雷傑納榮製藥 (REGN) 2019 Q4 法說會逐字稿

Welcome to Regeneron Pharmaceuticals Q4 2019 Earnings Conference Call. My name is Sylvia, and I'll be your operator for today's call. (Operator Instructions) Please note that this conference is being recorded.

歡迎參加 Regeneron Pharmaceuticals 2019 年第四季財報電話會議。我叫西爾維婭，我將擔任您今天通話的接線生。（操作員說明）請注意，本次會議正在錄音。

I will now turn the call over to Justin Holko. Justin, you may begin.

現在我將把通話交給賈斯汀·霍爾科。賈斯汀，你可以開始了。

Thank you, Sylvia. Good morning, good afternoon and good evening to everyone listening around the world. Thank you for your interest in Regeneron, and welcome to the fourth quarter 2019 conference call. An archive of this webcast will be available on our website. Joining me today are Leonard Schleifer, Founder, President and Chief Executive Officer; George Yancopoulos, Founding Scientist, President and Chief Scientific Officer; Marion McCourt, Senior Vice President and Head of Commercial; and Bob Landry, Executive Vice President and Chief Financial Officer.

謝謝你，西爾維亞。全世界的聽眾朋友們，早安、下午好、晚上好！感謝您對 Regeneron 的關注，歡迎參加 2019 年第四季電話會議。本次網路直播的錄影檔案將會發佈在我們的網站上。今天與我一同出席的有：創辦人、總裁兼執行長 Leonard Schleifer；創始科學家、總裁兼首席科學官 George Yancopoulos；資深副總裁兼商務主管 Marion McCourt；以及執行副總裁兼財務長 Bob Landry。

After our prepared remarks, we will open the call for Q&A. I would also like to remind you that remarks made on today's call include forward-looking statements about Regeneron. Such statements may include, but are not limited to, those related to Regeneron and its product and business, financial forecast and guidance, development programs and related anticipated milestones, collaborations, finances, regulatory matters, payer coverage and reimbursement issues, intellectual property, pending litigation and other proceedings and competition.

在我們發言完畢後，我們將開放問答環節。我還要提醒各位，今天電話會議上發表的言論包含 Regeneron 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、支付方覆蓋範圍和報銷問題、智慧財產權、未決訴訟和其他程序以及競爭相關的聲明。

Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in that statement. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission including its Form 10-K for the year ended December 31, 2019, which we are planning to file with the SEC tomorrow. Regeneron does not undertake any obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.

每項前瞻性聲明都存在風險和不確定性，可能導致實際結果和事件與該聲明中預測的結果和事件有重大差異。有關這些及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 2019 年 12 月 31 日止年度的 10-K 表格，我們計劃明天向美國證券交易委員會提交該表格。Regeneron公司不承擔任何公開更新任何前瞻性聲明的義務，無論是由於新資訊、未來事件或其他原因。

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

此外，請注意，今天的電話會議將討論 GAAP 和非 GAAP 指標。有關我們使用非公認會計準則財務指標以及這些指標與公認會計準則的調節表的信息，請參閱我們的財務業績新聞稿，該新聞稿可在我們的網站上查閱。有關這些措施的更多信息，請訪問我們網站的“投資者與媒體”版塊。通話結束後，鮑伯·蘭德里和投資者關係團隊將回答進一步的問題。

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

接下來，我將把電話交給我們的總裁兼執行長倫·施萊弗博士。

Thank you, Justin. Thank you to everyone for joining our call today. The fourth quarter capped off a strong 2019 for Regeneron. Our 3 growth drivers, EYLEA, DUPIXENT and Libtayo, drove double-digit growth on the top and bottom lines while we continue to make substantial investments in our innovative R&D pipeline.

謝謝你，賈斯汀。感謝各位今天參加我們的電話會議。第四季為 Regeneron 強勁的 2019 年畫上了圓滿的句號。我們的三大成長動力——EYLEA、DUPIXENT 和 Libtayo——在營收和利潤方面實現了兩大的成長，同時我們也持續對創新研發管線進行大量投資。

In the quarter, EYLEA global net product sales grew 11% to $2 billion, including U.S. EYLEA net sales growth of 13% to $1.22 billion, even with the launch of a new competitor. The full year, global net sales of EYLEA grew 12% to $7.5 billion. We remain confident as we expand our leadership position in wet AMD and diabetic eye diseases.

本季度，安禮全球淨產品銷售額成長 11% 至 20 億美元，其中美國安禮淨銷售額成長 13% 至 12.2 億美元，即便有新的競爭對手推出。安樂全年全球淨銷售額成長12%，達75億美元。我們依然充滿信心，不斷擴大我們在濕性老年黃斑部病變和糖尿病眼疾領域的領先地位。

DUPIXENT sales are now annualizing at $3 billion as we expand our footprint in the retreatment of Type 2 inflammatory diseases. Global net product sales grew 136% to $752 million in the fourth quarter. And just last week, we announced that the FDA accepted for priority review our filing in pediatric atopic dermatitis, which, if approved, will represent a breakthrough for children 6 to 11 years old suffering from this debilitating disease.

隨著我們在 2 型發炎性疾病再治療領域不斷擴大業務，DUPIXENT 的年銷售額現已達到 30 億美元。第四季全球淨產品銷售額成長136%，達到7.52億美元。就在上週，我們宣布 FDA 已接受我們關於兒童異位性皮膚炎的申請進行優先審查，如果獲得批准，這將代表著 6 至 11 歲患有這種衰弱性疾病的兒童的突破。

We are still in the early days of DUPIXENT with many global launches just starting and several potential new [indications] in late-stage development. As expected, the profits from our antibody collaboration with Sanofi continue to increase, creating further revenue and earnings diversification for Regeneron. On the strength of DUPIXENT, we generated profits of $104 million for the fourth quarter and $209 million for the full year, despite the losses associated with PRALUENT and KEVZARA.

DUPIXENT 目前仍處於早期階段，許多全球上市計畫才剛開始，還有幾個潛在的新適應症正處於後期開發階段。正如預期的那樣，我們與賽諾菲的抗體合作帶來的利潤持續增長，為再生元創造了進一步的收入和盈利多元化。儘管 PRALUENT 和 KEVZARA 造成了虧損，但憑藉 DUPIXENT 的強勁表​​現，我們在第四季度實現了 1.04 億美元的利潤，全年實現了 2.09 億美元的利潤。

To that end, we have been working hard to address PRALUENT and KEVZARA performance to further enhance profitability of the collaboration. In December, we and Sanofi announced a major restructuring of the alliance that will improve profitability, increase efficiency and enhance focus on DUPIXENT. We remain on track to close the transaction in the first quarter.

為此，我們一直在努力解決 PRALUENT 和 KEVZARA 的性能問題，以進一步提高合作的獲利能力。去年 12 月，我們和賽諾菲宣布對聯盟進行重大重組，這將提高盈利能力、提升效率並加強對 DUPIXENT 的關注。我們仍有望在第一季完成交易。

In Oncology, we continue to make progress both commercially and in R&D. Sales for Libtayo, our anti-PD-1 therapy, grew to $75 million in the fourth quarter. In the U.S., we extended Libtayo's leadership position as the #1 systemic treatment in cutaneous squamous cell carcinoma.

在腫瘤學領域，我們在商業和研發方面都持續取得進展。我們的抗 PD-1 療法 Libtayo 在第四季度的銷售額成長至 7,500 萬美元。在美國，我們鞏固了利妥昔單抗作為皮膚鱗狀細胞癌第一大系統性治療藥物的領先地位。

As we look to 2020 for Libtayo, we are excited about the late-stage data readouts in basal cell carcinoma and the interim analysis for our pivotal monotherapy study in nonsmall cell lung cancer. We are also making significant progress on our bispecifics program in oncology. We had a strong showing at the American Society of Hematology Meeting in December, where we presented initial data for a BCMAxCD3 antibody as well as updated data for our CD20xCD3 antibody. While each of these programs could be important individual treatments over time, they also represent validation of our bispecifics program, which, along with Libtayo, form a diverse and powerful toolkit to potentially address malignant diseases.

展望 Libtayo 在 2020 年的發展，我們對基底細胞癌的後期數據讀數以及非小細胞肺癌關鍵性單藥治療研究的中期分析感到興奮。我們在腫瘤學領域的雙特異性抗體計畫也取得了重大進展。我們在 12 月舉行的美國血液學會會議上取得了優異的成績，會上我們展示了 BCMAxCD3 抗體的初步數據以及 CD20xCD3 抗體的更新數據。雖然這些項目中的每一個都可能在一段時間內成為重要的個別治療方法，但它們也代表了我們雙特異性抗體計畫的驗證，該計畫與 Libtayo 一起構成了一個多樣化且強大的工具包，有可能解決惡性疾病。

Regeneron has a track record of tackling some of the world's most challenging health issues while creating long-term value to shareholders. Looking back at 2019, we achieved 6 important regulatory approvals across our growth drivers of EYLEA, DUPIXENT and Libtayo. Beyond these approvals, we made significant advances in our pipeline, which George will discuss.

再生元公司在解決一些世界上最具挑戰性的健康問題方面擁有良好的記錄，同時為股東創造了長期價值。回顧 2019 年，我們在 EYLEA、DUPIXENT 和 Libtayo 這三大成長驅動因素方面獲得了 6 項重要的監管批准。除了這些審批之外，我們的研發管線也取得了重大進展，喬治將對此進行討論。

Additionally, I would like to call your attention to the global health crisis on coronavirus. We have answered the call for help and are responding diligently with HHS to develop potential treatments. George will also further outline this effort.

此外，我還想提請大家注意新冠病毒引發的全球健康危機。我們已響應求助，正與美國衛生與公共服務部密切合作，積極開發潛在的治療方法。喬治也將進一步闡述這項工作。

Regeneron is entering 2020 from a position of financial strength. We have the necessary capital to advance and expand our wholly owned R&D pipeline. Additionally, we continue to seek value-creating business development with a focus on technologies that enable and accelerate our own technologies in drug discovery and development. And when market conditions create opportunity, we will continue to buy back shares under our share repurchase program, where we continue to see a significant dislocation between our share price and the long-term value of the company.

再生元公司以雄厚的財務實力進入2020年。我們擁有必要的資金來推進和擴大我們全資擁有的研發管線。此外，我們將繼續尋求創造價值的業務發展，重點關注能夠促進和加速我們自身藥物發現和開發技術的技術。當市場條件創造機會時，我們將繼續根據我們的股票回購計畫回購股票，因為我們仍然看到我們的股價與公司的長期價值之間存在重大錯位。

In conclusion, we are pleased with our continued operational and financial execution that is creating near and long-term value. We are entering 2020 with strong momentum, and we remain confident in our strategy and in our business.

總之，我們對公司持續的營運和財務執行感到滿意，這些都創造了短期和長期價值。我們帶著強勁的發展勢頭進入2020年，我們對我們的策略和業務仍然充滿信心。

Now I'll turn the call over to George.

現在我把電話交給喬治。

Thank you, Len. I will provide an overview of our diverse pipeline, which is made possible by our foundational technologies that allow us to rapidly identify and validate genetic targets and go quickly and efficiently to turnkey therapeutic solutions, whether through internally developed approaches, such as Velocigene, Velocimmune and the Regeneron Genetic Center, or important collaborative capabilities, such as those with Alnylam, Intellia, bluebird and others.

