莫德納 (MRNA) 2022 Q4 法說會逐字稿

Good morning, my name is Kevin, and welcome to Moderna's Fourth Quarter 2022 Earnings Call. (Operator Instructions) Please be advised this call is being recorded.

早上好，我叫凱文，歡迎來到 Moderna 的 2022 年第四季度財報電話會議。 （操作員說明）請注意，此通話正在錄音中。

At this time, I'd like to turn the call over to Lavina Talukdar, Head of Investor Relations at Moderna. Please proceed.

此時，我想將電話轉給 Moderna 投資者關係主管 Lavina Talukdar。請繼續。

Thank you, Kevin. Good morning, everyone, and thank you for joining us on today's call to discuss Moderna's Fourth Quarter and Full Year 2022 Financial Results and Business Update. You can access the press release issued this morning as well as the slides that we'll be reviewing by going to the Investors section of our website.

謝謝你，凱文。大家早上好，感謝您參加今天的電話會議，討論 Moderna 的第四季度和 2022 年全年財務業績和業務更新。您可以訪問我們網站的“投資者”部分，訪問今天上午發布的新聞稿以及我們將要審查的幻燈片。

On today's call are Stephane Bancel, our Chief Executive Officer; Stephen Hoge, our President; Arpa Garay, our Chief Commercial Officer; and Jamie Mock, our Chief Financial Officer.

參加今天電話會議的有我們的首席執行官 Stephane Bancel；我們的總裁 Stephen Hoge；我們的首席商務官 Arpa Garay；和我們的首席財務官 Jamie Mock。

Before we begin, please note that this conference call will include forward-looking statements made pursuant to the Safe Harbor provisions of the Private Securities Litigation Reform Act of 1995. Please see Slide 2 of the accompanying presentation and our SEC filings for important risk factors that could cause our actual performance or results to differ materially from those expressed or implied in these forward-looking statements.

在我們開始之前，請注意本次電話會議將包括根據 1995 年私人證券訴訟改革法案的安全港條款作出的前瞻性陳述。請參閱隨附演示文稿的幻燈片 2 和我們向美國證券交易委員會提交的重要風險因素可能導致我們的實際業績或結果與這些前瞻性陳述中明示或暗示的業績或結果存在重大差異。

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

有了這個，我現在將把電話轉給斯蒂芬。

Thank you, Lavina. Good morning or good afternoon, everyone. Welcome to our Q4 2022 conference call. Today, I will start with a quick business review of 2022. Stephen will then review our clinical programs before Arpa gives an update on our commercial progress and plans. Jamie will then present our financial results, and I will come back to share some thoughts on where we're heading.

謝謝你，拉維娜。大家早上好或下午好。歡迎來到我們的 2022 年第四季度電話會議。今天，我將從 2022 年的快速業務回顧開始。然後，在 Arpa 更新我們的商業進展和計劃之前，Stephen 將回顧我們的臨床項目。然後傑米將介紹我們的財務結果，我會回來分享一些關於我們前進方向的想法。

We are pleased to report today revenues of $19.3 billion for fiscal year 2022, GAAP net income of $8.4 billion and GAAP diluted earnings per share of $20.12. Cash and investment balances of $18.2 billion at the end of the year.

我們今天很高興地報告 2022 財年的收入為 193 億美元，GAAP 淨收入為 84 億美元，GAAP 攤薄後每股收益為 20.12 美元。年末現金和投資餘額為 182 億美元。

We continued our disciplined capital allocation policy. We're investing first in our company. In 2022, we invested $3.3 billion in R&D, our highest level of R&D investments ever. We invested $1.1 billion in SG&A and $400 million in capital investments. We made investments in Metagenomi for access to new gene editing enzymes and Carisma in oncology. We announced an investment in CytomX and the acquisition of OriCiro in Japan to continue to streamline our manufacturing processes. And just yesterday, we announced the collaboration with LifeEdit. $3.3 billion were returned to shareholders through a buyback of 23 million shares.

我們繼續執行嚴格的資本配置政策。我們首先投資於我們的公司。 2022 年，我們在研發方面投入了 33 億美元，這是我們有史以來的最高研發投資水平。我們在 SG&A 上投資了 11 億美元，在資本投資上投資了 4 億美元。我們對 Metagenomi 進行了投資，以獲取新的基因編輯酶和腫瘤學領域的 Carisma。我們宣布投資 CytomX 並收購日本的 OriCiro，以繼續簡化我們的製造流程。就在昨天，我們宣布了與 LifeEdit 的合作。通過回購 2300 萬股股票，向股東返還了 33 億美元。

I am proud of the strong results by our team in 2022 as we made history with a number of outstanding accomplishment for patients. In respiratory vaccines, we developed new products with remarkable speed, getting the mRNA-1273.214 against Omicron B1, the strain recommended by WHO, and mRNA-1273.222 against Omicron BA.5, the strain [asked] by the U.S. FDA. We developed 1273.222 in less than 2 months. We're able to protect millions of people from potentially severe disease resulting from new COVID strains.

我為我們的團隊在 2022 年取得的優異成績感到自豪，因為我們為患者創造了多項傑出成就，創造了歷史。在呼吸道疫苗方面，我們以驚人的速度開發新產品，獲得了針對WHO推薦菌株Omicron B1的mRNA-1273.214和針對美國FDA[要求]菌株Omicron BA.5的mRNA-1273.222。我們在不到 2 個月的時間內開發了 1273.222。我們能夠保護數百萬人免受新 COVID 毒株引起的潛在嚴重疾病的侵害。

Our RSV vaccine went from Phase I start to Phase III data in 24 months, and met its primary efficacy endpoint in the Phase III trial. In oncology, our Personalized Cancer Vaccine was the first demonstration of positive results from an mRNA cancer treatment in the randomized clinical trial.

我們的 RSV 疫苗在 24 個月內從 I 期開始到 III 期數據，並在 III 期試驗中達到了其主要療效終點。在腫瘤學方面，我們的個性化癌症疫苗首次在隨機臨床試驗中證明了 mRNA 癌症治療的積極結果。

In rare diseases, our propionic acidemia program showed early positive clinical results in a repeat dose chronic disease setting in reducing metabolic decompensation events in patients. And we announced what we hope will become the first effective inhaled mRNA therapy in humans as our partner, Vertex, entered a Phase I trial using our technology in the therapy for cystic fibrosis patients who lack CFTR protein.

在罕見疾病中，我們的丙酸血症項目在重複劑量慢性病環境中顯示出早期積極的臨床結果，可以減少患者的代謝失代償事件。我們宣布我們希望成為人類第一個有效的吸入 mRNA 療法，因為我們的合作夥伴福泰（Vertex）進入了 I 期試驗，使用我們的技術治療缺乏 CFTR 蛋白的囊性纖維化患者。

Finally, we had our first ESG Day and published our first ESG report, providing additional transparency in how we conduct our business.

最後，我們舉辦了第一個 ESG 日並發布了第一份 ESG 報告，為我們開展業務的方式提供了更高的透明度。

I want to take a moment this morning to touch on transition the Moderna Executive Committee. As we announced in late 2022, Marcello Damiani decided to retire as Chief Digital Officer after more than 7 years with the company. Marcello joined Moderna before our first clinical trial, and we are today, a digital-first company, as a big testament of his ability to scale digital resources. I'm grateful to Marcello for his contribution during the early years of Moderna.

今天早上我想花點時間談談 Moderna 執行委員會的過渡問題。正如我們在 2022 年底宣布的那樣，Marcello Damiani 在為公司工作 7 年多後決定從首席數字官的職位上退休。 Marcello 在我們的第一次臨床試驗之前加入了 Moderna，我們今天是一家數字優先的公司，這充分證明了他擴展數字資源的能力。我很感謝 Marcello 在 Moderna 早期所做的貢獻。

I am excited to have worked already with Brad Miller since early January. Brad brings a wealth of enterprise solution and platform organization experience in several of the top technology companies. This will be instrumental as Moderna scales into a fully-integrated biotechnology company.

我很高興自 1 月初以來就已經與 Brad Miller 合作。 Brad 在多家頂級技術公司擁有豐富的企業解決方案和平台組織經驗。這將有助於 Moderna 擴展為一家完全整合的生物技術公司。

I want to also share with you that Juan Andres, currently President of Strategic Partnership and Enterprise Expansion has informed me of his intention to retire and will be retiring at the end of May. Juan has played a tremendous role since joining Moderna in 2017 from Novartis, where he led all manufacturing for them. Juan served as Moderna's Chief Technology Operations and Quality Officer where he led the manufacturing from an early-stage clinical development company to a commercial company.

我還想與大家分享，現任戰略合作夥伴關係和企業擴展總裁 Juan Andres 已告知我他打算退休，並將於 5 月底退休。自 Juan 於 2017 年從 Novartis 加入 Moderna 以來，他發揮了巨大的作用，在那裡他領導了他們的所有製造。 Juan 曾擔任 Moderna 的首席技術運營和質量官，領導製造從一家早期臨床開發公司轉變為一家商業公司。

I believe Juan did a historic job with his team in 2020 and 2021 to scale Moderna for global commercial launch during the pandemic. It is literally unbelievable that he led the team from having made across our entire portfolio, less than 100 million doses in 2019 to more than 800 million doses in 2021, all during the pandemic. We, and hundreds of millions of people across the globe who received the Moderna COVID-19 vaccine, owe Juan our gratitude. I believe very few manufacturing leaders would have led such an achievement.

我相信 Juan 在 2020 年和 2021 年與他的團隊一起完成了歷史性的工作，在大流行期間擴大了 Moderna 的全球商業發布規模。令人難以置信的是，在大流行期間，他帶領團隊將我們的整個產品組合從 2019 年的不到 1 億劑增加到 2021 年的 8 億多劑。我們和全球數億接種了 Moderna COVID-19 疫苗的人都應該感謝 Juan。我相信很少有製造業領導者能夠取得這樣的成就。

Most recently, Juan has focused on building out our organization to support Moderna's growing pipeline, leading our efforts in producing of personalized cancer vaccine. Jerh, who used to work for Juan at Novartis, has joined us since early fall and has been leading manufacturing since then. I am thankful to Juan, who has ensured a very smooth transition, helping Jerh every step of the way. Upon his retirement at the end of May, Juan's responsibility will transition to Stephen Hoge, President of Moderna, to integrate PCV across all functions, with Jerh leading the manufacturing of PCV for multiple Phase IIIs, and of course, for getting commercial ready.

最近，Juan 專注於建立我們的組織以支持 Moderna 不斷增長的管道，領導我們生產個性化癌症疫苗的工作。 Jerh 曾在 Novartis 為 Juan 工作，自初秋加入我們並一直領導製造業。我很感謝 Juan，他確保了非常順利的過渡，並在每一步都幫助了 Jerh。 5 月底退休後，Juan 的職責將移交給 Moderna 總裁 Stephen Hoge，將 PCV 整合到所有職能部門，而 Jerh 將領導多個 III 期 PCV 的製造，當然，還要為商業化做好準備。

On behalf of the entire Moderna team, I want to thank Juan for his continued leadership and wish him and his wife, Marina, the best of a well-deserved retirement. I am deeply thankful to have counted him for so many years as a partner at Moderna, and more importantly, for more than 20 years as a friend and a mentor. We will miss him.

我代表整個 Moderna 團隊，感謝 Juan 一直以來的領導，並祝愿他和他的妻子 Marina 過上當之無愧的退休生活。多年來，我非常感謝他將他視為 Moderna 的合作夥伴，更重要的是，20 多年來，他一直是我的朋友和導師。我們會想念他的。

The company continues to expand at a rapid pace. We now have 3 commercial COVID-19 vaccine products. We have 4 development programs in Phase III. We have to expand our commercial portfolio very soon. Overall, we have 48 programs underway with a team of 3,900 team members, and now present on the ground in 16 commercial subsidiary across Americas, Europe and Asia Pacific. Our $18 billion of cash balance at the end of the year is enabling us to scale across research, clinical development, manufacturing, commercial and G&A.

公司繼續快速擴張。我們現在有 3 種商用 COVID-19 疫苗產品。我們在第三階段有 4 個開發項目。我們必須盡快擴大我們的商業組合。總體而言，我們擁有一支由 3,900 名團隊成員組成的團隊，正在進行 48 個項目，目前在美洲、歐洲和亞太地區的 16 個商業子公司開展實地工作。我們年底 180 億美元的現金餘額使我們能夠在研究、臨床開發、製造、商業和 G&A 方面進行擴展。

With that, let me now talk to Stephen.

有了這個，讓我現在和斯蒂芬談談。

Thank you, Stephane. Good morning or good afternoon, everyone. Today, I will review our progress against our key clinical programs.

