Analysts, here at BofA. Our next presenting company is 4D Molecular Therapeutics. I have some members from the management team here. Welcome guys, thank you for joining us. Maybe we can start with a couple of introductions from your side, and then, you know, you can give us a high-level overview of the company. I know you have some catalysts coming up, especially 2027 is gonna be a big year for the company. Maybe we can start with that. David, maybe if you want to start.
Yeah. Thanks Daniel, for having us. I'm David Kirn, Co-founder, President and CEO. Chris?
Yeah, thanks Daniel. Chris Simms, Chief Commercial and Business Officer.
Kristian Humer, CFO.
I can give the high level overview of the company. 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. You know, we're thrilled to be in phase III. The enrollment's 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.
I think we have a real opportunity here. Catalysts this year are, we have a two-year follow-up on a broad population of wet AMD patients with 4D-150 phase II. That's mid-year. second half of the year will be a DME two-year update. 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. Maybe let's just start with a high level question. You know, 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, you know, what are you hearing from physicians in terms of what the unmet need is right now for the treatment of wet AMD and, you know, how do you think 4D-150 could be differentiated in that market?
Yeah, 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. I think it's very promising for us. I think at a high level with 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. That's great. We're fundamentally in a completely different category. You know, 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. Should also translate into better visual outcomes over time.
Chris can really speak to, I think, you know, what's driving patients' and physicians' interest.
Yeah, happy to. You know, taking a little bit of a step back, if you're familiar with the category, it's a large space, I think valued at roughly $17 billion globally today with existing bolus anti-VEGF therapies. We expect that to continue to grow, largely driven by an aging patient population. These existing therapies are actually pretty efficacious. They do a good job of improving a patient's vision. The challenge is getting in and staying on therapy at a frequency that allows the patient to maintain that vision. 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. 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, 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. Not only have they said that, we've seen innovation prove that to be real. You look at the latest bolus therapy launches, Vabysmo, Eylea HD, all of those assets have extended durability by a week or two. Meaningful, certainly for a patient, maybe takes an injection per year out of their normal routine, but incremental. Despite that incrementality, those agents have become multi-blockbuster within a couple of years. I mean, Vabysmo is the greatest example of that.
I think with our approach, we ask the question, if an incremental benefit like that can be of commercial value measured into $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. It's a completely different paradigm. We think we are uniquely positioned to like really address this durability question in a way that hasn't been done before.
In addition to that, we think we could actually help patient maintain their vision over the rest of their lives, and that's pretty significant when you think about, you know, you go onto 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. If you can not only reduce treatment burden by 80-plus%, but also say to a patient, "You've got a good chance of holding onto your vision for the rest of your life," that's a completely different ballgame and a completely different treatment paradigm.
Yeah, great. There's a few competitors in the gene therapy space for wet AMD. You know, how do you view your product compared to those, and what do you think is your edge in this market?
Well, we think we're the best. Which shouldn't be surprising, 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. Subretinal surgery is just, it's great for proof of concept, but for commercialization it's really a non-starter. We have major advantages over the REGENXBIO product since we're intravitreal. I think our safety profile has really shined and differentiate us, differentiated us from the Adverum Biotechnologies product, you know, 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 as in addition to wet AMD and DR.
Yeah. For what it's worth, our doctor checks also indicate physicians think your product has the best profile so far. You mentioned you have a two-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 two years? 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. In wet AMD, you know, 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. 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- 10 injections a year, still failing therapy. In that population out to two years, we showed nearly an 80% treatment burden reduction compared to what they'd been getting using patients as their own control. That's huge. When we moved into a broad population, we showed about, again, an 80% reduction out through a year and a half.
When we looked at the patients that most closely mirror our phase III population, we had a 90% treatment burden reduction through a year and a half, with over 70% of patients injection-free, through a year and a half. Most importantly though, you know, given this is a large market and there are effective therapies, is our safety has been extremely favorable. There, you know, when we looked 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. It's been really phenomenal, and that's just during the first few months after treatment. After six months, we just don't see anything.
The safety's been really phenomenal. That, that's sort of what we've shown to date. We would expect the two-year update for the broad population and recently diagnosed population would be more of the same. You know, 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 know, you've reported data for injection freedom over time, but you've also shown, you know, significant treatment burden reduction. You know, where do you think physicians will be comfortable using a gene therapy product? You know, is it, you know, 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.
Yeah, it's a great question. First of all, safety has to be established, right? I think, and to David's point, we really differentiate on our profile as it relates to safety, no doubt. That's in a, in a, 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've been in hindsight, it had a safety issue which caused it to be a challenge from a commercial perspective. You gotta have safety, and we think our profile would support that. As far as the treatment burden, injection-free numbers, it's Like, doctors don't say it has to be X%. Like, there's no binary cutoff point. It has to be meaningful.
It's gotta be, for a gene therapy, a significant step change from the incrementality that they're getting with high-dose products or TKIs. 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, you see basically like in the broad population, injection-free rates of about 70% at a year and a half, 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. If our phase III data and profile comes out in that range, 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 one-time treatment. You know, realistically, that might not be the case for everyone. You know, what sort of durability do you think physicians would like to see? You know, maybe how are you thinking about potential redosing over time?
