雷傑納榮製藥 (REGN) 2019 Q1 法說會逐字稿

Good morning and welcome to the Regeneron Pharmaceuticals First Quarter 2019 Earnings Conference Call. My name is Brandon, and I'll be your operator for today. (Operator Instructions) Please note this conference is being recorded.

早安，歡迎參加 Regeneron Pharmaceuticals 2019 年第一季財報電話會議。我叫布蘭登，今天由我來為您接聽電話。（操作員說明）請注意，本次會議正在錄音。

And I will now turn it over to Mark Hudson. You may begin, sir.

現在我將把麥克風交給馬克·哈德森。先生，您可以開始了。

Thank you, Brandon. Good morning, and welcome to Regeneron Pharmaceuticals First Quarter 2019 Conference Call. An archive of this webcast will be available on our website for 30 days under Events.

謝謝你，布蘭登。早安，歡迎參加 Regeneron Pharmaceuticals 2019 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」欄位下保留 30 天。

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

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

I'd also like to remind you that remarks made on this call today include forward-looking statements about Regeneron. Such statements may include but are not limited to those related to Regeneron and its products and business, financial forecasts and guidance, development programs and related anticipated milestones, collaborations, finances, regulatory matters, intellectual property, pending litigation and competition. Each forward-looking statement is subject to risks and uncertainties that can cause actual results and events to differ materially from those projected in that statement. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission or SEC, including its Form 10-Q for the quarter period ended March 31, 2019, which has been filed with the SEC today. Regeneron does not undertake any obligation to update publicly any forward-looking statement, whether as a result of new information, future events or otherwise.

我還想提醒各位，今天電話會議上發表的言論包含 Regeneron 的前瞻性陳述。此類聲明可能包括但不限於與 Regeneron 及其產品和業務、財務預測和指導、開發計劃和相關預期里程碑、合作、財務、監管事項、智慧財產權、未決訴訟和競爭相關的聲明。每項前瞻性聲明都存在風險和不確定性，可能導致實際結果和事件與該聲明中預測的結果和事件有重大差異。有關這些及其他重大風險的更完整描述，請參閱 Regeneron 向美國證券交易委員會 (SEC) 提交的文件，包括其截至 2019 年 3 月 31 日的季度報告（10-Q 表格），該報告已於今日提交給 SEC。Regeneron公司不承擔任何公開更新任何前瞻性聲明的義務，無論是由於新資訊、未來事件或其他原因。

In addition, please note that GAAP and non-GAAP measures will be discussed in today's call. Information regarding our use of non-GAAP financial measures and a reconciliation of those measures to GAAP is available on our financial results press release, which can be accessed on our website.

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，請參閱我們網站上發布的財務業績新聞稿。

Once our call concludes, Bob Landry, Jay Markowitz and the IR team will be available to answer further questions.

通話結束後，Bob Landry、Jay Markowitz 和投資者關係團隊將回答進一步的問題。

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

接下來，我將把電話交給我們的總裁兼執行長倫·施萊弗博士。

Thanks, Mark. Good morning to everyone.

謝謝你，馬克。大家早安。

EYLEA and DUPIXENT kicked off a successful start to 2019. For the first quarter, total aggregate sales of all Regeneron-invented products were $2.27 billion, a 23% year-over-year increase. We are pleased with the early launch of Libtayo, our foundation immuno-oncology, and we made significant progress across our deep and diverse pipeline. EYLEA, which was approved in the U.S. late in 2011, continues to deliver in its eighth year in the market, with U.S. sales of $1.07 billion, a 9% year-over-year increase. I'm proud to say that EYLEA's growth has come without price increases. EYLEA has an established efficacy and safety profile with over 25 million injections sold worldwide. In addition to a demographic tailwind and approved indications, we view our pending new approval in diabetic retinopathy as a new opportunity potential -- to potentially drive growth.

EYLEA 和 DUPIXENT 為 2019 年開了個好頭。第一季度，Regeneron公司所有自主研發產品的總銷售額為22.7億美元，年增23%。我們對Libtayo的早期上市感到滿意，Libtayo是我們的基礎免疫腫瘤學產品，在豐富多樣的研發管線中也取得了重大進展。EYLEA 於 2011 年底在美國獲得批准，上市第八年繼續保持強勁勢頭，美國銷售額達 10.7 億美元，年增 9%。我很自豪地說，安樂死的成長並沒有伴隨價格上漲。EYLEA 具有良好的療效和安全性，全球銷售超過 2500 萬劑。除了人口結構有利因素和已批准的適應症外，我們認為糖尿病視網膜病變的新適應症正在等待批准，這為推動成長提供了新的機會。

While the potential to prevent patients with diabetic retinopathy from suffering blinding complications is very exciting, we recognize that it will require market development because it involves treating patients that are currently asymptomatic.

雖然預防糖尿病視網膜病變患者遭受致盲併發症的潛力令人非常興奮，但我們也意​​識到，這需要市場開發，因為它涉及治療目前沒有症狀的患者。

To test the hypothesis that higher doses may improve upon EYLEA's already market-leading profile, later this year we plan to advance into clinical development a high-dose formulation of aflibercept, and we continue to make progress on new molecular entities that have the potential to be even better.

為了驗證更高劑量是否能進一步提升 EYLEA 已然領先的市場地位，我們計劃在今年稍後推進高劑量阿柏西普製劑的臨床開發，並且我們將繼續在可能效果更佳的新分子實體方面取得進展。

Let me turn now to DUPIXENT, a product with the potential to change the course of allergic type 2 diseases. First quarter net sales globally were $374 million, and patient feedback testified to DUPIXENT's value proposition. We have seen growth in both atopic dermatitis and asthma, and we expect further growth to be amplified by expanded age groups, new geographies and additional indications.

現在讓我來談談DUPIXENT，這是一款有可能改變2型過敏性疾病進程的產品。第一季全球淨銷售額為 3.74 億美元，患者的回饋證明了 DUPIXENT 的價值主張。我們已經看到異位性皮膚炎和氣喘的病例都在增長，我們預計隨著年齡組擴大、地理拓展和適應症增加，病例還會進一步增長。

Moving now to Libtayo. In its first 2 quarters on the market, Libtayo has established a foothold in advanced cutaneous squamous cell carcinoma, or CSCC. We intend to build on that dermato-oncology foundation and expand into other indications.

現在轉到Libtayo。Libtayo 上市後的前兩個季度，已在晚期皮膚鱗狀細胞癌（CSCC）領域站穩腳跟。我們打算以此皮膚腫瘤學為基礎，拓展到其他適應症領域。

In addition to testing Libtayo in cancers in which PD-1 blockade is known to be effective, we consider it an important component of potential future combinations that have the potential to broaden activity and deepen responses.

除了在已知 PD-1 阻斷療法有效的癌症中測試 Libtayo 外，我們認為它是未來潛在聯合療法的重要組成部分，這些聯合療法有可能擴大療效並加深反應。

Last month, we announced a collaboration with Alnylam that combines each company's unique assets and abilities and enables us to pursue intercellular targets in the eye and central nervous system as well as a select number of targets in the liver. This deal exemplifies our business development strategy, and we continue to explore many new and exciting opportunities.

上個月，我們宣布與 Alnylam 合作，結合兩家公司的獨特資產和能力，使我們能夠研究眼睛和中樞神經系統中的細胞間靶點，以及肝臟中的一些特定靶點。這項交易體現了我們的業務發展策略，我們將繼續探索許多新的、令人興奮的機會。

Advancing our internal pipeline remains a key priority. Leveraging our scientific capabilities and our world-class genetics efforts and partnering with other scientific-driven companies is yet another way we plan to capitalize on our own research, productivity and innovation.

推動內部人才培育仍然是我們的首要任務。充分利用我們的科學研究能力和世界級的遺傳學成果，並與其他以科研為導向的公司合作，是我們計劃利用自身研究、生產力和創新能力的又一途徑。

In summary, our core franchises of EYLEA and DUPIXENT are growing, Libtayo is establishing itself as the foundation of our diversified and comprehensive immuno-oncology platform and has had early commercial success in its first indication. We are advancing a broad and deep pipeline, rich in opportunity for sustainable long-term growth.

總而言之，我們的核心產品 EYLEA 和 DUPIXENT 正在成長，Libtayo 正在確立其作為我們多元化和綜合性免疫腫瘤平台的基礎，並在其第一個適應症中取得了早期商業成功。我們正在推動廣泛而深入的產品線，蘊藏著實現可持續長期成長的豐富機會。

For more on that, I will now turn the call over to George.

關於這一點，我現在將把電話交給喬治。

Thank you, Len, and good morning to everyone.

謝謝你，Len，大家早安。

Let me begin with EYLEA, which remains the gold standard for retinal disease. Despite efforts by many others to develop drugs with superior visual outcomes, EYLEA remains the market leader based upon visual outcome and safety and is the measure upon which others' therapies are compared. In terms of additional indications from which EYLEA can benefit patients, we are looking forward to next week's FDA action date for our supplemental BLA in diabetic retinopathy. Furthermore, we are awaiting FDA action on our resubmitted filing for the EYLEA prefilled syringe, hoping to launch in the second half of 2019. As Len mentioned, we also plan to initiate clinical development of a higher dose formulation of aflibercept and we continue preclinical development of a new VEGF blocker. Earlier research efforts are focusing on gene therapy and other novel approaches.

讓我先從 EYLEA 開始，它仍然是視網膜疾病診斷的黃金標準。儘管許多其他藥物都在努力研發具有更優異視覺效果的藥物，但 EYLEA 仍以其視覺效果和安全性保持市場領先地位，並成為衡量其他療法的標準。至於 EYLEA 可以惠及患者的其他適應症，我們期待下週 FDA 對我們在糖尿病視網膜病變方面的補充生物製品許可申請的審批結果。此外，我們正在等待 FDA 對我們重新提交的 EYLEA 預充式註射器申請的處理結果，希望能在 2019 年下半年推出。正如 Len 所提到的，我們也計劃啟動更高劑量阿柏西普製劑的臨床開發，並繼續進行一種新的 VEGF 阻斷劑的臨床前開發。早期的研究工作主要集中在基因療法和其他創新方法。

I'd like to now turn to DUPIXENT, which is emerging as a new standard for type 2 diseases. In the first quarter of 2019, we achieved 3 important regulatory milestones: the FDA approval for adolescents aged 12 through 17 with atopic dermatitis; a positive EU opinion for severe asthma in adolescents and adults; and the U.S. and EU filing of our applications for chronic rhinosinusitis with nasal polyposis, for which we received priority review in the United States with an action date of June 26. We hope to bring the benefit of DUPIXENT to even younger atopic dermatitis patients. Our Phase III trial in pediatric patients ages 6 to 11 is now fully enrolled, and we expect to report results on this trial later this year. We also have an ongoing pivotal confirmatory study in eosinophilic esophagitis as well as studies with peanut and grass allergy.

