雷傑納榮製藥 (REGN) 2022 Q2 法說會逐字稿

Welcome to the Regeneron Pharmaceuticals Second Quarter 2022 Earnings Conference Call. My name is Bella, and I will be your operator for today's call. (Operator Instructions) Please note today's conference is being recorded.

歡迎參加再生元製藥公司2022年第二季財報電話會議。我是貝拉，將擔任本次電話會議的接線生。 （接線生說明）請注意，本次會議正在錄音。

I will now turn the call over to Ryan Crowe, Vice President, Investor Relations. You may begin.

現在我將把電話交給投資者關係副總裁瑞安·克羅。您可以開始了。

Thank you, Bella. Good morning, good afternoon and good evening to everyone listening around the globe. Thank you for your interest in Regeneron, and welcome to our second quarter 2022 earnings conference call. An archive of this webcast will be available on our Investor Relations website site shortly after the call ends.

謝謝貝拉。各位全球聽眾，早安、下午好、晚上好。感謝您對再生元公司的關注，歡迎參加我們2022年第二季財報電話會議。本次網路直播的存檔將在會議結束後不久發佈在我們的投資者關係網站上。

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

今天與我一同出席的有：創始人、總裁兼首席執行官倫納德·施萊弗博士；聯合創始人、總裁兼首席科學官喬治·揚科波洛斯博士；執行副總裁兼商務主管瑪麗昂·麥考特；以及執行副總裁兼首席財務官鮑勃·蘭德里。在我們分別致詞後，我們將進入問答環節。

I would also like to remind you that remarks made on this call today include forward-looking statements by Regeneron. Such statements may include, but are not limited to, those related to Regeneron and its products and businesses -- business, financial forecast and guidance, development programs and related anticipated milestones, collaborations, finances, regulatory matters, payer coverage and reimbursement issues, intellectual property, pending litigation and other proceedings 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.

我還要提醒各位，今天電話會議的發言包含Regeneron公司的前瞻性聲明。這些陳述可能包括但不限於與Regeneron及其產品和業務相關的內容，例如業務、財務預測和指導、研發項目及相關預期里程碑、合作、財務、監管事宜、支付方覆蓋範圍和報銷問題、知識產權、未決訴訟及其他程序以及競爭。每項前瞻性陳述都存在風險和不確定性，可能導致實際結果和事件與該陳述中預測的結果和事件有重大差異。

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, including its Form 10-Q for the quarterly period ended June 30, and 2022, which was filed with the SEC this morning. Regeneron does not undertake any obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise.

關於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提交的文件，包括截至6月30日的季度報告（10-Q表格）以及今天上午提交給美國證券交易委員會的2022年報告。 Regeneron不承擔任何更新前瞻性聲明的義務，無論是因為新資訊、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 the 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財務指標。有關我們使用非GAAP財務指標以及這些指標與GAAP的調節信息，請參閱我們網站上發布的財務業績新聞稿。

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

通話結束後，鮑勃·蘭德里和投資者關係團隊將隨時解答任何進一步的問題。

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

那麼，現在讓我把電話交給我們的總裁兼執行長倫‧施萊弗博士。倫？

Thank you, Ryan, and thank you to everyone joining today's call.

謝謝瑞恩，也謝謝今天參加電話會議的各位。

Regeneron had a strong second quarter with notable execution across R&D, commercial and business development functions. Total revenues increased by 20% when excluding contributions from our COVID antibody cocktail, with net sales for EYLEA, Dupixent and Libtayo each reaching new all-time quarterly highs and growing by double digits year-over-year on a constant currency basis.

再生元公司第二季業績強勁，研發、商業及業務拓展等各職能部門均表現優異。若不計入新冠抗體雞尾酒療法的貢獻，總收入成長了20%。其中，EYLEA、Dupixent和Libtayo的淨銷售額均創下季度歷史新高，以固定匯率計算，較去年同期成長兩位數。

In addition to exceptional commercial execution, we made significant pipeline progress with 3 regulatory approvals, 2 accepted regulatory filings and 1 positive Phase III readout. We also completed the acquisition of Checkmate Pharmaceuticals and the third quarter purchase of worldwide rights to Libtayo from Sanofi, both of which we believe will strengthen our oncology franchise in the near, medium and long term.

除了卓越的商業執行力，我們在產品研發管線方面也取得了顯著進展，獲得了3項監管批准、2項監管申報被接受以及1項積極的III期臨床試驗結果。此外，我們也完成了對Checkmate Pharmaceuticals的收購，並在第三季從賽諾菲手中購得Libtayo的全球權益。我們相信，這兩項收購都將在短期、中期和長期內增強我們在腫瘤領域的實力。

We also reported today preliminary, but promising anti-tumor activity and safety data for REGN5678, our PSMAxCD28 costimulatory bispecific in combination with Libtayo in patients with advanced metastatic castrate-resistant prostate cancer. George will have more to say on this shortly, but we believe this represents an important step towards validating our costimulatory approach to fighting cancer and potentially advancing the science of immuno-oncology.

今天，我們也發表了REGN5678（一種PSMAxCD28共刺激雙特異性抗體）聯合Libtayo治療晚期轉移性去勢抵抗性前列腺癌患者的初步但令人鼓舞的抗腫瘤活性和安全性數據。 George稍後將對此進行更詳細的說明，但我們相信，這代表著在驗證我們利用共刺激策略對抗癌症方面邁出了重要一步，並有可能推動腫瘤免疫學的發展。

Turning to our commercial performance. In the second quarter, EYLEA global net sales grew 13% at constant exchange rates to $2.5 billion. In the U.S., EYLEA net sales were $1.6 billion, up 14% year-over-year and outperforming anti-VEGF category growth of approximately 8%. Despite new competition, EYLEA's share was approximately half of the anti-VEGF category and 75% among branded agents, affirming its status as the gold standard anti-VEGF therapy.

接下來談談我們的商業業績。第二季度，安禮全球淨銷售額以固定匯率計算成長13%，達到25億美元。在美國，安禮淨銷售額為16億美元，較去年成長14%，遠超抗VEGF藥品類別約8%的整體成長。儘管面臨新的競爭，安禮在抗VEGF藥物品類中的市佔率仍約為一半，在品牌藥中更是高達75%，鞏固了其作為抗VEGF療法黃金標準的地位。

We believe aflibercept represents a significant potential growth opportunity going forward, given favorable demographic trends as well as the potential for aflibercept 8 milligrams to augment the category and complement our retinal franchise.

我們認為，鑑於有利的人口趨勢，以及阿柏西普 8 毫克有可能增強該類別並補充我們的視網膜產品線，阿柏西普在未來代表著巨大的潛在成長機會。

Regarding our investigational aflibercept 8 milligrams, the goal of our clinical program is to evaluate where the visual acuity among wet AMD and DME patients can be maintained or improved compared to EYLEA while extending the interval between doses. Equally important is maintaining the high bar for safety that has been set by EYLEA over the past 10 years, 55 million injections worldwide and 8 million patient years of experience. We anticipate pivotal results in late quarter 3 or early quarter 4. And with supportive data, a BLA submission completed by early 2023.

關於我們正在研究的阿柏西普8毫克製劑，我們的臨床計畫目標是評估在延長給藥間隔的同時，與EYLEA相比，該製劑能否維持或改善濕性AMD和DME患者的視力。同樣重要的是，我們要保持EYLEA過去10年來所樹立的高安全性標準，EYLEA在全球範圍內已累計注射5500萬次，積累了800萬患者年的經驗。我們預計將在第三季末或第四季初獲得關鍵性結果。如果數據支持，我們將在2023年初完成生物製品許可申請（BLA）的提交。

Dupixent continues to grow at a remarkable pace after 5 years and more than 450,000 patients treated since launch. In quarter 2, global and net product sales were $2.1 billion, an increase of 43% at constant exchange rates compared to last year, reflecting Dupixent's differentiated clinical profile and ability to effectively treat more and more patients with the type 2 inflammatory diseases where Dupixent is approved. In the U.S., we saw growth across all indications, including initial contributions from atopic dermatitis in patients as young as 6 months to 5 years of age and from eosinophilic esophagitis, both of which are indications approved by the FDA during the second quarter and represents the first approved systemic treatment options for these patients. We hope to add a third first-in-class indication for Dupixent later this year in patients with prurigo nodularis, which is currently under priority review with the FDA.

自上市五年來，Dupixent 已治療超過 45 萬名患者，並持續保持著令人矚目的成長動能。第二季度，Dupixent 全球淨銷售額達 21 億美元，以固定匯率計算，較去年同期增長 43%，這充分體現了 Dupixent 獨特的臨床優勢，以及其在已獲批的 2 型發炎性疾病領域有效治療更多患者的能力。在美國，所有適應症均實現了增長，其中包括 6 個月至 5 歲兒童異位性皮膚炎和嗜酸性食道炎的初步增長。這兩種適應症均已於第二季獲得 FDA 批准，是目前針對這些患者的首個核准全身性治療方案。我們希望今年稍晚能為 Dupixent 新增第三個首創適應症——結節性癢疹，目前正在接受 FDA 的優先審查。

In oncology, Libtayo net product sales grew 25% globally at a constant currency to $141 million in the second quarter of 2022, including 17% growth in the U.S. driven by non-melanoma skin cancer indications and monotherapy non-small cell lung cancer. We have long believed that the key to fully unlocking the opportunity in oncology is through differentiated combinations, with Libtayo possibly serving as our foundation for many of them. That belief was the basis for acquisition of the global rights to Libtayo.

在腫瘤領域，Libtayo 2022年第二季全球淨產品銷售額以固定匯率計算成長25%，達到1.41億美元，其中美國市場成長17%，主要得益於非黑色素瘤皮膚癌適應症和非小細胞肺癌單藥治療的強勁成長。我們一直堅信，充分挖掘腫瘤領域潛力的關鍵在於差異化的聯合療法，Libtayo有望成為我們眾多聯合療法的基礎。正是基於這項信念，我們收購了Libtayo的全球權益。

We plan to invest further in Libtayo-based combinations, pairing it with promising candidates in our oncology pipeline such as LAG3 antibody fianlimab and our many investigational bispecifics, as well as with candidates from external collaborations. We continue to make progress with these Libtayo combinations and intend to share initial data in the second half of this year from our emerging oncology pipeline, which George will discuss in more detail.

我們計劃進一步投資基於Libtayo的聯合療法，將其與我們腫瘤產品線中前景廣闊的候選藥物（例如LAG3抗體fianlimab和我們正在研發的多種雙特異性抗體）以及來自外部合作的候選藥物進行聯合治療。我們持續推動這些Libtayo聯合療法的研發，並計劃在今年下半年分享我們新興腫瘤產品線的初步數據，屆時George將對此進行更詳細的闡述。

Regarding the FDA's review of our Libtayo-chemo combo supplemental BLA for the treatment of non-small cell lung cancer, we are pleased with the progress that we have made as the FDA continues its review. However, we recently were informed that an FDA travel complication relating to scheduling a routine clinical trial satisfaction in Eastern Europe will likely delay their decision until after our September 19 PDUFA date. While any delay is disappointing, a new site inspection date has been scheduled. Therefore, we do not expect a lengthy extension of the review period, and we do not expect it to meaningfully impact our launch plans assuming FDA approval. We continue to actively work with the FDA, believing the ongoing review is otherwise progressing well and all other elements of the review remain on track.

