Good morning, everyone. I'm Sumanth Kulkarni, a senior biotechnology analyst here at Canaccord Genuity, and I'm very happy to have Voyager Therapeutics presenting here today. It's an exciting time for the company as their pipeline matures, and we're gonna get into the clinic some point soon. So for Voyager, we have Nate Jorgensen, who's the new CFO. We have Toby Ferguson, the Chief Medical Officer, and Trista Morrison, the Chief of Corporate Affairs. So with that, this is gonna be a very interactive type presentation. So if you have any questions, you know, please feel free to raise your hands. We'll have a mic out to you, so don't be shy about asking questions. But I probably should start with an Olympics question or something like that, but I won't.
So I'll have you guys say a few words, and then we can jump right into Q&A. So Nate, go ahead.
Well, thank you for having us here, Sumanth. I just joined as Voyager CFO about a month ago, so I'm still getting into the seat, but I'll just share what attracted me to Voyager. So first off, it's the CEO, Al Sandrock, caught my attention. Obviously, he's a legend from Biogen. And then, as I dug into Voyager more, what I realized is they took a systematic approach to reduce risk, and that's very attractive. So my background, going way back, is a PhD in neuroscience before I became an investor and worked on the sales side, and that actually kept me from investing in the CNS space. And that's because these diseases are not traditionally that well understood. It means their targets aren't good, the clinical trials are messy.
But what Voyager has done is focused on genetically validated targets, so going after good, high-quality targets that lower risk, and then on the clinical trial side, focusing on diseases that have surrogate endpoints. That means they don't have to spend $200 million to get an answer, and then with the surrogate endpoint, you can usually see an effect much easier. Another issue that has plagued the CNS space over the years is getting into the brain. Even Voyager itself had issues with direct injections of gene therapies. They developed their novel capsid platform. They can now deliver AAVs intravenously across the blood-brain barrier. This is a huge innovation for the entire field. And then finally, they've taken an approach of partnering assets and generating cash and building a sizable pipeline, 'cause there's still gonna be fails, failures.
But that's gonna de-risk, I guess, the probability of actually a colossal failure. And so all these together, I guess, makes me very excited about the opportunity at Voyager. So thank you for having us here.
Toby, same for you as well. Just, what attracted you to the company?
So it's great to be here, and thanks for the opportunity. My background really is as a neurologist and a drug developer, and that's sort of how I think about my career. And fundamentally, I welcome the chance to work with Al Sandrock again as one of the foremost neurology drug developers. But fundamentally, I think it's the technology that attracted me, this idea that based on careful work and this pivot from direct injection of capsids to now an approach where you can fundamentally give an AAV intravascularly, take advantage of the vasculature to enable broad biodistribution. So really solve one of the key technical challenges that faces CNS drug development writ large.
And then I really like the idea that, that there are a number of opportunities that you can leverage based on their discoveries around capsids and the receptors that drive that blood-brain barrier penetration. So really coming from--becoming an AAV company, but also more broadly, a neurogenetics company. And that, that really just excites me and that potential to bring forward transformative therapies for people with neurologic disease.
Trista, you've been part of the company for some time now. You've seen some additions to the team and changes. How has all that evolved and has your role evolved as well?
So I've been at Voyager for two years now, which makes me the old hat on the panel here. And you know, I would say in that two-year period, what I've been most impressed with is exactly the way that Al has assembled the team of experts that he wants around the table and brought in this incredible neurology expertise. I mean, Al himself is visionary in the neurology drug development field. He's brought in Toby, who has incredible experience and will probably blush when I say that he has a drug named after him. Tofersen is named for Toby Ferguson. And you know, Nate, I mean, I think finding someone with his background on the buy side, on the sell side, and a Ph.D. in neuro is incredible.
Not to mention our Chief Scientific Officer, who's not here with us today, 'cause some people are in the office doing work right now. And, he. I mean, he led the pivot of Voyager back in 2021. You know, Voyager was one of the first companies founded to do gene therapy for the brain, and one of the first to realize that injecting that directly via IP or IT was probably not gonna be ideal. And so he really led the pivot of the company with his team to develop the TRACER technology, which created these IV-delivered brain-penetrant capsids that have really become the backbone of so many of our programs. In fact, we have currently 13 partnered programs, and we have 4 wholly owned programs, the lead of which is actually in the clinic.
I'm sure we'll talk about that, as we go on.
Cool, thanks. So I think Al is missing. I'm gonna take him on a bus tour and call it Al-A-Palooza if he comes back. So, in case we'll start with your program, the anti-tau program. You have two programs targeting tau. Why are you so excited about tau as a target, and why would not this be like anti-amyloid beta all over again in terms of experience as you develop a drug?
So I think maybe I'll take that first shot. So I think most fundamentally, I think, I mean, there's a wealth of data, both human genetics in dementia, and a wealth of pathologic data that suggest as pathologic tau spreads from one part of the brain, the temporal cortex, to the rest of the brain, that's what drives disease progression and pathology in Alzheimer's. So there's a wealth of data that suggests it really is a critical feature of the disease. I think in addition, there's been some compelling data from some external ASOs in which you give an ASO intrathecally, and in that context, they've seen tau reduction and potential meaningful clinical change on CDR sum of boxes, albeit a bit early, but very early, but compelling.
