雷傑納榮製藥 (REGN) 2023 Q4 法說會逐字稿

Welcome to the Regeneron Pharmaceuticals' Fourth Quarter 2023 Earnings Conference Call. My name is Shannon, and I will be your operator for today's call.

歡迎參加再生元製藥 2023 年第四季財報電話會議。我叫香農，我是今天電話的接線生。

(Operator Instructions) Please note that this conference is being recorded.

（操作員說明）請注意，本次會議正在錄製中。

I will now turn the call over to Ryan Crowe, Senior Vice President, Investor Relations. You may begin.

我現在將把電話轉給投資者關係高級副總裁 Ryan Crowe。你可以開始了。

Thank you, Shannon. Good morning, good afternoon and good evening to everyone listening around the world. Thank you for your interest in Regeneron and welcome to our fourth quarter 2023 earnings conference call. An archive and transcript of this call will be available on the Regeneron Investor Relations website shortly after the call ends.

謝謝你，香農。世界各地的聽眾早安、下午好、晚上好。感謝您對再生元的關注，歡迎參加我們的 2023 年第四季財報電話會議。通話結束後不久，再生元投資者關係網站將提供本次通話的檔案和文字記錄。

Joining me today are Dr. Leonard Schleifer, Board Co-Chair, Co-Founder, President and Chief Executive Officer; Dr. George Yancopoulos, Board Co-Chair, Co-Founder, President and Chief Scientific Officer; Marion McCourt, Executive Vice President and Head of Commercial; Bob Landry, Executive Vice President and Chief Financial Officer; and Chris Fenimore, Senior Vice President and Controller.

今天與我一起出席的還有董事會聯合主席、共同創辦人、總裁兼執行長 Leonard Schleifer 博士； George Yancopoulos 博士，董事會聯合主席、共同創辦人、總裁兼首席科學官； Marion McCourt，執行副總裁兼商務主管；鮑伯·蘭德里，執行副總裁兼財務長；以及資深副總裁兼財務長 Chris Fenimore。

As many of you already know, Bob will retire from Regeneron after our Form 10-K is filed next week, and Chris has been appointed to become Regeneron's next CFO upon Bob's retirement. After our prepared remarks, the remaining time will be available for your questions. We anticipate today's call will last approximately 60 minutes.

正如你們許多人已經知道的那樣，Bob 將於下週提交 10-K 表格後從 Regeneron 退休，而 Chris 已被任命為 Bob 退休後的 Regeneron 下一任首席財務官。在我們準備好發言後，剩下的時間將用於回答您的問題。我們預計今天的通話將持續約 60 分鐘。

I'd like to remind you that remarks made on today's call may include forward-looking statements about Regeneron. Such statements may include but are not limited to, those related to Regeneron and its products and business, financial forecast and guidance, development programs and related anticipated milestones, collaborations, finances, regulatory matters, payer coverage and reimbursement issues, intellectual property, pending litigation and other proceedings, and competition.

我想提醒您，今天電話會議的言論可能包括有關再生元的前瞻性陳述。此類聲明可能包括但不限於與再生元及其產品和業務、財務預測和指導、開發計劃和相關預期里程碑、合作、財務、監管事項、付款人覆蓋範圍和報銷問題、智慧財產權、未決訴訟相關的聲明以及其他程序和競爭。

Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in that statement. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission, including its Form 10-K for the year ended December 31, 2023, which we expect to file with the SEC on Monday, February 5. Regeneron does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

每項前瞻性陳述都存在風險和不確定性，可能導致實際結果和事件與該陳述中的預測有重大差異。有關這些風險和其他重大風險的更完整描述可以在Regeneron 向美國證券交易委員會提交的文件中找到，其中包括截至2023 年12 月31 日的年度10-K 表格，我們預計將於週一向SEC 提交該表格，2 月 5 日。再生元不承擔任何更新任何前瞻性陳述的義務，無論是由於新資訊、未來事件或其他原因。

In addition, please note that GAAP and non-GAAP financial measures will be discussed on today's call. Information regarding our use of non-GAAP financial measures and a reconciliation of those measures to GAAP is available in our quarterly earnings results, press release and our corporate presentation, both of which can be accessed on the Regeneron Investor Relations website. Once our call ends, Bob, Chris and the IR team will be available to answer any further questions.

此外，請注意，今天的電話會議將討論公認會計原則和非公認會計原則財務指標。有關我們使用非公認會計準則財務指標以及這些指標與公認會計準則的調節的信息，請參閱我們的季度收益結果、新聞稿和公司演示文稿，這兩者都可以在再生元投資者關係網站上訪問。在我們的通話結束後，Bob、Chris 和 IR 團隊將可以回答任何進一步的問題。

With that, let me turn the call over to our President and Chief Executive Officer, Dr. Len Schleifer. Len?

接下來，讓我將電話轉給我們的總裁兼執行長 Len Schleifer 博士。萊恩？

Thank you, Ryan, and thank you to everyone joining today's call. Fourth quarter 2023 capped another strong year for Regeneron and Bob will walk you through our financial results. For my remarks today, I'd like to briefly look back at 2023 and then discuss what's to come in the year ahead.

謝謝瑞安，也謝謝參加今天電話會議的所有人。 2023 年第四季是 Regeneron 另一個強勁的一年，鮑伯將帶您了解我們的財務表現。在今天的演講中，我想簡單回顧一下 2023 年，然後討論未來一年的發展。

2023 was another remarkable year for Regeneron, highlighted by several significant achievements that better position the company to deliver sustainable growth and long-term shareholder value. At the start of the year, we identified 5 key strategic imperatives. First, obtaining FDA approval and successfully launching EYLEA HD. We did encounter a minor delay when we received the complete response letter in late June due to an issue at a third-party filler but this was quickly remedied and EYLEA HD was granted approval in mid-August.

2023 年對於再生元來說又是非凡的一年，取得了多項重大成就，使公司能夠更好地實現永續成長和長期股東價值。今年年初，我們確定了 5 項關鍵策略要務。首先，獲得FDA批准並成功推出EYLEA HD。由於第三方灌裝機的問題，當我們在 6 月底收到完整的回覆信時，我們確實遇到了輕微的延遲，但很快就得到了補救，EYLEA HD 於 8 月中旬獲得了批准。

With what we believe to be a best-in-class potential clinical profile, EYLEA HD is poised to become the new standard of care for patients with wet age-related macular degeneration and diabetic eye diseases. The launch is off to a great start, which Marion will discuss in a few minutes.

憑藉我們認為一流的潛在臨床特徵，EYLEA HD 預計將成為濕性老年黃斑部病變和糖尿病眼病患者的新護理標準。這次發布有了一個良好的開端，馬里昂將在幾分鐘內討論這一點。

Second, we had to defend our intellectual property related to EYLEA. We presented our best case and prevailed in the District Court, which found that one of EYLEA's formulation patents was both valid and infringed by a biosimilar aflibercept manufacturer. This favorable decision may have broad implications and could result in a delay to biosimilar aflibercept launches.

其次，我們必須捍衛我們與 EYLEA 相關的智慧財產權。我們提出了最好的案例，並在地方法院勝訴，該法院發現 EYLEA 的一項配方專利既有效，又被生物仿製藥阿柏西普製造商侵犯。這項有利的決定可能會產生廣泛的影響，並可能導致生物相似藥阿柏西普的上市延遲。

Third, we and our collaborator, Sanofi, needed to continue driving Dupixent growth not only by further penetrating previously approved indications by also reaching even more patients suffering from other diseases driven by Type 2 inflammation. In 2023, we did both. Dupixent global net product sales grew by 34% on a constant currency basis to $11.6 billion. Dupixent led in new-to-brand prescription share in the United States across all 5 of its approved indications.

第三，我們和我們的合作者賽諾菲需要繼續推動 Dupixent 的成長，不僅要進一步滲透先前批准的適應症，還要涵蓋更多患有由 2 型發炎引起的其他疾病的患者。 2023 年，我們兩者都做到了。 Dupixent 全球產品淨銷售額以固定匯率計算成長 34%，達到 116 億美元。 Dupixent 在美國所有 5 個已批准適應症的新品牌處方藥市場份額中處於領先地位。

We also had a major breakthrough in chronic obstructive pulmonary disease or COPD. In March, we reported strong data from the BOREAS study, which enrolled COPD patients with uncontrolled moderate-to-severe disease and evidence of type 2 inflammation. The FDA granted breakthrough therapy designation during the summer but required additional evidence of efficacy to support a regulatory filing. Based on this feedback, we and Sanofi decided to conduct an interim analysis on the replicate NOTUS study, which read out similarly compelling results, enabling our December sBLA submission and a potential U.S. launch for this indication as early as mid-2024.

我們在慢性阻塞性肺病（COPD）方面也取得了重大突破。今年 3 月，我們報告了 BOREAS 研究的強勁數據，該研究納入了患有未控制的中度至重度疾病且有 2 型發炎證據的 COPD 患者。 FDA 在夏季授予了突破性療法認定，但需要額外的療效證據來支持監管備案。根據這項回饋，我們和賽諾菲決定對重複的NOTUS 研究進行中期分析，該研究得出了類似的令人信服的結果，使我們能夠在12 月提交sBLA，並可能最早於2024 年中期在美國推出該適應症。

Fourth, we continued making progress toward our long-term goal of becoming a global leader in oncology. 2023 was highlighted by our regulatory submissions for linvoseltamab, our BCMA by CD3 bispecific in myeloma, and odronextamab, our CD20xCD3 bispecific in lymphoma, while continuing to advance other opportunities in solid tumors.

第四，我們在成為全球腫瘤學領導者的長期目標上不斷取得進展。 2023 年，我們向 linvoseltamab（針對骨髓瘤的 CD3 雙特異性 BCMA）和 odronextamab（針對淋巴瘤的 CD20xCD3 雙特異性）提交了監管申請，同時繼續推進實體瘤領域的其他機會。

And finally, we needed to advance our early-stage pipeline. And over the course of 2023, we presented intriguing proof of mechanism or proof-of-concept data across hematology and genetic medicines as well as other areas, including obesity with data from non-human primates. Many of these early programs, which George will run through in a few minutes, represent first or best-in-class opportunities that we believe can drive long-term growth for Regeneron.

最後，我們需要推進我們的早期管道。在 2023 年期間，我們透過非人靈長類動物的數據，在血液學和遺傳醫學以及其他領域（包括肥胖症）提供了有趣的機制證明或概念驗證數據。喬治將在幾分鐘內完成其中許多早期項目，這些項目代表了我們相信可以推動再生元長期成長的一流機會。

Accomplishments in 2023 have put us in a position of strength entering 2024. For this year, one of our strategic imperatives is to continue driving commercial execution, especially the ongoing launch of EYLEA HD, with the goal of accelerating the pace of conversion from other anti-VEGF agents.