關於FDA對我們用於治療非小細胞肺癌的Libtayo-化療聯合療法補充生物製品許可申請（BLA）的審查，我們對FDA審查過程中取得的進展感到滿意。然而，我們近期獲悉，由於FDA在東歐安排例行臨床試驗現場檢查時遇到的旅行問題，最終決定可能會推遲到9月19日PDUFA截止日期之後。儘管任何延誤都令人失望，但新的現場檢查日期已經安排妥當。因此，我們預計審查期不會大幅延長，即使獲得FDA批准，也不會對我們的上市計畫產生實質影響。我們將繼續積極與FDA合作，相信審查工作進展順利，所有其他環節均按計畫進行。

Regarding our COVID-19 response, Regeneron remains committed to combatting the virus by developing additional novel antibodies. We continue to work with the FDA to establish a regulatory pathway for these antibodies, which could potentially serve an important role in protecting immunocompromised individuals, who do not respond adequately to COVID-19 vaccines as well as treating infected patients, whom oral antiviral therapy is not appropriate.

關於新冠肺炎疫情應對措施，再生元公司始終致力於透過研發更多新型抗體來對抗病毒。我們正與美國食品藥物管理局（FDA）合作，為這些抗體建立監管途徑。這些抗體有望在保護免疫功能低下、對新冠疫苗反應不足的人群以及治療不適合口服抗病毒療法的感染患者方面發揮重要作用。

In closing, as I reflect on our performance in the first half of the year, I am very proud of our numerous achievements, which were only made possible by the dedicated Regeneron employees around the world. Together, we have continued to serve patients in need while strengthening the foundation of the company and leveraging our financial strength to better position Regeneron to achieve sustainable growth over time.

最後，回顧上半年的業績，我為我們所取得的許多成就感到無比自豪，而這些成就的取得離不開全球各地Regeneron員工的辛勤付出。我們齊心協力，在繼續為有需要的患者提供服務的同時，也夯實了公司的基礎，並充分利用我們的財務實力，使Regeneron能夠更好地實現長期可持續增長。

We are excited about the increasing commercial momentum for our core products and the important progress we have made in advancing our pipeline. Our strategy continues to focus on investing in our internal R&D capabilities while exploring potential collaborations that will enable us to fully realize the power of our science. We remain confident in the strategy and in our growth prospects as well as our ability to deliver breakthroughs to patients and value to shareholders.

我們對核心產品日益強勁的商業動能以及研發管線取得的重要進展感到振奮。我們的策略將繼續專注於投資內部研發能力，同時探索潛在的合作機會，以充分發揮我們的科學實力。我們對該策略、成長前景以及為患者帶來突破性進展並為股東創造價值的能力充滿信心。

Now, I'll turn the call over to George.

現在，我把電話交給喬治。

Thanks, Len. I will start with ophthalmology.

謝謝，Len。我先從眼科開始。

We are looking forward to the upcoming Phase III readouts of aflibercept 8 milligram in patients with diabetic macular edema and in wet age-related macular degeneration. PHOTON in patients with DME and PULSAR in patients with wet AMD will test whether the patients treated with 8 milligrams dose every 12 weeks or every 16 weeks can achieve non-inferior best corrected visual acuity at week 48 compared to the currently approved EYLEA 2-milligram dose every 8 weeks.

我們期待即將公佈的阿柏西普8毫克治療糖尿病性黃斑水腫和濕性老年黃斑部病變的III期臨床試驗結果。 PHOTON試驗（針對糖尿病性黃斑水腫患者）和PULSAR試驗（針對濕性老年性黃斑部病變患者）將檢驗，每12週或每16週接受8毫克阿柏西普治療的患者，在第48週時能否達到不劣於目前已獲批准的每8週2毫克阿柏西普治療方案（EYLEA）的最佳矯正視力。

Unlike studies from other sponsors in which patients were assigned to a dosing interval based on disease activity assessment following the loading phase, patients enrolled in the PHOTON and PULSAR studies were randomized at baseline into 1 of the 3 treatment groups, we believe will allow us to determine whether extent dosing can truly be achieved. If the studies are positive and the high safety standard established with EYLEA is maintained, we believe aflibercept 8 milligram would represent a significant clinical advance for patients, and we would target a U.S. regulatory filing by early 2023.

與其他申辦者的研究不同，這些研究並非根據負荷期後疾病活動度評估結果來決定患者的給藥間隔，而是在PHOTON和PULSAR研究中，患者在基線時被隨機分配到3個治療組之一。我們相信，這將有助於我們確定是否能夠真正實現理想的給藥方案。如果研究結果積極，並且能夠維持EYLEA所建立的高安全性標準，我們相信8毫克阿柏西普將代表著患者臨床治療的重大進步，我們計劃在2023年初向美國​​監管機構提交上市申請。

Moving to Dupixent, which continued to deliver notable milestones in the second quarter of the year. Dupixent was recently approved and chosen with atopic dermatitis as young as 6 months old, making Dupixent the first and only biologic medicine approved to treat atopic dermatitis from infancy through adulthood. Marion will talk more about this as well as about our recent earlier-than-expected FDA approval for a brand-new gastroenterology indication, eosinophilic esophagitis or EoE.

接下來談談Dupixent，它在今年第二季繼續取得了顯著的里程碑進展。 Dupixent近期獲準用於治療6個月及以上嬰兒的異位性皮膚炎，使其成為首個也是目前唯一一個獲準用於治療嬰幼兒至成人異位性皮膚炎的生物製劑。 Marion將詳細介紹Dupixent，以及我們近期提前獲得FDA批准用於治療嗜酸性粒細胞性食道炎（EoE）這一全新胃腸道適應症的情況。

Since receiving approval in adults and in adolescents age 12 and over, we have reported positive data in pediatric patients with EoE as young as 1 year of age. Our Phase III study in children 1 to 11 years of age met the primary endpoint, with 68% of patients on the higher Dupixent dose and 58% of the lower Dupixent dose achieving histological disease remission compared to 3% of children on placebo at 16 weeks.

自從獲準用於成人和12歲及以上青少年以來，我們已報告了在1歲及以上EoE患童中取得的正面數據。我們針對1至11歲兒童進行的III期研究達到了主要終點，接受較高劑量Dupixent治療的患者中有68%達到組織學疾病緩解，接受較低劑量Dupixent治療的患者中有58%達到組織學疾病緩解，而安慰劑組兒童的這一比例在16週時僅為3%。

EoE symptoms can be difficult to assess in these young patients, however, we also observed a numerical improvement in the EoE symptom score and in exploratory analysis, we recorded a 3.1% increase from baseline and body weight for age percentile for the higher dose group compared to 0.3% of the placebo on. These data will be discussed with the regulatory authorities, starting with the FDA, later this year.

在這些年輕患者中，嗜酸性粒細胞性食道炎（EoE）的症狀可能難以評估。然而，我們也觀察到EoE症狀評分有所改善。在探索性分析中，我們記錄到高劑量組的年齡別體重百分位數較基線水平提高了3.1%，而安慰劑組僅提高了0.3%。這些數據將於今年稍後與監管機構（首先是FDA）進行討論。

Regarding approvals for new indications expected in the near future. For prurigo nodularis, we received a PDUFA action date from the FDA of September 30 and the European Commission decision expected in the first half of 2023. Also in the first half of next year, we're also looking forward to the readout of the first Dupixent study in chronic obstructive pulmonary disease or COPD.

關於近期預計獲準的新適應症，我們已收到美國食品藥物管理局 (FDA) 於 9 月 30 日作出的處方藥用戶付費法案 (PDUFA) 審批決定，預計歐盟委員會將於 2023 年上半年作出決定。此外，我們也期待明年上半年公佈首個 Dupixent 治療慢性阻塞性肺病 (COPD) 的研究結果。

Moving on to Libtayo and oncology. As Len mentioned, we are excited to have acquired Sanofi stake in Libtayo, thereby gaining exclusive worldwide rights to a PD-1 inhibitor review as foundational for our oncology franchise, which has the potential to be utilized in numerous combinations with other candidates in our pipeline such as our costimulatory bispecifics, our CD3 bispecifics and novel checkpoint inhibitors such as fianlimab.

接下來談談Libtayo和腫瘤學。正如Len所提到的，我們很高興收購了賽諾菲在Libtayo的股份，從而獲得了PD-1抑製劑審查的全球獨家權利，這對於我們的腫瘤產品線至關重要，並且有潛力與我們研發管線中的其他候選藥物進行多種組合，例如我們的共刺激雙特異性抗體、CD3雙特異性抗體和新型檢查點抑製劑（如fianlimab）。

Regarding such combinations, I'd like to provide a brief update on our first clinical data from our costimulatory pipeline involving REGN5678, our PSMAxCD28 costimulatory bispecific, in combination with Libtayo. This combination is being studied in patients with advanced metastatic castrate-resistant prostate cancer, who have previously progressed on multiple antiandrogen therapies. These patients, unfortunately, have a poor prognosis, with approximately 1 to 2 years of life expectancy and with limited treatment options. Metastatic castrate-resistant prostate cancer is considered an immunologically cold tumor and is largely resistant to immune checkpoint inhibitor, with large trials of PD-1 antibodies showing monotherapy response rates in the single digits.

關於這類聯合療法，我想簡要介紹一下我們共刺激藥物研發管線的首個臨床數據，該管線涉及我們的PSMAxCD28共刺激雙特異性抗體REGN5678與Libtayo的聯合用藥。此聯合療法正在接受多種抗雄性激素療法治療後病情進展的晚期轉移性去勢抵抗性前列腺癌患者中進行研究。不幸的是，這些患者的預後很差，預期壽命約為1至2年，且治療選擇有限。轉移性去勢抵抗性前列腺癌被認為是一種免疫冷腫瘤，對免疫檢查點抑制劑大多有抗藥性，PD-1抗體的大型臨床試驗顯示，單藥治療的有效率僅為個位數。

As just announced today by Merck, the challenge of metastatic castrate-resistant prostate cancer in terms of the lack of efficacy for checkpoint inhibitors used in standard way is emphasized by the failure of their large Phase III trial in an earlier stage of this disease. Our costim program was designed to innovatively enhance responsiveness in these types of cold tumor classes such as prostate cancer and essentially turn these cold tumors into hot tumors.

正如默克公司今天剛剛宣布的那樣，轉移性去勢抵抗性前列腺癌（mCRPC）對常規免疫檢查點抑制劑療效不佳的挑戰，因其早期階段大型III期臨床試驗的失敗而更加凸顯。我們的協同刺激（costim）計畫旨在創新地提高前列腺癌等「冷腫瘤」的治療反應性，並最終將這些「冷腫瘤」轉化為「熱腫瘤」。

I remind you of the extensive preclinical data we have published supporting this hypothesis. Since 2019, we have been in careful dose escalation for this prostate cancer program in close collaboration with the FDA. In our study, patients are dosed weekly with REGN5678 in every 3 weeks with Libtayo. However, first dose of Libtayo was not co-administered until week 4, permitting a period of PSMAxCD28, leading to evaluate monotherapy safety and efficacy.