For redosing, we don't think it's gonna be necessary. You know, the retina's a very, very stable tissue, other AAV gene therapies have shown stability out through 10 years or more, and it's an elderly population. It's probably lifelong treatment. We don't think they're gonna need an injection in the same eye. A big opportunity for us commercially and for, to help patients is about 40% will get wet AMD in the other eye. I expect if they have great success in this eye, they're One or the other eye almost by definition, that's another 40% on top of the initial population. I think it's a huge opportunity, then maybe Chris, you could speak to the other part of the question.
Yeah. You know, Physicians don't say it has to last X amount of time. I think they just look at, you know, what is the treatment burden reduction that we're showing. I think practically we're gonna have to show long-term data over time to continue to prove that one, it continues to be efficacious in years out, and there's no biological reason that we think would prevent that from being the case. I think that'll come, and I think long-term safety is gonna be important as well. You know, 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 three- to five-year window for AMD from a modeling perspective.
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 at, in that range on the outside of their durability of treatment, so much of it by the fact that in AMD you have an older patient population. That's just some of the variables that we use when we think about, you know, length of treatment durability.
Okay, great. Maybe we can talk about the phase III program. You have two trials ongoing. You recently announced you completed randomization in 4FRONT-1, the North America trial. You know, what do you think drove kind of the accelerated enrollment in the trial, and, you know, do you think that's gonna boost enrollment in 4FRONT-2 as well now that you've completed the first trial?
Yeah. To 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. They really, really want something that's much more durable, if not lifelong, benefit. Then physicians, it's the data. You know, they look at our data and say, "Wow, this is intravitreal. It fits seamlessly into my practice," and they're getting safety profile that's not unlike aflibercept. And, you know, the treatment burden reduction is remarkable. I think it's really a combination of unmet need and our data.
Again, Chris has had a lot of those conversations and probably add some color to that.
Yeah, I Not a whole lot. I mean, we did something that I think is pretty obvious in hindsight, but we went out into all the clinical trial sites with a pretty robust phase II data set and said, "Hey, before you start up in phase III, let us 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 shared with them what the results were. We shared with them what we saw in terms of safety. 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. I think that created enthusiasm for them to talk to their patients about it.
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. Some of that we get through the physician conversation, and they parlay 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. The patient enthusiasm has been off the charts. 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 four reasons why we saw the pace of enrollment the way that we did.
Great.
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 gonna 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, you know, five short years in the clinic, we're enrolling at record speed, not only in 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. 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-
for these programs. Can you maybe remind us what you have seen so far? Has anything changed, like I guess on a blinded, you know, basis in the phase III trials? I know you have a steroid regimen as part of the trial. You know, how do you think that will play out in the real world once patients are now part of the clinical trial?
Yeah. This is a great question. Just starting from fundamentals, again, because we came in and we said we're gonna innovate and invent an optimized capsid that has the features we want, our dose levels are lower, our inflammation is much lower, if any. It set us up for success. The fact that we're seeing no significant inflammation or toxicity is not by chance. It's not luck. It was by design. We, you know, we took years to innovate where others just kind of took existing vectors, threw it in the clinic and hoped for the best. You know, we take great pride in that we're seeing exactly what we expected to see.
In terms of the safety, we've now reported, you know, 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. You know, we've had a, again, less than 3% kind of trace to one plus cells that could be detected maybe at one time point, and then are gone by the next time point. Not clinically meaningful whatsoever. Again, a remarkable outcome. That's, that's the safety profile. While we're not giving formal safety updates, we do watch the safety of every single patient on our phase III in a masked fashion. You know, we certainly haven't seen anything that changes our thesis that this is gonna be very safe and effective.
We do have a DSMC that also reviews the data every six 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. You know, 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. Patients probably can miss some doses. Yeah, we haven't I don't think we've heard of a single patient, you know, from the sites who said, "I'm not going on this because of eye drops." What they're trading is a jab in the eye and then blurry vision and pain for three days versus some drops.
They'll do that trade-off all day, every day.
Great. We have the first readout coming out in first half of next year. You know, what do you think would be good data there? What do you think is needed for commercial success?
Chris, you wanna speak to that?
I would go back, I think, to the comment I made earlier where, again, this is not a absolute binary kind of pivot point. Clearly you gotta meet your primary endpoint. You gotta demonstrate safety that we think needs to be kind of in the range of where we're a 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. When it comes to the treatment burden effect, the injection free, honestly, 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 it could, based upon, again, the design and the patient selection for phase III, that it may actually could be better than that. 'Cause 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 benefit in terms of treatment burden reduction to those patients. It makes sense biologically. You have healthier retinas. You're transducing retinal cells, therefore it would make sense that you'd probably get more expression and more of a treatment effect. Then in our phase III, we have a completely, at least in 4FRONT-1, a naive patient population. 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.
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. You know, have you had those conversations with FDA? Do you think there's a path forward there to apply with just 4FRONT-1?
