Good morning, everyone. Welcome to Barclays Global Healthcare Conference. My name is Gena Wang, I cover U.S. Specialty Biotech. It's my great pleasure to introduce our next presenting company, 4D Molecular Therapeutics. With us today, we have David Kirn, Chief Executive Officer and Chairman, and also we have Uneek Mehra, Chief Financial and Business Officer. So Dave, do you want to give a brief intro first?
Absolutely.
And then we dive into the questions?
Yeah. Well, thanks for having us. It's a pleasure to be here. We'll just start with a few slides to get us started. At 4D, we're harnessing the power of directed evolution to build out a product platform for large market opportunities. So our underlying platform is directed evolution, which is a Nobel Prize-winning technology. It allows us to invent customized delivery vehicles or vectors for any tissue in the body. This allows us to bring the doses down, improve safety, and improve cost of goods, and improve efficacy. So it's really a game changer for AAV gene therapy. We're currently in four therapeutic areas, three of which are in the clinic, including large market ophthalmology, lung, and cardiology.
Our pipeline is robust, and we have a number of upcoming catalysts for the rest of this year, with a primary focus on, again, large market ophthalmology with wet AMD, a big focus for our lead product, 4D-150, diabetic macular edema, eventually moving on to diabetic retinopathy. We also have a geographic atrophy program, for which we'll be filing an IND next quarter. Exciting times in large market ophthalmology, as well as our cystic fibrosis program and our Fabry disease program. In terms of our capabilities, we have in-house manufacturing for everything from GLP toxicology all the way through phase III material. It's a real strength of the company, and we have a very strong balance sheet with on the order of $600 million currently after our last raise. This is the product pipeline.
You can see a primary focus in large market ophthalmology, but also progress in pulmonology and cardiology. All these use vectors that we invented through directed evolution at 4D, that allow us to, again, treat these diseases with lower doses, safer, no inflammation of note, and superior efficacy. Briefly, 4D-150, our lead product for wet AMD, has the potential to be best in class for VEGF-driven diseases of the retina. You can see on the left the way this product, Vector R100, has been invented and designed. It's unique in being able to be delivered with a single intravitreal injection, similar to an Eylea injection.
One-time dosing, penetration through the barriers over the retina, and transduction broadly throughout the retina, including the macula for wet AMD and other DME and other vascular diseases. This is a capsid that's proprietary to the company, and it has some unique structural changes that allow it to achieve this delivery. We have two transgene payloads in the product, which address four different VEGF family members. So this allows us, we believe, to be the only company we're aware of that has a dual transgene system in the clinic that allows us to target all four drivers of the disease in a single product. 4D-150 is designed to achieve several things. One, and these are the unmet needs in wet AMD and DME. Number one, it's important to remember that patients lose vision over time.
So despite the success of the anti-VEGF market, patients lose vision. Why is that? Number one is patients are relatively non-compliant. They hate to get these injections every 4 to 8 to 12 weeks, and so, patients are generally undertreated. That leads to vision loss over time. Having a single, durable intravitreal injection that can give coverage continuously for 5+ years is really a game changer in terms of making sure patients are always on treatment. The second issue with the bolus VEGF therapies is that they dry the retina, and then the retina swells rapidly again, and they dry, and that oscillation leads to loss of vision over time. We believe with 4D-150, we can actually stabilize the retina anatomy and protect vision outcomes in the long run.
As we mentioned earlier, despite the efficacy of these products currently on the market, there are escape mechanisms, the primary one of which is VEGF-C overexpression, and we're able to target VEGF-C as well as express aflibercept in this product, and we think that could result in superior vision outcomes as well. We recently released data from the wet AMD PRISM trial. This is a phase I/II study, where we treated 15 patients in phase I, and then we just recently announced data in what we call the dose expansion phase, and that is essentially the hardest-to-treat patients in wet AMD, high disease burden, high disease anti-VEGF treatment requirements. We showed compelling safety and efficacy data in that population.
