福泰製藥 (VRTX) 2020 Q4 法說會逐字稿

Making prepared remarks on the call tonight, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Stuart Arbuckle, Chief Commercial Officer; and Charlie Wagner, Chief Financial Officer. Dr. David Altshuler, Chief Scientific Officer; and Dr. Bastiano Sanna, Chief of Cell and Genetic Therapies, will join the Q&A portion of the call following the prepared remarks.

今晚在電話會議上發表準備好的演講的有：Vertex 執行長兼總裁 Reshma Kewalramani 博士；商務長 Stuart Arbuckle；以及財務長 Charlie Wagner。首席科學官 David Altshuler 博士和細胞與基因療法主管 Bastiano Sanna 博士將在準備好的演講結束後參加電話會議的問答環節。

We recommend that you access the webcast slides on our website as you listen to this call. This conference call is being recorded, and a replay will be available on our website.

我們建議您在收聽本次電話會議的同時，請造訪我們網站上的網路直播投影片。本次電話會議正在錄音，錄音回放將在我們的網站上提供。

We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and our filings with the Securities and Exchange Commission. These statements, including, without limitation, those regarding Vertex's marketed CF medicines, our pipeline and Vertex's future financial performance, are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance we will review on the call this evening are non-GAAP.

我們將在本次電話會議上發表前瞻性聲明，這些聲明受到今天新聞稿和我們向美國證券交易委員會提交的文件中詳細討論的風險和不確定性的影響。這些聲明，包括但不限於有關 Vertex 已上市的 CF 藥物、我們的研發管線和 Vertex 未來財務業績的聲明，均基於管理層目前的假設。實際結果和事件可能與此有重大差異。我還想指出，我們今晚電話會議上將要討論的部分財務表現和指引是非GAAP準則的。

I will now turn the call over to Dr. Reshma Kewalramani.

現在我將把電話轉給雷什瑪·凱瓦拉瑪尼醫生。

I'll begin this evening's call with comments on our 2020 performance and then turn to the pipeline, including an overview of a number of our R&D programs and upcoming milestones. 2020 was an unprecedented year for governments, businesses and people around the globe. It was also a remarkable year for Vertex. Despite the challenges we all faced against the backdrop of the pandemic, Vertex delivered extraordinary commercial performance generating $6.2 billion in product revenues, representing more than 50% growth compared to 2019. We also meaningfully advanced the pipeline and significantly strengthened our financial position.

今晚的電話會議，我將首先對我們 2020 年的業績進行評論，然後轉向產品線，包括概述我們的一些研發項目和即將到來的里程碑。2020年對全球各國政府、企業和人民來說都是前所未有的一年。對Vertex來說，這也是意義非凡的一年。儘管在疫情的背景下我們都面臨著挑戰​​，但 Vertex 取得了非凡的商業業績，創造了 62 億美元的產品收入，比 2019 年增長了 50% 以上。我們也取得了實質進展，推進了產品管線建設，並顯著增強了財務實力。

Vertex has discovered and developed medicines that have transformed the treatment of cystic fibrosis. And the latest of these, TRIKAFTA, or KAFTRIO, as it's known in the EU, has the potential to treat up to 90% of patients with cystic fibrosis. In 2020, the first full year after TRIKAFTA approval in the U.S., the number of patients with CF treated with our medicines increased substantially. And by the end of the year, the vast majority of eligible patients, 12 years and older, in the U.S. were on TRIKAFTA.

Vertex公司發現並開發了改變囊性纖維化治療方式的藥物。其中最新的一種療法是 TRIKAFTA，或在歐盟被稱為 KAFTRIO，它有可能治療高達 90% 的囊性纖維化患者。2020 年，即 TRIKAFTA 在美國獲得批准後的第一個完整年度，接受我們藥物治療的囊性纖維化患者人數大幅增加。到了年底，美國絕大多數 12 歲及以上的符合條件的患者都接受 TRIKAFTA 治療。

In Q3, we received early approval for KAFTRIO in the EU and also secured reimbursement in England. By the end of the year, with direct access at marketing authorization in Germany, portfolio agreements in Ireland and Denmark and the reimbursement deal in the U.K., thousands of patients across the EU gained access to KAFTRIO. In terms of next steps in CF, we have line of sight to continued significant growth as we expand access to the triple combination to more patients in the EU, to cure approvals in new geographies as well as extend treatment to patients with rare mutations and younger populations, starting with the 6 to 11 year olds in the U.S. We're also advancing additional small molecule combination regimen and other approaches that will further define our long-term leadership in CF. Our goal remains to bring transformative therapies to all people with this disease.

第三季度，我們獲得了歐盟對 KAFTRIO 的早期批准，並在英國獲得了報銷。到了年底，隨著德國直接獲得上市許可、愛爾蘭和丹麥達成產品組合協議以及英國達成報銷協議，歐盟各地成千上萬的患者獲得 KAFTRIO 的使用權。就囊性纖維化 (CF) 的下一步發展而言，我們有望繼續實現顯著增長，具體措施包括：在歐盟擴大三聯療法的覆蓋範圍，讓更多患者獲得治療；在新的地區獲得治愈批准；並將治療範圍擴大到罕見突變患者和更年輕的人群，首先從美國的 6 至 11 歲兒童開始。我們也正在推進其他小分子聯合療法和其他方法，這將進一步鞏固我們在囊性纖維化領域的長期領先地位。我們的目標仍然是為所有患有這種疾病的人帶來變革性的療法。

2020 was also an important year for our pipeline. We delivered proof-of-concept in 2 disease areas and advanced several clinical programs, spanning multiple modalities, and we are now poised to move the VX-880 program into the clinic for type 1 diabetes, our seventh disease area in clinical development and our first cell-based therapy.

2020年對我們的管道建設來說也是重要的一年。我們在 2 個疾病領域實現了概念驗證，並推進了多個臨床項目，涵蓋多種治療方式。現在，我們準備將 VX-880 計畫推進到第 1 型糖尿病的臨床階段，這是我們臨床開發的第七個疾病領域，也是我們的第一個基於細胞的療法。

Turning to our financial position, which continues to strengthen. As we treat more patients, our revenues and profitability are growing, and we finished the year with $6.7 billion in cash. We are steadfast in our belief that the best way to drive continued growth and create long-term value is to reinvest this capital in innovation, both internal and external. With respect to external innovation, our strategy remains the same, invest in assets that complement our internal CF pipeline, seek assets that fit our R&D strategy and identify tools to add to our toolkit. What has changed is our position in CF and our growing financial firepower. Given where we are with TRIKAFTA and KAFTRIO plus line of sight to novel regimens and treatment for the last 10% and given our balance sheet, we are now in a position to focus on assets that fit our R&D strategy and consider assets in mid and late stage.

再來看我們的財務狀況，它持續增強。隨著我們接診的患者越來越多，我們的收入和獲利能力也在成長，到年底我們擁有 67 億美元的現金。我們始終堅信，推動持續成長和創造長期價值的最佳方法是將這些資本再投資於創新，包括內部創新和外部創新。在外部創新方面，我們的策略仍然不變，即投資於能夠補充我們內部CF產品線的資產，尋找符合我們研發策略的資產，並確定可以添加到我們工具包中的工具。改變的是我們在CF領域的地位以及我們日益增長的財力。鑑於 TRIKAFTA 和 KAFTRIO 的現狀，以及對最後 10% 的新療法和治療方案的展望，再加上我們的資產負債表，我們現在可以專注於符合我們研發策略的資產，並考慮處於中後期階段的資產。

Moving on to an update on the pipeline. I'll focus on our R&D portfolio outside of CF and provide additional detail, including upcoming milestones on a number of programs. In total, we are active in clinical development in 7 disease areas, spanning multiple modalities, including small molecule, gene editing and cell therapy with each program holding the potential to transform the course of the targeted disease.

接下來報告管道建設的最新進展。我將重點介紹我們在 CF 以外的研發組合，並提供更多細節，包括多個專案的即將到來的里程碑。我們目前在 7 個疾病領域積極進行臨床開發，涵蓋多種治療方式，包括小分子藥物、基因編輯和細胞療法，每個計畫都有可能改變目標疾病的進程。

I'll start with CTX001, our most clinically derisked program outside of CF, which we are developing with our partner, CRISPR Therapeutics. In December, groundbreaking clinical data in sickle cell disease and transfusion-dependent beta-thalassemia were published in the New England Journal of Medicine and presented in a plenary session at the American Society of Hematology Annual Meeting. These data demonstrated proof-of-concept and showed that CTX001 has the potential to be a onetime functional cure for people living with these diseases. We're also pleased to share that the first patient treated in the thalassemia study recently completed 2 years of follow-up and has enrolled in the long-term follow-up study. We are advancing through clinical development with urgency, and our goal is to be able to bring this therapy to patients as soon as possible.

我先從 CTX001 開始，這是我們在 CF 領域之外臨床風險最低的項目，我們正在與合作夥伴 CRISPR Therapeutics 一起開發該項目。12 月，《新英格蘭醫學雜誌》發表了鐮狀細胞疾病和輸血依賴型β-地中海貧血的突破性臨床數據，並在美國血液學會年會全體會議上進行了展示。這些數據證明了概念的正確性，並表明 CTX001 有可能成為治療這些疾病的一次性功能性療法。我們也很高興地宣布，地中海貧血研究中接受治療的第一位患者最近完成了 2 年的隨訪，並已加入長期隨訪研究。我們正在加快臨床開發進程，目標是盡快將這種療法帶給患者。

Over the course of 2021, there are 3 key milestones that will mark our progress with CTX001: first, the presentation of additional clinical data for more patients and for a longer duration of follow-up that will further define the efficacy and durability of this therapy; the completion of enrollment of our 2 ongoing studies of CTX001; and third, the progression of our discussions with regulators about the data needed for a filing package for approval of CTX001.

