Everyone I've got to go. Thanks very much. I'm Josh Schimmer from the Cantor Biotech Equity Research Team and very pleased to introduce from 4D Molecular Therapeutics, we have Kristian Humer, Chief Financial Officer, and Chris Simms, Chief Commercial Officer. Kristian, why don't we get things started? Give us a quick snapshot of where 4D is today and where the company is headed. Perfect. First of all, thank you, Josh, for having us. Really appreciate it. 4D, in terms of pipeline, we have our lead program, 4D-150, is in phase III for wet AMD. Our two phase III trials have fully enrolled. We're guiding to the first phase III trial to read out in Q2 of next year, and the second phase III trial to read out in the second half of next year. We will announce, towards the end of the month, the initiation of a phase III trial in DME, the next indication for 4D-150. We have a long program in 4D-710, where we'll provide an operational update towards the end of the year. That's a program in CF. From a cash perspective, we've got around $458 million in cash as of 6/30 this year, with cash runway into the second half of 2028. Okay, excellent. As we gear up for the 4FRONT clinical trial readouts, maybe not the ideal individuals, finance and commercial, to ask a clinical data question. But we'll give it a shot. We'll do our best. We'll give it a shot. It feels like wet AMD clinical trials of late have been full of surprises between the ABBV-RGX-314 data for Ocular Therapeutix and the DURAVYU data for EyePoint. As you look at those readouts, any lessons or takeaways as we think about 4D-150 in the 4FRONT trials? I can start with that. I think the first, maybe overstating the obvious, that I would point to is 4D-150 in our program scientifically couldn't be more different than I think the programs you referenced. We're gene therapy that expresses aflibercept. I think a key takeaway, again, stating the obvious most likely is that EYLEA is a really good drug. It performs well. The efficacy has been proven. It's been standard of care for well over a decade now, and I think the bar for success when you have a comparator of EYLEA is pretty high. We feel good about our chances. In essence, we express aflibercept, so that is EYLEA. It's the reason why we chose that as a protein to express with 4D-150, and we believe the data we've shown so far has shown strong progress, certainly as it relates to treatment burden reduction versus on-label EYLEA and the ability to preserve vision long term. That may not be a total surprise, but I think it's becoming evident as you see the data come through from some of these other programs, that the bar for efficacy and safety is high and as it should be. Okay. As we think about interpreting the 4FRONT results, I guess the primary goal is to show non-inferiority versus Q2 months EYLEA on BCVA, and I think based on the data we've seen from other programs, that seems like an achievable hurdle unless there's something weird that happens. Then as we move to the key secondary endpoint of reduction of EYLEA supplement injections. I guess on that metric, first, given some of the design changes from phase II to phase III, do you have a general sense of what you'd like to see in terms of that reduction, and at what point does it become clinically meaningful for specialists? Yeah. Great question. Our phase III program is 4FRONT-1 and 4FRONT-2, right? 4FRONT-1 is the first trial that is North America, so U.S. primarily with some sites in Canada as well. Before I get to, I think, the core of your question, maybe take a little bit of a step back and just remind the audience a little bit around just the history of this space and what's driven the evolution of this space. As many of you likely know, treating wet AMD has been done through bolus needles in the eye or intravitreal injections. Years ago, that started with LUCENTIS being a four week drug, at least per label, and then EYLEA comes out and says it's an eight-week drug, and it extends that durability a little bit further. What we've seen since then is largely an attempt to increase that durability in increments. You saw VABYSMO, which we think extended durability maybe by a couple of weeks, reduced maybe an average of an injection per year, and similar with EYLEA HD. What we endeavor to do is to not extend that durability or reduce that treatment burden by an increment of 15%, 20% is to do more of a paradigm change through a modality like an always-on continuous backbone therapy like 4D-150. As you referenced, Josh, what we've shown in our PRISM data, at least in wet AMD so far, is we've shown across a broad range of patients, so patients that historically were getting over 10 injections per year, so a pretty severe largely patient population, to patients that were more recently diagnosed, that we've shown treatment burden reduction rates in that 80+ or so percent range. A little bit of variability in that depending on the patient population, but generally, that's what we've demonstrated with the ability to preserve vision in concert with that significant reduction in treatment burden. We certainly believe that if we show that in our phase III program, we have a huge opportunity to change the treatment paradigm, and we think that translates to commercial success. To your question about how we've adapted the phase III program, we looked at some of the results from the phase II program. What we saw is that as patients were more recently diagnosed, so patients diagnosed in the last six months, that treatment burden effect that I referenced was more pronounced with those patients. Patients that were on therapy four or four years, we showed up to two years of treatment burden reduction rate in the mid-70s or so range. When you look at patients that were diagnosed within the prior six months, and then they went on 4D-150, we've now shown data up to two years in that patient population, and you see treatment burden reduction rates as measured by what you would have gotten on on-label EYLEA, full disclosure, in the mid-80s range. So a more pronounced effect. When we went into our phase III program, we said, how do we enhance for a patient population that's likely to have a higher level of response? We think in a more recently or newly diagnosed patient population is likely to do that for us. Our 4FRONT-1 trial is entirely treatment-naive. 