雷傑納榮製藥 (REGN) 2018 Q2 法說會逐字稿

Welcome to the Regeneron Pharmaceuticals Second Quarter 2018 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 2018 年第二季財報電話會議。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 Manisha Narasimhan, Head of Regeneron's Investor Relations. You may begin.

現在我將把電話轉交給 Regeneron 投資者關係主管 Manisha Narasimhan。你可以開始了。

Thank you, Sylvia. Good morning, and welcome to Regeneron Pharmaceuticals Second Quarter 2018 Conference Call. An archive of this webcast will be available on our website under Events for 30 days.

謝謝你，西爾維亞。早安，歡迎參加 Regeneron Pharmaceuticals 2018 年第二季電話會議。本次網路直播的存檔將在我們網站的「活動」欄位下保留 30 天。

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

今天與我一起參加電話會議的有：創始人、總裁兼首席執行官 Leonard Schleifer 博士；創始科學家、總裁兼首席科學官 George Yancopoulos 博士；高級副總裁兼商務主管 Marion McCourt；以及高級副總裁兼首席財務官 Bob Landry。在我們發言完畢後，我們將開放問答環節。

I would also like to remind you that remarks made on this call today include forward-looking statements about Regeneron. Such statements may include, but are not limited to, those related to Regeneron and its products and business, financial forecasts and guidance, development programs and related anticipated milestones, collaborations, finances, regulatory matters, intellectual property, pending litigation and competition. 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, or SEC, including its Form 10-Q for the quarter ended June 30, 2018, which will be filed with the SEC later today. Regeneron does not undertake any obligation to update publicly any forward-looking statements, whether as a result of new information, future events or otherwise.

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、智慧財產權、未決訴訟和競爭相關的聲明。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 (SEC) 提交的文件，包括截至 2018 年 6 月 30 日的季度 10-Q 表格，該表格將於今天晚些時候提交給 SEC。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 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, which can be accessed on our website at regeneron.com. 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 regeneron.com 上查閱。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。

Thanks, Manisha, and good morning to everyone who has joined us on today's call and webcast.

謝謝瑪妮莎，也向今天參加電話會議和網路直播的各位問好。

Regeneron delivered a strong second quarter as measured both by R&D progress as well as our financial results, reflecting our commitment to discovering important new drugs and translating those discoveries into successful commercial products. Our pipeline now has 19 drugs or drug candidates in development, with particularly good progress in allergic diseases and cancer. George will update you on our R&D efforts and highlight some notable progress across our pipeline.

Regeneron 第二季度業績強勁，無論從研發進展還是財務業績來看都是如此，這反映了我們致力於發現重要新藥並將這些發現轉化為成功的商業產品的承諾。我們目前有 19 種藥物或候選藥物正在研發中，在過敏性疾病和癌症領域取得了特別好的進展。George 將向大家報告我們的研發工作進展，並專注於我們產品線的一些顯著進展。

Our commercial efforts are focused on market-leading EYLEA; the ongoing launches of DUPIXENT, KEVZARA and PRALUENT; and our ongoing launch preparations for cemiplimab, our PD-1 inhibitor in cutaneous squamous cell carcinoma. Marion will update you on our progress.

我們的商業努力主要集中在市場領先的EYLEA；正在推出的DUPIXENT、KEVZARA和PRALUENT；以及我們正在進行的cemiplimab（一種用於治療皮膚鱗狀細胞癌的PD-1抑製劑）的上市準備工作。瑪莉安會向您報告我們的進度。

Operationally, we had a record performance on both the top and bottom line. Bob will review these results.

在營運方面，我們的營收和利潤都創下了歷史新高。鮑伯將審核這些結果。

So now I'd like to turn the call over to George.

現在我想把電話交給喬治。

Thanks, Len, and good morning, everyone.

謝謝Len，大家早安。

Let me begin by updating you on the status of EYLEA. A regulatory submission for EYLEA dosed every 12 weeks in neovascular age-related macular degeneration, or wet AMD, is currently under FDA review with a PDUFA date of August 11.

首先，讓我向大家報告EYLEA的最新情況。針對每 12 週給藥一次的 EYLEA 用於治療新生血管性老年黃斑部病變（濕性 AMD）的監管申請目前正在接受 FDA 審查，PDUFA 日期為 8 月 11 日。

Yesterday, Bayer, which commercializes EYLEA outside the United States, announced that the European Commission has approved a new treatment approach enabling early extension of the injection interval for patients with wet AMD. The new approach is based on the results from the ALTAIR study, in which after 52 weeks, 57% of patients had their next regularly scheduled EYLEA injection [and] an interval of 12 weeks or more, with many patients achieving interval of 16 weeks, the maximum interval allowed in the study. Study participants gained an average of 9 letters, including 50% of patients who gained 10 or more letters of vision at week 52. These results were largely maintained during the second year of the study. These data have not been submitted for review to the FDA.

昨天，拜耳公司（在美國以外地區銷售EYLEA）宣布，歐盟委員會已批准一種新的治療方法，使濕性AMD患者能夠儘早延長注射間隔。新方法是基於 ALTAIR 研究的結果，研究發現，52 週後，57% 的患者接受了下一次定期 EYLEA 注射，間隔時間為 12 週或更長，許多患者達到了 16 週的間隔，這是研究允許的最大間隔。研究參與者平均視力增加了 9 個字母，其中 50% 的患者在第 52 週視力提高了 10 個或更多字母。研究的第二年，這些結果基本上得以維持。這些數據尚未提交給FDA審查。

We would also like to report some recent success with higher dose formulations of aflibercept in preclinical studies, which we hope to advance into the clinic in 2019.

我們也想報告，在臨床前研究中，高劑量阿柏西普製劑取得了一些最新成功，我們希望在 2019 年將其推進到臨床階段。

Turning now to our immunology and inflammation programs. DUPIXENT, our interleukin-4 and interleukin-13 blocker, is approved for atopic dermatitis and is under investigation for other allergic diseases also known as atopic or Type 2 inflammatory diseases, including asthma, nasal polyps, eosinophilic esophagitis as well as food and inhaled allergies. DUPIXENT is approved for the treatment of adults with atopic dermatitis. And later this year, we expect a supplemental Biologics License Application, or sBLA, for adolescents with atopic dermatitis based on the positive top line data we announced in May. These data will be presented in more detail at a medical conference next month. DUPIXENT is also under regulatory review for asthma in adults and adolescents. In addition, we are conducting pediatric studies in both atopic dermatitis and asthma. Later this year, we are expecting pivotal results from our Phase III studies in nasal polyps, and we will be initiating our Phase III program in eosinophilic esophagitis as well as earlier clinical programs in both peanut allergy and grass allergy. The emerging DUPIXENT clinical data continues to support our hypothesis that interleukin-4 and interleukin-13 are the central drivers of allergic disease. Our interleukin-33 program complements DUPIXENT and has potential both as monotherapy and in combination with DUPIXENT. Interleukin-33 may be an important target in certain inflammatory diseases and is supported by evidence from work done at our Regeneron Genetics Center. We are currently investigating this molecule in asthma and atopic dermatitis.

接下來，我們將介紹我們的免疫學和發炎研究計畫。DUPIXENT 是我們的白血球介素-4 和白血球介素-13 阻斷劑，已獲準用於治療異位性皮膚炎，目前正在研究其對其他過敏性疾病（也稱為特應性或 2 型發炎性疾病）的療效，包括氣喘、鼻息肉、嗜酸性食道炎以及食物和吸入性過敏。DUPIXENT 已獲準用於治療成人異位性皮膚炎。今年晚些時候，我們預計將根據 5 月公佈的積極初步數據，提交針對青少年異位性皮膚炎的補充生物製品許可申請（sBLA）。這些數據將在下個月的醫學會議上進行更詳細的介紹。DUPIXENT目前也正在接受監管部門的審查，用於治療成人和青少年氣喘。此外，我們正在進行異位性皮膚炎和氣喘的兒科研究。今年晚些時候，我們預計將獲得鼻息肉 III 期研究的關鍵結果，我們將啟動嗜酸性食道炎的 III 期項目，以及花生過敏和草過敏的早期臨床項目。不斷湧現的 DUPIXENT 臨床數據繼續支持我們的假設，即白細胞介素-4 和白細胞介素-13 是過敏性疾病的核心驅動因素。我們的白血球介素-33 方案與 DUPIXENT 互補，既可作為單一療法，也可與 DUPIXENT 合併使用。白血球介素-33 可能是某些發炎性疾病的重要標靶，我們 Regeneron 遺傳學中心的研究也證實了這一點。我們目前正在研究這種分子在氣喘和異位性皮膚炎中的作用。

Now I'll turn to immuno-oncology, which continues to be an area of enormous focus for us. Our BLA for cemiplimab in cutaneous squamous cell carcinoma is currently under regulatory review, and the PDUFA date is in October. If approved, this will be the third PD-1 antibody to gain regulatory approval and the first in cutaneous squamous cell carcinoma, where we have observed response rate that have been among the highest reported with the PD-1 antibody for a solid tumor. Regulatory application for cemiplimab in cutaneous squamous cell carcinoma are also under review outside the United States.

現在我將轉向免疫腫瘤學，這仍然是我們非常關注的領域。我們針對 cemiplimab 治療皮膚鱗狀細胞癌的生物製品許可申請 (BLA) 目前正在接受監管審查，PDUFA 日期為 10 月。如果獲得批准，這將是第三種獲得監管部門批准的 PD-1 抗體，也是第一種用於治療皮膚鱗狀細胞癌的 PD-1 抗體。我們觀察到，在皮膚鱗狀細胞癌中，PD-1 抗體的反應率是實體腫瘤中報告的最高反應率之一。西米普利單抗治療皮膚鱗狀細胞癌的監管申請也在美國以外地區接受審查。

Non-small cell lung cancer is an important development opportunity for cemiplimab. Despite many efforts in the field, there is currently only one PD-1 antibody approved in first-line non-small cell lung cancer, and less than half the patients respond. We are pursuing a broad development strategy in lung cancer that encompasses patients with both low and high levels of PD-L1. Beyond first-line non-small cell lung cancer, we also have ongoing studies in other solid tumors, including second-line non-small cell lung cancer, second-line cervical cancer and basal cell carcinoma. Based on our review of recent data from competitor PD-1s in non-small cell lung cancer, we plan on increasing the size of our ongoing monotherapy Phase III study and expect it to read out in 2020. We're also reviewing any implications that these developments may have on our larger lung cancer program.

非小細胞肺癌是cemiplimab的重要發展機會。儘管該領域付出了很多努力，但目前只有一種 PD-1 抗體被批准用於一線非小細胞肺癌治療，而且只有不到一半的患者有療效。我們正在肺癌領域推行一項廣泛的研發策略，涵蓋了PD-L1水平低和高的患者。除了非小細胞肺癌一線治療外，我們還在其他實體腫瘤方面進行研究，包括非小細胞肺癌二線治療、子宮頸癌二線治療和基底細胞癌二線治療。根據我們對非小細胞肺癌中競爭對手 PD-1 的最新數據的審查，我們計劃擴大正在進行的單藥治療 III 期研究的規模，並預計將在 2020 年公佈結果。我們也在評估這些進展可能對我們更廣泛的肺癌計畫產生的任何影響。

We recognize how quickly the field of immuno-oncology is evolving and are committed to being at the leading edge. Despite all the advances in the treatment of cancer, many patients still remain without effective treatment options. In addition to use as monotherapy, we expect cemiplimab to be the foundation upon which we build combination therapies to address a variety of tumor types. To that end, we have 2 additional checkpoint inhibitors, LAG3 and CTLA-4, in clinical development. We're also exploring our checkpoint inhibitors in collaborative combinations with vaccines and cell therapy approaches.