And I also think fundamentally, I think it, to a really important point, the tools exist to, determine if you can actually have a biomarker-based effect, and in this case, tau PET. And so it's that, that tool that also enables that quick proof of concept that's critically important. So tau is a de-risked target. The technologies exist to do a relatively efficient trial, and, and the human data really supports it. So all those together really gets quite excited. I, I do think that if you look at the overall beta amyloid data, I think what you take away from that, it's an important, important first step for people with Alzheimer's. But fundamentally, you still, in most patients, still do see disease progression, and that really implies that there needs to be another treatment.
In particular, if you look at some of the Donanemab experience, patients with higher Tau didn't do quite as well. Fundamentally, it raises this concept. There likely needs to be additional treatments, one, and two, Tau is a very high-value target.
Cool. So with that as background, let's go into the antibody a little bit. We know you're targeting a different part of tau, so that's one point of differentiation. But as you head into a data set, what do you expect to see with that data set, and how would you qualify success on that?
So maybe just to reiterate a couple key points that you made, Sumanth. I think fundamentally, I think this antibody is to a different part of the protein than some of the other molecules that have failed previously, and it's designed to recognize pathologic tau. And what we've basically shown in preclinical models, that if you inject a bit of human pathologic tau into a mouse brain, you can impede substantially by about 70% that spread of pathologic tau. And we know, as I've highlighted earlier, that's the process that happens in humans. And so most fundamentally, using tau PET, we wanna see if we can impede that spread. And the antibody program, we've moved that antibody into the clinic. It's currently in a single ascending dose study.
We look forward to getting some data in the latter first half of next year to support a multiple ascending dose study in early AD patients. In that study is the one we'll bring forward some tau PET data we've guided to the latter half of 2026.
Got it. You also have a gene therapy approach to Tau. So could you, What excites you most about that approach versus the antibody approaches, and maybe could you compare and contrast that with the other approaches like antisense oligonucleotides and things like that?
So I think fundamentally what I'd highlight there, that is a gene therapy-based approach. It's intended to utilize these new TRACER AAV capsids that Voyager's identified, and fundamentally, that approach is one-time intravascular approach where you allow for IV administration. We think that gets you a couple things. One, it's once. Two, it's intravenous, and that route of administration we think is clearly differentiated from intrathecal. And three, fundamentally, it utilizes the vascular to get broader biodistribution throughout the CNS. And given those pieces of differentiation and the other data I highlighted earlier, particularly the importance of tau, the other promising early clinical data, that really gets us excited.
Got it. Let's move to your gene therapy programs now. Could you give us a little bit of background? You alluded to it, but the novel TRACER capsid that you have, what did you see in it, and what did others see in it? Because you've partnered it out many times over now.
Yeah. See, I think the partner point is a nice point to highlight a nd later Trista can comment as well. But there we've had a number of very productive partnerships, particularly Novartis and Neurocrine. I think the brief point to make there is we've had a long partnerships with them, but recently come back for additional partnerships, and that really, I think, is an important point that hopefully validates the technology, at least in their eyes currently. What I think we see is that we've developed a data set that has really enabled us to have three INDs coming next year. Our wholly owned SOD1 program, and then two of our partner programs with Friedreich's ataxia and GBA. And fundamentally, I think the next step really for the TRACER platform is to ask ourselves: Does it work in the clinic?
That's what I'm really excited to test. I'd highlight in particular the SOD1 program. Obviously, SOD1 ALS is near and dear to my heart. I think one of the key lessons we've learned from the Tofersen program, which is Biogen's intrathecally administered ASO, really there are a couple key biomarkers, both SOD1 measurement in the CSF and neurofilament measurement in the blood, that really give us a very reasonable and quick indication of how the molecule's doing. Do we get target engagement, i.e., SOD reduction? And do we get neurofilament reduction, i.e., do we modulate neurodegeneration? Neurofilament is particularly important in that it also gives you some idea about potential clinical effect, given that the Tofersen program established that relationship.
Got it.
I think it's maybe just worth adding there, you know. I think a lot of folks have anchored on... Because the tau antibody is our first program in the clinic, and we have guided to potentially having some tau PET imaging data in the second half of 2026, I think a lot of folks have anchored on that second half of 2026 as a potential value iNfLection point. But I think it's worth noting, you know, what Toby just said. We actually have 3 gene therapy programs tracking toward IND next year, in 2025. And what's interesting there, right, is that those are not going to go into healthy volunteers. Those are going to go into patients at therapeutic doses....