我在此提醒各位，我們已發表了大量臨床前數據來支持這個假設。自 2019 年以來，我們與 FDA 密切合作，謹慎地推進此前列腺癌計畫的劑量遞增。在我們的研究中，患者每 3 週接受一次 REGN5678 治療，並同時接受 Libtayo 治療。然而，Libtayo 的首次給藥直到第 4 週才開始，以便進行一段時間的 PSMAxCD28 治療，從而評估單一藥物治療的安全性和有效性。

Earlier today, we announced the first clinical data from 33 patients across 8-dose levels, which show dose-dependent antitumor activity. The key efficacy endpoint in the study is objective response rate defined as a greater than 50% decline of prostate-specific antigen or PSA from baseline and/or tumor shrinkage. PSA is a protein produced by the prostate gland and by prostate tumors and is most commonly used as a biomarker to diagnose and follow-up prostate cancer, as many metastatic castration-resistant prostate cancer patients have disease limited to bone lesions and cannot be assessed by conventional RECIST criteria.

今天早些時候，我們公佈了來自8個劑量水平的33名患者的首批臨床數據，結果顯示抗腫瘤活性呈現劑量依賴性。研究的關鍵療效終點是客觀緩解率，定義為前列腺特異性抗原（PSA）較基線下降超過50%和/或腫瘤縮小。 PSA是由前列腺和前列腺腫瘤產生的蛋白質，最常用於診斷和追蹤前列腺癌，因為許多轉移性去勢抵抗性前列腺癌患者的疾病局限於骨轉移，無法使用傳統的RECIST標準進行評估。

Preliminary data from the ongoing dose escalation portion trial across 8-dose level cohorts in a total of 33 patients showed dose-dependent antitumor activity as assessed by PSA values at the 5 lowest dose levels, which our preclinical models predicted might be subtherapeutic. There was almost no evidence of any antitumor activity, with only 1 of 17 patients showing a decrease in PSA. There were no greater than greater or equal to Grade 3 immune-related adverse events or irAEs these doses. The lack of antitumor activity among these patients was consistent with the approximate 6% response rate reported in other trials with anti-PD-1 monotherapy.

正在進行的劑量遞增部分試驗的初步數據顯示，在共33例患者中，8個劑量水平組的抗腫瘤活性呈劑量依賴性，以PSA值評估，在最低的5個劑量水平下觀察到，而我們的臨床前模型預測這些劑量水平可能低於治療水平。幾乎沒有證據顯示存在任何抗腫瘤活性，17例患者中僅有1例PSA值下降。這些劑量組均未出現≥3級的免疫相關不良事件（irAE）。這些患者缺乏抗腫瘤活性與先前抗PD-1單藥治療試驗中報告的約6%的緩解率相符。

At the next 3 dose levels, we began to see clear evidence of dose-dependent antitumor activity, which was generally seen within 6 weeks of starting the combination treatment. At dose level 6, 1 of 4 patients experienced a 100% decrease in PSA and a complete response in target lesions based on RECIST criteria. The patients discontinued therapy due to a grade 3 immune-related adverse events of the skin. That was considered to be a recurrence of preexisting condition, and have since resolved with treatment per investigator report. Despite termination of the treatment, he has maintained his 100% decrease in PSA and complete response in target lesions were approximately 10 months to date per investigator report.

在接下來的三個劑量水平中，我們開始觀察到明顯的劑量依賴性抗腫瘤活性，通常在開始合併治療後6週內即可觀察到。在第6個劑量水平，4例患者中有1例的PSA水平下降100%，且根據RECIST標準，標靶病灶達到完全緩解。該患者因出現3級免疫相關皮膚不良事件而停止治療。根據研究者報告，該不良事件被認為是原有疾病的復發，此後經治療後已緩解。儘管治療已終止，但根據研究者報告，截至目前，該患者的PSA水平仍維持在100%，且目標病灶也保持完全緩解，持續時間約為10個月。

We continue to see antitumor activity at the next dose level or dose level 7. And in our eighth and most recent dose level, 3 out of 4 patients had dramatic and rapid PSA reductions, 2 with greater than 99% reductions and 1 with an 82% reduction. Of the 2 patients with greater than 99% PSA reductions, one experienced a grade 3 case of mucositis, which has resolved, and the other experienced a grade 3 case of acute inflammatory demyelinating polyradiculopathy, which is ongoing.

我們在下一個劑量水平（即第7劑量水平）繼續觀察到抗腫瘤活性。在第8個也是最新的劑量水準中，4名患者中有3名PSA值顯著且迅速下降，其中2名患者PSA值下降超過99%，1名患者下降82%。在PSA值下降超過99%的2名患者中，1名患者出現3級黏膜炎，現已痊癒；另1名患者出現3級急性發炎性脫髓鞘性多發性神經根病變，目前仍在持續。

In terms of safety, very importantly, no grade 3 or higher irAEs were observed in patients without antitumor activity. And the occurrence of irAEs was correlated with antitumor activity. This is consistent with previous trials with anti-PD-1 immunotherapy wherein irAEs have been reported to occur at a higher rate in responding patients. No grade 4 irAEs or greater than or equal to grade 2 cytokine release syndrome have been observed in the trial to date.

就安全性而言，非常重要的是，在未觀察到抗腫瘤活性的患者中未觀察到3級或更高級別的免疫相關不良事件（irAEs）。 irAEs的發生與抗腫瘤活性有關。這與先前抗PD-1免疫療法的試驗結果一致，既往試驗報告道irAEs在有效患者中的發生率更高。迄今為止，該試驗中未觀察到4級irAEs或≥2級細胞激素釋放症候群。

There was one death that was considered unrelated to treatment. In this trial, irAEs are being treated according to standard management practices used for checkpoint inhibitors. We are planning on sharing more detailed data from this study at an upcoming medical meeting.

有一例死亡病例被認為與治療無關。在本試驗中，免疫相關不良事件（irAEs）的治療遵循免疫檢查點抑制劑的標準管理流程。我們計劃在即將舉行的醫學會議上分享這項研究的更詳細數據。

Let me remind you that through extensive preclinical research, we have hypothesized that augmenting T cell costimulation alongside PD inhibition could be a key to turning immunologically cold tumors hot. These preliminary data for our PSMAxCD28 costimulated bispecific provides the first clinical evidence supporting the promise of our broader pipeline of costimulatory bispecifics in diverse solid tumors as well as hematologic malignancies. By combining these costimulatory bispecific with Libtayo or with our CD3 bispecifics, we have the opportunity to create novel therapeutic synergies to address some of the most difficult-to-treat cancers. We look forward to partnering with the oncology community on this ambitious and potentially groundbreaking efforts.

我想提醒各位，透過廣泛的臨床前研究，我們假設增強T細胞共刺激並同時抑制PD可能是將免疫冷腫瘤轉化為免疫熱腫瘤的關鍵。我們PSMAxCD28共刺激雙特異性抗體的初步數據，首次提供了臨床證據，支持我們更廣泛的共刺激雙特異性抗體產品線在多種實體腫瘤和血液系統惡性腫瘤中的應用前景。透過將這些共刺激雙特異性抗體與Libtayo或我們的CD3雙特異性抗體合併使用，我們有機會創造新的治療協同效應，以應對一些最難治療的癌症。我們期待與腫瘤學界攜手合作，共同推動這項雄心勃勃且可能具有突破性意義的研究。

In addition to these exciting early data, we anticipate several important oncology milestones in the second half of the year. At the upcoming ESMO conference, we will provide updates on fianlimab, our LAG3 antibody in combination with Libtayo, in a Phase II cohort of metastatic melanoma that will hopefully confirm the encouraging combined efficacy that we previously reported in this setting. In addition, we will present initial data for ubamatamab, our MUC16xCD3 bispecific in metastatic ovarian cancer, where I'd like to remind you that we have also combination studies ongoing with both costimulatory bispecifics and Libtayo. We will also report initial data for our METxMET bispecific in advanced MET-altered non-small cell lung cancer as well for Libtayo monotherapy in neoadjuvant cutaneous squamous cell carcinoma.

除了這些令人振奮的早期數據外，我們預計今年下半年將在腫瘤學領域取得幾項重要的里程碑式進展。在即將召開的ESMO大會上，我們將公佈fianlimab（我們的LAG3抗體）與Libtayo聯合治療轉移性黑色素瘤的II期臨床試驗的最新進展，該試驗有望證實我們先前在該適應症中報道的令人鼓舞的聯合療效。此外，我們也將發表ubamatamab（我們的MUC16xCD3雙特異性抗體）治療轉移性卵巢癌的初步數據。在此，我想提醒各位，我們目前正在進行ubamatamab與這兩種共刺激雙特異性抗體和Libtayo的聯合治療研究。我們也將公佈METxMET雙特異性抗體治療MET基因改變的晚期非小細胞肺癌的初步數據，以及Libtayo單藥治療新輔助皮膚鱗狀細胞癌的初步數據。

Moving on to our hematology pipeline. Odronextamab has the potential to be the first C20xCD3 bispecific to be approved for both major types of advanced B-cell lymphomas, that is both follicular lymphoma and diffuse large B-cell lymphoma. Based on interim data from a cohort of patients, goes with our recently modified step-up regimen. We believe odronextamab may have the lowest rates of Grade 3 or higher cytokine release syndrome for this class of bispecifics, in follicular lymphoma and diffuse large B-cell lymphoma, while still maintaining the efficacy profile previously reported. We look forward to presenting these updated data and potentially submit a BLA for both indications in the second half of this year, pending feedback from the FDA.

接下來談談我們的血液學產品線。 Odronextamab有望成為首個獲準用於治療兩種主要類型晚期B細胞淋巴瘤（即濾泡性淋巴瘤和瀰漫性大B細胞淋巴瘤）的C20xCD3雙特異性抗體。基於一項患者群組的中期數據，該藥物與我們近期改進的階梯治療方案相符。我們相信，在濾泡性淋巴瘤和瀰漫性大B細胞淋巴瘤中，Odronextamab在此類雙特異性抗體中，3級及以上細胞激素釋放綜合徵的發生率可能最低，同時仍能維持先前報告的療效。我們期待公佈這些更新的數據，並可能在今年下半年根據FDA的回饋，提交針對這兩種適應症的生物製品許可申請（BLA）。

We also plan to share updated data for our BCMAxCD3 bispecific study in relapsed or refractory multiple myeloma by the end of the year. Pending regulatory feedback, we are planning to submit for regulatory approval in 2023. An umbrella study in multiple myeloma investigating BCMAxCD3 in combination with various standard of care products and investigational candidate is now open to enrollment, while we plan to initiate an additional study in early lines of multiple myeloma later this year.

我們計劃在年底前分享BCMAxCD3雙特異性抗體治療復發或難治性多發性骨髓瘤的最新研究數據。待監管機構回饋後，我們計劃於2023年提交上市申請。一項針對多發性骨髓瘤的傘式研究現已開始招募患者，該研究旨在探索BCMAxCD3聯合多種標準治療產品和在研候選藥物的療效。此外，我們計劃於今年稍後啟動一項針對早期多發性骨髓瘤患者的研究。

As you can see, the pace of innovation in our oncology pipeline has been accelerated, building upon Libtayo as a foundation, with data readouts for novel mechanisms for cancer indications that historically have not responded to immunotherapy, including with our Regeneron Genetics' medicines where we in collaborate continue to progress our pipeline and discovery engine. Our siRNA collaboration with Alnylam, a nonalcoholic steatohepatitis or NASH contains product candidates addressing various targets, including those discovered by the Regeneron Genetics Center. First data in NASH for ALN-HSD are anticipated this fall. We are progressing a second target, PNPLA3, into the clinic later this year, and we have recently identified an additional novel promising target for NASH SIP.

