雷傑納榮製藥 (REGN) 2022 Q4 法說會逐字稿

Welcome to the Regeneron Pharmaceuticals Fourth Quarter 2022 Earnings Conference Call. My name is Shannon, 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 2022 年第四季度收益電話會議。我叫 Shannon，我將擔任今天電話的接線員。 （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, Shannon. Good morning, good afternoon and good evening to everyone listening around the globe. Thank you for your interest in Regeneron and welcome to our fourth quarter 2022 earnings conference call. An archive of this webcast will be available on our Investor Relations website shortly after the call ends.

謝謝你，香農。早上好，下午好，晚上好，所有在全球收聽的人。感謝您對 Regeneron 的關注，歡迎參加我們 2022 年第四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 then open the call up 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。在我們準備好的評論之後，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 businesses, financial forecast and guidance, development programs and related anticipated milestones, collaborations, finances, regulatory matters, payer coverage and reimbursement issues, intellectual property, pending litigation and other proceedings and competition.

我想提醒您，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。此類聲明可能包括但不限於與 Regeneron 及其產品和業務、財務預測和指導、開發計劃和相關預期里程碑、合作、財務、監管事項、付款人覆蓋範圍和報銷問題、知識產權、未決訴訟和其他程序和競爭。

Each forward-looking statement is subject to risks and uncertainties that could cause actual results to differ materially from those projected in that statement. A more complete description for these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission including its Form 10-K for the year ended December 31, 2022, which we expect to file with the SEC on Monday, February 6. Regeneron does not undertake any obligation to update any forward-looking statements whether as a result of new information, future events or otherwise.

每份前瞻性陳述都存在風險和不確定性，這些風險和不確定性可能導致實際結果與該陳述中預測的結果存在重大差異。有關這些風險和其他重大風險的更完整描述，請參見再生元向美國證券交易委員會提交的文件，包括截至 2022 年 12 月 31 日止年度的 10-K 表格，我們預計將於週一向美國證券交易委員會提交該文件， 2 月 6 日。Regeneron 不承擔任何義務更新任何前瞻性陳述，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.

此外，請注意，今天的電話會議將討論 GAAP 和非 GAAP 措施。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。

Once our call concludes, Bob Landry and the IR team will be available to answer any further questions you may have.

一旦我們的通話結束，Bob Landry 和 IR 團隊將可以回答您可能有的任何進一步問題。

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

有了這個，讓我把電話轉給我們的總裁兼首席財務官 Len Schleifer。萊恩？

I'm the Chief Executive.

我是行政長官

Chief Executive Officer.

首席執行官。

But it's okay. Good morning to everybody. And for those of you experiencing the arctic freeze, I hope you're staying warm.

不過沒關係。大家早上好。對於那些正在經歷北極冰凍的人，我希望你們能保持溫暖。

Our strong fourth quarter performance kept a remarkable year of Regeneron, highlighted by significant achievements that better position the company to deliver sustainable growth and shareholder value. Fourth quarter 2022 revenue increased 14% compared to the prior year when excluding the impact of contributions from REGEN-COV and Ronapreve underscoring the commercial strength and increasing diversity of our business.

我們強勁的第四季度業績讓 Regeneron 保持了非凡的一年，突出的顯著成就使公司能夠更好地實現可持續增長和股東價值。排除來自 REGEN-COV 和 Ronapreve 的貢獻的影響，2022 年第四季度的收入比上年增長 14%，這凸顯了我們業務的商業實力和日益多樣化。

We also made several important advances across our pipeline during the quarter, notably the submission of a biologic license application for aflibercept 8 milligrams in neovascular age-related macular degeneration, or wet AMD as well as diabetic macular edema, or DME, positioning us for a potential U.S. launch in late August of this year.

在本季度，我們還在我們的管道中取得了幾項重要進展，特別是提交了 8 毫克阿柏西普治療新生血管性年齡相關性黃斑變性或濕性 AMD 以及糖尿病性黃斑水腫或 DME 的生物許可申請，使我們定位於可能於今年 8 月下旬在美國推出。

Additionally, we received FDA approval for Libtayo in combination with chemotherapy as a first-line treatment for advanced non-small cell lung cancer, making Libtayo only the second PD-1 or PD-L1 antibody approved in this setting, regardless of a patient's histology or PD-L1 expressions level.

此外，我們獲得了 FDA 批准 Libtayo 聯合化療作為晚期非小細胞肺癌的一線治療，使 Libtayo 成為在這種情況下批准的第二種 PD-1 或 PD-L1 抗體，無論患者的組織學如何或 PD-L1 表達水平。

We also presented data from our rapidly advancing oncology pipeline, including for fianlimab, our LAG-3 antibody in combination with Libtayo in advanced non-small cell lung cancer; odronextamab, our CD20xCD3 bispecific in B-cell lymphomas; and linvoseltamab, our BCMAxCD3 bispecific in multiple myeloma; finally, Dupixent was approved for prurigo nodularis in Europe.

我們還提供了來自我們快速發展的腫瘤管道的數據，包括 fianlimab，我們的 LAG-3 抗體與 Libtayo 聯合治療晚期非小細胞肺癌； odronextamab，我們的 CD20xCD3 雙特異性 B 細胞淋巴瘤；和 linvoseltamab，我們的 BCMAxCD3 雙特異性治療多發性骨髓瘤；最後，Dupixent 在歐洲被批准用於治療結節性癢疹。

Briefly reflecting on 2022, we ended the year with 3 strategic imperatives that we felt we had to accomplish in order to position the company for long-term growth. First, we had to fortify the medium and long-term outlook for our retinal franchise. Based on the positive results that we reported in September 22, we believe aflibercept 8 milligrams has the potential to change the treatment paradigm for patients with wet AMD and DME by becoming the new standard of care for these patients, positioning Regeneron for prolonged leadership in this category.

簡要回顧 2022 年，我們以 3 項我們認為必須完成的戰略任務結束了這一年，以便為公司的長期增長定位。首先，我們必須加強視網膜特許經營的中長期前景。基於我們在 9 月 22 日報告的積極結果，我們認為 8 毫克阿柏西普有可能通過成為這些患者的新護理標準來改變濕性 AMD 和 DME 患者的治療模式，從而使再生元在該領域長期處於領先地位類別。

Second, we needed to maintain and grow Dupixent leadership across a variety of type 2 allergic diseases. 2022 turned out to be a phenomenal year with Dupixent global net product sales approaching $8.7 billion and growing 44% at constant currency. Despite new competition, Dupixent maintained a leading market position in atopic dermatitis, asthma and nasal polyps and was also approved in new indications, geographies and younger populations, which George will detail shortly. Collectively, these 2022 approvals meaningfully expanded the Dupixent commercial opportunity, allowing the addressable population to increase by approximately 225,000 patients, bringing the total addressable population to over 7 million patients globally.

其次，我們需要保持和發展 Dupixent 在各種 2 型過敏性疾病領域的領導地位。 2022 年是非凡的一年，Dupixent 全球產品淨銷售額接近 87 億美元，按固定匯率計算增長 44%。儘管存在新的競爭，Dupixent 在特應性皮炎、哮喘和鼻息肉方面保持了領先的市場地位，並且還在新的適應症、地區和年輕人群中獲得批准，喬治將在稍後詳細介紹。總的來說，這些 2022 年的批准顯著擴大了 Dupixent 的商業機會，使可尋址人口增加了約 225,000 名患者，使全球可尋址人口總數超過 700 萬。

And third, we wanted to make significant progress towards becoming a leader in immuno-oncology, and 2022 turned out to be a crucial year. Key to this long-term goal was acquiring Sanofi's share of global rights to Libtayo, an antibody discovered by Regeneron, which was a necessary step towards realizing the full clinical and commercial potential of this foundational therapy. It also enables us to unlock combination opportunities from promising candidates in our oncology pipeline, including with our LAG-3 antibody, our costimulatory bispecifics and our 3 -- our CD3 bispecifics. Looking ahead, we expect 2023 to be another notable year with significant incremental progress across these imperatives as well as in other areas of our business.

第三，我們希望在成為免疫腫瘤學領導者的道路上取得重大進展，而 2022 年是關鍵的一年。這一長期目標的關鍵是獲得賽諾菲對 Libtayo 的全球權利份額，Libtayo 是再生元發現的一種抗體，這是實現這一基礎療法的全部臨床和商業潛力的必要步驟。它還使我們能夠在我們的腫瘤管道中釋放有前途的候選人的組合機會，包括我們的 LAG-3抗體、我們的共刺激雙特異性抗體和我們的 3——我們的 CD3雙特異性抗體。展望未來，我們預計 2023 年將是又一個值得注意的一年，在這些當務之急以及我們業務的其他領域都將取得重大進展。

We are preparing for a potential U.S. launch for aflibercept 8 milligrams in late August, given prescribers decade-plus experience with EYLEA. And now with the 48-week data for aflibercept 8 milligrams, which demonstrated comparable efficacy and safety to EYLEA, but with longer treatment intervals, we believe that over time, there is an opportunity for aflibercept 8 milligram to become the new standard of care for wet AMD and DME.

考慮到開處方者在 EYLEA 方面擁有 10 多年的經驗，我們正準備在 8 月下旬在美國推出 8 毫克的 aflibercept。現在有了 8 毫克阿柏西普的 48 週數據，證明了與 EYLEA 相當的療效和安全性，但治療間隔更長，我們相信隨著時間的推移，8 毫克阿柏西普有機會成為新的護理標準濕 AMD 和 DME。

We expect Dupixent to continue to strengthen its leadership position across approved type 2 allergic diseases based on its differentiated mechanism of blocking both interleukin-4 and interleukin-13. In 2023, we have an opportunity to reach even more patients with potential regulatory approvals in new diseases, geographies and younger populations that could add another approximately 500,000 patients globally to the [biologic] eligible population. Additionally, we look forward to the upcoming readout of our first Phase III study of Dupixent in COPD in the first half of this year.

我們預計 Dupixent 將基於其阻斷 interleukin-4 和 interleukin-13 的差異化機制，繼續加強其在批准的 2 型過敏性疾病領域的領導地位。到 2023 年，我們有機會接觸到更多在新疾病、新地區和年輕人群中獲得潛在監管批准的患者，這可能會在全球範圍內為 [生物] 合格人群增加大約 500,000 名患者。此外，我們期待今年上半年即將公佈的 Dupixent 在 COPD 中的第一個 III 期研究。

In oncology, we expect to continue rapidly advancing our pipeline. For our LAG-3 combination with Libtayo, we are moving forward with expansion beyond melanoma to include lung cancer and potentially other solid tumors.

在腫瘤學方面，我們希望繼續快速推進我們的管道。對於我們與 Libtayo 的 LAG-3 組合，我們正在向前推進，將其擴展到黑色素瘤以外，包括肺癌和其他潛在的實體瘤。

For our costimulatory bispecifics, in combination with Libtayo, we are continuing dose expansion in our Phase I/II PSMAxCD28 program in advanced prostate cancer. We also expect to report additional Phase I data from our EGFRxCD28 program in solid tumors and to present initial clinical data for our MUC16xCD28 program in recurrent ovarian cancer.