我們認識到免疫腫瘤學領域發展日新月異，並致力於保持領先地位。儘管癌症治療取得了許多進展，但許多患者仍缺乏有效的治療方案。除了作為單一療法外，我們期望 cemiplimab 能成為我們建構聯合療法的基礎，以應對各種類型的腫瘤。為此，我們還有 2 種額外的檢查點抑制劑 LAG3 和 CTLA-4 正在進行臨床開發。我們也正在探索將檢查點抑制劑與疫苗和細胞療法結合的聯合應用。

Our proprietary bispecific antibody platform is another key component of our immuno-oncology strategy. We are investigating our bispecific antibodies as single agents, in combinations with each other and in combination with our checkpoint inhibitors. Having a broad set of tools within immuno-oncology enables us to choose the best ones for each particular disease.

我們專有的雙特異性抗體平台是我們免疫腫瘤學策略的另一個關鍵組成部分。我們正在研究我們的雙特異性抗體作為單一藥物、彼此組合以及與我們的檢查點抑制劑組合的療效。免疫腫瘤學領域擁有廣泛的工具，使我們能夠為每種特定疾病選擇最佳工具。

Our lead bispecific program is a wholly-owned CD20xCD3 molecule, which has validated the concept and given us confidence in the platform as a whole. We remain very encouraged by the strong response rates that we have observed to date in both indolent and aggressive non-Hodgkin's lymphoma and expect to advance this program into registrational studies in 2019. Additional studies and data from this program will be presented at a medical conference later this year.

我們領先的雙特異性專案是完全自主研發的 CD20xCD3 分子，它驗證了這個概念，並使我們對該平台整體充滿信心。我們對迄今為止在惰性和侵襲性非何杰金氏淋巴瘤中觀察到的強勁反應率感到非常鼓舞，並期望在 2019 年將該計畫推進到註冊研究階段。該計畫的更多研究和數據將於今年稍後在醫學會議上公佈。

We are also advancing additional bispecific candidates into clinical development. Our MUC16xCD3 bispecific for ovarian cancer has entered clinical development, and our BCMAxCD3 bispecific for multiple myeloma will enter the clinic later this year. These bispecifics will be studied both as monotherapy and in combination with cemiplimab.

我們也正在推進其他雙特異性抗體候選藥物進入臨床開發階段。我們針對卵巢癌的 MUC16xCD3 雙特異性抗體已進入臨床開發階段，而我們針對多發性骨髓瘤的 BCMAxCD3 雙特異性抗體將於今年稍後進入臨床階段。我們將研究這些雙特異性抗體作為單藥療法以及與西米普利單抗聯合療法的療效。

Early next year, we expect to advance into clinical development an entirely new class of bispecific antibodies, which we will study in combination with the CD3 class of bispecifics as well as with cemiplimab.

預計明年年初，我們將推進一類全新的雙特異性抗體的臨床開發，我們將研究其與 CD3 類雙特異性抗體以及 cemiplimab 聯合使用的效果。

Turning now to fasinumab, our Nerve Growth Factor antibody for pain. We are continuing patient enrollment in the Phase III osteoarthritis program. Following an evaluation by an independent data monitoring committee, we are moving forward with only the lower dose regimens in this program. We anticipate sharing top line efficacy results from our first Phase III osteoarthritis study later this quarter.

接下來我們來談談法西單抗，這是一種用來治療疼痛的神經生長因子抗體。我們正在繼續招募骨關節炎 III 期臨床試驗的患者。經獨立數據監測委員會評估後，我們決定在該計畫中只採用較低劑量方案。我們預計將在本季稍後公佈首個 III 期骨關節炎研究的主要療效結果。

Now I'd like to provide a brief update on 3 of our wholly-owned earlier-stage programs. Let me begin with our C5 antibody. Our goal is to provide patients with a convenient, self-administered subcutaneous dosing option that doesn't require a high volume delivery device, and we have made significant progress toward this goal. In our Phase I study based on both pharmacodynamics and ex-vivo pharmacodynamic assays, a subcutaneous dosing regimen achieved the blood levels that we believe will be sufficient to prevent hemolysis in patients with paroxysmal nocturnal hemoglobinuria, or PNH. We expect to report a full data in an upcoming medical conference and plan to initiate Phase II studies for PNH in early 2019.

現在我想簡要介紹一下我們全資擁有的三個早期專案的最新進展。首先，讓我們從C5抗體開始。我們的目標是為患者提供一種方便的、可自行皮下注射的給藥方式，無需大容量給藥裝置，並且我們朝著這個目標取得了重大進展。在我們基於藥效學和體外藥效學檢測的 I 期研究中，皮下給藥方案達到了我們認為足以預防陣發性睡眠性血紅蛋白尿症 (PNH) 患者溶血的血中濃度。我們預計將在即將舉行的醫學會議上公佈完整數據，並計劃於 2019 年初啟動 PNH 的 II 期研究。

Another exciting early-stage molecule is our antibody to Activin-A, which we are investigating in the rare devastating disease called fibrodysplasia ossificans progressiva. We are pleased that enrollment in our potentially pivotal study is proceeding according to plan. We're also studying our Activin-A antibody in combination with our myostatin antibody in the setting of muscle atrophy and wasting, where in early studies, we demonstrated an approximately 8% increase in muscle mass. We plan to initiate by year-end the first of multiple Phase II studies to ascertain whether this increase in muscle mass translates into functional and/or metabolic benefits.

另一個令人興奮的早期分子是我們針對 Activin-A 的抗體，我們正在研究它對一種名為進行性骨化性纖維發育不良的罕見毀滅性疾病的療效。我們很高興這項可能具有決定性意義的研究的招募工作正在按計劃進行。我們也正在研究將我們的 Activin-A 抗體與我們的肌肉生長抑制素抗體聯合用於治療肌肉萎縮和消瘦，在早期研究中，我們證明了肌肉質量大約增加了 8%。我們計劃在年底前啟動多項 II 期研究中的第一項，以確定肌肉質量的增加是否能轉化為功能和/或代謝方面的益處。

We currently have 19 product candidates that are in various stages of clinical development. Each of these was discovered by us in our laboratories in Tarrytown, New York. I'm pleased to say that we remain on track for the goals that we laid out at the beginning of the year to advance 4 to 6 new product candidates into the clinic in 2018. Just in the first half of the year alone, we advanced 3 new molecules into clinical development.

我們目前有 19 個候選產品處於不同的臨床開發階段。這些物質都是我們在紐約州塔里敦的實驗室裡發現的。我很高興地宣布，我們仍按計劃朝著年初制定的目標前進，即在 2018 年將 4 至 6 個新的候選產品推進到臨床試驗階段。光是今年上半年，我們就推進了 3 個新分子進入臨床開發階段。

With that, I'd like to turn the call over to Marion.

接下來，我想把電話交給瑪莉安。

Thank you, George, and good morning, everyone.

謝謝你，喬治，大家早安。

I'd like to start with EYLEA, where global net sales in the second quarter were $1.66 billion, an increase of 13% year-over-year. In the U.S., EYLEA continues to be the market-leading branded anti-VEGF for retinal diseases. In the second quarter U.S. EYLEA net sales were $992 million, which represents 8% growth year-over-year. Based on net sales, EYLEA currently has approximately 70% of the overall branded U.S. anti-VEGF market.

我想先從安樂（EYLEA）說起，該公司第二季的全球淨銷售額為 16.6 億美元，年增 13%。在美國，EYLEA 仍然是治療視網膜疾病的市場領先的品牌抗 VEGF 藥物。第二季度，安禮在美國的淨銷售額為 9.92 億美元，年增 8%。根據淨銷售額計算，安永目前約占美國品牌抗 VEGF 市場 70% 的份額。

We are committed to maintaining our market leadership position with EYLEA, and we have identified meaningful growth opportunities. While EYLEA is well penetrated in wet AMD, there remains a large opportunity in diabetic eye disease. Less than 20% of patients diagnosed with clinically significant diabetic macular edema currently receive anti-VEGF therapy, and many others with diabetic macular edema are not even diagnosed. Approximately 25% of current EYLEA U.S. business is attributed to use in patients with diabetic macular edema. Additionally, we expect the market to grow in wet AMD because of the aging population and in diabetic retinal diseases due to the substantial increase in diabetes prevalence. We'd like to ensure that every eligible patient with diabetic retinal disease or wet AMD is treated with optimal therapy, which, in the vast majority of cases, is anti-VEGF therapy. To that end, in the coming weeks, we will be launching an initial branded television campaign for EYLEA in DME in multiple U.S. test markets.

我們致力於保持安樂產品的市場領導地位，並且我們已經發現了有意義的成長機會。雖然 EYLEA 在濕性 AMD 中滲透率很高，但在糖尿病眼部疾病領域仍有很大的發展空間。目前，在被診斷出患有臨床顯著糖尿病性黃斑水腫的患者中，只有不到 20% 的人接受抗 VEGF 治療，而其他許多患有糖尿病性黃斑水腫的人甚至沒有被診斷出來。EYLEA 目前在美國的業務約有 25% 歸功於其產品在糖尿病性黃斑水腫患者中的應用。此外，我們預期濕性 AMD 市場將因人口老化而成長，糖尿病視網膜疾病市場將因糖尿病盛行率大幅增加而成長。我們希望確保每位符合條件的糖尿病視網膜疾病或濕性老年黃斑部病變患者都能接受最佳治療，而絕大多數情況下，最佳治療方案是抗 VEGF 療法。為此，在接下來的幾週內，我們將在美國多個測試市場推出安怡 (EYLEA) 在 DME 領域的首個品牌電視廣告宣傳活動。

Another important potential growth driver for EYLEA is through gaining approval in additional retinal diseases and expanding label. We have submitted an sBLA for EYLEA in diabetic retinopathy population. It's estimated that there are approximately 3.5 million people in the U.S. who are diagnosed with diabetic retinopathy without DME. Of these, approximately 1 million patients have the greatest disease burden and are at risk for vision-threatening complications.

EYLEA 的另一個重要潛在成長動力是透過獲得其他視網膜疾病的批准並擴大適應症範圍。我們已提交 EYLEA 用於治療糖尿病視網膜病變族群的生物製品許可申請 (sBLA)。據估計，美國約有 350 萬人被診斷出患有糖尿病視網膜病變，但沒有糖尿病黃斑水腫 (DME)。其中，約有 100 萬患者病情最為嚴重，面臨發生威脅視力的併發症的風險。

Earlier this year, we reported positive top line data from the Phase III PANORAMA study of EYLEA in diabetic retinopathy, and we expect to report top line 52-week data later this year.

