Voyager Therapeutics, Inc. Aktie

Great. Thanks, everyone, for being here. I'm Yanan 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, Yanan.

Great. Great. I'm wondering if you can start us off with a brief overview of the company's initiatives.

Sure. So we have -- at the very beginning of the year, we put out a little shareholder letter that said there's 3 major things going on this year. One was related to tau. In fact, I called it the year of tau. And that was in part because there's a lot of data coming from multiple companies on tau. We've seen that so far already.

BIIB080, 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 VY-7523, 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 BIIB080 and to the tau silencing ASO that Novartis has. And that's why I call those 2 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 5 years of work, we have discovered these 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 for -- so this is the first test in humans now. We have 2 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 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 Neurocrine have said that they're entering the clinic with also a blood-brain barrier penetrant 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 2 different programs for -- 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 reason 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 is ALPL. And 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. 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 3 -- that's a high-level overview of the 3 major, I would say, catalysts for Voyager.

Great. Great. That's super helpful. If we can dive into the first area, which is tau efforts. As you said, there have been a few important readouts this year. Could you comment on BIIB080's finding? That's the siRNA, maybe more related to...

ASO.

Sorry, ASO. More related to your other tau program, like vector tau siRNA program. But maybe we can start there and also talk about some of the antibody data this year.

Yes. So first, I want to congratulate my former colleagues at Biogen for executing on that -- on BIIB080 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 the 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 BIIB080 were unprecedented in terms of efficacy, 50% roughly, 40% to 45%, 50% relative to placebo. Also on Mini-Mental Status Exam, again, unprecedented levels of efficacy. On CDR sum 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 BIIB080 did not. I mean there are some questions that were -- 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 III 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 ASOs like tominersen, 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, BIIB080 itself showed a steadily increasing incidence of acute confusional state, which obviously is not great for cognitive measurements in Alzheimer's patients. So -- 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, I wonder if that's due to some of the intrathecal ASO issues. But anyway, so 2 different diseases where tau silencing -- and by the way, Novartis is also entering Phase III. In fact, I believe they're already enrolling patients in Phase III with their tau silencing ASO. So it's 2 separate companies moving into Phase III with their tau silencing approaches. I think that means that -- and then there's a lot of other programs, I can tell you in tau that -- so I think it's a pretty exciting time for tau as a target.

Got it. Got it. I mean in terms of that confusional state AE, in your opinion, is that on target or not on target? Or could you...

Yes, I don't think it's on target because if you look at, for example, tau lowering and BIIB080, all 3 doses lowered tau, roughly the same levels. At the lowest level -- at the lowest dose, it was 50% lowering, at the highest level, 60%. If 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. Yes, that was what looked like an inverted dose response. That's one of the reasons why I don't think it's on target.

And then yes. 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 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 in at high doses, 100 milligrams plus into the small space of the lumbar cistern and 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 least what was apparent to the patients lasted for about a week. So anyway.

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

Not demonstrated. We don't have any drugs that are approved yet. So I think the preliminary data suggests that it's very promising. I'm old-fashioned. Once it's approved, then I'm more comfortable using words like demonstrated.

Right. Yes, sorry about using that too early. Yes. So that's exactly what I meant in terms of read-through to tau program, right? Let's now talk about the antibody approach. I think J&J reported data this year.

That was another readout, and that was a negative readout. 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 P301S 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 had like, I think, a 10% effect or so. But it was much less than bepranemab, put it that way.

Got it. Great. So let's talk about your upcoming data from your antibody program. So can you set us up in terms of the study design, what data we're going to see? And what's the bar for success?

Yes. 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, P301S tau 301S tau. 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 spread.

So far, that animal model had been 4 for 4 in predicting the human results. So the 2 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. Bepranemab, it did block the spread of tau in that model. And sure enough, bepranemab 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, positive predictive value, 2 negative. So I'm hoping it's 5 for 5 that was 7523 because in our hands, in that model, we have 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 bepranemab. Why? Because bepranemab 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 USB said -- UCB said that they are moving forward to Phase III with bepranemab. So that's a nice benchmark. We want to be at least as good, if not better, than bepranemab. And so we're going to look carefully at our tau PET imaging data later this year and benchmark it to bepranemab. And if we're not as good as bepranemab, we're going to terminate our program. We don't need anything less good than bepranemab.

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 Voyager to pursue on its own. By the way, one thing we could do is to shuttle it. One thing we showed in our Phase I 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 gantenerumab had a modest efficacy as an anti-amyloid antibody, but when they shuttled it and made it trontinemab, they improved the efficacy and the safety. So we have some options with our anti-tau antibody. But the first step is to get the readout that we're planning for in Q4.

Right. For bepranemab, the benchmark, is that tau PET data for tau reduction? Is that like 33% and 58%?

Yes, it was in the -- I would say, 40% to 50%. I mean they had 2 separate measures based on what -- it's a composite measure based on a region of interest, right? And so there's this -- what's called the Jack named after Clifford Jack temporal lobe tau measurement. And then there's more of a cortical composite where you look at all the cortical areas. So there's 2 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% based on those measures. So that's our benchmark, and we want to slow the spread of tau more than that.

I see.

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 -- so we're going to compare to placebo relative to placebo and the benchmark is bepranemab.

Yes. 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 think about -- or how should we think about the performance of the benchmark antibody on CDR-SB versus ADAS-Cog, right? It is not...

Yes. No, that's -- and by the way, are we seeing a pattern here that the anti-tau -- the tau targeting approaches have a bigger effect on cognitive measures than functional maybe? I don't know. It's an N of 2. But I would say that that's why we say it has to be at least as good. And I would also say that UCB has produced some tantalizing data that if you start off with people who are either carriers or noncarriers of APOE4 and particularly if you have low tau burden, you may have a bigger effect. Those are post-hoc analyses, and we have to take them with a little bit of caution. But I -- yes, so I think that we want to be at least as good or better on tau PET imaging, and we're going to seek a partner. And as I said, we may shuttle it.

Okay. Got it. Great. Yes, let's talk about VY-1706, vectorized tau siRNA. Can you help us understand the data you generated in NHP so far?

So what we have these very potent BBB penetrating capsids. We're very excited about the capsid we're using here a Gen 2 VCAP capsid. It's very potent. We do not want to be anywhere near 1E14 VG per kg because that's where -- that's typically where people have safety issues, right, the Sarepta and other drugs. So we want to be in the E13 dose range. And the maximum dose that we're going to be testing is 5E13 vg per kg. And with that, we have shown that we can get up to 60%, 70% knockdown across the brain at the highest dose.

But BIIB080 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 onetime 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, in Q1, we're going to be able to say whether or not the acute safety is there. And 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 there, we want to benchmark it against BIIB080, which we just talked about. So that's how I see that program. And it's going to be an ascending -- now 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 yes, so there'll be several cohorts, the highest dose being 5E13 vg 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 the 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 that we -- 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 that whether or not we've lowered tau, we can benchmark it against the BIIB080 too.

So -- 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 tau PET imaging data that's in the range required for an asset to be approved for Alzheimer's, that's also exciting.

I see. I see. The acute safety -- so that's the first -- of course, the first milestone, right? For that milestone, what is the signal that you will be monitoring?

Well, we're going to be carefully monitoring the patients. We have a very. With the FDA, we designed a study where we're going to be dosing a patient. We're going to be observing very carefully. And then we're going to dose the next patient after a careful. And then after all 3 patients are dosed in the first cohort, we're going to have an external safety monitoring committee that will say, yes, you can go to the next cohort.

So that's a pretty -- 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.

Got it. Got it.

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, thrombotic microangiopathy. And those are the 2 main things. And so we'll get in -- 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 mutagenesis and things and that we won't know for years.

And -- like how low are you -- is your starting dose going to be?

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

Not supposed to.

And so -- but we could have data early 2027. Is that going to be multiple dose cohorts data or just the starting dose?

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. Gene expression, it's a CSF tau and the PET imaging tau data will have to come later because that takes -- it takes longer to reduce tau.

That's right. And yes, I mean, typically, people show 12-month or 18-month tau PET data.

Got it. Yes. That's very helpful. Okay. So you have -- I guess you kind of answered my next question, which is how you think about your -- or how we should think about your development strategy for the antibody versus the siRNA that's right. But it sounds like the antibody will be partnering material, right?

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 going to be used in the clinic, it depends on the data. I would say that if you look at other diseases like spinal muscular atrophy, almost all infants in this country now get Zolgensma as infants, the SMA gene therapy that replaces SMN protein, right? And many patients also then if they're not fully treated by that gene therapy, they take SPINRAZA or they take risdiplam.

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 2 drugs to really maximize the efficacy and safety for patients. And so hopefully, we'll have choices here. If we both work, -- maybe we'll see ourselves using both one day. I don't know, but because a lot depends on what we see in terms of the data. But I wouldn't -- but the precedence in SMA is that people get gene therapy and often one additional treatment in addition that also increases SMN protein.

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?

We expect to see the CSF data next year.

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

Because we've already shown that we can see data in 3 to 6 months in the nonhuman primate on tau lowering. So you don't need 12 months.

Got it.

So 3 to 6 months is enough.

I see. I was wondering when -- which program will produce the first proof of concept for the BBB crossing capsid.

Yes, it's going to be a race between us and Neurocrine. And I don't care who wins. I'm rooting for both of us. So Neurocrine said they're going to enter the clinic this year and show data next year. We're saying we're entering the clinic this year. And so maybe it will be 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?

Yes. 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 -- 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 several other -- and we're not telling any -- they don't even tell me the name of the receptors, not that they don't trust me or anything. But it's -- yes, we want to keep it secret for now.

So when can we start to see potential getting into clinic and that kind of...

Wow, that's a bit of a ways off.

But do you think like there might be partnership activity before that happens?

So we're actively talking to partners. You'll remember in the early days of the novel capsids, we did a lot of business development. And I'm a big fan of business development because it brings in nondilutive 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 Voyager 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 NeuroShuttles.

Got it. Yes. Great. I think that's -- yes. I wonder like for the partnered programs. Obviously, you touched on Neurocrine.

9 partnered programs, 5 at Neurocrine, 3 at Novartis, 1 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.

I'm very flattered that Novartis chose our capsids for their next-generation SMA gene therapy. And so -- so -- and as you know, they're working on Huntington's, too. So we're very excited about the potential for gene therapy because I think it can provide transformative treatments for children and adults.

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

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

Yes. Our privilege. Thank you.

Hello, everyone, and welcome to H.C. Wainwright at Home Virtual Fireside with Voyager Therapeutics. I'm Patrick Trucchio, senior health care analyst at H.C. Wainwright and your host for today's event. It's my pleasure to be joined by President and CEO, Al Sandrock. Voyager is advancing two tau-targeted Alzheimer's programs towards clinical inflection points, including VY7523, an anti-tau antibody with tau PET imaging data expected in the fourth quarter of this year and VY1706, a tau silencing gene therapy that's recently received FDA IND clearance.

The pipeline also includes Voyager's TRACER Capsid Platform and a partner portfolio that features Neurocrine's planned Friedreich's ataxia trial start in the second half of this year. So with that, Al, welcome. It's a pleasure to have you with us today.

Nice to be here, Patrick. Thanks for inviting me.

So just maybe to start, what is Voyager built to do in neurology? And what do you have that others do not?

Yes. So we felt that neurotherapeutics was at a tipping point in the sense that we had -- we understood the targets we wanted to go after. The unmet need is enormous. And -- but the key barrier was the blood-brain barrier, a physical barrier that actually prevents most modalities from getting into the brain. And we felt that if we could solve the delivery issue, we would enable neurotherapeutics, not only enabling our own pipeline, but multiple other pipelines as well. And so we have technology where we can actually get AAV capsids across the blood-brain barrier.

But we also are now developing shuttles that will get protein therapeutics and oligonucleotides across the blood-brain barrier. So it's really to open up neurotherapeutics by solving the delivery issue into the brain.

Right, right. Great. And so now you now have three ways to get into the brain, AAV capsids, there's NeuroShuttle and then systemically dosed antibodies plus a small molecule collaboration. So how are you thinking about prioritizing these different programs?

Yes. So we always choose programs where we can -- since neurotherapeutics is difficult, right? So despite having all these targets, we may have more targets actually, I was thinking about the other day than oncology, but there's so much more going on in oncology. And I think the delivery issue is the problem. And so -- but we want to choose for our own pipeline programs where we can not only go after validated targets with our novel technology, but where we can de-risk quickly in the clinic.

And so we choose programs where we have biomarkers that will allow us to know whether we're on track. So for example, in Alzheimer's disease, we have amyloid PET imaging, tau PET imaging, fluid-based biomarkers, et cetera. For ALS, for example, for our small molecule program. We have neurofilament -- serum neurofilament, that is the blood test that tells you whether or not you're getting the drug to the right place and being active enough to save motor neurons from dying. So that plays the developability and the early de-risking plays into our thinking about our own pipeline, and that weighs heavily in our prioritization.

Yes, that's helpful. And before we dig deeper into the tau programs, maybe you can just give us some background on tau as a target and, sort of, why it's the right place to be concentrating the focus right now at Voyager?

Yes. So I think we just had recent validation in some ways that in a randomized double-blind, placebo-controlled human clinical trial of hundreds of patients, the Biogen BIIB080 data that tau actually is a validated target. When you look at that data on cognitive measures, it's actually superior to the anti-amyloid treatment effect sizes. On CDR sum of the boxes is comparable. And so -- and then there was a very clear-cut use of PET imaging and fluid-based biomarkers to help understand what's going on in that study.

So I think -- so that's why tau was felt like the right place. I'll say this, by the way, we had other programs. We had GBA1, SMA, but we were offered a lot of money by other companies to pursue those targets. And so of course, we have the ability to opt back in for a couple of those programs. So we're also interested in rare diseases, et cetera. But we felt that tau was a very good target because we can know whether our capsids are working, for example.

And that, right away, is of high value to our company to be able to prove with PET imaging and with fluid-based biomarkers that our capsids are safe, getting into the brain, expressing their payload. And then on top of that, these assets could be of enormous value. So that's why we chose to concentrate on tau.

Right. And so moving then to VY7523. This is the anti-tau antibody. Maybe you could describe this for the audience, what it binds, why you went after the C-terminal region? And how it was selected from more than 700 anti-tau antibodies?

Yes. So that program is actually sort of more of what I would call an old-fashioned program in the sense that we're not doing anything special on the delivery side. We do know that antibodies get in, but in very, very small quantities. But we felt that this was a very interesting antibody because we found that in an animal model where that expresses human tau where you inject Alzheimer's-derived material into the brain of animals that express human tau.

This particular antibody was better than any of the other ones that we tested in terms of blocking the spread of pathological tau in the brain. Moreover, it was selective for pathological forms of tau, and we think that could be incredibly important. In the case of anti-amyloid antibodies that turned out to be critical. So that's -- so we chose it empirically. We had no real preference for which epitope. We wanted the animal model that expresses human tau and that we think recapitulates the way pathological tau spreads in the Alzheimer's brain; we thought that this empirical approach will prove to be right.

And so far, by the way, we're correct that this animal model is very predictive. The 2 N-terminal antibodies that failed in the human clinical trials failed in this model. Bepranemab, the one antibody that seems to work actually works in this model, and we actually could have chosen an epitope very similar to bepranemab. It just wasn't quite as good as the epitope we chose. The C-terminal epitope is the best.

Moreover, it correctly predicted that the J&J antibody would fail. So far, it's 3 for 3 -- 4 for 4 in terms of correctly predicting the human clinical trial results. I'm hoping it's 5 for 5 with our antibody later this year when we look at our tau PET results.

Right. Terrific. And so now the Phase I multiple ascending dose trial is fully enrolled the 52 patients; the tau PET imaging data, as you mentioned, is expected later this year. Can you walk us through what that trial is designed to show, and maybe what it's not designed to show?

Yes. So it's really based -- it's not powered to show an effect definitively on clinical outcome measures such as CDR sum of boxes or ADAS-Cog. We will look at those measures, of course. But what it's mainly powered to do is to look at tau PET imaging. And we're going to look at 1 year, and we're going to see how we stack up to bepranemab. You'll recall that bepranemab did block the spread of tau, and it had actually statistically significant effect on ADAS-Cog in the entire population, not a subgroup, but in the whole population. It also had a trend in CDR sum of boxes, but it missed on that endpoint.

So we want to be as good -- or we want to be at least as good, if not better, than bepranemab. So what we're going to anchor on is the tau PET imaging results at 12 months, which we're going to see later this year. And we hope to be at least as good, if not better, than bepranemab on blocking the spread of pathological tau in the brain of humans with Alzheimer's disease.

Yes. That's helpful. And sort of partially answered this next question, but just again, without getting ahead of the data, what sort of magnitude and pattern of tau PET effect would you consider a clear positive? And you mentioned the external benchmark, but -- so maybe you can frame for us what external benchmark makes the most sense?

Yes. So we think that bepranemab is the best external benchmark because we have some idea of how tau PET imaging relates to clinical outcomes. We see that we're right on the edge of seeing some effects. And so we want to see greater than 50% slowing. Bepranemab had roughly 50%, depending on the brain region that you look at. So we want to compare region by region, and we want to see that we're at least as good, if not better, than bepranemab.

And we want to see that at 1 year. And the reason why we chose 1 year, by the way, because I know that's another question you've been asking, which is why not look at 18 months? And yes, you get more of an effect on tau PET imaging at 18 months. But bepranemab did show separation at 12 months. So if we don't show separation at 12 months, we're not at least as good or better, right? So as I said, we have a high bar now. We have to exceed bepranemab. And we know that at 12 months, bepranemab did start to show separation. So if we don't, we're not as good.

Right. That makes sense. And have you said or can you say which brain regions and which prespecified analysis are going to be part of this readout?

I don't want to get into that kind of detail. We're going to look at multiple regions. There's a region of interest, ROI-type assessment. Moreover, there's a composite measure that looks across multiple cortical areas. It's complicated because it depends on where the tau has already spread by the time you enroll a patient. So the starting point on the tau spread is different from patient to patient, depending on how advanced they are. So what we want to do is to look at regions where there's already some tau to see if we can block the spread within that region.

But even more importantly, perhaps is to look at whether or not we can slow the spread into regions where there isn't any tau at baseline. And so that's why -- so as you can see, it's region by region and depends on where you start off at baseline, what you want to look at more intensely. But the main thing is that it's mainly cortical areas, it's temporal lobe, frontal lobe, parietal lobe, tau in Alzheimer's disease spread to cortical areas. It doesn't spread to subcortical areas, it doesn't spread to the brainstem or the spinal cord. So it's a cerebral cortex for sure.

Right. And do the fluid tau biomarkers need to move in the same direction for you to believe the imaging result?

We'll look at them. I'm not really -- I want to anchor more on the tau PET imaging because we've seen data actually. Biogen had a trial where their antibody moved the most promising of tau PET biomarkers, the MTBR tau by 40%, clear cut effect by 40% and had no effect on tau PET imaging or clinical outcomes. So for this particular indication -- sorry, for this particular trial, I'm not really looking very hard at the clinical -- at the fluid-based biomarkers. It would be nice to see some movement. In fact, the antibodies that failed all moved to fluid-based biomarkers quite well. It had either minimal or no effect on tau PET imaging. So I'd rather anchor more on the tau PET.

Right. That's really interesting. And I think in the single ascending dose study, it showed cerebrospinal fluid to serum ratio of about 0.3%. Do we know that that's enough exposure to engage the pathological tau where it matters?

So that shows right away how much of the blood-brain barrier is an impediment, 0.3%, okay, which is, by the way, typical of every monoclonal antibody that we've looked at in humans, right? So we throw away 99.7% of the antibody that we inject intravenously. However, we know the concentration we need to achieve in the brain and in the spinal fluid in order to get the blocking effect. We know that from our animal studies. So we have an effective concentration we want to reach in the brain. And we know that we have reached that effective concentration because we use very high doses of intravenous antibody to make sure we have enough in the brain that exceeds that EC50, if you will, of blocking the spread. So we're pretty confident we're in the right dose range with this study.

So most prior tau antibodies have disappointed, as mentioned. And I'm wondering what your explanation is for why they failed and what specifically is different here?

Yes. So the epitope is different. And you might say, well, why does the epitope matter so much? So it turns out that in the extracellular space in the brain, and the reason why I'm focusing on the extracellular space is that we're trying to block the spread from one cell to another. And so there must be an extracellular phase where a particular pathological form of tau jumps from one cell to the other and then causes a template-driven misfolding in the receiving cell. When you look at the extracellular space, there's a lot of forms of tau; many of them are proteolytic fragments.

So there's many different fragments and different forms of tau. And one of those, obviously, or maybe some of them, maybe it's more than one, but some subset of those forms of tau are the ones that are responsible for this spreading, which we think is prion-like. And the explanation I have is that the N-terminal antibodies bind to the forms of tau that are not responsible for that pathological spread. And we think that -- and that's what this animal model indicates, and that's what the human trial indicates. We think that the C-terminal ones -- so whatever that pathological form is that's responsible for the spread, what we're saying is we think it contains the C-terminal domain.

And that's why we think the C-terminal epitope is critically important. We'll find out if we're right. But as I said, this is all based on empirical data from the animal model. But that's the thinking is that you have to bind to the forms of tau that are responsible for that spread from cell to cell.

Right. That's interesting. And then maybe moving on to VY1706. This is a tau silencing gene therapy. So here we have a onetime IV gene therapy to silence tau inside neurons. So maybe you can tell us why you're pursuing this approach as a potential treatment in Alzheimer's.

Yes. So the antibody relies on blocking the spread by binding to the correct forms of tau that are responsible for that spread. A whole different approach is to just decrease the expression of tau. And there, we don't have to worry about the epitope. We're going to just decrease all forms of tau. And the reason why we like that is that there's been some very good human proof of concept already. I mentioned the BIIB080 data in Alzheimer's disease where there was an effect on cognitive outcome measures.

Moreover, Novartis shared earlier this year that they have an antisense that silence the expression of tau, also an antisense oligonucleotide that actually seems to work in progressive supranuclear palsy, another tauopathy. And in fact, Novartis is now enrolling patients in a Phase III trial of their tau silencing antisense oligonucleotide. So we have two different diseases now; one is tauopathy and one Alzheimer's. Well, they're all tauopathies, obviously, one Alzheimer's and one a more rare tauopathy called PSP.

And so I like the idea of following an antisense oligonucleotide that has shown proof of concept in the humans, following that up with a gene therapy. Antisense shows that it could work, shows that it's safe after years of treatment, and then we can follow on with a more permanent solution, a onetime IV dose that does essentially the same thing as repeated intrathecal injections of an antisense. This actually happened in SMA.

You remember SPINRAZA was repeated antisense oligonucleotide treatment that was first approved for spinal muscular atrophy. Two years later, Zolgensma comes in and it becomes the standard of care for all infants with SMA. And then now some patients take both Zolgensma and SPINRAZA. If they need a little extra efficacy, they add SPINRAZA. So this paradigm of starting with an oligonucleotide-based treatment that shows proof of concept maybe even gets approved, followed by gene therapy has already happened for another neurological disease, and we want to follow the same path, if you will, for tauopathies.

Right. That's interesting. And you mentioned BIIB080 a few times now. This is Biogen's tau antisense program. Their data showed clinical slowing that was strongest at the lowest dose studied. I'm wondering why does the inverted dose -- what does the inverted dose response tell you about how deep tau lowering needs to be? And does it change any of your own dose thinking?

Yes, it does affect our thinking. And we always said we were going to look at that data as a guide for how much -- what we need to do because that was the first data that was large enough to actually show the correlation between effects on tau, tau silencing and clinical outcomes. So the lowest dose suggests that we may not need to go to the higher doses in our ascending dose first-in-human study. In fact, 50% decrease in tau, CSF total tau seems to be enough to produce a robust clinical effect on cognitive endpoints. So that does affect our thinking as your question implies.

Right. That's interesting. And VY1706 Phase I is open-label dose escalation up to 18 tau PET positive early Alzheimer's patients across the three cohorts. I think the dose is 5E13 vector genomes per kilogram. Maybe you could just talk us through kind of why that's the max dose?

Yes, because in our -- both in our mouse and in our nonhuman primate studies in the monkeys, we get 75 -- up to 75% reduction in tau expression at that 5E13 dose. We don't think we need to go to even 75%. As I just said, 50% reduction may be enough. So now that was our highest dose that we tested in our toxicology studies. It turned out it was -- that's safe enough to dose humans with. But like I said, why be aggressive -- why be so aggressive on the dose when Biogen themselves showed that 50% is enough.

So yes, we didn't test doses higher than 5E13 because we think -- we don't want to suppress tau. We don't want to silence tau completely anyway. We knew that. And it looks like the lower doses might be just fine.

Can you tell us what the next expected sort of catalysts are for this program? What should we be looking for next?

Well, we're going to be -- I look on it as three different inflection points. The first thing is, is it safe? We've seen some other blood-brain barrier penetrant capsids that were not safe. So key is safety. And by the way, these things tend to declare themselves with just 1 or 2 or 3 patients, and it happens early. So the first inflection point is, is it safe after we dose a few patients acutely? Then the next thing, and this will happen in the second half of next year is, okay, now that it's safe, does it express the gene that we want? Does the payload seem to be expressed?

And for that, we're going to look at spinal fluid tau levels. And if the tau reduction is occurring, then we know the gene must be expressed. And then the third, which will be, does the tau PET imaging result match or exceed what we see with BIIB080? And that will determine whether the asset is of value, and that will come after next year. So three different inflection points, one of which we think will occur early next year.

Right. Interesting. So then moving then to the TRACER platform NeuroShuttle and partner programs. TRACER is the Voyager's capsid discovery engine. Key features include crossing the blood-brain barrier with IV infusion, broad distribution to relevant regions in the brain. You've also identified the ALPL as one of your capsids primary BBB receptors. So why does identifying the receptor matter? And how does that differentiate TRACER from capsids targeting other receptors such as transferrin?

Yes. So it matters a lot because we want to be sure that our capsid will work in humans. And the history in this field is that you can get capsids that are very species specific. And so we now know that, for example, since we know it's ALPL, we can make the human form of ALPL and test whether or not our capsid binds to it. So that's very nice. The other thing that I think has become just as important of late is to make sure that we're not leveraging the same receptor that caused problems for other people.

So we know, for example, we just presented this at the ASGCT meeting earlier this year, our capsid binds to ALPL. It does not bind to the receptor that capsid as a receptor bound to. Moreover, we know that the capsid receptor doesn't bind to ALPL. So that's also very, very helpful for us to know. So for both efficacy and safety reasons, identifying the receptor can be of extreme value.

Yes. That's really helpful. That I think, partially or mostly answers the next question, but maybe I'll just ask it just to be sure if you wanted to add anything additional. But your capsid it does use a different BBB receptor than the capsid that was involved in a patient death in a competitor's suspended trial, and you've shown no cross-reactivity between the two.

So maybe you could tell us a little bit more about what happened there and just sort of why we should understand that the receptor difference translates into sort of the human safety difference.

Yes. So we don't know exactly what happened to that patient because it hasn't been published. It hasn't really been shared publicly to my knowledge. We know that the patient died within a few days of the very first dose, the first patient. And that's really all I really know. However, I can tell you that we actually had a pre-IND meeting with the FDA now 18 months or so ago. But after that event happened, we went back to the FDA and requested a Type C meeting, an additional meeting before we filed an IND, specifically because we figured FDA knew everything there was to know about that patient that died because it was an American patient and that they would help us modify our GLP toxicology studies, which we did.

So we actually added additional measures at the request of the FDA. And then we had a very nice process when we filed the IND with the FDA where we shared all that data. And so -- and then we just showed the 6-month GLP toxicology results at AAIC. And so I have to say, we feel very good about the collaboration with FDA. They know everything there is to know about what happened to that patient. We have yet to find out because it hasn't been made public, but working closely with the FDA, we filed this IND and they cleared it. And our toxicology results are available publicly, and we're very pleased with how beautifully those studies show not only the safety, but the efficacy of the doses that we're testing.

Great. Would you ever combine an extracellular anti-tau antibody with an intracellular tau silencing, or does one make the other unnecessary?

One may make the other one unnecessary. However, I always want to look at the monotherapy data and see, is there an opportunity to maybe lower the dose and improve safety or combine and improve the efficacy? That's always an option we have later, but we'll have to look at the data as monotherapy first. You may not need the extracellular tau antibody if you decrease the expression of all forms of tau. On the other hand, we're not decreasing it beyond 50%, right? So maybe there will be a little bit of tau that continues to spread and we can capture that with the antibody; we'll see.

Right. That makes a lot of sense. And then Neurocrine intends to start the first human trial with your Friedreich's ataxia capsid this half. What will you read across to your own CNS programs? And when do you have to decide between co-developing on a 60-40 split and/or taking milestones and royalties instead?

I don't know exactly when we're going to need to make that decision. They're just about to get started. So we know it won't be for a little while. But they are telling us that they expect to get some data even next year, that they're going to be dosing the first patient later this year, as you pointed out, and then that they're going to get some data next year. That's what they're saying. I hope to learn more at their upcoming R&D Day that they're going to have in December on the timing, and how they're thinking about the FA trial. But yes, the FA trial does leverage one of our BBB penetrant capsids.

And, boy, to have -- I think it would be further confirmation that the capsids derived from the TRACER platform are of value. And I'm sure our other partners, including Novartis and Alexion, will take notice of both our results, but also the Neurocrine results, and that may open up a whole other set of diseases that we may want to go after.

Right. That's interesting. And Novartis, I think they partially terminated two targets effective in February. So what should we take about -- is there any takeaway from that decision?

Well, they had a payload in mind. They tested the payload perhaps, and it didn't work as well in their pharmacology experiments as they wanted to. I should emphasize, though, that they're moving forward with three programs still, one of which is SMA, as I mentioned earlier, spinal muscular atrophy. By the way, Zolgensma is a very successful gene therapy product that they have, and it's -- we're honored that they are looking at our capsids for the next generation of SMA gene therapy.

And then also our Huntington's program, they acquired our Huntington's program, which we had already started, and that's progressing as well. So -- and then the third target is undisclosed. But yes, so they're still pursuing three programs. The other two, I guess, didn't pan out quite as well preclinically as they would have liked.

