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.

歡迎參加再生元製藥公司2023年第一季財報電話會議。我是Josh，將擔任本次電話會議的接線生。 （接線生說明）請注意，本次會議正在錄音。

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

現在我將把電話交給投資者關係副總裁瑞安·克羅。您可以開始了。

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.

謝謝喬希。各位全球聽眾，早安、下午好、晚上好。感謝您對再生元公司的關注，歡迎參加我們2023年第一季財報電話會議。本次網路直播的存檔將在會議結束後不久發佈在我們的投資者關係網站上。

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.

今天與我一同出席的有：聯合創始人、總裁兼首席執行官倫納德·施萊弗博士；聯合創始人、總裁兼首席科學官喬治·揚科波洛斯博士；執行副總裁兼商務主管瑪麗昂·麥考特；以及執行副總裁兼首席財務官鮑勃·蘭德里。在我們分別致詞後，我們將進入問答環節。

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.

我想提醒各位，今天電話會議的發言可能包含Regeneron的前瞻性聲明。這些陳述可能包括但不限於與Regeneron及其產品和業務、財務預測和指導、收入多元化、研發項目及相關預期里程碑、合作、財務、監管事宜、支付方覆蓋範圍和報銷問題、知識產權、未決訴訟和其他程序以及競爭相關的陳述。

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.

每項前瞻性聲明均受風險和不確定性因素的影響，這些因素可能導致實際結果和事件與聲明中預測的結果和事件有重大差異。有關這些風險和其他重大風險的更完整描述，請參閱Regeneron向美國證券交易委員會提交的文件，包括其截至2023年3月31日的季度報告（10-Q表格），該報告已於今天上午提交給美國證券交易委員會。 Regeneron不承擔任何更新前瞻性聲明的義務，無論是因為出現新資訊、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，本次電話會議將討論GAAP和非GAAP財務指標。有關我們使用非GAAP財務指標以及這些指標與GAAP的調節表的信息，請參閱我們的財務業績新聞稿和公司介紹，這些文件均可在我們的網站上查閱。電話會議結束後，Bob Landry和投資者關係團隊將解答您的其他問題。

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

那麼，現在讓我把電話交給我們的總裁兼執行長倫‧施萊弗博士。倫？

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.

謝謝瑞恩，也謝謝今天參加電話會議的各位。繼2022年取得顯著成就之後，再生元在2023年開局良好，這主要得益於重要的監管和研發管線進展、商業執行以及審慎的資本配置，所有這些都使公司能夠更好地實現可持續的長期增長，並隨著時間的推移為股東創造價值。

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.

喬治、瑪莉安和鮑伯稍後將詳細介紹我們第一季的業績。在此期間，我想就我們持續發展業務並同時實現收入和盈利來源多元化的目標作一次匯報，這也是Regeneron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.

我們在實現這一目標方面取得了顯著進展。過去四年，儘管總收入幾乎翻了一番，但安永在2023年第一季的營收佔比僅為57%，而2019年全年這一比例為88%。主要得益於Dupixent的成長，我們與賽諾菲的合作在2023年第一季的營收佔比達到25%，而2019年全年這一比例僅為6%。我們預計這種收入成長和多元化的趨勢將持續保持。

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，假設阿柏西普8毫克制劑（PDUFA日期為6月27日）獲得批准並成功上市，預計安麗2毫克製劑在我們收入中的佔比將有所下降，而阿柏西普8毫克制劑預計將對整體收入增長做出貢獻。此外，Dupixent仍維持高速成長，其全球淨產品銷售額（以固定匯率計算）較上年同期成長40%，主要得益於所有5項已獲準適應症的成長。

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 型發炎證據的 COPD 患者亞群中取得的積極 III 期結果，以及我們的 IL-33 抗體 itepekimab 在前吸煙者中取得的令人鼓舞的結果，代表著加速收入增長和多元化的更多重要機會。

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對公司營收做出顯著貢獻，這得益於去年我們收購了Libtayo的全球全部權益，以及近期Libtayo聯合化療用於治療晚期非小細胞肺癌的上市。此外，我們相信，我們的LAG-3抗體fianlimab與Libtayo聯合使用，有望成為黑色素瘤和非小細胞肺癌的重要治療方案，目前我們已在這兩種疾病的關鍵性研究中取得了進展。

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.

我們對 linvoseltamab（一種 BCMAxCD3 雙特異性抗體）的臨床療效前景感到非常振奮。相關最新數據將在即將召開的 ASCO 年會上公佈。我們仍按計劃於今年稍後提交生物製品許可申請 (BLA)，尋求加速批准其用於治療晚期多發性骨髓瘤。

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.

我們持續加大研發投入，期望能研發出具有差異化優勢的新型藥物，進而推動公司業務的長期有機成長。我們擁有近30個在研項目，涵蓋眾多治療領域和治療方式，尤其值得一提的是：我們在癌症治療領域研發的共刺激雙特異性抗體；我們在心血管和代謝疾病領域的早期研發管線；以及我們與Alnylam、Intellia、Decibel等公司的合作，這些項目有望推動公司中長期盈利、盈利和業務增長。

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.

在將發言權交給喬治之前，我想藉此機會感謝羅伊·瓦格洛斯博士近三十年來對再生元公司的貢獻。他擔任公司董事會主席近三十年，多年來為我們提供了寶貴的指導，並持續激勵我們努力將世界一流的科學成果轉化為藥物。羅伊博士將於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擔任的職務外，喬治和我將被董事會任命為聯合主席，而自2010年以來一直是再生元董事會成員的潘慧玲（Christine Poon）將被任命為董事會首席獨立董事。

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

那麼，我把電話交給喬治吧。

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，Len。 2023 年第一季度，Regeneron 和我們的合作計畫取得了多項重大里程碑式的成果，包括 Dupixent III 期 COPD 的積極數據、腫瘤產品線的進展，以及基因藥物計畫令人振奮的新里程碑。

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.

首先是Dupixent。今年3月，我們與賽諾菲的合作夥伴共同宣布，Dupixent是十多年來首個在慢性阻塞性肺病（COPD）III期臨床試驗中取得具有統計學意義和臨床意義的免疫作用機制治療藥物。我們的BOREAS試驗納入了中重度COPD患者，這些患者均存在2型發炎的證據。

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.

