Good afternoon and welcome once again to TD Cowen's 45th Annual Healthcare Conference. I'm Phil Nadeau, one of the biotech analysts here at Cowen. It's my pleasure to moderate a fireside chat with Voyager Therapeutics. We have with us here on the stage Nate Jorgensen, the CFO, and Toby Ferguson, CMO. Al Sandrock is in the building and he's on his way. He's just having some elevator issues. While we wait for Al, I 'd thought we'd kick it off. Toby, maybe I'll hand it to you. You had some good news this morning from the anti-tau antibody program . For those who didn't see it, could you briefly summarize the data and the significance?
Sure. Thanks for that. Happy to be here. Our lead clinical stage program is our anti-tau antibody program . Just to remind, this is an antibody that targets solely pathologic tau in the C-terminal epitope of tau. This morning we announced that we've completed a single ascending dose study in healthy volunteers across 48 subjects. In that context, we saw a very nice disproportionate PK, no safety events. We announced that we've initiated a MAD study in the context of that. The multiple ascending dose study will be in early Alzheimer's patients with a goal of having a readout on tau PET in the second half of 2026. I think holistically, why we like this antibody is, indeed, it does bind pathologic tau. It inhibited very nicely the spread in a preclinical mouse model of tau spread. It has the appropriate PK, which I just mentioned.
We're excited to test this antibody in patients. I should also note we have nice expected CSF penetration with a CSF-to-serum ratio of about 0.3.
On this morning's data, are there any plans to present it at a medical meeting or publish the single ascending dose data?
We plan to speak about it at a medical meeting in the second half of this year.
Great. Al, welcome. I think maybe we'll take it.
Sorry, guys.
No worries. We understand the elevators are crowded.
You have mic on?
Yes.
There we go. All right, cool. I'm going to make sure you're on mute.
Yeah, I'm just.
Pardon me?
Perfect. Al, we'll kick it over to you. Broad question. Can you summarize where Voyager is today? What's the state of the company? What are the strengths, the challenges, and how will Voyager create shareholder value over the next year?
That's a great question. We're a clinical stage neurotherapeutics company. We started life as a gene therapy-only company, but we strive to be a multimodality neurotherapeutics company. Let me explain how we're doing that. When Voyager got started, we were based on doing intraparenchymal gene therapy with standard AAV. That did not work out so well. Those programs got stopped. We stopped being a clinical stage company for a while. Luckily, our scientists had discovered capsids across the blood-brain barrier. I believe that was a breakthrough. We're back doing gene therapy in the CNS, but with novel capsids that cross the blood-brain barrier. After IV delivery, they get distributed across the brain quite well. What that led to was not only partnerships that brought in a lot of non-delivered revenue.
By the way, that's another thing to keep in mind is that we're always looking for new business development opportunities. In the near past, that was a single biggest driver of shareholder value, was doing new partnerships that increased shareholder value. In addition to doing these partnerships and getting our own pipeline, these capsids may be bringing us another platform, which will broaden the modalities that we can utilize to help patients. That's because we discovered the receptors by which these capsids cross the blood-brain barrier. In fact, the first one we published last year is called ALPL. It's a distinct receptor from transferrin receptor. We've started to investigate whether ligands against this receptor can be conjugated to various proteins, such as enzymes or antibodies, as well as oligonucleotides, to see if we can also deliver those across the blood-brain barrier after IV delivery.
I think that's pretty important because currently, for example, antibodies get in. They do get in, as Toby was saying when I was walking in. They do cross the blood-brain barrier, but typically, an antibody is 0.1-0.5% in terms of CSF-to-blood ratio. It's very inefficient. Also, oligonucleotides have to be injected intrathecally, creating a gradient, which can cause problems. If we can deliver these drugs across the blood-brain barrier using our shuttle, we now broaden the utility of the receptor discovery that I just mentioned. By the way, ALPL is just the first of several receptors. That's what I mean by multimodality neurotherapeutics company. As Toby was saying, our first program is actually we're already a multimodality company in the sense that our first program is an antibody against tau.
We go after diseases of very high unmet need. The other thing is that we choose programs that we think we can get proof of concept in humans rapidly and efficiently. Neurotherapeutics is a risky business. We wanted to be sure that we can get human proof of concept as efficiently as possible and choose targets that are validated by human genetics. That, in a nutshell, is where we are.
