Voyager Therapeutics, Inc.

for Alzheimer's disease and SOD1 gene therapy program for ALS. We currently have three wholly owned assets targeting Alzheimer's disease, including a new early research initiative just announced today to advance a vectorized anti-A-beta antibody. We'll talk more about this in a minute. Third, partnerships. Voyager has generated more than $200 million this year alone in non-dilutive partnering revenue. In Q2, we executed a license agreement with Sangamo around prion disease, bringing our total number of partnered programs to 11. These programs provide opportunities for additional milestone and or royalty revenue to Voyager, as well as opportunities to generate data with our capsids and, most importantly, to help patients. Finally, potential. specifically the potential to expand from gene therapy into other approaches of neurogenetic medicine. As those of you who attended our standing room only talk at ASGCT know, we are making good progress in our receptor program. After identifying a receptor for one of our capsid families, we have now also identified a ligand for this receptor, which has many of the characteristics required for transport of macromolecules across the blood brain barrier, or BBB. We are exploring the potential to leverage the receptor to shuttle non-viral genetic medicines across the BBB. We have also preliminarily identified two receptors for additional families of our tracer capsids, and we are conducting confirmatory research to further validate these discoveries. While this program is early, I am increasingly excited about the potential here to expand the reach of our technology into other approaches of neurogenetic medicine. Moving to slide five, as you can see, Voyager is advancing quite a robust pipeline. However, we are doing so efficiently. The four programs depicted in blue at the bottom of the slide are funded and executed by partners. They do not require significant investment of time or money from Voyager. Moving up the slide, the seven programs depicted in yellow represent our collaborative programs with Nurocrine. For these programs, Voyager is fully reimbursed for our collaborative research. The six programs depicted in orange at the top of the slide represent our Hoi On pipeline. This is where I will focus today. Turning to slide six, You can see that our wholly-owned pipeline now includes three programs for Alzheimer's disease. Our lead program is our humanized anti-Tau antibody, which is advancing towards initiation of IND enabling studies this year. We continue to expect to file an IND in the first half of 2024. Additionally, we continue to conduct early research on our Tau gene silencing program, which we introduced earlier this year. This program utilizes a vectorized siRNA delivered with a tracer capsid to reduce tau expression in the brain. Today, we are introducing another early research program in our Alzheimer's disease franchise. In this program, we are combining a vectorized anti-A beta antibody with a tracer capsid. I will turn the call over to Todd, who will talk more about this program momentarily. But first, I want to explain why Voyager has chosen to focus three of our six wholly-owned programs on Alzheimer's disease. On slide seven, a glance across the top row highlights some of the recent progress with anti-amyloid antibodies. These represent tremendous first steps toward modifying the course of Alzheimer's disease. Turning to the second row of milestones on this slide, There's an increasing body of data demonstrating the role of tau in Alzheimer's disease. I think of amyloid as the trigger and tau as the bullet. There's a tipping point at which increasing amounts of amyloid cause tau to spread, and that spread of tau is what causes neurodegeneration. The Lilly data reinforced this, demonstrating that anti-amyloid treatment showed greater clinical benefit in patients with lower tau versions. Ultimately, we need to better understand the clinical efficacy of anti-amyloid treatments by stage and subtype. We may already be starting to see evidence of complete responders, partial responders, and non-responders to anti-amyloid treatment based on recent Phase III data. Complete responders may not need any further treatment than anti-amyloid, but partial responders may be appropriate for a combination of anti-amyloid and anti-TAL therapies. and non-responders to anti-amyloid might be candidates for switching to anti-tyl-monotherapy. In short, this is a disease that affects millions of people. The field is making great progress against multiple targets, and there's still much work to be done. Now I'll turn the call over to Todd to talk about our new anti-amyloid gene therapy program.

