雷傑納榮製藥 (REGN) 2016 Q1 法說會逐字稿

Welcome to the Regeneron Pharmaceuticals Q1 2016 earnings conference call. My name is John, and I will be your operator for today's call.

歡迎參加 Regeneron Pharmaceuticals 2016 年第一季財報電話會議。我叫約翰，我將擔任您今天通話的接線生。

(Operator Instructions)

（操作說明）

Pleased note: The conference is being recorded.

請注意：本次會議正在錄影。

I will now turn the call over to Dr. Michael Aberman.

現在我將把電話交給邁克爾·阿伯曼博士。

Thank you, operator. And good morning and welcome to Regeneron Pharmaceuticals first-quarter 2016 conference call. An archive of this webcast will be available on our website under Events and Presentations for 30 days.

謝謝接線生。早安，歡迎參加 Regeneron Pharmaceuticals 2016 年第一季電話會議。本次網路直播的存檔將在我們網站的「活動與演示」欄位下保留 30 天。

Joining me on the call today are Dr. Leonard Schleifer, Founder, President and Chief Executive Officer; George Yancopoulos, Founding Scientist, President of Regeneron Laboratories, and Chief Scientific Officer; Bob Terifay, Executive Vice President, Commercial; and Bob Landry, 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：創辦人、總裁兼執行長 Leonard Schleifer 博士；Regeneron Laboratories 的創始科學家、總裁兼首席科學官 George Yancopoulos；商業執行副總裁 Bob Terifay；以及財務長 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 include forward-looking statements about Regeneron. Such statements may include, but are not limited to, those related to Regeneron and its products and businesses; sales and expense forecasts; financial forecasts; development programs; collaborations; finances; regulatory matters; intellectual property; and competition.

我還要提醒各位，本次電話會議中發表的言論包含 Regeneron 的前瞻性陳述。此類聲明可能包括但不限於與 Regeneron 及其產品和業務相關的聲明；銷售和支出預測；財務預測；開發計劃；合作；財務；監管事項；知識產權；以及競爭。

Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in such statements. 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 March 31, 2016, which was filed with the SEC this morning. Regeneron does not undertake any obligation to update publicly any forward-looking statement, whether as a result of new information, future events or otherwise.

每項前瞻性聲明都存在風險和不確定性，可能導致實際結果和事件與此類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，包括其截至 2016 年 3 月 31 日的季度 10-Q 表格，該表格已於今天上午提交給 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 on today's call. Information regarding our use of non-GAAP financial measures and a reconciliation of these measures to GAAP are 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.

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的資訊以及這些指標與公認會計準則的調節表，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, Michael, and a very good morning to everyone who has joined us on the call and webcast today.

謝謝邁克爾，也祝今天所有參加電話會議和網路直播的朋友們早安。

The first quarter of 2016 was busy, and we have a lot to share with you today. Our strategy remains, as always, to focus our unique capabilities in drug discovery and development on bringing important new medicines to patients in need. George will provide you with some of the recent exciting progress we have made in that regard.

2016年第一季非常忙碌，今天我們有許多內容可以跟大家分享。我們的策略一如既往，即集中我們在藥物發現和開發方面的獨特能力，為有需要的患者帶來重要的新藥。喬治將向你們介紹我們最近在這方面取得的一些令人振奮的進展。

From a high-level perspective, we had positive data readouts from three Phase 3 programs: Praluent for lowering LDL cholesterol in the apheresis setting; sarilumab in rheumatoid arthritis; dupilumab in atopic dermatitis. We also reported positive data from a Phase 2/3 study in osteoarthritis for fasinumab, our NGF antibody for pain, and we continue to make good progress with our earlier stage assets and discovery efforts.

從宏觀角度來看，我們獲得了三個 3 期項目的積極數據：Praluent 用於降低血漿置換療法中的 LDL 膽固醇；sarilumab 用於治療類風濕性關節炎；dupilumab 用於治療異位性皮膚炎。我們還報告了針對骨關節炎的 NGF 抗體 fasinumab 的 2/3 期研究的積極數據，該抗體用於治療疼痛，並且我們在早期資產和發現工作方面繼續取得良好進展。

Turning to our marketed products, EYLEA has continued to deliver solid growth, and we are able to increase our guidance for the year. Praluent's launch is still ongoing and has obviously faced a difficult reimbursement environment. While we fully understand payers' efforts to control costs, we do have serious concerns that appropriate patients are having undue difficulty getting approval for Praluent. We continue to be optimistic over the long term that Praluent will provide an important cholesterol-lowering option to many patients.

就我們已上市的產品而言，安樂雅持續保持穩健成長，因此我們能夠提高今年的業績預期。Praluent 的上市仍在進行中，顯然面臨艱難的報銷環境。雖然我們完全理解支付方為控製成本所做的努力，但我們確實非常擔心，合適的患者在獲得 Praluent 的批准方面遇到了不必要的困難。我們仍然對 Praluent 的長期前景持樂觀態度，認為它將為許多患者提供重要的降膽固醇選擇。

Bob Terifay will provide more detail on EYLEA and Praluent. Following that, Bob Landry will provide more detail on financial results for the first quarter of 2016, as well as updated guidance.

Bob Terifay 將提供有關 EYLEA 和 Praluent 的更多詳細資訊。接下來，鮑伯·蘭德里將提供 2016 年第一季財務業績的更多細節，以及更新後的業績指引。

Finally, we are approaching the potential approval and launch of two new products; sarilumab, our IL-6 receptor antibody for the treatment of rheumatoid arthritis is under review at the FDA. dupilumab is being developed for a number of indications, and we are targeting completion of our rolling BLA submission for moderate to severe atopic dermatitis in the third quarter of 2016.

最後，我們即將獲得兩款新產品的批准並上市；我們的 IL-6 受體抗體 sarilumab 用於治療類風濕性關節炎，目前正在接受 FDA 的審查。dupilumab 正在開發用於多種適應症，我們的目標是在 2016 年第三季完成中度至重度異位性皮膚炎的滾動生物製品許可申請 (BLA)。

With that, let me turn the call over to George.

那麼，我把電話交給喬治吧。

Thank you, Len, and a very good morning to everyone who has joined us today.

謝謝Len，也祝今天到場的各位早安。

Let me begin with an update on EYLEA. In addition to the Phase 2 co-formulated combinations of EYLEA with rinucumab, an antibody to the PDGF receptor, and nesvacumab, an antibody to angiopoietin-2. We have also commenced [Panorama], a Phase 3 study of EYLEA in non-proliferative diabetic retinopathy in patients without diabetic macular edema, or DME, which will evaluate whether EYLEA can improve their retinopathy.

首先，讓我向大家報告一下愛樂（EYLEA）的最新情況。除了 EYLEA 與 rinucumab（一種針對 PDGF 受體的抗體）和 nesvacumab（一種針對血管生成素-2 的抗體）的 2 期聯合製劑組合外，還有 EYLEA 與 rinucumab 和 nesvacumab 的 2 期聯合製劑組合。我們也啟動了 [Panorama]，這是一項針對非增殖性糖尿病視網膜病變患者（無糖尿病黃斑水腫 (DME)）的 EYLEA 3 期研究，旨在評估 EYLEA 是否可以改善他們的視網膜病變。

Additionally, the Diabetic Retinopathy Clinical Research Network, or the DRCR, initiated a related clinical study called Protocol W to evaluate the potential of anti-VEGF therapy in preventing worsening of severe non-proliferative diabetic retinopathy. This study will explore every 16-week dosing of EYLEA, which is the only anti-VEGF treatment being investigated in this study.

此外，糖尿病視網膜病變臨床研究網絡（DRCR）啟動了一項名為W方案的相關臨床研究，以評估抗VEGF療法在預防嚴重非增殖性糖尿病視網膜病變惡化的潛力。本研究將探討每 16 週一次的 EYLEA 給藥方案，EYLEA 是本研究中唯一正在研究的抗 VEGF 治療方法。

In February, we received two-year results from Protocol T, a government-sponsored study in patients with DME comparing the safety and efficacy of EYLEA versus Lucentis and Avastin. The primary efficacy endpoint for that study was at one year, which showed significantly better vision gain with EYLEA than either with Lucentis or Avastin. The second year of the study was not designed to rigorously compare the anti-VEGF agents, as the second-year results were increasingly confounded by variable dosing frequencies, as well as additional or adjunctive therapies, such as laser.

今年二月，我們收到了 Protocol T 的兩年結果，這是一項政府資助的針對 DME 患者的研究，比較了 EYLEA 與 Lucentis 和 Avastin 的安全性和有效性。研究的主要療效終點是一年時的結果，結果顯示，與 Lucentis 或 Avastin 相比，EYLEA 的視力改善效果明顯更好。研究的第二年並沒有設計成嚴格比較抗 VEGF 藥物，因為第二年的結果越來越受到劑量頻率變化以及雷射等附加或輔助療法的干擾。

Along these lines, it is important to point out there was a greater number of injections and substantially more use of laser associated with Avastin treatment in the overall population. Despite this, when compared with Avastin, EYLEA demonstrated a statistically significantly 5 letter gain, or an entire line of vision, in patients with poor vision at baseline.

由此可見，在整體人群中，與阿瓦斯汀治療相關的注射次數更多，雷射的使用也明顯更多。儘管如此，與 Avastin 相比，EYLEA 在基線視力較差的患者中顯示出統計學上顯著的 5 個字母的視力提升，或整整一行視力。

At two years, the rates of most ocular adverse events were similar across the three study groups. There was, however, statistically significant lower rate of arterial thromboembolic events, including non-fatal stroke, non-fatal myocardial infarction, and vascular death in the EYLEA group compared with the ranibizumab group.

兩年後，三個研究組中大多數眼部不良事件的發生率相似。然而，與雷珠單抗組相比，EYLEA 組的動脈血栓栓塞事件發生率在統計學上顯著降低，包括非致命性中風、非致命性心肌梗塞和血管性死亡。

Our Praluent launch is under way, and Bob Terifay will provide further details on the commercial front. Our 18,000 patient ODYSSEY outcome study is ongoing. The Data Monitoring Committee for this study has completed the first interim analysis, when 50% of the total events had accrued, based on unblinded study data.

我們的 Praluent 產品發布正在進行中，Bob Terifay 將提供有關商業方面的更多細節。我們正在進行一項針對 18,000 名患者的 ODYSSEY 結果研究。本研究的資料監測委員會已完成第一次中期分析，當時已累積 50% 的事件，該分析基於非盲研究資料。

In addition to reviewing the safety data, the DMC performed a futility assessment, and recommended the study continue with no changes. We remain blinded to the actual results of this analysis, and the study is ongoing. A second interim analysis for futility, as well as overwhelming efficacy, could potentially occur in the second half of 2016 when 75% of the targeted primary events have occurred.

除了審查安全性數據外，數據監測委員會還進行了無效性評估，並建議繼續進行研究，不做任何更改。我們目前仍不清楚這項分析的實際結果，而且研究仍在進行中。第二次中期分析（針對無效性以及壓倒性療效）可能會在 2016 年下半年進行，屆時 75% 的目標主要事件已經發生。

In March, we reported positive data from the Phase 3 ODYSSEY ESCAPE study in patients with heterozygous familial hypercholesterolemia who required chronic weekly or bi-weekly apheresis. Apheresis is an invasive, expensive and time-consuming therapy, given to the patients with the highest cholesterol levels and the greatest need.

