Conference Transcript - FDMT 2025-11-18

Operator

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

David Kirn, CEO

All right, thank you very much. I'm Dave Kern. Sometimes the R and the N merge, and it looks like Kim, so I get that a lot. So David Kern, good to see you. Co-founder and CEO of 4D, and Chris Sims 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, 4D150, 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 4150 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. 4710 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 1 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 costs 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 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 4150. This is a product that uses our proprietary capsid that we invented through directed evolution and then expresses a flibbercept, 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, 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 favorable safety profile. Chris will share that with you. Ease of commercial adoption. And we do expect top-line data from our ongoing Phase 3s called Forefront 1 and Forefront 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.

Christopher Simms, Other

Thank you, David. good morning everyone it's great to be here 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 40 150 is 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 two questions that stood out that we think is really important to the potential of 4D150. 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 number one 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 number one response was genotherapy at about 50% of respondents saying that's the modality in development that they think has the most potential, that's the most exciting. Nearly three times 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 four weeks. ILEA launches with a Q4 label. In the real world, ILEA's benefit and durability, we estimate it to be about an extra week, week and a half, versus Lucentis. With that small increment of a week or so, and many of you would probably know ILEA 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 Vibaismo. So Vibaismo takes that durability and adds another increment of another week and a half or so. So you can see these incremental benefits has resulted in massive commercial value, with the Bavismo projected to do well over $4 to $5 billion this year. Despite that, this market, as you can tell, is very cluttered. I want you just to take a moment and 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 in a lot of the statistics. But think about it from a patient perspective. If you're on an anti-VEGF for five years, we estimate on average you're getting 36 injections. That's 36 needles in the eye. It's kind of become rote, 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 four or five hours. It has an effect on their caregivers. They have to plan their life around this. It conflicts with often other comorbidities that they 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. These 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 4D150 can be a new paradigm, and our genetic medicine approach is based upon first our proprietary R100 vector, which was invented at 4DMT, and it expresses a flipercept and a VEGFC RNN, AI inhibitor. Our durability, we believe, is not going to be measured in weeks. We believe for many patients it's 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 4D150, which provides continuous control, so you eliminate that pulsating nature of the retinal fluid. Over time, 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 1-2 PRISM study. Just to orient you a little bit to this slide, We studied three populations that I'm going to break out the data on in the next couple of slides. The first population is Phase 1, 2A. It's a severe borderline recalcitrant patient population. These patients were receiving, on average, over 10.2 injections in the prior year, prior to 40 and 150. The Phase 2B is more of a broad population. Those patients were getting about four injections. Average time of diagnosis, about 1.8. probably more representative of the normal patient population that you'll see in a retina clinic on a 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? And as you'll 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 3 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 4D150 effect out to two years. So if you take that 10.2, you increase it, you double it for a two-year period, our mean injections out to two years after 40, 150 was 4.3, representing a significant reduction of nearly 80% of treatment burden reduction. Think about that. Patient was on pace to get 20 injections in the two-year time period after 40, 150, on average, patients got four. Look at the broad disease population. We didn't have enough history on these patients to compare it to their historical level of So we compared the broad disease and the recently diagnosed to a projected ilea-on-label. So ilea-on-label over a year-and-a-half period. And for these patients, we don't have two-year data. We just have to 18 months thus far. Over a year-and-a-half, you would get about nine injections. So what did it look like once you got 40 and 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, nine, closer to nine. And then when you look at the recently diagnosed, again, these are patients that were diagnosed in the prior six months. That patient population got an average of 0.7 over a year and a half period. Again, you compare that to what they would have received on on-label ILEA 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 programs with Forefront I and Forefront II. We would expect that 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 in 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 a year and a half were injection-free. 87% of patients received less than two injections over a year and a half time period. Again, that's compared to what otherwise would have been. We project a nine-injection schedule for ILEA. That informs our Forefront 1 and Forefront 2 Phase 3 program. So Forefront 1 and Forefront 2, our Phase 3 program is up and running. We started Forefront 1 at the end of March. We expect top-line data on Forefront 1 in the first half of 27 and top-line data on Forefront 2 in the second half. And those trials are designed largely around a treatment-naive patient population. Forefront 1, all treatment-naive. Forefront 2, up to 40% could have been diagnosed in the last six 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 4D150 is our safety data that we've shown so far really stands apart. as you can tell here we have now safety data through one and a half to up to three and a half years and it suggests a very consistent and a predictable intraocular inflammation ioi profile with phase three dose on the left hand side we have about 2.8 percent rates of two cases but those are up to 28 weeks or roughly six months really interesting is that after that six month time period no signs of inflammation whatsoever so and again that data goes out to over three and a half years so this is at least consistent if not better than what we see today with standard care reiterating our forefront one forefront two phase three program um obviously evaluating efficacy and safety and durability of a single interventional injection of 4150 both programs are up and running both trials have started uh forefront one we've just updated we've Over 200 of those 400 targeted patients have been enrolled in the trial, have been randomized. Forefront II as well initiated about July global studies. 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 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 that we shared this data back I think in July of this year is from our phase one study on DME. The first thing that stands out here is our safety profile. So DME in intravitual gene therapy, been an issue in the past with safety events. Our safety profile continues to be highly differentiating. So no interocular 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 1.6. You compare that to a projected on-label FLIPRCEPT 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 supplementary treatment frequency. And 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 one-time treatment that continuously expresses a flipper sap 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 lots of pricing flexibility so we can adapt to the market as needed and then from a clinic perspective it is an intravitual therapy so it doesn't require surgery like some other genetic medicines will require so it will seamlessly be integrated into the practice the formulation is a stable it resembles what you would have with anti-VEGF today so the acquisition process the storage in the clinic the same as what you would have today and we think with 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 4150 with Otsuka for Asia Pacific so from a financial perspective that provided us with $85 million up front, at least $50 million in cost sharing expected over the next three years related to our clinical development program, and up to $336 million in regulatory and commercial milestones and tiered double digit royalties in the Atsuka territory. This licensing is specific to Asia PAC, so we think that territory roughly represents It's about 10% of the global opportunity. So we retain 90% of the 4D150 value globally. Okay, with that, I'll have David come back up and talk about 4D710.

