Acumen Pharmaceuticals Inc (ABOS) 2023 Q4 法說會逐字稿

Ladies and gentlemen, thank you for standing by. Welcome to Acumen Pharmaceuticals full-year 2023 earnings conference call and webcast. (Operator Instructions)

女士們先生們，謝謝你們的支持。歡迎參加 Acumen Pharmaceuticals 2023 年全年收益電話會議和網路廣播。（操作員說明）

Please be advised that today's conference is being recorded. I would like now to turn the conference over to Alex Braun, Head of Investor Relations. Please go ahead.

請注意，今天的會議正在錄製中。我現在想把會議交給投資者關係主管亞歷克斯·布勞恩(Alex Braun)。請繼續。

Thanks, Michelle. Good morning and welcome to the Acumen conference call to discuss our business update and financial results for the year ended December 31, 2023. With me today are Dan O'Connell, our Chief Executive Officer; Dr. Jim Doherty, our President and Chief Development Officer; Dr. Eric Siemers, our Chief Medical Officer; and Matt Zuga, our Chief Financial Officer and Chief Business Officer.

謝謝，米歇爾。早安，歡迎參加 Acumen 電話會議，討論我們截至 2023 年 12 月 31 日止年度的業務更新和財務業績。今天與我在一起的有我們的執行長 Dan O'Connell； Jim Doherty 博士，我們的總裁兼首席開發長； Eric Siemers 博士，我們的首席醫療官；以及我們的財務長兼首席商務官馬特祖加 (Matt Zuga)。

Before we begin, we encourage listeners to go to the Investors section of the Acumen website to find our press release issued this morning and related slide presentation that we'll discuss today. Please note that during today's conference call, we may make forward-looking statements within the meaning of the federal securities laws, including statements concerning our financial outlook and expected business plans. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those described in the forward-looking statements.

在我們開始之前，我們鼓勵聽眾訪問 Acumen 網站的投資者部分，尋找我們今天早上發布的新聞稿以及我們今天將討論的相關幻燈片演示。請注意，在今天的電話會議上，我們可能會做出聯邦證券法含義內的前瞻性聲明，包括有關我們的財務前景和預期業務計劃的聲明。這些陳述存在風險和不確定性，可能導致實際結果與前瞻性陳述中所述的結果有重大差異。

Please see slide 2 of our corporate presentation, our press release issued this morning and our most recent annual and quarterly reports filed with the SEC for important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements.

請參閱我們公司簡報的幻燈片2、今天早上發布的新聞稿以及我們向SEC 提交的最新年度和季度報告，以了解可能導致我們的實際結果與前瞻性聲明中明示或暗示的結果存在重大差異的重要風險因素。聲明。

We undertake no obligation to update or revise the information provided on this call or in the accompanying presentation as a result of new information or future results or developments. After our prepared remarks, we'll turn -- we'll open the call for Q&A.

我們不承擔因新資訊或未來結果或發展而更新或修改本次電話會議或隨附簡報中提供的資訊的義務。在我們準備好的發言之後，我們將開始問答環節。

Now I'll turn the call over to Dan.

現在我將把電話轉給丹。

Thanks Alex. Good morning and thanks to everyone who is joining us today. 2023 was a landmark year for Acumen. Our monoclonal antibody for the treatment of early Alzheimer’s disease, ACU193, which recently received its non-proprietary name, sabirnetug, delivered positive and exciting Phase 1 results first presented at AAIC last July. You will hear more about these results and how they serve as the cornerstone for establishing sabirnetug’s differentiated therapeutic profile later on this call.

謝謝亞歷克斯。早安，感謝今天加入我們的所有人。 2023 年對 Acumen 來說是具有里程碑意義的一年。我們用於治療早期阿茲海默症的單株抗體 ACU193 最近獲得了非專有名稱 sabirnetug，去年 7 月在 AAIC 上首次展示了積極且令人興奮的 1 期結果。稍後您將在本次電話會議上聽到有關這些結果的更多信息，以及它們如何成為建立 sabirnetug 差異化治療方案的基石。

More recently, we welcomed Dr. Jim Doherty to Acumen as President and Chief Development Officer. Jim brings many years of experience in CNS drug development and we are delighted to have him join our leadership team.

最近，我們歡迎 Jim Doherty 博士加入 Acumen，擔任總裁兼首席開發長。Jim 帶來了多年的中樞神經系統藥物開發經驗，我們很高興他加入我們的領導團隊。

We believe Acumen entered 2024 from a position of strength. We remain highly focused on the execution of key program and strategic initiatives to further establish the therapeutic potential of sabirnetug’s best-in-class treatment option for the substantial early Alzheimer’s patient population.

我們相信 Acumen 在進入 2024 年時處於強勢地位。我們仍然高度關注關鍵計劃和策略性舉措的執行，以進一步確定 sabirnetug 一流治療方案對大量早期阿茲海默症患者群體的治療潛力。

This month, we presented additional CSF biomarker data and details about our A-beta oligomer target engagement assay from our Phase 1 INTERCEPT-AD study at the international conference on Alzheimer’s and Parkinson’s disease or AD/PD in Lisbon, Portugal.

本月，我們在里斯本舉行的阿茲海默症和帕金森氏症或AD/PD 國際會議上展示了更多CSF 生物標記數據以及有關我們的A-β 寡聚物靶標參與測定的詳細信息，這些數據來自我們的1 期INTERCEPT-AD 研究。葡萄牙。

We will also present analysis at the American Academy of Neurology Meeting in Denver this April, which will introduce the development plan for sabirnetug and the results from INTERCEPT-AD to this broad group of practicing and academic neurologists.