接受Dupixent治療的患者在臨床上表現出顯著的病情加重減少30%，肺功能顯著改善，生活品質也得到提升：這三項令人矚目的成果表明，Dupixent有望成為治療這種致命疾病的全新療法。我們期待在本月稍後即將舉行的美國胸腔科學會年會上，以最新研究成果報告的形式詳細介紹BOREAS研究的結果。我們也計劃與監管機構討論這些令人振奮的結果，並預計明年年中公佈重複進行的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.

我想提醒各位，我們也在嘗試用IL-33抗體治療一部分與COPD患者重疊的疾病，該抗體目前正處於III期臨床試驗階段，其依據是II期臨床試驗的積極概念驗證數據。我們Regeneron遺傳學中心的基因分析進一步支持了這一策略，該分析表明白細胞介素-33功能喪失與COPD風險降低有關。類似的基因分析也支持了Dupixent在COPD治療中的益處。

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，Dupixent 可以幫助更多患者，其療效不僅限於目前 FDA 批准的 5 種適應症，還能用於治療由 2 型發炎引起或加重的疾病，包括異位性皮膚炎、氣喘、伴隨鼻息肉的慢性鼻竇炎、嗜酸性食道炎和結節性癢疹。我們預計 FDA 將於 2023 年 10 月 22 日就 Dupixent 用於治療慢性自發性蕁麻疹做出決定。同時，我們也持續改進 Dupixent 的研發，使其更適用於其他可能對此方法有反應的 2 型發炎性疾病患者。

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.

接下來是腫瘤領域。隨著我們後期和早期研發管線的進展，我們期待今年能夠取得幾個重要的里程碑。首先是Libtayo。除了擴大在肺癌的應用外，Libtayo最近還被納入NCCN指南，用於新輔助治療皮膚鱗狀細胞癌（CSCC）。 Libtayo的美國藥品標籤也已更新，納入了更成熟的CSCC和基底細胞癌（BCC）數據，進一步證實了其在這些腫瘤類型中具有差異化的臨床特性，並滿足了上市後所有關於在這些適應症中獲得全面批准的承諾。

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令人振奮的全新聯合療法。首先是我們的LAG-3抗體fianlimab，我們正計劃開展一項涵蓋多種癌症適應症的廣泛關鍵性研究計畫。這些計畫的啟動源於我們在轉移性黑色素瘤一線治療中獲得的可靠且確證的數據，這些數據將在ASCO年會上進行更詳細的展示。這些數據表明，fianlimab-Libtayo聯合療法有望使緩解率達到單藥治療的兩倍左右，並延長無惡化存活期，而單藥治療是抗PD療法的標準。基於此，我們已啟動轉移性黑色素瘤和輔助治療的關鍵性試驗，並將於今年下半年啟動一項圍手術期黑色素瘤研究。此外，基於小樣本患者群組中令人鼓舞的數據，我們已啟動一項針對轉移性非小細胞肺癌的無縫銜接的II/III期關鍵性研究，並將很快啟動一項圍手術期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.

接下來是針對實體腫瘤的雙特異性抗體，我們正在研究它們與Libtayo合併用藥的療效。今年早些時候，ASCO泌尿生殖系統腫瘤學會（GU）公佈了我們的PSMAxCD28共刺激雙特異性抗體與Libtayo聯合治療晚期前列腺癌的初步人體試驗陽性數據。前列腺癌被認為是免疫冷腫瘤，對單獨使用抗PD-1療法反應不佳。未來12個月內，我們計劃公佈更多患者的最新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，以期在維持或增強抗腫瘤活性的同時，降低免疫介導的副作用。此外，在此期間，我們還計劃公佈MUC16xCD3雙特異性抗體與MUC16xCD28共刺激雙特異性抗體聯合治療晚期卵巢癌的數據，以及EGFRxCD28共刺激雙特異性抗體或與Libtayo聯合治療多種腫瘤類型的數據。

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.

我們的血液腫瘤治療產品線持續進行。在即將召開的美國臨床腫瘤學會（ASCO）年會上，我們將以口頭報告的形式公佈linvoseltamab的最新數據。 linvoseltamab是一種BCMAxCD3雙特異性抗體，已在多發性骨髓瘤晚期治療中進行了測試。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藥物的競爭激烈的市場中，linvoseltamab具有同類最佳的潛力，其療效、安全性和給藥方案均優於其他同類藥物。我們仍按計畫於今年下半年向美國監管機構提交linvoseltamab的上市申請。

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雙特異性抗體odronextamab，我們正按計劃推進，預計將於今年下半年完成其在美國和歐盟的上市申請，用於治療復發或難治性濾泡性淋巴瘤和瀰漫性大B細胞淋巴瘤。 Odronextamab在晚期復發或難治性濾泡性淋巴瘤治療中具有潛在的同類最佳療效，我們優化的遞增給藥方案在不影響療效的前提下，提高了其通用安全性。此外，我們啟動一項CD22xCD28共刺激雙特異性抗體合併odronextamab治療復發/難治性瀰漫性大B細胞淋巴瘤的首次人體研究，我們希望研究能進一步提高這些患者的抗癌效益。

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.

現在來說說基因藥物。首先是與Alnylam的合作，以及siRNA療法。就在上週，我們和Alnylam宣布了Alnylam APP計畫在早發性阿茲海默症治療的重要進展。在臨床試驗中，RNAi療法首次實現了對中樞神經系統中致病基因的持續沉默。在今天早上的財報電話會議上，我們的Alnylam合作夥伴詳細介紹了這些結果。我們的siRNA療法旨在阻止澱粉樣前體蛋白的生成，而不是在澱粉樣蛋白斑塊形成後清除它們，這為治療阿茲海默症提供了一種新的途徑。即使出現了清除澱粉樣蛋白的抗體，阿茲海默症仍然會對患者及其家庭造成毀滅性的影響。

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.

