Conference Transcript - VYGR 2026-09-08

Yanan Zhu, Analyst — Wells Fargo

Great. Thanks, everyone, for being here. I'm Yannan Zhu, one of the Biotech Analysts here. It's my great pleasure to be joined by Al Sandrock, CEO of Voyager Therapeutics. Thanks, Al, for being with us. Thanks for having me, Yannan. Great, great. I'm wondering if you can start us off with a brief overview of the company's initiatives. Sure.

Dr. Al Sandrock, CEO

So we have, at the very beginning of the year, we put out a little shareholder letter that said there's three major things going on this year. One was related to TAO. In fact, I called it the year of TAO. And that was in part because there's a lot of data coming from multiple companies on TAO. We've seen that so far already. BIB80, the tau silencing ASO from Biogen. Novartis had some data on PSP with a tau silencing ASO as well. And we ourselves are about to have data from our multiple ascending dose study with an antibody directed at the C terminal of tau. This is called VY7523. And we expect to see data in Q4 of this year, tau PET imaging data. In addition to that, we have a second program in tau, which is a gene therapy tau silencing approach where we're vectorizing an siRNA. So very similar in terms of mechanism of action to Bib80 and to the tau silencing ASO that Novartis has, and that's why I I call those two programs out, except that what we're doing is we're using AAV to express a vectorized siRNA to silence tau throughout the central nervous system. That's tau. The second piece is capsid POC. So after many years, approximately five years of work, we have discovered these blood-brain blood-brain barrier penetrant capsids that can get into the brain after IV delivery, get broad distribution throughout the central nervous system, and we're entering the clinic. So this is the first test in humans now. We have two programs that are testing these novel capsids in humans. One is the tau silencing gene therapy program that I already mentioned that we call 1706. We have announced that we have FDA clearance and Canadian regulatory clearance. We're activating sites as we speak. We expect to enroll the first patients this year and we have said that we will expect to share acute safety data in Q1 of next year and and also in the second half of next year we expect to share data that says that we're expressing the gene of interest, in this case, the tau silencing siRNA, in the second half of next year. So that's the capsid POC. I should also say that our partners at Neurocrin have said that they're entering the clinic with also a blood-brain barrier penetrant and capsid derived from our platform. For Friedreich's ataxia, they're entering the clinic this year and they said they expect to share data on that program next year. So two different programs that should provide proof of concept that our novel capsids work in humans. And the third thing and the final thing is we expected, we said that we would be showing more data on the NeuroShuttle platform. So this is not AAV gene therapy, but it's basically leveraging the receptors that we discovered from our novel capsids. So we reasoned that if these capsids get into the brain through the blood-brain barrier, they must be leveraging receptors to get there. We've discovered a handful of these receptors. The first one we've talked about publicly, it's ALPL. And not much the same way that companies are leveraging transferrin receptor and CD98, we have these other receptors that we are leveraging as a shuttle for all sorts of modalities, antibodies, enzymes, peptides, oligonucleotides. And we have said that we're going to share data.

Yanan Zhu, Analyst — Wells Fargo

In fact, we have a plan that we have an abstract accepted for a meeting in December where we're going to show a lot of animal pharmacology data as well as with ALPL the first of these receptors as well as some of the safety data associated with ALPL shuttles so those are the three that's a high-level overview of the three major I would say catalysts for voriger great great that's super helpful if we can dive into the the first area you know which is tau effort as you were you said there have been a few important readouts this year could you comment on a bib 080s finding That's the sRNA, maybe more related to your other tau program, like the vectorized tau sRNA program. But, you know, maybe we can start there and also talk about some of the antibody data this year.