如您所見，我們腫瘤產品線的創新步伐已顯著加快，這得益於Libtayo的成功研發。我們已獲得針對以往免疫療法無效的癌症適應症的新機制數據，包括我們與Regeneron Genetics合作開發的藥物。我們與Regeneron Genetics的合作將持續推進我們的產品線和發現引擎。我們與Alnylam合作開發的siRNA產品，用於治療非酒精性脂肪性肝炎（NASH），其候選藥物針對多種靶點，其中包括Regeneron Genetics中心發現的標靶。 ALN-HSD在NASH領域的首批數據預計將於今年秋季公佈。我們正在推進第二個標靶PNPLA3的臨床試驗，預計今年稍後啟動。此外，我們最近還發現了一個新的、有前景的NASH SIP標靶。

As we just published in the New England Journal of Medicine, we found unprecedented association of very rare SIP loss of function variants with lower risk of liver disease. In the largest association study examining protection from liver disease ever described, individuals with loss of function SIP bearing had about 53% lower risk of developing nonalcoholic fatty liver disease and about 54% lower risk of developing non-alcoholic cirrhosis. Regeneron and Alnylam are developing siRNA therapeutic candidate leads to advance to the clinic.

正如我們剛在《新英格蘭醫學雜誌》上發表的文章所述，我們發現極為罕見的SIP功能缺失變異與較低的肝病風險有前所未有的關聯。在迄今規模最大的肝病保護關聯研究中，攜帶SIP功能缺失變異的個體罹患非酒精性脂肪肝的風險降低了約53%，罹患非酒精性肝硬化的風險降低了約54%。 Regeneron和Alnylam正在開發siRNA治療候選藥物，以推進臨床試驗。

And with that, I will turn the call over to Marion.

接下來，我將把電話交給瑪莉安。

Thank you, George. Regeneron's commercial business achieved another strong quarter, demonstrating durable growth across our brands. We're building on the momentum of in-line brands, including EYLEA, Dupixent and Libtayo, and also accelerating the potential across our portfolio from new and anticipated future launches.

謝謝喬治。 Regeneron的商業業務又迎來了一個強勁的季度，旗下所有品牌都實現了持續成長。我們正鞏固現有品牌（包括EYLEA、Dupixent和Libtayo）的成長勢頭，同時也加速釋放新產品和即將上市產品的巨大潛力。

Let me start with EYLEA. Second quarter global net sales grew 13% year-over-year at constant currency to $2.5 billion. In the U.S., EYLEA net sales exceeded $1.6 billion, a 14% year-over-year increase driven by prescribing demand with strong demand continuing into the third quarter. EYLEA year-over-year growth significantly outpaced the category, gaining competitive share and further enhancing EYLEA's position as the anti-VEGF agent of choice for retinal disease. We continue to see durable growth based on patient flow and new patient starts, ongoing demographic trends such as the aging population and prevalence of diabetes support anticipated mid to high single-digit category growth for the foreseeable future.

首先，我想談談安麗（EYLEA）。第二季全球淨銷售額以固定匯率計算年增13%，達到25億美元。在美國，安利淨銷售額超過16億美元，較去年同期成長14%，這主要得益於處方需求的強勁成長，且這項強勁需求延續至第三季。安麗的年成長率顯著高於同類產品，不僅提升了市場份額，也進一步鞏固了其作為視網膜疾病首選抗VEGF藥物的地位。基於患者數量和新患者數量的持續增長，以及人口老化和糖尿病患病率上升等持續的人口趨勢，我們預計安麗在可預見的未來將保持中高個位數的增長率。

In diabetic eye disease, increasing diagnosis rates are also driving strong growth for EYLEA, with more than 55 million injections worldwide since launch and well over 1 million injections in the U.S. alone in the second quarter of 2022. Physicians continue to recognize and prefer EYLEA's differentiated efficacy and safety profile. We are confident in our ability to continue to build on our leadership over the long term.

在糖尿病眼疾領域，診斷率的不斷提高也推動了EYLEA的強勁成長。自上市以來，EYLEA全球注射量已超過5,500萬次，光是2022年第二季在美國的注射量就超過100萬次。醫生們持續認可並青睞EYLEA卓越的療效和安全性。我們有信心在未來繼續鞏固我們的領先地位。

Pending FDA approvals, there are potential incremental opportunities for EYLEA, including extending the dosing interval up to 16 weeks for diabetic retinopathy and treating in pre-term infants suffering from retinopathy of prematurity. In addition, our aflibercept 8 milligram investigational program garnered significant enthusiasm from the retinal community and has the potential to significantly enhance the anti-VEGF treatment paradigm.

在獲得FDA批准後，EYLEA有望拓展應用前景，例如將糖尿病視網膜病變的給藥間隔延長至16週，以及用於治療早產兒視網膜病變。此外，我們的阿柏西普8毫克研究計畫也引起了視網膜疾病領域的廣泛關注，並有望顯著改善抗VEGF治療模式。

Turning now to Libtayo. Global net sales in the second quarter grew 25% at constant currency to $141 million with U.S. net sales of $91 million. Libtayo continues to grow across all approved indications, including non-melanoma skin cancers, where Libtayo is the leading immunotherapy treatment. In monotherapy non-small cell lung cancer, we are generating increased utilization across a broader number of prescribers. We are launch-ready for the potential chemotherapy combination approval, which will significantly expand the patient opportunity and physician choice for Libtayo in treating lung cancer.

現在來看Libtayo。第二季度，Libtayo全球淨銷售額以固定匯率計算成長25%，達到1.41億美元，其中美國淨銷售額為9,100萬美元。 Libtayo在所有已核准適應症中均持續成長，包括非黑色素瘤皮膚癌，Libtayo在該領域是領先的免疫療法。在非小細胞肺癌單藥治療方面，我們正在推動更多醫生提高Libtayo的使用率。我們已做好上市準備，等待潛在的化療聯合用藥方案獲批，這將顯著擴大Libtayo在肺癌治療中的患者群體和醫生選擇範圍。

Regeneron's full ownership of Libtayo presents many exciting opportunities across our current and future oncology portfolio. Key thought leaders recognize our growing commitment to oncology and of high interest in the potential for Libtayo combinations to meaningfully advance the standard of care in many cancer indications. We are taking a measured approach to expanding our global commercial footprint in key international markets to maximize the impact of our innovations to patients and Regeneron. These capabilities and infrastructure will support Libtayo, and over time, future medicines.

再生元公司對Libtayo的全面收購為我們目前及未來的腫瘤產品組合帶來了許多令人振奮的機會。產業領袖們認可我們對腫瘤領域的持續投入，並對Libtayo聯合療法在多種癌症適應症中顯著提升治療標準的潛力抱持濃厚興趣。我們正採取穩健的策略，在關鍵國際市場拓展全球商業版圖，以最大限度地發揮我們的創新成果對病患和再生元公司的價值。這些能力和基礎設施將為Libtayo的研發以及未來的其他藥物提供支援。

And now turning to Dupixent. In the second quarter global Dupixent's net sales grew 42% year-over-year at constant currency to $2.1 billion. Dupixent's performance was yield by strong uptake across all indications, with recent launches performing well across new diseases, age groups and geographies. In the U.S., Dupixent's net sales grew 38% to $1.58 billion.

現在來看Dupixent。第二季度，Dupixent全球淨銷售額以固定匯率計算年增42%，達到21億美元。 Dupixent的業績成長主要得益於其在所有適應症中的強勁市場表現，近期上市的新適應症在新的疾病、年齡層和地區均取得了良好成績。在美國，Dupixent的淨銷售額成長38%，達到15.8億美元。

We continue to expand Dupixent's leadership position as the first line systemic treatment in atopic dermatitis. There's robust demand for Dupixent across the spectrum of moderate and severe disease as well as across age groups. With the recent approval in children as young as 6 months, Dupixent is the first and only biologic medicine approved to treat moderate to severe atopic dermatitis from infancy through adulthood, and the launch in our youngest patients is off to a very strong start based on initiations.

我們持續鞏固Dupixent作為異位性皮膚炎一線系統治療藥物的領先地位。 Dupixent在中重度異位性皮膚炎患者以及各個年齡層中均擁有強勁的需求。近期，Dupixent獲準用於6個月及以上嬰兒，使其成為首個也是目前唯一獲準用於治療嬰幼兒至成人中重度異位性皮膚炎的生物製劑。根據目前的用藥情況來看，Dupixent在低齡患者族群的上市取得了非常強勁的開局。

We are also preparing for the potential approval next month in prurigo nodularis, a dermatologic condition, where approximately 75,000 U.S. patients have no FDA-approved medicines and are most in need. In asthma, Dupixent is the #1 biologic prescribed by both allergists and pulmonologists. We continue to see strong growth in new patient starts and total prescriptions driven by Dupixent's differentiated profile, unique mechanism of action, ease of prescribing broad label and demonstrated efficacy and safety.

我們正積極準備迎接下個月Dupixent在結節性癢疹治療領域的潛在核准。結節性癢疹是一種皮膚病，約有75,000名美國患者目前尚無FDA批准的藥物，他們迫切需要此類治療。在氣喘治療方面，Dupixent是過敏科醫師和肺科醫師處方量最高的生物製劑。 Dupixent憑藉其差異化的特性、獨特的作用機制、易於開具的廣泛適應症以及已證實的療效和安全性，持續推動新患者用藥量和處方總量的強勁增長。

In nasal polyps, robust demand continues, with Dupixent capturing the majority of market share and increased prescribing from ENTs. In eosinophilic eosophagitis, our first gastroenterology indication, Dupixent is the only approved medicine for adults and children aged 12 and above. Early launch indicators have been favorable, with encouraging adoption from both allergists and gastroenterologists. In addition, we are expanding our outreach to educate patients and caregivers about Dupixent as a new therapeutic option that provides meaningful symptom relief.

在鼻息肉領域，市場需求依然強勁，Dupixent佔據了大部分市場份額，耳鼻喉科醫生的處方量也在增加。在嗜酸性粒細胞性食道炎（我們首個核准的胃腸道適應症）方面，Dupixent是唯一獲準用於12歲及以上成人和兒童的藥物。早期上市指標表現良好，過敏科醫師和胃腸科醫師均積極採用此藥。此外，我們正在擴大宣傳範圍，向患者及其照顧者普及Dupixent這項新型治療方案，以期有效緩解症狀。

Turning now to Dupixent in markets outside the U.S. In the second quarter, net sales grew 61% on a constant currency basis to $510 million, driven by robust growth across all indications. Regeneron continues to expand our presence in key international markets to bring Dupixent to patients. In summary, Dupixent is transforming the type 2 inflammatory disease landscape and has significant growth potential ahead, driven by further penetration in existing indications as well as from potential future indications.