2023 年的成就使我們在進入 2024 年時處於有利地位。今年，我們的戰略要務之一是繼續推動商業執行，特別是 EYLEA HD 的持續推出，目標是加快從其他反病毒藥物轉化的步伐。 - VEGF劑。

Another important launch milestone was achieved last month when the Center for Medicare & Medicaid Services assigned a permanent J-Code for EYLEA HD that will go into effect on April 1, 2024, at which point a potential reimbursement concern for physicians will be removed. We also need to continue to drive Dupixent growth in its currently improved indications as well as from the potential FDA approval and launch in COPD with an eosinophilic phenotype. If approved, Dupixent would represent the first meaningful advance in over a decade for the 300,000 patients in the United States suffering from this form of COPD and would be the first ever biologic approved for COPD.

上個月實現了另一個重要的發布里程碑，醫療保險和醫療補助服務中心為 EYLEA HD 分配了永久 J 代碼，該代碼將於 2024 年 4 月 1 日生效，屆時醫生潛在的報銷問題將被消除。我們還需要繼續推動 Dupixent 在其目前改善的適應症方面的成長，以及 FDA 潛在的批准和上市，用於治療嗜酸性粒細胞表型的慢性阻塞性肺病。如果獲得批准，Dupixent 將代表著十多年來對於美國30 萬名患有這種慢性阻塞性肺病的患者來說第一個有意義的進步，並且將是第一個被批准用於治療慢性阻塞性肺病的生物製劑。

In oncology this year, aside from continuing to build on the success of Libtayo in non-melanoma skin cancers and non-small cell lung cancer, we are excited about the potential launches of odronextamab and linvoseltamab, the latter of which has the potential to be the best-in-class bispecific for myeloma.

今年在腫瘤學領域，除了繼續鞏固 Libtayo 在非黑色素瘤皮膚癌和非小細胞肺癌方面的成功之外，我們對 odronextamab 和 linvoseltamab 的潛在上市感到興奮，後者有潛力成為同類最佳的骨髓瘤雙特異性藥物。

We also expect to make significant advances across our pipeline in 2024, with key readouts for fianlimab, our LAG-3 antibody in combination with Libtayo in metastatic melanoma and non-small cell lung cancer. Libtayo in adjuvant cutaneous squamous cell carcinoma and our Factor XI antibodies in thrombosis, which may inform pivotal studies.

我們也預計到 2024 年我們的產品線將取得重大進展，我們的 LAG-3 抗體 fianlimab 與 Libtayo 聯合治療轉移性黑色素瘤和非小細胞肺癌的關鍵結果。 Libtayo 在輔助皮膚鱗狀細胞癌中的應用以及我們的 XI 因子抗體在血栓形成中的應用，這可能為關鍵研究提供資訊。

We also plan to initiate clinical trials in obesity, geographic atrophy, hemophilia B and severe food allergies, in addition to expanding early studies of our CD28 co-stimulatory bispecific programs in solid and hematologic malignancies.

除了擴大 CD28 共刺激雙特異性計畫在實體腫瘤和血液惡性腫瘤的早期研究外，我們還計劃啟動肥胖、地理萎縮、B 型血友病和嚴重食物過敏的臨床試驗。

In closing, we had a strong 2023 and are poised to deliver in 2024 and beyond. Our pipeline of over 30 clinical programs is delivering important and differentiated innovations. Our commercial team is executing well. And we continue to look at ways to efficiently deploy capital to drive shareholder returns over time.

最後，我們在 2023 年取得了強勁的業績，並準備在 2024 年及以後實現目標。我們的 30 多個臨床項目正在提供重要且差異化的創新。我們的商務團隊執行良好。我們將繼續尋找有效部署資本的方法，以隨著時間的推移推動股東回報。

Before I hand it over to George, I want to take a moment to thank Bob Landry for his many contributions to Regeneron over his 10 years as our Chief Financial Officer. In addition to helping fortify Regeneron's financial strength and discipline, Bob has been an incredible mentor to many of Regeneron's current and future leaders, helped drive our financial results over the past decade, and worked tirelessly to ensure we have the resources needed to help improve the lives of patients around the world. Bob, on behalf of the entire Regeneron family, thank you, and we wish you continued good health and happiness.

在將其交給喬治之前，我想花點時間感謝鮑勃·蘭德里 (Bob Landry) 在擔任我們的財務長的 10 年間為再生元做出的許多貢獻。除了幫助增強再生元的財務實力和紀律之外，鮑勃還是再生元當前和未來許多領導者的出色導師，在過去十年中幫助推動了我們的財務業績，並孜孜不倦地工作以確保我們擁有幫助改善再生元所需的資源。世界各地患者的生活。鮑勃，代表整個再生元家族，謝謝您，我們祝您身體健康，幸福快樂。

As we first announced back in September upon Bob's retirement next week, Chris Fenimore will become the CFO of Regeneron. We all look forward to working closely with Chris in his new role knowing he brings a similar rigor and depth of financial knowledge that will ensure continuity and collaboration across the organization.

正如我們在 9 月首次宣布的那樣，鮑勃下週退休，克里斯費尼莫爾 (Chris Fenimore) 將成為再生元 (Regeneron) 的首席財務官。我們都期待在克里斯的新職位上與他密切合作，因為我們知道他帶來了類似的嚴謹性和深度的財務知識，這將確保整個組織的連續性和協作。

With that, I'll now turn the call over to George.

現在，我將把電話轉給喬治。

Thanks, Len. That was really an impressive overview, I have to say.

謝謝，萊恩。我不得不說，這確實是一個令人印象深刻的概述。

2023 was another year of firsts delivered by Regeneron, as well as together with our collaborators, all of which have the potential to change the practice of medicine. Starting with inflammation and immunology. As you heard from Len, we are planning yet another launch for Dupixent, this time in eosinophilic COPD, which would represent the sixth disease that this remarkable medicine is approved to treat, and the fifth for which it would be first in class. Dupixent's transformative potential in COPD is based on the unprecedented results from our first Phase III trial, BOREAS, which were then confirmed by our second Phase III trial notice, demonstrating that Dupixent treated patients had a 34% reduction in the annualized rate of moderate, severe COPD exacerbations.

2023 年是再生元以及我們的合作者共同創造的又一個第一，所有這些都有可能改變醫學實踐。從發炎和免疫學開始。正如您從Len 那裡聽到的，我們正計劃再次推出Dupixent，這次是針對嗜酸性粒細胞性慢性阻塞性肺病，這將是這種卓越藥物被批准治療的第六種疾病，也是同類首創藥物治療的第五種疾病。 Dupixent 在COPD 領域的變革潛力是基於我們的第一個III 期試驗BOREAS 的前所未有的結果，隨後我們的第二個III 期試驗通知證實了這一結果，表明Dupixent 治療的患者的中度、重度年化發生率降低了34%慢性阻塞性肺病惡化。

(technical difficulty)

（技術難度）

IL-33 blocking antibody, the pivotal AERIFY-I and II studies passed an interim futility analysis last year. The studies are now on track to complete enrollment in 2024 with an anticipated readout in 2025. If the Phase III results from these studies even approach the Phase II data reported in former smokers, where a 42% reduction in annualized exacerbation rate was observed, itepekimab has the potential to further transform the treatment paradigm for COPD.

IL-33 阻斷抗體、關鍵的 AERIFY-I 和 II 研究去年通過了中期無效分析。這些研究目前預計在 2024 年完成入組，預計於 2025 年公佈結果。如果這些研究的 III 期結果甚至接近戒菸者報告的 II 期數據（觀察到年化惡化率降低 42%），itepekimab有潛力進一步改變慢性阻塞性肺病的治療模式。

Later this year, we are planning on testing an innovative new treatment approach for severe food allergies using a combination of transient BCMAxCD3 bispecific intervention in patients receiving Dupixent therapy. As many of you know, allergic responses are driven by pathologically high levels of the immunoglobulin E or IgE. This is why many say the E in IgE stands for evil. About 40 years ago, it was discovered that interleukin-4 and interleukin-13 were the switch factors required for switching to IgE production.

今年晚些時候，我們計劃在接受 Dupixent 治療的患者中使用短暫 BCMAxCD3 雙特異性幹預組合來測試一種針對嚴重食物過敏的創新治療方法。正如許多人所知，過敏反應是由病理性高水平的免疫球蛋白 E 或 IgE 引起的。這就是為什麼許多人說 IgE 中的 E 代表邪惡。大約 40 年前，人們發現白血球介素 4 和白血球介素 13 是轉換為 IgE 產生所需的轉換因子。

Based on exciting preclinical data, including in nonhuman primates, as well as human data, our innovative approach has the potential to reverse severe allergies by, first, eliminating the long-lived plasma cells that serve as an IgE reservoir with the BCMAxCD3, followed by blocking of de novo immunoglobin class switching to IgE with the Dupixent.

基於令人興奮的臨床前數據（包括非人靈長類動物數據）以及人類數據，我們的創新方法有可能逆轉嚴重過敏，首先，消除使用 BCMAxCD3 作為 IgE 儲存庫的長壽命漿細胞，然後使用Dupixent阻斷從頭免疫球蛋白類別轉換為IgE。

We are looking forward to starting a small proof-of-concept study, which will inform next steps for this program. We believe this approach has the potential to benefit the millions of people suffering from severe allergies who are at constant risk, as tragically highlighted just last week by the widely reported death of yet another young person unknowingly exposed to a food allergen.

我們期待著開始一項小型概念驗證研究，這將為該計劃的後續步驟提供資訊。我們相信，這種方法有可能使數以百萬計患有嚴重過敏且始終處於危險之中的人受益，正如上週廣泛報道的另一名年輕人在不知情的情況下接觸食物過敏原死亡的悲劇所強調的。

Moving to oncology. Libtayo is the leading PD-1 antibody for non-melanoma skin cancers, including metastatic cutaneous squamous cell carcinoma, or CSCC, and basal cell carcinoma. We are looking forward to potentially expanding the currently approved CSCC indication to include adjuvant CSCC. And we expect results from potentially pivotal interim analysis in this setting in the second half of the year.

轉向腫瘤學。 Libtayo 是領先的 PD-1 抗體，用於治療非黑色素瘤皮膚癌，包括轉移性皮膚鱗狀細胞癌 (CSCC) 和基底細胞癌。我們期待有可能擴大目前批准的 CSCC 適應症，以包括輔助 CSCC。我們預計下半年可能會在這種情況下得出關鍵的中期分析結果。

Regarding Libtayo combinations, our most advanced is the combination with our LAG-3 antibody, fanlimab. As a reminder, our early clinical data in 3 separate first-line metastatic melanoma cohorts demonstrated potential for best-in-class efficacy when compared cross trial with the approved anti-LAG-3 PD-1 combination product, highlighted by objective response rates greater than 60% and estimated median progression-free survival of longer than 15 months. These early clinical data suggested that the Libtayo fanlimab combination may be one of the most exciting examples of a checkpoint inhibitor combination with clinically meaningful benefit and with the safety profile that is similar to that seen with anti-PD-1 monotherapy. We are expecting a potentially pivotal initial readout from our first-line metastatic melanoma trial by the end of this year. We also anticipate Phase II data in non-small cell lung cancer in late 2024.