3 月，我們報告了 ODYSSEY ESCAPE 3 期研究的積極數據，該研究針對需要每週或每兩週進行一次慢性血漿置換的雜合子家族性高膽固醇血症患者。血液分離術是一種侵入性強、昂貴且耗時的療法，適用於膽固醇水平最高、最需要這種療法的患者。

Our study showed that Praluent reduced the need for apheresis by 75% compared to placebo. 63% of Praluent patients no longer required apheresis, compared to 0% of the patients in the placebo arm. Praluent is the only PCSK9 inhibitor that has been studied in this apheresis setting, which represent some of the most severe hypercholesterolemic patients.

我們的研究表明，與安慰劑相比，Praluent 可減少 75% 的血漿分離術需求。Praluent 組有 63% 的患者不再需要血漿置換，而安慰劑組 0% 的患者不再需要血漿置換。Praluent 是唯一在血液分離術環境中進行研究的 PCSK9 抑制劑，該環境代表了一些最嚴重的膽固醇血症患者。

The adverse events that occurred more frequently in the Praluent-treated patients were injection site reactions and myalgia. We expect our supplemental BLA for the once-monthly dosing regimen of Praluent to be filed in the second quarter, which, if approved, will expand our dosing flexibility options.

Praluent 治療患者中較常見的不良事件是注射部位反應和肌肉痛。我們預計將在第二季提交 Praluent 每月一次給藥方案的補充生物製品許可申請 (BLA)，如果獲得批准，將擴大我們的給藥彈性選擇。

Turning now to our late-stage pipeline, where we had some very positive news. I would like to start with sarilumab, our IL-6 receptor antibody which is under review by the FDA for the treatment of rheumatoid arthritis. In March, we announced positive data from the Phase 3 MONARCH study of sarilumab versus HUMIRA, which demonstrated that sarilumab was superior to HUMIRA in the monotherapy setting in improving signs and symptoms of rheumatoid arthritis at 24 weeks.

現在讓我們來看看我們後期研發管線，我們有一些非常積極的消息。我想先介紹一下我們的 IL-6 受體抗體 sarilumab，它正在接受 FDA 的審查，用於治療類風濕性關節炎。3 月，我們公佈了 sarilumab 與 HUMIRA 的 3 期 MONARCH 研究的積極數據，結果表明，在單藥治療中，sarilumab 在 24 週時改善類風濕性關節炎的體徵和症狀方面優於 HUMIRA。

This was the first head-to-head study in the monotherapy study using a subcutaneously administered IL-6 inhibitor. The use of IL-6 inhibition in the monotherapy setting has been growing, and these data provide us with a competitive product profile. Data from the MONARCH study will be included in our European Submission, and is expected mid-year 2016.

這是第一個採用皮下注射 IL-6 抑制劑的單藥治療研究的頭對頭研究。IL-6 抑制劑在單藥治療中的應用日益廣泛，這些數據為我們提供了具有競爭力的產品概況。MONARCH 研究的數據將納入我們的歐洲提交資料中，預計將於 2016 年年中提交。

Turning now to dupilumab, our IL-4/13 blocking antibody, where we recently announced positive top-line data from the SOLO-1 and SOLO-2 monotherapy Phase 3 studies in adults with moderate to severe atopic dermatitis. These were the first Phase 3 studies of a systemic therapy to demonstrate a significant improvement in moderate to severe atopic dermatitis, and confirmed the positive data we had seen in our Phase 2b study.

現在我們來談談度普利尤單抗，這是一種 IL-4/13 阻斷抗體，我們最近公佈了 SOLO-1 和 SOLO-2 單藥治療 3 期研究在中度至重度異位性皮膚炎成人患者中的積極頂線數據。這是第一個證明系統療法能顯著改善中重度異位性皮膚炎的 3 期研究，證實了我們在 2b 期研究中看到的正面數據。

Overall, the studies demonstrate significant improvements in measures of disease severity, skin clearing, itching, quality of life, and mental health. We expect to present detailed data from the SOLO studies at an upcoming medical conference.

總體而言，這些研究表明，在疾病嚴重程度、皮膚清除、搔癢、生活品質和心理健康等方面均有顯著改善。我們計劃在即將舉行的醫學會議上公佈 SOLO 研究的詳細數據。

We continue to expect top-line data from the Phase 3 CHRONOS study, which explores dupilumab in combination with topical corticosteroids, in the second quarter of 2016. We expect to complete the rolling BLA submission for dupilumab in atopic dermatitis in the third quarter of 2016. I remind you that dupilumab has received breakthrough designation from the FDA for this indication in adults.

我們仍期待在 2016 年第二季獲得 3 期 CHRONOS 研究的主要數據，該研究探索度普利尤單抗與局部皮質類固醇聯合用藥的療效。我們預計將於 2016 年第三季完成 dupilumab 用於治療異位性皮膚炎的滾動生物製品許可申請 (BLA)。我提醒各位，度普利尤單抗已獲得美國食品藥物管理局 (FDA) 授予的突破性療法認定，用於治療成人該適應症。

In the first quarter of 2016, we initiated a LIBERTY AD CAFE, a Phase 3 study of dupilumab to support our European submission. This study investigates dupilumab with some common and topical corticosteroids in adult patients with atopic dermatitis who are not adequately controlled with, or intolerant to or ineligible for, systemic cyclosporine A treatment.

2016 年第一季度，我們啟動了 LIBERTY AD CAFE，這是一項 dupilumab 的 3 期研究，旨在支持我們向歐洲提交申請。本研究探討了度普利尤單抗合併一些常用和局部皮質類固醇治療成人異位性皮膚炎患者的療效，這些患者無法透過全身環孢素 A 治療得到充分控制，或者無法耐受全身環孢素 A 治療，或者不適合接受全身環孢素 A 治療。

In addition to the studies in the adult setting, we also plan to initiate a Phase 3 study in the atopic dermatitis indication in the pediatric population, once we have data from the ongoing Phase 2 pediatric study that is now fully enrolled. We expect these Phase 2 data in the second half of the year.

除了在成人環境中進行的研究外，我們還計劃在獲得目前正在進行的兒科 2 期研究（該研究已全部入組）的數據後，啟動針對兒童異位性皮膚炎適應症的 3 期研究。我們預計將在今年下半年獲得第二階段的數據。

We're also investigating dupilumab in other indications, including asthma, where we are currently enrolling our 1,700 patient pivotal study. We're also advancing clinical development in indications such as nasal polyps and eosinophilic esophagitis.

我們也正在研究度普利尤單抗在其他適應症的應用，包括氣喘，目前我們正在進行一項針對 1700 名患者的關鍵性研究。我們也正在推進鼻息肉和嗜酸性食道炎等適應症的臨床開發。

For fasinumab, our NGF antibody, earlier this week we announced positive data from our Phase 2/3 study in osteoarthritis, which provides us with our first safety and efficacy data with our subcutaneous dosing regimen. This was the first completed study using an antibody to NGF that performed extensive imaging of knee, hip and shoulder joints at screening and throughout the trial.

對於我們的 NGF 抗體 fasinumab，本週早些時候，我們公佈了其在骨關節炎 2/3 期研究中取得的積極數據，這為我們提供了皮下給藥方案的首個安全性和有效性數據。這是第一個使用 NGF 抗體完成的研究，該研究在篩選和整個試驗過程中對膝關節、髖關節和肩關節進行了廣泛的成像。

Interestingly, we found the subchondral insufficiency fractures and even osteonecrosis were present in this population at screening. Further, our findings in patients following fasinumab treatment are consistent with prior data, suggesting that there may not be a substantial increase in rapidly progressing osteoarthritis when an NGF antibody is used in the monotherapy setting. That said, it is a relatively small trial and we look forward to data from the much larger clinical studies that are under way.

有趣的是，我們在篩檢中發現該族群中存在軟骨下骨不全性骨折甚至骨壞死。此外，我們對接受 fasinumab 治療的患者的研究結果與先前的數據一致，表明在單藥治療中使用 NGF 抗體時，可能不會出現骨關節炎快速進展的顯著增加。儘管如此，這只是一項規模相對較小的試驗，我們期待著正在進行的更大規模的臨床研究的數據。

We've also seen some exciting developments in our earlier-stage programs. I would like to spend a few minutes on two areas: our efforts in genetics and our recent collaboration in the arena of gene editing. In March, we published a paper in the New England Journal of Medicine based on research that was conducted at the Regeneron Genetics Center, or the RGC.

我們在早期階段的專案中也看到了一些令人振奮的進展。我想花幾分鐘時間談談兩個面向：我們在遺傳學領域的努力以及我們最近在基因編輯領域的合作。今年 3 月，我們在《新英格蘭醫學雜誌》上發表了一篇論文，該論文基於 Regeneron 遺傳學中心（簡稱 RGC）進行的研究。

The publication showed that inactivating mutations in a gene called angiopoietin-like 4 were associated with a significantly reduced risk of coronary artery disease in humans. This is a great example that demonstrates how our efforts in the area of precision medicine can link genetic mutation information with real-world health outcomes to make actionable discoveries.

該出版品顯示，血管生成素樣 4 基因的失活突變與人類冠狀動脈疾病風險顯著降低有關。這是一個很好的例子，它表明我們在精準醫療領域的努力如何將基因突變資訊與現實世界的健康結果聯繫起來，從而做出可操作的發現。

Many of the findings from the RGC are already being used to inform Regeneron's robust and integrated R&D programs, and give us the ability to incorporate large-scale sequencing into our discovery and pipeline approaches. It also demonstrates the advantages of our unique combination of technologies.

RGC 的許多研究成果已用於指導 Regeneron 強大且全面的研發項目，並使我們能夠將大規模定序納入我們的發現和流程方法中。這也體現了我們獨特技術組合的優勢。

Using our proprietary VelociGene technology, we developed animal models that corroborated the human genetics findings, and we were able to use our VelociGene platform to create a fully human monoclonal antibody inhibitor of ANGPTL4 that reduced triglyceride levels in mice and non-human primates.

利用我們專有的 VelociGene 技術，我們開發了動物模型，證實了人類遺傳學的研究結果，並且我們能夠利用我們的 VelociGene 平台創建一種完全人源化的 ANGPTL4 單克隆抗體抑製劑，該抑製劑可降低小鼠和非人靈長類動物的甘油三酯水平。

We are also advancing a Phase 2 program for Regeneron1500, an antibody to ANGPTL3. ANGPTL3 is thought to play a central role in lipoprotein metabolism, and our genetic data show that patients with homozygous inactivating mutations of this gene report greater than 50% lower levels of LDL, HDL and triglycerides. Initial data from a small study in homozygous patients will be presented at the upcoming Annual Meeting of the National Lipid Association.

我們也正在推進 Regeneron1500（一種針對 ANGPTL3 的抗體）的 2 期臨床試驗計畫。ANGPTL3 被認為在脂蛋白代謝中起著核心作用，我們的基因數據顯示，攜帶該基因純合失活突變的患者，其 LDL、HDL 和三酸甘油酯水平降低 50% 以上。一項針對純合子患者的小型研究的初步數據將在即將舉行的全國脂質協會年會上公佈。

We recently entered into collaboration with Intellia Therapeutics with the aim of advancing CRISPR/Cas gene editing technology into in vivo therapeutic development. This was a logical fit for us, given our long-standing expertise on genetic engineering, combined with our industry-leading human genetics research with the RGC, which is already identifying important genetic targets. We believe that combining these capabilities with Intellia's technology holds real promise for serious diseases that have been historically difficult to address. And expands our ability to help patients where antibody-based therapies may not be the optimal approach.

