雷傑納榮製藥 (REGN) 2017 Q4 法說會逐字稿

Welcome to the Regeneron Pharmaceuticals Q4 2017 Earnings Conference Call. My name is Jason, and I will be your operator. (Operator Instructions) Also please note, this conference is being recorded. I will now turn the call over to Manisha Narasimhan. You may begin.

歡迎參加 Regeneron Pharmaceuticals 2017 年第四季財報電話會議。我叫傑森，我將是你的接線生。（操作說明）另請注意，本次會議正在錄音。現在我將把電話轉給瑪妮莎·納拉辛漢。你可以開始了。

Thank you, Jason. Good morning, and welcome to Regeneron Pharmaceuticals Fourth Quarter and Full Year 2017 Conference Call. An archive of this webcast will be available on our website under Events for 30 days. Joining me on the call today are Dr. Leonard Schleifer, Founder, President and CEO; Dr. George Yancopoulos, Founding Scientist, President and Chief Scientific Officer; and Bob Landry, Chief Financial Officer. After our prepared remarks, we will open the call for Q&A. 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, sales and expense forecasts, financial forecasts, 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-K for the year ended December 31, 2017, which will be filed with the SEC later today.

謝謝你，傑森。早安，歡迎參加 Regeneron Pharmaceuticals 2017 年第四季及全年電話會議。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。今天與我一起參加電話會議的有：創辦人、總裁兼執行長 Leonard Schleifer 博士；創始科學家、總裁兼首席科學官 George Yancopoulos 博士；以及財務長 Bob Landry。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、銷售和支出預測、財務預測、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 2017 年 12 月 31 日止年度的 10-K 表格，該表格將於今天晚些時候提交給 SEC。

Regeneron does not undertake any obligation to update publicly any forward-looking statement, whether as a result of new information, future events or otherwise. 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 at www.regeneron.com. Once our call concludes, Bob Landry and the IR team will be available to answer further questions.

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。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 www.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。

Thank you, Manisha, and good morning to everyone who has joined us on the call and webcast today. 2017 was a strong and significant year for Regeneron with important progress on clinical, commercial and regulatory fronts and solid financial results. We received regulatory approval for 2 important new drugs, Dupixent, an IL-4/IL-13 inhibitor for the treatment of moderate-to-severe atopic dermatitis; and Kevzara, an IL-6 receptor antibody for the treatment of rheumatoid arthritis. Both of these drugs have been approved in the U.S., Europe and Japan with launches underway in several countries. Our innovation engine continues to be productive. We currently have 15 product candidates in clinical development and expect to advance 4 to 6 new product candidates into the clinic this year. Our commercial pipeline and regulatory progress give us confidence that we are well positioned for sustainable long-term growth. Importantly, 2 of our product candidates, dupilumab for allergic diseases and cemiplimab for cancer, each represent a single molecule with the potential for significant opportunities across multiple diseases and are truly pipelines within a product.

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。2017 年對 Regeneron 來說是強勁且意義非凡的一年，公司在臨床、商業和監管方面取得了重要進展，並取得了穩健的財務表現。我們獲得了兩種重要新藥的監管批准，分別是用於治療中重度異位性皮膚炎的 IL-4/IL-13 抑制劑 Dupixent，以及用於治療類風濕性關節炎的 IL-6 受體抗體 Kevzara。這兩種藥物均已在美國、歐洲和日本獲得批准，目前正在多個國家上市。我們的創新引擎持續高效運轉。我們目前有 15 個產品候選藥物處於臨床開發階段，預計今年將有 4 至 6 個新的產品候選藥物進入臨床試驗階段。我們的商業產品線和監管進展讓我們有信心，我們已做好充分準備，實現可持續的長期成長。重要的是，我們的兩個候選產品，即用於治療過敏性疾病的 dupilumab 和用於治療癌症的 cemiplimab，各自代表著一種在多種疾病領域具有巨大潛力的單一分子，它們實際上是產品線中的各個環節。

Turning now to EYLEA. I would like to address the demographic trends that continue to favor EYLEA, the opportunities in diabetic eye diseases, which tend to be underdiagnosed and undertreated, an issue we plan to address, and our thoughts on some of the recent competitive developments. EYLEA has been in the market now for over 6 years in United States and despite no price increase since launch, it has continued to deliver impressive growth. EYLEA net sales grew 11% year-over-year in the U.S. and 19% year-over-year outside the U.S. Much of the recent growth in the U.S. was driven by demographic trends with an aging population as well as an overall increase in the prevalence of diabetes. These demographic trends are expected to continue in the coming years, providing an opportunity for continued growth. Focusing on diabetic eye diseases, currently, the majority of patients with diabetic eye disease are underdiagnosed and undertreated. And even when they are treated, they may not be receiving optimal anti-VEGF therapy, which in several studies, has been shown to be superior to laser therapy. Patients with diabetes are at risk for losing vision because of diseased blood vessels in the eye. Vascular leak leads to retinal swelling and vision loss or what is known as diabetic macular edema, a major indication where EYLEA is currently approved. Based upon physicians' survey data, approximately between 25% and 30% of our total EYLEA net sales in the United States come from DME. It is estimated that only 8% of patients diagnosed with DME receive treatment with an anti-VEGF agent, representing an important growth opportunity for EYLEA. The efficacy of EYLEA in DME has been proven over years in multiple studies, including those performed by independent groups. As a reminder, data from the NIH-sponsored comparative effectiveness Protocol T have demonstrated that at the end of 1 year, when the primary endpoint was assessed, EYLEA treatment resulted in significantly greater gains in visual acuity compared to both Lucentis and Avastin, particularly in those who had vision worse than 20/40. Diabetic retinopathy without diabetic macular edema, an indication we are investigating EYLEA in Phase III, is another important and attractive opportunity. About 3.5 million people in United States are diagnosed with diabetic retinopathy without diabetic macular edema. Of these, about 1 million patients have either proliferative diabetic retinopathy or severe non-proliferative diabetic retinopathy and in these patients who have the greatest unmet need and are at high risk for profound vision loss. The majority of patients with proliferative diabetic retinopathy are currently being treated with panretinal photocoagulation or laser therapy. In the CLARITY study, in patients with proliferative diabetic retinopathy, published in the Lancet, EYLEA resulted in superior visual outcomes compared to laser treatment. We anticipate in the first half of the year, top line data from our Phase III study of EYLEA in diabetic retinopathy, followed by a potential regulatory submission later this year. In addition, the DRCR.net is also conducting an independent Phase III study of EYLEA in the diabetic retinopathy indication. In addition to well-established efficacy and safety, another important aspect for physicians and patients is to have flexible dosing regimen that includes monthly dosing for those patients who may benefit from more frequent dosing as well as having the flexibility to have a longer interval between doses. EYLEA provides this important flexibility for physicians and patients and is approved for monthly as well as every other month dosing. In addition, we have submitted an sBLA for every 3-month dosing in wet AMD and expect an FDA decision in August. As a reminder, in our Phase III studies, we demonstrated that about 50% of patients could be dosed every 12 weeks. We also continue to advance our preclinical research on extended release and gene therapy approaches. We're focused on continuing to maintain our leadership position with EYLEA in the retinal space. Like you, we are well aware of emerging potential competitors for EYLEA. We will continue to execute on our long-term strategy, which includes growing the overall market, specifically in diabetic eye diseases, expanding the treatment interval options in the label and gaining approval in additional indications. We do not expect any new entrants until about the latter half of 2019. And even if approved, the first potential competitor will be limited initially to the wet AMD indication. EYLEA has set a very high bar by demonstrating efficacy and safety across a spectrum of retinal diseases, both in company-sponsored as well as independently conducted studies. The retinal community has deep experience with EYLEA, with about 8 million injections given in the United States alone since launch. There has been significant concern and debate as to whether long-term treatment with anti-VEGF agents can maintain early vision gains. For example, in a 5-year follow-up of the NIH-sponsored CAT study, comparing Lucentis and Avastin, early visual gains obtained with an anti-VEGF -- with anti-VEGF agents were not maintained over the long term. And in fact, visual acuity reported at year 5 was below baseline levels prior to treatment, and patients had lost on average over 3 letters compared to their original baseline and 20% of patients had progressed to become legally blind. Some have raised theoretical concerns that chronic VEGF inhibition in the eye might result in deleterious effect, such as geographic atrophy. But in contrast to the observation with intraocular Lucentis and Avastin in CAT and the theoretical concerns about chronic VEGF inhibition, we have shown that chronic regular treatment with EYLEA results in visual gains that were maintained through 4 years of follow-up. At the upcoming angiogenesis meeting at the Bascom Palmer Institute, real-world data on visual acuity outcomes following treatment with intravitreal anti-VEGF agents will address the issue of whether underdosing is contributing to poor visual outcomes over the long term. As a reminder, a variety of retinal diseases are treated by the same specialist, who can choose which buy and build products they want to use in their practice. We believe the extensive data, combined with real-world experience, broad label and treatment flexibility offered by EYLEA will make it an attractive treatment option for years to come. It will be quite a while before any emerging competitor can come close to matching the breadth of approved indications and the depth of long-term experience offered by EYLEA. Two potential competitive programs you may have been hearing about are a bispecific Ang-2 and VEGF antibody and a single-chain antibody fragment VEGF inhibitor. And many of our investors have asked for our thoughts on the competitive threats they pose. Both of these are studying higher molar concentrations of their drugs compared to the currently approved anti-VEGF drugs, with the primary goal of increasing visual acuity and/or extending the interval between injections. For example, the doses being investigated with the bispecific RG7716 are between 2x to 7x the molar concentration of the Lucentis comparator in the trial. The single-chain antibody fragment, brolucizumab, also known as RTH258, studied doses that were up to 12x the molar concentration of EYLEA. Despite this 12-fold increase in molar dose in both Phase III studies, the high dose of brolucizumab did not demonstrate superiority to EYLEA in terms of visual acuity, nor did it consistently extend the dosage interval to 12 weeks in all patients, as almost half the patients failed quarterly treatments and had to be returned to more frequent dosing. Brolucizumab demonstrated statistical noninferiority to EYLEA on vision in both studies. It was, however, slightly numerically, albeit not statistically, inferior to EYLEA on vision in both studies. There is a known potential risk of arterial thromboembolic events following the intravitreal use of VEGF inhibitors, as stated in our label as well as the Lucentis label. The Lucentis label additionally states that fatal events occur more frequently in patients with diabetic macular edema and diabetic retinopathy at baseline, who were treated with monthly Lucentis. Therefore, given the high molar doses studied by both potential competitors, it will be important to see the assessment by regulatory authorities regarding the balance of safety and efficacy that these new agents might provide, particularly in the elderly and in diabetics before we are able to evaluate the extent of competitive risk to EYLEA.