謝謝你，Len。我將概述我們多元化的產品線，這得益於我們的基礎技術，使我們能夠快速識別和驗證基因靶點，並快速高效地獲得交鑰匙治療解決方案，無論是透過內部開發的方法，例如 Velocigene、Velocimmune 和 Regeneron 基因中心，還是透過重要的合作能力，例如與 Alnylam、Intellia、bluebird 等公司的合作能力。

Starting with EYLEA. This weekend at the Bascom Palmer Angiogenesis meeting, we will present the 2-year data for the PANORAMA study in nonproliferative diabetic retinopathy, which showed a marked reduction in the risk of developing vision-threatening complications. At the same time, we will discuss the rationale for clinical testing of high-dose EYLEA currently in a Phase II trial in wet AMD that will provide initial safety and efficacy data. A Phase III trial in DME will begin midyear, closely followed by a Phase III study in wet AMD.

從愛麗莎開始。本週末在 Bascom Palmer 血管生成會議上，我們將公佈 PANORAMA 研究在非增殖性糖尿病視網膜病變方面的 2 年數據，該研究顯示，發生威脅視力的併發症的風險顯著降低。同時，我們將討論目前正在進行濕性 AMD II 期試驗的高劑量 EYLEA 臨床試驗的理由，該試驗將提供初步的安全性和有效性數據。針對糖尿病性黃斑水腫 (DME) 的 III 期試驗將於年中開始，緊隨其後的是針對濕性老年黃斑部病變的 III 期研究。

Moving on to DUPIXENT, our dual blocker of both the interleukin-4 and interleukin-13 pathways, which is changing the lives of so many people suffering from allergic diseases such as asthma, atopic dermatitis and chronic rhinosinusitis with nasal polyps, with more than 125,000 patients treated globally since launch.

接下來是 DUPIXENT，它是一種同時阻斷白細胞介素-4 和白細胞介素-13 通路的雙重藥物，正在改變許多患有過敏性疾病（如哮喘、特應性皮膚炎和伴有鼻息肉的慢性鼻竇炎）的人的生活，自上市以來，全球已有超過 125,000 名患者接受了治療。

Just last week, we announced that the FDA is undertaking a priority review to extend approval of DUPIXENT to children aged 6 to 11 years suffering from moderate to severe atopic dermatitis with a target PDUFA date of May 26, 2020. If approved, this will be the first biologic indicated for these children. We would hope that this approval will continue to reflect the remarkable efficacy and safety profile of DUPIXENT as evidenced by the absence of a black box warning or any associated serious infection risks, which are often seen with other neuromodulatory biologics and kinase inhibitors.

就在上週，我們宣布 FDA 正在進行優先審查，以將 DUPIXENT 的批准範圍擴大到 6 至 11 歲患有中度至重度異位性皮膚炎的兒童，目標 PDUFA 日期為 2020 年 5 月 26 日。如果獲得批准，這將是第一個獲準用於治療這些兒童的生物製劑。我們希望此次批准能夠繼續反映出 DUPIXENT 卓越的療效和安全性，正如其沒有黑框警告或任何相關的嚴重感染風險所證明的那樣，而這些風險在其他神經調節生物製劑和激酶抑製劑中經常出現。

While Marion will update you on quarterly performance, I would like to highlight other near and long-term opportunities for DUPIXENT. Eosinophilic esophagitis, or EoE, is a currently underdiagnosed but increasingly recognized serious allergic condition with limited effective treatment options. Following up on our promising proof-of-concept study, we will read out on the Phase II portion of our Phase II/III study in adults and adolescents by mid-year while the Phase III portion continues to enroll. Additionally, we are studying a Phase III study in pediatric EoE patients in the second half of the year.

Marion 將向大家報告季度業績，而我則想重點介紹 DUPIXENT 的其他近期和長期機會。嗜酸性食道炎（EoE）是一種目前診斷不足但日益受到重視的嚴重過敏性疾病，有效的治療選擇有限。繼我們前景可觀的概念驗證研究之後，我們將在年中公佈針對成人和青少年的 II/III 期研究的 II 期部分結果，同時 III 期部分將繼續招募受試者。此外，我們將在今年下半年進行一項針對兒童嗜酸性粒細胞性食道炎患者的 III 期研究。

On a related front, we are excited about our collaborator Aimmune's recent approval for Palforzia, an oral immunotherapy for peanut allergy. But there is still an enormous need for therapies for the treatment of food allergies, as many of these patients are at risk for EoE and other allergic conditions. We think DUPIXENT , studied in combination with Palforzia, has the potential to further improve the outcomes for these patients.

另據報導，我們的合作夥伴 Aimmune 近期批准了用於治療花生過敏的口服免疫療法藥物 Palforzia，我們對此感到非常興奮。但目前仍迫切需要治療食物過敏的療法，因為許多此類患者有罹患嗜酸性粒細胞性食道炎 (EoE) 和其他過敏性疾病的風險。我們認為，DUPIXENT 與 Palforzia 合併使用進行研究，有可能進一步改善這些患者的治療效果。

I'm also pleased to share the pivotal studies for DUPIXENT in the new indications we announced last November are kicking off. Studies for chronic spontaneous urticaria, prurigo nodularis and bullous pemphigoid have already started. The study in allergic bronchopulmonary aspergillosis will commence in the first half of this year.

我也很高興地宣布，DUPIXENT 在我們去年 11 月宣布的新適應症的關鍵性研究已經啟動。針對慢性自發性蕁麻疹、結節性癢疹和大皰性類天皰瘡的研究已經開始。過敏性支氣管肺麴菌病的研究將於今年上半年開始。

Now let's turn and spend a few moments on immuno oncology where we are strategically positioned to compete, enhance and extend the benefits of immunotherapy to many more patients than are currently benefiting today.

現在讓我們轉而花幾分鐘時間談談免疫腫瘤學，我們在這個領域擁有戰略優勢，可以參與競爭，增強免疫療法的益處，並使更多患者受益於免疫療法，而目前受益的患者比現在要多得多。

With Libtayo, we have an important opportunity to compete in the PD-1 treatment landscape combining Libtayo with other antibodies from our Velocigene and Velocimmune-derived toolkit, including bispecific antibodies. We are looking to enhance responsiveness for the more than half the patients that do not respond to PD-1 therapy alone. Moreover, such combinations have the potential to extend our reach to patients with cancers such as breast, colon, pancreatic and prostate, which show very limited response to checkpoint inhibition at this point.

有了 Libtayo，我們就有機會在 PD-1 治療領域中競爭，將 Libtayo 與我們 Velocigene 和 Velocimmune 衍生工具包中的其他抗體（包括雙特異性抗體）結合。我們希望提高超過一半對 PD-1 單獨療法無反應的患者的治療反應率。此外，這種組合療法有可能將我們的治療範圍擴大到乳腺癌、結腸癌、胰腺癌和前列腺癌等癌症患者，這些癌症目前對檢查點抑制劑的反應非常有限。

For Libtayo, in addition to being foundational to our combinatorial approach in oncology, we're expecting some near-term milestones. Later this year, the Independent Data Monitoring Committee will conduct prespecified interim analysis assessing overall survival for the pivotal Libtayo monotherapy study in nonsmall cell lung cancer. At the last quarterly update, we announced that an interim analysis of the first 361 randomized patients. The confirmed objective response rate as determined by investigators was 42% for Libtayo versus 22% for chemotherapy. Although promising in terms of indicating profound clinical activity for Libtayo in lung cancer, objective response rate is not a validated endpoint for regulatory approval in this setting.

對於 Libtayo 而言，除了是我們腫瘤學組合療法的基礎之外，我們還期待著一些近期里程碑的實現。今年晚些時候，獨立數據監測委員會將進行預先設定的中期分析，以評估利妥昔單藥治療非小細胞肺癌的關鍵性研究的總生存期。在上一季更新中，我們宣布對前 361 名隨機分組的患者進行中期分析。研究人員確定的確認客觀緩解率，Libtayo 為 42%，而化療為 22%。儘管Libtayo在肺癌治療中顯示出顯著的臨床活性，但客觀緩解率並非該領域監管批准的有效終點。

Our other pivotal lung cancer study in which Libtayo is being tested in combination with chemotherapy is more than 50% enrolled and is expected to fully enroll by midyear. While we are investigating different combination approaches with Libtayo in melanoma skin cancers, where less than half the patients benefit from PD-1 therapy alone, we believe patients with nonmelanoma skin cancers still remain underserved, and we are working to expand the available treatment options for these patients.

我們正在進行的另一項關鍵性肺癌研究，其中 Libtayo 與化療聯合使用進行測試，目前已完成 50% 以上的患者招募，預計將在年中完成全部招募。雖然我們正在研究 Libtayo 與黑色素瘤皮膚癌的不同聯合治療方案（其中不到一半的患者僅能從 PD-1 療法中獲益），但我們認為非黑色素瘤皮膚癌患者的治療仍然不足，我們正在努力擴大這些患者的可用治療選擇。

Libtayo remains the first and only approved therapeutic in advanced squamous cell carcinoma of the skin, or CSCC, with a safety profile that is similar to that of the other group PD-1 or PD-L1 inhibitors. Following on recent promising results with Libtayo in neoadjuvant CSCC, which we recently announced, we are now enrolling a registrational study in the adjuvant study setting as well as a follow-up neoadjuvant CSCC study. We are also looking forward to the potentially pivotal data readout for basal cell carcinoma of the skin in mid-2020. If the data are positive, we are hoping to proceed with the regulatory filing this year.

Libtayo 仍然是目前唯一獲準用於治療晚期皮膚鱗狀細胞癌 (CSCC) 的藥物，其安全性與其他 PD-1 或​​ PD-L1 抑制劑類似。繼我們最近宣布的 Libtayo 在新輔助 CSCC 治療中取得令人鼓舞的結果之後，我們現在正在進行一項輔助治療註冊研究以及一項後續新輔助 CSCC 研究。我們也期待 2020 年年中可能具有決定性意義的皮膚基底細胞癌數據讀數。如果數據是正面的，我們希望今年能夠推進監管備案工作。

And we continue to make exciting progress with our bispecific antibody platform. At the American Society of Hematology, or ASH meetings, we presented data from our first class of these antibodies, the CD3 bispecifics that are designed to bring a killer T-cell to a tumor and trigger the so-called Signal 1 in the T-cell activation process, leading to tumor cell destruction.

我們的雙特異性抗體平台也持續取得令人振奮的進展。在美國血液學會（ASH）會議上，我們展示了我們第一類此類抗體的數據，即 CD3 雙特異性抗體，其設計目的是將殺傷性 T 細胞帶到腫瘤處，並觸發 T 細胞活化過程中的所謂信號 1，從而導致腫瘤細胞破壞。

For REGN1979, our CD20xCD3 bispecific, we reported 95% overall response rates with 77 complete response rates in 22 late-stage follicular lymphoma patients. In late-stage diffuse large B-cell lymphoma, we observed 71% overall response rates, all of which were complete responses in 7 CAR-T naive patients.

對於我們的 CD20xCD3 雙特異性抗體 REGN1979，我們報告稱，在 22 名晚期濾泡性淋巴瘤患者中，總體緩解率為 95%，完全緩解率為 77%。在晚期瀰漫性大B細胞淋巴瘤中，我們觀察到71%的總緩解率，其中7位CAR-T初治患者均達到完全緩解。

Moreover and quite remarkably, we saw a 50% overall response rates in 12 patients who had failed CAR-T therapy, with 3 of these patients achieving a complete response to treatment with REGN1979. Clearly, this bispecific has demonstrated promising single-agent clinical activity in late-stage patients and supports initiation of a potentially pivotal Phase II program for REGN1979 in several monotherapy studies, including relapsed/refractory follicular lymphoma, relapsed/refractory DLBCL as well as several other non-Hodgkin's lymphoma subtypes. We are also planning to initiate chemotherapy combination studies this year in earlier lines of non-Hodgkin's lymphoma.

