Welcome, everybody, this afternoon. We've got 4D Molecular Therapeutics team with us. Uneek and Dhaval, thank you so much for joining me.
Thanks.
I appreciate you taking the time to come down to Miami and talk to us.
Thank you for having us here.
Excellent. Well, let's get started with a brief intro. Obviously, it's been a very exciting year for you guys. Lots of data this year and big updates coming relatively soon in 2025. So just maybe take a couple of minutes and set the stage here. What should we be looking forward to as we enter the new year?
Sure. Good afternoon, everyone. I'm Uneek Mehra, Chief Financial and Business Officer. So 4D Molecular Therapeutics, it's a next-generation platform and a clinical stage company focused on delivering vectors, very targeted, customized vectors that are modular to the target tissues. We have three of them in the clinic. The one, which is our lead product, is an intravitreal vector that targets the eye. We have an aerosolized vector that targets the lung. And then we have an intravitreal vector that targets the heart for Fabry disease. Our lead program, as John was referring to, we've had a number of exciting data releases this year, is focused on wet AMD right now as the first indication for our 4D-150 product, which is basically an intravitreal vector targeted for the back of the eye. There are other indications that will likely follow DME, DR that are behind the wet AMD.
It's our most advanced product. Our lung portfolio comprises of our 4D-710 vector that is targeted, as I said, an aerosolized vector for cystic fibrosis. We also have a preclinical program on alpha-1 antitrypsin. And then our 4D-310 vector for the heart. We are based in Emeryville in the Bay Area. And in terms of capabilities, 4D Molecular Therapeutics really has an end-to-end platform. It's based on directed evolution, which basically tests competitively the vectors in non-human primates. We have our own proprietary set of a billion capsids to choose from as a starting base. And then we have CMC to back that up end-to-end, all in-house. So combining that, that gives us a good proprietary advantage, which results in our lead program, which is now for wet AMD advancing rapidly Phase III, commencing the first Phase program begins in Q1 2025.
So John, to answer your question, that's just the baseline for 4D Molecular Therapeutics. Number of exciting updates coming up. We've released on wet AMD in February this year our data on very advanced patient population. We call it as a severe disease patient population. Dhaval can give you or contextualize that better for you. We also released in July this year broad patient population data, so which patients who are relatively lower need in terms of their treatment needs. And then, yeah, we have 52-week data coming up in February next year on that population, while we've already presented 52-week on the severe patient population.
Yeah, so lots to be excited about. Let's start with that wet AMD data that you just talked about. Obviously, Phase 2 data that you've already presented in both the more severe and broader patient population pretty clearly demonstrated a reduction in injection burden. But there's been plenty of debate in the market about that data. And a key concern there is durability. At the R&D day in September, we did see several patients getting, in the more severe patient cohort we're talking about here, getting their first rescue injection really quite late after 52 weeks even. Does this suggest loss of effect for the gene therapy over time? And maybe at what point should we expect to see stabilization in rescue need for these patients if the gene therapy is durable?
Yeah, Dhaval, you want to?
Yeah, I'm happy to take it, John. Thanks for the question. I think to just directly answer your question, we don't believe that this is a loss of effect that we're seeing. In fact, what we think this is due to is just the variable nature of wet AMD. And there's a couple of lines of evidence that kind of point to this. But before I do that, I just want to remind the audience about the population that we're really talking about here. And there's a tendency to kind of cross-compare a bunch of these studies and to understand this population. This is a high-need, recalcitrant disease patient population. In fact, it is the toughest to treat patient population we've ever seen in the history of wet AMD studies.
To give you a sense of that, in the year prior to entering the trial, these patients got 10 injections over 12 months. Despite all of these injections, they still came in with retinal thicknesses that were 120 microns greater than what we consider normal. Now, if you compare and contrast this to, for example, other gene therapies that are in development, that's 60 microns thicker than other gene therapy programs. It's 150 microns thicker than the baseline values of the TKI programs. These are literally the hardest to treat patients that we've ever seen in AMD.