現在我們來看看Dupixent在美國以外市場的表現。第二季度，以固定匯率計算，淨銷售額成長61%至5.1億美元，主要得益於所有適應症的強勁成長。 Regeneron將繼續拓展在關鍵國際市場的業務，以便將Dupixent帶給更多病患。總之，Dupixent正在改變2型發炎性疾病的治療格局，並具有巨大的成長潛力，這得益於現有適應症的進一步滲透以及未來潛在適應症的拓展。

In conclusion, our commercial execution delivered solid results for the second quarter, bringing our life-changing medicines to even more patients. Our in-line brands continue to perform well, and new launches provide additional opportunities for sustainable long-term growth.

總之，我們第二季的商業執行取得了穩健的業績，使更多患者能夠受益於我們改變生命的藥物。我們的現有品牌持續保持良好表現，而新產品的上市也為可持續的長期成長提供了更多機會。

Now I'll turn the call to Bob.

現在我把電話轉給鮑伯。

Thank you, Marion. My comments today on Regeneron's financial results and outlook will be on a non-GAAP basis unless otherwise noted.

謝謝你，瑪莉安。除非另有說明，我今天對再生元公司財務業績和展望的評論將基於非GAAP準則。

Regeneron's outstanding performance continued in the second quarter as our core business maintained a strong growth trajectory, and we have leveraged our strong financial position to complete 2 business development oncology transactions. Excluding global revenues related to the COVID-19 antibody cocktail, second quarter total revenues increased 20% year-over-year to $2.9 billion, demonstrating continued momentum across our business. Second quarter total diluted net income per share was $9.77 on net income of $1.1 billion.

在第二季度，Regeneron 的卓越業績得以延續，核心業務保持強勁增長勢頭，我們憑藉雄厚的財務實力完成了兩項腫瘤業務拓展交易。剔除與 COVID-19 抗體雞尾酒療法相關的全球收入，第二季總收入年增 20% 至 29 億美元，展現出公司業務的持續成長動能。第二季稀釋後每股淨收益為 9.77 美元，淨利為 11 億美元。

Beginning with collaboration revenue and starting with Bayer. Second quarter 2022 ex-U.S. EYLEA net product sales were $870 million, up 13% on a constant currency basis versus second quarter 2021. Total Bayer collaboration revenue was $358 million, of which $340 million related to our share of EYLEA net profits outside the U.S.

首先從合作收入和拜耳公司開始。 2022年第二季度，除美國以外，EYLEA淨產品銷售額為8.7億美元，以固定匯率計算，較2021年第二季成長13%。拜耳公司合作總收入為3.58億美元，其中3.4億美元與我們在美國以外地區EYLEA淨利潤中所佔份額有關。

Total Sanofi collaboration revenue was $678 million in the second quarter of 2022, improved 55% from the prior year driven by Dupixent.

2022 年第二季度，賽諾菲合作總營收為 6.78 億美元，比上年同期成長 55%，主要得益於 Dupixent 的強勁表​​現。

Finally, we recorded Roche collaboration revenue of $8 million related to Roche's sales of Ronapreve outside the U.S. We expect to record additional revenue from this collaboration in the fourth quarter of 2022.

最後，我們確認了與羅氏在美國以外地區銷售 Ronapreve 相關的 800 萬美元羅氏合作收入。我們預計將在 2022 年第四季確認來自該合作的額外收入。

Moving now to our operating expenses. R&D increased 7% year-over-year to $690 million, driven by higher headcount in costs to support our expanding pipeline, partially offset by lower development costs for REGEN-COV. In the second quarter of 2022, acquired IPR&D was $197 million, which includes a previously-disclosed $195 million charge related to our acquisition of Checkmate Pharmaceuticals. SG&A expense increased 14% (sic) [15%] year-over-year to $418 million, primarily due to costs related to growth initiatives for EYLEA and higher headcount to support our growing organization.

接下來是我們的營運費用。研發費用年增7%至6.9億美元，主要原因是為支援不斷擴大的產品線而增加的人員成本，但部分被REGEN-COV的研發成本降低所抵銷。 2022年第二季度，收購智慧財產權及研發費用為1.97億美元，其中包括先前揭露的與收購Checkmate Pharmaceuticals相關的1.95億美元費用。銷售、管理及行政費用年增14%（原文如此，應為15%）至4.18億美元，主要原因是與EYLEA成長計畫相關的成本以及為支持公司發展而增加的人員成本。

Cost of goods sold decreased 73% year-over-year to $137 million primarily due to sales of REGEN-COV in the prior year that did not reoccur. Finally, the second quarter 2022 effective tax rate was 13.6% compared to 17% in the prior year. The lower rate is partially related to the non-recurrence of REGEN-COV sales.

銷售成本年減73%至1.37億美元，主要原因是去年同期銷售的REGEN-COV產品在2022年第二季不再販售。此外，2022年第二季實際稅率為13.6%，而去年同期為17%。稅率下降的部分原因在於REGEN-COV產品的銷售不再銷售。

Shifting now to cash flow and the balance sheet. Year-to-date in 2022, Regeneron has generated $2.4 billion in free cash flow and ended the second quarter of 2022 with cash and marketable securities less debt of $11.3 billion.

接下來我們來看現金流和資產負債表。截至2022年第二季末，Regeneron已產生24億美元的自由現金流，其現金及有價證券減去債務後總額為113億美元。

We continue to deliver on our capital allocation priorities. Completing our acquisition of Checkmate Pharmaceuticals, the first acquisition of Regeneron's history and the purchase of Sanofi stake in Libtayo. In addition, we repurchased approximately $400 million of our shares in the second quarter of 2022, bringing our year-to-date total through July to over $1.1 billion. We continue to be opportunistic buyers where we see dislocation between our stock price and our intrinsic valuation.

我們持續推進資本配置優先事項。我們完成了對Checkmate Pharmaceuticals的收購，這是Regeneron歷史上首次收購，同時也收購了Sanofi持有的Libtayo股份。此外，我們在2022年第二季回購了約4億美元的股票，使截至7月份的年度累積回購總額超過11億美元。我們將繼續抓住機會，在股價與其內在價值出現偏差時進行買入。

I will now discuss updates to our full year 2022 guidance driven by the closing of the Libtayo transaction. We are updating full year R&D expense guidance to be in the range of $3.1 billion to $3.24 billion, an increase of $170 million at the midpoint from our previous guidance. Approximately 1/3 of the increase is driven by Regeneron now recording all R&D expense for Libtayo, which was previously shared with Sanofi. The remaining 2/3 reflects the recording of our full 50% share of antibody collaboration spend as incurred beginning in the third quarter of 2022. Previously, our share of antibody collaboration expenses was only partially expensed in the period incurred, with the remaining share added to the antibody collaboration development balance.

接下來，我將討論受Libtayo交易完成影響而對2022年全年業績指引的更新。我們將全年研發支出指引調整為31億美元至32.4億美元，較先前指引的中位數增加1.7億美元。其中約三分之一的成長源自於Regeneron現在將Libtayo的全部研發支出計入公司帳目，而此前這些支出是與賽諾菲共同承擔的。剩餘的三分之二則反映了我們從2022年第三季開始計入全部50%的抗體合作支出。此前，我們僅在發生期間將部分抗體合作支出計入費用，剩餘部分則計入抗體合作開發餘額。

We are updating full year SG&A expense guidance to be in the range of $1.74 billion to $1.84 billion. The updated range reflects the inclusion of 100% of Libtayo commercial expenses, which were previously shared with Sanofi net of anticipated synergies.

我們將全年銷售、管理及行政費用預期更新為17.4億美元至18.4億美元。更新後的預期範圍已包含Libtayo的全部商業費用，這些費用先前已扣除預期協同效應後與賽諾菲分攤。

We are also updating full year gross margin guidance to be in the range of 92% to 93%. The more favorable gross margin is due to the removal of the payment of Sanofi's share of U.S. Libtayo gross margin that was previously recorded in this slide. A complete summary of our latest full year guidance is available in our press release issued earlier this morning.

我們同時將全年毛利率預期更新至92%至93%之間。毛利率預期上調是由於剔除了先前計入的賽諾菲在美國Libtayo毛利率中所佔份額。有關我們最新全年預期的完整摘要，請參閱今天早些時候發布的新聞稿。

Let me conclude by highlighting 4 important financial modeling considerations related to the Libtayo transaction. First, effective July 1, Regeneron will record 100% of the global Libtayo net product sales. We previously recorded only U.S. Libtayo net product sales.

最後，我想重點介紹與Libtayo交易相關的四個重要的財務建模考量因素。首先，自7月1日起，Regeneron將確認Libtayo全球產品淨銷售額的100%。此前，我們僅確認了Libtayo在美國的淨銷售額。

Second, the Libtayo up-front payment, milestones and royalties will be recorded as an intangible asset on the balance sheet and amortized through cost of goods sold over the useful life of Libtayo. This amortization expense will be excluded from non-GAAP results.

其次，Libtayo的預付款、里程碑付款和特許權使用費將作為無形資產記入資產負債表，並在Libtayo的使用壽命內透過計入銷售成本進行攤提。此攤銷費用將從非GAAP財務報表中剔除。

Third, as you may recall, we will now pay 20% of our share of antibody profits to reduce the antibody development balance instead of the previous 10% arrangement. The quarterly development balance repayment going forward will be reflected in our P&L as incremental antibody R&D expense I mentioned earlier when discussing revised R&D guidance, with the remainder coming in the form of a reduction to antibody collaboration revenue. Therefore, the reduction of antibody collaboration revenue will be less than 20% of our share of antibody profits. As a result of the development balance repayment step-up, we expect to shorten the period to fully repay the development balance, resulting in an earlier and very significant inflection in collaboration profits in the other years.

第三，您可能還記得，我們​​現在將支付抗體利潤份額的20%來償還抗體研發餘額，而不是之前的10%。未來每季償還的研發餘額將反映在我們的損益表中，作為我先前在討論修訂後的研發指引時提到的新增抗體研發費用，剩餘部分將以減少抗體合作收入的形式體現。因此，抗體合作收入的減少額將低於我們抗體利潤份額的20%。由於研發餘額償還比例的提高，我們預計償還全部研發餘額所需的時間將縮短，導致其他年份的合作利潤出現更早且顯著的成長。

Finally, in the third quarter of 2022, we will record a one-time development balance repayment per the Libtayo transaction agreement of approximately $55 million in addition to our regular quarterly repayments, which we recorded as a deduction within the antibody collaboration revenue line.

最後，在 2022 年第三季度，我們將根據 Libtayo 交易協議記錄一筆約 5500 萬美元的一次性開發餘額償還款項，此外，我們還將按季度償還款項，這筆款項已作為抗體合作收入項下的扣除項記錄。

In conclusion, Regeneron is performing well, and we continue to make investments in our business, supported by our strong financial position to drive sustainable long-term growth.

總之，Regeneron 目前表現良好，我們將繼續加大對業務的投資，憑藉我們雄厚的財務實力，推動可持續的長期成長。

With that, I will pass the call back to Ryan.

這樣，我就把電話轉回給瑞恩了。

Thank you, Bob.

謝謝你，鮑伯。

Bella, that concludes our prepared remarks. We'd now like to open the call for Q&A with several callers in the queue. And to ensure we are able to address as many questions as possible, we will answer one question from each caller before moving to the next.

