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 Regeneron Pharmaceuticals 2022 年第二季度收益電話會議。我的名字是貝拉，今天我將擔任您的接線員。 （操作員說明）請注意今天的會議正在錄製中。

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

我現在將把電話轉給投資者關係副總裁 Ryan Crowe。你可以開始了。

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.

謝謝你，貝拉。早上好，下午好，晚上好，全世界的每一個人都在聽。感謝您對 Regeneron 的興趣，並歡迎參加我們的 2022 年第二季度收益電話會議。電話會議結束後不久，將在我們的投資者關係網站上提供此網絡廣播的存檔。

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.

今天加入我的是創始人、總裁兼首席執行官 Leonard Schleifer 博士； George Yancopoulos 博士，聯合創始人、總裁兼首席科學官； Marion McCourt，執行副總裁兼商務主管；和執行副總裁兼首席財務官 Bob Landry。在我們準備好發言後，我們將打開問答電話。

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.

我還想提醒您，今天在這次電話會議上發表的言論包括 Regeneron 的前瞻性陳述。此類聲明可能包括但不限於與再生元及其產品和業務相關的聲明——業務、財務預測和指導、開發計劃和相關的預期里程碑、合作、財務、監管事項、付款人覆蓋範圍和報銷問題、智力財產、未決訴訟和其他訴訟和競爭。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的預測存在重大差異。

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.

有關這些和其他重大風險的更完整描述，請參見 Regeneron 向美國證券交易委員會提交的文件，包括其截至 6 月 30 日的季度和 2022 年的 10-Q 表格，該表格於今天上午向美國證券交易委員會提交. Regeneron 不承擔任何義務更新任何前瞻性陳述，無論是由於新信息、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，GAAP 和非 GAAP 措施將在今天的電話會議中討論。有關我們使用非 GAAP 財務指標的信息以及這些指標與 GAAP 的對賬信息，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訪問。

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

一旦我們的電話結束，Bob Landry 和 IR 團隊將可以回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?

有了這個，讓我把電話轉給我們的總裁兼首席執行官 Len Schleifer 博士。倫?

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

謝謝你，Ryan，也謝謝大家加入今天的電話會議。

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.

Regeneron 第二季度表現強勁，在研發、商業和業務開發職能部門的執行情況顯著。剔除我們的 COVID 抗體雞尾酒的貢獻時，總收入增長了 20%，EYLEA、Dupixent 和 Libtayo 的淨銷售額均創下季度新高，並按固定匯率計算同比增長兩位數。

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.

除了出色的商業執行之外，我們還取得了重大的管道進展，獲得了 3 項監管批准、2 項已接受的監管文件和 1 項積極的 III 期讀數。我們還完成了對 Checkmate Pharmaceuticals 的收購，並在第三季度從賽諾菲（Sanofi）收購了 Libtayo 的全球權利，我們相信這兩項都將在近期、中期和長期加強我們的腫瘤學專營權。

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.

我們今天還報告了 REGN5678 的初步但有希望的抗腫瘤活性和安全性數據，我們的 PSMAxCD28 共刺激雙特異性聯合 Libtayo 用於晚期轉移性去勢抵抗性前列腺癌患者。喬治很快將對此發表更多意見，但我們相信這是朝著驗證我們抗擊癌症的共刺激方法和可能推進免疫腫瘤學科學邁出的重要一步。

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.

談到我們的商業表現。第二季度，按固定匯率計算，EYLEA 全球淨銷售額增長 13% 至 25 億美元。在美國， EYLEA 的淨銷售額為 16 億美元，同比增長 14%，超過了大約 8% 的抗 VEGF 類別增長。儘管有新的競爭，EYLEA 的份額約為抗 VEGF 類別的一半，在品牌藥物中佔 75%，肯定了其作為抗 VEGF 治療金標準的地位。

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 毫克的潛力來擴大該類別並補充我們的視網膜專營權，我們認為阿柏西普代表了一個重要的潛在增長機會。

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.

關於我們的研究性阿柏西普 8 毫克，我們臨床計劃的目標是評估與 EYLEA 相比，濕性 AMD 和 DME 患者的視力在哪些方面可以保持或改善，同時延長給藥間隔。同樣重要的是保持 EYLEA 在過去 10 年、全球 5500 萬次注射和 800 萬患者年經驗中設定的高安全標準。我們預計在第 3 季度末或第 4 季度初將取得關鍵成果。借助支持性數據，BLA 提交將於 2023 年初完成。

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.

Dupixent 在 5 年後繼續以驚人的速度增長，自推出以來已治療超過 450,000 名患者。第二季度，全球和淨產品銷售額為 21 億美元，按固定匯率計算比去年增長 43%，這反映了 Dupixent 的差異化臨床特徵和有效治療越來越多 Dupixent 所在的 2 型炎症性疾病患者的能力得到正式認可的。在美國，我們看到了所有適應症的增長，包括 6 個月至 5 歲患者的特應性皮炎和嗜酸性食管炎的初步貢獻，這兩個適應症都是 FDA 在第二季度批准的適應症，代表了首次批准這些患者的全身治療方案。我們希望在今年晚些時候為 Dupixent 增加第三個一流的適應症，用於治療結節性癢疹，目前 FDA 正在對其進行優先審查。

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.

在腫瘤學領域，Libtayo 2022 年第二季度全球淨產品銷售額按固定匯率計算增長 25% 至 1.41 億美元，其中包括在美國非黑色素瘤皮膚癌適應症和單藥治療非小細胞肺癌推動的 17% 增長。長期以來，我們一直認為，充分釋放腫瘤學機遇的關鍵是通過差異化組合，Libtayo 可能是我們其中許多組合的基礎。這種信念是獲得 Libtayo 全球權利的基礎。

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 的組合，將其與我們的腫瘤學管道中有希望的候選者配對，例如 LAG3抗體 fianlimab 和我們的許多研究雙特異性藥物，以及來自外部合作的候選者。我們繼續在這些 Libtayo 組合方面取得進展，並打算在今年下半年分享我們新興腫瘤學管道的初步數據，喬治將更詳細地討論這些數據。

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-chemo 組合補充 BLA 的審查，我們對 FDA 繼續審查所取得的進展感到高興。然而，我們最近獲悉，與在東歐安排常規臨床試驗滿意度相關的 FDA 旅行並發症可能會將他們的決定推遲到我們 9 月 19 日 PDUFA 日期之後。雖然任何延誤都令人失望，但已經安排了新的現場檢查日期。因此，我們預計審查期不會長期延長，並且我們預計它不會對我們的上市計劃產生有意義的影響（假設 FDA 批准）。我們將繼續與 FDA 積極合作，相信正在進行的審查進展順利，審查的所有其他要素仍在進行中。

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.

