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.

歡迎參加再生元製藥公司2022年第四季財報電話會議。我是Shannon，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, 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.

謝謝香農。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2022年第四季財報電話會議。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 then open the call up 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，我們將開放問答環節。

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、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 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與聲明中預測的結果有重大差異。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，包括截至2022年12月31日止年度的10-K表格，我們預計將於2月6日（星期一）向美國證券交易委員會提交該文件。 Regeneron不承擔因新資訊、未來事件或其他原因而更新任何前瞻性聲明的義務。

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，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。

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

通話結束後，鮑勃·蘭德里和投資者關係團隊將隨時解答您可能提出的任何其他問題。

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

那麼，現在讓我把電話交給我們的總裁兼財務長倫‧施萊弗。倫？

I'm the Chief Executive.

我是首席執行官。

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。大家早安。對於那些正在經歷極寒天氣的人們，希望你們注意保暖。

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.

我們強勁的第四季業績延續了Regeneron卓越的年度表現，公司取得的多項重大成就使其在實現永續成長和股東價值方面佔據更有利的地位。在剔除REGEN-COV和Ronapreve的貢獻後，2022年第四季營收較上年同期成長14%，凸顯了我們強大的商業實力和日益多元化的業務。

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.

本季度，我們在產品線方面也取得了幾項重要進展，特別是提交了用於治療新生血管性老年性黃斑部病變（濕性 AMD）和糖尿病性黃斑水腫（DME）的 8 毫克阿柏西普生物製品許可申請，​​這使我們能夠在今年 8 月下旬在美國推出該產品。

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 與化療聯合用於晚期非小細胞肺癌的一線治療，這使得 Libtayo 成為第二個獲準用於此用途的 PD-1 或​​ PD-L1 抗體，無論患者的組織學或 PD-L1 表達水平如何。

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.

我們也展示了我們快速推進的腫瘤治療產品線的數據，包括：fianlimab（我們的 LAG-3 抗體與 Libtayo 聯合用於治療晚期非小細胞肺癌）；odronextamab（我們的 CD20xCD3 雙特異性抗體用於治療 B 細胞淋巴瘤）；以及 linvoseltamabent（我們的 BCMAxCD3 雙特異性抗體用於治療 B 細胞淋巴瘤）；以及 linvoseltamabent（我們的 BCMAxCD3 結晶性抗體已用於治療。

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.

回顧2022年，我們總結了三項策略要務，認為必須完成這些要務才能確保公司能長期成長。首先，我們必須強化視網膜業務的中長期前景。基於我們在2022年9月公佈的正面成果，我們相信8毫克阿柏西普有望改變濕性老年黃斑部病變（AMD）和糖尿病黃斑水腫（DME）患者的治療模式，成為這些患者的新標準療法，從而使Regeneron在該領域保持長期領先地位。

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，我們需要在多種2型過敏性疾病領域維持並鞏固Dupixent的領先地位。 2022年是碩果累累的一年，Dupixent全球淨產品銷售額接近87億美元，以固定匯率計算成長了44%。儘管面臨新的競爭，Dupixent在異位性皮膚炎、氣喘和鼻息肉領域仍保持著市場領先地位，並且獲準用於新的適應症、地區和更年輕的人群，George稍後將詳細介紹。總而言之，2022年的這些核准顯著擴大了Dupixent的商業機會，使潛在患者群體增加了約22.5萬人，全球潛在患者總數超過700萬人。

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域的領導者方面取得顯著進展，而2022年恰逢其時。實現這一長期目標的關鍵在於收購賽諾菲持有的Libtayo全球權益份額。 Libtayo是由再生元公司發現的抗體，此次收購是充分發揮這項基礎療法的臨床和商業潛力的必要步驟。此外，它還使我們能夠從腫瘤產品線中那些極具潛力的候選藥物中挖掘聯合用藥的機會，包括與我們的LAG-3抗體、共刺激雙特異性抗體以及CD3雙特異性抗體進行聯合治療。展望未來，我們預計2023年將是另一個意義非凡的年份，在這些關鍵領域以及其他業務領域都將取得顯著的進展。

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.

鑑於處方醫生使用 EYLEA 已有十餘年經驗，我們正準備在 8 月下旬於美國推出 8 毫克阿柏西普。目前，8 毫克阿柏西普的 48 週數據顯示，其療效和安全性與 EYLEA 相當，但治療間隔更長。我們相信，隨著時間的推移，8 毫克阿柏西普有望成為濕性 AMD 和 DME 的新標準療法。

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.

我們預期，基於其阻斷白血球介素-4和白血球介素-13的獨特作用機制，Dupixent將繼續鞏固其在已核准的2型過敏性疾病領域的領先地位。 2023年，我們有機會透過針對新疾病、新地區和更年輕族群的潛在監管批准，惠及更多患者，預計這將使全球生物製劑適用人群增加約50萬人。此外，我們期待今年上半年公佈Dupixent治療慢性阻塞性肺病（COPD）的首個III期研究結果。

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.

在腫瘤領域，我們預計將繼續快速推進研發管線。對於LAG-3與Libtayo的聯合療法，我們正在推進其適應症的拓展，從黑色素瘤擴展到肺癌，並有可能擴展到其他實體腫瘤。

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抗體，我們正在與Libtayo聯合使用，繼續推進PSMAxCD28在晚期前列腺癌I/II期臨床試驗中的劑量擴展。我們也預期將發表更多EGFRxCD28在實體瘤I期臨床試驗中的數據，並發表MUC16xCD28在復發性卵巢癌的初步臨床數據。

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 公司內部，我們預計下半年將提交 odronextamab 用於治療濾泡性淋巴瘤和瀰漫性大 B 細胞淋巴瘤以及 linvoseltamab 用於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，我們也計劃加快推進下一代新冠病毒抗體的臨床開發。我們相信，該抗體能夠幫助數百萬未能透過疫苗接種產生足夠免疫反應的患者，並為需要其他替代療法的患者提供治療。目前，臨床生產相關工作已經啟動，我們預計今年稍後進入臨床開發階段。

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.