謝謝你，斯蒂芬。大家早上好或下午好。今天，我將回顧我們在關鍵臨床項目方面的進展。

I'll start with our respiratory vaccines. We have approved our Phase III development programs against the big 3 respiratory viruses, COVID-19, RSV and influenza. I'll share some additional data on these in a moment, including some presented this morning on our older adult RSV Phase III trial. We're also advancing a portfolio of next-generation programs against these viruses, including mRNA-1283, which is a next-generation COVID-19 booster that is referred to as rather stable. We also have multiple next-generation flu programs. We seek to increase the breadth of coverage against influenza by adding additional antigens that are not present in currently-available flu vaccines. Lastly, our respiratory portfolio includes a large number of combination vaccines to provide protection against multiple respiratory pathogens which has advantages for many stakeholders, including health care providers, payers and consumers. These include combinations of COVID, flu and RSV, as well as 2 pediatric vaccines that include additional viruses that are important in children, including hMPV and PIV3.

我將從我們的呼吸道疫苗開始。我們已經批准了針對三大呼吸道病毒 COVID-19、RSV 和流感的 III 期開發計劃。稍後我將分享一些關於這些的額外數據，包括今天早上在我們的老年 RSV III 期試驗中展示的一些數據。我們還在推進針對這些病毒的下一代程序組合，包括 mRNA-1283，這是一種被稱為相當穩定的下一代 COVID-19 助推器。我們還有多個下一代流感項目。我們尋求通過添加目前可用的流感疫苗中不存在的額外抗原來擴大流感的覆蓋範圍。最後，我們的呼吸道產品組合包括大量組合疫苗，可針對多種呼吸道病原體提供保護，這對包括醫療保健提供者、付款人和消費者在內的許多利益相關者都有好處。這些包括 COVID、流感和 RSV 的組合，以及 2 種兒科疫苗，其中包括對兒童很重要的其他病毒，包括 hMPV 和 PIV3。

As we prepare for endemic COVID in 2023 and beyond, we wanted to briefly recap the recent VRBPAC committee discussions and recommendations. At the January VRBPAC meeting, the committee voted to harmonize the primary series and booster dose vaccines, which is an important step to simplify future guidance. The FDA also indicated that it expects to convene VRBPAC to determine vaccine strain composition for the '23-'24 season in the second quarter of this year. We believe that our mRNA platform has demonstrated its ability to deliver variant match vaccines on accelerated time horizons, and we believe we are therefore well positioned to deliver whatever composition of the FDA and other public health agencies recommend.

在我們為 2023 年及以後的地方性 COVID 做準備時，我們想簡要回顧一下 VRBPAC 委員會最近的討論和建議。在 1 月份的 VRBPAC 會議上，委員會投票決定統一初級系列疫苗和加強劑量疫苗，這是簡化未來指南的重要一步。 FDA 還表示，預計將在今年第二季度召開 VRBPAC 會議，以確定“23-24”季的疫苗株組成。我們相信我們的 mRNA 平台已經證明了它能夠在加速的時間範圍內提供變異匹配疫苗，因此我們相信我們有能力提供 FDA 和其他公共衛生機構推薦的任何成分。

Now, moving to RSV. As you know, we shared the topline results from our Phase III RSV study in older adults earlier this year. And today, we shared additional data that was presented this morning at RSVVW. The top line results we've seen are incredibly encouraging, and we're grateful to the FDA for breakthrough therapy designation for mRNA-1345, which further emphasizes the significant health impact of RSV in older adults and the high unmet need.

現在，轉向 RSV。如您所知，我們在今年早些時候分享了我們在老年人中進行的 III 期 RSV 研究的主要結果。今天，我們分享了今天上午在 RSVVW 上展示的額外數據。我們看到的最重要結果令人難以置信地鼓舞，我們感謝 FDA 對 mRNA-1345 的突破性治療指定，這進一步強調了 RSV 對老年人健康的重大影響以及未滿足的高需求。

In the top line data presented in January, the mRNA-1345 demonstrated 83.7% vaccine efficacy and the primary endpoint of lower respiratory tract disease with 2 or more symptoms. 1345 was found to be generally well tolerated, and there were no safety concerns identified by the Data and Safety Monitoring Board.

在 1 月份公佈的頂級數據中，mRNA-1345 證明了 83.7% 的疫苗效力和具有 2 種或更多症狀的下呼吸道疾病的主要終點。發現 1345 的耐受性普遍良好，數據和安全監測委員會沒有發現任何安全問題。

In the data presented today at RSVVW, we confirmed that 1345 was well tolerated and has an acceptable safety profile. Solicited adverse reactions were mostly Grade 1 or Grade 2, and to date, most solicited adverse reactions were mild to moderate, with the most common adverse reactions being injection site pain, headache, myalgia and arthralgia. Vaccine efficacy was consistently high across all age groups and in participants with pre-existing comorbidities that are at highest risk.

在今天在 RSVVW 上提供的數據中，我們確認 1345 具有良好的耐受性並且具有可接受的安全性。徵求的不良反應大多為 1 級或 2 級，迄今為止，大多數徵求的不良反應為輕度至中度，最常見的不良反應為註射部位疼痛、頭痛、肌痛和關節痛。在所有年齡組和具有最高風險的既往合併症的參與者中，疫苗效力始終很高。

Please refer to the scientific and medical meetings section of the Moderna Investor Relations website to see the full RSVVW presentation. And we're very encouraged by these data, and look forward to file a Biologics License Application with the FDA in the first half of 2023, as things proceed. With the option of using a priority review voucher, we might see regulatory action on this filing in late 2023 or early 2024.

請參閱 Moderna 投資者關係網站的科學和醫學會議部分，查看完整的 RSVVW 演示文稿。我們對這些數據感到非常鼓舞，並期待隨著事情的進展，在 2023 年上半年向 FDA 提交生物製品許可申請。通過使用優先審查憑證的選項，我們可能會在 2023 年底或 2024 年初看到針對該申請的監管行動。

Now moving to flu. Last week, we shared with you data from our Phase III Immunogenicity and Safety study in the Southern Hemisphere, study P301. In this study, our first-generation vaccine, mRNA-1010, demonstrated superiority on 0 conversion rates for influenza A/H3 and H1 and superiority on geometric mean titers for H3 and non-inferiority on geometric mean titers for H1. MRNA-1010 did not meet non-inferiority on 0 conversion or titers for the 2 influenza B strains.

現在轉向流感。上週，我們與您分享了我們在南半球進行的 III 期免疫原性和安全性研究 P301 的數據。在這項研究中，我們的第一代疫苗 mRNA-1010 在流感 A/H3 和 H1 的 0 轉化率方面具有優勢，在 H3 的幾何平均滴度方面具有優勢，在 H1 的幾何平均滴度方面具有非劣效性。 mRNA-1010 在 0 轉化率或 2 種乙型流感病毒株的效價方面不符合非劣效性。

Our separate Phase III efficacy study in the Northern Hemisphere, study P302, has now accrued over 200 confirmed cases of influenza-like illness, almost all of which are influenza A. Which is expected -- this was expected as the overwhelming majority of influenza burden in older adults is caused by influenza A, including over 95% of hospitalization in the most recent season.

我們在北半球進行的獨立 III 期療效研究 P302 現已累計確診 200 多例流感樣疾病病例，幾乎所有病例都是甲型流感。這是意料之中的——這是預期的絕大多數流感負擔在老年人中，流感是由甲型流感引起的，包括最近一個季節超過 95% 的住院治療。

Now based on the case accrual in P302, we now expect the independent DSMB will review the first interim analysis of efficacy in that study in the first quarter of this year.

現在，根據 P302 中的病例累積，我們現在預計獨立的 DSMB 將在今年第一季度審查該研究中的第一次中期療效分析。

Now let's take a look at our latent vaccines on Slide 14. Our CMV vaccine is in an ongoing Phase III study, and we've begun dosing participants in the Phase I/II adolescent dose-ranging study. Our EBV vaccine to prevent infectious mononucleosis is in Phase I, while our EBV vaccine to prevent long-term sequelae of EBV is in pre-clinical development. We have 2 HIV Phase I trials ongoing, and our HSV vaccine is in preclinical.

現在讓我們看看幻燈片 14 上的潛伏性疫苗。我們的 CMV 疫苗正在進行 III 期研究，我們已經開始對 I/II 期青少年劑量範圍研究的參與者進行給藥。我們用於預防傳染性單核細胞增多症的 EBV 疫苗處於 I 期，而我們用於預防 EBV 長期後遺症的 EBV 疫苗處於臨床前開發階段。我們正在進行 2 項 HIV I 期試驗，我們的 HSV 疫苗處於臨床前階段。

And finally, our VZV program has begun dosing in participants in a Phase I/II study, which I will discuss further on the next slide. The VZV study is a Phase I/II randomized safety and immunogenicity study evaluating mRNA-1468 against Shingrix. This is a relatively large study, enrolling 500 0 negative older adults in multiple doses and dosing intervals, and a 12-month study follow-up. Over 35% of participants will be 70 years and older, which is in line with the largest disease burden of shingles.

最後，我們的 VZV 計劃已經開始在 I/II 期研究的參與者中給藥，我將在下一張幻燈片中進一步討論。 VZV 研究是一項 I/II 期隨機安全性和免疫原性研究，評估 mRNA-1468 對 Shingrix 的作用。這是一項相對較大的研究，以多次劑量和給藥間隔招募了 500 名 0 陰性老年人，並進行了 12 個月的研究隨訪。超過 35% 的參與者將年滿 70 歲，這符合帶狀皰疹的最大疾病負擔。

Now, let's take a look at our therapeutics portfolio on Slide 16, and I'll highlight a few of the programs. We recently reported strong top line data for our personalized cancer vaccine, which I will talk to in a moment. In Immuno-oncology, we are working to address disease burden beyond PCV with our checkpoint and triplet programs, both of which are in Phase I trials in various tumor types.

現在，讓我們看一下幻燈片 16 上的治療產品組合，我將重點介紹其中的一些項目。我們最近報告了我們個性化癌症疫苗的強勁頂線數據，我稍後會談到。在免疫腫瘤學方面，我們正致力於通過我們的檢查點和三重計劃來解決 PCV 以外的疾病負擔，這兩個計劃都處於針對各種腫瘤類型的 I 期試驗。

In rare diseases, our Phase I/II PA program continues to enroll patients and we are looking forward to selecting a dose of the expansion arm. I'll provide a brief update on that in just a moment.

在罕見疾病方面，我們的 I/II 期 PA 計劃繼續招募患者，我們期待著選擇一定劑量的擴展臂。稍後我將對此進行簡要更新。

Earlier this year, our partner, Vertex, announced an initiation of a Phase I trial in cystic fibrosis patients, which is our first inhaled pulmonary mRNA therapeutic program. And in Cardiovascular, we announced Relaxin has initiated dosing in the Phase I study. Both of these study initiations represent important milestones for Moderna as we expand our modalities in therapeutic areas.

今年早些時候，我們的合作夥伴 Vertex 宣布啟動囊性纖維化患者的 I 期試驗，這是我們的第一個吸入肺 mRNA 治療項目。在心血管方面，我們宣布 Relaxin 已在 I 期研究中開始給藥。隨著我們在治療領域擴展我們的模式，這兩項研究的啟動代表了 Moderna 的重要里程碑。

Now in December, we shared exciting top line data from our Phase II personalized cancer vaccine program, testing the combination of PCV and KEYTRUDA against KEYTRUDA alone in the setting of adjuvant melanoma. KEYTRUDA is the standard of care in that setting.

現在在 12 月，我們分享了來自我們 II 期個性化癌症疫苗計劃的令人興奮的頂線數據，測試了 PCV 和 KEYTRUDA 的組合在輔助黑色素瘤的情況下與單獨使用 KEYTRUDA 的對比。 KEYTRUDA 是該環境中的護理標準。

In this study, we showed the addition of our personalized cancer vaccine treatment mRNA-4157 to KEYTRUDA reduced the risk of recurrence or death by 44% compared to KEYTRUDA alone. This was the first demonstration of efficacy for an investigational mRNA cancer treatment in a randomized clinical trial, and we are pleased to announce that 4157 has received breakthrough therapy designation from the FDA. Along with our partner, Merck, we are excited about these results and expect to launch multiple late-stage confirmatory studies for PCV in 2023, starting with melanoma and then moving to non-small cell lung cancer.

在這項研究中，我們表明，與單獨使用 KEYTRUDA 相比，將我們的個性化癌症疫苗治療 mRNA-4157 添加到 KEYTRUDA 中可將復發或死亡的風險降低 44%。這是在隨機臨床試驗中首次證明研究性 mRNA 癌症治療的療效，我們很高興地宣布 4157 已獲得 FDA 的突破性治療指定。我們與我們的合作夥伴默克公司一起，對這些結果感到興奮，並期望在 2023 年啟動多項針對 PCV 的後期驗證性研究，從黑色素瘤開始，然後轉向非小細胞肺癌。

We are planning to explore additional indications for 4157, where we believe there is a strong biologic rationale for immune-stimulating approaches. These include early-stage and metastatic settings and will include indications where KEYTRUDA is not yet approved.

我們計劃探索 4157 的其他適應症，我們相信免疫刺激方法有很強的生物學原理。這些包括早期和轉移設置，並將包括 KEYTRUDA 尚未獲得批准的適應症。

Finally, we expect to release full data from our Phase II study at an oncology meeting this spring and in an upcoming publication.

