Voyager Therapeutics, Inc.

Q4 2022 Earnings Conference Call


spk02: Good morning and welcome to Voyager Therapeutics' 2022 Fourth Quarter and ERA Conference Call. All participants are now in listen-only mode. There will be a question and answer session at the end of this call. Please be advised this call is being recorded at the company's request. A replay of today's call will be available on the investor section of the company's website approximately two hours after completion of this call. I would now like to turn the call over to Pete Frenshue, Chief Financial Officer.
spk10: Thank you and good morning.
spk09: Joining me on today's call are Dr. Al Stanrock, our CEO, Dr. Todd Carter, our Chief Scientific Officer, and Alan Nunley, our Chief Business Officer. We issued our Q4 and year-end 2022 press release this morning. The press release and 10-K are available on our website. We plan to provide a brief summary of key highlights from the quarter and reserve the majority of time for your Q&A. In a moment, I will turn the call over to Al. Before I do this, I want to remind everyone that during this call, Voyager representatives may make forward-looking statements regarding future expectations, plans, and prospects. All forward-looking statements are inherently uncertain and are subject to risks and uncertainties that may cause actual results to differ materially from those indicated by these forward-looking statements. You are encouraged to review and understand the number of the material risks and uncertainties facing the company as described in the company's annual report on Form 10-K filed with the SEC this morning. All SEC filings are available on the company's website. Now it is my pleasure to turn the call over to Al.
spk11: Thank you, Pete, and good morning, everyone. I'd like to start by acknowledging the transformation Voyager has undergone in 2022. Since I became CEO last March, we have advanced a pipeline focused on some of the most significant unmet needs in neurology, achieved breakthrough innovations in novel capsid discovery, including the identification of a receptor for one class of capsids, and entered multiple high-value collaborations. Thanks to this progress, during a time when markets have been very difficult for much of the sector, we have created value for shareholders and we have made important steps toward creating value for patients. I believe we will continue to do so as we focus on the three pillars of our investment rationale. Our first pillar of value is our tracer capsid discovery platform. The Voyager team evaluated multiple libraries each with more than 20 million variants of AAV5 and AAV9 capsids to select those capsids that display increased transduction in the central nervous system following intravenous delivery. In preclinical studies, we have demonstrated more than 100-fold higher transgene expression in the brain compared to conventional AAV9 capsids. We have shown high levels of CNS expression at low doses, And we have demonstrated the ability to target specific cells, such as neurons or glial cells, while detargeting the liver and dorsal root ganglion cells. This is why I came to Voyager. Our scientists never cease to impress me with their innovation. Last year, they identified the receptor for one of our capsid families. And I'm looking forward to seeing what they've accomplished this year. I'm not the only one impressed by Voyager's innovation. The data we have generated have allowed us to secure partnerships with gene therapy leaders like Pfizer and Novartis and with neurology leaders like Neurocrin. Our second pillar of value, which our recent transaction with Neurocrin brought into the spotlight, is our CNS pipeline. This is the result of combining Voyager's novel tracer capsid platform with our deep knowledge of neuropharmacology and payload. We select diseases with high unmet need where the target is well validated by human genetics and human biology, and where biomarkers may enable a path to quickly and efficiently achieve proof of biology. We then design a payload, and our diverse payload capabilities allow us to access a wide variety of targets. We can use gene replacement to address loss of function mutations, vectorized siRNAs, to address toxic gain-of-function mutations, and vectorized antibodies to address extracellular or cell-surface CNS targets. As I mentioned, the value of our pipeline was recently illustrated through our strategic collaboration with Neurocrine Biosciences. This provided $175 million upfront and up to $4.2 billion in potential milestones for rights to our GBA1 gene therapy program for Parkinson's disease and three additional gene therapy programs directed to rare CNS targets. And this leads me to our third pillar of value, partnerships. We have a sound balance sheet enabled by our track record of generating non-dilutive collaboration revenue. Alan and Pete will expand more on that in a minute. I will just note that Voyager is open to a wide variety of collaboration structures to enable neurogenetic medicine. We've executed strategic collaborations around our pipeline programs, such as with NeuroPrint. We've completed CAPTED option and license agreements, such as with Pfizer and Novartis. And we are interested in and evaluating creative deal structures, such as opportunities to combine our CAPTED and receptor technology with cutting edge payloads and biologics. It is important to note that we are advancing and we intend to continue to advance wholly-owned programs. The non-diluted financing from our partnerships is a key enabler of our wholly-owned programs. Now, I will turn the call over to Alan to review the recent Novartis transaction.
