Hello, everyone, and welcome to the Seventh Annual H.C. Wainwright Neuro Perspective Summit. My name is Patrick Trucchio, and I'm Senior Healthcare Analyst at H.C. Wainwright. We have a robust agenda at the conference this year, with more than 25 companies presenting with their sessions available on demand through the conference portal. In addition, we're expecting a full day of panels and fireside chats with world-class KOLs on June 15th for the in-person portion of the conference. That said, it's my pleasure to welcome Voyager Therapeutics, a clinical-stage neurotherapeutics company advancing genetically driven medicines for serious CNS diseases. Voyager's pipeline includes multiple programs targeting tau, a gene therapy pipeline enabled by next-generation capsids. From the company, I'm excited to introduce President and CEO Al Sandrock. Al, welcome. Just at a high level, if we could, for those investors who are new to the story, if you could start us out with an overview of Voyager today, that would be helpful. Wonderful. Patrick, thank you very much for inviting me. It's an honor to be here. At a high level, I've been saying that this is the year of tau, and so far, halfway through, it's starting to look like it. We heard, for example, that BIIB080, Biogen's antisense oligonucleotide that knocks down the expression of tau, seems to be showing positive data. We'll learn a lot more at the AAIC meeting in July, but they're moving ahead to phase III, which is not a minor decision. It's not an inexpensive decision, so it must be good. That's what I'm hoping. We'll all learn more about that. As for ourselves, we have VY1706, which is a vectorized siRNA. It's an AAV gene therapy that does essentially the same thing mechanistically as BIIB080. In other words, it knocks down the expression of tau. We have another asset, an antibody against tau, against a C-terminal epitope, and we expect to see the tau PET imaging data later this year in the second half. Right. Terrific. Let's talk about the tau-targeting lead assets, starting first with VY7523. This is the anti-tau antibody with tau PET data expected in the second half of 2026. What would constitute a clear proof-of-concept signal? Yeah. We had multiple failures with anti-tau antibodies, most recent being the J&J antibody. We do have one example where there was at least some success, and that's bepranemab, the drug from UCB. It's not the same epitope as ours, but they did show a slowing of the progression of pathological tau in the brain by tau PET imaging on the order of about 60%. They also showed, in the full population, a statistically significant benefit on the ADAS-Cog, a cognitive measurement. They did not see a statistically significant effect on the CDR Sum of Boxes, a measure of both cognition and function. Kind of mixed clinical data, but certainly positive on the ADAS-Cog. What we're hoping to see is a tau impact better than the bepranemab antibody. Although, and look, we're going to look at clinical outcomes, but we don't think our study is powered to see an effect there. For all I know, we'll see some trends. Yeah. Maybe you could talk a little bit more about the biological rationale for 7523's epitope and mechanism and why it should succeed where prior anti-tau antibodies have struggled. Yeah. We made over 700 antibodies against tau. We had to choose, well, which one do we want to move forward? For that, we relied on the P301S mouse model. This is a mouse that expresses human tau. In that model, we inject Alzheimer's-derived pathological tau, so material from human brain, Alzheimer's material, and we look at the spread of pathological tau in that mouse. We chose this antibody because it had the most robust effect on that spread. I'll have to say, so far, the model has been quite predictive. It correctly predicted that the two N-terminal antibodies would fail. In other words, it didn't block the spread in that model. It correctly predicted that the J&J antibody would fail. In fact, we had an antibody very similar to that one that we could have chosen, but we didn't because it failed to block the spread of pathological tau in that model. It actually correctly predicted that there would be some effect from bepranemab. We chose ours because it was a little bit better than bepranemab, so hopefully we'll see that ours is better than bepranemab in the clinic. So far it's been quite predictive of the human clinical trial data. I'm pretty hopeful and that we'll see something. Right. Makes sense. VY1706 is a tau-lowering gene therapy using vectorized siRNA. Why is upstream MAPT mRNA lowering potentially more powerful than extracellular tau clearance? Yeah. The antibody approach relies on, first of all, you bind only to extracellular tau, likely because antibodies don't get inside cells. As you said, it targets extracellular tau. You also have to