And then later this year, in Q3, we'll also release data on a population extension, which is a broader population of patients with wet AMD. That's an exciting catalyst for the company. That'll be the phase III population. Then on to diabetic macular edema. We have an ongoing phase I/II study there, where we'll be doing a data release on a dose confirmation phase II in that population later this year, and then again, initiating phase III for wet AMD in Q1 of next year. To summarize the data from the dose expansion results that we released last month, first of all, we confirmed this is a single routine intravitreal injection for these patients with durable activity. We've reported data out to two years now.
Very favorable safety profile, so this is the first time there's been an intravitreal product that's not shown significant inflammation. That's a game changer for this whole gene therapy approach in large market ophthalmology. Overall, we saw a 90%, approximately, reduction in injection need in these patients after receiving the 4D-150 single dose administration up front. 84% of patients either had zero injections or one injection of an anti-VEGF as a rescue. 63% were completely injection-free. This is all through 24 weeks. Importantly, we did show a stabilization of the retinal anatomy, so we didn't see these oscillations in the 4D-150 arm that we saw in the aflibercept arm, so confirming that that stabilization was occurring, which we think should translate into long-term better vision outcomes.
Again, we updated our data from phase 1, showing a high degree of durability out to as long as two years of follow-up with patients being injection-free after a single dose of 4D-150. We have a strong cash balance to achieve each of these catalysts this year, and we have cash out to first half of 2027, and that includes funding for two large randomized phase 3s in wet AMD. So over to you, Gena.
Great. Thank you. So maybe I wanted to ask, you know, to be honest, this is the first time we saw very impressive safety data using intravitreal delivery, right, with AAV. That historically was known that there is no chance to be able to do that, and we did see a lot of inflammation from different programs. So maybe my question is, what did you do differently to make this happen? And then regarding the, say, AAV capsid, you know, what kind of modifications? And also, the other key part that you mentioned is also low dose-
Mm-hmm.
And what make low dose possible?
Yeah.
Mm-hmm.
So I'd say the short answer is what we did is we innovated. We took the time to innovate, and the rest of the field has sort of rushed ahead with vectors that they found in nature that were really not customized or not targeted in any way, and we don't do that in medicine typically. We target our therapies, we optimize that, and that's what we did. So we used this, again, directed evolution, Nobel Prize-winning technology, that allows us to invent customized vectors that will be lower dose, no inflammation, highly efficient. So how do we do that? We start by creating massive diversity. So we use a variety of molecular biology techniques to diversify the capsids that are present in nature, and we create a library of on the order of 1 billion different sequences.
Instead of picking one vector from nature and hoping for the best, we start with 1 billion, and then we administer it to a non-human primate, so we get as close to the human as we can get. In this case, we administered it intravitreally, and we asked the question: Which of those 1 billion vectors was the best at getting through all the barriers to AAV that prevent AAV from getting into the retina and transducing? What happens is we bring the retinal tissue back to the lab, we open it up, we isolate the genomes, and we create a new library that's much smaller this time. We administer at a lower dose do the same thing.
We do that iteratively 4-6 times, and we funnel down from a billion vectors to the best vector for a simple intravitreal delivery. And when we reverse engineer it, we found that this vector had ablated the sites on the AAV capsid that typically get stuck on this membrane, the internal limiting membrane, that sits over the retina, so it can get through, and then it has a peptide insertion at 60 different locations throughout the capsid that allow high efficiency uptake into the target cells in the retina. So it's a solution that nature came up with that would've taken us hundreds of years to figure out.
Mm-hmm. Okay, very good. Now, you identified this, at least so far-
Yeah.
You know, the data looks... safety looks very good. Like, what will be additional indication? I know wet AMD will move forward with phase 3, and you have a list of other eye indications you wanted to go after. So if you have a limited, say, balance sheet, and you have to select, you know, priority, what will be your priority among the list of indication you suggest?
