3/11/2025

speaker
Trista Morrison
Chief Corporate Affairs Officer

good afternoon and welcome to voyager therapeutics fourth quarter and year-end 2024 financial results conference call at this time all participants are in a listen-only mode there will be a question and answer session at the end of this call please note that today's call is being recorded a replay of today's call will be available on in the arrest investors section of the company website approximately two hours after the completion of this call i would now like to turn the call over to trista morrison Chief Corporate Affairs Officer at Voyager.

speaker
Investor Relations Representative
IR Representative

Good afternoon. We issued our fourth quarter 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.

speaker
Dr. Al Sandrock
Chief Executive Officer

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. And 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 multi-modality 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 Loiger 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 BY1706, 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% to 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 ADPD 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 propranamab 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 ADPD 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 TAO silencing program, working on the BY7523 single ascending dose analyses, and initiating the multiple ascending dose study. With that, we will open the call for questions. Operator?

speaker
Trista Morrison
Chief Corporate Affairs Officer

Thank you. As a reminder, to ask a question, please press star 1-1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1-1 again. One moment for questions.

speaker
Conference Call Operator / Moderator

Our first question comes from Jack Allen with Baird. You may proceed.

speaker
Jack Allen
Baird

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 TAO space. Any additional color you'd like to provide ahead of ADPD as it relates to things people should be looking out for? And then I have a quick follow-up as well on your partner programs.

speaker
Dr. Al Sandrock
Chief Executive Officer

Yeah. Hi, Jack. So, at ADPD, I hope to see data from the Pranamab as they, I believe they may be sharing their data on exposure PD relationships, so PKPD, which they didn't have a chance to share at the CTAD meeting last year. And also, more data on how much decrease in tau spreading do you need to see in order to see a clinically relevant effect? So 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 APOE for carrier status as well as initial tau burden. And 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. The, we also note that other companies have started to share data with their anti-Tau program. So, I know that, for example, ASI has been sharing data on fluid-based biomarkers with their anti-Tau that targets the MTBR region. And so, and I don't know whether other companies may also be starting to share data as well, but there's a lot of interest in Tau. There's also the tau silencing approaches that we know, for example, Biogen has. And I look forward to seeing any updates that might be on that.

speaker
Dr. Toby Ferguson
Chief Medical Officer

So, Lee, did you want to add anything to that? Well, I think I certainly agree with your comments and sort of echo the comments on exposure response, both initial PKPD 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?

speaker
Conference Call Operator / Moderator

Got it. Great. That's a very helpful caller.

speaker
Jack Allen
Baird

And then 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?

speaker
Dr. Nathan Jorgensen
Chief Financial Officer

Okay, thanks for the question, Jack. This is Nate Jorgensen, the CFO. And so what we have said is that there's $2.9 billion of developmental milestones. So these are milestones I think are not bio bucks like some companies report. But if you add all the bio bucks together, it's over $8 billion as Al mentioned. So 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 talked about externally. Got it. Are those milestones at all accounted for in your guidance, or are they additional upsides? No, they're not. So that's all upside to the mid-2027 cash runway guidance.

speaker
Nate Jorgensen

Perfect.

speaker
Jack Allen
Baird

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

speaker
Trista Morrison
Chief Corporate Affairs Officer

Our next question comes from Phil Navy with TD Cowan. You may proceed.

speaker
Dr. Al Sandrock
Chief Executive Officer

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 that ind can be filed next year well i mean uh the main thing is that we have to complete the glp talk study that we just found but we just started and that we need to be sure that we have a therapeutic window uh you know as we said our our uh Initial non-human primate study shows 50% to 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.

speaker
Phil Navy
TD Cowan

Perfect. And then 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?