接受單一劑量ALN-APP治療的患者，其腦脊髓液生物標記檢測顯示，APP生成量呈現劑量依賴性快速且持續下降，降幅高達90%。迄今為止，單劑量給藥的安全性和耐受性令人鼓舞。儘管由於先前非臨床慢性毒理學研究中發現一些保留意見，該研究的多劑量B部分在美國已部分暫停臨床試驗，但B部分已獲得加拿大監管部門批准，可在加拿大繼續進行。 A部分臨床試驗的病患大多在加拿大入組。

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。我們期待推進更多針對其他神經退化性疾病的候選藥物研發，這些疾病目前幾乎沒有或根本沒有治療選擇，例如阿茲海默症、肌萎縮側索硬化症（漸凍症）、帕金森氏症和亨廷頓氏症的其他標靶。

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領域取得這些令人振奮的進展外，我們還在肝臟標靶藥物方面持續取得進展，包括我們為非酒精性脂肪性肝炎（NASH）開發治療方案而採取的廣泛而多管齊下的策略。我們正在進行一項針對具有遺傳風險因子的NASH患者的ALN-HSD II期臨床研究，並繼續推進ALN-PNP的臨床開發。此外，我們也計劃推動其他近期經基因驗證的NASH標靶的研發。

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，我想重點介紹我們近期宣布與Sonoma Biotherapeutics公司在自體免疫疾病和發炎性疾病的調節性T細胞療法的發現、開發和商業化方面開展的合作。此次合作將結合我們業界領先的全人源抗體和T細胞受體發現與表徵技術，以及我們其他生物製劑候選藥物，並融合Sonoma在基因修飾Treg細胞療法開發和生產方面的創新方法。

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的研發引擎在早期和後期研發管線中都持續保持著高效率的運作。在將電話交給Marion之前，我還要感謝Roy Vagelos，他不僅是Regeneron全體員工的榜樣，也是業界眾多人士的典範。我希望我們能夠繼續努力，不辜負Roy在他卓越的職業生涯中所樹立的高標準。

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

接下來，我將把電話交給瑪莉安。

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.

謝謝喬治。我們第一季的業績展現了我們在多個治療領域的持續領先地位。綜合來看，我們已上市品牌、即將推出的新產品以及豐富的在研產品線，使Regeneron在多個疾病領域擁有獨特的優勢，能夠進一步鞏固我們的領先地位。

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.

安怡（EYLEA）美國第一季淨產品銷售額年減6%至14.3億美元。環比下降4%，這反映了需求量成長帶來的有利影響，但被批發商庫存水準環比下降、銷售相關扣減增加以及競爭壓力加劇所抵銷。安怡第一季佔了約70%的品牌市佔率。

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.

根據科學會議上的報告，視網膜領域對再生元公司的產品組合表現出越來越高的熱情，距離8毫克阿柏西普的PDUFA審批日期還有7週。 EYLEA是公認的抗VEGF治療的黃金標準，而8毫克阿柏西普有望像十多年前EYLEA上市時一樣，帶來顛覆性的變革。

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.

阿柏西普8毫克劑量在臨床試驗中顯示出改善視力的效果，且注射頻率更低，安全性與EYLEA相當，這正是視網膜專家告訴我們的，他們希望下一代藥物具備的優勢。上市準備工作正在順利進行中，我們期待在獲得FDA批准後，盡快將這項重要的治療選擇帶給患者。

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.

接下來是Regeneron腫瘤產品組合的基石藥物Libtayo。以固定匯率計算，Libtayo第一季全球淨銷售額成長49%，達到1.83億美元，其中包括來自賽諾菲在國際市場的600萬美元過渡銷售額。在美國，Libtayo淨銷售額成長39%，達到1.1億美元。隨著需求量的增長，Libtayo在晚期皮膚鱗狀細胞癌（CSCC）和晚期基底細胞癌（BCC）領域繼續保持市場領先地位。

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月美國食品藥物管理局（FDA）核准利妥昔單抗（Libtayo）合併化療用於第一線治療晚期非小細胞肺癌後，新患者開始接受利妥昔單抗治療的人數迅速成長。醫生們獲得了一項重要的全新治療選擇，同時，為提高品牌知名度和改善藥物可及性而採取的各項舉措也推動了利妥昔單抗在學術界和社區醫療機構的市場份額增長。在美國以外，利妥昔單抗的淨銷售額以固定匯率計算成長了67%，達到7,300萬美元，主要得益於持續成長的需求和更多國家的上市。歐盟委員會近期批准了利妥昔單抗聯合化療用於治療PD-L1陽性肺癌，我們正在努力爭取該新適應症的上市許可和醫保報銷。

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.

再來看看Dupixent。以固定匯率計算，第一季全球淨銷售額成長40%，達到24.9億美元。在美國，淨銷售額成長43%，達到19億美元，所有核准適應症的銷售量均顯著成長。憑藉其卓越的療效和安全性，Dupixent在其所有5個核准適應症中，均是新患者處方量排名第一的生物製劑。

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.

在異位性皮膚炎領域，Dupixent憑藉其獨特的機制、臨床療效和真實世界經驗，成為領先的全身性治療藥物。在中重度患者以及所有核准年齡層中，Dupixent的處方量持續強勁成長。此外，Dupixent具有獨特的優勢，能夠為6個月及以上的患者提供有效、安全、便利的治療方案，因此市場滲透率仍有巨大的提升空間。

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.

在結節性癢疹領域，Dupixent 是唯一獲得 FDA 批准的全身性治療藥物。上市進展順利，我們預計隨著我們利用自身在皮膚科領域的商業化能力為有需要的患者提供服務，市場將持續成長。在競爭激烈的氣喘領域，隨著初治患者和生物製劑轉換患者開始接受 Dupixent 治療，其市場份額持續擴大。此外，Dupixent 在鼻息肉治療領域也持續佔據市場主導地位，過敏科醫師和耳鼻喉科醫師的處方量不斷增加。

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.

