Biogen Inc (BIIB) 2021 Q4 法說會逐字稿

Good morning. My name is Madison, and I will be your conference operator today. At this time, I would like to welcome everyone to the Biogen Fourth Quarter Earnings Call and Financial Update. (Operator Instructions)

早上好。我的名字是麥迪遜，今天我將成為您的會議接線員。在這個時候，我想歡迎大家參加百健（Biogen）第四季度財報電話會議和財務更新。 （操作員說明）

I would now like to turn the conference over to Mr. Michael Hencke, Head of Investor Relations. Mr. Hencke, you may begin your conference.

我現在想將會議轉交給投資者關係主管 Michael Hencke 先生。 Hencke 先生，你可以開始你的會議了。

Good morning, and welcome to Biogen's Fourth Quarter 2021 Earnings Call. Before we begin, I encourage everyone to go to the Investors section of biogen.com to find the earnings release and related financial tables, including our GAAP financial measures and a reconciliation of the GAAP to non-GAAP financial measures that we will discuss today.

早上好，歡迎參加 Biogen 2021 年第四季度財報電話會議。在我們開始之前，我鼓勵大家去 biogen.com 的投資者部分查找收益發布和相關財務表格，包括我們的 GAAP 財務指標以及我們今天將討論的 GAAP 與非 GAAP 財務指標的對賬。

Our GAAP financials are provided in Tables 1 and 2, and Table 4 includes a reconciliation of our GAAP to non-GAAP financial results. We believe non-GAAP financial results better represent the ongoing economics of our business and reflect how we manage the business internally. We have also posted slides on our website that follow the discussions related to this call.

表 1 和表 2 提供了我們的 GAAP 財務數據，表 4 包括我們的 GAAP 與非 GAAP 財務結果的對賬。我們相信非公認會計準則財務業績更好地代表了我們業務的持續經濟狀況，並反映了我們如何在內部管理業務。我們還在我們的網站上發布了幻燈片，以跟踪與此電話會議相關的討論。

I would like to point out that we will be making forward-looking statements, which are based on our current expectations and beliefs. These statements are subject to certain risks and uncertainties, and our actual results may differ materially. I encourage you to consult the risk factors discussed in our SEC filings for additional detail.

我想指出，我們將根據我們目前的預期和信念做出前瞻性陳述。這些陳述受到某些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。我鼓勵您查閱我們提交給 SEC 的文件中討論的風險因素以獲取更多詳細信息。

Today, we will be discussing ADUHELM. ADUHELM is indicated for the treatment of Alzheimer's disease. Treatment with ADUHELM should be initiated in patients with mild cognitive impairment or mild dementia stage of disease, the population in which treatment was initiated in clinical trials. There are no safety or effectiveness data on initiating treatment at earlier or later stages of the disease then were studied. This indication is approved under accelerated approval based on reduction in amyloid beta plaques observed in patients treated with ADUHELM. Continued approval for this indication may be contingent upon verification of clinical benefit in a confirmatory trial or trials.

今天，我們將討論 ADUHELM。 ADUHELM 適用於治療阿爾茨海默病。 ADUHELM 治療應在患有輕度認知障礙或輕度癡呆疾病階段的患者中開始，即在臨床試驗中開始治療的人群。沒有關於在疾病早期或晚期開始治療的安全性或有效性數據，然後進行了研究。基於在接受 ADUHELM 治療的患者中觀察到的澱粉樣蛋白 β 斑塊減少，該適應症在加速批准下獲得批准。對該適應症的持續批准可能取決於在一個或多個驗證性試驗中驗證臨床益處。

ADUHELM can cause serious side effects, including amyloid-related imaging abnormalities or ARIA. ARIA is a common side effect that does not usually cause any symptoms, but can be serious. ADUHELM can cause serious allergic reactions. The most common side effects include ARIA, headache and fall. Please see full prescribing information and patient medication guide at aduhelm.com.

ADUHELM 可引起嚴重的副作用，包括澱粉樣蛋白相關的影像學異常或 ARIA。 ARIA 是一種常見的副作用，通常不會引起任何症狀，但可能很嚴重。 ADUHELM 可引起嚴重的過敏反應。最常見的副作用包括 ARIA、頭痛和跌倒。請在 aduhelm.com 上查看完整的處方信息和患者用藥指南。

On today's call, I am joined by our Chief Executive Officer, Michel Vounatsos; Dr. Priya Singhal, Interim Head of Research and Development; and our CFO, Mike McDonnell. We will also be joined for the Q&A portion of our call by Alisha Alaimo, President of our U.S. organization. (Operator Instructions)

在今天的電話會議上，我們的首席執行官 Michel Vounatsos 加入了我的行列； Priya Singhal 博士，研發臨時主管；和我們的首席財務官 Mike McDonnell。我們還將參加我們美國組織總裁 Alisha Alaimo 電話會議的問答部分。 （操作員說明）

I will now turn the call over to Michel.

我現在將把電話轉給米歇爾。

Good morning, everyone, and thank you for joining us. I will start by briefly reviewing our financial performance, and Mike will provide more details. For the fourth quarter, Biogen generated approximately $2.7 billion in revenue, representing a decrease of 4% year-over-year as we continued to experience the erosion of TECFIDERA revenue in the U.S. due to the impact of generic entry.

大家早上好，感謝您加入我們。我將首先簡要回顧一下我們的財務業績，Mike 將提供更多細節。第四季度，百健（Biogen）創造了約 27 億美元的收入，同比下降 4%，因為我們繼續經歷美國 TECFIDERA 收入由於仿製藥進入的影響而受到侵蝕。

Fourth quarter 2021 non-GAAP earnings were $3.39 a share. We believe this performance reinforces Biogen's ability to execute well. However, given a number of challenges we have faced recently, we announced that we will implement cost reduction measures, which are expected to yield approximately $500 million in annualized savings, and Mike will provide additional details.

2021 年第四季度非公認會計原則收益為每股 3.39 美元。我們相信這一表現加強了百健（Biogen）的良好執行能力。但是，鑑於我們最近面臨的一些挑戰，我們宣布將實施成本削減措施，預計每年可節省約 5 億美元，Mike 將提供更多詳細信息。

Let me now say a few words regarding the proposed National Coverage Determination, or NCD, for the class of monoclonal antibodies directed against amyloid for the treatment of Alzheimer's disease. As currently written, the proposed NCD calls for coverage with evidence development or a CED, which will provide reimbursement only for Medicare beneficiaries enrolled in an approved randomized controlled trial.

現在讓我就針對澱粉樣蛋白的單克隆抗體類用於治療阿爾茨海默病的提議的國家覆蓋範圍確定（NCD）說幾句話。正如目前所寫的那樣，擬議的非傳染性疾病要求覆蓋證據開發或 CED，這將只為參加批准的隨機對照試驗的醫療保險受益人提供報銷。

In reaching this proposed recommendation, the Center for Medicare and Medicaid Services, or CMS, highlighted 3 key areas of focus for this class of therapies, all of which have implications for ADUHELM. First, CMS believes there are gaps in the data on the clinical benefit of these therapies. Second, CMS believes more information is needed about the potential risks of removing amyloid, principally ARIA. And third, CMS would like additional data to be generated on the underrepresented communities in which Alzheimer's disease is more prevalent.

在達成這一提議的建議時，醫療保險和醫療補助服務中心 (CMS) 強調了此類療法的 3 個關鍵重點領域，所有這些領域都對 ADUHELM 有影響。首先，CMS 認為這些療法的臨床益處數據存在差距。其次，CMS 認為需要更多關於去除澱粉樣蛋白（主要是 ARIA）的潛在風險的信息。第三，CMS 希望獲得有關阿爾茨海默病更為普遍的代表性不足社區的更多數據。

These are also areas of focus for Biogen with many important initiatives already underway. We have committed to constructive engagement with CMS to address their concerns, and we agree with CMS that additional data may be helpful to continue to characterize the benefit-risk profile for this class of therapies.

這些也是百健（Biogen）的重點領域，許多重要舉措已經在進行中。我們已承諾與 CMS 進行建設性合作以解決他們的擔憂，並且我們同意 CMS 的觀點，即額外的數據可能有助於繼續描述此類療法的收益-風險特徵。

Now that ADUHELM is approved by the FDA, we believe the most helpful data generation can really only be generated from greater drug utilization in real-world practice. We also agree with CMS that the final NCD decision should not lead to a duplication of ongoing activities. As currently postured, however, we believe the proposed CED requirements will be prohibitive for patients, overly burdensome, costly to companies and duplicative of the data that will be generated from ongoing trials and the FDA's existing required post-marketing requirements.

既然 ADUHELM 已獲得 FDA 批准，我們相信最有用的數據生成實際上只能通過在現實世界實踐中更大的藥物利用來生成。我們也同意 CMS 的意見，即 NCD 的最終決定不應導致正在進行的活動的重複。然而，按照目前的情況，我們認為擬議的 CED 要求對患者來說將是令人望而卻步的，負擔過重，對公司來說成本高昂，並且與正在進行的試驗和 FDA 現有的上市後要求所產生的數據重複。

We believe the best way to address the concerns of CMS is to supplement the data from the ADUHELM Phase III studies. We generated data over 3,000 patients by taking a multipronged approach, leveraging the Phase IV confirmatory study, ENVISION; our EMBARK redosing study, which has enrolled approximately 1,700 patients; the ongoing ICARE AD registry; the ongoing Phase III studies of other antibodies in the class; and other ongoing and anticipated real-world data generation efforts. We believe this extensive data generation opportunity will adequately address any open question regarding the clinical efficacy and safety of amyloid beta lowering therapies.

我們認為解決 CMS 問題的最佳方法是補充 ADUHELM III 期研究的數據。我們採用多管齊下的方法，利用 IV 期驗證性研究 ENVISION，生成了超過 3,000 名患者的數據；我們的 EMBARK 重新給藥研究，已招募了大約 1,700 名患者；正在進行的 ICARE AD 登記；正在進行的同類其他抗體的 III 期研究；以及其他正在進行和預期的真實世界數據生成工作。我們相信，這種廣泛的數據生成機會將充分解決有關降低澱粉樣蛋白 β 療法的臨床療效和安全性的任何懸而未決的問題。

On this note, we expect to begin patient screening for the ENVISION study in May of this year with the primary completion date anticipated approximately 4 years later. This is expected to be a global placebo-controlled trial aiming to enroll 1,500 patients with MCI due to Alzheimer's disease or mild Alzheimer's disease with confirmation of amyloid beta pathology. The planned primary end point will be CDR-Sum of Boxes at 18 months, with a planned long-term extension for up to 48 months.

在這一點上，我們預計將於今年 5 月開始對 ENVISION 研究進行患者篩查，預計大約 4 年後完成主要完成日期。預計這將是一項全球安慰劑對照試驗，旨在招募 1,500 名患有阿爾茨海默病或輕度阿爾茨海默病的 MCI 患者，並確認澱粉樣蛋白 β 病理學。計劃的主要終點將是 18 個月的 CDR-Sum of Box，併計劃長期延長至 48 個月。

We believe this study, combined with the other studies I mentioned, should address the questions raised by CMS. Therefore, we will continue to advocate for an NCD that provides rapid and equitable patient access by providing coverage only for the patients identified as most appropriate for treatment in our FDA-approved label, which generally aligns to our Phase III clinical trial population.