speaker
Dr. Al Sandrock
Chief Executive Officer

Well, we're looking broadly across various diseases, various targets. You know, this is a receptor that allows for BBB penetrance of one of our leading classes of capsids. And that capsid gets in across the CNS pretty broadly. So that leaves open a lot of different diseases, both spinal cord as well as cerebral cortex and even subcortical diseases. And so, and then the kinds of drugs that we were thinking about transporting across the BBB would include proteins such as enzymes or antibodies. And also, we're starting to assess whether or not oligonucleotides can be transported as well. That leaves open a wide array of possibilities still. And so, beyond that, you might imagine what the best antibodies or enzymes for oligonucleotides we might be thinking about. And look, as we noted with the antibody, the RNP tower antibody, You know, we get a CSF to serum ratio of 0.3%, so 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 disease, and that provides a burden patients. It also produces a severe gradient in the CNS, which I think is limiting. So there's a lot of opportunities. Todd or Toby, do you want to add anything to that?

speaker
Dr. Todd Carter
Chief Scientific Officer

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

speaker
Phil Navy
TD Cowan

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

speaker
Trista Morrison
Chief Corporate Affairs Officer

Thanks, Phil. Our next question goes from Pete Stavaropoulos with Cantor Fitzgerald. You may proceed.

speaker
Pete Stavaropoulos
Cantor Fitzgerald

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

speaker
Dr. Toby Ferguson
Chief Medical Officer

Thanks, Pete. This is Toby. Good to hear from you. The, so I think fundamentally our belief on the knockdown approach with 7006 is a couple key points. As we've highlighted, we use our second generation tracer capsids. And so it will be injected IV once. And that gives us a couple of clear advantages. I think one is that it allows for better biodistribution, accessing the vasculature via ALPL. And so that's quite distinct from the gradient you get with an intrathecal injection in the lumbar space with an ASO. So I think that presents an opportunity for broader tau knockdown. And so that is, I think, quite an important point. And then 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 health care 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 26 will be an important inflection point. Of course, we have an IAD for our program in 2026 as well. So 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. And so 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 taus. And that was shown by TALPET, which is quite a remarkable observation. So there may be some broader latitudes. There may be space for sequencing of a beta amyloid therapy with an antibody and then a TAL knockdown approach as well.

speaker
Pete Stavaropoulos
Cantor Fitzgerald

All right. Thank you for that, Dan. And just one more question. You know, the way that we viewed the SOD1 gene silencing program is that, you know, it would provide proof of concept for the capsid and its ability to cross the blood-brain barrier efficiently, you know, by looking at changes in the NFL. you know, which we would hope to have seen, you know, similar to Toverson. You know, how are you thinking about establishing the human proof of concept? You know, which program will likely help you do so? Is there any agreement or expectation of a partner sharing some data or allowing you to, you know, once it's generated?

speaker
Dr. Toby Ferguson
Chief Medical Officer

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

speaker
Dr. Todd Carter
Chief Scientific Officer

I think you've got it, Toby.

speaker
Conference Call Operator / Moderator

All right.

speaker
Pete Stavaropoulos
Cantor Fitzgerald

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

speaker
Trista Morrison
Chief Corporate Affairs Officer

Thanks, Steve. Our next question goes from Lily Nisongo with Link. You may proceed.

speaker
Lily Nisongo
Link

Hi. Good afternoon. Two questions from my side. So the first one being on maybe comparing and contrasting the two approaches for tau. So 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?

speaker
Conference Call Operator / Moderator

Todd, do you want to take that? In the preclinical studies?

speaker
Dr. Todd Carter
Chief Scientific Officer

Sure. On the preclinical side, we've seen positive results from both. One aspect that we have discussed with the TAO antibody program is that we do see differences targeting different epitopes. So, 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 patients derived pathological tau into the brain of a mouse expressing human tau and look at the ability of a treatment to stop spreading. So the interminable fail antibodies didn't work. Our antibody does. Many other antibodies do not. I will say that the tau knockdown also shows efficacy in similar type models. And we aren't 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. And then we're also reducing the amount of tau on the recipient cell to then receive that pathological pre-adlyte material. So we think that there are interesting similarities, but also some key differences in the fundamental mechanisms of those two approaches.

speaker
Lily Nisongo
Link

Thank you. And as a follow-up, maybe could you provide a little bit of color in terms of the MAP study design? So, 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 the PraniMAP?