I think, certainly wet AMD is a large and growing market, and there's still a high unmet need, despite all the successful products there, so we do think we're highly differentiated there. Again, Vabysmo's had a very successful launch, and they get about a quarter of the patients out to 16 weeks. Most patients are less than, are more frequent than that. This would be something, with a single injection, we should be getting efficacy for at least 5 years or more. So it's a real game changer there. I think diabetic macular edema, that's a very large, rapidly growing market, and again, that's one where almost everything that works in wet AMD will work in DME as well, served by the same mediators.
Mm-hmm.
Diabetic retinopathy is an interesting opportunity long term, that we would explore, following safety in DME. And then we're excited about the 4D-175 asset for geographic atrophy, which essentially leverages, in a modular fashion, the same vector, the same delivery system. We've just swapped out the anti-VEGF transgene payload for, essentially a complement factor H payload. So I'd say that's, that's where the primary, focus for the company is.
Mm-hmm.
We're certainly excited about our lung programs and cardiology programs as well.
Mm-hmm.
They validate the platform itself.
Mm-hmm.
But in terms of the focus over the next few years has to be on large market ophthalmology.
Mm-hmm. Okay, very good. So now going back to the wet AMD data, I think, you know, you shared with us also initial data, very impressive. And one question I got is regarding, say, durability.
Mm-hmm.
Because you still have relatively short follow-up. You do have a patient have a little bit longer follow-up, and how do patient—I know you cannot disclose ahead of data update-
Mm.
How does it look, especially for the CST numbers, data? Would they maintain very well over time with a longer follow-up?
Durability is excellent with AAV in the retina.
Mm-hmm.
We know that-
Mm-hmm
From other programs as well as our emerging data. So we have data out to two years-
Mm.
-with patients who are injection-free with a nice, stable CST.
Mm.
But we also have other programs who've done subretinal surgery, for example, and implanted AAV in the retina, and they, they're seeing efficacy out to 4 years in wet AMD and out to 10 years in rare disease. So I think there's great data to say that once you get an AAV vector into the retina and the capsid disappears and leaves its DNA behind, that should be very, very durable over the course of 5-10+ years.
Mm-hmm. Okay. And I think the other data point is the protein level, and that could be a very important indication or biomarker.
Mm-hmm
To show maybe durability or clinical benefit. So are you planning to share that at some point?
At some point, we'll certainly share that-
Mm
And we see good durability.
Mm.
The biomarker of protein in the front of the eye is a kind of a crude tip-of-the-iceberg measurement of-
Mm
What's actually happening back in the retina, which is where-
Mm-hmm
All the action is with gene therapy.
Mm-hmm.
But it is a, it is a marker that we can look at to say, "Yes, is there still ongoing expression?" And confirm durability.
Have you been collecting-
Yeah
The protein data?
Yeah.
Okay.
Yeah, so we've seen that data, and we haven't-
Okay
Shared that publicly. We shared the early data more in the first couple of months-
Uh-huh
Showing high level expression, nice correlation with dose.
Mm-hmm.
A highly consistent expression for, you know, across patients in terms of the showing positive expression.
Mm-hmm.
Over time, we can share that data in terms of the durability.
Mm-hmm. Another question is, you know, the so far, your safety profile is so good, and you reached 60% or 63% injection-free rate.
Mm-hmm.
Do you think, you know, do you have the appetite to even dose up and have an even better clinical profile?
Yeah, so that's always a question that's critical in drug development, is when do you stop dose escalating? Here, at this time, we're thrilled with the 3E10 dose level. First of all, it's anywhere from 3%-20% of what others are using, so it's a very low dose compared to other programs. And it's given us great efficacy and great particularly in these highest patient highest-need patients who have the most disease severity. So while we believe we could safely dose escalate, and that's something we could explore, we're thrilled with the profile of the 3E10. And, you know, for a program like this, safety is so central for a large market ophthalmology program-
Mm-hmm
That we don't wanna risk it, and we're, we're thrilled with the 3E10. So we'll, again, reserve the right to explore higher doses just to understand the safety window, et cetera, but it's full speed ahead to phase 3 with the 3E10 dose level.