Thank you, Al. Please turn to slide eight. As Al mentioned, There are now multiple FDA-approved anti-amyloid antibodies for Alzheimer's disease. We think a vectorized anti-amyloid gene therapy may offer the benefit of providing similar disease-modifying efficacy with a single dose. Additionally, while more research is needed, there is biologic rationale to suggest that a gene therapy approach to targeting amyloid may reduce the risk of amyloid-related imaging abnormalities, or ARIA. In a gene therapy approach, the anti-amyloid antibodies are steadily secreted by cells in the central nervous system, and thus we would be avoiding high antibody concentrations that necessarily follow intravenous antibody infusions. Moreover, the antibody would first engage the beta amyloid deposited in and around amyloid plaques, rather than the beta amyloid deposited around blood vessels. Both mechanisms may reduce the risk of aria. Voyager has a long history of antibody expertise. Our lead program is our anti-tau antibody, VY-tau-01. Although VY-tau-01 is not a gene therapy, we previously shared data at the Alzheimer's Association International Conference in 2022, demonstrating that we had vectorized antibodies from this program and achieved substantial anti-tau antibody expression in the hippocampus, cortex, and CSF of mice. which was sustained seven months after a single administration. In addition, we have also vectorized an anti-HER2 antibody for the potential treatment of brain metastases from breast cancer. So this gives you a flavor for Voyager's work in antibodies as a whole and in vectorizing antibodies specifically. In this new program, we have vectorized an anti-A-beta antibody and delivered it using a novel capsid. Preliminary data in mice have shown target engagement with amyloid plaques following a single IV administration of the vectorized antibody with a BBB penetrant capsid. We have shown this using vectorized murine antibodies and vectorized humanized antibodies, and we are currently evaluating antibody payloads with our tracer capsids. I'll now turn the call back to Al.

Thank you, Todd. Turning to slide 9, as you can see, Voyager continues to execute on our milestones. We secured partnerships with Pfizer, Neurocrine, Novartis, and now Sangamo, and the company is well capitalized with approximately $273 million in cash on our balance sheet. We selected a development candidate for our anti-Tau antibody program for Alzheimer's disease, and we launched three new early-stage gene therapy programs, one for Huntington's disease and two for Alzheimer's disease. We also continue to add incredible talent to our team. Last quarter, we welcomed George Skangos to our board of directors. Earlier this month, we appointed Jacqueline Fahy Sandell as our chief legal officer, and she is already adding tremendous value. Looking forward, we continue our work to break through the barriers constraining the fields of gene therapy and neurology. We expect to identify a lead candidate for our wholly owned SOD1 ALS gene therapy program by the end of this year. As we look towards 2024 and 2025, we anticipate the potential for multiple IND filings across our wholly owned and collaborative and or licensed programs. This translates into multiple opportunities to earn milestone payments, and even more importantly, once clinical trials begin, several shots on goal to establish human proof of concept for our tracer capsids. Furthermore, there is potential to see early biomarker-based evidence of disease impact in some of these very difficult CNS indications. We continue to engage in active discussions with potential partners regarding collaboration and licensing arrangements around our platform and pipeline. In summary, it's a very exciting time at Voyager, and we look forward to continued execution this year and next. With that, we're happy to take any questions you may have. Operator?

Thank you so much, presenters. And as a reminder, to ask a question, you will need to press star 11 on your telephone. To answer a question, please star 11 again. And please stand by while we compile the Q&A roster. Your first question comes from the line of Jun Li of Truist Securities. Please ask your question.

And thanks for taking our questions.

On the Alzheimer's program, are you able to share any information regarding the choice of the antibody that you plan to vectorize? And how do you plan to mitigate risks associated with ARIA, for example? And I know you mentioned, you know, specifically plaques that are not on vessels. I'm curious. if there are certain antibodies you're aware of that can do that. And lastly, would you be able to fit an RNAi in the same contract? I'm thinking maybe a vectorized tau RNAi for a dual-pronged strategy. And I have a quick follow-up.

Thanks, June. This is Al Sandrock. We haven't disclosed which of the anti-amyloid antibodies we're going to vectorize yet. As you know, we have a choice of a few. And we're doing experiments on several of them now, or at least more than one anyway. We will disclose that at the right time in the future. The risk of ARIA is real, and Todd nicely pointed out the reasons why we think we're going to minimize the risk of ARIA with our vectorized antibody. Nevertheless, you know, it's something to keep in mind. There's two things I would say here. One is that the risk of ARIA is mostly in the first six months to one year of treatment. And so if ARIA were still a concern, we may wait until most of the risk has passed and therefore use the gene therapy as more of a maintenance after the initial treatment for six to 12 months. And then the second thing is that we are, we have some preliminary experiments regulating gene expression. with a small molecule, which we may be able to then turn on or turn off or adjust the dose in the future. So both are things we are actually contemplating at this point. In terms of RNAi, you know, you're right that we have a vectorized RNAi tau knockdown program. At the present time, we don't plan on combining the two into the same vector.