David Kirn, CEO

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 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 one to two months. This should initially be developed in patients who are not amenable to vertex modulators, so either they're null 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's 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 one, and we'll be updating data on gene expression both acutely in the first couple of months, but also long term anywhere from one to three 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 and 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, that is a sustainable income, or in the case of lung, starting with the cystic fibrosis product 4710, we have the ability to redose, 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 1 data release in December, next month. And then next year we'll have enrollment updates on Forefront 1 and Forefront 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 4710 development path including regulatory path updates and then again in 2027 first half we expect phase the first phase three to read out second after 27 we expect the second phase three to read out so as you can see we have an extremely um uh 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. Yes.

Speaker 4

Do you think repetitive dosing would be available for 4150?

David Kirn, CEO

It's interesting. So 4150, 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 redose. Thank you.

Speaker 1

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

David Kirn, CEO

Sure. You know, I think there are a number of products that are really trying to extend. As Chris said, you know, the whole game here has been to extend by a couple weeks each time, going from Lucentis to ILEA, then Vibaismo. We see the TKIs as a logical extension of that, and they'll look to, I'm sure, try to compete with Vibaismo, particularly in patients who have relatively mild disease. That's where they really focus. I think in contrast, 4150, this is essentially multi-year, 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 it really has the opportunity to dramatically improve vision outcomes. So we view this as more of a different category from the TKIs. This would be more like a CESFEMO, 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.

Speaker 4

Yes.

David Kirn, CEO

So it's interesting. It depends on the route. So we know that we can inject the contralateral eye with 4150 so that the same patient get two doses and two different 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 redose based on all the available animal data, and we expect we'll be able to do it in humans. So we would expect to redose there, whether it's at one year or two years.

Operator

We don't have that defined yet, but we will be able to read those.

David Kirn, CEO

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, it 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.

Speaker 4

Yes?

David Kirn, CEO

There's very, very strict guidelines, which they follow almost all the time, and in phase three, 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 three, and it'll be very rigorously enforced to make sure it's consistent. 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 if the patient's vision is protected. But nevertheless, we see this phenomenal treatment burden reduction, which is truly remarkable. I mean, 73% injection-free at a year and a half is really unheard of.

Operator

We run out of time.

David Kirn, CEO

Okay, thank you for the questions.