我們的嗜酸性粒細胞性食道炎藥物上市表現超乎預期。在美國獲批後的第一年，已有超過11,000名患者開始接受治療，這表明患者存在巨大的未滿足需求，也體現了我們強大的上市執行力以及與賽諾菲的密切合作。胃腸病學家和類固醇專家都認可Dupixent是新的治療標準，它顯著改善了患者的疾病症狀和生活品質。目前，我們正在進行一項新的患者宣傳活動，旨在提高公眾對嗜酸性粒細胞性食道炎治療領域最新科學進展的認識。

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.

除美國以外，Dupixent的淨銷售額為5.87億美元，按固定匯率計算增長了30%，這主要得益於已獲批適應症的增長以及在新地區的上市。近期，Dupixent在歐洲獲準用於治療兒童嗜酸性食道炎、結節性癢疹和異位性皮膚炎，預計將進一步推動其持續成長。

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.

總而言之，我們的商業產品組合持續多元化，涵蓋多種重大疾病，並在本季取得了穩健的表現。展望未來，憑藉現有產品組合的優勢，以及有望提升治療標準的預期上市產品，我們已做好充分準備，為更多患者提供服務。

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

接下來，我會把電話轉給鮑伯。

Thank you, Marion. My comments today on Regeneron's financial results and outlook will be on a non-GAAP basis unless otherwise noted. Regeneron 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，Marion。除非另有說明，我今天對Regeneron財務業績和展望的評論將基於非GAAP準則。 Regeneron在2023年第一季表現出色，財務表現穩健。第一季總營收年增7%至32億美元，Dupixent和Libtayo的加入使公司營收和獲利來源日益多元化。第一季稀釋後每股淨收益為10.09美元，淨利為12億美元，其中包括先前宣布的收購IPR&D帶來的0.42美元收益。

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.

首先來看合作收入，首先是拜耳。 2023年第一季，除美國以外，EYLEA淨產品銷售額為8.47億美元，以固定匯率計算，較2022年第一季成長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地區EYLEA淨利的份額有關。第一季度，賽諾菲合作總營收為7.98億美元，較去年同期成長26%，去年同期包含一項5,000萬美元的銷售里程碑，而今年該里程碑並未重現。

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，較上年增長53%。我們持續看到抗體合作帶來的獲利能力提升，並預期隨著Dupixent採用Regeneron公司新開發的生產工藝，藥物原料藥收率的提高，利潤率將進一步擴大。此外，我們在第一季確認了與羅氏合作的2.22億美元收入，該收入來自我們先前簽署的合約中關於Ronapreve在美國以外地區銷售的毛利份額。除非簽訂新合同，否則我們預計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.

接下來是營運費用。 2023年第一季研發費用年增28%至9.6億美元，我們持續投資於產品線以推動內生成長。研發費用的成長主要源自於人員增加及相關成本上升，以及公司不斷成長的產品線資金投入。目前，該公司產品線涵蓋約35個處於臨床開發階段的項目，其中超過15項正在進行後期研究，預計今年還將啟動更多研究。這些後期項目包括我們不斷擴大的fianlimab開發項目、即將開展的III期研究以及我們血液腫瘤資產的早期應用，此外還包括Dupixent和itepekimab的在研項目。由於Libtayo交易，我們現在將承擔這兩個項目50%的全部開發成本。

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.

由於對一家獨立的非營利病患援助組織的捐款增加、員工人數增加及相關成本上升，以及Libtayo交易的影響，銷售、管理及行政費用年增32%至5.15億美元。 2023年第一季合約營運成本為2.49億美元，較去年同期成長26%，主要原因是向賽諾菲交付的Praluent美國境外商業供應量增加以及Dupixent的生產成本上升。這些生產成本的報銷款項分別計入賽諾菲合作收入的其他收入。

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.

接下來我們來看現金流和資產負債表。 2023年第一季，Regeneron公司創造了12億美元的自由現金流。截至第一季末，我們持有的現金及有價證券（扣除債務）總額為123億美元。我們持續策略性地運用現金，以實現我們的資本配置優先事項，這些事項主要集中在投資創新（包括內部和外部創新）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.

第一季度，我們回購了近7億美元的股票，截至3月31日，我們現有授權範圍內還有31億美元的剩餘額度。此外，正如喬治所討論的，我們宣布與索諾瑪生物治療公司合作，透過預付款和股權投資的方式投資7500萬美元，為我們的科學研究能力增添新的方法。

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，我想就我們2023年的財務指引和展望做一些更新。我們將2023年COCM（臨床營運成本）指引調整為8.2億美元至8.8億美元，中位數增加9,000萬美元，反映了Praluent和Dupixent在美國境外向賽諾菲交付的商業供應量增加。重要的是，這些預計的新增支出將由賽諾菲報銷，因此對Regeneron 2023年的營業利潤基本上不會產生影響。預計賽諾菲提供的9,000萬美元新增報銷款中，約有一半將計入賽諾菲合作收入，其餘部分將計入其他收入。

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年其他收入將高於2022年。出於建模目的，預計2023年第二季其他收入將是2023年各季度中最低的，其餘大部分收入將在今年下半年確認。我們也將2023年的毛利率預期更新為89%至91%。毛利率預期的變化主要是由於產品組合的不利變化，以及位於紐約州北部的新填充/包裝工廠啟動成本的增加。

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，我們將實際稅率預期下調至10%至12%，這主要得益於高於預期的股權激勵扣除額。總之，Regeneron在2023年第一季持續保持強勁的財務業績，公司仍處於有利地位，預計今年剩餘時間及未來將進一步成長。

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

接下來，我會把電話轉回給瑞恩。

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.

謝謝鮑勃。喬希，我們的演講到此結束。現在進入問答環節。為了確保我們能夠回答盡可能多的問題，我們將在回答每位來電者的一個問題後再進行下一個問題。喬希，請開始吧。

(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富國銀行的 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.

好的。 Marion，或許您可以詳細談談目前EYLEA或Vabysmo的市場動態。鑑於本季業績疲軟，您提到Vabysmo正在搶佔部分市佔率。那麼，您能否詳細說明一下這些市場佔有率的來源？是市場轉向導致的嗎？還是您認為也包括一些新患者的加入？以及您對高劑量EYLEA上市後扭轉這種局面的信心如何？

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，我很樂意發表評論。正如我之前提到的，由於我們按季度環比報告業績，安樂死（EYLEA）的淨產品銷售額環比下降了4%。正如我所說，這受到多種因素的影響。當然，競爭壓力是其中之一，但我們也考慮到，儘管需求量略有增長，但批發商庫存水平環比下降以及整體銷售相關扣減額增加抵消了這一增長。

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.