今年早些時候，我們公佈了 EYLEA 治療糖尿病視網膜病變的 III 期 PANORAMA 研究的積極初步數據，我們預計將於今年稍後公佈 52 週初步數據。

Our regulatory submission for EYLEA dosed every 12 weeks is currently under FDA review. As George mentioned, earlier this week, European regulators approved EYLEA for an extended dosing regimen in wet AMD.

我們提交的每 12 週給藥一次的 EYLEA 的監管申請目前正在接受 FDA 的審查。正如喬治所提到的，本週早些時候，歐洲監管機構批准了 EYLEA 用於治療濕性 AMD 的延長給藥方案。

We have also recently submitted an sBLA for EYLEA in a prefilled syringe with potential launch in 2019.

我們最近也提交了 EYLEA 預充式註射器的補充生物製品許可申請 (sBLA)，該產品預計將在 2019 年上市。

Turning now to DUPIXENT. Global net sales in the second quarter of 2018 as reported by our collaborator Sanofi were $209 million. In the U.S., net sales in the second quarter were $181 million. Approximately 50,000 patients have been prescribed DUPIXENT since launch in the U.S. Underlying U.S. demand for DUPIXENT is strong, with total prescriptions up approximately 27% sequentially from the last quarter. New patient starts, another indicator of demand and average weekly NBRx in the second quarter were approximately 550 new patients excluding the holiday week. Overall, patient refill and persistence rates remain high, especially in comparison to other biologics.

接下來我們來看看DUPIXENT。根據我們的合作夥伴賽諾菲報告，2018 年第二季全球淨銷售額為 2.09 億美元。在美國，第二季淨銷售額為 1.81 億美元。自 DUPIXENT 在美國上市以來，已有約 5 萬名患者被開立了該藥。美國對 DUPIXENT 的潛在需求強勁，處方總量較上一季較上季成長約 27%。新患者就診量是衡量需求的另一個指標，第二季平均每週新患者就診量約 550 人次（不含假日）。總體而言，患者的續藥率和持續用藥率仍然很高，尤其是與其他生物製劑相比。

DUPIXENT prescribers remain highly satisfied, frequently referring to DUPIXENT as a drug that is transformational to the lives of their patients and their treatment practices. In the U.S., over 11,000 health care providers have prescribed DUPIXENT through the second quarter, with depth of prescribing continuing to increase.

DUPIXENT 的處方醫生仍然非常滿意，他們經常將 DUPIXENT 稱為一種能夠改變患者生活和治療實踐的藥物。在美國，截至第二季度，已有超過 11,000 名醫療保健提供者開立了 DUPIXENT 處方，而且處方量還在持續增加。

Consumer education and activation is an important component of the DUPIXENT launch. We've been encouraged by the impact of our unbranded disease state awareness campaign and plan to roll out a branded DUPIXENT television campaign in the coming weeks.

消費者教育和推廣是 DUPIXENT 上市的重要組成部分。我們所進行的非品牌疾病狀態認知宣傳活動取得了令人鼓舞的效果，並計劃在未來幾週內推出DUPIXENT品牌電視宣傳活動。

Outside the U.S., the launch of DUPIXENT in atopic dermatitis is underway in multiple major markets. During the second quarter, DUPIXENT was approved and launched in Japan, with additional launches anticipated in other countries over the remainder of 2018 and thereafter. Beyond adult atopic dermatitis, we look forward to the FDA's decision on DUPIXENT for moderate-to-severe asthma in adults and adolescents, with a PDUFA date of October 20.

在美國以外，DUPIXENT 用於治療異位性皮膚炎的藥物正在多個主要市場推出。第二季度，DUPIXENT 在日本獲得批准並上市，預計在 2018 年剩餘時間及以後將在其他國家/地區上市。除了成人異位性皮膚炎之外，我們還期待 FDA 對 DUPIXENT 用於治療成人和青少年中度至重度氣喘的決定，PDUFA 日期為 10 月 20 日。

Based on our clinical data, we believe that DUPIXENT offers a differentiated profile for -- among biologics for asthma, with a substantial decrease in exacerbation rate and consistent and clinically meaningful improvement in lung function. There remains significant unmet need in uncontrolled asthma, which accounts for an estimated 20% of diagnosed asthma patients. Currently, there are approximately 900,000 patients in the U.S. who are treated for uncontrolled moderate-to-severe asthma, who would be considered appropriate biologic therapy candidates. However, fewer than 10% of these patients are currently treated with a biologic. In addition, we also anticipate meaningful opportunities for DUPIXENT in adolescent and pediatric atopic dermatitis, pediatric asthma, nasal polyps and eosinophilic esophagitis, which are all at late-stage development.

根據我們的臨床數據，我們認為 DUPIXENT 在氣喘生物製劑中具有差異化優勢，可顯著降低氣喘急性發作率，並持續、有臨床意義地改善肺功能。未控制氣喘患者的需求仍然很大，估計佔已確診氣喘患者的 20%。目前，美國約有 90 萬名患者正在接受治療，他們患有無法控制的中度至重度氣喘，這些患者都被認為是合適的生物療法候選人。然而，目前只有不到 10% 的這類患者接受生物製劑治療。此外，我們也預期 DUPIXENT 在青少年和兒童異位性皮膚炎、兒童氣喘、鼻息肉和嗜酸性食道炎方面具有重要的應用前景，這些疾病目前都處於後期研發階段。

Global net sales in the second quarter for PRALUENT as recorded by Sanofi were $74 million, representing a 61% -- increase of 61% compared to the second quarter of 2017. Earlier this year, we reported positive data from the ODYSSEY cardiovascular OUTCOMES study and have made a regulatory submission in both the U.S. and Europe. Over time, as OUTCOMES data are potentially included in the label and as guidelines are anticipated to change, we expect commercial uptake to be positively impacted. We continue to engage in discussions with payers to simplify utilization management criteria and to improve access for patients in return for flexible pricing. In the second quarter, we announced that we would lower the net price of PRALUENT in exchange for straightforward physician prescribing and more affordable patient access.

根據賽諾菲記錄，PRALUENT 第二季全球淨銷售額為 7,400 萬美元，與 2017 年第二季相比成長了 61%。今年早些時候，我們公佈了 ODYSSEY 心血管結果研究的積極數據，並已在美國和歐洲提交了監管申請。隨著時間的推移，由於 OUTCOMES 數據可能會被納入標籤，且指南預計也會發生變化，我們預計商業推廣將受到正面影響。我們繼續與支付方進行討論，以簡化利用管理標準，並改善患者的就醫途徑，從而換取靈活的定價。第二季度，我們宣布將降低 PRALUENT 的淨價，以換取醫生開立處方更加便捷，患者能夠以更實惠的價格獲得該藥物。

We're pleased that PRALUENT was chosen as the exclusive PCSK9 inhibitor on the Express Scripts' national formulary. The agreement took effect on July 1, so it is too early for us to assess the impact. This is a competitive space, with many decisions yet to be made. We continue to engage with other payers and remain committed to minimizing barriers related to access and affordability for patients.

我們很高興 PRALUENT 被 Express Scripts 選為國家藥品目錄中唯一的 PCSK9 抑制劑。該協議於7月1日生效，因此現在評估其影響還為時過早。這是一個競爭激烈的領域，還有許多決定尚未做出。我們將繼續與其他支付方合作，並致力於最大限度地減少患者在獲得醫療服務和負擔能力方面遇到的障礙。

Moving to KEVZARA. Global net sales as recorded by Sanofi were $24 million in the second quarter as demand improved. Within the IL-6 subcutaneous class, KEVZARA now has approximately 26% of dispensed NBRx share and 10% share of TRx launched to date. Recently, KEVZARA was launched in a prefilled pen and is now the only biologic RA therapy in the U.S. that is available in a button-free pen. The KEVZARA prefilled pen is uniquely activated by pressing the pen against the skin. Data have shown that pens are preferred over syringes by RA patients taking chronic subcutaneous injections.

搬到 KEVZARA。賽諾菲公佈的第二季全球淨銷售額為 2,400 萬美元，原因是需求有所改善。在 IL-6 皮下注射劑類別中，KEVZARA 目前約佔已發行 NBRx 份額的 26%，以及已上市 TRx 份額的 10%。最近，KEVZARA 以預先填充筆的形式推出，目前是美國唯一一種無需按壓即可使用的生物類風濕性關節炎治療藥物。KEVZARA預先填充筆的獨特之處在於，只需將筆尖按壓在皮膚上即可啟動。數據顯示，對於需要長期皮下注射的類風濕性關節炎患者來說，注射筆比注射器更受歡迎。

We continue to make strides in growing the IL-6 class through improved understanding of mechanism of action. Along with its differentiated clinical profile, KEVZARA is positioned to be preferred biologic for those patients who are inadequate responders or intolerant to TNF antibodies. We continue to improve market access, with an estimated 92% of commercial lives having coverage.

我們透過不斷加深對作用機制的理解，在IL-6類藥物的研發方面取得了長足進展。憑藉其獨特的臨床特性，KEVZARA有望成為對TNF抗體反應不足或不耐受的患者的首選生物製劑。我們持續改善市場准入，預計目前已有 92% 的商業人壽獲得保險保障。

I'd now like to turn to cemiplimab, our PD-1 antibody. We are preparing for an anticipated approval and launch of cemiplimab in advanced cutaneous squamous cell carcinoma later this year. If approved, this will be the third PD-1 antibody to market but the first for cutaneous squamous cell carcinoma. Our PDUFA date is in October 2018, and we expect a decision by the European Medicines Agency in the first half of 2019. In the U.S., our specialized field-based oncology team is trained and prepared for launch. Commercial supply is ready to ship immediately following approval. As a reminder, cemiplimab is a collaboration product with Sanofi, where in the U.S., we will take the commercial lead and record sales.

現在我想談談cemiplimab，我們的PD-1抗體。我們正在為 cemiplimab 有望於今年稍後獲批並上市治療晚期皮膚鱗狀細胞癌做準備。如果獲得批准，這將是第三種上市的 PD-1 抗體，但卻是第一種用於治療皮膚鱗狀細胞癌的抗體。我們的 PDUFA 日期是 2018 年 10 月，我們預計歐洲藥品管理局將在 2019 年上半年做出決定。在美國，我們專業的現場腫瘤治療團隊已經接受培訓並做好了啟動準備。商業供貨在獲得批准後即可立即發貨。再次提醒大家，cemiplimab 是與賽諾菲合作的產品，在美國，我們將主導商業推廣並創造銷售佳績。

Now I'll turn the call over to Bob.

現在我把電話交給鮑伯。

Thanks, Marion, and good morning, everyone.

謝謝你，瑪麗昂，大家早安。

As Len referenced at the start of this call, Regeneron had strong top and bottom line financial results. Today, I'll discuss the details of our second quarter 2018 financial results as well as highlight changes to our full year 2018 guidance line items.

正如 Len 在本次電話會議開始時提到的那樣，Regeneron 的營收和利潤都表現強勁。今天，我將詳細討論我們 2018 年第二季的財務業績，並重點介紹我們 2018 年全年業績指引的變化。

For the second quarter of 2018, we earned $5.45 per diluted share on non-GAAP net income of $624 million. These results represent a 31% and 28% year-over-year increase in our non-GAAP diluted EPS and net income, respectively. Total revenues grew 9% year-over-year to $1.61 billion. Continued drivers of this growth are performance of EYLEA both in the U.S. as well as ex U.S. and a decrease in the loss in connection with the commercialization of antibodies resulting from higher DUPIXENT sales, which was partially offset by no longer having a contribution from Sanofi in connection with the discovery and preclinical development agreement that ended in December 2017.

