福泰製藥 (VRTX) 2019 Q4 法說會逐字稿

Good evening. Welcome to the Vertex Full Year and Fourth Quarter 2019 Financial Results Conference Call. This is Michael Partridge, Senior Vice President of Investor Relations for Vertex. Making prepared remarks on the call tonight, we have Dr. Jeff Leiden, Chairman and CEO; Dr. Reshma Kewalramani, Chief Medical Officer; Stuart Arbuckle, Chief Commercial 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.

晚安.歡迎參加 Vertex 2019 年全年及第四季財務業績電話會議。這是 Vertex 公司投資者關係資深副總裁 Michael Partridge。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；首席醫療官雷什瑪·凱瓦拉馬尼博士；首席商務官斯圖爾特·阿巴克爾；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, our pipeline 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。

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. We saw many investors and analysts at the JPMorgan Conference 2 weeks ago. So I'll spend just a few moments highlighting our 2019 achievements in what we believe sets Vertex apart for the future.

謝謝你，麥可。各位晚上好。兩週前，我們在摩根大通會議上見到了許多投資人和分析師。因此，我將花幾分鐘時間重點介紹我們在 2019 年的成就，我們認為這些成就將使 Vertex 在未來脫穎而出。

2019 was a truly remarkable year for Vertex. All parts of our business met or exceeded the goals we set at the start of the year. And as a result, we are very well positioned to bring our CF medicines to many more people and to advance our broad pipeline in additional diseases in 2020.

2019 年對 Vertex 來說是意義非凡的一年。我們業務的各個方面都達到或超過了年初設定的目標。因此，我們完全有能力在 2020 年將我們的 CF 藥物帶給更多的人，並推動我們在其他疾病領域的廣泛研發。

In cystic fibrosis, the U.S. approval of TRIKAFTA for patients 12 and older in October, 5 months ahead of our PDUFA date, was the most significant milestone to date in our efforts to bring new CF medicines to all people with this disease. TRIKAFTA is a remarkable medicine that holds the potential to treat up to 90% of all people with CF. As you'll hear from Stuart, the U.S. launch of TRIKAFTA in patient ages 12 and older is off to a very strong start. There's clear interest in TRIKAFTA across all groups of eligible patients, and the early feedback from both patients and doctors is highly positive.

在囊性纖維化領域，TRIKAFTA 於 10 月獲得美國批准，適用於 12 歲及以上患者，比我們的 PDUFA 日期提前了 5 個月，這是我們迄今為止在努力為所有患有這種疾病的人帶來新的 CF 藥物方面取得的最重要里程碑。TRIKAFTA 是一種非常有效的藥物，預計將治療高達 90% 的囊性纖維化患者。正如您將從斯圖爾特那裡聽到的那樣，TRIKAFTA 在美國 12 歲及以上患者中的上市取得了非常強勁的開端。TRIKAFTA 在所有符合條件的患者群體中都表現出了明顯的興趣，患者和醫生的早期回饋都非常積極。

Outside the U.S., in 2019, we reached a number of key reimbursement agreements for our CF medicines that will allow many thousands of new patients to begin treatment with our CFTR modulators in countries, including England, France, Spain, Australia and many others throughout 2020.

2019 年，在美國以外，我們與包括英國、法國、西班牙、澳洲等許多國家達成了多項重要的 CF 藥物報銷協議，這將使成千上萬的新患者能夠在 2020 年開始使用我們的 CFTR 調節劑在包括英國、法國、西班牙、澳洲等在內的許多國家接受治療。

We're also making excellent progress advancing and broadening our pipeline beyond CF. As we enter 2020, we are now in the clinic with multiple new medicines in 5 diseases outside of CF. We continue to implement our strategy of advancing a portfolio of medicines into clinical development for each of the disease areas. Key programs include alpha-1 antitrypsin deficiency. Our AAT program, where we have multiple small molecule correctors in the clinic, aimed at addressing the underlying cause of disease in both the liver and the lung. These include VX-814, which has recently entered Phase II clinical development.

我們在推進和拓展囊性纖維化以外的產品線方面也取得了顯著進展。進入 2020 年，我們目前在 CF 以外的 5 種疾病的臨床試驗中推出了多種新藥。我們將繼續推進針對各個疾病領域的一系列藥物進入臨床開發階段。重點項目包括α1抗胰蛋白酶缺乏症。我們的 AAT 計劃，目前在臨床中使用了多種小分子矯正劑，旨在解決肝臟和肺部疾病的根本原因。其中包括最近進入 II 期臨床開發的 VX-814。

Beta-thalassemia and sickle cell disease, where we announced clinical data for 2 patients treated with CTX001, a onetime CRISPR-Cas9 ex vivo gene editing therapy, which suggest that we may be able to functionally cure these diseases.

我們發表了 2 名接受 CTX001（一種一次性 CRISPR-Cas9 體外基因編輯療法）治療的 β 地中海貧血和鐮狀細胞疾病患者的臨床數據，這表明我們可能能夠從功能上治癒這些疾病。

FSGS, where our first small molecule aimed at halting the progression of the disease will move into Phase II development in 2020. And type 1 diabetes, where we are developing an autologous islet transplantation therapy with cells alone and a second with a combination of cells and a device to correct islet cell function and potentially transform the treatment of this disease.

