Good morning, everyone, and thank you for joining the 2024 H.C. Wainwright 26th Annual Global Investment Conference. I'm Dr. Jade Montgomery, an associate biotech research analyst at the firm, and I'd like you to please join me in welcoming Linda Rubinstein, CFO of Adverum Biotechnologies, a clinical-stage gene therapy company focused on redefining the treatment of common incurable ocular diseases. Linda? Thank you, Jade, and thanks for having us to present at the H.C. Wainwright Conference. So I am delighted. I'm sorry, can you help me advance the slides? Nope. It did earlier. Thank you. you're welcome Okay, I'm delighted to tell you about Adverum. We are a company that is focused on ocular gene therapy for highly prevalent diseases. Our lead program, Ixo-Vec, which will go into phase III in the first half of next year, is a gene therapy for wet AMD. It uses our proprietary 7m8 vector, which is a modified AAV2. That's the gold standard for transducing the back of the eye, and we use 7m8 to deliver the gene for aflibercept or Eylea, which has been the gold standard for treating wet AMD, and we turn the eye into a biofactory, and it produces its own anti-VEGF. Our goal for this therapy is that it's a functional cure, one-and-done therapy. We have unparalleled data. At the 6E10 dose that we're taking into phase III, we have 76% of patients who are injection-free at six months, which is a potential best-in-class clinical profile. The vast majority of our patients preferred Ixo-Vec to their prior injections in a pre-specified survey, and importantly, the efficacy and safety data that we've reported in our LUNA interim analysis is similar to or better than what we've seen in our OPTIC study at 2E11, where the clinical benefit has been shown out to three years and a favorable long-term safety profile. We will be starting phase III in the first half of next year. As I mentioned, our next data release is in Q4, and we will also provide the phase III trial design in Q4. We had $174 million in cash in June, and our runway is into 2025. Wet AMD is a large and growing opportunity. There are 1.5 million patients in the US, 20 million globally. There are over 200,000 new cases of wet AMD each year, and up to 42% of patients develop wet AMD in the second eye within 2 to 3 years of the initial diagnosis, and this is growing as the populations age. There is significant societal burden for this disease. The standard of care is to get anti-VEGF injections intravitreally, meaning into the eyeball, every month or two or three, as treatment intervals lengthen. And it's a burden on patients, on their caregivers, on payers, and on healthcare systems, and it speaks to the need for a one-and-done functional cure. In the real world, patients who receive anti-VEGF typically start to lose vision beginning in the second year, and patients have poor long-term vision outcomes as a result of either undertreatment or oscillations in the amount of fluid in the eye, and it's this fluctuation of fluid that can lead to scarring and to vision loss. So, there is an unmet need to have something that will allow patients to have constant anti-VEGF on board, and gene therapy is the ideal solution for that. The current standard of care, as I mentioned, is anti-VEGF. Eylea has been the standard of care. With the latest generation, most folks expect that the market will be split between Vabysmo, which was Roche's drug, approved approximately two years ago, and Eylea high dose. Speaking to the need for new agents, Vabysmo has gone to over a $4 billion run rate just in two years after launch, and that's for extending most patients out to no more than 12 weeks, even though it's rated for up to 16 weeks. The TKIs are the next wave of innovation that's coming, and they purport to offer patients six months of interval between injections, but they too require supplemental injections. The only therapy that has the potential to be transformational is gene therapy, both to provide that functional cure and to provide both preserve vision gains and potentially improve long-term vision outcomes. I'd like to walk you through our data. We have OPTIC data from our first-in-human trial that we reported last year at AAO out to 3 years. This was our first-in-human trial. We began dosing patients in wet AMD. We started enrolling at 6E11, which is the highest dose we've ever tested. We went down to the 2E11 dose, and we did both doses with very short courses of corticosteroid prophylaxis, either 13 days of oral or six weeks of eye drops, including a taper. We took patients who had been previously treated with anti-VEGF therapy and were anti-VEGF responsive, and those patients were eligible for supplemental injections after receiving gene therapy if they lost vision of 10 letters or more, so that's about two lines on an eye chart. If they had an increase in fluid, so central subfield thickness or fluid, which is an anatomic marker of how much fluid there is in the eye, so an increase of 75 microns from baseline, or a vision-threatening hemorrhage, and we followed patients out to two years in the initial study, and the three-year extension for up to five years of follow-up is ongoing. These were very high-need patients who had received an average of 10 annualized anti-VEGF injections in the year prior to receiving Ixo-vec. You can see that patients had reasonably good vision at 20/50. They were somewhat wet, with an average of 400 for the CST, and as you can see below, we've had follow-up for between 3 and 4.5 years in the most recent data presentation. We have industry-leading treatment burden reduction, where over 50% of patients were injection-free at the three-year mark. You can see that it was 60% at one year, and then most of those patients remained injection-free through year two and through year three, and there was an 84% reduction in treatment burden. We did this while still maintaining vision. You can see that vision was maintained across the two years and now out to three years in the extension trial. And you can also see, it's a little hard