對於我們的共刺激雙特異性藥物，與 Libtayo 相結合，我們正在繼續擴大晚期前列腺癌 I/II 期 PSMAxCD28 計劃的劑量。我們還希望報告我們的 EGFRxCD28 實體腫瘤項目的更多 I 期數據，並提供我們的 MUC16xCD28 項目在復發性卵巢癌中的初步臨床數據。

And within Hema, we anticipate second half regulatory submissions for odronextamab in follicular lymphoma and diffuse large B-cell lymphoma as well as linvoseltamab in refractory multiple myeloma.

在 Hema 內部，我們預計下半年將提交 odronextamab 治療濾泡性淋巴瘤和瀰漫性大 B 細胞淋巴瘤以及 linvoseltamab 治療難治性多發性骨髓瘤的監管申請。

In 2023, we also plan to rapidly move forward with clinical development of our next-generation COVID-19 antibody, which we believe could help protect the millions of (inaudible) patients who were unable to [map] a sufficient immune response from vaccination and treat those who require other alternatives. Activities enabling clinical manufacturing have commenced, and we expect to enter clinical development later this year.

2023 年，我們還計劃快速推進下一代 COVID-19 抗體的臨床開發，我們相信這可以幫助保護數百萬（聽不清）無法通過疫苗接種獲得足夠免疫反應的（聽不清）患者和治療那些需要其他選擇的人。支持臨床製造的活動已經開始，我們預計將在今年晚些時候進入臨床開發。

In closing, 2022 was a pivotal year at Regeneron, and we expect to continue making significant progress in 2023. Our strategy remains focused on investing in our internal R&D capabilities which has historically generated a high rate of return.

最後，2022 年是 Regeneron 的關鍵一年，我們預計將在 2023 年繼續取得重大進展。我們的戰略仍然專注於投資我們的內部研發能力，這在歷史上產生了高回報率。

We remain confident in our near and long-term growth prospects with approximately 35 pipeline candidates currently progressing through clinical trials. We will also continue looking for opportunities to complement these internal efforts by exploring potential collaborations. With our commercial capabilities continue to drive revenue growth and our strong financial position, Regeneron is extremely well positioned to continue delivering breakthroughs for patients and value to shareholders.

我們對我們的近期和長期增長前景充滿信心，目前約有 35 名管道候選人正在通過臨床試驗取得進展。我們還將繼續尋找機會，通過探索潛在的合作來補充這些內部努力。憑藉我們的商業能力繼續推動收入增長和我們強大的財務狀況，Regeneron 非常有能力繼續為患者帶來突破並為股東創造價值。

Now I will turn the call over to George.

現在我將把電話轉給喬治。

Thanks, Len.

謝謝，萊恩。

I would like to briefly walk you through our pipeline's progress in 2022 and touch upon what lies ahead in 2023.

我想簡要介紹一下 2022 年我們管道的進展情況，並談談 2023 年的前景。

In ophthalmology, we presented pivotal -- positive pivotal results for aflibercept 8 milligram in wet AMD and DME. These trials showed that aflibercept 8 milligram extended dosing intervals to every 12 or even 16 weeks for the vast majority of patients through 48 weeks without compromising the visual improvement or safety seen with EYLEA. These are truly unprecedented and potentially game-changing results who have not -- which have not been achieved using any other anti-VEGF agents.

在眼科領域，我們展示了阿柏西普 8 毫克治療濕性 AMD 和 DME 的關鍵性積極結果。這些試驗表明，阿柏西普 8 毫克可將絕大多數患者的給藥間隔延長至每 12 週甚至 16 週，直至 48 週，而不會影響 EYLEA 所見的視力改善或安全性。這些確實是前所未有的，並且可能會改變遊戲規則的結果，而這些結果是使用任何其他抗 VEGF 藥物都沒有實現的。

Moving to Dupixent. In 2022, Dupixent became the only biologic approved in atopic dermatitis, for infants as young as 6 months of age, the first treatment for prurigo nodularis and the first treatment in the United States for eosinophilic esophagitis. And just this week, we obtained the European Commission approval for eosinophilic esophagitis as well. In addition, we submitted a supplemental BLA for chronic spontaneous urticaria and shared positive Phase III data in children with eosinophilic esophagitis.

搬到 Dupixent。 2022 年，Dupixent 成為唯一獲批治療特應性皮炎的生物製劑，適用於 6 個月大的嬰兒，是美國首個治療結節性癢疹和嗜酸性粒細胞性食管炎的藥物。就在本週，我們也獲得了歐盟委員會對嗜酸性粒細胞性食管炎的批准。此外，我們還提交了一份針對慢性自發性蕁麻疹的補充 BLA，並分享了嗜酸性粒細胞性食管炎兒童的 III 期陽性數據。

Dupixent is now approved in 5 related type 2 allergic conditions, and our data shows that these diseases are mediated by IL-4 and IL-13 driven type 2 inflammation because many patients suffer from systemic type 2 inflammation, they often suffer from several of these diseases concurrently. And thus, Dupixent has the potential to holistically address these patients multiple type 2 conditions for which Dupixent is approved.

Dupixent 現在被批准用於 5 種相關的 2 型過敏性疾病，我們的數據顯示這些疾病是由 IL-4 和 IL-13 驅動的 2 型炎症介導的，因為許多患者患有全身 2 型炎症，他們經常患有其中的幾種疾病並發。因此，Dupixent 有可能全面解決這些患者的多種 Dupixent 獲批的2型疾病。

While many other immunomodulators are associated with worrisome immunosuppression and carry boxed warnings, Dupixent's safety profile supports its approval in infants. In 2023, we are looking forward to the initial results of BOREAS, the first Dupixent Phase III study in patients with chronic obstructive pulmonary disease, or COPD.

雖然許多其他免疫調節劑與令人擔憂的免疫抑制有關並帶有黑框警告，但 Dupixent 的安全性資料支持其在嬰兒中的批准。 2023 年，我們期待 BOREAS 的初步結果，這是第一個針對慢性阻塞性肺疾病或 COPD 患者的 Dupixent III 期研究。

Our Dupixent COPD Phase III studies have enrolled patients with elevated blood eosinophils aiming to select the patients with COPD driven by type 2 inflammation. The BOREAS study passed an interim futility analysis in 2020, an encouraging event, which triggered the start of the replicate Phase III NOTUS study. We are looking forward to the readout of BOREAS with the primary endpoint of annualized rate of acute, moderate and severe COPD exacerbations expected in the first half of '23.

我們的 Dupixent COPD III 期研究招募了血液嗜酸性粒細胞升高的患者，旨在選擇由 2 型炎症驅動的 COPD 患者。 BOREAS 研究在 2020 年通過了中期無效性分析，這是一個令人鼓舞的事件，它觸發了重複的 III 期 NOTUS 研究的開始。我們期待著 BOREAS 的讀數，其主要終點是 23 年上半年預計的急性、中度和重度 COPD 惡化的年化率。

Moving on to oncology. 2022 was an important year for our oncology programs. Libtayo was approved by the FDA in combination with chemotherapy in first-line, non-small cell lung cancer, irrespective of histology or PD-L1 expression levels, an achievement met by only one other PD-1 or PD-L1 targeting agent.

繼續腫瘤學。 2022 年是我們腫瘤學項目重要的一年。 Libtayo 被 FDA 批准與化療聯合用於一線非小細胞肺癌，無論組織學或 PD-L1 表達水平如何，只有一種其他 PD-1 或 PD-L1 靶向劑達到了這一成就。

Libtayo is also emerging as an essential backbone of our oncology pipeline as several programs in combination with Libtayo are starting to yield encouraging data. First, I'll discuss our LAG-3 antibody, fianlimab in combination with Libtayo, where we have recently shown positive data from a second confirmatory cohort of PD-1 naive metastatic melanoma patients and reported encouraging results from a smaller dataset in non-small cell lung cancer patients. These initial results suggest that the fianlimab Libtayo combination has a potentially best-in-class profile in melanoma and we are advancing broad pivotal programs in both melanoma and lung cancer. Phase III studies in metastatic melanoma in adjuvant melanoma are already enrolling, we have plans to soon initiate another Phase III study in perioperative melanoma as well as Phase II/III studies in first-line advanced as well as perioperative non-small cell lung cancer.

Libtayo 也正在成為我們腫瘤管道的重要支柱，因為與 Libtayo 結合的幾個項目開始產生令人鼓舞的數據。首先，我將討論我們的 LAG-3 抗體 fianlimab 與 Libtayo 的結合，我們最近在其中展示了來自 PD-1 初治轉移性黑色素瘤患者的第二個驗證隊列的陽性數據，並報告了來自非小樣本中較小數據集的令人鼓舞的結果細胞肺癌患者。這些初步結果表明，fianlimab Libtayo 組合在黑色素瘤中具有潛在的同類最佳特徵，我們正在推進黑色素瘤和肺癌的廣泛關鍵項目。轉移性黑色素瘤輔助黑色素瘤的 III 期研究已經在招募中，我們計劃很快啟動另一項圍手術期黑色素瘤 III 期研究以及一線晚期和圍手術期非小細胞肺癌的 II/III 期研究。

Other notable Libtayo combination used from this year was the early but very encouraging data with our PSMAxCD28 costimulatory bispecific in advanced metastatic castrate-resistant prostate cancer, a tumor type considered immunologically cold with multiple recent Phase III failures demonstrating that prostate cancer is largely unresponsive to anti-PD-1 therapy in other (inaudible) as well as in other types of chemo combination.

今年使用的其他值得注意的 Libtayo 組合是早期但非常令人鼓舞的數據，我們的 PSMAxCD28 共刺激雙特異性在晚期轉移性去勢抵抗性前列腺癌中，一種被認為免疫冷的腫瘤類型，最近多次 III 期失敗表明前列腺癌在很大程度上對抗-其他（聽不清）以及其他類型的化療組合中的 PD-1 療法。

Our proof-of-concept study of our PSMAxCD28 costimulatory bispecific, we observed first evidence that combining this new class of bispecifics with anti-PD-1 can confirm profound responsiveness to tumors previously thought to be cold and unresponsive to anti-PD-1 therapy with 3 out of the 4 patients treated at the highest dose levels showing greater than 90% reductions within 6 weeks of initiating combination therapy in the prostate cancer biomarker, PSA. Following up on these early but exciting results, we're continuing to enroll patients in this study, and we are planning to present additional data at medical meetings in 2023.

