So, Dhaval Desai, Chief Development Officer. So, thank you very much to, you know, the whole team here from 4D Molecular Therapeutics, being able to join us this morning or this afternoon. We're very grateful for that. Thanks for having us. Absolutely. So we have a lot of ground to cover today. Maybe to start things off, I know we had the chance to meet recently at the ASRS meeting in Sweden, and we'll definitely look forward to going through some of the updates for 4D-150 and wet AMD. But to start off, maybe you could first give us an overview of how 4D is approaching gene therapy overall, specifically the programs you're most excited about near term for the retina. Yeah, sure. So thanks for having us, and I look forward to sharing this, the spotlight here today with our great team. So, you know, when we think about different therapeutic areas as a platform and product company, we think about genetic medicines. And we utilize a Nobel Prize-winning technology called directed evolution to invent customized vectors for any tissue in the body. So when we think about the retina, you know, the holy grail for the retina, for gene therapy and other genetic medicines is a simple, safe intravitreal injection with a very low inflammation and toxicity rate- Mm-hmm ... and a high degree of transduction of the retina, in a durable fashion. That's what we at 4D have delivered. So we've used directed evolution to invent a capsid called R100, an AAV delivery vehicle that can be used by a very low dose, simple intravitreal injection with no significant inflammation, high degree of transduction and gene expression. So, that's a game changer. Then what we can do for any set of diseases that we want to treat, we can put in different genetic payloads to treat that disease. So in the case of 4D-150, our wet AMD asset and diabetic retinopathy asset, we express Aflibercept plus a second transgene that knocks out VEGF-C. A single product, we can knock out four different VEGF family members. We administer by a simple, low-dose, safe intravitreal injection, and that product is now moving rapidly towards phase 3. We'll speak about that today, I'm sure. And then 4D-175 is our geographic atrophy asset. That leverages the same exact capsid that we've now shown is safe and delivers in a high efficiency. And now we've just swapped out the transgene payload to knock out a key master regulator of the complement factor pathway, complement factor H. So using this vector that we invented, that's proprietary to us, we can go after a large number of large market opportunities in retina. Mm-hmm. Absolutely. Very helpful. So you mentioned leveraging the R100 intravitreal vector across ophthalmology programs. Obviously, then you have other vectors for other indications as well. Absolutely. You know, when we started, you know, we knew that, you know, this had never been done before, so we really wanted diversification to mitigate risk. So we invented an intravitreal vector for low-dose intravitreal delivery to the retina, a vector for aerosol delivery to lung airways, and then a vector for low-dose IV delivery to the heart. And in each case, we either selected a monogenic disorder like cystic fibrosis in the lung- Mm-hmm ... or Fabry disease in the heart, where it was just a simple replacement of a missing gene, or in the case of the eye diseases, we elected to express a validated therapeutic, like in the case of 4D-150, for Aflibercept, to really mitigate target risk. So what's great is to be standing here ten years later and say that all three of those vectors have been validated in the clinic to deliver- Mm-hmm ... best-in-class delivery at significantly lower doses than the competition, and that those lower doses result in better safety and better cost of goods. And all of this allows us to go into large market opportunities and not be just wedded to rare disease. Right. No, very helpful. And, you know, also, before we dive into some of the recent data, maybe you could note for some of our newer viewers, I know you've kind of alluded to this, the design of 4D-150 has the dual transgene payload, Aflibercept and VEGF-C RNAi. Can you speak to how that could address some of the limitations of conventional AAV vectors and also sort of your capsid sequence optimization approach? Sure. So maybe I'll kind of speak to the design, and then maybe- Mm-hmm ... turn it over to Dhaval for, to kind of explain the unmet needs that we're addressing and when, wet AMD and DME. Mm-hmm. So the design, as I said, is to start with the capsid, the delivery vehicle. We use directed evolution to do that, a best-in-class, low-dose intravitreal delivery. We then thought about the transgene payload, and we asked the question, you know, "What's the most effective protein therapeutic currently on the market?" And it was Aflibercept, so we expressed the protein for that, and that's secreted from the transduced cells in the retina. And then we asked the question: "Well, what other targets are out there?" Because there was still room in the genome to add another payload. And we looked across the landscape there and felt the most validated at that time was VEGF-C, a mediator of resistance to anti-VEGF-A therapies. And so we put in the RNAi for VEGF-C. So, you know, this is something that other therapies can't do, including other gene therapies, is target all four family members in a single product. We also have a proprietary, promoter system that increases the expression levels of the Aflibercept, from our vector as well. So it's a differentiated capsid, and it's a differentiated payload within that. And I think our data to date supports that very strongly. Maybe I'll turn it over to Dhaval Desai, our new Chief Development Officer, to speak to sort of the unmet needs that we're addressing with 4D-150. Yeah, thanks, David. And Matt, as you know, you know, you've covered this space for a for a while, and the folks that are on the call kind of understand this as well, is that, you know, Lucentis was a great drug, and every subsequent iteration that we've had has gotten a little bit better, right? So we've gone 4 weeks to 8 weeks, 8 to 12, 12 to 16, but at the end of the day, it doesn't really address kind of the problem that we still see with wet AMD and every retinal disease, and that is that it requires somebody to physically put an injection into an eyeball. Over time, data has shown us that, where you start with 8-12 injections and whatever it may be in year 1, by the time you hit year 7, and you're down to 2-3. With that drop in injection comes a drop in visual acuity, and it's across the board. When you do long-term follow-up, it's always there. You're talking about elderly patients that generally need a companion to go into a doctor's office to get a shot. Those visits generally tend to be 2-3 hours at a time, and so over a