Voyager Therapeutics - Q1 2024

Transcript

Operator (participant)

Good afternoon and welcome to Voyager Therapeutics first quarter 2024 financial results conference call. At this time, all participants are in listen-only mode. There will be a question-and-answer session at the end of this call. Please note that today's conference is being recorded. A replay of today's call will be available on the Investors section of the company's website approximately two hours after completion of this call. I would like to turn the call over to Trista Morrison, Chief Corporate Affairs Officer.

Trista Morrison (Chief Corporate Affairs Officer)

Thank you, and good afternoon. We issued our first quarter 2024 financial results press release this afternoon. The press release and 10-Q are available on our website. Joining me on today's call are Dr. Al Sandrock, our Chief Executive Officer, Dr. Toby Ferguson, our Chief Medical Officer, and Dr. Todd Carter, our Chief Scientific Officer. We will also be joined for the Q&A portion of the call by our Chief Operating Officer and Principal Financial Officer, Robin Swartz. 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.

Now I will turn the call over to Al.

Al Sandrock (CEO)

Thank you, Trista, and good afternoon, everyone. Please turn to slide three. I'd like to start by thanking the Voyager team for their dedication to creating transformative genetic medicines. We made tremendous progress advancing these medicines in the first quarter. We just announced that we have obtained IND clearance for our anti-tau antibody, VY-TAU01, for Alzheimer's disease, and we expect to announce the dosing of the first subject in a single ascending dose trial in healthy volunteers in the coming week or so. Our gene therapy pipeline also advanced during the quarter, with development candidates selected in the GBA1 and Friedreich's ataxia programs partnered with Neurocrine. These programs, along with our wholly owned SOD1 ALS program, are advancing toward IND filings in 2025. In March, we appointed Dr. Toby Ferguson as our Chief Medical Officer. Toby is an exceptional biotech executive with deep experience advancing novel therapies for CNS diseases.

This includes tofersen, the first genetically targeted therapy to be FDA-approved for SOD1 ALS, and the first treatment to receive accelerated approval based on plasma neurofilament light chain response. Toby has hit the ground running, and we look forward to his leadership of our emerging clinical portfolio. In January, we announced an expansion of our relationship with Novartis through a new strategic collaboration and capsid license agreement to advance potential gene therapies for Huntington's disease and spinal muscular atrophy. This agreement, together with the public offering we completed in January, brought $200 million of total consideration to Voyager in the first quarter. This bolstered our balance sheet and extended our runway into 2027, and we expect that it will enable us to achieve multiple clinical data readouts.

Finally, we presented a robust set of data at the recent AD/PD and ASGCT meetings, including data on our multiple tau targeting programs in our second-generation capsids. Given this significant progress, we believe Voyager is emerging as a leader in neurogenetic medicine. Our pillars of value are summarized on slide four. First, we have a strong pipeline of 4 wholly owned and 13 partnered programs, with the first expected to enter clinical trials in the coming weeks and the potential for three more to follow next year. Second, we have an industry-leading platform designed to overcome the delivery challenges inherent to CNS gene therapies. Our TRACER platform enables us to create novel capsids that, following IV delivery, harness the extensive cerebrovascular tissue to enable widespread payload distribution across multiple brain regions and cell types.

These capsids have demonstrated translatability in multiple species and have enabled the selection of multiple development candidates in our wholly owned and partnered gene therapy programs. Third, we have blue-chip partnerships anchored by TRACER's potential to transform the treatment of CNS diseases. In addition to Neurocrine, our partners include Novartis and Alexion. In total, our partnered programs could generate up to $8.2 billion in longer-term milestone payments. Finally, we continue to explore the potential to leverage receptors we have identified to shuttle non-viral genetic medicines into the brain. Ultimately, we aim to expand from gene therapy and antibodies into other modalities of neurogenetic medicine, broadening our impact. With that, I'll turn the call over to Toby.

Toby Ferguson (Chief Medical Officer)

Thank you, Al, and good afternoon. Please turn to slide five. This slide summarizes the 4 wholly owned programs and our 13 partner programs that Al mentioned earlier. Part of what attracted me to Voyager is that these programs are focused on targets validated by human biology and human genetics. As a drug developer and former practicing neurologist, I've dedicated my career to improving the lives of people living with neurologic diseases. While our understanding of the genetic and biological basis of CNS diseases has advanced considerably, translating that understanding into new therapies has been hindered by challenges with crossing the blood-brain barrier. I believe that the progress that Voyager has made in this regard is transformative and provides an unprecedented opportunity to redefine the treatment of CNS diseases.