speaker
Dr. Toby Ferguson
Chief Medical Officer

Thank you. This is Toby. So, it's actually a question. I think what we fundamentally had maybe a couple points. So I think what we've learned about our antibody, including the clinical work and up through the SAD, is that the antibody, for mine, it binds pathologic tau, which differentiates it from some other antibodies, including UCBs, that we have appropriate PK. We've got good CSF penetration. So in that context, we really think in the MAD study, we can drive to an effective determination of if we have a signal, I'll bet. particularly in the context of what we've seen thus far. And that's important. I think in terms of the population, what we've learned from bupanumab is that the lower tau may be important in this context and or APOE status. And so 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 of ADPD 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. So we'll certainly continue to monitor the field and adjust as we're able. I will highlight, I think that's what I'll end.

speaker
Dr. Al Sandrock
Chief Executive Officer

And 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. And, you know, here in this case, wouldn't it be fair to say, Toby, that given the data with buprenumab, particularly the safety, and also our single ascending dose results. We're planning to push the dose pretty high, right? And 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. And so that's the plan. And as Toby says, you know, we'll be monitoring the situation with all the other data coming out.

speaker
Conference Call Operator / Moderator

Certainly agree. Thank you for the call.

speaker
Trista Morrison
Chief Corporate Affairs Officer

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

speaker
Samantha Semenkow
Citi

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. And 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 there would be very helpful. Thank you.

speaker
Dr. Al Sandrock
Chief Executive Officer

Well, 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. You know, look, I mean, but even Denali, who are the leaders in TFRs, are also looking at CD98, right, as another shuttle, another shuttle vehicle. So why would that be? And I guess it's because every receptor is going to have its own safety distribution and kinetics. And so 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. But as time goes on, we may be able to be more selective. So it could be plug and play. But as we learn more about these various shuttles, we may start to tailor them to the right disease and the right target. That's how I see it now. Of course, it'll be great to get more data to see whether we're right about that.

speaker
Samantha Semenkow
Citi

Very helpful. And just as a follow-up, is there anything you can share about what that clinical data set could look like sometime later this year for the non-viral shuttle? Thanks very much.

speaker
Dr. Al Sandrock
Chief Executive Officer

Well, obviously, we're going to start by showing data in animals. So it's obviously going to be in vivo data that's going to count the most. And 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. And we hope to be able to show more than one payload as well, see how plug and play it actually could be. So that's what we're hoping to show, and we're working hard on that. We'll see whether we can get there.

speaker
Samantha Semenkow
Citi

Great. Looking forward to it.

speaker
Dr. Todd Carter
Chief Scientific Officer

I think, Al, you captured it. I mean, we remain very excited by that and hopefully look forward to sharing that later this year.

speaker
Conference Call Operator / Moderator

Thanks, Samantha.

speaker
Trista Morrison
Chief Corporate Affairs Officer

Our next question comes from June Lee with Truist Securities. You may proceed.

speaker
June Lee
Truist Securities

Hi, good afternoon. This is Median for June, and congrats on the progress. A couple on capsules for us as well. So given that for SOD1 ALS program, the recap Gen 2 is going to be the same for VY1706, what are the data points that gives you the confidence that the neurotoxin that you have seen is not related to the Capsid?

speaker
Dr. Al Sandrock
Chief Executive Officer

Well, there's two reasons. One is the timing of the adverse event. So in the case of the SOD1 program, in the initial time points in the several days after we inject, we do see the expected slight bump in liver function tests and in neurofilament levels. And that's exactly where other programs have seen, have shown those kinds of adverse events with IV delivered AAV. And that's to be expected. But the capsid clears from the bloodstream within days. And then what we saw was with a delay of about three months, we saw then the neurofilaments start to go back up. And that was coincidence with some neurological adverse events observed at cave size. And then when you look histologically, you see evidence of neurodegeneration. So it's that delay, which is when expression has really come into play, that we see the adverse events. And so 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 of payloads, and we see no such adverse events in non-human primates, even at doses that have, that are comparable to what we tested with SOD1, and even at the two- to three-month time point. So, it's both of those pieces of evidence that gave us a lot of confidence that it was the payload and not the capsid.