關於Libtayo組合，我們最先進的是與我們的LAG-3抗體fanlimab的組合。提醒一下，我們在3 個獨立的一線轉移性黑色素瘤隊列中的早期臨床數據表明，與已批准的抗LAG-3 PD-1 組合產品進行交叉試驗時，具有同類最佳療效的潛力，突出顯示客觀緩解率更高超過 60%，估計中位無惡化存活期超過 15 個月。這些早期臨床數據表明，Libtayo fanlimab 組合可能是檢查點抑制劑組合中最令人興奮的例子之一，具有臨床意義的益處以及與抗 PD-1 單一療法相似的安全性。我們預計到今年年底我們的一線轉移性黑色素瘤試驗將獲得潛在的關鍵初步結果。我們也預計將於 2024 年末獲得非小細胞肺癌的 II 期數據。

On to bispecifics, starting with solid tumors. In the dose escalation trial of our EGFR by CD28 costimulatory bispecifics combined with Libtayo, we have observed promising activity in microsatellite stable colorectal cancer with higher doses of (inaudible). In terms of safety, so far, we have not seen an increase in immune-related adverse events with (inaudible). Based on these encouraging early data, which will be presented at a scientific forum later this year, we will be initiating expansion cohorts across several solid tumors in the first half of the year. In 2024, we are also planning to provide updates for our MUC16xCD3 and MUC16xCD28 program in advanced ovarian cancer.

關於雙特異性，從實體腫瘤開始。在我們的 EGFR 透過 CD28 共刺激雙特異性藥物與 Libtayo 聯合進行的劑量遞增試驗中，我們觀察到較高劑量（聽不清楚）對微衛星穩定大腸直腸癌的有希望的活性。在安全性方面，到目前為止，我們尚未看到與免疫相關的不良事件增加（聽不清楚）。基於這些令人鼓舞的早期數據（這些數據將在今年稍後的科學論壇上公佈），我們將在今年上半年啟動針對幾種實體瘤的擴展隊列。 2024 年，我們也計劃為晚期卵巢癌的 MUC16xCD3 和 MUC16xCD28 計畫提供更新。

Next, our bispecific for hematology oncology. For linvoseltamab, or BCMAxCD3 bispecific for multiple myeloma, FDA acceptance of our BLA submission is expected later this month. And the EMA recently accepted our MAA submission. These submissions were supported by a potentially best-in-class profile in late-line myeloma in terms of efficacy, safety, dosing, as well as convenience. A confirmatory Phase III study as well as studies in earlier stages of myeloma and premalignant disease are enrolling or will soon begin enrolling patients.

接下來，我們的雙特異性血液腫瘤學。對於 linvoseltamab 或治療多發性骨髓瘤的 BCMAxCD3 雙特異性藥物，FDA 預計將於本月稍後接受我們提交的 BLA。 EMA 最近接受了我們提交的 MAA。這些提交的資料得到了晚期骨髓瘤在療效、安全性、劑量和便利性方面可能是同類最佳的資料的支持。一項驗證性 III 期研究以及骨髓瘤和癌前疾病早期階段的研究正在招募或即將開始招募患者。

For odronextamab, our CD20xCD3 bispecific for non-Hodgkin's lymphoma, the FDA decision for our BLA is expected by its March 31 PDUFA date, and the EU decision is expected in the second half of the year. In terms of additional recent news for our oncology and immunology pipeline, this week, we announced the formation of Regeneron cell medicines unit, and that we are acquiring full development and commercialization rights for 2seventy bio's pipeline of investigational immune cell therapies.

對於odronextamab（我們用於治療非霍奇金淋巴瘤的CD20xCD3 雙特異性藥物），FDA 預計將在3 月31 日的PDUFA 日期之前對我們的BLA 做出決定，歐盟預計將在今年下半年做出決定。就我們的腫瘤學和免疫學管道的最新消息而言，本週，我們宣布成立再生元細胞藥物部門，並且我們正在獲得 2seventy bio 的研究性免疫細胞療法管道的全部開發和商業化權利。

We have worked with 2seventy since 2018 on many of these programs and are excited about the opportunity to continue advancing our collective efforts. After deal closing, certain 2seventy employees will join Regeneron cell medicines and continue to work on addressing cancer and other serious diseases in novel ways, including by combining Regeneron's antibody capabilities with CAR-T therapies.

自 2018 年以來，我們一直與 2seventy 合作進行許多此類項目，並且很高興有機會繼續推進我們的集體努力。交易完成後，部分 270 名員工將加入 Regeneron 細胞藥物公司，繼續致力於以新穎的方式解決癌症和其他嚴重疾病，包括將 Regeneron 的抗體能力與 CAR-T 療法結合。

Moving from immunology and oncology to obesity and metabolic diseases. Despite all the enthusiasm surrounding GLP-1 agonist for obesity, it has been increasingly recognized that the profound weight loss is accompanied by substantial muscle loss, accounting for up to as much as 40% of the weight loss. This potentially irretrievable muscle loss can be catastrophic for patients and may even lead to major public health concerns in the future.

從免疫學和腫瘤學轉向肥胖和代謝疾病。儘管人們對 GLP-1 激動劑治療肥胖的熱情很高，但人們越來越認識到，體重減輕的同時伴隨著大量的肌肉損失，佔體重減輕的比例高達 40%。這種潛在的不可挽回的肌肉損失對患者來說可能是災難性的，甚至可能在未來導致重大的公共衛生問題。

We have previously shown that our antibodies targeting myostatin and Activin A have the potential to preserve and grow muscle in human trials. Based on these data as well as additional data in obese nonhuman primates, we believe that inhibiting these pathways on top of GLP-1 receptor agonism, has the potential to achieve comparable overall reductions in body weight but with improved quality of the weight loss, resulting in more fat loss while preserving or actually increasing muscle mass.

我們先前已在人體試驗中證明，我們的針對肌肉生長抑制素和激活素 A 的抗體具有保存和生長肌肉的潛力。基於這些數據以及肥胖非人靈長類動物的其他數據，我們相信，在 GLP-1 受體激動劑的基礎上抑制這些途徑，有可能實現可比的總體體重減輕，同時改善體重減輕的質量，從而在保持或實際增加肌肉質量的同時減少更多的脂肪。

In mid-2024, we plan to start our first clinical trial to evaluate the combination of our muscle preservation antibodies in combination with semaglutide. Also in 2024, we are anticipating proof-of-concept data for a Factor XI antibodies in the setting of prevention of venous thromboembolism after knee replacement surgery. Based on preclinical and healthy volunteer data, our antibody approach demonstrated more complete Factor XI blockade compared to competing approaches in development for coagulation disorders. And the program is on a rapid path to a registrational trial starting late this year or early next year.

2024 年中期，我們計劃開始第一個臨床試驗，以評估我們的肌肉保存抗體與索馬魯肽的組合。同樣在 2024 年，我們預期將獲得因子 XI 抗體在預防膝關節置換手術後靜脈血栓栓塞的概念驗證數據。基於臨床前和健康志願者的數據，與針對凝血障礙的競爭方法相比，我們的抗體方法表現出更完全的 XI 因子阻斷。該項目正在迅速進入今年年底或明年初開始的註冊試驗。

We'll now conclude with our efforts in genetic medicines. Our siRNA collaboration with Alnylam has demonstrated successful silencing of genes in the liver and for the first time for siRNA, in the brain. Proof of principle was achieved for ALN-APP last year and we are anticipating additional data from that program this year, including from patients who have received multiple doses. Based on the success, we are looking forward to new siRNA programs targeting CNS diseases entering the clinic this year, such as ALN-SOD for ALS patients with SOD1 mutations.

現在我們將結束我們在基因醫學方面的努力。我們與 Alnylam 的 siRNA 合作已成功證明了肝臟中基因的沉默，並且首次在大腦中實現了 siRNA 基因沉默。 ALN-APP 去年獲得了原理驗證，我們預計今年該計劃會提供更多數據，包括接受多次劑量的患者的數據。基於這項成功，我們期待今年針對中樞神經系統疾病的新siRNA計畫進入臨床，例如針對SOD1突變的ALS患者的ALN-SOD。

Our collaboration with Intellia on CRISPR gene editing continues to advance, where we together produced the first example of CRISPR-based gene editing of a pathological gene in human beings. This initial program for our lead indication of TTR amyloidosis with cardiomyopathy is now in the first in vivo CRISPR program clear to enter Phase III studies in the United States.

我們與 Intellia 在 CRISPR 基因編輯方面的合作不斷推進，我們共同製作了第一個基於 CRISPR 的人類病理基因基因編輯的例子。我們針對 TTR 澱粉樣變性心肌病變的主要適應症的初始項目現已成為第一個體內 CRISPR 項目，已明確進入美國 III 期研究。

Together with Intellia, we also hope to be the first to use CRISPR technology to insert a corrective gene for deficiency disease. We recently achieved IND clearance for our CRISPR-based gene insertion program for Factor IX and initiated the lead-in portion of a clinical trial to evaluate it as a potential cure for hemophilia B.

我們也希望與 Intellia 一起成為第一個使用 CRISPR 技術插入缺陷性疾病來糾正基因的公司。最近，我們基於 CRISPR 的因子 IX 基因插入計畫獲得了 IND 批准，並啟動了臨床試驗的導入部分，以評估其作為治療 B 型血友病的潛在療法。

Moving to genetic hearing loss. We were the first U.S.-based company to announce hearing restoration in a young child suffering from genetic hearing loss after treatment with our novel gene therapy approach. We are excited by these early results for this ultra-rare disease and look forward to advancing to the clinic additional programs potentially address more common forms of monogenic hearing loss. These data represent validation of our viral-based gene therapy program, in this case, locally delivered to the cells of the inner ear.

轉向遺傳性聽力損失。我們是第一家宣布患有遺傳性聽力損失的幼兒在接受我們的新型基因治療方法治療後聽力得到恢復的美國公司。我們對這種極其罕見疾病的早期結果感到興奮，並期待將更多項目推進到臨床，以解決更常見的單基因聽力損失形式。這些數據代表了我們基於病毒的基因治療計劃的驗證，在本例中，基因治療計劃局部遞送至內耳細胞。

Beyond these efforts, we have made significant investments in leveraging our monoclonal and bispecific antibody expertise to use these agents to systematically deliver virally based genetic-based payloads directly to specific tissues in the body non-amenable to local delivery, such as to muscle and the central nervous system. Based on encouraging preclinical data, we will be progressing these approaches to the clinic in the coming years.

除了這些努力之外，我們還進行了大量投資，利用我們的單克隆和雙特異性抗體專業知識，使用這些試劑系統地將基於病毒的基於基因的有效負載直接傳遞到體內不適合局部傳遞的特定組織，例如肌肉和骨骼。中樞神經系統。基於令人鼓舞的臨床前數據，我們將在未來幾年將這些方法推進到臨床。

Finally, concluding with another notable first-in-class program involving a combination of an siRNA with an antibody, in this case to block the C5 complement target. Normally, one needs very high levels of infuse the antibody to achieve sufficient efficacy because of high target levels regarding C5. But our siRNA cotreatment dramatically lowers C5 target burden, allowing lower and more convenient antibody dosing. We recently shared encouraging initial data from a Phase III study in patients with PNH, which supported our hypothesis that this combination approach could provide better efficacy and control of breakthrough hemolysis with more convenient dosing.

