Because it's being broadcast.
All right, welcome everybody. Thank you. It's a pleasure to be here. I'm David Kirn, co-founder and CEO of 4D Molecular Therapeutics, or 4DMT.
Welcome.
Okay, we'll be giving some brief introductory remarks with a brief slide deck here today and then get into Q&A. 4D-150 is our lead product for wet AMD and DME. Key updates here are the Forefront One phase III trials underway and enrolling briskly, which is very exciting, with over 50 clinical trial sites activated to date, and with a target of 100 total for Forefront One. 4D-150, to remind you, is the first known genetic medicine to receive RMAT designation, which is essentially biologics breakthrough for both wet AMD and DME. This is a summary of the program.
This is a phase III candidate designed to disrupt the global market for retinal vascular diseases and really improve patient outcomes in wet AMD and DME. I'll go through each of these sections one by one, but this is a multi-billion dollar market opportunity estimated to be about $20 billion by the time we get to the market. This product addresses the primary clinical unmet need for patients and physicians in the space, which is greater durability with retained safety. We have a very favorable safety profile, which is very similar to Eylea itself, which is what we produce from the agent. This product is administered through a routine intravitreal injection in the clinic, so there's really seamless integration in terms of the injection and storage of the product in the clinic.
We think there's a very favorable impact on economic outcomes for the physicians, the retina specialists based on the buy-and-bill reimbursement model, which Chris will speak to later. We do expect top-line data from the wet AMD pivotal trials in 2027. Let's talk about this market opportunity. You can see here the growth of this market over time. Now, that light blue part of the bar is Eylea. That's what we express from 4D-150. We just express it continuously, 24 hours a day, seven days a week in the retina itself directly through our genetic medicine approach. Eylea has been in over 60 million eyes to date with an excellent safety and efficacy profile, and we're just delivering in a smarter, better way.
You can also see importantly here that new color at the top of the bars at later years is the Vabysmo launch, just showing how successful that launch has been. Really, just by adding a couple of weeks of durability, whereas we talk in terms of months, if not years, of additional durability. This illustrates how quickly commercial launches can go in this space. It's important to remember as we move from Lucentis, which was a landmark product in its day at Genentech, moving to Eylea and then Vabysmo, these are really incremental improvements in durability of a couple of weeks in each case to a couple of months at the most. If you see just going from Eylea to Vabysmo, it's really a reduction in treatment burden of a little over 20%, and yet it's a massive blockbuster.
Imagine what we can do with a treatment burden injection reduction of 80-90%, which is what we're seeing in our phase II trials. Now, let's talk about primary unmet need. We think of this really as a backbone therapy. Patients will come in, get a short-acting VEGF to get under control, then get 4D-150, and now they're protected essentially for many years. In this age of the population of wet AMD, it'd essentially be the rest of their life. They are going to have treatment on board 24/7 and dramatically reduce their need for injections. Some patients may never get another injection in their life. Others may get one or two a year, but dramatically less than what they would have otherwise got. With a favorable safety profile, why wouldn't a patient elect to do that?
The other thing that's important is with the steady expression, we think we can solve this problem of the sawtooth retinal anatomy going up and down, which leads to vision loss over time. As you can see here, our model is this, and we've shown this in some of our phase I-II data, is that we really stabilize that CST. And that makes sense, right? The aflibercept's getting produced all day, every day, you're not going to have this sawtooth pattern, which leads to blindness. So we think in addition to a major transformative improvement in treatment, burden reduction and convenience for the patient could also over time lead to improved visual outcomes. Now, what's the data that we showed with 4D-150 to date? We've had a very broad, robust phase I-II program with this product, probably the most comprehensive ever done prior to a phase III.
As you see on the left, we started with the hardest to treat patients, patients who were getting on the order of 10 injections the preceding year. Very high need, average of four to five years of disease already with a lot of fibrosis, kind of the hardest to treat population. Nevertheless, in that population, we decreased injection burden by about 83% over the year following treatment. They went from 10 injections to less than two. We then moved into a broad population looking at both early and late-stage patients.