pick the right epitope. Because the problem with extracellular tau is that there's a mixture of multiple fragments of tau, and we don't know which of those proteolytic fragments, if you will, are the ones responsible for the cell-to-cell spread of pathological tau. You have to have the right epitope, and you're trying to capture the extracellular taus going from one cell to the neighboring cell. The tau-lowering strategy doesn't worry about epitope. It's going to lower all forms of tau. It's going to form a lower intracellular, as well as extracellular tau, also lowers normal tau as well. Look, the data that Biogen has showed and published now, the phase I data, substantially different. It doesn't just block the spread. It actually decreases pathological tau, even in areas with preexisting pathological tau, so fundamentally different mechanism. The clinical trial results so to date suggest that you may get a fundamentally different effect on pathological tau in the brain. As I said earlier, we'll see the clinical impact of that at AAIC. Yeah. That's helpful. Next one I think we've addressed somewhat, but maybe we can just revisit this a little bit more. What I'm wondering is why does VY1706 address, or what does it address biologically that an anti-tau antibody may not reach? Do you view VY7523 and VY1706 as competing tau modalities, or are they complementary? How should we think about these two? Yeah, look, it's very likely we'll choose the best approach. I wouldn't necessarily preclude the possibility of combination. If you use the gene therapy, you would knock down the expression of all forms of tau. Perhaps there would be a role for the antibody as well. My bet, though, is that you're going to probably pick the one that works the best. Yeah. That's helpful. As well, the next, we've addressed this somewhat, but maybe you could revisit a bit more. Just after we've seen several of these anti-tau disappointments across the field, what's giving you that increased confidence now that tau remains a valid therapeutic target? Well, listen, it's the best correlated. Tau pathology tracks with clinical Alzheimer's disease better than any other biomarker. The BIIB080 data, as I was saying, shows some very promising results. I think if you look at the human biology, we believe that amyloid triggers tau pathology. There are patients who have a brain full of amyloid, but if they don't get the pathological tau forming and spreading across the brain, they don't get demented, or at least not until very late in life. There are clear-cut examples where the tau looks like it's really more responsible for driving the clinical worsening in Alzheimer's disease. Right. That makes sense. How should investors think about the relationship between tau PET lowering and eventual clinical benefit? That's where the Biogen BIIB080 data that we hope to see next month and at the AAIC will be helpful because they have several dose groups. I expect the tau lowering might be different across the dose groups. Although if they've maxed out on the dose response curve, maybe they all show similar. This took a while for us to learn with amyloid. How much amyloid lowering do you need to get to see a clinically significant clinical effect? Turned out they had to lower amyloid quite substantially. We don't understand that relationship between tau lowering and the clinical benefit yet, the more data that we get from all these clinical trials, the more we'll understand. We have some evidence from bepranemab. We'll have much more from BIIB080, the field is learning that. That's going to be what I'm going to be trying to learn as much as possible over this summer in July, but also over the coming years. Right. That's really interesting. Is there any aspect of the Biogen, either top-line release or the upcoming data that maybe you think is not as well understood or appreciated by investors? Well, Biogen missed on the primary endpoint. They said that in their press release, right? I've always been saying, let's not be too overly concerned about the P value in a phase II trial. Phase II trials are rarely powered at 90% level for a statistical significance. Look, they missed on the P value because it was a dose response statistic. If you don't have a dose response, you're not going to get a statistically significant P value. What Biogen said in the press release was that all doses looked effective. Perhaps as I was alluding to earlier, perhaps you're in the flat part of the dose response curve. If that's the case, all doses will look roughly the same. When you have a variable measurement, like CDR Sum of Boxes, there's a one-third chance that any one of those would have looked better than the other just by chance, right? I think they hinted that the lowest dose may have had the most efficacy. I think that's just as much likely to be due to chance as