Welcome back, everyone. Next, we have Adverum Biotechnologies. It trades on the Nasdaq under the symbol ADVM. It's a clinical stage company that aims to establish gene therapy to preserve sight for life in highly prevalent ocular diseases, with the aspirations of developing functional cures to restore vision and prevent blindness. Please welcome Jason Au. Welcome back to the conference, Jason. The floor is yours. Great. Thank you so much. Good morning. Good afternoon, everyone. As introduced, my name is Jason Au. I'm the Executive Director of Corporate Communications and Investor Relations here at Adverum. We are investigating an ocular gene therapy with the potential for a one-and-done therapeutic approach for wet age-related macular degeneration. With that, we'll move forward through the traditional forward-looking statements. I'll get right into talking about the wet AMD marketplace. This may be the first large market indication for a gene therapy. As it stands right now, the gene therapies on the market and most under investigation are for more of the rare disease, such as Duchenne's muscular dystrophy, that are on the market. The pricing structure is vastly different than what we're approaching. First, when we look at the epidemiology in the market, this is a highly prevalent and very large market, 20 million patients worldwide. It's only growing, especially with the boomer population advancing in age. It's a large bolus of patients that are going to be projected to, you know, again, have wet AMD moving forward in the subsequent years. It's an approximately $13.5 billion market estimated by 2035, if not larger. It's a large annual incidence. Over 200,000 are diagnosed every year in the United States and up to 42% develop bilateral disease within two to three years, meaning if a patient has wet AMD in one eye, they have a 42% chance of getting wet AMD in the other eye. This is a very large market, high incidence, high prevalence. As I alluded to from an economics perspective, this is a vastly different approach to what many are familiar with, with systemic or kind of body-wide gene therapies right now, where it requires a very high dose. It's very expensive. It's a very high cost of goods. Ocular gene therapy, obviously, is in the eye. It requires over a thousand-fold lower dose than what is required for systemic. It's a much lower COGS. It has a very different cost and pricing structure, where we anticipate this looking more like tens of thousands, hundreds of thousands, millions of patients, you know, treated at a cost structure and a price structure that is completely different than what's currently on the market and being investigated for these systemic gene therapies. Now, wet AMD is a disease that is essentially manifested through an abnormal amount of vasculature development behind the retina, within the retina, that allows this fluid to kind of permeate into the retina and causes detachment and ultimately the photoreceptor death in the retina. This is essentially mediated by a growth factor called VEGF. The current treatments, which I'll talk through, are anti-VEGF. This is a very large chunk of what's currently spent from Medicare Part B. It's 12% from Part B budget. This is significant, of course. This doesn't even include the upwards of $80 billion spent on fractures in the United Sates as well, with actually vision loss and impairment being the key contributor to fracture risk. Again, there's a lot of comorbidities and downstream effects that come with the challenges of vision loss, especially with wet AMD. Now, for a market environment, I'll talk through this, but we do anticipate seamless practice integration to ease commercial adoption. I'll talk more about what that looks like a little bit later. What Ixo- vec is, and this is the therapy that's under investigation, which I'll talk through, that Adverum is pursuing, is essentially taking aflibercept, which is a very well-characterized anti-VEGF. It's the gold standard in the field. It's been used in over 70 million eyes, put into a gene therapy vector into the eye. What that essentially does is it changes the retina, the eye, to become a biofactory, continuously and sustainably producing anti-VEGF. Now, talk a little bit about the current standard of care. There are significant challenges to the current standard of care, which is essentially patients right now come in every month, every two months, if they're lucky, every three to four months, but it's usually every month to every two months, into the doctor's office to get a shot in their eye to essentially keep this fluid at bay to really dry out the retina. This is very challenging for a variety of reasons. Of course, having a needle in the eye is not a nice experience. A lot of patients have comorbidities. Sometimes it's not just treating the wet AMD in an eye. You might have geographic atrophy, for example, or other diseases. It's going to be very challenging to actually get to the doctor's office. These are people in their 60s, 70s, 80s. They have children, grandchildren, vacations planned. Sometimes, you know, one could drive, and then when you start to lose vision, they can't drive anymore. This is a very large reliance on caregivers, whether it's family or professional. It can be all leading to missed injections. If you have missed injections, you don't get that retina