There we showed overall an 83% reduction, but when we moved into recently diagnosed patients, patients who were diagnosed in the last six months who had a healthy retina, did not have a lot of fibrosis or fluid pockets that would inhibit transduction in that retina where we could get the highest quality transduction with the asset, we saw over 90% treatment burden reduction. And about 80% of those patients or so at one year were injection-free. Okay, what about the safety? All this efficacy is nice, but you have to have safety in this large market indication as a gene therapy. What we are seeing is highly predictable tolerability. First of all, patients are on a transient eye drop regimen for corticosteroids, which patients are happy to trade for injections into their eye.
The vast majority of patients, over 95% of patients, get off their steroid taper on time and have little or no inflammation. In fact, our inflammation is only mild when we see it, and it's less than 3% of patients at any time point. That is very comparable to what you might see with a biologic like Eylea. Really best-in-class safety, which is highly differentiating. I think this plus the efficacy is why the enrollment in our trials goes so quickly. This is an interesting slide showing the inflammation or lack there of in DME. Each cell on these charts is a visit. Each row is a patient, and each column is a visit date. What you can see is these patients are followed over time. If there's no inflammation, it's green. If there's even trace inflammation, it would be light green.
You can see this is all dark green. No evidence of any inflammation in diabetic macular edema, which is felt to be the hardest to treat population with a gene therapy. We see fantastic safety and marked contrast to say what has been seen in some other AV populations in other AV therapies in DME. Now, let's talk about the clinical and commercial adoption. Chris will get into this later. From a payer standpoint, I think payers are going to like this because it is adherence by design. Patients do not need to keep coming back. Most patients fall off therapy over time. They get vision loss, complications, which cost money to the system, and patient quality of life decreases. Here, patients are getting continuously treated, which should lead to better vision outcomes, better socioeconomic benefits that can justify payers reimbursing this in a healthy way.
From a clinic standpoint, these clinics are very busy being able to reduce the overflow of patients by having less dosing, but still getting the economic benefit upfront with the buy-and-bill model. We think will be very attractive to physicians and will actually help them increase their revenue, not decrease it. Finally, the Forefront One and Two clinical trials are phase III trials here. This is the high-level design. It's a randomized two-arm study comparing 4D-150 to standard aflibercept dosing, looking at BCVA, non-inferiority as the primary endpoint, and also showing, we believe, a significant reduction in treatment burden on the 4D-150 arm. Patients get bolus therapy upfront to get the disease acutely under control. We treat with either standard aflibercept or 4D-150 and follow patients. The 4D-150 patients only get additional aflibercept if they need it. There are very strict criteria for that.
Importantly, the patients who come on this study are frontline patients, so healthy retina should be excellent transduction. Importantly, to get into the study, the patient has to show a significant response to the anti-VEGF aflibercept, meaning that we're only enrolling patients who will respond to 4D-150 as well. Supplemental injection criteria were very carefully designed by the best academic and industry experts in the retinal field to win both on BCVA, non-inferiority, and on treatment burden reduction. These are the timelines. You can see high-level data, 52-week primary endpoint data in the second half of 2027 with Forefront One and Forefront Two. Our cash takes us into 2028. We are funded already all the way out through the end of these trials. Given what we're seeing in terms of Enrollment and site opening, we actually hope to bring these timelines in.
Once we hit roughly 50% enrollment, we would expect to give updates on that, but we expect to be able to beat these timelines. Finally, 4D-150 is a major focus for the company. We have an opportunity in DME as well. 4D-710 is our product for cystic fibrosis lung disease. It's an inhaled product, great safety profile, great transduction of airways. We're hoping now to optimize the dose level in the patient population that would then allow us to go into phase III. We'll be giving an update on that program in the second half of the year. With that, I'll, I guess, invite you up to the podium and take it from there. Great.
Good to see you.
