Q4 2024 Voyager Therapeutics Inc Earnings Call
Speaker Change: 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.
Speaker Change: Please note that today's call is being recorded. A replay of today's call will be available in the Investor's 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 Corporal Affairs Officer at Voyager.
Speaker Change: Good afternoon. We issued our fourth quarter and year end 2024 financial results press release this afternoon. The press release and 10K are available on our website.
Speaker Change: 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.
Speaker Change: Joining us for Q&A are Dr. Toby Ferguson, Archie's Medical Officer, Dr. Todd Carter, Archie's Scientific Officer, and Dr. Nathan Jorgensen, Archie's Financial Officer [inaudible]
Speaker Change: 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 2 of today's deck.
Speaker Change: 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.
Good afternoon everyone, and thank you for joining us.
Speaker Change: As Trista said, we plan to keep our remarks brief and prioritize your questions.
Speaker Change: On Flight 3, I want to remind you of why we're so excited about Voyager.
Our pipeline includes four holy owned and 13 partner programs.
Speaker Change: We have already begun to generate clinical data and we have multiple opportunities to generate more in the coming years.
Speaker Change: 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.
Speaker Change: I think most of you are familiar with our Tracer Capsid platform for IV delivered CNS-targeted gene therapies
Speaker Change: We are 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.
Speaker Change: Finally, our partnerships have been a significant source of non-deludive revenue for us.
Speaker Change: That's a big reason we are able to report $332 million in cash as of the end of 2024.
Speaker Change: 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.
Speaker Change: 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.
Speaker Change: Despite continued setbacks in the field, it is possible to create a gene therapy that drives value for patients and investors.
Zoljiazma proves this. [inaudible]
Speaker Change: I want to emphasize that many of the foundational principles behind those gentlemen's technical and commercial success are principles, Lawager also adheres to.
Speaker Change: This includes focusing on genetically validated targets and severe diseases with high unmet need.
Speaker Change: It also includes IV delivery, which we view as critical to commercial viability.
Speaker Change: We believe I.D. delivered A.V. Capsis will be required to enable gene therapy in most CNS diseases, given the limitations of localized delivery.
Speaker Change: 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.
Speaker Change: I'm not going to belabor this point, but I do think it is important to differentiate boarders' approach from the braver teen therapy field.
On slide four, you can see our pipeline.
Speaker Change: I won't go into a lot of detail here, other than to point out that our SOD-1 Silent Singing 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.
Speaker Change: At the same time, I will note that VY 1706, our tile silencing gene therapy has moved forward into IND enabling studies and is advancing toward IND in 2026.
Speaker Change: On Slide 5, I will notice you more quick highlights from the quarter and upcoming milestones to watch.
Speaker Change: I mentioned that BY-706, which was selected as a development candidate in Q4 2024, has now advanced into IND-enabling studies.
Speaker Change: We are really excited about the data from our three month non-human primate studies, where we are seeing 50% to 73% knockdown of Tao Messenger RNA, quite broadly across the brain.
Speaker Change: 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 .
Speaker Change: Our anti-tow antibody, BY-7523, performed well in a recently completed, single ascending dose study.
Speaker Change: There were no serious adverse events and we saw dose proportional pharmacokinetics as well as the CSF to serum ratio of 0.3% consistent with other monoclonal antibodies approved for the treatment of Alzheimer's disease.
Speaker Change: Finally, I want to point out that in Q4 2024, UCB's Pratimab demonstrated for the first time that an anti-tile antibody can impact talcumulation in the human brain, and that this may correlate with clinical benefit.
Speaker Change: It's important to acknowledge the study didn't meet its primary endpoint of the CDR from the boxes
Speaker Change: But our team walked out of a CTAD meeting feeling better about our anti-tile antibody than when we walked in.
Speaker Change: Looking forward, I think there are several opportunities this year for third-party data to continue to build excitement for Tau.
Speaker Change: Murk has antibody data expected in mid 2025 and I look forward to seeing what we learn at ADPD in April , AIC in July and CTAD in the fall.
Okay, I promised I would keep it short
Speaker Change: I just want to thank all of our employees for their hard work [inaudible]
Speaker Change: especially pushing to achieve those end-of-year goals like getting the development candidate for the Tau silencing program, working on the BY-75-23 single and funding dose analyses, and initiating the multiple sending dose studies.
With that, we will open the call for questions [inaudible]
Operator
Speaker Change: Thank you. As a reminder, to ask a question, please press star 11 on your telephone and wait for your name to be announced. To withdraw your question, please press star 11 again. One moment for questions.
