Voyager Therapeutics - Earnings Call - Q4 2024

Executive Summary

• Q4 2024 was primarily a strategic and pipeline-focused quarter; collaboration revenue fell to $6.3M from $90.1M in Q4 2023 and $24.6M in Q3 2024, driving a net loss of $34.5M and diluted EPS of -$0.59 as prior-year Novartis-related revenue recognition did not recur.
• Management highlighted progress in tau programs: VY1706 (tau silencing gene therapy) advanced into IND-enabling studies with 50–73% cortical tau mRNA knockdown in NHPs; VY7523 (anti-tau antibody) entered a MAD study after a clean SAD safety/PK readout and CSF:serum 0.3% ratio.
• Cash, cash equivalents and marketable securities were $332.4M at 12/31/2024, with runway guided to mid-2027; partnerships represent meaningful optionality (developmental milestones of ~$2.9B and >$8B “bio-bucks” potential), not included in runway guidance.
• Estimate comparisons from S&P Global were unavailable for Q4 2024 due to access limits; upcoming catalysts include AD/PD data (April 2025), 2025 INDs for partnered GBA1/Friedreich’s ataxia programs, and H2 2026 tau PET from VY7523 MAD, which may shape investor sentiment in the near term.

What Went Well and What Went Wrong

What Went Well

• Tau programs advanced materially: VY1706 selected as development candidate and moved to IND-enabling studies; NHP data showed 50–73% reduction in tau mRNA across cerebral cortex after single IV dose, supporting translational potential.
• VY7523 anti-tau antibody SAD study demonstrated acceptable safety/tolerability, dose-proportional PK, and CSF:serum 0.3% ratio; MAD initiated in AD patients, aiming for tau PET signal in H2 2026.
• Strong balance sheet and partnership leverage: $332.4M in cash at YE 2024; CFO cited ~$2.9B in developmental milestones and >$8B total potential bio-bucks, with upside not embedded in mid-2027 runway guidance.

What Went Wrong

• Collaboration revenue dropped sharply: $6.3M in Q4 2024 versus $90.1M in Q4 2023 and $24.6M in Q3 2024, reflecting lapping of $80M Novartis-related revenue recognized in Q4 2023 and lower recognition under current collaboration agreements; net loss widened to $34.5M.
• R&D expenses increased to $35.6M in Q4 2024 (from $25.8M in Q4 2023) due to program-related spending and facilities costs, elevating operating loss to -$38.3M.
• SOD1 ALS program (VY9323) no longer advancing due to payload issues; while it extended cash runway, it removes a nearer-term potential clinical proof-of-concept avenue within Voyager-owned programs.

Transcript

Operator (participant)

Good afternoon and welcome to Voyager Therapeutics' Q4 and year-end 2024 financial results conference call.[Operator's Instructions]. I would now like to turn the call over to Trista Morrison, Chief Corporate Affairs Officer at Voyager.

Trista Morrison (Chief Corporate Affairs Officer)

Good afternoon. We issued our Q4 and year-end 2024 financial results press release this afternoon. The press release and 10-K are available on our website. On today's call, Dr. Al Sandrock, our Chief Executive Officer, will briefly review key recent and upcoming milestones, and we will reserve most of our time for your Q&A. Joining us for Q&A are Dr. Toby Ferguson, our Chief Medical Officer; Dr. Todd Carter, our Chief Scientific Officer; and Dr. Nathan Jorgensen, our Chief Financial Officer.

Before we get started, I would like to remind everyone that during this call, Voyager representatives may make forward-looking statements, as noted in slide two of today's deck. These statements are based on our current expectations and beliefs. They are subject to risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings, which are available on our website, for additional detail. Now, I will turn the call over to Al.

Al Sandrock (CEO)

Good afternoon, everyone, and thank you for joining us. As Trista said, we plan to keep our remarks brief and prioritize your questions. On slide three, I want to remind you of why we're so excited about Voyager. Our pipeline includes four wholly owned and 13 partnered programs. We have already begun to generate clinical data, and we have multiple opportunities to generate more in the coming years. We are particularly excited about our two wholly owned programs targeting tau, which we view as the most important target in Alzheimer's disease. We also have two platforms to enable CNS delivery. I think most of you are familiar with our TRACER capsid platform for IV-delivered CNS-targeted gene therapies. We're also generating data with our ALPL-based non-viral shuttle. I am hopeful we will be able to share some of that data with you later this year.

Finally, our partnerships have been a significant source of non-dilutive revenue for us. That's a big reason we are able to report $332 million in cash as of the end of 2024. With $8.2 billion in potential future milestone payments, we believe partnerships will continue to contribute significantly to our bottom line. As I always say, we are open for additional business. We are always discussing new partnership opportunities. While we are building a multimodality neurotherapeutics company here, I want to make a comment about gene therapy, which comprises much of our current pipeline. Despite continued setbacks in the field, it is possible to create a gene therapy that drives value for patients and investors. Zolgensma proves this. I want to emphasize that many of the foundational principles behind Zolgensma's technical and commercial success are principles Voyager also adheres to.