Dr. Al Sandrock, CEO

Yeah, so first I want to congratulate my former colleagues at Biogen for executing on that, on Bib80 and for showing the results. and telling us we learned a lot by listening to what they shared with us at the scientific meetings this year, as well as their publications on the earlier phase trial. But the way I look at it at a high level, I think it does validate tau as a target for Alzheimer's disease. I think the data on the cognitive measures such as ADAS-COG with Bid Beatty were unprecedented in terms of efficacy 50% roughly 40 to 45 50% relative to placebo he also on many mental status exam again unprecedented levels of efficacy on CDR some of boxes it was sort of in the same range as the anti amyloids in the 20 ish percent range 25% maybe curiously not so much of an effect on activities of daily living, which the anti-amyloid antibodies actually have no problem showing effects on ADLs, but for some reason, the tau silencing beta did not. I mean, there were some questions that came out of that study as well, like why is there what seems like an inverted dose response curve, and they themselves, Biogen themselves, say that they're moving into phase three with the lowest dose which they think is in the sweet spot if you will it's hard to understand fully why the dose response was apparently inverted I think it could I think it relates more to off-target effects perhaps associated with intrathecal ASO because we've seen things like this with other ASO's like tome nurse and for example at the highest dose showed worsening of clinical scores and ventricular enlargement. You see with other ASOs things like inflammation in the spinal fluid. I think there's some untoward effects from intrathecal ASOs that may have played a role here. In fact, Bibbadiot shell itself showed a steadily increasing incidence of acute confusional state which obviously is not great for cognitive measurements in Alzheimer's patients. But overall, as I said, I think it does validate tau as a target in Alzheimer's. In addition, Novartis has been sharing data with the tau silencing ASO for PSP, and they showed a very nice separation in neurofilament relative to placebo. They also showed actually what they call encephalopathy in a few patients again wonder if that's due to some of the intrathecal ASO issues but anyway so two different diseases where tau silencing and by the way Novartis is also entering phase three in fact I believe they're already enrolling patients in phase three with their tau silencing ASO so it's two separate companies moving into phase three with their TAO silencing approaches. I think that means that, and then there's a lot of other programs I can tell you in TAO that, so I think it's a pretty exciting time for TAO as a target.

Yanan Zhu, Analyst — Wells Fargo

Got it, got it. I mean in terms of that confusion of state, AE, in your opinion is that, you know, is that on target or not on target or could...

Dr. Al Sandrock, CEO

See, I don't think it's on target because if you look at, for example, tau lowering in Bib80, all three doses lowered tau roughly the same levels. At the lowest level, at the lowest dose, it was 50% lowering. At the highest level, 60%. You look at tau PET imaging, too, not much separate. So I think we're on sort of the plateau in terms of the biology, if you will. the effects on tau lowering are sort of on the plateau of the dose response, yet there was a what looked like an inverted dose response. That's one of the reasons why I don't think it's on target, you know. And then, yeah, so IONIS has published actually earlier this year, there's some untoward effects of intrathecal ASOs on neuronal function. For example, firing of action potential synaptic transmission, and you know, they speculate in those published papers that it's due to either effects on ion channels or on maybe neurotransmitter receptors. I mean, we saw it in the old days with Spinraza, you get temporary hind limb paralysis in the animals. And so you put these highly negatively charged antisense oligonucleotides at high doses, 100 milligrams plus, into the small space of the lumbar cistern, and then you get this steep gradient. It's not surprising, perhaps, that you might get these. And then the acute confusional state began a week after injection and lasted for about a week, at At least what was apparent to the patients lasted for about a week, so anyway.

Yanan Zhu, Analyst — Wells Fargo

Got it, got it, very helpful. And let's also, so sounds like you think the tau antisense or tau direct reduction approach intracellularly, in your mind, has demonstrated clinical benefit in Alzheimer's, right?

Dr. Al Sandrock, CEO

Demonstrated, you know, we don't have any drugs that are approved yet so I think the preliminary data suggests that it's very promising but you know I'm old-fashioned you know once it's approved then I'm more comfortable using words like demonstrated right yeah sorry using that too liberally yeah so that's that's exactly what I meant in terms of read through to how proof right let's now talk about the antibody approach.

Yanan Zhu, Analyst — Wells Fargo

I think J&J reported data this year.

Dr. Al Sandrock, CEO

That was another readout and it was a negative readout.

Yanan Zhu, Analyst — Wells Fargo

Right.

