then that's an absolute game-changer. And of course, for some patients, if that means that 4D-150 is the last needle in the eye that they'll ever need, and we think that will be true for some, then that's incredible.

But it doesn't have to be curative. And the good news is that we work in a space where there's great bolus anti-VEGF options available today. There's more in development. And for patients that need occasional supplementation with a 4D-150 backbone therapy in place, physicians and patients have and will have great options to choose from.

Got it. So what proportion of patients still needing supplementation with EYLEA or another injectable VEGF? What proportion would be acceptable? And in terms of like from the physician and patient perspective, what does that look like from a treatment burden perspective? Like do they mind that they would still have to go into the office at some frequency? Or is that part of normal standard of care anyways?

Yes. I think it's -- I'll start with the end. I think it's part of normal standard of care and the frequency of visitation back to the office will depend upon how recently you were treated with 4D-150. So upon initiation, you're likely to be -- have to come back a little bit more frequently to assess how you're doing. And assuming that you do well, that interval for revisiting would get extended out over time. And to your other question, I don't think there's a magical number that says if you're at this binary point, then physicians think you're successful or not.

But what I would tell you is when we share the data that we generated from our Phase II PRISM study, which broadly showed like a 50% treatment-free rate at 52 weeks and about 80% to 90% treatment burden reduction across a broad range of different patient types, that profile from a physician and a patient standpoint was received very favorably. So we believe if we show something like that and maybe even better in Phase III, then we have, I think, a massive opportunity on our hands.

Got it. And then let's talk more about PRISM because that's your Phase II study that kind of helps support going into 4FRONT-1 and 4FRONT-1. Can you remind us what have you seen so far in PRISM? And I believe you're going to give an update on the 2-year data from that study coming up in a few months now. Can you help set expectations for what does good look like for that as well?

Sure. So PRISM is really several -- a couple of studies as a program, a Phase I/II program. And we, as good drug developers, studied a broad range of patients with wet AMD. It's quite a heterogeneous disease. It waxes and wanes over time. So we felt that was important. And so first-in-human studies, we started in the most severe patient population. So these are patients who had 10 injections on average in the prior year, 10 needles in the eye, if you can believe that. And then still had very swollen, thickened retinas despite that.

Many have had disease for anywhere from 4 to more than 10 years -- so in that population, we still saw what we thought was very compelling efficacy and biological activity with treatment burden reductions on the order of 70% to 80%. A significant proportion of patients either went to 0 or only 1 injection a year. That -- what was important about that was that is likely where the product will first be used in the market. And so showing that kind of efficacy where others have failed is really very, very valuable. Safety was phenomenal there. No significant adverse events at all.

And I'll get to kind of a summary safety statement in a minute. We also looked then at a broad population, a Phase IIb population where we took 30 patients who look more like a routine clinic, some severe, some less severe and a broad range. There, we saw, again, about an 80% treatment burden reduction, about 50% of patients injection-free at 1 year, 1.5 years follow-up. And again, there, just like in the severe population, we saw constant treatment burden reduction across each increment of time.

So there was no evidence that it was waning over time. It was stable as expected with the gene therapy, which we expect would be lifelong expression. So that's what we've shown there when we looked at the most recently diagnosed population. So patients we got to earlier when the retina was healthier. There, we saw a 90% treatment burden reduction and about nearly 3/4 of patients were injection-free at the middle of the second year at 18 months.

So very compelling efficacy, far above a bar that would make this a highly successful product. The injection is routine as an outpatient simple intravitreal just like EYLEA. So nothing there. And so the last box to check was safety, and that's critical with a market like this. And there, what we've seen is a very good safety profile with no serious or significant clinical adverse events.

And at the Phase III dose with the Phase III steroid regimen, out of just over 70 patients that we've put into the public domain so far, we only had 2 who had very mild inflammatory cells detected at a single time point, so not clinically significant. So we're pretty thrilled with the safety profile. In terms of what we expect at the 2-year mark, more of the same. Just boring is good for us, continued safety, continued treatment-burden reduction at roughly the same level, and that's fully what we expect to see.

Got it. And then based on just what's known about the mechanism of expressing VEGF intraocularly, is there any risk known like scientifically about like late-onset inflammation? Yes, let's start with that.

So short answer is no. In terms of -- when we think about inflammation with a product like this, there's kind of the capsid itself, the delivery vehicle that's only there for several weeks and then it's gone. So you kind of cover with steroid eye drops while that's clearing. But then you think about what's the protein that I'm producing with my therapy. And in this case, it's aflibercept. Good news is we know aflibercept has been in over 60 million eyes safely. So it's very, very de-risked in terms of knowing it's non-inflammatory, knowing that it's well tolerated and not immunogenic.

Got it. And based on what you know about the expression profile of your vector, what would you expect to see on duration of benefit?

On the duration?

On duration, like durability of expression?

Well, we would expect -- based -- so AAV, what happens is it goes to the nucleus of the cell, the target cell. And then the protein dissolves the carrier. And then you're just left with a circular piece of DNA, which is inert. So that should be there the rest of the patient's life. And unless the tissue is turning over, it should be lifelong expression. And in fact, the retina does not turn over. And so it should be lifelong expression.

There is data -- the longest follow-up data with AAV in the retina is with Luxturna for LCA2, a rare disease, and that's shown really nice stable efficacy out through 10-plus years. So we think it's going to be lifelong and not wane, and I think patients are going to love that.

Yes. I think it's an important point because I think for a lot of investors, at least like hemophilia and like liver-vector gene therapy is, I think, the greatest kind of piece of like AAV gene therapy exposure for investors. That's an interesting point.

Well, I think that's a really -- that's an important point is -- people hear gene therapy, many think of very, very high doses IV. They think of $1 million to $2 million price tag. They think about the risk of serious IV toxicities. That's not the game we're playing. Our dose is -- I think, 1 billion of their dose probably. And it's just localized in the eyes, you're not getting that systemic exposure. Our cost of goods because of that, because of the low dose is less than $1,000. So, it gives us big pricing flexibility.

Yes. Can we talk more about that? Like how do you -- because the things like in like retina therapy, there's a huge part of it is fitting in with the current practice dynamics in a buy-and-bill setting and working with these practices and the financial aspect of the practices as well. How do you think about kind of fitting into that ecosystem with respect to the gene therapy and understanding that you have some nice COGS leverage here?

Yes, I can take that one. So I think, first of all, we think we fit pretty seamlessly into the current logistics of a retina practice. Starting -- I'll come to the reimbursement part of that in a second, but it's important to highlight that because we are intravitreal delivery, we think the storage, the distribution channel, all of those things that a physician is really used to today would be the same as what they would experience if they're injecting bolus anti-VEGF.

Yes. Is there anything different from like a handling perspective, like site certification or like a temperature fridge or anything like that?

It's a good question because often that is the case for other gene therapies or unique modalities. For us, it's not. So again, pretty seamless logistics operations, pretty seamless integration into the operational flow of a retina clinic. The difference would be, as you alluded to, we do think it would be a buy-and-bill product. So all of the things that come with buy-and-bill that exist today, the opportunity to earn margin on these products and all of those things, we think, would be true for us as well.

And while it's way too early to speculate on what pricing would be, certainly, it would be higher than a single bolus injection of a branded anti-VEGF. And so when you think about practice economics, practice economics are driven by, first of all, it is the price of the medicine. Reimbursement is a function of that. So we think the value of reimbursement on what is likely to be a higher price point, in combination with the fact that you get that reimbursement upfront.

And then there's other follow-on implications for capturing patients that otherwise would have been lost to follow-up, and we think an implication for helping with practice capacity where you put all those things together, we actually think our practice economics proposition would be better than what they experience today with current bolus therapeutics. We just got to do some education as to what comprises that because the formula is a little different than what the current paradigm is. But I've had the opportunity to talk to many physicians about that concept and how it differs. They get it pretty quickly.

Understood. And then with respect to the competitive landscape, there's 2 other programs that are in Phase III gene therapy programs for wet AMD. Can you talk about the differences between those programs and your approach?

Sure. I can start and then Chris can weigh in. So again, the issue with AAV is the standard wild-type AAVs that other groups have used cannot be used intravitreally to get to the retina. There are barriers. So we did directed evolution to get over -- through those barriers and come out of the vector that could pass through and then transduce back of the eye very efficiently. There are other -- 2 other gene therapies we're aware of in Phase III.

One is overcoming the problem with the vector by doing a subretinal surgery. So implanting high-pressure fluid containing their vector by detaching the retina surgically and infusing at high-pressure that material into the retina with the hope that they can sort of force the vector into cells and get enough expression to have efficacy. So -- that is REGENXBIO partnered with AbbVie.

That subretinal approach has been very, very slow to enroll, as you might imagine, because most patients don't like the idea of that surgery and the physicians in a busy practice. It's just kind of a nonstarter for many of them. So that is going to be reading out, I believe, in the second half of this year. But again, it's been very slow to progress, and we think commercially, we will have distinct advantages. But we would expect and hope that, that would be effective because it will be expressing continuous anti-VEGF, which should work.

The other competitor is Adverum. This is a group that has a vector that was evolved in mice for intravitreal. When it went into primates in humans, it's had issues with being inflammatory, which if you have severe long-standing inflammation, it can last -- result in serious adverse events such as vision loss, which they've seen in the diabetic population, but they're still -- so they've shut down diabetic eye disease, but they are still developing it in Phase III for wet AMD. So we keep an eye on them. But again, we started about 5 years behind them, and we've sprinted right past them because of our lack of safety issues. So we think, again, we have a big competitive advantage there.

Got it. And do you believe that the safety issues seen with the Adverum program are more driven by vector or by dose or by capsid? And how is your approach different on those kind of major characteristics?

Yes. So it's driven by the capsid. And so the capsid dose, the vector dose is critical. They started with much higher doses than we needed because, again, the vector is not apparently not as efficient. That forced because of the toxicity, which is related to the total dose and we believe the immunogenicity of that vector, they had to drop the dose, which made a lot of sense. And when they did that, the tolerability was improved.

And then they spent a number of years trying to optimize the steroid regimens, including oral steroid regimens and the like to try to combat the front-of-the-eye inflammation that they were seeing that they felt resulted in the severe toxicities in DME -- so they're in Phase III, and that should be effective. I think the big question there is just the safety and can that be maintained. Physicians really don't want to be managing complex steroid regimens and putting patients back on steroids after they go off. And that's something that their early programs were grappling with.

Makes sense. And clearly, between these 2 programs, they're both partnered or sold to larger pharma companies. How are you thinking about the strategic landscape for gene therapy approaches in wet AMD?

I'll kick it off and then hand it over to Chris and Kristian. If you think broadly about treatment in neovascular disease of the retina, which is soon to be a $20 billion market that we'll be launching into, there's going to be a wide range of bolus anti-VEGF therapies with different mechanisms of action, different price points. There will be TKIs, there's going to be VABYSMO competing with TKIs. There's going to be some new combination mechanism products. There's going to be biosimilars.

So it's going to be a complex space there. But if you think about the backbone therapy, which we believe is going to be the basal that everybody should get and then they can rescue with these bolus therapies. There's only a few, and we believe we're clearly the market leader there at this point in time. And again, we got to finish our Phase III and prove that holds up. But to date -- we have best-in-class data and a best-in-class opportunity.

So I would think that if you are interested in a $20 billion market and you think that these foundational backbone therapies are going to be a critical component of that, and we have the best in that class, then there's going to be very significant interest. But we hired Chris because he has experience building U.S. sales forces, and we think we can do it and really capitalize on a lot of value for our shareholders.

Yes. I think you kind of covered it. I don't think you can potentially have a very disruptive backbone therapy type of asset in a multibillion-dollar growing market without having significant strategic interest, probably stating the obvious. That said, to David's point, like the beauty about retina, both in the U.S. and ex-U.S. as well, is that you don't need a large pharma partner to commercialize. Like I've done this 2, 3 times in different settings and launch new medicines in retina in the U.S. and your total commercial footprint is probably less than 150 headcount.

And there's not many multi-blockbuster therapeutic areas where that really is the commercial footprint that you need. So very scalable even for a start-up biotech like us. So we'll plan to do that. And certainly, that's part of my responsibility. And should there be strategic interest, we'll entertain those conversations when the time is right, but we're also well prepared to go it alone, and we can do that.

Got it. And how do you think about that piece of when the time is right?

You need Phase III data in hand. So we're in execution mode. We've said publicly, we're in the first half of next year, we'll have 4FRONT-1 data. And shortly after that, we'll have 4FRONT-2. So that's the key time point for us. So we've got an exciting year ahead of us.

Yes, totally. And then zooming in on 4FRONT-1 or both 4FRONT-1 and 4FRONT-2 a little bit. Can you talk to us about the -- on the Phase III, there's 2 key differences on the patient population and the rescue criteria. Can you describe those changes that you made from the Phase II to Phase III and what impact that has on probability of success for the study?

Sure. So I think overall, the minor changes we made going from PRISM Phase IIb to Phase III, we think overall will increase the likelihood of success, albeit we think it was already very high. We refined the patient population to exclude patients who did not have a robust response to a bolus aflibercept just to make sure we read out those 10% are relatively resistant, which makes sense. And I think that's one minor addition we've made. And then we've also made sure that patients -- the CST, the thickness of the retina is capped, such that if they had anatomical abnormalities like PEDs, they'll be weeded out.

So those are just a couple of refinements that should, if anything, make things better. And then in terms of the supplemental injection criteria, we made some very small changes to make sure we did everything we could to protect the BCVA endpoint, which is Phase III, you got to hit your primary endpoint. Primary endpoint is BCVA non-inferiority. And we don't think it will materially change the reduction in treatment burden. Again, all these are set by the best investigators in the field that we're fortunate to work with, as do other companies.

So we think if anything, this has increased the likelihood of success. I think in terms of what good looks like, I think just look at our Phase IIb data, that's -- if we hit something close to 80% to 80-plus percent, that's a huge win. And the safety profile that we've shown, if that holds up, that's a huge win. And then there will be a significant portion who are injection-free for a year, 2 years or more. And I think that will be a big win because there's no other treatment class that is going to achieve that.

Yes. And then as you think about -- let's say we're having this conversation a year from now, you're preparing to be a commercial-stage company. How are you equipped from a manufacturing and commercial -- I think Chris mentioned just you don't need hundreds of people, you need kind of more like dozens from like a sales perspective. So can you talk to us about manufacturing and commercial footprint?

Sure. So complex biologics manufacturing is critical. It's important to get it right early and not have significant changes as you develop the product if you can avoid it. And we've got a phenomenal AAV team. They've made, I think, more different AAV vectors by far than any other group in the world. And they've been on it from day 1 with a really efficient manufacturing process.

And we made all our own material in-house up until Phase III and then roughly half of the second trial will be material from a CDMO that we've already tech transferred to, so there's a world-class, AAV-experienced CDMO. So that material is going into Phase III to make sure the bridging is done in Phase III. We'll do our qualification batches and then we'll be set for launch. And as we said before, the doses here are very, very small. So with one manufacturing run, you can make thousands and thousands of doses and stockpile those in advance of the launch.

Got it. And then I guess in our last minute here, what do you think investors misunderstand most about the company?

I'd say they -- well, I'd say they don't appreciate the massive opportunity that we have with an AAV in a large market indication. I think they've been programmed to believe that AAV is for rare disease, got to charge $1 million because you're only going to get to treat patients once and then the population is gone. We're putting that on its head and say with innovation, you can actually access high-incident-rate massive markets like a $20 billion retinal market with gene therapy.

And we get why they don't get that yet or not all of them get it, certainly some do, but because it's never been done before. But when I think the penny drops that they realize, oh my God, the opportunity here to fully disrupt a massive market is -- it's a phenomenal business opportunity. So I think really, early story we're getting there.

Got it. All right. Great. Well, on that note, thank you guys so much for joining. We really appreciate it.

All right. Thanks for having us.

Lisa Walter, biotech analyst here at RBC Capital Markets. Thanks for joining us at the RBC's 2026 Global Healthcare Conference. This session, we have 4D Molecular Therapeutics, and we have the pleasure of hosting Chris Simms, who is the Chief Commercial and Business Officer; and Kristian Humer, who is the Chief Financial Officer. Chris, Kristian, thanks so much for joining us today. How are you both doing?

We're great. It's great to be here. Thanks for the opportunity.

Thank you for having us. It's been a good day.

Well, it's great to have you both here.

So team, maybe a big picture question for you. FDMT has made really tremendous progress over the last 4 years, launching 2 pivotal studies for Wet AMD, you are on the verge of launching a pivotal study for DME. You have an enviable cash position and potential to transition to a commercial stage company within maybe the next 2 to 3 years. So with all the progress, what do you think remains the biggest misconceptions about the story? And what are investors missing?

Yes, I can start with that. And Kristian, feel free to add additional color. So I think there's a couple of things. First of all, I think we're setting out to reset a treatment paradigm to do something that hasn't been done before. And I think whenever you're endeavoring to do something that's bold in that nature, it's sometimes hard to fully appreciate the potential until you see it. So I think that's very true for us. We're trying to evolve the treatment paradigm for retinal disease, notably AMD and DME from this bolus therapeutic process where patients are treated on some frequency of 4, 8, 12 weeks to a backbone for retina treatment paradigm where you have a safe effication is always onboard treatment that's been supplemented as required. That's a big change from what I think the market has experience in the past, and I think that inherently creates some challenges with how does that play out in the market.

And the other part of that is the market itself has become more cluttered, right? It's a highly competitive space today. There's lots of other assets in development. We think our profile is uniquely positioned to make a real meaningful difference and reset the treatment paradigm, certainly with a lifelong safe efficacious backbone therapy in place.

But admittedly, in a space where there's lots of other treatment alternatives in a bolus nature available, sometimes it's challenging at this stage to see what the true commercial potential of that is. We believe highly in the commercial value.

Then there's the other part, Lisa, that I think will get proven with time, but a function of being a gene therapy is that you are sometimes burdened with some of the gene therapy challenges of the past, right? People hear gene therapy, they want to see the evidence of safety in the real world. And we're working through that. What we're really proud of, though, is that in the clinical development that we've done so far, we believe our molecule 4D-150 certainly differentiates on safety. We hope to prove that certainly in our Phase III program, which, as you referenced, is -- has been enrolling at a very high pace. And I think through our development program and ultimately, commercialization we'll show what the opportunities for a treatment like this.

Thanks for that, Chris. Well, I do have another big picture question on regulatory. We're experiencing some volatility right now with the FDA as the commissioner has stepped down recently. And so given your in pivotal stage and you are still a little developing the pivotal for the DME study. Is there any risk to your communication with the FDA, given all the volatility that's going on?

There's nothing of note that's unique to our conversations with the FDA. We acknowledge the volatility, but we would say that our interactions have been very productive, nothing that's come up that would give us any concern. Again, I think part of that relates back to -- while we are gene therapy, we're not in gene therapy for a rare disease. Our Phase III program is very traditionally designed. So if you look at our Phase III program for Wet AMD, it's -- the design is similar to what you've seen in other pivotal programs, like the biosmilar Eyleas and so on. So I don't think there's anything that's overly unique or unusual about how we've developed the 4D-150 in our Phase III program. So I think that is conducive to pretty up the middle FDA interactions.

The other thing I would say, you referenced our plans to start our DME trial, so we hope to start that in the third quarter of this year. Very excited about the opportunity there, by the way, in DME, a huge unmet need. And we have regulatory alignment from both the FDA, EMA and Japan for a single DME trial. So we plan to do a single trial globally. We'll do it in partnership with Otsuka, which is our partner for Asia Pacific. And again, our regulatory interactions for that trial continue to be very productive and nothing new or different in those interactions that would cause us any change to what we've assumed previously.

