STIFEL 2026 HEALTHCARE CONFERENCE - 4D MOLECULAR THERAPEUTICS INC

All right. Good morning, everyone. Welcome to the Stiefel Healthcare Conference. My name is Colleen Cousy. I'm one of the senior analysts here covering biotech. And this morning, I am very happy to have with us the team from 4DMT, including CFO Christian Humer and Chief Commercial and Business Officer Chris Sims. They'll give a formal presentation, and then we'll dive into some Q&A. Awesome. Thank you, Colleen, and good morning. We appreciate the opportunity this morning to share the 4DMT story. My name is Chris Simms, as Colleen mentioned, the Chief Commercial and Business Officer. Just as a note, we may be making some forward-looking statements. More information can be found on our website or in our SEC filings. So some key takeaways for today. So first of all, we're really excited at 4DMT with the progress that we've made on our lead program 4D150, which is going to take up pretty much the entire presentation today. We have other things in development, but most of our focus right now is on our LEAD program 4D 150. And I think the reasons for that will be obvious as I go through the deck. 4D-150 is our lead retina program. We believe it has the potential to establish a new treatment paradigm for the treatment of wet age-related macular degeneration. Some key reasons why we believe that to be possible. First of all, we're pursuing 4150 to be a backbone therapy with the potential for lifelong continuous disease control from a single intravitreal dose and injection. Second, our target product profile, which we'll review in a little more detail in a few slides, addresses what we view as the key unmet need of patients in this space, the preservation of vision while reducing treatment burden with the opportunity for some patients to be injection free for a lifetime and as we'll go through that's that's quite a shift from current standard of care and what patients currently experience the third point is that our clinical trial data our phase three design and strong execution positions as well for success I'll touch a little bit more on that as well and the fourth point really important when it comes to commercial adoption is that patients physicians and payers together are expected to drive we believe robust and broad commercial adoption we believe we have the possibility to address some really important unmet needs across all of these all of the stakeholders which ultimately will be the foundation for our commercial strategy sorry FYI the The countdown clock is not moving, if that matters. Just as a reminder why we believe we're uniquely positioned to achieve this, let's take a look at the design of 4D150. It's designed for a low-dose targeted delivery of aflipiracept, producing transgenes to the retina with, again, a single intravitreal injection. At the core to our product design is our vector. The R100 capsid was invented and developed at 4DMT, it's proprietary. And we believe that that capsid allows us to be very unique in our approach to using the gene therapy for treating retinal disease. Specifically, the R100 vector allows us do three things that are really important. First of all, it allows us take a low dose intravitreal injection approach. Second, it allows us to be targeted in the delivery to retinal tissue specifically. And third, we believe it has the potential for minimal toxicity and inflammation. And when we combine the R100 capsid with our payload, specifically the fact that it includes aflipiracept, which is commonly known, of course, as ILEA, which has been dosed in over 64 million eyes since it was launched, we think the combination of that provides a direct retina-specific therapeutic effect that has the potential for lifelong expression for patients. And so why is that important? Well, let's take a moment to consider the biology of wet AMD. Wet AMD is a disease. It's chronic. It is variable. It has heterogeneous. It always there. And the current treatment paradigm today is episodic and finite with bolus injections. injections. These bolus injections work really well. We see that when patients are diagnosed often they get up front loading doses of two or three injections and then they're put on some sort of a schedule of extension based upon the need. It could be a month, it could be every other month based again on what the physician deems is appropriate. But that creates an oscillation and a peak and trough in the treatment of the disease. The challenge with that is that you have a chronic always-on disease and you have a treatment approach that's episodic. So again, you see those peaks and troughs. And what that results in for many patients is, one, a significant treatment burden that's hard to maintain over time. That significant treatment burden often results in the lack of continuous disease control. And for many patients, the combination of those two things means that over time they actually lose vision, which is unfortunate because we know that these therapies we know that VEGF suppression actually causes a patient to gain vision upon diagnosis however the current bolus treatment approach often results in that vision being lost as patients are unable to sustain the treatment burden so we believe a better approach is a backbone therapy so with 4150 simply we take a backbone therapy approach that we believe provides continuous disease control and we've matched the therapy with the chronic nature of the disease and and the potential for that is illustrated in this next slide which is we think it solves for what we refer to as the continuous control gap the continuous control Gap is simply this as I mentioned patients lose vision today and current bolus therapies despite gaining vision initially the burden of treatment causes vision to to be lost over time and we see that in the real world somewhat