雷傑納榮製藥 (REGN) 2023 Q1 法說會逐字稿

Welcome to the Regeneron Pharmaceuticals First Quarter 2023 Earnings Conference Call. My name is Josh, and I will be your operator for today's call. (Operator Instructions) Please note that this conference is being recorded.

歡迎來到 Regeneron Pharmaceuticals 2023 年第一季度收益電話會議。我叫喬什，我將擔任今天電話會議的接線員。 （操作員說明）請注意，正在錄製此會議。

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

我現在將把電話轉給投資者關係副總裁 Ryan Crowe。你可以開始了。

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

謝謝你，喬希。早上好，下午好，晚上好，所有在世界各地收聽的人。感謝您對 Regeneron 的關注，歡迎參加我們 2023 年第一季度的收益電話會議。電話會議結束後不久，將在我們的投資者關係網站上提供該網絡廣播的存檔。

Joining me today are Dr. Leonard Schleifer, Co-Founder, President and Chief Executive Officer; Dr. George Yancopoulos, Co-Founder, President and Chief Scientific Officer; Marion McCourt, Executive Vice President and Head of Commercial; and Bob Landry, Executive Vice President and Chief Financial Officer. After our prepared remarks, we will open the call for Q&A.

今天加入我的是聯合創始人、總裁兼首席執行官 Leonard Schleifer 博士； George Yancopoulos 博士，聯合創始人、總裁兼首席科學官；執行副總裁兼商務主管 Marion McCourt；執行副總裁兼首席財務官 Bob Landry。在我們準備好發言後，我們將打開問答環節。

I would 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, revenue diversification, 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，在今天的電話會議上發表的言論可能包括有關再生元的前瞻性陳述。此類陳述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、收入多元化、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、知識產權財產、未決訴訟和其他訴訟以及競爭。

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-Q for the quarterly period ended March 31, 2023, which was filed with the SEC this morning. Regeneron does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

每份前瞻性陳述都受到風險和不確定性的影響，這些風險和不確定性可能導致實際結果和事件與該陳述中預測的結果和事件存在重大差異。在再生元向美國證券交易委員會提交的文件中可以找到對這些風險和其他重大風險的更完整描述，包括今天上午向美國證券交易委員會提交的截至 2023 年 3 月 31 日的季度 10-Q 表。 Regeneron 不承擔更新任何前瞻性陳述的任何義務，無論是由於新信息、未來事件或其他原因。

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

此外，請注意，今天的電話會議將討論 GAAP 和非 GAAP 指標。有關我們使用非 GAAP 財務措施以及這些措施與 GAAP 的對賬信息，請參閱我們的財務業績新聞稿和我們的公司介紹，可在我們的網站上訪問。一旦我們的通話結束，Bob Landry 和 IR 團隊將可以回答進一步的問題。

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

有了這個，讓我把電話轉給我們的總裁兼首席執行官 Len Schleifer 博士。萊恩？

Thank you, Ryan, and thank you to everyone joining today's call. Following our significant achievements in 2022, Regeneron is off to a good start in 2023, highlighted by important regulatory and pipeline advances, commercial execution and prudent capital allocation, all of which position better the company to deliver sustainable long-term growth and shareholder value over time.

謝謝你，Ryan，也感謝大家參加今天的電話會議。繼我們在 2022 年取得重大成就之後，再生元在 2023 年開局良好，突出體現在重要的監管和管道進展、商業執行和審慎的資本配置，所有這些都使公司能夠更好地實現可持續的長期增長和股東價值時間。

George, Marion and Bob will cover details of our first quarter performance in a few moments. In the meantime, I would provide an update on our goal of continuing to grow our business while simultaneously diversifying our revenue and earnings streams, which is part of our long-term vision for Regeneron.

稍後，George、Marion 和 Bob 將詳細介紹我們第一季度的表現。與此同時，我將提供有關我們繼續發展業務同時實現收入和盈利來源多元化的目標的最新信息，這是我們對 Regeneron 的長期願景的一部分。

We have made substantial progress toward achieving that goal. Over the past 4 years, while total revenues have nearly doubled, EYLEA accounted for only 57% of total revenues in the first quarter of 2023 compared to 88% of total revenues for the year 2019. Driven primarily by the growth of Dupixent, our Sanofi collaboration accounted for 25% of our total revenues in the first quarter of 2023 compared to only 6% of our total revenues in 2019. We expect this trend of revenue growth, along with diversification to continue.

我們在實現該目標方面取得了實質性進展。在過去 4 年中，雖然總收入幾乎翻了一番，但 EYLEA 僅佔 2023 年第一季度總收入的 57%，而 2019 年佔總收入的 88%。主要受 Dupixent 增長的推動，我們的賽諾菲2023 年第一季度，合作占我們總收入的 25%，而 2019 年僅占我們總收入的 6%。我們預計這種收入增長趨勢以及多元化將繼續下去。

For example, assuming the approval and successful launch of aflibercept 8 milligrams, which has a June 27 PDUFA date, EYLEA 2 milligrams is expected to become a smaller share of our revenues, while aflibercept 8 milligrams is expected to contribute to overall revenue growth. In addition, Dupixent remains in a high-growth mode, with global net product sales up 40% on a constant currency basis compared to the prior year quarter, driven by growth across all 5 approved indications.

例如，假設批准並成功推出 aflibercept 8 毫克（其 PDUFA 日期為 6 月 27 日），EYLEA 2 毫克預計將成為我們收入的較小份額，而 aflibercept 8 毫克預計將有助於整體收入增長。此外，Dupixent 仍處於高增長模式，在所有 5 個獲批適應症的增長推動下，全球產品淨銷售額按固定匯率計算較上年同期增長 40%。

We believe the positive Phase III results for Dupixent in the subpopulation of COPD patients with evidence of type 2 inflammation, as well as the promising results for our IL-33 antibody itepekimab in former smokers represent additional significant opportunities to accelerate revenue growth as well as diversification.

我們相信 Dupixent 在有 2 型炎症證據的 COPD 患者亞群中的積極 III 期結果，以及我們的 IL-33 抗體 itepekimab 在前吸煙者中的有希望的結果代表了加速收入增長和多樣化的額外重要機會.

Our oncology portfolio is also starting to make a meaningful contribution to our top line, with last year's acquisition of full global rights to Libtayo and the recent launch of Libtayo in combination with chemotherapy in advanced non-small cell lung cancer. Moreover, we believe that fianlimab, our LAG-3 antibody, in combination with Libtayo, has the potential to become an important therapy in both melanoma and non-small cell lung cancer, where we have already advanced to pivotal studies.

我們的腫瘤產品組合也開始為我們的收入做出有意義的貢獻，去年收購了 Libtayo 的全部全球權利，最近推出了 Libtayo 聯合化療治療晚期非小細胞肺癌。此外，我們相信，我們的 LAG-3 抗體 fianlimab 與 Libtayo 聯合使用，有可能成為黑色素瘤和非小細胞肺癌的重要療法，我們已經在這方面進行了關鍵研究。

We are also quite excited about the emerging clinical profile for linvoseltamab, our BCMAxCD3 bispecific. Updated data for which will be presented at the upcoming ASCO Annual Meeting. We remain on track to submit a BLA seeking accelerated approval in late-stage myeloma later this year.

我們也對我們的 BCMAxCD3 雙特異性 linvoseltamab 的新興臨床概況感到非常興奮。更新後的數據將在即將召開的 ASCO 年會上公佈。我們仍有望在今年晚些時候提交一份 BLA，尋求加速批准用於晚期骨髓瘤。

We continue to invest in our research and development engine and expect it will deliver new differentiated medicines that will drive organic growth over time. Our broad development pipeline of nearly 3 dozen programs spans many different therapeutic areas and modalities, notably: Our co-stimulatory bispecifics in cancer; our early pipeline in cardiovascular and metabolic diseases; as well as our collaborations with Alnylam, Intellia, Decibel and others are expected to drive medium- and long-term revenue growth, profitability and diversification.

我們繼續投資於我們的研發引擎，並期望它將提供新的差異化藥物，隨著時間的推移推動有機增長。我們近 3 打項目的廣泛開發管道跨越許多不同的治療領域和方式，特別是：我們在癌症中的共刺激雙特異性藥物；我們在心血管和代謝疾病方面的早期管道；以及我們與 Alnylam、Intellia、Decibel 和其他公司的合作預計將推動中長期收入增長、盈利能力和多元化。

Before handing over to George, I'd like to take a moment to recognize the contributions that Dr. Roy Vagelos has made to Regeneron over the nearly 3 decades that he has served as our Board Chair. Over the years, he has provided invaluable guidance and he continues to inspire us as we work to turn world-class science into medicines. Roy will retire from the Board after his current term ends next month. At that time, in addition to our current roles in the company, George and I will be appointed by the Board to serve as co-Chairs, and Christine Poon, a member of Regeneron's Board since 2010, will be appointed as the Board's Lead Independent Director.

在交給 George 之前，我想花點時間來表彰 Roy Vagelos 博士在擔任我們董事會主席的近 3 年中為 Regeneron 做出的貢獻。多年來，他提供了寶貴的指導，並在我們努力將世界一流的科學轉化為藥物的過程中繼續激勵著我們。 Roy 將在下個月任期結束後從董事會退休。屆時，除了我們目前在公司的職位外，喬治和我將被董事會任命為聯席主席，自 2010 年以來一直擔任再生元董事會成員的 Christine Poon 將被任命為董事會首席獨立董事導演。

With that, let me turn the call over to George.

有了這個，讓我把電話轉給喬治。

Thank you, Len. The first quarter of 2023 delivered multiple significant milestones for Regeneron and for our collaborations, from the positive Dupixent Phase III COPD data to progress in our oncology pipeline, as well as exciting new landmarks from our genetic medicines programs.

謝謝你，萊恩。 2023 年第一季度為 Regeneron 和我們的合作帶來了多個重要的里程碑，從積極的 Dupixent III 期 COPD 數據到我們腫瘤管線的進展，以及我們基因藥物項目令人興奮的新里程碑。

Starting with Dupixent. In March, together with our Sanofi collaborators, we announced that Dupixent was the first immune mechanism of action treatment to produce statistically significant and clinically meaningful results in a Phase III trial for COPD in over a decade. Our BOREAS trial enrolled COPD patients with moderate to severe disease and evidence of type 2 inflammation.

從 Dupixent 開始。 3 月，我們與我們的賽諾菲合作者一起宣布，Dupixent 是十多年來第一個在 COPD III 期試驗中產生具有統計學意義和臨床意義的治療免疫機制。我們的 BOREAS 試驗招募了患有中度至重度疾病和 2 型炎症證據的 COPD 患者。

Dupixent-treated patients demonstrated a clinically meaningful 30% reduction in exacerbations, a significant improvement in lung function as well as quality of life benefits: An impressive trifecta in a potential paradigm-changing treatment for this deadly disease. We are looking forward to presenting the detailed BOREAS results in a late-breaking presentation at the upcoming American Thoracic Society Meeting later this month. We also plan to discuss these exciting results with regulatory authorities and expect to report results mid next year for the replicate Phase III NOTUS study.

