All right, great. Thanks very much. It's my pleasure to be moderating this panel with the Voyager team. With me is Nate Jorgensen, CFO, and Toby Ferguson, Chief Medical Officer, named after Todd Carter, or is it the other way around?
Maybe we can start and have each of you just kind of give us a snapshot of Voyager as a company, how the company's changed since it went public, where you are with your new pipeline, and then we can go from there. T hank you.
Thank you. I'll start with that. At a high level, Voyager is a neurogenetics company, and it's led by Al Sandrock, a legendary drug developer. His mission, and actually his life work, has been trying to develop therapies that modify the disease in the CNS space. That's really what Voyager is trying to do.
When he talks about Voyager, he talks about the four P's. The four P's are the pipeline, the platform, the partnerships, and the potential. The pipeline, we have four wholly owned assets plus two assets with Neurocrine Biosciences that we have an opt-in for. The lead program is a tau antibody that's actually in healthy volunteers right now. Beyond that, we have a SOD1 gene therapy that we plan to file an IND next year.
Then also next year, Neurocrine Biosciences plans to file INDs for GBA and Friedreich's ataxia. T hose are the programs we have opt-ins for. B ehind that, we have a tau knockdown program. It's a gene therapy program that we'll talk about later that we plan to file an IND in 2026. So that's our pipeline.
The other comment I'll make here is that the company has done a lot of work trying to de-risk its pipeline. W e only focus on targets that are genetically validated, so we reduce the biological risk. W e like to focus on indications where we have biomarkers so we don't have to run massive trials and take a bunch of risk. T his is a slight tangent, but going way back, I have a Ph.D. in neuroscience. I spent 10 years as an investor.
When I was an investor, I never liked to invest in the CNS space because it was so risky. But when I saw Voyager, I realized that there's something different here. They're doing all this work to moderate risk. Actually, it changes the risk profile from a neuro company to something more similar to a rare disease company.
I'm very excited about what's going on here in the pipeline. That's the second P, the pipeline. The second P is the platform. The platform is the capsids or the TRACER platform that they've developed here. What they did is they took over 200 million variants of AAV5 and AAV9 and injected them into multiple species, including multiple primates, to look for capsids that can specifically get across the blood-brain barrier.
This is a big approach that they took a few years ago. T his is going to Paul's earlier question about how has the company changed over the years. T hey went through a massive strategic pivot when they went from directly injecting into the brain to developing these capsids that can get across the blood-brain barrier. T hat, in the end, transformed the entire company and allowed the third P, which is the partnerships.
R ight now, we have 14 partnerships. T hese partnerships have brought in over $500 million in the last couple of years. Al so, there's a potential for over $8.2 billion in milestones. T hat's really transformed the company. T hat's the reason why we can invest in the internal pipeline and the platform and why we have $345 million in cash. T he fourth P is the potential.
We're going to continue to push the company into a multi-modality program or a company where we're developing shuttles off of technology that we're pulling out of the capsid program. W e identified one of the receptors that gets the capsids across the blood-brain barrier, ALPL.
We think we can use that, for instance, to develop shuttles to deliver oligos, antibodies, and other types of modalities. I t's very exciting to execute on Al's big mission here. I know I took a lot of time here, I'll stop and see if Toby has anything else to add.
Nate, I think you nicely covered it. I think maybe I just make the comment of sort of what attracted me to Voyager really in the broadest context was the potential of the platforms to use a couple of P's there. F undamentally, I spent many years at Biogen before I was at Voyager.
Getting things across the blood-brain barrier as a therapeutic, particularly a genetically designed therapeutic, an ASO or an siRNA or a gene therapy, was always a struggle. And so really the idea that you could leverage identification of particular receptors that are expressed on vascular cells and then get things into the brain in a broad distribution really is quite attractive and would be an important step for the field holistically.
Makes sense. OK, so we've talked a number of times now about your next-gen capsids. Y ou leverage this receptor, ALPL, to get capsids into the brain via IV delivery. It reminds me a lot of the transporter space and how that's kind of broken open in blood-brain barrier. Do you want to talk a little bit about this target, the discovery of it as a way to shuttle drugs into the brain? I guess, why is this kind of a good and exciting strategy at a high level?