我們也將在今年 4 月於丹佛舉行的美國神經病學會會議上發表分析報告，向眾多實踐和學術神經病學家介紹 sabirnetug 的開發計劃和 INTERCEPT-AD 的結果。

If you haven't already taken a look at our Phase 1 results in their entirety, I encourage you to go to our website, where you can find archived presentations, webcasts, and releases detailing the sabirnetug data. For us, it's difficult to overstate the significance of these results and how they position sabirnetug in the broader anti A-beta field.

如果您還沒有完整地查看我們第一階段的結果，我鼓勵您訪問我們的網站，在那裡您可以找到詳細介紹 sabirnetug 資料的存檔簡報、網路廣播和發布。對我們來說，很難誇大這些結果的重要性以及它們如何將 sabirnetug 在更廣泛的抗 A-β 領域中定位。

We knew going into our Phase 1 study that sabirnetug possessed high selectivity for A-beta oligomers. Why does this matter? Unlike A-beta monomers and insoluble amyloid plaque, A-beta oligomers are toxic and distinct in important ways, in particular to neurons and synapses. Our approach with sabirnetug is to selectively target toxic A-beta oligomers and as a consequence, to protect synapses in a way that may provide additional therapeutic benefit to patients, especially from an efficacy perspective.

在進入第一階段研究時我們知道 sabirnetug 對 A-β 寡聚物具有高選擇性。為什麼這很重要？與 A-β 單體和不溶性澱粉樣斑塊不同，A-β 寡聚物具有毒性且在重要方面具有獨特性，特別是對於神經元和突觸。我們使用 sabirnetug 的方法是選擇性地靶向有毒的 A-β 寡聚物，從而以可能為患者提供額外治療益處的方式保護突觸，特別是從功效角度來看。

The INTERCEPT-AD results exceeded our expectations and provide a substantial amount of data indicating sabirnetug’s drug effect. Overall, we see multiple paths towards sabirnetug’s next-generation differentiation on efficacy, safety, or both, any of which would be beneficial to patients as compared to existing options.

INTERCEPT-AD 結果超出了我們的預期，並提供了大量數據表明 sabirnetug 的藥物作用。總體而言，我們看到 sabirnetug 在功效、安全性或兩者方面實現下一代差異化的多種途徑，與現有選擇相比，其中任何一條都將對患者有利。

I'm pleased to note that we're making great progress with the launch of our Phase 2 study, ALTITUDE-AD, which remains on track to initiate in the first half of this year. Simultaneously, we are also on track to initiate our subcutaneous Phase 1 study expected for mid 2024.

我很高興地註意到，隨著第二階段研究 ALTITUDE-AD 的啟動，我們正在取得巨大進展，該研究仍有望在今年上半年啟動。同時，我們也預期在 2024 年中期啟動皮下 1 期研究。

And with that, I'd like to hand the call over to Eric.

說到這裡，我想把電話轉給艾瑞克。

Thanks, Dan. And thanks to those listening in to the call today. I'm very pleased with the progress with the clinical development of sabirnetug last year and thus far in 2024. With our achievements last year, we are well positioned to potentially deliver a differentiated treatment to the Alzheimer's community. I'll provide a brief update on feedback we have received from the scientific community on our Phase 1 INTERCEPT-AD results, and then review our study design for our next trial, ALTITUDE-AD.

謝謝，丹。感謝今天收聽電話會議的人們。我對去年和 2024 年迄今 sabirnetug 的臨床開發取得的進展感到非常高興。憑藉去年的成就，我們有能力為阿茲海默症社群提供差異化的治療方法。我將簡要介紹我們從科學界收到的有關 INTERCEPT-AD 第一階段結果的回饋，然後審查我們下一次試驗 ALTITUDE-AD 的研究設計。

Recall that our Phase 1 top-line results were announced in July of last year at AAIC and we had subsequent updates throughout the second half of the year on the fluid biomarker results as those were analyzed. The totality of the Phase 1 data has only recently become available and can now be evaluated by the broader external community.

回想一下，我們的第一階段頂線結果於去年 7 月在 AAIC 上公佈，我們在下半年對液體生物標記結果進行了後續更新，並進行了分析。第一階段的全部數據最近才公開，現在可以由更廣泛的外部社區進行評估。

We believe the fluid biomarker results have helped to relate the mechanism of sabirnetug to its downstream pharmacologic activity. As first reported in July, a dose-dependent increase in target engagement approaching an Emax was found in CSF and a reduction in plaque measured by amyloid PET was seen at the highest doses of sabirnetug in the multiple-ascending dose cohorts.

我們相信液體生物標記結果有助於將 sabirnetug 的機制與其下游藥理活性聯繫起來。正如7 月首次報道的那樣，在多劑量遞增的劑量組中，在最高劑量的sabirnetug 中，發現腦脊髓液中的目標參與度呈劑量依賴性增加，接近Emax，並且通過澱粉樣蛋白PET 測量發現斑塊減少。

Importantly, after just three administrations of sabirnetug in the multiple ascending dose portion of the study, patients demonstrated downstream improvements across TAU and amyloid biomarkers in CSF, which are the two main pathologic hallmarks of Alzheimer's disease. Remarkably, there were additional clear effects on synaptic biomarkers, suggesting sabirnetug's target engagement of neurotoxic oligomers may protect synapses after only three administrations of drug.