Dupixent 治療的患者表現出具有臨床意義的 30% 的惡化減少、肺功能的顯著改善以及生活質量的益處：在這種致命疾病的潛在範式改變治療中令人印象深刻的三重奏。我們期待著在本月晚些時候即將召開的美國胸科學會會議上以最新的突破性報告展示詳細的 BOREAS 結果。我們還計劃與監管機構討論這些令人興奮的結果，並期望在明年年中報告複製 III 期 NOTUS 研究的結果。

I would remind you that we are also trying to address an overlapping COPD population with our IL-33 antibody, which is in Phase III studies based on positive Phase II proof-of-concept data. This approach is further supported by genetic analysis from our Regeneron Genetics Center, which demonstrated association of loss of function in interleukin-33 with reduced COPD risk. Similar genetic analysis supported the role for a Dupixent benefit in COPD.

我想提醒您，我們也在嘗試用我們的 IL-33 抗體解決重疊的 COPD 人群，該抗體正處於基於陽性 II 期概念驗證數據的 III 期研究中。我們的 Regeneron 遺傳學中心的遺傳分析進一步支持了這種方法，該分析表明 IL-33 功能喪失與 COPD 風險降低有關。類似的遺傳分析支持 Dupixent 在 COPD 中的作用。

The BOREAS COPD data indicates that Dupixent can help even more patients beyond the 5 current FDA-approved indications and diseases caused or exacerbated by type 2 inflammation, including atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis and prurigo nodularis. We are also expecting an FDA decision for Dupixent for chronic spontaneous urticaria on October 22, 2023, and we are continuing to tailor Dupixent development to patients with other type 2 inflammatory diseases, most likely to be responsive to this method.

BOREAS COPD 數據表明，除 FDA 目前批准的 5 種適應症和由 2 型炎症引起或加重的疾病外，Dupixent 還可以幫助更多患者，包括特應性皮炎、哮喘、慢性鼻竇炎伴鼻息肉、嗜酸性粒細胞性食管炎和結節性癢疹。我們還期待 FDA 於 2023 年 10 月 22 日對 Dupixent 做出治療慢性自發性蕁麻疹的決定，我們將繼續為患有其他 2 型炎症性疾病的患者定制 Dupixent 開發，這些患者最有可能對這種方法有反應。

Moving to oncology. With the progress of our late and early stage pipeline, we are looking forward to several important milestones this year. Starting with Libtayo. In addition to expanded use in lung cancer, Libtayo was recently added to the NCCN guidelines for neoadjuvant treatment of CSCC. The Libtayo U.S. label was also recently updated with more mature CSCC and BCC data, supporting its differentiated clinical profile in these tumor settings and satisfying all post-marketing commitments that require full approval in these indications.

轉向腫瘤學。隨著我們後期和早期管道的進展，我們期待著今年的幾個重要里程碑。從 Libtayo 開始。除了擴大在肺癌中的應用外，Libtayo 最近還被添加到 NCCN 指南中以用於 CSCC 的新輔助治療。 Libtayo 美國標籤最近也更新了更成熟的 CSCC 和 BCC 數據，支持其在這些腫瘤環境中的差異化臨床特徵，並滿足所有需要在這些適應症中獲得完全批准的上市後承諾。

Regarding our exciting new combinations with Libtayo. Starting with fianlimab, our LAG-3 antibodies, for which we are planning a broad pivotal program spanning several cancer indications. These efforts were triggered by our robust and confirmed data in first-line metastatic melanoma patients, which will be presented in further detail at ASCO, suggesting that the fianlimab-Libtayo combination could produce about double the response rates with longer progression-free survival, the anti-PD monotherapy standard. Based on this, we have already initiated pivotal trials in metastatic and adjuvant melanoma, and we will start a study in perioperative melanoma in the second half of the year. In addition, based on promising data in small patient cohorts, we started a seamless Phase II/III pivotal study for treatment of metastatic non-small cell lung cancer, and we will soon start a Phase II study in the perioperative setting.

關於我們與 Libtayo 的激動人心的新組合。從我們的 LAG-3 抗體 fianlimab 開始，我們正在為此計劃一項涵蓋多種癌症適應症的廣泛關鍵計劃。這些努力是由我們在一線轉移性黑色素瘤患者中獲得的可靠且確認的數據引發的，這些數據將在 ASCO 上進一步詳細介紹，這表明 fianlimab-Libtayo 組合可以產生大約兩倍的反應率和更長的無進展生存期，抗PD單藥治療標準。基於此，我們已經啟動了轉移性和輔助性黑色素瘤的關鍵試驗，我們將在下半年啟動圍手術期黑色素瘤的研究。此外，基於小患者隊列中有希望的數據，我們開始了一項無縫的 II/III 期轉移性非小細胞肺癌治療關鍵研究，我們將很快開始一項圍手術期的 II 期研究。

Next, the bispecifics for solid tumors, which are being investigated in combination with Libtayo. Earlier this year, ASCO's GU represented initial positive first-in-human data for our PSMAxCD28 costimulatory bispecific in combination with Libtayo in advanced prostate cancer, the tumor type considered immunologically cold and largely unresponsive to anti-PD-1 therapy alone. Over the next 12 months we plan to present updated PSMAxCD28 data in more patients, some of which will have been prophylactically treated with our anti-IL-6 receptor antibody, sarilumab, to potentially reduce the severity of immune-mediated side effects while maintaining or improving antitumor activity. Also during this time frame, we plan to present data in advanced ovarian cancer for both our MUC16xCD3 bispecific in our MUC16xCD28 costimulatory bispecific as well as data in several tumor types from our EGFRxCD28 costimulatory bispecific, or in combination with Libtayo.

接下來是實體瘤的雙特異性藥物，正在與 Libtayo 聯合研究。今年早些時候，ASCO 的 GU 代表了我們的 PSMAxCD28 共刺激雙特異性藥物與 Libtayo 聯合治療晚期前列腺癌的初步陽性首次人體數據，這種腫瘤類型被認為免疫冷，對單獨的抗 PD-1 療法基本上沒有反應。在接下來的 12 個月裡，我們計劃在更多患者中提供更新的 PSMAxCD28 數據，其中一些患者將接受我們的抗 IL-6 受體抗體 sarilumab 的預防性治療，以潛在地降低免疫介導的副作用的嚴重程度，同時維持或提高抗腫瘤活性。同樣在此時間範圍內，我們計劃在我們的 MUC16xCD28 共刺激雙特異性中展示我們的 MUC16xCD3 雙特異性的晚期卵巢癌數據，以及來自我們的 EGFRxCD28 共刺激雙特異性或與 Libtayo 組合的幾種腫瘤類型的數據。

Our hematology oncology pipeline continues to advance. In an oral presentation at the upcoming ASCO Annual Meeting, we will present updated data for linvoseltamab, our BCMAxCD3 bispecific tested in late-line multiple myeloma. We believe these data will show that linvoseltamab has the best-in-class potential with differentiated efficacy, safety and a favorable dosing schedule in the competitive environment of relapsed/refractory multiple myeloma treatment candidates. We remain on track for a regulatory submission in the United States in the second half of this year for linvoseltamab.

我們的血液腫瘤學管道繼續推進。在即將舉行的 ASCO 年會上的口頭報告中，我們將介紹 linvoseltamab 的最新數據，我們的 BCMAxCD3 雙特異性抗體在晚期多發性骨髓瘤中進行了測試。我們相信，這些數據將表明，在復發/難治性多發性骨髓瘤治療候選人的競爭環境中，林伏賽他單抗具有同類最佳的潛力，具有差異化的療效、安全性和有利的給藥方案。我們仍有望在今年下半年在美國提交 linvoseltamab 的監管申請。

For odronextamab, our CD20xCD3 bispecific, we are on track to complete U.S. and EU regulatory submissions for both relapsed or refractory follicular lymphoma and diffuse large B-cell lymphoma in the second half of this year. Odronextamab in late-line relapsed or refractory follicular lymphoma has a potential best-in-class efficacy profile, and our optimized step-up dosing regimen has improved our generic safety profile without impacting efficacy. Also, we have initiated a first-in-human study of our CD22xCD28 costimulatory bispecific in combination with odronextamab in relapsed/refractory DLBCL, which we hope could further improve upon the anticancer benefit for these patients.

對於我們的 CD20xCD3 雙特異性藥物 odronextamab，我們有望在今年下半年完成美國和歐盟針對複發或難治性濾泡性淋巴瘤和瀰漫性大 B 細胞淋巴瘤的監管提交。 Odronextamab 在晚期復發或難治性濾泡性淋巴瘤中具有潛在的同類最佳療效，我們優化的遞增劑量方案在不影響療效的情況下改善了我們的通用安全性。此外，我們已經啟動了我們的 CD22xCD28 共刺激雙特異性結合 odronextamab 治療復發/難治性 DLBCL 的首次人體研究，我們希望這可以進一步提高這些患者的抗癌益處。

Now to genetics medicines. Starting with our collaboration with Alnylam, and siRNA therapeutics. Just last week, we and Alnylam announced an important update for our Alnylam APP program in early onset Alzheimer's disease. For the first time, an RNAi therapeutic demonstrates sustained silencing of a pathological gene in the central nerve system in a clinical trial. In the earnings call this morning, our Alnylam collaborators provided additional details on these results. Our siRNA approach aims to prevent production of amyloid precursor protein as opposed to clearing existing amyloid plaques after they have already formed, providing a new way to potentially address Alzheimer's disease, which will still have a devastating impact on patients and their families even with the emergence of amyloid-clearing antibodies.

現在到遺傳藥物。從我們與 Alnylam 和 siRNA 療法的合作開始。就在上週，我們和 Alnylam 宣布了針對早發性阿爾茨海默病的 Alnylam APP 計劃的重要更新。 RNAi 療法首次在臨床試驗中證明了中樞神經系統病理基因的持續沉默。在今天上午的財報電話會議上，我們的 Alnyam 合作者提供了有關這些結果的更多詳細信息。我們的 siRNA 方法旨在防止澱粉樣蛋白前體蛋白的產生，而不是在現有的澱粉樣蛋白斑塊形成後清除它們，這提供了一種可能解決阿爾茨海默氏病的新方法，即使出現這種疾病仍將對患者及其家人造成毀滅性影響澱粉樣蛋白清除抗體。

Patients treated with single doses of ALN-APP experienced dose-dependent, rapid and sustained reduction of up to 90% in APP production as assessed by biomarkers in cerebrospinal fluid. The safety and tolerability profile with single dosing is encouraging so far. While the multi-dose Part B portion of the study is on partial clinical hold in the United States due to finding reserved in prior nonclinical chronic toxicology studies, Part B has already received regulatory approval to proceed in Canada, where the majority of the part A clinical trial patients had been enrolled.

接受單劑量 ALN-APP 治療的患者經歷了劑量依賴性、快速和持續的 APP 生產減少高達 90%，這是通過腦脊液中的生物標誌物評估的。到目前為止，單次給藥的安全性和耐受性情況令人鼓舞。由於先前的非臨床慢性毒理學研究中保留的發現，該研究的多劑量 B 部分部分在美國處於部分臨床暫停狀態，但 B 部分已獲得監管批准在加拿大進行，其中 A 部分的大部分已招募臨床試驗患者。

Detailed results from the study will be presented in an upcoming medical meeting. We are looking forward to advancing additional development candidates for the many other neurodegenerative diseases that currently have few or no therapeutic options such as other targets for Alzheimer's as well as for ALS or Lou Gehrig's disease, Parkinson's and Huntington's.

