Voyager Therapeutics Inc (VYGR) 2024 Q4 法說會逐字稿

Good afternoon and welcome to Voyager Therapeutics fourth-quarter and year-end 2024 financial results conference call. (Operator Instructions) Please note that today's call is being recorded. A replay of today's call will be available in the Investors section of the company website approximately two hours after the completion of this call.

下午好，歡迎參加 Voyager Therapeutics 第四季和 2024 年年終財務業績電話會議。（操作員指示）請注意，今天的通話正在錄音。今天的電話會議重播將在電話會議結束後約兩小時在公司網站的「投資者」部分提供。

I would now like to turn the call over to Trista Morrison, Chief Corporate Affairs Officer at Voyager.

現在我想將電話轉給 Voyager 首席企業事務官 Trista Morrison。

Good afternoon. We issued our fourth-quarter and year-end 2024 financial results press release this afternoon. The press release and 10-K are available on our website.

午安.我們今天下午發布了 2024 年第四季和年終財務業績新聞稿。新聞稿和 10-K 可在我們的網站上查閱。

On today's call, Dr. Al Sandrock, our Chief Executive Officer, will briefly review key recent and upcoming milestones, and we will reserve most of our time for your Q&A. Joining us for Q&A are Dr. Toby Ferguson, our Chief Medical Officer; Dr. Todd Carter, our Chief Scientific Officer; and Dr. Nathan Jorgensen, our Chief Financial Officer.

在今天的電話會議上，我們的執行長 Al Sandrock 博士將簡要回顧近期和即將到來的關鍵里程碑，我們將保留大部分時間供您問答。與我們一起參與問答的是我們的首席醫療官 Toby Ferguson 博士；我們的首席科學官 Todd Carter 博士；以及我們的首席財務官 Nathan Jorgensen 博士。

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. 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.

在我們開始之前，我想提醒大家，在這次電話會議中，Voyager 代表可能會做出前瞻性陳述，如今天的簡報第 2 張投影片中所述。這些陳述是基於我們目前的期望和信念。它們受風險和不確定性的影響，我們的實際結果可能存在重大差異。我鼓勵您查閱我們向美國證券交易委員會提交的文件中討論的風險因素，您可以在我們的網站上找到這些文件以獲取更多詳細資訊。

Now I will turn the call over to Al.

現在我將電話轉給 Al。

Good afternoon, everyone, and thank you for joining us. As Trista said, we plan to keep our remarks brief and prioritize your questions.

大家下午好，感謝大家的參與。正如特里斯塔所說，我們計劃簡短地發言並優先回答您的問題。

On slide 3, I want to remind you of why we're so excited about Voyager. Our pipeline includes 4 wholly owned and 13 partnered programs. We have already begun to generate clinical data, and we have multiple opportunities to generate more in the coming years.

在投影片 3 上，我想提醒您為什麼我們對 Voyager 如此興奮。我們的研發管線包括4個全資項目和13個合作項目。我們已經開始產生臨床數據，在未來幾年我們還有機會產生更多的數據。

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.

我們對我們兩個全資擁有的針對 tau 的計畫感到特別興奮，我們認為 tau 是阿茲海默症中最重要的目標。我們還有兩個平台可以實現 CNS 交付。

I think most of you are familiar with our TRACER capsid platform for IV-delivered, CNS-targeted gene therapies. 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.

我想你們大多數人都熟悉我們用於靜脈注射、中樞神經系統標靶基因治療的 TRACER 衣殼平台。我們也利用基於 ALPL 的非病毒太空梭產生數據。我希望我們能在今年稍後與大家分享一些數據。

Finally, our partnerships have been a significant source of non-dilutive revenue for us. That's a big reason we are able to report $332 million in cash as of the end of 2024. And with $8.2 billion in potential future milestone payments, we believe partnerships will continue to contribute significantly to our bottom line.

最後，我們的合作關係一直是我們非稀釋性收入的重要來源。這就是我們能夠報告截至 2024 年底現金 3.32 億美元的一個重要原因。而且，憑藉未來潛在的 82 億美元里程碑付款，我們相信合作夥伴關係將繼續為我們的盈利做出重大貢獻。

As I always say, we are open for additional business. We are always discussing new partnership opportunities. While we are building a multimodality neurotherapeutics company here, I want to make a comment about gene therapy, which comprises much of our current pipeline.

正如我常說的，我們願意開展更多業務。我們一直在討論新的合作機會。當我們在這裡建立一家多模態神經治療公司時，我想對基因療法發表一些評論，它構成了我們目前的大部分產品線。

Despite continued setbacks in the field, it is possible to create a gene therapy that drives value for patients and investors. Zolgensma proves this. I want to emphasize that many of the foundational principles behind Zolgensma's technical and commercial success are principles Voyager also adheres to. This includes focusing on genetically validated targets in severe diseases with high unmet need.

儘管該領域不斷遭遇挫折，但仍有可能創造出一種為患者和投資者帶來價值的基因療法。Zolgensma 證明了這一點。我想強調的是，Zolgensma 技術和商業成功背後的許多基本原則也是 Voyager 所遵循的原則。這包括重點關注未滿足大量需求的嚴重疾病中經過基因驗證的目標。

It also includes IV delivery which we view as critical to commercial viability. We believe IV delivered AAV capsids will be required to enable gene therapy in most CNS diseases given the limitations of localized delivery. The potential of our IV capsids to efficiently deliver across the blood brain barrier. not only in infants, is presumably why Novartis came to us for an SMA gene therapy partnership. I'm not going to belabour this point, but I do think it is important to differentiate Voyager's approach from the broader gene therapy field.

它還包括我們認為對商業可行性至關重要的靜脈注射給藥。我們認為，考慮到局部遞送的局限性，大多數中樞神經系統疾病都需要透過靜脈遞送 AAV 衣殼來實現基因治療。我們的靜脈注射衣殼具有有效跨越血腦屏障的潛力。不僅僅針對嬰兒，這大概就是諾華與我們建立 SMA 基因療法合作的原因。我不想詳細闡述這一點，但我確實認為將 Voyager 的方法與更廣泛的基因療法領域區分開來很重要。

On slide 4, you can see our pipeline. I won't go into a lot of detail here other than to point out that our SOD1 silencing gene therapy program did move back into the research stage as we announced last month. The payload did not meet our target profile, and we are going to need to identify a new payload to advance that program. At the same time, I will note that VY1706, our tau silencing gene therapy, has moved forward into IND enabling studies and is advancing toward IND in 2026.

在投影片 4 上，您可以看到我們的管道。我不會在這裡詳細闡述，只想指出，正如我們上個月宣布的那樣，我們的 SOD1 沉默基因治療計劃確實重新進入了研究階段。有效載荷不符合我們的目標配置，我們需要確定一個新的有效載荷來推進該計劃。同時，我要指出的是，我們的 tau 沉默基因療法 VY1706 已進入 IND 支持研究階段，並將於 2026 年推進 IND。

On slide 5, I will note a few more quick highlights from the quarter and upcoming milestones to watch. I mentioned that VY1706, which was selected as a development candidate in Q4 2024, has now advanced into IND enabling studies. We are really excited about the data from our three-month, non-human primate studies, where we are seeing 50% to 73% knockdown of tau messenger RNA quite broadly across the brain. We have previewed a little of this data in our corporate deck on our website, and we will share more at the AD/PD conference in April.

在第 5 張投影片上，我將簡要介紹本季的一些亮點以及即將關注的里程碑。我提到，VY1706 於 2024 年第四季被選為開發候選藥物，目前已進入 IND 支持研究階段。我們對為期三個月的非人靈長類動物研究的數據感到非常興奮，我們發現整個大腦中 tau 信使 RNA 的敲除率普遍為 50% 至 73%。我們已經在我們網站的公司簡報中預覽了一些這些數據，並將在 4 月的 AD/PD 會議上分享更多資訊。

Our anti-tau antibody VY7523 performed well in a recently completed single ascending dose study. There were no serious adverse events, and we saw a dose proportional pharmacokinetics as well as a CSF to serum ratio of 0.3%, consistent with other monoclonal antibodies approved for the treatment of Alzheimer's disease. We initiated a multiple ascending dose study in Alzheimer's patients, and we expect initial tau PET data in the second half of 2026.

