Good afternoon, everyone. Thank you for attending the Jefferies Healthcare Conference. My name is Clara Dunn from Biotech Research. We are very pleased to have Uneek Mehra, Chief Financial Officer, and Dhaval Desai, Chief Development Officer from 4D Molecular Therapeutics, to join us today. Very welcome. So, Uneek, I believe you have some slides to run through first. Why don't you go ahead, and we will have some Q&A after.
All right. Thanks, Clara. Good afternoon, everyone. We have a few slides. Is there a clicker? Yeah. Give me the clicker. So the standard forward-looking statements, any risks are there in our 10-Q. 4D Molecular Therapeutics, it's a leading next-generation AAV company. As you can see here, we have a proven platform. It's built on a directed evolution platform, which is a Nobel Prize-winning technology. Modular in nature, we design our own vectors, we design our own payloads. Clinical stage in four therapeutic areas: the eye, the lungs, the heart, as well as we have an early-stage program for the neurology side. Three different routes of administration. So intravitreal for the eye, aerosol for the lungs, and then intravenous for the heart. Our lead program is 4D-150, which is in wet AMD. We've got strong data that we've presented throughout 2024, and we'll keep updating that in 2025.
We'll get to that in the later part of the slides. 4D-710 and 4D-310 are our sort of rare disease programs, one in cystic fibrosis and the other in Fabry disease. And then we have now started to build and scale up into late-stage capabilities on the retinal side on 4D-150, which I said is our most advanced program. Give a very quick look at our retinal team. I mean, this is a space that is right now dominated by the big pharma companies. You have Regeneron, you have Genentech. We are getting there with our team now. Across our team, the four people that you see here, between Bob, Dhaval is right now here, he'll address on the data, Chris, as well as Carlos. I think between the team that you see, six approvals, five launches. So we know the space pretty well.
We understand what it takes to get a product developed and commercialized in the space. Pretty excited with that. Most of the Wet AMD drugs that you can see are listed out here. So you can see the broad sort of experience that the team has. Quick framing of the opportunity here is when you look at genetic medicine, you will see what are the typical barriers for a conventional genetic medicine. Right now, I think as soon as you talk about gene therapy, genetic medicine, people associate it with a rare disease sort of a population. So low epidemiology, low prevalence. It's a complex route of administration. Even the pathway for approval needs to be a lot more creative because it's not really well established. Cases in mind, take a look at bluebird bio, take a look at BioMarin for the small population of data that is there.
It's also associated. People look at that and say, okay, will you be able to commercialize? Because typically very high manufacturing costs from a CMC perspective, as well as the prices that you see right now for gene therapies are in hundreds of thousands of dollars, if not in millions. So where do we stack up against that? The 4D-150 program, it's targeted for a high prevalence, large market opportunity. The product we have designed, and we'll walk you through that, is an intravitreal, which is what current retinal physicians use all the time. So it's a very standard route. We have alignment with the FDA in the U.S. and with EMA in Europe. We've got the RMAT designation and the PRIME designation, which means our regulatory path is pretty clear, unlike a lot of other sort of gene therapy products that are being developed.
Interesting thing that I'd like to point to here is our cost of goods of manufacturing, given our CMC and our in-house manufacturing, is less than $500 per dose. So that gives us tremendous flexibility to do highly competitive pricing, which basically means we are completely changing the paradigm of how the gene therapy is really perceived in the market. So with that backdrop, I'm going to transition it to some clinical data, and we'll wrap up for Q&A. So I'll hand it over to Dhaval.
Thanks, Uneek.
So our technology is based on two concepts. The first is the viral capsid that we're using. So this is a modified AAV2. And we used a process called directed evolution to create a capsid that really was optimized to do three things. The first is minimize the immune response. The second was the ability to selectively transduce retinal cells. And the third was the ability to do that at a low dose administered via an intravitreal injection. We think some of the results that I'm about to show you are a result of succeeding in finding that capsid, which is R100. When combined with the therapeutic payload, it creates our lead therapeutic asset called 4D-150. And once administered and transduced into retinal cells, unlike any other gene therapy out there for retinal disease, it produces two transgenes.
The first is a transgene that we all know and love in the retinal space, and that's an aflibercept. The second is a VEGF-C silencing mRNA. The program was called a PRISM, and it was done in three parts. The first two parts, the phase I and IIA, were done in the most severe patient populations, and we're mainly looking to figure out what does the safety and efficacy profile look like, as well as determine doses for moving into the next phase of study. In the phase IIB, the population extension, once we had an efficacy and safety profile, we enrolled closer to more naive patients, patients that were less heavily pretreated, that had shorter durations of disease, and in a subpopulation of that is these really recently diagnosed within six months that had seen as little as one anti-VEGF injection prior to enrollment into study.