該研究的詳細結果將在即將召開的醫學會議上公佈。我們期待著為目前很少或沒有治療選擇的許多其他神經退行性疾病推進更多的開發候選藥物，例如阿爾茨海默氏症以及肌萎縮側索硬化或盧伽雷氏病、帕金森氏症和亨廷頓氏症的其他目標。

In addition to these exciting developments in central nervous system diseases, we are continuing our progress with liver targeted medicines, including our broad and multipronged approach to develop treatments for NASH, or nonalcoholic steatohepatitis. We're enrolling a Phase II study of ALN-HSD in NASH patients with genetic risk factors, continuing clinical development of ALN-PNP, and we are planning to progress additional more recently genetically validated NASH targets as well.

除了在中樞神經系統疾病方面取得這些令人振奮的進展外，我們還在繼續推進肝臟靶向藥物的研發，包括我們廣泛和多管齊下的方法來開發治療 NASH 或非酒精性脂肪性肝炎的方法。我們正在對具有遺傳風險因素的 NASH 患者進行 ALN-HSD 的 II 期研究，繼續進行 ALN-PNP 的臨床開發，我們還計劃推進更多最近經過基因驗證的 NASH 目標。

Finally, I would like to highlight our recently announced collaboration with Sonoma Biotherapeutics' discover, develop and commercialize regulatory T cell therapies for autoimmune and inflammatory diseases. This collaboration will bring together our industry-leading technologies for the discovery and characterization of fully human antibodies and T cell receptors, as well as our additional biologics candidates with Sonoma's pioneering approach to developing and manufacturing gene modified T reg cell therapies.

最後，我想強調一下我們最近宣布的與 Sonoma Biotherapeutics 的合作，發現、開發和商業化針對自身免疫性疾病和炎症性疾病的調節性 T 細胞療法。此次合作將匯集我們用於發現和表徵全人抗體和 T 細胞受體的行業領先技術，以及我們其他候選生物製劑與 Sonoma 開發和製造基因修飾 T reg 細胞療法的開創性方法。

In conclusion, Regeneron's R&D engine truly continues its productivity in both late and early-stage pipeline. Before turning the call over to Marion, I would also like to thank Roy Vagelos for serving as a role model for all of us at Regeneron as well as for so many others across the industry. I hope that we can continue to live up to the high standards that Roy has set over his distinguished career.

總之，Regeneron 的研發引擎真正在後期和早期管道中繼續其生產力。在將電話轉給 Marion 之前，我還要感謝 Roy Vagelos 為我們所有人以及整個行業的許多其他人樹立了榜樣。我希望我們能夠繼續不辜負羅伊在他傑出的職業生涯中設定的高標準。

With that, I will turn the call over to Marion.

有了這個，我會把電話轉給馬里恩。

Thank you, George. Our first quarter performance demonstrates ongoing leadership across multiple therapeutic categories. Taken together, our in-market brands anticipated near-term launches and extensive development pipeline uniquely position Regeneron to expand our leadership across multiple disease areas.

謝謝你，喬治。我們第一季度的業績證明了在多個治療類別中的持續領先地位。總而言之，我們的市場品牌預計近期推出和廣泛的開發管道使 Regeneron 處於獨特的地位，以擴大我們在多個疾病領域的領導地位。

First quarter EYLEA U.S. net product sales declined 6% year-over-year to $1.43 billion. On a sequential quarter basis, EYLEA U.S. net product sales decreased 4%, reflecting the favorable impact of higher demand volume, offset by lower sequential wholesaler inventory levels, higher sales-related deductions and increasing competitive pressure. EYLEA captured approximately 70% branded share in the first quarter.

第一季度 EYLEA 美國產品淨銷售額同比下降 6% 至 14.3 億美元。按季度計算，EYLEA 美國產品淨銷售額下降 4%，反映出需求量增加的有利影響，被較低的連續批發商庫存水平、較高的銷售相關扣減和增加的競爭壓力所抵消。 EYLEA 在第一季度佔據了大約 70% 的品牌份額。

Based on presentations at scientific meetings, the retina community has expressed increasing enthusiasm about Regeneron's portfolio with the aflibercept 8-milligram PDUFA date, now 7 weeks away. EYLEA is the well-established gold standard anti-VEGF treatment and aflibercept 8-milligram has the potential to be as paradigm changing as EYLEA when it was introduced more than a decade ago.

根據科學會議上的介紹，視網膜界對 Regeneron 的產品組合表達了越來越高的熱情，現在距離 aflibercept 8 毫克 PDUFA 日期還有 7 週。 EYLEA 是公認的金標準抗 VEGF 治療，阿柏西普 8 毫克有可能像十多年前推出的 EYLEA 一樣改變範式。

In clinical trials of aflibercept 8-milligram demonstrated improvements in visual acuity with less frequent injections and a safety profile comparable to EYLEA, exactly what retina specialists have told us they need in a next-generation medicine. Launch preparations are well underway, and we look forward to bringing this important treatment option to patients following FDA approval.

在 aflibercept 8 毫克的臨床試驗中，證明了注射頻率降低後視力得到改善，安全性與 EYLEA 相當，這正是視網膜專家告訴我們的下一代藥物所需要的。上市準備工作正在順利進行，我們期待在 FDA 批准後為患者提供這一重要的治療選擇。

On to Libtayo, which is foundational to Regeneron's oncology portfolio, first quarter global net product sales grew 49% on a constant currency basis, reaching $183 million, which includes $6 million from Sanofi transition sales in international markets. In the U.S., net sales grew 39% to $110 million. Libtayo continues to lead the market in both advanced CSCC and advanced BCC as demand volume increases.

至於作為再生元腫瘤產品組合基礎的 Libtayo，第一季度全球產品淨銷售額按固定匯率計算增長了 49%，達到 1.83 億美元，其中包括來自賽諾菲在國際市場的過渡銷售額的 600 萬美元。在美國，淨銷售額增長 39% 至 1.1 億美元。隨著需求量的增加，Libtayo 在先進的 CSCC 和先進的 BCC 領域繼續引領市場。

Following last November's FDA approval of Libtayo in combination with chemotherapy for first-line advanced non-small cell lung cancer, new patient starts have accelerated as physicians of Libtayo has an important new treatment option, initiatives to raise brand awareness and improve access have driven share gains in both the academic and community settings. Outside the U.S., Libtayo net sales grew 67% on a constant currency basis to $73 million, driven by steadily increasing demand and additional country launches. The European Commission recently approved Libtayo in combination with chemotherapy for PD-L1 positive lung cancer, and we are in the process of securing access and reimbursement for this new indication.

繼去年 11 月 FDA 批准 Libtayo 聯合化療治療一線晚期非小細胞肺癌後，新患者開始加速，因為 Libtayo 的醫生有一個重要的新治療選擇，提高品牌知名度和改善可及性的舉措推動了市場份額在學術和社區環境中都有所收穫。在美國以外，Libtayo 的淨銷售額按固定匯率計算增長了 67%，達到 7300 萬美元，這得益於穩步增長的需求和更多國家/地區的推出。歐盟委員會最近批准了 Libtayo 聯合化療治療 PD-L1 陽性肺癌，我們正在確保這一新適應症的准入和報銷。

Turning to Dupixent. First quarter global net sales grew 40% on a constant currency basis to $2.49 billion. In the U.S., net sales grew 43% to $1.9 billion, with notable volume growth across all approved indications. Driven by its outstanding efficacy and safety profile, Dupixent is the #1 prescribed biologic for new patients in all 5 of its approved indications.

轉向 Dupixent。第一季度全球淨銷售額按固定匯率計算增長 40% 至 24.9 億美元。在美國，淨銷售額增長 43% 至 19 億美元，所有獲批適應症的銷量均有顯著增長。憑藉其出色的療效和安全性，Dupixent 在其所有 5 個批准的適應症中成為新患者的第一處方生物製劑。

In atopic dermatitis, Dupixent is the leading systemic treatment based on its unique mechanism of action, clinical profile and real world experience. Strong prescribing trends continue across moderate and severe disease and across approved age ranges. There's also significant opportunity to further increase market penetration as Dupixent is uniquely positioned to provide an effective, safe and convenient treatment for patients 6 months and older.

在特應性皮炎中，Dupixent 是基於其獨特的作用機制、臨床特徵和真實世界經驗的領先的全身治療。強勁的處方趨勢在中度和重度疾病以及批准的年齡範圍內持續存在。由於 Dupixent 具有獨特的優勢，可以為 6 個月及以上的患者提供有效、安全和方便的治療，因此還有進一步提高市場滲透率的重要機會。

In prurigo nodularis, Dupixent is the only FDA-approved systemic treatment. Launch update is progressing well, and we anticipate ongoing growth as we leverage our dermatology commercialization capabilities for patients in need. Across the competitive asthma space, Dupixent continues to gain market share as naive and biologic switch patients are initiated on treatment. Dupixent also continues to capture the majority of market demand in nasal polyps with increased prescribing from allergists and ENTs.

在結節性癢疹中，Dupixent 是唯一獲得 FDA 批准的全身治療藥物。發布更新進展順利，我們預計隨著我們為有需要的患者利用我們的皮膚科商業化能力而持續增長。在競爭激烈的哮喘領域，隨著天真和生物開關患者開始接受治療，Dupixent 繼續獲得市場份額。隨著過敏症專家和耳鼻喉科醫師的處方增加，Dupixent 還繼續佔據鼻息肉的大部分市場需求。

Our cytosolic esophagitis launch is exceeding expectations. In the first year following U.S. approval, more than 11,000 patients have initiated therapy, demonstrating extensive unmet patient need and our strong launch execution and collaboration with Sanofi. Both gastroenterologists and analogists have embraced Dupixent as the new standard of care setting meaningful improvements in disease symptoms and quality of life for those now on therapy. A new patient campaign is underway to raise awareness of the scientific advancements in treatment of eosinophilic esophagitis.

我們推出的細胞溶質性食管炎超出了預期。在美國批准後的第一年，超過 11,000 名患者開始了治療，表明患者的廣泛需求未得到滿足，以及我們強大的上市執行力和與賽諾菲的合作。胃腸病學家和類比學家都將 Dupixent 作為新的護理標準，為正在接受治療的患者設定了疾病症狀和生活質量的有意義的改善。一項新的患者運動正在進行中，以提高人們對嗜酸性粒細胞性食管炎治療科學進步的認識。

Outside the U.S., Dupixent net sales were $587 million, growing 30% on a constant currency basis, driven by growth across approved indications and launches in new geographies. Recent European approvals of eosinophilic esophagitis, prurigo nodularis and atopic dermatitis in young children are expected to contribute to Dupixent's ongoing growth.