此外，值得注意的是，在 12 名 CAR-T 療法失敗的患者中，我們看到了 50% 的整體緩解率，其中 3 名患者對 REGN1979 治療達到了完全緩解。顯然，這種雙特異性抗體已在晚期患者中表現出有希望的單藥臨床活性，並支持啟動 REGN1979 的潛在關鍵性 II 期項目，該項目涉及多項單藥治療研究，包括復發/難治性濾泡性淋巴瘤、復發/難治性瀰漫性大B細胞淋巴瘤以及其他幾種非霍奇金淋巴瘤亞型。我們也計劃今年啟動針對早期非何杰金氏淋巴瘤的化療合併治療研究。

At the same ASH meeting, we presented preliminary data for our second CD3 bispecific, REGN5458, our BCMAxCD3 bispecific in late-stage multiple myeloma. Remarkably, the first patient in this program was dosed at the beginning of 2019, and we were able to show initial efficacy and safety data at the ASH meeting later the same year.

在同一屆 ASH 會議上，我們展示了我們的第二個 CD3 雙特異性抗體 REGN5458 的初步數據，該抗體是用於治療晚期多發性骨髓瘤的 BCMAxCD3 雙特異性抗體。值得一提的是，該計畫的首例患者於 2019 年初接受治療，同年晚些時候，我們在 ASH 會議上展示了初步的療效和安全性數據。

In the higher of the 2 initial doses, objective responses were observed in 3 out of 4 patients, 2 of which achieved MRD negativity. These were all very advanced patients who had failed a median 7 lines of prior systemic therapy, including anti-CD38. We are currently enrolling higher-dose escalation cohorts.

在初始劑量較高的那組 2 例患者中，4 例患者中有 3 例觀察到客觀緩解，其中 2 例達到 MRD 陰性。這些都是病情非常嚴重的患者，他們之前接受過平均 7 線全身性治療，包括抗 CD38 治療，但均告失敗。我們目前正在招募高劑量遞增組患者。

This year, we also advanced our novel second class of bispecifics into the clinic. These bispecifics are referred to as CD28 or costim bispecifics because they activate the CD28-mediated costimulatory signal, also known as Signal 2 that is normally required to optimize cell killing by T-cells. Researchers have avoided targeting this T-cell activation pathway for almost 15 years ever since the disastrous clinical trial involving a CD28 superagonist, which indiscriminately activated T-cells in the bodies of healthy volunteers leading to cytokine storm and severe toxicity.

今年，我們也將我們新型的第二類雙特異性抗體推進了臨床試驗階段。這些雙特異性抗體被稱為 CD28 或共刺激雙特異性抗體，因為它們激活了 CD28 介導的共刺激信號（也稱為信號 2），該信號通常是 T 細胞優化殺傷細胞所必需的。自從那次災難性的臨床試驗以來，研究人員已經近 15 年沒有針對這種 T 細胞活化途徑進行研究了。那次試驗涉及一種 CD28 超級激動劑，該激動劑不加區分地激活了健康志願者體內的 T 細胞，導致細胞激素風暴和嚴重毒性。

In contrast, our CD28 bispecifics are designed to avoid this problem by locally engaging T-cells only at the tumor site, as validated by our preclinical studies, some of which were published a few weeks ago in Science Translational Medicine and which demonstrated synergistic activity when costims were combined with Libtayo or with other bispecifics, even for tumors historically unresponsive to PD-1 blockade.

相較之下，我們的 CD28 雙特異性抗體旨在透過僅在腫瘤部位局部與 T 細胞結合來避免這個問題，這已透過我們的臨床前研究得到驗證，其中一些研究結果已於幾週前發表在《科學轉化醫學》雜誌上，這些研究表明，當共刺激分子與 Libtayo 或其他雙特異性抗體聯合使用時，即使對於歷史上對 PD-1 阻斷反應的協同活性。

At the end of last year, we enrolled our first patients in the clinical trial of our first costim, PSMAxCD28 in combination with Libtayo in advanced prostate cancer patients. We expect additional costims to enter in the clinic in 2020.

去年年底，我們招募了第一批患者參與臨床試驗，試驗內容是我們的首個共刺激藥物 PSMAxCD28 與 Libtayo 聯合用於治療晚期前列腺癌患者。我們預計 2020 年將有更多客製化產品進入診所。

Now I'd like to move on to the rest of our pipeline. With the C5 blocker, pozelimab, our goal is to achieve a more complete blockade of inappropriate complement activation compared to the currently available therapies and to do this with a more convenient, self-administered subcutaneous dosage form. Results from an initial 6-patient cohort of our Phase II study in paroxysmal nocturnal hemoglobinuria patients announced in December showed that our subcutaneous weekly regimen of pozelimab, maintained lactate dehydrogenase, a biomarker for red blood cell damage, at normal levels at week 8.

現在我想繼續介紹我們流程的其餘部分。使用 C5 阻斷劑 pozelimab，我們的目標是與目前可用的療法相比，更徹底地阻斷不適當的補體激活，並且採用更方便的、可自行皮下給藥的劑量形式。12 月發表的 II 期研究初步 6 名陣發性睡眠性血紅蛋白尿患者隊列結果顯示，我們每週一次的皮下注射 pozelimab 方案，使乳酸脫氫酶（紅血球損傷的生物標記）在第 8 週時維持在正常水平。

Importantly, we are uniquely positioned to test a novel approach by combining pozelimab with our partner, Alnylam's anti 5 -- anti-C5 siRNA, which has the potential to maximize efficacy while further significantly reducing dosing frequency. This will be the first in a series of opportunities for combination of our antibodies with siRNA. We will be initiating our potentially pivotal program with pozelimab as well as combinations with the siRNA this year.

重要的是，我們擁有獨特的優勢來測試一種新方法，即將 pozelimab 與我們的合作夥伴 Alnylam 的抗 5——抗 C5 siRNA 相結合，這有可能最大限度地提高療效，同時進一步顯著降低給藥頻率。這將是我們抗體與siRNA結合的一系列機會中的第一次。今年我們將啟動一項可能具有關鍵意義的項目，該項目將使用 pozelimab 以及與 siRNA 的組合療法。

I'd like to provide an update on a few other late-stage programs. Earlier this year, with top line results of the Phase II study of garetosmab, our Activin A antibody for fibrodysplasia ossificans progressiva, a devastating orphan disease in which patient's muscles, tendons and ligaments are progressively replaced by bone, forming a second skeleton that traps them in their own bodies, often leading to asphyxiation.

我想向大家報告其他幾個後期專案的最新進展。今年早些時候，我們公佈了 garetosmab II 期研究的主要結果，garetosmab 是一種用於治療進行性骨化性纖維發育不良症的 Activin A 抗體，這是一種毀滅性的罕見病，患者的肌肉、肌腱和韌帶逐漸被骨骼取代，形成第二副骨骼，將他們困在自己的體內，常常導致窒息。

In the 44-patient study, garetosmab demonstrated a nearly 90% reduction in formation of new bone lesions compared to placebo. This treatment has the potential to transform the course of this disease. We plan to discuss the data with the regulators as well as initiate a study in pediatric patients.

在一項包含 44 名患者的研究中，與安慰劑相比，garetosmab 使新骨病變的形成減少了近 90%。這種療法有可能改變這種疾病的進程。我們計劃與監管機構討論這些數據，並啟動一項針對兒科患者的研究。

In 2020, we are also planning a regulatory submission for evinacumab, our ANGPTL3 antibody for homozygous familial hypercholesterolemia patients. We are also anticipating readout of the fasinumab or anti-NGF studies in osteoarthritis pain, including the long-term safety study as well as Phase III studies comparing it to naproxen and NSAIDs.

2020 年，我們也計劃向監管機構提交 evinacumab 的申請，這是一種用於治療純合子家族性高膽固醇血症患者的 ANGPTL3 抗體。我們也期待法西單抗或抗 NGF 治療骨關節炎疼痛的研究結果，包括長期安全性研究以及將其與萘普生和非類固醇抗發炎藥物進行比較的 III 期研究。

Finally, I'd like to finish by discussing our partnership with BARDA, part of the office of preparedness and response to the Department of Health and Human Services. Together, we hope to exploit our rapid response capabilities to address emerging infectious disease outbreaks. We initially built this program and worked with BARDA to address the 2012 MERS epidemic. MERS is a coronavirus closely related to the Wuhan virus that is causing the current global public health emergency. Then in 2014, we turned our rapid response capabilities to focus on Ebola, working together with BARDA and the World Health Organization, progressing therapeutic candidates in just 6 months and resulting in the potential cure even for sickest Ebola patients as was recently published in the New England Journal of Medicine and allowing for an ongoing rolling submission to the FDA for approval of our life-saving antibody cocktail.

最後，我想談談我們與美國生物醫學高級研究與發展局 (BARDA) 的合作關係，BARDA 是美國衛生與公眾服務部緊急準備和應變辦公室的一部分。我們希望共同利用我們的快速反應能力來應對新出現的傳染病疫情。我們最初建立了這個程序，並與 BARDA 合作應對 2012 年的中東呼吸症候群 (MERS) 疫情。中東呼吸道症候群（MERS）是一種冠狀病毒，與目前引發全球公共衛生緊急事件的武漢病毒密切相關。2014 年，我們將快速反應能力轉向伊波拉病毒，與美國生物醫學高級研究與發展局 (BARDA) 和世界衛生組織合作，僅用 6 個月就取得了治療候選藥物的進展，並有可能治愈最嚴重的伊波拉患者。這項成果最近發表在《新英格蘭醫學雜誌》上，並使我們能夠持續向美國食品藥物管理局 (FDA) 提交申請，以獲得我們拯救生命的抗體雞尾酒療法的批准。

As BARDA announced just this week, we are now extending our collaboration with them to address the Wuhan coronavirus. We're already scaling up one set of potential antibody treatments that could be available for testing or for [pass in] use in patients within a few months as well as a new set of treatments that could be available soon thereafter.

正如美國生物醫學高級研究與發展局（BARDA）本周宣布的那樣，我們現在正在擴大與他們的合作，以應對武漢冠狀病毒。我們已經在擴大一組潛在抗體療法的規模，這些療法可能在幾個月內即可用於測試或患者試用，同時我們還在擴大另一組療法的規模，這些療法可能很快也會推出。

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

接下來，我將把電話交給瑪莉安。

Thank you, George. We closed out 2019 on a high note with continued commercial execution across our portfolio, our core EYLEA and DUPIXENT [business]

謝謝你，喬治。2019 年，我們以優異的成績收官，旗下所有產品組合、核心業務安樂死和度普利康都持續取得商業成功。

(technical difficulty)

（技術難題）

commercial

商業的

(technical difficulty)

（技術難題）

in oncology.

在腫瘤學領域。

Starting with EYLEA. In the fourth quarter, we recorded our best performance in terms of volume and net sales since launch in 2011. Global net sales grew 11% year-over-year to more than $2 billion, and U.S. net sales grew 13% to $1.22 billion versus the prior year. Growth was driven by increases to both market share and market expansion.