What did we see? In the phase I, IIA, the most severe of the patient populations treated in wet AMD till this day, roughly 10 injections in the 12 months prior to entering study. What you see in the OCT and the BCVA is sustained disease control equivalent to an aflibercept given every eight weeks in the yellow line. The solid blue line is 4D-150 given at the 3E10 dose. You see stable anatomy, stable visual acuity. Interestingly, we were able to achieve this with 44% of patients not needing a single supplemental injection in the 52 weeks following 4D-150. To put that into context, Vabysmo, which is the current market leader from Roche, did $4 billion in sales this year, gets 45% of patients to every 16-week dosing.
When you move into the broader population, closer to their time of diagnosis, roughly 50% of these patients were within six months of their diagnosis of wet AMD. What you see is that the control gets a lot tighter, the line is almost flat, and you start seeing patients gain visual acuity as you would expect them to. Interestingly, you get that result with even more patients being able to do that without needing a supplemental injection. In this case, 70% of patients did not need a supplemental injection over the course of 52 weeks. It's Kaplan-Meier estimate because we have complete follow-up to week 32. Full 52-week data will be presented in the Q1 of next year.
And then a subset of this population looking at just those patients that were enrolled within six months of their diagnosis, roughly two-thirds of them had only seen one prior anti-VEGF injection. You see that control get even tighter and even more visual acuity now in the four- to five-letter range, and more patients being able to achieve that without needing a single supplemental injection in the follow-up period. We know that none of that happens without safety, which has been the bogey in the gene therapy field. This is where we believe some of that engineering of the capsid shows up. No 4D-150-related serious adverse events. The IOI rates that we see look comparable to the monoclonal antibodies that are the current standard of care in wet AMD.
Most importantly, none of the things that keep people up at night in the retina community and that we've seen with some of the recently approved drugs, things like hypotony, vasculitis, endophthalmitis, choroidal effusions, et cetera. Importantly, in the DME population where we've seen other gene therapy programs really run into trouble, of the 22 patients that we've treated to date, we have not seen any IOI events. That takes us to what's next, and we're excited to announce that in the Q1 of next year, we'll be enrolling patients in our first of two phase III programs called the 4FRONT-1 program. In this trial, 500 patients will be randomized one-to-one to receive either 4D-150 at the 3E10 dose or Aflibercept given every eight weeks. Both groups will get three loading doses of a Aflibercept.
Thereafter, the 4D-150 arm will get sham, and the Aflibercept arm will get an Aflibercept every eight weeks, with sham given in between the visits where you don't get an injection. And so why do we think this trial is set up to win and de-risk? First and foremost, you have to understand response in anti-VEGF in wet AMD. These are the CST curves for the most recently approved anti-VEGF agents. And what I point out to you is that all of the benefit that you see in the anatomy happens after the first three injections. Every injection that happens thereafter is meant to maintain that benefit that you've seen. And the same is true for visual acuity. After the three injections, by the time you hit week 52, the difference between those is less than a letter.
Every injection that a patient receives after the third load is meant to hold a patient at that level. I mentioned to you already that both arms will be getting three loading doses. What we're asking 4D-150 to do is what it has already shown that it can do in the phase IIB. In the phase III, we'll be moving to a treatment-naive patient population, which is even tighter control. We believe that at the end of 52 weeks, we'll be able to show non-inferiority to an Aflibercept dose every two weeks with a significant reduction in the treatment burden. Uneek?
Yeah, I think that sets us up. I'm going to just come here so I can talk a little here. That sets us up. Look at the profile here. This is what we call as the trifecta: safety, very strong so far, efficacy, durability, and then a mode of administration that physicians currently are used to just intravitreal in the office, in and out. So our value proposition to the patients is pretty clear now as the profile is developing in terms of significant reduction, in terms of their getting injected in the eye every time they come to the office. For the retina specialists, we believe this will fit their current workflow and their practice. It's still a buy-and-build model under Medicare Part B. Most of these patients, remember, are very senior, 75 plus under Medicare Part B.
It will also free up their practice capacity for other retinal diseases like geographic atrophy. Then finally, payers, we will, when Dhaval presented the data, 80%-85% reduction in annualized injections. That should fit into their overall savings from a population health basis, both in terms of drug and the visits. And we believe that this strong value proposition sets us up to win commercially across all the stakeholders. Our final slide is basically to just give a perspective on the upcoming near-term milestones. The green checkmarks are the data points that we've already announced in the earlier part of 2024. We have a 52-week landmark on our population extension, the broad set of patients in February coming up. And then we have updates to our other programs coming up in early 2025. More importantly, our phase III starts in Q1 2025.
Strong cash balance, $551 million as of at the end of last quarter. So we believe we have the runway that we need to be able to get these trials into motion and beyond. And with that, I think we'll end our presentation and back to you, Clara. I think we'll stay here so we can just answer questions.
Great. Thanks for the great presentation. So let's start with Wet AMD. So now that you're heading into the first pivotal trial in Wet AMD, so could you walk us through the rationale for the phase III trial design you just briefly touched upon? And could you also talk about in what ways have you really de-risked the trial?
To the slide for the same question.
