Q3 2024 Voyager Therapeutics Inc Earnings Call

Toby Ferguson

Thanks, Al, and good afternoon. Please turn to slide 4. This slide summarizes the four wholly owned programs and 14 partner programs that Al mentioned earlier. Today, we are going to focus on our tau-targeting programs for Alzheimer’s disease.
Turning to slide 5, the point I want to make here is that we view tau as a critically important target for the treatment of Alzheimer’s disease. As you can see an image on the left of this slide, the spread of pathological tau as identified on tau PET imaging correlates closely to Alzheimer’s disease progression as measured by Braak clinical pathologic staging. Additionally, exploratory clinical data from Biogen’s BIIB080 tau knockdown program showed a reduction in pathological tau as well as potentially greater slowing of clinical disease progression than seen with anti-amyloid antibodies.
So, in short, we think targeting tau has the potential to impact Alzheimer’s disease progression and do so in a significant way. This is why Voyager is pursuing two approaches to targeting tau: our anti-tau antibody VY7523 and our tau-silencing gene therapy.
On slide 6, I want to highlight how the team selected our anti-tau antibody. We started with more than 700 antibodies across the mid-domain and C-terminus of tau. We first focused on antibodies targeting pathological tau. This was important with the anti-amyloid antibodies. Several that failed such as solanezumab or bapineuzumab were shown to have insufficient target engagement with aggregated forms of amyloid beta, while the approved anti-amyloid antibodies all target the aggregated species.
We narrowed the funnel through further in vitro and in vivo studies. We evaluated antibodies targeting various epitopes across tau including in the mid-domain and the C-terminus of tau. In a mouse seeding model of human pathological tau spread, the C-terminal-targeted antibody Ab01, the mirror inversion of VY7523 decreased the spread of injected pathological human tau by approximately 70%. Based on these data and the specificity for pathological tau, we selected VY7523 as our clinical candidate.
We also conducted a series of head-to-head studies in the same model against other antibodies. These data are summarized on slide 7.
In the first head-to-head study, we evaluated murine 7523 against murine versions of Biogen’s gosuranemab and Lilly’s zagotenemab. These antibodies both targeted the N-terminus of tau and both failed their primary end points in clinical trials. Both were ineffective at reducing tau spread in the model, while our C-terminal targeted antibody again blocked tau spread. This gave us confidence that the model had negative predictive value.
In the second head-to-head study, we compared our C-terminal targeted antibody to UCB’s bepranemab, which targets the mid-domain. In our models, both antibodies inhibited tau spread. Based on these data, we were eager to see the results from the bepranemab clinical trial, because we thought that if this antibody could impact tau in a clinical trial, then our model might also have positive predictive value.
Turning to slide 8, I want to summarize the recent bepranemab data shared at the 2024 CTAD meeting. I want to start by noting that the primary endpoint CDR sum of boxes was not met in the full study population. This is important to acknowledge.
Now, I would like to note that bepranemab inhibited the accumulation of tau in human brain by 33% to 58%. We saw this as establishing that an antibody can be used to inhibit the spread of pathological tau in the brain. This finding should not be underestimated as I think that after the failure of the N-terminal anti-tau antibodies, there was uncertainty in the industry as to whether an antibody approach could impact tau accumulation. As it turns out, it can.
I also want to note that bepranemab slowed cognitive decline by 21% to 25% versus placebo per ADAS-Cog 14. Additionally, in sub-group analyses, it seems that patients with the greatest reduction in tau burden had more consistent clinical benefit, although we will need to see more detailed PK/PD and PD clinical correlation analysis.
Finally, bepranemab demonstrated an acceptable safety profile with brain hemorrhagic and inflammatory changes similar to placebo. What does this mean for Voyager’s VY7523? I would say that these data give us increasing confidence that antibody targeting the appropriate epitope of tau can slow the accumulation of tau in the brain of Alzheimer’s patients. And that this slowing may offer a clinically significant benefit in some patients. This was a top-line data presentation, and there is certainly more work to be done here. And we look forward to seeing the additional data.
Slide 9 provides an overview of our Phase 1 clinical development plan for VY7523. During the third quarter, we completed enrollment and dosing of healthy volunteers in our single ascending dose trial. We expect to report top-line safety and pharmacokinetic data in the first half of next year. We expect to initiate a multiple ascending dose trial in patients with early Alzheimer’s disease next year and generate initial tau PET imaging data in the second half of 2026.
At this point, we don’t see anything in the bepranemab data that would shift our thinking here. If anything, the data reaffirmed that tau PET imaging is the critical outcome we want to focus on, and we have planned a very efficient trial focused on that outcome. We found the safety profile of bepranemab encouraging and look forward to exploring the full range of dosing possibilities.
I mentioned earlier that we are advancing two approaches to targeting tau for Alzheimer’s disease. We focused a lot on the antibody approach today in light of the recent third-party data.
But I will now turn the call over to Todd to touch on our other approach.