Toby, introduce us to the data that was presented this morning. You mentioned that the MAD study has started. Al, can you brief us on the design of that trial and what you would consider proof of concept when the data ultimately readout?
I could, but I'd rather have Toby tell us the design because he's the Chief Medical Officer.
Thanks, Al. Put simply so that it'll be a multiple-ascending dose study. Of course, the primary outcomes will be safety. Fundamentally, I think the concept I'd like to highlight is that we know in human beings that the spread of tau, which you can image with tau PET, is what correlates with clinical symptoms. Fundamentally, we think that this is the key biomarker in the study. The point here being that this process is what correlates with disease. This process is the key feature of Alzheimer's disease. If we can significantly impact that, we think it'll be quite a positive result. We do think it's quite important where anybody binds pathologic tau, and that may offer some upsides as we're able to explore potentially high doses in that concept.
We'll, of course, also look at other fluid biomarkers, various forms of tau, MTBR243, among other things. Fundamentally, it's really about the fluid biomarkers and most importantly, tau PET. We recently saw phase two data from UCB's Bepranemab. I'm sure I didn't say that correctly.
What did you guys learn from that, and how's that informed your development of 7523?
I think at the high level, I think the key point of that study was fundamentally that it was the first time that an antibody clearly showed on tau PET that you could impact tau biology. That is the key takeaway. Two, of course, the study did not meet its primary endpoint of CDR-Sum of Box es, but we did see a potential effect on ADAS-Cog. I think the other key learning is that fundamentally, they had some information on both APOE status and tau status. I think the key takeaway there is that the older population, perhaps a lower tau population, may be a key population to explore in terms of potential biologic or clinical effects.
Yeah, can I add? I think that it's hard to show clinical effects in relatively small numbers of patients. You usually need hundreds of patients if you're going to use CDR-Sum of B oxes as your primary endpoint. This was typical of the early days of the anti-amyloid therapies. The other thing I would say is I saw the cup as half full on the Bepranemab because prior to that, no antibody had shown even biological activity. The two N-terminal antibodies against tau failed. We had chosen our antibody because it was different in the sense that it blocked the spread of tau in this model in animals where you inject human pathological tau and look for the spread.
Prior to even knowing the results of Bepranemab, we said, you know, our antibody is kind of similar to that one in that they both block the spread of tau. We were actually looking very carefully at that data. If it had not showed any activity, we were going to drop our own program. I even said that at a conference. The fact that it blocked the spread of tau, very clearly so, was, to me, pretty important news. First time we ever saw that with an anti-tau. Now what we have to do is figure out how much block we need to get a clinically significant effect. I think the field is going to figure this out. We are going to get more data from UCB. We are going to get data from the Merck antibody, actually a C-terminal antibody like ours, this year.
We're going to get data from the J&J antibody. I think it's next year. As in the case of the anti-amyloid when multiple antibodies were tested at various epitopes, we learned a lot. I think we're in the early stages, but we're seeing a little bit of hope here in the sense that Bepranemab had biological activity, as Toby mentioned.
Can you talk a bit more about how you're going to evaluate the results from those next antibodies and what you hope to learn from those trials?
In the case of anti-amyloid, it was very important to establish a couple of things. One is on the drug itself. What is the relationship between exposure and biological effect, so-called PK/PD relationship? That's quantifiable, but it's based on, and every drug is going to have its own PK/PD relationship. I hope that we'll learn about that from Bepranemab. The other thing is that the second thing is how much biological activity do you need to get a clinically relevant effect? That you actually should work for any, regardless of the drug. In fact, if you look at some of the documents published by the Clinical Pharmacology Group at FDA, they actually plotted the relationship between biology and disease for all the different anti-amyloid antibodies. When you do that, you see a very clear relationship.
I think those are the two key pieces of information that I'm looking for.
Al, I just sort of doubled down on the exposure-response relationship. Fundamentally, I mean, how much tau change do you need to have a clinical effect? There, we like the idea, we'll remind folks that in the beta-amyloid world, some of the initial antibodies that bound both wild-type and mutant forms of beta-amyloid, you didn't have much of an effect. Solanezumab, for example, here we think potentially binding pathologic tau could be quite important, allowing you to explore sort of potentially greater reductions of pathologic tau.
You meant pathologic forms of amyloid, not mutant forms?
Excuse me, that's correct. In terms of the patient populations to enroll, Toby, I think you mentioned that there were subpopulations in which it looked like Bepranemab worked better than others. What's Biogen's most recent thinking on who to enroll into their trial? Would you do low-tau patients or APOE4 non-carriers, or are you still thinking that an all-comers trial is likely?