I'm delighted to join the company as we prepare to enter the clinic and realize the full potential of our pipeline of neurogenetic medicines. Turning to slide six, I want to focus for a moment on two of our wholly owned programs that target tau. We believe tau is a critically important target for the treatment of Alzheimer's disease. The presence of tau pathology in the brain is a cardinal feature of AD. Further, the spread of tau pathology through the brain closely correlates with clinical decline and can be visualized with tau PET imaging. Importantly, recent third-party clinical data generated using an intrathecally administered tau ASO have shown that reducing tau was associated with favorable trends on clinical outcomes.

As Al mentioned, we're excited to announce that VY-TAU01, our anti-tau monoclonal antibody, obtained IND clearance, and we look forward to announcing in the coming weeks the initiation of a single ascending dose trial in healthy volunteers. I'll talk more about that trial in a moment. First, a bit of background on this program. VY-TAU01 aims to inhibit the cell-to-cell spread of the extracellular forms pathological tau in the brain. In contrast to third-party anti-tau antibody approaches that have targeted the N-terminus of tau and have been unsuccessful in the clinic, VY-TAU01 targets the C-terminal epitope of pathological tau. We believe the epitope matters. In a preclinical in vivo model of tau spread, the murine surrogate of VY-TAU01 inhibited tau spread by approximately 70%, while N-terminally directed antibodies had no significant effect. This indicates the negative predictive value of this model.

We look forward to establishing whether or not it has positive predictive value as we advance into clinical trials. Importantly, and in parallel, we are progressing a tau silencing gene therapy approach intended to inhibit the production of tau protein. This program deploys a tau-targeted siRNA packaged into an IV-administered TRACER capsid. Using this approach, we've demonstrated robust reductions in tau mRNA and protein across the brain following a single IV administration in mice expressing human tau. We believe this program has the potential to provide a transformative single-dose treatment for Alzheimer's disease, and we anticipate filing an IND in 2026. Turning to slide seven, as I mentioned, we anticipate the announcement of dosing of the first subjects in our single ascending dose trial, VY-TAU01, in the coming weeks. This will be a single-site study in which we expect to enroll approximately 48 participants.

The primary aim of the trial is to generate initial safety and PK data that will inform a subsequent multiple ascending dose trial. We expect to conduct the multiple ascending dose trial with participants with early Alzheimer's disease. We expect to initiate this trial next year and generate initial tau PET imaging data in 2026 that has the potential to show slowing of tau spread. Turning to slide eight. In addition to our programs targeting tau, we are also advancing three gene therapy programs for which we expect to file INDs next year. They include our wholly owned SOD1 silencing program targeting the genetic cause of SOD1 ALS, the Neurocrine partnered frataxin gene replacement program targeting the genetic cause of Friedreich's ataxia, and the Neurocrine partnered GBA1 gene replacement program.

Mutations in GBA1 represent both one of the most common genetic causes of Parkinson's disease as well as the cause of other GBA1-related diseases. Each of these programs leverages an IV-administered blood-brain barrier penetrating TRACER capsid and has the potential to provide a single-dose disease-modifying treatment. We look forward to advancing this promising suite of programs into clinic. With that, I'll turn the call over to Todd.

Todd Carter (Chief Scientific Officer)

Thanks, Toby. Please turn to slide nine. In support of our advancing gene therapy pipeline, we were pleased to present a robust set of data on the potential clinical translatability, manufacturing, and overall performance of our TRACER capsids at the American Society of Gene and Cell Therapy annual meeting last week. Voyager scientists presented a total of 12 abstracts at the meeting, and I'd like to review a few highlights. First, we presented new data on our second-generation IV-delivered TRACER capsids. This session was standing room only, with a line out of the door and down the hall, which I think speaks to the high level of interest in novel capsids engineered to cross the blood-brain barrier. Our second-generation capsids showed further enhanced blood-brain barrier penetrance and reduced liver expression compared to our own first-generation TRACER-derived capsids.

These second-gen capsids demonstrated robust transduction of 50%-75% of cells across diverse brain regions, with upwards of 95% transduction in certain key cell types, such as Purkinje neurons, at a clinically relevant dose of 3x10^13 vector genomes per kilogram. This also included transduction of 98% of dopaminergic neurons of the substantia nigra and over 80% of spinal motor neurons. Importantly, our TRACER capsids have enabled selection of development candidates for the three lead gene therapy programs that Toby just reviewed. We presented data at ASGCT on VY9323, our wholly owned SOD1 silencing gene therapy, which uses a second-generation TRACER capsid. The data demonstrated that a single IV dose of VY9323 at the 3x10^13 vector genomes per kilogram dose reduced SOD1 mRNA by up to 80% in spinal cord motor neurons in non-human primates.