spk12: Thank you, Al. Please turn to slide four. As Al said, Voyager is open to a variety of collaboration structures. Earlier this year, we announced a strategic collaboration with Nurocrin to advance our GBA1 gene therapy program, as well as three new gene therapy programs directed to rare CNS targets. We received $175 million up front and are eligible for up to $1.5 billion in potential development milestones and up to $2.7 billion in potential commercial milestones, tiered royalties on net sales, program funding, and an option to elect 50-50 cost and profit sharing in the U.S. for the GBA I program following the Phase I readout. This type of cost and risk sharing structure provides transformational value for Voyager, and it is one of a variety of structures we have executed. We have also entered CAPSID option and license agreements with Pfizer and Novartis. Last year, Pfizer exercised its option to a CAPSID against the CNS target And earlier this month, Novartis exercised its options to capsids against two neurologic disease targets. As a reminder, Voyager received $54 million upfront from Novartis when this option agreement was signed in March 2022. For the last year, Novartis has been evaluating our capsids. Their decision to license capsids for two CNS targets triggers $25 million in option exercise fees and Voyager is eligible to receive up to $600 million in associated development, regulatory, and commercial milestone payments, as well as mid- to high-single-digit tiered royalties based on the net sales of Novartis products incorporating the license capsid. Novartis also retains the right over the next 18 months to expand the scope of options to evaluate and license capsids for up to two additional CNS targets, subject to their availability for $18 million per target and a $12.5 million fee per target upon exercise of the option to license the capsid, as well as milestones and royalties. It's important to note here that we at Voyager view Novartis as one of the current leaders in the gene therapy field. Their decision to license our novel intravenous AAV capsids to enable gene therapies for CNS diseases is very exciting. We look forward to continuing this relationship. Now I will turn it over to Pete to review our balance sheet.
spk09: Thank you, Alan. Please turn to slide five. Voyager is committed to maintaining a strong balance sheet that supports advancement of its platform and pipeline. As of December 31, 2022, we reported cash, cash equivalents, and marketable securities of $118.8 million. As Alan described, earlier this year we received $175 million from Neurocrine, and we will now receive $25 million from Novartis for the exercise of the options. On a pro forma basis, when you factor in Neurocrine and Novartis payments, the company has cash, cash equivalents, and marketable securities of approximately $320 million. Voyager is committed to maintaining a strong balance sheet and financial discipline. We expect that our cash, cash equivalents, and marketable securities, together with amounts expected to be received as reimbursements for development costs under the Nurocrime collaborations, will be sufficient to meet our planned operating expenses and capital expenditure requirements into 2025. This enables the advancement of our two wholly owned programs, the anti-Tau antibody for Alzheimer's disease, and the SOD1 gene therapy for ALS into clinical trials. We expect the filing of IMDs for both programs in 2024. And Al will now expand on these and other programs in our pipeline.
spk11: Thanks, Pete. And now on slide six, you can see that Voyager has four programs advancing through late research. As Pete stated, Two of these programs are wholly owned, our humanized anti-tau antibody for Alzheimer's disease and SOD1 gene silencing program for ALS. Our anti-tau program is differentiated from others that have not demonstrated clinical efficacy in that we target the C-terminal rather than the N-terminal region. Moreover, our antibody blocks the spread of pathological tau in animal models, whereas the N-terminal antibodies don't. We believe that both of these distinguishing features may prove to be very important as we attempt to block the spread of pathological tau in patients with Alzheimer's disease. In January, we selected a humanized development candidate to advance into IND-enabling studies. Data that led to the selection of this candidate will be presented at the ADPD conference in Sweden later this month. Voyager expects to initiate a GLP toxicology study this year in order to enable a potential IND filing in the first half of 2024. Our SOD1 ALS program combines a potent siRNA construct with a CNS-trophic blood-brain barrier penetrant novel tracer-derived capsid. Proof of concept for the therapeutic hypothesis has been demonstrated by Tilfersen, an investigational drug sponsored by Biogen and Ionis, as shown in a September 2022 New England Journal of Medicine publication. Tilfersen is currently under review by FDA, and if approved, could blaze a trail that we could then follow with a gene therapy solution. We are continuing to conduct non-human primate studies to select our lead candidates. which we expect will occur in the first half of this year, and we continue to expect to file an IND in 2024 for this program as