Okay.
Gena, if I may add to that, I think prior to the release of this dataset, I think the biggest overhang for us was to demonstrate safety.
Mm-hmm.
I think everybody had questions about gene therapy safety.
Mm-hmm.
What we've now shown with about 41 patients in the treatment arm is that this safety is so clean for us. I mean, the data speaks for itself. We've seen no significant inflammation, so that gives us the confidence that, A, we are on the right dose, and to David's point, we wouldn't like to sort of experiment just for the sake of it. I think 3E10, which is our high dose, seems to be pretty robust in terms of safety.
Mm-hmm.
That addresses and has already started to address a lot of outside concerns on safety in gene therapy.
Okay. So I think the reason I'm asking is maybe related questions. I'm pretty sure you, you know, have spoken to many doctors, right? Retinal doctors there.
Mm-hmm.
So what is their feedback, you know, for those, like, have less experience with gene therapy but more doing the traditional injection? And what are their feedback, what they are looking for, the clinical profile for them to willing to switch-
Mm-hmm
From their current practice with, say, Vabysmo and the high-dose Eylea to this-
Mm
Future gene therapy? And, you know, what are the clinical profile they are looking for?
Yeah, I could start on that, and then you-
Mm
Uneek can weigh in as well.
Yeah.
I think what we've found is physicians just need to be educated because there were some high-profile problems with other gene therapy programs, right? Some retinal surgery, some inflammation with another program. So coming in, they, they have this sense, "Oh, gene therapy, it's, it's, it's gonna be toxic. They have to have off-the-chart efficacy, and it's only gonna be used in a small population." And that's fundamentally not what we're finding, is once we show this degree of safety and lack of inflammation, what we see is a rapid reversal of that approach and, and a rapid uptake. So if you look at the enrollment on our phase II studies, it was about double what we expected. It was incredibly rapid, which tells us the physicians want this, the patients want this. It's simple, it's convenient.
As long as it's safe, the uptake's gonna be rapid. So if we think about high-dose Eylea or Vabysmo, which are, you know, great and have kind of extended the, you know, the duration of efficacy, reduced the frequency a little bit by a few weeks, none of those will have any injection-free rate. So if you think about ours is transformative, just the fact that we talk about injection free for a year or two years or more, it's really a game changer. But I think it starts with the need to see the safety.
Mm-hmm.
We find that once physicians see that safety, their whole approach to this gene therapy changes and their perceptions change.
Yeah, and a quick bolt on to David's comments. It was very purposeful that we started in these highly advanced, high treatment burden patients, because that's a population of patients that is not in control right now, regardless of any current standard of care therapy. And then we've now purposely also going into population extension with a broader patient population. So it's part of our overall strategy to demonstrate success of this product across a broad section. And we feel, I think the profile that is emerging from this should be pretty compelling, not only for these high treatment need patients, but also, as part of our commercial thinking, we are going to be targeting patients who are logistically challenged, those who cannot get to the clinic. Just as a reminder, these are 70-80-year-old patients who are generally presenting themselves with the disease.
Getting even to the clinics, where they are dependent a lot on their caregivers, is a big burden for them. I think our approach of long durability combined with safety should be appealing to a lot of these patients.
Mm-hmm. So maybe that lead to the question on the phase 3, patient population, right? I do see our phase 2 is a very severe patient, and if you look at baseline, CST is so high, I haven't seen any other clinical trials, you know, ignore the-
Yeah. Yeah, yeah.
CST, like, over 400, like 450, right?
Yeah.
So now going to the Phase III, exactly, you know, what you comment, what will be the ideal patient population baseline so you can, with the data readout, you can max out the potential commercial opportunity there?
Well, I can speak to the phase 3, and Uneek can speak to the commercialization.
Mm-hmm.
But we expect it to be more of what we call the population extension cohort-
Mm.
