Awesome. All right, everyone, I think we're going to go ahead and get started. Thank you for joining us in the room and online today at TD Cowen's 2025 45th Annual Healthcare Conference. I'm Joe Thome, one of the senior biotech analysts here on the team at Cowen. It is my pleasure to have with us today the team from Adverum Biotechnologies. In the room with us today, we have President and CEO Laurent. We have the CFO, Linda, and the Chief Development Officer, Star, with us today for a discussion. Laurent's going to kick things off with a brief overview of the company and some patient videos. Great. Thank you, Joe. Thanks for having us. Very happy to present some of our data. Actually, something that we don't hear from often is patients who actually have wet AMD, mostly because of their age and the complexity of their disease, which I think is going to be an interesting first we're pioneering here at TD Cowen. These are my forward-looking statements. We're developing Ixo-vec, which is an aflibercept encoding vector that's delivered intravitreally. It's been evolved in multiple species to cross the inner limiting membrane and transduce the retina and the choroid, which is where the disease is active. As you can tell from the bottom line panel, we've actually been able to demonstrate that with this viral vector, we can actually deliver aflibercept out to five years in every single patient we've tested it. Stable levels, potentially lifelong benefit for these patients. That's what we studied when we started over six years ago in our OPTIC trial, looking at two doses, 6E11, 2E11, with a short prophylactic regimen. What we've seen is that unlike today's standard of care, we can really preserve vision. So BCVA is fully maintained out to four years. We presented that last year. What's particularly exciting is that the biomarker of disease activity, CST, which is a marker of fluid you measure by OCT, is actually dropped by over 100 microns and stays down through the length of the study. This is potentially a truly disease-modifying effect. We see that in this swim lane plot, where we see actually the number of injections prior to receiving Ixo-vec on the left. After a single injection, you can see the% of patients that are free of injection year- over- year with actually less and less over time. That was actually a remark made by Dominik Fischer when we presented that last December. He said, "This is truly disease-modifying." This is potentially really exciting for patients who are elderly, have other comorbidities, to actually be able to, with a single injection, get the treatment benefit. In LUNA, we tested lower doses, 2E11, same as OPTIC, but also a lower dose of 6E10. This is the one-year data we just presented recently at Angiogenesis in the U.S. You can see, again, we have a best-in-class efficacy profile with 54% of the patients totally free of injection at year one, no injections after that, which is what we've seen also in OPTIC, and then really great reduction in treatment burden. This is what we see in those hardest-to-treat patients. If we look at patients that have six or less injections, the data is even better with 75% of the patients free of injection at year one. Of course, safety for all wet AMD treatment is paramount. What we could see is actually a very favorable safety profile with minimum inflammation that's seen as actually anterior chamber cells and vitreous chamber cells that are very well controlled without local prophylactic regimen we administer. We asked patients actually how they think about the treatments and whether they prefer it over what they had before. You can see that 93% preferred it to what they had before. 95% said they want to get it in the other eye. 96% said they would recommend it to family and friends. What does that translate into for patients as far as how they see? You're going to see a couple of patients from our LUNA trial from Dr. Sean Adrean, including Lois, who actually had disease in both eyes. Joe was the first patient in LUNA treated with 6E11. I'll let them speak for themselves. My name is Lois, and I'm 91 years young. I was a daycare provider for 29 and a half years. I have macular degeneration. My name is Joe. I'm 71 years old. I'm retired from 30 years of transportation. I've been treated for AMD. I get up in the morning. I drink coffee. I say my rosary. I puddle around. I puddle around all day long. I do not know what I do. I go visit my son and his family that lives a door away from me. Dad and Uncle Tony. Yeah. I have many grandchildren, around 20 grandchildren and great grandkids. I think it's like 27, 28 or something. Sage. My wife, Gigi, we've been together 10 years. We have our dog, Sage. She's our service therapy dog. We take her every place. We have a lot of fun. Joe is our first patient in the LUNA study. He only has one eye that has wet macular degeneration. Once he qualified for the study and we gave him an injection, he hasn't required any injections now for over a year. I had six injections, and it wasn't getting better. Once I started the trial, after one injection, everything started getting better. Every time I went, it was better. I didn't have any aftereffects, any side effects from the actual injections. Ian, how are you doing today? Good, fine. That's good seeing you. Lois is our second patient in the LUNA trial. Prior to being enrolled in the trial, both eyes have required multiple injections in order to maintain her wet macular degeneration and keep her having good vision. When there was an opportunity to treat one of her eyes, she was very excited. I got one shot, and I haven't had one since in that eye. This is the bad eye. My left eye is my bad eye. My bad eye has turned out not to be a good eye. Now I can tell the difference from