drying that you need to keep the disease at bay. You have essentially vision loss over time. A lot of barriers to treatment, and this is really driven by this need to have monthly injections over time. Now, on the right-hand side of the screen is an interesting survey that was done by the American Society of Retina Specialists. It asked the physicians for what is the greatest unmet need in treating wet AMD. What rose to the top is greater durability. Again, it's this concept of having a therapy that hopefully can keep these patients not having to come back every month or every two months and kind of following this treat and extend paradigm, although I'll talk about why that has limitations in a moment. Underscoring this is, again, what we are developing here at Adverum Biotechnologies is this gene therapy approach. It's called Ixo-vec. It's really designed to address the unmet needs of these patients with wet AMD by delivering this sustained aflibercept expression by, again, having that eye become that biofactory, which I'll talk a little bit more about. The therapies that have been developed over time, really starting with Lucentis back in 2006, labeled here as more in the first generation bolus therapies, that really led to that initial vision gain when you really start first drying out the retina. Interestingly, no therapy since then has really improved on that initial vision gain. It's all been around durability and extending the dosing interval. What patients don't want to have to do is come back to the doctor's office every month. If they can get to every two months or three months, that is a significant benefit to their lifestyle and having to live with this very, you know, chronic condition for life. This doesn't go away. We can kind of see over time the extended dosing intervals go from four weeks to eight weeks. There are now these TKI implants under investigation that have a target of 26 weeks, although no data yet on repeat implants. That really moves and shifts to the gene therapy approach in the top right-hand corner. That is what we're working on, this concept of vectorized aflibercept. This is, again, designed to deliver potentially lifelong injection freedom through a one-and-done therapeutic approach. This allows a reduction in treatment burden and potential for lifelong vision preservation. Sustained aflibercept mitigates the patient drop-off, which I'll talk about a little bit in a moment. Ixo-vec, like I said, is designed to deliver the stable aflibercept. Right now, if we look at real-world data, these patients get this initial boost in vision. What happens is that it essentially decays over time for a variety of reasons. One is that the therapies are not perfect. The other is burden to treatment. To get a patient back at a regular interval for one, two, three, four, five, six, seven years, however long that patient is alive, can be extremely challenging. We see here that upwards of 50% of patients on these anti-VEGF bolus treatments actually drop by two years, upwards of 60% by five years. Even these patients that stay on this well-maintained treatment regimen over time, the unfortunate kind of aspect of this treat and extend, and you're kind of almost reacting to the fluid buildup that you then treat with anti-VEGF, is that you kind of have this oscillating pattern of fluid and this kind of pulsatile nature of injecting these anti-VEGFs. What happens over time is you essentially get vision impairment and ultimately vision loss. What we are aiming to do here with Ixo-vec is to kind of bring this curve up to where you maintain these gains for the rest of your life. We're doing that by never letting the anti-VEGF levels go down, right? It's this continued expression of anti-VEGF in the site of disease in the eye versus this reactive nature. What this really looks like here on the top here is that current standard of care, whether it be four weeks, every eight weeks, 16 weeks, upwards of 24 weeks, is that you have this kind of fluid oscillation, as I was alluding to, right? The fluid builds up based off of the disease. You go to the retina specialists. They see this. They treat with an anti-VEGF. The retina dries out, goes back down. You are trying to figure out the optimal treatment, the treat and extend paradigm for how long you can go in between treatments. The fluid builds back up. It goes down again. It builds back up. It goes back down again. You kind of have this, again, oscillating pattern of fluid buildup as well as kind of retinal thickness over time. This is obviously not ideal. This can lead to fibrosis, scarring, and loss of ultimately the photoreceptors, the retinal pigment epithelium, and vision loss over time. What we are investigating here is, again, Ixo-vec. The real value proposition here is that you are eliminating these fluid oscillations over time because you have this sustained durable expression of the anti-VEGF, the aflibercept, in the retina, exactly where the disease is. You have this long-term protein expression leading to durable and stable visual and anatomical outcomes. You're not getting this retinal thickness oscillation or fluctuation nor fluid. We've at Adverum with Ixo-vec, since our phase I study, demonstrated sustained aqueous aflibercept levels now up to five years. This is a very long time in our field, for up to five years, showing that