4FRONT-2 has a blend of treatment-naive in some patients that were previously treated, and that satisfies a European regulatory requirement. That's an important change. Important, though, to recognize all of the phase III pivotal programs for retinal disease, A and B, primarily, you look at any of the approved medicines, they've all been studied in a naive patient population. We're not breaking precedent with our design. While there are some nuance changes to retreatment criteria and enrollment criteria that I can certainly go into, largely, we think our design for our 4FRONT program resembles the traditional design that you've seen of trials in this space. The control arm versus standard of care being EYLEA, which is being treated on label with the possibility of supplementation, and importantly, the primary endpoint being non-inferiority in vision at week 52. So largely consistent with history with a couple of adaptations that I just referenced. I guess, in the real-world practice, is there a standard approach for those patients who are being watched for PRN EYLEA? Is there a standard reinjection criteria? Is there an array of practice? How does that align with the criteria that you've selected in 4FRONT? Yeah, that's a great question. For those that know retina, it's probably not a lot that's standard. What is standard is I think most physicians, when it comes to treating patients in the real world with bolus therapies that exist today, use a treat and extend approach. So they start out and say, hey, I'm going to start treating you probably on label, probably every month for the first couple of injections. Then their approach is to say, I'm going to try and extend you to the maximum interval possible without under-treating you, with preserving vision and controlling anatomy. What a doctor will use to determine how long that interval is or how soon they will retreat can be highly varied. Some doctors say any retinal fluid whatsoever, regardless of what's going on with vision, is going to get a reinjection. Others will say, hey, there's some fluid. If it's been stable, it hasn't been a change in fluid for a while and your vision's been stable, I'm okay with it continue to let you go without a retreatment. So there is some variability. There's an art and a science to that. How do we approach that from a clinical trial setting? Because you can't just leave it out there and say, you decide, physician, especially in a phase III program. So you want to control that. We basically design criteria in consultation with thought leaders and KOLs in this space that says, hey, we're going to need something to guide when a patient gets a supplemental treatment that's on 4D-150. What should that be? We talk to the physicians. We have an expert panel that guides us on that. We look at what other programs in this space have done, and we try and come up with things that certainly help us ensure that we have maximum chances of success in our phase III program. But at the same time, you've got to balance whether those criteria are relevant in the real world. We think our criteria that we've designed for our phase III retreatment or supplemental criteria accomplishes that. In the real world, naturally, the PRN criteria will require fewer injections than Q2-month EYLEA. Yeah. As you think about the hurdle rate for 4FRONT-1 and what you need to show, not just to have a positive trial, but to convince the specialists that you really are reducing injection burden, not against Q2-month EYLEA, but what they're currently practicing. How do you think about the type of data you need to be generating to make that case? Yeah. I think a couple things. I'll push back a little bit on the statement that in the real world, you actually get dosed less than Q2-week EYLEA. That's true for some patients. It's not true for all patients. In fact, what the data shows is that half of patients on EYLEA, and we've actually just ran this data recently. We have an investor day plan that largely focused on commercial topics on the 21st of October. Quick plug. Everyone should join. We'll go into this in more detail. But what that data would show as we looked at it is that half of patients actually get treated more frequently than Q8 EYLEA. So there's a good portion of patients that are on a Q4, Q6. By the way, the reduction in that as newer agents like VABYSMO and EYLEA HD have come out has been incremental. It hasn't been massive. In fact, our data would suggest that if at most, those newer agents have reduced the average number of bolus injections a year by about one. So the aggregate is like six or seven over a course of a year if you're on standard therapy, if you're in the maintenance phase. Half of those patients