Great. Hello everybody, Luca Issi, Senior Biotech Analyst here at RBC Capital Markets, and today is our great privilege to have Adverum for a fireside chat, representing the company we have Laurent Fischer, Chief Executive Officer, as well as Linda Rubinstein, Chief Financial Officer. So, thanks so much for joining us. How are you guys doing today? Thank you for having us and for a great conference. Appreciate being here. Great, great, great. Maybe Laurent, we have a long list of questions, but I'd always like to start kind of big picture. Can you just maybe walk us through what progress has the organization made over the last few months, and most importantly, what's ahead here for Adverum? Yeah, absolutely. So we have a gene therapy program for wet age-related macular degeneration, a viral vector called Ixo-vec, which is an aflibercept encoding AAV.7m8-made vector that can be injected intravitreally that actually makes the retina produce low level of aflibercept Eylea for as long as we've measured in patients for a half year at stable levels. And that's really unique in the sense that it allows patients to avoid these painful frequent injections, stabilize their vision, and the fluctuation in the fluid that results from these bolus injections and the standard of care, which is the test and treat. We presented recently at Macular Society data from a phase II study called LUNA, showing that we have essentially 68%-83% of the patients at six months that are free of injection. Compares very well to what we've seen in our OPTIC study, which is now at past three years, where we actually have a year one, year two, year three—more than half of the patients completely free of injections with stable visions and dry eyes. So clearly, a best-in-class efficacy. We—part of the goal of this study was to also optimize the prophylactic regimen. We have the best efficacy. We have potent capsid. But when you inject trillions of vectors in someone's eyes, you expect an immune response. So we have looked at multiple local regimens that seem to have a good control, and we'll be presenting the interim analysis, the full 26-week data from the LUNA study at the ASRS meeting in Stockholm on July 17th, and looking forward to sharing this data. Awesome. Then beyond that, we've guided that we intend to start phase III in the first half of next year. We'll be engaging with FDA based on the 26-week data for our end-of-phase II interactions and providing program and regulatory update in Q4. Super helpful, super helpful. Maybe one more bigger picture question. We get that a decent amount from investors. The journey for you in terms of, like, gene therapy and wet AMD, you know, obviously started a while ago. At the same time, you know, the current standard of care has made reasonable progress recently. You know, if you think about like high-dose Eylea, faricimab, now we have the TKIs in the mix as well. Just walk us through a big picture. Why you remain fired up about gene therapy and why you believe that gene therapy can offer something unique to the patients that are maybe not served today with the current standard of care? I think that's a great question. We see how in retina, modest incremental benefits and interval in treatment injection lead to multi-billion dollar products. You mentioned faricimab for Vabysmo, which is nearly a $4 billion product. And this is clearly an improvement, right? And that's why there's such rapid adoption of novel treatment and technologies in the space. We actually happen to have 10 patients out of 60 that were on Vabysmo at both doses that entered LUNA trial. So far, every single one of these patients is free of injection up to 32 weeks. So that's clearly better, right? If you're a patient that is diagnosed with wet AMD, you know one thing for sure. You'll have lifelong disease that requires lifelong treatment. Whether that treatment is every few weeks or every few months, you'll need something, except if you have an implant, the Port Delivery System, which currently is not available. But that would be one way, and it needs to be refilled every six months, or gene therapy. So at six months, things look promising for the TKIs, but I'm pretty sure that at year one, year two, year three, you'll have 0 or less than 10% of the patients that will require nothing else. For us, at three years, it's 53% free of injection, overall 83% reduction in anti-VEGF. I think this is truly best of class. So we're offering a lifelong solution, lifelong treatment for what is a lifelong disease for these patients that are in their 60s, 70s, sometimes 90s. The fact of just having to go, sometimes drive an hour to get an injection in the eye. If they're hospitalized and they miss that injection, fluid comes back, vision goes down. We know that there's a lot of data showing that this fluctuation in fluid in the retina leads to poor vision outcome. It's that trampoline effect on the retina that leads to fibrosis signal and poor vision. By stabilizing the vision, we see many patients that gain, you know, 15 letters, three lines of vision, and they say they see better. They see better colors. They