在 2021 年，我們將迎來 3 個關鍵里程碑，標誌著我們在 CTX001 方面取得的進展：首先，我們將迎來 3 個關鍵里程碑，標誌著我們在 CTX001 方面取得的進展：首先，我們將公佈更多患者的更多臨床數據，並延長隨訪時間，以進一步明確該療法的療效和持久性；其次，我們將完成正在進行的 2 項 CTX001 研究的審組工作；

In our alpha-1 antitrypsin deficiency, or AATD program, we're focused on the development of small molecule correctors to address the Z-AAT protein folding defect, the underlying cause of this disease, and thereby, treat both lung and liver manifestations of the disease. Our most advanced molecules VX-864, which is progressing through a dose-ranging Phase II proof-of-concept study. The goal of the study is to assess safety, PK and levels of functional AAT protein. The study continues to enroll in dose patients, and we expect to have the results in the first half of this year. Consistent with our portfolio approach, that is to say our strategy of advancing multiple molecules simultaneously through early clinical development for each target across our disease areas, we are also on track to advance an additional small molecule AAT corrector into the clinic in 2021.

在我們的α-1抗胰蛋白酶缺乏症（AATD）計畫中，我們專注於開發小分子矯正劑，以解決Z-AAT蛋白折疊缺陷（該疾病的根本原因），從而治療該疾病的肺部和肝臟表現。我們最先進的分子 VX-864 正在進行劑量範圍 II 期概念驗證研究。研究的目標是評估安全性、藥物動力學和功能性 AAT 蛋白質水平。研究仍在招募劑量組患者，我們預計將在今年上半年獲得結果。與我們的投資組合策略一致，即我們針對每個疾病領域內的每個靶點，同時推進多個分子進入早期臨床開發階段的策略，我們也正按計劃推進另一種小分子 AAT 矯正劑於 2021 年進入臨床階段。

Our lead molecule in the APOL1-mediated FSGS program, VX-147, is also currently being studied in a Phase II proof-of-concept study, evaluating the safety, PK and reduction of proteinuria over 13 weeks. We expect to have results from this study in 2021. We also have a second molecule for APOL1-mediated kidney disease that is now completing Phase I.

我們 APOL1 介導的 FSGS 計畫中的先導分子 VX-147 目前也在 II 期概念驗證研究中進行研究，評估其安全性、藥物動力學以及 13 週內蛋白尿的減少。我們預計將於 2021 年獲得這項研究的結果。我們還有第二種用於治療 APOL1 介導的腎臟疾病的分子，目前正在完成 I 期臨床試驗。

In our pain program, we have a molecule that continues to progress through Phase I, and we have at least one additional NaV1.8 inhibitor that we expect to enter the clinic this year.

在我們的疼痛治療計畫中，我們有一種分子正在繼續推進 I 期臨床試驗，我們至少還有一種 NaV1.8 抑制劑有望在今年進入臨床階段。

Lastly, we submitted the IND for VX-880, our first cell therapy for type 1 diabetes, towards the end of last year, and we are very pleased that the FDA recently cleared the IND. This allogeneic cell transplant program has the potential to transform the treatment of type 1 diabetes. In type 1 diabetes, insulin-producing islet cells are destroyed. Our approach is to replace these cells with fully differentiated stem cell-derived pancreatic islet cells. This approach follows the well-established precedent of cadaveric islet cell transplants, which have proven clinical benefit. Advancement of VX-880 is a significant achievement. It is Vertex's first cell-based therapy to enter the clinic, and it is the only fully differentiated pancreatic islet cell program in development. We expect to initiate the Phase I/II clinical trial, which is a single-arm study of people with severe, difficult-to-control type 1 diabetes in the coming months. The goal of this study is to assess safety and measures of glycemic control. We are focused on quickly getting the clinical trial up and running, and we look forward to updating you as we make more progress over the course of this year.

最後，我們在去年底提交了VX-880（我們首個用於治療第1型糖尿病的細胞療法）的IND申請，我們非常高興FDA最近批准了該IND申請。這項異體細胞移植計畫有可能改變第 1 型糖尿病的治療方式。1 型糖尿病中，產生胰島素的胰島細胞遭到破壞。我們的方法是用完全分化的幹細胞衍生的胰島細胞來取代這些細胞。這種方法遵循了屍體胰島細胞移植的成熟先例，已被證明具有臨床益處。VX-880 的研發是一項重大成就。這是 Vertex 公司首個進入臨床階段的細胞療法，也是目前唯一正在開發的完全分化的胰島細胞療法。我們預計將在未來幾個月內啟動 I/II 期臨床試驗，這是一項針對患有嚴重、難以控制的 1 型糖尿病患者的單臂研究。本研究旨在評估安全性和血糖控制措施。我們正專注於盡快啟動臨床試驗，並期待在今年取得更多進展後及時向您報告。

With that overview, I'll now hand it off to Stuart.

有了以上概述，我現在將交給斯圖爾特。

Thank you, Reshma. I am pleased to review, with you, our continued strong commercial performance. Our Q4 global revenues were $1.6 billion, with full year revenues of $6.2 billion. This reflects significant growth over 2019 as we launched TRIKAFTA and KAFTRIO in the U.S. and EU, respectively. As expected, in addition to considerable continued U.S. demand for our medicines, we saw a significant increase in revenues from outside the U.S. in the fourth quarter, following the approval and launch of KAFTRIO.

謝謝你，雷什瑪。我很高興與各位一起回顧我們持續強勁的商業表現。我們第四季全球營收為 16 億美元，全年營收為 62 億美元。這反映了 2019 年的顯著增長，因為我們分別在美國和歐盟推出了 TRIKAFTA 和 KAFTRIO。正如預期的那樣，除了美國對我們藥品的持續旺盛的需求外，隨著 KAFTRIO 獲得批准並上市，我們在第四季度也看到了來自美國以外地區的收入大幅增長。

Starting in the U.S. It is now well over a year since the launch of TRIKAFTA, and we have made tremendous progress in bringing TRIKAFTA to nearly all eligible patients, 12 and older, as reflected in our Q4 revenues. In 2021, our commercial focus now turns to maintaining the very high rates of persistence and compliance that we have seen to date, and we anticipate that these rates will normalize over the coming months. We expect the majority of near-term growth of TRIKAFTA in the U.S. to come from approvals in rare mutations and younger age groups. TRIKAFTA was recently approved for patients 12 and older with rare mutations, and the FDA recently accepted the sNDA for 6 to 11 year olds and granted it priority review. We expect an approval around midyear.

從美國開始，TRIKAFTA 上市至今已超過一年，我們在將 TRIKAFTA 推廣到幾乎所有符合條件的 12 歲及以上患者方面取得了巨大進展，這體現在我們第四季度的收入中。2021年，我們的商業重點轉向維持迄今為止我們所看到的非常高的續約率和合規率，我們預計這些比率將在未來幾個月內恢復正常。我們預計 TRIKAFTA 在美國的近期成長主要來自罕見突變和年輕年齡層的批准。TRIKAFTA 最近獲準用於治療 12 歲及以上患有罕見突變的患者，FDA 最近接受了針對 6 至 11 歲兒童的補充新藥申請 (sNDA)，並授予其優先審查資格。我們預計年中左右會獲得批准。

In Europe, enthusiasm and interest in KAFTRIO amongst the CF community is high. Our fourth quarter revenues reflect substantial uptake of KAFTRIO across all countries where patients have access. Most notably in the larger markets of Germany and England, where the majority of eligible patients have already been initiated. We are seeing similar uptake in other countries where we have secured reimbursement agreements, including Ireland, Scotland, Wales and Denmark. We remain focused on continuing the launch in these countries as well as completing new reimbursement agreements to provide all eligible patients across the EU with access to our medicines. We have high confidence that, as was the case in the U.S., ultimately the vast majority of CF patients in the EU will be treated with KAFTRIO.

在歐洲，囊性纖維化患者群體對 KAFTRIO 的熱情和興趣很高。我們第四季度的收入反映了 KAFTRIO 在所有患者能夠獲得治療的國家/地區的顯著普及。尤其是在德國和英國這樣的大市場，大多數符合條件的患者已經開始接受治療。我們在其他已達成報銷協議的國家也看到了類似的接受度，包括愛爾蘭、蘇格蘭、威爾斯和丹麥。我們將繼續專注於在這些國家推出產品，並完成新的報銷協議，以便讓歐盟所有符合資格的患者都能獲得我們的藥品。我們非常有信心，就像在美國一樣，最終歐盟絕大多數 CF 患者都將接受 KAFTRIO 治療。

However, while the destination is the same, the journey to get there will be different. In addition to the time and work required to secure new reimbursement agreements, the COVID-19 pandemic also presents significant uncertainties around the rate of uptake for our medicines. We are conducting fully virtual launches in the EU amidst evolving country level COVID lockdowns. The ability of patients to attend in-person consultations with their physicians as the pandemic continues is a dynamic we are monitoring closely.

然而，雖然目的地相同，但到達目的地的旅程卻截然不同。除了獲得新的報銷協議所需的時間和精力外，COVID-19 疫情也為我們的藥物普及率帶來了很大的不確定性。在歐盟各國新冠疫情封鎖措施不斷變化的情況下，我們正在進行完全線上的產品發表會。隨著疫情持續蔓延，患者能否親自到醫師處進行諮詢是值得我們密切關注的動態。

I will now outline what's next for Vertex's CF franchise and how to think about future growth. We recently shared with you an updated and expanded view of the CF market opportunity based on an accumulation of new data from registries and other sources around the world. We now estimate that there are 83,000 patients living with CF in the U.S., Europe, Canada and Australia. Today, we are treating around half of these patients. Notably, this leaves more than 30,000 additional patients in these regions who could benefit from our medicines and who are not treated today. Approximately 2/3 are 12 and older, and we expect to reach these patients through the continued launch, uptake and reimbursement of KAFTRIO in the EU and through approvals and reimbursement agreements in other countries, such as Australia and Canada. The remaining 1/3 of patients are in lower age groups or have other mutations, and we are making progress towards reaching these patients through label expansions.

