福泰製藥 (VRTX) 2019 Q3 法說會逐字稿

Good evening. This is Michael Partridge, Senior Vice President of Investor Relations. Tonight, we will review with you Vertex's business progress and provide our third quarter financial results.

晚安.這是投資者關係高級副總裁邁克爾·帕特里奇。今晚，我們將與大家一起回顧Vertex的業務進展，並提供我們第三季的財務表現。

Making prepared remarks on the call tonight, we have Dr. Jeff Leiden, Chairman and CEO; Stuart Arbuckle, Chief Commercial Officer; Dr. Reshma Kewalramani, Chief Medical Officer; and Charlie Wagner, Chief Financial Officer. 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.

今晚在電話會議上發表準備好的演講的有：董事長兼首席執行官傑夫·萊頓博士；首席商務官斯圖爾特·阿巴克爾；首席醫療官雷什瑪·凱瓦拉馬尼博士；以及首席財務官查理·瓦格納。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, the continuing development and commercialization of our triple combination regimens for cystic fibrosis, Vertex's other programs and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

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、我們用於治療囊性纖維化的三聯療法的持續開發和商業化、Vertex 的其他項目以及 Vertex 未來的財務業績的聲明，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。

I will now turn the call over to Dr. Jeff Leiden.

現在我將把電話交給傑夫·萊頓博士。

Thanks, Michael. Good evening, everyone.

謝謝你，麥可。各位晚上好。

2019 has been a year of significant progress for Vertex across all parts of our business as we've continued to execute on our clear and differentiated strategy to create transformational medicines by investing in serial scientific innovation. Our significant growth in revenues from treating more people with CF globally has enabled continued investment in both internal and external innovation to create future medicines. And we are making rapid progress across our pipeline in our efforts to advance additional potentially transformative medicines, both in CF and multiple other serious diseases.

2019 年對 Vertex 而言是業務各個方面都取得重大進展的一年，我們繼續執行清晰且差異化的策略，透過投資連續的科學創新來創造變革性藥物。我們透過在全球範圍內治療更多囊性纖維化患者而獲得的收入大幅增長，使我們能夠繼續投資於內部和外部創新，以創造未來的藥物。我們在研發管線方面取得了快速進展，致力於推進更多可能具有變革意義的藥物，這些藥物不僅用於治療囊性纖維化，還用於治療多種其他嚴重疾病。

Our strategy is working and has positioned the company for continued growth in 2020 and for years to come. I'm pleased to review with you some of our recent accompaniments. First to CF. I'm proud to say that last week's FDA approval for TRIKAFTA marks the most significant step to date in our more than 20-year journey toward our future goal of curing CF for every person with this disease.

我們的策略正在奏效，使公司在 2020 年及未來幾年能夠持續成長。我很高興與大家一起回顧我們最近的一些伴奏曲目。首先是CF。我很自豪地說，上週 FDA 對 TRIKAFTA 的批准標誌著我們在 20 多年的旅程中邁出了最重要的一步，朝著治癒每一位囊性纖維化患者的未來目標邁進。

I joined Vertex as CEO 8 years ago, right before we received our first approval for KALYDECO to treat the cause of CF for a small group of patients in the U.S. Today, approximately 45,000 patients worldwide are eligible for one of our 4 CF medicines, and we're treating thousands of patients in more than 30 countries around the world.

8 年前，我加入 Vertex 擔任首席執行官，就在我們獲得 KALYDECO 在美國首次獲批用於治療一小群囊性纖維化患者的病因之前。如今，全球約有 45,000 名患者符合我們 4 種囊性纖維化藥物的用藥條件，我們正在為全球 30 多個國家的數千名患者提供治療。

I would like to again thank the patients, families, caregivers, physicians and advocates, as well as the CF Foundation, who have been on this journey with us over the past 2 decades. The approval of TRIKAFTA would not have been possible without the unwavering support of the entire CF community.

我再次感謝病人、家屬、照護人員、醫生和倡議者，以及囊性纖維化基金會，感謝他們在過去二十年中與我們一路同行。如果沒有整個囊性纖維化群體的堅定支持，TRIKAFTA 的批准是不可能實現的。

I would also like to highlight the significant progress we've made throughout 2019 in securing reimbursement for our medicines outside the U.S. Most notably, we recently announced new reimbursement agreements for ORKAMBI and SYMKEVI in England, Spain, Australia and Scotland. I'm pleased that eligible patients in these countries now have a medicine to treat the underlying cause of their CF for the first time, and that we were able to work collaboratively with governments to reach agreements that will appropriately value the scientific innovation and clinical benefit of our medicines.

我還想重點介紹一下我們在 2019 年為美國以外的藥品爭取報銷方面取得的重大進展。尤其值得一提的是，我們最近宣布了 ORKAMBI 和 SYMKEVI 在英國、西班牙、澳洲和蘇格蘭的新報銷協議。我很高興這些國家的符合條件的患者現在第一次有藥物可以治療他們的囊性纖維化根本病因，而且我們能夠與各國政府合作達成協議，從而適當地重視我們藥物的科學創新和臨床益處。

Now to our pipeline. Today, we have multiple different potentially transformative medicines in clinical development spanning 5 specialty diseases, and we're entering a period of significant clinical development progression and data generation for these programs.

現在來說說我們的管道。目前，我們有多種具有潛在變革意義的藥物正在進行臨床開發，涵蓋 5 個專科疾病，我們正進入這些計畫臨床開發進展和數據生成的重大時期。

In fact, we expect multiple proof-of-concept data readouts and the initiation of key proof-of-concept studies through 2020 that will represent important risk-lowering events for our pipeline.

事實上，我們預計到 2020 年將有多項概念驗證資料公佈，並啟動關鍵的概念驗證研究，這將代表我們產品線的重要風險降低事件。

Our pipeline investments have, for several years, followed a disciplined strategy focused on causal biology, building highly predictive preclinical models and developing biomarkers early in development to lower risk and increase our probability of success in the clinic. And we only work on transformative medicines for serious diseases that create and sustain significant value for patients, society and our shareholders.

多年來，我們的研發管線投資一直遵循著嚴謹的策略，專注於因果生物學，建立高度預測的臨床前模型，並在研發早期開發生物標誌物，以降低風險並提高我們在臨床上取得成功的機率。我們只致力於研發能夠為病人、社會和股東創造並維持重大價值的、治療嚴重疾病的變革性藥物。

Our external investments are aligned with this strategy and encompass multiple therapeutic modalities. We have increased our external investment in line with our growing cash flow by acquiring new development programs and building a toolkit of new technologies that will enable us to develop breakthrough medicines in diseases such as type 1 diabetes, Duchenne muscular dystrophy, hemoglobinopathies and others.

我們的外部投資與此策略一致，涵蓋多種治療方式。隨著現金流的成長，我們增加了外部投資，收購新的研發項目，並建立了一套新技術工具包，這將使我們能夠開發出治療 1 型糖尿病、杜氏肌肉營養不良症、血紅蛋白病等疾病的突破性藥物。

Most recently, we acquired Semma Therapeutics with the goal of developing a cellular therapy that both alone and, in combination with an implantable device, has the potential to cure type 1 diabetes. This acquisition is a perfect example of our efforts to bring in promising development programs that complement our internal R&D efforts, are aligned with our strategy and provide significant opportunities for further growth beyond CF.

最近，我們收購了 Semma Therapeutics，目標是開發一種細胞療法，單獨使用或與植入式設備結合使用，都有可能治癒第 1 型糖尿病。此次收購完美地體現了我們引進有前景的研發專案的努力，這些專案與我們的內部研發工作相輔相成，符合我們的策略，並為CF以外的進一步成長提供了重要的機會。

The execution of our corporate and research strategies has produced a highly differentiated profile for both near-term and long-term growth. As we continue to expand access to our medicines worldwide and gain approvals for new medicines, we are well positioned for further revenue and earnings growth and for continued reinvestment in innovation that create future medicine. I look forward to updating you on our progress over the coming months, and we'll now turn the call over to Stuart to talk in more detail about our commercial performance and the launch of TRIKAFTA.

我們公司及研究策略的執行，為近期及長期成長打造了高度差異化的格局。隨著我們不斷擴大全球藥品的可及性並獲得新藥批准，我們已做好充分準備，實現進一步的收入和利潤增長，並繼續投資於創新，創造未來的藥物。我期待在接下來的幾個月向大家報告我們的進展，現在我們將把電話交給斯圖爾特，讓他更詳細地談談我們的商業表現和 TRIKAFTA 的推出。

Thanks, Jeff. Tonight, I'll briefly review our commercial performance for the third quarter and discuss our expectations for the ongoing launch of TRIKAFTA in the U.S.

謝謝你，傑夫。今晚，我將簡要回顧我們第三季的商業業績，並討論我們對 TRIKAFTA 在美國持續推出的預期。

Our third quarter total product revenues were $950 million, a 21% increase compared to the third quarter of 2018. This increase is as a result of treating more patients globally with our medicines.

我們第三季產品總營收為 9.5 億美元，比 2018 年第三季成長了 21%。這一增長是由於我們在全球範圍內使用我們的藥物治療了更多患者。

Uptake across multiple products and in multiple populations drove revenue growth over the past year, most notably from SYMDEKO and SYMKEVI in patients ages 12 and older. We also saw revenue growth as a result of expansion into younger patients, including children in the U.S. ages 2 to 5 years for ORKAMBI and ages 6 to 11 years for SYMDEKO. Outside the U.S., we continue to make progress in achieving reimbursement for our CF medicines, ORKAMBI and SYMKEVI, as evidenced by our recent announcements regarding reimbursement in England, Spain, Scotland and Australia. Together, our progress in these countries underscores the positive outcomes that can be achieved when we and governments work collaboratively and flexibly toward providing access for patients.

過去一年，多種產品和多種人群的接受度推動了收入成長，其中 SYMDEKO 和 SYMKEVI 在 12 歲及以上患者中的接受度最為顯著。由於產品線擴展到更年輕的患者群體，我們也看到了收入增長，其中包括美國 2 至 5 歲兒童（ORKAMBI）和 6 至 11 歲兒童（SYMDEKO）。在美國以外，我們在為我們的 CF 藥物 ORKAMBI 和 SYMKEVI 爭取報銷方面繼續取得進展，正如我們最近宣布的關於在英國、西班牙、蘇格蘭和澳大利亞獲得報銷的公告所證明的那樣。我們共同在這些國家取得的進展凸顯了當我們和各國政府攜手合作、靈活地為病人提供醫療服務時，所能取得的正面成果。

Now to the approval and launch of TRIKAFTA in the U.S. TRIKAFTA is Vertex's fourth medicine to treat the underlying cause of CF and was approved by the FDA last week to treat people with CF ages 12 years and older with at least one F508del mutation. The speed of the FDA approval is a reflection of not only the strength of the TRIKAFTA data, but also of the community's shared urgency to provide patients with a medicine that treats the underlying cause of their disease. And I am pleased to report that the first patients have already been prescribed TRIKAFTA by their physicians, underscoring the strong interest in the medicine.