在美國以外，Dupixent 的淨銷售額為 5.87 億美元，按固定匯率計算增長了 30%，這主要受獲批適應症的增長和新地區上市的推動。最近歐洲批准了幼兒嗜酸性粒細胞性食管炎、結節性癢疹和特應性皮炎，預計將有助於 Dupixent 的持續增長。

In summary, our commercial portfolio continues to diversify across many serious medical conditions and delivered solid results in the quarter. Moving forward, we are well positioned to serve even more patients driven by the strength of our existing portfolio, coupled with anticipated launches that have the potential to advance standards of care.

總之，我們的商業產品組合繼續在許多嚴重的醫療條件下多樣化，並在本季度取得了可觀的業績。展望未來，在我們現有產品組合的優勢以及有可能提高護理標準的預期發布的推動下，我們有能力為更多患者提供服務。

With that, I'll turn the call to Bob.

有了這個，我會把電話轉給鮑勃。

Thank you, Marion. My comments today on Regeneron's financial results and outlook will be on a non-GAAP basis unless otherwise noted. Regeneron performed well in the first quarter of 2023 with solid financial results. First quarter total revenues increased 7% year-over-year to $3.2 billion as Dupixent and Libtayo contribute to increasingly diversified revenue and earning streams. First quarter diluted net income per share was $10.09 on net income of $1.2 billion, which included a previously announced $0.42 impact of acquired IPR&D.

謝謝你，馬里恩。除非另有說明，否則我今天對 Regeneron 的財務業績和前景的評論將基於非公認會計原則。 Regeneron 在 2023 年第一季度表現良好，財務業績穩健。由於 Dupixent 和 Libtayo 為日益多元化的收入和收入來源做出貢獻，第一季度總收入同比增長 7% 至 32 億美元。第一季度每股攤薄淨收益為 10.09 美元，淨收益為 12 億美元，其中包括先前宣布的收購 IPR&D 的 0.42 美元影響。

Beginning with collaboration revenue and starting with Bayer. First quarter 2023 ex-U.S. EYLEA net product sales were $847 million, up 4% on a constant currency basis versus first quarter 2022. Total Bayer collaboration revenue was $357 million, of which $332 million related to our share of EYLEA net profits outside the U.S. Total Sanofi collaboration revenue was $798 million in the first quarter and grew 26% versus last year's first quarter, which included a $50 million sales milestone that did not recur this year.

從合作收入開始，從拜耳開始。 2023 年第一季度（美國除外） EYLEA 產品淨銷售額為 8.47 億美元，按固定匯率計算比 2022 年第一季度增長 4%。拜耳合作總收入為 3.57 億美元，其中 3.32 億美元與我們在美國以外的 EYLEA 淨利潤份額相關。賽諾菲合作總收入為 798 美元第一季度銷售額為 100 萬美元，與去年第一季度相比增長了 26%，其中包括今年沒有出現的 5000 萬美元的銷售里程碑。

Our share of profits from the commercialization of Dupixent and Kevzara was $637 million, an increase of 53% versus the prior year. We continue to see increasing profitability from our antibody collaboration and expect further margin expansion as we begin to realize drug substance yield improvements from a new Regeneron developed manufacturing process for Dupixent. Finally, we recorded Roche collaboration revenue of $222 million in the first quarter for our share of gross profits from ex U.S. sales of Ronapreve related to a previously signed contract. We do not expect to record any additional revenue from Ronapreve in 2023, absent a new contract.

我們從 Dupixent 和 Kevzara 的商業化中獲得的利潤份額為 6.37 億美元，比上一年增長 53%。我們繼續從我們的抗體合作中看到盈利能力的提高，並預計隨著我們開始從再生元為 Dupixent 開發的新製造工藝中實現原料藥產量的提高，利潤率將進一步擴大。最後，我們在第一季度記錄了羅氏合作收入 2.22 億美元，這是我們在美國以外銷售與先前簽署的合同相關的 Ronapreve 的毛利份額。如果沒有新合同，我們預計 2023 年不會從 Ronapreve 獲得任何額外收入。

Moving now to operating expenses. First quarter 2023 R&D expense increased 28% year-over-year to $960 million as we continue to invest in our pipeline to drive organic growth. The increase in R&D was primarily driven by higher headcount and related costs and funding of the company's growing pipeline, which now encompasses approximately 35 programs in clinical development in more than 15 ongoing late-stage studies with additional study starts expected this year. These late-stage programs include our expanding fianlimab development program, upcoming Phase III studies and early reliance for our hem onc assets, as well as ongoing development programs for Dupixent and itepekimab for which we now record our full 50% share of development costs as a result of the Libtayo transaction.

現在轉向運營費用。 2023 年第一季度研發費用同比增長 28% 至 9.6 億美元，因為我們繼續投資於我們的管道以推動有機增長。研發的增加主要是由於公司不斷增長的管道的人員增加和相關成本以及資金的增加，該管道現在包括大約 35 個臨床開發項目，超過 15 個正在進行的後期研究，預計今年將開始更多的研究。這些後期項目包括我們不斷擴大的 fianlimab 開發項目、即將進行的 III 期研究和對我們的 hem onc 資產的早期依賴，以及 Dupixent 和 itepekimab 的持續開發項目，我們現在記錄了我們全部 50% 的開發成本份額作為Libtayo 交易的結果。

SG&A expense increased 32% year-over-year to $515 million due to higher contributions to an independent, not-for-profit patient assistance organization, higher headcount and related costs, and the impact of the Libtayo transaction. First quarter 2023 COCM was $249 million, up 26% versus last year, due to increases in shipments of ex-U.S. commercial supplies of Praluent to Sanofi and manufacturing costs for Dupixent. Reimbursements for these production costs are recorded as part of other revenue in Sanofi collaboration revenue respectively.

SG&A 費用同比增長 32% 至 5.15 億美元，原因是對獨立的非營利性患者援助組織的捐款增加、員工人數和相關成本增加以及 Libtayo 交易的影響。 2023 年第一季度 COCM 為 2.49 億美元，比去年增長 26%，這是由於美國以外地區的出貨量增加。 Praluent 向賽諾菲的商業供應和 Dupixent 的製造成本。這些生產成本的報銷分別記為賽諾菲合作收入中其他收入的一部分。

Shifting now to cash flow and the balance sheet. In the first quarter of 2023, Regeneron generated $1.2 billion in free cash flow. We ended the first quarter with cash and marketable securities, less debt, of $12.3 billion. We have continued to strategically deploy our cash to deliver on our capital allocation priorities, which are focused on investing in innovation, both internal and external, as well as returning capital to shareholders.

現在轉向現金流和資產負債表。 2023 年第一季度，Regeneron 產生了 12 億美元的自由現金流。第一季度結束時，我們擁有 123 億美元的現金和有價證券，減去債務。我們繼續戰略性地部署我們的現金，以實現我們的資本分配優先事項，重點是投資於內部和外部的創新，以及向股東返還資本。

We purchased nearly $700 million of our shares in the first quarter with $3.1 billion remaining under our existing authorization as of March 31. Additionally, as George discussed, we announced the collaboration with Sonoma Biotherapeutics, investing $75 million through an upfront payment and equity investment to add a new approach to our scientific capabilities.

我們在第一季度購買了近 7 億美元的股票，截至 3 月 31 日，我們的現有授權剩餘 31 億美元。此外，正如喬治所討論的，我們宣布與 Sonoma Biotherapeutics 合作，通過預付款和股權投資投資 7500 萬美元，為我們的科學能力添加一種新方法。

I'd like to conclude with some select updates to our financial guidance and outlook for 2023. We are updating 2023 COCM guidance to be in the range of $820 million to $880 million, an increase of $90 million at the midpoint, reflecting increased shipments of ex-U.S. commercial supplies for Praluent and Dupixent to Sanofi. Importantly, these anticipated incremental expenses will be reimbursed by Sanofi, generally resulting in a neutral impact to Regeneron's 2023 operating profit. Approximately half of the incremental $90 million of reimbursements from Sanofi are expected to be recorded as Sanofi collaboration revenue, with the balance recorded as other revenue.

最後，我想對我們的 2023 年財務指南和展望進行一些精選更新。我們正在更新 2023 年 COCM 指南，使其在 8.2 億美元至 8.8 億美元之間，中點增加 9000 萬美元，反映了出貨量的增加前美國Praluent 和 Dupixent 的商業供應給賽諾菲。重要的是，這些預期的增量費用將由賽諾菲報銷，通常會對再生元 2023 年的營業利潤產生中性影響。賽諾菲增加的 9000 萬美元報銷中的大約一半預計將記為賽諾菲合作收入，其餘記為其他收入。

As a result, we now expect 2023 other revenue to be higher than 2022 other revenue. For modeling purposes, second quarter 2023 other revenue is expected to be the lowest of the 2023 quarters, with the vast majority of the remaining other revenue to be recorded in the second half of this year. We are also updating our 2023 gross margin to be between 89% to 91%. The change in expected gross margin is primarily driven by an unfavorable change in product mix, as well as an increase in the start-up costs associated with our new fill/finish facility located in Upstate New York.

因此，我們現在預計 2023 年的其他收入將高於 2022 年的其他收入。出於建模目的，預計 2023 年第二季度的其他收入將是 2023 年季度中最低的，其餘大部分收入將在今年下半年錄得。我們還將 2023 年的毛利率更新為 89% 至 91%。預期毛利率的變化主要是由於產品組合的不利變化，以及與我們位於紐約州北部的新灌裝/塗飾設施相關的啟動成本增加。

Finally, we are lowering our guidance for our effective tax rate to 10% to 12%, reflecting the benefit of higher than previously anticipated stock-based compensation deductions. In conclusion, Regeneron continued to deliver robust financial results in the first quarter of 2023, and the company remains well positioned to drive further growth in the remainder of the year and beyond.

最後，我們將我們的有效稅率指導下調至 10% 至 12%，反映出高於先前預期的基於股票的薪酬扣除的好處。總之，Regeneron 在 2023 年第一季度繼續提供強勁的財務業績，並且該公司仍處於有利地位，可以在今年剩餘時間及以後推動進一步增長。

With that, I will now pass the call back to Ryan.

有了這個，我現在將把電話轉回給瑞安。

Thank you, Bob. Josh, that concludes our prepared remarks. We'd now like to open the call for Q&A. To ensure we are able to address as many questions as possible, we will answer one question from each caller before moving to the next. Please go ahead, Josh.

謝謝你，鮑勃。喬希，我們準備好的發言到此結束。我們現在想打開問答環節。為確保我們能夠解決盡可能多的問題，我們將先回答每個來電者的一個問題，然後再轉到下一個問題。請繼續，喬希。

(Operator Instructions) Our first question comes from Mohit Bansal with Wells Fargo.

（操作員說明）我們的第一個問題來自 Wells Fargo 的 Mohit Bansal。

Great. Maybe, Marion, if you could elaborate a little bit on the EYLEA, or Vabysmo dynamic at this point a little bit. Given the weakness in the quarter, you did mention that Vabysmo is taking some share. So if you could elaborate on where the share is coming from? Is it more of a switch? Or do you think it is also some new patient starts? And your confidence level in terms of flipping this situation once high-dose EYLEA comes along.