接下來，我將概述 Vertex 的 CF 系列產品接下來的發展方向以及如何看待未來的成長。我們最近根據從世界各地註冊機構和其他來源收集的新數據，與您分享了對 CF 市場機會的最新和擴展觀點。我們現在估計，美國、歐洲、加拿大和澳洲共有 83,000 名囊性纖維化患者。如今，我們正在治療其中大約一半的患者。值得注意的是，這意味著這些地區還有超過 30,000 名患者可以從我們的藥物中受益，但目前尚未接受治療。其中約 2/3 為 12 歲及以上，我們希望透過在歐盟持續推出、推廣和報銷 KAFTRIO，以及在澳洲和加拿大等其他國家獲得批准和報銷協議，來惠及這些患者。其餘 1/3 的患者年齡較小或患有其他突變，我們正在透過擴大適應症範圍來逐步惠及這些患者。

Finally, I'd like to take a moment to recognize the CF teams at Vertex, both in the U.S. and internationally, for their unwavering dedication despite the unprecedented global challenges of the past year. And I would also like to thank the CF community for their partnership as we work together to bring transformative medicines to patients around the world.

最後，我想藉此機會表彰 Vertex 在美國和國際上的 CF 團隊，感謝他們在過去一年中面對前所未有的全球挑戰時所展現出的堅定不移的奉獻精神。我還要感謝囊性纖維化社群的合作，我們共同努力，為世界各地的患者帶來變革性的藥物。

Charlie will now review our fourth quarter and full year results and financial guidance.

查理接下來將審核我們第四季和全年的業績及財務預期。

Thanks, Stuart. In the fourth quarter of 2020, we continued our exceptionally strong financial performance. And of note, Q4 was our first quarter with more than $1 billion of sales for the triple combination, a significant accomplishment for the commercial team.

謝謝你，斯圖爾特。2020年第四季度，我們繼續保持了非常強勁的財務表現。值得一提的是，第四季是我們三合一產品銷售額首次突破 10 億美元大關的季度，這對商業團隊來說是一項重大成就。

Fourth quarter total product revenues were $1.6 billion, a 29% increase compared to 2019, bringing our full year revenues to $6.2 billion, an increase of more than 50% compared to 2019 revenues of $4 billion. Our fourth quarter revenues included $1.21 billion in the U.S. and $421 million in revenues outside the U.S. Our ex-U. S. revenues for the quarter grew 70% over the prior year, driven by the uptake of KAFTRIO and our other medicines following the completion of several reimbursement agreements over the last year.

第四季產品總營收為 16 億美元，比 2019 年成長 29%，使全年營收達到 62 億美元，比 2019 年的 40 億美元營收成長超過 50%。我們第四季的營收包括美國境內的 12.1 億美元營收和美國境外的 4.21 億美元收入。由於去年完成了幾項報銷協議，KAFTRIO 和其他藥品的銷量大幅增長，推動了該季度美國的收入比上年同期增長 70%。

Our fourth quarter 2020 combined R&D and SG&A expenses were $539 million compared to $496 million for the fourth quarter of 2019. And our full year expenses were $1.98 billion compared to $1.69 billion in 2019. Our full year expenses reflected increased cost to support the rapid global expansion of our CF business as well as targeted investment in expanding our pipeline into new disease areas and progressing our high priority clinical programs.

2020 年第四季度，我們的研發與銷售、管理及行政費用合計為 5.39 億美元，而 2019 年第四季為 4.96 億美元。我們的全年支出為 19.8 億美元，而 2019 年為 16.9 億美元。我們全年的支出反映了為支持 CF 業務在全球範圍內的快速擴張而增加的成本，以及對將我們的產品線擴展到新的疾病領域和推進我們的高優先臨床項目的有針對性投資。

Our remarkable growth in revenues, combined with disciplined spending, resulted in a 2020 operating margin of 56% and operating income of $3.49 billion, an increase of 95% compared to 2019. Net income was $2.72 billion compared to $1.39 billion for 2019. With continued substantial revenue growth and profitability, we finished the year with $6.7 billion in cash. Consistent with our corporate strategy, our top priority for capital deployment is reinvestment in innovation, both internally in our R&D programs and externally through business development aligned with our R&D strategy. For example, in 2020, we executed important collaboration agreements with Affinia, Skyhawk Therapeutics and Moderna. Additionally, we also used over $500 million of cash to acquire Vertex shares through our ongoing share repurchase program. The primary purpose of this program is to offset dilution and has proved very effective with nearly 2.5 million shares repurchased.

我們收入的顯著成長，加上嚴格的支出控制，使得 2020 年的營業利潤率達到 56%，營業收入達到 34.9 億美元，比 2019 年成長了 95%。淨收入為 27.2 億美元，而 2019 年為 13.9 億美元。憑藉持續強勁的收入成長和獲利能力，我們在年底擁有 67 億美元的現金。與我們的集團策略一致，我們資本部署的首要任務是再投資於創新，包括內部研發專案和外部與研發策略一致的業務發展。例如，2020 年，我們與 Affinia、Skyhawk Therapeutics 和 Moderna 簽署了重要的合作協議。此外，我們也透過持續的股票回購計劃，動用了超過 5 億美元的現金來收購 Vertex 的股票。該計劃的主要目的是抵消股權稀釋，事實證明非常有效，已回購近 250 萬股股票。

Now to guidance. Our 2020 performance reflected considerable TRIKAFTA uptake as we achieved nearly full penetration of eligible patients in the U.S. as well as strong uptake of KAFTRIO in key EU countries where patients have access. For 2021, we project that we will achieve total product revenues of $6.7 billion to $6.9 billion, reflecting 10% growth at the midpoint. This guidance reflects our expectations for currently approved products in regions where we are reimbursed plus an expectation of TRIKAFTA approval for the 6- to 11-year old population in the U.S. in mid-2021.

現在進入指導環節。2020 年，我們的表現反映了 TRIKAFTA 的顯著普及，我們在美國幾乎完全涵蓋了符合條件的患者，同時 KAFTRIO 在歐盟主要國家也得到了廣泛應用，這些國家的患者可以獲得治療。我們預計 2021 年產品總收入將達到 67 億美元至 69 億美元，中位數為 10%。該指南反映了我們對目前已批准的產品在我們獲得報銷的地區的預期，以及對 TRIKAFTA 於 2021 年年中在美國 6 至 11 歲人群中獲得批准的預期。

In our 2021 revenue guidance, there are fewer significant variables compared to 2020. However, an important continuing factor is rates of patient persistence and compliance. We saw high rates of persistence and compliance with TRIKAFTA maintained in the U.S. throughout 2020, and we expect these levels to normalize throughout 2021. This dynamic is factored into our guidance as is uncertainty related to the ongoing pandemic.

與 2020 年相比，我們 2021 年的收入預期中，重要的變數較少。然而，一個重要的持續因素是患者的堅持率和依從性。2020 年，我們看到美國對 TRIKAFTA 的堅持率和遵守率一直很高，我們預計 2021 年這些水準將恢復正常。這種動態因素以及與持續疫情相關的不確定性都已納入我們的指導方針中。

As Stuart mentioned, moving forward, we expect to see further contribution to international revenues with subsequent waves of reimbursement agreements and launches in the EU as well as other ex-U. S. geographies. However, the timing of these agreements is not predictable and they are, therefore, not included in our 2021 guidance.

正如史都華所提到的，展望未來，我們預計隨著歐盟以及其他美國以外地區後續一系列的報銷協議和產品上市，將為國際收入做出進一步貢獻。南地理學。然而，這些協議的達成協議時間無法預測，因此，它們並未納入我們 2021 年的績效指引中。

For non-GAAP OpEx, we are guiding to a range of $2.25 billion to $2.3 billion. We expect to continue allocating greater than 70% of OpEx to R&D with year-over-year growth largely driven by investment in our pipeline programs in order to advance key programs further into the clinic and generate important proof-of-concept data in 2021. Our non-GAAP tax rate for 2020 was 21%, and we are guiding to a range of 21% to 22% this year.

對於非GAAP營運支出，我們預計在22.5億美元至23億美元之間。我們預計將繼續將 70% 以上的營運支出分配給研發，年成長主要得益於對研發管線計畫的投資，以便在 2021 年將關鍵計畫進一步推進到臨床階段，並產生重要的概念驗證數據。2020 年我們的非 GAAP 稅率為 21%，我們預計今年的稅率將在 21% 至 22% 之間。

In closing, 2020 was a tremendously successful year for Vertex and our business, and we look forward to continuing our growth and significant profitability in 2021.

總而言之，2020 年對於 Vertex 和我們的業務來說是極其成功的一年，我們期待在 2021 年繼續保持成長並取得顯著的盈利。

Now back to Reshma for a few closing remarks.

現在請雷什瑪作最後總結發言。

Thanks, Charlie. 2020 was an unprecedented and grueling year for the entire world. And while these challenges have not yet subsided, I have confidence that science will lead the way out of the pandemic, and we look forward with optimism. Throughout the past year, Vertex has demonstrated our resilience in the face of these challenges, and this was reflected in our business performance and pipeline progress.

謝謝你，查理。2020年對全世界來說都是前所未有的、極度艱難的一年。儘管這些挑戰尚未消退，但我相信科學將引領我們走出疫情，我們滿懷樂觀地展望未來。在過去一年中，Vertex 展現了我們在面對這些挑戰時的韌性，這體現在我們的業務表現和專案進度中。

Vertex has a proven track record of creating breakthrough medicines and transforming lives. We have an ambition to transform many more diseases, and our pipeline of small molecules, cell and genetic therapies are poised to do just that.

Vertex在研發突破性藥物和改變人們生活方面擁有卓越的業績記錄。我們雄心勃勃，致力於改變更多疾病的治療現狀，而我們的小分子、細胞和基因療法產品線也正蓄勢待發，準備實現這一目標。

Thanks, and we'll now open the call to questions.

謝謝，現在開始接受提問。

(Operator Instructions) Our first question comes from the line of Cory Kasimov with JPMorgan.