現在來說 TRIKAFTA 在美國的核准和上市。 TRIKAFTA 是 Vertex 公司用於治療 CF 根本病因的第四種藥物，上週獲得 FDA 批准，用於治療 12 歲及以上且至少攜帶一個 F508del 突變的 CF 患者。FDA 的快速批准不僅反映了 TRIKAFTA 數據的強大，也反映了整個社區迫切希望為患者提供一種能夠治療其疾病根本原因的藥物。我很高興地報告，醫生已經為首批患者開了 TRIKAFTA 處方，這凸顯了人們對這種藥物的濃厚興趣。

The label for TRIKAFTA is broad. Any patient in the U.S. aged 12 years or older with at least 1 F508del mutation is eligible. We estimate that there are approximately 18,000 patients in the U.S. who fit these criteria, representing by far the largest population of CF patients eligible for one of our CF medicines at the time of the launch.

TRIKAFTA 的標籤意義很廣泛。美國境內任何 12 歲或以上且至少攜帶 1 個 F508del 突變的患者均符合資格。我們估計，美國約有 18,000 名患者符合這些標準，這代表了在我們推出 CF 藥物時，符合條件的 CF 患者群體中人數最多的群體。

Of the 18,000 patients eligible for TRIKAFTA, approximately 6,000 are those with 1 F508del mutation and 1 minimal function mutation who until now have not yet have treatment for the underlying cause of their CF. The remaining approximately 12,000 patients are those who were already eligible for one of our CF medicines. And most of these patients are currently being treated with KALYDECO, ORKAMBI or SYMDEKO.

在符合 TRIKAFTA 條件的 18,000 名患者中，約有 6,000 名患者攜帶 1 個 F508del 突變和 1 個最小功能突變，但到目前為止，他們還沒有接受針對其 CF 根本原因的治療。其餘約 12,000 名患者都是已經符合我們 CF 藥物使用條件的患者。目前大多數患者正在接受 KALYDECO、ORKAMBI 或 SYMDEKO 的治療。

Revenue growth in 2020 will be driven primarily by treatment of new minimal function patients. And over time, we expect that the vast majority of the 6,000 new minimal function patients will be treated with TRIKAFTA. We also expect that a significant proportion of patients currently on KALYDECO, ORKAMBI or SYMDEKO will switch to TRIKAFTA over time.

2020 年的收入成長將主要由新確診的輕微功能障礙患者的治療所推動。隨著時間的推移，我們預計 6000 名新增的輕微功能障礙患者中的絕大多數將接受 TRIKAFTA 治療。我們也預計，目前使用 KALYDECO、ORKAMBI 或 SYMDEKO 的患者中，相當一部分人會隨著時間的推移轉而使用 TRIKAFTA。

The large number of eligible patients, coupled with the capacity constraints of CF centers to schedule and actually initiate such a large volume of patients, are important factors in why it may take longer for the TRIKAFTA launch to reach its peak level of uptake compared to prior launches.

符合條件的患者數量眾多，加上囊性纖維化中心在安排和實際啟動如此大量患者方面的能力限制，是導致 TRIKAFTA 的推出可能需要比以往的推出更長時間才能達到其最大接受度的重要因素。

Reimbursement is an additional factor in the launch of TRIKAFTA. We expect to obtain broad reimbursement from both commercial and government payers in the U.S. similar to our experience with prior CF medicines. We've already begun discussions with payers following the approval and the initial feedback has been positive, based on the strength of the clinical data and payers' understanding of the disease-modifying benefits that our medicines provide.

報銷是 TRIKAFTA 推出的另一個因素。我們預計，與我們先前治療囊性纖維化的藥物一樣，我們將從美國的商業和政府支付方獲得廣泛的報銷。獲批後，我們已經開始與支付方進行討論，初步回饋是正面的，這得益於臨床數據的可靠性以及支付方對我們藥物所帶來的疾病改善益處的理解。

These dynamics are reflected in our updated total 2019 CF revenue guidance of $3.7 billion to $3.75 billion that we provided at the time of the TRIKAFTA approval last week. We will also take these factors as well as early uptake trends into account as we set guidance for 2020 early next year.

這些動態反映在我們更新後的 2019 年 CF 總收入預期中，即 37 億美元至 37.5 億美元，該預期是在上週 TRIKAFTA 獲得批准時提供的。在明年年初制定 2020 年指導方針時，我們也會將這些因素以及早期的市場接受趨勢考慮在內。

In summary, I'm pleased that we are bringing our medicines to many more patients around the globe, and with the trajectory of our continued revenue growth.

總而言之，我很高興我們的藥品能夠惠及全球更多患者，而且我們的收入也持續成長。

With that, I will now turn the call over to Reshma to review recent pipeline progress.

接下來，我將把電話交給雷什瑪，讓她回顧最近的管道進度。

Thanks, Stuart. I would first like to echo Jeff's comments about the significance of the TRIKAFTA approval both for Vertex and for the CF community. It's truly amazing to think that it was in early 2016 that our scientists first synthesized elexacaftor, the next-generation corrector that became a key part of TRIKAFTA. And in a little under 4 years, Vertex was able to bring that molecule from the lab through development and now to patients in the U.S. It's a remarkable story of drug development, and I'd like to thank the entire CF community for their support in getting us to this milestone.

謝謝你，斯圖爾特。首先，我想附和 Jeff 的評論，即 TRIKAFTA 認證對於 Vertex 和 CF 社群都具有重要意義。令人難以置信的是，早在 2016 年初，我們的科學家就首次合成了 elexacaftor，這種新一代矯正劑後來成為 TRIKAFTA 的關鍵組成部分。在不到 4 年的時間裡，Vertex 公司就成功地將這種分子從實驗室研發出來，現在又讓美國的病患受益。這是一個非凡的藥物研發故事，我要感謝整個囊性纖維化群體給予我們的支持，使我們達到了這個里程碑。

As we celebrate this milestone, we're also working diligently to bring TRIKAFTA to more patients globally and to gain approvals for younger patients. We're on track to seek additional regulatory approvals for TRIKAFTA outside the U.S., first in Europe, then in additional countries globally. And we are also now enrolling a Phase III study of TRIKAFTA in children ages 6 to 11 years.

在我們慶祝這一里程碑的同時，我們也在努力將 TRIKAFTA 帶給全球更多患者，並爭取為更年輕的患者獲得批准。我們正按計劃尋求 TRIKAFTA 在美國以外的更多監管部門的批准，首先是歐洲，然後是全球其他國家。目前，我們正在進行一項針對 6 至 11 歲兒童的 TRIKAFTA III 期研究。

Outside of CF, we are entering a period of significant data generation and clinical development progress. We expect multiple, important clinical data readouts from our pipeline beginning later this year and the progression of multiple molecules into Phase I and Phase II studies throughout 2020.

除了囊性纖維化領域之外，我們正進入一個數據產生和臨床開發取得重大進展的時期。我們預計今年稍後將公佈我們研發管線中的多個重要臨床數據，並在 2020 年全年推進多個分子進入 I 期和 II 期研究。

In sickle cell disease and beta thalassemia, we expect to provide the first clinical data from the Phase I/II studies of the novel gene-editing therapy CTX001 later this year with our partner CRISPR Therapeutics. The data we expect to disclose will include measurements of safety and efficacy for patients with beta thalassemia and sickle cell disease treated with CTX001.

在鐮狀細胞疾病和β地中海貧血方面，我們預計今年稍後與我們的合作夥伴CRISPR Therapeutics一起提供來自新型基因編輯療法CTX001 I/II期研究的首批臨床數據。我們預期揭露的數據將包括使用 CTX001 治療 β 地中海貧血和鐮狀細胞疾病患者的安全性和有效性測量結果。

In our AAT program, we have now finalized the design of a Phase II proof-of-concept study for our first oral small molecule corrector VX-814 and expect to begin the study this quarter. This study is expected to enroll approximately 50 patients with AAT deficiency who have 2 Z mutations and will evaluate multiple doses of VX-814 compared to placebo for 28 days. The primary endpoints will be the change in level of functional AAT protein in the blood as well as safety and tolerability.

在我們的 AAT 專案中，我們現在已經完成了首個口服小分子矯正劑 VX-814 的 II 期概念驗證研究的設計，預計將於本季度開始研究。這項研究預計將招募約 50 名患有 AAT 缺乏症且攜帶 2 個 Z 突變的患者，並將評估 VX-814 多劑量與安慰劑相比，持續 28 天。主要終點將是血液中功能性 AAT 蛋白質水平的變化以及安全性和耐受性。

We expect to obtain data from the study in 2020. In addition to VX-814, we're also developing a second AAT corrector VX-864, which is currently in Phase I development.

我們預計將於 2020 年獲得該研究的數據。除了 VX-814 之外，我們也正在開發第二款 AAT 校正器 VX-864，目前正處於第一階段開發中。

In pain, we're advancing multiple selective NaV1.8 inhibitors through late-stage research and early clinical development including our ongoing Phase I study of VX-961.

在疼痛治療領域，我們正在推進多種選擇性 NaV1.8 抑制劑進入後期研究和早期臨床開發階段，包括我們正在進行的 VX-961 的 I 期研究。

And in FSGS, we are on track to complete our Phase I study of VX-147 in healthy volunteers later this year. VX-147 is our first oral small molecule inhibitor of APOL1 function. And if we are successful in Phase I, our plan is to initiate a Phase II proof-of-concept study in 2020, where we would evaluate the ability of VX-147 to reduce protein levels in the urine. This would represent an important biological proof-of-concept for this program.

在 FSGS 方面，我們正按計劃於今年稍後完成 VX-147 在健康志願者中的 I 期研究。VX-147 是我們首個口服小分子 APOL1 功能抑制劑。如果我們在第一階段取得成功，我們的計劃是在 2020 年啟動第二階段概念驗證研究，屆時我們將評估 VX-147 降低尿液中蛋白質水平的能力。這將為該專案提供重要的生物學概念驗證。

And similar to other pipeline programs, we are advancing multiple additional molecules for APOL1-mediated kidney diseases in late-stage research. With the launch of TRIKAFTA and the advancement of our pipeline of multiple other potentially transformative medicines across 5 serious diseases, 2020 is positioned to be a year of significant growth and pipeline progression for Vertex.

與其他研發管線計畫類似，我們正在推動多個針對 APOL1 介導的腎臟疾病的分子進入後期研究階段。隨著 TRIKAFTA 的推出以及我們在 5 種嚴重疾病領域其他多種潛在變革性藥物的研發管線的推進，2020 年有望成為 Vertex 實現顯著增長和研發管線進展的一年。

I'll now turn the call over to Charlie.

現在我將把電話交給查理。

Thanks, Reshma. In addition to Stuart's comments on the performance of our CF products, tonight I'll review our third quarter financial results, our 2019 financial guidance and make a few comments on our financial trajectory for 2020. All of the results and guidance I will discuss tonight are non-GAAP.

謝謝你，雷什瑪。除了 Stuart 對我們 CF 產品表現的評論之外，今晚我將回顧我們第三季度的財務業績、2019 年的財務指導，並對我們 2020 年的財務軌跡發表一些評論。我今晚將要討論的所有結果和指導意見均不符合GAAP準則。

As Stuart mentioned, we saw a continued double-digit growth in total product revenues in the third quarter of 2019 compared to 2018 based largely on the uptake of SYMDEKO and SYMKEVI. Our third quarter 2019 combined R&D and SG&A expenses were $416 million compared to $379 million for the third quarter of 2018.