blue and black. Even at nighttime, I can tell. I can read now. I'm going to get back into my crossword puzzles. I always read the paper, and I have to drag out that little glass and look for it. I didn't have to today. I didn't have to all this month. In the morning, I lay in the bed without the glasses, and I count my oranges. I can see them better. Oh, there's five on that stem instead of only two, which is good. It is getting better. It is getting better. Now, if we can get this eye over here going, then I'll be able to go to the barn dance. With a potential therapy that may be just one injection using gene therapy, I think that would really be a game changer for these patients that need these chronic consistent therapies in order to both improve and maintain their vision. Going every month, every four weeks was a hassle. It was uncomfortable. Those shots, it felt like after I'd leave, it felt like I had glass in that eye. I would have to drive 80 miles. I could not see anything because the lights completely changed. It was like a halo over the red lights, the brake lights, the headlights. I could not see. I wound up having to spend the night 80 mi away from home and then going the next day when it was daytime. You get anxious knowing this on my calendar. You start getting nervous and anxious. You go, "Oh, no." It is scary to see that needle coming out. Just a couple of days later, you're still scratching and digging. It just was uncomfortable. It just would be great just to want. In the LUNA trial, my patients on the Ixo-vec therapy have had steroid prophylaxis. So far, I haven't had any patients that have had inflammation in the eye after their steroid prophylaxis has finished. I believe my vision would have gotten steadily worse. Now it's almost 100%. This really helped me. I'm grateful that I was given the opportunity. I highly recommend it to anybody going through the same thing. Can we do better than what we said before? By choosing the right dose, the right prophylaxis, we can really say that we've optimized the treatment. You've heard about the treatment burden, what patients go through, the experiences. I want to play one quick other video, which is actually you've seen Joe at one year. This is at two years. Look at the difference in his whole demeanor, that freedom injection that's sort of like is very, very transformational. This is kind of a quickly on an iPhone because he didn't have time. Since my last video, my vision has improved 100%. What's funny was when we were there at the lake, I could hear people saying, and my wife was saying, "Listen to them. They're saying, 'Who are those people? Are they filming a movie? Who are they?'" Since getting the Ixo-vec shot, my life has really changed. I'm free to do a lot more. Just like when I was younger before I had this situation, I travel more. I drive more. I enjoy life more. I was really worried while I was losing my vision that I'd go blind, not to see my grandchildren grow up. It's just improved my life 100%. I see a lot better than ever before. I mean, I completely transformed our whole property. I planted trees, plants. I have a green thumb. Your vision is one of the most important things you have in your life. Do it. The only thing I can say, do it. Don't wait. It's well worth it. Long journey to get to where we are today. We just announced we started a phase three trial. We've actually established a tenfold safety margin with more than four years of follow-up, which gives us great confidence in the ability to deliver a safe and effective profile down the road. Obviously, we just started enrolling in this phase three trial. It'll be subject to meeting the primary endpoint in our phase three, which is actually non-inferiority in BCVA compared to aflibercept on label every eight weeks, both in treatment naive and treatment experienced patients. Very excited to announce again that we start enrolling in screening patients in the last few days. We reestablished kind of something that is now very predictable, reliable, both on the ability to show long-term efficacy at year one and post year one through year four, as you've seen. We have had no new onset of inflammation at week 30, all patients free of inflammation at year one, two, three, and four. We think that establishes a very nice benefit-risk profile. We look forward to exciting conversation with Joe. Perfect. Awesome. Some really impactful videos. That's a really nice addition. Maybe to kick things off, I mean, it seems like from the videos, the patients were two different age groups. One was 70 over, the other was over 90. One had disease in both eyes, the other had one eye. It seems like the therapy could be pretty broadly applicable. How do you think about sort of the ideal gene therapy patient? Obviously, there's innovation on extended products and different mechanisms. Who's the ideal patient for gene therapy if there is one? Yeah. I mean, I think what we've seen is a profile that gives us best-in-class efficacy with more than 54% of the patients free of injection. In the hardest-to-treat patients, 75%, and maybe a more average patient. Potentially, with a favorable safety profile, easily to manage with steroid eye drops, that's a broadly acceptable therapy. You have heard about how patients hate needles, hate to come back for these injections. Initially, we think that the 15%-20% of the patients that are the hardest to treat, like all new treatment in wet AMD, will be the first one to be eligible. Beyond that, ideally, if you can gain your vision, which happens in the first three injections, and then maintain it, a majority of patients would benefit from it. There is really nothing else that really offers that one-and-done potential. Perfect. When you think about what you've been