雷傑納榮製藥 (REGN) 2018 Q3 法說會逐字稿

Welcome to the Regeneron Pharmaceuticals Q3 2018 Earnings Conference Call. My name is John, and I'll be your operator for today's call. (Operator Instructions) Please note, the conference is being recorded. And I will now turn the call over to Manisha Narasimhan, Head of Investor Relations.

歡迎參加 Regeneron Pharmaceuticals 2018 年第三季財報電話會議。我叫約翰，我將擔任您今天通話的接線生。（操作員說明）請注意，會議正在錄音。現在我將把電話交給投資人關係主管瑪妮莎‧納拉辛漢。

Thank you, John. Good morning, and welcome to Regeneron Pharmaceuticals Third Quarter 2018 Conference Call. An archive of this webcast will be available on our website under Events for 30 days. Joining me on the call today are Dr. Lenoard Schleifer, Founder, President and Chief Executive Officer; Dr. George Yancopoulos, Founding Scientist, President and Chief Scientific Officer; Marion McCourt, Senior Vice President and Head of Commercial; and Bob Landry, Senior Vice President and Chief Commercial Officer. After our prepared remarks, we will open the call for Q&A.

謝謝你，約翰。早安，歡迎參加 Regeneron Pharmaceuticals 2018 年第三季電話會議。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。今天與我一起參加電話會議的有：創辦人、總裁兼執行長 Lenoard Schleifer 博士；創始科學家、總裁兼首席科學官 George Yancopoulos 博士；高級副總裁兼商務主管 Marion McCourt；以及高級副總裁兼首席商務官 Bob Landry。在我們發言完畢後，我們將開放問答環節。

I would also like to remind you that remarks made on this call today include forward-looking statements about Regeneron. Such statements may include, but are not limited to, those related to Regeneron and its products and business, financial forecasts and guidance, development programs and related anticipated milestones, collaborations, finances, regulatory matters, intellectual property, pending litigation and competition. Each forward-looking statement is subject to risks and uncertainties that could cause actual results and events to differ materially from those projected in that statement. A more complete description of these and other material risks can be found in Regeneron's filings with the United States Securities and Exchange Commission, or SEC, including its Form 10-Q for the quarter ended September 30, 2018, which was filed with the SEC earlier 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.

我還要提醒各位，今天電話會議上發表的言論包含 Regeneron 的前瞻性陳述。此類聲明可能包括但不限於與 Regeneron 及其產品和業務、財務預測和指導、開發計劃和相關預期里程碑、合作、財務、監管事項、智慧財產權、未決訴訟和競爭相關的聲明。每項前瞻性聲明都存在風險和不確定性，可能導致實際結果和事件與該聲明中預測的結果和事件有重大差異。有關這些及其他重大風險的更完整描述，請參閱 Regeneron 向美國證券交易委員會 (SEC) 提交的文件，包括其截至 2018 年 9 月 30 日的季度 10-Q 表格，該表格已於今天早些時候提交給 SEC。Regeneron公司不承擔任何公開更新任何前瞻性聲明的義務，無論是由於新資訊、未來事件或其他原因。

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

此外，請注意，今天的電話會議將討論 GAAP 和非 GAAP 指標。有關我們使用非公認會計準則財務指標以及這些指標與公認會計準則的調節表的信息，請參閱我們的財務業績新聞稿，該新聞稿可在我們的網站上查閱。

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

通話結束後，鮑伯·蘭德里和投資者關係團隊將回答進一步的問題。

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

接下來，我將把電話交給我們的總裁兼執行長倫·施萊弗博士。

Thank you, Manisha does such a fabulous job in Investor Relations, we should, at least, get her name right. It's Manisha Narasimhan.

謝謝，Manisha在投資者關係方面做得非常出色，我們至少應該把她的名字寫對。她是瑪妮莎·納拉辛漢。

Good morning to everyone who has joined the call. In the third quarter, we generally delivered record financial results, an important pipeline progress. EYLEA sales continue to grow. For the first time, U.S. EYLEA net quarterly sales surpassed $1 billion. Also, for the first time, third quarter worldwide DUPIXENT sales exceeded $0.25 billion. And DUPIXENT was recently approved for -- as its second major indication. Additionally, we launched Libtayo, our first approved immuno-oncology therapy.

各位早安，歡迎參加本次電話會議。第三季度，我們整體取得了創紀錄的財務業績，專案進展順利。EYLEA的銷售額持續成長。美國安禮公司季度淨銷售額首度突破 10 億美元。此外，DUPIXENT 第三季全球銷售額首次超過 2.5 億美元。DUPIXENT 最近獲準用於——這是它的第二個主要適應症。此外，我們還推出了 Libtayo，這是我們第一個核准的免疫腫瘤療法。

For EYLEA, we significantly strengthened the franchise through a recently expanded label for less frequent dosing and the potential for a new indication in diabetic retinopathy. And we expect to advance a high-dose formulation of aflibercept into the clinic in the first half of next year.

對於 EYLEA，我們透過最近擴大其標籤範圍（減少給藥頻率）以及在糖尿病視網膜病變方面的潛在新適應症，顯著加強了其產品線。我們預計明年上半年將高劑量阿柏西普製劑推進臨床試驗。

Libtayo, our first commercial entry into the exciting and fast-evolving area of immuno-oncology, is the foundation upon which we intend to build with multiple additional agents and approaches in many different cancer settings. We have described DUPIXENT as a pipeline in a product and it is living up to that potential. Compared to other approved biologics for asthma, DUPIXENT has a differentiated profile and label. The recent asthma approval, together with the ongoing robust launch in atopic dermatitis, positive Phase III results in chronic rhinosinusitis with nasal polyps and positive Phase II results in eosinophilic esophagitis validate the scientific hypothesis that the IL-4/IL-13 pathway is responsible for a spectrum of allergic or type 2 diseases. You'll hear more from Marion about the launch of DUPIXENT in asthma and atopic dermatitis, and George will update you on our clinical programs.

Libtayo 是我們首次進軍令人興奮且快速發展的免疫腫瘤學領域的商業產品，也是我們計劃在多種不同癌症治療領域中開發多種其他藥物和方法的基礎。我們曾將 DUPIXENT 描述為產品中的一條管道，而它正在不負眾望，展現出這種潛力。與其他核准的氣喘生物製劑相比，DUPIXENT 具有不同的特性和標籤。最近氣喘的核准，加上異位性皮膚炎的持續強勁上市，慢性鼻竇炎伴鼻息肉的 III 期積極結果，以及嗜酸性食道炎的 II 期積極結果，都證實了 IL-4/IL-13 通路是多種過敏性疾病或 2 型疾病的罪魁禍首的科學假設。您將從 Marion 那裡聽到更多關於 DUPIXENT 在氣喘和異位性皮膚炎治療中的上市情況，George 將向您介紹我們的臨床計畫。

We've continued to make steady progress with our other commercialized products. From PRALUENT, our LDL cholesterol-lowering PCSK9 antibody, we anticipate that the U.S. treatment guidelines for lipid lowering will be updated shortly. We hope the updated guidelines will facilitate greater access and support increased use of the PCSK9 class. Although it gets drowned out in the debate about drug prices, the fact remains that cardiovascular disease is the number one cause of death in the United States and high LDL cholesterol is a major cause of cardiovascular disease.

我們其他商業化產品也持續取得穩定進展。我們研發的降低低密度脂蛋白膽固醇的PCSK9抗體藥物PRALUENT預計很快就會促使美國更新降血脂治療指引。我們希望更新後的指引能促進更多人獲得和支持PCSK9類藥物的使用。儘管在關於藥品價格的爭論中，心血管疾病被掩蓋了，但事實仍然是，心血管疾病是美國的第一大死因，而高 LDL 膽固醇是心血管疾病的主要原因。

Our earlier pipeline continues to progress. At the beginning of the year we set a goal of advancing 4 to 6 new molecules into clinical development. I'm happy to report that to date, we've already advanced 4 new molecules into clinical development. These include a bispecific antibody for ovarian cancer, a new antibody for pain, a leptin receptor agonist and an antibody to CTLA-4. We also expect to advance into the clinic by year-end a BCMAxCD3 bispecific antibody for multiple myeloma. We now have 7 approved drugs, and our clinical pipeline has 20 private candidates, standing a range of therapeutic areas. All of these molecules were discovered by our scientists.

我們之前的管道項目仍在繼續。年初時，我們設定了將 4 至 6 個新分子推進臨床開發的目標。我很高興地報告，到目前為止，我們已經將 4 個新分子推進到臨床開發階段。其中包括用於治療卵巢癌的雙特異性抗體、用於治療疼痛的新抗體、瘦素受體激動劑和 CTLA-4 抗體。我們也預計在年底前將用於治療多發性骨髓瘤的 BCMAxCD3 雙特異性抗體推進到臨床階段。我們目前有 7 種核准藥物，我們的臨床研發管線中有 20 個私人候選藥物，涵蓋多個治療領域。這些分子都是我們科學家發現的。

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

接下來，我將把電話交給喬治。

Thanks Len, and a good morning, everyone. I'd like to begin with EYLEA. In August, our supplemental biological application, or sBLA, which approved for EYLEA dosed every 12 weeks up to 1 year of effective therapy in wet age-related macular degeneration, or wet AMD. EYLEA is now the only anti-VEGF drug for the treatment of wet AMD that offers the flexibility to optimally treat patients regardless of whether they require fixed-interval dosing of 4, 8 or 12 weeks. In September, the FDA accepted our sBLA for EYLEA in diabetic retinopathy, with an action date in May 2019. This sBLA was based on the data from the Phase III PANORAMA study, which investigated the use of EYLEA in patients with mildly-severe to severe non-proliferative diabetic retinopathy without diabetic macular edema. Positive 6 months top line results from PANORAMA were announced in March 2018.

謝謝Len，大家早安。我想先從愛樂（EYLEA）說起。8 月，我們的補充生物製品許可申請 (sBLA) 獲批，用於治療濕性老年黃斑部病變 (濕性 AMD)，每 12 週給藥一次，有效治療時間最長可達 1 年。EYLEA 是目前唯一用於治療濕性 AMD 的抗 VEGF 藥物，無論患者需要 4 週、8 週或 12 週的固定間隔給藥，它都能靈活地為患者提供最佳治療。9 月，FDA 接受了我們針對糖尿病視網膜病變的 EYLEA 的 sBLA 申請，並於 2019 年 5 月做出決定。這項 sBLA 是基於 III 期 PANORAMA 研究的數據，該研究調查了 EYLEA 在患有輕度至重度非增殖性糖尿病視網膜病變（無糖尿病黃斑水腫）的患者中的應用。PANORAMA 的 6 個月主要業績於 2018 年 3 月公佈。

Just a couple of weeks ago, we announced positive data from the 1-year time point from this same study. On the primary endpoint at 1 year after initial monthly dosing period followed by every 8- or every 16-week treatment, 80% and 65% of patients, respectively, experienced a 2-step or greater improvement from baseline on the diabetic retinopathy severity scale compared to only 15% of patients receiving sham injections. The results were highly statistically significant with the p-value less than 0.0001.

就在幾週前，我們公佈了同一項研究一年後的結果。在初始每月給藥期後 1 年的主要終點，隨後每 8 週或每 16 週進行一次治療，分別有 80% 和 65% 的患者在糖尿病視網膜病變嚴重程度評分上較基線改善了 2 級或更多，而接受安慰劑注射的患者中只有 15% 達到此改善。結果具有高度統計意義，p 值小於 0.0001。

Regarding the 2 key secondary endpoints, which achieved statistical significance based on the prespecified hierarchical analysis compared to sham injection, treatment with EYLEA reduced vision-threatening complications by 82% to 85%, and the development of center-involved diabetic macular edema by 68% to 74%. Diabetic retinopathy is the leading cause of blindness in working age adults in the United States.