sustained period of time, that's just not feasible. What our hope is with 4D-150 is to really be able to address this concept of give them an injection, and a certain percentage of patients, you'll be functionally cured, and for others, you may need a top off, and that's maybe one or two over the course of a year or two to kind of hold you steady. The second part of this is this concept of interval dose and kind of what that does to the neural tissue of the retina, and we've all seen the sawtooth patterns of either Q4 or Q8, whatever it may be. Mm-hmm. And so what we kind of like in that, too, is almost like a CTE, right? When you have that constant pounding of neural tissue, what happens is, in the long term, you just have bad things that happen, and we think that by holding that tissue steady with a steady level of anti-VEGF always being on board, we're going to avoid some of those long-term bad things that potentially could happen: fibrosis, geographic atrophy, et cetera. Mm-hmm. So that's how we think the approach of 4D-150 really has the potential to change the way we treat wet AMD, as opposed to just kind of extending intervals. Mm-hmm. Well, that makes a lot of sense. I mean, in thinking about your approach, obviously there's the dose expansion, the population extension cohorts. You're evaluating patients that have had upwards of 10 annual anti-VEGF injections, down to maybe 4 approximately. When we think about safety, the annualized anti-VEGF injection reduction that we've seen, need for supplemental Aflibercept and stabilization of the BCVA, and/or CST components, what do you think is most clinically meaningful from what we've seen so far from the single 4D-150 injection? Well, well, I can kick it off, Matthew, and then turn it over to the- Mm-hmm ... the experts on the call. Yeah, we're thrilled with the safety, so up to about 139 patients to date with wet AMD who received the 4D-150, and we have about a 2% mild inflammation rate, so very similar to what you see with Eylea or Lucentis or Vabysmo. So we're thrilled- Right ... with the safety. That was the first box we needed to check. And then, if you look at the efficacy, what we did, which I think is just good drug development led by Bob Kim, is start in the highest need patients, the most difficult patients. First in human, you haven't proven safety yet. You haven't proven efficacy. Let's go into the hardest to treat patients. And so when we think about the phase I and the phase IIa and the highest need patients, so-called dose exploration and dose expansion patients, that's where, again, patients had received on average about 10 injections in the prior year, a very thickened retinas and CST. Patients had, you know, on average, about half of the patients had more than 5 years of disease duration. So start in the hardest to treat, prove safety, prove biological activity, which we reported that out in February at Angiogenesis, where we showed about a 63% injection-free rate at six months in the hardest- Mm-hmm ... to treat patients. We also saw a flattening of that CST, just as we expected to see, and we saw the expected sawtooth up and down CST on Aflibercept, so I think that was a really strong proof of concept. And that allowed us to then go into the what we call population extension, which is essentially just a very broad population. So it still has the most severe, but it's also got some patients, about half, who look more like a phase 3 population. Still pre-treated, but, you know, kind of better starting place, and so we've been able to look at a broad spectrum of patients, show activity in the hardest to treat, activity in the so more earlier patients. If you look at some of the data we released at ASRS, if you look at patients who, say, had just one or two prior injections on the swim lane plot, you can see, you know, over 80% injection-free rate at six months. So I think what we're gonna see is similar benefit across all populations here, but when we think about a phase 3 population, we think about getting this to the market, the lowest risk possible. We want to move into that earlier population, and we can do that now based on the safety that we've shown. Mm-hmm. So maybe I'll turn it over to Carlos and just say a few words about how he views the data to date. ... Thank you, David. Yeah, I think you covered the most important points. You know, really the safety piece is really critical. You know, for me as a retina specialist and as a drug developer, that was the biggest barrier for gene therapy. And I think that 4D-150, very clearly, given the totality of the data, addressed that pretty nicely. And the point that David made around the great drug development that Bob has led, you know, over the past few years at the team is actually quite important because we know that neovascular AMD patients have a very heterogeneous response. So we're used to look at the mean change in BCVA for the pivotal trials, but the reality is that when you do a spaghetti plot, you see this wide variance in responses among the different patients, even when they're treatment naive. Now, when you add on top of that the duration of the disease, you have this, not only the variability, but also the lower BCVA outcomes as well. So I praise the team as a drug developer for going to that, you know, population first. And even in that difficult-to-treat population, you see there's very clear signals for efficacy as well, and across all of the different populations. And this really reminded me some of the challenges that we were going through when we were developing faricimab. You know, if you're familiar with the phase 1 data for faricimab, we only have about 24 patients, you know, kind of, you know, prove the safety and some random signals around the efficacy. And really, you know, reminded me about that potential we saw early on faricimab, about the potential that I see nowadays with 4D-150 for patients with AMD and DME as well. That's very helpful. Thank you. Then kind of speaking to the American Society of Retina Specialists updates, we saw the 24-week landmark analysis from the population extension cohort. As you've alluded to, that included the anatomic control without fluctuations. That was the 3E10 dosing being brought forward, potentially for phase 3, and without significant inflammation, utilizing the corticosteroid regimen. So one question I wanted to ask the team was that, following that 24-week update, we did see some pullback in the stock that may have been sort of challenging to decipher, considering the consistent benefit and durability from 4D-150. What are some of your high-level thoughts here on what any critiques could have been in terms of warranting that or any further perspective you have there? Yeah. Thanks, Matthew. You know, we noticed very much so. It was not subtle. Right. You know, we've had a