The Fifth Annual H.C. Wainwright Ophthalmology Virtual Conference 2025. My name is Daniel Smith, and I'm an H.C. Wainwright Equity Research Associate in Biotechnology. With that said, let me introduce our presenter for the session. I'd like to welcome Linda Rubinstein, CFO of Adverum Biotechnologies, who are developing potential one-and-done gene therapies for debilitating ocular diseases. Adverum trades on the NASDAQ under the ticker ADVM. The floor is yours. Thank you. I'm pleased to present to you Adverum. Here are our forward-looking statements. We are developing a potential best-in-class treatment for wet AMD. We are in Phase III with Ixo-vec, our intravitreal gene therapy, which delivers the transgene for aflibercept, which has been the gold standard for wet AMD. Good afternoon, everyone, and thank you for joining the Fifth Annual H.C. Wainwright Ophthalmology Virtual Conference 2025. My name is Daniel Smith, and I'm an H.C. Wainwright Equity Research Associate in Biotechnology. With that said, let me introduce our presenter for the session. I'd like to welcome Linda Rubinstein, CFO of Adverum Biotechnologies, who are developing potential one-and-done gene therapies for debilitating ocular diseases. Adverum trades on the NASDAQ under the ticker ADVM. The floor is yours. Thank you. I'm pleased to present to you, Adverum. Here are our forward-looking statements. We are developing a potential best-in-class treatment for wet AMD. We are in Phase III with Ixo-vec, our intravitreal gene therapy, which delivers the transgene for aflibercept, which has been the gold standard for wet AMD treatment. Our gene therapy enables the retina to make sustained aflibercept for as long as measured, and we think potentially for life. Our data have been outstanding, with what we believe to be the best efficacy and a favorable safety profile in patients with wet AMD. Notably, in our OPTIC and LUNA trials, we have achieved 50% injection freedom and an 80% treatment burden reduction in hard-to-treat patients. When we surveyed patients in our LUNA trial, they overwhelmingly preferred Ixo-vec over their prior treatments. Our Phase III ARTEMIS trial is enrolling rapidly and ahead of schedule, speaking to the enthusiasm of our investigators and patients. Before we dive into the clinical data, let's take a step back for me to tell you about Ixo-vec and the unmet need in wet AMD. Here is a schematic for Ixo-vec. It's composed of our proprietary 7m8 capsid, which is engineered to cross the inner limiting membrane and transduce the back of the eye. Created by directed evolution, it's been the gold standard for transducing the retina. The second portion is the transgene for aflibercept, which we deliver to the back of the eye, turning the eye into a biofactory for aflibercept. Wet AMD, as you know, is a large market. There remains a significant unmet need. There are over 1.5 million patients in the U.S., over 20 million globally, and about 25,000 U.S. patients are diagnosed annually, and around half end up developing bilateral disease. It's a very large market with a pool of patients that's continually replenishing and actually growing as our population ages. There's still unmet need, even though we've had anti-VEGF therapy for the last 20 years. Under treatment causes vision decline in the real world. There are lots of reasons that patients miss injections, and greater durability has become the leading unmet need in this space. That was repeated in the most recent retina specialist survey from ASRS that was just released last week. In the real world, patients, when they're diagnosed, see vision improvement when they go on anti-VEGF, but they lose those vision gains and eventually see vision declines. Approximately 40% stop anti-VEGF therapy over two years and over half stop over five years, speaking to the remaining large unmet need. The benefit of having a treatment that can maintain vision over time would end up being the holy grail for this field. Here you can see the competitive landscape. It's a very dynamic space with new entrants looking to extend treatment intervals. We've seen dramatic shifts with rapid and large adoption of new products that offer only a couple or few weeks of extended time between treatments. Only gene therapy offers the potential to be transformational and have patients injection-free. As I noted, retina specialists continue to think that gene therapy is the most exciting up-and-coming modality, according to the ASRS survey that was released last week, because it addresses that large unmet need for extended duration. Let me walk you through our Phase I OPTIC trial and our Phase II LUNA trial results. OPTIC was a first-in-human trial in wet AMD. This is a heavily treated patient population with severe disease activity who required frequent anti-VEGF treatments. We evaluated Ixo-vec at the two higher doses of 6E11 and 2E11 with short courses of steroid prophylaxis, including a 13-day course of oral prednisone and a six-week regimen of steroid eye drops. The two-year results from the study were previously published, and they showed excellent visual and anatomic response and substantial reduction in treatment burden with both doses of Ixo-vec. We observed lower rates of inflammation at the 2E11 dose, and I'm going to show you the four-year long-term extension data here. These were heavily treated patients, as you can see, with a mean of approximately 10 annualized injections in the year before receiving Ixo-vec. Despite this, patients maintained their vision over time out to four years, as you can see on the top. On the bottom, they saw a significant decline in central subfield thickness, or CST. That's an indirect