具體來說，就競爭壓力而言，我認為這是抗VEGF藥物領域整體的競爭動態，並非特別指某個特定產品，而是整個競爭格局的體現。我要指出的是，本季我們維持了70%的品牌市場份額，在整個抗VEGF藥物領域，我們的市佔率約為46%。因此，EYLEA的療效已達到業界標準。非常重要的是，正如我剛才提到的，我們期待8毫克阿柏西普的上市，預計大約7週後就能上市。

Thanks, Marion. Josh, next question, please.

謝謝，瑪莉安。喬希，下一個問題。

Our next question comes from Robyn Karnauskas with Truist.

下一個問題來自 Truist 的 Robyn Karnauskas。

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?

關於LAG-3，我有一些問題。考慮到一線黑色素瘤市場，你們很快就會公佈數據。所以——我想這應該是一個多方面的問題。您認為這種聯合療法要達到怎樣的成功標準才能有競爭力？另外，當您考慮如何打入一線黑色素瘤治療中納武利尤單抗和免疫檢查點抑製劑單藥治療的市場時，您能否幫我們了解一下這些市場究竟有多大，以便我們更好地評估這一市場機會？

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.

正如我們先前報導的，基於我們的兩個驗證性隊列，我們觀察到總體緩解率較PD-1標準療法顯著提高，幾乎翻了一番，且無進展生存期（PFS）也大幅延長。如果我們能夠達到接近這些數值，並同時保持令人滿意的安全性（我們在小型研究中已經觀察到良好的安全性），那麼如果我們能夠重現或接近這些結果，我們相信這將為該疾病的治療樹立全新的標準。

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，第一線黑色素瘤治療的機會非常巨大，但我們也在黑色素瘤治療領域內進行橫向、早期等多方面的探索。我們目前正在進行輔助治療和新輔助治療的研究。我們也將把研究拓展到其他癌症領域，包括肺癌等等。因此，我們認為這是一個重大的機遇，如果我們能夠充分利用早期研究中獲得的數據，我們就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，請回答下一個問題。

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

下一個問題來自 TD Cowen 公司的 Tyler Van Buren。

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，監管方面還有什麼工作要做嗎？你們開始討論標籤問題了嗎？還有，請原諒我的追問，Marion，為了方便溝通，也為了回應你事先準備好的發言稿中的第一個問題，你能量化一下本季度EYLEA庫存下降的影響嗎？

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.

關於監管方面的最新進展，我們不予置評。我想說的是，我們期待FDA在6月27日的核准結果，希望之後能盡快上市。 Marion，你可以談談庫存狀況。

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。我可以詳細解釋一下。關於你提到的安禮（EYLEA）產品，雖然庫存仍在正常範圍內（正常範圍是5到10天），但2023年第一季末的庫存水準比2022年第四季末低了大約3天。我相信你們都會計算一下，這會對第一季的淨銷售額造成約7000萬美元的負面影響。

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

謝謝瑪麗昂和泰勒。喬什，請進入下一個問題。

Our next question comes from Terence Flynn with Morgan Stanley.

下一個問題來自摩根士丹利的特倫斯·弗林。

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.

我只是想了解Dupixent在加拿大的商業佈局，因為它有可能用於治療慢性阻塞性肺病（COPD）。您能否談談這方面是否需要額外的投入或支出？另外，能否談談如何利用槓桿效應來推動未來的發展？

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，我很樂意發表評論。當我們想到Dupixent以及我們涵蓋的各種治療疾病領域和專科醫生時，我們確實能感受到一種令人驚嘆的協同效應。您以COPD的上市為例。顯然，目前我們的氣喘和鼻息肉適應症已經上市。展望COPD，這將是一個非常重要的上市，正如George所說，它有望以一種前所未有的方式幫助患者。

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市場佈局，尤其是在涵蓋呼吸專家和肺科醫生方面。但正如您在皮膚科適應症領域所見，我們也會與賽諾菲密切評估，確定哪些領域可能需要額外的市場覆蓋，以及哪些領域有足夠的協同效應。我們會對此進行非常嚴謹和周全的考慮。但您可以放心，我們一定會確保在慢性阻塞性肺病這一重要適應症的商業化方面投入足夠的精力。

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.

瑪莉昂，還有一點很有意思，過敏症專家似乎真的了解第2型發炎的概念。事實上，2型發炎並不是一系列互不相關的疾病，而是一系列相關疾病的集合。

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家聊天，我說，如果你仔細觀察氣喘患者，會發現很多患者都有鼻息肉。如果你和皮膚科醫生交流，他們也開始意識到，在治療異位性皮膚炎時，例如同時患有氣喘的患者，鼻息肉的治療對他們是有益的。

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確實很獨特。正如Marion所說，我們正在與包括過敏科醫生、皮膚科醫生、肺科醫生以及一些耳鼻喉科醫生在內的主要醫生進行溝通。我們正在涵蓋所有領域，其中許多領域涵蓋多種疾病。

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。我也要補充一點，在慢性阻塞性肺病領域，繼Dupixent之後，我們有望迎來第二個產品，這也同樣令人振奮。因此，這將是未來幫助患者的一個重要領域。

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.

關於您提出的槓桿問題，首先，歡迎回來。很高興您重返團隊。今天早上我們發布了10-Q報告，其中提到了我們在抗體聯盟中的份額，預計本季將年增約300個基點。再次強調，這相當於該交易經濟效益的一半。因此，正如Marion所說，我們開始看到非常可觀的槓桿效應，而這種效應應該會持續到COPD適應症領域。

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，我們與賽諾菲以及其他所有相關方都保持著非常密切的合作關係。而且，我認為可以毫不誇張地說，我們對Dupixent在所有現有適應症以及未來有望取得的適應症方面都抱有同樣的期望。

Thanks, everyone. Next question please, Josh.