我們認為，這項研究與我提到的其他研究相結合，應該能夠解決 CMS 提出的問題。因此，我們將繼續倡導一種非傳染性疾病，通過只為我們 FDA 批准的標籤中確定為最適合治療的患者提供保險，該標籤通常與我們的 III 期臨床試驗人群一致，從而提供快速和公平的患者訪問。

We also believe this multipronged approach will allow for more equal access in all communities. We have concerns that the restrictions of the proposed CED would unfairly exclude access for patients in underserved communities and geographically remote areas. In contrast, we expect both ENVISION and our ICARE AD registry, which seeks to enroll up to 6,000 participants, to obtain more representative data from those communities by aiming to enroll 16% to 18% of U.S. participants from Black and Hispanic population.

我們還相信，這種多管齊下的方法將允許所有社區獲得更多平等機會。我們擔心擬議的 CED 的限制會不公平地排除服務不足的社區和地理位置偏遠地區的患者的訪問權。相比之下，我們預計 ENVISION 和我們的 ICARE AD 登記處（旨在招募多達 6,000 名參與者）通過旨在招募 16% 至 18% 的美國黑人和西班牙裔人口參與者來從這些社區獲得更具代表性的數據。

In summary, we will advocate for a final CED that strikes a better balance between patient access for an FDA-approved therapy today and the desire for additional data that can only be gathered over time and with higher levels of drug utilization in the real world. We look forward to discussing this consideration with CMS and working towards a final decision that is in the best interest of patients.

總之，我們將倡導最終的 CED，在患者獲得 FDA 批准的治療與希望獲得更多數據之間取得更好的平衡，這些數據只能隨著時間的推移和在現實世界中更高水平的藥物使用而收集。我們期待與 CMS 討論這一考慮因素，並努力做出符合患者最大利益的最終決定。

Beyond the NCD last quarter, we presented additional data from the ADUHELM Phase III clinical trial showing the effect on downstream tau Alzheimer's biology and the correlation between plasma p-tau reduction and less cognitive and functional decline. In addition, we published the Phase III ARIA findings in JAMA Neurology.

除了上個季度的非傳染性疾病，我們還提供了來自 ADUHELM III 期臨床試驗的額外數據，顯示了對下游 tau 阿爾茨海默病生物學的影響以及血漿 p-tau 減少與認知和功能衰退減少之間的相關性。此外，我們在 JAMA Neurology 上發表了 III 期 ARIA 研究結果。

As we look forward, we aim to expand both within and beyond neuroscience with a focus on 4 pillars to drive growth and value creation. First, we intend as a company to build on our strong foundation in neuroscience, where we currently have 26 programs in clinical development.

展望未來，我們的目標是在神經科學內外擴展，重點關注 4 個支柱來推動增長和價值創造。首先，作為一家公司，我們打算在我們在神經科學領域的堅實基礎上再接再厲，目前我們有 26 個臨床開發項目。

Second, we have what we believe to be 2 compelling Phase III programs in lupus. This is a therapeutic area with a different risk profile, and we are continuing to evaluate additional opportunities in specialized immunology.

其次，我們有我們認為是 2 個引人注目的狼瘡 III 期項目。這是一個具有不同風險特徵的治療領域，我們正在繼續評估專業免疫學的更多機會。

Third, over the last several years, we have also built a very successful new business with our biosimilars. We recently announced an agreement to sell our stake in the Samsung Bioepis joint venture to Samsung Biologics, with Biogen remaining in our current role as the commercialization partner for the Samsung Bioepis anti-TNF portfolio and ophthalmology programs. We currently anticipate that this transaction will close in mid-2022. Once closed, going forward, we will have an expanded ability to pursue the biosimilars business on our own as we aim to bring more biosimilar products to more patients in more geographies. Mike will provide more details.

第三，在過去幾年中，我們還利用我們的生物仿製藥建立了非常成功的新業務。我們最近宣布了一項協議，將我們在 Samsung Bioepis 合資企業中的股份出售給 Samsung Biologics，Biogen 將繼續擔任我們目前作為 Samsung Bioepis 抗 TNF 產品組合和眼科項目的商業化合作夥伴的角色。我們目前預計該交易將於 2022 年年中完成。一旦關閉，展望未來，我們將有更大的能力自行開展生物仿製藥業務，因為我們的目標是為更多地區的更多患者帶來更多生物仿製藥產品。邁克將提供更多細節。

And lastly, we are also focused on accelerating our efforts in digital health to support our commercial and pipeline programs while also creating opportunities for potential digital therapeutics. To this point, we have built a dedicated digital health portfolio, which includes the recently announced new collaboration with TheraPanacea with the aim of leveraging our significant database, but also machine learning, artificial intelligence to develop digital health solution that may improve patient care, accelerate drug development and further the understanding of underlying pathologies.

最後，我們還專注於加快我們在數字健康方面的努力，以支持我們的商業和管道計劃，同時也為潛在的數字治療創造機會。到目前為止，我們已經建立了一個專門的數字健康產品組合，其中包括最近宣布與 TheraPanacea 的新合作，旨在利用我們重要的數據庫、機器學習、人工智能來開發可以改善患者護理、加速藥物開發和進一步了解潛在的病理。

Our progress across these 4 pillars provides us with the potential for 2 future waves of growth as we launch in new therapeutic areas and build new franchises. First, over the next few years, we believe we have a significant potential in Alzheimer's disease and depression, 2 large therapeutic areas with significant and unmet needs. In Alzheimer's disease, we have a deep pipeline of clinical and preclinical assets leveraging multiple modalities and targets, including both amyloid and tau. With ADUHELM and lecanemab, Biogen and Eisai have 2 out of the 4 potential anti-amyloid antibody therapies that are either approved or in late-stage development. In depression, we are collaborating with Sage Therapeutics on zuranolone, which we believe has the potential to provide a valuable new option for patients suffering from major depressive disorder and postpartum depression.

隨著我們在新的治療領域推出並建立新的特許經營權，我們在這 4 個支柱上的進展為我們提供了未來兩波增長的潛力。首先，在接下來的幾年中，我們相信我們在阿爾茨海默病和抑鬱症方面具有巨大潛力，這兩個大型治療領域的需求顯著且未得到滿足。在阿爾茨海默病方面，我們擁有豐富的臨床和臨床前資產管道，利用多種模式和目標，包括澱粉樣蛋白和 tau。憑藉 ADUHELM 和 lecanemab，百健（Biogen）和衛材（Eisai）擁有 4 種潛在的抗澱粉樣蛋白抗體療法中的 2 種，這些療法要么已獲批准，要么處於後期開發階段。在抑鬱症方面，我們正在與 Sage Therapeutics 合作開發 zuranolone，我們相信這有可能為患有重度抑鬱症和產後抑鬱症的患者提供有價值的新選擇。

We believe our second future waves of growth anticipated in the mid- to late 2020s will be driven by a number of diverse therapeutic areas, including stroke, Parkinson's disease and lupus with some of these programs already in Phase III. These anticipated future waves of growth will be supported by our diversified pipeline, which today includes 32 clinical programs, 10 of which are in Phase III or filed.

我們相信，我們預計在 2020 年代中後期出現的第二波未來增長將受到許多不同治療領域的推動，包括中風、帕金森病和狼瘡，其中一些項目已經處於 III 期。這些預期的未來增長浪潮將得到我們多元化管道的支持，目前包括 32 個臨床項目，其中 10 個處於 III 期或已提交。

Additionally, outside of our core business, we are pleased to have recently exercised an option for mosunetuzumab, a late-stage investigational bispecific antibody targeting CD20 and CD3 in development by Genentech for oncology and potentially other indications. Exercise of this option will provide Biogen with a profit share, while Genentech will lead strategy and implementation with an expected FDA filing in the near future. This builds on Biogen and Genentech's long history of productive collaboration, which began with rituximab.

此外，在我們的核心業務之外，我們很高興最近行使了 mosunetuzumab 的選擇權，這是一種針對 CD20 和 CD3 的後期研究雙特異性抗體，由 Genentech 開發，用於腫瘤學和潛在的其他適應症。行使這一選擇權將為百健（Biogen）提供利潤份額，而基因泰克（Genentech）將領導戰略和實施，並在不久的將來向 FDA 提交文件。這建立在百健（Biogen）和基因泰克（Genentech）從利妥昔單抗開始的長期高效合作的基礎上。

Our focus in 2022 will remain on execution and agility as we expect a number of important milestones. This includes the continued launch of ADUHELM in the U.S., the launch of VUMERITY in the EU and our expected entry into the U.S. biosimilars market with BYOOVIZ. We expect 5 data readouts, 3 of which are in Phase III; and the completion of 3 regulatory filings in Alzheimer's disease, depression and biosimilars.

我們在 2022 年的重點仍將放在執行和敏捷性上，因為我們預計會有許多重要的里程碑。這包括繼續在美國推出 ADUHELM、在歐盟推出 VUMERITY 以及我們預期與 BYOOVIZ 進入美國生物仿製藥市場。我們預計有 5 個數據讀數，其中 3 個處於 III 期；完成 3 項阿爾茨海默病、抑鬱症和生物仿製藥的監管備案。

Before I turn the call over to Priya for an update on our progress in R&D, I want to first say how impressed I am by what I have seen from Priya, both as the Head of Safety and Regulatory Science and most recently as our acting head of R&D. Her ability to lead, her strategic thinking and her subject matter expertise give me the utmost confidence in her ability to advance our pipeline while we work to name a permanent successor.

在我將電話轉給 Priya 以了解我們在研發方面的最新進展之前，我想先說一下我對 Priya 的所見所聞印象深刻的研發。她的領導能力、戰略思維和主題專業知識讓我對她在我們努力任命永久繼任者時推進我們管道的能力充滿信心。

Please go ahead, Priya.

請繼續，普里亞。

Thank you, Michel, and good morning, everyone. First, I want to say what an honor it is to serve as Acting Head of R&D at Biogen. Biogen has a track record in developing life-changing therapies in MS and SMA. With a deep and diverse R&D pipeline, Biogen aims to bring impactful medicines to patients suffering from neurological and immunological diseases characterized by significant unmet need. As this is my first earnings call within this role, I would like to review a few areas that I'm especially excited about.

謝謝你，米歇爾，大家早上好。首先，我想說的是，擔任百健（Biogen）研發代理負責人是多麼榮幸。 Biogen 在開發 MS 和 SMA 改變生命的療法方面有著良好的記錄。憑藉深入而多樣化的研發管道，Biogen 旨在為患有神經和免疫疾病的患者帶來有影響力的藥物，這些疾病的特點是顯著未滿足的需求。由於這是我在這個職位上的第一次財報電話會議，我想回顧一下我特別興奮的幾個領域。

First, we believe that Biogen has a unique opportunity to lead in Alzheimer's disease, not only because we are advancing an industry-leading Alzheimer's pipeline, but also because of the proactive focus we have placed on continued data generation for aducanumab. This includes ENVISION, the planned post-marketing Phase IV study; the ongoing EMBARK redosing study; and obtaining real-world data through the ICARE AD registry. We believe data from patients treated with aducanumab in the real-world settings with greater drug utilization is the best way to complement the extensive clinical data generated on aducanumab to date in addition to the ongoing and planned clinical trials.