我們最近與 Intellia Therapeutics 展開合作，旨在推進 CRISPR/Cas 基因編輯技術在體內治療開發中的應用。鑑於我們在基因工程領域擁有長期累積的專業知識，再加上我們與RGC合作進行的行業領先的人類遺傳學研究（該研究已經確定了重要的基因靶點），這對我們來說是一個合乎邏輯的選擇。我們相信，將這些能力與 Intellia 的技術相結合，對於歷史上難以治療的嚴重疾病來說，具有真正的希望。並擴大了我們幫助那些抗體療法可能不是最佳治療方案的患者的能力。

We continue to make progress in immuno-oncology. Regeneron2810, our PD-1 antibody program, has entered a Phase 2 potentially registrational study in cutaneous squamous cell carcinoma. We will be presenting some preliminary Phase 1 data at the upcoming annual ASCO conference.

我們在腫瘤免疫學領域不斷取得進展。我們的 PD-1 抗體計畫 Regeneron2810 已進入皮膚鱗狀細胞癌的 2 期潛在註冊研究階段。我們將在即將舉行的ASCO年會上公佈一些初步的1期臨床試驗資料。

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

接下來，我想把電話交給鮑伯·特里費。

Thank you, George, and good morning, everyone.

謝謝你，喬治，大家早安。

During the first quarter of 2016, we continued to see strong sales growth for EYLEA, or aflibercept, injection, both in the United States and the rest of the world. We've made substantial progress in securing access and reimbursement for Praluent, or alirocumab, among US payers.

2016 年第一季度，EYLEA（阿柏西普）注射液在美國和世界其他地區的銷售額持續保持強勁成長。我們在確保美國支付方能夠獲得 Praluent（或 alirocumab）的治療和報銷方面取得了實質進展。

In addition, the European launch for Praluent continues to progress. We also are now preparing for the potential US launches of sarilumab and dupilumab over the next 12 to 15 months.

此外，Praluent 在歐洲的上市工作也持續進行。我們目前也正在為未來 12 至 15 個月內在美國推出 sarilumab 和 dupilumab 做準備。

Starting with EYLEA, first-quarter US net sales grew 44% year over year. Net US EYLEA sales in the first quarter were $781 million. Net ex-US EYLEA sales in the first quarter were $419 million, which represents 44% growth year over year on a reported basis. We continue to see quarter-over-quarter increases in our US market share leadership for EYLEA in the FDA-approved anti-VEGF market, both in terms of dollar sales as well as injections, as reported by 207 retinal specialists in our quarterly market research survey.

以安樂為例，安樂第一季美國淨銷售額年增 44%。安理國際第一季在美國的淨銷售額為7.81億美元。第一季安樂（EYLEA）除美國以外的淨銷售額為 4.19 億美元，以報告數據計算，年增 44%。根據我們季度市場調查中 207 位視網膜專家的報告，我們在 FDA 批准的抗 VEGF 市場中，EYLEA 在美國市場份額的領先地位持續逐季增長，無論是按美元銷售額還是注射量計算都是如此。

We're encouraged about the future growth opportunities for EYLEA, based upon the recently reported two-year results of the independently conducted Protocol T comparative study of EYLEA versus ranibizumab versus bevacizumab in patients with diabetic macular edema. However, I should point out that we are closely monitoring pressures on EYLEA sales as the year progresses. There are currently a series of proposals for the Centers for Medicare and Medicaid services regarding physician reimbursement for physician-administered Medicare Part B buy-and-bill drugs, which could lead toward physicians favoring the use of off-label, repackaged bevacizumab, or in large-volume retinal practices ranibizumab, due to the provision of direct-to-physician financial incentives from the manufacturer.

根據最近發表的獨立進行的為期兩年的 Protocol T 比較研究的結果，我們對 EYLEA 的未來成長機會感到鼓舞。該研究比較了 EYLEA 與雷珠單抗和貝伐珠單抗在糖尿病黃斑水腫患者的療效。不過，我應該指出，隨著時間的推移，我們將密切關注安永的銷售壓力。目前，醫療保險和醫療補助服務中心正在就醫生使用醫療保險 B 部分自費藥物的報銷問題提出一系列提案，這可能導致醫生傾向於使用標籤外重新包裝的貝伐珠單抗，或者在視網膜疾病治療量大的診所中使用雷珠單抗，因為製造商會向醫生提供直接的經濟激勵。

Regeneron believes that EYLEA is clearly differentiated from both bevacizumab and ranibizumab. Physicians and patients should not be denied access to any drug therapy that is deemed appropriate; therefore, we and scores of other manufacturers, patient advocacy groups, and industry associations will or have already submitted objections to CMS and Congress, recommending the physician's choice be preserved and alternative schemas to reduce healthcare costs should be explored.

再生元公司認為，EYLEA 與貝伐單抗和雷珠單抗都有明顯的差異。醫生和患者不應被剝奪獲得任何被認為合適的藥物治療的權利；因此，我們和許多其他製造商、患者權益倡導團體和行業協會將或已經向美國醫療保險和醫療補助服務中心 (CMS) 和國會提交反對意見，建議保留醫生的選擇權，並探索降低醫療保健成本的替代方案。

Turning now to Praluent, as reported by Sanofi, net sales in the first quarter were $13 million, which understates the actual physician and patient demand. As I've reminded you over the last several quarters, we anticipated that it would take some time for commercial and government payers to conduct formulary reviews, make reimbursement coverage decisions, and begin to process patient claims. I am pleased to tell you that as of April 1, approximately 74% of commercially insured lives and 91% of Medicare insured lives have access to Praluent.

現在來看 Praluent，根據賽諾菲公司報告，第一季淨銷售額為 1300 萬美元，低估了醫生和患者的實際需求。正如我在過去幾個季度中不斷提醒大家的那樣，我們預計商業和政府支付方需要一些時間來進行處方集審查、做出報銷範圍決定並開始處理患者索賠。我很高興地告訴大家，截至 4 月 1 日，約 74% 的商業保險投保人和 91% 的聯邦醫療保險投保人可以使用 Praluent。

We've recently seen an improvement in the number of prescriptions that are successfully being filled. Highlighting our approved coverage, as well as our share of voice among healthcare professionals, the most recent nationally syndicated prescription audits for the week ended April 22, 2016, indicates that Praluent captured approximately 50% of new prescriptions in the class.

我們最近發現，成功配藥的處方數量增加。為了突出我們已批准的承保範圍以及我們在醫療保健專業人員中的影響力，截至 2016 年 4 月 22 日當週的最新全國聯合處方審核顯示，Praluent 在該類別中獲得了約 50% 的新處方。

Unfortunately, due to unprecedented strict utilization management criteria and very tedious prior authorization paperwork and documentation that the pharmacy benefits managers and health plans have put in place, many patients who are eligible for treatment with a PCSK9 inhibitor have not had their prescriptions filled. Frustrated by this process, healthcare professionals are limiting the prescriptions to the sickest of patients; the prescription volume for the PCSK9 inhibitor class is limited.

不幸的是，由於藥房福利管理機構和健康計劃實施了前所未有的嚴格利用管理標準以及非常繁瑣的事先授權文件和記錄，許多符合 PCSK9 抑制劑治療條件的患者尚未獲得處方藥。由於這個過程令人沮喪，醫療專業人員將處方限制在病情最嚴重的患者身上；PCSK9 抑制劑類藥物的處方量有限。

We're focusing our efforts improving the prescription process through the payers and specialty pharmacies. We're also working with physicians' offices to ensure that the prescription process is better understood on a payer-by-payer basis.

我們正集中精力透過支付方和專科藥局來改善處方流程。我們也在與醫生辦公室合作，以確保各個支付方都能更了解處方流程。

Over the last several weeks, we've seen two payers loosen their utilization management criteria, removing the requirement for prior ezetimibe therapy. ODYSSEY outcomes data, if positive, will be a key driver in shaping the future success of Praluent.

在過去的幾周里，我們看到兩家支付方放寬了其使用管理標準，取消了先前接受依折麥布治療的要求。如果 ODYSSEY 的結果數據是正面的，那將成為塑造 Praluent 未來成功的關鍵驅動因素。

Outside of the United States, Praluent was approved in the EU in September of 2015, with product now available in several countries. Reimbursement discussions are currently under way with several governments across Europe. Outside the United States, it remains a difficult reimbursement market, with some countries awaiting outcomes data.

在美國以外，Praluent 於 2015 年 9 月在歐盟獲得批准，目前該產品已在多個國家上市。目前正與歐洲多個國家的政府就報銷事宜進行磋商。在美國以外，醫療報銷市場仍然困難重重，一些國家仍在等待結果數據。

We have submitted a BLA to the US Food and Drug Administration for sarilumab, our interleukin-6 receptor inhibitor for rheumatoid arthritis, and have been granted a PDUFA date of October 30, 2016. We will be co-promoting sarilumab with Sanofi/Genzyme in the United States, and are actively recruiting our field-based team. Co-promotion decisions for other countries will be made over time.

我們已向美國食品藥物管理局提交了 sarilumab（一種用於治療類風濕性關節炎的白細胞介素-6 受體抑制劑）的生物製品許可申請 (BLA)，並已獲得 2016 年 10 月 30 日的處方藥用戶付費法案 (PDUFA) 批准日期。我們將與賽諾菲/健贊在美國共同推廣 sarilumab，並積極招募我們的現場團隊。與其他國家聯合推廣的決定將視情況而定。

We're excited about the potential US launch for sarilumab. Given the central role of interleukin-6, and the inflammation contributed to the signs and symptoms of rheumatoid arthritis, and more importantly, disabling joint destruction, we believe that IL-6 inhibitors should be used early, following tumor necrosis factor, or TNF, inhibitor failure.

我們對 sarilumab 在美國的潛在上市感到興奮。鑑於白細胞介素-6 的核心作用，以及發炎對類風濕性關節炎的體徵和症狀，更重要的是對致殘性關節破壞的影響，我們認為，在腫瘤壞死因子（TNF）抑制劑失效後，應儘早使用 IL-6 抑制劑。

Recently issued US and European guidelines support the use of IL-6 inhibitor class in earlier lines of treatments. This is particularly relevant for those patients who cannot take combination therapies with methotrexate. With multiple players competing in the anti-IL-6 marketplace, this should contribute to improved physician awareness and understanding of the inadequacy of TNF inhibitor cycling and the need for early IL-6 inhibitor treatment.

美國和歐洲近期發布的指南支持在早期治療中使用 IL-6 抑制劑類藥物。這一點對於不能接受甲胺蝶呤合併治療的患者來說尤其重要。由於有多家廠商在抗IL-6市場競爭，這應該有助於提高醫師對TNF抑制劑循環治療不足以及早期IL-6抑制劑治療必要性的認識和理解。

Subcutaneously administered sarilumab has strong clinical data in terms of the improved signs and symptoms of rheumatoid arthritis, and prevention of bone damage in methotrexate-inadequate responders. Similar improvements in the signs and symptoms of RA have been reported in TNF inhibitor-inadequate responder population.

皮下注射沙利魯單抗在改善類風濕性關節炎的體徵和症狀以及預防甲氨蝶呤療效不佳患者的骨損傷方面具有強大的臨床數據。在 TNF 抑制劑反應不足的患者群體中，也報告了 RA 的徵兆和症狀的類似改善。

We continue to prepare for the potential US launch of dupilumab, our IL-4 and IL-13 inhibitor, which we expect in 2017. There are approximately 1.6 million patients with inadequately controlled moderate to severe atopic dermatitis in the United States. We have been co-promoting dupilumab in the United States. Co-promotion decisions for other countries will be made at a later date.

