Okay, let's get started. My name is Yanan Zhu. I'm one of the biotech analysts here at Wells Fargo. It is my great pleasure to introduce our next company for this fireside chat, presentation for us, fireside chat, Voyager Therapeutics. With me are the management team members, Al Sandrock, CEO of the company, Nathan Jorgensen, CFO, and Toby Ferguson, Chief Medical Officer. I think Al will start us off with a brief presentation. Thanks, Al.
Great. Thanks, Yanan. Yeah, so thanks for this opportunity, Yanan, to present briefly. Shouldn't take too long. I will be making some forward-looking statements. So just to you know, summarize our overall story, you know, why would you wanna invest in Voyager? It's about the four Ps. We have a pipeline of not only wholly owned assets, but 14 partnered programs. We just added one this morning. You may have seen the press release, and we have one asset, VY-7523, in the clinic in a single- ascending dose trial, and we have three gene therapies with IND filings slated for next year with potential for clinical data in the 2025, 2026 timeframe. We actually have. We believe we have a leading platform for CNS gene therapy.
As you know, gene therapy for the CNS is often hampered by the inability to deliver AAV, particularly to the deep gray structures, but broadly, it's a struggle with current capsids, so my company's scientists have figured out a way to generate new capsids that will cross the blood-brain barrier after IV delivery, and this is the reason for all those partnerships that the other companies have seen the same thing we've seen and wanted to work with us. Speaking of partnerships, we do have some very strong partnerships, including, you know, this morning we announced another one with Novartis, which we hold in high regard. They're a leader in gene therapy, essentially in research development, but also commercialization.
with, you know, some milestones that could theoretically generate up to $8.2 billion over the long term, and finally, we have the potential to expand into other forms of neurogenetic medicines, and we're leveraging the discovery of the receptors for our leading, some of our leading classes of capsids, to see if we can deliver other sorts of macromolecules across the blood-brain barrier after IV delivery. This is a snapshot of our pipeline, just updated this morning.
You know, at the top are the wholly owned programs, and on the bottom are the partnerships, some of which are true collaborations in the sense that our scientists generate not only the capsids, but the payload, and go all the way to IND, fully reimbursed by our partners, and then they take the programs and move them into the clinic. The others are simply capsid licenses, where they license a capsid for a particular indication, and then they take it and run with it on their own. Just wanted to spend the rest of this talk just touching on a pretty important target for us, tau, and so important, in fact, that we have two programs directly against it. One is VY-7523, which is a simple antibody.
It's actually not a gene therapy, ironically, for a gene therapy company. Our first program is a simple passive antibody, and I wanna explain to you why we moved that one forward and how it's differentiated in the subsequent slides. In addition to that, we have a gene therapy for tau, where we're gonna silence the gene using a vectorized siRNA approach, and for that, we're anticipating an IND in 2026. So let me tell you why we chose to move forward with VY-7523.
It really hinges on the fact that we relied heavily on this mouse model, where you take human pathological tau, so you basically, you purify paired helical filaments from human Alzheimer's patients, and you inject them into the animal, and here we inject them into mice that are transgenic mice for P301S mice. After a few days, as you can see, we seed them with this paired helical filaments at 9 weeks, and then at 15 weeks, we sacrifice the animals and look to see how far that, how much that tau, pathological tau, has spread.
We rely on this model because it's well known that in Alzheimer's disease, you get a very stereotypical spreading from the temporal lobe into the medial temporal lobe, and then to other parts of the cortex, which you can now see in individual patients over the long term with tau PET imaging. We chose this particular antibody. We had several to choose from. In fact, we had five very exciting antibodies, actually. Still had to choose one of those. How would you choose them? We chose this model to tell us which one to go forward with, because it blocked the spread robustly and consistently, as you can see here. Ab01 is the murine equivalent, essentially, of VY-7523.