Todd Carter

Thanks, Toby, please turn to slide 10. In addition to our antibody-based approach, we are also advancing the tau-silencing gene therapy program. This program deploys a tau-targeted siRNA, packaged in an IV-administered TRACER capsid. Using this approach, we have demonstrated robust productions in human tau in mRNA and protein across the brain following a IV single administration in mice that express human tau as shown on the slide.
It is also important to note that the recent data that Toby mentioned showed that reducing tau expression was associated with favorable trends on clinical outcomes and pathological tau as measured by PET imaging. We view these data as supportive for a knockdown approach and believe that the one-time IV gene therapy could provide benefits over repeated [physical] therapy.
This program remains on track for US IND and Health Canada CTA filings in 2026. I will now turn the call back over to Al.

Alfred Sandrock

Thanks, Todd. As you can see on slide 11, there continues to deliver on expectations for 2024. We have advanced the pipeline, our platform, and our partnerships. Our strong cash position of $345 million at the end of the third quarter is expected to provide runway into 2027, enabling multiple data readouts. This cash figure doesn’t include the recent payments from Novartis or Neurocrine, which were received in October, nor does it calculate any future potential milestones from our 14 partnered programs.
With a robust slate of clinical milestones expected into the next 12 to 24 months, a maturing partnership portfolio with top-tier collaborators and cash runway into 2027, we believe Voyager is poised to drive significant value creation over both the near and long term.
Finally, I’d like to thank all of our employees for their hard work and dedication to improving the lives of patients. With that, we will open the call for questions.

Operator

Thank you. At this time, we will conduct the question-and-answer session. (Operator Instructions)
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Good afternoon. Thanks for taking our questions, and congrats on the progress. First, a follow-up to your comments on the tau PET imaging. We’re curious whether you have more insight as to how to translate the tau PET imaging results like we saw from Roche’s B into cognitive improvements. Any additional thoughts now that you’ve had a bit more time to let the CTAD data set in?
Do you think it’s a question of selecting the right patients, selecting the right endpoint, and any thoughts on how to get that tau PET imaging data to translate into a clinical improvement and cognitive benefits?

Toby Ferguson

So maybe I’ll start that question, Toby. So I think fundamentally, I think that — I’ll reset the point that the — where the tau PET imaging, we saw clear data in the whole population that you did not — you slow the accumulation of tau.
And then I think the other point to make is that when you looked in some of the other populations, particularly the lower tau populations, you saw perhaps a slightly greater lesson of accumulation in that context. So do you think as we move forward, really understanding the population will be critical in the terms of perhaps tau burden, which seems to be the main point. And then I think the — the other point I think is we’ll look forward to understanding the full dose response in terms of sort of the tau reduction in the context of PK/PD. We look forward to that data from UCB moving forward. Those are my initial faults.