are getting more frequent than Q8, and then a portion are certainly getting less than Q8. So they're the patients that have less severe disease, they're likely at a Q10, Q12. Some patients get up to Q16. But the general belief that, hey, patients don't need Q8 is actually not true in the real world, and it largely is driven by there's a high degree of variability in patient types. We even see this in our data. We see patients that were getting 10 injections in the prior year in our PRISM data that up to nine, 10 months were supplement-free, and all of a sudden they needed a couple of injections, and then they go back on a period of time when they're supplement-free again. We think that speaks to the high variability of the disease. Again, I think if we can, over a longer period of time, reduce that regardless of what interval you're on by orders of magnitude 70%, 80%, 90%, which we think we have a chance of doing, that's highly significant regardless of whether you're a patient that was on Q8 exactly, or getting every six weeks, or getting every 12 weeks. Okay. And you pointed out that VABYSMO was an incremental improvement- Yeah. over EYLEA, as we kind of rerun the math from the VABYSMO lens. Is it kind of roughly similar? Do you feel like the burden of evidence is a little higher because the duration of activity of VABYSMO is also a little higher? Yeah. A touch, but a bit again on the margins. So it's like what we've seen so far in our data that we've run is there's still, I think, north of 40% of patients on VABYSMO that are not getting a Q8 frequency in terms of their retreatment criteria. And admittedly, I think in aggregate, there's a lot of patients that are getting Q12 or Q16, which is amazing for those patients. I think it's also important to know, because sometimes we get this question saying, and I get this a lot from a commercial lens, which is, hey, Chris, what patients would a doctor not consider 4D-150 for? And my knee-jerk is like, I don't think anyone should not be considered for 4D-150 if you can preserve vision for the life of the patient. But I think practically what some doctors may look at is if you have some patients that do fine on one, two, three bolus injections a year, which is a relatively lower treatment burden for those patients, they may be least considered for a long-acting therapy like ours. However, the data that we've seen in the category would suggest that probably less than 20% of the patients, maybe even less than 15, fall into that category where two or three injections per year seems to be adequate for their ongoing maintenance of disease. Since 4FRONT-1 is being studied with lead-in EYLEA, how would it be used in the real world? Would you expect them to have flexibility to use VABYSMO or EYLEA for a lead-in? Yeah. Or high-dose EYLEA? Yeah, exactly. Listen, if a patient responds to anti-VEGF therapy, I think the biggest thing before you get introduced to a gene therapy that is lifelong is that you are responsive to anti-VEGF therapy. I think what the science would suggest, and I think regulators would agree, is that if you respond to EYLEA, you are likely to respond to VABYSMO and vice versa as well. We do not anticipate a criteria where because we use EYLEA in our clinical trial setting, that that is the drug that you have to show a response to. We think there is flexibility there, and we think that is reflected in what happens in the real world today. There is still a fair amount of switching as well that occurs in this space today. Yeah. Patients often stay on the maintenance therapy, but there is evidence that patients will get switched from one brand to another for a variety of reasons. Wet AMD practice is primarily a Part B buy-and-bill type landscape. Yeah. That obviously introduces a number of commercial considerations, both from the payer perspective, and they are willing to pay for 4D-150, depending on how you think about pricing it, which maybe we can talk about, and then also obviously practice economics themselves. Maybe can address those two angles around access and reimbursement. Yeah, absolutely. Let me first start with, before we get too deep into the reimbursement mechanics, I think it is important for your audience to be reminded that at least for wet AMD, over 90% of patients are Medicare. An older patient population presents in the elderly. So no surprise the vast majority of patients, their insurance is via Medicare. Of that 90%, 92% that is on Medicare, for simple modeling, half of them are on a Medicare Advantage plan of some sort, and the other half fall on a Medicare fee or direct reimbursement from CMS, so the Medicare fee for service. And the importance of understanding that payer mix, if you will, is because of what you just suggested. It is a buy-and-bill model, which means that physicians acquire the medicine, they take on the responsibility for getting reimbursed for the medicine, and they administer it in their office. Right? So Medicare Part B buy and bill. The thing that helps us as 4D-150 is that we think we tuck into that process pretty seamlessly. The method we think of distribution for 4D-150 would be the same as anti-VEGF therapy today. The storage requirements would be the same. The injection itself in terms of doctors can use whatever gauge needle, the volume of the medicine, all of that would resemble what they would be used to today for any of anti-VEGFs they use. And that, it is in the weeds a little bit, but it is really important because in these busy retina clinics, of course, they are seeing