在我們的 PSMAxCD28 共刺激雙特異性藥物的概念驗證研究中，我們觀察到第一個證據表明，將這種新型雙特異性藥物與抗 PD-1 抗體相結合可以證實對先前被認為是冷腫瘤且抗 PD-1 治療無反應的腫瘤具有深刻的反應性在接受最高劑量水平治療的 4 名患者中，有 3 名在開始前列腺癌生物標誌物 PSA 的聯合治療後 6 週內顯示出超過 90% 的減少。繼這些早期但令人興奮的結果之後，我們將繼續招募患者參與這項研究，我們計劃在 2023 年的醫學會議上展示更多數據。

We also presented our first clinical data for a CD3 bispecific in a solid tumor. For ubamatamab, our MUC16xCD3 bispecific in development for advanced ovarian cancer. As a single agent in a Phase I dose escalation study in heavily pretreated recurrent ovarian cancer patients, we observed a 4% overall response rate with a 31% response rates in a small subset of patients with high MUC16 expressing tumors. We expect initial dose escalation data later this year for ubamatamab with Libtayo as well as for our MUC16xCD28 costimulatory bispecific with Libtayo in advanced ovarian cancer. We also expect updated clinical data for our EGFRxCD28 costimulatory bispecific in combination with Libtayo in various solid tumors later this year.

我們還展示了實體瘤中 CD3 雙特異性的第一個臨床數據。對於 ubamatamab，我們的 MUC16xCD3 雙特異性藥物正在開發中，用於治療晚期卵巢癌。作為針對經過大量預處理的複發性卵巢癌患者進行的 I 期劑量遞增研究中的單一藥物，我們觀察到 4% 的總體緩解率和一小部分 MUC16 高表達腫瘤患者的 31% 緩解率。我們預計今年晚些時候 ubamatamab 與 Libtayo 以及我們的 MUC16xCD28 共刺激雙特異性藥物與 Libtayo 在晚期卵巢癌中的初始劑量遞增數據。我們還期待在今年晚些時候更新我們的 EGFRxCD28 共刺激雙特異性藥物與 Libtayo 聯合治療各種實體瘤的臨床數據。

Moving on to our hematology oncology pipeline. At the American Society of Hematology, or ASH, Annual Meeting, we presented new data from odronextamab, our CD20xCD3 bispecific as well as linvoseltamab our BCMAxCD3 bispecific. For odronextamab, we presented pivotal Phase II (inaudible) data. Odronextamab in third or later line relapsed or recurring follicular lymphoma has a potential best-in-class efficacy profile with 82% of patients responding and 92% of these responders achieving a complete response with encouraging durability.

繼續我們的血液學腫瘤學管道。在美國血液學會年會上，我們展示了我們的 CD20xCD3 雙特異性藥物 odronextamab 以及我們的 BCMAxCD3 雙特異性藥物 linvoseltamab 的新數據。對於 odronextamab，我們提供了關鍵的 II 期（聽不清）數據。 Odronextamab 在三線或更高線的複發性或複發性濾泡性淋巴瘤中具有潛在的同類最佳療效，82% 的患者有反應，其中 92% 的反應者實現了完全反應，並具有令人鼓舞的持久性。

Our optimized step-up dosing regimen has improved odronextamab's safety profile while retaining efficacy similar to the prior dosing regimen. In third or later line relapse or recurrent diffuse large B-cell lymphoma, odronextamab demonstrated efficacy regardless of prior CAR T experience and a safety profile generally similar to that seen in follicular lymphoma.

我們優化的遞增給藥方案改善了 odronextamab 的安全性，同時保持與之前給藥方案相似的療效。在三線或更晚線復發或複發性瀰漫性大 B 細胞淋巴瘤中，無論先前的 CAR T 經驗如何，odronextamab 都證明了療效，並且安全性與濾泡性淋巴瘤中的安全性大體相似。

We are planning regulatory submissions in the second half of 2023 for both indications, which we hope will support potential accelerated approvals. In 2023, we anticipate initiating several Phase III studies in follicular lymphoma and diffuse large B-cell lymphoma, including in earlier lines of therapy. These trials will serve as confirmatory studies which could potentially support conversion to full approval. We also expect to initiate a proof-of-concept study of our CD22xCD28 costimulatory bispecific in combination with odronextamab in diffuse large B-cell lymphoma, which we hope could further add to the anticancer benefit for these patients.

我們計劃在 2023 年下半年針對這兩種適應症提交監管申請，我們希望這將支持潛在的加速批准。 2023 年，我們預計將啟動幾項針對濾泡性淋巴瘤和瀰漫性大 B 細胞淋巴瘤的 III 期研究，包括早期治療。這些試驗將作為驗證性研究，可能支持轉換為完全批准。我們還希望啟動我們的 CD22xCD28 共刺激雙特異性結合 odronextamab 治療瀰漫性大 B 細胞淋巴瘤的概念驗證研究，我們希望這可以進一步增加這些患者的抗癌益處。

For linvoseltamab, our BS -- BCMAxCD3 bispecific antibody, we presented efficacy and safety data from our pivotal Phase II study in third or later line multiple myeloma at ASH. Early, deep and durable responses were observed in patients with high disease burden, and these responses may improve with longer follow-up.

對於 linvoseltamab，我們的 BS - BCMAxCD3 雙特異性抗體，我們展示了我們在 ASH 的三線或更晚線多發性骨髓瘤的關鍵 II 期研究的療效和安全性數據。在具有高疾病負擔的患者中觀察到早期、深度和持久的反應，這些反應可能會隨著更長時間的隨訪而改善。

In 2023, we plan to initiate a confirmatory Phase III study of linvoseltamab in second line multiple myeloma and are on track for a BLA submission in the second half of the year. As with odronextamab, we plan to initiate combination studies for linvoseltamab with costimulatory bispecifics in the near future.

2023 年，我們計劃在二線多發性骨髓瘤中啟動 linvoseltamab 的驗證性 III 期研究，並有望在今年下半年提交 BLA。與 odronextamab 一樣，我們計劃在不久的將來啟動 linvoseltamab 與共刺激雙特異性藥物的聯合研究。

I'd also like to update some additional clinical programs. Our antibody blocking Factor XI for anticoagulation in an antibody that activates the NPR1 receptor for heart failure are both completing proof of mechanism trials.

我還想更新一些額外的臨床項目。我們的抗體阻斷因子 XI 用於激活心力衰竭 NPR1 受體的抗體中的抗凝作用正在完成機制試驗的證明。

Moving on to Regeneron genetics medicine. Regarding our collaboration with Alnylam in siRNA therapeutics, we are planning a broad and multipronged approach to develop treatments for NASH, nonalcoholic steatohepatitis. We are initiating a Phase II study of ALN-HSD in NASH patients with genetic risk factors. We also dosed first subjects in the first in-human study of another siRNA medicine in development for NASH, ALN-PNP, which targets a different gene and can be potentially combined with ALN-HSD in appropriate patients. We have discovered additional NASH targets, which we have validated using our Regeneron Genetics Center, including [Side B], which will potentially be the next NASH therapeutic candidate to enter the clinic. With regard to our collaboration with Alnylam for central nervous system targets, our initial dose escalation study is ongoing.

繼續研究再生元遺傳學醫學。關於我們與 Alnylam 在 siRNA 療法方面的合作，我們正在計劃採用廣泛且多管齊下的方法來開發 NASH（非酒精性脂肪性肝炎）的治療方法。我們正在對具有遺傳風險因素的 NASH 患者啟動 ALN-HSD 的 II 期研究。我們還在針對 NASH 開發的另一種 siRNA 藥物 ALN-PNP 的首次人體研究中對第一批受試者進行了給藥，該藥物靶向不同的基因，並可能在適當的患者中與 ALN-HSD 聯合使用。我們發現了其他 NASH 目標，我們已經使用我們的 Regeneron 遺傳學中心驗證了這些目標，包括 [B 面]，這可能是下一個進入臨床的 NASH 治療候選者。關於我們與 Alnylam 在中樞神經系統靶標方面的合作，我們正在進行初始劑量遞增研究。

Our collaboration with Intellia in CRISPR-based therapeutics is expected to progress further in 2023, building on continuing data readouts from the Phase I study of NTLA-2001 in transthyretin amyloidosis in both cardiomyopathy and neuropathy patients, which provided the first demonstration in humans that CRISPR-based technologies can deliver up to 90% reduction of the pathological gene product for over a year.

我們與 Intellia 在基於 CRISPR 的療法方面的合作預計將在 2023 年取得進一步進展，基於 NTLA-2001 在心肌病和神經病患者轉甲狀腺素蛋白澱粉樣變性 I 期研究中的持續數據讀出，該研究首次在人類身上證明 CRISPR基於技術的技術可以在一年多的時間裡減少高達 90% 的病理基因產物。

Regarding our gene therapy efforts, our collaborators at Decibel Therapeutics recently announced that a clinical trial has been authorized by both the U.S. FDA and the U.K. MHRA for DB-OTO, a virally delivered gene therapy designed to restore hearing to individuals with otoferlin-related hearing loss. A Phase I/II study in patients 2 years of age and younger is expected to initiate in the first half of 2023 with initial data from the first [cohort] of patients anticipated in the first quarter of 2024.

關於我們的基因治療工作，我們在 Decibel Therapeutics 的合作者最近宣布，一項針對 DB-OTO 的臨床試驗已獲得美國 FDA 和英國 MHRA 的授權，這是一種病毒傳遞的基因療法，旨在恢復與 otoferlin 相關聽力的個人的聽力損失。一項針對 2 歲及以下患者的 I/II 期研究預計將於 2023 年上半年啟動，預計將於 2024 年第一季度獲得第一批[隊列]患者的初步數據。

I'd like to conclude with our next-generation COVID-19 efforts. As we recently announced, we have identified a potent broadly neutralizing COVID-19 antibody, which, unlike other neutralizing antibodies find outside of the so-called receptor binding domain, or RBD, of the [spike] protein. This antibody retains activity against all the viral variants seen throughout the pandemic because it binds to an epitope that has remained highly conserved, greater than 99.9% across all known variants. The vast majority of antiviral antibodies generated as a result of vaccination or due to natural infection target the RBD domain, which results in overwhelming selective pressure driving the emergence of these resistant variants. We hope that by targeting this unique and conservative epitope outside of the RBD, this antibody will also retain its activity in the face of future variants. We plan to initiate clinical trials to test this antibody this year, and we are looking to develop it in both treatment and prophylactic setting.

我想以我們在下一代 COVID-19 方面的努力作為總結。正如我們最近宣布的那樣，我們已經確定了一種有效的廣泛中和 COVID-19 抗體，與其他中和抗體不同，該抗體發現在 [刺突] 蛋白的所謂受體結合域或 RBD 之外。該抗體保留了針對整個大流行期間出現的所有病毒變體的活性，因為它結合了一個高度保守的表位，在所有已知變體中保守性超過 99.9%。由於接種疫苗或由於自然感染而產生的絕大多數抗病毒抗體都靶向 RBD 結構域，這導致壓倒性的選擇壓力推動了這些抗性變體的出現。我們希望通過靶向 RBD 之外的這個獨特且保守的表位，該抗體在面對未來的變體時也能保持其活性。我們計劃在今年啟動臨床試驗來測試這種抗體，我們正在尋求在治療和預防環境中開發它。

In conclusion, Regeneron's R&D engine continues its productivity, including the early-stage pipeline. Just in the first weeks of this year, we have initiated clinical studies for 2 new drug [candidates] and we anticipate clinical trials starting or IND submission for up to 10 new therapeutic candidates this year as well as for additional indications for candidates that are already in the clinic.