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. That's definitely our plan. I think for wet AMD, there's probably a path, but the reality is also because we were doing good drug development and de-risking things, we have two studies that are pretty close to each other. You know, readout for 4FRONT-1's gonna be first half next year, 4FRONT-2 second half. How much do we really gain versus the benefit of having, you know, filing on both in Europe, U.S. and in Europe and Japan?
You know, we're still looking at that, but I think we're really well-positioned even with just filing off two studies right now.
Makes sense.
That's our base case.
How are you thinking about the commercial strategy now that you're getting closer to pivotal data? You know, how do you think this type of product would fit into the buy and bill model of retinal practices? Would it be any different from, like, any of the other currently approved therapies?
The ways that it's different is better. Most of it is, I mean, 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 I've 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 were blown away by the profile. They're like, "This is really IVT. It can store it at the same temperature as our current eye injections." Like, that's massive. 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. 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. The retina community, I think, has largely perfected that business model with, you know, bolus therapies and how they create economics through that. The dynamics of our medicine is gonna be priced higher, of course, because the value that we reflect over long-term treatment burden reduction, the value of getting reimbursed up front is of significance to them.
The value of capturing patients on a therapy that accounts for what likely multiple years of treatment versus a lot of patients fall off current therapies within 1 year, one and a half years. That's incremental value. We think there's an economic story that actually improves the buy and bill economics for a retina clinic with our profile. Yeah. 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 onto their vision.
I also think there's a value story that'll 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. We think we've got some unique elements that position us really strongly there commercially.
Great. You recently announced, or I guess last year you announced the partnership with Otsuka for your for, you know, commercial realization in Asia Pacific. You know, how are you thinking about rest of the world? Are you gonna do it yourselves? Do you think it would make sense to find another partner for Europe or other regions?
Chris, you wanna speak to that?
Yeah, happy to. I think we're keeping all options on the table, honestly. We have said consistently and continue to believe that 4D-150 creates value for all patients globally. When it comes to Europe and basically ex-U.S. excluding Asia Pac, which Otsuka has, we're gonna keep options on the table. If 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 are the right set of terms, we reserve the option to commercialize ourselves. 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. The amount of commercial investment pre-launch, the size of the team, was the same in both dynamics. Small biotech, large top five pharma. We can, we can take on that commercialization challenge ourselves if that's what we think is strategically the best option for us.
Just to clarify, you know, that what wasn't said but is definitely our plan is we will commercialize ourselves in the U.S.
Yeah.
Chris is, you know, the right guy to do that. He's done it I think two or three 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, you know, recent gene therapy, you know, filings have, you know, faced roadblocks. You know, what's your strategy there?
Yeah. I, so, you know, with complex biologics, it's a real issue, right? It's probably one of the most common causes of a failed BLA. You know, 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, you know, let's see if we can't manufacture ourself GMP." We were highly successful. We took six 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. It's a, it's a phenomenal team all the way up into phase III.
Of course you need to do a technology transfer to a commercial facility, which we've achieved already. Again, ideally you'd have at least 50% of the material in one of your phase III come from the commercial facility, which we are now in the middle of achieving. We need to do our qualification batches, which we're in the middle of doing. I think everything's on schedule. We have a great CDMO who's been a real leader in this space. I think between our innovation, 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.
Yeah
as well. You know, how are you thinking about that opportunity? I think you're expecting to initiate your phase III trial soon.
Yeah.
You know, what are the gating factors before you can start the trial?
You know, I can speak to the practicality. Q3 is our guidance for starting that study, and we're on track for that. We're really excited. I think there's gonna be phenomenal excitement there, and excellent enrollment, mirroring I think what we saw on wet AMD. As Chris will tell you in a minute, the, probably the unmet need in DME may be even higher. We're really excited. I think mid-year this year we'll give an update on the final study design after final regulatory interactions. What we've guided to is a BCVA non-inferiority, five loading doses, which is standard in DME, and then a, you know, a final sample size somewhere in the range of 300 or 400 is where we're currently guiding. We'll update that soon.
I think Chris can speak to the real opportunity in DME, which is huge.
Yeah, I mean, as you likely know, DME is the second largest indication in this bolus anti-VEGF space today. It's undertreated and it's under-penetrated in terms of the market value. There's more patients, the challenge with staying on therapy is greater in DME than even in AMD. When you listen to physicians and they talk about treating DME patients, they think about whether a patient's gonna stay on therapy, they worry about whether that patient's gonna get lost to follow-up. 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. That benefit is of high significance.
The fact that, listen, we by design solve one of the biggest challenges in healthcare medicine, which is adherence to therapy. Once you get 4D-150, it's there, it's constant, it's always present. Solving that in a DME patient population is really meaningful. We, I actually think there's this 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. 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 wanna leave you out.
No, absolutely. Appreciate it. Appreciate it. 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. like, it doesn't include the commercial ramp-up yet. That's something that we anticipate to finance post 4FRONT-1.
Great. Think with that we're out of time, so thanks again for joining us, guys.
Thanks for having us.
Good to be here.
Thank you.