Jack Allen: Our first question comes from Jack Allen, with Baird, you may proceed to the next question.
Jack Allen: Thanks so much for taking the questions and congratulations to the team on the progress. I guess maybe I'll start where you left off your opening remarks there. You mentioned some external readouts that could be interesting in the palace 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 program. Program.
Speaker Change: Yeah, hi, Jack. So at ADP, I hope to see data from the Pranemab.
Speaker Change: as they, I believe they may be sharing their data on exposure PD relationships of PKPD, which they didn't have a chance to share at the CTAD meeting last year. And then also,
More data on what how much? [inaudible]
Speaker Change: A decrease in tout spreading, do you need to see in order to see a clinically relevant effect?
Speaker Change: So that's one thing I'm going to be hoping to see
The other thing might be more information about subgroups.
Speaker Change: where a greater efficacy can be seen. They started to talk about that a little bit at CTAD, for example, the effect of APOE4 carrier status, as well as initial tile burden. And there may be more information on that as we learn more about which are the ideal patients. [inaudible]
to be treated with an anti-cow approach.
Speaker Change: We also note that other companies have started to share data with their anti-calc program so I know that for example ASI has been sharing data on fluid-based file markers. [inaudible]
with their anti-tow that targets the MTBR region.
and so...
Speaker Change: And I don't know where the 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.
Speaker Change: that we know, for example, Biogen has, and I look forward to seeing any updates that might be on that. So, Evie, did you want to add anything to that?
Halle, I think-
Toby Ferguson: I certainly agree with your comments and so echo the comments on exposure response, both initial PKPD but also in particular the CalPAT to clinical relationships. I do think on the subpopulations that for example I'd like to see details on.
The Tao, Lo Tao, or if we group they describe beautifully curious.
Toby Ferguson: What they think support for APA Wee is, is it just that those individuals without APA Wee and Leo have low-tow, or are some other defining characters with that population.
Toby Ferguson: Got it. Great. That's a very helpful color. And then more on the finance side, but I just wanted to ask, it seems like the two programs with neurocran on the gene therapy partner are expected to enter the clinic.
or other than INDs filed.
Toby Ferguson: 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.
Toby Ferguson: Thanks for the question Jack, this is Nate Jorgensen, the CFO .
And so what we have said is that there's...
Toby Ferguson: 2.9 billion of developmental milestones, so these are milestones, I think.
or not BioBucks, like some companies report, but if you add all the BioBucks together, it's over 8 billion as...
Toby Ferguson: Al Manchin, so there are some, I think, pretty meaningful milestones over the next few years that couldn't help extend our cash runway past the mid-2027 guidance that we talked about externally.
Toby Ferguson: Got it. Are those milestones that all accounted for in your guidance, or are they? [inaudible]
Additional left side. No, they're not there.
So that's all upside to the mid-2027 cash runway guidance.
Speaker Change: Perfect, thanks so much. Those are my first questions, but they will hop back in the queue. Congrats again on the progress.
Speaker Change: Our next question comes from Phil Nadeau with TD Cowan, you may proceed to the next question.
Speaker Change: Good afternoon. Thanks for taking our questions. A couple from us. First on the pow-jean silencing I&D. Can you give us some details about what needs to be completed before the I&D can be filed next year?
Speaker Change: Well, I mean, the main thing is that we have to complete the GLP talk study that we just found, but we just started, and we need to be sure that we have a therapeutic window, you know, as we said, our, our. [inaudible] yeah, yeah, yeah
Speaker Change: Initial non-human primates study shows 50 to 73 percent knockdown, which is exactly in the range.
Speaker Change: that we want. We just have to be sure that now we don't have any safety issues that allow for the right dose to produce that level of silence.
Speaker Change: Perfect. And then a second question on the ALPL shuttle. Can you discuss where that could be most applicable? What indications are you thinking that would be most useful for and any sense on when one of those candidates could advance? Let's go.
While we're looking broadly across various diseases, various targets.
Speaker Change: You know, this is a receptor that allows for BBB penetrance of one of our leading classes of capsis. And that capsid gets in across the CMS pretty broadly.
Speaker Change: So, to that leaves open a lot of different diseases, both spinal cord as well as cerebral cortex and even subcortical diseases.
Speaker Change: And so, and then the kinds of drugs that we were thinking about transporting across the BBB would include protein such as enzymes.
or Antibody. [inaudible]
Speaker Change: And also, we're starting to assess whether or not all of your music types can be...