And so you look in the ipsilateral hippocampus on the same side of the injection, and you look to see the spread on the other side, on the contralateral brain. And you can see we blocked the spread by approximately 70% with Ab01. That by itself would probably not have been enough for us to move forward. What we liked about it is that this model would have predicted the failure of the two N-terminal antibodies that have already gone into humans and failed in the clinic. So we took the Biogen N-terminal antibody and the Lilly N-terminal antibody, and subjected them to the exact same experiments as we did with Ab01. And we found that they did not block the spread in head-to-head experiments, either within the ipsilateral hippocampus or the contralateral hippocampus.
So in other words, with these two failed antibodies, that this model had negative predictive value. That's what got us pretty excited about the fact that we may. We have something that's quite differentiated. The key question now: does it have positive predictive value? For that, we wanted to highlight that there is an antibody that UCB and Roche are moving forward, called bepranemab. We actually looked at this antibody in the exact same experimental paradigm, the murine forms of the antibody. What we found is that it also blocks the spread, maybe not quite as well, but pretty robustly, in the 50%-42% range, as you can see.
And so we think that this is important to note because this is the first test of whether or not this murine model that we relied on so heavily could have positive predictive value. And so I just wanted to summarize the three key findings then in this mouse seeding model that got us to move VY-Tau, VY-7523 into the clinic. First, that we see consistent and robust inhibition of spreading in the model. That the N-terminal anti-tau antibodies that failed in the clinic also failed in the model, i.e., negative predictive value, and that we have an example of an antibody that was positive in the model, reading out, we understand next quarter. And so we think there's potential read-through to our antibody of that result. So we're watching that very closely.
Just to give you a quick update on where this program is. It's in a phase I, single- ascending dose study in healthy volunteers. And what we're trying to do with this is to see whether or not we get the PK we would predict from our animal studies, because we understand the PK/PD relationship in the animals. We know how much exposure you have to have in the blood to get you the exposure you need in the brain to block the spread. And what we wanna do is be sure we reach those exposures when we dose humans. And that's really the simple question that we're trying to answer in this single-ascending dose study. Of course, we always evaluate safety as well.
And so, that is, I'm happy to say we filed an IND with FDA last year, and that we initiated the trial, the single-ascending dose trial this year, and it's on track to keep us on track for this program overall. Which, as I said earlier, you know, we expect tau PET imaging results from the multiple ascending dose study in 2026. So that's a quick summary of the lead program, VY-7523, our anti-tau antibody. And just to remind you, as I said earlier, it's such an important target that we have a second program. This is a different approach, where we're just silencing the gene, decreasing the expression of all forms of tau inside cells.
What we've shown and presented at scientific meetings is that in a murine model where we're expressing human tau, we can actually decrease the expression of tau quite robustly by around 80% across the brain. As you can see, cortex, hippocampus, brainstem, thalamus, based on not only in terms of messenger RNA, but also in terms of protein. So, it's a very different approach. It's somewhat akin to the approach that another company is generating with BIIB080, an antisense that also decreases the expression of tau. So, those are our two tau programs that I wanted to quickly summarize before the actual fireside chat. And for that, I'm gonna invite my colleagues to come up and answer questions along with me.
Great. Thanks, Al. Very interesting presentation. A lot of questions, if you don't mind. So you know, that you highlighted this very interesting read-through catalyst from UCB/Roche antibody just around the corner.
Mm-hmm.
Can you define what success would look like so that we can be, you know, ready, given your deep experience in the Alzheimer's drug development?
The main thing I'd like to see myself is an effect on tau spreading by tau PET imaging. Because, you know, I, I'm a big fan of making sure we understand the relationship between PK and PD, not just in animals, as I was trying to explain earlier, but to see if we can replicate that in humans. That's always the first step. Can you replicate the PK/PD relationship in humans? That's the and if we can, that's huge. We would also like to at least see a trend, perhaps, in the clinical measurements. It's a fairly decent-sized study, but I always worry about clinical measurements in neuroscience.