anything else. Yeah. These are all the things that we're going to be learning soon. With the VY1706 IND clearance, this is a very important milestone. What does entering the clinic with a tau-lowering Alzheimer's gene therapy mean for Voyager in the field? Well, first of all, I think it's important for Voyager and the field for two reasons. One is this is the first time that we're using a blood-brain barrier penetrant capsid, where we can give an AAV capsid just once, IV, and it should lower the expression of tau across the brain. That by itself will be quite an achievement to be able to do gene therapy in the brain with an intravenous single dose. The other thing is, boy, if we can get something equivalent to BIIB080, but with a one-time dose rather than repeated intrathecal injections. When you're trying to treat millions of patients, intrathecal injections is going to be cumbersome for patients and for doctors and for medical centers. Imagine if you could do, instead of intrathecal, IV, and do it just once and get essentially a long-term effect that's equivalent. I think both on the sort of proving the concept that an intravenously delivered AAV capsid, a novel capsid that can penetrate into the brain and get gene expression broadly, that's an important milestone if that were to happen. Second, to be able to treat millions of patients potentially with Alzheimer's disease, with a once and done gene therapy that could lower the expression of tau, and get results similar, we hope, to what the Biogen will show this summer. That's another important milestone. Yeah. That's helpful. I guess which of the biomarkers in this trial would be most decision-enabling for VY1706? Is it CSF tau, phospho-tau species, tau PET, NfL, MRI, or another measure? We're going to be looking at multiple measures. At this point, it's important to be exploratory in an early phase trial. I would say that among the fluid-based measurements, there are various measurements of pathological tau, phosphorylated forms of tau, like p-tau181, p-tau217. They can be measured in either blood or in spinal fluid. The one that we're going to focus the most on is the tau PET imaging, because that is actually looking at the spread of pathological tau in the brain. I should say that all humans, by the way, will form pathological tau, and I hate to even call it pathological tau because if all humans get it's not really pathologic. With aging, we have now learned that we can misfold tau and have it aggregated or clumped in a very tiny region of the brain called The R hinal Cortex. It's only when you have amyloid that it starts to spread. It's the spread of tau that's actually abnormal in Alzheimer's, not the presence of pathological tau in a tiny part of the brain. It's the spreading like a wildfire across the brain that we'd like to try to block, because that's what we think causes disease. That's where the tau PET imaging is the best way to look at that spread, and that's why we're going to focus on that. How do you define the therapeutic window for tau lowering, just given tau's normal physiologic functions? Here again, we're going to be looking very carefully at the Biogen data. Biogen target approximately 50%-70% lowering with BIIB080. We're all purposely avoiding 100% reduction, right? Because, as I said earlier, and as you just pointed out, tau is a normal protein, and we're knocking down all forms of tau. We're hoping to see very nice clinical effects, great benefit for patients. We wanted to kind of match the BIIB080 data. That's why I said earlier that is there a possibility for combination. The gene therapy's not going to be 100% knockdown. It's going to be 50%-70%. Maybe that's where a contribution of an additional antibody treatment could potentially, that targets only the pathological forms of tau, that you could see where combination could play a role. As I said earlier, I think most of us would prefer a monotherapy. Right. In the safety and tolerability side, what should we be looking for, and what are the key considerations for a systemic AAV delivery? The key thing is that we don't get the capsid effects. We know that the main adverse events from AAV historically have been, for example, liver toxicity. We've seen that in humans. There's a thing called thrombotic microangiopathy, so-called TMA, and that leads to loss of platelets, and all sorts of other issues. Multiple organs are often affected. People treat that with complement inhibitors. TMA is another risk. Recently, there's a theoretical risk of insertional mutagenesis that REGENXBIO has seen in one of their patients. All those are potential risks. Capsid had a patient who had an issue with an intravenously delivered AAV, in a patient with STXBP1. We still don't have a lot of details on what exactly happened in that patient, hopefully we'll learn that some more. Those are