All right, welcome. Morning, everyone. I'm Lisa Walter, Senior Biotech Analyst here at RBC Capital Markets. Thanks for joining us at RBC's inaugural Ophthalmology Conference. This morning we have gene therapy pioneers at Adverum Biotechnologies. Joining us today we have Laurent Fischer, President and CEO; Linda Rubinstein, Chief Financial Officer; and Star Seyedkazemi, who is the Chief Development Officer. Laurent, Linda, and Star, thanks so much for joining us. How are you all doing today? Doing great. Thanks for having us. Thank you for having us, Lisa. Congratulations on this excellent inaugural conference. We're very proud to see how it's come along. Yes, thank you. Thanks so much. Laurent, maybe we can start with a big picture overview of Adverum for people who might not be familiar with the company. Can you give us an overview of what's going on with Adverum and what are upcoming catalysts people should be paying attention to? Absolutely. First of all, you know we were very excited to present this year already four-year data from our initial study, OPTIC, and one-year data from a phase II-B study, LUNA. We are an ocular gene therapy company. We're a pioneer in the use of intravitreal delivery for gene therapy. We dosed our first patient with Ixo-vec over six years ago. That patient actually had received over 109 injections over a period of 10 years. That patient is still free of injection to date. Our hope is to actually offer patients a one-and-done treatment and preserve vision for life. We are now actually starting our phase III trial. We were the first to start that phase III trial, ARTEMIS, which is a US study looking at patients that are both treatment experienced and treatment naive. We have been able now, with all the data, to show that we have a very reliable long-term efficacy with an improvement actually in the freedom of injection year over year, which is quite interesting because I think we stabilize the retina and with very predictable long-term safety. We are very excited to actually address the key unmet medical need for patients with wet AMD, which is actually reduce their treatment burden. We have actually asked patients who became very experienced in our first two studies whether they preferred Ixo-vec to their current standard of care. Overwhelmingly, they preferred it. The dose we're taking actually into the clinic in phase III now, very excitingly, 6E10 with a steroid prophylactic regimen that's very well tolerated and they find very easy to manage, is what we think will be a very attractive product profile to really address this very large and growing market. It's over $12 billion and growing. Really, the standard of care has evolved with some minor improvement in reduction of treatment burden. There's really no other product that has shown the one-and-done potential to preserve vision with stable fluid and stable vision over multiple years. We've actually also presented that Ixo-vec can actually deliver aflibercept, which has been used in over 70 million eyes in patients as long as we measured it, over five years. This is a very exciting opportunity. There's a clear unmet medical need to avoid this fluctuation in CST, which results in poor vision. I think most importantly, to address the fact that 40% of the patients within two years stop their treatment altogether and more than half over three years. The opportunity to actually save patients' visions, offer something that's going to be easily adopted and fit into the practice of retina, which requires those are very busy practices, is something that we're very excited about. We started the phase III trial. We are actively enrolling at multiple sites. We look forward to providing more updates and long-term data on our trials. This is obviously something that we've been focusing on because we know that there's an unmet need. The practices are very busy. They're overburdened with patients. The patient want it. We think that with a single intravitreal injection, we can get a majority of patients free of injection, potentially for life. We think something that will be well accepted by the practices and by the payers where we can actually be very cost-effective. Exciting times for us. We will be obviously providing updates later this year. Thanks, Laurent. Thanks for that overview of Adverum. I just want to touch on what's core to the technology, given this is a gene therapy approach. Adverum has pioneered the development of this AAV.7m8 capsid specifically for the retina. Can you remind us how this capsid differs from the naturally occurring AAV2, which also has some tropism for the retina? What advantages does 7m8 offer here? Excellent questions. We indeed were identified by directed evolution AAV.7m8 as the best vector, which is a 10-amino acid loop on the surface of the virus that allows it to cross the inner limiting membrane and transduce the retina and the choroid. That capsid is now in three clinical programs, ours and two others. One by a French company, GenSight. The other one by an American company, Ray Therapeutics. So far, it's been really the gold standard showing that it can really deliver intravitreally the vector to the