首先，我們相信百健（Biogen）擁有引領阿爾茨海默病的獨特機會，不僅因為我們正在推進行業領先的阿爾茨海默病管道，還因為我們積極關注持續的 aducanumab 數據生成。這包括 ENVISION，計劃中的上市後 IV 期研究；正在進行的 EMBARK 重做研究；並通過 ICARE AD 註冊表獲取真實數據。我們相信，除了正在進行和計劃中的臨床試驗之外，在真實世界環境中使用 aducanumab 治療的患者的數據具有更高的藥物利用率，是補充迄今為止在 aducanumab 上產生的廣泛臨床數據的最佳方式。

We also continue to gain potential insights from the aducanumab Phase III clinical data regarding Alzheimer's disease biology and the treatment effect of aducanumab. On this particular point, Biogen recently presented additional data from the ENGAGE and EMERGE Phase III trials at the annual CTAD meeting last November. The important analysis of this data showed that in addition to reducing amyloid plaques in the brain, aducanumab treatment also resulted in changes in downstream tau Alzheimer's disease biology, specifically soluble phospho-tau, or p-tau, as seen in both CSF and plasma.

我們還繼續從 aducanumab III 期臨床數據中獲得有關阿爾茨海默病生物學和 aducanumab 治療效果的潛在見解。在這一點上，百健（Biogen）最近在去年 11 月的 CTAD 年度會議上展示了 ENGAGE 和 EMERGE III 期試驗的額外數據。對這些數據的重要分析表明，除了減少大腦中的澱粉樣蛋白斑塊外，aducanumab 治療還導致下游 tau 阿爾茨海默病生物學的變化，特別是在腦脊液和血漿中看到的可溶性磷酸化 tau 或 p-tau。

In this analysis, we evaluated over 7,000 plasma samples from more than 1,800 subjects from the EMERGE and ENGAGE Phase III trials to investigate the effect of aducanumab treatment on plasma p-tau181. The result showed a time and dose-dependent reduction in p-tau181 over 78 weeks with aducanumab treatment in both Phase III trials. The reduction in plasma p-tau181 from baseline to week 78 in this analysis was significantly correlated with change in amyloid PET over the same time period and was also significantly associated with less clinical decline across all primary and secondary outcome measures, assessing cognition and function in both studies. These findings are consistent with the hypothesis that aggregated forms of amyloid may mediate soluble tau phosphorylation.

在這項分析中，我們評估了來自 EMERGE 和 ENGAGE III 期試驗的 1,800 多名受試者的 7,000 多份血漿樣本，以研究 aducanumab 治療對血漿 p-tau181 的影響。結果顯示，在兩項 III 期試驗中，使用 aducanumab 治療 78 週後 p-tau181 的時間和劑量依賴性降低。在該分析中，血漿 p-tau181 從基線到第 78 週的減少與同一時期內澱粉樣蛋白 PET 的變化顯著相關，並且還與所有主要和次要結果測量的臨床下降減少顯著相關，評估認知和功能兩項研究。這些發現與聚集形式的澱粉樣蛋白可能介導可溶性 tau 磷酸化的假設一致。

With regard to our AD pipeline, we are excited about lecanemab, our other anti-amyloid antibody in Alzheimer's disease that is being developed in collaboration with Eisai. In Phase II, lecanemab did not utilize a titration period, demonstrated rapid and robust reduction of amyloid plaques and showed an ARIA incidence of around 10%. We look forward to the Phase III readout expected in the second half of this year.

關於我們的 AD 管道，我們對 lecanemab 感到興奮，這是我們與衛材合作開發的另一種治療阿爾茨海默病的抗澱粉樣蛋白抗體。在 II 期，lecanemab 沒有使用滴定期，顯示出澱粉樣斑塊的快速和穩健減少，並顯示 ARIA 發生率約為 10%。我們期待預計在今年下半年發布的第三階段數據。

Beyond our programs targeting amyloid, we are also pursuing a multi-modality approach focused on other targets in Alzheimer's. First, we have BIIB080, which is an ASO that we believe facilitates tau mRNA degradation and has demonstrated both a time and dose-dependent reduction of CSF phospho and total tau in Phase I. We anticipate starting the Phase II study of BIIB080 by midyear.

除了我們針對澱粉樣蛋白的計劃外，我們還在尋求一種針對阿爾茨海默病其他目標的多模式方法。首先，我們有 BIIB080，它是一種 ASO，我們認為它促進 tau mRNA 降解，並已證明 I 期 CSF 磷酸化和總 tau 的時間和劑量依賴性降低。我們預計在年中開始 BIIB080 的 II 期研究。

Second, we are also planning for the near-term initiation of a Phase I study for BIIB113, a small molecule inhibitor of O-GlcNAcase, or OGA, an enzyme believed to catalyze the removal of post-translation modification of tau protein. Evidence suggests that O-GlcNAcylation of tau attenuates aggregation. By inhibiting OGA, we aim to increase the O-GlcNAcylation of tau to potentially inhibit tau aggregation and thereby slow clinical decline.

其次，我們還計劃近期啟動 BIIB113 的 I 期研究，BIIB113 是 O-GlcNAcase 或 OGA 的小分子抑製劑，OGA 是一種據信可催化去除 tau 蛋白翻譯後修飾的酶。證據表明 tau 的 O-GlcNAcylation 減弱了聚集。通過抑制 OGA，我們的目標是增加 tau 的 O-GlcNAcylation 以潛在地抑制 tau 聚集，從而減緩臨床衰退。

Having developed the first FDA-approved therapy to address a defining pathology of Alzheimer's, we believe that Biogen is uniquely positioned with the right expertise, experience and access to modalities to lead in Alzheimer's disease. This is a complex disease requiring a multifaceted approach and continued investment as we work to build on the scientific learnings of ADUHELM and develop the next wave of potential Alzheimer's therapies.

在開發了第一個 FDA 批准的治療阿爾茨海默病的定義病理學後，我們相信百健（Biogen）具有獨特的定位，擁有正確的專業知識、經驗和獲得治療阿爾茨海默病的方式的機會。這是一種複雜的疾病，需要多方面的方法和持續的投資，因為我們致力於在 ADUHELM 的科學知識基礎上發展並開發下一波潛在的阿爾茨海默氏症療法。

I would now like to talk about depression. I believe that zuranolone, with a novel mechanism of action, may provide an important new treatment option for patients suffering from major depressive disorder and postpartum depression.

我現在想談談抑鬱症。相信具有新作用機制的zuranolone可能為重度抑鬱症和產後抑鬱症患者提供重要的新治療選擇。

The reported clinical data generated to date from multiple clinical trials showed the following: First, in earlier studies, an improvement in depressive symptoms has been observed as early as day 3. Second, zuranolone has displayed a consistent safety and tolerability profile with no observed evidence of weight gain, sexual dysfunction, euphoria or increased suicidal ideation. Third, the SHORELINE Phase III open-label study showed that approximately 80% of patients who responded to the initial course of 50 milligrams of zuranolone needed at most 1 additional treatment total during their time in the 1-year study.

迄今為止，多項臨床試驗報告的臨床數據顯示如下：首先，在早期的研究中，早在第 3 天就觀察到抑鬱症狀有所改善。其次，zuranolone 顯示出一致的安全性和耐受性，但沒有觀察到證據體重增加、性功能障礙、興奮或自殺意念增加。第三，SHORELINE III 期開放標籤研究表明，在 1 年研究期間，大約 80% 對 50 毫克 zuranolone 初始療程有反應的患者總共需要最多 1 次額外治療。

Fourth, in the WATERFALL Phase III study, zuranalone reduced depressive symptoms in patients suffering from MDD, both with and without elevated anxiety. Fifth, zuranolone has shown improvements in depressive symptoms in postpartum depression. For zuranolone, we look forward to 2 Phase III readouts this year: the CORAL study in MDD and the SKYLARK study in PPD.

第四，在 WATERFALL III 期研究中，zuranalone 減輕了患有 MDD 的患者的抑鬱症狀，無論是否增加焦慮。第五，zuranolone 在產後抑鬱症中的抑鬱症狀有所改善。對於 zuranolone，我們期待今年有 2 個 III 期讀數：MDD 中的 CORAL 研究和 PPD 中的 SKYLARK 研究。

The next area I would like to highlight is stroke. Last year, we were excited by the results from the Phase II study of BIIB131, formerly known as TMS-007, in acute ischemic stroke. Administration of the current standard of care, pharmacological thrombolytic tPA, is limited to a short therapeutic window: within 4.5 hours following the acute onset of stroke symptoms. This short time window is meant to mitigate the risk of intracranial hemorrhage, which is the most concerning adverse event associated with tPA.

我想強調的下一個領域是中風。去年，我們對 BIIB131（以前稱為 TMS-007）在急性缺血性中風中的 II 期研究結果感到興奮。目前的護理標準藥物溶栓 tPA 僅限於較短的治療窗口：在中風症狀急性發作後的 4.5 小時內。這個短時間窗口旨在降低顱內出血的風險，這是與 tPA 相關的最令人擔憂的不良事件。

In the Phase IIa study of BIIB131, acute stroke patients were randomized to receive BIIB131 or placebo out to 12 hours from their last known normal. The primary objective of the study was safety. And of the 52 patients who received BIIB131, none experienced symptomatic intracranial hemorrhage compared to 1 out of the 38 patients who received placebo. This was despite an extended treatment window where patients, on average, received BIIB131 at 9.5 hours after the onset of acute stroke symptoms.

在 BIIB131 的 IIa 期研究中，急性中風患者被隨機分配接受 BIIB131 或安慰劑治療，直到他們最後一次已知正常的 12 小時內。該研究的主要目標是安全性。在接受 BIIB131 的 52 名患者中，沒有人出現症狀性顱內出血，而接受安慰劑的 38 名患者中只有 1 人出現。儘管延長了治療窗口，患者平均在急性中風症狀發作後 9.5 小時接受 BIIB131。

Additionally, BIIB131 showed a statistically significant improvement versus placebo on the Modified Rankin Scale, or MRS, a registrational end point of functional independence. Furthermore, the rate of recanalization or improvement of vessel blood flow in patients who had a visible vessel occlusion was approximately 58% at 24 hours in those who had received BIIB131 as compared to 27% of patients who received placebo.

此外，與安慰劑相比，BIIB131 在改良 Rankin 量表或 MRS（功能獨立的註冊終點）上顯示出統計學上的顯著改善。此外，接受 BIIB131 治療的患者在 24 小時內有可見血管閉塞的患者的血管再通率或改善率約為 58%，而接受安慰劑治療的患者為 27%。

We believe BIIB131 may have the potential to be a best-in-class thrombolytic for the treatment of acute ischemic stroke by extending the time -- treatment time window out to 24 hours with an appropriate efficacy and safety profile. We are currently evaluating the next steps in the development for BIIB131. In addition to BIIB131, we also continue to advance a Phase III study for BIIB093 in large hemispheric infarction based upon the effects observed on mortality and cerebral edema in the Phase II study.