關於 2 個關鍵次要終點，根據預先設定的分層分析，與假注射相比，這兩個終點達到了統計意義。 EYLEA 治療使威脅視力的併發症減少了 82% 至 85%，使中央糖尿病性黃斑水腫的發生率減少了 68% 至 74%。在美國，糖尿病視網膜病變是導致工作年齡成年人失明的主要原因。

What is perhaps underappreciated is the rate at which nonsystematic patients can develop serious complications that threaten their vision. Strikingly, within the first year PANORAMA, more than 1/3 of previously asymptomatic diabetic retinopathy patients who were treated with EYLEA went on to develop vision-threatening complications or diabetic macular edema. EYLEA markedly reduced these complications and reversed the anatomic severity of the disease. These results underscore the potential value of earlier intervention in diabetic retinopathy.

人們或許低估了非系統性患者出現嚴重併發症並威脅視力的速度。值得注意的是，在 PANORAMA 研究中，在第一年內，超過 1/3 的先前無症狀的糖尿病視網膜病變患者接受了 EYLEA 治療，結果發展為威脅視力的併發症或糖尿病黃斑水腫。EYLEA 顯著減少了這些併發症，並逆轉了疾病的解剖學嚴重程度。這些結果凸顯了早期介入糖尿病視網膜病變的潛在價值。

In addition to data from our PANORAMA study, the government-funded Diabetic Retinopathy Clinical Research Network is conducting its own Phase III study of EYLEA in diabetic retinopathy. This study, known as protocol W, is ongoing.

除了我們 PANORAMA 研究的數據外，政府資助的糖尿病視網膜病變臨床研究網絡也正在進行 EYLEA 治療糖尿病視網膜病變的 III 期研究。這項研究，即W方案，正在進行中。

Turning to the competitive landscape. In our view, there isn't any product in the near term that can have a substantially different safety and efficacy profile compared to EYLEA. EYLEA is approved in a number of retinal diseases and has demonstrated safety and efficacy with over 20 million doses administered worldwide. It doesn't appear that any potential near-term engines can provide substantially different dosing flexibility, duration or visual gains than are already achievable with EYLEA. Nevertheless, we believe that higher dose formulations of aflibercept might provide additional or longer-lasting benefit and thus, we're advancing this program into clinical development in 2019.

接下來，我們來看看競爭格局。我們認為，在短期內，沒有任何產品能夠在安全性和有效性上與EYLEA有實質的不同。EYLEA 已獲準用於治療多種視網膜疾病，並已證明其安全性和有效性，全球已使用超過 2000 萬劑。近期內似乎沒有任何潛在的引擎能夠提供與 EYLEA 已經實現的劑量靈活性、持續時間或視覺效果有實質的不同。儘管如此，我們相信更高劑量的阿柏西普製劑可能會帶來額外的或更持久的益處，因此，我們將在 2019 年推進該計畫進入臨床開發階段。

I'd now like to turn to DUPIXENT, our antibody that blocks the interleukin-4, interleukin-13 pathway that we are investigating in multiple allergic diseases. Just a couple of weeks ago, DUPIXENT was approved by the FDA for its second major indication, asthma in adults and in adolescents. DUPIXENT is approved for 2 important types of patients with uncontrolled asthma, those with moderate-to-severe disease with eosinophilic phenotype and those who require oral corticosteroids to manage their disease. With DUPIXENT, the newest biologic-approved for the treatment of asthma, we have demonstrated an unprecedented profile. As noted in our label, in our pivotal studies of patients with moderate-to-severe eosinophilic asthma, we reduced severe exacerbations by up to 67% compared to placebo, and increased FEV1, a measure of lung function critical in asthma, by 29% to 33% compared to 14% to 16% from placebo. In addition, DUPIXENT is the only biological approved for oral corticosteroid-dependent asthma regardless of the eosinophilic phenotype and the only asthma biological that offers patients self-administration.

現在我想談談DUPIXENT，這是一種阻斷白細胞介素-4、白細胞介素-13通路的抗體，我們正在研究它對多種過敏性疾病的療效。就在幾週前，DUPIXENT 獲得了 FDA 的批准，用於治療成人和青少年氣喘，這是它的第二個主要適應症。DUPIXENT 獲準用於治療兩類重要的未控制氣喘患者：一類是中度至重度嗜酸性粒細胞表型氣喘患者，另一類是需要口服皮質類固醇來控制病情的患者。DUPIXENT是最新獲準用於治療氣喘的生物製劑，我們已展現出前所未有的療效。正如我們的標籤中所述，在我們對中重度嗜酸性氣喘患者的關鍵研究中，與安慰劑相比，我們使嚴重急性發作減少了高達 67%，並且使 FEV1（氣喘中一項重要的肺功能指標）增加了 29% 至 33%，而安慰劑組的增幅為 14% 至 16%。此外，DUPIXENT 是唯一獲準用於治療口服皮質類固醇依賴性氣喘的生物製劑，無論嗜酸性粒細胞表型如何，也是唯一可供患者自行給藥的氣喘生物製劑。

The U.S. launch in asthma is under way, as you will hear from Marion. A regulatory application for asthma is currently under review by European regulators. We expect a decision in the second quarter of 2019. In terms of ongoing clinical development of DUPIXENT in asthma, we're currently enrolling patients between the ages of 6 and 11 years and are planning a separate Phase III study in patients aged 6 months to 5 years.

正如馬里恩將要告訴你的，美國氣喘藥物的上市工作正在進行中。目前，歐洲監管機構正在審查一項針對氣喘的監管申請。我們預計將於2019年第二季做出決定。就 DUPIXENT 在氣喘治療方面的持續臨床開發而言，我們目前正在招募 6 至 11 歲的患者，並計劃對 6 個月至 5 歲的患者進行單獨的 III 期研究。

In October, we announced that the 2 Phase III studies of DUPIXENT in chronic rhinosinusitis with nasal polyps, DUPIXENT significantly reduced nasal polyps' size, nasal congestion severity and need for systemic corticosteroid and/or surgery. Patients with inadequate control of disease struggle with pain, nasal discharge, the inability to smell and difficulty breathing. The current standard of care, which includes the use of oral and intranasal corticosteroids -- often, along with surgery, is often inadequate. These are the first pivotal trial results in chronic rhinosinusitis with nasal polyps showing the interleukin-4 and interleukin-13 are key drivers of this disease.

10 月，我們宣布了 DUPIXENT 治療慢性鼻竇炎伴隨鼻息肉的 2 項 III 期研究結果，DUPIXENT 顯著縮小了鼻息肉的大小，減輕了鼻塞的嚴重程度，並減少了對全身性皮質類固醇和/或手術的需求。疾病控制不佳的患者會遭受疼痛、鼻涕、嗅覺喪失和呼吸困難的困擾。目前的治療標準包括使用口服和鼻內皮質類固醇——通常還需要手術——但往往效果不佳。這是慢性鼻竇炎伴隨鼻息肉的首個關鍵性試驗結果，顯示白細胞介素-4 和白細胞介素-13 是該疾病的關鍵驅動因素。

Of note, more than 3/4 of patients in these trials also suffer from other type 2 inflammatory conditions, including asthma, allergic rhinitis and NSAID-exacerbated respiratory disease. In a prespecified group of patients with comorbid asthma, DUPIXENT significantly improved lung function asthma control, providing the first evidence that DUPIXENT can treat inflammation from the upper to the lower airway in the same patient. Detailed results for the nasal polyp studies will be presented at a future of medical conference. We intend to make a regulatory submission to the FDA in this indication the first quarter of 2019.

值得注意的是，這些試驗中超過 3/4 的患者還患有其他 2 型發炎性疾病，包括氣喘、過敏性鼻炎和非類固醇抗發炎藥物加重的呼吸系統疾病。在預先指定的一組合併氣喘的患者中，DUPIXENT 顯著改善了肺功能和氣喘控制，首次證明 DUPIXENT 可以治療同一患者從上呼吸道到下呼吸道的發炎。鼻息肉研究的詳細結果將在未來的醫學會議上發表。我們計劃於 2019 年第一季就此適應症向 FDA 提交監管申請。

DUPIXENT has now demonstrated late-stage safety and efficacy in 3 allergic or atopic or type 2 inflammatory diseases, atomic -- atopic dermatitis, asthma and now, chronic rhinosinusitis with nasal polyposis. As we've observed in our studies, patients with one such condition often suffer from allergic diseases as well -- other allergic diseases. We are committed to extending DUPIXENT's approval into younger age groups and geographies, and broadening it to additional type 2 allergic indications.

DUPIXENT 目前已在 3 種過敏性或異位性或 2 型發炎性疾病中證明了後期安全性和有效性，包括異位性皮膚炎、氣喘，以及現在的慢性鼻竇炎伴鼻息肉。正如我們在研究中觀察到的那樣，患有此類疾病的患者通常也會患上其他過敏性疾病。我們致力於將 DUPIXENT 的批准範圍擴大到更年輕的年齡層和地區，並將其擴展到其他 2 型過敏適應症。

In atopic dermatitis, we recently reported positive data from Phase III study of DUPIXENT in adolescents with moderate-to-severe atopic dermatitis. These results were the basis of a regulatory submission in the U.S. for patients between the ages of 12 and 17 years. This morning, we announced that the FDA has accepted for prior review the sBLA for DUPIXENT in adolescent patients 12 to 17 years of age with moderate-to-severe atopic dermatitis whose disease was inadequately controlled with topical therapies or for whom topical treatment was medically inadvisable. Currently, there are no FDA-approved systemic biologic medicines to treat adolescents with moderate-to-severe atopic dermatitis. The target date for the FDA decision is March 11, 2019. We're also currently conducting studies in younger patients between the ages of 6 months and 5 years as well as in patients between the ages of 6 and 11 years.

在異位性皮膚炎方面，我們最近報告了 DUPIXENT 在中重度異位性皮膚炎青少年中的 III 期研究的積極數據。這些結果成為向美國監管機構提交針對 12 至 17 歲患者的申請的基礎。今天上午，我們宣布 FDA 已接受 DUPIXENT 的補充生物製品許可申請 (sBLA) 進行事先審查，該藥物用於治療 12 至 17 歲患有中度至重度異位性皮膚炎的青少年患者，這些患者的病情無法通過局部治療得到充分控制，或者局部治療在醫學上不建議進行。目前，尚無FDA核准的全身性生物製劑用於治療中度至重度異位性皮膚炎青少年患者。FDA 預計於 2019 年 3 月 11 日做出決定。我們目前也正在對 6 個月至 5 歲的年輕患者以及 6 至 11 歲的患者進行研究。

In terms of other diseases, we initiated our Phase II/III study of dupilumab in adults and adolescents with eosinophilic esophagitis. We've also recently started our Phase II study of dupilumab in peanut allergy. This program is being conducted in collaboration with Immune Therapeutics. A Phase II study of dupilumab for grass allergy is currently under way and a Phase II/III study in COPD is being planned.

在其他疾病方面，我們啟動了度普利尤單抗治療成人和青少年嗜酸性食道炎的 II/III 期研究。我們最近也啟動了度普利尤單抗治療花生過敏的 II 期研究。該計畫是與免疫治療公司合作進行的。目前正在進行針對草過敏的dupilumab II期研究，並計劃進行針對慢性阻塞性肺病的II/III期研究。

We view our interleukin-33 program as a complement to DUPIXENT. The Regeneron Genetics Center, in collaboration with Geisinger Health System in the U.K. Biobank, has confirmed and extended observations linking the interleukin-33 pathway to both COPD and asthma. We're studying our interleukin-33 antibody both as monotherapy as well as in combination with DUPIXENT and asthma where we have 3 trials in progress and in COPD, where we have 1. We plan, by year-end, to initiate 2 Phase II studies in atopic dermatitis: 1 will be anti-IL-33 monotherapy; and the other will combine anti-IL-33 with DUPIXENT.

