Stifel 2026 Healthcare Conference - VOYAGER THERAPEUTICS INC

All right. Thanks very much. Happy to be here moderating a fireside chat with Al Sandrock, CEO of Voyager Therapeutics. Obviously, Al has a tremendous amount of experience and wealth of knowledge in the neurology space. So I'll try to surprise him with some other questions too. But maybe to start, Al, do you want to just give an update, an overview of the Voyager pipeline, efforts in the tau space and then we'll kind of dive deeper into some of the uh other data from biogen and other key questions there yeah so we're focused on neurotherapeutics we were born as a gene therapy uh in the cns company we are uh but we i view ourselves as a multi-modality neurotherаpeutics company i'd say that uh we have a sort of a catalyst rich period coming up and i'd say it's related to the first one would be the tau antibody that we expect to read out actually this quarter. And then we have FDA clearance to introduce our gene therapy tau knockdown program. And we expect the dose to first patient in the coming months. Neurocrine also has one of our capsids going into Friedreich's ataxia. So two shots on goal to see whether we can validate our newly discovered blood-brain barrier penetrant capsids and see if we can safely dose patients and get evidence of gene expression. And yeah, so I think those are, and you know, when it comes to the gene therapy. We expect to see acute safety early. Capsid-related safety tends to declare itself early. And then it'll take probably about a year after we start dosing to see evidence of gene expression in the brain. In the case of our tau knockdown program, if we see tau going down, it must be because our vectorized siRNA is being expressed in cells. And then the third uh readout would be eventually to see whether or not our knockdown program affects tau pet imaging and there's a lot of data that's not only come out already but will continue to come out that will help us understand the relationship between tau biomarkers and how much of an effect you need on tau before you get clinically significant effects and we're starting to see some of that data this year with bib 80 for example yep yep okay well maybe let's start with the bib 80 readout right i mean i we thought it was promising proof of concept but somewhat confounded by um by the dose response that maybe it's not an inverse dose response but certainly they weren't getting more benefit as they push the dose what do you make of the totality of the data yeah so i think there's several pieces of data that i think we should look at together in addition to bib 80 so we have bib 80 an intrathecal aso knocking down the expression of tau we have a novartis intrathingal aso that also knocks down the impression of tau that that read out this year and then we recently had the arrowhead shuttled sirna where we've seen at least the high level data in a press release i think all three are very helpful as we think about the bib 80 data so we saw what was well the the trial failed on the primary endpoint which was a statistic a dose response statistic based on cdr some boxes and if anything yeah there was a slight downward trend in terms of and so that's going to destroy any attempt at seeing a dose-response statistic but nevertheless i think overall as you said i think it validates tau as a target. On ADAS-COG, we see an effect size superior to the anti-amyloids. We saw that with MMSC, the mini-mental status as well, superior tothe anti- amyloids on CDR sum of boxes at the lowest dose. Certainly you saw in the same range, if you will, an effect size in the 20, mid 20% range, similar to the antiamyloid. But if you look at So let's start with the biology. When you look at CSF or fluid-based tau biomarkers, from the lowest dose to the highest dose, there wasn't much change. At the lowest dosage, it was a 40% reduction. At the highest dosage it was 50%. So you're at the flat part of the dose-response curve in terms of tau knockdown. But I think what happened was that what we saw was a dose-dependent increase in a transient acute confusional state. And I think that, I think, is due to intrathecal ASOs having off-target effects. We've seen that with other intratHecal ASO's, several others. And IONIS actually published this year papers on transient neuronal inhibition as well as neuronal activation phenomena that can occur with oligonucleotides regardless of sequence. So it's probably related to having a highly negatively charged oligonucleotide, high extracellular concentrations. And remember, you have to give relatively high doses intrathecally in the lumbar cistern if you want to get enough exposure up in the brain. Because there's a pretty steep gradient from the lombar castern up to the cortex and even more reduction as you get into deep cortical structure. So to protect those exposures up there, you've got to give excessive amounts down in the lumbar cistern. So I think that what we've had was