綜上所述，2022年是Regeneron的關鍵一年，我們預計2023年將繼續取得重大進展。我們的策略仍然是專注於投資內部研發能力，這在歷史上產生了很高的報酬率。

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.

我們對近期和長期的成長前景充滿信心，目前約有35個在研候選藥物正在進行臨床試驗。我們也將繼續尋求機會，透過探索潛在的合作來補充這些內部研發工作。憑藉我們強大的商業能力持續推動收入成長以及穩健的財務狀況，Regeneron 完全有能力繼續為患者帶來突破性進展，並為股東創造價值。

Now I will turn the call over to George.

現在我將把電話交給喬治。

Thanks, Len.

謝謝你，Len。

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

我想簡要地向大家介紹我們管道在 2022 年的進展情況，並展望一下 2023 年的計劃。

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，我們發表了阿柏西普8毫克治療濕性老年黃斑部病變（AMD）和糖尿病黃斑水腫（DME）的關鍵性陽性結果。這些試驗表明，在48週的療程中，絕大多數患者使用阿柏西普8毫克後，給藥間隔可延長至每12週甚至16週，且不影響與EYLEA方案相同的視力改善效果或安全性。這些結果是前所未有的，並且可能具有顛覆性意義，因為其他任何抗VEGF藥物都未能達到這樣的療效。

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.

接下來是Dupixent。 2022年，Dupixent成為唯一獲準用於治療異位性皮膚炎的生物製劑，適用於6個月及以上的嬰幼兒；同時也是首個獲準用於治療結節性癢疹的藥物，以及美國首個獲準用於治療嗜酸性粒細胞性食道炎的藥物。就在本週，我們也獲得了歐盟委員會批准用於治療嗜酸性粒細胞性食道炎。此外，我們也提交了用於治療慢性自發性蕁麻疹的補充生物製品許可申請（BLA），並公佈了兒童嗜酸性粒細胞性食道炎的積極III期臨床試驗數據。

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目前已獲準用於治療5種相關的第二型過敏性疾病。我們的數據顯示，這些疾病是由IL-4和IL-13驅動的2型發炎介導的。由於許多患者患有全身性2型炎症，他們往往同時患有多種此類疾病。因此，Dupixent可望全面解決這些患者在Dupixent獲準治療的多種第二型疾病問題。

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.

儘管許多其他免疫調節劑都與令人擔憂的免疫抑制有關，並帶有黑框警告，但Dupixent的安全性數據支持其獲準用於嬰幼兒。我們期待在2023年獲得BOREAS研究的初步結果，這是首個針對慢性阻塞性肺病（COPD）患者的Dupixent III期臨床試驗。

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期研究已招募了嗜酸性粒細胞水平升高的患者，旨在篩選出由2型發炎驅動的COPD患者。 BOREAS研究於2020年通過了中期無效性分析，這是一個令人鼓舞的事件，並由此啟動了重複的III期NOTUS研究。我們期待BOREAS研究的結果，其主要終點是急性、中度和重度COPD加重的年化發生率，預計將於2023年上半年公佈。

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.

接下來談談腫瘤學。 2022年對我們的腫瘤學課程來說是重要的一年。 Libtayo獲得FDA批准，可與化療聯合用於一線治療非小細胞肺癌，且不受組織學類型或PD-L1表達水平的限制，這一成就此前僅有一種PD-1或PD-L1靶向藥物取得過。

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 也逐漸成為我們腫瘤產品線的重要支柱，因為多個與 Libtayo 聯合用藥的計畫已開始取得令人鼓舞的數據。首先，我將討論我們的 LAG-3 抗體 fianlimab 與 Libtayo 的合併用藥方案。我們近期在第二個 PD-1 初治轉移性黑色素瘤患者的驗證性隊列中獲得了積極數據，並在非小細胞肺癌患者的小樣本數據集中也報告了令人鼓舞的結果。這些初步結果表明，fianlimab 與 Libtayo 的聯合用藥方案在黑色素瘤領域可能具有同類最佳的療效，我們正在推進黑色素瘤和肺癌領域的關鍵性研究計畫。轉移性黑色素瘤和輔助治療黑色素瘤的 III 期臨床試驗已開始招募患者，我們計劃很快啟動另一項圍手術期黑色素瘤的 III 期臨床試驗，以及一線治療晚期和圍手術期非小細胞肺癌的 II/III 期臨床試驗。

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 Libtayo 聯合療法的其他值得關注的應用是，我們 PSMAxCD28 共刺激雙特異性抗體在晚期轉移性去勢抵抗性前列腺癌中的早期但非常令人鼓舞的數據。前列腺癌是一種免疫冷腫瘤，最近的多項 III 期臨床試驗失敗表明，前列腺癌對其他（聽不清楚）抗 PD-1 療法以及其他類型的化療聯合療法基本上無反應。

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.

在我們針對PSMAxCD28共刺激雙特異性抗體的概念驗證研究中，我們首次觀察到，將這類新型雙特異性抗體與抗PD-1抗體聯合使用，可以顯著提高先前被認為對PD-1抗體療法無反應的「冷腫瘤」的療效。在接受最高劑量治療的4名患者中，有3名患者在開始合併治療後的6週內，前列腺癌生物標記PSA水平下降超過90%。基於這些令人振奮的早期結果，我們正在繼續招募患者參與這項研究，並計劃在2023年的醫學會議上公佈更多數據。

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.