2018 年第二季度，我們每股攤薄收益為 5.45 美元，非 GAAP 淨收入為 6.24 億美元。這些結果分別代表我們的非GAAP稀釋後每股盈餘和淨收入年增31%和28%。總營收年增 9%，達到 16.1 億美元。推動這一成長的持續因素是EYLEA在美國和美國以外地區的業績，以及DUPIXENT銷售額成長帶來的抗體商業化相關虧損的減少，但部分被2017年12月終止的發現和臨床前開發協議中賽諾菲的貢獻所抵消。

EYLEA net product sales in the United States grew 8% to $992 million compared to $919 million in the second quarter of 2017. U.S. EYLEA distributor inventory experienced a modest decrease in the quarter as compared to the first quarter of 2018, yet remained within our normal 1- to 2-week targeted range. U.S. EYLEA's gross-to-net percentage remain relatively constant compared to both the second quarter of 2017 and first quarter of 2018. In the second week of June 2018, we increased the existing EYLEA discount offered to physician practices regardless of volume.

EYLEA 在美國的淨產品銷售額成長了 8%，達到 9.92 億美元，而 2017 年第二季為 9.19 億美元。與 2018 年第一季相比，美國 EYLEA 經銷商的庫存在本季度略有下降，但仍在我們正常的 1 至 2 週的目標範圍內。與 2017 年第二季和 2018 年第一季相比，美國安禮集團的毛利率保持相對穩定。2018 年 6 月第二週，我們提高了向醫生診所提供的現有 EYLEA 折扣，無論診所業務量如何。

Ex U.S. EYLEA net product sales, which are recorded by our collaborator Bayer, were $666 million for the 3 months ended June 30, 2018, representing an 18% operational and 23% reported increase on a year-over-year basis. We remain encouraged by continued ex U.S. EYLEA growth. Through the first 6 months of 2018, ex U.S. EYLEA net sales increased 26% on a reported basis versus the comparable period in 2017.

除美國以外，EYLEA 淨產品銷售額（由我們的合作夥伴拜耳記錄）在截至 2018 年 6 月 30 日的三個月內為 6.66 億美元，年增 18%（按營運計算）和 23%（按報告計算）。我們對安禮美國以外地區的持續成長感到鼓舞。2018 年上半年，除美國以外，EYLEA 的淨銷售額按報告基準計算比 2017 年同期成長了 26%。

Total Bayer collaboration revenue for the 3 months ended June 30, 2018, grew 25% year-over-year to $263 million, of which $246 million was derived from the share of net profits from EYLEA sales outside the U.S. The $264 million, which represents year-over-year growth of 29%, compares favorably against the $191 million realized for the 3 months ended June 30, 2017.

截至 2018 年 6 月 30 日的三個月，拜耳合作總營收年增 25% 至 2.63 億美元，其中 2.46 億美元來自安永在美國以外地區的銷售淨利份額。 2.64 億美元的營收年增 29%，與截至 2017 年 6 月 30 日的三個月的 1.91 億美元相比，表現更為出色。

Total Sanofi collaboration revenue was $238 million for the second quarter of 2018 compared with $222 million for the second quarter of 2017. Total Sanofi collaboration revenue line item primarily consists of reimbursement of Regeneron-incurred R&D expenses, reimbursement of Regeneron-incurred commercialization-related expenses and the recognition of deferred revenue from the immuno-oncology upfront payments, partly offset by our share of losses in connection with the commercialization of antibodies. The year-over-year increase in Sanofi revenue as of the second quarter 2018 included a $53 million decrease in our share of losses in connection with the commercialization of DUPIXENT, PRALUENT and KEVZARA and higher Sanofi R&D reimbursement revenue associated with our increased investment in immuno-oncology. Offsetting these revenue increases is the 2017 expiration of the discovery and preclinical development agreement, under which we recorded $44 million of revenue in the second quarter of 2017 compared to no revenue this quarter. Additionally, during the second quarter of 2018, we realized $29 million less reimbursement of Regeneron research and development expenses under the antibody license and collaboration agreement from decreased reimbursement levels with DUPIXENT versus second level -- second quarter of 2017.

2018 年第二季度，賽諾菲合作總營收為 2.38 億美元，而 2017 年第二季為 2.22 億美元。賽諾菲合作總收入項目主要包括：報銷 Regeneron 發生的研發費用、報銷 Regeneron 發生的商業化相關費用以及確認免疫腫瘤預付款的遞延收入，部分被我們應承擔的抗體商業化相關損失所抵消。截至 2018 年第二季度，賽諾菲營收年增，其中包括與 DUPIXENT、PRALUENT 和 KEVZARA 商業化相關的虧損份額減少了 5,300 萬美元，以及由於我們在免疫腫瘤學領域加大投資而帶來的賽諾菲研發報銷收入增加。抵銷這些收入成長的是 2017 年發現和臨床前開發協議的到期，根據該協議，我們在 2017 年第二季錄得 4,400 萬美元的收入，而本季則沒有收入。此外，在 2018 年第二季度，由於 DUPIXENT 的報銷水平低於 2017 年第二季度的水平，我們根據抗體許可和合作協議減少了 2900 萬美元的 Regeneron 研發費用報銷。

In the second quarter 2018, we recognized a loss of $69 million in connection with the commercialization of antibodies compared to a loss of $122 million in the second quarter of 2017. As I briefly touched on earlier, the lower share of loss was primarily attributed to higher global net sales of DUPIXENT, KEVZARA and PRALUENT and lower commercialization expenses for PRALUENT, partly offset by an increase in both DUPIXENT and KEVZARA commercialization expenses.

2018 年第二季度，我們在抗體商業化方面確認了 6,900 萬美元的虧損，而 2017 年第二季度則虧損了 1.22 億美元。正如我之前簡要提到的，虧損份額降低主要歸因於 DUPIXENT、KEVZARA 和 PRALUENT 的全球淨銷售額增加以及 PRALUENT 的商業化費用降低，但部分被 DUPIXENT 和 KEVZARA 商業化費用的增加所抵消。

I want to make a few comments regarding our share of losses associated with the commercialization of the alliance products. Sanofi and Regeneron have ongoing worldwide product launches for DUPIXENT, KEVZARA and PRALUENT. We are pleased that the alliance is beginning to realize profits in certain markets and indications, such as with DUPIXENT for atopic dermatitis in the U.S. However, we are still incurring necessary launch expenses for new indications in new markets, and these expenses continue to weigh on the alliance's profitability.

我想就我們在聯盟產品商業化過程中所承擔的損失份額發表幾點看法。賽諾菲和再生元正在全球推出DUPIXENT、KEVZARA和PRALUENT等產品。我們很高興看到聯盟開始在某些市場和適應症領域實現盈利，例如在美國，DUPIXENT 用於治療異位性皮膚炎。然而，我們仍在為新市場的新適應症承擔必要的上市費用，這些費用繼續對聯盟的獲利能力構成壓力。

In the first half of 2018, the alliance incurred significant expenses related to the expected U.S. asthma launch in addition to other ex U.S. launch and prelaunch spend across the alliance portfolio. For the second half of 2018, the collaboration is expecting to launch in approximately 30 new markets across the alliance portfolio as well as incur prelaunch expenses for additional markets and indications expected to launch in 2019 and beyond. We and Sanofi are working diligently to ensure we have the appropriate level of investment to support these opportunities. As the sales of our alliance products continue to grow, we expect to improve the collaboration's profitability.

2018 年上半年，該聯盟除了在美國以外地區開展其他業務的上市和上市前支出外，還產生了與預期在美國推出氣喘產品相關的重大支出。2018 年下半年，該合作計畫預計將在聯盟產品組合的約 30 個新市場推出，並為預計在 2019 年及以後推出的其他市場和適應症承擔上市前費用。我們和賽諾菲正在努力確保我們擁有適當的投資水準來支持這些機會。隨著我們聯盟產品的銷售持續成長，我們預計合作的獲利能力將會提高。

Turning now to expenses. Non-GAAP R&D expenses were $470 million for the second quarter of 2018 as compared to $440 million for the second quarter of 2017. The increase in non-GAAP R&D expense was the result of continued late-stage clinical developments for cemiplimab and fasinumab programs and higher R&D headcount and facility-related costs, partially offset by a decrease in DUPIXENT development costs and the discontinuation of certain development programs. Our non-GAAP unreimbursed R&D expense, which is calculated as the total GAAP R&D expense less R&D reimbursements from our collaborators, was $286 million for the 3 months ended June 30, 2018, compared to $196 million for the 3 months ended June 30, 2017. Almost half of this year-over-year increase is attributable to the expiration of the Sanofi antibody discovery and preclinical agreement at the end of 2017. The remaining increases were primarily driven by higher research and development activities for partnered and wholly-owned programs. Our press release includes the information required to calculate unreimbursed non-GAAP R&D expense.

接下來談談費用。2018 年第二季非 GAAP 研發費用為 4.7 億美元，而 2017 年第二季為 4.4 億美元。非GAAP研發費用的增加是由於cemiplimab和fasinumab計畫持續的後期臨床開發以及研發人員和設施相關成本的增加，部分被DUPIXENT開發成本的減少和某些開發項目的終止所抵消。截至 2018 年 6 月 30 日的三個月，我們的非 GAAP 未報銷研發費用（計算方法為 GAAP 研發總費用減去合作方的研發報銷）為 2.86 億美元，截至 2017 年 6 月 30 日的三個月為 1.96 億美元。近一半的同比增長是由於賽諾菲抗體發現和臨床前協議於 2017 年底到期所致。其餘成長主要由合作項目和全資項目研發活動的增加所驅動。我們的新聞稿包含了計算未報銷的非GAAP研發費用所需的資訊。

Primarily, due to previously announced modifications to our ongoing NGF program, we are lowering and tightening our full year 2018 guidance for non-GAAP unreimbursed R&D expense to be in the range of $1.21 billion to $1.26 billion from our previous guidance of $1.23 billion to $1.31 billion. Non-GAAP SG&A expense was $324 million for the second quarter of 2018 as compared to $262 million for the 3 months ended June 30, 2017. The higher SG&A expenses in the second quarter of 2018 were primarily due to an increase in commercialization-related expenses for EYLEA and prelaunch expenses for cemiplimab and DUPIXENT in adult and adolescent asthma. Given year-to-date activity and projected second half 2018 spend, we are tightening full year 2018 non-GAAP SG&A expense to be $1.34 billion to $1.39 billion from $1.325 billion to $1.395 billion.