able to show so far in terms of injection reduction and kind of injection freedom, based on your KOL conversations, what are physicians kind of most looking at? Is it that reduction? Is it freedom? Do they have set bars that they're looking at or no? I mean, I think in the past, people have tried to extend treatment by a few weeks. Now we see we can get to 80+% treatment reduction. Injection freedom is the highest bar for treatment for wet AMD for patients that, as you mentioned, could be 65 and older, one in 500 over the age of 65, one in 5 over the age of 90 have a combination of either wet or dry AMD. I think that a bar of at least 50% injection freedom with the gene therapy is what we should expect. We achieve that in order to treat patients. In our ARTEMIS trial, we're going to have both naive and experienced patients. I expect that bar could be higher even for us. That's kind of the minimum to be expected. I think that gene therapy is really the only kind of way to deliver that without repeated injection or an implant that needs to be refilled, for example. Maybe we can dive into that a little bit because that's been a point of comparison between different gene therapy programs, is where specifically you're seeing the benefit and who you enroll in sort of the pivotal study. What were you seeing in the LUNA study in terms of patients that were maybe a little bit more treatment experienced versus those that maybe were a little bit more treatment naive? Yeah. If you look at the gene therapy field, obviously, there are multiple ways to inject the gene. The initial approaches were subretinal, requiring a surgery, much more complex, less applicable to a mass market indication of wet AMD, and with actually slightly less efficacy than what we've seen for reasons we can talk about. On the intravitreal gene therapy, we're the pioneer. We have now that very long-term data showing that benefit-risk that I talked about, very long-term reliable efficacy and predictable safety that's favorable, easy to manage. What we've seen, if you compare in similar patient population, 54% of the patients free of injection versus 37%. A 46% difference, relative difference in efficacy. If you look at a more average patient, six injections or less a year prior, we had 75% compared to 57%. Again, more than 30% difference. I think we have established best-in-class efficacy. I think if you think about what's unique about gene therapy versus other therapies that you keep reinjecting, where you can switch around, gene therapy, you have one shot, one opportunity to get the best efficacy and being free of injection. We believe that this has resulted in a lot of excitement around our program. That's why we've been able to initiate our phase three trial slightly ahead of schedule. A lot of excitement of 150 sites wanting to participate. Actually, the three KOL that were mentioned or press release are KOLs that had experience. Some of these patients, they've seen the long-term benefit. There is no other therapy where you actually talk about data at three, four, five years. It's all one year, two year, and then it kind of goes away. I think if you think about one of we have an excellent set of care. However, 40% of the patients stop by year two, 55% by year three. It's hard to argue that that treatment is actually adapted to the disease. You have heard about the treatment burden. You heard about the patient experience. Those patients often need somebody to drive them. They skip injections. We know in the real world, they go from five to four to three injections, and they lose vision. I think we have an opportunity to really transform that set of care by delivering steady levels of aflibercept for life with a viral vector that requires roughly a six-month monitoring and a six-month prophylaxis with steroid eye drops that is actually very favorable and easy to manage. When you look at now, you've seen data from the phase one out for several years. We have the phase two experience. Some patients seem to perform very, very well. Others either need a little bit of a top-off or maybe do not see as well of a response. Have you been able to kind of pick apart which patients might do better or not? I mean, it's an interesting question because when a patient is diagnosed, the retina specialists have no idea whether they're going to need an injection every four weeks, every eight weeks, every 12 weeks, every 16 weeks. There is not a measure that predicts the need for anti-VEGF. What we've seen is that even in those hard-to-treat patients requiring 10 injections, we do really well. In our phase one study, we had very few patients that required multiple rescues. There was also less stringency around that. I think we're going to learn more in the ARTEMIS and AQUARIUS trial, where we have actually both treatment naive and treatment experienced, whether there are predictive factors. From what we've seen, maybe the number of injections or the fluid at baseline could be a factor. We don't know for sure yet. Again, we've shown really robust levels of aflibercept in all these patients, more than any of our competitors. Some of the competitive programs do use sort of a booster injection after the gene therapy. I guess, how do you think about that? Why don't you include a booster? Does that sort of limit, in your eyes, maybe some of the comparability between the programs we've seen so far? What's really interesting about this phase three design is that there's clear FDA guidance that you need to have three injections prior to giving the gene therapy, which is what we're doing in ARTEMIS. We've actually had only one patient in all of our data that required a rescue at week four. We don't need a rescue after the gene therapy because we have very robust expressions. Others