retina and the choroid. Our vector has actually a simple aflibercept codon optimized transgene with a global promoter. It's demonstrated that it can deliver very robust levels of aflibercept as long as we measured it, which is through five years and across a 10-fold level. We have been able to go from initially 6E11 to now 6E10 and show that we still deliver therapeutic levels with Ixo-vec, which is very exciting. Thanks, Laurent. I do want to dive into some of the data that you've shown with LUNA and OPTIC. Maybe a more bigger picture question and one that is on investors' minds is, what impact is the recent kind of shakeup at the FDA going to have on gene therapy developers such as yourselves? We've now lost Peter Marks as head of CBER. How are you thinking about this? Is this going to be a negative across the board? Is this going to be more of an indication-specific issue? Is it too early to draw any conclusions? Obviously, we're all following carefully what's happening within the FDA. Peter Marks obviously was in charge of the division when the first gene therapies, gene editing treatments were approved. Clearly, it had a huge impact on the field. There's clearly a very large team that's there that's continuing to kind of advance the programs. I think if you go back to what we're offering, which is a true transformational impact product, very differentiated, that both physicians and patients want, I think we are hopeful that our governments will continue to support innovation and to really help focus on the benefits for patients and for payers and providers. I think this is an interesting time. We think that we are fitting very well within the paradigm of using your own body to treat itself potentially that people are looking at. Got it. Thanks, Laurent. I do have maybe more of a commercial question, maybe Star, and Laurent, you might be both poised to answer this. Just trying to figure out where things stand with the current wet AMD treatment landscape. Laurent, you already kind of touched on this with your opening remarks. How might things evolve with biosimilars entering the market? You have these longer-acting tyrosine kinase inhibitors also in late-stage development. As well, two other gene therapy developers in addition to yourselves. Is there going to be room for all modalities here beyond the monoclonal anti-VEGFs? It's a very good question. Clearly, this is a market that has excellent treatments. In fact, nothing has been shown to be superior to Eylea. Unfortunately, OPTIC has shown that adding VEGF-C and D did not add any benefits. Clearly, Eylea is still the best actually anti-VEGF. There's no other class that's shown to be better to date. We don't really know what the TKI will do. They'll require two implants being injected per year plus rescue. Maybe some improvements. Again, anti-VEGFs have not been bettered to date. Even Vabysmo, which is a bispecific, is non-inferior to Eylea, but not superior. We think that delivering Eylea for life with a single injection is probably the best approach to address this market. That's what we're doing. We're also doing it in a way that fits in the standard of care and the buy-and-bill model. That will be widely adopted by the retina specialists. That's what we hear. In fact, we hear that initially, while they intend to treat the hardest to treat patients with gene therapy, down the road, they see that up to 50% of the patients could benefit from gaining vision with the first three injections and then maintaining it. I think you've had essentially always two treatments that were competing for the market. They still are the dominant. Also recognizing there's been a generic market with Avastin actually having pretty much, I think, 40% of the patients. The competition with generics will probably be around that, around Avastin, and will evolve over time. We do not see essentially a drop in the use of either a biosimilar or Eylea HD. We think this is a market that accepts novelty. Having the best durability will really support gene therapy. Only gene therapy can offer that. Laurent, there's been a strong view from some of the investment community that it's going to be difficult to incorporate a longer-acting treatment like a gene therapy, given that there's maybe a financial incentive in these retina clinics to inject patients chronically and often, and that gene therapies are going to be a little bit too disruptive to the business model of the retina clinic. What is your pushback to that? I think there's a lot of education that needs to happen because a few things are reality in those clinics. First of all, they do lose 40% of their patients within two years. That means those patients do not generate revenue for the practice. If they could capture, let's say, the equivalent of five years of revenue in a single injection, it would accelerate the revenue for the practice and also free up time for these clinics that are very busy and could do other things. That's one thing that's really important. I think the others is that when we look at the practice economics that we've done, we've done the work, it's actually positive, not only dollar-wise, but saving time. There's