well. Our other two preclinical programs, the GBA1 gene therapy for Parkinson's disease and other GBA1-mediated diseases, and the frataxin gene therapy program for Friedreich's ataxia, are being advanced in collaboration with NeuroCrit. NeuroPrint is fully funding both of these programs through phase one, at which point Voyager has an option to co-develop and co-commercialize the assets in the United States. We also continue to advance multiple early research initiatives, including a vectorized antibody for brain metastases associated with HER2-positive breast cancer, and a vectorized siRNA approach to enable specific knockdown of mutant Huntington and MSH3 in Huntington's disease. Today, I'm also excited to introduce a new gene therapy program for Alzheimer's disease. Slide seven shows the rationale for our new research effort in Alzheimer's disease, which builds upon our TAU expertise. This new program targets intracellular TAU with a vectorized siRNA gene silencing approach. We know that tau pathology closely correlates with Alzheimer's disease progression and cognitive decline. An siRNA gene therapy approach could enable us to knock down tau within neurons. This could be efficacious by itself and also has the potential to complement extracellular approaches such as our anti-tau antibody effort. The unmet need in Alzheimer's disease is enormous. And while we're extremely encouraged by the recent advances with anti-amyloid antibodies, we believe that combination therapies may improve outcomes, much as they have in oncology. This could mean combining anti-amyloid and anti-Tau approaches or combining extracellular and intracellular Tau approaches. We are currently evaluating an siRNA Tau gene silencing payload with our intravenous brain penetrant novel capsules. Turning to slide eight, in summary, Voyager has demonstrated our ability to execute and create value through 2022 and into 2023. In addition to advancing our pipeline, we entered into multiple important collaborations and significantly strengthened our balance sheet. Looking towards 2023, We continue our work to break through the barriers constraining the fields of gene therapy and neurology. We intend to identify a lead candidate for our SOD1 ALS program, and we will advance our GBA1 and protaxin programs collaboratively with Neurocrin. We will continue to share the exciting data we are generating at scientific conferences, including at the ADPD conference later this month. And finally, we continue to engage in active discussions with potential partners around our platform and pipeline. I want to take a moment to thank everyone on the Voyager team for their incredible work in 2022. Together, I look forward to continuing to build Voyager in the next year, and we are off to a great start. With that, we are happy to take any questions you may have. Operator?
spk02: Thank you, ladies and gentlemen. If you have a question or a comment at this time, please press star 1-1 on your telephone. If your question has been answered, you wish to move yourself from the queue, please press star 1-1 again. One moment for our first question. Our first question comes from Jack Allen with Baird. Your line is open.
spk05: Great. Thank you so much, and congratulations to the team on all the progress made over the course of the quarter. I guess to start, I was hoping we could talk broadly about the tracer capsids and their move towards the clinic. I know that you have your ALSOD1 program that's wholly owned and you're guiding towards an IND in the first half of 2023. But do you expect that to be the first tracer-castin to move towards an IND, or could it be a partnered program that progresses as well on a similar timeline or maybe even a more rapid timeline? How should we think about those gene therapy assets moving into the clinic? And then I have a few follow-ups as well, if I may.
spk11: Hi, Jack. This is Al Sandrock. So actually, our IND for SOD1-ALS is planned for 2024. And it may very well be the very first capsid in the clinic from tracer platform. But it's hard to know because, you know, we have these multiple partner programs. And of course, the timelines for these partner programs are in their hands. And so it'll be neck and neck likely. So, but I think that roughly in the 2024-2025 timeframe is when a lot of these IMDs will come into play. Todd, do you have anything to add to that?
spk07: Sounds right, Al.
spk11: Thank you.
spk05: Great. And then, if I may, just a few brief follow-up programs. There's been a lot of headlines around the procurement of non-human primates, particularly the supply coming out of Cambodia. And I think Charles River Labs is, you know, slowing their imports. I wonder if you had any comments on your ability to get your hands on these non-human primates and what kind of confidence you have on your preclinical timelines moving forward. And then maybe outside of that question, I wanted to touch on just the Pfizer and Novartis relationships. It's really great to see the two major leaders in gene therapy opt into some programs, but they also decided to not opt into some other programs. And I was wondering if... those rights to those targets revert back to you, and if there's any work that you could leverage on those targets to wrap the advanced assets towards the clinic.