重要的是，在該研究的多次遞增劑量部分中僅服用3 次sabirnetug 後，患者就表現出了腦脊髓液中TAU 和澱粉樣蛋白生物標誌物的下游改善，這是阿茲海默症的兩個主要病理標誌。值得注意的是，對突觸生物標記也有明顯的影響，這表明 sabirnetug 的神經毒性寡聚物的靶向作用可能僅在給藥 3 次後就可以保護突觸。

As Dan mentioned, our team recently returned from AD/PD in Lisbon. The feedback to our data package at medical conferences has been very positive. The excitement around our INTERCEPT-AD results caused us to be even more enthusiastic about beginning our next study, ALTITUDE-AD.

正如 Dan 所提到的，我們的團隊最近從里斯本的 AD/PD 回來。醫學會議上對我們的數據包的回饋非常積極。INTERCEPT-AD 結果帶來的興奮讓我們更熱衷於開始下一項研究 ALTITUDE-AD。

ALTITUDE-AD is planned as a randomized, double-blind, placebo-controlled three-arm study designed to evaluate the clinical efficacy, safety, and tolerability of sabirnetug, with approximately 180 participants per arm for a total of 540 participants with MCI or mild dementia due to Alzheimer's disease. We intend to use the iADRS at 18 months as the primary outcome measure. The study is planned to include a one-year open-label extension.

ALTITUDE-AD 計劃作為一項隨機、雙盲、安慰劑對照的三臂研究，旨在評估sabirnetug 的臨床療效、安全性和耐受性，每臂約180 名受試者，總共540 名患有MCI或輕度的受試者阿茲海默症引起的癡呆症。我們打算使用 18 個月時的 iADRS 作為主要結果指標。該研究計劃包括為期一年的開放標籤擴展。

Based on the results from INTERCEPT-AD, the doses for ALTITUDE-AD will be 35 milligrams per kilogram and 50 milligrams per kilogram, both dosed every four weeks. Extensive PK/PD modeling of our Phase 1 data, especially with regard to target engagement and consideration of safety data, led to the selection of these doses.

根據 INTERCEPT-AD 的結果，ALTITUDE-AD 的劑量將為每公斤 35 毫克和每公斤 50 毫克，每四公斤給藥一次。我們對第一階段數據進行了廣泛的 PK/PD 建模，特別是在目標參與和安全數據考慮方面，導致了這些劑量的選擇。

Both of these dose levels may produce clinical efficacy and we are keen to see whether they will differentiate in terms of the overall benefit risk ratio. Importantly, this study is designed as a registration-eligible study for sabirnetug, and we look forward to providing further updates as the study initiates and progresses.

這兩種劑量水平都可能產生臨床療效，我們很想知道它們是否會在整體獲益風險比方面有所不同。重要的是，這項研究被設計為 sabirnetug 的註冊資格研究，我們期待隨著研究的啟動和進展提供進一步的更新。

In short, our Phase 1 results have allowed us to move to our next study that will more definitively investigate how uniquely targeting A-beta oligomers may lead to a best-in-class treatment for patients with Alzheimer's disease.

簡而言之，我們的第一階段結果使我們能夠進入下一項研究，該研究將更明確地研究獨特的靶向A-β 寡聚物如何為阿茲海默症患者帶來一流的治療。

And with that, I'll turn the call over to Jim.

然後我會把電話轉給吉姆。

Thanks, Eric and good morning, everyone. I [would] like to thank Dan and the entire team at Acumen for their warm welcome. I've been onboard for nearly two months now and in that time, I've grown even more excited about the potential for A-beta oligomer selectivity to offer a next-generation Alzheimer’s treatment.

謝謝埃里克，大家早安。我要感謝 Dan 和 Acumen 整個團隊的熱情歡迎。我已經入職近兩個月了，在這段時間裡，我對 A-β 寡聚物選擇性提供下一代阿茲海默症治療的潛力感到更加興奮。

At its heart, I see the sabirnetug program as testing a very clear hypothesis. A-beta oligomers are neurotoxic amyloid species in the brain. By targeting these oligomers, sabirnetug may offer a differentiated profile compared to other AD therapies, including the potential for greater efficacy or reduced side effects like ARIA.

從本質上講，我認為 sabirnetug 程式正在測試一個非常明確的假設。A-β 寡聚物是大腦中具有神經毒性的澱粉樣蛋白。透過針對這些寡聚物，與其他 AD 療法相比，sabirnetug 可能會提供差異化的特性，包括提高療效或減少 ARIA 等副作用的潛力。

The Phase 1 INTERCEPT-AD results show that sabirnetug can indeed bind to its intended target and improve downstream Alzheimer's biomarkers. We believe there is great potential for this approach to be beneficial to patients and it's incumbent on us to progress our clinical program efficiently and strategically to maximize sabirnetug's value for patients and shareholders.

1 期 INTERCEPT-AD 結果表明 sabirnetug 確實可以與其預期標靶結合併改善下游阿茲海默症生物標記。我們相信這種方法具有造福患者的巨大潛力，我們有責任高效、策略性地推進我們的臨床項目，以最大限度地提高 sabirnetug 為患者和股東帶來的價值。

To support the ALTITUDE-AD trial, we have contracted with a highly experienced CRO with a strong track record in AD that should provide advantageous for trial recruitment and site readiness. As Dan mentioned earlier, we are also planning to initiate a Phase 1 bioavailability study in healthy volunteers for a subcutaneous formulation of sabirnetug in mid-2024.

為了支持 ALTITUDE-AD 試驗，我們與一位經驗豐富的 CRO 簽訂了合同，該 CRO 在 AD 方面擁有良好的記錄，這將為試驗招募和現場準備提供有利的條件。正如 Dan 之前提到的，我們也計劃於 2024 年中期在健康志願者中啟動 sabirnetug 皮下製劑的一期生物利用度研究。

We believe a competitive product profile for sabirnetug includes a subcutaneous option to offer additional flexibility and convenience for patients and caregivers, and we have a productive collaboration with Halozyme for that work stream.