With that said, the first reason we don't believe that this is a loss of effect is that we now have patients that are out two and a half years that have not needed a supplemental injection, showing a clear benefit in control of anatomy, control of visual acuity without a loss of any sort of therapeutic effect. The second concept is there's this notion out there that the need for a supplemental injection is the lead indicator for loss of effect. If you go back and look at that same cohort that we talked about, there are patients that got an injection early and then didn't need one for the rest of the study. In addition, there's patients that got it and then went a period of over eight months without needing a supplemental injection, and I tie it back to what I said in the beginning.
These were patients that when they came in the door needed, on average, 10 injections in the 12 months prior.
I 'm glad you brought up some of those patient-by-patient values, Dhaval, because when I look at that more severe patient population from the September update, one of the things that stood out to several people that I heard nervous complaints about were a handful of patients. Again, you say a handful of patients get a rescue injection early, don't need follow-up. There are a handful of patients that go quite a long time without needing rescue. But then after they get rescued for the first time, thereafter start to get a lot more shots, some of them even returning to what looked like baseline frequency of injection. So what's going on with those patients?
What's differentiating those patients who have increasing needs over time from patients who don't have increasing needs over time?
Yeah, and let's just be clear, like the number of patients that actually frequently.
We're talking about a couple, like two or three.
Yeah, categories are very, very small, right? So the way we kind of look at the whole group of patients, there are patients that clearly have just too high of a need that 4D-150 is not going to solve. And those patients declare themselves early. You can see it, and they're at the bottom of it, and they just need an injection right after, and they continue to need it. We've seen these patients in clinic, right? So there are patients that are currently that live in our clinics that are on Eylea two milligrams every 12 weeks. And there are patients that live on Eylea every two weeks. These tend to be those ones that are the higher need.
What we think is what we're seeing in these patients that kind of get one and then need a couple of others is 4D-150 had developed levels where they were holding them for the initial period, but that's not enough to hold them the rest of the way. So it's not like we're seeing a diminution of the effect. It's just it was good enough to cover them for that initial window in the load, but maybe not so much thereafter. We can't tell that difference from just a flare of disease, for example. Patients will have, for example, in the real world, if they're on Q12 week therapy, have a breakthrough bleed, need to kind of be brought back under control, and then go back on whatever their regular schedule is. So with this small of patients, I think it's impossible to tell.
We'll wait till the Phase III to really kind of say, like, all right, what does that look like, and just one last piece on the loss of effect. There's no evidence that has shown us in gene therapies to date that there is a diminution of effect. For example, both Adverum and REGENXBIO have shown data out now to four years.
Intraocular.
Yeah, intraocular, correct. And Luxterna most recently, at last ASRS, presented data from nine years out without a diminution in effect. So those three things, we don't believe that this is a loss of effect, just basically the variability of AMD, and especially in this patient population.
Makes sense. The other major concern that the market seemed to have, and the other metric that people seem very focused on, is injection freedom as opposed to just reduction in injection burden. Now, in that more severe patient population in that September update, you dropped below 50% injection freedom rates by 12 months in those patients. So when you speak to docs, when you do market research with patients, how important is injection freedom, full injection freedom relative to a reduction in injection burden?
Yeah.
Is there a key threshold there?
Yeah, it's a great question. And just what I'll tell you is that those results that we just talked about, especially in that population, 44% being injection free, showing a reduction, a mean reduction of 80% in the treatment burden, we believe that's a tremendous result. And every piece of feedback that we've gotten from clinicians as part of our discussions during the ramp-up for Phase III program has validated that. No other compound has generated that sort of data. And to just put it in a frame of reference, Vabysmo now, which is the market leader, just reported two-year sales of north of $4 billion, achieved that by getting 45% of patients, much easier patients, just to Q16 week dosing. And so we do think that it is a very, very robust result. Now, in terms of that injection free, we know it is important.
But we don't think there is a line in the sand that clinicians are going to draw to say whether we're going to use this or not. Based again on the feedback that we've received, we believe that injection burden reduction is one of the most important outcomes that we're looking at because clinicians understand that this is a lifelong disease that is highly variable. And what we're solving for, the big problem, is that loss of vision that happens early because patients just drop off of therapy. Up to 40% are not even getting treatment in year two.
What about payers? What is the impact of injection freedom relative to injection burden reduction from a pricing and reimbursement perspective?