sometimes 60, 70, 80 patients a day. So if you can minimally disrupt their practice flow, that is important. So operationally, we think we fit in really well there. From a reimbursement standpoint, there are two big pieces that are important with reimbursement that you just touched on. One is how are payers going to look at it, right? As important in a buy-and-bill model is how do physicians get reimbursed and how does it affect their practice economics? Because retina clinics today, they make a profit, they make a margin on the drugs that they inject. If you have a therapy that says, we can reduce your treatment amount by 80%, the knee-jerk reaction is, what's that going to do to my practice economics? We think we have a good story on both of those elements. First of all, what we have heard from payers as we have done research is that payers recognize a few things that are really important. The caveat, Medicare Advantage payers. We do not go talk to CMS at this point in time, but Medicare Advantage payers who manage Medicare lives on behalf of CMS. Those payers will tell us a few things. 80% in recent research suggests that the importance of long-term vision preservation is, 80% would say that is really, really important. 100% said there is a need for new advanced therapies to treat wet AMD. 93% in our most recent survey suggested that they have a concern about patients losing vision over time because of persistence to therapy, which is things we also see in our real world data. We think the payer enthusiasm for a therapy like 4D-150 that could potentially reduce treatment burden by 80%+ and preserve vision long term is really high. Of course, how favorable they will be will often be a function of, well, what will we price it at? That is to be determined. We think we have massive pricing flexibility. We do not think this is a million-dollar therapy. We do not even think it is a $100,000 therapy at this point in time. But exactly where pricing will fall will be determined at a different point in time. We think we are in a good position to provide value from a payer perspective, notably the Medicare Advantage plans. Excuse me. Then from a physician standpoint, how it affects their practice economics is a really important dynamic as well. A couple of things that we highlight that it is important. First of all, today when you make money on these current bolus injections, it is a function of the price, right? You get reimbursed as a percentage of the list price. Just for illustration, if your reimbursement is 5% of a $2,000 drug, your net gross margin is $100. While we do not know our price, it certainly will not be equivalent to one bolus injection, right? It will be a higher price point. The value of getting reimbursed up front, not having to wait for increments over time, plus the value of reimbursement on a higher price point is favorable, we think, for a physician from an economics perspective. What that exactly looks like will ultimately be determined by what the price point is. That is one. The other point is, we think at this point that we will have the ability to price to capture multi-years of value. Again, this gene therapy is always on board. We think it is going to be helping preserve vision for years to come. Again, for your audience, just to illustrate this, if the pricing ultimately reflects, again, just for illustration, five years of value, it's important to recognize today, patients getting bolus treatment are not on therapy for five years. In fact, 40% fall off therapy for a host of reasons by the time they get to 18 months, and it continues to drop off over those years. If you have a therapy that economically you can capture the value of a patient that otherwise would have had to stay on therapy for five years, it's easy to recognize the incremental value to a practice of a therapy that can deliver that. Those are a couple of things that we point to when we talk to doctors around how this could certainly affect their practice from an economics and an operational standpoint, but we think it could affect it in a positive way. Capturing multi-years of value for an elderly patient population, I could envision a payer maybe having or pushing back a little bit if they don't necessarily feel a patient may live 5 more years. That would potentially be a little ageist. A little morbid, but yes. That may not even be legal. Right I do not know how you think about navigating that particular dynamic. I am not sure if that would be a particular dynamic we would have to navigate to your point. However, should we have to, I think there is a couple of other things that need to be considered in that conversation. First of all, today, unfortunately, yes, it is an older patient population, but we hear a lot of stories. We do a lot of research with payers. We are going to highlight some of that at our commercial investor day in October. I think we could all appreciate the impact that losing your vision would have on anybody, but particularly an older patient. At this stage in their life, vision is a source of independence, it is often a source of identity. So while yes, you may be injecting a therapy that would last for longer than the patient may actually, unfortunately, stay alive, we think that is the exception to the norm. As well, we think we can say, hey, while the patient is on therapy, we can help preserve their vision. So what is the value of keeping healthy vision for the duration of that patient's life? I think that is immense. I think that is game changing. Patients