我們相信 sabirnetug 具有競爭力的產品配置包括皮下選項，可為患者和照護者提供額外的靈活性和便利性，並且我們與 Halozyme 就該工作流程進行了富有成效的合作。

Before I turn the call over to Matt, I'd like to take a moment to highlight the excitement we observed at the 2024 AD/PD conference a few weeks ago. We are clearly entering a new era for the diagnosis and treatment of Alzheimer's disease with novel therapeutics, increasingly more precise biomarkers, and diagnostics that will in turn help the field develop even better treatments.

在將電話轉給 Matt 之前，我想花點時間強調我們在幾週前的 2024 AD/PD 會議上觀察到的興奮之情。我們顯然正在進入阿茲海默症診斷和治療的新時代，新的療法、越來越精確的生物標記和診斷技術將反過來​​幫助該領域開發更好的治療方法。

Having just recently joined Acumen, I can clearly sense to the team's pride in how the INTERCEPT-AD biomarker data have contributed to the perception that AD is a treatable disease. In particular, the effects observed on downstream fluid biomarkers after only three administrations of drug underscore the potential of sabirnetug in targeting A-beta oligomers for the treatment of early AD. We believe sabirnetug's clinical development will continue to move this field forward from this perspective.

最近剛加入 Acumen，我可以清楚地感受到該團隊對 INTERCEPT-AD 生物標記數據如何有助於人們認識到 AD 是一種可治療疾病的自豪感。特別是，僅給藥三次後就觀察到對下游液體生物標記的影響，強調了 sabirnetug 在靶向 A-β 寡聚物治療早期 AD 方面的潛力。我們相信，從這個角度來看，sabirnetug的臨床開發將繼續推動這一領域向前發展。

And now I'll hand the call over to Matt to discuss the financials.

現在我將把電話轉給馬特討論財務問題。

Thanks, Jim. As a reminder, our full-year 2023 financial results are available in the press release we issued this morning and in our 10-K we will file later today. We ended 2023 with approximately $306 million in cash and marketable securities on the balance sheet, which provides us with the financial resources to deliver against our strategic objectives.

謝謝，吉姆。謹此提醒，我們的 2023 年全年財務業績可在今天上午發布的新聞稿中找到，並在今天晚些時候提交的 10-K 報告中找到。截至 2023 年底，我們的資產負債表上約有 3.06 億美元的現金和有價證券，這為我們提供了實現策略目標的財務資源。

The increase from the prior year is due to the net proceeds from our public offering last July of approximately $122 million as well as approximately $30 million from K2 HealthVentures as part of the debt financing we announced in November of up to $50 million. Our cash on hand is expected to support our current clinical and operational activities into the first half of 2027.

與前一年相比的成長是由於我們去年7 月公開發行的淨收益約為1.22 億美元，以及來自K2 HealthVentures 的約3000 萬美元，作為我們在11 月宣布的高達5000 萬美元債務融資的一部分。我們手頭上的現金預計將支援我們目前的臨床和營運活動到 2027 年上半年。

R&D expenses were approximately $42.3 million in 2023. The increase over the prior year was primarily due to increased costs related to materials, drug manufacturing costs, consulting, and personnel. G&A expenses were $18.8 million in 2023, with the increase over the prior year, primarily the result of costs related to personnel and consulting. This led to a loss from operations of $61.1 million in 2023.

2023 年研發費用約 4,230 萬美元。較前一年增加的主要原因是材料、藥品製造成本、諮詢和人員相關成本增加。2023 年的一般管理費用為 1,880 萬美元，較前一年有所增加，主要是由於人員和諮詢相關成本的結果。這導致 2023 年營運虧損 6,110 萬美元。

Our positive Phase 1 results in 2023 are a clear reflection of our strong drug development capabilities, which we have further elevated with Jim's experience and insight. We are well capitalized to execute on our upcoming Phase 2 ALTITUDE-AD study and to develop a subcutaneous formulation. We are committed to delivering on the opportunity ahead of us and look forward to providing additional updates this year as we advance sabirnetug for the benefit of patients, caregivers, and shareholders.

我們在 2023 年取得的第一階段積極成果清楚地反映了我們強大的藥物開發能力，借助 Jim 的經驗和洞察力，我們進一步提高了這種能力。我們有充足的資金來執行即將進行的 2 期 ALTITUDE-AD 研究並開發皮下製劑。我們致力於抓住擺在我們面前的機會，並期待今年提供更多更新，因為我們為了患者、照護者和股東的利益而推進 sabirnetug。

And with that, we can open the call for Q&A. Operator?

這樣，我們就可以開始問答環節了。操作員？

(Operator Instructions)

（操作員說明）

Neena Bitritto-Garg, DB.

尼娜·比特里托-加爾格，DB。

Hey guys, thanks for taking my question. So I was just wondering about -- I know you mentioned recently that you may consider doing an interim analysis in the ALTITUDE-AD study in order to determine whether or not you should start a Phase 3 study. Can you just walk us through, I guess, the rationale for doing that interim analysis, some of the protocol adjustments that you're expected to make in ALTITUDE-AD based off of recent regulatory feedback? And then anything you can share in terms of how you're thinking about the criteria for that interim analysis would be great? Thank you.

