Good day. Thank you for standing by. Welcome to the Q4 2023 Voyager Therapeutics Earnings Conference Call. At this time, all participants are in a listen-only mode. Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker today, Peter Pfreundschuh, Chief Financial Officer. Please go ahead.

Thank you. And good afternoon. Joining me on the call today is Dr. Al Sandrock, our CEO, and Dr. Todd Carter, our Chief Scientific Officer. We issued our Q4 and year-end 2023 financial results press release this afternoon. The press release and 10-K are available on our website. In a moment, I will turn the call over to Al. Before I do this, I want to remind everyone that, during this call, Voyager representatives may make forward-looking statements as noted in slide 2 of today's deck. These forward-looking statements include future expectations, plans, and prospects. All forward-looking statements are inherently uncertain and are subject to risks and uncertainties that may cause actual results to differ materially from those indicated by these forward-looking statements. You are encouraged to review and understand the various material risks and uncertainties facing the company as described in the company's most recent annual report on Form 10-K filed with the SEC this afternoon. All SEC filings are available on the company's website. Now, it is my pleasure to turn the call over to Al.

Thank you, Pete. And good afternoon, everyone. Please turn to slide 3. I'd like to start by defining Voyager's position as an emerging leader in neurogenetic medicine. First, our pipeline. We anticipate having at least four wholly owned and partnered CNS programs in the clinic by the end of 2025, with the potential to generate clinical data in 2025 and 2026. Our most advanced programs are an anti-tau antibody for Alzheimer's disease and our SOD1 gene therapy program for amyotrophic lateral sclerosis, or ALS. I will talk more about both programs in a few minutes. Second, our platform. Voyager is working to solve the delivery challenges inherent to CNS gene therapies with our TRACER capsid discovery platform. We have demonstrated high transduction in multiple brain areas at relatively low doses with detargeting of the liver and dorsal root ganglia across multiple species. We have also shown blood-brain barrier penetrance across multiple animal species, and we have identified a receptor that is expressed in humans. Third, partnerships. In January of 2024, we received $100 million from Novartis in a combination of upfront payment and equity investment to develop gene therapies for Huntington's disease and spinal muscular atrophy. This brings our total of partnered programs to 13, with the potential to generate $8.2 billion in longer-term milestone payments. While this is a “biobucks” number, it is not factored into our cash runway guidance. I will note that some of it is becoming real. Earlier this week, we triggered a $5 million milestone payment upon selection of a lead development candidate for our Neurocrine partnered Friedreich's ataxia program. All this has given us a strong balance sheet, which we expect to provide runway into 2027, removing our financial overhang and enabling us to potentially generate value-creating clinical data in 2025 and 2026. Finally, potential. We have already demonstrated our strength as a leader in CNS capsid technology. We now aim to expand from gene therapy and antibodies into other modalities of neurogenetic medicine, potentially broadening our impact. We continue to explore the potential to leverage Receptor X to shuttle non-viral genetic medicines across the blood-brain barrier and look forward to sharing data on this in the future. On slide 4, I want to take a moment to acknowledge just how much Voyager has achieved recently. Following the Novartis collaboration, we closed a $100 million public offering. We closed 2023 with approximately $231 million in cash. When you add the $100 million from Novartis and the $100 million from the offering, that brings us to a pro forma cash number of approximately $431 million as of December 31, 2023. We’re also progressing our GLP toxicology work with our anti-tau antibody, VY-TAU01, for Alzheimer's disease and remain on track for an IND filing in the first half of this year. We achieved two development candidate selections with gene therapy programs: one, our wholly owned SOD1 ALS gene therapy and one with our Neurocrine partnered Friedreich's ataxia program. We also generated data with our wholly owned tau silencing gene therapy program, showing robust reductions in human tau mRNA and protein in a mouse model, which Todd will share more on later. All of these milestones are helping us build a robust pipeline, as you can see on slide 5. I do want to note that the wholly owned programs at the top of the slide denoted in orange are the only programs we fund. The rest of our pipeline is funded by our partners. While I won't go into detail on all of these today, I do want to dig into some of our wholly owned programs, particularly our anti-tau antibody, our tau knockdown gene therapy, and our SOD1 ALS gene therapy. Moving to slide 6, when I look at the Alzheimer's space, I'm encouraged by the progress, particularly the approval of two anti-amyloid antibodies. I view tau as the next exciting target in this field. We've long known that the spread of pathological tau correlates to the progression of Alzheimer's disease. In fact, Alzheimer's disease progression is characterized by Braak staging, which is based on the spread of pathological tau. Our anti-tau antibody, VY-TAU01, is differentiated from other approaches based on the epitope of targets, which is located in the C terminal rather than the N terminal or mid domain, and has been shown to inhibit the spread of pathological tau by more than 70% in preclinical studies. We are currently progressing through IND-enabling studies and remain on track to file an IND in the first half of this year. We plan to initiate a single ascending dose study this year in healthy volunteers, and we plan to initiate a multiple ascending dose study next year in patients with early stages of Alzheimer's disease. We hope to generate proof of concept data for slowing the spread of pathological tau via PET imaging in 2026. I'll now turn it over to Todd to talk about another approach we are developing to target tau.