我們也發表了首個CD3雙特異性抗體在實體腫瘤中的臨床數據。此抗體為我們正在開發的用於治療晚期卵巢癌的MUC16xCD3雙特異性抗體ubamatamab。在一項針對先前接受過大量治療的複發性卵巢癌患者的I期劑量遞增研究中，ubamatamab作為單藥治療，我們觀察到總緩解率為4%，在MUC16高表達腫瘤患者的一小部分亞組中，緩解率達到31%。我們預計今年稍後公佈ubamatamab合併Libtayo以及MUC16xCD28共刺激雙特異性抗體合併Libtayo治療晚期卵巢癌的初步劑量遞增數據。此外，我們也預計今年稍後公佈EGFRxCD28共刺激雙特異性抗體合併Libtayo治療多種實體瘤的最新臨床數據。

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.

接下來談談我們的血液腫瘤產品線。在美國血液學會（ASH）年會上，我們發表了 odronextamab（一種 CD20×CD3 雙特異性抗體）和 linvoseltamab（一種 BCMA×CD3 雙特異性抗體）的最新數據。關於 odronextamab，我們公佈了關鍵的 II 期臨床試驗數據（聽不清楚）。在第三線或後續治療的複發性或再發性濾泡性淋巴瘤中，dronextamab 展現出潛在的同類最佳療效，82% 的患者有效，其中 92% 的有效患者達到完全緩解，且療效持久性令人鼓舞。

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提高了 odronextamab 的安全性，同時維持了與先前給藥方案相似的療效。在第三線或後續復發或復發性瀰漫性大B細胞淋巴瘤中，無論患者先前是否接受過 CAR-T 療法，odronextamab 均顯示出療效，且其安全性與濾泡性淋巴瘤患者基本相似。

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.

我們計劃於2023年下半年就這兩個適應症提交監管申請，希望能夠獲得加速批准。 2023年，我們預計將啟動多項針對濾泡性淋巴瘤和瀰漫性大B細胞淋巴瘤的III期臨床試驗，包括早期治療方案。這些試驗將作為驗證性研究，並有望支持最終獲得全面批准。此外，我們也計劃啟動一項概念驗證研究，評估我們的CD22xCD28共刺激雙特異性抗體與odronextamab聯合用於治療瀰漫性大B細胞淋巴瘤的療效，希望能進一步提升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.

對於我們的 BS-BCMAxCD3 雙特異性抗體 linvoseltamab，我們在 ASH 會議上公佈了其在第三線或後續治療多發性骨髓瘤患者中的關鍵性 II 期研究的療效和安全性數據。在疾病負荷高的患者中觀察到了早期、深度且持久的緩解，而這些緩解可能隨著追蹤時間的延長而進一步改善。

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，我們計劃啟動linvoseltamab用於二線多發性骨髓瘤治療的III期確證性研究，並預計在下半年提交生物製品許可申請（BLA）。與odronextamab一樣，我們計劃在不久的將來啟動linvoseltamab與共刺激雙特異性抗體的聯合用藥研究。

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.

我還想更新一些其他的臨床項目。我們用於抗凝血的抗體（阻斷因子XI）和用於治療心臟衰竭的活化NPR1受體的抗體，這兩個項目都正在完成機制驗證試驗。

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.

接下來談談Regeneron的遺傳醫學。關於我們與A​​lnylam在siRNA療法方面的合作，我們計劃採取廣泛且多管齊下的策略來開發非酒精性脂肪性肝炎（NASH）的治療方案。我們正在啟動一項針對具有遺傳風險因子的NASH患者的ALN-HSD II期臨床試驗。此外，我們也啟動了另一項在研NASH siRNA藥物ALN-PNP的首個人體試驗，並已對首批受試者進行了給藥。 ALN-PNP靶向不同的基因，並有可能與ALN-HSD聯合用於合適的患者。我們還發現了其他NASH靶點，並已通過Regeneron遺傳學中心進行了驗證，其中包括[Side B]，它有望成為下一個進入臨床試驗的NASH候選治療藥物。關於我們與A​​lnylam在中樞神經系統標靶方面的合作，我們的初始劑量遞增研究正在進行中。

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，這建立在 NTLA-2001 治療心肌病和神經病患者的轉甲狀腺素澱粉樣變性 I 期研究的持續數據讀取之上，該研究首次在人體中證明，基於 CRISPR 的技術可以在一年多的時間內將病理基因減少 90%。

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，我們的合作夥伴Decibel Therapeutics近期宣布，其病毒載體基因療法DB-OTO已獲得美國FDA和英國MHRA的臨床試驗批准。 DB-OTO旨在幫助患有耳蛋白相關聽力損失的患者恢復聽力。一項針對2歲及以下患者的I/II期臨床試驗預計將於2023年上半年啟動，首批患者的初步數據預計將於2024年第一季公佈。

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.

最後，我想談談我們下一代新冠病毒（COVID-19）的研發進展。正如我們近期所宣布的，我們已經發現了一種強效的廣譜中和性新冠病毒抗體。與其他中和抗體不同，這種抗體標靶的是病毒刺突蛋白受體結合域（RBD）以外的區域。由於此抗體結合的抗原決定基高度保守（在所有已知變異株中保守性超過99.9%），因此它對疫情期間出現的所有病毒變異株均保持活性。絕大多數透過疫苗接種或自然感染產生的抗病毒抗體都針對RBD結構域，這導致了巨大的選擇壓力，從而推動了抗藥性變異株的出現。我們希望，透過靶向RBD之外這獨特且保守的抗原決定位，這種抗體也能在未來的變異株面前保持活性。我們計劃今年啟動臨床試驗來測試這種抗體，並致力於將其開髮用於治療和預防。

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的研發引擎持續高效運轉，包括早期研發管線在內。光是今年年初的幾週內，我們就啟動了兩種新藥候選藥物的臨床研究，預計今年將有多達10種新的治療候選藥物啟動臨床試驗或提交新藥臨床試驗申請（IND），此外，我們還將針對已進入臨床試驗的候選藥物的其他適應症開展臨床試驗。

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

那麼，接下來就交給瑪莉安了。

Thanks, George.