We've been misled by them in either direction in the past, but meaning that sometimes they're positive when they turn out not to be positive, and sometimes they're negative when it turns out that the drug works. So I'm a little cautious about the clinical outcome measures, but, you know, the tau PET imaging results, I think, should be clear, I hope.
Okay. Toby, did you want to add something to that?
Al, I certainly agree on the clinical would be nice, but I think the tau PET is sort of the key. I think the other thing I'd add is they have some biomarkers in the study, and their antibody recognizes both pathologic and wild-type forms of tau. So really making sure that they reduce pathologic tau in the context of the study would be quite important as well. So some measures of target engagement to go along with the tau spreading.
You mean, is that a property of the UCB antibody or for both of yours then?
The UCB antibody recognizes both pathologic and wild type. Our antibody is specific for pathologic. Go ahead.
That could turn out to be important. As you know, in the history of anti- amyloid antibodies, the ones that were not specific for pathological forms of A-beta did not work as well, because then they don't engage target in the brain as well. So I think Toby's point is a very good one. You know, if it's a negative result, that could read through to ours, and we may need to make an, you know, a tough decision, but we want to be sure it's a true negative, too. And that's where I think the biomarkers on target engagement would be important. So I may have to wait for a scientific presentation rather than just a press release, because sometimes those details don't get into a press release, you know?
Right. Given their antibody reduces both type of tau, mutant and wild type, would we be able to tell the reduction of either form, or you know, the measurement is on total tau and no further? Yeah.
It specifically depends on the assays they've developed, whether or not they have pathologic-specific assays as well as total tau assays. And that.
We don't know yet.
I don't know those details.
Okay. Got it, got it.
But there is movement in the field in this direction, right?
Okay.
The field is moving forward to better and better assays for tau that could define the two, distinguish between the two.
Got it. And,
Those are not any of the prepared questions, by the way.
Right. No, no, no. This is great. Great. Very intriguing part. So you mentioned that if it's if their study is negative... Oh, sorry, I remember what I was going to ask. So the patient number and duration of the follow-up, by your assessment, it's still in a range that can give you, you know, false positive or false negative result. It's not large enough to form a definitive conclusion. Is that right?
I think that if you focus on biomarkers, it's probably large enough and long enough.
Okay.
If you focus on clinical outcome measures, then, you know, it may not be large enough, right?
Okay.
Because, you know, the variability of clinical outcome measures is always a little tricky to predict ahead of when you're powering a study.
Right.
So then you may find out when you do the study that the variability or something, or something about the patient population wasn't what you had thought it would be, and therefore, you have to be, I think I've learned over the years to be very cautious about interpreting clinical outcome measures. I'm a neurologist myself, and, you know, sometimes the bedside examinations can be tricky.
Got it. Got it. And, the two domains being targeted are not identical. One is-
Yeah.
One is C- term, right?
That's right.
Any thoughts? Is it a bit surprising that both did the job or it makes sense?
You know, we don't know exactly the mechanism of the spread in which species of tau is important for that cell-to-cell spreading, which a lot of people believe is like a prion-like mechanism. I actually believe that myself. There's a lot of complexity in what is in the extracellular space in terms of tau. There's a lot of proteolytic fragments, and there's a number of forms of extracellular tau, but also we don't really know which ones are the critical ones that mediate that prion-like spreading. That's why we've kind of relied empirically on this mouse model, where we inject human tau, human pathological tau, and we see. We were looking for the block of spread, and we relied on that model.
We'll see if that was the right move.
... Right. And then lastly, on this particular topic, you did make the comment, if the UCB data is negative, meaning it doesn't show on PET imaging any change, you consider it can also read through to your program, and you have to make hard decisions, but the domains are different.
Yeah, they are different. Yeah.
Have you made the decision a priori, that if they're negative, you wouldn't even, you know, pursue-
Yeah
-the possibility?