This includes focusing on genetically validated targets in severe diseases with high unmet need. It also includes IV delivery, which we view as critical to commercial viability. We believe IV-delivered AAV capsids will be required to enable gene therapy in most CNS diseases, given the limitations of localized delivery. The potential of our IV capsids to efficiently deliver across the blood-brain barrier, not only in infants, is presumably why Novartis came to us for an SMA gene therapy partnership. I'm not going to belabor this point, but I do think it is important to differentiate Voyager's approach from the broader gene therapy field. On slide four, you can see our pipeline. I won't go into a lot of detail here other than to point out that our SOD1 silencing gene therapy program did move back into the research stage as we announced last month.

The payload did not meet our target profile, and we are going to need to identify a new payload to advance that program. At the same time, I will note that VY1706, our tau silencing gene therapy, has moved forward into IND-enabling studies and is advancing toward IND in 2026. On slide five, I will note a few more quick highlights from the quarter and upcoming milestones to watch. I mentioned that VY1706, which was selected as a development candidate in Q4 2024, has now advanced into IND-enabling studies. We are really excited about the data from our three-month non-human primate studies, where we are seeing 50%-73% knockdown of tau messenger RNA, quite broadly across the brain. We have previewed a little of this data in our corporate deck on our website, and we will share more at the AD/PD conference in April.

Our anti-tau antibody, VY7523, performed well in a recently completed single-ascending dose study. There were no serious adverse events, and we saw dose-proportional pharmacokinetics as well as a CSF-to-serum ratio of 0.3%, consistent with other monoclonal antibodies approved for the treatment of Alzheimer's disease. We initiated a multiple-ascending dose study in Alzheimer's patients, and we expect initial tau PET data in the second half of 2026. Finally, I want to point out that in Q4 2024, UCB's bepranemab demonstrated for the first time that an anti-tau antibody can impact tau accumulation in the human brain and that this may correlate with clinical benefit. It's important to acknowledge the study didn't meet its primary endpoint of the CDR Sum of Boxes, but our team walked out of the CTAD meeting feeling better about our anti-tau antibody than when we walked in.

Looking forward, I think there are several opportunities this year for third-party data to continue to build excitement for tau. Merck has antibody data expected in mid-2025, and I look forward to seeing what we learn at AD/PD in April, AAIC in July, and CTAD in the fall. Okay, I promised I would keep it short. I just want to thank all of our employees for their hard work, especially pushing to achieve those end-of-year goals like getting the development candidate for the tau silencing program, working on the VY7523 single-ascending dose analyses, and initiating the multiple-ascending dose study.

With that, we will open the call for questions. Operator?

Operator (participant)

Thank you. [Operator's Instructions] Our first question comes from Jack Allen with Baird. You may proceed.

Jack Allen (Senior Research Analyst)

Thanks so much for taking the questions, and congratulations to the team on the progress. I guess, Al, maybe I'll start where you left off, your opening remarks there. You mentioned some external readouts that could be interesting in the tau space. Any additional color you'd like to provide ahead of AD/PD as it relates to things people should be looking out for? I have a quick follow-up as well on your partner programs.

Al Sandrock (CEO)

Yeah, hi, Jack. at AD/PD, I hope to see data from the bepranemab, I believe they may be sharing their data on exposure-PD relationship, so PK/PD, which they didn't have a chance to share at the CTAD meeting last year. Also, more data on how much decrease in tau spreading you need to see in order to see a clinically relevant effect. That's one thing I'm going to be hoping to see. The other thing might be more information about subgroups where greater efficacy can be seen. They started to talk about that a little bit at CTAD, for example, the effect of APOE4 carrier status as well as initial tau burden. There may be more information on that as we learn more about which are the ideal patients to be treated with an anti-tau approach.

We also note that other companies have started to share data with their anti-tau program. I know that, for example, Eisai has been sharing data on fluid-based biomarkers with their anti-tau that targets the MTBR region. I do not know whether other companies may also be starting to share data as well, but there is a lot of interest in tau. There are also the tau silencing approaches that we know, for example, Biogen has. I look forward to seeing any updates that might be on that. Toby, did you want to add anything to that?

Toby Ferguson (Chief Medical Officer)

Al, I certainly agree with your comments and sort of echo the comments on exposure response, both initial PK/PD, but also in particular the tau PET to clinical relationships. I do think on the subpopulations, for example, I'd like to see details on the low tau or APOE group they described previously. Curious what they think the pull-through of APOE is. Is it just that those individuals without an APOE allele have low tau, or is there some other defining characteristic of that population?

Jack Allen (Senior Research Analyst)

Got it. Great. That's very helpful color. More on the finance side, but I just wanted to ask, it seems like the two programs with Neurocrine on the gene therapy front are expected to enter the clinic, or at least the INDs filed this year. Any additional color you can provide as it relates to thoughts on upcoming milestones from either Neurocrine or additional external partnerships that you've forged as well over the years?

Nathan Jorgensen (CFO)

Thanks for the question, Jack. This is Nate Jorgensen, the CFO. What we have said is that there's $2.9 billion of developmental milestones. These are milestones that I think are not biobucks like some companies report, but if you add all the biobucks together, it's over $8 billion, as Al mentioned. There are some, I think, pretty meaningful milestones over the next few years that could help extend our cash runway past the mid-2027 guidance that we talk about externally.