我們的抗 tau 抗體 VY7523 在最近完成的單次遞增劑量研究中表現良好。沒有出現嚴重不良事件，我們觀察到劑量比例藥物動力學以及腦脊髓液與血清的比率為 0.3%，這與其他獲準用於治療阿茲海默症的單株抗體一致。我們對阿茲海默症患者進行了多項劑量遞增研究，預計在 2026 年下半年獲得初步 tau PET 數據。

Finally, I want to point out that in Q4 2024, UCB's bepranemab demonstrated for the first time that an anti-tau antibody can impact tau accumulation in the human brain and that this may correlate with clinical benefit. It's important to acknowledge the study didn't meet its primary endpoint of the CDR sum of boxes, but our team walked out of the CTAD meeting feeling better about our anti-tau antibody than when we walked in.

最後，我想指出的是，2024 年第四季度，UCB 的 bepranemab 首次證明抗 tau 抗體可以影響人類大腦中的 tau 積累，並且這可能與臨床益處相關。必須承認，這項研究並未達到 CDR 框架總和的主要終點，但我們的團隊在離開 CTAD 會議時對我們的抗 tau 抗體的感覺比剛進來時更好。

Looking forward, I think there are several opportunities this year for third-party data to continue to build excitement for tau. Merck has antibody data expected in mid-2025, and I look forward to seeing what we learn at AD/PD in April, AAIC in July, and CTAD in the fall.

展望未來，我認為今年第三方數據有幾次機會繼續為 tau 帶來興奮。默克預計將在 2025 年中期獲得抗體數據，我期待看到我們在 4 月的 AD/PD、7 月的 AAIC 和秋季的 CTAD 上了解到的情況。

Okay. I promised I would keep it short. I just want to thank all of our employees for their hard work, especially pushing to achieve those end-of-year goals like getting the development candidate for the tau silencing program, working on the VY7523 single ascending dose analyses, and initiating the multiple ascending dose study.

好的。我保證我會長話短說。我只想感謝我們所有員工的辛勤工作，尤其是努力實現那些年底目標，例如獲得 tau 沉默計劃的開發候選藥物、開展 VY7523 單次遞增劑量分析以及啟動多次遞增劑量研究。

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

現在，我們將開始提問。操作員？

Thank you. (Operator Instructions)

謝謝。（操作員指令）

Jack Allen, Baird.

傑克艾倫、貝爾德。

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

非常感謝您回答這些問題，並祝賀團隊的進步。我想，艾爾，也許我應該從你的開場白開始講。您提到了一些在 tau 空間中可能有趣的外部讀數。您是否希望在 AD/PD 之前提供任何與人們應該關注的事情相關的額外信息，然後我也會快速跟進您的合作夥伴計劃。

Yeah. Hi, Jack. So at AD/PD I hope to see data from the bepranemab, as they -- I believe they may be sharing their data on exposure PD relationships, so PK/PD, which they didn't have a chance to share at the CTAD meeting last year. And also, more data on how much decrease in tau spreading do you need to see in order to see a clinically relevant effect. So that's one thing I'm going to be hoping to see.

是的。嗨，傑克。因此，在 AD/PD 會議上，我希望看到來自 bepranemab 的數據，因為我相信他們可能會分享有關暴露 PD 關係的數據，因此 PK/PD 數據在去年的 CTAD 會議上他們沒有機會分享。此外，為了看到臨床相關的效果，您需要看到更多關於 tau 擴散減少程度的數據。所以這是我希望看到的一件事。

The other thing might be more information about subgroups where greater efficacy can be seen. They started to talk about that a little bit at CTAD, for example, the effect of APOE4 carrier status, as well as initial tau burden, and there may be more information on that as we learn more about which are the ideal patients to be treated with an anti-tau approach.

另一件事可能是有關可以看到更大功效的亞群的更多資訊。他們在 CTAD 上開始討論這個問題，例如 APOE4 攜帶者狀態以及初始 tau 負擔的影響，隨著我們更多地了解哪些患者最適合接受抗 tau 方法治療，可能會有更多關於這方面的信息。

We also note that other companies have started to share data with their anti-tau program. So I know that for example, Eisai has been sharing data on fluid-based biomarkers with their anti-tau that targets the MTBR region. And I don't know whether other companies may also be starting to share data as well, but there's a lot of interest in tau. There's also the tau-silencing approaches that we know, for example, Biogen has, and I look forward to seeing any updates there might be on that.

我們還注意到其他公司已經開始與他們的抗 tau 計劃共享數據。因此我知道，例如，衛材 (Eisai) 一直在與其針對 MTBR 區域的抗 tau 共享基於液體的生物標記數據。我不知道其他公司是否也開始共享數據，但人們對 tau 很感興趣。我們也知道一些 tau 沉默方法，例如 Biogen 所擁有的，我期待看到有關該方面的任何更新。

Toby, did you want to add anything to that?

托比，你還有什麼要補充嗎？

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

嗯，我想我當然同意你的評論，並同意關於暴露反應的評論，包括初始 PK/PD，特別是 tau PET 與臨床關係。我確實認為，就亞群而言，我想了解關於 tau（低 tau）或他們之前描述的 [APOE] 組的詳細資訊。他們認為 APOE 的拉動動作是什麼。是因為沒有 APOE 等位基因的個體的 tau 水平較低，還是該群體還有其他的決定性特徵？

And then, more on the finance side, but I just wanted to ask, it seems like the two programs with Neurocrine on the gene therapy front are expected to enter the clinic or at least for the INDs filed this year. Any additional color you could 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?

然後，更多關於財務方面的問題，但我只是想問一下，似乎 Neurocrine 在基因治療方面的兩個項目有望進入臨床，或至少在今年提交 IND。您能否提供任何與即將到來的里程碑相關的想法，無論是來自 Neurocrine 還是您多年來建立的其他外部合作夥伴關係？

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

好的。謝謝你的提問，傑克。這是財務長 Nate Jorgensen。所以，我們說過，我們有 29 億美元的發展里程碑。所以我認為這些里程碑並不像一些公司報告的那樣是生物金錢。但如果將所有生物錢加在一起，正如 Al 所提到的那樣，總額將超過 80 億美元。因此，我認為未來幾年將有一些非常有意義的里程碑，這些里程碑可以幫助我們將現金流延長至我們對外談到的 2027 年中期指引之後。

Got it. And are those milestones at all accounted for in your guidance or are they additional upsides?

知道了。這些里程碑是否已經在您的指導中體現了，或者只是額外的好處？

No, they're not. So that's all upside to the mid-2027 cash runway guidance.

不，不是。因此，這對 2027 年中期的現金流指引來說都是有利的。

Phil Nadeau, TD Cowen.

菲爾·納多（Phil Nadeau），TD Cowen 公司。

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

午安.感謝您回答我們的問題。我們中的一對夫婦。首先，關於tau基因沉默IND，您能否向我們詳細介紹一下明年提交該IND之前需要完成哪些工作？

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

嗯，最重要的是我們必須完成我們剛剛發現的 GLP 毒性研究——我們剛剛開始，然後我們需要確保我們有一個治療窗口。正如我們所說，我們最初的非人類靈長類動物研究顯示敲低率為 50% 到 73%，這正是我們想要的範圍。我們只需確保現在不存在允許該劑量的任何安全問題——以正確的劑量產生該程度的沉默。

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?

完美的。然後，第二個問題關於 ALPL 太空梭。您能討論一下它最適用於哪些地方嗎？您認為哪些跡象最有用？您認為其中哪一位候選人何時可以晉級？

Well, we're looking broadly across various diseases, various targets. This is a receptor that allows for BBB penetrant of one of our leading classes of capsids. And that capsid gets in across the CNS pretty broadly. So that leaves open a lot of different diseases, both spinal cord as well as cerebral cortex and even subcortical diseases.