偉大的。也許，Marion，如果你能在這一點上詳細說明一下 EYLEA 或 Vabysmo 動態。鑑於本季度的疲軟，您確實提到 Vabysmo 正在佔據一些份額。那麼，您是否可以詳細說明份額的來源？它更像是一個開關嗎？還是您認為這也是一些新患者的開始？一旦高劑量 EYLEA 出現，您對扭轉這種情況的信心水平。

Sure, very happy to comment. And as I noted, as we're reporting on the quarter performance on a sequential basis, we did see with EYLEA, if I look at a sequential quarterly basis, we did see with EYLEA a net product sales decrease of 4%. As I mentioned, it was driven by a number of factors. Certainly, competitive pressure is one, but we also reflected on while we had slightly higher demand volume. It was offset by lower sequential wholesaler inventory levels and overall higher sales-related deductions.

當然，很高興發表評論。正如我所指出的，當我們按順序報告季度業績時，我們確實看到 EYLEA，如果我看一個連續的季度基礎，我們確實看到 EYLEA 的淨產品銷售額下降了 4%。正如我所提到的，它是由許多因素驅動的。當然，競爭壓力是其中之一，但我們也在需求量略高的情況下進行了反思。它被較低的連續批發商庫存水平和整體較高的與銷售相關的扣除額所抵消。

Specifically as it relates to competitive pressure, I would say that this is overall competitive dynamic in the anti-VEGF category, not something that we would necessarily identify with a particular product, more the totality of competition. I will comment that in the quarter, we certainly maintained a 70% branded share and over at approximately, I believe it was a 46% share in the overall anti-VEGF category. So certainly standard of care with EYLEA. And very importantly, we look forward to launching aflibercept 8 milligram, as I mentioned now, is about 7 weeks away.

特別是因為它與競爭壓力有關，我想說這是抗 VEGF 類別的整體競爭動態，而不是我們必須識別特定產品的東西，更多的是競爭的整體。我要評論的是，在本季度，我們肯定保持了 70% 的品牌份額，並且超過了大約，我相信它在整個抗 VEGF 類別中的份額為 46%。因此，EYLEA 當然是標準護理。非常重要的是，我們期待著推出 aflibercept 8 毫克，正如我現在提到的，大約 7 週後。

Thanks, Marion. Josh, next question, please.

謝謝，馬里恩。喬希，請問下一個問題。

Our next question comes from Robyn Karnauskas with Truist.

我們的下一個問題來自 Robyn Karnauskas 和 Truist。

Just some questions on LAG-3, and thinking about the first-line melanoma market and you're going to be having data relatively soon. So what -- I guess it's a multipart question. What is the bar for success, do you think, for the combination to be competitive? And when you think about penetrating into the nivo and checkpoint monotherapy buckets for first-line melanoma, can you help us understand how big these buckets are to actually model this opportunity better?

只是關於 LAG-3 的一些問題，並考慮一線黑色素瘤市場，您將很快獲得數據。那又怎樣——我想這是一個由多個部分組成的問題。您認為成功的門檻是什麼，才能使合併具有競爭力？當您考慮進入一線黑色素瘤的 nivo 和檢查點單藥治療桶時，您能否幫助我們了解這些桶有多大，以便更好地模擬這個機會？

Well, as we've already reported, based on our 2 confirmatory cohorts, we are seeing remarkable overall response rate increases over the PD-1 standard alone, almost doubling with much longer PFS. If we get anywhere near these numbers along with a satisfactory safety profile, which we had seen a favorable safety profile in the small studies, but if we reproduce or come anywhere close to reproducing these results, we believe that this will establish an entirely new standard of care for this disease.

好吧，正如我們已經報告的那樣，基於我們的 2 個驗證隊列，我們看到總體反應率比單獨的 PD-1 標準顯著提高，幾乎翻了一番，而且 PFS 更長。如果我們接近這些數字以及令人滿意的安全性，我們在小型研究中看到了良好的安全性，但如果我們重現或接近重現這些結果，我們相信這將建立一個全新的標準對這種疾病的護理。

And as we all know, the first-line melanoma opportunity is very large, but we're also moving laterally and earlier and so forth into many additional applications within the melanoma opportunity itself. We're going -- we're already now in adjuvant and entering neoadjuvant studies. We'll also be going to other cancer settings, including lung cancer and so forth. So we consider this a major opportunity, and we can only help to -- if we approach the data that we've already seen in our earlier studies, it really has a chance to make a huge difference for these patients.

眾所周知，一線黑色素瘤的機會非常大，但我們也在橫向和更早地進入黑色素瘤機會本身的許多其他應用程序。我們要去——我們現在已經在進行輔助研究並進入新輔助研究。我們還將前往其他癌症環境，包括肺癌等。所以我們認為這是一個重要的機會，我們只能幫助——如果我們處理我們在早期研究中已經看到的數據，它真的有機會為這些患者帶來巨大的改變。

Thanks, George. Josh, please move to the next question.

謝謝，喬治。喬希，請轉到下一個問題。

Our next question comes from Tyler Van Buren with TD Cowen.

我們的下一個問題來自 Tyler Van Buren 和 TD Cowen。

For high-dose EYLEA, is there anything left to do on the regulatory front? And have you guys started labeling discussions yet? And forgive me for the follow-up, but just briefly for housekeeping and related to your response to the first question in prepared remarks, Marion, can you quantify the impact of the lower EYLEA inventory for the quarter?

對於高劑量 EYLEA，監管方面還有什麼要做的嗎？你們開始給討論貼標籤了嗎？並請原諒我的後續行動，但只是簡單地進行內務管理，並與您對準備好的評論中的第一個問題的回答相關，Marion，您能否量化本季度 EYLEA 庫存減少的影響？

So on the regulatory update, we don't comment on ongoing stuff. I'd like to say we're looking forward, hopefully, to the action of the FDA on June 27 and the launch promptly thereafter. Marion, you can comment on the inventories.

因此，在監管更新方面，我們不會對正在進行的事情發表評論。我想說的是，我們滿懷希望地期待 FDA 在 6 月 27 日採取行動，並在此後迅速推出。 Marion，你可以對庫存發表評論。

Sure, Tyler. I can give you the detail there. So while still within the normal range of inventory related to your question on EYLEA in the quarter in the normal range is 5 to 10 days, our inventory levels were approximately 3 days lower at the end of the first quarter of 2023 compared to the end of the fourth quarter of 2022. And when you do the calculation on that, as I'm sure you all will do, that's a negative impact in the first quarter net sales of approximately $70 million.

當然，泰勒。我可以在那裡給你細節。因此，儘管本季度與您關於 EYLEA 的問題相關的庫存仍在正常範圍內，正常範圍是 5 到 10 天，但我們的庫存水平在 2023 年第一季度末比 2023 年第一季度末低了大約 3 天2022 年第四季度。當你對此進行計算時，我相信你們都會這樣做，這對第一季度的淨銷售額產生了大約 7000 萬美元的負面影響。

Thanks, Marion and Tyler. Moving to the next question please, Josh.

謝謝，馬里恩和泰勒。 Josh，請轉到下一個問題。

Our next question comes from Terence Flynn with Morgan Stanley.

我們的下一個問題來自摩根士丹利的 Terence Flynn。

I was just wondering on the commercial footprint for Dupixent here, given the potential for another indication with COPD. If you could talk about any additional footprint or spend that's required there. And again, maybe just how to think about leverage on the forward.

考慮到 COPD 的另一種適應症的可能性，我只是想知道 Dupixent 在這裡的商業足跡。如果你能談談那裡需要的任何額外足跡或支出。再一次，也許只是如何考慮對前鋒的影響。

Sure, very happy to comment. And as we think of Dupixent and all the different therapeutic disease areas and specialists that we cover with some indications, there certainly is an amazing and wonderful synergy. And you give an example with COPD launch potentially. And obviously, today, we're in market with our asthma indication and with nasal polyps. As we look forward with COPD, it's a really important launch, an indication to help patients in a way potentially that, as George described, hasn't been achieved ever for this population.

當然，很高興發表評論。當我們想到 Dupixent 以及我們涵蓋的所有不同治療疾病領域和專家時，我們肯定會產生驚人而美妙的協同作用。你舉了一個可能啟動 COPD 的例子。顯然，今天，我們在市場上有哮喘適應症和鼻息肉。正如我們對 COPD 的期待一樣，這是一個非常重要的發布，表明可以以一種潛在的方式幫助患者，正如 George 所描述的那樣，這種人群從未實現過。

So we have the opportunity to use our existing footprint, specifically in covering respiratory specialists, pulmonologists. But we'll also evaluate very closely with Sanofi, as you've seen us done in dermatology indications, where we might need some additional coverage and where the synergy is adequate, and we'll be very disciplined and very thoughtful about that. But you can be assured that we'll make certain that we appropriately give commercialization effort to such an important indication of COPD.

因此，我們有機會利用我們現有的足跡，特別是在覆蓋呼吸專家、肺病專家方面。但我們也會與賽諾菲進行非常密切的評估，就像你看到我們在皮膚病學適應症方面所做的那樣，我們可能需要一些額外的覆蓋範圍，並且在協同作用足夠的地方，我們會非常有紀律和非常周到。但您可以放心，我們將確保我們對 COPD 的這種重要適應症進行適當的商業化努力。

And it's interesting, just to add a little bit to that, Marion, that the allergists seem to have really understood the concept of type 2 inflammation. And the fact that type 2 inflammation is not a collection of individual unrelated diseases, it's a collection of related diseases.

有趣的是，Marion，只是補充一點，過敏症專家似乎真的理解了 2 型炎症的概念。事實上，2 型炎症不是個別不相關疾病的集合，而是相關疾病的集合。

And I was speaking to an allergist the other day and said when you take an asthma patient, if you look carefully, many of them will have nasal polyps. And if you talk to dermatologists, they're beginning to understand that when they're treating atopic dermatitis, people who have concomitant asthma, for example, they get a benefit there.

前幾天我和一位過敏症專科醫生說，當你接診哮喘患者時，如果你仔細觀察，他們中的許多人都會有鼻息肉。如果你和皮膚科醫生交談，他們會開始明白，當他們治療特應性皮炎時，例如，伴有哮喘的人，他們會從中受益。

So I think Dupixent really is kind of unique. And we are talking to the main doctors, including the allergists, the dermatologists and the pulmonologists, with some of the ENT, as Marion said. We're covering them all, and many of them are covering multiple diseases.

所以我認為 Dupixent 確實是獨一無二的。正如 Marion 所說，我們正在與主要醫生交談，包括過敏症專家、皮膚科醫生和肺科醫生，以及一些耳鼻喉科醫生。我們涵蓋了所有這些，其中許多涵蓋多種疾病。

Yes. I'll add to the enthusiasm here too in COPD, the potential to have a second product following Dupixent as well. So this will be a very important future area for helping patients.

是的。我也會增加對 COPD 的熱情，也有可能在 Dupixent 之後推出第二個產品。因此，這將是未來幫助患者的一個非常重要的領域。

So with regards to your question on leverage, first off, welcome back. Nice to have you back on the team. You'll see with the issuance of our 10-Q this morning with regards to our share of the antibody alliance, we're going to pick up quarter year-over-year for the quarter, roughly 300 basis points. And again, that's half the economics on the transaction. So we're beginning to see really great leverage in to Marion's comment that should continue on with the COPD indication.

