All right, good afternoon, and welcome everyone to H.C. Wainwright's fourth annual Ophthalmology Conference. My name is Matthew Caufield. I'm a senior biotechnology analyst here at H.C. Wainwright. This afternoon, we're fortunate to be joined by Adverum Biotechnologies, and specifically, we're grateful to welcome Laurent Fischer, Chief Executive Officer, Linda Rubinstein, Chief Financial Officer, Star Seyedkazemi, Chief Development Officer, and also Peter Soparkar, Chief Operating Officer. So thank you very much to Adverum for making time for us this afternoon. Thank you, Matt. Thank you, guys. So maybe to start off, I know we had the chance to connect at the ASRS meeting recently in Sweden, and we definitely want to go through some of those Ixo-vec updates in wet AMD. But maybe to begin, you could give us an overview of how Adverum is approaching wet AMD gene therapy overall, and specifically, what you're excited about in the near term for the retina. Of course. So Adverum was a pioneer in gene therapy, and we're the first to actually design a vector that could be administered intravitreally, which is the way the current anti-VEGFs are administered in an outpatient office, simple intravitreal injections. So we actually designed a capsid that is unique, with a 7m8 loop that allows it to cross the ILM, and that vector has a proprietary aflibercept codon and essentially transduces your cell to actually make aflibercept for years and potentially for life. We've followed patients out the past 5 years now, so we have the longest data set, both efficacy and safety, and now we presented a very large number of patients at ASRS, showing that we can really provide a functional cure for more than half of the patients. So our ability to deliver a functional cure, allowing patients to preserve sight for life without having any injection, is something that we're aspiring to and that we continue to see with our data, which is really remarkable and the best in class from what we can tell. No, it's been very exciting to, to follow the progress. So Laurent, you mentioned the AAV.7m8, 7m8 vector capsid for aflibercept. Can you talk a little bit about how that can address maybe some of the limitations with conventional AAV vectors, just in gene therapy overall? So originally, the gene therapy vector were native AAV vectors that had to be administered subretinally, which required a vitrectomy, a complex surgery. Now, there are ways to deliver them with a suprachoroidal approach, which has also some challenges. So we actually identified and licensed a vector that came from UC Berkeley that has a 10 amino acid loop on the surface, and that vector allows to be administered intravitreally. It actually crosses the inner limiting membrane that protects the back of the eye, the retina, and the choroid. So it can cross that membrane and then essentially transduce the cells and have them become a bioreactor, where they make their own aflibercept for life. We actually measure the level of aflibercept in the front of the eye, and we've demonstrated that these levels are completely stable for the past 3.5 years, even longer, and we continue to measure that. So this is really unique. There's another vector that came from the same lab, called R100, that has shown also the ability to transduce the ILM. And so what's unique about our vector is that it has a single transgene of aflibercept, and we really can deliver robust levels, and as a result, see a high percent of patients being free of injection and the greatest efficacy to date. So we've also seen that we don't see a drop in the efficacy. We're able to drop the you know, tenfold from our original study and still see, you know, best-in-class efficacy with very good safety. So we're very excited about what's coming up, which is essentially showing that we have established long-term efficacy and safety. We've selected a 6 x 10^10 dose for our phase III trial and we know that with local corticosteroid prophylaxis, we can manage the immune response that you expect when you inject, you know, billions of caps in the eye. That patients, you know, most of the patients have minimal or no inflammation at to 26 weeks. We also know that from our OPTIC trial, you know, 93% of the patients have no inflammation at year 1, 100% year 2. We continue to follow them, and this gives us great confidence in the ability of this program and this gene therapy product to have a transformative impact for the majority of patients who need it. Yeah, very exciting. Absolutely. So before we dive into some of the recent data, I wanted to point out, as you mentioned, there's the Phase 2 LUNA trial and also the Phase 1 OPTIC extension trial for wet AMD patients. And then the company also recently received the FDA's Regenerative Medicine Advanced Therapy, or RMAT designation. Can you briefly comment on how that could facilitate pivotal trial dialogue with the agency, and potential for expedited or priority review for Ixo-vec once at that stage? Yes. So, RMAT is a designation that acknowledges the unmet medical need that remains for the treatment of wet AMD and the potential for regenerative medicine to really transform that treatment. It's, in a way, similar to what we have in Europe with the PRIME designation that we have as well. Right. That enables to have, you know, more interaction with regulators more frequently, both formal and informal, to help advance those programs and inform those programs. It also allows, potentially, for