主要原因是，由於先前宣布對我們正在進行的 NGF 計劃進行修改，我們將 2018 年全年非 GAAP 未報銷研發費用的預期從之前的 12.3 億美元至 13.1 億美元下調並收緊至 12.1 億美元至 12.6 億美元。2018 年第二季非 GAAP 銷售、一般及行政費用為 3.24 億美元，截至 2017 年 6 月 30 日的三個月為 2.62 億美元。2018 年第二季較高的銷售、一般及行政費用主要是由於 EYLEA 的商業化相關費用增加，以及 cemiplimab 和 DUPIXENT 在成人和青少年氣喘領域的上市前費用增加。鑑於今年迄今的活動和預計 2018 年下半年的支出，我們將 2018 年全年非 GAAP 銷售、一般及行政費用從 13.25 億美元至 13.95 億美元下調至 13.4 億美元至 13.9 億美元。

Sanofi reimbursement of Regeneron commercialization-related expenses, a line item found within Sanofi collaboration revenue, was $106 million for the second quarter of 2018. We are tightening our full year 2018 guidance for reimbursement of Regeneron commercialization-related expenses to be $455 million to $485 million from $450 million to $485 million.

2018 年第二季度，賽諾菲向 Regeneron 支付的商業化相關費用（該費用包含在賽諾菲合作收入中）為 1.06 億美元。我們將 2018 年全年與 Regeneron 商業化相關的費用報銷預期從 4.5 億美元至 4.85 億美元收緊至 4.55 億美元至 4.85 億美元。

Before turning to taxes, in the second quarter 2018, we realized $34 million of other income within the other income and expense line item. This was partly driven by the recognition of unrealized gains on equity securities due to the adoption of ASU 2016-01 in 2018. This is compared to having reported $24 million of other expense in the second quarter of 2017, which was primarily attributable to the loss on extinguishment of debt that we realized related to last year's Tarrytown lease transaction. Please see our 10-Q for more details on the year-over-year change.

在討論稅收之前，2018 年第二季度，我們在其他收入和支出項目下實現了 3,400 萬美元的其他收入。這部分是由於 2018 年採用 ASU 2016-01 而確認了股權證券的未實現收益。相較之下，2017 年第二季報告的其他支出為 2,400 萬美元，這主要是由於去年 Tarrytown 租賃交易相關的債務清償損失所致。有關同比變化的更多詳情，請參閱我們的 10-Q 表格。

With regard to taxes. Our effective tax rate in the second quarter of 2018 was 16% compared to 26% for the second quarter of 2017, driven primarily by the enactment of the Tax Cuts and Jobs Act, which lowered the U.S. corporate tax rate. The rate was also impacted by improved results from our international operations as compared to the second quarter of 2017. As we continue to assess the full impact of the new tax law, including some onetime items, we now expect our full year 2018 effective tax rate to be in the range of 13% to 16% from our previous guidance of 15% to 18%. While our effective tax rate guidance has been lowered for 2018, we do expect that over the next few years, our effective tax rate will be in the mid- to high teens. Given the recent passage of the new tax law, we are still awaiting regulatory or other guidance that could impact our future effective tax rate.

關於稅收方面。2018 年第二季度，我們的實際稅率為 16%，而 2017 年第二季度為 26%，這主要是由於《減稅與就業法案》的頒布降低了美國企業稅率。與 2017 年第二季相比，國際業務業績的改善也對利率產生了影響。鑑於我們仍在評估新稅法的全面影響，包括一些一次性項目，我們現在預計 2018 年全年實際稅率將在 13% 至 16% 之間，而我們先前預期的為 15% 至 18%。雖然我們下調了 2018 年的實際稅率預期，但我們預計在未來幾年內，我們的實際稅率將維持在十幾到二十幾的水平。鑑於新稅法近期已通過，我們仍在等待可能影響我們未來實際稅率的監管或其他指引。

Turning next to cash flow and the balance sheet. Regeneron ended the second quarter of 2018 with cash and marketable securities of $3.7 billion and generated an excess of $800 million of free cash flow for the 6 months ended June 30, 2018. We calculate free cash flow as net cash provided by operating activities less capital expenditures. Our capital expenditures for the 3 months ended June 30, 2018, were $112 million and totaled $191 million for the 6 months ended June 30, 2018. We are tightening and lowering our full year 2018 capital expenditure guidance to $410 million to $450 million from our prior range of $420 million to $480 million.

接下來來看現金流量表和資產負債表。截至 2018 年第二季末，Regeneron 持有現金及有價證券 37 億美元，並在截至 2018 年 6 月 30 日的 6 個月內產生了超過 8 億美元的自由現金流。我們將自由現金流計算為經營活動產生的現金流量淨額減去資本支出。截至 2018 年 6 月 30 日止的三個月，我們的資本支出為 1.12 億美元；截至 2018 年 6 月 30 日止的六個月，我們的資本支出總額為 1.91 億美元。我們將 2018 年全年資本支出預期從先前的 4.2 億美元至 4.8 億美元下調至 4.1 億美元至 4.5 億美元。

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

那麼，我想把電話轉回給瑪妮莎。

Thank you, Bob. Sylvia, this concludes the end of our prepared remarks. We would now like to open the call for Q&A.

謝謝你，鮑伯。西爾維亞，我們準備好的演講到此結束。現在我們開始問答環節。

(Operator Instructions) And our first question comes from Robyn Karnauskas from Citi.

（操作員說明）我們的第一個問題來自花旗銀行的 Robyn Karnauskas。

I just had a question. Given that data is coming up soon in pain in OA, maybe you could help us understand a little bit. I know you're just -- you have the low dose. What would be clinically meaningful data? And the OA market is very complex, so maybe help us understand some of the market stats around where this drug might be used within this population.

我有個問題。鑑於骨關節炎疼痛的數據即將公佈，或許您可以幫助我們更了解一些情況。我知道你只是——你劑量很低。哪些數據才具有臨床意義？OA市場非常複雜，所以或許可以幫我們了解一些關於這種藥物在該族群中可能使用情況的市場統計數據。

Thanks, Robyn. It's Len. I think what we've said about this program all along is that we would anticipate, based on the data we have and the [Compelo] program, that the efficacy that's been demonstrated is good efficacy and would on efficacy considerations alone be a useful addition to the therapeutic armamentarium in osteoarthritis, especially as a non-opiate pain -- new pain class. The -- so we're anticipating that the Phase III data we have should show some efficacy. But obviously, we have to see it. The safety, of course -- the long-term safety, which won't be answered from this study because this study is not a long-term safety, is something that we can only wait for the data. As you know, we lowered the dose to a dose that the independent committee felt was appropriate to continue, so we're pleased with that. And our Compelo program is continuing. But it's all going to have to wait until we really have a long-term data to know just exactly the promise of this program. So I think it remains a high-risk, high-reward program. George, I don't know if you want to add anything.

謝謝你，羅賓。是倫。我認為我們一直以來對這個項目的評價是，根據我們掌握的數據和[Compelo]項目，我們預計已經證明的療效是良好的療效，僅從療效角度來看，它將成為骨關節炎治療手段的有用補充，特別是作為一種非阿片類止痛藥——一種新的止痛藥類別。因此，我們預期我們掌握的 III 期數據應該會顯示出一定的療效。但很顯然，我們必須親眼看看。當然，安全性問題——長期安全性問題，由於這項研究並非長期安全性研究，因此無法回答這個問題，我們只能等待數據出來。如您所知，我們將劑量降低到獨立委員會認為合適的劑量，我們對此感到滿意。我們的 Compelo 項目仍在繼續。但這一切都要等到我們真正獲得長期數據後才能知道這個計畫的前景究竟如何。所以我認為這仍然是一個高風險、高回報的專案。喬治，我不知道你是否還有什麼要補充的。

No, I think you covered it all.

不，我覺得你已經說得很清楚了。

Our next question comes from Chris Raymond from Piper Jaffray.

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

So Roche has talked about their Lucentis prefilled syringe as sort of a key component of driving market share gains, and I think as they put it sort of across all lines of therapy. So I understand you guys filed an sBLA for a similar device last quarter, I think for EYLEA, but you're probably talking about a 2019 launch. So just maybe talk about the competitive dynamic, I guess, between now and then. And first of all, is it your view that this is a big differentiator for Roche as they're saying? And are there any countermeasures you can employ between now and then?

羅氏公司曾表示，他們的 Lucentis 預充式註射器是推動市場佔有率成長的關鍵組成部分，而且我認為正如他們所說，它適用於所有治療領域。我了解到你們上個季度為類似設備提交了sBLA申請，我想是為EYLEA公司提交的，但你們可能指的是2019年上市。所以，我想，或許可以談談從現在到那時之間的競爭格局。首先，您是否認為這像羅氏所說的那樣，是羅氏的一大差異化優勢？那麼從現在到那時，你可以採取哪些因應措施呢？

Yes. I think that we have not seen this as a big shift in market share. Maybe Marion wants to go into depth on that?

是的。我認為我們還沒有看到市場份額發生重大變化。或許瑪莉安想深入探討這個問題？

Sure. Happy to. In fact, in the fairly comprehensive survey data we use of physician prescribing, it would suggest that we're continuing to see share growth with EYLEA opposite Lucentis. And certainly, over the life cycle of the brand as EYLEA has grown, we've taken equal share of about 20 market share points both from Lucentis and from Avastin. So while we do think having a prefilled syringe available, and as I mentioned in my comments, that will be later in 2019 potentially, we believe having that extension, that line extension, and that delivery system will be helpful to physicians. We don't see it as, in any way, a negative to our current profile and marketplace as we're competing. And certainly, the performance we're showing, the share growth we're showing and the preference clearly in physicians prescribing for wet AMD with EYLEA is important as it is in DME.

當然。樂意之至。事實上，在我們所使用的相當全面的醫生處方調查數據中，這表明我們繼續看到安樂死的市場份額在與盧森蒂斯的競爭中增長。當然，隨著安怡品牌在其生命週期內的發展，我們已經從 Lucentis 和 Avastin 手中奪取了大約 20 個百分點的市場份額。因此，雖然我們認為預充式註射器的出現是必要的，而且正如我在評論中提到的，這可能要到 2019 年晚些時候才能實現，但我們相信，擁有這種延長線、延長管路和輸送系統將對醫生有所幫助。我們並不認為這會對我們目前的形象和市場地位產生任何負面影響，因為我們仍在參與競爭。當然，我們所展現的業績、我們所展現的市場份額增長，以及醫生在為濕性 AMD 患者開具 EYLEA 處方時所表現出的明顯偏好，都與 DME 患者的情況一樣重要。

Our next question comes from Ying Huang from Bank of America Merrill Lynch.

下一個問題來自美國銀行美林證券的黃穎。

Maybe I want to ask one on the PD-1 program in non-small cell lung cancer. Can you talk about the rationale behind the increase in enrollment? Is it driven by powering increase? Is it driven by assumption of the comparator arm or whatever you learned from the Merck program? And then also, the availability of Keytruda in certain markets, would that affect your enrollment in this program or not?

也許我想問關於 PD-1 在非小細胞肺癌治療的應用。能談談招生人數增加背後的原因嗎？這是由電力成長驅動的嗎？這是基於對照組的假設，還是基於你從默克計畫中學到的東西？此外，Keytruda 在某些市場的供應情況是否會影響您參加此專案？

Yes. I think you did a good job answering your own question. Certainly, the original smaller study, the positive study with the PD-1 antibody in first-line non-small cell, the data looked more robust than the second study. Clearly, the agent is very active, but the relative effect compared to control was not quite as robust in the second study. And so we adjusted based on our power calculations and, based on those results, the size of our study. So it's basically entirely as you described. And certainly, of course, we take into account what's available where and what the standard of care is in different territories in terms of where we carry out our studies and how we enroll them. So yes, that's about it.