Right. So pre-existing antibodies to AAV exclude a meaningful share of patients from gene therapy. So I'm wondering, do we know how large that exclusion will be in the Alzheimer's population? And how close are the AI-designed stealth capsids to solving it?

Well, we have -- we're estimating about 50% of people will end up being anti-AAV positive when we screen. And so that's roughly -- that's still a huge number of patients, obviously, that are available for treatment. I would also say that our stealth capsids are looking -- showing promise. It may make it so that we can treat an additional 10% or 15% of patients. It's not going to solve every preexisting antibody because they're going to have different epitopes that the preexisting antibodies bind to. But we chose one of the major ones. And so that may also increase the population by 10% or 15%, we think.

Right. And so I think you promised us more NeuroShuttle data this year. What would it need to show for you to take a wholly owned program forward? And how much does the sort of ability to redose change the strategy versus a onetime AAV?

Well, the one -- just to answer your second question first is, if the anti-tau antibody works, VY7523, and as you just pointed out, 0.3% gets into the brain. So if we -- I would shuttle that thing because there, having this longer half-life that ALPL shuttles afford is going to be massively important. And with the anti-amyloid having a short half-life doesn't matter so much because it binds irreversibly to the extracellular plaque. Here, we're going to want more 24/7 coverage. So that would be one obvious application. But yes, we're going to show some data.

We just got our abstract accepted to a scientific meeting in December of this year. I forget the name of the meeting. It's not one that I normally attend, but we're going to be showing some -- a lot more data on the ALPL shuttle at that meeting.

That's helpful. And then maybe just some financial and strategic questions. So I think ended the quarter with approximately $148.8 million and reiterated runway to 2028. Can you tell us which of the catalysts and programs does that runway take you through?

Well, it takes us through the tau PET imaging data for the VY7523 later this year. It takes us through VY1706, the tau silencing through the three inflection points that we've talked about. And -- but the assumption has always been that for these large indications like Alzheimer's, there's no way Voyager can do it all on its own. So the intention is to partner at some point. But hopefully, we will partner after we've achieved human proof of concept that they work. And then that should be very good for our shareholders.

So with that understanding that a partner is likely needed for Alzheimer's because it's a very large indication, what would they need to see beyond the tau PET result? And how quickly after the data could these discussions be underway?

Well, I mean, I'm always open for business, Patrick. And so if they want to start discussions even today, even before we get the results, I'm here. And yes, I think they would want to see what we wanted. For VY7523, I think they would like to see something that's at least as good as bepranemab or better.

We are going to be looking at clinical outcomes. We're not powered to hit any of them with a p-value, but they're going to be looking at the trends we see. And if the trends look better than bepranemab, then I think they could get very interested. I think every -- personally, what I've heard from my colleagues that I talk to is that the BIIB080 data only makes tau more interesting. And my understanding is that there's a large number of companies now that are very interested in tau, big pharma companies included.

So how should we think about just sort of business development broadly and the strategy going forward? Particularly, as you bring forward the ALPL program and some of these other programs, how are you thinking about, sort of, business development as well as, sort of, non-dilutive financing for, sort of, the core programs?

Yes. No, I'm a big fan of business development because we're small, and there's no way we can pursue all of the very, very important and interesting targets for neurological diseases ourselves. And if we can do deals like the ones we've done so far, and we've done a variety of deals, we've done capsid licenses for diseases of their choosing. They have to be -- they have to name those diseases because they're target-based. All the way to -- they've acquired programs that we've had in our pipeline. And we've got hundreds of millions of dollars, upfront, non-dilutive revenue, and that's been critically important for us.

So I'm always open for business. And if the capsid licenses and the capsid partnerships that we formed are any indication, you can see that I'm open to anything that makes sense for our shareholders and for patients. And the shuttles are very, very interesting to a lot of companies. So if somebody wants to work with us on one or more of those shuttles, I'm all ears.

And what do you think investors maybe are missing about the story at this stage?

I wish I knew because I'm pretty bullish. I think what people are missing perhaps is that neuro is at a tipping point and that if we could just solve the blood-brain barrier issues, these newer modalities, the protein therapeutics, the oligonucleotide and the AAV gene therapy, they're going to be transformative if we could just get them across the blood-brain barrier. And so if our data on either the shuttles or the AAV or both show promise, I think it opens up a lot of -- not only for our wholly owned pipeline, but a lot of opportunities for partnership as well.

So, we have a little bit of extra time. So I'd like to maybe go back on VY7523 and ask a follow-up there. So assuming if we have that positive tau PET signal in the fourth quarter, do you know what the next study could look like? Is it a sort of a Phase II, a Phase II/III? And would it need to include sort of clinical endpoints as the primary?

Yes. Well, our partner would have something to say about that. But I would think that the next study could be a Phase II/III because if you power a study for clinical outcome measures, so I think -- look, if we establish that we have a very interesting effect on tau PET imaging, the next step is to make sure that we have an effect on clinical outcome measures. And so -- and then if you think about powering the study for clinical outcome measures, that's a pretty large study, almost the size of the Phase III study. So why wouldn't you then think about it as a Phase II/III study? That's how I would think about it. But of course, our partners will help us think that through.

Right. Terrific. Well, I think that does bring us to the end of our session. So thank you so much to Al and to Voyager for joining us. Really exciting year for the pipeline. We're really excited about these drugs. So looking forward to the next data sets and catching up with you in the future. So thanks again to Al and to everyone for attending. Have a great rest of your day and week.

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I will now turn the call over to our TD Cowen host, Phil Nadeau to kick off. Thank you.

Thanks, Rebecca, and welcome, everyone. Thanks for joining this chat with Al Sandrock, the President and CEO of Voyager Therapeutics. We're hoping today to cover kind of 2 broad topics. One is Voyager's own programs and getting an update on those. And then second, as many of you are aware, Al has been deeply involved in the development of drugs for Alzheimer's for decades. So with some notable events coming up, particularly in July, we're hoping to get his opinion on the current landscape. So Al, maybe I'll kick it to you to start. Could you give us a brief state-of-the-company overview on Voyager? You sent a very interesting letter to shareholders to kick off the year.

With the year half over, perhaps give us a progress report.

Well, thank you very much for inviting me, Phil, and it's a pleasure to talk to you. Sure. Yes, we sent this letter to shareholders, to stakeholders, we said. There were 3 parts to it. The first was that this was -- we thought this was going to be a transformative year for tau, and it is shaping up to be that way. We have our own 2 tau assets on track, and I know we'll talk more about that in a minute. The second piece was that we were going to be validating our brain-targeted capsids in humans, and we're on track for that, too. In fact, one of those is the tau asset, the tau knockdown gene therapy. And then our partners at Neurocrine have indicated they plan to dose the first patient in the FA gene therapy trial this year.

And by the way, I should say that the 1706 tau knockdown gene therapy, we just announced that the FDA cleared our IND. So we're good to go in the clinic, and we're planning to enroll the first patient in the second half of this year. So that's on track. And then finally, on our shuttles, we said we're going to be demonstrating the value of the shuttles. We're continuing to study the shuttles in vivo this year in NHPs. We're going to characterize the safety profile with our first of the shuttles, the ALPL-directed shuttle. So stay tuned on that. So -- but so far, I'm feeling pretty optimistic.

In the letter, you called 2026 the year of tau. Can you discuss why this year is important for the tau field and maybe go into a little bit more detail why it's important for tau -- for Voyager's own tau programs in particular?

Yes. So I do think that the next stage of disease-modifying therapies is going to be based on tau. We know we have -- look, we made a breakthrough a few years ago in the sense that we had the very first disease-modifying treatments, the anti-amyloid -- but on average, they're about 25% to 30% effective on the CDR-sum of boxes, which is the regular -- the registrational endpoint that FDA essentially requires for disease-modifying treatments. So there's still a long way to go to really help the patients.

And I think tau is going to be at least part of the solution for that. And I think this year is the year of tau because we have a pretty big readout coming out on BIIB080. BIIB080 is the Biogen antisense oligonucleotide that decreases the expression of tau, all forms of tau. And they announced in a press release that they had failed on the primary endpoint, but that all doses were effective. That's -- so I think the failure was due to the dose response statistic that they had.

But we're going to see the data in mid-July at the AAIC, and I expect to see pretty interesting results. I don't think they would have moved this program into Phase III, which is not an inexpensive proposition if you include not only the Phase III trials, but also the manufacturing required, that's a big investment. And so I see that as a positive indication, but we'll have to wait for the data to be -- to know more. But -- and then for ourselves, we have our gene therapy, which could be a once-and-done IV treatment that is similar in terms of mechanistic effects on tau to the BIIB080. And then we have our own tau antibody, 7523 that we are still expecting on track. We still expect to see the tau PET imaging efficacy data in the second half of this year.

Great. Diving into each of those programs first, I think maybe we'll start with 7523 the antibody moved to 1706 and then talk about Biogen in a bit of detail towards the end. But I guess first on VY7523, can you describe the design of that for those less familiar? What part of the tau molecule does bind? And how could it be differentiated from other tau antibodies that have been in development?

Yes. So the main thing is that it's differentiated on two points. One, the epitope. We have a C-terminal epitope, and all the other antibodies targeted different epitopes, either N-terminal or mid-domain. And so -- and the only other company that I know of that's targeting the C-terminal epitope is Merck, and they have announced that they're moving from Phase I to Phase II. But the data that we've seen so far is mostly on the N-terminal and mid-domain. So that's one differentiation.

And also, we target -- we have specificity for pathological forms of tau, which I think could turn out to be important. If you don't bind to -- if you bind to normal forms of tau, non-pathologic, you may have less drug available to target the pathological forms. For the anti-amyloid antibodies, it turned out to be pretty darn important that they were specific for pathological forms of amyloid. So the same might apply here.

Can you briefly review the preclinical data that support the development of 7523?

Yes. So this was basically based on an empirical finding. So we had made over 700 antibodies against all sorts of epitopes on the tau molecule. And so how do you choose which one to move forward with? So the first thing was we said, let's choose an antibody that's specific for pathological forms of tau. But we still had about half a dozen antibodies that were specific for pathological forms at various epitopes along the molecule.

So how do you choose among those half a dozen? So we chose to use this animal model where a mouse -- a transgenic mouse is expressing human tau, and into that mouse, you inject into the brain Alzheimer's disease-derived pathological tau. So it's rich in paired helical filaments, which probably -- which come from the neurofibrillary tangles in Alzheimer's brain.

And so we take human pathological tau, inject it into a mouse expressing human tau, and we say, does the antibody block the spread of pathological tau in that animal, both within the same region that you inject, but also across the brain, for example, on the contralateral side to other regions? And because that is what happens in humans that you get spread of pathological tau out of the temporal cortex into other areas of the cortex.

And we chose the antibody we chose, the C-terminal antibody 7523 because it was the best at blocking that spread. Now you might say, well, why rely on an animal model? Well, we had no other way of really choosing which of the antibodies would be the best -- and the other thing is that I gained more and more confidence in this model as it started to correctly predict the human results.

So for example, the N-terminal antibodies that failed in the clinic, both of them failed in this animal model to block the spread of tau. Moreover, bepranemab, the one antibody that does block the spread by about 60% or so, the UCB antibody, that does block the spread in this model, not quite as well as our antibody, but it does block the spread. So we predicted that it would block the spread and certainly, it did. And then we also had looked at, in our hands the J&J antibody.

And we actually had an antibody right near the same epitope. And we chose not to pursue it because it did not block the spread of pathological tau in that model. So it's 4 for 4 in terms of predicting the human results. And so we'll see if it holds true with our antibody. But -- so far, that animal does seem to predict the effect of antibodies on the spread of pathological tau in human Alzheimer's brain.

7523 is currently in a Phase I single-ascending-dose study, multiple-ascending-dose trial. Can you review the design of that study and summarize the results that have been released to date?

Yes. So actually, we already completed the single-ascending-dose study. That was a normal healthy volunteer study where the primary endpoints were safety and pharmacokinetics. We did find that it was well tolerated across all 6 ascending dose cohorts. And there were no serious adverse events or severe adverse events or infusion reactions. So we were very pleased with the safety and tolerability profile. Moreover, when we looked at the serum concentrations, it did increase in a dose proportionate manner.

And the CSF-to-serum ratio was 0.3%, exactly where we would have thought. We said between 0.1% and 0.5%. So very typical of monoclonal antibodies in terms of the ability to get into the brain. And so having seen those results in the single-ascending-dose study in healthy volunteers, we did enroll in a separate study, the multiple-ascending-dose study, which is going to read out, as I said, in the second half of this year.

In that study, we are looking at tau PET imaging as the primary endpoint and we're also going to look at some other fluid-based biomarkers in tau. So -- and by the way, the PK was also in line with other monoclonal antibodies in the single-ascending-dose study. It was 22 to 29 days, which supports the monthly dosing that we're using in the MAD portion of the study.

What do you need to see from the tau PET and the tau biomarkers to advance 7523 to the next stage of development?

Yes. We want to see an effect that is at least as good as bepranemab, and we'd love to see it be better than the effect of bepranemab because bepranemab failed to hit on the primary endpoint on the CDR-sum of the boxes, although I should remind everybody that it did have a p-value less than 0.05 on ADAS-Cog, the cognitive endpoint in the overall population, not a subgroup. So there was evidence of efficacy on cognitive endpoints with bepranemab. We'd love to see an effect on tau PET imaging that's at least as good as bepranemab before we want to move forward with it.

And what would be the next steps for the program? Would you conduct a Phase II similar to UCB and Biogen? Or would it be possible to move directly into a potentially pivotal Phase II/III?

Well, look, we've always said that Alzheimer's disease is probably too big for Voyager to go it alone. So we're going to immediately look for a partner. But conceptually, what you could do is go to a Phase II/III trial and take a dose and based on the multiple-ascending-dose study and move forward into a randomized double-blind, placebo-controlled trial.

Great. Moving to VY1706. Can you discuss the structure of 1706?

Yes. 1706 is an AAV gene therapy. So it's -- it employs a capsid that comes from our TRACER platform, a brand-new, novel capsid that is designed to cross the blood-brain barrier after intravenous delivery. And the payload is a vectorized siRNA. So the siRNA will decrease the expression of all forms of tau. So mechanistically, very similar to BIIB080, which is an antisense oligonucleotide that decreases the expression of all forms of tau. So that's the -- so this is a pioneering science. I mean it's a BBB-penetrant capsid, IV delivery, and it's a one-time treatment.

And what we've seen is that we can get knockdown similar to what Biogen has seen with their antisense oligonucleotide. So we -- this is obviously because it's pioneering, we want to be sure that we do this safely. And so we've had a close communication with FDA. We had a pre-IND meeting that we also had a Type C meeting. And of course, you can expect that we had a pretty robust discussion around the IND itself. And as I said earlier, I'm happy to say that the FDA has cleared us to enter the clinic, and we plan to do so in the second half of this year.

How much scrutiny did the FDA put on the capsid itself? Is the FDA comfortable with capsids being delivered to the brain and in particular, engineered, blood-brain-barrier-targeted capsid? Does that -- did that raise any concerns with the FDA? Or is it relatively standard the review process?

Well, no, FDA was very careful, asked a lot of actually very good questions. We, for example, talked about the fact that we knew the receptor, it's ALPL. We talked about the fact that it's different from the receptor that's ever been seen tried before with any other BBB-penetrant capsid. They asked a lot of interesting questions about off-target effects, et cetera, et cetera. So no, I mean, FDA was very, very careful, scrutinized the safety and also had a lot of very good input on how to design our Phase I trial properly so that we properly monitor for safety. Do you want me to tell you a bit about the Phase I design or...

Yes, that would be great.

Yes. So it's -- so what we're currently planning is a multi-site, open-label, dose escalation study in up to 18 patients across 3 dose cohorts. And the highest dose is not going to exceed 5e13 vgs per kg. So the reason why we mentioned that is that we've always said that we didn't want to get up to the E14 vgs per kg range, which is where people have seen problems with systemically delivered with AAV, right? So we're well below that at 5e13 at the highest dose.

And of course, since it's a 3 dose -- 3-cohorts-dose escalation, we're going to obviously start at even lower doses. They're going to be adult patients with early Alzheimer's disease, and we're going to be making sure that they have tau -- a pathological tau in the brain by -- confirmed by tau PET imaging. The primary endpoint, of course, is going to be safety and tolerability. But we're also going to be looking at the effect on tau biology, which would include fluid-based outcome measures such as CSF biomarkers of tau and then also looking at the spread of pathological tau by tau PET imaging. So the way I think about this study and how it's going to read out, the first piece of information we'll get is acute safety.

Is the drug safe after giving it IV. As we all know, the capsid clears from the body pretty rapidly. So we'll be looking at acute safety. The second stage is do we have evidence of gene expression. And for that, we're going to rely on CSF biomarkers. And then finally, do we have proof-of-concept that the asset could be effective for helping patients with Alzheimer's disease. And for that, we're going to be focusing on tau PET imaging.

And what we're hoping to do is to bridge to the BIIB080 data. BIIB080 will tell us the relationship between effects on tau PET imaging and clinical outcomes, and we'll learn a lot about that in July, I think, at the AAIC. So now what we hope to do is see whether we can achieve similar effects on tau PET imaging with our gene therapy.

Great. Maybe taking a step back, ahead of the BIIB080 data, what is the evidence that mRNA silencing or silencing of tau can reverse the course of tauopathies once aggregation has begun? Is there anything compelling either from the genetics or preclinical development?

Well, I think there's a lot of really interesting human data that suggests that tau pathology is key. First of all, the staging of Alzheimer's disease actually is based on where tau is spreading. And so what that means is that the worsening in clinical outcomes is actually better correlated with tau pathology than it is with any other biomarker. The second is that we have very clear-cut examples of patients who can have a brain full of amyloid -- but without pathological spread of tau, they seem to be relatively immune to that or resistant to that buildup of amyloid in the brain.

So they may still have cognitive impairment, but very, very delayed or sometimes no evidence of cognitive impairment at all. So it does look like amyloid by itself is not necessarily enough to cause cognitive decline in Alzheimer's disease patients. And in fact, the main role of amyloid might be to trigger tau pathology. So that's the human biology evidence. But I would say that one of the most compelling pieces of data comes from the Phase I data that Biogen has showed and now published by Melanie Shulman and colleagues very recently. What it shows is that with BIIB080, which lowers -- which decreases expression of tau, you actually remove pathological tau from the brain.

So you get a decrease in tau PET signal relative to baseline, very different actually from the antibody, bepranemab, which blocks the spread of tau, but doesn't necessarily remove it from where it had pre-existed. So that's a fundamentally different result that you actually remove pathological tau from the brain in areas where it was present at baseline. And then what you see is a clinical effect that seems pretty interesting. Now the issue with the Phase I study was that it was -- there was no placebo group. There was no control group. So you have to then do cross-trial comparisons.

And what Biogen did was they compared it to another study called the TANGO study, which enrolled patients roughly contemporaneously with the BIIB080 study. And they used propensity-score matching to find a population in the placebo-treated patients that matched the BIIB00-treated patients. And what they saw was a pretty big effect size, if you can believe cross-trial comparisons, and we have to always take that with a bit of a grain of salt, but the effect size was quite large as large as 2 points on the CDR-sum of boxes, which when you compare to the anti-amyloids, which are about a 0.5 effect size, that's a massive -- that's a much bigger treatment effect. So we'll see if that's confirmed in the placebo-controlled, randomized trial setting as we'll see at the AAIC. But if that's true, then we could be seeing efficacy better than we see with the anti-amyloids.

Two questions on 1706. First, I forgot to ask you, when could data be available from the Phase I, the initial data as well as the top-line data? And then second, any thoughts on using 1706 in combination with 7523?

Yes. So in terms of when we're going to see data, I look on it, as I said, 3 sort of pieces of information, acute safety, which should be -- if the patients are fine after a couple of weeks of treatment, that's, I think, big news. I think it will be the first time that we can use a BBB-penetrant capsid that can be safely used in humans. Then the next would be fluid-based biomarkers that could -- where we could see evidence of gene expression.

And for that, we're going to need some more time. And then as I said, asset proof of concept, which is 12-month tau PET imaging. So that will be later. So 3 different stages. And the timing is going to be based on how well we enroll, how rapidly we enroll. So I'm not giving out time lines quite yet, but you can imagine that it's going to be over the next 18, 24 months, I would say.

Great. As we transition into some of the other molecules in the field. I just kind of want to get a little bit more of your thoughts on comparing and contrasting the modalities. So we have ASOs, siRNA and antibodies directed against tau. You touched a little bit about how the siRNA versus antibodies differ. Any thoughts on pluses and minuses of each of those modalities more generally?

Yes. So with antibodies, you have to be sure you choose the right epitope. Antibodies don't -- we don't think get inside cells appreciably. So we're trying to capture the pathological tau as it's spreading from one cell to another. And in our case, we have an antibody that's specific for pathological tau, forms of tau. So very different than an antisense or an siRNA approach where there's no epitope that's involved. You knock down all forms of tau, both the non-pathologic as well as the pathologic forms.

And so -- and then it's intracellular as well as extracellular tau. So just -- I think it's -- you hit tau much harder, if you will, with the antisense and siRNA approach. But yes, but the data that we're going to see this summer should tell us whether that's a safe approach and whether or not it portends for better efficacy.

Great. I should say if anyone has additional questions, please e-mail them to me [email protected], and I'd be happy to ask Al on your behalf. So moving to that data this summer, I guess there are pluses and minuses based on our interpretation, the positive is that there was robust tau biomarker reduction and a signal on cognition. So that was the first in the tau class. The lack of dose response on CDR-SB and limited data detail did leave a lot of questions. So I think we're all looking forward to AAIC in July.

Maybe by way of background, can you remind us of the role you played in guiding the Ionis collaboration and the initial development of diranersen? I believe that the Ionis collaboration was expanded to include Alzheimer's under your leadership when you're Head of R&D at Biogen. Can you remind us what role you played here?

Yes. Well, I was -- I championed the initial collaboration with them on SPINRAZA for spinal muscular atrophy and then I was an internal champion for that. I was Chief Medical Officer at the time. And then when we thought about expanding, I was Chief Medical Officer. And as you can imagine, I was a big fan of that. It was partly because the science was great. There was -- we could address targets with a brand-new modality. But also, I really respected the scientists at Ionis, and I thought great science done by great people.

And we had -- and we could address targets that we couldn't address before with small molecules or even biologics. So I was -- yes, I was a big fan of that collaboration. And yes, and I was -- I also -- I think I was -- I forget whether I was Head of R&D or CMO when we brought BIIB080 into the clinic. But yes, I was a champion of that approach as well.

Great. I think the key question that investors are debating as we head into AAIC is whether diranersen's impact on cognition is a true biologic effect and the chances it will succeed in a Phase III trial that has a cognitive primary endpoint. At a high level, how are you thinking about those questions? And how would you use the data to present at AAIC to inform the answers?

Yes. So the data is going to be a randomized double-blind, placebo-controlled trial with 3 different doses. What we know is that it did not hit on the primary endpoint, which was a dose-response statistic. There's some risk. Biogen took a bit of a risk with using that statistic because the CDR-sum of boxes is a highly variable endpoint, right? And we know that the sample size, the lowest dose had the smallest sample size relative to the other 2 doses.

Moreover, if you look at the Phase I data, even though there was a separation between dose groups early on, ultimately, the dose groups kind of come together, if you will. So by 18 months, even the lower doses start to catch up, if you will. And so the dose-response statistic was a bit of a gamble, but I think they did that because the sample size had been reduced from the original sample size, which was, I think, twice as large. So maybe that's why -- I mean, I wasn't there when they made all these decisions, so I'm speculating, Philip.

But anyway, so -- but I think it was -- so what we heard is that all doses showed an effect on cognitive outcomes. That's what I read in the press release. I think I also saw the word compelling in there somewhere. And so what I'm thinking is that maybe they were on the flat part of the dose-response curve, if you will, and that could actually be bad if you have a dose-response statistic. If all doses look similar, then you're not going to hit on that endpoint.

And maybe that's what we'll see. And then if you think, well, if you're on the flat part of the dose-response curve, there's a 1/3 chance that any of those dose -- dose groups would look superior to the other, right? I mean, just by chance alone. So I'm not even certain that there's an inverted dose-response because there was some hint that I think the lowest dose might have been the most effective. That could have been just due to chance if they're on the flat part of the curve and they're all roughly the same in terms of efficacy.

Remember, that dose -- that lowest dose also is the smallest sample size. So I bet the error bars are bigger there. So I think -- I suspect that there's no statistically significant difference between dose groups is the point I'm trying to make, I guess. That's what I'm thinking. And then, of course, what we heard was that there may have been some more adverse events at the highest dose.

And in the history of Alzheimer's trials, for example, if you remember the gamma-secretase inhibitors and even some of the beta-secretase inhibitor trials, some of the adverse events associated with those drugs affected cognition. So if you had more adverse events in the highest dose that affect cognition, then that could make that highest dose look less efficacious, right? So I'm going to be checking to see whether the adverse events had -- could have had any effect on cognition itself. There's no evidence of that in the Phase I trial, but you never know when you see -- when you have a larger study.

Is there a particular magnitude of CDR-SB change that would convince you the change is real? Is something too small? Is there a threshold or is it more about the consistency among the data...

Yes. And on that, I prefer to use the percentage -- is how I said 25% to 30% effect for the anti-amyloid. The reason why I don't use the absolute values like 0.5 or 2 on the Sum of Boxes for this -- to answer this question is that the number -- if you use the absolute value, it depends a lot on what happens in the placebo group. And that can be -- that can vary from trial to trial depending on the population that you choose, right? So if you say percentage effect-size, you can compare across trials, if you will, and compare across populations.

So having said that, I think we all want to see something north of 25% for sure, north of 30% would be even better because we don't want something that's identical to the anti-amyloids in effect size, right? We want something that's better. Of course, if it works in people who don't respond to anti-amyloids at all, then even a 25% or 30% effect-size is still meaningful, but, I'd love to see an effect-size that's north of 30%. Whether we'll see that or not, I have no idea.

And on the placebo group in particular, what rate of decline in CDR-SB would you anticipate over 76 weeks? Like what would be a normally acting placebo group? Is there any way to know that without looking at the baseline?

It should be pretty comparable because the population is similar to the anti-amyloid trials. So it should be comparable to that, but I would say that I don't think you have to worry about that if you just use the percentage difference from placebo as your primary endpoint. And in fact, that's what's in the FDA labels. If you look at donanemab, it's 22% on CDR-sum of boxes. I think for lecanemab, it's, I think, 27%, something like that. So that's why I say that -- but I would expect it to be comparable sort of 0.5:1 range.

Got it. And in terms of the difference between the doses, it could be random as you suggested. Biogen suggested it's possible that the essential functions of the tau protein for microtubule function are inhibited too much at the higher doses, suggesting that knockdown past a certain threshold could be disrupting cellular homeostasis. Is that a possible explanation? Or do you think it's more likely just random?

Yes. So if you look at knockout animals, for example, they actually are fairly normal up until they get older. So they survive full knockout. They survive -- they're actually fertile, but you see some abnormalities as they get into the older age. And there is some view that tau, which is a microtubule-associated protein, is important in stabilizing microtubules. And so that's why I mentioned earlier, I'm going to be checking to see whether or not some of the adverse events had something to do with cognition.

In other words, they affected neuronal function. Could they have affected neuronal function in some way? I don't know that that's what we're going to see. But I would say that we're all kind of shying away from 100% knockdown. Remember, the knockout animals are 100% knockdown, right? And so Biogen, I think, was targeting somewhere between 50% and 80%, and we're targeting a similar range because I think we're all nervous about knocking it down 100%, if you will.

And we've discussed the CDR-SB endpoint. How are you going to assess the other cognitive endpoints that have been -- that were included in the study? Can you describe kind of the type of data that will make you more confident in diranersen effect? And also what type of data would make you less confident?

Yes. So there's complexity there. So I keep talking about CDR-sum of boxes because that was the primary endpoint. And it is -- has been traditionally the endpoint required by FDA for disease-modifying treatments for Alzheimer's disease. And that's because it's a mixture of cognitive outcomes and functional outcomes. So there are 6 subscales, 3 cognitive, and 3 functional on the CDR-sum of boxes.

What I read in the press release was that it had an effect on cognitive endpoints. I don't know what that means. Does that mean that it didn't have an effect on the functional subscales of CDR-sum of the boxes or what? I don't know -- maybe I'm reading too much into the press release. But the ADAS-Cog is a purely cognitive endpoint. And that's a tried-and-true endpoint. Remember, all the cholinesterase inhibitors and memantine were approved based on ADAS-Cog as the primary endpoint. So that's a validated endpoint for cognition.

So I'll be looking at that and see if the -- and see if they show the data on the subscales of CDR, was there more of an effect on the cognitive endpoints? And do you see that confirmed with ADAS-Cog? The other things that I'm going to be very interested to see is the effect on what I would call more functional outcomes. And one of the best measures of that are the activities of daily living, the ADLs. And there are ADL scales that are sort of tailored for this population, the MCI, mostly the MCI and early dementia patients.

And so those are things like activities of daily living, can they function independently essentially, and there's various subscales of that. That's going to be of interest to me. In the case of the anti-amyloids, they had a bigger effect on ADL scales than on the cognitive scales. And to me, I mean, if you talk about what's meaningful for patients, it's the ability to live independently, right? And so I think that's a pretty important piece to look at. So we'll have to see whether there's a difference, if you will, between cognitive and functional, and these other scales will tell us a bit more about that.

I'd assume that you'd want to see some level of consistency among the different cognitive endpoints and similarly among the different functional endpoints in order to be more confident that the data is real. Is that fair?

Yes, I would say so. But I mean, look, cognitive endpoints are not unimportant. So a drug that affects cognition is highly welcome, particularly if it slows the worsening in cognitive decline, my goodness, that's huge. But yes, for that to happen and see no effect on functional endpoints that speak to whether or not they can live relatively independently, that would be weird, right? I mean you'd love to see consistency across both because they're both clinically meaningful to me and to the patients, right?

And so yes, I guess -- but could a drug have more of an effect on cognition than on functional? Maybe. But I'd have to understand more why that's the case because a lot of the functional endpoints are related to the ability to think clearly, right, and to have a fairly normal cognitive skill. So...