Holistic, I think, Voyager got to ALPL and, frankly, a number of other receptors empirically. I mean, they had design screens in primates where they could actually measure not just vector genomes in tissue, which can be inside or outside the blood-brain barrier, but of transduction in neurons. T hey did that efficiently.
T hey identified ALPL. I think what we've learned initially about ALPL was that it gets a virus particle across the brain. We know it's tissue nonspecific alkaline phosphatase. It's widely expressed.
I think the idea that we've now or then we're now interrogating sort of not only can that molecule get a virus particle across, which we've shown in multiple primate species, now the question becomes, can it get other things across the BBB? In that context, we're interested in enzymes. We're interested in oligonucleotides. We're interested in antibodies.
I think holistically, I mean, Al has highlighted we view ourselves as a neurotherapeutics company or neurogenetics company. There may be some targets that are perfectly well suited and appropriate for gene therapy.
There may be other targets where you want a more intermittent knockdown of something, for example. A brain shuttle approach is more appropriate. If we want to be a holistic neurogenetics company, we would like to have both those options in terms of design and therapeutics.
I think, I mean, if you look, the brain shuttle field has focused on TFR almost to the exclusion. Maybe there's a little bit of data on CD98 as well. We really think that sort of understanding each of these molecules, and we think that ALPL could provide additional opportunities.
I think one thing we'll highlight is that if you look at sort of human genetic databases, loss of heterozygous loss of ALPL is quite well tolerated. So there's a potential therapeutic margin there that's important. So really understanding these characteristics is sort of the next step. We're acutely aware of TFR and sort of how it compares. We're working on that, but it's early days.
The TFR approaches with the Fabs and the antibodies, I mean, they are directly and selectively binding TFR. W hen you're designing one of these capsids, to what degree is this empirical versus targeted delivery that's mimicking endogenous ligands? Does that make sense?
It does. E ssentially, what we know about the viral particle is we know it specifically binds to ALPL. F urthermore, we know the geometry of that binding. So we know that particular interaction and the specificity of the interaction.
T hat specificity, though we haven't shared a lot of detail, we can use that to design a number of things that can bind to ALPL or antibodies, et cetera, that can specifically drive things across the BBB.
OK. I guess, you know, I feel like the best way to really quantify the potency of something like this is to sort of talk about the data you have and showing you get broad biodistribution in the brain, but also talking about the data in the context of dose. Right? Obviously, it would be cool if you didn't have to dose it either the E15 or either the E16. C an you just maybe speak to the biodistribution target engagement on one end and then the dosing TI on the other end?
Sure. I think that the power of ALPL is it's broadly distributed on vasculature. W hen you look in our preclinical data in mice or primates, depending on the target, SOD1, we've shared both, and tau we've shared with mice. W hat you see across multiple neuronal populations, substantia nigra, cortex, spinal cord, is transduction in the range of 50% to 90%, depending on cell populations, also multiple neurons and glia.
T hat's in an adult CNS. T hat level of broad transduction across CNS has not been observed until the development of these types of capsids. T hat's really important. In that context, I think the idea what folks in the past have done, either with direct injection or intrathecal injection or even in individuals less than 2, is because you get poor biodistribution, they've been driving up the dose.
Of course, we've seen when you drive up that dose, you have a number of AAV-related safety events, certainly when you get into the E15 ranges that we've all heard of. I think the promise of the therapeutic index of this widespread, robust transduction based on a distinct molecular interaction is you can drive your dose ranges down into the E13, hopefully E13 range that really is quite different.
T hat gives you, potentially, most importantly, a safety-important improved therapeutic index. A lso, frankly, with gene therapy, a COGS-improved approval as well.
Just from another sort of safety perspective, there's been reminders from data elsewhere recently that immunogenicity is one of the biggest things we're trying to kind of solve against with AAV. How do your capsids compare, just at least preclinically, in terms of their safety profile compared to other commonly dosed AAV serotypes?
They are derived from AAV9, AAV5, and it's going to be a program by program, and we haven't really shared our tox data yet, but I think the tox data will sort of drive that, but fundamentally, I think we'll have to look for the known safety issues, liver, other events, essentially.