我們認為我們的白細胞介素-33項目是DUPIXENT的補充。Regeneron 遺傳學中心與英國 Geisinger 健康系統生物銀行合作，證實並擴展了將白細胞介素-33 通路與 COPD 和氣喘聯繫起來的觀察結果。我們正在研究白細胞介素-33抗體作為單藥療法以及與DUPIXENT聯合用於治療氣喘（目前有3項試驗正在進行）和慢性阻塞性肺病（目前有1項試驗正在進行）的療效。我們計畫在年底前啟動2項針對異位性皮膚炎的II期研究：1項為抗IL-33單藥療法；另一項為抗IL-33與DUPIXENT聯合療法。

I would now like to switch to the very exciting field of immuno-oncology, which continues to be an area of focus for us and where we have recently made important strides. At the end of September, Libtayo, the brand name of cemiplimab-rwlc, became not only the first PD-1 antibody approved by the FDA for the treatment of advanced cutaneous squamous cell carcinoma or CSCC, but the first treatment of any kind ever approved for this cancer. The response rate for this very high unmet need cancer setting were among the highest ever reported for a PD-1 treatment in a solid tumor. Outside the United States, a regulatory application for Libtayo is being reviewed by the European Medicines Agency, with the decision expected in the first half of 2019. There are currently no EMA-approved treatments for advanced cutaneous squamous cell carcinoma.

現在我想轉到非常令人興奮的免疫腫瘤學領域，這仍然是我們關注的領域，而且我們最近在這個領域取得了重要進展。9 月底，Cemiplimab-rwlc 的商品名 Libtayo 不僅成為 FDA 批准用於治療晚期皮膚鱗狀細胞癌 (CSCC) 的首個 PD-1 抗體，而且成為有史以來第一個獲準用於治療這種癌症的藥物。針對這種極度缺乏治療需求的癌症，PD-1 療法在實體腫瘤治療中的反應率是迄今為止報告的最高反應率之一。在美國以外，Libtayo 的監管申請正在接受歐洲藥品管理局的審查，預計將於 2019 年上半年做出決定。目前尚無獲得歐洲藥品管理局 (EMA) 批准的治療晚期皮膚鱗狀細胞癌的藥物。

As we have stated before, we consider non-small cell lung cancer to be an important potential indication for Libtayo. Our Phase III program in non-small cell lung cancer is enrolling as planned. Based on our review of emerging data in this evolving field, and as we had indicated on our last quarterly call, we have double the size of our trial comparing Libtayo monotherapy to chemotherapy in PD-L1 high patients, from 300 patients to approximately 700 patients. We're also conducting Phase III studies of Libtayo and second-line non-small cell lung cancer and in combination with chemotherapy and with an anti-CTLA-4 antibody in the first line. While these studies are being conducted with a commercially available CTLA-4 antibody, I'm pleased to report that our own CTLA-4 antibody is now in clinical development.

正如我們之前所說，我們認為非小細胞肺癌是利妥昔單抗的一個重要潛在適應症。我們的非小細胞肺癌 III 期臨床試驗計畫正在按計劃進行患者招募。根據我們對這一不斷發展的領域中湧現的數據的審查，正如我們在上一次季度電話會議上所指出的那樣，我們比較 Libtayo 單藥療法與化療在 PD-L1 高表達患者中的療效的試驗規模已經翻了一番，從 300 名患者增加到大約 700 名患者。我們目前也正在進行 Libtayo 的 III 期研究，用於治療二線非小細胞肺癌，以及與化療和第一線抗 CTLA-4 抗體合併治療。雖然這些研究是使用市售的 CTLA-4 抗體進行的，但我很高興地報告，我們自己的 CTLA-4 抗體目前正處於臨床開發階段。

Turning now to our bispecific antibody platform. The leading program here is our fully owned CD20xCD3 antibody. Next month, at the Annual Meeting of the American Society of Hematology, or ASH, we will be presenting additional data in B-cell malignancies.

接下來我們來看看我們的雙特異性抗體平台。我們領先的專案是我們完全自主研發的 CD20xCD3 抗體。下個月，我們將在美國血液學會（ASH）年會上公佈更多 B 細胞惡性腫瘤的數據。

Our second bispecific antibody to enter the clinic targets MUC16 and CD3 for ovarian cancer. By year-end, we expect our BCMAxCD3 bispecific antibody to enter clinical development for the treatment of multiple myeloma. We've also announced that we will be addressing an entirely new class of bispecifics into the clinic starting the first half of 2019.

我們第二個進入臨床的雙特異性抗體標靶 MUC16 和 CD3，用於治療卵巢癌。預計到今年年底，我們的 BCMAxCD3 雙特異性抗體將進入治療多發性骨髓瘤的臨床開發階段。我們也宣布，從 2019 年上半年開始，我們將把一類全新的雙特異性抗體引入臨床。

Continuing on the theme of immuno-oncology. In the third quarter, we entered into a collaboration with bluebird bio to discover, develop and commercialize new CAR-T and other cell therapies for cancer. This collaboration represents a great example of 2 companies with synergistic technologies, working together to try to make a significant advancement in the field.

繼續探討免疫腫瘤學這個主題。第三季度，我們與 bluebird bio 合作，共同發現、開發和商業化用於治療癌症的新型 CAR-T 和其他細胞療法。此次合作是兩家擁有互補技術的公司攜手合作，力求在該領域取得重大進展的絕佳範例。

Moving on. Our late-stage pipeline has made progress, and I would like to focus on a few programs. In the third quarter, we announced positive top line efficacy data for fasinumab, our Nerve Growth Factor, or NGF, antibody in patients with chronic pain from osteoarthritis of the knee or hip. The study met both co-primary endpoints and all key secondary endpoints at week 16, showing that we can achieve efficacy with low doses that mitigate treatment associated with arthropathy at least during the study period. We have 3 Phase III studies with fasinumab ongoing in osteoarthritis, including our long-term safety study.

繼續。我們的後期研發管線已經取得了進展，我想重點介紹幾個專案。第三季度，我們公佈了膝關節或髖關節骨關節炎慢性疼痛患者的神經生長因子（NGF）抗體 fasinumab 的積極療效數據。該研究在第 16 週達到了兩個共同主要終點和所有關鍵次要終點，表明我們可以透過低劑量來實現療效，至少在研究期間可以減輕與關節疾病相關的治療。我們正在進行 3 項針對骨關節炎的 fasinumab III 期研究，其中包括我們的長期安全性研究。

As most of you know, pain represents an area of high unmet need. To that end, we've recently advanced another molecule for pain into clinical development, a fully human antibody to the GFR alpha-3 neurotrophic factor receptor.

正如你們大多數人所知，疼痛代表著一個亟待滿足的巨大需求領域。為此，我們最近將另一種用於治療疼痛的分子推進到臨床開發階段，這是一種針對 GFR α-3 神經營養因子受體的全人源抗體。

Our clinical programs in cardiovascular metabolism are moving ahead. We're enrolling Phase III studies of PRALUENT in adults with homozygous familial hypercholesterolemia in addition to pediatric studies in heterozygous and homozygous familial hypercholesterolemia. We recently received regulatory approval for PRALUENT as a treatment of patients with heterozygous familial hypercholesterolemia, undergoing at risk. And finally, FDA has accepted for review an sBLA for PRALUENT potential treatment of reduced major adverse cardiovascular events with the target action date of April 28, 2019.

我們在心血管代謝領域的臨床計畫正在穩步推進。除了針對雜合子和純合子家族性高膽固醇血症兒童進行的兒科研究外，我們也正在招募患有純合子家族性高膽固醇血症的成年人參與 PRALUENT 的 III 期研究。我們最近獲得了監管部門的批准，PRALUENT 可用於治療患有雜合子家族性高膽固醇血症且有風險的患者。最後，FDA 已接受 PRALUENT 的補充生物製品許可申請 (sBLA)，該藥物預計將用於減少重大不良心血管事件，目標審批日期為 2019 年 4 月 28 日。

Alirocumab, our anti-CTLA-3 antibody is in a Phase III clinical development study in homozygous familial hypercholesterolemia, whereas received orphan and breakthrough designations. We're also enrolling patients in a Phase II study of alirocumab in heterozygous familial hypercholesterolemia and refractory hypercholesterolemia and another Phase II study in severe hypertriglyceridemia. In terms of our other clinical programs in December, at the annual ASH meeting, we will also be presenting additional data from our wholly owned C5 antibody program. We expect to initiate a Phase II study of the subcutaneously administered molecule in patients with paroxysmal nocturnal hemoglobinuria or PNH, in the first half of 2019.

我們的抗 CTLA-3 抗體 Alirocumab 正在進行治療純合子家族性高膽固醇血症的 III 期臨床開發研究，同時獲得了孤兒藥和突破性療法認定。我們也正在招募患者參與一項針對雜合子家族性高膽固醇血症和難治性高膽固醇血症的 alirocumab II 期研究，以及另一項針對嚴重高三酸甘油脂血症的 II 期研究。至於我們的其他臨床項目，在 12 月的 ASH 年度會議上，我們也將展示更多我們全資擁有的 C5 抗體項目的數據。我們預計將於 2019 年上半年啟動針對陣發性睡眠性血紅蛋白尿症 (PNH) 患者的皮下注射分子 II 期研究。

Another exciting molecule in our pipeline is our Activin-A antibody, where we currently have a potentially pivotal Phase II study ongoing in a rare disease called fibrodysplasia ossificans progressiva.

我們研發管線中另一個令人興奮的分子是我們的 Activin-A 抗體，我們目前正在進行一項可能具有關鍵意義的 II 期研究，用於治療一種名為進行性骨化性纖維發育不良的罕見疾病。

Finally, I would just like to highlight, within the next 3 months, our Regeneron Genetics Center expects to hit the 500,000 mark of human sequence, a milestone few, if any centers, have ever achieved.

最後，我想強調的是，在接下來的 3 個月內，我們的 Regeneron 遺傳學中心預計將達到 50 萬人類別序列的里程碑，這是極少數（如果有的話）中心曾經達到的里程碑。

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

接下來，我想把電話交給瑪莉安。

Thank you, George, and good morning, everyone, I'd like to start with EYLEA, where global net sales in the third quarter were $1.68 billion, an increase of 11% year-over-year. U.S. net sales of EYLEA were $1.02 billion, a 7% year-over-year increase. This increase was driven by overall market growth in both wet AMD and DME, position preference and the aging population as well as the increase in the prevalence of diabetes.

謝謝喬治，大家早安，我想先介紹一下安樂，該公司第三季全球淨銷售額為 16.8 億美元，年增 11%。安樂在美國的淨銷售額為 10.2 億美元，較去年同期成長 7%。這一增長是由濕性 AMD 和 DME 的整體市場成長、位置偏好、人口老化以及糖尿病盛行率的增加所推動的。

Based on net sales, EYLEA currently holds about 70% of the overall branded U.S. and anti-VEGF markets. In an effort to educate consumers and raise brand awareness and interest, we recently launched a pilot EYLEA DTC campaign for approved indications in selected markets. Beyond the approved indications of wet AMD, DME, retinal vein occlusion and diabetic retinopathy with DME, we see potential opportunity for EYLEA in diabetic retinopathy. As you just heard from George, we recently reported positive data in this indication and expect a regulatory decision in the U.S. in May of next year. Following this potential approval, we plan to initiate a focused campaign to drive adoption in this large untapped indication. Additionally, in August, we announced that the FDA approved an sBLA for EYLEA for a modified every 12-week dosing schedule for wet AMD after 1 year of effective treatment. This makes EYLEA the only approved anti-VEGF drug for wet AMD with 4-, 8- and 12-week dosing, specifically referenced in its label.

根據淨銷售額計算，安永目前佔據美國品牌藥和抗 VEGF 市場約 70% 的份額。為了教育消費者並提高品牌知名度和興趣，我們最近在選定的市場針對已批准的適應症推出了安永DTC試點推廣活動。除了已批准的濕性 AMD、DME、視網膜靜脈阻塞和伴有 DME 的糖尿病視網膜病變的適應症外，我們看到 EYLEA 在糖尿病視網膜病變方面具有潛在的應用前景。正如喬治剛才所說，我們最近公佈了該適應症的積極數據，並預計美國監管機構將於明年五月做出決定。如果獲得這項潛在批准，我們計劃發起一項重點宣傳活動，以推動該藥物在這一尚未充分開發的領域中得到應用。此外，8 月我們宣布，FDA 批准了 EYLEA 的補充生物製品許可申請 (sBLA)，用於治療濕性 AMD，有效治療 1 年後可採用改良的每 12 週給藥方案。這使得 EYLEA 成為唯一獲準用於治療濕性 AMD 的抗 VEGF 藥物，其標籤中明確提到了 4 週、8 週和 12 週的給藥方案。

I'd like to spend a moment discussing our prefilled syringe for EYLEA. As previously announced, we received a Complete Response Letter from the FDA. We remain confident that we will be able to satisfy the agency's request, which included the completion of usability study evaluating a single injection in approximately 30 patients. We plan to make a regulatory submission in the first half of 2019. Our launch time lines for the prefilled syringe have not changed, and we continue to be on track for an expected 2019 launch.