Finally, as part of our strategy to mitigate the risks of developing TRACER capsid-derived product candidates and maximize the probability of success in the clinic, Voyager has been working to identify the receptors that mediate the delivery of these capsids into the CNS and confirm their expression in humans. At ASGCT, we identified tissue-nonspecific alkaline phosphatase, or ALPL, formerly known as Receptor X, as the highly conserved receptor expressed on the brain vasculature that mediates the delivery of TRACER capsids VCAP-101 and VCAP-102 across the blood-brain barrier. These capsids bind human, primate, and murine ALPL isoforms, further strengthening our confidence in the clinical potential of TRACER capsids. More broadly, these data establish ALPL as a novel brain delivery shuttle, and we are exploring the opportunity to leverage this receptor to deliver multiple therapeutic modalities across the blood-brain barrier. We look forward to sharing these data in the future.

Collectively, the data package we presented at ASGCT represents the most extensive validation to date of the potential clinical translatability of our TRACER capsids, and we look forward to evaluating their ability to transform the course of a broad range of neurological diseases. I will now turn the call back over to Al.

Al Sandrock (CEO)

Thanks, Todd. Turning to slide 10. You can see Voyager has had an incredibly strong start to the year. As I mentioned before, this would not be possible without the hard work and dedication of our employees. I know many of them are listening, so I want to say again, thank you. With a robust slate of upcoming clinical milestones, a maturing partnership portfolio, and cash runway into 2027, we believe Voyager is poised to drive significant value over both the near and long term. With that, we will open the call for questions. Operator?

Operator (participant)

Thank you. At this time, we'll conduct the question-and-answer session. As a reminder to ask a question, you will need to press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. Please stand by while we compile the Q&A roster. Our first question comes from the line of Joon Lee of Truist Securities. Your line is now open.

Mehdi Goudarzi (Biotech Equity Research Analyst)

Hi. Good afternoon and congrats on the great progress. This is Mehdi on for Joon. Last week, at ASGCT, you showed great data related to Receptor X, ALPL. So could you please elaborate on the ways that you are planning to use this knowledge for delivery of the other modalities to CNS? Specifically, do you think antisense oligos and LNPs could see similar levels of transcytosis seen with AAVs? Thank you.

Al Sandrock (CEO)

Yeah, thanks for the question. This is Al Sandrock. So briefly, we know that these receptors mediate the transport of these very large AAV capsids across the BBB. And what we're going to do now is to make ligands against the receptor, conjugate them to various macromolecules to see if we can get them to cross the BBB, we believe, by transcytosis. And the range of molecules we could look at includes protein therapeutics as well as oligonucleotides, and we're progressing those experiments as we speak. Todd?

Todd Carter (Chief Scientific Officer)

Thanks, Al. So we are looking at a variety of different modalities. As Al indicated, we're looking at antibodies, oligos, other sorts of proteins. Al mentioned that we're in the process of identifying ligands, and we have identified some ligands, and we're looking forward in the future to hopefully sharing some of those data when we're ready to.

Mehdi Goudarzi (Biotech Equity Research Analyst)

Appreciate it. Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Jack Allen of Baird. Your line is now open.

Jack Allen (Biotech Senior Research Analyst and VP)

All right. Thanks so much for taking the questions, and congratulations on the progress. I wanted to ask about some of the work you presented at ASGCT around the optimization of manufacturing. How are you thinking about optimizing manufacturing before you bring candidates into the clinic with your gene therapies, and what do you expect the benefits will be as it relates to COGS of your more potent gene therapies as well?

Al Sandrock (CEO)

Well, I'll start, and I'll ask Todd to help here. So we're planning to use HEK293 cells to manufacture these products. We have a very robust internal technical operations team. And part of the development candidate selection, we assess manufacturability as well as the downstream as well as upstream processes. And of course, we're going to be verifying percentage of full capsids, partially full capsids, as well as empty capsids. And so we assess manufacturability as part of the development candidate selection. Todd?

Todd Carter (Chief Scientific Officer)

So as Al mentioned, we do have that manufacturability is a key component. It's actually part of our whole assessment of our novel capsids as we identify them. In each case, the payload can make a difference. So that for any given program, we have to establish the manufacturability with the capsid in question and the particular payload for the disease indication as well. All that goes into our assessment, and we begin with research-grade material. And then once we develop the development candidate, then we proceed to the process development to move that into manufacturability. You also asked a question about COGS.

And of course, it's not exactly necessarily a one-to-one trade-off, but you can imagine as we're looking with our novel capsids that have a potency approximately about an order of magnitude greater than what the dose is currently used in the clinic, we expect to see substantial savings because we need much less material to deliver the same level or actually greater levels of delivery to the CNS than the conventional capsids.

Al Sandrock (CEO)

Yeah. I would just add, Jack, that in addition to the lower doses, what we note is that we're going to transfer the process to a CDMO for manufacturing. The CDMO world has really come up to speed in terms of scalability. We're now seeing scale, and every time you increase the scale, we actually reduce the cost. At the pace that it's going, we expect to see continued advancement in that area as well.