正如 Stuart 所提到的，與 2018 年相比，2019 年第三季產品總收入持續保持兩位數成長，這主要得益於 SYMDEKO 和 SYMKEVI 的普及。2019 年第三季度，我們的研發與銷售、管理及行政費用合計為 4.16 億美元，而 2018 年第三季為 3.79 億美元。

The significant growth in revenues and disciplined spending in the third quarter resulted in operating income of $403 million, a 37% increase compared to the third quarter of 2018. Net income for the third quarter of 2019 was $322 million compared to $282 million in the third quarter of 2018.

第三季營收大幅成長，加上支出控制得當，營業收入達到 4.03 億美元，比 2018 年第三季成長了 37%。2019 年第三季淨收入為 3.22 億美元，而 2018 年第三季淨收入為 2.82 億美元。

Our year-to-date financial results show similar trends of strong revenue growth and disciplined spending resulting in exceptional operating income growth. Our total CF revenues through the third quarter of 2019 were $2.75 billion, a 27% increase over the same period in 2018.

今年迄今的財務表現顯示出類似的趨勢，即強勁的收入成長和嚴格的支出控制，從而帶來了卓越的營業收入成長。截至 2019 年第三季度，我們的 CF 總營收為 27.5 億美元，比 2018 年同期成長了 27%。

Our year-to-date combined R&D and SG&A expenses were $1.2 billion compared to $1.13 billion for 2018, resulting in year-to-date operating income of $1.19 billion for 2019 compared to $763 million for 2018.

截至目前，我們的研發和銷售、管理及行政費用合計為 12 億美元，而 2018 年為 11.3 億美元，導致 2019 年截至目前的營業收入為 11.9 億美元，而 2018 年為 7.63 億美元。

As our profitability and cash flow increase as a result of treating more CF patients globally, we have a clear strategy and intention to reinvest in both internal and external innovation to create future medicines. To date, in 2019, we've invested approximately $1.5 billion in cash in external innovation through new acquisitions and collaborations.

隨著我們在全球範圍內治療越來越多的囊性纖維化患者，我們的盈利能力和現金流不斷增加，我們有明確的策略和意圖，將對內部和外部創新進行再投資，以創造未來的藥物。截至 2019 年，我們已透過新的收購和合作，在外部創新方面投入了約 15 億美元的現金。

We ended the quarter with approximately $4 billion in cash and marketable securities compared to $3.2 billion at the end of 2018. I would note, however, that we completed our $950 million acquisition of Semma Therapeutics early in the fourth quarter, so that outflow was not yet reflected in our third quarter cash balance.

本季末，我們持有約 40 億美元的現金和有價證券，而 2018 年底為 32 億美元。不過，需要指出的是，我們在第四季初完成了對 Semma Therapeutics 的 9.5 億美元收購，因此這筆資金流出尚未反映在我們第三季的現金餘額中。

As we look ahead to Q4 and 2020 and beyond, we expect continued increases in cash flow to provide more flexibility for additional deals to fuel our long-term growth.

展望第四季、2020 年及以後，我們預期現金流將持續成長，為更多交易提供更大的靈活性，以推動我們的長期成長。

Now to 2019 guidance and high-level thoughts on our financial trajectory for 2020. As you know, we revised upward our guidance of total CF revenues with the approval of TRIKAFTA last week. And we are tonight reiterating our 2019 guidance for total CF product revenues, combined R&D and SG&A expenses and our anticipated effective tax rate.

接下來是 2019 年的業績指引以及 2020 年財務發展方向的整體展望。如您所知，在上週獲得 TRIKAFTA 的批准後，我們上調了 CF 總收入預期。今晚，我們將重申我們對 2019 年 CF 產品總收入、研發和銷售、管理及行政費用以及預期有效稅率的預期。

The midpoint of our 2019 revenue guidance reflects strong 23% growth over 2018, and we are well positioned to continue our trajectory of significant revenue growth in 2020 driven primarily by the launch of TRIKAFTA in the U.S. The exact rate of revenue growth will depend, in large part, on the TRIKAFTA launch dynamics that Stuart reviewed earlier, specifically the capacity of CF centers to schedule and initiate the large volume of new and existing patients likely to seek treatment with TRIKAFTA.

我們 2019 年營收預期中位數反映了較 2018 年強勁成長 23%，我們已做好充分準備，在 2020 年繼續保持顯著的營收成長勢頭，這主要得益於 TRIKAFTA 在美國的上市。收入成長的具體速度將在很大程度上取決於 Stuart 先前提到的 TRIKAFTA 上市情況，特別是囊性纖維化中心安排和啟動大量可能尋求 TRIKAFTA 治療的新舊患者的能力。

With significant revenue growth expected in 2020, we will also increase our investments in innovation, particularly following our recent acquisitions of Exonics and Semma. While Vertex operating expenses have typically grown in the range of 10% to 14% per year over the last few years, our current expectation is that the rate of growth will be somewhat higher in 2020 as we invest in research and preclinical manufacturing for cell and genetic therapies, in support of our programs in type 1 diabetes, DMD and other diseases.

預計 2020 年營收將大幅成長，我們將加大對創新的投入，尤其是在我們最近收購了 Exonics 和 Semma 之後。雖然 Vertex 的營運費用在過去幾年中通常每年增長 10% 到 14%，但我們目前的預期是，隨著我們投資於細胞和基因療法的研究和臨床前生產，以支持我們在 1 型糖尿病、DMD 和其他疾病方面的項目，2020 年的增長率將會更高一些。

Importantly, we expect our revenue growth to significantly outpace any increases in operating expenses, which will drive continued increases in operating income and expansion of operating margins.

重要的是，我們預計收入成長將顯著超過營運費用的任何成長，這將推動營業收入的持續成長和營業利潤率的擴大。

Currently, we plan to issue revenue and other financial guidance for 2020 at our Q4 earnings call, once we've seen a few months of the TRIKAFTA launch. I'm pleased with the continued performance of our business and look forward to updating you over coming months.

目前，我們計劃在第四季度財報電話會議上發布 2020 年的收入和其他財務指導，屆時我們將看到 TRIKAFTA 上線幾個月的情況。我對我們業務的持續表現感到滿意，並期待在接下來的幾個月向您報告最新進展。

With that, I'll hand the call back to Jeff.

這樣，我就把電話轉回給傑夫了。

Thanks, Charlie. As we near the end of 2019, Vertex is on track to meet or exceed each of the key goals we outlined for you at the start of the year.

謝謝你，查理。2019 年即將結束，Vertex 正按計劃實現或超越我們在年初為您設定的每一個關鍵目標。

An important and often overlooked part of our success is the strength of the team we have in place to execute on our strategy and drive the success of the business. With the launch of TRIKAFTA, increasing revenues from treating more people with CF globally, a pipeline that is expanding and progressing rapidly, and a strong and diverse team committed to our strategy of serial innovation, we have never been in a stronger position than we are today.

我們成功的一個重要且經常被忽視的因素是我們擁有一支強大的團隊，他們能夠執行我們的策略並推動業務成功。隨著 TRIKAFTA 的推出，全球範圍內治療更多囊性纖維化患者帶來的收入不斷增長，產品線快速擴展和推進，以及一支致力於持續創新戰略的強大而多元化的團隊，我們從未像今天這樣處於如此強大的地位。

With that, I will open the line to questions.

接下來，我將開放提問環節。

(Operator Instructions) And our first question comes from Salveen Richter, Goldman Sachs.

（操作說明）我們的第一個問題來自高盛的薩爾文·里希特。

Maybe just starting with a question on the reimbursement decisions that have played out recently in England and Spain and Australia and Scotland. How should we view the uptake trajectory in these regions and any implications for the fourth quarter?

或許可以先從最近在英國、西班牙、澳洲和蘇格蘭發生的報銷決定入手提問。我們該如何看待這些地區的市場接受度趨勢，以及這對第四季有何影響？

Yes, Salveen. Thanks for the questions. This is Stuart. So obviously, we're thrilled. It's been a very productive quarter in terms of new reimbursement agreements, which is great as we complete the journey from discovering these medicines to getting access for patients.

是的，薩爾文。謝謝大家的提問。這是斯圖爾特。所以，我們當然非常激動。就新的健保報銷協議而言，這是一個成果豐碩的季度，這很好，因為我們完成了從發現這些藥物到讓患者獲得這些藥物的整個過程。

In terms of the uptake, overall I would say, really the considerations are the same in each of the markets. And the way I would think about it is, firstly, the various administrations have to put in place the process to allow physicians to prescribe these medicines. And as an example, in England, they quoted that they were hoping to get that solved within 30 days. So obviously, there's a bit of a lag before we can even start initiating patients. And then after that, really I would be thinking about the number of patients that we have there in each of those markets. We expect in those markets, much like the other markets around the world, that we will, over time, initiate the vast majority of those patients on one of the CFTR modulators that's been reimbursed.

就市場接受度而言，我認為，各市場的具體考量其實都是一樣的。我的想法是，首先，各級政府必須制定相應的流程，允許醫生開立這些藥物的處方。例如，在英國，他們表示希望在 30 天內解決這個問題。顯然，在我們能夠開始接診患者之前，還需要一些時間。然後，在那之後，我真正會考慮的是我們在每個市場中有多少患者。我們預計，在這些市場，就像在世界其他市場一樣，隨著時間的推移，我們將讓絕大多數患者開始使用已獲報銷的 CFTR 調節劑。

Across the world, in general, across products, across geographies, we tend to see initiation rates in the 80% to 90% range. As you know, not everybody unfortunately can stay on the medicines, so we see persistence rates across products, across markets, somewhere in the 80% to 90% range. And so when we do eventually reach steady-state, it's a function of those 2 things. Then we need to factor in a compliance rate. The compliance rates on our medicines are as good as I've ever seen in my time in the industry. They're across products, tend to be in the 80% to 85% range. So those are the kinds of factors I would be taking into account.

總的來說，在全球範圍內，無論產品種類還是地域範圍，我們往往看到啟動率在 80% 到 90% 之間。如您所知，不幸的是，並非每個人都能堅持服用藥物，因此我們看到，各個產品、各個市場的用藥持續率都在 80% 到 90% 之間。因此，當我們最終達到穩態時，這取決於這兩個因素。然後我們還需要考慮合規率。我們藥品的使用依從率是我在這個行業以來見過的最好的。它們適用於各種產品，成功率通常在 80% 到 85% 之間。所以這些都是我會考慮的因素。

So that tells you a little bit about where we're likely to get to at steady-state. Really then the question is, how long is it going to take us to get to kind of peak levels of uptake? And that really is governed by kind of a couple of things. One is the size of the eligible patient population. If you take somewhere like England, it's 5,000 patients. That's a very large number. All of those patients are treated in the 40 CF centers in England. And so just like here in the U.S., there is a capacity constraint that the centers have to actually being able to see all of those eligible patients. And that's probably the biggest kind of rate limiter.

所以這可以讓你大致了解我們在穩定狀態下可能會達到什麼狀態。那麼真正的問題是，我們需要多久才能達到吸收率的峰值？這實際上取決於幾個因素。一是符合條件的患者群體規模。以英國為例，約有 5000 名患者。這是一個非常大的數字。所有這些患者都在英格蘭的 40 個囊性纖維化中心接受治療。因此，就像在美國一樣，這些中心也存在容量限制，無法接診有符合資格的患者。而這或許是最大的限速器類型。

So we certainly expect to get to the vast majority of those patients. It's just likely to ramp up over time.