謝謝大家。喬希，下一個問題。

Our next question comes from Christopher Raymond with Piper Sandler.

下一個問題來自克里斯托弗·雷蒙德和派珀·桑德勒。

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.

如果您不介意的話，我想再問一個關於Dupixent的問題。 Len，我知道您不談論監管方面的互動。但是，當你們拿到COPD數據時，我覺得你們給我的一個很明確的信號是，你們希望就BOREAS項目單獨與監管機構進行一些討論。

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.

能否請您概述一下，一旦與FDA進行討論，您打算如何傳達討論結果？另外，我們曾向關鍵意見領袖（KOL）諮詢過相關數據，他們的回饋基本上一致，都對這款藥物印象深刻。但我們反覆聽到的一種說法是，300以上的臨床閾值似乎有些隨意，而這款藥物對臨床評分低至200到250的患者也可能有效，甚至可能帶來益處。您對此有何看法？您打算如何利用這一點？

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。那麼，讓我先從監管方面說起。顯然，我們現在看到的是一項非常積極的研究——我是指一項三期臨床試驗，正如我們之前提到的，這項研究不僅改善了患者的病情加重情況，還改善了他們的肺功能、生活品質以及所有其他納入統計分析的指標。

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，當一項如此嚴謹的研究開展，並且——我不知道我們目前有多少患者，但數量龐大——擁有一個非常龐大的患者商業數據庫，以及如此多的適應症時，我認為賽諾菲和再生元都同意，我們應該與FDA討論此事，看看他們對是否需要提交申請有何看法。目前我們沒有任何最新消息可以告訴您，如果會議結束後有任何進展，或者有了明確的結論，我相信賽諾菲和再生元會找到合適的溝通方式。

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.

至於臨界值之類的，我覺得現在討論還為時過早，除了堅持試驗中設定的臨界值300之外。這就是我們進行商業化的起點。至於未來的研究，例如其他研究，我們當然會考慮。但我要提醒大家，正如George和Marion所提到的，我們的IL-33抗體可以涵蓋更大的人群，儘管可能會有一些重疊。所以我們本來可以涵蓋很多很多患者，這是一個幫助那些不幸遭受進行性肺功能喪失之苦的人們的絕佳機會。

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，關於你的評論，你提到了患者人數。我可以補充一點，截至3月份，全球已有超過60萬名患者在57個國家接受Dupixent治療。

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

沒錯。這充分說明了該產品的售後服務體驗非常出色。

Absolutely. Next question, please.

當然。請問下一個問題。

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

下一個問題來自加拿大皇家銀行資本市場的布萊恩亞伯拉罕。

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.

換個話題，您最近和您的搭檔報告了APP在阿茲海默症方面的數據。我很好奇，除了阿茲海默症之外，這項原理驗證還可能帶來哪些新的適應症？您能否盡快將APP擴展到您提到的其他神經退化性疾病領域？您對該專案的整體安全性有多大信心？

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.

我們認為這些數據確實具有顛覆性意義。我的意思是，這是人類歷史上首次能夠在腦內使用這種令人興奮的siRNA技術，並以遠超預期的程度抑制一種重要的致病基因。顯然，這可能對阿茲海默症本身產生重大影響。但正如您所指出的，其應用遠不止於此。每一種神經退化性疾病都與其他類型的中樞神經系統疾病有關。我們正在與Alnylam公司合作進行多個專案。我們在所有這些中樞神經系統靶點方面都與他們保持著獨家合作關係。

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.

基於初步臨床研究令人振奮的成果，我們正努力加速許多計畫的推進。同時，我們也在努力加快許多進度滯後的專案。因此，我們堅信這將為治療各種腦部疾病和神經精神疾病（而不僅僅是神經退化性疾病）開闢一條全新的途徑。

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.

我們正處於激動人心的時刻。我們必須謹慎行事。我們必須寄望初步結果，包括安全性等方面，能夠保持穩定。一切都還處於早期階段，我們無法確定最終結果。但是，我們觀察到，即使使用低劑量，目標值也能顯著降低，這讓我們充滿希望，相信我們能夠找到一個足夠大的治療窗口，適用於多種可能透過這種療法治療的疾病。

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.

所以我想補充兩點：在另一個頻道上，我想您可能會看到我們Alnylam公司的朋友們討論的一些數據，這些數據不僅會展現出令人印象深刻的結果，還會說明療效的持久性。另外，我想補充一點，其實是想呼應George之前說過的話。禮來公司和百健公司最近發表的清除澱粉樣蛋白斑塊的抗體研究結果非常重要。但正如George所說，即使有了佐劑，阿茲海默症仍然會給患者帶來巨大的負擔。

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，這個過程仍在繼續，澱粉樣蛋白的致病作用尚未結束。正如喬治所說，或許我們需要另一種方法，例如在上游層面阻止澱粉樣蛋白的產生，甚至找到一種更有效的應對澱粉樣蛋白持續致病過程的方法——我認為，這正是抗體數據想要告訴我們的。

Okay, thank you. Josh, next question please.

好的，謝謝。喬希，下一個問題。

Our next question comes from Salveen Richter with Goldman Sachs.

下一個問題來自高盛的薩爾文·里希特。

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?

那麼，關於EYLEA高劑量製劑未來將佔據更大的收入份額，您能否透露一下與支付方的討論情況，以及如何考慮納入藥品目錄的問題？

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，我們積極參與上市準備工作的各個方面。這當然包括所有與上市前活動相關的要素和機制，以及上市前的各項準備。我們擁有一支非常專業的市場准入、支付方和定價團隊。在適當的時候，他們一定會與支付方和其他對我們上市工作至關重要的客戶進行溝通。此外，憑藉我們十多年來在安理國際（EYLEA）的經驗，我們對這個客戶群非常了解，因此我們期待獲得FDA的批准，並順利開展上市活動，同時與所有客戶利益相關者攜手合作。

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.

我還要再次強調，在視網膜領域，關鍵意見領袖和處方醫生至關重要，他們對這款產品充滿熱情，因為這款產品有望在視力、療效持續時間和安全性方面真正改變患者的治療體驗，而安全性正是他們從愛立信滴眼液（EYLEA）中了解到的。因此，我們非常興奮，期待著產品的上市，我們已經做好了充分的準備。

Okay. Next question, please.