我想花點時間討論一下我們為愛立信（EYLEA）生產的預充式註射器。正如先前宣布的那樣，我們收到了 FDA 的完整回覆函。我們仍然有信心能夠滿足該機構的要求，其中包括完成一項可用性研究，評估對大約 30 名患者進行單次注射的效果。我們計劃在 2019 年上半年提交監管申請。我們的預填充注射器上市時間表沒有改變，我們仍然按計劃在 2019 年上市。

Turning now to DUPIXENT. Global net sales in the third quarter of 2018, as reported by our collaborator, Sanofi, were $263 million, including $220 million in U.S. Let me start with DUPIXENT in atopic dermatitis. Underlying U.S. demand for DUPIXENT remained strong, with total prescriptions, or TRx, up approximately 17% quarter-over-quarter sequentially. Prescriber depth and breadth continues to improve, with now over 12,300 healthcare providers having prescribed DUPIXENT to over 60,000 patients.

接下來我們來看看DUPIXENT。根據我們的合作夥伴賽諾菲報告，2018 年第三季全球淨銷售額為 2.63 億美元，其中美國銷售額為 2.2 億美元。讓我先從治療異位性皮膚炎的 DUPIXENT 開始說起。美國對 DUPIXENT 的潛在需求依然強勁，處方總量（TRx）較上季成長約 17%。處方醫生的深度和廣度持續提高，目前已有超過 12,300 名醫療保健提供者為超過 60,000 名患者開立了 DUPIXENT 處方。

Despite the strength of this launch, the vast majority of patients with moderate-to-severe atopic dermatitis have not been treated with DUPIXENT. Educating patients about DUPIXENT as a potential new treatment is an important area of focus. To this end, we recently launched a national-branded television campaign and are encouraged by the early results. Outside the U.S., the ongoing launch of DUPIXENT in atopic dermatitis is progressing well. As George announced, the sBLA for DUPIXENT in adolescents with atopic dermatitis has been filed and granted Priority Review by the FDA with an action date in March 2019. If approved, this will allow the benefits of DUPIXENT to be extended to patients as young as 12 years of age. We estimate that the number of adolescent patients is about half that of the adult atopic dermatitis population. In addition, we've also submitted an application for our 200-milligram auto injector for DUPIXENT.

儘管此次上市取得了巨大成功，但絕大多數中重度異位性皮膚炎患者尚未接受 DUPIXENT 治療。對患者進行有關 DUPIXENT 作為一種潛在新療法的教育是一個重要的關注領域。為此，我們最近推出了一項全國性的品牌電視宣傳活動，並對初步結果感到鼓舞。在美國以外，DUPIXENT 在異位性皮膚炎領域的持續上市進展順利。正如喬治所宣布的那樣，DUPIXENT 用於治療青少年異位性皮膚炎的補充生物製品許可申請 (sBLA) 已提交，並已獲得 FDA 的優先審評資格，預計將於 2019 年 3 月做出決定。如果獲得批准，這將使 DUPIXENT 的益處惠及年僅 12 歲的患者。我們估計青少年患者人數約為成人異位性皮膚炎患者的一半。此外，我們也提交了DUPIXENT 200毫克自動注射器的申請。

Turning now to asthma, which is the most recently approved indication for DUPIXENT. As you heard from George, we believe DUPIXENT is a highly differentiated biologic for the treatment of asthma. The launch is under way and feedback from positions has been positive. We've only been in the market for a couple of weeks now, so it is too early to provide any detailed launch metrics. We estimate there are approximately 775,000 to 900,000 adult and adolescent patients in the U.S. with moderate-to-severe asthma that have uncontrolled persistent symptoms that despite standard-of-care therapy may be suitable for treatment with a biologic therapy. Currently, only about 11% of these patients are treated with a biologic. One of the key considerations for physicians treating asthma patients is to limit or avoid the use of oral steroids to control the disease. We estimate that the oral corticosteroid-dependent population represents approximately 25% to 30% of the approximate 775,000 to 900,000 patients with uncontrolled persistent asthma eligible for a biologic. DUPIXENT is a nonsteroid treatment option for these patients. With that in mind, we're optimistic about the asthma launch, with the goal of making DUPIXENT a preferred first-line biologic for indicated patients with moderate-to-severe asthma. Early efforts to engage both allergists and pulmonologists are well under way, and the reception has been positive. Many allergists are already familiar with DUPIXENT in atopic dermatitis, and these doctors are also treating patients with asthma. We're actively working at educating and creating awareness of DUPIXENT's differentiate profile with pulmonologists. We look forward to providing further updates on the launch in the months ahead.

現在我們來談談氣喘，這是DUPIXENT最近核准的適應症。正如喬治所說，我們認為DUPIXENT是一種高度差異化的生物製劑，可用於治療氣喘。該計畫正在啟動中，各崗位回饋積極。我們進入市場才幾個星期，所以現在提供任何詳細的上市指標還為時過早。我們估計，美國約有 775,000 至 900,000 名成人和青少年患者患有中度至重度氣喘，其症狀持續未得到控制，儘管接受了標準治療，但可能適合接受生物療法治療。目前，只有約 11% 的這類患者接受了生物製劑治療。醫生在治療氣喘患者時，需要考慮的關鍵因素之一是限製或避免使用口服類固醇來控制病情。我們估計，在約 775,000 至 900,000 名患有未控制的持續性氣喘且符合生物製劑治療條件的患者中，依賴口服皮質類固醇的人約佔 25% 至 30%。DUPIXENT 是針對這些患者的一種非類固醇治療選擇。考慮到這一點，我們對氣喘藥物的上市持樂觀態度，目標是使 DUPIXENT 成為中重度氣喘患者的首選第一線生物製劑。目前已進行與過敏科醫師和肺科醫師合作的早期工作，反應積極。許多過敏症專家已經熟悉 DUPIXENT 在異位性皮膚炎中的應用，這些醫生也用它來治療氣喘患者。我們正在積極努力，向肺科醫生普及DUPIXENT的差異化特性，提高他們的認識。我們期待在未來幾個月內為大家帶來更多關於產品發布的最新消息。

I'd now like to turn to Libtayo, our PD-1 antibody. On September 28, the FDA approved Libtayo for the treatment of patients with metastatic cutaneous squamous cell carcinoma or locally advanced CSCC who are not candidates for curative surgery or curative radiation. We continue to expect a decision by the European Medicines Agency in the first half of 2019. The launch of Libtayo is a major milestone and the first step in our goal of establishing Regeneron as a major player in the immuno-oncology space. Upon FDA approval, the oncology sales force quickly mobilized to make Libtayo the standard of care for CSCC by engaging medical oncologists and most surgeons, targeting centers specializing in skin cancers.

現在我想談談我們的 PD-1 抗體 Libtayo。9 月 28 日，FDA 核准 Libtayo 用於治療不適合接受根治性手術或根治性放射治療的轉移性皮膚鱗狀細胞癌或局部晚期皮膚鱗狀細胞癌患者。我們仍然期待歐洲藥品管理局在 2019 年上半年做出決定。Libtayo 的推出是一個重要的里程碑，也是我們實現將 Regeneron 打造成免疫腫瘤學領域主要參與者這一目標的第一步。在獲得 FDA 批准後，腫瘤銷售團隊迅速行動起來，透過與腫瘤內科醫生和大多數外科醫生合作，將 Libtayo 打造成 CSCC 的標準療法，重點關注專門治療皮膚癌的中心。

So far, feedback from medical community has been positive. On October 24, Libtayo was included in the updated National Comprehensive Cancer Network, NCCN Guidelines for CSCC. Libtayo received a 2A evidence rating, the only systemic therapy with an NCCN rating in CSCC. From a payer's standpoint, we've been successful in establishing broad access in reimbursement coverage, so patients in need can get access to the treatment quickly. Recall that CSCC is the most common form of skin cancer and is responsible for an estimated 4,000 to 8,000 deaths each year in the U.S. It currently accounts for approximately 20% of all skin cancers in the U.S., with a number of newly diagnosed cases expected to rise annually. We look forward to providing further update on the launch at a later time.

目前為止，醫學界的回饋是正面的。10 月 24 日，Libtayo 被納入更新後的美國國家綜合癌症網絡 (NCCN) 皮膚鱗狀細胞癌 (CSCC) 指南。Libtayo 獲得了 2A 級證據評級，是唯一獲得 NCCN 評級的 CSCC 系統療法。從支付方的角度來看，我們已成功建立了廣泛的報銷覆蓋範圍，因此有需要的患者可以迅速獲得治療。請記住，皮膚鱗狀細胞癌 (CSCC) 是最常見的皮膚癌，據估計每年在美國造成 4,000 至 8,000 人死亡。目前，CSCC 約占美國所有皮膚癌的 20%，預計每年新確診病例的數量都會增加。我們期待在稍後提供更多關於此次發表會的最新消息。

Switching to PRALUENT. Global net sales in the third quarter recorded by Sanofi were $80 million, representing a 62% increase compared with the third quarter of 2017. We've submitted data from the cardiovascular outcome study to regulatory agencies in U.S. and the EU and anticipate decisions in the second half of 2019. We are also expecting that the lipid-lowering treatment guidelines in the U.S. will be updated shortly. These updated guidelines may facilitate greater access and support, increased use of the PCSK9 inhibitor class. We're continuing payer engagement and remain the exclusive PCSK9 inhibitor on the Express Scripts national commercial formulary. Based on net sales, our market share in the U.S. has grown significantly since the addition to the ESI formulary, up to 40% in the third quarter, with the number of prescriptions continuing to increase steadily.

改用 PRALUENT。賽諾菲第三季全球淨銷售額為 8,000 萬美元，比 2017 年第三季成長 62%。我們已將心血管結果研究的數據提交給美國和歐盟的監管機構，預計在 2019 年下半年收到決定。我們也預計美國的降血脂治療指南也將很快更新。這些更新後的指南可能會促進更多人獲得和支持，從而增加 PCSK9 抑制劑類藥物的使用。我們將繼續與支付者保持溝通，並且仍然是 Express Scripts 全國商業處方集中唯一的 PCSK9 抑制劑。自從我們的產品被納入 ESI 處方集以來，以淨銷售額計算，我們在美國市場的份額顯著增長，第三季度達到 40%，處方數量也持續穩步增長。

Moving to KEVZARA. Global net sales as recorded by Sanofi were $25 million in the third quarter as demand improved. Within the IL-6 subcutaneous class, KEVZARA now has 42% of dispensed NBRx share and 20% share of TRx.

搬到 KEVZARA。賽諾菲第三季全球淨銷售額為2,500萬美元，需求改善。在 IL-6 皮下注射劑類別中，KEVZARA 目前佔 NBRx 分配份額的 42% 和 TRx 分配份額的 20%。

I'll now turn the call over to Bob.

現在我將把電話交給鮑伯。

Thanks, Marion, and good morning, everyone. I'm pleased to report both solid top line results and strong operational performance for the third quarter of 2018. We are encouraged by EYLEA and DUPIXENT sales growth, progress across our portfolio and improvement in our operating leverage as reflected in the reduction of our full year 2018 expense and tax guidance line items.