spk11: Thanks, Jack. This is Al again. I'll answer the non-human primate question, and I'll have Alan Nunnally answer the Pfizer Novartis question. But, yeah, no, it's a real serious problem. You know, every company that I know of in this industry relies on non-human primates. for one thing or another. And of course our tracer platform begins in the non-human primates. And so it's a serious problem. I'm not aware as of today of any delay in our programs, but you know, I'm keeping my fingers crossed because anything can happen. And so I hope this gets resolved because there are a lot of patients waiting for drugs. And this is a, Pretty bad news for the whole industry, I think.
spk07: Todd? Yeah, I'll just add that we do use multiple vendors to try to reduce that risk, but it's a risk we're looking at very closely.
spk12: Alan, you want to? Sure. Jack, this is Alan. Thanks for the question on Pfizer and Novartis. So in each of those relationships, there was one target for Pfizer and one target for Novartis that they did not exercise an option to attach it. So the rights with respect to our capsids for those targets do revert to Voyager. But because the programs are being prosecuted entirely on the partner side, Pfizer and Novartis, we don't have information about the program or any rights in the programs. So we just simply have back the rights to do those targets ourselves or to partner on those targets with our tracer capsids with other parties.
spk05: Great. Thank you so much for the multiple questions, and congratulations again on the progress.
spk10: One moment for our next question. Our next question comes from June Lee with Truist. Your line is open.
spk04: Hi. Congrats on the progress, and thanks for taking our questions. I have a question on the target receptor you identified. Is the receptor X sufficient for AAV delivery, or is there a co-receptor or co-ligand that is necessary to complete the process of AAV delivery? And also, with the identification of this receptor X, are you considering, you know, delivery modalities other than AAV, such as coding the LNP or fusing it to ASO or SRNA? And I have a follow-up question. Thank you.
spk07: Yeah, hi. This is Todd. Thank you for the questions. On receptor X and the question of a co-ligand, we have not identified a co-ligand. We know and have shown that the receptor is sufficient to increase transduction in vitro settings. So the increased expression of it alone can result in dramatically increased uptake and transduction. And we have ongoing experiments to further elucidate that in a vivo setting. With regard to the question about delivery of other things, it's something we're actively exploring, delivery of other modalities. And we have some early exploratory work right now that's ongoing.
spk04: Great. And, you know, with this, with your capsids, by how much are you able to lower the systemic dosing in humans compared to, for example, Zolgensma, which has a dosing of about 10 to the 14th?
spk07: Hi, Todd again. So that's a great question. And it depends upon the target tissue and the amount of delivery you need. So our goal is to improve the therapeutic index and deliver sufficient or hopefully even the possibility of more than sufficient to the target tissues. And you can do that in two ways. One, at a given dose, you can deliver more to, say, the brain. which results in the ability to lower the dose and result in delivering less to the liver, for example, to off-target tissues. So it's this ratio of on-target to off-target that's the question. In addition, we have shown, for example, with some of our capsids, that we can dramatically reduce the dose 10 to 50-fold and still get dramatic delivery into the CNS of non-human primates. So, both of those goals are something we've seen with our capsids. I think at a minimum, what we're looking for is to go from the E14, a level that's seen quite often with the AAV9 and related capsids, and to get into the E13 per kilogram or lower doses.
spk04: Great. And one final question for me. You know, I know it's difficult to given your potential milestones from your three collaborators. But curious if you're able to provide any cash fund-raising guidance based on the $320 million in performer cash, and if you're planning for any, you know, capital expenditures related to in-house manufacturing scale-up or et cetera in the next few years. Thank you.
spk09: Yeah, June, this is Pete. So part of our actual presentation today, I think we did provide cash flow guidance with regards to runway. We said that we were going into 2025 with regards to the balance sheet and our ability there. I do want to highlight a couple things. I think we have a really strong balance sheet. We started this year with $320 million between our Nurocrine transaction as well as the Novars transaction. Our balance sheet cash flow projections, I want to do say, They do not include the future potential milestones associated with the collaborations that are existing. So that actually can actually extend that runway further beyond those projections. With regards to our burn for 2022, our burn was actually $78 million. And overall, we were a very capital-efficient organization with regards to our expenditures and deployment of cash. our cash flow projections for 2023, although we don't provide specific guidance with regards to that, we do anticipate those projections to actually go up year on year, although that's really in the advancement of our wholly owned program. I think as we described for you guys here today. I think for the most part, you know, it is our anticipation that as we move forward over the next couple of years, that our costs will increase somewhat meaningful associated with the development of our programs, especially as we get into clinical trials. However, with that being said, one of the things that we've done really well as an organization is we've actually been able to do non-dilutive financing associated with our programs. And as you can see, over the last six months or so, we actually generated over $200 million in non-dilutive financings associated with the deals that we did. You know, it is our overall goal and game plan to continue to be able to finance the company into the future based upon additional non-dilutive deals that we can do, but also be able to mitigate kind of costs through partnerships and other types of arrangements.
