Hi, thank you again for taking the time to join us at Baird's Healthcare Conference. My name is Jack Allen. I'm a senior biotech analyst here at Baird, covering a number of companies in the cell and gene therapy space. One of the very exciting ones here today is Voyager Therapeutics. I'm joined by Al Sandrock today on the stage. Thanks so much for taking the time to join us. Al- Thanks, thanks for having me, Jack. Yeah, Al, Voyager is working on a really innovative approach to gene therapy with these capsids that are tissue targeting. Maybe just to start, can you talk about the TRACER technology and how it allows you to target specific- Sure tissues with these AAV capsids? Yeah, so, you know, I've always believed that one of the big challenges for CNS, for neurotherapeutics, is delivery. I was attracted to the company because they've solved, I believe, the delivery issues for AAV gene therapy. What TRACER does is, it sort of starts... It continues on with a story that started in academia, where people found that you can actually do what's called directed evolution of capsids and get them to cross the BBB, blood-brain barrier, with IV delivery. In academia, they could only get it to work in mice. The history behind these capsids is that they can be very species-specific. The TRACER platform actually starts in non-human primates, actually in cynos. What the scientists at Voyager do is they start with AAV9, which is the king of neurotropic capsids, or AAV5, which also gets into the brain, but also has a lower incidence of pre-existing antibodies. Then they take certain parts of the capsid that essentially are stick out essentially, and could affect tropism, and they make random mutations in those loops. And they know that they can change these loops without disrupting the capsid integrity. So they make lots of different mutations, essentially substitutions or insertions, little peptide insertions, and they do this kind of randomly, and they made many, many millions of variants. 20 million per library, actually. And they inject thousands of capsids into a single monkey, and they barcode them so that only the capsids that get into the brain are recognized. And then by sequencing the gene product that comes from what got into the brain, they know which capsid actually enabled that. So it's a very clever platform, it's very empirical, and they also... So in addition to starting in cynos, they actually look for messenger RNA rather than just looking at DNA, because if you look at DNA, it could just be that the capsids got stuck to the blood vessel, never actually got into the brain. So they actually look for— So the capsid has to get the gene into the cell, produce episomes in order for it to be recognized by TRACER. And it's produced some amazing capsids that are manyfold better than AAV9. And you know, for that reason, Pfizer, Novartis, Neurocrine, and Sangamo have you know done deals with us to leverage these capsids. Yeah, it does really feel like over the last couple of years, a lot of your partners have come to the realization that we need more targeted tissue-specific- Yeah ... capsids to expand the, you know, risk-benefit profile of these gene therapies. Absolutely, including, you know, if you take Pfizer and Novartis, these are companies experienced in gene therapy, not only in development, but commercialization, right? And they spent a year sort of kicking the tires with our capsids before they opted in. So we had nothing to do with those experiments. They did them in their own labs, and after a year, they opted in each one of those companies. So I think it's, you know, to me, it's a lot—there's a lot of external validation here. Yeah, and maybe to put a finer point on it, how much more tissue specific are these versus AAV9? I believe there's one that's a 1,000-fold- Yeah ... more specific. Thousand-fold. Yeah. We're not interested unless they're at least an order of magnitude better, but we now have capsids that are 100-fold or 1,000-fold better. And at the same time, you know, the remarkable thing is, not only do they get into the brain better, but they de-target the liver, which is a source of toxicity, and they also generally de-target the dorsal root ganglion neurons, another source of toxicity. So we got lucky in a sense that they get into the brain better, but they don't get into these organs that cause toxicity. Moreover, they're so potent that we think we can lower the dose. In fact, we have presentations at scientific meetings where we inject 10^12 VGs/kg. You know, but our goal is to go at least an order of magnitude below E14 VGs per kg, which is what people generally use, for systemic delivery. And so we think we can really widen the therapeutic window by lowering the dose and using capsids that de-target these other organs that cause toxicity. Yeah, it's really interesting science. I guess maybe rounding out on the scientific side, there's a receptor that you've identified? Yeah. I know you're keeping it proprietary to yourself- Yeah, we call it Receptor X. But can you talk a little bit about how that plays a role? Yeah ... in your validation of the platform? Yeah. More generally. So one of our leading class of capsids, our scientists discovered the receptor, which is present on the blood-brain barrier, as well as the cells that this capsid transduces. And we figured out in molecular terms, by and large, how the capsid leverages this receptor to cross the BBB, which requires transcytosis, release into the brain, and then it has to bind again to another