關於我們對 COVID-19 的反應，Regeneron 仍然致力於通過開發更多的新型抗體來對抗病毒。我們將繼續與 FDA 合作，為這些抗體建立監管途徑，這可能在保護對 COVID-19 疫苗沒有充分反應的免疫功能低下的個體以及治療口服抗病毒治療的感染患者方面發揮重要作用不適當。

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，當我回顧我們上半年的表現時，我為我們取得的眾多成就感到非常自豪，這些成就只有全球敬業的 Regeneron 員工才能實現。我們一起繼續為有需要的患者提供服務，同時加強公司的基礎，並利用我們的財務實力更好地定位 Regeneron，以實現隨著時間的推移實現可持續增長。

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.

我們對核心產品不斷增長的商業勢頭以及我們在推進管道方面取得的重要進展感到興奮。我們的戰略繼續專注於投資我們的內部研發能力，同時探索使我們能夠充分發揮科學力量的潛在合作。我們對戰略和我們的增長前景以及我們為患者帶來突破和為股東創造價值的能力仍然充滿信心。

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

現在，我將把電話轉給喬治。

Thanks, Len. I will start with ophthalmology.

謝謝，萊恩。我將從眼科開始。

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.

我們期待即將在糖尿病性黃斑水腫和濕性年齡相關性黃斑變性患者中使用阿柏西普 8 毫克的 III 期讀數。 DME 患者中的 PHOTON 和濕性 AMD 患者中的 PULSAR 將測試與目前批准的 EYLEA 2 毫克相比，每 12 週或每 16 週接受 8 毫克劑量治療的患者是否可以在第 48 周達到非劣於最佳矯正視力每 8 週給藥一次。

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.

與其他贊助商的研究不同，在這些研究中，患者被分配到基於負荷階段後疾病活動評估的給藥間隔，參加 PHOTON 和 PULSAR 研究的患者在基線時被隨機分配到 3 個治療組中的 1 個，我們相信這將使我們能夠確定是否可以真正實現劑量劑量。如果研究結果是積極的並且與 EYLEA 建立的高安全標準得以維持，我們認為阿柏西普 8 毫克將代表患者的重大臨床進展，我們的目標是在 2023 年初向美國監管機構備案。

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.

轉移到 Dupixent，該公司在今年第二季度繼續實現了顯著的里程碑。 Dupixent 最近被批准用於治療 6 個月大的特應性皮炎，這使 Dupixent 成為第一個也是唯一一個被批准用於治療從嬰儿期到成年期的特應性皮炎的生物藥物。 Marion 將更多地談論這一點以及我們最近早於預期的 FDA 批准一種全新的胃腸病學適應症，嗜酸性食管炎或 EoE。

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.

自從在成人和 12 歲及以上的青少年中獲得批准以來，我們報告了在 1 歲以下的 EoE 兒科患者中的陽性數據。我們在 1 至 11 歲兒童中進行的 III 期研究達到了主要終點，在 16 週時，68% 的較高 Dupixent 劑量患者和 58% 較低 Dupixent 劑量的患者實現了組織學疾病緩解，而安慰劑組為 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.

在這些年輕患者中很難評估 EoE 症狀，但是，我們還觀察到 EoE 症狀評分的數值改善，在探索性分析中，我們記錄到與較高劑量組相比，年齡百分位數的體重與基線相比增加了 3.1%到0.3%的安慰劑上。這些數據將在今年晚些時候與監管機構進行討論，首先是 FDA。

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.

關於預計在不久的將來批准的新適應症。對於結節性癢疹，我們收到 FDA 的 PDUFA 行動日期為 9 月 30 日，歐盟委員會的決定預計在 2023 年上半年。同樣在明年上半年，我們也期待著第一個慢性阻塞性肺疾病或 COPD 的 Dupixent 研究。

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.

繼續研究 Libtayo 和腫瘤學。正如 Len 所提到的，我們很高興能夠收購賽諾菲在 Libtayo 的股份，從而獲得 PD-1抑製劑審查的全球獨家權利，作為我們腫瘤學特許經營權的基礎，該特許經營權有可能與我們管道中的其他候選人進行多種組合例如我們的共刺激雙特異性藥物、我們的 CD3 雙特異性藥物和新型檢查點抑製劑，例如 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.

關於這種組合，我想簡要介紹一下我們的共刺激管道中的第一個臨床數據，其中涉及 REGN5678，我們的 PSMAxCD28 共刺激雙特異性，與 Libtayo 相結合。這種組合正在晚期轉移性去勢抵抗性前列腺癌患者中進行研究，這些患者之前在多種抗雄激素治療方面取得了進展。不幸的是，這些患者預後不良，預期壽命約為 1 至 2 年，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，並且對免疫檢查點抑製劑有很大的抵抗力，PD-1抗體的大型試驗顯示單一療法的反應率只有個位數。

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在以標準方式使用的檢查點抑製劑缺乏療效方面的挑戰通過他們在該疾病早期階段的大型 III 期試驗的失敗而得到強調。我們的 costim 計劃旨在創新性地增強對這些類型的冷腫瘤類別（如前列腺癌）的反應性，並從根本上將這些冷腫瘤轉變為熱腫瘤。

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.