Alfred Sandrock

And I would just add that this relationship between how PET effects and disease effects on clinical outcomes are agnostic to the drug or to the approach, right? So there are more than one — there’s more than one drug-targeting tau over the next couple of years. I think we’ll learn this relationship better, what degree of tau PET imaging translates to what clinical outcome. And I agree with Toby that selecting the right patients, particularly with respect to tau burden, for example, may be very important.

Perfect. That’s helpful. Then a follow-up on the SOD1 silencing gene therapy for ALS. You note in the press release in your prepared remarks that the initial trial could generate proof of concept based on biomarkers. Is that something that we could possibly see in 2026? Is that something that’s within 12 months of the US IND?

Toby Ferguson

So we haven’t guided to timing of the biomarker results. The points I can make is that one will go into the silent population, of course, and two will start in — populate in — at doses with potentially applications given the severity of the disease. In that context, we do think results would be [reasonably brough up].

Alfred Sandrock

And maybe I could add that certainly in the case of the person clinical development plan and the trials that have been published in the New England Journal, you can start to see effects on SOD1 levels in spinal fluid. And about — is it 12 week?

Toby Ferguson

12 weeks.

Alfred Sandrock

And then effects on plasma neurofilament, which is a surrogate outcome that’s reasonably likely to predict clinical outcomes and was the basis of approval by FDA of the person, that measurement should also yield data in the first say six months or so. So if that’s any precedent, that gives you an idea of the timing that it takes to see both logical effect and the outcomes on clinically relevant surrogate outcomes like NFL.

That’s very helpful. And last question, an accounting question from us. The $15 million from Novartis, the $3 million from Neurocrine, how will those be booked? Are those going to be booked in the fourth quarter of this year or will they be spread out over the life of those agreements?

Alfred Sandrock

It will be booked in the fourth quarter.

Perfect. Thanks for taking our questions. Congrats again on the progress.

Operator

Jack Allen, Baird.

Jack Allen

Great. Thanks so much for taking the questions and congrats on the progress. I wanted to ask about an aspect of the Voyager story that’s more in its infancy and that being the blood brain shuttle programs. I was hoping you could just provide some context as to where those programs sit and when you maybe you could look to bring an asset into the clinic. I know there’s been a lot of activity in the space with AbbVie ‘s acquisition of Aliada and then also Roche providing some initial proof of concept data from their beta amyloid asset there as well.

Alfred Sandrock

Well, Jack, I’ll start and I’ll ask Todd to provide more color, but I would say that we’re very excited about the potential of leveraging the receptors we identify through our capsid shuttle other macromolecules across the BBB. And as you pointed out, trontinemab — the data with trontinemab, which leverages transparent receptor is looking very promising as an approach to get anti-amyloid antibodies into the brain.
And so we’re very excited about that. We’re still in the preclinical stages. We haven’t been — we’re not close enough to the clinic yet to guide on when we would enter the clinic. Todd. Do you want to provide more color on that?

Todd Carter

Thanks, Al. So Jack, as you do point out, we are excited by it, and we know that these acceptors — and we do have different receptors in different capsid families. They can mediate transcytosis or delivery across the blood brain barrier or a large molecule, the AAV capsid. So there’s reason to believe that they should be able to deliver other things. But hopefully in the future, we’ll be able to share data on that.
I think the other aspect is that we’re seeing with receptors such as transferrin that there’s the opportunity for additional receptors to have an impact, because we expect that each receptor could have its own profile, both for pharmacokinetics and safety that could really give an opportunity for different receptors for different diseases and indications.

Jack Allen

Great. That’s great context. Maybe just one brief follow-up, you’ve been incredibly successful in partnering your gene therapy library of capsids, even in the context of these pre-clinical assets. Any comments as it relates to potential partnerships around the blood brain shuttle programs? And is that something you have an appetite for before moving this into the clinic?

Alfred Sandrock

Well, Jack. This is Al. Yeah, I’m always interested and willing to talk to potential partners. This is exactly the kind of thing where there could be expertise in other companies that could really be very complementary to our shuttle program. So always opening — always open to talking to potential partners about these kinds of things and really accelerate the program.