現在我想談談DUPIXENT，它正在成為2型糖尿病治療的新標準。2019 年第一季度，我們取得了 3 個重要的監管里程碑：FDA 批准用於治療 12 至 17 歲青少年異位性皮膚炎；歐盟對青少年和成人重度哮喘給予積極意見；以及在美國和歐盟提交了治療慢性鼻竇炎伴鼻息肉的申請，我們在美國獲得了優先審評資格，審評結果將於 6 月 26 日公佈。我們希望讓較年輕的異位性皮膚炎患者也能受惠於 DUPIXENT。我們針對 6 至 11 歲兒科患者的 III 期試驗現已全部招募完畢，我們預計將於今年稍後公佈該試驗的結果。我們目前也正在進行嗜酸性食道炎的關鍵性驗證研究，以及花生和草過敏的研究。

DUPIXENT is delivering on its pipeline-in-a-product promise, demonstrating positive data in multiple allergic type 2 diseases, confirming our hypothesis that interleukin-4 and interleukin-13 are the key drivers of allergic type 2 disease in general. Many of these different manifestations of an overactive type 2 inflammation occur simultaneously in the same patient. For example, in our adolescent atopic dermatitis trials, more than 90% had at least 1 other allergic condition, with more than 50% suffering from comorbid asthma. Obviously, there would be a huge patient benefit if they can take a single medicine for multiple diseases. Interestingly, there are numerous case studies published by outside investigators indicating benefit for dupilumab in an assortment of additional type 2 related conditions, such as alopecia areata and bullous pemphigoid, that we have yet to study formally, and we are considering confirmatory studies in these settings.

DUPIXENT 正在兌現其產品管線的承諾，在多種 2 型過敏性疾病中展現出積極的數據，證實了我們的假設，即白細胞介素-4 和白細胞介素-13 是 2 型過敏性疾病的主要驅動因素。2 型發炎過度活躍的許多不同表現形式可能同時發生在同一患者身上。例如，在我們針對青少年異位性皮膚炎的試驗中，超過 90% 的患者至少患有 1 種其他過敏性疾病，其中超過 50% 的患者同時患有氣喘。顯然，如果患者能夠服用一種藥物來治療多種疾病，將對他們大有裨益。有趣的是，外部研究人員發表了許多案例研究，顯示度普利尤單抗對其他一些 2 型相關疾病（如斑禿和類天皰瘡）有益，我們尚未正式研究這些疾病，我們正在考慮在這些情況下進行驗證性研究。

Of course, it is possible to treat numerous immune diseases with drugs that are broadly immunosuppressant or to treat a single disease with drugs that are more disease specific. DUPIXENT is the rare example of a drug that has efficacy across a range of type 2 diseases that tend to afflict the same patient, with a favorable safety profile that has permitted development in teenagers and young children.

當然，可以用廣效免疫抑制劑治療多種免疫疾病，也可以用針對特定疾病的藥物來治療單一疾病。DUPIXENT 是一種罕見的藥物，它對多種 2 型疾病（這些疾病往往會影響同一患者）都有效，並且具有良好的安全性，因此可以在青少年和幼兒中進行開發。

In addition to DUPIXENT, we and Sanofi are also testing Regeneron 3500, our fully human anti-IL-33 antibody, in asthma, atopic dermatitis and COPD. The first of these proof-of-concept trials to read out is in asthma, where we expect to report top line results by midyear.

除了 DUPIXENT 之外，我們和賽諾菲還在測試 Regeneron 3500，這是一種全人源抗 IL-33 抗體，用於治療氣喘、異位性皮膚炎和 COPD。首個公佈結果的概念驗證試驗是氣喘試驗，我們預計在年中公佈初步結果。

I will shift gears now from our efforts with immunotherapies in non-oncologic settings to our immunotherapy efforts to treat cancer, starting with our PD-1 antibody, Libtayo. Last month, the European regulatory body issued a positive opinion for advanced cutaneous squamous cell carcinoma. This follows a September 2018 U.S. approval which made Libtayo the third FDA-approved PD-1 antibody and the first approved medicine of any kind for patients with advanced cutaneous squamous cell carcinoma. To extend Libtayo's benefit in this disease, the second most common skin cancer, we will be starting a Phase III adjuvant trial this quarter and a neoadjuvant trial in the third quarter. We are also evaluating Libtayo in the most common skin cancer, that is basal cell carcinoma, where we have fully enrolled the locally advanced cohort of our potentially pivotal trial.

現在，我將把主題從我們在非腫瘤領域進行的免疫療法工作轉移到我們在癌症治療方面的免疫療​​法工作，首先介紹我們的 PD-1 抗體 Libtayo。上個月，歐洲監管機構對晚期皮膚鱗狀細胞癌發布了正面意見。在此之前，Libtayo 於 2018 年 9 月獲得美國批准，成為 FDA 批准的第三種 PD-1 抗體，也是首個獲準用於治療晚期皮膚鱗狀細胞癌的藥物。為了擴大 Libtayo 在這種疾病（第二大常見皮膚癌）的療效，我們將在本季啟動 III 期輔助治療試驗，並在第三季啟動新輔助治療試驗。我們也正在評估 Libtayo 在最常見的皮膚癌—基底細胞癌中的療效，目前我們已經完成了局部晚期患者群的招募，這項試驗可能具有關鍵意義。

Moving to lung cancer. Despite the head start of other -- of multiple other programs, Libtayo has the opportunity to become 1 of only 2 PD-1 antibodies approved for the first-line treatment of metastatic non-small cell lung cancer, the most common cause of cancer death. Our Libtayo monotherapy trial, which we doubled in size, is about 2/3 enrolled. We will soon begin enrolling patients in our Phase III non-small cell lung cancer trial comparing Libtayo plus chemotherapy to chemotherapy alone. This study will enroll both squamous and non-squamous non-small cell lung cancer patients regardless of PD-L1 expression.

轉而討論肺癌。儘管其他多個項目已經取得了領先優勢，但 Libtayo 有機會成為僅有的兩種獲準用於一線治療轉移性非小細胞肺癌（癌症死亡的最常見原因）的 PD-1 抗體之一。我們擴大了一倍規模的 Libtayo 單藥治療試驗已招募了約 2/3 的患者。我們很快就會開始招募患者參與我們的 III 期非小細胞肺癌試驗，該試驗將比較 Libtayo 聯合化療與單獨化療。本研究將招募鱗狀非小細胞肺癌患者和非鱗狀非小細胞肺癌患者，無論其PD-L1表現如何。

Beyond Libtayo, bispecific antibodies are another key component of our immuno-oncology strategy. We will present updated efficacy and safety data for our CD20xCD3 bispecific antibody at 2 European hematology conferences in June. The data will include promising early results with higher doses, longer-term follow-up and efficacy in specific patient subpopulations such as CAR-T failures.

除了 Libtayo 之外，雙特異性抗體是我們免疫腫瘤學策略的另一個關鍵組成部分。我們將於 6 月在 2 個歐洲血液學會議上發表我們 CD20xCD3 雙特異性抗體的最新療效和安全性數據。數據將包括更高劑量、更長期的隨訪以及在特定患者亞群（如 CAR-T 治療失敗者）中的療效等方面的令人鼓舞的早期結果。

Encouraged by high rates of deep and durable responses, we're on track to initiate 2 potentially registrational Phase II studies: the first in advanced relapsed refractory follicular lymphoma by midyear, and another in advanced relapsed refractory diffuse large B-cell lymphoma, or DLBCL, by the end of the year. We're enrolling patients in early studies testing our other 2 clinical-stage CD3 bispecific antibodies, MUC16xCD3 for platinum-resistant ovarian cancer and BCMAxCD3 for relapsed or refractory multiple myeloma. Based on currently available results from BCMA-targeted CAR-T and other approaches, there is still room for improvement. A fully human bispecific BCMAxCD3 with favorable pharmacokinetics and lacking potential immunogenic features may provide the foundation for additional combination approaches. As far as we know, our bispecific platform is the only one that does not use artificial linkers, mutations or other unnatural sequences.

受深度和持久反應率高的鼓舞，我們正按計劃啟動 2 項潛在的註冊性 II 期研究：第一項研究將於年中啟動，針對晚期復發難治性濾泡性淋巴瘤；另一項研究將於年底啟動，針對晚期復發難治性瀰漫性大 B 細胞淋巴瘤 (DLBCL)。我們正在招募患者參與早期研究，測試我們另外 2 種臨床階段的 CD3 雙特異性抗體，MUC16xCD3 用於治療鉑耐藥性卵巢癌，BCMAxCD3 用於治療復發或難治性多發性骨髓瘤。根據BCMA靶向CAR-T療法和其他方法目前的現有結果，仍有改進的空間。具有良好藥物動力學特性且缺乏潛在免疫原性的全人源雙特異性BCMAxCD3可能為其他聯合療法奠定基礎。據我們所知，我們的雙特異性平台是唯一不使用人工連接子、突變或其他非天然序列的平台。

We're also advancing our entirely new class of bispecific antibodies, as we will soon begin clinical testing of our first co-stimulatory or co-stim bispecific, [REGN5678], which is designed to bind prostate-specific membrane antigen, or PSMA, and CD28. We hope that our clinical studies will replicate our preclinical observations that this new class of co-stim bispecific has limited toxicity while synergizing with Libtayo as well as with the CD3 class of bispecifics. Since prostate cancer has shown real but limited responsiveness to PD-1 therapy, we believe it may therefore be an ideal opportunity to detect a clear signal of additional activity if the combination of Libtayo and PSMAxCD28 results in a substantially higher response rate than previously observed with PD-1 blockade.

我們也正在推進我們全新的雙特異性抗體類別，因為我們很快就會開始對我們的第一個共刺激或共刺激雙特異性抗體[REGN5678]進行臨床試驗，該抗體旨在結合前列腺特異性膜抗原（PSMA）和CD28。我們希望我們的臨床研究能夠重現我們的臨床前觀察結果，即這種新型共刺激雙特異性抗體毒性有限，同時也能與 Libtayo 以及 CD3 類雙特異性抗體產生協同作用。由於前列腺癌對 PD-1 療法表現出真實但有限的反應，我們認為，如果 Libtayo 和 PSMAxCD28 的聯合治療能夠比先前觀察到的 PD-1 阻斷療法產生更高的反應率，那麼這可能是檢測額外活性的明確信號的理想機會。

The ability to test multiple combinations of our own checkpoint inhibitors, CD3 bispecifics and co-stim bispecifics is a differentiated feature of our immuno-oncology pipeline. However, heightening the immune response via combination approaches carries inherent risks, as occurs with CAR-T therapies. For example, in our initial study combining our CD20xCD3 bispecific with our PD-1 antibody, in which approximately 30 patients with advanced lymphoma have been treated with the combination, we observed enhanced cytokine release syndrome, or CRS, that might have been associated with increased tumor response but also with increased toxicity, including unfortunately 2 fatalities potentially related to the CRS. We plan to modify the dosing regimen, with the goal of minimizing toxicity while potentially capturing the potentially increased activity.

我們免疫腫瘤學研發管線的一個獨特之處在於，我們能夠測試我們自己的檢查點抑制劑、CD3 雙特異性抗體和共刺激雙特異性抗體的多種組合。然而，透過聯合療法增強免疫反應存在固有的風險，就像 CAR-T 療法一樣。例如，在我們最初的研究中，我們將 CD20xCD3 雙特異性抗體與 PD-1 抗體結合，對大約 30 名晚期淋巴瘤患者進行了聯合治療，我們觀察到細胞因子釋放綜合徵 (CRS) 增強，這可能與腫瘤反應增強有關，但也與毒性增加有關，不幸的是，其中有 2 例死亡可能與 CRS 有關。我們計劃修改給藥方案，目標是在盡可能減少毒性的同時，盡可能提高療效。

Over the coming months and years, we expect to advance a steady stream of bispecifics into clinical development. Just to remind you, Regeneron 1979, CD3 bispecifics other than those targeting MUC16 and BCMA and our new class of co-stim bispecifics are all wholly owned by Regeneron.