Jack Allen (Senior Research Analyst)

Got it. Are those milestones at all accounted for in your guidance, or are they additional upsides--

Nathan Jorgensen (CFO)

No, they're not. That is all upside to the mid 2027 cash runway guidance.

Jack Allen (Senior Research Analyst)

Perfect. Thanks so much. Those were my first questions, but maybe I'll hop back in the queue. Congrats again on the progress.

Al Sandrock (CEO)

Thanks, Jack.

Operator (participant)

Our next question comes from Phil Nadeau with TD Cowen. You may proceed.

Phil Nadeau (Managing Director and Senior Research Analyst)

Good afternoon. Thanks for taking our questions. A couple from us. First, on the tau gene silencing IND, can you give us some details about what needs to be completed before the IND can be filed next year?

Al Sandrock (CEO)

the main thing is that we have to complete the GLP-tox study that we just started, and that we need to be sure that we have a therapeutic window. As we said, our initial non-human primate study shows 50%-73% knockdown, which is exactly in the range that we want. We just have to be sure that now we don't have any safety issues that allow for that dosing, for the right dose to produce that level of silencing.

Phil Nadeau (Managing Director and Senior Research Analyst)

Perfect. A second question on the ALPL shuttle. Can you discuss where that could be most applicable? What indications are you thinking that would be most useful for, and any sense on when one of those candidates could advance?

Al Sandrock (CEO)

We're looking broadly across various diseases, various targets. This is a receptor that allows for BBB penetrance of one of our leading classes of capsids. That capsid gets in across the CNS pretty broadly. That leaves open a lot of different diseases, both spinal cord as well as cerebral cortex and even subcortical diseases. The kinds of drugs that we were thinking about transporting across the BBB would include proteins such as enzymes or antibodies. Also, we're starting to assess whether or not oligonucleotides can be transported as well. That leaves open a wide array of possibilities still.

Beyond that, you might imagine what the best antibodies or enzymes for oligonucleotides we might be thinking about. As we noted with the antibody, our anti-tau antibody, we get a CSF to serum ratio of 0.3%. Literally 99.7% gets thrown away. It'd be great if we could get more of the antibody into the brain. Also, all ASOs currently are intrathecally administered for CNS diseases, and that provides a burden to patients. It also produces a severe gradient in the CNS, which I think is limiting. There are a lot of opportunities. Todd or Toby, do you want to add anything to that?

Todd Carter (Chief Scientific Officer)

I think you've captured most of it, Al. The other part of your question was moving things forward. While we haven't shared any data, we're hoping to share more of our early work later this year.

Phil Nadeau (Managing Director and Senior Research Analyst)

That's very helpful. Congrats again on the progress.

Al Sandrock (CEO)

Thanks, Phil.

Operator (participant)

Our next question comes from Pete Stavropoulos with Cantor Fitzgerald. You may proceed.

Pete Stavropoulos (Director of Biotech Equity Research)

Yeah. Good afternoon, and congratulations on all the progress, and thank you for taking our questions. First question I have, as we look forward for the tau silencing gene therapy, I'm wondering if you can talk about the key differences we should expect from tau silencing, excuse me, tau silencing versus targeting antibodies. Thinking about the Biogen data for 080, what's your view on the combination approach, meaning a tau silencing or knockdown with a monoclonal approach?

Toby Ferguson (Chief Medical Officer)

Thanks, Pete. This is Toby. Good to hear from you. I think fundamentally our belief on the knockdown approach with 7006 is a couple of key points. One, as we've highlighted, we'll use our second-generation TRACER capsids, and it will be injected IV once. That gives us a couple of clear advantages. I think one is that it allows for better biodistribution, accessing the vasculature via ALPL. That is quite distinct from the gradient you get with an intrathecal injection in the lumbar space with an ASO. We think that presents an opportunity for broader tau knockdown. That is, I think, quite an important point. In addition, the fact that it's IV in one time, we think, is clearly some benefits both for the patient and potentially for the healthcare system in terms of ease of uptake.

I think the other point I'd make is that, of course, the Biogen data, which comes out, we think, in mid-Q3 of 2026, will be an important inflection point. Of course, we have an IND for our program in 2026 as well. We think that's an important pairing.

In terms of the antibody, I think fundamentally the premise of the antibody is slightly different that you're trying to impede spread. The idea there is that you would want to target that to a population in which tau is not yet spread. On the other hand, for the knockdown approach, you look at the data that Biogen has shared. In that case, you can remove pre-existing tau. That was shown by tau PET, which is quite a remarkable observation. There may be some broader latitudes. There may be space for sequencing of a beta amyloid therapy with an antibody and then a tau knockdown approach as well.

Pete Stavropoulos (Director of Biotech Equity Research)

Thank you for that. Just one more question. The way that we viewed the SOD1 gene silencing program is that it would provide proof of concept for the capsid and its ability to cross the blood-brain barrier efficiently by looking at changes in the NfL, which we would hope to have seen similar to tofersen. How are you thinking about establishing the human proof of concept? Which program will likely help you do so? Is there any agreement or expectation of a partner sharing some data or allowing you to once it is generated?