我提醒您我們已發表支持這一假設的大量臨床前數據。自 2019 年以來，我們一直在與 FDA 密切合作，為這個前列腺癌項目謹慎增加劑量。在我們的研究中，患者每 3 周用 Libtayo 每週服用一次 REGN5678。然而，第一劑 Libtayo 直到第 4 週才共同給藥，允許一段時間的 PSMAxCD28，從而評估單藥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 33 名患者的 8 個劑量水平的第一個臨床數據，這些數據顯示出劑量依賴性的抗腫瘤活性。該研究的關鍵療效終點是客觀反應率，定義為前列腺特異性抗原或 PSA 從基線和/或腫瘤縮小下降超過 50%。 PSA 是一種由前列腺和前列腺腫瘤產生的蛋白質，最常用作診斷和隨訪前列腺癌的生物標誌物，因為許多轉移性去勢抵抗性前列腺癌患者的疾病僅限於骨病變，無法通過以下方式評估傳統的 RECIST 標準。

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.

來自 8 個劑量水平隊列的正在進行的劑量遞增部分試驗的初步數據顯示，共有 33 名患者的劑量依賴性抗腫瘤活性由 5 個最低劑量水平的 PSA 值評估，我們的臨床前模型預測這可能是亞治療性的。幾乎沒有任何抗腫瘤活性的證據，17 名患者中只有 1 名顯示 PSA 降低。這些劑量不存在大於或等於 3 級免疫相關不良事件或 irAE。這些患者缺乏抗腫瘤活性與其他抗 PD-1 單藥治療試驗中報告的大約 6% 的反應率一致。

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 3 個劑量水平，我們開始看到明顯的劑量依賴性抗腫瘤活性證據，這通常在開始聯合治療的 6 週內看到。根據 RECIST 標準，在劑量水平 6 時，4 名患者中有 1 名 PSA 下降 100%，靶病灶完全緩解。由於 3 級與免疫相關的皮膚不良事件，患者停止了治療。這被認為是先前存在的疾病的複發，並且根據研究人員的報告已經通過治療解決了。儘管治療終止，他的 PSA 仍保持 100% 的下降，並且根據研究者的報告，迄今為止，靶病變的完全緩解時間約為 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.

我們繼續在下一個劑量水平或第 7 劑量水平看到抗腫瘤活性。在我們的第 8 次和最近的劑量水平中，4 名患者中有 3 名 PSA 顯著和快速降低，2 名降低超過 99%，1 名 82 ％ 減少。在 PSA 降低超過 99% 的 2 例患者中，1 例經歷了 3 級黏膜炎，已經消退，另一例經歷了 3 級急性炎症性脫髓鞘性多發性神經根病，目前仍在進行中。

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.

在安全性方面，非常重要的是，在沒有抗腫瘤活性的患者中未觀察到 3 級或更高級別的 irAE。並且irAEs的發生與抗腫瘤活性相關。這與之前的抗 PD-1 免疫療法試驗一致，其中據報導 irAE 在有反應的患者中發生率更高。迄今為止，在試驗中未觀察到 4 級 irAE 或大於或等於 2 級細胞因子釋放綜合徵。

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.

有一名死亡被認為與治療無關。在這項試驗中，irAE 正在根據用於檢查點抑製劑的標準管理實踐進行治療。我們計劃在即將召開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.

讓我提醒您，通過廣泛的臨床前研究，我們假設在抑制 PD 的同時增加 T 細胞共刺激可能是使免疫冷腫瘤變熱的關鍵。我們的 PSMAxCD28 共刺激雙特異性藥物的這些初步數據提供了第一個臨床證據，支持我們在多種實體瘤和血液系統惡性腫瘤中更廣泛的共刺激雙特異性藥物管道的前景。通過將這些共刺激雙特異性藥物與 Libtayo 或我們的 CD3 雙特異性藥物相結合，我們有機會創造新的治療協同作用來解決一些最難治療的癌症。我們期待與腫瘤學界合作開展這項雄心勃勃且可能具有開創性的工作。

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.

除了這些令人興奮的早期數據外，我們預計下半年會有幾個重要的腫瘤學里程碑。在即將舉行的 ESMO 會議上，我們將在轉移性黑色素瘤的 II 期隊列中提供 fianlimab 的最新信息，我們的 LAG3抗體與 Libtayo 組合，有望證實我們之前在此環境中報告的令人鼓舞的聯合療效。此外，我們將提供 ubamatamab 的初步數據，我們的 MUC16xCD3 雙特異性在轉移性卵巢癌中，我想提醒您，我們還正在進行與共刺激雙特異性和 Libtayo 的組合研究。我們還將報告我們的 METxMET 雙特異性治療晚期 MET 改變的非小細胞肺癌以及新輔助皮膚鱗狀細胞癌 Libtayo 單藥治療的初步數據。

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.

繼續我們的血液學管道。 Odronextamab 有可能成為第一個被批准用於兩種主要類型的晚期 B 細胞淋巴瘤的 C20xCD3 雙特異性，即濾泡性淋巴瘤和瀰漫性大 B 細胞淋巴瘤。根據一組患者的中期數據，我們最近修改了升壓方案。我們認為，對於這類雙特異性藥物，在濾泡性淋巴瘤和瀰漫性大 B 細胞淋巴瘤中，odronextamab 可能具有最低的 3 級或更高級別細胞因子釋放綜合徵的發生率，同時仍保持先前報導的療效概況。我們期待著提供這些更新的數據，並可能在今年下半年提交這兩種適應症的 BLA，等待 FDA 的反饋。

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.