我們相信 BIIB131 有可能成為治療急性缺血性中風的同類最佳溶栓劑，通過將治療時間窗延長至 24 小時，並具有適當的療效和安全性。我們目前正在評估 BIIB131 開發的下一步。除了 BIIB131，我們還根據在 II 期研究中觀察到的對死亡率和腦水腫的影響，繼續推進 BIIB093 在大半球梗死中的 III 期研究。

I would now like to turn my attention to specialized immunology. We currently have 2 Phase III assets in SLE, including dapirolizumab pegol in collaboration with UCB; and BIIB059, our anti-BDCA2 antibody developed in-house at Biogen. These 2 assets represent potential first-in-class molecules in SLE.

我現在想把注意力轉向專門的免疫學。我們目前在 SLE 擁有 2 個 III 期資產，包括與 UCB 合作的 dapirolizumab pegol；和 BIIB059，我們在 Biogen 內部開發的抗 BDCA2 抗體。這兩項資產代表了 SLE 中潛在的一流分子。

BIIB059 also has the potential to be a first-in-class biologic in cutaneous lupus erythematosus, or CLE. CLE is a skin-based autoimmune disease that can be associated with severe scarring and dyspigmentation. In the Phase II LILAC study, the CLE part of the study also met its primary end point by demonstrating a dose response of BIIB059 on the percent change from baseline in the CLASI-A score, a standardized scale measuring CLE disease activity, at week 16 in individuals with CLE.

BIIB059 也有可能成為皮膚紅斑狼瘡或 CLE 的一流生物製劑。 CLE 是一種基於皮膚的自身免疫性疾病，可能與嚴重的疤痕和色素沉著相關。在 II 期 LILAC 研究中，該研究的 CLE 部分還通過在第 16 週證明 BIIB059 對 CLASI-A 評分（一種測量 CLE 疾病活動的標準化量表）相對於基線的百分比變化的劑量反應，達到了其主要終點在患有 CLE 的人中。

Furthermore, a higher CLASI-50 response rate, or number of individuals with a 50% or greater improvement from baseline in the CLASI-A score, was observed in patients who received BIIB059 at week 16. Based upon these results, we are currently planning to also initiate a pivotal study for BIIB059 in CLE this year.

此外，在第 16 週接受 BIIB059 的患者中觀察到更高的 CLASI-50 反應率，或 CLASI-A 評分從基線改善 50% 或更多的個體數量。基於這些結果，我們目前正在計劃今年還將在 CLE 啟動一項針對 BIIB059 的關鍵研究。

Next, I will touch upon ALS. ALS has been a very key focus area for Biogen for many years. And we remain encouraged by the data from the Phase III VALOR study of tofersen, where despite missing the primary end point of a statistically significant change from baseline to week 28 in the ALSFRS, we believe there are trends favoring tofersen across multiple secondary and exploratory measures of biological and clinical activity. We are continuing to collect data in the VALOR open-label extension, and we are actively recruiting for the ATLAS presymptomatic study.

接下來，我將介紹 ALS。多年來，ALS 一直是 Biogen 的一個非常關鍵的關注領域。我們仍然對 tofersen 的 III 期 VALOR 研究的數據感到鼓舞，儘管在 ALSFRS 中錯過了從基線到第 28 週的統計學顯著變化的主要終點，但我們相信在多個次要和探索性措施中存在有利於 tofersen 的趨勢生物學和臨床活性。我們將繼續在 VALOR 開放標籤擴展中收集數據，並且我們正在積極招募 ATLAS 症狀前研究。

Many SOD1-ALS patients have received access to tofersen through the global expanded access program, which is available in countries where local regulations permit it and where we hope to secure long-term access. Further, we are engaged with regulators to determine the next steps for the program.

許多 SOD1-ALS 患者已通過全球擴大訪問計劃獲得了 tofersen 的訪問權，該計劃可在當地法規允許的國家以及我們希望確保長期訪問權的國家獲得。此外，我們正在與監管機構合作，以確定該計劃的後續步驟。

Aside from the areas I've highlighted, Biogen continues to grow and diversify the R&D pipeline, which now includes 32 clinical programs. New additions include the exercise of the option with Ionis on BIIB115, an investigational ASO with the potential for extended dosing intervals in SME as well as the recent initiation of a Phase I study in Angelman syndrome, a rare genetic neurodevelopmental disorder that affects the nervous system and causes severe physical and learning disabilities with symptoms beginning in infancy. Importantly, I believe that 2022 will be a significant year for Biogen's pipeline given the number of important readouts expected, including the lecanemab Phase III in Alzheimer's disease, key readouts in neuropsychiatry for both zuranolone in depression and BIIB104 in schizophrenia and BIIB078 in ALS.

除了我強調的領域外，百健（Biogen）繼續發展和多樣化研發管道，現在包括 32 個臨床項目。新增內容包括在 BIIB115 上與 Ionis 一起行使期權，這是一種研究性 ASO，有可能在 SME 中延長給藥間隔，以及最近啟動的 Angelman 綜合徵 I 期研究，這是一種影響神經系統的罕見遺傳性神經發育障礙並導致嚴重的身體和學習障礙，症狀從嬰儿期開始。重要的是，鑑於預期的重要讀數的數量，我相信 2022 年對於百健（Biogen）的管道來說將是重要的一年，包括阿爾茨海默病中的 lecanemab III 期、抑鬱症中的 zuranolone 和精神分裂症中的 BIIB104和 ALS 中的 BIIB078 的神經精神病學中的關鍵讀數。

In closing, I believe Biogen has assembled an extensive pipeline of programs informed by generics, a deep understanding of disease biology, specialized modality expertise and digitalization. Therefore, I believe Biogen is uniquely positioned to shape the future of therapeutics in neurology and specialized immunology and make a difference in patients and their caregivers' lives.

最後，我相信百健（Biogen）已經通過仿製藥、對疾病生物學的深刻理解、專業的模式專業知識和數字化，構建了廣泛的項目管道。因此，我相信百健（Biogen）具有獨特的優勢，可以塑造神經病學和專業免疫學治療的未來，並改變患者及其護理人員的生活。

I will now pass the call over to Mike.

我現在將把電話轉給邁克。

Thank you, Priya, and good morning, everyone. Thank you for joining us. I'll focus my commentary on fourth quarter results along with some discussion regarding the full year 2021.

謝謝你，普里亞，大家早上好。感謝您加入我們。我將把我的評論集中在第四季度的業績以及一些關於 2021 年全年的討論上。

Total revenue for the fourth quarter of $2.7 billion declined 4% versus the prior year at both actual and constant currency. Total revenue for the full year of $11 billion declined 18% versus the prior year at actual currency and 19% at constant currency. This decline was mostly driven by TECFIDERA generic entry in the United States.

第四季度的總收入為 27 億美元，按實際匯率和固定匯率計算，與去年同期相比下降了 4%。按實際匯率計算，全年總收入為 110 億美元，與上年相比下降 18%，按固定匯率計算下降 19%。這種下降主要是由 TECFIDERA 仿製藥進入美國推動的。

Non-GAAP diluted earnings per share in the fourth quarter was $3.39. Full year non-GAAP diluted earnings per share was $19.22. Total MS revenue inclusive of OCREVUS royalties in the fourth quarter was $1.8 billion. Global TECFIDERA revenue in the fourth quarter was $486 million. U.S. revenue was $161 million. Outside of the U.S., TECFIDERA revenue of $326 million increased by 13% versus the prior year, with 7% growth in underlying patients.

第四季度非 GAAP 攤薄後每股收益為 3.39 美元。全年非公認會計原則攤薄後每股收益為 19.22 美元。包括 OCREVUS 特許權使用費在內的第四季度 MS 總收入為 18 億美元。第四季度全球 TECFIDERA 收入為 4.86 億美元。美國的收入為 1.61 億美元。在美國以外，TECFIDERA 收入為 3.26 億美元，比上年增長 13%，基礎患者增長 7%。

VUMERITY fourth quarter global revenue was $125 million as compared to $39 million in the fourth quarter of 2020. We expect VUMERITY to continue to grow both in the U.S. and outside the U.S. TYSABRI fourth quarter global revenue of $513 million increased 8% versus the prior year, benefiting from positive channel dynamics in the U.S., and we were pleased to see continued global patient growth.

VUMERITY 第四季度全球收入為 1.25 億美元，而 2020 年第四季度為 3900 萬美元。我們預計 VUMERITY 將在美國和美國以外地區繼續增長。TYSABRI 第四季度全球收入為 5.13 億美元，比去年同期增長 8% ，受益於美國積極的渠道動態，我們很高興看到全球患者持續增長。

Moving to SMA, global fourth quarter SPINRAZA revenue of $441 million decreased 12% versus the prior year. In the U.S., SPINRAZA revenue of $150 million decreased by 6% versus the prior year, as we saw continued impact from competition. However, we were encouraged to see that discontinuations moderated somewhat versus Q3 of this year. U.S. SPINRAZA revenue increased 7% versus the prior quarter, inclusive of some favorable pricing and channel dynamics. Outside the U.S., SPINRAZA revenue of $291 million decreased 14% versus the prior year due to competition and pricing pressure. We continue to believe that SPINRAZA can return to growth over the medium to long term.

轉向 SMA，全球第四季度 SPINRAZA 收入為 4.41 億美元，與去年同期相比下降了 12%。在美國，由於競爭的持續影響，SPINRAZA 的收入為 1.5 億美元，較上年下降了 6%。然而，我們感到鼓舞的是，與今年第三季度相比，停產數量有所緩和。美國 SPINRAZA 收入與上一季度相比增長了 7%，其中包括一些有利的定價和渠道動態。在美國以外，由於競爭和定價壓力， SPINRAZA 的收入為 2.91 億美元，較上年下降 14%。我們仍然相信 SPINRAZA 可以在中長期內恢復增長。

Total ADUHELM revenue for the fourth quarter was $1 million. Moving to our biosimilars business. Fourth quarter revenue of $221 million increased 12% versus the prior year, with increased volume partially offset by pricing pressure. Our Q4 biosimilars revenue benefited from a onetime price adjustment of approximately $10 million.

ADUHELM 第四季度的總收入為 100 萬美元。轉向我們的生物仿製藥業務。第四季度收入為 2.21 億美元，較上年同期增長 12%，增加的銷量部分被定價壓力所抵消。我們的第四季度生物仿製藥收入受益於約 1000 萬美元的一次性價格調整。

Last week, we announced that we have entered into an agreement to sell our equity stake in our biosimilar joint venture, Samsung Bioepis, to Samsung Biologics for aggregate consideration of up to $2.3 billion. We believe this represents an attractive financial return given that our cumulative investment in the joint venture was $727 million.