Yeah, we haven't heard anything. I think there is definitely a desire to get annualized reductions as low as possible because that's what impacts pricing and the payer reimbursement. But I think at least in the preliminary research, it hasn't come out as it has been more with the investor community, the fixation on injection freedom, so to speak.
Just one other point on that is that all of that information is based upon whatever Phase III trial will read out. I will also point out to you that as you move to a broader population and a more recently diagnosed population, as will be the case Phase III, that proportion of patients that are injection free goes up.
Wants to be immediately higher.
Yeah, well, let's talk about that Phase III design then. The design that you've proposed to me seems highly likely to succeed, at least on the primary endpoint, BCVA non-inferiority. The comp arm is ineligible for rescue, for instance, while the gene therapy arm is. But is success on that non-inferiority endpoint sufficient to drive commercialization, certainly for approval? But does that alone give you confidence in the commercial landscape?
So again, just to directly answer your question, yes, we do believe that it is sufficient to drive commercialization. And you have to point no further than the example I just gave you. So Vabysmo, which is now in its second year of launch doing north of $4 billion, was approved on a non-inferiority endpoint compared to every eight-week Eylea. That is the same comparator arm that we're using in the forefront programs. In terms of kind of the other points, let me just kind of tackle them piece by piece. So this concept of the rescue arm needing not getting, not being eligible for injections. In terms of the primary endpoint in non-inferiority and visual acuity, whether you get Q4 week Eylea or Q8 week Eylea, it has never made an impact in terms of improved visual acuity outcomes.
So in terms of the primary endpoint, whether you get every four week or every eight week eligible for rescue or not, it hasn't mattered, right? You just go back to the registrational program.
Dhaval, is that even true in those patients who, in that subset of patients who end up being the much more severe patients who have CST thickness that is not adequately dried by Q8 week Eylea?
It may be true. And remember, in that Phase I and Phase II , we did allow for rescues, right? And we still were equivalent to Eylea. In the treatment naive population, we've never seen that. So what we're seeing in the, what we're testing in Phase III, we've never seen dose intensity make a difference. And for those of you that are curious and want to look it up, the VIEW 1, VIEW 2 trials are what Eylea was approved on. And there was no difference in visual acuity in the Q4 week dosing versus the Q8 week dosing. In fact, that fixed dose regimen, any of the ongoing trials that are allowing for supplemental and are powered for visual acuity are really just doing it to game the system.
The more supplemental injections that the control arm gets, the higher the likelihood of them being able to show a treatment burden reduction because in terms of visual acuity, it has never mattered.
Interesting. All right. You also haven't yet specified the criteria for VEGF responsiveness, which is a criteria for randomization. Is it reasonable to assume that the vast majority of patients are going to make that cut given what we know from the VEGF trials?
Yeah, for sure. I mean, as you know, our team has kind of been involved with north of eight approvals in AMD and diabetic eye disease with all of the major anti-VEGF agents besides Eylea. And what we can tell you is the response criteria that we've put in place leverages all of that experience and basically allows for a rapid enrollment rate into the trial. So we don't believe we're going to be losing a lot of patients based on that response criteria.
Is it possible for the majority of patients after two loading doses, you see the bulk of the benefit you're ever going to see on BCVA, the bulk of the benefit you're ever going to see on thickness for a normally responsive patient? Is it fair to say that after two shots, the baseline for the trial, you might not know whether a patient is going to fall into a more or less severe category relative to where the Phase I and Phase II data was?
Yeah, I think that's reasonable to say if we didn't employ the response criteria that we're employing. I think based upon the response criteria that we've put into place, we'll have a good understanding of what type of responders these patients are.
Okay, fair enough. You've also not specified criteria for rescue injection, though you have mentioned that you're trying to balance the need for BCVA maintenance for the non-inferiority endpoint and a desire to minimize the supplemental injections. How should we think about where that balance is set in the Phase IIIs relative to where you were setting rescue injection criteria for the Phase 2s?
Yeah, I mean, so again, having kind of leveraged the drug development expertise of our entire team, first and foremost, the trial is set up to win on the primary endpoint. Without that, you have nothing. And then secondarily, we've optimized that secondary outcome of treatment burden reduction because we know that is a clinically relevant outcome that clinicians are going to care about. Part of the reason for going into treatment naive patients is that you can almost set your watch by what they're going to do at the end of the year, right? Roughly six to eight letters. And that doesn't matter what agent you treat them with or what interval you treat them with. Every wet AMD study that has been in Phase III setting in treatment naive population has shown us roughly that number and the reduction of about 130-160 microns.
