Thanks, Toby Ferguson, CMO, and Nate Jorgensen, CFO from Voyager, and maybe we should start off with just a quick introduction of Voyager before we get into the Q&A.
Sure. Happy to start there. So, broadly speaking, Voyager is a neurotherapeutics company, really with a focus on neurogenetics and combining the power of neurogenetics with solving some of the fundamental delivery issues in the CNS, with our near-term focus on AAV capsids in that context, and more broadly in the future, other methods of shuttling things into the CNS. I'd highlight that we currently have four wholly owned programs. The near-clinical stage programs there are a clinical stage antibody program for Tau, a SOD1 AAV gene therapy program with an IND projected in mid-2025, and a Tau knockdown program for Alzheimer's with an IND in 2026, and then an APOE program that's earlier. We also have some high-caliber partnerships with 14 partner programs, probably most notably Novartis and Neurocrine.
I'll make a note that two Neurocrine programs with Friedreich's ataxia and GBA-related disorders also have planned INDs next year. Nate, anything you want to add on the final slides?
No, I think that's right.
Very nice. So maybe starting with Alzheimer's, you have a multi-platform, multi-target approach to the disease. Tell us about that and how you could see it evolving over the next five years?
Yeah. So I think maybe the first comment is, I mean, we've seen transformation in the space in terms of the initial approval of the beta amyloid therapies. Voyager's really focused on Tau as the next important target for Alzheimer's disease. And this is because, I think there's a preponderance of clinical data that suggests that in humans who have Alzheimer's, that progression is related to Tau spread. So that's a really important concept, is the idea that Tau burden drives clinical disease. There's also some genetic data supporting Tau as a target. And then I think also importantly, there's been emergent data from ASO programs where you've knocked down Tau. And in that context, there's, albeit early, a potential, large clinical effect. So lots of evidence pointing to the importance of Tau as a target. Voyager in particular, we're taking a two-pronged approach.
We have our antibody that's in the clinic. So this is a conventional antibody. It targets pathologic Tau. In that context, the idea is that it could interrupt that transmission of Tau as it moves from place to place in the nervous system. In addition, we have a vectorized siRNA approach, which utilizes our novel TRACER capsids, which allow for a one-time IV administration of a capsid and get that with substantial transduction throughout the CNS in both neurons and glial cells. So I think holistically, I think we're going to see the evolution of the space of, as we learn about how individuals respond to beta amyloid and those therapies are they complete responders, those individuals likely will not need additional treatments. Partial responders likely would need additional treatments of which we think Tau therapies are a very good candidate for that.
And then, as would folks who don't respond to beta amyloid, Tau, Tau we think is likely the next, the next step for treating that patient population. I think the lessons we need to learn for Tau are, one, obviously to continue to advance these programs, learning about the exposure-response relationships of Tau knockdown or impeding of Tau spreading and clinical effect. I think also holistically, it's important to point out that the biomarker space is evolving substantially for Tau, such that I think from a clinical perspective, you'll start to get to understand earlier in clinical practice sort of the burden people will carry in terms of both beta amyloid biomarkers and fluid Tau biomarkers that will make sort of understanding their responses and treatment assignments, much easier than current methods, which are more imaging or CSF-based.
Great. And maybe staying on Tau with VY7523, tell us about the drug properties that get your team most excited about the opportunity there and why you think this is sort of the, the, the pharmacology of this antibody might be superior to what's been tried previously?
Maybe I'll tell a little bit of sort of how this antibody came to be. Voyager had developed an in vivo model of Tau spread. In this context, you have a mouse, you take human pathologic Tau and inject that into the mouse, and you can chart histologically that spread. The underlying hypothesis is if you can impede that spread, because we know it's important in people, this could be an effective therapy. In that context, we looked at a number of antibodies binding across multiple epitopes and domains within Tau, and we picked the one that empirically works the best. I think that's sort of one key property. The other key property is that we particularly focused on pathologic Tau such that our antibody is a pathologically targeted Tau molecule.
I think the other piece of data that we really got us excited about this antibody is that in our model of Tau spread, there have been a number of other antibodies that have failed in the clinic, particularly some N-terminal antibodies, and neither of those antibodies worked on our model of Tau spread. So we thought our model could have some good positive and negative predictive value, positive predictive value fully in range to be determined. But I think fundamentally targeting pathologic Tau, pathologic species, I do think we look forward to also fully exploring the dose ranges as we move forward.
When you did the comparison of your agent versus bepranemab in that model of human Tau spread in the mouse, I'm just curious, both lowered the pathological Tau, but did you do any additional analyses, dig it into, you know, the residual and ask the question, well, what's the difference? Or maybe there aren't the assays at this point to do that characterization.