And so, you know, I think, I think it's reasonable to think that it won't take too long to get, you know, potentially a handful of patients and get some meaningful data there. So we haven't guided specifically on that because we're letting Toby work out the clinical development plan on the SOD1 ALS gene therapy program. And the other two programs, the GBA1 and the Friedreich's ataxia programs, are both partnered with Neurocrine, and so we don't comment specifically on the timelines for those other than to say IND in 2025. But I think there's a lot of opportunities that could come ahead of that tau antibody data in the second half of 2026, and also that make that not a binary proposal.
So given the level of expertise we have here on SOD1 ALS, I'm gonna ask you a biomarker-related question. NfL reduction.
Mm-hmm.
What is, in your view, considered a clinically relevant reduction in NfL?
I presume you mean in SOD1 ALS?
In SOD1 ALS and in sporadic ALS as well, if you compare and contrast those.
Okay. So I think it's a great question, and I think you have to sort of take it disease by disease. But fundamentally, I'd go back to the Tofersen data, and that, in that program, there was approximately 40% reduction in the CSF. What I will say is that, that—I'm sorry, that was CSF SOD reduction. For Tofersen, we saw about 75% reduction of neurofilament. What we know is that reduction translated to... I think there was a very recent clinical real-world experience paper published last week about early experience with Tofersen, and what I highlight there is about half of the patients were either stable or improved. And I'll just pause there.
As a neurologist who used to treat ALS patients, I never thought I would be able to say I could give someone an ALS drug that led to improvement. So I think that we know that 75% leads to a transformative effect in ALS, and so I think that's the data we have. I think you could make an argument that lower levels are likely to be meaningful also, but they have to be outside the range of both biologic and assay variability, and so I think that's sort of the simple question. And that's based on data both in sporadic ALS and broad ALS, I mean, and SOD ALS. That's about 20-25%.
Got it. Given you have, like, an antisense oligonucleotide, if you compare that to a gene therapy, what would be the relative quickness of action of either of those compounds in terms of NfL reduction, and does that matter?
So I think in Tofersen, the experience, you started to see by 12 weeks an initial separation, and certainly by 16 weeks and thereon, you saw the maintenance of that reduction, and that's an ASO. I think in... You likely have similar time courses in a gene therapy, though we don't know that yet. I think one potential complicating feature is some programs, there was a recent publication by the Prevail group, that showed that very early on after you administer AAV, you get a spike of neurofilament that then comes down, and so you have to understand those relationships as well.
Right. How confident can you be on whether your SOD1 ALS gene therapy could be a one-time thing?
I think fundamentally, we believe, based on the siRNA we've constructed, that it will continually produce that knockdown, and so all current data suggest it would be a one-time therapy.
Got it.
But fundamentally, that remains to be determined in the clinic.
Yep. Understood.
Yeah, and I think there's emerging data on that, that you know, we find really interesting. I mean, Al talks a lot about the Spinraza Zolgensma relationship and how, you know, Spinraza was able to come to the market quickly as an ASO, have a significant difference in both... and for patients and become a very successful drug. Zolgensma, then, a gene therapy, comes to the market and becomes the market leader, but more recently, there has been data showing that for some patients who receive the gene therapy and still have some progression, adding Spinraza on top, right? Now, you're not having to maybe give it as frequently, but topping off with a little Spinraza has been shown to have some benefits. So, you know, it... I think there's a lot of benefits to that approach, right? You start with an ASO.
You have an opportunity to also evaluate the drug and make sure in humans that it is doing what you want it to do and not doing things you don't want it to do before you come and follow with a gene therapy, sort of permanent solution. And then if you need a little more, you have that opportunity, right, to level up. So, I mean, we'll see if that continues in the neuro field, but, you know, perhaps that could be a future in SOD1 ALS if all goes well with our program.
So when you eventually get to the stage where you have your SOD1 gene therapy in clinical trials, how do you expect the split of patients to be between patients who are naive patients and patients already on Tofersen?
I think fundamentally, that's gonna likely vary by geography, depending on the approvals. But I think the working assumption would be that a number of folks will be on Tofersen, and then you'll have some naive patients as well, maybe.
Got it. Okay.
There'll be-
Is that a target that could be considered, quote, unquote, "good" from a regulatory perspective on that?
I think the key regulatory question really will be, of course, safety, but fundamentally, are you getting the appropriate SOD and neurofilament reductions? We know based on Tofersen experience that that can serve as a regulatory approval, at least for accelerated approvals. And so I think that it likely can be in either population.
Okay. So just going back to your capsid platform, we're seeing increasing competition from companies creating these blood-brain barrier penetrant intravenous type capsids. What makes you different? You're in the lead, it looks like. What could make others leapfrog you, and how are you gonna prevent that?
I think the foremost question I would say is, we've gotten to the point where it's time to test these in the clinic, and that's really, I think, the point I'd make there is we intend to do that as quickly as possible with these INDs in next year. I think that's the most fundamental point. But if you look, I think, at the agreed, there are a number of companies coming to the fore. I think where we differentiate clearly is the breadth of our data. We have shown that it works in a mouse, it works in two primate species. We've identified the receptor. We know the receptor is expressed in human vasculature. We know that it's still present in disease conditions.
