All right, thanks everyone for joining the Oppenheimer Healthcare Conference on day one here. Last company here, my name is Frank Brisebois. I'm one of the biotech analysts at the firm, and the company to present here is Adverum. From the company, we have Laurent Fischer, CEO. We have Linda Rubinstein, CFO, and Star—help me out, Star. Seyedk azemi. Seyedkazemi. I got it. To join, I appreciate you guys joining. Thank you very much. I know it's a busy time at the company. Maybe for those that aren't too aware, I think a lot of people know the space a little bit, but I think it's worth digging into as much as they might think they know the space. I think the space is evolving. If you could just give us a little background on the company, that would be helpful. Sure. Very nice to see everybody. Thank you, François, for inviting us. Adverum has been developing an intravitreal gene therapy and started the program over six years ago. We're the first, actually, to identify a capsid that was designed and evolved to cross the ILM after being injected intravitreally. It doesn't require surgery or a complex suprachoroidal approach. It is really the most practical approach that fits in the current standard of care. This AAV.7m8 capsid, which is the gold standard, is in three clinical programs by two other companies as well as Adverum. It essentially encodes a codon-optimized aflibercept that is essentially incorporated in the retina and the choroidal cells to actually express aflibercept after a single injection for life. Because we've been at it for six years, we already have shown that we have steady aflibercept levels past five years at every dose we tested. We're able to actually drop the dose by tenfold and see that we have a best-in-class efficacy with excellent safety only using a local prophylactic with steroid eye drops. If you think about it conceptually, this is kind of aflibercept 3.0 with a single injection. We have your cells make their own aflibercept for five years, probably for life. What we need to control is the first few months, maybe up to one year of the immune response that are related to the viral vector that we use to deliver that transgene. A very elegant way to actually address the clear unmet need in wet AMD, which is the need for frequent injections. Even with the latest and greatest like a Vabysmo bispecific antibody, if you look at the DTC, it's advertised as you have a chance of being up to every four months injection-free or having an injection every four months. It's not true for all patients because what is interesting about wet AMD is that when patients are treated, you don't know when their treatment, if they're going to require frequent injection or very few injections. This is kind of one of the challenges. That's why if you think about the field, when you start testing this gene therapy product where the goal is to be injection-free, in my opinion, you actually start with treatment experienced patients where we understand the treatment burden. You take the hardest-to-treat patients that require 10 annualized injections, and then you treat them and follow them for one, two, three, four years in our case. We can show that more than half are free of injection for four years. That is kind of the technology we are the first to do. There is a subretinal approach that is kind of ahead of us, which was tested first in rare disease. I mentioned suprachoroidal, which requires about 100-fold more vectors. Some challenges as well there. We think this is a really transformative new treatment for wet AMD patients and something that patients will want, not only in the eye that they receive it in, but in the other eye, and we would recommend it to their family and friends. We actually asked that question in our phase IIb study and it was overwhelmingly patients prefer this approach with Ixo-vec to what they've received before. This is an exciting time. We're about to start a phase III trial. The first phase III, Artemis, will be 284 patients comparing a single dose of Ixo-vec after three loading doses of Eylea to Eylea every eight weeks. It is a one-year endpoint. A very elegant study that will enroll approximately half treatment-experienced patients. Those patients, we know exactly what they had before, and that's going to compare to the standard of care today. We are also going to have half treatment-naive patients. That will give us the broadest label. It is important because we know, again, that gene therapy, because it has a higher bar from an efficacy perspective, but also requires a slightly more complex management of the immune response for the first few months, will be first used in those patients that require frequent injections. We wanted to have the broadest label as we get to the market to make sure it was broadly adopted and reimbursed, things that we think our design will help address. Okay, I almost want to go through everything you went through there and just slow it down to like half speed to make sure no one—because there's a lot you delivered there that's been underappreciated. I think the space is dealing with that. I think people used to think of gene therapy as a one-and-done, and that's it. It's super expensive, and it's been difficult, and it's a small population and whatnot. Just to start, maybe to go back, the one thing I think is important is Vabysmo's success is a good thing probably for you guys just in terms of the market. If you could just kind of help people understand how big this market really is and what kind of numbers Vabysmo is putting up right now. The market is about $9 billion. It's growing to be $12-$15 billion. There's obviously 1.5 million people in the U.S. that have wet AMD, about 880,000 are treated regularly. Actually, what's important to understand is that Vabysmo is on its way to becoming a $4 billion drug, I think, within the next year. Growing very rapidly because it offers less frequent injections. We have excellent treatments. If you could give them every four to six weeks, what patients need, people would preserve their vision, but it's painful. Patients get five injections the first year, four the second year, and three after that. Those are the ones that stay on treatment. 