上週，我們宣布已達成協議，將我們在生物仿製藥合資企業 Samsung Bioepis 中的股權出售給 Samsung Biologics，總對價高達 23 億美元。鑑於我們對合資企業的累計投資為 7.27 億美元，我們認為這代表了可觀的財務回報。

It's important to note that we will continue to record revenue and costs associated with the commercialization of BENEPALI, IMRALDI and FLIXABI with economics that will be substantially unchanged from what you have seen previously. So we are pleased with this transaction because we not only maintain the commercialization rights that we have, but we will also have an expanded ability to pursue additional biosimilars products on our own going forward. Closing of this transaction is currently anticipated in mid-2022, contingent on the effectiveness of the securities registration statement filed by Samsung Biologics and satisfaction of certain regulatory and other customary closing conditions.

需要注意的是，我們將繼續記錄與 BENEPALI、IMRALDI 和 FLIXABI 商業化相關的收入和成本，其經濟性與您之前所見的情況基本相同。因此，我們對此次交易感到滿意，因為我們不僅保留了我們擁有的商業化權利，而且我們還將有更大的能力在未來自行尋求更多的生物仿製藥產品。目前預計該交易將於 2022 年年中完成，具體取決於三星生物製藥提交的證券登記聲明的有效性以及某些監管和其他慣例成交條件的滿足情況。

Total anti-CD20 revenue in the fourth quarter of $414 million decreased 1% versus the prior year. RITUXAN revenue of $153 million decreased 29% versus the prior year due to the impacts of COVID-19 and continued erosion from biosimilar competition. OCREVUS royalty revenue of $261 million increased 29% versus the prior year. As a reminder, the effective royalty rate for OCREVUS royalties resets each calendar year.

第四季度的反 CD20 總收入為 4.14 億美元，與去年同期相比下降了 1%。由於 COVID-19的影響和生物仿製藥競爭的持續侵蝕， RITUXAN 的收入為 1.53 億美元，較上年下降 29%。 OCREVUS 特許權使用費收入為 2.61 億美元，較上年增長 29%。提醒一下，OCREVUS 版稅的有效版稅率會在每個日曆年重置。

Fourth quarter gross margin was 76% of revenue, down from 83% in Q4 of 2020. And the reduction in gross margin versus prior year was primarily due to a $164 million charge for ADUHELM inventory and purchase commitments in excess of forecasted demand.

第四季度毛利率為收入的 76%，低於 2020 年第四季度的 83%。毛利率與上年相比下降的主要原因是 ADUHELM 庫存和採購承諾的 1.64 億美元費用超過了預測需求。

Moving now to expenses and the balance sheet. Q4 non-GAAP R&D expense was $700 million, which includes a $60 million opt-in payment to Ionis for BIIB115 and a cost of approximately $50 million for the exercise of our option with Genentech for the bispecific antibody mentioned earlier. We will share any operating profits and losses for this program in the low to mid-30% range in the United States.

現在轉到費用和資產負債表。第四季度非 GAAP 研發費用為 7 億美元，其中包括向 Ionis 支付 6000 萬美元用於 BIIB115的選擇支付費用，以及約 5000 萬美元用於行使我們與基因泰克對前面提到的雙特異性抗體的選擇權。我們將分擔該計劃在美國的低至中 30% 範圍內的任何運營盈虧。

Non-GAAP SG&A was $785 million, including approximately $155 million related to ADUHELM. Eisai's reimbursement of U.S. SG&A costs of approximately $45 million is reflected in the collaboration profit sharing line. Fourth quarter collaboration profit sharing reduced our net operating expense by $67 million, which includes reimbursement of approximately $140 million from Eisai related to ADUHELM commercialization, partially offset by $75 million of net profit sharing expense related to our collaboration with Samsung Bioepis.

Non-GAAP SG&A 為 7.85 億美元，包括與 ADUHELM 相關的約 1.55 億美元。衛材報銷的美國 SG&A 成本約為 4500 萬美元，反映在合作利潤分享線中。第四季度的合作利潤分享使我們的淨運營費用減少了 6700 萬美元，其中包括來自衛材的與 ADUHELM 商業化相關的約 1.4 億美元的報銷，部分被與三星 Bioepis 合作相關的 7500 萬美元的淨利潤分享費用所抵消。

During Q4 of this year, our effective non-GAAP tax rate was approximately 17%. During 2021, we repurchased approximately 6 million shares of our common stock for a total value of $1.8 billion. No shares were repurchased in the fourth quarter of 2021. As of December 31, 2021, there was $2.8 billion remaining under the share repurchase program, which was authorized in October of 2020. Our weighted average diluted share count was approximately 147 million shares for the fourth quarter.

今年第四季度，我們的有效非公認會計原則稅率約為 17%。 2021 年，我們回購了約 600 萬股普通股，總價值為 18 億美元。 2021 年第四季度沒有回購任何股票。截至 2021 年 12 月 31 日，2020 年 10 月授權的股票回購計劃下剩餘 28 億美元。我們的加權平均稀釋後股票數量約為 1.47 億股。第四季度。

In 2021, we generated approximately $3.6 billion in cash flow from operations. Capital expenditures were $258 million, and free cash flow was approximately $3.4 billion. We ended the year with $7.3 billion in debt, $4.7 billion in cash and marketable securities and $2.6 billion in net debt. In addition, our $1 billion revolving credit facility was undrawn as of the end of the year. Overall, we remain in a very strong financial position with significant cash and financial capacity to grow the business over the long term.

2021 年，我們從運營中產生了約 36 億美元的現金流。資本支出為 2.58 億美元，自由現金流約為 34 億美元。到年底，我們的債務為 73 億美元，現金和有價證券為 47 億美元，淨債務為 26 億美元。此外，截至年底，我們的 10 億美元循環信貸額度尚未提取。總體而言，我們仍然處於非常強勁的財務狀況，擁有大量現金和財務能力來長期發展業務。

Let me now turn to our full year guidance for 2022. We expect full year 2022 revenue to be between $9.7 billion and $10 billion. This financial guidance assumes minimal ADUHELM revenue in 2022, continued declines in RITUXAN revenue due to biosimilar competition as well as continued erosion of TECFIDERA revenue in the U.S. due to generic entry. This guidance also assumes the potential entry of TECFIDERA generics in the EU as early as the first half of 2022 as the outcome of the ongoing challenges to TECFIDERA market protection is difficult to predict. We expect the decreased revenue from these high-margin products to reduce our gross margin percentage as compared to 2021.

現在讓我談談我們對 2022 年的全年指導。我們預計 2022 年全年收入將在 97 億美元至 100 億美元之間。該財務指導假設 ADUHELM 2022 年收入最低，RITUXAN 收入因生物仿製藥競爭而持續下降，以及由於仿製藥進入美國 TECFIDERA 收入持續下降。該指南還假設 TECFIDERA 仿製藥最早可能在 2022 年上半年進入歐盟，因為 TECFIDERA 市場保護面臨的持續挑戰的結果難以預測。我們預計，與 2021 年相比，這些高利潤率產品的收入減少將降低我們的毛利率百分比。

We expect full year 2022 non-GAAP diluted EPS to be between $14.25 and $16. Our guidance assumptions are highly dependent on the final National Coverage Determination, which is currently uncertain. If the final NCD, which is expected in April, is not broader than the draft NCD, our anticipated results and guidance may be impacted.

我們預計 2022 年全年非公認會計原則攤薄後每股收益將在 14.25 美元至 16 美元之間。我們的指導假設高度依賴於目前不確定的最終國家覆蓋範圍確定。如果預計在 4 月發布的最終 NCD 不比 NCD 草案更廣泛，我們的預期結果和指導可能會受到影響。

This guidance assumes that we will not have any write-offs of ADUHELM inventory in 2022, which is valued at approximately $225 million as of the end of 2021. This guidance also assumes reasonable levels of utilization of our manufacturing capacity dedicated to our Alzheimer's disease programs. If our manufacturing capacity is underutilized, we will incur incremental period costs, which are not reflected in our guidance.

本指南假設我們在 2022 年不會註銷 ADUHELM 庫存，截至 2021 年底，其價值約為 2.25 億美元。本指南還假設我們的阿爾茨海默病項目專用製造能力的利用率達到合理水平.如果我們的製造能力未得到充分利用，我們將產生增量期間成本，這未反映在我們的指導中。

We expect non-GAAP R&D expense to be between $2.2 billion and $2.3 billion, and our non-GAAP SG&A expense to be between $2.5 billion and $2.6 billion. This non-GAAP SG&A expense estimate includes approximately $400 million in support of the launch of ADUHELM, of which approximately $145 million would be reimbursable by Eisai and reflected in the collaboration profit sharing line.

我們預計非 GAAP 研發費用將在 22 億美元至 23 億美元之間，我們的非 GAAP SG&A 費用將在 25 億美元至 26 億美元之間。這一非 GAAP SG&A 費用估計包括大約 4 億美元，用於支持 ADUHELM 的推出，其中大約 1.45 億美元將由衛材報銷，並反映在合作利潤分享項目中。

These R&D and SG&A expense estimates reflect the implementation of previously disclosed cost reduction measures, which are expected to yield approximately $500 million in annualized savings, of which approximately $350 million is expected to be realized in 2022. These savings are expected to be achieved through various initiatives, which may include downsizing of our global Alzheimer's infrastructure, the savings from which would be shared with Eisai; and operating efficiency gains across SG&A and R&D. These savings are expected to be offset by approximately $200 million in additional investments in our pipeline and strategic initiatives. In the event of a final NCD that is not broader than the draft NCD, we anticipate taking further cost reduction measures, which are not reflected in our guidance to further align our cost base with our revenue base. Some of the savings from these further cost reduction measures would be shared with Eisai.

這些研發和 SG&A 費用估計反映了先前披露的成本削減措施的實施情況，預計這些措施將產生約 5 億美元的年度節約，其中約 3.5 億美元預計將在 2022 年實現。這些節約預計將通過各種方式實現舉措，其中可能包括縮減我們全球阿爾茨海默氏症基礎設施的規模，節省的資金將與衛材分享； SG&A 和 R&D 的運營效率提升。預計這些節省將被我們對管道和戰略計劃的額外投資約 2 億美元所抵消。如果最終的 NCD 不比 NCD 草案更廣泛，我們預計會採取進一步降低成本的措施，這些措施並未反映在我們的指導中，以進一步使我們的成本基礎與我們的收入基礎保持一致。這些進一步降低成本的措施所節省的部分資金將與衛材分享。

We expect our non-GAAP tax rate for 2022 to be between 15.5% and 16.5%. And we assume that we will utilize a portion of the remaining share repurchase authorization of $2.8 billion throughout the year, although this will depend on a variety of factors, including our business development activities.

我們預計 2022 年的非公認會計原則稅率將在 15.5% 至 16.5% 之間。我們假設我們將在全年使用剩餘的 28 億美元股票回購授權的一部分，儘管這將取決於多種因素，包括我們的業務發展活動。

Foreign exchange rates as of December 31, 2021, are assumed to remain in effect for the year, net of hedging activities. We have not included any impact from potential acquisitions or large business development transactions as both are hard to predict or any impact of potential tax or health care reform.