總之，Regeneron 的研發引擎繼續保持其生產力，包括早期管道。就在今年的前幾週，我們已經啟動了 2 種新藥 [候選藥物] 的臨床研究，我們預計今年將開始臨床試驗或提交 IND 以提交多達 10 種新的治療候選藥物，以及為已經獲得批准的候選藥物提供額外的適應症在診所裡。

So with that, I will turn it over to Marion.

因此，我將把它交給 Marion。

Thanks, George.

謝謝，喬治。

The fourth quarter capped off a strong year of execution and growth, delivering results across our commercial portfolio. We expanded into new indications, which, coupled with our existing business, is expected to drive meaningful growth in 2023 and beyond. We look forward to several important potential approvals and subsequent launches this year, providing additional opportunities for growth.

第四季度為執行和增長強勁的一年畫上了句號，在我們的商業組合中取得了成果。我們擴展到新的適應症，加上我們現有的業務，預計將在 2023 年及以後推動有意義的增長。我們期待著今年獲得幾項重要的潛在批准和隨後的發布，從而提供更多的增長機會。

Starting with EYLEA, where we announced in January, fourth quarter U.S. net sales of $1.5 billion, full year 2022 net sales were $6.3 billion, representing 8% year-over-year growth and outpacing total growth of the anti-VEGF category for the year. At the end of the fourth quarter, EYLEA category share was approaching previous levels of approximately 50% of injections. This followed the short-term shift earlier in the quarter where EYLEA was negatively impacted by a temporary increase in use of off-label compounded Avastin. During this time, there was a short-term closure of a not-for-profit patient co-pay assistance fund, which we opened later in the quarter.

從我們在 1 月份宣布的 EYLEA 開始，第四季度美國淨銷售額為 15 億美元，2022 年全年淨銷售額為 63 億美元，同比增長 8%，超過了全年抗 VEGF 類別的總增長.第四季度末，EYLEA 類別份額接近之前的水平，約佔注入量的 50%。這是在本季度早些時候的短期轉變之後發生的，當時 EYLEA 受到臨時增加使用非標籤複合阿瓦斯汀的負面影響。在此期間，我們在本季度晚些時候開設了一個非營利性患者共同支付援助基金，該基金短期關閉。

We believe we have substantially recovered from the issue encountered in the fourth quarter. We continue to expect competitive pressures but remain confident in Regeneron's overall retinal franchise as we look forward to our potential upcoming aflibercept 8 milligram launch.

我們相信我們已經從第四季度遇到的問題中大幅恢復。我們繼續期待競爭壓力，但對 Regeneron 的整體視網膜專營權仍然充滿信心，因為我們期待即將推出的 aflibercept 8 毫克。

In summary, our retinal franchise leads the anti-VEGF category with EYLEA as the current standard of care and aflibercept 8 milligram, if approved, offering a differentiated clinical profile that can potentially shift the treatment paradigm.

總之，我們的視網膜專營權以 EYLEA 作為當前的護理標準和 aflibercept 8 毫克，在抗 VEGF 類別中處於領先地位，如果獲得批准，將提供可能改變治療模式的差異化臨床特徵。

Turning to Libtayo. Total fourth quarter global net sales were $169 million, growing 44% on a constant currency basis. In the U.S., net sales grew 36% to $110 million with contributions across all indications. In advanced non-melanoma skin cancers, we continue to build our leadership position in the PD-1 class. In lung cancer, Libtayo continues to see steady growth in utilization in prescribers. Customer ordering has accelerated following the chemotherapy combination approval last November. We are working to maximize launch uptake by increasing depth and breadth of prescribers.

轉向 Libtayo。第四季度全球淨銷售額總額為 1.69 億美元，按固定匯率計算增長 44%。在美國，淨銷售額增長了 36%，達到 1.1 億美元，對所有適應症都有貢獻。在晚期非黑色素瘤皮膚癌中，我們繼續在 PD-1 類中建立領導地位。在肺癌方面，Libtayo 的處方藥使用率繼續穩步增長。去年 11 月化療組合獲批後，客戶訂購速度加快。我們正在努力通過增加處方的深度和廣度來最大限度地提高上市率。

Early launch indicators are positive, community and academic centers have welcomed Libtayo's expanded role as an important treatment option in advanced non-small cell lung cancer. There are more than 200,000 new cases of lung cancer per year in the U.S. alone for which Libtayo is an important treatment option.

早期啟動指標是積極的，社區和學術中心歡迎 Libtayo 作為晚期非小細胞肺癌的重要治療選擇擴大作用。僅在美國，每年就有超過 200,000 例肺癌新病例，而 Libtayo 是一種重要的治療選擇。

Outside the U.S., Libtayo net sales grew 60% on a constant currency basis to $59 million driven by steady demand growth and additional launches as we secure access and reimbursement globally. We continue a targeted approach to extend our global commercial footprint in priority international markets designed to maximize opportunities for Libtayo in potential future medicines.

在美國以外，Libtayo 的淨銷售額按固定匯率計算增長了 60%，達到 5900 萬美元，這得益於穩定的需求增長和我們在全球範圍內確保訪問和報銷的額外發布。我們繼續採取有針對性的方法來擴大我們在優先國際市場的全球商業足跡，旨在為 Libtayo 在潛在的未來藥物方面提供最大的機會。

Finally, turning to Dupixent, where in the fourth quarter, global net sales grew 42% on a constant currency basis to $2.45 billion. In the U.S., net sales grew 44% to $1.94 billion, with strong growth continuing across atopic dermatitis, asthma, nasal polyps with additional contributions from recent launches in the eosinophilic esophagitis and prurigo nodularis. Dupixent is well positioned to expand market penetration and drive revenue growth across established new and potential future indications in 2023 and beyond.

最後，轉向 Dupixent，第四季度全球淨銷售額按固定匯率計算增長 42% 至 24.5 億美元。在美國，淨銷售額增長 44% 至 19.4 億美元，特應性皮炎、哮喘、鼻息肉等領域繼續保持強勁增長，最近在嗜酸性粒細胞性食管炎和結節性癢疹領域推出的產品也做出了額外貢獻。 Dupixent 處於有利地位，可以在 2023 年及以後擴大市場滲透並推動已建立的新適應症和潛在未來適應症的收入增長。

Atopic dermatitis, Dupixent's largest indication continues to rapidly grow across all age groups, firmly establishing Dupixent as the preferred systemic therapy for patients with moderate to severe disease. There continues to be rapid uptake in younger populations, further confirming Dupixent's differentiated efficacy and safety profile. We've also seen meaningful early adoption in prurigo nodularis where Dupixent is the only FDA-approved medicine for this debilitating disease. We expect ongoing uptake of Dupixent as the launch progresses and physicians identify patients' need.

特應性皮炎是 Dupixent 最大的適應症，在所有年齡組中繼續快速增長，堅定地確立了 Dupixent 作為中度至重度疾病患者首選全身療法的地位。年輕人群繼續快速吸收，進一步證實了 Dupixent 的差異化療效和安全性。我們還看到了在結節性癢疹中有意義的早期採用，其中 Dupixent 是 FDA 批准的唯一一種治療這種衰弱性疾病的藥物。我們預計隨著發布的進行和醫生確定患者的需求，Dupixent 將持續被接受。

Dupixent continues to perform well in the highly competitive biologic asthma space with steady market share gains and strong growth in total prescriptions and new patient starts. In nasal polyps, Dupixent's differentiated clinical profile continues to drive uptake as the leading first line treatment option in patients requiring systemic therapy.

Dupixent 在競爭激烈的生物哮喘領域繼續表現良好，市場份額穩步增長，總處方和新患者開始強勁增長。在鼻息肉中，Dupixent 的差異化臨床特徵繼續推動其成為需要全身治療的患者的領先一線治療選擇。

In the eosinophilic esophagitis, the launch is going exceptionally well, finally offering physicians and their patients a treatment to effectively manage the underlying mechanism of the disease. Patients treated with Dupixent have experienced dramatic improvements in their symptoms and quality of life. We've seen rapid uptake across both gastroenterologists and allergists. We also continue to advance our clinical efforts in younger patients where there is also substantial unmet need.

在嗜酸性粒細胞性食管炎方面，該藥物的上市進展非常順利，最終為醫生及其患者提供了一種有效管理疾病潛在機制的治療方法。接受 Dupixent 治療的患者的症狀和生活質量得到顯著改善。我們已經看到胃腸病學家和過敏症專家的快速接受。我們還繼續推進我們在年輕患者中的臨床工作，這些患者也有大量未滿足的需求。

Outside the U.S., Dupixent net sales worth $513 million, growing 37% on a constant currency basis, driven by rapid uptake across approved indications and launches in new geographies. In Europe, Dupixent was approved for prurigo nodularis in December. And earlier this week, Dupixent was also approved for eosinophilic esophagitis. We expect these new indications to contribute to Dupixent's ongoing international growth.

在美國以外，Dupixent 的淨銷售額為 5.13 億美元，按固定匯率計算增長了 37%，這主要得益於批准適應症的快速採用和在新地區的推出。在歐洲，Dupixent 於 12 月被批准用於治療結節性癢疹。本週早些時候，Dupixent 也被批准用於嗜酸性粒細胞性食管炎。我們預計這些新適應症將有助於 Dupixent 持續的國際增長。

In summary, during 2022, we executed on our core focus to deliver life-changing medicines to patients. Our commercial initiatives and strategies are driving increases in market penetration for our [in-line brands] and optimizing the potential of new and upcoming launches. Taken together, we are confident in Regeneron's future and are well positioned to deliver long-term and sustainable growth.

總之，在 2022 年期間，我們執行了我們的核心重點，為患者提供改變生命的藥物。我們的商業舉措和戰略正在推動我們 [在線品牌] 的市場滲透率提高，並優化新產品和即將推出的產品的潛力。總而言之，我們對 Regeneron 的未來充滿信心，並有能力實現長期和可持續的增長。

Now I'll turn the call to Bob.

現在我會把電話轉給鮑勃。

Thank you, Marion.

謝謝你，馬里恩。

My comments today on Regeneron's financial results and outlook will be on a non-GAAP basis, unless otherwise noted.

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 ended 2022 with a strong fourth quarter with continued execution driving positive results across the business. Excluding contributions from REGEN-COV and Ronapreve, fourth quarter total revenues increased 14% year-over-year to $3 billion, driven by growth across our core brands. Fourth quarter diluted net income per share was $12.56 on net income of $1.4 billion.

Regeneron 以強勁的第四季度結束了 2022 年，持續的執行推動了整個業務的積極成果。不包括來自 REGEN-COV 和 Ronapreve 的貢獻，第四季度總收入同比增長 14% 至 30 億美元，這得益於我們核心品牌的增長。第四季度每股攤薄淨收益為 12.56 美元，淨收益為 14 億美元。

Beginning with collaboration revenue and starting with Bayer. Fourth quarter 2022 ex U.S. EYLEA net product sales were $839 million, up 7% on a constant currency basis versus fourth quarter 2021. Total Bayer collaboration revenue was $355 million, of which $324 million related to our share of EYLEA net profits outside the U.S.