I think we're all going to be focused on the cognitive and functional endpoints. Biogen has disclosed, however, that the treatment drove a robust and sustained reduction in both CSF tau and tau PET signal across the dose arms. Is there anything in particular you're looking for in the tau biomarker data itself? -- is one measure more important than the other? Or -- and what would -- I guess, how will you evaluate that data?

Yes. So I have been -- I'm going to focus a lot more on the tau PET imaging on any of the fluid-based biomarkers because I'm not certain that any of the fluid-based biomarkers have reached the level of validation, if you will. So for example, Biogen themselves presented, I think it was a year ago at AD/PD that the TANGO study, the anti-tau antibody that failed on tau PET imaging and on clinical outcome measures, it had a 40% effect on -- I think it was MTBR-tau, if I'm not mistaken, which is -- which was considered at the time to be the best of the fluid-based tau biomarkers.

So it had a nice effect on the -- and it had no effect on tau PET imaging or on clinical outcome measures. So right now, I have to say I'm going to focus a lot more on tau PET imaging than on the fluid-based biomarkers. I do think that the fluid-based biomarkers may tell you a little bit about target engagement, if you will, or at least how robustly the antisense decreases the expression of tau. I think that's important. But in terms of clinically relevant outcomes, I think the tau PET imaging is closer to that.

And what I'm hoping, Phil, is to learn what we haven't figured out, it took us many years to figure this out with the anti-amyloids -- is how much of an effect on tau PET imaging do you need to see a clinically significant outcome. In the case of anti-amyloid, you'll recall, it had to be a very robust decrease in amyloid plaque burden to see even a modest effect on clinical outcomes.

Drugs that had some effect on reducing amyloid-PET -- amyloid plaque burden actually did not have a very big effect at all on clinical outcomes. So that was -- so you had to have a big effect on amyloid plaques to see any effect on clinical outcomes. I don't know if that's what the case is here with tau. But trying to understand the relationship between tau PET imaging and clinical outcomes is a pretty important thing for the field. And for me, that's what I'm going to try to really hope we understand more of at the AAIC meeting.

And on the adverse event profile, you noted some adverse events could impact cognition and that may have impacted the efficacy at the highest dose. What else about the safety profile will you pay attention to? Are there other SAEs or AEs that you would find particularly troubling?

Well, there are AEs associated with intrathecal antisense oligonucleotide administration. We saw -- remember with tominersen, we saw some evidence of enlargement of the cerebral ventricles and et cetera. So there are some sort of class-effect, if you will, adverse events associated with intrathecal antisense oligonucleotides. There may be some inflammation in the spinal fluid, inflammatory markers going up with repeated intrathecal injections.

Now if the lowest dose is the most effective, fortunately, for patients, it's only every 6-month dosing rather than every 3 months. So that's fantastic news. But -- so yes, so I'll be looking at sort of class-effect-type adverse events. And then, of course, are there any adverse events that could be linked to the loss of tau function of normal tau, not the pathological tau, but how much normal wild-type tau do we need to retain in neurons for there to be no adverse effects.

So I'll be looking for adverse effects that could tie into that -- to the function of normal tau in neurons. And then tau is also expressed in other tissues. So cardiac tissue, muscle. I don't expect anything to see any adverse events in those, but it's something that I myself will keep an eye on.

I'll get an e-mail question that puts a nice bow on that -- the conversation we just had. And it is, could you ask Al his level of conviction that the community walks away from the detailed 080 data with the view that the drug is having a real and clinically relevant effect with an acceptable safety profile. So I guess how confident are you that conclusion is leading?

Yes. Just keep in mind that I tend to be on the optimistic side, Phil, you've known me for years. And -- but I think the fact that they have decided to move to Phase III -- and Chris Viehbacher has not been shy about cutting programs, terminating programs, things that are not going to be commercially viable or helpful to patients.

The fact that he and his team decided to move to Phase III, that's -- I think we're going to -- I think I'm going to walk away from AAIC feeling pretty confident that we have an approach that could really help patients and be substantially -- yes, I think I'm going to walk away thinking that they have a robust benefit-risk profile. That's what I'm hoping anyway. But as I said, the caveat is that I'm -- some would say, ridiculously optimistic.

As you noted, Biogen is moving forward into a pivotal study. How would you design a registrational study for diranersen? And what do you think is the most appropriate endpoint? Would you use CDR-SB? Would it depend on what data we see in July?

Yes. Well, it's always a negotiation. I'm sure they're going to have an End-of-Phase II meeting with FDA, and there's going to be a discussion. The precedent, as we've seen now, is that FDA likes CDR-sum of boxes because they always want to see effects on cognition and on function, and the CDR looks at both. So, I don't know whether FDA will back off from that requirement, I doubt it. And I don't know whether Biogen is going to want them to back off.

There may be a nice effect on CDR-Sum of boxes -- and so there would be no risk in having that as the primary endpoint. I think it's probably going to be an 18-month study. And yes, there's a certain requirement for a safety database. But I think if you power the study to hit the -- at 90% power to hit the primary endpoint, you're probably going to have a nice robust safety database as well.

So -- and then the FDA has some comfort around intrathecal antisense oligonucleotide treatments, right? There's already 2 that have been approved, SPINRAZA for SMA and tofersen for ALS. So it's not like it's the first -- it will be the first approved intrathecal ASO. I mean, the only difference here is that Alzheimer's disease and tau pathology is a cortical disease, it involves the cerebral cortex.

I would say that SMA and tofersen are more spinal cord diseases. And so since you inject the antisense intrathecally, there's a gradient, right? So the antisense has to go further, if you will, and maintain exposures that are high enough up in the cerebral cortex. But Biogen has showed quite nicely in the Phase I trial that you get very robust effects on tau-PET imaging in the cerebral cortex. So that gradient [Technical Difficulty]

Hello, everyone, and welcome to the seventh Annual H.C. Wainwright Neuro Perspective Summit. My name is Patrick Trucchio, and I'm a senior health care 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 15 for the in-person portion of the conference with a broad CNS drug development focus across multiple indications from depression and epilepsy to BBB delivery.

With 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. Well, Patrick, thank you very much for inviting me. It's an honor to be here. Yes. So at a high level, I've been saying that this is the year of tau. And so far, halfway through, it 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. But so we'll all learn more about that. As for ourselves, we have VY-1706, which is a vectorized siRNA. So it's an AAV gene therapy that does essentially the same thing mechanistically as BIIB80. In other words, it knocks down the expression of tau. And then we 00have another asset, an antibody against tau against the C-terminal epitope. And we expect to see the tau PET imaging data later this year in the second half.

Right. Terrific. So let's talk about the tau targeting lead assets, starting first with VY-7523. This is the anti-tau antibody with tau data expected in the second half of 2026. What would constitute a clear proof-of-concept signal?

Yes. So we had multiple failures with anti-tau antibodies, most recent being the J&J antibody. But 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%.

And they also showed in the full population, a statistically significant benefit on the ADAS-Cog, cognitive measurement. They did not see a statistically significant effect on the CDR sum of boxes, a measure of both cognition and function. So 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. But for all I know, we'll see some trends.

Yes. And maybe you can talk a little bit more about the biological rationale for 7523's epitope in mechanism and why it should succeed where prior anti-tau antibodies have struggled.

Yes. So we made over 700 antibodies against tau. And so we had to choose, well, which one do we want to move forward. And for that, we relied on the P301S mouse model. This is a mouse that expresses human tau. And 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.

And 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 2 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. And it actually correctly predicted that there would be some effect from bepranemab.

Now 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. But so far, it's been quite predictive of the human clinical trial data. So I'm pretty hopeful and that we'll see something.

Okay. Makes sense. And VY-1706 is a tau lowering gene therapy using vectorized siRNA. Why is upstream MAPT mRNA lowering potentially more powerful than extracellular tau clearance?

Yes. So the antibody approach relies on, first of all, you bind only to extracellular tau likely because antibodies don't get inside cells. So 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. And so you have to have the right epitope and you have to -- and you're trying to capture the extracellular tau is 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 lower intracellular as well as extracellular tau, also lowers normal tau as well. And 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. And the clinical trial results to date suggest that you may get a fundamentally different effect on pathological tau in the brain. And as I said earlier, we'll see the clinical impact of that at AAIC.

Yes. That's helpful. Next one, I think we've addressed somewhat, but maybe we can just revisit this a little bit more. And what I'm wondering is, why does VY-1706 address or what does it address biologically that an anti-tau antibody may not reach? And do you view 7523 and 1706 as competing tau modalities? Or are they complementary? How should we think about these 2?

Yes. I mean, look, it's very likely we'll choose the best approach. But I wouldn't necessarily preclude the possibility of combination. So if you use the gene therapy, you would knock down the expression of all forms of tau. And 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.

Yes. That's helpful. And as well, the next -- we've addressed this somewhat, but maybe you can 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. And I think if you look at the human biology, we believe that amyloid triggers tau pathology.

And so -- and there are patients who have a brain full of amyloid. But if they don't get the tau -- pathological tau forming and spreading across the brain, they don't get demented or at least not until very, very late in life. So 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. And how should investors think about the relationship between tau PET lowering and eventual clinical benefit?

Yes. So that's where the Biogen BIIB080 data that we hope to see next month 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.

But what we really -- 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.

But 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, and the field is learning that. So that's going to be what I'm going to be trying to learn as much as possible over the coming -- over the 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? But 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. I think what's more -- and look, they miss 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. So perhaps, as I was kind of 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. And then when you have a variable measurement like CDR sum of the boxes, there's a 1/3 chance that any one of those would have looked better than the other just by chance, right?

And I think they hinted that the lowest dose may have had the most efficacy. So that's either -- I think that's just as much likely to be due to chance as anything else. So these are all the things that we're going to be learning soon.

And so with the VY-1706 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, it's -- I think it's important for Voyager and the field for 2 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 treat -- 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 onetime 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.

So imagine if you could do instead of intrathecal IV and do it just once and get essentially a long-term effect that's equivalent. So 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 one major piece of -- that's an important milestone if that were to happen.

And 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, those -- that's another important milestone.

Yes. That's helpful. And which of the -- I guess, which of the biomarkers in this trial would be most decision enabling for VY-1706? Is it CSF tau, phospho-tau species, tau PET, NfL, MRI or another measure?

Yes. So 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 [indiscernible].

They can be measured in either blood or in spinal fluid. But 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, it's not really pathologic.

But with aging, we have now learned that we can misfold tau and have it aggregated or clump in a very tiny region of the brain called the rhino cortex. It's only when you have amyloid that it starts to spread. So 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. So 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. And 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?

Yes. So here, again, we're going to be looking very carefully at the Biogen data. Biogen target approximately 50% to 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. And so we wanted to kind of match the BIIB080 data. That's why I said earlier, is there a possibility for combination? If you don't -- if you -- the gene therapy is not going to be 100% knockdown. -- going to be 50% to 70%.

And maybe there's -- 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. But as I said earlier, I think most of us would prefer a monotherapy.

Right. So on the safety and tolerability side, what should we be looking for? And what are the key considerations for a systemic AAV delivery?

Well, 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 thrombo 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. So TMA is another adverse -- there's another risk. There's also -- recently, there's a theoretical risk of insertional mutagenesis that REGENXBIO has seen in one of their patients. And so all those are potential risks.

I would say that we don't -- capsid, I had a patient who had an issue with an intravenously delivered AAV in a patient with STXBP1. We don't know -- we still don't have a lot of details on what exactly happened in that patient. And hopefully, we'll learn that some more.

But those are the safety considerations, and we've done a lot of work in preclinical studies to understand the risks of VY-1706 and to mitigate those risks. We're doing a very careful study in patients. And so -- but we're going to be always watching out for the safety issues that could crop up.

Right. Great. And so beyond Alzheimer's, the Neurocrine partner, Friedreich's ataxia program is expected to enter the clinic this year. What would clinical entry validate for the 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. And again, our BBB penetrant capsid should -- 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. But the disease also affects the brain. That's why it's called Friedreich's ataxia. The ataxic comes from the brain disorder and children suffer from that. And 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? And how does it differentiate between other competitor capsids in the space?

Yes. So knowing the receptor is very helpful. First of all, it's the best way to know if there's a human homolog. If you know the receptor, you can check, does the human have a homolog. And 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.

So the first ones that were discovered only worked in mice and only in certain strains of mice. So 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 to ALPL, where we can maybe shuttle large molecule drugs into the brain without the use of AAV. So that's the significance of ALPL in my mind.

Right. That's interesting. And 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 and 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, work quite effectively and safely. And that would be a huge boon for patients and eventually Voyager shareholders if any of those milestones come through.

And just looking ahead on the sort of the internal versus partnered pipeline, how do you decide whether programs remain wholly owned versus partnered?

Well, I'm always open to partnerships, particularly since our partners bring their own expertise. And there's so many targets that we could go after in the brain, so many diseases that are -- where genetic medicines or a gene therapy approach could be helpful for patients that there's no way we could do it all.

So 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, likely after we get proof of concept. So yes, so -- and we've done partnered programs for all these reasons.

Right. And just as a final question, with the cash runway extending into 2028, I'm wondering, as we look out over the next 1.5 years or so, what would success look like for Voyager across VY-7523,-1706 as well as the partnered programs and the TRACER platform?

Yes. So hopefully, with VY-7523, 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.

So capsid proof of concept and also to prove that we have an asset that's similar to BIIB080 that with a onetime IV, we can achieve something pretty similar. And 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. And then, of course, we're always in discussions with potential partners. So that's how I see it.

Right. Terrific. Well, it's an exciting time for Voyager. It's always a pleasure to catch up with you, Al. So thank you very much for joining us. Thanks, 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.

Hello, everyone. I'm Pete Stavropoulos, biotech analyst at Cantor, and welcome to our webinar series to discuss the blood-brain barrier processing technologies. We recently hosted Voyager to discuss their NeuroShuttle platform for delivering protein-based therapeutics across the blood-brain barrier. And today, we're continuing the series with a look at their tracer AAV capsid platform for CNS gene therapy.

To sort of set the stage, the blood-brain barrier has a central role and has been a central bottleneck in CNS growth booming, especially for gene therapies, limiting the ability of systemically delivered AAVs to achieve broad efficient transduction in the brain. However, we have emerging gene therapy platforms with engineered AAV capsid optimized for blood-brain barrier crossing. We're also seeing growing strategic interest in the space over the past several years. There's been numerous partnerships and transactions centered around this AAV technology, capital technology and unsort the increasing recognition that the delivery and precision approaches are key to unlocking significant value for CNS gene therapy.

We're excited to have with us today Voyager, joined by Todd Carter, the CSO; and Mathieu Nonnenmacher, I don't know if [indiscernible], sorry about that, Vice President of Gene Therapy. So welcome, thank you for taking the time. And let's start off with the introduction of yourselves and a snapshot of Voyager.

Right. Thanks, Pete. Very glad to speak with you again, and we had a great conversation a couple of weeks ago, and I'm happy to be talking about the capsids. I'm Todd Carter, CSO here at Voyager. I have been here not quite 10 years, have been in the field for a while and really excited to talk about our -- what we think are some really exciting work we're doing in the capsid space. Mathieu?

Hi, very glad to be here. Thank you for having us. My name is Mathieu Nonnenmacher. I'm the VP of Gene Therapy. I have been with Voyager for about 11 years now, where I've been leading mostly the novel capsid discovery program. I'm a virologist by training, and I spent my post grad before joining Voyager, [indiscernible] working on the cell biology of AAV vectors. Very glad to be here.

Thank you for that. Todd, do you want to give a resnap of the company?

Yes. So you're showing our pipeline slide here, but maybe just a general intro to Voyager. We're seeing us focused neurogenetics therapy company. And we're known, I think, for novel BBB-penetric capsids that we're going to be talking about today. Now these have a really broad delivery throughout the CNS after a systemic onetime intravenous injection. And one of the things that hopefully we'll talk about are the lower off-target tissue deliveries as we detarget the liver as well.

In addition, and what we talked about a couple of weeks ago was all that work led us into the discovery receptors that we can use to get other things across the blood-brain barrier in a shuttle fashion. This year, in particular, is pretty important to us. We like to talk about it as the year of tau. So there are lots of readouts around tau in the field that have been coming out this year, and we have 2 programs in that area tracking in the clinic.

One is a monoclonal antibody targeting tau. It's differentiated by where it targets and specificity for pathological to tau. We'll have tau pet data readouts in the second half of this year. And the second thing is the single dose gene therapy using one of Mathieu's tracer capsids. We'll be delivering a vectorized SiRNA to knockdown tau and RNA and protein, and that will be filing an IND and getting into the clinic in the second half of this year as well.

And then finally, related to that aspect of things. We also have a partnership with Neurocrine for gene therapy for [indiscernible] also with another -- with a novel IV DBP penetrate capsid that will be moving to an IND this year.

All right. So your discovery platform enables sort of continuous capsid innovation, tail of properties for specific indications. We're going to get into a little bit of detail on that in a short while. However, how does that sort of translate into your partnerships? You did mention Neurocrine partnership strategy today. Can you just talk about your current partnerships and you did mention some of the Neurocrine milestones, but any others that we should expect?

So we've actually, I think, been pretty fortunate with our capsid partnerships. And the religamic from what I'll describe as maybe a pure licensing of our capsids. So we've got partners with Neurocrine, Alexion and Novartis. So a pure capsid license, it might be a case where they take our capsids and do their own work with them, advance their own programs, and we have multiple examples of that where they're working on CNS deliver the approaches.

We have partnerships where it's fully collaborative. So for example, with Novartis, we've got Huntington's disease program, where we are working quite closely with them. We do work internally. All that should be inversed. So it really supports all of our de-therapy work. And we have partnerships with Neurocrine that are similar. I mentioned the FA program. There's a GBA1 program. And then finally, I'll just call out with Novartis. There's an example of spinal muscular atrophy, where they've licensed the program from us and they're working on additional work. And of course, Novartis is one of the most well-known gene therapies with their spinal muscular atrophy [indiscernible] gene therapy.

So what we've been fortunate there is all of that has really allowed us to bring in close to $0.5 billion in revenue, mostly nondilutive over the past several years, across all of these programs in addition to which a lot of our work is just fully supported as what we're enhancing those. And all these programs are really enabled and by the novel BD penetrate capsids, the engineered capsids from the foundation of all of those relationships.

Okay. I probably won't disagree neuro indications are also in high-risk endeavors because of biological complexity and the tiles are delivering large therapeutics efficiently across the blood-brain barrier. What are some of the ways you at Voyager navigate through these risks to sort of increase or trying to increase the probability of success?

So there are multiple kinds of risks in the way we think about it. There's the target risk, there's the delivery risk. And then there's -- all of that also is included in, I'll call it, the clinical risk or the ability to get a readout in a cost- and time-effective fashion. And we try to address all of those.

So on the delivery side, we think we're solving that these novel capsids in the gene therapy space really, as I mentioned, delivered broadly at low doses for AAV, and we think we're solving that delivery challenge. What that allows us then to do is take things that on the target side, and actually ask the question because I think one of the biggest issues in the field has been that we haven't really been able to answer the question of is a given target truly the appropriate therapeutic target or mechanism to treat a particular disease.

We haven't been able to deliver to ask and answer those questions, call them the delivery problem should do that. So what we're doing are starting with the things that we think are the most validated on the neuro side, meaning they're genetically validated in the best cases or potentially clinically validated by other mechanisms. So we're able to take that risk, plan on the delivery side, where we're solving that and then take the lowest risk targets forward first.

On the efficient path to clinical demonstration, right, the challenge -- one of the challenges in neuro has been, it takes a long time, particularly in their neurodegeneration to see whether or not the treatment could be working. And so to deal with that, we are taking paths where we can identify an effect, I'll call it a pharmacodynamic or pharmacological effect quickly. For example, for tau, we can look at tau knockdown, the gene therapy. To give us an idea of whether our treatment is working in a pharmacological sense. But then there are also clear ways to look at efficacy.

So in a tow knockdown fashion, that is tau PET, where there are now pretty well understood in the effective ways and tracers for PET imaging of pathological tau. That's the approach we're taking to both derisk the earlier stage and to be able to get to that proof of biology and proof of concept in the plan as quickly as possible. So we can either identify that yes, we're working and we can identify the dose that we'll work moving forward. Or on the other side, we can cut our losses and move to something else as quickly as possible.

Okay. So how should we think about the blood-brain barrier as a bottleneck for CNS gene therapy. More specifically, can you just walk us through how the blood-brain barrier has constrained both the development and scalability of gene therapies?

So some of this overlaps a bit with the last question, but the blood-brain barrier, I think we all understand it, it excludes 98% or more of small molecules and large therapeutics. Some small molecules can get across and you can do work to design and try to improve that delivery. Large therapeutics to date have been pretty challenging, the antibodies, et cetera. And of course, there are several approaches that people are taking to try to achieve that.

But really, that blood-brain barrier has prevented us from tackling most of the targets that we want to be able to target, whether they're oligonucleotide-based antibody-based or proteins. By using gene therapy, we can actually deliver many of these things. If it's a gene therapy, we can express the protein or enzyme directly in the CNS. If it's a knockdown approach, like a tau knockdown program, we can directly express knockdown siRNA to target, in this case tau or whatever the particular mRNA it is. So really expect to that question of being able to deliver the right treatment for the right therapeutic area to the region.

The other challenge is achieving broad or uniform distribution. So there are some approaches you can do intrathecal delivery or you're injecting into the effectively cerebral spinal fluid around the spinal column. You can do direct injection into the brain and some other similar routes. What those typically do those, they can give you a delivery, but they can do so in a way where you get a large gradient or a very substantial gradient. So delivering [indiscernible] into the intrathecal space, very high levels around final cord and then lesser amounts into the regions further into the brain, that could very well be appropriate for some diseases, but not so appropriate for other diseases where the particular regions that you want to hit don't really reflect that distribution.

The same is true for [indiscernible] or a direct delivery into the brain, and Voyager has some experience because we spend time trying to optimize that. However, again, if you inject say, gene therapy into a very focal point in the brain, you get some distribution and some delivery, and you can change that a bit depending upon the serotype you use. But ultimately, you still end up with a very significant gradient, a very high amount of vector delivered at the point of delivery and lesser amounts as you move away from that.

So one of the benefits of tackling this by using the vascular system is a vascular system is pretty widely distributed for good reason. And so by piggybacking on what we think are normal distribution methods or BBB crossing mechanisms we really hard is that ability. So maybe, Mathieu, I don't know if you had a couple of comments there.

Sure, sure. And I completely agree with what Todd just said. So you can look at the blood-brain barrier as the main implies, an obstacle to the diffusion of molecules, especially large biologics to the brain. But if you look at it as a gene therapy person, this is also an exceptionally good distribution network for the brain. And so the brain is a very energy-hungry organic requires -- it doesn't have its own energy storage. So it requires constantly nutrients, oxygen and everything it needs to function with very high energy demands. And in order to achieve this, it uses an extremely dense [indiscernible] network with a brain barrier, just 400 miles of blood vessels in a human brain. That's about 20 square meters of total vascular surface as an exchange service between the bloodstream and the brain cells.

And it is generally believed that every cell in the brain is within 20 microns of a blood vessel. So if you can find a way to officially transport your biologics across these vascular network, you get an exceptionally good distribution -- distribution system for every region of the brain, including the deep brain regions.

So this is really how the field has been looking at the BBB from the very beginning. It's an exceptionally good way of bringing things into the brain if you can find a way to cross it.

All right. There's sort of a clear shift towards engineering capsids, specifically for crossing this barrier rather than relying on naturally occuring [indiscernible]. Mathieu, you're sort of drawing on your experience advancing this technology, especially gene-based therapies have your role in developing a platform of Voyager as well. Can you give us a quick overview how you're leveraging the blood-brain barrier transport system to enable efficient delivery of gene therapies or large drugs into the CNS?

I'll start and then ask Mathieu to jump in. So really, Voyager started as using some of those delivery routes that I mentioned earlier. We started looking at [indiscernible] intrathecal delivery. And when we kept bumping up against these challenges, and these challenges I mentioned were the very large gradients, a very focal delivery, you can end up with a patchy and inconsistent or not homogeneous delivery. And that led us into the thought that if we could harness the vasculature and the way that Mathieu described, that could enable us to really deliver much more homogeneously and even at lower doses. Mathieu, do you want to talk them through kind of how we got where we are on this?

No, absolutely. So especially in the field of AAV capsid evolution. So that idea of randomly introducing sequences on the AAV capsid surface to impart some new properties has been around since 2003, 2006. In the case of the BBB precisely, it really came down to then government's early work when you would at Caltech and then at the [indiscernible] who came up with the first capsid that could truly traverse the BBB in a mouse model very efficiently. And that was such a paradigm shift to see what capsid directed evolution could do. So that capsid PHP was about 50x more efficient than AAV9, which arguably is the most efficient natural AAV when it comes to crossing the BBB.

And that's really reignited the field very efficiently to see what capsids could do when they were properly engineered. And then Voyager jumped pretty much at the same time around 2016, 2017 with the tracer platform, and we were the first lab to demonstrate efficient BBB crossing in nonhuman primates with the [indiscernible], first of all, that we introduced in 2021. And then with the VTAP102 that came a little bit later with the identification of the receptor. But so all these different progress first in mouse than in nonhuman primates. We're done very rapidly after the technology for directed evolution was perfected to allow these discoveries.

And so -- since then, we and others have come up with multiple versions of these [indiscernible] crossing capsids, multiple mechanisms and receptors. And we really believe that this is now an inflection point where the delivery part of the gene therapy is turning into something that has been sold or partially sold, and that really opens the gate for many high precision therapeutics to affect multiple brain regions and indications. So the years to come will be extremely exciting with multiple clinical validations of those capsids in patients and so on.

What do you believe are some of the core design principles that sort of may ultimately determine whether a blood-brain barrier across the gene therapy platform succeeds?

So, so far, it's been really the implementation of a function first discovery pipeline. Really, the difference between the work of [indiscernible] and then the work of Voyager and others and our predecessors was that there was a very strong and specific functional readout for those capsid screens that relies on gene expression and not just the physical accumulation of viral particles in a particular region of the brain. So I'm not going to go into the details just yet. We will get back to this later. But I think really that was the first principles of capsid library design and the enrichment, the screening method that was relying on gene expression that really made the difference between all these new generation of capsids and the previous ones.

All right. So one question I have is, why does AAV sort of remain the preferable modality for CNS gene therapy? And what are specific advantages of AAV versus others?

So there's multiple reasons for that. AAV has -- is extremely good for nondividing sales. You can provide lifelong expression of the transgene, providing that the cells are postmitotic, which is the case for neurons, for example, and mostly for astrocytes as well in the brain.

It is viewed as a very low immunogenicity vector by comparison with, let's say, adenovirus, for example, that triggers a very strong immune response, AAV start to be much more healthy. It is a very simple virus to engineer. It has virtually no leftovers of viral genes in the final factor. It is completely devoid of potentially toxic viral genes. It only keeps the terminal repeats as the score of its previous life as of ours.

And another fundamental advantage that AAV particles might have in the brain is because of their small size. They're only 25 nanometers in diameter, which makes them very capable of diffusing in the brain tissue where the extra similar states start to be constraining. Any particle larger than 7 nanometers in diameter is supposed to get stuck at some point in the [indiscernible] space, which severely limits the potential use of, let's say, LNPs or other larger LPs or viruses, but AAV because they're so tiny, they're among the smallest viruses in existence, they can actually [indiscernible] very efficiently throughout the brain tissue on several -- on relatively long distances.

And they do have a very good track record of success from CNS diseases. If you look at [ Zolgensma ], this has been used, I think, in close to 4,000 patients to date, and this is close to -- as close as it gets to what we would call a miracle drug, most of these kids are still live today. They would certainly have died from their disease if it was not for the drug itself.

And the viral vectors are still to date, I believe, the best options to deliver relatively large payloads, large genes, and they can be tunable for cell-specific disease specificity. They offer a lot of options and layers of specificity that can be used to control gene expression and eventually the safety and the efficacy of the therapeutics.

Pete, a little bit of that to mostly agree with Mathieu. The downsides can be that we're pretty limited on size. And I think that's probably the biggest challenge of AAV. But for those where we can deliver the payloads we want to, though very low pathogecity, the ability that we're able to achieve with these very blood-brain barrier for entry capsids to get that broad delivery is really excellent and that the proven durability of expression, I think, are very strong positives.

And yes, it is a onetime treatment. So that makes it also a pretty unique option.

Without integrating into the genome.

We have seen multiple improved AAV gene therapies. They've demonstrated meaningful efficacy. And as you mentioned, durability in patients [indiscernible] the example. As sort of the field has incurred, what have been -- what have this program sort of taught us about the relationship of our transaction efficiencies, clinical outcomes and safety. And as those lessons sort of inform the next gen CNS gene therapies that are being designed and developed today?

Yes. So maybe again, I'll start and then ask Mathieu to get in to add. In terms of some of the key challenges that could be addressed, it really is the AAVs did not evolve to cross into the brain and do their thing, they evolve to go in -- to get into reasonably accessible tissues to replicate and then harness other viruses to provide all the machinery. I mean that's one of the things about AAV is why it can have such a particularly specific genome and why it's in and of itself, it doesn't have the pathogenicity seen with some others is because it's a natural [indiscernible] from and uses other viruses to do its journey work.

But because of that, at least partially because of that, it doesn't need to target the brand. And so to target the brain, Mathieu and his team have really had to engineer that capability and now the benefit of doing that is we could start harnessing some of the endogenous mechanisms for doing so and get that product delivery.

We also know that natural [indiscernible], can work in very young patients, presumably because of the blood-brain barrier isn't fully formed yet. The challenge there is it becomes much less effective in adults and not even adults, but as the children mature into older children than those -- the CNS areas aren't as available. And then the current narrow therapeutic window of CNS gene therapy. So as the field has tried to treat more and more diseases, we've been pushing the doses higher and higher to get the kind of delivery expression that we think we need to have efficacy. But as we do so, deliver, as an example, AADs can naturally go to the liver, but we've been pushing the delivery to even higher and higher, and we've seen some of the challenges around that with some of the safety outcomes.

And so one of the things that we always need to do is to build in not only deliver it to the tissues we want to target, but to look for opportunities to de-target those tissues that -- like the liver that we don't want to deliver to. I don't know if, Mathieu, you've got any other comments.