also patient demand, right? We know that direct-to-consumer of Vabysmo has actually increased that market share. We've seen from our patient preference data that overwhelmingly, patients prefer this to the standard of care. We think that patients have a voice, and they will ask for it. A combination of these three factors, including the fact that it's likely to be cost-effective for Medicare Part B that treats those patients for life, and we can offer a very cost-effective solution. I think all the factors are actually driving towards adoption. We hear that from the clinics that really understand their data. We're doing a lot of work with them. Clearly, a lot of education. I think a lot of misinformation when it comes to that perception will be actually additive and accelerating to the revenues of the practices. Thanks, Laurent. Maybe we can talk now about some of the clinical data that you've collected here with Ixo-vec. In the LUNA study, Adverum has gotten data here from two dose levels across 60 patients. Can you remind us first, what was the target wet AMD population that was enrolled here? Were these mild, moderate, or severe patients? Both our OPTIC and LUNA trial enrolled the hardest to treat patients that required 10 injections annualized, which is where we think initially, at least, gene therapy will be used. In that patient population at 6E 10, and 1 year, we had 54% of the patients that were free of injection and over 90% reduction in treatment burden. Can you remind us about the change in the prophylaxis regimen? Optic was using a shorter course of steroids. In Luna, you kind of opted to explore four different regimens, including steroid eye drops, implants, and oral steroids. Can you just walk us through what was explored in Luna? What ultimately did you determine was the best regimen to move forward with? Yeah. Let me introduce it, and then I'll Star to answer the question. In OPTIC, we started with oral steroids, which is essentially the way immune response to viral caps and gene therapy has been managed forever. We're the first to use steroid eye drops, difluprednate, as a very short course to actually see if that could do as well as oral steroids, which are poorly tolerated in elderly patients in particular. It worked quite well. We realized that we didn't cover the peak immune response, which lasts up to 12-16 weeks in non-human primates. In LUNA, we decided to explore both a prophylactic that would require only the retina specialist to manage it, which is the Ozurdex implant, and one that was steroid eye drops for the longer period of time that covers that peak immune response. We wanted to understand whether the oral steroids had an impact on the immune response and the contribution to some of the mild ocular inflammation that we'd see. That was the premise for the LUNA trial. Now let's Star answering what we did exactly, what we ended up finding out, and how that informed our phase III prophylactic regimen. Thank you, Laurent. Absolutely. As you said, we were the first. We learned a lot through these experiences in our very comprehensive evaluation through both OPTIC and LUNA. I think have really informed the field. In LUNA, we learned that, in fact, oral prednisone did not provide any incremental benefits. That was really welcome news, given what Laurent mentioned earlier in this elderly population. They do not tolerate prednisone well. In addition, we learned that a single Ozurdex implant was effective early on. It did not last long enough. Essentially, what we also learned was that the simple steroid eye drops, difluprednate prophylaxis regimen, was highly effective. It was very well tolerated. It was considered very easy or easy to manage by all patients that received it. This is the regimen that we have decided to advance to our pivotal program in combination with the lowest dose, the 6E10 dose of Ixo-vec, which we think is going to provide not only the excellent efficacy that we have seen throughout our development program, but an excellent safety profile with it. Star, can you maybe expand on the safety profile? What did you see in LUNA in terms of safety? Maybe before we get to LUNA, we should talk about OPTIC, right? Because in OPTIC, we studied 6E11, 2E11. And we have now four years of follow-up. We can say that the long-term safety looks excellent with no inflammation at year one, year two, year three, year four. What's important is that with gene therapy, you need to essentially manage the immune response to the viral capsid for the first few weeks or months. That's what we've learned along the way. That's really, I think, an important factor. Let's talk about LUNA. I'll pass on to Star. Thanks, Laurent. Yeah, absolutely. With LUNA, we saw even a better safety profile with Ixo-vec. It was very well tolerated. We saw no Ixo-vec-related serious adverse events. There was no new onset inflammation beyond week 30 with the 6E10 dose. All inflammation resolved by week 52. In LUNA, we saw lower rates of inflammation. If there were, there were very few patients that had inflammation whatsoever versus what we observed in OPTIC. As a result, fewer patients required any steroids for