嘿夥計們，謝謝你提出我的問題。所以我只是想知道 - 我知道您最近提到您可以考慮在 ALTITUDE-AD 研究中進行中期分析，以確定是否應該開始第 3 階段研究。我想，您能否向我們介紹一下進行臨時分析的基本原理，以及您預計根據最近的監管反饋在 ALTITUDE-AD 中進行的一些協議調整？然後，您可以分享一下您如何看待中期分析的標準嗎？謝謝。

Thanks Neena. This is Dan. Maybe I'll quickly take that. So great question. In terms of the interim analysis, these will not be analysis that change in any way the ALTITUDE-AD protocol. They're really intended to provide some early visibility on data to allow us to make a decision as to whether to progress towards a Phase 3 study. So these are not -- they're not futility analyses, they're not -- they're no longer expansion analyses, but they will be employed just for the purposes of getting some early visibility to -- in an effort to potentially minimize the white space between the Phase 2 and the Phase 3.

謝謝妮娜。這是丹.也許我會很快接受。很好的問題。就中期分析而言，這些分析不會以任何方式改變 ALTITUDE-AD 協議。它們的真正目的是提供一些數據的早期可見性，以便我們能夠決定是否進行第三階段研究。因此，這些不是——它們不是徒勞的分析，它們不再是——它們不再是擴展分析，但它們的使用只是為了獲得一些早期的可見性——以盡量減少潛在的影響。第2 階段和第3 階段之間的空白區域。

Okay. Got it. That's super helpful. And then, I guess any changes that you may consider making to the ALTITUDE-AD design based off of feedback from the planned donanemab AdComm?

好的。知道了。這非常有幫助。然後，我猜您可能會考慮根據計劃中的 donanemab AdComm 的反饋對 ALTITUDE-AD 設計進行任何更改？

Thanks, Neena. So I don't think we have any A-priority expectations to make changes based on the AdComm. The AdComm is an interesting development for the field, certainly should serve as a good venue for exploring some of the considerations associated with the TRAILBLAZER-2 design and the overall donanemab data set. We do -- as perhaps you're referencing, we anticipate using the iADRS at 18 months as our primary outcome measure in ALTITUDE-AD. And barring some unforeseen change in development with the AdComm, we'll continue to use the iADRS as our primary.

謝謝，妮娜。因此，我認為我們沒有任何基於 AdComm 進行更改的優先期望。AdComm 是該領域的一個有趣的發展，當然應該成為探索與 TRAILBLAZER-2 設計和整體 donanemab 資料集相關的一些考慮因素的良好場所。我們確實這樣做 - 正如您可能提到的那樣，我們預計在 18 個月時使用 iADRS 作為 ALTITUDE-AD 的主要結果衡量標準。除非 AdComm 的開發發生一些不可預見的變化，否則我們將繼續使用 iADRS 作為我們的主要工具。

Awesome. Thank you.

驚人的。謝謝。

Thomas Shrader, BTIG.

托馬斯·施拉德 (Thomas Shrader)，BTIG。

Hey, good morning. This is [Sam] on for Tom. Thanks for taking our questions. So for subcu, is maintenance therapy and immediate application for subcu dosing? And what are your thoughts on integrating any subcu dose option in the open-label extension part of the ALTITUDE-AD study? Thank you.

嗨，早安。這是[山姆]為湯姆代言的。感謝您回答我們的問題。那麼對於 subcu 來說，是維持治療還是立即塗抹 subcu 劑量呢？您對將任何 subcu 劑量選項納入 ALTITUDE-AD 研究的開放標籤擴展部分有何想法？謝謝。

So Sam, thanks for your question. And I think the quick answer on that is the next phase of development for subcu beyond the Phase 1 is yet to be determined or decided. So our immediate focus is on getting this Phase 1 healthy volunteer bioavailability PK study done as a means to really inform what the next dosing strategy and study might be for a Phase 2 or as you mentioned, there are a couple of different options that might be available to us in the future. But I think for the near-term, we're focused on executing the Phase 1 as the primary gate prior to describing in greater detail the Phase 2 plans.

山姆，謝謝你的問題。我認為對此的快速回答是，除了第一階段之外，subcu 的下一階段開發尚未確定或決定。因此，我們目前的重點是完成第一階段的健康志願者生物利用度PK 研究，作為真正了解第二階段的下一個劑量策略和研究的方法，或者正如您所提到的，可能有幾種不同的選擇將來可供我們使用。但我認為，短期內，我們的重點是執行第一階段作為主要大門，然後再更詳細地描述第二階段計畫。

Thank you.

謝謝。

Paul Matteis, Stifel.

保羅馬蒂斯，斯蒂菲爾。

Hi, this is James on for Paul. Thanks for taking our question. Maybe just a quick one on the Phase 2. I guess, can you talk about how you powered the study and what you're looking to see in terms of being a clear win there? And then maybe just quickly on -- again, following up on this interim, just at a high level, curious if you're thinking about the biomarkers or clinical scales or just kind of a collection of both of those data sets, just curious what you can share in terms of what that may actually consist of? Thanks very much.

大家好，我是詹姆斯替保羅發言。感謝您提出我們的問題。也許只是第二階段的快速介紹。我想，你能談談你是如何推動這項研究的，以及你希望看到什麼才能取得明顯的勝利嗎？然後也許很快 - 再次，在高水平上跟進這一過渡時期，好奇你是否正在考慮生物標誌物或臨床量表，或者只是這兩個數據集的集合，只是好奇什麼您可以分享一下它實際上可能包含哪些內容嗎？非常感謝。

Thanks, James. And Eric, do you want to take that one?

謝謝，詹姆斯。艾瑞克，你想買那個嗎？

Yeah, sure. Thanks, Dan. So for our Phase 2 ALTITUDE-AD study, as I mentioned, it's 540 participants with 180 per arm. That, for the iADRS, gives you pretty typical power for a Phase 2 study. So we feel like that should really answer the question in terms of how the program develops. We'll also look at a variety of biomarkers, most of which we looked at in our Phase 1 study too.