Yeah. So the rationale for the phase III design is pretty simple. So the first thing that you start with is any new agent that's been approved in Wet AMD has done so in a treatment-naive patient population, with the exception of Roche's Port Delivery System, which is a surgical implant. Those were previously treated patients. The second is that the primary endpoint set by the FDA, the non-inferiority margin for visual acuity, was set on a treatment-naive patient population. So moving to a treatment-experienced population introduces a variability that we really don't know kind of how to maintain. And the third part is that we know what this patient population is going to do. We know that at the end of 52 weeks, they gain roughly six to eight letters.
We know that at the end of 52 weeks, the CST, the central subfield thickness, goes down by about 140-160 microns, and as I mentioned to you already, we know that after the first three injections, most of that benefit has been derived and that we are asking 4D-150 to do exactly what it has already shown us in a more severe patient population. We expect it to repeat the same, if not better, in the phase III trial.
Great. And then could you remind us, why did you decide on treatment-naive patients? And how should we think about the enrollment pace for the first pivotal trial once it's initiated? And how should we think about the enrollment when, whether it's competing for patients with Wet AMD treatment in different modalities such as TKI?
Yeah. So we talked a little bit about why treatment-naive, right? And so that's there. I think the second part in terms of enrollment, I was the Chief Development Officer at Iveric Bio prior to this, and we've got that GA trial enrolled in 11 months. We believe that we'll get this somewhere in the neighborhood of 12 to 15 months, depending upon a number of different factors. And our hope is to beat even that estimate. And the way we think about enrollment versus TKIs or anything else that's out there is that we know that there's a number of different studies out there that are competing, some of them taking only treatment-naive, some of them taking a mix of naive and experienced. And so as we roll into that study, we will be the only trial, from my understanding, that will take treatment-naive only.
And so our ask of all of our clinical sites is going to be, give us your naïves first and let those treatment experiences go to all the other studies that are accepting them. We believe that our track record of getting trials enrolled like GATHER2, like TENAYA and LUCERNE, like Archway will help us here in getting this thing done within that 12- to 15-month timeframe, if not earlier.
And the only thing I'll add to what Dhaval said is our own personal experience in terms of our phase III studies, phase I, phase II. All of the 4DMT wet AMD trials have enrolled faster than scheduled. So we see tremendous enthusiasm from clinical sites thus far, and we hope that continues also into our phase three program.
Terrific. And then how should we think about the second pivotal trial for Wet AMD? When should we expect to get some more details on the second pivotal trial and what will it look like? And will it also enroll patient-naive patients?
Yeah. So ideally, your global registration program has two identical studies. And that's the plan here. 4FRONT-2 will look identical to Forefront One. That is pending just some final EMA feedback. But at the end of the day, our aim is to have both trials be identical.
Terrific. So maybe let's move on to DME. You will announce initial data in DME in early January. Could you help us set some expectation on what should we expect for the data?
So I mean, I think our update that we've just given with our Q release right now is that we will provide the clarity on the DME SPECTRA program in early January. Details as to what all that will include, that will come about in January. So stay tuned for that.
Gotcha. So you've already shared some safety data in the first 22 patients from the Spectra trial. And it so far looks very clean. So what's your confidence that the safety profile will hold in long term?
Yeah. So I'll take it. I mean, I think we feel very strongly about where we are in terms of safety. In fact, we believe that of all the gene therapy products out there, we're differentiated on our safety profile being what we think is best in class. And I think it goes back to all of the work that we did originally on the capsid and making sure that it does exactly what we designed it to do.
Yeah. I think when you look at that, and we didn't have time to go through our directed evolution platform, but it's a competitive screening out of the target. We start with a target vector profile in the eye for the target tissue.
By the fact that our R100 vector came out of that process, I think it's testament to the fact that that's what we are now seeing both in the safety and efficacy at such a low dose.
Great. And then for cystic fibrosis, what do you plan to present in mid-2025? And could you help us set some expectation for the data disclosure next year?
Yeah, sure. I think our cystic fibrosis program, it's relatively earlier stage than our wet AMD and the retinal programs. The goal there is we are seeing excellent gene expression in the lungs through aerosol version. So the first time we are actually dose de-escalating because we want to understand the full profile across the various doses. So what you should expect to hear in the middle of next year is an update on how we have enrolled the lower doses and what we are seeing. The main objective is to establish the strong gene expression that we are seeing with functional benefit like an FEV1. And so once we have that, that should be part of an update in the middle of next year.
Terrific. And lastly, how should we think about the BD opportunity and partnership strategy for 4D?
Yeah. I mean, we are blessed that we have many exciting programs. There are, of course, a company of our size with the resources that we have. We can probably prioritize a few of those largely the large market opportunities in wet AMD and DME. The other programs are up for partnership, but at the right terms, at the right time. Even on the ophthalmology programs, we believe we have an opportunity outside of the U.S., and we will try to find the right partner. So partnership is always important to us, given the number of programs we have. And stay tuned for that as we provide more updates.
Fantastic. Thank you for the informative session, and I will wrap up here. Thank you, everyone.
Thank you, everyone, for listening to us.