So fundamentally, I think we have done about all you can do to establish the potential translatability of this into humans. The next thing to do is test it in humans. I think if you look at some of the other data packages, they have some of these pieces, but not in its entirety.
Got it.
I think it's just flattering that some people are trying to copy. 'Cause what they've done at Voyager, obviously before I joined, is pretty spectacular, and so there, there's gonna be competition, but as he said, we have the most robust data set, and that's why some of the partners keep coming back to us.
Right. So you had this whole receptor X. I kind of like that, like the mysterious factor, but we now know it's ALPL, right, for non-viral delivery. So, you have any updates for us on that front?
I think what I'd say is, one, we're excited to share the identity. And I think fundamentally, what it broadly opens up is the concept that you can use this receptor, and perhaps some of the other receptor families we identified, to really understand, can they be used to deliver other modalities across the CNS? Oligonucleotides, antibodies, proteins, et cetera. And fundamentally, we are working to understand that potential. We'll be excited to share data when we can, but it opens up this idea that Voyager could be broadly a neurogenetics company, not just an AAV company.
Got it. Are there any known downsides of targeting ALPL that you had to manage around to, to make it behave?
Currently, we don't understand there to be any downsides, but we will have to test in clinic.
Right. 'Cause I think there's some implication with bone density and things like that. Do you expect to hit up against those kinds of things?
As I said, we've seen if you look in human genetic databases, that loss is well tolerated, and so this is sort of our guiding principle, but fundamentally, we'll test in the clinic.
Okay. Trista, did you want to say something? I think I-
Oh, I was just gonna say that, you know, that work is still relatively early, but I think you're spot on to ask about it because I do think that we're all really excited about that, about the potential to have, you know, not just this incredible leading platform for delivering AAV across the blood-brain barrier, but potentially a whole other platform, right, of non-viral delivery, leveraging ALPL and potentially other receptors that we're beginning to identify through our work. So I think there's a lot there if the science pans out.
Mm-hmm. Got it. We have a couple of minutes left. I'll go into partnership-type questions. You have so many things going on, right? When you evaluate external partnerships, how do you make the decision on what you keep internal versus what you can farm out externally?
Yeah. So that's a good question that we talk a lot about internally, about what we want to focus on, and some of the discipline around how we want to manage risk goes into it. Like, we want to go after really well-validated targets internally. If we think it's too risky, obviously, it's something maybe more appropriate for a partner with deeper pockets, and it's the same in terms of the clinical trial. So it's trying to strike that balance. What I like about what Voyager has done is basically taking the Sanofi model or the Sanofi Regeneron model, where that Sanofi deal with Regeneron transformed them. It allowed them to build the platform that they needed to and get the pipeline going, and that's what Voyager's done.
Look at all the shots on goal that they've been able to to develop in their pipeline because of these partnerships. So we're gonna continue to push on on some of these partnerships. I think there's a lot of opportunity, opportunities out there. The CNS space is, is, is huge. There's a lot of targets to go after, and so I think we will continue to see this. And I think there's... Toby has some ideas, and we're gonna continue to pursue them.
Got it. So you would still be actively pursuing external partnerships?
I think this is a great strategy. The market's so big that even, you know, when we share some of the upside, it's still massive upside. We only, you know, need a few of these pipeline hits to win, for Voyager to win. And right now, as Trista mentioned earlier, we have four wholly owned and 13 partnered programs. I mean, that's a lot of shots on goal. A lot of those are massive markets. Alzheimer's, huge, 6 million patients. So we can share some of the upside, share the risk, and we'll continue to take those partnership deals.
Got it.
Yeah, and I would just add to that, I mean, you know, to emphasize, we are, we are interested in doing trials where we think we can quickly and efficiently get to meaningful data, right? The reason that we're doing the SAD and then the MAD study with the tau antibody is because of the interest we have in seeing that tau PET imaging data, which we think we can get to relatively quickly and efficiently, and will actually be able to show if we're impacting the spread of tau. We're not interested in doing large Alzheimer's trials. When it comes to, you know, partnerships in large indications, we have frequently said it's a question of when, not a question of if. We, we don't have any intention of doing those kinds of large, very expensive trials....
No, with the smaller indication, like SOD1 ALS, I mean, no one knows better than Toby that there are some efficient biomarker-based paths to market, so we'll see.
You have a few seconds left, I'll squeeze one in. In the event that investors are missing something about the story from where you sit, what do you think that might be?
So I think, well, we touched on two things already that I think investors don't completely appreciate, and the first thing is when I talked about the de-risking or the reduced risking that's gone on at Voyager in terms of targets and the clinical trial design. And that I think provides Voyager a different profile than a lot of the CNS space. That's not appreciated. And the second thing is we're gonna have these four different clinical programs next year. With the approach that we're focusing on surrogate endpoints, means that clinical data is gonna come soon. So this is—next 12 to 18 months is gonna be a very exciting times in terms of potential clinical data, and I don't think that's quite appreciated yet by-
Good morning, everyone. I'm Sumanth Kulkarni, a senior biotechnology analyst here at Canaccord Genuity, and I'm very happy to have Voyager Therapeutics presenting here today. It's an exciting time for the company as their pipeline matures, and we're gonna get into the clinic some point soon. So for Voyager, we have Nate Jorgensen, who's the new CFO. We have Toby Ferguson, the Chief Medical Officer, and Trista Morrison, the Chief of Corporate Affairs. So with that, this is gonna be a very interactive type presentation. So if you have any questions, you know, please feel free to raise your hands. We'll have a mic out to you, so don't be shy about asking questions.