在接下來的幾個月和幾年裡，我們預計將有源源不絕的雙特異性抗體進入臨床開發階段。再次提醒您，Regeneron 1979、針對 MUC16 和 BCMA 的 CD3 雙特異性抗體以及我們新推出的共刺激雙特異性抗體均完全歸 Regeneron 所有。

Leaving now immuno-oncology and moving to pain. As we have emphasized previously, fasinumab, our anti-NGF antibody, involves a high-risk program due to long-term safety issues involving increased treatment-associated arthropathies and total joint replacements with this class. On April 30, the Data Monitoring Committee recommended continuing the program at the ongoing lower doses where we previously reported positive efficacy results.

現在離開免疫腫瘤科，轉到疼痛科。正如我們之前所強調的那樣，我們的抗 NGF 抗體 fasinumab 屬於高風險項目，因為長期安全性問題包括治療相關性關節疾病增加以及此類藥物需要全關節置換。4月30日，數據監測委員會建議繼續以我們先前報告有積極療效結果的較低劑量進行該計畫。

These are just a few highlights of Regeneron's homegrown pipeline. Let me conclude with comments about the Regeneron Genetics Center, or the RGC, and our Alnylam collaboration. In March, the RGC provided to the global research community exome sequences from the first 50,000 UK Biobank participants. Sequences are linked to detailed de-identified electronic health records, imaging and other health-related information provided through a collaboration among the UK Biobank, Regeneron and GlaxoSmithKline. Regeneron is also leading a separate effort to sequence the remaining 450,000 UK Biobank participants, which we intend to complete by 2020 and is being funded by a consortium of biopharma companies including Alnylam, AbbVie, AstraZeneca, BMS, Biogen, Pfizer and Takeda.

以上僅是 Regeneron 自主研發產品線中的幾個亮點。最後，我想談談 Regeneron 遺傳學中心（簡稱 RGC）以及我們與 Alnylam 的合作。今年 3 月，RGC 向全球研究界提供了來自英國生物銀行首批 50,000 名參與者的外顯子組序列。序列與詳細的去識別化電子健康記錄、影像和其他健康相關資訊相關聯，這些資訊是透過英國生物銀行、再生元公司和葛蘭素史克公司之間的合作提供的。Regeneron 也主導另一項工作，對英國生物銀行剩餘的 45 萬名參與者進行測序，我們計劃在 2020 年完成這項工作，這項工作由包括 Alnylam、AbbVie、AstraZeneca、BMS、Biogen、Pfizer 和 Takeda 在內的生物製藥公司聯盟資助。

Finally, I would like to acknowledge our new collaboration with Alnylam. Regeneron and Alnylam's technologies are complementary, and our companies share a commitment to patients and to science. The emphasis of our joint work will be on diseases of the eye and CNS, and we will also work jointly in certain targets expressed in the liver, including C5, where we each have clinical-stage assets.

最後，我想宣布我們與 Alnylam 開展新的合作。Regeneron 和 Alnylam 的技術是互補的，我們兩家公司都秉持著對病人和科學的共同承諾。我們的合作重點將放在眼部和中樞神經系統疾病上，我們還將共同研究肝臟中表達的某些靶點，包括 C5，我們各自都擁有處於臨床階段的 C5 相關資產。

Regeneron's antibodies are optimal for secreted and cell surface targets. Alnylam's siRNA enables us to extend our therapeutic reach to inside the cell.

再生元公司的抗體對分泌型和細胞表面標靶具有最佳療效。Alnylam 的 siRNA 使我們能夠將治療範圍擴展到細胞內部。

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

這樣，我就把電話交給瑪莉安了。

Thank you, George, and good morning, everyone.

謝謝你，喬治，大家早安。

I'd like to start with EYLEA. For the first quarter, U.S. EYLEA net product sales grew 9% year-over-year to $1.07 billion. Overall market growth continues to be driven by the aging population, increasing diabetes prevalence and physician preference for EYLEA. EYLEA is the world's leading anti-VEGF branded therapy for retinal disease based on its broad range of indications, demonstrated safety profile, dosing flexibility and established physician confidence. EYLEA market share continues to grow in the overall U.S. anti-VEGF market. This includes branded products and off-label repackaged Avastin. In the branded U.S. market, EYLEA has about 70% share of net product sales. Among payers, EYLEA continues to secure approximately 90% first-line access. We're committed to further strengthening our leadership position for EYLEA through continued innovation in dose and delivery as well as label expansion opportunities.

我想先從愛樂（EYLEA）說起。第一季度，美國安禮製藥淨產品銷售額年增 9%，達到 10.7 億美元。人口老化、糖尿病盛行率上升以及醫生對EYLEA的偏好，持續推動市場整體成長。EYLEA 是全球領先的抗 VEGF 品牌視網膜疾病治療藥物，其適應症範圍廣、安全性高、劑量靈活，並已獲得醫生的信賴。EYLEA 在美國整體抗 VEGF 市佔率持續成長。這包括品牌產品和重新包裝的非適應症用阿瓦斯汀。在美國品牌產品市場，安怡佔了約 70% 的淨產品銷售額。在支付方中，EYLEA 繼續保持約 90% 的第一線使用率。我們致力於透過在劑量和給藥方式方面的持續創新以及標籤擴展機會，進一步鞏固我們在安樂死領域的領先地位。

Diabetes is our largest growth opportunity. Very shortly, we expect to hear from the FDA on our filing submission for EYLEA in diabetic retinopathy. Diabetic retinopathy is not a benign condition. Patients with moderately severe and severe nonproliferative disease are at risk for potential blindness. Given the compelling data from our PANORAMA trial, we think this is an important opportunity to help patients avoid these serious complications. If approved, we have comprehensive plans to develop this market. Our focus will be on raising awareness of the benefits of treating diabetic retinopathy, encouraging early intervention for appropriate patients and ensuring EYLEA is the first-line anti-VEGF treatment for diabetic retinopathy patients.

糖尿病是我們最大的成長機會。我們預計很快就會收到 FDA 對我們提交的用於治療糖尿病視網膜病變的 EYLEA 申請的回應。糖尿病視網膜病變並非良性疾病。中度至重度非增殖性疾病患者有失明的風險。鑑於我們 PANORAMA 試驗的有力數據，我們認為這是一個幫助患者避免這些嚴重併發症的重要機會。如果獲得批准，我們有全面的市場開發計劃。我們將專注於提高人們對治療糖尿病視網膜病變益處的認識，鼓勵對合適的患者進行早期幹預，並確保 EYLEA 成為糖尿病視網膜病變患者的第一線抗 VEGF 治療藥物。

Turning now to DUPIXENT, where global net product sales in the first quarter were $374 million. In the U.S., net product sales reached $303 million, representing a 159% year-over-year growth. Total prescriptions, or TRx, in the U.S. grew 18% quarter-over-quarter. This was driven by growth in adult atopic dermatitis and in our new asthma indication, which launched in the fourth quarter. In March, the FDA also approved DUPIXENT in adolescent atopic dermatitis, which we anticipate will contribute to incremental growth. Across all indications, prescriber experience and depth continued to improve. Approximately 16,000 health care providers have prescribed DUPIXENT, and we continue to see strong prescribing trends. Weekly new-to-brand prescriptions, or NBRx, for the quarter averaged 950 patients per week, up from approximately 700 in the prior quarter.

現在來看看DUPIXENT，其第一季的全球淨產品銷售額為3.74億美元。在美國，淨產品銷售額達到 3.03 億美元，年增 159%。美國處方總量（TRx）較上月增加 18%。這主要得益於成人異位性皮膚炎和我們在第四季度推出的新氣喘適應症的成長。今年 3 月，FDA 也批准了 DUPIXENT 用於治療青少年異位性皮膚炎，我們預計這將有助於其銷售成長。在所有適應症中，處方醫師的經驗和專業知識都在不斷提高。大約有 16,000 名醫療保健提供者開立了 DUPIXENT 處方，而且我們繼續看到強勁的處方趨勢。本季每週新開立處方（NBRx）平均為每週 950 名患者，高於上一季的約 700 名患者。

In atopic dermatitis, more patients are now benefiting from DUPIXENT, including those with both moderate and severe disease. Prescriber depth has grown, as evidenced by nearly 200% year-over-year increase in a number of providers who have prescribed DUPIXENT to 5 or more patients.

在異位性皮膚炎領域，越來越多的患者現在受益於 DUPIXENT，包括中度和重度患者。處方醫生數量有所增加，這從每年為 5 名或以上患者開立 DUPIXENT 處方的醫生數量增長近 200% 便可見一斑。

Additionally, patient awareness has improved, benefiting from our promotional and educational campaigns. As a reminder, we estimate the target patient population most in need to be 300,000 to 400,000 adults, and just a small minority of patients have received DUPIXENT since launch.

此外，由於我們的宣傳和教育活動，患者的意識也提高了。提醒一下，我們估計最需要治療的目標患者群體是 30 萬至 40 萬成年人，但自上市以來，只有一小部分患者接受了 DUPIXENT 治療。

We've also see an important opportunity in adolescent patients with atopic dermatitis. DUPIXENT is the first biologic approved in this patient group who remain uncontrolled using topical therapies. While it's very early, market launch reaction has been extremely positive. Our promotional efforts are focused on the same allergists and dermatologists who currently treat adults with atopic dermatitis, plus pediatric dermatologists and pediatric allergists. We've also been encouraged by payer receptivity to extending DUPIXENT access to this younger patient population. Additionally, we anticipate data from our pediatric study in atopic dermatitis ages 6 to 11 later this year.

我們也看到了青少年異位性皮膚炎患者的重要治療機會。DUPIXENT 是首個獲準用於治療局部治療仍無法控制病情的該類患者的生物製劑。雖然現在下結論還為時過早，但市場反應非常正面。我們的推廣工作主要針對目前治療成人異位性皮膚炎的過敏科醫生和皮膚科醫生，以及兒科皮膚科醫生和兒科過敏科醫生。我們也欣慰地看到，支付方願意將 DUPIXENT 的使用範圍擴大到更年輕的患者群體。此外，我們預計將於今年稍後公佈針對 6 至 11 歲兒童異位性皮膚炎的研究數據。

Turning now to asthma, where DUPIXENT is quickly establishing a competitive market presence in the U.S. DUPIXENT has a differentiated clinical and safety profile compared to other asthma biologics. It has a first-in-class mode of action that substantially reduces exacerbations and provides clinically meaningful improvement in lung function for [all] approved patient population, and is the only asthma biologic that can be self-administered. Since DUPIXENT's asthma launch last October, we estimate the asthma biologic market has grown by more than 10%. Nearly 75% of DUPIXENT asthma patients are new to biologics, and significant opportunity remains for subsequent growth. Uptake has been driven by allergists who have experience using DUPIXENT in atopic dermatitis and also pulmonologists, who are highly receptive to DUPIXENT efficacy, use in steroid-dependent patients and self-administration. Additionally, we are excited about launching in markets outside the U.S. DUPIXENT was recently approved in Japan, and we expect an EU regulatory decision midyear.

現在我們來看看氣喘，DUPIXENT 正在美國迅速建立起具有競爭力的市場地位。與其他氣喘生物製劑相比，DUPIXENT 具有差異化的臨床和安全性特徵。它具有同類首創的作用機制，可大幅減少病情加重，並為所有核准患者群體提供具有臨床意義的肺功能改善，而且是唯一一種可以自行給藥的氣喘生物製劑。自去年 10 月 DUPIXENT 氣喘藥物上市以來，我們估計氣喘生物製劑市場成長超過 10%。近 75% 的 DUPIXENT 氣喘患者是首次使用生物製劑，後續成長仍有很大的機會。DUPIXENT 的普及主要得益於過敏科醫生（他們在異位性皮膚炎中使用過 DUPIXENT）以及肺科醫生（他們對 DUPIXENT 的療效、在類固醇依賴性患者中的應用以及自我給藥方式非常認可）。此外，我們很高興能在美國以外的市場推出DUPIXENT。 DUPIXENT最近在日本獲得批准，我們預計歐盟監管機構將在年中做出決定。

Finally, in June, we expect to hear from the FDA on our proposed indication in chronic rhinosinusitis with nasal polyps. This should help further differentiate DUPIXENT from the competition by demonstrating that the same treatment can address multiple related type 2 conditions that often present in the same patient.