從合作收入開始，從拜耳開始。 2022 年第四季度美國 EYLEA 淨產品銷售額為 8.39 億美元，按固定匯率計算比 2021 年第四季度增長 7%。拜耳合作總收入為 3.55 億美元，其中 3.24 億美元與我們在美國境外的 EYLEA 淨利潤份額相關。

Total Sanofi collaboration revenue was $836 million in the fourth quarter and grew 61%, driven by Dupixent. Our share of profits from the commercialization of Dupixent and Kevzara was $619 million, an increase of 60% versus the prior year. We also recognized a $50 million sales-based milestone in the fourth quarter of 2022 due to achievement of $2.5 billion of ex U.S. sales of antibody collaboration products on a rolling 12-month basis.

在 Dupixent 的推動下，第四季度賽諾菲合作總收入為 8.36 億美元，增長 61%。我們從 Dupixent 和 Kevzara 的商業化中獲得的利潤份額為 6.19 億美元，比上一年增長了 60%。我們還確認了 2022 年第四季度銷售額達到 5000 萬美元的里程碑，原因是在連續 12 個月的基礎上抗體協作產品在美國以外的銷售額達到了 25 億美元。

Finally, we recorded Roche collaboration revenue of $396 million in the fourth quarter for our share of gross profits from ex U.S. sales of Ronapreve related to a previously signed contract.

最後，我們在第四季度記錄了羅氏合作收入 3.96 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。

Moving now to our operating expenses. Fourth quarter 2022 R&D expense increased 43% year-over-year to $911 million, driven by the impact of the Libtayo transaction with Regeneron now recording all R&D expense for Libtayo and our full 50% share of antibody collaboration R&D spend for Dupixent and itepekimab as well as additional costs incurred in connection with the company's late-stage pipeline and increasing clinical manufacturing activities and higher headcount-related costs.

現在轉到我們的運營費用。 2022 年第四季度研發費用同比增長 43% 至 9.11 億美元，這是受與 Regeneron 的 Libtayo 交易的影響所推動，現在記錄 Libtayo 的所有研發費用以及我們在 Dupixent 和 itepekimab 抗體合作研發支出中的全部 50% 份額作為以及與公司後期管道和增加臨床製造活動相關的額外成本以及與員工人數相關的更高成本。

SG&A expense increased 17% year-over-year to $579 million due to higher headcount and related costs, incremental costs to fully support the global commercialization of Libtayo and higher contributions to an independent not-for-profit patient assistance organization. Product gross margin in the quarter increased to 93% as compared to 86% in the prior year. The improved gross margin was driven by a favorable change in product mix and no longer having to pay Sanofi for their share of U.S. Libtayo gross profits. Finally, fourth quarter 2022 effective tax rate was 11.3% compared to 12.6% in the prior year.

SG&A 費用同比增長 17% 至 5.79 億美元，原因是員工人數和相關成本增加、為全面支持 Libtayo 的全球商業化而增加的成本以及對獨立非營利患者援助組織的更高貢獻。本季度的產品毛利率從去年同期的 86% 上升至 93%。毛利率的提高是由產品組合的有利變化推動的，並且不再需要向賽諾菲支付其在美國 Libtayo 毛利潤中的份額。最後，2022 年第四季度的有效稅率為 11.3%，而去年同期為 12.6%。

Shifting now to cash flow and the balance sheet. For full year 2022, Regeneron generated $4.4 billion in free cash flow, favorably impacted by our first quarter 2022 payment from the U.S. government for sales of REGEN-COV that were recorded in the fourth quarter of 2021. We ended 2022 with cash and marketable securities [less debt] of $11.6 billion.

現在轉向現金流和資產負債表。 2022 年全年，Regeneron 產生了 44 億美元的自由現金流，這得益於我們在 2022 年第一季度從美國政府支付的 2021 年第四季度記錄的 REGEN-COV 銷售付款。我們在 2022 年底以現金和有價證券結束[減去債務] 116 億美元。

We continue to deliver on our capital allocation priorities in 2022 by deploying approximately $3.4 billion towards business development and share repurchases while continuing to fund our internal R&D efforts. In 2022, we executed approximately $1.3 billion in business development initiatives, including the acquisitions of Checkmate Pharmaceuticals in the exclusive worldwide rights to Libtayo.

我們將繼續在 2022 年實現我們的資本配置優先事項，將約 34 億美元用於業務發展和股票回購，同時繼續為我們的內部研發工作提供資金。 2022 年，我們執行了約 13 億美元的業務發展計劃，包括收購 Checkmate Pharmaceuticals 在 Libtayo 的全球獨家權利。

We also purchased approximately $2.1 billion of our shares in 2022, including $431 million in the fourth quarter. This morning, we announced a new $3 billion share repurchase authorization reflecting our continued confidence in our business and our pipeline. We remain buyers of our shares at current levels, and this new authorization enables us to continue returning capital directly to shareholders.

我們還在 2022 年購買了約 21 億美元的股票，其中包括第四季度的 4.31 億美元。今天早上，我們宣布了一項新的 30 億美元股票回購授權，反映出我們對我們的業務和管道的持續信心。在目前的水平上，我們仍然是我們股票的買家，這項新授權使我們能夠繼續直接向股東返還資本。

I'd like to conclude with our initial financial guidance and outlook for 2023. We expect 2023 SG&A spend to be in the range of $2.13 billion to $2.28 billion. This primarily reflects the full year impact of global Libtayo commercialization expenses, the build-out of our international commercial infrastructure in select markets and higher headcount to support our growing organization.

我想以我們對 2023 年的初步財務指導和展望作為結束。我們預計 2023 年的 SG&A 支出將在 21.3 億美元至 22.8 億美元之間。這主要反映了全球 Libtayo 商業化費用的全年影響、我們在特定市場的國際商業基礎設施的建設以及為支持我們不斷發展的組織而增加的員工人數。

We expect our 2023 R&D expense to be in the range of $3.725 million to $3.925 billion. As George mentioned, we have numerous strategically important development programs advancing in 2023, including late-stage studies for our fianlimab, Libtayo combination in melanoma and lung cancer in confirmatory Phase III studies for odronextamab, both in FL and DLBCL and linvoseltamab in myeloma.

我們預計 2023 年的研發費用將在 372.5 萬美元至 39.25 億美元之間。正如 George 提到的，我們在 2023 年有許多具有戰略意義的重要發展計劃，包括我們的 fianlimab 的後期研究，黑色素瘤的 Libtayo 組合和肺癌的 odronextamab 的驗證性 III 期研究，包括 FL 和 DLBCL 和 linvoseltamab 的骨髓瘤。

In addition, we continue to advance programs in our early pipeline across multiple therapeutic areas including with collaborators such as Alnylam and Intellia positioning us for long-term growth. This range also includes the full year impact of the Libtayo transaction, we are now recording all development expenses for Libtayo and recognizing our full 50% share of development expenses for Dupixent and itepekimab.

此外，我們繼續在多個治療領域推進我們早期管道中的項目，包括與 Alnylam 和 Intellia 等合作者的合作，使我們能夠實現長期增長。該範圍還包括 Libtayo 交易的全年影響，我們現在記錄了 Libtayo 的所有開發費用，並確認了我們在 Dupixent 和 itepekimab 開發費用中的全部 50%份額。

COCM is expected to be in the range of $720 million to $800 million, similar to 2022 reflecting the gradual phase-in of a new Regeneron developed manufacturing process for Dupixent that is designed to improve drug substance yields. We expect our capital expenditures in 2023 to be in the range of $825 million to $950 million. These expenditures will support the continued expansion of our manufacturing facilities, including ongoing construction of a fill/finish facility as well as the previously announced expansion of R&D facilities at our Tarrytown, New York headquarters.

COCM 預計將在 7.2 億美元至 8 億美元之間，與 2022 年相似，反映了再生元為 Dupixent 開發的旨在提高藥物產量的新製造工藝的逐步採用。我們預計 2023 年的資本支出將在 8.25 億美元至 9.5 億美元之間。這些支出將支持我們製造設施的持續擴張，包括正在進行的灌裝/塗飾設施建設以及之前宣布的紐約塔里敦總部研發設施的擴建。

Finally, we anticipate 2023 gross margin to be between 90% to 92% and our effective tax rate to be in the range of 11% to 13%. In addition to our full year financial guidance, we expect higher interest income in 2023, given our greater cash balance plus higher interest rates as compared to last year, which will favorably impact other income and expense. We also expect 2023 other revenue to be slightly lower than 2022. Finally, as I said in November, we no longer expect to record any material other operating income or expense in 2023 or beyond, absent a new transaction.

最後，我們預計 2023 年的毛利率將在 90% 至 92% 之間，我們的有效稅率將在 11% 至 13% 之間。除了我們的全年財務指導外，我們預計 2023 年的利息收入會更高，因為我們的現金餘額比去年更高，加上利率比去年更高，這將對其他收入和支出產生有利影響。我們還預計 2023 年的其他收入將略低於 2022 年。最後，正如我在 11 月份所說，如果沒有新交易，我們預計不會在 2023 年或以後記錄任何重大的其他營業收入或支出。

In conclusion, Regeneron continued to deliver robust financial results in 2022, and we are well positioned to drive continued growth in 2023 and beyond.

總之，Regeneron 在 2022 年繼續提供強勁的財務業績，我們有能力推動 2023 年及以後的持續增長。

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.

謝謝你，鮑勃。

Shannon, 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 on to the next. Shannon, please go ahead and poll for questions.

香農，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，我們將回答每個來電者的一個問題，然後再繼續下一個問題。香農，請繼續投票提問。

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

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

Congratulations on the results. Regarding EYLEA, it'd be great to hear the latest on what you're seeing in the marketplace with respect to Vabysmo. Apparently, Roche is not seeing switches from Vabysmo back to EYLEA, despite what we are hearing from the KOLs. So any additional color there would be helpful.

祝賀結果。關於 EYLEA，很高興聽到您在市場上看到的關於 Vabysmo 的最新消息。顯然，儘管我們從 KOL 那裡聽到了什麼，羅氏並沒有看到從 Vabysmo 回到 EYLEA 的轉變。所以任何額外的顏色都會有幫助。

Tyler, yes, and let me comment that certainly, EYLEA performance in the market, as I reported, continues to be very strong. A quick reminder on the year, growing at 8% to $6.3 billion, and certainly, a very strong competitive performance.

泰勒，是的，讓我評論說，正如我所報告的那樣，EYLEA 在市場上的表現當然非常強勁。快速回顧這一年，增長 8% 至 63 億美元，當然，這是非常強勁的競爭表現。

We're conscious of competition in the marketplace. But to give a bit of an update, we continue to hear that faricimab use has been modest and results, in some cases, have resulted in patients switching back to other agents, including EYLEA, probably most frequently EYLEA. Certainly, we look forward to continued efforts on EYLEA this year as the standard of care. And as you know, from many of us talking to KOLs, they're incredibly enthusiastic about the launch -- potential launch of aflibercept 8 milligram coming later this year.