嗯，我們廣泛地研究各種疾病、各種目標。這是一種能夠允許我們的主要衣殼類別之一滲透 BBB 的受體。這種衣殼可以廣泛地進入中樞神經系統。因此，這留下了許多不同疾病的懸而未決的問題，包括脊髓疾病、大腦皮質疾病甚至皮質下疾病。

And then the kinds of drugs that we would -- we were thinking about transporting across the CBD would include proteins such as enzymes or antibodies. And also, we're starting to assess whether or oligonucleotides can be transported as well. That leaves open a wide array of possibilities still. And so, beyond that, you might imagine what the best antibodies or enzymes for oligonucleotides you might be thinking about.

然後，我們考慮運送穿越中央商務區的藥物種類包括酵素或抗體等蛋白質。此外，我們正在開始評估寡核苷酸是否也可以被運送。這仍然留下了廣泛的可能性。因此，除此之外，您可能還會想像您可能正在考慮的寡核苷酸的最佳抗體或酵素是什麼。

And, look, as we noted with the antibody, that [RNP] tau antibody, we get a CSF to serum ratio of 0.3%. So literally 99.7% gets thrown away. It'd be great if we could get more of the antibody into the brain. Also, all ASOs currently are intrathecally administered for CNS diseases, and that provides a burden to patients. It also produces a severe gradient in the CNS, which I think is limiting. So there's a lot of opportunities.

而且，正如我們在抗體 [RNP] tau 抗體中觀察到的那樣，我們得到的 CSF 與血清比率為 0.3%。因此實際上 99.7% 都被丟掉了。如果我們能夠將更多的抗體注入大腦，那就太好了。此外，目前所有 ASO 都是透過鞘內給藥來治療中樞神經系統疾病，這給患者帶來了負擔。它還會在中樞神經系統產生嚴重的梯度，我認為這是有限制的。所以有很多機會。

Todd or Toby, do you want to add anything to that?

Todd 或 Toby，你們還想補充什麼嗎？

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

我認為你已經掌握了大部分內容，艾爾。你問題的另一部分是推動事情向前發展，雖然我們還沒有分享任何數據，但我們希望在今年稍後分享更多早期工作。

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

這非常有幫助。再次恭喜您的進展。

Pete Stavropoulos, Cantor Fitzgerald.

皮特·斯塔夫羅普洛斯、費茲傑拉領唱者。

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

是的。下午好，祝賀您取得的所有進展，並感謝您回答我們的問題。我的第一個問題是，當我們期待 tau 沉默基因療法時，我想知道您是否可以談談我們應該從 tau 沉默與靶向抗體中期望的主要區別。考慮到 Biogen 080 的數據，您對組合方法有何看法，即使用單克隆方法進行 tau 沉默或敲低？

Thanks, Pete. This is Toby. Good to hear from you. So I think fundamentally that our belief on the knockdown approach with 1706 is a couple of key points. One, as we've highlighted it, we'll use our second-generation TRACER capsids. And so, it will be injected IV once. And that gives us a couple clear advantages.

謝謝，皮特。這是托比。很高興收到你的來信。因此，我認為從根本上來說，我們對 1706 擊倒方法的信念有幾個關鍵點。首先，正如我們所強調的那樣，我們將使用第二代 TRACER 衣殼。因此，將進行一次靜脈注射。這給我們帶來了一些明顯的優勢。

I think, one, is that it allows for better bio distribution, accessing the vasculature via ALPL. And so that's quite distinct from the grading you get with the intrathecal injection in the lumbar space with an ASO. So I think that presents an opportunity for broader tau knockdown.

我認為，首先，它能夠實現更好的生物分佈，並透過 ALPL 進入血管。這與使用 ASO 在腰椎空間進行鞘內注射所獲得的分級截然不同。所以我認為這為更大範圍的 tau 敲除提供了機會。

And so that is, I think, quite an important point. And then I'll -- in addition, the fact that it's IV and one time, we think is clearly some benefits both for the patients and potentially for the healthcare system in terms of ease of uptake.

所以我認為，這是非常重要的一點。然後我會 — 此外，事實上，它是靜脈注射並且是一次性的，我們認為，在易於接受方面，這顯然對患者和潛在的醫療保健系統都有一定的好處。

I think the other point I'd make is that of course the Biogen data, which comes out, we think, in mid-Q3 of '26, will be an important inflection point. And of course, we have an IND for our program in 2026 as well. So we think that's an important pairing.

我想說的另一點當然是，我們認為 26 年第三季中期發布的 Biogen 數據將是一個重要的轉捩點。當然，我們的計畫在 2026 年也會有一個 IND。因此我們認為這是一個重要的配對。

In terms of the antibody, I think fundamentally the premise of the antibody 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 tau has not yet spread.

就抗體而言，我認為從根本上來說，抗體的前提與試圖阻止傳播略有不同。因此，你的想法是，你要將其定位到 tau 尚未擴散的人群中。

On the other hand, for the knockdown approach, you look at the data that Biogen has shared. In that case, you can move pre-existing tau. And that was shown by tau PET, which is quite a remarkable observation.

另一方面，對於擊倒方法，您可以查看 Biogen 共享的數據。在這種情況下，您可以移動預先存在的 tau。tau PET 顯示，這是一個相當了不起的觀察結果。

So there may be some broader latitudes. There may be space for sequencing of a beta amyloid therapy with an antibody, and then a tau knockdown approach as well.

因此可能會存在一些更廣泛的自由度。可能有空間對使用抗體的β澱粉樣蛋白療法進行排序，然後也採用tau敲低方法。

All right. Thank you for that. Just one more question. The way that we viewed the SOD1 gene silencing program is that, it would provide proof of concept for the capsid and its ability to cross the blood brain barrier efficiently. By looking at changes in the NFL, we would hope to have seen similar to tofersen.

好的。謝謝你。還有一個問題。我們認為 SOD1 基因沉默程序將為衣殼及其有效穿過血腦屏障的能力提供概念證明。透過觀察 NFL 的變化，我們希望看到與托弗森類似的事情。

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?

您如何考慮建立人類概念驗證？哪個程式可能會幫助您做到這一點？一旦產生數據，是否有任何協議或期望讓合作夥伴共享或允許您共享數據？

Pete, this is Toby again. So I think you've rightly keyed in on the fact that the next opportunities to generate capsid POC really sit with the Friedreich ataxia and/or the GBA program, which are partnered with Neurocrine. I'll just remind that INDs for those programs are coming up this year.

皮特，我又是托比。因此我認為您正確地意識到了這樣一個事實：下一個生成衣殼 POC 的機會實際上在於與 Neurocrine 合作的 Friedreich 共濟失調和/或 GBA 計劃。我只是想提醒一下，這些項目的 IND 將於今年公佈。

And I think what I'd say is, holistically, Neurocrine is running those programs. But we have a strong collaboration with them across the development teams. And in both cases -- in Friedreich's, there's an opportunity for biomarker measurement in terms of frataxin levels. And then in GBA, there's an opportunity for biomarker measurement in terms of both enzyme GCase levels and substrate levels. So in both cases, both programs offer the opportunity to understand that the capsids are working.

我想說的是，從整體上看，Neurocrine 正在運行這些程式。但我們與他們在整個開發團隊中都保持著密切的合作。在這兩種情況下——在弗里德賴希病中，都有機會根據 frataxin 水平進行生物標記測量。然後在 GBA 中，有機會根據酶 GCase 水平和底物水平進行生物標記測量。因此，在這兩種情況下，這兩個項目都提供了了解衣殼如何發揮作用的機會。

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

感謝您回答我們的問題，並對所取得的進展表示祝賀。

Lili Nsongo, Leerink.

Lili Nsongo，Leerink。

Two questions from my side. So the first one being on maybe comparing and contrasting the two approaches for tau. So for pre-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 pre-clinical studies?