Well, Chris, since you've bring up the DME study, maybe let's dive into that a little bit more. What is your latest thinking here on the trial design? I know we're going to get the update in the third quarter. But should we expect this trial designed to follow what we have seen in the past with other programs?

Yes. I don't think we will share the more specific details on trial design in a couple of months as we get closer to the initiation of that trial. But I think for investors, you could assume that you can look at what we've done historically with our trial design for Wet AMD and assume we'll take the same approach and philosophy as we go into DME. So we believe designing trials for a pivotal program need to be done in a way where the data that's produced obviously allows you to get regulatory approval but also the data that's produced is conducive to a physician and looking at that data and translating it to -- in clinic usage. We don't always see that in some recent trial designs. We think that's important to design it in a way where that Phase III data set has applicability to clinic usage.

So again, while we haven't got the final details of our Phase III DME study ready to be shared, I think you should expect that it will also be very, I think, standard and traditional in its approach similar to how we've done 4FRONT-1 and 4FRONT-2 for AMD.

Should there be some similarities with the 4FRONT trials, maybe in terms of rescue criteria or steroid use?

Yes. I -- we -- I don't know the -- we haven't shared the exact rescue criteria, but I think certainly, rescue criteria will be applied. The exact specifics are not ready to be shared just yet. But certainly, I think it would be somewhat similar to what we have in the Wet AMD trial. And yes, we'll most likely have a prophylactic steroid regiment as well. The details of that, again, to be shared. But I wouldn't expect anything all that significantly different from both what we've done in 4FRONT-1 and what we've seen in other Phase III DME program from Roche, Genentech, Regeneron and so on.

Got it. That's helpful. Well, maybe let's just talk about the larger retinal landscape for a second. For the last 20 years, this market for Wet AMD and DME included has really been dominated by intravitreal delivery of these anti-VEGF biologics. And these drugs are safe and they improve vision and the branded market has really grown into the largest area of ophthalmology therapeutics. So where does the unmet need lie for Wet AMD? And does it differ for a disease like DME, which affects a bit of a different patient population?

Yes. It's a great question. And it's amazing, actually, as you mentioned that it's -- we're about 20 years since, I think, the introduction of LUCENTIS. So for 20 years, the treatment of these diseases has been done through a needle in the eye at some frequency. And of course, that creates a whole host of treatment burden challenges. And needle in the eye, it's fairly a road standard procedure. Retina docs do it multiple times a day. But you have to think that, that treatment paradigm is due for a different approach and we think we can deliver that.

So -- and you mentioned these therapies help patients gain vision. And that's correct. You see in all these Phase III programs upon initiation of therapy, depends on what the patient's baseline vision was. But on average, a patient -- a Wet AMD patients are going to gain 5 to 7 or so letters on average at the start of a trial. But what's really interesting, and what's really unfortunate is despite these medicines being highly efficacious, real-world data would suggest that even if you stayed on therapy for 2, 3 or even up to 5 years, more likely than not, you've actually lost that vision that you gained initially. And you actually see this. When real world data, you gain that 5 to 7 letters, but over time, that vision slowly erodes and in fact, many patients when you get into year 2 and 3 are actually have worse vision than they had when they were initiated on therapy.

And there's a couple of reasons for that. One is a lot of these patients can be undertreated, sometimes there's lapse in therapy. This is where the treatment burden issue comes to life. And sometimes there's anatomical issues like fibrosis or atrophy that may show up, which has an effect on vision.

But what we also know, and we've seen this in a number of data sets is that the constant regular suppression of VEGF has resulted in patients holding on to that vision for the long term. So there's been studies down where LUCENTIS is dosed monthly. And amazingly, that vision gain that I referenced happens and the retaining of that vision is flat for many years. So you know that if you are a constantly controlling the disease with VEGF therapy, patients can hold on to that vision.

And we've also seen that data, by the way, with a drug that Genentech has called Susvimo, which is the implant, which does the same thing. It controls VEGF continuously. It's always there. It's always on. And you see, as a result of that, patients hold on to that vision long term.

Our view is that with a 4D-150 gene therapy approach is that you can do that, you can hold on to that vision for many years, but you do it obviously through a biological approach.

So in many ways, we think we can produce Susvimo-like long-term vision outcomes but not have to do it through an invasive implant type of approach.

Got it. And Chris, to me 2026 is really a kind of a landmark year for Wet AMD in terms of development of new therapeutics for having -- or we already had a pivotal readout in 1 of the long-acting TKIs. We're expecting more in the latter half of the year. And we're also going to get our first pivotal gene therapy readout as well later in the year for a subretinal approach. So how might all these readouts, as the data comes in, how is this going to shape your strategy -- your commercial strategy for 4D-150, which is going to start to read out later for beginning in first half 2027 with 4FRONT-1?

Yes. It's a very dynamic space, as you just referenced, the next 12 months is going to be pretty exciting. And I think a lot of those readouts are going to be informative.

I think a couple of things I would say. First of all, all of these programs, certainly the TKIs are looking to extend durability, as are we, right? They're looking to add another week or 2 of durability because treatment burden is an issue, and we know it's an issue when we've seen medicines like the biosimilar Eylea HD, which extends durability by a week or 2 come to market. We all know the commercial success that have resulted in that. So we know durability matters. Those agents are trying to extend durability a little bit further as well. And I think there's a market for that, should they prove to be successful in their Phase III program.

I think the difference for us versus the TKIs or any other bolus therapy that's in development is that we're not trying to extend durability by a week or 2. We're looking to establish a backbone for retina that for patients holds the promise of months and unlikely years for many patients. I've never needed another bolus injection again. And that's a whole different category, we believe, and a whole different value proposition for patients and providers and also for payers.

So that's how we differentiate. We think it's great for patients and providers that you have a broad list of bolus supplemental therapeutics you choose from, should you need to supplement.

And then as far as the other gene therapies in development, we think we also differentiate from those as well. Clearly, we have a -- our delivery is intravitreal which is highly important. It allows you to seamlessly integrate into a retina practice, its's a pretty standard procedure compared to other programs that have a surgical subretinal approach, and that can be, I think, pretty prohibitive for retina clinic to adopt just based upon the time it would take to deliver that other medicine.

So we think we're uniquely positioned. We think our delivery, our safety data and certainly efficacy data that we've generated thus far supports that.

Got it. That's very helpful, Chris. And the branded Wet AMD market is worth about $10 billion today. The DME market, the branded market is worth about $4 billion. That's a $14 billion market between those 2 indications. What slice of that could 4D-150 capture?

That's a great question. That's -- and growing, right?

And growing.

So we actually project that the global anti-VEGF market kind of in our launch horizon could actually be valued as high as $20 billion as the population ages.

So I'll tell you, we ask this question to physicians a lot based upon our target product profile. We get numbers that I think are very encouraging. We don't think our 4D-150 as being a niche type of product. We actually think if we generate the data we expect to in Phase III, that backbone therapy approach should be considered for the majority of patients.

I actually -- the feedback that we get from physicians when we take them through our profile and the data that we've generated, I asked a question that's similar but a little bit different, which is based upon all the Wet AMD patients that you have in your clinic, what patient do you think you would not consider for a therapy like this. And what we get is there's a handful of patients that are seemingly controlled with 2 or 3 injections per year. And that's the group that physicians are likely to not consider 4D-150 for, at least initially. And we think that represents maybe 10% of the overall AMD population. The majority of patients need -- on average, the number of injections about 6 to 7 per year with many patients need 8 to 10, if not more.

So we think there's a segment where we're likely to be used less, but the overall population, we think, over 90%, at least physicians would consider us for those patients based upon their treatment burden need. Of course, there's lots of other factors that will come into play, insurance and so on and coverage, but that's how we view the opportunity.

All right. Very helpful. And Chris, maybe on pricing. I think many investors are used to hearing these multimillion dollar price tags for gene therapies. Of course, these are typically gene therapies that are developed for rare diseases. Wet AMD, DME, these are not rare diseases, whatsoever. So how are you thinking about pricing gene therapy for an ocular indication where there's already a large established market with price points that are also already established?

Yes. Of course. And I love that question because it gives us a chance to also distinguish between what you just referenced, which is sometimes a gene therapy, you hear gene therapy, and you instantly think small patient population, got to charge $3 million to have a business case. That's not us at all, right? There's, I think, over 600,000 patients in the U.S. alone that are on anti-VEGF therapy in any given year and about, I think, 100,000 to 150,000 of those are new to treatment in that year. So you have a fairly high incident rate that continuously brings you, I think, a nice bolus of patients that are considered for treatment. And of course, that's just a function of the aging population. So those things have to be considered when you think about things like pricing.

So while it's way too early to say what we think our price will be because it's going to be determined by a number of factors, our Phase III data, the market and so on, we -- I can tell you that we will not be in the $1 million price range. In fact, I'd be surprised if we were higher than $100,000. Where we felt ultimately, we'll make that decision once we get further along in our preparation process.

The only other point I would make, and we've said this publicly before, because of the volume and because of our expertise in manufacturing, again, we're delivering a relatively low dose at 310. We think we can deliver a cost of goods profile, which is probably less than $1,000. So that gives us a lot of room to be competitive and potentially disruptive in a large category as it relates to our pricing decision.

I think that is very different in terms of what happens with gene therapy in rare disease. So it's very helpful to kind of get your thinking around it.

And I do want to touch on the opportunity outside of the United States since this is part of your strategy. You have this partnership with Otsuka on the Japan, APAC region, EU. Obviously, the anti-VEGFs are sold widely there. So how are you thinking about the opportunity for 4D-150 in those regions?

Yes. So first, just to reiterate the obvious, I guess, U.S. is priority #1. And we think that would be our first launch market, and that's how we're planning our commercialization strategy.

That said, our development program has been intentionally designed to allow for global, what we probably think is global approval. So 4FRONT-1, the first Phase III trial that completed enrollment at the end of March. That's a U.S., North America, U.S. and Canada trial. 4FRONT-2 is a global trial. So we have sites in the U.S. and Asia Pacific, South America and in Europe. And 4FRONT-2 also has a little bit of a different patient population. So 4FRONT-1 is entirely treatment-naive and 4FRONT-2 is a blend of naive and experienced patients. That experienced patient population is in direct response to an EU regulatory requirement. Those patients could have been diagnosed in the prior 6 months. So we've designed our pivotal program for global adoption.

So I do think the European market is of interest. Certainly, Asia Pacific is a market of interest as well, which is why Otsuka was motivated to do the partnership with us that they've done. So we believe there's an opportunity globally and certainly at the top 5 European countries would be on that list. When and how we go about that is still a strategy that needs to be developed, but it's within our model to assume significant value there.

And the last thing I would say about that is the patient need that we think we solve for, again, a therapy that's constantly on treating the disease 24/7 because the disease is constantly on. That patient need is not a U.S.-only need. That patient need exists globally, unfortunately, in this disease. And you can make the argument that in certain countries where access to care, like access to a retina doc is not as easy as it may be in countries like the U.S. or Canada, that having a therapy that you can administer to a patient that may not be able to get back in to see you from months from that point in time, could actually solve a pretty significant need in those markets.

So I think our value proposition and our story and what we can ultimately deliver in terms of ongoing treatment and the potential to preserve vision would be up interest to a number of, I think, European countries and payers.

Got it. That's super helpful. And on the 4FRONT trial, these are your 2 pivotal studies that are ongoing. Because these are non-inferiority trials, and they have a rescue criteria in them. And the rescue criteria is relatively strict if a patient loses 5 letters and has, I believe, 50-micron or greater increase in CST is your rescue criteria, they would get a supplementary injection of anti-VEGF. So under that umbrella, how could a non-inferiority study when you get rescue possibly fail? How could it not possibly meet the primary endpoint?

Well, we think we've derisked the Phase III program as much as we can while also maintaining its relevance in terms of the data that it will present. You never want to say that things are guaranteed. That's not a -- that's just not the nature of the business that we find ourselves in. But the criteria we think are reasonably designed. We did that in collaboration with world experts in retina. We did that by looking at similar criteria from other drugs that have been approved to make sure that whatever we choose to be the retreatment criteria is relevant and physicians will look at that and say that represents something that's meaningful to how I treat my patients.

But yes, I think we've tried to do as much as we can to derisk the program. You never know until you know and you turn that data card over. It's the nature of being in this business, but we think we're as derisked as you can be and looking forward to seeing those results in the first half of next year.

So some of the secondary endpoints of this trial, I think, are going to be a lot of interest, like reduction in injection burden. Is there a bar you have in mind that would really facilitate commercial adoption of the gene therapy?

So yes, it's a great question. It comes up a lot. I guess where I hesitate a little bit in the answer is because sometimes you can give a number, you think that 1 percentage below or above that number, define success. And the reality is it's not that. So I'll refer to, I think the conversations we have with the retina docs, and we take them through our program, and we show them our Phase II data, which you show treatment-free rates, 50% to 70% depending on the population, overall treatment burden reduction in the 80% to 90% range. I'll guarantee you anything from our Phase III program that comes within that realm of treatment burden reduction would be a huge out of the park home run by far. I don't think it has to be in that range, physicians will tell you that.

The last point I'll share with you, Lisa, on that question is we just -- we did market research asking doctors around, hey, how many patients would you use a product like this in. And the first time we did it 8 months ago, we tested a 60% -- I'm sorry, no, a 70% treatment free rate and a 90% treatment burden reduction. And then we did it a month ago and we tested a 50%. So a lower treatment free rate and an 80% treatment burden reduction. The percentage of patients that doctors would say they would choose the product for was exactly the same in those 2 data sets.

So I guess it just proves that there's no like magic number per se. But again, I think if we're in that range of 50% treatment-free, 80-plus percent treatment burden reduction at week 52, then we think that's a huge success.

Got it. Well, Chris, maybe just in the last minute or so we have here, you have a couple of catalysts coming up. We're supposed to see 2-year follow-up from PRISM and broad and recently diagnosed patient population. What should we expect to see here in update?

So it's a continuation. So we've already shared 18-month data on that patient population. So our expectation is just more of the same. We think that data would -- it should just represent the same overall treatment burden kind of reduction rate just out to a longer time period and hopefully, of course, the continuation of safety.

Got it. And you're also expecting to share an update from the DME SPECTRA trial as well, correct?

That's correct. That's coming up in the back half of this year.

Okay. Got it. Well, I think we're a bit out of time. But Kristian, maybe a question for you since we have you here. Can you maybe just remind us of the cash position and the runway. And what the runway is expected to cover in terms of your clinical programs?

Sure. Happy to. So as of the end of Q1, we had $558 million in cash. We are guiding to cash runway into the second half of 2026 -- 2028. And what it doesn't include that cash runway is basically the commitment to the commercial build-out that we would need to do post 4FRONT-1 day.

Got it. Very helpful, Kristian. Chris, Kristian, thank you so much for joining me today. I hope you enjoy the rest of your day.

Thank you. Thank you for having us.

Pleasure.

Analyst here at BofA. Our next presenting company is 4D Molecular Therapeutics. I have some members from the management team here. So welcome, guys. Thank you for joining us. Maybe we can start with a couple of introductions from your side, and then you can give us a high-level overview of the company. And I know you have some catalysts coming up, especially 2027 is going to be a big year for the company. So maybe we can start with that. So David, maybe if you want to start.

Yes. Thanks, Daniel, for having us. I'm Dave Kirn, Co-Founder, President and CEO.

Chris?

Thanks, Daniel. Chris Simms, Chief Commercial and Business Officer.

Kristian Humer, CFO.

So I can give the high-level overview of the company. So 4D Molecular Therapeutics is really a leader in next-generation AAV gene therapy. We're a platform and product company with a lead asset 4D-150 in Phase III for wet AMD and soon to be in Phase III for diabetic macular edema as well. We believe we really have the opportunity to be a best-in-class, highly durable backbone therapy for these neovascular diseases of the retina. So we're thrilled to be in Phase III. The enrollment has been extremely rapid, probably double what we expected going into it, showing a lot of enthusiasm from patients and physicians.

There have been a number of surveys that have come out that show that physicians in this field are most excited about 4D-150 and gene therapy writ large. So I think we have a real opportunity here. Catalysts this year are -- we have a 2-year follow-up on a broad population of wet AMD patients with 4D-150 Phase II, that's midyear. And then second half of the year will be a DME 2-year update. And then next year will be -- first half of next year will be the first Phase III readout and the second Phase III readout will be in the second half.

Okay. Great. So maybe let's just start with a high-level question. The wet AMD market is becoming increasingly competitive. There's a lot of new products coming out, a lot of innovation there. You mentioned some of the surveys. What are you hearing from physicians in terms of what the unmet need is right now for the treatment of wet AMD? And how do you think 4D-150 could be differentiated in that market?

Yes, I'll kick it off and then hand it over to Chris, our Chief Commercial Officer, who's done a lot of work in this area, and I think it's very promising for us. But I think at a high level, the way we view this is there's a lot of noise and a lot of competition for incremental improvements in bolus anti-VEGF therapies, and that's great. But we're fundamentally in a completely different category. What we're looking at with the way AAV gene therapy works in the retina, it's likely lifelong therapy, continuous expression every day for the rest of the patient's life, which we think really will translate into markedly improved quality of life, major reductions in treatment burden. Some patients may never get another treatment and should also translate into better visual outcomes over time. And Chris can really speak to, I think, what's driving patients and physicians' interest.

Yes, happy to. So you take a little bit of a step back and you're familiar with the category, it's a large space. I think valued at roughly $17 billion (sic) [ $14 billion ] globally today with existing bolus anti-VEGF therapies, and we expect that to continue to grow, largely driven by an aging patient population. And these existing therapies are actually pretty efficacious. They do a good job of improving the patient's vision. The challenge is getting in and staying on therapy at a frequency that allows the patient to maintain that vision. And of course, the process of administering the medicine being a needle an injection in the eye on some frequency is burdensome beyond the other factors of getting to the clinic and so on.

So the unmet need, to your question, has been the same unmet need for years. You go back and look at surveys 10, 15 years ago and you ask doctors, "Hey, what's the biggest unmet need?" It's always been we need agents that are more durable, more durable means that we can reduce the treatment burden for patients, we can reduce the complexities of delivering these treatments in our office. And not only have they said that, we've seen innovation prove that to be real. So you look at the latest bolus therapy launches, Vabysmo, EYLEA HD, all of those assets have extended durability by a week or two.

So meaningful, certainly for a patient, maybe takes an injection per year out of their normal routine, but incremental. But despite that incrementality, those agents have become multi-blockbuster within a couple of years. I mean Vabysmo is the greatest example of that. So I think with our approach, we asked the question if an incremental benefit like that can be of commercial value measured in the $4-plus billion in terms of top line revenue globally, what could the commercial value be if an agent like 4D-150 that we're not looking to extend durability by a week or two.

We think for a lot of patients, it would be the last injection they'll ever need and for others, we're looking at durability improvements that are measured in months or years. So it's a completely different paradigm. So we think we are uniquely positioned to like really address this durability question in a way that hasn't been done before. And in addition to that, we think we could actually help patients maintain their vision over the rest of their lives. And that's pretty, pretty significant when you think about -- you go on to these therapies for the benefit of keeping your vision.

A lot of these therapies don't allow you to keep your vision because you get undertreated just because, again, of the challenges of administration. So if you can not only reduce treatment burden by 80-plus percent, but also say to a patient, you've got a good chance of holding on to your vision for the rest of your life, that's a completely different ball game and a completely different treatment paradigm.