spk04: Great. Thanks for taking our questions and congrats on the execution last year. Looking forward to your progress.
spk02: Sure. Thank you.
spk10: One moment for our next question. Our next question comes from Dane Leon with Raymond James.
spk02: Your line is open.
spk06: Hi, thanks for taking the questions. Could you just maybe take us more specifically through the steps of the program focused on SOD 1 this year that will help de-risk the program getting into the IND phase in the earlier part of next year? You know, said differently, what do you still need to do? experiment-wise to get to that lead drug candidate, and then what do you need to do to actually finish the talk studies required to get the IND open? Thank you.
spk11: Hi, Dane. This is Al. I'm going to turn it over to Todd in a minute. Yeah, I think that there's some key milestones here. First is nominating a development candidate. In other words, combining a transgene with one of our capsids, and we have a capsid profile that we've already developed that we think we need in order to be effective in SOD1 ALS. I think an important thing to track for us is what's going on with Tilfersen. As you know, there's going to be an FDA advisory committee this month, and the decision by FDA will come next month. That'll give us a lot of you know, insight into how to develop this drug and even how to get it approved and make it available to patients. So, and, you know, after the development candidate is identified, we'll have to start GLP talk studies. And we'll, and of course, there's going to be important interactions with FDA as we approach the IND, which we plan for next year. It's still on track for next year. Todd, do you have anything to add to that?
spk07: I think you've captured the bulk of it, Al. I mean, the next steps are the identification of the lead nomination that Al mentioned. We're still tracking to the first half of this year on that, and we're reasonably on track for our IND filing in 2024. Thank you.
spk02: One moment for our next question. Our next question comes from Yun Zong with VTIG. Your line is open.
spk01: Hi. Good morning. Thank you very much for taking the question. I noticed that none of the pipeline program is actually using the vectorized antibody approach. And given that you had reported HER2 data in the past, what kind of indication do you think a vectorized antibody approach could be suited for?
spk11: Hi, this is Al. I'll start and ask Todd to continue. But yeah, I mean, I think it's a very powerful technology that's been developed here at Voyager over the years. And it's going to be suitable for any target that is extracellular or on the cell surface of either neurons or glial cells or other kinds of cells, non-neuronal cells in the CNF. So that actually is a pretty large number of targets. And look, our lead program For tau is the antibody. It's a passive immunotherapy, as you've pointed out. But we always have the option to vectorize it later. We feel like it's the shortest path, very efficient, cost-effective, and rapid path to get proof of concept, just using it as a passive immunotherapy. After we get the proof of concept, then we have multiple options available to us. Todd?
spk07: And we see that a lot of potential value in our vectorized antibody platform, and we remain pretty excited about it. Our VHER2 program, we're still interested and excited about that. It's at an earlier stage, much like our HD program. We're hopeful that the data will continue to be generated and result in advancement of that program. And we're always interested in other approaches with the vectorized antibody platform as well.
spk01: Okay, so my next question is on the collaboration with Neurocrine. I believe the FA program and also some additional gene therapy programs were part of an older collaboration with Neurocrine. So is it reasonable to assume that now they are also going to be based on tracer technology platform?
spk11: Yeah, this is Al Sandrock again. The original Neurocrine deal was signed before the availability of the tracer capsids. But it's fair to say that we are, both companies are now very interested in moving forward for Friedreich's and those other two programs that you mentioned with the novel capsids.
spk02: Okay, great. Thank you very much. One moment before our next question. Our next question comes from Laura Chico with Wedbush. Your line is open.