好，當然。謝謝，丹。因此，正如我所提到的，我們的 ALTITUDE-AD 研究第 2 階段有 540 名參與者，每隻手臂 180 名。對於 iADRS 來說，這為您提供了相當典型的第二階段研究能力。所以我們覺得這應該要真正回答程式如何開發的問題。我們還將研究各種生物標誌物，其中大部分我們也在第一階段研究中研究過。

And so it will be really interesting to see after 18 months of treatment, TAU's biomarkers response since we actually already saw a response after just three doses in essentially three months. So we're looking forward to that.

因此，在 18 個月的治療後看到 TAU 的生物標記反應將非常有趣，因為實際上我們在三個月內僅注射了 3 劑疫苗後就已經看到了反應。所以我們對此充滿期待。

In terms of what goes into the interim analyses, we're not going to get into details about that. I guess I can say that it's an algorithm that doesn't include just one thing. And so -- and again, as Dan mentioned, the utility of that is to reduce the white space between a Phase 2 and a Phase 3 trial because if the algorithms look positive, one of the things that it tells you is that the study design of the Phase 2 study is good.

至於中期分析的內容，我們不會詳細介紹。我想我可以說這是一種不只包含一件事的演算法。因此，正如 Dan 所提到的，其用途是減少第 2 階段和第 3 階段試驗之間的空白，因為如果演算法看起來是積極的，那麼它告訴您的一件事就是研究設計第二階段研究的結果很好。

And a lot of times, what creates white space in drug development programs is redesigning studies. And if we don't have to do that, that will cut down on our white space. So that's how we plan to use those algorithms.

很多時候，在藥物開發專案中創造空白的是重新設計研究。如果我們不必這樣做，就會減少我們的空白空間。這就是我們計劃使用這些演算法的方式。

Thanks, that’s super helpful.

謝謝，這非常有幫助。

Colin Bristow, UBS.

科林布里斯托，瑞銀集團。

Oh, hi, this is Kim on for Colin. And thank you for taking our questions. Just a quick one following the earlier question on the subcu formula, since the earlier question was more centered around for maintenance study. So for subcu as an initial therapy, like as in the upcoming subcu bioavailable study, what dosing charts and dosing schedules are you currently thinking, especially with regards to Eisai's recent pushbacks for subcu dose as initial therapy, do you think it is reasonable to start with some lower doses and test out for the safety first? Thank you.

哦，嗨，我是科林的金。感謝您回答我們的問題。只是在前面關於 subcu 公式的問題之後快速回答一下，因為前面的問題更集中在維護研究上。因此，對於subcu 作為初始治療，就像即將進行的subcu 生物利用度研究一樣，您目前正在考慮什麼劑量圖表和給藥方案，特別是考慮到衛材最近拒絕將subcu 劑量作為初始治療，您認為開始治療是否合理使用一些較低的劑量並首先測試安全性？謝謝。

Go ahead, please.

請繼續。

Yes. No, I think those are all great questions and all questions that we really don't have an answer to at this early point. I mean we don't have even our healthy volunteer data yet. So those are all things to be considered. I think it's interesting that broadly in the field, people are talking about maybe starting with -- starting off with IV administration and then switching to subcu as more of a maintenance dose. So that's not just something that we're thinking about, it's something that a lot of people are thinking about. But we'll just need to get actual data before we start to narrow things down on those questions.

是的。不，我認為這些都是很好的問題，而且我們目前還沒有真正答案。我的意思是我們甚至還沒有健康的志工資料。所以這些都是需要考慮的事情。我認為有趣的是，在該領域廣泛地，人們正在談論可能從靜脈注射開始，然後改用 subcu 作為更多的維持劑量。所以這不僅是我們正在考慮的事情，也是很多人正在考慮的事情。但在我們開始縮小這些問題的範圍之前，我們只需要取得實際數據。

Okay, thank you. And maybe a quick follow-up question, if we may. So how do you view some of the evolving data in the field include the most recent update from Roche's trontinemab? Thank you.

好的謝謝。如果可以的話，也許還有一個快速的後續問題。那麼，您如何看待該領域不斷變化的一些數據，包括羅氏 trontinemab 的最新更新？謝謝。

Sure. I can take that. I think we noted at the AD/PD that trontinemab data, which is early but encouraging. We took the view that targeting oligomers as a differentiated mechanism from a gantenerumab shuttle construct, which is the trontinemab.

當然。我可以接受。我認為我們在 AD/PD 上註意到 trontinemab 數據，這是早期但令人鼓舞的。我們認為，標靶寡聚物是與 gantenerumab 穿梭構建體（即 trontinemab）不同的機制。

And so we're very much committed to exploiting the oligomer targeted mechanism of sabirnetug and generating evidence in support of it as a treatment option and feel -- that the field, in general, is large enough to accommodate a variety of different product formats and options. So it's interesting and something we're looking at but staying very focused on execution for sabirnetug.

因此，我們非常致力於開發sabirnetug 的寡聚物靶向機制，並產生支持其作為一種治療選擇的證據，並且我們認為，總體而言，該領域足夠大，可以容納各種不同的產品形式，並且選項。所以這很有趣，我們正在研究，但仍然非常關注 sabirnetug 的執行。

Geoff Meacham, Bank of America.

傑夫‧米查姆，美國銀行。

Good morning. This is Jason on for Geoff. Thank you so much for taking our questions, and congratulations on the progress. I wanted to ask maybe a little bit more broadly, we've seen the publication of a number of recent studies that have found that a number of the signals or biomarkers for amyloid beta appear quite some time before the symptoms.