So, unfortunately, strictly speaking, we don't have the ability to do that characterization, but we did see, just to remind of the data, that our antibody reduced spread by about 70% and the UCB antibody by about 60%. And so similar levels of reduction, perhaps slightly better with ours.
Okay. Maybe since we're on the topic of the UCB molecule, you know, what's Voyager's current thinking around the ideal early AD population given what you've seen from their recent data readout?
Yeah. So I think maybe just to recap a key point from that readout, I think fundamentally where was the field before this readout and after this readout. I think the key data there is that there's been some, a lot of overhang in the field from a Tau antibody approach in general, given prior failures. And how this data moves the field forward, I think, is there's a clear ability that an antibody can impede the spread of Tau, as based on Tau-PET, important biomarker. So that data was clear in the whole population. And when you looked at pre-specified other populations, low Tau, for example, perhaps a slightly greater effect. We'll continue to sort of explore the dose response of that effect moving forward.
Okay. You've mentioned, I think in previous calls that it would be really interesting or informative to understand the PK/PD relationship for that asset. Thinking about the importance of PK/PD, is that something you'd want to front-load into your studies or integrate early on to help inform you about whether you're in the right population or just to help you accelerate into later phase development?
Yeah. I think it, I mean, I think it's a nice thought, but fundamentally that requires a relatively large study. And I think our initial take-home message from the UCB data is try to understand the right population to maximize the signal, particularly on Tau-PET, and we think that tool really will allow us to test efficiently does our antibody impede Tau accumulation.
Okay. Some prior anti-Tau approaches, started in, primary Tauopathies and moved to AD. You know, what's your current thinking about the potential applicability of VY7523, across the spectrum of diseases that'd be driven by Tau?
I think fundamentally we feel in terms of obtaining proof of concept in terms of Tau spread that Alzheimer's is the right disease to go to first, and that really is based on the concept that we know that stereotyped spread occurs in humans and we can measure that with Tau-PET. You don't see that same stereotyped, easily measurable spread in other populations. That being said, once, if we're fortunate enough to sort of impede Tau spread with our antibody, we could consider other indications.
Got it. Maybe you could talk about the recent trontinamab data. There was a single death in that study, and some cerebral amyloid angiopathy. Can you talk about those observations and how it may or may not apply to your program?
Yeah. So I think it's been a general question in the field whether or not the sort of imaging and ARIA-related, like imaging effects and bleeding observations that occur with beta amyloid therapies are applicable to Tau therapies. And I think the current data sets haven't shown a clear link. There is a baseline level of amyloid angiopathy in these populations. And so there is some baseline risk. I think in particular the UCB data was particularly informative here. The team looked quite closely using MRI tools and looked at sort of rates of bleeding across these two populations as well as rates of imaging abnormalities and didn't see any clear differences. So I think the current data suggests that these imaging and clinical findings are consistent with beta amyloid therapies, but less clearly Tau.
Mm-hmm.
Of course, in that context, of course, we'll image folks and we'll continue to understand if there a signal does emerge.
Maybe turning to the gene therapy approaches, you have a vectorized siRNA for Tau and a vectorized antibody for A-b eta. Do both of those programs use the same capsid?
I think we haven't actually clearly said which capsid for which program, but what I will say is that for the SOD1 program, we've highlighted this is a second-generation capsid based off our disclosed ALPL receptor. And that's our program heading to IND next year. The other, we have a number of other choices across other programs. Over time, we expect to learn how to tailor these choices. But for right now, they all will clearly be based off our TRACER technology, is what I can say.
And then, have you, in terms of the gene therapies, you've prioritized Tau, or there is no priority for either the A- beta approach or the Tau approach?
So the Tau-based approach is. That's a clinical program is moving forward. We expect an IND in 2026. And so that knockdown. That's clearly an important program for us. I think the other point I'd make is that about that time of that IND, Voyager's BIIB080 program will have a large phase two readout of over 700 participants. So expect to be there, to be the coincidence of that large clinical data set, our IND, with hopefully some data about capsids prior to that.
Okay. And then anything about the fact that, you know, alkaline phosphatase is the receptor by which it gets in that helps you maybe reframe the behavior of this gene therapy relative to prior gene therapies? And what I mean by that is, you know, dose response has been something that's ambiguous sometimes for certain gene therapies. Does alkaline phosphatase give you confidence that you'll be able to dial it into an effective dose more easily?
So I think what I'd say is, in general, in the concept of dosing gene therapies, particularly for CNS-related disorders, we've always been struggling with biodistribution. And so in that context, you're often driving up doses. And so you're on the upper end of that dose-response curve. And that has clear issues in terms of not only manufacturing, but safety and has driven some of the concerns. And so the extent that we can, with a specific receptor-based delivery to the CNS, drop down our doses, I think you can explore potentially the lower ranges of the dose-response and hopefully dial it in better. We will see how, where we land as we move through toxicology and first-in-human studies.