on the left, patients had a dramatic drop in fluid with CST reductions that were then maintained out to three years. We measured fluid levels, aflibercept levels in the eye. We did aqueous humor taps, and we looked at how much aflibercept we could measure. Importantly, what we saw at twelve weeks has been sustained out as far as we've measured it in patients. Also importantly, there wasn't really a minimum threshold level for clinical benefit. All patients who are on this chart received a therapeutic benefit from having Ixo-Vec gene therapy, with either treatment burden reduction or being supplemental injection-free. We also have a very strong safety profile, where Ixo-Vec was generally well-tolerated through three years of follow-up. There was inflammation that was dose-dependent, but it didn't impact vision, and when it was present, it responded to local corticosteroids. Importantly, 14 of 15 patients were inflammation-free at year one and 100% at year two. As the field gets comfortable that inflammation, which is to be expected when you inject billions of treatments in the eye, can be detected, treated, managed, and goes away, we think that profile will be not just approvable, but widely adopted by physicians and patients. Importantly, we now have a long-term safety data and a tenfold safety margin because the dose that we're taking into phase III, 6E10, is tenfold lower than the highest dose we've tested, 6e11, where the patients are doing great in our trial. As the field has matured, there's been increasing focus on these fluid fluctuations or oscillations, as I mentioned, and, having those fluid fluctuations be correlated with bad vision outcomes. You can see that by quartile, those patients with the most fluid fluctuations have the greatest vision deterioration, and you can see that even within quartiles. So how is that relevant for our program? Well, you know, if you have, fluid fluctuations, you can, you know, you'll see vision deterioration. So what you want to do is have stable long-term, levels of aflibercept on board so that you can have stable, anatomic measurements. So in this case study, we had a patient who had received nine intravitreal injections prior to enrolling in our optic trial. Each of those blue dots is a patient visit and a CST measurement, and you can see that all of the CST measurements are high, and in the latter part of the year, when the patient is getting injections every four weeks, it doesn't seem to be affecting, you know, the fluid levels. But if you look at the right, where you can see the OCT scans of the patients, you can see those Gothic arches in the top two high levels of fluid. But in the second one, which was the screening visit, the patient received Ixo-Vec, two weeks later, came in to be randomized, and you can see the fluid is dramatically reduced. It shows that it's not just that some patients are responsive to anti-VEGF, but it just doesn't last long. So that's why you see these very high levels of CST and fluid fluctuations, but with one dose of Ixo-Vec, this patient's fluid levels diminished dramatically and were maintained out to now three and a half years, and interestingly, the patient who had been treated for multiple years before enrolling in our therapy saw vision increases, so we're very thrilled with that profile. We took the learnings from our OPTIC phase I trial and are conducting our LUNA phase II trial. This trial was fully enrolled in August, and we presented interim data for six months in July at ASRS, and I'll walk you through that data. In this trial, we randomized 60 patients between two dose levels: the 2e11 lower dose from OPTIC and the new lower 6E10 dose. Baseline was at the screening dose, and the primary endpoint is vision at one year. Patients were randomized to four steroid regimens. We were looking at drops alone, drops plus Ozurdex, which is an intravitreal implant, a bio-erodible implant of dexamethasone, and looking at both of those local regimens, with and without oral. It was the same supplemental injection criteria, except that at all visits, we needed to have the CST increase from baseline confirmed by a central reading center. At this data release, we had fifty-eight patients. Two had discontinued for reasons unrelated to Ixo-Vec, and importantly, you can see that patients had been exposed to a wide variety of anti-VEGF agents in the year prior to joining the trial. These patients, here you see the data for each of the LUNA doses, plus the OPTIC doses, data for comparison. These patients were similarly, requiring high levels of treatment, with 10 annualized injections in the year prior. There was slightly better vision, at twenty thirty-five or twenty forty, and, slightly drier eyes, but, you know, still need. Similar to OPTIC, about a third of the patients hadn't yet had cataract surgery... at the 6E10 dose that we're taking forward, we have, the same kind of treatment burden reduction that we saw in OPTIC. We also had the same kind of very high injection-free rate at 76%, also consistent with OPTIC. Here you can see the swim lane, where you can see all of the patients. You can see the range of therapies that they had over time. You can see a lot of switching, right, as physicians are trying to get improved efficacy. You can see the screening dose of aflibercept and then one dose of Ixo-Vec, and then the large majority of patients, overall, 79% were injection free. Seven participants had one injection, five had more than one injection. Frankly, even the folks with additional injections are success stories. One had an injection at four and 10 weeks, only one patient at four weeks, and that patient has since been injection free for nine months, and the physician was raving about the results. This is a subset of the LUNA patients, 29 of the 60, who had received up to six injections in the year prior, and you can see that the injection-free rate is even greater with overall a 90% injection-free rate across both doses. This is a subset of LUNA that looks only at the patients who received Vabysmo or faricimab