But I probably should start with an Olympics question or something like that, but I won't. So I'll have you guys say a few words, and then we can jump right into Q&A. So Nate, go ahead.
Well, thank you for having us here, Sumanth. I just joined as Voyager CFO about a month ago, so I'm still getting into the seat, but, I'll just share what attracted me to Voyager. So first off, it's the CEO, Al Sandrock, caught my attention. Obviously, he's a legend from Biogen. And then, as I dug into Voyager more, what I realized is they took a systematic approach to reduce risk, and that's very attractive. So my background, going way back, is a Ph.D. in neuroscience before I became an investor and worked with the sales side, and that actually kept me from investing in the CNS space. And that's because these diseases are not traditionally that well understood. It means their targets aren't good, the clinical trials are messy.
But what Voyager has done is focused on genetically validated targets, so going after good, high-quality targets that lower risk, and then on the clinical trial side, focusing on diseases that have surrogate endpoints. That means they don't have to spend $200 million to get a, get an answer, and then with the surrogate endpoint, you can usually see an effect much easier. Another issue that has plagued the CNS space over the years is getting into the brain. Even Voyager itself had issues with direct injections of gene therapies. They developed their novel capsid platform. They can now deliver AAVs intravenously across the blood-brain barrier. This is a huge innovation for the entire field. And then finally, they've taken the approach of partnering assets, and generating cash and building a sizable pipeline, 'cause there's still gonna be fails, failures.
But that's gonna de-risk, I guess, the probability of actually a colossal failure. And so all these together, I guess, makes me very excited about the opportunity at Voyager. So thank you for having us here.
Toby, same for you as well, just, what attracted you to the company?
So, it's great to be here, and thanks for the opportunity. My background really is as a neurologist and a drug developer, and that's sort of how I think about my career. Fundamentally, I welcome the chance to work with Al Sandrock again as one of the foremost neurology drug developers. But fundamentally, I think it's the technology that attracted me. This idea that, based on careful work and this pivot from direct injection of capsids to now an approach where you can fundamentally give an AAV intravascularly, take advantage of the vasculature to enable broad biodistribution. So really solve one of the key technical challenges that faces CNS drug development writ large.
And then I really like the idea that there are a number of opportunities that you can leverage based on their discoveries around capsids and the receptors that drive that blood-brain barrier penetration. So really coming from becoming an AAV company, but also more broadly, a neurogenetics company. And that really just excites me and that potential to bring forward transformative therapies for people with neurologic disease.
Trista, you've been part of the company for some time now. You've seen some additions to the team and changes. How has all that evolved and has your role evolved as well?
So I've been at Voyager for two years now, which makes me the old hat on the panel here. You know, I would say in that two-year period, what I've been most impressed with is exactly the way that Al has assembled the team of experts that he wants around the table and brought in this incredible neurology expertise. I mean, Al himself is visionary in the neurology drug development field. He's brought in Toby, who has incredible experience and will probably blush when I say that he has a drug named after him. Tofersen is named for Toby Ferguson. You know, Nate, I mean, I think finding someone with his background on the buy side, on the sell side, and a Ph.D. in neuro is incredible.
Not to mention our Chief Scientific Officer, who's not here with us today, 'cause some people are in the office doing work right now. And, I mean, he led the pivot of Voyager back in 2021. You know, Voyager was one of the first companies founded to do gene therapy for the brain, and one of the first to realize that injecting that directly via IP or IT was probably not gonna be ideal. And so he really led the pivot of the company with his team to develop the TRACER technology, which created these IV-delivered brain-penetrant capsids that have really become the backbone of so many of our programs. In fact, we have currently 13 partnered programs, and we have four wholly owned programs, the lead of which is actually in the clinic.
So I'm sure we'll talk about that, as we go on.
Cool, thanks. So I think Al is missing. I'm gonna take him on a bus tour and call it Alapalooza if he misses that. So, in case we'll start with your program, the anti-tau program. You have two programs targeting tau. Why are you so excited about tau as a target, and why would not this be like anti-amyloid beta all over again in terms of experience as you develop a drug?
So I think maybe I'll take that first shot. So I think most fundamentally, I think, I mean, there's a wealth of data, both human genetics in dementia, and a wealth of pathologic data that suggest as pathologic tau spreads from one part of the brain, the temporal cortex, to the rest of the brain, that's what drives disease progression and pathology in Alzheimer's. So there's a wealth of data that suggests it really is a critical feature of the disease. I think in addition, there's been some compelling data from some external ASOs in which you give an ASO intrathecally, and in that context, they've seen tau reduction and potential meaningful clinical change on CDR sum of boxes, albeit a bit early, but very early, but compelling.