我們正繼續為dupilumab（一種IL-4和IL-13抑制劑）在美國的潛在上市做準備，預計2017年上市。美國約有 160 萬中度至重度異位性皮膚炎患者病情控制不佳。我們一直在美國共同推廣度普利尤單抗。其他國家的聯合推廣決定將在稍後做出。

With that, let me turn the call over to our Chief Financial Officer, Bob Landry.

接下來，我將把電話交給我們的財務長鮑伯·蘭德里。

Thanks, Bob, and good morning to everyone who has joined us today.

謝謝鮑勃，也祝今天到場的各位早安。

In the first quarter of 2016, non-GAAP net income per diluted share decreased 11% to $2.57 versus first quarter of 2015, and non-GAAP net income of $293 million decreased 13% versus first quarter of 2015. Regeneron's 2016 non-GAAP net income primarily excludes non-cash share-based compensation expense, and includes an adjustment for income taxes. A full reconciliation of GAAP to non-GAAP earnings is set forth in our earnings release.

2016 年第一季，非 GAAP 每股攤薄淨收益較 2015 年第一季下降 11% 至 2.57 美元，非 GAAP 淨收益為 2.93 億美元，較 2015 年第一季下降 13%。Regeneron 2016 年的非 GAAP 淨收入主要不包括非現金股份支付費用，並包括所得稅調整。我們的獲利報告中列出了 GAAP 收益與非 GAAP 收益的完整調整表。

Total revenues in the first quarter of 2016 were $1.2 billion, which represented year-over-year growth of 38% over the first quarter of 2015. Net product sales were $784 million in the first quarter of 2016 compared to $545 million in the first quarter of 2015.

2016 年第一季總營收為 12 億美元，比 2015 年第一季年增 38%。2016 年第一季淨產品銷售額為 7.84 億美元，而 2015 年第一季為 5.45 億美元。

EYLEA net product sales in the United States were $781 million in the first quarter of 2016 compared to $541 million in the first quarter of 2015, which represents an increase of 44%. Sequential quarter-over-quarter growth was an increase of 5%.

2016 年第一季度，EYLEA 在美國的淨產品銷售額為 7.81 億美元，而 2015 年第一季為 5.41 億美元，成長了 44%。環比增長 5%。

During the first quarter of 2016, EYLEA experienced a slight decrease in US distributor inventory levels as compared to the fourth-quarter 2015, but continues to be within our normal 1- to 2-week targeted range. As Len mentioned, we are updating our full-year 2016 US EYLEA guidance to be year-over-year growth of between 20% and 25% from the previously provided guidance of approximately 20% growth.

2016 年第一季度，安怡美國經銷商的庫存水準與 2015 年第四季相比略有下降，但仍在我們正常的 1 至 2 週的目標範圍內。正如 Len 所提到的，我們將 2016 年全年美國安永銷售額預期從先前的約 20% 的成長預期調整為年增 20% 至 25%。

Ex-US EYLEA sales were $419 million in the first quarter of 2016, as compared to $292 million in the first quarter of 2015, representing a 44% increase on a reported basis. On an operational basis, or constant-currency basis, sales increased approximately 48%. Product revenue from ex-US EYLEA sales is recorded by our collaborator, Bayer.

2016 年第一季度，EYLEA 在美國以外的銷售額為 4.19 億美元，而 2015 年第一季為 2.92 億美元，按報告數據計算增加了 44%。以營運成本或固定匯率計算，銷售額成長了約 48%。來自美國以外地區的EYLEA產品銷售收入由我們的合作夥伴拜耳公司記錄。

In the first quarter of 2016, Regeneron recognized $146 million from our share of net profits from EYLEA sales outside the US. Total Bayer collaboration revenue for the first quarter of 2016 was $180 million.

2016 年第一季度，Regeneron 從美國以外地區 EYLEA 的銷售淨利潤中確認了 1.46 億美元。2016 年第一季拜耳合作總營收為 1.8 億美元。

I would also like to take this moment to highlight our recently expanded collaboration with Bayer, following our agreement to jointly develop the co-formulation of our antibody to Ang2 in EYLEA. In connection with this agreement, Bayer made a $50 million upfront payment to us, which was a receivable at March 31, 2016, and Regeneron has the potential to earn up to $80 million in development milestones.

我還想藉此機會重點介紹我們最近與拜耳擴大的合作，此前我們已達成協議，共同開發針對 EYLEA 的 Ang2 抗體的聯合製劑。根據這項協議，拜耳向我們支付了 5,000 萬美元的預付款，截至 2016 年 3 月 31 日，這筆款項為應收帳款，而 Regeneron 有可能在研發里程碑中獲得高達 8,000 萬美元的收益。

The $50 million upfront payment has been deferred, and will be recognized over the estimated performance period. Similar to our EYLEA agreement, Regeneron has exclusive commercial rights within the US, and will retain all of the profits from any US sales.

5000萬美元的預付款已被延期，將在預計的業績履行期內確認。與我們和 EYLEA 達成的協議類似，Regeneron 在美國擁有獨家商業權利，並將保留美國銷售的所有利潤。

Finally, a reminder for the EYLEA franchise -- the second quarter of 2016 will be the final quarter in which we incur the royalty expense in connection with our agreement with Genentech related to global EYLEA sales. In fact, I'm pleased to announce that this royalty will officially end in two more days.

最後提醒一下EYLEA特許經營權－2016年第二季將是我們與Genentech就全球EYLEA銷售達成的協議中產生特許權使用費的最後一個季度。事實上，我很高興地宣布，這項特許權使用費將在兩天後正式結束。

Turning now to our Sanofi collaboration, total Sanofi collaboration revenue was $220 million for the first quarter of 2016. The Sanofi collaboration revenue line primarily consists of reimbursement of Regeneron-incurred R&D expenses, reimbursement of Regeneron commercialization-related expenses, and our share of profits or losses in connection with commercialization of antibodies.

現在來說說我們與賽諾菲的合作，2016 年第一季賽諾菲合作的總收入為 2.2 億美元。賽諾菲的合作收入主要包括：報銷 Regeneron 產生的研發費用、報銷 Regeneron 的商業化相關費用，以及我們與抗體商業化相關的利潤或虧損份額。

In the first quarter of 2016, our share of the collaboration's losses, in connection with commercialization of antibodies, primarily Praluent, was $99 million, which can be found in table 4 of our earnings release. Netted within the collaboration losses were the global sales of Praluent, as recognized by our collaborator, Sanofi, of $13 million for the first-quarter 2016.

2016 年第一季度，我們在抗體商業化（主要是 Praluent）相關的合作虧損中所佔份額為 9,900 萬美元，詳情請參閱我們的收益報告表 4。合作損失包括 Praluent 的全球銷售額，我們的合作夥伴賽諾菲確認，2016 年第一季銷售額為 1,300 萬美元。

Turning now to expenses, non-GAAP R&D expense was $392 million for the first quarter. Our unreimbursed R&D expense, which is calculated as total GAAP R&D expense, less R&D reimbursements from our collaborators and R&D non-cash share-based compensation expense, was $164 million for the first three months of 2016. Our press release includes all of the information that is required to calculate unreimbursed non-GAAP R&D expense. For 2016, we'd like to reiterate our previously provided guidance for non-GAAP unreimbursed R&D to be in the range of $875 million to $950 million.

現在來看費用，第一季的非GAAP研發費用為3.92億美元。2016 年頭三個月，我們的未報銷研發費用（以 GAAP 計算的研發總費用減去合作方的研發報銷費用和研發非現金股份支付費用）為 1.64 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 2016 年，我們重申先前提供的非 GAAP 未報銷研發費用的指導意見，即在 8.75 億美元至 9.5 億美元之間。

Non-GAAP SG&A expense was $230 million for the first-quarter 2016. We continue to expect non-GAAP SG&A expense in 2016 to be in the range of $925 million and $1 billion.

2016 年第一季非 GAAP 銷售、一般及行政費用為 2.3 億美元。我們繼續預期 2016 年非 GAAP 銷售、一般及行政費用將介於 9.25 億至 10 億美元之間。

Before I move on from our operating expenses, I'd like to take a moment to discuss the new guidance component we announced this morning, Sanofi reimbursement of Regeneron commercialization-related expenses, which represents reimbursement of internal and external costs in connection with preparing to commercialize, or commercializing, as applicable, Praluent, sarilumab, and, effective in the first quarter of 2016, dupilumab. This is a line item found within Sanofi collaboration revenue, and is referenced in table 4 of our press release.

在繼續討論我們的營運費用之前，我想花點時間討論一下我們今天早上宣布的新指導方針部分，即賽諾菲對再生元商​​業化相關費用的報銷，其中包括對準備商業化或商業化（如適用）Praluent、sarilumab 以及（自 2016 年第一季度起生效的）dupilumab 相關的內部和外部成本的報銷。這是賽諾菲合作收入中的一個項目，在我們的新聞稿表 4 中有所提及。

Going forward, we believe that providing guidance for this number will help in modeling the Sanofi collaboration revenue line item. For the first quarter of 2016, the reimbursement of Regeneron commercialization-related expenses was $73 million, and we expect this expense in 2016 to be in the range of $320 million and $370 million.

展望未來，我們相信提供該數字的指導將有助於對賽諾菲合作收入項目進行建模。2016 年第一季度，Regeneron 商業化相關費用的報銷金額為 7,300 萬美元，我們預計 2016 年的這項費用將在 3.2 億美元至 3.7 億美元之間。

Turning now to our non-GAAP tax adjustment, cash tax as a percentage of non-GAAP pre-tax net income for this quarter continues to be lower than our GAAP effective tax rate, primarily due to the tax impact of non-cash share-based compensation. On a non-GAAP basis, cash tax as a percentage of non-GAAP pre-tax net income for the first quarter of 2016 was approximately 38%.

現在來看看我們的非GAAP稅務調整，本季現金稅佔非GAAP稅前淨收入的百分比繼續低於我們的GAAP有效稅率，這主要是由於非現金股份支付的稅務影響。以非GAAP準則計算，2016年第一季現金稅佔非GAAP稅前淨收入的百分比約為38%。

For 2016, our guidance for cash tax as a percentage of non-GAAP pre-tax income remains at 35% to 45%. As previously reported, this includes a one-time tax of approximately $222 million related to the Sanofi immuno-oncology agreement. I'd also like to reiterate that the non-GAAP tax impact of the immuno-oncology upfront payment will be spread equally throughout 2016.

2016 年，我們對現金稅佔非 GAAP 稅前收入百分比的預期仍為 35% 至 45%。正如之前報導的那樣，這其中包括與賽諾菲免疫腫瘤協議相關的約 2.22 億美元的一次性稅款。我還要重申，免疫腫瘤預付款的非GAAP稅務影響將在2016年全年平均分攤。

Our capital expenditures for the first quarter of 2016 were $104 million. Given our latest review of capital expenditures, we are tightening and lowering our full-year 2016 capital expenditures guidance to a range of $550 million to $625 million, from $580 million to $680 million. These expenditures continue to build upon our manufacturing expansions in 2015, which include expanding our facilities in Rensselaer, New York, and Limerick, Ireland, as well as the continued expansion of our Tarrytown, New York, headquarters.