我們還計劃在今年年底前分享我們在復發或難治性多發性骨髓瘤中的 BCMAxCD3 雙特異性研究的更新數據。在等待監管反饋的情況下，我們計劃在 2023 年提交監管部門批准。一項針對多發性骨髓瘤的綜合性研究，結合各種標準護理產品和研究候選人調查 BCMAxCD3，現已開放註冊，同時我們計劃在早期啟動一項額外研究今年晚些時候出現多發性骨髓瘤。

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，我們的腫瘤學管道的創新步伐已經加快，以 Libtayo 為基礎，數據讀出了歷史上對免疫療法沒有反應的癌症適應症的新機制，包括我們的 Regeneron Genetics 藥物合作繼續推進我們的管道和發現引擎。我們與 Alnylam（一種非酒精性脂肪性肝炎或 NASH）的 siRNA 合作包含針對各種目標的候選產品，包括 Regeneron 遺傳學中心發現的那些。 ALN-HSD 的第一個 NASH 數據預計將於今年秋季發布。我們將在今年晚些時候將第二個目標 PNPLA3 推進臨床，我們最近確定了 NASH SIP 的另一個新的有希望的目標。

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.

正如我們剛剛在《新英格蘭醫學雜誌》上發表的那樣，我們發現非常罕見的 SIP 功能喪失變異體與肝病風險降低之間存在前所未有的關聯。在有史以來最大的關於肝病保護的關聯研究中，患有 SIP 軸承功能喪失的個體患非酒精性脂肪性肝病的風險降低了約 53%，患非酒精性肝硬化的風險降低了約 54%。 Regeneron 和 Alnyam 正在開發 siRNA 治療候選藥物，以推進臨床。

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

有了這個，我會把電話轉給 Marion。

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.

謝謝你，喬治。 Regeneron 的商業業務實現了又一個強勁的季度，展示了我們品牌的持續增長。我們正在利用包括 EYLEA、Dupixent 和 Libtayo 在內的在線品牌的勢頭，並通過新的和預期的未來發布來加速我們產品組合的潛力。

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.

讓我從 EYLEA 開始。第二季度全球淨銷售額按固定匯率計算同比增長 13% 至 25 億美元。在美國，EYLEA 的淨銷售額超過 16 億美元，同比增長 14%，這是由處方需求推動的，強勁的需求持續到第三季度。 EYLEA 的同比增長顯著超過了該類別，獲得了競爭份額，並進一步增強了 EYLEA 作為視網膜疾病首選抗 VEGF 藥物的地位。我們繼續看到基於患者流量和新患者開始的持續增長，持續的人口趨勢，如人口老齡化和糖尿病支持的流行，預計在可預見的未來中到高個位數的類別增長。

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.

在糖尿病眼病方面，診斷率的提高也推動了 EYLEA 的強勁增長，自推出以來全球注射量超過 5500 萬次，僅在美國，2022 年第二季度的注射量就超過 100 萬次。醫生繼續認可並偏愛 EYLEA 的差異化有效性和安全性概況。我們有信心在長期內繼續鞏固我們的領導地位。

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 FDA 批准之前，EYLEA 有潛在的增量機會，包括將糖尿病視網膜病變的給藥間隔延長至 16 週，以及治療患有早產兒視網膜病變的早產兒。此外，我們的 aflibercept 8 毫克研究計劃獲得了視網膜社區的極大熱情，並有可能顯著增強抗 VEGF 治療範式。

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.

現在轉向Libtayo。第二季度全球淨銷售額按固定匯率計算增長 25% 至 1.41 億美元，美國淨銷售額為 9100 萬美元。 Libtayo 在所有批准的適應症中繼續增長，包括非黑色素瘤皮膚癌，其中 Libtayo 是領先的免疫療法治療。在單藥治療非小細胞肺癌中，我們正在增加更多處方者的使用率。我們已準備好接受潛在的化療組合批准，這將顯著擴大 Libtayo 治療肺癌的患者機會和醫生選擇。

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.

Regeneron 對 Libtayo 的完全所有權為我們當前和未來的腫瘤學產品組合提供了許多令人興奮的機會。主要思想領袖認識到我們對腫瘤學的日益承諾以及對 Libtayo 組合在許多癌症適應症中有意義地提高護理標準的潛力的高度興趣。我們正在採取審慎的方法來擴大我們在主要國際市場的全球商業足跡，以最大限度地提高我們的創新對患者和再生元的影響。這些能力和基礎設施將支持 Libtayo，並隨著時間的推移支持未來的藥物。

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.

現在轉向 Dupixent。第二季度，全球 Dupixent 的淨銷售額按固定匯率計算同比增長 42% 至 21 億美元。 Dupixent 的表現得益於所有適應症的強勁吸收，最近推出的產品在新疾病、年齡組和地區表現良好。在美國，Dupixent 的淨銷售額增長了 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.

我們繼續擴大 Dupixent 作為特應性皮炎一線全身治療的領導地位。在中度和重度疾病範圍以及各個年齡組中，對 Dupixent 的需求都很旺盛。隨著最近在 6 個月大的兒童中獲得批准，Dupixent 是第一個也是唯一一個被批准用於治療從嬰儿期到成年期的中度至重度特應性皮炎的生物藥物，並且在我們最年輕的患者中的推出是基於啟動的一個非常好的開端.

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.

我們還準備下個月在結節性癢疹中獲得批准，這是一種皮膚病，大約 75,000 名美國患者沒有 FDA 批准的藥物，並且最需要。在哮喘方面，Dupixent 是過敏症專家和肺病專家開出的第一大生物製劑。由於 Dupixent 的差異化特徵、獨特的作用機制、易於開出廣泛的標籤以及證明的有效性和安全性，我們繼續看到新患者開始和總處方的強勁增長。

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.

在鼻息肉方面，強勁的需求仍在繼續，Dupixent 佔據了大部分市場份額，並增加了來自 ENT 的處方。在嗜酸性食管炎（我們的第一個胃腸病學適應症）中，Dupixent 是唯一獲批用於成人和 12 歲及以上兒童的藥物。早期的啟動指標是有利的，過敏症專家和胃腸病學家都鼓勵採用。此外，我們正在擴大我們的外展範圍，向患者和護理人員宣傳 Dupixent 作為一種新的治療選擇，可提供有意義的症狀緩解。

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.