I also think fundamentally, I think to a really important point, the tools exist to determine if you can actually have a biomarker-based effect, and in this case, tau PET. So it's that tool that also enables that quick proof of concept that's critically important. So tau is a de-risked target. The technologies exist to do a relatively efficient trial, and the human data really supports it. So all those together really gets quite excited. I do think that if you look at the overall beta-amyloid data, I think what you take away from that, it's an important, important first step for people with Alzheimer's. But fundamentally, you still, in most patients, still do see disease progression, and that really implies that there needs to be another treatment.
In particular, if you look at some of the Donanemab experience, patients with higher tau didn't do quite as well. Fundamentally, it raises this concept. There likely needs to be additional treatments, one, and two, tau is a very high-value target.
Cool. So with that as background, let's go into the antibody a little bit. We know you're targeting a different part of tau, so that's one point of differentiation. But as you head into a dataset, what do you expect to see with that dataset, and how would you qualify success on that?
So maybe just to, just to reiterate a couple key points that you made, Sumanth. I think fundamentally, I think this antibody is to a different part of the protein than some of the other molecules that have failed previously, and it is designed to recognize pathologic Tau. And what we've basically shown in preclinical models, that if you inject a bit of human pathologic Tau into a mouse brain, you can impede substantially by about 70% that spread of pathologic Tau. And we know, as I've highlighted earlier, that's the process that happens in humans. And so most fundamentally, using Tau PET, we wanna see if we can impede that spread. And the antibody program, we've moved that antibody in the clinic. It's currently in a single ascending dose study.
We look forward to getting some data in the latter first half of next year to support a multiple ascending dose study in early AD patients. And in that study is the one we'll bring forward some tau PET data we've guided to the latter half of 2026.
Got it. You also have a gene therapy approach to tau, so could you, what excites you most about that approach versus the antibody approaches, and maybe could you compare and contrast that with the, other approaches like antisense oligonucleotides and things like that?
So I think fundamentally what I'd highlight there, that is a gene therapy-based approach. It's intended to utilize these new TRACER AAV capsids that Voyager's identified, and fundamentally, that approach is one-time intravascular approach where you allow for IV administration. We think that gets you a couple things: one, it's once; two, it's intravenous, and that route of administration we think is clearly differentiated from intrathecal; and three, fundamentally, it utilizes the vascular to get broader biodistribution throughout the CNS. And given those pieces of differentiation and the other data I highlighted earlier, particularly the importance of tau, the other promising early clinical data that really gets us excited.
Got it. Let's move to your gene therapy programs now. Could you give us a little bit of background? You alluded to it, but the novel TRACER capsid that you have, what did you see in it, and what did others see in it? Because you've partnered it out many times over now.
I think the partner point is a nice point to highlight, and Adrian Trister can comment as well, but there we've had a number of very productive partnerships, particularly Novartis and Neurocrine. I think the brief point I'd make there is we've had long partnerships, and they've recently come back for additional partnerships, and that really, I think, is an important point that hopefully validates the technology, at least in their eyes currently. What I think we see is that we've developed a data set that has really enabled us to have three INDs coming next year: our wholly owned SOD1 program, and then two of our partner programs with Friedreich's ataxia and GBA. And fundamentally, I think that the next step really for the TRACER platform is to ask ourselves, does it work in the clinic?
And that's what I'm really excited to test. I'd highlight, in particular, the SOD1 program. Obviously, SOD1 ALS is near and dear to my heart. I think one of the key lessons we've learned from the Tofersen program, which is Biogen's intrathecally administered ASO, really, there are a couple key biomarkers, both SOD1 measurement in the CSF and neurofilament measurement in the blood, that really give us a very reasonable and quick indication of how the molecule's doing. Do we get target engagement, i.e., SOD1 reduction, and do we get neurofilament reduction, i.e., do we modulate neurodegeneration? And neurofilament is particularly important in that it also gives you some idea about potential clinical effect, given that the Tofersen program established that relationship.
Got it.
I think it's maybe just worth adding there, you know. I think a lot of folks have anchored on... Because the tau antibody is our first program in the clinic, and we have guided to potentially having some tau PET imaging data in the second half of 2026, I think a lot of folks have anchored on that second half of 2026 as a potential value iNfLection point. But I think it's worth noting, you know, what Toby just said. We actually have three gene therapy programs tracking toward IND next year, in 2025, and what's interesting there, right, is that those are not going to go into healthy volunteers. Those are going to go into patients at therapeutic doses.
So, you know, I think, I think it's reasonable to think that it won't take too long to get, you know, potentially a handful of patients and get some, some meaningful data there. So we, we haven't guided specifically on that because we're letting Toby work out the clinical development plan on the SOD1 ALS gene therapy program. And the other two programs, the GBA1 and the Friedreich's ataxia programs, are both partnered with Neurocrine, and so we don't comment on specifically on the timelines for those other than to say IND in 2025. But I, I think there's a, a lot of opportunities that could come ahead of that tau antibody data in the second half of 2026, and, and also that make that not a binary proposal.