Thanks, David, for a great discussion. My name is Kelly Xu, one of the biotech analysts here. Maybe first a question just focused on the wet AMD program as you already entered pivotal phase. We see the current wet AMD treatment landscape continue to evolve with the idea about similar snows on the market, and based on your internal market research and our interactions with the ophthalmology community, how are ophthalmologists perceiving gene therapy in wet AMD at this moment? What are the key criteria they're looking for for gene therapy clinical trial in wet AMD? How did you design your trials to meet those criteria? I know you already touched upon it, but mostly we want to focus around the physician feedback.
Perfect.
Yeah, I can maybe start with that. And maybe David, you can add extra color commentary. But great question, Kelly, and thanks for the opportunity to be here. No doubt the anti-VEGF space is becoming more competitive and more cluttered. I think to your point, you see introductions of biosimilars and other new agents. Universally, though, all of the new introductions in this space are bolus therapeutics. The remaining need for both physicians and patients is durability and the reduction of treatment burden. Despite new introductions, Vabysmo, as David referenced, has been a significant commercial success for Roche. The treatment burden reduction and the need for greater durability continues to be the highest unmet need. We hear that both from patients and from physicians.
We believe our 4D-150 profile and our approach provides probably the greatest potential paradigm shift when it comes to a meaningful treatment burden reduction. Again, not measured in a couple of weeks, but measured in months, if not years, that could, we think, revolutionize the field and take a real shot at solving that treatment burden need. We do not think that is in the same realm of a biosimilar or many of the existing bolus therapeutics. Physician feedback, as we have started our phase III program, very much validates that. The interest has been significant from both physicians and from patients. The design of the trial, as David went through, is intended to show a treatment burden reduction relative to standard of care, which is Eylea today.
Great. Thanks for the insights, Chris. Do you hear a number from a physician survey? What percentage of the wet AMD patients could be suitable for a gene therapy?
I think any wet AMD patient that is responsive to anti-VEGF should be suitable for our gene therapy. We think that the portion of patients that are non-responders to anti-VEGF is probably pretty low, probably less than 5%. We think everyone should be a good candidate for a gene therapy that expresses a known agent, being aflibercept, that's known to be highly efficacious. Thus, our vision and our goal for 4D-150 is to be a potential backbone therapy. We do not think of it as a niche product. We think of it as a potential therapeutic that could set a new standard that honestly every patient could be considered for. For those patients that may need supplemental treatments, the good news is that the field has many supplemental bolus therapeutics that you could choose from for those patients when and if they need it.
We are designing this, and I think 4D-150 has a potential appeal for anyone that has demonstrated a VEGF response.
Great. You recently announced the first patient enrolled for your pivotal trial. Curious, what has been the study site's feedback, and how do you anticipate enrollment pace? Will treatment in naive patients be hesitant to take a gene therapy? Also, how do you need to compete with other programs, for example, like TKI companies?
Sure, I can start, and then Chris can weigh in. It is certainly a competitive space, as you say. We are highly differentiated because, again, our target product profile has massive transformative potential for this field in terms of many years of durability. We have seen phenomenal excitement and enrollment in terms of site openings and enrollment to date. We have also reported that on our prior phase II studies. I think that differentiation really helps with the enrollment. It is remarkable that with something like a gene therapy that we could be going into a frontline setting. I do not think anybody ever thought that was feasible. Yet here we are enrolling very well in a frontline setting, which I think is a testament to our safety and efficacy data to date that patients and physicians would want to make that bet.
Our Forefront One is entirely first-line untreated patients. Forefront Two does allow about a third to 40% of patients can be recently treated with, say, one to three prior injections, so not completely untreated, but still very early stage, great retinal health for transduction. We think we're really well positioned. Chris, anything to add?
I agree. The Enthusiasm, I think, from the sites that are part of our pivotal program has been incredibly high. It's too early to give specific updates on enrollment, but suffice it to say that what we're seeing in the early days has exceeded our expectations. We think that's ultimately going to be good evidence for what the demand is and the interest is in our profile. It's really as simple as this. If you're a physician talking to a patient about treatment options, and you can say, "Hey, you have a 50% chance of a therapeutic that could get you to three months of durability," or a 50% chance of a therapeutic that may get you to six months, or a greater than 50% chance of having multi-year durability, provided everything else being equal and safety is intact, then it's very clear, I think, what the preference would be.