spk00: Hey, good morning, guys. Thanks very much for taking the question. I guess I have one related to neurocon collaboration as well. Wondering specifically for the Parkinson's, the GBA1 program, if you could speak a little bit more to kind of the thought process leading to kind of exercising the co-development, co-commercialization option. Obviously, still early days here, but just wondering if you could maybe discuss that a little further in terms of What would incentivize you or make this a promising deal to opt in to continue there? And then second, there's been a recent approval in the Friedreich's ataxia space. Just wondering how that might change or influence kind of the path forward here. Thanks very much.
spk11: Hi, Laura. This is Al Sandrock again. Yeah, so, you know, for very common diseases like Parkinson's disease and Alzheimer's disease, It's hard to imagine that Voyager would be able to go all the way to late stage clinical trials, which tend to be rather large, or to commercialization. So it was never a question of whether we would partner those. It was always a question of when. And, you know, our colleagues at Norquin was very excited about the program. I should say that it was a very competitive process. A lot of people are excited, were excited about GBA1PD because it makes so much sense, I think. It's a highly validated target. And so we decided to do the deal, and it provided non-dilutive revenue for us to pursue other programs, and we just outlined one new one this morning. In terms of opt-in, it's after phase one, and we don't know what the phase one trial design is yet. It's up to Nuroquin to tell us, but it's very possible that after phase one, we'll see whether or not The gene therapy produces the enzyme, which we should be able to measure in the spinal fluid, and whether or not it reduces the substrates that build up abnormally in the spinal fluid in GBA1 carriers with Parkinson's disease. So that, so after proof of biology, perhaps, but again, it depends on what the phase one trial design is, and we have, we don't know what that is yet, but that's a possibility, what I just outlined. In terms of the approval of the drug by Riata, the NRF2 activator, I think it's very, very exciting. This is a disease that had no treatments until last week, and it's a terrible disease. And, you know, I don't, I think it's very encouraging for the whole field. It's, and so, Friedreich's ataxia is a, I think, you know, what happens typically is that after the first approval, Other companies get involved, and it just lifts all boats. And so, I think it's only good news for us.
spk12: Thank you very much. This is Alan. One thing just to add on the options for cross-profit share. It's a good way for preserving optionality for Voyager. As Al said, we'll get to take a look at the data from that phase one trial. see how we're situated, and we'll have an attractive option between the U.S. 50-50 cost-profit share and really healthy milestone and royalty track. So, we're happy to be able to preserve that optionality after the phase one.
spk07: Thank you. Any other comment on the CFA? In addition to what Al said, the mechanisms by which the RIADA drug, omogaloxalone, works are different from our gene therapy approach. And so,
spk11: exclusive at all so we're quite excited about that yeah and and i should have had that you know it gives us a an idea of of what the phase three trial needs to be we now know what the outcome measure uh uh should be for a regulatory approval we see what happens to you know we see the change in that outcome measure over the course of time so we can now better power our studies I mean, it's just a huge, hugely positive event, I believe, for patients with retinitis A taxia.
spk10: Thanks very much.
spk02: One moment for our next question. Our next question comes from Sumat Kilkarni with Candiacorp. Your line is open.
spk08: Hi. Congrats on the quarter. This is actually Ross asking questions on behalf of Sumat. Actually, I have two questions. In regards to receptor X that you've identified, Given that you've been developing these novel capsids for some time now, what are your latest thoughts on the level of receptor expression and variability across primates and mice? And what's your confidence level on how that might translate to humans?
spk07: Hi, this is Todd. So, we know that receptor X is expressed in the right cells and in the right places in all of the species and mice and non-human primates and in humans. We know that the capsids bind the orthologs for all those species, and that the orthologs, the protein versions from each of those species enhance transduction in our in vitro studies. And so we think that the translation to the humans is greatly de-risked, and there's a greater chance of success because of all of this data.
spk08: Okay. And then kind of a quick follow-up is, is there any potential for these capsids to efflux out of the brain? If so, how might this concern be mitigated if this is kind of an area of concern?
spk11: Well, you know, we do check all the other organs when we, the tracer platform allows us to actually look at messenger RNA, the expression of these capsids in multiple organs simultaneously. And what we find is actually, if anything, decreased transduction in places like the liver. So many of our novel capsids, which are, you know, potently get into the CNS, they tend to detarget the liver, for example. Have we looked at every single organ? No, not yet. So far, it doesn't look like there's significant efflux, at least to the point where we get transduction of organs in the periphery. Todd, do you want to add anything?