40% stop treatment within two years. Those patients are lost to follow-up, and they're lost. They're They're probably going to lose their vision. They also are lost to the practices and the practice economics where they actually don't generate revenue for the retina specialists. It is one market where, because there's a buy-and-bill process, there's actually quite a bit of revenue that actually happens to really make the practices quite profitable, which is why they've been bought by private equity. You have multiple groups that account for a big chunk of the market. I think this is a pretty unique market in that respect. We are really excited that we can actually help address the patient's unmet need. If you look at the retina specialists, there is a survey every year that asks, what are the unmet medical needs? It's really longer-acting anti-VEGF, less frequent injection, durable vision preservation. We have seen that to four years with a single injection. In the real world, patients actually gain vision after the first three to four injections, so fairly quickly. Then they lose vision because they just don't get enough treatment. We can actually bend that curve and allow them to have that steady level of aflibercept on board to preserve their vision and keep their eyes dry, essentially. That's really the difference that we offer, which is quite transformative. As you said, gene therapy originally for rare diseases, millions of dollars for hundreds of thousands of patients. This is millions of patients at a cost of probably tens of thousands of dollars or sub $100,000. I would say as an analogy, there's only one super long-acting anti-VEGF. It's actually Susvimo, which is that implant that you put in the eye and refill every year. I think the cost that was announced was about $16,900 the first year and then $16,000 per year. Imagine that we are likely to preserve life for life with a single injection for these patients. They live about 10 to 15 years. It's all Medicare Part B patients. About 12% of the budget of Medicare goes to anti-VEGF for wet AMD. We could, if we charge three to five years of the current annualized standard of care, be very cost-effective and cost-saving while fitting in that kind of practice economics. These are all the nuances of this very unique market that will determine success from an adoption perspective. We believe, based on our interactions and conversations with the large retina practices and the retina specialists, that this will fill an unmet medical need that will fit also in their current practice models. It's interesting because what we're hearing too from physicians is Vabysmo doesn't necessarily last that long for a lot of patients in the real world. Despite that, people discontinuing, and this will lead to blindness, right, if you don't get your shots. Despite all that, we've got a real multi-multi-time blockbuster. I think it's an important part of the story. Now there's some data that you talked about there. I think the big question that keeps confusing people is how severe is your patient. The most severe patient is obviously the one that might be the first to think about a gene therapy. Then again, the data between reduction of treatment frequency and treatment freedom basically changes depending on the baseline. The baseline is described differently by different companies. It would be super helpful if we kind of run through as good as a cross comparison as you possibly can without everyone knows the issues, but everyone's doing it. If you guys can go through a little bit where your data stands compared to others, that would be helpful. I'll start and then Star can chime in. Maybe we'll show you actually one slide now, and Linda can post that, which is essentially the swim lane plots from our Luna trial, which was in patients who required 10 LUs injection. Half of them had a little amount of fluid, some of them had a lot of fluid. You can see those dots on the left-hand side. They actually received a lot of different treatments, including Vabysmo, right? That dark green light is Vabysmo for SMM. You can see that they're doing really, really well, right? We had 54% of the dose we're taking into phase III, totally free of injection at year one. By the way, no new injection after that, which is something we've seen in our program that others have not demonstrated at least yet. Then 75% had less than one injection. If we compare that to 4DMT, which just presented their data, in fact, what they have is 37% of the patients versus 54% injection-free at year one. That is despite having a rescue at week four for every single patient. They only have 52% that have less than one injection to a 75%. We roughly have 45%-50% greater efficacy. That is kind of looking at the most comparable patient population at the same time point, the closest we can compare those two studies. They are obviously different studies. It is apples to oranges. I want to put that disclaimer out there, but I think it is very similar. They went to what they called a broader patient population, which is essentially just patients who require less anti-VEGF. In their case, patients required 4.4 injections in the year prior. We looked at the same patient population on the next slide. Our patients had 4.7 actual injections to their 4.4, so very close, right? In fact, what they showed in that patient population is that they had 57% of their patients who were injection-free to over 75%. They show 70% that had 0.1 injections to 100%. I think, again, showing that when you compare in similar patient population, we have much greater efficacy. They looked at very recently diagnosed patients, less than six months, only had 2.7 injections. There they have actually slightly better results, as you would expect. I would make the argument that these patients that required very little treatment are probably not the ones that will be eligible for gene therapy. They'll be the ones that will get Vabysmo or ILM or maybe even the TKI down the road. We really are focused on the broadest patient population and the hardest-to-treat patient. That's actually these two patient populations we just presented. I think also from a phase III perspective where we're going to take treatment experience and treatment naive. The treatment naive, you don't really know if they're going to fall in. Do they need 10, or do they need 2? We don't care because we know that we're going to do well in