Great. Welcome back everyone to H.C. Wainwright's Global Investment Conference. My name is Matthew Caulfield, I'm a Senior Biotech Analyst here at H.C. Wainwright, and we're very grateful to be joined by 4D Molecular Therapeutics. We have David Kirn, CEO and co-founder, and also Chris Sims, Chief Commercial Officer. Thank you very much to both of you for being here today. We're going to start off today with a presentation by David, and then we're going to switch into our fourth fireside format following that. David?
Perfect, please. Thank you, Matthew, for having us. It's a pleasure to be here.
Absolutely.
At 4D Molecular Therapeutics, we believe our lead product, 4D-150, is really positioned for Phase 3 and commercial success in wet AMD and diabetic eye disease. We will walk through our robust safety profile, our efficacy across a broad range of patients with wet AMD and DME. We will speak about our Phase 3 design, which we think is significantly de-risked and is being done under both PRIME and RMAT designations. We believe we have a very significant commercial opportunity that we will cover. In terms of safety, we have a very clean safety profile with no significant inflammation or toxicities to date. This is critical in a large market indication like wet AMD and diabetic eye disease. To get into some of those specifics, we have had no serious adverse events related to 4D-150 and none of the bad things that sometimes people worry about in this disease indication.
No hypotony, endophthalmitis, or other serious conditions. Over 97% of patients have no inflammation whatsoever, and there are just a couple of patients who had very mild cells present in a day or two and then resolved. Great safety profile and easy to administer, topical steroids. In terms of our efficacy, we have a very robust and broad data set in wet AMD and now in DME. We have looked at the most severe patients, then moving to a broad population and ultimately to more recently diagnosed patients. We have seen a robust, consistent treatment burden reduction of anywhere from 78% to 94%, which again would be a target product profile that would be a potential blockbuster. Let us get into some of the details.
Prism is our Phase 1/2 program where we looked at these three distinct patient populations, starting at the left with the most treatment-resistant, recalcitrant severe patients. This represents probably 5% to 10% of the entire population. What a logical place to start with a new therapy in this space. Then moving to our Phase 2b, where we looked at a broad population of 30 patients with more of a standard spectrum of wet AMD severity. Looking most recently at the Phase 2b subgroup of patients diagnosed in the last six months, a healthier retina, better transduction capability. This is the population you will see later that we are going into for Phase 3. Broad population. What we see is a robust, consistent treatment burden reduction in all three of these areas. On the left, you see the most severe patients.
These patients were getting 10 injections over the course of the prior 12 months, so almost monthly treatment. Despite that, came in with very poorly controlled disease. Nevertheless, in this population, we reduced the treatment burden by 83%. Really a remarkable result. In a broad population, when we compared it to standard on-label Eylea, we saw an 83% treatment burden reduction in the broad population. In recently diagnosed patients where we think gene therapy might give the most, most efficient transduction, especially we see a 94% reduction. Breaking that down to the number of injections patients had, you can see patients on the far right only had 0.3 injections over the course of an entire year on average, whereas in the severe recalcitrant, we brought that down from 10 injections on average to 1.8. The majority of patients are getting either zero injections or just one injection.
If you look at the recently diagnosed on the far right, which is similar to the Phase 3 population, we had 80% had no injections over the course of a year, and 87% had either zero or one. Our Forefront population takes all of these learnings, and we really focused in on these treatment-naïve, recently diagnosed patients. We further enriched this population for response and benefit by saying we're going to exclude patients with CSCs over 500, which usually are associated with anatomical abnormalities that really are treatment resistant. Also looking at patients diagnosed in the last five years and then who respond to aflibercept in a run-in period prior to randomization. This is our DME population showing a similar reduction of nearly 80% in treatment burden versus standard on-label aflibercept, showing, as expected, that something that works in wet AMD is also highly active in DME.
Let's talk about our Phase 3 program that's currently underway. We think this is de-risked significantly and is set up for success, and we do have strong regulatory alignment with both FDA and the EMA. Thinking about the Phase 3 design, we think about the patient population first and how are patients treated and then what are the key endpoints. In terms of population, as I said, these are newly diagnosed patients, no prior therapy in Forefront 1. Forefront 2 does allow for a small number of prior injections in a subset of patients on that study, but all patients in that six months or less treatment duration. In order to get randomized on this trial, patients have to show a response to aflibercept, so we're enriching for patients who respond well to standard aflibercept, which is the agent expressed by 4D-150.