最後，以另一個值得注意的一流項目作為結論，該項目涉及 siRNA 與抗體的組合，在本例中是為了阻斷 C5 補體標靶。通常，由於 C5 的目標水平很高，因此需要非常高水平的抗體輸注才能達到足夠的功效。但我們的 siRNA 共治療顯著降低了 C5 標靶負擔，從而允許更低且更方便的抗體劑量。我們最近分享了一項針對PNH 患者的III 期研究的令人鼓舞的初步數據，這些數據支持了我們的假設，即這種組合方法可以透過更方便的劑量提供更好的療效和對突破性溶血的控制。

Based and building on these data, we continue to enroll our Phase III studies in PNH and myasthenia gravis. We're also planning to extend this combination approach to geographic atrophy and dry AMD. While this combination is expected to have manageable systemic toxicities, including elevated risk of infections, we believe that our approach has several potential advantages over recently approved complement inhibiting agents for GA, which are delivered directly into the eye and have resulted in rare but serious cases of retinal vasculitis, sometimes resulting in permanently impaired vision.

基於這些數據，我們繼續進行 PNH 和重症肌無力的 III 期研究。我們也計劃將這種組合方法擴展到地理性萎縮和乾性 AMD。雖然這種組合預計具有可控的全身毒性，包括感染風險升高，但我們相信，與最近批准的GA 補體抑制劑相比，我們的方法具有幾個潛在優勢，補體抑制劑直接輸送到眼睛中，導致罕見但嚴重的病例視網膜血管炎，有時會導致永久性視力受損。

In conclusion, Regeneron's R&D engine continues to grow and deliver many firsts, including differentiated early, mid- and late-stage opportunities. And we are looking forward to additional progress in 2024.

總之，再生元的研發引擎持續成長並創造了許多第一，包括差異化的早期、中期和後期機會。我們期待 2024 年會取得更多進展。

Before I turn the call over to Marion, I would like to add my thanks and appreciation to Bob for his many years of devoted efforts and leaderships, and welcoming and look forward to adding Chris Fenimore to our leadership team.

在將電話轉給馬里昂之前，我想對鮑勃多年來的奉獻努力和領導表示感謝和讚賞，並歡迎並期待克里斯·費尼莫爾加入我們的領導團隊。

With that, I will turn it over to Marion.

這樣，我就把它交給瑪莉安。

Thanks, George. Our business delivered strong results in the fourth quarter and for the year. Over the course of 2023, we successfully launched EYLEA HD, grew Dupixent across approved type 2 inflammatory diseases and expanded Libtayo's presence in lung and non-melanoma skin cancers. We look forward to several potential approvals this year in new therapeutic categories, including in COPD with Dupixent and a hematologic oncology using new treatment modalities.

謝謝，喬治。我們的業務在第四季度和全年取得了強勁的業績。 2023 年，我們成功推出了 EYLEA HD，在已批准的 2 型發炎性疾病領域發展了 Dupixent，並擴大了 Libtayo 在肺癌和非黑色素瘤皮膚癌中的應用。我們期待今年新治療類別的多項潛在批准，包括使用 Dupixent 治療慢性阻塞性肺病和使用新治療方式的血液腫瘤治療。

I'll start with our retinal franchise. In January, we announced fourth quarter combined U.S. EYLEA HD and EYLEA net product sales of $1.46 billion. In its first full quarter, EYLEA HD net product sales were $123 million, based on growing demand and positive early physician experience. EYLEA HD is already being used across a broad range of patient types, including those switching from EYLEA, other branded agents or Avastin, as well as modest but increasing use in treatment-naive patients.

我將從我們的視網膜專營權開始。一月份，我們宣布第四季美國 EYLEA HD 和 EYLEA 產品淨銷售額總計為 14.6 億美元。基於不斷增長的需求和積極的早期醫生經驗，EYLEA HD 在第一個完整季度的產品淨銷售額為 1.23 億美元。 EYLEA HD 已在廣泛的患者類型中使用，包括那些從 EYLEA、其他品牌藥物或阿瓦斯汀轉用的患者，以及在初治患者中的適度但不斷增加的使用。

In the fourth quarter, EYLEA HD and EYLEA together secured 49% of the anti-VEGF category share, despite increasing competition and changing market dynamics. This share gain was driven by the differentiated efficacy and safety profile of our medicines as well as a short-term disruption in compounded Avastin due to a quality issue at a large supplier that has since been resolved.

儘管競爭日益激烈且市場動態不斷變化，但第四季度 EYLEA HD 和 EYLEA 共同佔據了抗 VEGF 類別 49% 的份額。這一份額成長的推動因素是我們藥品的差異化功效和安全性，以及由於一家大型供應商的品質問題導致複方阿瓦斯汀的短期中斷（該問題已解決）。

Since launch, we have made significant progress in securing access and reimbursement for EYLEA HD. More than 2/3 of eligible lives are now covered, with the vast majority having first line or single step edit access. Medicare fee-for-service, which represents approximately 45% of total category use, claims are being paid across 100% of jurisdictions using a miscellaneous J-Code.

自推出以來，我們在確保 EYLEA HD 的使用和報銷方面取得了重大進展。現在超過 2/3 的符合條件的生命已被覆蓋，其中絕大多數具有一線或單步編輯存取權限。醫療保險按服務收費約佔總類別使用量的 45%，100% 的司法管轄區均使用各種 J 代碼支付索賠。

Looking ahead in 2024, we remind you that the first quarter is typically impacted by payer reauthorizations and that EYLEA HD will remain subject to a miscellaneous J-Code. However, in late January, we achieved another important launch milestone with CMS's assignment of a permanent J-Code for EYLEA HD that will go into effect on April 1. This will provide additional reimbursement confidence for those physicians hesitant to prescribe before a permanent J-Code based on their negative experiences with other new eye disease medicines.

展望 2024 年，我們提醒您，第一季通常會受到付款人重新授權的影響，並且 EYLEA HD 將繼續遵守各種 J 代碼。然而，在一月下旬，我們實現了另一個重要的啟動里程碑，CMS 為EYLEA HD 分配了永久J 代碼，該代碼將於4 月1 日生效。這將為那些在永久J 代碼之前猶豫是否開藥的醫生提供額外的報銷信心。根據他們對其他新眼病藥物的負面經歷編寫的代碼。

Overall, we are very excited about the future of our retinal franchise. We continue to see physicians prescribe EYLEA HD in both treatment experienced and treatment-naive settings as EYLEA HD is increasingly recognized as the new standard of care.

總的來說，我們對視網膜系列的未來感到非常興奮。隨著 EYLEA HD 越來越被認為是新的護理標準，我們不斷看到醫生在有治療經驗和未接受過治療的環境中開出 EYLEA HD 處方。

Now to Dupixent, where fourth quarter 2023 global net sales grew 31% on a constant currency basis to $3.2 billion and U.S. net sales grew 28% to $2.5 billion. With more than 800,000 patients on therapy worldwide, Dupixent is one of the most important biologic medicines for patients across the spectrum of diseases. Additionally, it continues to have significant growth potential based on new and upcoming indications.

現在來看 Dupixent，以固定匯率計算，2023 年第四季全球淨銷售額成長 31%，達到 32 億美元，美國淨銷售額成長 28%，達到 25 億美元。 Dupixent 在全球有超過 80 萬名患者接受治療，是針對各種疾病患者最重要的生物藥物之一。此外，根據新的和即將出現的適應症，它仍然具有巨大的成長潛力。

In the U.S., Dupixent leads new-to-brand prescription share across all 5 approved indications, an important leading indicator for future growth. In addition, Dupixent already leads total prescription share in 4 or 5 approved indications and we are approaching share leadership in biologic asthma.

在美國，Dupixent 在所有 5 個批准適應症的新品牌處方份額中處於領先地位，這是未來成長的重要領先指標。此外，Dupixent 已經在 4 或 5 個已批准適應症的總處方份額中處於領先地位，並且我們正在接近生物性氣喘領域的份額領先地位。

In atopic dermatitis, Dupixent's largest indication, physicians continue to prescribe Dupixent as a therapy of choice. Despite increased competition over the course of 2023, fourth quarter Dupixent new-to-brand prescription share in AD modestly increased sequentially compared to the third quarter 2023, driven by its differentiated mechanism of action, clinical results and trusted safety profile, including approval in patients as young as 6 months of age.

對於異位性皮膚炎（Dupixent 最大的適應症），醫生繼續將 Dupixent 作為首選療法。儘管2023 年競爭加劇，但由於其差異化的作用機制、臨床結果和值得信賴的安全性（包括患者的批准），第四季度Dupixent 在AD 領域的新品牌處方份額較2023 年第三季度略有增長年僅6個月大。

Dupixent's U.S. label was recently updated with efficacy and safety data for patients with moderate to severe hand or foot atopic dermatitis. Dupixent is the only biologic medicine with data in the label supporting use for this subset of patients with this hard-to-treat disease.

Dupixent 的美國標籤最近更新了針對中度至重度手足異位性皮膚炎患者的療效和安全性數據。 Dupixent 是唯一一種標籤上有數據支持用於患有這種難治性疾病的患者的生物藥物。

Beyond atopic dermatitis, growth also continues in asthma and nasal polyps, both of which are already blockbuster indications. The recent launches for eosinophilic esophagitis, known as EoE, and prurigo nodularis further contributed to Dupixent's performance and represent indications of significant growth potential. In EoE, which prior to Dupixent's approval had no FDA-approved treatments, nearly 25,000 patients in the U.S. alone have already initiated therapy on Dupixent. The FDA's recent approval of Dupixent in pediatric EOE extends this indication to patients as young as 1 year of age, where approximately 20,000 children in the U.S. being treated for EoE with unapproved therapies. Patient initiations also continue to accelerate in prurigo nodularis, solidifying Dupixent as the standard of care for multiple dermatologic conditions.

除了異位性皮膚炎之外，氣喘和鼻息肉也持續成長，這兩種疾病都已經是重磅適應症。最近推出的嗜酸性粒細胞性食道炎（EoE）和結節性癢疹進一步提升了 Dupixent 的業績，並表明了其巨大的成長潛力。在 EoE 中，在 Dupixent 批准之前沒有 FDA 批准的治療方法，僅在美國就有近 25,000 名患者已經開始 Dupixent 治療。 FDA 最近批准 Dupixent 用於兒童 EOE，將這種適應症擴展到了年僅 1 歲的患者，美國約有 20,000 名兒童正在接受未經批准的療法治療 EoE。結節性癢疹患者的開始使用也持續加速，鞏固了 Dupixent 作為多種皮膚病護理標準的地位。

In summary, Dupixent is delivering on its potential as one of the most important biologic medicines of our generation with significant remaining opportunity for growth. We anticipate bringing Dupixent to many more patients this year across approved indications. The pediatric EoE launch is already underway, and we are actively preparing to launch Dupixent in eosinophilic COPD pending potential FDA approval later this year.

