Great. Thanks very much, everybody. It's my pleasure to be moderating this panel with the Voyager Therapeutics team. With me is Al Sandrock, Toby Ferguson, and Nate Jorgensen. I'm going to ask Al to provide maybe a three to five-minute overview of Voyager, the platform, your key programs, and then, Al, we will dive deeper into Q&A. Thanks so much for taking the time, and I'll let you take it away.
You're welcome. Thanks for having us, Paul. Yeah, Voyager, we're a neurotherapeutics company leveraging human genetics to find the best targets and to use biomarkers to efficiently reduce risk, provide proof of concept. We have two platforms. One of them is emerging, and the other one is more established. The first one I'll talk about is our gene therapy capsid discovery platform.
Here, what we're trying to do is improve the delivery of AAV gene therapy into the brain by finding novel capsids that cross the blood-brain barrier after intravenous injection. It's not just for convenience. It's actually a better way to get genes expressed across the central nervous system by leveraging the vasculature. We believe it's also safer. Many of the capsids we discovered are so potent, we can go to lower doses and detarget the liver.
I believe we've got a lot of good external validation on this platform because we have great partnerships with people like Novartis, a leader in gene therapy, Neurocrine, a leader in CNS therapy. We also have a partnership with AstraZeneca Alexion. What these partnerships have done is we have 13 of them, and they have provided some very nice non-dilutive revenue. Some of the programs are going to be entering the clinic soon.
I'll be talking about that in a minute when I talk about our programs. The emerging platform is where we've taken the discovery of the receptors that some of these capsids leverage to get across the blood-brain barrier. We're making ligands against those receptors to shuttle other types of drugs across the blood-brain barrier, much the way people are currently using transferrin receptors to get things into the brain and muscle.
That is an emerging platform. We discovered a new receptor last year. We announced one of them called ALPL. We are excited about that emerging platform, and we look forward to sharing data on that this year. Our two key programs, internal key programs, are both centered around tau. The first one, the lead one, is actually not even a gene therapy at all. It is a regular antibody against tau, the C-terminal epitope.
We just announced that we completed the single ascending dose study in normal healthy volunteers, and we are moving to a multiple ascending dose study in Alzheimer's disease patients. We expect to read out the second half of next year in that program. We have a gene therapy tau knockdown program where we are decreasing the expression of tau across the CNS using AAV gene therapy.
I would just want to highlight two of the 13 partner programs because they're nearing INDs. One of them is Friedreich's ataxia. Our FA program is partnered with Neurocrine. We're expecting IND this year. The other one is GBA1 for GBA1-mediated diseases, namely Gaucher's and GBA1 Parkinson's disease. That IND is also expected for this year. That, in a nutshell, is where we are. We have a strong—we just announced we have a cash balance of $330 million. We have runway into mid-2027.
Yep. Okay. Great. Thank you, Al. Maybe I want to start and ask a couple of platform scientific questions, and then we can talk about tau from multiple angles. Maybe to start, I mean, you brought up the transferrin analogy, which was going to be embedded in my first question. Maybe for ALPL and some of the other receptors that I think you have not disclosed, but maybe just ALPL specifically, what is its role in the blood-brain barrier?
How confident are you that you can actually kind of leverage it without interfering with its endogenous function? I mean, that has ultimately been the big source of innovation in transferrin, where some of the earlier constructs led to internalization, or you can have hematologic issues. It has been an iterative process to be able to do that safely now with Denali. Where are we with your time?
Yeah. We are getting more and more excited as data emerge. Already, we know that humans—if you look in the human genetics literature, like gnomAD platforms like that—that humans are pretty tolerant of loss of function mutations in ALPL. For example, heterozygous knockouts, if you will, of ALPL are fine. They are normal human beings. That, I think, portends well. I would say that even Denali, the leaders in transferrin receptor, are looking at CD98, for example.
You might ask, you know, why are they looking at a second receptor if the first one is perfect? It is probably not perfect. I would just say that each receptor is going to have its own distribution, kinetics, and safety profile. I think we may end up needing more than one shuttle for the right situation.