all these patient populations. That's not necessarily the case for other companies. Okay, there's a lot there. How do you stack on safety? It seems like you guys have the most experience, the most time on therapy. Everyone with gene therapy is terrified about safety. How do you guys stack there? Yeah, so maybe Star, and we can show you some of the heat map with our safety and then the long-term safety, because I think, again, gene therapy, the benefit is that with actually Ixo-vec, we see the transgene for four years. We can maybe show you first the four-year efficacy and then the four-year safety. Then we'll show you the very detailed Luna patient-by-patient, visit-by-visit safety. At a high level, what I will say is that with Ixo-vec, we see none of these vision-threatening safety events, uveitis, vasculitis, retinitis. They're all really essentially front-of-the-eye, anterior chamber or vitreous cells that are all managed with topical steroids or local steroids. I think it's a very acceptable safety profile. We will show you what patients think about that prophylaxis, right, and how they think about the whole treatment, which is essentially an important aspect of treatment decision is the patient's perspective. Maybe just quite quickly, the high-level doses that we studied and just very quickly the efficacy and the safety. Linda, I wonder if we could maybe go to slide four where we talk about the five years of clinical experience that we have just to provide an overview and the picture because this is the longest data set in terms of duration with intravitreal gene therapy that's available that's leading to where we are in phase III. That is why we consider phase III to be very much de-risked. We have five-plus years of clinical experience with Ixo-vec starting at the higher dose of 6E11 and 2E11, which we studied in OPTIC. That really set the standard, if you will, in terms of efficacy and safety in which we saw some anterior intraocular inflammation, which was manageable, but we wanted to enhance and improve upon in phase II. You can see on the right side of the slide, we took the 2E11 dose forward into Luna, and we studied a new lower dose at 6E10, all combined with enhanced steroid prophylaxis, which included simple eye drops, and we looked at other options. Ultimately, we concluded that steroid eye drops about a six-month duration is perfectly fine to minimize the risk of inflammation in these patients. With 6E10, as Laurent walked you through, we see best-in-class efficacy. Now we have an optimized, if you will, benefit-risk profile that we're advancing to phase III. If you go to the next slide, you see now the rates of inflammation. You can see all the way at the right side there with the 6E10 dose. Essentially, we had no patients who at 52 weeks in our Luna trial had 1+ inflammation, if you will, in the anterior chamber. These are cells that are easily detected and seen with simple slit lamp exams that retina specialists perform. No one had inflammation by the 52-week time point. Overall, only one patient throughout the period of follow-up had 1+ cells with the 6E10 dose. You can see this is significantly lower than what we observed in our earlier trials and as such really represents a de-risk profile, which is both from a safety perspective optimized and is providing the best opportunity for patients to achieve freedom from injection, which should still be the goal with gene therapy for wet AMD. Okay, that's super helpful. I guess you look at the data, it seems kind of undeniable. What has been, you guys have thought about the data inside out. The market's been a little funky, to say the least, I'd say. What are people missing here? Because we're moving on to phase III, right? What is the issue? What are people misunderstanding about the story? I think this data from our competitors was presented just over the weekend. Maybe it'll take a little bit of time to re-understand this cross-trial comparison and patient population. We actually presented the data also at AngioGenesis. Charlie Wykoff presented it in a very thorough Q&A. We also, since we presented part of it last year at Fluoretina, the feedback from the retina specialists has been overwhelmingly positive. In fact, we've got over 150 sites that have already signed up to be part of a phase III trial. Why? Because they've seen that there is the program. They've seen that steroid eye drops is actually very easy to manage and that patients had no problem with it. They also see that patients prefer the treatment we offer to what they had before and would want it in the other eye and actually would also recommend it to family or friends. This is really a huge net positive. If we zoom into the dose and the prophylaxis we're taking into phase III, you can see that it's 100%. It's hard to do better than that. I think there's still some confusion about the differences across these programs. Certainly, the retina specialists that see the patients, see the benefits of the patients, we were at various meetings, all want to be part of it because they really understand this is transformational. I think with gene therapy, you've got one shot, one opportunity to get the best outcome. You cannot redose. I think people will be very carefully looking at which one they pick once they get on the market. That being said, there's been two anti-VEGF competing in the market, two TKIs. There are two injectable intravitreal gene therapy. I think with the totality of the data and the label, we'll be able to compete with them very effectively. However, I will point out that we have patients six years out that had 109 injections, received a single injection or free of injection for six-plus years. We don't see any reason to doubt that our transgene will not be durable. This is kind of a unique opportunity. I think that overall, gene therapy, gene editing has been a bit disliked by the investors, unfortunately. This is certainly, for me, one area where because of the dose we're giving, which is 60/10, so 1,000 to 10,000 lower than what you give systemically, the manufacturing cost is very reasonable. We can charge a price that's very reasonable. The associated immune response is all local and manageable with steroid eye drops. It's not systemic steroids or worse, right, conditioning. I think there's a bit of a