see better at night. They can stop using magnifying glasses. For them, it's truly transformative. That's why we're very excited, because we think we provide a truly, you know, not just incremental, but truly transformational benefit for patients, at a cost of certainly needing to take steroid eye drops for a few weeks or a few months. But if you think about corneal transplant, for example, the 40,000 of those, you know, every year in the U.S., these patients have clear vision, but they need an eye drop or steroid a day. It's non-adverse, and it's well tolerated, easy to manage. Got it. Super helpful. Avoiding, avoiding the trampoline effect. I'm going to use that one. I think it's very, very powerful. And Linda, if you have anything to add, feel free to jump in at any time. Maybe just, just kind of one question. I want to reflect back on the journey here. So obviously, you know, you had OPTIC, and then you're, you're optimizing now the dose in LUNA. But just maybe big picture, walk us through what were some of the key learnings from OPTIC that you're actually using in, in LUNA here? So a few things. First of all, OPTIC was our first in-human study. We started a dose that turns out to be the highest dose we've ever used in patients, which is very unique in the field of gene therapy. We know we start with a low dose that's suboptimal and go up. And in fact, if you look at every program, whether it's RegenX or 4DMT, everybody went up and then went back down. So everybody hit a ceiling on safety and went down. We just hit that ceiling. And the first dose we tested, we went down in dose. We're able to show that we still had great benefit. And then we went back and in non-human primate tested an even lower dose, which is the one we're testing now in LUNA, showed that we still had very steady level of aflibercept expression. That's very consistent to now we've proven in the LUNA trial where we showed those protein levels be very consistent and delivering therapeutic levels. We're also the only ones that have shown, and that's the benefit of having started that study over five years ago, that with our capsid, in patients, the levels that are completely steady for four and a half years. So very likely to be a lifelong benefit. There's been recent presentations of other vectors that show a loss in transgene between six months and year two. So I think it's going to be important to look at this data and look across all the different programs, whether they do deliver that therapeutic payload for long term and whether it really translates into that potential functional cure, meaning a majority of patients being free of injections for life. So that's really what we've learned. The other thing we've learned is that we were the first to test steroid eye drops as a prophylactic. In the field is all oral steroids. We know those are poorly tolerated, particularly in elderly patients. And we noticed that we could actually control the inflammation with steroid eye drops. The course was too short, but what we learned is that even with only six weeks, 40 patients are free of any inflammation, period. And then 25%, 26% required some steroid drops up to one year, but they were off steroid eye drops at year two. So we know that there's some variability in how patients respond, as you see in non-human primate and as you'd expect. But we can control it with local steroids to optimize that in our LUNA trial to try to understand two things. One, do we need systemic steroids to control the local inflammation? The eye is typically immune privileged, but is it really true? Nobody tested that. And actually, we answered that question. No, we don't need oral steroids. So that was a huge win from LUNA. The second one is, can we actually take away the responsibility of the prophylactic from the patient and give in the hand of their retina specialist the treatment and the prophylactic? And Ozurdex is giving you that, you know, burst of steroids that lasts for a few weeks. We were hoping they would last long enough that we'd needed nothing else, but we found out that, you know, even though in uveitis it lasts for 12-16 weeks, it was never tested in the setting of gene therapy where the peak immune response is probably day 25-day 90. And we had early breakthrough. So we added steroid eye drops with that new, you know, potential go-forward regimen of an Ozurdex plus steroid eye drops. We see that we have excellent control at both doses we tested in LUNA. So that's very encouraging. And again, trying to optimize the prophylaxis is really to really learn how to manage the side effects of any of these gene therapies. They all have it. And, regardless of the route of administration, you see that you need to manage kind of the immune response. And I think that's part and parcel for regenerative medicine. Sure, sure. No, that's helpful. Another learning I'd point out is that we use criteria for supplemental injections where if patients lose vision, have fluid go up, or have a hemorrhage, they get a supplemental injection of Eylea 2 mg. Of course, we were very early in, you know, devising this regimen and pretty