貝拉，我們的演講到此結束。現在我們開始問答環節，前面有幾位聽眾正在排隊等候。為了確保我們能夠回答盡可能多的問題，我們會先回答每位聽眾的一個問題，然後再回答下一位。

Bella, please go ahead and poll for questions.

貝拉，請開始進行投票徵集問題。

(Operator Instructions) And our first question comes from the line of Mohit Bansal from Wells Fargo.

（操作員說明）我們的第一個問題來自富國銀行的 Mohit Bansal。

Yes. Congrats on the quarter and data.

是的。恭喜你取得良好的季度業績和數據。

Maybe a question on high-dose EYLEA DME trial, especially with the loading dose, sticking to that. If you go back in the memory lane, it seems like the use of 5 loading doses only came along after the DRCR protocology because I couldn't find anything which -- where, in the history, we suggest that you should use 5 loading doses. Could you please talk a little bit about that?

或許可以問一個關於高劑量EYLEA DME試驗的問題，特別是關於負荷劑量的問題。回顧一下，似乎5劑負荷劑量的使用是在DRCR方案之後才出現的，因為我找不到任何資料表明——在以往的研究中，我們建議使用5劑負荷劑量。您能否就此談談？

And also, what is the realistic utility of fourth and fifth loading dose even for standard dose EYLEA, especially in the context of one year-long trial?

此外，即使對於標準劑量的 EYLEA 而言，第四劑和第五劑負荷劑量的實際效用是什麼？尤其是在為期一年的試驗中？

Yes. Those are really interesting questions, and I get into the details of very specific points of the REGN. Many of these, as you point out, have not been directly studied in sort of head-to-head studies, so we would have to maybe offline discuss some of these issues. But as I said, details that would require a lot of experimentation maybe answered.

是的，這些問題很有意思，我會深入探討REGN的一些具體細節。正如你所指出的，其中許多問題還沒有透過直接比較研究來驗證，所以我們可能需要私下討論一下。但正如我所說，一些需要大量實驗才能解答的細節問題或許可以得到解答。

Bella, the next question, please.

貝拉，請問下一個問題。

Your next question comes from the line of Evan Seigerman from BMO Capital.

你的下一個問題來自 BMO Capital 的 Evan Seigerman。

I'd love for you to expand on kind of some of the next steps for 5, 6, 7, 8. What do you want to see in additional cohort 8 patients, and even at potentially higher dose cohorts to move into a registrationally-directed trial?

我希望您能詳細介紹第 5、6、7、8 組的一些後續步驟。您希望在第 8 組的其他患者中看到什麼，甚至在可能更高劑量的隊列中看到什麼，以便進行註冊性試驗？

Yes. No, thanks. We are obviously very excited about these data that have long been coming. As you all know, we had to go through a very careful dose escalation starting with very low doses. But what we've now seen at the dose level 6, 7 and 8 have really been very exciting.

是的。不，謝謝。我們當然對這些期待已久的數據感到非常興奮。大家都知道，我們必須非常謹慎地逐步增加劑量，從極低劑量開始。但現在我們在劑量等級 6、7 和 8 上看到的結果確實令人振奮。

I think that what we're going to be doing is we're going to be continuing to expand the number of patients at these dose levels. We're going to continue to evaluate the tumor activity as well as the safety, and we hope that we're going to see that the responses remain profound and durable. While the safety, hopefully, most of them will resolve and be managed well. And if we continue down that path, we will, as you say, also continue to explore the dose levels and so forth.

我認為我們接下來會繼續擴大這些劑量水平下的患者數量。我們會繼續評估腫瘤活性和安全性，並希望看到療效能保持顯著且持久。至於安全性問題，希望大多數問題都能解決並妥善控制。如果我們繼續沿著這條路走下去，正如您所說，我們也會繼續探索其他劑量水平等等。

But the level of tumor activity, and balance by the safety events that we're seeing on doses, are occurring at levels where we think that they could be providing a new standard for benefit risk before this population. I think that it's important to point out and remind everybody, I mean, I said it, but just to say it again, the irAEs were only seen in the patients who had profound antitumor activity. That is, the patients who didn't benefit did not really indicate in terms of higher level irAEs to have significant safety concerns. And that is, of course, what you want to see. But the patients who have the benefit, the safety is limited to those. You're not doing harm to the patients that you're not benefit.

但是，我們觀察到的劑量水平所對應的腫瘤活性和安全性事件之間的平衡，已經達到了我們認為可以為該人群提供新的獲益風險標準。我認為有必要指出並提醒大家，我之前已經說過，但為了再次強調，免疫相關不良事件（irAEs）僅出現在具有顯著抗腫瘤活性的患者中。也就是說，未獲益的患者並沒有出現更高程度的irAEs，因此沒有表現出明顯的安全性問題。這當然是我們希望看到的。獲益的患者，其安全性也僅限於這些患者。你不會對未獲益的患者造成傷害。

Okay. I guess, we're ready for the next question.

好的。我想，我們可以開始下一個問題了。

Thanks, George.

謝謝你，喬治。

Bella, next question, please.

貝拉，請問下一個問題。

Your next question comes from Tyler Van Buren from Cowen.

你的下一個問題來自 Cowen 公司的 Tyler Van Buren。

He must be on mute. We don't hear a question, but maybe we could take the opportunity to amplify you a little further and repeat what George said about the safety M.O. And you would think...

他一定是靜音了。我們沒聽到問題，但或許我們可以藉此機會再補充你的意思，重複喬治關於安全措施的說法。你會覺得…

Can you hear me? Sorry, it's Tyler.

你聽得到我說話嗎？抱歉，我是泰勒。

I wanted to ask about PULSAR and PHOTON, just a follow-up. Can you elaborate on the decision to randomize patients to the 12-week and 16-week arms prior to assessing the response to loading doses? Since patients can only be rescued during that first year or move down in dosing interval and not moved up to a less frequent regimen even though they might be doing well, doesn't this make the comparison to the (inaudible) study is difficult? And given this, how do you expect to communicate the data to the physicians when we see it?

我想就 PULSAR 和 PHOTON 研究再問一個後續問題。您能否詳細說明在評估負荷劑量反應之前，將患者隨機分配到 12 週組和 16 週組的決定？由於患者只能在第一年內進行挽救治療或縮短給藥間隔，而不能即使病情好轉也改為給藥頻率更低的方案，這是否會使與（聽不清楚）研究的比較變得困難？有鑑於此，您打算如何將數據傳達給醫師？

Well, we have to be -- we were somewhat confused by the whole of the business data, and it's meaning its intent. Because of the confusing study design, we're basically only have to see how well patients are doing. You don't shift them. So if you take your best patients and you shift them, for example, to a Q12 or Q16 regimen, and we say, X percent of patient concern this regimen, you're not really understanding how good your drug is and what percent of the patients can actually achieve that dosing regimen. We know, and we've already published on this that patients who do well can be dramatically extended.

嗯，我們必須承認——我們對整個業務數據及其意圖感到有些困惑。由於研究設計令人費解，我們基本上只能觀察患者的療效，而不能改變他們的用藥方案。所以，如果你把療效最好的患者換成Q12或Q16方案，然後我們說X%的患者適合這種方案，你其實並不能真正了解你的藥物療效如何，以及有多少患者能夠真正達到這種給藥方案。我們知道，而且我們已經發表過相關研究，療效好的患者的療程可以顯著延長。

We're trying to answer a very different question, which we think is going to be very, very important to the community, which is where we can truly achieve extended dosing. And whether you can prospectively put people into these dosing regimens and get substantial numbers of them to stay at the dosing regimen. Because we're giving the higher dose of EYLEA, which we believe has this ability to maintain more patients at these longer intervals. So we really believe that this would represent a significant clinical advance and would also clarify how to use these drugs as opposed to the prior somewhat confusing approaches.

我們正在嘗試回答一個截然不同的問題，我們認為這個問題對整個社區至關重要，那就是我們能否真正實現延長給藥間隔。我們能否讓患者接受這些給藥方案，並讓相當一部分患者堅持下去。因為我們使用的是較高劑量的EYLEA，我們相信它能夠幫助更多患者維持更長的給藥間隔。所以我們堅信，這將是一項重大的臨床進展，並且能夠明確這些藥物的使用方法，從而改變之前那些令人困惑的做法。

That's helpful. And just a brief follow-up. On YouTube, if we're going to be able to be...

這很有幫助。還有一個簡短的後續問題。在 YouTube 上，如果我們能夠…

I think we have to move to the next one. I'm sorry, Tyler. Bella, can we go to the next question?

我想我們得進入下一題了。抱歉，泰勒。貝拉，我們能進入下一題嗎？

We'll deal with that privately, Tyler. Sorry.

泰勒，我們會私下處理這件事。抱歉。

Sure. And your next question comes from the line of Salveen Richter from Goldman Sachs.

當然。你的下一個問題出自高盛的薩爾文·里希特之口。

This is Andrea on for Salveen.

這是安德里亞代表薩爾文報道。

Can you walk us how to think about implications from the potential Medicare negotiation provision to high-dose EYLEA given that there is no distinct IP there, but there will be a biosimilar for the regular dose by mid-'24?

鑑於目前沒有獨立的智慧財產權，但到 2024 年中期將出現常規劑量的生物相似藥，您能否為我們解釋一下，潛在的醫療保險談判條款對高劑量 EYLEA 的影響是什麼？

Yes. It's a complicated question that until we see the final language in how it's interpreted and how it's actually implemented, as to whether and how we file for the high dose, whether or not there'll be separate considerations for high dose versus the standard dose EYLEA.

是的。這是一個複雜的問題，在我們看到最終的措辭如何解釋和實際執行之前，我們無法確定是否以及如何申請高劑量，也無法確定高劑量與標準劑量 EYLEA 是否會有不同的考慮。

If there was -- if it turns out that there are -- if it turns out that there are separate -- we get a separate BLA, obviously, you get -- I can't remember what if that says now 11 or 12 years before this comes into play. And based on our current understanding of the bill, we believe that a new BLA would constitute a new biologic product, and therefore, the 8 milligrams would not be subject to price negotiations in years.

如果——如果事實證明確實存在——如果事實證明存在單獨的——我們顯然會獲得一份單獨的生物製品許可申請（BLA），那麼——我記不清法案上寫的是什麼了，如果法案上寫的是11或12年前就生效的話。根據我們目前對法案的理解，我們認為新的BLA將構成一種新的生物製品，因此，這8毫克劑量在未來幾年內將不受價格談判的影響。

But we have to see what the final bill looks like and how it's interpreted. So we're as anxious to see some of that as you or Salveen. So we will keep you informed about thinking as the bill is finalized and starting to be interpreted.

但我們必須先看看最終法案的文本以及它如何被解讀。所以，我們和您以及薩爾文一樣，都迫切地想要了解法案的內容。因此，一旦法案最終定稿並開始被解讀，我們會及時向您通報我們的想法。

Thanks, Len. Bella, next question, please.

謝謝，Len。 Bella，下一個問題好嗎？

Your next question to the line of Matthew Harrison from Morgan Stanley.

你的下一個問題將由摩根士丹利的馬修·哈里森提出。

I was wondering if you could comment maybe a bit more broadly on costims, and how the impact of today's data makes you think about investment in additional tumor types or a broader investment across costims and other combinations?