Got it. Thanks for that. You know, your deal with Sangamo, it's really interesting because, you know, they got the licensure capsids for the prion disease, yet, you know, just a month later, Prevail, a subsidiary of Eli Lilly, announced an agreement with Sangamo to develop a novel capsid for Prevail's Parkinson's program. I mean, it's confusing and amusing at the same time. We would appreciate it if you could elaborate a little bit on the deal, given your competitive position on a similar gene therapy program for Parkinson's. Thank you.

Yeah, thanks, June. Well, I really can't speak to Pervail's strategy here. However, I can verify that Gengamo did come to us seeking the capsid for the prion disease program.

But, you know, just a quick follow-up.

I mean, obviously, you know, are you concerned at all, or are there mechanisms in place to ensure that whatever they may learn from your cap that is not, you know, states within Sangamo or maybe between you and Sangamo, but not to lead to competitors?

Well, you know, we trust Sangamo. I know the scientists and the CEO there very well. We think they'll take good care of our capsid as well as any of the intellectual property around them.

Thank you.

Thank you so much. Your next question comes from the line of Laura Chico, Fred Bush. Please ask your question.

Hi, this is Ingrid on for Laura Chico. Thank you for taking our question. One question for Pete. Pete, how should we be thinking about R&D expense trajectory as you're heading into 2024? You'll be in a position to file an IND, and so how much of a pickup should we be expecting here?

Yeah, Ingrid, appreciate the question. And we don't really provide tremendous guidance with regard to forward-looking burn or R&D expenses going forward into 2024 at this point. I would say this, if you do look at our R&D burn for the first six months of this year and in the most recent quarter, our burn is up about 50-plus percent on the R&D side. Overall, from a financial perspective, you see that that's from an OpEx perspective. From a cash flow perspective, our overall burn is kind of tracking and tracing to about 15% higher. That's on a six-month basis. So if you look at last year in 2022, our burn was $78 million for the full year. Our first six months of this year is $45 million on a net basis. that translates to that 15% increase. So hopefully that helps you.

Thank you. Appreciate it.

May I add that, you know, your concern, I guess, about burn, you know, it's a good concern. I would say that we will continue to exercise financial discipline, that these early stage programs are relatively, you know, they're not very intensive in terms of resource requirements for early stage programs. And I also say that we choose programs based on our ability to rapidly achieve proof of concept and to de-risk as quickly as possible in the clinic. And so, but I want to end by saying, reiterating that we will continue to exercise financial discipline and maintain a healthy cash runway.

And Al, I agree with you wholeheartedly. I think that really shows in the cash balance that we have as the close of the quarter. $273 million on the balance sheet, a good runway going forward, and we continue to reiterate that that carries us into 2025. Thank you.

Thank you so much. Your next question comes from the line of Jack Allen of Beard. Please go ahead.

This is the team and all the progress made over the quarter, and thanks for taking the question. I guess the one key question I have is around the Tau antibody IND in the first half of next year. I guess any additional color you could provide as it relates to pre-IND activities that need to be completed to get that IND done and submitted? Yeah.

So, Jack, this is Al. You know, we did have feedback from the FDA in the form of a pre-IND interaction earlier this year. And so our timelines are based on what we learned on that feedback and what more needs to be done to get to an IND. The main thing, of course, is the toxicology studies, the GLP tox studies that we will be initiating shortly, as well as, of course, skewing up manufacturing so we can start dosing patients. And I'm happy to say that we're on track on all these fronts. And we continue to believe we'll file an IND in the first half of next year.

Great, thanks so much.

Thank you so much. Your next question comes from the line of Bill Nadeau of TD Colvin. Please go ahead.

First, on the SUD1 ALS gene therapy program, can you discuss in a bit more detail the work you're doing to identify the lead candidate? What experiments in particular do you think will differentiate among the candidates that you have in development currently?

Great question. I'm going to ask Todd to answer that.

So thanks for the question. We're really excited about our capsids and their ability to cross the BBB. We're in the process of finding the optimal, combining the optimal transgene with the optimal capsid. And so we're doing experiments and non-human primates to find that optimal combination.

And Mickey might be asking about, you know, how did you choose the particular siRNA?

So our process, we have a long history of vectorizing siRNAs at Voyager. We have a process by which we first screen, identify siRNAs, and then begin screening the vectorization components of that. We look at a whole variety of different characteristics. So we look at specificity for the gene. We look at the ability to knock it down with that requisite specificity, make sure that we don't have substantial off-target effects, and all of those things come together to identify the optimal transient.