Toby Ferguson (Chief Medical Officer)

Pete, this is Toby again. I think you've rightly hinted on the fact that the next opportunities to generate capsid POC really sit with the Friedreich's Ataxia and/or the GBA program, which are partnered with Neurocrine. I'll just remind that INDs for those programs are coming up this year. I think what I'd say holistically is Neurocrine is running those programs, but we have a strong collaboration with them across the development teams. In both cases, in Friedreich's, there's an opportunity for biomarker measurement in terms of protection levels. In GBA, there's an opportunity for biomarker measurement in terms of both enzyme GCase levels and substrate levels. In both cases, both programs offer the opportunity to understand if the capsids are working. Todd, anything to add?

Todd Carter (Chief Scientific Officer)

I think you've got it, Toby

Pete Stavropoulos (Director of Biotech Equity Research)

All right. Thank you for taking our questions, and congratulations on the progress.

Al Sandrock (CEO)

Thanks, Pete.

Operator (participant)

Our next question comes from Lili Nsongo with Leerink. You may proceed.

Todd Carter (Chief Scientific Officer)

Hi. Good afternoon. Two questions from my side. The first one being on maybe comparing and contrasting the two approaches for tau. Preclinically so far, can you give us a little bit of perspective in terms of potential differences you've seen between the two approaches in preclinical studies?

Al Sandrock (CEO)

Todd, do you want to correct that? On the preclinical study?

Todd Carter (Chief Scientific Officer)

On the preclinical side, we've seen positive results from both. One aspect that we have discussed with the tau antibody program is that we do see differences targeting different epitopes. For example, our C-terminal targeted epitope works quite well in terminal targeted antibodies that have failed in the clinic, failed in our seeding models. This is a model where we inject Alzheimer's patient-derived pathological tau into the brain of a mouse expressing human tau and look at the ability of a treatment to stop spreading. The N-terminal failed antibodies did not work. Our antibody does. Many other antibodies do not. I will say that the tau knockdown also shows efficacy in similar type models. We are not driven by specific epitope with a tau knockdown approach.

For the tau knockdown, we think we might be hitting a mechanism in two ways. One, we're reducing the amount of tau and subsequent pathological tau to spread cell to cell. We are also reducing the amount of tau on the recipient cell to then receive that pathological pre-amplified material. We think that there are interesting similarities, but also some key differences in the fundamental mechanisms of those two approaches.

Lili Nsongo (VP of Biotechnology Equity Research)

Thank you. As a follow-up, maybe could you provide a little bit of color in terms of the MAD study design? I know you haven't shared the whole design at this point, but maybe could you give us a little more in terms of how the study design has been impacted or informed by the results that we've seen with bepranemab?

Toby Ferguson (Chief Medical Officer)

Thank you. This is Toby. It's an excellent question. I think fundamentally, maybe a couple of points. I think what we've learned about our antibody, including the preclinical work and up through the SAD, is that the antibody, for mine, it binds pathologic tau, which differentiates it from some other antibodies, including UCB's, that we have appropriate PK. We've got good CSF penetration. In that context, we really think in the MAD study, we can drive to an effective determination of if we have a signal on tau PET, particularly in the context of what we've seen thus far. That's important. I think in terms of the population, what we've learned from bepranemab is that the lower tau may be important in this context and/or APOE status.

What we've shared so far is that we've adjusted the thinking based on these data to focus on the earlier MCI and AD populations, which are necessarily lower in tau. I do think we'll need to be ready to respond to learnings as they continue to evolve. We've already highlighted that we're hoping to hear some discussions with AD/PD on the deeper side of these two subpopulations and/or exposure response. In addition, we've highlighted some other potential readouts in the field as well. We'll certainly continue to monitor the field and adjust as we're able. I will highlight, yeah, I think that's what I'll end.

Al Sandrock (CEO)

I might want to add that in the case of Alzheimer's, the history of Alzheimer's clinical trials, sometimes multiple ascending dose studies, for example, with the anti-amyloid antibodies, have provided some really meaningful information in terms of the effect on PET imaging. In this case, wouldn't it be fair to say, Toby, that given the data with bepranemab, particularly the safety and also our single ascending dose results, we're planning to push the dose pretty high, right? At the highest dose, we're going to really take a look at how much we can impede the spread of tau by PET imaging and also look at fluid-based biomarkers. That's the plan. As Toby says, we'll be monitoring the situation with all the other data coming out.

Toby Ferguson (Chief Medical Officer)

Certainly agree, Al.

Lili Nsongo (VP of Biotechnology Equity Research)

Thank you for the color.

Operator (participant)

Our next question comes from Samantha Semenkow with Citi. You may proceed.

Samantha Semenkow (VP and Biotech Equity Research Analyst)

Hi. Good afternoon, and thanks very much for taking the question. Just sort of a forward-looking question for me. I'm wondering if you can share anything about how plug and play you think your ALPL shuttle, non-viral shuttle, could be. Based on what you've learned so far in your discovery work, is it feasible that you could see shorter delivery times once you've worked through development, say, for each type of molecule you're looking to transport? Or is it more expected that, say, every enzyme or every oligonucleotide you're looking to transport would have its own set of unique challenges that you would need to optimize for? Any color you can share that would be very helpful. Thank you.