Jack Allen (Biotech Senior Research Analyst and VP)

Yeah. That's great. Can I just ask one final question on that? I know we haven't really gotten this far in the gene therapy space, but how does shelf life of these products play a role when you think about the commercial applicability of these manufacturing scale here?

Al Sandrock (CEO)

Shelf life. Wow, that's a question I hadn't thought about yet. But anybody here has an answer to that?

Todd Carter (Chief Scientific Officer)

We do assess the shelf life. Of course, for a gene therapy, we typically would need to require it to be held at particular cold temperatures. All that is part of the evaluation for stability, both short-term and long-term. That's an important part of our manufacturability and our process development.

Jack Allen (Biotech Senior Research Analyst and VP)

Thanks, Todd. Got it. Thanks so much. Congrats on the progress.

Todd Carter (Chief Scientific Officer)

Thank you.

Al Sandrock (CEO)

Thanks.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Patrick Trucchio of H.C. Wainwright & Co. Your line is now open.

Patrick Trucchio (Managing Director)

Thanks. Good afternoon and congrats on all the progress. Just a couple of follow-up questions from me. The first is I'm wondering if you can discuss any potential read-through that you'll be looking for from the advisory committee meeting on June 10 regarding donanemab in Alzheimer's disease to your Alzheimer's programs. And then separately, just a follow-up on the ASGCT data, specifically the data in human tau mouse model that showed reduction in tau mRNA levels up to 90% and 50%-70% reduction in tau protein. Can you tell us how this data compare with prior generation capsids and how the data may support advancement of tau silencing gene therapy IND in 2026?

Al Sandrock (CEO)

Thanks, Patrick. I'll answer the first question, and maybe I'll ask Todd to answer the second one. On the first question, well, it'll be a very interesting advisory committee. We do have a vectorized anti-amyloid program in our pipeline as well, so we're watching that advisory committee with interest. I think a lot of the questions might be unique to donanemab and may not pertain very much to our program. Nevertheless, there might be some important features. For example, what are the outcome measures that are going to be important for approval? And of course, that's always something that we need to keep an eye on. But that's down the line for us. We have to get into the clinic first. So that's the kind of thing we may be paying attention to, but it'll be an interesting meeting. Todd?

Todd Carter (Chief Scientific Officer)

So on our tau knockdown program, the data that you're referring to, we showed some at AD/PD and also at ASGCT. The knockdown in the mouse was with a mouse-capable capsid. So we use that really to assess the payload and also to hopefully demonstrate, and we feel that we did, that the payload has the ability to knock down tau, both mRNA and protein, at a clinically relevant dose. So we think that that's what we showed in those mouse studies. With regard to the payload, we were able to see at a well-tolerated and safe dose in those animals delivering sufficient vector to the brain that we saw quite remarkable knockdown of the mRNA in those animals. So it's building that proof of concept for the knockdown, and we're moving forward now and evaluating the novel capsids for non-human primates and humans with the payloads in question.

We're looking forward to sharing more of that in the future.

Patrick Trucchio (Managing Director)

Great. Thanks so much.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Phil Nadeau of TD Cowen. Your line is now open.

Phil Nadeau (Managing Director and Senior Biotechnology Research Analyst)

Good afternoon. Congrats on the progress, and thanks for taking our questions. First couple on VY-TAU01. Have you disclosed what doses you are going to be exploring in this single ascending dose trial? And can you talk a little bit how you're going to use the pharmacokinetic data that you gather to determine what doses should be explored in the MAD trial? How will you, I guess, extrapolate from the single dose to the multiple doses, and particularly for peripheral versus maybe crossing the blood-brain barrier? Thanks.

Toby Ferguson (Chief Medical Officer)

Thanks for the call. This is Toby. We haven't disclosed our doses, but broadly speaking, we've examined our candidates in our preclinical model of tau spread where we've shown that we see reduction by about 70% of the spread of pathologic tau in our mouse models. In addition, we've done preclinical work in primates. I think, fundamentally, this is a single ascending dose study in about 48 patients over multiple cohorts. We expect, based on that data, to get both, of course, safety information as well as PK information peripherally that we think we can appropriately translate into doses for the MAD in mid-2025. Broadly, we want to aim to estimate sort of the underlying exposures needed to get appropriate exposure in the brain to treat the disease.

Al Sandrock (CEO)

Yeah. And Phil, I may want to add that, I mean, based on our preclinical studies, including at NHPs, we don't want to anticipate any major surprises. This is likely to be very similar to other monoclonal antibodies, and therefore, the brain-to-plasma ratio will be in the 0.1%-0.5% range. And as Toby said, we know the exposures that we need to get into the brain to inhibit tau spreading in the model that we use to choose the antibody. So that'll give you some idea. And of course, we do expect that trial to inform the dose range in the upcoming multiple ascending dose trial.