Thank you, Al. Please turn to slide 7. In addition to our anti-tau antibody approach, we are also working on a tau silencing gene therapy. This approach leverages a TRACER derived BBB-penetrant AAV capsid to deliver vectorized tau-targeted siRNA. As shown, the single intravenous administration of our tau-silencing gene therapy in a humanized tau mouse model caused robust reductions in human tau mRNA and protein. This was observed across multiple brain regions. In some regions, we have seen up to a 90% reduction in tau mRNA. This work will be presented at the 2024 AD/PD conference. Given these promising data, Voyager has prioritized this program and advanced it into research. We anticipate an IND filing in 2026. I'll just echo what Al said here. We see tau as an incredibly important target for Alzheimer's disease, so much so that we're pursuing multiple modalities, both an antibody and a gene therapy. We are encouraged by the early data for both of these programs and look forward to continuing to share at scientific conferences. In addition, I want to share a little data from our SOD1 ALS gene therapy program. We announced the selection of a development candidate for this program in December of 2023, and some of the data behind this decision are shown on slide 8. As you can see, a single IV dose of our development candidate in non-human primates resulted in 73% and 82% reductions in SOD1 mRNA in cervical and lumbar spinal cord motor neurons, respectively. These are quite significant reductions in some of the key cell types affected by the disease. Additionally, we think an added benefit is that the effect is not limited to the spinal cord. When you look at approaches of injecting a medicine intrathecally, you often see steep gradients of effects dropping off once you move away from the injection site. But because our IV approach leverages the vascular system to deliver across the blood-brain barrier, we see not only strong knockdown along the spinal cord but also lowering of the brainstem and motor cortex, which we believe will be important in addressing ALS. This program continues to progress toward an IND filing in mid-2025. Now I'll turn the call back to Al.

Thank you, Todd. Turning to slide 9, you can see Voyager has started the year off strong, and we continue to execute on our milestones. We began the year with our second Novartis collaboration, this time to advance gene therapies for Huntington's disease and spinal muscular atrophy. We then raised $100 million through a public offering in January of 2024, providing runway into 2027. Just this week, we announced the selection of a development candidate for our Neurocrine partnered Friedreich's ataxia gene therapy program, which triggered a $5 million milestone. I want to close by acknowledging all of the hard work of the Voyager team, which has allowed us to progress as much as we have. Looking forward, Voyager is well capitalized to advance at least four wholly owned and partnered CNS programs into the clinic this year and next. And with our financial overhang removed, we look forward to potentially generating value-creating clinical data in 2025 and 2026. With that, we're happy to take any questions you may have. Operator?