accelerated review and approval, which is one of the benefits of RMAT. So this helps us, you know, engage with the FDA and make sure that we can finalize the Phase III program, and we look forward to updating everybody on the Phase 3 design in the fourth quarter, as we are having those conversations now, and with a goal to harmonize the phase III program for the approval of Ixo-vec in wet AMD. And we recently saw the landmark 26-week interim analysis from the ongoing phase 2 LUNA trial, with the gene therapy's potential best-in-class profile for injection freedom, along with favorable safety at 26 weeks. So at this point, we've seen safety, annualized anti-VEGF injection rate reduction, need for supplemental aflibercept, impact, and stabilization in BCVA and CST. Are any one or more of these the most clinically relevant from your perspective, as far as kind of making a difference in people's lives? Obviously, you know, the goal for patients with wet AMD to preserve their vision, right? Right. One of the sides that allows you to preserve your independence, your quality of life. The current standard of care makes them fettered to their retina specialist. Some patients have had over 100 injections in both eyes. I was speaking to a retina specialist this morning in New York, that was, you know, seeing a patient who said, "When are these gene therapies coming? And so the fact that with one single injection, we show that we can deliver levels of aflibercept that are therapeutic for years, potentially for life, that nobody else has demonstrated, that we have more than half of the patients that are essentially functionally cured and preserve their vision and keep their eyes dry. So CST is a marker fluid, which is essentially s hows the disease activity. The fact we can really stop the disease, and we, we have a disease-modifying effect, for me, is really remarkable. But this all, you know, this is all numbers, right? So which one is better? And, you know, I think 76% free of injection at six months is amazing. We've seen 53% at three-year, at 2E11. We've seen when we look at patients that have less need for frequent injections to up to six a year, it's even up to 100%. So maybe there's a day where we can imagine that the majority of patients will be free of injection. We think that's the bar that gene therapy should aspire to. I know that some people talk about just reduction of treatment burden, but I think we've seen that with Eylea HD and the TKIs. We want to do better than that because you have months of doing that. The thing that's really important is that in these, you know, studies, we take the hard-to-treat patients, including patients who are on Vabysmo, and some had 10 injection annualized. But we asked them one simple question, which is really: Do you prefer the treatment with Ixo-vec at six months versus the treatment you had before? And those were treated in the best care centers or the best ophthalmologists, but they required frequent injections. And 88% of the patients said that they preferred Ixo-vec, and 93% said they would want in the other eye. What does that mean? That there's a clear unmet need. And what is patient preference? It's a measure of effectiveness, it's efficacy, it's safety, it's quality of life, it's burden of the prophylaxis that we gave them. And despite all of that, it's overwhelmingly showing that we address an unmet medical need that nobody else has shown either. So I'm particularly excited when I hear patients telling us how much better they see. And there's, you know, we look at BCVA, which is the primary endpoint. It's, you know, black letters on a white background. You've had your eyes examined like, and that's why I'm wearing glasses.... but, but we know there's more to quality vision than that. And those patients tell us that they see better at night, they see better colors, they can go back to doing crossword puzzles. That is probably because we avoid these, you know, fluctuations, CST, that trampoline effect on the retina that we know leads to poor vision. And for me, that's the other thing, that's the future of gene therapy. Like, how can we demonstrate that as a benefit, and how do we really think about what these patients need? But we now know what we can deliver. We know what patients want. They've told us they want it in that eye, and in the other eye, they have bilateral disease. So this is really, you know, a moment in time for gene therapy, where I see that path to phase III and a path to market for something that will have a huge impact to preserve vision for millions of people. A nd really appreciating sort of the cumulative profile of Ixo-vec. So kind of looking at the landmark 26-week interim analysis for Ixo-vec, we saw that 76% of patients, as you mentioned, with previously greater than or equal to 10 annualized anti-VEGF injections, were injection-free at the 6E10 dosing, with significant reduction in annualized anti-VEGF and 90% reduction for 6E10, and then supported by BCVA and CST control. We did see some investor pullback that may have been challenging to decipher, considering the consistent benefit and durability presented. What are some of your high-level thoughts here, and are there any critiques that you believe could warrant further perspective from that update? So, I think, you know, first of all, it's important that we need to continue to educate the field about the data we've generated and the profile that we see, and that's why we keep presenting