最後，我們希望在今年春天的腫瘤學會議上和即將出版的出版物中發布我們 II 期研究的完整數據。

Now moving to PA. Since our update with our -- at our R&D Day, the PA Paramount study has made good progress. Our fourth cohort is now fully enrolled, and we're currently enrolling patients in our fifth cohort which doses at 0.9 milligrams per kilogram every 2 weeks. We are encouraged that to date, we have not observed any dose-limiting toxicities. And we're also encouraged that all patients and families have opted to continue treatment electively in our Open-Label Expansion study across all prior dose cohorts.

現在搬到賓夕法尼亞州。自從我們在研發日更新我們的信息以來，PA Paramount 研究取得了良好進展。我們的第四個隊列現已完全註冊，我們目前正在為我們的第五個隊列招募患者，每 2 週劑量為每公斤 0.9 毫克。我們感到鼓舞的是，迄今為止，我們尚未觀察到任何劑量限制性毒性。我們也感到鼓舞的是，所有患者和家屬都選擇在我們所有先前劑量隊列的開放標籤擴展研究中選擇性地繼續治療。

Now, the next step in this trial will be to review available data and determine a dose for expansion.

現在，該試驗的下一步將是審查可用數據並確定擴展劑量。

I'll now hand the call over to Arpa Garay, who will provide an update on our commercial activities. Arpa?

我現在將電話轉給 Arpa Garay，他將提供有關我們商業活動的最新信息。阿帕？

Thank you, Stephen, and good day to everyone. I will start with a review of sales on Slide 20.

謝謝你，斯蒂芬，祝大家有美好的一天。我將從幻燈片 20 上的銷售回顧開始。

In the fourth quarter, total product sales were $4.9 billion. In the U.S., our sales were $1 billion, sales in Europe approximated $2.2 billion, and sales in the rest of the world were $1.6 billion. We ended the full year strong, with total product sales for 2022 of $18.4 billion. Sales in the U.S. for the full year were $4.4 million, sales in Europe were $6.7 million, and in the rest of the world were $7.3 billion. We are reiterating approximately $5 billion in COVID sales for delivery in 2023 from our currently-signed advanced purchase agreements and deferrals. And we do expect additional sales from key markets such as the U.S., EU and Japan.

第四季度，產品總銷售額為 49 億美元。在美國，我們的銷售額為 10 億美元，在歐洲的銷售額約為 22 億美元，在世界其他地區的銷售額為 16 億美元。我們以強勁的勢頭結束了全年，2022 年的產品總銷售額為 184 億美元。美國全年銷售額為 440 萬美元，歐洲銷售額為 670 萬美元，世界其他地區銷售額為 73 億美元。我們重申，根據我們目前簽署的提前採購協議和延期協議，2023 年交付的 COVID 銷售額約為 50 億美元。我們確實預計來自美國、歐盟和日本等主要市場的銷售額會增加。

Slide 21 summarizes the current composition of sales for 2023. We have advanced purchase agreements from Canada, Kuwait, Switzerland, Taiwan and the United Kingdom. We expect these sales to be recognized upon delivery of vaccines in the second half of 2023. Additionally, we expect further sales from deferrals from 2022 contracts. These deferrals are from the countries listed on the slide, and are expected to be mainly recognized from deliveries in the first half of 2023. Together, these advanced purchase agreements and deferrals totaled approximately $5 billion in sales for 2023.

幻燈片 21 總結了 2023 年的當前銷售構成。我們有來自加拿大、科威特、瑞士、台灣和英國的高級採購協議。我們預計這些銷售額將在 2023 年下半年交付疫苗時得到確認。此外，我們預計 2022 年合同的延期將進一步銷售。這些延期採購來自幻燈片中列出的國家/地區，預計將主要從 2023 年上半年的交付中確認。這些提前採購協議和延期採購總計 2023 年的銷售額約為 50 億美元。

We do expect additional sales from key markets, including the United States, EU and Japan, as well as Australia and other countries in Asia and Latin America. In the U.S., contracting discussions with commercial customers are ongoing, and we will provide visibility into expected U.S. sales at a future date after we complete these discussions.

我們確實預計來自主要市場的額外銷售額，包括美國、歐盟和日本，以及澳大利亞和亞洲和拉丁美洲的其他國家。在美國，與商業客戶的合同討論正在進行中，我們將在完成這些討論後的未來某個日期提供對預期美國銷售額的可見性。

In our discussions with commercial customers in the U.S., it is clear to us that our customers recognize that COVID is still a substantial health burden. Throughout 2022, COVID continued to be a leading cause of hospitalizations and deaths.

在我們與美國商業客戶的討論中，我們很清楚，我們的客戶認識到 COVID 仍然是一個巨大的健康負擔。在整個 2022 年，COVID 仍然是住院和死亡的主要原因。

If you look to the chart on the left-hand side, what you'll see here is data available through September of 2022, COVID was the third leading cause of death in the United States only after heart disease and cancer.

如果您查看左側的圖表，您將在此處看到截至 2022 年 9 月的可用數據，COVID 是美國僅次於心髒病和癌症的第三大死因。

And if you look to the right-hand side, (technical difficulty) four months for the fall and winter season from October 1, 2022, (technical difficulty) 2023, hospitalizations from COVID in the U.S. are nearly 450,000, more than double from flu and nearly 3x higher than RSV in that same 4-month period. There continues to be a clear need to protect against severe COVID infections and our customers recognize that.

如果你看右邊，（技術難度）從 2022 年 10 月 1 日開始的秋冬季節的四個月，（技術難度）2023 年，美國因 COVID 住院的人數接近 450,000，是流感的兩倍多並且在同一 4 個月期間比 RSV 高出近 3 倍。顯然仍然需要防止嚴重的 COVID 感染，我們的客戶也認識到這一點。

Given this need, we estimate the U.S. fall 2023 COVID market volume to be approximately 100 million doses. We base this assumption after looking at 2022 vaccination rates, and including potential recommendation for 2-dose booster series for high-risk individuals. Taken together, the doses administered represent roughly 30% of the U.S. population.

鑑於這種需求，我們估計美國 2023 年秋季 COVID 市場容量約為 1 億劑。我們在查看了 2022 年的疫苗接種率之後做出了這一假設，並包括了針對高風險個體的 2 劑加強系列的潛在建議。總的來說，所服用的劑量約占美國人口的 30%。

A few factors that can impact this volume include viral evolution, regulatory recommendations as well as vaccine understanding and uptake by consumers. Moderna's commercial organization is prepared for the transition to a commercial market in the U.S.

可能影響這一數量的幾個因素包括病毒進化、監管建議以及消費者對疫苗的理解和採用。 Moderna 的商業組織已準備好向美國的商業市場過渡。

Let me now take you through how we have been preparing to go to market. First and foremost, we are committed to access, which I will explain in greater detail in just a moment. To ensure coverage of our vaccine, we are engaged in discussions with private customers as well as public entities such as the VA, CDC and the Department of Defense. We are increasing awareness and educating consumers as well as healthcare providers about the benefits of booster vaccinations in alignment with public health agencies such as CDC and ACIP. We are reaching healthcare providers and consumers through innovative digital outreach programs. We have built the infrastructure needed to fulfill customer orders and shipments, and our commercial and medical organizations have been scaling to execute on this plan, and we are ready for the transition to a commercial market in the United States.

現在讓我向您介紹一下我們是如何準備上市的。首先，我們致力於訪問，稍後我將對此進行更詳細的解釋。為確保我們疫苗的覆蓋範圍，我們正在與私人客戶以及公共實體（例如 VA、CDC 和國防部）進行討論。我們正在與 CDC 和 ACIP 等公共衛生機構合作，提高消費者和醫療保健提供者對加強疫苗接種益處的認識和教育。我們通過創新的數字外展計劃接觸醫療保健提供者和消費者。我們已經建立了完成客戶訂單和發貨所需的基礎設施，我們的商業和醫療組織一直在擴展以執行該計劃，我們已準備好過渡到美國的商業市場。

Very importantly, as we enter the commercial phase of the endemic COVID market, we want to emphasize our commitment to vaccines access for everyone in the United States regardless of their ability to pay. For all insured individuals in the United States, consistent with preventative health services requirements, current reimbursement rules will be sustained. As an ACIP-recommended vaccine, Moderna's COVID vaccine will continue to be available for 0 out-of-pocket costs for individuals with insurance. And we are proud to say that for uninsured or underinsured people in the United States, Moderna will be launching a patient assistance program that will provide COVID-19 vaccines at no cost.

非常重要的是，當我們進入地方性 COVID 市場的商業階段時，我們想強調我們對讓美國每個人都能獲得疫苗的承諾，無論他們的支付能力如何。對於美國的所有投保個人，根據預防性健康服務要求，將維持當前的報銷規則。作為 ACIP 推薦的疫苗，Moderna 的 COVID 疫苗將繼續為有保險的個人提供 0 自付費用。我們可以自豪地說，對於美國沒有保險或保險不足的人，Moderna 將啟動一項患者援助計劃，該計劃將免費提供 COVID-19 疫苗。

Let me now summarize our COVID vaccine outlook. In 2023, we expect COVID sales of approximately $5 billion. In addition, we are expecting sales from U.S. commercial market orders, EU, Japan and other countries. We will provide visibility into these sales after we complete ongoing discussions with governments and with customers.

現在讓我總結一下我們對 COVID 疫苗的展望。 2023 年，我們預計 COVID 銷售額約為 50 億美元。此外，我們預計來自美國商業市場訂單、歐盟、日本和其他國家的銷售。在完成與政府和客戶的持續討論後，我們將提供這些銷售的可見性。

We recognize COVID continues to be a burden to healthcare systems, and this continues to be an important point as we discuss the value of booster vaccinations with our customers. In the U.S., we expect commercial market volumes to be approximately 100 million doses in 2023, and Moderna's commercial organization is prepared for the transition to a commercial endemic market. Last but not least, we are committed to patient access in the United States.

我們認識到 COVID 仍然是醫療保健系統的負擔，並且在我們與客戶討論加強疫苗接種的價值時，這仍然是一個重要的觀點。在美國，我們預計 2023 年的商業市場容量約為 1 億劑，Moderna 的商業組織已準備好向商業地方性市場過渡。最後但同樣重要的是，我們致力於在美國為患者提供服務。

I now want to turn to another launch in the respiratory vaccine space that the commercial team is preparing for, our RSV vaccine in 2024. As you heard from both Stephane and Stephen earlier, we are very pleased by our Phase III RSV vaccine results. Stephen's organization will be filing for the approval soon, and we expect we may be approved in late 2023 or early 2024. With the potential approval fast approaching, I'm very excited for the RSV vaccine launch, and I want to provide additional color into the launch plans.

我現在想談談商業團隊正在準備的呼吸道疫苗領域的另一次發射，即我們將於 2024 年推出的 RSV 疫苗。正如你之前從 Stephane 和 Stephen 那裡聽到的那樣，我們對我們的 III 期 RSV 疫苗結果感到非常滿意。 Stephen 的組織將很快申請批准，我們預計我們可能會在 2023 年底或 2024 年初獲得批准。隨著潛在批准的快速臨近，我對 RSV 疫苗的推出感到非常興奮，我想為它提供額外的顏色發射計劃。

The RSV launch will leverage the existing commercial infrastructure that is already in place for COVID and we will continue to invest to support it, ensuring strong execution. Both COVID and RSV markets overlap considerably as we look at our target customers as well as potential target patients and audiences, and we will leverage this overlap between the 2 markets. We will ensure awareness of RSV disease and the associated economic burden of RSV in older adults across key stakeholders such as healthcare providers and payers. Upon approval of our RSV vaccine, we will educate consumers on key attributes of our vaccine. These planned activities will be initiated in 2023 and in full force upon approval. We have the added benefit of an in-place commercial infrastructure built for COVID. Many of these resources can be leveraged for flu as well into the future.

RSV 的發布將利用 COVID 已經存在的現有商業基礎設施，我們將繼續投資以支持它，確保強大的執行力。當我們著眼於我們的目標客戶以及潛在的目標患者和受眾時，COVID 和 RSV 市場都有很大的重疊，我們將利用這兩個市場之間的重疊。我們將確保關鍵利益相關者（如醫療保健提供者和付款人）對 RSV 疾病和 RSV 相關的老年人經濟負擔的認識。在我們的 RSV 疫苗獲得批准後，我們將向消費者宣傳我們疫苗的關鍵特性。這些計劃中的活動將於 2023 年啟動，並在獲得批准後全面生效。我們擁有為 COVID 構建的就地商業基礎設施的額外好處。這些資源中有許多可以用於流感以及未來。

I look forward to keeping you updated on our progress throughout this year. And with that, I will turn it over to Jamie.

我期待著讓您了解我們今年的最新進展。有了這個，我會把它交給傑米。

Thanks, Arpa, and hello, everyone. This morning, I will cover our 2022 financial performance and provide a framework for our 2023 financial outlook.

謝謝，Arpa，大家好。今天上午，我將介紹我們 2022 年的財務業績，並為我們的 2023 年財務展望提供一個框架。

Moving to our fourth quarter results, starting on Slide 29. Total product sales decreased by 30% year-over-year to $4.9 billion. The decrease in 2022 was mainly driven by lower sales volume compared to overall higher demand in the prior year. Cost of sales was 39% of product sales compared to 14% of product sales in 2021. The key driver of the increase in cost of sales as a percent of product sales was a catch-up royalty payment to the National Institute of Health, or NIH, of $400 million, representing 8% of product sales in the fourth quarter.