Our first question comes from Jack Allen with Baird.

Congratulations to the team on all the progress made throughout the quarter. My question is fairly high level, but it relates to all three of the assets that you anticipate moving forward towards clinical studies. You reviewed the ALS program, the Friedreich's ataxia program externally, and then the internal Alzheimer's program that you're prioritizing. How should we think about vector selection across all three of these assets? Do they feature the same vector? Are they each using novel vectors? And as you move towards the clinic, I guess to what degree can you translate preclinical results across these programs and clinical results from early clinical data to the latest pipeline assets that are going to move forward as well?

I'll start and then I'll turn it over to Todd for his comments. So with respect to the capsid, we haven't disclosed which capsid. Every one of these programs, we will use one of our novel capsids discovered through the TRACER platform. They will be delivered IV. We anticipate we will use doses well below E14 vg/kg because those are the doses that have jumped from safety issues with other AAV programs. We select these capsids based on a capsid profile that we create for every single disease and every single target based on the fact that these diseases reside in different parts of the nervous system. Also, we want to be sure that we target the cells that are necessary while detargeting the cells that may cause toxicity. That leads us to these capsid profiles. Luckily, we have an array of capsids we can choose from and our partners can choose from. Todd?

I don't have a lot to add to your comments, Al, you hit the major points. As Al mentioned, we identify a profile for the capsids that are specifically oriented to each disease that we're going after. Of course, it's a different payload in each case. You're talking about stereotypes, there's a capsid that is effectively the envelope that delivers that payload. We really try to hit each of those components that Al mentioned to give us the best opportunity for success and to reduce any potential risks of tolerability issues.

I think Jack had a question about predictability, I think, of preclinical models. We chose targets, Jack, that we think are validated based on human genetics or human studies of other types, including controlled clinical trials. What we aim to do is to do pharmacology in animals. For us doing clear pharmacological studies in non-human primates, where you don't have the availability of so-called models of disease, may be just as informative, or perhaps more informative, to help us choose the right capsid because the size of the animals are obviously different from mice and the delivery characteristics may be more similar to humans. I hope that helps with that part of the question.

The next question comes from the line of David Hoang with Citi.

This is Sam Beck on for David. Congrats on the progress. Just if you could provide any color on how we should think about collaboration revenues for 2024, if there are any significant potential near-term milestones for partners that can lead to any lumpiness in quarterly revenues?

We don't provide specific guidance with regards to collaboration revenue, especially new collaborations per se. We have been very fortunate, and as part of today's announcement and what came out earlier this week was further validation that the collaborations that we already have in place, specifically the collaboration around the FA program with Neurocrine is advancing and moving forward. This continues to validate the science in the organization and also brings to the company additional cash flow revenues that we had not previously projected as part of our overall cash runway. That's an additional $5 million as we discussed in today's conference call. I do think as you look at our financials for the close of 2023, we do have pretty significant revenues this year. That was largely driven through, originally, the first deal that we did with Neurocrine at the beginning of 2023, the subsequent option to license agreement with Novartis earlier in the year, and then, of course, the final collaboration or the second collaboration with Novartis around the SMA program, as well as the HD program. 2023 was a banner year for us, I think, from a revenue generation and cash flow perspective. Obviously, going forward, we're going to be very open to business development discussions and always open to conversations. There could be further revenue generation associated with our capsid platform as you think about 2024, and definitely milestones for our existing 13 partnered programs. So, I think it's important to just be mindful that we don't provide guidance here, but we do believe that there could be further revenue generation as we move forward into 2024.

This question comes from the line of Jay Olson with Oppenheimer.

Congrats on all the progress. We have a question about the TAU01 program since there are some near-term readouts for competing tau-targeted therapies, including Phase 2 readouts from an anti-tau mid-domain antibody from Roche and UCB and OGA inhibitor from Lilly. Can you just talk about the potential read across to your own TAU01 program and maybe more broadly to the tau targeting strategy? And then I have a follow-on, if I could, please?