Phil Nadeau (Managing Director and Senior Biotechnology Research Analyst)

That's really helpful. And then second, on the frataxin candidate, would you be able to disclose anything new about the candidate that was chosen? Anything notable that you'd be willing to tell us about what differentiated that candidate from the others?

Al Sandrock (CEO)

Well, so that's a Neurocrine program, and so we don't want to disclose these things. Suffice it to say that the development candidate, we had a set of criteria for the capsid as well as the capsid-plus-payload combination, both in terms of its mechanistic effects in animals as well as manufacturability. And we'll ask Neurocrine to answer your question.

Phil Nadeau (Managing Director and Senior Biotechnology Research Analyst)

Fair enough. Thanks for taking our questions. Congrats again on the progress.

Al Sandrock (CEO)

Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Ry Forseth of Guggenheim Securities. Your line is now open.

Ry Forseth (VP)

Hi. This is Ry from Debjit's team at Guggenheim. From the ASGCT data, now with Gen 3 technology maturing where you're able to navigate pre-existing neutralizing antibodies, how are you framing the market opportunity expansion given the preclinical profile you're seeing to date?

Al Sandrock (CEO)

I'll start, and maybe Toby or Todd can add. But yes, so you noticed at one of our posters that we are looking, we're leveraging TRACER to see whether we can make modifications to capsids that affect immunogenicity. And by that, what we're doing is we're looking to see whether pre-existing antibodies in humans can bind to the capsids, actually, and therefore affect how they perform in the clinic. And so obviously, if we can find novel capsids that can evade, if you will, the pre-existing antibodies, more patients would be available for treatment. In addition, I would note that we and others are going to be evaluating ways in which we can lower pre-existing antibody levels. And as you know, several other companies are investigating the use of various enzymes that can degrade pre-existing antibodies.

So that would be another way to achieve essentially the same thing, which is to try to get more patients to be eligible for our treatments. Toby?

Toby Ferguson (Chief Medical Officer)

I would agree with Al. I think the only point I would make in addition is that this may be particularly important in adult populations. There may be select pediatric populations where this is not as much of a concern. That may represent some opportunity.

Ry Forseth (VP)

Fascinating work. Thanks.

Al Sandrock (CEO)

Thanks, Ry.

Operator (participant)

Thank you. Thank you. One moment for our next question. Our next question comes from the line of David Hoang of Citigroup. Your line is now open.

David Hoang (Director and Senior Analyst)

Hi there. Congrats on the progress, and thanks for taking my question. I guess first, I just want to ask about how you think about the anti-tau antibody fitting into the treatment landscape of Alzheimer's as compared to the tau silencing gene therapy that you also have. What could be the advantages versus maybe disadvantages of each of those modalities? And then maybe just a second question. Have you interrogated, or to what extent have you interrogated other transporters besides ALPL for crossing the blood-brain barrier? And if you've done that work, how did ALPL compare to other potential transporters? Thanks.

Al Sandrock (CEO)

So I'll start on the first question, and then Toby, I'll ask Toby to help with that one. And then Todd, maybe you can answer the second question. So anti-tau versus tau silencing. So very different approaches. Anti-tau, we expect to bind to extracellular forms of tau. And as Todd said earlier, what we're trying to do is to block the spread of pathological tau, which we demonstrated quite nicely in an animal model where we inject human pathological tau into the animals and look at spread. The tau knockdown is a very different, so that's an antibody that will need to be given on a regular basis, probably on the order of every month or so, every four weeks, we anticipate. The tau knockdown is a gene silencing that will be done by gene therapy. So that will be a once-and-done, essentially.

It decreases the expression of all forms of tau. It's akin to others have used an antisense approach to decrease the expression of tau. It's a different mechanism of action. We'll have to see the first thing is which one works the best. Then we'll see whether or not it can be done once-and-done or whether it'll need to be regular infusions. Toby?

Toby Ferguson (Chief Medical Officer)

Thank you, Al. I think what I would add is in concert, we fundamentally, at this point, don't have enough clinical data to understand the potential completeness of treatments with either any of these modalities. I think first and foremost, the most important point is determining which ones work. And we're excited to have two opportunities to test tau for our programs, both the antibody program and the knockdown program. I do think moving forward, we'll need to look and try to understand the combination as well. And that is a potential to be investigated in the future.

Al Sandrock (CEO)

Todd, you want to take the second question?

Todd Carter (Chief Scientific Officer)

Sure. The second question, just to recap, would be the evaluation of ALPL in the context of other potential shuttles or shuttle targets for BBB delivery. So we absolutely would need to evaluate ALPL in the context of other receptors such as transferrin, and there are a few others. While we're not in a position to share any data today, you can imagine that anything we would choose to move forward would need to perform at least as well as the existing BBB transporters. And so that would be part of our assessment and our evaluation. And looking forward to, hopefully, in the future, being able to share more about our work in that area.