I mean, we'll look forward to sharing broader details later in the year. Fundamentally, I think the idea is looking for the populations that have low enough tau where you think you can have an effect. I think conceptually, the idea is that if tau has spread, as evidenced by tau PET imaging or fluid markers of that, fundamentally, that may be a bit late, particularly for this mechanism of action. Shifting the bias of your study inclusion study populations, those lower tau burdens but still positive, is likely the way to go. Of course, if you have no tau, it wouldn't be an appropriate population.
Got it. UCB excluded patients with prior antibody therapy from its phase II trial. Would you expect to do the same for 7523, or is there some interest in having some patients to look at a combination regimen?
I think really, fundamentally, this is a phase I B study where you're really looking at safety and initial biologic effects. In this context, fundamentally, we need to understand if this antibody works, then biologic activity first order.
Moving on to the siRNA-mediated tau silencing program, VY1706. Can you discuss the structure of 1706, and how do you think it could be differentiated from an antibody?
I think fundamentally, it approaches the question from a different point of view. I mean, we have strong belief in tau and what we know about it from the human genetics, human biology. Therefore, it's worthy of two attempts to change tau biology in humans. This really is predicated on the idea that you can knock down tau within cells and have a potential effect. That idea is there are a couple of things that really support that. Fundamentally, I think I'd highlight in the context of Biogen's BIIB080 program, they've shown that an ASO, which is again a way to knock down message and prevent production of tau protein, the context of that program, they showed some pretty remarkable data where pre-form tau is measured by tau PET actually decreased. You have human beings who have laid down some tau.
I think before that dataset, we always thought that would persist. In this context, we showed that Voyager showed that that tau could be reduced. I think fundamentally, it approaches the question from a different point of view. You allow tau knockdown to happen. You can remove tau. Really, that expands the idea that you don't need to interfere with cell-cell transmission, which is an antibody, but instead prevent formation. I think conceptually, it also opens up the idea that you could potentially treat a broader range of people with different amounts of tau and different spreads of tau. I think finally, the other point I'd make is that you don't need to.
I guess two questions on 1706 specifically. One, was it affected by the recent toxicity findings for another program? Two, when do you think you could file an IND?
I'll start with the second question first. IND is planned for 2026. I think we shared some data around when we paused the progress of our SOD program. Just to highlight, we used those programs, this program and the tau doctor, used the same capsid. What we very clearly showed in the context of the 1706 data that we shared is we looked at four different candidates, all using the same capsid. In that context, we saw no safety concerns. We had seen some elevations in neurofilament in the SOD program. We saw no elevations in neurofilament. Fundamentally, same capsid, but none of the concerns that led us to clearly conclude that it was the cargo in the SOD program that was the issue.
Maybe to dive into that data a bit more in a bit more detail, what tissues were affected, which ones were not, and can you go into the data that gives you confidence it was the payload and not the capsid in a bit more detail?
I think I'll highlight, I referred to the neurofilament, but let me take you through that in a bit more detail. Fundamentally, neurofilament is a marker of neuron and axon integrity. It fundamentally highlights potential nervous system damage. In the context of the SOD1 cargo, what we observed is initially a very small spike in neurofilament consistent with many other AAV therapies. In fact, quite small in that context. Later on, towards the latter part of the three-month primary toxicology study, we saw a large increase in neurofilament consistent with the time at which the cargo was being expressed and then the time at which you saw clinical observations. Clinical observations and in terms of movement and then also this neurofilament spike. It's really that time course of the neurofilament expression consistent with cargo expression that is key data.
In addition, in the context of the tau 1706 program, at those latter time points with a different cargo but the same capsid over four different constructs, we saw none of that neurofilament elevation, no clinical observations in the monkey studies that time.
What's the current status of the SOD1 program, and when could you be back opening?
For that program, we've highlighted that, of course, we want to look for other payloads. We're ongoing. I think that really depends on us and also our ability to identify a payload that meets high criteria, essentially at the point where it's close to or near ready for toxicology studies. We'll keep looking, but we don't have definite time.
Maybe moving on to the Neurocrine and partner programs, can you remind us of the structure of the Neurocrine collaboration and the disclosed candidates and development?