That's an excellent question. We acknowledge that there are several antibodies that target different parts of the tau molecule, and there may be some overlap in efficacy. We strongly believe that the specific epitope is crucial, as evidenced by our observations with amyloid antibodies. The successful ones were all targeting the N-terminal region. In contrast, the C-terminal and mid-terminal anti-amyloid antibodies were less effective. For tau, we selected the C-terminal based on animal studies where we administered human pathological tau and observed the blockade of its spread to other brain areas. We chose the C-terminal because it was the most effective in preventing that spread. We actually developed several antibodies targeting other specific regions of pathological tau, around six in total. After testing them, we decided to utilize a spreading assay in animals to determine which epitope to focus on. In summary, a positive outcome highlights tau as a viable target, whereas a negative result could indicate that we may have chosen an incorrect epitope. If it concerns a C-terminal antibody, we need to pay attention to that. However, even among antibodies in the same region, their capacity to block spread can vary, so we should be cautious in our interpretations. Todd, do you have anything to add?

I think you captured it. The point at the end there that Al made was we can identify – and through our studies, we did – antibodies that targeted epitopes very close to one another on the tau protein. Some of those antibodies would work quite well in our screening assay and others would not, and it really depended upon a particular epitope. I will just reiterate that, in our assays, the internal antibodies that have failed in the clinic to date failed in that assay as well. So, we're taking something forward that was quite robust and targets pathological tau specifically.

If I could squeeze in a follow-up question about recent discussions at the FDA, can you just comment on their plans to more broadly use biomarkers for the accelerated approval of gene therapies?

We read that with great interest, and I applaud the use of surrogate markers, if you will. These are diseases with such terrible consequences for patients. If we can use a surrogate biomarker to get accelerated approval and then confirm in a confirmatory trial, I think the patients get access to the drugs earlier. I think it's a valid approach. Personally, for the right disease and the right surrogate marker, this is exactly the right approach for patients.

Maybe just looking at regulators outside the US, any takeaways from the positive CHMP opinion for tofersen?

That's another great example. As we all know, tofersen did not meet the primary endpoint, which was a clinical outcome measure of the ALS functional rating scale, but it did show a strong effect on neurofilament. The US approved it based on that as a surrogate biomarker, which is reasonably likely to predict clinical efficacy. Last week, Europe followed suit and allowed for tofersen's approval, likely based on the use of neurofilament as a surrogate biomarker. We'll need to wait for the regulatory EPAR to understand their reasoning fully. It's important to note that the main outcome measure that was positive was the NfL, with strong support from other clinical outcome measures, but the statistically significant one was NfL. So, it seems Europe may be thinking along similar lines.

Our next question comes from the line of Ry Forseth with Guggenheim Securities.

This is Ry Forseth from the team at Guggenheim. Two questions from us. One, could you highlight the features of your VY-TAU01 Phase 1b clinical plan that you would point to as competitive advantages relative to historical or ongoing tau clinical efforts? And our second question is, what lessons from lecanemab and other A-beta targeting therapies would you point to as most informative for the design of a tau targeting clinical program and specifically your VY-TAU01 program?