好的，請問下一個問題。

Our next question comes from Akash Tewari with Jefferies.

下一個問題來自傑富瑞集團的阿卡什·特瓦里。

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?

為了更清楚說明美國安眠藥（EYLEA）的市場動態，其市佔率下降了5%，庫存受到7,000萬美元的影響，價格也隨之下調。能否詳細說明本季淨價格受到的影響，以及2023年下半年價格走勢的預期？此外，我們是否應該預期安眠藥的市佔率將維持在70%，還是隨著高劑量安眠藥的上市，市佔率可能會再次成長？

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.

那麼，讓我先談談其中的一些問題，其他人可能也想補充。首先，我想說的是，關於市場佔有率變化的一些計算並不完全準確。本季市佔率確實有所下降，但並沒有您提到的那麼嚴重。如果我縱觀整個第一季的市場份額，正如您所描述的，這是一個競爭更加激烈的市場，競爭對手眾多，其中既有價格非常低廉的，也有其他類型的。總的來說，安永目前的業績表現非常強勁，我們今天正著眼於未來的產品組合規劃以及阿柏西普8毫克製劑的上市。

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.

至於具體的定價和最終價格計算方法，我無法提供具體數字。但我認為，我們已經就庫存、整體競爭壓力以及我們為即將推出的同類新品所做的準備工作（我們希望在獲得FDA批准後儘快上市）等方面，向您提供了一定的透明度。

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

正如瑪麗昂所提到的，顯然，從環比來看，需求略有增長。因此，很明顯，我們受到了瑪麗昂所提及的那些因素的抵消。

All right. Next question, please.

好的，請問下一個問題。

Our next question comes from Chris Schott with JPMorgan.

我們的下一個問題來自摩根大通的克里斯·肖特。

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?

我剛剛有個關於IL-33在慢性阻塞性肺病（COPD）中作用的問題。我想，您在Dupixent研究設計和結果方面的成功，應該大大增強了您對該專案的信心。那麼，您能否詳細談談，從整體上看，您認為這兩種藥物會如何相互作用？

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，因為我們所有的決定，以及所有促使我們進行這項特定研究並選擇特定COPD患者群體使用Dupixent的數據，都是基於許多因素。此外，我們的Regeneron遺傳學中心也提供了非常強大的人類遺傳學證據，表明該藥物具有活性，尤其是在我們實際觀察到活性的領域。所有這些都增強了我們的信心——因為我們在規劃和設計IL-33研究時採用了相同的標準、相同的方法等等，而且所有因素都匯聚在一起，並取得瞭如此顯著的成效，這無疑讓我們相信，同樣的方法也必將使IL-33研究取得成功。

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.

正如我們之前提到的，Dupixent 的療效非常顯著。它不僅顯著減少了急性惡化次數，還達到了其他所有重要的終點指標，其中最重要的是肺功能的改善。此外，除非使用真正有效的藥物，讓患者能真切感受到肺功能和生活品質的改善，否則很難達到如此顯著的生活品質提升。

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.

IL-33 的遺傳優勢非常顯著。我們正在進行 III 期研究，而 II 期研究的亞群正是我們進行 III 期研究的亞群。在 II 期研究中，我們已證實 IL-33 可使病情加重次數減少 42%。該亞組與我們正在使用 Dupixent 的患者群體有部分重疊。我們認為，我們已經有機會為這個長期未滿足醫療需求的群體帶來巨大的改變，因為長期以來，針對該群體的新型藥物缺乏有效的作用機制。 Dupixent 已經取得了突破，我們希望 IL-33 也能取得突破。這對於長期飽受病痛折磨、幾乎看不到希望的患者來說，意義非凡。它真的能為這個群體帶來巨大的改變。

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?

我只是想重複一下，喬治可能已經說過兩三次了，但或許值得再說一次。過去，藥物研發的流程是：先根據一些生物學原理或其他因素確定一個靶點，然後進行I期和II期臨床試驗，並希望II期試驗的結果能預示III期臨床試驗的走向。顯然，現在仍然沿用這種方法。但喬治提到的是，我們可以用一種獨特的方式，將我們的基因見解疊加到I期和II期臨床試驗之上，進行觀察、驗證，並判斷：阻斷某個靶點是否真的會產生有益效果？這個標靶是否與我們正在治療的疾病有關？

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?

我知道喬治已經說過三次了，但我認為值得再說一次。這確實能增強你的信心，而這種信心在很多方面都是Regeneron獨有的，那就是我們如何獲得這些基因資訊。很多人問我們，想想全世界有多少人做過基因測序，等我說完喬治可以回答，我知道我們已經對其中很大一部分人進行了測序，並將這些數據與所有匿名化的醫療信息結合起來。我們以多種方式利用這些信息，不僅用於識別靶點，還用於驗證我們在特定靶點和特定疾病方面所做的工作。喬治，我們究竟做了多少？

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

我們已經看到了大約一半接受基因定序的人類。

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.

我的意思是，那是一個包含數百萬資料的大型資料庫。我認為，你聽到的正是這一點，這或許可以解釋為什麼我們對Dupixent以及現在的抗IL-33藥物比其他人更有信心。

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.

既然如此，我就稍微展開一下，解釋一下它的運作方式。我們所做的，是辨識那些模擬藥物阻斷或加劇第2型路徑的作用的基因變異。我們發現，對於Dupixent，那些模擬Dupixent作用的基因變異，能夠保護人們免受慢性阻塞性肺病（COPD）的侵害，尤其是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.

IL-4/13路徑活性增強與疾病進展相關。顯然，事實的確是如此。我的意思是，這是人類遺傳學研究的成果，它是一個非常強大的預測指標。正如Len所說，我們對IL-33也進行了同樣的研究，發現基因變異會模擬阻斷或加劇該路徑。正如我之前所說，我們之所以能夠在研究中取得高成功率，秘訣之一就是我們將其視為未來決策的依據。

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.

下一個問題來自古根漢證券的亞廷·蘇內賈。

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?