Operator

Joon Lee, Truist Securities.

Joon Lee

Hey. Congrats on the progress and thanks for taking our questions. Your plans for 7523 MAD study in 2025 imply that you may be — maybe you’ve seen something positive in SAD study or am I being too liberal with my interpretation? And for the SAD study due in the first half of ’25, in addition to safety, what are you tracking that could give us some incremental conviction on the drug? Thank you.

Toby Ferguson

Joon, this is Toby. Thank you for the question. Just to remind, the SAD study is in healthy volunteers. And so really the data we’re looking from the SAD study is PK initially [in the just disease] and do we have the appropriate exposures to pick doses for the MAD study and some initial read on safety? So really, it’s not a — it’s not in patient. That’s the key point.

Operator

Jay Olson, Oppenheimer.

Jay Olson

Hey. Congrats on the progress and thanks for providing this update. We have a few questions. Based on the bepranemab data that you saw, what’s your latest thinking on the potential read across to your own 7523 program? And is there any additional data from UCB that you would be interested in seeing? And then I have a follow-up.

Alfred Sandrock

Well, look, I think — Jay, this is Al. I mean, this is the first time we’ve seen that an antibody could have biological effects in the brain in humans, right? And so that’s — I look on that as positive, right, that an antibody approach could affect the biology of tau spreading in the brain.
Even before we knew about the bepranemab data, we did say that there could be readthrough, because we had tested the UCB antibody, which binds to a mid-domain region versus our antibody, which binds to the C-terminal region in an animal where we look for this — we look at the spread of pathological tau in a mouse expressing human tau, where we inject pathological tau from Alzheimer’s brains into the animal.
And we said before the CTAD, before we knew anything about the bepranemab data that the UCB antibody was pretty comparable to our antibody in blocking the spread and actually distinguishable from the N-terminal-directed antibodies that did not block the spread in that same model and which also failed in the clinic. And so we still believe that there could be read-through, and we also expect that the safety perhaps would also be similar in the sense that the antibody is binding to extracellular tau.
I would say the other differentiating feature of our antibody relative to the UCB antibody is the fact that our antibody is specific for pathological forms of tau. We don’t know how important that is; we’ll find out. But that is another feature. So that’s where we stand, Jay.
Todd, do you want to add anything?

Todd Carter

I agree with everything you said, Al. The other thing to mention, there was a question about additional data from UCB, and I think it will be important for us to see what additional data come out on some of the PK and PD — that PK/PD relationship.
As Al has pointed out, the relationship between reduction of tau accumulation and potential cognitive benefit that it appears is pretty interesting, and we see that as very encouraging. Those are in some groups. I think seeing more detail about target engagement and that relationship will really be important to interpret the results.

Jay Olson

Great. Thank you for that. And then maybe just as a follow-on, how are you thinking about prioritizing 7523 versus your tau-silencing gene therapy, and then the potential for combining either of your anti-tau approaches with anti-amyloid antibodies?

Alfred Sandrock

Well, I would say that they’re both high priorities. Am I allowed to say that two things are both high priorities? And look, we’ve always said that tau was a pretty — very important target that we think it’s the next step in helping Alzheimer’s patients that the anti-amyloid treatments got us started, but we need to do better for patients.
And so I think they’re both high priorities. They’re very different approaches in many ways. And so we’ll find out which is the better approach.
In terms of combining or with the anti-amyloid antibodies, I do think that there could be a place for combining. I would say that it would be in those patients that seem to have a partial response to the anti-amyloid antibodies. If they have no response to the anti-amyloid antibodies, there’s no sense in continuing the drug. If they’ve had a full response to anti-amyloid antibodies, which may be the case in some patients — if you’re not progressing or at all in your disease on anti-amyloid antibodies, there’d be no reason to add anything else.
So I think time will help us. Time will tell what the heterogeneity of the treatment response is to the anti-amyloid antibody therapies in humans as we see the drugs being rolled out. And then by the time we’re ready to think about that combination approach, I think we’ll have more data on how many patients respond fully, how many respond not at all and how many respond partially.
But I would say that we would want data initially as monotherapy too, first, to see that — make sure that our drug is active and then have some understanding of the doses that we would want to use.