That we've enrolled 32 patients, and we'll be reporting that data out in Q3 this year. But we expect it to have some of the patients who are in the dose expansion, so very severe, but also includes some patients who have less advanced disease, less high disease severity, high treatment needs. So it'll be more of a broad blend, such that we can get a broad label. But we also want to include, again, about a quarter or so of these patients who are the highest need, which, you know, to date, other programs haven't really tried to address those patients. They've really just kind of excluded them and left them behind, and we think that's a great opportunity for us. You want to speak to the-
Yeah.
Approved label?
I think that combines to... First, of course, we want to make sure that we are non-inferior on the visual acuity level. So we get the approval, and then our plan is, right now, at least it's shaping up, is to really have these 20%-25% patient population, which is highly advanced, as a beachhead population, but then going into the logistically challenged. And by that time, I think there will be sufficient experience with gene therapy that even the broader population, we will get some share. And it's such a big market, we fully anticipate there will be multiple players in the market, but we are definitely planning to be a dominant player in the overall market.
Mm-hmm. So regarding now the new guidance, like, non-inferiority, and so maybe, like, any initial thoughts on the potential, you know, I mean, the phase III trial design? Yeah.
Yeah, as we said, broad patient-
Mm
-population.
Mm.
Non-inferiority, based on BCVA, and usually-
Mm
That's 4-4.5 letters, non-inferiority.
Mm-hmm.
We've signaled publicly that we expect to have approximately 225 patients per arm-
Mm.
So there'll be a standard of aflibercept control arm and either one or two doses in the phase III, and we'll get further guidance on that in Q3.
Mm-hmm.
And then we'd be tracking, basically, the need for, first of all, BCVA over time, and it'd be a 12-month endpoint, primary. And then also tracking the need for supplemental injections to try to understand how many injections are we essentially taking out of the system compared to what patients were getting previously or compared to the aflibercept control arm.
Mm-hmm.
And then we'll also be tracking that CST to confirm that stabilization of the anatomy of the retina. We'd love to get that in the label as well.
Mm-hmm.
Anything else you want to add?
Yeah, and, you know, it's just a reminder that we are probably the only wet AMD therapy that has both RMAT and PRIME designation. So we have great collaboration between the European and U.S. agencies in terms of this, and we've announced publicly that our goal is to start the phase 3 early 2025, so Q1 next year. So we are full steam ahead in terms of planning for those, the first of the confirmatory phase 3 trial.
Okay.
I think that's a great point about PRIME and RMAT, is it just shows you that the regulatory agencies, as well as a high number of KOLs and physicians, understand the unmet need here. There's still a significant unmet need, otherwise you can't get those such designations. We think we're the first ophthalmology product to ever have both.
Okay, good. I know we-
Yeah,
Almost running out of time, and maybe quickly on your CF program. So maybe, like, your expectation for cohort two and where the threshold you are looking for, and then also related questions of frequency of dosing, mainly is the durability, you know?
Sure.
This together, like, how viable that will be for the commercial asset.
Yeah. So 4D-710 is our cystic fibrosis product, and it's a vector that we invented for a safe, efficient delivery to the airways and penetration through the thickened mucus in cystic fibrosis patients, and also with resistance to pre-existing antibodies in the population, so it's relatively non-immunogenic. We deliver a modified version of the CFTR gene that's missing. In the first couple of cohorts in phase I, we've shown extremely high levels of expression. Over 90% of cells in the airways, when we do biopsies and brushings, are expressing, including basal cells, which are long-lived cells in the lung. We've seen evidence of protein expression that's about four times normal.
As you mentioned, we're dose deescalating to try to get more in a physiologic range prior to going into pivotal studies. We expect this is a product that we could redose approximately every two to three years if we need to, and we think that's an excellent commercial opportunity, and we think there's strong data to support that feasibility of redosing in this population. So we'll give further guidance on FDA interactions on Phase III in this quarter. And then mid-year, we'll give a data update on how the patients are doing at these lower doses, as well as additional follow-up with the high doses.
Mm-hmm. Okay, good. Well, thank you very much.
Thank you very much.
Thank you so much.
Thank you, everyone.