much people use the same criteria and they, you know, tweak them on the edges. In the first trial, we required that those criteria be met for the first injection, but not later. I think that we in the field have understood that you want to have set parameters for those injections so that you can truly compare each of the arms in the trial. So we have a much more robust analysis in a LUNA trial where these two doses are masked and every rescue injection has to be essentially reviewed and accepted by a central reading center. So I think our ability to identify whether there's a true dose response or not, which I think we'll know better on the 10-26 weeks interim analysis, is really the case. And obviously, we're very confident that we have by far the best efficacy of any program to date and also the ones that have shown it the longest. So those two parameters of a target product profile that's commercially viable with the best efficacy, best-in-class efficacy, with a measurable safety profile that's easily understood. It's AC cells in the anterior chamber that are seen by a slit-lamp. Most of them are traces. They're not symptomatic. Patients don't have flares, light sensitivity, pain, and they're all managed with local steroids. It's something that is, you know, very favorable for patients. And, you know, we believe that the majority of patients would select that treatment versus their prior history. And as I mentioned earlier, we were very lucky to, you know, enroll 10 patients with Vabysmo. Every single one of them is free of injection now up to past 32 weeks. So we'll provide an update on these patients as well. Got it. Got it. Super helpful. Maybe just reflecting on the journey. I mean, I remember in OPTIC, there were a few cases, but there were some cases of inflammation that occurred a little bit later in the game, like weeks after these patients were taking off steroids, right? So I think there's a component where you have to manage inflammations in the acute settings as soon as you actually deliver the gene therapy. But there were a few cases later in the game. I guess two questions. One, do we ever got to the bottom of what was driving those late inflammations? I mean, the virus should be gone. And, you know, is this the transgene? Is this the promoter? Is this like, so one, do whatever if we get to the bottom of it? And two, how do we know that we can avoid those going forward? Because I remember talking to KOL, some of them were like, yeah, if I have inflammations in the acute setting, that's okay. But if I have kind of an idiosyncratic event that can happen anytime, many weeks after I took my patients off steroids, that's a different conversation. So any, any thoughts on all that? So, I think you know, the cases we saw, the dose of toxicity of hypotony was actually in a different indication, which is DME. And that was actually only at the 6E11 dose, only when patients were not adequately managed with inflammation. And we didn't know that we should measure the ocular pressure to see that in these patients that have microvascular disease, acute renal failure, digital amputation, or stents, they actually had a ciliary body that produced the aqueous humor that's responsible for the pressure in the eye that was shutting down because of inflammation. And of the few couple of patients we found late and, you know, the pressure dropped, they lost some vision. After that, we were able to actually manage every single patient, prevent it and treat it. We didn't see that in the high dose in OPTIC in wet AMD patients at all, and not in the low dose. We've never seen anything like that. We've monitored, of course, very carefully ocular pressure in all patients. It's completely stable. But I think in the 6E11 dose, some patients required actually steroid eye drops for a few weeks, some even a few years. For these patients who are free of injection for three years, having a steroid eye drop a day is totally fine. We think this is, you know, we can do better optimize based on the dose. And what we really have seen in non-human primates now in patients is that we can drop the dose and still have aflibercept levels that are very much within therapeutic range. That is not being seen with the capsid where they drop the dose to improve the safety, but they have compromised the efficacy and they see actually, I think, much less efficacy. So for a gene therapy product, we're thinking about the long-term game. The ability to have the best efficacy and the best TPP is what we're looking for and optimizing the prophylaxis, making sure it's manageable. So we haven't seen, again, cases of late inflammation or recurring inflammation on the doses we're testing in wet AMD patients at all. Got it. Got it. Super helpful. Maybe, Linda, you mentioned it earlier already, but, can you maybe talk about how you're envisioning a potential phase III trial here, how you're thinking about the potential design here? Obviously, there's a little bit of a debate out there between non-inferiority versus superiority, and we'd love to pick your brain on that one. So just maybe any, any thoughts on how