2016 年第一季度，我們的資本支出為 1.04 億美元。鑑於我們對資本支出的最新審查，我們將 2016 年全年資本支出指引範圍從 5.8 億美元至 6.8 億美元收緊並下調至 5.5 億美元至 6.25 億美元。這些支出延續了我們在 2015 年的生產擴張計劃，其中包括擴大我們在紐約州倫斯勒和愛爾蘭利默里克的工廠，以及繼續擴大我們在紐約州塔里敦的總部。

We ended the first quarter of 2016 with cash and marketable securities of $1.4 billion. As we've previously mentioned, we have been opportunistically entering into agreements to reduce the number of our outstanding warrants that we issued in 2011 in connection with our convertible debt. In the first quarter of 2016, we paid $242 million to reduce these outstanding warrants.

截至 2016 年第一季末，我們持有現金及有價證券 14 億美元。正如我們之前提到的，我們一直在伺機達成協議，以減少我們在 2011 年發行的與可轉換債券相關的未償認股權證的數量。2016 年第一季度，我們支付了 2.42 億美元來減少這些未償付的認股權證。

Before I conclude my remarks, I would briefly like to highlight certain financial components of the recent collaboration with Intellia Therapeutics. The April 2016 agreement grants Regeneron access to Intellia's CRISPR technology platform, as well as the right to discover and develop up to 10 targets on an exclusive basis over the course of the six-year agreement.

在結束演講之前，我想簡要地重點介紹一下最近與 Intellia Therapeutics 合作中的一些財務方面的內容。2016 年 4 月的協議授予 Regeneron 使用 Intellia 的 CRISPR 技術平台的權利，以及在六年協議期間獨家發現和開發多達 10 個靶點的權利。

In return, we paid a $75 million upfront payment to Intellia, which we anticipate recording as R&D expense in the second quarter of 2016, but plan to exclude from non-GAAP net income. The agreement also requires Regeneron to purchase up to $50 million of Intellia's shares contingent upon Intellia consummating its initial public offering.

作為回報，我們向 Intellia 支付了 7,500 萬美元的預付款，我們預計將在 2016 年第二季將其計入研發費用，但計劃將其從非 GAAP 淨收入中排除。該協議還要求 Regeneron 購買超過 5,000 萬美元的 Intellia 股份，前提是 Intellia 完成首次公開募股。

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

那麼，我想把電話轉回給麥可。

Thanks, Bob. Operator, at this time, we will open up the call for our Q&A period.

謝謝你，鮑伯。接線員，現在我們將開啟問答環節。

Thank you. And I will begin the question-and-answer session.

謝謝。接下來我將開始問答環節。

(Operator Instructions)

（操作說明）

Geoffrey Porges, Leerink Partners.

Geoffrey Porges，Leerink Partners。

Thank you very much, and appreciate the chance to ask the question but also the 10-Q being filed today. It was very helpful with all the detail. I suppose a couple of questions. George, first on Dupilumab. Now you have the first Phase 3 readout, what incrementally, have you learned from that in terms of the profile of Dupilumab?

非常感謝，也很感謝有機會提問，以及今天提交的 10-Q 表格。它提供的細節非常詳盡，很有幫助。我想問幾個問題。喬治，第一個接受度普利尤單抗治療。現在你們已經有了第一個 3 期臨床試驗結果，從中你們對 Dupilumab 的特性有了哪些新的認識？

But how does that also what you might focus on and potentially invest on for that molecule in the future? And then secondly, just on Medicare Part B you alluded to that and called it out in our risk and in the Q. What are you learning in the comment period and will you be submitting comments or are you aware of other comments and do you think there is any chance that this is going to be modified or altered in the schedule or scope? Thank you.

但這是否也意味著你未來可能會專注於並投資該分子？其次，關於醫療保險B部分，您在我們的風險評估和問答環節中都提到了這一點。您在意見徵詢期內了解到了什麼？您會提交意見嗎？或您是否了解其他意見？您認為該計劃的進度安排或範圍是否有可能進行修改或變更？謝謝。

All right. Well, this is George, I will take the Dupilumab question. I guess the more important thing that we learned from the two Phase 3 studies in atopic dermatitis was, number one, that we confirmed the impressive efficacy and the important benefit to patients and essentially, every single efficacy readout that we explored.

好的。我是喬治，我來回答關於度普利尤單抗的問題。我想我們從兩項異位性皮膚炎的 3 期研究中學到的最重要的一點是，第一，我們證實了其顯著的療效和對患者的重要益處，而且基本上我們探索的每一個療效指標都得到了證實。

So obviously that is very gratifying and comforting when one actually sees data that is as promising as your earlier data and suggests it can really make an important difference to the moderate-to-severe patients who really need new therapies to attack their disease. In addition the safety profile was also very comforting and we report extensively on it and it really does suggest that it is going to have a very important benefit risk profile for patients.

所以，當看到像您之前的數據一樣有希望的數據，並且表明它真的能對那些真正需要新療法來對抗疾病的中重度患者產生重要影響時，這顯然是非常令人欣慰和鼓舞的。此外，其安全性也令人非常放心，我們對此進行了廣泛的報道，這確實表明它對患者來說具有非常重要的獲益風險比。

I think that basically for atopic dermatitis, it really means that it is all green lights and all speed ahead and that we're really excited that we could be really bringing forward, as the FDA has designated a breakthrough therapy for these patients in need. As you know, we also have a pivotal study in asthma that has already been read out and we're in the midst of our first Phase 3, which is now our second confirmatory study in that indication as well.

我認為，對於異位性皮膚炎來說，這基本上意味著一切都已獲批准，我們將全力推進，我們非常興奮能夠真正地將這種療法帶給有需要的患者，因為 FDA 已經將其認定為突破性療法。如您所知，我們還有一項針對氣喘的關鍵性研究，該研究結果已經公佈，我們目前正在進行第一個 3 期臨床試驗，這也是我們針對此適應症的第二個確證性研究。

So Dupilumab is a very, very exciting program. As I already told you about today, I told you that in terms of the atopic dermatitis population, we're also moving to the pediatric population there as well, which is also an important unmet need area.

所以，Dupilumab是一個非常非常令人興奮的項目。正如我今天已經告訴你們的，就異位性皮膚炎患者群體而言，我們也正在將目光轉向兒科患者群體，這也是一個重要的未滿足需求領域。

In terms of the Part B, we fully understand that healthcare costs need to be appropriately controlled in this country. However, the approach that has been proposed by Medicare Part B would limit options for physicians and patients to give appropriate therapies to patients who need them.

關於B部分，我們完全理解我國的醫療保健成本需要適當的控制。然而，Medicare B 部分提出的方法會限制醫生和患者為有需要的患者提供適當治療的選擇。

For example, in the case of the retinal space, you could lead to physicians being required simply by the economics that are in place to force them to use an off-label repackaged bevacizumab, which, at least in the Protocol T trial, was shown in DME not to be as effective as the other therapies, they could be forced to be used for economic reasons. We see that a number of manufacturers as well as a number of congressmen and patient advocacy groups recognize that you have to preserve physicians' choice, so there will be a number of complaints and letters going into Congress, including our own.

例如，在視網膜空間方面，由於現有的經濟狀況，醫生可能會被迫使用重新包裝的非適應症貝伐珠單抗，而至少在 Protocol T 試驗中，貝伐珠單抗在治療糖尿病性黃斑水腫 (DME) 方面不如其他療法有效，因此出於經濟原因，醫生可能會被迫使用這種藥物。我們看到，許多製造商、國會議員和患者權益倡導團體都認識到，必須維護醫生的選擇權，因此將會有許多投訴和信件提交給國會，包括我們自己的投訴和信件。

Just to add, there are literally hundreds of congressmen who have said that this should not be done. There are others who have said that the unintended consequences that we're concerned about must be managed, the retinal groups, the ophthalmology groups, and that's not to mention all of the other interested parties, such as cancer and what have you. So I think many observers, which we are not experts on, but many observers in Washington would suggest that this seems unlikely but we'll have -- we're certainly going to do our best on this as well.

補充一點，實際上有數百名國會議員表示不應該這樣做。還有一些人表示，我們所擔心的意外後果必須加以控制，例如視網膜組織、眼科組織，更不用說其他所有相關方了，例如癌症等等。所以我認為，雖然我們不是這方面的專家，但華盛頓的許多觀察家會認為這似乎不太可能，但我們當然也會盡我們最大的努力。

I'm going to remind people to try to keep themselves to one question. I will let this one slide this time, Geoff. (laughter)

我要提醒大家盡量只提一個問題。這次我就放過你了，傑夫。（笑聲）

Chris Raymond, Raymond James.

克里斯·雷蒙德，雷蒙德·詹姆斯。

Thanks. Yes, so just one question here. So just on the PD-1, I'm struck by the news that this cutaneous squamous cell trial could be pivotal. I know Sanofi kind of broke that news last week, but I was wondering if you could provide a little more color on where this trial fits in with the overall development plans? And just looking at clinicaltrials.gov, there's not a ton of detail, and obviously, there is a lot of breadth of labeling potential with that type of molecule, so if you could maybe talk about where you plan to take this? That would be great.

謝謝。是的，這裡只有一個問題。就 PD-1 而言，我注意到這個皮膚鱗狀細胞癌試驗可能具有關鍵意義。我知道賽諾菲上週已經公佈了這一消息，但我很想知道您能否更詳細地介紹一下這項試驗在整體研發計劃中的位置？從 clinicaltrials.gov 網站上看，細節並不多，而且顯然，這類分子在標籤標註方面有很大的潛力，所以您能否談談您計劃如何推進這項研究？那太好了。

Well, we are implementing a highly integrated and very comprehensive effort in immunotherapy, and the -- it's obviously a very competitive area. And I think that there's a lot of room for people to make inroads here, provide new approaches and new benefits to patients and really make a difference in certain disease settings.

我們正在免疫療法領域實施一項高度整合且非常全面的舉措，而且——這顯然是一個競爭非常激烈的領域。我認為，人們在這裡有很多可以取得進展的空間，可以為患者提供新的方法和新的益處，並在某些疾病領域真正發揮作用。

How we're going to do that and how we hope to bring the best results to patients with the best combination is something that, at this point, that I think, or our thinking behind it, in this very competitive space, would rather keep largely to ourselves. Sorry for not informing you more but we just think that we have a very robust and highly integrated and comprehensive effort here and we intend to hopefully deliver important new approaches to patients.

我們將如何做到這一點，以及我們希望如何透過最佳組合為患者帶來最佳療效，我認為，在這個競爭非常激烈的領域，我們最好還是把這些想法或說我們背後的思考方式主要保留在我們自己手中。很抱歉未能向您提供更多信息，但我們認為我們在這裡開展了一項非常強大、高度整合和全面的工作，我們希望能夠為患者帶來重要的新方法。

Terence Flynn, Goldman Sachs.

Terence Flynn，高盛集團。

Congrats on all the pipeline progress, so just wondering for Dup, I know it's a little bit early but as we just think about the launch trajectory here, maybe you can just give us your perspective? Is this more likely to be a Praluent-type launch or more like EYLEA? And if you won't answer that directly, maybe you can just walk us through some of the factors we should consider as we think about the ramp. Thank you.

恭喜你們在產品線方面取得的所有進展！ Dup，我知道現在問這個問題有點早，但當我們考慮產品發布軌跡時，您能否分享一下您的看法？這比較像是 Praluent 式的上市，還是比較像 EYLEA 式的上市？如果你不能直接回答這個問題，或許你可以為我們介紹一下我們在考慮坡道時應該考慮的一些因素。謝謝。

Sure. It is Len, since we were all as a -- both you guys and us, were spot on EYLEA and Praluent, (laughter) I don't know why we wouldn't take a shot at Dupilumab. I think the fact is, obviously, we can't answer that directly, Terence, and since we've been, we and all of us, everybody has been wrong multiple times, that these things unfold as they unfold.