And if I remember correctly, Todd, we used a mouse-specific capsid with one of these vectorized SIRNAs and got some very nice data in mouse models of SOD1 ALS.

That's true. On the G93A 5.1 animal model, we saw greatly extended lifespan and loader capacity retained, and we presented that at conferences as well.

That's really helpful. And then one last question from us. The slides note that there are discussions ongoing for potential partnerships. Can you give us some sense of what type of partnerships you're interested in and what do you think would create value for the company and shareholders?

Yeah, so thanks. Well, as you can see, we have a history of doing a variety of different types of deals, I'd say on one end of the spectrum. We have a deal that we did with Pfizer Novartis, where it's basically a CAPSID licensing agreement. We do very little work after they choose a CAPSID. They have all the capabilities in-house to prosecute those programs, and they run with it. On the other extreme, I would say we have the neurocrime collaboration, where it's more of a, you know, a program collaboration around GBA1 and 3 undisclosed neurotargets, as well as the prior arrangements around fudroxetaxia. And for these, you know, we're much more sort of research collaborators, if you will. They reimburse us for our expenses, but we're working hand in hand with them. But the programs are theirs. They make all the decisions. We try to be as collaborative and helpful as possible. And then we have, you know, those I would say are the two extremes. And we can do anything in between those. Look, we want to help patients, and we want to grow shareholder value over time. And we'll do whatever makes sense for both. That's very helpful. Thanks for taking our questions.

Thank you so much. Your next question comes from the line of Yanan Zhu of Wells Fargo Securities. Please ask your question.

Hi. Thanks for taking our question. This is Kuan Ang for Yanan. So I have a two-part question for the new anti-A-beta program. So first, I know you don't want to disclose the asset, but may I ask, would you be targeting like monomer, A-beta monomer, oligomer, or fibril? And I think Tom mentioned engagement with the plague. Does that mean it's targeting the fibril? And the second part is, I assume the tissue concentration you want to achieve might be different from the naked antibody strategy. So, what would be the tissue concentration you are targeting, and as a speculation, what would be the dose level that would be required to achieve that tissue concentration? Thank you.

I'll take the first question, and I'll ask Todd to answer the second one. In terms of the antibody, you know, we will not be targeting, we will not be using antibodies that target the monomer. Those don't work, actually. Solanuzumab is a clear example that just hasn't worked. We will be targeting, we will be using antibodies that favor the soluble oligomers as well as insoluble fibrils. And, you know, examples of that would include, for example, educanumab and licanumab, both of which are selective for aggregated forms of A-beta, either the large soluble oligomers, including protofibrils, and as well as the fibular amyloid that's present in the amyloid class. And the reason why we choose those is that there's very good validation, obviously, in human clinical trials. And of course, they have been FDA approved. One of them has even been fully approved recently. So I think the presence is there for that. And Todd, do you want to take the second one?

I think so. I want to confirm that I heard the second one correctly. It's a question about the vectorized antibody and how it differs from the straight antibody. Is that right?

Right. And the tissue concentration you plan to achieve and probably the dose level that might be required. Thank you.

So I can't comment specifically on the tissue concentrations and the doses we'll be going into. Clearly, we can take what the learnings are from the field on the antibody concentrations needed for efficacy. What we think a potential advantage of the vectorization is beyond the single dose, which of course could have implications for being able to treat large numbers of patients. But as we talked about in the call, we hope to avoid the Potential reactions that you get when you infuse an antibody, you necessarily get a peak of delivery, a peak of antibody exposure in the vascular system. We'll be secreting in a constitutive fashion, so we hope to avoid that high exposure, and we hope that we expect to encounter the plaques in the brain before it's encountered in the blood vessels. We hope to have some advantages there as well.

Yeah, so I guess a summary of that would be that we're sort of targeting the AUC side of things rather than the C-Max that we achieve with antibodies because C-Max is more related to ARIA and AUC is more related to efficacy. I would also say that we know the concentrations in spinal fluid you have to achieve with both of those antibodies. And, you know, they're in the typical range, 0.1% to 0.5% brain plasma ratio. So, and then there's a lot of published information from animals as to what antibiotic concentrations are needed for removal of amyloid. So, the nice thing is, you know, this is a de-risk program in many ways. We're going after a highly validated target. We have a lot of quantitative information that we can use for drug development. We understand the major side effects and thoughts about how to mitigate those. And that's the kind of thing that we like to go after, highly validated targets with efficient paths to proof of concept.

Got it. Super helpful. Thank you, Al and Todd.

