4D Molecular Therapeutics (FDMT) - Guggenheim 3rd Annual Healthcare Innovation Conference - 4D MOLECULAR THERAPEUTICS INC

All right. Welcome back to the Guggenheim Healthcare Innovation Conference. My name is Eddie Hickman, one of the biotech analysts here. I'm welcomed now by two members of the 4D Molecular Therapeutics team, CFO Christian Humer and Chief Commercial and Business Officer Chris Sims. Gentlemen, thank you so much for joining us. Chris, maybe, you know, I know you have a presentation prepared. So maybe for those who aren't familiar with the story, maybe give a sort of a brief overview and then we'll get into Q&A. Yeah, happy to. So, hi, everyone. And Eddie, thanks for the opportunity to be here. As Eddie mentioned, Chris Simms, Chief Commercial and Business Officer. I'll take you through a little bit of a presentation that gives you a bit of an overview of our company, what we see as the opportunity, and more detail on our lead asset. But before I do that, Eddie, to your question, a little bit on 4DMT. So 4DTMT is a genetic medicine company founded about 13 years ago, headquartered in the Bay Area. What's unique about us is that we take a very different approach, and we'll talk a little bit more about this, to how we actually develop key vectors to deliver our genetic medicines. We leverage technology that's Nobel Prize winning out of Berkeley that basically uses directed evolution to select vectors that are super targeted to the tissues that they need to transduce and deliver the medicine and by implication of that don't transduced cells that they shouldn't connect with company as I mentioned been around for about 13 years we're super excited our lead program and I'll go through in a few moments is in phase three we expect top-line data on that program in the second quarter of next year in the second half it's for wet AMD and again I'll through that in more detail in the slides here so maybe I'll just take the next 10 minutes or so and go through these two yeah that helps thank you so as a reminder I may be making some forward-looking statements there's more information of course about our SEC filings that can be found on our website a couple of key takeaways from my short presentation today first and foremost our lead asset again it's called 4d 150 we believe has the potential to establish a new treatment paradigm for wet AMD for your audience if they're not familiar with the size of the wet AMD category or broadly the anti VEGF category that's used to treat retinal disease the category globally is worth about 16 billion dollars and has been growing steadily and despite that size of that category there's still significant unmet need that again I'll go through in a few moments that we believe we are uniquely positioned to address a bit of a shameless plug I don't have a lot of time to go through all the commercial opportunity here today but if you reference our website we recently had a R&D investor day focused largely actually on the commercial opportunity wherein we go through a lot more of the detail as to why we think the commercial opportunities quite significant for 4150 some of the other key takeaways that we think are important first of all we believe 4150 as a backbone therapy as the potential for lifelong continuous disease control from a single dose the target product profile of 4150 is that we believe it can meet needs of both patients that by preserving their vision while significantly reducing the treatment burden and with the opportunity for for injection freedom. A little bit more on that. The current standard of care is frequent bolus injections into your eye of anti-VEGF. Those therapies are highly efficacious. We know they work well. However, as I'm sure you can appreciate, a patient needs to go to a doctor's office on some frequency. For some patients, that's monthly. For others, it's every two months or three months. Depends upon your treatment need. But over time, that creates significant treatment burden, both for the patient, the caregivers, and so on. And what happens in the real world is that patients ultimately become, are not treated as frequently as they need to be, and therefore they lose vision that otherwise they should be gaining. So our profile, we believe, has the potential with a single injection, which delivers the medicine they need continuously, we can help a patient preserve that vision for the rest of their lives, we think, with the potential for significant treatment burden reduction. the other key takeaway is that our phase three program and our phase phase three design we think is set up to position us for success and i'll go through a little bit more as to what that design looks like and i think very importantly from a commercial perspective um patients physicians and payers together we think are expected to um be excited and evidence so far and the work we've done would suggest that we meet the needs of all those stakeholders And we think by doing so, we can drive significant commercial adoption. A little bit on the science of why we think we're uniquely positioned to achieve what I just described. So 4150 is designed for targeted delivery of aflipiracept, producing transgenes to the retina with a single intravitreal injection. Core to the product design, and it's unique to us, it comes out of the science that I referenced earlier, is the R100 capsid that was developed internally. It's proprietary to us, and what that R100 capsid allows us to do is three things that are really important. First, it allows us to take a low-dose approach and deliver the medicines through an intervitreal injection. An IBT injection is a procedure that physicians know well. They do it hundreds of times today with existing therapies. The reason that's important is that other therapies, gene therapies in development take a sub-retinal or surgical approach, so being able to deliver intravitrally is a huge advantage when it comes to adoption. Our CAPSID also allows us to target the retinal cells specifically and not transduce cells that we shouldn't be transducing, therefore I think the third thing is that then has an implication for the dose, but also then has the implication for what we believe is a very very favorable toxicity and safety profile, which is critical for gene