regardless of the durability of the bolus therapy that patients are being treated with a big piece of development for a lot of new therapies that are trying to enter in this space is increasing the durability by increments and while we know that to be important we've seen that with historical recent launches none of these therapies how for the alpha the potential of continuous disease control for the for the life of the patient so we believe with 4150 as a backbone therapy we could control or we could close that continuous control gap and thereby allowing patients the possibility of preserving vision for the rest of their lives in addition to significantly reducing the burden of treatment. This slide recaps some results from our phase two trial that we've shared previously. Specifically we look here at the 15 patients that are within the recently diagnosed population. The reason we highlight that patient population being recently diagnosed is that they're most comparable to the patients that we're studying in our phase three program. And again, I'll go through those details in a few minutes. And what we see from our PRISM results is actually quite encouraging. So here we see on the left-hand side that out to two years you see good steady control of central subfield thickness. So it's a biomarker in essence for anatomical control. That's really important when it comes to treating this disease. Physicians often reference that as a marker for whether they retreat or not. And we also see a nice continuous maintenance of visual acuity as evidenced by the bottom left-hand chart. Again, back to the slide a couple of minutes ago where we said, you know, closing that continuous control gap requires that you maintain vision to be steady over a long period of time. actually see that with our phase two results from from prism and in addition on the right hand side where we've been able to deliver that in the context of significant treatment burden reduction specifically again over two years patients got an average of 1.6 supplemental injections and if you compare that to what they would have received if they were being treated on label with ilea at a q8 weak frequency that's an 87% treatment burden reduction. And really importantly, 66% of those patients out to two years were injection-free. Of course, none of this matters if you don't have a safety profile. That's acceptable. And what we see with the 71 patients that have been treated with the phase three dose is a safety profile that's very encouraging. We had two cases of inflammation early on that were mild and transient and were resolved within the 20-week prophylactic steroid regimen that we administered. After that 20-week period, we saw no cases of 4D150-related inflammation events. And really importantly, there were no cases of serious adverse events observed at any time point. So no cases if occlusive or non-occlusive retinovasculitis, choroidal effusions, or endophthalmitis, or apotony. So from a product profile standpoint, point. To summarize, 4150, we believe, is designed to achieve what we view as an ideal product profile that has the potential to be best in class for treating wet AMD by providing a backbone therapy and the possibility of continuous disease control. We've listed the five supporting elements that underpin that value proposition on the right. I won't take you through all of them, but I will point out at the bottom, it's a point I think worth worth reiterating, which is the fact that 4150 is designed to be delivered as a single in-office intervitreal injection. The reason that's really important is that retina clinics are super busy. Often today, retina doctors are administering 50, 60, upwards of 80 bolus injections to patients in an injection clinic. So therefore, a product that fits seamlessly into that process is really important for real-world adoption. And further, the fact that it's a single intravitreal injection from a commercial perspective means that the 4150 will be reimbursed, we believe, through the buy and bill reimbursement model, which is, of course, very familiar to retina clinics today. Just a couple of comments on our Phase 3 program, Forefront 1 and Forefront 2, a global program designed for global approval. We've had great interaction and supportive interactions with regulatory agencies from the FDA and EMA, where we have RMAT and prime designations, respectively. We've also had very productive interactions with PMDA. Both trials are fully enrolled and, again, powered for the stringent criteria of about four letters of difference in the non-inferiority of vision at Week 52. side note as well as you'll see on this slide the majority of patients in these trials are treatment naive with an exception of forefront to where a portion can be treated up to a maximum of six months that's really important because I think that's the first time that an interventional gene therapy has gone into an essence or frontline patient population and the fact that we were able to do that and we enrolled both trials within about a 12-month period we think is is a strong indication of the unmet need and the enthusiasm both from physicians as well as as well as patients just a couple of notes on the trial design again we'll point out that our phase 3 wet AMD trials are fairly standard designs so we compare 4150 to a on label control arm of flip recept with a week 52 endpoint measuring non-inferiority in vision it's important as well to highlight that we think we've optimized for the patient population the two bottom on green boxes that are highlighted there talks about how we we believe we've done that specifically we cap the entry criteria on it from an anatomical standpoint to 500 microns and in addition to that we require that patients show a at least a 15% reduction in CST or a complete resolution of retinal fluid to