a, you know, you maxed out on tau reduction with the ASO because ASOs, you know, they're okay for knockdown. SiRNAs are a little bit better because they're catalytic. But you couldn't do much more than 50% knockdown, but the untoward effects, these transient neurological issues degraded i think the primary endpoint which you know getting confusional state in a patient with alzheimer's disease is bound to affect of course uh endpoints right um also there's this peculiar thing where with tau related drugs it seems that you have a bigger effect on cognition than on function yeah activities of daily living did not look that great in bib 80 either. Maybe that's related to the acute confusional state. What I wonder is, is it masking a potentially even bigger effect if you could achieve, say, 70% knockdown? You can't do that with an ASO because now you really have problems with higher doses, right? And so I wanted to point out the Arrowhead data. Oh, before we go to Arrowhead, let's go to Novartis. So they have an intrathecal aso also injected into the lumbar cistern that was positive in psp so much so that they're moving into phase three they also report encephalopathy a transient encefalopathy which i think is akin to this acute confusional state so two intrathingal asos and i don't think it's related to tau i think it'srelated to these transient neurological effects that we've seen with many others. We even saw with Spinraza in the early days. So let me get back then. Arrowhead is a very different approach. It's SIRNA, but it's not intrathecal. It systemically delivered shuttle, and they did not report an acute confusional state or anything like it or encephalopathy. So I think that that's, so I think, I really do think it's intrathingal ASOs. And that gets back to 1706. You know, our approach is more akin to Arrowhead. We get broad distribution. We don't have steep gradients because we have a BBB penetrant capsid that we're using. And actually, we get no extracellular concentrations of siRNA because we make the siRNA in the cell. The gene therapy is an intracellulary production of si RNA. So I think I find all this kind of encouraging for our programs. Yep. So with the BIB80 data, there's a much larger effect on CSF tau versus tau PET. I'm wondering, to what degree do you think that that's a byproduct of intrathecal administration, inflating the CSF biomarker, versus the possibility that tau PET is kind of rate limited to how much of the protein the brain can clear, and that in itself is never going to be nearly as high as the knockdown you can get? Yeah, so it could be that there's more than one pool of pathological tau in a cell. It could bethat there's a more reversible pool of that pathologic tau and a more irreversible pool. So if you look at, for example, neurofibrillary tangles, it's hard to imagine that much of that is going to be reduced by just inhibiting the synthesis of new tau. They look like pretty darn permanent structures, if you will. On the other hand, I think pathological tau can exist in what I would call condensates before they become involved in NFTs. And I think that probably is reversible. And so I suspect that with tau-PET imaging, we're going to see all pathological tao in either sort of phase, if You will, in either form. and that we're only going to be able to see the reduction, at least by blocking synthesis. Now, if there's a way to remove tau from the NFTs, I don't know of any right now, but I noticed that this morning there was a protein degrader company that is targeting tau. I don'T know if that's going to affect the NFTS, but anyway, so that's my interpretation. Yep, okay. And then as it relates to the gene therapy approach, first off, I guess talk about what makes you comfortable with irreversibly knocking down tau, that this will be safe. Yeah, that's one of the reasons why we were waiting for Bib 80, right? So in our animal studies, we can knock down tau even to 70% without seeing any untoward effects. there are humans there are there are genetic variants of tau that where you get loss of function variants in tau that are tolerated in humans quite well as you know paul because you've written about this you know tau is a microtubule stabilizing protein right but there's lots of microtzubule stabilising proteins there's redundancy in the system so whereas i think tau plays a pretty important role during development. I think in the adult, the redundancy allows us to reduce tau by certainly 50%, maybe even 70% without any problems. I think with the patients who were followed for 18 months, the transient confusional state notwithstanding, I didn't see any other long-term effects that are concerning. right so and and so I think we're I think I'm pretty comfortable and you know Alzheimer's patients arguably have declared that they have too much talent and it's a fatal disease we forget sometimes that Alzheimer's disease is a terrible disease and it and so and there are patients who