我有兩個問題。因此，第一個可能是比較和對比兩種 tau 方法。那麼就迄今為止的臨床前研究而言，您能否就您在臨床前研究中看到的兩種方法之間的潛在差異給我們提供一些看法？

Todd, do you want to touch that in the preclinical study?

托德，你想在臨床前研究中談一下這個嗎？

Sure. On the preclinical side, we've seen positive results from both. One aspect that we have discussed with the tau antibody program is that we do see differences targeting different epitopes. So for example, our C-terminal targeted epitope works quite well. In terminal targeted antibodies that have failed -- in the clinic failed in our seeding models. This is a model where we inject Alzheimer's patients' derived pathological tau into the brain of a mouse expressing human tau and look at the ability of a treatment to stop spreading. So the in-terminal failed antibodies didn't work. Our antibody does; many other antibodies do not.

當然。在臨床前方面，我們看到了兩者的正面成果。我們在 tau 抗體計劃中討論過的一個方面是，我們確實看到針對不同表位的差異。例如，我們的 C 端標靶表位效果很好。在我們的接種模型中，臨床中失敗的終端靶向抗體也失敗了。在這個模型中，我們將阿茲海默症患者衍生的病理性 tau 注入表達人類 tau 的小鼠大腦中，並觀察治療阻止擴散的能力。因此，末端失敗的抗體沒有起作用。我們的抗體確實如此；許多其他抗體則沒有。

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 hitting a mechanism in two ways. One, we're reducing the amount of tau and subsequent pathological tau to spread cell to cell. And then we're also reducing the amount of tau on the recipient cell to then receive that pathological prion-like material.

我想說的是，tau 敲低在類似模型中也表現出有效性，我們採用 tau 敲低方法時不受特定表位的驅動。因此，對於 tau 敲除，我們認為我們可能透過兩種方式觸及機制。首先，我們正在減少 tau 的數量以及隨後在細胞間傳播的病理性 tau。然後我們也減少受體細胞上的 tau 數量，以便接收病理性朊病毒樣物質。

So we think that there are interesting similarities, but also some key differences in the fundamental mechanisms of those two approaches.

因此，我們認為這兩種方法有有趣的相似之處，但在基本機制上也存在一些關鍵差異。

Thank you. And as a follow-up, maybe could you provide a little bit of color in terms of the MAD 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 bepranemab?

謝謝。作為後續問題，您能否就 MAD 研究設計提供一些詳細資訊？所以我知道您現在還沒有分享整個設計，但也許您能否給我們更多關於研究設計如何受到 bepranemab 研究結果的影響或指導的資訊？

Thank you. This is Toby. So it's excellent question. I think what we -- fundamentally, maybe a couple of points. So I think what we've learned about our antibody, including preclinical work and up through the SAD is that the antibody, prominin, it binds pathologic tau, which differentiates it from some other antibodies including UCB's. That we have appropriate PK; we've got good CSF penetration.

謝謝。這是托比。這是非常好的問題。我認為從根本上來說，可能有幾點。因此我認為，包括臨床前工作和 SAD 在內的我們對抗體的了解是，抗體 prominin 可以結合病理性 tau，這使它有別於包括 UCB 在內的一些其他抗體。我們有適當的PK；我們的腦脊髓液滲透性很好。

So in that context, we really think in the MAD study, we can drive to an effective determination of if we have a signal on that, particularly, in the context of what we've seen thus far. And that's important.

因此，在這種情況下，我們確實認為，在 MAD 研究中，我們可以有效地確定我們是否有相關訊號，特別是根據我們迄今為止所見的情況。這很重要。

I think in terms of the population. What we've learned from bepranemab is that the lower tau may be important in this context and/or ApoE status. And so what we've shared so far is that we've adjusted the thinking based on these data to focus on the earlier MCI and AD populations, which are necessarily lower tau.

我是從人口角度來思考的。我們從 bepranemab 中了解到，在這種情況下，較低的 tau 可能很重要和/或 ApoE 狀態。因此，到目前為止，我們所分享的是，我們已經根據這些數據調整了思路，將重點放在早期的 MCI 和 AD 人群，他們的 tau 水平必然較低。

I do think we'll need to be ready to respond to learnings as they continue to evolve. We've already highlighted that we're hoping to hear some discussions with AD/PD on the deeper side of these two subpopulations and/or exposure response. In addition, we've highlighted some other potential readouts in the field as well. So we'll, certainly, continue to monitor the field and adjust as we're able.

我確實認為我們需要做好準備，以應對不斷發展的學習。我們已經強調過，我們希望聽到一些關於 AD/PD 的關於這兩個亞群和/或暴露反應的更深層次的討論。此外，我們還強調了該領域的一些其他潛在讀數。因此，我們肯定會繼續監測該領域並盡我們所能進行調整。

I will highlight we -- yeah, I think that's what I'll call and --

我要強調的是──是的，我想這就是我所說的--

I might want to add that in the case of Alzheimer's, the history of Alzheimer's clinical trials. Sometimes multiple sending dose studies, for example, with the anti-amyloid antibodies that provided some really meaningful information, in terms of the effect on PET imaging.

我可能想補充一點，就阿茲海默症而言，阿茲海默症臨床試驗的歷史。有時，多次發送劑量研究，例如抗澱粉樣蛋白抗體研究，在對 PET 成像的影響方面提供了一些真正有意義的資訊。

And, here in this case, wouldn't it be fair to say, Toby, that given the data with bepranemab, particularly the safety, and also our single ascending dose results. We're planning to push the dose pretty high, right? And at the highest dose, we're going to really take a look at how much we can impede the spread of tau by PET imaging. And also look at fluid-based biomarkers. And so that's the -- plan and as Toby says, we'll be monitoring the situation with all the other data coming out.

在這種情況下，托比，這樣說不公平嗎？鑑於 bepranemab 的數據，特別是安全性，以及我們的單次遞增劑量結果。我們打算把劑量提高到相當高，對嗎？在最高劑量下，我們將透過 PET 成像真正觀察我們能對 tau 擴散的阻止程度。並且也要觀察以液體為基礎的生物標記。這就是計劃，正如托比所說，我們將密切關注所有其他數據的發布。

Sort of like real.

有點像真的。

Samantha Semenkow, Citi.

Samantha Semenkow 的花旗銀行。

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

對我來說這只是一個前瞻性的問題。我想知道您是否可以分享一些關於 ALPL 太空梭、非病毒太空梭的即插即用功能的資訊。根據您迄今為止在發現工作中所了解到的信息，一旦您完成開發，您是否有可能看到更短的交付時間，例如對於您想要運輸的每種分子類型。或者更可以預料的是，您想要運輸的每種酵素或每種寡核苷酸都會有一系列獨特的挑戰，您需要對其進行最佳化。您能分享的任何顏色都將非常有幫助。

Thank you.

謝謝。

Well, that's an interesting question. I mean, in some ways, the TFR-based shuttles have been a plug and play in the sense that it's worked for multiple different kinds of modalities, and we're starting to see data emerging that even beyond proteins that oligonucleotides may also be transported.

嗯，這是一個有趣的問題。我的意思是，在某些方面，基於 TFR 的太空梭已經是一種即插即用的技術，因為它適用於多種不同類型的模式，而且我們開始看到新出現的數據，甚至除了蛋白質之外，寡核苷酸也可以運輸。

Look, I mean, but even Denali, who are the leaders in TFRs, are also looking at CD98, right, as another shuttle vehicle.

你看，我的意思是，即使是 TFR 領域的領導者 Denali，也將 CD98 視為另一款太空梭。

So why would that be? And I guess it's because every receptor is going to have its own safety, distribution, and kinetics. And so it could be that for certain targets and certain diseases, it's more optimal to use one shuttle over another. I think time will tell. Right now, I think the field really only has one or really two shuttles that they can turn to, so everybody's using those. But as time goes on, we may be able to be more selective.