從愛麗莎開始。第四季度，我們在銷量和淨銷售額方面取得了自 2011 年推出以來的最佳業績。全球淨銷售額年增 11%，超過 20 億美元；美國淨銷售額年增 13%，達 12.2 億美元。成長是由市場份額和市場擴張的雙重推動的。

EYLEA's sales grew in diabetic eye disease and in wet AMD despite a new anti-VEGF market entrant. Also while not a material driver of performance in the quarter, we introduced the EYLEA prefilled syringe in mid-December and anticipate full market supply in March. The overall anti-VEGF market continues to grow at a steady mid- to high single-digit pace, underpinned by the aging population and increasing prevalence of diabetes. Our renewed strategy and incremental 2019 investments enhanced wet AMD leadership and drove further penetration in diabetic eye disease, which has EYLEA growing faster than the market across all indications.

儘管抗 VEGF 市場出現了新的競爭者，但 EYLEA 在糖尿病眼部疾病和濕性 AMD 領域的銷售額仍然成長。此外，雖然這不是本季業績的實質驅動因素，但我們在 12 月中旬推出了 EYLEA 預填充注射器，並預計 3 月將全面進入市場供應。受人口老化和糖尿病盛行率上升的推動，抗 VEGF 市場整體持續以穩定的中高個位數速度成長。我們重新制定的策略和 2019 年的增量投資增強了濕性 AMD 的領先地位，並推動了糖尿病眼部疾病領域的進一步滲透，使得 EYLEA 在所有適應症中的成長速度都超過了市場平均水平。

As we have seen for the last several quarters, the growth rate in diabetic eye disease exceeds the growth rate in wet AMD. Accordingly, the wet AMD business represents less than 60% of total U.S. EYLEA net product sales.

正如我們在過去幾季所看到的，糖尿病眼疾的成長率超過了濕性老年黃斑部病變的成長率。因此，濕式 AMD 業務佔 EYLEA 美國淨產品銷售額的不到 60%。

In 2020, we have significant opportunities to advance EYLEA's leadership position. In wet AMD, we are executing initiatives designed to position EYLEA as the preferred first-line treatment. Beyond wet AMD, we see tremendous opportunity in diabetic eye disease as patients remain largely underdiagnosed and undertreated. We're investing in targeted initiatives with physicians and consumers to increase diagnosis and treatment rates as well as applying technologies to support screening and diagnosis.

2020年，我們有很多機會來提升安永的領導地位。在濕性 AMD 治療中，我們正在實施旨在將 EYLEA 定位為首選第一線治療方案的各項措施。除了濕性老年黃斑部病變之外，我們看到糖尿病眼疾領域也蘊藏著巨大的機遇，因為患者在很大程度上仍未被診斷和治療。我們正在投資針對醫生和消費者的定向舉措，以提高診斷和治療率，並應用技術來支持篩檢和診斷。

The totality of our clinical profile, safety record, dosing flexibility, breadth of indications and established reimbursement give us confidence in the future for EYLEA.

EYLEA 的臨床概況、安全記錄、劑量靈活性、適應症範圍以及已建立的報銷機制，使我們對 EYLEA 的未來充滿信心。

Turning to Libtayo. Fourth quarter global net sales were $75 million. In the U.S., where sales were $61 million, we've quickly established Libtayo as the leading systemic treatment for the advanced cutaneous squamous cell carcinoma, or CSCC. Approximately 60% of CSCC patients now receive anti PD-1 therapy. And in the anti-PD-1 class, Libtayo has nearly 90% share of new patients.

轉向Libtayo。第四季全球淨銷售額為7500萬美元。在美國，Libtayo 的銷售額達到了 6,100 萬美元，我們迅速將其確立為治療晚期皮膚鱗狀細胞癌 (CSCC) 的領先全身性藥物。目前約有 60% 的 CSCC 患者接受抗 PD-1 治療。在抗 PD-1 藥物中，利妥昔單抗佔據了近 90% 的新患者份額。

In 2020, we're investing to increase our commercial presence, including expanding our field force to strengthen Libtayo's position as the standard of care in CSCC. Additionally, launch preparations for a potential approval in basal cell carcinoma are underway.

2020 年，我們將加強投資力度，擴大我們的商業影響力，包括擴大我們的銷售團隊，以鞏固 Libtayo 作為 CSCC 標準護理的地位。此外，針對基底細胞癌的潛在批准，相關上市準備工作正在進行中。

Outside the U.S., initial CSCC launches are ongoing and led by our collaborator, Sanofi. We're encouraged by early prescribing trends and continue to see progress with access and reimbursement. Overall, we're very pleased with the early impact we have made with Libtayo.

在美國以外，CSCC 的初步上市工作正在進行中，由我們的合作夥伴賽諾菲主導。我們對早期的處方趨勢感到鼓舞，並持續看到在獲取和報銷方面取得進展。總的來說，我們對Libtayo早期所取得的成效非常滿意。

And finally to DUPIXENT. Global net sales in the fourth quarter were $752 million. In the U.S., net sales reached $605 million, representing 134% growth as compared to the prior year. We continue to see strong prescribing trends across all indications, with total prescriptions growing approximately 18% compared to the third quarter. Weekly new-to-brand prescriptions at quarter end were approximately 1,500 patients per week. Atopic dermatitis remains a significant growth driver for DUPIXENT. The brand continues to outpace other biologic launches in dermatology, and there is significant room for further penetration.

最後是DUPIXENT。第四季全球淨銷售額為7.52億美元。在美國，淨銷售額達 6.05 億美元，比上年成長 134%。我們繼續看到所有適應症的處方趨勢強勁，與第三季度相比，處方總量增加了約 18%。季度末每週新增品牌處方量約 1,500 例。異位性皮膚炎仍然是DUPIXENT的重要成長驅動因素。該品牌在皮膚科領域持續領先其他生物製劑產品，並且還有很大的市場滲透空間。

We're expanding the market through increased prescribing across both moderate and severe disease. Additionally, the recent adolescent launch is contributing to growth, aided by physician experience and comfort with DUPIXENT's efficacy and safety profile. As Len mentioned, we eagerly await the potential FDA approval in 6 to 11-year olds, where there is significant disease burden for young patients and their families.

我們正在透過增加對中度和重度疾病患者的處方量來擴大市場。此外，最近針對青少年推出的產品也促進了市場成長，這得益於醫生們對 DUPIXENT 的療效和安全性的經驗和信心。正如 Len 所提到的，我們熱切期盼 FDA 批准該藥物用於 6 至 11 歲兒童，因為這個年齡層的兒童及其家庭面臨嚴重的疾病負擔。

In asthma, DUPIXENT is outperforming other recent biologic launches, with nearly 80% of DUPIXENT asthma patients being new to biologic treatment. We continue to demonstrate that our strategy to grow and compete in this market is working. There is significant opportunity to advance DUPIXENT's market position with less than 15% of eligible patients currently receiving biologic treatment. We recently began the rollout of our asthma direct-to-consumer TV campaign. Although early, our campaign is generating positive results from leading indicators.

在氣喘治療領域，DUPIXENT 的表現優於其他近期上市的生物製劑，近 80% 的 DUPIXENT 氣喘患者是首次接受生物製劑治療。我們不斷證明，我們在這個市場中發展和競爭的策略是行之有效的。目前只有不到 15% 的符合條件的患者接受生物製劑治療，因此 DUPIXENT 的市場地位有很大的提升空間。我們最近開始推出氣喘直接面向消費者的電視廣告宣傳活動。雖然活動尚處於早期階段，但從領先指標來看，我們的活動已經取得了積極成果。

Finally, our launch in chronic rhinosinusitis with nasal polyps is off to a strong start. Patients are initiating on DUPIXENT regardless of prior surgery. Prescribing is being driven by both allergists and ENTs, including many new DUPIXENT prescribers. We see tremendous growth potential with DUPIXENT and remain committed to advancing DUPIXENT prescribing to many more patients by way of expanded indications, age groups and geographies.

最後，我們在慢性鼻竇炎伴隨鼻息肉領域的推出取得了強勁的開端。無論之前是否接受過手術，患者都可以開始使用 DUPIXENT。處方主要由過敏科醫生和耳鼻喉科醫生推動，其中包括許多新的 DUPIXENT 處方醫生。我們看到了 DUPIXENT 的巨大成長潛力，並將繼續致力於透過擴大適應症、年齡層和地理範圍，讓更多患者能夠使用 DUPIXENT。

In closing, we delivered strong growth across our core commercial franchise in the fourth quarter and throughout 2019. We are entering 2020 with significant momentum and confidence to drive the future.

綜上所述，我們在第四季和 2019 年全年核心商業特許經營領域實現了強勁成長。我們帶著強勁的發展動能與十足的信心邁入2020年，引領未來。

I'll turn the call over now to Bob.

我現在把電話交給鮑伯。

Thank you, Marion. For the fourth quarter 2019, Regeneron delivered another quarter of strong revenue and EPS growth. Fourth quarter 2019 revenues grew 13% to $2.17 billion driven by continued growth of our core brands, EYLEA, Libtayo and DUPIXENT. Non-GAAP diluted net income per share grew 10% year-over-year to $7.50 on non-GAAP net income of $858 million.

謝謝你，瑪莉安。2019 年第四季度，Regeneron 再次實現了強勁的營收和每股盈餘成長。2019 年第四季營收成長 13% 至 21.7 億美元，這主要得益於我們核心品牌 EYLEA、Libtayo 和 DUPIXENT 的持續成長。非GAAP稀釋後每股淨收益年增10%至7.50美元，非GAAP淨收益為8.58億美元。

Let me remind everyone, when comparing to the prior year, the fourth quarter 2018 revenues included $149 million catch-up benefit related to the modification of the IO discovery agreement with Sanofi, which makes this quarter's growth even more impressive.

我想提醒大家，與去年同期相比，2018 年第四季的營收包含了與修改與賽諾菲的 IO 發現協議相關的 1.49 億美元的追趕收益，這使得本季的成長更加令人印象深刻。

Since Marion discussed our U.S. EYLEA results, I will start with our Bayer and Sanofi collaborations. Starting with the Bayer collaboration. Ex U.S. EYLEA net product sales, which are reported to us by Bayer, were $783 million, representing growth of 8% on a reported basis and 9% on a constant currency basis. Total Bayer collaboration revenue for the fourth quarter of 2019 grew 6% year-over-year to $321 million, of which, $298 million was derived from our share of net profits from EYLEA sales outside the U.S.

既然 Marion 已經討論了我們在美國 EYLEA 的成果，那我就先從我們與拜耳和賽諾菲的合作說起。從與拜耳的合作開始。根據拜耳公司向我們報告，除美國以外，EYLEA淨產品銷售額為7.83億美元，按報告匯率計算成長8%，以固定匯率計算成長9%。2019 年第四季拜耳合作總營收年增 6% 至 3.21 億美元，其中 2.98 億美元來自我們在美國以外地區銷售 EYLEA 產品所獲得的淨利份額。

Total Sanofi collaboration revenue in the fourth quarter was $427 million. Regeneron recognized a profit of $104 million from the commercialization of non-IO antibodies compared to a loss of $44 million in the prior year period. Increases were driven primarily by higher DUPIXENT net sales partially offset by the rollout of the DUPIXENT asthma DTC campaign as well as incremental cost to support ongoing global DUPIXENT launches.

賽諾菲第四季合作總收入為 4.27 億美元。Regeneron公司從非免疫腫瘤抗體的商業化中獲得了1.04億美元的利潤，而去年同期則虧損了4,400萬美元。成長主要由 DUPIXENT 淨銷售額增加所推動，但部分被 DUPIXENT 氣喘 DTC 活動的推出以及支援 DUPIXENT 持續全球上市的額外成本所抵銷。

Moving to our expense base, starting with R&D. Non-GAAP R&D expenses were $581 million for the fourth quarter of 2019, an increase of 9% compared to prior year. Non-GAAP unreimbursed R&D expense, which is calculated as the total non-GAAP R&D expense less reimbursements from our collaborators, was $393 million for fourth quarter 2019, an increase of 13% compared to the prior year. Higher R&D expense is a result from broadening and advancing our pipeline of wholly owned drug candidates, particularly in oncology.