Based upon where we're at, we're fairly confident we're going to get that non-inferiority margin. Based on that rescue criteria that we've kind of leveraged, not only our internal experience, but Phase III programs that are using different criteria, that we're going to have a robust reduction in treatment burden.
I would love to keep torturing you on wet AMD, but I'm acknowledging that we have a limited amount of time. So I would like to be able to talk at least a little bit about some of those other programs that you mentioned. Obviously, a lot of irons in the fire there. So let's start with CF, where we've seen a reasonable amount of early data already. Obviously, that program is still developing, but clearly shows strong CFTR delivery, strong enough that you've even stepped down dosing. Are there concerns with super physiological CFTR expression, concerns with broader tissue expression than native CFTR that drove you to do that?
No, we don't think so. I mean, I think this is what we've seen is we went from the one E15 dose to two E15, saw super physiological levels of transgene expression. I think as part of good drug development, we want to make sure that we are answering the question, what does normal look like? This is again an unexplored or uncharted territory in terms of the science that we are developing. So our desire is, and we've implemented that to go down a couple of doses lower to just understand how that translates to expression and more importantly, to functional benefits like FEV1.
Let's talk about FEV1. The benefit there is a little bit tough to see at this point. Obviously, these patients so far have high baseline FEV1. There's only a few patients available on the endpoint, et cetera. What should we be expecting to see in further updates as we get more patients into those go forward dose cohorts?
Yeah, I think our original, given that the safety was not yet established, we enrolled patients with higher FEV1. Now, I think our desire is to enroll patients going forward with lower FEV1 so that we can try to make it more clear the impact of FEV1. I think when you talk to CF Foundation, you want to see a 5%-7% improvement in FEV1, and I think that's our goal now with this new additional patients.
Which obviously you can't see unless you've got patients with a baseline.
Baseline, which are lower.
Yeah. The other endpoint that you wanted to talk about a lot, I guess it was this year when we saw the updated data there, are those patient-reported outcomes, those PRO endpoints, which the CF Foundation likes to see, but so far have not been regulatory endpoints at all. So what are your current thoughts about the inclusion of PRO endpoints for the regulators and how that might influence trial design going into?
So I think our discussions, both with the CF Foundation and the regulators, it highlights it will be a totality of data, which will be the quality of life parameters. There are other metrics like the lung clearance index that are being talked about. And then how that ultimately, though, John, I think they need to correlate with FEV1 at some stage. So I think once we get that data, there's also a second biopsy that we are implementing now as with the amendment. I think as the data matures and we will have an update in the middle of next year, that totality should tell us the true picture.
Yeah. Also, last one on CF, maybe the modulator combo strategy was something that has been on the table, has been something that you've been thinking about for quite some time. There was a guidance to have a modulator combo cohort starting second half of this year. What's your current thinking on that population, on the currently modulator eligible population, subpopulations there that you think are relevant?
I think we are still excited with that. We have pre-clinical data which shows synergy in that population with the combination with an agent. I think the question comes to portfolio prioritization. We clearly have a lot on our plate. So this will be more a question of, and we will provide an update in terms of how we prioritize, but our excitement on that combination still continues.
Last question as we move into the passing period here. Speaking of portfolio prioritization, obviously there's a big update that you just guided to coming in the beginning of January. Lots of programs that have been waiting in the wings a little bit here while wet AMD and also CF to a certain extent develop. Fair to expect the focus to continue to be on those lead programs? Where else should we be most acutely excited about coming into that January update?
Yeah, in the January update, we'll provide clear portfolio prioritization. I mean, of course, wet AMD, DME, these are our lead programs. We want to stretch our cash runway as much as possible on these programs. But the excitement on the other programs, be it with partnerships or whether we sort of think of innovative structures around that, we will provide an update on that as well.
We look forward to hearing a lot more on the BD potential and where you intend to go next.
Lots to think about, but we are blessed with the platform we have and the number of programs.
Sadly, we are more than out of time.