The VY-TAU, the Phase 2 program that we hope to get proof of concept based on tau PET imaging, our current plan – and we still have more work to do to actually get input from investigators and FDA, obviously. But the current plan is to enroll early-stage Alzheimer's patients, probably at Braak stage two, perhaps three, but early-stage by Braak staging as well, and look for the spread of tau to other regions in the brain, other cortical regions that we know that tau will spread to. The great thing about Alzheimer's disease is that it has a very stereotypical spreading pattern. So we can look at regions of interest in the brain and see whether or not we're reducing the spread. In some ways, we want to recapitulate the data we saw quite robustly in the animals we talked about earlier, where we used human pathological tau and looked at the spread. So whether that's a competitive advantage or whether it's – we chose the program because we liked the fact that we can get proof of concept on the spread of tau very efficiently. We think we can do it on the order of 25 or so patients per group in a one-year duration, and proof of concept, proof of principle on the spread. So, that's our current plan. As I said, we're still a couple of years away. So that may change, but that's our current plan. In terms of lessons from lecanemab, in a way, I mentioned it earlier that epitope matters a lot, that early-stage patients are probably where you need to go, and that you need to have a robust effect. The other distinguishing feature of aducanumab and lecanemab and donanemab is that you have a very robust effect on the amyloid PET imaging in one year. So, we hope to see a robust, clear-cut effect on tau PET imaging. If we don't see that, we're not going to move forward. We need to see the fact that we've got not only targeting enrichment but a clear pharmacodynamic effect on the tau spreading hypothesis, if you will. If we don't see that, we're not going to move forward with that program. But as we talked about earlier, we still have the tau silencing program behind that, which takes a different approach to a very important target.

This question comes from the line of Phil Nadeau with TD Cowen.

A couple from us. First on the SOD1 program. In the past, you'd guided towards starting GLP-1 tox for the program in the first half of 2024. We see that you're getting towards an IND next year. Is the GLP-1 tox on schedule? Any changes to the timelines ahead of the IND filing?

Actually, no. There's been no change in the timing. This is exactly the timeline that we had planned from the very beginning.

Second on the VY-TAU01, a follow-up to the prior question. On the Phase 1a and 1b, appreciating that proof of concept will be generated by the PET scans, what PD markers will we be able to look at from the Phase 1a and 1b in advance of getting that PET scan data to make sure you're on the right track? Will it simply be pharmacokinetics? Will you have good data on target engagement or any other PD biomarkers that you'll be able to look at to make sure or to ensure that you're on the right track towards producing the PET proof of concept data?

On the Phase 1a, that's going to be a single ascending dose study in normal healthy volunteers. So we're not going to get any pharmacodynamic or target engagement data. We will be getting data on safety and PK and try to get to the point where we identify the optimal doses to move into the Phase 1b trial based on safety and PK. Then in the Phase 1b – I may have called it Phase 2 trial; we will be – there are a whole pathway of tau-related biomarkers we could look at. The primary one that we're going to pay attention to is tau PET imaging because, as I said earlier, we will take advantage of the stereotypical spread of tau and look at regions of interest in the brain to test the spreading hypothesis, if you will. But there are a number of additional biomarkers we will be looking at. In addition to CSF biomarkers for tau, we're lucky to have some blood biomarkers of covalently modified forms of tau that we can look at, such as p-tau and various phosphorylated forms of tau. People have seen efficacy on those, certainly in the anti-amyloid trials, but also in some of the tau trials as well. For example, BIIB080, the tau ASO that Biogen is pursuing. I think that we'll look at all of them. But our decision-making, Phil, is going to be primarily based on the tau PET imaging for the reasons I stated earlier.

This question comes from the line of Joon Lee with Truist Securities.

This is Mehdi on for Joon and congrats on the quarter. So could you please elaborate on the choice of artificial micro RNAs over a vectorized siRNA or shRNA for tau silencing candidate of yours? And I have a follow-up.

Of course, our payloads are the vectorized siRNA, or technically a vectorized form of the pri artificial microRNAs. We have a lot of experience. We've been doing this for many, many years at Voyager on how to vectorize these things. You identify the siRNA, it sits within a particular cassette. When expressed, it will get processed – is processed in a nucleus and exported into the cytoplasm. We think vectorizing the siRNAs with a single dose delivers a level of expression, and these are a catalytic type of approach where the siRNA continues to be used by the processing mechanisms in the cell to knock down the mRNA. We know we can get quite specific in targeting of the mRNAs involved, and our whole process of selecting these things involves careful attention to things like the processing, the lack of up targets, and that sort of thing. So we're comfortable and actually very enthusiastic about the siRNA approach we take.