接下來我們來看看費用組成，先從研發開始。2019 年第四季非 GAAP 研發費用為 5.81 億美元，比去年同期成長 9%。2019 年第四季，非 GAAP 未報銷研發費用（計算方法為非 GAAP 研發總費用減去合作方的報銷）為 3.93 億美元，比去年同期成長 13%。研發費用增加是由於我們擴大和推進了我們全資擁有的候選藥物管線，尤其是在腫瘤領域。

We are also funding jointly developed molecules with strategic external partners. In November, we announced a research collaboration with Vyriad, focusing on the development of new oncolytic virus-based treatments for cancer. Taken together, we continue to expect 2020 R&D expenses to increase.

我們也資助與外部策略夥伴共同開發分子。11 月，我們宣布與 Vyriad 進行研究合作，專注於開發基於溶瘤病毒的新型癌症療法。綜合來看，我們仍預期 2020 年研發支出將會增加。

Next, non-GAAP SG&A expense was $446 million for the fourth quarter of 2019. This represents a 9% year-over-year increase driven by higher headcount and related costs in commercialization expenses related to both EYLEA and DUPIXENT. We expect non-GAAP SG&A expenses to increase in 2020 as we invest for further growth in our 3 core brands, EYLEA, DUPIXENT and Libtayo.

其次，2019 年第四季的非 GAAP SG&A 費用為 4.46 億美元。這代表著同比增長 9%，主要原因是安樂死 (EYLEA) 和度普利康 (DUPIXENT) 的商業化費用以及相關人員數量的增加。我們預計 2020 年非 GAAP 銷售、一般及行政費用將會增加，因為我們將投資於我們的 3 個核心品牌 EYLEA、DUPIXENT 和 Libtayo，以實現進一步成長。

In the fourth quarter of 2019, combined non-GAAP cost of goods sold and cost of collaboration and contract manufacturing were $208 million compared to $109 million in the fourth quarter of 2018. The year-over-year increase in cost of goods sold was primarily due to the company's obligation to pay Sanofi its share of Libtayo U.S. gross profits, third-party royalties on Libtayo U.S. sales and higher inventory reserves and write-offs. The year-over-year increase in cost of collaboration and contract manufacturing was primarily due to recognition of manufacturing costs associated with higher sales of DUPIXENT.

2019 年第四季度，非 GAAP 銷售成本和合作及合約製造成本總計為 2.08 億美元，而 2018 年第四季為 1.09 億美元。銷售成本年增主要是由於公司有義務向賽諾菲支付其在美國銷售 Libtayo 的毛利潤份額、向第三方支付 Libtayo 美國銷售額的特許權使用費以及更高的庫存準備金和減值損失。合作和合約製造成本同比增加主要是由於確認了與 DUPIXENT 銷量增加相關的製造成本。

Shifting to cash flow and the balance sheet. For full year 2019, Regeneron generated $2 billion in free cash flow. We ended the year with cash and marketable securities of nearly $6.5 billion. Recall, last November, we announced a $1 billion share repurchase program. In the fourth quarter, we repurchased approximately $250 million worth of shares in open market transactions. We continue to repurchase shares opportunistically.

轉而關注現金流和資產負債表。2019 年全年，Regeneron 創造了 20 億美元的自由現金流。年底時，我們持有的現金和有價證券近65億美元。回想一下，去年11月，我們宣布了10億美元的股票回購計畫。第四季度，我們透過公開市場交易回購了價值約 2.5 億美元的股票。我們會繼續伺機回購股票。

Now let me take a minute to discuss the restructuring of our antibody agreement with Sanofi. As we previously disclosed, the anticipated benefits of this proposed restructured agreement are improved profitability, increased efficiencies and simplification. Upon closing of the deal, we expect this transaction to be immediately accretive to Regeneron. We are working diligently to ensure an expedient close to the transaction this quarter. As such, we will provide annual guidance by the end of the first quarter to account for the various line items impacted by the restructured antibody agreement.

現在請容許我花一分鐘時間討論一下我們與賽諾菲的抗體協議重組事宜。正如我們之前所揭露的那樣，這項擬議的重組協議的預期好處是提高獲利能力、提高效率和簡化流程。交易完成後，我們預計此交易將立即為 Regeneron 帶來收益成長。我們正在努力確保本季盡快完成交易。因此，我們將在第一季末提供年度業績指引，以反映重組抗體協議對各項指標的影響。

Given the expected timing of the transaction closing, continue to model Regeneron's financials for the first quarter as you have historically. Note that our first quarter non-GAAP EPS results are typically lower than the fourth quarter of the prior year due to trends in tax rate and other seasonal market dynamics. We are generally comfortable with consensus non-GAAP EPS estimates for the full year. However, our quarterly reported increases from the beginning of the year to the end of the year will be more pronounced than what current consensus reflects.

鑑於交易完成的預期時間，請繼續按照以往的做法對 Regeneron 第一季的財務狀況進行建模。請注意，由於稅率趨勢和其他季節性市場動態，我們第一季的非GAAP每股收益通常低於上年第四季。我們總體上對全年非GAAP每股收益的普遍預期感到滿意。然而，我們公佈的年初到年末的季度成長幅度將比目前的普遍預期更為顯著。

In conclusion, the fourth quarter capped off a strong year for Regeneron. We are pleased with our financial results and operational performance. We look forward to providing more details on the restructured antibody agreement in 2020 annual guidance later this quarter.

總之，第四季為Regeneron強勁的一年畫下了圓滿的句點。我們對財務業績和營運表現感到滿意。我們期待在本季度稍後發布的 2020 年年度業績指引中提供有關重組抗體協議的更多細節。

With that, I'd like to turn the call back to Justin.

那麼，我想把電話轉回給賈斯汀。

Thank you, Bob. We'd now like to open the call for Q&A. (Operator Instructions)

謝謝你，鮑伯。現在我們開始問答環節。（操作說明）

Please go ahead, Sylvia.

請繼續，西爾維亞。

(Operator Instructions) And our first question comes from Terence Flynn from Goldman Sachs.

（操作說明）我們的第一個問題來自高盛的 Terence Flynn。

Maybe just 2 for me. One on -- the first is with respect to bispecifics. Maybe, George, what gives you confidence that these will be successful in solid tumors? I know you guys have a number of different targets you're going after and waiting to see the data, but just maybe remind us what gives you confidence there?

對我來說，可能就兩個吧。一、二特異性抗體。喬治，是什麼讓你確信這些藥物對實體腫瘤有效呢？我知道你們有很多不同的目標正在追踪，並且正在等待數據，但能不能提醒我們一下是什麼讓你們對這些目標充滿信心？

And then just on DUPI. Can you give us the sales split by indication or maybe the prescriber mix?

然後就只用DUPI了。能否提供按適應症劃分的銷售數據，或是處方醫生構成數據？

George, why don't you start, and then, Marion, you can take the DUPI question.

喬治，你先來吧，然後，瑪麗昂，你可以回答 DUPI 問題。

Okay. So first of all, we have no reason to think that they wouldn't be. I know that there's a lot of speculation, but it hasn't really been tested with reagents like our bispecifics to see whether solid tumors are indeed -- are more resistant or not, but that notwithstanding, in case single-agent therapy is not as effective for solid tumors, that is why we are preparing for that possibility with our various combinations. And our combinations include both combinations with these new classes of bispecs called costims, which dramatically increase responses, at least in preclinical models, in the solid tumor setting, but also combinations with Libtayo and other kinds of checkpoint inhibitors and immunomodulatory agents.

好的。所以首先，我們沒有理由認為他們不會。我知道有很多猜測，但還沒有真正用像我們的雙特異性抗體這樣的試劑進行測試，看看實體瘤是否真的更具抗藥性，但儘管如此，如果單藥療法對實體瘤效果不佳，這就是為什麼我們正在用各種組合療法來應對這種可能性。我們的組合療法包括與被稱為costim的新型雙特異性分子組合，這些分子至少在臨床前模型中顯著提高了實體瘤的療效；此外，還包括與Libtayo和其他類型的檢查點抑制劑和免疫調節劑的組合。

So the notion is though we're hopeful for single-agent activity, we are prepared that just like in many other cancers and many other treatment settings, that combinations are going to be the key to success, and we have a real exciting set of combination opportunities in the solid tumor space setting, as I said, particularly with our costim bispecifics added to our CD3 bispecifics as well as our PD-1 but other additional immunomodulatory agents. I'll turn the next question over to Marion about the DUPIXENT.

因此，儘管我們對單藥治療的療效抱持希望，但我們也做好了準備，就像在許多其他癌症和許多其他治療環境中一樣，聯合治療將是成功的關鍵。正如我所說，我們在實體瘤領域擁有一系列令人興奮的聯合治療機會，特別是將我們的 costim 雙特異性藥物添加到我們的 CD3 雙特異性藥物以及 PD-1 和其他額外的免疫調節劑中。下一個問題我將交給 Marion，問她關於 DUPIXENT 的問題。

Sure. Happy to -- and this relates to your question on the breakdown of sales and performance for DUPIXENT. First, I'll just comment that we're seeing strong performance in sales growth and NBRx across all the indications. We haven't specifically given a breakdown by indication. Again, I confirm strength and strong performance and competitive performance in areas where we have competitors. But I can give you a little bit of in terms of how we're seeing the majority of our sales in NBRxs in atopic dermatitis, that's then followed by asthma, and then third would be the nasal polyps, where we're also seeing encouraging performance.

當然。樂意效勞－這與您提出的DUPIXENT銷售額和業績細分的問題有關。首先，我想說的是，我們看到所有適應症的銷售成長和 NBRx 都表現強勁。我們沒有依指標進行具體細分。我再次確認，我們在有競爭對手的領域擁有強大的實力和優異的表現，並保持著競爭力。但我可以簡單介紹一下，我們目前在 NBRxs 方面的銷售額主要來自異位性皮膚炎，其次是氣喘，第三是鼻息肉，我們在鼻息肉方面的表現也令人鼓舞。

Our next question comes from Geoff Meacham from Bank of America.

下一個問題來自美國銀行的傑夫‧米查姆。

This is [Alex] on for Geoff. I have 2, 1 on EYLEA and 1 on PRALUENT. So for EYLEA, how are you guys thinking about the ongoing Beovu launch? Specifically, do you view the earlier 12-week dosing as driving drug choice by prescribers? And any color you can give on ongoing or anticipated impact to rebates you provide for EYLEA to maintain formulary status.

這是Alex替Geoff上場。我有兩張，一張是EYLEA的，一張是PRALUENT的。那麼對於愛樂（EYLEA）來說，你們對正在進行的Beovu產品上市有什麼看法？具體來說，您是否認為早期 12 週給藥方案會影響處方醫師的藥物選擇？以及您能就您為 EYLEA 維持處方集地位而提供的回扣的持續或預期影響給出的任何顏色。

And then on PRALUENT, we've noted that the price reductions for the PCSK9 class has had an outside -- outsized benefit to Repatha volumes. Could you talk about the sales effort you and Sanofi have been taking in the U.S.? And what was the feedback from physicians and payers? And I guess, ultimately, how do you hope bringing these efforts entirely in-house will help drive volumes for PRALUENT?