假設扣除對沖活動後，截至 2021 年 12 月 31 日的匯率在當年保持有效。我們沒有包括潛在收購或大型業務發展交易的任何影響，因為兩者都難以預測或潛在稅收或醫療改革的任何影響。

I will now turn the call back over to Michel for his closing remarks.

現在，我將把電話轉回給 Michel，以完成他的閉幕詞。

Thank you, Mike. In summary, 2021 was an eventful year for Biogen. ADUHELM is now the first FDA-approved treatment targeting a defining pathology of Alzheimer's disease. But as we all know, this is a complex disease, which will require continued investment in research over the years to come.

謝謝你，邁克。總而言之，2021 年對百健（Biogen）來說是多事之年。 ADUHELM 現在是 FDA 批准的第一個針對阿爾茨海默病定義病理學的治療方法。但眾所周知，這是一種複雜的疾病，需要在未來幾年繼續投資研究。

ADUHELM is an important first step, and we remain focused on advancing our leading portfolio with the goal of further addressing the remaining unmet needs for patients. We hope that over time, we'll be able to bring additional impactful treatment options, which will build on the scientific learnings from ADUHELM, similar to the waves of innovation we have seen in oncology.

ADUHELM 是重要的第一步，我們將繼續專注於推進我們領先的產品組合，目標是進一步滿足患者剩餘的未滿足需求。我們希望隨著時間的推移，我們將能夠帶來更多有影響力的治療選擇，這將建立在 ADUHELM 的科學知識基礎上，類似於我們在腫瘤學中看到的創新浪潮。

Before I conclude, let me touch on Biogen's strong commitment to corporate responsibility. Climate, health and equity are deeply interrelated challenges that demand bold action, and that's why we are working to advance a healthier, more sustainable and equitable world.

在結束之前，讓我談談 Biogen 對企業責任的堅定承諾。氣候、健康和公平是相互關聯的挑戰，需要採取大膽的行動，這就是為什麼我們正在努力推動一個更健康、更可持續和更公平的世界。

Through our signature initiative, Healthy Climate, Healthy Lives, and other efforts, our goal is to create new ways of doing business that positively impact the way we live and the way we deliver for patients. We are proud that our leadership actions and transparency in this area has been recognized recently by the Dow Jones Sustainability World Index, Corporate Knights Global 100 and JUST 100. Through this work, we aim to create shareholder value by meeting the needs of our patients, employees, the environment and the communities we serve.

通過我們的標誌性倡議、健康氣候、健康生活和其他努力，我們的目標是創造新的經營方式，對我們的生活方式和我們為患者提供服務的方式產生積極影響。我們感到自豪的是，我們在這一領域的領導行為和透明度最近得到了道瓊斯可持續發展世界指數、Corporate Knights Global 100 和 JUST 100 的認可。通過這項工作，我們旨在通過滿足患者的需求來創造股東價值，員工、環境和我們服務的社區。

In closing, I would like to reiterate that we are committed to engaging with CMS and other stakeholders with the hope of finding an appropriate path forward for the patients and access of ADUHELM. We will now open the call for questions.

最後，我想重申，我們致力於與 CMS 和其他利益相關者合作，希望為患者和 ADUHELM 的訪問找到一條合適的前進道路。我們現在將打開問題的電話。

(Operator Instructions) Your first question comes from the line of Robyn Karnauskas with Truist Securities.

（操作員說明）您的第一個問題來自 Truist Securities 的 Robyn Karnauskas。

Given the recent deal that you did with Samsung, you now have more cash. Could you just talk a little bit about your thoughts on how you might want to utilize that cash? And is that -- was there a near-term acquisition or things that you're looking at? Or is it just something that gives you optionality?

鑑於您最近與三星達成的交易，您現在擁有更多現金。你能談談你對如何使用這些現金的想法嗎？那是 - 是否有近期收購或您正在關注的事情？或者它只是給你選擇的東西？

Thanks for the question. As you know, we have a strong balance sheet, and we are continuously looking at how we can deliver long-term shareholder value. So we are actively working on some business development opportunities to enrich our pipeline, complement our portfolio in line with our strategy. And we will look at the deals based on their own merit, and we are working on that.

謝謝你的問題。如您所知，我們擁有強大的資產負債表，並且我們一直在研究如何為股東創造長期價值。因此，我們正在積極尋找一些業務發展機會，以豐富我們的管道，根據我們的戰略補充我們的產品組合。我們將根據交易本身的優點來看待這些交易，我們正在努力。

Yes, and I'll just add to that, Robyn. I mean as we said in our prepared remarks, we're pleased with the transaction. It represents a very attractive return relative to the capital that we invested. And the first priority will be to get the transaction closed, as you saw in the release around the deal. The proceeds will come in gradually over time. And so the first priority would be to get the transaction closed, and we'll continue to explore all of our options around BD deals of all sizes and we will continue our share buyback program as well. And the pipeline remains robust. We look at a lot of opportunities, and we have an extremely healthy balance sheet, as Michel said, and this will only make it healthier.

是的，我會補充一點，Robyn。我的意思是，正如我們在準備好的評論中所說，我們對這筆交易感到滿意。相對於我們投資的資本，它代表了非常有吸引力的回報。正如您在圍繞交易的發布中看到的那樣，首要任務是完成交易。隨著時間的推移，收益將逐漸進入。因此，首要任務是完成交易，我們將繼續探索圍繞各種規模的 BD 交易的所有選擇，我們也將繼續我們的股票回購計劃。管道仍然強勁。正如米歇爾所說，我們看到了很多機會，我們的資產負債表非常健康，這只會讓它更健康。

And Robyn, if I may, an important consideration is now that we can create more value with our biosimilars portfolio, more products, more geographies.

Robyn，如果可以的話，一個重要的考慮是現在我們可以通過我們的生物仿製藥組合、更多產品、更多地域創造更多價值。

Okay. We'll go ahead and take our next question from Michael Yee with Jefferies.

好的。我們將繼續回答 Michael Yee 和 Jefferies 的下一個問題。

I guess my question is in regards to ADUHELM, what you are actively doing to try and change the NCD decision? And again, to reiterate, if it's not changed dramatically, you guys would look to cut -- further cut expenses. So can you talk about what that would entail? And under what scenario that might change? For example, if BAN was positive. Maybe just outline the thoughts and the road map for ADUHELM in 2022.

我想我的問題是關於 ADUHELM，你正在積極做什麼來嘗試改變 NCD 的決定？再次重申，如果沒有發生巨大變化，你們會尋求削減 - 進一步削減開支。那麼你能談談這會帶來什麼嗎？在什麼情況下可能會改變？例如，如果 BAN 為正。也許只是概述 ADUHELM 在 2022 年的想法和路線圖。

Thank you, Mike. I will get started and then my colleagues will come in. First of all, we take into account with a lot of caution all the areas of focus that CMS has communicated. And based on those, we look at all the initiatives underway in order to scientifically fulfill the question they have being on the benefits risk, being on ARIA, being on disparity.

謝謝你，邁克。我會開始，然後我的同事會進來。首先，我們非常謹慎地考慮到 CMS 所傳達的所有重點領域。基於這些，我們審視了所有正在進行的舉措，以科學地解決他們在收益風險、ARIA 和差異方面的問題。

And we have a lot going on, from international studies, EMBARK and ENVISION on top of the Phase III. And now the time together with CMS to engage into a broad, real-world evidence set of initiatives already underway, like ICARE AD. But we are contemplating even more. That could be disease registry and more. So we are engaging with CMS constructively, demonstrating empathy to try to find the path forward that will be the best for patients. Alisha?

我們還有很多事情要做，從國際研究、EMBARK 和 ENVISION 到第三階段。現在是時候與 CMS 一起參與已經在進行的廣泛的、真實的證據集，例如 ICARE AD。但我們正在考慮更多。這可能是疾病登記等。因此，我們正在建設性地與 CMS 合作，表現出同理心，試圖找到對患者最有利的前進道路。艾麗莎？

Yes. Thank you, Michel, and hello, Michael. Thank you for the question. In regards to what we've been doing as an organization, during the past 3 weeks, we have met with CMS to share our perspective and answer any of the questions that they have. And you will see that we'll be submitting our in-depth comments in the coming days, obviously, during this comment period.

是的。謝謝你，米歇爾，你好，邁克爾。感謝你的提問。關於我們作為一個組織所做的事情，在過去的 3 周中，我們與 CMS 會面，分享我們的觀點並回答他們提出的任何問題。您會看到我們將在接下來的幾天內提交我們的深入評論，很明顯，在這個評論期內。

In parallel, we've also been educating physicians and policymakers and advocates about what this would actually mean for patients. I think a lot of people, as you've seen, have been quite confused by the draft NCD and what a CED actually means to them. And as you've likely seen, many stakeholders have had similar concerns. So we've seen patients, patient advocates, HCPs, other manufacturers and industry groups like bio and pharma, also sharing their perspectives quite publicly. And there is 1 week remaining for the open comment period, and we are very much looking forward to this final decision in April, so the community has more clarity.

與此同時，我們也一直在教育醫生、政策制定者和倡導者這對患者的實際意義。正如你所見，我認為很多人都對 NCD 草案以及 CED 對他們的實際意義感到困惑。正如您可能已經看到的那樣，許多利益相關者也有類似的擔憂。因此，我們已經看到患者、患者倡導者、HCP、其他製造商和行業團體（如生物和製藥）也公開分享他們的觀點。公開評論期還剩 1 週，我們非常期待 4 月份的最終決定，讓社區更加清晰。

And that brings me now to the comment period, where you may have seen over -- and I think as of today, it's around 2,600, 2,700 public comments submitted to CMS and again, with still 1 week remaining. I think it's important for everyone to remember and to keep in mind that CMS indicates on their website that the most helpful comments are ones that cite published clinical evidence. And when you actually separate the comments out from the dementia specialist, you will see that many of them are against this draft NCD.

現在讓我進入評論期，您可能已經看過了——我認為截至今天，大約有 2,600 條、2,700 條公眾評論提交給 CMS，而且還剩 1 週。我認為每個人都必須記住並牢記 CMS 在他們的網站上指出，最有幫助的評論是引用已發表的臨床證據的評論。當您真正將評論與癡呆症專家分開時，您會發現其中許多人反對該非傳染性疾病草案。

With prior comment periods, we have seen that in the final days. You tend to see more letters that are heavily researched and referenced. And as I've said before, you will see ours being posted in the coming days. So we do remain engaged actively with all stakeholders. We do remain engaged, obviously, still with CMS, and we are looking forward to the final decision in April.

在之前的評論期中，我們已經在最後幾天看到了這一點。您往往會看到更多經過大量研究和參考的信件。正如我之前所說，您將在未來幾天看到我們發布的內容。因此，我們仍然與所有利益相關者積極互動。顯然，我們仍然與 CMS 保持聯繫，我們期待著 4 月份的最終決定。

And so Mike, in your question on the cost measures, as we said in our prepared remarks, our guidance does assume that the final NCD would allow for meaningful patient access over time. That does not translate into material revenue in 2022, but it would create more open access than what we saw in the draft.