spk07: Sure. There's opportunities in both directions to your question, actually. And one is if we want to deliver to the CNS, which has been our focus, looking for those capsids that deliver better to the CNS, and less well to the off-target tissues. And the novel capsid discovery team does a process that involves iteration. So there are initial screens, and then there are secondary maturation screens. And what we found is we can identify capsids with increased delivery to the CNS. And then through the maturation process, we can identify variants that have similar or increased delivery to the CNS and then altered delivery to other tissues. And so we can identify a panel of capsid variants and then select those that match our capsid profile for a given disease. And that capsid profile that Al mentioned earlier is something that we do build for each of the diseases, and that includes the tissues we want to target and the tissues that we want to avoid for potential off-target risk. On another opportunity side is that we have the potential to deploy tracer in other tissues as well. And so if we're able to identify capsids that target muscle or other tissues, those present opportunities for licensing with others as well. So that there's a lot of opportunity in the tracer platform.
spk02: Thank you. One moment for our next question. Our next question comes from Yanlin Zhu with Wells Fargo. Your line is open.
spk03: Hi. Thanks for taking the questions and congrats on the quarter. So first the question, on salt 1 als gene therapy development path given the upcoming topherson adcom and padufa i'm wondering if you could comment on the validity of neurofilament light chain as a surrogate marker for efficacy and if it turns out that fda accepts this surrogate marker do you think that would uh be the same path for a gene therapy program as well? Thank you.
spk11: That's a great question. It's something I think we're all tracking. I do believe myself that neurofilament can be relied upon as a surrogate marker of efficacy, but I'm not a regulator. And whether FDA decides that it's a valid surrogate endpoint for approval, we'll find out very soon. Nevertheless, I think we can still use it as a way to decrease risk. And we can use it even in the earliest clinical trials to track whether or not our gene therapy is affecting at least a nerve fiber integrity as measured by neurofilament release. So I think it's a very useful surrogate marker of efficacy, regardless of what the FDA decision is. The FDA decision, if they do use it or consider it a valid endpoint for approval, that just makes the approval pathway even shorter on behalf of patients. But, you know, in addition to NFL, Biogen has, and IONIS have published in a New England journal that you can look at soluble SOD1 levels itself in the spinal fluid as sort of a target engagement biomarker. And we could do the same thing as well. We should be reducing the expression of SOD1 as spinal fluid. So both of these measures are very useful to help us understand whether our gene therapy is on the right track. And we plan to use all of it.
spk03: Got it. And another question on the collaborating, the partnership programs, the licensing with regard to tracer. To what extent Pfizer and Novartis have studied the tracer catheter in conjunction with their target? Have they conducted any animal studies, for example? And then on Novartis, for the two additional targets that they may decide to pursue with some significant fees, is there a timeline when they might have to make the decision to go with the option with $18 million per target payment.
spk12: Yeah, so maybe this is Alan. I'll take the second piece first. So the ability for Novartis to expand to two additional targets, they have 18 months to decide whether they'd like to do that. to choose either to add one or two targets under the agreement. If they do, it would track the same terms as the original agreement, which is $18 million per target if they add a target, and then the same $12.5 million per exercise with the $300 million in potential milestones downstream to high single-digit royalties. So they have 18 months to make that decision. And I'm sorry, now I've talked too long and missed the first part of the question. If you could just repeat that.
spk03: Right. So thanks for those answers. And have Pfizer and Novartis studied the tracer capsids together with their specific targets in animal models? So to what extent have they done work before they opted into the tracer capsids?
spk12: Right. Apologies. So in each instance, both Pfizer and Novartis had a one-year period to evaluate whichever of our capsids they wanted to look at to consider for exercise. So they conducted their own experiments on their end to help them decide which and whether they would like to exercise on which capsid. So at the end of that process, Pfizer exercised an option for its neurologic target, and Novartis has just exercised for two of the CNS targets after their own evaluation. There's a subset of information that's shared back to us that is not intended to be specific to their targets, but to help Voyager understand the results of the experimentation with our capsids in the hands of our partners. So that information is valuable to us as we learn more and more about our own capsids.
spk03: Great. Thanks for the color. And lastly, just wondering on the tracer, on the evolution of the tracer capsids. So first of all, are you conducting additional experiments and have additional efforts for further reducing the capsid load? i.e. with even more potent and more CNS-selective tracer capsids? And when might we have some update on that? And also, how about targets outside the CNS? Will we hear about some update on that front? Thanks for taking all the questions.