所以關於你關於槓桿的問題，首先，歡迎回來。很高興你回到團隊。你會看到今天早上我們發布了關於我們在抗體聯盟中的份額的 10-Q，我們將在本季度同比增長大約 300 個基點。再一次，這是交易經濟的一半。所以我們開始看到對 Marion 的評論有很大的影響力，應該繼續使用 COPD 適應症。

Obviously, we work very closely with Sanofi and all of these. And I believe it's fair to say we're equally excited about the potential for the future of Dupixent in all the current and, hopefully, future indications.

顯然，我們與賽諾菲和所有這些公司密切合作。我相信可以公平地說，我們對 Dupixent 在所有當前和未來跡像中的未來潛力同樣感到興奮。

Thanks, everyone. Next question please, Josh.

感謝大家。下一個問題，喬希。

Our next question comes from Christopher Raymond with Piper Sandler.

我們的下一個問題來自 Christopher Raymond 和 Piper Sandler。

Maybe another Dupixent question, if you don't mind. Len, I know you don't talk about regulatory interactions. But when you had the COPD data, I think the signal that I got from you guys that seemed to be pretty strong was that you were hoping to have some discussions with the agency on BOREAS alone.

也許是另一個 Dupixent 問題，如果您不介意的話。 Len，我知道你不會談論監管互動。但是，當您獲得 COPD 數據時，我認為我從你們那裡得到的信號似乎非常強烈，即您希望僅就 BOREAS 與該機構進行一些討論。

Just kind of -- maybe can you map out how you anticipate communicating the results of that discussion with FDA once it happens? And then maybe a second part of that question is, our KOL checks have been pretty consistent when we asked them about this data. They're very impressed. But one of the things we've heard consistently is that this cutoff or clinical is to greater than 300 as sort of arbitrary and that this drug would see and maybe add value to patients with clinical accounts as low as 200 to 250. Just maybe your thoughts on this, and how you anticipate to sort of take advantage of that.

只是有點——也許你能規劃一下一旦討論發生，你將如何與 FDA 溝通討論的結果？然後也許這個問題的第二部分是，當我們向他們詢問這些數據時，我們的 KOL 檢查非常一致。他們印象深刻。但是我們一直聽到的一件事是，這個截止值或臨床值大於 300 是一種任意的，並且這種藥物會看到並可能為臨床帳戶低至 200 到 250 的患者增加價值。也許你的對此的想法，以及您期望如何利用它。

Yes. Well, let me start with the regulatory aspect. The -- obviously, what we're all staring at is an incredibly positive study -- I mean a Phase III setting, where, as we've mentioned, that we not only improve people's exacerbations, but we also improved their lung functions and the lung function and their quality of life, and all these other measures that were also part of the statistical hierarchy.

是的。好吧，讓我從監管方面開始。 - 顯然，我們都在盯著的是一項非常積極的研究 - 我的意思是 III 期設置，正如我們提到的那樣，我們不僅改善了人們的惡化，而且還改善了他們的肺功能和肺功能和他們的生活質量，以及所有這些也是統計層次結構一部分的其他措施。

So when you have a very robust study like that, and you have -- I don't know how many patients we currently have, but it's a huge number, a very large patient commercial database and so many indications, I think Sanofi and Regeneron concur, that this is something that we should be discussing with the FDA to see how they feel about whether or not there is a potential filing. We don't have any update for you, if it's something once we have that meeting, if it's something definitive, I'm sure Sanofi and Regeneron will figure out a way to properly communicate that.

所以當你有這樣一個非常強大的研究時，你有——我不知道我們目前有多少患者，但這是一個巨大的數字，一個非常大的患者商業數據庫和如此多的適應症，我認為賽諾菲和再生元同意，這是我們應該與 FDA 討論的事情，看看他們對是否有潛在的備案有何看法。我們沒有任何更新給你，如果這是我們開會後的事情，如果它是確定的，我相信賽諾菲和再生元會想出一種正確溝通的方法。

In terms of cutoffs and what have you, I think it's a little bit premature to talk about that, other than to say you stick with what you brought to the trial, which is a cutoff of 300. And that's where you commercialize. But the future work one can look at in other studies, that's something obviously we'll think about. But I remind you as George and both Marion mentioned, our IL-33 antibody gives a larger, although somewhat overlapping population potentially. So we really could have cover many, many, many patients, a great opportunity to help people with what has been really a very unfortunate progressive loss of lung function.

就截止點和你有什麼而言，我認為現在談論這個有點為時過早，除了說你堅持你帶到試驗中的東西，這是 300 的截止點。這就是你商業化的地方。但是人們可以在其他研究中看到未來的工作，這顯然是我們會考慮的事情。但我提醒您，正如 George 和 Marion 提到的那樣，我們的 IL-33 抗體提供了更大但可能有些重疊的群體。所以我們真的可以覆蓋很多很多病人，這是一個很好的機會來幫助那些非常不幸的肺功能逐漸喪失的人。

Yes. Len to your comment, you were talking about numbers of patients. I can fill in there that as of March worldwide, we had over 600,000 patients on Dupixent in 57 countries.

是的。 Len to your comment，你在談論病人的數量。我可以補充說，截至 3 月，全球範圍內，我們在 57 個國家/地區有超過 600,000 名患者使用 Dupixent。

Right. So that speaks a lot to the post-marketing experience of the product.

正確的。因此，這對產品的上市後體驗有很大影響。

Absolutely. Next question, please.

絕對地。請下一個問題。

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

我們的下一個問題來自 RBC Capital Markets 的 Brian Abrahams。

Shifting gears, you recently reported with your partner, APP data in Alzheimer's. I'm curious what this proof of principle potentially opens up beyond this indication? How quickly you can expand into some of the other neurodegenerative diseases that you mentioned, and your level of confidence overall in the safety of the program.

換檔，您最近與您的合作夥伴報告了阿爾茨海默氏症的 APP 數據。我很好奇這個原理證明可能會在這個指示之外打開什麼？你能以多快的速度擴展到你提到的其他一些神經退行性疾病，以及你對該項目安全性的總體信心水平。

Well, we think that the data were really game changing. I mean this is the first time in human history that one has been able to use this very exciting siRNA technology within the brain and silence, to a very high degree, higher-than-expected levels an important pathological gene. Obviously, this could have important implications for Alzheimer's itself. But as you point out, the application goes way beyond that. To every neurodegenerative disease, there are also other types of CNS diseases as well. We have a number of programs that we're working with Alnylam. We have an exclusive relationship with them on all of these CNS targets.

嗯，我們認為數據真的改變了遊戲規則。我的意思是，這是人類歷史上第一次有人能夠在大腦中使用這種非常令人興奮的 siRNA 技術，並以非常高的程度、高於預期的水平沉默重要的病理基因。顯然，這可能對阿爾茨海默氏症本身產生重要影響。但正如您所指出的，該應用程序遠不止於此。對於每一種神經退行性疾病，還有其他類型的中樞神經系統疾病。我們有許多與 Alnylam 合作的項目。我們與他們在所有這些 CNS 目標上都有獨家關係。

And we're trying to expedite a lot of them based on the exciting results from this initial clinical work into the clinic. And we're also trying to expedite many of our programs that are behind as well. So we really think this opens up an entirely new way of addressing a whole assortment of brain diseases and neuropsychiatric diseases, not just neurodegenerative diseases.

我們正試圖根據這項初步臨床工作進入臨床的令人興奮的結果來加快其中的許多工作。我們也在努力加快我們落後的許多計劃。所以我們真的認為這開闢了一種全新的方法來解決各種腦部疾病和神經精神疾病，而不僅僅是神經退行性疾病。

We're in exciting times. We have to go cautiously. We have to hope that the initial results, in terms of the safety profile and so forth, hold up. We're all in the early days, and we don't know for sure. But the low doses with which we saw this very marked reduction in the target give us a lot of hope that we can have a sufficient therapeutic window that will be applicable to these large variety of disease that could potentially be addressable by this modality.

我們正處在激動人心的時刻。我們必須謹慎行事。我們必須希望在安全概況等方面的初步結果能夠站得住腳。我們都處於早期階段，我們不確定。但是，我們看到這種非常顯著的目標減少的低劑量給了我們很大的希望，我們可以有一個足夠的治療窗口，適用於可能通過這種方式解決的這些種類繁多的疾病。

So I just wanted to add to that, 2 things: streaming on a different channel, I think you might find some further data being discussed by our friends at Alnylam, which will speak to not only impressive result, but the durability of the effect. And one of the other things I want to comment is really to echo something George said. The recent amyloid plaque clearing antibody results by Lilly previously, by Biogen, are really quite important. But as George said, even with the adjuvant, there's still going to be a tremendous burden of Alzheimer's disease.

所以我只想補充一點，兩件事：在不同的頻道上播放，我想你可能會發現我們在 Alnylam 的朋友正在討論一些進一步的數據，這不僅可以說明令人印象深刻的結果，還可以說明效果的持久性。我想評論的另一件事是真正回應喬治所說的話。 Lilly 之前 Biogen 的最近澱粉樣斑塊清除抗體結果確實非常重要。但正如喬治所說，即使有了佐劑，阿爾茨海默病仍然會帶來巨大的負擔。

But what the data seem to be speaking towards is that the process is ongoing, is that the pathologic role of amyloid is not over. And as George said, having another way, perhaps upstream, stopping the production of amyloid, maybe even a more advantageous way to deal with the ongoing process that amyloid seems to be generating, which is what the antibody data, I think, seems to be speaking to us.

但數據似乎表明該過程仍在進行中，即澱粉樣蛋白的病理作用尚未結束。正如喬治所說，有另一種方法，也許是上游，停止澱粉樣蛋白的產生，甚至可能是一種更有利的方法來處理澱粉樣蛋白似乎正在產生的持續過程，我認為這就是抗體數據似乎是對我們說話。

Okay, thank you. Josh, next question please.

好的謝謝。喬希，請問下一個問題。

Our next question comes from Salveen Richter with Goldman Sachs.

我們的下一個問題來自高盛的 Salveen Richter。

So with regard to EYLEA high-dose becoming the larger share of revenue on the forward here, can you give us any color here on discussions with payers and how to think about formulary fit?

因此，關於 EYLEA 高劑量成為此處前瞻性收入的更大份額，您能否在這裡給我們一些關於與付款人的討論以及如何考慮處方集適合度的顏色？

So Salveen, we are actively involved in all aspects of launch preparation. And certainly, that includes all elements and levers associated with premarket activities and then getting ready for the launch activities. We do have in place a very sophisticated market access, payer and pricing team. And at the appropriate times, they most definitely will be involved with payers and other organized customers that will be important in our launch efforts. Additionally, this is a customer base that we know very well from our -- over a decade experience with EYLEA, so we look forward to potential FDA approval and launch activities and working with all of our customer stakeholders.