總之，Dupixent 正在發揮其作為我們這一代最重要的生物藥物之一的潛力，並具有巨大的成長機會。我們預計今年將 Dupixent 帶給更多已批准適應症的患者。兒科 EoE 的上市已經在進行中，我們正在積極準備在嗜酸性粒細胞性慢性阻塞性肺病 (COPD) 中推出 Dupixent，等待 FDA 在今年稍後批准。

And finally, to Libtayo. Fourth quarter global net sales grew 43% year-over-year on a constant currency basis to $244 million, with U.S. net sales of $155 million. Libtayo continues to lead the category in non-melanoma skin cancers, and we've made progress in penetrating the non-small cell lung cancer market. In 2024, we expect continued growth across all indications, advancing our goal to exceed $1 billion in annual Libtayo net sales. In conclusion, 2024 provides the opportunity to further build Regeneron's market-leading positions with our medicines across even more therapeutic areas.

最後，到 Libtayo。以固定匯率計算，第四季全球淨銷售額年增 43%，達到 2.44 億美元，其中美國淨銷售額為 1.55 億美元。 Libtayo 繼續在非黑色素瘤皮膚癌領域處於領先地位，並且我們在滲透非小細胞肺癌市場方面取得了進展。到 2024 年，我們預計所有適應症都將持續成長，從而推動 Libtayo 年度淨銷售額超過 10 億美元的目標。總之，2024 年，再生元將有機會利用我們的藥物在更多治療領域進一步確立市場領先地位。

Now I'll turn the call over to Bob.

現在我將把電話轉給鮑伯。

Thank you, Marion. My comments today on Regeneron's financial results and outlook will be on a non-GAAP basis unless otherwise noted. Regeneron ended 2023 with strong performance in the fourth quarter. Excluding contributions from Ronapreve, total revenues increased 14% year-over-year to $3.4 billion, primarily driven by sales growth and margin expansion from Dupixent the launch of EYLEA HD and strong sales growth from Libtayo. Fourth quarter diluted net income per share was $11.86 on net income of $1.4 billion.

謝謝你，馬里昂。除非另有說明，我今天對再生元的財務表現和前景的評論將基於非公認會計原則。再生元以第四季度的強勁表現結束了 2023 年。不包括 Ronapreve 的貢獻，總營收年增 14%，達到 34 億美元，這主要得益於 Dupixent 的銷售成長和利潤率擴張、EYLEA HD 的推出以及 Libtayo 的強勁銷售成長。第四季稀釋後每股淨利為 11.86 美元，淨利為 14 億美元。

Moving to collaboration revenue and starting with Bayer. Fourth quarter 2023 ex U.S. EYLEA net product sales were $890 million, up 4% on a constant currency basis versus the prior year. Total Bayer collaboration revenue was $377 million, of which $345 million related to our share of EYLEA net profits outside the U.S.

轉向合作收入並從拜耳開始。 2023 年第四季（不含美國）EYLEA 產品淨銷售額為 8.9 億美元，以固定匯率計算比上年增長 4%。拜耳合作總收入為 3.77 億美元，其中 3.45 億美元與我們在美國以外的 EYLEA 淨利潤中所佔的份額有關。

Total Sanofi collaboration revenue grew 19% in the fourth quarter of 2023 to $993 million. Excluding a $50 million sales milestone recorded in the fourth quarter of 2022, Sanofi collaboration revenue grew 26%. Our share of collaboration profits was $886 million, an increase of 43% versus the fourth quarter of 2022, driven by Dupixent's continued volume growth and improving margins.

2023 年第四季度，賽諾菲合作總營收成長 19%，達到 9.93 億美元。不包括 2022 年第四季創下的 5,000 萬美元銷售里程碑，賽諾菲合作收入成長了 26%。在 Dupixent 銷售持續成長和利潤率提高的推動下，我們的合作利潤份額為 8.86 億美元，較 2022 年第四季成長 43%。

Reimbursements for manufacturing of commercial supply, a component of Sanofi collaboration revenues, declined 36% versus the prior year due to the implementation of a new higher-yielding manufacturing process. At the end of 2023, the Sanofi development balance was $2.33 billion, reflecting a net decrease of $534 million compared to the balance as of December 31, 2022. Recall, this decrease is primarily recorded as a reduction to our share of collaboration profits. We continue to expect this balance to be fully reimbursed in the next few years, which would result in a significant step-up in our Sanofi collaboration profits.

由於實施了新的更高產量的製造工藝，賽諾菲合作收入的一部分——商業供應製造的補償比上年下降了 36%。截至 2023 年底，賽諾菲的開發餘額為 23.3 億美元，與截至 2022 年 12 月 31 日的餘額相比淨減少 5.34 億美元。回想一下，這一減少主要記錄為我們的合作利潤份額的減少。我們仍然預計這筆餘額將在未來幾年內全額償還，這將導致我們與賽諾菲的合作利潤大幅增加。

Other revenue was $213 million in the fourth quarter of 2023, up 66% versus the prior year, primarily driven by higher royalties from Novartis on sales of ILARIS and an increase in our share of [Arcelis] profit from (inaudible). The increase in other revenue also reflects higher reimbursements for increased shipment volumes of ex-U.S. commercial supplies of Praluent to Sanofi.

2023 年第四季的其他收入為2.13 億美元，比上一年增長66%，這主要是由於諾華公司銷售ILARIS 的特許權使用費增加以及我們在[Arcelis] 利潤中的份額增加（聽不清）。其他收入的增加也反映出美國以外地區出貨量增加的報銷額增加。 Praluent 向賽諾菲的商業供應。

Moving now to our operating expenses. Fourth quarter 2023 R&D expense grew 13% year-over-year to $1.03 billion, which reflects continued investment in our growing pipeline. R&D growth was primarily driven by higher headcount and related costs, funding of our advancing late-stage programs and increased clinical manufacturing activity. SG&A grew 7% from the prior year to $622 million in the fourth quarter, reflecting higher headcount and related costs and higher commercialization expenses, including costs to support the launch of EYLEA HD in prelaunch activities for an anticipated 2024 hem/onc product launches. Fourth quarter COCM declined 12% from the prior year quarter to $210 million. Recall that we are reimbursed for these costs.

現在轉向我們的營運費用。 2023 年第四季研發費用年增 13% 至 10.3 億美元，反映出我們對不斷成長的產品線的持續投資。研發成長主要是由於人員數量和相關成本的增加、後期專案的資金投入以及臨床生產活動的增加所推動的。第四季銷售、行政管理費用較上一年增長7%，達到6.22 億美元，反映出員工人數和相關成本以及商業化費用的增加，包括在預計2024 年hem/onc 產品發布的預發布活動中支援EYLEA HD 發布的成本。第四季 COCM 較去年同期下降 12%，至 2.1 億美元。請記住，我們會報銷這些費用。

Now to cash flow and the balance sheet. In 2023, Regeneron generated $3.9 billion in free cash flow, ending the year with cash and marketable securities less debt of approximately $13.5 billion. In 2023, we repurchased over $2.2 billion of our shares with approximately $1.5 billion remaining authorized for repurchase as of December 31, 2023. Since we began repurchasing our shares in 2019, we have bought back approximately $12 billion worth and planning to continue to make opportunistic repurchases.

現在來看看現金流量和資產負債表。 2023 年，Regeneron 產生了 39 億美元的自由現金流，年底現金和有價證券減去債務約 135 億美元。 2023 年，我們回購了超過22 億美元的股票，截至2023 年12 月31 日，仍有約15 億美元授權回購。自2019 年開始回購股票以來，我們已回購了價值約120 億美元的股票，並計劃繼續機會主義回購。

Now moving to our financial guidance for 2024. Note that these guidance ranges do not assume the completion of any business development transactions that were not completed as of today, including our recently announced agreement to acquire preclinical and clinical programs from 2seventy bio. Starting with R&D expense in 2024, which is anticipated to be in the range of $4.3 billion to $4.5 billion. As George just discussed and as we highlighted at the JPMorgan Conference, our pipeline continues to expand, with a growing number of registration-enabling studies ongoing are expected to initiate this year. These include potentially pivotal studies for fianlimab, Phase III studies in earlier lines of odronextamab and linvoseltamab in our C5 programs.

現在轉向我們的 2024 年財務指導。請注意，這些指導範圍並不假設截至今天尚未完成的任何業務開發交易的完成，包括我們最近宣布的從 2seventy bio 收購臨床前和臨床項目的協議。從 2024 年的研發費用開始，預計將在 43 億美元至 45 億美元之間。正如喬治剛剛討論的那樣，正如我們在摩根大通會議上所強調的那樣，我們的管道繼續擴大，預計今年將啟動越來越多的註冊支持研究。其中包括 fianlimab 的潛在關鍵研究、我們 C5 計畫中 odronextamab 和 linvoseltamab 早期系列的 III 期研究。

In addition, we expect to bring 8 to 10 new molecules into the clinic in 2024. We expect 2024 SG&A spend to be in the range of $2.5 billion to $2.65 billion. This reflects increased promotional activities for the ongoing launch of EYLEA HD investments to support 2 anticipated hem/onc product launches and higher headcount to support our growing organization inclusive of our ongoing international expansion.

此外，我們預計 2024 年將 8 至 10 個新分子帶入臨床。我們預計 2024 年 SG&A 支出將在 25 億至 26.5 億美元之間。這反映了為支持 2 個預期的 hem/onc 產品發布而正在進行的 EYLEA HD 投資的促銷活動的增加，以及為支持我們不斷發展的組織（包括我們正在進行的國際擴張）而增加的員工人數。

COCM is expected to be in the range of $850 million to $910 million. This range reflects lower drug substance manufacturing costs for Dupixent, offset by higher Dupixent volumes, and higher production costs for other collaboration products, including EYLEA HD for Bayer. Recall, we are reimbursed for COCM expenses and, as a result, we expect reimbursement from Sanofi, which are recorded as a component of Sanofi collaboration revenue, to be slightly lower in 2024 as compared to 2023. We expect the 2024 gross margin on net product sales to be in the range of 89% to 91%. We also expect our effective tax rate to be in the range of 10% to 12%.

COCM 預計在 8.5 億至 9.1 億美元之間。這一範圍反映出 Dupixent 原料藥製造成本較低，但被較高的 Dupixent 產量和其他合作產品（包括拜耳的 EYLEA HD）較高的生產成本所抵消。回想一下，我們得到了 COCM 費用的報銷，因此，我們預計 2024 年來自賽諾菲的報銷（作為賽諾菲合作收入的一部分）將略低於 2023 年。我們預計 2024 年的淨毛利率產品銷量將在89%至91%之間。我們也預計有效稅率將在 10% 至 12% 之間。

Finally, we expect capital expenditures to be in the range of $825 million to $950 million, which reflects expansion of our R&D facilities at our Tarrytown, New York headquarters, as well as continued expansion of our manufacturing capabilities, including ongoing construction of a fill/finish facility in Rensselaer, New York.

最後，我們預計資本支出將在 8.25 億美元至 9.5 億美元之間，這反映了我們在紐約塔里敦總部的研發設施的擴建，以及我們製造能力的持續擴大，包括正在進行的填充/位於紐約州倫斯勒的成品工廠。

In addition to our full year guidance, we expect U.S. net product sales of Praluent to be lower in 2024 as compared to 2023 due to changes in payer coverage. We also expect 2024 net product sales for Inmazeb to be in line with 2023 revenues with nearly all 2024 revenues expected to be recorded in the fourth quarter.