measure of fluid on the retina. They maintained that benefit out to four years. Here you can see the injection rates. This is every single injection that patients received in the year leading up to Ixo-vec, as well as since. You can see that nearly half of patients remain injection-free out through four years. The proportion of injection-free patients remains consistent in each year of follow-up and, in fact, improves, suggesting that we have a disease-modifying effect. You can see that for those patients who did receive injections, the treatment burden reduction was dramatic. Ixo-vec was quite safe at the 2E11 dose. It was generally well tolerated through four years. There was no vasculitis, retinitis, choroiditis, vascular occlusions, or hypotony. When there was inflammation, it was dose-dependent. It didn't impact vision, and it responded to local corticosteroids, and all inflammation resolved by year one. In the field, it's thought that the bolus nature of anti-VEGF therapy and of the disease is what contributes to vision declines. I want to show you a case study from OPTIC. Here's a patient who had very high CST levels. You can see approaching 700. The patient was receiving, here in this bottom left, injections every four to five weeks before receiving Ixo-vec. That's about as frequently as you could expect to receive the anti-VEGF drug. You might think the patient is no longer responsive to anti-VEGF, but that's not the case. What we think is happening is the patient was seeing fluid reductions and then fluid increases. You see the seesaw version, that activity that would contribute to vision reduction over time. That is borne out because between the screening dose and receiving Ixo-vec two weeks later, sorry, the screening dose of aflibercept and coming in two weeks later to receive Ixo-vec, the fluid was declined and mostly gone. As you can see, while having sustained aflibercept on board, that patient now remains injection-free through four years and in fact saw a seven-letter gain in vision over that time. With the results of our OPTIC trial, our goals in LUNA, our Phase II trial, were to select the optimal dose for Phase III and to select the optimal prophylactic regimen. LUNA is a double-masked randomized trial where we looked at two doses of Ixo-vec, the 2E11 dose, the lower dose from OPTIC, and a new lower 6E10 dose. Sixty patients were randomized, thirty to each dose. They received a longer course of prophylaxis. We evaluated four different steroid regimens, and patients remained eligible for supplemental injection with the same criteria that we used in LUNA. These patients were also heavily treated with a mean annualized 10 injections per year prior to receiving Ixo-vec, and that's consistent with OPTIC. In these patients, we saw a consistent dramatic reduction in treatment burden and injection-free rates that continued to be above 50% at one year, also consistent with OPTIC. Here you can see again every single patient in LUNA. You can see the mix of anti-VEGF therapies that they received in the year prior, showing that docs were trying to get to better efficacy and switching out, trying different therapies. There were patients who were on VABYSMO. There was one patient who got EYLEA every two weeks, so equivalent to receiving EYLEA high dose. All of those patients received benefit with, as you can see, more than half of patients being injection-free and the patients who did receive injections having a dramatic reduction in treatment burden. This is across all of LUNA. There was a small subset of patients who had received fewer injections in the year prior to receiving Ixo-vec, and in those patients who had received only six injections in the prior year, the injection-free rate was even higher at 75%. It makes sense that the patients who have a lower treatment burden would do even better with gene therapy. Here you can see that at both doses, the patients maintained their vision levels, best-corrected visual acuity. They also improved or maintained their CST or anatomic measures consistent with OPTIC. If you look at the patients in LUNA and divide them by how wet they were at baseline, the patients who had higher CST levels of 300 µm or higher at baseline in the light green experienced a drop in CST, and that was maintained over time. The patients who were drier at baseline of 300 or less maintained their CST levels. When you look at the dotted lines, those are the injection-free patients. You can see that it wasn't the supplemental injections that were in any way goosing the results. On this slide here, we can show that the supplemental injection-free patients at the bottom had the same maintenance of visual acuity as all patients at the top. Importantly, when we look at our aflibercept levels, what we produce at the eye, this is all of the measures that we've had since the beginning of OPTIC. Each line is an individual patient, and the dots show the measurements for those patients over time. We've overlaid both the LUNA and OPTIC results here. Importantly, there are a few things to notice. One is that what we observe early on at 12- 14 weeks when the first aqueous humor taps were done is what we see consistently out as far as we measure, and that's out to four to five years for the OPTIC patients. We think that these patients have the potential to keep these sustained aflibercept levels for life. The second is that there is no minimum threshold for efficacy. You can see that we had injection-free patients and patients with dramatic treatment burden reductions across all different levels of aflibercept that we measured. We think that's because we're measuring the aflibercept in the aqueous humor or