therapies. Of course, we provide or we combine our R100 capsid with a therapeutic payload that includes inflipracept, and when you put those two things together and you deliver it to the retinal cells where it's needed the most, you get long-term expression and we believe long- term disease control. A little bit on what's different about us and what the unmet need is. simply what this slide tells us is that wet AMD is a chronic disease it's always there and today it's treated episodically right through bolus injections at some level of frequency and we think the ideal match of the ideal therapy rather is a therapy that treats the disease with a chronic therapy and that's where we get excited about a backbone therapy of 4150 where it's all on it's already in the disease as opposed to the episodic nature of treatment today so we believe we if you match the therapy with the biology of the disease you get much better outcomes and that's in essence what we show here with our positioning around being a continuous backbone therapy where in essence we know the disease is always present and in a therapy like 4150 that is continuously producing the drug that treats a disease we think is the ideal match. And what that translates to is that today in the real world, what happens is that patients actually come in, they're diagnosed, and quite often they get a couple of early bolus shots of anti-VEGF and they gain vision, which is great, right? Vision, they gain five to ten liters in vision upon initiation of therapy. However, because of the treatment burden that I described earlier, it's quite common that over time a lot of patients fall-off therapy or they become undertreated, that results in that vision that they initially gained, they lose it. And therefore, we think that creates a continuous control gap. And therefore the opportunity with the backbone therapy is to preserve that initial gain of vision and allow a patient to do that while also significantly reducing the treatment that goes along with that over the life of the patient. This slide just highlights some high-level results that we've generated through our program development so far. What we show here is the two-year results of the recently diagnosed patient population. So our Phase 1-2 PRISM study looked at wet AMD patients across a broad range. So we show data on patients that had a high burden and then we saw data on patient that had more moderate burden as well as patients that were more recently diagnosed. We show the recently diagnosed patient populations on this slide because it most resembles the the patients that we're studying in our phase three program. And the results that we saw through our phase two with this patient population were quite astounding. We're out to two years. You see in the top left, you see that central subfield thickness or CST, a marker of anatomy, was very controlled. And as well on the bottom, you see the best corrected visual acuity. Remember in the previous slide, I showed that most patients that vision falls off. We actually showed that maintenance of vision, again, out to 2 years. And importantly, we did that with an average of 1.66 supplemental injections over that two-year period. So when you compare that to what a patient would have had to receive if they were treated on label with the standard of care, which is ILEA, if they are getting treated Q8 with ILEAA over that two- year period, they would have been on pace to get 12 injections. So think about the impact of that to a patient. Instead of getting 12, you got 1.6. So that translates to about an 87% burden reduction in treatment. And importantly, 66% of patients, again, out to two years were supplement-free, so the only thing that they needed was 4D150 to maintain that vision. Of course, none of this matters without safety. And what we have shown so far and what we show on this slide is the 71 patients that we've studied thus far with our Phase III dose. And what we see is that there were two cases of mild and transient inflammation that was resolved with the topical prophylactic steroid. There were no 4150-related inflammation events after that period. And importantly, based upon some of the history in this space, where other programs have had more severe inflammatory events, we did not see any evidence of 4150 related serious adverse events. things like occlusive or non-occlusive vasculitis, no endophthalmitis or choroidal effusions. So we're pretty excited about the safety profile. We think it's a major differentiating factor for our program. And I will take us through, this is a summary of our target product profile. And the simple version of this is that we believe we could be a backbone with therapy that provides for continuous disease control. The thing that I'll highlight is the bottom right element here, where we talk about it being a single office intervitreal injection. The reason that's important is what I referenced earlier. These clinics that administer these therapies are super busy. A lot of these retina doctors will see 50, 60, 70 patients a day delivering intervitral injections. So our product, because it's an intervitural injection like the current products they administer today, we fit seamlessly into the current practice operations and the practice flow of patients. And importantly, we also will be reimbursed using the very familiar buy and bill reimbursement model that retina practice is used quite frequently. I mentioned earlier we're in phase three. In a moment, I'll take you through a high-level summary of our phase three trial design, but our two phase three programs are forefront one and forefront two. Standard non-inferior designs. Forefront one is a North American trial. We enrolled 523 patients. We actually finished enrollment about four months faster than we initially projected we expect results in forefront one in the second quarter of 2027 and forefront two is our global trial with sites the us europe south america and asia we also expect we expect result in the forefront two program in the back half of 20 27. a little bit on the design of four for at the forefront program again for your audience that's familiar with this space our design is very standard there's nothing out of the ordinary here it's comparing a 4150 arm versus a control