Again, I think it's sort of what Toby was implying, is that we wanna believe that it's a true negative. So if there really wasn't target engagement in the brain, then it's hard to interpret a negative result, right? So we'd have to look at the data in its totality. But yeah, I think look, we have to be responsible with the shareholders' money, and we relied on this model. If it's positive, fantastic, you know. But if it's negative, we have to take a good, hard look. And like I said, we have another program, the vectorized siRNA for tau. So it's not like we're not a binary company. You know, we don't, we're not dependent on a single asset, and we wanna be prudent with our shareholders' money.
Great. If I may follow that, line of thought in terms-
I don't know whether Nate wants to add to that, since he's my CFO.
Right, of course.
I think you're exactly right, but it's difficult to answer these questions in the hypothetical, 'cause there's so many different scenarios to consider, but we're gonna be prudent here.
Yeah, good, good to know. Then on the siRNA tau, you know, down-regulating tau from inside the cell, and there, you know, Biogen, Ionis, as you alluded to, does have this antisense program, and Biogen actually made some interesting moves recently. They, they're pulling the program forward. They're reducing the trial size in order to read out the data early. What do you read into that?
Well, obviously, I don't know all the reasons why they reduced the sample size, but I'm pretty excited by the data because it does show an effect on tau PET imaging. It actually shows a decrease in tau PET signal, and they've even seen at least a trend or indications that it's slowing the progression of disease. And so gotta pay attention to that. That could be the first sort of real human evidence that intervening against tau could work, you know. Toby, you want to add something to that?
I mean, I just sort of would double down, Al, on a couple of those statements you said, that the remarkable two pieces of data I find quite remarkable in that program are that the preformed, pre-existing tau, which you could see on tau PET, was dissolved. So by inhibiting the mRNA for tau, you allow the cell to endogenously remove pre-existing tau. So that's a remarkable observation. And then I think you add on top of that, that at least based on the early stage comparisons that the Biogen team made, that you see an effect on the CDR Sum of Boxes of about one to three points. It likely, that, of course, will need to be confirmed as true, but if your effect size in that is in that range, that's a substantial-
That's huge
... potential effect for people with Alzheimer's.
Yeah.
So those two pieces of data really gets excited about our program, which is a one-time IV gene therapy. But we think these data in some ways de-risk that tau target and that approach.
Got it. So this is a... I was gonna ask, but these are different deliveries because they are different modalities. Are you confident that you can deliver to the cells that can be reached by an antisense introduced intracranially? So you just mentioned this is your IV capsid technology, so presumably, it should reach those neurons, right?
The fundamental premise of the TRACER capsid platform, yet to be proven in humans, but certainly shown nicely in our preclinical data in non-human primates, is that you're using the vasculature, which allows broad biodistribution throughout the CNS, the motor cortex, the spinal cord, the deeper cortical tissues, astrocytes and neurons, to a much greater extent than you would for other modalities. So really harnessing that vasculature is the whole aim of the TRACER platform for better biodistribution, hopefully better knockdown, and hopefully better efficacy.
Got it. Very, very helpful. Thank you. So that IND is 2026-
Correct.
for that program?
Correct.
Got it, okay. Quite a few catalysts to watch for the tau, the dual approach. Thank you. Another timely topic is that you just got another opt-in for a target from Novartis today, announced earlier today. I think, Al, you have quite a few partner programs. Could you take the opportunity to give us an overview and what could we expect, or, you know, what to read into today's announcement?
I think you should read into it that you know, Novartis, that is arguably the best gene therapy company in the world. You know, Zolgensma is the most successful gene therapy product out there. It's transformative for SMA babies. We're honored that they would do yet another deal with us. Remember, they've been working with our capsids in their own labs for quite some time now. I don't even know exactly all the experiments they've been doing with our capsids, but suffice it to say that the results, they must like the results, because they wanted to do another deal with us. It's an honor, and in this situation, you know, this is a capsid license, right? So they're gonna take our capsid and run with it, you know.