we have this sustained expression of aflibercept. How we do this, our product is kind of two components here. One is the vehicle, if you will, of delivering the optimized coding sequence for aflibercept. Kind of in the middle here, you see this red and blue and gray. That's the gene sequence for aflibercept. We need a way to get that into the eye. The eye, of course, doesn't want to let anything into the retina. It has this barrier, if you will, called the inner limiting membrane. That's very challenging to get things across. We use an adenoviral-based vector in the natural adenovirus called AAV2. This actually doesn't cross that inner limiting membrane or ILM really at all. What we did is something called directed evolution, where we changed some parts of the loop structure. This is kind of the outside of the capsid in a variety, you know, thousands, tens of thousands of different permutations of these loops, adding in amino acids, kind of changing the structure a little bit. We found one that was really good at penetrating that ILM. That was the one that we went with. It was called a 7M8 vector or capsid. We put that aflibercept coding sequence into the capsid. That's ultimately what gets injected through an intravitreal. This gets injected into the vitreous, kind of that gel-like substance of the eye. That goes into the retina. That transduces or gets into the cells, and then those cells become the biofactories. These are the cells that produce aflibercept for potentially the rest of that patient's life for that durable suppression of that growth factor called VEGF. It's an anti-VEGF. It's removing that component and helping control the disease. I alluded to this a little bit about intravitreal delivery. Ixo-vec is delivered as an intravitreal one-time in-office injection. This is very important, where essentially all of the current anti-VEGFs are delivered through an intravitreal injection. When we say that this really is able to integrate into the standard practice workflow, this is what we mean, that we're not introducing a new administration approach. This is well in line with what the doctors are doing, 10, 20, 30, 40, 50 injections per day already. This just slots right in there with that. This reduces procedural risks and potential complications. It's scalable, very accessible. Patients already are used to this. It's, you know, patient-friendly. This is in contrast to other gene therapy approaches that have different routes of administration called suprachoroidal or subretinal. Suprachoroidal requires specialized delivery devices just based off of how it's delivered at the eye, has a higher risk of complications, and it also requires much higher doses. With much higher doses, it does increase the inflammation risk. Subretinal does require a vitrectomy. This is conducted through a surgery. There are obvious limitations and just scalability limitations from that perspective. It has increased risk of retinal detachment or infection. It's limited to pseudophakic patients. Studies have shown long-term retinal pigment epithelium atrophy, as well as transgenes, that protein that's delivered, that gene sequence of aflibercept, reduction over time. Intravitreal really is the ideal administration approach for ocular gene therapy. I alluded to this, how Ixo-vec can seamlessly integrate into retinal practices' economic model. The current approach right now is the buy-and-bill model for these practices. With IVT administration, it easily integrates into the buy-and-bill economics of the practice. It also has the potential to increase and accelerate revenue and profitability. If you think about it, you are pulling forward one, two, three, four, five years' worth of anti-VEGF injections and front-loading that for the physician. You are also capturing and monetizing potential lifelong benefit of patients that would otherwise be lost to follow-up. If you recall, upwards of 50% in two years, close to 57%, 60% over five years, patients are basically lost to follow-up for a variety of reasons, barriers to getting the treatment. It's not working well. They just can't stand getting an injection in the eye anymore, et cetera. If you're able to not only monetize those patients, you're also benefiting those patients, of course, as well, right? Instead of having to have an injection every month or every two months for three, four, or five years, and I'll show you the data for this, you can get upwards of a little bit over 50% of patients with one injection for the rest of your life. That's a huge value proposition to both the providers and the patients. There's also the component from a payer perspective that there is potential to be cost-effective to the healthcare system. This is really to reducing utilization, again, not having to come back every single month for an injection, taking chair time up, and other indirect costs if you think about other negative downstream medical effects, comorbidities, fracture risk, as well as a very large issue, and especially in the U.S. In particular, we spend over $80 billion on fractures. Vision loss, like I said, is a large contributor to that. Review this, and there's data to support that it can be cost-effective to the healthcare system. It also offers these payers greater predictability in managing long-term expenses and patient outcomes. You don't have that variability