轉到我們的第四季度業績，從幻燈片 29 開始。產品總銷售額同比下降 30% 至 49 億美元。 2022 年的下降主要是由於銷量下降，而去年總體需求較高。銷售成本佔產品銷售額的 39%，而 2021 年佔產品銷售額的 14%。銷售成本佔產品銷售額百分比增加的主要驅動因素是向美國國立衛生研究院支付的追加特許權使用費，或NIH，4 億美元，佔第四季度產品銷售額的 8%。

In December 2022, we entered into a non-exclusive patent license agreement with the National Institute of Allergy and Infectious Diseases and institute or center of the NIH to license certain patent rights concerning stabilizing prefusion coronavirus spike proteins and the resulting stabilized proteins for the use in COVID-19 vaccine products or 2P technology. Pursuant to the agreement, we have agreed to pay low single-digit royalties on future net sales of our COVID-19 vaccines.

2022年12月，我們與美國國家過敏和傳染病研究所以及美國國立衛生研究院的研究所或中心簽訂了一項非排他性專利許可協議，以許可有關穩定預融合冠狀病毒刺突蛋白和由此產生的穩定蛋白的某些專利權，用於COVID-19 疫苗產品或 2P 技術。根據協議，我們已同意為我們 COVID-19 疫苗的未來淨銷售額支付低個位數的特許權使用費。

Our cost of sales also includes a charge of $297 million for inventory write-downs related to excess and obsolete COVID-19 products, an expense for unutilized manufacturing capacity, and CMO wind-down costs and related charges of $376 million, and a loss on firm purchase commitments and related cancellation fees of $281 million. These charges other than royalties are driven by costs associated with surplus production capacity, overall lower demand and a shift to our most recent Omicron BA.4/5 targeting COVID-19 bivalent booster.

我們的銷售成本還包括 2.97 億美元的與過剩和過時的 COVID-19 產品相關的庫存減記費用、未使用製造能力的費用、CMO 停產成本和 3.76 億美元的相關費用，以及損失2.81 億美元的確定購買承諾和相關取消費用。除特許權使用費外，這些費用是由與產能過剩、整體需求下降以及轉向我們最新的針對 COVID-19 二價助推器的 Omicron BA.4/5 相關的成本驅動的。

Research and development expenses were $1.2 billion, which increased by 87% versus prior year. The increase in R&D spend continues to be driven by our clinical trial expenses, particularly with our Phase III studies for RSV, seasonal flu and CMV. The increase in R&D was also driven by the acquisition of a Priority Review Voucher and an increase in personnel-related costs due to increased headcount.

研發費用為 12 億美元，比上年增長 87%。研發支出的增加繼續受到我們臨床試驗費用的推動，尤其是我們針對 RSV、季節性流感和 CMV 的 III 期研究。研發的增加還受到優先審評憑證的獲得以及員工人數增加導致的人員相關成本增加的推動。

Selling, general and administrative expenses were $375 million, also reflecting an increase of 87% year-over-year. The growth in spending was primarily driven by continued investments in personnel and outside services in support of our marketed products and company build-up.

銷售、一般和管理費用為 3.75 億美元，同比增長 87%。支出的增長主要是由對人員和外部服務的持續投資推動的，以支持我們銷售的產品和公司的建設。

The effective tax rate was 11% compared to 10% last year. After-tax net income decreased by 70% to $1.5 billion. Diluted earnings per share in Q4 decreased by 68% to $3.61.

有效稅率為 11%，而去年為 10%。稅後淨收入下降 70% 至 15 億美元。第四季度稀釋後每股收益下降 68% 至 3.61 美元。

Now turning to our full year 2022 financial results on Slide 30. Total product sales for the full year 2022 were $18.4 billion, an increase of 4% year-over-year. The growth was mainly attributable to customer mix and a higher average selling price in 2022 in certain markets. Cost of sales was 29% of product sales compared to 15% of product sales last year. The increase was driven by higher write-downs for excess and obsolete inventory related to our COVID-19 vaccines, unutilized manufacturing capacity and losses related to future purchase commitments for raw materials. The key drivers for these charges are similar to the drivers in Q4. Costs associated with surplus production capacity, overall lower demand for the year, in particular from low-income countries, and rapid product advance shift from our original vaccine to Omicron targeting COVID-19 bivalent boosters. The previously-mentioned catch-up royalty payment NIH of $400 million is also a driver of the increase year-over-year.

現在轉向我們在幻燈片 30 上的 2022 年全年財務業績。2022 年全年的產品總銷售額為 184 億美元，同比增長 4%。增長主要歸因於客戶組合和某些市場 2022 年更高的平均售價。銷售成本佔產品銷售額的 29%，而去年佔產品銷售額的 15%。增加的原因是與我們的 COVID-19 疫苗相關的過剩和過時庫存的減記增加、未使用的製造能力以及與未來原材料採購承諾相關的損失。這些費用的主要驅動因素與第四季度的驅動因素類似。與產能過剩相關的成本、今年總體需求下降（尤其是來自低收入國家的需求）以及產品從我們的原始疫苗快速轉移到針對 COVID-19 雙價助推器的 Omicron。前面提到的 4 億美元的 NIH 追加特許權使用費也是同比增長的推動因素。

The effective tax rate was 13% compared to 8% last year. As a reminder, we had a net operating loss carryforward of $2.3 billion at the end of 2020, which resulted in a non-recurring benefit to the reported tax rate in 2021. After-tax net income of $8.4 billion decreased 31% versus prior year. The decrease of net income was primarily due to higher cost of sales, higher other operating expenses and a higher effective tax rate. Diluted EPS decreased 29% to $20.12.

有效稅率為 13%，而去年為 8%。提醒一下，我們在 2020 年底結轉的淨經營虧損為 23 億美元，這對 2021 年報告的稅率產生了非經常性收益。稅後淨收入為 84 億美元，比上一年下降了 31% .淨收入的減少主要是由於銷售成本增加、其他運營費用增加以及有效稅率增加。稀釋每股收益下降 29% 至 20.12 美元。

Now turning to cash and cash deposits on Slide 31. We ended 2022 with cash and investments of $18.2 billion, compared to $17 billion at the end of the third quarter. The increase was driven by our commercial activity. Cash deposits for future product supply reduced from $3.8 billion at the end of the third quarter to $2.6 billion by the end of the year.

現在轉向幻燈片 31 上的現金和現金存款。到 2022 年底，我們的現金和投資為 182 億美元，而第三季度末為 170 億美元。增長是由我們的商業活動推動的。用於未來產品供應的現金存款從第三季度末的 38 億美元減少到年底的 26 億美元。

Now turning to Slide 32. I wanted to give an update on the progress we have made on our capital allocation priorities. Our top investment priority has been and will continue to be reinvesting in our base business across multiple areas.

現在轉到幻燈片 32。我想介紹一下我們在資本配置優先事項方面取得的最新進展。我們的首要投資重點已經並將繼續在多個領域對我們的基礎業務進行再投資。

Research and development spending increased 65% year-over-year from $2 billion in 2021 to $3.3 billion in 2022, and we are projecting an additional increase to approximately $4.5 billion in 2023. The clinical data from our PCV, RSV and flu trials were encouraging and further validates the potential of our mRNA technology. We are also investing in our digital capabilities, the commercial build-out of the organization as well as expanding our manufacturing footprint. We plan to significantly accelerate our capital expenditures in 2023 as we expand both our international and U.S. manufacturing footprint.

研發支出同比增長 65%，從 2021 年的 20 億美元增至 2022 年的 33 億美元，我們預計到 2023 年將進一步增至約 45 億美元。我們的 PCV、RSV 和流感試驗的臨床數據令人鼓舞並進一步驗證了我們 mRNA 技術的潛力。我們還投資於我們的數字能力、組織的商業建設以及擴大我們的製造足跡。隨著我們擴大國際和美國製造足跡，我們計劃在 2023 年大幅加快資本支出。

Our second investment priority is to seek attractive external investments and collaboration opportunities that will enable and complement our platform. We've recently announced several new transactions, and I'm happy to report that we have successfully closed our acquisition of OriCiro Genomics in the first quarter of 2023. OriCiro is a great example of the companies we are evaluating to enable our mRNA platform. It will create substantial value from both the speed and cost viewpoint and impact our pre-clinical, clinical and commercial pipeline for years to come.

我們的第二個投資重點是尋求有吸引力的外部投資和合作機會，以支持和補充我們的平台。我們最近宣布了幾項新交易，我很高興地宣布，我們已於 2023 年第一季度成功完成對 OriCiro Genomics 的收購。OriCiro 是我們正在評估以啟用我們的 mRNA 平台的公司的一個很好的例子。從速度和成本的角度來看，它將創造巨大的價值，並在未來幾年影響我們的臨床前、臨床和商業管道。

Our collaboration with LifeEdit, which we announced yesterday, is another example for an attractive external investment opportunity. We believe the combination of Moderna's mRNA platform with LifeEdit's proprietary gene editing technologies, including base editing capabilities, has the opportunity to advance potentially life transformative or curative therapies for some of the most challenging genetic diseases.

我們昨天宣布的與 LifeEdit 的合作是具有吸引力的外部投資機會的另一個例子。我們相信，Moderna 的 mRNA 平台與 LifeEdit 的專有基因編輯技術（包括鹼基編輯功能）的結合，有機會為一些最具挑戰性的遺傳疾病推進潛在的生命變革或治愈療法。

We are in multiple active discussions regarding additional external collaboration opportunities, and we will be disciplined in our approach.

我們正在就額外的外部合作機會進行多次積極討論，我們將嚴格遵守我們的方法。

After evaluating internal and external investment opportunities, we then assess additional uses of cash. In 2022, we repurchased 23 million shares for $3.3 billion at an average price of $143 per share. And we have $2.8 billion of share repurchase authorization remaining.

在評估內部和外部投資機會後，我們會評估現金的其他用途。 2022 年，我們以每股 143 美元的平均價格以 33 億美元的價格回購了 2300 萬股股票。我們還有 28 億美元的股票回購授權。

Now, let's turn to our 2023 financial framework on Slide 33. As Arpa mentioned earlier, we currently have COVID vaccine sales of $5 billion contracted for delivery in 2023. Also, we are actively working on preparing for the private market and government contracts in the U.S. and additional contracts for Europe, Japan and other key markets.

現在，讓我們轉到幻燈片 33 上的 2023 年財務框架。正如 Arpa 之前提到的，我們目前有 50 億美元的 COVID 疫苗銷售合同，將於 2023 年交付。此外，我們正在積極準備私人市場和政府合同美國以及歐洲、日本和其他主要市場的附加合同。

To help you with your modeling purposes, we expect first half '23 sales to be approximately $2 billion. Our total cost of sales includes the cost of goods manufactured, third-party royalties, as well as logistics and warehousing costs. We expect full year 2023 reported cost of sales to be 35% to 40% of sales. This includes royalties of approximately 5% of sales, which are payable to UPenn and CellScript for modified chemistry licenses, and to NIAID and NIH for the 2P license that I mentioned earlier. The increase in cost of sales as a percent of product sales compared to 2022 is primarily driven by presentation mix change as we move from a pandemic to endemic setting, with single-dose application significantly increasing in volume.

為了幫助您實現建模目的，我們預計 23 年上半年的銷售額約為 20 億美元。我們的總銷售成本包括商品製造成本、第三方特許權使用費以及物流和倉儲成本。我們預計 2023 年全年報告的銷售成本將佔銷售額的 35% 至 40%。這包括大約 5% 的銷售額的版稅，對於修改後的化學許可，應支付給 UPenn 和 CellScript，對於我之前提到的 2P 許可，應支付給 NIAID 和 NIH。與 2022 年相比，銷售成本佔產品銷售額的百分比有所增加，這主要是由於隨著我們從大流行病環境轉變為地方病環境，呈現組合發生了變化，單劑量應用的數量顯著增加。

Longer term, as the endemic market normalizes and we add additional respiratory and other products, we expect our cost of sales as a percent of sales will significantly decrease in the rates we're experiencing in 2023.

從長遠來看，隨著流行病市場的正常化以及我們增加了額外的呼吸產品和其他產品，我們預計我們的銷售成本佔銷售額的百分比將在 2023 年顯著下降。

For R&D and SG&A, we expect full year expenses to be approximately $6 billion, with approximately $4.5 billion in R&D. The increase is driven by our maturing development portfolio and the global scale up of our company. We expect a negligible provision for income tax in 2023. And finally, we expect capital expenditures of approximately $1 billion. The increase is primarily due to investments in expanding our manufacturing footprint.

對於研發和 SG&A，我們預計全年支出約為 60 億美元，其中研發費用約為 45 億美元。這一增長是由我們成熟的開發組合和我們公司的全球規模擴大推動的。我們預計 2023 年的所得稅撥款可以忽略不計。最後，我們預計資本支出約為 10 億美元。這一增長主要是由於對擴大我們的製造足蹟的投資。

This concludes my remarks concerning our financial performance, and I will turn the call back over to Stephane.