我們意識到市場上的競爭。但要提供一點更新，我們繼續聽說 faricimab 的使用是適度的，結果在某些情況下導致患者轉回其他藥物，包括 EYLEA，可能最常見的是 EYLEA。當然，我們期待今年繼續努力將 EYLEA 作為護理標準。正如你所知，我們中的許多人都與 KOL 交談過，他們對此次發布非常熱情——可能會在今年晚些時候推出 aflibercept 8 毫克。

Next question, please.

請下一個問題。

Our next question comes from the line of Matthew Harrison with Morgan Stanley.

我們的下一個問題來自 Matthew Harrison 與摩根士丹利的對話。

Matt, we don't hear you.

馬特，我們聽不到你的聲音。

Sorry, could you not hear me, Len?

對不起，你能聽不見我說話嗎，萊恩？

We hear you now.

我們現在聽到你了。

Yes, we can.

我們可以。

Okay. All right. Sorry. So I was just wondering if you could comment on COPD and what you view as clinically meaningful in terms of result there. Other companies have reported sort of 15%. But I think in the past, you've talked about that as not being a particularly high bar. So maybe you could just talk about how you view clinical meaning from this.

好的。好的。對不起。所以我只是想知道你是否可以評論 COPD 以及你認為在結果方面具有臨床意義的內容。其他公司報告了大約 15%。但我認為在過去，你談到這不是一個特別高的標準。所以也許你可以談談你如何看待這個的臨床意義。

Well, we powered our futility analysis as well as our clinical trial to deliver what we believe would be clinically meaningful benefit if the study proves positive, which we hope it will. And remember, we're going to be looking at both exacerbations, but also improvement in lung function. So it will be a sort of integration of the benefit that patients can receive from both those measures. I remind you that in other settings in asthma, in particular, Dupixent has distinguished itself from other immunomodulators in delivering pretty substantial improvements in pulmonary lung function.

好吧，我們為我們的無效性分析和臨床試驗提供了動力，以提供我們認為如果研究證明是積極的則具有臨床意義的益處，我們希望它會如此。請記住，我們不僅要關注病情惡化，還要關注肺功能的改善。因此，這將是患者可以從這兩種措施中獲得的好處的一種整合。我提醒您，特別是在哮喘的其他環境中，Dupixent 在顯著改善肺功能方面與其他免疫調節劑不同。

So it's not only all about exacerbations, but we hope to have significant improvements in exacerbations as well as in lung functions which will hopefully provide important benefits to patients.

因此，這不僅與惡化有關，而且我們希望在惡化和肺功能方面有顯著改善，這有望為患者帶來重要益處。

Thank you. Next question, please.

謝謝。請下一個問題。

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

我們的下一個問題來自卡特古爾德與巴克萊銀行的合作。

You do have some APP data on the horizon here with Alnylam. I would love to kind of hear your thoughts on how you're thinking about that. And if we should be thinking about that as more just a proof of concept or as a potential product opportunity even with intrathecal delivery? And if, I guess, more of the former, how much of this is sort of a gating factor to really kind of expanding the effort here potentially dramatically across a number of CNS diseases.

使用 Alnylam，您確實有一些即將出現的 APP 數據。我很想听聽您對您的想法。我們是否應該將其更多地視為概念驗證或潛在的產品機會，即使是鞘內給藥？如果，我猜，更多的是前者，那麼這在多大程度上是一個門控因素，可以真正擴大這裡的努力，可能會在許多中樞神經系統疾病中顯著擴大。

Well, as you say, the important thing about that aspect of the Alnylam collaboration is together, we were hoping for the first time to see if we could develop technology that would actually allow us to do what's been done now by Alnylam and others in the liver to bring it to other tissues, particularly to the central nervous system in this case. So this -- the first study, which is focused on APP, is really a proof of concept that can we get this technology to work.

好吧，正如你所說，Alnylam 合作的重要方面是在一起，我們希望第一次看到我們是否能夠開發出真正允許我們做 Alnylam 和其他人現在所做的事情的技術肝臟將其帶到其他組織，在這種情況下尤其是中樞神經系統。因此，這是第一項針對 APP 的研究，它確實是我們能否讓這項技術發揮作用的概念證明。

We view it as a potential sort of platform enabler, meaning that if we see anything here, and obviously, these are challenging things to be first and to do something that nobody has ever done before. And it's obviously very early in the program. But the goal is to establish proof of principle that this type of technology, which looks like it can be pretty effective in the liver, can it work outside of the liver, particularly in the CNS. So this would be a platform enabler.

我們將其視為一種潛在的平台推動者，這意味著如果我們在這裡看到任何東西，很明顯，這些都是具有挑戰性的事情，需要首先做一些以前沒有人做過的事情。很明顯，它還處於計劃的早期階段。但我們的目標是證明這種技術在肝臟中看起來非常有效，但它能否在肝臟之外發揮作用，尤其是在中樞神經系統中。所以這將是一個平台推動因素。

Thanks, George. Next question, please.

謝謝，喬治。請下一個問題。

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

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

Congrats on all the progress. So with the potential approval coming this summer, I'm curious how we should be thinking about the launch cadence for high-dose aflibercept just considering some elements like the introduction of prefilled string, the J-code and maybe your overall strategy and how you're thinking about converting market segments and where you're initially focused.

祝賀所有的進步。因此，隨著今年夏天可能獲得批准，我很好奇我們應該如何考慮高劑量 aflibercept 的發布節奏，只考慮一些元素，如預填充字符串的引入、J 代碼以及你的整體戰略以及你如何正在考慮轉換細分市場以及您最初關注的領域。

Give us a second, we'll disconnect all the Roche people on the call, so we can get you our strategy. In all seriousness, obviously, there's a lot of thought that's going to go in between now and what we hope will be our late August approval on pricing, on rollout, on targeting, on strategy, et cetera, et cetera, but we're working on that. We have to get our label. We have to get it approved, and we'll have everything else ready to go. The initial launch will be with a vial, and then we hope down the road, not too far with the prefilled range.

等一下，我們會斷開所有羅氏人員的通話，這樣我們就可以為您提供我們的策略。顯然，嚴肅地說，從現在到我們希望在 8 月下旬批准定價、推出、目標、戰略等等，我們會有很多想法，但我們正在努力。我們必須得到我們的標籤。我們必須讓它獲得批准，我們將準備好其他一切。最初的發射將是一個小瓶，然後我們希望在未來，預裝範圍不會太遠。

Marion, I don't know if you want to give away any of your secrets at this point.

Marion，我不知道你現在是否願意透露你的任何秘密。

I would just say that we have a highly experienced team in commercialization, and we certainly will be ready for the launch. And in the meantime, we're very focused on our participation in the market today with EYLEA but certainly more to come, and we absolutely look forward to the potential launch of 8 milligrams.

我只想說，我們在商業化方面擁有一支經驗豐富的團隊，我們當然會為發布做好準備。與此同時，我們非常關注我們今天與 EYLEA 一起參與市場，但肯定會更多，我們絕對期待 8 毫克的潛在推出。

Obviously, the Vabysmo launch has not turned the market sideways on us. It's real competition. But that, I think, there's a window that's sort of closing for them to compete against 2 milligrams, we hope and then 8 milligrams, we hope could become the standard of care. So lots to look forward to later in the year.

顯然，Vabysmo 的推出並沒有讓市場轉向我們。這是真正的競爭。但是，我認為，有一個窗口可以讓他們與 2 毫克競爭，我們希望然後是 8 毫克，我們希望它能成為護理標準。今年晚些時候有很多值得期待的事情。

Certainly. Thank you. Next question, please.

當然。謝謝。請下一個問題。

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

我們的下一個問題來自 BMO Capital Markets 的 Evan Seigerman。

Maybe a follow-up to Matt's question. Can you just speak to what you saw in the (inaudible) interim efficacy analysis of the BOREAS trial? And just any additional color on the level of benefit versus placebo that triggered the initiation of the NOTUS trial?

也許是馬特問題的後續行動。您能否談談您在 BOREAS 試驗的（聽不清）中期療效分析中看到的內容？以及觸發 NOTUS 試驗啟動的關於獲益水平與安慰劑水平的任何其他顏色？

All I can say is that we powered it to deliver we thought would be a clinically significant improvement. There was a combination of measures of exacerbations and lung function improvement, and we haven't disclosed what those numbers were.

我只能說，我們為它提供動力，以實現我們認為在臨床上具有重大意義的改進。有加重和肺功能改善的綜合措施，我們還沒有透露這些數字是多少。

And we remain blinded to that interim analysis, Evan, so. Next question, please.

我們仍然對中期分析視而不見，埃文，所以。請下一個問題。

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

我們的下一個問題來自高盛的 Salveen Richter。

With regard to the oncology portfolio, what do you consider the most meaningful milestones for the next 12 months and particularly here the PSMAxCD28 asset?

關於腫瘤產品組合，您認為未來 12 個月最有意義的里程碑是什麼，尤其是 PSMAxCD28 資產？

Well, we obviously have some important submissions we need to get in later in the year, as we mentioned, for our CD3 bispecifics. And we need to continue to get data later in the year with more patients with PSMAxCD28 bispecifics as well as from some of the other costim bispecifics. And we have to move aggressively enrolling the additional studies we plan for LAG-3. So -- and we have to make Libtayo even more successful, we hope, in the marketplace around the world. So lots to do.

好吧，正如我們提到的，我們顯然有一些重要的提交需要在今年晚些時候提交，用於我們的 CD3 雙特異性藥物。我們需要在今年晚些時候繼續獲取更多使用 PSMAxCD28 雙特異性藥物以及其他一些 costim 雙特異性藥物的患者的數據。我們必須積極採取行動，招募我們為 LAG-3 計劃的額外研究。所以——我們必須讓 Libtayo 在全球市場上更加成功，我們希望如此。有很多事情要做。

I don't know if George or Marion have anything else to add there.

我不知道 George 或 Marion 是否還有其他要補充的。

Yes. I think it's -- it was really critically important for us to validate individual agents in each class. That was our strategy. We wanted to develop the best-in-class checkpoint inhibitors, such as our PD-1 antibody, Libtayo; such as our LAG-3 antibody, fianlimab. We wanted to establish [CD3] bispecifics that were best-in-class and that were working in hem-onc settings, but also in solid tumor settings. And then, of course, we want to validate that this incredible principle of costimulatory bispecifics that we introduced into the world, which were truly magical in animal studies with essentially working like turnkey agents to synergize with the other 2 classes in animal studies that we could reproduce that sort of activity in humans.