We look at injection with 4D-150 or aflibercept and then follow patients every eight weeks for either supplemental injections or routine injections on the aflibercept arm. Primary endpoint is BCVA, non-inferiority at 52 weeks, very standard. Key secondary will be treatment burden reduction on the 4D-150 arm. This is the expected timelines. Forefront 1 has been rolling extremely well, which we think reflects a great commercial opportunity here and the desire of patients and physicians to have a long-acting agent like this. We brought in guidance methodically as we've gotten more enrollment completed. Now we're looking at being fully enrolled by Q1 of 2026, significantly ahead of schedule, and then data in the first half of 2027. Forefront 2 is just underway, but is enrolling well, and we expect top-line data in the second half of 2027.
Importantly, our cash runway takes us all the way into 2028, so we have cash beyond the Phase 3 readouts. Let's talk about the commercial opportunity, and Chris will follow up on this later, but we really think this is a product that fits seamlessly into the clinic flow, which is essential for a large market like this. We think we have strong pricing flexibility due to our low expected cost of goods. We think it's a real, important commercial opportunity. For patients, the value proposition here would be reduction in treatment burden. It would be adherence by design, meaning patients stay on therapy, probably the rest of their life, given the long-term expression of aflibercept from 4D-150. We also think that this sustained aflibercept expression right in the retina where you need it should, over time, result in vision preservation.
We talked about the low expected cost of goods and pricing. This fits seamlessly into the clinic flow, so no special handling. It's handled just like an Eylea or Viviesma would be, and stored in the standard refrigerators, on site. To wrap up, 4D-150, we think, has great potential in wet AMD and in DME, and we do have a very exciting cystic fibrosis product for aerosol delivery called 4D-710 that we can cover at a later date. Thank you, Matthew, and we'll take questions.
Yeah, no, David, that was really helpful, a really robust in vitro platform and, you know, other candidates as well within the pipeline. Maybe to go into the Q&A, in thinking about 4D-150, the lead asset that you're, that you've been describing, what more can you tell us about the ongoing injection burden reduction versus injection free rate? How do these play into the upcoming Phase 1/2 Prism trial data for up to two years in wet AMD patients?
Yeah, I can kick it off and then turn over to Chris, but you know, I think what we see is a robust, consistent treatment burden reduction and strong durability, which is expected in this field. There's strong evidence in the field that AAV gene therapy to the retina is going to be durable, likely for the rest of the patient's life, and these patients who are typically in their 70s or 80s. We expect strong durability over time. The precise % of patients who get zero or one injection or two injections is really going to depend on how treatment resistant they were coming into the study. That treatment burden reduction we expect to be consistent over time and give long durability. Chris, do you want to speak to?
Yeah, I can maybe add a little bit more color. When it comes to treatment burden reduction and injection free rates, Matthew, I think one of the things that we're really encouraged by from our Prism data set is that we saw that, and David took it through that at a high level. We saw that effect across different ranges of patient types, be it a largely recalcitrant patient population that was getting 10 plus injections in the prior year, and you saw a significant delta there in treatment burden reduction north of 80%, and you certainly saw that in a more recently diagnosed population. We'll look to provide updates out to two years on that severe and moderate patient population. I think we'll give that update later this year.
We would expect that treatment burden reduction rate to be consistent with what we've shown so far, which should be a good marker of longer term durability. It's encouraging, and as we touched upon, we've taken those learnings and then designed our Phase 3 program to reflect where we see that efficacy benefit to be the greatest, notably in a more recently diagnosed or a naive patient population, which is how we've designed our Phase 3 program to enrich for those patients.
No, that's great. Very helpful. I mean, I think it also speaks to some of the heterogeneity that exists among wet AMD patients, for instance, within the space.
Yes, certainly. There's no two patients that are exactly alike. Sometimes the challenge is you don't know which patient upon diagnosis is going to need more or less treatment. There's a lot of heterogeneity, which is why physicians today with really efficacious agents adopt a treat and extend or a PRN type of protocol when it comes to treatment because there's no two patients that are exactly alike. That said, I think the thing that it's important to recognize is that while there's a variety and variation in terms of the frequency of treatment, large market databases would suggest that most patients in wet AMD and certainly DME are undertreated in the real world. If you have an agent, and that's for a variety of reasons, patient adherence comes into play and other variables.