Okay. Great. There are a few competitors in the gene therapy space for wet AMD. How do you view your product compared to those? And where do you think is your edge in this market?

Well, we think we're the best, which shouldn't be surprising. But actually, we think there's actually very good data behind that statement. First of all, I don't think there's any doubt that an intravitreal product has massive commercial advantages over a subretinal product. So subretinal surgery is just -- it's great for proof of concept, but for commercialization, it's really a nonstarter. So we have major advantages over the AbbVie REGENX product since we're intravitreal. And then I think our safety profile has really shined and differentiated us from the Adverum and Lilly products to the point where they're not even in DME, they can't go in because of the blinding events they had. DME is a major opportunity for us in addition to wet AMD and DR.

For what it's worth, our doctor checks also indicate physicians think your product has the best profile so far. So you mentioned you have a 2-year update coming up for the broad patient population. Can you maybe remind us what you've shown so far? I think the last update was 18 months. What should we expect to see at 2 years? And you've also shown data for different patient populations. Maybe you can talk about kind of like the evolution of the patients you've treated and what you've seen in terms of efficacy there.

Sure. So in wet AMD, our team has done a phenomenal job of really having a very robust Phase I and Phase II program to really set us up for success in Phase III. So we started in the hardest-to-treat patient population, one of the hardest-to-treat populations ever studied. And that was sort of on average, 8 to 10 injections a year still failing therapy. And in that population out to 2 years, we showed nearly an 80% treatment burden reduction compared to what they've been getting using patients as their own control. So that's huge. And then when we moved into a broad population, we showed about, again, an 80% reduction out through 1.5 years.

And when we look at the patients that most closely mirror our Phase III population, we had a 90% treatment burden reduction through 1.5 years with over 70% of patients injection-free through 1.5 years. Most importantly, though, given this is a large market and there are effective therapies is our safety has been extremely favorable. So there -- when we look very, very closely every several weeks for any evidence of inflammation in the eye, the most we can find is about 3% of patients might have a single time point where they have a few trace cells that we can see in the eye, but nothing clinically significant.

So it's been really phenomenal, and that's just during the first few months after treatment. After 6 months, we just don't see anything. So the safety has been really phenomenal. So that's sort of what we've shown to date. So we would expect the 2-year update for the broad population and recently diagnosed population would be more of the same, more safety and just more stability of the treatment burden reduction over time.

Great. What do you think is the profile that physicians are looking for, for this type of product? You've reported data for injection freedom over time, but you've also shown significant treatment burden reduction. Where do you think physicians will be comfortable using a gene therapy product? Is it just significant treatment burden reduction? Is it injection freedom that they're looking for?

Well, I think Chris has probably interviewed more physicians on this than anybody in the world. So I'll leave it to him.

Yes, it's a great question. So first of all, safety has to be established, right? And I think to David's point, we think we really differentiate on our profile as it relates to safety, no doubt. But that's in a category where you have effective and safe medicines available, I launched a drug called Beovu at Novartis several years ago, highly efficacious, highly potent, maybe even more so than it should have been in hindsight, but it had a safety issue, which caused it to be a challenge from a commercial perspective. So you got to have safety. And we think our profile would support that.

As far as the treatment burden injection-free numbers, it's -- doctors don't say it has to be X percent. Like there's no binary cutoff point. It has to be meaningful. It's got to be for a gene therapy, a significant step change from the incrementality that they're getting with high-dose products or TKIs, but there's no magical number. What I'll tell you is that when we take them through the profile that we've seen through the PRISM data, which David just alluded to. So you see basically like in the broad population, injection-free rates of about 70% at 1.5 years, overall treatment burden reduction rates in the 80%, 90% range across a broader population, they're blown away by that. We don't believe commercially, it has to be at that level to be a strong commercial success. But if our Phase III data and profile comes out in that range, then that would be a significant change -- leap change forward for physicians and patients for sure.

Okay. Great. You mentioned there's potential for this being a onetime treatment. But realistically, that might not be the case for everyone. What sort of durability do you think physicians would like to see? And maybe how are you thinking about potential redosing over time?

So for redosing, we don't think it's going to be necessary. The retina is a very, very stable tissue. So other AAV gene therapies have shown stability out through 10 years or more, and it's an elderly population. So it's probably lifelong. So we don't think they're going to need injection in the same eye. A big opportunity for us commercially and to help patients is about 40% will get wet AMD in the other eye. And so I expect if they have great success in this eye, they're going to want in the other eye almost by definition. So that's another 40% on top of the initial population. So I think it's a huge opportunity. And then maybe, Chris, you could speak to the other part of the question.

Yes. So there's no -- physicians don't say it has to last X amount of time. I think they just look at what is the treatment burden reduction that we're showing. I think practically, we're going to have to show long-term data over time to continue to prove that one continues to be efficacious in years out, and there's no biological reason that we think would prevent that from being the case. So I think that will come, I think long-term safety is going to be important as well. But for the purpose of modeling, and I'll throw out numbers that we use just to model what the market opportunity and ultimately, we'll probably have to use that for figuring out things like pricing.

We look at a 3- to 5-year window for AMD from a modeling perspective. But again, that's not to say that's how long we think the drug lasts, but that's often the window that patients are on therapy in the real world today in that range on the outside of their durability of treatment, somewhat driven by the fact that in AMD, you have an older patient population. So that's just some of the variables that we use when we think about length of treatment and durability.

Okay. Great. Maybe we can talk about the Phase III program. So you have 2 trials ongoing. You recently announced you completed randomization in 4FRONT-1, the North America trial. What do you think drove kind of the accelerated enrollment in the trial? And do you think that's going to boost enrollment in 4FRONT-2 as well now that you're complete -- you've completed the first trial?

Yes. The second question, yes, absolutely, and we're seeing that. We're seeing the same level of excitement and enrollment momentum. I think what drove the enrollment in the first study 4FRONT-1 bodes very, very well for commercialization, and that is high unmet need in the opinion of the patients. So they really, really want something that's much more durable, if not lifelong benefit. And then physicians, it's the data. They look at our data and say, "Wow, it's intravitreal, it fits seamlessly into my practice," and they're getting safety profile that's not unlike aflibercept. And the treatment burden reduction is remarkable. And so I think it's really a combination of unmet need and our data. And again, Chris has had a lot of those conversations and probably add some color to that.

Yes, not a whole lot. I mean we did something that I think is pretty obvious in hindsight, but we went out to all the clinical trial sites with a pretty robust Phase II data set and said, "Hey, before you start up in Phase III, let's just make you aware of what we've seen so far as we've taken this asset through development from Phase I to Phase II." And we've shared with them what the results were. We shared with them what we saw in terms of safety. And I mean, that's just, I think, putting a little bit more evidence around we've got a really good drug, and it is unique and it's different than what you've been I think, used to before. And I think that created enthusiasm for them to talk to their patients about it.

And then what's really, I think, amazing and encouraging for us is we're starting now to get a better sense as to what patients think. And some of that we get through the physician conversation, and they probably rely how patients react when they present them with a gene therapy and a clinical trial option in a world where you have a lot of other therapies to choose from. And by the way, you're presenting that to naive patients. And the patient enthusiasm has been off the charts. So I think that combined with a highly engaged -- a great drug, a highly engaged physician audience, a great team to kind of roll it out and really strong patient enthusiasm for a profile like this is, I think, the 4 reasons why we saw the pace of enrollment.

Great.

And Daniel, let me just expand on that for just a minute. I think it's remarkable to think where we came from with gene therapy initially was people thought this is a dangerous therapy. It's going to be $1 million a dose. Boy, it's got to be curative. You can only go into rare diseases where it's fatal. We flipped that on its head. And we said, no, if you actually innovate and we used a Nobel Prize-winning technology to innovate and create a new vector that had the features we want, we could flip that on its head and take this into large market, high incident rate diseases. No one thought that was possible.

And yet here after 5 short years in the clinic, we're enrolling at record speed, not only in a large market indication in patients who are in their 70s and 80s for the most part. It's in patients who are treatment naive, like frontline therapy. So nobody thought that was possible. It's really remarkable, I think, what the team and the product has accomplished.

Great. Safety, like you mentioned, has been a big point of focus for these programs. Can you maybe remind us what you've seen so far? Has anything changed, I guess, on a blinded basis in the Phase III trials? And I know you have a steroid regimen as part of the trial. How do you think that will play out in the real world once patients are not part of the clinical trial?

Yes, it's a great question. So just starting from fundamentals, again, because we came in and we said we're going to innovate and invent and optimize a capsid as features we want, our dose levels are lower. Our inflammation is much lower, if any. And it set us up for success. So the fact that we're seeing no significant inflammation or toxicity is not by chance. It's not luck. It was by design. And we took years to innovate where others just kind of took existing vectors threw it in the clinic and hope for the best. So we take great pride in that, that we're seeing exactly what we expected to see. In terms of the safety, we've now reported treatment of over 400 patients with 4D-150, which is, again, a remarkable accomplishment, and we haven't reported any serious adverse events or significant toxicity. We've had, again, less than 3% kind of trace to 1 plus cells that could be detected maybe at one time point and then are gone by the next time point. So not clinically meaningful whatsoever.

Again, a remarkable outcome. So that's the safety profile. And while we're not giving formal safety updates, we do watch the safety of every single patient in our Phase III in a masked fashion. But we're -- we certainly haven't seen anything that changes our thesis that this is going to be very safe and effective. And we do have a DSMC that also reviews the data every 6 months who, again, would tell us if there was a problem.

The steroid regimen is probably overkill, to be honest, it's about 20 weeks of topical steroid drops. Each month, you reduce the number of drops until you're basically on de minimis drops by the end. Compliance seems to be very good. But even if it's not, it's probably overkill regimen. So patients probably can miss some doses. But we haven't -- I don't think we've heard of a single patient from the sites who said, I'm not going on this because of eye drops because what they're trading is a jab in the eye and then blurry vision and pain for 3 days versus some drops, they'll do that trade-off all day every day.

And so we have the first readout coming out in the first half of next year. What do you think would be good data there? What do you think is needed for commercial success?

Chris, do you want to speak to that?

I would go back, I think, to the comment I made earlier where, again, this is not an absolute binary kind of pivot point. So clearly, you got to meet your primary endpoint. You got to demonstrate safety that we think needs to be kind of in the range of where standard of care is currently. We feel good about both of those based upon how the trials have been designed and the performance of the drug as we've seen it through development thus far. And then when it comes to the treatment burden effect, the injection-free, honestly, I -- if it's in the range of what we've seen through PRISM, I think we have a massive home run. We'll see where the data falls. We actually think there's reasons why based upon, again, the design and the patient selection for Phase III that it may actually could be better than that.

Because again, if you look at our efficacy results that we've shown through PRISM, you look at patients that were more recently diagnosed, you do see a proportional treatment burden reduction to those patients. And it makes sense biologically, you have healthier retinas, you're transducing retinal cells. So therefore, it would make sense that you probably get more expression and more of a treatment effect. And then in our Phase III, we have a completely -- at least in 4FRONT-1, naive patient population. So there's a scenario where you actually see, I think, a potential improvement versus what the treatment burden and injection-free rates were from Phase II. But even if that's not the case, if we're in that range of Phase II, we're in a really good spot for commercial success, I believe.

Great. There's been a lot of talk, especially in ophthalmology about the potential for approvals based on a single trial. Have you had those conversations with FDA? Do you think there's a path forward there to apply with just 4FRONT-1?

So we've not specifically had that conversation around wet AMD. We have for DME, diabetic macular edema, and we have alignment with both the U.S. FDA and EMA in Europe to do a single filing for DME. So that's definitely our plan. I think for wet AMD, there's probably a path, but the reality is also is because we were doing good drug development and derisking things, we have 2 studies that are pretty close to each other. Readout for 4FRONT-1 is going to be first half next year, 4FRONT-2 second half. So how much do we really gain versus the benefit of having filing on both in Europe, -- U.S. and in Europe and Japan. So we're still looking at that, but I think we're really well positioned even with just filing off 2 studies right now, that's our base case.

How are you thinking about the commercial strategy now that you're getting closer to pivotal data? And how do you think this type of product would fit into the buy-and-bill model of retinal practice? Would it be any different from like any of the other currently approved therapies?

The ways that it's different is better. So -- but most of it is -- I mean, so it's buy-and-bill, the distribution model, we think, is the same as currently exists. It's again supported by the fact that it's an intravitreal delivery, and that's really important. When we -- I recently had the opportunity to share our product profile and our development plans with a group of practice managers, which run some of the largest retina clinics in the country, they love -- they were blown away by the profile. They're like, this is really IVT, they can store it at the same temperature as our current I guess, that's massive.

So I think commercially, that bodes well for us. The buy-and-bill model, we think will fit within that because it's largely a Medicare Part B and office administration product. And I actually think the economics, this comes up a lot when it comes to retina clinics. People are aware that physicians make profit on these medicines because of the buy-and-bill model. And the retina community, I think, has largely perfected that business model with bolus therapies and how they create economics through that. But the dynamics of our medicine being -- is going to be priced higher, of course, because of the value that we reflect over long-term treatment burden reduction, the value of getting reimbursed upfront is of significance to them.

The value of capturing patients on a therapy that would have -- that accounts for what likely multiple years of treatment versus a lot of patients fall off current therapies within a year, 1.5 years. So that's incremental value. So we think there's an economic story that actually improves the buy-and-bill economics for a retina clinic with our profile.

So yes, I'm pretty excited about that. And I think there's a great, I think, overlap of value for physicians and their clinics, clearly value for patients and the treatment burden reduction and the potential to hold on to their vision. And I also think there's a value story that will be interesting for payers as well, notably when you can show the reduction of treatment burden and the value -- and the preservation of vision for years. So we think we've got some unique elements that position us really strongly there commercially.

Great. You recently announced, I guess, last year, you announced the partnership with Otsuka for commercialization in Asia Pacific. How are you thinking about rest of the world? Are you going to do it yourselves? Do you think it would make sense to find another partner for Europe or other regions?

Chris, do you want to speak to that?

Yes, happy to. So I think we're keeping all options on the table, honestly. So we have said consistently and continue to believe that 4D-150 creates value for all patients globally. And when it comes to Europe and basically ex-U.S., excluding Asia Pac, which Otsuka has, we're going to keep options on the table. So we'll look at a partnership opportunity if the terms and the details of that are right, if the factors there are not available to us or the terms aren't what we think is the right set of terms, then we'll -- we reserve the option to commercialize ourselves. And by the way, that's one of the unique things about retina. You can do that.

You don't need to be a large top 10 pharma to commercialize in this space. I've done it twice. I did it at Novartis, and I did it at Iveric with the launch of a GA drug, same customer base. And the amount of commercial investment prelaunch, the size of the team was the same in both dynamics, small biotech, large top 5 pharma. So we can take on that commercialization challenge ourselves if that's what we think is strategically the best option for us.

And just to clarify that what wasn't said, but it is definitely our plan is we will commercialize ourselves in the U.S. And Chris is the right guy to do that. He's done it, I think, 2 or 3 different times with different companies, including Novartis, Genentech and Iveric. So we're in good hands.

How are you thinking about manufacturing? I think that's a place where recent gene therapy filings have faced roadblocks. So what's your strategy there?

Yes. So with complex biologics, it's a real issue, right? It's probably one of the most common causes of a failed BLA. And because of that, we invested in CMC very, very early on in the company's evolution. One of the first things we did was build a manufacturing pilot plant. When we went into the clinic, we said, "Okay, let's see if we can manufacture ourselves GMP." We were highly successful. We took 6 different products into the clinic, all internally manufactured, didn't have a single failed lot, never had a trial delayed because of a quality issue with manufacturing. So it's a phenomenal team, all the way up in Phase III.

And then, of course, you need to do a technology transfer to a commercial facility, which we've achieved already. And then again, ideally, you'd have at least 50% of the material in one of your Phase IIIs comes from the commercial facility, which we are now in the middle of achieving. And then we need to do our qualification batches, which we're in the middle of doing. So I think everything is on schedule. We have a great CDMO who's been a real leader in this space. And so I think between our innovation and our CMC team plus this commercial CDMO, we're really in a great position.

Great. Maybe in the last couple of minutes, we can talk about DME as well. How are you thinking about that opportunity? And I think you're expecting to initiate your Phase III trial soon. What are the gating factors before you can start the trial?

Yes. I can speak to the practicalities. So Q3 is our guidance for starting that study, and we're on track for that. We're really excited. I think there's going to be phenomenal excitement there and excellent enrollment mirroring, I think, what we saw in wet AMD. As Chris will tell you in a minute, probably the unmet need in DME may be even higher. So we're really excited. I think midyear this year, we'll give an update on the final study design after final regulatory interactions. But what we've guided to is a BCVA noninferiority, 5 loading doses, which is standard in DME and then a final sample size somewhere in the range of 300 to 400 is where we're currently guiding. And we'll update that soon. And then I think Chris can speak to the real opportunity in DME, which is huge.

Yes. I mean, as you likely know, DME is the second largest indication in this bolus anti-VEGF space today, but it's undertreated and it's underpenetrated in terms of the market value. There are more patients and the challenge with staying on therapy is greater in DME than even in AMD. So when you listen to physicians and they talk about treating DME patients, they think about whether a patient is going to stay on therapy and they worry about whether that patient is going to get lost to follow-up. So the benefit of significant treatment burden reduction for a patient that often has a lot of other stuff going on or younger, the burden of getting into the office can be greater.

So that benefit is of high significance and the fact that, listen, we, by design, solve one of the biggest challenges in health care medicine, which is adherence to therapy because once you get 4D-150, it's there, it's constant, it's always present. So solving that in the DME patient population is really, really meaningful. So I actually think there's a scenario where in a commercial setting after a couple of years, you actually could see DME be a larger indication because of those factors than even AMD. So we're pretty excited about that opportunity.

Great. Maybe last question, Kristian. What's your current cash runway and what's included in that? I didn't want to leave you out.

Yes, absolutely. I appreciate it. I appreciate it. So as of the end of Q1, we had $458 million in cash and cash equivalents. Cash runway, we're guiding to sometime second half of 2028. Look, it doesn't include the commercial ramp-up yet. That's something that we anticipate to finance post 4FRONT-1.

Great. I think with that, we're out of time. So thanks again for joining, guys.

Thanks for having us.

Good to be here.

Thank you.

Hi. Good morning, everyone. I'm Ellie Merle, one of the biotech analysts here at Barclays. Thank you for joining us here in Sunny Miami. Very happy to have 4D Molecular Therapeutics here with us today for a fireside or I should say, beachside chat. Joining us from 4D is Kristian Humer, Chief Financial Officer; and Chris Simms, Chief Commercial and Business Officer. Thank you both so much for making the time and joining us today. To start, could you just give us a high-level overview of the company, your platform and programs?

Yes. Thanks, Ellie. I can take that. So good morning, and great to be here, and thank you for the opportunity. So 4D Molecular Therapeutics, it's a next-generation gene therapy company. We were founded about 12 years ago. We differentiate ourselves. We believe our platform directed evolution allows us to develop vectors and capsids that are more tissue-specific and thereby allows us to deliver, I think, doses that are at a safer level and ultimately allows us to go into therapeutic areas and diseases that are more large market versus more rare disease like markets like many gene therapies are targeting.

Our lead program is an asset called 4D-150, currently making great progress through Phase III, which we can speak more about in a little while. It's for retinal disease, lead indications for wet age-related macular degeneration and hoping to start a Phase III as well for diabetic macular edema later this year. So making great progress there with 4D-150, we also have a program in cystic fibrosis as well. So that's a high-level overview of 4DMT. We're pretty excited about the momentum we have and the potential to impact patients in large markets.