No, that sums it up pretty well. I mean this is always a problem of drug development about finding the right therapeutic window, the delivery, the natural thing for most existing AAV capsids and AAV9 is no exception. And in Zolgensma, many patients have been manifesting some signs of liver toxicity shortly after dosing, which fortunately normalized after a while. But this is definitely one of the aspects of capsid engineering that can be built in to minimize lever exposure while maximizing the brain exposure.

And we were fortunate enough to achieve such properties with some of our first-generation and second-generation capsids especially the ALPL binders that we have developed more recently at Voyager. So those capsids show not only a huge improvement of brain transduction between 50 and 200 fold above 89%, but also a very noticeable detargeting of the liver. We think that about 10 to 15 fold less AAV particles end up in the liver, thanks to those capsid modifications.

So this is really, really an essential and a central aspect of capsid biology that engineering can address.

Okay. It means you just touched on a bunch of safety concerns for [indiscernible] drawback. But are there any other no safety concerns with AAV9 serial type [indiscernible]?

So there are definitely. The liver toxicity is the most common one. I mean -- you will notice on this table that the majority of these clinical approaches are using extremely high doses of AAV. So we consider anything that is higher than 114 viral genomes per kilo of body weight is considered a high dose. And those can come fortunately not often with noticeable liver impact and an elevation of liver enzymes and potential long-term toxicity to the liver.

And other than that, there has been also, in some patients, unfortunately, this is a much less common in them, but there has been some best philosophies associated with AAV9 vectors especially, but also AAV8. These are not very well understood safety reactions against AAV vectors that are still being actively investigated. They can take multiple forms, TMA, HLH, capillary leak syndrome. They're fortunately extremely rare. They affect maybe less than 1% of patients in total, from all the patients that have been dosed with AVs, but the major source of toxicity is definitely liver toxicity. And this is usually seen only with doses of 513 or more barren genomes per kilo. This is something that doesn't typically happen at the doses were engineered capsids would be used in the clinic, fortunately.

I have to think -- sorry, Pete to interrupt. But we also have to comment on a little bit on capsid over last summer, where the -- that's the BBB penetrant capsid company that tragically had the death of the patients, and that was AAV9 capsid as well. So that's minimal work that's been done there. They share a little bit of information and data. We know that our capsids use different receptors than their capsids, so are very differentiated from them in that case. But it does speak to -- you need to know what we're doing and we need to pay attention to these things. I think on the liver side that Mathieu mentioned and some of these others, one of the things that we can do is build upon all the work that's been done to date to mitigate all those risks.

So the immunosuppression that really was identified to, I think it effectively saw the issue with Zolgensma and the liver toxicity. And then the other ways we have in solving them, which are really make the therapeutic more effective, lower the dose and then de-target things like the liver.

Okay. Just to be clear that I heard you right, do you think sort of the window of taxes to be started at about [indiscernible].

So this is generally what is assumed from preclinical studies in nonhuman primates. And this has been seen every patient that has manifested liver toxicity, for example, with those with a dose of 5e13 or higher, if I'm not mistaken, which is the majority of the clinical trial currently happening because they are using natural AAV capsids. And in order to achieve the pharmacology, you need to ramp up the dose to those levels.

So there is definitely -- I mean the dose is the poison when it comes to toxicity and safety. And there's definitely a dose-dependent effect of AAV vectors, particularly when it comes to liver toxicity.

And I think we're going to touch on your capsid issue. So just quickly, briefly, the primary routes of AAV administration to the CNS that's being used in clinical development today. And sort of how do they -- how do they in respect of biodistribution profiles sort of differ and ultimately clinical implications?

You might take that, Mathieu?

Sure. Absolutely. So right now, in terms of the patient number, the most common dosing route has been IV with Zolgensma, which has proven to be effective in very young patients, so 2 years -- 2 years old or younger. And these typically start to achieve a very margin as very, very bran-wide distribution in both the superficial, the cortical and the deep brain regions.

Now among the other dosing paradigms, and many of those have been actually tested at Voyager in the early days of the company, intrathecal has been used pretty widely, especially when it comes to diseases of the final cohort and the brainstem. So this can be quite successful despite the limitation of the PR membrane that limits the transduction of the spinal neurons. It's an actual physical membrane between the spinal cord itself and the CSF. And also, it sometimes translates into higher exposure of the dose with ganglia, which can lead also to some potential toxicities. But overall, that's a method that can work fairly well for spinal cord diseases.

After that, this is really indication-specific. So cisterna magna can be used as well for relatively wide distribution in the brain. So this is a relatively invasive method. This is not something benign. And usually, dose direct injection methods not only are a little bit more invasive, but also translating very steep gradients of transgene expression around the injection site that quickly taper off when you go a little bit deeper in the tissue because the brain tissue is relatively solid and compact and even AAV vectors do not diffuse that far across the parenchyma from the injection site.

In the case of Huntington's disease, for example, from [ UniQure ] in order to achieve a wide enough distribution, you need to perform 8 burr holes in the skull and 8 separate injection sites, which is quite an invasive method. And even then, it seems that there might be some speed gradients around the injection site where you will have a lot of gene expression immediately around the needle track that quickly tapers off in just a few centimeters away.

We see another potential issue with local delivery methods, which are the fact that the rate of diffusion of at particles in the brain tissue do not really scale up linearly with the dose on the brain size. There's physical constraints on the distance that a particle can be used through a solid medium. And a human brain is about 15x bigger than a cat brain. And so whatever you learn from preclinical studies [indiscernible] might not linearly translate into your patients just for a matter of scale and volumetric scale of the brain tissue.

There are a few cases though where local delivery can be highly desirable and Voyager was a very good example of that in our very early years with the Parkinson's disease program with delivery of an ADC and coating vector. So the idea here was to turn some neurons present in the [indiscernible] neurons like expressing ADC, which is an enzyme that can metabolize [indiscernible] to dopamine. And for the success of this therapy, it was absolutely essential that the expression of the charging be limited exclusively to the prepayment neuron. So in that case, that's one of the few instances where local delivery is not a constraint, but it's actually an asset. It's a feature. You cannot deliver those vectors throughout the entire brain, because god knows what would happen if every neuron becomes a dopaminergic neuron.

And so that's one example where local delivery is actually almost the only way to perform this gene therapy efficiently. So ID can solve a lot of problems, but this is not necessarily the kind of [indiscernible] for every single indication and every single disease. Some of them still require some more localized intervention.

[indiscernible] have little bit of a difficulty with the slide deck, but we'll just continue until it's solved. And also, which sort of disease areas of neuroscience are most likely to sort of benefit from the blood-brain barrier crossing AAV capsid, sort of like what is the low-hanging fruit?

Yes. So maybe there are a few. As I mentioned at the beginning, we tried to derisk on the target side since we're exploring delivery side to begin with. And by doing that, we'd like to look at the genetic diseases, there's a clear through line. There's genetic -- significant genetic evidence [indiscernible], right? Things like [indiscernible]. We've had -- we've had SOD1 programs, Huntington's disease, you can look at [indiscernible] and others. And another example of that is GBA1 for Parkinson's given that GBA1 is a common -- the most common mutation found in Parkinson's disease mutations.

Something like Tau, there's -- while -- while tau is not genetically linked to Alzheimer's disease, it is genetically linked to neuro degeneration, their mutations in tau that now the cost neuro degenerative disorders. And of course, tau itself is heavily implicated in things like product traumatic encephalopathy in addition to Alzheimer's disease. And so there are sporadic diseases that have a very clear through line particular targets.

Oncology is another example where often the blood-brain barrier is a literal barrier that prevents the therapeutic from acting in the brain. And so you might clear in the periphery that you could have metastasis to occur in the brain at all and then the predicted area. So if you can deliver across -- you've been taking something that has been shown to work it gets a particular cancer, and just provide that in the compartment where that therapy has been previously prevented from region.

And so those are some of the areas that we think are really the -- I don't know, low-hanging fruit is kind of a front term, it's neuroscience, so there isn't a lot of true low hanging fruit, but I think there are really opportunities in all of those.

Okay. Next slide, sort of from an investment perspective, there's a lot of focus on capsid innovation as a key differentiator. So how do you sort of think about the key design principles when developing capsid that can cross the blood-brain barrier, what properties actually matter most for clinical translation?

You can start, Mathieu.

So I mean, in this case, really the key differentiators are really the transaction efficiency in the brain. So we think that hitting about 50% of brain sales at a dose that is way below the expected toxicity for a hold of AAV would be the pharmacology criteria that we're going after. And seeing some significant targeting of peripheral tissue at this dose is a plus. I mean it's definitely something that we really like to see.

In addition to that, there are some indication-specific features that can be more like which cell types in the brain does your capsid target the most, some capsids appear to be mostly neurotrophic. Some of them are more widespread in terms of their similar preference. The advantage of gene therapy and viral vectors, especially the modularity of the approach. You don't have to do all the selection and the work at the capsid level. You can also work on the payload level to complement the capsid profit.

At the end of the day, the distribution of the gene therapy is a the diagram of capsid trophism route of injection and cassette control. So these really gives you a lot of options to tailor your gene therapy vector to the disease. But really mostly having favorable pharmacology and if possible, the targeting from very [indiscernible] tissues. And then we can come back later to the translatability aspect, which we think is absolutely fundamental to new capsid design as well.

I think that's worth commenting here as well, sorry to interrupt Pete, but that translatability gets to something that we built in. I mean, in a sense, we learned a little bit the hard way, but we built it in very early, and I think it's been really critical to developing our current client capsid platform. And that's ultimately the requirement that we needed to see multi-cross DCs activity across multiple species. And that stems from some of what Mathieu was describing earlier, whereas the amazing work that came out of Caltech with the Deverman in these mice that showed you can deliver something into the brain after an intravenous injection, but it was limited. It did not cross in other species and in fact, it's not even crossing the multiple strains of mice.

And so pretty early on, we discovered that you can identify using that functional readout, the expression-based readout that Mathieu described that we had to get the technology to do, something that worked really well in one species, but the chance that, that would translate into humans is pretty low. So we built it in even though it took a little extra work and more experiments to do so. But I think that's been critical to getting to the kind of translatability that we expect to have in humans.

A little bit of more work, and was that for you? Or was it for Mathieu? [indiscernible] you increase sort of derisk a bit more, the translability.

What it is, and I think we've got evidence that it actually did so. And hopefully, we'll have some time to talk about receptor discovery because I think that's the key output. It isn't just the hypothesis, it's that we're seeing it play out in real time.

Okay. I guess sort of talking about the receptor. When you think about engineering, the next gen capsids, sort of how do you approach identifying and validating the right receptor, sort of what characteristics matter most in terms of expression and trapping and ultimately translational relevance?

That's a Mathieu question.

That's it. Thank you. So that has really become an absolutely key aspect of capsid engineering. Once again, this was pioneered by directly the work of Ben Deverman. I mean, when he identified the receptor for the [indiscernible] capsid, which turned out to be [indiscernible] that was really the first evidence that a direct capsid receptor interaction was the main mechanism for crossing the BBB. And that really started this receptor chase that every capsid developer guarding to because this just gives you so much confidence about the potential translatability of your capsid in patients or allows you to exclude capsids based on their lack of interaction with a human receptor.

So because AAV capsids are biological entities, and they do rely on putting interaction to accomplish their work. This, in turn, triggers a lot of specificity. There's a lot of species specifically about protein-protein interaction. People who've been working for a long time on transferring receptor in the shuttle field know very well what I'm talking about because a single amino acid in the transferring receptor can prevent your therapeutics to buy into the monkey eyes form, for example, whereas it can bind very well to the humanize form. So we're talking about that level of specificity.

And in the case of AAV capsids, the translatability across species and humans across preclinical species and humans has been a major block in the advancement of the field. [indiscernible] is an example. And so the identification of the receptor that is mediating the properties of the capsid is absolutely key to this day to the success and the translation of these gene therapies between preclinical models and humans. So that doesn't mean you have to design your capsids with a specific receptor in mind. Most of the existing screens, including tracer or empirical screeners that rely on the biology and the function of the capsids first. So you put your library in a monkey and you wait for the monkey to do the work and to determine which capsids are going to reach the brain and which ones are going to get excluded. And the receptor identification comes up posterior.

An interesting part of this is that the receptors that come out of those empirical screens typically are very new and unexpected. These are not the ones that you would expect from expression patterns, abundance in the BBB and so on. They usually are quite surprising in terms of their biology. And -- but you cannot argue with the function. I mean these receptors work. They can carry a giant bioparticles or 4 mega daltons across the BBB. And so that means they are very high-capacity transport systems. So that's one aspect of it.

And to recall, evolution screen of the capsids followed by the identification of the mechanism of the receptor, which is absolutely essential for the translatability to humans. And then you have the mirror image of this now that is becoming more and more common in the field is to specifically tailor capsids to force them to engineer with a particular receptor, a priori. And this has been done very successfully with the transferring receptor. For example, they are extremely potent capsids these days that have been purposely designed to interact with TFR, and they do transport themselves across the BBB into the brain with very high efficiency, and there's multiple other receptors that are being used right now to evolve the capsids in a very design first way and function second, if you will.

So this has really opened an entire field instead of working with the black box, which was the case until recently where nobody knew what mechanism those engineered capsids were using. We were just happy that they were doing what they were doing. Now this has morphed into a much more controlled, much more scientific, if you will, way to see how the captive interacts with the cells, how they perform their transcytosis across the BBB and maybe also the targeting of the wholesale at the end to mediate their eventual transaction.

And just again, maybe double down on a little bit of that. It's hard to overstate the importance of knowing what the receptor is and being able to show that our capsid binds not only the nonhuman primate receptor and the rodent receptor form of the receptor, but it also binds the human ortholog. And that gives us just a very high level of confidence that it should translate into humans. And then we can look at what the capsids are doing in the mouse, doing in the monkeys, we can do dose response studies and show the equivalent in those species, all of which just really enables the programs as we move to the human.

Okay. So is there any trade-offs between, let's say, broad brain distribution versus cell type specificity and sort of how do you optimize for that? Even though you sort of alluded to it a little bit earlier in terms of expression in particular cells?

So we don't really believe so. If I want to focus on the most recent capsids that Voyager developed, they appear to be very broad in terms of sales preference. They can target exercise very efficiently as well as neurons, various types of neurons and even oligodendrocytes to a very significant extent. And these are aspects that you can control later on by changing your construct and your promoter or enhancer within your payload. We think that it would be better to have a versatile capsid to begin with that you can later tailor to specific cell preference and indication rather than being constrained by your capsid preference and then not being able to evolve it into targeting different cell types.

So there are some excellent capsids out there that appear to have mostly a neuronal preference, and we have identified such capsids as well at Voyager, but there's really something with a broad specificity capsid with a universal capsid [indiscernible] blank canvas for you to keep evolving those gene therapy vectors in whatever way you want and still working with the same capsid.

I don't want to downplay the importance of having a capsid that will be soon validated in human patients because getting this out of the way, basically allows you to really start plug-in different payloads into a capsid that has been essentially derisked. And so that could lead to much faster development of gene therapy drugs provided at least the transport part has been validated in humans.

Okay. And next slide, just go a little bit deeper into it. Once the therapeutic is in the CNS, how should we be thinking about the role of the construct, design, promoters and enhancers, et cetera?

Sorry, it's fundamental, and it's really guided by the indication itself. Some indications require a very specific gene dosage. For example, if you think about red syndrome, where too much of the [indiscernible] will be detrimental, too little will be decremental. And so in this case, we have options for a slightly more sophisticated construct than what is illustrated here. But even working with cell-specific or disease-specific promoters or enhancers can be extremely good, that can also really help to target the peripheral tissues. If you work with the neuron specific promoter, let's say, human synapsin 1 to site a very, very well-known one, you simultaneously present transgene expression in the liver, the heart, the muscle, all the tissues outside of the brain in addition to focusing your expression in neurons, which is extremely precious for some indications.

And there's multiple ways to do this. You can use microRNA targets. I think this is going to be addressed a little bit later. You can use logic circuits. You can use very sophisticated regulatable promoter to control the expression of your transgene. So once again, I want to reiterate that once the capsid does the job of bringing the payload where it belongs, that really opens multiple options to engineer very sophisticated control and regulation mechanisms if needed.

And then you have other indications for which this doesn't appear to be so important. Diseases, for example, that can be addressed by cross correction with secreted genes such as lysosomal storage diseases, for example, or therapeutic antibodies who can work not only on the cells that are being made in, but also the neighboring cells. In this case, it's generally admitted that the level of expression is not that important. Those transgenes and those proteins are not start to be very toxic even at high level. And so in this case, just a very strong promoter that would provide this therapeutic protein across the entire body and across the entire brain might be completely adequate.

Genome editing, for example, you don't really need to be cell-specific or tissue specific. If you have a gene mutation, it is present throughout your entire body. So it shouldn't be a major issue to modify it in other cells than the ones that you're already targeting. Same thing for RNA interference. If your target RNA is not present in the cell, then it doesn't truly matter. If it is present, your micro RNA will not get down and everybody is happy.

So it's really modality specific, indication specific. But again, having a capsid that goes everywhere or at least goes everywhere in the brain offers a lot of interesting possibilities to play around with the payload and the genome construct.

Okay. And just, I guess, one of the take-home messages was the promoter-driven control is sort of a way to help mitigate some of the toxicities like liver and DRG versus remind just on the capsid alone?

Absolutely. So promoter strength and self-specific can be leveraged to really, really tailor and control the expression of your transgene.

Okay. And next slide, sort of building on that theme of controlling beyond promoter enhancers, other modifications that shape both efficacy and safety...

This is a very interesting approach. I mean that was actually pioneered by [indiscernible] Brown, I think when he was in [indiscernible] lab, and the idea was to prevent the expression of transgene from [ lentiviral ] vectors in immune cells. So the very first iteration of this system, which relies on endogenously expressed microRNA to prevent transient expression, so it is Bryan Brown, not [indiscernible]. So that was initially used to prevent expression of a foreign protein in antigen presenting cells. So that was a microRNA called [indiscernible] that was used to prevent expression. But since that system has been expanded to multiple other modalities, it's extremely elegant because you don't need to introduce much into your bio vector. You just introduce a few sequences that will be targeted by a microRNA that is abundant in the cell type where you want to shut down expression.

For example, miR-122 is very well known in the liver. It's a very highly expressed micron in the liver and only in the liver. So if your genome cassettes contains a miR-122 binding sequence at the end, you will completely shut down the transgene expression in the liver in the hepatocytes. You can use miR1 for the muscle, for example, that is -- there's been some very good work from [indiscernible] in humans to prevent unwanted expression of the transgene in the heart and the skeletal muscle by using miR1 target sequences.

And more recently, the lab of [indiscernible] has come up with a way to minimize transgene expression in the [indiscernible] 83, which appears to be highly expressed in the DRG neurons, but not so much in brain neurons. So that's a very subtle, an elegant way to prevent and add the specificity layer to your expression cassette. It's a very interesting approach that Voyager has been using as well.

All right. Next slide. We did touch on this toxicities sort of related to AAV that sort of repeatedly emerge. When you do look across the data and just briefly because we did touch on it, what are the sort of the largest toxicity risk? And what are some of the rare ones that you actually look out for or should be looking out for?

So again, like I mentioned a bit earlier, the most common form of AAV toxicity, and this is especially visible and high dose is the liver tox. There's multiple hypotheses to what drives it. There's a combination of direct toxicity to the liver vasculature. So there's a lot of interesting work on this that has been pioneered by [indiscernible] who was working with Jim Wilson. And she has performed some very elegant experiments in nonhuman primates suggesting that there's a direct injury to the liver vasculature that can be caused by high dose AAV that translates into multiple pathogenic evolutions of the liver.

And in addition to that, there is also potential capsids antigen presentation by immune cells in the liver and elsewhere that can lead to a CD8 cytotoxic response. So typically, those are managed by steroid, sirolimus injections. There's also more recently the emergence of a role of the complement activation in AAV toxicity, and this is true for both liver tox and vascular toxicity also, which is more rare. And so that is currently managed in the clinic using complement inhibitors.

And so this is really the most common manifestation of AAV tox that usually happens at 5e13, 1e14 or even more [indiscernible] and this is not something to be overlooked. I mean this has resulted in patients death in some instances. So this is something that we really need to keep an eye on. But again, something that capsid engineering should help a lot.

And it should help in 2 ways. One way is by directly verdetargeting, which we and others have been observing repeatedly in our capsids and also the fact that those capsids will be effective at lower doses. So the goal really is to reduce the doses if possible, to 5e13 and below to really minimize the probability of liver tox occurrence.

And the second major tox that has been really emerging from clinical trials. The reason why I'm saying that it's because these are not toxicities that are observed in preclinical models, including nonhuman primates, which is quite annoying, should I say. So those are typically more vascular toxicities, vasculopathies. They do have different manifestations that they can all be grouped under the guys of basically damage to the blood vessels that are caused by high dose AAV. Fortunately, those are much, much more rare. These are still freak accidents or incidents in AAV trials, but we're spending a lot of work and efforts trying to understand those pathologies a bit more.

Again, these are most likely pathology that could be minimized by lowering the dose. So this is really the key aspect of capsid engineering. And the more engineering is happening to more first generation, second generation, third generation capsids will be made, the lower the dose that will be necessary to achieve the right pharmacology, like the [indiscernible] for the brain, we think, is an achievable goal. We have had some very encouraging pharmacology with some of our vectors at doses of 1e13 viral genome per kilo in the brain in our VY-1706 to program.

So we do believe that with more efforts in capsid engineering and optimization, we should be able to reach satisfactory brain pharmacology at 2030 or less. This is going to take a few more years. But I think this is something that is achievable. And we're already seeing this in preclinical models for muscle capsids, for example. There are multiple examples out there of engineered muscle trophic capsids that show efficacy at 5e12 biogenomes per kilo, at least sub-13 bio genomes per kilo, which is extremely encouraging for the future of the field.

And overall, I must also note that even though the field is extremely worried about some of those findings, the SAEs that are observed in patients, so far, grouping all the clinical use of AAV vectors, the rate of SAEs has been about 5% and patient death, which are always extremely unfortunate, are about 0.5% in terms of AAV treatment in the clinic, which could [indiscernible] I think on par with many, many other drugs outside of the gene therapy field.

One other AAV sort of to touch on is DRG on the next slide. Just how is monitoring clinical trials and what's the clinical significance of DRG toxicity?

So there has been observations mostly in nonhuman primates of [indiscernible] caused by high virus doses. I think in patients, if I'm not mistaken, there has been 1 occurrence of measurable clinical pathology that was due to the DRG tox with an RH10 vector, if I'm not mistaken. So it appears that [indiscernible] in particular, might be oversensitive to the [indiscernible] toxicity at doses that are currently being used in the clinic and that appear to be perfectly safe.

Now what Voyager -- with Voyager Therapeutics is implementing in all our preclinical experiments is a very careful follow-up of neurofilament levels in the CSF and in the blood to make sure that we keep a very close eye on the RG pathology. And at every first sign of NFL elevation, we consider that these doses are starting to get a little bit high. So we keep a very, very close eye on potential neurotoxic and especially DRG pathology by closely monitoring NFL levels in the CSS serum.

And typically, in order to advance our programs further to the clinic, we like to define our therapeutic window as a region where we have satisfactory brain pharmacology with little or no NFL elevation for following injection of our capsids at the mill. So we keep a very close eye on it.

And maybe I'll add to it. I think in the clinic, it really is almost observational in terms of monitoring for it. I think Mathieu is entirely correct that when you look in the nonhuman primates, there has been [indiscernible] findings as you push the dose. And do you think that's probably because ERG. You see this in intravenous. You see this in intrathecal delivery. It's basically these neurons kind of sit on both sides, both -- on both sides of the blood-brain barrier, so they're just susceptible. They did hit or targeted by the gene therapy treatments.

But the small immunochemical findings that can be seen in the monkeys rarely, actually convert to something that looks observational or clinically meaningful. And so that's been one of the things that the field has been learning. But as we push the dose into the high E13 per kilogram, that's when you start to manifest. And so when a great way of dealing with that, in addition to the kinds of things that Mathieu described, where you're going to have the mirror binding site, et cetera, is just to lower your dose because if you go on a low enough dose, then PAUSE aren't seeing the DRG is particularly hard and you can avoid some of the issues.

And in particular, avoid any issues where you're actually pushing with this high enough to have the clinical manifestations, which appear to be extremely rare in humans.

All right. I guess one major innovation is the development of a family of capsids that you -- that you've innovated and you have the ability to officially cross the blood brain barrier and trans do cells across diverse brain regions. Just walk us through the discovery process for these capsids?

Mathieu, that's yours.

Sure. Well, I mean so for the tracer platform, it's a system that is conceptually extremely simple. So we started like many of our predecessors by engineering peptide display and capsid library. So there's many ways to randomize the surface of AAV capsids. The one we chose was to introduce short stretches of completely randomized I mean, as said, 6 or 7 amino acids in key locations on the capsid surface that are very tolerant to mutations and that are very, very exposed. And the idea really was to create a de novo binding domain for BBB receptor or anything else by introducing these completely randomized sequence.

And due to the recent innovations in AB library design and all this is an extremely powerful system. We can test more than 100 million variants in every single biopaing experiment in our animals. And really, the innovation of the tracer platform was to use an RNA-based recovery system that restricts the enrichment of the capsids to neurons. So we have a neuron-specific expression of the capsid library RNA. And so in order to see an enrichment of these particular mutants, you needed to transduce neurons efficiently. So I'm not sure I'm doing a very good job at explaining. But that's really the innovation of tracer versus previous approaches is that in order for your capsid to pop out of the screen, it needs to transduce neurons, absolutely.

And this is really what we want to achieve at the end of the day. So this is really a function first system where you focus exclusively under the biological function of your variants. And so following a few rounds of enrichment like this, followed by deep sequencing analysis for which the peptide display approach is particularly appropriate, you start seeing some sequences emerging out of your monkeys and your mice. And this is really the crux of the tracer platform is when you start seeing these sequences rising above the genetic noise, you know that you're on to something.

And after this, we have some other systems that are being implemented to keep multiple single capsids and testing relatively large pools. And in the case of the capsids that are pursued the more seriously now by Voyager, the [indiscernible] series, that system allowed us to actually identify a whole family of those. There was more than 20 capsids that seem to have similar performances, and they all have the same motive that is here on the deep panel with the figure on the left. They had this SPH motive, which is absolutely indispensable for the interaction with ALPL of these capsids. And really, that was the first time we saw such a large family of capsids. And in addition, they were capable of identical performance in mice and nonhuman primates, which is exceedingly rare in AV capsid evolution. Typically, you go towards a single species. And in that case, having the spend species properties was extremely interesting to us because that immediately derisked a lot of the clinical development for these capsids.

And so the identification of the receptor came afterwards, took us about a year to get to the receptor and it turned out to be a very interesting protein called ALPL, Alkaline phosphatase that is very abundant on the brain vasculature. You can see that on the right, these outstandings of ALPL in human brain sections. And they also expressed at high levels in nonhuman primates and in mouse. Those are very, very highly conserved proteins. They are present all the way from bacteria to mammals. And so they are very basic bricks of leading beams. And so we think this is one of the reasons why those capsids are working so well across species because they can bind to these very, very highly conserved alkaline phosphatase receptor.

So that was the read the story of the tracer platform and how that led us to discover some of these first nonhuman primate capsids. This one was not the first, but it's clearly one of the most interesting that we have in stock at this point.

All right. Next slide, and you've got to find 2 of the capsids. What are some of the key characteristics and attributes you're sort of focusing on when selecting the capsids from both safety and efficacy, but also when you think about commercialization in the [indiscernible]?

Absolutely. So this is really what is represented on the Venn diagram here. You want to maximize the pharmacology, so you want to capsid that is even better in the brain than the first generation. If possible, minimize the peripheral tissue exposure, especially the liver. And ideally retain the good manufacturability of the capsule. And so we were extremely lucky with the second-gen capsids that came out of the [indiscernible] because they actually showed those 3 characteristics in one single package. They were showing another 4, 5-fold increase in brain transduction in nonhuman primate. They were retaining their properties in mouse, which was essential. They were showing even further decrease in liver exposure compared to the first-generation capsids, and they were still extremely, extremely favorable in terms of manufacturability.

It is hard to make AAV. This is probably one of the most complex drugs to make at this point. It is a very complex process. And those capsids are quite equivalent to AAV9 in terms of manufacturing process and efficiency. So this is something that is absolutely crucial. Gene therapies are very expensive drugs. The cost of goods for gene therapy vector production is extremely high. And so if you deal with a capsid that is difficult to make, that is definitely going to impede your capacity to manage large conditions and to evolve it to the clinic. And so in order to move towards clinical development, we think a good capsid has to fulfill at least those 3 properties, and of course, the translation.

And then I'll add, we can use the methods that have been already developed for efficient and relatively cost-effective ways of producing things like AAV9. So we require that all of our capsids have those key manufacturability criteria. So we can use similar techniques. We have a tech ops group that knows what they're doing, and we can take advantage of these economies of scale when we produce our material.

Okay. Next slide, please. So how do you view ALPL sort of mechanistically -- similar to transparent in terms of transcytosis or are they meaningful differences that you'd like to highlight. But also just curious of whether the transformers there will pop up on your screens?

So ALPL is quite different from transferring receptor. And as I mentioned before, this is not necessarily something that would have popped out from a list that would have gone after immediately transfer and there was very good reasons for people to do after transferring. It was known for having a very high capacity to transcytose [indiscernible] transferring across blood vessels. It has a very high recycling rate. ALPL doesn't seem to have any of this. ALPL steady state is at the cell surface. It doesn't seem to have a particularly fast and endocytosis rhythm. And it is -- we think it is induced by the binding of the virus itself.

So the interesting thing about ALPL is that it tells us that you can start looking outside receptors that appear to have the right profile for transcytosis. This is not a transmembrane coating. This is a GPI-anchored protein, which is also a different category. And yes, it works. So that actually expanded our horizon a little bit as to what constituted a good transcytosis receptor in the BBB because this protein was not supposed to. It is not famous for having a very high recycling rate or any such thing.

And it turns out that it doesn't seem to be indefensible, which is really where the function-first approach really shines because regardless of the biology that we know about a given receptor, the virus tells you what works and what doesn't work. And so this is really a fundamentally different way to identify good BBB shuttles. By looking first at what can carry this giant 25-nanometer nanoparticle across the blood vessels and ALPL was one of those.