think that is game changing as well. What is the follow-on benefits of being able to maintain your independence and so on? All of this will become a core part of our economic story because again, we think we will be able to show data that in contrast to all the other bolus therapies that exist where vision in the real world is lost, what is the value of actually preserving the patient's vision for multiple years? We think that is quite significant, and I think that becomes a part of the story to illustrate to payers why we can have that effect. Coming back to the reinjection criteria that are used currently in the real world. With the launch of 4D-150, do you expect to push practice towards the reinjection criteria that was used in 4FRONT, or is the approach more, let's say fair, whatever you're doing, fine, keep doing that, and you can layer 4D-150 on top? Yeah. Well I've worked in retina since 2013 now. I know what you're going to say. You know what I'm going to say. I think commercially, we always remind physicians this is what the label says. This is what we can share promotionally. This is the evidence that exists. I think a lot of doctors say, "That's great information, Chris. Thank you very much, and this is what I'm going to do. Exactly. Knew that's where you were going. Yeah, exactly. Our role is to certainly educate. We think the criteria are super relevant, and I think some physicians will look to that and say, I'll use that as an input to how I'll decide. Let's be real and pragmatic, right? Yeah. Their revisit monitoring schedule, I think most retina physicians will approach that using their own expertise and make the decision that they think is right. Is it possible for 4D-150 to be provided as a prefilled syringe? We hear a lot about how important that is amongst the current- Yeah. treatment options. Is it relevant? Is it feasible? I think interesting, we think possibly feasible. In full disclosure, not something that's on the top of our priority list right now. Again, I had the good fortune of launching the first prefilled syringe for LUCENTIS at Genentech many years ago, and that was materially beneficial to a busy retina clinic because as you can appreciate, if you're injecting 50, 60, upwards of 80 patients a day, if you can save three minutes per each injection and the steps required, it matters. The significance of that is different for a gene therapy, that you're probably not going to be treating 50 times a day, certainly not in the first several years. So the time savings, the convenience benefit is not the same in our context as I think it is in a bolus therapy context. Yep. There are some major players in this space currently who may perceive 4D as a threat to their existing businesses. How might you consider entering the market cognizant of that dynamic as a small company, and do you feel like you'd benefit from a strategic partner to really go toe-to-toe with the big players in this space? I love that question for several reasons. I've launched medicines in retina in both large company settings. I did it at Genentech, I worked at Novartis, and I've launched medicines in a small company. I worked at Iveric Bio and built and led the team that launched IZERVAY prior to the acquisition to Astellas. Actually, both contexts, you can be super successful, and it can be a lot of fun, and you can have a good impact for patients. I love the opportunity to launch in a small, nimble biotech like 4D-150 and like we did at Iveric Bio. It gives you speed, gives you flexibility. I think it gives you better proximity and closeness to your physician and patient base that sometimes is harder to capture in a large company environment, not impossible, and I like that dynamic. The other important thing is, listen, in the U.S., there's about 2,500- 3,000 retina docs. 2,500- 2,600 account for probably about 95% of all VEGF treatments today. You don't need a 500-person or 1,000-person commercial team to scale a market of that size. I've done it several times. Largely, the commercial footprint is, I don't know, 100- 150 people, somewhere in there. Small biotechs like 4D-150 can certainly take that on. We did it at Iveric in a similar situation, and we'll plan to do it here. Long answer, but short is we don't need a strategic partner to commercialize, we think either U.S. or Europe, and our plans would suggest we're going to do it ourselves. All right. Kristian, maybe frame for us what we should be looking for beyond what we've talked about for 4D in the coming months and years. Sure. Again, the key things to look for is the 4D-150, the 4FRONT-1 data readouts in Q2 of next year, and 4FRONT-2 second half of next year. All eyes are on that. I think in closing, what I would like to say, and something that's still not understood enough, is that we really do fundamentally believe we have the potential to really change the treatment paradigm here for wet AMD patients and DME patients. This is not going to be a niche opportunity if we continue to see the activity that we're seeing as of right now, and so it matters. It matters to incumbents, and it will matter to us. Do you have adequate manufacturing capacity for what could be very meaningful early demand? We do, yes. We've switched to a third-party manufacturer, and we're preparing exactly for that scenario and are fully prepared. Excellent. Terrific discussion. Thank you, Kristian and Chris, for joining. Thanks, everyone, for tuning in, and very much looking forward to the event upcoming in New York. Thank you. Thanks, Josh. Thank you.