huge number of conversations with investors, with analysts, and I think the people who understand the story very much feel like it was a positive, solid update in a broader population than what we've shown before. I think the pushback that we've seen, which I think is typical of gene therapy, is people want more durability. And when they saw- Right ... you know, it's, it's standard when you move into an earlier stage population with gene therapy, that you need to cover them with a week four injection while transgene expression is ramping up. Whereas in the end-stage patients who had already had 10 injections in the prior year, we didn't need to do that. Right. So I think some people saw that and said, "Well, wait a minute, why are they doing that?" And then they said, "Well, 24 weeks is now really just 20 weeks." You know, so I think what surprised us is people, instead of just saying, "I'm gonna wait for more data," kind of, you know, made different moves. That's why we're really excited to, you know, show the longest available data on every patient in September at Euretina. Right ... because that, we believe, is gonna really show the durability here. And we can get into the details, but, you know, we're gonna have anywhere from sort of 9-ish to 12-ish months on that population extension, which includes both, both heavily pretreated... not heavily pretreated, but, but pretty severe disease activity, and then more some newly diagnosed patients who would be more like the Phase 3 population. So we get to see both of those. And then for our more, you know, highly previously heavily pretreated eye treatment need Phase 1 and 2 dose expansion patients, we'll have on the order of 2.5 years maximal follow-up. So I think we're gonna be able to answer for people the clear durability that we have. And, you know, it's not just us. Don't just believe us. If you look at AAV subretinal injection for Luxturna- Mm-hmm ... those patients are out now 10 years and still benefiting and expressing. If you look at, you know, REGENXBIO or Adverum, you know, they- Mm-hmm ... they may struggle with route of delivery and inflammation, but they've shown clear, meaningful efficacy that's stable out through 3-5 years. So- Mm-hmm ... AAV in the retina is durable. We're gonna show that durability, and we think that's gonna check an important box for investors who really feel like they need to see that prior to going into phase 3 in Q1 next year. Mm-hmm. That's very helpful. So one point that we had the opportunity to discuss was any pushback related to the Aflibercept loading doses. I know there's the second Aflibercept dose, or loading dose at week 4. At least from my takeaway, it seems it's relevant that Aflibercept would have subsided prospectively by 8-12 weeks prior to a 24-week analysis. Are there any further important points to consider here from the loading dose design, or any changes or perspectives that you can offer? Yeah, as I said before, you know, we—it's standard as these treatments move towards Phase 3, and it's really based on an ethical safety concern, that if you don't- Sure ...cover patients during that ramp-up of gene expression, which again starts at about 1-2 weeks, but really probably doesn't peak till 8-12 weeks. It's just purely saying in wet AMD, if patients are left untreated, they could have a bleed, and so let's give that. Now, have we seen a difference in efficacy based on that week 4? No, absolutely not. Mm-hmm. We think that the patients who, for example, population extension, we had a number of patients who missed the week 4 and only got the pre-4D-150 loading dose. Those patients did just as well, and in fact, the high dose, all 3 were still injection-free. So it's not impacting efficacy beyond 8 weeks, but it's really something that we need to, we wanted to pilot prior to Phase 3, because in Phase 3, you're going to want to protect patient safety and then have that primary readout all the way out at week 52. Mm-hmm. And so, you know, that, that's why the change from the Phase 1/2 population, severe population, where they already had had 10+ injections the prior year, versus this population, which was more broad, some newly diagnosed and needed that protection and loading. And then in Phase 3, we'll definitely want to include that. Our competition in terms of TKIs and gene therapy, we have anywhere from 3-5 loading doses in their Phase 3. Mm-hmm. Yeah. That's very helpful for that context. Yeah. And then also thinking about the update at week 24 for the 3E10 dose, we saw the mentioned 89% reduction in annualized injection rate, which is really strong. 93% of patients receiving zero or one injections, and 77% being injection-free, and then obviously, the corresponding single-digit BCVA improvement, no significant inflammation, with a topical corticosteroid regimen. This seems like an incredibly consistent profile. Are there any other points that you've heard raised from the investment community that you feel warrant further clarification? Well, I think, you know, we're lucky enough to have attracted incredible talent here on this call with Dhaval- Mm-hmm ... and Carlos. So maybe, you know, a lot of what brought them to us is not only the team that we built and everything else, but the data. Mm-hmm. So maybe starting with Dhaval and then Carlos, you guys can speak to what you see in that data and how you contextualize that in terms of other therapies. Yeah. Thanks, David. So a couple of things, Matthew, and I think there's this tendency to get caught up with this, you know, injection-free number. And certainly- Mm-hmm ... there will be a significant portion of patients once the Phase 3 reads, that will, at the end of a year, be functionally cured, right? Will not need another injection. And just think about those words. For a disease like wet AMD, we've never been able to say something like that. And so for those patients, this thing is going to be a boon. Now, even if you go back to the population, the dose expansion program, where patients came in with 10 injections prior, even if you needed a rescue, right? And so that means in the second year, you get 2 injections versus 12 the year before. I would venture, and I'll turn it over to Carlos and our retina specialist on the call-... that patients that are in your office would jump at that opportunity. Mm-hmm. And so while we do think injection-free is very, very meaningful, you know, having a reduction of that magnitude for patients, we think is a game changer. Carlos? Mm-hmm. Thank you, Dhaval. I think you said it very... Oh, Carlos, I think you got muted. We cannot hear you. I think you're muted. Oh, I'm so sorry. Hopefully, you now can hear me. Well, I was just, you know, kind of, first thanking Dhaval because I think he laid it down very nicely. And, you know, I was just reflecting that sometimes in