Transport as well [inaudible]
That leaves open a wide array of possibilities, so and-
Speaker Change: to serum ratio, 0.3%, so literally 99.7% gets thrown away.
Speaker Change: They'd be great if we could get more of the antibody into the brain. Also, all ASOs currently are interethically administered for CNS disease.
Speaker Change: and that provides a burden to patients. It also produces a severe gradient in the CNS, which I think is my meeting, so there's a lot of opportunity. Todd or Toby, do you want to add anything to that? No, no, no, no, no.
Speaker Change: I think you've captured most of it out. The other part of your question was moving things forward and while we haven't shared any data or hoping to share more of our early work later this year.
That's very helpful. Congrats again on the progress.
Thanks Philip
Speaker Change: Our next question comes from Pete Stavaropoulos with Canterbury Cheryl, you may proceed.
Pete Stavaropoulos: Yeah, good afternoon and congratulations on all the progress and thank you for taking our question. First question I have, you know, you know, as we look forward for the towel science and gene therapy, you know, I'm wondering, you know, if you can talk about the key differences we should expect from how silencing.
Speaker Change: Excuse me, Towson Singh versus Targeting Antibodies, and thinking about the biogen data for 080, you know, what's your view on the combination of meaning a tell sound thing or not sound with a monoclonal approach? [inaudible]
Thanks, Pete, this is Toby. Good to hear from you.
Speaker Change: The, so I think fundamentally that our belief on the knockdown approach.
with 7006, this is a couple of two points one. [inaudible]
Speaker Change: As we've highlighted it, we'll use our second generation Tracer Capses and so it will be injected IV once.
Speaker Change: And that gives us a couple of clear advantages. I think one is that it allows for better by distribution, accessing the Vascotervia ALPL.
Speaker Change: And so that's quite distinct from the great you get with the interethical injection of one bar space with an ASO. So I think that presents an opportunity for broader hell knockdown.
Speaker Change: And so that is, I think, quite an important point. And then in addition, the fact that it's IDM one time we think present is clearly some benefits both for the patient and potential for the healthcare system in terms of ease of uptake.
I think Yellow Point I'd make. [inaudible]
Speaker Change: is that, of course, the biogen data which comes out, and we think in mid Q3-26 will be an important inflection point and
Speaker Change: Of course, we have an ID for our program in 2026 as well. So we think that's an important pairing. In terms of the antibody...
Speaker Change: I think fundamentally the premise of the end body is slightly different than you're trying to impede spread. And so the idea there is that you would want to target that to a population in which talism not yet spread. On the other hand, for the knockdown approach, you look at the-
Speaker Change: Data Debye agent has shared. In that case, you can move pre-existing town, and that was shown by Talpet, which quite a remarkable observation. So there may be some broader attitudes, there may be space for sequencing of a beta emeloic therapy with an antibody, and then a town knockdown approach as well.
Speaker Change: All right, thank you for that then. Just one more question, you know...
Speaker Change: The way that we viewed the Southern one, Gene Soundsing program. . .
Speaker Change: It would provide proof of concept for the capsidant ability to cross the library barrier efficiently by looking at the changes in the NFL.
Speaker Change: We would hope to have seen similar to Toe Ferguson. How are you thinking about establishing the human proof of concept? Which program will likely help you do so? Is there any agreement or expectation of a partner sharing some data or allowing you to once it's generated? Yes.
Speaker Change: Sophie, this is Sophie again. So I think, I think you've randomly keyed on the fact that the next opportunities to generate Capsid POC really sit with the Friedrichs Attaxia, and or the GBA program which are partnered with Nuregrine,
Speaker Change: coming up this year. And I think what I'd say is Melissa is Jorgensen is running those programs.
Speaker Change: We have a strong collaboration with them across the development teams and in both cases in Friedreich 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.
Speaker Change: NZMG case levels and subsequent levels. So in both cases both programs off the opportunity to understand that the castes are working.
Todd, anything to add? I think you've got it, Toby.
Speaker Change: All right, thank you for taking our questions and not the resolution of Sumant Kulkarni's
Speaker Change: Nice to meet you. Part X question goes from Lili Nsongo with Lili Nsongo, you may proceed.
Lily Nisongo: Hi, good afternoon. Two questions from my side. So, the first one being on maybe comparing and contrasting the two approaches for how. So, per clinically so far, can you give us a little bit of perspective in terms of potential differences you've seen between the two approaches in per clinical studies? [inaudible]
Todd, do you want to check that? [inaudible]
in the three clinical studies.