membrane, get into a neuron or a glial cell, uncoat, and produce episomes. And this receptor seems to mediate that. We actually have now discovered two additional receptors for two other classes. So this is really giving us well, put it this way: the fact that we have a human homologue for these receptors really increases the chances that it's gonna work in humans. I mean, look, we also look for cross-species validation, so we're not satisfied with just the-- We don't want a cyno-only capsid, right? Yeah. And so we test multiple non-human primate species. Some of these capsids even work in mice. But now, when you know the receptor, and the receptor is present in humans, well, I think it's the best you can do prior to actually doing the human experiment. When you say you have multiple receptors, is it multiple receptors with the same vector? Or- No, it's- Is it multiple different vectors? ... 3 different classes of capsids. Yeah. Each one has its own receptor. Interestingly, they don't use the same receptor. Yeah. There's at least three that we know of so far, and potentially more. Could the availability of that receptor also be leveraged outside of gene therapy work- Yeah as well, you know, target tissue delivery of a small molecule or antibodies? Yeah. Like, how do you think about leveraging that knowledge as you move forward? Yeah, that's a really exciting area that we've been working on this year. We've discovered a ligand for the receptor that has many of the characteristics you want for a ligand that binds to a receptor and then releases. So it has to bind, but then it has to release on the other side, otherwise it doesn't get out into the brain, right? We found a ligand that has many of the characteristics required. We're now conjugating a ligand to other macromolecules like nucleic acids, ASOs, siRNAs- Yeah ... and proteins, to see if we can leverage this receptor to get delivery across the BBB without the use of AAV, so non-viral delivery. It's sort of like what Denali does with transferrin receptor, except that we know our receptor isn't transferrin. Is that an area that you think Voyager would look to pursue internally? Or would you look to, you know, maintain Voyager as primarily a gene therapy company? I know you do have the passive antibody that you look to bring into the clinic, and we're looking forward to talking about that as well. Yeah. But how do you think about balancing all of the different ways you can go- Yeah with the science at Voyager? So we have to be mindful of our operating expense. So we're doing the pilot experiments now, which we think we can do with not that much spend. But then, if we want to now turn this into another platform, essentially a drug delivery platform, we're gonna need to have a whole set of capabilities that we don't have. We need chemists, for example. We're thinking about how we could do that. Do we do it with partners? You know, it's either rent, buy or build, or partner. You know, we're thinking about all those options. And you've talked a lot about the CNS-specific capsids. Are all of the receptors targeting the CNS, or do you have tissue-tropic receptors for other, or sorry, capsids for other organs as well? Yeah. Have you found any receptors in that work? Yeah, we haven't done that work. Okay. Yeah. We're really focusing on the brain right now. Again, another potential way to partner. If there are partners interested in other tissues, I'd love to figure out a way to work with them. Yeah. You know. When might we expect the next presentation of data from the TRACER capsid- Yeah ... kind of portfolio library? So the most obvious one is ASGCT, which is in the spring, you know, and we're still on time to get abstracts submitted for that. Love to figure out if there's an earlier time point, but we haven't quite figured out when and where, but... Because we have a lot of data emerging that, you know, and so the earliest would be ASGCT. Okay. And are the focuses still CNS and cardiac, or are you looking at other tissues as well? Focus is still mainly CNS. Okay. We're also starting to look at skeletal muscle- Okay ... and cardiac muscle. We have some data coming out, actually, as we speak, on some of these. Because a lot, you know. And part of it is that many of the diseases that involve the brain also involve... Well, not many, but some of them involve skeletal muscle and cardiac muscle. Friedreich's ataxia, for example, the program that we're partnered with Neurocrine on, affects the heart as well as the brain, right? Mm-hmm. So, it'd be nice to have capsids that can transduce both organs. There are also diseases that affect skeletal muscle and brain, right? So it's not quite neuro, but it's related, we believe, in some ways, by the disease. Would you look to use, you know, two capsids in combination ever or in succession? We could think about that. What's the immune profile- Yeah ... after someone's exposed to these capsids? Yeah. Well, you can't do it in sequence, probably. Okay. Yeah. But, I'd like to find a single capsid that could do both, right? That would be the simplest, most expedient path forward, and potentially the safest. Great. I think we've really talked a lot about the TRACER technology more generally. Maybe we could shift gears and talk about the internal pipeline. Sure. Can you provide just a brief overview for those less familiar with the pipeline you're building out? Mm-hmm. I think you laid out the plan- Yeah ... in the last couple of months. Yeah. So in terms of late-stage research, we have two programs. The