那為什麼會這樣呢？我猜測這是因為每個受體都有其自身的安全性、分佈和動力學。因此，對於某些目標和某些疾病來說，使用一種太空梭比使用另一種太空梭更為理想。我想時間會證明一切。目前，我認為賽場上實際上只有一兩架太空梭可以使用，所以每個人都在使用它們。但隨著時間的推移，我們可能會更有選擇性。

So it could be plug-and-play, but as we learn more about these various shuttles, we may start to tailor them to the right disease and the right target. That's how I see it now. Of course, it'll be great to get more data to see whether we're right about that.

因此它可以是即插即用的，但隨著我們對這些不同太空梭的了解越來越多，我們可能會開始根據正確的疾病和正確的目標對它們進行客製化。我現在就是這樣認為的。當然，如果能獲得更多數據來驗證我們的觀點是否正確那就更好了。

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

這非常有幫助。作為後續問題，您能否分享一下今年稍後非病毒太空梭的臨床前數據集是什麼樣子的？非常感謝。

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

嗯，顯然，我們將從展示動物數據開始。因此，顯然體內數據是最重要的。我們希望與一些基於 TFR 的太空梭進行比較，比較 ALPL，以開始了解它有何不同以及 ALPL 是否具有某些優勢。我們希望能夠展示多個有效載荷，看看它實際上有多麼的即插即用。但是——這就是我們希望展示的，我們正在為此努力，看看我們是否能夠實現目標。

Great. Looking forward to it. Thanks very much.

偉大的。非常期待。非常感謝。

Todd do you want to (multiple speakers)

托德你想（多位發言者）

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

不，我想，艾爾，你抓住了它。我的意思是，我們可能對此感到非常興奮，並希望在今年晚些時候分享這一點。

Thanks, Samantha.

謝謝，薩曼莎。

Joon Lee, Truist Securities.

Joon Lee，Truist Securities。

This is Mehdi on for June and congrats on the progress. A couple on capsids for us as well. So given that for SOD1 ALS program, the recap Gen 2 is going to be the same for VY1706, what are the data points that gives you the confidence that the neurotox that you have seen is not related to the capsid?

這是六月的 Mehdi，祝賀他的進步。我們也有一些關於衣殼的資訊。因此，考慮到對於 SOD1 ALS 計劃，Recap Gen 2 將與 VY1706 相同，哪些數據點可以讓您確信您所看到的神經毒素與衣殼無關？

Well, there's two reasons. One is the timing of the adverse events. So in the case of the SOD1 program, in the initial time points, in the several days after we inject, we do see the expected slight bump in liver function tests and in neurofilament levels. And that's exactly where other programs have seen -- have shown those kinds of adverse events with IV delivered AAD. And that's to be expected. But the capsid clears from the bloodstream within days.

嗯，有兩個原因。一是不良事件發生的時間。因此，就 SOD1 計劃而言，在最初的時間點，也就是注射後的幾天內，我們確實看到肝功能測試和神經絲水平出現預期的輕微上升。而其他項目也確實發現了這一點 — — 已經證明了透過靜脈注射 AAD 會出現此類不良事件。這是可以預料到的。但衣殼會在幾天之內從血液中清除。

And then what we saw was with a delay of about three months, we saw then the neurofilaments start to go back up. And that was coincidence with some neurological adverse events observed at case size. And then when you look histologically, you see evidence of neurodegeneration. So it's that delay, which is when expression has really come into play, that we see the adverse events. And so the timing is not right for capsids, much more consistent with expression of the payload.

然後我們看到，大約三個月後，神經絲開始恢復。這與在病例規模中觀察到的一些神經系統不良事件是一致的。然後，當你從組織學角度觀察時，你會看到神經退化的證據。所以，正是在這種延遲，也就是表達真正發揮作用的時候，我們才看到了不良事件。因此，對於衣殼來說，時機尚不成熟，與有效載荷的表達更加一致。

The other thing is that we use the exact same capsid with four other constructs with various promoters and various payloads. And we see no such adverse events in non-human primates. Even at doses that are comparable to what we tested with SOD1 and even at the two to three month time point. So it's both of those pieces of evidence that gave us a lot of confidence that it was the payload and not the capsid.

另一件事是，我們使用完全相同的衣殼和其他四種具有不同啟動子和不同有效載荷的構建體。我們在非人類靈長類動物中沒有看到此類不良事件。即使劑量與我們用 SOD1 測試的劑量相當，甚至在兩到三個月的時間點。所以這兩份證據都讓我們非常有信心它是有效載荷而不是衣殼。

(multiple speakers) Maybe I'll just add. When -- sorry, when Al talks about what we're looking at, we're looking at histopathology, we're looking at NFL as a biomarker, and we're looking at clinical science. So none of those -- we see none of that with the capsid with these other payloads.

（多位發言者）也許我只需要補充一點。當 — — 抱歉，當 Al 談到我們正在研究的內容時，我們正在研究組織病理學，我們正在將 NFL 作為生物標誌物進行研究，我們正在研究臨床科學。因此，我們在這些其他有效載荷的衣殼上沒有看到任何這些情況。

Ry Forseth, Guggenheim Securities.

古根漢證券的 Ry Forseth。

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

嘿，我是 Debjit 團隊的 Ry。返回第三方讀數。我確信決策矩陣非常大，但我們希望了解具體的結果以及這些結果如何對您的臨床前基因治療或 7523 MAD 工作產生影響。也許概述瞭如何根據數據對這些程序進行調整。

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

您說的是有關抗體的第三方數據嗎？

Either silencing efforts or antibodies.

要么抑制努力，要么抗體。

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

我明白了，是的。因此，我認為最重要的數據之一將來自強生公司的抗體研究，我們將於明年公佈這些數據。我這樣說主要是因為這是一項大規模研究，控制得很好，規模大，時間長，可以很好地了解首先我們是否看到不同的抗體對 tau 擴散的影響。換句話說，重現 UCB 所顯示的結果，然後更好地掌握阻止 tau 擴散是否會產生臨床顯著後果，這是我們希望看到的。因此我認為我們必須等待強生公司的數據，我認為是在明年。

In terms of the knockdown approaches, what's remarkable about the [BIIB080] data for me anyway is the fact that you actually reduce the tau PET signal, which I didn't think would be possible because I always thought that the pathological tau was in neurofibrillary tangles, which is pretty much not going to be reduced by simply reducing the synthesis of new tau. But that's exactly what Biogen has shown.

就敲減方法而言，[BIIB080] 數據對我來說最顯著的特點是它確實降低了 tau PET 信號，我認為這是不可能的，因為我一直認為病理性 tau 存在於神經纖維纏結中，而僅僅減少新 tau 的合成幾乎無法降低這種纏結。但這正是 Biogen 所展現的。

And what's intriguing is that, they seem to see a pretty big clinical benefit of that. Now, the flaw there is that, there was no control group in that study, but they've done a great job comparing it to natural history and to the control groups of other trials. And it does look like a large effect.

有趣的是，他們似乎看到了其相當大的臨床益處。現在，存在的缺陷是，該研究中沒有對照組，但他們在將其與自然歷史和其他試驗的對照組進行比較方面做得很好。而且它確實看起來效果很大。

I would think that with the passage of time, we will know even better whether or not that clinical effect is real and durable. And so those are the kinds of things I'm going to be looking at.

我認為隨著時間的推移，我們將更加清楚這種臨床效果是否真實且持久。這些就是我要關注的事情。

Of course, we always want to know, answer the question, does epitope matter? In the case of the anti-amyloid antibodies, epitope did really matter. He's now speaking about the antibody programs, of course. And then the only other question is, is it important to be specific for pathological forms of tau versus all forms of tau? UCB was not specific for the pathological forms of tau. Ours is, and I believe many of the other antibodies are as well that are coming down the pipe.