in the year prior to Ixo-Vec. There were 10 patients. They also had an annualized 10 injections in the year prior to receiving Ixo-Vec, and we were very pleased that none of these patients has yet required a supplemental injection, suggesting that we may have improved efficacy over Vabysmo, which is one of the most effective agents out there, this newly approved bispecific that's becoming the standard of care. Importantly, we did all that while maintaining vision. You can see the absolute BCVA on top. The two purple lines are LUNA, where we maintained vision. We're comparing it to OPTIC in the dotted blue line, where patients started with lower vision, but patients maintained that over time, and on the bottom, you can see the fluid reductions, both for LUNA, where patients started drier, as well as for OPTIC, and those decreases were maintained. This subset analysis looks just at the patients who haven't received supplemental injections to make sure that those vision and anatomic measurements aren't driven by the supplemental injections. And you can see that even the patients who are supplemental injection free have the same vision and anatomic benefits. This is a subset, a different subset analysis of CST, where we've looked at the LUNA patients who were relatively dry at baseline in dark green. Those are the patients with CST levels of no more than 300 at baseline versus the wetter patients, who were greater than 300 at baseline. As you might expect, the drier patients remained at a steady state for CST, and the wetter patients had a decrease and then maintained that over time. That's not something that's been seen consistently across all wet AMD gene therapies. On this slide, we've taken the purple dots, which are the aflibercept levels that we measured in LUNA, and overlaid those on the long-term OPTIC data. You can see that at week 14, which is when we measured in LUNA, basically, the levels overlap the levels that we've seen in OPTIC, where we've now shown long-term benefit out to three-plus years, and that gave us confidence in picking the 6E10 dose for phase III. Importantly, LUNA was very well tolerated. There were no Ixo-Vec-related serious adverse events. All Ixo-Vec-related AEs were mild or moderate. There were none of the episcleritis, vasculitis, retinitis, choroiditis, vascular occlusion, hypotony that we've seen with other programs. The most common Ixo-Vec-related adverse events were dose-dependent, anterior inflammation. When it was there, it responded to local corticosteroids, and we've had anterior pigmentary changes with no impact on vision. Important learnings: we have demonstrated that, oral corticosteroids don't add benefit, and, we've shown, with our more robust prophylaxis in this trial that we can improve the, safety profile relative to OPTIC. On this slide, the heat maps you can show for, each of the visits, the measurement of, AC cells and VC cells. And you can see that on the top, in the Ozurdex plus drops arm, and on the bottom, in the drops-only arm, there was only mild to moderate inflammation. There were a few cases, and as I mentioned, all of those were addressed with local corticosteroids and were responsive. On this slide, we compare at the top, the AC cells for LUNA with OPTIC, and you can see the improved profile. So we're very excited about moving into phase III with one of these local prophylactic regimens. One new kind of data that we reported with our interim analysis is our pre-specified patient preference survey. We asked patients, "Would you prefer Ixo-Vec therapy over the prior treatments you received for wet AMD? Would you want to receive Ixo-Vec therapy in your other eye if you had wet AMD in both eyes?" The overwhelming majority of folks said yes. 88% would like their—like LUNA, liked Ixo-Vec better than their prior therapy, and 93% would take it in the second eye. This is an important measure. Certainly, we want to have patient preference taken into account, and that's an important initiative for FDA as part of their 21st Century Cures Act. But it also speaks to the benefit of the therapy because this patient preference takes into account not just Ixo-Vec, but also the corticosteroid regimens and the experience that patients have had. And then 100% of patients who were at the lower dose and in the drops-only arm said that they would want Ixo-Vec in their second eye. Well, I want to show you some cross-trial comparisons. These are always fraught, but we say that Ixo-Vec has had the greatest treatment burden reduction. And so on the left, we're showing the annualized reduction in injection burden for Ixo-Vec in blue and purple versus REGENXBIO suprachoroidal in gold and brown and versus 4DMT in gray. And you can see that Ixo-Vec has the greatest treatment burden reduction, and we're the only in-office gene therapy. You know, there's subretinal, but it doesn't perform as well and requires surgery. But we're the best one out there and the only one that's presented long-term data. More meaningful, at this, relatively shorter endpoint of six months, we think, is the injection-free rate, and you can see even greater differentiation with Ixo-Vec being 15 percentage points or so greater than the next best therapy. Importantly, here on the right, I'm looking at a subset of what I just showed you, and so this is, Ixo-Vec versus the 4DMT gene therapy, where we show the 15 percentage point difference. If we look at the most recent data that 4DMT put out in their population extension data, and you compare it to the Ixo-Vec, sorry, to the LUNA subpopulation of patients requiring one to six injections, you can see that that 15 percentage point benefit is maintained and perhaps even greater in this, population that needed, fewer injections in the year prior. We are thrilled with the data that we've presented. We think that we have potential best-in-class profile with unmatched efficacy, a great safety profile, and durability. We're very excited to move into phase III in the first half of next year and to put out data in the fourth quarter. Thank you.