But our hope is that we can move forward with a systemic therapy that's at substantially lower doses than previously used.
Got it, and maybe we can move on to the rare neurological work. And maybe Debjit could bring me the second page 'cause it's not here. So I'm working off the top of my head, but in terms of your SOD1 ALS program, let me ask it in a really provocative way. Why isn't tofersen just good enough?
Yeah. So maybe, in all transparency, I led the tofersen program at Voyager.
It's actually named after him too.
I think the key learning from that program was a couple. One, you really know what you need to achieve in terms of biomarker reduction to provide eventual clinical benefit. That really is SOD reduction on the order of 30%, neurofilament reduction on the order of 50%-70%. That eventually provides a transformative clinical benefit. I think the other lesson learned from that program, perhaps the hard way, is that is a monthly lumbar puncture. That is quite reasonable for biodistribution in the spinal cord, which is that there may be some opportunity in terms of further biodistribution into the cortex. That's one key point. Our approach with delivery through the vasculature should potentially achieve broader biodistribution.
Then I think it's also important not to underestimate the idea of a monthly OP in a sick population and the burden on the patients and the burden on the infrastructure that may represent.
Mm-hmm.
And so if you come to the situation with a therapy that you could, it was a one-time IV administration with a potential for broader biodistribution, perhaps greater efficacy and ease, improved ease of access and administration that could be beneficial for patients.
So maybe just backtracking a little bit then, your idea of using a gene therapy in the context of Alzheimer's would also alleviate some of the clinical operation burden of a therapy that you need to go in and get imaging, you need to be dosed at some frequency and aspects like that. Is that a way to think about it?
We certainly would agree that the idea that a one-time therapy that's safe and effective certainly would represent less burden than LPs or IV administration of some frequency. I mean, I think first and foremost, of course, it has to be efficacious.
What about the VY9323 capsid? Is that the first-generation capsid?
So it's a second-generation capsid. It's derived from our disclosed ALPL receptor family and really is our first wholly-owned program that will test that capsid in people. And maybe back to some of the prior points I made about tofersen, really the opportunity of a SOD1 ALS program, not for the people with SOD1 ALS, but for the Voyager approach is that it allows us very quantitatively to understand the effect of giving our capsid to individuals. And really, if we see SOD1 reduction, we think that will tell us about target engagement and really the ability of the capsid to get across the BBB. So we think we can test that very efficiently. The neurofilament levels will tell us how much we can, how the drug itself is doing.
If we see reductions in the levels of 50%, we know we have a drug as well. And so we can really understand the platform implications based on that and also the implications for the drug as a whole, both with SOD1 and neurofilament.
Got it. And sort of, a natural evolution that's been discussed, given that you've identified the receptor that uptakes the capsid is the development of some other modality to leverage that receptor to get into the central nervous system. You don't have to name any particular indication, but like, how is Voyager thinking about, you know, where to utilize that feature, for the development of other, modalities targeted to the central nervous system?
So maybe I'll tackle this in a sort of a, as a general comment about modalities. I think fundamentally, as we look at ALPL and the other receptors we've identified, we expect they'll each have their own characteristics that may make them useful in certain indications. We'll learn those over time. I think in what we were excited about, the sort of shuttle-based approach is the idea that receptors we identified through our gene therapy platform, we're now looking to see if ALPL and the other ones can be used to get an antibody across the BBB, a nucleotide, an anti-nucleotide, a nucleotide across the BBB or an enzyme. And so we really think that it allows us to sort of broaden the way we deliver therapeutics across the BBB, albeit early, but we're quite excited by this platform.
Because you're looking into space and there's a lot of attention about crossing the BBB, do you have any particular concerns you see with the transferrin approaches for crossing the BBB?
I mean, I think, I mean, if you referenced the trontinamab data, I mean, clearly that data is quite remarkable in terms of sort of the effective reduction they've seen in amyloid, certainly compared to the native antibody before they coupled it. And so I think there's some nice proof of concept there. I think there clearly have been, I think that we're quite positive about it, emphasizing the importance of the field. There are perhaps some safety signals around anemia and other events there we need to keep an eye on and see how they emerge. I think our fundamental position would be that the field is really focused on transferrin because other opportunities, say, other than CD98 really haven't been identified.
Our position is we really need to explore the full range of things that can get stuff across the CNS in a receptor-mediated way. We'd likely think that additional receptors will have value in that regard.
Are we, are we talking like tens of receptors that you guys have identified or?
I don't think we've disclosed how many, to be frank, but certainly more than one.
Okay. I'll just assume hundreds.