接下來是愛立信。我想談談持續有利於 EYLEA 的人口趨勢、糖尿病眼疾領域的機會（這些疾病往往診斷不足且治療不足，這是我們計劃解決的問題），以及我們對近期一些競爭發展的看法。EYLEA 在美國市場已經上市超過 6 年，儘管自上市以來價格沒有上漲，但其銷售仍持續成長，令人矚目。EYLEA在美國的淨銷售額較去年同期成長11%，在美國以外地區的淨銷售額較去年同期成長19%。近期美國市場的成長主要受人口老化以及糖尿病盛行率整體上升等人口趨勢的推動。預計這些人口趨勢將在未來幾年持續下去，為持續成長提供機會。目前，糖尿病眼疾患者中絕大多數未得到診斷和治療。即使接受治療，他們可能沒有接受最佳的抗 VEGF 療法，而多項研究表明，抗 VEGF 療法優於雷射療法。糖尿病患者由於眼部血管病變，有失明的風險。血管滲漏會導致視網膜腫脹和視力喪失，也就是所謂的糖尿病黃斑水腫，這是 EYLEA 目前核准的主要適應症。根據醫生調查數據，我們在美國 EYLEA 總淨銷售額中約有 25% 至 30% 來自 DME。據估計，只有 8% 的 DME 患者接受了抗 VEGF 藥物治療，這對 EYLEA 來說是一個重要的成長機會。多年來，多項研究（包括獨立研究小組進行的研究）已經證明 EYLEA 對 DME 的療效。提醒一下，美國國立衛生研究院資助的比較療效方案 T 的數據顯示，在 1 年結束時，當評估主要終點時，與 Lucentis 和 Avastin 相比，EYLEA 治療顯著提高了視力，尤其是在視力低於 20/40 的患者中。糖尿病視網膜病變（不伴隨糖尿病黃斑水腫）是另一個重要且有吸引力的機會，我們正在對 EYLEA 進行 III 期臨床試驗以研究此適應症。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。其中約有 100 萬名患者患有增殖性糖尿病視網膜病變或嚴重的非增殖性糖尿病視網膜病變，這些患者的需求未被滿足，並且面臨嚴重的視力喪失風險。目前大多數增殖性糖尿病視網膜病變患者正在接受全視網膜光凝固或雷射治療。在《柳葉刀》雜誌發表的 CLARITY 研究中，對於患有增殖性糖尿病視網膜病變的患者，EYLEA 治療取得了比雷射治療更優異的視覺效果。我們預計今年上半年將公佈 EYLEA 治療糖尿病視網膜病變的 III 期研究的主要數據，隨後可能會在今年稍後向監管機構提交申請。此外，DRCR.net 也正在進行一項針對糖尿病視網膜病變適應症的 EYLEA 獨立 III 期研究。除了療效和安全性已得到充分證實外，對於醫生和患者而言，另一個重要的方面是靈活的給藥方案，包括每月一次的給藥方案（適用於可能受益於更頻繁給藥的患者），以及延長兩次給藥間隔的靈活性。EYLEA 為醫生和患者提供了這種重要的靈活性，並獲準每月給藥一次，以及每隔一個月給藥一次。此外，我們已針對濕性 AMD 的每 3 個月給藥方案提交了補充生物製品許可申請 (sBLA)，並預計 FDA 將於 8 月做出決定。提醒一下，在我們的 III 期研究中，我們證明大約 50% 的患者可以每 12 週接受一次給藥。我們也持續推進緩釋和基因治療方法的臨床前研究。我們致力於繼續保持與EYLEA在視網膜領域的領先地位。和您一樣，我們也清楚意識到安樂死可能面臨的新興競爭對手。我們將繼續執行我們的長期策略，其中包括擴大整體市場，特別是糖尿病眼疾市場，擴大標籤中的治療間隔選擇，以及獲得其他適應症的批准。我們預計在 2019 年下半年之前不會有新的參與者。即使獲得批准，第一個潛在的競爭對手最初將僅限於濕性 AMD 適應症。EYLEA 透過在公司贊助的研究和獨立進行的研究中證明其對多種視網膜疾病的療效和安全性，樹立了非常高的標準。視網膜領域對 EYLEA 有著豐富的經驗，自上市以來，光是在美國就已進行了約 800 萬次注射。長期使用抗 VEGF 藥物治療能否維持早期視力改善效果，一直備受關注且爭論。例如，在 NIH 資助的 CAT 研究的 5 年追蹤中，比較了 Lucentis 和 Avastin，使用抗 VEGF 藥物獲得的早期視力改善未能長期維持。事實上，第 5 年報告的視力低於治療前的基線水平，患者平均比最初的基線水平下降了 3 個字母以上，20% 的患者發展為法定盲人。有人提出了理論上的擔憂，認為長期抑制眼部 VEGF 可能會導致有害影響，例如地圖狀萎縮。但與 CAT 中使用眼內注射 Lucentis 和 Avastin 的觀察結果以及對慢性 VEGF 抑制的理論擔憂相反，我們已經證明，長期規律地使用 EYLEA 治療可獲得視力改善，並且在 4 年的隨訪期內得以維持。在即將於巴斯康帕爾默研究所舉行的血管生成會議上，玻璃體內注射抗 VEGF 藥物治療後視力結果的真實世界數據將探討劑量不足是否會導致長期視力結果不佳的問題。需要提醒的是，同一位專家可以治療多種視網膜疾病，他可以選擇在診療過程中使用哪些購買和製造的產品。我們相信，EYLEA 豐富的臨床數據、真實的臨床經驗、廣泛的適應症和靈活的治療方案，將使其在未來幾年內成為一種有吸引力的治療選擇。任何新興競爭對手想要在核准適應症的廣度和長期經驗的深度上與安永公司匹敵，還需要相當長的時間。您可能聽說過的兩個潛在的競爭項目是雙特異性 Ang-2 和 VEGF 抗體和單鏈抗體片段 VEGF 抑制劑。許多投資者都詢問我們對他們所構成的競爭威脅的看法。這兩種藥物都在研究比目前已核准的抗 VEGF 藥物更高的摩爾濃度，其主要目標是提高視力和/或延長注射間隔。例如，正在研究的雙特異性 RG7716 的劑量是試驗中 Lucentis 對照藥物摩爾濃度的 2 倍至 7 倍。單股抗體片段 brolucizumab（又稱 RTH258）的研究劑量高達 EYLEA 摩爾濃度的 12 倍。儘管在兩項 III 期研究中摩爾劑量增加了 12 倍，但高劑量 brolucizumab 在視力方面並未顯示出優於 EYLEA 的效果，也未能始終如一地將所有患者的給藥間隔延長至 12 週，因為幾乎一半的患者每季度治療失敗，不得不恢復到更頻繁的給藥。兩項研究均表明，Brolucizumab 在視力方面具有統計上的非劣效性，不遜於 EYLEA。然而，儘管在統計上沒有顯著差異，但在兩項研究中，它在視覺方面都略遜於 EYLEA。已知玻璃體內注射 VEGF 抑制劑後有動脈血栓栓塞事件的潛在風險，如我們的標籤以及 Lucentis 標籤中所述。Lucentis 的標籤也指出，對於基線患有糖尿病性黃斑水腫和糖尿病性視網膜病變的患者，每月接受 Lucentis 治療後，致命事件的發生率更高。因此，鑑於兩個潛在競爭對手研究的高摩爾劑量，在評估 EYLEA 面臨的競爭風險程度之前，監管機構對這些新藥可能提供的安全性和有效性平衡（尤其是在老年人和糖尿病患者中）的評估將非常重要。

Turning to Dupixent, our drug for the treatment of moderate-to-severe atopic dermatitis continues to gain momentum in the ongoing launch. Global fourth quarter net sales of Dupixent were $139 million, representing a 56% increase compared to the third quarter of 2017. Apart from a dip in the early part of the year due to the holidays and required reauthorizations at the beginning of the year, we are continuing to see a strong weekly number of approximately 500 new-to-brand scripts as tracked by the NBRx number. The prescriber number has increased to over 8,500 and the first renewal rate remains high at above 90%. The feedback from physicians and patients continues to be positive about the efficacy and safety of the product, although we are hearing some frustrations about the processes that payers have put in place in order to get the prescription approved even where formulary decisions have been made. We and our collaborator, Sanofi, are working to ensure that eligible patients have fair access to this important breakthrough medication. Our market research indicates that some health care providers are prescribing Dupixent to their most severe patients, which suggest there is significant continued growth potential. We continue to work on raising patient awareness and on educating patients and health care providers about new treatment options as well as working on improving access. The launch of Dupixent outside the United States is underway, with the drug now approved in several European countries and in Europe -- and in Japan. The emerging clinical data with dupilumab strengthen our belief that the IL-4/13 pathway is a key driver of several allergic or type-2 diseases. We have recently submitted a supplemental BLA for dupilumab in the uncontrolled asthma setting and expect a regulatory decision in the second half of this year. George will provide you with an update on the ongoing development programs with dupilumab in several indications. We, along with our collaborator, Sanofi, have recently increased our financial commitment to these programs in an effort to accelerate and expand the dupilumab in IL-33 antibody programs. Bob will address the details of the financial agreement. The launch of Kevzara for the treatment of rheumatoid arthritis is underway in United States as well as in countries outside the U.S. On the access front in the U.S., we have payer contracts that took effect at the beginning of the year with some offering favorable positioning and market access to Kevzara. Outside the U.S., the drug continues to receive favorable reimbursement reviews and country-specific launches are underway.

再來看看用於治療中重度異位性皮膚炎的藥物 Dupixent，該藥物在持續的上市過程中不斷獲得成功。Dupixent 第四季全球淨銷售額為 1.39 億美元，比 2017 年第三季成長 56%。除了年初因假期和年初需要重新授權而導致的下滑外，根據 NBRx 數據，我們繼續看到每週約有 500 個新品牌處方保持強勁增長。處方醫師人數已增加至 8,500 多人，首次續約率仍維持在 90% 以上。儘管我們聽到一些關於支付方為批准處方而製定的流程（即使在已做出處方集決定的情況下）的抱怨，但醫生和患者的反饋仍然對該產品的效果和安全性持積極態度。我們和我們的合作夥伴賽諾菲正在努力確保符合條件的患者能夠公平地獲得這種重要的突破性藥物。我們的市場調查顯示，一些醫療保健提供者正在給病情最嚴重的患者開立 Dupixent 處方，這表明該藥物具有巨大的持續成長潛力。我們將繼續努力提高患者的意識，教育患者和醫療保健提供者了解新的治療方案，並努力改善醫療服務的可近性。Dupixent 在美國以外地區的上市工作正在進行中，該藥物目前已在幾個歐洲國家和歐洲以及日本獲得批准。dupilumab 的最新臨床數據強化了我們對 IL-4/13 路徑是多種過敏性疾病或 2 型疾病的關鍵驅動因素的信念。我們最近提交了度普利尤單抗用於治療未控制氣喘的補充生物製品許可申請，​​預計將在今年下半年獲得監管部門的決定。George 將向您介紹 dupilumab 在多種適應症方面的最新研發進展。我們與合作夥伴賽諾菲最近增加了對這些項目的資金投入，以期加速和擴大度普利尤單抗在 IL-33 抗體項目中的應用。鮑伯將負責處理財務協議的細節。Kevzara 用於治療類風濕性關節炎的上市計劃已在美國以及美國以外的國家展開。在美國，我們在年初與一些支付方簽訂了合同，其中一些合約為 Kevzara 提供了有利的市場地位和准入條件。在美國以外，該藥物繼續獲得良好的報銷審查，並且正在針對特定國家/地區推出。

Turning now to Praluent. We will be presenting data from the 18,000-patient ODYSSEY cardiovascular OUTCOMES study on March 10 at the meeting of the American College of Cardiology. To be clear, the study has not yet been unblinded. We believe that the PCSK9 inhibitor class holds tremendous promise despite the slow initial uptake and we look forward to providing you with additional information after the OUTCOMES data become available. 2018 will be an important year for Regeneron with several significant events anticipated, including 2 new potential approvals, dupilumab in asthma and cemiplimab, a PD-1 antibody, in advanced cutaneous squamous cell carcinoma, which will mark our entry into the exciting and rapidly evolving field of immuno-oncology. We anticipate completion of the cemiplimab BLA submission in the first quarter and are preparing for the launch. While our initial indication will be advanced cutaneous squamous cell carcinoma, additional studies are either underway or planned in several other indications, including first and second line non-small cell lung cancer and cervical cancer. As recently announced, we, along with our collaborator, Sanofi, have increased our investment in immuno-oncology, with the aim of advancing and accelerating these important programs. On the corporate front, we have recruited a new Head of Commercial, who will be joining us later in the quarter.