謝謝你，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.

第四季為我們強勁的執行和成長年畫上了圓滿的句號，我們的商業產品組合均取得了顯著業績。我們拓展了新的適應症，加上現有業務的持續成長，預計將在2023年及以後推動顯著成長。我們期待今年能獲得幾項重要的潛在批准，並隨後推出新產品，這將為我們帶來更多成長機會。

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.

首先是安麗（EYLEA），我們在1月份宣布，其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藥物類別的整體增長。第四季末，安麗的市佔率接近先前約50%的水平。此前，由於非適應症用藥阿瓦斯汀（Avastin）的暫時性使用增加，安麗的銷售額在本季度初曾出現短期波動。在此期間，我們暫時關閉了一個非營利患者自付費用援助基金，該基金已於本季後期重新開放。

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.

我們相信已基本擺脫第四季遇到的問題。我們預計仍將面臨競爭壓力，但對再生元整體的視網膜產品線充滿信心，並期待即將推出的8毫克阿柏西普。

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.

總而言之，我們的視網膜產品線在抗 VEGF 類別中處於領先地位，EYLEA 是目前的標準療法，而 aflibercept 8 毫克（如果獲得批准）將提供差異化的臨床特徵，有可能改變治療模式。

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.

接下來談談利必妥（Libtayo）。第四季全球淨銷售額達1.69億美元，以固定匯率計算成長44%。在美國，淨銷售額成長36%至1.1億美元，所有適應症均有貢獻。在晚期非黑色素瘤皮膚癌領域，我們持續鞏固在PD-1抑制劑領域的領先地位。在肺癌領域，利必妥的處方量持續穩定成長。自去年11月化療聯合療法獲得批准以來，客戶訂購量顯著增加。我們正努力透過擴大處方醫師的覆蓋率和深度，最大限度地提高上市後的市場接受度。

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.

早期上市指標顯示利妥昔單抗（Libtayo）療效顯著，社區和學術中心均對其作為晚期非小細胞肺癌重要治療選擇的作用表示歡迎。光是在美國，每年就有超過20萬例新增肺癌病例，利妥昔單抗是這些患者的重要治療選擇。

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.

在美國以外地區，Libtayo的淨銷售額按固定匯率計算增長了60%，達到5900萬美元，這主要得益於持續的需求增長以及隨著我們在全球範圍內獲得市場准入和醫保報銷而推出的更多新產品。我們將繼續採取有針對性的策略，在重點國際市場擴大我們的全球商業版圖，旨在最大限度地提升Libtayo在未來潛在藥物中的應用機會。

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.

最後來看Dupixent，其第四季全球淨銷售額以固定匯率計算成長42%，達到24.5億美元。在美國，淨銷售額成長44%，達到19.4億美元，其中異位性皮膚炎、氣喘和鼻息肉的強勁成長勢頭持續，嗜酸性食道炎和結節性癢疹等新上市適應症也貢獻了部分銷售額。 Dupixent已做好充分準備，預計在2023年及以後擴大市場滲透率，並在現有適應症、新適應症和潛在適應症領域推動收入成長。

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.

異位性皮膚炎是Dupixent最大的適應症，在所有年齡層的患者中持續快速增長，鞏固了Dupixent作為中重度異位性皮膚炎患者首選全身治療方案的地位。在年輕族群中，Dupixent的接受度也持續快速成長，進一步證實了其差異化的療效和安全性。此外，Dupixent在結節性癢疹的早期應用也取得了顯著成效，它是目前唯一獲得FDA批准用於治療這種致殘性疾病的藥物。我們預計，隨著上市的進展和醫生對患者需求的不斷了解，Dupixent的使用率將持續上升。

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.

在競爭激烈的生物製劑氣喘領域，Dupixent 持續保持良好表現，市場份額穩步增長，處方總量和新患者數量均實現強勁增長。在鼻息肉治療方面，Dupixent 差異化的臨床療效使其繼續成為需要全身性治療患者的首選第一線治療方案。

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.

在嗜酸性食道炎領域，Dupixent 的上市進展異常順利，終於為醫生及其患者提供了一種能夠有效控制疾病根本機制的治療方案。接受 Dupixent 治療的患者症狀和生活品質均顯著改善。我們看到，胃腸病學家和過敏症專家都迅速接受了這種藥物。我們也持續推進針對年輕患者的臨床研究，因為這些患者也存在著巨大的未滿足需求。

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的淨銷售額達5.13億美元，以固定匯率計算成長37%，這主要得益於已獲批准適應症的快速普及以及在新地區的上市。在歐洲，Dupixent於去年12月獲準用於治療結節性癢疹。本週早些時候，Dupixent又獲準用於治療嗜酸性食道炎。我們預期這些新適應症將有助於Dupixent持續的國際成長。

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.

總而言之，2022年，我們始終秉持著為病患提供改變生命的藥物這個核心目標。我們的商業舉措和策略正在推動現有品牌的市場滲透率提升，並優化新產品和即將上市產品的潛力。綜上所述，我們對Regeneron的未來充滿信心，並已做好充分準備，實現長期永續成長。

Now I'll turn the call to Bob.

現在我把電話轉給鮑伯。

Thank you, Marion.

謝謝你，瑪莉安。

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，我今天對 Regeneron 的財務業績和展望的評論將以非 GAAP 準則為基礎。

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.

再生元公司2022年第四季業績強勁，持續的執行力推動了公司各項業務的積極成長。剔除REGEN-COV和Ronapreve的貢獻，第四季總營收年增14%至30億美元，主要得益於核心品牌的成長。第四季稀釋後每股淨收益為12.56美元，淨利為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.

首先從合作收入和拜耳公司開始。 2022年第四季（不含美國），EYLEA淨產品銷售額為8.39億美元，以固定匯率計算，較2021年第四季成長7%。拜耳公司合作總收入為3.55億美元，其中3.24億美元與我們在美國以外地區EYLEA淨利潤中所佔份額相關。

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.