因此，我們當然有信心能夠接觸到絕大多數患者。隨著時間的推移，這種情況很可能會加劇。

In terms of '19, we haven't included any adjustment in our '19 guidance, just because those reimbursement agreements have come so late in the year. And obviously, we need to work our way through the administrative things I've just told you about before we can actually start initiating patients.

至於 2019 年，我們沒有在 2019 年的業績指引中做出任何調整，因為這些報銷協議是在年底才達成的。顯然，在我們真正開始接診病人之前，我們需要先處理完我剛才提到的那些行政事務。

Great. And then just a second question about the AAT program. Could you just comment on how many dose cohorts you're looking at? And what the doses are? And could this transition into a registrational trial?

偉大的。那麼，關於AAT項目，我還有第二個問題。能否說明一下您正在研究多少個劑量組？劑量是多少？這能否轉化為註冊試驗？

Salveen, it's Reshma. So as I said in my prepared remarks, I think that you're going to see this Phase II dose-ranging study for VX-814 look and feel very much like our CF studies. It's going to be about 50 people or so, a few dose cohorts. And a very reasonable time frame.

薩爾文，我是雷什瑪。正如我在準備好的演講稿中所說，我認為你們將會看到 VX-814 的 II 期劑量範圍研究看起來和感覺起來都非常像我們的 CF 研究。大概會有 50 人左右，分成幾個劑量組進行試驗。而且時間安排非常合理。

I'll stay away from the specifics around the doses and such. And I do think that this is going to be important in getting to our Phase III study because this is indeed the study that's going to help us select the right dose. So in that respect, I think it's going to be very important.

關於劑量之類的具體細節，我就不多說了。我認為這對我們進入 III 期研究非常重要，因為這項研究確實將幫助我們選擇合適的劑量。所以從這個角度來看，我認為這非常重要。

And our next question comes from Michael Yee of Jefferies.

下一個問題來自傑富瑞集團的麥可葉。

Two questions. Congrats on all the progress and the TRIKAFTA approval. Maybe you could just frame some of the expectations around the uptake of TRIKAFTA early on, and whether you would expect centers to prioritize all the het/min patients first. You would think that would be logical. So even though there is swapping from others, how much of a priority is that for the het/mins first?

兩個問題。恭喜所有取得的進展以及TRIKAFTA的批准。或許您可以儘早闡明一些關於 TRIKAFTA 接受度的預期，以及您是否希望各中心優先考慮所有 het/min 患者。你可能會覺得這很合乎邏輯。即使有其他人在進行交換，那麼對於 het/mins 來說，這種交換的優先順序有多高？

And then the other question relates to a follow-up on AAT. Maybe Reshma, I think we all listened to the 8-hour workshop, but they seem to be quite interested also in functional data. So how confident are you that if we get positive data on AAT that a primary endpoint of just AAT would be sufficient for approval?

另一個問題與 AAT 的後續研究有關。或許雷什瑪，我想我們都聽了那場 8 小時的研討會，但他們似乎對功能性數據也很感興趣。那麼，如果我們獲得 AAT 的積極數據，您有多大把握認為僅以 AAT 為主要終點就足以獲得批准？

Mike, it's Stuart here. I'll take the TRIKAFTA question, and then Reshma will talk to AAT. So in terms of TRIKAFTA, obviously, we were thrilled to get the approval so quickly. As you know, the label is broad. Anybody with 1 F508del mutation, that's approximately 18,000 patients here in the U.S. Of those 18,000, about 6,000 are patients who have a minimal function mutation on the other allele. And as you well know, those are the patients who don't currently have a medicine to treat the underlying cause of their disease today.

麥克，我是史都華。我來回答 TRIKAFTA 的問題，然後 Reshma 會和 AAT 談談。所以就 TRIKAFTA 而言，顯然，我們很高興能這麼快就獲得批准。如你所知，這個標籤涵蓋範圍很廣。在美國，大約有 18,000 名患者攜帶 1 個 F508del 突變。在這 18,000 名患者中，約有 6,000 名患者在另一個等位基因上攜帶最小功能突變。如您所知，這些患者目前還沒有藥物可以治療他們疾病的根本原因。

In terms of uptake, again, this is going to be governed by a couple of things. One is the absolute capacity at CF centers that is, by far and away, the largest number of eligible patients we've ever had for any new product launch. For instance, more than twice as big as we had when we introduced ORKAMBI back in July 2015. So clearly, the capacity of centers is going to be a challenge.

至於普及程度，同樣取決於幾個因素。一是 CF 中心的絕對容量，就目前而言，這是我們有史以來任何新產品上市時符合資格的患者人數最多的一次。例如，比我們在 2015 年 7 月推出 ORKAMBI 時規模大了兩倍以上。顯然，各中心的容量將是一個挑戰。

In terms of prioritizing patients, Mike, we've heard just about everything from every different center. And I think if you talk to 1 center, you'll get 1 response. If you talk to another, you'll get another. Some have said that they will prioritize het/mins. Some have said that they will treat their most severely impacted patients, irrespective of what their mutation is. Others have said, they were going to treat patients as they are coming in.

麥克，關於優先考慮患者的問題，我們幾乎從各個醫療中心都聽到了各種各樣的說法。我認為，如果你聯繫一個中心，你只會得到一個回應。如果你跟另一個人說話，你就會得到另一個人。有人表示他們會優先考慮 het/mins。有些人士表示，無論患者的基因突變類型為何，他們都會盡力救治病情最嚴重的患者。其他人則表示，他們將按照病人入院的順序進行治療。

So yes, I'd love to tell you there's one answer to how patients are going to be treated, but I think it's as individual as individual centers. What I can tell you though is, to a center, they will tell you that they expect to treat the vast majority of those minimal function patients over time. And indeed, expect the vast majority of those who are currently being treated with SYMDEKO and ORKAMBI also to transition over time. But the real rate limiter to that is going to be just their ability to process all of those patients through the limited number of centers that there are. Reshma, AAT.

所以，是的，我很想告訴你，對於如何治療病人有一個統一的答案，但我認為這取決於各個醫療中心的具體情況。但我可以告訴你的是，對於醫療中心來說，他們會告訴你，他們希望隨著時間的推移，能夠治療絕大多數功能障礙患者。事實上，目前接受 SYMDEKO 和 ORKAMBI 治療的絕大多數人也會隨著時間的推移而轉變。但真正的限制因素將是他們能否透過數量有限的中心來處理所有這些患者。Reshma，AAT。

Right. With regard to the AAT workshop that took place just a couple of months ago, we were really pleased to be there. It was nice to be invited to be with the community and with the agency. I thought that there was real recognition of the disease, the gravity of the disease and the high unmet need. It was also interesting to see that our approach, a small molecule corrector, remains the only one that holds the potential to treat both the liver and the lung disease.

正確的。對於幾個月前舉辦的 AAT 研討會，我們非常高興能夠參加。很高興受邀與社區和機構成員交流。我認為人們真正認識到了這種疾病，認識到了這種疾病的嚴重性以及尚未滿足的巨大需求。有趣的是，我們採用的小分子矯正劑方法仍然是唯一有可能同時治療肝臟和肺部疾病的方法。

With regard to where the agency is, I found them to be very open-minded and acknowledged the -- that the -- that in the augmentation companies to date have gotten the approvals based on AAT levels, and that's the data point that's there. And I was also encouraged by their comments that they're going to work with each individual sponsor based on their approach to determine exactly what the Phase III trials could look like.

關於該機構的立場，我發現他們非常開明，並且承認——迄今為止，增強公司都是根據 AAT 水平獲得批准的，而這就是現有的數據點。他們的聲明也讓我感到鼓舞，他們將根據每個贊助商的具體情況與他們合作，以確定 III 期試驗的具體形式。

And our next question comes from Phil Nadeau of Cowen and Company. Phil, your line is on mute. And our next question comes from Alethia Young of Cantor Fitzgerald.

下一個問題來自 Cowen and Company 的 Phil Nadeau。菲爾，你的線路已靜音。下一個問題來自 Cantor Fitzgerald 公司的 Alethia Young。

And congrats on all the progress you've made. I guess, kind of two. I wanted you to talk a little bit about the Semma deal and how it fits in your world of innovative medicines, but still it's a kind of a much bigger addressable market and different angle from where you guys are going. And separately like in the United Kingdom, I know there's -- you said 5,000, do you think there is like a scenario where people -- there'll be some sorts of controls as far as, kind of, I would assume all the patients are warehoused, to some degree. So is there any kind of management that might happen there that we should think about in our models?

恭喜你所取得的所有進步。我想，算是兩種吧。我想請您談談與 Semma 的交易，以及它如何融入您們的創新藥物領域，但它仍然代表著一個更大的潛在市場，而且與您的發展方向也不同。還有，例如在英國，我知道有——你說有 5000 例，你認為是否存在這樣一種情況：人們——會有一些控制措施，比如，我假設所有病人都會在某種程度上被隔離起來。那麼，在我們的模型中，是否應該考慮可能出現的任何管理措施？

Yes. Thanks, Alethia. This is Jeff. I'll take the Semma question, and then Stuart will take the England question.

是的。謝謝你，阿萊西亞。這是傑夫。我來回答關於塞瑪的問題，然後史都華來回答關於英格蘭的問題。

With regards to Semma, I'd just start off reminding you that type 1 diabetes is a disease that fits our strategy perfectly, right? It's a serious disease, about 1.25 million patients in the U.S. that are treated in a relatively small number of centers by endocrinologists, so you can certainly reach them with a specialty sales force. And interestingly, despite the fact that insulin has been around and has saved their lives for almost 100 years now, it turns out that insulin therapy for these type 1 patients is not really a very good long-term way of returning them to normal glycemia or normal hemoglobin A1C levels and so they, as you know, suffer from very high rates of cardiovascular disease as well as from multiple hypoglycemic episodes. So there's a large unmet need obviously with this patient subset, and it fits our strategy.

關於 Semma，我首先要提醒你，1 型糖尿病這種疾病非常符合我們的策略，對吧？這是一種嚴重的疾病，在美國約有 125 萬名患者，他們只能在相對較少的中心接受內分泌科醫生的治療，因此你完全可以透過專業的銷售團隊接觸到他們。有趣的是，儘管胰島素已經存在並拯救了他們近 100 年的生命，但事實證明，對於這些 1 型糖尿病患者來說，胰島素療法並不是使他們的血糖或糖化血紅蛋白 A1C 水平恢復正常的良好長期方法，因此，正如您所知，他們患有非常高的心血管疾病，並且經常發生低血糖發作。顯然，這部分患者群體存在著很大的未滿足需求，這符合我們的策略。

We also knew for more than 15 years, that if you can successfully transplant islets into these patients, you can essentially cure the disease. There were a number of studies of small numbers of patients who were transplanted with cadaveric islets under immunosuppression. And many of those patients were not only cures, they were long-term cures. Some of those patients are out more than a decade.

15 多年來，我們都知道，如果能成功地將胰島移植到這些患者體內，基本上就能治癒這種疾病。有一些研究對接受免疫抑制治療的少量患者進行了屍體胰島移植。而其中許多患者不僅痊癒了，而且是長期痊癒。有些患者已經康復超過十年了。

So there were really 2 issues with type 1 diabetes, and we've been watching it as one of our diseases of interest for some time. I'd say obviously, David Altshuler is a diabetologist as well as a geneticist, so he has been keenly interested in this disease.