當然。是 Len，因為我們——包括你們和我們——都對 EYLEA 和 Praluent 的評價非常準確，（笑聲）我不知道為什麼我們不嘗試 Dupilumab。特倫斯，我認為事實顯然是，我們無法直接回答這個問題，而且因為我們一直以來，我們所有人，每個人都犯過很多次錯誤，這些事情都是順其自然地發展的。

The fact is to consider, obviously, is that you're already obviously seeing the PBS taken notice of this. I saw this in somebody's report that this is the next big class that they are worried about. There are a lot of patients out there that might fit our label, assuming we get the label, but I'm sure they are going to be, there's going to be utilization management, make sure they've tried there topical steroids or whatever that they really have the right diagnosis, et cetera, et cetera

顯而易見，PBS 已經注意到了這一點。我在一份報告中看到，這是他們接下來最擔心的一個大班級。假設我們能獲得標籤，那麼有很多患者可能符合我們的診斷標準。但我相信他們肯定會符合，我們會進行用藥管理，確保他們嘗試過外用類固醇或其他治療方法，確保他們確實得到了正確的診斷等等。

Now whether there will be warehousing of patients, quote, unquote, people lining up to get it, I -- it's just really impossible for us to tell but I would suspect that this will be one of those launches that will be patient-driven that as people get on the drug, if the results in the real world are anywhere near as close to the results we have seen in our Phase 3 trial so far, I am sure that, that patient drive will be tremendous.

至於是否會有大量患者排隊等候，我們真的無法判斷，但我懷疑這將是由患者驅動的藥物上市。如果真實世界的結果與我們目前在 3 期試驗中看到的結果非常接近，我相信，隨著人們開始服用這種藥物，患者的積極性將會非常高。

Because this is a terrible disease that people been suffering with for decades. Adults now have it without anything at all new to really help them in make a difference. If you look at -- whether you measure this by quality-of-life metrics, the increased risk of suicide, just the terrible burden that this puts on patients, we're optimistic that this drug can make a difference for them. So we're hopeful for a good launch but how that -- the actual ramp and whether it takes us awhile to get it going and what the coverage looks like and all of that, it's just too early to tell.

因為這是一種可怕的疾病，人們已經遭受了幾十年​​的折磨。現在成年人也擁有了它，但沒有任何新的方法真正幫助他們做出改變。無論從生活品質指標、自殺風險增加，或是其他任何方面來看，這種疾病給患者帶來的沉重負擔，我們都樂觀地認為這種藥物能為他們帶來改變。所以我們希望發布會一切順利，但是實際的進展情況，例如是否需要一段時間才能啟動，以及覆蓋範圍如何等等，現在說這些都為時過早。

Adnan Butt, RBC Capital Markets.

阿德南巴特，加拿大皇家銀行資本市場。

This is Ashland on for Adnan. Thank you for the question. Could you please put the Fasinumab safety data into context, given that the FDA has -- seems to have already been focused on safety in general?

這是阿什蘭為阿德南做的報道。謝謝你的提問。鑑於FDA似乎一直非常關注藥物安全性，能否請您將Fasinumab的安全性數據放在更廣闊的背景下解讀？

Well, maybe I will make a brief comment and then if George has anything to add, obviously, he is welcome. The-- our feeling is that, as George said in his talk, is that we did something in which we think was pretty important which is, we did an extensive and detailed screening of patients with x-rays and RIMs before they were ever exposed to drugs.

嗯，我可能會簡單說幾句，如果喬治有什麼要補充的，當然，我們非常歡迎他發言。我們的感覺是，正如喬治在他的演講中所說，我們做了一件我們認為非常重要的事情，那就是，在患者接觸藥物之前，我們用 X 光和 RIM 對患者進行了廣泛而詳細的篩檢。

That demonstrated that some of these things that people were concerned about might be somewhat induced by drug were really fairly prevalent in the population, whether they be insufficiency fractures, whether they be osteonecrosis, and so on. So I think that, that was important and I do think that the FDA has come around to thinking that this has to be looked at carefully and we've -- and that's what we're doing and the right patients have to be studied and that is also what we're doing.

這表明，人們擔心的一些可能由藥物引起的疾病，無論是骨質疏鬆性骨折、骨壞死等等，在人群中其實相當普遍。所以我認為這一點很重要，而且我認為FDA已經意識到必須認真審視這個問題，而我們正在做的就是認真審視這個問題，必須對合適的患者進行研究，這也是我們正在做的。

They also have had concerns about whether or not any one of these drugs individually, or as a class, could have effect on sympathetic nerves and sympathetic nervous system function. We also looked at that pretty well and we will have more to tell you about that in upcoming meetings but we didn't see any evidence at all so that so far, things look reasonable.

他們也擔心這些藥物中的任何一種，或作為一類藥物，是否會對交感神經和交感神經系統功能產生影響。我們也對此進行了相當深入的研究，我們將在接下來的會議上向大家詳細介紹，但我們完全沒有發現任何證據，所以到目前為止，情況看起來還算合理。

But as, I think as George said, it is a small study and we are underpowered to pick a very small increases in some of these things and that is why we're going to study thousands and thousands of patients in our Phase 3 program.

但正如喬治所說，這是一項小規模研究，我們沒有足夠的統計能力來檢測出某些指標的微小增長，這就是為什麼我們要在 3 期臨床試驗中研究成千上萬的患者。

Yes, and to add to that, I think that the -- one of the biggest underlying fears for this class, certainly by outside people but also by ourselves, was that the very small increase in certain arthropathy events, certain joints pathologies, that was seen particularly in combination with NSAIDs, but also a small increase even in monotherapy might actually be reflecting a much bigger, somewhat invisible problem that there was a bigger destructive process that would then be seen over longer periods in time and so forth. This is why we did this, as Len said, this extensive imaging of both the index joints but also non-index joints to see whether overall, the skeleton was really changing. As we've already said, the thing that was very gratifying was that, unfortunately, for these patients suffering from this important problem, there is already significant skeletal pathology at baseline.

是的，而且我認為，對於這類患者來說，最大的潛在擔憂之一，當然也包括外界人士和我們自己，是某些關節病事件、某些關節病變的輕微增加，尤其是在與非類固醇抗發炎藥聯合使用時，但即使在單一療法中也略有增加，這可能實際上反映了一個更大的、某種程度上不易察覺的問題，即某種程度上存在一個更大的破壞性過程，該過程將正如 Len 所說，這就是我們進行這項檢查的原因，我們對索引關節和非索引關節進行了廣泛的成像，以查看骨骼整體是否真的發生了變化。正如我們之前所說，令人欣慰的是，不幸的是，對於這些患有這種重要疾病的患者來說，他們在基線時就已經存在嚴重的骨骼病變。

These patients have the so-called subchondral insufficiency fractures and you can even see undiagnosed osteonecrosis in these patients and so forth. These events, both in the index and the non-index joints, were not dramatically increased by treating with NGF and one fear, for example, was that these asymptomatic subchondral insufficiency fractures may be happening much more frequently with drug and intervention leading to much higher incidences of events down the line. So it was very comforting not to see this.

這些患者患有所謂的軟骨下骨不全性骨折，甚至在這些患者中還可以看到未確診的骨壞死等等。無論是在索引關節或非索引關節中，這些事件都不會因使用 NGF 治療而顯著增加。例如，人們擔心，這些無症狀的軟骨下骨不全骨折可能會隨著藥物和介入措施的實施而更頻繁地發生，導致日後事件發生率更高。所以沒看到這些真是讓人很欣慰。

That said, there remain, as with any drug, and certainly with the drug this active, there will continue to be risks associated with treatment but one has to balance that with all of the benefits that could be provided. Pain is a very serious problem for a lot of people, especially people suffering from osteoarthritis and the options, obviously, as you know, are quite limiting with no new mechanism of action drugs added to this field for decades. So the possibility and the opportunity that a new mechanism of action for class that might have different profile and also different risk profile as compared to, for example, opiates and NSAIDs and other drugs with serious risks, we think and offer important option for patients.

也就是說，任何藥物都存在風險，這種活性藥物尤其如此，治療過程中肯定會存在風險，但必須權衡其帶來的所有益處。疼痛對許多人來說都是一個非常嚴重的問題，尤其是對骨關節炎患者而言。顯然，如你所知，由於幾十年來該領域沒有新增任何作用機制的藥物，治療選擇非常有限。因此，我們認為，對於這類藥物而言，如果存在一種新的作用機制，其特性和風險特性可能與鴉片類藥物、非類固醇抗發炎藥和其他具有嚴重風險的藥物有所不同，那麼它就為患者提供了一個重要的選擇。

This is Michael. I just want to make sure we -- I added because when talking about pain, you really have to keep into context of really what an epidemic in the United States in terms of drug, opioids abuse and overdose with quadrupling the number of opioid deaths in the past number of years as well as from the CDC website, nearly 0.5 million people died from drug overdoses from 2000 to 2014; almost 80 Americans die every day from an opioid overdose. I just think you have to keep into context that pain -- having a new pain medicines can really -- is really important.

這是邁克爾。我只是想確保我們——我補充說，因為在談論疼痛時，你真的必須考慮到美國藥物濫用和阿片類藥物過量服用已經達到了多麼嚴重的程度，過去幾年阿片類藥物死亡人數翻了兩番，而且根據美國疾病控制與預防中心網站的數據，2000 年至 2014 年間，近 50 萬人死於藥物過量；我認為你必須把疼痛——尤其是服用新的止痛藥——放在具體的語境中看待，這真的非常重要。

Ying Huang, Bank of America.

黃穎，美國銀行。

Just first on the CMS proposal again. I think you guys mentioned in DMU, you do have superiority against some of the other medications but in AMD, I was wondering if you guys can provide your thought on whether it could be classified as so-called therapeutically submitter cost and therefore, it could be subject to a reference pricing in the second Phase of that demo.

再次成為CMS提案的第一名。我認為你們在DMU中提到過，你們的藥物確實比其他一些藥物具有優勢，但在AMD方面，我想知道你們能否就其是否可以歸類為所謂的治療提交成本，從而是否可以在該演示的第二階段中受到參考定價的影響發表一下看法。

And then also on the ODYSSEY outcomes trial, I know the trial is powered -- 90% power to show 15% CV risk reduction. Maybe you can provide us on whether you think the payers would be excited about that 15% CV risk reduction. Thank you.

此外，關於 ODYSSEY 結果試驗，我知道該試驗具有足夠的統計效力——90% 的統計效力可以顯示 15% 的心血管風險降低。您能否告訴我們，您認為支付者是否會對降低 15% 的心血管風險感到興奮？謝謝。

So Ying, which question do you want answered because Michael's holding up a sign that says one question. Even though he loves you, he said -- which ones does he want?

所以英，你想讓麥可回答哪個問題？因為麥可舉著一個牌子，上面寫著一個問題。即使他愛你，他說──他想要哪一個？

Len, you are the boss. (laughter)

萊恩，你是老大。（笑聲）

Not true. Which question, Ying?

並非如此。英，你問什麼問題？

All right. Maybe second is probably more Important, from my perspective.

好的。從我的角度來看，或許第二點更重要。

Well, it's -- I think that the outcomes data, as we saw with ezetimibe, it's not simply a matter of statistical significance. I think what people will be looking for is the robustness and the quality of the data set, et cetera, et cetera. Certainly, we powered the study based on expert input of where they thought that would be if we saw the results, that would be a meaningful results for patients.