life, we come across these inflection points, and I've been following the gene therapy area for a while now. In fact, I was actually the late-stage lead on Roche when we had a collaboration with 4DMT. So I've been paying a special attention to the company for a while now. I, I understand, you know, some of the challenges that people have when they think about what's the future and what's going to be the place of genetic medicines coming, you know, here. But, you know, given the data that we have, as Dhaval mentioned, I think that we're probably approaching an inflection point where the potential for 4D-150 that I see as a physician, as a retina specialist, given the needs that I see in my patients and their families, and in addition, the experience that I got, you know, through Susvimo and Vabysmo, I think that 4D-150 has the potential to be a medicine that's going to be for all patients, and that's going to be significantly able to not only improve their vision, but actually sustain their vision over time with a significantly improvement in their quality of life, given the less frequent needs of coming to visit your doctor. And that has a huge impact in us as a society at large as well. So I think in summary, to me, you know, as I said, at the beginning, the safety was the first and most important thing. Second, the efficacy signals that we're seeing in such a diverse population so far, I think are the most important pieces. And given what we know of anti-VEGFs and how they behave, I think that we can expect very good, very good outcomes for these patients once we actually narrow down, you know, our population to be studied. And that brings me to the fact that it probably... I know that we have so many cohorts that some people may actually get lost in the details. But I definitely think that given the data that we have, there's a lot of promise and potential for the drug. Yeah, absolutely, especially with the durability and, and safety profile. So one key point, at least from speaking with KOLs on my end, is the importance of gene therapy benefit and durability balanced with inflammation minimization, and particularly the related prophylactic regimen, common for retinal gene therapies. How do you best differentiate 4D-150's profile so far, and what are important takeaways regarding the current prophylactic regimen? ... Bob Kim, you want to take that one first, and then Dhaval and Carlos can weigh in? Sure. So, the safety, obviously, as we've been discussing it, is paramount, and- Mm-hmm ... we've had excellent results with a very simple topical steroid regimen. Essentially, a 20-week tapering regimen of a potent topical steroid, and it's been very effective. We're very happy with it, and so we do plan to take that forward into Phase III. But at the same time, we recognize that physicians may want other generics, for example, steroid options. And outside the U.S., where maybe the mix of steroids that are available in different countries is different, we want to provide some flexibility, so that's why we've been exploring alternative steroid regimens. But- Mm-hmm ... and, but those regimens, importantly, don't include any kind of oral dosing. We're just exploring a local ocular treatments and not encountered any, you know, any issues. Experience has been very good with other steroids. Yeah, the only other comment that I would add to that, Bob, you know, having- Yeah ... worked on retinal therapeutics that had had inflammation issues, most notably oral sitagliptin- Yeah ... is that the amount, meaning the number of patients that have these events, is important. But just as important is the severity and the nature of the types of events that you're seeing. And the benefit here is that what we're seeing here is, you know, kind of plus one type of cell, things that are either not treated or just kind of readdressed by using topical steroids. And so nothing like occlusive vasculitis, nothing, no hypotony, no any of those things that really kind of scare retina specialists when we're treating patients. And so it's important to note that not only have we had a great experience with just topical, and that the numbers are low, but the nature of the events that we're seeing are not anything like things that rise to the level of really being concerning to the retina community. Mm-hmm. Well, that's very helpful. I mean, I guess your perspective would also be that compliance is something that is not going to be sort of an uphill issue with, with patients, that they'd be willing to- Mm ... to go those 5 or so months on the topical therapy following injection? We've not had problems with compliance. Great. Okay, very helpful. Then also from our KOL conversations, the point was made that potentially 1%-2%, or even more, inflammation in retinal gene therapy could be considered very safe overall, along with responsiveness to the prophylactic corticosteroid regimen. Do you feel there's a threshold that would potentially be pushing the limits of what could be acceptable for incidence of any inflammation for retinal gene therapies, just in general? Well, maybe I'll kick it off and then hand it to Carlos for that. You know, I think, again, we have about a 2% mild inflammation rate. Mm-hmm. That's 2% of patients, not 2% of time points. So if you look at the time points- Right ... it's more or less than 0.1% of time points will actually have any inflammation, and that's very competitive with Aflibercept and Vabysmo. So I think we're right in that sweet spot of where we hope to be. You know, Carlos, do you want to kind of speak to profile of inflammation that would be acceptable to practicing physicians? Thank you, David. Yeah, I think you're spot on. You know, I think that, you know, probably a good guesstimate is around the 2% mark. Now, more important than that number, is the, the severity of the inflammation, like David mentioned. That's really important. Mm-hmm. You know, not all inflammations are the same, and definitely not all of the consequences of all of the different intraocular inflammation that can happen is the same. Given the safety profile that we have seen so far, we're very confident that we're gonna be able to deliver a product, you know, that it's gonna be able to give the sustained efficacy that sustained delivery of VEGF gives, with a safety profile comparable to that of the other anti-VEGFs currently in the market. With the additional benefit that because of the fact that we don't need to give injections, you know, 4, 5, or 6 times a year, there's also the hypothetical benefit of reducing the risk of endophthalmitis with each injection. So- Mm I think that overall, the benefits that 4D-150 can bring to our patients, their families, and to us as physicians in our clinics, and also lower a little bit of the burden that we have in clinics right now. And now that, you