So given the level of expertise we have here on SOD1 ALS, I'm going to ask you a question on a biomarker-related question, NfL reduction.
Mm-hmm.
What is, in your view, considered a clinically relevant reduction in NfL?
I presume you mean in SOD1 ALS?
In SOD1 ALS and in sporadic ALS as well, if you compare and contrast those.
Okay. So I think it's a great question, and I think you have to sort of take it disease by disease, but fundamentally, I'd go back to the Tofersen data, and in that program, there was approximately 40% reduction in the CSF. What I will say is that... I'm sorry, that was CSF SOD reduction. For Tofersen, we saw about 75% reduction of neurofilament. What we know is that reduction translated to... I think there was a very recent clinical real-world experience paper published last week about early experience with Tofersen, and what I highlight there is about half of the patients were either stable or improved. And I'll just pause there.
As a neurologist who used to treat ALS patients, I never thought I would be able to say I could give someone an ALS drug that led to improvement. And so I think that we know that 75%, it leads to a transformative effect in ALS. And so I think that's the data we have. I think you could make an argument that lower levels are likely to be meaningful also, but they have to be outside the range of both biologic and assay variability. And so I think that's sort of the simple question, and that's based on data both in sporadic ALS and broad ALS, I mean, and SOD ALS, that's about 20-25%.
Got it. Given you have like an antisense oligonucleotide, if you compare that to a gene therapy, what would be the relative quickness of action of either of those compounds in terms of NfL reduction, and does that matter?
So I think into firsthand the experience, you started to see by 12 weeks an initial separation, and certainly by 16 weeks and thereon, you saw the maintenance of that reduction. And that's an ASO. I think you likely have similar time courses in a gene therapy, though we don't know that yet. I think one potential complicating feature is some programs, there was a recent publication by the Prevail group that showed that very early on after you've administered AAV, you get a spike of neurofilament that then comes down, and so you have to understand those relationships as well.
Right. How confident can you be on whether your SOD1 ALS gene therapy could be a one-time thing?
I think fundamentally, we believe, based on the siRNA we've constructed, that it will continually produce that knockdown, and so all current data suggests it would be a one-time therapy.
Got it.
But fundamentally, that remains to be determined in the clinic.
Yep. Understood.
Yeah, and I think there's emerging data on that, that, you know, we find really interesting. I mean, Al talks a lot about the Spinraza Zolgensma relationship and how, you know, Spinraza was able to come to the market quickly as an ASO, have a significant difference in both and for patients, and become a very successful drug. Zolgensma, then, a gene therapy, comes to the market and becomes the market leader, but more recently, there has been data showing that for some patients who receive the gene therapy and still have some progression, adding Spinraza on top, right? Now, you're not having to maybe give it as frequently, but topping off with a little Spinraza has been shown to have some benefit. So, you know, I think there's a lot of benefits to that approach, right?
You start with an ASO, you have an opportunity to also evaluate the drug and make sure in humans that it is doing what you want it to do and not doing things you don't want it to do before you come and follow with a gene therapy, sort of permanent solution. And then if you need a little more, you have that opportunity, right, to level up. So, I mean, we'll see if that continues in the neuro field, but, you know, perhaps that could be a future in SOD1 ALS, if all goes well with our program.
So when you eventually get to the stage where you have your SOD1 gene therapy and clinical trials, how do you expect the split of patients to be between patients who are naive patients and patients already on Tofersen?
I think fundamentally, that's gonna likely vary by geography, depending on the approvals. But I think the working assumption would be that a number of folks will be on Tofersen, and then you'll have some naive patients as well.
Got it. Okay.
It'll be-
Is there a target that could be considered a quote, unquote, "good from a regulatory perspective" on that?
I think the key regulatory question really will be, of course, safety, but fundamentally, are you getting the appropriate SOD and neurofilament reductions? We know based on Tofersen experience that that can serve as a regulatory approval, at least for accelerated approvals. And so that establishing that data, it likely can be in either population.
Okay. So just going back to your capsid platform, we're seeing increasing competition from companies creating these blood-brain barrier penetrant intravenous type capsids. What makes you different? You're in the lead, it looks like. What could make others leapfrog you, and how are you gonna prevent that?
I think the foremost question I would say is, we've gotten to the point where it's time to test these in the clinic, and that's really... I think the point I'd make there is we intend to do that as quickly as possible with these INDs in next year. I think that's the most fundamental point. But if you look, I think at the, agreed, there are a number of companies coming to the fore. I think where we differentiate clearly is the breadth of our data. We have shown that it works in a mouse, it works in two primate species. We've identified the receptor. We know the receptor is expressed in human vasculature. We know that it's still present in disease conditions.
So fundamentally, I think we have done about all you can do to establish the potential translatability of this into humans. The next thing to do is test it in humans. I think if you look at some of the other data packages, they have some of these pieces, but not, but not in its entirety.