此外，在 PRALUENT 上，我們注意到 PCSK9 類藥物的價格下調對 Repatha 的銷售產生了巨大的外部效益。您能否談談您和賽諾菲在美國的銷售工作？醫生和支付方的回饋如何？我想，最終，您希望將這些工作完全納入公司內部，如何幫助 PRALUENT 提升銷售？

Sure, Marion?

當然可以，瑪莉安？

Sure. So let me first comment on EYLEA performance. And certainly, we worked very hard and have been in a competitive market with EYLEA for many years and certainly have established a very strong market leadership position. It's very early days for the newest competitor in the marketplace. But what I will affirm is that EYLEA has a profile that is incredibly well-received and is referred to as the standard of care by our retinal specialists and injectors. Specifically, it's things like the clinical profile as it relates to impact on visual acuity, multiple indications experienced not only clinically, but with an established safety profile, reimbursement, dosing flexibility and also now dosage delivery with the prefilled syringe.

當然。首先讓我來談談EYLEA的表現。當然，我們付出了巨大的努力，多年來一直與安樂在競爭激烈的市場中競爭，並且已經建立了非常強大的市場領導地位。對於市場上最新的競爭者來說，現在還處於非常早期的階段。但我可以肯定的是，EYLEA 的口碑非常好，被我們的視網膜專家和注射醫生譽為護理標準。具體來說，它包括與視力影響相關的臨床概況、多種適應症（不僅在臨床上，而且在已確立的安全概況）、報銷、劑量靈活性以及現在使用預填充注射器進行劑量輸送等因素。

So EYLEA has an incredibly compelling profile. As to competition, both competition historically and future competition, it becomes a matter of physicians determining what is the risk benefit of using a different product. And certainly, there will be ample opportunity for retina specialists to make the choice in prescribing that's best for them.

所以安怡擁有極具吸引力的品牌形象。至於競爭，無論是歷史上的競爭還是未來的競爭，都取決於醫生如何判斷使用不同產品的風險效益。當然，視網膜專家將有足夠的機會選擇最適合患者的處方。

But to date, we hear very, very positive feedback in EYLEA, certainly, our most recent indication in diabetic eye disease. Diabetic retinopathy is very important. As we described, we did put forward earlier in 2019 a new strategy to make sure that we were making (inaudible) from our position in the wet AMD marketplace and then also expanding in diabetic eye disease. So I think we feel really good about the performance that we saw in 2019, but we also see an awful lot of work ahead. Because as I mentioned, there's tremendous unmet need and disease burden and diabetic eye disease that we have not impacted yet, so a lot of work going forward.

但到目前為止，我們在 EYLEA 中收到了非常非常積極的回饋，這無疑是我們最新的糖尿病眼部疾病適應症。糖尿病視網膜病變非常重要。正如我們所描述的，我們在 2019 年初提出了一項新策略，以確保我們能夠從我們在濕性 AMD 市場的地位中獲利，並進一步拓展糖尿病眼部疾病領域。所以我覺得我們對 2019 年的表現非常滿意，但我們也看到了前方還有很多工作要做。正如我之前提到的，目前存在著巨大的未滿足需求和疾病負擔，以及我們尚未觸及的糖尿病眼病，因此未來還有很多工作要做。

You also have asked a question related to pricing in EYLEA. We don't give information on our pricing strategies. But I will say that we are very committed to physicians having choice of prescribing in all the categories in which we have competition, and it's really important that doctors make the right choice for their patients. So we'll continue to take that position in the marketplace.

您也詢問了有關安永定價的問題。我們不公開定價策略方面的資訊。但我要說的是，我們非常致力於讓醫生在我們所有存在競爭的類別中擁有處方選擇權，醫生為他們的患者做出正確的選擇真的非常重要。因此，我們將繼續在市場上採取這種立場。

I'll move over to PRALUENT quickly. As was announced in the restructuring of our arrangement with Sanofi, Regeneron is now very pleased to be running the PRALUENT business in the U.S. It's early days in the future. Certainly, we'll have more to say about our positioning in the market and our strategy in the marketplace. But I think at this point, it's probably best that we let it go until the end of the restructuring agreement and the finalization of that transaction.

我會盡快轉到 PRALUENT。正如我們在與賽諾菲的重組協議中所宣布的那樣，Regeneron 現在非常高興能夠在美國經營 PRALUENT 業務。未來還處於早期階段。當然，我們之後也會就我們在市場中的定位和市場策略發表更多看法。但我認為，目前最好還是等到重組協議結束、交易最終完成後再處理此事。

And just to add to Marion's points. She mentioned benefit-risk for EYLEA and also safety for EYLEA. And I think it's very important to mention that physicians, of course, are very sensitive to this. And in settings where efficacy and durability are considered similar, they're going to pay very close attention to things like inflammation. And then certainly, in the head-to-head studies, EYLEA was shown to have about 4 full lower levels of inflammation. These are the sort of things that physicians pay close attention to when efficacy and durability are considered rather similar.

我再補充一下瑪莉安的觀點。她提到了EYLEA的收益風險以及安全性。我認為非常重要的一點是，醫生當然對此非常敏感。在療效和持久性被認為相似的環境中，他們會非常密切地關注發炎等因素。而且，在直接對比研究中，EYLEA 的發炎程度明顯比 EYLEA 低約 4 倍。當療效和持久性被認為相當相似時，醫生們會密切注意這些方面。

Our next question comes from Chris Raymond from Piper Sandler.

我們的下一個問題來自Piper Sandler公司的Chris Raymond。

Just a couple. So just maybe first, maybe continuing on the EYLEA front. I think I heard you guys say that there was no stocking benefit in Q4 from the availability of the prefilled syringe. So maybe can you talk about -- it seems there's a tailwind potentially in -- for the first quarter. And maybe if you can put some brackets around that, that would be helpful.

就幾個。所以或許首先，或許可以繼續推進EYLEA計畫。我好像聽你們說過，第四季預充式註射器的供應並沒有帶來庫存收益。所以，您能否談談——看起來第一季可能會有順風——的情況？如果你能在上面加些括號，那就很有幫助了。

And then maybe for Bob. I think I heard you say, Bob, in your prepared remarks that you were comfortable with 2020 EPS consensus. And so I know you guys are still in the process of trying to figure out how you're going to guide in the parameters, et cetera. But should we view this as a signal that maybe you guys are comfortable guiding to EPS at some point?

然後或許是為了鮑伯。鮑勃，我想我聽到你在事先準備好的演講稿中說過，你對 2020 年每股收益的普遍預期感到滿意。所以我知道你們還在努力弄清楚如何引導參數等等。但這是否意味著你們可能願意在某個時候引導每股盈餘（EPS）呢？

Go ahead, Marion.

請繼續，瑪莉安。

So let me take the first part on EYLEA. And yes, you did hear me correctly, that while we introduced the prefilled syringe for EYLEA in mid-December, it did not have an impact, a material impact. And certainly, we were at normal stocking levels, days on hand, in the fourth quarter.

那麼，讓我先來談談EYLEA。是的，你沒聽錯，雖然我們在 12 月中旬推出了 EYLEA 的預充填式註射器，但它並沒有產生任何實質的影響。當然，第四季我們的庫存水準和庫存天數都處於正常水準。

One thing I'll describe to you is we very deliberately have introduced the prefilled syringe in a staggered way. And this was obviously with such a large product so that there would be market experience and we would have a gradual introduction. We do plan to have availability of full market supply by the March timeframe. And then physicians and offices will be able to make the decision as to whether they choose to use the prefilled syringe, which does have tremendous convenience and has had very positive early market feedback if the vial will be available as well if there are instances where an office or a physician would like to use the vial. We do anticipate, however, though, that the prefilled syringe will be very popular in the marketplace, and over time, will be the majority of our use, but it has been a staggered introduction.

我要向你們說明的是，我們非常謹慎地採取了分階段引入預充式註射器的方式。顯然，推出如此大型的產品是為了累積市場經驗，以便逐步引入。我們計劃在三月實現市場供應全面恢復。然後，醫生和診所就可以決定是否選擇使用預充式註射器，這種注射器確實非常方便，並且早期市場反饋非常積極；如果診所或醫生想要使用小瓶，小瓶也可以提供。不過，我們預計預充式註射器將在市場上非常受歡迎，隨著時間的推移，將成為我們主要的產品，但這卻是一個分階段的推廣過程。

Chris, with regards to your question on guide, we are in a unique situation. By now we would have given guidance at JPMorgan. We would have reconfirmed it on this call. And we just wanted to give you a sense -- a little bit direction instead of everyone driving blind with regards to where 2020 is expected to come. So again, we did our analysis and determined that we are comfortable with current consensus as it exists for full year EPS, and we are not envisioning to give full EPS guidance at the end of the quarter. We will give other guidance as has been typical with maybe a little -- a few enhancements included.

克里斯，關於你提出的指南問題，我們目前的情況比較特殊。到目前為止，摩根大通本應已經給予指導意見。我們本可以在這次通話中再次確認。我們只是想給大家一些方向感，而不是讓大家對 2020 年的發展方向一無所知。因此，我們再次進行了分析，並確定我們對目前的全年每股盈餘預期感到滿意，因此我們不打算在本季末給予完整的每股盈餘指引。我們將像往常一樣提供其他指導，可能還會進行一些改進。

Our next question comes from Evan Seigerman from Crédit Suisse.

我們的下一個問題來自瑞士信貸的埃文·塞格曼。

Congrats on the progress last year. So on Libtayo and nonsmall cell lung cancer, what gives you confidence that this trial will hit on the OS interim in high PD-L1 patients? And if successful, would you file on this data? And how would you potentially position Libtayo versus other checkpoint inhibitors?

祝賀去年的進展。那麼，關於 Libtayo 治療非小細胞肺癌，是什麼讓您相信這項試驗會在 PD-L1 高表達患者的 OS 中期達到預期效果？如果成功，你會根據這些數據提交訴狀嗎？那麼，您認為Libtayo與其他檢查點抑制劑相比，其潛在定位是什麼？

George, why don't you start?

喬治，你為什麼不先開始呢？

Yes. So as we said, response rates are not regulatory approval endpoint. However, historically, they've been shown to be a very good indicator for the activity. And in the setting of checkpoint inhibitors, they tend to correlate pretty well with what you see in terms of overall survival. And so our already reported response rates, where we've almost doubled the response rate, certainly suggests profound clinical activity and is a real positive indicator. Of course, until we see the interim data, we won't know. But I think that, that would put Libtayo in a very small space of agents that are now showing profound monotherapy activity in PD-L1 positive settings. So it would be a very exciting position to be in on top of its already demonstrated impressive, best-in-class activity in the nonmelanoma skin space.

是的。正如我們所說，回應率並不是監管部門批准的最終結果。然而，從歷史數據來看，它們已被證明是衡量活動的一個非常好的指標。而且，在檢查點抑制劑的背景下，它們往往與整體存活率密切相關。因此，我們已經報告的反應率，幾乎翻了一番，這無疑表明了顯著的臨床活性，是一個真正的積極指標。當然，在看到中期數據之前，我們無法知道結果。但我認為，這將使 Libtayo 躋身於目前在 PD-L1 陽性環境中顯示出顯著單藥治療活性的極少數藥物之列。因此，在非黑色素瘤皮膚領域已經展現出令人印象深刻的、一流的活性之後，這將是一個非常令人興奮的局面。

Our next question comes from Geoffrey Porges from SVP Leerink (sic) [SVB Leerink].