現在轉向美國以外市場的 Dupixent。在所有跡象的強勁增長的推動下，第二季度的淨銷售額按固定匯率計算增長了 61% 至 5.1 億美元。 Regeneron 繼續擴大我們在主要國際市場的影響力，將 Dupixent 帶給患者。總之，Dupixent 正在改變 2 型炎症性疾病的格局，並在現有適應症和潛在的未來適應症進一步滲透的推動下，具有顯著的增長潛力。

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，我們的商業執行在第二季度取得了可觀的成果，為更多患者帶來了我們改變生活的藥物。我們的在線品牌繼續表現良好，新推出的產品為可持續的長期增長提供了額外的機會。

Now I'll turn the call to Bob.

現在我將把電話轉給 Bob。

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，馬里恩。除非另有說明，否則我今天對 Regeneron 的財務業績和前景的評論將基於非公認會計原則。

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.

由於我們的核心業務保持強勁的增長軌跡，再生元的出色表現在第二季度繼續保持，並且我們利用我們強大的財務狀況完成了兩項業務開發腫瘤學交易。不包括與 COVID-19 抗體雞尾酒相關的全球收入，第二季度總收入同比增長 20% 至 29 億美元，表明我們業務的持續發展勢頭。第二季度每股攤薄淨收益為 9.77 美元，淨收益為 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.

從合作收入開始，從拜耳開始。 2022 年第二季度（美國除外） EYLEA 淨產品銷售額為 8.7 億美元，按固定匯率計算，與 2021 年第二季度相比增長 13%。拜耳合作總收入為 3.58 億美元，其中 3.4 億美元與我們在美國以外的 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.

在 Dupixent 的推動下，賽諾菲在 2022 年第二季度的合作總收入為 6.78 億美元，比上年增長了 55%。

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，我們記錄了與羅氏在美國以外銷售 Ronapreve 相關的 800 萬美元的羅氏合作收入。我們預計在 2022 年第四季度，該合作將產生額外收入。

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.

現在轉到我們的運營費用。研發同比增長 7% 至 6.9 億美元，原因是支持我們不斷擴大的管道的成本增加，部分被 REGEN-COV 的開發成本降低所抵消。 2022 年第二季度，收購的 IPR&D 為 1.97 億美元，其中包括先前披露的與我們收購 Checkmate Pharmaceuticals 相關的 1.95 億美元費用。 SG&A 費用同比增長 14% (sic) [15%] 至 4.18 億美元，這主要是由於與 EYLEA 的增長計劃相關的成本以及為支持我們不斷發展的組織而增加的員工人數。

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.

銷售成本同比下降 73% 至 1.37 億美元，這主要是由於去年 REGEN-COV 的銷售沒有再次發生。最後，2022 年第二季度的有效稅率為 13.6%，而去年為 17%。較低的利率部分與 REGEN-COV 銷售的非重複性有關。

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.

現在轉向現金流和資產負債表。 2022 年年初至今，Regeneron 已產生 24 億美元的自由現金流，到 2022 年第二季度結束時，現金和有價證券減去債務為 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.

我們繼續履行我們的資本配置優先事項。完成我們對 Checkmate Pharmaceuticals 的收購，這是對 Regeneron 歷史上的首次收購，以及對賽諾菲在 Libtayo 的股權的收購。此外，我們在 2022 年第二季度回購了約 4 億美元的股票，使我們截至 7 月的年初至今總額超過 11 億美元。我們仍然是機會主義買家，我們看到我們的股價與我們的內在估值之間存在錯位。

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.

我現在將討論在 Libtayo 交易完成的推動下對我們 2022 年全年指導的更新。我們正在將全年研發費用指引更新至 31 億美元至 32.4 億美元之間，比我們之前的指引增加了 1.7 億美元。大約 1/3 的增長是由 Regeneron 推動的，現在記錄了 Libtayo 的所有研發費用，該費用以前與賽諾菲共享。剩餘的 2/3 反映了自 2022 年第三季度開始我們在抗體合作支出中的全部 50% 份額的記錄。此前，我們在抗體合作費用中的份額僅在發生期間支出了一部分，剩餘份額被添加到抗體協作發展平衡。

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.

我們正在更新全年 SG&A 費用指導，使其在 17.4 億美元至 18.4 億美元之間。更新後的範圍反映了 100% 的 Libtayo 商業費用，這些費用之前與賽諾菲共享，扣除預期的協同效應。

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.

我們還將全年毛利率指引更新為 92% 至 93%。更有利的毛利率是由於取消了之前在這張幻燈片中記錄的賽諾菲在美國 Libtayo 毛利率中的份額。我們今天上午早些時候發布的新聞稿中提供了我們最新的全年指導的完整摘要。

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，讓我強調與 Libtayo 交易相關的 4 個重要的財務建模考慮因素。首先，從 7 月 1 日起，Regeneron 將記錄全球 Libtayo 淨產品銷售額的 100%。我們之前只記錄了美國 Libtayo 的淨產品銷售額。

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、里程碑和特許權使用費將在資產負債表上記錄為無形資產，並在 Libtayo 的使用壽命內通過銷售商品成本進行攤銷。此攤銷費用將不包括在非公認會計原則結果中。

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 20% 的抗體利潤份額來減少抗體開發餘額，而不是之前的 10% 安排。未來的季度開發餘額償還將反映在我們的損益表中，作為我之前在討論修訂的研髮指導時提到的增量抗體研發費用，其餘部分以抗體合作收入的減少形式出現。因此，抗體合作收入的減少將不到我們在抗體利潤中的份額的 20%。由於開發餘額償還的增加，我們預計將縮短全額償還開發餘額的期限，從而導致其他年份的合作利潤出現更早且非常顯著的拐點。

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 交易協議記錄約 5500 萬美元的一次性開發餘額還款，除了我們的常規季度還款外，我們將其記錄為抗體合作收入線中的扣除項。

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 表現良好，我們將繼續對我們的業務進行投資，並在我們強大的財務狀況的支持下推動可持續的長期增長。

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

這樣，我會將電話轉回給 Ryan。

Thank you, Bob.