know, we're talking so much about sustainability in reducing the waste and the unused instruments as well, is gonna be very meaningful for us as a society. Mm-hmm. Dhaval, you've really hit the ground running in a large number of conversations with all sorts of different investigators and key opinion leaders. You know, what, what's your take-home message there with regards to what they're seeing in terms of the safety, tolerability, and efficacy? Yeah, I mean, so I think one of the things that jumped off, and I'll just, I'll speak a little bit about kind of as I was evaluating 4D and coming here, right? And part of those conversations were discussions with KOLs, is that, you know, this is a best-in-class safety profile to date, as we've seen in gene therapy. Mm. You know, having the rate and the nature of inflammatory events be what they are is kind of table stakes for entering a patient population where we have really, really good treatment options. And then the efficacy profile equally. You know, I think if we were to show up even with 50% of patients being injection-free, I think that automatically changes the way we think about the treatment of wet AMD from jump. Sure. So I think the potential for this drug is tremendous, and I think that's reflected in what the KOLs that know the data are expressing to us. ... Mm-hmm. No, absolutely, and very encouraging so far. So, one question, appreciating that CST fluctuations can be characteristic of chronic standard of care anti-VEGF, what are the important takeaways in terms of how these fluctuations can be detrimental to vision? And then more specifically, how 4D-150 can potentially help address the characteristic peak and trough fluctuations in CST? Let's see, Dhaval, you want to start, and then we'll check in with Carlos? Yeah, for sure. I mean, we know that the CST can vary in AMD, and typically, you know, the typical response pattern that we see in first-line AMD is about a reduction of about somewhere in the neighborhood of 140 microns at the end of a calendar year of treatment. And so our thought process is in a similar population, you'd see that type of reduction and just kind of holding them there. Now, AMD is notoriously variable in terms of its activity inter-patient-wise. And so part of the evidence that kind of points to that is if you look at, for example, the Harbor data and specifically the PRN arm and the number of patients that needed just a varying number of injections, it fluctuates tremendously. And it really comes down to a patient-by-patient, individualized case of treatment and whether or not, you know, it's gonna be 4D-150 the entire way, 4D-150 ±, you know, kind of an injection here or there. But I think at the end of the day, what we'll wind up seeing and what we'll wind up understanding is that having a basal level of anti-VEGF on board is going to be important for the optimal treatment of these patients and holding CST- Mm-hmm ... at a flatline. Carlos, maybe I'll pass it to you and/or Bob for additional comment. Thank you, Dhaval. Yeah, Matt, I think you're spot on in your question, referring to the CST sawtooth pattern that we see over time. And there's definitely been a lot of data saying that those sawtooth pattern, that fluctuation, is associated with worse outcomes for patients and definitely with, you know, short durability of treatment frequency. I think that, you know, what we need to keep in mind here, and really to do is a mindset shift. Here, we're talking about sustained delivery over time, and I think that the pathophysiology of the disease is gonna be impacted differently than when we use bolus injections on a monthly, bi-monthly, or even every, you know, four-month dosing regimens. Mm-hmm. The data that we have right now is available from Susvimo. I mean, if you look at the Susvimo trials, you see that that fluctuation of CST is actually not present. And Peter Campochiaro published last year a sub-analysis of those patients who had fluctuation or fluid, and what you can see is that definitely the impact... Well, first of all, the variability and the fluctuation of fluid was lower than with IVT treated patients with that bolus injections. And second, in those patients where they had fluctuation of fluid, the impact of vision was way lower, quite minimal, actually, quite frank. So given the data that we have, the mechanism of action, the safety profile of 4D-150, I think we can expect something like this. So I think I'm expecting a change in the paradigm of how we think and how we treat the disease as well. Bob, anything else from your side? No, I think you guys covered it. Very helpful. So another question is, reaching the 24-week window and the steroid prophylactic regimen being completed, should this suggest that safety signals become potentially less likely as time moves forward? In other words, once getting beyond the prophylactic regimen and staying off, are patients out of the woods with regard to inflammation? I mean, this is kind of at a high level. Obviously, it's not any sort of guarantee, but just conceptually, is it sort of out of the woods at a certain point? Well, maybe I'll kick it off and hand it to Bob. I think, you know, the history of gene therapy is that it's really the inflammation to the input capsid, which eventually is cleared. Mm-hmm. So usually, if you see that sort of inflammation, it's in the first several weeks or maybe up to a month or two, but it's pretty rare that you have nothing, and then just something shows up. Right ... out of, we can talk about the Adverum cases where they saw the hypotony at month nine, but that was actually predicted by front of the eye inflammation and toxicity much earlier. But Bob, do you wanna kind of speak to the timing of the steroid regimen and what% of our patients are coming off steroids, without having problems? Right. So, again, the steroid taper in the wet AMD program has been 20 weeks, and so we've reported out to, you know, 24 weeks for most of our studies. And- Mm-hmm ... we haven't reported consistently beyond that. I think we'll be doing that in September. But I think it's fair to say that very much what you see at week 24 is kind of we're not really seeing late-onset new inflammation. I think we've in our phase 1 dose exploration cohorts we have reported high-level safety information, and so we've seen nothing that really changes the profile, no new inflammation in those patients. And I will say, but Bob's correct, we haven't given the detailed- Yeah ... incremental data, but we have given top-line 36-week or more data on, you know, 139 patients now. Mm-hmm. You know, again, that 2% rate of mild inflammation holds, and we haven't seen late issues. Mm-hmm. Yeah, that, that's very helpful. So kind of thinking about the clinical perspective, for advanced wet AMD patients, high treatment burden, you