這裡是艾迪希克曼，我是亞廷的記者。我想請您談談FDA關於抗VEGF試驗設計的指導草稿？這是否會對您對高劑量方案的看法產生影響？

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

我認為這對我們，對我們的項目，沒有任何影響。

Thank you, Len. Next question, please.

謝謝你，Len。請問下一個問題。

Our next question comes from David Risinger with SVB Securities.

下一個問題來自SVB證券的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。那我就直接進入正題吧。 Len，您在開場白中提到公司正在逐步實現收入來源多元化，減少對EYLEA的依賴。您能否談談您對EYLEA近期在美國銷售成長的預期，包括Regeneron推出HD後EYLEA整體的銷售前景？

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.

既然你直奔主題，那我就直接回答你的問題。我們不提供未來銷售額具體量化指標的預測。但從定性角度來看，正如Marion所說，我們預期EYLEA和8毫克阿柏西普的組合將隨著時間的推移成為公司成長的支柱產品。

Okay, thank you. Next question, please.

好的，謝謝。請問下一個問題。

Our next question comes from Hartaj Singh with Oppenheimer.

下一個問題來自奧本海默公司的哈塔吉·辛格。

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?

關於linvoseltamab，我有個問題想請教一下。在ASH會議上，您公佈了I期臨床試驗數據，我猜應該是劑量範圍數據。您在ASH上展示的數據確實很有趣。在ASCO會議上，我們應該期待看到什麼？會有劑量擴展數據嗎？ ASH會議上公佈的患者治療持續時間數據呢？ FDA在批准申請前需要看到哪些數據？

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，我想你們將會看到我們關鍵性二期臨床試驗數據的更新，也就是目前已經比較成熟的數據。我們希望在提交給FDA的生物製品許可申請（BLA）之前，會進一步更新這些數據。所以數據會非常接近最終結果。我們認為隨著數據的成熟，結果會更好。因為我們都知道，隨著對患者的追蹤時間延長，緩解率等指標會逐漸提高。但這些數據將顯示我們認為該藥物具有同類最佳的療效潛力，以及基於我們即將在ASCO年會上公佈的關鍵性研究結果所證明的在理想給藥方案下的安全性。

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兩個問題。

Our next question comes from Carter Gould with Barclays.

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?

抱歉打擾安怡了。我想簡單問一下，你們在第一季提到的價格壓力具體指的是什麼？是季節性因素造成的嗎？還是說這會成為未來市場格局中更長期的趨勢？

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，我想先簡單談談BCMA的故事，因為我對它特別感興趣。雙特異性抗體領域是由Regeneron公司開創的，我認為我們是第一家將雙特異性抗體應用於患者的公司。顯然，現在這個領域競爭非常激烈，有時很難區分你擁有的產品與競爭對手的產品，你會看到別人聲稱擁有某種特性，而你卻聲稱擁有另一種特性，如此往復。

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.

但如果你客觀地看待這個問題，我認為對於BCMAxCD3計畫來說，你確實可以看到一種差異化的分子，並且有潛力成為同類最佳。抗體並非都一樣，雙特異性抗體也並非都一樣。它們之間確實存在差異。臨床試驗項目也並非都一樣。我強烈建議你仔細考慮並進行比較。現在有人問到EYLEA的問題。 Marion，你來回答一下。

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，回到你關於競爭格局和價格壓力的問題。我認為，如果你觀察抗VEGF藥物領域，並回顧過去幾季的情況，你會發現競爭壓力一直在增加。這在一定程度上會影響價格格局，而且這種趨勢還會持續下去。

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.

但我只想分享並提醒大家，在VEGF類藥物領域，真正獲得認可的是產品特性。以EYLEA為例，它一經上市便改變了整個品類，而它的成功並非源自於最低的價格，對吧？其實，長期以來一直都有價格低廉甚至非常低廉的替代品，但真正讓醫生和病人最終選擇它的，是產品特性。

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，這始終是未來需要關注的一個非常重要的動態因素，而且隨著阿柏西普8毫克獲得FDA批准，我們即將把新產品推向市場，這無疑會引起處方醫生的極大興趣。但正如您所說，該類藥物的價格壓力將持續存在。然而，最重要的是產品特性和患者體驗到的臨床療效。

Thanks. Last question, please.

謝謝。最後一個問題。

Our last question comes from Evan Seigerman with BMO.

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.

我想請您詳細談談您從醫生那裡聽到的關於8毫克劑量的一些回饋。最好能詳細說明他們計劃如何使用這個劑量，以及假設該劑量在六月獲得批准。

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.

當然，隨著產品上市，醫生有機會使用並選擇合適的患者，實際處方狀況的更新將變得更加重要。我們顯然已經與醫療團隊做了大量工作，並與專家一起研究了臨床數據。為了儘早回答您的問題，我認為該產品適用於各種被認為合適的患者。適用人群範圍很廣。當然，當醫生考慮接診新患者時，該產品非常有吸引力。

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.

顯然，目前我們有很多患者對EYLEA並不熟悉。但未來，問題在於：為什麼不給新患者推薦一個既能提供EYLEA所有視力改善效果和安全性，又能提供更持久療效的產品呢？因為醫生都知道患者會感到焦慮，不希望接受不必要的眼部注射。同樣，有些患者可能使用其他產品（例如EYLEA或其他抗VEGF產品）後病情控制良好。但醫生們希望給他們更持久的治療機會，在某些情況下，如果該產品屬於抗VEGF類產品，還能改善視力並延長療效。

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.

所以我認為，吸引患者的因素既包括那些可能正在考慮轉換抗VEGF治療類別的患者，也包括潛在的新患者。希望這些資訊對您有所幫助，我期待著有一天我們能為您提供具體的市場經驗數據。

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.

謝謝瑪莉昂，也謝謝所有撥入電話的朋友們，謝謝你們對再生元公司的關注。對於排隊等候的朋友們，我們深表歉意，因為我們沒能一一解答。一如既往，投資者關係團隊隨時準備好解答大家可能存在的任何問題。再次感謝大家，祝大家今天愉快！

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。感謝各位的參與。您可以斷開連線了。