我們的下一個問題來自 SVP Leerink (sic) [SVB Leerink] 的 Geoffrey Porges。

Bob, just on the comment about accretion. Could you just give us a sense if the status quo prevailed, would your operating margin be consistent with last year or better? And then, presumably, the intention of the agreement is that we would see operating margin improvement, and that's how you get to it being accretive. So could you just comment on that?

鮑勃，我只是想就吸積現象的評論做個回應。能否請您大致說明一下，如果維持現狀，您的營業利潤率能否與去年持平或更高？然後，可以推測，該協議的目的是為了提高營業利潤率，從而實現獲利成長。您能否就此發表一下看法？

And then just a second question for George. You mentioned the costim program, and I think we're all interested in seeing the first clinical data from that. That's not on your 2020 highlights. So should we be assuming that we don't see any clinical disclosure on the PSMA program until next year?

我還有一個問題想問喬治。您提到了 costim 項目，我想我們都很想看到它的第一批臨床數據。那可不是你2020年的精彩時刻。那麼我們是否可以假設，在明年之前我們不會看到有關 PSMA 項目的任何臨床披露資訊？

Bob, do you want to start?

鮑勃，你想先開始嗎？

So Geoff, I would concur with the assumptions that you made. I mean certainly, we've mentioned that KEVZARA and PRALUENT have been a sizable drain with regards to the alliance profitability that we've shown. So certainly, the changes that are going to be made and coupled with the incoming royalties that we expect to get will certainly help our going-forward margins.

所以傑夫，我同意你所做的假設。我的意思是，當然，我們已經提到過，KEVZARA 和 PRALUENT 對我們展示的聯盟盈利能力造成了相當大的消耗。因此，即將進行的變革，再加上我們預期將獲得的版稅，肯定有助於我們未來的利潤率。

George?

喬治？

Well, as Geoff, you probably followed closely with our first-class of bispecs, whenever you have a new class of agents and you're working with the FDA, of course, the first purpose is to be moving as carefully and as safely as possible.

嗯，傑夫，你可能密切關注了我們第一代雙倍劑量製劑的進展，每當你研發出一類新的製劑並與美國食品藥品監督管理局 (FDA) 合作時，當然，首要目標是盡可能謹慎、安全地推進。

And so for our first bispec, it took a long time to get to efficacious dose levels. When we finally got there, we had actually show that we have gotten there with a pretty safe approach, which now other people are trying to emulate. And then we were able to pretty rapidly, as I described with our second dose level, get to efficacious dose levels with our second CD3 bispecifics. So now the CD28 class represents once again a new class. We are hoping that we're going to repeat that sort of experience. And the timing of it, of course, is dependent on so many factors.

因此，對於我們的第一個雙光譜儀來說，達到有效劑量水平需要很長時間。當我們最終達到目標時，我們實際上已經證明，我們是透過一種相當穩健的方式來達到目標的，現在其他人正在試圖效仿這種方式。然後，正如我之前描述的那樣，我們的第二個劑量水平很快就達到了有效劑量水平，我們的第二個 CD3 雙特異性抗體也達到了有效劑量水平。所以現在 CD28 類別又代表了一個新類別。我們希望能夠再次獲得這樣的經驗。當然，具體時間取決於諸多因素。

So depending on how it goes, we may reach effective dose levels sooner rather than later and get data sooner rather than later. But the major point is that we're working with the FDA and with our collaborators to make sure that we use this innovative new approach as safely as possible. So it all depends on how the dose escalation goes and when we get to what we think are the effective dose levels, and it could be sooner or it could be a little later.

所以，根據進展情況，我們可能很快就能達到有效劑量水平，並很快獲得數據。但最重要的是，我們正在與美國食品藥物管理局 (FDA) 和我們的合作者一起努力，以確保我們盡可能安全地使用這種創新方法。所以這一切都取決於劑量遞增的進展情況，以及我們何時達到我們認為的有效劑量水平，這可能會早一些，也可能晚一些。

And all we're hoping is that we're going to see the same sort of profound activity that we saw with our first-class of bispecifics, which is really suggesting that they may be best-in-class. And if we can now layer on a completely new class that has synergistic activity, I think that will be very exciting and important for patients for all these settings where they're not responding right now to immunotherapy or where their responses are not as optimal as we'd want.

我們只希望能夠看到與第一批雙特異性抗體一樣的顯著活性，這確實表明它們可能是同類最佳。如果我們現在能夠疊加一種具有協同作用的全新藥物類別，我認為這對於目前對免疫療法沒有反應或反應不如我們預期的患者來說，將會非常令人興奮和重要。

Our next question comes from Yatin Suneja from Guggenheim Partners.

下一個問題來自古根漢合夥公司的亞廷·蘇內賈。

And congrats on a very good quarter. Just a question on a C5 antibody that you have. Give us a little bit more insight into how you are thinking about broadening the development. Are there disease indication that you could potentially prioritize, which might not be as competitive and might be a little bit broader? And then a quick one for Bob on the Sanofi collaboration. Relative to Q3, are there particular factors that might have impacted the results in Q4?

恭喜你們本季業績非常出色。我有一個關於您擁有的C5抗體的問題。請您更詳細地介紹一下您是如何考慮拓展發展的。是否有一些疾病指標可以優先考慮，這些指標可能競爭不那麼激烈，範圍也可能更廣一些？然後，鮑伯需要快速回答一個關於賽諾菲合作的問題。與第三季相比，是否存在某些特定因素可能影響了第四季的業績？

Thank you. George, why don't you start in C5 and then, Bob.

謝謝。喬治，為什麼不先從 C5 開始，然後是鮑伯呢？

Yes. As you said, we agree with you. We believe that there are a lot of settings for C5 beyond the PNH setting. I think that what we've disclosed so far and what we're talking about right now is the PNH. Why? Because the data are so clear-cut in terms of what the high bar that we have to reach to believe that we have something that could be a real improvement for patients and for the class. And so once we hit that bar there, we would be pretty confident then that it would also continue to maybe be a real advance for patients and best-in-class in all these other settings that you referred to. So we're certainly not ignoring those, but what we're talking about and focusing about right now is the really well-understood space of PNH.

是的。正如你所說，我們同意你的觀點。我們認為，除了 PNH 設定之外，C5 還有很多其他設定。我認為我們目前所揭露的以及我們現在正在討論的都是陣發性夜間血紅蛋白尿症 (PNH)。為什麼？因為數據非常明確地表明，我們必須達到很高的標準才能相信我們擁有某種能夠真正改善病人和班級狀況的東西。因此，一旦我們達到那個標準，我們就會相當有信心，它也可能繼續成為患者的真正進步，並在您提到的所有其他領域中成為一流的。所以我們當然不會忽略這些，但我們現在談論和關注的是 PNH 這個真正被充分理解的領域。

Great. And Bob?

偉大的。鮑伯呢？

Yes. The question with regards to whether or not the Sanofi deal has given us benefit versus -- in Q4. I would say we continue to go after operating expenses for PRALUENT and KEVZARA, and we did see some of that in Q4. Again, this is an issue that we've been going after. And we've had some success in terms of lowering the operating expenses associated with that.

是的。關於賽諾菲交易是否為我們帶來收益的問題是——在第四季。我想說，我們繼續努力降低 PRALUENT 和 KEVZARA 的營運費用，我們在第四季度確實看到了一些成效。再次強調，這是我們一直在努力解決的問題。我們在降低相關營運費用方面取得了一些成功。

We did take a restructuring charge in Q4, and you'll see that outlined in our earnings announcement that was issued earlier this morning. And the big benefits you will begin to see will take place kind of effective Q1, where, as we speak right now, we're changing the operations of the businesses.

我們在第四季度提列了重組費用，您可以在今天早上發布的獲利公告中看到相關說明。您將在第一季開始看到顯著的好處，正如我們現在所說，我們正在改變企業的運作方式。

So I just wanted to add to my comments on the C5. As I said, we set a pretty high bar for ourselves with just our antibody. And as we've announced, the data suggests that, that antibody is meeting that high bar by itself, on its own, which I think puts us in a very, very exciting position because now we have the opportunity to even take it to a completely new level with this exciting collaborative opportunity with the Alnylam siRNA. So the fact that our antibody by itself is looking like it might be meeting this high bar of being a best-in-class agent, providing big advantages to patients on its own, having the opportunity to then combine it with the siRNA, really, I think, is very exciting for the field and for patients.

所以我想補充一下我對C5的看法。正如我所說，僅憑我們的抗體，我們就為自己設定了一個相當高的目標。正如我們所宣布的那樣，數據顯示，該抗體本身就達到了很高的標準，我認為這讓我們處於一個非常非常令人興奮的位置，因為現在我們有機會通過與 Alnylam siRNA 的激動人心的合作，將其提升到一個全新的水平。因此，我們的抗體本身似乎有望達到一流藥物的高標準，能夠為患者帶來巨大的優勢，並且有機會將其與 siRNA 結合使用，我認為這對這個領域和患者來說都非常令人興奮。

Let me just clarify one other thing. With regards to Q4 on the alliance profitability, we were -- we did incur significant expenses associated with the asthma DTC campaign, which had a rollout effective in Q4. And I'm sure a lot of people have seen that throughout the quarter.

我再澄清一件事。關於第四季度聯盟獲利情況，我們確實產生了與氣喘 DTC 活動相關的重大支出，該活動於第四季度正式推出。我相信很多人在本季度都看到了這一點。

And the following question comes from Yaron Werber from Cowen.

以下問題來自 Cowen 公司的 Yaron Werber。

Yes. I have a couple of questions. The first one is, George, maybe for you on Libtayo, and maybe help us understand a little bit as you think about the hazard ratio versus what KEYNOTE showed. And if I recall correctly, KEYTRUDA was able to get stopped early. Obviously, there was no PD-1 approved then and that study had about 305 patients. The hazard ratio was 0.5. Do you think you got sufficient power with a bigger sample to essentially match or beat that hazard ratio?

是的。我有幾個問題。第一個問題是，喬治，也許你對 Libtayo 感興趣，也許你能幫助我們更好地理解風險比率與 KEYNOTE 所展示的內容之間的關係。如果我沒記錯的話，KEYTRUDA 被及早阻止了。顯然，當時還沒有核准的 PD-1 藥物，而且那項研究大約有 305 名患者。風險比為 0.5。你認為更大的樣本量是否足以使你獲得足夠的統計功效，從而基本上達到或超過該風險比？

And then, maybe, Bob, for you. Just -- it sounded you're comfortable with consensus you mentioned for this year. When we're looking at consensus, non-GAAP is around $25.90 in earnings. Are you comfortable with that, including the restructuring? Or are you comfortable with that even excluding the restructuring?

然後，或許，鮑勃，也為你。聽起來你對今年的共識表示滿意。從普遍預期來看，非GAAP收益約為25.90美元。你是否接受這些安排，包括重組？或者，即使不考慮重組，你也能接受嗎？

Go ahead, George.

請繼續，喬治。

Yes. Well, as you said, we have the power. And the expectation is that if we were to hit an interim, we would have a hazard ratio that would be comparable, analogous to those seen by KEYTRUDA in its monotherapy first-line lung studies. So that is the expectation. The power is there to potentially see that in the interim analysis. Bob?

是的。正如你所說，我們擁有這種力量。預計如果達到中期目標，我們將獲得與 KEYTRUDA 在其單藥一線肺癌研究中觀察到的風險比相當的風險比。這就是預期。在期中分析中，我們有能力看到這一點。鮑伯？

To the question on comfortability in the restructuring. We are comfortable with the consensus with the restructuring built into that. And again, let me remind you, as I stated on the call, the first quarter non-GAAP EPS results are typically lower than the fourth quarter of the prior year due to trends in tax rate and other seasonal market dynamics.