現在轉向Praluent。我們將於 3 月 10 日在美國心臟學會會議上公佈 ODYSSEY 心血管結果研究（涉及 18,000 名患者）的數據。需要說明的是，研究尚未揭盲。儘管 PCSK9 抑制劑類藥物最初推廣緩慢，但我們相信它具有巨大的發展前景，我們期待在 OUTCOMES 數據公佈後向您提供更多資訊。2018 年對 Regeneron 來說將是重要的一年，預計將發生幾件重大事件，包括兩項新的潛在批准：用於治療氣喘的 dupilumab 和用於治療晚期皮膚鱗狀細胞癌的 PD-1 抗體 cemiplimab，這將標誌著我們進入令人興奮且快速發展的免疫腫瘤學領域。我們預計將在第一季完成 cemiplimab 生物製品許可申請的提交，並正在為上市做準備。雖然我們最初的適應症是晚期皮膚鱗狀細胞癌，但針對其他幾種適應症，包括一線和二線非小細胞肺癌和子宮頸癌，其他研究正在進行或計劃中。正如最近宣布的那樣，我們與合作夥伴賽諾菲一起增加了對免疫腫瘤學的投資，目的是推進和加速這些重要項目。公司方面，我們招募了一位新的商務主管，他將於本季稍後加入我們。

With that, I would now like to turn the call over to George.

接下來，我想把電話交給喬治。

Thank you, Len, and a very good morning to everyone who has joined us today. As Len mentioned, 2018 is shaping up to be a very busy and important year for Regeneron. I'd like to begin with Dupixent in atopic dermatitis, where the drug is currently approved for use in adult patients. However, there is an unmet need in pediatric atopic dermatitis patients, where the current treatment options are limited. We're conducting 3 Phase III studies in atopic dermatitis in children between the ages of 6 months and 17 years. The first of these, in children between the ages of 12 and 17 years is fully enrolled, and we expect to report data by mid-year in -- mid -- supplemental BLA in the United States in the second half of the year. In asthma, we have reported positive data from 3 separate pivotal studies of dupilumab, with profound benefits on the 2 major endpoints of exacerbation and improvement in lung function, as measured by FEV1. These improvements were observed in the overall population and were even more pronounced in the patient population with a more allergic phenotype as defined by biomarkers, such as eosinophils, corresponding to approximately half of the patients in these studies. One of our pivotal studies was conducted in a severe patient population that was dependent on oral steroids. In this severe population, patients treated with dupilumab saw a significant reduction in their exacerbations as well as improvements in their lung function. These findings were even more striking since more than half the patients in this study were able to completely eliminate their use of oral steroids. We, along with our collaborator, Sanofi, have submitted a supplemental BMA (sic) [BLA] in -- as an indication and look forward to a regulatory decision in the second half of the year.

謝謝Len，也祝今天到場的各位早安。正如 Len 所提到的，2018 年對 Regeneron 來說將是非常忙碌和重要的一年。我想先談談 Dupixent 在異位性皮膚炎中的應用，該藥物目前已獲準用於治療成人患者。然而，目前兒童異位性皮膚炎患者的治療選擇有限，且有未被滿足的需求。我們正在對 6 個月至 17 歲兒童的異位性皮膚炎進行 3 項 III 期研究。第一項研究針對 12 至 17 歲的兒童，目前已全部招募完畢，我們預計將在今年年中公佈數據——下半年將在美國進行補充生物製品評估 (BLA)。在氣喘治療方面，我們報告了3項獨立的關鍵性dupilumab研究的積極數據，在FEV1測量的肺功能改善和病情加重這兩個主要終點方面均取得了顯著療效。這些改善在整體人群中均有觀察到，並且在具有更明顯的過敏表型（由嗜酸性粒細胞等生物標誌物定義）的患者群體中更為明顯，這些患者約佔這些研究患者的一半。我們的一項關鍵研究是在依賴口服類固醇的重症患者群體中進行的。在這群重症患者中，接受度普利尤單抗治療的患者病情加重次數顯著減少，肺功能也得到改善。這些發現更加引人注目，因為這項研究中超過一半的患者能夠完全停止使用口服類固醇。我們與合作方賽諾菲已提交補充生物製品許可申請（BLA），作為一項適應症，並期待在今年下半年獲得監管部門的決定。

A Phase III study of dupilumab in pediatric asthma patients, between the ages of 6 and 11 years, is ongoing. We have compelling Phase II data for the use of dupilumab in other allergic indications as well, including nasal polyps and eosinophilic esophagitis, and have scientific rationale to believe that dupilumab could be used in several additional indications, including food and inhaled allergies. Two Phase III studies of dupilumab in nasal polyps are now fully enrolled and we expect top line data at the end of the year. A positive Phase II data in eosinophilic esophagitis was believed to result from unidentified food allergies, bolsters our belief that dupilumab has the potential to be used in food allergies themselves. This is further supported by our preclinical models, which have shown that dupilumab accelerates and improves desensitization to food allergies. Our first study in people with food allergy will be with peanuts and conducted in collaboration with Immune Therapeutics. We expect to initiate this Phase II study in the second half of the year. We also expect to initiate a Phase II study of dupilumab for desensitization of patients with allergies to airborne allergens later this year. One of the most exciting opportunities and benefits that dupilumab can provide to patients is that it may be able to simultaneously address multiple manifestations of allergic disease in the same patient. As has been widely appreciated previously, and as confirmed in many of our own studies, patients suffering from one allergic disease often suffer from another. For example, in our atopic dermatitis program, about 40% of the patients had asthma and up to 50% of the patients had allergic rhinitis. In the initial attempts to explore such opportunities in allergic patients, we recently reported in the Journal of Allergy and Clinical Immunology that dupilumab significantly improved allergic rhinitis associated nasal symptoms in patients with uncontrolled persistent asthma. Regeneron 3500, our antibody to the interleukin-33 ligand, is an exciting program that we believe has the potential, both on its own as well as in combination with dupilumab to bring benefit to patients. Research performed by our Regeneron Genetics Center team has provided genetic validation for interleukin-33 as a strong target. For example, there are common gain of function variants in interleukin-33 that increase the risk of asthma, while loss of function mutations conversely decrease the risk. Preclinical data that we have generated has shown that IL-33 could work in a manner that's complementary to dupilumab. We're currently planning studies of this IL-33 antibody in asthma, COPD and atopic dermatitis.

一項針對 6 至 11 歲兒童氣喘患者的 dupilumab III 期研究正在進行中。我們擁有令人信服的 II 期數據，證明 dupilumab 可用於治療其他過敏性疾病，包括鼻息肉和嗜酸性食道炎，並且有科學依據相信 dupilumab 可用於治療其他幾種疾病，包括食物過敏和吸入性過敏。兩項針對鼻息肉的度普利尤單抗 III 期研究現已全部完成入組，我們預計在年底獲得初步數據。嗜酸性食道炎的 II 期積極數據被認為是未識別的食物過敏所致，這增強了我們對 dupilumab 有潛力用於治療食物過敏本身的信念。我們的臨床前模型也進一步支持了這一點，這些模型表明，度普利尤單抗可以加速和改善對食物過敏的脫敏作用。我們將首次對食物過敏患者進行研究，研究對象為花生，並將與 Immune Therapeutics 公司合作進行。我們預計今年下半年啟動這項二期臨床試驗。我們還計劃在今年稍後啟動 dupilumab 的 II 期研究，用於治療對空氣傳播過敏原過敏的患者。dupilumab 能為患者帶來的最令人興奮的機會和益處之一是，它可能能夠同時解決同一患者的多種過敏性疾病表現。正如先前人們普遍認識到的，也正如我們自己的許多研究證實的那樣，患有一種過敏性疾病的患者往往會患上另一種過敏性疾病。例如，在我們進行的異位性皮膚炎治療計畫中，約有 40% 的患者患有氣喘，高達 50% 的患者患有過敏性鼻炎。在最初探索此類機會的過敏患者中，我們最近在《過敏與臨床免疫學雜誌》上報道，度普利尤單抗顯著改善了未控制的持續性氣喘患者的過敏性鼻炎相關鼻症狀。Regeneron 3500 是我們針對白細胞介素-33 配體的抗體，這是一個令人興奮的項目，我們相信它本身以及與 dupilumab 聯合使用都有潛力為患者帶來益處。我們 Regeneron 遺傳學中心團隊進行的研究已從遺傳學角度證實白細胞介素-33 是一個強有力的標靶。例如，白細胞介素-33 中常見的獲得功能變異會增加氣喘的風險，而失去功能突變則會降低氣喘的風險。我們獲得的臨床前數據顯示，IL-33 可以以與 dupilumab 互補的方式發揮作用。我們目前正計劃進行針對氣喘、慢性阻塞性肺病和異位性皮膚炎的IL-33抗體研究。

I'd like to turn now to immuno-oncology, which continues to be one of the most exciting areas of development for us, where we have adopted a multipronged approach encompassing checkpoint inhibitors, such as cemiplimab, our PD-1 antibody, bispecific antibodies as well as other modalities. Having multiple approaches available under one roof will give us the flexibility and nimbleness to explore the use of combination therapies. We've used cemiplimab as the foundational therapy upon which we will build additional combinations in a thoughtful and logical manner. Our recent positive study with cemiplimab in patients with advanced cutaneous squamous cell carcinoma, most of whom had failed surgery and multiple lines of prior therapies, demonstrated an impressive response rate of 46%, which is among the highest observed to date with a PD-1 targeting agent in solid tumors. Importantly, a majority of the responses were durable. The safety profile observed has been generally consistent with this class. Based on these data, we expect to complete our regulatory submission to the FDA by the end of the first quarter, with the European union submission expected in the first half. Cemiplimab has been granted breakthrough designation status by the FDA for cutaneous squamous cell carcinoma. Because of the intense activity in the PD-1 -- PD-L1 space with over 1,000 ongoing clinical studies, many were surprised that we were able to identify an important unmet medical need setting that yielded such robust demonstration of activity and which has provided us with a fast to market opportunity. To be clear, we view cutaneous squamous cell carcinoma as a significant and important opportunity on its own. However, and just as importantly, this cancer setting allowed us to obtain a foothold into the arena of immuno-oncology and we hope will establish cemiplimab as a foundation for our future combination approaches. We're also making significant progress with cemiplimab in our other indications, such as first and second line non-small cell lung cancer and several other settings where we either have ongoing or planned studies. We're exploring the use of cemiplimab both as monotherapy and also in combination with other molecules, such as our own additional checkpoint inhibitors, immunomodulators, such as CD-38 and multiple vaccines approaches and perhaps the most interestingly in combination with molecules coming from a bispecific platform. Speaking of a bispecific technology, we think you can offer opportunities related to those seen with cell-based therapy, such as the CAR-T approaches. We believe if our BioSpecifics can approach the level activity seen with the CAR-T, there is a production administration, which is more akin to that of traditional biologics might provide a major advance for patients. Our lead program here, CD20-CD3 bispecific continues to advance in the clinic. After careful dose escalation process to mitigate the side effects of cytokine release syndrome, we've recently reported dosing levels that have achieved 50% response rates without any dose-limiting toxicity, and we continued dose escalation. We are encouraged by the activity that we are observing at these higher dose levels and look forward to reporting these data as they mature at a future meeting. We expect to move 2 additional CD3 bispecific candidates into the clinic this year, the bispecific antibody to MAC16 and another to BCMA. Fasinumab, our Phase III NGF antibody program for pain, continues to advance in the clinic with Phase III studies in osteoarthritis and chronic lower back pain. We don't have time to discuss all of our early-stage programs or the additional candidates that we plan to advance into clinical development this year. However, one early-stage program that I would like to highlight is the combination of our Activin A and GDF8 antibodies. Regeneron scientists made the discovery that Activin A might be as, if not more, important in GDF8, also known as myostatin for controlling muscle mass in primates. Consistent with this, we recently announced that a combination of Activin A and GDF8 antibodies resulted in dose-dependent increases in muscle volume of up to 8% after a single dose in normal healthy volunteers with an acceptable safety profile. We're expecting to commence follow-up clinical studies of this combination. As a reminder, we're also studying our Activin A antibody alone as monotherapy in the ultra orphan disease, fibrodysplasia ossificans progressiva, or FOP.