Lily Nisongo: Sure. On the preclinical side, we've seen positive results from both.
Lily Nisongo: One aspect that we have discussed with the Tal antibody program is that we do see differences in different episodes.
So for example, our C-Terminal targeted epitope looks quite well.
Lily Nisongo: in Terminal Targeted Antibodies that are failed in the clinic, failed in our seeding models, which is a model where we inject all-time risk patients' derived ecological towel into the brain of a mouse expressing human towel and look at the ability of a treatment to stop spreading. So the in-terminal failed antibody didn't work.
Our antibody does, many other antibodies.
Lily Nisongo: 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. So for the Tau knockdown, we think we might be
Lily Nisongo: hitting on mechanism in two ways, one, for reducing the amount of towel and subsequent pathological towel to spread cell to cell, and then we're also reducing the amount of towel on the recipient cell to then receive that pathological pre-autmine material.
Lily Nisongo: So we think that they're interesting similarities but also some key differences in the fundamental mechanism of the field approaches.
Speaker Change: Thank you. And as a follow-up, maybe could you provide a little bit of color in terms of the max 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 problem out.
Toby Ferguson: Thank you very much, Mr. Toby. So it's actually a question. I think what we put them in maybe a couple of points.
Speaker Change: So I think what we've learned about our antibody, including the critical work it up through through the alarm.
Speaker Change: Sad is that the antibody, remind it binds a pathologic towel which differentiates it from others some other antibodies including UCBs.
Speaker Change: that we have for PCA, we've got good CSF penetration. So in that context, we really think in the NAD study, we can drive to an effective determination if we have a single one out there, particularly the context of what we've seen thus far. [inaudible]
and that's important. I think in terms of the population... [inaudible]
Speaker Change: What we've learned from the Panamab is that the lower tile may be important in this context.
Speaker Change: and and or able we status and so what what we shared so far is that we [inaudible]
Speaker Change: We've adjusted the thinking based on these data to focus on the earlier MTI and AD populations, which are necessarily lower in town.
Speaker Change: I do think we'll need to be ready to respond to learning as they continue to evolve You've already highlighted that we're hoping to hear some discussions ADPD on the deeper side of these two subpopulations and or exposure response [inaudible]
Speaker Change: In addition, we've highlighted some other potential readouts in the field as well. So we'll certainly continue to monitor the field.
Speaker Change: and Adjustance as we're able. I will highlight, I think that's what I'll call it. And I might want to add, then in the case of Alzheimer's, the history of Alzheimer's clinical trials.
Speaker Change: Sometimes multiple sending dough studies, for example, with the anti-amaloid antibodies that provided some really meaningful information, it turns the effect on pet imaging. And, you know, here in this case.
Toby Ferguson: Wouldn't it be fair to say, Toby, that given the data with the Pranamab, 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. [inaudible]
Toby Ferguson: 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
Toby Ferguson: You know, we'll be monitoring the situation with all the other data coming down.
Thurley Ryall
Thank you for the calling.
Toby Ferguson: Our next question comes from Samantha Semenkow with City, you may proceed.
Samantha Zemenkow: Hi, good afternoon, and thanks very much for kicking the question.
Samantha Zemenkow: 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-biral 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?
Samantha Zemenkow: Transport would have its own set of unique challenges that you would need to optimize for any color you can share that would be very helpful. Thank you.
Samantha Zemenkow: Well, that's an interesting question. I mean, in some ways, the TFR-based Charles.
Samantha Zemenkow: Have been a sort of plug-and-play in the sense that it's worth it for multiple different kinds of modalities and we're starting to see data emerging that even beyond proteins that all even use these sites may also be transported.
Samantha Zemenkow: You know, look, I mean, but even Denali who are the leaders in PFRs are also looking at CD-98, right, as another shuttle, another shuttle at vehicle.
Samantha Zemenkow: So, why would that be? And I guess it's because every receptor is going to have its own safety, distribution, and kinetics.
Samantha Zemenkow: And so it could be that for certain targets and certain diseases. [inaudible]
Samantha Zemenkow: 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. I think it's more selective.
So it could be plug-and-play [inaudible]
Samantha Zemenkow: But as we learn more about these various shuttles, we may start to tailor them to the right disease and the right target
Samantha Zemenkow: 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 Change: It's 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 Change: 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.
Speaker Change: to some of the TFR-based shuttles comparing LPL to start to get an idea of how different it is and whether there are certain advantages.
to LPL .
Speaker Change: and we hope to be able to show more than one payload as well. See how plug-and-play it actually could be.