當然，我們總是想知道，回答這個問題，表位重要嗎？就抗澱粉樣蛋白抗體而言，抗原決定位確實很重要。當然，他現在談論的是抗體計畫。那麼唯一的另一個問題是，針對病理形式的 tau 而不是所有形式的 tau 進行特異性檢測是否重要？UCB 對 tau 的病理形式沒有特異性。我們的抗體是這樣的，而且我相信許多其他的抗體也不斷出現。

In the case of anti-amyloid antibodies, it was important to be specific for pathological forms of amyloid. So we'll see if that also applies to the tau.

對於抗澱粉樣蛋白抗體來說，針對澱粉樣蛋白的病理形式進行特異性檢測非常重要。因此我們將看看這是否也適用於 tau。

Toby, Todd, what did I forget?

托比，托德，我忘了什麼？

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

也許我會強調默克的讀數。它是一種C端表位病理抗體。這是一項針對生物標記的簡短研究，但為您提供了初步機會來回答這個問題：表位 - C 端表位是否可以產生至少總 tau？這也是一個重要的概念。

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

謝謝。也許我們還想問一個問題。對於四月份的 AD/PD NHP 基因治療數據，您能否提供進入大腦相對於肝臟的載體百分比的分佈數據？如果沒有的話，也許您可以以為我們闡述航海家號對這些措施的實用性的思考。

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

所以，我們 — — 例如，在 AD/PD 上，我們將展示 tau 敲除計畫。我們將描述顯示遞送的數據，包括我們在大腦和周邊組織中實現的載體數量和藥理學敲除。因此，它可能不是百分比格式，但我們將討論向重要位置的遞送，其中包括目標和我們認為的非目標組織。

Jay Olson, Oppenheimer.

傑伊奧爾森、奧本海默。

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

哦，嘿，感謝您提供此更新。我們對將在 AD/PD 上展示的 tau 沉默計劃的新臨床前數據有一個疑問。您能談談您計劃達到的 tau mRNA 敲低目標水平嗎？大腦中是否存在對 tau mRNA 和蛋白質減少更重要的特定區域？

Well, I'll start with the last question. And maybe, Todd, you can answer the first question.

好吧，我先問最後一個問題。托德，也許你可以回答第一個問題。

So when I think of Alzheimer's disease, it's a cortical disease, the cerebral cortex, and it starts in the temporal lobe, but then it spreads to all the other major cortical regions. So to me, the key region in the CNS that we need to look at for tau silencing is the cerebral cortex, pretty broadly.

所以當我想到阿茲海默症時，它是一種皮質疾病，即大腦皮層，它始於顳葉，但隨後擴散到所有其他主要皮質區域。所以對我來說，我們需要觀察的中樞神經系統 tau 沉默的關鍵區域是大腦皮層，範圍相當廣泛。

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

Al 之前提到了我們瞄準的大致範圍，即 50% 到 73%。這就是我們正在研究的擊倒的一般範圍。我們可以——而且我們的研究表明，我們在非人靈長類動物的一些關鍵區域，特別是皮層中實現了廣泛的敲低，我們認為我們需要實現這些類型的敲低並對疾病產生影響。

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

好的，太好了。謝謝。那麼您能否評論一下您對 tau 沉默計畫適應症的看法？您會從阿茲海默症開始治療嗎，或者您會從其他 tau 蛋白疾病開始治療嗎？

Well assuming, we don't partner it. We would -- look our intention is to partner it and so it may be our partners decides, which indications to go after, but you make a really good point here, which is that there are a variety of tau-opathies that we could go after. The most well-known ones, of course, are TSP progressive supranuclear palsy. There's also frontotemporal dementia due to tau, mutations in tau. And then there are a lot of other diseases as well, including potentially chronic traumatic encephalopathy.

好吧，假設我們不與其合作。我們會 — — 看起來我們的意圖是與之合作，因此可能是我們的合作夥伴決定追蹤哪些適應症，但你在這裡提出了一個很好的觀點，那就是我們可以追蹤多種 tau 病。當然，最著名的是 TSP 進行性核上性麻痺。由於 tau 基因突變，也會導致額顳葉失智症。還有很多其他疾病，包括潛在的慢性創傷性腦病。

And so -- but I do think that we -- if it stays in our hands, we will probably look very hard at Alzheimer's disease first, where the -- a lot of us do believe that tau is a really important target for Alzheimer's disease, and that -- and then so much is known about the natural history of Alzheimer's disease and how to make measurements both fluid-based as well as imaging measurements. So we're going to take full advantage of all that knowledge and look hard at Alzheimer's disease first. That's our approach. What do you think, Toby?

所以 — — 但我確實認為 — — 如果它仍在我們手中，我們可能會首先認真研究阿茲海默症，其中 — — 我們很多人確實相信 tau 是阿茲海默症的一個真正重要目標，而且 — — 然後我們對阿茲海默症的自然史以及如何進行基於液體的測量以及成像測量有了更多的了解。因此，我們將充分利用所有這些知識，首先認真研究阿茲海默症。這就是我們的方法。托比，您覺得怎麼樣？

I agree, Al. And maybe I'd amplify that fundamentally, I mean, we've seen with the [baby] data how critical tau PET can be. And this is best worked out in Alzheimer's disease.

我同意，艾爾。或許我會從根本上進一步闡述這一點，我的意思是，我們已經透過 [嬰兒] 數據看到了 tau PET 的重要性。這對於治療阿茲海默症最為有效。

Looking at some of the other tauopathies, use of tau PET and in some cases, flu biomarkers, is less well settled. And so one of our core tenets is that you go into diseases where you can get critical concept around the biomarker tools relatively quickly. In this case, for the tauopathies, we think that really sits with Alzheimer's. I certainly think the other indications are interesting once you've shown that.

從其他一些 tauopathies 來看，tau PET 和某些情況下的流感生物標記的使用還不太確定。因此，我們的核心原則之一是，當您研究疾病時，您可以相對快速地獲得有關生物標記工具的關鍵概念。在這種情況下，對於 tauopathies，我們認為它確實與阿茲海默症有關。一旦你展示了這一點，我當然認為其他跡象會很有趣。

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

偉大的。謝謝。也許我可以問一個有關 ALPL 的後續問題。您是否做過任何實驗來比較 ALPL 穿梭機與其他血腦屏障穿梭機（如轉鐵蛋白受體）並查看它們之間有何差異？

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

我們尚未分享該數據，但我們正在與 TFR 進行比較。

Patrick Trucchio, H.C. Wainwright Company.

帕特里克·特魯基奧，H.C.溫賴特公司。

Just a couple of follow-up questions on the VY7523. Just 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-tau space and those that are upcoming, I'm wondering how the MAD study design may position VY7523 for differentiation? And then separately, I'm wondering, the cash runway extending into mid-2027, how will you balance investment in internal programs versus potential licensing or business development opportunities?.

我只想問幾個關於 VY7523 的後續問題。首先，我想知道 SAD 數據如何影響 MAD 研究的劑量水平和頻率的選擇。然後分別來說，僅考慮到抗 tau 領域的競爭讀數以及即將到來的讀數，我想知道 MAD 研究設計如何定位 VY7523 以實現差異化？然後另外，我想知道，現金跑道延伸到 2027 年中期，您將如何平衡內部專案的投資與潛在的許可或業務發展機會？

Maybe I’ll start and then turn it over to Nate. So, I think in terms of the SAD data, just to reiterate, we saw dose-proportionate PK, an acceptable safety profile for a molecule in the single-sending dose study, and we saw a CSF serum ratio of 0.3%, which is quite consistent with approved molecules.

也許我會開始，然後把它交給 Nate。因此，我認為就 SAD 數據而言，只需重申一下，我們看到了與劑量成比例的 PK，這是單次劑量研究中分子的可接受的安全性特徵，並且我們看到 CSF 血清比率為 0.3%，這與批准的分子非常一致。

And then I think I'd lay on top of that the observed safety and the broader bepranemab study didn't highlight any risk of [ARIA]. So really what the SAD data gave us was the confidence in the MAD study to move forward with our planned doses.