所以邁克，在你關於成本措施的問題中，正如我們在準備好的評論中所說，我們的指導確實假設最終的非傳染性疾病將允許隨著時間的推移有意義的患者訪問。這不會轉化為 2022 年的物質收入，但它會創造比我們在草案中看到的更多的開放獲取。

Should that not be the case, we are doing scenario planning now. On the cost measures, we mentioned our plan of a $500 million cost measure, of which we estimate we will get $350 million in 2022, which is assumed in our guidance. And we will invest about $200 million of that in a variety of different initiatives, including product launches. And in the event that we have a much more restrictive NCD, we will need to look at the elements of that.

如果不是這樣，我們現在正在做情景規劃。在成本衡量方面，我們提到了我們的 5 億美元成本衡量計劃，我們估計到 2022 年我們將獲得 3.5 億美元，這是我們的指導假設的。我們將把其中約 2 億美元投資於各種不同的計劃，包括產品發布。如果我們有一個限制性更強的非傳染性疾病，我們將需要研究其中的要素。

We certainly will be flexible in looking at allocating resources between ADUHELM and lecanemab. We mentioned in our SG&A, it's assumed that we have a $400 million ADUHELM support estimate, and we obviously would take a hard look at that as well other costs we could take out in order to offset any potential impacts on inventory, potential write-downs and excess capacity charges, which are not reflected in our guidance.

我們當然會靈活地考慮在 ADUHELM 和 lecanemab 之間分配資源。我們在 SG&A 中提到，假設我們有 4 億美元的 ADUHELM 支持估計，我們顯然會認真考慮我們可以採取的其他成本，以抵消對庫存的任何潛在影響，潛在的減記和過剩產能費用，這些費用並未反映在我們的指導中。

And Mike, as a closing comment, if I may. As a company, we are fully committed to deliver on this data being -- the international study being the real world ones. And we believe that this extensive data generation will adequately address any open question raised by CMS.

邁克，作為最後的評論，如果可以的話。作為一家公司，我們完全致力於提供這些數據——國際研究是真實世界的數據。我們相信，這種廣泛的數據生成將充分解決 CMS 提出的任何懸而未決的問題。

And we'll go ahead and take our next question from Matthew Harrison with Morgan Stanley.

我們將繼續向摩根士丹利的 Matthew Harrison 提出我們的下一個問題。

I was hoping you could just clarify on the TECFIDERA EU contribution to guidance and what we're going to learn this year, which may either help us understand if that revenue is at risk this year. Or if you could continue to expect to see it, and that could be potential upside to your current guidance?

我希望您能澄清一下 TECFIDERA 歐盟對指導的貢獻以及我們今年將要學習的內容，這可能有助於我們了解今年的收入是否面臨風險。或者，如果您可以繼續期待看到它，這可能是您當前指導的潛在優勢？

Sure, Matthew. Thanks for the question. And there is a -- we believe there is the potential for generic entry at some point in the first half of 2022. We do believe that we're entitled to market protection, and we're certainly going to do all we can to assert that. But we did reflect in our guidance, as we mentioned in our opening remarks and in our press release, that we do assume that there could be some generic entry somewhere in the first half of 2022.

當然，馬修。謝謝你的問題。還有一個——我們相信在 2022 年上半年的某個時候有可能進入仿製藥。我們確實相信我們有權獲得市場保護，我們當然會盡我們所能來斷言那。但正如我們在開場白和新聞稿中提到的那樣，我們確實在我們的指導中反映了這一點，我們確實假設在 2022 年上半年的某個地方可能會有一些通用條目。

So this is assumption driven at the same time for TEC, at the same time as already communicated, we are launching VUMERITY in 20 markets within the EU.

因此，這是 TEC 的假設，同時正如已經傳達的那樣，我們正在歐盟的 20 個市場推出 VUMERITY。

And we'll go ahead and take our next question from Umer Raffat with Evercore.

我們將繼續回答 Umer Raffat 和 Evercore 的下一個問題。

I wanted to focus on BAN2401 for a second and really just 2 questions there. One, can you help us understand the magnitude of missed doses in the Phase III? Because I recall you increased the sample size by 200 patients. And I wonder if that percentage increase versus the original sample size reflects the amount of missed doses. And secondly, the primary analysis, is that ITT? Or will that screen out the rapid progressors or certain subsets of patients based on some of the learnings from ADUHELM?

我想專注於 BAN2401 一秒鐘，實際上只有 2 個問題。一，您能幫助我們了解第三階段漏服劑量的大小嗎？因為我記得你將樣本量增加了 200 名患者。我想知道與原始樣本量相比，該百分比增加是否反映了錯過劑量的數量。其次，主要分析是 ITT 嗎？還是會根據 ADUHELM 的一些經驗篩選出快速進展者或某些患者子集？

Priya?

普里亞？

Thank you for the question. So just stepping back, I just want to reiterate that Clarity AD will read out in Q3 this year, and we remain very excited about that outcome.

感謝你的提問。所以退一步說，我只想重申，Clarity AD 將在今年第三季度宣讀，我們仍然對這一結果感到非常興奮。

I cannot really comment on the details of the statistical analysis plan. But what I can tell you is that any learnings that can be incorporated have been incorporated, and that the primary end point remains the CDR-Sum of Boxes. So we look forward to the readout. Thank you.

我無法真正評論統計分析計劃的細節。但我可以告訴你的是，任何可以合併的知識都已被合併，主要終點仍然是 CDR-Sum of Boxes。所以我們期待著讀數。謝謝你。

And we'll go ahead and take our next question from Marc Goodman with SVB Leerink.

我們將繼續接受 SVB Leerink 的 Marc Goodman 的下一個問題。

So look, there's 2 key events, right? We have the CMS decision that we're waiting on; and then obviously, we have the lecanemab data in the third quarter. So just kind of wondering your thought process of -- if the first one goes disappointing, do you make the changes? Or are you waiting for the lecanemab data?

所以看，有兩個關鍵事件，對吧？我們正在等待 CMS 的決定；然後很明顯，我們有第三季度的 lecanemab 數據。所以只是想知道你的思考過程——如果第一個令人失望，你會做出改變嗎？還是您在等待 lecanemab 數據？

Because we're kind of wondering whether you're going to break down the Alzheimer's infrastructure before you get that data. And how much business development is being impacted by those 2 decisions? I mean are you looking at these BD opportunities right now regardless of what happens with those events?

因為我們有點想知道你是否會在獲得這些數據之前破壞阿爾茨海默氏症的基礎設施。這兩個決策對業務發展的影響有多大？我的意思是，無論這些事件會發生什麼，您現在是否正在關注這些 BD 機會？

Thanks for the very fair question. As I communicated, we will remain as a team, agile and flexible. And obviously, we will do everything we can to preserve our operating results while delivering on the strategy. We do believe in leca, but we will take some aggressive steps should the NCD remain on the current form.

感謝您提出非常公平的問題。正如我所傳達的，我們將作為一個團隊保持敏捷和靈活。顯然，我們將盡一切努力在實施戰略的同時保持我們的經營成果。我們確實相信 leca，但如果 NCD 保持目前的形式，我們將採取一些積極的措施。

And I think, Marc, I would just add that the -- how much of our infrastructure we would allocate to lecanemab versus not, et cetera, that really depends on what the final NCD says. It's across the entire class, and that would really depend on the specifics of how the final NCD reads. I would say on BD, we will continue our BD efforts regardless. Those are ongoing, and they're always ongoing.

我想，Marc，我只想補充一點——我們將分配多少基礎設施給 lecanemab，等等，這真的取決於最終 NCD 的內容。它貫穿整個班級，這實際上取決於最終 NCD 讀取方式的具體情況。我會在 BD 上說，無論如何，我們都會繼續我們的 BD 努力。這些都在進行中，而且一直在進行。

And we'll go ahead and take our next question from Salveen Richter with Goldman Sachs.

我們將繼續向高盛的 Salveen Richter 提出我們的下一個問題。

In light of the recent opt-in for the Roche compound, does this signal a greater structural move into oncology? And are there any other areas you're looking at as you pursue BD?

鑑於最近選擇加入羅氏化合物，這是否預示著腫瘤學的更大結構性轉變？在追求 BD 時，您還關注其他領域嗎？

No. I mean it's a continuation of the very good partnership that we have with Genentech since rituximab, and we have benefited from a remarkable cash flow contribution that we all appreciate and even now, even if there are biosimilars. So it's a continuation. It's not a shift of strategy.

不。我的意思是，這是自利妥昔單抗以來我們與基因泰克建立的良好合作夥伴關係的延續，我們受益於顯著的現金流貢獻，我們都讚賞甚至現在，即使有生物仿製藥。所以這是一個延續。這不是戰略的轉變。

I communicated the 4 pillars of growth, and we remain focused on those. And we believe that we are set for long-term shareholder value generation by sticking -- by staying the course and delivering on those.

我傳達了增長的四大支柱，我們仍然專注於這些。我們相信，我們將通過堅持——堅持到底並兌現這些目標，為長期的股東價值創造做好準備。

And we'll go ahead and take our next question from Cory Kasimov with JPMorgan.

我們將繼續回答 Cory Kasimov 與摩根大通的下一個問題。

I wanted to follow up on the Phase III lecanemab study. And can you comment on the enrolled patient population in terms of adequate representation for underrepresented communities that may address the CMS concerns you spoke to? And just with regards to Mike's comment you just made on NCD and waiting for this data, wouldn't it be your expectation that a final NCD could be changed if we have robust positive Phase III results from other Alzheimer's programs later on in the year?

我想跟進 III 期 lecanemab 研究。您能否就可能解決您所談及的 CMS 問題的代表性不足社區的充分代表性來評論已登記的患者群體？就邁克關於您剛剛對非傳染性疾病發表的評論並等待這些數據而言，如果我們在今年晚些時候從其他阿爾茨海默氏症項目中獲得穩健的第三階段陽性結果，您是否會期望最終的非傳染性疾病可以改變？

Priya?

普里亞？

Yes. Thank you for the question. I think that Eisai will comment on the underrepresented population percentage, but it is actually very robust. And we are very encouraged by the efforts made to include this population in the Clarity AD.

是的。感謝你的提問。我認為衛材會評論代表性不足的人口百分比，但它實際上非常強大。我們為將這些人群納入 Clarity AD 所做的努力感到非常鼓舞。

With regards to the outcome of the NCD and how it might impact lecanemab, I think that, that remains to be seen currently. It is a class -- the NCD is addressing the entire class. But we believe that there is hope at the end of the road here. So we look forward to seeing the final outcome in April. Thank you.

關於 NCD 的結果以及它如何影響 lecanemab，我認為目前還有待觀察。這是一個班級——NCD 正在解決整個班級。但我們相信，在這條路的盡頭，還有希望。因此，我們期待在 4 月看到最終結果。謝謝你。

So I think that we all have to do a better job including diverse population unfortunately affected with the high level of incidence for the disease in interventional studies and real-world studies. And this is what we are doing. And I think, I hope, that this will be well received by CMS.

因此，我認為我們都必須做得更好，包括不幸地在干預研究和現實世界研究中受到疾病高發病率影響的不同人群。這就是我們正在做的事情。我認為，我希望這會受到 CMS 的好評。

And we did communicate that for the ENVISION study, we aim to reach from 16% to 18% of diverse population, the same in real world with ICARE AD. So moving forward, we'll gather much more data, and the same for the other real-world evidence opportunities that we are sharing with CMS.