treatment of inflammation. Again, this rate was also lower. Overall, the enhanced steroid regimen that we incorporated, particularly the steroid eye drops, was highly effective and resulted in a very favorable safety profile. Got it. Since we touched on safety, maybe we can move to efficacy. The primary endpoint in LUNA was at 52 weeks. What results did you see in terms of percentage injection-free? How did the BCVA and CST look? Sorry? Sure. As you mentioned, the primary endpoint in LUNA was BCVA. In this patient population, which, as Laurent described, these were highly treated, treatment-experienced patients. They had received on average about 10 injections annually and had already improved vision by the time they enrolled in our study. With Ixo-vec at both doses, vision was maintained throughout the period of follow-up. We also saw reduction in CST, so fluid reduction, which was maintained throughout the one-year period. This was even more pronounced among patients that entered the study with higher levels of fluid at baseline. All of this, of course, was accompanied by significant treatment burden reduction. Patients went from having received about 10 injections to one to one and a half injections the year following Ixo-vec. That's equivalent to over 80%, 88% to be exact, with 6E10 in treatment burden reduction, with 54% of patients remaining injection-free at the one-year time point. In a subgroup of patients that required fewer injections the year prior to entering LUNA, we had 75% of patients that were free of injection at the one-year time point. All of this is supported by the evidence that we've presented with respect to aqueous humor aflibercept levels, that are within therapeutic range at an early time point, the earliest time point we've measured it, and then remain consistent throughout the period of follow-up. In LUNA, we've measured it out to one year with both doses. Of course, in our OPTIC study, as Laurent mentioned, we've measured it out to five years. We see the same consistency regardless of dose with consistent healthy cells generating aflibercept levels. That really, I think, positions Ixo-vec as the best treatment that can provide this long-term, durable injection freedom for patients after a single injection. One and done remains alive and well within the Ixo-vec development program. I think one thing I wanted to add to what Star was saying is that what was particularly exciting for me is that while we dropped the dose by tenfold, establishing that 10x safety margin out to four plus years now, we also were able to show that even in patients that have a lot of fluid at baseline, we saw a very nice drop. That drop is completely sustained regardless of whether patients had a rescue or not. Clearly, the transgene alone, which we know is expressed by week six, pretty much is sufficient to keep those patients with a lot of fluid dry. Those were patients who had fluid despite having 10 injections the year prior, so really kind of resistant patients. As Star mentioned, when we go to a broader patient population similar to that subgroup analysis, it's very possible that we'll see a much greater% of patients free of injection than the 54% we've seen in those hard-to-treat patients. We've seen 54%-75%. That with the one and done, I think, is no comparison really in the industry so far. I know you didn't ask about this, Lisa, but some of the most exciting data that we generated in LUNA was a pre-specified patient preference survey in which patients overwhelmingly stated that they preferred Ixo-vec. Over 90% said that they preferred it over their previous standard of care, that they would want to receive it in their second eye, and that they would refer Ixo-vec to their family or friends. This was very exciting for us and validating with respect to the patient's experience. Thanks for mentioning the survey there, Star. It kind of suggests that there could be patient demand for a long-acting therapy like Ixo-vec. Laurent, I just want to capture it. Did you say you think in the phase III, given it's going to be a little bit more of an early population, you could expect better results on the injection-free rate? Yeah. I think that 54% was really in the hardest-to-treat patients, 10 annualized injections the year prior. If you look at, we'll have both treatment-experienced and treatment-naive. Of course, in treatment-naive patients, you don't exactly know what their treatment burden will be. Because when they're diagnosed, there's no test or biomarker to say how often they'll need an injection. Across the board, we know that six injections a year is sort of like the average, right? If we think about that six injections per year, that maps out to those subgroup of patients, relatively small, where we had 75% free of injections. Only one patient had one injection over the period of one year of this subgroup. I think there's a potential to really live up to that promise of being free of injection for life with a one and done. Preserving vision for life, I think, is really possible. Again, remembering that we're living in a world where in trials, all the drugs look really good. In the real world, vision declines