six months. We'll present nine months in the fourth quarter. We also continue to present long-term data from OPTIC, because we already have presented and published three years data, peer review, two years data. We continue to present that long-term data. I think the, you know, the macro environment, the small cap biotech, have been hurt particularly badly in this cycle. There's also some uncertainty around the election. It's in stark contrast- Sure ... what we hear from investors, where we have conversations with very high-quality investors. They're very interested in coming into the story, and more importantly, with the retina specialists. You know, we meet with the retina specialists at all these conferences. They all want to participate in Phase III. And what they hear from their patients, the educated patients know about these new regenerative medicine, this gene therapy product, that are about to enter Phase III, and they want to be part of it. So, you know, still a bit of a disconnect. We're hoping to change that. I think, you know, we're very excited about the program. I think patients and physicians are excited about the program, and eventually, as we keep educating the market and the field, I think we'll be able to change that trajectory to really support our phase III trials. And, you know, we're well-capitalized. We have cash into the end of next year, but obviously we need to fund the phase 3, and that's a combination of, you know, ex-US partnership, royalty financing, and equity. And that's the goal o bviously, the next 3-6 months is to focus on that. Very exciting. I think one important point from the update was the reported maintained BCVA visual acuity and the CST fluid control outcomes at both dose levels. Can you speak further to the importance of stabilizing the fluctuations in CST compared to standard of care, and how that could potentially translate to visual acuity maintenance or benefit on therapy? Yes. So, so two things. I think one of them is fluctuation in the CST, which, you know we can extend, and patient not getting as in, you know, as many injections as they need, the fluid comes back. We see that even in the label of, you know, approved product, that CST goes up and down. Right. People talk about it as a trampoline effect on the retina. I think it's a good description, because imagine those fragile cells in elderly patients, when there are stretched, there are pro-fibrotic signaling, and there's quite a bit of data showing that the more fluctuation, the worse long-term vision outcome. So if we can reduce those to zero or near zero by actually having steady levels of aflibercept, stable CST, I think that's what is going to translate into better vision long term. And we see that. Of course, one of the main reasons people lose vision is that they stop taking their injections or they don't get enough, right? In addition to the fluctuations. So we also address that. The other one is that, particularly with patients that are fluid resistant, they have a lot of fluid baseline, the ability to drop it and maintain it long term, which we've shown, you know, 6 months at 6×10^10 and 2×10^11 in LUNA, but also much longer term, 3 years plus in OPTIC, is really showing the durability and the potency of our vector. Others have shown that they see a drop, it goes back to baseline. They also have, you know, a lot of late, I mean, early-ish injection, like 20 weeks after the booster that they use in the for the 4DMT program, for example, they have a lot of patients that start getting rescued, which for me, shows that they see a sharp drop in efficacy when they, when they lower the dose. We haven't seen that. If you look at the CST and BCVA from the two doses we're evaluating LUNA, they completely overlap. So we have that confidence that we're giving patients an efficacy margin that will allow them to get the greatest benefit for gene therapy product. I don't think that's the case with 4DMT, for example. And we've also established a tenfold safety margin by dropping from 6E11, where we had long-term efficacy and safety, to 6E10. So I think we've really done the work over the years to establish that long-term target product profile, and this is gene therapy. You know, looking at six months is great, but looking at one, two, three, four, five years, and many of our patients are past five years, is really what matters. Sure. I think that perspective may be, not quite there yet, because who knew that you could potentially be free of injection and have a functional cure for some patients? Yeah, absolutely. So, I mean, just conceptually, the fluctuations on standard of care for CST, it's really just an artifact of the injections coming and wearing off a nd coming back every, you know, one to two months, essentially. It comes back, CST goes up, we poke them in the eye with an anti-VEGF goes back down, comes back up. And we've shown actually, you know, in some of the case studies that we have in our corporate deck, you can see that when patient miss one single injection, sometimes they gain, like, 100 microns or more of fluid, which is a lot of fluid, and then it goes back down. But a lot of people, when they're 65, 75, 85, 90-year-old, like several of our patients, there are many reasons why they can't come to their appointment. They may be hospitalized. Their 7-year-old kid may not be able to take them to their appointments. Sometimes drive 3-4 hours. If you look at the map of the retina specialists, you're