我對我們的財務業績的評論到此結束，我將把電話轉回給斯蒂芬。

Thank you, Jamie, Arpa and Stephen. Let me now share some thoughts about where we're heading.

謝謝 Jamie、Arpa 和 Stephen。現在讓我分享一些關於我們前進方向的想法。

I'm really excited to see our mRNA platform and the investments we have made in science over the last 11 years lead to such a promising pipeline. We anticipate a number of important developments.

我真的很高興看到我們的 mRNA 平台和我們在過去 11 年中對科學的投資導致瞭如此有前途的管道。我們預計會有一些重要的發展。

Let me start with our first franchise, respiratory vaccines. In COVID boosters, we are working for the switch to U.S. commercial market, and we anticipate being able to quickly meet the full 2023 market needs for updated vaccines after VRBPAC and the FDA make this transaction in the spring of 2023. We plan to submit RSV vaccine for regulatory approval in the first half of 2023, and as you heard from Arpa, we'll be ready to launch the RSV vaccine in late '23 or early '24.

讓我從我們的第一個專營權呼吸道疫苗開始。在 COVID 助推器方面，我們正在努力轉向美國商業市場，我們預計在 VRBPAC 和 FDA 於 2023 年春季完成此交易後，能夠快速滿足 2023 年市場對更新疫苗的全部需求。我們計劃提交 RSV疫苗將於 2023 年上半年獲得監管批准，正如您從 Arpa 那裡聽到的那樣，我們將準備在 23 年底或 24 年初推出 RSV 疫苗。

In flu vaccine, for Northern Hemisphere, mRNA-1010 Phase III trial, the Data and Safety Monitoring Board is expected to complete its interim efficacy analysis in the first quarter of 2023. Our second franchise Latent virus vaccine. It's progressing very well with a broad spectrum of programs. In our large CMV Phase III study, we look to complete the enrollment. For EBV, HIV and VZV programs, our next milestone will be Phase I data.

在流感疫苗方面，針對北半球的 mRNA-1010 III 期試驗，數據和安全監測委員會預計將在 2023 年第一季度完成其中期療效分析。我們的第二個特許經營潛伏病毒疫苗。它在廣泛的項目中進展順利。在我們的大型 CMV III 期研究中，我們希望完成註冊。對於 EBV、HIV 和 VZV 項目，我們的下一個里程碑將是第一階段數據。

Turning to Slide 37, let me review the milestone for mRNA therapeutics programs. For personalized cancer treatment, we expect to start our Phase III study in partnership with Merck in adjuvant melanoma, and we expect to rapidly expand to additional tumor types, including non-small cell lung cancer. Full Phase II data will be presented at an upcoming oncology meeting and published in a top quality medical job.

轉到幻燈片 37，讓我回顧一下 mRNA 治療項目的里程碑。對於個性化癌症治療，我們希望與默克公司合作開展 III 期輔助黑色素瘤研究，我們希望迅速擴展到其他腫瘤類型，包括非小細胞肺癌。完整的 II 期數據將在即將舉行的腫瘤學會議上公佈，並在高質量的醫學工作中發表。

In PA, we plan to select those and begin the expansion arm of our Phase I/II study.

在賓夕法尼亞州，我們計劃選擇那些並開始我們的 I / II 期研究的擴展臂。

MMA, we will have Phase I/II data. The next milestone for heart failure for Relaxin will be Phase I data in patients. In Inhaled therapeutics, our partner Vertex expects to complete its single ascending dose study and initiate a multiple ascending dose study.

MMA，我們將獲得 I/II 期數據。 Relaxin 心力衰竭的下一個里程碑將是患者的 I 期數據。在吸入療法方面，我們的合作夥伴 Vertex 預計將完成其單次遞增劑量研究並啟動多次遞增劑量研究。

To continue to build the best version of Moderna, we have established 7 priorities for 2023. Priority number one, execute the operational and sales plan for COVID booster for fall of '23. Priority #2, build an unrivaled seasonal respiratory vaccine franchise. Priority #three, execute a bold campaign of cancer vaccine studies. Priority #4, advance rare metabolic disease programs. Priority #5, drive rapid advancement and growth of our latent vaccine portfolio. Priority #6, deliver the next-generation pipeline and platform. As we said before, this is just the beginning. And Priority #7, build a culture of perpetual learning and strengthen our processes and digital system as we want to scale the company to another level.

為了繼續構建最佳版本的 Moderna，我們為 2023 年確定了 7 個優先事項。第一優先事項是執行 23 年秋季 COVID booster 的運營和銷售計劃。優先事項 #2，建立無與倫比的季節性呼吸道疫苗專營權。優先事項#three，執行一項大膽的癌症疫苗研究運動。優先事項#4，推進罕見代謝病項目。優先事項 #5，推動我們潛在疫苗產品組合的快速發展和增長。優先事項 #6，交付下一代管道和平台。正如我們之前所說，這僅僅是個開始。優先事項#7，建立一種永久學習的文化並加強我們的流程和數字系統，因為我們希望將公司擴展到另一個層次。

On Slide 39, some key dates for 2023 Moderna Investor Days. April 11 will be our Annual Vaccine Day. September 13 will be Annual R&D Day, where we'll present development pipeline key updates. And December 7 will be our second ESG Day.

在幻燈片 39 上，2023 年現代投資者日的一些關鍵日期。 4 月 11 日將是我們的年度疫苗日。 9 月 13 日將是年度研發日，屆時我們將展示開發管道的關鍵更新。 12 月 7 日將是我們的第二個 ESG 日。

Now that we have delivered on the promise of mRNA science with our first product launched, our mission has evolved. Our mission is to deliver the greatest possible impact to people through mRNA medicine. We are passionate about our ability to have a profound impact on humanity. We believe we have the technology to eliminate or greatly reduce human suffering caused by respiratory viruses, latent viruses, many cancers, (inaudible) diseases and the growing list of other diseases. We believe we can have an impact on these treatments with our therapeutic first and then with our clean editing programs. This is just the beginning. With that, the team and I are happy to now take your questions. Operator.

既然我們已經推出了第一個產品，兌現了 mRNA 科學的承諾，我們的使命就發生了變化。我們的使命是通過 mRNA 醫學為人們帶來最大可能的影響。我們對我們對人類產生深遠影響的能力充滿熱情。我們相信我們擁有消除或大大減少由呼吸道病毒、潛伏病毒、許多癌症、（聽不清）疾病和越來越多的其他疾病引起的人類痛苦的技術。我們相信，我們可以首先通過我們的治療，然後通過我們的干淨編輯程序對這些治療產生影響。這僅僅是個開始。有了這個，我和我的團隊很高興現在可以回答你的問題。操作員。

(Operator Instructions) First question comes from Salveen Richter with Goldman Sachs.

（操作員說明）第一個問題來自高盛的 Salveen Richter。

Could you speak to the regulatory strategy for flu, given the miss on the B strains for immunogenicity and if you're confident into the interim efficacy analysis given the dominating prevalence of A strains here.

你能談談流感的監管策略嗎，考慮到 B 株的免疫原性缺失，以及你是否對中期療效分析有信心，因為 A 株在這裡占主導地位。

I'll take that. Look, I think the honest answer is we're still have incomplete information to provide guidance on the regulatory strategy. At this point, we are looking to the efficacy results from the P302 study that I described, which will guide us on that filing strategy. It's important to note that efficacy, ultimate demonstration of non-inferior efficacy against an approved vaccine was always going to be required for full approval, and that the only thing that you could do with immunogenicity would be an accelerated approval path with an obligation to subsequently demonstrate efficacy.

我會接受的。看，我認為誠實的答案是我們仍然沒有完整的信息來提供監管策略的指導。在這一點上，我們正在尋找我描述的 P302 研究的療效結果，這將指導我們制定該申請策略。重要的是要注意，對於已批准疫苗的有效性，非劣效性的最終證明始終是完全批准所必需的，並且您對免疫原性唯一可以做的就是加速批准途徑，並有義務隨後證明療效。

And so right now, we are actually very encouraged that the data that we've seen from our immunogenicity and safety study, which is running the Southern Hemisphere, P301, shows superiority on 3 out of 4 endpoints for the influenza A strains, which drive the overwhelming majority of disease, and the population of interest here are older adults, and account for over 99% of the cases in our efficacy study. And so that first interim efficacy analysis that we're conducting now in P302 will involve over 200 cases, 99% of them are influenza A, and it will be our first chance to really see the performance of the vaccine in terms of prevention of influenza-like illness from Flu A.

所以現在，我們實際上非常鼓舞，我們從我們的免疫原性和安全性研究中看到的數據，該研究正在南半球進行，P301，顯示 A 型流感毒株的 4 個終點中的 3 個具有優勢，這驅動絕大多數疾病和這裡感興趣的人群是老年人，在我們的療效研究中佔病例的 99% 以上。因此，我們現在在 P302 進行的第一次中期療效分析將涉及 200 多個病例，其中 99% 是甲型流感，這將是我們第一次有機會真正了解疫苗在預防流感方面的表現- 類似甲型流感的疾病。

That is the first interim analysis. And so it's quite possible, as you would expect in any efficacy study, and we've all got some experience now with these respiratory efficacy studies, that we may end up -- need to go to a second subsequent interim analysis and accrue even more cases to demonstrate either non-inferiority or superiority in that study. And so what we'll do is we will wait for the results from the DSMB, the independent DSMB, and guidance from that. Based on those results, obviously, if we do see efficacy, that is the gold standard for proceeding with regulatory filing and full approval. If we do not yet meet that threshold, then we'll be looking forward to subsequent interim analyses in that study.

這是第一個中期分析。因此，很有可能，正如您在任何功效研究中所期望的那樣，我們現在都對這些呼吸功效研究有了一些經驗，我們可能最終需要進行第二次後續中期分析並積累更多在該研究中證明非劣效性或優效性的案例。因此，我們要做的是等待 DSMB、獨立的 DSMB 的結果以及來自該機構的指導。根據這些結果，顯然，如果我們確實看到了療效，那就是進行監管備案和全面批准的黃金標準。如果我們還沒有達到這個門檻，那麼我們將期待在該研究中進行後續的中期分析。

Our next question comes from Gena Wang with Barclays.

我們的下一個問題來自巴克萊銀行的 Gena Wang。

Just quickly follow Salveen's question. Do you need to show superiority in order to receive approval regarding the efficacy study? And then quickly on the revenue. Did I hear correctly the existing contract of $5 billion mainly will be in the second half '23? If that's the case, is it fair to say that total COVID revenue in 2023 should be around $7 billion?

快速回答 Salveen 的問題。您是否需要展示優勢才能獲得有關功效研究的批准？然後很快就收入了。我沒聽錯嗎，現有的 50 億美元合同主要是在 23 年下半年？如果真是這樣，那麼說 2023 年 COVID 總收入應該在 70 億美元左右是否公平？

And then regarding the $2 billion in the first half '23, how much will be from the U.S. market, i.e., out of estimated 100 million doses in the U.S., what could be your market share?

然後關於 23 年上半年的 20 億美元，有多少來自美國市場，即在美國估計的 1 億劑中，你的市場份額是多少？

I'll take the first question. So first on superiority. You do not need to demonstrate superiority to get a flu vaccine approved. That's well precedented. Non-inferior efficacy is the threshold. Our goal, though, over time is absolutely to develop a superior influenza vaccine. And so if we don't see it with the first-generation product, which is mRNA-1010, I would note that we have 4 other programs -- flu programs in development, different stages of clinical trials, that are looking to do even better than perhaps flu mRNA-1010. And our goal over time would be to demonstrate that we have a superior influenza vaccine. But it is not actually required for approval non-inferiority should suffice.

我先回答第一個問題。所以首先是優勢。您無需證明優勢即可獲得批准的流感疫苗。這是有先例的。非劣效性是閾值。不過，隨著時間的推移，我們的目標絕對是開發一種更優質的流感疫苗。因此，如果我們沒有在第一代產品 mRNA-1010 中看到它，我會注意到我們還有 4 個其他項目——正在開發的流感項目、臨床試驗的不同階段，它們甚至都在尋求做可能比流感 mRNA-1010 更好。隨著時間的推移，我們的目標將是證明我們擁有更好的流感疫苗。但實際上並不需要批准非劣效性就足夠了。

I'll turn it over to Arpa, I think, for the other questions?

我想我會把它交給 Arpa 來解決其他問題？

Sure. Yes, I can take the second question. In terms of the total sales, we are anticipating about $2 billion of the $5 billion in the first half of the year, and none of that $2 billion is coming from the U.S. market. The remaining advance purchase agreements that we have of $3 billion will be coming in the second half of this year. Now, that $5 billion is just the total that we have from advanced purchase agreements as well as deferrals from 2022. We do anticipate additional sales from the U.S., Japan, EU and other markets, and we believe the majority of these sales will be in the second half of 2023.