除了我們的全年指引外，由於付款人涵蓋範圍的變化，我們預計 2024 年 Praluent 在美國的產品淨銷售額將低於 2023 年。我們也預期 Inmazeb 2024 年的產品淨銷售額將與 2023 年的收入保持一致，2024 年幾乎所有收入預計將在第四季度記錄。

Finally, we anticipate other revenue in 2024 to be in line with 2023, with the second half expected to be higher than our first half. Overall, Regeneron performed well in 2023 and our continued investments position the company to drive long-term shareholder value.

最後，我們預計 2024 年的其他收入將與 2023 年持平，下半年預計將高於上半年。總體而言，再生元在 2023 年表現良好，我們的持續投資使該公司能夠推動長期股東價值。

Before I conclude, I'd like to sincerely thank Len and George for their kind words. It has been an honor to serve as Regeneron's CFO for these past 10 years, and I have appreciated all of my interactions with each of you in the investment community. I wish Chris Fenimore much success in this role and have the utmost confidence that he and the rest of the management team will continue to deliver breakthrough medicines for patients and value to shareholders.

在結束之前，我要真誠地感謝萊恩和喬治的善意之言。在過去的 10 年裡，我很榮幸擔任再生元的財務官，我非常感謝與投資界各位的所有互動。我祝福 Chris Fenimore 在這一職位上取得成功，並對他和管理團隊的其他成員將繼續為患者提供突破性藥物並為股東創造價值充滿信心。

Thank you, and I wish you all continued success. With that, I will pass the call back to Ryan.

謝謝大家，祝大家繼續成功。這樣，我會將電話轉回給 Ryan。

Thank you, Bob, and congratulations again. This concludes our prepared remarks. We will now open the call for Q&A. To ensure we are able to address as many questions as possible, we will answer 1 question from each caller before moving to the next.

謝謝你，鮑勃，再次恭喜。我們準備好的演講到此結束。我們現在將開始問答徵集。為了確保我們能夠解決盡可能多的問題，我們將回答每個來電者提出的 1 個問題，然後再轉到下一個。

Shannon, can we go to the first question, please?

Shannon，我們可以回答第一個問題嗎？

(Operator Instructions) Our first question comes from the line of Tyler Van Buren with TD Cowen.

（操作員說明）我們的第一個問題來自 Tyler Van Buren 和 TD Cowen 的路線。

Great. And I'd like to say congratulations to you as well, Bob. I wish you well during your retirement. It's been a privilege to work with you. And Chris, I look forward to working with you as well.

偉大的。我也想向你表示祝賀，鮑伯。祝您退休期間一切順利。很榮幸能與您合作。克里斯，我也期待與你合作。

So in the opening, Len mentioned accelerating the rate of conversion of patients from other agents to EYLEA HD. So can you discuss the different factors at play that will accelerate the rate over the year, which I assume includes a permanent J-Code and also the robust sampling effort that is impacting 2 mg sales?

因此，Len 在開場白中提到了加快患者從其他藥物轉向 EYLEA HD 的速度。那麼，您能否討論一下將在一年內加快銷售速度的不同因素，我認為其中包括永久的 J 代碼以及影響 2 毫克銷售的強勁抽樣工作？

Sure, Tyler. I'm happy to answer. So as I mentioned, we're very encouraged by the early performance of EYLEA HD in the market, and a number of factors early are driving that success. First, it's the clinical data, which is now showing in the actual market real-world setting the efficacy, safety and durability of EYLEA HD, all very important factors. As we look to the future, physicians will build upon their early experience. And as I mentioned, that experience is coming from conversion patients from branded agents broadly, Avastin, and also, in some cases, naive patients. But going forward, I would share that, in addition to ongoing experience and confidence, the reimbursement consideration is very, very important for physicians, and some are hesitant to prescribe a product that doesn't have a permanent J-Code.

當然，泰勒。我很高興回答。正如我所提到的，我們對 EYLEA HD 在市場上的早期表現感到非常鼓舞，而早期的許多因素推動了這一成功。首先是臨床數據，現在在實際市場中展示了 EYLEA HD 的功效、安全性和耐用性，這些都是非常重要的因素。當我們展望未來時，醫生將藉鏡他們早期的經驗。正如我所提到的，這種經驗來自於廣泛使用阿瓦斯汀品牌藥物的轉化患者，在某些情況下，也來自於未接受過治療的患者。但展望未來，我想分享的是，除了持續的經驗和信心之外，報銷考慮因素對醫生來說非常非常重要，有些人對於開出沒有永久 J 代碼的產品猶豫不決。

So we do look forward to that occurring April 1 and beyond based on CMS's recent update. And then in addition to reimbursement confidence, we've made progress certainly in payer coverage. We anticipate making more. And certainly, the experience in market to date with EYLEA HD has been very favorable for physicians. And that is, probably, the most important, those differentiating characteristics of the product.

因此，根據 CMS 的最新更新，我們確實期待 4 月 1 日及以後發生這種情況。除了報銷信心之外，我們在付款人覆蓋範圍方面也取得了一定進展。我們預計會生產更多。當然，迄今為止 EYLEA HD 的市場經驗對醫生來說非常有利。這可能是最重要的，即產品的差異化特徵。

Our next question comes from the line of Brian Abrahams with RBC Capital Markets.

我們的下一個問題來自加拿大皇家銀行資本市場部門的布萊恩亞伯拉罕斯 (Brian Abrahams)。

Congrats to both Bob and Chris. I was wondering if you could maybe talk a little bit about the differentiation of the emerging obesity portfolio as you move into the next wave of studies. I know a patent filing revealed that the antibody tethered GLP-1 shows very competitive weight loss in animal models. So I'm wondering where you see that differentiating most? Is it tolerability and distribution or dose frequency or somewhere else? And then I know others are pursuing myostatin as well on top of GLP-1s. Just curious where you see your biggest competitive advantage there.

祝賀鮑勃和克里斯。我想知道，當您進入下一波研究時，您是否可以談談新興肥胖組合的差異化。我知道專利申請顯示，連接 GLP-1 的抗體在動物模型中顯示出非常有競爭力的減肥效果。所以我想知道您在哪裡看到了最大的差異化？是耐受性和分佈還是劑量頻率還是其他什麼地方？然後我知道其他人也在 GLP-1 的基礎上尋求肌肉生長抑制素。只是好奇您最大的競爭優勢在哪裡。

Okay. Well, let me start with the latter first, in terms of muscle preservation. Other people have related approaches, but we're the only ones, we're the ones who discovered that there are 2 key ligands or growth factors that control muscle size: myostatin, myostatin 1, we call it, and Myostatin 2 or Activin A. And we're the only ones that have specific blocking antibodies for those 2. And we are testing them together and individually.

好的。好吧，讓我先從後者開始，就肌肉保存而言。其他人也有相關的方法，但我們是唯一的人，我們是發現控制肌肉大小的2 個關鍵配體或生長因子的人：肌肉生長抑制素、肌肉生長抑制素1（我們稱之為肌肉生長抑制素1）和肌肉生長抑制素2 或激活素 A .我們是唯一擁有針對這兩種抗體的特異性阻斷抗體的公司。我們正在對它們進行一起和單獨測試。

And the reason why that's important is it's going to be a combination of both efficacy and safety that matters here. So we're going to see which approach does the best in terms of the muscle preservation in the face of the profound muscle loss that you can see with GLP-1 agonist treatment. But we're also going to see the safety profiles. And I think that, that's going to be so critical because safety is so important here.

這之所以重要，是因為它將是功效和安全性的結合。因此，我們將看看在面對 GLP-1 激動劑治療導致的嚴重肌肉流失時，哪種方法在保留肌肉方面效果最好。但我們也會看到安全概況。我認為，這將非常重要，因為安全在這裡非常重要。

Other people are just testing one of these agents alone. I believe, the myostatin and others are testing very broad approaches such as trying to block the receptors for these factors. The problem with the receptor blockade approach is that the receptors that are used by these factors are also used by over a dozen other ligands that have very diverse biologic functions. And you can easily imagine that by blocking so many diverse functions, you might end up having all sorts of safety issues which you're not going to want to be able to be dealing with in the setting of a treatment that's intended to optimize obesity and body weight loss and give benefit to the patients.

其他人只是單獨測試其中一種藥物。我相信，肌肉生長抑制素和其他藥物正在測試非常廣泛的方法，例如試圖阻斷這些因子的受體。受體阻斷方法的問題在於，這些因子所使用的受體也被十多個具有非常不同的生物功能的其他配體所使用。你可以很容易想像，透過阻止如此多的不同功能，你最終可能會遇到各種安全問題，而在旨在優化肥胖和肥胖的治療中，你不希望能夠處理這些問題。體重減輕，給患者帶來好處。

So our programs are very different in that we discovered the 2 key regulators, The 2 key growth factors. We have separate antibodies blocking them both. And we're evaluating them separately and together in the setting of GLP-1 receptor agonist, to see what gives us the best benefit vis-a-vis muscle preservation as well as safety profile.

因此，我們的計劃非常不同，因為我們發現了 2 個關鍵調節因子，2 個關鍵成長因子。我們有單獨的抗體來阻止它們。我們正在 GLP-1 受體激動劑的背景下單獨和一起評估它們，看看什麼給我們帶來相對於肌肉保存和安全性的最佳益處。

While we're doing that, as we said, we're initiating those trials this year, we are also developing unimolecular solutions. So whichever approach works best, we hope to have the possibility of having a tethered GLP-1, as you put it, associated with the right set of antibody molecules. So they will have the advantage of having a unimolecular solution that can provide all-in-one benefit in terms of providing, hopefully, the best convenience profile and potentially once-a-month dosing, together with providing not only the weight loss, the profound weight loss that one is seen with GLP-1 receptor agonist, but now complemented by providing muscle preservation but with the safest possible approach. So we think that we have the most unique program in terms of addressing all these possibilities. And we're very, very excited about these programs.

正如我們所說，我們在今年啟動這些試驗的同時，我們也在開發單分子解決方案。因此，無論哪種方法效果最好，我們都希望有可能將束縛的 GLP-1（如您所說的）與正確的抗體分子群相關聯。因此，他們將擁有單分子解決方案的優勢，該解決方案可以提供一體化的好處，希望能夠提供最佳的便利性和可能每月一次的劑量，同時不僅可以減輕體重，使用GLP-1 受體激動劑可以顯著減輕體重，但現在盡可能安全的方法提供肌肉保護來補充體重。因此，我們認為我們擁有解決所有這些可能性的最獨特的計劃。我們對這些計劃感到非常非常興奮。

Our next question comes from the line of Mohit Bansal with Wells Fargo.

我們的下一個問題來自富國銀行的莫希特·班薩爾 (Mohit Bansal)。

Thank you, Bob, for all your help over the years. Maybe one question for Marion. Can you just comment on the trends in the anti-VEGF market, underlying trends? I mean, is the market growing or you are growing fast, as fast as it's been in the past, or is it slowing down a little bit? And in that context, how do you see the outlook for high dose EYLEA plus EYLEA going forward, with the underlying demand out there?