out of luck if you're in the, you know, Upper Midwest, close to Reno. Right. There's just one retina specialist that's five hours away. So that burden means that, you know, a lot of patients lose vision over time, and that's what the IRIS database shows. Charlie Wykoff presented that, which shows that every year, they get less injection, and every injection that you get gives you 0.68 letters. So people just don't get enough aflibercept. So we give them aflibercept at low levels, probably forever, right? That's really the difference between what we're offering the standard of care. No, it makes, makes sense. And then also from the landmark 26-week interim analysis, we saw support for the 6E10 dosing moving forward, and the topical difluprednate alone corticosteroid regimen, specifically providing for absent or minimal inflammation at the 26-week timeframe, with the potential for Ozurdex, IVT, dexamethasone. What do you think are the important takeaways from the prophylactic corticosteroid regimen, at least at this point? So I think we were the first to evaluate steroid eye drops in our OPTIC study for the field. Right. I think that's been now used by others and become so, like, the standard. We were able to confirm that we really don't need oral steroids to actually minimize the immune response to intravitreal gene therapy. Sure. That was an important lesson because we know it's poorly tolerated. The other lesson is that an Ozurdex alone does not give you sufficient duration of coverage based on the peak immune response that we see, so you need to add steroid eye drops. So we feel the steroid eye drops work well. We're still evaluating whether that additional injection, that additional Ozurdex, provides additional benefit or not, and we'll, you know, provide updates on which one the prophylactic regimen we're taking forward in Phase 3 in the fourth quarter. But we're very happy to see that we had essentially excellent control with, you know, no patients at 6/10 on that difluprednate alone drop, that required any additional drops to manage inflammation. So we feel that-... We really understand now the ideal prophylactic regimen moving forward, and the 6E10 is, you know, gives us that best-in-class efficacy and safety. So just to understand- Oh, sorry. Oh, sorry. Please. I was going to say, Star, I don't know if you wanted to add anything- Okay ...to the profile I was saying. Yes, I think, you said it, well, Laurent. We designed the study to not only evaluate a lower dose than we had previously studied and have long-term durability in terms of efficacy and safety. So we've done that in terms of evaluating the 6E10 dose, which we, we saw, as we covered already, very promising efficacy results for evaluating this dose for the first time. And from a safety perspective, we see a better profile, in still, still the anticipated, response that you would see, which is an immune response. We also had a chance to then, as you, rightly highlight, Matt, to look at these different steroid regimens, and I think we conclude that locally administered corticosteroids are perfectly fine. It's perfectly adequate and effective to manage the anticipated immune response that we expect to see between the two locally administered regimens, which is either a difluprednate regimen, 22-week course. It provided great coverage upfront and in the later phases with regard to inflammation, particularly with the 6E10 dose. And we also see the same with the combination, and I think, you know, with the Ozurdex and difluprednate regimen, we are waiting to see some of the longer-term outcomes, which we'll be reviewing this year. And I think we can then determine what the best regimen is going to be moving forward, but ultimately, it's going to be locally administered. We don't need oral steroids- Right ... and with the 6E10 dose, we have a clear path forward in terms of our Phase III strategy. I think it's important to clarify that what, when we talk about inflammation, what are we talking about? We're talking about cells in the front of the eye that are easily diagnosed with a slit lamp exam and can be, you know, monitored. They're not symptomatic, and they're just managed with eye drops. So this is really, I think the important message, is that immune response is an easy to manage, easy to monitor, and easy to have under control. So it's really, you know, people think about gene therapy and think about, you know, we haven't seen any retinitis, any hypotony. In every single program, you may see blips, you know, for 4DMT a patient with 3+ cells that presented at week 24. That will probably happen because patient have a history of prior infections, and so they may be more prone to inflammation. I think we just need to really educate the field and the market on how to monitor these patients, and I think what we know, because we have the long-term data past 2 years, is that, you know, the first 6 months, you monitor them more frequently, then once they are prophylaxis, less frequently, and then you go along to monitor them quarterly every 6 months, right? This is really, I think, a pretty now well-understood approach based on our data, our program. We can certainly claim that and talk about that as a profile that we feel will be very, very acceptable by retina specialists. And we heard from the patient that even at the earliest time point after the prophylaxis, they overwhelmingly love it and absolutely want this product. Oh, understood. So then just