Great. Yes, maybe starting with 4D-150, there's a lot of programs approved and in development in the wet AMD space. Where do you think 150 sits within all of that?

Yes, great question. And you're so right. The retina field has become very interesting, especially as of late. Interesting, someone reminded me this week that it's been, I think, 20 years since the introduction of LUCENTIS this year. It was launched in 2006. And the introduction of anti-VEGF many years ago truly revolutionized the space, and it has been incredibly impactful on the overall rates of blindness. Unfortunately, patients with wet AMD and some of these diseases would have gone blind years ago. So anti-VEGF therapy has been transformational from that regard. However, tied to that, as the space has grown, I think we project the overall anti-VEGF market to be worth about $20 billion in our launch window. So very much a large market has been growing steadily, but that's attracted a lot of interest.

And the goal of pretty much all new innovation in this space has been to increase durability. And I think if you look -- thinking about that from a patient's perspective, you can understand why that's important. The current therapies are administered as a needle or an injection in the eye on some level of frequency, it's every month or every 6 or 8 weeks depending upon the need of the patient. So if you can reduce that treatment burden, clearly, that's impactful for the patient. It's impactful for their lifestyle, but also is really important for a clinic. These clinics are really busy. So the goal of all new innovation seems to have been around how do you increase the durability without sacrificing the patient's vision.

And that's where we come in. So 4D-150 being a genetic medicine approach, we express aflibercept known as EYLEA, I think from a branded context. So a very safe, highly effective standard of care medicine, but we do it in a continuous manner. So our goal is not to increase durability by a week or 2 or a month. We actually think we can affect durability as measured in years. And for some patients, it may be the last injection they need for the rest of their lives. So that's how we differentiate.

We're not a bolus therapy. We're not looking for an incremental benefit. We actually think we have the opportunity to be a backbone therapy that's always there, providing constant disease control, constant coverage for patients. And our data would show that we believe we have the potential to reduce treatment burden by 80%, 90% versus an incremental benefit. And in addition to that, we think we have the opportunity to allow patients to hold on to their initial vision gains potentially for the rest of their lives. So we think that's transformational. And that's how we differentiate versus the -- many of the other activities that are in the space that are going for incremental benefit.

And in terms of gene therapy specifically, there are some other gene therapies that have been in development and that are in development for wet AMD. Can you talk about your construct and sort of what you view as differentiating from 150?

Yes, absolutely. So yes, you're right. There's a number of other -- there's a couple of other companies that are looking at the same modality that we are. We -- and it's a great market. It's a big market. So we think there's room for lots of players. However, when you think about this from a patient and a physician or a retina clinic perspective, these clinics are busy. Obviously, 60, 70, 80 patients per physician in some days. So they need a modality that fits seamlessly into the practice. So other modalities, for example, require a subretinal surgery. So that's not convenient for the patient. It's not convenient for the practice. 4D-150 is a simple intravitreal injection, the same mode of delivery that EYLEA or any other anti-VEGF would have. So our approach is it's seamless integration. It's easy delivery to the patient. It's a single injection, which is what physicians are very used to doing.

In addition to that, the challenge with gene therapy in the past has been -- for some programs has been safety, particularly the intravitreal approach. And we think we've solved that through our science. So the fact that we took the time through our directed evolution platform to find the right vector that was developed using a nonhuman primate model. We think we have a vector that allows us to, again, target the right tissue in the retina for expression of aflibercept. And because we can do that, we can deliver a lower dose. So our dose for our Phase III program is 310. So we think that approach allows us to maintain efficacy, which we see in our data, while at the same time, having a stronger safety profile.

Great. And yes, speaking about the efficacy and safety profile, can you walk us through the data that you've seen in Phase II?

Yes. So we've -- our 2 Phase II data sets is a program called PRISM for wet AMD and SPECTRA for DME. I'll speak to PRISM first. So PRISM is a fascinating data set. When the team developed this well before my time at 4DMT, we actually started PRISM looking at the most hardest to treat patients. So if you look at our Phase I/II PRISM data, it's actually that patient cohort of about 30 patients are patients that were prior to 4D-150 we're getting on average 10 injections in the prior year. And some of those patients were on therapy for, I think, over 4 years. And despite that intensive level of prior treatment, their average CST levels were still above 400, which in the retina field, that's pretty high. That's largely uncontrolled.

So after 4D-150, what we've seen in that patient population, and we now have shown data, by the way, on that sub cohort of PRISM patients after 2 years is we see a treatment burden reduction over that 2-year period of about 80%, which is life changing if you think about that from a patient's perspective. They were on pace to get about 20 injections in the 2-year period. And after 4D-150, the average number of supplemental injections that, that patient cohort received was about 4. And with that, their CST and vision was maintained. So we think that's transformational, and that's in a very hard-to-treat patient population.

We also looked at the patients in PRISM that were more recently diagnosed. And the reason we looked at that patient population is that, that's the patient characteristics that most resemble our Phase III program. So our Phase III program is in treatment-naive patients. So we looked at patients that were recently diagnosed within the prior 6 months, and our treatment burden effect that we saw within that patient population, and we've seen this out to 18 months is in the 90% range, where about 73% of those patients are actually injection-free at 18 months as well.

So it gives you a perspective that we have a significant effect on treatment burden reduction for these patients, which is why patients and physicians care the most about. We see that now out to 18 or 24 months and the consistency of that has been really, really strong through our PRISM program. And importantly, nothing in this space matters in terms of new development if you don't have a safety profile that's at least consistent with what current standard of care is. And our safety profile is right in line with that. We see an intraocular inflammation rate of less than 3%.

And as we move from Phase II to Phase III, what are your expectations for how this will translate from Phase II to Phase III? And what would you say is kind of the threshold for what would be clinically meaningful in the context of the broader wet AMD landscape for you to see in Phase III?

Yes. So there's a couple of things, right? So we view that from that angle of, as you just mentioned, going from Phase II to Phase III. We also think about it from going from Phase III to commercialization and how does it translate from the clinical trial setting to the commercial setting. So once we designed our Phase III program, and we saw that efficacy impacted the more recently diagnosed patient population, we designed our Phase III program to be largely on a treatment-naive population. So we would hope and expect that the treatment effect that we saw out of PRISM from Phase II that I just referenced that 70% of patients that were injection-free over 90% treatment burden reduction. That is the guide that we have going into Phase III.

And then again, because we -- in Phase III, we have selected for a treatment-naive population. For the most part, our second Phase III trial actually combines treatment naive and some patients that were previously treated. So we would expect to see a similar type of result as you go through Phase III. I'll tell you, though, that's informed by our Phase II experience. If you talk to a physician and you ask them what's meaningful for them and their patients in terms of treatment burden reduction, their numbers are nowhere in that range.

And what we've seen in this space most recently, like the VABYSMO or EYLEA HD that has launched, so bolus therapies, highly efficacious and their benefit has been a couple of more weeks of durability. If you average that couple of weeks, you get like a 20%, maybe 25% incremental treatment burden reduction based on their profile. And with that incremental benefit, those therapies have become multi-blockbuster commercial successes. So again, it just points to the fact that any benefit in terms of reducing the treatment burden, increasing durability without sacrificing efficacy is highly meaningful to both physicians and patients. So we're not playing for that incremental benefit. We think we have a shot at being much higher than that. And we think our Phase III program is set up to help us deliver that.

Great. And from a safety perspective, obviously, safety of gene therapy, even ocular has been a major focus. You obviously haven't seen major safety events so far. But can you talk about what gives you confidence in the safety profile here, particularly when we're in a market where there are drugs that have been available for 20 years, biosimilars with strong safety profiles?

Yes. And that's exactly right. I mean that context is really important because this is why safety matters as much as it does is because physicians and patients have alternate therapies with really good safety profiles. So you have a choice that you can make. So we believe our safety profile that we've seen consistently, by the way, through our DME and our AMD patient population is, first and foremost, informed by the fact that our science is different. And it goes back to the point I made earlier. Our R100 capsid has been developed in-house. It was developed through a nonhuman primate model. It allows us to be more specific in terms of the retinal cells that we target and therefore, transduce. We don't transduce cells that are not in the retina and the anterior segment, for example. And we think that's at the foundation as to why our safety is differentiated.

And that also allows us to deliver a dose because the dose of the drug actually gets to where it needs to work and doesn't go elsewhere, we can deliver a lower dose in 3E10. So we think that is the primary reason why we're seeing the differentiating safety profile that we are. In addition to that, as a safety net, and this is common in gene therapy, we'll have -- we have in our clinical trial program a prophylactic steroid regimen. So patients take steroids up to 20 weeks, Durezol, and that tapers over that 20-week period. So that provides an additional safety net, if you will. And that really covers the time period where the capsid is wearing off and then allows further get you to the period where the cells are just expressing aflibercept.

So we believe our -- the safety data we've seen so far has driven primarily by the science, but by that overall approach to it. And as you mentioned, that's critically important in this space, largely because of the fact that you have really good efficacious and safe alternatives, so safety has to be strong.

Great. And how is enrollment going in the Phase III? And kind of any more granularity you can give us in terms of the time lines for when we'll get data?

Yes, do you want to take that one, Kristian?

Sure. From an enrollment perspective, things have been going great. We just announced a couple of weeks ago that we're fully enrolled in 4FRONT-1. The readout is expected sometime first half of 2027. Enrollment for 4FRONT-2 is on track. We're guiding to enrollment completion sometime second half of this year with data readout second half of 2027.

Major 2027 for you?

Major 2027. I'll just add some color on enrollment. So I started at 4DMT right when the team was deciding on the Phase III design, and we had this conversation around do we go into a treatment-naive population? Or do you do a blended population? And historically, all of these pivotal programs, the EYLEA and the advisers of the world, their Phase III programs were all done in treatment-naive populations for a bunch of reasons. One is that regulators need to show a vision benefit and the patient was previously treated, there's a ceiling on the potential vision benefit you could see.

So we follow tradition. Our Phase III program is pretty traditionally up the middle in terms of the design. There's nothing out of the ordinary, there's no superiority type of designs that we're going for. It's a very standard design, which is aligned with what the precedent has been. However, it was a real debate internally is like this is a gene therapy. The frontline approach to patients with a gene therapy has never been done before. And it raised the question is like what will enrollment be like because there's not a lot of precedent that you can look to.

We set out with an 18-month target of enrollment, and we thought that was pretty ambitious. Our 4FRONT-1 program, we've pretty much finished enrollment in about 11 months. We point to that. I get excited about that personally as the person responsible for our commercial strategy, I think that's a good proxy for demand. I think it's a good proxy for just the interest that physicians and patients have. So we think it's quite remarkable that we've been able to enroll a frontline gene therapy program in 11 months. And by the way, we upsized that. Initially, the target end was 400. We think when enrollment is wrapped up here on the first trial will be north of 500. And so we were able to do all of that within 11 months, which we think is remarkable and points to the unmet need and the demand.

Great. And how should we think about your strategy in DME with 150?

Yes, I love that question. So as I'm sure you know and many of the audience members knows, in this space, wet AMD is the largest market, if you will, it's the largest indication as measured by commercial potential. DME is second behind that at rough -- last time I checked around 60% of the overall value. However, the unmet need in DME is actually, in many ways, greater. So there's more patients and these patients are often more under treated. So they don't stay on therapy for as long as many physicians would like them to. There's a number of reasons for that. Some of it relates to lifestyle. It's a younger patient population and so on.

So we think a safe efficacy is always there backbone therapy like 4D-150 actually is the ideal profile for a DME patient in particular, because of the reasons I just mentioned. So we're super excited to start our DME program. We have alignment with the FDA and EMA on a single DME trial. We hope to start the Phase III program in Q3 of this year. We're going to run it as a global program. We have a partnership with Otsuka for 4D-150. They have Asia Pacific rights. So because we're starting this program with a partnership with them, we'll do it with them and include Asia Pac in our global program. But we're really excited to get this DME program going. We think it's a huge unmet need. And commercially, I think there's a scenario because of the unmet need in DME being more pronounced that with time, should all things go well in the commercial setting, DME actually may be a bigger commercial opportunity than even AMD.

Interesting. Pivoting to your cystic fibrosis program, you have an update expected in the second half. Can you walk us through sort of what we can expect to learn at that update and what you're looking to see?

Yes. So we haven't given full guidance on our update in the second half, but we are looking at that program. We have a great partnership with the CF Foundation, and they're largely funding that program as well. So we're looking to design the Phase II in collaboration with the regulatory authority to make sure that we are following their guidelines. So we'll provide more updates on just exactly what we can disclose on the CF program later this year. But suffice it to say, we're excited about the program. We think it has significant potential. We have a great partnership with the CF Foundation. And I forget the exact number we're looking to enroll, but we want to get a Phase II up and running in our CF program and then hopefully get momentum on that as we go into...

Yes. The goal there is really we want to be in a position at the end to show kind of the investors 12 patients' worth of data with 12 months of follow-up. So we really have data that informs us kind of where the program is and what we can do with the program.

Okay. Makes sense. From a cash runway perspective, these are large markets, expensive to commercialize. You also have gene therapy manufacturing. Remind us of your cash runway and how you're thinking about the potential commercialization if Phase III studies are successful?

Absolutely. Maybe I'll start with the cash runway. Our cash as of the end of last year was $514 million. We're guiding to cash runway into the second half of 2028. That funds us well us for 4FRONT-1 as well as 4FRONT-2. What it doesn't fund is the commercial ramp-up that we would look to fund post-4FRONT-1. From a commercial perspective and kind of where you mentioned -- kind of the key thing I want to stress, and Chris, I'm sure, is going to go into this is the COGS of 4D-150, just to stress, they're below $1,000 per injection. That gives us a lot of flexibility in terms of where we would like to price therapy. And two, also, it's the key reason why we think we can scale up and really compete with the incumbent therapies in wet AMD.

Yes. And the thing I would add is, so I've commercialized new medicines in the retina therapy area a couple of times now, IZERVAY, IVERIC and Novartis before that. So this therapy area, it's fascinating in many ways. One of them is you have large market opportunities, right? You have these massive commercial successes. However, the commercial footprint you need for that is actually quite scalable. So small companies like us can actually commercialize ourselves and certainly in the U.S. and in Europe as well if we need to do that.

So the overall commercial, for example, footprint you need in terms of employee numbers is 120, 130. That's about 60 people in the field and so on. So you can do that as a small company, you don't need to be a large pharma to successfully scale and commercialize in this therapeutic area. So to Kristian's point, when the timing is right, well, our plans are to do that certainly in the U.S. and possibly Europe as well. We think we can go it alone and looking forward to that point in time.

How are you thinking about pricing? I mean you have the entry of biosimilars. You also have retina specialists that make money from doing injections and now you're giving them a proposition of you need to do a lot less of that if this is successful. So how does that work from an economics perspective?

Yes. It's a really important question, absolutely. So the way we think about pricing is, first and foremost, it starts with what value are you delivering for the payer and the patient and the physician. So we think with our profile, that value equation will be very different than anything else in development. I think it would be highly compelling. And we'll be flexible in terms of our pricing approach and adapt to whatever we think the right price is to maximize patient access. We don't think of 4D-150 is a niche product. We actually truly believe we have the opportunity to be a backbone therapy, which means, in my view, the majority of patients should have availability and access to it.

And with the cost of goods profile that Kristian referenced of less than $1,000, we don't need to price it in the hundreds of millions of dollars that sometimes people think of when they think of gene therapy. So we'll be adaptable and flexible and ultimately follow a price strategy that allows the most patients to get access to the therapy.

And on the practice economics point, which is really important, if you understand today how practices make money with these bolus therapies, it's based upon the price of the medicine and the percentage of that price that they receive in increments based upon the bolus administration. The big benefit with the 4D-150 is that certainly our price will not be the same as a single injection of bolus therapy. Our value is much higher than that. So you get the benefit of upfront reimbursement on a higher price point.

We also can help with things, for example, 40% of patients today are off of bolus therapies within the first year or 18 months. That -- when you think about it from an economic standpoint, that's also value that's lost to the practice. If you're capturing that patient on a 4D-150, not only do you get the clinical benefit of the potential of preserving vision for years, you also get the economic benefit. So the economic story to a clinic in a buy-and-bill model, we think with our profile is actually better than the current approach. It's just you have to think about it a little bit differently.

That's helpful context. Well, I really appreciate both of you joining us today. Certainly an exciting year ahead for 4D. So thank you for making the time.

Thank you.

Thank you so much, Ellie.

Thank you.

Hi, everyone. Thanks for being here today. My name is Ranveer Gathwala. I'm a Vice President in the Healthcare Investment Banking Group at JPMorgan. We are very pleased to have 4D Molecular Therapeutics with us today. Today, we're joined by Dr. David Kirn, Founder and CEO of 4D Molecular Therapeutics. Dr. Kirn will run through a presentation, and I'll moderate with some questions for Q&A afterwards.

With that, I'll hand it over to Dr. Kirn to run through the presentation. Thank you.

All right. Thank you, and good morning. Thanks for having us present today, and thanks to all of you for being here bright and early. Again, I'm Dave Kirn, Co-Founder and CEO of 4D. And at 4D, we're developing a new backbone for retinal care and moving the field beyond the need for lifelong injections. So I'll be sharing with you some of our recent accomplishments as well as the future potential of the company.

So this is our overview slide for the presentation. We'll be covering the vision for 4D as well as our pipeline. We'll then move into 4D-150, our lead product candidate for neovascular diseases of the retina, give you an overview of that product as well as our 2025 accomplishments. We'll then move on to the markets and talk about how big and growing those are and help you understand why there's still significant unmet medical needs in those markets. We'll then move on and talk about Phase III and commercialization, what our strategy is there to really derisk the approval and the commercial potential of the product, and we'll finish up with our catalysts for '26.

So at 4D, we're redefining genetic medicines. We're developing and we hope to commercialize durable and disease-targeted therapeutics for large market genetic -- large market diseases. And our lead product, as we said, is 4D-150. This is our pipeline. We've got a pipeline of next-generation locally delivered AAV genetic medicines, really focusing on 4D-150, moving that towards approval and global commercialization.

So our retina franchise leverages R100. This is a proprietary capsid or delivery vehicle, a vector that we invented using our platform of directed evolution, which allows us to have a simple, safe, routine intravitreal product for patients. So 4D-150 is currently being developed in wet AMD and DME. As you'll see today, we have 2 Phase IIIs ongoing with excellent enrollment in wet AMD, and we expect to initiate a Phase III in DME or diabetic macular edema in Q3 of this year. We're thrilled to have a partnership with Otsuka. For Asia Pacific rights, 4D retains all U.S., European and rest of world rights for the product.

4D-175 is our geographic atrophy product candidate. This is a product that has an open IND. It expresses complement factor H for the treatment of [ GA ]. We think this has a GA. This has great potential, and we are seeking partnerships to further the development of this asset. We do have a lung franchise, 4D-710 for cystic fibrosis. This is in Phase II and is fully funded by the Cystic Fibrosis Foundation. And we also have 4D-725 for alpha-1 antitrypsin disease, and this is fully funded by a CIRM grant.

So now let's focus on our lead asset, 4D-150. Our goal with this product is to transform the standard of care for large market retinal vascular diseases with a safe in-office and durable lifelong backbone therapy. 2025 was really a breakout year. Our team did a phenomenal job, and I'm really excited to outline the accomplishments here today. So first of all, we continue to report out very strong Phase I/II and Phase IIb clinical trial results with 4D-150, showing excellent safety. Product has been well tolerated with no clinically significant inflammation at our Phase III dose now in over 80 patients reported.