謝謝你，鮑勃。

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，我們準備好的發言到此結束。我們現在想在隊列中有幾位來電者的情況下打開問答電話。並且為了確保我們能夠解決盡可能多的問題，我們將回答每個來電者的一個問題，然後再轉到下一個問題。

Bella, please go ahead and poll for questions.

貝拉，請繼續調查問題。

(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。祝賀季度和數據。

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?

也許是關於高劑量 EYLEA DME 試驗的問題，尤其是在負荷劑量下，堅持這一點。如果您回到記憶通道，似乎只有在 DRCR 協議之後才使用 5 次加載劑量，因為我找不到任何東西——在歷史上，我們建議您應該使用 5 次加載劑量.你能談談這個嗎？

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?

而且，即使對於標準劑量 EYLEA，第四和第五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。這些都是非常有趣的問題，我將詳細介紹 REGN 的非常具體的點。正如你所指出的，其中許多問題還沒有在面對面的研究中被直接研究過，所以我們可能不得不離線討論其中的一些問題。但正如我所說，需要大量實驗的細節可能會得到解答。

Bella, the next question, please.

貝拉，請下一個問題。

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

您的下一個問題來自 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?

我希望你能擴展 5、6、7、8 的一些後續步驟。你想在額外的 8 組患者中看到什麼，甚至在可能更高劑量的隊列中進入註冊-定向審判？

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。我們顯然對這些早已到來的數據感到非常興奮。眾所周知，我們必須從非常低的劑量開始進行非常謹慎的劑量遞增。但是我們現在看到的劑量水平 6、7 和 8 確實非常令人興奮。

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.

我認為我們要做的是繼續擴大這些劑量水平的患者數量。我們將繼續評估腫瘤活動以及安全性，我們希望我們將看到反應仍然深刻和持久。雖然安全，但希望它們中的大多數將得到解決並得到很好的管理。如果我們繼續沿著這條路走下去，正如你所說，我們還將繼續探索劑量水平等等。

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，腫瘤活動的水平，以及我們在劑量上看到的安全事件的平衡，正在發生在我們認為它們可以為這一人群之前的利益風險提供新標準的水平上。我認為重要的是要指出和提醒大家，我的意思是，我說過，但我再說一遍，irAEs 只見於具有高度抗腫瘤活性的患者。也就是說，沒有受益的患者在更高水平的 irAE 方面並沒有真正表明存在重大的安全問題。這當然是你想看到的。但受益的患者，安全僅限於那些。你沒有對你沒有好處的病人造成傷害。

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

好的。我想，我們已經準備好回答下一個問題了。

Thanks, George.

謝謝，喬治。

Bella, next question, please.

貝拉，下一個問題，請。

Your next question comes from Tyler Van Buren from Cowen.

您的下一個問題來自 Cowen 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。我們沒有聽到任何問題，但也許我們可以藉此機會進一步擴大您的範圍，並重複 George 關於安全 M.O. 所說的話。你會想...

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

你能聽到我嗎？對不起，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?

我想問一下 PULSAR 和 PHOTON，只是一個後續。您能否詳細說明在評估對負荷劑量的反應之前將患者隨機分配到 12 周和 16 週組的決定？由於患者只能在第一年獲救，或者在給藥間隔期間降低，並且即使他們可能做得很好，也不能提高到頻率較低的治療方案，這是否會使與（聽不清）研究的比較變得困難？鑑於此，當我們看到數據時，您希望如何將數據傳達給醫生？

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.

好吧，我們必須——我們對整個業務數據感到有些困惑，這意味著它的意圖。由於令人困惑的研究設計，我們基本上只需要看看患者的表現如何。你不轉移它們。因此，如果您選擇最好的患者，然後將他們轉移到 Q12 或 Q16 方案，我們說，X% 的患者關注這種方案，您並沒有真正了解您的藥物有多好，以及有多少百分比患者實際上可以實現該給藥方案。我們知道，並且我們已經發表了關於表現良好的患者可以顯著擴展的信息。

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.

我們試圖回答一個非常不同的問題，我們認為這對社區來說非常非常重要，這是我們可以真正實現延長給藥的地方。以及您是否可以前瞻性地讓人們接受這些給藥方案並讓大量的人留在給藥方案中。因為我們給予更高劑量的 EYLEA，我們相信它有能力在這些更長的時間間隔內維持更多的患者。因此，我們真的相信這將代表一項重大的臨床進展，並且還將闡明如何使用這些藥物，而不是之前有些令人困惑的方法。

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。只是一個簡短的跟進。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?

我認為我們必須進入下一個。對不起，泰勒。貝拉，我們可以進入下一個問題嗎？

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

我們會私下處理的，泰勒。對不起。

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

當然。你的下一個問題來自高盛的 Salveen Richter。

This is Andrea on for Salveen.

這是 Andrea 在 Salveen 上。

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?

鑑於那裡沒有明顯的知識產權，你能否告訴我們如何考慮潛在的醫療保險談判條款對高劑量 EYLEA 的影響，但到 24 年中期將有常規劑量的生物仿製藥？

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，直到我們看到最終語言如何解釋以及如何實際實施，至於我們是否以及如何申請高劑量，是否會單獨考慮高劑量與標準劑量 EYLEA .

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.

如果有 - 如果事實證明有 - 如果事實證明有單獨的 - 我們得到一個單獨的 BLA，顯然，你得到 - 我不記得如果現在 11 年或 12 年怎麼說在這開始之前。並且根據我們目前對該法案的理解，我們認為新的 BLA 將構成一種新的生物製品，因此，8 毫克將不會在幾年內進行價格談判。

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.

但我們必須看看最終的法案是什麼樣的，以及它是如何解釋的。所以我們和你或 Salveen 一樣渴望看到其中的一些。因此，隨著法案最終確定並開始被解釋，我們會及時通知您有關想法的信息。

Thanks, Len. Bella, next question, please.

謝謝，萊恩。貝拉，下一個問題，請。

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

您對摩根士丹利的 Matthew Harrison 的下一個問題。

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?