（操作員說明）我們的第一個問題來自摩根大通的 Cory Kasimov。

Two of them for you. For -- on the AAT program, has the IDMC been taking regular looks at the 864 safety database? And would you characterize this as a situation where no news is good news on the safety front? Or is that still premature where you are in enrollment? And then also on this program, what's the -- in terms of relative levels of functional serum AAT, what would give you conviction that you're on to something here and provide added confidence going into the next stage of development?

給你兩份。關於 AAT 項目，IDMC 是否定期查看 864 安全資料庫？你會把這種情況描述為「在安全方面沒有消息就是好消息」嗎？或者，就你們目前的招生階段而言，現在談論這些還為時過早？此外，在這個專案中，就功能性血清 AAT 的相對水平而言，什麼才能讓你確信你在這裡找到了某種方法，並為進入下一階段的開發提供更多信心？

Cory, this is Reshma. Let me take both of those questions for you. The AATD program is indeed followed very carefully, as we do all of our programs, honestly, from a safety perspective, and that is just part of what we do. So that is ongoing. With regard to levels and maybe broadly speaking, what are we really looking for from this VX-864 Phase II proof-of-concept study, really 3 things. The first is safety. This is the first time that VX-864 is going to patients with AATD. The second is PK and exposure. And the third is increases in functional AAT levels. I'm also going to be looking to see if there's a dose effect relationship. The key here, remember, is that this is our first time to close the loop on cracking the biology. That's to say, if we see levels of functional AAT increase in this study, we see a dose effect, what that tells us is that the mechanism that we projected to be the mechanism that could target both lung and liver raise AAT levels, we got it.

科里，這位是雷什瑪。讓我來回答這兩個問題。AATD 專案確實得到了非常嚴格的執行，就像我們執行所有專案一樣，坦白說，這是出於安全考慮，也是我們工作的一部分。所以這件事還在進行中。就層級而言，或許更廣泛地說，我們真正希望從這項 VX-864 II 期概念驗證研究中獲得什麼，實際上是 3 件事。首先是安全問題。這是 VX-864 首次用於治療 AATD 患者。第二點是PK和暴露量。第三點是功能性AAT水準的提升。我也會研究是否有劑量效應關係。記住，關鍵在於這是我們第一次徹底破解生物學難題。也就是說，如果我們在本研究中觀察到功能性 AAT 水平升高，觀察到劑量效應，這告訴我們，我們預測的可以同時靶向肺部和肝臟提高 AAT 水平的機制，我們得到了。

And as I always say, we divide drug development at Vertex into 2 parts: cracking the biology, pouring on the chemistry. Pouring on the chemistry is the easier. It is not easy, but it's the easier of the 2 parts. And so that's what we're really looking for is assessment of safety, PK, and we're looking for elevations of functional AAT levels.

正如我常說的，我們在 Vertex 將藥物開發分為兩部分：破解生物學，推進化學。堆砌化學知識更容易。這並不容易，但卻是兩部分中比較容易的那部分。因此，我們真正想要評估的是安全性、藥物動力學，以及功能性 AAT 水平的增加。

Our next question comes from the line of Salveen Richter with Goldman Sachs.

我們的下一個問題來自高盛的薩爾文·里希特。

So one question here on the CF guidance. Could you just comment on how you're accounting for uncertainty related to the pandemic? And what reimbursement agreements or approvals could be expected this year that are not accounted for? And then secondly, you made a comment about your BD strategy, and I recognize while it's aligned with R&D. But at the same time, is there any clarity you can give us with regard to areas of focus, size of deals? And how much of an interest do you have in technologies as you look to kind of fill your toolbox there?

關於CF指南，這裡有一個問題。您能否談談您是如何應對與疫情相關的不確定性的？今年還有哪些尚未計入的報銷協議或批准預計會出台？其次，您對您的 BD 策略發表了評論，我承認它與研發是一致的。但同時，您能否就重點領域、交易規模等方面給予一些明確的說明？您對拓展自身技能方面的技術有多大興趣？

Sure. Salveen, this is Reshma. Why don't I start us off with the second part of your question, and then I'm going to ask Stuart to just comment a little bit more on the launch dynamics in the EU and a little bit more about the U.S. I think that will cover your question on CF. So Salveen, with regard to BD, what we're really talking about here is an interest that is exactly the same as the strategy we've laid out for many years, probably the last 8 years now. We are interested in assets that complement our internal efforts in CF. We're interested in assets that fit our R&D strategy. And you know our R&D strategy is very, very diligent. We are very serious about the causal human biology and biomarkers and transformative potential, specialty markets. It has to fit all of that, and we're looking for tools that fit our toolkit.

當然。薩爾文，這位是雷什瑪。不如我先回答你問題的第二部分，然後我請Stuart再就歐盟和美國的上市動態做一些補充說明。我想這樣應該就能解答你關於CF的問題了。所以薩爾文，關於 BD，我們真正想表達的是我們多年來（可能最近 8 年）制定的策略，這與我們一直以來的策略完全一致。我們對能夠補充我們內部CF業務的資產感興趣。我們對符合我們研發策略的資產感興趣。你知道，我們的研發策略非常非常嚴謹。我們非常重視人類生物學、生物標記及其變革潛力，以及專業市場。它必須符合所有這些要求，我們正在尋找適合我們工具包的工具。

We've transacted in these areas. A lot of the recent transactions, like Affinia and Skyhawk and Ribometrix, fit those tools, and you should expect to see us continue doing that. We've also transacted on -- I think Semma is a great example. It's a good one to talk about today given the clearance of the IND. Acquisitions like Semma that fit our R&D strategy like a glove and those that have transformative potential. And if you're thinking about, okay, what kind of falls in and what falls out, you can think back to a slide we showed at JPMorgan with our funnel, if you will, that goes through our criteria, certain diseases fall in. Clearly, things like CF and AATD and APOL1-mediated kidney disease, but other examples of diseases that fall in would be Huntington's disease, would be polycystic kidney disease. And then there are diseases that fall out because they don't fit our criteria, criteria like specialty markets or understanding of causal human biology or having biomarkers that translate well.

我們已在這些地區進行過交易。最近很多交易，例如 Affinia、Skyhawk 和 Ribometrix，都符合這些工具的使用標準，你們應該會看到我們繼續這樣做。我們也進行過交易——我認為 Semma 就是一個很好的例子。鑑於IND已批准，今天討論這個話題很合適。像 Semma 這樣與我們的研發策略完美契合，且具有變革潛力的收購專案。如果你在想，好吧，哪些疾病符合條件，哪些疾病不符合條件，你可以回想一下我們在摩根大通展示的幻燈片，上面有一個漏斗圖，它按照我們的標準進行分類，某些疾病符合條件。顯然，囊性纖維化、AATD 和 APOL1 介導的腎臟疾病等都屬於此類，但其他一些疾病的例子包括亨廷頓病和多囊性腎病。還有一些疾病因為不符合我們的標準而被排除在外，這些標準包括特殊市場、對人類生物學因果關係的理解，或具有能夠很好地轉化的生物標記。

Stuart, I'm going to turn it over to you to tell us a little bit about the CF market.

斯圖爾特，接下來就交給你來給我們介紹一下CF市場吧。

Yes. Thanks, Reshma. So Salveen, just I'm going to break down what's incorporated into our guidance into U.S. and ex-U. S. and talk about what the drivers of growth are. So in the U.S., as you know, the vast majority of eligible patients across all patient groups have been initiated on TRIKAFTA in the U.S. during the course of 2020. And so incorporated in our guidance is the kind of the annualized effect of those patients having been initiated, offset to some degree by persistence and compliance, which we expect to normalize during the course of 2021. In terms of growth drivers for the U.S., probably the most notable is the expected approval of TRIKAFTA for 6 to 11 year olds, which we expect to happen in the midyear.

是的。謝謝你，雷什瑪。所以薩爾文，我將詳細介紹我們的指導方針包含哪些內容，這些方針適用於美國和美國以外的國家。S. 並討論成長的驅動因素是什麼。因此，如您所知，在美國，2020 年期間，所有患者群體中絕大多數符合條件的患者都已開始接受 TRIKAFTA 治療。因此，我們的指導意見中納入了這些患者開始接受治療的年度化影響，這種影響在一定程度上被堅持和依從性所抵消，我們預計這種情況將在 2021 年期間趨於正常化。就美國的成長動力而言，最值得關注的可能是 TRIKAFTA 對 6 至 11 歲兒童的預期批准，我們預計這將在年中發生。

Moving to ex-U. S. We have obviously launched the KAFTRIO triple combination in those markets where we do have reimbursement agreements, like the U.K. and Ireland and Denmark or markets where you can get early access like Germany. And the majority of patients actually have already been initiated in those markets, the launch has gone very strongly. We do anticipate, obviously, initiating more patients in those countries. But we have only included in our guidance countries where we already have pricing and reimbursement agreements.

搬到前美國。S. 我們顯然已在那些我們有報銷協議的市場推出了 KAFTRIO 三聯療法，例如英國、愛爾蘭和丹麥，或者在像德國這樣可以提前獲得該療法的市場。而且在這些市場中，大多數患者實際上已經開始接受治療，上市情況非常強勁。我們顯然預計會在這些國家招收更多患者。但我們的指導方針僅涵蓋了我們已經達成定價和報銷協議的國家。

So to the last part of your question, which is then where else would we be seeking pricing and reimbursement. The major countries in the EU, where we were continuing to seek reimbursement are like France, Spain and Italy. Obviously, as Charlie said in his prepared remarks, it's impossible for us to predict exactly the timing of when we will reach those agreements. And for that reason, we don't include them in our guidance. Outside of the EU, obviously, the major countries are Australia and Canada. In both of those, we have filed for regulatory approval and are also in parallel seeking reimbursement approval as well. Again, those are not included within our guidance.