是的。我認為你很好地回答了自己的問題。當然，最初的規模較小的研究，即PD-1抗體在非小細胞一線治療中取得陽性結果的研究，其數據看起來比第二項研究更可靠。顯然，該藥物非常有效，但與對照組相比，其相對效果在第二項研究中並不那麼顯著。因此，我們根據功效計算結果調整了研究規模。所以基本上完​​全正如你所描述的那樣。當然，我們在進行研究和招募受試者時，也會考慮到不同地區的醫療資源和照護標準。是的，差不多就是這樣。

Next question comes from Geoffrey Porges from Leerink.

下一個問題來自 Leerink 的 Geoffrey Porges。

Are you on mute?

你開啟了靜音模式嗎？

Geoff, we can't hear you.

傑夫，我們聽不到你說話。

Sorry about that. A couple of financial questions for Bob. Bob, could you just confirm what free cash flow was in Q2? I think you gave us the number for the first half of the year. And then what's driving the change compared to Q1? But more importantly, as we look to the commercialization of cemiplimab, are you going to have a second collaboration losses line that you report? And related to that, as your financial reporting gets more and more complicated, is there anything you think that you can do to simplify it so that investors really understand the value and what the outlook is? Because we're getting more and more of these collaborations and more and more costs and sort of puts and takes in each of those lines, and the variance in terms of consensus expectations is all over the place. So have you thought about any way in which you can simplify things? I appreciate it.

抱歉。我有幾個財務方面的問題想問鮑伯。Bob，你能確認一下第二季的自由現金流是多少嗎？我想你已經給了我們上半年的數據。那麼，與第一季相比，是什麼因素導致了這種變化？但更重要的是，隨著 cemiplimab 的商業化，你們是否會公佈第二條合作損失報告？與此相關的是，隨著財務報告變得越來越複雜，您認為有什麼方法可以簡化報告，以便投資者真正了解公司的價值和前景？因為這類合作越來越多，成本也越來越高，每條線上都有利弊權衡，而各方對合作的共識預期卻千差萬別。那麼，你有沒有想過有什麼方法可以簡化事情呢？謝謝。

Yes. Geoff, I'll take the last question first. And as you know, just kind of giving the dialogue we've had, I mean, Len is constantly challenging me and my team to obviously make these things interpretable, in which the true value of the company comes out by looking at financial statements. There's no doubt it's complicated. We do our best, inclusive of documents we post at the JPMorgan meeting in January with regards to getting into detail, with regards to the modeling, and we will continue to do that and continue to take your concerns under consideration with regards to that. On your first question, with regards to cash flow, there is a pretty big difference between Q1 and Q2. I think you meant Q1 2018 versus Q2 2018. We had no tax payments in the first quarter of 2018. And we did in the quarter 2 of 2018, which is why we had $800 million in total, roughly $500 million-$300 million split, something along that line. With regards to cemiplimab, we are still under discussions with regards to exactly how we're going to show that, Geoff, and we'll put more out at that time at a later date. Thanks.

是的。傑夫，我先回答最後一個問題。如你所知，就我們先前的對話而言，Len 一直在挑戰我和我的團隊，要求我們把這些事情解釋清楚，透過查看財務報表來體現公司的真正價值。毫無疑問，這很複雜。我們將盡最大努力，包括在 1 月摩根大通會議上發布的詳細文件，包括建模方面的內容，我們將繼續這樣做，並繼續考慮您在這方面的擔憂。關於你的第一個問題，即現金流方面，第一季和第二季之間存在著相當大的差異。我想你指的是2018年第一季和2018年第二季。2018年第一季我們沒有繳任何稅。我們在 2018 年第二季確實做到了，所以我們總共有 8 億美元，大約是 5 億美元對 3 億美元，大致如此。關於cemiplimab，Geoff，我們仍在討論具體如何展示它，稍後我們會公佈更多資訊。謝謝。

Our next question comes from Matthew Harrison from Morgan Stanley.

下一個問題來自摩根士丹利的馬修·哈里森。

If I could ask maybe a question on the C5 inhibitor that you talked about. Can you just talk about -- when you talk about blood level sufficient, are you comparing this to Soliris or ALXN1210? And what's your view on sort of how the market is going to develop? And what you think is the appropriate bar to look at as you develop this molecule?

我可以問一個關於您提到的C5抑制劑的問題嗎？您能否具體談談——當您談到血液濃度充足時，您是將其與 Soliris 還是 ALXN1210 進行比較？你認為市場會如何發展？那麼，在開發這種分子時，您認為合適的參考標準是什麼？

Yes. Well, we're talking about our evaluation based on our assays of our molecule compared to what's known in the public domain as well as using our own pharmacodynamic assays and measures of how well we're doing at inhibiting complement. So it's integrating all of that data. What we see that's important out there is to provide patients with a convenient, home self-administered subcutaneous regimen that makes their life a lot easier and that keeps their disease in better control with less breakthrough. So we're trying to make their lives easier and better while delivering better disease control. That's our goal.

是的。嗯，我們指的是根據我們對分子的檢測結果，將我們的評估與公開領域已知的結果進行比較，同時使用我們自己的藥效學檢測和衡量指標來評估我們在抑制補體方面的表現。所以它整合了所有這些數據。我們認為，目前最重要的是為患者提供方便的居家皮下注射治療方案，這能讓他們的生活輕鬆許多，並能更好地控制病情，減少復發。因此，我們努力讓他們的生活更輕鬆、更美好，同時更好地控制疾病。這就是我們的目標。

So just to be very clear in case if people aren't familiar with what George was saying. We not only measure our blood levels to determine whether we achieved what we wanted. We take the blood out of patients and do an ex-vivo assay to see whether that blood can suppress in a standard assay for complement activation, and we achieved the blood level that fully suppresses that. Of course, that's not quite the same thing as doing it with disease, but it -- we expect and hope it will be a good predictor.

為了避免有人不熟悉喬治剛才說的話，我再解釋一次。我們不僅要測量血液指標來確定是否達到了目標。我們從病人身上抽取血液，進行體外試驗，看看這种血液是否能在標準的補體激活試驗中起到抑製作用，我們達到了能夠完全抑制補體激活的血液水平。當然，這與用疾病來預測疾病並不完全相同，但我們期望並希望它能成為一個好的預測指標。

Our next question comes from Josh Schimmer from Evercore ISI.

我們的下一個問題來自 Evercore ISI 的 Josh Schimmer。

Two quick ones. First of all, it looks like the commercial JV with Sanofi may have been trending towards declining loss. But based on the commentary and the guidance, is it correct that you expect that trend to reverse temporarily towards greater losses in the second half of '18? If so, when do you expect that to return to kind of improving the losses and that it will eventually become profitable? And then quickly on the C5 antibody, what do you anticipate the dosing frequency will be for the subcu injection?

兩個簡短的問題。首先，看起來與賽諾菲的商業合資企業虧損可能正在減少。但根據評論和指導，您是否認為這一趨勢將在 2018 年下半年暫時逆轉，導致更大的損失？如果情況屬實，您預計何時虧損能夠有所改善，並最終實現盈利？那麼，關於 C5 抗體，您預期皮下注射的給藥頻率是多少？

Josh, I'll take the first question, and we're not going to give guidance with regards to when we think the collaboration is going to turn profitable. And yes, directionally, in the second quarter, to your point, it is trending in the right direction. Again, my comments that were made with regards to the second half spend, we are going to be entering a very crowded and very competitive asthma class. And we need to ensure, given the strength of our antibody, that we have enough support, that Marion has enough support with the Sanofi alliance behind us to ensure that it is a very, very successful launch, and we come out of the gates very strong right away. And again, we're not going to give in terms of quarterly our profitability guidance on that note.

喬希，我來回答第一個問題。至於我們認為這項合作何時才能獲利，我們不會給出任何指導意見。是的，從方向上看，正如你所說，第二季度的發展趨勢是正確的。再次重申我之前關於下半年支出的評論，我們將進入一個非常擁擠、競爭非常激烈的氣喘治療領域。鑑於我們抗體的強大功效，我們需要確保我們有足夠的支持，確保 Marion 在賽諾菲聯盟的支持下有足夠的支持，以確保產品上市非常非常成功，並且我們能夠一鳴驚人。再次重申，我們不會就此給出季度獲利預期。

So as far as the dosing

所以，關於劑量方面…

(technical difficulty)

（技術難題）

typically, one likes to think that the minimum acceptable interval, although obviously, [there is insulin] and others are way more than that, would be a weekly dosing. And that's what we're able to achieve in our study. Whether we can go longer than that, we'll just have to see as we get more into this. But right now, we -- our comments reflect a weekly subcutaneous dosing regimen that we intend to move forward.

通常來說，人們傾向於認為最短可接受的間隔是每週一次給藥，儘管顯然，胰島素和其他藥物的給藥間隔要長得多。這就是我們在研究中能夠達到的成果。我們能否堅持更長時間，還需要隨著研究的深入才能見分曉。但就目前而言，我們的評論反映了我們打算繼續進行的每週皮下注射給藥方案。

Our next question comes from Carter Gould from UBS.

我們的下一個問題來自瑞銀集團的卡特古爾德。

I guess for Len and George. You mentioned your higher dose aflibercept and moving forward that. How fast do you think that could potentially get on the market? And any indication from your initial work what you think you can get the treatment interval out to?

我想是為了萊恩和喬治吧。您提到了您正在服用更高劑量的阿柏西普，以及接下來的治療方案。你認為這款產品最快多久能上市？根據你最初的研究結果，你認為治療間隔可以延長到多久？

Yes. I think it's a little bit early to go into that, Carter. Obviously, we have a tremendous amount of experience doing these types of studies, both on the preclinical and the clinical. We've worked diligently to come up with a higher-dose formulation. And we think that, that is something that would extend the half life. It's a competitive field, so we probably don't want to comment much more about that.

是的。卡特，我覺得現在討論這個問題還太早。顯然，我們在進行這類研究方面擁有豐富的經驗，包括臨床前研究和臨床研究。我們努力研發了更高劑量的配方。我們認為，這樣做可以延長半衰期。這是一個競爭激烈的領域，所以我們可能不想對此發表更多評論。

Our following question comes from Phil Nadeau from Cowen and Company.

接下來的問題來自 Cowen and Company 的 Phil Nadeau。

Question on DUPIXENT reimbursement. Can you talk about any trends -- notable trends that you saw in DUPIXENT reimbursement in atopic dermatitis in Q2? Was there anything that eased that allowed the new prescriptions to grow so significantly? And then as you prepare for the launch of DUPIXENT in asthma, what are you doing to ensure access to patients as that launches?

關於DUPIXENT報銷的問題。您能否談談第二季度在異位性皮膚炎的DUPIXENT報銷方面觀察到的任何趨勢——一些值得注意的趨勢？是否存在某種因素緩解了新處方藥數量的顯著增長？在準備推出用於治療氣喘的 DUPIXENT 時，你們採取了哪些措施來確保患者能夠獲得該藥物？

So before Marion addresses the access issue, I just want to say what we continue to hear, and we maybe didn't mention enough, is that the feedback from patients continues to be really, really satisfying. And it makes us -- it sort of reminds us why all of us are doing what we're doing. People who are miserable with this disease have felt and told us that it was life-changing for them. And so as I've said on previous calls, it is nice that the data that you saw and we saw in our clinical trials seems to be translating very well in the real world, where patients are experiencing, on an individual basis, the kind of benefit that the data that we achieved in the controlled setting would have predicted. So that is very nice, and both the doctors and the patients are extremely satisfied. And as I said before, thank goodness we've also seen no new side effects to concern people, so the tolerability out in the real world is also very good. So from my perspective, I would guess that is probably the biggest thing that's driving the continued use and growth. And of course, there is blocking and tackling that Marion can address, if she likes.