We are actually doing head-to-head experiments right now against transferrin receptor to understand what are the differences, what are the advantages, and what are the potential disadvantages. In terms of your first question, which is, what is the role of ALPL? It's actually unclear. We don't really know what it's supposed to be doing, why it's on the blood-brain barrier, and what its role is.
Okay. Okay. What have you shown, Al, as it relates to biodistribution and the percent of the capsid that is actually crossing the blood-brain barrier?
We know that if we look at the capsid that leverages ALPL, we get broad brain distribution and spinal cord. We get very good neuronal and glial cell transduction with AAVs directed against ALPL. We also like the fact that we know there's a human homologue for ALPL. That portends well that our capsid will cross species.
That's no small matter because in this field, it turns out that some of these blood-brain barrier crossing AAVs are actually very species-specific, sometimes even strain-specific. To know that the receptor is present in humans is actually very comforting.
Right. Right. Right. Okay. Okay. Very interesting. Anything that you've seen preclinically that, again, getting back to this question of targeting ALPL, anything you've seen preclinically that you see as kind of dose-limiting where you oversaturate the receptor or some sort of endogenous function is interfered with? Or at this point, have you just not really found anything?
We just haven't found anything yet that concerns us. As I said, we look forward to sharing all that data this year sometime.
Yeah. Okay. Great. All right. Let's talk about tau because you and I did panels where we talked about tau when you were at Biogen. I think I do not want to put words in your mouth, Al, but I have a decent memory. I think your view evolved over time that targeting intracellular tau with an ASO in that case, or in this case, a gene therapy expressing an siRNA might be the way to go because the antibody might be restricted to accessing a small percent of tau.
Where do you stand now on the role of the silencing approach and the antibody approach? Why do you think both are still valuable in developing?
Yeah. You're right about that. As you know, the Biogen N-terminal directed anti-tau antibody didn't work. We were actually not—it's published now—and we weren't able to show even a biological effect. There was another N-terminal directed antibody by another company that also failed.
My view of antibodies was starting to—I was getting less optimistic about that approach, whereas the BIIB080 program, which everybody knows about, the antisense that knocks down the expression of tau, actually is looking very promising. When I came to Voyager and I found out that we had anti-tau antibodies, I wasn't all that enthusiastic about it.
What I found out was that they were using a really interesting animal model that actually, I think, started in Steve Paul's lab when he was an academic before he came to Voyager, where you take human pathological tau purified from Alzheimer's brains and you inject it into the mouse that's a transgenic mouse for P301S tau. You look at the spread of tau in the animal. They had a few antibodies that blocked the spread. Voyager did. I shouldn't say they.
I should say we now. At the time, I was still not officially in the company. What was interesting is that the N-terminal antibodies that were tested in that same model failed. That animal model seemed to predict, at least in a negative way, the failure of the N-terminal antibodies. That caught my interest. More recently, we found that some of the other domains actually worked. We had some in the mid-domain, some in the C-terminal, etc.
We actually had about half a dozen. We had to choose which one. We just chose the one that was the most robust and consistent in that model. In the meantime, UCB had a mid-domain antibody, and we actually had a mid-domain antibody too that I thought would be the first test of whether it had positive predictive value. As I said, the animal model had negative predictive value. Does it have positive predictive value? We even said before we learned of the UCB results that that would weigh heavily on our decision about what to do with our own antibody.
Lo and behold, the mid-domain antibody, which we would have predicted would be positive based on the animal model, did show, I think, a pretty convincing effect on the accumulation of tau in humans. That is why my interest in anti-tau antibodies has been reinvigorated, if you will. We're still in early days. I do not want to throw away the notion that an antibody directed against the right epitope might actually be beneficial for patients.
Right. Okay. How far can you take this in a sort of capital conservative way to generate additive data that then might interest a [strategian]?