I think there, again, our ALPL capsid, for example, we substantially detarget the liver, so we think we'll have an improved therapeutic margin there as well, and then you'll have, of course, you'll have target-related potential safety, so I think it will be program by program that will reveal that, but holistically, with those reduced doses, we think that's a potential opportunity for us.
OK. Do you want to talk a little bit more about SOD1 and why you chose this as a lead program?
I think holistically, I think where we are at with the TRACER platform is Voyager's put together a really excellent package of effective transduction broadly in three primate species, effective transduction in mice, as we've noted a couple of times, identification of receptor. I don't think what you could do preclinically is sort of done.
Fundamentally, the next step really is do the capsids work in humans. That's why we focused on the SOD1 program. Fundamentally, we know that reduction of SOD1 in human beings provides an effective treatment for SOD1 ALS.
The target has been substantially de-risked. The next step really is, from our point of view, is, OK, we know that target's de-risked, but does the capsid function effectively? In this context, the tofersen program showed that you could reduce SOD1 in the CSF by about 30% to 40%.
You can get reduction of neurofilament as well. I think if you look at those two biomarkers, I think SOD1 is a measure of target engagement, really asking, does the molecule do what it should be doing? Neurofilament actually gives you a hint. It gives you actually not a hint, but a clear understanding of proof of concept, even clinically, because we know neurofilament is structural. It's found in neurons that shed in degeneration in the CSF and blood.
T he levels in ALS actually represent your clinical progression rates. F undamentally, reductions in neurofilament have a clinical implication. W e know that the tofersen program showed reductions in the 60% range, which provided a substantial clinical benefit.
H olistically, measurement of SOD1 will tell us, is our capsid getting into the brain? Is the siRNA functioning effectively? I t will prove out the capsids. Measurement of neurofilament will prove out the drug.
OK. Makes sense. Y ou obviously know tofersen intimately well. Why do you think tofersen tops out at around 40% SOD1 knockdown? B ased on the data you have for your capsids, do you think you can push that to 70% or 80% or something that might actually drive more clinical benefit?
It's a great question. I think holistically, it's important to remind that SOD1 is measured in the CSF. And that CSF represents an aggregate well, actually, first, SOD1 is widely expressed in neurons, rather homogeneously.
R eally, when you measure in the CSF, that represents sort of the aggregate knockdown in spinal cord and brain. T he spinal cord is about 10% of neural tissue. The other 90% is the brain and cerebellum. H olistically, what that 30% to 40% represents is probably substantially greater reduction in the cord and less reduction in the cortex, particularly deeper tissue.
Because you remember when ASOs are administered, you administer into the lower lumbar space. T hey sort of spread their highest there and least concentration in the deeper parts of the brain. A capsid administered once IV will much more broadly distribute, and we've shown preclinically.
Really, the opportunity with an approach like an IV approach is that you get broader knockdown, particularly in the cortical tissues, motor cortex, where motor neurons we know degenerate in ALS, et cetera.
OK. OK. Makes sense. W e've talked about this on neurofilament. But neurofilament can be noisy. How do you think about the utility of neurofilament in a small proof of concept study? H ow many patients? How long do you think you might need to follow patients to be able to see something that's clear-cut?
Here, I think maybe just [on] neurofilament really. I think fundamentally, it can be noisy. I t's certainly not as noisy as a clinical tool. I think that's the general position I would make. And that therefore, you can measure in the tofersen program.
You saw a neurofilament signal in the range of sort of 12 weeks and beyond. You started to see emergence of that neurofilament signal. C ertainly, by three months or six months, you saw clear evidence of reductions.
I think I would point the group to the initial phase one experience with tofersen, where you had just small numbers of patients, single digits, small double digits of patients that got you neurofilament signals that were clear, particularly retrospectively. T he assay you pick is important. You can do it in not that many patients.
I think one distinction from SOD1 would be that one thing we'll have to be cognizant of. Other external programs have shown when you inject capsids into the CSF, that you can get an early neurofilament signal based on the capsids and DRGs. We'll, of course, have to keep an eye on that.
OK. Makes sense. Nate, can I ask you a question about this program? From a commercial perspective, we kind of talk about this in some other areas. But gene editing, gene therapy for an older population, have you kind of thought through that, what the setup might sort of look like?