Al Sandrock (CEO)

That's an interesting question. I mean, in some ways, the TfR-based shuttles have been a sort of plug and play in the sense that it's worked for multiple different kinds of modalities. And we're starting to see data emerging that even beyond proteins, that oligonucleotides may also be transported. Look, I mean, but even Denali, who are the leaders in TfRs, are also looking at CD98, right, as another shuttle vehicle. Why would that be? I guess it's because every receptor is going to have its own safety, distribution, and kinetics. It could be that for certain targets and certain diseases, it's more optimal to use one shuttle over another. I think time will tell. Right now, I think the field really only has one or really two shuttles that they can turn to. So everybody's using those.

As time goes on, we may be able to be more selective. It could be plug and play. As we learn more about these various shuttles, we may start to tailor them to the right disease and the right target. That is how I see it now. Of course, it will be great to get more data to see whether we are right about that.

Samantha Semenkow (VP and Biotech Equity Research Analyst)

That's very helpful. Just as a follow-up, is there anything you can share about what that preclinical data set could look like sometime later this year for the non-viral shuttle? Thanks very much.

Al Sandrock (CEO)

Obviously, we're going to start by showing data in animals. It's obviously going to be in vivo data that's going to count the most. We expect to be comparing to some of the TfR-based shuttles, comparing ALPL to start to get an idea of how different it is and whether there are certain advantages to ALPL. We hope to be able to show more than one payload as well, see how plug and play it actually could be. That's what we're hoping to show. We're working hard on that. We'll see whether we can get there.

Samantha Semenkow (VP and Biotech Equity Research Analyst)

Great. Looking forward to it.

Al Sandrock (CEO)

Todd, do you want to?

Todd Carter (Chief Scientific Officer)

No, I think, Al, you captured it. I mean, we've been very excited by that and hopefully look forward to sharing that later this year.

Al Sandrock (CEO)

Thanks, Samantha.

Operator (participant)

Our next question comes from Joon Lee with Truist Securities, you may proceed.

Mehdi Goudarzi (Biotech Equity Research)

Hi. Good afternoon. This is Mehdi on for Joon and congrats on the progress. A couple of capsids for us as well. Given that for the SOD1 ALS program, the V-cap Gen2 is going to be the same for VY1706, what are the data points that give you the confidence that the neurotox that you had seen is not related to the capsid?

Al Sandrock (CEO)

There are two reasons. One is the timing of the adverse event. In the case of the SOD1 program, in the initial time points and the several days after we inject, we do see the expected slight bump in liver function tests and in neurofilament levels. That is exactly where other programs have shown those kinds of adverse events with IV-delivered AAV. That is to be expected. The capsid clears from the bloodstream within days. What we saw was with a delay of about three months, we saw the neurofilaments start to go back up. That was coincidence with some neurological adverse events observed at cage site. When you look histologically, you see evidence of neurodegeneration. It is that delay, which is when expression has really come into play, that we see the adverse events.

The timing is not right for capsids, much more consistent with expression of the payload. The other thing is that we use the exact same capsid with four other constructs with various promoters and various payloads. We see no such adverse events in non-human primates, even at doses that are comparable to what we tested with SOD1 and even at the two to three-month time point. It is both of those pieces of evidence that gave us a lot of confidence that it was the payload and not the capsid.

Toby Ferguson (Chief Medical Officer)

Thank you. [Crosstalk]

Todd Carter (Chief Scientific Officer)

Maybe I'll just add. When Al talks about what we're looking at, we're looking at histopathology. We're looking at NfL as a biomarker. We're looking at sort of clinical signs. None of those, we see none of that with the capsid with these other payloads.

Mehdi Goudarzi (Biotech Equity Research)

Thank you very much.

Operator (participant)

Our next question comes from Ry Forseth with Guggenheim Securities. You may proceed.

Ry Forseth (VP)

Hey, this is Ry from Debjit's team. Back to the third-party readouts. I'm sure the decision matrix is very large, but we wanted to get a grasp on the particular outcomes and how those outcomes would be actionable for your either preclinical gene therapy or 7523 MAD efforts. Maybe outline how adjustments could be made to these programs in response to the data?

Al Sandrock (CEO)

Are you talking about the third-party data with antibodies?

Ry Forseth (VP)

Either silencing efforts or antibodies.

Al Sandrock (CEO)

I see. One of the biggest pieces of data is going to come in terms of antibodies from the J&J study, which will read out next year. I say that mainly because it is a large study, well-controlled, and large and long enough to get a pretty good idea of whether or not, first of all, do we see an effect on the spread of tau with a different antibody? In other words, reproduce what UCB has shown. Also, get a much better handle on whether or not there is a clinically significant consequence to that impeding of tau spread, which we hope to see. I think that we will have to wait for the J&J data, which I think is next year.

In terms of the knockdown approaches, what's remarkable about the BIIB080 data for me anyway is the fact that you actually reduce the tau PET signal, which I didn't think would be possible because I always thought that the pathological tau was in neurofibrillary tangles, which is pretty much not going to be reduced by simply reducing the synthesis of new tau. That is exactly what Biogen has shown. What's intriguing is that they seem to see a pretty big clinical benefit of that. The flaw there is that there was no control group in that study. They have done a great job comparing it to natural history and to the control groups of other trials. It does look like a large effect. I would think that with the passage of time, we will know even better whether or not that clinical effect is real and durable.