Speaker Change: But so that's what we're hoping to show and that we're working hard on that and we'll see whether we can get there.
Great, looking forward to it.
Al Sandrock: I think you captured it. I mean, we may be very excited by that and hopefully look forward to sharing that later this year.
Thanks so much [inaudible]
Speaker Change: Part X question goes from Joon Lee, the true security he may proceed.
Speaker Change: Hi, good afternoon, this is Mahdi on for June and Congress on the Progress, a couple on Capsules for us as well. So, given that for Sub-One ALS program, the recapture too is going to be the same for...
Speaker Change: Riy 1706. What are the data points that gives you the confidence that the neural flux that you have seen is not related to the capsid? [inaudible]
Speaker Change: Well, there's two reasons. One is the timing of the adverse event, so in the case of the SOD1 program.
Speaker Change: in the initial time points in the several days after we inject. We do see the expected slight bomb in the reflection test.
Speaker Change: and in their filament levels. And that's exactly where other programs have seen have been, have shown those kinds of adverse amounts that I've been delivered AAB.
Speaker Change: and that's to be expected. But the caps are clear from the bloodstream within days.
Speaker Change: And then what we saw was with a delay of about three months, we saw that the Neurotherlamans start to go back up.
Speaker Change: and that was coincidences with some neurological adverse events observed at Cape side. And then when he looked histologically, you see evidence of neurodegeneration. So it's that delay, which is when expression has...
Speaker Change: has really come into play that we see the adverse events. And so the timing is not right for the capsis, much more consistent with the expression of the payload.
Speaker Change: The other thing is that we use the exact same capsis [inaudible]
with four other constructs of various promoters and various... [inaudible]
Go to Beadaholique.com for all of your beading supplies needs!
Payloads and we see no such...
Speaker Change: Adverse Events, and non-human primates, even at doses that are comparable to what we tested with SOD1 and even at the two to three months time point. So both of those pieces of evidence that gave us a lot of confidence that it was the payload and not the capsules.
Speaker Change: Thank you for helping me out. Sorry, when I'll talk about what we're looking at, we're looking at histopathology, we're looking at NFL as a bio marker, and we're looking at sort of clinical signs. So none of those, we've seen none of that with the capsules with these other payloads.
Thank you very much, my pleasure [inaudible]
Speaker Change: Our next question comes from Ry Forseth, who can I am security, you may proceed.
Speaker Change: Hey, this is Rye from the subjects team, back to the third party readouts.
Speaker Change: 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 75, 23 med efforts.
Speaker Change: Maybe outline how adjustments could be made to these programs in response to the data.
Are you talking about the third party data with antibodies? The third party?
Either, either as talented in efforts or in antibodies.
I'll see. Yeah.
Speaker Change: So, you know, I think one of the biggest pieces of data is going to come in terms of antibodies from the Jay and Jay study.
Speaker Change: 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 [inaudible]
Speaker Change: to be see an effect on the spread of towel with a different antibody. In other words, reproduce what…
Speaker Change: with UCB has shown, but then also get a much better handle on whether or not there there's a clinically significant consequence to that impeding of power spread, which we hope to see. [inaudible]
Speaker Change: So I think that will 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 80 data for me anyway is the fact that you actually reduce
Cao-Pet Sigma.
Speaker Change: which I didn't think would be possible because I always thought that the pathological tower was in their fibrillary tangles which is pretty much...
Speaker Change: and not going to be reduced by simply reducing the synthesis of New Tau. But that's exactly what Biden has shown.
Speaker Change: and what's intriguing is that they seem to see a pretty big clinical benefit of that.
Speaker Change: Now the flaw there is that there was no control group in that study, so 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 was the passage of time.
Speaker Change: We will know even better whether or not that clinical effect is real and durable [inaudible]
Speaker Change: So those are the kinds of things I'm going to be looking at. Of course, we always want to know, answer the questions. Does Epitope matter in the case of the anti-ambuloid antibodies? Epitopes did really matter. He's now speaking about the antibody program of course.
Speaker Change: And then the only other question is that it's important to be specific for pathological forms of...
Speaker Change: Cao versus all forms of Cao. UCB was not specific for the pathological forms of Cao. R's is, and I believe many of the other antibodies are as well that are coming down the pipe. In the case of anti-amuloid antibodies, it was important. And I believe that the pathological forms of Cao and the other antibodies are as well that are coming down the pipe.
Speaker Change: to be specific for pathological forms of amyloids, so we'll see if that also applies to the path. Toby Todd, what did I forget?