Got it.
I think it's just flattering that some people are trying to copy. 'Cause what they've done at Voyager, obviously before I joined, is pretty spectacular. And so there, there's gonna be competition, but as he said, we have the most robust data set, and that's why some of the partners keep coming back to us.
Right. So you, you had this whole Receptor X. I kinda like that, like the mysterious factor, but we now know it's ALPL, right, for non-viral delivery. So, you have any updates for us on that front?
I think what I'd say is, one, we're excited to share the identity. And I think fundamentally what it broadly opens up is the concept that you can use this receptor, and perhaps some of the other receptor families we identified, to really understand, can they be used to deliver other modalities across the CNS? Oligonucleotides, antibodies, proteins, et cetera. And fundamentally, we are working to understand that potential. We'll be excited to share data when we can, but it opens up this idea that Voyager could be broadly a neurogenetics company, not just an AAV company.
Got it. Are there any known downsides of targeting ALPL that you had to manage around to make it behave?
... Currently, we don't understand there to be any downsides, but we will have to test in clinic.
Right. 'Cause I think there's some implication with bone density and things like that. Do you expect to hit up against those kinds of things?
As I said, we've seen that if you look in human gene databases, that loss is well tolerated, and so this is sort of our guiding principle, but fundamentally, we'll test in the clinic.
Okay. Trista, did you want to say something? I think I-
Oh, I was just gonna say that, you know, that work is still relatively early, but I think you're spot on to ask about it because I do think that we're all really, really excited about that, about the potential to have, you know, not just this incredible leading platform for delivering AAV across the blood-brain barrier, but potentially a whole other platform, right, of non-viral delivery, leveraging ALPL and potentially other receptors that we're beginning to identify through our work. So I think there's a lot there if the science pans out.
Mm-hmm. Got it. So we have a couple of minutes left. I'll go into partnership-type questions. So you have so many things going on, right? When you evaluate external partnerships, how do you make the decision on what you keep internal versus what you can farm out externally?
Yeah, so that's a good question that we talk a lot about internally, about what we want to focus on, and some of the discipline around how we want to manage risk goes into it. Like, we wanna go after really well-validated targets internally. If we think it's too risky, obviously it's something maybe more appropriate for a partner with deeper pockets, and it's the same in terms of the clinical trial. So it's trying to strike that balance. What I like about what Voyager has done is basically taking the Sanofi model or the Sanofi/Regeneron model, where that Sanofi deal with Regeneron transformed them. It allowed them to build the platform that they needed to and get the pipeline going, and that's what Voyager's done.
Look at all the shots on goal that they've been able to develop in their pipeline because of these partnerships. So we're gonna continue to push on some of these partnerships. I think there's a lot of opportunity, opportunities out there. The CNS space is huge. There's a lot of targets to go after, and so I think we will continue to see this. And I think there's... Toby has had some ideas, and we're gonna continue to pursue them.
Got it. So you would still be actively pursuing external partnerships?
I think it is a great strategy. The market's so big that even, you know, when we share some of the upside, it's still massive upside. We only, you know, need a few of these, of these pipeline hits to win, for Voyager to win. And right now, as Trista mentioned earlier, we have four wholly owned and 13 partnered programs. I mean, that's a lot of shots on goal. A lot of those are massive markets. Alzheimer's, huge, 6 million patients. So we can share some of the upside, share the risk, and we'll continue to take those partnership deals.
Got it.
Yeah, and I would just add to that, I mean, you know, to emphasize, we are, we are interested in doing trials where we think we can quickly and efficiently get to meaningful data, right? The reason that we're doing the SAD and then the MAD study with the tau antibody is because of the interest we have in seeing that tau PET imaging data, which we think we can get to relatively quickly and efficiently and will actually be able to show if we're impacting the spread of tau. We're not interested in doing large Alzheimer's trials. When it comes to, you know, partnerships in large indications, we have frequently said it's a question of when, not a question of if. We, we don't have any intention of doing those kinds of large, very expensive trials.
Got it.
Now, with a smaller indication, like SOD1 ALS, I mean, no one knows better than Toby that there are some efficient biomarker-based paths to market, so we'll see.
We have a few seconds left. I'll squeeze one in. In the event that investors are missing something about the story from where you sit, what do you think that might be?
So I think, well, we touched on two things already that I think investors don't completely appreciate. And the first thing is when I talked about the de-risking or the reduced risking that's gone on at Voyager in terms of targets and the clinical trial design. And that I think provides Voyager a different profile than a lot of the CNS space. That's not appreciated. And the second thing is we're gonna have these four different clinical programs next year. With the approach that we're focusing on surrogate endpoints means that clinical data is gonna come soon. So this is—next 12-18 months is gonna be a very exciting times in terms of potential clinical data, and I don't think that's quite appreciated yet by investors either.
Got it. Thanks. So we look forward to a busy year next year.
Yeah.
Thanks a lot.
Thank you for having us.
Thank you.
Thank you. Thanks, everyone, for attending and tuning into the webcast as well.