最後，我們預計在 6 月會收到 FDA 對我們提出的治療慢性鼻竇炎伴鼻息肉適應症的批准。這應該有助於進一步將 DUPIXENT 與競爭對手區分開來，證明同一種治療方法可以解決同一患者經常出現的多種相關的 2 型疾病。

I'd now like to turn to Libtayo. In the U.S., first quarter net product sales were $27 million, driven by a prescription demand. Building on our success since launch, Libtayo's brand awareness among the medical community has increased substantially. We made further progress in establishing Libtayo as a standard of care in advanced CSCC across all lines of therapy. Our launch update has benefited from broad payer access, with nearly all Medicare, commercial and Medicaid lives covered. We expect the number of patients on Libtayo to grow based on demographics, enhancement in patient identification and physician referrals. Libtayo is the only FDA-approved treatment for advanced CSCC and the only anti-PD1 or PD-L1 with a category 2A recommendation in the National Comprehensive Cancer Network, or NCCN.

我現在想轉向Libtayo。在美國，第一季淨產品銷售額為 2,700 萬美元，主要受處方需求推動。自推出以來，Libtayo 取得了成功，在醫療界的品牌知名度也大幅提升。我們在確立 Libtayo 作為晚期 CSCC 所有治療方案的標準療法方面取得了進一步進展。我們的產品更新得益於廣泛的支付方覆蓋，幾乎涵蓋了所有醫療保險、商業保險和醫療補助計劃的參保人員。我們預計，隨著人口統計數據的變化、患者識別能力的提高以及醫生轉診，Libtayo 的患者數量將會增加。Libtayo 是唯一獲得 FDA 批准用於治療晚期 CSCC 的藥物，也是唯一獲得美國國家綜合癌症網絡 (NCCN) 2A 類推薦的抗 PD-1 或​​ PD-L1 藥物。

Now onto PRALUENT. Just over a week ago, the FDA approved PRALUENT to prevent cardiovascular events. PRALUENT is the first and only PCSK9 inhibitor with data showing a meaningful reduction in all-cause mortality, and we're pleased the data describing this mortality effect was included in the updated label. In this highly competitive market, we continue to be focused on patient affordability and payer access.

接下來是PRALUENT。就在一周多前，FDA 批准了 PRALUENT 用於預防心血管事件。PRALUENT 是第一個也是唯一一個有數據顯示能顯著降低全因死亡率的 PCSK9 抑制劑，我們很高興描述這種降低死亡率效果的數據被納入了更新後的標籤中。在這個競爭激烈的市場中，我們將繼續專注於患者的經濟承受能力和支付者的准入。

Turning to KEVZARA. Within U.S. IL-6 subcutaneous class, KEVZARA now has an estimated 45% share of new patients-dispensed drug, or NBRx, and 26% share of total scripts, or TRx. We're working to accelerate KEVZARA growth by securing a greater share of the IL-6 market and growing the market, which is currently estimated at $450 million in the U.S.

轉向 KEVZARA。在美國 IL-6 皮下注射類藥物中，KEVZARA 目前估計佔新患者配藥量 (NBRx) 的 45% 份額，佔總處方量 (TRx) 的 26% 份額。我們正在努力透過確保在IL-6市場獲得更大的份額並擴大市場來加速KEVZARA的成長，目前美國市場規模估計為4.5億美元。

Now I'll turn the call over to Bob.

現在我把電話交給鮑伯。

Thanks, Marion, and good morning to everyone. Today, I will discuss our first quarter 2019 financial progress, highlight various items and events that impacted our results and provide updates to our full year guidance line items, which can be found in our press release that was issued earlier this morning.

謝謝你，瑪麗昂，大家早安。今天，我將討論我們 2019 年第一季的財務進展，重點介紹影響我們業績的各種項目和事件，並更新我們的全年業績指引，這些指引可以在我們今天早上早些時候發布的新聞稿中找到。

For the first quarter 2019, we reported non-GAAP diluted net income per share of $4.45 on non-GAAP net income of $518 million. Total revenues were $1.71 billion, a 13% year-over-year increase. Revenue growth continued to be driven by global sales of EYLEA, an increase in both Sanofi and Bayer collaborations and Libtayo net sales. For the first quarter of 2019, global net product sales of EYLEA were $1.74 billion, an increase of 8% year-over-year. U.S. EYLEA net product sales increased due to higher sales volume partly offset by an increase in sales-related deductions primarily due to higher discounts. U.S. distributor inventory experienced a slight quarter-over-quarter decrease, yet remained within our normal 1- to 2-week targeted range.

2019 年第一季度，我們公佈的非 GAAP 稀釋後每股淨收益為 4.45 美元，非 GAAP 淨收益為 5.18 億美元。總收入為 17.1 億美元，年增 13%。營收成長繼續由EYLEA的全球銷售額、賽諾菲和拜耳合作的成長以及Libtayo的淨銷售額推動。2019 年第一季度，安樂全球淨產品銷售額為 17.4 億美元，較去年同期成長 8%。由於銷售量增加，美國安禮公司淨產品銷售成長，但部分被銷售相關扣款增加所抵消，這主要是由於折扣增加所致。美國分銷商庫存較上月略有下降，但仍在我們正常的 1 至 2 週目標範圍內。

Ex-U. S. EYLEA net product sales recorded by our collaborator Bayer were $669 million, representing a 7% reported and a 15% operational or constant currency basis increase year-over-year. Total Bayer collaboration revenue for the first quarter of 2019 was $276 million, of which $249 million was derived from our share of net profits from EYLEA sales outside the U.S. The $249 million represents year-over-year reported growth of 7% compared to the first quarter of 2018.

前美國根據我們的合作夥伴拜耳公司記錄，S. EYLEA 的淨產品銷售額為 6.69 億美元，按報告匯率計算年增 7%，按營運匯率或固定匯率計算年增 15%。2019 年第一季拜耳合作總營收為 2.76 億美元，其中 2.49 億美元來自我們在美國以外地區銷售 EYLEA 產品所獲得的淨利潤份額。與 2018 年第一季相比，這 2.49 億美元年增了 7%。

Total Sanofi collaboration revenue was $246 million for the first quarter of 2019, a 30% year-over-year increase. We are projecting the Sanofi collaboration revenue line to increase over the remaining quarters of 2019. The year-over-year increase in Sanofi collaboration revenue was primarily driven by lower losses associated with the commercialization of non-IO antibodies, driven in part by higher net sales of DUPIXENT, and an increase in the antibody reimbursement of Regeneron commercialization expenses. These increases were partly offset by a decrease in reimbursement of research and development costs under the IO discovery and development agreement with Sanofi, as the amended December 31, 2018 agreement narrowed the scope of reimbursement -- reimbursable activities to the BCMAxCD3 and MUC16xCD3 programs.

2019 年第一季度，賽諾菲合作總營收為 2.46 億美元，年增 30%。我們預計賽諾菲合作計畫的營收將在 2019 年剩餘的幾個季度內成長。賽諾菲合作收入年增率主要得益於非免疫腫瘤抗體商業化相關損失的減少，部分原因是 DUPIXENT 淨銷售額增加，以及 Regeneron 商業化費用的抗體報銷增加。這些成長部分被與賽諾菲簽訂的 IO 發現和開發協議中研發費用報銷的減少所抵消，因為 2018 年 12 月 31 日修訂的協議縮小了報銷範圍——可報銷活動僅限於 BCMAxCD3 和 MUC16xCD3 項目。

Second, Sanofi collaboration revenues associated with cost reimbursements from Sanofi for bulk drug manufactured by Regeneron were also adversely impacted by timing.

其次，賽諾菲為再生元生產的原料藥支付的成本補償相關的賽諾菲合作收入也受到了時間上的不利影響。

In the first quarter of 2019, we recognized a loss of $28 million in connection with the commercialization of non-IO antibodies, which compares favorably to a loss of $75 million in the first quarter of 2018. As noted, the lower share of loss versus the first quarter of 2018 was primarily attributable to higher global net product sales of DUPIXENT partly offset by an increase in DUPIXENT commercialization expenses to support the U.S. launch in asthma and ongoing global launches in atopic dermatitis.

2019 年第一季度，我們在非 IO 抗體的商業化方面確認了 2800 萬美元的虧損，與 2018 年第一季 7500 萬美元的虧損相比，情況有所好轉。如前所述，與 2018 年第一季相比，虧損份額下降主要是由於 DUPIXENT 全球淨產品銷售額增加，但部分被 DUPIXENT 商業化費用增加所抵消，這些費用增加是為了支持 DUPIXENT 在美國哮喘領域的上市以及正在進行的全球異位性皮膚炎上市。

Turning now to expenses. Non-GAAP R&D expenses were $583 million for the first quarter of 2019 compared to $458 million for the first quarter of 2018. The year-over-year increase in non-GAAP R&D expense was the result of the expansion and progression of our earlier-stage pipeline, an increase in Libtayo development expenses, higher clinical manufacturing costs and higher headcount and headcount-related costs. This increase in R&D spend is consistent with our 2019 guidance and previously communicated commitment to reinvest the tax savings we're realizing from the enactment of the 2017 Tax Cuts and Jobs Act into research and development.

接下來談談費用。2019 年第一季非 GAAP 研發費用為 5.83 億美元，而 2018 年第一季為 4.58 億美元。非GAAP研發費用年增，是由於早期產品線的擴張和進展、Libtayo開發費用的增加、臨床生產成本的增加以及人員編制和與人員編制相關的成本的增加所致。此次研發支出的增加與我們 2019 年的指導方針以及先前宣布的承諾相一致，即把我們從 2017 年《減稅與就業法案》的實施中獲得的稅收節省再投資於研發。

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 $419 million for the quarter of 2019 compared to $278 million for the first quarter of 2018. Included in our updated non-GAAP unreimbursed R&D guidance are projected program initiation expenses related to our recently announced Alnylam collaboration. Despite the inclusion of these initiation expenses, we are maintaining the top end of our guidance and tightening the range. The $400 million upfront collaboration agreement payment to Alnylam will be recorded as an R&D expense in the second quarter but will be excluded from reported non-GAAP R&D expenses. As a reminder, Regeneron's year-over-year increase in full year non-GAAP unreimbursed R&D guidance is primarily attributable to higher clinical trial and manufacturing costs to support Regeneron's wholly-owned programs, including 4 to 6 new molecules expected to advance into the clinic in 2019 on top of the 5 molecules that were advanced into the clinic in 2018, and lower Sanofi reimbursement as a result of the amended IO discovery and development agreement.

2019 年第一季度，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 4.19 億美元，而 2018 年第一季為 2.78 億美元。我們更新的非GAAP未報銷研發指導中包括了與我們最近宣布的Alnylam合作相關的預計專案啟動費用。儘管計入了這些啟動費用，我們仍維持預期上限，並收緊預期範圍。向 Alnylam 支付的 4 億美元預付合作協議款項將在第二季度計入研發費用，但不會計入報告的非 GAAP 研發費用。需要提醒的是，Regeneron 全年非 GAAP 未報銷研發預期同比增加，主要歸因於支持 Regeneron 全資擁有的項目的臨床試驗和生產成本上升，其中包括預計在 2019 年進入臨床階段的 4 至 6 個新分子（加上 2018 年進入臨床階段的 5 個分子賽），以及由於菲諾協議的

Next, non-GAAP SG&A expense was $362 million for the first quarter of 2019, a 22% year-over-year increase. The year-over-year increase was driven by higher headcount and headcount-related costs primarily to support the DUPIXENT, asthma and Libtayo launches, higher contributions to independent not-for-profit patient assistance organizations and an increase in U.S. commercialization-related promotional expenses for DUPIXENT.