然後我認為最重要的是觀察到的安全性和更廣泛的 bepranemab 研究沒有突出任何風險[詠嘆調]。因此，SAD 數據實際上給予了我們對 MAD 研究繼續推進我們計劃劑量的信心。

And frankly, as Al highlighted earlier, to try to push those doses to levels where we can clearly test the hypothesis of whether or not this antibody will impede the spread of pathologic tau. In terms of differentiation for the competitors and what are we looking for. I think fundamentally the study will be designed to look for tau PET signals.

坦白說，正如 Al 先前所強調的那樣，試著將這些劑量推高到我們可以清楚地檢驗這種抗體是否會阻礙病理性 tau 擴散的假設的水平。就競爭對手的差異化以及我們所尋求的東西而言。我認為從根本上來說，這項研究的目的是尋找 tau PET 訊號。

And so really what we're trying to do, I think frankly, is see where we compare to the other antibodies that are modulating tau PET signals, particularly UCB. And I think our simple aspiration here would be that we are at least as good as, if not better than that, given our specificity for pathologic tau.

所以坦白說，我們真正想要做的是看看我們與調節 tau PET 訊號的其他抗體（特別是 UCB）相比有何不同。我認為我們在這裡的簡單願望是，考慮到我們對病理性 tau 的特異性，我們至少可以達到相同的水平，甚至更好。

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

是的，我可以補充一點，看，你說到點子上了，我們的目標是嘗試區分並利用我們的抗體取得最好的效果。我還想說，我們知道在 Todd 之前提到的動物模型中阻止 tau 擴散所需的劑量或大腦中的水平，我們將人類病理性 tau 注射到 P301S 基因轉殖小鼠體內。因此，我們希望確保超過這些，如果你願意的話，可以達到阻止傳播的 EC50 值。我們非常有信心，利用現有的劑量，我們可以達到這個目標。我們將根據所做的單次遞增劑量研究進行選擇。

And, Nate, do you want to answer the second half of the question?

內特，你想回答問題的後半部嗎？

Yeah. So what I will say is that we understand the financing market out there and the cash runway to mid-2027 is important to us. We would be very thoughtful if we would do any type of transaction or then which would shorten that. We'd have to bring in some really interesting assets that potentially with the clinical -- near-term clinical catalysts.

是的。所以我想說的是，我們了解現有的融資市場，到 2027 年中期的現金流對我們來說很重要。如果我們要進行任何類型的交易或縮短這一時間，我們會非常謹慎。我們必須引入一些真正有趣的資產，這些資產可能具有臨床—近期臨床催化劑的角色。

In terms of the other types of deals, those are something that Al always talks about that he's open to. Like, there's -- I think, opportunities out there for us to do additional BD deals to potentially bring in money or potentially take our some of our pipeline assets and bring it to another partner, of course, for the right price.

就其他類型的交易而言，艾爾一直表示他願意接受這些交易。就像，我認為，我們有機會進行額外的 BD 交易，從而可能帶來資金，或者可能將我們的一些管道資產帶給另一個合作夥伴，當然，以合適的價格。

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

是的，我的意思是——看看我們的歷史，我們做過任何事情，從簡單的衣殼許可，其他公司拿來衣殼並用它來運行，到我們可能在這裡啟動的實際項目的合作夥伴關係，然後我們可以繼續在這裡工作，由合作夥伴報銷。這表明我們願意建立任何對合作夥伴和我們自己都有意義的合作關係。我希望我們能繼續做這樣的事。

Yun Zhong, Wedbush Securities.

韋德布希證券公司的 Yun Zhong。

The first question is on the MAD study. Was the initiation earlier than you had expected? Because I believe the original guidance was very broadly in 2025?

第一個問題是關於 MAD 研究的。啟動儀式是否比你預期的早？因為我相信最初的指導範圍非常廣泛，是在 2025 年？

And the second question is, I know that you compared the anybody approach versus the knockdown approach and compared the mechanism of action. Given the timing, do you think it's possible that the knockdown program could potentially catch up to be a more promising approach as compared to the antibody approach?

第二個問題是，我知道您比較了任何人的方法和擊倒方法，並比較了作用機制。考慮到時機，您是否認為敲減程序有可能成為比抗體方法更有前景的方法？

Maybe I'll take the -- this is Toby. So we guided our -- we did start the study a bit earlier than our guidance. And I think this just reflects the clinical team is up and going and executing. And then, Yun, can you clarify your second question for me, please?

也許我會接受──這是托比。因此我們進行了指導——我們確實比指導時間早了一些開始這項研究。我認為這只是反映出臨床團隊正在啟動並執行任務。然後，Yun，你能為我澄清一下你的第二個問題嗎？

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

哦，我知道抗體方法領先於敲除方法，但考慮到 Al 談到了這種機制以及 Biogen 數據，您是否認為敲除方法最終可能比抗體方法更有希望治療 AD？

Oh, I mean, what I'd say here is, we have two different approaches, and I think one, we have some early data from Biogen suggesting that knockdown could be quite clinically efficacious. Al's highlighted that this was a natural history comparator and a (comparison cohort) in another study with effect on CDR sum of boxes that was maybe 2 to 3 times greater than what is a class of observed for amyloid therapy. So essentially a very large effect with a knockdown approach. So that's very exciting within the constraints of a intrathecally administered ASO.

哦，我的意思是，我在這裡要說的是，我們有兩種不同的方法，我認為，第一，我們有來自 Biogen 的一些早期數據，表明擊倒可能具有相當的臨床效果。Al 強調指出，這是一個自然史比較器，在另一項研究中，其對 CDR 盒總數的影響可能是澱粉樣蛋白治療所觀察到的一類影響的 2 到 3 倍。因此，本質上，採用擊倒方法可以產生非常大的效果。因此，這在鞘內注射 ASO 的限制內非常令人興奮。

Antibody-based approaches, I think the data we have there is the UCB data, which is the main clinical data sets. And that effect was slightly different. And so I think the potential there is potentially different. But fundamentally to me, the question is more going to be of the appropriate sequencing and the appropriate risk benefit and what is appropriate to the disease stage of individuals as we previously discussed.

基於抗體的方法，我認為我們擁有的數據是 UCB 數據，這是主要的臨床數據集。但效果略有不同。因此我認為那裡的潛力可能有所不同。但對我而言，從根本上來說，問題更多的在於適當的排序和適當的風險收益，以及正如我們之前討論過的適合個別疾病階段的治療方法。

So really there may be a point in time when you want to stop spread in a low-tau population early in disease. Or there may be a population of time when someone has a broader spread of tau when you want to take a knockdown approach. Or you may learn their differential responses across different patient populations.

因此，實際上可能存在一個時間點，你需要在疾病早期阻止其在低 tau 人群中傳播。或者，當您想採取擊倒方法時，可能存在某個時間段內某人的 tau 分佈更為廣泛。或者您可能了解不同患者群體的不同反應。

So I think fundamentally Alzheimer's is complex and physicians and patients are going to need options in terms of to fully treat this disease.

因此，我認為從根本上來說，阿茲海默症很複雜，醫生和患者需要採取一些措施才能全面治療這種疾病。

I would add that. I believe we're still on the very early stages of learning about how and how to best approach this target. If you look back at the anti-amyloid field, it took us decades to learn from each other and to get to the point where we finally had some drugs that were approved.

我想補充一點。我相信我們仍處於學習如何以及如何最好地實現這一目標的早期階段。如果回顧抗澱粉樣蛋白領域，我們花了幾十年的時間互相學習，才最終研發出一些核准的藥物。

We're just in the very beginning stages. We're only just now starting to see biological effects that are starting to be seen in humans. And I think there's going to be a lot to learn. And I think for right now, the prudent thing to do is to pursue both programs and we will make data driven decisions. Internal data as well as external data. We will learn from those and we will make data driven decisions.