Yeah. So that's a really interesting question, in fact. All the programs we are doing now and we seek to do in the future are going to have the common characteristic of being very capital efficient to get to proof of concept. There's a very high unmet need in neuro, particularly neurodegenerative diseases, partly because people haven't been successful to find drugs that work. So it's high risk.
The good thing is that the field is developing biomarkers, both fluid-based, blood-based, as well as CSF-based, and imaging biomarkers that can de-risk. I believe that an effect on multiple biomarkers would be intriguing. It certainly would have been for me if I were still at a large company as a buyer. I think the key question now is, well, what's the clinical benefit? That's the part that it took a while, for example, for anti-amyloid antibodies.
We had to learn that you had to have a substantial effect on amyloid burden in order to get a clinically meaningful effect. That took years with multiple different drugs to learn that relationship between the effect on tau imaging and clinical. That is going to happen because multiple people are looking at that. We expect data even this year, as well as next year. That, I think, is going to be very helpful. We're going to pay a lot of attention to that.
Yep. Yep. Okay. Makes a lot of sense. As it relates to that Biogen and Ionis data next year, are you optimistic that that's going to be positive? If so, what's the read-through to your gene therapy?
Yeah. Look, I don't know if Toby's online, and I want to give him a chance. Toby, are you on? I guess he's not. I guess I'll answer the question. Yeah, I'm pretty optimistic. Look, I mean, the data that they've shown so far, particularly as time has gone on, we have to interpret it carefully because there was no control group, right? It was a single-arm study.
They have done a great job, I believe, in comparing it to natural history using propensity matching, as well as the control group of an anti-tau antibody trial. In both comparisons, it's looking very interesting. In fact, the first thing is, surprisingly, you get a decrease in tau expression even in the areas that already had expression.
These tau PET ligands bind to pathological tau, which we believe is in neurofibrillary tangles. Now, if you were to ask me years ago, I would have said those tangles are pretty irreversible, that just by decreasing the synthesis of new tau that they would [mantle].
Yeah. Kind of like the issue with BACE and Alzheimer's, right?
Yeah. Yeah. Exactly. BACE did not work, right? Because the plaques were not removed. Here, it looks like the tangles are going away, which is quite a wonderfully surprising result. The second thing is that the effect size, again, these are cross-trial, if you will, comparisons. The effect size looks much larger than the effect sizes we get with the anti-amyloid treatments. For both of those reasons, I am actually pretty optimistic, and I wish Biogen well.
Yep. Yep. Okay. Great. I want to cover a few of your other programs. I guess on the FA program, which I know there's some limits to what you can say because it's partnered with Neurocrine, maybe just talk about what the target product profile is there. With your platform, do you think you can simultaneously address the neurological component, sure, the cardiac component?
Also with frataxin specifically, right? There's this pronounced need, I think, to avoid overexpression in certain tissues, especially the liver. Maybe talk about the degree to which you think you could thread the needle on all three of those things, which would certainly be the best-case scenario.
Yeah. Okay. Yeah. As you just pointed out, there's a neurological component and a cardiac component. The neurological component is disabling even in children, right, and teenagers. It is the cardiac component that ends up being fatal as they get older. Both should be addressed. Our AAV, we have AAV capsids that will transduce both heart and central nervous system.
I think that's a distinguishing feature of the program that we have partnered with Neurocrine. We aim to have clinically beneficial effects on both cardiac and CNS function. As you know, there's a precedent now for a drug to be approved for the CNS side of the disease because SKYCLARYS, which was acquired by Voyager, was approved based on a functional rating scale for Friedreich's ataxia. That sets a nice regulatory precedent for that pathway.
Alexion has, I think, gotten, according to what I read from them, that they have some agreement with the FDA on parameters to address the cardiac function, which I believe involves echocardiography and perhaps fluid-based measurements. I think there's going to be a path forward for the heart as well. The product profile, to try to answer your question, is going to need to address both the heart and the brain or the nervous system, I should say.
The safety issue, yeah. Overexpressing frataxin seems to be harmful. Now, we know also that heterozygote carriers, which express 30%-50% of frataxin, are normal. You don't really need to do a lot. You don't want to express too much, right? In fact, 50% would be enough. 50% of normal seems to be enough because the carriers are completely fine. That produces a nice little window.