Durability, which is a central feature to the promise of this product candidate, has been strong and consistent throughout 1.5 to 2 years of follow-up in a diverse range of patient populations. So we've seen incredibly consistent results over time. Execution of Phase III has been outstanding. We've seen really excellent enrollment on 4FRONT-1 and 4FRONT-2 in wet AMD, and this has really accelerated over time as we've released additional data on the product.

2025 was also an important year for diabetic macular edema and that potential opportunity for us, where we got both FDA and EMA alignment on performing a single Phase III study for approval. Now this is really unheard of in retina to be able to get a major market approval with a single trial, and we think this reflects the fact that these regulatory agencies acknowledge the unmet need that continues for these patients and 4D-150's ability to meet that need. And we do now have RMAT designation for DME in addition to wet AMD. This is a breakthrough designation for biologics.

We also hired, as you'll see today, an industry-leading retina team for both development and commercialization. And as I said, we closed a partnership with Otsuka in the Asia Pacific region while retaining important U.S. and European and rest of world rights. Financials, as you'll see today, we're in a strong financial position. We did close a $100 million raise in Q4. This gives us a runway out into the second half of 2028, which is more than 12 months beyond 4FRONT-1 Phase III top line data readout. So it was a great year for us, and our team did a phenomenal job.

So let's talk about the 4FRONT-1 Phase III enrollment. Well, this has been significantly exceeding initial expectations from the beginning and has really accelerated in the second half of the year after we released additional data on the product. So as physicians become more aware of 4D and its safety and its durability potential, this has really ramped up enrollment dramatically. And we're thrilled to announce today that we've actually passed 400 patients enrolled or randomized and/or approved to be randomized as of today. So a phenomenal job to get 400 patients on in less than 9 months' time.

We do still continue to expect enrollment completion in Q1 with approximately 480 total patients. These are treatment-naive patients. So this enrollment that's occurring is in frontline patients, which really tells you something about the safety profile and the acceptance by the physicians community for this product opportunity.

Now 4FRONT-2 is a global study. In this case, it's 60% treatment-naive patients, approximately 40% who have received anywhere from 1 to 4 prior treatments, so still relatively recently diagnosed. This study is now open in the U.S., in multiple countries in Europe, Latin America and in Asia Pacific, including Japan. So we're thrilled with the momentum here, and we do expect completion of enrollment in the second half of this year.

So I talked about a leadership team. None of this is possible without phenomenal people, and we're thrilled to have this team for development and commercialization of retina therapeutics. So I'll start with Julie Clark, our CMO, has been in the industry for more than 20 years. Dhaval Desai, our Chief Development Officer, also a 20-year veteran with tons of experience in retina. And then Chris Simms, our Chief Commercial and Business Officer, 25-plus years in the industry. This team has worked together at multiple companies, including companies such as Novartis and Iveric. So they work very successfully together to develop and commercialize products. They've been involved with products such as Lucentis, Beovu and IZERVAY most recently. So this team knows how to get products approved and commercialize them.

We're also thrilled to announce that we have Glenn Sblendorio now on our Board of Directors. Glenn was the CEO of Iveric, helped to build that company and get the IZERVAY product approved and launched prior to acquisition by Astellas. So a phenomenal team. We're really lucky to have them.

Okay. Now let's talk about the retinal vascular disease market. This is a huge and growing market, as you'll see, and there's still residual unmet needs that we hope to address. So we believe 4D-150 can be highly disruptive in this rapidly growing market. It's $17 billion approximately annually for all anti-VEGF therapies and $14 billion specifically for wet AMD and DME, which are the current diseases that we're addressing. There's approximately 9 million people in U.S., Europe and Japan with these diseases. So very high prevalence of 9 million and a new 600,000 or so patients are diagnosed every single year.

So this is a large population that we're addressing a large market. And these diseases continue to be top causes of permanent vision loss. So we think of this as being -- these are being diseases that have pretty good treatments, and we do, but the end result for most patients is still losing their vision and ultimately going blind. These populations are growing rapidly. So not only is the population aging, but we also see an increasing incidence of diabetes. So a large growing market, and we believe we can be highly disruptive in this market with an effective therapy in 4D-150.

So let's talk a little bit about the patient journey. So most of these patients with wet AMD are in their 70s or 80s. So a big part of the way they still enjoy life, enjoy their families, their grandkids, their friends is through their vision. It's central to who they are, how they encounter the world and to their independence. When they start to lose vision with diseases like wet AMD, this has a huge impact on their life. And it's terrifying for them, frankly. So this leads to isolation, loss of autonomy and need to rely on caregivers, leads to a lot of uncertainty in their future, fear and depression.

Fortunately, there are effective therapies for this disease with bolus anti-VEGF treatment. You can see an example here of an injection into the eye. But the problem with this therapy, albeit it's biologically highly active, is that these patients are now locked into the need for lifelong injections. And these are repetitive -- typically every month or 2, where they and their caregiver need to go into the clinic, have all that anxiety that build up, get an injection in the eye, which can cause pain and blurry vision. And this is really burdensome to their lives and the lives of their caregivers. And imagine getting this diagnosis and knowing you need to do this for the rest of your life, going into the clinic every month or 2 for these injections. So good news is effective biological therapies, but there's still a huge unmet need. And unfortunately, despite all this burden, as you'll see in a minute, patients still lose vision.

So this is an example at the top in red of the treatment regimen for on-label aflibercept, the market leader. And you can see that patients -- each of those needles is a day out of their life and all the anxiety leading up to it and for their caregivers. So you look at that, we're talking about approximately 30 injections over 5 years. Now that doesn't even take into account all the other clinic visits that they may need to have or all their other medical visits for other medical conditions. So this is an incredible burden.

Now in theory, if patients were able to sustain this, you could see the vision improves in this graph and then would be maintained. But unfortunately, in the real life, that's not what occurs. This regimen is just too burdensome for patients to adhere to. So what happens? In the real world, this is data from a TRUCKEE study, a very highly cited real-world study about anti-VEGF treatments in these patients. Fully 40% of patients, even in countries where these therapies are readily available, 40% will go off therapy and discontinue it within a year. Think about that.

You know you need these injections to maintain your vision, maintain your independence, be able to see your grandkids and yet 40% discontinue. They just can't do it. So think about that. And all of these patients will then ultimately lose vision and most will ultimately become blind. So that's a big problem.

What about the other 60%? Well, in the real world, these patients continue to lose vision. We believe that's associated with the fact that they don't stay on the on-label regimen and they eventually get fewer and fewer injections over time. And this leads to relentless vision loss. So again, these patients are doing their best. Their caregivers are doing their best, but they're still constantly losing vision over time. So there still remains a huge unmet need despite our knowledge of this disease and effective therapies.

So what if we had a continuous backbone therapy? And what we mean by that is a therapy where with a single dose into the eye, patients could have the potential for lifelong continuous anti-VEGF therapy without the need for these bolus injections. And what we believe that would look like, and there's actually real-world data to support this, is that vision would be maintained and their quality of life would be dramatically improved by not having to come into the clinic for these repeat bolus injections. So this would be a phenomenal exciting outcome for patients. And as you'll see in a minute, we think 4D-150 has the potential to meet this potential.

So what's the evidence that physicians still recognize that durability, more of a backbone therapy need is still the #1 need in the field. Well, every year, there's -- the American Society for Retinal Specialists does a survey called the PAT survey, very well cited, very well regarded. And every year, the #1 need, the #1 most important thing that physicians think about when they prescribe to a patient is sustained efficacy. It's that durability, that need to give patients longer times of treatment between injections. And this has been consistent despite the approval of aflibercept and VABYSMO and other agents. So still a huge unmet need.

Now there have been improvements in durability, moving from Lucentis to EYLEA. In the real world, it's estimated this added about 14 days in between injections. So to us, 14 days sounds like almost nothing. But for patients, this was huge. And in fact, you can see the commercial launch of this, the first 3 years, over $3 billion of EYLEA was sold because there was such a desperate need for this despite it only being about a 30% reduction in treatment burden.

Moving to VABYSMO. This has been over a $4 billion launch in the first 3 years for an additional 14-day increment. So think about that. 14-day increments are leading to blockbuster drug opportunities. That's how much patients need this and want this. And importantly, none of these agents has the potential for long-term injection-free durability of a year or 2 years or even lifelong. That's never in the cards.

Okay. So what's the evidence that physicians -- this is not us talking. This is physicians, independent physicians in the U.S. and Europe, approximately 1,000 are surveyed for this. When they are asked, what excites you the most in the pipeline of novel retinal therapies. The #1 most exciting thing is gene therapy. Now think about that. We think in other areas of medicine, people are worried about the toxicity of IV AAV gene therapy. There's been commercialization issues in hemophilia. It's very different in the retina. These physicians know that gene therapy has the potential to address the high unmet need, which is these burdensome bolus injections lifelong for patients and vision loss.

So gene therapy is actually noted as the #1 most exciting asset in about 50% of the cases. And the next closest one is TKIs, which are about 1/3 of that. So think of that. This is consistent with what we hear when we go to the clinics, and it's consistent with the enrollment rate we're seeing in treatment-naive patients on 4FRONT-1. Physicians and patients really want this. And we would argue we're the only gene therapy that can be administered with a simple, safe intravitreal injection without significant toxicity in both wet AMD and DME.

So what would this look like on the market if we can continue these results in Phase III and continue them in the real world? Well, quite simply, this would be paradigm shifting. You're going from thinking about increments of durability in terms of 14 days. Here, you're thinking about months, years, potentially lifelong. We also have shown treatment burden reductions of 80% to 90%. And we also have shown patients have the potential to be injection-free for many years. We have patients out well beyond 3 years, completely injection-free despite previously receiving approximately 10 injections a year. So this is paradigm-shifting potential.

So how do we do that? So we start with a proprietary capsid that we invented through directed evolution on the left. This allows us to do safe low-dose intravitreal injection. And what we express is the market leader. This is not new biology. This is not a new target. This is not a new molecule. This is aflibercept. This has been in over 60 million eyes safely and effectively. We're just delivering it in a better way, a continuous expression in the retina right where it's needed. We also add an additional molecule to knock out a fourth VEGF family member called VEGF-C.

So this is the design. What have we seen in terms of safety? So this is over 70 patients with wet AMD. The dark green means there's no inflammation. So these patients are studied every month or while they're on study for many years, looking very, very carefully for inflammation. You can see no inflammation from 6 months on in any patient. And even in the first 6 months when the capsid is there, we had less than 3% of patients had a single mild case of cells present, not clinically meaningful, and patients all got off their steroid eye drops. So we're really excited about this consistent safety, and we think this really is what's driving enrollment.

DME, similar outcome. And people worry about DME because it's more inflammatory. So if you're going to see an inflammatory signal, you're probably going to see it in DME. And yet here, 9 patients at the Phase III dose, 0 inflammation at any time point through 60 weeks. So really, this is game-changing safety potential and again, is driving the excitement.

Now what about efficacy? So we've studied 4D-150 in a broad range of different patient populations, both in wet AMD and DME. So in wet AMD, we actually started with the hardest-to-treat patients, which is typical in drug development and is important for commercialization, but this is probably the population we'll start with before broadening out to all patients with wet AMD. And you can see here, these patients were getting about 10 injections prior to coming on study. So if you use patients as their own control, we would have expected over a 2-year period, these patients to get about 20 injections. Think about that, 20 injections, everyone being a day off with your caregiver going in, having the anxiety, getting the injection, we reduced the need for treatment with 4D-150 by almost 80%. We took 80% of those injections and that discomfort that anxiety out of the system.

And importantly, what you can see here is we -- at the bottom in blue, we break it down in 6-month increments. That effect is constant, 1.3 injections on average, 1.2 on average, 1.2 on average. So this is durable and consistent and predictable, which is what physicians and patients want. Importantly, on this study, we showed stable visual acuity, which was equivalent to aflibercept on label with extra supplementation. Retinal anatomy was stabilized. We didn't see these fluctuations that you typically see, nice and stable retinal anatomy, which means we're protecting the retina and preserving vision. And importantly, in this population, no meaningful inflammation signal.

So what happens when we move earlier line? These are not less severe patients. They're just patients who are more recently diagnosed, where the retina is more intact, perhaps more able to be transduced at a highly efficient level. What we see here at 1.5 years is an over 90% reduction in treatment burden compared to on-label aflibercept. So more than 90% reduction if we can get to these patients early. Importantly, visual acuity, stable and maintained, retinal anatomy, no fluctuations and excellent safety.

Now what does it look like in this population when we break it down by individual patients. Fully 73% of these patients at 1.5 years had no injections. So they went into this thinking I'm going to get about 9 injections over that time frame. That's what they were told until they went on our study. 73% of those patients have not had a single additional injection. Think about that impact on their life, on their vision. Importantly, this is the population that most clearly mirrors our Phase III population. So this is very comparable to our Phase III population, we're seeing these kind of results.

Okay. What about DME? We have less data here, but at the high dose, Phase III dose here, we see about an 80% reduction. So it's consistency between different patient populations of 80% to 90-plus percent reduction in treatment burden. And at over a year's time, 44% of these patients with DME were completely injection-free. And again, we showed you excellent safety in these patients.

So let's talk about our global Phase III program. Again, we've designed this program for global approval and global commercialization. So let's start with wet AMD. We believe we've really derisked this product with our clinical data. We showed this continued strong, highly consistent data in Phase I and Phase IIb populations, and we've seen it across a broad range of patients. So that's important. We're not going in blind to Phase III, and we've done extensive dose ranging in these studies, and we've always seen a consistent dose response. So we know we have the right dose.

We're using a standard gold-plated Phase III design. So these are straight down the middle, noninferiority for BCVA study designs that have been used for VABYSMO approvals, aflibercept approvals. Regulatory agencies are very comfortable with these and familiar with these. So very standard for global approvals.

We've optimized the Phase III population. So we've looked at that data from the Phase I to IIb studies and said, we can identify the patients who are most likely to have the most significant benefit on this study to give us the best possible chance for approval. So these are recently diagnosed naive patients, as you'll see on both studies and then one study allows patients to have a few prior injections. We've also required that patients on study have aflibercept response to make sure we have responsive patients. And we've excluded patients with severe outlier retinal fluid accumulation. So we think we've optimized the population for success. And importantly, we have global regulatory alignment with the U.S. FDA, where we have RMAT breakthrough designation; EMA, where we have PRIME designation and in Japan with the PMDA.

So let's talk about DME. Well, again, we think we're in a similar position here, continued strong Phase I/II results reported last year, industry standard trial design here, BCVA non-inferiority. And we have global regulatory alignment with FDA and EMA on performing a single Phase III study for approval. So again, very -- it's very unusual. We're not aware of another instance where a company has been allowed to do that for a second indication with their lead product in this space. And we think, again, it's a recognition of the unmet need and the potential of 4D-150.

So now let's talk about what this looks like as we move forward. So again, as we said before, if we achieve this target product profile in Phase III in the real world, this is a paradigm shift. So what would this look like commercially? And again, we're thrilled to have Chris Simms, who's on our team, who's been very successful in launching multiple major retina products, including IZERVAY, Beovu and was involved in Lucentis as well. So from a global scalability standpoint, we have best-in-class manufacturing. We've tech transferred to a commercial CDMO, a very well-known and successful CDMO. So we think we're in great shape from a manufacturing standpoint.

We have a very favorable cost of goods margin. We're talking less than $1,000 potentially, and we think this gives us strong pricing flexibility. This is not an indication area where you need a huge sales force. This is something we believe we can truly build ourselves successfully. We're thinking in Chris' experience to address the 2,500 or so retina specialists who really matter in the U.S. This is a field rep force of 100 or less. So this is something that a company of our size and profile could really achieve to address this market.

Importantly, we have Otsuka in the Asia Pacific to address that market. In terms of payers, we think we can really provide a unique value proposition here with the potential to dramatically reduce treatment burden, keep patients on therapy, so adherence will be, by definition, improved because the product is always there being made in the retina. And we think that the vision protection piece of this will be very important to payers as well. What is the vision preservation worth, maintaining independence, what's that worth? So we think it puts us in a very strong position. We do believe we can fit seamlessly into the buy-and-bill model, which is used in the U.S. So we think we'll be very successful fitting into that model.

And as I said before, we have very flexible pricing. We're not thinking about pricing this like a rare disease gene therapy at $1 million. We can price this to be successful in a large market like wet AMD and DME. And again, our low cost of goods allows us to have a lot of flexibility in how we price.

What about the practice? It's critical that the physicians want to use this. Well, this fits seamlessly into their clinic flow, same refrigeration and storage, same needle to inject, same injection procedure that they do thousands of times a day in the U.S. alone. So this fits seamlessly into that workflow, seamlessly into their storage capabilities. We think their practice economics can be enhanced, and I don't have a lot of time to get into that today, but think about getting -- being able to get that additional financing for several years of benefit upfront. Well, that's -- you think about the net present value of money, that's phenomenal for physicians to be able to do that, bring that forward and not have to worry about so many of their patients going off therapy and being lost to follow-up.

Having fewer bolus injections also means more clinic capacity. Most of these clinics are at full capacity. So if they can open up more capacity, they can treat patients with GA with new agents there and/or do other procedures. So this, we think, overall will be fantastic for retina physicians in their clinics.

Okay. So we have a very catalyst-rich 2026 and first half of '27. There's a lot going on. But in wet AMD, we expect to complete 4FRONT-1 enrollment in Q1, 4FRONT-2 enrollment in Q2. We'll have top line data for 4FRONT-1 in the first half of 2027. Importantly, midyear this year, we'll be releasing 2-year data going from 1.5 to 2 years in that PRISM Phase IIb population, particularly that population that most closely reflects the Phase III population. So again, further derisking as we expect those results to be very consistent.

DME, we'll be finalizing the Phase III design and initiating that study in Q3. This is a second huge shot on goal for us. And we will be releasing additional SPECTRA Phase I/II data in DME out at 2 years of follow-up in the second half of 2026. So there's a lot going on here, a lot of catalysts, and we're very excited for this year. Importantly, we're in a strong financial position. Our cash at the end of 2025 was about $514 million in cash and cash equivalents. And that runway, we believe, with all of this activity will last into the second half of 2028, more than 1 year beyond top line Phase III data. So we think we're well positioned to achieve these catalysts and beyond.

Okay. So key takeaways, continue reporting strong Phase I/II data in wet AMD and DME, continued Phase III execution and momentum there, and we expect to deliver that top line wet AMD data in the first half of 2027 from 4FRONT-1.

So thank you for your attention. I'd love to take some questions now. Thank you.

Thanks, Dave. Quick one for me. Safety is big in ophthalmology and looks to be a big strength of your program. Could you maybe touch us to how you're seeing such great safety so far in your program versus past gene therapy approaches?

Yes. Thanks for the question. I mean the big hurdle with gene therapy initially was just getting it into the retina. It wasn't feasible with conventional vectors. And that's why these subretinal surgical approaches were developed, which are burdensome and really not commercializable at scale. So it's good for proof of concept. But to get a vector that we could use intravitreally and get through all the barriers in front of the retina to an AAV and give high-level transduction in the retina really required innovation. It required hard work, creativity and innovation. And that's what our directed evolution platform provides is we have a library of 1 billion vector sequences, and we identified the one out of 1 billion that was best at achieving what you're seeing in the clinic.