still die from Alzheimer's Disease thousands of patients with Alzheimer's are dying every day. And even though we have the anti-amyloids, you know, a lot of people can't take them. If you're an APOE4 homozygote, you're probably not going to be prescribed anti-amyloid because of the risk of aria. And by the way, when we talk about Bibedi and we say the CDR is on the same range as anti-amelloids, they achieve that without any risk of area. so um and even heterozygotes with apo e4 care you know which there are a lot of hetero zygotes who have alzheimer's disease they many people are not being treated because of the risk of aria it's higher and even heterosegots right so anyway i i think tau is the next big thing for treating alzheimers patients with a bad disease and and i think we should try to figure out a way to help those patients. Yeah. So with the gene therapy approach, um, how are you thinking about the therapeutic index for capsid related safety issues? Maybe if there's any context you can kind of give around the dose range that you are planning on studying and how that kind of compares to like, you know, where we saw tox for Alevitis or some of these other AVs that ran into like liver or hlh or things like that yeah so uh there there's two things that give us hope with our capsids one is that we're using a lower dose so uh most all to my knowledge of the systemically given a b treatments are in the e14 1e14 bgs per kg range our highest dose is not going to be higher than 5E13 VGs per kg. So we are at a lower dose. Second is we have a capsid that detargets the liver 30-fold relative to AV9. And so, as you know, patients have died from the sirepta gene therapy from liver failure, and so the fact that we detarget the liver is also helpful. Now, we will use immunosuppressive treatments at the time of administration, but our talk studies were quite promising on the safety front, and we had a very robust discussion with FDA. You know, we had a pre-IND meeting that was more than a year before we submitted the IND. I went back. We decided to go back to FDA after the Capsida patient died to say, what did FDA know about what happened to that patient? So we can incorporate their feedback into our GLP talk studies. And we did so. And we made additional measurements. And then we submitted our IND, we had a robust discussion with FDA. I'm pretty confident that we are doing the very best we can in the interest of patient safety. Yep. Yep. Okay. Makes sense. So maybe talk about like the planned timing of the disclosures from the gene therapy data. So you said obviously early data, insight into safety, and then maybe the next two sort of layers of PD insights that you'll get. Yeah, so the first is, you know, we think Q1, we still think acute safety. Much of it is going to be capsid-related, right? I mean, because capsid issues occur early. Then about a year after we start dosing, we will measure CSF tau PD. And then sometime after that, and we haven't even guided to when we would get the PET image. and that would tell us whether we have an asset that can help alzheimer's patients does that answer your question yeah it does i think you know maybe to just drill down on that like what have we learned from other programs and the degree to which pet lags knock down yeah so you we can feels like that's driven by like the actual brain versus the actual modality is that fair yeah well yeah like whatever the endogenous well well so listen i mean you know when we look at messenger RNA we knock it down rapidly but tau has a slow turnover so we we have to wait for tau but but you know in our studies for example at three months after we give our gene therapy we see tau knocking going down in non-human primates and then we see further knock down in six months but then I think for pet imaging I think you need at least a year um and uh and what's responsible for that lag probably due to sensitivity of pet imaging you know but also the pet signal grows so there's accumulation in this in the region at baseline you know when the patients come in they have certain regions of the brain that already have tau and the tau signal the pet signal grows within that region, and then it spreads to other regions. And that's a cell-to-cell spread likely. And, and that, that takes time to, to, to occur. And therefore it takes time to see an effect on those. Yep. Okay. Makes sense. And maybe last question on the gene therapy side, we can talk about your antibody as well, but just as you think about getting a product like this to market, you know, most innovation we've seen in the gene therapy spaces happen in rare diseases where there's you know greater flexibility around the size of the safety database of the trials you need to do is your assumption that for the gene therapy you're going to kind of have to operate and run more of like a lacanumab like program or is there an in-between potential here i think there's an in between potential but on the other