Operator

Lili Nsongo, Leerink.

Lili Nsongo

Hi, good afternoon, and thank you for taking our question. So I guess the question for me. So the first one, as we await for in-patient data — so in 2026 for the tau-targeted antibodies, are there any plans to potentially test previously developed C-terminal antibodies in preclinical models to try to further confirm the negative predictive values of the model you use in a more region-specific approach.

Alfred Sandrock

Well, if we — if there’s another neg antibody that’s negative, I think that would be a pretty interesting study to do, particularly if it’s not internal, right? So I’m not sure doing any more N-terminal-directed antibodies would add much. But if there’s an antibody targeting a different epitope that fails, then it might be interesting to do that experiment that you’re proposing, Lili.

Lili Nsongo

Yes, because it was my that both Hoffmann-La Roche and then Ljungberg had some see feature in [limbic antibody]. I think it could be really interesting technical data as we await.
And I guess maybe segue into my second question, so regarding the UCB data and the challenges that they’ve had in the overall population, would that compel you to potentially start the development in-patient in maybe a smaller, more targeted patient population? So I guess my question is, does the results of the study compel you to maybe have more stringent inclusion criteria in the initial in-patient study for the antibody?

Alfred Sandrock

Yeah. Hi, Lili. This is Al. And I’ll start and I’ll ask Toby to add his comments, but I would say that we would be very open to that idea. We would like to see if we can differentiate from bepranemab, if at all possible. And it could be that the choice of patient population could be a way to boost the efficacy that we see, particularly on the clinical outcome measures and get more clarity.
Toby noted in his comments, there were sub-groups, particularly those that were pre-specified — I think it was the APOE4 non-carrier, low-tau-burden patients who seem to do better. And those are exactly the patients where the effect on tau accumulation was more pronounced. So I’d be open to that.
Even though it’s a smaller population, we’re talking about a gigantic population overall, the Alzheimer’s disease patients and to have a targeted treatment for a smaller population that’s still quite large, by the way, would be of interest. Toby?

Toby Ferguson

So, I think, Al, you captured it nicely. I think the only other comment I’d make is that when we did look at the bepranemab data, they had segregated their low and high tau populations. There really weren’t that many low tau patients in the study overall, about a 80-20 ratio approximately. And so I think more data there, that is suggestive data, but we look forward to the breakdown of those data.

Lili Nsongo

Appreciate it. Maybe just a follow-up. So we will be waiting for initial safety and PK data in healthy volunteers in the first half of 2025. But I was wondering maybe if you could give a little more granularity in terms of when we should expect an update on the potential design of the in-patient study?

Alfred Sandrock

I think she’s interested in the design of the multiple ascending dose study.

Toby Ferguson

Yes, thanks, Lili. So I think as we — once we get closer to the start, which will start next year, we’ll share the details of the design.

Operator

Patrick Trucchio, H.C. Wainwright & Co.

Patrick Trucchio

Good afternoon. Thanks very much. Just a couple of questions for me. The first is just a follow-up on the earlier comment regarding the appropriate patient population for the tau program for the antibody program. Can you discuss what level of tau PET burden do you think could be appropriate of baseline based on this — learnings from this recent data and particularly as we approach that Phase 1b trial with 7523.
And then separately as we think about or as we look ahead to the tau-silencing gene therapy, I’m wondering if you can talk about the advantages or differences we should expect from the tau-silencing gene therapy as compared to these tau-targeting antibodies.
And then secondly, what remains to be completed to ensure that the 2026 IND and CTA filings remain on track for the tau-silencing gene therapy? And then lastly, if you could, just talk about the anticipated capsid and advantages of the Voyager platform as compared to some of these others in the field developing a similar approach?