我想請您就 cosims 做一些更廣泛的評論，以及今天的數據如何影響您對投資其他腫瘤類型或更廣泛地投資 cosims 和其他組合的看法？

That's a great question. I think you bring up a great point. And I think those of us who have been in this field now we're, of course, so excited by the early promise of immunotherapy, checkpoint inhibitors, and particularly PD-1 antibodies. But of course, over the years, it's been recognized that only a small percentage of tumors, even in responding -- even in the most responsive cancers, not all the patients respond and for many tumor classes, as we just saw with Merck's announcement, their failure today, in many classes, there's almost no detectable activity.

這是一個很好的問題。我認為你提出的觀點非常重要。我們這些在這個領域工作的人，當然對免疫療法、免疫檢查點抑制劑，尤其是PD-1抗體的早期前景感到非常興奮。但是，多年來，人們逐漸意識到，即使是反應最好的癌症，也只有一小部分腫瘤有效——並非所有患者都能從中獲益。而且，正如我們今天看到的默克公司所宣布的失敗案例，在許多類型的腫瘤中，幾乎檢測不到任何療效。

So the holy grail in the field that people have been looking for is an answer to the question of how do you activate immunotherapy in all of these cold tumors, Which is, unfortunately, the vast majority of cases, both solid tumors and hemologic malignancies. And so we went down this path based on the science that we could add the second signal, Signal 2, to the first signal that could activate T cells.

因此，該領域人們一直在尋找的終極目標，就是如何激活所有這些「冷腫瘤」（不幸的是，絕大多數病例，包括實體瘤和血液系統惡性腫瘤）的免疫療法。我們基於這樣的科學原理，選擇了這條研究路徑：我們可以在第一個訊號的基礎上添加第二個訊號（訊號2），從而活化T細胞。

And these preliminary data suggest that, that hypothesis might be right, and that we are on the way to this holy grail, that this is, we believe, very early data, we have a long way to go. But it's a spectacular indication that we have done or we are in the midst of doing, on the path doing exactly what we set out to do, which is to turn immunotherapy cold tumors into hot tumors with dramatic antitumor activity. And the implications here based on all the preclinical data suggest that this is going to be broadly applicable.

這些初步數據表明，這個假設或許是正確的，我們正朝著最終目標邁進。當然，我們認為這些數據還處於非常早期的階段，我們還有很長的路要走。但這無疑是一個令人振奮的跡象，表明我們已經或正在朝著既定目標穩步前進，那就是將免疫療法「冷腫瘤」轉化為具有顯著抗腫瘤活性的「熱腫瘤」。基於所有臨床前數據，這些發現表明，這種方法將具有廣泛的應用前景。

And as you all know, we have been developing a very broad costimulatory pipeline across many, many tumor classes, and several of them are already in the clinic. I mentioned we have the prostate data. We have ongoing studies with a costim for ovarian cancer. We have other costims that are in the clinic for -- and we have other costims that are going to be entering into the clinic over the next short period of time. These are going to cover all sorts of cancers from the lung cancers that don't respond to hematologic malignancies, and so forth and so on.

如大家所知，我們一直在開發針對多種腫瘤類型的廣泛共刺激藥物研發管線，其中一些已經進入臨床試驗階段。我剛才提到過，我們已經掌握了攝護腺癌的數據。我們正在進行一項針對卵巢癌的共刺激藥物研究。我們還有其他一些共刺激藥物正在臨床試驗中，在未來一段時間內，我們還有一些共刺激藥物將進入臨床試驗。這些藥物將涵蓋各種癌症，包括對血液系統惡性腫瘤無反應的肺癌等等。

So we really think that this could be groundbreaking and taking immunotherapy now to the next level where all of us in the field, we're hoping it was going to go with the early advances with checkpoint inhibitors, and have been frustrated over the, obviously the last decade or so that we haven't been able to get there. This may be the way we get there for the field. We've a very broad pipeline of costimulatory bispecifics.

因此，我們真心認為這項技術可能具有突破性意義，能夠將免疫療法推向新的高度。我們這個領域的所有人都希望它能像早期免疫檢查點抑制劑一樣取得突破，但在過去十年左右的時間裡，我們一直未能如願，這讓我們感到非常沮喪。這項技術或許能為我們帶來突破。我們擁有非常廣泛的共刺激雙特異性抗體研發管線。

By the way, we believe this validates the concept of the combinations, not only with Libtayo and the PD-1 class, but also with our CD3 class of bispecifics because it suggests that the preclinical data, which is so strongly supported now with this clinical data, might also be very predictive for that class. So a lot of exciting possibilities across very broad areas, diverse solid tumor hematological malignancies. This is, I think, could represent the next breakthrough for immunotherapy.

順便一提，我們認為這驗證了聯合療法的概念，不僅適用於Libtayo和PD-1類藥物，也適用於我們的CD3類雙特異性抗體，因為它表明，目前臨床數據已強有力地支持了臨床前數據，而這些臨床數據也可能對該類藥物具有很強的預測性。因此，在非常廣泛的領域，包括各種實體腫瘤和血液系統惡性腫瘤，都存在著許多令人興奮的可能性。我認為，這可能代表著免疫療法的下一個突破。

Yes. And Matt, it's Len. Let me just add to what George said.

是的。還有，馬特，是倫。我補充一下喬治剛才說的話。

In terms of the investment side, we're prepared and we're able to make the investment across many different areas that George is talking about. And having under one roof all the agents, owning all of Libtayo, having the variety of costims, having a variety of the CD3 bispecs and having all that knowledge, we think -- and the ability to invest puts us in a really terrific position. It is early going. We have to work through the safety.

就投資方面而言，我們已經做好準備，並且有能力在喬治提到的許多不同領域進行投資。我們擁有所有代理商，擁有Libtayo的全部股份，提供各種客製化服務，提供各種CD3雙語服務，並掌握所有這些知識，我們認為——再加上投資能力，使我們處於非常有利的地位。現在還處於早期階段，我們需要克服安全隱患。

But to me, it's sort of reminiscent of once you start to see the excitement around the CAR T cells. And the CAR T cells actually provide a pretty good lesson in that they give very high levels of activity, response rate, 75% in some tumors are higher. And when you get those very high response rates, you also got very high levels of these immune reactions. You had -- and you look at the labels, you'll see 25% grade 3 neurologic adverse events and a whole bunch of other, not to mention, all the cytokine release syndrome.

但對我來說，這有點像當初CAR-T細胞療法風靡一時的時候。 CAR-T細胞療法確實給我們上了一課，它們活性很高，有效率也很高，某些腫瘤的有效率甚至高達75%。但高有效率也伴隨著高水準的免疫反應。看看說明書，你會發現25%的患者會出現3級神經系統不良事件，以及其他一系列不良反應，更不用說細胞激素釋放症候群了。

So I think that this is sort of an equivalent stage. We've got this tiger by the tail, I really believe, and George has described it well. And the amazing thing that should be echoed is that the preclinical data was extremely valuable.

所以我認為這和之前的情況類似。我們就像抓住了老虎的尾巴，我真的這麼認為，喬治也描述得很好。還有一點非常重要，那就是臨床前數據極為寶貴。

So Regeneron is not a company that just has all these molecules that we've acquired from others. These are home-going molecules, home tested, home validated, et cetera. There's a whole collection. We couldn't be more excited. I could keep going on, but maybe I'm getting waved off. We should take the next question.

所以，Regeneron 不是一家只擁有從其他公司收購的分子的公司。這些都是我們自主研發、測試、驗證等等的分子。我們擁有一個完整的分子庫。我們無比興奮。我還可以繼續說下去，但也許該結束了。我們應該回答下一個問題了。

No. I just want to add and build on what Len said.

不，我只是想補充和完善Len所說的內容。

I think just like you said, in some ways, the CAR Ts in terms of high efficacy, particularly in hematologic malignancies, because that's where it's seen. High efficacy seen along with the AEs in terms of the responding patients. That's a good analogy. But I do have to point out the many differences.

我覺得就像你說的，在某些方面，CAR-T療法確實療效顯著，尤其是在血液系統惡性腫瘤方面，因為這類療法最常用於治療這些疾病。療效顯著的同時，不良反應也較少，與緩解患者的療效相符。這是一個很好的類比。但我必須指出兩者之間存在著許多差異。

These are off-the-shelf reagents, okay, which God forbid, if there is a safety issue, it can be stopped. And it's much easier as we're already demonstrating to create a whole pipeline across a whole variety of broad cancers. And unlike the CAR T world right now anyway, these are dramatic effects in solid tumors, which were never really seen before by any other modality.

這些都是現成的試劑，萬一出現安全問題，可以立即停止使用。而且，正如我們已經證明的那樣，這更容易建立針對多種癌症的完整治療方案。與目前的CAR-T療法不同，這些試劑在實體腫瘤中展現出顯著療效，這是其他任何療法都從未達到的。

So this is actually pretty exciting. There are analogies there in terms of dramatic efficacy, but also very important differences here that establish this as a potential breakthrough new class.

所以這確實令人振奮。雖然在顯著療效方面存在相似之處，但也存在一些非常重要的差異，這些差異使之成為潛在的突破性新類別。

Okay. Thank you, George and Len. Next question, please, Bella.

好的。謝謝喬治和萊恩。貝拉，請問下一個問題。

Sure. Your next question comes from the line of Chris -- Tim Anderson with Wolfe Research. .

當然。你的下一個問題來自克里斯——沃爾夫研究公司的提姆·安德森。

A question on the 5, 6, 7, 8 data. You report out one CR, but no other response rate data using RECIST criteria. So I'm wondering if there's anything else you can say about tumor shrinkage beyond that one CR in those upper 3 cohorts?

關於第5、6、7、8組數據，我有個問題。您報告了一例完全緩解（CR），但沒有提供其他基於RECIST標準的緩解率數據。所以我想知道，除了這例CR之外，您能否就上述三個隊列中的腫瘤縮小情況提供其他資訊？

And then to clarify, you mentioned a hosted grade 3 AEs in the press release. And some of those, to me, don't seem like the classic immune-related AEs. So are you -- I'm hoping you can clarify which of those you consider to be irAEs, maybe you consider all of them to be?

另外，我想澄清一下，您在新聞稿中提到了3級不良事件。在我看來，其中一些似乎是非典型的免疫相關不良事件。所以，您—我希望您能澄清一下，您認為哪些屬於免疫相關不良事件（irAE），或者您認為所有都屬於？

I think we've given a lot of detail, and we're going to be giving a lot more details, obviously, in the upcoming meetings.

我認為我們已經提供了很多細節，而且顯然，在接下來的會議中，我們將提供更多細節。

Suffice it to say that as I mentioned, for most of these patients actually, or many of these patients, they don't have lesions outside of the bone, which is why we use PSA as the indicator of total disease activity because you don't have that many lesions, okay? So that's the end point of why we're focusing on the PSA.