hand you know here so first of all alzheimer's disease is so common if you can do a once and done iv treatment that can lower tau and let's say and we've seen that 50 percent lowering should be sufficient wouldn't that be great because if you look at sma every infant gets zolgensma in this country right shortly after birth right and then that's like the baseline treatment and then if patients need more of an SMN-inducing protein, SMN protein-indUCING treatment, they get either Spinraza or Ristaplan. So you can have, and I'd say a lot of people are getting additional treatments beyond the gene therapy, but the gene therapy provides sort of the baseline. I could easily see that happening in Alzheimer's, because to treat millions of people with intrathecal ASOs, or even sub-Q-delivered s-i-r-n-a's is it's it's a lot it's a lot um and uh um so anyway so um i do think it's going to have to be larger than the rare disease trials of course it's gonna and it's gonna have to have a lot of to be powered to see an effect on probably cdr some of the boxes so it's not going to be small right but we're not also i would say that there's improvements in cost of goods for for aav therapies every year as companies scale the cost of goods is going down and we're not going to have to charge the kind of you know i mean look at the prices people are charging for rare disease because you have to we have to you know make ends meet right with with alzheimer's there's volume right we can we can be commercially successful without charging a high price yep okay so makes sense um on the antibody side uh you know obviously that's an approach with tau and you know to some extent synuclein where there's been this overarching question around attacking an intracellular target you know there's a number of failures for each a little bit of promising data but just maybe in like the context of that talk about your antibody why it's differentiated and why you think that approach still has some merit yeah so um i call it the dark horse because nobody thinks it's going to work, but I think there's a decent chance. Otherwise, it wouldn't be in our pipeline. It's differentiated because, first of all, our antibodies specific for pathological forms of tau in the anti-amyloid space, that turned out to be pretty darn important, partly because you don't want antibodies binding to normal tau and essentially be a sink for the intended target, which is pathological tau. Second is that it worked in an animal model that I have relied heavily on. So we had literally hundreds of antibodies against tau. How do you choose the right one? And we relied heavily on an animal mode that actually Steve Paul, who was the original CEO of Voyager, brought in from Cornell. This is a mouse that expresses human tau, the P3ONS mouse. And you inject paired helical filaments from Alzheimer's brain, human Alzheimer's brain, into one region of the brain, usually the hippocampus. So then you look for accumulation in the ipsilateral hippocampsus of pathological tau. And then you see it spread to the other, to the contralateral hippocampa, transynaptically. And so the belief there is that the biology that underlies that accumulation and spread is similar to what's going on in humans because in humans, that's the characteristic of Alzheimer's. When we talk about Brock staging of Alzheimer'S, it's based on where tau has spread, not where amyloid is. And this model correctly predicted that the N-terminal antibodies would fail. The N-terminel antibodies that failed in the clinic failed in this model. It correctly predicted that bapanamab would block the spread of tau, did so by about 50%. And you will recall that Pranamab was positive on ADAS-CoV in the whole population of pre-specified secondary endpoint. So it was not a post-hoc analysis. It's failed on the CDR sum of boxes to be, but there was a trend. And by the way, UCB is moving forward, it sounds like, with Pranumab. It also correctly predicted the failure of the J&J antibody, which we learned about roughly a year ago. We actually had an antibody very close to the epitope that J&J targeted. We did not pursue that because it didn't work as well as our antibody in that model. So, so far, that animal model is four for four in predicting the human clinical, three on the negative side and one on the positive side. So hopefully we're five for five when we announce our results. Yep. Do you want to talk about study and data timing there? Yeah, so we've said Q4, so any day now. And the study's powered to show an effect on tau PET imaging. It's a multiple ascending dose study where we are dosing. We haven't disclosed the actual doses, but we did a single ascending dose study previously. So we know the dose that we need to give to achieve the exposure we need to get in the CNS based on CSF sampling. So we know we're well above the EC50, or I guess here it's the IC50, for affecting tau spread. So, hey, you know what? I'm an eternal optimist, as