那麼，對於你問題的最後一部分，那就是我們還能在哪裡尋求定價和報銷呢？我們一直在尋求補償的歐盟主要國家包括法國、西班牙和義大利。正如查理在事先準備好的演講稿中所說，顯然我們不可能準確預測何時能夠達成這些協議。因此，我們沒有將它們納入我們的指導方針中。歐盟以外，主要國家顯然是澳洲和加拿大。對於這兩項，我們都已提交監管部門的批准申請，同時同時也尋求報銷批准。再次強調，這些內容不包含在我們的指導方針中。

And then if I can just kind of turn to the longer term because obviously, 2021 is sort of 1 year in a long journey that we've been on. We continue to believe that we will be able to treat up to 90% of patients with CFTR modulators like the triple combination over time. That has for a long time been our goal and continues to be our goal, and we still feel very confident, if not more confident than ever, that we're going to get there over time.

然後，如果我能把目光轉向更長遠的未來，因為很顯然，2021 年只是我們漫長旅程中的一年。我們仍然相信，隨著時間的推移，我們將能夠使用 CFTR 調節劑（如三重療法）治療高達 90% 的患者。這長期以來一直是我們的目標，並將繼續是我們的目標，我們仍然非常有信心，甚至比以往任何時候都更有信心，我們終將實現這個目標。

Our next question comes from the line of Phil Nadeau with Cowen.

我們的下一個問題來自 Phil Nadeau 與 Cowen 的對話。

I also had a follow-up on AAT and VX-864. I was curious whether the team has come to any further understanding of what tripped up VX-814 was -- or the issues idiosyncratic to the molecule or class effect. And maybe an extension of that, in the past, you had noted a difference in exposures between healthy volunteers and patients with AATD. In any way, could that be a sync effect because there's a lot of protein aggregating the liver? And if so, how could that be overcome?

我還對 AAT 和 VX-864 進行了後續調查。我很好奇該團隊是否對 VX-814 的問題所在有了更深入的了解——或者說是該分子特有的問題，還是類別效應的問題。或許可以進一步推斷，過去您曾注意到健康志願者和 AATD 患者之間的暴露情況有差異。無論如何，這會不會是因為肝臟中聚集了大量蛋白質而產生的同步效應？如果真是如此，該如何克服呢？

Sure. This is Reshma. Let me answer those questions for you. I think the best way to think about the AATD program is the following. We are very enthusiastic about the mechanism because it's the only one that holds the potential to treat both liver and lung. 814 was simply not the right molecule. And unsurprisingly, because the study was terminated early, we didn't fully enroll it and patients who were enrolled didn't all complete the trial. There's not much more we can learn there. We are looking forward to VX-864 and those results. The study is enrolling. We are dosing patients, and we need to be a little bit more patient, but it's not that much longer now. We will have the results this half -- this first half of 2021.

當然。這是雷什瑪。讓我來回答這些問題。我認為理解 AATD 項目的最佳方式如下。我們對這種機制非常感興趣，因為它是唯一有可能同時治療肝臟和肺部疾病的機制。814 根本不是正確的分子。不出所料，由於研究提前終止，我們沒有完全招募受試者，而且已招募的患者也並非全部完成了試驗。我們在那裡能學到的東西已經不多了。我們期待VX-864及其測試結果。研究正在招募受試者。我們正在給病人用藥，我們需要更有耐心一些，但時間已經不多了。我們將在本半年—2021年上半年—公佈結果。

Our next question comes from the line of Michael Yee with Jefferies.

我們的下一個問題來自 Jefferies 的 Michael Yee。

Congrats on a great quarter and great year to close out. I had 2 questions. One was on BD, maybe Reshma or the team, mid to late stage can span a whole gamut of size and market cap and certainly, financial resource capacity. Vertex is a much bigger company now, much more cash, but mid and late stage and different sizes can mean different things to different people. Can you maybe just comment about where Vertex's balance sheet or where you strategically feel comfortable along the range of sizes of what that can be, whether that's $5 billion, $10 billion, $15 billion? Maybe just think about that, which is the other side of doing a deal. And then the second question, you made a nice comment about CF and how you're advancing the cycle there. I know there was a super corrector that had really high levels of chloride transport and there's also a once-daily potentiator. Can you just remind us where those are? And if those are still moving forward and doing well?

恭喜你們本季和本年度都取得了優異的成績，並圓滿結束了這一年。我有兩個問題。其中一位是 BD，可能是 Reshma 或團隊，中後期階段可能涵蓋各種規模和市值，當然還有財務資源能力。Vertex 現在是一家規模大得多、現金流充裕得多的公司，但對於不同的人來說，中後期階段和不同規模的公司可能意味著不同的事情。您能否就 Vertex 的資產負債表狀況，或您在策略上認為其規模在哪個範圍內比較合適（例如 50 億美元、100 億美元、150 億美元）發表一下看法？或許你應該想想這一點，這就是交易的另一面。然後是第二個問題，你對 CF 以及你如何推進那裡的治療週期發表了很好的評論。我知道有一種超級矯正劑，其氯離子轉運能力非常高，還有一種每日一次的增強劑。可以提醒我們一下那些地方在哪裡嗎？如果這些項目仍在進行並且進展順利呢？

Michael, it's Reshma. Let me take the second question first, and then I'll come back around and talk a little bit more about BD. So the once-a-day potentiator is VX-561. And you're right, we have been busy at work. David Altshuler, the team in San Diego have been busy at work with the development of more correctors. We have the combination of VX-121, let's call it, a next-gen corrector; VX-561, that's the once-a-day potentiator; and teza, that's made its way through Phase II development. And you'll remember the agency asked us to also do a monotherapy study with VX-561. All of that's been completed. And what we're really doing now is looking at all of the data, planning forward to our regulatory interactions. And as soon as we get through all of those, we'll certainly give you an update on that program.

邁克爾，我是雷什瑪。讓我先回答第二個問題，然後再回來多談談BD。所以每天一次的增強劑是 VX-561。你說得對，我們一直忙於工作。David Altshuler 表示，聖地牙哥的團隊一直忙於開發更多的校正器。我們結合了 VX-121（我們稱之為下一代矯正劑）、VX-561（每天一次的增強劑）和 teza（已經完成了 II 期開發）。您應該還記得，該機構還要求我們對 VX-561 進行單藥治療研究。所有這些都已完成。我們現在真正做的是查看所有數據，為未來的監管互動做好規劃。一旦我們完成所有這些工作，我們一定會向您報告該專案的最新進展。

Just remember, at a high level, drug development in CF going forward is going to be completely different than anything that's come before it because there is no placebo anymore. And so, don't be surprised if you don't hear from me on this program until we are through all of the conversations and we're ready to give you concrete next steps. But I'm very pleased with how that's progressed.

請記住，從宏觀層面來看，囊性纖維化藥物的未來研發將與以往任何藥物研發都截然不同，因為不再有安慰劑效應了。所以，在完成所有對話並準備好向您提供具體的下一步措施之前，如果您沒有收到我關於這個項目的任何消息，請不要感到驚訝。但我對目前的進展非常滿意。

Okay. Let's tackle BD. Let me take a couple of minutes and just really walk you through this in a little bit of detail. When I think about where we are in terms of the business today and where we're going, and then try to give you a little bit more color and texture behind capital allocation and BD, here's a way to put it all together. The -- if you look at the company 3 years ago, so back to January 2018, we were active in the clinic with programs and patients. So I'm not counting healthy volunteers, just patient-based studies in CF and pain. That's it. That's where we were. Fast forward 3 years, and we are now -- if I count the type 1 diabetes program, which is going to be going into patients very quickly, we're looking at molecules in 6 disease areas right now in patients, right? And if I count the pain molecule in healthy volunteers, that's 7. So it's very different.

好的。讓我們來探討一下BD。讓我花幾分鐘時間，詳細地跟你講解一下。當我思考我們公司目前的業務狀況以及未來的發展方向，並試圖為大家更詳細地介紹資本配置和業務拓展時，我找到了一個將所有內容整合起來的方法。如果你回顧一下公司三年前的情況，也就是 2018 年 1 月，我們當時在診所開展項目，服務患者。所以，我沒有統計健康志願者，只統計了囊性纖維化和疼痛的患者研究。就是這樣。我們當時就在那裡。快進到 3 年前，現在——如果我把即將很快投入臨床應用的 1 型糖尿病計畫也算進去的話——我們目前正在研究 6 個疾病領域的分子，對吧？如果我統計健康志願者體內的疼痛分子數量，那就是 7 個。所以情況非常不同。

If I think about revenues, 2018, January, I think we have closed out the previous year at something a little bit north of $2 billion. And if I think about cash, again, a little bit north of $2 billion. Where we are today? We closed out 2020 with revenues of more than $6 billion in cash, close to $7 billion. We are indeed in a different place. And it's really that different place that allows us to think about mid- and late-stage assets. And that's a way of indicating the balance sheet and the strength of the balance sheet.

如果以 2018 年 1 月的收入為例，我認為我們上一年的收入略高於 20 億美元。如果考慮到現金，那也略高於 20 億美元。我們今天身處何處？2020 年末，我們的現金收入超過 60 億美元，接近 70 億美元。我們現在所處的境地確實不同了。正是這種不同的視角，讓我們能夠思考中後期資產。這是一種體現資產負債表及其穩健程度的方法。

I want to be very clear that the strategy is exactly the same what I outlined previously. And if I just focus in on the assets that fit our R&D strategy, we are now able to look at, for example, Phase II assets, assets that might be in Phase III. And those are assets that we're going to look at. We're also going to continue to look at tools for our toolkit. I'm not looking at -- I have no preconceived notions about the timing of a transaction and I have no preconceived notions about the dollar amount of a transaction. It has to fit our R&D strategy. It has to be transformative. We have to be able to add value. And when we find that asset and we have the patience and the judgment to be very thoughtful about that, we're going to be ready to evaluate.