早安.這是傑森替傑夫發言。非常感謝您提出我們的問題，並祝賀我們的進展。我想問得更廣泛一點，我們看到了最近發表的許多研究，這些研究發現β澱粉樣蛋白的許多訊號或生物標記在症狀出現之前很長一段時間就出現了。

I think specifically regarding the ratio of A-beta 42 to A-beta 40 pops up 14 years prior to the onset of symptoms. And I'm curious, has that influenced the design of some of your clinical studies, do you think you may need to go a little bit earlier, or do you feel that early AD is sufficient enough for either a reversal of the symptoms or delaying them?

我特別認為 A-β 42 與 A-β 40 的比率會在症狀出現前 14 年出現。我很好奇，這是否影響了您的一些臨床研究的設計，您認為您可能需要早一點進行，還是您認為早期 AD 足以逆轉症狀或延遲他們？

Yes. So Dan, do you want me to take that one?

是的。那麼丹，你想讓我拿那個嗎？

Yes, sure.

是的，當然。

It is a great question. So yeah, one of the ways that the field has made some real progress in the last 10 years and maybe even the last 20 years is the understanding of this fact that, as you point out, that you develop the plaques 15 to 20 years before you develop any symptoms.

這是一個很好的問題。所以，是的，該領域在過去 10 年甚至過去 20 年取得一些真正進展的方式之一就是了解這一事實，正如您所指出的，您在 15 到 20 年前就開發出了斑塊您出現任何症狀。

And there has been a thought in the field that if you were going to target amyloid or A-beta in one way or another, that because of that time period, you actually had to do it before people had any symptoms at all. And there are ongoing studies and they have been ongoing. -- there have been studies of what's called preclinical Alzheimer's disease. So in other words, you have the plaques, but you don't have any symptoms yet.

該領域有一種想法，如果你要以某種方式針對澱粉樣蛋白或 A-β，那麼由於那個時期，你實際上必須在人們出現任何症狀之前就這樣做。正在進行的研究也一直在進行中。 ——對所謂的臨床前阿茲海默症進行了研究。換句話說，你有斑塊，但還沒有任何症狀。

Thus far, none of those studies have been successful. I think there's a lot of reasons for that. Partly, the study design is much more complicated. The studies need to be longer or some technical reasons why that's a challenge. But what's really important, I think, is that for drugs like lecanemab and donanemab and potentially even aducanumab, you're seeing a signal in people who have either MCI or mild dementia with Alzheimer's pathology.

到目前為止，這些研究都沒有成功。我認為這有很多原因。在某種程度上，研究設計要複雜得多。研究需要更長的時間，或者有一些技術原因導致這是一個挑戰。但我認為，真正重要的是，對於像 lecanemab 和 donanemab 甚至可能是 aducanumab 這樣的藥物，你會在患有 MCI 或阿茲海默症的輕度癡呆症患者中看到一個信號。

And the reason why that's so important is that means you don't have to go all the way back to that preclinical stage where the study designs are much more challenging and not as well worked out. So we feel really good about the fact that we are in this population of MCI plus mild dementia. Other drugs are starting to see a signal there. And apparently, what that means is that's not too late in the process. And that's, I think, a really good insight for the field broadly.

這之所以如此重要，是因為這意味著您不必一路回到臨床前階段，在該階段，研究設計更具挑戰性，而且還沒有得到很好的解決。因此，我們對自己屬於輕度認知障礙和輕度癡呆人群這一事實感到非常高興。其他藥物也開始在這方面看到訊號。顯然，這意味著這個過程還不算太晚。我認為，這對該領域來說是一個非常好的見解。

Interesting, thanks for the color. And then maybe a quick follow-up, if I may. The FDA released draft guidance for Alzheimer's earlier this month. I think one of the big takeaways here is that really codified the drive or push to maybe shorten the length of clinical studies potentially using, again, kind of biomarkers and other indicators rather than waiting for several years that it might take to detect a meaningful change. And I'm again kind of curious, has that translated to your discussions with the regulators and again, are we thinking ahead to maybe a shorter Phase 3 if need be?

有趣，謝謝你的顏色。如果可以的話，也許可以快速跟進。FDA 本月稍早發布了阿茲海默症的指南草案。我認為這裡最大的收穫之一是真正編纂了驅動力或推動力，以縮短可能再次使用生物標記和其他指標的臨床研究的長度，而不是等待幾年才能檢測到有意義的變化。我再次有點好奇，這是否轉化為您與監管機構的討論，並且我們是否正在考慮在需要時縮短第三階段？

Yes, having read the draft guidance like a lot of times for these draft guidance, it's a little hard to read between the lines, and they certainly did have some language in there about shortening timelines based on using biomarkers, but then they talk about a validated biomarker but what is validated to really mean.

是的，在閱讀了很多次指南草案後，字裡行間有點難以理解，而且他們確實有一些關於基於使用生物標誌物來縮短時間表的語言，但隨後他們談論了經過驗證的生物標誌物，但經過驗證的真正意義是什麼。

So there's still a number of things that need to be worked out. It may be that they were directing some of those comments to just taking an antibody that is IV and then converting it to subcu. I think that's probably the most straightforward case for more of a reliance on the biomarkers.

所以還有很多事情要解決。他們可能將其中一些評論指向僅採用 IV 抗體，然後將其轉換為 subcu。我認為這可能是更多依賴生物標記的最直接的例子。

But at this early stage, we've not really considered using a biomarker alone to try to get accelerated approval for sabirnetug because, of course, the payers, at least to this point, haven't really offered to reimburse for accelerated approval. So we'll continue to watch that very closely. But at this point, I don't think we have enough information to make any real changes in what we would anticipate would be our Phase 3 design.