Maybe I'll highlight the Merck readout.
It's a secret elevator.
Speaker Change: Ted Lust is named by the short study focused on biomarkers [inaudible]
Speaker Change: but gives you an initial chance to answer that question, Ken and Napato, the sequel of Napato reduced, at least told how, and so that's it.
The important concept as well.
So, we, we, let's see.
Speaker Change: At ADPD, we will present on the town knockdown program that we will describe data.
Speaker Change: Schilling Delivery, both in terms of the amount of vector and knock downs from ecology 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 type of tissues. [inaudible]
Thank you.
Speaker Change: Our next question goes from Jay Olson with Oppenheimer, you may proceed [inaudible]
Speaker Change: Oh, hey, thanks for providing us update. We have a question about the new pre-clinical data for the TOWS silencing program to be presented at ADPD. Can you talk about the target level of TOW mRNA knockdown that you plan to achieve and? [inaudible]
Speaker Change: Are there any particular brain regions that are more important for TAO, mRNA, and protein reduction?
Thank you very much.
Speaker Change: 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 [inaudible]
Speaker Change: 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. And so,
Speaker Change: To me, the key region in the CNS that we need to look at for child science is the cerebral cortex to be broadly.
Drone.
So Al mentioned earlier.
Speaker Change: 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 a lot of knockdown in some of these key regions, the cortex in particular in the non even primate. [inaudible]
Speaker Change: that we think we need to achieve those kinds of lockdown and have an impact on the disease. [inaudible]
Speaker Change: Okay, great. Thank you. And then, can you comment on how you're thinking about indications for the TAL assignment program? Would you start with Alzheimer's disease or are there other TAL opportunities that you would start with?
Well
Speaker Change: There's also frontal temporal dementia due to tal mutations in tal. And then there are a lot of other diseases as well, including potentially chronic traumatic and stuff allopathy.
Speaker Change: And so, but I do think that we, you know, if it stays in our hands, we will probably look very hard at Alzheimer's in these first where the
Speaker Change: where, you know, a lot of us do believe that Tao is a really important target for Alzheimer's disease and that, and so much is known about the natural history of Alzheimer's disease and how to make measurements.
Toby Ferguson: So fluid base as well as imaging measurements. So we're going to take full advantage of all that knowledge and look hard at all time versus these first. That's our approach. What do you think? I agree on it. Maybe I sort of amplified that fundamentally, I mean, we've always seen with the...
This is the best workout in Alzheimer's disease. This is the best workout in Alzheimer's disease.
Toby Ferguson: looking at some of the other tile-off at these use of tile-pad and some gets flew by markers is less well-settled and so...
One of our core tenets is that
Toby Ferguson: to go into diseases where you can get proof of concept around the biomarker tools relatively quickly, and in this case, for the tall operatives, we think that really sits with Alzheimer's. I certainly think the other indications are interesting once you've shown that. [inaudible]
Speaker Change: 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 Transfan Receptor and see what the differences are?
Speaker Change: We haven't shared that data, but we are in the process of comparing to CFR.
Speaker Change: Okay, great. We'll look forward to that. Thanks for taking all the questions.
You're welcome.
Speaker Change: Our next question goes from Patrick Trucchio, with H.E.W. Inwriting Company, you may proceed.
Patrick Trucchio: Thanks. Good afternoon. Just a couple of questions on the DUI 7523. Just
Speaker Change: The first I'm wondering how the sad data influence selection of dose levels and frequency for the mad study and then separately, just given the competitive readouts in the anti-taus space.
Speaker Change: and those that are upcoming. I'm wondering, you know, how the mad study design may position the Y-75-23 for differentiation.
Speaker Change: And then separately, I'm wondering, you know, 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 Change: could be all start and then inferred over Nadeau. So I think in terms of the sad data, just to reiterate, we saw just proportionate PK
Speaker Change: The observed safety in the broader program study didn't hold it any risk of power yet. So really what the sad data gave us was the confidence. [inaudible]
Speaker Change: in the match study to move forward with our planet doses.
Jack Allen: And frankly, I was out in a hurry earlier to try to push those doses to levels where we can clearly test the hypothesis of whether this antibody would pee the spread of how toxic cow.
in terms of...
Jack Allen: Differentiation for the competitors and what we're looking for, I think fundamentally [inaudible]
The study will be designed to look for a tough at signals.
Jack Allen: And so really what we're trying to do, I think frankly, is...