現在我想談談免疫腫瘤學，這仍然是我們最令人興奮的發展領域之一，我們採用了多管齊下的方法，包括檢查點抑制劑（如cemiplimab）、我們的PD-1抗體、雙特異性抗體以及其他療法。在同一屋簷下擁有多種治療方法，將使我們有靈活性和敏捷性去探索聯合療法的應用。我們以cemiplimab為基礎療法，在此基礎上，我們將以深思熟慮和合乎邏輯的方式構建其他聯合療法。我們最近對晚期皮膚鱗狀細胞癌患者進行的 cemiplimab 研究取得了積極成果，這些患者大多接受過手術和多種先前的治療，但均告失敗。研究顯示，cemiplimab 的有效率高達 46%，這是迄今為止在實體瘤中使用 PD-1 標靶藥物觀察到的最高有效率之一。重要的是，大多數回饋都具有持久性。觀察到的安全性能與此類產品基本一致。根據這些數據，我們預計將在第一季末完成向美國食品藥物管理局 (FDA) 的監管申報，並預計在上半年完成向歐盟的申報。Cemiplimab 已被 FDA 授予治療皮膚鱗狀細胞癌的突破性療法認定。由於 PD-1 至 PD-L1 領域非常活躍，有超過 1000 項正在進行的臨床研究，因此，我們能夠找到一個重要的未滿足的醫療需求領域，並取得如此強勁的療效，這讓我們感到非常驚訝，也為我們提供了快速上市的機會。需要明確的是，我們認為皮膚鱗狀細胞癌本身就是一個重要且意義重大的機會。然而，同樣重要的是，這種癌症治療環境讓我們得以進入免疫腫瘤學領域，我們希望將 cemiplimab 確立為我們未來聯合治療方案的基礎。我們在其他適應症方面也取得了顯著進展，例如一線和二線非小細胞肺癌以及其他一些我們正在進行或計劃進行研究的領域。我們正在探索 cemiplimab 的單藥療法以及與其他分子（例如我們自己的其他檢查點抑制劑、免疫調節劑（如 CD-38）和多種疫苗方法）聯合使用，或許最有趣的是與來自雙特異性平台的分子聯合使用。說到雙特異性技術，我們認為它可以提供與細胞療法（例如 CAR-T 療法）相關的機會。我們相信，如果我們的生物特異性療法能夠達到 CAR-T 療法的活性水平，那麼其生產管理方式將更類似於傳統生物製劑，這可能會為患者帶來重大進步。我們的主要項目 CD20-CD3 雙特異性抗體在臨床試驗中持續取得進展。經過仔細的劑量遞增過程以減輕細胞因子釋放綜合徵的副作用後，我們最近報告了劑量水平，在沒有任何劑量限制性毒性的情況下達到了 50% 的反應率，我們繼續進行劑量遞增。我們對在高劑量水平下觀察到的活性感到鼓舞，並期待在未來的會議上報告這些數據。我們預計今年將另外 2 種 CD3 雙特異性候選藥物推進臨床試驗，分別是針對 MAC16 的雙特異性抗體和針對 BCMA 的雙特異性抗體。Fasinumab 是我們用於治療疼痛的 III 期 NGF 抗體項目，目前正處於臨床階段，正在進行骨關節炎和慢性下背痛的 III 期研究。我們沒有時間討論我們所有的早期項目，也沒有時間討論我們計劃今年推進臨床開發的其他候選藥物。不過，我想重點介紹一下我們早期階段的一個項目，那就是將我們的 Activin A 和 GDF8 抗體結合起來。再生元公司的科學家發現，Activin A 在 GDF8（也稱為肌肉生長抑制素）中可能同樣重要，甚至更重要，它能夠控制靈長類動物的肌肉質量。與此相符的是，我們最近宣布，Activin A 和 GDF8 抗體的組合在正常健康志願者單次給藥後，可使肌肉體積增加高達 8%，且具有可接受的安全性。我們預計將開始對該組合療法進行後續臨床研究。提醒大家，我們也正在研究我們的 Activin A 抗體單獨作為單藥療法治療罕見疾病進行性骨化性纖維發育不良症（FOP）。

Lastly, I want to take a moment to comment on our recently announced consortium of biopharma companies to help fund (inaudible) 500,000 individuals in the United Kingdom Biobank. The Regeneron Genetics Center expects to carry on and complete this work by the end of next year, providing a near-term treasure trove of genetic insights coupled with clinical imaging and other rich phenotype data, which is available in the UK Biobank. Importantly, these results will be made available publicly, providing the first such Big Data Research -- Resource that all researchers worldwide will have access to. Many believe that this will serve as a great accelerant for both academic and biopharma research. We think it makes a great statement that so many from the biopharma community have stepped forward to help co-fund this effort, including AbbVie, Alnylam, AstraZeneca, Biogen and Pfizer.

最後，我想花一點時間談談我們最近宣布的生物製藥公司聯盟，該聯盟旨在幫助資助（聽不清楚）英國生物銀行的 50 萬名個體。再生元遺傳學中心預計將於明年年底前完成這項工作，屆時將提供豐富的遺傳學見解，以及臨床影像和其他豐富的表型數據，這些數據均可在英國生物銀行中找到。重要的是，這些結果將公開發布，提供首個全球所有研究人員都可以存取的大數據研究資源。許多人認為這將極大地促進學術研究和生物製藥研究的發展。我們認為，包括艾伯維、Alnylam、阿斯特捷利康、百健和輝瑞在內的眾多生物製藥界人士挺身而出，共同資助這項工作，這本身就是一個很好的例子。

And with that, I would like to turn the call over to Bob Landry.

接下來，我將把電話交給鮑伯·蘭德里。

Thank you, George, and good morning, everyone. Regeneron posted strong fourth quarter 2017 financial results. We finished the year with continued sequential growth within our global EYLEA franchise, positive momentum with our U.S. Dupixent launch, the execution of several business development transactions and expanded funding for cemiplimab and dupilumab under our Sanofi collaboration. In the fourth quarter of 2017, we earned $5.23 per diluted share from non-GAAP net income of $607 million. For the full year 2017, we earned $16.32 per diluted share from non-GAAP net income of $1.9 billion. This represents a year-over-year increase in non-GAAP diluted EPS and net income of 72% for the fourth quarter and a year-over-year increase of 44% in non-GAAP diluted EPS and net income for the full year of 2017. Regeneron's fourth quarter 2017 non-GAAP net income excludes noncash share-based compensation expense, the $25 million upfront payment made in connection with our agreement with Decibel Therapeutics, the income tax effect of non-GAAP reconciling items in a one-time provisional charge related to enactment of the Tax Cuts and Job Act. A full reconciliation of GAAP to non-GAAP earnings is set forth in our earnings release, which can be found on our website. Total revenues in the fourth quarter of 2017 were $1.58 billion and $5.87 billion for the full year 2017, which represented year-over-year growth of 29% for the 3 months ended December 31, 2017, and 21% for the full year of 2017. EYLEA net product sales in the United States were $975 million in the fourth quarter 2017 and $3.7 billion for the full year 2017, compared to $858 million in the fourth quarter of 2016 and $3.32 billion for the full year 2016, which represents an increase of 14% and 11%, respectively. U.S. EYLEA distributor inventory experienced a slight increase as compared to the third quarter of 2017, yet remained within our normal 1- to 2-week targeted range. Ex-U. S. EYLEA net product sales, which are recorded by our collaborator, Bayer, were $637 million in the fourth quarter of 2017, representing a 28% increase over the fourth quarter of 2016 on a reported basis and 23% on a constant currency basis. For the full year 2017, global EYLEA net product sales were nearly $6 billion. In the fourth quarter of 2017, Regeneron recognized $231 million from our share of net profits from EYLEA sales outside the United States and $802 million for the full year 2017. Total Bayer collaboration revenue for the fourth quarter of 2017 was $297 million and $938 million for the full year 2017. In the fourth quarter of 2017, the company reported that the results from 2 Phase II studies of EYLEA in combination with nesvacumab, an antibody to Ang-2, did not provide sufficient differentiation to warrant Phase III development. Consequently, Bayer collaboration revenue in the fourth quarter of 2017 includes $37 million of revenue related to the acceleration of the recognition of deferred revenue from the upfront payment previously received from Bayer. Total Sanofi collaboration revenue was $200 million for the fourth quarter of 2017 and $877 million for the full year 2017. The 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 antibody and immuno-oncology upfront payments, partly offset by our share of losses in connection with the commercialization of antibodies. Global sales of Dupixent, Praluent and Kevzara, as recorded by our collaborator, Sanofi, for the fourth quarter of 2017 were: Dupixent, $139 million; Praluent, $63 million; and Kevzara, $9 million. For both Dupixent and Kevzara, the sales were almost exclusively U.S. based. Despite higher Dupixent and Praluent sales in the fourth quarter of 2017, our share of losses in connection with commercialization of Dupixent, Praluent and Kevzara was $114 million compared to a loss of $126 million in the fourth quarter of 2016. As a reminder, we anticipated a higher alliance loss in connection with the commercialization of antibodies in the fourth quarter of 2017 versus the third quarter as the alliance's profitability was negatively impacted this quarter by increased global launches to support Kevzara and Dupixent. Regeneron's share of losses in connection with the commercialization of antibodies for the full year 2017 was $443 million as compared to losses of $459 million for the full year 2016. The fourth quarter 2017 Sanofi collaboration revenue did benefit from an acceleration of the recognition of deferred revenue in connection with the termination of the antibody discovery agreement on December 31, 2017. However, as mentioned during last quarter's call, the $130 million of 2017 annual funding from Sanofi under the antibody discovery agreement was fully utilized during the first 9 months of 2017, which attributed to the lower reimbursement of Regeneron R&D expenses realized this quarter as compared to the first 3 quarters of 2017. In the fourth quarter of 2017, other revenue was $107 million versus $52 million during the fourth quarter of 2016. This increase was primarily due to the reimbursements from our collaborator, Teva, for the development of fasinumab, along with a $35 million fasinumab development milestone the company earned and recognized into revenue. For further details, you can find a summary of the full year components of other revenue in the MD&A section of our 10-K, which will be filed later today.