Dr. Al Sandrock, CEO

The antibody against the mid-domain did not work. And by the way, we actually had an antibody in an overlapping epitope, which we chose not to pursue because it failed to block the spread of pathological tau in the P3ONS mouse that we use to determine which is the best antibody to move forward into the clinic with so we would have predicted that that antibody probably would not block the spread of tau and it did it had like I think a 10% effect or so or it was but it was much less than Bopranimab put it that way got it great so then you know let's talk about your upcoming data from from your antibody program so can you set us up in terms of the study design what data we're gonna see and what's the bar for success yeah so this is a multiple ascending dose study where we're going to show data from the third cohort and what we did was we chose doses based on the single ascending dose study that we had already done in Normal Healthy Volunteers where we measured CSF and plasma exposure. And we know that with the doses that we're giving in this multiple ascending dose study, we are achieving exposures in the brain that should block the spread of tau. And as I said, we relied heavily on this animal model where these are transgenic mice that express human tau, P301stau, and in that model you inject paired helical filaments from human Alzheimer's brain into one side of the brain, into a particular region, and we look at the spread of pathological tau across the brain. And what we're saying is, what we're hoping is that whatever biology is responsible for that spread from cell to cell is recapitulated in that mouse model expressing human tau. And we chose our antibody because it was the best, it was the most robust at blocking that So far, that animal model has been four for four in predicting the human results. So the two N-terminal antibodies, the one from Biogen and the one from Lilly, fails to block the spread of tau in that model, pathological tau, and sure enough, they failed in the clinic. The pranumab, it did block the spread of tau in that model, and sure enough, the pranumab does block the spread of tau in the human, as shown by tau PET imaging very clearly. And it also predicted that the J&J antibody would not block the spread of tau. So far, one positive predictive value, two negative. So I'm hoping it's five for five. That was 75-23 because in our hands, in that model, we had the best effect, the most robust efficacy on blocking the spread of tau. And that is, by the way, what we're hoping to see in the humans. We want to be as good, at least as good, if not better than Bepranimab. Why? Because Bipranimab did have an effect on ADAS-COG, on cognition. You'll remember that even in the overall population, the p-value was less than 0.05 on ADAS-COG, but the p-value on the CDR sum of boxes was not less than 0.05. So we saw that Roche exited that partnership with UCB. But in their last earnings call, I believe UCB said that they are moving forward to phase three with Bipranimab. So that's a nice benchmark. We want to be at least as good, if not better, than Bipranimab. And so we're going to look carefully at our TALPED imaging data later this year and benchmark it to Bipranimab. And if we're not as good as Bipranimab, we're going to terminate our program. program. We don't need anything less good than buprenumab. But if we're at least as good or better, now I'm interested, and we're going to look for a partner for that program because Alzheimer's disease is too big for a little company like Borger to pursue on its own. By the way, one thing we could do is to shuttle it. You know, one thing we showed in our phase one single ascending dose study is that we get 0.3% into the brain. The brain to plasma ratio is 0.3%. So we literally throw away 99.7% of the antibody. If we shuttle it, maybe we can make it even better. We certainly can get more into the brain. And you'll recall that gantanarumab had a modest efficacy as an anti-amyloid antibody, but when they shuttled it and made it trontinimab they improve the efficacy and the safety so so we have some options with our anti-tau antibody but the first step is to get the readout that we're planning for the in q4 right for the pranamab the the benchmark is that how you know PET data for tau reduction is that like 30 three and fifty-eight percent yeah it was in the in the third I would say forty to fifty percent I mean they had two separate measures based on what what it you know it's a composite measure based on a region of interest right and so there's this what's called the jack named after Cliff Clifford jacks temporal lobe tau measurements and then there's a more of a cortical composite where you look at all the cortical areas so there's two different ways of looking at tau PET imaging and relative so it didn't really decrease tau it slowed the spread of pathological tau by about 40 50 percent based on those measures so that's our benchmark and we want to slow the spread of tau more than that I see right thanks yeah that's relative to placebo and by the way our multiple ascending dose study does have placebo each dose each cohort had placebo patients that were randomized as well so we can come so we're going to compare to placebo relative to placebo and bench and the benchmark is but pranamab yeah right right right but what's your thoughts on let's say you did reach that benchmark or you exceeded it right but how do you how do you think about or how should we think about the performance

Yanan Zhu, Analyst — Wells Fargo

of the benchmark antibody on CDRS-B versus ADAS-COG, right?

Dr. Al Sandrock, CEO

It's not Tau-Tau. Yeah, no, that's, you know, and by the way, are we seeing a pattern here, you know, that the anti-Tau, the Tau targeting approaches have a bigger effect on cognitive measures than functional maybe? I don't know, but it's an N of two, so. But I would say that, that's why we say it has to be at least as good. And I would also say that, you know, UCB has produced some tantalizing data that if you start off with people who are either carriers or non-carriers of APO, E4, and particularly if you have low tau burden, you may have a bigger effect. Those are post hoc analyses, so you have to take them with a little bit of caution. But So I think that we want to be at least as good or better on TauPet imaging, and we're going to seek a partner. And as I said, we may shuttle it.

Yanan Zhu, Analyst — Wells Fargo

Got it.