Yeah, I can take this one. The two programs that we're going to file the IND this year are FA, so Friedreich's ataxia, and GBA. That's what they've guided to publicly is that it'll be in the clinic. These are partnerships, but we do have an opt-in. We can opt in and we'll own now 40% of Friedreich's ataxia. The opt-in for GBA is 50%. Those opt-ins occur after some initial phase one data. We're very excited about those two programs because those now could be the initial proof of concept of our capsids. Of course, we'll have to defer to Neurocrine about when that data is going to come. Of course, being gene therapies, they're going to go right into patients. It shouldn't be too long before we get that data.
Maybe on protection specifically, what would be the design of a first-in-human trial? If you can, what endpoints could you look at that could provide human proof of concept?
I can't comment explicitly on what Neurocrine is thinking, but I can comment in the field. What I'd highlight here is the emergence of measurement of protection as a key endpoint, both potentially in the heart and other tissues. Of course, you'll also want to look in this context as gene therapy, you want to look at the CSF as well. I think the opportunities, there are a number of regular pathways that have been paved by Skyclarys , for example, and using the mFARS there. There are accepted clinical endpoints. There are emerging biochemical endpoints. In between those two, you can look at cardiac function as another potential surgery endpoint, which has been accepted by the FDA given the work of Alexion. I think really there's an established development path that exists in a framework that exists.
Similar questions on GBA1 gene therapy. What could be the design of a first-in-human trial?
There again, I think you're really trying to ask yourself is, are the capsids having the appropriate biologic activity? That's your initial first question. Here you have the, in case of GBA, you can look at GCase levels and are you increasing those levels appropriately? I think importantly, are you decreasing the substrates that are considered part of the problem in the GBA-mediated disease here? It's the biological biomarkers that have been established in the field.
Neurocrine has talked about two separate potential diseases, Gaucher's, which is homozygous deletion of GBA1, and Parkinson's, which is typically heterozygous.
Any thoughts on the safety and efficacy that would be necessary for either of those diseases to become standard?
In Gaucher's, particularly the more severe neuronal type, it's rare. CBER has guided that for rare serious diseases, biomarker-type data might be sufficient for approval. As Toby said, demonstrating that the enzyme is released into the spinal fluid and showing that the substrate, which builds up abnormally, goes down, that would certainly be convincing biochemical evidence that the gene therapy is doing what it needs to do in the CNS. In Parkinson's, obviously, you could look at the same biological measures, but I suspect you'd have to do a full-fledged phase III trial with UPDRS as the primary endpoint.
Moving on to the capsid engineering program, you referenced ALPL in your opening remarks. What are the next steps in that program?
I mean, look, we're always looking for capsids that are tailored to the needs of our customers, including ourselves and the patients. Every disease resides in different tissues. For example, we just had an example, Friedreich's involves both the heart and the CNS, whereas GBA is exclusively in the CNS. The other thing is within the CNS, there are certain cell types that you'd like to transduce. Capsids that are specific for one cell type or another, glial cells, neurons, and then what cell population of neurons. There is always improvement that you can make in terms of capsids and delivery. I think that also new capsids will identify new receptors, which will be also opportunities to make shuttled vehicles, if you will, shuttle vehicles for other modalities.
You have specifically identified ALPL as part of a capsid program. Would you consider going into other modalities such as LNPs or other delivery modalities using the same targeting mechanism?
There are companies that are taking LNPs and putting things on them, if you will, that target them to various tissues and cells. That would be a very nice application. We do not do LNP work ourselves, but that is a perfect example where a partnership would be helpful. We are starting to talk to some companies about that.
Within that capsid engineering program, are there other receptors that you're targeting? What's the next big discovery that's going to emerge from the Voyager ?
We already have more than one receptor. We have not talked about the identity of those. It is a pretty interesting pattern developing, I will say. Yeah, right now we are prosecuting ALPL, comparing it to TfR. How good is it relative to what I think is the gold standard for shuttle these days? We will see what the other receptors do in terms of comparison to ALPL and to TFR.
Moving on to some corporate questions. You have two pillars to the company, the partner programs and your internal programs. Can you give us some breakdown of the internal effort and cost that is focused on your internal programs versus the partner programs? Do you feel like that mix is ideal currently, or would you rather shift it in one direction?