Certainly more than one.
But it's okay that we don't have a number, but I'm curious, like, are you, is it emerging that you're able to now target specific regions of the brain as you characterize different receptors? Does it seem like you can tune into a particular therapy, a particular disease and go there, and avoid, you know, targeting portions of the brain that sort of either it would be deleterious to hit or, you know, just would be a waste of drug?
Yeah. I mean, it's probably a bit early to say, but clearly different receptors will have different patterns of transduction and it's not entirely homogenous across cells, neurons, glia, and other populations. And so the short answer is yes, but the details remain to be worked out. I think when you start combining a capsid with a certain receptor plus promoters of certain cell type specificities, you will get to a place where you can tune gene therapies to a much greater extent than currently exist.
Got it, and then you've done a lot of partnering work so far, a great way to monetize the products that you've been able to produce and at the same time, you know, fuel your internal pipeline going forward. What does partnering look like going forward, and you know, maybe you could just paint the strategy there.
Maybe I'll give that one to Nate.
Yeah. So the company's done an amazing job monetizing the capsids. And so it's actually over $500 million in the last few years. There are targets out there that we, that other people are interested in that we haven't outlicensed. So there's opportunities for us to continue to do that. And we plan to do that to, as you said, to fund the, the pipeline and platform. It's been very valuable over the last few years. We now have four internal programs. You know, a lot of that was funded through these capsid deals. And so we'll continue to do it.
Wonderful. Any questions from the audience? Debjit? Go ahead.
Yeah. I was just gonna ask about the Tau antibody. Is that an antibody that is peripheral antibody or does it actually cross the blood-brain barrier? [audio distortion]
So it's.
[audio distortion]
It's a very classic, conventional IV-administered antibody. We do know based on preclinical data that we get CSF exposure to plasma exposure of about 0.1%-0.5%, very consistent with a classic IgG. I mean, that said we.
[audio distortion]
Correct.
So because you're using IgG, you don't have activation of immune cells as the mechanism for clearance, if I'm not mistaken, right?
Correct. This antibody does not have effector function. We think really the underlying therapeutic hypothesis is that the binding of Tau in the extracellular space prevents the transmission and templation of Tau in other neural populations. It's not about clearance of Tau, aggregated Tau.
Why was that the rationale when going after Tau and not using something that has an effector domain?
Really, because I think if you look at what happens in humans based on Tau-PET imaging and based on neuroanatomical staging, what you see over time is that Tau is initially highly localized in the temporal lobe and then gradually you get local spread and gradually that spread occurs throughout the remainder of the cortex. And it's that spread that correlates with clinical disease progression. So really what you're trying to do is interrupt that spread instead of clear pre-existing plaques. And so the idea here is that the antibody will impede that cell-to-cell transmission that causes the progression of clinical symptoms.
And is there any rationale to clear both extracellular and intracellular Tau? And could there be a future where you see gene therapy used in tandem with your antibody?
I think if you look at the BIIB080 data, that it highlights that there likely is a very strong rationale for reduction of Tau overall. And what you see with that dataset is that you can get substantial reduction of Tau. And I think they used Tau-PET in that study. I think the remarkable learning from that study was that even pre-existing Tau as imaged by Tau-PET was decreased. That observation that you could clear that Tau, that was unexpected and quite positive. They did make some clinical comparisons in that study. It's early. They did some propensity score matching to another Alzheimer's study called Tango and then a natural history dataset. But they saw an effect on CDR sum of boxes in that comparison of two to two and a half points.
Just to remind in context, the beta amyloid therapies are a half a point to a point approximately. And so that really highlights the potential of Tau reduction in and of itself. And then I think in terms of when you layer on Tau spread, I think you could layer on that sort of. There's the idea that we've seen with the beta amyloid therapies is that the high Tau populations may not seem to do as well, particularly say you look at the donanemab ad board discussion was informative in that regard. There may be a space where you beta amyloid therapies and Tau antibodies come earlier in disease, but after you've had progression of disease and deposition of Tau across multiple neural populations, you need to take an approach where you reduce Tau with an siRNA.
Mm-hmm. Worst case scenario, not saying that's gonna happen, but if you ended up finding the strongest signal in non-APOE4 carriers and low Tau, what does that market look like?
So I think we've formally looked at that, but fundamentally it remains certainly for our company an interesting market. I mean, it's a relatively small population compared to the overall population, but the scale, of course, is very, very large.
Okay.
Still very sizable.
Yeah.
Obviously you can take just a portion of Alzheimer's, even that gets a 10%. That's still, you know, 600,000 patients.
Yeah. Wonderful. Well, we have 13 seconds left, so I think we'll just end here. Thank you so much for your time.
Thanks for your time. Appreciate the opportunity.