In terms of?
In terms of Medicare. I mean, tofersen commercially is off to a decent start. But is it just too early to really?
It's a little bit early to think about it. But I'll tell you, just the long-term vision of Voyager is to bring some of these forward, bring some of the rare indications forward commercially, because we think we can handle that.
Things like Alzheimer's, there's a lot of interest from large pharma where we think once we get into clinical proof of concept, we can hand them out. But we think we can handle this in terms of, on the SOD1 ALS side, that we can commercialize it. T here's thoughts internally about how there can be novel ways to push it. I think it's a bit early for us to share anything more than that, though.
Yep. Yep. OK. Anything else you want to add on SOD1?
No. I think it just sort of really emphasizes that strategy of a validated target and proving out the capsids.
OK. Y ou'll have your IND next year, likely to treat your first patient shortly after that. I know it's probably yet to be determined at least specifically. But what could the general cadence of a trial like this look like? Would you have to dose patients one at a time? How might that look?
I mean, I think we haven't really shared details here. But holistically, what I can say is, I mean, it's still a gene therapy. And we still have to sort of design the trial in the context of a novel gene therapy.
Yep. OK. OK. Do you want to talk a little bit about your FA program, partnered with Neurocrine?
It's partnered with Neurocrine Biosciences. I think I can't say a ton, because it is partnered with Neurocrine Biosciences. F undamentally, it uses our TRACER platform capsids. These capsids should get into the CNS. W e would aspire to treat the CNS symptoms. They're derived from parental AAV capsids.
T hey potentially can have other effects in heart and other tissues. W e're excited that there's an IND coming for that program next year. W e have that and GBA IND next year with partnership with Neurocrine Biosciences. R eally, we're at this stage, we're getting the capsids into the clinic. It's really the most important next step.
Well, based on the preclinical data that you have, how high do you think you can drive frataxin levels in the brain and the heart?
I don't think we should. Unfortunately, I don't think we can share.
Y ou're comfortable that you can get significant exposure in the heart with what you're doing?
What I'll say generally is consistent with the parenteral AAV capsids.
Do you have a view on what Lexeo recently talked about with the FDA and their regulatory path and the way that they're quantifying frataxin?
I think the holistic view there is that Lexeo has done some nice work with the FDA. And it's clear that they are thinking what would be a more efficient pathway for regulatory development.
I think the immunosensitized chemistry based on frataxin area and then the LVMI really provides a nice pathway. In that context, I would think that if you're going to study neurologic changes, you can also study cardiac changes. And so that may provide some opportunity.
Yep. OK. Makes sense. Toby, can you talk about tau briefly?
Maybe Tau. I think holistically what I'd say is Tau is what we consider sort of the most important next step in Alzheimer's. T here is a lot of data suggesting human genetic, human pathologic, human Tau PET, natural history data all suggest that the spread of Tau from initially the temporal region of the brain to the rest of the cortex is what drives disease pathology. In that context, Voyager has two Tau programs.
We have a Tau antibody program. We have a Tau knockdown program. The antibody program is an antibody that binds specifically to pathologic Tau. This antibody was selected based on a preclinical model of Tau spreading, where you have a genetic mouse, you inject human Tau. If you inject this antibody, you can substantially, by 70%, arrest that spread.
Because that spread is what we think drives clinical progression in humans, we think that's an important assay. I think that was one piece of data that got us excited about this program. The other piece of data was that the two prior N-terminal Tau antibodies that had been known to fail in the clinic also failed in this model.
W e felt this model had good negative predictive value. In that context, that made us feel comfortable with this model had some utility. I think the recent UCB data, we tested that antibody in our clinic, in our model, excuse me. W e showed that that inhibited spread by about 60%. I think the UCB data at a high level highlighted that an antibody approach to Tau for the first time decreased the spread of Tau. T hat's an important step.
Interestingly, Eisai showed a much smaller data set that showed a similar result in three patients. And so that's been an important step for the field. Clearly, the UCB data did not meet its primary endpoint CDR sum of boxes. Also important to note, though, on a prespecified secondary, ADAS-Cog, they had a potential effect.