我想非常明確地說明，這一策略與我之前概述的策略完全一致。如果我專注於符合我們研發策略的資產，我們現在可以專注於例如 II 期資產、可能處於 III 期的資產。這些都是我們將要考察的資產。我們也會繼續研究工具包中的工具。我不會去關注－我對交易的時間沒有任何先入為主的觀念，我對交易的金額也沒有任何先入為主的觀念。它必須符合我們的研發策略。它必須具有變革性。我們必須能夠創造價值。當我們找到這樣的資產，並且有足夠的耐心和判斷力去認真考慮它時，我們就會準備好進行評估。

Our next question comes from the line of Geoff Meacham with Bank of America.

下一個問題來自美國銀行的傑夫‧米查姆。

Just 2 main ones. Charlie or Stuart, you guys recently updated your assumptions on the CF epidemiology. Can you address what data helped you -- helped lead you down that path? And whether this updated view of the CF market by patients is reflected in your 2021 outlook? And then second question, Reshma, when you look at the pipeline and strategy, you guys have been obviously busy on the BD front, but essentially have maintained somewhat of a rare disease or specialized focus. I know you've been reluctant to label yourself an orphan drug company, but is it fair to say that future BD could be similar or as a bigger company, could you go after larger indications that share the same spirit of having transformational efficacy?

主要只有兩個。Charlie 或 Stuart，你們最近更新了關於囊性纖維化流行病學的假設。你能說說哪些數據對你有幫助——引導你走上這條道路嗎？患者對囊性纖維化市場的這種最新看法是否反映在您的 2021 年展望中？第二個問題，Reshma，從你們的研發管線和策略來看，你們顯然在業務拓展方面非常忙碌，但基本上仍然保持著對罕見疾病或特殊疾病的關注。我知道你們一直不願意將自己定義為孤兒藥公司，但可以這樣說嗎？未來的BD公司是否也會如此？或者，作為一家規模更大的公司，你們能否著眼於具有變革性療效的更廣泛的適應症？

I'm going to ask Stuart to comment on CF epidemiology first, and then I'll come back for your second question.

我先請 Stuart 談談 CF 的流行病學，然後再回來回答你的第二個問題。

Geoff, thanks for the question. So as you noted, and just to ground everybody, we recently updated our view on the epidemiology of CF in the U.S., Canada, Europe and Australia from 75,000 patients living with CF in those countries or regions to 83,000. And the reason that drove that change was really improvements in data quality and capture in the various registries and, indeed, some establishment of new registries in these regions. We periodically review all that data. And on our latest review, it was obvious to us that over the last few years, the epidemiology had increased.

傑夫，謝謝你的提問。正如您所指出的，為了讓大家了解實際情況，我們最近更新了對美國、加拿大、歐洲和澳洲 CF 流行病學的看法，從這些國家或地區 75,000 名 CF 患者增加到 83,000 名。而推動這項變革的真正原因是各個註冊機構的數據品質和採集方面的改進，以及這些地區一些新註冊機構的建立。我們會定期審查所有這些數據。在我們最近的審查中，很明顯，在過去的幾年裡，流行病學有所增加。

Just to answer a question you didn't ask, but one that we have been asked consistently is, was that increase concentrated in any one country, any one region? And it really wasn't. It was really an across-the-board phenomenon and something that's not uncommon as well in rare and orphan diseases is when you have really great transformative medicines, often you see increases in the number of eligible patients, and we believe that was also a factor here. In terms of whether that new epidemiology is included in our long term -- our 2021 guidance. Absolutely, it is. That's the denominator that we are using now. And indeed, a number of those patients are already being treated with our CFTR modulators in the U.S., Canada, Australia and the EU.

我來回答一個你沒問，但我們一直被問到的問題：這種成長是否集中在某個國家或某個地區？但事實並非如此。這確實是一種普遍現象，而且在罕見疾病和孤兒病領域也並不少見，那就是當出現真正具有變革意義的藥物時，通常會看到符合條件的患者人數增加，我們認為這也是造成這種情況的一個因素。至於是否將這種新的流行病學納入我們的長期——我們的 2021 年指導方針中。沒錯，確實如此。這就是我們現在使用的分母。事實上，在美國、加拿大、澳洲和歐盟，許多患者已經接受我們的 CFTR 調節劑治療。

Geoff, it's Reshma. I'm really glad you asked the question about rare disease and orphan drugs. So you know the reason I don't like calling us a rare disease company because we aren't a rare disease company. What we are is a company that is about specialty markets. And the best example I can give you of that is type 1 diabetes and our Semma acquisition. So when you think about type 1 diabetes, it's well over 2 million people, right? So far away from being a rare disease that suffer from type 1 diabetes. And the key there is that the Semma acquisition and the cell-based therapy holds the potential to be transformative. So you're very correct, that is a key that we are looking for. And the type 1 diabetics are treated by endocrinologists, a specialty group. So really, the key for us is not rare disease, but specialty markets, and type 1 diabetes is the best example.

傑夫，我是雷什瑪。很高興你問到了關於罕見疾病和孤兒藥的問題。所以你知道我為什麼不喜歡稱我們為罕見疾病公司，因為我們不是一家罕見疾病公司。我們是一家專注於專業市場的公司。我能舉出的最好的例子就是第 1 型糖尿病和我們對 Semma 的收購。所以，說到第 1 型糖尿病，患者人數超過 200 萬，對吧？距離患有第1型糖尿病這種罕見疾病還很遠。關鍵在於，Semma 的收購和基於細胞的療法有可能帶來改變。你說得完全正確，這正是我們正在尋找的關鍵。而第 1 型糖尿病患者則由內分泌科醫師（專科團隊）進行治療。所以對我們來說，關鍵不在於罕見疾病，而在於專業市場，1 型糖尿病就是最好的例子。

Our next question comes from the line of Mohit Bansal with Citigroup.

我們的下一個問題來自花旗集團的 Mohit Bansal。

Couple of questions. One for Stuart, if you could help me understand that you did talk a little bit about new prevalence numbers for CF in these developed markets. But when you look beyond these markets, likes of Latin America or even going as far as China, I understand the prevalence is lower there, incidence is lower per -- on a population basis, but it's not 0. Do you still think about expansion opportunities outside of these core markets at this point? The second part is more on the R&D side. As you mentioned, so can you help us understand for VX-147 trial, how are you thinking about meaningful reduction in proteinuria there? Because these patients, if I understand correctly, they start at urine protein to creatinine ratio of 9 or 10 at sometimes.

我有幾個問題。Stuart，我有個問題想請教你，你之前確實談到了一些關於這些已開發市場中囊性纖維化最新盛行率的數據。但是，如果把目光投向這些核心市場之外的地區，例如拉丁美洲，甚至遠至中國，我了解到那裡的盛行率較低，每千人中的發病率也較低，但並非為零。您目前是否仍在考慮在這些核心市場之外進行擴張？第二部分則較著重於研發方面。正如您所提到的，您能否幫助我們了解 VX-147 試驗中，您是如何看待顯著降低蛋白尿的？因為如果我理解正確的話，這些患者的尿蛋白與肌酸酐的比值有時高達 9 或 10。

Sure, sure. Stuart, do you want to start? And then I'll take 147.

當然，當然。斯圖爾特，你想開始嗎？然後我選147。

Yes. Mohit, so absolutely, you're right. The 83,000 patients living with CF is specific to the U.S., Canada, EU and Australia. But in terms of other markets, we continue to believe that there are patients in other countries that we could serve. Indeed, we have established an affiliate in Brazil, and we are in the process of securing reimbursement for our medicines down there. The issue really with the epidemiology in some of these other countries is that it's much less robust, much less mature, and we have much less confidence in it than we do in some countries, like the U.S. and the EU, where the prevalence of the disease is much higher and there are much more established and long-standing registries. So we continue to see opportunity to serve patients outside of those core markets, but those are the ones where we have a really, really good handle on the epidemiology.

是的。莫希特，你說的完全正確。患有囊性纖維化的 83,000 名患者主要分佈在美國、加拿大、歐盟和澳洲。但就其他市場而言，我們仍然相信其他國家也有我們可以服務的患者。事實上，我們已經在巴西設立了分支機構，目前正在辦理藥品在巴西的報銷手續。其他一些國家的流行病學問題在於，它遠不如美國和歐盟等國家那麼穩健、成熟，我們對它們的信心也遠不如美國和歐盟等國家。在這些國家，疾病的盛行率要高得多，而且有更完善、更長期的登記系統。因此，我們仍然看到為核心市場以外的患者提供服務的機會，但這些核心市場是我們對流行病學掌握得非常非常清楚的市場。

And Mohit, about your question with regard to VX-147, to remind everyone, that's the small molecule that we are studying in Phase II proof-of-concept for FSGS, focal segmental glomerulosclerosis. You're right, it's a disease that is unfortunately unrelenting heavy proteinuria usually in the nephrotic range, so more than 3 grams. And what happens to these patients is they either progress onto dialysis or to transplantation. We're looking here as we are for all of the programs for a transformative effect and to me that would be double-digit protein reduction. As I said, for the AATD question with regard to what are we looking for from the Phase II study, safety, first time it's going into patients, PK, and in this regard, proteinuria and a double-digit decrease in proteinuria would be great to see in something that I'm going to be looking for. I'll remind everyone that we do expect the results from that study this year.

莫希特，關於你提出的 VX-147 的問題，提醒大家一下，VX-147 是我們正在進行 II 期概念驗證研究的小分子藥物，用於治療局部節段性腎小球硬化症 (FSGS)。你說得對，這是一種不幸的疾病，會導致持續性大量蛋白尿，通常處於腎臟疾病範圍，也就是超過 3 克。這些患者最終要麼接受透析治療，要麼接受器官移植。我們在這裡尋找所有能夠產生變革性效果的項目，對我來說，那就是兩位數的蛋白質減少。正如我所說，關於 AATD 的問題，關於我們希望從 II 期研究中看到什麼，安全性，首次應用於患者，藥物動力學，在這方面，蛋白尿，如果蛋白尿能有兩位數的下降，那就太好了，這也是我將要關注的內容。我提醒大家，我們預計今年會公佈這項研究的結果。

Our next question comes from the line of Paul Matteis with Stifel.