The distribution of ALPL is quite different from transferring receptor. It's mostly expressed on arterial vessels and capillaries, whereas transferring is mostly on the venous side of things. So it's a different subpopulation of blood vessels that seem to express it. The biology of ALPL with relation to age and disease is also a little bit different. It appears that ALPL is expressed at higher and higher levels when people age. Transferrin receptor is quite the opposite. It seems to be expressed more into younger people, and then it goes down with age. So they don't have much in common really, except that they both work in carrying AAV across the BBB.

And to answer your second question, I am not aware that anybody in the field has ever identified TFR as a capsid receptor in an empirical screen. We know that if you engineer an AAV capsid to bind to TFR, it is going to become a very successful brain capsid. But so far, this has worked only with the human TFR. And I don't know if it's a matter of species. I don't know if the monkey TFR or the mouse TFR is not very prone to interacting with AAVs. But as far as I know, nobody has empirically discovered the TFR binding capsid in a library screen. And that's still a mystery for the field that nobody has really an answer for at this point.

So yes, that's -- there's another fundamental difference for that almost between TFR and ALPL, which is transferring receptor is the textbook receptor for class remediated endocytosis and trafficking whereas ALPL just like most of GPI proteins, traffic with lipid rafts using a completely different trafficking route that goes to the golgioparatis by retort transport. At least most of the lipid [indiscernible] proteins are supposed to do that. So completely different.

And so if I heard you correctly, in general, ALPL doesn't sort of move, but once you actually engage it, I guess, on that site where the [indiscernible] then it's sort of [indiscernible]?

Yes, which is quite common. I mean this is what we know from our own in vitro experiments and also from what is known about ALPL function, it's not a transporter. It's not something that catches things and bring them into cells. That's not its primary function. The primary function of the ALPL is to defer things on the outside of the cell. But it's very common in trafficking and endocytosis that when you start binding multiple receptors on the cell surface and you cluster them, especially big cluster around a spherical particle like an AAV capsid, they can start curbing the platform membrane and that in turn triggers endocytosis. This is a pretty common mechanism of endocytosis, especially in the lipid wraps and especially with GPI proteins because they do not have a cytoplastic tail. And so that's the only way they know that they need to form an endosome.

If you start clustering them around a particle outside the cell. This is not fundamentally surprising from a trafficking point of view.

Okay. All right. Sort of moving on to next slide. Just walk us through [indiscernible] I would emerge from the broader capsid family? And are there -- in some of the preclinical data that increase our confidence in this capsid that made it the one to advance?

So the 102 emerged because of two things. It was one of the tough capsids in terms of rain transaction in primates and in mice. And you also started with a noticeable level of liver detargeting. And that -- it kind of stood out the other family of ALPL binders in a screen because of this.

At baseline, for first-generation capsid already has some very interesting properties. I mean had a very, very favorable biodistribution in the brain like 10- to 20-fold more viral genomes per sale compared to 89. And 16 to 50 to 200-fold higher transgene expression compared to AAV9 depending on the brain regions. So -- and these properties were pretty much identical between nonhuman primates and mice. So that capsid already cannot had it all to begin with. It had hybrid transaction, liver-detargeting and mirror image of behavior or actually identical behavior across rodents and primates.

So it already had pretty much everything we liked. The only thing we did by performing the step-wise evolution into our Gen 2 capsid, which is the one that is mostly being advanced to clinical programs these days, was that we introduced another level of brain targeting enhancement by 3, 4-fold and we further reduced the liver exposure. So the Gen 2 capsids that we're using now is a really optimized version of BKAP-102 that is just pushing everything to the max and that is being even more effective and we hope even safer than the 102.

The mechanism is the same. They do interact with ALPL the same way. We have not really been able to identify and to pinpoint the mechanistic reason why the second-gen capsule was better than the first gen. This is probably a very subtle difference. They are proceeding pretty much the same way except the Gen 2 is even better. It's a big 1 or 2 on steroids, if you want.

All right. So you are telling if you look at your broad CNS transduction multiple brain regions with the dose of [indiscernible]. What do you think about those as a key differentiator for this next gen sort of capsid?

Yes, it's absolutely key. It's absolutely key. Depending on the CapEx and the program, we really believe that low E13 doses might be sufficient at least from what we gathered from our NHP studies, including GLP tox studies. Those capsids are extremely effective at 1, 2 E13 viral genomes per kilo with certain payloads. The efficiency of the payload can vary across the programs, the promoters and so on. But the capsids themselves, we think are extremely effective. And most importantly, at those doses, we have almost no signal at all coming from the liver. So we always keep an eye on AST and ALT, the deliver tox markers or bilirubin, there is absolutely no change in the level of liver enzymes at the doses that give us the pharmacology that we want in the brain. So this is absolutely key.

Your therapeutic window is massively enhanced by using capsids. To give you an idea, the second gen capsid was the first time where we saw that we could transduce more cells in the brain than in the liver with a ubiquitous promoter and an IV dosing. We could actually reach more neurons and astrocytes than we hit hepatocytes. So that was a first even for us, for [indiscernible] capsid. And this is what we're working with right now, mostly.

Okay. Sort of how do you think about the consistency of transduction across the different brain regions?

No, absolutely. I mean those typically give a very margins distribution, especially across the gray matter. Typically, you have much less transient expression in the white matter. But across the gray matter, it seems to be extremely margins. There's always regions that are hit a little bit less than others. The heapecampus is a very well-known example among capsid engineers. The thalamus is usually transduced at very high levels. The dentate nuclei, the lateral geniculate nuclei are regions that gets targeted very, very, very efficiently. We don't know why. There's no obvious difference in vascular density or any such thing. But there's always some nuances across brain regions. But compared to local delivery, this is day and night.

If you look at cell staining, like with an example on the [indiscernible] the left, it turns out that the expression of the transgene across single cells is much more margins than you would get with more local delivery methods. We really believe the vasculature in the brain works like a sponge with this really dense network and distribute the capsids in a very homogenous way across the entire brain tissue. And so these participate in the margin as expression that you see. Of course, you will never or at least not before a very long time, you will never have exactly one copy per cell across every cell in the brain. That would be just like a dream for gene therapy, but these are things that you can work with later with controlled assets and so on. Of course, the ideal gene therapy would be 2 copies per cell in every cell, just to mining what happens with chromosomes. But this is not yet something that we can do with our existing cases, but working on it.

I will say, and I'll add to the slide that you're showing, Pete. If you look on the upper the left, there is a measure of the number of vector genomes per cell out of these different brain regions. And what you can see is it's a logarithmic scale. But we're on the order of 1 to 2, and that's generally even the [indiscernible], on the order of a few vector genomes per cell. Contrast that with direct injection where you might have hundreds of copies per cell around the region where it's injected and then make gradient away from there. So that homogeneity across the brain is just an order of magnitude better if you're trying to get broad delivery than any of the local delivery methods.

And I guess that goes into the next question, which is basically how important is deep parenchymal penetration for therapeutic targets that you're pursuing?

For some...

I mean I think -- so yes, I mean we could talk a lot about the intraparenchymal delivery. I think there are some indications that Mathieu pointed out earlier, where it could be particularly useful. But generally, for most of the diseases that we want to target, we want to see broader delivery. And through a combination of the broad delivery and if you need more cell-specific tweaking it by promoters or other methods that Mathieu described as the way we tackling.

All right. Next slide. So we did talk about liver tox and also DRG. And so here, we have an example of and some data from your platform in terms of how be targeted both the liver and DRG. How does that -- how do you think about the dose levels and sort of therapeutic window?

So the liver the targeting gives you a lot more freedom about what you want to do. But in gene therapy in general and in every drug development, we're still going to -- we're going to get as close as possible to the minimal dose that provides us with our wanted pharmacology. In terms of liver toxicity, we know that we could go much higher with those capsids if we wanted to, but there's really no point whatsoever to keep ramping up the capsid dose provided that you reach your desired pharmacology in the brain. The DRG -- the DRG detargeting, sorry, is a little bit less spectacular with 102, there was some significantly lower DRG expression and better genomes.

This is something that we anticipate to solve or this is something that will take advantage of the lower dose that we can use and reach our desired pharmacology. This is still the same answer. And I'm sorry if I give that answer over and over, but really, the lower dose is the key with capsid engineering. If you can reach your brain pharmacology with 2e13 viral genomes per kilo, then that automatically solves a lot of the other programs that could arise at much higher doses. If you inject those patients with 10x less vector than what is being used with [indiscernible] with or without the DRG targeting with or without liver detargeting, you would anticipate much less adverse events than what has been observed with AAV9 capsids.

So this is really the absolute key is the right pharmacology at much lower dose and the translatability between preclinical models and patients. That is the absolute key to capsid engineering for us.

And I'll just add, I don't know, I mean we're probably running up against time here. But the second-gen capsid that we're using for our town knockdown program. So you're showing the first gen capsid data, but we're 30-fold detargeted from the liver, for example, with the second gen capsid. So we have a tenfold lower dose and then on top of that, we have 30-fold reduction in delivery to the liver and early targeting of the liver. And so it's really something that we lean into and think is important for the novel case.

Yes, we are running over time, [indiscernible] if you guys have it. It's okay, it's good to go through the program thoroughly. But next slide, just, I guess, quickly walk us through the rationale for going after to with the vectorized siRNA?

Sure. So I'll jump in and Mathieu can jump in where you feel appropriate. But -- the -- so for Alzheimer's disease, there is the kind of 2 process model where amyloid beta builds up is plaques that traders misfolding and spread of tau this misfolded tau throughout the brain in this very stereo type fashion. The spreads -- that stereotype spread has led to the prion-like spread hypothesis.

So based on that, this misfolded tau accumulates in neurons and there's probably some toxicity as it's accumulating and when it begins aggregating. But over neurodegeneration really begins to aggregates forms [indiscernible] plaques and kills the cells. So the therapeutic hypothesis is if we can reduce the expression of tau, both starting an mRNA and then with protein, we can do two things. We can reduce the burden on a cell that is already having an issue with misfold protein, this [indiscernible] tau. But we also reduced that sales contribution to the next cell down the line, and then we reduce tau in the recipient cell, allowing us to have less of an impact.

And so we're seeing this potentially play out in a non-gene therapy fashion with [indiscernible] delivered. It needs to be delivered every 3 or 6 months. But it appears and some data they released a couple of years ago in a preliminary fashion be having a pretty meaningful impact on pathological tau in Alzheimer's patients and also a surprisingly strong impact on cognitive and other clinical endpoints.

So fundamental hypothesis is that we're reducing tau protein ultimately starting with the mRNA and that reduces both the burden on sort of donor and recipient cells and then treating Alzheimer's in that fashion.

The next slide, just an overview of some of the preclinical data that you've generated to date?

So one of the key models that we like to use is a mouse model. This mouse expresses human to tau. This is a case where the mouse is a P301 mouse expresses a mutant form of tau that accumulates pathological tau. What you can see in the middle, our data showing that we had expressions we got vector genome delivered in orange. And in that middle, you can see a pretty remarkable reduction in tau mRNA. This is all after a single dose of our gene therapy, tau updown gene therapy, where we're up to 97% reduction in its first tau talent in this particular case. And then we see both mRNA and then tau protein. And ultimately, that results in a 97% to 98% reduction of pathological [indiscernible] in that mouse.

So that therapeutic hypothesis I mentioned, tau reduction resulting in a decrease in pathological forms of tau accumulating, that's what this model shows.

All right. And next slide, in nonhuman primates treated with is a single dose of [indiscernible] how do you interpret the level of tau mRNA reduction here? Is it sort of within the range that you believe is either for clinical efficacy?

Yes. So it is. And we can see a lot of that, not only from a lot of work we've done in the mice, but more importantly, data that are coming out of the clinic in humans with BV80 where 50% plus a little more appears to be showing efficacy as well as safety in those repeat dosing intrathecal trials. So again, what I showed you before what Pete showed you before were the mouse data. These are nonhemoprimate data. It's a single dose of our tau knockdown gene therapy, and we're looking at 5 or 11 weeks to almost 3 months after dosing at single dose. And in red, in the middle, you can see we're getting 50% to 75% knockdown broadly through the internal cortex, the HIPAA campus and the [indiscernible] frontal cortices of the monkey after that single dose.

So look, we're getting a broad delivery, a single dose and reduction well within the realm of where BBB showing these results in the tumor. On the far right, we've touched on this, but that's showing that 30-fold targeting in the liver. So at this dose, and that's an important point. This is a 1.313 per telegram dose. That's well within the range that Mathieu was describing earlier, tenfold lower than Zolgensma in the clinic, and we're seeing great knockdown and this 30-fold targeting in the liver in these animals.

How -- so the data look like at 5 and 11 weeks of full [indiscernible]? How does quickly do the mRNA reduction sort of translate into protein changes? And I guess, theoretically pathological changes?

So the protein itself, tau protein in monkeys and humans has a fairly long half-life to tell me order of 3 weeks or so. And so you need to give it 5 or so half-life to begin to approach an equilibrium. That's why it was important to go out to at least 11 weeks here. We expect this to continue, if not improve in terms of reduction on the protein side as we go out to even longer time points.

And how are you thinking about the dose response relationship in terms of vector exposure, biodistribution and sort of down [indiscernible]?

So all that work is ongoing. We hope to say more about that in some upcoming discussions from our GLP and our dose finding studies. Again, this is sort of a remarkably low dose. You can see here there's a 3e12 and 1e13. We have a dose response here between those 2 doses. Given what we've seen in the mouse, one of the benefits of our ALPL capsid is its remarkable consistency between the mouse and the monkey, which gives us this relationship that we can translate between those 2, giving us greater confidence that it should translate into humans as well. So we think this is likely to hold up.

Okay. [indiscernible] ask you the last question, anything else you'd like to sort of highlight about the program or overall the platform?

Yes. So the platform is exciting. Mathieu's talked through a lot of the details. The fact that the empirical process has led us to these capsids with receptors that we wouldn't have known to go forward in the first place is really exciting. The process that Mathieu devised to look for things that across PCs played out, not only in where we see it working in both mice and monkeys for this particular capsid family, but also when we look at the receptor responsible and being able to translate that to the human form of the receptor.

And for Voyager, this year, is an important year. We were getting the tau antibody data, but we will be going into the clinic with this tau knockdown and hopefully demonstrating in humans that this will translate and work well and be safe. And so it's a really important year for us, and we're really excited for the back half of this year.

Okay. Last question, the next key milestones for the patent platform over the next sort of 2 years, let's say? And when should we expect to hear about some of the other receptor candidates?

So I think the most important milestone is in the clinic, getting the capsids in the clinic. I mentioned that for this program. I also mentioned earlier, the neurocrine program, which will be moving into the clinic in the second half of this year as well. And I think those are the most important. I think, Mathieu, you might have a few comments on other milestones.

Sure. I mean I agree with you that nothing is more important at this point than validating our capsids in patients. In the meantime, the team keeps working on further improvement of capsids. As I said, we are always striving for this 13 dose in our capsids in the brain. Voyager has been doing some work with a little bit less involvement and intensity, maybe on non-CNS issues, some of which will be disclosed at the upcoming ASGCT conference in May in Boston. And we keep working on some other aspects of capsids like stealth capsids to avoid preexisting antibodies in a fraction of the patients and other aspects as well. So it's a continuous evolution. It's a process.

We keep identifying new capsids, new receptors as well, some of which are feeding directly also into the neuro shadow platform because every new BBB receptor is potentially extremely important. And so the work is carrying on, no problem. There's still a lot to do. But again, 2026 is going to be absolutely fundamental for us.

Great to hear. So thank you very, very much for your time. I know that we went over a little bit, but not a big deal. I love these conversations. So looking forward to the progress. I'm looking forward to some of the catalysts, a little bit of clinical data with this platform, but as well as the other [indiscernible] blood-brain barrier protein technology. Really looking forward to that. And thank you, and thank your audience.

Thank you, Pete. I appreciate the discussion as always.

Thank you for having us.

Hello, everyone. I'm Pete Stavropoulos biotech analyst at Cantor and welcome to our first of 2 webinars with Voyager to discuss its blood-brain barrier crossing technologies. It's an exciting time for the field. The blood-brain barrier has been a sort of a bottleneck in CNS drug development preventing many promising therapeutics from reaching their targets in the brain.

Today, however, there's a wave of delivery platforms designed to actively settle therapeutics across the barrier and is gaining momentum. Over the past 5 years, we've seen more than 25 partnerships and strategic transactions centered around these technologies, highlighting the growing recognition of the potential One of the biggest examples of this trend was AbbVie's $1.4 billion acquisition of Aliado Therapeutics in October 2024. And there are numerous other examples.

These platforms are already demonstrating potential to dramatically expand the reach of CNS drug development, and they will unlock a lot of value from neuro indications. We're excited to have with us Voyager Therapeutics who has a differentiated blood-brain barrier crossing platform and is developing a pipeline of brain penetrant therapeutics. So today, we have with us Todd Carter, Chief Scientific Officer; and Vasilis Kariolis, Vice President of nonviral Therapeutics. So welcome. Thank you for taking the time, and we'll start off with an introduction of yourselves and a snapshot of Voyager for those not familiar

Thanks, Pete. Really appreciate the opportunity to join and talk about this. It's work we're very excited to share. I'm Todd Carter. I'm CSO. I've been here at Voyager, not quite 10 years, been in biotech for a couple of decades working on whole set of different kinds of modalities. I'm looking forward to the discussion today. [indiscernible]

Yes. And thanks for the intro pet. I'm excited for the discussion today and share the enthusiasm about the brain delivery field. My name is [ Mohali ] Kariolis, as you mentioned, Vice President of nonviral Therapeutics here at Voyager. I've been with Voyager for about 1.5 years now. And prior to that, spent the better part of 9 years at Denali helping with their transport vehicle platform and the associated programs.

Awesome. A little bit of background about Voyager and where you are currently?

Yes. So Voyager, we're seeing us focused neurogenetics therapy company. And we're mostly known for our novel blood brain barrier per gene therapy capsids. These are entirely novel capsids that came out of what we call our tracer platform that we may have the opportunity to talk about a bit. .

But we're able to dose systemically using intravenous injections and get broad delivery across the CNS, including the brain. And we have lower delivery to off-target tissues such as the liver. Now that work led us into the shuttle platform space based on the receptors that we identified that were responsible for that blood-brain barrier penetration.

This year, 2026 is particularly important to us. We like to talk about it as the year of tau because the whole field, if you look across it, we have many readouts in the field that are going to be important around how. So we have 2 programs in that area that are tracking in the clinic.

One is not a blood-brain barrier penetrant technology, but it's a tale monoclonal antibody, where we'll have tau PET data reading out in the second half of the year. And the second is a single-dose gene therapy using 1 of our novel BBB penetrant capsids to deliver a vectorize SIR that knocks down taurine and protein.

And so that will be going into the clinic later this year. We also have a partnership with Neurocrine for a gene therapy for [indiscernible] That's, again, with one of our novel intravenous blood-brain barrier penetrant capsids that will be moving into the clinic this year. So all of this really is we have that tile antibody, but everything else is based on our BBB crossing technologies, 1 that is the AAV capsids and the second is the platform that Mohali is helping build around developing shuttles to get a variety of things across the blood brain barrier.

Next slide. How should we think about the blood-brain barriers, rolling CNS drug development? How has this barrier historically limited development of therapeutics for neurological indications.

The [indiscernible] barrier, I think as most of us know, excludes 98% or greater percent of small molecules and large therapeutics, like proteins, enzymes, antibodies, et cetera. People have taken a variety of approaches to do this to get whatever it is you want to get into the brain. You can dose very high to get into the brain. That's what people tend to do with the antibodies. .

The benefit of antibodies is they can be highly specific, so relatively safe. And that's where the efficacy is seen with things like [ aducanumab, canimab, ] the anti-amyloid when benefit of the TA antibody is those appear to be remarkably safe. So we're able to push the doses pretty high on antibodies.

People also use alternative routes like intrathecal or direct brain injection. People have tried that or have been using that for gene therapies for all of the nucleotide-based therapies, like ASOs or siRNAs and while there are the likely opportunity there, particular diseases that can see benefit, it's pretty challenging to get quite broad delivery and safe distribution that you usually want for most neuro diseases.

And so we're pretty excited by these next-gen CNS therapies like our novel [indiscernible] like the shuttles to enhance brain penetration and get that broad delivery with either lower doses or improve the therapeutic window.

Can you just briefly walk us through the mechanisms that the brain sort of uses to transport molecules across the blood-brain barrier that you're going to eventually leverage?

Yes. And I'll say a couple of things, and then maybe Mohali can jump in give us his thoughts as well. But basically, what we know is getting things into the brain, the body needs to do that. There are active processes that we hope to piggyback on we need to transport things across the blood-brain barrier. And these different opportunities, different receptors gives us the opportunity to identify these novel ways of doing that. Mohali?

Yes. Just to go a little deeper on that point, Todd, I think you set up the challenge of the blood brain barrier for drug delivery, but it's important to recognize that it doesn't only keep out the drugs that we're trying to get in.

It's actually a barrier to all of the macromolecules the brain needs to properly function. And so in order to maintain the integrity of that barrier for safety, but allow the brain to get access to everything that it needs to properly function.

There's this network of active transporters that the body has evolved over time to bring things these important nutrients from the blood and actively bring them into the brain. And that's such a critical concept because we can actually begin to exploit these endogenous pathways for drug delivery.

We can engineer platforms that bind to those receptors and hit you ride in, ended to highlight something that Todd briefly mentioned, the blood-brain barrier is so extensive. There are over 400 miles of vasculature within the BBB.

And so you can achieve this really uniform drug distribution and delivery across the CNS and into deep brain regions by leveraging this native biology that exists already. And something to highlight, Pete, is that when we often think about receptor-mediated transcytosis or that process of pitching a ride in and leveraging these native receptors, we often go to those pathways that are well studied in the field like transferrin receptor or Glut1 or CD98 but the brain needs so many different things to function.

There are many RMT pathways. And I would suggest that there are a number that the field has yet to figure out. And so what's really exciting about the time we're in now, is the concept of leveraging RMT for drug delivery to the brain is starting to be proven out. the different ways that you can go about doing it.

I think we're still discovering more and newer pathways in. So we're at this really neat state where this process has been proven out. And now we get to go see how many different ways we can go and leverage it.

Awesome. How do you see these delivery technologies or changing the success rate of neuroscience drug development?

Yes. So I think the delivery has historically been a problem. Todd mentioned you having to dose really high in order to get drugs where they need to go. I think one of the most recent examples you can point to for how transformative these approaches can be is actually [indiscernible] as an amyloid antibody that was tested on its own and didn't really achieve the clinical success that the field was hoping for. .

Now Roche have ended their TFR binding brain shuttle to that exact antibody, and it has now set the standard for what plaque reduction in amyloid clearance looks like, both in terms of safety with respect to RA the kinetics of plaque clearance as well as the total reduction. And so this was an antibody that has an active shuttling was not efficacious in the clinic and now is starting to set the bar for what amyloid therapeutics look like.

So I think it highlights how when you can lower the doses, you can get more drug into brain. We end up widening the therapeutic windows, and we're able to actually start to ask the question will these drugs be efficacious. There's not a lack of good therapeutic targets in the CNS.

Historically, it's been a lack of an ability to get the drugs that hit those targets there. And so with these brain delivery platforms, we're going to start to see much safer, more efficacious drugs because we're being able to deliver them to where they need to go. Todd...

Also add in a little bit that I think classic small molecules have traditionally only been a drug class that we could get effective delivery. And as we mentioned earlier, the that majority of those will be pet deliver because various targets can be challenged. The things you need to do to make something bring penetrant to make the other characteristics you want.

It might be somewhat mutually exclusive. And we have these other routes that we can use intrathecal or direct injection, but those can be difficult dosing for patients and health care systems or just not suitable fraud delivery.

So I think one of the things that we're hoping to see and that there's evidence already, is that we're able to access targets that are beyond the targets that can be typically achieved with small molecules, for example, or maybe even antibodies. And so that opens up a whole new class of targets that we can begin to interrogate.

I mean you just mentioned it's got neuroma and there, how they put it on to the shuttle suddenly changed success. But overall, do you think historical drug failure is were due to drug target and biology versus the delivery limitations and entry into the CNS.

So that's a good question. I think that my hedging answer to that is we don't know. And the reason is because we couldn't test -- the hypothesis weren't tested. We weren't getting good enough delivery to know whether we were accessing the right targets. So I think that over the past decade or a little more, we've seen these relative targets that Mohali mentioned be identified.

That's really been the key part of the genomics and genetics revolution I think we've seen in the periphery and in cancer, a lot of progress now that we can go after those. What we need to do now is test that in the CNS, and we need these delivery mechanisms to be able to test that.

All right. which disease areas of [indiscernible] are most likely to benefit from this shuttle technologies? And what's sort of the low-hanging fruit?

Yes. So I don't know, in neuro, I don't know if there is a little hanging fruit. I think -- but there are opportunities on some things like [ gantenerumab ] is a good example. You had a drug class these anti-amyloid that clearly can be efficacious and there's a clear test of if you improve delivery, can you improve efficacy and, in that case, even reduce the safety concerns.

So one area are things where we have tens of success can we rapidly test those to see if we can get even better success or greater therapeutic indices. I think others are in a neuro degeneration. We have a whole set of these genetically acidified targets. And those are some of the first places to check. And that's certainly something, as I mentioned, we see ourselves as a neurogenetics company, and that's why because the -- some of the biggest derisking on targets, I think, are the genetically validated targets.

Nature has already done the experiment for you in some ways to say that these genes and these targets are important for the disease. And so things that are genetically validated, I think, are going to be the equivalent of a low-hanging fruit. I think there are others with chronic diseases where if -- for something like a gene therapy, where you're on and done or a shuttle based approach where you can go intravenously and get the broad delivery, that's another place where the mode of delivery ends up being pretty important because some of these diseases, if you want to go on and get direct injection into the spinal column or into the brain and repeated way, those just aren't really going to be feasible.

So I think that there are opportunities there. Mohali, do you have any thoughts on this?

Yes. I think you highlighted a couple of real drivers there, right? One of them is up until a few years ago, these delivery technologies still had yet to bear out clinically. And so in order to not stack the risk too much, it's about taking therapies that had hints of success, whether it's the amyloid or what's seen a lot of interest is actually the lysosomal storage disorders where peripheral enzyme replacement therapy has been quite effective to treat the peripheral manifestations of diseases, and that has really been the proven ground for these delivery technologies.

Now what's exciting is with the approach relatively derisked now for brain delivery, we can start to go into some of these additional areas that Todd mentioned. The genetically validated targets that may have been intractable and asking the platform question and novel biology on the therapeutic target may have seemed like a bridge too far.

It's no longer the case because these delivery platforms have proven out. So I'm excited to see where we can go particularly in these new spaces with the genetically validated targets.

So one thing that I might just comment on is with how knockdown in particular, last year or 1.5 years ago, Biogen reported some very early but very, very promising data with their to knockdown ASO [indiscernible] delivered. It hits the TadmRNAwith an ASO if the data that we're expecting later this year, that data looks as positive as the preliminary readout suggested that it could be. That's a great validation for a knockdown approach, and then we're able to move very quickly in with our gene therapy. And so one and done with an intravenous delivery with our gene therapy there. So that's another example.

So there are a number of active transport technologies that are emerging to shuttle biologics across the blood-brain barrier. What are some of the key design principles that you believe will determine whether these platforms succeed?

Right. That sounds like a Mohali question.

Yes. There are a couple of things to think about, right? One of them is what receptors are you targeting? And I think that's one of the things I'll highlight about Voyager's approach is our unbiased screen to identify functionally validated receptors gives us some unique angles to ask the delivery question in terms of what can you target in order to achieve it.

But at the end of the day, for me, it's 3 big things. It's really about delivery to the brain broadly biodistribution and of course, safety. And what do I mean by those? So for delivery, it comes down to how much drug can you actually get into the brain where age to go? And what does that delivery profile look like?

So using some real examples, we're very familiar with what TFR can do. It can rapidly deliver drug to brain and then you see a fairly rapid clearance peripherally and in brain, and that's due to the expression of TFR peripherally and map binding and basically clearing out a lot of your TFR binding drug.

And so what that does is it can limit the extent of brain delivery over time. On the other hand, what we've shown by targeting ALPL is that we have some differentiated kinetics because that high clearance associated with peripheral binding is not there.

So binding to ALPL can achieve sustained brain uptake for weeks after dose. Now it's important to note that both profiles are really valuable but it's about having the optionality and building up different types of platforms that get you different delivery profiles.

And that's pretty linked to biodistribution as well, that second pillar that I think about, which -- when we think about technologies for their CNS delivery, sometimes it's easy to forget that a lot of these receptors are expressed peripherally and throughout the body as well.

And so how much expression outside of the BBB is there can actually have a huge impact on the duration of exposures and where your drug goes, just like we were talking about for TFR.

And you can even go deeper on that biodistribution question and say, okay, if this is a good target to deliver you to brain, where is this target expressed within the brain and how does that influence the kinetics and the distribution of your CNS penetrant drug once you've actually got it across the blood brain barrier.

And so that delivery and biodistribution angle, I think, dictate a lot of the ultimate efficacy in your drug and last and certainly not least, which is kind of co-mingled with those other 2 is safety. So safety is really tightly related to where your blood brain barrier target is expressed and certainly relative to biodistribution.

Where are you pushing your drug by adding this binding to it. And a lot of it comes down to on target. So for a given RMT target, what is its native function? And how are you engaging it -- are you doing something that disrupts the important physiology that's there naturally, the brain has evolved to express these receptors for a critical reason. It's on the brain vasculature because it's important.

So we don't want to be messing with the native function of those receptors. And then the other thing with respect to safety that we need to start thinking more about or continue to think more on is the co-expression of therapeutic targets and blood-brain barrier targets. Again, the blood-brain barrier targets are often expressed in a lot of peripheral tissues.

And we can generate novel biology for binding the RMT target with the shuttle and a therapeutic target a fab bound antibody, for example, and sometimes bringing those receptors close together can be a good thing and sometimes that can lead to some unwanted effects. And so thinking very carefully from a safety perspective about how we're engaging these receptors, not just at the blood brain barrier, but in concert with the overall therapeutic as one molecule is something we need to continue to really be focused on.