我們才剛處於起步階段。我們現在才剛開始看到在人類身上出現的生物效應。我認為還有很多東西要學習。我認為就目前而言，明智的做法是推行這兩個計劃，並做出以數據為基礎的決策。內部資料以及外部資料。我們將從中吸取教訓，並做出以數據為依據的決策。

Yanan Zhu, Wells Fargo Securities.

朱亞南，富國證券。

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

首先，我想問一下有關腦穿梭方法的後續研究。艾爾，我想你已經提到了這一點。從您的角度來看，基於 TFR 的大腦穿梭機的限制是什麼？您希望在哪些方面對其進行區分？然後我會跟進 tau 計劃。謝謝。

Well, from what I see, there is evidence of hematologic adverse events, which is not surprising given the function of a transferrin receptor. And even when you use ligands for different epitopes on the transferrin receptor, you still see some adverse events, because even if you don't block the transfer receptor, you probably lead to its internalization and therefore you end up with loss of function type adverse events.

嗯，據我所知，有血液學不良事件的證據，考慮到轉鐵蛋白受體的功能，這並不奇怪。甚至當你使用針對轉鐵蛋白受體上不同表位的配體時，你仍然會看到一些不良事件，因為即使你不阻斷轉移受體，你也可能會導致其內化，因此最終會導致功能喪失類型的不良事件。

If you look at the human genetics database, humans are not very well -- very tolerant of loss of function mutations in transferring receptors. It's a pretty critical pathway. So now in contrast, humans seem to be pretty tolerant of loss of function mutations. Well, I should say more tolerant of loss of function mutations of ALPL. So that could be an advantage. Of course, time will tell. But I would say that's one of the potential advantages, but there could be more as we learn more.

如果你查看人類遺傳學資料庫，你會發現人類對於轉移受體功能喪失突變的容忍度並不太高。這是一條相當關鍵的途徑。相較之下，人類似乎對功能喪失突變具有相當的耐受性。嗯，我應該說對 ALPL 功能喪失突變有更高的容忍度。所以這可能是個優勢。當然，時間會證明一切。但我想說這是潛在的優勢之一，但隨著我們了解的更多，可能會有更多。

Great, thanks for --

很好，謝謝--

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

亞南，讓我再補充一點，我認為我們有時會忘記藥物的基本特性，例如 PK 和半衰期。我之前提到過動力學和分佈。因此我們也會關注這些事情。這並不是說基於 TFR 的方法沒有前景，它們很有前景。事實是如此令人充滿希望，這就是為什麼我們對使用基於太空梭的方法來改善基因療法以外的其他治療方式的想法如此興奮。

Got it. Yep. Thank you for the insight. On the tau antibody program, I was wondering if it's fair to say that the Merck's antibody is even more similar to your antibody than the UCB antibody is? Have you compared in your tau animal model directly your antibody against Merck's antibody and what might be the findings?

知道了。是的。感謝您的見解。關於 tau 抗體計劃，我想知道是否可以說默克公司的抗體比 UCB 抗體與您的抗體更相似？您是否在 tau 動物模型中直接比較了您的抗體與默克的抗體，結果是什麼？

And lastly, I was wondering about your thoughts on effector function for the general tau antibody approach, if you can comment on whether yours is effector or not and why does that matter, if it does? Thank you.

最後，我想知道您對一般 tau 抗體方法的效應子功能的看法，您是否可以評論一下您的方法是否是效應子，如果是，那為什麼重要？謝謝。

Yeah, I can take this. This is Todd. I do think you're right. In a lot of ways, the Merck antibody is more similar to C-terminal antibody. We have not shared any data comparing the C-terminal Merck antibody to ours. So we don't have that to share.

是的，我可以接受。這是托德。我確實認為你是對的。在很多方面，默克抗體與C端抗體更加相似。我們尚未分享任何將 C 端默克抗體與我們的抗體進行比較的數據。因此我們沒有可以分享的東西。

On the effector function, it's an interesting question. And we've gone with effectively a known IgG4, human IgG4 for our antibody. The evidence to date suggests that to have an effect in these spreading models, and it looks like perhaps with bepranemab in the clinic that you don't need effector function, and eliminating -- it eliminates or reduces some risk around a neuroinflammation, we think. So we've gone with an hIgG4 for our antibody.

關於效應功能，這是一個有趣的問題。我們有效地採用了已知的 IgG4，即人類 IgG4 作為我們的抗體。迄今為止的證據表明，為了在這些擴散模型中發揮作用，並且在臨床上使用貝普拉尼單抗可能不需要效應功能，並且消除 - 我們認為它可以消除或降低神經發炎的一些風險。因此我們採用 hIgG4 作為抗體。

Sumant Kulkarni, Canaccord Genuity.

Sumant Kulkarni，Canaccord Genuity。

Apologies if this was asked before. And Al, I know you gave a quick history lesson there on anti-amyloid products for Alzheimer's. But what are the key results you need to see or learnings from external programs that might lead you to making a firm go-no-go decision on your anti-tau antibody program? Or would you need to see internal results in order to make that decision? And what might those internal results look like?

如果之前問過這個問題，請見諒。艾爾，我知道你簡單介紹了一下治療阿茲海默症的抗澱粉樣蛋白產品的歷史。但是，您需要從外部程序中看到哪些關鍵結果或學到哪些知識，才能讓您對抗 tau 抗體計劃做出堅定的決策？或者您需要看到內部結果才能做出決定？那麼這些內部結果會是什麼樣的呢？

Yeah. I mean, that's a tough question to answer. What I'm looking for, Sumant, is really how much of an effect on tau spreading do you have to see to see a minimally clinically significant effect. So, in the case of the anti-amyloid antibodies. And by the way, you can learn from different antibodies against different epitopes. But the key question is how much of an effect on amyloid PET imaging did you need to see to see an effect on CDR sum of boxes, which is the required endpoint for approval. And you can actually draw a graph with all the different antibodies and see that if you don't get to a certain level of amyloid lowering, you don't get a big enough effect on CDR sum of boxes.

是的。我的意思是，這是一個很難回答的問題。蘇曼特，我真正想知道的是，要看到對 tau 擴散有多大的影響，才能看到具有最小臨床顯著性的影響。因此，就抗澱粉樣蛋白抗體的情況而言。順便說一句，您可以從針對不同表位的不同抗體中學習。但關鍵問題是，您需要看到對澱粉樣蛋白 PET 成像有多大的影響才能看到對 CDR 框架總和的影響，這是獲得批准所需的終點。您實際上可以繪製包含所有不同抗體的圖表並發現如果沒有達到一定程度的澱粉樣蛋白降低，則對 CDR 框總和的影響就不會足夠大。

So that's precisely the thing I think I would like to see with the anti-tau antibodies. And I would say that, anything less than a roughly 30% effect on CDR sum of boxes, I would say probably not clinically meaningful. So that's what I'm looking for is what is the effect on tau PET imaging that gives us a 30% effect on CDR sum of boxes.

所以這正是我希望在抗 tau 抗體中看到的。我想說的是，對 CDR 框總數的影響小於大約 30% 的任何影響，可能都沒有臨床意義。所以我要尋找的是，對 tau PET 成像有何影響，使 CDR 盒總和產生 30% 的影響。

Once we know that for sure, then we can look at our antibody and say, okay, it met that hurdle or not. I think it's going to take a little bit more time to get that. It took more than a decade to generate that data for the anti-amyloid antibodies and various companies sharing their data. So -- and like I said, I think we're in the early stages still of the tau directed antibodies.

一旦我們確定了這一點，我們就可以觀察我們的抗體，並說，它是否達到了那個障礙。我認為要實現這一目標還需要一些時間。產生抗澱粉樣蛋白抗體的數據以及各公司共享其數據花了十多年的時間。所以 — — 就像我說的，我認為我們仍處於 tau 定向抗體的早期階段。

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

謝謝。現在我想將電話轉回給 Al Sandrock 博士，請他做最後發言。

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

感謝大家今天的加入我們，我們期待很快能再次與你們交談。

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

謝謝。會議到此結束。感謝您的參與。您現在可以斷開連線。