arm of a flipper step dosed on label primary endpoints at 52 weeks the endpoint is non-inferiority of vision and in the US that's defined by a margin of four and a half letters and again I won't go through the details here but we have established both selection criteria for patients to get enrolled in the trial and in essence showing a responsiveness to VEGF is the primary one and having a cap on CST levels and in addition to that needing to show a response to VegeF of about a 10% reduction in CST levels. This slide again goes through a little bit more of the detail of the supplemental criteria and again they're listed here. The supplemental criteria drives whether a patient can be retreated to through the through the clinical trial program and as I touched on earlier these are our key milestones so top line data in the first or starting the second quarter of next year on forefront one top line day on forefront two in the second half and financially in a strong position with cash runway expected to run into the second half of 2028 so hopefully that was helpful for your audience as context and maybe we can go to Q&A. Yeah, very helpful. No, thank you for running through that overview and definitely have a few questions to follow up as you think about, as you have phase three data coming. When we think about how the space has moved over the past couple of years with sort of idea to increase or sort of decrease the injection burden, who is the ideal patient for a therapy like this in a sense of, you know, with patients going on biosimilars, there's now high-dose ilea, there's Vibismo, there're other options that are all attempting to sort of extend that treatment paradigm. Where do you see as the optimal patient for a treatment like this? Yeah, it's a great question, Eddie. So you're right. I mean, everything that's in development, both historically and what's in current development, it''s all in the pursuit of an increment of durability. Like when you think about what Vibissimo did versus ilea and so on, it ''s all extended durability, which translates in the real world about a couple of weeks, we're taking a different approach. We're not trying to incrementally extend durability. We actually think, again, a chronic disease should have an always-on chronic therapy. So the reason I think it's important to understand that the question I actually ask physicians, I started off asking, like, hey, what's your ideal patient? And we have answers for that. But more and more, I now ask, like what's the patient that you wouldn't consider this for again you have to assume safety like there's a lot of things that have to be true safety and real world efficacy and all those things we'll see in our phase three program and of course you need to make sure you can get reimbursed and the reality is the physicians would say with time the majority of their patients they would consider for a therapy like this it provides baseline basal type level of treatment um and and i think the the nuance around that though is the patients that are most likely to be treated initially in the real world are patients that you just referenced, are patients that have that higher need of disease. And that's for the primary, the practical reason of those are the patients that are most motivated and physicians are looking for an alternative treatment for because they have the patient, they again have the highest level of disease burden. But we see when we talk to doctors that while that's primarily the patients that I think represent the source of volume out of the gate, call it in the first six to nine months of a launch window, once real world safety is established, once the physicians have confidence in reimbursement, they absolutely believe that a broader patient population that has either moderate disease burden or lower disease burden would be considered, again, for the primary benefit of having an always-on chronic kind of like backbone therapy that provides continuous disease control. So that's how we think about it. We think it certainly will take time to get there, but that's what we hear from physicians. When we talk to some, you know, KOLs that are, you know, regularly using the anti-VEGF therapies that are out there, a lot of them admit that, like, in the real world, they end up over-treating because they don't have the rescue criteria that they have to be strict by. And the second they see any bit of fluid they want to inject because they know that that patient is going to eventually lose vision. I'm curious about what your perspective of the sort of link between CST and BCVA is in terms of how important it is to keep that fluid level at zero And is the idea of having sort of a constant VEGF trap already always around to sort of keep sopping up VEGA as it comes up to the point where you wouldn't have an accumulation of fluid ever or at least be mitigated? Yeah, I think that there's an art and a science to how physicians treat patients today. Some physicians have this, you know, see fluid, treat fluid somewhat irrespective of what's going on with vision. Some doctors are more tolerant with fluid depending upon whether vision has remained stable. I think our value proposition is that, to your point, we provide constant VEGF, I think, control. And for some patients, that means you don't need supplementation. For other patients, it means you may need occasional supplementation, but it's an important point you just made. And what's evolving in this field as well is this conversation around what's more important to have the retina constantly dry at all time points, regardless of vision, or is it more important to minimize the oscillations in fluid? And what we see with current bolus therapies is that certainly they're very efficacious, they control fluid, they lower fluid, but what happens, they do it in a bolus oscillating manner, so you get this pulsating nature to retinal fluid. So it goes up, you treat, it comes back down again. And there's a belief that it's that variability in fluid control that over time creates anatomical issues, can lead to fibrosis and so on. So we believe one of the key things that we can provide anatomically because of that constant VEGF suppression is actually more steady control, so you don't get that pulsating nature of