其次，2019 年第一季的非 GAAP SG&A 費用為 3.62 億美元，較去年同期成長 22%。同比成長主要由人員增加和與人員相關的成本增加所驅動，這些成本主要是為了支持 DUPIXENT、氣喘和 Libtayo 的上市；此外，對獨立非營利性患者援助組織的捐款增加，以及 DUPIXENT 在美國的商業化相關推廣費用增加。

We are lowering and tightening our previous 2019 guidance for non-GAAP SG&A expense. Also, as a reminder, the year-over-year increase in our guidance is primarily driven by increased spend to support launches for DUPIXENT and Libtayo, as well as incremental spend to support the potential new growth opportunity of EYLEA in diabetic retinopathy and increased patient assistance programs. Sanofi reimbursement of Regeneron commercialization-related expenses, a line item found within Sanofi collaboration revenue, was $119 million for the first quarter of 2019. We are lowering and tightening our full year 2019 guidance for Sanofi reimbursement of Regeneron commercialization-related expenses.

我們將下調並收緊先前對 2019 年非 GAAP 銷售、管理及行政費用的預期。另外，提醒一下，我們年度業績預期的同比增長主要得益於為支持 DUPIXENT 和 Libtayo 的上市而增加的支出，以及為支持 EYLEA 在糖尿病視網膜病變領域潛在的新增長機會而增加的支出，以及患者援助計劃的增加。2019 年第一季度，賽諾菲向 Regeneron 支付的商業化相關費用（該費用包含在賽諾菲合作收入中）為 1.19 億美元。我們正在下調並收緊 2019 年全年賽諾菲對 Regeneron 商業化相關費用的報銷預期。

For the 3 months ended March 31, 2019, combined non-GAAP cost of goods sold and cost of collaboration and contract manufacturing were $174 million compared to $108 million in the first quarter of 2018. With regards to COGS, remember that it includes Sanofi's share of gross profits in connection with our commercialization of Libtayo in the United States. The year-over-year increase in cost of collaboration and contract manufacturing was primarily due to higher expenses in connection with planned process validation of our Limerick manufacturing facility, higher inventory write-offs and reserves and the recognition of drug substance manufacturing costs associated with higher sales of DUPIXENT. Regeneron's process validation expenses and inventory write-offs and reserves for first quarter of 2019 were $44 million higher than the first quarter of 2018. While these sorts of charges and activities can be difficult to predict, we currently don't expect to see increases of this magnitude to impact any of our next 3 quarters.

截至 2019 年 3 月 31 日的三個月內，非 GAAP 合併銷售成本和合作及合約製造成本為 1.74 億美元，而 2018 年第一季為 1.08 億美元。關於銷售成本，請記住，它包括賽諾菲在美國銷售 Libtayo 所產生的毛利份額。合作和合約製造成本同比增加主要是由於與利默里克製造工廠計劃的工藝驗證相關的費用增加、庫存註銷和準備金增加，以及與 DUPIXENT 銷售額增加相關的藥物原料製造成本確認增加。2019 年第一季度，Regeneron 的製程驗證費用、庫存減損和準備金比 2018 年第一季高出 4,400 萬美元。雖然這類費用和活動難以預測，但我們目前預計未來三個季度內不會出現如此大幅度的成長，從而影響我們的業績。

Turning now to taxes. Our effective tax rate was 15.6% for the first quarter of 2019 compared to 18.3% for the first quarter of 2018. As a result of incurring the $400 million Alnylam upfront collaboration expense in the U.S., we are lowering our full year 2019 effective tax rate to be 11% to 13%. The impact of the lower effective tax rate will likely be seen later in the year, as the tax benefit to stock-based compensation has historically been weighed towards the fourth quarter of the year.

接下來談談稅務問題。2019 年第一季度，我們的實際稅率為 15.6%，而 2018 年第一季為 18.3%。由於在美國產生了 4 億美元的 Alnylam 前期合作費用，我們將 2019 年全年實際稅率降低至 11% 至 13%。較低的實際稅率的影響可能會在今年稍後顯現，因為股票選擇權激勵的稅收優惠歷來都集中在每年的第四季。

Turning next to Regeneron's first quarter 2019 cash flow and March 31, 2019 balance sheet. Regeneron ended the first quarter with cash and marketable securities of $5.57 billion and generated free cash flow of $823 million for the quarter. We calculate free cash flow as net cash provided by operating activities less capital expenditures. Included in both balances was the first quarter 2019 receipt of $462 million of consideration from Sanofi related to the amended IO discovery and development agreement. Our capital expenditures for the first quarter, which has historically been our lowest spend quarter, was $74 million. Based on our latest projections, we are lowering and tightening our full year 2019 capital expenditure guidance.

接下來來看 Regeneron 公司 2019 年第一季現金流量表和 2019 年 3 月 31 日資產負債表。再生元公司第一季末持有現金及有價證券55.7億美元，當季自由現金流為8.23億美元。我們將自由現金流計算為經營活動產生的現金流量淨額減去資本支出。兩筆餘額中均包含 2019 年第一季從賽諾菲收到的 4.62 億美元對價，該對價與修訂後的 IO 發現和開發協議有關。第一季（歷來是我們支出最低的季度）的資本支出為 7,400 萬美元。根據我們最新的預測，我們將下調並收緊 2019 年全年資本支出預期。

Under the terms of the recently signed collaboration agreement with Alnylam, we are obligated to make an upfront payment of $400 million and have also agreed to purchase $400 million of Alnylam equity, which equates to approximately 4.44 million common shares at the agreed-upon price of $90 per share. Subject to Hart-Scott-Rodino clearance, we anticipate closing this transaction and paying the $800 million during the second quarter.

根據最近與 Alnylam 簽署的合作協議條款，我們有義務預付 4 億美元，並且還同意購買價值 4 億美元的 Alnylam 股權，這相當於以每股 90 美元的約定價格購買約 444 萬股普通股。在哈特-斯科特-羅迪諾反壟斷法批准後，我們預計將在第二季完成這筆交易並支付 8 億美元。

Additionally, we will provide Alnylam with a specified amount of funding at program initiation and that lead candidate designation, and Alnylam will be eligible to receive up to $200 million in clinical proof-of-principle milestones for eye or CNS programs. The clinical proof-of-principle milestones are not expected in 2019.

此外，我們將在計畫啟動和被指定為領先候選計畫時向 Alnylam 提供一定數量的資金，Alnylam 將有資格獲得高達 2 億美元的眼科或中樞神經系統計畫臨床原理驗證里程碑資金。預計2019年不會達到臨床原理驗證里程碑。

With that, I would like to turn the call back to Mark.

那麼，我想把電話轉回馬克。

Thanks, Bob. That concludes our prepared remarks. Before we get into Q&A, we'll have Len just say something.

謝謝你，鮑伯。我們的發言稿到此結束。在進入問答環節之前，我們先請 Len 說幾句。

Yes, one late breaking news. We just received a note. I'm pleased to inform you that the European Commission has informed us that on the 6th of May, it adopted the EC -- implementing decision for DUPIXENT extension of the indication with the treatment of adults and adolescents with severe asthma with type 2 inflammation characterized by raised blood eosinophils and/or raised FeNO, and the addition of the 200 milligram dose strength in both the prefilled syringe and the prefilled pen format. So the final full indication for DUPIXENT is now DUPIXENT -- and this is in Europe -- is indicated in adults and adolescents 12 years and older as add-on maintenance treatment for severe asthma with type 2 inflammation characterized by raised blood eosinophils and/or raised FeNO, who are inadequately controlled with high dose inhaled corticosteroids plus another medicinal product for maintenance treatment.

是的，一則突發新聞。我們剛剛收到一則訊息。我很高興地通知您，歐盟委員會已通知我們，5 月 6 日，它通過了關於 DUPIXENT 適應症擴展的 EC 實施決定，將適應症擴展至治療患有嚴重哮喘的成人和青少年，其特徵是血液嗜酸性粒細胞增多和/或 FeNO 增多，並增加了 200 毫克劑量規格，包括兩種預填充注射器和預填充筆。因此，DUPIXENT 的最終完整適應症現在是：DUPIXENT——這是在歐洲——適用於 12 歲及以上的成人和青少年，作為重度哮喘的附加維持治療，其特徵是血液嗜酸性粒細胞升高和/或 FeNO 升高，這些患者使用高劑量吸入性皮質類固醇和另一種藥物進行維持治療仍無法充分控制病情。

Now we can go to questions.

現在我們可以進入問答環節了。

Thanks, Len. Operator, we'd like to open up the call for Q&A. (Operator Instructions) Operator, you may open the line.

謝謝你，Len。接線員，我們現在開始問答環節。（操作員指示）操作員，您可以開通線路了。

(Operator Instructions) And from Cowen, we have Yaron Werber.

（操作說明）來自 Cowen 的 Yaron Werber。

Congrats on the launch of dupi. I have a question about dupi trend so far in asthma. It sounds like you really are capturing a nice share in terms of 75% are first-to-biologic, so I have a 2-part question. Number one, in terms of prior authorizations, what are you seeing for this new class versus the IL-5 class? And then secondly, when you're mentioning a 10% market growth, we're calculating the IL-5s are roughly doing about $1.5 billion right now, depending on how you project growth. Are you kind of talking about 10% of that as sort of a comp? And how do you see that market growing?

恭喜dupi上線。我有一個關於氣喘治療中杜必利（Dupi）趨勢的問題。聽起來你們確實佔據了相當不錯的市場份額，75% 的患者都是第一批使用生物製劑的患者，所以我有兩個問題。首先，就事先授權而言，您認為這種新型飛機與IL-5型飛機相比有何不同？其次，當你提到 10% 的市場成長時，我們計算出 IL-5 目前的收入約為 15 億美元，具體數字取決於你如何預測成長。你是指把其中的 10% 作為某種補償嗎？您認為這個市場會如何成長？

Sure. So let me take a start. I'll go to the last comments on the growth of the asthma biologics market. In our calculation with some of those you described, we look at all the biologics products that are currently indicated in the U.S. for asthma. And then since the launch of DUPIXENT for asthma, we're seeing the size of that market in total grow by about 10%, so certainly inclusive of DUPIXENT, which we believe is significantly driving the growth, but also in combination with the IL-5 category you mentioned and also we would include Xolair, of course, as a biologic product within the asthma market.

當然。那麼，就讓我先來吧。最後，我想談談氣喘生物製劑市場的成長情況。在計算您所描述的某些因素時，我們會考慮目前在美國獲準用於治療氣喘的所有生物製劑產品。自 DUPIXENT 上市治療氣喘以來，我們看到該市場的整體規模成長了約 10%，這當然包括我們認為顯著推動成長的 DUPIXENT，但也包括您提到的 IL-5 類別，當然，我們也將 Xolair 作為氣喘市場的生物製劑產品納入其中。

The next piece going back. We do see some very favorable indicators still somewhat early in launch. And most compelling of course is the profile and the unique aspects of DUPIXENT that is being showcased by allergists already experienced with DUPIXENT from atopic dermatitis, but also pulmonologists; both the clinical profile, safety profile and the fact that patients can self administer. Again, early in the reimbursement cycle, I will comment only on DUPIXENT. It's probably best that I not comment on access for competitive therapies. But I can share that in early days, while we continue to work closely with payers, we have been pleased with the ability for patients to receive reimbursement and for physicians to participate and have ease of prescribing. So while we'll continue to work closely in that area early days, all aspects of the launch uptake on both patient experience, prescriber experience and patient access have been quite favorable.