我們的下一個問題來自保羅·馬泰斯與史蒂費爾的合作系列。

A couple of quick follow-ups. On the BD side, I know there's been a lot of discussion around potential indications or disease areas you're interested in. But if you take a step back, you guys have your hands in gene therapy, editing, mRNA, a bunch of different tools. Are there any platform modalities that you don't have your hand in that are especially interesting to you? And then on APOL1, one quick follow-up, Reshma. We did a few doc calls and the feedback was how you interpret the proteinuria data, in part, depends on the severity of the population and how heavily pretreated they've been by the standard of care. Is there anything you can tell us about the patients you're enrolling in this study?

幾個後續問題。在 BD 方面，我知道大家已經就潛在的適應症或您感興趣的疾病領域進行了許多討論。但如果你退後一步來看，你們已經涉足基因療法、基因編輯、mRNA 等一系列不同的工具領域。有沒有一些你尚未涉足，但你特別感興趣但目前還沒有嘗試過的平台模式？然後，在 APOL1 上，還有一個簡短的後續問題，Reshma。我們與幾位醫生進行了電話溝通，得到的回饋是，如何解讀蛋白尿數據，部分取決於患者群體的病情嚴重程度以及他們接受標準治療的程度。您能否向我們透露一些關於您正在招募參與這項研究的患者的資訊？

Yes. With regard to the patients that we're enrolling, these are patients with heavy proteinuria. There is some -- as you say, there's some background treatment that patients can be placed on including steroids. But unfortunately, these treatments are not particularly effective. And even when you sometimes can see effect, the durability is often not there. So we're studying heavy proteinurics, and that's what we're looking at.

是的。我們正在招募的患者都是嚴重蛋白尿的患者。正如你所說，有一些基礎治療可以給患者使用，包括類固醇。但遺憾的是，這些治療方法效果並不理想。即使有時能看到效果，但持久性往往也不夠。所以我們正在研究重度蛋白尿患者，這就是我們關注的重點。

With regard to your question about tools for our toolkit and what do we have. We are really about transforming diseases. And when you are committed to transforming diseases, the key is to not let the tool be limiting. You know that a small minority of the protium can be impacted by small molecules, for example. And so if we're going to target a disease and we can't get there by small molecules, we're certainly going to get there with one of the other modalities. And I'm going to ask David Altshuler just to give you a couple of words on mRNA therapies that we are working on, some of the collaborations we've done and give you a sense of where we are with our gene editing tools.

關於您提出的關於我們工具包中工具以及我們擁有哪些工具的問題。我們致力於真正改變疾病的現狀。當你致力於改變疾病的現狀時，關鍵在於不要讓工具成為限制因素。你知道，例如，一小部分質子會受到小分子的影響。因此，如果我們想要治療某種疾病，但小分子藥物無法達到治療目的，那麼我們肯定會採用其他療法之一。接下來，我將請大衛‧阿爾特舒勒 (David Altshuler) 簡單介紹一下我們正在研究的 mRNA 療法、我們進行的一些合作，並讓大家了解一下我們在基因編輯工具方面所取得的進展。

David, do you want to make a couple of comments?

大衛，你想補充幾點嗎？

Sure. Thanks, Reshma. As you've said, our strategy starts with the disease and we select a target which is validated as playing a causal role in the underlying biology of the disease. And then we either invent or, through partnership, we'll find the tools and technologies needed. In the case of CF, aiming for therapies to get at the last 10% of people who don't make a protein and won't benefit from our CFTR modulators, we've collaborated with multiple companies, including Moderna, as you mentioned, for mRNA therapy.

當然。謝謝你，雷什瑪。正如您所說，我們的策略是從疾病著手，我們選擇一個已被證實對疾病的潛在生物學機制起因果作用的目標。然後，我們要么自己發明，要么透過合作找到所需的工具和技術。就囊性纖維化而言，為了治療最後 10% 無法產生蛋白質且無法從我們的 CFTR 調節劑中受益的人群，我們與多家公司合作，包括您提到的 Moderna 公司，開展 mRNA 療法。

In other cases, we've identified a small molecule approach but we think that adding, for example, protein degradation technology, such as through our collaboration with Kymera, or drugging RNA, I should say, as with our collaborations with Ribometrix or SkyHawk, are the right way to approach those diseases. And you will continue to see us do deals and partnerships where there's a particular technology that opens up a target that we think has transformational potential, and we'll continue to do those as time goes on.

在其他情況下，我們已經確定了一種小分子方法，但我們認為，例如，透過與 Kymera 的合作，添加蛋白質降解技術，或者應該說，透過與 Ribometrix 或 SkyHawk 的合作，對 RNA 進行藥物治療，才是治療這些疾病的正確方法。你們將會看到我們繼續進行交易和合作，尤其是在某些特定技術能夠為我們認為具有變革潛力的目標領域帶來變革的情況下，隨著時間的推移，我們將繼續這樣做。

Our next question comes from the line of Alethia Young with Cantor.

我們的下一個問題來自阿萊西亞·楊和坎托爾的血脈。

Congrats on all the progress. And I guess, I just want to talk a little bit about this VX-880 IND. Can you talk a little bit more about kind of your clinical trial plans and designs or how you kind of plan on navigating in light of COVID in that transplant population?

祝賀你們取得的所有進展。我想，我只是想稍微談談這款 VX-880 IND。您能否再詳細談談您的臨床試驗計劃和設計，或者您打算如何應對新冠疫情對移植人群的影響？

Yes. Alethia, thanks so much for the question. I'm really very enthusiastic about the VX-880 program. This is the cell-based therapy program for type 1 diabetes. It's actually pretty remarkable that we are at a point where we can now very seriously think about this therapy going to patients and being on the brink of being able to see results. This is a disease and an approach and a clinical trial that I would think about like CTX001 in our CRISPR approach to beta-thal and sickle cell disease. It's a single-arm trial. The cell therapy product goes directly into patients. There's no healthy volunteer step. And I would say that in a reasonable number of patients, we're going to be able to tell what the performance of our therapy is, the measures that we are looking at, the outcomes are very straightforward, glucose, hemoglobin A1c, C-peptide level. And so I think this is the brink of something very special, and I'm very eager to see this program progress.

是的。Alethia，非常感謝你的提問。我對VX-880專案充滿熱情。這是針對第1型糖尿病的細胞療法項目。實際上，我們現在能夠非常認真地考慮將這種療法應用於患者，並且即將看到療效，這確實非常了不起。這是一種疾病、一種方法和一項臨床試驗，我認為它類似於我們用 CRISPR 技術治療 β-地中海貧血和鐮狀細胞疾病的 CTX001。這是一項單臂試驗。細胞療法產品直接注射到患者體內。沒有健康的志工步驟。我認為，在相當數量的患者中，我們將能夠判斷我們的療法的效果如何，我們正在觀察的指標，結果非常直接，包括葡萄糖、糖化血紅蛋白A1c、C肽水平。所以我認為這是一個非常特別的時刻即將到來，我非常渴望看到這個專案取得進展。

Any impacts from COVID, do you think? Or is it going to be pretty straightforward to navigate that?

你認為新冠疫情會造成哪些影響？或者說，操作起來會非常簡單直接？

Yes. COVID is something that is top of mind for all of our clinical trials for sure. But that being said, this is an approach that is done in specialized centers, and I don't see us having a lot of challenge with it if the COVID pandemic continues in this way, which is to say vaccines are coming, people have learned how to manage and hospitals are able to continue to do clinical trial work, and so that part looks pretty good to me.

是的。新冠疫情無疑是我們所有臨床試驗中最需要關注的問題。但話雖如此，這種方法是在專門的中心進行的，如果新冠疫情繼續這樣發展下去，我認為我們不會遇到太大的挑戰，也就是說，疫苗即將問世，人們已經學會瞭如何應對，醫院也能夠繼續進行臨床試驗工作，所以這方面看起來相當不錯。

Our next question comes from the line of Gena Wang with Barclays.

我們的下一個問題來自 Gena Wang 與巴克萊銀行的合作。

I will also follow Alethia's question regarding 880. Just wondering, Reshma, any particular benefit -- goal of benefit you want to achieve with, say, glucose or anything you can share with us that will lead to the next step for this program? And my second question is regarding the CTX001 for the complete the trial enrollment completion anticipated in 2021, that's 45 patients each for beta-thalassemia, sickle cell, could that be registration trial for the next step?

我也會關注 Alethia 關於 880 的問題。Reshma，我想問一下，你希望透過這個計畫達到什麼具體的益處——比如說，降低血糖水平，或者其他任何可以和我們分享的、能夠幫助我們推進下一步計劃的益處？我的第二個問題是關於 CTX001，預計在 2021 年完成試驗招募，即 45 名 β-地中海貧血患者和 45 名鐮狀細胞貧血患者，這是否可以作為下一步的註冊試驗？

Okay. There are 2 questions, one about CTX001 and one about type 1 diabetes. Let me take the CTX001 question first, and then we'll come back around to type 1 diabetes. So with CTX001, really remarkable, but you are correct. We are looking to complete enrollment in both trials, beta-thalassemia and sickle cell disease, and we're looking to do that in 2021. And yes, I do anticipate that the patients that we're studying in these trials that are ongoing will be the patients that constitute the regulatory package. As you've heard us talk about before, we've initiated those conversations, but we have not yet completed them. So we're looking forward to doing so this year. But yes, I do expect these patients to be the composition of our filing package.

好的。有兩個問題，一個關於 CTX001，一個關於第 1 型糖尿病。讓我先回答 CTX001 的問題，然後再回到第 1 型糖尿病的問題。所以，CTX001確實非常出色，但你說得對。我們希望完成β-地中海貧血和鐮狀細胞疾病兩項試驗的受試者招募工作，並計劃在2021年完成。是的，我預計我們正在進行的這些試驗中研究的患者將構成監管方案中的患者。正如你們之前聽我們談到的那樣，我們已經啟動了這些對話，但尚未完成。所以我們期待今年能做到這一點。是的，我希望這些患者能夠構成我們提交的資料。

On the VX-880 program and what are we looking for. So first things first. This is the first time that the -- these fully differentiated, stem cell-derived, insulin-producing islet cells are going into patients. So what we're really looking for is to get to our clinic trial sites with urgency. We're looking to get the cells dosed. We're evaluating safety and the outcome measures are really fairly straightforward, C-peptide, glucose, hemoglobin A1c. And what we're looking for here is, obviously, to see an impact in terms of bringing down blood sugar and being able to see C-peptide level drive, an indication that there is insulin. It's a little too early to call exactly what the results will be and such. But I am very excited that we're on the brink of enrolling patients and getting these trials up and running.