謝謝你，鮑勃，多年來你的幫助。也許有一個問題要問馬里昂。能否簡單評論一下抗 VEGF 市場的趨勢、潛在趨勢？我的意思是，市場正在成長，或者你正在快速成長，與過去一樣快，還是成長速度有所放緩？在這種情況下，您如何看待高劑量 EYLEA 聯合 EYLEA 的未來前景以及潛在需求？

Sure, Mohit. So there is variation between quarters and years as it relates to anti-VEGF category growth. Overall, though, the category is healthy from a growth standpoint, unfortunately, based on the number of individuals with diabetes or diagnosed with diabetes. On a brighter note, aging population is good. So overall, we see it as healthy category growth. But there is variability. And as an example, there has been some decline by a couple of points between last year and this year overall.

當然，莫希特。因此，季度和年份之間存在差異，因為它與抗 VEGF 類別的成長有關。但不幸的是，總體而言，從患有糖尿病或被診斷出患有糖尿病的人數來看，從成長的角度來看，該類別是健康的。從好的方面來看，人口老化是件好事。總的來說，我們認為這是健康的品類成長。但存在可變性。舉個例子，去年和今年相比，整體下降了幾個百分點。

Our next question comes from the line of Christopher Raymond with Piper Sandler.

我們的下一個問題來自克里斯托弗·雷蒙德和派珀·桑德勒的對話。

Maybe just another EYLEA question. I know you guys don't want to get sort of too granular on your pricing strategy, but we've been struck that, even with the 2-milligram format revenue contracting in the last couple of quarters, our checks show that it's really not a market share issue. In fact, share of that format remains up around an all-time high. So one would think that, that's been price erosion that's been driving that.

也許只是 EYLEA 的另一個問題。我知道你們不想太詳細地制定定價策略，但我們感到震驚的是，即使過去幾個季度 2 毫克格式的收入出現收縮，我們的檢查顯示，這確實不是市場份額問題。事實上，這種格式的份額仍然保持在歷史最高水準。所以人們會認為，這是價格侵蝕造成的。

Just understand this may be a strategy to maximize the HD launch, in broad stroke, can you talk about what we should be expecting in 2024? Do you expect further price erosion for that 2-milligram format? Or have things sort of leveled off?

只是理解這可能是最大化高清發布的策略，概括地說，您能談談我們在 2024 年應該期待什麼嗎？您預計 2 毫克規格的價格會進一步下跌嗎？或者事情已經趨於平穩了嗎？

Yes. I'm not sure we want Marion to get into the details of our strategies, pricing, rebates, things like that. But we can say, Marion, you could add thoughts, that we view it as a very competitive marketplace. There has been some price erosion on some of the products in the marketplace. We're starting at a new point with EYLEA HD. We think we priced it well. It was received well. It was intended to match on a yearly basis. And so we think the actual price point was fine.

是的。我不確定我們是否希望馬里昂了解我們的策略、定價、回饋等細節。但我們可以說，馬里昂，你可以補充一些想法，我們認為這是一個競爭非常激烈的市場。市場上一些產品的價格出現了一些下滑。我們以 EYLEA HD 為新起點。我們認為我們的定價很好。反響很好。它的目的是每年進行一次配對。所以我們認為實際的價格點還不錯。

I don't know if Marion wants to add anything at all but we don't like to comment specifically on those competitive dynamics.

我不知道馬里昂是否想添加任何內容，但我們不想具體評論這些競爭動態。

Yes. Chris, really nothing in everyone to add to that.

是的。克里斯，每個人都沒有什麼可以補充的。

Our next question comes from the line of Colin Bristow with UBS.

我們的下一個問題來自瑞銀集團的 Colin Bristow。

And all the best in the future, Bob. Maybe a couple more on the muscle sparing myostatin program. I'm curious, George, what are your thoughts around the potential concerns of myostatin targeting, increases or preserves muscle volume but the muscle is less functional. And then any thoughts on the regulatory pathway that you would utilize for these muscle-sparing assets?

鮑勃，未來一切順利。也許還有更多關於肌肉保護肌生長抑制素計畫的內容。我很好奇，喬治，你對肌肉生長抑制素靶向、增加或保持肌肉體積但肌肉功能較差的潛在問題有何看法。那麼您對這些肌肉保護資產的監管途徑有什麼想法嗎？

Regulatory. Okay. So first of all, we've done extensive work in preclinical models. And these antibodies have already been in humans. We believe that our studies are actually showing that this muscle is functional and certainly very important from both the metabolic and energy expenditure point of view. So, so far, those studies are very supportive of this whole approach.

監管。好的。首先，我們在臨床前模型方面做了大量工作。而這些抗體已經存在於人類體內。我們相信，我們的研究實際上表明這塊肌肉是有功能的，並且從代謝和能量消耗的角度來看當然非常重要。因此，到目前為止，這些研究非常支持整個方法。

I should also say there's a variety of regulatory pathways that we're pursuing here. Obviously, the easiest, which would come from the possible results that we're seeing in the animal studies, is if there's incrementally more weight loss, that might suffice as a regulatory strategy. Alternatively, if it's just the quality of the white loss, then we would have to show functional outcomes in terms of strength and so forth and so on.

我還應該說，我們正在尋求多種監管途徑。顯然，最簡單的方法（來自我們在動物研究中看到的可能結果）是，如果體重減輕逐漸增加，這可能足以作為一種監管策略。或者，如果只是白色損失的質量，那麼我們就必須在強度等方面顯示功能結果。

So those are still early in the thinking. We have to see from these initial studies. But as I said, if we simply see increased weight loss, that would be the simplest way forward. And then you have more weight loss but better body composition data, and may also -- may be better metabolic benefits, which we also see in muscle, which could also provide additional pass-through approval. So it depends on those results that we're going to get from the initial studies.

所以這些還處於早期思考階段。我們必須從這些初步研究中看到。但正如我所說，如果我們只是看到體重減輕，那將是最簡單的前進之路。然後你會得到更多的體重減輕，但更好的身體組成數據，而且可能還有更好的代謝益處，我們在肌肉中也看到了這一點，這也可以提供額外的傳遞批准。因此，這取決於我們將從初步研究中獲得的結果。

I should also mention, in terms of additional programs that we have, obesity. I mean, these are things that are here and now that we're doing these clinical trials and we hope to be getting results over the course of the next year, 1.5 years that could really inform in terms of all these questions that you have and really validate that there's real promise here. But remember, we're doing a lot of other things as well in obesity that are in earlier stages.

我還應該提到，就我們的其他計劃而言，肥胖。我的意思是，這些都是現在我們正在進行的臨床試驗，我們希望在明年（1.5 年）內得到結果，這些結果可以真正解決您所遇到的所有這些問題，真正驗證這裡有真正的希望。但請記住，我們還在早期階段的肥胖問題上做了很多其他的事情。

So for example, as you probably know, we discovered a brand-new promising target in obesity using our Regeneron Genetics Center, the largest big data set on the planet in terms of human sequence linked to electronic health records, and identified, in some ways, one of the most exciting new targets in obesity that's been ever discovered. And we have a variety, it's called GPR75, it was published in a prominent paper in Science about a year or so ago. And we have a variety of promising and not-that-far-away approaches from the clinic in terms of blocking this target for weight loss. And I think that we presented at JPMorgan early preclinical data using siRNA approaches that look very exciting.

例如，正如您可能知道的那樣，我們利用我們的再生元遺傳學中心發現了一個全新的有希望的肥胖目標，該中心是地球上最大的與電子健康記錄相關的人類序列大數據集，並以某種方式確定了這一目標，是迄今為止發現的最令人興奮的肥胖新目標之一。我們有一個品種，叫做 GPR75，大約一年前發表在《科學》雜誌上的一篇著名論文中。在阻止這個減肥目標方面，我們有多種有希望且距離臨床不遠的方法。我認為我們在摩根大通展示了使用 siRNA 方法的早期臨床前數據，看起來非常令人興奮。

I should also mention that, in terms of smaller programs and so forth, we have things like a very exciting leptin receptor-activating antibody that have had very promising human data as well. So there's a lot of things going on but I think the muscle preservation program and how it goes forward is going to be very interesting to look at over the next year, 1.5 years.

我還應該提到，就較小的項目等而言，我們擁有諸如非常令人興奮的瘦素受體激活抗體之類的東西，它也有非常有希望的人類數據。因此，有很多事情正在發生，但我認為肌肉保存計劃及其進展如何在明年（1.5 年）內將會非常有趣。

Our next question comes from the line of Evan Seigerman with BMO Capital Markets.

我們的下一個問題來自 BMO 資本市場的 Evan Seigerman。

I have one final question for Bob. So Bob, you've done an outstanding job managing the financials of the business and helping drive shareholder returns over the past decade. Looking ahead, how do you believe Regeneron can best use its rapidly growing cash balance to further drive investor returns in the next decade of Regeneron? And thanks for everything, Bob.

我有最後一個問題要問鮑伯。鮑勃，在過去的十年裡，您在管理企業財務和幫助提高股東回報方面做得非常出色。展望未來，您認為再生元如何最好地利用其快速增長的現金餘額來進一步推動再生元未來十年的投資者回報？感謝你所做的一切，鮑伯。

Evan, thanks for the question, and thanks for the video that we were able to show at my retirement party. It was great.

埃文，謝謝你的提問，也感謝我們能夠在我的退休聚會上播放的影片。太好了。

On that question, George just laid out earlier today, we have so many opportunities with regards to our kind of research and development. And again, I mean I'm going to hand the mantle over to Chris but his #1 priority within capital allocation is to make sure that, that is kind of fully funded. Len and George do a great job with regards to making sure what we're bringing into the clinic as opportunities, and they're going to continue to do that, and there's just a lot coming, particularly when I said kind of 8 to 10 INDs.

關於這個問題，喬治今天早些時候剛剛指出，我們在研究和開發方面有很多機會。再說一遍，我的意思是我要把這個職責交給克里斯，但他在資本配置方面的第一要務是確保資金充足。萊恩和喬治在確保我們將什麼作為機會帶入診所方面做得很好，他們將繼續這樣做，而且還會有很多事情，特別是當我說 8 到 10 種時IND。

Proud on buybacks. Maybe I've kind of circled the victory too much on that with regards to how much we bought back and at what price. But we have a good methodology here that Chris is ingrained with, and he'll continue to do that. And with regards to business development, I mean, just because we can doesn't mean we're going to force something. It has to be right, it has to be a franchise, has to be modalities. You've heard George mention that has to be kind of incremental to what we currently have in the clinic here with regards to RGC and the targets we develop, and all of that. So we will remain prudent on that. Continue to be proud of the free cash flow that we're generating. And I trust that Chris, George, Len and the Board will optimize it and put it to great use.

為回購感到自豪。也許我在關於我們回購了多少以及以什麼價格回購的問題上過多地圍繞著勝利。但我們這裡有一個克里斯根深蒂固的良好方法論，他將繼續這樣做。關於業務發展，我的意思是，僅僅因為我們可以，並不代表我們會強迫某些事情。它必須是正確的，必須是特許經營權，必須是模式。你聽過 George 提到，在 RGC 和我們設定的目標等方面，這必須是我們目前診所的增量。因此我們對此將保持謹慎態度。繼續為我們產生的自由現金流感到自豪。我相信克里斯、喬治、萊恩和董事會將優化它並充分利用它。

Our next question comes from the line of Salveen Richter with Goldman Sachs.