第四季賽諾菲合作總營收為 8.36 億美元，年增 61%，主要得益於 Dupixent 的強勁表​​現。我們從 Dupixent 和 Kevzara 的商業化中獲得的利潤份額為 6.19 億美元，較上年同期成長 60%。此外，由於過去 12 個月內（不包括美國）抗體合作產品的銷售額達到 25 億美元，我們在 2022 年第四季確認了 5,000 萬美元的銷售里程碑。

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，我們在第四季度錄得羅氏合作收入 3.96 億美元，這是我們根據先前簽署的合同，從美國以外地區銷售 Ronapreve 產品中獲得的毛利份額。

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.

接下來是我們的營運費用。 2022年第四季研發費用年增43%至9.11億美元，主要受Libtayo交易的影響，Regeneron現在將Libtayo的所有研發費用計入公司帳目，同時我們也承擔了Dupixent和itepekimab抗體合作研發支出中50%的全部份額。此外，公司後期研發管線、不斷增加的臨床生產活動以及人員成本增加也產生了額外費用。

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.

由於員工人數增加及相關成本上升、為全面支持Libtayo全球商業化而增加的成本，以及對一家獨立的非營利性患者援助組織的捐款增加，銷售、管理及行政費用（SG&A）同比增長17%至5.79億美元。本季產品毛利率增加至93%，而去年同期為86%。毛利率的提高主要得益於產品組合的有利變化，以及不再需要向賽諾菲支付其在美國Libtayo毛利分成。最後，2022年第四季實際稅率為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.

接下來我們來看現金流和資產負債表。 2022年全年，Regeneron公司產生自由現金流44億美元，這主要得益於美國政府在2022年第一季支付的REGEN-COV銷售款項，該款項已在2021年第四季確認入帳。截至2022年底，公司持有現金及有價證券（扣除債務）共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.

2022年，我們繼續推動資本配置優先事項，投入約34億美元用於業務拓展和股票回購，同時繼續為內部研發工作提供資金。 2022年，我們執行了約13億美元的業務拓展計劃，其中包括收購Checkmate Pharmaceuticals公司，以取得Libtayo的全球獨家經銷權。

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.

2022年，我們也回購了約21億美元的公司股票，其中包括第四季的4.31億美元。今天上午，我們宣布了一項新的30億美元股票回購授權，這反映了我們對公司業務和產品線的持續信心。我們將繼續以當前價位買入公司股票，而這項新的授權使我們能夠繼續直接向股東返還資金。

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.

最後，我想談談我們對2023年的初步財務指引和展望。我們預計2023年的銷售、管理及行政費用（SG&A）將在21.3億美元至22.8億美元之間。這主要反映了Libtayo全球商業化支出的全年影響、我們在特定市場建立國際商業基礎設施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年的研發支出將在372.5萬美元至39.25億美元之間。正如喬治所提到的，我們在2023年有許多具有重要戰略意義的研發項目正在推進，包括fianlimab的後期研究、Libtayo聯合療法在黑色素瘤和肺癌中的應用、odronextamab在濾泡性淋巴瘤和瀰漫性大B細胞淋巴瘤中的確證性III期研究，以及linvoseltamab在多發性骨髓瘤中的應用。

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，我們持續推進早期研發管線中涵蓋多個治療領域的項目，包括與Alnylam和Intellia等合作夥伴的合作，為長期成長奠定基礎。該範圍也包含了Libtayo交易的全年影響，我們目前已將Libtayo的所有研發費用計入財務報表，並確認Dupixent和itepekimab研發費用中我們應承擔的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.

預計2023年COCM支出將在7.2億美元至8億美元之間，與2022年基本持平，這反映了Regeneron公司為Dupixent開發的新型生產工藝的逐步投入使用，該工藝旨在提高藥物活性成分的產量。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。這些支出將用於支持我們生產設施的持續擴建，包括正在建設中的填充/包裝設施，以及先前宣布的位於紐約州塔里敦總部研發設施的擴建項目。

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年毛利率將在90%至92%之​​間，實際稅率將在11%至13%之間。除了全年財務預期外，鑑於我們現金餘額增加以及利率較去年有所上升，我們預計2023年利息收入將有所增長，這將對其他收入和支出產生積極影響。我們也預計2023年其他收入將略低於2022年。最後，正如我在11月份所說，除非發生新的交易，否則我們預計2023年及以後不會再確認任何重大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.

總而言之，Regeneron在2022年繼續取得了強勁的財務業績，我們已做好充分準備，在2023年及以後繼續推動成長。

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.

謝謝你，鮑伯。

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，我們的發言到此結束。現在進入問答環節。為了盡可能回答所有問題，我們將先回答每位來電者的一個問題，然後再進行下一位的提問。香農，請開始提問吧。

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

（操作說明）我們的第一個問題來自 Cowen 的 Tyler Van Buren。

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.

恭喜您取得這樣的成績。關於安眠藥（EYLEA），很想了解您在市場上觀察到的關於Vabysmo的最新情況。儘管一些意見領袖（KOL）表示Vabysmo可能會轉回安眠藥，但羅氏方面似乎並沒有看到這種情況。所以，如果您能提供更多相關信息，那就太好了。

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。我還要補充一點，正如我之前報道的，安禮在市場上的表現依然非常強烈。簡單回顧今年的情況，安禮的銷售額成長了8%，達到63億美元，這無疑是一項非常出色的競爭表現。

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.

我們意識到市場競爭的存在。但就目前情況而言，我們持續了解到法瑞西單抗的使用量有限，在某些情況下，患者因療效不佳而轉而使用其他藥物，包括艾力達（EYLEA），其中艾力達可能是最常見的選擇。當然，我們期待今年繼續推動艾力達作為標準治療方案的研發。如您所知，我們與許多關鍵意見領袖（KOL）交流後發現，他們對阿柏西普8毫克製劑的上市——預計將於今年晚些時候上市——抱有極大的熱情。

Next question, please.