所以 Salveen，我們積極參與發射準備的各個方面。當然，這包括與上市前活動相關的所有要素和槓桿，然後為發布活動做好準備。我們確實擁有一支非常成熟的市場准入、付款人和定價團隊。在適當的時候，他們肯定會與付款人和其他有組織的客戶合作，這對我們的發布工作很重要。此外，這是一個我們非常了解的客戶群——十多年的 EYLEA 經驗，因此我們期待潛在的 FDA 批准和啟動活動，並與我們所有的客戶利益相關者合作。

I'll also mention again the importance in the retinal space of the key opinion leaders and prescribers and the enthusiasm they have for a product that really can be a game changer for their patients in terms of visual acuity, duration and the safety profile they've come to know with EYLEA. So we're very enthusiastic and look forward to the launch opportunity, and we'll be ready.

我還會再次提到關鍵意見領袖和處方者在視網膜空間的重要性，以及他們對一種產品的熱情，這種產品在視力、持續時間和他們的安全性方面確實可以改變患者的遊戲規則。我們已經了解了 EYLEA。所以我們非常熱情並期待發布機會，我們會做好準備。

Okay. Next question, please.

好的。請下一個問題。

Our next question comes from Akash Tewari with Jefferies.

我們的下一個問題來自 Jefferies 的 Akash Tewari。

So just to clarify the moving parts on U.S. EYLEA, there was a 5% market share loss, a $70 million inventory impact and then lower price. Any color on what the net price impact was on the quarter, and how it should evolve in the back half of '23? And additionally, should we expect EYLEA market share to hold at 70% going forward, or potentially start to grow again as high-dose EYLEA launches?

因此，為了澄清美國 EYLEA 的活動部件，市場份額損失了 5%，庫存影響達 7000 萬美元，然後價格下降。關於淨價格對本季度的影響，以及它在 23 年下半年應該如何演變的任何顏色？此外，我們是否應該期望 EYLEA 的市場份額在未來保持在 70%，或者隨著高劑量 EYLEA 的推出可能再次增長？

So let me take some of the items, and others may want to jump in here, too. But first, I would say that some of the calculation related to market share shift is not exactly correct. There was some decline in the quarter, but not to the height that you mentioned. When I look at market shares through the entirety of the first quarter period, then as described, it is a more competitive market, a variety of, obviously, competitors, very low cost and others. And overall, EYLEA performance is in a very strong situation as we look today to planning for our future portfolio and the aflibercept 8-milligram launch.

所以讓我拿走一些物品，其他人可能也想加入這裡。但首先，我要說一些與市場份額轉移相關的計算並不完全正確。本季度有所下降，但沒有達到您提到的高度。當我查看整個第一季度的市場份額時，正如所描述的那樣，這是一個競爭更加激烈的市場，顯然有各種競爭對手，成本非常低等等。總的來說，EYLEA 的表現非常強勁，因為我們今天期待著規劃我們未來的產品組合和 aflibercept 8 毫克的推出。

As to the specifics of pricing and calculation to the net, I can't give you specifics on that number. But I do think that we gave you some transparency on the overall item related to inventory, overall competitive pressures and then our preparation for our next launch in the category coming up shortly, we hope, following FDA approval.

至於定價和網絡計算的具體細節，我不能給你具體的數字。但我確實認為，我們在與庫存相關的整體項目、整體競爭壓力以及我們為即將推出的下一次發布做準備方面提供了一些透明度，我們希望在 FDA 批准後。

Obviously, as Marion mentioned, on a sequential basis, demand was modestly up. So obviously, we were offset by the factors that Marion referred to.

顯然，正如 Marion 所提到的，在連續的基礎上，需求略有上升。很明顯，我們被 Marion 提到的因素所抵消。

All right. Next question, please.

好的。請下一個問題。

Our next question comes from Chris Schott with JPMorgan.

我們的下一個問題來自摩根大通的 Chris Schott。

I just had a question on the IL-33 in COPD. I guess just the success you've had with your kind of study design and results with Dupixent increase at all your confidence in that program. And just, I guess, maybe just elaborate little bit on, how you see kind of those 2 agents kind of interacting as we think about the space overall?

我剛剛對 COPD 中的 IL-33 有疑問。我猜你在 Dupixent 的研究設計和結果方面取得的成功增加了你對該計劃的信心。而且，我想，也許只是詳細說明一下，當我們考慮整個空間時，您如何看待這兩個代理的互動？

Yes. We are more optimistic, obviously, that all of our decisions, all of the data that led us to do the particular study and the particular population of patients in COPD with Dupixent was made based on a lot of factors. And we also had, from our Regeneron Genetics Center, very strong human genetic evidence suggesting that it would have activity particularly where we actually saw activity. And so all of that gives us confidence -- since we use the same criteria, the same approaches and so forth to plan and design our IL-33 study, certainly, the fact that everything that went into one and it all worked so remarkably well gives us confidence that the same approaches will lead to success with the IL-33.

是的。顯然，我們更加樂觀，我們所有的決定，導致我們進行特定研究的所有數據以及使用 Dupixent 的 COPD 患者的特定人群都是基於許多因素做出的。我們還從我們的再生元遺傳學中心獲得了非常有力的人類遺傳證據，表明它會有活動，特別是在我們實際看到活動的地方。因此，所有這些都給了我們信心——因為我們使用相同的標準、相同的方法等等來計劃和設計我們的 IL-33 研究，當然，事實上，所有的東西都融入其中，而且都非常有效讓我們相信同樣的方法將導致 IL-33 的成功。

The results with Dupixent were really outstanding, as we've already mentioned. Not only a clinically meaningful reduction in exacerbations, but we hit all these other important endpoints, most importantly, improvement in lung function, as well as you rarely hit these quality of life improvements unless you have a really active agent that the patients can really feel the difference for their function and for their quality of life.

正如我們已經提到的，Dupixent 的結果非常出色。不僅在臨床上有意義地減少了惡化，而且我們達到了所有其他重要終點，最重要的是，肺功能得到改善，而且你很少能達到這些生活質量的改善，除非你有一種患者能真正感受到的真正有效的藥物他們的功能和生活質量的差異。

With IL-33, the genetics is very strong. We have a Phase II study in the subgroup that we're doing the Phase III study in. It was in that group. We have demonstrated a 42% reduction in exacerbations in the Phase II study. This will be an overlapping population with our Dupixent population. We think we already have a chance to really make a huge difference for this high unmet need population that really has had no new mechanism of action of drugs brought to help these patients for a very, very long time. We have one with Dupixent, and we're hoping to hit another one with IL-33. And this could make such a huge difference for these patients who have been suffering for so long without much hope. It could really make a big difference for this population.

對於 IL-33，遺傳學非常強大。我們在我們正在進行 III 期研究的小組中進行了 II 期研究。它在那個小組中。我們已經證明在 II 期研究中急性加重減少了 42%。這將是與我們的 Dupixent 種群重疊的種群。我們認為我們已經有機會真正為這個高度未滿足的需求人群帶來巨大的改變，這些人群在非常非常長的時間裡確實沒有新的藥物作用機制來幫助這些患者。我們有一個 Dupixent，我們希望用 IL-33 打另一個。對於那些長期遭受痛苦而沒有太大希望的患者來說，這可能會帶來巨大的不同。它真的可以為這個人群帶來很大的不同。

I just wanted to repeat, maybe George said it probably 2 or 3 times, but maybe it's worth saying a fourth time. In yesteryear, the way you did drug development is you identified a target based on some biology or what have you, you did your Phase I and Phase II, and you hope that Phase II was an indicator for how your Phase III was going to turn out. And obviously, that's how it is still done today. But what George mentioned is that we can layer on top of it in sort of a unique way our genetic insights and look and validate and say, is it reasonable to expect that if you block a certain target that you're going to have a beneficial effect? Is that target associated with the disease you're treating?

我只是想重複一遍，也許喬治說了 2 或 3 次，但也許值得說第四次。在過去，您進行藥物開發的方式是根據某些生物學或您擁有的東西確定目標，您進行了 I 期和 II 期，並且您希望 II 期是您的 III 期將如何轉變的指標出去。顯然，今天仍然是這樣做的。但 George 提到的是，我們可以以一種獨特的方式在它之上疊加我們的遺傳洞察力，並觀察和驗證並說，如果你阻止某個目標，你將有一個有益的預期是合理的嗎影響？該目標與您正在治療的疾病有關嗎？

And I know George said it 3 times, but I think it's worth saying a fourth time. That really gives you added confidence that's uniquely Regeneron in many respects, how we can get this genetic information. People ask us a lot, if you think about the number of people that have been sequenced in the world, George can comment when I'm done, I know we've sequenced a large part of them and coupled that with all this medical, anonymized medical information. We use that in so many ways, not only to identify targets, but to validate the work we're doing in specific targets, specific diseases. George, how much have we done?

我知道喬治說了 3 次，但我認為值得說第四次。這真的讓你更有信心，再生元在許多方面都是獨一無二的，我們如何才能獲得這些遺傳信息。人們問我們很多，如果你想一想世界上已經測序的人數，George 可以在我完成後發表評論，我知道我們已經對其中很大一部分進行了測序，並將其與所有這些醫療相結合，匿名醫療信息。我們以多種方式使用它，不僅是為了確定目標，而且是為了驗證我們在特定目標、特定疾病方面所做的工作。喬治，我們做了多少？

We've seen about half of all the humans who have been sequenced.

我們已經看到了大約一半的被測序的人類。

So I mean, that's a large database of millions. And I think that, that is what you're hearing is that that's why we had more confidence perhaps than others did with Dupixent and now with anti-IL-33.

所以我的意思是，這是一個包含數百萬的大型數據庫。我認為，這就是你所聽到的，這就是為什麼我們比其他人對 Dupixent 和現在對抗 IL-33 更有信心。

Since when expand it a little bit, just let you know how it works. What we do is we identify genetic variations that mimic the blocking of a drug or exacerbation of this type 2 pathway. And what we showed for Dupixent, for the genetic variations that mimic Dupixent, those people were protected from COPD, particularly the type 2 COPD patients.

從什麼時候擴展它一點點，讓你知道它是如何工作的。我們所做的是識別模擬藥物阻斷或這種 2 型通路惡化的遺傳變異。我們為 Dupixent 展示的，對於模仿 Dupixent 的遺傳變異，這些人受到保護免受 COPD，特別是 2 型 COPD 患者。

Whereas increased activity of the IL-4/13 path was associated with more disease. And obviously, that turned out to be the case. I mean it's human genetics. It's a very, very powerful predictor. And we've done the same thing, as Len said, with IL-33, where we have genetic variation at mimics blocking the pathway or exacerbating the pathway. And as I've said, this is one of the secrets to our ability to have high success rates in our studies is we use that as a criteria to make our decisions going forward.

而 IL-4/13 通路的活性增加與更多疾病相關。顯然，事實確實如此。我的意思是這是人類遺傳學。這是一個非常非常強大的預測器。正如 Len 所說，我們對 IL-33 做了同樣的事情，我們在模擬物中有遺傳變異來阻斷通路或加劇通路。正如我所說，這是我們能夠在研究中獲得高成功率的秘訣之一，我們將其用作做出未來決策的標準。

Okay. Thank you. Next question please, Josh.

好的。謝謝。下一個問題，喬希。

Our next question comes from Yatin Suneja with Guggenheim Securities.