簡而言之，正如我之前提到的，實際上對於大多數患者，或者說很多患者來說，他們的病灶並不在骨骼之外，這就是為什麼我們使用PSA作為疾病整體活動的指標，因為病灶並不多，明白嗎？所以這就是我們關注PSA的最終原因。

We do believe that many of the irAEs are the sort of irAEs that you do see with both PD-1 therapy, and as Len mentioned, also with CAR T therapy. And I think we indicated every single grade 3 that we had and indicated that actually, even though these are very early data in the treatment of most of these patients, many of these are actually already resolving or resolved. And we're going to continue to follow these patients and look for, hopefully, as we remember cohort 6, that one patient, the reason we highlighted them is they were the first responding patients, and we've now had almost a year follow-up, and we have this very impressive durability of response there. The other cohorts are much more recently treated, and that's why we're not giving that much follow-up because these are patients who are in the very early months of being treated.

我們相信，許多免疫相關不良事件（irAE）與PD-1療法以及Len所提到的CAR-T療法中常見的irAE類型相同。我們已經指出了所有3級irAE，並指出，儘管這些數據對於大多數患者而言還處於治療初期，但其中許多irAE實際上已經消退或正在緩解。我們將繼續追蹤這些患者，並希望能夠看到，就像我們之前提到的第6組患者一樣，我們之所以重點關注他們，是因為他們是首批獲得緩解的患者，而且我們已經對他們進行了近一年的隨訪，觀察到了非常顯著的療效持久性。其他組別的患者接受治療的時間較短，因此我們沒有進行太長時間的隨訪，因為這些患者仍處於治療的早期階段。

But obviously, you hear it in our voices probably, those of us who have commented. We think this really has the potential to be game changing the field of immunotherapy and taking immunotherapy to the next level, and also game changing for our oncology program and for our company.

但很顯然，從我們這些發表評論的人的語氣中，你們可能已經聽出來了。我們認為這項技術真的有可能徹底改變免疫療法領域，將免疫療法推向新的高度，同時也將徹底改變我們的腫瘤計畫和公司。

Thank you. Bella, the next question, please? I think we have time for 2 more.

謝謝。貝拉，下一個問題可以嗎？我想我們還有時間再問兩個問題。

All right. question comes from the line of Chris Raymond from Piper Sandler.

好的。這個問題出自克里斯雷蒙（Chris Raymond）在派柏桑德勒（Piper Sandler）電影中的一句台詞。

Maybe back to EYLEA in the high-dose format for a second. So our checks have indicated a pretty good chunk of Vabysmo patients are actually EYLEA patients, and specifically, EYLEA patients who are on a higher frequency dose regimen. I guess maybe a 2-part question here.

或許我們可以再回到高劑量方案的EYLEA上來討論一下。我們的調查顯示，相當一部分Vabysmo患者其實也是EYLEA患者，尤其是那些接受高頻率給藥方案的EYLEA患者。我想這裡可能包含兩個問題。

First, maybe talk about the plan to sort of mitigate this either before the high dose format or even after? And I guess is the plan with the high dose, one would expect that switching paradigm for the high-dose EYLEA would be easier than Vabysmo? Is that sort of part of the plan?

首先，或許可以談談在採用高劑量方案之前或之後，如何緩解這個問題？我猜想，如果採用高劑量方案，人們會認為高劑量EYLEA的模式轉換應該比Vabysmo更容易吧？這是否是計劃的一部分？

And then the second part is our checks also indicate surprisingly low awareness of this high dose format among docs. Are these signals at odds with what you're seeing? Or is that correct? And outside of actually just having the data presented.

其次，我們的調查也顯示，醫師們對這種高劑量給藥方式的認知度出奇地低。這些跡象與您觀察到的情況相矛盾嗎？還是說情況確實如此？除了提供數據之外，還有其他需要考慮的因素嗎？

(inaudible) -- By the way, we don't market products before they're approved. So it's not surprising that there is a non-awareness of a product that's an investigational product.

（聽不清楚）－順便說一下，我們不會在產品獲得批准之前就進行市場推廣。所以，人們對一款還在試驗階段的產品缺乏了解也就不足為奇了。

Marion can comment on the...

瑪莉安可以就此發表評論…

Sure. Let me take a start on some of the situation in the market, and perhaps George will add to that.

當然。我先談談目前的市場情勢，或許喬治會補充一些內容。

First, let me comment that obviously, we presented today very strong results on the growth of EYLEA, standard of care in the marketplace both in the U.S. and the worldwide information. Today, in the branded category, U.S. anti-VEGF category, we have 75% of the branded market. We are approaching 50% of the overall market.

首先，我想強調的是，我們今天公佈了安理國際（EYLEA）在美國和全球市場成長的強勁業績，其產品已成為市場上的標準護理產品。目前，在美國品牌抗VEGF藥物市場，我們佔了75%的市場份額，並且正朝著50%的整體市場份額邁進。

So truly, EYLEA is the standard of care. It's probably best that faricimab, organization comment on where their product is being used. I'll comment anecdotally that early days, the response has been fairly muted, fairly low-grade use in concentrated accounts rather than market wide.

所以，EYLEA 確實是治療標準。最好還是讓 faricimab 的生產商來評論一下他們的產品在哪些地方使用。就我個人經驗而言，早期市場反應相當平淡，使用範圍也較有限，主要集中在少數客戶，而非整個市場。

As for the future, we're very excited and optimistic that the aflibercept 8 milligram will represent a new standard of care with true durability of dosing and the same type of efficacy and safety that we see with EYLEA. So we're really excited. And certainly, our clinical organization has put together trial designs to truly test the durability of the product, and then we'll allow the commercial organization to determine what the best strategy is for launch if and when we get FDA approval.

展望未來，我們非常興奮和樂觀地認為，8毫克阿柏西普將代表一種新的治療標準，具有真正的劑量持久性，並且療效和安全性與EYLEA相當。因此，我們感到非常振奮。當然，我們的臨床團隊已經制定了試驗方案，以真正檢驗該產品的持久性，之後，我們將委託商業團隊在獲得FDA批准後，確定最佳的上市策略。

All right. Let me just add to that, that it's important to point out that the reason why EYLEA has become the leading anti-VEGF agent, branded VEGF agent, is because it allows most of the EYLEA patients to go on longer interval dosing and have -- and be very satisfied with the response.

好的。我還要補充一點，需要指出的是，EYLEA之所以成為領先的抗VEGF藥物（品牌VEGF藥物），是因為它可以讓大多數EYLEA患者進行更長時間的給藥間隔，並且對療效非常滿意。

Now of course, as with any disease and situation, not every patient is going to do perfectly well. And we know that there's a small percentage of patients, who do need more frequent EYLEA. And of course, if one has a new untested agent that doctors haven't seen, their hope in the place that they would first try in the small percentage of patients who don't -- who are not doing well. And of course, that's why it's being used in that setting.

當然，任何疾病和情況都是如此，並非所有患者都能完全康復。我們知道，有一小部分患者需要更頻繁地使用EYLEA。當然，如果有一種未經檢驗的新藥，醫生們從未見過，他們就會寄望於先在少數病情進展不佳的患者身上嘗試。當然，這就是為什麼這種新藥會用於這種情況的原因。

Now our goal scores with the high dose of EYLEA is to take now the best-in-class agent and hopefully produce even better results in terms of allowing the small percentage of patients, who are being dosed more frequently or even the patients who are now on 8-week regimen or 12-week regimen to go to more extended regimen, and that's the whole point of the design in the study.

現在，我們使用高劑量 EYLEA 的目標是，利用目前最好的同類藥物，希望能夠取得更好的效果，使少數接受更頻繁給藥的患者，甚至目前接受 8 週或 12 週療程的患者，能夠接受更長時間的療程，而這正是該研究設計的全部意義所在。

So I don't think there's any surprises that it's a small percentage of very hard-to-treat patients where somebody would try an untested agent that they're hoping might work better. But we have a real logical rational way that we are now taking EYLEA, bringing forth this high-dose formulation and hope to extend the benefits that we're already seeing with this tried and true in terms of both safety and efficacy reagent, and even expand it and get even for the small percentage of patients longer dosing and even extend maybe everybody else.

所以，我認為，只有極少數難治性患者會嘗試未經檢驗的藥物，希望效果更好，這並不令人意外。但我們現在採取了一種非常合乎邏輯的合理方法，即研發 EYLEA，推出這種高劑量配方，希望能夠延續這種久經考驗、安全性和有效性都已得到驗證的藥物的益處，甚至擴大其應用範圍，使少數患者能夠延長用藥時間，並可能惠及所有其他患者。

Okay. Thanks, George. Bella, last question, please.

好的。謝謝你，喬治。貝拉，最後一個問題。

Sure. And your last question comes from the line of Carter Gould with Barclays.

當然。你最後一個問題來自巴克萊銀行的卡特古爾德。

I guess now that you fully own sort of Libtayo, can you update us on kind of where you stand on a subcutaneous formulation, given what we've seen data from some of your competitors there and the importance of that to kind of keep pace?

我想既然您已經完全擁有了 Libtayo，鑑於我們從一些競爭對手那裡看到的數據以及保持競爭力的重要性，您能否向我們介紹一下您在皮下製劑方面的立場？

And I guess, looking down the road, then can you talk about the feasibility of potentially co-formulating Libtayo with one of these bispecifics -- costimulatories? And if that's even feasibly possible, recognizing it's a ways away?

那麼，展望未來，您能否談談Libtayo與這些雙特異性抗體（即共刺激劑）之一共同配製的可行性？即便這在技術上可行，也需要時間驗證？

You can imagine we're working on subcu. We'll give you some details, I think, down the road later this year.

您可以想像我們正在研發子晶片。我想，今年晚些時候我們會提供一些細節。

In terms of co-formulation, we have a strong view that if you're doing it for gamesmanship or patent work and all that kind of stuff, that's one thing. But we -- what we're more focused on is getting the optimal dosing and the optimal regimen, and they're not likely to be the same in many of these settings. It's only useful if you're going to try to have a single regimen that covers both.

就聯合製劑而言，我們強烈認為，如果是為了博取眼球或申請專利之類的目的，那是一回事。但我們更關注的是找到最佳劑量和最佳治療方案，而這兩者在許多情況下不太可能相同。只有當你試圖找到一種能夠同時涵蓋兩者的單一治療方案時，聯合製劑才有意義。

So -- but we're a long way from worrying about that. We're far more focused on the fact that we've turned cold to hot, which is a big damn deal, at least in our eyes.

所以——但我們離擔心這還遠。我們現在更關注的是我們已經把冷門變成了熱門，這可是件大事，至少在我們看來是這樣。

And obviously, it hasn't escaped yours or I'm sure anybody's attention that now, with this just appreciated new data where it looks like we're on the way of turning cold tumors to hot in combination with Libtayo, we are, in retrospect, very happy that we now have taken on sole ownership of Libtayo.

顯然，您或我相信任何人都已經註意到，現在有了這些剛剛獲得的新數據，看起來我們正走在將冷腫瘤與 Libtayo 結合使用，從而將冷腫瘤轉化為熱腫瘤的道路上，回想起來，我們非常高興現在我們已經完全擁有了 Libtayo。

Thanks, Len and George, I think that's all we have time for today. Bella, could you please conclude the call?

謝謝Len和George，我想我們今天時間就到此為止了。 Bella，你能結束通話嗎？

Thank you. And this concludes today's conference call. Thank you for your participation. You may now disconnect.

謝謝。今天的電話會議到此結束。感謝您的參與。您可以斷開連線了。