I think digging into the exposure response and understanding the population will be an important next step for that UCB data. In that context, we're excited to get the Tau antibody into early AD patients and really double down on, we think Tau PET is the right tool to understand, can we successfully impede that spread of Tau?
I think the knockdown program, that program, again, an IV one-time administered gene therapy, really predicated on the idea that with broad Tau knockdown, you could potentially have a transformative effect for AD.
That's really Biogen's BIIB080 data. They did some statistical matching, looking at a natural history population and another trial cohort, and showed an effect on CDR sum of boxes of two to two and one-half points approximately, which, if holds up in later data, could be quite exciting. I will note that we expect to file IND for that program in 2026. It's about the time that Biogen's large phase two study will be reading out as well. That could be an important coincidence.
What are the next steps for your antibody program?
The antibody program, right now, we're in a healthy volunteer single-ascending dose study. We intend to have a readout of that study and really file the IND, I'm sorry, start the trial next year for the MAD program.
T hat's something you'd likely partner at some point?
I think clearly, for the Alzheimer's programs in general, that you really would look to partner those programs after initial data.
For Tau, from a gene therapy perspective, I guess, do you feel like that's a target, especially given the size of the population, where there's going to be concerns around permanent knockdown? How do you get kind of comfortable with that?
I think it's always a question, particularly with the gene therapy. I think fundamentally, if you look at the data we have thus far, preclinical models, Tau knockdown seems to be quite well tolerated, one. Two, if you look at the long-term experience in Tau knockdown with the BIIB080 program, it's been very well tolerated. T his will, of course, be an ongoing process. But early data right now suggests that you can do this safely in people and preclinically.
It will be an evolving understanding.
The other comment there is that Alzheimer's, as you know, is a serious disease. It's not like hemophilia, where there's other good alternatives out there. So I think the bar is going to be a little different for us. But I think it's something we'll continue to watch.
No, that makes sense, and maybe particularly important if the effect sizes that Biogen's observed bear out.
Right. I guess the last program, and I know you might be limited a bit on what you can say. But I did want to talk a little bit about GBA, because I do think it's a super interesting genetic target in PD. What can you describe there?
Again, relatively limited. But I think fundamentally, it gives you an opportunity in Gaucher's disease. I t gives you an opportunity in GBA-related PD. Sorry. We have an opportunity for option there.
I think what I'll simply say about these programs holistically is there's a clear opportunity based on biomarkers to understand sort of, is your gene therapy doing what it should be doing, measurement of GCase, measurement of substrate.
T hat's exciting. Working through how you get a proof of concept, I think holistically, the Neurocrine team will have to work through that, particularly in PD. And I think there'll be some emerging opportunities. But that'll be an interesting challenge.
It seems like in Tau and SOD1, proof of concept is easier to describe, whereas in FA and PD, it's a little bit murkier. Is that fair?
I think that's holistically fair. I think, obviously, the cardiac discussions with Lexeo provide some path there.
Right. The CNS side.
The CNS side, it's still mFARS.
Do we feel like in mFARS that there's much of a placebo effect?
I don't think there's certainly not over a 12-month trial. There's not a substantial placebo effect. There are also sub-scores of the MFARS, like upright stability. They're particularly sensitive. One thing interesting about, if you look at Reata data, for example, there was actually some initial improvements and then sort of lessening of progression over time. I think the signals are there. But it's still a clinical tool. It still has those inherent problems.
For GBA and FA, can you measure for frataxin or GCase in the CSF? I guess, is that measurement even relevant, given that the protein is working in the lysosome or the mitochondria?
Well, I think the challenge with these kind of programs is you can only measure it in CSF or perhaps peripherally in neuronally derived vesicles. But fundamentally, what you have to do preclinically is build those relationships. So what happens in the CSF, you know what happens in tissues.
You have to work to build those relationships.
All right. Well, maybe in the last minute or so, Nate, do you want to talk about your balance sheet of Voyager, how far that takes you through all this?
Yeah, w e have $345 million in cash, and the reason why we have that is because of all these partnerships, that's really driven the company to build out their pipeline and their platform, so that gets us into 2027 well beyond. Clinical catalysts in 2026.
Great. All right. Thank you both very much. Appreciate it.
Thank you both.
Thank you.