但在這個早期階段，我們並沒有真正考慮過單獨使用生物標誌物來嘗試獲得 sabirnetug 的加速批准，因為當然，至少到目前為止，付款人還沒有真正提出為加速批准提供報銷。因此，我們將繼續密切關注這一情況。但目前，我認為我們沒有足夠的資訊來對我們預期的第三階段設計做出任何真正的改變。

Got it. Thank you again for the color.

知道了。再次感謝您的顏色。

Anand Ghosh, H.C. Wainwright.

阿南德‧戈什 (Anand Ghosh)，H.C.溫賴特。

Hey, hi, thank you. The first question is probably, what are some of the advantages of iADRS over CDR-SB and the rationale behind choosing iADRS over CDR-SB for the ALTITUDE study? And the second thing is there has been a lot of correlations made based on how much of plaque reductions you were seeing and what's the probability of success in terms of some of these anti-A-beta immunotherapy trials.

嘿嘿，謝謝你。第一個問題可能是，iADRS 相對於 CDR-SB 有哪些優勢，以及在 ALTITUDE 研究中選擇 iADRS 而不是 CDR-SB 的理由是什麼？第二件事是，根據您看到的斑塊減少量以及其中一些抗 A-β 免疫療法試驗的成功機率，建立了許多相關性。

Are there other associations, which has been done with other biomarkers such as tau181 or 217, where at least some modeling-based studies can tell you to what extent you might need to see a change in these two biomarkers so as to kind of have an impact in either CDR-SB or iADRS? Thanks.

是否還有其他關聯（已與其他生物標記（例如tau181 或217）建立關聯，至少有一些基於模型的研究可以告訴您可能需要在多大程度上看到這兩種生物標誌物的變化，以便在某種程度上了解對 CDR-SB 或 iADRS 有何影響？謝謝。

Yes, maybe I can try to take that one, too. As far as the use of the iADRS versus the CDR Sum of Boxes, one of the things that was interesting in the recent draft guidance was that they no longer called out the CDR Sum of Boxes. And they've actually presented it at public meetings, the idea that in the previous draft guidance where they did mention the CDR Sum of Boxes, they didn't mean to endorse that as sort of the only scale.

是的，也許我也可以嘗試接受那個。就 iADRS 與 CDR Sum of Boxes 的使用而言，最近的指南草案中有趣的事情之一是他們不再呼叫 CDR Sum of Boxes。他們實際上已經在公開會議上提出了這個想法，在先前的指南草案中，他們確實提到了 CDR 盒子總和，但他們並不打算認可它作為唯一的尺度。

But what they did say in this most recent draft guidance is that a scale that's a composite of cognitive measures and functional measures may have real utility. And that's what the iADRS is. It's a combination of cognitive measures from ADAS-Cog and then functional measures from a scale called ADCS-ADL.

但他們在最新的指南草案中確實說過，認知測量和功能測量相結合的量表可能具有真正的實用性。這就是 iADRS。它結合了 ADAS-Cog 的認知測量和 ADCS-ADL 量表的功能測量。

So we think that it's very positive actually in terms of our use of the iADRS. I would assume that [lilies] and the TRAILBLAZER studies, that's their primary, they were happy to see that. So yeah, I think that's a really good clarification from FDA in terms of that -- those kind of scales.

因此，我們認為，就我們使用 iADRS 而言，這實際上是非常積極的。我認為 [lilies] 和 TRAILBLAZER 研究是他們的主要研究，他們很高興看到這一點。所以，是的，我認為 FDA 在這種規模方面做出了非常好的澄清。

In terms of correlations between plaque reduction and clinical benefit, I think what's really becoming a consensus opinion now is that you actually have to get plaque below a certain threshold. And this is something that we at Acumen been saying for a long time, is that if you're going to target plaque, you have to basically get rid of it.

就減少斑塊和臨床益處之間的相關性而言，我認為現在真正成為共識的是，實際上必須將斑塊降低到某個閾值以下。這是我們 Acumen 長期以來一直在說的，如果你要針對牙菌斑，你基本上必須清除它。

And so the goal seems to be based on existing data that you want to get below 25, say -- or at most 30. So if you want to -- if your target is plaque, that's what you need to do. But again, our target is not plaque, our target is oligomer. So it will be interesting to see what effects we have on plaque. But with our differentiated mechanism, that's really not the construct of our development plan.

因此，目標似乎是基於您希望低於 25 或最多 30 的現有數據。所以，如果你想——如果你的目標是牙菌斑，那就是你需要做的。但同樣，我們的目標不是牙菌斑，我們的目標是低聚物。因此，看看我們對牙菌斑有何影響將會很有趣。但由於我們的差異化機制，這確實不是我們發展計畫的建構。

Thanks.

謝謝。

I show no further questions at this time. I would now like to turn the call back over to Alex Braun for closing remarks.

我目前沒有提出任何進一步的問題。我現在想將電話轉回給亞歷克斯·布勞恩 (Alex Braun)，讓其致閉幕詞。

Thanks, Michelle, and thanks for everyone for taking the time to tune in today. We are always available at the company. For any follow-up questions, please be in touch and have a great day. Thanks.

謝謝米歇爾，也謝謝大家今天抽空收聽。我們隨時為您服務。如有任何後續問題，請與我們聯繫，祝您有美好的一天。謝謝。

This concludes today's conference call. Thank you for your participation. You may now disconnect.

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連線。