謝謝你，瑪麗昂，大家早安。我很高興地向大家報告，2018 年第三季公司營收和營運業績都表現穩健。EYLEA 和 DUPIXENT 的銷售成長、我們產品組合的進展以及營運槓桿的改善（體現在我們 2018 年全年費用和稅收指導項目的減少）都令我們感到鼓舞。

For the third quarter of 2018, we earned $5.87 per diluted share on non-GAAP net income of $675 million. These results represent a 47% and 44% year-over-year increase in our non-GAAP diluted EPS and net income, respectively. Total revenue grew 11% year-over-year to $1.66 billion, driven by performance of U.S. EYLEA, revenue increases for both the Sanofi and Bayer collaborations in growth within other revenue. EYLEA net product sales in the United States grew 7% to $1.02 billion compared to $953 million in the third quarter of 2017. U.S. EYLEA distributor inventory decreased in the quarter as compared to the second quarter of 2018, yet remained within our normal 1- to 2-week targeted range.

2018 年第三季度，我們每股攤薄收益為 5.87 美元，非 GAAP 淨收入為 6.75 億美元。這些結果分別代表我們的非GAAP稀釋後每股盈餘和淨收入年增47%和44%。總營收年增 11% 至 16.6 億美元，主要得益於美國安永的業績表現，以及賽諾菲和拜耳合作項目的收入成長和其他收入的成長。EYLEA 在美國的淨產品銷售額成長了 7%，達到 10.2 億美元，而 2017 年第三季為 9.53 億美元。與 2018 年第二季相比，美國 EYLEA 經銷商的庫存在本季度有所下降，但仍保持在我們正常的 1 至 2 週的目標範圍內。

As disclosed in our last earnings call, commencing in the second week of June, we increased the existing EYLEA discount that we offered to physician practices regardless of volume. As a result, there was a slight degradation in EYLEA's gross-to-net percentage in the third quarter of 2018 compared to both the third quarter of 2017 and first half of 2018.

正如我們在上次財報電話會議上所披露的那樣，從 6 月第二週開始，我們提高了向醫生診所提供的 EYLEA 折扣，無論其業務量如何。因此，與 2017 年第三季和 2018 年上半年相比，安樂 2018 年第三季的毛利率略有下降。

Effective October 1, 2018, we started shipping and recording U.S. net sales of Libtayo. As a reminder, for Libtayo, in the U.S., we are the commercial lead and will record product sales. Sanofi has exercised its option to co-promote Libtayo in the U.S.

自 2018 年 10 月 1 日起，我們開始出貨並記錄 Libtayo 在美國的淨銷售額。再次提醒，對於 Libtayo 在美國，我們是商業主導方，並將記錄產品銷售額。賽諾菲已行使在美國共同推廣Libtayo的選擇權。

Ex U.S., EYLEA net product sales, recorded by our collaborator Bayer, were $655 million for the 3 months ended September 30, 2018, representing a 20% operational and 16% reported increase on a year-over-year basis. Total Bayer collaboration revenue for the 3 months ended September 30, 2018, grew 12% year-over-year to $264 million, of which $243 million was derived from the share of net profits from EYLEA sales outside the U.S. The $243 million, which represents year-over-year growth of 18%, compares favorably to the $205 million realized for the 3 months ended September 30, 2017.

根據我們的合作夥伴拜耳公司記錄，除美國以外，安理國際製藥 (EYLEA) 2018 年 9 月 30 日止三個月的淨產品銷售額為 6.55 億美元，年增 20%（按營運計算）和 16%（按報告計算）。截至 2018 年 9 月 30 日的三個月，拜耳合作總營收年增 12% 至 2.64 億美元，其中 2.43 億美元來自安樂死（EYLEA）在美國以外地區的銷售淨利份額。這 2.43 億美元年增 18%，與截至 2017 年 9 月 30 日的三個月的 2.05 億美元相比，表現更為出色。

Total Sanofi collaboration revenue was $256 million for the third quarter of 2018 compared to $245 million for the third quarter of 2017. The year-over-year revenue increase was driven by 3 factors: first, we realized a $59 million decrease in our share of losses in connection with the commercialization of DUPIXENT, PRALUENT and KEVZARA; second, higher Sanofi R&D reimbursement revenue associated with our increased investment in immuno-oncology; and third, higher Sanofi commercialization reimbursement revenue associated with increased investment in commercialized products. Offsetting these 3 factors is the 2017 expiration of the Sanofi antibody discovery and preclinical development agreement, under which we recorded $38 million of revenue in the third quarter of 2017 compared to no revenue this quarter.

2018 年第三季度，賽諾菲合作總營收為 2.56 億美元，而 2017 年第三季為 2.45 億美元。年比收入成長主要受以下三個因素驅動：首先，我們在 DUPIXENT、PRALUENT 和 KEVZARA 的商業化過程中，虧損份額減少了 5900 萬美元；其次，由於我們在免疫腫瘤學領域的投資增加，賽諾菲研發報銷收入增加；第三，由於對已商業化產品的投資增加，賽諾菲研發收入增加，賽諾費收入增加。抵銷這三個因素的是，賽諾菲抗體發現和臨床前開發協議於 2017 年到期，根據該協議，我們在 2017 年第三季錄得 3,800 萬美元的收入，而本季度則沒有收入。

In the third quarter of 2018, we recognized the loss of $39 million in connection with the commercialization of products from the antibody license and collaboration agreement with Sanofi, which compares favorably to a loss of $98 million in the third quarter of 2017 and a loss of $69 million in the second quarter of 2018. The lower share of loss versus the third quarter of 2017 was primarily attributed to higher global net sales of DUPIXENT and PRALUENT and continued cost containment for PRALUENT, partly offset by an increase in DUPIXENT commercialization expenses. Despite incurring necessary launch expenses for new indications in new markets, from a financial standpoint the alliance had its best performing quarter. While we experienced improved operating leverage in the third quarter of 2018, we expect the alliances' financial results to remain variable for the next few quarters as we continue to incur launch expenses for new indications in new markets. Compared to the third quarter of 2018, we are expecting a higher alliance loss in the fourth quarter of 2018 in connection with the commercialization of these antibodies.

2018 年第三季度，我們確認了與賽諾菲抗體許可和合作協議產品商業化相關的 3,900 萬美元虧損，與 2017 年第三季的 9,800 萬美元虧損和 2018 年第二季的 6,900 萬美元虧損相比，情況有所改善。與 2017 年第三季相比，虧損份額下降主要歸因於 DUPIXENT 和 PRALUENT 的全球淨銷售額增加以及 PRALUENT 成本的持續控制，但部分被 DUPIXENT 商業化費用的增加所抵消。儘管在新市場推出新適應症需要支付必要的上市費用，但從財務角度來看，該聯盟迎來了業績最好的季度。儘管我們在 2018 年第三季實現了營運槓桿的改善，但我們預計，由於我們將繼續為新市場的新適應症投入上市費用，聯盟的財務表現在未來幾季仍將不穩定。與 2018 年第三季相比，我們預計 2018 年第四季由於這些抗體的商業化，聯盟損失將會更大。

Before turning to expenses, I'm going to briefly comment on our third quarter 2018 other revenue. In the third quarter of 2018, other revenue was $117 million versus $62 million in the third quarter of 2017. This increase was primarily driven by the recognition of a higher amount of deferred revenue from Teva and Mitsubishi Tanabe, including amounts related to the recognition of a portion of the $60 million and $20 million development milestones achieved from Teva and Mitsubishi Tanabe, respectively, in the third quarter of 2018.

在討論支出之前，我將簡要評論我們 2018 年第三季的其他收入。2018 年第三季其他營收為 1.17 億美元，而 2017 年第三季為 6,200 萬美元。這一增長主要是由於確認了來自 Teva 和三菱田邊製藥的遞延收入的增加，其中包括與確認 2018 年第三季度分別從 Teva 和三菱田邊製藥獲得的 6000 萬美元和 2000 萬美元開發里程碑款項的一部分相關的金額。

Other revenues also increased from the recognition of revenue related to our agreement with Biomedical Advanced Research Development Authority, or BARDA, to develop, test and manufacture an antibody therapy for the treatment of Ebola virus infection. As a reminder, you can find a summary of the components of other revenue in the MD&A section of the 10-Q.

其他收入也因確認與我們和生物醫學高級研究發展局（BARDA）達成的協議相關的收入而增加，該協議旨在開發、測試和生產用於治療伊波拉病毒感染的抗體療法。提醒一下，您可以在 10-Q 的 MD&A 部分找到其他收入組成部分的摘要。

Non-GAAP R&D expenses were $497 million for the third quarter of 2018 as compared to $460 million for the third quarter of 2017. The increase in non-GAAP R&D expense was the result of an increase in Libtayo clinical cost and higher R&D headcount and facility-related cost, partly offset by a decrease in DUPIXENT development cost. 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 $311 million for the 3 months ended September 30, 2018, compared to $227 million for the 3 months ended September 30, 2017. As highlighted earlier, $38 million of this increase is attributable to the expiration of the Sanofi antibody discovery and preclinical agreement at the end of 2017. The remaining increases were driven by our share of higher immuno-oncology clinical costs and R&D activities associated with the growing number of wholly owned programs. Our press release includes the information required to calculate unreimbursed non-GAAP R&D expense.

2018 年第三季非 GAAP 研發費用為 4.97 億美元，而 2017 年第三季為 4.6 億美元。非GAAP研發費用的增加是由於Libtayo臨床成本的增加以及研發人員數量和設施相關成本的增加，部分被DUPIXENT開發成本的減少所抵消。截至 2018 年 9 月 30 日止的三個月，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 3.11 億美元，截至 2017 年 9 月 30 日止的三個月為 2.27 億美元。如前所述，這筆成長中的 3,800 萬美元是由於賽諾菲抗體發現和臨床前協議於 2017 年底到期所致。其餘成長主要由我們承擔的免疫腫瘤臨床成本增加以及與全資擁有的項目數量不斷增長相關的研發活動所致。我們的新聞稿包含了計算未報銷的非GAAP研發費用所需的資訊。

We are lowering and tightening our full year 2018 guidance for non-GAAP unreimbursed R&D expense to be in the range of $1.19 billion to $1.225 billion from our previous guidance of $1.21 billion to $1.26 billion. Non-GAAP SG&A expense was $326 million for the third quarter of 2018 as compared to $259 million for the 3 months ended September 30, 2017. The higher SG&A expenses in the third quarter of 2018 were primarily due to an increase in contributions to independent not-for-profit patient assistance organizations and higher launch expenses for Libtayo and DUPIXENT in adult and adolescent asthma.

我們將 2018 年全年非 GAAP 未報銷研發費用的預期從先前的 12.1 億美元至 12.6 億美元下調至 11.9 億美元至 12.25 億美元。2018 年第三季非 GAAP 銷售、一般及行政費用為 3.26 億美元，截至 2017 年 9 月 30 日的三個月為 2.59 億美元。2018 年第三季較高的銷售、一般及行政費用主要是由於對獨立非營利性病患援助組織的捐款增加，以及 Libtayo 和 DUPIXENT 在成人和青少年氣喘領域的上市費用增加。

We are lowering and tightening our full year 2018 non-GAAP SG&A expense to be $1.33 billion to $1.37 billion from $1.34 billion to $1.39 billion. Based on this revised guidance, we expect a higher SG&A spend level in the fourth quarter of 2018. This higher spend is driven by EYLEA expenses, including DTC and DUPIXENT expenses, including DTC and patient support programs.

我們將 2018 年全年非 GAAP 銷售、一般及行政費用從 13.4 億美元至 13.9 億美元下調至 13.3 億美元至 13.7 億美元。根據此修訂後的指導意見，我們預計 2018 年第四季銷售、一般及行政費用支出水準將會提高。支出增加主要由安永（EYLEA）的支出（包括直接面向消費者的支出）和度普利康（DUPIXENT）的支出（包括直接面向消費者的支出和病患支援計畫）所驅動。

Sanofi reimbursement of Regeneron commercialization-related expenses, a line item found within Sanofi collaboration revenue, was $107 million for the third quarter of 2018. We are lowering and tightening our full year 2018 guidance for reimbursement of Regeneron commercialization-related expenses to $430 million to 5 -- $455 million from $455 million to $485 million. For the 3 months ended September 30, 2018, as compared to the same period in 2017, non-GAAP cost of goods sold declined principally due to better cost absorption at our Limerick, Ireland commercial manufacturing facility. Cost of collaboration and contract manufacturing increased due to higher sales volumes of both EYLEA outside the U.S. and Sanofi collaboration antibodies as well as the recognition of manufacturing costs associated with our agreement with BARDA. These increases were partially offset by lower validation cost at our Limerick facility.