Awesome. I kind of ask a question or [indiscernible] not going to answer. Have you identified any receptors that sort of are a little bit more selective towards crossing the blood-brain barrier and let's say, have limited or no expression in [indiscernible]

So we disclosed ALPL as a receptor that we're building the first version of the neuro shuttle on, and we look forward to discussing some of the other receptors that are coming in soon.

On ALPL in particular, one of the reasons that we're excited about is we have this very differentiated PK profile where fatter we know goes up as pretty well, but it is rapidly cleared. ALPL we get more into the brain, and then we're able to maintain that much longer because we don't have this peripheral clearance. .

But we believe that's because ALPL is not expressed as broadly as transparent is. So there's an example where we think the different expression patterns are really driving important differences in how the receptor works.

That's great. All right. So I guess part of my question was, will these platforms sort of be a plug and play? Or will target an overall therapeutic approach and mobility impact the overall design of these candidates. In other words, even the need to explore multiple formats and it's less of a plug and play that we sort of alluded to the sensitivity of the design maybe. .

Yes. Maybe I'll take this, Todd, and then you got some stuff to add. so Ultimately, what we want to do by building platform technologies is to invest in the first therapeutic and hopefully make the subsequent ones a little bit more plug and play building on the derisked platform. I think the reality is that every therapeutic is going to require a few tweaks to it.

So having a toolbox within your platform of different flavors to match the platform to the therapeutic will likely have to be the case.

What I will say is that the first program through will derisk the overall approach of binding a particular receptor, so we can rapidly leverage that platform de-risking to have more confidence in subsequent programs in the pipelines we build on top of that.

And then within therapeutic modalities, I think Pete, you were alluding to this, it's probably going to be a little bit more plug and play. So for an algo delivery platform, for example, you work things out like the conjugation sites and chemistries and the affinities required.

You'll tweak a little bit when you move from oligo to oligo just to make sure that the safety and the exposures and the stabilities hold when you change in the actual oligo [indiscernible] but that will be more or less plug-and-play. You're not rebuilding the platform from the ground up each time.

Okay. So how should we be thinking about the relationship between the blood-brain barrier receptor sort of binding affinity and balance at the blood brain barrier and the sort of the efficacy of transcytosis into the brain.

Yes. So I mean, that's a great question because at its foundation, it highlights the importance of engaging blood-brain barrier receptors in an optimal way. It's not just enough to bind to a receptor. You have to do it in a way that's tailored to match the receptors native biology.

Remember, we're not looking to create any new biology with these platforms. we're looking to take advantage of a natural process that already exists without ideally altering it at all.

And so the short answer is that every receptor is going to have its own native biology, it's expression, it's trafficking, it's kinetics, what causes it to internalize. And so approaches are going to have to be empirically determined for every receptor.

And I'll give you 1 example. You just like hypothetical, if a receptor takes 10 minutes to move across the cells from the blood side to the brain side. You don't want to bind to it so tightly that it takes you an hour to fall off, for example, you want to match that affinity and more specifically, the kinetics of binding so that you're falling off in about 10 minutes when that receptor makes it to the other side.

And so these considerations are some of the most impactful design criteria when you're thinking about building a platform that determine how effectively these blood-brain barrier receptors can actually be exploited. But every receptor is going to be a little bit different, and it's about leveraging the native biology and understanding the native biology enough first to figure out how to leverage it.

Okay. I guess -- I mean you sort of again alluded to it, but like do different receptors, ALPL transpire into CD98 have sort of different optimal affinity windows based on the intrastrafpicin kinetics?

Absolutely. And I think you see that play out in some of the data that we've shown with the ALPL platform and that the field has shown on CD98 and TFR where -- just the kinetics of brain uptake alone give you a lot of information about the receptor turnover and kinetics of trafficking that you're exploiting and they're going to be very receptor specific.

So again, it just comes back to engaging a receptor in ways that Lee that's native trafficking is untouched as possible.

All right. How well does the affinity exposure relationship observed in rodents translate to nonhuman primates and then ultimately to humans.

Yes. So this is one of those questions that it's fun to get now as opposed to maybe 3 or 4 years ago because we're at a really exciting time where we are generating more and more clinical data with the TFR based approaches.

So we can actually start to answer the totality of your question, not just the preclinical side of it. And I think at a high level, it looks great for TFR. A couple of things that maybe I'll highlight a lot of times, we start in the mouse because that's how we can derisk some of the biology of new receptors and iterate quickly.

But the mouse has a notoriously leaky blood-brain barrier relative to higher order species like nonhuman primates and certainly humans. And so when we look at mouse data, there are much higher levels of passive drug in brain so in a lot of ways, we underestimate the need for and the value of these delivery platforms when all we're looking at is mouse data.

But it certainly becomes more clear when you pull it up into nonhuman primates the important sub and the value of active delivery, you get meaningful drug concentrations of brain. So as I mentioned, that relationship has scaled really well for TFR from mouse all the way to humans. And we've seen evidence from mouse to nonhuman primates as a field, not just for TFR, but for CD98 as well, and we're looking forward to generating some of that data on LPL.

And I'll point out that we can get additional insights for the mouse to nonhuman primates actually from the capsid world and from some of our own tracer capsids where that correlation is now held. We've seen from mouse to nonhuman primates for ALPL as far as our tracer capsids do.

So early days overall for drawing those relationships and those correlative but so far, what we see in mouse for the receptors that have been studied in nonhuman primates is fairly predictive and certainly, the nonhuman primate data to the clinical data relative to TFR and what's been published has held well and is pretty exciting because, again, to me, it proves this idea of receptor-mediated transcytosis not that it's a TFR specific thing, but that is this idea of leveraging native receptors more broadly.

And so it really opens the aperture for what you can go after and do.

All right. So how should we think about selection of isotype backbone and [indiscernible] function? Is this something that will be sort of 100% modular and plugging play?

Depends on how you design your platform from the start, a lot of these antibody fragment-based shuttles are done with that in mind where it is plug-and-play. The beauty of these fragments, whether they're fab or single domains or SCBs, is that you can append them to just about anything.

And when we're talking about therapeutic antibodies specifically, that shuttle moiety is fairly independent from the ICE that you're looking for or certainly Fc modifications if you're -- if you want to modulate and optimize Fc-gamma receptor binding and effector function, for example, or FcRn binding to confer differential clearance rates. So the shuttle platforms broadly can be thought of as plug and play to different antibody backbones.

All right. Is there a possibility of marrying this tax to extended half-life or not?

Yes. So I would clarify this tech and what you mean by that

[indiscernible]

Yes, broadly speaking -- and I'll explain why I wanted that clarification. So it's an intriguing idea to try to get better exposures in blood for your transport platform because ultimately, what did case brain delivery is how much you have in blood.

If it's not in blood and you don't saturate the uptake mechanism, there is no brain uptake. So the more you can keep around in blood the longer, the more brain uptake you have.

The challenge to reducing that to practice can come from the magnitude of clearance that some of these brain transport receptors are capable of. So transparent receptors clearance rates are so high because of how fast or how broadly it's expressed peripherally and how fast it recycles that applications of these half-life extending technologies that [ Bio 2, ] maybe threefold improvement in terminal half-life on a monoclonal antibody, can compete with the clearance of TFR.

But if you move to a more neutral or a receptor like ALPL where we don't see that type of accelerated or higher clearance peripherally, then it becomes a really intriguing idea because you're going from -- we've shown data out to 3 weeks now. So with TFR, if you're doubling 3 or 4 days of exposure, that's meaningful.

But if you're doubling weeks upon weeks of exposures with ALPL now, now it puts you in a whole different regime in terms of what you might be able to achieve for dosing. So the short answer to your question is, yes, you should be able to marry these. I think the more nuanced answer has to do with you've got to do it on a platform that doesn't have such high clearance in order to really see the value of doing it.

And that's one of the things we're excited to look at for ALPL.

Okay. So what are the key safety risks regulators are sort of watching [indiscernible] subtle technologies? Is it risk due to target receptor expression patterns. Is it design of the Fc region and effective function? Or is it specific to the target, a amyloid beta or a combination?

It's all of the above. I mean, we're still early days in these active transporters. And again, sometimes we think about these things in pieces, we have a blood-brain barrier transporter, but that's expressed everywhere else. We have a therapeutic and sometimes that's expressed outside the CNS.

When you put them together, and it's no longer a therapeutic in a shuttle. It's just multi functional molecule that can do a lot of different things. So I think all of the things you touched on are going to be critical aspects of safety as we continue to translate these obviously, top of mind for the field and the agencies right now are the anemia risks seen with TFR.

A lot of it is going to continue to be the acute IRRs that could potentially come from binding the receptor particularly if you have a factor function on these molecules and triggering an immune response.

We have to be careful about that. And that's the acute over time under chronic settings, it's more about how are you impacting that native receptor that you're trying to exploit for brain delivery. What's the normal function? Are you altering it? Does that lead to any detrimental effects and that's part of the anemia for TFR.

And I'll highlight what I kind of said earlier as well I think one of the unique things about these shuttled molecules is that they're multi specific. And so you can end up getting new biology and new pharmacology that comes from bridging whatever your therapeutic is supposed to do with your shuttle technology and so if we're binding a blood-brain barrier receptor and a therapeutic target, not at the blood-brain barrier, what's happening?

Are you creating some unwanted effect and so all of these things are top of mind, certainly as we engineer and characterize new platforms and certainly when we start to translate them clinically.

Maybe I'll just add a couple of things as well. Just as we look at transfer and ALPL so Mohali's point about you've got in some ways almost 2 different on-target potential safety concerns that you have to consider. There's the on target for the shovel aspect and then there's the on target for the therapeutic that Mohali mentioned.

And if you think about transparent, the anemia, et cetera, for something like ALPL we know that we don't see evidence of any issues we don't expect to because we don't express on the cell type that drives that transferring. And we have ALPL expression and other things in bone, et cetera. So we know where to look, and we're doing all the right experiments to look at all that.

But then on the target side of things, the benefit, hopefully, is that you're delivering more of your therapeutic to the places you want to deliver as well as maybe to some other places that you don't necessarily need to deliver. In the case of something like gantenerumab, where suddenly you're delivering parts that actually reduced the [indiscernible] risk associated with anti-amyloid, which was a bit of a surprise, but a welcome one in that context. So we have these different things to look for and both the shuttle based on target the pay loan based on target and then of course, the off targets associated with all those.

All right. That's why I had a series of questions, but I want to make sure that we get to Voyager's candidate. Which of these sort of receptors do you see the most and least promising and why?

When you say which of these receptors, so transparent versus ALPL or?

All of them, like out of those, which ones do you think -- I mean, obviously, we know that transparent -- you guys have been successful what's left we hear that other groups are targeting, do you think has the least probability of success or perhaps some toxicity known versus a higher probability of actually allowing it to be leveraged.

So I'll make -- I'll say a couple of things maybe on the little bit on capsid side, too, and then ask Mohali to jump in with his thoughts. On one of the things that we're actually really excited about, we've talked -- we're talking a lot about ALPL on our platform side. But our capsid work which is what led to this.

It was particularly we find interesting because we screen millions of different variants and identified capsid across the blood-brain barrier without knowing what's driving it. It was an empirical approach. What we've been able to do is to take that and then identify the receptors responsible for delivery across the blood-brain barrier. ALPL is the first one, but we have multiple other receptors now that we know can deliver these large -- very, very large macro molecules that are [indiscernible] across the blood-brain barrier.

So now we have a diverse set of receptors that we can then explore for delivering antibodies, all of those, et cetera through. Now ALPL is the first one through and that was, in many ways, a test case. Could we apply an AAV receptor, BDP receptor for other things. And the data that we're showing we're generating say that we can. So that makes us very excited for the others.

The other thing that's really interesting from a Voyager platform perspective is that these receptors we're identifying are not anything we would have expected to find. So these empirically identified receptors are not things that we would have chosen or we think anybody else would necessarily have chosen, given the typical things that people look for.

And so we're really excited about those opportunities. So in a way, what I'm saying is for these novel things that we now have in our toolbox, I don't know the answer to your question because we need to do more work to be able to look at it. What I do know is that if we take ALPL is the first 1 through with Voyager specific set, we're seeing very differentiated kinetics, very differentiated PK profile that gives us what we think a good opportunity.

We don't think any single receptor is going to be perfect for all diseases, and so we're going to need this toolbox. Mohali, do you have any thoughts on kind of the existing set that's out there?

I'll just put a finer point on what you just said because I think that's worth repeating. There is -- I don't think that there's 1 or 2 or maybe even 3 receptors that are ideal. When we think about the opportunity that's in front of us, it's about expanding the scope of what we define as neuro therapeutics by thinking about all the different types of drugs that we want to deliver all the different indications.

And when you start to do that, the number of different types of delivery profiles and capabilities becomes pretty big. And it's pretty inconceivable to think that TFR or TFR and another receptor is going to solve all those problems in the most efficient and optimal way.

So Pete, it's really about figuring out how many of these receptors can actually mediate meaningful drug delivery to brain, what are those properties in terms of the kinetics of distributions, all the things we talked about before.

And how do those uniquely enable the types of drugs we want to get across. So I don't necessarily view them as good or bad receptors. I view them as what are they uniquely good at doing? And how many of those can we stack up to enable all the different types of neuro therapeutics that we want to go after for patients.

Got it . All right. You briefly touched on this Todd. But anything else you want to add in terms of the discovery process and what were sort of the key steps and insights that led you to focus on ALPL as a receptor of interest?

So it was what I mentioned before, that empirical approach, we identified and have identified multiple capsid families that use different receptors. And so there will be multiple capsids quite often the targeted and these captions are related. I mentioned that we know by definition, if it gets an AAV across that it can get a large macromolecule across.

Of course, with AAV, essentially, what we're doing is we're adding a function, and we've shown this in our studies with ALPL and presented this that most of the activities of the AAV capsid already are left intact. So we know that we can deliver an AAV across the cobrand barrier and then other aspects, the other intrinsic properties is that AAV capsid simply still apply.

So it can get into cells and do all the kind of complicated biology that the capsid needs to be able to do to deliver its vector genome into a cell to get it into the nucleus, it en coats, it forms an episome and begins to express different receptors and may be expressed.

Well, they're expressed in the vasculature they would have to be to deliver across the blood-brain barrier, but they can be expressed in different ways in different cell types on the other side. And so what you can see is the opportunity to have different kinds of profiles where a particular capsid -- sorry, a particular receptor set might give you delivery into neurons once it crosses might to onto delivery into both astrocytes and neurons.

And they give you delivery into other tissues of interest peripherally. So you might want something that gets into the brain and muscle for example. Transfer might be an example, assuming it has the other kinetics and PK characteristics, good for whatever disease you want to go after, but there might be other diseases where you want different sort of subsets of tissues that you want to target as well.

And the exciting thing about the receptor discovery that's really become an engine for us is that we get these novel receptors that have these different profiles based on their capsids that we wouldn't have ever predicted in the first place.

What's the natural function of ALPL receptor and what feature of that biology make it sort of well suited for targeting?

So that's an interesting question. I don't know that a specific biology does. Maybe Mohali has some thoughts on that, too. It's a phosphatase. So it's what we call it a GPI-anchored protein, meaning there's a particular attachment to the membrane that can be cleaned and it could be released into the blood stream.

It's interesting because as you look at the capsid side of things, there are multiple GPI-anchored proteins that have been involved in getting captures across the blood-brain barrier but we now know that transfer and sort of the reverse direction can be used to get casted across.

It started as a shuttle approach, and now we know we can get assets across as well, and that is not a GPI inc protein. And so there's a diversity there. The specific phosphatase biology of it is probably not what's important, I don't believe. I think its involvement in that transcytosis that trafficking across the blood-brain barrier is what's important about it?

And then why this particular protein is involved in that, I think we don't know. And it's, again, what we're learning is that there are these multiple receptors that we wouldn't have hypothesized to be important to turn out to be.

All right. Is ALTL, do you view it as mechanistically similar to TFR or CD98 in some transcytosis or are there just meaningful differences that you should highlight?

Yes. Go ahead, Mohali.

Yes. There are probably differences. But to Todd's point, we still don't really understand for ALPL and I would argue for TFR and even C9, Glut1, some of the other receptors, the actual mechanism of transcytosis once he gets within the cell, I think what's worth highlighting is that in that set alone DR is a single-pass transmembrane iron trafficker, CD98 heavy chain is actually a shapalone for the light [indiscernible] transporters, ALPL as a GPI linked, postal is a multi-pass glucose transporter. So all of these very phenotypically and functionally diverse receptors have shown the ability to be brain transporter.

So just looking at the diversity of inherent native biology, I would say there's a mechanistic difference there. And it speaks to the diversity of things the brain needs and just the opportunity to go using approaches like Tracer figure out what else we can leverage and exploit to get these brain uptakes.

But there are certainly some differences we just need to do a little bit more work to mechanistically understand what they are and how these things work.

So how does engaging a GPI-anchored receptor changed the to traffic in pathway compared with like classical transmembrane recipes like TFR.

I'll go back to, we probably don't know a lot of the answer to that yet. Todd mentioned that a lot of the early work in the AAV field for brain delivery. Certainly, the work in mouse early for things like Live that never actually translate into humans because we don't have that. The early AAV work ALPL included, highlighted a few different GPI.

So AP is not uniquely the GPI that's been shown to confer brain delivery. So there's certainly a class property for these types of anchored proteins that what makes them special in terms of being able to transport into the brain. I mean, unless Todd, you have other ideas, I think it's still something that we need to figure out and mechanistically is poorly understood.

Yes. [indiscernible] I think, is sadly a black box to the deal right now. And it's interesting, you mentioned I mean your question Pete was around how do these change transcytosis I don't -- we don't know that they do and Mohali pointed out that the goal would be back to, right? We want to piggyback but not alter in a perfect scenario.

Of course, we knew that doing anything can procure things to some degree. We want to minimize that as much as possible. But right now, I think we still have a lot to learn.

Right. I'm not sure if this is a black box as well, but like when you do have GPI-anchored receptors like ALPL are there any advantages in terms of avoiding lysosomal degradation.

I think right now, we don't know the answer to that. I think we're seeing we can most likely and Mohali, correct me if you see it differently. But I think we still end up in the lysosome. And in fact, lysosomal based degradation can be -- you can use that to your advantage in some situations.

If you want to release your payload or things of that nature. So I think there are both opportunities and challenges associated with getting into and through the lysosome.

Yes. I would just highlight that I would caution against a binary view and not that, that's what we're discussing right now, but these trafficking pathways as much of a black box as they are.

They're very complex. And it's not that each receptor has a singular pathway that it takes. There's some amount that gets recycled back to the cell surface -- there's some amount that goes across the cell in transcytosis, and there is some amount that will go naturally to the lysosome just to regulate the kinetics of native receptor expression.

And so it's about how much of your receptor goes to each one of those different pathways that dictates the amount of drug delivery to brain. And we just need to do more work to understand how the GPIs are doing it relative to other things like the single-pass membrane receptors to TFR.

I'll comment just there as part of an earlier question that you've got this particular slide up One of the things about ALPL and our ability to find and what we saw coming out of the capsid screens is as part of our caps and screens, because of what Mohali mentioned, where the first brain penetrant capsids were identified in mice, but they only worked in mice, they didn't translate into nonhuman primates.

And in fact, they didn't even translate broadly throughout all strains of mice and so we've built in the need to identify and screen for things that were cross DCs and cross pics across nonhuman primates, different nonhuman primate species and when possible into rodents.

And so what we identified, we identified caps that were able to do so. And it turns out that it's pretty important. It's important because once we started discovering the receptors, we understood why and it made sense. We were binding parts of the receptor that were conserved between species -- the ALPL acids were across PCs, again, in mice, multiple nonhuman primate species.

And once we knew the receptor, we could test the human ortholog of the receptor and show that we were able to also by the human form that in invitro studies, mediated transcytosis in vitro with the human as well as the nonhuman primate mouse.

But also can give us a leg up on knowing where and what to target on the shuttle side. So it gives us a lot of information and ability to move the Shuttle based platform forward pretty quickly.

All right. So from a safety consideration, what are the theoretical safety concerns for ALPL engagement? Any potential safety signals from human genetics or loss of function.

So we mentioned this a bit earlier, but ALPL is important, has an important role in mineralization skeletal and implement our [indiscernible] and folks that carry mutations in their ALPL gene. If it gets around 30% of lower activity, overall, that can result in this hyper mineralization and some complications.

And so that gives us something to look for. We know that the -- when you look at the genetics, there are there are data out there where you can evaluate kind of the risk. So if you look at databases with Nomad and others, they can give you an evaluation of the risk of loss of function and based on the carriers in the population.

And when you do that, transparent comes up is very highly concerning. And we know that that's true. The transfer and humans have a pretty low tolerance for loss of function in the transfer ALPL can tolerate much more loss of function, but it's still something that we need to take a look at. And so we're doing those experiments and evaluating that to look in the bone, in particular for any issues there.

Alright. Next slide. One of the attractive features of the neurocog platforms is apparent applicability to different payloads, different payroll types. How flexible is the system when paired with different therapeutic cargoes such as enzymes, advisor oligos?

So we're getting started with this. And Mohali, maybe you can answer that.

Yes. So what we've shared to date is the delivery of antibodies using these shuttles, and it's looking quite differentiated. I think we've mentioned it a couple of times now with its exposure profiles relative to what can be achieved with existing platforms, say, like we're targeting TFR, and that's something we're really excited about.

We look forward to sharing some more data in the future as we continue to see how well ALPL pairs with some of these other therapeutic modalities that are top of mind for all of us.

All right. So next slide. In the preclinical studies, you just mentioned now and before different PK sort of became you demonstrate sustained brand exposure for ALPL settled last in about 3 weeks. Do you believe that sustained brand exposure is primarily driven by improved transcytosis or by little clearance once the antibody reaches the brain.

Yes. This is a good question because I think the field has learned that there are differences when all you're doing is looking at concentration. Certainly, I think the lessons out of the CD98 data, where there is a lot of retention in brain as opposed to continual active uptake -- so this has been a question on top of mind for us.

And we believe that this extended exposure profile that we're seeing both in blood and brain is not only differentiated from TFR but is a direct result of having this less clearance from ALPL periphery. And what this allows us to do is keep those blood concentrations higher for longer. And that's critically important because in order to get into the brain, you need concentrations in blood that allow you to saturate in our case, ALPL binding and that uptake mechanism at the blood-brain barrier.

So this is what happens with the neuro shuttle and the data that you have on the slide here is that the exposures are high enough peripherally that we're taking advantage of active uptake and what we're showing here for at least 3 weeks post dose.

And we've run the studies out for 3 weeks here, but are looking forward to seeing just how far can we continue to take advantage of this active uptake? Again, it comes back to that preservation of peripheral exposure. So this looks to us to be continual uptake over time as opposed to retention and brain in the acute week or so. Right?

Do you expect a linear relationship between systemic dose and brain exposure? Or does sort of transport saturate at higher concentrations?

Yes. I mean, just theoretically, every receptor is going to have a saturating amount that you can use to get in. It's expressed at a certain level, and it turns over at a certain frequency. And those 2 things together will dictate how much drug you can get into brain by binding it.

So I would expect a linear relationship up into that point of saturation. I think what we're seeing here for the data on ALPL is certainly saturating. And then as you start to dose down and get below that saturation threshold, I would expect a linear dose.

Net in preclinical studies, are you seeing differences in regional brain distribution following ALPL mediated delivery?

So one of the things that I'll comment back on that we touched on briefly before is these data, along with what we see with TFR and other targets, I think, highlight the value of leveraging receptors and RM at the blood-brain barrier because that 400 miles of brain vasculature that makes up the blood-brain barrier gives you access as long as your receptor expression profile is pretty uniform, which ALPL seems to be to all of the different brain regions across the CNS.

And access to the deeper brain regions in particular that are really hard to get to if you're not leveraging an active process. So we don't really see a lot of regional distribution, and I think it's tied back to this ability to leverage the totality of the blood-brain barrier for this type of transport.

Are there any cells that neuro federal targets within the CNS? And is there any way to sort of enrich in certain cell types versus just published say you want to in ASL?

Yes, it's a good question, and this is a theoretical one about what do you want your shuttle to do and how active is it once you get into the brain? We talked about that a little earlier. So this data is showing actually binding to and colocalization with neurons and cell uptake in neurons. So we were a little bit surprised at from the start because there's not reported to be a lot of ALT expression on neurons.

This data and the histology is repeated out enough that we're very confident in the conclusion that we're associated with neurons in this case and seeing uptake. But I think it just comes down to what you want your platform to do or you're seeing broad delivery and the ability in this case to associate with the cells in the prince.

All right. you briefly touched on this a little bit earlier in terms of the way that you've validated across species. But how confident are you that this cross-species conservation will translate to consistent brain barrier transport efficacy instruments.

Yes. So the biology of the receptor appears to be fairly conserved both in terms of function as well as expression from these mouth all the way to human. So I think the confidence is pretty high that what we're seeing in terms of delivery here will be recapitulated as we move it to Sin, and we look forward to doing those experiments in nonhuman primates, which will be a big I think, confidence boost and derisk on the way to human.

And I'll just add to that a second bet because it's hard to imagine better data packages to suggest that kind of translatability. We know what the receptor is. We know where we find, we can show across these Cs that don't work. So I think we're about as betas translatable as it can be without just testing it in humans.

All right. Next slide. The data suggests that ALPL shuttled antibodies achieved plaque engagement comparable to transparent settled antibodies after a single IV dose looking at the images, both the shuttle seems -- or appears to achieve broad brain distribution.

The ALPL ourselves show continued uptake between day 3 and '14. What does that sort of tell us about the pharmacokinetics of this receptor transport and the durability of receptor engagement.

Yes. So I think this speaks to something that we were talking about a couple of questions ago, Pete, which was that are we just doing receptor uptake in retention in brain? Or is this actually active uptake over the entire PK profiles that we show I think this data, in particular, is a really good 1 to point to active uptake over those entire 3 weeks in this case that we were showing, where we do see some active transport on the acute the rate time point.

But really, the value is the area under the curve of drug exposure or the AUC here. And these data were generated 2 weeks after dose, what you have on the slide. I think what's really exciting is to think about, and these are experiments that we're looking forward to doing. But if we're already at TFR's level 2 weeks after dosing. And we know that we have weeks to go in terms of sustained brain exposures and uptake post single dose.

What does this start to look like after a month or even 2 months after dosing. That's where you can start to really take advantage of those extended exposure profiles to drive target engagement and ultimately, therapeutic efficacy from a single dose that we just can't with a TFR-based approach.

So did you see any differences in regional penetration or cellular localization LP versus the TFR approaches?

Certainly not regional distribution. I think TFR is hard because and there's a lot of catabolism and cell uptake once it gets into the brain. But certainly, in this model of immuno decoration, we don't really see any differences in where you can access the plaques that you decorate from a spatial perspective from the 2 platforms?

Got it. So I guess a little bit of speculation or a question of like, is it correct to say there's gradual accumulation in the brain. And if so, could this lead to an improved sort of safety profile if you're -- what's the target amyloid beta, say, lower rates of REA?

So definitively, this data suggests that there is a slower immuno decoration of plaques over time. Now by 2 weeks, we're at what TFR can do acutely. So we are achieving similar levels and hope to be able to show more. But the relationship to ARIA, I think is one that's still a little bit of a open-ended question in the field as to what is actually causing it?

And how are the results Todd mentioned trontinumab lack of ARIA, a reduction of ARIA was a little bit of a surprise to the field. So without having a much clearer understanding of the mechanism of ARIA and what's driving its reduction with TFR targeting -- it's just pure speculation at this point as to whether other approaches, how that's going to translate out.

Next slide. So in certain diseases, such as Alzheimer's, ALPL expression appears to be elevated. To what extent could higher LTO levels in Alzheimer's allow for like lower effective doses or improved tolerability versus targeting another receptor, again, probably speculation, but we're likely to speculate.

Well, Todd?

I mean I'll say just a few words. So we've been looking at this quite a bit as we think about our capsid programs that are moving forward as well as the shuttle stuff. And then the changes that have been reported, they're not huge. They're not massive changes. We know that different [indiscernible] set slightly different levels of ALPL expression. We can show kind of a consistent level of delivery through them.

When we look at different ages of monkeys, we can show a pretty consistent level of delivery. And so we don't see that as necessarily a problem because we know that we can get into younger animals quite well.

And if we look, say, a mice with some amount of increase maybe 1.5 to twofold levels of difference. But overall, we don't think it's going to be a challenge.

There might be a little opportunity there that you mentioned, Pete. But overall, I think it's just more of a good thing that we're able to predict -- we think we're going to be able to predict what doses we're going to need to go into humans with and be able to trust that.

Okay. Two more questions, quick ones, I promise. What would be the next key milestone or what are the next set of key milestones for the neuro shuttle platform over the next 2 years? And when can we expect to hear additional receptor candidates.

So one of the things that we hope to be sharing more and more data as we continue. So things like nonhuman primate data. We mentioned that we had a program, but we haven't disclosed what that program is.

And so a milestone for us would be to share the program and the status of that program. and really building the key data sets that we are in the process of doing and sharing those it forms like this and at conferences.

Have you shared when we should expect to hear about the first candidate?

No.

Okay. I'm impressed. All right. So how should we view the neuro shareholder program in terms of potential BD activity -- are you thinking about companies bringing assets to you and sort of coupling to technology? Or are you thinking about licensing now specific candidates? How do you be thinking about this platform and BD activity?

So Pete, that's a great question. And I think we can point to what we've done on the capsid side as our model for this because we've had -- we have examples, I think, of most, if not all, of what you just described in the case side.

So we've got partnerships with Novartis with Neurocrine with [ Alexion on Macassa. ] We have programs where we're collaborating directly with a partner like we're working on the programs together. And in a sense, there's a payload and a delivery mechanism or a delivery capsid is very similar. And that's enabled us to bring in over $400 million of non-diluted revenue over the past 4 or 5 years.

So we've been pretty successful with that on the [indiscernible] And I think we look to be doing the same sorts of things. So with Novartis, they licensed our capsids for their SMA program. They have [indiscernible] already in the clinic. So they're looking at it for perhaps follow-ons for that.

And in that case, that's just a license where they're taking the capsid and doing their own payload work. We have Honeykons program at Novirus,wewe're working closely together. We've got the FA program moving into the clinic with Neurocrine, where we've collaborated on that.