after two years. Patients go from five injections year one to four to three after the second year. That's probably half of what they need to preserve their vision. I think the potential to really have a huge impact in that patient population in a user-friendly, retina specialty practice-friendly manner is something that I think is going to be very transformative. Laurent, I do want to talk about the phase III, the ARTEMIS study that just launched. Can you give us any idea about how enrollment is going? I know it just launched last month, so it's still very early. Any data points that we can dive into? Has the first patient been dosed? How many sites are open? Anything you can share with us about how the pivotal launch is going? Star is in charge of our clinical operations and project management, so she can talk about that. What we're very excited to see is the level of enthusiasm. We had over 150 sites that wanted to participate in the US alone, so well beyond the number of sites we had in the LUNA trial, but also including the LUNA trial. Star can give a high-level update. Of course, we don't provide guidance on enrollment, as you know, in trials. Star. Exactly. We were very pleased to be the first intravitreal gene therapy program to initiate our phase III program. Enrollment is going great. We have started screening at multiple sites and taking advantage of the great experience that we gained in LUNA. I think all things are on track. We look forward to providing further updates as part of formal disclosures. Unfortunately, I don't know if you're aware of there's a program that supports patients kind of co-pay for Medicare that has kind of had some challenges. As a result, a lot of patients have to go back into Avastin or inferior treatments. We think that despite the fact that there are several phases for enrolling, of course, Good Days are no longer, we've actually screened a significant number of both naive and experienced patients. As a result, they have a chance of getting either the standard of care or something better or two more standards of care, hopefully. We're very excited about this time for Ixo-vec and Adverum to be in phase III. Yes, we have heard about the co-pay assistance issue affecting some of the AMD therapies and even the geographic atrophy therapies. We are following this issue. To your point, it sounds like that is providing some incentive for patients affected by this to motivating them to enroll in a clinical trial. Is that fair to say? Absolutely. I think that's an opportunity for physicians who basically would have to give step-down therapy to generic Avastin as the only option potentially for these patients to actually offer them the best in care. I think this is a good opportunity for this patient and for the practices to offer something that's going to be potentially transformative. Got it. Laurent, I know Adverum had some preclinical data of dosing non-human primates in the second eye. Are there any plans to begin dosing patients in the clinic in their second eye? Yeah. Excellent question. We presented that. We published it now. It is out there. We were able to show that when you dose the first eye, you do not see any neutralizing antibodies develop in the second eye. That privileged compartment has been sort of confirmed. We did dose the second eye after peak immunogenicity with super therapeutic doses. Even in that context, there was no difference in inflammation. We saw therapeutic levels of aflibercept. Similar to what Regenxbio has shown with the dose of second eye, we expect to dose in the same range of 15-20 patients by the time we file the BLA. That is kind of what regulators have asked globally. That is the plan, absolutely. That is still coming up. Of course, we had several patients, even in OPTIC and LUNA, that had disease in both eyes. They would like to get it in the other eye because the worst eye that gets the experimental drug, the gene therapy, became the better eye. Now they want it in the other eye because they keep injecting in that other eye. I think this is something that we'll want to generate data on by the time we launch the product. Got it. Thanks, Laurent. We're almost out of time. Maybe just one for Linda. Linda, can you remind us of the cash position in the runway here? Sure. Excuse me. Our cash at September was north of $150 million. We have guided that our cash will extend us into the second half of 2025. Maybe just a quick follow-up. What levers are at your disposal to extend the cash runway? Sure. We have stated that we have multiple levers available to us. They include equity, BD, revenue interest financing. We are having conversations across all of those. We believe Ixo-vec is well positioned as a best-in-class product candidate and has tremendous interest and will ultimately fund the company in the ways that enable us to maximize shareholder value across those options. Got it. Thanks, Linda. We are at time. Laurent, Star, Linda, thank you so much for joining us this morning. I really appreciate your time today. Hope you enjoy the rest of our conference. Thanks, everybody. Thanks so much, Lisa. Thanks, everybody. Really appreciate it. Bye.