to get randomized into our trial that's important for a couple of reasons but one of the key points is that we believe it helps protect vision but also reduces variability in the data set and of course the other element of the design which is fairly common is that patients are eligible for supplemental treatment and what this slide shows is the criteria and the reference point that guides the supplemental treatment in our trial so I won't go through the details but the criteria are very important certainly they need to be clinically relevant and we believe we've designed them for their primary goal of protecting vision which is our primary endpoint clearly you need to protect against vision first and foremost without that treatment burden reduction is certainly not as relevant so 2026 has been an exciting execution focus year for us as I just covered we finish enrollment in our two phase three trials. We're really excited for 2027 where we have top-line readout on both forefront one and forefront two. Forefront one is scheduled for readout of results in the second quarter and forefront two in the 2nd half of 2027. Financially in a strong cash position and with cash runway expected into the second half of 2028 thank you for the opportunity and thanks for the time great thanks for that presentation Chris I know we don't have the clinical team here today but maybe I'll jump off of some of the last comments you're talking about on the trial design to start so you you really designed to this study in a thoughtful way so maybe if you could just kind of hit on again what you feel like you've done to increase the probability of success for these phase three trials? Yeah, I'll maybe go into a little bit more detail, Colleen. It's a really important question. So first of all, I will point out again that our phase three trials are primarily a naive patient population. And that's important for a couple of reasons. One, it aligns with FDA guidance. The FDA requires that you show a vision benefit in these trials. And showing a vision a vision benefit in essence requires that you study patients that are naive. so therefore they have vision to gain. The other reason that's important for us is we saw clearly through our PRISM results, I just showed the recently diagnosed patient population, but we had a very impactful result across all patients through our phase two program, regardless of their disease severity. However, where we saw that result be most pronounced were in patients that were recently diagnosed. So in our PISM study, that was measured by patients diagnosed within the prior six months. And I think biologically that makes sense as well, right? A more recently diagnosed patient has more healthy retinal cells and therefore more healthy tissue that we transduce with our product approach. So I think those designs are really, really important. And then the design around what governs a retreatment is critical. I didn't go through the details in my presentation, but the high level is that to qualify for a supplemental treatment in our trial, you need to hit a number of criteria. The first is a combination of showing a five-letter loss in addition to a 50-micron increase or a 10-letter loss by itself or a 100-microns increase in anatomy. And that's reference versus the average of vision at week four and eight and the lowest point of anatomy, I think, after the first two loading doses. So that's important because one, it helps govern, I think reduce what we believe is variability in those results. But secondly, we think we've designed those supplemental criteria to protect against primarily our primary endpoint of vision. As I mentioned, first and foremost, hit your primary endpoint. If that means you sacrifice some re-treatment and therefore a treatment burden reduction on the margins, we think that's acceptable. But you first gotta, I think, design those criteria to protect against your primary endpoint. Great, and in terms of the rescues rate in the trial, what's kind of the expectation on what our investors should be focused on? Yeah, we hesitate to give a specific number because it becomes a binary conversation at that point, but what I think is important to share is we've shared through a number of different audiences the results we saw through our phase one, two PRISM study, and the general summary of those treatment burden reduction rates, if you will, kind of fell into the 80 to 90% range out to two years, depending upon the patient population that you were looking at. So patients that were more severe, clearly the treatment burden reduction rate was a little bit lower there, I think in the mid to high 70s. Patients that were recently diagnosed, we saw treatment burden rates in the high 80s. And then in conjunction with that, you saw treatment-free rates into 40, 50, or 60% across those patient populations as well. What I will tell you is that when we show those results to any retina physician anywhere in the world, they will tell us that's paradigm shifting. That's way beyond anything that's incremental in development and has the potential to completely change their practice and how they think about treating that disease. We don't think we have to be at that level, but certainly with the data that we've seen so far, we think we're well-positioned to be in that range or be in a range that's highly relevant. And has the FDA given much guidance in terms of the retreatment criteria or how they view rescues in the context of this trial? They have. I mean, we've shared, of course, our design with the FDA through our regulatory interactions. They've been supportive of our design. We haven't received any direction or feedback on it related to, I think sometimes the question comes up about the timing of retreatments relative to your primary endpoint. We haven'T received that feedback, we think, partly