Al Sandrock (CEO)

And then Todd, I think maybe David was also asking whether we have other receptors as well and how we're looking at those, perhaps, and comparing them to ALPL.

Todd Carter (Chief Scientific Officer)

So we have identified some other receptors. We have multiple capsid families that target different receptors. So in terms of our novel receptor discovery, we have identified a few, and we are in the process of evaluating all of them for non-viral delivery.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Jay Olson of Oppenheimer & Co.. Your line is now open.

Matthew Chung (Biotechnology Equity Research Associate)

Oh, hi. This is Chung on the line for Jay. Thanks for taking the question, and congrats on the progress. Maybe a two-part question on the ALPL target you've disclosed. Just first, I'm just wondering if you can talk about the expression variability of ALPL in humans and maybe whether the expression may change over time with aging or with some underlying diseases. And secondly, for the development of other therapeutic modality or delivery modality using ALPL, are you planning to do that internally or through collaborations? Thank you.

Al Sandrock (CEO)

Todd will answer the first question. I'll answer the second one.

Todd Carter (Chief Scientific Officer)

All right. So on the first question, differences or changes of ALPL expression. So we can look at different genetic variation of ALPL, and we're in the process of doing that. In terms of the expression level, we know that ALPL is expressed at a quite robust level starting at birth from the databases and also from internal work in preclinical models. That expression goes up a bit with age. So if anything, we might expect even better delivery in older populations. But all the evidence to date suggests that the level of expression in the vasculature is quite robust even starting at a very early age.

Al Sandrock (CEO)

Yeah. In terms of the second question, we do expect to be doing a lot of the work internally, and we have already started to do that. But we're always looking for collaborations that can enhance that discovery and development effort. Stay tuned.

Matthew Chung (Biotechnology Equity Research Associate)

Yes. Thank you so much.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Sumant Kulkarni of Canaccord Genuity. Your line is now open.

Sumant Kulkarni (Biotechnology Senior Analyst)

Good afternoon. Nice to see all the progress, and thanks for taking our questions. I guess these are welcome questions for Dr. Toby Ferguson. So on your SOD1 ALS program, given the limited patient population and because tofersen is on the market already, do you expect to involve tofersen in preclinical work, and how do you expect eventual trial recruitment to play out for Voyager's SOD1 ALS program?

Toby Ferguson (Chief Medical Officer)

Thanks for the question. So fundamentally, I think first, I'd reiterate. Tofersen, obviously, is approved, and I think it's approved on the basis of a biomarker, particularly neurofilament. And it is indeed a disease-modifying therapy for ALS administered once intrathecally. I think what I point to in our programs.

Al Sandrock (CEO)

Once a month.

Toby Ferguson (Chief Medical Officer)

Excuse me. Once a month. Correct.

Al Sandrock (CEO)

Yeah.

Toby Ferguson (Chief Medical Officer)

What I point to in our programs is that we did discuss recently at ASGCT, really, the transduction data. I think I'll highlight that to start. In motor neurons, we saw 80%-93% transduction and up to 68% in cortex when we looked at second-gen VCAP capsids. So that's really quite important. And that was administered with an intravenously administered dose. In the context of our VY9323 program, we saw a 73% reduction of SOD1 mRNA and 82% in motor neurons in the cord. So I think fundamentally, we'll take some lessons learned from tofersen, particularly around the biomarkers. We'll apply these to our clinical development program. We think this provides an opportunity to understand not only the potential proof of concept in people with SOD1 ALS but also the potential importance for our TRACER platform as a whole.

Al Sandrock (CEO)

Sumant, maybe I'll add that if we look forward to the potential approval of our SOD1 gene therapy, I'll note that in the case of SMA, Spinraza was approved a couple of years prior to Zolgensma. The two are used sort of in some ways concurrently in the real world. For example, we're aware that many patients can get treated with Zolgensma right after birth, and then if necessary, they add Spinraza. Taking a gene therapy doesn't preclude continued treatment with tofersen when necessary. I think if we take a page from the SMA story, we could see both products, tofersen, as well as hopefully our SOD1 gene therapy, being used together, essentially, by physicians to treat their patients optimally.

Sumant Kulkarni (Biotechnology Senior Analyst)

Got it. And as a quick follow-up, what percentage reduction on NfL is considered clinically relevant in the SOD1 ALS context? We've seen the data that Biogen had, but what would be considered clinically relevant, I guess, for what's out there already and for a gene therapy?

Toby Ferguson (Chief Medical Officer)

So I think we've all seen the reductions that Biogen has highlighted with neurofilament reductions. I think fundamentally, what a clinically relevant reduction is not clear. But I guess the points I would highlight is it has to be substantially greater than the variability of your assay and biologic variability and that the tofersen data does inform the magnitude of reduction needed.