嗯，我認為——正如我們從依澤替米貝的研究中看到的那樣，結果數據不僅僅是統計顯著性的問題。我認為人們會關注的是資料集的穩健性和品質等等。當然，我們進行這項研究是基於專家們的意見，他們認為如果我們看到結果，這些結果對病人來說將具有意義。

But of course, it's not just one number; it's not just a statistical significance. You want to see how the whole data set looks like, and I think somebody said about ezetimibe, they had statistical significance but if you blink, you could miss it and we tried to design a study and set the parameters such that if we saw the result, we could feel confident about it, that we were making a difference in these outcomes to patients.

當然，這不僅僅是一個數字；這不僅僅是統計顯著性。你想看看整個資料集是什麼樣子，我想有人說過關於依折麥布，他們有統計意義，但如果你眨一下眼，你可能就會錯過它，所以我們嘗試設計一項研究並設定參數，以便如果我們看到結果，我們就能確信我們正在改變患者的這些結果。

Ying, I can't leave the EYLEA one hang out there. I'm sorry.

瑩，我不能讓EYLEA那個掛在那兒不管。對不起。

I appreciate it, Bob.

謝謝你，鮑伯。

If you remember back to the VIEW-1 and VIEW-2 studies, we actually designed studies that compared ourselves to what was a standard of care branded agent which was ranibizumab monthly and we studied EYLEA dose, both monthly as well as every eight weeks. What we saw is very similar results with the EYLEA every eight-week dosing into the Lucentis' every four week dosing.

如果你還記得 VIEW-1 和 VIEW-2 研究，我們實際上設計了一些研究，將我們自己與當時的標準治療品牌藥物雷珠單抗（每月一次）進行了比較，我們研究了 EYLEA 的劑量，包括每月一次和每八週一次。我們發現，EYLEA 每八週給藥一次與 Lucentis 每四周給藥一次的結果非常相似。

This is a major advantage to elderly patients who can't get into the physician's office on a regular basis. So they are not therapeutically equivalent. EYLEA has a longer durability of effect. I would also point out there are data in a subset of patients in the VIEW studies that indicates that there are patients who are more refractory to anti-VEGF therapy, especially those who have received prior anti-VEGF therapy, who may need more anti-VEGF treatment, and what we're seeing in those patients, we are able to drive them up better with EYLEA than with Lucentis.

對於無法定期前往醫生診所就診的老年患者來說，這是一項重大優勢。因此，它們在治療上並不等同。EYLEA 的藥效更持久。我還想指出，VIEW 研究的部分患者數據表明，有些患者對抗 VEGF 療法的反應較差，尤其是以前接受過抗 VEGF 療法的患者，他們可能需要更多的抗 VEGF 治療。我們發現，在這些患者中，使用 EYLEA 比使用 Lucentis 能更好地提高他們的治療效果。

George also. I (laughter) -- I also have to make a few comments here. I think, really, Bob touched on an important point, that our drug showed compared to, at the time, optimum standard of care that doubling the interval could produce at least as good results from the -- in terms of visual acuity but also even better results in terms of controlling vascular leak and retinal swelling and so forth. I think that we all have to really consider that maybe, and I hate to say it, because some people are going to say, hey, don't challenge the physicians here but I think the physicians here and we understand the limitations of the real world and practice are doing a huge disservice to patients in terms of the systematic under treatment that is probably occurring in this field.

喬治也是。我（笑）——我也要在這裡補充幾點。我覺得，鮑伯確實觸及了一個重要的點，那就是我們的藥物與當時的最佳標準治療相比，將治療間隔延長一倍至少可以產生同樣好的效果——在視力方面，甚至在控制血管滲漏和視網膜腫脹等方面也能取得更好的效果。我認為我們都必須認真考慮一下，雖然我很不願意這麼說，因為有些人會說，嘿，別質疑這裡的醫生，但我認為這裡的醫生，我們理解現實世界的局限性，但就這個領域可能存在的系統性治療不足而言，他們正在對患者造成巨大的傷害。

There is an enormous drive to try to get patients less trips to the office, less injections. You've probably seen the release of recent data with long four- and five-year follow-ups, and after you take the patients over the more controlled phases of the study where they are getting, in general, in most studies, monthly treatment, are very carefully monitored treatment, they essentially lose almost all their vision gain over this -- later years of four- and five-year follow-ups.

目前各方都在大力推動減少患者去診所的次數和注射次數。您可能已經看到最近發布的數據，其中包含長達四到五年的追蹤。在研究中，患者進入了更受控制的階段，通常情況下，在大多數研究中，他們接受的是每月一次的治療，並且治療過程受到非常仔細的監測。然而，在之後的四年或五年追蹤中，他們基本上失去了所有視力改善。

We believe that the data and the evidence suggests that this is really due to systematic under treatment, patients getting less and less treatment and particularly, in that setting. If you want to deliver the best care to patients, you should be delivering the best agent that has the longest duration of action and we think that the only agent that is really demonstrated that convincingly is EYLEA.

我們認為，數據和證據表明，這實際上是由於系統性治療不足造成的，患者接受的治療越來越少，尤其是在那種環境下。如果你想為患者提供最好的護理，你應該提供作用時間最長的最好藥物，我們認為唯一真正令人信服地證明這一點的藥物是 EYLEA。

So I think to save patients' visions, you saw the long-term trials. Patients are losing visions. Physicians are not doing the right things by their patients; they are systematically under treating and particularly, in those settings, they should be getting the best drug that protects patients against this vision loss.

所以我認為，為了保護患者的視力，你們也看到了長期試驗。患者正在失去視力。醫生們沒有盡到對病人應盡的責任；他們系統性地治療不足，尤其是在這些情況下，他們應該給病人使用最好的藥物來保護病人免受這種視力喪失的影響。

It would be a disservice if, in fact, incentives and so forth are driven to the use of an inferior agent which will cost patients -- think about it. Your patient, who can't drive. Your patient, who can't read. You're now given a drug. All of a sudden, you gain two or three lines of visions; that changes the world literally for you. Okay. You could do things you can't do before and now we've develop a system that allows you to lose that. I think we have to think about how we want to practice medicine in this country if we create a situation that allows that.

如果實際上激勵措施等導致使用劣質藥物，從而讓患者付出代價，那將是一種損害——想想看。您的病人，他不能開車。你的病人，他不識字。現在給你服用了一種藥物。突然間，你獲得了兩三條視線；這徹底改變了你的世界。好的。你以前能做很多事，但現在我們開發了一個系統，讓你失去這些能力。我認為，如果我們創造了一個允許行醫的環境，我們必須思考我們希望在這個國家如何行醫。

I think the physicians, George, are right there with you, and it would be hard for me to imagine that once the physicians are heard on this subject that Avastin, an off-label inferior product by a -- based on a government study could be set the standard.

喬治，我認為醫生們和你的想法完全一致。我很難想像，一旦醫生就此問題發表意見，阿瓦斯汀（Avastin）這種未經批准的劣質產品——基於一項政府研究——會成為標準。

So, okay, next question.

好的，下一個問題。

Robyn Karnauskas, Citigroup.

Robyn Karnauskas，花旗集團。

Congratulations on all the innovation. I feel like one of the few companies where there's so much going on, on the call and you provide clarity.

祝賀你們所取得的所有創新成就。我覺得你們公司是少數幾家在電話會議上討論很多事情，但你們又能把事情解釋得如此清晰的公司之一。

I guess, I'm going to go to Sarilumab and ask a question about the opportunity, because Sanofi does highlight this a lot and I feel like it's -- those of us on the Street are more skeptical about the opportunity. Help us understand how -- what your view is of Sarilumab and how you think about this. It's is a competitive space, there's stuff coming up behind it from AbbVie. How are you thinking about the strength of that data and do you have any understanding of the strategy and how you could take share from the current market or expand the current market?

我想，我應該去問問 Sarilumab 的相關情況，因為賽諾菲確實經常強調這一點，但我感覺——我們這些華爾街人士對這個機會持懷疑態度。請協助我們了解您對Sarilumab的看法以及您對此的看法。這是一個競爭激烈的領域，艾伯維公司也即將推出相關產品。您如何看待這些數據的效力？您是否了解該策略以及如何從現有市場份額中奪取份額或擴大現有市場份額？

So, I'm sure -- Robyn, thanks for your comments about innovation. Obviously, George and I have tried to build a Company for the last three decades that is driven by, truly driven by science and innovation so we appreciate you taking note of that. Bob can comment without giving away all of our intricate strategy on what the opportunity for IL-6 might be.

所以，我確信——羅賓，謝謝你對創新的評論。顯然，在過去的三十年裡，喬治和我一直努力打造一家真正由科學和創新驅動的公司，所以我們很高興您注意到這一點。Bob 可以發表評論，但不會洩露我們關於 IL-6 機會的複雜策略。

Robyn, as I pointed out earlier, I think when that Genentech launched Actemra into the US marketplace, it was very much a market dominated by growing TNF inhibitors, and they were a single company trying to educate on the role of IL-6 in rheumatoid arthritis and the potential benefits of using an IL-6 inhibitor earlier. It is always more beneficial -- we've seen this, for example, in the statin class, whereas more and more statins became available, they grew the market.

羅賓，正如我之前指出的那樣，我認為當基因泰克公司將Actemra引入美國市場時，該市場很大程度上被不斷增長的TNF抑製劑所主導，而他們是一家試圖普及IL-6在類風濕性關節炎中的作用以及更早使用IL-6抑製劑的潛在益處的公司。這樣做總是更有益的——例如，在斯他汀類藥物中，隨著越來越多的斯他汀類藥物上市，市場也隨之擴大。

We believe that this is the opportunity for this class that we can educate physicians more. One, as I said earlier, on the central role of IL-6 in both the signs and symptoms of RA, but as well as in joint destruction, which we feel is very important. Physicians need to understand they shouldn't stay with the TNF inhibitor which, over time, each additional TNF inhibitor does not deliver the efficacy that they receive with the first TNF inhibitor, so there's a benefit of moving to a new class and IL-6 really does have a central role, both in symptoms as well as bone destruction.

我們相信，對於這個班級來說，這是一個可以更好地教育醫生的機會。第一，正如我之前所說，IL-6 在 RA 的體徵和症狀中起著核心作用，在關節破壞中也起著核心作用，我們認為這一點非常重要。醫生需要明白，他們不應該一直使用 TNF 抑制劑，因為隨著時間的推移，每增加一種 TNF 抑制劑都無法達到第一種 TNF 抑制劑的療效，所以改用新的藥物類別是有益的，而 IL-6 確實在症狀和骨破壞方面都起著核心作用。

I also -- just to add that there's something about -- there is some historical accidents have occurred here. And the order of the drugs came along and having to deal with pricing and with methotrexate being the main state, it's a very cheap drug; it is effective. But it is not the most innocuous drug in the world from its side effects and what have you, and there are many people, I'm told particularly women, who don't like being on the product and there seems to be movement towards monotherapy.

我還要補充一點，這裡曾經發生過一些歷史事故。然後，藥物的訂購流程就出現了，我們不得不考慮定價問題，而甲氨蝶呤是主要藥物，它是一種非常便宜的藥物；而且療效顯著。但它並非世界上最無害的藥物，因為它有副作用等等，而且據我所知，很多人，特別是女性，不喜歡服用這種藥物，而且似乎有趨勢是採用單一療法。

Remember, methotrexate, some have argued that for some drugs, methotrexate provides the immunosuppression for the Biologics so that any immune-related, if you will, blockade of effect doesn't appear as quickly. Suffice it to say, maybe George can comment on that more, but I can say that when we look head to head against the market leader, AbbVie, in the monotherapy setting, you've seen our data.