Thank you so much. Your next question comes from the line of Matthew Hershenhorn of Oppenheimer. Please go ahead.

Hey, guys. Congrats on all the progress. This is Matt on for Jay, and thanks for taking our questions. So, we were wondering if you had any thoughts following Biogen's acquisition of RIATA, which obviously reflects a pretty high value for the Friedreich's Ataxia opportunity. So, how are you thinking about any differentiating factors for your FA gene therapy program, obviously pros and cons, potentially versus SkyCloris, which you have collaborated with Neurocrin, and any advantages as a potential later follower? And then for Pete, if you could just please remind us any timing on the potential for milestones from that FAA program, that would be very helpful. Thank you both.

All right, I'll start, and I'll ask Pete to talk about the milestones. But yeah, so I was excited to see that Biogen acquired RIATA. RIATA drug, rexanilone, was the very first drug ever approved for FAA. It shows evidence of disease modification in the sense that it slows the worsening. This was all published in Annals of Neurology, and I thought that the data were pretty convincing when I first saw the paper that was published. And so I think it's a breakthrough, and I'd love for us to also continue on that trend and make further progress. I think that, you know, with FA, the complexity, the slight complexity here is that it involves the central nervous system, but also the heart. And the Reata drug really targets the CNS side of things because the outcome measure that they looked at was more oriented toward neurological outcomes. And so, obviously, this is a program that is in the hands of NeuroCrit and their decision. But it can't hurt to have regulatory precedents established by another company, outcome measures that work. and that have been accepted by regulators. And look, here it's a, you know, we want to replace the gene. It's autosomal recessive, so the patients who have the disease basically aren't making frataxin. We need to replace frataxin in some way. Well, and our approach, of course, is to use gene therapy. And, you know, and you have to get the dose right here because too much for taxing is probably not good either. So this is all in the capable hands of our colleagues at Nurocrin, and I'll let them answer the question more specifically with respect to the program.

Yeah, Matt, with regards to specific guidance on milestones associated with the FA program, which I think was, The second part of your question, so what we've provided in the past is kind of a full summary of what the 2019 Nurocrine Agreement looks like in terms of future milestones. Those milestones are about $1.4 billion approximately. We have not guided or provided detailed guidance with regards to what the specific next milestones are on that program. But I do think what I would highlight, not just for Nurocrine, but also for some of our other partnerships, We do have a number of milestones that potentially could come due in the next couple years here on all those partnerships. As Al alluded to earlier, we've got 11 partner programs now, seven with Nurocrine alone, three in the original 2019 agreement, which includes FA. Those milestones have not been factored into our cash runway as of yet, and potentially, could benefit us greatly as we move forward here.

So that would be what I would say with regards to that. Okay. That's very helpful. Really appreciate the answer. Thanks and congrats again.

Thanks, Matt. Thank you so much.

All right. And our next question comes from the line of Ross Fadeland of Canaccord Genuity. Please go ahead.

Ross on for Samant Kulkarni. I've got a question in regards to the antibiotic programs they have going on. Given that you now have an anti-TAL antibody and also a vectorized anti-TAL antibody program, what does this mean in context for prioritizing spend levels on the relatively expensive Alzheimer's programs versus the other programs in your pipeline? Thank you.

Yeah, thanks for the question. So actually, we do not have a vectorized antibody against tau program. We have essentially a passive intravenously administered antibody, monoclonal antibody, not vectorized. After we achieve proof of biology, hopefully we will achieve that. And if we do, we have the choice then of moving forward with either continuing with the passive antibody or going to vectorization. So I just wanted to clarify that. And, you know, I mean, the whole approach here is to choose programs where we can get proof of biology very efficiently. For example, the antibody to tau. We think we can do a proof of biology experiment in humans with about 25 patients per dose group in a one-year study. And with tau PET imaging, we think we can determine whether we block the spread of pathological tau. And so we like that because it's a rapid path to de-risking and proof of biology. And then after that, as I said, we have a choice of vectorizing or not. I hope that clarifies or answers your question.

Yeah, thank you.

Thank you so much. And presenters, there are no further questions at this time. I would now like to turn the conference back to you for closing remarks.

Well, thank you very much for all the great questions. And if you have any further questions, obviously, we're ready to, please call us and we'll do our best to answer them. But thank you very much for your interest in Voyager.

Thank you, presenters, and this concludes today's conference call. Thank you for participating, and you may now disconnect. Have a good day.