所以在 Marion 談到就醫途徑問題之前，我只想說，我們一直聽到，而且我們可能沒有充分提及的是，患者的回饋一直都非常令人滿意。它讓我們——它在某種程度上提醒我們，我們所有人為什麼要做我們正在做的事情。患有這種疾病的人都深有體會，並告訴我們，這種疾病改變了他們的生命。正如我在先前的電話會議中所說，很高興看到你們和我們在臨床試驗中看到的數據似乎在現實世界中得到了很好的體現，患者在個體層面上體驗到了我們在受控環境下獲得的數據所預測的那種益處。這非常好，醫生和病人都非常滿意。正如我之前所說，值得慶幸的是，我們也沒有發現任何新的副作用會引起人們的擔憂，因此，在現實世界中的耐受性也非常好。所以從我的角度來看，我猜這可能是推動其持續使用和成長的最大因素。當然，如果瑪莉安願意的話，她也可以處理阻擋和擒抱的問題。

Sure. Happy to. And to give a little bit more specificity on the access for DUPIXENT in atopic dermatitis, among commercial payers today, we have coverage with over 90% for -- over 90% of covered lives. But then if we get a little bit more specific, and to give you the numbers, the percentage is about 65% of commercial lives have access to DUPIXENT following only 1 or 2 topical medications. So we've made significant progress. And we did make some meaningful progress as well in the second quarter, picking up another one of the major insurance companies. So I think we feel really good about that progress. But I would also say that what -- to Len's point, what is really driving the demand we're seeing, such as this 27% increase in TRxs that I referenced in the quarter-on-quarter comparison. And of course, the number was 25% in the quarter-on-quarter comparison in the first quarter. This type of demand is becoming -- is coming because of the tremendous results that physicians are seeing in prescribing their toughest cases now moving into additionally not only their severe but starting to move into their more moderate cases and the tremendous value that patients are seeing. As for asthma, we very much look forward to the launch. We certainly, at the appropriate time, will engage in payer discussions. And of course, I think some of the differentiating characteristics are really important to keep in mind. The clinical profile that George referenced and also in my comments differentiated by our profiles that relates to the impact we're seeing with DUPIXENT in moderate-to-severe asthma, a reduction of exacerbations and also the consistency that we see in lung function is really, really important. A second differentiating characteristic I've mentioned is the patients will be able to administer product self or at home, and that also is a distinguishing feature that is important. So we look forward to launch. We're ready, and we certainly will engage with payers at the right time.

當然。樂意之至。為了更具體地說明 DUPIXENT 在異位性皮膚炎治療中的應用情況，目前商業保險支付方已涵蓋超過 90% 的受保人口。但是，如果我們更具體地說，並給出具體數字，那麼大約 65% 的商業人群在僅使用 1 或 2 種外用藥物後即可獲得 DUPIXENT。因此，我們取得了顯著進展。我們在第二季也取得了一些實質進展，成功拿下另一家大型保險公司。所以我覺得我們對所取得的進展非常滿意。但我也想說——正如 Len 所說，是什麼真正推動了我們看到的需求，例如我在季度比較中提到的 TRx 增長 27%。當然，第一季環比成長了 25%。這種需求正在出現——這是因為醫生在治療最棘手的病例時看到了巨大的療效，現在不僅擴展到重症病例，而且開始擴展到中度病例，並且患者也看到了巨大的價值。至於氣喘治療，我們非常期待它的上市。我們當然會在適當的時候與付款方進行討論。當然，我認為一些區別特徵非常重要，需要牢記在心。George 提到的臨床特徵，以及我在評論中提到的，與我們觀察到的 DUPIXENT 對中重度氣喘的影響相關的特徵，即減少病情加重以及肺功能的穩定性，真的非常重要。我提到的第二個區別特徵是患者可以自行或在家中使用該產品，這也是一個重要的區別特徵。我們期待著發表會的到來。我們已經做好準備，並且一定會在合適的時機與支付方進行接洽。

Our next question comes from Cory Kasimov from JPMorgan.

下一個問題來自摩根大通的科里·卡西莫夫。

A follow-up on DUPIXENT. So out of the 50,000 or so patients that have been treated with the product in the commercial setting thus far, do you have a good sense of the proportion of those that have overlapping allergic disease, co-morbidities and maybe even more specifically in terms of asthma? I'm curious how common this is.

關於DUPIXENT的後續通報。那麼，在迄今為止的商業環境中接受該產品治療的約 50,000 名患者中，您是否清楚地了解有多少人患有重疊的過敏性疾病、合併症，甚至更具體地說，患有氣喘？我很想知道這種情況有多普遍。

Yes. I don't think we have the real world data. But we know from our controlled studies, obviously our controlled studies are a collection of the moderate-to-severe atopic dermatitis patients. And as Marion just told you, the doctors tend to provide their more serious patients or put their more serious patients on first. So what's been happening in the real world, you might think might be patients who actually have more disease and more co-morbidities. But in our controlled studies of the moderate-to-severe population on the order of 30% to 40% had co-morbid asthma, and 60% to 70% had at least one other co-morbid allergic condition. So obviously, among the atopic dermatitis population, the moderate to severe, there is a very substantial amount of co-morbidity with other allergic conditions.

是的。我認為我們沒有真實世界的數據。但我們從對照研究得知，顯然，我們的對照研究對像是中度至重度異位性皮膚炎患者。正如瑪麗昂剛才告訴你的那樣，醫生們往往會優先安排病情更嚴重的病人就診。所以，在現實世界中，你可能會認為患者實際上患有更多疾病和更多併發症。但在我們的對照研究中，中度至重度人群中約有 30% 至 40% 的人患有合併氣喘，60% 至 70% 的人至少患有一種其他合併過敏性疾病。顯然，在異位性皮膚炎患者族群中，中度至重度患者與其他過敏性疾病的合併症非常普遍。

Our next question comes from Geoff Meacham from Barclays.

下一個問題來自巴克萊銀行的傑夫·米查姆。

I want to ask you on PRALUENT. Post-ODYSSEY and post the price cut in some populations, how would you characterize access today versus 12 months ago? And then what do you think is the tipping point for the class overall just to expand into a broader population?

我想問您關於 PRALUENT 的問題。在 ODYSSEY 計畫實施後，以及部分地區降價之後，您如何評估如今的醫療服務獲取情況與 12 個月前相比？那麼，你認為這個班級整體擴展到更廣泛人群的轉折點是什麼？

Thanks for the question, Geoff. I think the answer is that access is definitely improving, in the sense that the artificial barriers that are out there, these complicated questions, requirements for documentation, et cetera, et cetera, are slowly being removed. I think we saw that with Express Scripts, where they went to a short physician at a station. I think others will be moving to it. But the tipping point, I actually think may come with sort of practice guidelines coming from a variety of sources, where it is -- it will be -- I expect that people will -- practice guidelines will demand that patients who can't get their LDL down to an appropriate level when they have cardiovascular disease, with existing therapies, it will be standard practice, not optional, to go to a PCSK9 inhibitor. That probably will be the tipping point, but we'll see. Thanks.

謝謝你的提問，傑夫。我認為答案是，准入條件肯定在改善，因為人為設置的障礙，例如複雜的問題、文件要求等等，正在慢慢被消除。我認為我們從 Express Scripts 的案例中看到了這一點，他們當時聘請了一位駐站的矮個子醫生。我認為其他人也會搬到那裡去。但我認為真正的轉捩點可能來自各種來源的實踐指南，屆時——我預計人們將會——實踐指南將要求，對於患有心血管疾病且無法通過現有療法將 LDL 降至適當水平的患者，使用 PCSK9 抑製劑將成為標準做法，而不是可選項。那很可能是個轉捩點，但我們拭目以待。謝謝。

The following question is from Matthew Luchini from BMO Capital.

以下問題來自 BMO Capital 的 Matthew Luchini。

You touched on this a little bit in the answer on the last questions, but I was curious if you could provide a bit more color on the types of patients that are receiving DUPIXENT in terms of disease severity? And how you think expansion into more moderate patients is going to evolve over the next 3, 6, 12 months?

您在回答上一個問題時稍微提到了這一點，但我很好奇您能否就接受 DUPIXENT 治療的患者類型（按疾病嚴重程度劃分）提供更詳細的說明？您認為未來 3 個月、6 個月、12 個月內，向更多中度患者族群擴展治療方案將會如何發展？

So I think that it's not unusual that physicians in their first experience will try some of their very, very toughest patients. So that would have been in the earlier launch days. As we now see the improvement in performance, as evidenced by numbers of physicians who are prescribing -- depth of prescribing TRxs and the NRx numbers that I shared. We now know that physicians and also nurse practitioners, PAs who use DUPIXENT are already starting to move from severe into their more moderate patients as they evolve into a broader experience. It's hard to give you exact numbers on that. That I don't have, but we are seeing evidence through discussions and through prescribing depth. Having said that, if we were in times back thinking that we probably have roughly 300,000 to 400,000 potential patients who would have moderate-to-severe disease in the U.S., we really are only at a relatively small percentage of touching patients. So we have an awful lot more work to do and a lot more potential for DUPIXENT in atopic dermatitis.

所以我認為，醫生在初次執業時遇到一些非常非常棘手的病人並不罕見。那應該是在產品發布初期的時候。正如我們現在所看到的，績效有所提高，這可以從開處方的醫生人數、處方深度、TRx 和 NRx 數量中看出，正如我分享的那樣。我們現在知道，使用 DUPIXENT 的醫生、執業護理師和醫師助理已經開始從治療重症患者轉向治療中度患者，因為他們的經驗正在不斷累積。很難給出確切的數字。我沒有這方面的數據，但我們正在透過討論和深入研究來尋找證據。話雖如此，如果我們回到過去，認為美國可能有大約 30 萬到 40 萬潛在患者患有中度至重度疾病，那麼我們實際接觸到的患者比例其實只相對較小。因此，我們還有很多工作要做，DUPIXENT 在異位性皮膚炎方面還有很大的潛力。

Yes. I think that our DTC that you referenced earlier, Marion, in your remarks, should help, at least. We anticipate that, that should help achieve that.

是的。我認為，瑪麗昂，你在之前的演講中提到的我們的DTC至少應該會有所幫助。我們預計，這應該有助於實現這一目標。

Yes. Thank you, Len, for the mention there. And then just to be clear because we've covered a lot, we are going to be launching a DUPIXENT on-air TV campaign nationally shortly. We got great response to the disease state awareness campaign, as evidenced by many, many touches to our websites and patients coming for additional information and even physicians mentioning that they were seeing patients because they had been engaged by disease state awareness. We do think it's the right time to evolve into the branded campaign and very much look forward to having that on-air so that patients are educated and we support efforts to get them the care they need.