所以，1 型糖尿病實際上有兩個問題，我們已經關注它一段時間了，它是我們感興趣的疾病之一。很顯然，大衛·阿爾特舒勒既是糖尿病專家又是遺傳學家，所以他對這種疾病非常感興趣。

And the 2 problems were, there weren't enough cadaveric islets, and so you needed a different way to make islets. And the other problem was the need for immunosuppression was potentially limiting to the number of patients that you can reach. So we were watching companies who were addressing those 2 problems for the last 2, 3 years. And over the last 6 to 8 months, we were convinced that Semma has actually solved both of those problems. So on the first month, they have figured out how to take ES cells or even iPSC cells, and successfully differentiate them into human islet, these are human cells, in an industrial fashion. So they can make industrial levels of human islets. And they've shown that those islets in animal models actually are able to cure diabetes when they're transplanted. So that was the solution of the islet number problem.

兩個問題是，屍體胰島數量不足，因此需要用不同的方法來製造胰島。另一個問題是，免疫抑制的需求可能會限制你能接觸到的患者數量。所以在過去的2、3年裡，我們一直在關注那些致力於解決這兩個問題的公司。在過去的 6 到 8 個月裡，我們確信 Semma 實際上已經解決了這兩個問題。因此，在第一個月，他們找到如何利用胚胎幹細胞甚至誘導多能幹細胞，並以工業化的方式成功地將它們分化成人類胰島細胞（這些都是人類細胞）。所以他們可以生產工業規模的人類胰島。他們已經證明，在動物模型中，移植這些胰島細胞確實能夠治癒糖尿病。這就是胰島數量問題的解決方案。

And then they've also invented a device that is able -- in which you can put the islets, that's able to protect them from the immune response. And so Semma really has 2 products. They have what we call naked islets that they can transplant into the liver just like cadaveric islets are transplanted into the liver, that does require immunosuppression. And they have a second product which is the islets in the device, which we believe can be transplanted ultimately without immunosuppression. And that obviously opens up the number of patients that can be treated substantially.

而且他們還發明了一種裝置，可以將胰島放入其中，從而保護胰島免受免疫反應的影響。所以 Semma 其實只有兩款產品。他們擁有我們稱為裸露胰島的組織，可以像移植屍體胰島一樣移植到肝臟中，但這確實需要免疫抑制。他們還有第二種產品，即設備中的胰島，我們相信最終可以在不抑制免疫的情況下進行移植。這顯然會大幅增加可以接受治療的患者數量。

So in summary, it's a disease that fits our strategy perfectly. It's a specialty disease. It's a disease of high unmet need, and it's a disease in which these recent scientific breakthroughs have given a new approach towards a transformative therapy. So it was a perfect fit, and when we saw that, we were able to move pretty quickly.

總而言之，這種疾病非常符合我們的策略。這是一種特殊疾病。這是一種亟需治療的疾病，而最近的科學突破為這種疾病的治療帶來了新的變革性方法。所以這簡直是天作之合，當我們看到這一點時，我們就能迅速採取行動了。

And Alethia, on expectations for England, I want to go back to kind of what I said earlier about uptake in all markets. As you said, there's about 5,000 eligible patients in England for the various medicines and across the various age ranges and genotypes that are included in the agreement we struck with the NHS. If you look at the uptake rates around the world for those products across patients and genotypes and age ranges, it's, as I said, in the 80% to 90% range in terms of how many of those patients have been initiated in similar markets around the world. Again, not every patient can stay on the medicine. The persistence rates, again, are somewhere in the 80% to 90% range. So if you factor those 2 things in and think about where might we be when we get to kind of steady-state, then that could be somewhere around 3,500 patients could be persistent on a CFTR modulator, if you just take those assumptions and kind of pick the mid-range of all of those other markets around the world.

至於對英格蘭的預期，Alethia，我想回到我之前所說的關於所有市場接受度的問題。正如您所說，在英格蘭，大約有 5000 名符合條件的患者可以使用各種藥物，涵蓋了我們與英國國家醫療服務體系 (NHS) 達成的協議中涉及的各個年齡層和基因型。如果你看一下這些產品在全球範圍內針對不同患者、基因型和年齡層的接受率，正如我所說，在世界各地類似的市場中，這些產品的接受率在 80% 到 90% 之間。同樣，並非所有患者都能堅持服用這種藥物。持續率再次達到 80% 到 90% 左右。所以，如果你把這兩件事考慮進去，想想當我們達到某種穩定狀態時，我們可能會處於什麼狀態，那麼如果你接受這些假設，並選取世界各地所有其他市場的中位數，那麼大約會有 3,500 名患者能夠持續使用 CFTR 調節劑。

In terms of warehousing, that isn't something that we've heard discussed in the U.K. Obviously, there's been a lot of pent-up demand for these products, and so we've heard about people wanting to be initiated. I have not heard of people saying that they're likely to warehouse their patients in anticipation of the triple. Clearly, that's something that could happen. As I say, it's not something that I've heard talked about in the U.K.

就倉儲而言，我們還沒有聽說英國有人討論過這個問題。顯然，這些產品的需求一直很旺盛，所以我們聽說有人想要加入。我還沒聽到有人說他們可能會把病人集中起來，以應對即將到來的三重危機。顯然，這種情況有可能發生。正如我所說，我在英國從未聽說過這件事。

And our next question is from Cory Kasimov of JPMorgan.

下一個問題來自摩根大通的科里·卡西莫夫。

I'll ask one about one of the few countries you don't have a formal agreement in yet, with France. So can you remind us how many patients are already on one of your approved CF drugs over there? And how we should think about revenue recognition once a deal ultimately comes through in that country?

我會問其中一個問題，那就是你們尚未與少數國家（例如法國）簽署正式協議的情況。那麼，您能否告知我們目前有多少患者正在服用貴公司核准的囊性纖維化藥物？那麼，一旦交易最終在該國完成，我們應該如何考慮收入確認問題？

And then on the pipeline side, regarding CTX001 for beta thal and sickle cell, are you able to elaborate at all on the type of data we could expect to see later this year in terms of patient numbers or duration of follow-up you would have at that point?

那麼，在研發管線方面，關於用於治療β地中海貧血和鐮狀細胞貧血的CTX001，您能否詳細說明一下，就患者數量或隨訪持續時間而言，我們今年晚些時候可以期待看到哪些類型的數據？

Cory, it's Stuart. I'll start on France. You're right, France is one of the few markets now where we don't have a reimbursement agreement in place. We are in very active discussions with the French authorities and I'm certainly hopeful that we'll be able to bring those discussions to a successful conclusion as we have recently in Spain, in Scotland, in England and Australia. You're correct, there are a number of patients who are taking ORKAMBI in France. ORKAMBI was available through an early access program for patients 12-plus. And within the French system, there's approximately 1,100-or-so patients who are currently receiving ORKAMBI.

科里，我是史都華。我先從法國開始。你說得對，法國是目前少數幾個我們還沒有達成報銷協議的市場之一。我們正在與法國當局進行非常積極的磋商，我當然希望我們能夠像最近在西班牙、蘇格蘭、英格蘭和澳洲一樣，成功地完成這些磋商。你說得對，法國有很多患者正在服用 ORKAMBI。ORKAMBI 可透過早期准入計畫提供給 12 歲及以上的患者。在法國的醫療體系中，目前約有 1,100 名左右的患者正在接受 ORKAMBI 治療。

In terms of revenue recognition and how that might change, I'll turn that over to Charlie.

至於收入確認以及可能的變化，我將把這個問題交給查理來解答。

Yes. Cory, this is Charlie. For revenue recognition, we have been recording revenue at a relatively low value for sales into France. Currently, when we land on an agreed-upon price, we will book a catch-up of prior period revenue, which will equal the difference between the negotiated price and the price at which we've been booking revenue. That revenue, as it comes through the prior period revenue, our intention would be to non-GAAP that out as [obviously] it won't repeat. And then going forward, we'll book revenue at the contracted price.

是的。科里，這是查理。在收入確認方面，我們對銷往法國的銷售額一直以相對較低的數值記錄收入。目前，當我們達成一致價格時，我們會確認先前期間的收入，該收入將等於協商價格與我們先前確認收入的價格之間的差額。由於這部分收入來自前期收入，我們打算將其按非GAAP準則剔除，因為（顯然）它不會重複出現。然後，今後我們將以合約價格確認收入。

Cory, with regard to CTX001 and the beta-thalassemia and sickle cell programs, here's kind of where we are. We have about half a dozen sites open for beta thal, about a dozen sites open for sickle cell. The studies are enrolling. I think you must have heard our partners at CRISPR comment on the fact that we will be in a position to share data this quarter. I think what you should expect to see is safety and tolerability first and foremost, unsurprisingly in this Phase I/II study. And on the efficacy side, certainly hemoglobin levels, hemoglobin F levels will be very interesting amongst other things.

Cory，關於 CTX001 以及 β-地中海貧血和鐮狀細胞貧血項目，我們目前的情況大致如下。我們有大約六個治療β-地中海貧血的治療點，大約十幾個治療鐮狀細胞貧血的治療點。研究正在招募受試者。我想您一定已經聽到了我們的合作夥伴 CRISPR 的評論，他們表示我們將在本季能夠共享資料。我認為，在本次 I/II 期研究中，最應該關注的是安全性和耐受性，這並不令人意外。就療效而言，血紅蛋白水平，特別是血紅蛋白 F 水平，將會非常有趣。

And our next question comes from Paul Matteis of Stifel.

下一個問題來自 Stifel 公司的 Paul Matteis。

Congrats on the progress. I have a couple of questions, one on AAT and one on the triple in the U.K. On AAT, I was wondering if you could talk a little bit about the mechanics of the assay you're using to corroborate the functionality of the AAT levels produced by VX-814, or I guess, secreted. How important is that assay and the output from it to the top line readout in validating the efficacy of the drug?

恭喜你取得進展。我有幾個問題，一個是關於 AAT 的，另一個是關於英國的三重檢測的。關於 AAT，我想知道您能否談談您用來證實 VX-814 產生的 AAT 水平（或我猜是分泌的）的功能性的檢測方法的機制。此檢測方法及其輸出結果對於驗證藥物療效的最終結果有多重要？

And then as far as discussions with NHS go, Stuart, I was wondering if you could just give us the latest on where your conversations are regarding reimbursement for the triple? And whether or not an agreement there is gated by EMA approval?

至於與英國國家醫療服務體系 (NHS) 的討論，斯圖爾特，我想問你能否告訴我們關於三聯療法報銷事宜的最新進展？而協議是否需要獲得EMA的批准？

Sure. Sure. This is Reshma. Let me tackle the AAT [out] assay question. So as you've seen our data in the animal models, you'll remember the slide to the left panel shows you what happens with VX-814 and with VX-864 treatment. And the y-axis there is actually functional AAT level. So what we've been measuring in the animal studies is what we will be measuring in the human studies. And it's a reasonably easy -- I never like to say easy in terms of a clinical trial, but it's a reasonably simple assay and it's the same functional assay that you've seen us do in the animal studies.