because we're not a finite treatment. I think other treatments that are designed to be, you know, six months or something in that range, that conversation we think is more relevant where it's clear that those treatments are no longer present. we're not a finite treatment we're lifelong so therefore I think the the relevance of that is different for our approach great and can you also touch on the the prophylactic steroid regimen in your phase threes and and your confidence that the safety profile that you've seen before will be replicated yeah so I think on safety as you know it's super important right on any therapy but certainly with the history of gene therapy I think that's what most people pay attention to first and foremost understandably so I would say a couple things I think first we think our safety profile is driven by our science I talked about the r100 vector the fact that that vector has been selected to be very tissue specific is really important because as I mentioned that allows us one to take a low dose and clearly there's evidence the more you push the dose the more you run the risk of having potential safety events so that's really important It also means that we don't believe we're transducing cells, particularly in the anterior segment, that we shouldn't be. So, therefore, we think that has implications for safety as well. But in addition to that, out of an abundance of safety, as you referenced, we do have a 20-week prophylactic steroid regimen, which is very common in all of these trials. For us, it's a 20‑week Durazol treatment. It's tapered over that 20‑wick period. and I'll tell you it's one of the questions that I certainly had upon when I joined 4D a couple of years ago was what would be physician and patient receptivity to that and I've been blown away with the fact that I have yet to hear one physician that's in our clinical trials express any patient hesitancy about that treatment whatsoever and I think when you and what they remind me of when I asked that question is well certainly that that has has some of the potential logistical challenges for patients. But a lot of these patients are used to taking topical drops for other reasons. And the possible benefit of reducing treatment burden by 80% or for many patients the potential of being treatment free for the rest of their lives far outweighs any inconvenience that may be associated with a temporary topical steroid regimen. And a bit of a side note, but I'll tell you one of the things we talked about this at a recent investor day one of the things that really is exciting for me from a commercial perspective is when we start to talk to patients about what a therapy like this would mean for them and their life the anxiety it could reduce the response we get is overwhelmingly positive so we somewhat tangential but we think the the patient interest and the potential of 4150 to have a significant effect on a patient's life certainly, I think, counterbalances any concern that folks may have about a temporary topical steroid regimen. Great. And we have a couple other gene therapy, what AMD treatment's reading out in the next, you know, number of months here. Can you maybe just walk us through some of the differences we should be aware of between your trial design and some of that competing trial designs? Yeah. Well, first of all, I I think across retina overall, as you all know, there's a lot of things going on. And that's not surprising, right? It's like, listen, it's a $16 billion category today. It's grown consecutively over the years, driven by an aging population, also driven by there has been new innovative therapies that have come to market. But all of these therapies continue to pursue, at least the boldest ones, like increments of durability gain. Again, important, we saw with the BISMO, a benefit of maybe 10 to 14 days, and it became a $4 billion drug. So I'm not dismissing the importance of durability. It's critically important. However, we believe there's a new way to approach this. We're not trying to increase durability by a couple of weeks. We're trying to have a continuous disease control backbone therapy that matches the biology of wet AMD. And the other gene therapy programs are trying to do the same thing. So we welcome that. I think it's good for patients. It's good the overall space to see significant innovation come to bear. We clearly believe we have differences versus the other gene therapy programs, Regenexx. I think we expect data from their program later this year. We're rooting for them. We think it could be good proof of concept. The big difference there, though, is Regenex is a program, it's a gene therapy delivered through a subretinal surgery. That is not, I mentioned earlier how we can seamlessly, I think, integrate into current retina practices and their operations. A subretina surgery does not do that. It's not necessarily convenient. takes the physician out of the clinic and has to go into the OR. I think it's great proof of concept, but clearly being intravitrally delivered and being able to administer it in a clinic, which is what they're used to doing multiple times a day right now, is, we believe, a key advantage. The other program is from Adverum slash Lilly. They were acquired last year. Similar approach to ours in that it's intravitreal. However, a couple things I think that are a difference in enough note, they take a very different high-dose approach. versus us by orders of magnitude. We think they may have to, just because their vector is different, it's not as tissue specific as we are. And I think a lot of the community is gonna look closely at that data to see what the safety profile looks like. We referenced earlier some of the issues with gene therapy. I think that program in particular has had a history of having some pretty severe inflammatory events. Whether