about how much and how many anti-VEGF treatments you would need. You are paying and expecting for that one. Now, to get a little bit more into the data here, our clinical programs consisted of a phase I study called OPTIC, a phase II study called LUNA, and we're currently in phase III studies. The first pivotal phase III is called ARTEMIS, and I'll get into that. We have demonstrated long-term benefits for at least four years of follow-up at the 2E11 dose. We also looked at 6E11, but I won't be presenting that today as 2E11 is more close to the go forward dose that we use in the phase III, which is 6E10. Again, an order of magnitude even lower than what we are showing here. The long-term benefit is that we demonstrated nearly 50% remain injection-free through four years, so nearly 50%. This was in the OPTIC trial. Very notably here is that the injection-free percentage by year actually goes up after year one. We see 53%, 67%, 73%. I highlight this because it really is indicative of the potential as Ixo- vec being a disease-modifying approach. We're not just maintaining and treating the disease, but modifying the disease. This really is through, again, not having that pulsatile nature of anti-VEGF and not having this fluid and retina oscillation over time, less scarring, less fibrosis. This is really demonstrated in the data here from an injection-free perspective. We also demonstrate maintained anatomic and visual endpoints through four years. This is through the BCVA, or best-corrected visual acuity, as well as central subfield thickness, CST. We see a robust reduction in treatment burden, over 80% reduction in annualized anti-VEGF treatments every year. You can see the numbers here. It was very well tolerated with a favorable safety profile. 100% of these patients were inflammation-free at year one through year four. When we move into our phase II study, this was a double-masked study. This was at the 2E11 dose that I'm presenting right here. We were looking at potential best-in-class injection-free rates with over 50% injection-free in hard-to-treat or high-burden patients. These are patients that have an average annual mean number of injections of over 10 over the prior year. Over 50%. For those patients that actually have less than six injections, so a lower treatment burden, we have over a 75% injection-free rate. Over 50% injection-free rate, 75% injection-free rate for those hard-to-treat and lower treatment-burden patients, respectively. We are also, again, showing very consistent with the OPTIC trial in industry-leading treatment burden reduction. Over 80% reduction in annualized anti-VEGF injections, favorable safety profile at the 6E10 dose, which, again, is the go-forward dose for ARTEMIS. No Ixo-v ec-related SAEs, no new onset of inflammation after week 30, and no participant had inflammation at or beyond week 52. Once again, consistent with OPTIC, we were able to show maintained BCVA and CST, as well as fluid maintenance or fluid reduction, depending on that baseline CST value. Very, very nice data from both the phase I and phase II. Unique to Adverum and unique to LUNA is that we had a pre-specified patient preference survey as part of LUNA. This is a really interesting survey and very important. When we look, and I'll read this to you in the top left here, we asked these patients questions. Would you prefer Ixo- vec over your prior treatment? Yes, 93%. Would you want Ixo- vec in your other eye if you had bilateral wet AMD? Why that's important, if you recall, when I first introduced this, almost 50% of patients develop bilateral wet AMD over the course of their life. 95% said yes. Would you recommend Ixo- vec to your family and friends? 96% said yes. We had different steroid routines, which I didn't go into, but the steroid regimen that we are moving forward with pretty much into the ARTEMIS study. When you look at those patients in LUNA, 100% of those patients on that phase III regimen of 6E10 and the steroid eye drops that we're moving forward with supported its use bilaterally and would recommend it to friends and family. 100%. I think this really supports the potential here of Ixo- vec. Moving into the phase III study, we have applied all of our learnings, five years of clinical experience, really understanding the prophylactic steroid routine to minimize inflammation. All of those learnings went into our phase III program. Our first study is called ARTEMIS. This is a U.S.-based study. It's a non-inferiority design. Our second phase III study planned to start and initiate in the second half of this year is called AQUARIUS. This is going to be conducted to be a global study. These studies have really been thoughtfully designed to maximize the probability of clinical, regulatory, and commercial success. The reason I say that really is when you look at real-world data and you kind of see this histogram of patients for real-world injection frequency, there's a large diversity here of patients. Some only need one. Some need upwards of 13. What we've demonstrated in the LUNA study is that we have shown very good efficacy, over 50% injection-free in these hard-to-treat patients, again, around 10 injections in the prior year annualized, as well as 75% in those patients that had less than six injections in the prior year. This is notable because in ARTEMIS, we are enrolling both