So we fully predicted we'd see results like this, much lower doses, highly efficient expression and lower doses and means essentially much lower inflammation risk. And essentially, we are seeing no significant inflammation. So it's about innovation. It's about the vector itself. It's also about aflibercept. This is not a novel TKI with lots of different mechanisms of action that are unknown. This is a molecule that's been in 60 million eyes safely and effectively. So that's what we're producing. So I think for all those reasons, it's been a safe and effective product.

Amazing. And a bit earlier, you showed us a slide that showed a lot of the physicians from the survey were more excited about gene therapy versus your traditional TKI approach. If you could add some more color as to maybe how some of those conversations are going with physicians that you've spoken with or any additional color from that survey, that would be.

Yes. Well, I mean, the beauty of the survey, it's not us doing it. It's independent. It's a third-party validated survey. It's 1,000 retina physicians, U.S. and Europe, so U.S. and rest of world. So it's really the gold standard. But it's consistent with what our team is hearing. We have a phenomenal external engagement team. We have a pre-commercial team, and they're hearing all the same things from physicians that, hey, if you can give me something that's safe, it's a routine intravitreal injection, and you can give lifelong -- potentially lifelong durability of expression and benefit, they're going to flock to it.

And so that's what we've seen. We think we're fundamentally in a different category. There are other bolus therapies in development, including TKIs and other. We see those as kind of competing with each other in that space of incremental benefit or something that gives kind of continuous production for years, if not lifelong. It's just fundamentally a different category. And we think in that category, we're alone in terms of having a safe, simple intravitreal product for wet AMD and DME.

Amazing. Thank you. And what -- if any read-through from -- I think the Street is kind of looking at TKI Phase III readouts from Ocular and EyePoint. Are there any -- do you think there's any read-through from those upcoming readouts? And what are your thoughts on those specifically?

Yes. I think fundamentally, for us, there's no read-through. I mean it's a totally different treatment class, totally treatment -- different study design in the case of SOL-1. But we wish them the best. We hope there are other options for patients. And again, we could see those competing with VABYSMO, for example. But again, our product is distinctly different. It's a different class. It's far longer durability and continuous expression. And again, we're talking about aflibercept market leader. That's the molecule we're producing, and that really derisks our program significantly and just puts it in a different category.

Amazing. And maybe further to that, you have a great lineup of data and upcoming catalysts for the year. What do you think good data would look like for the PRISM wet AMD study and maybe the DME study as well?

Yes. We're excited about those catalysts, both in wet AMD and DME. We think it's going to be more of the same. It's going to be pretty boring, hopefully, and we believe it will be of just continued safety, continued durability. Again, we've shown in these 6-month increments that the benefit we're seeing is constant, stable, it's predictable. And we hope to just continue seeing more of the same with an additional 6 months of follow-up in wet AMD and an additional year of follow-up in DME.

Great. Maybe a final one. The Otsuka partnership that you talked about in the presentation, maybe you can give us some more color about that relative economics or what made you excited to go ahead and do that deal?

Yes. Yes, we're thrilled with the deal. We think it's highly validating. Look, Otsuka is a great company. Their diligence process was incredibly thorough from everything from regulatory to manufacturing, analytical development, quality control, clinical data, they saw it all. And so coming in with what we believe is one of the best Asia Pacific-only deals that's ever been done in terms of the economics with such a high-quality company like that is phenomenal.

So we're thrilled to be working with them. The economics were great, $85 million upfront and another $50 million of cost coverage we estimate over the next couple of years. That's $135 million, which then helps us to fund the DME program, which is a big value driver for us. So we think that, that plus the financing really unlock that potential, and we're thrilled to be working with them.

Amazing. Thanks so much, Dr. Kirn. Really appreciate your time with us today.

All right. Thank you.

Hello, ladies and gentlemen. Thank you for standing by, and welcome to our investor webcast today. As a reminder, today's call is being recorded.

With that, I will hand the call over to Julian Pei, Head of Investor Relations, who will make introductory comments.

Good morning, and thank you for joining our webcast to discuss interim Phase I data from our AEROW trial in cystic fibrosis. Before we begin, I encourage everyone to visit our Investor Relations website, where you can find a press release describing this update. A recording of this webcast and presentation materials will also be accessible on the website after the completion of this call.

We remind you here, we may be making forward-looking statements. For further details, you can visit our website or our SEC filings.

On the call today with prepared remarks will be Dr. David Kirn, our Co-Founder and CEO; Dr. Jennifer Taylor-Cousar from National Jewish Health and Lead Principal Investigator in the AEROW trial; and Dr. Felix Ratjen, Co-Head of the Cystic Fibrosis Center at SickKids Research Institute of the University of Toronto. After the prepared remarks, Kristian Humer, our Chief Financial Officer; and Melissa Calton, our Vice President of Early Stage Product Development, will also join us for Q&A.

With that, I'll now hand the presentation over to David.

Thank you, Julian, and good morning, everyone. It's great to be with you today. Thanks for joining us. As a reminder, our mission with 4D-710 is to deliver a durable, variant-agnostic, disease-modifying treatment for people with cystic fibrosis lung disease who still face high unmet needs.

Our 5 headlines in participants in the most recent lower dose cohorts 3 and 4 will be described today and are summarized here. First, 4D-710 was well tolerated. Second, clinically meaningful lung function activity improvements were demonstrated through 1 year of follow-up by 2 validated and complementary endpoint measurements. Third, clinically meaningful respiratory-related improvements were demonstrated through 1 year of follow-up by a validated cystic fibrosis quality of life questionnaire.

Fourth, Phase II enrollment is now underway with the Phase II dose level being 2.5E14 vector genomes, and this is the Cohort 4 dose level that you'll hear about today. This was the lowest dose used in Phase I. Fifth, understanding durability is critical for lung genetic diseases of medicines and due to expected cell turnover in lung epithelium, and therefore, we do expect to eventually have the opportunity to redose patients.

We're excited to share for the first time to our knowledge in medical history, paired biopsy data from CF participants in this trial treated with 4D-710. And these data show that CFTR expression not only is robust at 1 month, but persists for at least 1 year and remains within or above our target therapeutic range. This reinforces the platform potential of our A101 vector technology for cystic fibrosis and other lung diseases.

On the next slide, you'll see a summary of the cystic fibrosis disease condition. So cystic fibrosis is a life-shortening genetic disease and variances in CFTR lead to sticky mucus, chronic lung infections and progressive respiratory failure. In addition to modulators when available, supportive treatments are very intensive, burdensome and time-consuming for patients that they need to carry out every single day of their lives.

Historically, before CFTR modulators, life expectancy was just 40 years. Over 100,000 people worldwide, including 40,000 in the U.S., face this daily treatment burden. And while modulators have changed the course of disease for many people with CF, tens of thousands remain without effective options and don't benefit fully from modulators. The need is urgent, and that's why we're here to deliver a truly disease-modifying durable therapy for every person with CF lung disease to alleviate this high burden.

The concept of gene therapy in cystic fibrosis is not a new one. Unfortunately, over the last 2 decades, all of the approaches have failed to date. And the reason is simply due to ineffective gene delivery and expression. So the need was clear when we started this program nearly 10 years ago, and that is there's an urgent need for truly effective AAV vectors for gene delivery and expression to unlock clinical benefit for these people with CF.

Here's the 4D-710 design and how we administer it. So our vector technology solves the problem that the field has had in CF. We used a Nobel Prize winning technology called Directed Evolution to invent A101, a novel AAV vector to be mucus penetrant to transduce all airway cell types and to resist preexisting immunity. We then administer this vector via the FDA-approved and routinely used AeroEclipse II breath-actuated nebulizer, and this ensures reliable and widespread airway delivery of droplets throughout the airways containing 4D-710.

Next, our CFTR transgene. We use an extremely well-validated transgene payload with a minimal targeted modification to fit within the AAV vector while preserving its normal channel function, normal structure and regulation. This highly functional design has been developed and validated by numerous investigators in the field for over 20 years and has demonstrated correction of CF disease phenotypes in numerous preclinical models, including the ferret and the pig model of CF as well as human airway models.

Now with 710, we've combined our next-generation A101 vector, a highly functional CFTR transgene and an FDA-approved nebulizer system for efficient pan-airway delivery. In summary, we believe this gives us the opportunity to deliver a potentially durable, redoseable, variant-agnostic, disease-modifying therapy directly to the lung airways of people with CF.

I'll now hand the presentation off to Dr. Taylor-Cousar to review the AEROW study design and clinical data. Jen?

Thanks, David. I'm going to start by reviewing the study design and baseline characteristics of participants in the Phase I trial. So let's first review the framework for this Phase I trial. Our focus was really on dose finding. We focused primarily on the safety of 4D-710 and CFTR expression levels by studying lung tissue biopsies and brushings collected via bronchoscopy approximately 4 weeks post dosing. Our goal was to identify a dose level that resulted in physiologically relevant cell transduction and CFTR localization patterns. Our control biopsy samples for these analyses are from people without CF. Finally, we also look for evidence of clinical activity using multiple complementary pulmonary endpoints. Based on the totality of this data, we selected our Phase II dose.

As previously disclosed, our dose ranging started at 1x 10 of the 15 vector genomes, which was well tolerated. We then escalated to 2x 10 of the 15 vector genomes. This dose level was discontinued for further study due to both high transgene expression that also ended up within the lung interstitium, not one of the target tissues and one related serious adverse event that subsequently resolved.

After careful review of the data from the higher doses with the safety review team and the Cystic Fibrosis Foundation, we proceeded to explore lower doses. We also amended the protocol to add new clinical activity endpoints, including one called lung clearance index as well as optional bronchoscopy at a minimum of 1 year post dosing to evaluate the long-term durability of transgene expression. The additional lung assessments include more sensitive measures of early disease, the lung clearance index that I mentioned, measured by multiple breath washout. We really wanted to better capture clinical activity and subtle improvements in small airways in the small number of participants that we're studying. We'll review these in more detail in the coming slides.

Now let's review data from the lower dose cohorts, 5 x 10 to the 14th and 2.5 x 10 to the 14th vector genomes. This first slide shows the baseline characteristics of the participants who received 1 of the 2 lower doses. 8 of 9 were variant ineligible for CFTR modulators. The lung disease based on percent predicted FEV1 ranged from mild disease to moderately severe dysfunction. But notably, all participants had abnormal lung clearance index or LCI, that measure that's very sensitive to detect early disease, especially in the small airways.

Earlier, David mentioned quality of life. So we use the validated cystic fibrosis quality of life measure, particularly the respiratory domain, and it's assessed on a scale from 0 to 100 with 100 being the best. You can see that there was a wide range in the baseline quality of life scores with most people being below 80 points.

Now let's move on to safety and tolerability. First, we're going to look at the immediate safety through day 14. We saw adverse events commonly associated with nebulized therapies that resolved within minutes to about a week. The lower dose is half that of the higher dose. So administration is under an hour for that dose, which is very much appreciated by participants, particularly when thinking about dosing it again.

This slide actually looks at the longer-term safety and tolerability. Overall, excellent safety and tolerability beyond the immediate post-dosing period. There was one non-pulmonary adverse event in the 5x 10 of the 14th vector genome cohort possibly related to steroid administration rather than 4D-710. There were no 4D-710 related adverse events beyond day 14, except in one participant with a transient Grade 1, so very mild elevated liver enzyme value that resolved completely within a month. And this can be typical of underlying CF as we frequently see increases and decreases transiently in this patient population.

So we talked about the clinical safety data. Now let's look at the expression data. We presented this data previously, but wanted to provide you with a quick summary of our analysis methods for lung biopsy and for what the 2 methods are used. In situ hybridization or ISH, measures CFTR mRNA expression is highly specific and most useful for quantitation for dose selection purposes. Immunohistochemistry or IHC, is highly sensitive and is useful to confirm translation into CFTR protein and is used to qualitatively study expression patterns.

That being said, as reviewed before, based on our best knowledge from review of literature, our target expression profile is shown here, where we aim to really achieve widespread expression across all collected lung epithelial samples and no impact from pre-existing immunity. Specifically, we believe that achieving expression in approximately 10% to 25% of cells is a reasonable target. And we want to see a normal staining pattern and minimize expression in undesired cell types like in interstitial cells.

First, we use our ISH method on commercially available non-CF and CF lung samples to establish an expected level of endogenous CFTR mRNA. Non-CF samples showed approximately 10% mean of cells positive. And this measurement is consistent with target functional ranges that are described in the literature.

Here, we showed the mean percent positive epithelial cells following single dose administration of 4D-710. We are very pleased to observe a consistent dose response and expression levels in Cohort 4, the 2.5 x 10 to 14 vector genome dose meet our target of 10% to 25% cells positive.

So now let's look at the IHC or immunohistochemistry data, which again stains for protein. As shown before, here's what non-CF and CF lung samples look like with the IHC assay. So the non-CF is on the top. Again, we believe overexpression may not be ideal as it could lead to protein missorting and as a result, reduced protein function and even unfavorable altered ion balance in the cells.

So looking at the staining in our highest dose in contrast with a normal lung sample shown on the right, you can see abnormal staining patterns, including staining in the interstitium as indicated by the red arrows. Let's compare that to the opposite end of our dose ranging at the lowest dose of 2.5 x 10 to the 14th vector genomes in Cohort 4. We see normal localization patterns, including minimal interstitial staining. Again, control lung tissue is shown in the photomicrograph to the right. So putting all 3 of these image panels side by side, the highest dose, the selected Phase II dose and non-CF control, we believe we're at an optimized dose for further development in Phase II.

In summary, and combining the safety data reviewed earlier with a complete set of biopsy and brushing data, we feel confident in our selection of the lowest dose of 2.5 x 10 to the 14th vector genomes going forward.

So let's move into the clinical activity data, and I'll invite Dr. Ratjen to join me in presenting this section as he has been a pioneer in the field on MVW or multiple breath washout.

Go ahead.

First, let's take a step back and review the different ways we study lung disease in CF and what they measure. It's important to understand that CF is a disease that affects the entire lung but starts in the small airways and eventually progresses into the large to mid airways. Historically, for more than a decade, FEV1 has been the gold standard for clinical trials and clinically accepted primary endpoint to measure lung function and correlate to disease progression, particularly survival. This has primarily been driven by precedent success in CF trials and routine use in current CF care infrastructure.

However, it does measure the large airways rather than the small airways. The field is now moving towards less effort-dependent, less variable and more sensitive methods to complement FEV1, and that is lung clearance index. So we added this to the AEROW trial.

Looking at quality of life endpoints, the CFQ-R respiratory domain remains the most validated endpoint for pulmonary symptoms, which are people's reporting of the day-to-day impact of their disease. This instrument has generally not been associated with significant placebo effects. Finally, we're also looking at high-resolution computer tomography scans in an exploratory fashion, which can show structural improvements. While initial data look promising, we're still performing comprehensive detailed analyses, and we will share these at future medical conferences.

I'll now hand it over to Dr. Ratjen to review LCI in more detail.

Well, thank you, Jen. Hello, everyone. I'm Felix Ratjen. I'm the Program Head in Translational Medicine at SickKids Research Institute, Professor at the University of Toronto and Co-Head of the CF Center at SickKids in Toronto, Canada. I've spent most of my career focusing on developing and validating clinical endpoints for cystic fibrosis, especially those that help us better understand lung function and disease progression, such as the lung clearance index that I will talk about now.

So before we dive into the clinical data from AEROW trial, I'd like to briefly set the stage for why we measure lung function, particularly using FEV1 and LCI has been so central to CF research and care and how these endpoints actually complement each other in capturing both larger and smaller airway disease.

So let's first look at FEV1 or forced expiratory volume in 1 second. It's measured by spirometry and primarily reflects large airway disease, so how well the large airways are functioning. It is effort dependent, meaning it requires good patient cooperation. And while it's well correlated with clinical outcomes like survival and exacerbations, it is not very sensitive to early or mild disease. That means subtle changes, especially in the small airways can be missed with this technology.

So let's look at LCI, and this is where it comes in. So LCI, it means the lung clearance index and measures -- the measurement is done using multiple washout, and it measures how effectively a gas is cleared from the lungs. And it is a marker of small airways rather than large airway disease. It is not effort dependent, because it's measured while the participant is breathing at rest. It makes it easier for a broader range of participants, including children, and it's much more sensitive to early changes in lung function even when FEV1 is still normal. LCI is increasingly recognized by regulators, especially for pediatric studies, and it's now the primary or key efficacy endpoints in many trials in cystic fibrosis.

In summary, while FEV1 remains the gold standard due to its history and regulatory acceptance, LCI 2.5 provides complementary information, especially for detecting early disease and subtle treatment effects. Using both together gives us a more complete picture of lung health and treatment impact in cystic fibrosis. This is why there's a growing interest in LCI as an endpoint and the CF Foundation is supporting a national resource centers for studies using this endpoint as well as collecting this data and reach its natural history, which is a natural history study intended to be used as an external comparator for future CF registrational trials.

So I mentioned that FEV1 is linked to survival and LCI has also been linked to other endpoints. So LCI has been shown to be abnormal in people with CCF with normal FEV1 in more than 20 studies now, and it predicts futures -- it does predict future outcomes. It is linked to later abnormalities in spirometry and FEV1. It predicts pulmonary exacerbations and has also been shown to predict survival as shown on this slide.

So I will now show you some data from clinical studies that have looked at LCI and how it captures treatment effects. And this is demonstrated on this slide for a treatment called hypertonic saline. In this crossover study of only 19 patients with cystic fibrosis, LCI showed a statistically significant improvement with hypertonic saline, a treatment that we know has a modest treatment effect compared to isotonic saline as an inactive control with an effect size of 1.16 units.

Notable, this sample size was much smaller compared to what would have been required for FEV1, which we looked at as well in this study, which showed a modest benefit of 1.8% with a standard deviation of 12, highlighting the high variability of the assay. The required sample size to achieve statistical significance would have been 351 as opposed to 19 or less with LCI. This really underscores why LCI is increasingly valued as a sensitive and less variable endpoint for capturing meaningful changes in lung function, even when other measures may not show significant differences.

And to highlight that, I will show you some data from the ORKAMBI trials in pediatric patients with cystic fibrosis. As I mentioned before, in pediatric studies, LCI has now become an established primary efficacy endpoint. What you see here are data from the trial with the CFTR modulator ORKAMBI, where LCI robustly demonstrate treatment response at every time point, and you can see how it differentiates from the placebo group without overlap of the confidence intervals. In contrast, FEV1 shows more variability and greater overlap between the treatment and placebo groups, making it less sensitive for detecting changes in this population.

Looking ahead, ongoing longitudinal studies like REACH will provide prospectively assessed data in individuals not on TRIKAFTA, serving as a contemporary control for nuclear acid-based trials such as gene therapy trials. Importantly, these studies also include LCI as a key outcome measure, further reinforcing its value in both clinical research and future therapeutic development.

I'll now hand it back to Jen to review some clinical activity data from the AEROW study.

Thanks, Felix. So going to the next slide, this is the summary of the available results for the participants who dosed with 5 or 2.5 x 10 to the 14th vector genomes. We are showing the mean changes at all evaluable time points between 3 to 12 months versus baseline per group and percent predicted FEV1, LCI and CFQ-R. All data points showed greater improvements in those dosed with 2.5 x 10 to the 14th vector genomes, the dose we selected for Phase II versus 5 x 10 to the 14th vector genomes.

So at this point, I'd like to show you some participant level activity, starting with the dose of 5 x 10 to the 14th vector genomes. This first participant is one with normal baseline FEV1. Her LCI was not available since she was enrolled prior to the LCI amendment. Although the participant had an initial decline in FEV1 and CFQ-R from 6 to 12 months, there was a small improvement in percent predicted FEV1 and CFQ-R. In CFQ-R, time points above the minimal clinically important difference of 4 points are outlined in green on the right.