Sumant Kulkarni (Biotechnology Senior Analyst)

Thank you.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Yanan Zhu of Wells Fargo Securities. Your line is now open.

Yanan Zhu (Senior Analyst of Biotechnology Equity Research)

Great. Thanks for taking our questions, and congrats on the progress. So first, I was wondering about the ALPL receptor. Is there expression of this receptor on any other tissue, and how does that potentially impact or not impact a brain delivery drug in terms of delivery into other tissues? Thanks.

Todd Carter (Chief Scientific Officer)

Sure. This is Todd. I can take that question. So thank you for it. So the ALPL is expressed across the vasculature in the entire body and in some other cell types. However, what we think is going on is that AAV capsids, AAV gene therapies, do not need to harness these other mechanisms to get into other tissues. But the blood-brain barrier is blocking for most conventional capsids, or all conventional capsids, to get into the brain. So the harnessing of ALPL to cross the blood-brain barrier is really only important to get into the brain. What we also see is that the use of ALPL is giving us some significant cross-species activity. So it provides us not only with in vitro evidence of cross-species activity in transcytosis assays but also in vivo cross-species activity, which we see in multiple species.

So we have examples of four species: African green monkeys, cynomolgus macaques, marmosets, and mice. And ultimately, what we're able to see is that at relatively low doses, we're able to achieve these kinds of high delivery and transduction that Toby mentioned: 80% of motor neurons in the spinal cord, 95% in Purkinje neurons, 98% of dopaminergic neurons in the substantia nigra. And then finally, I'll just comment that with regard to the tissue and cell delivery, what we're seeing is a significant detargeting from the liver. That's probably not specifically driven by ALPL. Our hypothesis is that's based on other characteristics of the capsid. But we see a quite substantial detargeting from the liver with the simultaneous increase in delivery into the CNS.

Yanan Zhu (Senior Analyst of Biotechnology Equity Research)

Great. That's very nice to hear. And also at ASGCT, there are quite a few presentations on BBB penetrating capsid work from different industry players. And some of them also begin to touch upon receptors. I think you might have started a trend. Just wondering, after taking a survey of the landscape, how do you feel of your BBB capsid and where it stands in the landscape? Thanks.

Al Sandrock (CEO)

Maybe I'll start, and Todd will complete the answer. But so listen, it's great to see that a lot of people are finding what we found years ago and that yeah, I mean, I think what we're seeing is that I think the world appreciates the need for new capsids that cross the blood-brain barrier so as to improve delivery. And look, the competition is heating up. I would say that we're very proud of our capsids. As Todd said, we get the key cells that are relevant for the diseases of interest. We get 80%-90%, as Todd just mentioned, of cells transduced at relatively low doses of 3x10^13 VGs per kg. And we have demonstrated in vivo multiple cross-species experiments have been done with 3 different non-human primate species as well as mice. Knowing the receptor is also very helpful.

And then look, we have already selected three development candidates, two with our partners at Neurocrine and one is wholly owned. We expect to be in the clinic soon. So Todd?

Todd Carter (Chief Scientific Officer)

I think you've captured everything that I was going to say, Al. And I do think the important point, in addition to the cross-species activity, is over the past quarter or so, those three candidates that we're moving into the clinics. We think the next step is really the clinic.

Yanan Zhu (Senior Analyst of Biotechnology Equity Research)

Got it. Yep. Yep. Got it. Thank you. Very helpful.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Laura Chico of Wedbush. Your line is now open.

Laura Chico (Managing Director)

Good afternoon, and thanks very much for taking the questions. Just one housekeeping question. I believe there was one milestone payment that was triggered in the second quarter. But curious if you could just kind of elaborate or if you've disclosed any additional milestones that we should be watching out for over the remainder of 2024. And then I have a quick follow-up for you.

Robin Swartz (COO and Principal Financial Officer)

Hi. This is Robin. Thank you for the question. So we were very pleased with the advancement of our Neurocrine programs and the achievement of the DC milestone. However, we don't provide guidance on potential future milestone payments across the 13 partner programs. It is also important to note that further milestone payments are not included in our cash guidance, which is into 2027.

Laura Chico (Managing Director)

Okay. Thank you very much. And then in terms of follow-up, obviously, there's a lot of discussion on the ALPL receptor data from ASGCT. But I'm wondering if you can just talk, perhaps to Al, strategically, what would happen in terms of the direction of focus for Voyager with the VY-TAU01 data? If that reads out positively in the patients, what does that mean strategically in terms of the focus? Obviously, that's as an antibody right now. But how does that shift or change the focus on other TRACER programs, assuming success there?