know, they're readily familiar with standard of care VEGF-A therapy. ... Would you foresee potential wet AMD gene therapy patients also potentially attempting Vabysmo or Eylea HD prior to gene therapy candidacy? I know you spoke a little bit to sort of the dose expansion cohort, the population extension cohort. What do you see as sort of the prototypical patient journey for these folks? Yeah, well, I'll kick it off and then hand it over to the experts. I, I think just at a high level, what we're thrilled about is the safety and efficacy we've seen across all populations. Right. We haven't even gotten to the naive patients, where we're going to see the best results. Mm. But, we've had patients anywhere from 1 to 2 prior injections all the way to, you know, 14 years of disease, Right ... and activity across all of that, which gives us great promise. But maybe we start with Dhaval and then go to Carlos in terms of the patient journey and what to try before 4D-150 or, or whether they go straight to 4D-150. Yeah, you know, I mean, I think you to think about that, right? You just think about putting yourself in the patient's shoes, right? And so we, in the field, we kind of take IVT as just, you know, this is what we do, it's run-of-the-mill. Mm-hmm. But for the average Joe and Jane that's walking around, they're getting an injection in the eye is a terrifying thing. And even if you've had it- Sure ... right, you just don't want to do it. And so, the option, you know, certainly there will be patients that go to Vabysmo, there will be patients that go to Eylea HD. But if you're a patient and you have this, you know, kind of concept in front of you, we, we can give you- continue to give you injections, but give you less. Or I could give you this one shot, and potentially you may be cured, X percentage of patients were. And if you need one, you're probably going to need maybe one, maybe two. For a patient- Mm ... I mean, it's a very clear choice, and it all, again, depends upon what the data is and what that conversation unfolds to. But eventually, what we would foresee happening is that retina specialists will eventually adopt a setting of either you'll start with a gene therapy, and that'll be your basal rate, and it'll be kind of our next evolution of treat and extend, or patients will - that are on high need, will just come onto this therapy and get, you know, kind of their touch-ups when they need them. But Carlos, you still treat patients, so what - how do you see adopting something like this? I think 4D-150 is a drug for all patients. Mm-hmm. With that said, you know, of course, the biggest population that we have in our clinics are previously treated populations. So just for the sake of number, it's very likely that most patients that are going to be offered 4D-150 initially are probably going to be previously treated patients. But, you know, I think that over time, you know, you'll see more and more conversion. This actually mimics a lot of how, you know, we as a, as a field actually behave. You know, this is actually a similar pattern that you've seen over the past couple of years with Vabysmo, you know- Mm ... coming into the market. Happened the same, you know, to Eylea, to milligrams, you know, a few years ago as well. So I expect this to happen as well, but as I said, 4D-150 is a drug that's going to be for all patients. Drugs like faricimab that tackled more than two cytokines or pathways, you know, they're very strong drugs, probably going to be- you know, have a, a very important play as well, you know, for some of those recalcitrant, difficult-to-treat patients that, you know, we will still have, where they might need that, you know, additional blockade, to maximize that efficacy. But I definitely see that 4D-150 will be a cornerstone in our, in our therapeutic option. And then lastly, I just wanted to double down on what Dhaval mentioned, and we have data actually from the Susvimo trials that shows that patient preference questionnaire, that when they were asked, they overwhelmingly preferred PDS over intravitreal injections. Mm. The most frequent reasons were, you know, fear of the procedure and just, you know, the frequency of the injections as well. It's not a small task. I mean, for us, you know, it's easy to do injections, and you know, we don't think too much about it, but for the patients and their family members, particularly those who have not been diagnosed before, it's an overwhelming moment, where we have to- Mm ... basically exercise our bedside manner to comfort them and help them, you know, understand what's going to happen. No, I agree with that. I think there's a huge demand for durability and obviously balanced with safety. So kind of leading from that, with some of the long-term follow-up that we've seen, the 4D-150 phase 1 long-term data for 3E10 dosing has shown patients with injection freedom beyond 52 weeks and remaining injection-free through approximately 2 to 2.5-year follow-up. What do you think are some of the most important conclusions, at least at this stage, from the long-term data that we've seen? Yeah, I think, Matthew, it's that durability, you know, that's the- Yeah ... beauty of this is, as Dhaval and Carlos and Bob have said, you know, Lucentis took us to four weeks, Eylea took us to eight weeks, maybe Susvimo and Vabysmo are sort of 12-16 weeks. Mm-hmm. These are patients throughout 2-2.5 years who are getting- Right ... 10 prior injections the preceding year, 10, who now have a CST that is flatlined at- Mm ... -110 microns from baseline. BCVA, which is rock stable, 62-63 out at 2-2.5 years. That does not happen by chance. Sure. Right? So, like, to us, that's like proof positive that this thing is durable- Mm ... and it's going to, it's going to be a game changer. I think as, as Dhaval said, some patients will be cured. That's awesome. Some patients will go from 12 injections to one or two, but everybody's going to be benefiting. And so, you know, we're through that data. We understand people want to see more durability data, which we look forward to sharing, you know- Mm ... at the September data release, and, I think we'll answer that question. Yeah ... anything I missed from anyone else on the call about those three patients? ...Well, just, you know, just in general, I think, in terms of this concept of durability, we've seen nothing that would suggest, for example, that the treatment just stops working, and I think David outlined the prior history in the field, that just doesn't happen in retinal gene therapy. I think Bob alluded to the fact that, you know, the patient population is heterogeneous, and the response in the clinical community to dealing with that with the intravitreal bolus therapies has been the so-called treat and extend paradigm. Mm-hmm. And so to date, that has kind of extended patients