2018 年第三季度，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 1.07 億美元。我們將 2018 年全年與 Regeneron 商業化相關的費用報銷預期從 4.55 億美元至 4.85 億美元下調至 4.3 億美元至 4.55 億美元。截至 2018 年 9 月 30 日的三個月內，與 2017 年同期相比，非 GAAP 銷售成本下降，主要原因是我們在愛爾蘭利默里克的商業製造工廠的成本吸收能力有所提高。由於 EYLEA 在美國以外的銷售量增加以及賽諾菲合作抗體的銷量增加，以及與 BARDA 達成的協議相關的製造成本的確認，合作和合約製造的成本也隨之增加。這些增長被我們利默里克工廠較低的驗證成本部分抵消。

Turning now to taxes. Our effective tax rate in the third quarter 2018 was 6.5% compared to 31.3% for the third quarter 2017, driven primarily by the enactment of the Tax Cuts and Jobs Act as well as onetime tax benefits associated with tax planning in connection with this act. Our tax rate continues to benefit from the Federal tax credit for research activities, stock-based compensation and income earned in foreign jurisdictions with tax rates lower than the U.S. The third quarter of 2018 also included a GAAP income tax benefit of $11.9 million that was an adjustment to the provisional amount recorded as of December 31, 2017 for the U.S. Tax Reform Act, which was related to the remeasurement of the company's U.S. net deferred tax assets.

接下來談談稅務問題。2018 年第三季度，我們的實際稅率為 6.5%，而 2017 年第三季度為 31.3%，這主要是由於《減稅與就業法案》的頒布以及與該法案相關的稅務規劃所帶來的一次性稅收優惠。我們的稅率繼續受益於聯邦政府對研發活動、股票選擇權激勵以及在稅率低於美國的外國司法管轄區所賺取的收入的稅收抵免。 2018 年第三季還包括 1,190 萬美元的 GAAP 所得稅收益，這是對截至 2017 年 12 月 31 日記錄的暫定金額的調整，該調整與美國稅收改革法案有關，涉及公司美國淨遞延所得稅資產的重新計量。

As we await additional regulatory guidance and continue to assess the full impact of the new tax law, including some onetime items, we now expect our full year 2018 effective tax rate to be in the range of 11% to 13% from our previous guidance of 13% to 16%. While our effective tax rate guidance has been lowered for 2018, we expect that over the next few years, our effective tax rate will be in the mid- to high-teens.

在我們等待更多監管指導並繼續評估新稅法的全面影響（包括一些一次性項目）之際，我們現在預計 2018 年全年實際稅率將在 11% 至 13% 之間，而我們之前的指導為 13% 至 16%。雖然我們下調了 2018 年的實際稅率預期，但我們預計在未來幾年內，我們的實際稅率將在十幾到二十幾個百分點之間。

Turning next to cash flow and the balance sheet. Regeneron ended the third quarter of 2018 with cash and marketable securities of $4.1 billion and generated an excess of $1.1 billion of free cash flow from the 9 months ended September 30, 2018. We calculate free cash flow as net cash provided by operating activities less capital expenditures. Our capital expenditures for the 3 months ended September 30, 2018 were $106 million. In total, $298 million for the 9 months ended September 30, 2018. We are lowering and tightening our full year 2018 capital expenditure guidance to $360 million to $390 million from our prior range of $410 million to $450 million.

接下來來看現金流量表和資產負債表。截至 2018 年第三季末，Regeneron 持有現金及有價證券 41 億美元，並在截至 2018 年 9 月 30 日的 9 個月內產生了超過 11 億美元的自由現金流。我們將自由現金流計算為經營活動產生的現金流量淨額減去資本支出。截至 2018 年 9 月 30 日的三個月內，我們的資本支出為 1.06 億美元。截至 2018 年 9 月 30 日的 9 個月內，總計 2.98 億美元。我們將 2018 年全年資本支出預期從先前的 4.1 億美元至 4.5 億美元下調至 3.6 億美元至 3.9 億美元。

On the BD front, as George mentioned, we entered into a collaboration with bluebird bio. In connection with the execution of the collaboration agreement, we also agreed to purchase 420,000 shares of bluebird common stock for $100 million. As part of the agreement, $37 million, the amount paid in excess of the fair market value of the shares purchased, will be credited against our funding obligation for collaboration research.

在 BD 方面，正如 George 所提到的，我們與 bluebird bio 展開了合作。為配合合作協議的執行，我們也同意以 1 億美元的價格購買 42 萬股 bluebird 普通股。作為協議的一部分，超過所購買股份公允市場價值的 3,700 萬美元將用於抵扣我們合作研究的資金義務。

Before I hand the call back to Manisha to commence Q&A, I also wanted to highlight in an exciting announcement Regeneron made in September regarding a new agreement with the State of New York to support economic development in the capital region. Over the next 7 years, Regeneron has committed to investing $800 million to expand facilities and create 1,500 new full-time jobs in New York State. This expansion will be supported by $140 million in economic development incentives from New York State.

在將電話交還給瑪妮莎開始問答環節之前，我還想重點介紹一下 Regeneron 公司在 9 月發布的一項激動人心的公告，即與紐約州達成一項新協議，以支持首都地區的經濟發展。未來 7 年，Regeneron 承諾投資 8 億美元，用於擴大設施，並在紐約州創造 1500 個新的全職工作。此次擴建將獲得紐約州提供的 1.4 億美元經濟發展獎勵資金支持。

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

那麼，我想把電話轉回給瑪妮莎。

Thank you, Bob. John, that concludes the prepared remarks. We'd now like to open the call for Q&A.

謝謝你，鮑伯。約翰，準備好的演講稿到此結束。現在我們開始問答環節。

(Operator Instructions) And our first question is from Geoff Meacham from Barclays.

（操作員說明）我們的第一個問題來自巴克萊銀行的傑夫·米查姆。

This is Greg Harrison on for Geoff. Can you talk us through the trends you're seeing recently with payer access for DUPIXENT? Have asthma patients been able to get access? And how is this prepared -- how is this compared with the launch in atopic dermatitis?

這裡是格雷格·哈里森，他代替傑夫發言。您能否為我們介紹一下您最近觀察到的DUPIXENT支付方准入趨勢？氣喘患者是否能夠獲得治療？那麼，這種療法是如何準備的呢？與異位性皮膚炎的上市療法相比，它有何不同？

So -- certainly it's early days, Greg, in the launch for asthma. But I can certainly report that with DUPIXENT, for the new asthma indication, we are making steady progress and very pleased with initial dialogue with payers. But I'll just remind everyone that this is only our third week in market with the asthma launch. Then as a comment, you alluded to atopic dermatitis and payer coverage. Certainly, we see the majority of the market with adequate coverage. And of course, that reflects in the uptake we're seeing with DUPIXENT performance.

所以——格雷格，氣喘的推廣當然還處於早期階段。但我可以肯定地報告，對於用於治療氣喘的新適應症 DUPIXENT，我們正在穩步推進，並且對與支付方的初步對話非常滿意。但我還是要提醒大家，我們的氣喘產品上市才三週。然後，你在評論中提到了異位性皮膚炎和醫療覆蓋範圍。當然，我們看到市場上的大部分產品都得到了充分的覆蓋。當然，這也體現在我們看到的 DUPIXENT 效能的提升。

Our next question is from Carter Gould from UBS.

我們的下一個問題來自瑞銀集團的卡特古爾德。

I guess, when -- given all the commentary coming out of the White House around Part B proposals and HHS, just wanted to get to your latest thoughts on sort of that messaging. And anything that you guys can do to either mitigate that front on either on the -- yes, leave it there.

我想，鑑於白宮就 B 部分提案和衛生與公眾服務部發表的所有評論，我只是想了解一下您對此類資訊傳遞的最新看法。你們如果能做任何事來緩解這方面的局面——是的，就到此為止吧。

Yes. Thanks for the question, Carter. Obviously, it's tough to know what's going to actually become policy given a lot of these announcements were pre-election. I do think the administration is serious about trying to do something with drug pricing. But whether or not they'll be able to get in, in a demonstration project, which covers a large fraction of the country starting in the year 2020, with international reference pricing, I think that's a wide big open, big question mark at this time.

是的。謝謝你的提問，卡特。顯然，考慮到許多此類聲明都是在選舉前發布的，很難知道哪些最終會成為政策。我認為政府確實認真考慮在藥品定價方面採取一些措施。但是，他們能否參與到一項從 2020 年開始、覆蓋該國大部分地區的示範項目中，並採用國際參考定價，我認為這目前還是一個巨大的未知數。

Our next question is from Cory Kasimov from JP Morgan.

下一個問題來自摩根大通的科里·卡西莫夫。

I'm curious how you're looking at the market opportunity for DUPIXENT and moderate eosinophilic asthma population. When considering the low biologic penetration you referred to for severe asthmatics to date. So I guess, given those historic dynamics, do you think you'll be able to penetrate much of the moderate patients in the first year or so the product's launch or should we really be focused on severe?

我很想知道您如何看待DUPIXENT在中度嗜酸性氣喘患者群體中的市場機會。考慮到您提到的迄今為止重度氣喘患者生物滲透率較低的問題。所以，考慮到這些歷史因素，您認為在產品上市的第一年左右，您能否打入大部分中度患者群體，還是我們應該真正專注於重度患者？

I'm going to let Marion answer that question after I just make one brief comment. The market has yet to see a self-administered product. And it is -- penetration is expected to be exceedingly low for the moderate population when you have to get to the doctor's office either an infusion or hang around there for half a day, et cetera, et cetera. Marion?

我先簡單說一句，之後就讓瑪莉安來回答這個問題。市面上還沒有出現過可供患者自行使用的產品。確實如此——對於中等收入人群來說，如果需要去醫生辦公室輸液或在那裡待上半天等等，那麼藥物滲透率預計會非常低。瑪莉安？

Yes. So I'd add to that, that it's not unusual that physicians, and in this case, it's pulmonologists and allergists, will often use a product, DUPIXENT in this case, for asthma, on some of their tougher patients first. I'll share this, anecdotally, the reports we're getting have been very, very positive. So over time, most definitely, I think we'll have to assess not only with severe but also the moderate patients. And I think that continuum will evolve over market experience. But there are really compelling reasons why, and that relates to the clinical profile of DUPIXENT in asthma, its overall efficacy not only in exacerbations, lung function, OCS reduction and quality of life, but then also the broad category of patients that we achieved in our label. Moderate-to-severe patients, of course, EOs greater than 150, OCS-dependent, regardless of phenotype or EOs. As Len mentioned, another element that we're hearing that is just so important is that we are the only asthma biologic to offer both at-home, self-administration. And when physicians want to, they can always start a patient in the office to help educate and train them. But this is a really important factor in the ability to have broader use. And then, the other item I'd add is that, of course, with DUPIXENT, we're not launching a new product, we're launching a new indication. So allergists who already had experience with DUPIXENT. And we already have shown an established safety profile. So we're really excited about the launch. It's very, very early days. I look forward to giving you reports in the future.