speaker
Dr. Todd Carter
Chief Scientific Officer

Thank you. Very helpful. Sorry, when Al talks about what we're looking at, we're looking at histopathology, we're looking at NFL as a biomarker, and we're looking at sort of clinical signs. So none of those, we see none of that with the capture with these other payloads.

speaker
Conference Call Operator / Moderator

Thank you very much. Our next question comes from Rye Fortes with Guggenheim Securities.

speaker
Trista Morrison
Chief Corporate Affairs Officer

You may proceed.

speaker
Rye Fortes
Guggenheim Securities

Hey, this is Rai 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.

speaker
Dr. Al Sandrock
Chief Executive Officer

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

speaker
Rye Fortes
Guggenheim Securities

Either silencing efforts or antibodies.

speaker
Dr. Al Sandrock
Chief Executive Officer

I see. Yeah. You know, I think one of the biggest pieces of data is going to come in terms of antibodies from the J&J study, which we'll read out next year. And I say that mainly because it's 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. but then also get a much better handle on whether or not there's a clinically significant consequence to that impeding of tau spread, which we hope to see. So I think that we'll have to wait for the J&J data, which I think is next year. In terms of the knockdown approaches, you know, what's remarkable about the BIV-80 data, for me anyway, is the fact that you actually reduce 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. But that's exactly what Biogen has shown. And what's intriguing is that they seem to see a pretty big clinical benefit of that. Now, the flaw there is that there was no control group in that study, but they've done a great job comparing it to natural history and to the control groups of other trials. And 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. And so those are the kinds of things I'm going to be looking at. Of course, we always want to know, 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. And then 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 it comes down the pipe. In the case of anti-amyloid antibodies, it was important to be specific for pathological forms of amyloid, so we'll see if that also applies to the PAL. Toby, Todd, what did I forget?

speaker
Dr. Toby Ferguson
Chief Medical Officer

Maybe I'll highlight the Merck readout. It's a C-termal epitope pathological antibody. It's a short study focused on biomarkers, but gives you an initial chance to answer the question, can an epitope, a C-tribal epitope, produce at least total tau?

speaker
Conference Call Operator / Moderator

And so that's an important concept as well.

speaker
Rye Fortes
Guggenheim Securities

Thanks for that. And maybe just one more question from us. With the April ADPD-NHP gene therapy data, will you provide distributional data in terms of the percent of vector that goes to the brain relative to the liver? And if not, maybe you could frame for us, Voyagers, thinking on the utility of those kinds of measures.

speaker
Dr. Todd Carter
Chief Scientific Officer

So, we, let's see. At ADPD, we will present on the TAL Knockdown Program. We will describe data showing delivery, both in terms of the amount of vector and knockdowns, the pharmacology that we achieve in the brain and vector. in peripheral tissues as well. So, it may not be in a percentage format, but we'll be talking about delivery to the important locations, and those include on-target and what we think of off-target tissues.

speaker
Conference Call Operator / Moderator

Thank you.

speaker
Trista Morrison
Chief Corporate Affairs Officer

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

speaker
Jay Olson
Oppenheimer

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 ADPD. Can you talk about the target level of tau mRNA knockdown that you plan to achieve, and are there any particular brain regions that are more important for tau mRNA and protein reduction?

speaker
Dr. Al Sandrock
Chief Executive Officer

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

speaker
Dr. Todd Carter
Chief Scientific Officer

So Al mentioned earlier, The general range that we're targeting, we're seeing 50 to 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, and the non-human primate that we think we need to achieve those kinds of knockdown and to have an impact on the disease.

speaker
Jay Olson
Oppenheimer

Okay, great. Thank you. And then, can you comment on how you're thinking about indications for the TAL silencing program? Would you start with Alzheimer's disease, or are there other TALopathies that you would start with?

speaker
Dr. Al Sandrock
Chief Executive Officer

Well, assuming we don't partner it, we would, look, our intention is to partner it, and so it may be our partner that decides which indications to to go after, but 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 TSP, progressive supranuclear palsy. There's also frontal temple dementia due to tau, mutations in tau. And then there are a lot of other diseases as well, including potentially chronic traumatic encephalopathy. But 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. And then 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. So 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?