Those are the kinds of things I'm going to be looking at. Of course, we always want to answer the question, does epitope matter? In the case of the anti-amyloid antibodies, epitope did really matter. He's now speaking about the antibody programs, of course. The only other question is, is it important to be specific for pathological forms of tau versus all forms of tau? UCB was not specific for the pathological forms of tau. Ours is, and I believe many of the other antibodies are as well that are coming down the pike. In the case of anti-amyloid antibodies, it was important to be specific for pathological forms of amyloid. We will see if that also applies to tau. Toby, Todd, what did I forget?

Toby Ferguson (Chief Medical Officer)

Maybe I'll highlight the Merck readout. It's a C-terminal epitope pathologic antibody. It's a short study focused on biomarkers, but gives you an initial chance to answer the question, can an epitope, a C-terminal epitope, reduce at least total tau? That is an important concept as well.

Ry Forseth (VP)

Thanks for that. Maybe just one more question from us. With the April AD/PD NHP gene therapy data, will you provide distributional data in terms of the % of vector that goes to the brain relative to the liver? If not, maybe you could frame for us Voyager's thinking on the utility of those kinds of measures.

Todd Carter (Chief Scientific Officer)

At AD/PD, we will present on the tau knockdown program. We will describe data showing delivery, both in terms of the amount of vector and knockdown for pharmacology that we achieve in the brain and vector in peripheral tissues as well. It may not be in a percentage format, but we'll be talking about delivery to the important locations. Those include on target and what we think of off-target tissues.

Operator (participant)

Thank you. Our next question comes from Jay Olson with Oppenheimer. You may proceed.

Jay Olson (Biotechnology Equity Research Analyst)

Oh, hey. Thanks for providing this update. We have a question about the new preclinical data for the tau silencing program to be presented at AD/PD. Can you talk about the target level of tau mRNA knockdown that you plan to achieve? Are there any particular brain regions that are more important for tau mRNA and protein reduction?

Al Sandrock (CEO)

I'll start with the last question. Maybe Todd, you can answer the first question. When I think of Alzheimer's disease, it's a cortical disease, the cerebral cortex. It starts in the temporal lobe, but then it spreads to all the other major cortical regions. To me, the key region in the CNS that we need to look at for tau silencing is the cerebral cortex pretty broadly.

Todd Carter (Chief Scientific Officer)

Al mentioned earlier the general range that we're targeting. We're seeing 50-73%. That's the general range of knockdown that we're looking at. We can get and we're showing that we get broad knockdown in some of these key regions, the cortex in particular, in the non-human primate that we think we need to achieve those kinds of knockdown and have an impact on the disease.

Jay Olson (Biotechnology Equity Research Analyst)

Great. Thank you. Can you comment on how you're thinking about indications for the tau silencing program? Would you start with Alzheimer's disease, or are there other tauopathies that you would start with?

Al Sandrock (CEO)

Assuming we don't partner it, we would look. Our intention is to partner it. Maybe our partner decides which indications to go after. You make a really good point here, which is that there are a variety of tauopathies that we could go after. The most well-known ones, of course, are PSP, progressive supranuclear palsy. There is also frontotemporal dementia due to tau, mutations in tau. There are a lot of other diseases as well, including potentially chronic traumatic encephalopathy. I do think that if it stays in our hands, we will probably look very hard at Alzheimer's disease first, where a lot of us do believe that tau is a really important target for Alzheimer's disease.

So much is known about the natural history of Alzheimer's disease and how to make measurements, both fluid-based as well as imaging measurements. We're going to take full advantage of all that knowledge and look hard at Alzheimer's disease first. That's our approach. What do you think, Toby?

Toby Ferguson (Chief Medical Officer)

I agree, Al. Maybe I'd sort of amplify that fundamentally, I mean, we've seen with the BIIB080 data how critical tau PET can be. This is best worked out in Alzheimer's disease. Looking at some of the other tauopathies, use of tau PET and in some cases fluid biomarkers is less well-settled. One of our core tenets is that you go into diseases where you can get proof of concept around the biomarker pools relatively quickly. In this case, for the tauopathies, we think that really sits with Alzheimer's. I certainly think the other indications are interesting once you've shown that.

Jay Olson (Biotechnology Equity Research Analyst)

Great. Thank you. Maybe if I could ask one follow-up on ALPL. Have you done any experiments to compare the ALPL shuttle to other blood-brain barrier shuttles like transferrin receptor and see what the differences are?

Al Sandrock (CEO)

We haven't shared that data, but we are in the process of comparing to TfR.

Jay Olson (Biotechnology Equity Research Analyst)

Great. We'll look forward to that. Thanks for taking all the questions.

Al Sandrock (CEO)

You're welcome.

Operator (participant)

Our next question comes from Patrick Trucchio with H.C. Wainwright & Company. You may proceed.