you're thinking about the phase III and how you could potentially design a trial. Absolutely. We know a lot based on the FDA guidance. So we know that gene therapy trials require following patients for a year for the primary endpoint, which needs to be vision. The comparator would be Eylea every eight weeks for us. You can compare versus Eylea versus Lucentis. We prefer the non-inferiority trial. Of course, we have to talk to FDA and confirm a number of our assumptions. But that's the approach that has been used for Vabysmo and Eylea high dose and we think makes sense for us. You know, we think it's a trial that would be easily enrolled and well executed. And also one that would fit, you know, global regulatory applications potentially because it's being used for multiple drugs that are on the market. So we're excited about, you know, taking this 26-week data that we'll be presenting at ASRS in Stockholm in July and using that for an end-of-phase II meeting and interaction with FDA EMA to finalize the phase III protocol. And I think great progress. I think one of the unique aspects of those different programs, as you mentioned, is they fall under different divisions. The TKIs are under CDER. We're under CBER. Of course, CDER has had some major changes. And CBER, I think, is probably a little different in the way they think about global trials, harmonization between EMA and FDA. So it's an exciting time. There are a lot of companies that are going in front of regulators and we're having both informal and formal meetings. We look forward to reporting our updates on the regulatory and phase III plans in the fourth quarter of this year. Can you run a trial solo? Do you need a partner? We can actually operationally run it solo. We obviously are hoping to find our next series partner to partly fund the trial. I brought a team from Allergan, now AbbVie, that was in charge of enrolling one of the largest trials in NASH with 12,000 liver biopsies. Those are people who are now in-house, at Adverum. I think we're very capable of enrolling these trials, ourselves. But, obviously, we are looking for ex-U.S. partner to, you know, co-develop and eventually commercialize the product outside of the U.S. It's in a market where you can commercialize in the U.S. as well, right? There are 2,000 retina specialists would be the target for the commercialization. So it's something that is tractable for a small company. Fairly concentrated market for sure. Yep. Maybe I ask you about competition earlier in the context of therapy that are outside your main category, right? But how are you thinking about competition within your category? We obviously have 4D Molecular Therapeutics in the mix as well with some, you know, pretty, pretty interesting data. Now, obviously, RegenX is in the mix too. It's a little bit more an orthogonal process given obviously subretinal and superchoroidal versus you guys are obviously, focused on intravitreal. But what are your big picture thoughts on where your data fits versus some of your competitors? Yeah. So, I mean, there are only, you know, two peer-reviewed publications on two-year phase I or II studies, ours and RegenX. But those came out a month ago. Even with a, you know, subretinal approach, there seems to be less efficacy in that program than what we've demonstrated, at two-year. And I think it's a challenge to do subretinal approach for large indication, which is why they are moving to a superchoroidal approach, which seemed to work reasonably well, but requires doses that are in the E12, so potentially up to 100-fold higher than what we're using in our trial with efficacy that is, somewhat inferior to what we've seen. I think, you know, 4DMT is a very similar capsid, two-transgene, aflibercept and a second-inverted shRNA. I haven't seen the contribution or the potential liability of that second-transgene. But they also have efficacy that is somewhat lower than what we've seen at the dosing at the doses they're testing. And they, you know, have data on 5 patients that are out to two years. And I think that's a pretty small, you know, sample to inform where they're going. I think what is interesting is that they are going after now a core expansion that is patients that require less frequent injections. And that is in itself maybe an admission that they're not as effective, as powerful as what we see. The patient that we treated required 10-year annualized injection the year prior. And, we see those, you know, 68%-83% being free of injection in six months. I think they see 60% and 50% at the two doses testing in six months. But I haven't seen any data at year one, year two, year three. So we have that long-term data. So I have confidence that at the doses we're testing, we're providing long-term benefit, long-term freedom of injection. And we haven't seen that in 4DMT, though they have, you know, learned from some of the lessons and optimized some of our prophylactic regimens. So, you know, I think there's a lot of room for multiple treatment. There's a Vabysmo Eylea HD. There's two TKIs, you know, two dry AMD treatments. It's a very large market, 1.5 million