Jack Allen: See where we compare to the other antibodies that are modulating the health at signals, and particularly UCB, and I think our civil aspiration here would be that we are at least as good as if not better than that, given our specific pathologic talent. [inaudible]
Speaker Change: Yeah, man, 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 put the best foot forward with our antibody. And I would also say that we know the doses.
Speaker Change: Where we know the levels in the brain that were needed to impede the spread of tout in that animal model that Todd mentioned earlier, where we inject human pathological tout
into P3-O1F transgenic mice.
Speaker Change: And so we want to be sure we exceed those, those what the EC50, if you will, for that effect of impeding spread and we were pretty confident we can get there with the doses that we have. We will be choosing based on the single sending those studies that we did. [inaudible]
Speaker Change: And Nate, do you want to answer the second half of the question? Yeah, totally.
Speaker Change: What I will say is that we understand the financing market out there in the cash runway to mid-2027 is important to us. We would be very thoughtful if we do any type of transaction or-
Speaker Change: and which would shorten that, would have to bring in some really interesting asset that potentially with the clinical near term clinical catalyst.
Speaker Change: In terms of the other types of deals, does there is something that Al always talks about that he's open to? 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 Change: Yeah, I mean, look, if you look at our history, we've done, you know, anything from simple capsid licenses.
Speaker Change: where the other company takes the capsid and runs with it.
Speaker Change: versus, you know, partnerships on actual programs as we may have started here and then we may continue to do the work here. We inverse 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. [inaudible]
Thank you.
Speaker Change: Ardite's question comes from Yun Zeng with what both securities he may proceed.
https://www.youtube.com.uk
Yun Zong: Hi, good afternoon, thank you very much for listening to questions. The first question is on the MAT study.
Speaker Change: It was the initiation earlier than she had expected, because I believe the original guidance was very broadly in 2025.
Speaker Change: And the second question is, I know that you compare the anybody approach versus the knockdown approach and the mechanism action given the timing that do you think it's possible that the knockdown [inaudible]
Speaker Change: Program could potentially catch up to be a more promising approach as compared to the
Divya Osector, Tim.
Toby Ferguson: This is Toby. So we guided or we did start the study a bit earlier than our guidance. And I think just this just reflects the the clinical team is up and going and executing. And then maybe I can help you clarify your second question for me, please.
Speaker Change: Oh, I know that the antibody approach is ahead of the knockdown approach, but given I think I'll talk about this mechanism and also the biasing the data, do you think eventually the knockdown approach could potentially be more promising than the antibody approach?
Speaker Change: and Tom Selleck. Thank you. Thank you. Thank you. Thank you. Thank you.
for AP.
Ah!
Yep.
What I say here is we...
We have two different approaches that I think. [inaudible]
Speaker Change: One, we have some early data from biogen suggesting that knockdown could be quite clinically efficacious. I'll highlight it that this was a natural history comparator and a comparison code and other study with effect on senior some of boxes that was maybe
Two to three times greater than...
Speaker Change: then sort of what is a plastic observed for baby amulet therapy. So potentially a very large effect is not that approach.
Speaker Change: So that's very exciting within the constraints of the, in particular, administer ASO, anybody based approaches, I think the data we have there is
Speaker Change: is the UCB data, which is a main fun for data sets. And that effect was slightly different. And so I think the potential there is potentially different but fundamentally to meet the questions we're going to be of. [inaudible]
Speaker Change: of the appropriate sequencing and the appropriate risk benefit and what is the appropriate disease stage of individuals as we previously discussed. So, really,
Speaker Change: There may be a point time when you're gonna stop spread in a low-town population early in disease [inaudible]
Speaker Change: There may be a population in time when someone has broader spread of talent you want to take a knockdown approach or you may learn their different response across different population populations. So I think fundamentally all time is complex and physicians and patients are going to need options.
In terms of typically treat this disease [inaudible]
I would add that
Speaker Change: I believe we're on the very early stages of learning about how and how to best approach this target. You know, if you look back at the anti-Amaloid field, it took us decades.
to learn from each other. [inaudible]
Speaker Change: and to get to the point where we finally had some drugs that were approved.
Speaker Change: We're just in the very beginning stages. We're only just now starting to see biological effects that are, you know...
We are a chronic disease in environment and...
Speaker Change: I think this can 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 versus as well as external data. We will learn from those and we will make data-driven decisions.
Sounds good. Thank you.
. . . . . . .
Speaker Change: Our next question comes from Yanan Zhu, with Wells Fargo Security, Sumit Proceed . . .
Speaker Change: Thanks for taking the questions. First I wanted to ask about maybe a follow-up on the brain shadow approach.