A little different from the ones we did earlier this year, where we, you know, for Huntington's, for example, we are making the payload and the capsid, and actually making the whole gene therapy product, up to IND, and then they take over from there. So, so I guess that was the other point I wanted to make, is that we have a range of partnerships. Some are pure capsid licenses, and some are partnerships, where we actually participate much more heavily, up until the IND stage, and actually make the product ourselves, and we're happy with either. In the latter case, of course, we're fully reimbursed. So what I like about these partnerships from the financial point of view, is that we get some non-dilutive revenue.
We also take things off our P&L, and then we participate toward the end, or along the way, actually, with milestones, development milestones, and then we get royalties on the back end, too. So, to me... And then there's so many targets in the CNS, right? I mean, it takes a lot of genes to put together a brain, I frequently say, so there's a lot of gene therapy opportunities. There's a lot of opportunities for genetic medicine in the CNS, and there's no way we could pursue them all ourselves. So having these partnerships with great partners like Novartis is just great for the company. Nate, did you want to add anything?
No, that's exactly right. And these partnerships allow us to fund the continued platform and pipeline work, and it's been important to the company in the past. I think it's gonna be continued to the company going forward in terms of their funding strategy. We don't have to rely on the public markets all the time, which, as everybody knows, the last few years have been a challenge, and that's been a keystone, I guess, part of Voyager and their ability to build this amazing capsid franchise and expanding these targets is this platform. So we'll continue with it.
Yeah, the vast majority of our $350 million cash balance comes from non-dilutive revenue-
Yeah
... that we get from these kinds of partnerships, right? I mean, we did do one financing this year on the back of one of those, but, you know, I mean, so we're very grateful for that, and it does allow us to fund our own stuff, including the fourth P, which is, can we figure out a way to leverage our receptors to do other kinds of non-viral delivery, for example? Which, as you know, a lot of people are very interested in these days, and I am, too.
Could we think that, you know, potential deals on that could mature?
I'm always open to, you know... I always say my door is always open. I love talking to potential partners about anything. Always depends on you know, on the actual deal itself and then, you know, whether it's favorable to our shareholders is of paramount importance, and is it value creating?
Got it. Got it. Maybe just to close the loop on the Novartis deal, I was just wondering, you now have five targets. Are these all the same capsid, or are they five different-
Mm-hmm.
or are they three different types? So how-
Yeah, we get that question a lot, and we don't disclose the answer. They could all be the same capsids. So the capsid could be the same for all of them, for all we know. Remember, they're the ones that choose.
Yeah.
We always update them, by the way. Every time we get another generation of capsids, we do a presentation, and they can choose, they can swap out one they were working on with a new one, if they wish. I would say that, you know, for us, it depends on the disease and where we have to get the gene therapy to, in terms of cells. What cell types, neurons versus astrocytes, which neurons? We also look at the targeting of various cells, and so we have a capsid profile for our programs. We pre-specify this is the kind of capsid we want to see, and then we look to see, do we have one?
I'm happy to say that for the programs that we have, for example, the SOD1 ALS program, we have a capsid that, I mean, Toby couldn't be happier, right?
Quite happy.
With the capsid we have. So, you know, so, yeah, so it's a long answer to say that I can't really answer it, but it could be the same capsid or it could be different ones.
Got it. Okay. That, that's very helpful. So let's do talk about your gene therapy pipeline. These will include your partner program, but also, you know, more importantly, you have your internal gene therapy pipeline. What are the most advanced programs, and what milestones can investors look forward to?
Toby, you want to take that?
Sure. So our most advanced gene therapy program, our wholly owned, is our SOD1 program. So that's an AAV capsid that, as Al said, we're quite happy with. That the cargo is an siRNA to knock down SOD1, and that's very consistent with our goal here of taking our novel capsids and pairing them with well-validated targets. The tofersen program at Biogen, which I led at one point, that program has shown and validated knockdown of SOD1 and SOD1 ALS as an appropriate target. So we're moving that program quickly forward. Toxicology studies are ongoing. We have an IND plan for mid 2025, and we're on track for that.