to understand from a timing standpoint, should the final prophylactic kind of outline for phase III be available to share the, by the end of this year? Is that- We've guided that in the fourth quarter. We'll actually provide an update on the phase III trial. That will include the dose we've already announced, 6E10. The design, which is, you know, will be one dose compared to aflibercept every eight weeks and the prophylactic regimen. So, Okay ... state update in the fourth quarter, on the specifics of the phase 3 trial. But at a high level, I think we feel very confident, based on our ongoing conversations, that we'll have a very much standard type of, non-inferiority study. We know that's one year f or gene therapy, and BCVA is the primary endpoint. There are obviously opportunities to show clear benefits from a, you know, treatment burden and pharmacoeconomics as well, which I think w ill be very interesting. Well, very exciting. We think that, you know, freedom of injection is really the highest bar and the promise, and that, you know, having at least 50% of the patient being free of injection for gene therapy should be the bar that everybody looks at as a really promising product. No, and very exciting for patients. I mean, folks that have been on these chronic injections, you know, indefinitely, it's, it's a huge game changer for them, potentially. And then one thing I was going to say about the Phase III is that, you know, we, we hear that, you know, other gene therapy program have actually used boosters at week 4 after the gene therapy. Based on our data, we've only had one patient out of 60 that needed something at week 4, and we don't think that it warrants actually putting an additional burden of an extra injection at week 4 to actually mitigate the, you know, gene therapy expression level. We don't see a need for that, and we haven't seen that in our trials. So that's another advantage that we can offer with Ixo-vec. No, understood. And then kind of one key point from speaking with KOLs is obviously the importance of gene therapy benefit and durability, balanced with inflammation minimization and the related prophylactic regimen that we're discussing, which is common to retinal gene therapies. I mean, that's not an Ixo-vec exclusive component. How would you best differentiate Ixo-vec's profile so far, and kind of what do you think would be the distinguishing factors from a prophylactic regimen standpoint? S o I think this is a great way to think about it, because with gene therapy, you're thinking about addressing a lifelong disease with a lifelong benefit- Right ...one and done for most patients. So that's benefit-risk shifts over time, right? So you could say in the first six months, you're gonna need steroid eye drops you have, you're gonna be free of injection, your vision is, you know, stable, great. But in one year, most patients will be completely off steroid eye drops. They'll still be free of infection, they'll still have stable vision. At two years, everybody will be free of inflammation based on what we know from Optic, and more than half will be free of injection with stable vision and dry eyes. So that benefit-risk, and that's because we're the pioneer and we started that study six years ago, we actually have that, right? So we can go back and show that we provide long-term benefit-risk that really outweighs any other program, 'cause nobody has that data yet. And we're continuing to follow these patients, you know, to 10 years as long as we can. Obviously, some are 90-year-old patient; we may not be able to follow them as long as we'd like to, but we really continue to see that benefit-risk improving over time. And that difference between the standard of care, again, the new treatment and development, keeps that delta keeps expanding, right, as we follow the patients, and that benefit-risk keeps improving over time. So I think we've optimized on the dose with an intravitreal capsule that can be administered in the office, that fits in the standard of care and the treatment paradigm, even in the buy and bill model of the retina specialist, which is important for adoption. We've offered something that patients say they prefer to what they're getting today, and we're giving them a prophylactic regimen that is only drops you need to put in your eyes a few times a day that you taper off over time, that, you know, for most patients, have no consequences at all, right? So we're very comfortable that we're establishing a path and a product profile that is really second to none. Do you feel that patients can be relied upon from a compliance standpoint to follow through with the taper and the regimen? You know, that, that is really why we tested the Ozurdex implant, because we're thinking that removing that additional potential risk could actually- Right ... be an important factor. What we've learned from OPTIC is that even in patients who stopped because they were hospitalized, forgot their drops, even if they came back with one or two plus cells, they were always responsive. So I think it's important to educate the patient about the need, to make sure they take their prophylaxis- Sure ... and then follow up to make sure that there's no, you know, cells in the front of the eye. But we haven't seen that as a huge issue. We continue to, obviously, educate the patients. Obviously, it seems like since there are multiple programs that are gonna use our prophylactic regimen that we've pioneered with eye