是的。謝謝Len在那裡提到我。最後，為了明確起見，因為我們已經談了很多，我們即將在全國推出 DUPIXENT 的電視廣告宣傳活動。疾病狀態認知活動得到了很好的反響，這體現在我們的網站訪問量非常大，患者前來獲取更多信息，甚至有醫生提到他們接診的患者都是因為參與了疾病狀態認知活動。我們認為現在是時候發展成為品牌宣傳活動了，我們非常期待該活動上線，以便讓患者了解相關知識，並支持他們獲得所需護理的努力。

Our following question comes from Brian Skorney from Baird.

接下來的問題來自 Baird 公司的 Brian Skorney。

Thanks for fitting me in with a couple of quick questions on the pipeline. On the BCMA bispecific antibody, just given the subpar results we have seen so far with the ADC BCMA antibody compared to the CAR BCMA, I mean, just what do you think about the bispecific pathway could make it more competitive with CAR? And I just wanted to get your thoughts on the role of IL-33 in COPD versus IL-4, IL-13. Would a signal for 3500 make COPD a potential target for DUPIXENT? Or is there just a much better bio plausibility around IL-33 for COPD?

感謝您抽出時間讓我快速問幾個關於管道的問題。關於 BCMA 雙特異性抗體，鑑於目前我們看到的 ADC BCMA 抗體與 CAR BCMA 相比效果不佳，我的意思是，您認為雙特異性途徑如何使其更具競爭力，與 CAR 競爭？我只是想聽聽您對 IL-33 在 COPD 中的作用與 IL-4、IL-13 相比有何看法。如果訊號達到 3500，COPD 是否會成為 DUPIXENT 的潛在標靶？或者說，IL-33 在 COPD 中是否具有更好的生物學合理性？

George?

喬治？

Yes. Well, certainly, I think there is quite a bit of data not only from us but from others. But certainly, preclinically, there is no question that the activity in animal models of the bispecific compared to an ADC is 2 entirely different classes. And we certainly also compared them preclinically versus CAR-T approaches. And certainly, the bispecific much more closely approaches CAR-T-type of activity. So we are very excited about our BCMA bispecific in terms of it now, very soon, we're going to start hopefully seeing how it's going to be performing in patients. And as I mentioned, we also have coming up combination approaches with additional classes of bispecifics that will also be very relevant to the BCMA program as well as a way to potentially finer tune or amplify its activity in terms of what we see there. So we're very excited about that program. In terms of IL-33 and dupilumab for COPD, I think that there is a lot of questions in the field right now about how to pursue some of the biologics in the COPD setting and exactly what the implications are in terms of the biology, some of the genetics, what they call the so-called overlap syndrome. There's a substantial number of patients with COPD that have asthma overlap. And so there's a lot of questions there. And right now, we are really thinking about all this in terms of figuring out exactly what we're going to be doing also with COPD.

是的。當然，我認為不只我們自己，還有其他方面也有很多數據。但可以肯定的是，在臨床前研究中，雙特異性抗體在動物模型中的活性與抗體藥物偶聯物（ADC）的活性完全不同，這點毋庸置疑。當然，我們也進行了臨床前研究，將它們與 CAR-T 療法進行了比較。當然，雙特異性抗體的活性更接近 CAR-T 型抗體。所以，我們現在對我們的 BCMA 雙特異性抗體感到非常興奮，希望很快我們就能看到它在患者身上的表現。正如我之前提到的，我們即將推出與其他雙特異性抗體類別相結合的方法，這些方法也將與 BCMA 項目非常相關，並且有可能根據我們目前所看到的，對其活性進行更精細的調整或增強。所以我們對這個項目感到非常興奮。就 IL-33 和 dupilumab 用於 COPD 而言，我認為目前該領域有很多問題，例如如何在 COPD 治療中使用一些生物製劑，以及在生物學、遺傳學方面，以及所謂的重疊綜合徵方面，究竟會產生哪些影響。相當一部分慢性阻塞性肺病患者同時患有氣喘。所以這裡有很多問題。現在，我們正在認真思考所有這些問題，以便弄清楚我們究竟要如何應對慢性阻塞性肺病。

Our following question comes from Terence Flynn from Goldman Sachs.

接下來的問題來自高盛的 Terence Flynn。

This is Jason Jakoby on for Terence. Just another one on dupi. So with the adolescence expansion for atopic derm next year, can you just help us think about the potential patient numbers in the U.S. for this population versus the adult numbers, where I think you said it's like 300,000?

這裡是傑森‧雅各比，替特倫斯報道。又一個關於dupi的。鑑於明年異位性皮膚炎將擴展至青少年人群，您能否幫我們估算一下美國青少年人群的潛在患者數量與成人患者數量（我記得您說過成人患者數量約為 30 萬）相比如何？

Yes. This is Marion. We actually have not yet given specificity on the size of the adolescent patient population. We very much look forward to (inaudible) the potential launch in this area. And certainly, in the -- we'll be very happy in the future to provide more insight there.

是的。這是瑪莉安。我們實際上還沒有具體說明青少年患者群體的規模。我們非常期待（聽不清楚）該領域的潛在發布。當然，未來我們非常樂意提供更多這方面的見解。

Our following question comes from Adnan Dunn (sic) [Adnan Butt] from Guggenheim Securities.

我們接下來的問題來自古根漢證券的 Adnan Dunn（原文如此）[Adnan Butt]。

Maybe one on EYLEA. Len and George, some channel checks indicate that memories of the inflammation episode with EYLEA still linger a bit. So is that resolved? Is that EYLEA inflammation right now normalized back to clinical data? And then, Len, you have talked about the potential differences on safety. Do you think inflammation is something that could be different for EYLEA versus new agents?

或許可以寫一篇關於EYLEA的文章。Len 和 George，一些頻道的調查顯示，你們對 EYLEA 引起的發炎事件仍然記憶猶新。這個問題解決了嗎？目前EYLEA發炎是否已恢復到臨床數據正常值？然後，Len，你談到了安全方面的潛在差異。你認為EYLEA與其他新藥相比，其發炎反應是否可能有所不同？

Yes. So as far as the increase in intraocular inflammation, there's no doubt that there was a spike. To the best that we could do at looking at every variable, it seemed to trace to several batches of syringes. But of course, in the absence of doing a controlled trial, one can't be certain. But what we can say is that when -- the background rate typically is about 1 to 2 cases of inflammation per 10,000 injections. The marketplace notices when you get to 5 per 10,000 or 10 per 10,000. They notice it quite a lot. And I can tell you that we spiked up above the 1 to 2, and we don't think we quite got to 10. But we certainly are now back to the baseline of 1 to 2, and we monitor this very carefully. Not to break our arms patting ourselves in the back, I think that we handled that very transparently with all the various retinal associations and ophthalmologic groups. We shared the data directly with the key opinion leaders and anybody who wanted to see it. Marion's team was out there. We got lots of positive feedback. I'm sure we lost some customers doing that, but I think that we're winning them back because of transparency and the fact that we've got the rate down. Now in terms of new agents, yes, inflammation could be a differentiating factor. I mean, I think I've seen rates in some of the newer types of agents that are up to 15 per 100, 150 per 1,000, 1,500 per 10,000. Remember, we're talking about -- in the outside -- in the world as we monitor it, we're looking at rates of 1 to 2 per 10,000. So yes, if those rates don't come down dramatically, I don't think that we would be overly concerned about the competitive nature. I just want to say that, to emphasize, that we look very carefully at the competition. We don't see anything coming along that is going to be highly differentiated from the data that we've seen from our molecule. And remember, we have recently gotten, as George highlighted, an approval in Europe based on a study that the FDA hasn't seen yet, the ALTAIR study, where we got a label that allowed for extension of a dosing through a treat and extend dosing regimen in the first year, where 57% of the people were able to get at the end of the year to an intended regimen of 12 weeks or more. And a lot of -- still gaining an average of about 9 letters and many patients achieving an interval of 4 months. So I think EYLEA has incredible profile, and it's the -- we don't see anything coming along that disrupts that profile. And we certainly don't see anything that can have the broad number of indications for a very long time that we have in our emphasis on diabetes.

是的。因此，就眼內發炎的增加而言，毫無疑問，出現了一個高峰。我們盡最大努力檢查了所有變量，結果似乎與幾批註射器有關。當然，在沒有進行對照試驗的情況下，人們無法確定。但我們可以肯定的是，背景發生率通常約為每 10,000 次注射 1 至 2 例發炎。當你的銷量達到每萬銷量 5 或每萬銷量 10 時，市場就會注意到。他們對此非常在意。我可以告訴你，我們的峰值超過了 1 到 2，而且我們認為我們還沒有達到 10。但我們現在肯定已經回到了 1 到 2 的基線水平，我們會非常仔細地監測這一點。我不想自誇，但我認為我們與各個視網膜協會和眼科團體處理這件事的方式非常透明。我們直接與關鍵意見領袖以及任何想看的人分享了數據。馬里恩的團隊當時就在那裡。我們收到了很多正面的回饋。我確信這樣做會讓我們失去一些客戶，但我認為，由於透明度和我們降低了利率，我們正在贏回他們。就新藥而言，發炎可能是個區別因素。我的意思是，我見過一些新型經紀人的佣金率高達每 100 美元 15 美元，每 1000 美元 150 美元，每 10000 美元 1500 美元。記住，我們說的是——在外部——在我們監測的世界中，我們看到的發病率是每萬人 1 到 2 例。所以，如果這些利率沒有大幅下降，我認為我們不會過度擔心競爭問題。我只想強調一點，我們會非常仔細地研究競爭對手。我們目前沒有看到任何與我們從分子中觀察到的數據有顯著差異的新事物出現。別忘了，正如喬治所強調的那樣，我們最近在歐洲獲得了批准，依據的是 FDA 尚未看到的 ALTAIR 研究。該研究的標籤允許在第一年透過治療和延長給藥方案來延長給藥時間，其中 57% 的人在一年結束時能夠達到 12 週或更長時間的預期治療方案。而且很多患者平均還能獲得大約 9 個字母，許多患者達到了 4 個月的間隔。所以我認為安怡擁有非常出色的形象，而且──我們看不到任何會破壞這種形象的事情發生。我們當然看不到有其他疾病能在很長一段時間內像糖尿病一樣具有如此廣泛的適應症。

I do think it is worth emphasizing, your question, the point that you raised, about how the eye is such a sensitive readout for inflammation. And obviously, having the experience -- the wealth of experience that we have and understanding of this and also our ability to sort of track these things and so forth, yes, I think it's really important. I think that if a physician is treating a patient, they have to take into account the risks and the experience and the confidence that they would have in any particular agent.

我認為值得強調的是你提出的問題，即眼睛對發炎的敏感程度。顯然，擁有經驗——我們擁有的豐富經驗和對這方面的理解，以及我們追蹤這些事情的能力等等，是的，我認為這非常重要。我認為，如果醫生在治療病人時，他們必須考慮到風險、經驗以及對任何特定藥物的信心。

All right. Operator, that concludes our call for today. I know there were couple of few in the queue. Please send us an e-mail. We're available for follow-up calls.

好的。操作員，今天的通話到此結束。我知道隊伍裡有幾個人。請給我們發送電子郵件。我們可提供後續電話服務。

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

謝謝。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。