是的。我認為這是 - 驗證每個班級中的個別代理人對我們來說真的非常重要。那是我們的策略。我們想開發一流的檢查點抑製劑，例如我們的 PD-1 抗體 Libtayo；比如我們的LAG-3抗體，fianlimab。我們想要建立同類最佳的 [CD3] 雙特異性藥物，它們既適用於 hem-onc 設置，也適用於實體瘤設置。然後，當然，我們想驗證我們引入這個世界的這個令人難以置信的共刺激雙特異性原理，它在動物研究中真的很神奇，基本上像交鑰匙代理一樣工作，與動物研究中的其他 2 個類別協同作用，我們可以在人類身上重現那種活動。

And so us obviously, it takes years to get to that point, but we feel we're in a very exciting position right now because, as I said, the individual classes are validated. We're starting to see impressive combination opportunities. We talked about combining 2 checkpoints, combining our LAG-3 with PD-1, where it looks like we have maybe taken first line melanoma to a different point where patients can get a lot more benefit from this combination. And now having validated those, we're expanding much more broadly.

所以我們顯然需要數年時間才能達到這一點，但我們覺得我們現在處於一個非常令人興奮的位置，因為正如我所說，各個課程都得到了驗證。我們開始看到令人印象深刻的組合機會。我們談到了結合 2 個檢查點，將我們的 LAG-3 與 PD-1 結合起來，看起來我們可能已經將一線黑色素瘤帶到了一個不同的點，患者可以從這種組合中獲得更多的好處。現在已經驗證了這些，我們正在更廣泛地擴展。

Same thing with the CD3 bispecifics. We're growing that franchise now that we've shown that our platform works, and we're working both in hem-onc and outside in solid tumor settings. And the fact that our first costim bispecific delivered the sort of exciting early data that it delivered really gets us, very excited about the possibility now that we have this whole rollout.

CD3 雙特異性抗體也是如此。我們正在擴大特許經營權，因為我們已經證明我們的平台是有效的，而且我們在 hem-onc 和實體腫瘤環境中都在努力。事實上，我們的第一個 costim 雙特異性藥物提供了它提供的那種令人興奮的早期數據，這真的讓我們非常興奮，因為我們已經有了整個推出的可能性。

We have several of these costim bispecifics in the clinic, clearing their dose escalation safety settings, and we're now going to be rolling out data from these combinations, more data from the PSMA costim bispecific in prostate cancer in more patients, but we're also going to be reporting on a series of other costims, including not only in combinations that we've already talked about in solid tumors, but in the hem-onc space where we're very excited, obviously, about our CD20xCD3 bispecific by itself and our BCMAxCD3 bispecific by themselves, as Len said, we're both filing for those, hopefully, by the end of the year.

我們在臨床上有幾種這樣的 costim 雙特異性藥物，清除了它們的劑量遞增安全設置，我們現在將推出這些組合的數據，更多來自 PSMA costim 雙特異性藥物在更多患者中的數據，但我們'我們還將報告一系列其他共生成分，不僅包括我們已經在實體瘤中討論過的組合，還包括我們非常興奮的 hem-onc 空間，顯然，我們的 CD20xCD3 雙特異性本身和我們的 BCMAxCD3 雙特異性，正如 Len 所說，我們都希望在今年年底之前申請這些。

But also initiating earlier line studies. But just as importantly, we're going to be initiating combination with these costim bispecifics, which we think yet again, if these continue to work like they work not only in the animal models, but now how they're looking in the early human study, these could really leapfrog the individual agents to a whole place where they're really changing the practice of medicine and delivering much more benefit to patients, which is what we're all about.

但也開始了早期的線路研究。但同樣重要的是，我們將開始與這些 costim 雙特異性結合，我們再次考慮，如果它們繼續發揮作用，就像它們不僅在動物模型中起作用，而且現在它們在早期人類中的表現一樣研究，這些真的可以跨越個體代理到一個真正改變醫學實踐並為患者帶來更多利益的整個地方，這就是我們的全部。

Yes. I don't think George's point, can be overstated. Cancer cures in serious advanced tumors are still far and few between. And there's still tremendous need which makes this a very dynamic treatment marketplace because people want that extra benefit because it's not like they're getting cures -- we haven't cured lung cancer or we haven't cured most serious cancers.

是的。我不認為喬治的觀點被誇大了。嚴重晚期腫瘤的癌症治愈率仍然相差甚遠。並且仍然存在巨大的需求，這使得它成為一個非常有活力的治療市場，因為人們想要額外的好處，因為這不像他們正在得到治愈——我們還沒有治愈肺癌，或者我們還沒有治愈最嚴重的癌症。

So the ability to have foundational individual treatments and then get more by combining them really does position us to leapfrog, to use George's word, in the treatment paradigm out in the world because patients and their doctors are very sensitive to improve outcomes because there's still tremendous, tremendous need.

因此，擁有基礎個體治療然後通過組合獲得更多治療的能力確實使我們能夠在世界範圍內的治療範式中實現跨越式發展，用喬治的話來說，因為患者和他們的醫生對改善結果非常敏感，因為仍然有巨大的，巨大的需求。

Thank you. Next question, Shannon.

謝謝。下一個問題，香農。

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

我們的下一個問題來自 Mohit Bansal 與 Wells Fargo 的合作。

Maybe staying with COPD. So talking to some KOLs and reading some papers, it seems like IL-13 has some implication into fibrosis as well. Now so the question is, could -- do you think there could be a beneficial effect of IL-13 blockade and its impact on fibrosis on COPD over and above blocking inflammation? And if yes, do you think a 1-year trial would be enough to see that?

也許繼續患有慢性阻塞性肺病。因此，與一些 KOL 交談並閱讀一些論文後，IL-13 似乎對纖維化也有一些影響。現在的問題是，您是否認為 IL-13 阻斷及其對 COPD 纖維化的影響除了阻斷炎症之外還有其他有益作用？如果是，您認為 1 年的試用期是否足以證明這一點？

I think you bring up really interesting points. We were actually involved in some of the experiments years ago that showed that IL-13 could actually cause fibrosis in animal models. And certainly, we do believe that long term, like in many of the diseases that we studied so far, that the benefit of Dupixent in blocking both IL-4 and IL-13 can continue to accrue for the patient in terms of preventing the chronic inflammation that results in so much of this remodeling that you talked about, we believe this may be true in asthma.

我認為你提出了非常有趣的觀點。事實上，我們幾年前就參與了一些實驗，這些實驗表明 IL-13 實際上可以在動物模型中引起纖維化。當然，我們確實相信，從長遠來看，就像我們目前研究的許多疾病一樣，Dupixent 在阻斷 IL-4 和 IL-13 方面的益處可以繼續為患者帶來預防慢性導致您談到的如此多的這種重塑的炎症，我們相信這在哮喘中可能是正確的。

And we're actually involved in programs and studies to show that some of the same things that you're talking about will also benefit in that you will prevent long-term remodeling that decreases lung function over time as structural changes in the asthmatic patients and we believe that, that may also be true, of course, in COPD.

我們實際上參與了一些項目和研究，以表明您正在談論的一些相同的事情也將受益，因為您將防止長期重塑，這種重塑隨著時間的推移會隨著哮喘患者的結構變化而降低肺功能，並且我們相信，當然，對於慢性阻塞性肺病，這也可能是正確的。

But first, we need, as you say, the shorter-term studies to be positive, but we do believe that if they produce the type of data that we're hoping, Dupixent produces the type of data we're hoping it could in COPD, that longer-term studies, like you say, could end up showing even longer-term benefits in terms of exactly the type of remodeling and fibrotic changes that result in permanent loss of function, lung function in these patients. So we think that you're totally right, but it will probably, as you say, take longer-term studies to actually pick that up.

但首先，正如你所說，我們需要短期研究是積極的，但我們確實相信，如果它們產生了我們希望的數據類型，Dupixent 就會產生我們希望它能夠產生的數據類型慢性阻塞性肺病，就像你說的那樣，長期研究最終可能會在重塑和纖維化變化的確切類型方面顯示出更長期的益處，這些變化會導致這些患者永久喪失功能，肺功能。所以我們認為你是完全正確的，但正如你所說，可能需要更長期的研究才能真正接受這一點。

Thanks, George. Next question, Shannon.

謝謝，喬治。下一個問題，香農。

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

我們的下一個問題來自 Colin Bristow 與 UBS 的對話。

I wanted to sort of push a little more on the [due COPD] readout. And just trying to understand what's underpinning your confidence here. It certainly feels like you're more enthusiastic than what we're hearing out of Europe. Is this primarily based on the threshold set for BOREAS interim and these were sufficiently robust that you just -- you feel good about the ultimate result? Or is there something else you can point us to?

我想在 [應有的 COPD] 讀數上多推一點。只是想了解是什麼支撐著你的信心。肯定感覺你比我們從歐洲聽到的更熱情。這是否主要基於為 BOREAS 臨時設置的閾值，並且這些閾值足夠強大，您只是 - 您對最終結果感覺良好？或者您還有什麼可以指出我們的嗎？

Yes. I wouldn't over under-read our situation right here. And it almost doesn't matter because Regeneron is a data-driven enterprise, and we're all going to see the data coming up, we hope later this quarter. We are totally blinded to the evaluation that was done on the interim analysis. We have said we set it at a reasonable bar, but it was only a fraction of the patients. So you never know how this is going to turn out. We would not be as confident about something like this compared to another classic type 2 inflammatory disease. So you have that on the negative side. But on the positive side, you do have the fact that we've selected patients who have [eosinophils] and we had this interim analysis. Bottom line is we look forward to the data as well as you do.

是的。我不會低估我們這裡的情況。這幾乎無關緊要，因為 Regeneron 是一家數據驅動的企業，我們都將看到數據出現，我們希望在本季度晚些時候。我們完全不知道對中期分析所做的評估。我們說過我們將其設置在一個合理的標準，但這只是一小部分患者。所以你永遠不知道結果會如何。與另一種經典的 2 型炎症性疾病相比，我們對這種情況的信心不足。所以你有消極的一面。但從積極的方面來看，我們確實選擇了患有 [嗜酸性粒細胞] 的患者，並且我們進行了中期分析。底線是我們和您一樣期待數據。

Thanks, Len. Next question, Shannon.

謝謝，萊恩。下一個問題，香農。

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

我們的下一個問題來自 Chris Raymond 和 Piper Sandler 的台詞。

Maybe a broader question on the VEGF retinal market. Last year, at AAO, there was a lot of discussion and debate around the potential impact on retinal specialist practices if intravitreal therapies for geographic atrophy are approved. And some folks were talking about, just back of the envelope, this could drive a pretty sizable like 30-some percent increase in injection volume, the practices just from treating geographic atrophy patients.

也許是關於 VEGF 視網膜市場的更廣泛的問題。去年，在 AAO 上，有很多討論和辯論圍繞著如果地理萎縮的玻璃體內療法獲得批准對視網膜專家實踐的潛在影響。有些人在談論，就在信封的後面，這可能會導致注射量增加 30% 左右，這些做法僅來自治療地圖樣萎縮患者。

As you guys think about this dynamic, we've heard some KOLs sort of offer up potential fix to that, that they would move in a more accelerated fashion to longer duration, longer-acting therapies for wet AMD. Are you guys seeing that? Is that something that we should be thinking about in terms of a driver from short-acting to longer acting?