Al Sandrock (CEO)

Well, Laura, thanks for the question. I think what you're implying is that we would have a choice of whether we proceed with the VY-TAU01 program as an intravenous antibody or whether we could vectorize the antibody. We actually do have that option. We may actually do both, in fact. I've always been thinking, though, that strategically, it wouldn't make sense for a Voyager, a small company like us, to try to go into phase III or commercialize in Alzheimer's disease. It's too large, too expensive. So we've always thought we will likely get a partner if the VY-TAU01 program is positive. But I do think that the option to potentially vectorize a once-and-done antibody could be of high interest to us. And we'll make that decision when the time comes.

Laura Chico (Managing Director)

Thanks very much.

Operator (participant)

Thank you. One moment for our next question. Our next question comes from the line of Joon Lee of Truist Securities. Your line is now open.

Mehdi Goudarzi (Biotech Equity Research Analyst)

Hi. Following Laura's question, last week in ASGCT, Regeneron suggested in some of the presentation that compared to cassette-inserted vectorized antibodies, the expression of, sorry, cassette-inserted antibodies, the vectorized antibodies had lower expression. Do you expect the same for your vectorized antibody platform in general and specifically for the Alzheimer's vectorized antibody? Could you share any plans that you have for a preclinical data update in this program?

Al Sandrock (CEO)

Yeah. Let me start, and then I'll ask Todd to help. So when we vectorize an antibody, we did show at a meeting, I think it was last year or two years ago, that we can vectorize an anti-amyloid antibody and get enough expression to bind to amyloid plaques in transgenic mice. And correct me if I'm wrong on that, Todd. So we can get enough expression to bind to amyloid plaques in animals. We'll have to see. My view is that a lot's going to change relative to IV. So we're going to lose the Cmaxes, if you will, the high concentrations that you get immediately after IV dosing. We expect to have more constitutive expression from within the central nervous system.

So we expect that we'll have mainly glial cells producing the antibody as we've shown in the past and that we will and so it'll be sort of an inside-out, if you will, approach rather than giving it IV and having it cross the vasculature to get into the brain. It'll be made in the brain directly. And then we would be able to look in animal models at not only binding to amyloid plaques, but we will be assessing whether or not we can lower amyloid plaques. And there's some precedents we can follow in vivo studies that have been done with the anti-amyloid antibodies. And then, of course, we'll have to see whether or not we affect any adverse events.

One concept would be that the rates of ARIA may be affected by the fact that we don't get the Cmaxes and we have constitutive expression from within the brain. We'll have to see if that's true. There are some animal models that mimic ARIA. Whether they truly are ARIA or not, well, I'm not certain. But we can even assess that. Finally, I would say that one of the things we're investigating right now is whether or not we can regulate the expression of the antibody with a small molecule. And so a regulable vectorized antibody program would, I think, be ideal. And so those are the kinds of things we're thinking about in terms of preclinical experiments that would help us get to a development candidate. Todd, did you want to add anything?

Todd Carter (Chief Scientific Officer)

I can add a little bit. So while the VY-TAU01, the focus there is on the antibody itself, not on a vectorized form, we do have substantial experience going back several years on vectorization of antibodies in general, including tau antibodies and the amyloid that Al mentioned and others. And we found that the payload can matter quite a bit, the structure of the vector payload, the vector genome, and of course, the promoter. So there are a lot of things that we can do, some of which Al mentioned, to tweak the expression level, not just on the promoter but by the kinds of cells, the specific cell types that you target as well. And so we'll be looking at all of those characteristics when we move any vectorized form of a gene therapy-based antibody forward.

Al Sandrock (CEO)

I would just add that in the real world, being able to give it a vectorized anti-amyloid once IV and not have to give it every other week or every month could really relieve the strain on the healthcare system that I think we're witnessing now with antibody treatments for Alzheimer's disease.

Mehdi Goudarzi (Biotech Equity Research Analyst)

Very helpful. If I can sneak in one last question. Between now and second half of 2026 that you hopefully present PET imaging data for VY-TAU01, how we should think about cadence of any interim data release related to your findings along the way.

Al Sandrock (CEO)

Toby?

Toby Ferguson (Chief Medical Officer)

I think what we've highlighted for the SAD program, it will inform the MAD program. I think really the key data readout in that timeframe really is the MAD data in the latter half of 2026.

Mehdi Goudarzi (Biotech Equity Research Analyst)

Yep. Thank you very much.

Operator (participant)

Thank you. I'm showing no further questions at this time. I'll now like to turn it back to Al Sandrock for closing remarks.

Al Sandrock (CEO)

Thank you, everyone, for joining us today. Feel free to follow up directly with any questions. Thanks again. Bye.

Operator (participant)

Ladies and gentlemen, this concludes today's presentation. Thank you once again for your participation. You may now disconnect.