A quick addition to this question. Is it different from shRNA backbone or artificial micro RNA backbone, so the type of promoters that you use?

I heard shRNA. What was your other…?

Artificial micro RNA.

It is effectively an artificial micro RNA, but it is an entirely artificial one that it – those that we choose do not exist in the endogenous expression. But it is an artificial micro RNA. It is different from an shRNA, which those hairpins are involved in other types of processing that result in reductions in RNA. So it is distinct.

Lastly, there have been multiple N-terminal targeting antibodies for tau and several for the microtubule binding domain. It seems that you're the only one with the C-terminal targeting. Can you please provide some insight on how the selection of C-terminal has been like less prevalent?

It turns out that there are two other companies that are also targeting the C-terminal that we're aware of. There could be more, but Merck, for example, is in Phase 1 with a C-terminal monoclonal antibody, and Lundbeck is also in Phase 1 with a C-terminal targeting antibody. You're right that there are a couple of other – at least these two other, maybe three other companies targeting the microtubule binding region. I think many of us select these antibodies that are specific for pathological forms of tau. We had a number against various regions as well. How do you pick which one of those? They're all selected for pathological forms of tau. And so, some have chosen, for example, cellular uptake assays or cellular toxicity assays. We happen to choose the in vivo spreading assay where you inject human pathological tau into the brain of mice, and we look at the spread. Who knows which one of these assays is the right one to use? It's hard to know until we see the human data to say, oh, that's the one that was most predictive. But we like the fact that it's a biological – that it's a spreading assay in vivo that starts with human pathological tau. That's why we chose the C-terminal directed antibody, but we're not the only ones that chose the C-terminal.

A couple of other points. You mentioned the N-terminal antibodies. And those have – I think, almost without fail, they have not succeeded in the clinic. I mentioned this earlier, in the vivo model that Al described, those antibodies do not work in that model. Our antibodies are different from those that, to date, have failed in clinic. We've often chosen the epitope. When we say C terminal, these other antibodies that target the C terminal region target distinct epitopes in the C terminal region. So even different antibodies in what we might call the C terminal region are likely to be distinct from one another as well.

So far, when you look at the N-terminal antibodies, it seems that the animal has negative predictive value. What we don't know is whether it also has positive predictive value. But that's the point I think you were trying to make on the N-terminal.

This last question comes from the line of Sumant Kulkarni with Canaccord.

It's actually a follow-up to a question that I had asked on the last quarterly update and it relates to GLP tox on the anti-tau antibody. You'd mentioned that there were some nuances to running those studies and your slides today say you still expect to complete these studies in the first quarter? So could you shed any specifics on what more needs to be done so you can hit your timeline for an IND submission in the first half of this year?

Well, the nuances are that there's an antibody that binds specifically to human pathological tau. So, typical tox studies are done in wild type animals. To look at on-target toxicity, there is no wild type animal that can be used to evaluate on-target toxicity. The nuance is that you have to do studies in animals that are expressing human pathological tau. Otherwise, there's no target. The problem is that those animals are sick because they carry human pathological tau. So, it's very hard to do long-lasting studies in animals that are sick. But we have a lot of confidence in the toxicology package we chose. You'll recall that we did have a pre-IND meeting last year. I think it was almost a year ago. I think it was March of last year where we had an interaction with the FDA. A lot of our work is – actually, all of our work is based on that interaction. We're on track to achieve our goal of filing the IND in the first half of this year, sometime in the next couple of months or so. We hope to start the first-in-human studies shortly thereafter.

Thank you. At this time, I'm showing no further questions and would now like to turn the call back to Dr. Sandrock for closing remarks.

Well, I just wanted to say thank you to everyone for joining us today and please feel free to follow-up directly with any questions. Thank you.

Thank you. And thank you for your participation in today's conference. This does conclude the program, and you may now disconnect.