from maybe 4 weeks to 10, 12, maybe 16 weeks. I think what we're looking at, in one sense, could be instead of weeks, we're converting that to months, and then for a subpopulation, that will include the rest of their life. So it's kind of shifting that treat and extend paradigm, you know, exponentially. No, absolutely. It's very exciting- Mm ... to, to see the progress. Sorry, was someone gonna add to that? Yeah, I mean, and I'll just add one more point to that, Matt. I mean, between Bob working on Lucentis, Carlos on faricimab, Susvimo, Lucentis, myself on brolucizumab, we've covered, you know, kind of all the anti-VEGFs that have been developed. And to be sitting here now talking about, you know, potentially curing patients, I mean, that is just a tremendous thing to think about, and it's why I think we're all really excited about being at 4D and what we're doing here. Absolutely. I mean, very, very encouraging, especially for patients as well. So thinking about next steps, the company's commented on plans for phase 3 development for 4D-150 at the 3E10 dose, along with topical Durezol, difluprednate corticosteroid regimen. What do you think are important considerations for phase 3, you know, from this viewpoint? And what updates or points could be forthcoming for the near term? Well, we've said publicly, you know, well, by the end of this quarter, which is September- Mm-hmm ... we will give our high-level final study design for Phase 3. Mm-hmm. You know, as we said before, we have RMAT and PRIME designation, which is really a remarkable achievement. It's similar to Breakthrough for small molecules. So we've had multiple interactions with EMA and FDA on this study. We think we're gonna have a study design that's completely aligned with what they want to see. We'll expect to give the details on that Phase 3 and our plans there at the same time as the data release in September at EURETINA. Mm-hmm, mm-hmm. So that'll all be as a package deal. We'll be able to say, "Hey, here's activity across all populations that we've seen. Here's the activity in the population that most represents phase 3. Here's a phase 3 design that goes with that." And, you know, we've said previously, we expect to start the phase 3 in Q1. Mm-hmm. Maybe, you know, I open it up to others on the call to kind of speak to thoughts around, you know, patient populations or other important considerations. Mm-hmm. Well, you know, maybe I'll start by saying that, you know, regarding the patient population, we know already, as I mentioned, that not only about 20% of the patients need more frequent injections, even with strong agents like faricimab, but we also know that even when treated ideally, you know, as the current standard of care, you know, at the highest regimen, which is monthly, we still leave about 40% of the patients not being able to achieve that 20/40 or better vision, which is very important because that's the driving vision for people here in the United States. Mm-hmm. Additionally, you know, when you look at the long-term follow-up of patients, you do see a decline in vision over time related to the decrease in the number of injections. That was, as it was emphasized earlier today, and I think that, you know, 4D-150 will actually help us, you know, bridge that gap. When it comes to the phase 3 trial, as David mentioned, I think the team has done already a tremendous job at, you know, fine-tuning the phase 3 trial design. And I'm confident that, you know, given our-- given the data that we have, how anti-VEGFs behave, we're gonna be, we have a high probability of success for sure. Well, you want to say a few words about it, or Bob? Yeah, I mean, the only thing that I'll kind of mention is that, you know, you think about injection burden and kind of where we're at, and all of the studies that we've ever seen in wet AMD have been, with this exception of Susvimo, have been in a treatment-naive population. We have not generated any data in that population to date, and still some of the things that we're seeing really kind of blow our minds and are stellar. And so we think as we kind of advance more towards what a Phase 3 population is going to look like, and we haven't kind of said exactly what that's going to be yet. We think that the results are only going to get better and ensure the best outcome for our patients and for the company as well. Yeah, and I think David mentioned we started out cautiously in a high-need population, but as our- Right ...safety experience has grown, we've moved steadily it earlier and earlier, and with that has come just an acceleration of investigator enthusiasm. Mm-hmm. So, we're now running into a problem where if we open a cohort, the investigators are kind of competing enthusiastically for limited slots. And so we have created some disappointment. You know, it's a good problem to have, but the speed of enrollment of the cohorts just accelerated over time, even though we're going earlier and earlier in the disease. Mm-hmm. You know, very encouraging. Mm-hmm. So, with the phase 2 PRISM trial, 52-week landmark analysis expected in February, and the interim phase 2 follow-up data that we're discussing coming in September, we've touched on this a little bit, but what do you think would really define success for investors? Like, what's the best way to frame at least the September update? I mean, is it to see consistent durability, a reduction in annualized anti-VEGF, obviously safety, kind of the broader population perspective. What are some, some important talking points for folks to, to take away? I think all of the above. I think all of the above. Yeah. You know, safety's paramount. Until you check that box, everyone says, "Fine, I don't care about safety- Right. -anymore. Safe, now tell me about efficacy." So that's fine. And, I think what we'd want to see is across each of these populations, so the hardest-to-treat, most advanced, longest disease duration patients that we had on the Phase 1 and the Phase 2, we'll look at all those patients. Mm-hmm. And we'd like to, you know, again, we've had 89% on-the-nose reduction in injection frequency, both in that population and the broader population extension. But at a high level, we'd love to see a, you know, continued very high degree of reduction in overall injections, a significant injection-free percentage- Mm-hmm ... out at the approximately that 52-week time point and beyond. And then we would expect to see, again, even better injection-free rates in the less advanced patients, so say, patients less than six months since their treat- since their diagnosis. Maybe you look at the patients who have one or two injections, as we did in the swim lane plot before. Mm-hmm. We would expect that the overall reduction should be consistent across everybody, but the actual injection-free rate is just gonna get