If you have an agent that provides continuous expression of aflibercept, you solve for that adherence issue, which is one of the biggest challenges today when it comes to long-term maintenance of vision outcomes. That's exciting for our potential, we believe.
Yeah, no, absolutely. I mean, considering those that may view injection freedom as the only relevant metric for gene therapy success, how would you respond to this in terms of two to five-year durability and beyond, overall treatment burden reduction, and how the wet AMD patient population plays into that?
Yeah, I can kick it off and then Chris can speak to it. I mean, first thing I would say, injection free is a non-issue for the physicians in the field. Viviesma was a blockbuster after three years, three years after their launch, so over a $4 billion a year drug, they have no injection-free patients. This concept of injection-free was really an artificial construct that was created by other companies unnecessarily. We have a very strong injection-free rate, about 80% at one year in the patients who are newly diagnosed. The goal was overall treatment burden reduction across the board for everybody. The exact number of injections each patient is going to get is going to be dependent on their underlying biology, but everybody's going to benefit. We think this really resets the entire disease as a backbone therapy, and then patients can get additional injections as needed.
As I said before, the data across lots of programs says AAV retinal gene therapy is going to be extremely durable, probably the rest of the patient's life.
Yeah, I would agree. I mean, I think for a significant number of patients, and we'll see what that data looks like in our Phase 3 program, but a lot of patients getting 4D-150 is likely to be the last injection they'll ever get. That's incredibly exciting. For others, you'll need occasional supplementation. We see this in not just our data sets, but other programs that are in development as well. No doubt injection-free would be amazing, and some patients, I think, will have that benefit. If you talk to physicians or patients, and you say, hey, you have the potential for injection-free, or you may need occasional supplementation, and your durability then is measured in months, if not years for some patients, that's game-changing.
Absolutely.
We know that to be true to David's point, which is we've seen agents in this space launch with an extended benefit of a couple of weeks, maybe, of durability. You can imagine, and that's been highly motivating. Those products, with Vabysmo in particular, became like a $4 billion drug, I think the last estimates for Roche. The benefit is, as a week and a half to two weeks of durability, you can imagine how compelling the potential for months or years of durability would be for a patient.
Yeah, for sure. I mean, that highlights the current injection burden with standard of care.
Yeah, and it's real. Not only is the treatment burden an issue for patients and their caregivers that we've modeled out, it'll take eight to ten hours for many patients to get into the clinic, get their treatment, all the workup, and then get home. While the procedure itself is measured in often minutes, the actual injection, the burden to a patient is a day, if not more. It's not just the patient, it's their caregiver as well. Alleviating and reducing that is a huge benefit to the patient. I'll tell you, in retina clinics around the world, and especially in the U.S., they need solutions and innovation to help with their capacity issue as well. You have a growing patient population, and you don't have new retina doctors coming on the stream fast enough to keep up with the growth in patient demand.
Ultimately, that capacity constraint that exists in many retina practices needs to be solved, we believe, through game-changing agents that provide real meaningful durability. 4D-150 could be a great solution for that as well.
For sure. Absolutely. In the context of the wide range of patient populations studied, what are important distinctions between the high-need, high-burden patients versus the lower-need, recently diagnosed wet AMD patients?
Let's say the recently diagnosed patients aren't necessarily low-need. They just remain undefined. The fact that we see such a high injection burden reduction of 94% in those patients and 80% had zero injections over the course of the first year, to me, suggests that it's something about having a retina that doesn't have significant fibrosis yet, doesn't have atrophy yet, where you can get very high-level transduction. In the patients who had the recalcitrant resistant disease, getting 10 injections a year and four of it were 10 years of disease, there you start to get sort of anatomical changes in the retina, such as fibrosis and atrophy that I think lead to, certainly we dramatically benefit those patients, but it's not going to be the same number of injection-free patients, for example, at a year that you would get in a retina that's fully intact.
I think the bottom line message is we get, I think, very significant blockbuster reductions in treatment burden across the board, but the percent of patients who will get no further injections, at least for the first year, are highest when you move into that newly diagnosed population.