You know, I can't think of a more clear-cut way to demonstrate that one of our novel capsids work in humans. We have a target engagement biomarker essentially in the SOD1 levels in spinal fluid, and we have basically a surrogate marker of clinical outcome in plasma neurofilament. In fact, FDA approved tofersen based on plasma neurofilament, right? So, boy, it's a really clear way of really testing our capsids in humans. And, you know, so we're excited about the IND that we're slated for next year.
That's to Al's point. It's a very quantitative understanding of what we need to see. I mean, we know that about 30% reduction of SOD1 and about 60%-70% reduction of neurofilament led to a clinical effect. And so it's. I can think of almost no other program we have such precise knowledge of how the biomarkers translate.
The clinical effect, by the way, and he's kind of modest because he led the program, but there was a recent paper out of Germany, 16 patients treated with tofersen. Eight of them had no worsening of the ALSFRS, the functional rating scale. And some had six-
Six of eight.
Six of eight, and then some had even improved.
Six of eight improved.
Improved, right? So, you know, roughly half either no worsening or improvement, you know, you just don't see that in ALS. I used to see ALS patients myself. That's a game changer. And so, you know, my hat's off to Biogen and Toby for getting that approved for, on behalf of patients, 'cause it's a terrible disease.
Wow!
I'm hoping that our gene therapy can also be transformative, you know, for patients.
Got it. Yeah, that's very helpful. Thank you for pointing to that, literature, evidence. Maybe we can touch on the, CNS penetrant capsids. So that's obviously your, what you're most known for, in the industry. You know, you've been the leading force on that front. I think it feels like competition is increasing. Genentech recently did a deal with, Sangamo for their, CNS penetrant IV-delivered capsid. How are you thinking about differentiation, and how do you stay at the forefront?
Yeah, no, it's you know, the old saying, Imitation is the sincerest form of flattery. We were leaders. I think we still are leaders, but the competition is catching up. And you know, we're not the only ones with BBB penetrant capsids. I'm still very proud of the fact that we check for multiple things cross-species, you know. Does it work across multiple, not only non-human primate species, but some of them even cross into mice? Do we know the receptor? Do we know the de-targeting? Do we have a clear understanding of the dose, the relationship between dose, percentage of cells transduced?
We look at multiple brain regions, because like I said, for a particular disease, you wanna be sure that you get this to the cells that where you need the therapy to go to. So to me, it's the thoroughness, the breadth, and yeah, we're gonna try to continue to be leaders. But as usual, in this industry, when you do something that's important, people will compete with you. Which I think is great for patients at the end of the day.
Got it. Got it. I think we only have one minute left. Al, and the team, any parting thoughts for what investors are missing about the story?
Only that, you know, we are in the clinic. We're not a binary company. We have enough cash to get to some important inflection points, and that we're gonna be prudent with our shareholders' money, and we're gonna be looking at all the data out there to make the best possible decisions. You guys wanna add anything?
What I would say is we have four wholly owned programs, and we have fourteen partnered programs, and last week we had 13, and look at all this progress. We're not getting credit for those. You look at our stock price, I mean, it's trading basically at cash. We only need one or two of those to work, justifies this whole company and the value going forward, and it'll be a long-term success in terms of an investment, so this is a great time to obviously get in, and so I think that's missing, and that's the story we're trying to tell.
We would have to go oh for 18?
Yeah, hopefully, we can do better than that.
Yeah, I think that would. Yeah. I think we're gonna do. I hope we'll do a lot better than oh for 18.
Wonderful. I think we're out of time. Thanks to the Voyager management team for this very enlightening session.
Thank you.
Thank you.
Thank you.