So I really think our CEO likes to say we're open for business in all reasonable discussions. But we're hoping to do all of those things much as we've done with the caid platform as the narrow shuttle matures.

All right. Any closing remarks I'd like to make or highlight something?

I think that just the excitement of this around this, the novelty of the receptors that we're finding and the first 1 through showing this very differentiated PK profile is really exciting on the neuro shuttle side. On the capsid side, we'll be seeing what those do in the clinic this year, both on FA and Town knockdown.

We have these 2 programs on tau, on gene therapy and 1 on an antibody that we'll be making substantial progress in hitting inflection points this year. And so really, we've got a lot going on.

And I think in about a month or so, maybe we've got a deep dive with you, Pete specifically on the [indiscernible] will be exciting to talk about.

We'll be excited. I'm looking forward to seeing some proof of concept human data for the capsid. Thank you very much, Todd. Thank you very much, Mohalia. I appreciate your time, and thank you to the audience for allowing me to keep you wait.

Thanks, Pete.

Great. Thanks very much. It's my pleasure to be moderating this chat with the CEO of Voyager Therapeutics, Al Sandrock, who sure many folks know well from his current role and famous roles as prior. Al, maybe we can get into it and talk more about Voyager and some of the key events this year for you guys in the broader neuro space. If you want to just give a quick snapshot of 2025 as a year for Voyager and the key things that people should be focused on, and then we'll do more specifics?

Yes. So first of all, we have -- we've been calling it the year of tau. We have 2 assets directed against tau. We have -- 1 is an antibody, a C-terminal antibody that we expect to get tau PET imaging data by the end of the year in a multiple ascending dose study. And then the second is the gene therapy tau knockdown asset, very much akin to BIIB080 which, by the way, has a pretty important readout coming up midyear time frame.

Second sort of pillar of value would be that we get -- this is the first year that we put our capsids, our newly discovered BBB penetrant capsids into the clinic. And we have 2 assets doing that. One is the tau knock down gene therapy, I just mentioned, but the other 1 is a neurocrine partnered program for Friedreich's ataxia. So we should be getting set up, if you will, this year for getting a proof of concept that our capsids can work and produce gene expression broadly in the brain.

And the third is that we plan to show more data on our shuttle platform that we're developing which is kind of an outgrowth of our capsid discovery platform. So 3 important pillars, if you will, of potential inflection points this year.

Yes. Okay. Great. All right. Well, let's start off with the year of tau. When you think about the scientific evidence behind tau versus a beta, maybe 2 questions. One, can you sort of help contrast for people where each plays a role in the driver of disease? And then second, like how clear is it that tau is truly a disease driver and not an innocent bystander?

Yes. So that's a very important question. So first of all, if you look at human genetics, it turns out that it's really hard to implicate tau based on human genetics for Alzheimer's. In fact, we do know, of course, that mutations in tau can cause neurodegeneration, but at least to diseases like frontal temporal dementia, for example. So the genetics would not necessarily imply that tau is important. But I would look at a lot of other data, including human data, in particular in, for example, in the South American cohort, the PSEN1 mutants. So over 1,000 of them in Colombia. And if you look at those patients, they all get demented roughly in their early 40s, and they develop a lot of amyloid accumulation and then they get tau progression. But there were a few outliers, people who did not get demented in the early 40s, even though they carried this highly penetrant mutation. And when you look at those patients, it looks -- they don't get demented until they're 70s. It turns out that they have a brain full of amyloid, but they didn't get the normal progression of tau pathology, which strongly implicates that the real cause of dementia is actually not amyloid, but it's tau. So a lot of people say, tau is better correlated with cognitive decline. And I think those are clear cut examples of that.

And so I believe that -- so when you look at natural history studies, whether it's in sporadic Alzheimer's disease or familial Alzheimer's disease, the first abnormalities are in the A beta pathways. You get abnormalities in A beta, in the brain, include biomarkers. And then later on, you get tau accumulating and spreading in the brain. And the staging of Alzheimer's is actually based on where tau has spread to. So the back-end brock staging is based on spreading a pathological tau. And it's a very characteristic spreading pattern, follows a very similar course from patient to patient. And my belief is that amyloid is necessary to trigger that spread of tau progression, the spread of pathological tau in the brain. And that -- in fact, getting a little bit of misfolded tau in a particular part of the temporal lobe called the rhinal cortex is actually part of normal aging. So the initial misfolding and hyperphosphorylation if you will, of tau is actually not pathologic. It's part of normal aging, but the spreading outside of that region into the other parts of the brain is what's actually abnormal and what causes the progression of disability -- of dementia in Alzheimer's disease.

Yes. Okay. That's a great overview, Al. So I guess in the context of that, right, the BIIB08 data this year is going to be a big catalyst for the space, especially for your gene therapy program. Do we have anything to look to that can kind of give us a guide on how much we might need to lower tau for clinical benefit?

Well, that's 1 of the things we need to learn more. In the case of the amyloid treatments, we had -- there was a lot of sort of trial and error, if you will. The initial anti-amyloid antibodies did not show a very significant effect on the cognitive endpoints. And that's -- and so we had to learn that epitope mattered, that the stage of disease mattered, that it was important to screen to make sure patients actually had Alzheimer's and actually had amyloid, et cetera, et cetera. But it took a lot of early failures and eventual successes to learn how much amyloid reduction you need to get a clinically significant effect and it turned out to -- there had to be a substantial amount of lowering. And so we're in the early stages of tau now. We're having failures. And basically, the antibodies or the treatments that actually didn't lower the -- or it didn't affect the spreading of tau. That's not very helpful, right? So we know the epitopes that led to those failures. So we're learning about which epitopes matter and which don't matter. But what we don't have enough of is examples of drugs that help -- that actually have effects on tau spreading and to know what the relationship needs to be between how much tau lowering or how much blockade of tau spread, how much is necessary to produce that cognitive outcome that we desire.

Yes. Okay. Very interesting. For your siRNA gene therapy and then we'll talk about your antibody, but maybe just talk about your confidence that with this gene therapy, you can get robust knockdown that's in the 60%, 70%, 80% range in the right areas to bring that matter to Alzheimer's?

Yes. So we use these novel blood-brain barrier penetrant capsids, precisely because we get broad brain distribution of our gene therapy. And I think that's what you need. The tau is spreading from 1 cortical region to the other. So the key thing to hone in on is what are all the cortical regions that the gene therapy can get to. And how much does it lower the expression of tau in those regions. And we've looked at hippocampus, central rhinal cortex, temporal cortex, frontal cortex. Essentially, all the cortical regions get affected roughly similarly in the sort of 50% to 75% range. And that's very similar to what you get with BIIB08. So we're kind of trying to replicate what BIIB08 does except for the onetime IV gene therapy where the siRNA is actually produced by the cells in the brain.

And from a development perspective, so let's say the BIIB08 data are positive. How do you think about the development path here? And we've obviously -- and we might be in a more fluid situation with the FDA and leadership over the next few years, so we'll see how it goes. But for right now, right, it feels like we're in a -- maybe a more stringent FDA environment with gene therapy, it's hard to say. So what's your thought on the development path? And kind of the safety database or safety evidence you might need to get a product like this for market -- to market for a non-orphan disease?

Yes. So we've actually had couple of touch points with FDA on this tau knockdown gene therapy program. We had a pre-IND meeting about a year ago. And then we asked for and received a Type C meeting more recently. Because we wanted to get their latest thinking on how to do the studies in the safest possible way. Any other learnings that -- because FDA, they know everything that's going on in the U.S. They can't necessarily tell everybody everything that they've learned. But I think when you go with the program, they share a very important information and so we actually didn't have to, but we decided we would have another Type C meeting. And I can say that we're having -- we're not having any difficulty interacting with the FDA, and we're getting a lot of really good interactions -- helpful interactions, I would say, with FDA.

So with that as a backdrop, I'd say, look, our first step is to see if we can lower tau in the brain. And again, we're going to rely on tau PET imaging primarily. And here, as opposed to blocking the spread of pathological tau, we're going to be asking to see whether or not we can reduce from baseline of pathological to, which is what BIIB080 showed in their Phase I trial. That's a pretty striking result that you get a reduction from baseline just by blocking the synthesis of new tau, which suggests that the parent helical filaments is or pathological tau, it's not like -- it's in some sort of dynamic equilibrium because if you block the production of tau, you actually remove it seems the pathological tau, which is pretty striking.

Yes, absolutely. Good. Well, let's talk about the antibody now. So we -- I think the oversimplified negative case on the antibody approach is that all these antibodies try to stop the spread of exosome or tau, but the vast majority of it is inside the cell. But you were alluding to kind of different binding domains, different properties, these antibodies. So what's the case for why you think your antibody could actually show a change on tau PET where others have failed?

So first of all, we did see a hint of 1 of the antibodies actually working. So the terminal antibodies both failed, the Biogen one and the Lilly one, but they didn't do anything on tau PET imaging. But the Bepranemab, the UCB antibody did affect the spread of pathological tau. So for the first time, an antibody was able to do it, that was a mid-domain not a terminal.

Now, so we had hundreds of antibodies to choose from. And at Voyager, we decided to focus on 2 things. One, we wanted to get antibodies that were specific for pathological forms of tau, because the Priam-like hypothesis, if you will, of how tau spreads requires that there's a pathological form of tau that gets secreted that it's in -- and hopefully, it's in the extracellular space accessible to the antibody and that, that pathological form of tau gets into the neighboring cell and in a template-driven manner, usurps the normal tau essentially informs pathological tau that neighboring cell. So we wanted to catch it while it's moving from 1 cell to the other. And so we said a, we want something that's specific for pathological forms of tau. By the way, in the case of anti-amyloid, that turned out to be really important, that only the antibodies that bind the pathological forms of amyloid actually work. The ones that don't do that don't work.

The second was that we relied on this animal model, where it's a mouse that expresses human tau, and we inject Alzheimer's brain material into the mouse. And we look for the spread in the brain of the mouse. And we look for the antibodies the most robustly, that the antibody, the most robustly blocks that spread and most reproducibly.

Now we could have chosen a mid-domain antibody ourselves. We had 1 in the mid-domain that was pathologic tow specific, but we didn't choose that. We could have chosen 1 in MTBR. But -- and by the way, Interestingly, none of the end terminal specific antibodies that we had blocked the spread. So that animal model correctly predicted the failure of the anterminal antibodies, which I thought was pretty interesting. It actually also correctly predicted that Bepranemab would block the spread somewhat. But ours was better. And so we relied empirically on this animal model because there's really no other way that we thought where you could choose among the handful or so of pathologic specific anti-tau antibodies.

Right. Okay. So you have your MAD data coming up later this year, correct?

That's right. .

So what do you think is a realistic goal for what you could see on tau PET?

So what we're hoping to see is an effect that's better than Bepranemab because Bepranemab, by the way, not only did a block to spread of tau by tau PET imaging, it actually had an effect on ADAS COG. It was a prespecified secondary endpoint, and it was not a subgroup analysis. So it actually did show some evidence of clinical efficacy. The problem is it failed on CDR sum of boxes, which was the primary endpoint. So I had mixed results on cognitive or cognitive/functional endpoints clinical outcome measures. And we know that CDR is what FDA is going to want to see in a pivotal trial, right? So what we hope to see is that we have a bigger effect on the spread of pathological tau by tau PET imaging than Bepranemab had and therefore, have a more clear-cut effect on clinical outcomes.

Of course, we want our studies too small to really evaluate clinical outcome measures. But we're hoping that if we have a bigger effect on impeding the spread of pathological tau that we will eventually have a bigger effect on the clinical outcome measures that are required for approval.

When in the disease, if you're trying to stop the spread, when in the disease do you have to intervene? Do you have to intervene even earlier than you might within ASO, which seems to be blocking the production and clearing intracellular or is that the wrong way to think about it?

No, I don't think that's the wrong way necessarily. So -- but as I mentioned, by the time you have even mild cognitive impairment, you've actually reached the maximum of amyloid burden in the brain, ironically. Even though it's very -- still very early, amyloid is maxed out by the time you're even at MCI. Tau is different. Tau is still progressing and hasn't quite reached the maximum amount of pathological accumulation or spread in the brain, even at the MCI stage. So I do think that the -- and we've done trials now in MCI and early mild patients. I think that's a pretty good population to target for tau. In other words, you don't have to go as early as you might have to with anti-amyloid. Now we'll learn later this -- maybe in a year or so from other studies, Lilly and Biogen, whether or not earlier anti-amyloid treatment, even before you have mild cognitive impairment, could actually be more effective. That's a pretty important study. My prediction is that it will be more effective because there it hasn't quite maxed out yet. But the BIIB080 or the knockdown treatments, to your point, may not need to go as early as MCI. So even if you progressed into the mild to moderate dementia state, maybe even moderate, I don't know, but if you can remove the pathological tau, it has a chance of helping those patients.

Yes. Okay. Great. So maybe take a step back, Al, and just talk a little bit about like the novel capsid platform, right? Because we can talk about this through the lenses of tau, different ones but platform more broadly. But when do we get proof of concept, right, that this thesis is correct around you can give these capsids IV, you get greater, greater brain penetrants, wider therapeutic index, like when will we get the answer there?

Yes. So we have 2 shots on goal this year. So we start with -- so we have our tau knockdown gene therapy. We're planning to file an IND in Q2 of this year. And we hope to be in the clinic in the second half of this year. So that's our own wholly owned program. And then Neurocrine has said that they are planning to file an IND and be in the clinic this year as well with 1 of our novel capsids for Friedreich's ataxia. So that's 2 sort of shots, if you will, on human proof of concept.

Now in the case of gene therapy trials, you have to do the studies in patients with disease. And you have to use doses that have a chance of helping the patient. It's considered unethical to do anything else. And so we should be able, at some point next year, I would say, to be able to start to get evidence that we can dose safely and get gene expression in the brain. And I think that's going to rely primarily on fluid-based biomarkers initially.

Ultimately, as I said, tau PET imaging, but that's going to require some more time.

Yes. Okay. Great. And you're also working on a brain shuttle as well using ALPL?

Yes. So we have a brain so these capsids. It turns out that these capsids are a great way to probe for receptors that can be leveraged to get things into the brain. And so we've leveraged those capsids as we've now discovered 5 to 8 receptors, many of them were actually surprising. I mean you would never have guessed that they would be receptors for BBB penetrant. But it turns out -- and then the first 1 of these is ALPL. ALPL is kind of surprising. It's a GPI linked protein, you wouldn't necessarily think that would be the greatest way to get across the BBB, but it turns out it's a very good way to get across the BBB. We've now made ligands against ALPL. We're going to use them as shuttles much the way people do with TFR transparent receptor.

Right. Okay. And what do you see as the most interesting potential applications of that technology?

So far, our ALPL shuttles are quite differentiated from the TFR-based shuttles. So we have very different PK. So we have a much longer half-life. So if you want to block something, for example, 24/7, most of the time when you block, you don't -- you want a 24/7 coverage, right? TFR has a short half-life. By a week, usually, it's gone unless it's bound to something in the brain. Ours will be -- even 3 weeks later, we still have very nice exposure. So we haven't even calculated the half-life yet, it's so long. So that's a nice characteristic for many applications. It also has no effect on any of the hematologic adverse events. We would like actually looked at reticulocyte count. We have no effect. Of course, we may have our own safety issues. So we're going to be looking carefully at that this year. We're doing nonhuman primate studies. And so we -- and so -- and also the distribution is different. TFR distributes broadly into many other tissues in the body, not just the brain. ALPL has a different distribution pattern. So -- and we have, like I said, 5 to 8 different receptors. Each 1 is going to have its own safety, distribution and pharmacokinetic profile. And I think that's going to give us a lot of flexibility in choosing the right shuttle for the right application.

Yes, makes sense. What would be the safety risk with ALPL, if anything? Like do we -- is there anything from genetics or loss of function or anything like that?

So in humans, if you have severe loss of function, so greater than 70%, you can get -- there's a disease called hypophosphatasia, which is bone and teeth mineralization issues. So -- but the human genetics would indicate that it has to be a severe loss of function. And so hopefully, we'll thread the needle so that we don't have that much loss of function.

Right. Okay. And from a company building perspective, Al, like how much do you want to take all this stuff forwardly yourself versus -- because I'm sure you could do BD around, a novel shuttle or different products like that. You've obviously done some with Neurocrine, but what's sort of the 2- to 3-year vision from here?

Yes. No, you can expect us to -- we're always talking to potential partners. If you look at what we did with capsids, we did a number of partnerships. We have a total of 5 programs right now with Neurocrine. We have 3 programs with Novartis, 1 with AstraZeneca because they inherited the Pfizer rare disease portfolio. And so I like these -- so look, if our shuttles work, there's no way a little Voyager can do all the potential targets, my goodness. It would be hard even for a large company to address all the targets, right? So the way to do that is to leverage partners. For example, in our -- with our Neurocrine programs for FA and GBA, we actually not only -- they do all the heavy lifting essentially to get to an IND and even to Phase 1. And then we have the ability to opt in, 40% of U.S. rights for FA and 50% for GBA1. Those are really good not only for patients because it gets these programs into the clinic, but it's good for our shareholders, too, because not only do we get the milestone payments and royalties potentially, but we may be able to opt in for a bigger chunk. So those are the kinds of things that I'll do all day long with the right partners. And I believe Neurocrine, Novartis and AstraZeneca, they're very good partners. They know what they're doing, and we learn from each other.

Yes. Okay. Great. Well, thank you, Al. It's great conversation, as always. And yes, best of luck this year. We're all rooting for [ you, Al ].

Thank you very much, Paul. Thanks for having me.

Hello, everyone, and welcome to Oppenheimer's 36th Annual Life Science Conference. I'm Jay Olson, one of the biotech analysts here at Oppenheimer, and it's a pleasure to welcome you to our discussion with Voyager Therapeutics. And it's an honor to introduce the legendary Al Sandrock, CEO of Voyager. And with that, I want to thank you so much for making time for us here today, Al. It's always a pleasure to catch up with you. And I'll turn it over to you in case you'd like to make some, I guess, opening remarks for anyone in the audience who's not completely familiar with Voyager and maybe bring us up to speed on that amazing letter that you wrote to shareholders to start the year.

Great. Yes. Thanks, Jay. Thanks for inviting me to your conference. It's a pleasure to talk to you, as always. And yes, let me start with that letter. We sent out a letter at the beginning of the year to -- just to summarize what we think is a pretty important year for us coming up. And there's basically 3 pillars of value. The first is centered around a particular target, which is tau, and we have 2 shots on the tau target that I'd like to talk about.

Second is gene therapy that this is the year we're going to put 2 different gene therapy assets into the clinic, utilizing our novel blood-brain barrier penetrant capsids. One is a Neurocrine partnered program and one is a wholly owned Voyager program.

And then finally, the third pillar would be our emerging neuroshuttle platform, where we're taking receptors that we know can deliver capsids into the brain and making shuttles that will bring all sorts of other drugs into the brain. So that's what we said in the letter, and it was pretty well received, Jay, because when we went to JPM, almost everybody I talked to already read it. So they kind of knew our story. By the way, I would also add that we're well capitalized and that we have cash into 2028. So with that, I'll let you ask the questions.

Okay. Absolutely. Thanks for that setup. And I totally agree with you. Your letter was very well received, and I think it made its way around the investor community, even those who may not be shareholders of Voyager were very interested in and fascinated by that letter. And yes, really some really visionary comments, not just about Voyager, but about the industry as a whole. So thank you for setting that up.

And yes, maybe just to start with the first pillar, if we could please dive into your anti-tau antibody program, 7523. There was a lot of discussion following UCB's bepranemab Phase II results at CTAD last year. And then more recently, J&J discontinuing posdinemab. I guess how should we think of tau as a target? We get a lot of questions from investors about external validation of tau as a target for Alzheimer's. And also just, I guess, the ideal modality for targeting tau.

Yes. No, I've been thinking about tau for a long time. And it turns out that I think this year, we will learn from third-party data a lot more about tau. You just mentioned one of them, J&J, we will be -- they will be presenting data at an upcoming meeting in March, the AD/PD meeting, but we'll also hear from Biogen with their antisense oligonucleotide and perhaps some other compounds because many companies are targeting tau.

And I think the reason for that is that first of all, the accumulation of tau or what I should say is the spread of tau in the brain happens in a very stereotypic manner in Alzheimer's disease. In fact, the staging of Alzheimer's disease is based on how far tau has spread in the brain. And so this characteristic spread, we think is responsible for the neurodegeneration in the brain. In fact, there are some examples of patients who have a lot of amyloid in their brain, but who are not demented and don't get demented until the tau starts to spread.

So it's very clear that tau's spread in the brain, the misfolded aggregated tau that's spreading in the brain, the pathological tau that's spreading in the brain is actually better correlated with clinical decline than actually even amyloid. So Jay, the funny thing is back in the day when we were developing anti-amyloid antibodies, and I was in my former company, I got a lot of criticism for developing anti-amyloid even when there were a lot of failures, you'll remember, the first few anti-amyloid antibodies failed. And then of course, it turns out anti-amyloid antibodies work. But already back then, I was already thinking that we should be also looking at tau.

And behold, the anti-amyloid antibodies do work, but there's still a big unmet need because they don't -- they certainly aren't a cure, and we'd love to get better treatments. So anyway, so we think it's a pretty important target, and we'll learn more, like I said, this year. Now you touched on bepranemab. That was a UCB antibody that for the first time, actually showed -- it was kind of a mixed story in the sense that it's the first time that it showed an effect on the spread of tau.

As I said, that's what we're trying to impede is the spread of pathological tau in the brain. And the bepranemab drug was the first one that showed an effect on that. Two earlier antibodies and terminal directed antibodies had failed to block even the spread, but that one did. And it actually also had an effect on ADAS-Cog, which is a tried and true clinical measure that people have been using for decades actually. And that actually hit on the -- as a secondary endpoint. But the trouble is that the primary endpoint, CDR sum of boxes was negative.

So that's why I say it's a mixed picture. But now we're seeing at least a drug that works in terms of the biology of blocking the spread of pathological tau. Now what we don't know is how much biology do you need to get a clinically meaningful effect. We see, as I said earlier, a hint of an effect, but maybe we need to block it better to see a bigger -- to see a more consistent effect, shall I say, across clinical measures. And so I'm looking forward to seeing the data from J&J, which is just a couple of weeks away now at the AD/PD meeting.

And what I want to know is, does it block the spread as well as bepranemab or better or worse? If it doesn't block the spread at all, well, then it's not going to work, right? But if it blocks the spread of pathological tau and does it better than bepranemab and it still doesn't have a clear-cut clinical effect. Now I'd say we'd be worried that the antibody approach may not be the right approach.

That's why the second shot on goal that I mentioned earlier, the VY1706 gene therapy also is of interest. And Biogen's BIIB080 is the best test of that approach. In that situation, instead of using an antibody, which will only bind extracellular forms of tau, the knockdown approach will decrease the expression of all forms of tau throughout the brain.

And Biogen's Phase I data showed an inkling of efficacy actually. The trouble was there was no placebo group or control group. But boy, it sure looked like it had a very interesting clinical effect, potentially a very large effect when you compare it to natural history data. But also, it had a dramatic effect on the pathological tau by tau PET imaging. It actually decreased. It didn't just block the -- slow the -- impede the spread of pathological tau, it actually decreased the pathological tau in all areas of the brain that they looked at. So quite a dramatically different effect. And that's why I think that's also a very important test for tau as a target.

Okay. Understood. Thank you so much for that super comprehensive overview and covering the different approaches to targeting tau. One of the things that comes up sometimes with investors is how to -- going back to the antibody approach, thinking about how to sequence treatment with tau antibodies versus Abeta antibodies. And we've always kind of been fascinated by the donanemab studies that were they stratified patients by tau. And I know they got kind of a broad label for treatment of Alzheimer's regardless of tau levels as long as they were amyloid positive. But the data didn't look all that great in high tau patients. So how should we think about the sequencing of anti-amyloid versus anti-tau antibodies in Alzheimer's patients?

Yes. So that was -- it's a very interesting question. They had a pretty rich discussion at the FDA Advisory Committee meeting, you'll recall on this. So the effect of the donanemab was much better in the low tau burden group than in the high tau burden group. And I think the committee was starting to think, well, should we maybe only approve it for the low tau or contemplating that possibility. But the problem is then you'd require tau PET imaging on everybody, and there was no approved tau PET ligand. It would have been a morass. It's hard enough to do the diagnostics now to get people on anti-amyloid.

So I think that's why they avoided that. But nevertheless, that does suggest that you want to catch the tau before it has -- before the burden in the brain is too high, right, before the burden of pathological tau is too high. And so the way I've been thinking about it is that we have some early Alzheimer's trials even before people have symptoms with the anti-amyloids.

Both the Biogen Eisai drug, lecanemab and the Lilly drug are in this, if you will, presymptomatic stage, certainly people before they even have mild cognitive impairment. I'm looking forward to those results. My bet is that the anti-amyloid antibodies will work better in that group. And -- but I think that the tau antibodies probably also will work better before the tau has spread very far. BIIB080 though shows that you can actually decrease the tau even after it's already been spread in the brain.

So it could be that you want to start with anti-amyloid really early, perhaps even before symptoms, the way we treat cholesterol as a biomarker before we have the first heart attack or any symptoms. And then we then maybe want to treat with tau if the anti-amyloid doesn't prevent Alzheimer's disease from appearing. Once Alzheimer's disease starts to appear, you probably need to then use the tau approaches. That's how I've been thinking about it. We'll see if that's true.

Okay. Excellent. I appreciate those insights. And we're definitely looking forward to those 2 studies reading out. Also looking forward to, as you mentioned, the detailed results from J&J's Phase IIb autonomy study of fasinumab coming up at ADPD. I guess where would you like to focus on that data set? And what kind of read across would you like investors to take away from that data set to 7523 when we see the full data for fasinumab?

Yes. So we already know from their press or their announcement that it didn't have an effect on clinical measures. So it didn't work on the clinical outcomes. That's all we know so far. So what I'm very interested in knowing is whether or not they actually had a biological effect on the spread of pathological tau. As I said earlier, if it doesn't affect the spread of pathological tau, it's not surprising, it's not going to work clinically. If on the other hand, it does work on the spread of tau, then I think it's kind of a referendum on whether the antibody approaches work.

Now if I had to bet, at this point, I would bet that it didn't block the spread of tau very well because we actually looked at that. We had an antibody against a very similar epitope at Voyager, which we could have chosen to put into the clinic. And we didn't choose it because it doesn't block the spread of tau very well, that antibodies against that epitope. So I think as in the case of anti-amyloid, epitope really matters.

In the case of Abeta 42, N-terminal drugs are the only ones that worked. The mid-domain and the C-terminal antibodies didn't work. Here, I'm hoping it's the opposite that the C-terminal antibodies like ours against the -- our anti-tau will work, and we already know the N-terminal ones don't. So whether the mid-domain or the MTBR antibodies work, we'll see. But I think epitope is going to end up mattering quite a lot if antibodies work at all.

Okay. Excellent. Appreciate those predictions. That's good to know great set up for...

We'll see if I'm wrong. But our animal -- our -- because we have a spreading model in the animal using human Alzheimer's material, and that epitope didn't work as well. So that's what I'm betting. But of course, sometimes animal models don't predict the humans very well. So we'll see.

Okay. All right. And then I guess with regards to your own clinical progress with 7523, congrats on completing the enrollment in the MAD portion of your study. You presented data at CTAD on the SAD portion. Can you just remind us about how the emerging clinical profile of 7523 looks based on what you've observed so far?

Yes. So far, what we've done -- what we've looked at is preliminary safety and the pharmacokinetics. In terms of safety, it was very, very safe. And actually, all the anti-tau antibodies, the safety profile looks quite good. So that's good. And then the pharmacokinetics are exactly as we would have predicted for a typical antibody in the sense that the brain to plasma ratio, if you will, or CSF to serum ratio in this case, is 0.3%, which is right in the middle of the 0.1% to 0.5% range of typical monoclonal antibodies. And also the half-life would support the once a month -- every 4-week dosing that we're employing in the multiple ascending dose study.

Okay. All right. Sounds good. And then since we're anticipating getting a look at the MAD portion of the Phase I study for 7523 in the second half of this year, one question that we get is, will you include tau PET imaging data? And how would you like to set investors' expectations ahead of that data readout later this year?

Yes. No, in fact, that's how -- the MAD was designed specifically to look at tau PET imaging. It's powered to see an effect on slowing the spread of pathological tau in the brain based on tau PET imaging. In fact, that's really the only biomarker that I would rely on for -- because fluid-based biomarkers are available, but they give -- but sometimes the fluid-based biomarkers are positive and the tau PET imaging is negative. And to me, it's the spread of pathological tau that we want to impede. So that's the key endpoint.

And I hope we're better than bepranemab because, as I said, bepranemab gave mixed results. And so if we're better than bepranemab, I think that will be pretty exciting. And I've always said we would need a partner going into Phase III in Alzheimer's is too large an endeavor for a small company like Voyager. So hopefully, we'll find a partner. We also have this shuttle technology, and we've seen how shuttled anti-amyloid antibodies can actually be even better than the unshuttled antibodies. And so we have the option to make a shuttled anti-tau antibody as well. So that's something that we could potentially think about as well.

Okay. Those are good options to have. Anything that you can share with us on the baseline characteristics for the patients in the MAD portion of your study? And I know you said that tau PET imaging is the biomarker to look at, but are there any other biomarkers that you plan to show that we should pay any attention to?

Yes. So the population will be early Alzheimer's disease, so people with mild cognitive impairment and early mild dementia, very typical of the patients enrolled in the other tau trials, actually also the amyloid trials. So that's not unusual. And it turns out that's a pretty good population to use tau PET imaging to look for impeding the spread. So that's why we chose that population. I don't think it will be unusual when people see the population we chose.

And then -- sorry, your second question was what -- the other biomarkers. Yes. So I will -- we will look at some fluid-based biomarkers. People -- there's all different isoforms of pathological tau. There's a variety of look at. But I would say that those are potentially, I would view as sort of target engagement type biomarkers because, for example, Biogen published that in their trial with one of their antibodies that failed to affect any clinical measure or tau PET imaging.