spk07: Hi, this is Todd. So with regard to CNS, non-CNS application. Our focus has been on the CNS. That's what we spend the bulk of our efforts on so far, so I can't commit to any timelines. It's certainly something that we're interested in exploring on the non-CNS side. With regard to the continued evolution of our tracer capsids, that's absolutely something that we're seriously pursuing. We continue to mature our capsids and to develop The team looks at different loops on the AAV capsid surface. We use different starting capsids, different parental capsids, and all those processes continue. We'll be presenting data at the upcoming ASGCT. This is, I think, the next conference that we'll be showing some new data, and we'll continue to share the work that comes out of our tracer platform as it arises.
spk03: Great. Thank you. Looking forward to the ASGCT presentation. Thanks.
spk02: One moment for our next question. Our next question comes from Jay Olson with Oppenheimer. Your line is open.
spk13: Congrats on all the progress, and thank you for taking our questions. Can you talk about how the lessons learned from your SOD1 gene therapy for ALS will inform your early research initiative in tau, siRNA, and then Since there are a number of interesting CNS targets that could be targeted by siRNAs, you optimize gene financing payloads. What sort of other new research initiatives are you considering? And then I won't follow on, if I could, please.
spk11: Hi, Jay. I'll start, and Todd will continue. But yeah, no, listen, this, I believe this ability to vectorize siRNAs is a huge, you know, capability that we have at Voyager honed over the years. It's, you know, it's not an easy thing to find siRNAs. And we published on some of the thinking that goes into it, how many versions we test, et cetera, and how we address things like over harnessing the potential. And so, yeah, I mean, I think that, you know, the siRNA, vectorized siRNA for SOD1. There'll be lessons learned there that we will apply to all of our future siRNA programs, including TAO. Todd?
spk07: So one of the good things about working here at Voyager is we can deploy different kinds of payloads. Those include the vectorized antibodies that we talked about, the gene replacement, and then the siRNA that we're talking about here. Some of the honing that we did that Al mentioned came through our first-generation Huntington's program. We continue to pursue a Huntington's approach as well. That was an early exploratory program that we announced earlier this year. That's a dual approach where we're looking to knock down both in an allele-specific way the mutant form of Huntington and MSH3, which is a genetic modifier of Huntington's disease. So we have a lot of effort in the siRNA approach. We've honed that expertise over the years, and we're looking forward to deploying that in these programs in addition to the other payload abilities that we have.
spk11: Yeah, and maybe I could add that the Huntington's program is a allele-specific siRNA, which is also not straightforward to develop, and Voyager scientists have figured out how to do that. I would also add that there's a lot of mutations that are toxic gain-of-function mutations for CNS disorders. So, having this capability of knocking down gene expression is very, very helpful and opens up a large number of targets for us to pursue.
spk13: Actually, that's super helpful. And then if I can please ask one follow-on with the advancement of your anti-Tau antibody Can you just talk about how that will fit in with your SIR and natal gene silencing program and, I guess, how the two modalities could be potentially complementary and fit into the future treatment landscapes for Alzheimer's?
spk07: Hi. This is Todd again. So, thank you for the question. We're excited about tau as a target. As neurodegenerative targets go, it's validated. We think that our antibody approach, so we mentioned earlier the antibody approach against tau came out of a vectorized antibody program. And we identified a series of antibodies that worked extremely well in our animal models and are differentiated by both the efficacy in our animal models and the epitope that we target. And so we're continuing to move that forward. That said, there's still other approaches that could be really effective potentially in tauopathies, and we think that vectorized siRNA to reduce tau is one of those. So, the reduction of tau intracellularly is, while it still affects tau, it's an independent mechanism of affecting tau than a tau antibody. So, I think those approaches are interesting as solo approaches, but they're also potentially interesting in combination. And, of course, then there's the potential to combine with other Alzheimer's disease therapies as well, including the anti-amyloids that have recently received accelerated approval. So I think Al would say we're in a bit of a renaissance of neurodegeneration and Alzheimer's disease, and we're pretty excited about all of this progress.
spk13: Great. Thank you for taking the questions.
spk02: And I'm not showing any further questions at this time. I turn the call back over to Al Sandrock for any closing remarks.
spk11: Thank you, everyone, for joining us today. Please feel free to follow up with us directly with any other questions. Thanks again. Bye.
spk02: Ladies and gentlemen, this concludes today's presentation. We now disconnect and have a wonderful day.

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