當然。是的，我可以回答第二個問題。就總銷售額而言，我們預計今年上半年的 50 億美元中約有 20 億美元，而這 20 億美元中沒有一個來自美國市場。我們剩餘的 30 億美元預購協議將在今年下半年交付。現在，這 50 億美元只是我們從 2022 年的預購協議和延期採購協議中獲得的總額。我們確實預計美國、日本、歐盟和其他市場會有額外的銷售，我們相信這些銷售中的大部分將在2023年下半年。

And then your market share regarding the U.S. market?

那麼你們在美國市場的市場份額是多少？

We continue to believe in the strong, differentiated profile of our products. We do not have any updates on market share projections as we are currently in discussions with customers right now for fall 2023 contracting.

我們繼續相信我們產品的強大、差異化的形象。我們沒有關於市場份額預測的任何更新，因為我們目前正在與客戶討論 2023 年秋季的簽約事宜。

Next question comes from Matthew Harrison with Morgan Stanley.

下一個問題來自摩根士丹利的馬修哈里森。

Great. I was hoping to ask about the regulatory strategy for PCV, and specifically, how you're thinking about the potential for filing off the Phase II data set, as well as how you're thinking about the time lines for enrollment in the Phase III program and how that may impact the time line for potentially filing off the Phase II data set?

偉大的。我想問一下 PCV 的監管策略，具體來說，你是如何考慮提交 II 期數據集的可能性的，以及你是如何考慮 III 期註冊的時間線的計劃以及這可能如何影響可能提交第二階段數據集的時間表？

Great. So we're obviously really pleased yesterday to announce that we received FDA breakthrough designation therapy for the PCV program. And what that allows us to do is very rapidly accelerate our conversations with the FDA and other regulators on the path forward for filing 4157. As you noted, the Phase IIb study that we've run is a randomized study compared against, really, the standard of care which is KEYTRUDA alone, and has already shown a quite significant benefit at 41% reduction of the rate of recurrence and -- or death. And that study is ongoing, and so we're continuing to follow over time and conduct additional interim analyses. And it's possible that those -- in fact, we would hope that those data mature and continue to get stronger and stronger. And so it is entirely possible that in our discussions under breakthrough with the FDA and others that we will come up with a path forward for beginning the filing process based on that Phase II and potentially proceeding with an accelerated approval.

偉大的。因此，昨天我們顯然非常高興地宣布，我們的 PCV 項目獲得了 FDA 的突破性治療指定。這使我們能夠做的是非常迅速地加快我們與 FDA 和其他監管機構就提交 4157 的前進道路的對話。正如您所指出的，我們進行的 IIb 期研究是一項隨機研究，與實際上，單獨使用 KEYTRUDA 的護理標準已經顯示出相當顯著的益處，復發率和死亡率降低了 41%。這項研究正在進行中，因此我們會隨著時間的推移繼續跟進並進行額外的中期分析。而且有可能那些 - 事實上，我們希望這些數據成熟並繼續變得越來越強大。因此，在我們與 FDA 和其他機構的突破性討論中，我們完全有可能提出一條前進的道路，以開始基於第二階段的備案流程，並有可能繼續加速批准。

Now as you know, in this country, and I think it's where your question is coming from, as well globally, if there is a path forward there, we haven't yet engaged with the FDA on because the breakthrough happened yesterday. But if there is a path forward there, it would require us to rapidly enroll a confirmatory Phase III study. And in fact, there's more and more attention on perhaps requiring that those Phase III studies be enrolled prior to an accelerated approval.

現在正如你所知，在這個國家，我認為這是你的問題的來源，以及全球，如果那裡有前進的道路，我們還沒有與 FDA 接觸，因為昨天發生了突破。但如果那裡有前進的道路，那將需要我們迅速註冊一項確認性 III 期研究。事實上，越來越多的關注可能要求在加速批准之前註冊這些 III 期研究。

And so for that reason, ourselves and Merck are working really quickly now to try and stand up that confirmatory Phase III melanoma study and enroll as fast as possible. Now, we're not ready yet to guide on how quickly that will be, but we are fully aware of the fact that in fact, if there is a path forward for accelerated approval, the enrollment of that Phase III may begetting, and therefore, we want to have it enrolled as quickly as possible.

因此，出於這個原因，我們自己和默克公司現在正在非常迅速地開展工作，以嘗試支持確認性 III 期黑色素瘤研究並儘快註冊。現在，我們還沒有準備好指導這將有多快，但我們充分意識到，事實上，如果有加速批准的前進道路，那麼 III 期的註冊可能會產生，因此，我們希望盡快註冊。

So at this point, we've just received the breakthrough designation, we're engaging with regulators, and we're going to try and develop that path forward. But it is theoretically possible that there is an accelerated approval path and that we would need to enroll that Phase III study based on recent regulatory guidance, more generally to the industry. And working hard to make sure that we can do that as fast as possible here, while continuing to conduct the additional interim analyses and see the maturity of this data continue to proceed, and hopefully, the strength of the benefit provided by the combination to be further validated.

所以在這一點上，我們剛剛獲得了突破性的指定，我們正在與監管機構合作，我們將嘗試開發這條前進的道路。但從理論上講，有可能有一條加速的審批路徑，我們需要根據最近的監管指南，更廣泛地向行業註冊該 III 期研究。並努力確保我們能夠在這裡盡快做到這一點，同時繼續進行額外的中期分析並看到該數據的成熟度繼續進行，並希望合併所提供的好處的強度是進一步驗證。

Next question comes from Edward Tenthoff with Piper Sandler.

下一個問題來自 Edward Tenthoff 和 Piper Sandler。

Great. And thanks for all the detail on the call today. My question, I had to go back to flu form and just with respect to the follow-on candidates, including I think the one that's pentavalent hemagglutinin and then fixed hemagglutinin and then also into the neuraminidase, the candidates at that neuraminidase, what should be our expectation both in times of timing for data here? And how do you ultimately see your seasonal flu product offering kind of evolving?

偉大的。並感謝今天電話會議的所有細節。我的問題，我不得不回到流感形式，關於後續候選物，包括我認為是五價血凝素，然後是固定血凝素，然後是神經氨酸酶，那個神經氨酸酶的候選物，應該是什麼我們對此處數據時間的期望？您最終如何看待季節性流感產品的演變？

So let me start with the most advanced program, obviously, is our 1010 program, which we've talked about. And we have done an update to that vaccine that we think will increase the B immunogenicity for those populations for whom that matters, and we expect to advance that in clinical study quite quickly.

因此，讓我從最先進的程序開始，顯然是我們已經討論過的 1010 程序。我們已經對該疫苗進行了更新，我們認為它會增加那些重要人群的 B 免疫原性，我們希望在臨床研究中迅速推進這一點。

That, in combination with the efficacy data that we were just talking about with P302, probably is the most important information for guiding our next step on the second-generation products. Our multiple -- sorry, penta and hexavalent vaccines as well as the 1020, 1030 programs, which include neuraminidase, as you said, are all in various Phase I studies. And as we've shown repeatedly hopefully over the last couple of years, we can proceed very quickly in the subsequent Phase III in pivotal studies once we select 1 of those candidates to move forward. But the really important gating information is understanding how is our first generation product performing in terms of efficacy as a first mRNA flu vaccine. And so we are waiting for that information before proceeding forward.

結合我們剛剛談到的 P302 的療效數據，這可能是指導我們下一步開發第二代產品的最重要信息。我們的多重 - 抱歉，五價和六價疫苗以及 1020、1030 項目，如你所說，其中包括神經氨酸酶，都處於各種 I 期研究中。正如我們在過去幾年中一再充滿希望地展示的那樣，一旦我們選擇其中一名候選人繼續前進，我們就可以在隨後的第三階段關鍵研究中非常迅速地進行。但真正重要的門控信息是了解我們的第一代產品作為第一種 mRNA 流感疫苗的功效如何。因此，我們在繼續之前等待該信息。

But we do expect that at least one, if not multiple, of these second-generation products would move into subsequent pivotal studies, Phase III studies. And in those cases, because we would be looking to demonstrate some form of superiority either against a broader range of influenza strains or better protection against influenza-like illness because we've included additional antigens, we would expect those studies to include both immunogenicity and safety and efficacy end points as we move forward. And so we'll make a selection on which ones we might move forward based on the ongoing interim analysis of efficacy from our 1010 program.

但我們確實希望這些第二代產品中至少有一個（如果不是多個）將進入後續的關鍵研究，即 III 期研究。在這些情況下，因為我們希望證明某種形式的優勢，要么針對更廣泛的流感病毒株，要么更好地預防流感樣疾病，因為我們已經包含了額外的抗原，我們希望這些研究包括免疫原性和隨著我們前進，安全性和有效性終點。因此，我們將根據我們 1010 計劃正在進行的療效中期分析，選擇我們可以推進的項目。

We don't have another way to update at this point on which one we'll move forward.

目前我們沒有其他方法可以更新，我們將繼續前進。

Next question comes from Michael Yee with Jefferies.

下一個問題來自 Jefferies 的 Michael Yee。

A couple follow-up on the flu vaccines and also a PCV question for Stephen. I guess -- could you clarify -- do you have a hypothesis around why the B-strains were not non-inferior and what the ramifications are for that? Either for this flu vaccine, but also for the infection study, and what that would mean for combinations? So first of all, just to clarify what's going on there with the B-strain, the ramifications for flu vaccine.

一些關於流感疫苗的後續行動以及斯蒂芬的 PCV 問題。我想——你能澄清一下嗎——你是否有關於為什麼 B 菌株不是非劣效性的假設，以及它的後果是什麼？無論是針對這種流感疫苗，還是針對感染研究，這對組合意味著什麼？所以首先，只是為了澄清 B 型毒株的情況，即流感疫苗的後果。

And then my second question is on PCV. Obviously, we're excited about the adjuvant data. There is also a competitor reading out in metastatic melanoma this summer so I wanted to understand how we should compare and contrast that? And if you could walk us through how to think about metastatic and what competitors might show?

然後我的第二個問題是關於 PCV。顯然，我們對輔助數據感到興奮。今年夏天還有一個競爭對手在轉移性黑色素瘤上宣讀，所以我想了解我們應該如何比較和對比它？如果你能告訴我們如何考慮轉移以及競爭對手可能表現出什麼？

So first on the flu, on the B. We're still looking into the data, and we're going to develop a more complete picture of what we think happened in the influenza B immunogenicity study.

所以首先是關於流感，關於 B。我們仍在研究數據，我們將更完整地了解我們認為在 B 型流感免疫原性研究中發生的情況。

I would note a couple of things that are important. The first is these are active comparator studies. And so when you look at non-inferiority on 0 conversion or titers, it's important to note that we're going against the standard-dose influenza vaccine active comparator. And between the Phase II study and the Phase III Southern Hemisphere study, there were changes in the composition of those active comparators and the comparator used, and so that can drive some difference.

我會注意到一些重要的事情。首先是這些是積極的比較研究。因此，當您查看 0 轉化率或滴度的非劣效性時，請務必注意我們反對標準劑量流感疫苗活性比較劑。在 II 期研究和 III 期南半球研究之間，那些活躍比較器的組成和使用的比較器發生了變化，因此可以產生一些差異。

The second thing I would note is that they were different populations, and so we went from a Northern Hemisphere to a Southern Hemisphere. And obviously, that can drive some differences in background history of influenza illnesses.

我要注意的第二件事是他們是不同的人群，所以我們從北半球走到了南半球。顯然，這會導致流感疾病背景史的一些差異。

But the third and perhaps maybe most relevant is we did expect that the influenza B neutralizing titers were lower. As you remember, we shared with the Phase II data about a year ago. We did have lower neutralizing HAI titers for the influenza B strains. And for our older adult influenza vaccine, we thought that was acceptable because at the end of the day, our goal was only to achieve non-inferiority, not to demonstrate superiority. Whereas for the influenza A strains, we really wanted to maximize those neutralizing titers and potential for benefit because influenza A really is what drives illness in older adults, which is our first generation...

但第三點，也許也是最相關的一點是，我們確實預計乙型流感中和滴度較低。您還記得，我們大約在一年前分享了 II 期數據。我們對乙型流感病毒株的中和 HAI 滴度確實較低。對於我們的老年人流感疫苗，我們認為這是可以接受的，因為歸根結底，我們的目標只是實現非劣效性，而不是證明優勢。而對於甲型流感毒株，我們真的希望最大限度地提高中和效價和潛在的獲益，因為甲型流感確實是導致老年人患病的原因，這是我們的第一代......

So we did focus heavily on the influenza A. We were aiming at non-inferiority on the influenza B. And as you said, we did not make non-inferiority on those, and we'll continue to pull apart the reasons as to why. But we have already identified an update that would allow us to improve immunogenicity against the Bs to the extent that is important going forward, not just in younger populations but perhaps from an overall regulatory perspective.

所以我們確實非常關注甲型流感。我們的目標是乙型流感的非劣效性。正如你所說，我們沒有對這些進行非劣效性研究，我們將繼續分析原因.但我們已經確定了一項更新，這將使我們能夠將針對 B 的免疫原性提高到對未來發展很重要的程度，不僅是在年輕人群中，而且可能從整體監管的角度來看。

And so we've made that update, we're actually going to be evaluating that in the clinical study very shortly here. And we expect that we'll be able to address that lower immunogenicity that we saw on the Bs quite quickly.