I do not want to talk about Neurocrine's program, but there are ways to limit the expression by doing things in the payload. Some other companies have leveraged those. I do not want to go too far into that because I might be spilling the beans on what is a Neurocrine program. I would also say that our capsids are nice in that what we found out was that when we get BBB-penetrant capsids, they tend to detarget the liver. That is one of the organs we are worried about with overexpression of frataxin.
Yep. Yep. Okay. Great. Do you want to briefly touch upon GBA? I mean, I think the rationale in Gaucher's is pretty intuitive. As it relates to GBA Parkinson's, I think the one thing I've wondered with a number of these genetic targets, and the answer is not going to be all equal, is just like, is simply fixing the genetic defect going to be enough?
Or is that one of a number of biological hits combined with environmental hits? I guess maybe I would flip that around on you. With rescuing GBA, what's the optimistic case that that's actually going to have a disease modifying?
I think that Parkinson's is a heterogeneous disease. I think there's, as you were kind of pointing out there in some ways, there's going to be multiple factors, right? Perhaps there's going to be more than one biological cause, if you will. I do think that there's a lot implicating the lysosomal pathways as important for Parkinson's, even in those that are not GBA1 carriers. There are lots of other genes that tend to affect the lysosomal pathways, the endolysosomal pathways.
Actually, that's not just for Parkinson's, by the way. I think the endolysosomal pathways seem to be involved in a variety of neurodegenerative diseases. GBA is a way to address the lysosomal pathway. Clearly, in some of these GBA1 carriers, since they have the same allele as in the homozygous case you get at Gaucher, they're clearly loss-of-function alleles because in the homozygous state, they cause Gaucher, right?
If we pick those alleles that we're pretty certain are loss-of-function, by the way, the other way we know that is that the substrate goes up. The substrates for the enzyme, GC ase, are elevated because the enzyme's not working properly. If we pick those patients, I think there's a pretty decent chance that we can help those patients. Of course, as always, what stage do you have to get in? Do you have to get in early? Of course, we always say the earlier, the better. I'm pretty hopeful. The only way to know is to do the human experiment, I believe.
Yep. Yep. Okay. Great. I know you have a number of other efforts ongoing. You have the non-viral ALPL shuttle program. What else would you like to highlight in the last couple of minutes, Al, for people to take away here?
Yeah. I think it's the fact that we do have this other emerging platform that we seek to become more of a multi-modality or a modality-agnostic neurotherapeutics company. Our flywheel is going to be neuro, leveraging, as I said, human genetics, leveraging all the development of new biomarkers to de-risk in a capital-efficient manner. I'm growing a great team.
It's too bad Toby couldn't come on because he's one example of the great team I'm assembling. We have a strong cash balance. As I said, we ended the year with $330 million in cash, and we have cash into mid-2027. I am very excited about the company, and I hope you are too. Can't hear you, Paul.
Yeah. No, I think it's great. It's always a pleasure talking to you guys. The science is super interesting. Maybe just to wrap up, when do you think you will have clinical proof of concept from some of these new IND programs? Is there any guidance you can give? Like as 2026, are we all?
Yeah. We have the guidance that the anti-tau program is second half of 2026. I've also said that the Neurocrine programs, both of them, we have IND scheduled for this year. The only thing I would say without being specific, because those are Neurocrine programs, is that with gene therapy programs, you don't do normal healthy volunteer studies, as we just did with the tau program.
You have to do studies in patients, and you have to use doses that have a chance of helping the patients. That provides a potential for fairly early readout, particularly on biological measures that can tell us that the gene is being expressed in the right locations in the brain and elsewhere. I do think that I think 2026 is going to be a great year for us. I certainly hope so. I don't know.
Yeah. Okay. Great. Looking forward to staying in touch, Al. Thank you very much, and thanks to the team as well. We appreciate it.
Thank you.
All right. Talk to you guys soon.