drops, there'll be more awareness of that and more education about that, but clearly something that's top of mind. We wanna make sure that our patients are safe and they understand it. But I will tell you that if you tell them that they could be free of injections, but they have to take an eye drop a day, they'll take the eye drop. Right. That's very motivating. So from our KL conversations, one point was made that potentially 1%-2%, or maybe slightly higher than that, inflammation in retinal gene therapy in general could be considered very safe, along with responsiveness to the corticosteroid prophylaxis. Do you feel there's a threshold that would potentially be pushing the limits of what could be acceptable in terms of incidence of inflammation in retinal gene therapy? So, you know, as I mentioned, in our OPTIC trial, where we had suboptimal prophylaxis, we had 93% of the patients free of inflammation. Right. And here, 100%, year two. And I think it's really the type of inflammation, so these are only anterior chamber cells and some pigmentary changes that we see that do not impact vision, and how they're managed, right? So can you identify them? Are they easy to manage? Do they go away with local treatment? Those are probably the most important factors, rather than an absolute percentage. I think people have these percentages in mind because they are thinking about the rare vision-threatening events from earlier, programs like, you know, Beovu, for example, unfortunately, and others that had these rare vision-threatening events. So I don't think there's a bright line. I think it's overall for all drugs, it's benefit-risk, and obviously benefit-risk over time, right? So we're really focusing on that long-term benefit and how to manage the inflammation. So I think this is... You know, we were very happy to hear from, you know, the dozens of retina specialists we've spoken with at ASRS and since, as part of planning for the phase 3 that we plan to initiate f irst half of next year. All of them feel that the safety profile looks great. Very happy with where we are today. Again, as I mentioned, importantly, it's the long-term safety and the long-term benefit-risk that matters. We continue to show this data, and it's looking really very, very promising. Yeah, very encouraging. So another comment from retina specialists has been to appreciate the heterogeneous nature of Wet AMD in terms of potential variability in patient response to conventional therapies, and also really whether or not they're taking, you know, coming back for the standard of care injections. But when we consider patients that require a supplemental aflibercept injection or hypothetical benefit from maybe even a follow-up Ixo-vec injection, hypothetically speaking, down the line, can you speak to your thoughts there in terms of being injection-free versus the patient that may still need some sort of follow-up into the future? And how even in those scenarios, hypothetically speaking, it's still really a pretty material change from what they'd be used to with every month or every other month injections. ... So this is a great question, right? Because there's no biomarker that tells you how often you need, an injection in the eye when you're diagnosed with Wet AMD, right? It's experimentation essentially. You know, you come in, and you try to treat and extend and see how far you can go. And we know that some patients can go to 12 weeks with Eylea or Vabysmo, but some actually are still in every 5-6 weeks, right? Even with these newest agents. We took in our study the hardest to treat, right, that needed 10 injections, and we had 10 patients with Vabysmo, right? So they tried everything. They tried the latest bispecific, and actually turns out that 10 out of 10, 100%, are free of injections despite trying the latest and greatest, you know, anti-VEGF. So when we go to patients who need less anti-VEGF, 6 or less, we see actually that 90% of all across both doses, 100% at 6E10 are totally free of injectio. So I think in the real world, our data will work even better. But let's talk about the few patients that needed more than one injection. I'll give you a really good case study. We have one patient that came in our trial, and that's the only one that needed a rescue at week four, by the way, the only one. That patient received an injection every 4 weeks for years and could never go more than 4 weeks. He couldn't go 5 weeks, he had fluid, vision was coming down. That patient received Ixo-vec as a rescue at week 4, a second one week 10. That patient is now 9 months plus, free of injection, with stable vision. For that patient, one of the worst outcomes, by the way, in our trial, and one of the best technically, if you look at% reduction of... Has now been free of injection for 9 months. It's completely transformative. That patient came crying of joy in her retina specialist's office- because it had never happened. So even with patients where there was actually some need for boosters, which could be for a hemorrhage or a little bit of fluid- Right ... coming out, those patients have on board aflibercept that protects their vision, maintains their eye dry, and even if they skip a visit because they're on their cruise, because they're retired, or they're hospitalized because they fell, their vision is protected by what we delivered with Ixo-vec, with that biofactory effect. And s o the benefit goes beyond being free of injection, preserving vision, and really