the front of the eye. It's being made in the back of the eye, which is where it needs to operate. In non-human primates, we've seen that the measures that the aflibercept levels at the back of the eye are fully seven-fold higher than what we measure in the front of the eye. If we look just at the 6E10 dose that we are advancing in our Phase III trials, you can see that those are within the therapeutic range where we saw such a dramatic benefit in OPTIC out long term. Here is the safety data for LUNA. What I want to show you on these heat maps is that, number one, LUNA continues to be well tolerated. There are no Ixo-vec-related SAEs, and we can see that the extended local prophylaxis was highly effective in minimizing inflammation across both doses. Inflammation, if it occurred, responded to local steroids, resolved over time. No patients had inflammation at week 52 or at any subsequent visit. With the 6E10 topical dose, which is what we are taking forward into Phase III, only a single patient in LUNA had inflammation at any time point, and that resolved prior to week 52. On this slide, importantly, what I want to show you is a comparison with OPTIC. Our goal in studying both the lower dose and the enhanced prophylaxis was to demonstrate that we could reduce the need for patients to receive steroids over time. You can see that in LUNA, fewer patients needed steroids beyond prophylaxis. Total steroid use was reduced, and as I showed you, the overall incidence of inflammation was greatly reduced. Mission accomplished. We also included a patient preference survey in LUNA. We asked patients what they thought of our prophylactic regimen and of Ixo-vec. We were pleased that the vast majority of patients found Ixo-vec easier, very easy to manage. Nobody found it difficult to manage. Sorry, the steroid regimen, nobody found it difficult to manage. Patients overwhelmingly preferred Ixo-vec. 93% said that they preferred it over their prior treatments. 95% said they would want it if they had wet AMD in both eyes. Even more said that they would recommend it to family and friends. At the dose and prophylactic regimen that we're taking into Phase III, 100% preferred Ixo-vec. We are advancing into Phase III with the 6E10 dose. That's at a ten-fold lower dose than the highest dose that we tested in OPTIC, where the patients out past four years are doing great and where we expect to have best-in-class efficacy and a favorable safety profile. Let me tell you about our Phase III program. This is the ARTEMIS Phase III trial. It is enrolling. We are thrilled with the pace at which we are enrolling, which is faster than our initial projections. Approximately 284 patients are being randomized into two cohorts. Half will receive Ixo-vec plus sham. The other half will receive aflibercept 2 mg every eight weeks. Both sets of patients receive three loading doses, and their responsiveness to anti-VEGF is measured after two doses, and then they're randomized to one of the two arms. Both arms are eligible for supplemental aflibercept, and the criteria are consistent with LUNA. We will evaluate patients and look at their vision. The primary endpoint is non-inferiority in best-corrected visual acuity at an average of 52 - 56 weeks. Importantly, we are enrolling a broad population in ARTEMIS, both treatment-naive and previously treated patients with a range of vision, with the goal of demonstrating that Ixo-vec is an appropriate treatment for a broad population of wet AMD patients. Here I want to show you some competitive data. We are quite pleased that Ixo-vec has shown the best-in-class efficacy with the highest injection-free rates of any ocular gene therapy, whether subretinal or intravitreal, and a dramatic difference of over 45% relative to our closest competitor. You can see this across hard-to-treat patients on the left, and you can also see this where the treatment does even better, and we maintain that treatment differential in the easier-to-treat patients on the right. Ixo-vec, because it's addressing wet AMD, has the potential to be a gene therapy for a large market indication, right? Wet AMD has the potential to be the first mass market indication for a gene therapy. That's a different paradigm from what we've seen for orphan disease gene therapy because wet AMD has a high prevalence and a large annual incidence of new patients and new eyes developing wet AMD. The large patient population and the low volumes needed for delivery to the eye enable a low cost of goods and also potential mass market pricing that could be in the tens of thousands of dollars for millions of patients, not millions of dollars for thousands of patients. As you know, Ixo-vec, as sustained delivery of aflibercept, which itself has been a mega blockbuster anti-VEGF administered to over 70 million eyes by retina specialists, allows us to expect that we'll have seamless integration into retina practices and the potential for broad adoption. Here you can see, based on data from the IRIS registry, how patients sort out. We expect that initially gene therapy, as with most new therapies, will be adopted in the patients with the higher treatment need. Over time, we expect that all wet AMD patients will want the benefit of potential injection freedom and lower treatment burden. With that, I'd like to wrap up and say that we are very excited with the pace of our Phase III. We expect to start our second Phase III trial Aquarius in the second half of this year. We expect to put out additional two-year long-term follow-up data from our LUNA trial in the fourth quarter of this year and are working very hard to bring this trial, bring this therapy to wet AMD patients. Thank you.