Dr. Al Sandrock, CEO

Yeah, let's talk about VY1706, vectorized Tau siRNA. can you help us understand the the data you generated in NHP so far so what we you know we have these very potent BBB penetrant capsids we're very excited about the capsid we're using here it's a gen 2 B cap capsid it's very potent we We did not want to be anywhere near one E14 VGs per kig, because that's typically where people have safety issues, right, the Sarepta and other drugs. So we wanted to be in the E13 dose range, and the maximum dose that we're going to be testing is five E13 VGs per kig. And with that, we have shown that we can get up to 60, 70 percent knockdown across the brain at the highest dose. But Bib80 has shown us that maybe you don't need more than 50% knockdown, so we may not need to go to that highest dose. So this will be a study where we do a one-time intravenously delivered AAV vectorized siRNA against tau and we're going to be looking at CSF tau as a measurement do we actually so first thing is safety we're going to say you know in q1 we're going to be able to say whether or not the acute safety is there and you know when you have problems with capsids it generally occurs early. And so Q1 acute safety. Later in the year we hope to show data on spinal fluid tau levels because if we're seeing a decrease in tau, CSF tau, we must be getting expression of the vectorized siRNA. So by the end of next year we should be able to say that it's safe and that we're getting gene expression in the brain. Now, whether or not that asset, as a tau silencing asset, has legs in Alzheimer's disease, we're going to need to wait for the tau PET imaging data, which will be after next year. And then there, we want to benchmark it against Bib80, which we just talked about. So that's how I see that program. And it's going to be an ascending, you know, now with With gene therapy, you have to, even your lowest dose has to have a chance of helping patients. Otherwise, it's not ethical. So our lowest dose will have some tau-lowering capabilities. And so, yeah, so there'll be several cohorts, the highest dose being 5E13 BGs per kg. By the way, in addition to the lower dose, our capsid detargets the liver 30-fold relative to AAV9. So in addition to the lower dose, we're using a capsid that basically detargets the liver. So that's why we're pretty excited about the capsid, because it's very potent. We can use lower doses, and because it detargets the liver. And we have the biomarkers. We have CSF tau, we have tau PET imaging where we can determine whether or not we're getting it into the brain, into the cortex, because we have the PET imaging. And we can measure CSF tau to know whether or not we've lowered tau and we can benchmark it against BAB80, too. And so I think that the program, if it shows that our capsids are safe and effective, I think that's pretty big for our field and then if later on we show that we have top head imaging data that's in the range required for an asset to be approved for Alzheimer's that's also exciting I see the acute safety so that's the first of course the first milestone right for that milestone what is the the signal that you will be monitoring well we're gonna be met we're gonna be carefully monitoring this the patients we have a very we're with the FDA we design a study where we're gonna be dosing a patient we're gonna be observing very carefully and then we're gonna dose the next patient after a careful. And then after all three patients are dosed in the first cohort, we're going to have an external safety monitoring committee that will say, yep, you can go to the next cohort. So that's a pretty, you know, so it's an external safety monitoring committee that says we can go to the next cohort. And they won't say that unless they think it's safe.

Yanan Zhu, Analyst — Wells Fargo

Got it. Got it.

Dr. Al Sandrock, CEO

And we'll be looking at all, look, I mean, when you look at AAV, I mentioned liver, right? The common toxicities associated with AAV are liver, something called TMA, thrombomicroangiopathy. And those are the two main things. And so we'll get it from, you can imagine all the measurements we're making in the clinic to make sure that we have neither TMA nor liver. There are some other issues, such as insertional immunogenesis and things, and that we won't know for years.

Yanan Zhu, Analyst — Wells Fargo

And how low is your starting dose going to be?

Dr. Al Sandrock, CEO

We haven't said that. And Trista is telling me I can't say that because I haven't said it yet.

Yanan Zhu, Analyst — Wells Fargo

I'm supposed to. But we could have data early 2027. Is that going to be multiple dose cohort data? or just the starting dose?

Dr. Al Sandrock, CEO

Well, all we've said is that in 2027, we'll know whether the acute safety is there and whether or not we have evidence of gene expression based on tau lowering in the spinal fluid. Right, okay.

Yanan Zhu, Analyst — Wells Fargo

Right, right, right. Gene expression, it's a CSF tau, and the PET imaging tau data will have to come later because that takes longer to reduce tau. and yeah i mean typically people show 12 month or 18 month tau pet data so okay got it yeah yeah yeah that's that's very helpful um okay so you you have um i i guess you you kind of answered my next question which is how you strategize uh how you think uh think about your or how we should think about your development strategy for the antibody versus the siRNA or vectorize.