I think L, you touched on this.
Speaker Change: 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 from the tile program. Thank you.
Speaker Change: Well, from what I see, there is evidence of hematologic adverse events.
Speaker Change: which is not surprising given the function of transgender receptor and even why you use ligands for different epitopes on the transgender receptor.
You still see some adverse events because...
Speaker Change: Even if you don't block the transfer receptor, you probably lead to its internalization and therefore you end up with loss of function type, you know, adverse events.
Speaker Change: If you look at the human genetics database, humans are not very well very tolerant of lots of function mutations and transfer interceptors. It's a pretty critical pathway. So now in part, you're asked.
Speaker Change: So, humans seem to be pretty tolerant of loss of function mutations, I should say more tolerance of loss of function mutations of the LPL. So that could be an advantage.
Speaker Change: Of course, time will tell, but I would say that that's one of the potential advantages, but there could be more as we learn more.
Speaker Change: Great. Thanks for, you know, let me, let me add one more piece, Yanan, Patrick, you know, is that,
Speaker Change: 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.
Speaker Change: That's not the same as the TFR-based approaches, you know, are not promising. They are promising . . .
Speaker Change: The fact so promising that that's why we're so excited about the idea of using a shuttle-based approach to prove delivery of other modalities beyond these therapists [inaudible]
Speaker Change: Thank you for the insight. On the Tao antibody program, I was wondering if it's fair to say that the Merck antibody is even more similar to your antibody than the UCB antibody is?
Have you compared in your Tao animal model? [inaudible]
Speaker Change: Directly your antibody with against Merck's antibody and what might be the findings. And lastly, I was wondering about your thoughts on effective function for the how antibody, the general how antibody approach. [inaudible]
Speaker Change: If you can comment on whether it yours is effector null or not, and why does that matter? If it does, thank you.
Speaker Change: Hi, I can take this, this is Todd. I do think you're right. In a lot of ways, the Murk antibody is more similar to sea terminal antibody. We've not shared any data comparing the sea terminal Murk antibody to ours, so we don't have that to share.
Speaker Change: on the effector function. It's an interesting question, and we've gone with effectively unknown IGG-4, human IGG-4, for our antibody. The evidence to date suggests that
to have an effect. [inaudible]
Speaker Change: in the spreading models, and it looks like perhaps the panemab and the clinic that you don't need a factor function and eliminating it eliminates or reduces some some risk around the neuroinflammation we think. So we've gone with HIDG 4 for our entire body. [inaudible]
Great, thank you very much for all the color.
. . . .
Speaker Change: Our next question goes from Sumant Kulkarni, with Kenneth Orginuti, he may proceed.
Suman Kulkarni: Good afternoon, and thanks for taking a question. Apologies for this, I was asked before and I know you gave a quick history lesson there on anti-analytic products far as I must but what are the key results you need to see are learning from external programs that might lead you to making a firm go no where decision on your anti-tow anti-body program or would you need to see internal results in order to make that decision and what might those internal results look like?
Speaker Change: Yeah, I mean, that's a tough question to answer. What I'm looking for, Sumant, is really how much of an effect on towel spreading? Do you have to see, to see a minimally clinically significant effect?
So, in the case of the anti-analroid antibodies. [inaudible]
Speaker Change: And by the way, you can learn from different antibodies against different epitopes [inaudible]
Speaker Change: But the key question is how much of an effect on amyloid cat imaging did you need to see? To see an effect on CDR from boxes, which is the required point for approval and you could actually draw a graph of all the different antibodies. [inaudible]
Speaker Change: 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 from the boxes.
Speaker Change: So that's precisely the kind of thing I think I would like to see with the anti-tow antibodies.
and I would say that. [inaudible]
Speaker Change: Um, you know, anything less than a roughly 30% effect on CDR song boxes?
Speaker Change: I would say it's probably not clinically meaningful. So that's what I'm looking for is what is the effect on taupe and imaging?
Speaker Change: that gives us a 30% effect on CDR formal boxes. Once we know that for sure, then we can look at our antibody and say, okay, it met that hurdle or not.
Speaker Change: 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-pout, I mean, sorry, the anti-aneloid antibody and various companies sharing their data. So, and like I said, I think we're in the early stages still of the of the Tile Direct and Anthem, please.
Got it, thanks [inaudible]
Speaker Change: Thank you. I would now like to turn the call back over to Dr. Allison Rock for any closing remarks.
Speaker Change: Thank you everyone for joining us today and we look forward to speaking with you again soon.
Thanks for watching!