我們的下一個問題來自古根海姆證券公司的 Yatin Suneja。

This is Eddie Hickman on for Yatin. I was wondering if you could talk about the draft guidance from the FDA on the anti-VEGF trial designs? And if that impacts your outlook on the high-dose program at all?

這是 Yatin 的 Eddie Hickman。我想知道您是否可以談談 FDA 關於抗 VEGF 試驗設計的指南草案？如果這會影響您對高劑量計劃的看法？

I don't think that has any impact on us, on our program.

我認為這對我們和我們的計劃沒有任何影響。

Thank you, Len. Next question, please.

謝謝你，萊恩。請下一個問題。

Our next question comes from David Risinger with SVB Securities.

我們的下一個問題來自 SVB Securities 的 David Risinger。

Yes. And I guess I'll just go straight to the question. Len, you had mentioned in your opening remarks the ongoing diversification of the company's revenues away from EYLEA. Could you please discuss your expectations for EYLEA U.S. sales growth in the near term, including the total EYLEA franchise prospects after Regeneron launches the HD?

是的。我想我會直接進入問題。 Len，你在開場白中提到了公司收入的持續多元化，遠離 EYLEA。您能否談談您對 EYLEA 美國近期銷售增長的預期，包括 Regeneron 推出 HD 後 EYLEA 特許經營權的整體前景？

Let me go right to the answer since you ran right to the question. We don't give future guidance on specific quantitative measures of our sales. On a qualitative basis, Marion has said, that we're anticipating that the combination of EYLEA and 8 milligrams aflibercept will be a growth franchise over time for the company.

既然您直接回答了問題，那麼讓我直接回答。我們不會就我們銷售額的具體量化指標提供未來指導。 Marion 表示，在定性基礎上，我們預計 EYLEA 和 8 毫克 aflibercept 的組合將隨著時間的推移成為公司的增長專營權。

Okay, thank you. Next question, please.

好的謝謝。請下一個問題。

Our next question comes from Hartaj Singh with Oppenheimer.

我們的下一個問題來自 Hartaj Singh 和 Oppenheimer。

Just a quick question on linvoseltamab. At ASH, you presented a Phase I data, and these were your dose ranging, I guess, data. Really interesting data you present at ASH. At ASCO, what should we expect to see? Will it be dose expansion data? And then any duration also on the patients from ASH? And then what would FDA like to see before you can go ahead and submit the application?

只是一個關於 linvoseltamab 的快速問題。在 ASH，您提交了 I 期數據，我猜這些是您的劑量範圍數據。您在 ASH 上展示的數據非常有趣。在 ASCO，我們應該期待看到什麼？會是劑量擴展數據嗎？那麼 ASH 患者的持續時間是多少？那麼在您繼續提交申請之前，FDA 希望看到什麼？

Well, I think you're going to actually see an update on our pivotal Phase II data, the actual data that was a little bit more maturing, with a further update we will be hoping to submit to the FDA for our BLA. So the data will be very close. We think the data will even get better as it matures. Because as we all know, response rates and so forth get better with time as you follow these patients. But these data are going to show what we believe are the potential to have best-in-class efficacy, as well as safety in the favorable dosing schedule based on the results that we'll show from our pivotal study at the upcoming ASCO.

嗯，我認為你實際上會看到我們關鍵的 II 期數據的更新，實際數據更成熟一些，我們希望進一步更新提交給 FDA 用於我們的 BLA。所以數據會非常接近。我們認為隨著數據的成熟，數據甚至會變得更好。因為眾所周知，當您跟踪這些患者時，響應率等會隨著時間的推移而提高。但這些數據將顯示我們認為有可能具有一流的療效，以及基於我們將在即將舉行的 ASCO 上展示的關鍵研究結果的有利給藥方案的安全性。

All right. Thank you, George. I think we have time for 2 more questions.

好的。謝謝你，喬治。我想我們還有時間再問 2 個問題。

Our next question comes from Carter Gould with Barclays.

我們的下一個問題來自巴克萊銀行的卡特古爾德。

Sorry to belabor EYLEA. I guess just simply, what's the pricing pressure that you guys highlighted in Q1. Was that a seasonal dynamic? Or would you characterize it as that? Or something more permanent around that market landscape going forward?

抱歉打擾了 EYLEA。我想簡單地說，你們在第一季度強調的定價壓力是什麼。那是季節性的動態嗎？或者你會這樣描述它嗎？還是圍繞該市場前景的更持久的東西？

Before Marion answers that, I just want to come back to the BCMA story a little bit, because it's one that I'm particularly excited about. The bispecific field, which was initiated by Regeneron in terms of using bispecifics, I think we were the first to put the bispecific into patients, has obviously become a very crowded space and it's sometimes hard to differentiate what you've got compared to what the competition has and you look at somebody claiming one thing and you're claiming another and so on and so forth.

在 Marion 回答這個問題之前，我只想稍微回到 BCMA 的故事，因為這是一個讓我特別興奮的故事。雙特異性領域，由 Regeneron 在使用雙特異性方面發起，我認為我們是第一個將雙特異性應用於患者的，顯然已經成為一個非常擁擠的空間，有時很難區分你得到的和你得到的競爭已經發生了，你看著有人聲稱一件事，而你正在聲稱另一件事，依此類推。

But if you take a dispassionate view, I think for the BCMAxCD3 program, you could really see a differentiated molecule and the potential to be best-in-class. Antibodies are not all created equal. Bispecifics are not all created equally. You do see differences. Clinical trial programs and not all created equally. This is one I'd really encourage you to think a very careful look at and compare. Now there was some question on EYLEA. Marion, you're going to answer that.

但如果你冷靜地看待 BCMAxCD3 項目，你真的可以看到一個差異化的分子和成為同類最佳的潛力。抗體並非生而平等。雙特異性藥物並非都是平等創造的。你確實看到了差異。臨床試驗計劃並沒有平等地創建。這是我真正鼓勵您仔細考慮和比較的一個。現在有一些關於 EYLEA 的問題。 Marion，你會回答這個問題。

Sure. And Carter, getting back to your question on the competitive dynamic and pricing pressure. I think if you look at the anti-VEGF category and look at it over time, go back multiple quarters, there has been increasing competitive pressure. And that does then have a corollary to some extent on pricing dynamic, and that would go forward.

當然。卡特，回到你關於競爭動態和定價壓力的問題。我認為，如果你觀察抗 VEGF 類別並隨著時間的推移觀察它，回到多個季度，就會發現競爭壓力越來越大。這確實在某種程度上對定價動態產生了推論，並且會繼續下去。

But I just want to share and remind all that in the category, in the VEGF category, what really is rewarded is product profile. And as we look at a product like EYLEA that launched and was a game changer in the category, that was profile not being the least costly, right? There's been a low-cost alternative, very low-cost alternative for a very, very long time, but it was the product profile that made the difference for prescribers and patients.

但我只是想分享並提醒大家，在類別中，在 VEGF 類別中，真正被獎勵的是產品簡介。當我們看到像 EYLEA 這樣的產品推出並改變了該類別的遊戲規則時，它的配置文件並不是成本最低的，對吧？很長一段時間以來，一直有一種低成本的替代品，非常低成本的替代品，但正是產品概況對處方者和患者產生了影響。

So that will always be a very important dynamic to look at going forward, and certainly has strong interest for prescribers as we bring a new product into the marketplace following FDA approval with aflibercept 8 milligram. But to your point, pricing pressure will continue in this category. But what's most important is product profile and the clinical attributes that the patient experiences.

因此，這將永遠是展望未來的一個非常重要的動力，並且肯定會引起處方者的強烈興趣，因為我們在 FDA 批准 aflibercept 8 毫克後將新產品推向市場。但就您的觀點而言，這一類別的定價壓力將繼續存在。但最重要的是產品概況和患者體驗的臨床屬性。

Thanks. Last question, please.

謝謝。最後一個問題，請。

Our last question comes from Evan Seigerman with BMO.

我們的最後一個問題來自 BMO 的 Evan Seigerman。

I'd love to have you expand on some of the feedback you've been hearing from physicians regarding the 8-milligram dose. Maybe some color as to how they plan on using it and assuming approval comes June.

我很想請您詳細說明您從醫生那裡聽到的關於 8 毫克劑量的一些反饋。也許關於他們計劃如何使用它並假設 6 月獲得批准的一些顏色。

So of course, the updates on actual prescribing will be even more important as the product comes into the marketplace and physicians have an opportunity to use it and select patients. We obviously have done a lot of work with our medical team, looked at the clinical data with specialists. And to give you an early answer to your question, I think there's opportunity for a variety of patients that are deemed to be appropriate candidates. And there's a range. Certainly, when physicians are considering new patient starts, it's very attractive.

因此，當然，隨著產品進入市場並且醫生有機會使用它並選擇患者，實際處方的更新將變得更加重要。我們顯然與我們的醫療團隊一起做了很多工作，與專家一起研究了臨床數據。為了儘早回答您的問題，我認為有機會為各種被認為是合適人選的患者提供機會。而且是有範圍的。當然，當醫生考慮開始新患者治療時，這是非常有吸引力的。

We obviously have a strong portion of patients that are naive to EYLEA today, but in the future, the question becomes, why wouldn't you start a new patient with a product that gives you all the visual acuity benefits and safety of EYLEA, but it also gives you that durability and duration? Because obviously, physicians know their patients are anxious and don't like to have more injections in the eye than they need to. Similarly, you might have a patient that's very well controlled on another product, maybe EYLEA, maybe another product in the anti-VEGF category. But you'd like to give them that opportunity for duration and, maybe in some cases, if the product is in another area of the anti-VEGF category, improved visual acuity and duration.

今天，我們顯然有很大一部分患者對 EYLEA 還很天真，但在未來，問題就變成了，你為什麼不讓新患者開始使用一種能為你提供 EYLEA 所有視力益處和安全性的產品，但它還為您提供耐用性和持續時間？因為很明顯，醫生知道他們的病人很焦慮，不喜歡在眼睛裡註射比他們需要的更多的藥。同樣，您可能有一位患者在使用另一種產品時控制得很好，可能是 EYLEA，也可能是抗 VEGF 類別中的另一種產品。但是你想給他們持續時間的機會，也許在某些情況下，如果產品屬於抗 VEGF 類別的另一個領域，則可以提高視力和持續時間。

So I would say it's the combination of interest for patients who might be broadly anti-VEGF category switch patients, or the potential for new patients as well. I hope that helps, and I look forward to the day when we can give you specifics for market experience.

所以我想說這是對可能是廣泛抗 VEGF 類別轉換患者的患者的興趣的結合，或者對新患者的潛力也是如此。我希望這對您有所幫助，我期待著有一天我們可以為您提供市場經驗的細節。

Thank you, Marion, and thanks to everybody who dialed in, and for your interest in Regeneron. We apologize to those remaining in the queue that we did not have a chance to get to. As always, the IR team is available to answer any remaining questions that anyone may have. Thank you once again, and have a great day, everyone.

謝謝你，Marion，感謝所有撥入電話的人，感謝你對 Regeneron 的關注。對於我們沒有機會到達隊列中的那些人，我們深表歉意。與往常一樣，IR 團隊可以回答任何人可能提出的任何遺留問題。再次感謝你們，祝大家有美好的一天。

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

謝謝。今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。