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摩根士丹利的馬修·哈里森。

Matt, we don't hear you.

馬特，我們聽不到你說話。

Sorry, could you not hear me, Len?

對不起，Len，你沒聽到我說話嗎？

We hear you now.

我們現在聽到你們的聲音了。

Yes, we can.

是的，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。不好意思。我只是想問您能否談談慢性阻塞性肺病（COPD）的情況，以及您認為在臨床意義上，什麼樣的結果才算有意義。其他公司報告的有效率大概是15%。但我記得您之前說過，這個標準並不算高。所以，您能否談談您是如何看待這個結果的臨床意義的？

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.

我們進行了無效性分析和臨床試驗，旨在確保如果研究結果呈陽性（我們希望如此），就能帶來我們認為具有臨床意義的益處。請記住，我們將同時關注病情加重和肺功能改善。因此，患者將從這兩個方面獲益。我還要提醒各位，在氣喘治療的其他領域，Dupixent 在改善肺功能方面顯著優於其他免疫調節劑。

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.

所以，這不僅僅是關於病情加重的問題，我們還希望在病情加重和肺功能方面取得顯著改善，這有望為患者帶來重要的益處。

Thank you. Next question, please.

謝謝。請問下一個問題。

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

我們的下一個問題來自卡特·古爾德在巴克萊銀行的表現。

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.

您目前確實有一些關於Alnylam的APP數據即將公佈。我很想聽聽您對此的看法。我們應該將其視為概念驗證，還是將其視為潛在的產品機會，即使採用鞘內給藥？如果更傾向於前者，那麼這在多大程度上會成為我們真正擴大研究範圍，並將其應用於多種中樞神經系統疾病的障礙？

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.

正如您所說，Alnylam合作的這一方面的關鍵在於，我們希望首次開發出一種技術，能夠將Alnylam和其他公司目前在肝臟中實現的療法推廣到其他組織，特別是中樞神經系統。因此，這項以APP為重點的首項研究，實際上是這項技術可行性的概念驗證。

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賦能技術，這意味著如果我們在這裡看到任何成果——當然，這些都是極具挑戰性的，因為要成為第一個做前人未曾做過的事情。而且目前計畫還處於非常早期的階段——我們的目標是驗證這種技術（它在肝臟中似乎非常有效）是否也能在肝臟以外的組織，特別是中樞神經系統中發揮作用。因此，它將成為一個平台賦能技術。

Thanks, George. Next question, please.

謝謝，喬治。請問下一個問題。

Our next question comes from the line of 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。

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.

恭喜你們取得的所有進展。鑑於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阿柏西普的上市節奏，需要考慮一些因素，例如預填充藥管的引入、J 代碼，以及你們的整體戰略，例如你們如何考慮市場細分以及你們最初的重點領域。

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.

請稍等片刻，我們會斷開羅氏所有參與通話的人員，以便向您介紹我們的策略。說真的，顯然，從現在到我們希望在八月底獲得定價、上市、目標市場、策略等等方面的批准之間，還有很多事情需要考慮，但我們正在努力。我們必須先拿到標籤，獲得批准，其他一切都準備就緒。首批上市產品將採用小瓶包裝，之後我們希望不久就能推出預灌封系列。

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

瑪麗昂，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.

我想說的是，我們擁有一支經驗豐富的商業化團隊，我們肯定已經為產品上市做好了充分準備。目前，我們正專注於安樂死（EYLEA）在市場上的推廣，但未來肯定會有更多產品推出，我們非常期待8毫克劑量的上市。

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的上市並沒有徹底顛覆市場格局。它帶來了真正的競爭。但我認為，他們與2毫克劑量（我們希望如此）和8毫克劑量（我們希望如此）的藥物競爭的窗口期正在逐漸關閉，這些藥物最終可能會成為標準療法。所以，今年晚些時候有很多值得期待的事情。

Certainly. Thank you. Next question, please.

當然可以，謝謝。請問下一個問題。

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

下一個問題來自 BMO 資本市場的 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?

或許可以接著Matt的問題問一句。您能否談談您在BOREAS試驗（聽不清楚）中期療效分析中觀察到的情況？以及，能否補充一些關於療效與安慰劑相比如何促使啟動NOTUS試驗的資訊？

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，我們盡全力實現了我們認為具有臨床意義的顯著改善。我們綜合考慮了病情加重和肺功能改善的多項指標，但具體數值我們尚未公佈。

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

埃文，我們對那份中期分析報告仍然一無所知。那麼，請問下一個問題。

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薩爾文·里希特。

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?

就腫瘤產品組合而言，您認為未來 12 個月內最重要的里程碑是什麼？特別是 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.

正如我們之前提到的，我們顯然需要在今年稍後提交一些重要的CD3雙特異性抗體的臨床試驗申請。此外，我們還需要在今年稍後繼續收集更多PSMAxCD28雙特異性抗體以及其他一些costim雙特異性抗體的患者數據。同時，我們必須積極推進LAG-3後續研究的受試者招募工作。我們希望Libtayo在全球市場能取得更大的成功。所以，我們還有很多工作要做。

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

我不知道喬治或瑪莉安是否還有什麼要補充的。

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——對我們來說，驗證每個類別中的單一藥物至關重要。這就是我們的策略。我們希望開發出同類​​最佳的免疫檢查點抑制劑，例如我們的PD-1抗體Libtayo；以及我們的LAG-3抗體fianlimab。我們希望建立同類最佳的[CD3]雙特異性抗體，使其不僅在血液腫瘤治療中有效，而且在實體腫瘤治療中也有效。當然，我們也希望驗證我們引入的共刺激雙特異性抗體這一神奇原理——它們在動物實驗中表現出驚人的效果，幾乎可以像即用型藥物一樣與其他兩類藥物協同作用——能否在人體中重現這種活性。

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.