Patrick Trucchio (Managing Director of Equity Research)

Thanks. Good afternoon. Just a couple of follow-up questions on the VY7523. First, I'm wondering how the SOD data influenced selection of dose levels and frequency for the MAD study. Separately, just given the competitive readouts in the anti-tau space and those that are upcoming, I'm wondering how the MAD study design may position VY7523 for differentiation. Separately, I'm wondering with the cash runway extending into mid-2027, how will you balance investment in internal programs versus potential licensing or business development opportunities?

Toby Ferguson (Chief Medical Officer)

I'll start and then turn it over to Nate. I think in terms of the SOD data, just to reiterate, we saw dose-proportionate PK, an acceptable safety profile for a molecule in the single-ascending dose study. We saw a CSF serum ratio of 0.3, which is quite consistent with approved molecules. I'd layer on top of that sort of the observed safety in the broader bepranemab study did not highlight any risk of ARIA. What the SOD data gave us was the confidence in the MAD study to move forward with our planned doses. Frankly, as Al had highlighted earlier, to try to push those doses to levels where we can clearly test the hypothesis of whether or not this antibody will impede the spread of tau, pathologic tau.

In terms of differentiation for the competitors and what are we looking for, I think fundamentally the study will be designed to look for tau PET signals. Really what we're trying to do, I think frankly, is see where we compare to the other antibodies that are modulating tau PET signals, particularly UCB. I think our simple aspiration here would be that we are at least as good as, if not better than that, given our specificity for pathologic tau.

Al Sandrock (CEO)

Yeah. May I add that, look, you hit the nail on the head in the sense that our aim is to try to differentiate and put the best foot forward with our antibody. I would also say that we know the doses or we know the levels in the brain that were needed to impede the spread of tau in that animal model that Todd mentioned earlier where we inject human pathological tau into P301S transgenic mice. We want to be sure we exceed the EC50, if you will, of that effect of impeding spread. We are pretty confident we can get there with the doses that we will be choosing based on the single-ascending dose studies that we did. Nate, do you want to answer the second half of the question?

Nathan Jorgensen (CFO)

Yeah. What I will say is that we understand the financing market out there and the cash runway to mid-2027 is important to us. We would be very thoughtful if we do any type of transaction which would shorten that. We'd have to bring in some really interesting assets that potentially with the near-term clinical catalysts. In terms of the other types of deals, those are something that Al always talks about that he's open to. I think opportunities out there for us to do additional VD deals to potentially bring in money or potentially take some of our pipeline assets and bring it to another partner, of course, for the right price.

Al Sandrock (CEO)

If you look at our history, we've done anything from simple capsid licenses where the other company takes the capsid and runs with it versus partnerships on actual programs that we may have started here. We may continue to do the work here, reimbursed by the partner. That just goes to show we're open to any kind of partnership that makes sense for the partner and for us. I hope we continue to do those kinds of things.

Operator (participant)

Thank you. Our next question comes from Yun Zhong with Wedbush Securities. He may proceed.

Yun Zhong (Director and Biotech Equity Research Analyst)

Hi. Good afternoon. Thank you very much for taking the questions. The first question is on the MAD study. Was the initiation earlier than you had expected? Because I believe the original guidance was very broadly in 2025. The second question is, I know that you compared the antibody approach versus the knockdown approach and compared the mechanism of action. Given the timing, do you think it's possible that the knockdown program could potentially catch up to be a more promising approach as compared to the antibody approach?

Toby Ferguson (Chief Medical Officer)

This is Toby. We did start the study a bit earlier than our guidance. I think this just reflects the clinical team is up and going and executing. Maybe I can help. Can you clarify your second question for me, please?

Yun Zhong (Director and Biotech Equity Research Analyst)

I know that the antibody approach is ahead of the knockdown approach. Given, I think Al talked about this mechanism and also the Biogen data, do you think eventually the knockdown approach could potentially be more promising than the antibody approach for AD?

Toby Ferguson (Chief Medical Officer)

What I'd say here is we have two different approaches. I think one, we have some early data from Biogen suggesting that knockdown could be quite clinically efficacious. Al highlighted that this was a natural history comparator and a comparison code in another study with an effect on CDR Sum of Boxes that was maybe two to three times greater than sort of what is a classic observed for beta-amyloid therapy. Potentially a very large effect with the knockdown approach. That's very exciting within the constraints of an intrathecally administered ASO. Antibody-based approaches, I think the data we have there is the UCB data, which is the main clinical dataset. That effect was slightly different. I think the potential there is potentially different.

Fundamentally, to me, the question is more going to be of the appropriate sequencing and the appropriate risk-benefit and what is appropriate to the disease stage of individuals as we previously discussed. There may be a point in time when you want to stop spread in a low tau population early in disease. There may be a population in time when someone has broader spread of tau and you want to take a knockdown approach. You may learn there are differential responses across different patient populations. I think fundamentally, Alzheimer's is complex. Physicians and patients are going to need options in terms of to fully treat this disease.

Al Sandrock (CEO)

I would add that I believe we're still in the very early stages of learning about tau and how to best approach this target. If you look back at the anti-amyloid field, it took us decades to learn from each other and to get to the point where we finally had some drugs that were approved. We're just in the very beginning stages. We're only just now starting to see biological effects that are starting to be seen in humans. I think there's going to be a lot to learn. I think for right now, the prudent thing to do is to pursue both programs. We will make data-driven decisions, internal data versus as well as external data. We will learn from those, and we will make data-driven decisions.