patients treated and 200,000 new patients per year. So I think that, you know, it's good for the field to advance outpatient type of gene therapy product for those mass market indications that will be really transformative in the field. I think people think of, you know, gene therapy as a multi-million dollar product for hundreds of thousands of patients. What here is going to be more like tens of thousands of dollars, a price of maybe 3-5 times an annual cost of the current anti-VEGF, which would be eventually very cost-effective and cost savings, but for potentially millions of patients. That's why we're, you know, very excited about the transformative potential of Ixo-vec in wet AMD patients. Got it. Super helpful. Maybe just one question I meant to ask maybe earlier, but I'm going a little bit backwards here. But remind us what you have seen in terms of expression of the transgene and whether you saw a good correlation between evidence of expression and, you know, the patients that are actually injection-free. You know, last time I looked at the data again, small N, and it's obviously difficult to maybe overinterpret, but all is going to be careful not overinterpreting that data. But maybe we didn't see like the perfect correlation there. Any thoughts on that? So this is a really, really interesting question in the field. You know, anti-VEGF and Eylea has been around for, what, 20 years almost. And I always ask, especially when you see a patient for the first time, what do you tell them? You tell them you're going to be on every four weeks, every six weeks, every eight weeks. Do you look at them in the eyes and say your macula looks thicker or your OCT is thicker? They don't know, right? So there's not a marker of the need for anti-VEGF or the level of anti-VEGF, which, you know, is an interesting paradigm, right? I think Regeneron, I'm sure, has looked for that for a decade or more. So what we've seen is that, and what we know from non-human primate is that the levels that are expressed in the retina are seven-fold higher than what you measure in the front of the eye. So we haven't seen a correlation between the level of measure in the front and the efficacy we've seen. And in fact, we have a few patients at both doses in LUNA that have levels that are below the limit of detection of assay, which is 25 ng/mL, that have zero injection. Therefore, sufficient level in the retina where, you know, if you think about conceptually, in the bolus treatment, this patient make a lot of VEGF, you shut it down, VEGF goes down, comes back up, then it goes down. When you have constant levels of Eylea on board, you're going to basically keep VEGF very low, right? So yes, there are a few patients, in fact, only 10 out of 60, like 10% out of 66 patients that have more than one injection. We have overall 75% free of injection, 90% reduction, 90% anti-VEGF. A few patients that have only one injection, you know, and then very few that have four injection, which I don't understand if there are criteria, but no, there's not a threshold or direct correlation between the levels and the efficacy. We see that the benefit of that stable level of aflibercept that we've seen every single patient up to 4.5 years translate into, you know, clearly the best efficacy and the best clinical benefits in the field. Not something seen with other programs, like in the RegenX paper, right? They saw a reduction in their protein levels out to two years. Two years. Sure. Sure. Sure. Helpful. Maybe the last one, going back to the phase III. Can you use OTC at home or is that something that can be used at some point down the line? Like, how, how, how, you know, for the Ixo-vec experience? That is something that we can use, you know, whether we will use it remains to be seen, but yeah. There's a lot of technology coming to bear. Yeah, I think, you know, we were, I was particularly excited about the OCT at home. Unfortunately, during COVID, it was not widely available. You can get enough machines to retest it. But I think down the road, that will be something that will evolve. I think right now the cost is not quite there. But eventually, yes, why couldn't you monitor even with a camera from an iPhone potentially, you know, or something, you know, much more convenient? But yes, there are definitely studies that were done. And I don't think that's something you could do in a phase III trial, because patients have to be seen anyway and there are other kind of rigor in the protocol. But down the road, I think that's absolutely something that would make a lot of sense once it's kind of widely deployed. I don't think, unfortunately, it is yet. But it makes perfect sense. And down the road, I'm sure that will be where things will evolve with more kind of remote access and remote monitoring of disease. Got it. Got it. Super helpful. One more question, but no more time. So, Laurent and Linda, thanks so much for joining us. Thanks, everyone, for joining and all the best for the rest of the conference. Absolutely. Thanks a lot. Thank you so much. Appreciate it. Thank you. Thank you, Linda. Appreciate it. Yeah. Yeah.