顯然，達到那個階段需要數年時間，但我們感覺現在正處於一個非常令人振奮的階段，因為正如我所說，各個類別的藥物都已得到驗證。我們開始看到令人矚目的聯合用藥機會。我們討論過將兩種免疫檢查點抑制劑聯合使用，例如將我們的 LAG-3 與 PD-1 聯合使用，這似乎將一線黑色素瘤治療提升到了一個全新的高度，患者可以從這種聯合療法中獲益更多。現在，在驗證了這些聯合療法之後，我們正在更廣泛地擴展應用範圍。

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。既然我們已經證明我們的平台有效，我們正在拓展這條產品線，並在血液腫瘤和實體腫瘤領域同時進行研究。我們首個共刺激雙特異性抗體所獲得的令人振奮的早期數據，讓我們對整個產品線的推廣前景充滿信心。

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.

我們目前有幾種共刺激雙特異性抗體在臨床上進行試驗，正在完成劑量遞增安全性評估。現在，我們將陸續公佈這些聯合療法的數據，包括更多前列腺癌患者使用 PSMA 共刺激雙特異性抗體的數據。此外，我們還將報告一系列其他共刺激抗體，不僅包括我們先前在實體腫瘤中討論過的聯合療法，還包括血液腫瘤領域的聯合療法。顯然，我們對 CD20xCD3 雙特異性抗體和 BCMAxCD3 雙特異性抗體的單獨療效感到非常興奮。正如 Len 所說，我們正在提交這兩種抗體的上市申請，希望能在年底前完成。

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.

但我們也啟動了更早期的粒線體研究。同樣重要的是，我們將啟動與這些共刺激雙特異性抗體的聯合治療。我們認為，如果這些抗體能夠像在動物模型中以及目前在早期人體研究中那樣繼續發揮作用，它們將真正超越單一藥物，達到一個全新的高度，從而徹底改變醫學實踐，為患者帶來更多益處——而這正是我們所追求的。

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。我認為喬治的觀點一點也不為過。對於嚴重的晚期腫瘤，癌症治癒仍然寥寥無幾。而且需求依然龐大，這使得癌症治療市場非常活躍，因為人們想要獲得額外的益處，畢竟他們無法獲得治癒——我們還沒有治癒肺癌，也沒有治癒大多數嚴重的癌症。

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，能夠擁有基礎的個別治療，然後透過將它們結合起來獲得更多療效，確實使我們能夠跨越式發展，用喬治的話來說，就是在世界範圍內的治療模式中實現跨越式發展，因為患者和他們的醫生都非常重視改善治療效果，因為仍然存在巨大的需求。

Thank you. Next question, Shannon.

謝謝。香農，下一個問題。

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

我們的下一個問題來自富國銀行的 Mohit Bansal。

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?

或許可以繼續研究慢性阻塞性肺病（COPD）。我和一些意見領袖（KOL）交流過，也讀了一些論文，感覺IL-13似乎也跟纖維化有關。所以問題是，除了抑制發炎之外，阻斷IL-13及其對COPD纖維化的影響是否可能帶來其他好處？如果答案是肯定的，您認為為期一年的試驗是否足以驗證這一點？

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.

我認為您提出的觀點非常有趣。幾年前，我們參與了一些實驗，這些實驗顯示IL-13確實會在動物模型中誘發纖維化。當然，我們相信，從長遠來看，就像我們迄今為止研究的許多疾病一樣，Dupixent透過阻斷IL-4和IL-13，可以持續為患者帶來益處，例如預防導致您提到的大量重塑的慢性發炎。我們認為這在氣喘中也可能適用。

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專案和研究，以證明您所說的某些事情也會有益處，因為您可以防止長期重塑，從而防止氣喘患者的肺功能隨著時間推移而下降，因為結構變化會導致肺功能下降。我們相信，這當然也可能適用於 COPD。

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，正如您所說，我們需要短期研究的結果呈現陽性。我們相信，如果短期研究能夠產生我們所期望的數據，例如Dupixent在慢性阻塞性肺病（COPD）治療中能夠產生我們所期望的數據，那麼正如您所說，長期研究最終可能會顯示出更長期的益處，尤其是在改善導致肺功能永久性喪失的肺部重塑和纖維化改變方面。所以我們認為您完全正確，但正如您所說，這可能需要更長期的研究才能真正證實。

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瑞銀集團的 Colin Bristow。

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?

我想就[慢性阻塞性肺病]的讀數再深入探討一下。我只是想了解您信心的來源。感覺您比我們從歐洲聽到的要樂觀得多。這主要是基於BOREA中期研究設定的閾值，而這些閾值足夠可靠，所以您對最終結果感到滿意嗎？或者您還有其他可以補充的資訊嗎？

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。我不會低估我們目前的處境。而且這幾乎無關緊要，因為再生元是一家數據驅動型企業，我們都將看到即將公佈的數據，我們希望在本季稍後就能看到。我們對中期分析的評估結果完全不知情。我們說過我們設定的標準是合理的，但那隻是一小部分患者。所以你永遠無法預知結果會如何。與另一種經典的第二型發炎性疾病相比，我們對這類疾病的信心不如對其他疾病那麼強。所以這是不利的一面。但有利的一面是，我們選擇了嗜酸性粒細胞增多的患者，並且進行了中期分析。總之，我們和你們一樣期待數據。

Thanks, Len. Next question, Shannon.

謝謝，倫。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克里斯·雷蒙德和派珀·桑德勒。

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.

或許可以就VEGF視網膜市場提出一個更廣泛的問題。去年，在AAO年會上，圍繞玻璃體內注射治療地圖狀萎縮療法可能對視網膜專科醫生診療產生的影響，展開了熱烈的討論和辯論。有些人粗略估計，僅治療地圖狀萎縮患者一項，就可能使注射量大幅增加30%左右。

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?