我們的下一個問題來自 Salveen Richter 與高盛的對話。

And Bob, you truly will be missed, and enjoy the next stage of life here. With regard to your GA program, can you outline what's contributing to your confidence in the systemic approach here, and what data you've seen to support it given the move from animal models to Phase III?

鮑勃，我們真的會想念你，並在這裡享受下一階段的生活。關於您的 GA 計劃，您能否概述一下是什麼讓您對這裡的系統方法充滿信心，以及在從動物模型轉向 III 期的過程中您看到了哪些數據來支持它？

Okay, geographic atrophy. So basically, the excitement is that, as we show data from our combination approach, we believe that we have the most effective way of blocking the body's C5 activity. The C5, which is active in the eye, is essentially all coming from the liver. And we've shown now in our PNH studies, when we revealed the data from the first portion of our Phase III program, that it looked like we had the best-in-class activity in terms of decreasing the C5 activity.

好吧，地理萎縮。所以基本上，令人興奮的是，當我們展示我們的組合方法的數據時，我們相信我們擁有阻斷人體 C5 活性的最有效方法。在眼睛中活躍的 C5 基本上全部來自肝臟。現在，當我們公佈 III 期計畫第一部分的數據時，我們在 PNH 研究中表明，我們在降低 C5 活性方面​​似乎擁有一流的活性。

So if you block it at the source, then you don't have to block it in the eye. And if you block it at the source, then you don't suffer from all the concerns and side effects and so forth that you have from having to block it in the eye. So you block it where it's coming from, then you don't have to treat local in the eye. You can avoid the local side effects.

所以如果你從源頭堵住了，那就不用從眼睛裡堵住了。如果您從源頭阻止它，那麼您就不會遭受因必須在眼睛中阻止它而產生的所有擔憂和副作用等問題。所以你把它從它來的地方擋住，然後你就不必治療眼睛的局部了。您可以避免局部副作用。

The concern with systemic blockade is it comes with increased risks of infections and so forth. So we will have to come up with a strategy, which we're working on, to try to mitigate that in the elderly population that suffers from GA. We believe that we may need for that an approach to identify the patients who might be at risk in those settings. Because we certainly know that, for example, patients with PNH and myasthenia gravis who are immunosuppressed and so forth, not only with our agent but certainly with this whole class of agents, can suffer from serious systemic infections when you block C5.

對系統性封鎖的擔憂是它會增加感染等風險。因此，我們必須制定一項我們正在研究的策略，試圖減輕患有遺傳性遺傳疾病的老年人口的情況。我們認為，我們可能需要一種方法來識別在這些環境中可能面臨風險的患者。因為我們當然知道，例如，免疫抑制的 PNH 和重症肌無力等患者，不僅使用我們的藥物，而且肯定使用整類藥物，當您阻斷 C5 時，可能會遭受嚴重的全身感染。

So we are coming up with a way to mitigate that, in part by probably selecting out the patients who are at the highest risk. But in terms of efficacy, the fact that you block it at the source should make it much more effective than trying to block it indirectly in the eye while avoiding all of the serious local side affects you can get in the eye, including this horrific retinal vasculitis, which is associated with sudden and permanent blindness.

因此，我們正在想出一種方法來緩解這種情況，部分方法是選擇風險最高的患者。但就功效而言，從源頭阻斷它的事實應該比試圖在眼睛中間接阻斷它更有效，同時避免可能對眼睛產生的所有嚴重的局部副作用，包括這種可怕的視網膜血管炎，與突然和永久性失明有關。

Thanks, George. I think we have time for 2 more questions.

謝謝，喬治。我想我們還有時間再問兩個問題。

Our next question comes from the line of David Risinger with Leerink Partners.

我們的下一個問題來自 Leerink Partners 的 David Risinger。

Yes. And first, I wanted to offer my congrats as well and best wishes to you, both Bob and Chris. So I have a commercial question on linvoseltamab, please. It's clearly generated best-in-class results and a more attractive profile for patients. But Regeneron has to displace the incumbents. So could you discuss your plans to convert prescribers to linvoseltamab?

是的。首先，我也想向鮑伯和克里斯表示祝賀和最美好的祝福。我有一個關於 linvoseltamab 的商業問題。它顯然產生了一流的結果，並且對患者更具吸引力。但再生元必須取代現有企業。那麼您能否討論一下將處方者轉為林沃司他單抗的計劃？

Thank you, David. I'm anxious to answer but Len will, of course, go first.

謝謝你，大衛。我很想回答，但萊恩當然會先回答。

No, I just wanted to give a little history, David. You actually [ramp]. You may even have asked the exact question, I'm not sure, when we were launching EYLEA and we had to displace Lucentis by the behemoth Roche. There are some lessons in there that it can be done with starting with a really good molecule, as you described, one that is potentially be best-in-class and then strong execution at the commercial front. We've done it. We're not afraid of the 800-pound gorilla. We hope to put that gorilla on perhaps a weight loss program and get in there and show them what we can do.

不，我只是想講一些歷史，大衛。你實際上[斜坡]。我不確定，當我們推出 EYLEA 時，您甚至可能問過確切的問題，我們不得不用龐然大物羅氏取代 Lucentis。正如您所描述的，其中有一些教訓可以從一個非常好的分子開始來完成，該分子可能是同類中最好的，然後在商業方面具有強大的執行力。我們已經做到了。我們不怕800磅重的大猩猩。我們希望讓那隻大猩猩參加一個減肥計劃，然後向他們展示我們能做什麼。

Marion, any comments? I just want to put that historical perspective out there.

馬里昂，有什麼意見嗎？我只是想把歷史觀點放在那裡。

Thank you, David, for the question. And I'm going to be a bit redundant, so I'll be short. But my comment was to say it always starts with the best-in-class molecule. It's about the science. And certainly, you've seen us across therapeutic areas launch into competitive categories, both in the anti-VEGF category and then, more recently, bringing great products into the marketplace. So we do look forward to this opportunity. And it fits quite beautifully with our oncology team, our onc will be onc/hem team. And certainly, we will be very ready for that launch and look forward to helping patients with linvo.

謝謝大衛提出問題。我會有點多餘，所以我會簡短地說。但我的評論是，它總是從一流的分子開始。這是關於科學的。當然，您已經看到我們在各個治療領域推出了競爭性類別，包括抗 VEGF 類別，以及最近將出色的產品推向市場。所以我們非常期待這個機會。它非常適合我們的腫瘤團隊，我們的 onc 將是 onc/hem 團隊。當然，我們將為此次發布做好充分準備，並期待為 linvo 患者提供協助。

Okay. Thanks, Len and Marion. Shannon, last question, please.

好的。謝謝，萊恩和馬里昂。香農，請提出最後一個問題。

Our last question comes from the line of Carter Gould with Barclays.

我們的最後一個問題來自卡特·古爾德與巴克萊銀行的對話。

I'll echo all the prior comments about Bob, and best of luck. Maybe just on the 2seventy deal, Len and George. How should we think about this? Was this more about sort of protecting the rights of the assets that you already kind of partnered on or really around sort of getting access to that manufacturing facility? And does that have implications then as we think about your business development going forward and maybe change kind of your willingness to move further down that path of cellular therapies?

我會回應之前關於鮑勃的所有評論，祝你好運。也許就在 270 交易上，萊恩和喬治。我們該如何思考這個問題？這更多的是為了保護您已經合作的資產的權利，還是真正為了獲得該製造設施的使用權？當我們考慮您未來的業務發展並可能改變您進一步沿著細胞療法的道路前進的意願時，這是否會產生影響？

I'll let George comment on the scientific rationale, which drives pretty much everything we do. Just to mention from a business development point of view, we have been a long-standing partner with 2seventy when they were still part of bluebird. We've invested in them, both in equity and, frankly, in development. So this was something that was well known.

我會讓喬治評論科學原理，它幾乎推動了我們所做的一切。從業務發展的角度來說，當 2seventy 還是藍鳥的一部分時，我們就已經是他們的長期合作夥伴了。我們對它們進行了投資，包括股權投資，坦白說，還有發展投資。所以這是眾所周知的事。

George can comment how we see this fitting in?

喬治可以評論一下我們如何看待這種契合嗎？

Yes. We're excited about the existing programs. But what we're even more excited about is as we know that the history of many diseases but cancer in particular, is about combination approaches. And thus far, even in the setting of this collaboration, the CAR-T space has been separate from the biologics space. And even though we were working together as separate companies, it was a little harder to really move forward in an expedited fashion. The incredible opportunities that I believe that we have to combine what we think is the largest and most exciting portfolio of biologics in immunotherapy, together with cell therapy approaches.

是的。我們對現有計劃感到興奮。但更令我們興奮的是，我們知道許多疾病（尤其是癌症）的歷史都是關於組合方法的。到目前為止，即使在本次合作的背景下，CAR-T 領域也與生物製品領域是分開的。儘管我們作為獨立的公司一起工作，但要真正快速推進還是有點困難。我相信，我們必須將免疫療法領域中最大、最令人興奮的生物製劑組合與細胞療法結合起來，這是令人難以置信的機會。

Nobody else has really tried that. Nobody else has really led that. Now that we're really together all in with our new selected colleagues from 2seventy and their capabilities, we believe that we will now have the first opportunity to really try this new set of combination approaches against cancer. That is, combining our large portfolio of biologics in the immunotherapy space with their cell therapy capabilities and expertise, that brings a whole new level of combinations to the immunotherapy field. We believe we will be alone in that capability until somebody else tries to copy us and do what we're doing here. And that's what we're really excited about, in addition to just moving forward the existing cell therapy programs that we've been working on them for 5 years or more.

沒有其他人真正嘗試過。沒有其他人真正領導過這一點。現在，我們真正與 2seventy 中新選出的同事及其能力融為一體，我們相信，我們現在將有第一次機會真正嘗試這套新的抗癌組合方法。也就是說，將我們在免疫治療領域的大量生物製劑與其細胞治療能力和專業知識相結合，為免疫治療領域帶來了全新水平的組合。我們相信，在其他人試圖複製我們並做我們在這裡所做的事情之前，我們將是唯一有這種能力的人。這就是我們真正感到興奮的事情，此外我們繼續推進現有的細胞治療項目，我們已經研究了 5 年或更長時間。

All right. Thanks, Len and George, and thanks to everyone who dialed-in today for your interest in Regeneron. We apologize to those remaining in the queue that we did not have a chance to hear from. As always, the Investor Relations team here at Regeneron is available to answer any remaining questions you may have. Thank you once again, and have a great day.

好的。謝謝萊恩和喬治，也感謝今天撥通電話的所有人對再生元的興趣。我們向那些留在隊列中但沒有機會收到訊息的人表示歉意。像往常一樣，再生元的投資者關係團隊可以回答您可能遇到的任何剩餘問題。再次感謝您，祝您有美好的一天。

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。