Alfred Sandrock

Well, that’s a lot of questions, Patrick, but we’ll knock them off one by one here. So I’ll take the first one, and then maybe Toby can take the second. And Todd, you can take the third one.
But anyway, on the appropriate patients, the cut off that UCB shared data with us was a pre-specified cutoff, but it was not the median. In fact, there were many fewer patients, I think, in the low tau burden subgroup versus the high tau. I think that was because it was pre-specified.
Hopefully, we’ll see more data on the full range of tau burden. All we have is that one piece of data to go on. I think we would need more to be more specific about the tau burden. Toby, you can let me know if you disagree with that.
Okay. And then on the tau KD, I think you were asking, how do we make sure that we stay like — I’ll be on track. And so maybe Toby and Todd, do you want to help me with those questions?

Toby Ferguson

So maybe I’ll start and ask Todd to fill in. So the pre-clinical development is proceeding. I think the key next steps are sort of pivotal step of doing the toxicology studies.

Todd Carter

All right. So the standard ID-enabling studies would be part of the process. You also asked about differentiation for the tau knockdown versus the antibody approach, I believe. And I think the BIIB080 data, which is an ASO-delivered that has shown some really interesting clinical data to date versus the antibody approaches. But what we’ve seen in the BIIB080 data are not only signs that you could reduce the accumulation of tau, but you may be able to reduce tau burden — pathological tau burden as measured by PET in some cases below starting burden, which is a pretty remarkable finding.
When you look at those sorts of data and even with the recent bepranemab data, that also seem to suggest that an impact on tau PET imaging results can impact clinically, I think there is a accumulating evidence in a clinical benefit with the gene therapy approach, of course.
Here we’re talking about a once and done approach. We can dose once. We know that our vectors — and this gets into a little bit of the Voyager platform question as well — that our capsids can deliver quite broadly throughout the CNS. We can get delivery not only to the — I’ll call it the shallower regions of the brain, but also the deeper structures with that single dose.
And so we think there could be some substantial benefits for a tau knockdown approach. It is also an intercellular effect. The antibody has an impact presumably based on the prion spreading hypothesis as the pathological tau spreads from cell to cell. So an intercellular reduction of tau could have an impact not only in reducing that cell-to-cell spread, but also in an intercellular way.
So those two approaches, I think, are both interesting. There are signs of for both those mechanisms that they could work. And in the end, it’s even possible there could be combination approaches.

Alfred Sandrock

So Toby, do you want to add on potential clinical outcomes?

Toby Ferguson

So there, I think the BIIB080 data, in particular, really emphasized along with the recent bepranemab data, the importance of tau PET. And to Todd’s PowerPoint in the BIIB080 knockdown-based approach or a knockdown-based approach, you can see the removal of both pre-existing pathological tau and prevention of further accumulation and in somewhat earlier timeframes, six months or so, which is distinct from slowing accumulation. This is particular to the tau knockdown approach.
In addition, you can also see clear signals in the CSF biomarkers. And so there is a chance based on biomarkers to get a relative quick read on how the molecule is performing.

Patrick Trucchio

And what about the — do you think the effect size? I mean, it’s hard —

Toby Ferguson

It’s early data that the — I mean, if you look at the propensity score matching that Biogen performed, they looked at a comparison to other study called TANGO, they looked at the natural history study and there, that effect size was 2 to 2.5 points on CDR sum of boxes as a reminder of the effects on the [amyloid] 0.4 to 0.9 points what’s approximately on CDR sum of boxes. So potentially, larger effect size as well, which gives you an additional opportunity to potentially (technical difficulty) signal with smaller sample size.

Operator

I’m showing no further questions at this time. I would now like to turn it back to Al for closing remarks.

Alfred Sandrock

Thank you, everyone, for joining us today, and we look forward to speaking with you again soon.

Operator

Thank you for your participation in today’s conference. This does include the program. You may now disconnect.