各位在思考這種動態時，我們聽到一些意見領袖提出了一個可能的解決方案，即加快研發長效、療程更長的濕性老年黃斑部病變（AMD）療法。你們也看到這種趨勢了嗎？這是否應該成為我們從短效療法轉向長效療法的驅動因素？

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，我認為除了這些實踐方面的問題之外，最主要的驅動因素還是患者希望減少眼部注射的次數。每次眼部注射都存在發炎或其他更嚴重併發症的風險，例如出血、視網膜剝離等等。因此，在獲得相同療效的情況下，減少注射次數對患者來說當然更好，尤其是在減少眼部注射次數方面。此外，減少患者就診次數也對患者更有利。這些患者通常是老年患者，他們需要照顧者。

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.

從臨床實務的角度來看，許多醫生的診所都忙於大量的注射，如果能減少注射次數就能達到同樣的效果，他們當然希望能節省更多時間。從臨床角度來看，減少注射次數無疑能節省更多時間，也更有利於醫師進行工作。但我認為，最終醫生還是會和病人共同決定，因為減少眼部注射次數對病人來說更安全、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.

此外，我們也不應忽視這樣一個事實：如果治療地圖狀萎縮的方法廣泛應用，它們確實會產生副作用。這些療法實際上會加重患者的黃斑水腫，而黃斑水腫自然也需要相應的治療。

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

謝謝。香農，我們還有時間再問兩個問題。

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克里斯·肖特。

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.

僅就 Costim 平台而言，我想一旦確定了這些產品的合適劑量，考慮到大多數患者可選擇的治療方案有限，您是否預期會有加快審批流程的途徑？或者我們仍然需要考慮即使在註冊研究階段也需要謹慎行事，因為您需要在安全性和有效性之間取得平衡？

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.

當然，我們堅信，當某種療法存在巨大的醫療需求且別無他法時，就有機會申請加速審批。我們都了解FDA的新指南，他們希望關鍵性研究能夠順利進行，我記得他們用過「進展順利」這個詞。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晚期前列腺癌患者身上觀察到的療效，不僅存在這種需求，而且肯定會有機制讓患者盡快使用這種療法。

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.

記住，正如您所說，主要問題在於始終關注安全性。當然，我們正在盡一切努力降低風險。但請記住，到目前為止，安全性和有效性之間基本上是緊密相關的。也就是說，不良事件都發生在那些獲益顯著的患者身上。因此，從監管機構、醫生以及坦白說，從患者的角度來看，這種風險/回報比更具吸引力。

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.

簡而言之，我們認為不會操之過急，以免魯莽行事。我們必須謹慎。但我們確實認為，如果我們遵循FDA制定的新方法，我們就有機會獲得加速審批。

Thanks, Len. Last question, please, Shannon.

謝謝，倫。香農，最後一個問題。

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

我們的最後一個問題來自 Truist 的 Robyn Karnauskas。

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.

好的。那麼，我再補充一下之前的問題。對於您的MUC16xCD28和MUC16xCD3組合，您預期其安全性如何？您認為這種組合在療效和安全性方面與CD28[CPI]組合相比如何？另外，我知道FDA之前對CD28超激動劑的劑量有所擔憂，您認為您的初步數據是否會降低CD28雙特異性抗體對劑量的需求？

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.

嗯，這裡面有很多好問題。我先從最後說起。的確，在我們啟動這個計畫的時候，人們對先前使用CD28激活劑的經驗非常擔憂，因為這些激活劑會在全身範圍內激活，導致患者出現非常可怕的後果，幾乎扼殺了整個領域。我們發明了這種新方法，將CD28的活化精確地限制在腫瘤表面等部位。

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也對此表示擔憂，正如您所說，他們要求我們採用非常保守的劑量遞增方案。我們不得不嘗試五到六個劑量水平，才最終達到我們認為的有效劑量水平，並開始觀察到我們後來報導的顯著抗腫瘤活性。我們希望隨著經驗的積累，能夠證明我們在臨床前研究中所取得的成果在人體試驗中也同樣有效。

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 所說的免疫相關不良事件的副作用與過去使用非特異性 CD28 超激動劑所觀察到的毒性完全無關，它們實際上更有針對性和機制性，也就是說，我們產生了一種可能針對腫瘤的多克隆 T 細胞反應，其中一些反應與患者的組織發生了交叉反應，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.

所以我們希望，隨著其他藥物的劑量遞增階段推進，我們能夠更快達到有效劑量。正如我們在關於MUC16xCD3的海報中所展示的，目前來看，它的安全性是可以接受的。

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，無論是CD3與MUC16xCD28聯合使用，還是MUC16xCD28與Libtayo聯合使用，都能像PSMAxCD28那樣，產生類似的市場協同效應，增強抗腫瘤活性，並有望保持令人滿意的安全性。但這仍有待觀察，因此我們正在謹慎地進行聯合用藥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.

但我想再次強調，對於我們這些從事這些計畫超過十年的人來說，能夠走到今天這一步是多麼令人興奮！現在，各種藥物和藥物類別都已得到驗證，我們可以將它們組合搭配使用。正如Len所說，這個領域的歷史就是，當你擁有有效的藥物並開始將它們組合起來時，你就能實現跨越式發展，達到一個全新的水平，從而改變癌症的治療方式。這正是我們努力的目標──拯救更多生命，延長更多生命，令人無比振奮。

Thanks, George.

謝謝你，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.

今天的時間就到這裡了。感謝所有撥入電話會議的朋友，也感謝大家對Regeneron的關注。對於排隊等候但未能一一解答的朋友，我們深感抱歉。一如既往，投資者關係團隊隨時準備好解答您的任何問題。再次感謝大家，祝您有美好的一天，週末愉快！

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。您可以斷開連線了。