謝謝你，喬治，大家早安。再生元公司公佈了2017年第四季強勁的財務業績。今年年底，我們的全球 EYLEA 業務持續成長，美國 Dupixent 上市勢頭良好，完成了多項業務發展交易，並擴大了與賽諾菲合作的 cemiplimab 和 dupilumab 的資金。2017 年第四季度，我們實現非 GAAP 淨利 6.07 億美元，每股攤薄收益為 5.23 美元。2017 年全年，我們每股攤薄收益為 16.32 美元，非 GAAP 淨收入為 19 億美元。這意味著第四季非GAAP稀釋後每股盈餘和淨收入年增72%，2017年全年非GAAP稀釋後每股盈餘和淨收入年增44%。Regeneron 2017 年第四季非 GAAP 淨收入不包括非現金股份支付費用、與 Decibel Therapeutics 達成協議而支付的 2500 萬美元預付款、與《減稅與就業法案》頒布相關的非 GAAP 調整項目的一次性暫定費用的所得稅影響。我們的獲利報告中列出了 GAAP 與非 GAAP 收益的完整調整表，該報告可在我們的網站上找到。2017 年第四季總營收為 15.8 億美元，2017 年全年總營收為 58.7 億美元，截至 2017 年 12 月 31 日的三個月年成長 29%，2017 年全年年增 21%。2017 年第四季，EYLEA 在美國的淨產品銷售額為 9.75 億美元，2017 年全年為 37 億美元，而 2016 年第四季為 8.58 億美元，2016 年全年為 33.2 億美元，分別成長了 14% 和 11%。與 2017 年第三季相比，美國 EYLEA 經銷商的庫存略有增加，但仍在我們正常的 1 至 2 週的目標範圍內。前美國2017 年第四季度，S. EYLEA 的淨產品銷售額（由我們的合作夥伴拜耳公司記錄）為 6.37 億美元，按報告基準計算比 2016 年第四季度增長了 28%，按固定匯率計算增長了 23%。2017 年全年，安樂全球淨產品銷售額接近 60 億美元。2017 年第四季度，Regeneron 從美國以外地區 EYLEA 的銷售淨利潤中確認了 2.31 億美元，2017 年全年確認了 8.02 億美元。2017 年第四季拜耳合作總營收為 2.97 億美元，2017 年全年合作總營收為 9.38 億美元。2017 年第四季度，該公司報告稱，EYLEA 與 Ang-2 抗體 nesvacumab 聯合進行的 2 項 II 期研究結果未能提供足夠的差異化優勢，不足以支持 III 期開發。因此，2017 年第四季拜耳合作收入包括 3,700 萬美元的收入，這筆收入與加速確認先前從拜耳收到的預付款的遞延收入有關。2017 年第四季度，賽諾菲合作總營收為 2 億美元；2017 年全年，合作總營收為 8.77 億美元。賽諾菲合作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抗體和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。根據我們的合作夥伴賽諾菲的記錄，2017 年第四季 Dupixent、Praluent 和 Kevzara 的全球銷售額分別為：Dupixent，1.39 億美元；Praluent，6,300 萬美元；Kevzara，900 萬美元。Dupixent 和 Kevzara 的銷售額幾乎全部來自美國。儘管 2017 年第四季 Dupixent 和 Praluent 的銷售額有所成長，但我們在 Dupixent、Praluent 和 Kevzara 商業化方面的虧損份額為 1.14 億美元，而 2016 年第四季的虧損為 1.26 億美元。提醒一下，我們預計 2017 年第四季度與抗體商業化相關的聯盟虧損將高於第三季度，因為本季度為支持 Kevzara 和 Dupixent 而增加的全球上市活動對聯盟盈利能力產生了負面影響。2017 年全年，再生元公司在抗體商業化方面的虧損為 4.43 億美元，而 2016 年全年虧損為 4.59 億美元。2017 年第四季賽諾菲合作收入確實受益於 2017 年 12 月 31 日抗體發現協議終止後遞延收入的加速確認。然而，正如上個季度電話會議中提到的那樣，根據抗體發現協議，賽諾菲提供的 1.3 億美元 2017 年年度資金在 2017 年前 9 個月已全部用完，這導致本季度 Regeneron 研發費用的報銷額低於 2017 年前三個季度。2017 年第四季其他營收為 1.07 億美元，而 2016 年第四季為 5,200 萬美元。這一增長主要是由於我們的合作夥伴 Teva 為開發 fasinumab 支付的款項，以及公司獲得併計入收入的 3500 萬美元 fasinumab 開發里程碑付款。有關更多詳情，您可以在我們今天稍後提交的 10-K 表格的 MD&A 部分找到其他收入全年組成部分的摘要。

Turning now to expenses. Non-GAAP R&D expenses was $444 million for the fourth quarter of 2017 and $1.78 billion for the full year 2017. Our non-GAAP unreimbursed R&D expense, which is calculated as the total non-GAAP R&D expense less R&D reimbursements from our collaborators, was $265 million for the 3 months ended December 31, 2017, and $877 million for the full year 2017. Our press release includes all the information as required to calculate unreimbursed non-GAAP R&D expense. For 2018, we'd like to reaffirm our previously provided guidance for non-GAAP unreimbursed R&D to be in the range of $1.23 billion to $1.33 billion.

接下來談談費用。2017 年第四季非 GAAP 研發費用為 4.44 億美元，2017 年全年為 17.8 億美元。截至 2017 年 12 月 31 日止的三個月內，我們的非 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研發報銷）為 2.65 億美元，2017 年全年為 8.77 億美元。我們的新聞稿包含了計算未報銷的非GAAP研發費用所需的所有資訊。對於 2018 年，我們重申先前提供的非 GAAP 未報銷研發費用的預期，在 12.3 億美元至 13.3 億美元之間。

Next, non-GAAP SG&A expense was $348 million for the fourth quarter of 2017 and $1.11 billion for the full year 2017. As noted on our November 2017 earnings call, we realized a higher SG&A expend level in the fourth quarter of 2017 as compared to the first 3 quarters of 2017, primarily due to incremental spend on our 2 recently launched products, Dupixent and Kevzara, an increase in commercialization-related expenses associated with EYLEA as well as prelaunch expenses for the anticipated 2018 U.S. approvals for cemiplimab in cutaneous squamous cell carcinoma and dupilumab for asthma. The increased 2017 fourth quarter spend was also influenced by the acceleration of discretionary expenses to secure tax deductions in 2017. We reaffirm our previous guidance for non-GAAP SG&A expense in 2018 to be in the range of $1.35 billion and $1.45 billion. The increase in our forecasted 2018 non-GAAP SG&A expense is primarily driven by increased commercial support for Dupixent, both atopic dermatitis and potential asthma indication; EYLEA with an increased focus on diabetic eye disease; Praluent, which incorporates increased spending post ODYSSEY OUTCOMES results; and cemiplimab. Sanofi reimbursement of Regeneron commercialization related expenses, a line item found within Sanofi collaboration revenue, was $118 million for the fourth quarter of 2017 and $369 million for the full year 2017. We reaffirm our full year 2018 guidance for Sanofi reimbursement of Regeneron commercialization-related expenses in 2018 to be in the range of $450 million and $500 million. Non-GAAP cost of goods sold and non-GAAP cost of collaboration and contract manufacturing increased for the fourth quarter 2017 compared to the same period in 2016, primarily due to drug substance manufacturing costs associated with the sales of Dupixent and increases in Limerick's manufacturing start-up costs, which were anticipated. We are pleased to report that in December 2017, our facility in Limerick underwent a successful FDA preapproval inspection, resulting in a license to manufacture Praluent for the U.S. market.

其次，2017 年第四季非 GAAP SG&A 費用為 3.48 億美元，2017 年全年為 11.1 億美元。正如我們在 2017 年 11 月的收益電話會議上所指出的，與 2017 年前三個季度相比，我們在 2017 年第四季度實現了更高的銷售、一般及行政費用支出水平，這主要是由於我們最近推出的兩款產品 Dupixent 和 Kevzara 的增量支出，與 7EYLEA 癌症成本dupilumab（用於治療氣喘）預計於 2018 年在美國獲得批准而產生的上市前費用。2017 年第四季支出增加也受到 2017 年為獲得稅收減免而加快可自由支配支出的影響。我們重申先前對 2018 年非 GAAP 銷售、一般及行政費用的預期，介於 13.5 億美元至 14.5 億美元之間。我們預測 2018 年非 GAAP 銷售、一般及行政費用增加，主要原因是 Dupixent（用於治療異位性皮膚炎和潛在的哮喘適應症）的商業支持增加；EYLEA（用於治療糖尿病眼病）的商業支持增加；Praluent（在 ODYSSEY OUTCOMES 研究結果後增加了支出）和 cemipabab 公佈的增加。賽諾菲對 Regeneron 商業化相關費用的報銷（該費用包含在賽諾菲合作收入中）在 2017 年第四季為 1.18 億美元，在 2017 年全年為 3.69 億美元。我們重申對賽諾菲在 2018 年報銷 Regeneron 商業化相關費用的全年預期，即 2018 年報銷金額在 4.5 億美元至 5 億美元之間。2017 年第四季非 GAAP 銷售成本和非 GAAP 合作及合約製造成本較 2016 年同期有所增加，主要原因是與 Dupixent 銷售相關的藥物原料製造成本以及利默里克製造啟動成本的增加，而這些成本均在預期之內。我們很高興地宣布，2017 年 12 月，我們在利默里克的工廠成功通過了 FDA 的預先批准檢查，獲得了為美國市場生產 Praluent 的許可證。

Turning now to taxes. Our effective tax rate was 69% and 42% for the fourth quarter and full year 2017, respectively, as compared to approximately 26% and 33% for the fourth quarter and full year 2016. The effective tax rate for both the fourth quarter and full year 2017 was negatively impacted by the provisional charge related to the remeasurement of the company's U.S. net deferred tax assets upon the December 2017 enactment of the Tax Cut and Jobs Act, partly offset by the tax benefit associated with stock-based compensation. Excluding the impact of the Tax Cut and Jobs Act, our effective tax rate would have been 10% and 27% for the fourth quarter and full year of 2017. For the full year 2018, we are reaffirming our guidance for our effective tax rate to be in the range of 15% and 19%, which includes the estimated impact of the Tax Cut and Jobs Act. As discussed at the JPMorgan conference last month, the 2018 benefit that we expect to realize from U.S. corporate reform, is being reinvested into the business by increasing our investment in research and development and additional expansion of our U.S. facilities to support future growth. This has been incorporated into our 2018 guidance.

接下來談談稅務問題。2017 年第四季和全年的實際稅率分別為 69% 和 42%，而 2016 年第四季和全年的實際稅率分別約為 26% 和 33%。2017 年第四季和全年的實際稅率均受到與公司美國淨遞延所得稅資產重新計量相關的暫定費用的負面影響，該費用是由於 2017 年 12 月《減稅與就業法案》的頒布而產生的，部分被與股票期權激勵相關的稅收優惠所抵消。如果排除《減稅與就業法案》的影響，我們 2017 年第四季和全年的實際稅率分別為 10% 和 27%。對於 2018 年全年，我們重申對實際稅率的預期，即在 15% 至 19% 的範圍內，其中包括《減稅與就業法案》的預期影響。正如上個月在摩根大通會議上所討論的那樣，我們預計從美國企業改革中獲得的 2018 年收益，將透過增加研發投入和進一步擴大美國工廠來重新投資於業務，以支持未來的成長。這一點已納入我們 2018 年的指導方針中。

From a cash flow and balance sheet perspective, we ended the fourth quarter of 2017 with cash and marketable securities of $2.9 billion and generated full year free cash flow in excess of $1 billion. Our capital expenditures for the full year 2017 were $273 million. As we entered 2018, we are reaffirming our previous capital expenditure guidance of between $420 million and $500 million. A principal driver of increased capital expenditures in 2018 is for the expansion of a portion of our facilities at our Rensselaer, New York manufacturing location as well as expenditures from our Limerick manufacturing facilities and continued expansion and renovation of our laboratory space within our Tarrytown, New York facilities.