It actually had a 40% effect on the most popular, if you will, tau fluid-based biomarker, the MTBR tau. So there was a 40% decrease in that fluid biomarker, but there was no effect on tau PET imaging in that study. They actually presented that at last year's ADPD meeting. So that told me that, boy, you can't rely on that fluid-based biomarker because there was a clear-cut effect on that, but there was no effect on tau PET imaging. So that's why I say I'm banking more or I'm placing more emphasis on the tau PET imaging.

Okay. All right. Well, we will look forward to that. And then once you see that data, how do you plan to make a go/no-go decision on 7523? And then once you have that decision, if you do plan to advance into Phase II, can you maybe talk about any initial thoughts on a new study design?

Yes. Again, I think the partnership -- I think we'd have to get a partner. Even Phase II is -- I don't want to -- it's too big for a small company like Voyager to venture too far beyond the multiple ascending dose study on our own. So -- and then the design, I think, would be, again, early, early -- again, as you know, the amyloid field is moving to earlier and earlier stages. I think for tau, we could stay in that early MCI and mild dementia patients because you can go later with tau treatments, I think. And so I think we'd stay with that. That's what I would do. But of course, we'd have to wait for our partner to tell us what they would want to do and have a discussion. But that's what I would have a propensity toward studying that population.

Okay. All right. Yes, we definitely appreciate your partnership strategy, and we've always thought that the Biogen Eisai partnership is kind of a model for sort of not only risk sharing, but resource sharing in development of large-scale Alzheimer's studies and clinical development programs. So definitely appreciate that.

Well, yes, Jay, I mean, look, Alzheimer's is such a huge opportunity, right? So sharing the upside doesn't bother me. But I would like to share the risk and the cost, right? And so sharing the upside makes sense for such a large opportunity, I believe, in particular.

Agreed. Totally agreed. Okay. So unless there are other comments you'd like to share on the antibody approach, I definitely want to talk about 1706, your tau silencing program with your innovative TRACER capsid. We're super excited about that. Can you maybe remind us about the preclinical data that you've reported so far? And then how does the degree of tau mRNA or protein reduction compare to other tau silencing programs? You mentioned BIIB080. I guess, how do those 2 compare?

Yes. So BIIB080 was about a 60% reduction, and we're targeting 50% to 70%. In fact, that's what we find in our nonhuman primate studies that we get that at a pretty low dose, too. So the gene therapy that -- so we want to go to lower doses because, obviously, it has a higher likelihood of being safer and also it's better on cost of goods, right?

So remarkably, at 1.3e13 vgs per kg, which is about an order of magnitude lower than people typically use for intravenously delivered AAV, we see 50% to 70% knockdown, our target knockdown range, which is right where by BIIB080 -- which is what BIIB080 achieves. So -- and then we also, on top of that low dose, we have a capsid that detargets the liver by 30-fold.

So -- because as you know, liver toxicity can be very dangerous for patients. In fact, we had some other companies that had some patients who died from liver failure. So we're very conscious about the safety, and we're very conscious about trying to get to that level of reduction that BIIB080 achieved. And hopefully, we'll see some nice treatment effects of that level of reduction later this year when BIIB080 data are shared.

Okay. Okay. That makes sense. Yes, we're definitely looking forward to that as well. And then anything you could share with us with regards to your FDA interactions on the NDA filing thus far? And then I guess, a similar question, any initial thoughts on your Phase I study design?

Yes. Well, all I can -- well, we did have a productive interaction with FDA about a year ago actually, and they helped us think about the GLP toxicology studies, and we even contemplated some initial trial designs. So we expect to file an IND in the second quarter of this year, and we expect to start in the clinic in the second half of this year, first patient in, in the second half.

And -- we haven't really disclosed the design of the trial yet. But based on what I just said earlier about how much I believe in tau PET imaging and how Biogen's BIIB080 has such a remarkable effect on that, that you can bet that we're going to be looking at tau PET imaging very closely with our gene therapy asset.

Okay. All right. Well, since you mentioned BIIB080, I definitely want to follow up on that and the Phase II CELIA study results expected midyear. I know people ask you this. It's a tricky question. Any predictions on the study outcome? And I guess, do you expect anything that you learned from BIIB080 to influence your view on 1706?

Well, BIIB080, Biogen has already published -- actually the paper actually just came out recently. They have been presenting it for quite a while, but they saw a pretty interesting effect on multiple clinical outcome measures. And even though there was no control group in the study itself, when you compare it to natural history studies or to the placebo group of a similar study in terms of the patients enrolled, it's a pretty dramatic effect, much bigger than the anti-amyloid antibodies.

So I'm hoping that they reproduce that in this well-controlled trial, randomized controlled trial. And the prediction would be that they would have a bigger effect on CDR sum of boxes than any of the anti-amyloid treatment so far, including the shuttled anti-amyloid antibodies. So I think that could be quite exciting for the field.

Okay. All right. That makes perfect sense. And I know a lot of people are excited about that. We kind of talked a little bit about this, but maybe if you could highlight some key differences between 1706 and BIIB080 in terms of, well, first of all, the route of administration, but also potentially the biodistribution in the CNS.

Yes. So BIIB080 is an intrathecally administered antisense oligonucleotide. It's either going to be every 3 months or every 6 months. They're testing both, but that's a repeated intrathecal injection. All antisense oligonucleotides injected into the lumbar cistern will produce a gradient, so that the exposure is going to get lower and lower as you go up the neuraxis up the spinal cord and lower -- and still lower as you get up to the brain and lowest in the deep gray structures.

But Biogen has already showed that you get enough into the cerebral cortex to get a dramatic effect on tau PET imaging. So -- but there is going to be this gradient. Ours is a onetime IV drug, and it just produces in the brain the siRNA that will continually be produced. There is no gradient because we leverage the vasculature to get broad distribution into the central nervous system. So those are the key differences. Mechanistically, though, they're pretty similar in the sense that they both decrease the expression of all forms of tau.

Okay. All right. And also, we did touch upon this a little bit earlier, but can you just talk about where the anti-tau mechanism fits into the future treatment landscape? And who is the ideal patient population for anti-tau therapy?

Well, I think that it's either going to be given to patients who don't respond very well to anti-amyloid antibodies or it's going to be maybe combined. In fact, one company is already testing the concept, this combination idea. So if the anti-amyloid is working in a particular patient, unless it's a cure, you're probably going to want to add something that will stop Alzheimer's in its tracks. And I think that's where the tau treatments would come in handy.

And then the other thing with tau, by the way, is that we only talked about Alzheimer's disease. There's a whole host of other tauopathies that we can also think about going after such as PSP. In fact, there's a lot of data that suggests that traumatic encephalopathy is a tauopathy. So there's a whole host of other tauopathies that we could go after. So very exciting, actually.

Okay. And -- that's super helpful. And yes, a lot of opportunities there. Maybe just to follow up on one point you made earlier about the anti-amyloid studies in preclinical Alzheimer's populations. Assuming those are positive, would you want to move a tau approach into the preclinical setting?

We might want to, but I'm not sure you need to because tau spreading happens later. So even when you get somebody in the mild cognitive impairment or early Alzheimer's stage, it's still early in terms of the natural history of pathological tau in the brain. So you may not need to go that early, but of course, you'd have to go -- somebody may want to do that experiment because my prediction is if you could go earlier, it would be even more effective, but you may not have to in the case of tau.

Okay. Okay. Makes sense. And I know we're running out of time, but if I could squeeze in a couple of questions on your neuro shuttle platform. And first, congrats on all the progress that your team has made in characterizing ALPL as a novel target for crossing the blood-brain barrier. And you had some early characterization of ALPL versus transferrin receptor shuttles. Can you just highlight the key differentiating features for your ALPL shuttle?

Yes. So the key thing is that we have very different pharmacokinetics. So transferrin receptor shuttle drugs have a very short half-life. So unless it's bound to something in the brain, it clears very rapidly. And that's because TFR shuttled drugs go to many other tissues and not just the brain. It goes to heart, it goes to muscle and some people have actually leveraged the fact that it goes to muscle, as you know.

The other thing is that there are hematologic adverse events and you see decreased reticulocyte counts and stuff. So ALPL is differentiated in the sense it has a much longer half-life because the distribution in the body is different. And we see no effect on reticulocyte count. So we're still learning. It's still early, but I think so far, we see different -- clear cut differentiation from transferrin receptor.

And yes, it could be quite an important new shuttle that we could use for a whole host of other diseases. For example, I mentioned tau. You don't want a short half-life if you need to maintain coverage for 24 hours, 7 days a week. Many antagonists, you want to maintain antagonism 24/7. And a short half-life is not great for that. And you don't want to have to be injecting it every week either, right? And so that's where I think for certain targets, ALPL may be a preferred shuttle.

Okay. That makes sense. And so definitely appreciate the potential benefits for different targets. What about therapeutic modalities? Are antibodies the modality that you think works best with the ALPL shuttle? Are there other modalities that you're thinking of?

Yes. So we're looking at antibodies. We're looking at peptides. We're also looking at oligonucleotides. Certainly, our first foray will probably be more protein therapeutics. But we're definitely also looking at oligonucleotides because, as I said, this intrathecal injection, some of these ASOs have to be injected every month, which is quite a burden to the health care system, not to mention the patients. So -- and also you get this gradient. So if we could shuttle it, we would not have to deal with the gradient. We could have less frequent injections, IV, much more convenient. And so that would be the goal.

Okay. I apologize, we've got a little bit over. Maybe one last really quick question. Any comments you could share with us on your partnered programs with Neurocrine on FA or GBA1 gene therapies?

Yes. So Neurocrine has said that the FA program using one of our novel TRACER-derived capsids will also go into the clinic this year. I think they're planning to file an IND this year, and they've indicated they're going to move into the clinic this year. So that's our second gene therapy, if you will, that I already mentioned, shot on goal. They also say the GBA program is progressing, but they haven't said when they're going to enter the clinic yet. And they've also stated that a couple of the other programs that we have partnered with them are also progressing.

Okay. All right. Well, thank you for the extra time here. Apologies for going over a little bit. It's always a pleasure catching up with you and learning from your pearls of wisdom. And congrats on all the progress. Thank you so much, Al.

Thank you, Jay. Thank you. Goodbye.

Our pleasure. Thanks, everybody.

Happy to be here and moderating this chat with Al Sandrock, CEO of Voyager. I'm sure everyone knows Al, who's here listening in and got to know Al at his days at Biogen. So Al, maybe just give a quick overview of Voyager, and then we can do a fireside chat and dive deeper into different programs.

Yes. Great. So we are a multi-modality neurotherapeutics company, where we're trying to optimize delivery. We have 2 platforms. We have a gene therapy platform where we're discovering capsids that cross the blood-brain barrier after IV delivery. And that platform identifies not only the capsids, but then the receptors that the capsids leverage to get into the brain. We're now going to be looking to see if we can use them as shuttles.

And the first one of these is called ALPL. So you see that's already appearing on our pipeline chart there. So the idea is that these are validated receptors in the sense that we know they can carry large viral particle across the BBB. And so we're going to make ligands against these receptors and conjugate oligonucleotides, put them on various protein therapeutics and optimize delivery. So multi-modality focused on optimizing delivery.

We have a heavy emphasis in Alzheimer's disease, as you can see. And we have multiple partner programs with some great partners, Neurocrine, Novartis and AstraZeneca. And so we have -- we're heavily into gene therapy. And I guess I should end by saying we have one program that is in Phase I. It's in a multiple ascending dose study, the anti-tau antibody, which we expect to read out next year.

Maybe of note is that there are -- there's a lot going on in tau, as you know, Paul. And we think that not only our program, which will read out next year could be an inflection point. There's J&J that has an antibody that we expect to read out in early next year. And then there's BIIB080, the Biogen antisense oligonucleotide that we expect to read out in midyear. I think both of those could have read-through to our programs because we also have an antibody and an siRNA tau silencing gene therapy as well.

Yes. Okay. Great. Well, on the antibody side, I think some people, myself, someone included, have interpreted the failures of other antibodies as maybe concerning that maybe the antibody strategy for tau can't really access the majority of the target. What would you say to that? And how do you think the shot on goal here is fundamentally different from what hasn't worked?

Yes. So it's funny because when I first started as CEO of Voyager, I was asked -- actually, I was still on the Board. I wasn't even CEO and my first meeting I was asked what my opinion was of the tau antibody. Todd will remember that meeting well. And remember, I had just come off a big failure with the Biogen terminal antibody. And so I was all set to kill it until I heard a couple of things.

First of all, that the animal model that Steve Paul brought in from Cornell was used to pick this antibody. It's a pretty intriguing model. It's a mouse model that expresses human tau. It's a P301S human transgenic mouse model of tauopathies essentially. And what you do is you take Alzheimer's brain-derived paired helical filaments and you inject it into the brain in one region and you look at the spread of tau because after all, what's pathologic in Alzheimer's is the spread of tau out of the template lobe.

In fact, we all get a little bit of pathological tau, if you will. I use that in quotes because if we all get it, it can't be pathological. But in all -- in normal people, it stays in the rhinal cortex. It only starts to spread in the presence of amyloid. So it's the spread of tau that's abnormal.

This model, we hope will predict whether or not antibodies work. The 2 N-terminal antibodies that failed in the clinic failed to block the spread of tau in that animal model. In fact, in a side-by-side study, we had essentially a 0 effect of one of the N-terminal antibodies, and we had a 70% effect on blocking the spread with our antibody. I thought that was pretty interesting.

Yes. That is interesting.

And because the issue always is, well, we had -- so the other thing we did was we chose an antibody that was specific for pathological forms of tau. In case of amyloid, that was important that we had antibodies that were specific for pathological forms of an amyloid. But even that, we had half a dozen or so antibodies specific for pathological forms of tau scattered across the tau molecule, and we had to pick one of those.

And so I use this -- we use this animal model empirically thinking that whatever mechanisms mediate the spread in humans might be replicated in that mouse model expressing human tau.

When exactly does that spread start? And what does that tell us about the window for intervention for the tau antibody strategy?

So if you look at the natural history of Alzheimer's disease, the first thing that happens is abnormalities with amyloid. And then secondarily, you see an effect on tau. If you look at normal human aging, as I said, we all accumulate a little bit of misfolded tau in the part of the temporal lobe called the rhinal cortex.

And it's only when you get amyloid that you spread beyond that region. If you look at, for example, the Columbian cohort of PSEN1 patients, it's about 2,000 or so of those patients. There are people who have a brain full of amyloid who actually -- a few people who don't get demented.

In fact, in that cohort, the natural history is that you get demented sort of in your mid-40s, plus or minus just a year or 2. So it's very, very regular. It's a single gene mutation. A few patients actually don't get demented until their 70s or 80s. And when you look at those patients, -- they have a brain full of amyloid, but they actually have -- they don't spread tau normally.

So in that situation, it looks like it's a spread of tau that's more critical for causing dementia. It's data like that, that makes me think that the spread of tau is actually pretty critical. And now we're starting to understand how amyloid can trigger the spread of tau, but that's a whole other story.

Okay. So what's the development path for actually showing in people pharmacodynamically that this antibody is different than what's been tested before?

Well, the -- so there's 2 types of measurements for tau. There's fluid-based biomarkers and tau PET imaging. We're going to rely more heavily on tau PET imaging. And the main reason for that is that Biogen presented some interesting data at the AD/PD meeting earlier this year, where you remember they had that N-terminal antibody that failed.

What they showed at AD/PD this year is that there was a 40% effect on MTBR tau, a fluid-based biomarker. And MTBR tau is the one that people were most excited about because it correlated the best with tau PET imaging. But in that trial, there was a 40% effect on MTBR tau, no effect on tau PET imaging and no effect on clinical measurements. The lesson that I learned from that is you got to be a little cautious with fluid-based tau biomarkers. I don't think we know enough about them. I don't know that we know enough to rely on any one of them for sure. But tau PET imaging does look like the real thing.

And you'd be focused on specific brain regions. Yes. So you have to -- the idea wouldn't be you're removing the tau from...

No. The [indiscernible] actually removes tau from where it was.

Which is actually really...

Which is pretty darn remarkable. But here, what we're looking at is -- so we're going to have people at various brock stages, right, Stage 2, 3, 4, et cetera. So what we're going to have to do is look where is it predicted to go next. If you start at Stage 2, you're predicted to go to Stage 3. And so what we're looking for is whether it can impede developing into that next stage, if you will.

Yes. Yes. Okay. And so is that the kind of question you can actually answer in a Phase I trial? Or is that Phase II work?

Yes. We believe our trial is well powered to see an effect on tau spread based on tau PET imaging using that kind of mechanism.

Okay. Super interesting. And if that's positive, what would you do with that asset? Would you actually try to take that fully forward through a IIb or partner it?

Well, we're too small, I think, to even think about commercializing it for sure. And if you're not going to commercialize it, it's better if you have a partner do Phase III -- and so the question is whether or not we would have all the questions answered to go into Phase III. Some people would say we would potentially because we're doing more than one dose. So you have to know the dose. And yes, so I think we would be looking for a partner.

Yes. Okay. Okay. And then on the tau silencing approach. So I, like you, share a lot of enthusiasm for the Biogen Ionis anti-tau program. So let's say those data are positive. How much read-through and derisking would that have on something like VY-1706?

Well, I think it reads through quite a lot because what we have is a vectorized siRNA, very similar concept. You're just decreasing the expression of tau. It should affect all forms of tau, intracellular, extracellular, epitope doesn't matter here, obviously. So I think it reads through quite well.

And what we're looking for is do we see again whether or not there's a decrease in tau PET signal. That's a remarkable thing is that I used to think neurofibrillary tangles were pretty irreversible. And these tau PET ligands are specific for pathological forms of tau. To see a decrease relative to baseline must mean that there's some equilibrium if you will.

There's some sort of endogenous clearance mechanism...

Yes, because if you just block the central system...

That could have easily just look like a base inhibitor tau.

Yes, exactly, but that's not what we saw. So -- and then compounded with that, the effect size, if we can believe the comparisons to natural history and to the placebo groups of other trials. It looks very -- because the effect size is pretty large. So both of those, the imaging and the clinical outcome measures portend well for pretty interesting effect, I think.

So I mean, I think I can understand that the gene therapy approach would have tremendous advantages just from like a patient convenience and access perspective. On the other side, like across the gene therapy space, right, it feels like every other program, there's some sort of inflammatory SAE. And for certain rare diseases, that kind of risk is acceptable.

Not saying Alzheimer's is not a terrible disease, but are we ready for a gene therapy that could target this big of a population? Like if you run a program that has a 500, 600-person safety database, like are you worried that you're bound to see something that could kind of shift the risk benefit against you?

Yes. Well, first of all, if you look at the data we showed, in nonhuman primates. We use a relatively low dose.

Where are you relative to others?

So we're at 1.3 E13 vgs per kg, which is essentially an order of magnitude lower than the E14 vgs per kg doses that are typically used for systemic AAV. So we're an order of magnitude lower. That's because of the BBB penetration. It's a very potent. And so we get 50% to 80% knockdown across the brain with that one injection of that one pretty low dose.

The second thing is that we use a capsid that's detargeting the liver by 30-fold. So not only is it a lower dose, we detarget the liver. So as you know, other companies have shown liver toxicity, including -- it could cause death. So look, I agree that safety should be very good. But on the other hand, Alzheimer's is a pretty bad disease. I mean I think we often think of it as -- but it's fatal and it's pretty bad before you die. So it's always a benefit risk.

Yes. Yes. Do you think we are out of the woods on any on-target risk with knocking down all forms of tau in all areas of the brain, including "healthy tau" I don't even know if we know the function of tau in adult brains, but how do you may...

Well, there are some conditional knockout experiments that have shown some subtle differences. So first of all, even just regular knockouts, the animals are surprisingly viable. You would have thought that.

The full knockout?

Yes, the full knockout, knockout from embryogenesis the animals are actually viable. They're a little smaller. They're even fertile. And so that right off the bat tells you there's probably some redundancy. But if you look carefully, there are some problems in the brain. And then -- so now we have to turn to conditional knockout, which is more similar to the situation that we have here.

There are some subtle differences in very specific parts of the brain. But that's something we're going to also learn a lot from BIIB080 because not only do they -- have they been following those patients from the Phase I trial for many years now, but we have hundreds of patients now exposed to BIIB080. And so the safety piece of that trial readout is just as important, I think, as the efficacy.

That's where the antibody may have -- I mean, look, bepranemab was incredibly safe. It did block the spread of tau. And look, if you have an antibody that's specific for pathological forms of tau, you would predict that there's going to be less safety liability. But of course, it has to work. So...

Yes. Okay. So what's rate limiting for VY-1706 for getting that into the clinic?

We got to do the usual GLP tox and get the manufacturing ready to do our first in-human studies, but we are on track, and we expect to do that next year.

Yes. Well, maybe let's like use that program as just sort of an opportunity for you to go a little bit deeper into the mechanism by which this crosses the BBB. I know you kind of first screen the capsids and then work backwards on mechanism. But what have you learned on how this works?

And I think you and I have had these conversations around the analog to transferrin with transferrin, there's this concern around interfering with the receptor and how do you kind of toy with that? Is that at all a concern here with ALPL?

Yes. So we have disclosed that the capsid we're going to be using in this program is an ALPL utilizing capsid. It's -- so with transferrin receptor, we have hematologic adverse events. We don't see that with ALPL. We don't see it with our shuttles. And we don't think we're going to see it with our gene therapies as well.

Gene therapy is once and done essentially. So even if you have an effect, it's going to be very temporary. Now if we make a shuttle, though, we're going to have repeated dosing, and that's where we have to be cautious about potential safety issues. And that's something we're going to learn about now. But the advantage of gene therapy is that capsid is employed, gets across the BBB and the capsid itself has gone pretty rapidly. So I think that the liability here is low relative to sort of the endogenous function of ALPL -- that's my guess.

Yes. Okay. Great. What do you want to talk about next?

Whatever you want to, man. I mean, look, we have a bunch of partnered programs.

I know, you guys are more limited in what you can say in those, but I'm still going to try. Frataxin gene therapy, I think, is tremendously interesting.

I agree.

Now can you talk about the capsid? And do you think that this is the kind of thing where you can treat both neurological and cardiac in one? And can you do that safely?

Yes. So we -- so this is Neurocrine's program, so I have to be a little cautious. But yes, here, we have -- we need a capsid that crosses into the heart and into the brain as well. And so it's likely not to be the same capsid that you would use for purely brain disorder, right?

I think that -- and by the way, AAV9 or AAVrh10 or AAVrh74, they actually generally work in the heart unmodified. So AAV, sort of the natural strains, if you will, transduce the heart pretty well. What we've done is then discovered capsid that also gets into the brain because I think you have to do both. And I'm excited about what Lexia was told us about the path to approval.

I mean, right ventricular biopsy and left ventricular mass, right? One -- a single-arm trial with natural history comparison, I'm pretty excited. I don't think they're going to get very much brain transduction, and it's called Friedreich's ataxia for a reason. The disability, especially in children and teenagers is the ataxia.

Now the cardiomyopathy is what kills the patients, but usually later in life, so both are important. And so ours would be differentiating, I think, in the sense that we would not only have the cardiac effects fully, but we would also potentially have the brain effects as well.

Maybe it's premature to ask this question, but just when you think about your TPP, I cover Lexia, I think the data is really promising. And I actually think there's a lot of scientific support in this disease that you may only need a little bit of frataxin.

In fact, you don't want too much.

Right, right, exactly. Definitely not in the liver, too. Now they're making, I think, in the kind of low to mid-single-digit frataxin amounts. Like do you have anything from your animal work that predicts how much you might be able to make in the heart and the brain with kind of the human dose range you predict?

Yes. We do. But I can't say. Yes, I think now I'm getting into Neurocrine territory, but I think there are ways of predicting, where you're going to land in humans based on animal work.

Yes. Okay. And GBA1 gene therapy, Gaucher's, Parkinson's makes a lot of sense. If you're successful in Gaucher's with something like this, how derisking is that actually of Parkinson's?

Well, that's an interesting question. 10% of patients with Parkinson's are -- have mutations in GBA1. And there is data even in sporadic PD that there are lysosomal problems in -- perhaps not every patient with Parkinson's. But I think there's pretty good data that suggests that GBA, G case is involved in Parkinson's.

I think one of the main reasons for that is that we know that alpha-synuclein metabolism is partly controlled by enzymes in the lysosome like GCase. And so, since I believe that alpha-synuclein is central to Parkinson's disease and since lysosomal enzymes like GCase can affect the metabolism of alpha-synuclein, I think there's a pretty good chance that it could be effective in Parkinson's. I'm looking at my CSO, Todd, to see if he's agreeing with me or not.

Okay. Now from a delivery perspective, the deep brain or the structures involved in motor function have been harder. I mean, I think like for the ASO LRRK2 program, like can you deliver there your approach?

So we've already shown this, I believe. We look at pretty much every brain region. How many -- we look at 14 regions, I think, when we do.

My brain only has 6.

Well, we look at 14. And so -- including the spinal cord, of course. But yes, we get that -- so we leverage the vasculature with IV delivery, and we get transduction in the deep brain structures just as well as we get with. In fact, in the nigrostriatal neurons, have we shown this data that we have 98% of neurons transduced of the dopaminergic neurons transduced.

That's amazing.

Yes. And in the caudate, putamen, we get very high levels of transduction. So leveraging the vasculature is actually a pretty good way to get down to those deep gray structures.

Right. Right, right. Okay. Okay. Interesting. Maybe taking a step back, a hot topic that is not directly impacting you right now, but maybe will someday. How are you kind of making sense of maybe evidence on both sides of the argument around CBER and how flexible they'll be in gene therapy?

Well, I mean, we all saw what happened with uniQure, right? And I mean, I wasn't privy to all the conversations they had with FDA and everything. Listen, I do think that for these rare diseases, in particular, -- it's kind of hard to do well-controlled trials typically. So I would hope that they stick to their previous -- what they said previously that relatively small single-arm study with natural history comparisons are going to do the trick.

I'm always of the opinion that if the effect sizes are large on hard endpoints, it's kind of hard to argue that the drug works, right? But there is this idea that with conditional approval, you're willing to accept that some of the time you're going to approve drugs that could -- could be ineffective. But you have to do the confirmatory study, right? And so I think our -- I'm very proud of the fact that our industry has shown that, for example, the ALS drug.

I mean those guys from Amylyx were.

Amylyx, I mean, look, they showed what can be done. They got the drug approved based on accelerated approval. The confirmatory trial did not confirm. They took the drug off the market. The more we do that kind of thing to do the right thing in our industry, the more likely we are to get things like accelerated approval. And I think these rare diseases, particularly these horrible childhood diseases, I mean, I would hope FDA bends over backwards.

Yes. Yes. So for Voyager, in 2026, how many more clinical stage programs do you expect to have?

Well, we're certainly expecting the tau silencing gene therapy in the clinic by then. We hope Neurocrine is in the clinic. We do have the ability to opt in after Phase I. I don't think we'll be ready to opt in next year because it will just be getting started. But at some point, we may be able to opt into those.

And I don't know, the tau antibody, if that's positive, that will still be in the clinic. We'll be looking for a partner. Yes. Is that all, twisted? Did I get them all right?

And then one last thing. You have APO gene therapy. What do you -- how similar or different is this to what Lexia is trying to do there?

Well, here, they had 3 different programs. So I'm always confused as to which one.

So we never saw the program with the Christ Church, I don't believe. right?

I never saw it. I knew that was one...

That was kind of the...

That was the third one...

That was the next gen.

I think -- yes. So what we're trying to do -- I don't know what they're doing exactly, but what we're trying to do is to decrease the expression of the E4 and increased expression of E2. E2 is considered the protective allele, but -- and while maintaining overall levels of APOE constant. And so we're trying to switch from the harmful allele to the protective allele. And the reason why we're excited about this.

Are you silencing E4? Are you trying to compete E4?

We're trying to silence E4, and we're going to increase APOE expression essentially. Okay. So if you're homozygous -- if you're a homozygous for E4, you have a 90% likelihood of getting Alzheimer's disease. It's almost like a single gene mutation.

And these patients are typically demented in their 50s. So they get it at a younger age, and it's a more rapid course. And we had a patient come in who showed a picture of her family. So she got diagnosed in her 50s. She had a very good job, and she was having memory issues at work. She had to stop working. She showed a picture of her family and more than half of her family had been affected.

And so here, these are people who've seen their relatives suffer and they're worried about their own children, too. And so if we can prevent Alzheimer's in those patients by converting from E4 to E2 essentially, that would be a huge positive.

We have a couple of minutes left. Anything else you'd be interested in talking about that you're passionate about?

Yes. Well, TDP-43 is something we did, and we just talked about that. ALS, we had a program in SOD1-ALS gene therapy that we had to terminate because the payload was toxic essentially. TDP-43, we think, is central to ALS, probably 90% of cases, you see certainly inclusions of TDP-43 in the cytoplasm.

How might you actually address that with a small molecule? -- kind of move it back to the nucleus change it at the RNA level.

Well, so the issue here is that TDP-43 has normal functions. If we get rid of TDP-43, we're in trouble, right? And so TBio is making small molecules that affect the condensates. So TDP-43 seems to be sequestered into these condensates in the cytoplasm of cells. And they have a way to screen for drugs, high-throughput screen to get small molecules that remove the TDP-43 from the condensates so they can get back into the nucleus and affect the splicing so that in other words, restore the normal function of TDP-43.

I can't think of too many other ways to target TDP-43. I mean, because you have to be delicate. Also, you don't want to affect stress granule formation because TDP-43 is often found in stress granules as well and stress granules are important for cells to deal with stress. So we had very high hurdle for this program, and they took all the risk and they met the hurdle.

Honestly, I didn't think -- I thought it would be hard for them to achieve what they did. We got very excited when they showed us the data and we paid them a single-digit million dollar milestone. And so we're pretty excited about that as well. So we're -- look, we are a multi-modality neurotherapeutics company. I wanted to underscore that. We have gene therapy. We have the emerging shuttle platform. We even have a small molecule. We are agnostic as to the modality. We want to go after some of the worst diseases affecting humans, and we want to apply the best modality that fits the target and the disease.

And what we're trying to do is optimize delivery. So many examples now, [ ponezumab ], gantenerumab. Avidity and [indiscernible] arguably with ASOs, solving delivery for these newer modalities.

Reaching of the acquire...

We think it's going to be very helpful.

Yes. Yes. Okay. Great. Thank you, Al. Appreciate it. Always.

Thank you.