We love the partner programs because our partners pay for them, and we're going to continue to pursue those. In terms of our burn, we just put out guidance that our cash runway gets to mid-2027. As of last quarter, we had $245 million. We're in a good cash position. That cash is going to fund our 300, sorry, $345 million. That cash funds our internal program. We're in a pretty strong position here. Of course, as Al said, we're always open to doing additional deals and bringing additional non-dilutive funding into the program or into the company.
How much more capacity do you have to take on external partnerships? How many is too many?
If we still get partners to pay for them, we can scale.
I would say that these partnerships are different. Some are pure capsid licenses where they take the capsid and they run with it. There are no internal FTEs involved. Of course, they pay us upfront and they pay us milestones. That has no effect on our internal workforce. Some of the other programs, though, are actually programs. It includes payload, and we actually work on that internally. It is fully paid for, but we still have to have our internal people and lab space, etc. Look, we are always open to talking to partners. I think they really increase our reach, and we hope to serve more patients through those.
Does Voyager Therapeutics have all the internal capabilities it needs to continue to develop its pipeline, or are there any technologies or other capabilities that you'd look to in-license or acquire?
If you ever had somebody say they have all the capabilities they need, I think you have to be a little bit cautious about that statement. No, we don't have all the capabilities we need. That's another reason, by the way, to do partnerships. The one that we're really building is the non-gene therapy platform and non-gene therapy products assets. We've hired some excellent people, those who've done it in other companies, those who have expertise in how to make shuttles, how to conjugate various molecules to these shuttles. That is something we are definitely building and look forward to telling you about the assets that come out of that effort.
What do you think investors are missing about Voyager Therapeutics? What do you think is most misunderstood among the investment community on Voyager Therapeutics' programs or its prospects?
Yeah, can I take that one? Then maybe you guys can add to it. I think what people are missing, I think there's a general disillusionment with gene therapy right now. Look, what we're going after are diseases where there's really no other treatment. I mean, okay, Alzheimer's, there's a treatment, but boy, the unmet need remains high. We're going after very serious diseases. Second is our novel capsids provide a unique opportunity here. I think Toby may have mentioned in the Tau Knockdown program, we have a slide where we show that 1.13 vector genomes per kilogram dose, one dose, gets 50-80% knockdown of Tau. First of all, that is an order of magnitude lower than intravenous doses that people have been using. That portends well for safety.
As you know, for IV-delivered AAV, safety issues generally are dose-dependent, and you see them at E14 VGs per K. The other thing is cost, COGS. As you know, commercialization is difficult if you have to charge huge amounts of money. If you can lower the dose by an order of magnitude, and then you couple that with the huge improvements that CDMOs are making. Three years ago when I first joined Voyager Therapeutics, CDMOs really could not make gene therapy products very efficiently or very consistently. That has changed. There has been a sea change in that. I am happy to say that you can rely on CDMOs. The scale, they are scaling up quite well so that the cost of goods is generally going down. This is exactly what happened with biologics. Remember the old days for proteins, antibodies?
It was super expensive to field, figure out how to make biologics efficiently. When you go after diseases of high unmet need, and I just told you that CBER, for example, is willing to bend over backwards, that they will consider accelerated approval based on biological biomarkers. They said that. High unmet need, cost of goods, better capsids where we could use lower doses and get high efficiency in the brain. I'm an optimist, and I think people might have been missing some of these key events that are going on in the field.
Maybe I just add that we have, with all the technological points Al made, I think we have 13 partner programs and our own internal program. So we do not have just one or two shots on goal. We have multiple shots on goal in the context of an approach where we are really looking at de-risked targets, where you have appropriate biomarkers, and with these novel capsids. It is all that together, not just a conventional AAV9-based gene therapy.
Yeah, I would echo what Toby just said. A lot of investors focus on the four internal programs. There are 13 programs with partners that have $2.9 billion worth of pre-commercial milestones. That is a lot of money that is on the table. If you start to dig into some of those partnerships, it is things like SMA with Novartis. When you look at the royalty that we disclosed, it is a sizable royalty. These have value, a lot of value, and everybody just looks over the top of them. We are trying to convince people, but it is a big fight to get people to dig into 13 different programs, you know.
When you're a pre-commercial company, you're always looking at cash runway and what are the things that can be achieved until your cash runs out.
Yeah, that's true for us too. Remember, partner programs are fully paid for already. If anything, we get money, we get income if they succeed. The $300 million plus that Nate talked about, that's for our internal use only. The partner programs are fully paid for until we opt in.
That's great. With that, I think we're out of time. I'd like to thank the team for a very interesting discussion.