從現金流量和資產負債表的角度來看，截至 2017 年第四季末，我們擁有 29 億美元的現金和有價證券，全年自由現金流超過 10 億美元。2017 年全年資本支出為 2.73 億美元。進入 2018 年，我們重申先前設定的資本支出指引目標，即 4.2 億美元至 5 億美元。2018 年資本支出增加的主要驅動因素是擴大我們在紐約州倫斯勒製造基地的部分設施，以及來自我們在利默里克製造基地的支出，還有我們位於紐約州塔里敦設施內的實驗室空間的持續擴建和翻新。

Finally, as announced in early January, Regeneron and Sanofi agreed to accelerate and expand the investment for the clinical development of cemiplimab to a minimum of $1.64 billion, an increase of nearly $1 billion over the budget set forth in the original immuno-oncology license and collaboration agreement and to allocate additional funds to certain activities relating to the development of dupilumab and Regeneron 3500, our IL-33 antibody. As part of the agreement, the company agreed to grant a limited waiver of the lock-up in the Amended and Restated Investor Agreement so that Sanofi may sell up to an aggregate of 1.4 million shares of Regeneron common stock through the end of 2020, representing approximately 6% of the shares of Regeneron common stock Sanofi currently owns. If we do not elect to repurchase such shares from Sanofi, Sanofi may sell the applicable number of shares, subject to certain daily and quarterly limit in one or more open market transactions.

最後，正如 1 月初宣布的那樣，Regeneron 和 Sanofi 同意加快並擴大 cemiplimab 臨床開發的投資，至少達到 16.4 億美元，比最初的免疫腫瘤學許可和合作協議中規定的預算增加了近 10 億美元，並將額外資金分配給與 dupilumab 和 Regeneron 3500（我們的 IL-33 抗體活動相關的某些抗體活動。作為協議的一部分，該公司同意對修訂和重述的投資者協議中的鎖定期給予有限豁免，以便賽諾菲可以在 2020 年底前出售至多 140 萬股 Regeneron 普通股，約佔賽諾菲目前持有的 Regeneron 普通股的 6%。如果我們不選擇從賽諾菲回購此類股份，賽諾菲可以在一次或多次公開市場交易中出售相應數量的股份，但須遵守一定的每日和每季限額。

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. Jason, that concludes our prepared remarks. We'd now like to open the call for Q&A.

謝謝你，鮑伯。傑森，我們的演講稿到此結束。現在我們開始問答環節。

(Operator Instructions) And our first question comes from Alethia Young from Crédit Suisse.

（操作說明）我們的第一個問題來自瑞士信貸的 Alethia Young。

I just want to talk a little bit more about immuno-oncology. It seems like it was kind of underappreciated when we talked to investors. But can you talk a little bit more about your PD-1 strategy and your bispecific strategy, how does it all put together and maybe just a little bit more color on what you're doing in BCMA?

我想再多談談免疫腫瘤學。我們和投資者交流時發現，他們似乎低估了它的價值。您能否再詳細談談您的 PD-1 策略和雙特異性策略，它們是如何結合起來的，以及能否再詳細介紹一下您在 BCMA 所做的工作？

Sure. We're very excited, obviously, about our PD-1 program in that, as we noted, I think we surprised a lot of people by finding an important indication, which was very responsive to our antibody and we were hoping to get a rapid approval. And as we said, we think this setting is actually a pretty important one, perhaps on par with that of melanoma and with substantial growth opportunity. But as we also said, we think that not only is it important indication in and of itself, but it serves as a foundation to have our PD-1 antibody serve as a foundation for combination approaches going forward. We have a series of additional combination opportunities, some of which we've already initiated, whether it be with things like a variety of vaccines, in many cases that we're partnering with, or with additional checkpoint inhibitors that we've developed internally, but perhaps we're more excited about our bispecifics. As we've noted, our first bispecific is finally getting to dosing levels that are showing pretty substantial efficacy in our early trials. And we think if our bispecifics start approaching, which we think they're beginning to, the sort of type of responses that people are pointing with CAR-T, they could really represent a very, very important opportunity. And the thing that's also exciting about it is, our strategy includes both combining our bispecifics with our PD-1 as well as our bispecifics with each other. We have a number of bispecifics that at least in our preclinical models look like they can be added, if not synergistic, in their responses. And because these are all coming from our laboratories and we have the ability to study them preclinically as well as the ability to expedite studying them clinically, we think this offers enormous opportunity for us to really try these combinations and look for advances that they can actually provide together. So for us, it's a very exciting opportunity. We think we already have our foothold as we said, and we hope, in the near future, to be establishing not only our first bispecific, but a series of additional bispecifics, as we said we will be putting at least 2 in the clinic this year and a whole series of them shortly thereafter. So we think it's an exciting time and it's a lot of opportunity.

當然。顯然，我們對 PD-1 計畫感到非常興奮，正如我們所指出的，我認為我們發現了一個重要的適應症，這讓很多人感到驚訝，該適應症對我們的抗體反應非常強烈，我們希望能夠迅速獲得批准。正如我們所說，我們認為這種研究背景實際上非常重要，或許可以與黑色素瘤相提並論，並且具有巨大的發展潛力。但正如我們所說，我們認為這不僅本身就是一個重要的指標，而且還為我們的 PD-1 抗體作為未來聯合療法的基礎奠定了基礎。我們還有一系列額外的組合機會，其中一些我們已經啟動，無論是與各種疫苗（在許多情況下我們都是合作夥伴）還是與我們內部開發的其他檢查點抑製劑，但我們或許對我們的雙特異性抗體更感到興奮。正如我們所指出的，我們的第一種雙特異性抗體終於達到了劑量水平，並在早期試驗中顯示了相當大的療效。我們認為，如果我們的雙特異性抗體開始接近（我們認為它們已經開始接近了）人們用 CAR-T 療法所觀察到的那種反應，它們真的可能代表著一個非常非常重要的機會。更令人興奮的是，我們的策略包括將我們的雙特異性抗體與 PD-1 結合，以及將我們的雙特異性抗體彼此結合。我們有一些雙特異性抗體，至少在我們的臨床前模型中，它們似乎可以在反應中相互促進，甚至產生協同作用。而且由於這些藥物都來自我們的實驗室，我們有能力對它們進行臨床前研究，也有能力加快對它們進行臨床研究，我們認為這為我們提供了巨大的機會，讓我們能夠真正嘗試這些組合，並尋找它們能夠共同帶來的進步。所以對我們來說，這是一個非常令人興奮的機會。正如我們所說，我們認為我們已經站穩了腳跟，並且我們希望在不久的將來，不僅能夠建立我們的第一個雙特異性抗體，還能建立一系列額外的雙特異性抗體，正如我們所說，我們今年至少會將 2 個抗體投入臨床試驗，並在不久之後投入一系列抗體。所以我們認為這是一個令人興奮的時刻，蘊藏著許多機會。

Next we have Geoffrey Porges from Leerink Partners.

接下來是來自 Leerink Partners 的 Geoffrey Porges。

A quick -- a financial one and a R&D one, quickly. Bob, on the SG&A, it stepped up significantly and you highlighted that, and it looks as though it's going to be annualizing in 2018 at much the same rate as Q4. Could you talk about what the drivers are there? Have you sort of stood up your sales forces yet for both asthma and for the PD-1? And is there any sense that you might be able to redeploy some of your commercial expense away from Praluent over towards Dupixent, some of those other opportunities, perhaps tightening up on that SG&A ratio? And then quickly just, George, could you tell us what sort of dosing you expect to be likely for your bispecifics now you've learnt more about the characteristics of the first one?

盡快－一個財務方面的問題，一個研發方面的問題。Bob，關於銷售、一般及行政費用，它大幅上漲，你也強調了這一點，而且看起來 2018 年的年化增長率將與第四季度大致相同。您能談談那裡的司機有哪些嗎？你們是否已經組成了氣喘和PD-1的銷售團隊？您是否考慮將部分商業支出從 Praluent 轉移到 Dupixent 或其他一些機會上，從而降低銷售、管理及行政費用比率？然後，喬治，你能否快速告訴我們，既然你已經對第一種雙特異性抗體的特性有了更多了解，你預計你的雙特異性抗體的劑量會是什麼樣的？

Sure. Geoff, I'll answer the first one. And probably something that we haven't given a ton of color about, but with regards to the kind of our fourth quarter SG&A spend, we always kind of get this annual, seasonal EYLEA increase as we have to kind of reauthorize the insurance coverage and the reverification processes that we have. Again, obviously, the docs like this. So when the EYLEA patients come in, in the early January, the insurance is already in place and this is not a kind of a whole new start for them. So we do incur a decent amount of incremental spend that you don’t necessarily see during the first 3 quarters in 2017 in the fourth quarter. And again we did something similar in 2016. Again as we incurred in the fourth quarter of 2017, we are picking up spend for Kevzara and Dupixent. Again after controlling Praluent for the first 3 quarters, we did additionally have an increase in Praluent fourth quarter spend. And as I alluded to, we did accelerate, Geoff, some 2017, in particular, G&A expenses into the fourth quarter that probably ideally would have been a January incurring. So, again, that's creating a little bit of the bump that you're seeing when you compare the first 3 quarters of 2017. As we've talked -- as we get into 2018, again, we're putting a lot of money with regards to Dupixent in atopic dermatitis. We also have a lot of money laid out with regards to the launch of asthma, which, as you know, is going to be a very, very competitive field. And again, we continue on with Kevzara and we're assuming positive ODYSSEY OUTCOMES results on Praluent, and we're putting the necessary dollars behind that.

當然。傑夫，我來回答第一個問題。可能我們還沒有詳細說明，但就我們第四季度的銷售、一般及行政費用而言，我們總是會收到年度季節性的EYLEA增長，因為我們必須重新授權保險範圍和重新驗證流程。顯然，文件就是這樣做的。因此，當 EYLEA 患者在 1 月初入院時，保險已經到位，這對他們來說並不是一個全新的開始。因此，我們在 2017 年第四季確實產生了相當可觀的增量支出，而這些支出在前三個季度並不一定會被看到。2016年我們又做了類似的事。正如我們在 2017 年第四季所發生的那樣，我們正在增加對 Kevzara 和 Dupixent 的支出。在前三個季度控制了 Praluent 之後，我們第四季又增加了 Praluent 的支出。正如我之前提到的，Geoff，我們確實將一些 2017 年的 G&A 費用提前計入了第四季度，而這些費用原本很可能在 1 月份產生。所以，這再次造成了你在比較 2017 年前三個季度時看到的略微增長。正如我們之前討論過的——進入 2018 年，我們再次投入大量資金用於 Dupixent 在異位性皮膚炎方面的應用。我們在氣喘治療領域的推出也投入了大量資金，如您所知，這將是一個競爭非常激烈的領域。此外，我們繼續推進 Kevzara 項目，並假設 Praluent 的 ODYSSEY OUTCOMES 試驗結果為正面，我們將為此投入必要的資金。

Okay. And Geoff, this is George. Just regarding to your question about the bispecific, I think that a couple of very important things that we learned, and I think these are some of the reasons why this is such an attractive class and, in particular, may offer some advantages over some of these cellular therapy approaches, where a lot of the major concern is controlling the cytokine release storm and other adverse events in which the cells might be attacking the host. Most importantly, we've learned that we can actually gradually up the dose in time in an individual patient. So we can start with a lower dose, gradually remove the target, and so we don’t get an immediate blast of cytokine release storm and then we continue to dose up. And we've now gotten up where we reported recently at ASH our doses between 5 milligrams to 8 milligrams in terms of efficacy where we reported these efficacy numbers of about 50% response rate, and we also reported there that we had gotten to 12 milligram as a dose and we reported the safety profile there, but now we've even gone further beyond that dose. These are still relatively low doses compared to standard biologics, but we've certainly seen that it seems like it really dramatically ups the efficacy range when you get to these levels. But I think a huge advantage here is understanding that you can gradually increase the dose and this way you really ameliorate the onset of these adverse events and you can keep them under control and then get up to the higher doses. And then, of course, another major advantage is, if need be, you can back off the dose if you actually have to. But as a class now, I think that we understand the doses that we have to get to for efficacy, we would also have to gradually get to those doses in an individual patient so that they can be well tolerated.