first one, ironically, is not a gene therapy. It's a program that was actually started by Steve Paul, back when he was the CEO. You may recall that we had a collaboration with AbbVie, which was to vectorize anti-tau antibodies. So as a part of that program, Voyager scientists discovered some very interesting antibodies. They started with antibodies that are specific for pathological forms of tau, but there were still about a half a dozen of those. And so the question is: How do you choose among them? And they were scattered across the tau molecule. So they did a very interesting experiment, where they take Alzheimer's disease paired helical filaments, and inject them into animals, and they look at the spread of tau. The antibodies that we chose to move forward with block the spread by 70%, whereas the N-terminal antibodies, those are the ones that have gone to the clinic and failed, they don't block it at all. And if the data are coming out that in humans, you know, we all get tau in the medial temporal lobe as we age. So it. I don't think you can call it pathological tau, because if we all get it, then it's normal. But these misfolded, aggregated forms of tau stay in the medial temporal lobe, unless you start to get amyloid accumulation. Mm. Amyloid seems to trigger the spread of tau. It's the spread of tau, not the actual initial accumulation, that's pathologic, and our antibody blocks the spread. Yeah. So, so that's why I'm pretty excited about it. It's also a very efficient path to clinical proof of concept. We think we can do a trial, a one-year trial with 25 patients per group, and get proof of concept on whether or not we can block the spread of tau, the pathological spread of tau in Alzheimer's disease. So this program goes into the clinic, we hope, in the first half of next year. We already have a development candidate. We've humanized it, we've had interactions with FDA, and we're beginning the process to get us into an IND, which is planned for the first half of next year. The second program is actually an AAV gene therapy. It's a vectorized siRNA to decrease the expression of SOD1 in patients with SOD1-mediated ALS. This follows in the footsteps of Tofersen- Mm ... which was approved, as you know, earlier this year, an antisense oligonucleotide that lowers the expression of SOD1. I like this program because, first of all, it could be the very first program that demonstrates that one of our capsids works. Second, is that it follows a validated target, and we can use the measurements that Biogen used to de-risk the program. So Biogen looked at CSF SOD1 levels as a target engagement biomarker, and they looked at neurofilament as a surrogate marker of clinical efficacy. We plan to follow the same pathway. These biomarkers are, I believe, well-validated for, particularly for use in this situation. Now, that's so that program will be 2025 in the clinic. We hope in the sort of mid-year. But there's three other programs that could be AAV programs, that could be in the clinic in 2025. They're partnered programs. So two of them are in Neurocrine's hands. They're the partnerships that we have with them on Friedreich's ataxia and GBA. We believe, since those are the lead programs, that those are the programs that Neurocrine means to talk about when they say they're gonna have two gene therapies planned for 2025. Yeah. Yeah. We have Sangamo. We just did a deal with Sangamo earlier this year, where they plan to take one of our capsids into prion diseases- Yeah ... in 2025. So there could be four shots on goal, if essentially, with one, with one of our capsids in 2025. That's a minimum, I think, because I don't know the timelines for the Novartis and Pfizer programs. Yeah. Since those are capsid licenses, it's pretty hands-off in terms of Voyager. For all I know, they could be planning to go into the clinic in that timeframe, but I just don't know. But they would be leveraging one of our capsids that they licensed. So I think in 2025, we'll have some capsids. I capsids. I believe that there's a strong likelihood that, you know, there's gonna be one or two at least, if not four or five shots on goal in 2025. Yeah, it's an exciting time. I guess maybe, a lot to chew on there. We can step back to the tau and then move through the progression chronologically. Sure! In tau, you mentioned a 25-patient cohort, and- Mm-hmm ... maybe four cohorts is what you've talked about before. Yeah. How quickly do you think you can enroll that study if you get it underway in the first half of next year? And you said about a year of follow-up. Yeah ... and some amount of time to do- So- ... the PET imaging. Is that gonna take longer than a year, given- No. Or when do you place the PET imaging? We would use the second-generation tau PET ligands that have already been used by the various companies in the amyloid trials. Look, it's a large population. It's Alzheimer's disease- Yeah ... probably people in the mild cognitive impairment to mild dementia category. There are lots of those patients, and so I don't think recruitment will be a problem. We, as a field, have learned how to get these patients into trials. Mm. Hundreds have been enrolled in the various anti-amyloid phase III trials, and so I think. And then whether or not we'll do it in combination with those other drugs, I don't know. I'd rather just do a clean. You know, our first trial, you know, I'd rather just do it without combining. But ultimately, you know, I do believe that tau-directed therapies could be combined with the