Yun Zhong (Director and Biotech Equity Research Analyst)

Sounds good. Thank you.

Operator (participant)

Our next question comes from Yanan Zhu with Wells Fargo Securities. You may proceed.

Yanan Zhu (Senior Equity Research Analyst)

Great. Thanks for taking the questions. First, I wanted to ask about maybe a follow-up on the brain shuttle approach. I think, Al, you touched on this. What is the limitations of the TfR-based brain shuttles that you see at your vantage point and therefore areas that you might hope to differentiate it in? I have follow-ups on the tau program. Thank you.

Al Sandrock (CEO)

From what I see, there is evidence of hematologic adverse events, which is not surprising given the function of a transferrin receptor. Even when you use ligands for different epitopes on the transferrin receptor, you still see some adverse events because even if you do not block the transferrin receptor, you probably lead to its internalization. Therefore, you end up with loss of function-type adverse events. If you look at the human genetics database, humans are not very tolerant of loss of function mutations in transferrin receptors. It is a pretty critical pathway. In contrast, humans seem to be pretty tolerant of loss of function mutations, or I should say more tolerant of loss of function mutations of ALPL. That could be an advantage. Of course, time will tell. I would say that that's one of the potential advantages, but there could be more as we learn more.

Yanan Zhu (Senior Equity Research Analyst)

Great. Thanks.

Al Sandrock (CEO)

Let me add one more piece, Yanan, is that we sometimes forget about the fundamental properties of drugs such as PK and half-life. I mentioned kinetics and distribution previously. We will be looking at those things too. That is not to say that the TfR-based approaches are not promising. They are promising. In fact, so promising that that is why we are so excited about the idea of using a shuttle-based approach to improve delivery of other modalities beyond gene therapy.

Yanan Zhu (Senior Equity Research Analyst)

Got it. Thank you for the insight. On the tau antibody program, I was wondering, is it fair to say that the Merck antibody is even more similar to your antibody than the UCB antibody is? Have you compared in your tau animal model directly your antibody against Merck's antibody and what might be the findings? Lastly, I was wondering about your thoughts on effector function for the general tau antibody approach, if you can comment on whether yours is effector null or not, and why does that matter if it does? Thank you.

Todd Carter (Chief Scientific Officer)

Yeah. Hi. I can take this. This is Todd. I do think you're right. In a lot of ways, the Merck antibody is more similar to C-terminal antibody. We have not shared any data comparing the C-terminal Merck antibody to ours, so we don't have that to share. On the effector function, it's an interesting question. We've gone with effectively a null, an IgG4, human IgG4 for our antibody. Evidence to date suggests that to have an effect in these spreading models, and it looks like perhaps with bepranemab in the clinic, that you don't need effector function. Eliminating it eliminates or reduces some risk around neuroinflammation, we think. We've gone with an IgG4 for our antibody.

Yanan Zhu (Senior Equity Research Analyst)

Great. Thank you very much for the color.

Operator (participant)

Our next question comes from Sumant Kulkarni with Canaccord Genuity. You may proceed.

Sumant Kulkarni (Managing Director and Senior Biotechnology Research Analyst)

Good afternoon, and thanks for taking our question. Apologies if this was asked before. Al, I know you gave a quick history lesson there on anti-amyloid products for Alzheimer's. What are the key results you need to see or learning from external programs that might lead you to making a firm go-no-go decision on your anti-tau antibody program? Would you need to see internal results in order to make that decision? What might those internal results look like?

Al Sandrock (CEO)

That's a tough question to answer. What I'm looking for, Sumant, is really how much of an effect on tau spreading do you have to see to see a minimally clinically significant effect? In the case of the anti-amyloid antibodies, and by the way, you can learn from different antibodies against different epitopes. The key question is, how much of an effect on amyloid PET imaging did you need to see to see an effect on CDR Sum of Boxes, which is the required endpoint for approval? You can actually draw a graph of all the different antibodies and see that if you don't get to a certain level of amyloid lowering, you don't get a big enough effect on CDR Sum of Boxes. That's precisely the kind of thing I think I would like to see with the anti-tau antibodies.

I would say that anything less than a roughly 30% effect on CDR Sum of Boxes is probably not clinically meaningful. That's what I'm looking for, is what is the effect on tau PET imaging that gives us a 30% effect on CDR Sum of Boxes? Once we know that for sure, then we can look at our antibody and say, "Okay, it met that hurdle or not." I think it's going to take a little bit more time to get that. It took more than a decade to generate that data for the anti-tau—I mean, sorry, the anti-amyloid antibodies and various companies sharing their data. Like I said, I think we're in the early stages still of the tau-directed antibodies.

Sumant Kulkarni (Managing Director and Senior Biotechnology Research Analyst)

Got it. Thanks.

Operator (participant)

Thank you. I would now like to turn the call back over to Dr. Al Sandrock for any closing remarks.

Al Sandrock (CEO)

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

Operator (participant)

Thank you. This concludes the conference. Thank you for your participation. You may now disconnect.