下一塊要放回去。雖然目前發佈時間還比較早，但我們確實看到了一些非常有利的跡象。當然，最引人注目的是 DUPIXENT 的特性和獨特之處，這不僅體現在經驗豐富的過敏症專家（他們已經用 DUPIXENT 治療過異位性皮膚炎）身上，也體現在肺科醫生身上；包括其臨床特性、安全性以及患者可以自行給藥的事實。再次強調，由於目前仍處於報銷週期的早期階段，我只會評論 DUPIXENT。我最好還是不要對競爭性療法的獲取途徑發表評論。但我可以透露，在初期階段，雖然我們仍在與支付方密切合作，但我們對患者能夠獲得報銷以及醫生能夠參與並輕鬆開處方感到滿意。因此，雖然我們早期仍將繼續在該領域密切合作，但就患者體驗、處方醫生體驗和患者獲取途徑而言，產品上市的各個方面都相當令人滿意。

From Goldman Sachs, we have Terence Flynn.

來自高盛的特倫斯·弗林。

Maybe just a 2-part on Regeneron 1979. Just wondering when you guys will have visibility on if the Phase II trials will be or will not be registration-enabling in lymphoma? And then, the 2 deaths that you mentioned, can you give us any more context there with respect to either the dose or if they were an FL or a DLBCL? And anything on prior treatment history?

或許可以寫一篇關於 Regeneron 1979 的兩部分文章。請問你們什麼時候才能確定 II 期試驗結果是否能夠用於淋巴瘤的註冊？還有，您提到的兩例死亡病例，您能否提供更多關於劑量、是否為濾泡性淋巴瘤或瀰漫性大B細胞淋巴瘤等方面的背景資訊？之前有治療史嗎？

Well, we will be certainly informing you when we know that these are registrational studies. In terms of the toxicities, I just want to remind you, as I noted in my comments, that these were seen in combination with PD-1, and as I noted, that in some ways it indicates that the theoretical concept of combining these 2 classes actually increases immune activation, is actually pertaining in the situation here. And what we believe is that we have ways of adjusting the dosing regimen so that we can avoid the increased cytokine release syndrome, while capturing the potentially increased activity of combining these 2 classes.

一旦我們確定這些是註冊研究，我們一定會通知您。關於毒性方面，我只想提醒各位，正如我在評論中提到的，這些毒性是在與 PD-1 聯合使用時觀察到的，而且正如我所指出的，這在某種程度上表明，將這兩類藥物結合起來實際上會增強免疫激活的理論概念，實際上與這裡的情況相符。我們相信，我們可以透過調整給藥方案來避免細胞激素釋放症候群的發生，同時發揮這兩種藥物合併使用可能帶來的活性增強作用。

So Terence, just to amplify on the registrational aspect. It's not that we're being coy. I think it -- there will be registration if the data are adequate. So obviously, we'll let what -- I think what George is trying to say is we'll let you know when we have the data. We intend these to be registrational if the data continues to be as good as it was in the early studies.

所以 Terence，我再補充一下註冊方面的內容。我們並非故作神秘。我認為──如果資料充足，就會有人登記。所以很明顯，我們會…我想喬治想說的是，我們會在拿到數據後通知你們。如果資料繼續保持早期研究中的良好狀態，我們計劃將這些註冊研究納入研究範圍。

From JPMorgan, we have Cory Kasimov.

來自摩根大通的科里·卡西莫夫。

Wanted to follow-up on the bispecific programs -- and recognizing that it's still, obviously, relatively early days -- how do you see the durability of response from 1979 stacking up against CAR-T therapies and the importance of this parameter for future broad commercial uptake? And as you're gathering experience in CAR-T-experienced patients as well, how do you see 1979 initially slotting into the marketplace?

我想跟進雙特異性療法計畫——當然，我們也意識到現在還處於相對早期的階段——您認為 1979 年的療效持久性與 CAR-T 療法相比如何？這項參數對於未來廣泛的商業應用有多重要？而且，隨著您在 CAR-T 療法患者方面累積經驗，您認為 1979 最初將如何進入市場？

Well, we have reported on durability and we'll continue to report on it in the upcoming conference. Most patients who remain on treatment maintained their responses. In terms of versus CAR-T, as I noted, we will be reporting on promising early results in post CAR-T failures at the upcoming meeting. So we think that there's a lot of opportunity here for the CD20 bispecific both in the relapsed refractory setting where we're setting it in. It's obviously going to be much more convenient and amenable therapy to more patients who don't have to go through the whole process that's required for CAR-T therapies. The possibility that it can actually also work in individuals who have failed CAR-T therapies is very exciting, let alone the possibility that with its profile and the way we give it that we can also be moving relatively rapidly into the frontline settings as well. So we think this is a very exciting opportunity that can really address a lot of the need in lymphoma, from the later-stage patients who have failed every other kind of therapy eventually to a frontline therapy that could really impact the disease in the earliest of patients.

我們已經報導過耐用性方面的問題，我們將在即將召開的會議上繼續報導這個問題。大多數繼續接受治療的患者都維持了治療效果。至於 CAR-T 療法與 CAR-T 療法的比較，正如我所提到的，我們將在即將舉行的會議上報告 CAR-T 療法失敗後的一些有希望的早期結果。因此，我們認為 CD20 雙特異性抗體在復發難治性環境中有很多應用機會，而我們目前正是將其應用於該領域。顯然，這種療法會更加方便，也更容易被更多患者接受，因為他們不必經歷 CAR-T 療法所需的整個過程。它甚至有可能對 CAR-T 療法失敗的患者也有效，這令人非常興奮，更不用說憑藉它的特性和給藥方式，我們還可以相對迅速地將其應用於一線治療。因此，我們認為這是一個非常令人興奮的機會，可以真正滿足淋巴瘤治療的許多需求，從最終對所有其他療法都無效的晚期患者，到能夠真正影響早期患者的一線療法。

And just to amplify slightly for those who are not dupixionados. We've reported previously the rather striking response data, including a high percentage of complete responses at what we think would be the effective doses. And so when you start to see that in these very treatment-experienced patients, it gets pretty exciting pretty quickly.

再稍微解釋一下，給那些不熟悉雙關語的人聽。我們之前曾報道相當引人注目的反應數據，包括我們認為的有效劑量下完全緩解率很高。所以，當你在這些接受過很多治療的患者身上看到這種情況時，你會很快感到非常興奮。

From UBS, we have Carter Gould.

來自瑞銀集團的卡特古爾德。

I wanted to, I guess, drill down a little bit more onto the decision to move dupi into a Phase III in COPD. I think before you had talked about that being a little bit more of like a Phase II/Phase III study, it seems like it's a fully fleshed-out kind of Phase III. And maybe just speak to your level of confidence there given sort of the mixed history with or negative history with the IL-5? And kind of what gives you confidence there?

我想更深入地探討將度匹林推進 COPD III 期臨床試驗的決定。我認為在你之前提到這更像是一項二期/三期研究之前，它似乎已經是一項非常完善的三期研究了。鑑於IL-5的歷史褒貶不一，甚至可以說是負面歷史，或許您能談談您對它的信心程度嗎？是什麼讓你在這方面充滿信心？

Maybe I'll let George answer on as well, but I would say that one is -- comes more under the category of we'll need to see the data rather than a high degree of confidence, based upon some earlier studies. When we had done atopic dermatitis, when we had done our first asthma studies where we saw these clear-cut effects on FEV1 and even on loss of asthma control and dramatic responses in the AV, of course, you had a much higher degree of confidence. COPD is, I think, much tougher. It's worth looking at, but we wouldn't rank this as something we have high degree of confidence in.

也許我會讓喬治也來回答一下，但我認為，其中一個問題——更像是我們需要看到數據才能得出結論，而不是基於一些早期研究而有很高的把握。當我們進行異位性皮膚炎研究，當我們進行第一次氣喘研究時，我們看到了對 FEV1 的明確影響，甚至對氣喘控制的喪失以及 AV 的顯著反應，當然，你會更有信心。我認為，慢性阻塞性肺病要棘手得多。值得關注，但我們對此並沒有很高的信心。

Yes. I think what Len is alluding to is that COPD is a very complex disease. And the problem is that in the real world, the data suggests it is indeed quite complicated in terms of it's impacted by asthma and type 2 diseases. And so there are a lot of patients who have COPD whose diseases worsened with these related type 2 toxicities. The problem is finding the right patients to treat and also negotiating with the FDA, who likes to study cleaner diseases. So I think as Len said, it's going to be -- it's a complicated story, and we'll see what the data says.

是的。我認為 Len 的意思是，慢性阻塞性肺病是一種非常複雜的疾病。而問題在於，現實世界的數據表明，就其受氣喘和 2 型疾病的影響而言，情況確實相當複雜。因此，許多患有 COPD 的患者，由於這些相關的 2 型毒性，病情加重了。問題在於找到合適的病人進行治療，以及與美國食品藥物管理局（FDA）進行談判，因為FDA更喜歡研究更「乾淨」的疾病。所以我覺得就像 Len 說的那樣，情況會很複雜，我們拭目以待數據會怎麼說。

From Barclays, we have Geoff Meacham.

來自巴克萊銀行的傑夫·米查姆。

This is Greg Harrison on for Geoff. Could you tell us maybe a little more about your overall strategy in the complement space? And what type of differentiation do you think you'd need to see with pozelimab to make it competitive in PNH, whether that's efficacy or dosing convenience? And what other types of additional indications could you potentially pursue there?

這裡是格雷格·哈里森，他代替傑夫發言。能否再詳細介紹一下您在互補品領域的整體策略？您認為 pozelimab 需要具備哪些差異化優勢才能在 PNH 領域具有競爭力，無論是療效還是給藥便利性？除此之外，你還可以考慮哪些其他類型的額外指標？

So I think it's a little bit early to get into that sort of competitive assessment. Obviously, as George mentioned, we've got the ability to combine that with some siRNA from Alnylam that we're going to be working with them. The potential there might have some unique features. It's just a little early to say where we will slot it. We'll have to see how the data develops, but obviously, we're going to look at efficacy, we're going to look at interval, et cetera.

所以我覺得現在進行這種競爭性評估還為時過早。顯然，正如喬治所提到的，我們有能力將它與 Alnylam 的一些 siRNA 結合起來，我們將與他們合作。那裡的潛力可能具有一些獨特的特徵。現在說我們會把它放在哪裡還為時過早。我們得看看數據如何發展，但顯然，我們會專注於療效、間隔等等。

From SVB Leerink, we have Geoffrey Porges.

來自 SVB Leerink 的 Geoffrey Porges。

A couple of quick ones on R&D. First, George, could you just give us a sense of when you might be in a position to make a decision on your NGF program, specifically whether it's go or no go and whether that might be some savings to the otherwise upward trend in R&D? And then secondly, just to go back on the combination, it definitely sounds like you've had a setback on the PD-1 bispecific combination, but what are your thoughts on the PD-1 combination with the co-stim molecule? How quickly might that advance? Are you concerned about some of the same either immunotoxicity liabilities or else TLS liabilities?