amyloid-directed therapies. Yeah, that brings up another. So you would prefer to do a tau-only- Yeah ... in a non-experience- Yeah ... fit amyloid patient population? Because certain of the anti-amyloid antibodies affect tau spreading on their own. Yeah. So we don't want to complicate things. Not all of them, by the way, but certain of them do. So I'd rather just do a clean tau-only, and then once we've got that data, there, we could, there would be options on, on where to go. Yeah, I guess let's speak about those options briefly. Would you pursue a passive antibody approach, or- Yeah ... I know you have a tau, you know, vectorization- Yeah ... opportunity. Yeah. You already have a tau-silencing gene therapy- Yeah ... I I believe, in preclinical development. So if it works, my propensity right now, and it's, you know, premature and perhaps, but I would prefer to keep that program going into phase three and try to get, ultimately, to get the antibody approved by itself, and I would also initiate a vectorized tau antibody program. That's another thing, you know, we don't we talked about TRACER, which is a capsid platform. Voyager scientists know how to build payloads, too. We can vectorize antibodies. We've presented data at scientific meetings. So even though there's size limits on what you can put in an AAV, both the heavy and light chain can be put into an AAV, and you can actually vectorize an antibody to be secreted by intrinsic CNS cells. In fact, one of our early-stage programs vectorizes an anti-amyloid antibody. So, and then we also know how to vectorize siRNAs. And so the payload capabilities of Voyager for AAV are pretty, pretty impressive also. Yeah, it really is a diverse platform that you have- Yeah ... of technologies at Voyager. I guess to that end, you know, you mentioned Voyager's lead gene therapy candidate is the SOD1- Yeah - gene therapy. I think you're, you've signaled that you expect to, nominate a lead development candidate- Yeah - in the coming months? In the coming months, yeah. Okay. Before the end of the year, that's our goal, is to nominate a development candidate. What aspects are kind of up in the air still? Yeah. I can't imagine you're making all of the decision. Yeah ... you know, in the next couple months, you've probably decided on certain aspects. What- Yeah ... what's up in the air and what's been decided? So right now, what we're trying to do is to make sure that the capsids that we have, which, you know, we use reporter genes as payloads, work well with now the actual payload, which is the vectorized siRNA. So it's a combination of capsid and payload that we want to verify would work. And so we have several combinations of those that we're testing, and we'll pick the best one. And that's in non-human primates. Yeah - you're going to be doing that testing? That's in non-human primates. I know there was an importation ban on non-human primates. Has that affected Voyager in any way? Not yet ... to perform? Not yet. All right. Knock on wood. Yeah. You know, our scientists have been figuring out. Well, we use multiple vendors to decrease that risk, and so far we haven't been affected by that. And you continue to use the same approach to mitigate against that risk- Yeah ... moving forward? Yeah. That's right. I guess, is it fair to say you have the assets that you need to execute on that? Oh, yeah ... guidance for SOD1? Yeah. At the minimum. Well, those experiments are already underway, so- Yeah ... we have the NHPs. Great. Maybe we can shift gears and talk a little bit about the partnerships. You, you've mentioned them a number of times. I think they're really great outside validation. It's been really incredible to see, honestly, over the last couple of years, the growth of the partnerships, right? The Pfizer deal- Yeah ... built up by the Novartis deal, and then around- Yeah ... a major healthcare conference in early January of last year- Yeah ... that was a large deal with- Yeah ...... Neurocrine, a leader in the CNS space. Yeah. Maybe for those less familiar, could you just contextualize the deals and kind of how you think about partnerships moving forward? Yeah. I know there's infinite ways to structure these. We've seen- Yeah ... different structures as well. Well, I think of them as bookends, you know. So we have the capsid-only licenses. So the Pfizer and Novartis were ones where they take a capsid, it's exclusive to the target, so we won't work on that target with anybody else or ourselves. They take our capsid and, as I said, they run with it. They know how to do all the development work, manufacturing, et cetera. On the other side end of the book shelf is the Neurocrine partnership, which, you know, were true program collaborations. And there, I mean, we get fully reimbursed, but our scientists are working hand in hand but including our technical operations scientists on figuring out the manufacturing process. And so we get fully reimbursed, and then after phase 1, we have the option to opt in for U.S. rights, 50% for GBA and 40% for FA. Yeah. And so those are sort of. And then, you know, there's everything in between those two. And we're open to any structure that makes sense. Do you continue to remain quite active? I know it's been a very busy time. Yeah. Yeah. Yeah. But, um- Yeah, we're talking to- How would you characterize the activity? I'd say pretty much anybody who's interested in gene therapy in the brain, we're probably talking to them- Yeah ... I'd say. And so, yeah. Are there any inflection points that potential partners are