我想知道您是否可以更廣泛地評論一下成本，以及今天數據的影響如何讓您考慮對其他腫瘤類型的投資或對成本和其他組合的更廣泛投資？

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。我認為你提出了一個很好的觀點。我認為我們這些現在已經在這個領域工作的人，當然對免疫療法、檢查點抑製劑，尤其是 PD-1 抗體的早期前景感到非常興奮。但是，當然，多年來，人們已經認識到只有一小部分腫瘤，即使是在反應中——即使在最有反應的癌症中，並不是所有的患者都有反應，對於許多腫瘤類別，正如我們剛剛在默克公司的公告中看到的那樣，他們今天的失敗，在許多課程中，幾乎沒有可檢測到的活動。

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，人們一直在尋找的該領域的聖杯是如何在所有這些冷腫瘤中激活免疫療法的問題的答案，不幸的是，絕大多數情況下，實體瘤和血液惡性腫瘤都是如此。所以我們沿著這條路走下去，基於我們可以將第二個信號信號 2 添加到第一個可以激活 T 細胞的信號的科學。

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，這個假設可能是正確的，我們正朝著這個聖杯前進，我們相信，這是非常早期的數據，我們還有很長的路要走。但這是一個驚人的跡象，表明我們已經或正在做的事情，正在做我們打算做的事情，即將免疫療法的冷腫瘤轉變為具有顯著抗腫瘤活性的熱腫瘤。基於所有臨床前數據的影響表明，這將是廣泛適用的。

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.

眾所周知，我們一直在開發一個非常廣泛的共刺激管道，涵蓋許多腫瘤類別，其中一些已經在臨床中。我提到我們有前列腺數據。我們正在進行一項針對卵巢癌的聯合研究。我們還有其他在診所中的成本 - 我們還有其他成本將在接下來的短時間內進入診所。這些將涵蓋來自對血液系統惡性腫瘤無反應的肺癌等各種癌症，依此類推。

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.

所以我們真的認為這可能是開創性的，並且現在將免疫療法提升到一個新的水平，我們在該領域的所有人，我們希望它能夠與檢查點抑製劑的早期進展相一致，並且顯然對在過去十年左右的時間裡，我們無法到達那裡。這可能是我們到達該領域的方式。我們有一個非常廣泛的共刺激雙特異性管道。

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.

順便說一句，我們相信這驗證了組合的概念，不僅與 Libtayo 和 PD-1 類，而且與我們的 CD3 雙特異性類，因為它表明臨床前數據，現在得到了這種臨床的大力支持數據，也可能對該類具有很強的預測性。因此，在非常廣泛的領域，各種實體瘤血液系統惡性腫瘤中存在許多令人興奮的可能性。我認為，這可能代表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，是萊恩。讓我補充一下喬治所說的話。

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.

在投資方面，我們已經做好準備，我們能夠在喬治所說的許多不同領域進行投資。我們認為，在一個屋簷下擁有所有代理商，擁有所有 Libtayo，擁有各種成本，擁有各種 CD3 雙規格並擁有所有這些知識 - 投資能力使我們處於非常好的位置。走的還早。我們必須通過安全工作。

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，這有點讓人想起一旦你開始看到圍繞 CAR T 細胞的興奮。 CAR T 細胞實際上提供了一個很好的教訓，因為它們提供了非常高水平的活性和反應率，在某些腫瘤中，75% 的反應率更高。當你得到那些非常高的反應率時，你也會得到非常高水平的這些免疫反應。你有 - 你看看標籤，你會看到 25% 的 3 級神經系統不良事件和一大堆其他的，更不用說，所有的細胞因子釋放綜合徵。

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.

所以我認為這是一個相當的階段。我們已經抓住了這隻老虎的尾巴，我真的相信，喬治已經很好地描述了它。令人驚奇的是，臨床前數據非常有價值。

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.

因此，Regeneron 並不是一家只擁有我們從其他人那裡獲得的所有這些分子的公司。這些是回家的分子，家庭測試，家庭驗證等等。有一個完整的集合。我們再興奮不過了。我可以繼續說下去，但也許我被甩了。我們應該回答下一個問題。

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

不，我只是想補充一下 Len 所說的話。

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.

我想就像你說的那樣，在某些方面，CAR Ts 在高效方面，特別是在血液系統惡性腫瘤中，因為它是被看到的地方。就響應患者而言，與 AE 一起觀察到的高療效。這是一個很好的類比。但我必須指出許多不同之處。

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.

這些是現成的試劑，好吧，上帝保佑，如果有安全問題，可以停止。而且我們已經證明了創建一條跨越各種廣泛癌症的完整管道要容易得多。無論如何，與現在的 CAR T 世界不同，這些都是對實體瘤的顯著影響，這是以前任何其他方式從未真正看到過的。

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.

所以這實際上非常令人興奮。在戲劇效果方面存在類比，但這裡也有非常重要的差異，將其確立為潛在的突破性新課程。

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

好的。謝謝你，喬治和萊恩。下一個問題，貝拉。

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

當然。您的下一個問題來自 Wolfe Research 的 Chris -- Tim Anderson。 .

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 5、6、7、8 數據的問題。您使用 RECIST 標準報告了一個 CR，但沒有其他響應率數據。所以我想知道在上面的 3 個隊列中，除了一個 CR 之外，關於腫瘤縮小，你還有什麼可以說的嗎？

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?

然後澄清一下，您在新聞稿中提到了託管的 3 級 AE。對我來說，其中一些似乎不像經典的免疫相關 AE。你也是——我希望你能澄清一下你認為哪些是 irAE，也許你認為所有這些都是？

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，很明顯，我們將在即將舉行的會議中提供更多細節。

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.

可以這麼說，正如我所提到的，對於這些患者中的大多數，或者其中許多患者，他們沒有骨外病變，這就是為什麼我們使用 PSA 作為總疾病活動的指標，因為你沒有沒有那麼多病灶，好嗎？這就是我們關注 PSA 的目的所在。

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.