好的。傑夫，這位是喬治。關於你提出的雙特異性抗體的問題，我認為我們學到了一些非常重要的東西，我認為這些也是為什麼這類抗體如此吸引人的原因之一，特別是，它們可能比一些細胞療法更有優勢，因為細胞療法的主要問題是控制細胞因子釋放風暴和其他不良事件，在這些事件中，細胞可能會攻擊宿主。最重要的是，我們了解到，我們實際上可以隨著時間的推移逐步增加單一患者的劑量。因此我們可以從較低的劑量開始，逐漸去除靶點，這樣就不會立即引發細胞激素風暴，然後我們繼續增加劑量。我們現在已經達到了最近在 ASH 會議上報告的劑量範圍，在 5 毫克到 8 毫克之間，在療效方面，我們報告的療效數據為約 50% 的反應率，我們還報告了我們已經達到 12 毫克的劑量，並報告了安全性概況，但現在我們甚至超過了這個劑量。與標準生物製劑相比，這些劑量仍然相對較低，但我們已經看到，當達到這些水平時，療效範圍似乎確實大幅提高。但我認為，這裡一個巨大的優勢在於，你可以逐漸增加劑量，這樣就能真正減輕這些不良反應的發生，你可以控制住它們，然後逐漸增加劑量。當然，另一個主要優點是，如有必要，您可以減少劑量。但就目前而言，我認為我們已經了解了達到有效劑量所需的劑量，我們也必須逐步地讓單一患者達到這些劑量，以便他們能夠很好地耐受。

I had a question for Geoff, by the way. I remember you said, oh, if in our muscle program, we produce 5% to 10% increases in muscle mass, you'd get pretty excited. So what do you think about that?

順便問一下，我有個問題想問傑夫。我記得你說過，哦，如果我們的增肌計畫能讓肌肉量增加 5% 到 10%，你會非常興奮的。你對此有何看法？

He has no time to answer right now, he has already shut out the line. Next question?

他現在沒時間回答，他已經掛斷了電話。下一個問題？

And next we have Chris Raymond from Piper Jaffray.

接下來是來自Piper Jaffray的Chris Raymond。

I had a question on fasinumab and also Kevzara, if you don’t mind. So just on fasinumab. Just looking at the long-term safety study (inaudible) I think, which looks to be reading out this year, what if you could maybe put some brackets around the sort of margin there on the safety side in terms of what you think will be acceptable in light of in need for, obviously, non-opioid alternatives? And then also on Kevzara. I think it's fairly clear now that offering a lower cost is not necessarily an important thing for payers and PBMs, especially in the immunology space. And, in fact, may even hurt you, just wondering if you can talk about what can be done now with Kevzara to inflect that revenue curve upward?

如果您不介意的話，我想問一下關於fasinumab和Kevzara的問題。所以就只用了法西單抗。僅從長期安全性研究（聽不清楚）來看，我認為該研究結果將於今年公佈，您能否就安全性方面的安全範圍，以及您認為在需要非阿片類藥物替代品的情況下，哪些安全範圍是可以接受的，給出一些建議？然後還有 Kevzara。我認為現在很明顯，對於支付者和藥品福利管理機構來說，提供更低的價格並不一定是一件重要的事情，尤其是在免疫學領域。事實上，這甚至可能會對你造成傷害，我只是想知道你現在可以和 Kevzara 談談如何才能使收入曲線向上轉變？

Right. So maybe George will comment on the NGF and then (inaudible) I'll will take the Kevzara question.

正確的。所以喬治可能會對NGF發表評論，然後（聽不清楚）我會回答凱夫札拉的問題。

Right. As you said, the story with NGF, we think, is one where there is an enormous opportunity balanced by a significant risk. I think a lot of people are aware of the risk about this issue of potentially accelerating arthritis in some patients and the question of degree of tolerance of this acceleration. We remind you, one of the theories with this acceleration may simply be that when you cause pain relief, people overuse their joints, but still the mechanism is not that well understood. In terms of the benefit-risk profile understanding what could be tolerated, I -- we can't answer that exactly, but we think that what we are using as a sort of barometer is that these patients are already late-stage patients who are, in many cases, candidates for total joint replacements. So I think that, that's a good way to sort of gauge the adverse events and how they're impacting. If overall, you are not causing an increase in the total number of joints that are adversely affected to the point where you need to get a total joint replacement, and if anything it may be you're preventing such events, while in some patients you're causing this acceleration, I think that would be considered a favorable benefit-risk profile, if overall in the vast population you're relieving pain. So if you're relieving pain in the large percentage of population and you are not contributing or if anything, you're preventing total joint replacement, I think that would be viewed as a profound positive.

正確的。正如你所說，我們認為，NGF 的故事是一個機會巨大但風險也很大的故事。我認為很多人都意識到這個問題有風險，即可能會加速某些患者的關節炎病情發展，以及患者對這種加速發展的耐受性。我們提醒您，關於這種加速現象的理論之一可能是，當您緩解疼痛時，人們會過度使用關節，但其機制仍未被充分理解。就獲益風險概況而言，了解可以容忍什麼，我們無法準確回答這個問題，但我們認為，我們用作一種晴雨表的是，這些患者已經是晚期患者，在很多情況下，他們都是全關節置換術的候選人。所以我認為這是一種衡量不利事件及其影響的好方法。如果總體而言，你沒有導致受影響的關節總數增加到需要全關節置換的程度，而且你甚至可能正在預防這種情況的發生，儘管在某些患者中你導致了這種加速，我認為如果總體上在廣大患者群體中你正在緩解疼痛，那麼這將被認為是有利的收益風險比。所以，如果你能緩解很大一部分人的疼痛，而且不會導致關節置換手術，甚至還能防止關節置換手術，我認為這將被視為一件意義重大的好事。

As to the Kevzara question, we refuse to believe that a drug with the strong profile that Kevzara has and the favorable pricing that we have offered cannot make sense in an environment where cost of medicines is a major concern. We applaud the actions of CVS, who gave us -- who recognized that and gave us a good position on the formulary. We would be very disappointed and will be very vocal if it can't be that a drug with such good properties and such favorable pricing can't make strong headway. So we've got our work cut out, our new Head of Commercial is up to the challenge, and so we will report back to you as we go.

至於 Kevzara 的問題，我們始終認為，像 Kevzara 這樣具有強大療效且價格優惠的藥物，在藥品成本成為主要關注點的環境下，是沒有道理的。我們讚賞 CVS 的行動，他們認識到這一點，並給予我們在藥品目錄中良好的地位。如果一種具有如此優良特性和如此優惠價格的藥物無法取得重大進展，我們將感到非常失望，並且會大聲疾呼。所以我們面臨著艱鉅的任務，我們新任商務主管能夠應對挑戰，我們會隨時向您報告進度。

Next we have Ying Huang from Bank of America Merrill Lynch.

接下來是來自美國銀行美林證券的黃穎。

First of all, maybe on ODYSSEY OUTCOMES study since it's going to read soon. You competitor Repatha did not show any benefit in cardiovascular mortality. So how important do you think it'll be for your drug, Praluent, to show that benefit? And then secondly, can you talk about life cycle management strategy for EYLEA now that it seems to -- is not going to be going forward into Phase III?

首先，或許可以關注 ODYSSEY OUTCOMES 研究，因為它很快就要公佈結果了。你的競爭對手Repatha在降低心血管死亡率方面並沒有顯示出任何益處。那麼，你認為你的藥物 Praluent 能否展現出這種療效有多重要？其次，鑑於安樂死似乎不會進入第三階段，您能否談談安樂死的生命週期管理策略？

Sure. So just to cover ODYSSEY, I don't think that's worth, Ying, speculating too much on what this result or what that result might be since we don't know the results. But we will know the results by the March 10 ACC event. So I think, we will all look at the events together basically and we'll be able to judge then. About EYLEA -- in terms of EYLEA, let me just say that I think we've tried to highlight a couple of things. People ask us a lot of about competition. I think it takes a lot to compete in this space. You need a drug that can be given as safely and effectively, you need a drug that can be given as frequently as monthly because patients who turn out that every other month is not enough. Doctors desperately want to be able to give them monthly and you need to have that in the label so you can get reimbursed for that higher dosing. You need a drug that has evidence of the long-term maintenance of vision, which has been a question in this field. And you need drugs that -- a drug that has all the indications covered. The new entrants have yet to start or only about to start Phase III trials. The RTH is just about to start or maybe just getting underway in terms of DME. And so they will be coming to market sometime, we believe, in 2019 based on their disclosures, which would come to market without, as far as we can tell, a monthly label. So you can't use it monthly without a DME label since they haven't been even started their Phase III trials. And, of course, when we developed EYLEA, we struck a very careful balance, which is what we tried to emphasize between safety and efficacy. When you give these anti-VEGF agents in the eye, they go into the systemic circulation. In fact, the very doctor who presented the RTH data was the one who was the most critical that he didn't want to give our drug to his grandmother because of some subset and the risk of some systemic thromboembolic events. When you now start to give 6x to 12x the molar dose into the eye, it's hard to ignore the fact that safety, particularly, for example, in diabetics, which hasn't been evaluated yet, and the careful safety evaluation that the agency will give, that's going to be an important part of this whole formula. So I don't think that the demise of EYLEA, I think has been greatly exaggerated, as the saying goes. But in terms of following on, we too struggle when you've got to the heart of the disease, which is excess VEGF causing leakiness of blood vessels, and you can block VEGF so exquisitely, you're not going to get too much down the road by adding other agents. We looked at Ang-2, others looked at PDGF, we looked at it, we didn't see a difference. It would not surprise us if the bispecific from Roche showed some nice activity because they're testing it against 0.3 milligrams of Lucentis at some -- at a strong multiple of that dose. In terms of our own efforts, we've got as we mentioned preclinical work ongoing in formulation to give you longer-term delivery of EYLEA as well as gene therapy. But at the end of the day, we all got to -- in this field got to the heart of this disease pretty quickly and that's why it's been hard for anybody to surpass these very powerful anti-VEGF agents. George, you want to add to that?