關於研發，簡單提幾句。首先，喬治，你能否大致說明一下，你何時才能就你的 NGF 項目做出決定，具體來說，是啟動還是停止該項目，以及這是否能為研發領域原本不斷增長的趨勢節省一些資金？其次，回到組合療法的問題上，聽起來您在 PD-1 雙特異性組合療法方面確實遇到了挫折，那麼您對PD-1 與共刺激分子的組合療法有什麼看法呢？這一進程可能會以多快的速度推進？您是否擔心免疫毒性或腫瘤溶解症候群（TLS）方面的風險？

Okay. Well, first, on the NGF. As I mentioned, the independent data and safety monitoring board gave the go-ahead just last week for us to continue with the program. So we -- they will continue to monitor the study, and when we unblind the study and so forth we'll be able to better assess what the efficacy/safety ratio is and where the program is going. So that's the story on NGF. I wouldn't necessarily classify the CD20xCD3 combination with PD-1 as a setback. As I said, I mean, what it really indicates is a pretty dramatic increase in immune activation. As you know, of course, these sorts of things were the things that demonstrated excitement in approaches like CAR-T therapies. In fact, it was noted in many cases that the people who had -- the patients who had the highest immune activation had the highest antitumor responses, and we think this is likely to be the case in this setting as well. The benefit that we have with the ability to individually titrate and give them in a different sequence allows us to much better fine-tune the timing of the immune activations and allow us to better take advantage of the immune activation while controlling the potential cytokine release syndrome. So we actually think it's actually an exciting indicator of combined immunoactivation. And so we're very excited, both of the combinations of our CD3 bispecifics with PD-1 but also CD28 bispecifics with PD-1 and CD3 bispecifics with the CD28 bispecifics. All 3 of those sets of combos afford an incredible exciting set of opportunities that in animal studies have really been game-changing. And so we can only hope that we can achieve the same sort of benefit/risk in patients that we're seeing in those settings.

好的。首先，關於 NGF。正如我之前提到的，獨立的數據和安全監測委員會上週剛剛批准我們繼續進行該計畫。因此，我們將繼續監測這項研究，當我們揭盲研究等等之後，我們將能夠更好地評估療效/安全性比率以及該計畫的發展方向。這就是關於NGF的故事。我並不認為 CD20xCD3 與 PD-1 的組合是一種挫折。正如我所說，我的意思是，這實際上表明免疫活化程度顯著提高。當然，如你所知，正是這些事情展現了人們對 CAR-T 療法等方法的興奮之情。事實上，在許多情況下都注意到，免疫活化程度最高的患者，其抗腫瘤反應也最強，我們認為這種情況在這種情況下也可能成立。我們能夠單獨滴定並以不同的順序給予藥物，這給我們帶來了好處，使我們能夠更好地微調免疫激活的時間，並使我們能夠更好地利用免疫激活，同時控制潛在的細胞因子釋放綜合徵。所以我們認為這實際上是聯合免疫活化的一個令人興奮的指標。因此，我們非常興奮，無論是 CD3 雙特異性抗體與 PD-1 的組合，或是 CD28 雙特異性抗體與 PD-1 的組合，以及 CD3 雙特異性抗體與 CD28 雙特異性抗體的組合。這三組組合都提供了一系列令人難以置信的令人興奮的機會，在動物研究中真正具有變革意義。因此，我們只能希望能夠在患者身上實現與在這些情況下所看到的相同的益處/風險比。

From Morgan Stanley, we have Matthew Harrison.

來自摩根士丹利的馬修·哈里森。

I was hoping you could talk a little bit about the adjuvant studies that you're running in Libtayo? And maybe just comment how we should think about the data that you have in sarcoma informing those other skin cancer studies? And just your confidence around what we know so far on the molecule about those adjuvant studies?

希望您能談談您在Libtayo進行的輔助治療研究？或許您可以談談我們應該如何看待您在肉瘤方面掌握的數據，並將其應用於其他皮膚癌研究？那麼，對於我們目前所了解的關於該分子以及這些佐劑研究的信息，您有多大信心？

Well, I think in cutaneous squamous cell carcinoma, obviously, the very impactful efficacy that we saw in the later-stage patients gives us a lot of confidence that in the earlier-stage patients, as is usually the case with cancer treatments, that one will be seeing even better benefit. And obviously this increases very substantially the number of patients in those indications who might be able to benefit if our adjuvant and neoadjuvant trials in the cutaneous squamous cell carcinoma produce that sort of data that would be possible based on the data that we've seen in the late-stage patients. So that will be, I think, a very exciting way to increase the benefit to a large number more of patients who don't have satisfactory treatments right now, and avoid them progressing to these later and much more debilitating stages. Similarly, in lung cancer, we're excited with our opportunity there in terms of our first-line setting. And of course, we're also hoping to move into earlier settings there as well.

我認為，在皮膚鱗狀細胞癌中，很顯然，我們在晚期患者中看到的顯著療效讓我們很有信心，在早期患者中，就像癌症治療通常的情況一樣，將會看到更好的療效。顯然，如果我們在皮膚鱗狀細胞癌的輔助和新輔助試驗中能夠產生基於我們在晚期患者中看到的數據的那種數據，那麼這些適應症中可能受益的患者數量將大大增加。我認為，這將是一個令人興奮的方法，可以增加更多目前沒有令人滿意的治療方案的患者受益，並避免他們發展到後期更嚴重的階段。同樣，在肺癌領域，我們對一線治療的機會感到興奮。當然，我們也希望能夠進入更早的設定階段。

From Bank of America, we have Ying Huang.

來自美國銀行的是黃穎。

So you mentioned that the total prescriptions for DUPIXENT increased 18% quarter-over-quarter and then new patients coming at about -- right now -- at 950 per week. Can you provide a little bit more clarity about the breakdown between the patients coming from adolescent atopic dermatitis versus adult atopic dermatitis versus asthma? Where exactly are you seeing the most growth?

您提到 DUPIXENT 的總處方量較上季增加了 18%，而目前每週新增病患人數約為 950 人。您能否更清楚地說明青少年異位性皮膚炎患者、成人異位性皮膚炎患者和氣喘患者之間的組成差異？您認為成長最快的領域具體是哪些？

So it's early days, so we're not at this time giving specific breakouts by indication. But I certainly can give you a feel for performance. First, as you summarized some of the points that I'd made during the call, on NBRxs as one measures -- or new branded scripts on a weekly basis, we are seeing a significant increase. When we look at this quarter's rate on a weekly basis of 950 versus prior quarter at about 700 scripts per week. So we're very pleased. What is occurring is that we're actually seeing growth in all of our indications, which is a very exciting profile for DUPIXENT. We continue to help more adult atopic dermatitis patients, so we're seeing growth in that realm. Additionally, as I mentioned during the discussion of the call, we are seeing a very nice start to the launch of asthma, both from a standpoint of DUPIXENT's profile but also from the standpoint of being very competitive to other agents that are currently being used as biologics for the treatment of asthma. And then finally, the most recent indication for adolescents is one that has been transformational certainly for patients and their families, but also as we hear stories all the time from physicians who are treating these patients. These poor young adolescents are very often challenged to participate at school, in their activities on a daily basis, and we're hearing just wonderful stories on the difference that DUPIXENT is making for them. So while very early in this launch, we're excited to be helping so many, and we see continued growth across atopic dermatitis, asthma and all the various age groups we're now covering.

現在還處於早期階段，所以我們目前不會給出具體的突破指標。但我肯定可以讓你感受到性能上的差異。首先，正如您在電話會議中總結的一些要點一樣，以 NBRxs（每週的新品牌處方）為衡量標準，我們看到了顯著的增長。我們來看本季每週的處方量為 950 份，而上一季每週的處方量約為 700 份。我們非常高興。目前的情況是，我們所有適應症都出現了成長，這對 DUPIXENT 來說是一個非常令人振奮的前景。我們持續幫助更多成年異位性皮膚炎患者，因此我們看到該領域的業務正在成長。此外，正如我在電話會議討論中提到的，我們看到 DUPIXENT 在哮喘領域的上市開局非常不錯，無論是從 DUPIXENT 的概況來看，還是從它與其他目前用作哮喘生物製劑的藥物的競爭力來看，都是如此。最後，針對青少年的最新適應症無疑對患者及其家庭產生了變革性的影響，我們也經常聽到治療這些患者的醫生講述他們的經歷。這些貧困的青少年經常在學校和日常活動中面臨挑戰，我們聽到了很多關於 DUPIXENT 給他們帶來的改變的精彩故事。雖然這項服務推出時間還很短，但我們很高興能夠幫助到這麼多人，並且我們看到在異位性皮膚炎、哮喘以及我們現在覆蓋的所有不同年齡層中，服務都在持續增長。

From Piper Jaffray, we have Chris Raymond.

來自 Piper Jaffray 的 Chris Raymond。

This is Ally Bratzel on for Chris this morning. Another question on DUPIXENT. We've gotten pretty consistent physician feedback from multiple points that the DUPIXENT sampling plan was suboptimal, at least, for dermatologists. So I guess more recent feedback says that's improved lately. Could you just give us some background or color on your DUPIXENT sampling plan, especially as additional indications are launching?

這裡是艾莉‧布拉澤爾，今天早上她代替克里斯為大家報道。關於DUPIXENT的另一個問題。我們從多方獲得了相當一致的醫生回饋，認為 DUPIXENT 的抽樣方案並不理想，至少對於皮膚科醫生來說是如此。所以我覺得最近的回饋顯示情況有所改善。能否請您介紹DUPIXENT的試用計劃，特別是考慮到其他適應症的推出？

Sure. So first, I will share that it is very important to us that patients receive DUPIXENT and physicians have the experience that they need. There are availability of samples in the marketplace today. So as you indicate, we do have a sampling program, but we also think it's very important that as patients are initiated on therapy, they're able to stay on therapy. And we also have a number of support services that help patients and their prescribing physicians make sure that patients can navigate payer reimbursement and once on DUPIXENT can actually stay on therapy. We believe at this point, we have the number of samples correct in the market to support our various indications.

當然。首先，我想強調的是，對我們來說，確保患者能夠接受 DUPIXENT 治療，以及醫生擁有所需的經驗，都非常重要。目前市面上已有樣品出售。正如您所指出的，我們確實有一個抽樣計劃，但我們也認為，當患者開始接受治療時，能夠堅持治療是非常重要的。我們還有一系列支援服務，幫助患者及其處方醫生確保患者能夠順利獲得支付方的報銷，並且一旦開始使用 DUPIXENT，就能真正堅持治療。我們相信，目前市場上已有足夠數量的正確樣本來支持我們的各種說法。

So let me just amplify on that -- what Marion just said, because I think it is a tension between wanting to make it as easy as possible for the doctors and patients on the one hand, and on the other hand, the greater good we think of getting -- forcing, if you will, payers to make decisions so that everybody can get access. And payers are very sophisticated. As one payer said to me, "Keep it up, Len. We love those samples. It's like free drug. And we'd like you to keep going forever." So there is this tension of forcing payers to make a decision on the one hand and striking the right balance for making it easy for patients to initiate. The launch, the number of patients getting on the drug is really quite remarkable, so we think we've got that balance working.

所以，讓我再補充一下——瑪麗昂剛才說的，因為我認為這是一種矛盾：一方面，我們希望盡可能方便醫生和病人；另一方面，我們認為應該追求更大的利益——迫使支付方做出決定，以便每個人都能獲得醫療服務。而且支付方也非常精明。一位付款人對我說：“繼續加油，倫。”我們很喜歡這些樣品。這就像免費的毒品。我們希望您能一直堅持下去。 」 因此，一方面要迫使支付方做出決定，另一方面又要找到合適的平衡點，讓患者更容易開始治療，這就造成了一種矛盾。當藥物上市以來，接受治療的患者人數確實非常可觀，所以我們認為我們已經找到了平衡點。

From BMO, we have Matthew Luchini.