the safety considerations, and we've done a lot of work in preclinical studies to understand the risks of VY1706, and to mitigate those risks, we're doing a very careful study in patients. We're going to be always watching out for the safety issues that could crop up. Right. Great. Beyond Alzheimer's, the Neurocrine partner, Friedreich's ataxia program is expected to enter the clinic this year. What would clinical entry validate for a TRACER platform. Well, there it's another TRACER-derived capsid to treat a disease that affects not just the brain, but also importantly, the heart. Again, our BBB penetrating capsid, Neurocrine will have chosen a capsid that will affect the heart as well as the brain. The problem with AAV gene therapy, unless you do modifications on AAV, it may get to the heart quite well, and some people are approaching FA by doing gene therapy, but targeting the heart. The disease also affects the brain, that's why it's called Friedreich's ataxia. The ataxia comes from the brain disorder, and children suffer from that. So we'd like to address both the heart and the brain, and we're hoping that our TRACER-derived capsid will do so. What does the ALPL receptor discovery tell you about the reproducibility and translatability of TRACER-derived IV delivery to the brain? How does it differentiate between other competitor capsids in the space? Yeah, knowing the receptor is very helpful. First of all, it's the best way to know if there's a human homologue. If you know the receptor, you can check, does the human have a homologue? This is important because in the history of AAV capsid discovery, you can discover capsids that work really well in experimental animals, but they often don't even cross species. The first ones that were discovered only worked in mice, and only in certain strains of mice. That's probably the biggest. The other thing is you can also, what we've done is we say, "Okay, if ALPL can transduce capsids, maybe we can make shuttles that bind ALPL, where we can maybe shuttle large molecule drugs into the brain without the use of AAV." That's the significance of ALPL in my mind. Right. That's interesting. With roughly $2.4 billion in potential milestones across collaborations, how should investors think about the timing, probability, and strategic value of those partnerships? Well, we just got our IND cleared. Neurocrine has indicated they're going to be in the clinic. We have multiple other collaborations, some with Novartis, some with Alexion AZ. I'm hoping that we're going to show that these capsids work quite effectively and safely, that would be a huge boon for patients, eventually Voyager shareholders, if any of those milestones come through. Just looking ahead on the sort of the internal versus partnered pipeline, how do you decide whether a program should remain wholly owned versus partnered? Well, I'm always open to partnerships, particularly since our partners bring their own expertise. There's so many targets that we could go after in the brain, so many diseases that were genetic medicines or a gene therapy approach could be helpful for patients, that there's no way we could do it all. As long as the Voyager shareholder gets a benefit, I like the concept of working with partners. Now, in the case of Alzheimer's disease, it is so large that we've always said we're going to seek a partner, at some point, right? Right. Likely after we get proof of concept. Yeah. We've done partnered programs for all these reasons. Right. Just as a final question, with the cash runway extending into 2028, I'm wondering, as we look out over the next year and a half or so, what would success look like for Voyager across VY7523, 1706, as well as the partnered programs and the TRACER platform? Yeah. Hopefully with VY7523, we're going to show best-in-class tau PET data with an antibody, and that should hopefully attract a partner. 1706, we're going to be able to use that to say, "Hey, these TRACER-derived capsids can work in humans." Capsid proof of concept, and also to prove that we have an asset that's similar to BIIB080, that with a one-time IV, we can achieve something pretty similar. Then we have the Neurocrine FA program that's slated to go into the clinic this year as well. Boy, as we look into 2027, we could start to see early data in both FA and AD. Remember, when you do gene therapy trials, you have to treat patients, and you have to use doses that could help the patients. Then, of course, we're always in discussions with potential partners. That's how I see it. Right. Terrific. It's an exciting time for Voyager, and it's always a pleasure to catch up with you, Al. Thank you very much for joining us. Thanks for Voyager for attending the conference, and thanks for everyone else for being with us. Have a great rest of your day and a great rest of your conference. Thank you, Patrick.