我們確實相信，許多 irAE 是您在 PD-1 療法中看到的那種 irAE，正如 Len 提到的，在 CAR T 療法中也是如此。而且我認為我們指出了我們擁有的每一個 3 級，並指出實際上，儘管這些是大多數這些患者治療的早期數據，但其中許多實際上已經解決或解決了。我們將繼續跟踪這些患者，並希望，正如我們記得第 6 組那樣，有一個患者，我們強調他們的原因是他們是第一批響應的患者，我們現在已經跟踪了將近一年-up，我們在那裡有非常令人印象深刻的響應持久性。其他隊列的治療時間要晚得多，這就是為什麼我們沒有進行那麼多隨訪的原因，因為這些患者處於接受治療的最初幾個月。

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.

但很明顯，你可能從我們的聲音中聽到了，我們這些評論過的人。我們認為這確實有可能改變免疫治療領域並將免疫治療提升到一個新的水平，也有可能改變我們的腫瘤學項目和我們公司的遊戲規則。

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

謝謝你。貝拉，下一個問題好嗎？我想我們還有時間再做 2 個。

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

好的。問題來自 Piper Sandler 的 Chris Raymond。

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.

也許回到高劑量形式的 EYLEA 一秒鐘。所以我們的檢查表明，相當多的 Vabysmo 患者實際上是 EYLEA 患者，特別是接受更高頻率劑量方案的 EYLEA 患者。我想這裡可能是一個兩部分的問題。

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，也許可以談談在高劑量形式之前甚至之後減輕這種情況的計劃？我猜是高劑量的計劃，人們會期望高劑量 EYLEA 的轉換範式會比 Vabysmo 更容易？這是計劃的一部分嗎？

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.

然後第二部分是我們的檢查也表明文檔中對這種高劑量格式的認識出奇地低。這些信號與您所看到的不一致嗎？或者這是正確的？實際上只是呈現數據之外。

(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）——順便說一句，我們不會在產品獲得批准之前銷售產品。因此，人們不知道作為研究產品的產品並不奇怪。

Marion can comment on the...

馬里昂可以評論...

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

當然。讓我先談談市場上的一些情況，也許喬治會補充一下。

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，讓我評論一下，很明顯，我們今天展示了 EYLEA 的增長非常強勁的結果，這是美國市場和全球信息市場的護理標準。今天，在品牌類別，美國抗 VEGF 類別中，我們擁有 75% 的品牌市場。我們正在接近整個市場的 50%。

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.

確實，EYLEA 是護理的標準。最好讓 faricimab 組織評論他們的產品在哪裡使用。我會軼事地評論說，早期的反應相當溫和，在集中賬戶而不是在市場範圍內使用相當低級。

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.

至於未來，我們非常興奮和樂觀地認為，阿柏西普 8 毫克將代表一種新的護理標準，具有真正的給藥持久性以及與 EYLEA 相同的療效和安全性。所以我們真的很興奮。當然，我們的臨床組織已經整合了試驗設計，以真正測試產品的耐用性，然後我們將允許商業組織確定如果我們獲得 FDA 批准的最佳策略是什麼。

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。讓我補充一點，重要的是要指出 EYLEA 之所以成為領先的抗 VEGF 藥物，品牌 VEGF 藥物，是因為它允許大多數 EYLEA 患者進行更長時間的給藥間隔並且具有 -並對反應非常滿意。

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，與任何疾病和情況一樣，並非每個患者都會做得很好。我們知道有一小部分患者確實需要更頻繁的 EYLEA。當然，如果一個人有一種新的未經測試的藥物，醫生還沒有見過，他們希望他們會首先在一小部分沒有這種藥物的患者身上進行嘗試——他們做得不好。當然，這就是它在該環境中使用的原因。

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，我們對高劑量 EYLEA 的目標得分是現在服用同類最佳的藥物，並希望在允許更頻繁給藥的一小部分患者甚至現在的患者方面產生更好的結果採用 8 周方案或 12 周方案進行更長時間的方案，這就是研究設計的重點。

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.

因此，我認為只有一小部分非常難以治療的患者會嘗試未經測試的藥物，他們希望這種藥物可能會更好地發揮作用，這並不奇怪。但是我們有一個真正合乎邏輯的合理方式，我們現在正在服用 EYLEA，推出這種高劑量配方，並希望擴大我們已經看到的這種經過驗證的試劑在安全性和有效性方面的益處，甚至擴大它並為一小部分患者提供更長的劑量，甚至可能延長其他所有人。

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

好的。謝謝，喬治。貝拉，最後一個問題，請。

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

當然。你的最後一個問題來自於 Barclays 的 Carter Gould。

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?

我想現在您完全擁有某種 Libtayo，鑑於我們從那裡的一些競爭對手那裡看到的數據以及跟上步伐的重要性，您能否向我們介紹您對皮下配方的立場？

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?

而且我想，展望未來，您能否談談將 Libtayo 與其中一種雙特異性藥物（共刺激物）共同製定的可行性？如果這甚至是可行的，那麼認識到它還有很長的路要走嗎？

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

你可以想像我們正在開發 subcu。我想，我們會在今年晚些時候給你一些細節。

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.

在共同製定方面，我們有一個強烈的觀點，如果你是為了遊戲技巧或專利工作以及所有類似的東西而這樣做，那是一回事。但是我們 - 我們更關注的是獲得最佳劑量和最佳方案，並且在許多這些環境中它們不太可能相同。僅當您要嘗試使用涵蓋兩者的單一方案時，它才有用。

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——但我們離擔心這個問題還有很長的路要走。我們更關注我們已經變冷變熱的事實，這是一件大事，至少在我們眼裡是這樣。

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，它並沒有逃過你的視線，或者我相信現在有人注意到了，有了這些新數據，看起來我們正在將冷腫瘤與 Libtayo 結合起來，我們正在回想起來，很高興我們現在擁有了 Libtayo 的唯一所有權。

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，我想這就是我們今天的全部時間。貝拉，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.

謝謝你。今天的電話會議到此結束。感謝您的參與。您現在可以斷開連接。