looking towards now? Do they want to see clinical proof? Like I'd imagine in some conversations, people look for different things from a platform before they want to get involved. Is anything to keep an eye on as it relates to the partnership discussions? I think they're very interested in cross-species reactivity. Many of them know the history of where you can have very species-specific capsids. So the fact that we have data now, we typically look at three different non-human primate species, you know, cynos, African green monkeys, and marmosets. We also look at mice, many of our capsids cross all these species. They also like the receptor, the fact that we know that there's a receptor, and any of the descendants of the capsid for which we know the receptor, we also know the receptor for, and so that is of keen interest to many people. The other thing they ask frequently about is dose. You know, we want to be at least an order of magnitude below E14. So, you know, our target is E13 VGs per kg, sort of in the mid-range there. Then we also are, people ask about liver and DRG targeting. So it's really about therapeutic window. Yeah. Could we take a second and step back and talk about dose and cost of goods? I guess, how are the TRACER capsids manufactured today? Yeah. Having these order of magnitude lower doses should reduce the cost of goods substantially- Yeah ... and expand the opportunity- That's right ... for gene therapy. But how do you think about that dynamic? Yeah ... as you develop these capsids? So there are basically two platforms by which you manufacture AAV, either Sf9, which is an insect cell line, or HEK293, which are mammalian cells. Voyager historically was an Sf9 company, but the manufacturing advancements in HEK have progressed so well that we are now mostly an HEK company. Actually, TRACER starts with HEK, so we actually had to discover the capsids, and then initially we were thinking we'd have to move them to Sf9, but now we stay in HEK. I can tell you the improvements in manufacturing at CDMOs has been just exponential over just the last few years. So not only are they in suspension cultures, they're scaling up to 1,000-liter bioreactors, and I'm hearing now that they're up to 2,000 some places. We've seen the data with 1,000-liter bioreactors, and I'm very confident in that. We have. We actually have two 200-liter bioreactors at Voyager. Right. So we scale up to 200 liters, and we test to see whether we can manufacture it. But it's mainly gonna be HEK. Yep. So, yeah, the doses are an order of magnitude lower, at least. Right. Yeah, so it makes the cost of goods much more attractive. Who's responsible for manufacturing with a capsid-type partnership? Or I guess it's better to say a transgene- Yeah ... partnership with- Yeah ... the Pfizer, Novartis case. Yeah. Who's expand- So, for Pfizer and Novartis, they do the manufacturing. You provide them the recipe, and they go- Yeah ... and make the vaccine. Well, they're actually doing a lot of their own technical operations- Okay ... work themselves. Yeah. With Neurocrine, we're much more partnered on that. How do you think, looking back at the big picture, I'm sure you get this question all the time, you've made a number of great partnerships. How do you preserve, you know, rights to the internal shareholders of Voyager, rather than partners- Yeah ... partnering out too much? That's always a tricky balance, right? We've got a lot of non-dilutive revenue. We have cash runway into 2025. We ended Q2 with $273 million in cash, which is very nice to have. But you give away a piece of the future. So we have to be cautious about that, but there are so many targets in the CNS, there'd be no way we could prosecute them all anyway, right? I don't think we've reached the limit yet, but we do wanna have enough things in our, as a wholly owned pipeline, where we haven't given away too much of the future, but it's a tricky balancing equation, and so. I guess in the same vein, how do you also control that you're putting it in the hands of people that are gonna execute? Yeah ... with that, with that capsid? We're very conscious of that. We have partnered with great companies where we... You know, we don't want anything to mar our capsids, right? I mean, and so we have a lot of trust in all four of these companies that we've partnered with so far. Yeah. And there are protections in place that, you know, don't allow the use of the capsids- Yeah ... externally as well? One of the things we made sure we built up was a good IP, legal, group, and they are very, very... I believe they've done a fantastic job protecting our rights. Great. Well, that wraps up the questions I have, Al. I don't know if you had any closing remarks, but thank you again for taking the time to join us. No, thank you for inviting me. Yeah, no, I think you captured it. We're about a platform that produces novel capsids that we need for CNS delivery. We have a pipeline of really exciting, I believe, neurotherapeutics programs. We have partnerships that are not only validating, but they produce revenue. Actually, we already get revenue from that, and hopefully future revenue as well. And finally, we have the potential that these receptors could lead to non-viral forms of delivery. So I would say we're really on our path to a neurogenetic medicines company that we think could be pretty exciting. Yeah, it's exciting times. Thank you again for taking the time- Thank you ... to join us, and thank you all in the audience. Thank you, Jack. Thank you. Thank you.