Right. No, that makes sense. Could you speak a bit more to how the Phase 3 program has been enriched for anti-VEGF responsiveness?
Yeah, coming into this, we knew we were getting phenomenal results in patients diagnosed in the last six months. We said, let's focus there. The first study is treatment-naïve patients. They will get three loading doses of aflibercept on study. That's very standard for these kinds of trials, and it's what FDA is used to seeing. The second study allows 40% of patients to have had one to four prior injections, but still diagnosed in the last six months. That enrichment is to get patients earlier in the disease, healthier retinas, and then also to say on study they must have a significant response in terms of their CST to an aflibercept bolus to confirm aflibercept responsiveness. We also weed out patients who have a CST over 500, which is again due to sometimes large PEDs and other anatomical issues.
We've taken that population where we see phenomenal results, and we've even further enriched it to make sure we get the maximum benefit in phase 3.
Understood. You know, thinking about the landscape, if we continue to see a consistent and durable profile for 4D-150, and there is ultimately FDA approval, how do you foresee the commercial experience for patients and prescribers? Is this a therapy that could be utilized in the most extreme patients first and then more broadly adapted? Obviously, there's responsiveness to the more recently diagnosed patients that you're describing.
Yeah, it's a great, great question, Matthew. Again, we're developing this for, we think, all patients that have wet AMD or DME eventually. We're not saying it's just for a recently diagnosed or a more recalcitrant patient population. That said, in the real world, what we see happening continuously is that when you launch a new medicine, and I had the experience of launching a number of new medicines in this retina field, you often get used in the patients that have the highest need. Those are existing patients, often they're on Q8 or Q6 or Q4 existing bolus therapeutics. That's the patients you're going to get tested on initially upon introduction. What physicians normally do is once they get comfortable with real-world safety with that patient population, they start to expand to a more recently diagnosed or a more naive patient population. That's a graduation that we see normally.
I think that makes clinically, that makes sense, right? I mean, if you have a new therapeutic, you're probably going to look at patients that are in your office and say, "Hey, I'm looking for something else, doctor, something that can often alleviate the treatment burden." That's the graduation of adoption, if you will, that we would anticipate. What we're really excited about is, contrary to other agents that might be in development that may work more, better for a healthier patient, if you will, our data so far through our Prism program notably has been very robust across a wide range of patients. Again, even if you were, I think we had patients on average diagnosis of four years and getting 10 injections a year.
Right.
It took the treatment burden down by over 80%. When we get tested on that patient population, we believe we'll be able to perform very well.
Especially with the efficacy in earlier diagnosis, I think that even makes more of a case for intervention.
Yeah, I think that will support that graduation I spoke to, is that once physicians get comfortable with certainly the safety profile, which has been very differentiating for us, the likelihood they'll move to a more recently diagnosed patient population, we think, is very real.
Absolutely. I know we only have a minute or two left here, but importantly, the company has reported over $400 million in cash and equivalents funding operations into 2028, which specifically surpasses the Phase 3 Forefront 1 and Forefront 2 52-week top line expected in 2027. What do you view as the greatest disconnects between demonstrated platform success that we've discussed today and investor sentiment?
I think part of it is just educating, you know, that there is a real market here. I think there are gene therapies out there that have gotten approved and not been able to commercialize. We think the retina space and the wet AMD and DME space is very, very different. The physicians are very different. They're early adopters. They're highly innovative and entrepreneurial. I think it's just that education that there is a huge commercial opportunity here, in contrast to maybe some of the rare disease gene therapy programs. There's a survey from the American Society of Retina Specialists, ASRS, called the PAT survey. They do it every year. They ask physicians what are you most excited about in for novel therapies in neovascular retina diseases? Gene therapy is number one.
We know in that space, we're the only company that's had a clean safety profile with a simple intravitreal injection and robust efficacy across a broad range. So 50% say gene therapy is number one, and the next closest is about 18% with TKI. I think that tells you there's a huge market here. Our enrollment rate, again, highly accelerated, also tells you there's a lot of interest in this. It's telling that story that there's not only great clinical activity and safety here, but there's a huge commercial market opportunity.
Absolutely. With that, to be respectful of everyone's time, I'd like to thank David and Chris at 4D Molecular Therapeutics. Great conversation as always.
Thanks for having us.
Thanks, Matthew.
Thank you, everyone.