treatment-naive and treatment-experienced patients. It is really designed to generate a robust data set reflecting the real-world needs of patients. To close, Ixo-vec really is a differentiated approach in the ocular gene therapy space. We are, as I talked about, vectorizing a proven de-risked anti-VEGF protein called aflibercept that's been used in over 70 million eyes worldwide. We are using an evolved 7M8 adenoviral-based capsid, which is the gold standard for retinal transduction. We have a potential best-in-class profile where we've demonstrated over 50% injection-free rate and an over 80% treatment burden reduction in hard-to-treat patients. We have a favorable and well-understood safety profile. That phase III ARTEMIS study patient population that we're looking at really supports a broad label both in those treatment-naive and treatment-experienced patients that should help facilitate wide adoption in the practice. We have near unanimous preference for Ixo-vec as demonstrated in that pre-specified survey in the LUNA study. I talked a little bit about favorable practice economics where we do anticipate seamless integration into the current retina practice that should be favorable to, again, both providers, payers, and most importantly, patients. With that, I'll stop there. I'm happy to answer any questions. Wonderful. Thank you so much for that. Let's jump in. Can you walk us through what makes Ixo- vec different from other treatments for wet AMD? Sure. Yeah, I think maybe I'll just reiterate a few points that, you know, importantly here is with the current treatments out there, these anti-VEGF bolus treatments, is that they are, again, that kind of pulsatile nature where you have to come in every month, every two months. That is negative for the patient just from a burden to get to the doctor's office perspective and having to get a needle injected every month. It's also very bad for the eye anatomy, right? When you have this kind of oscillation of fluid over time, you get the scarring, fibrosis, loss of vision. Really the value proposition here is that if you can put that anti-VEGF protein aflibercept into a mechanism, an approach that really changes that eye into a biofactory where you have this continued expression of an anti-VEGF over time, what you can see and what we've demonstrated is a potential disease-modifying effect where you are getting a really good outcome over time where over 50% of patients have a one-and-done approach where they don't need any subsequent injections. This is a very different paradigm shift than what currently exists out there. Perfect. How does the Ixo- vec align with how retina specialists already treat wet AMD today? Sure. Yeah. This really gets back to right now the lion's share of patients are treated through intravitreal injections. These are what the current products are on the market. This is what the patients are used to. These retinal specialists are doing high-volume injections in a lot of these offices, 10, 20, 30, 40, 50 injections a day. This is what they're used to. It's what the patients are used to in the buy-and-bill model. From an economic perspective, it's what they're used to. This really just slots right in there. This is different than what I presented earlier from other approaches that are pursuing a suprachoroidal or subretinal approach that have their own limitations and challenges. This really fits into the practice, evolving practice economics, ever-evolving practice economics, as well as from a payer perspective where, again, we believe and research supports that this can potentially be very positive from a payer perspective as well from a predictability, as well as decreasing utilization both direct and indirect from a cost perspective. Talk about some of the next major milestones for the company. Yeah. We're that LUNA phase II LUNA study that I was talking about. We're presenting long-term two-year data in Q4 of this year. That'll be a really nice data set hopefully to come out a little bit later in a few quarters here. We also anticipate starting that other confirmatory pivotal phase III study called AQUARIUS in the second half of this year. Please talk a little bit about the cash runway. Sure. Yeah. We have cash into the second half of this year. We are very confident in our ability to fund both ARTEMIS and AQUARIUS. The phase III programs, our current enrollment and then screening is going extremely well. It's actually above internal projections right now that we have for that. We're very excited. The interest from both an investigator and patient perspective has been extremely strong. We have great momentum. We feel very confident through the different levers that we have in front of us to finance the company from BD to equity to royalties-based financing moving forward. There are some levers that we have available that we are actively pursuing and more to come on that. We feel very confident just due to that very positive momentum and the high recognition, I would say, from both doctors and investigators about the potential of Ixo- vec and really that data package, what we have from the phase I and phase II so far. Perfect. Thank you, Jason. Important work you're doing here with Adverum Biotech on the Nasdaq: ADVM. We thank you for joining us on the conference today. Thank you very much. All right, everyone. We'll be right back.