protecting your eyesight from those, you know, inevitable lack of injection that happens with the current standard of care. And as you mentioned, 40% of the patients stop treatment altogether within three years in the US. Three years. So what happens to these patients, right? They may have dementia, they lose vision, right? I mean, they may be hospitalized. They may be, you know, too far from Reno, you know, they may not have somebody who can take them for a 3-hour visits. Because the visit is actually, you measure vision and fluid, it's fairly quick, but if you have to wait for the injection, the retina specialist can give up to 100 injections per day. You may have to wait 2 hours to get your turn, you know, to be injected. It's painful, it's time-consuming. So the treatment burden is such that patients stop a treatment that protects their vision, and it tells you the opportunity we have here. I think it's really incredible. If you think about this market, you know, every percentage point penetration in this market, if you look at an annualized, let's, let's say 3-5 years of the cost of treatments, would be what we could charge and be cost-effective because we're going to give probably 10 years of benefit. Let's assume that every percentage point of market share that we penetrate would be $350 million. So all we need is 3% market share to capture $1 billion. And we see what we've done in patients with Vabysmo, we've seen the patient preference, we see more than half of the patient free of injection. So I think this is a pretty extraordinary opportunity, and we're very excited to be able to make this available to patients as soon as possible, in one eye, and eventually we'll talk about bilateral study, which we'll want to talk about, as part of the BLA filing and package. Because 42% of the patients have bilateral disease, and they obviously want it, 93% want it in both eyes. No, it's, that's very helpful. I mean, it's nice to think of aflibercept kind of running in the background, so to speak, thanks to- Yep ... to Ixo-vec, potentially. Exactly. That's a- Very, very informative. ... great way to think about it. Yeah. So kind of along the lines of safety, so reaching the 26-week window, patients approaching completion of the steroid prophylactic regimen, should this suggest that safety signals become potentially less likely moving forward? Or in other words, once getting beyond the prophylactic regimen and staying off of it, are patients less likely to face subsequent issues regarding inflammation? Just at kind of a high level, not- Yeah, so at a high level, what we know from our experience in OPTIC and the non-human primate, is that there's a peak immune response that lasts roughly around 3-4 months. But in some individuals, non-human primate or humans, you know, inflammation lasts longer, right? So we want to keep monitoring it. We think that, you know, there may be a few patients that require longer steroids, prophylaxis, but that's all fine because it's all, again, manageable with local steroids. And we know from OPTIC that eventually it goes away, right? We've seen this inflammation going down over time. So we have that long-term view from OPTIC of what is happening. We've shown that by lowering the dose, extending the prophylaxis, we're doing quite a bit better in the LUNA trial, and that was the goal, right? Similar efficacy, and, you know, OPTIC is a good, good safety, but we want to do better than that. We have the long-term safety from OPTIC to really rely on to guide us towards that improved, you know, product profile. Then kind of switching to the LUNA trial. For the LUNA trial demographics, those wet AMD patients had faced upwards of greater than 10 annualized anti-VEGF injections prior to treatment, so a very high burden patient population. How do you view that translating to the real world in terms of the types of wet AMD patients pursuing or being eligible, even from an insurance standpoint, potentially, to pursue a gene therapy that would be approved? So that's a great question. So we, we've seen from, you know, first in humans to phase 2, that we expanded sort of like the pool of patients, taking patients that were more dry, better controlled. They still require, on average, same injections, but we also had a number of patients, almost half, that had 6 or less injections. These patients did even better. So they went from 76% to overall 90% being free of injection across both doses. So we've seen that those patients are likely to do even better. So that, for me, makes sense, right? Because they need less anti-VEGF. We provide a robust level of anti-VEGF, so they're less likely to be rescued. We're not taking just the really, really hard-to-treat patients. I think as far as, you know, what we see, right, is that patients, if they don't respond well and they can't extend treatments, after 3-4 injections with one treatment, they're gonna switch to the next and the next, potentially. So there's a lot of switching around, but hopefully, the majority of the patients, once they've tried a couple of things, will realize that maybe they can have an opportunity to be free of injections. So if we actually think about the payer for wet AMD, unlike DME, where it's private payers, this is actually Medicare Part B. Medicare Part B spends $3.5 billion a year on anti-VEGF for wet AMD, and these patients are essentially, once they start, Medicare will cover their cost for life. So if we were to charge 3-5 years of