speaker
Dr. Toby Ferguson
Chief Medical Officer

Toby Lowe I agree, Alan. And maybe I'd sort of amplify that fundamentally, I mean, we've seen with the data how critical TauPet can be. This is best worked out in Alzheimer's disease. Looking at some of the other telepathies, use of telpet and, in some cases, flu biomarkers is less well settled. And so one of our core tenets is that you go into diseases where you can get proof of concept around the biomarker tools relatively quickly. And in this case, for the telepathies, we think that really sits with Alzheimer's. I certainly think the other indications are interesting once you've shown that.

speaker
Jay Olson
Oppenheimer

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?

speaker
Dr. Al Sandrock
Chief Executive Officer

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

speaker
Conference Call Operator / Moderator

Okay, great. We'll look forward to that. Thanks for taking all the questions. You're welcome.

speaker
Trista Morrison
Chief Corporate Affairs Officer

Our next question goes from Patrick Trucchio with HC Wainwright and Company. You may proceed.

speaker
Patrick Trucchio
HC Wainwright and Company

Thanks. Good afternoon. Just a couple of follow-up questions on the BY7523. Just the first, I'm wondering how the SAD data influenced selection of dose levels and frequency for the MAD study, and then separately, Just, you know, given the competitive readouts in the anti-tao space and those that are upcoming, I'm wondering, you know, how the MAD study design may position BY7523 for differentiation. And then separately, I'm wondering, you know, with the cash runway extending into mid-2027, how will you balance investment in internal programs versus, you know, potential licensing or business development opportunities?

speaker
Dr. Toby Ferguson
Chief Medical Officer

Maybe I'll start and then turn it over to Nate. So I think in terms of the SADD data, just to reiterate, we saw dose proportionate PK, an acceptable safety profile for a molecule in the single study, and we saw a CSF serum ratio of 0.3, which is quite consistent with approved molecules. And then I think I'd layer on top of that the sort of the observed safety and the broader propranamib study didn't highlight any risk of ARIA. Really, what the SAD data gave us was the confidence in the MAD study to move forward with our planned doses and, frankly, as Al had highlighted earlier, to try to push those doses to levels where we can clearly test the hypothesis as to whether or not this antibody would impede the spread of how . 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 And so 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, and particularly UCB. And 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.

speaker
Dr. Al Sandrock
Chief Executive Officer

Yeah, may I add that, look, you hit the nail on the head in the sense that we do, our aim is to try to differentiate. And, you know, put the best foot forward with our antibody. And 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. And so, we want to be sure we exceed those, the EC50, if you will. that effect of impeding spread and and we're pretty confident we can get there with the doses that we have um we will be choosing uh based on the single ascending dose studies that we did uh and nate do you want to answer the second half of the question yeah so 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 or

speaker
Dr. Nathan Jorgensen
Chief Financial Officer

then which would shorten that. We'd have to bring in some really interesting asset that potentially with the clinical near-term clinical catalyst. In terms of the other types of deals, those are something that Al always talks about that he's open to. There's, I think, opportunities out there for us to do additional BD 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.

speaker
Dr. Al Sandrock
Chief Executive Officer

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

speaker
Conference Call Operator / Moderator

Thank you.

speaker
Trista Morrison
Chief Corporate Affairs Officer

Our next question comes from Yun Zong with Wedbush Securities. You may proceed.

speaker
Yun Zong
Wedbush Securities

Hi. Good afternoon. Thank you very much for taking the questions. The first question is on the MAT study. Was the initiation earlier than you had expected? Because I believe the original guidance was very broadly in 2025. And the second question is, I know that you compared the antibody approach versus the knockdown approach. compared to 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?

speaker
Conference Call Operator / Moderator

Maybe I'll take the... This is Toby.