misunderstanding and probably somehow this also perception that this will not fit in the current practice economics because it will take away the revenue. We now know from doing a lot of work, and we just hired, as Chief Commercial Officer, Jason Mitchell, which is employee number three at Apellis, who built that franchise at Apellis. We really understand that this will be very helpful because, as I mentioned, 40% of the patients stop treatment altogether within two years. We hear from some of the larger practices, they lose 55% within three years. This is lost patient, lost revenue, and for the patients, lost vision. We can address all of that in a manner that's going to be very well accepted. Even if we captured 3% of the market only the first year, there will be a billion dollar plus. We're very excited about this opportunity. We see a great alignment with the retina specialists. If you listen to the webcast, even our competitors' webcast, they actually use our data to showcase this, particularly like patient preferred. We have the data. We follow the patients, and we present our data. We believe that this data in the end and the outcome that we see with patients will be what matters most for the prescribers and the patients. That's great. Have you seen an evolution of the KOL's interest over the past couple of years with more data, or has it been? Absolutely. Absolutely. I think you're absolutely right. Historically, all gene therapy programs have run into some dose-limiting toxicities. That's kind of common for the field. We're able to, as Star showed, dose down tenfold, established that 10x safety margin over four years. With this data, I will tell you, showing zero inflammation at week 52, no new inflammation after 30 weeks, all managed with topical steroids and that degree of injection freedom. The other thing that we've shown is the four-year follow-up from a patient from Optic, where there's less and less need for rescues over time, implies that there's a disease management component that's completely underestimated. When the retina specialists have seen this data, the excitement about the program, the level of KOLs that were not necessarily involved that are now involved with the program, that has joined us as advisors and will be involved in the phase III trial, has completely transformed. It has been completely transformed on the expert side. We're hoping that the investor side will catch up to what we hear and that they'll realize that this is a pretty unique potential as looking at a fully de-risked phase III program with a multi-billion dollar opportunity with only a very small capture of the market. It's an exciting time for retina. There are a lot of changes, but we fit in all of this evolution of the economics and the introduction of the generics for Eylea, for example, that's supposed to generate $1 billion. All of these are going to be step edits. Eventually, what we're going to capture is patients that are on Eylea that require frequent injection first. Once that happens, we'll eventually be able to capture more of the market. Again, 15%-20% of the market will be a multi-billion dollar product. We think there's a lot of upside from there, particularly because we're going to be potentially saving a lot of money for Medicare. With this current administration, having a somewhat natural way to manufacture Eylea yourself in the eye, we think there's an opportunity to actually have conversation that will help accelerate the understanding and the positive perspective of this particular gene therapy program. Interesting. No, investors sure like to disconnect. That's nice. I'm really glad that you touched on the physician incentive because that is something that is extremely important in some medical fields more than other medical fields. Here, the economics and having a good answer and reason behind everything is extremely important. I'm glad you touched on that. I think we kind of touched on most things. You guys are moving forward with the phase III. Is there anything else I should have asked that we didn't have a chance to get to, or? I think we're excited to have over 150 sites in the U.S. that express interest for phase III. We're excited to start talking about the phase III enrollment start, enrollment completion. We think there's a lot of momentum. Recent phase III trial enrolled pretty well. The fact that we have both experienced and eye patients would help the enrollment as well. I think that's a real plus. I think given the size of the market, there's a lot of interest from potential ex-U.S. partners as well to work with companies like ours that have a fully de-risked program where we've been underpromising and over-delivering, whether it's the regulatory feedback we've received. Some others have changed at the last minute, a lot of things on their studies. They're hard to understand. We've been consistently transparent about what we think is the opportunity, what we're planning to do for the phase III. We look forward to keeping the community updated on our progress and getting this treatment to patients who really want it, need it, where we could save their vision. I'm very excited about this year. I think it's going to be transformative. We know that this is a product also that we can manufacture at scale. We have a CDMO that's been manufacturing all of our lots. This is something that's going to be a really, really attractive opportunity in the U.S. for patients and for the practices. We talked about the practice economics. We're focusing on that a lot because we think that's the misunderstanding and the perception that still exists that we need to correct. When we have these conversations with people who understand the data, that's very positive, I will tell you. Of course, ex-U.S. as well. The second study will be U.S. and ex-U.S. We've had PRIME designation and ILAP. We look forward to also starting the second trial, which will be U.S. and ex-U.S. sites. Excellent. You're in a very exclusive club of 3% market penetration, blockbuster. That is what I thought was very interesting too. Thank you very much for the time. I really appreciate it. Thank you very much for inviting us and for the excellent questions. We appreciate it. Thank you for helping educate the market as well. Thank you. Thank you. Thank you. That's all.