來自 BMO 的有馬修·盧奇尼。

Just wanted to come back to the CRS scene with 1979 and, recognizing what you've said so far, I'm just wondering if you might be able to put any more color around similarities or differences between the 2 patients that experienced CRS and those that didn't perhaps in terms of prior -- number of prior lines of therapy, types of therapy, if they were both seen in FL or DLBCL, for example? Any other color you can provide would be helpful.

我只是想回到 1979 年的 CRS 討論，鑑於您之前所說的，我想知道您是否可以進一步闡述一下經歷 CRS 的兩名患者與未經歷 CRS 的兩名患者之間的相似之處或不同之處，例如既往治療方案的數量、治療類型，以及他們是否都患有濾泡性淋巴瘤 (FL) 或瀰漫性大 BCL 細胞淋巴瘤 (BDL) 等？如果您能提供其他顏色訊息，那就太好了。

Well, maybe I can just start by reminding you that in some ways this is very analogous to our early experience with the CD20xCD3 monotherapy. In those early studies, actually, with our lowest doses, we actually saw pretty profound CRS. And what the team didn't realize that we had the ability -- like I said, this is one huge advantage with these biologics, for example, compared to things such as CAR-T therapies -- that we can literally dial up and dial down the doses and adjust sequences and divide the doses, and we were able to control it. So now as we got to the much higher doses with much higher activities, as Len pointed out, where we're seeing in late-stage patients high proportions of not only overall responses but complete responses, this now comes with much less CRS than we saw in the early days because we learned how to adjust, divide and sequence the dose of the individual therapy. We think that we're exactly in an analogous situation with the CD20 combination with the PD-1. We're now at much lower doses of the CD20 in combination with the PD-1, but giving it in the way that we had avoided the CRS. We are now seeing it again, which tells us that we have higher immune activation, and we're going to just do the same sorts of things that we did by taking advantage of our ability to divide the doses and sequence, the regimens and so forth. And we're hoping, in the same way that we did with the bispecific on its own, we'll be able to take advantage of this increased immunoactivation but avoid the CRS. So we think these are really exciting times. We've seen it before. We got to what we believe now are, as Len said, the actual effective doses in these late-stage patients with the monotherapy and we hope we'll now be able to do the same thing with the combination delivery, even more efficacy without having to pay too much of a price in terms of increased toxicity.

嗯，或許我可以先提醒各位，在某些方面，這與我們早期使用 CD20xCD3 單藥療法的經驗非常相似。實際上，在早期的研究中，即使使用最低劑量，我們也觀察到了相當嚴重的 CRS。團隊沒有意識到我們有能力——就像我說的，這是這些生物製劑的一大優勢，例如，與 CAR-T 療法等相比——我們可以真正地增加和減少劑量，調整順序和分割劑量，而且我們能夠控制它。所以現在，隨著劑量和活性大幅提高，正如 Len 指出的那樣，我們看到晚期患者不僅總體緩解率很高，而且完全緩解率也很高，這與早期相比，CRS 的發生率要低得多，因為我們學會瞭如何調整、分割和安排個體治療的劑量。我們認為，CD20 與 PD-1 的組合情況與此完全類似。我們現在使用劑量低得多的 CD20 與 PD-1 合併治療，但給藥方式卻避免了 CRS。我們現在再次看到了這種情況，這告訴我們免疫活化程度更高了，我們將採取與之前相同的措施，利用我們分劑量、分順序、治療方案等的優勢。我們希望，就像我們單獨使用雙特異性抗體一樣，能夠利用這種增強的免疫活化作用，同時避免 CRS。所以我們認為這是一個非常令人興奮的時代。我們以前見過這種情況。正如 Len 所說，我們已經找到了我們認為對這些晚期患者進行單藥治療的實際有效劑量，我們希望現在能夠透過聯合用藥達到同樣的效果，在不增加太多毒性的情況下獲得更高的療效。

Plus I think one has to think ahead. We have a lot of other bispecifics, I think as George mentioned earlier, where you're going into some cancers where you don't see very many responses at all. And the notion that you can actually come -- get these enhanced combined immune activations, I think, is as important for these other programs as it is for 1979, where actually you do quite fine as you get up to much higher doses. So I think this has really a potentially profound implications for our other programs.

而且我認為人應該有遠見。我們還有很多其他的雙特異性抗體，我想正如喬治之前提到的那樣，你可以用它們來治療一些癌症，而這些癌症的治療效果並不理想。我認為，能夠真正獲得這些增強的聯合免疫活化這個概念，對於其他項目來說，與 1979 年一樣重要，因為在 1979 年，隨著劑量的增加，你的效果實際上會非常好。所以我認為這對我們的其他項目可能會產生非常深遠的影響。

Very good point.

說得很有道理。

From Baird, we have Brian Skorney.

來自 Baird 的有 Brian Skorney。

Bob, maybe just kind of characterize, when we look at the earnings going ahead, there's a little bit of retrenchment on the year-over-year basis in the first quarter compared to last year. So I know you guys don't provide bottom line guidance, but just maybe kind of from a target perspective, do you see 2019 as a year of EPS growth and do you think it's just kind of the one-time items giving the little drag? Or should we kind of expect 2019 to be more flattish and look towards 2020 and beyond to see a return to growth?

鮑勃，或許可以這樣概括一下，當我們展望未來的收益時，與去年同期相比，第一季的收益略有下降。我知道你們不提供獲利預測，但從目標角度來看，你們認為 2019 年每股盈餘會成長嗎？你們認為只是某些一次性項目造成了輕微的拖累嗎？或者我們應該預期 2019 年經濟將較為平穩，並將目光投向 2020 年及以後，期待經濟能恢復成長？

Yes. Brian, so thanks. So we're not going to give guidance on this call with regards to EPS. It's just not what we've done previously. And we tried to highlight with regards to gives and takes during the first quarter. I mean, certainly with regards to our cost of collaboration manufacturing, calling out the delta which was a big increase year-over-year, we don't talk much about our supply chain other than saying we think it's best-in-class. These are very difficult antibodies that we continue to make and sometimes things like that happen. With regards to R&D, our guidance holds. We raised the lower end of our guidance, but that's because of the Alnylam transaction that we're going to execute in the middle of second quarter. We're taking on initiations. And upon doing that, there will be payments to Alnylam. So we still are comfortable with regards to where we are from our guidance point of view. I will say expenses in Q1 from RD -- R&D came in a little hotter than usual, but for the rest of the year we still feel comfortable with the guidance levels we've provided previously.

是的。布萊恩，謝謝你。因此，本次電話會議我們不會就每股收益給予任何指引。這跟我們以前的做法完全不同。我們試圖在第一季重點強調付出與回報方面的問題。我的意思是，當然，就我們的合作製造成本而言，我們指出成本同比大幅增長，但我們很少談論我們的供應鏈，只是說我們認為它是業內最好的。這些是非常難合成的抗體，我們一直在努力生產，但有時也會發生這樣的事情。關於研發方面，我們的指導原則仍然有效。我們提高了業績預期下限，但這主要是因為我們將在第二季中期完成對 Alnylam 的收購。我們正在接受入會儀式。這樣做之後，Alnylam 將收到款項。所以從我們的指導角度來看，我們仍然對我們所處的位置感到滿意。我想說，第一季的研發支出——研發支出比往常略高，但對於今年剩餘時間，我們仍然對先前提供的指導水準感到滿意。

I mean I do think to remind us a bit, the way we see the business, the top line are -- the products that have come out of Regeneron -- are continuing to grow. And the expenses are growing primarily because the research organization is just so doggone productive. I think it was mentioned that we put maybe 4, 5 molecules in the clinic last year, we expect to put a similar number this year and we have a steady flow projected for the year for 2020 and beyond. So with that, obviously, we feel we should be investing in our research, because we think it has the potential to deliver great returns.

我的意思是，我想提醒大家一點，就我們看待業務的方式而言，營收成長——Regeneron 公司推出的產品——正在持續成長。而開支不斷增長的主要原因是該研究機構的生產力實在太高了。我想之前有人提到過，我們去年可能將 4、5 個分子推進了臨床試驗，我們預計今年也會推進類似的數量，並且我們預計 2020 年及以後都會有穩定的進展。因此，很顯然，我們認為應該加大對研究的投入，因為我們認為它有可能帶來豐厚的回報。

And from Cantor Fitzgerald, we have Alethia Young.

而來自坎托·菲茨杰拉德的則是阿萊西亞·楊。

Just one on Alnylam. I wanted you guys just talk a little bit more about how you're thinking about using this platform technology versus the antibodies, and also think you'd -- might go after larger or more rare opportunities. And just your general perspective on the platform safety as well.

Alnylam 上只有一個。我希望你們能再多談談你們是如何考慮使用這種平台技術而不是抗體的，以及你們是否考慮過——可能會去追求更大或更罕見的機會。還有，您對平台安全性的整體看法是什麼？

Yes. Well, we have enormous hope that Alnylam is going to be a transformational opportunity. Why? Because both sides bring, I think, a lot of unique and very exciting capabilities to the table. We've been obviously doing a lot of biology and genetics, particularly in the eye and also in the CNS that we haven't really talked about and most, if not the vast majority of the targets there are intercellular targets. And obviously, Alnylam has the capability with their technology to start addressing some of these intercellular targets in these 2 spaces that are challenging with other approaches. And so this allows us to take advantage of our genetics, all the information coming out of our Regeneron Genetics Center, all the biology we've been doing, all the animal modeling that we've been doing, and now take advantage of them with a whole new platform, not antibodies that, as you know, are limited to extracellular targets, secretive proteins and cell surface receptors, but an assortment of intercellular targets that we now think we can address both in the eye and CNS and address a whole new series of diseases where we have enormous knowledge and capability based on our genetics and our biology efforts. So it's really coming together, I think, of 2 great like-minded companies with very complementary approaches that we think, together, we can really make a difference particularly in these spaces.

是的。我們非常希望 Alnylam 能成為一個具有改變意義的機會。為什麼？我認為，雙方都具備許多獨特且令人興奮的能力。我們顯然做了很多生物學和遺傳學方面的研究，尤其是在眼睛和中樞神經系統方面，但我們還沒有真正討論過這些，而且大多數（如果不是絕大多數）靶點都是細胞內靶點。顯然，Alnylam 憑藉其技術有能力開始解決這兩個領域中一些其他方法難以解決的細胞間目標。因此，這使我們能夠利用我們的遺傳學、Regeneron遺傳學中心的所有資訊、我們一直在進行的生物學研究、我們一直在進行的動物模型研究，現在可以利用一個全新的平台來利用它們，而不是像您所知的那樣，僅限於細胞外靶點、分泌蛋白和細胞表面受體的抗體，而是一系列細胞內靶點。我們現在認為，我們可以在眼部和中樞神經系統中解決這些問題，並解決一系列全新的疾病。基於我們的遺傳學和生物學研究，我們在這方面擁有豐富的知識和強大的能力。所以，我認為這真的是兩家志同道合、方法互補的優秀公司走到了一起，我們相信，攜手合作，我們一定能夠真正有所作為，尤其是在這些領域。

Operator, this concludes today's call. Thank you, everyone, for joining. Again, Bob Landry, Jay Markowitz and the IR team will be around to answer any further questions. Thank you.

接線員，今天的通話到此結束。謝謝大家的參與。鮑勃·蘭德里、傑伊·馬科維茨和IR團隊將再次解答任何進一步的問題。謝謝。

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

謝謝。女士們、先生們，今天的會議到此結束。感謝您的參與。您現在可以斷開連線了。