The next participant had a baseline FEV1 of around 80%. She had a small decrease in her percent predicted FEV1 and quality of life score, but subsequent improvements, which correspond with decreases, which is an improvement in LCI. Due to an exacerbation at the month 12 visit, as indicated by the open circles and the bar, we show her 15-month visit.

Next participant is a 34-year-old male with moderate disease to a baseline lung function in the 60s. He had fluctuating percent predicted FEV1 over a small range of 2% to 4%, but an improvement in his LCI and in his quality of life. Because the participant's LCI didn't pass the quality control at month 12, another measurement was performed at month 15 and is shown here. His respiratory specific quality of life improved greatly, again, shown on the right and well above the MCID of 4 points.

So now let's look at some individual participant level data with the 2.5 x 10 of the 14th dose, our selected dose for Phase II. The first participant, a 26-year-old male with moderate disease, so an FEV1 at baseline under 60%, showed a meaningful improvement in his LCI and CFQ-R respiratory domain scores across multiple time points. This FEV1 improvement was greatest at 6 months. He had a pulmonary exacerbation at 12 months and the site was asked to bring him back again to repeat his lung clearance index at the 15-month visit. His respiratory specific quality of life improved greatly and again well above the MCID as shown on the right.

The next participant is a 54-year-old female with mild disease. She demonstrated consistent response in FEV1 of about 7% at 3 different time points, and that correlated with an improvement in her LCI, so decrease. Her CFQ-R score was also above the MCID at 2 time points.

Next participant, participant 3, was dosed by the site off protocol because the person was actually having a pulmonary exacerbation at baseline, resulting in a low baseline measurement compared to their prior screening values. Nonetheless, the participant lung function and CF quality of life scores rebounded after dosing with 4D-710. Because of genotyping of a relative, this participant was actually able to gain access to the recently approved triple combination modulator, Alyftrek and began that drug at month 8, which made clinical activity confounded and not further evaluable. However, encouragingly, the combination was safe and really interestingly, the participant's lung function and respiratory symptom score remained well above baseline while on the combination.

So to summarize the interim Phase I update, all data points show greater improvements in those dosed with 2.5 versus 5 x 10 to 14th vector genomes. And again, this is the dose we selected to use in Phase II.

So in conclusion, the focus of Phase I of the program was to establish safety of inhaled administration of the transgene, show that it achieved physiological and relevant CFTR expression levels and evidence of clinical activity. The focus of our ongoing enrollment in Phase II of the program is to demonstrate that inhalation of 4D-710 leads to stability and/or improvement in large airway disease as measured by FEV1, improvement in small airway disease as measured by LCI and improvement in respiratory symptoms as measured by the validated CF quality of life respiratory domain score. And then to show improvement of evidence in other measures of pulmonary disease such as decreased mucus burden on high-resolution CT scan, which we didn't have time to show today.

I'll now hand it back over to David.

Thanks, Jen. This slide presents first-time data showing that our AAV-based approach delivers durable CFTR expression in the lung even at the lowest Phase II dose for 1 year or more. Participants underwent optional bronchoscopy at 1 year or beyond showed persistent expression levels in airway epithelial cells measured by ISH, which remained within target therapeutic range at 1 to 3 years, matching those seen in non-CF controls. This validates both our lung biology hypothesis and the effectiveness of our vector strategy.

So why is this important? This is the first time that paired lung biopsies have been obtained in CF participants. These data confirm durable transgene expression after a single dose for anywhere from 1 to 3 years. And importantly, this durability is observed even at the lowest dose level of 2.5E14, supporting our decision to move forward with this dose in Phase II.

Now looking ahead, because lung epithelial cells naturally turn over, we anticipate that repeat dosing will be an opportunity for us to maintain therapeutic benefit in these participants. The durability data here inform our future redosing strategy, and we're actively collecting more paired biopsy data at the Phase II dose. The bottom line is that this is a major validation of our AAV platform in the lung. So stay tuned. We'll have more data on durability and redosing coming soon in 2026.

Now we couldn't do this alone. We have amazing KOLs and PIs at our sites, such as you've heard from today. And we continue to be gratified to have a very productive long-term relationship with the Cystic Fibrosis Foundation, and this really continues to deepen with their recent $11 million investment round. We're extremely grateful for their collaboration and for their support.

So in summary, we're on track to complete Phase II enrollment in the first half of 2026 while continuing to collect additional paired biopsy data at the selected dose to inform our redosing strategy. As the program advances, we'll finalize our approach based on emerging durability and clinical activity data, and we plan to share a comprehensive program update in the second half of 2026. We're excited to continue generating meaningful data and moving closer to making 4D-710 available to people with CF as a durable variant-agnostic disease-modifying treatment for those with remaining high unmet need. Stay tuned for more milestones and updates as we move forward.

So thank you for your attention. Thanks to Dr. Ratjen and Dr. Taylor-Cousar, and we'll now take your questions. Operator?

[Operator Instructions] Our first question is from Jonathan Miller from Evercore.

Congrats on all the data. I guess just high level for me, the patient level data that you gave today does highlight how variable both patient journey and monitoring can be even for outcomes like LCI, which is clearly a more sensitive measure. So could you talk a little bit about the Phase II strategy, what we should be expecting in terms of the homogeneity of patients there and what we should be expecting about the number of patients needed to get reliable measures for LCI and FEV1 in the Phase II?

And then just secondly, why is expression decrease over time not proportional with dose? It seems like the 2.5E14 dose is somehow more durable than 5E14, at least based on the one slide that you showed. Just curious about that, too.

Well, thanks, Jonathan, for that. I'll answer the first question quickly and then turn it over to Jen for the questions around Phase II. I think it's probably too early to say exactly what the kinetics will be of gene expression decreasing over time by dose. We certainly noticed the same thing that we're gratified that the Phase II dose, the lowest dose continues to be in the therapeutic range at 12 months. But I think with more data, we'll see if those kinetics of decay of the expression vary based on dose or not, but that's certainly suggested here.

So I think over time, we'll get more data at the lowest dose, our Phase II dose, and we'll understand better. This will really inform redosing, right? This plus the clinical activity will determine whether the redosing is somewhere between 12 to 18 months as we initially believed or even longer. But that's sort of how we think about that. So stay tuned on that, and we'll see if that holds up over time.

Jen, do you want to speak to sort of Phase II and how the patients will be selected and how we'll look for consistent results on LCI and other outcomes?

It's a great question and observation that there is a lot of variability. We're planning to add an additional 6 participants for the Phase II dosing at that level. And we'll again limit the number of people who can be in the study based on FEV1, but we don't want to limit so much that we can't enroll this phase of the study. So again, we'll have people who have lung function above 40% and less than 100%. There will be some variability, but we're hoping with the addition of 6 more participants that we can see a more consistent response in a trend -- the continued trend in the right direction.

Our next question is from Ryan Mcelroy from Leerink.

You have Ryan on for Mani. Congrats on the update. Maybe just between the expression and the clinical data, we obviously saw some wide error bars. Can you just talk about any correlation you're seeing at this Phase II dose between those 2? And then maybe just one on the regulatory front. Can you just talk about any of your initial conversations that you've had with the FDA and where they stand on this FEV1 versus LCI debate as an endpoint moving forward? And do we plan to get more clarity on that in the second half of next year?

Absolutely. Thanks for the question. So you raised a number of important points there. In terms of regulatory interactions, we've had very productive interactions with FDA throughout development of this -- of 4D-710, and we'll definitely have more in 2026 to really hone in on what that Phase III design will look like. As Felix said today, the LCI has been used as the primary efficacy endpoint in pediatrics for both European and U.S. studies and is really emerging as a very useful endpoint. So stay tuned on that after we have further conversations with FDA.

Jen, do you want to speak to kind of correlation between transgene expression and LCI and other clinical endpoints?

Yes, it's a great question. And it goes back to the first answer really that in people with CF, their response is not always consistent. So for example, I have a lot of experience with designing and running the modulator trials. And you can have somebody who has a huge response in their sweat chloride and a more subtle response in their FEV1 and vice versa. We don't expect that we'll see 100% correlation between outcome markers in any circumstance, and we're seeing that here. And again, this is a very small number of participants. Again, we hope to see trends of those things correlating, but we know in people with CF, both without treatment and with treatment of various different treatments that their responses are not always 100% correlating with each other based on varying outcome measures.

Yes. Thank you for the question. Felix, do you want to just comment on use of LCI as a regulatory endpoint?

Yes. I think that's an important question and a bit of a moving target. So the EMA has already accepted that as a primary efficacy endpoint in the pediatric studies. And I think -- so the FDA is more and more open to this endpoint as well. And some of the ongoing studies such as REACH, which I mentioned, which is really designed to provide contemporary controls using adults as well where there's currently a bit less information for LCI. And there have been discussions with the FDA, and they are more open to it.

So again, the way to look at this is more that we look at this as complementary approaches, not just using one endpoint. And we see this also for LCI versus FEV1, the different people show efficacy in one versus the other endpoint with more overall showing effects in LCI.

Thank you, Felix. And if you wouldn't mind just maybe commenting on kind of the range of LCI improvements that you think are clinically meaningful as it's a relatively new endpoint for some people.

Yes. So -- and you can look at this both in absolute and relative terms. Most of the studies have looked at absolute changes in LCI and have seen changes between 0.5 and 2 LCI units. So -- and I showed you some of the ORKAMBI data, which showed about 1 LCI absolute change. So what is seen in the current data, albeit in a small sample size is in the range of what we've seen in previous studies of interventions that are established in the field of cystic fibrosis.

Yes. I think that's a very important point. Thank you, Felix. Next question.

Our next question is from Gena Wang from Barclays.

So I think, David, we had a debate in the past regarding this approach. So when I look at the data, I know you're using ORKAMBI, we are discussing about the AOCI as a potential approvable endpoint. But the bottom line is FEV1, we already follow this 12 months to 15 months. If we see like such a modest FEV1 benefit, and we have to try to understand better of the AOCI, which ORKAMBI actually is a fair comparison. It's such a modest clinical benefit. I can foresee this will phase out very quickly. We have a much better drug already coming to the picture.

So here, my question is, is that really the -- do you think that this is really viable moving forward? And then also, I know you do have a very good funding from others so that you do not spend too much money from your own in terms of investment moving this forward. So maybe like just give us a sense how much that will cost going to the next stage.

Well, thanks, Gena. I'll answer that and then turn it over to Jen. But we think very much this is a very strong clinical activity signal in these patients. Obviously, these are very small numbers, but you have patients with modulator range responses on LCI at multiple time points and even in FEV1 in some patients at the Phase II dose. So we think there's very much a strong activity signal here.

In terms of the finances of the company, we are very fortunate to have this fully funded by our partners at the Cystic Fibrosis Foundation into the second half of 2026. So from a company burn rate, there's really no impact of this program at this time. And based on further data, we'll make decisions on further funding as we go into -- go towards Phase III.

Jen, could you kind of speak to the effect size we're seeing here and how these patients compare to maybe patients who are eligible for modulators?

Absolutely. I think it's really important for us to go take a step back to where we were. So back in 2012 when ivacaftor was approved, it was approved for only people who have the G551D mutation. And all the rest of the people with CF could see that those -- that group of people had this amazing new therapy and they didn't have anything. So when ORKAMBI came along, yes, the effect was more modest, but it stabilized a huge group of people who previously had nothing but symptomatic therapies. And so it improved their FEV1 modestly. It improved their quality of life modestly, but it did decrease their pulmonary exacerbation rate, which we know correlates with survival.

So again, with that modest improvement, half of the patients in the United States had a drug that at least stabilized them. The people right now who don't have a modulator at all feel incredibly desperate as they see over 90% of people eligible for these other very effective therapies. And so even stabilizing that group of people, so they're not having so many hospitalizations, not missing so much school, not missing so much work would be a huge gain for that group of people who is really desperate right now with no other option for therapy.

I have a quick follow-up regarding -- I think you said enrollment criteria, 40 to less than 100 for FEV1. Wouldn't that be too wide a range that cover 2 different -- too many different types of a patient population. We do know Alyftrek did not show superiority on FEV1 versus the -- sorry, I'm blanking out the previous triple combo -- but it did show -- yes, that's right. So like because one part of the reason is FEV1, you basically -- you could reach the peak depends on what kind of baseline you enroll. So that could be a very important data point to think about it. And then the other important data point that everyone is checking is the sweat chloride. Have you thought about that as well?

So to answer your second question first, so sweat chloride is impacted by systemically administered therapy, so I would not expect to be actually affected by an inhaled therapy. So we won't measure sweat chloride for this administration because we're just administering to the lungs. It's not getting into the other tissues as we've shown previously from the nonhuman primate models.

In terms of your first question, we're using the standard range of FEV1 that we use in most of our trials in cystic fibrosis. So yes, there is a range, but we want this drug to work for people in that range. Over 100, it's very hard to show a difference in FEV1. But in that range of 40 to less than 100, we have been able to show it with multiple different therapies, even if you go back to the days of Pulmozyme, for example, or the inhaled antibiotics. So we think that's a reasonable range to also have enough participants to enroll the study.

Thanks, Jen. Thanks, Gena, for the question. And just a follow-up on that. Obviously, a small data set here. But if these results with LCI and FEV1 and quality life were to be reproduced in larger patient numbers, how do you think patients who have no modulator therapies available would think about this and would they be willing to try it.

Yes. As I was mentioning, this group of people is really feeling quite desperate and their quality of life is highly impacted. There have been several different studies by different groups showing how difficult daily life is and how high the symptom burden and treatment burden is in this group. So I think people will be very interested in trying this therapy as soon as it became available.

Our next question is from Tommie Reerink from Goldman Sachs.

This is Tommie on for Salveen and congrats on the progress. We were wondering if you could just give us a bit more color on your redosing strategy and how that factors into your future development? And if there's anything that you can update us on a potential accelerated path here?

Well, thanks, Tommie, to you and Salveen, for the question. So maybe I'll take that and then Jen can weigh in as well. But in terms of redosing, there's very good data from multiple groups, including our own in primates and in the ferret model to show that aerosol redosing with AAV is feasible. In fact, we don't expect any lower expression with repeat dosing. We can get into the biology of why that is. But it's very clear from those studies that redosing should be highly efficient and give us similar expression levels as the first dose.

So the real question then becomes when do we redose? And I think that will be driven by the data on gene expression durability. We're thrilled that we're seeing expression out to 12 months or more, all the way out to 3 years, but at 12 months, at least with the Phase II dose. So we'll get more data on the durability of this profound LCI effect we're seeing and on transgene expression and then decide on redosing. Going into this, we hypothesized it'd be roughly 12 to 18 months. And I think our data certainly today, while early, is consistent with that.

In terms of the potential for accelerated approvals and how we expect to go to Phase III. I think after we get additional Phase II data and more durability on Phase I, we can go back to -- with the Cystic Fibrosis Foundation support and have conversations with FDA around accelerated approvals. And we are excited to be able to leverage access to this REACH study, which can serve as an external control group for Phase III.

Jen, would you like to amplify any of that?

I agree with everything you said, David. I think I would just add that we will be working also with the FDA on the redosing plan. So for sure, we want to look at the durability of gene expression, but also it would be incredibly helpful to look at the changes in LCI over time, and we'll gain more experience with that with this expanded dose cohort over time.

Thanks, Jen, and thanks, Tommie.

Our next question is from Daniel Giraldo from Bank of America.

Congrats on the update. I was just wondering if you could speak a little more on the LCI as an endpoint for adults. And maybe you talked about how it's been used for pediatric patients and maybe milder disease, but how well do you think it is measuring clinical benefit in more advanced or severe patients? And how are you going to take that into account for the enrollment criteria for the next patients? Is there going to be sort of range you're looking to enroll in terms of the LCI for that next cohort? And maybe more long term, how are you thinking about developing this program fully? Or is this something you would consider partnering after you acquire more data next year?

Well, thanks, Daniel, to you and Tazeen. So great questions. So maybe I'll take the business development one first and then turn it over to Felix. I think in terms of developing this, we're thrilled to be partnered with the Cystic Fibrosis Foundation, and we're happy to be driving it forward together and retaining 100% of the worldwide rights. Over time, we'll be opportunistic about whether or not we partner this or maintain U.S. rights. I think we're open to both, and we just really want to get more data before we make a final decision there. But I think I expect over time, there will be increasing interest in partnerships on this program.

In terms of your question for Felix, one of the first questions I asked when I met him as I said, if we were starting CF modulator therapies today, what would your primary endpoint be if you kind of ignore the historical precedent? If we're starting over today, would you use LCI or FEV1 and you immediately said, well, LCI, it's more sensitive, it's more reproducible, less variable. So that was very telling to me. But Felix, do you want to speak to kind of the use of LCI as an approvable endpoint and kind of where have we been and where are we going?

Yes. So I mean, thank you for the question. And I think it was mainly geared towards adults in terms of how well it performs in this age group. And just to look back, I mean, the reason many of the data in pediatric patients is because we didn't really have another endpoint to work with. And so we had to move on and use LCI. But -- it doesn't mean that it's not a useful endpoint in adults as well. I didn't show you the data for the open label -- not open-label open observational study that was done by the CF Foundation, which was called PROSPECT after ORKAMBI became available to patients. And that included both pediatric and adult patients. And it was consistently seen that both in children and adults, LCI was able to show about 3x the treatment effect that you saw with FEV1.

So I think -- and the REACH data that we will now become available and they should -- we will take a first dive into these data early next year when we have repeated measures for the adult population will also help us to further define the natural variability of this measure in contemporary patients and especially adults because for pediatric, we already have those data. So I think it has been a bit of a moving target, but things have changed in CF because overall, the disease is so much better treatment treated in both children and adults.

And so the need has also changed in terms of the outcome measures. And regulatory authorities have recognized that and are more open to it. They still want to see data on FEV1, no question about it. But again, looking at this as a complementary data set that could be very helpful is certainly the way I would look at it. And it is more sensitive, and it will capture more patients responding to therapy.

Thanks, Felix and thanks Daniel for the question.

Our next question is from Clara Dong from Jefferies.

Congrats on the progress. So maybe just a follow-up question on the redosing. So how are you thinking about the epithelial cell turnover rate in CF? And what does that really imply for the optimal redosing interval in your view? And then how are you thinking about LCI as an early trigger for redosing, especially if expression persists, but what if we see LCI begins top and then if there are minimal expression floor, will you consider redosing kind of mandatory even if clinical metrics are still stable?

Thank you, Clara, for the question. So the way we think about redosing is really going to be looking at that durability data. Again, we're thrilled to see expression out to anywhere from a year out to 3 years depending on the dose level. So I think we'll continue to get more data on paired biopsies at 12 months or beyond. In mice, the lung turnover half-life is about 1.5 years. So humans should be at or above that in terms of timing for lung turnover. But again, in CF being inflammatory, that could shorten it. So we estimated we'd be in a 12- to 18-month redosing window and our data certainly today, while early is consistent with that.

I think Felix, my feeling is that LCI would be a much better measure to follow to determine when we should redose when a treatment effect is wearing off because it would -- I think it would be a leading indicator before we see changes in FEV1. Do you agree with that?

Yes, I concur with that because the early changes are always in the small airways, and this is reflected by mucus plugging and LCI is very sensitive in capturing changes in mucus plugging. So I think it will be helpful in that sense. I mean the reality for the epithelial cell data is that there aren't a ton of data, longitudinal data in CF that you can rely on. So I think this program actually gives us novel insight into that.