treatment, knowing that they're gonna be covered for 10 years, Medicare Part B would save potentially 50% of its budget on wet AMD by actually encouraging patients to get on gene therapy sooner. So I think the only thing that truly matters is that patients are responsive to Anti-VEGF. We ensure that by making sure t hat we see an improvement in fluid and a response by giving them a dose of aflibercept to make sure they're responding, and then after that, it doesn't matter. I think from an adoption perspective, it's always going to be the hardest-to-treat patient that have tried everything else. But then we also know that if you are 6 or less injection, you've got 90% of chance of being free of injection. Who is not going to take it, right? So- Right. I think from a reimbursement, you know, the fact that you have a single payer taking care of these patients, it's a little different in DME, potentially, where in DME, patients are younger, there were private payers, there's compliance issues. They don't necessarily need a lot of injections. So it's an interesting market, and it's an anti-VEGF market that, you know at certain point, we'll be looking at again. But I think 70% of the market is wet AMD, 42% is bilateral That's our primary focus with all the arrows, you know, aligning on the payer, the reimbursement, the adoption, and frankly, the fact for these patients who are elderly, they're less mobile, so being free of injection, being free of having to go back to their retina specialist is also important over time. Sure. I mean, definitely an impact for their, just the quality of their life in general. So from the clinical perspective then, advanced wet AMD patients with high treatment burden, they're very familiar with standard of care anti-VEGF therapy. Kind of in this patient population that we're talking about, would you foresee potential wet AMD gene therapy patients also having to attempt Vabysmo or Eylea HD prior to candidacy for gene therapy? Could you foresee that that would be sort of the next step prior to- So- ... a gene therapy or not necessarily? So I'm not sure there needs to be kind of a step edit. But we know that it happens, right? And we've seen that in our study where we have 10 patients that went from Eylea to other anti-VEGF to Vabysmo, and all of these 10 patients now are free of injections. So from my perspective, it doesn't really matter if patients have been recently diagnosed and get on gene therapy, or they've been diagnosed for 5 years or 10 years, get on gene therapy. Once they're on gene therapy, they have one shot at being free of injection, and I think they'll want to focus on the gene therapy product, gives them the highest odds of being free of injection and preserving their sight for life, and that's what we've seen with Ixo-vec, with the best target product profile. So I think we'll see how the market evolves. I think we offer a substantial benefit. We also see, and I've noticed, you know, that Eylea HD and Vabysmo are doing direct to consumer. Patients clearly are going to ask for these drugs. I would imagine that we would also be able to do direct to consumer and talk about freedom of injection. That may also have an impact on adoption. Again, you know, every percentage market share we can gather is potentially $350 million. So we're gonna be very focused on creating a study design that leads to a label that has the broadest applicability as far as patient population, and start educating payers about the benefit and potential for even savings from their side. So I think it's one of these unique, really, spaces where we could have a significant benefit for patients and overall save money for the healthcare systems. And I think that definitely makes sense, especially from a strategic standpoint. So kind of going back to the OPTIC trial, the Phase 1 OPTIC trial has shown long-term benefit through three years, along with safety and, and tolerability from single intravitreal injection of Ixo-vec. What do you think are the important conclusions based on the long-term follow-up that we've seen so far? Three conclusions for me is that w e could actually lower the dose and preserve best-in-class efficacy, with more than half the subject being free of injection past 3 years. Nobody's shown that, and I think that bar, of 50% freedom of injection, should be the bar for gene therapy. I think anything below that probably is not worth moving forward into Phase 3, in my opinion. So we really want to focus on the highest bar, because that's what regenerative medicine does. That's why we got RMAT, and that's why we got PRIME. The other thing is that safety is very manageable and keeps improving, and inflammation, even with suboptimal prophylaxis, wanes over time, and after year one is essentially not an issue. We had one patient that had cataract surgery that required to go back on drops for a complex cataract surgery, but that's the only patient we've seen that with. So we're not really concerned about long-term safety. We see that it looks very, very good, and we continue to follow these patients, and we'll continue to present the data as well on these patients. I think the other learning lesson is that steroid eye drops work well, but they need to be given slightly longer than what we did in our initial OPTIC trial, and that's how we took those lessons and adapted them into LUNA to re-identify the optimal dose and the optimal prophylaxis. So unlike other gene therapy product, that sort of-