do. What will also be interesting is that for the first time in the phase three trials, we'll be able to look at the reduction in treatment burden. We'll have already one less injection than our competitors that will have that early booster or rescue. We don't see the need to do that. Again, we've got the highest expression of protein levels with aflibercept totally stable through five years. We have the highest level of efficacy. We don't need it. It's going to make a difference in how this will be reflected likely in the label. When you think about the enrollment criteria for the phase three, you are including both the newly diagnosed treatment naive and those that do have a little bit more experience. Can you go into a little bit about that discussion? Because again, to draw parallels, others are not including that treatment experience population. What is that going to mean in terms of the readout and maybe eventual commercial uptake? Yeah. We thought it was important to include both treatment experienced patients and treatment naive because we know that initially, the treatment experienced are going to be the ones that get gene therapy. We know it's important to generate data that will be in the label that we can use to actually educate retina specialists about the benefit and the benefit-risk profile of Ixo-vec. We also thought it was important to look at treatment naive because these are the patients that will get the early vision gains and will be able to maintain it. By doing both, we can reduce the variability in the response. We can reduce the size of the trial. We have a more efficient trial and a broad label that will really map out to how we expect these gene therapy products to be approved. If you're only going to treatment naive patients, you take a bit more of a risk because you don't know how much treatment burden they'll need. You will have more variability, so you need a larger trial. I think multiple ways that we think this trial actually would provide the best information for randomized specialists to actually select the best gene therapy product down the road. Perfect. In terms of the inflammation profile, the company's done, I think, a good job at kind of incorporating new data and monitoring and kind of changing what you're using in terms of a prophylactic steroid regimen. Maybe can you kind of walk us through that? How have you arrived at your phase three prophylactic regimen? What are you seeing? We're the first to use actually steroid eye drops as prophylaxis. We saw that it worked well. It was too short in the first studies. We extended it. Because we had also explored alternative prophylactic regimen, we were able to show that a slightly longer prophylactic regimen seemed to be potentially slightly even better and also well tolerated. We ended up having a six-month steroid eye drop prophylaxis in our phase three trial, which we know is well tolerated. We use it in both arms. It actually simplifies the masking of the study. In the end, there's no benefit of adding either oral steroids or Ozurdex implants. We're able to go forward with the simplest regimen. We also presented data showing that this was very easy to manage or easy to manage for all patients. Nobody thought it was difficult to manage. That combination of efficacy, safety on the very few patients that had 1+ cells, AC cells, and the patient's ability to comply with those drops was very important for us. That is how we ended up with what we think is an excellent and very manageable prophylactic regimen. Maybe can you talk a little bit about the KOL feedback on inflammation in these patients? I guess if you do have a breakthrough, how bad is a drop? From the video, it seems like at least the patients that were treated there were fine after their course. If a patient does have a breakthrough, is that the end of the world? I guess kind of how are you thinking about that? Again, inflammation is actually non-symptomatic cells that are easily seen in a slit lamp exam in the office and all manageable and responsive to steroid eye drops. In the worst-case scenarios, we had patients that lost their actually steroid eye drops, the difluprednate, or were hospitalized and did not take it with them. They came back with some cells in front of the eye, immediately responded to the steroid eye drop. Very easy to manage, non-symptomatic, non-vision threatening. Again, something that we have not seen any new inflammation after week 30, none at year one, none at year two, three, and four. We think that the first six months to a year, you need to really closely monitor these patients. They are seen every four weeks. That is very similar to the way patients are treated in the real world when they are newly diagnosed. After year one, you can actually extend these intervals. They'll be monitored probably every three to six months and then every six months. Perfect. You launched, obviously, the first phase three this week. Can you kind of walk us through the cadence of any differences between the two phase three studies and kind of how you see these kind of reading out as best as you can? Yeah. Artemis is our first phase 3 trial, as I mentioned, U.S. only, 284 patients, non-inferiority to Eylea on label every eight weeks. This is enrolling now, both treatment and treatment experience. Aquarius we just announced as well, global study with U.S. sites as well, likely similar in design, non-inferiority to Eylea every eight weeks. There may be slight changes based on some requirements by EMA to have a non-inferiority of four letters, not 4.5. It may be a slightly larger study. Once we have all the feedback and all the elements of that, we'll be actually providing updated guidance. We like to under-promise and over-deliver when it comes to not