retinal fluid. And we believe there's a good case to be made for what that could relate to in long-term outcomes, particularly with maintaining the health of the retina and therefore, I think, helping patients preserve vision long-terms. Do we know what the sort of relative concentration of a flibrocept in the eye would be, you know, after the vector versus like two milligram versus eight milligram of Vigeneron's product in a sense? Like, is there any benefit of eight milligram compared to like that you're not using eight milligram as a comparator here in terms of it's the same active API? Yeah, we don't know the exact answer to that, but I think it's important to understand that from how 4150 works is that you don't measure a flipper step that's being produced in the vitreous of the eye, right? Because the unique thing about the R100 vector is that it's designed to actually transduce retinal cells and importantly not transduced cells that are not in the retina. So, therefore, the aflipiracept production actually happens in the retina where it's most needed. And we think that's important, but it does then have an implication for it. It makes it more challenging to tap the vitreous, for example, and measure aflapiracep levels. And I think all of these, certainly ILEA-HD at a higher dosage seems to have a durability benefit versus regular ILEAF a couple of weeks. And I think all of these agents seem to be pursuing that incremental benefit as well. Again, our benefit and what we think we can provide a patient is not measured in another couple of weeks of durability. So, you know, if those agents take a Q6 week patient to Q8 or a Q10 to Q12, our benefits are so much further beyond that. It doesn't really matter that much relative to those other products. No, that's helpful. And as we think going forward, phase three trials can sort of be derailed by catastrophic vision loss due to other issues. How are you mitigating the possibility of that happening, especially in a placebo arm in your study due to sort of extraneous retinal conditions or other eye conditions? Well, I mean, hopefully you designed the trial well and you powered it well and that these things can happen in a clinical trial setting. and you know you hopefully your randomization accounts for that in in both arms but we also think have been very thoughtful around what type of patients should be enrolled in the trial i think we have a world-class clinical operations and development team that runs the execution of this very tightly and observes all of these events in partnership with our reading center on on literally a daily and our hourly basis and and again I think we provide certainly when it comes to vision loss that you reference the key thing for us is making sure that the retreatment criteria that we define that I kind of skimmed through a little quickly in the presentation but those retreatment criteria are primarily designed to protect the primary endpoint so enter if a patient is losing vision catch it intervene early because at the end of the day, what's most important is that you hit your primary endpoint. If that means that your, you know, treatment burden reduction rate is five or 10%, maybe below where you saw it in PRISM, we don't, that's not a big deal relative to the attractiveness of our TPP. But you first and foremost, protect your primary endpoints. So therefore, retreat and intervene when you need to. Very helpful. And in terms of the expectations for the clinical data coming, you know next year, you have patients, you have one study that's treatment, even one that has a mix. What can we learn differently about how the drug works between those two populations? Do we expect differences in how we should analyze those two studies? Yeah, it's a good question. So, I mean, I'll take people back to our PRISM data. So what we saw in our PISM data is that patients that were recently diagnosed, which you think is the best proxy for our phase three patient population. So patients were recently diagnosed within the prior six months are the patients that we saw the most pronounced effect as it related to treatment burden reduction, right? After two years, I think we see like an 87% treatment burden reduction in that population, like over 60% of patients are injection-free. So, you know, we think that's a good, I mean, I think that part of the reason why we look at that patient population in our Phase III program, but the difference between Forefront I and II I think are slight because even the patients in Forefront II that could have been previously treated, it's up to a maximum of six months. And we have that in forefront, too, to satisfy European regulatory requirements. So they wanted some patients that were prior treated. So even those patients that are recently diagnosed at the six months, I think, will largely behave like a more recently diagnosed patient population. So there may be a slight delta in terms of, like, the vision and gain because you have a portion of patients that were previously treated. But we don't expect anything of significance between the two trials beyond that. Got it. What other indications are you looking at? DMA still on the table? Yeah, DMA, we actually, it's more than on the table. We started the trial about two months ago. So we're excited about the opportunity for diabetic macular edema. We're actually excited about it. We're excited to talk about the potential for this type of a modality for diabetic eye disease in general. Yeah, we'll look forward to that. Christian, I said I'd get to you at the very end for a financial recap. So maybe tell us how you're going to fund all these different programs and two phase threes and everything happy to happy to eddie so uh as as chris mentioned we have a little bit over 430 million dollars in cash and cash equivalents as of the end of q2 um we're guiding to cash runway into the second half of 2028 that does not include that cash runway guns does not includes spend that we need to commit post forefront one some big spend in particular around commercial stuff that we want to commit to once we know what the data looks like great i think that's all the time we have uh you know good luck and we'll look forward to seeing data next year thanks guys thank you thank you for having us