所以我們已經進行了更新，我們實際上很快就會在臨床研究中對其進行評估。我們希望我們能夠很快解決我們在 B 上看到的較低的免疫原性。

But as I said a moment ago, what really matters is efficacy and efficacy against influenza disease. And in this case, we really do see that as influenza A related for our first-generation product. But we will obviously be updating influenza B-strain for other subsequent generation of products. And it's important to note that that's really important as you get into pediatric populations where influenza B is a burden of disease, particularly in the young.

但正如我剛才所說，真正重要的是對流感疾病的療效和療效。在這種情況下，我們確實認為甲型流感與我們的第一代產品有關。但我們顯然會為其他後續產品更新 B 型流感毒株。重要的是要注意，當你進入乙型流感是疾病負擔的兒科人群時，這一點非常重要，尤其是在年輕人中。

Now on the question of PCV, we're pretty encouraged by the adjuvant melanoma data. We do have some early metastatic data, as you'll note from our prior Phase I studies. And in the Phase II, there was some Stage IV disease as well in that study. We did not conduct it only in first-line metastatic, and so we're actually looking forward to understanding the performance of a competitive product in that space because it may actually identify an opportunity for us to move into earlier stages of treatment.

現在關於 PCV 的問題，我們對輔助黑色素瘤數據感到非常鼓舞。正如您從我們之前的 I 期研究中註意到的那樣，我們確實有一些早期轉移數據。在 II 期，該研究中也存在一些 IV 期疾病。我們並沒有隻在一線轉移中進行它，所以我們實際上期待了解競爭產品在該領域的表現，因為它實際上可能為我們找到進入早期治療階段的機會。

Now for now, our approach has been to focus on places where checkpoint including KEYTRUDA, our standard of care and have demonstrated a really strong signal, which is why you see us expanding from adjuvant melanoma into adjuvant non-small cell, and ultimately, will go first into other adjuvant indications where we really think there's the most immediate biologic benefit or biologic rationale for potential benefit that we'll be looking to demonstrate.

現在，我們的方法一直專注於包括 KEYTRUDA 在內的檢查點，我們的護理標準已經顯示出非常強烈的信號，這就是為什麼你看到我們從輔助黑色素瘤擴展到輔助非小細胞瘤，並最終將首先進入其他輔助適應症，我們確實認為有最直接的生物學益處或我們將尋求證明的潛在益處的生物學原理。

But obviously, as others start to move into the space. If they show benefits in other lines of therapy, we will absolutely want to proceed very quickly in those directions as well. So we're looking forward to those results, and we'll obviously launching them as everyone else will.

但很明顯，隨著其他人開始進入這個領域。如果它們在其他治療方面顯示出益處，我們絕對希望在這些方向上也能非常迅速地推進。所以我們期待著這些結果，我們顯然會像其他人一樣推出它們。

Next question comes from Tyler Van Buren with Cowen.

下一個問題來自 Tyler Van Buren 和 Cowen。

For RSV, a few years from now, do you expect it to be a 2, 3 or perhaps a 4-player market when including J&J? And how do you believe that the tolerability profile compares to others based upon the full data presented this morning?

對於 RSV，幾年後，如果包括強生在內，您預計它會成為一個 2 人、3 人還是 4 人的市場？根據今天早上提供的完整數據，您如何認為耐受性概況與其他概況相比？

Sure. I can maybe -- I'll take the first portion of that question. At this point, there are obviously 3 companies that have read out their Phase III pivotal efficacy studies and are proceeding right now to filing. I think -- I don't have a specific view on J&J, maybe Arpa can offer perspectives on that, but it is an adenoviral vector program, and otherwise still unclear about the regulatory path forward.

當然。我也許可以——我會回答這個問題的第一部分。在這一點上，顯然有 3 家公司已經宣讀了他們的 III 期關鍵療效研究，並且現在正在著手提交申請。我認為——我對 J&J 沒有具體的看法，也許 Arpa 可以提供對此的看法，但它是一個腺病毒載體項目，否則仍不清楚未來的監管路徑。

Now on the question of reactogenicity and tolerability profile. As we presented today or as our collaborator presented today at RSVVW, we do see, we think, a favorable tolerability profile. Grade 3 adverse reactions, whether local or systemic, were all below 2% for any of the individual symptoms. And actually compared relatively favorably with a placebo in that arm, often maybe 1.5x as frequent as what we're seeing in placebo, which we think is a compelling overall reactogenicity profile.

現在關於反應原性和耐受性的問題。正如我們今天或我們的合作者今天在 RSVVW 上所展示的那樣，我們認為，我們確實看到了良好的耐受性概況。任何個別症狀的 3 級不良反應，無論是局部的還是全身的，均低於 2%。實際上，與那隻手臂中的安慰劑相比，它相對有利，通常可能是我們在安慰劑中看到的頻率的 1.5 倍，我們認為這是一個令人信服的整體反應原性概況。

We then think the other parts of the benefit of the product are obviously efficacy. We're incredibly pleased. If you look at the most common definition of cases, so RSV lower respiratory tract disease involving 2 symptoms, which has been relatively consistent across the different products. We have seen very high efficacy 83%, which we really think is among the best. And as we presented today, that efficacy actually holds up beautifully as you look at older populations, those over the age of 70, as well as those with high-risk comorbidities. Those would drive the majority of the expense associated with caring for patients, older adults with respiratory disease from RSV.

然後我們認為產品的其他部分的好處是明顯的功效。我們非常高興。如果你看一下最常見的病例定義，那麼 RSV 下呼吸道疾病涉及 2 個症狀，這在不同的產品中是相對一致的。我們已經看到非常高的效率 83%，我們認為這是最好的。正如我們今天介紹的那樣，當你觀察老年人群、70 歲以上的人群以及患有高危合併症的人群時，這種療效實際上非常好。這些將推動與照顧患有 RSV 呼吸系統疾病的患者、老年人相關的大部分費用。

So overall, it's very difficult, obviously, to do cross-trial comparisons. And ultimately, it will fall for public health officials to make those decisions, but we are really encouraged by both the efficacy and tolerability profile of 1345, and look forward to filing and ultimately to the commercialization of that product. Arpa, would you like to add anything in terms of your perception of the market going forward?

所以總的來說，顯然很難進行交叉試驗比較。最終，將由公共衛生官員做出這些決定，但我們對 1345 的療效和耐受性概況感到由衷的鼓舞，並期待該產品的申報並最終實現商業化。 Arpa，你想補充一下你對未來市場的看法嗎？

Sure. So I would say we do anticipate it being at least the 3-player market with Moderna, Pfizer and GSK. There is a possibility of a 4-player market if J&J has a regulatory path forward with their adenovector virus vaccine. Nothing more to add there.

當然。所以我想說我們確實預計它至少是 Moderna、輝瑞和葛蘭素史克的三人市場。如果強生（J&J）的腺病毒疫苗有一條監管路徑，就有可能出現一個 4 人市場。沒有更多要添加的了。

Our next question comes from Jessica Fye with JPMorgan.

我們的下一個問題來自摩根大通的 Jessica Fye。

Following up on flu or mRNA-1010, just to be very clear. If you hit on non-inferiority in the efficacy Northern Hemisphere study, do you think that mRNA-1010 would be approvable in spite of missing on non-inferiority on the B strains? And related to that, would you envision the approval only being for older adults?

跟進流感或 mRNA-1010，只是為了非常清楚。如果您在 Northern Hemisphere 療效研究中發現了非劣效性，您認為 mRNA-1010 會得到批准，儘管 B 菌株的非劣效性缺失嗎？與此相關，您是否認為批准僅適用於老年人？

And on RSV, can you comment on the expectation for dosing frequency for your RSV vaccine? And how do you think about the value and potential pricing of that vaccine, maybe benchmarking off other vaccines for that age group?

關於 RSV，您能否評論一下您對 RSV 疫苗接種頻率的預期？您如何看待該疫苗的價值和潛在定價，也許會以該年齡段的其他疫苗為基準？

So let me take the flu stuff first. So again, the full approval gold standard is a head-to-head efficacy study. And so if we demonstrate non-inferior efficacy against an approved vaccine in the population which we're studying in which in this case in P302 is 50-plus adults. We do believe that could form the basis of an approval. At the end of the day, immunogenicity results, in particular, are only surrogates for efficacy, and ultimately, efficacy is the gold standard. That's what's required for traditional approval, and that's why we're running the P302 study.

所以讓我先吃流感的東西。因此，完全批准的金標準再次是一項頭對頭的療效研究。因此，如果我們在我們正在研究的人群中證明對已批准疫苗的非劣效性，在這種情況下，P302 是 50 多歲的成年人。我們確實相信這可以構成批准的基礎。歸根結底，尤其是免疫原性結果只是療效的替代指標，最終，療效才是金標準。這就是傳統批准所需要的，這就是我們進行 P302 研究的原因。

So it will depend upon how our conversation with regulators around that data package, but it is certainly plausible. And in fact, one might say likely that if we meet efficacy in the efficacy study that, that would be sufficient to move forward for a full approval. It doesn't mean that there may not be questions about demonstrating non-inferior immunogenicity with influenza B strains or other things in subsequent studies, but we do believe there's a possibility there. But at the end of the day, it will be dependent upon data and discussions with regulators, including the FDA. And so we'll wait till we have that data and have those conversations, but I think it's certainly a possibility.

因此，這將取決於我們如何與監管機構圍繞該數據包進行對話，但這肯定是合理的。事實上，有人可能會說，如果我們在療效研究中達到療效，那將足以推進完全批准。這並不意味著在後續研究中可能沒有關於證明 B 型流感毒株或其他東西的非劣免疫原性的問題，但我們確實相信存在這種可能性。但歸根結底，這將取決於數據和與包括 FDA 在內的監管機構的討論。所以我們會等到我們有了這些數據並進行這些對話，但我認為這肯定是有可能的。

Now as it relates to age for approval, we're currently studying mRNA-1010 only in older adults. And so as I said, the P301 was in 18-plus, P302 is in 50-plus, and that's really where we see the broadest recommendations for seasonal influenza vaccines and where we have been most focused initially on building out our respiratory portfolio. We will evaluate our influenza vaccine, in fact, many of our store vaccines in younger populations over time. But we'll have to do age deescalation, dose finding and then bridge down from an immunogenicity perspective, very much like what we did with COVID. And so our initial filings for approval, if they proceed based on data, would be in adults and older adults principally. And then eventually, we would follow on with pediatric populations.

現在因為它涉及到批准年齡，我們目前只在老年人中研究 mRNA-1010。正如我所說，P301 在 18 歲以上，P302 在 50 歲以上，這確實是我們看到季節性流感疫苗最廣泛的建議，也是我們最初最關注建立我們的呼吸道產品組合的地方。我們將評估我們的流感疫苗，事實上，隨著時間的推移，我們的許多商店疫苗都在年輕人群中使用。但我們必須進行年齡降級、劑量發現，然後從免疫原性的角度進行橋接，就像我們對 COVID 所做的一樣。因此，如果我們根據數據進行，我們最初申請批准的申請將主要針對成年人和老年人。然後最終，我們將繼續關注兒科人群。

And as I said a moment ago in response to Michael's question, that may involve using updated B antigens to increase immunogenicity in that population. But again, that's subsequent studies that we would do in children.

正如我剛才在回答邁克爾的問題時所說的那樣，這可能涉及使用更新的 B 抗原來增加該人群的免疫原性。但同樣，這是我們將在兒童中進行的後續研究。

Could you remind me of the second question?

你能提醒我第二個問題嗎？

For RSV, what are you thinking for dosing frequency? And how do you think about value and potential pricing of that vaccine, maybe benchmarking off of other vaccines for that age group?

對於 RSV，您如何看待給藥頻率？您如何看待該疫苗的價值和潛在定價，也許是針對該年齡段的其他疫苗的基準？

Sure. So I'll let Arpa take the second part of that question.

當然。所以我會讓 Arpa 回答這個問題的第二部分。

First on frequency. It is not yet clear on how frequently people will need an RSV vaccine. It's a seasonal virus, a seasonal epidemic of disease that shows up. Most of us have been exposed to RSV all over a dozen times over the course of our life. And what really happens from a biology perspective is as we get older, our ability to maintain high neutralizing titers to protect us goes down, and what we have is breakthrough disease and ultimately, a disease leads to substantial cost and morbidity and even some mortality in older adults.

首先是頻率。目前尚不清楚人們需要多長時間接種一次 RSV 疫苗。這是一種季節性病毒，一種出現的季節性疾病流行病。在我們的一生中，我們大多數人已經接觸過 RSV 十多次。從生物學的角度來看，真正發生的事情是隨著年齡的增長，我們維持高中和效價以保護我們的能力下降，我們所患的是突破性疾病，最終，一種疾病會導致高昂的成本和發病率，甚至導致一些死亡率老年人。

We do not -- we have not yet had approved vaccines, and so what we don't yet know is what's the frequency of vaccination. Is it going to be seasonal every year, or is it going to be less than seasonal every couple or few years? But what's pretty clear, based -- from my perspective, based on the epidemiology of RSV infection, is that we do see RSV fairly regularly as adults, and unfortunately, over time, it breaks through more frequently, and so there probably will need to be repeated boosting to protect against RSV.