All right. Thank you, Felix. So thank you all for joining us today. I think we're out of time, but we really appreciate your attention and interest. We thank Dr. Ratjen and Taylor-Cousar for their incredible insights today. We thank you for that. And of course, we thank the Cystic Fibrosis Foundation, all the participants on our Phase I AEROW clinical trial.

We look forward to hearing from all of you. Please reach out any time to Julian Pei, our Head of Investor Relations or our CFO, Kristian Humer, and we look forward to hearing from you. And thank you for your attention today.

Good morning, and welcome to the Jefferies 2025 Healthcare Conference. It's my pleasure now to introduce David Kirn, CEO; and Chris Simms, Chief Commercial Officer of 4D Molecular Therapeutics.

All right. Thank you very much. I'm Dave Kirn, sometimes the R and N merge and it looks like Kim, so I get that a lot. So David Kirn, good to see you. Co-Founder and CEO of 4D, and Chris Simms and I will be tag-teaming this. Chris is our Chief Commercial Officer. So this is 4D Molecular Therapeutics at a glance. We're developing an adaptable genetic medicines portfolio, including a focus on ophthalmology and pulmonology.

Our lead asset, 4D-150 is a potential backbone therapy that really dramatically reduces the treatment burden on patients with wet AMD and DME. So this really has an opportunity to be a highly disruptive product in a market that's roughly $17 billion annually. We think 4D-150 has a potential to really transform this field given its safety, clear efficacy with treatment burden reductions that you'll see later in the presentation, and it fits seamlessly into the commercial flow of a busy retina practice, which we believe gives us an advantage for commercialization.

And unlike most gene therapies, cost of goods here is very, very low. So we have great pricing flexibility. 4D-710 is our aerosol delivered genetic medicine for cystic fibrosis. This product delivers a CFTR transgene throughout the airways with highly reproducible transduction and gene expression, and we'll be updating this program later in December from our Phase I program. So gene therapy generally has a number of limitations that have held the field back.

I think you're all well aware of these, particularly with intravenous therapies. There have been issues with safety, high cost of goods, most of these products are used in rare diseases. So a one-and-done therapy in a very rare disease isn't a great business model. We've really flipped that on its head through innovation using a Nobel Prize-winning technology called directed evolution to invent best-in-class gene therapies that really overcome the hurdles with first-generation gene therapies.

This allows us to address large markets and particularly large high incident markets such that we have an ongoing revenue stream and not just a one-and-done in rare diseases. So a much better business model and it allows us to help more patients. Given the optimization of these vectors, this allows us to use routine routes of administration.

They're clinically easy to administer and also gives us best-in-class safety because we can really bring the doses down and these capsids are much less immunogenic compared to other gene therapies. We already talked about the low cost of goods and low prices, which we believe will help with commercialization. So this is 4D-150. This is a product that uses our proprietary capsid that we invented through directed evolution and then expresses aflibercept, which is the market leader in wet AMD.

So this is basically taking a product that's been in over 60 million eyes safely and effectively and just producing it 24 hours a day, 7 days a week from -- right from the retina where it needs to be, which dramatically reduces treatment burden for patients and protects them when they're not getting regular anti-VEGF injections. So we said this is a $17 billion and growing market. Chris will address that. And we believe this really addresses the highest unmet need, which is the high treatment burden. Patients hate it, and they stop showing up, which leads to vision loss over time.

So we believe this will be much more convenient for patients and actually will protect their vision much better than bolus anti-VEGFs. We have a very safe -- favorable safety profile. Chris will share that with you, ease of commercial adoption, and we do expect top line data from our ongoing Phase III, it's called 4FRONT-1 and 4FRONT-2 in first half of 2027 for the first study and second half of 2027 for the second study. All right. I'm going to turn it over to Chris, our Chief Commercial Officer. Chris?

Thank you, David. Good morning, everyone. It's great to be here. I appreciate the opportunity to share more about 4D Molecular Therapeutics. So I'm going to share a little bit more on like the market, the opportunity and why we think, particularly 4D-150 is well positioned to transform the treatment paradigm for retinal disease. This slide you see here is a snapshot of a couple of questions from a survey that was administered by The American Society of Retina Specialists, ASRS.

We ask a lot of questions to do this every year. But 2 questions that stood out that we think is really important to the potential of 4D-150. On the left is a question around which factors are most important to a physician when they select an anti-VEGF agent. You'll see the #1 response there is sustained efficacy. It's been sustained efficacy or otherwise called durability increases for the last 10 years despite some incremental advances, which I'll share more about.

The other question here that really hits home for us is the question of which pipeline treatment for wet AMD excites you the most. And as you can tell, by far, the #1 response was gene therapy at about 50% of respondents saying that's what -- that's the modality in development that they think has the most potential, that's most exciting, nearly 3x higher than the second choice, which is TKIs that are also in development. So that is one of several points that make us believe that we have a real opportunity here.

And as I just mentioned, we know that incremental benefit and durability translates to significant commercial potential. If you're familiar with the market at all, years ago, I started my career in commercial on LUCENTIS back at Genentech and LUCENTIS was largely known as a Q4 drug, so every 4 weeks. EYLEA launches with a Q4 label, in the real world, EYLEA's benefit and durability, we estimated it to be by the extra week, 1.5 weeks versus LUCENTIS.

With that small increment of a week or so, and many of you would probably know EYLEA became a multi-blockbuster drug well over $3 billion in a couple of years after launch. And then just recently, a couple of years ago, Roche launched VABYSMO. So VABYSMO takes that durability and adds another increment of another 1.5 weeks or so. So you can see these incremental benefits has resulted in massive commercial value with VABYSMO projected to do well over $4 billion to $5 billion this year.

Despite that, this market, as you can tell, is very exciting. And I want you just to take a moment to think about this from a patient perspective. We're going to go into more data on treatment burden reduction and so on, which is really important and a lot of the statistics. But think about it from a patient perspective. If you're on an anti-VEGF, for 5 years, we estimate on average, you're getting 36 injections. That's 36 needles in the eye. It's kind of become wrote, right? People are very used to this.

These medicines are highly efficacious. However, 36 times over that time period is not just the few seconds it takes to inject the medicine. For a patient, that means hours out of their schedule. So they're losing 4 or 5 hours. It has an effect on their caregivers. They have to plan their life around this. It conflicts with often other comorbidities that you have. And a lot of patients will tell you that despite this being done quite regularly, they have a lot of anxiety. So any reduction in that treatment burden is highly meaningful.

And again, we know that to be true because we see this, this incremental durability or treatment burden reductions has resulted in big commercial opportunity. So our solution is we're not aiming for an incremental benefit. We think 4D-150 can be a new paradigm, and our genetic medicine approach is based upon, first, our proprietary R100 vector, which is invented at 4DMT, and it expresses aflibercept and our VEGF-C RNAi inhibitor. Our durability, we believe, is not going to be measured in weeks.

We believe for many patients is years and sometimes for the rest of their lifetime. So as I'll show you, we're not looking for an extra week of durability. We believe for a patient, if you can have a proposition that says, hey, we're not giving you an extra week, but we could potentially reduce those number of injections by 80% or more. And for some patients, it might be the last injection they need for the rest of their life. It's highly meaningful.

The other thing that's really important here is when you look at these current injections, they're bolus therapies, right? So you inject, you dry the fluid, fluid comes back, you inject again. So it creates this pulsating nature in the retinal thickness. Over time, you'll see fibrosis develop, and that fibrosis can also then lead to a loss of vision. So most patients gain vision upon initiation of therapy, but it's quite common that over a period of time with these bolus therapies, you see that vision actually return to baseline, if not worse.

So patients lose vision despite the initial efficacy. Our belief is that it's a sustained expression like a 4D-150, which provides continuous control. So you eliminate that pulsating nature of the retinal fluid over time, but it also will allow patients to hold on to that initial vision gain. So it's not just a treatment burden reduction, it's also the potential for the maintenance of vision over a longer period of time. We've shown data across our Phase I/II PRISM study.

Just to orient you a little bit to this slide, we studied 3 populations that I'm going to break up the data on in the next couple of slides. The first population is Phase I/IIa. It's a severe borderline recalcitrant patient population. These patients were receiving on average over 10.2 injections in the prior year prior to 4D-150. The Phase IIb is a more of a broad population. Those patients were getting about 4 injections.

Average time of diagnosis is about 1.8, probably more representative of the normal patient population that you'll see in the retina for any kind of given day. And then we broke that even further and said, hey, what does the efficacy effect look like if you look at patients that were just recently diagnosed. As -- you see in the coming slides, you see an increased effect and certainly efficacy as you move to a more recently diagnosed population, which has informed our Phase III program.

So let me just take you through what those results look like. First of all, that severe patient population that I mentioned, patients that were getting on average, 10.2 injections in the prior year. We just released this data that shows the 4D-150 effect out to 2 years. So if you take that 10.2 and you increase it -- you double it for a 2-year period, our mean injections out to 2 years after 4D-150 was 4.3, representing a significant reduction of nearly 80% of treatment burden reduction for patients. Think about that.

Patient was on pace to get 20 injections in the 2-year time period, after 4D-150 on average, patients got 4. Look at the broad disease population, we didn't have enough history on these patients to compare it to their historical level of injections. So we compared the broad disease in the recently diagnosed to a projected EYLEA on label. So EYLEA on label over 1.5 years period. And for these patients, we don't have 2-year data. We just have 18 months thus far. Over 1.5 years, you would get about 9 injections.

So what did it look like once you've got 4D-150? For the broad disease population, the treatment burden reduction was about 82%, so an average of 1.6 versus what would have been, we think, 9, closer to 9. And then when you look at the recently diagnosed, again, these are patients that were diagnosed in the prior 6 months. That patient population got an average of 0.7 over a 1.5 year period. Again, you compare that to what they would have received on on-label EYLEA of 9, a treatment burden reduction of 92%.

So we think these results are definitely paradigm changing. Of course, as I'll go into in a couple of slides, this informs our Phase III program of 4FRONT-1 and 4FRONT-2 . And we would expect that patient population because it's more treatment naive to more resemble the effect that we see in the recently diagnosed population on this slide. It shows the same data effect, but it just breaks it out by injection-free versus number of injection status.

I'll orient you to the recently diagnosed population here again on the right side of the slide. So recently diagnosed, 73% of patients out to 1.5 years were injection-free, 87% of patients received less than 2 injections over 1.5 years' time period. And again, that's compared to what otherwise would have been, we projected 9 injection schedule for EYLEA. That informs our 4FRONT-1 and 4FRONT-2 Phase III program. So 4FRONT-1 and 4FRONT-2, our Phase III program is up and running. We started 4FRONT-1 at the end of March.

We expect topline data on 4FRONT-1 in the first half of '27 and topline data on 4FRONT-2 in the second half. And those trials are designed largely around a treatment-naive patient population, 4FRONT-1, all treatment naive; 4FRONT-2, up to 40% could have been diagnosed in the last 6 months, everyone else are treatment naive. So we think we've enriched those trials to reflect the more recently diagnosed population, which we think increases the odds of success.

Of course, all of this efficacy, which we think is highly impressive, doesn't matter in a world where you don't have safety that's at least consistent with standard of care. We think one of the things that really differentiates 4D-150 is our safety data that we've shown so far really stands apart. As you can tell here, we have now safety data through 1.5 to up to 3.5 years, and it suggests a very consistent and a predictable intraocular inflammation or IOI profile with Phase III dose.

On the left-hand side, we have about 2.8% rates of 2 cases, but those are out to 28 weeks, so roughly 6 months. Really interesting is that after that 6-month time period, no signs of inflammation whatsoever. So -- and again, that data goes out to over 3.5 years. So this is at least consistent, if not better, than what we see today with standard of care. Reiterating our 4FRONT-1, 4FRONT-2 Phase III program, obviously, evaluating the efficacy and safety and durability of a single intravitreal injection of 4D-150.

Both programs are up and running. Both trials have started, 4FRONT-1, we've just updated with over 200 of those 400 targeted patients have been enrolled in the trial, have been randomized, 4FRONT-2 as well initiated about July, global study. So the other thing that's important to point out here is we've designed this program for global registration. So we think these designs and the inclusion criteria allows us to develop a global program. Next couple of slides is -- so everything that I was just shown was on wet AMD.

The next couple of slides is on DME. So the second largest market opportunity for the anti-VEGF space. The first thing -- we shared this data back, I think, in July of this year is from our Phase I study on DME. The first thing that stands out here is our safety profile. So DME in intravitreal gene therapy has been an issue in the past with safety events. Our safety profile continues to be highly differentiating. So no intraocular inflammation at any time point or any dose level in DME.

And while the numbers are small, we also saw a similar effect in terms of efficacy. So in the DME patient population, the average number of injections at the 60 weeks was about -- was 1.6. You compare that to our projected on-label aflibercept as well, which would be roughly 7, you see a 78% reduction in treatment burden for the DME patient population on the right, you see how that breaks out by treatment or supplemental treatment frequency. As David mentioned earlier, we believe this allows us to, I think, have a very strong compelling commercial value proposition, reduction in treatment burden.

Certainly, I think that's important for patients and it connects to their quality of life and freedom. One of the biggest challenges in medicine, and certainly, it's true in the anti-VEGF space is the adherence to therapy. When you have a onetime treatment that continuously expresses aflibercept for a lifetime of the patient, you have adherence by design. There's a benefit in preserving vision long term as well that we think is highly important certainly to payers.

And as was mentioned earlier, our cost of goods is relatively low, and we think that gives us a lot of pricing flexibility so we can adapt to the market as needed. And then from a clinic perspective, it is an intravitreal therapy, so it doesn't require a surgery like some other genetic medicines will require. So it will seamlessly be integrated into the practice. The formulation is a stable that resembles what you would have with anti-VEGF today.

So the acquisition process and storage in the clinic is the same as what you would have today. And we think with our profile, it could also help with clinic capacity and patient flow. The last thing to touch on, we're very excited to announce just a couple of weeks ago that we have signed an exclusive licensing agreement for 4D-150 with Otsuka for Asia Pacific.

So from a financial perspective, that provided us with $85 million upfront, at least $50 million in cost sharing expected over the next 3 years related to our clinical development program and up to $336 million in regulatory and commercial milestones and tiered double-digit royalties in the Otsuka territory. This licensing is specific to Asia-Pac. So we think that territory roughly represents about 10% of the global opportunity. So we retain 90% of the 4D-150 value globally. Okay. With that, I'll have David come back up and talk about 4D-710. David?

All right. Thanks, Chris. So now we're going to deal with the lead product in our pulmonary franchise. This leverages a vector that we invented through directed evolution for aerosol delivery throughout the entire lung airways in humans from the large airways, small airways all the way to the alveoli using a commercially approved and routine nebulizer device. And what's exciting about this is it delivers the CFTR transgene. So it's fundamentally curing the disease at its -- right at the source of the disease.

With this product in Phase I, we've reported very high-level reproducible and dose-related expression on biopsies and lung brushings in all patients on this Phase I study. We've reported out roughly 15 patients to date, all of whom had high-level expression throughout the airways at roughly 1 to 2 months. This should initially be developed in patients who are not amenable to Vertex modulators.

So either there are no mutations, or they have rare mutations that do not bind the modulators and/or patients who are intolerant of the modulators can also enroll in the study. So we're really targeting the patient population with the highest unmet medical need, and we think this really gives us an opportunity for very accelerated development and approval in this indication. To date, the product has been extremely safe, especially at the Phase II doses.

And we've seen very promising anecdotal data on functional benefit in terms of lung function as well as quality of life. The lung endpoints for this study -- lung function endpoints are lung clearance index or LCI as well as standard FEV1. So later in December this year, we'll be reporting out data on roughly 16 patients across all dose levels in this Phase I, and we'll be updating data on gene expression, both acutely in the first couple of months, but also long term, anywhere from 1 to 3 years out, which will be very important seminal data for the field.

And we'll also be updating data on some of these novel endpoints such as LCI, high-resolution CT scanning for anatomical changes and then quality of life. So we have a robust and focused pipeline here for diseases that are either high incident rate in the case of wet AMD and DME as a sustainable income or in the case of lung, starting with the cystic fibrosis product, 4D-710, we have the ability to re-dose, we believe.

And so both of these should be sustainable commercial markets for the company and will allow us to benefit huge numbers of patients. You can see the expected milestones on the right. The most near-term catalyst will be our cystic fibrosis Phase I data release in December, next month. And then next year, we'll have enrollment updates on 4FRONT-1 and 4FRONT-2. We expect to complete enrollment on those studies next year.

And then also give program updates on the DME program. We're excited to get that started as well as program updates on the 4D-710 development path, including regulatory path updates. And then again, in 2027, first half, we expect phase -- the first Phase III to read out. Second half of '27, we expect the second Phase III to read out. So as you can see, we have an extremely full catalyst calendar coming up.

All right. So thank you for your attention, and we can open it up to any questions from the floor.

Do you think repetitive dosing will be available for 4D-150?

It's interesting. So 4D-150, we don't think it will be necessary in the same eye, but we do have an opportunity to treat the contralateral eye. So patients will have the opportunity to get a second dose. About 40% of patients will develop wet AMD in the contralateral eye. And so we will re-dose, but in the other eye. We think injection in the first eye should lead to essentially lifelong expression. So we don't think we'll need to re-dose.

How do you see commercial positioning vis-a-vis the tyrosine kinase inhibitors in development?

Sure. I think there are a number of products that are really trying to extend. As Chris said, the whole game here has been to extend by a couple of weeks each time going from LUCENTIS to EYLEA then VABYSMO. We see the TKIs as a logical extension of that. And they'll look to, I'm sure, try to compete with VABYSMO, particularly in patients who have relatively mild disease. That's where they really focused. I think in contrast, 4D-150, this is essentially multiyear, if not lifelong therapy.

So it's a different category, and it really protects the patients continually for that long duration, even if they miss their clinic visits, they're protected. We think really has the opportunity to dramatically improve vision outcomes. So we view this as more of a different category from the TKIs. This will be more like a Susvimo, if you're familiar with the port delivery system from Roche. That's not been a commercial success because of the difficulty with the surgery, but it has been an incredible success for vision preservation. And we think we can achieve that, but just with a simple intravitreal injection. Thanks for the question.

[indiscernible].

So it's interesting. It depends on the route. So we know that we can inject the contralateral eye with 4D-150, so the same patient gets 2 doses in 2 of the eyes. We don't think we need it in the same eye because, again, it's such durable expression in the retina. There's data out to 10 years or more with other AAV programs. In the lung, it does appear to be feasible to re-dose based on all the available animal data, and we expect we'll be able to do it in humans, so we would expect to re-dose there.

Whether it's at 1 year, 2 years, we don't have that defined yet, but we will be able to re-dose. There are -- it's just that with the clearance techniques that these patients use to clear their lung of all the mucus that holds those antibodies and then the very, very efficient nebulizer device that just puts the vector right on top of the airway. We've seen excellent transduction even in the face of preexisting antibodies. So it doesn't appear to impact it.

[indiscernible].

Very, very strict guidelines, which they follow almost all of the time. And in Phase III, they'll be required to. But we had criteria such as 75 microns CST worsening or 10 of vision. We've tightened those up a little bit even further for the Phase III, and it will be very rigorously enforced to make sure it's consistent.

[indiscernible].

No. The physicians and the FDA wouldn't have allowed us to do that. It really protects patient vision. So we step in at the appropriate time to make sure patients' vision is protected. But nevertheless, we see this phenomenal treatment burden reduction, which is truly remarkable. I mean 73% injection-free at 1.5 years is really unheard of.

We run out of time.

Okay. Thank you for the questions.