當你們考慮這種動態時，我們聽說一些 KOL 提供了潛在的解決方案，他們將以更快的方式轉向持續時間更長、作用更長的濕性 AMD 療法。你們看到了嗎？就從短效到長效的驅動因素而言，這是我們應該考慮的事情嗎？

Yes. I mean I think despite all of these practice aspects, the primary driver will be that patients would prefer to get a needle in the eye less frequently. With every time you put a needle in the eye, there is a risk of inflammation or more serious complications, hemorrhages, detachments, things like that. So the less you have to do that and get the same benefit is better for the patients from the needle-in-the-eye perspective. And it's better for the patient from the number of times they have to come to the doctor's office. These are elderly patients frequently; they have to have a caregiver.

是的。我的意思是，我認為儘管有所有這些實踐方面，但主要的驅動因素將是患者更願意不那麼頻繁地在眼睛裡打針。每次將針刺入眼睛時，都有發生炎症或更嚴重並發症、出血、脫落等類似情況的風險。因此，從針刺眼的角度來看，您需要做的越少並獲得相同的好處對患者就越好。從他們必須來醫生辦公室的次數來看，這對患者來說更好。這些通常是老年患者；他們必須有一個照顧者。

From a practice perspective, certainly, as many doctors' offices are overwhelmed by -- in the number of injections that they're giving and that they could free up time with -- if you could get the same result. From a practice point of view with less frequent injections. Certainly, that would free up more time and would drive them. But I believe at the end of the day, docs do make the decision with their patient on this primarily because less injections in the eye are just safer and more convenient for the patient.

從實踐的角度來看，當然，許多醫生的辦公室已經不堪重負——他們提供的注射次數和他們可以騰出時間的——如果你能得到相同的結果。從實踐的角度來看，注射頻率較低。當然，這會騰出更多時間並推動他們。但我相信在一天結束時，醫生確實會就此與患者一起做出決定，主要是因為減少眼部注射對患者來說更安全、更方便。

Well, we also shouldn't lose sight of the fact that if treatments for geographic atrophy become much more -- take off and become much more prevalent that they do have a side effect. They're actually increasing levels of macular edema in these patients, which will, of course, necessitate a treatment there as well.

好吧，我們也不應該忽視這樣一個事實，即如果地理萎縮的治療變得更加 - 起飛並變得更加普遍，它們確實有副作用。他們實際上增加了這些患者的黃斑水腫水平，當然，這也需要在那裡進行治療。

Thanks. We have time for 2 more questions, Shannon.

謝謝。香農，我們還有時間再問 2 個問題。

Our next question comes from the line of Chris Schott with JPMorgan.

我們的下一個問題來自摩根大通的 Chris Schott。

Just on the costim platform, I guess once you land on the right dose for these products, do you expect that there could be accelerating filing pathways given the few options available for most of these patients? Or do we still need to think about needing to go slowly even with the registrational studies as you're kind of balancing, I guess, safety versus efficacy.

就在 costim 平台上，我想一旦你為這些產品找到了正確的劑量，你是否期望鑑於這些患者中的大多數可用的選擇很少，會有加速的申請途徑？或者我們是否仍然需要考慮即使在註冊研究中也需要緩慢進行，因為我想你是在平衡安全性和有效性。

Well, we certainly believe that when you're in something where there's tremendous medical need and no alternative, that there will be opportunities to move for accelerated approval. We're all aware of the new FDA guidelines that they want you to be underway with your pivotal studies are well underway, I think, is a phrase they use. So we're taking that into account. But there's no question that if we can reproduce the efficacy that we saw in these late-stage prostate cancer patients. There's not only the need, but there will be a mechanism to get that to patients as quickly as possible.

好吧，我們當然相信，當您處於有巨大醫療需求且別無選擇的地方時，就會有機會加快審批速度。我們都知道新的 FDA 指導方針，他們希望你正在進行你的關鍵研究正在進行中，我認為，這是他們使用的一個短語。所以我們正在考慮這一點。但毫無疑問，如果我們能夠重現我們在這些晚期前列腺癌患者身上看到的療效。不僅有需要，而且會有一種機制盡快將其提供給患者。

Remember, the main issue, as you referred to, is keep being mindful of the safety. And of course, we're doing everything we can to mitigate that. But remember, thus far, for the most part, there's been an extremely tight linkage of safety and efficacy. That is the adverse events occurred in those patients who were having the substantial benefit. So that makes the risk/reward even more attractive from a regulator's and a doctor's and frankly, a patient's perspective.

請記住，正如您所提到的，主要問題是要時刻注意安全。當然，我們正在盡一切努力減輕這種情況。但請記住，到目前為止，在大多數情況下，安全性和有效性之間存在極其緊密的聯繫。那就是在那些獲得實質性益處的患者中發生的不良事件。因此，從監管機構和醫生以及坦率地說，患者的角度來看，這使得風險/回報更具吸引力。

So the short answer is we think we're not going to go too fast where one would be reckless. We have to be careful. But we do think there is an opportunity for an accelerated approval if we follow the new approach the FDA has laid out.

所以簡短的回答是，我們認為我們不會走得太快，否則會魯莽行事。我們必須小心。但我們確實認為，如果我們遵循 FDA 制定的新方法，就有機會獲得加速批准。

Thanks, Len. Last question, please, Shannon.

謝謝，萊恩。最後一個問題，香農。

Our last question comes from the line of Robyn Karnauskas with Truist.

我們的最後一個問題來自 Robyn Karnauskas 與 Truist 的對話。

Great. So just a follow-up on the prior question. So for your MUC16xCD28 and MUC16xCD3 combination, what are you expecting regarding the safety profile? And how do you think about that type of combination efficacy and safety wise versus a CD28 [CPI] combo? And just a follow-up to that. I know the FDA was concerned back in the day about dosing up with CD28 superagonist, like do you think that your initial data might alleviate some of the needs of (inaudible) doses for CD28 bispecifics.

偉大的。所以只是對先前問題的跟進。那麼對於您的 MUC16xCD28 和 MUC16xCD3 組合，您對安全性有何期望？與 CD28 [CPI] 組合相比，您如何看待這種組合的有效性和安全性？這只是後續行動。我知道 FDA 在當天就擔心 CD28 超激動劑的劑量，就像你認為你的初始數據可能會減輕 CD28 雙特異性（聽不清）劑量的一些需求一樣。

Well, a lot of good questions in there. I'll start from the end first. For sure, when we started the program, there was very serious concerns about previous experience with general CD28 activators that activated all over the body that resulted in really horrific situations for patients, which almost killed the field. We invented this new approach to tightly limit where we were limiting CD28 activation right at the tumor surface and so forth.

好吧，裡面有很多好問題。我將從頭開始。可以肯定的是，當我們開始這個項目時，人們非常擔心以前使用通用 CD28 激活劑的經驗，這些激活劑會激活全身，導致患者處於非常可怕的境地，這幾乎扼殺了這個領域。我們發明了這種新方法來嚴格限制我們在腫瘤表面等處限制 CD28 激活的位置。

And of course, there was a concern from the FDA, which is why, as you said, they made us employ a very, very conservative dose escalation program. We had to go through 5 or 6 dose levels just to get to where we thought were the active dose levels where we then start to see the rather dramatic antitumor activity that we began to report. We are hoping that as we get more experience and show that what we had demonstrated preclinically is really holding true in humans.

當然，FDA 也有顧慮，正如你所說，這就是為什麼他們讓我們採用非常非常保守的劑量遞增計劃。我們必須經歷 5 或 6 個劑量水平才能達到我們認為的活性劑量水平，然後我們開始看到我們開始報告的相當顯著的抗腫瘤活性。我們希望，隨著我們獲得更多的經驗，並證明我們在臨床前所展示的在人類身上確實適用。

In fact, the side effects that Len was talking about immune-related adverse events are totally unrelated to the sort of toxicities that were seen with nonspecific CD28 superagonist in the past, they were really much more on target and on mechanism that is we were generating a presumably a polyclonal T cell response against the tumor and some of that cross-reacted to tissues in the patients, and that's what we were seeing.

事實上，Len 談到的免疫相關不良事件的副作用與過去使用非特異性 CD28 超激動劑所見的那種毒性完全無關，它們實際上更符合我們正在產生的目標和機制大概是針對腫瘤的多克隆 T 細胞反應，其中一些與患者的組織發生交叉反應，這就是我們所看到的。

So we're hoping that increasingly, we might be able to move a little bit more quickly through some of these dose escalation stages to get to the active doses with these other agents. What we're seeing so far, as we've presented in our posters on MUC16xCD3 that right now, it's having an acceptable safety margin.

因此，我們越來越希望，我們可能能夠更快地通過其中一些劑量遞增階段，以使用這些其他藥物達到活性劑量。到目前為止，我們所看到的，正如我們在 MUC16xCD3 上的海報中所展示的那樣，它具有可接受的安全裕度。

And we also hope to see that when combined, either the CD3 combined with the MUC16xCD28 or when the MUC16xCD28 is combined with Libtayo that we will see the same sort of things that we saw with the PSMAxCD28 that will be getting, hopefully, market synergy and increase in the antitumor activity with hopefully a satisfactory safety window. And -- but that remains to be seen, and that's why we're carefully going through the combination studies and the dose escalation studies.

我們也希望看到結合使用時，無論是 CD3 與 MUC16xCD28 結合，還是當 MUC16xCD28 與 Libtayo 結合時，我們將看到我們在 PSMAxCD28 中看到的相同類型的東西，希望市場協同作用和增加抗腫瘤活性，希望有一個令人滿意的安全窗。而且——但這還有待觀察，這就是為什麼我們要仔細進行聯合研究和劑量遞增研究。

But once again, I mean, just to say how, I mean, exciting it is for those of us who've been working on these programs for over 10 years to be at this point where the individual agents and the individual classes are now validated and we now get to mix and match these things. And as Len said, the history of the field is when you have active agents and you start combining this, you can then leapfrog and get to the next level that would change the practice of medicine for these cancers. That's what we're aiming to do to try to save more lives, extend more lives, and it's an exciting place to be in.

但再一次，我的意思是，我的意思是，對於我們這些已經在這些項目上工作了 10 多年的人來說，現在各個代理人和各個班級都得到驗證是多麼令人興奮我們現在開始混合搭配這些東西。正如 Len 所說，該領域的歷史是當你有了活性藥物並開始將它們結合起來時，你就可以跨越式發展並達到一個新的水平，這將改變這些癌症的醫學實踐。這就是我們旨在挽救更多生命、延長更多生命的目標，這是一個令人興奮的地方。

Thanks, George.

謝謝，喬治。

That's all the time we have for today. 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 questions you may have. Thank you once again, and have a great day and a nice weekend.

這就是我們今天的全部時間。感謝所有撥入的人以及您對 Regeneron 的興趣。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 團隊可以回答您的任何問題。再次感謝您，祝您度過美好的一天和愉快的周末。

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

今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。