關於重組過程中舒適度的問題。我們對已達成的共識以及其中所包含的重組方案感到滿意。再次提醒各位，正如我在電話會議上所說，由於稅率趨勢和其他季節性市場動態，第一季的非GAAP每股收益通常低於去年第四季。

And maybe, George, just for you. When the interim initially -- that study was based on 361 patients, KEYTRUDA stopped with the same response rates based on 305. So are you thinking that the next 240 patients are going to have a better response than the first 361 in the study to be able to match the hazard ratio? Or is there -- it depends on how many patients are in that interim analysis, and it could be another one?

或許，喬治，這只是為你準備的。最初中期研究基於 361 名患者，而 KEYTRUDA 停止研究時，基於 305 名患者的反應率與先前相同。所以您認為接下來的 240 名患者的療效會比研究中的前 361 名患者更好，從而能夠達到相同的風險比？或者還有另一種可能——這取決於中期分析中有多少患者，也可能是另一種情況？

When you're talking about ratios...

當你在談論比例時…

One second, George, before you get into it. I just wanted to comment so there's no misunderstanding. You cited a hazard ratio of 0.5, and I think that was for the chemo combo therapy. In 024, for the overall survival hazard ratio, it was 0.6. And in 042, just to double check, it was 0.69. So I just want to make sure we have the right hazard ratios out there. Sorry. Go ahead, George.

喬治，等一下，你再開始吧。我只是想說明一下，以免產生誤會。你提到的風險比是 0.5，我認為那是針對化療的合併治療。在 024 年，整體存活風險比為 0.6。為了再次確認，042 的值是 0.69。所以我只是想確保我們有正確的風險比率。對不起。請繼續，喬治。

Well, yes, I was going to say, well, the hazard ratio actually was 0.63 for KEYNOTE-024 and 0.69 for KEYNOTE-042. But you also mentioned the ratio. So the first 361 patients in that interim analysis, what we announced was the response rates. And our ratio for response rates in those patients was actually better than the ratio of any response rates that have been reported by KEYTRUDA in first-line lung setting. However, the data was immature. That's response rate data. The hazard ratio that you're referring to is overall survival. That requires much more mature data where you're following patients out for, obviously, survival.

嗯，是的，我正要說，KEYNOTE-024 的風險比率實際上是 0.63，KEYNOTE-042 的風險比率是 0.69。但你也提到了比例。因此，在中期分析中，我們發表的是前 361 名患者的回應率。而且，我們這些患者的反應率實際上比 KEYTRUDA 在第一線肺癌治療中報告的任何反應率都要好。然而，這些數據尚不成熟。這是回復率數據。你提到的風險比指的是整體存活率。這需要更成熟的數據，顯然需要追蹤患者的生存情況。

So the early data, it was that, obviously, we're reporting on the more mature response rate data which are pretty close or should reflect what the ultimate data will look like. The survival data, we have to wait and see for those events to start accruing. And what we said is the ratio of the response rate is very favorable when you compare that because in all the studies that have either succeeded or failed, the response rate data ends up being pretty predictive of the overall survival hazard ratio. And what we are saying is that as the data is maturing now, we have the power if we have overall survival hazard ratios akin to those sorts of between 0.6 to 0.7 numbers, that as the data matures, we will have the power to see that.

所以早期數據顯示，顯然，我們報告的是更成熟的回應率數據，這些數據非常接近或應該能夠反映最終數據的樣子。生存數據方面，我們需要等待並觀察這些事件開始累積的情況。我們說過，當你比較時，反應率的比率非常有利，因為在所有成功或失敗的研究中，反應率數據最終都能很好地預測總體生存風險比。我們想說的是，隨著數據的成熟，如果我們的整體生存風險比達到 0.6 到 0.7 之間的數值，隨著數據的成熟，我們將有能力看到這一點。

Great. Thanks for the question, Yaron. We have several callers still in the queue. (Operator Instructions) We'll try to get to 2 or 3 more, if we can.

偉大的。謝謝你的提問，亞倫。我們還有幾位來電者在排隊等候。（操作說明）如果可以的話，我們會努力再弄 2 到 3 個。

Our following question comes from Mohit Bansal from Citigroup.

接下來的問題來自花旗集團的 Mohit Bansal。

Great. And it's pretty amazing that -- to see double-digit growth in EYLEA after so many years. Could you please help us characterize this growth a little bit further in terms of AMD versus non-AMD indications? I know you have been putting more effort in the diabetic eye diseases. So as we go forward, how do you envision that segment growing over time, actually?

偉大的。令人驚嘆的是，經過這麼多年，安怡還能達到兩位數的成長。能否請您進一步分析這種成長在 AMD 和非 AMD 適應症的特徵？我知道你一直在糖尿病眼疾領域投入更多精力。那麼展望未來，您認為這個細分市場將如何隨著時間的推移而發展？

Marion?

瑪莉安？

Sure. So I'm happy to comment. As I mentioned, the overall market is growing, obviously, driven by demographics, and then also the diabetic population, sadly, is growing as well. I really don't have specificity to give you on market growth particular by indication, but I can give you some of the trends that I think will be helpful.

當然。所以我很樂意發表評論。正如我之前提到的，整體市場顯然正在成長，這主要是由人口結構變化所推動的，令人遺憾的是，糖尿病患者人數也在增加。我確實沒有特定的市場成長指標可以給出，但我可以給你一些我認為會有幫助的趨勢。

We are seeing greater growth in our EYLEA business coming from diabetic eye disease while still growing and performing very competitively in wet AMD, not only in the fourth quarter, but through the entirety of last year.

我們看到，在糖尿病眼疾領域，EYLEA 業務的成長更為顯著，同時在濕性 AMD 領域也保持著強勁的成長勢頭和極具競爭力的表現，不僅在第四季度如此，而且在去年全年都是如此。

In terms of going forward, though, as I mentioned before, the source of business is shifting somewhat. So as we looked at the fourth quarter performance, I shared with you that our EYLEA business for wet AMD is just under 60% of the business. So that's a migration to a greater source of business coming from diabetic eye disease. And then if we looked at the overall business, I would also add in probably, if you do the math, that leaves maybe about 30% of business coming from diabetic eye disease and approximately 10% of business coming from retinal vein occlusion.

但就未來發展而言，正如我之前提到的，業務來源正在發生一些變化。因此，當我們回顧第四季度業績時，我曾向大家透露，我們用於濕式 AMD 的 EYLEA 業務佔總業務的近 60%。所以，這代表著糖尿病眼疾這個更大業務來源的轉移。然後，如果我們從整體業務來看，我還要補充一點，如果你計算一下，那麼大約 30% 的業務來自糖尿病眼病，大約 10% 的業務來自視網膜靜脈阻塞。

Our following question comes from Cory Kasimov from JPMorgan.

接下來的問題來自摩根大通的科里·卡西莫夫。

Another one for Marion. Can you just talk about how the commercial approach for DUPI for kids aged 6 to 11 with atopic derm might be different than the older populations you currently serve and what your market research suggests about the potential pent-up demand in the segment?

又給瑪莉安一個。您能否談談針對 6 至 11 歲患有異位性皮膚炎的兒童的 DUPI 商業策略與您目前服務的年齡較大的人群有何不同，以及您的市場調查表明該細分市場存在哪些潛在的潛在需求？

Sure. So as I reflect on atopic dermatitis for adults, adolescents first, I share with you that we're in the early days. For atopic dermatitis with adults, we've only really captured about 20% of the population of moderate to severe patients that are in need. Adolescents, obviously, has been a more recent launch. The adolescent population is approximately maybe half or so of the adult population for atopic dermatitis.

當然。所以，當我反思成人（首先是青少年）異位性皮膚炎時，我想告訴大家，我們還處於早期階段。對於成人異位性皮膚炎，我們目前只真正接觸到了大約 20% 的中重度患者群體。顯然，青少年族群是最近才開始涉足的領域。青少年罹患異位性皮膚炎的人數約佔成年人口的一半左右。

As we come into pediatrics, obviously, we don't have an indication there. We're doing our final preparation work for the launch. We're very excited about this population because these -- these very young patients are suffering tremendously as is their entire family. I think the experience that we've had with adults and adolescents bodes well for our ability to be very successful with the pediatric indication as soon as we have the approval. So we look forward in the future to giving more insight and more content on our strategy, size of population and our go-to-market profile. But we feel very, very, very positively about what's happened to date in atopic dermatitis and where we're going in the future. Frankly, we -- FDA-willing, we cannot wait for this indication so we could help more patients.

進入兒科領域後，顯然，我們並沒有相關的適應症。我們正在為發表會做最後的準備工作。我們對這個群體感到非常興奮，因為這些非常年輕的患者以及他們的整個家庭都承受著巨大的痛苦。我認為，我們在成人和青少年領域累積的經驗預示著，一旦獲得批准，我們在兒科適應症方面也能取得非常大的成功。因此，我們期待在未來提供更多關於我們的策略、人口規模和市場推廣概況的見解和內容。但是，我們對異位性皮膚炎迄今為止的進展以及未來的發展方向感到非常、非常、非常樂觀。坦白說，我們——只要獲得 FDA 批准，就迫不及待地想要獲得這項適應症，以便幫助更多的患者。

Thank you. We're bumping up at the top of the hour. We're going to go for one more question.

謝謝。我們會在整點報時。我們再問最後一個問題。

Our final question comes from Hartaj Singh from Oppenheimer & Co.

最後一個問題來自奧本海默公司的哈塔吉·辛格。

Great. Just wanted to ask Bob one question, Bob. I know you had indicated that for 2020, you would see increases in the non-GAAP SG&A and R&D. And I think you've already given some sort of guidance, thinking about consensus earnings. But could you sort of flesh that out a little bit as to whether you expect that to grow below, I guess, revenue and sort of differentiate between the 2?

偉大的。我只想問鮑伯一個問題，鮑伯。我知道您曾表示，2020 年非 GAAP 銷售、一般及行政費用和研發費用將會增加。我認為，考慮到市場普遍預期的獲利情況，你已經給了一些指導意見。但您能否詳細解釋一下，您是否預期該項成長會低於收入水平，並區分一下這兩者？

Yes. Hartaj, thanks for the question. I'm going to wait until we iron that out with regards to -- at the end of Q1, where we give our guidance related to that. There's a lot of moving parts associated with exactly what the KEVZARA and PRALUENT responsibilities are going to look, the deal closing timing associated with that, and possibly the related modification of the agreement, which may allow us to change the financial presentation associated with that. So there's, again, a lot of moving parts, so if you can just kind of park that question until the end of into March.

是的。哈塔吉，謝謝你的提問。關於這個問題，我打算等到第一季末，也就是我們給予相關指引的時候再做決定。KEVZARA 和 PRALUENT 的具體職責、相關的交易完成時間以及可能的相關協議修改（這可能會改變相關的財務報表）都涉及許多變數。所以，這裡有很多變數，所以如果你能把這個問題暫時擱置到三月底就好了。

Great. Thanks, Bob. Apologies to folks in the queue who we did not get to and for running late here on the call this morning. The IR team and Bob will be around after the call to take any of your questions. Thank you.

偉大的。謝謝你，鮑伯。對於排隊等候但未能聯繫上的朋友們，以及今天早上電話會議的遲到，我們深表歉意。IR團隊和Bob將在通話結束後解答您的任何問題。謝謝。

Ladies and gentlemen. This concludes today's conference. Thank you for participating. You may now disconnect.

女士們，先生們。今天的會議到此結束。感謝您的參與。您現在可以斷開連線了。