you know, Paul. And I've been there before when everybody says it's not going to work, and sometimes things still work anyway. Right. So hopefully we'll be lucky again. Patients need something, you Know? Yep. Patients needs better treatments for Alzheimer's. we're far away from a cure yep do you as you think about tau pet um are you are you hoping to see a reduction or is even like slowing the accumulation good enough i don't think we'll see a reduction uh because we're um i think we're going to slow the accumulation and spread and we want and we have the pranamab as a benchmark we need to be at least as good as the pranimab better, which is a pretty tall order. They had about a 50% effect. So we want to be north of that. Yep. Yep, okay. And then if that is positive, what are the next steps there? You see yourself developing that independently? Well, we've always said we need a partner. For Alzheimer's, we need a partner at some point, right? Because it's too big even to do late stage trials. Could you take it any farther yourself? Yeah, I think we probably could. Well, look, as you know, I'm stepping down as CEO in the next few months, and Robin Schwartz, who's my successor, is sitting over there. That's going to be her decision. I'll help her. I will be on the board with her decision, but I think there's a lot of opportunities here. I think we could potentially move to a phase two trial. We could shuttle it with our ALPL shuttle. I thinks our ALP shuttle would be perfect for that drug actually um and we've been you know we always talk to potential partners as you know we've done a lot of deals paul and i'm always open for business and uh there's some people who've said you know when we get data on that come back right and so we'll we'll talk to people and uh you know so there's lots of options there makes sense um makes sense on the uh alpl shuttle um i mean it's just super interesting to have an alternative to to the tfr1 uh approach how does alpl compare and you know four-year shuttle i guess well i guess this was sort of this was kind of discovered right where you sort of screen capsids found out they got across the blood-brain barrier and then kind of backed backed into how they were getting there um are they are you comfortable that it's juste alpl that was sortof explaining that finding and that you can really isolate it to that and then leverage that pathway? Yeah, if you take out ALPL or capsids, don't cross. And we've made shuttles against ALPL, and they do cross. We plan to share a lot of this data. We have done in vivo pharmacology in mice and in non-human primates, and we're going to be sharing that next month at the antibody engineering meeting in San Diego. I can tell you when you think about shuttles, there's three things to think about. distribution in the body pharmacokinetics and safety and each shuttle is going to have it be distinguished on those three fronts so alpl has a much more limited distribution in the body as you know tfrs will shuttle things into muscle as well as brain and to several other tissues as well with alpl it's much more restricted it's more biased to the blood brain barrier yeah and that allows it to have a much longer half-life so if you have it in the blood for longer there's more opportunity to keep getting into the brain if you will and third is that it has no effect on any of the hematologic issues that we've seen with tfr now patients who have complete loss of function mutations in alpl or severe ones have bone mineralization problems. So you can bet we've looked very, very carefully at some of those parameters. Luckily, there's very good ways to assess that in animals. And so we'll be sharing much of that in December. With the TFR1 space, companies have found ways to at least better bias their antibodies towards receptor expressed in a given tissue type. Can you do that with ALPL, avoid bone um we haven't explored that fully yet i bet they're like you need to do that um i i don't think we do uh right now so far you know because as i said in humans you have to have pretty severe loss of function before you see any problems with bone and we're going to share some data that suggests that uh maybe we don't need to yeah okay in the last minute here al anything else you want to add about voyager and uh prospects ahead catalyst rich period coming up um you know after all the you know when i came we had just discovered these capsids we're finally at the point where neurocrine is taking one of these capsides into fa we're taking one of these capsaids into alzheimer's with tau and uh and boy if that works you know as a neuro drug developer to be able to cross the blood-brain barrier with with a capsid or with the shuttle is boy i'm salivating at the prospect and don't forget the dark horse this antibody we're about you know nobody nobody expects it to work but sometimes things still work anyway all right well any day we look forward to it all right thanks al appreciate it