關於 VX-880 項目，我們正在尋找什麼？那麼，首先要做的就是…這是首次將這些完全分化的、幹細胞衍生的、能產生胰島素的胰島細胞移植到病人體內。因此，我們真正需要的是盡快抵達我們的臨床試驗地點。我們正在想辦法給細胞注射藥物。我們正在評估安全性，結果指標其實相當簡單明了，包括 C 肽、葡萄糖、糖化血紅蛋白 A1c。顯然，我們在這裡尋找的是能夠降低血糖並觀察 C 肽水平變化的影響，這表明胰島素正在發揮作用。現在預測結果還為時過早。但我很興奮，我們即將開始招募患者並啟動這些試驗。

Our next question comes from the line of Brian Skorney with Baird.

我們的下一個問題來自 Brian Skorney 和 Baird 的對話。

Also sticking on the type 1 diabetes program. I was wondering if you can kind of help us understand how your program differs from sort of the historical islet cell transportation -- transplantation as I understand it comes from stem cells, but maybe kind of walk us through any engineering or process that goes into the derivation of the cell that ultimately gets transplanted and how you sort of plan to try to mitigate immunosuppressive effects?

同時，我也在堅持參加第1型糖尿病治療計畫。我想請您幫我們了解一下您的方案與傳統的胰島細胞移植有何不同——據我所知，傳統的胰島細胞移植來自幹細胞，但您能否為我們詳細介紹一下最終移植的細胞的製備過程中涉及的工程技術或流程，以及您計劃如何減輕免疫抑製作用？

Yes. What a great question. And again, thanks so much for asking it. I guess you must be hearing my enthusiasm just brimming over. So the way I would think about the type 1 diabetes program is really 2 programs, and I would think of them as 2 separate programs. The first one, the one for which the IND just cleared, let's call that one the naked cell program. I would expect that there are maybe 60,000 people who could benefit from that naked cell program. That program does require immunosuppression. And the way I get to 60,000 is maybe there are 10,000, 15,000 people who have type 1 diabetes, have end-stage renal disease because of their type 1 diabetes and, for that reason, have had a renal transplant and are on immunosuppressives anyway. And then maybe another 40,000 or so people with very brittle diabetes, who would be comfortable with immunosuppression for the benefits that the cell therapy would bring them.

是的。真是個好問題。再次感謝你的提問。我想你一定能感受到我滿腔的熱情吧。所以我認為第 1 型糖尿病項目實際上是 2 個項目，我會把它們看作是 2 個獨立的項目。第一個項目，也就是IND剛剛批准的那個項目，我們姑且稱之為裸細胞計劃。我估計可能有 6 萬人能從這個裸細胞計畫中受益。該項目確實需要使用免疫抑制劑。我得出 60,000 這個數字的方法是，可能有 10,000 到 15,000 人患有 1 型糖尿病，由於 1 型糖尿病而患有終末期腎病，因此接受了腎移植手術，並且無論如何都在服用免疫抑製劑。此外，可能還有大約 4 萬名患有非常脆弱的糖尿病的人，他們願意接受免疫抑制治療，以獲得細胞療法帶來的益處。

Now of course, the high fruit here is the cells plus device program. For that second program, we are in late preclinical development. The really important thing to know there is that the Semma team prior to acquisition, and one of the reasons we were so excited about the Semma team coming into Vertex is that they designed using the right material, the right geometry and a clear understanding of how to avoid the pitfalls of fibrosis, allowing oxygen to flow, allowing insulin and glucose to flow but not allowing the immune cells to attack the cell-based therapy. So that program is particularly exciting because that does not require immunosuppressives. As we make progress on that program, we'll certainly keep you updated but that is making its way through preclinical development -- late preclinical development right now.

當然，這裡最有價值的成果是細胞加設備方案。對於第二個項目，我們目前處於臨床前開發的後期階段。真正重要的是要知道，在被收購之前，Semma 團隊（我們非常興奮地看到 Semma 團隊加入 Vertex 的原因之一）採用了正確的材料、正確的幾何形狀，並且清楚地了解如何避免纖維化的陷阱，從而允許氧氣流動、胰島素和葡萄糖流動，但又不允許免疫細胞攻擊基於細胞的療法。所以這個項目特別令人興奮，因為它不需要使用免疫抑制劑。隨著該計畫的進展，我們一定會及時向您報告最新情況，但目前該計畫正處於臨床前開發階段——現在正處於臨床前開發的後期階段。

Our last question comes from the line of Liisa Bayko with Evercore ISI.

我們的最後一個問題來自 Evercore ISI 的 Liisa Bayko。

I'm just going to jump on the bay, and I can ask a couple more questions on this note. Can you maybe speak to sort of how durable a pancreatic islet cell transplantation is today? What you think might be different with VX-880? And then a little bit about durability, I understand it's quite durable. And then just a final question on inventory. Were there any inventory build in Europe, let's say, given the recent launch there of TRIKAFTA or anything like that to note?

我這就上線，我還可以再問幾個問題。您能否談談目前胰島細胞移植的持久性如何？您認為VX-880會有哪些不同？關於耐用性，我了解到它非常耐用。最後還有一個關於庫存的問題。鑑於 TRIKAFTA 最近在歐洲推出，是否有在歐洲建立任何庫存或其他類似情況值得注意？

This is Reshma. Well, I'll start with type 1 diabetes and keep on that theme, and then I'll ask Charlie to comment on inventory.

這是雷什瑪。好，我就先從第 1 型糖尿病開始，並圍繞這個主題展開，然後再請查理談談庫存問題。

Okay. So the question that you asked is an excellent one, and it is how should we think about our cell-based therapy vis-à-vis what's been done with pancreas transplant or islet cell transplant. All right. So maybe 3 or 4 key things to know. The most important, by far, in a way, the most important thing to know is this. We know exactly what causes type 1 diabetes. It's autoimmune destruction of the pancreatic islet cells. And we know that when you can replace those cells, be it by whole pancreas transplant or islet cell transplants, you get benefit. So we know those 2 things.

好的。所以你提出的問題非常好，那就是我們應該如何看待我們以細胞為基礎的療法與胰臟移植或胰島細胞移植之間的關係。好的。所以大概有三、四件要了解的關鍵事情。從某種意義上來說，最重要的事情莫過於此。我們已經確切地知道第1型糖尿病的病因。這是胰島細胞的自身免疫性破壞。我們知道，當能夠替換這些細胞時，無論是透過全胰臟移植或胰島細胞移植，都能獲得益處。所以我們知道了這兩件事。

What's the problem? Well, the problem is the quantity and quality of islet cells. That is actually the essence of the problem, not that we don't know that this will work. We know it will work. And the real, real seminal discovery here that the Semma team made, and that was so exciting to us is they developed a way to take stem cells differentiated, fully differentiated into insulin-producing islet cells and make that in industrialized quantities. And so now what we have is the quantity and quality of cells to give, to transfuse, to transplant into patients with type 1 diabetes. So that's really what the real discovery here has been and why this program is so exciting to us.

出了什麼問題？問題在於胰島細胞的數量和品質。這其實才是問題的本質，並不是我們不知道這樣做會成功。我們知道它會奏效。Semma 團隊在這裡取得的真正具有開創性的發現，讓我們感到非常興奮的是，他們開發了一種方法，可以將幹細胞分化、完全分化成產生胰島素的胰島細胞，並進行工業化生產。所以現在我們有了足夠多、足夠優質的細胞，可以輸注、移植給第 1 型糖尿病患者。所以，這才是真正的發現所在，也是這個計畫讓我們如此興奮的原因。

Charlie, from that excitement to an inventory question, that I'm going to ask you to address.

查理，從剛才的興奮勁兒到接下來我要請你解答的一個庫存問題。

Yes. Thanks. And I'm going to take this opportunity actually to give applaud to our colleagues in the supply chain and manufacturing organization. I think the most noteworthy comment I can make about inventory is that those teams have worked flawlessly throughout the pandemic to ensure that we have inventory available for our patients, to ensure that we were ready for the KAFTRIO launch in Europe and to ensure that we'll be ready for future launches in 2021. I think your question, of course, is specifically about the impact on revenue. I could tell you that there was nothing noteworthy in the fourth quarter or in our 2021 guidance related to inventory levels.

是的。謝謝。我還要藉此機會向我們供應鏈和製造部門的同事們表示讚揚。關於庫存，我認為最值得一提的是，這些團隊在整個疫情期間都完美地完成了工作，以確保我們有足夠的庫存提供給患者，確保我們為 KAFTRIO 在歐洲的上市做好準備，並確保我們為 2021 年的未來上市做好準備。我認為你的問題當然是關於對收入的影響。我可以告訴你，第四季或我們 2021 年的庫存水準預期中沒有任何值得注意的地方。

This concludes today's question-and-answer session. I will now turn the call back to Michael Partridge for closing remarks.

今天的問答環節到此結束。現在我將把電話轉回給麥可‧帕特里奇，請他作總結發言。

Thanks, operator. So we're at the 1-hour mark. We will conclude the call here. I know there are other folks in the queue who didn't get a question but the Investor Relations team is in the office tonight and happy to take your questions. And thank you very much for connecting tonight.

謝謝接線生。現在已經過去1小時了。通話到此結束。我知道還有其他人在排隊，但他們還沒有機會提問，不過投資者關係團隊今晚在辦公室，很樂意回答您的問題。非常感謝大家今晚的參與。

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

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