speaker
Dr. Toby Ferguson
Chief Medical Officer

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

speaker
Yun Zong
Wedbush Securities

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

speaker
Dr. Toby Ferguson
Chief Medical Officer

I mean, what I say here is we have two different approaches. And I think, one, we have some early data from Biogen suggesting that knockdown could be quite clinically efficacious. Alice highlighted that this was a natural history comparator and a comparison to another study with an effect on CDR sum of boxes that was maybe two to three times greater than sort of what is observed for beta amyloid therapy. So essentially a very large effect of the knockdown approach. So 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 data sets. And that effect was slightly different. And so I think the potential there is potentially different. But 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've previously discussed. So really, there may be a point in time when you want to stop spread in a low-town population early in disease, or there may be a population in time when someone has broader spread of town when you want to take a knockdown approach. Or you may learn there are different responses across different patient populations. So I think fundamentally, Alzheimer's is complex. And physicians and patients are going to need options in terms of to fully treat this disease.

speaker
Dr. Al Sandrock
Chief Executive Officer

I would add that I believe we're still in the very early stages of learning about how and how to best approach this target. You know, 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, you know, that are starting to be seen in humans. And I think there's going to be a lot to learn. And I think for right now, the prudent thing to do is to pursue both programs, and we will make data-driven decisions, internal data as well as external data.

speaker
Conference Call Operator / Moderator

We will learn from those, and we will make data-driven decisions. Sounds good. Thank you.

speaker
Trista Morrison
Chief Corporate Affairs Officer

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

speaker
Yanan Zhu
Wells Fargo Securities

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? And then I have follow-ups on the TAO program. Thank you.

speaker
Dr. Al Sandrock
Chief Executive Officer

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

speaker
Yanan Zhu
Wells Fargo Securities

Great, thanks for.

speaker
Dr. Al Sandrock
Chief Executive Officer

You know, let me add one more piece, Jan, and I, you know, is that you know, we sometimes forget about the fundamental properties of drugs, you know, such as PK and half-life. And so I mentioned kinetics and distribution previously. And so we'll be looking at those things too. That's not to say that the TFR-based approaches, you know, are not promising. They are promising. In fact, so promising that that's why we're so excited about the idea of using a shuttle-based approach to improve delivery of other modalities beyond gene therapy.

speaker
Yanan Zhu
Wells Fargo Securities

Got it. Yep, yep. 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. And 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.

speaker
Dr. Todd Carter
Chief Scientific Officer

Yeah, 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, and we've gone with effectively 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 the banimab in the clinic that you don't need effector function, and eliminating it eliminates or reduces some risk around neuroinflammation, we think. So, we've gone with an HIDG4 for our antibody.

speaker
Yanan Zhu
Wells Fargo Securities

Great.

speaker
Conference Call Operator / Moderator

Thank you very much for the cover.

speaker
Trista Morrison
Chief Corporate Affairs Officer

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

speaker
Suman Kulkarni
Canaccord Genuity

Good afternoon, and thanks for taking my question. Apologies if this was asked before, and Al, I know you gave a quick history lesson there on anti-amyloid products for Alzheimer's, but 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, or would you need to see internal results in order to make that decision, and what might those internal results look like?

speaker
Dr. Al Sandrock
Chief Executive Officer

Yeah, I mean, that's a tough question to answer. What I'm looking for, Suman, is really how much of an effect on tau spreading do you have to see to see a minimally clinically significant effect? So in the case of the anti-amyloid antibodies, and by the way, you can learn from different antibodies against different epitopes. But 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? And you can actually draw a graph of all the different antibodies and see that, you know, 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. So, that's precisely the kind of thing I think I would like to see with the anti-tau antibodies. And I would say that, you know, anything less than a roughly 30% effect on CDR sum of boxes, I would say is probably not clinically meaningful. So, 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-amyloid antibodies and various companies sharing their data. And like I said, I think we're in the early stages still of the tile-directed antibodies.

speaker
Conference Call Operator / Moderator

Got it. Thanks.

speaker
Trista Morrison
Chief Corporate Affairs Officer

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

speaker
Dr. Al Sandrock
Chief Executive Officer

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

speaker
Trista Morrison
Chief Corporate Affairs Officer

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

Disclaimer

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