我們確實傳達了對於 ENVISION 研究的信息，我們的目標是覆蓋 16% 到 18% 的不同人群，這與 ICARE AD 在現實世界中的情況相同。因此，展望未來，我們將收集更多數據，對於我們與 CMS 共享的其他真實世界證據機會也是如此。

And we'll go ahead and take our next question from Jay Olson with Oppenheimer.

我們將繼續回答傑伊奧爾森和奧本海默的下一個問題。

Since self-administered subcu formulation of ADUHELM could fall under the purview of Medicare Part D and, therefore, lie outside the scope of a potential CED if it's finalized, could you comment on where Biogen stands with regard to the development of subcu ADUHELM? I think you did a bioequivalent study a few years ago. So is subcu something that could be a relatively near-term option?

由於 ADUHELM 的自我管理 subcu 製劑可能屬於 Medicare D 部分的範圍，因此，如果最終確定，則不在潛在 CED 的範圍內，您能否評論 Biogen 在 subcu ADUHELM 開發方面的立場？我想你幾年前做過生物等效性研究。那麼 subcu 可能是一個相對近期的選擇嗎？

So we will comment certainly on the life cycle management opportunity. Priya will say a few words. But I just want to outline and come back to the first area of concern communicated in the draft NCD, which is basically benefit risk and questioning the hypothesis and the class in terms of mode of action and positive impact on the patients. And this, obviously, is independent from any formulation. Priya?

因此，我們肯定會評論生命週期管理機會。普里亞會說幾句話。但我只想概述並回到 NCD 草案中傳達的第一個關注領域，這基本上是利益風險以及在作用方式和對患者的積極影響方面質疑假設和類別。顯然，這與任何表述無關。普里亞？

Thank you for the question, and thanks, Michel, for those comments. We will definitely be building on our prior learnings in ADUHELM subcutaneous formulation development, and we are currently engaging with regulators on having a robust plan forward for this development. So that is ongoing. Thank you.

謝謝你的問題，也謝謝米歇爾的這些評論。我們肯定會以我們之前在 ADUHELM 皮下製劑開發方面的經驗為基礎，我們目前正在與監管機構合作，為這一開發製定一個強有力的計劃。所以這是正在進行的。謝謝你。

And we will take our next question from Geoff Meacham with Bank of America.

我們將向美國銀行的 Geoff Meacham 提出我們的下一個問題。

This is Jason on for Geoff. I wanted to connect the dots a little bit on your earlier comments about capital allocation. Specifically, what are the priorities here? And what is going to be the deciding factor? Is it candidly going to be the final NCD decision in terms of how things are meted out? Or are activities ongoing?

這是傑森的傑夫。我想把你之前關於資本配置的評論聯繫起來。具體來說，這裡的優先事項是什麼？什麼是決定因素？就如何處理事情而言，它是否會成為最終的非傳染性疾病決定？還是正在進行活動？

Yes, Jason, thanks for the question. Mike speaking. And just reiterating a bit of what we said before, we are constantly looking at options around BD deals of all sizes, different opportunities, early stage, late stage across -- it runs the gamut, primarily focused on neuroscience, which is our focus. And we will continue to do that, and we will continue to invest in our pipeline. And that is regardless of the outcome on the NCD, and it's regardless of the fact that we have now incremental cash if we get the -- once the Samsung transaction closes.

是的，傑森，謝謝你的提問。邁克說話。只是重申我們之前所說的一點，我們一直在尋找各種規模的 BD 交易的選擇，不同的機會，早期階段，後期階段——它涵蓋了整個範圍，主要集中在神經科學，這是我們的重點。我們將繼續這樣做，我們將繼續投資於我們的管道。這與 NCD 的結果無關，也與我們現在擁有增量現金的事實無關，如果我們得到 - 一旦三星交易完成。

So I think we have a healthy balance sheet. That's unchanged, $4.7 billion of cash and marketable securities at the end of the year, a modest amount of net debt, less than 1 turn. And we have a $1 billion revolver that's undrawn. So we will continue to actively pursue BD. That strategy is unchanged, and I don't see a significant shift in strategy in terms of NCD outcome or Samsung transaction or anything else. We will continue to explore all of our options around BD actively, and we are doing that.

所以我認為我們有一個健康的資產負債表。這沒有改變，到年底有 47 億美元的現金和有價證券，少量的淨債務，不到 1 轉。我們還有一把價值 10 億美元的左輪手槍尚未動用。所以我們會繼續積極追求BD。該策略沒有改變，我認為在非傳染性疾病結果或三星交易或其他任何方面的策略都不會發生重大轉變。我們將繼續積極探索我們圍繞 BD 的所有選擇，我們正在這樣做。

And we will take our next question from Brian Abrahams with RBC Capital Markets.

我們將向RBC Capital Markets 的Brian Abrahams 提出下一個問題。

On lecanemab, just a couple of quick follow-ups on that. Just can you give us a sense of any COVID impact to data collection in that study. Are your plans for accelerated -- filing for accelerated approval still intact in light of the NCD? And any modifications that you might need to make to infrastructure upon success to accommodate for the more frequent dosing versus ADUHELM.

在 lecanemab 上，只是幾個快速跟進。您能否讓我們了解一下 COVID 對該研究中數據收集的任何影響。鑑於非傳染性疾病，您的加速審批計劃是否仍然完整？以及成功後您可能需要對基礎設施進行的任何修改，以適應與 ADUHELM 相比更頻繁的給藥。

Priya?

普里亞？

Thank you for the question. So I can say that lecanemab is on track to read out. As previously communicated, this will be in Q3 of 2022. So at this point, we don't expect any changes to that along with Eisai. So that's number one.

感謝你的提問。所以我可以說 lecanemab 有望被讀出。如前所述，這將在 2022 年第三季度進行。因此，在這一點上，我們預計不會與衛材一起發生任何變化。所以這是第一名。

And second, I think that there are no real other changes to communicate on the outcomes or on the measures that have been included in the study. So is there another question that I'm missing here?

其次，我認為沒有真正的其他變化可以就結果或研究中包含的措施進行交流。那麼我在這裡還缺少另一個問題嗎？

Patient follow-ups due to the pandemic. I know it's a global study with a lot of sites.

因疫情對患者進行隨訪。我知道這是一項涉及很多網站的全球研究。

Yes. And I think that it's been managed really well, so I don't expect any delays in terms of the readouts. And I think your second question was about accelerated approval. As you know, they have Breakthrough -- we have Breakthrough Designation on this product. And there will be a filing. We are intent on filing. The filing -- many components have already been filed. And once the filing is complete, that will be communicated.

是的。而且我認為它的管理非常好，所以我預計讀數不會有任何延遲。我認為你的第二個問題是關於加速批准。如您所知，他們有突破——我們在這個產品上有突破指定。並且會有備案。我們打算歸檔。備案——許多組件已經備案。備案完成後，將進行溝通。

I think that the most important thing to remember here is that while it might go in as an accelerated filing, the confirmatory study for lecanemab is the Clarity AD, which will read out this year. So I do expect the Clarity AD confirmatory study to read out during the review period for this program. I hope that clarifies.

我認為這裡要記住的最重要的事情是，雖然它可能會作為加速申請提交，但對 lecanemab 的確認性研究是 Clarity AD，它將在今年宣讀。因此，我確實希望 Clarity AD 確認性研究能夠在該計劃的審查期間宣讀。我希望澄清。

I just want to outline once more that we are working very closely with Eisai at finding synergies in terms of capabilities of both organizations and how we can optimize the value for both compounds.

我只想再次概述一下，我們正在與衛材密切合作，尋找雙方組織能力方面的協同效應，以及我們如何優化這兩種化合物的價值。

I think we have time for one more question.

我想我們還有時間再問一個問題。

And we will take our last question from Salim Syed from Mizuho.

我們將向瑞穗的 Salim Syed 提出最後一個問題。

Great. Michel, I wanted to address a bit of an elephant in the room. And I asked this question constructively, and I hope you can appreciate that. So obviously, people talk about misalignment between management and the Board at Biogen. And business development is obviously a key focus for you guys, and I appreciate all the commentary that you guys are looking at deals of all sizes, early stage, late stage. But in your view, is there a misalignment here that would make meaningful BD something difficult in 2022? Or has something changed that we can now expect that to occur?

偉大的。米歇爾，我想對房間裡的一頭大象講話。我建設性地問了這個問題，我希望你能理解。很明顯，人們談論百健（Biogen）管理層和董事會之間的不一致。業務發展顯然是你們的重點，我很欣賞你們正在研究各種規模的交易的所有評論，早期階段，後期階段。但在您看來，這裡是否存在偏差，會使 2022 年有意義的 BD 變得困難？還是發生了一些我們現在可以預期會發生的變化？

Thank you, Salim, for giving me the opportunity to answer this question. I will invite you to look at all the BD deals that were performed during the past 5 years versus the previous 5 years. And I think this will give you an idea about the alignment.

謝謝你，薩利姆，讓我有機會回答這個問題。我將邀請您查看過去 5 年與過去 5 年執行的所有 BD 交易。我認為這會給你一個關於對齊的想法。

But it doesn't mean that it's an easy road. It means that we have challenge as management. We really need to have open discussion between the Board and management to secure that we are in the best position to allocate capital. But we were able and we continue to be able to work together in order to move forward the organization in the best strategic position, the way we believe we are today compared with the period before.

但這並不意味著這是一條容易的道路。這意味著我們作為管理層面臨挑戰。我們確實需要在董事會和管理層之間進行公開討論，以確保我們處於分配資本的最佳位置。但我們能夠並且我們繼續能夠共同努力，以使組織處於最佳戰略地位，我們相信我們今天與以前相比的方式。

Look at the 4 pillars of growth. Look what we are doing with biosimilars. We are enriching the cash flow generation opportunity. And even if we are in the unfortunate situation of losing the rituximab and TECFIDERA and a delay launch by almost a year eventually if NCD is positive for ADUHELM, we are still in a multibillion cash flow generation opportunity. We work together very closely.

看看增長的 4 個支柱。看看我們在用生物仿製藥做什麼。我們正在豐富產生現金流的機會。即使我們處於失去利妥昔單抗和 TECFIDERA 的不幸情況，並且如果 NCD 對 ADUHELM 有利，最終將推遲近一年推出，我們仍然處於產生數十億現金流的機會。我們非常密切地合作。

So thank you all for this good engagement. And I would like really to reiterate that we are committed to engaging with CMS and all the other stakeholders with the hope of finding an appropriate path for immediate patient access to ADUHELM. Thank you all for your attention today.

因此，感謝大家的良好參與。我真的想重申，我們致力於與 CMS 和所有其他利益相關者合作，希望找到一條合適的途徑，讓患者立即獲得 ADUHELM。感謝大家今天的關注。

And this concludes today's call. Thank you all for your participation. You may now disconnect.

今天的電話會議到此結束。謝謝大家的參與。您現在可以斷開連接。