是的。因此，我想補充一點，醫生（在本例中是肺科醫生和過敏科醫生）經常會先對一些病情較重的哮喘患者使用某種產品（在本例中是 DUPIXENT），這並不罕見。我從一些非正式管道了解到的情況來看，我們收到的報告都非常非常正面。所以隨著時間的推移，我認為我們肯定不僅要對重症患者進行評估，還要對中度患者進行評估。我認為這種連續性會隨著市場經驗的累積而演變。但其中確實有令人信服的理由，這與 DUPIXENT 在氣喘治療中的臨床表現有關，它不僅在緩解病情加重、改善肺功能、減少口服糖皮質激素用量和提高生活品質方面具有整體療效，而且還適用於我們在藥品標籤中涵蓋的廣泛患者群體。當然，中度至重度患者，EO 大於 150，依賴 OCS，無論表型或 EO 如何。正如 Len 所提到的，我們聽到的另一個非常重要的因素是，我們是唯一一家提供居家自我給藥的氣喘生物製劑公司。如果醫生願意，他們隨時可以在診間接診病人，以幫助教育和訓練他們。但這對於能否更廣泛地應用來說，確實是一個非常重要的因素。此外，我還要補充一點，當然，對於 DUPIXENT，我們推出的不是一款新產品，而是一種新的適應症。因此，需要有使用DUPIXENT經驗的過敏科醫師。我們已經展現了良好的安全記錄。所以我們對這次發布感到非常興奮。現在還為時過早。我期待未來能向您報告工作。

And -- this is George, I just want to emphasize about the clinical profile that Marion brought up, which is that particularly for moderate patients, they still can have pretty substantial reduction in their lung functions. I mean, when you are talking about biologicals, that may be the first biological really can have clinically meaningful impact on lung function, that can really make a difference in patients' lives. And that is something that has a really potential to essentially have a real impact on patients' lives. And together with its safety profile, I think there's a lot of rationale for penetrating into the moderate population.

還有──我是喬治，我只想強調瑪莉安提到的臨床情況，那就是，特別是對於中度患者而言，他們的肺功能仍然可能會大幅下降。我的意思是，說到生物製劑，這可能是第一個真正能對肺功能產生臨床意義影響的生物製劑，它真的能改變病人的生活。而這確實有可能對患者的生活產生真正的影響。考慮到它的安全性，我認為它有很多理由打入中等收入人群市場。

Our next question is from Chris Raymond from Piper Jaffray.

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

Just a question on the DUPIXENT peanut allergy study or work that you're doing with Aimmune. Can you maybe talk about a little bit in detail about the objectives of this work, maybe the strategy even? I think you've talked about being able to potentially improve on Aimmune's experience in desensitizing kids during the up-dosing period. But maybe just frame for us what is -- there's obviously a lot of opportunity in food allergy not just peanut allergy. What does success look like from this initial trial? And where do you think that could take you in terms of sort of penetrating that other market -- that bigger market?

我有一個關於DUPIXENT花生過敏研究或您與Aimmune公司合作進行的工作的問題。您能否詳細談談這項工作的目標，甚至是策略？我認為您曾談到過，在劑量遞增期間，有可能改善 Aimmune 在兒童脫敏方面的經驗。但或許應該先給我們闡明現狀——顯然，食物過敏領域有很多機會，不只是花生過敏。從初步試驗來看，成功是什麼樣的？你認為這能幫助你打入另一個市場——更大的市場嗎？

Just to get into the signs for a second. I think that everybody has to understand that the reason you have allergies is you have a certain kind of immunoglobulin known as immunoglobulin E that is bound to the surface of mast cells and basophils. And once it interacts with allergen, it clusters on the surface of these cells, resulting in degranulation, release of histamine and other allergic mediators. That's the fundamental basis of allergy. For those of you who don't know, interleukin-4 and interleukin-13 are the IgE switch factors. When you try desensitization therapy, the whole goal of that therapy, fundamentally, is to reprogram the immune system and make the immune system make good antibody, or immunoglobulin G, as in George, instead of immunoglobulin E, as in Ellen. So -- and when you are trying desensitization, you don't really have a natural way of actually impacting whether these cells that are involved in the response go to IgG or IgE. IL-4 blockade and IL-13 blockade are the fundamental drivers. So in any setting of desensitization, giving DUPIXENT should do or drive exactly the kind of reprogram that you want, that historically has been very difficult to achieve. And in animal studies, the results are pretty much black and white. So we believe that in almost any setting of desensitization, whether it be peanut, grass, whether it be with any approach, the whole goal is to stop making IgE and to start making IgG. That is exactly what DUPIXENT can do. So what we hope success in that study is faster ability to tolerate higher doses of the peanut during the whole desensitization, decrease the number of patients who have allergy-mediated side effects, mostly GI side effects that limit their ability to take or stay on the treatment. All of these will be indicators that DUPIXENT is doing exactly what we think it should be doing, which is driving more IgG and preventing the body from making the IgE and thus, reprogram the body away from allergy. And this is just the beginning. If it works in peanut, it has a signal here, it should be applicable to essentially every form of desensitization available by whatever modality.

簡單來說，就是關於這些標誌。我認為每個人都必須明白，你之所以會過敏，是因為你體內有一種叫做免疫球蛋白 E 的免疫球蛋白，它與肥大細胞和嗜鹼性粒細胞的表面結合。一旦與過敏原相互作用，它就會聚集在這些細胞的表面，導致細胞脫顆粒，釋放組織胺和其他過敏介質。這就是過敏的根本原因。對於那些不了解的人來說，白細胞介素-4和白細胞介素-13是IgE轉換因子。當你嘗試減敏療法時，該療法的根本目標就是重新編程免疫系統，使免疫系統產生良好的抗體，即免疫球蛋白 G（如喬治體內的抗體），而不是免疫球蛋白 E（如艾倫體內的免疫球蛋白 E）。所以——當你嘗試脫敏治療時，你實際上並沒有一種自然的方法來影響參與反應的這些細胞是產生 IgG 還是 IgE。IL-4阻斷和IL-13阻斷是根本驅動因子。因此，在任何減敏治療中，給予 DUPIXENT 都應該能夠或推動你想要的那種重新編程，而這種編程在歷史上是很難實現的。在動物研究中，結果幾乎都是非黑即白的。因此我們認為，在幾乎任何脫敏治療中，無論是花生、草，或任何方法，最終目標都是停止產生 IgE 並開始產生 IgG。這正是DUPIXENT能夠做到的。因此，我們希望這項研究能夠取得成功，即在整個脫敏過程中更快地提高對更高劑量花生耐受性，減少出現過敏性副作用（主要是胃腸道副作用）的患者人數，這些副作用會限制他們接受或堅持治療的能力。所有這些都表明 DUPIXENT 正在發揮我們認為它應該發揮的作用，即促進 IgG 的產生，阻止身體產生 IgE，從而重新編程身體，使其不再過敏。而這只是個開始。如果這種方法對花生有效，那麼它在這裡就具有一定的參考價值，並且應該適用於任何形式的脫敏治療，無論採用何種治療方式。

Our next question is from Geoffrey Porges from Leerink.

我們的下一個問題來自 Leerink 公司的 Geoffrey Porges。

Just a follow-up on DUPIXENT a little bit. Could we -- could you just address the question of the adolescent indication and what your expectations are there? And you mentioned the population. But would you expect adoption to be faster or slower there? And then, just back to the asthma launch, could you comment on whether you think this is going to be actively managed by payers, whether there'll be step edits and rebates involved? Or do you think that you're largely going to sort of be able to price more or less at the same price as you have in AD and have unrestricted access?

關於DUPIXENT，我再補充一點後續資訊。您能否談談青少年指標的問題，以及您對這方面的期望？你也提到了人口問題。但你認為那裡的普及速度會更快還是更慢？那麼，回到氣喘藥物的上市問題，您能否評論一下，您認為支付方是否會積極管理這項藥物，是否會有階梯式調整和回扣之類的措施？或者您認為基本上可以按照與 AD 相同的價格定價，並享有不受限制的訪問權限？

Geoff, before Marion answers, we invite you to come by, we might have an antiviral antibody we can give you.

傑夫，在瑪莉安回答之前，我們邀請你來一趟，我們或許可以提供抗病毒抗體。

I'd appreciate that.

我會很感激的。

So addressing your comments first on DUPIXENT uptake in adolescents. Well, as I mentioned, we very much look forward to the indication in helping this group of patients with moderate-to-severe disease and the agony that goes with that, for both them and their families. We would anticipate that the uptake should be similar to potentially a bit faster than what we saw in adult atopic dermatitis. And I think it's for 2 reasons. I want to be a little conservative in saying similar but the reason why I think realistically, it might be a little bit faster for these patients is that physicians now have experience with DUPIXENT. And the product is becoming well known, just the prescribing is increasing. And for that reason, coupled by the fact that this is an alarming disease for adolescents, we believe it's very important that we get the word out quickly and there's great excitement and enthusiasm in the market for this indication for this group of patients who are truly suffering. Your second question related to asthma and payer uptake. It's very early days. This is our third week of launch so things are going well. There's been great receptivity to the clinical profile of the product. But I think I'd rather come back and give more detail on payer specificity as we have more time in market.

首先，我想回應您關於青少年使用DUPIXENT的評論。正如我之前提到的，我們非常期待這項適應症能幫助這群患有中度至重度疾病的患者，減輕他們及其家人所承受的痛苦。我們預計其吸收率應該與我們在成人異位性皮膚炎中看到的吸收率相似，甚至可能更快一些。我認為有兩個原因。我想謹慎一些，但我認為，從現實角度來看，這些患者的治療速度可能會更快一些，因為醫生現在有了使用 DUPIXENT 的經驗。該產品正變得越來越有名，處方量也不斷增加。正因如此，再加上這種疾病對青少年來說非常令人擔憂，我們認為迅速傳播這一信息非常重要，而且市場上對這一適應症給予這群真正遭受痛苦的患者帶來了極大的興奮和熱情。你的第二個問題與氣喘和健保覆蓋率有關。現在還為時過早。這是我們產品上市的第三週，一切都很順利。該產品的臨床特性獲得了廣泛的認可。但我認為，等我們有更多時間在市場上推廣後，再回來詳細闡述支付方具體情況。

I just wanted to add to the pediatric side of this is that in systemic steroids, whether they're absorbed from -- lathering lots of it on or with systemic versa treatment in adolescents during their growth spurts is a big deal. So I think that's another reason why doctors might want to move to early adoption.

我只想補充一點兒科方面的情況，那就是全身性類固醇，無論是透過皮膚吸收，或是在青少年生長發育高峰期進行全身性維拉西坦治療，都是一件大事。所以我認為這是醫生們可能想要儘早採用新技術的另一個原因。

Our next question is from Matthew Luchini from BMO Capital.

下一個問題來自 BMO Capital 的 Matthew Luchini。

Just on DUPIXENT, we've had the DTC campaign ongoing now for a little while. I was wondering if you could give us an update or your latest view on the patient mix that's currently receiving the drug for atopic dermatitis? As well as perhaps your view on current persistence or refill rates? That's something that I don't think was mentioned in the earlier marks.

就 DUPIXENT 而言，我們的 DTC 行銷活動已經進行了一段時間了。我想請您提供目前接受該藥物治療異位性皮膚炎的患者群體構成情況的最新資訊或您的看法？您對目前的續約率或補貨率有何看法？我認為之前的評分中並沒有提到這一點。

Sure. So let me take persistence and refill rates first. So the persistency that we've commented on in the past at the 12-month point being approximately 80%, continues. So we see strong persistency with DUPIXENT. Similarly, on the first script, refill is an important factor. We still see that at over 90%. So these are indicators that when patients go on DUPIXENT therapy for atopic dermatitis, they want to stay on therapy because their lives are better. The second piece you mentioned is a little bit on the DTC. I believe it was part of the question. And also the types of patients. So similar to the comment I made before, it's not unusual for physicians to start with their most severe patients but it's clearly now, we're getting penetration not only with severe but also moderate patients. And we really thought it was part of our responsibility to -- for this disease and for patients to potentially previously had given up because therapies were not really helping them at all. We thought that this product was absolutely ideal for an on-air branded campaign. We're still only in months of that branded DUPIXENT TV campaign. It was preceded as some would recall by a disease awareness campaign and we thought that was the right order to do things. We've been in national broadcast mode with the DUPIXENT TV campaign now since about the August time frame. So we're several months in. The signs we've seen so far are encouraging.