當然。當然。這是雷什瑪。讓我來解答AAT[out]檢測的問題。正如您在動物模型中看到的數據一樣，您應該還記得左側面板的幻燈片顯示了 VX-814 和 VX-864 治療後的結果。而那裡的 y 軸實際上代表的是功能性 AAT 水平。因此，我們在動物研究中測量的指標，也將在人體研究中測量。而且這相對來說比較容易——我從不喜歡在臨床試驗中用「容易」這個詞，但這確實是一個相對簡單的檢測方法，而且它與我們在動物研究中所做的功能性檢測方法相同。

Yes. Paul, just on the U.K., just to be crystal clear, the current agreement, the one that we announced last week, the current commercial agreement, does not include the triple combination. It includes KALYDECO and its approved indications, ORKAMBI and SYMKEVI. So triple is not included. Obviously, there's a very high level of awareness of the triple combination, both in the CF community and the NHSE. But access to the medicine in the U.K. is going to be governed by our ability to get EMA approval in the first instance.

是的。保羅，就英國而言，為了說清楚，目前的協議，也就是我們上週宣布的協議，目前的商業協議，不包括三方合併。其中包括 KALYDECO 及其核准適應症、ORKAMBI 和 SYMKEVI。所以三重奏不包含在內。顯然，無論是囊性纖維化患者群體或英國國家醫療服務體系（NHSE），人們對三聯療法的認知度都非常高。但是，在英國能否獲得這種藥物，首先取決於我們能否獲得歐洲藥品管理局 (EMA) 的批准。

And our next question comes from Phil Nadeau of Cowen and Company.

下一個問題來自 Cowen and Company 的 Phil Nadeau。

Sorry about before, I think I was on mute. First on the Trikafta launch in the U.S., I think you've mentioned a couple of times that capacity will be limiting to getting new patients on therapy. Do you have a sense of exactly what that capacity is at CF centers? How many patients could see their physician every month, every quarter, every year during 2020?

抱歉，之前我好像是靜音的。首先是關於Trikafta在美國的上市，我想您已經多次提到，其產能將限制新患者接受治療。您是否了解囊性纖維化中心的特定治療能力？2020 年，每個月、每季、每年分別有多少病人能夠去看醫生？

Yes. Phil, it's Stuart. Yes, capacity at CF centers is -- we hear from the CF centers all the time. We heard it in the run-up to the launches of ORKAMBI and SYMKEVI, and we've heard it when talking to them about how they're planning to approach the launch of Trikafta. Essentially, the regulatory step there, just to be clear, is it's the same 275 centers who are seeing all of their CF patients. And whilst there is a huge amount of enthusiasm about Trikafta, they've got other patients who are coming in for their regular visits. They've got patients who are not yet eligible for Trikafta. Obviously, they've also got people, sadly, who are being admitted with exacerbations and things like that. So whilst Trikafta is very, very important to them, they have a lot of other things that are going on as well.

是的。菲爾，我是史都華。是的，CF 中心的容量是－我們經常從 CF 中心聽到這樣的回饋。我們在 ORKAMBI 和 SYMKEVI 上市前就聽過這種說法，在與他們討論他們計劃如何推出 Trikafta 時，我們也聽過這種說法。簡而言之，監管方面的做法是，所有囊性纖維化患者都由相同的 275 個中心接收。雖然人們對 Trikafta 表現出極大的熱情，但他們還有其他患者前來定期復診。他們有一些病人目前還不符合使用Trikafta的條件。顯然，令人遺憾的是，他們也收治了一些病情加重或其他類似情況的患者。所以，雖然 Trikafta 對他們來說非常非常重要，但他們還有很多其他事情要做。

As I said, in total, there is 18,000 patients who are eligible for Trikafta in the United States who will be treated at the 275-or-so CF centers. As I said, it was about 8,500 patients who were eligible for ORKAMBI, about 12,000 for SYMKEVI. And so that's why we think, whilst we think we're going to get to very high levels of uptake overall over time, it may be that it takes us a little bit longer to get to those kind of peak levels of uptake than it did with ORKAMBI and SYMKEVI.

正如我所說，在美國，共有 18,000 名符合 Trikafta 治療條件的患者，他們將在大約 275 個囊性纖維化治療中心接受治療。正如我所說，大約有 8,500 名患者符合 ORKAMBI 的條件，大約有 12,000 名患者符合 SYMKEVI 的條件。所以這就是為什麼我們認為，雖然隨著時間的推移，我們的整體接受度將會非常高，但達到這種峰值接受度可能需要比 ORKAMBI 和 SYMKEVI 更長的時間。

Got it. Okay. And then second question, just a follow-up to Paul's prior question on the U.K., the press reports about the current agreement that you have, have mentioned that in order for the triple to be reimbursed in the U.K., it'll be subject to a NICE -- an evaluation by NICE. Can you talk a little bit more about that process? Is that a different process than what you've had before, just cure reimbursement? Or is the triple kind of starting from the ground floor and need to go through the whole process that your medicines have had to go through in the past?

知道了。好的。第二個問題，是針對保羅先前關於英國的問題的後續提問。媒體通報你們目前的協議提到，為了在英國獲得三重賠償，需要經過 NICE 的評估。能再詳細談談這個過程嗎？這和您之前經歷的僅僅是醫療費用報銷的流程有什麼不同嗎？或者說，三重療法是不是意味著要從頭開始，需要經歷藥物過去所經歷的整個過程？

Yes. Great question, Phil. So -- yes, we will be submitting the triple combination to NICE pending EMA and CHMP positive recommendation. We said that we will submit that and discuss the timing of when we will submit that with the NHS and NICE. And we've agreed and we made public that we are planning to do that in around January 2021. The reason for that is a couple of fold: one, that it will allow us to collect additional long-term data, as we are currently in the U.S. through our open-label extension studies, and we know how important that long-term data is in terms of demonstrating the benefit of CFTR modulators. We've seen that with KALYDECO. We've seen that with ORKAMBI, and now SYMKEVI. The more data we get, the more you get to see the long-term benefits these types of agents have.

是的。問得好，菲爾。所以——是的，我們將向 NICE 提交三重療法，等待 EMA 和 CHMP 的積極推薦。我們表示會提交該報告，並與英國國家醫療服務體系 (NHS) 和英國國家衛生與臨床優化研究所 (NICE) 討論提交時間。我們已經達成一致，並公開表示計劃在 2021 年 1 月左右實施該計劃。原因有二：一是這將使我們能夠收集更多長期數據，因為我們目前在美國進行開放標籤擴展研究，我們知道這些長期數據對於證明 CFTR 調節劑的益處有多重要。我們已經從 KALYDECO 身上看到了這一點。我們已經從 ORKAMBI 身上看到了這一點，現在又看到了 SYMKEVI 的出現。我們獲得的數據越多，就越能看出這類代理人帶來的長期好處。

The second reason why that timing we think is an appropriate time to be submitting is that NICE is currently undergoing a review of its methodology. As you may know, and as we've made quite public, we have some concerns about the approach that NICE takes to evaluating medicines in terms of their ability to truly value appropriately medicines like ours that have the kind of long-term benefits that ours have, and we are hopeful that through that methods review that there may be some changes to the evaluation methodology which allow them to better value the types of benefits that our medicines bring. So we've committed to submitting the triple. January 2021 is when we've said that we will do that. And hopefully, that explains the reasons why we've agreed on that time line.

我們認為此時提交是合適的第二個原因是，NICE 目前正在對其方法進行審查。正如您可能知道的，也正如我們公開表示的那樣，我們對 NICE 在評估藥物方面採取的方法有一些擔憂，認為他們無法真正恰當地評估像我們這樣具有長期益處的藥物的價值。我們希望透過方法審查，評估方法能夠有所改變，從而更好地評估我們藥物帶來的益處。所以我們決定提交這三份文件。我們曾表示將在2021年1月完成這項工作。希望這能解釋我們為什麼會同意這個時間表。

And our next question comes from Matthew Harrison of Morgan Stanley.

下一個問題來自摩根士丹利的馬修·哈里森。

I was hoping maybe we could spend a minute on 147. Can you just talk about exactly what data you expect to have available next year? And given that data, I assume on some renal parameters, what you would expect to look at in terms of a next study?

我希望我們能花一分鐘討論一下147號公路。能否具體談談您預計明年能獲得哪些數據？根據這些數據，我假設會關註一些腎臟參數，您認為下一步的研究應該關注哪些方面？

Sure. So just to catch everybody else up to speed on VX-147, this is the molecule that's targeted at the APOL1 access. And there is a known disease called FSGS, focal and segmental glomerulosclerosis, a type of kidney disease that unfortunately is relentless and really has only one outcome, and that is progression to either end-stage renal disease transplant or death. It's really a very significant renal disease.

當然。為了讓大家了解 VX-147 的最新情況，這是一種針對 APOL1 通道的分子。還有一種叫做 FSGS（局部節段性腎小球硬化症）的已知疾病，這是一種腎臟疾病，不幸的是，它是一種無情的疾病，實際上只有一個結果，那就是發展到終末期腎病、腎移植或死亡。這確實是一種非常嚴重的腎臟疾病。

The way it manifests itself is proteinuria. That is to say protein in the urine. So where we are right now with the VX-147 program is we're in Phase I doing the SAD/MAD. We anticipate that we're going to be ready to go to Phase II, the dose ranging study, next year, 2020. And while it's too early to call exactly when we're going to have results, I expect it to be a very modest-sized study, given the small patient population that has this disease and the very grievous nature of the disease.

它的表現形式是蛋白尿。也就是說，尿液中含有蛋白質。所以，目前 VX-147 專案正處於第一階段，也就是 SAD/MAD 階段。我們預計明年（2020 年）就可以進入 II 期劑量範圍研究。雖然現在斷言何時才能得出結果還為時過早，但考慮到患有這種疾病的患者人數較少，而且這種疾病的性質非常嚴重，我預計這將是一項規模非常小的研究。

So in that dose ranging study that'll get off and running in 2020, I anticipate the endpoint there is going to be proteinuria, which is very convenient because that is the endpoint of significance, and it is the proof of biological activity.

因此，在 2020 年即將啟動的劑量範圍研究中，我預計終點將是蛋白尿，這非常方便，因為蛋白尿是具有重要意義的終點，也是生物活性的證明。

Reshma, you want to talk about the other molecule [provided]?

雷什瑪，你想談談另一種分子嗎？

Yes, sure, sure. Just like in cystic fibrosis and what you've seen us do there, we have a portfolio of molecules for this as well, for the APOL1-mediated kidney diseases. So while VX-147 is the one that's in the lead and going through its SAD/MAD, there's a whole portfolio of molecules but behind that in late preclinical, and those will also be making their way through the clinic.

好的，當然可以。就像我們在囊性纖維化領域所做的那樣，我們也擁有一系列針對 APOL1 介導的腎臟疾病的分子。因此，雖然 VX-147 目前處於領先地位，正在進行 SAD/MAD 試驗，但仍有一整套分子產品組合處於臨床前後期階段，這些分子也將進入臨床試驗階段。

And our next question comes from Brian Abrahams of RBC Capital Markets.

下一個問題來自加拿大皇家銀行資本市場的布萊恩亞伯拉罕。

Congratulations on all the progress. Two questions from me on Trikafta. I guess, first off just given how early this was approved. Anything that you guys need to do in parallel more than typical post-marketing clinical work, preclinical tox or [CAR-T] to maintain it on the market? And then any education or awareness that you plan to do around some of the side effect nuances versus ORKAMBI or SYMDEKO? I'm sort of curious how we should think about compliance and persistence ending up, given the cocktail's overall benefit-risk maybe relative to, say, SYMDEKO?