changing the design of these studies. We like to have all the feedback. Stay tuned for that. Very excited to have multiple sites that are already screening both treatment naive and treatment experienced patients for ARTEMIS. Perfect. The one patient on the video did have disease in both eyes. It sounds like she wants to get the therapy in the next one. Can you tell us a little bit about the potential ability to eventually dose in both eyes, what we know from there, and how will that be incorporated in the clinical trial setting at all? That's a great question. As you mentioned, the patient, Lois, really wants to get gene therapy in the other eye because she gets now every injection every four to eight weeks in the other eye. We plan to have actually at least 15 patients that have experience with bilateral injection. We do know from our own data in non-human primate that you can do that. Even when we did the most challenging test, we saw no difference in inflammation and very robust protein level in the other eye. We think it's going to be totally doable. We plan to design that as a separate discrete study that will probably include patients from multiple trials. We're still having conversation with regulators about exactly what that looks like. As you probably know, Regeneron actually has shown that you can actually treat both eyes and have excellent results. We look forward to providing updates. Roughly 15-plus patients with bilateral experience prior to BLA filing is what regulators in the U.S. have requested. Perfect. Can you talk a little bit about sort of the current cash runway and kind of how you're thinking about financing the phase three program? What options are available? Yeah, I'll take that. We had $153 million in cash at the end of September. Our runway takes us into the second half of this year. We will need to bring in financing since our trial won't be done at that point. We have every confidence that we'll be able to fund this. There's tremendous, I think, potential for Ixo-vec as a potential best-in-class agent in this enormous market. We are looking at a combination of BD. As you'd imagine, there's a tremendous amount of interest in Ixo-vec and/or royalty financing and/or equity. We'll be pulling one, two, or three of those levers in the not-too-distant future. That is pretty similar to what has been done by others in the field. There has been a combination of these different types of ways to finance these large-scale trials. Very excited about the momentum and the interest in what we see as a potential best-in-class product. Gene therapy, as you have heard from patients, is really something that we believe is going to be transformational. When we speak to the retina specialists, there is a great level of enthusiasm for gene therapy, in particular, as a modality for wet AMD. Perfect. Maybe to talk about reimbursement a little bit because it seems like it's never too early to start thinking about that based on what we've seen so far. Obviously, this isn't going to be your $2 million per dose gene therapy. Maybe if you could talk a little bit about that. What are the differences with Ixo-vec that maybe we haven't seen so far in the market and how you can make sure you're going to have a strong launch from that perspective? I mean, I think that's one of the biggest opportunities to educate the market about how different ocular gene therapies are from systemic gene therapy. First of all, the doses you administer are like 1,000-10,000-fold less. Therefore, the cost of goods, right? We don't expect this to be a million-dollar treatment for 1,000 patients. Rather, tens of thousands of dollars for millions of patients. The cost of goods are very reasonable. We really are focused on delivering something that's going to be cost-effective and cost-saving. If we charge an equivalent of three to five years of the current standard of care, we think this is going to be a multi-billion-dollar product that would be actually cost-savings for the system. A lot of these patients are over the age of 65. They cover everybody, Medicare Part B. We also need to really understand we're doing a lot of work with practice economics to see how that fits into those practices that actually, as you know, see a lot of patients. They lose a lot of patients who actually disappear. They're trying to optimize their practice economics. And for the practices that really understand those numbers really well, they're actually very excited about gene therapy being something that can augment kind of their business and save actually time for these patients. I think it's a win-win-win for all stakeholders. Perfect. Yeah. Yesterday, on our ophthalmology panel, the KOL said that gene therapy was going to be the most exciting advancement in the next 10 years. They did call out that the practice economics do need to be established. I guess how clear is that process? How much work has been done with anything else that you can draw on versus everything you have to do kind of de novo here? We're doing a lot of this work ourselves. The practices that have access to large amounts of data and understand their data are very excited about it. The practices that see so many new patients do not even realize that they lose 40% or 55% of the patients, so they discount that. When you really ask them and look at their own data, they actually really realize this is an opportunity. I think there's a misperception and education and learnings, frankly, that we have to do the practice. That's what we're doing now, spending a lot of time. We hired a Chief Commercial Officer to really do the work, and it's been received very positively. Perfect. Awesome. That we are at time. Thank you all for joining us. Thank you for the discussion. Thank you. Thanks a lot.