當然。那麼，我先來說說堅持率和補貨率。因此，我們過去提到的12個月時約80%的持續性仍然存在。因此，我們看到DUPIXENT具有很強的持久性。同樣，對於第一張處方來說，補藥量是一個重要因素。我們仍然看到這種情況發生在 90% 以上。所以這些跡象表明，當異位性皮膚炎患者接受 DUPIXENT 治療時，他們希望繼續接受治療，因為他們的生活得到了改善。你提到的第二部分有點像DTC。我認為這是問題的一部分。還有患者的類型。所以和我之前的評論類似，醫生們通常都會先治療病情最嚴重的病人，但現在很明顯，我們不僅在重症患者中，而且在中度患者中也取得了進展。我們真的認為這是我們的責任——對於這種疾病，對於可能已經放棄治療的患者來說，因為治療對他們根本沒有任何幫助。我們認為這款產品非常適合用於電視品牌推廣活動。DUPIXENT品牌電視廣告宣傳活動才進行了幾個月。有些人可能還記得，在此之前我們開展了一項疾病意識宣傳活動，我們認為這是做事的正確順序。從八月左右開始，我們就一直在全國播出 DUPIXENT 電視廣告。到現在已經好幾個月了。目前來看，種種跡象令人鼓舞。

Our next question is from Terence Flynn from Goldman Sachs.

下一個問題來自高盛的 Terence Flynn。

I know you are unlikely to give EYLEA guidance for 2019, but maybe you could just talk about the puts and takes heading into next year? It looks like we're on track for another double-digit year of branded growth here. So just wondering if we think that, that should continue heading into '19. And then you mentioned this higher dose formulation of EYLEA. Maybe what have you learned here that drove this decision? And what would actually be required to bring that to market?

我知道您不太可能給出 2019 年 EYLEA 的業績指引，但或許您可以談談明年的發展趨勢？看來我們有望連續第二年實現兩位數的品牌成長。所以我想知道，我們是否認為這種情況應該延續到 2019 年。然後您提到了EYLEA的高劑量配方。你在這裡學到了什麼，才促使你做出這個決定？那麼，要將這項技術推向市場，究竟需要哪些條件呢？

So maybe George can take the higher dose, and then we can comment about the market.

所以也許喬治可以服用更高劑量，然後我們就可以對市場發表評論了。

Well, in terms of a higher dose, I guess the point is that we remain impressed with the fact that EYLEA has stood up to so much competition in that no one has really been able to come up seemingly with a fundamentally different profile in terms of benefit, effects on vision, or duration of treatment. And so we thought that it was time, especially because we've been working on this in the labs for a while, to see whether just giving a higher dose of EYLEA can actually take EYLEA past what is now, we think, the gold standard in the field and see if we could either improve the benefit and/or extend the duration of the interval. And so we're poised. We've been working on this for a while, and we're going to be putting in the clinic this year.

就更高劑量而言，我想重點是，EYLEA 經受住瞭如此多的競爭，至今為止還沒有人能夠真正拿出在療效、對視力的影響或治療持續時間方面有根本不同優勢的產品，這一點仍然讓我們印象深刻。因此，我們認為現在是時候了，特別是因為我們已經在實驗室裡研究了一段時間，看看僅僅增加 EYLEA 的劑量是否真的能讓 EYLEA 超越我們認為目前該領域的黃金標準，看看我們是否可以提高療效和/或延長治療間隔。所以我們已經準備就緒。我們已經為此努力了一段時間，今年我們將把診所建成。

Next year, 2019.

明年，2019年。

Sorry, 2019. Yes. I'm already operating in 2019.

抱歉，2019年。是的。我現在已經進入2019年了。

In terms of the market growth, we see nothing that will change the underlying demographics for -- the increase in diabetes and the increase in AMD, continuing to grow the market somewhere in the mid- to high- or low-double-digit growth over time. Those demographics do not seem to be letting up at all. Obviously, where we fit in there based on competition, what have you, we'll have to see how all that plays out, but I'll echo what George says. We haven't seen anything that's disruptive. We certainly haven't seen a drug -- even the most touted drug by the sponsor, RTH, it seems to me they have forgotten that the retinal specialists are actually some of the smartest guys out there as physicians. And they can do math and they can multiply 75% times about 50% and come up with a lot lower number than 75%. So it seems to me that EYLEA has a really good profile. In addition, what we saw in the diabetic retinopathy studies was we think quite remarkable. I think it was startling too many how many frequent it was that people untreated with asymptomatic diabetic retinopathy given placebo just watch for year and a large fraction of them, about 1/3 actually develops vision-threatening complications. And this can be dramatically prevented and reduced not only improve the diabetic retinopathy but prevent the progression of the diabetic retinopathy. And we think that, that's a big deal. It's going to take some reeducation out there of both patients and physicians, but we think that's a fundamental advance. Remember that diabetes and diabetic eye disease is one of the leading still causes -- leading causes of blindness in adults.

就市場成長而言，我們認為沒有什麼能改變潛在的人口結構——糖尿病和 AMD 的增加，將使市場在一段時間內繼續保持中高或低兩位數的成長。這些人口結構變化似乎絲毫沒有減緩的跡象。顯然，我們能否在競爭中佔有一席之地，等等，我們得看看最終結果如何，但我同意喬治的說法。我們還沒有發現任何具有破壞性的事情。我們當然還沒有看到任何藥物——即使是贊助商最熱衷的藥物RTH——在我看來，他們似乎忘記了視網膜專家實際上是醫生中最聰明的人之一。他們會做數學題，他們可以把 75% 乘以 50%，得出比 75% 小得多的數字。在我看來，EYLEA 的品牌形象非常好。此外，我們在糖尿病視網膜病變研究中看到的情況，我們認為非常引人注目。我認為，很多人驚訝地發現，許多未接受治療的無症狀糖尿病視網膜病變患者，即使服用安慰劑，也會觀察一年，而其中很大一部分人（約 1/3）實際上會發展成威脅視力的併發症。而且，這種情況可以顯著預防和減少，不僅可以改善糖尿病視網膜病變，還可以阻止糖尿病視網膜病變的進展。我們認為，這意義重大。這需要對患者和醫生進行一些再教育，但我們認為這是一個根本性的進步。請記住，糖尿病和糖尿病眼疾仍然是成人失明的主要原因之一。

And our last question is from Ying Huang from Bank of America.

最後一個問題來自美國銀行的黃穎。

I have one for NGF. In the recently released Phase III top line, you saw the placebo adjusted rate of adjudicated arthropathy at about 2%. And now we saw the Pfizer tanezumab at ACR showing less than 1.5% incidence of RPOA. I was just wondering whether you think that this kind of safety is acceptable for the FDA and for the treating physicians? And what's the gating factor for the long-term safety in your Phase III trial? And then next, if you could give us a little bit more color on the collaboration with bluebird, exactly what kind of target and what kind of therapy you're focusing on?

我有一個用於NGF的。在最近公佈的 III 期主要結果中，安慰劑調整後的關節病變發生率約為 2%。現在我們在 ACR 上看到輝瑞 tanezumab 的數據顯示，RPOA 的發生率低於 1.5%。我只是想知道您是否認為這種安全措施能夠被美國食品藥物管理局（FDA）和治療醫生接受？那麼，你們的 III 期試驗中，長期安全性的把關因素是什麼？接下來，您能否詳細介紹一下與 bluebird 的合作，具體來說，你們的目標群體和治療方向是什麼？

Thanks, Ying. Let me just comment on the tanezumab, and then maybe George can comment on bluebird or ask him about fasinumab. But I have to say that I think we know that in any drug dosing, any drug development program, getting the dose right is really, really important. And that becomes super important when you have a very steep dose response curve for side effects. And we think that our approach has been to really try and get that dose right. And we're hopeful that the very low dose that we got that is still able to produce what's basically so far at least best-in-class efficacy results have not stayed the course study comparisons and all that. But really good efficacy results thus far. But perhaps, as George said in his prepared remarks, we're mitigating the safety. In terms of safety, I don't think it's just going to be the adjudicated arthropathies, which -- that probably would be an acceptable level. But I also think there's a question of whether or not this event, this treatment will lead to more or less joint replacements. There's some evidence, I believe you've seen in the other development program, certainly, and hours of high doses that you would see more joint replacements. And that probably would not be acceptable. Our program is very carefully monitored by an independent DSMB, which has met recently and advised us to continue development at these low doses where we've demonstrated the efficacy. So we hope that we've got the dose right. Being first here may not be nearly as important as being right where -- because if not, we'll leave as much room for error in this program as it might be in others. George can talk about bluebird.

謝謝你，穎。我先說說tanezumab，然後George或許可以評論一下bluebird，或是問他關於fasinumab的情況。但我必須說，我認為我們都知道，在任何藥物劑量、任何藥物研發項目中，劑量的準確性都至關重要。當副作用的劑量反應曲線非常陡峭時，這一點就變得特別重要。我們認為我們的方法就是努力把劑量控制在適當的範圍內。我們希望，我們所獲得的極低劑量仍然能夠產生目前為止至少是同類最佳的療效結果，並且在研究比較等方面沒有停滯不前。但目前為止，療效效果確實很好。但或許正如喬治在事先準備好的演講中所說，我們正在降低安全性。就安全性而言，我認為不僅僅是已裁定的關節病，雖然這可能是一個可以接受的水平。但我認為還有一個問題，那就是這次事件、這種治療方法是否會導致更多或更少的關節置換手術。我相信你在其他研發項目中也看到了一些證據，例如長時間的高劑量用藥，這會導致更多的關節置換手術。那恐怕是不可接受的。我們的專案受到獨立資料安全監測委員會 (DSMB) 的非常嚴格的監督，該委員會最近召開會議，建議我們繼續以我們已經證明有效的低劑量進行開發。所以我們希望劑量合適。在這裡排名第一可能遠不如排名正確重要——因為如果不是這樣，我們在這個項目中就會像在其他項目中一樣，留下很多出錯的餘地。喬治會談論藍鳥。

Just to just add to that. As you know, we are continuing our long-term safety study with NGF. And as Len said, I mean, the most important data is to see what the benefit will be compared to adverse events with, we believe at this point, since we seem to have mitigated against at least the arthropathies, the total joint replacements numbers are going to be very important. Certainly, with the competitor's program, that is a concern, and we'll have to see whether our dose gets around that. In terms of bluebird, I think, for us, this is a very exciting collaboration. Clearly, they've demonstrated and they've developed their technologies and abilities to develop these CAR-T therapies. What we bring to the table is, we bring new targets and new reagents, whether they be antibodies or T-cell receptor-related reagents that can target new targets, that can be put into and made into chimeric antigen receptors by bluebird to be put into their cells and used up via their therapeutic approach. So we're very excited about putting together our ability to bring new targets and new ways to make these chimeric antigen receptors together with their ability to take those forward and deliver them to patients. And we think this is a real synergistic collaboration between 2 companies with very complementary capabilities and we're hoping to be able to change the future there.

補充一點。如您所知，我們正在繼續進行 NGF 的長期安全性研究。正如 Len 所說，我的意思是，最重要的數據是看看與不良事件相比，其益處是什麼。我們認為，在這一點上，既然我們似乎已經減輕了至少關節病的影響，那麼全關節置換的數量將非常重要。當然，對於競爭對手的方案來說，這確實令人擔憂，我們需要看看我們的劑量是否能解決這個問題。就藍鳥樂團而言，我認為，對我們來說，這是一次非常令人興奮的合作。顯然，他們已經展示並發展了開發 CAR-T 療法的技術和能力。我們帶來的是新的靶點和新的試劑，無論是抗體還是T細胞受體相關試劑，它們都可以靶向新的靶點，可以被bluebird公司製成嵌合抗原受體，然後放入他們的細胞中，並通過他們的治療方法加以利用。因此，我們非常興奮地將我們獲取新標靶和製造嵌合抗原受體的新方法的能力，與他們推進這些標靶並將其交付給患者的能力結合起來。我們認為這是兩家能力互補的公司之間真正的協同合作，我們希望能夠改變那裡的未來。

Thanks, George. Operator, that concludes our prepared -- our call today. I know we weren't able to get through all your questions, but please send me an e-mail and we will schedule a follow-up call with you.

謝謝你，喬治。接線員，我們今天的通話到此結束。我知道我們沒能解答您所有的問題，但請給我發一封電子郵件，我們會安排一次後續通話。

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

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