We hear that from physicians when we survey them as to what they're most excited about in terms of innovation, and it is gene therapy. We think we see that in terms of patient interest and motivation for our clinical trials as well.
Great. The two-year data of 4D-150 from phase I to II and the 18-month data from phase IIB cohorts are expected in Q4 of this year. Maybe you could help us set some expectations on what investors should be looking for in the longer-term follow-up data.
Sure. I think there's great data from many different AV programs in the retina saying that we'll get high durability. There's no evidence of waning expression for Luxturna out to 10 years or Regenex with subretinal injection out to four years. I think we would expect to show that. Now, how you demonstrate durability, I think, is to really look at the treatment burden reduction per unit time and show that between 6 and 12 months, 12 to 18, 18 to 24, it's consistent that you're getting that consistent benefit throughout. We've already shared data on long-term expression data showing that that's stable. I think we'd expect to continue to show that benefit of anywhere from 80-95% treatment burden reduction depending on the population that we're looking at and continued excellent safety because that's absolutely critical, and that's something that we've uniquely been able to achieve with an interventional injection.
Great. On one of the slides, you touched upon payer coverage. It's still early days, but I'm curious your reimbursement strategy, payer strategy. Given this is a very large market opportunity for a large market for wet AMD, how should we think about the pricing point relative to the available therapies in the context of how much treatment reduction you have achieved from early phase data?
Yeah, it's a great question. I think a couple of comments. One, from a payer perspective, an important thing to understand is, at least for the wet AMD patient population, 90% of patients in that category are Medicare patients. The payer is going to be defined as being either Medicare fee-for-service or under a Medicare Advantage plan. Largely, a fairly good payer environment to be launching in. DME is similar, but you get more of a commercial payer profile within that patient population. As you alluded to, reimbursement and payer decision and coverage is a proxy for ultimately pricing. It's way too early to speculate as to what we think a price point would be. The thing that we're really confident about, though, is we have a cost of goods profile that we've said publicly is less than $1,000, maybe even less than $500.
We think that provides us with an incredible amount of flexibility. Once you get to that point in time you make decisions on pricing, it is multifactorial. Part of that decision-making is clearly your clinical benefit and the profile that you see in your phase III program, but also it is the environment that you are operating in. It is hard to anticipate what exactly the environment will look like in our launch window and several years from now. We believe with our relatively low cost of goods profile, we can be adaptable and be flexible based upon whatever that environment looks like. The last thing I would add is from a philosophy standpoint, when we say that we believe 4D Molecular Therapeutics could be a backbone therapy, that means it is a therapy that should be available and accessible to all patients.
Our pricing philosophy, I think, would be designed to support that broad access profile.
Fantastic. Maybe on DME, diabetic macular edema. You also recently received the RMAT designation for 4D-150. Can you talk about how the RMAT designation could facilitate the regulatory paths in both indications?
I think, so first of all, to our knowledge, we're the only biologics that's achieved this. RMAT, which is essentially Biologics Breakthrough Designation for both wet AMD and DME with the U.S. FDA, and then also PRIME designation in Europe for wet AMD, and we helped to get DME as well there. I think it's just a vote of confidence in the data we've shown to date and the transformative potential that FDA and EMA are recognizing by giving us that designation. It's really, I think, an incredible endorsement of what they're seeing in our data and the potential for patients. I think in the long run, the idea is that we should be getting more frequent, efficient interactions as needed with both regulatory bodies. Over time, we think it could translate into a more streamlined review process. Anything to add to that, Chris?
Okay. Also, for the 50-week data update from Spectra in Q3 of this year, what should we expect?
Yeah, so that would be 12-month data. We've reported out 36-week or roughly 9-month data there already. We'd be updating that safety profile. Again, it's really a very stellar, important safety profile for DME, which puts us really all alone as an interventional therapy, gene therapy there. We'll update the efficacy data. These patients are relatively advanced, and we also have very strict rescue criteria there. Probably underestimates the treatment burden reduction we're going to see in a phase III. Nevertheless, very promising data there. More on both of those endpoints out at 12 months.