Dr. Al Sandrock, CEO

But it sounds like the antibody will be partnering material, Well, look, we've said that Alzheimer's disease is too big for Voyager to take on all by itself. So we're going to look for a partner for both assets. But I wanted to generate proof of concept data in humans before we look for a partner. And hopefully, we'll achieve that. got it now how they're gonna be used in the clinic you know it depends on the data you know I would say that if you look at other diseases like spinal muscular atrophy you know almost all infants in this country now gets old gensma as infants the SMA gene therapy that replaces SMN protein right and And many patients also then, if they're not fully treated by that gene therapy, they take Spinraza or they take Ristoplam. So there are situations that we've already seen where you don't have to solve all the problems just with the gene therapy, that maybe you use two drugs to really maximize the efficacy and safety for patients and so hopefully we'll have choices here you know if we both work maybe we'll see ourselves using both one day I don't know but because it because a lot depends on what we see in terms of the data but I wouldn't but but the precedence in SMA is that people get gene therapy and often one additional treatment in addition that also increases SMN protein.

Yanan Zhu, Analyst — Wells Fargo

Got it. So let me, I forgot or I missed this, for the CSF tau data, is that after the early 2027 safety, acute safety update?

Dr. Al Sandrock, CEO

Well we expect to see the CSF data next year.

Yanan Zhu, Analyst — Wells Fargo

Next year, sometime next year, right? Okay. So I was trying to think...

Dr. Al Sandrock, CEO

Because you know we've already shown that we can see data in three to six months on in the non-human primate on on tau lowering so you don't need you don't need 12 months got it so three to six months is enough I see I was wondering when which program will produce the first proof of concept for the BBB the BBB crossing capsule yeah it's gonna be a race between us and neurocrine right and I don't care who wins I'm rooting for both of us so neurocrine says they're going to enter the clinic this year and show data next year we're saying we're going to we're entering the clinic this year and so maybe but at least simultaneous I don't know right right got it got it let's talk about the NeuroShuttle program okay can you remind us the data you have generated so far and what are the key development efforts there yeah so we reason that if these capsids get into the brain by crossing the blood-brain barrier they must be leveraging receptors on the blood-brain barrier to get into the brain and we've discovered a handful of novel receptors that I can tell you you would never have guessed could be used as shuttles. And so the first of these is ALPL and we have already shown data that it's differentiated from transferrin receptor which everybody else seems to be using. And so we have data coming up at a scientific meeting in December where we're going to show lots of animal pharmacology and more than one species on what sorts of drugs you can get into the brain proteins peptides oligonucleotides perhaps also we're going to be sure that it's safe so as you know transferrin receptor shuttles sometimes cause hematologic adverse events we're not going to have that I don't think because we have no change in reticulocyte count because we're not leveraging you know we're not affecting transferrin but people who have humans with loss of function mutations in ALPL can have a different disease called hypophosphatasia which is a decreased bone and teeth mineralization now you have to have pretty severe loss of function so one of the things we've been looking very carefully is can we shuttle drugs in while producing no problems on the bone in other words can we shuttle things with ALPL without causing a defect in bone mineralization so we'll be showing some of that data too got it got it but you do have multiple additional we have we have several other and we're not telling anybody they don't even tell me the name of the receptors not that they don't trust me or anything but but it's yeah we want to keep it secret right right for now so so when can we start to see potential you know getting into a clinic and all that kind of Wow shoot that's a bit of a ways off but do you think like there might be partnership activity yeah will that happen so we're actively talking to partners you know you remember in the early days of the novel capsids we did a lot of business development yeah and I'm a big fan of business development because brings in non-dilutive revenue and also there's so much to do in the CNS that I can't possibly we can't possibly do it all at Borger anyway so we've done some very nice deals and you can bet that I am open for business when it comes to partnering also in the neuro shuttles got it yeah great um i i think that's uh yeah i i wonder like for the partner programs you know you know obviously obviously you touched on neurocreen yeah nine partner programs five at neurocreen three at novartis one at alexion which was originally at pfizer and i think boy, if we show that our capsids are safe and effective, man, I think that our partners are going to be very interested. You know, I'm very flattered that Novartis chose our capsids for their next generation SMA gene therapy. You know, and so, and, you know, so, and as you know, they're working on Huntington's too. So, so we're very excited about the potential for gene therapy because I think it can provide transformative treatments for children and adults.

Yanan Zhu, Analyst — Wells Fargo

Got it. Got it. Great. Great. I think with that, we're out of time for this session. Thank you so much, Al.

Dr. Al Sandrock, CEO

You're welcome. Thank you for having me. Appreciate it.

Yanan Zhu, Analyst — Wells Fargo

Yeah, our privilege. Thank you.