我們還沒有——我們還沒有獲得批准的疫苗，所以我們還不知道接種疫苗的頻率是多少。它是每年都會有季節性，還是每隔幾年或幾年就會不那麼季節性？但非常清楚的是，基於——從我的角度來看，基於 RSV 感染的流行病學，我們確實經常看到 RSV 成年後，不幸的是，隨著時間的推移，它更頻繁地爆發，因此可能需要重複加強以防止 RSV。

At the end of the day, the initial recommendations will come from ACIP as well as from regulators around that frequency, and we will have to defer to them on how they want to administer and roll out the RSV vaccines. Whether they want to follow a flu model, which would be annual to make sure that we get the broadest amount of protection, or that they want to initially roll out RSV vaccines and then follow over time for the durability of that efficacy. At this point, none of us, none of the 3 products that have read out in Phase III, have a clear answer on the durability of that efficacy, although we would expect it to wane as it does against natural RSV infection over time in older adults.

在一天結束時，最初的建議將來自 ACIP 以及圍繞該頻率的監管機構，我們將不得不聽從他們如何管理和推出 RSV 疫苗。他們是否想遵循每年一次的流感模型，以確保我們獲得最廣泛的保護，或者他們是否想首先推出 RSV 疫苗，然後隨著時間的推移進行跟踪以確保這種功效的持久性。在這一點上，我們中沒有人，在 III 期中讀出的 3 種產品中，沒有人對這種功效的持久性有明確的答案，儘管我們預計它會隨著時間的推移而減弱，因為它在對抗自然 RSV 感染時會隨著時間的推移而減弱成年人。

Arpa, do you want to take the next part of the session?

Arpa，你想參加會議的下一部分嗎？

Sure, yes. I can take the question on pricing. So overall, from a pricing philosophy perspective, Moderna is committed to pricing that reflects the value of our vaccines in terms of what they deliver to patients, to societies and the healthcare systems, while also ensuring full access for patients regardless of their ability to pay. So with that broader principle around pricing, we will be looking at the full recommendations that come out of ACIP as we get the filing and the ACIP recommendations to look at what the full value that could be provided back is based on things, as Stephen mentioned, around dosing frequency. And the pricing will be based on both value and access.

當然，是的。我可以回答有關定價的問題。因此，總的來說，從定價理念的角度來看，Moderna 致力於定價，以反映我們的疫苗在為患者、社會和醫療保健系統提供的產品方面的價值，同時確保患者能夠充分獲得疫苗，無論他們的支付能力如何.因此，根據關於定價的更廣泛的原則，我們將在收到申請時查看 ACIP 提出的完整建議，以及 ACIP 的建議，以了解可以提供的全部價值是基於事物的，正如 Stephen 提到的, 大約給藥頻率。定價將基於價值和訪問。

I'm not able to share any additional details on what sort of range that pricing might fall into, but it will be consistent with our overall pricing philosophy.

我無法分享有關定價可能屬於哪種範圍的任何其他詳細信息，但這將與我們的整體定價理念保持一致。

Our next question comes from Ellie Merle with UBS.

我們的下一個問題來自瑞銀的 Ellie Merle。

Just another on flu, just -- any more details on the titer level specific that you saw or when we'll get more details on the titer levels? And then how should we think about the importance of having titers above that 40 benchmark versus demonstrating non-inferiority. Like I guess, what is the comparator vaccine titers in your Phase III say did very well and were well above 40? How should we think about the implications then, say, you're at 30 or near 40, what that would mean from a regulatory standpoint as well as a commercial standpoint in interpreting the immunogenicity idea?

只是另一個關於流感的問題，只是 - 關於您看到的特定滴度水平的更多詳細信息，或者我們何時會獲得更多關於滴度水平的詳細信息？然後我們應該如何考慮滴度高於 40 基準與證明非劣效性的重要性。就像我猜的那樣，你說的 III 期比較疫苗效價是多少，效果很好並且遠高於 40？那麼，我們應該如何考慮其影響，比如說，你 30 歲或接近 40 歲，從監管角度和商業角度解釋免疫原性概念意味著什麼？

All very good questions, and I think the short answer is we're looking into that data right now, and we will provide an update. I'm not exactly sure when we will have that, but we do have the Vaccines Day investor meeting coming up in April of the spring, and then obviously, we'll be looking to publish that data and share it as it comes in and is it available.

所有非常好的問題，我認為簡短的回答是我們現在正在研究這些數據，我們將提供更新。我不確定我們什麼時候會有那個，但我們確實在春天的 4 月舉行了疫苗日投資者會議，然後很明顯，我們將尋求發布這些數據並在它進來時分享它，是可用的麼。

You've highlighted 1 of the key challenges in active comparator studies in particular, which is that you can see high titers but actually because you're looking at a ratio, say for whatever reason, your active comparator does really well against one of the strains, that can impact your ability to tease non-inferiority statistically. And at the end of the day, the challenge is even more complicated as you look at older adults where, for instance, the influenza B strains are not a big driver of efficacy or disease, and so we will look at all of that as well regulators.

您特別強調了主動比較器研究中的一個關鍵挑戰，即您可以看到高滴度，但實際上因為您正在查看一個比率，無論出於何種原因，您的主動比較器確實比其中一個做得更好壓力，這會影響您在統計上取笑非劣勢的能力。歸根結底，當你觀察老年人時，挑戰會更加複雜，例如，B 型流感毒株並不是療效或疾病的主要驅動因素，因此我們也會研究所有這些監管機構。

I would note that it is well precedented. In fact, many of the currently approved influenza vaccines have, in the past, missed on non-inferiority for -- and influenza B-strain end points here over there and still haven't received full approval or accelerated approvals. And the reason for that is, as we've said sort of throughout, that at the end of the day, influenza B is not a primary driver of concern and it is known to be among the different strains of influenza in the virus -- in the vaccines of lower import for disease in older adults. In fact, 1 of the 4 strains, there have been active debates about the B/Yamagata strain as to whether or not it's gone extinct, and even should be removed from quadrivalent vaccines in many of the recent WHO and other debates.

我會注意到這是有先例的。事實上，許多目前獲批的流感疫苗在過去都沒有達到非劣效性——以及這裡那裡的 B 型流感毒株終點，而且仍未獲得完全批准或加速批准。其原因是，正如我們從頭到尾所說的那樣，歸根結底，B 型流感並不是引起關注的主要驅動因素，而且眾所周知，它屬於病毒中的不同流感病毒株——在老年人疾病的較低進口疫苗中。事實上，B/Yamagata 菌株是 4 種菌株中的一種，它是否已經滅絕，甚至在最近的許多 WHO 和其他辯論中甚至應該從四價疫苗中刪除。

And so influenza B is a well-trodden path for many of these vaccines as well as now for mRNA-1010, where there is differential performance, and ultimately, there is precedent for moving forward where you do not technically need non-inferiority on immunogenicity or seroconversion endpoints and still moving forward because of the lower concern about that disease in older adults.

因此，對於其中許多疫苗以及現在的 mRNA-1010 來說，B 型流感是一條成熟的道路，它們具有不同的性能，最終，在技術上不需要免疫原性的非劣效性的情況下，有向前推進的先例或血清轉化終點，並且仍在向前推進，因為老年人對該疾病的關注度較低。

So we will look at that data. We will develop our strategy. We will obviously engage with regulators with that data, and ultimately determine a path forward. The most important thing for us, though, in the near term is continuing with the efficacy study trying to establish whether or not we have non-inferior or even superior efficacy for mRNA-1010 in its current form against influenza A, which is really where we think payers and public health officials will have the most attention because it is prevention of that disease, not the immunogenicity endpoint, prevention of influenza-like illness, hospitalizations, that is the primary objective of the vaccine and that's where we're focusing our attention right now.

因此，我們將查看該數據。我們將製定我們的戰略。我們顯然會與監管機構就這些數據進行接觸，並最終確定前進的道路。不過，對我們來說，近期最重要的事情是繼續進行療效研究，試圖確定我們目前形式的 mRNA-1010 是否具有非劣效甚至優於甲型流感的療效，這確實是我們認為付款人和公共衛生官員將受到最多的關注，因為它是預防這種疾病，而不是免疫原性終點，預防流感樣疾病、住院，這是疫苗的主要目標，也是我們關注的地方現在註意。

Our next question comes from Joseph Stringer with Needham.

我們的下一個問題來自 Joseph Stringer 和 Needham。

Two from us, the first one on 4157 KEYTRUDA combo program. Just curious, if you could give us a little bit more color on how we should think about the cadence of the additional trial starts? Is it something that will be a more stepwise and measured approach, or should we expect sort of a full force kind of multiple trial starts approach?

我們有兩個，第一個在 4157 KEYTRUDA 組合程序上。只是好奇，您是否可以給我們更多關於我們應該如何考慮額外試驗開始的節奏的顏色？這將是一種更加循序漸進和慎重的方法，還是我們應該期待一種全力以赴的多次試驗開始方法？

And then secondly, on rare disease, outside of your M&A, GSD and PA programs, what is the next rare disease program that we can expect to enter the clinic?

其次，在罕見疾病方面，除了你們的併購、GSD 和 PA 項目之外，我們可以預期進入臨床的下一個罕見疾病項目是什麼？

So on 4157, I think I'll just reiterate our prior guidance, I don't want to expand it, to say that we are trying to move into those pivotal studies, Phase III confirmatory Stage IV melanoma and non-small cell lung cancer, both adjuvant settings, this year. And we -- you can look at the history of Merck and their ability to execute those studies, enroll quite quickly and now working together with us, we hope to be able to at least do that well. And we will look to enroll those at least as quickly as other confirmatory Phase III studies and similar populations have been run generally. But I don't think we're going to provide more specific guidance on enrollment time horizon except to say we want to go as fast as possible.

所以在 4157 上，我想我只是重申我們之前的指導，我不想擴大它，說我們正試圖進入那些關鍵研究，III 期確認性 IV 期黑色素瘤和非小細胞肺癌，這兩個輔助設置，今年。我們——你可以看看默克公司的歷史和他們執行這些研究的能力，很快就註冊，現在與我們一起工作，我們希望至少能夠做到這一點。我們將尋求至少與其他驗證性 III 期研究和類似人群普遍開展的一樣快地招募這些人。但我認為我們不會就註冊時間範圍提供更具體的指導，只是說我們希望盡快進行。

I will also clarify, too, that from an accelerated approval perspective, if that pathway were to become available based on the current Phase II data, which again is subject to future conversations with regulators, that we would want to have started those confirmatory studies. We wouldn't have needed to complete enrollment, but definitely, we want to be demonstrating that we're moving forward in those confirmatory studies as quickly as possible. And so we have double impetus. We're moving fast in enrolling them in the near term.

我還將澄清，同樣，從加速批准的角度來看，如果該途徑基於當前的 II 期數據可用（這再次取決於未來與監管機構的對話），我們希望已經開始這些驗證性研究。我們不需要完成註冊，但我們肯定希望證明我們正在盡快推進這些驗證性研究。所以我們有雙重動力。我們在短期內快速招收他們。

Now in the rare disease space, programs moving out of pre-clinical and clinical. The first I would say is we do have a clinical program for MMA, which you referenced, but that MMA program is another place where we expect to see additional data following on, hopefully, the continued strong performance of the propionic acidemia PA program. And then the pre-clinical development space, we have programs against OTC and PKU, so proteinuria and a urea cycle disorder OTC, and those are both programs that we would hope to move into clinical testing in short order. We haven't specifically guided on the timing of that yet.

現在在罕見病領域，項目正在從臨床前和臨床階段轉移。我首先要說的是，我們確實有一個 MMA 臨床計劃，您提到了這一點，但是 MMA 計劃是我們希望在丙酸血症 PA 計劃持續強勁表現之後看到更多數據的另一個地方。然後是臨床前開發空間，我們有針對 OTC 和 PKU 的項目，因此蛋白尿和尿素循環障礙 OTC，這些都是我們希望在短期內進入臨床測試的項目。我們還沒有具體指導時間。

Ladies and gentlemen, this does conclude the question-and-answer portion of today's call. I'd like to turn the call back over to Stephane for any closing remarks.

女士們，先生們，今天電話會議的問答部分到此結束。我想將電話轉回給 Stephane 以聽取任何結束語。

Thank you very much, everybody, for joining us and for the many thoughtful questions. We look forward to hosting you for Vaccine Day on April 11. It will be live in Boston, for those of you who can join us, and also, of course, virtual. Have a great day. Thank you.

非常感謝大家加入我們並提出許多深思熟慮的問題。我們期待在 4 月 11 日的疫苗日接待您。它將在波士頓現場直播，供那些可以加入我們的人使用，當然還有虛擬的。祝你有美好的一天。謝謝。

Ladies and gentlemen, this does conclude today's presentation. You may now disconnect, and have a wonderful day.

女士們，先生們，今天的演講到此結束。您現在可以斷開連接，並度過美好的一天。