記住，甲氨蝶呤，有人認為，對於某些藥物，甲氨蝶呤可以提供生物製劑的免疫抑製作用，這樣任何與免疫相關的（如果你願意這麼說的話）作用阻斷就不會那麼快出現。總而言之，或許喬治可以對此發表更多評論，但我可以肯定地說，當我們在單一療法領域與市場領導者艾伯維進行正面較量時，你們已經看到了我們的數據。

We had a superior result, so --

我們取得了優異的成績，所以——

But I also do, just to finish the story, Sarilumab is not a me-too drug. I don't want to do cross-comparison trial data right now but I think if you look at the prescribing information for subcutaneous Actemra, and you look at the results, we reported, with our product, we are very encouraged about the product profile that our product, which has higher binding affinity to IL-6 is going to offer in the marketplace; maybe George wants to comment on that.

但為了完整地講述這個故事，我還要補充一點：Sarilumab 不是一種仿製藥。我現在不想做交叉比較試驗數據，但我認為，如果你看看皮下注射 Actemra 的處方信息，再看看我們報告的產品結果，我們對該產品在市場上的產品特性感到非常鼓舞，該產品對 IL-6 具有更高的結合親和力；也許喬治想對此發表評論。

I think it is important to just highlight a few things because once again, it all comes down to the patients and doing the best by the patients, and I think as Bob and Len already mentioned, if you look at the signs, it doesn't necessarily make sense to start all patients, particularly patients in monotherapy settings with the TNF and that may be a historical accident. It also doesn't make sense to just continue patients cycling on TNF. If there is an alternative that can deliver them better symptomatic relief.

我認為有必要強調幾點，因為歸根結底，一切都取決於患者，取決於如何為患者做到最好。而且，正如鮑伯和倫已經提到的那樣，如果你觀察一下症狀，你會發現對所有患者，特別是接受 TNF 單藥治療的患者，進行 TNF 治療未必有意義，這可能只是一個歷史遺留問題。繼續讓病人循環使用 TNF 也是沒有道理的。如果有其他方法可以更好地緩解他們的症狀。

So we think there is enormous opportunity for this class. Importantly, in this class and as Bob said, the most -- one of the most important things that I think that patients and physicians are concerned about is irreversible bone loss. That is one thing you can't get back and that is one thing that is looked at in this field.

所以我們認為這個班級有很大的發展機會。重要的是，正如鮑伯所說，在這個班級裡，我認為病人和醫生最關心的事情之一就是不可逆的骨質流失。這是你無法挽回的事情，也是這個領域需要關注的事情之一。

As you know, Actemra is now growing through a subcutaneous formulation. If you look in the label, there is less -- according to the subcutaneous formulation that is used there in terms of the innovation of the irreversible bone loss, there is less than 50% inhibition by the subcutaneous formulation in terms of Actemra, in terms of the irreversible bone loss.

如您所知，Actemra 目前正透過皮下注射劑型不斷發展壯大。如果你查看標籤，你會發現－根據皮下製劑在治療不可逆骨質流失的創新作用，Actemra 皮下製劑對不可逆骨質流失的抑制率不到 50%。

If you look at our study, we offer two doses and if they both get approved, our higher subcutaneous dose give greater than 90% inhibition of irreversible bone loss. So as Bob said, these are not identical agents. This is not a me-too; there's important differences and there is an important opportunity to do better by patients in terms of the monotherapy setting and in terms of not just cycling through drugs that maybe aren't working for the patients and putting them on a different mechanism of action drug.

如果您查看我們的研究，我們會發現我們提供了兩種劑量，如果這兩種劑量都獲得批准，我們較高的皮下劑量可以抑制超過 90% 的不可逆骨質流失。正如鮑伯所說，這些並不是完全相同的代理人。這不是複製舊方法；兩者之間存在重要差異，並且在單藥治療方面，我們有機會更好地為患者服務，而不僅僅是不斷更換可能對患者無效的藥物，並讓他們使用作用機制不同的藥物。

I will also say that there have been, let me call it, commercial gains that have been played out there in that in negotiations that have gone on with the PBMs, where people have used certain multiple indications as a way to drive use and other indications from what we can tell and I think the PBMs are wising up to that and moving to indication-specific pricing and negotiations. We actually feel that we might be entering the market at a reasonably good time where, with a lot of dynamics going on in a good product, you can make inroads. Now I don't think this is going to be an easy road and I wouldn't be -- I don't think you can just assume that we are going to jump in and grab huge market share right off the bat but I think it's -- we can build this into a significant opportunity over time. It is more of -- going to be like a slow and steady.

我還要說，在與藥品福利管理機構 (PBM) 進行的談判中，有人利用某些多重適應症來推動藥品使用和其他適應症，從我們的角度來看，這其中存在著商業利益。我認為 PBM 已經意識到這一點，並開始轉向針對特定適應症的定價和談判。我們覺得我們進入市場的時機可能相當不錯，因為好的產品會帶來許多動態變化，我們可以藉此取得進展。現在我認為這不會是一條輕鬆的路，我也不認為——我認為你不能想當然地認為我們會立刻搶佔巨大的市場份額，但我認為——隨著時間的推移，我們可以把它發展成一個巨大的機會。更像是——會像慢而穩。

Alethia Young, Credit Suisse.

Alethia Young，瑞士信貸。

Congrats on everything you have going on there. Just going back to the Praluent trends that you said in your script, I guess you said that 50% of new -- Praluent got 50% of the new script. Can you just talk about what behavior might be driving that 50%? Is it something that you're adjusting or changing that is resounding in the profile?

恭喜你在那裡取得的一切成就。回到你在劇本中提到的 Praluent 的發展趨勢，我想你說的是，50% 的新劇本——Praluent 獲得了 50% 的新劇本。您能否談談是什麼行為導致了這 50% 的差異？個人資料中體現的，是您正在調整或改變的某些方面嗎？

I think it's hard to know for sure, and we only have another minute here so I don't want to get into great detail, but one thing that is important is that the -- there's new coverage that's come into play, particularly in the Medicare space, which was really only recently coming on where, in those plans, they chose a -- which was most of them, a single agent as the priority drug. We were, I think, selected about 90% of the time.

我覺得很難確定，而且我們只有一分鐘時間了，所以我不想深入細節，但有一點很重要——新的保險覆蓋範圍已經生效，尤其是在醫療保險領域，這實際上是最近才出現的，在這些計劃中，他們選擇了一種——大多數計劃都選擇了一種單一藥物作為優先藥物。我認為，我們大約有 90% 的機率被選中。

I think that there is some new coverage, new utilization management and obviously, we're working hard at this, but I don't think you can consider one week a trend, whether it's going one direction. It's just a data point. But right now, the market seems to be split roughly, more or less, equally, based on that data point, how that goes over time, obviously, that is what the competitive marketplace is all about.

我認為現在有一些新的覆蓋範圍和新的利用管理措施，顯然，我們正在為此努力，但我認為你不能把一周的情況當作一種趨勢，無論它朝著哪個方向發展。這只是數據點而已。但就目前來看，市場似乎大致平分秋色，根據這個數據點來看，隨著時間的推移情況會如何變化，顯然，這就是競爭性市場的本質所在。

But I think our most important effort right now has to be on making sure that the right patients get access to drug and that is really where both companies are focused; it is an important thing for the class. The patients who need drug have to get an opportunity to have access to it.

但我認為，我們現在最重要的工作是確保合適的患者能夠獲得藥物，這也是兩家公司真正關注的重點；這對整個產業來說都是一件重要的事情。需要藥物的患者必須有機會獲得藥物。

Operating, we have time for just one last question.

現場還有時間回答最後一個問題。

Matthew Harrison, Morgan Stanley.

馬修·哈里森，摩根士丹利。

Thanks for fitting me in. I had just two-related Praluent questions. You said that two payers had loosened their criteria. I'm wondering if you can just be more specific about that? Who they were and exactly what they loosened?

謝謝你安排我過來。我只有兩個與Praluent相關的問題。你說過有兩家付款方放寬了付款條件。請問您能否更具體地說明一下？他們是誰？他們究竟鬆開了什麼？

And then you were talking about an improvement in the number of RXs that were filled; is that just more people getting through the utilization management criteria? Could you just be more specific about that comment as well? Thanks.

然後您提到處方配藥數量的增加；這是否只是因為更多的人符合了用藥管理標準？您能否更具體地解釋一下那條評論？謝謝。

Sure. Our contracts with the payers don't allow us to disclose the specific ones who have changed their utilization management criteria but what I can say, as I did earlier, what they did is removed a trial period of 12-plus weeks of Zetia after maximally-tolerated statin therapy from their utilization management criteria. That was setting up a delay in access to PCSK9 inhibition. The physicians were having to put them on Zetia and then wait and it was causing a real backlog for the doctors. So that has been removed by two of the payers.

當然。我們與付款方的合約不允許我們透露具體是哪些付款方更改了其使用管理標準，但我可以像我之前所說的那樣說，他們所做的就是從其使用管理標準中刪除了在最大耐受性他汀類藥物治療後使用 Zetia 12 週以上的試用期。這將導致 PCSK9 抑制劑的獲取延遲。醫生們不得不給他們服用澤替尼，然後等待，這給醫生們造成了很大的工作積壓。所以，其中兩家付款方已經取消了這項付款。

In terms of the improvement of the number of people going through the hub, I think what I can say is, one, the -- as Len said, payers have come on board now and so especially Medicare patients now are getting access to therapy. I think the other thing is that the physicians as well as the specialty pharmacies are better understanding how to make the prescription process better. Now that's not -- it's not easy right now; we continue to work on improving it but at least it has gotten better for some patients.

就透過該中心就診的人數的改善而言，我認為我可以說的是，第一，正如 Len 所說，支付方現在已經加入進來，因此特別是 Medicare 患者現在能夠獲得治療。我認為另一點是，醫生和專科藥局都更了解如何改善處方流程。現在情況並非如此——目前還不容易；我們仍在努力改進，但至少對一些患者來說情況已經有所改善。

So just one last comment from -- this is Len, in our effort to answer all of your questions, what we're trying to do is give you some insight into our thinking, like why we went forward with something. We're not trying to make cross-trial comparisons per se. We're trying to give you an idea of why we went forward and what we saw, how would felt we were differentiated. What we can say out in the marketplace, obviously, will be limited based on what we actually get in various labels that are pending.

最後，我是 Len，我想再補充一點——為了回答你們所有的問題，我們想讓你們了解我們的想法，例如我們為什麼要做某件事。我們並不是要進行跨試驗比較。我們想讓您了解我們為什麼會這樣做，我們看到了什麼，以及我們覺得自己有何不同。顯然，我們在市場上能說的話，會受到各種待定標籤實際結果的限制。

With that, I would just say that we are pleased that the innovation machine continues to turn and produce lots of exciting things that we'll hope to update you in the scientific literature, and in the presentations that are upcoming, lots of things we -- George did not get a chance to talk about that are exciting. So we appreciate your interest and we hope you -- to continue to be able to update you over time. Thank you very much.

最後，我想說，我們很高興看到創新機器繼續運轉，並產生了很多令人興奮的成果，我們希望能在科學文獻和即將進行的演講中向大家匯報這些成果，還有很多我們——喬治——沒有機會談到的令人興奮的事情。感謝您的關注，我們希望能夠繼續為您提供最新資訊。非常感謝。

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

女士們、先生們，今天的會議到此結束。感謝您的參與。您現在可以斷開連線了。