Great. You have received FDA alignment with using a single phase III trial as the basis for BLA submission for DME. Curious, can you also elaborate on what are the key trial design elements that you aligned with FDA and what are the final items you need to finalize with the regulatory agency?
Yeah, so first of all, I mean, the fact that FDA has said we don't need two large randomized trials for a large market like DME is remarkable. It's remarkable for any therapy, but let alone for a gene therapy. Again, nobody thought a few years ago that would be possible that our phase III would be in frontline patients in wet AMD, that we would have RMAT for both indications, and that we'd be looking at a single trial to get an approval in a huge market with blockbuster potential in DME. I think that's the first and foremost thing. What we did align with them on is the sample size of being a little bit over between 300 and 350 patients roughly. We aligned on the primary endpoint of BCVA, non-inferiority, the patient population, high-level supplemental injection criteria, similar to what we have with wet AMD.
Details remain to be worked out, but the high-level portions of those studies were well aligned with FDA, and we now believe with EMA as well.
How do you think about the funding path for the DME trial? Do you consider any partnership for this indication?
Yeah, so I think just to level set on funding. We have, as of March quarter ending, $458 million. That takes us on our wet AMD programs all the way to data readout and beyond. Now, DME is currently unfunded, and we've always maintained that there are two alternative paths for funding that we are evaluating. One is non-equity alternative financing. We're talking to several sort of debt providers because currently we have none, as well as partnerships which are geographically focused, which is very encouraging because there is a lot of interest in the programs, both on wet AMD and DME. We are looking to do those ex-U.S. partnerships, and that should be probably the best source of funding for DME. As soon as we have updates on that, we will inform as well as commence the phase III for DME.
Great. For cystic fibrosis program, where you are right now? In the past, you have talked about reducing strategy. Maybe what's the next step and when?
Yeah, so we're actually really excited about the 4D-710 program, simple aerosol delivery. We know based on some of our preclinical data and preclinical data from a number of other groups that repeat dosing with aerosol delivery should be feasible. We expect the durability should be measured in years, not months. We would envision a redosing regimen on the order of every year and a half to three years, somewhere in there, which is a great opportunity because it means that this is an ongoing market. It's a sustainable market for us. It's not just treat patients once and then never come back. It's good for patients. It's good for us. We spent the last year and a half, two years getting the dose level right. We actually saw our first dose level.
We realized in retrospect based on biopsy data that we were Overexpressing, getting too much gene expression. Again, in terms of gene therapy, we help people think about the field. Nobody ever thought it would be possible to get expression in the lungs of a CF patient, let alone Overexpress. We achieved that. We have now marched the dose down, and very careful assessment of biopsies are now in more of a physiologic range. We expect to report out in these kind of nine patients at these lower doses. We will report out in the second half of the year data on FEV1, lung clearance index, which is a very precise measurement for looking at smaller airways, which is very important, and then quality of life measures. We now think we are in the right dose range, the right patient population.
We'll lock down that effect size, and then we're having discussions with FDA shortly about phase III designs.
Maybe lastly, what are the Clinical Data Catalysts and the milestones in the next 12 to 18 months?
Yeah, it's great.
Yeah.
Yeah, certainly we have data coming out on DME next quarter, which we expect to confirm the activity and safety. Longer-term durability in wet AMD, I don't think there's going to be any surprises there. We know how the biology works there. It should be durable. We do expect to give enrollment updates on the phase III enrollment and site openings, and that would be right now, it's not formal guidance, but we expect maybe after 50% of the patients are enrolled, we might give an update. We could update our guidance on time to 52-week data, primary data readout, and then give an update on kind of our cash runway past data. Of course, the second half of the year, we'll be having data on 4D-710 and regulatory update on phase III for that.
We'd expect to do that alongside the Cystic Fibrosis Foundation, so that'd be another Catalyst as their continued support. Anything I missed, Jannie?
No, I think the only other would be potential partnerships/funding arrangements as and when they happen.
Fantastic. We'll wrap up our session here, and thanks everyone for joining us, and thanks for the team.