祝賀你們取得的所有進展。關於Trikafta，我有兩個問題。我想，首先是因為這項提案獲準的時間非常早。除了典型的上市後臨床研究、臨床前毒理學研究或[CAR-T]研究之外，你們還需要並行哪些其他工作來維持該產品在市場上的銷售？那麼，您計劃開展哪些教育或宣傳活動，以提高人們對 ORKAMBI 或 SYMDEKO 等藥物副作用細微差別的認識呢？我有點好奇，考慮到這種組合療法的整體效益風險，我們應該如何看待合規性和持續性最終會如何，例如相對於 SYMDEKO 而言？

Sure. Let me start this off and then I'll ask Stuart to comment on education and on compliance persistence. So obviously, we were thrilled with the quick approval of Trikafta. And I do think it reflects the benefit and the very nice tolerability of this medicine.

當然。讓我先拋磚引玉，然後我會請史都華就教育和合規堅持性發表意見。所以，我們對Trikafta的快速核准感到非常高興。我認為這反映了這種藥物的益處和非常好的耐受性。

With regard to what to expect in the post-marketing setting, nothing really unusual or different. You know that we have a study in F-gating and F/RF patients that we had already initiated. So those are continuing, but no, nothing else that's different or unusual. Stuart?

至於售後市場方面，沒有什麼特別或不同之處。你知道我們已經啟動了一項關於 F 門控和 F/RF 患者的研究。所以這些事情還在繼續，但是，沒有其他不尋常或不尋常的事情發生。史都華？

Yes. Brian, in terms of Trikafta and its benefit/ risk profile, as you would expect, we will be being as fulsome as we can in our discussions with physicians on both the benefits of the molecules and the adverse events that we've seen from the studies. As you know, the benefit-risk profile is very positive as a result of that, in terms of what we expect in terms of compliance rates. I would expect them to be very high just as they have been with our other CFTR modulators. As I mentioned earlier, yes, we see them in a very tight range across ORKAMBI, SYMDEKO and KALYDECO. They're in that sort of 80% to 85% range in terms of compliance with the medicine. Given the benefit-risk profile that we've seen with Trikafta, I would expect it to be right in that range, if not towards the top end of that range. Obviously, we'll see how it plays out in the real world, but that would be my expectation.

是的。Brian，就Trikafta及其益處/風險概況而言，正如你所預料的那樣，我們將在與醫生的討論中盡可能全面地介紹這些分子的益處以及我們從研究中看到的不良事件。如您所知，因此，就我們預期的合規率而言，收益風險比非常積極。我預計它們會非常高，就像我們其他 CFTR 調節劑一樣。正如我之前提到的，是的，我們在 ORKAMBI、SYMDEKO 和 KALYDECO 中都看到了它們非常緊密的聯繫。他們的用藥依從性大概在 80% 到 85% 之間。鑑於我們對 Trikafta 的收益風險比，我預計它的價格應該在這個範圍內，甚至可能接近這個範圍的上限。顯然，我們會看看現實世界會如何發展，但這只是我的預期。

And our next question comes from Geoff Meacham of Bank of America.

下一個問題來自美國銀行的傑夫‧米查姆。

Big congrats on the fast approval of Trikafta. So a question for Stuart. Through the rollout, I guess, what are the lessons that you guys have learned with getting reimbursement secured with KALYDECO, say, going back years ago or SYMDEKO more recently? It's really focused on how you can reduce the insurance access barrier. So that's question one. And the second is, what percent roughly would you assume need some sort of co-pay assistance? And what are you guys doing for that? And I have a follow-up.

熱烈祝賀Trikafta快速獲得批准。那麼，我問史都華一個問題。在推廣過程中，我想請教各位，在透過 KALYDECO（例如幾年前）或 SYMDEKO（例如最近）獲得報銷方面，你們有哪些經驗教訓？它主要關注如何降低獲得保險的門檻。這是第一個問題。第二個問題是，您認為大約有多少百分比的人需要某種形式的共同支付援助？你們為此做了些什麼？我還有一個後續問題。

Yes, so Geoff, in terms of what have we learned in terms of getting access here in the U.S., I would say, going back all the way to KALYDECO through ORKAMBI and SYMDEKO, we've seen very broad reimbursement. And actually that reimbursement has been put in place pretty quickly. Now, obviously, it's a range across all of the government and commercial payers, and so some move faster than others, some move slower than others. But in general, we've seen them move pretty quickly, and we've ended up with kind of rapid and broad reimbursement. I think the thing that gives me hope that, that will happen is obviously we've been out there with these payers now for 7 years in the U.S. They have a very, very good sense of how severe this disease is, the benefits that our medicines have, and the team is out there now talking with payers. And to date, as I say, in terms of the reaction we've had, the reaction to date has been very positive. So I feel very good that our team is very well prepared to secure broad access.

是的，Geoff，就我們在美國獲得市場准入方面學到了什麼而言，我想說，從 KALYDECO 到 ORKAMBI 和 SYMDEKO，我們看到了非常廣泛的報銷。事實上，這項報銷措施已經很快落實到位。顯然，這涉及到所有政府和商業支付方，因此有些進展快，有些進展慢。但總的來說，我們看到他們的行動相當迅速，最終也獲得了快速而廣泛的報銷。我認為讓我覺得這件事會成功的原因是，我們已經在美國與這些支付者合作了7年。他們非常清楚地了解這種疾病的嚴重性，以及我們藥物的益處，而我們的團隊現在正在與支付者進行溝通。正如我所說，到目前為止，就我們收到的回饋而言，回饋非常積極。因此，我非常欣慰地看到我們的團隊已經做好了充分的準備，能夠確保廣泛的訪問權限。

In terms of insurance barriers, yes, there'll always be some. We have a great team here which is trained to do just this, to help patients out, provide support to them as they navigate the insurance barriers. In terms of what are we going to do in supporting those patients who may have financial needs? We have the standard suite of offerings that you would expect, and certainly our commitment is that we are going to do everything we can do to make sure that no patient is left behind because of their ability to pay.

就保險障礙而言，是的，總是會存在一些障礙。我們這裡有一支優秀的團隊，他們接受過專門的培訓，能夠幫助患者，為他們克服保險方面的障礙提供支援。那麼，我們將如何幫助那些可能有經濟困難的患者呢？我們提供您所期望的標準服務，並且我們承諾，我們將盡一切努力確保沒有患者因為支付能力而落下任何醫療服務。

Okay. And then just a follow-up for Reshma or maybe even Jeff. When you think about opportunities to diversify outside of CF, you guys have a lot, and it seems like Aaron's been working pretty hard. But beyond the pain program, most of them are early though, so I want to ask you what's the capacity or even how much of a priority is bringing on later-stage assets as you begin to see the leverage in the P&L from the Trikafta launch?

好的。然後，或許可以給雷什瑪或傑夫一個後續問題。當你們考慮在CF之外進行多元化發展的機會時，你們有很多機會，而且看起來Aaron一直在努力。但除了止痛項目之外，它們大多還處於早期階段，所以我想問您，隨著 Trikafta 的推出在損益表中開始發揮作用，您有能力或優先考慮引入後期資產嗎？

Yes. Look, it's a great question, Geoff. Maybe I'll take that one. We have been working hard, the entire team, on getting these deals, but -- I was showing our Board today that I think we've done more deals in 2019 than we've done -- than we did in 2016, '17 and '18 combined. And that's a good thing obviously. We have both diversified our pipeline and we've also considerably built our toolbox. And you should expect to see us continue to do that.

是的。你看，傑夫，這是一個很好的問題。或許我會選那個。我們整個團隊一直在努力達成這些交易，但是——我今天向董事會展示了，我認為我們在 2019 年達成的交易比 2016 年、2017 年和 2018 年加起來還要多。這顯然是好事。我們既實現了產品線多元化，也大大豐富了我們的工具庫。你們應該會看到我們繼續這樣做。

I think we've been pretty consistent all along in saying what you probably shouldn't expect to see us do is to buy on-market assets, or very late-stage assets, to essentially buy revenue growth. We don't really need revenue growth. Our CF franchise will provide that well into the 2020s. And so we're in a very nice position of being able to invest in earlier-stage assets where, by the way, we think we can get much better value and also add much more value from our own internal development and regulatory group so that we can build much -- much better value, both for patients and for our shareholders. And so you should expect to see us to continue to do deals, early stage assets where we can add value; technologies, particularly the bolt-on to our gene-editing strategy, which, as you know, we have broadened considerably over the last year and more of those deals. But I don't think you'll see us do the very late stage -- certainly not on-market products or very late stage products.

我認為我們一直以來都相當一致地表示，你們可能不應該指望我們購買市場上的資產或處於非常後期階段的資產，以此來獲取收入成長。我們其實並不需要營收成長。我們的CF特許經營權將持續到2020年代。因此，我們現在處於一個非常好的位置，可以投資於早期階段的資產，順便說一句，我們認為我們可以從中獲得更大的價值，並且還可以透過我們自己的內部開發和監管團隊創造更大的價值，從而為患者和我們的股東創造更大的價值。因此，你們應該會看到我們繼續進行交易，收購早期資產，以增加價值；技術，特別是我們基因編輯策略的附加技術，正如你們所知，我們在過去一年中已經大大擴展了這一策略，並且進行了更多此類交易。但我認為你不會看到我們從事後期研發——當然不會從事已上市產品或後期研發。

I just wanted to add to that, you mentioned the pipeline and where we are. You already talked about pain. It's actually interesting to note how many molecules we have already into mid-stage development. So CTX001 is already in Phase I/II. AAT, we expect to be in Phase II. It will start this quarter, 2019; and FSGS, I expect to be in Phase II next year.

我只是想補充一點，你提到了管道以及我們目前所處的位置。你已經談到疼痛了。值得注意的是，我們已經有許多分子進入了中期研發階段。所以 CTX001 已經進入 I/II 期臨床試驗階段了。AAT，我們預計進入第二階段。它將於 2019 年本季開始；而 FSGS，我預計明年將進入第二階段。

And our next question comes from Liisa Bayko of JMP Securities.

下一個問題來自 JMP Securities 的 Liisa Bayko。

I just wanted to ask a couple of questions about the pipeline. The first is for the AAT program. I notice you're focusing on patients with 2 Z mutations. Can you maybe just break down the AAT population into its kind of mutation types to better understand what kind of group you're addressing with that small molecule corrector, the first one?

我只是想問幾個關於管道的問題。第一個是針對AAT計畫的。我注意到您主要關注的是具有 2 個 Z 突變的患者。您能否將 AAT 族群按突變類型進行分類，以便更了解您使用第一個小分子矯正劑所針對的是哪一類族群？

So you're right that there are different subgroups of patients who have alpha-1 antitrypsin deficiency, but the majority of patients have the Z mutation. The majority of patients who are ill have the Z mutation. So 90%-plus have the Z-Z mutation. So no surprise that, that's the group that we're focused on.

所以你說得對，患有α-1抗胰蛋白酶缺乏症的患者有不同的亞組，但大多數患者都有Z突變。大多數患病患者都帶有 Z 基因突變。所以超過90%的人都有Z-Z突變。所以毫不奇怪，我們把重點放在了這個群體上。

All right. That make sense. And then sort of similar question, I know a little bit about FSGS. You're kind of qualifying in these the -- as mediated by APOL1, is that, again, the majority of FSGS cases? I'm just curious about that one.