they've solved for that or not, I think we'll see as we see the phase three data. Great, and you touched on, this is a really busy marketplace. There's the first generations, there's a longer acting, there's the biosimilars that have come on, TKs are in development, a number of other gene therapies. So how do you see gene therapy fitting into the broader treatment paradigm within WET-AMD? Yeah, and I appreciate the fact that it is a busy marketplace, but again, I'll point out it's busy for a reason. It's busy because there's lots of value there, but it's also busy because despite it being a large market, there's still a lot of significant unmet need. So the way we see our approach as being different is back to what I mentioned earlier. We're not a bolus therapy. We're a finite therapy. We're an increment of durability gain. We believe we can be a backbone therapy that provides 24-7 continuous disease control and therefore matches the therapy with the biology of the disease. We think that's really relevant. Physicians tell us it's really irrelevant. And interestingly, sometimes people about a gene therapy and they look at other gene therapies and other therapeutic areas and we sometimes get lumped into that category we think we're different from that as well because when we're low dose we're locally delivered um and and the fact that you know we're we're specific to um to the retina means that you now from a dosing and an approach standpoint where we stand apart versus anything else that's being delivered so we we think we have very clear differentiation we think from a patient need standpoint this approach of a backbone therapy fits with what doctors will tell us would be the ideal approach for treating this disease um and we actually we don't think this is an approach that is going to be kind of of used for just a small minority of patients. We actually think, the question that I ask physicians more and more is less around like, what are the patients you would use it for? It's more around considering this profile and the potential of a safe, always-on backbone therapy, what patients would you not consider it for. And there's some answers to that, but largely I think the general feedback we get is there's a very real possibility that this therapy could be like a backbone, basal type of approach for the majority of patients with wet AMD. Great, and I think historically, there's been some investor pushback that, oh, in this market, or in this disease, doctors are paid to inject, and you could be kind of taking away some of their patients. How have you kind of reached alignment, or you think you've reached alignment with the physicians in the clinics? Right, it's a really important variable, of course, in the real world. Bullets, anti-VEGF therapies, I've worked on them for 13, 14 years in different capacity. Yeah, it's they're reimbursed through a buy and build model. So in essence position positions purchase the medicine they take responsibility for administering them and then they get reimbursed with a Profit margin attached to that and that's that's become a pretty viable economic model So sometimes the the quick reaction when you hear 80% treatment burden reduction rates is a while You're going to reduce revenue by 80% and we're like well not necessarily But first of all, all of the current reimbursement today is a function of the price of the medicine So, while we don't know what the price would be, it's way too early to kind of go into details on that. What we do know is that it's not going to be the price at a single bolus anti-VEGF, so it'll be, you know, higher than that by a certain amount. We'll see where that lands. But what that translates to for a clinic is that you get reimbursed on a higher price medicine, but you get that up front. So the value that upfront capture is really important. The other part of the economic equation is today, we didn't talk a lot about this, but you look at real world data, over a five year period, up to 60% of patients that started on therapy at time zero are no longer on therapy, at year five. And that's value loss from a retina clinic standpoint. So if you're able to capture that again with a single therapy that's priced potentially over that, considering the value over that time window, that's a huge amount of incremental value for the clinic. And the last point that I think is important, 40% of retina docs that we survey would tell you that today their clinic is at capacity. They have a hard time seeing additional patients. I personally experienced that. I launched, as you know, a medicine called iZervay for geographic atrophy. One of the challenges was, how do you fit another bolus injection into a very busy clinic because of this capacity concern so we could reduce over time treatment rates the way that we just described we think there's a direct effect on that as well on the capacity constraints of a clinic and and that you know can free up a clinic to pursue different revenue opportunities so we think the economic value proposition of 4150 is actually better than the current treatment paradigm albeit recognizing that it's different great well I know we're just about out of time here unfortunately so maybe if you just want to wrap it up Chris you know what are Christian what are the kind of the the main reasons why investors should be paying attention to 40 MT over these next six to twelve months look fundamentally it's it's what Chris said I think we we really do believe this is 41 50 as the potential to treat to change the treatment paradigm for these patients and it's a big market it's meaningful it's gonna impact patients physicians and you know the the the current landscape and the current providers of wet AMD treatments because this has the potential to become the treatment of choice great thank you so much thank you thank you