當然。所以，就奧德賽而言，英，我認為沒有必要太多猜測這個結果或那個結果會是什麼，因為我們不知道結果。但我們將在3月10日的ACC賽事上知道結果。所以我覺得，我們基本上會一起觀察這些事件，然後才能做出判斷。關於 EYLEA——就 EYLEA 而言，我想說的是，我認為我們已經努力強調了幾點。人們經常問我們關於競爭的問題。我認為在這個領域競爭非常困難。你需要一種可以安全有效地給藥的藥物，你需要一種可以每月給藥一次的藥物，因為患者發現每兩個月給藥一次是不夠的。醫生們非常希望能夠每月給病人服用一次這種藥物，而你需要在標籤上註明這一點，這樣你才能獲得更高劑量的報銷。你需要一種有證據表明能夠長期維持視力的藥物，這一直是該領域的問題。你需要一種能夠涵蓋所有適應症的藥物。新加入的試驗者尚未開始或即將開始 III 期臨床試驗。就DME而言，RTH可能剛開始，或者說才剛起步。因此，根據他們的披露，我們相信他們會在 2019 年的某個時候上市，而且據我們所知，上市時不會有月度標籤。所以，由於他們甚至還沒有開始進行 III 期試驗，因此如果沒有 DME 標籤，您不能每月使用它。當然，我們在研發愛樂（EYLEA）時，非常謹慎地權衡了安全性和有效性，這也是我們努力強調的重點。當你在眼睛注射這些抗 VEGF 藥物時，它們會進入全身循環。事實上，提出 RTH 數據的那位醫生，正是最持批評態度的那位，他因為某些亞群和一些全身性血栓栓塞事件的風險，而不願給他的祖母服用我們的藥物。現在，當開始向眼睛注射 6 倍至 12 倍摩爾劑量時，很難忽視安全性問題，特別是對於糖尿病患者而言，這方面尚未進行評估，而監管機構將進行仔細的安全性評估，這將是整個計算公式中的一個重要部分。所以，我不認為EYLEA的倒閉被大大誇大了，正如俗話所說的。但就後續治療而言，我們也遇到了困難，因為一旦觸及疾病的核心——過量的 VEGF 導致血管滲漏，而 VEGF 又被如此精確地阻斷，那麼後續添加其他藥物也不會取得太大進展。我們研究了Ang-2，其他人研究了PDGF，我們也研究了，我們沒有發現任何差異。如果羅氏的這種雙特異性抗體顯示出一些不錯的活性，我們不會感到驚訝，因為他們正在以相當高的劑量倍數，用 0.3 毫克的 Lucentis 對其進行測試。就我們自身的努力而言，正如我們之前提到的，我們正在進行臨床前研究，以期為您提供更長期的 EYLEA 給藥方案以及基因療法。但歸根結底，我們所有人很快就在這個領域找到了這種疾病的核心，這就是為什麼沒有人能夠超越這些非常強大的抗 VEGF 藥物的原因。喬治，你想補充什麼嗎？

Yes, I just want to build on it just a little bit. I mean, we have been working very hard for a very, very long time, more than 20 years now, to build on the benefit that EYLEA provides. And obviously, it's been hard because the bar has been set so high with EYLEA, and I think Len referred to the data. Just imagine that, I mean, with brolucizumab they gave 12x the molar dose of EYLEA and they could not demonstrate any advantages vis-à-vis the primary endpoint visual acuity. In fact, as Len mentioned, they were numerically inferior in both studies and they couldn't also extend substantially on the intervals, meaning that almost half their patients failed their quarterly interval so they -- that allows them to maybe allow to have about 50% of the people or so on quarterly dosing, which is just like EYLEA. So EYLEA has such a high bar and the only way is that so far people are trying to address it is by giving much, much higher molar doses and these molar doses are not really achieving demonstrable at least in terms of visual acuity or in terms of interval -- any advantages, and I think it just shows the bar has been set very high. And I think the flip side is the safety concern. And when you have something that you have such a long track record with safety and with also long-term demonstration of ability to maintain the visual gain that is something else that Len referred to. There is very other -- there is no other agent, which have been shown in long-term studies to actually maintain the initial vision gains. That's a very, very high bar. And when Len refers to treating relatives or parents, I think that right now EYLEA would certainly for me be the drug of choice based on the safety and efficacy profile to be treating anybody that I care about.

是的，我只是想在此基礎上再稍微完善一下。我的意思是，我們已經非常非常努力地工作了很長時間，超過 20 年，以鞏固 EYLEA 帶來的益處。顯然，這很難，因為EYLEA的成功標準太高了，我想Len也提到了相關數據。試想一下，我的意思是，當他們使用 brolucizumab 時，給予了 EYLEA 12 倍的摩爾劑量，但他們無法證明其在主要終點視力方面有任何優勢。事實上，正如 Len 所提到的，他們在兩項研究中的數量都處於劣勢，而且他們也無法大幅延長給藥間隔，這意味著幾乎一半的患者未能按季度給藥，因此他們——這使得他們或許只能允許大約 50% 的人按季度給藥，這就像 EYLEA 一樣。所以 EYLEA 的標準非常高，目前人們嘗試解決的唯一方法是給予更高的摩爾劑量，但這些摩爾劑量並沒有真正取得可證明的優勢，至少在視力或間隔方面沒有，我認為這只是表明標準設定得非常高。我認為另一方面是安全問題。而且，當你擁有一項在安全性方面有著長期良好記錄，並且在長期內也證明了其能夠保持視覺增益的能力時，這也是 Len 所提到的另一點。除此之外，沒有其他藥物——沒有其他藥物在長期研究中被證明能真正維持最初的視力改善效果。那可真是個非常非常高的標準。當 Len 提到治療親屬或父母時，我認為就目前而言，根據安全性和有效性，EYLEA 對我來說肯定是治療我關心的任何人的首選藥物。

Operator, we have time for one last question. I know there are many people in the queue who are not going to be able to get on the call, but please send me an e-mail and we'll follow-up with you after the call.

操作員，我們還有最後一個問題。我知道排隊的人中有很多可能無法參加通話，但請給我發一封電子郵件，通話結束後我們會與您聯繫。

We have Cory Kasimov from JPMorgan.

我們邀請到了摩根大通的科里·卡西莫夫。

I actually had 2 of them regarding Dupixent. First, I'm wondering if you can talk more about the payer process for Dupixent that's led to some of the frustration you mentioned in your prepared remarks. Curious what's maybe new or different there? Is that unforeseen step adds or prior auths or something else, and kind of how you see this dynamic evolving over the course of the year? And then the second part of the Dupi question is asking just -- about the relative breakdown of atopic dermatitis patients between adults, adolescents and pediatrics. I know you just started the ped Phase III, but how much of an interim boost might that adolescent patient population represent given that you'll have Phase III data there in 2018. That's also a population we still a lot of the comorbidities that are so common in pediatric patients.

實際上，我收到兩份關於Dupixent的諮詢。首先，我想請您詳細談談Dupixent的支付流程，您在準備好的演講稿中提到，正是這個流程導致了一些人感到沮喪。好奇那裡可能有什麼新的或不同之處？這個意料之外的步驟是增加一些額外步驟、事先授權還是其他什麼？您認為這種動態在這一年會如何演變？然後，Dupi 問題的第二部分詢問的是——成人、青少年和兒童中異位性皮膚炎患者的相對組成。我知道你們剛開始兒科 III 期臨床試驗，但考慮到你們將在 2018 年獲得 III 期臨床試驗數據，青少年患者群體能帶來多大的中期提升呢？這個群體中仍然存在許多兒科患者常見的合併症。

Thanks, Cory, for the question. So on the second one, we don't have a quantitative answer for you at this time in terms of what we might see the uptake in pediatrics or adolescents, but we do know there are a lot -- a lot of patients there. But until we get the label and, et cetera, et cetera, and able to promote it , we really can't give you too much of a feel. In terms of the frustrations we mentioned, the process that Sanofi and Regeneron have undertaken has actually gone very well. Remember, we had very rapid coverage from CVS and Express Scripts, almost first day coverage there literally. And we have continued to grow. We're -- someways in 80%, 85% of the plans, we've made some sort of a decision already on coverage. So we're doing well on that. The frustration I was referring to is that we still hear that unfortunately and regrettably and we hope to shine a light on that, perhaps we should start a #deniedRx. But people despite being on the right side of the need, the appropriate patients, failed all the right agents and then some, the paperwork has gotten frustrating because I think the payers are concerned about the size of this class. And in some cases, they're using their standard tricks. We're going to have to figure out ways to fight back. If somebody wants to tweet about Rx -- deniedRx, it would be okay with me, we'd love to collect some of these stories and hear about how the paperwork has been, or the denials have been unfair. We're not suggesting there's a new problem out there that's unique to Dupixent. This is an industry-wide problem that the payers are making it tougher. Praluent is a very good example. Payers are making it very tough for doctors to fill out the forms. We've made some progress now. And some of the payers certainly are acting responsibly. It's not a monolith out there, and we want to get as many people on the drug, who should be on the drug and make that process as easy as we can.

謝謝科里提出的這個問題。所以關於第二個問題，目前我們還沒有量化的答案來回答兒科或青少年群體的接受度，但我們知道那裡有很多患者。但是，在我們拿到唱片公司等等，能夠進行宣傳之前，我們真的無法給你太多的感覺。就我們提到的那些令人沮喪的問題而言，賽諾菲和再生元所採取的措施實際上進展得非常順利。請記住，CVS 和 Express Scripts 的供貨速度非常快，幾乎是第一天就供貨了。我們一直在不斷發展壯大。在 80% 到 85% 的計劃中，我們已經對承保範圍做出了一些決定。所以，我們在這方面做得很好。我所指的沮喪之處在於，我們仍然會聽到這樣的說法，令人遺憾和痛心，我們希望能夠揭露這一點，也許我們應該發起一個#deniedRx（拒絕處方）活動。但是，儘管這些人符合需求，是合適的患者，卻未能聯繫到所有合適的代理人，甚至更多，但文書工作卻令人沮喪，因為我認為付款方擔心這類患者的人數太多。在某些情況下，他們使用了慣用的伎倆。我們必須想辦法反擊。如果有人想在推特上發布關於 Rx -- deniedRx 的內容，我不會反對的，我們很樂意收集這些故事，了解申請流程是怎樣的，或者拒簽是怎樣的。我們並不是說存在 Dupixent 獨有的新問題。這是一個行業普遍存在的問題，而支付方卻讓情況變得更加複雜。Praluent 就是一個很好的例子。支付方設置了重重障礙，讓醫生填寫表格變得異常困難。我們現在取得了一些進展。而且，部分付款方確實在履行責任。情況並非一成不變，我們希望盡可能多的應該服用這種藥物的人都能服用，並儘可能簡化這個過程。

Well, we should just add that, just to remind you, you said we're early in our program with the pediatric atopic dermatitis, one of our Phase III studies is fully enrolled and for the 12 to 17 age group, we hope to submit a supplemental BLA by the end of this year. So we're hoping that, that opportunity is in terms of benefiting the younger patients is going to be pretty forthcoming.

嗯，我們還要補充一點，提醒一下您，您說過我們的兒科異位性皮膚炎計畫還處於早期階段，我們的一項 III 期研究已經全部招募完畢，針對 12 至 17 歲年齡組，我們希望在今年年底前提交補充生物製品許可申請 (BLA)。所以我們希望，能夠讓年輕患者受益的機會很快就會到來。

Operator, that concludes our call for today. And as I mentioned, we'll be available in our office for follow-up questions.

操作員，今天的通話到此結束。正如我之前提到的，我們會在辦公室接待後續提問。

Thank you.

謝謝。

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

謝謝各位女士、先生。今天的會議到此結束。感謝您的參與，您現在可以斷開連接了。