better as you move upstream into these less advanced patients. Mm-hmm. So I think we would view that as success. Again, we'd love to show that continued stabilization of the CST in the injection-free patients, that that's just locked in. And then, you know, we were very encouraged... The numbers are small, but, we're very encouraged by the improvement in BCVA in that population extension, even in patients who, you know, had had many prior injections, which is- Mm-hmm ... unlikely. In a newly diagnosed, you expect the 6-8-letter improvement, but in somebody who's already received 4, 5, 6 injections, to see improved BCVA is, it's an interesting signal. So I think that's essentially what we would view as a positive update, and confirming- Mm-hmm ... that durability that people understandably want to see. Okay, very helpful. Anything to add from anyone else on that? Anything I missed? No. Okay. Very helpful. Maybe just taking a quick step back, like, what do you think are the greatest burdens to getting one or more gene therapies across the finish line from an approval standpoint? Is it ultimately just the BCVA non-inferiority to Aflibercept, the reduced injection burden? Like, what do you think are kind of the key components to success? Yes, both. You know, that's, that's what we want to do, is it's, it's critical that we show safety- Right ... that we show, non-inferiority on BCVA, and we hope that over years of time, that could even be superiority. It's not designed for that, obviously. Mm. So but we have to show safety, we have to show BCVA non-inferiority, and at the same time, it's very important to show that, again, that reduction in overall treatment burden in a significant percentage of patients who are injection-free at that 52-week primary endpoint. So, you know, it's all the above, and I, I think we- Yeah ... I think maybe, you know, Dhaval and Carlos can speak a little bit to, you know, coming in new, looking at this. I think we're gonna be really smart and really strategic, these guys are incredibly experienced, on how to design that phase 3 to win, to make sure we don't have any risk of losing on BCVA, or we mitigate it as much as possible, of- Mm ... of hitting on BCVA non-inferiority, but at the same time, showing, for commercial purposes, a significant reduction in the need for injections. Dhaval, you wanna- Sure ... comment on how you thread that needle? Yeah, I mean, you know, the benefit that we have here is that AMD, it, you know, is very predictable. It's as predictable as rain in April, right? Mm. And so we know in a naive population, you know, that over the course of a year, you're gonna get somewhere between six and eight letters, right? Depending on where you start. You're gonna have a reduction of about 140 microns, depending on where you start. And to the point that David made, you know, around the table, we have, you know, experience in developing and delivering phase 3 trial designs of almost every single major anti-VEGF that's out there. And so we'll use that experience- Mm ... to ensure that we hit exactly what the agency is asking us for, and we know what we're aiming at. That's great. Carlos? Thank you. I think everything was hit. You know, definitely, you know, the BCVA is the most important thing. You know, the achieving that non-inferiority primary endpoint, it's critical to us, and that's what we're- Sure ... what we're actually prioritizing. The frequency of injections as well, but then most importantly as well, you know, as Bob mentioned, you know, is the safety, too. So I think that, you know, hitting those, you know, and having the financial ability to be able to execute on that confidently, I think are the things that we need, and I think we're, that we're in a great position as a company to be able to deliver this for patients around the world. There's one other dimension that's kind of, it's just a nice angle, is that, when you worry about drug supply for trial, we just worry about one vial per patient. So- Actually, that's a really important point, Matthew, that maybe some investors aren't aware of, is our cost of goods here is de minimis. It's less than $1,000. You know, it's. Mm ... it's not a problem. When we think about pricing, might be 3-5 years' worth of Eylea or something in that- Mm ... I mean, just a thought experiment on how to approach it. Cost of goods is gonna be exceedingly low. So this is not your gene therapy for a genetic disorder, where it's a price in a box. Mm-hmm. This is something where our cost of goods are less than $1,000, so the margins are gonna be very healthy here. Mm-hmm. Well, that, that's very helpful. And then maybe just in our last minute or two, I wanted to underscore that, you know, the 4D platform is very broad, above and beyond, wet AMD. There's also the Phase 2 SPECTRA trial in DME, and then obviously programs in CF, Fabry. Are there any other, top-of-mind catalysts or points that you think are worth mentioning over the next coming quarters? Yeah. Well, we're laser focused on 4D-150 for wet AMD. That's job one, two, and three. But at the same time- Right ... we have, the, this very diversified opportunity and pipeline. And so DME, you know, we did announce, twenty-two patients treated there. No significant- no, no evident toxicity, no inflammation reported, which is pretty remarkable, with up to 36 weeks of follow-up. So that opens up DME widely for us, and, and we'll be pursuing that and updating the program in Q4. Obviously, DR, diabetic retinopathy, is right behind that, as an opportunity. Mm-hmm. Geographic Atrophy is a product that Bob Kim designed and now has an open IND and will be initiating treatment with that Geographic Atrophy agent, leveraging the same exact vector and modularity to de-risk that program. So that'll be starting. FPI will be in the second half of this year. Mm-hmm. And as we said before, Phase 3 starting in Q1. The Fabry Disease program is now off clinical hold. We look forward to following up on that and seeing if there's possibilities after we show safety with the new immune regimen of accelerated approvals there. Because, again, the efficacy with that has been quite remarkable in the first six patients. And then Cystic Fibrosis continues to over-perform in terms of safety and delivery, and now it's just finding that right dose to optimize the FEV1 response. Mm-hmm. No, it's been very encouraging to, to see the broad progress. So with that, as we get close to the hour here, I definitely want to give my strong congratulations and, and appreciation to 4D for their progress and for taking time to speak with us this afternoon. So to David and team, thank you guys very much, and to all of our viewers, thank you as well for, for tuning in. Thank you, Matthew. Thanks for having us. Excellent. Thanks for the opportunity. Have a great day. You too. Thank you.