好的。這說得通。然後還有類似的問題，我對 FSGS 略知一二。你似乎符合這些條件——透過 APOL1 介導，這是否再次成為大多數 FSGS 病例？我只是對此感到好奇。

Sure. Sure. So that one's a little bit different. So FSGS is a heterogeneous group of etiologies that we lump in that. FSGS is actually named after its finding on pathology. But there is a homogeneous group within that, that is mediated by APOL1. So we are not pursuing all FSGS. We are pursuing APOL1-mediated FSGS. It's a group of -- it's a homogeneous subgroup of all of FSGS. And it turns out that there's actually other groups of renal disease that are also mediated by APOL1, but the one we're focused on is APOL1-mediated FSGS.

當然。當然。所以這個有點不一樣。所以 FSGS 是一組病因各異的疾病，我們將其歸為一類。FSGS 的命名實際上是根據其病理學發現而定的。但其中存在一個同質群體，該群體由 APOL1 介導。所以我們並非對所有局部性節段性腎絲球硬化症患者都進行治療。我們正在研究 APOL1 介導的 FSGS。它是一組——它是所有 FSGS 的一個同質子群。事實證明，還有其他一些腎臟疾病也是由 APOL1 介導的，但我們關注的是 APOL1 介導的 FSGS。

And the reason, Liisa, is because there's very strong human genetics evidence that APOL1 is the cause of that disease.

莉薩，原因在於有非常強有力的人類遺傳學證據表明，APOL1 是導致這種疾病的原因。

Okay. Great. And then I guess, how do you know that the FSGS is related to that? And I guess, of FSGS patients, what -- how prevalent is this particular group?

好的。偉大的。那麼，你怎麼知道 FSGS 與此有關呢？那麼，在 FSGS 患者中，這個特定群體有多普遍呢？

Yes. So you know I happen to be a nephrologist so I really like this topic but I'll keep it short. And here's what I'll say. Maybe the 2, 3 important points to mention are, amongst African-American patients who have FSGS, 70-plus percent have FSGS that's related to APOL1. So the vast, vast majority. And the only other important point I'll make for today's call is that there are studies, really nicely done studies that look at patients who have APOL1-mediated FSGS versus not, those patients had more serious disease that is more progressive. As Jeff said, it is a causal factor here, and that's why we are so interested in this disease and in this pathway.

是的。你知道，我恰好是腎臟科醫生，所以我很喜歡這個主題，但我會盡量簡短地回答。我要說的是：或許需要提及的 2,3 個重要點是，在患有 FSGS 的非裔美國患者中，70% 以上的 FSGS 與 APOL1 相關。所以絕大多數人。今天我要提到的另一個重要觀點是，有一些研究，一些非常優秀的研究，比較了患有 APOL1 介導的 FSGS 的患者和未患有 APOL1 介導的 FSGS 的患者，發現這些患者的病情更嚴重，進展也更快。正如傑夫所說，這是一個致病因素，這就是為什麼我們對這種疾病和這條通路如此感興趣的原因。

And the way you know is just by sequencing. This [isn't a legal], it's been described in the merger.

而判斷方法就是透過排序。這（並非法律問題），合併協議中已經有所描述。

And our next question comes from Geoff Porges of SVB Leerink.

下一個問題來自 SVB Leerink 的 Geoff Porges。

And just to change the direction a little bit, Charlie, could you tell us what the free cash flow was in the quarter? And then give a little bit more clarification on operating margins?

查理，為了稍微轉換話題，你能告訴我們本季的自由現金流是多少嗎？然後能否再詳細解釋一下營業利益率？

And then Stuart, could you tell us the total number of patients on one of your CF medicines? And the breakdown of KALYDECO -- U.S. for the KALYDECO, ORKAMBI and SYMDEKO, just so we kind of level set our models?

那麼，Stuart，你能告訴我們你們的某種囊性纖維化藥物共有多少病人正在服用嗎？那麼，KALYDECO——美國地區KALYDECO、ORKAMBI和SYMDEKO的細分情況，我們能否對各自的模型進行一些比較，以便更好地進行統一分析？

Sure, Geoff. On the free cash flow in the quarter, we can follow-up with you afterwards on that. As I highlighted, we ended the quarter with about $4 billion in cash, that did not include the Semma -- the disbursement for Semma, which happened shortly after. What you can see though with our performance this year is that we are on track to end the year with more cash than we started the year, and that's even after spending nearly $1.5 billion on business development during the year. So the operating leverage and the cash flow generation continues to be very strong.

當然可以，傑夫。關於本季的自由現金流，我們之後可以再與您聯繫。正如我所強調的那樣，我們本季末擁有約 40 億美元的現金，這還不包括 Semma 的款項——Semma 的款項是在不久之後支付的。但從我們今年的業績可以看出，我們預計在年底前實現比年初更多的現金流，即便我們在這一年中已在業務發展方面花費了近 15 億美元。因此，經營槓桿和現金流生成能力依然非常強勁。

Second part of your question was around operating margin. We've run in the kind of low to mid-40s in the first half of the year. We do expect -- you've seen -- you saw a little bit of a ramp-up in expenses in the third quarter, there's an additional ramp-up in the fourth quarter. So we should end the year in that low to mid-40s range. Again, a significant increase over last year, which was around 39%. And so with the continued growth of the business on the top line and disciplined spending, we continue to drive operating margins up, and you could expect that into 2020 as well.

你問題的第二部分是關於營業利益率的。今年上半年，氣溫一直在華氏40度左右徘徊。我們預計——你們也看到了——第三季支出略有增加，第四季還會進一步增加。所以我們應該可以以40%左右的成長率結束這一年。與去年相比，增幅同樣顯著，去年增幅約 39%。因此，隨著業務收入的持續成長和支出的嚴格控制，我們不斷提高營業利潤率，預計到 2020 年也將如此。

And Geoff, in terms of the breakdown of -- I think it was just KALYDECO you wanted U.S., ex U.S.?

傑夫，就具體情況而言——我想你想要的只是 KALYDECO，美國，前美國？

Well, the 3 markets.

嗯，就是這三個市場。

All right. I've got all 3. So KALYDECO U.S. was $163 million in the quarter, ex U.S. was $87 million; ORKAMBI was $199 million in the quarter in the U.S., $98 million ex U.S.; and SYMDEKO/SYMKEVI the U.S. was $349 million and ex U.S. was $55 million in the quarter.

好的。我已經掌握了全部 3 項數據。 KALYDECO 美國本季營收為 1.63 億美元，美國以外地區營收為 8,700 萬美元；ORKAMBI 美國本季營收為 1.99 億美元，美國以外地區營收為 9,800 萬美元；SYMDEKO/SYMKEVI 本季營收為 3.49 億美元，美國以外地區營收為 50 萬美元。

And Geoff, this is Charlie. I would add you've been pretty consistent in looking for the details on this. Going forward, we're going to move away from some of this detail. Obviously now with the triple approval, we've got a portfolio of medicines that are going to allow us to treat the vast majority of patients. Within the medicines, there is a significant level of label overlap, and we see a significant level of switching, and we'd expect even more switching with the triple. As a result, the very, very detailed breakdown by product becomes less meaningful over time. So moving forward, our intention would be to report total CF revenues and break that out by product. We will also break out our U.S. and ex U.S. revenues, but we will move away from providing very detailed product by geography revs.

傑夫，這位是查理。我想補充一點，你在尋找這方面的細節方面一直非常認真負責。接下來，我們將不再關注這些細節。顯然，現在有了三項批准，我們擁有了一系列藥物，可以治療絕大多數患者。在這些藥物中，標籤重疊程度很高，我們看到大量的轉換，我們預計三聯療法會導致更多的轉換。因此，隨著時間的推移，按產品進行的非常非常詳細的細分變得越來越沒有意義。因此，接下來，我們的目標是公佈 CF 總收入，並按產品進行細分。我們也將分別列出美國和美國以外地區的收入，但我們將不再按地區提供非常詳細的產品收入數據。

And our last question comes from Whitney Ijem of Guggenheim.

最後一個問題來自古根漢美術館的惠特尼·伊傑姆。

A couple of quick follow-ups. First on Semma. They had previously guided to a first half '20 start for the naked cell program, I believe. Is that still on track? And then for FSGS, just curious, are there any plans to do sort of a basket study of renal diseases driven by APOL1? Or as you mentioned, are you kind of specifically focusing on FSGS for the near term?

幾個後續問題。塞瑪首發。我記得他們之前曾指導裸細胞計畫在 2020 年上半年啟動。計劃還在按部就班地進行嗎？至於 FSGS，我很好奇，是否有計劃對 APOL1 驅動的腎臟疾病進行某種籃子研究？或者正如您所提到的，您是否在近期內特別關注 FSGS？

Yes. Whitney, this is Jeff, I'll take the Semma question and Reshma will take the FSGS question. In terms of Semma, we are very pleased actually with the progress in both programs, the naked cells and the device [put] cells. I think it's a little early, as they're in discussions with regulators, to assign a precise date to when they will start clinical trials, but I do anticipate it to be in the near future, meaning this isn't a program that's 3 to 5 years out or anything like that. But stay tuned. As they and we finish our discussions with regulators, we can give you a little more certainty.

是的。Whitney，我是 Jeff，我來回答 Semma 的問題，Reshma 來回答 FSGS 的問題。就 Semma 而言，我們對這兩個項目的進展都非常滿意，無論是裸細胞還是植入裝置細胞。我認為現在確定臨床試驗的具體開始日期還為時過早，因為他們仍在與監管機構進行討論，但我預計會在不久的將來開始，這意味著這不是一個需要 3 到 5 年才能啟動的計畫。敬請期待。待我們與監管機構的討論結束後，我們將能為您帶來更多確定性。

With regard to the FSGS question, it's a good question about basket trials as -- but no, that's not our approach. The FSGS component compared to, for example, non-diabetic kidney disease that also has a APOL1-mediated component. They're actually different enough that the FSGS patients are much more sick. The progression is faster, and the levels of protein are very high. So we think that there is a real high unmet need there, that we have to go at it first and get there and then we'll get to the others. So our focus here is FSGS APOL1-mediated, and we're going to do that as a stand-alone trial.

關於 FSGS 問題，這是一個關於籃式試驗的好問題——但是，不，這不是我們的方法。與例如非糖尿病腎病變（也具有 APOL1 介導成分）相比，FSGS 成分有所不同。實際上，它們之間的差異足夠大，FSGS 患者的病情要嚴重得多。進展速度更快，蛋白質含量也非常高。所以我們認為那裡存在著非常大的未滿足需求，我們必須先解決這個問題，然後再去解決其他問題。因此，我們這裡的重點是 FSGS APOL1 介導的疾病，我們將把它作為一項獨立的試驗來進行。

Thank you, everyone. [Thanks] to the analysts for their questions. If you have additional questions, the Investor Relations team will be available in the office tonight. Have a good evening.

謝謝大家。感謝各位分析師提出的問題。如果您還有其他疑問，投資者關係團隊今晚將在辦公室為您解答。祝你晚上愉快。

Ladies and gentlemen, this does conclude your conference call. You may now disconnect.

女士們、先生們，本次電話會議到此結束。您現在可以斷開連線了。