FSGS，我們首個旨在阻止疾病進展的小分子將於 2020 年進入 II 期開發階段。對於第 1 型糖尿病，我們正在開發一種僅使用細胞的自體胰島移植療法，以及另一種將細胞與一種裝置結合的療法，以糾正胰島細胞功能，並有可能改變這種疾病的治療方式。

Importantly, these pipeline programs now span multiple modalities, including small molecules where Vertex has excelled in the past, but also new approaches such as cell and genetic therapies. For these new modalities, we've acquired or partnered with leading companies who have the best teams and unique expertise to manufacture and deliver transformational therapies for diseases that fit our strategy.

重要的是，這些研發管線計畫現在涵蓋多種模式，包括 Vertex 過去擅長的小分子藥物，以及細胞和基因療法等新方法。對於這些新療法，我們已經收購或與擁有最優秀團隊和獨特專業知識的領先公司建立了合作關係，以生產和提供符合我們策略的疾病變革性療法。

And in business development, we completed more transactions in 2019 than in the 4 prior years, including our acquisitions of Semma with a leading cell therapy approach for type 1 diabetes, and Exonics, the leader in gene editing for DMD and DM1.

在業務發展方面，我們在 2019 年完成的交易比前 4 年都多，其中包括收購了擁有 1 型糖尿病領先細胞療法的 Semma 公司，以及 DMD 和 DM1 基因編輯領域的領導者 Exonics 公司。

In summary, 2019 was the culmination of almost a decade of focused execution against our strategy of discovering and developing transformative medicines for serious diseases in specialty areas, by focusing on validated targets and predictive biomarkers that will improve the probability of clinical success. Our strategy is playing out exactly as we had planned and will position us for continued short-term and long-term growth. The company has never been stronger or better positioned for future success in CF and beyond.

總而言之，2019 年是我們近十年來專注於執行策略的成果，該策略旨在透過專注於已驗證的標靶和預測性生物標記物，提高臨床成功的機率，從而發現和開發針對特定領域嚴重疾病的變革性藥物。我們的策略正按計劃順利實施，這將使我們在短期和長期內持續成長。公司從未像現在這樣實力雄厚，也從未像現在這樣為未來在囊性纖維化及其他領域取得成功做好了充分準備。

Let me now turn the call over to Reshma, who will talk in more detail about the year ahead.

現在我將把電話交給雷什瑪，她將更詳細地談論未來一年的情況。

Thanks, Jeff. Our 2019 progress has positioned us for continued growth in 2020 and for many years to come. We are focused on bringing our CF medicines to more people, advancing our pipeline and building financial strength to support continued investment in internal and external innovation. In 2020, we expect to gain approval for the triple combination in Europe in patients 12 years and older and to submit TRIKAFTA for approval in the U.S. for children ages 6 to 11.

謝謝你，傑夫。我們在 2019 年取得的進展為我們在 2020 年及未來多年持續成長奠定了基礎。我們致力於讓更多人受益於我們的 CF 藥物，推進我們的研發管線，並增強財務實力，以支持對內部和外部創新的持續投資。2020 年，我們預計將在歐洲獲得針對 12 歲及以上患者的三聯療法的批准，並向美國提交 TRIKAFTA 的批准申請，用於 6 至 11 歲的兒童。

Beyond CF, we are advancing multiple molecules in our pipeline through late preclinical and early clinical development and are now entering a period of multiple proof-of-concept data readouts and clinical advances with potentially transformative medicine. With our AAT program, we recently initiated a Phase II proof-of-concept study of the small molecule corrector VX-814 in patients with 2 copies of the Z mutation and expect data from the study in 2020. In APOL1-mediated FSGS, we completed a Phase I study of VX-147 in late 2019 and expect to initiate an open-label Phase II proof-of-concept study in 2020 to evaluate the reduction in protein levels in the urine with VX-147.

除了 CF 之外，我們正在推進管線中的多個分子進入臨床前後期和臨床早期開發階段，現在正進入多個概念驗證資料讀取和臨床進展的時期，這些進展有可能帶來變革性的醫學成果。透過我們的 AAT 項目，我們最近啟動了針對攜帶 2 個 Z 突變拷貝的患者的小分子矯正劑 VX-814 的 II 期概念驗證研究，並預計將於 2020 年獲得該研究的數據。在 APOL1 介導的 FSGS 中，我們在 2019 年底完成了 VX-147 的 I 期研究，並計劃在 2020 年啟動一項開放標籤的 II 期概念驗證研究，以評估 VX-147 降低尿液中蛋白質水平的效果。

In pain, having established proof-of-concept data from NaV1.8 inhibition with VX-150 in multiple Phase II studies, our focus is now to find the optimal molecule or molecules to advance into mid- and late-stage studies. We are continuing to advance a portfolio of medicines into clinical development, and we'll be advancing an additional molecule into Phase I development in the first half of 2020. We have discontinued Phase I development of VX-961 because it did not display an optimal PK and tolerability profile.

在疼痛治療方面，我們已經通過多項 II 期研究，利用 VX-150 抑制 NaV1.8 建立了概念驗證數據，現在我們的重點是找到一種或多種最佳分子，以推進到中期和後期研究。我們正在繼續推進一系列藥物進入臨床開發階段，並將於 2020 年上半年推進另一種分子進入 I 期開發階段。由於 VX-961 沒有表現出最佳的藥物動力學和耐受性特徵，我們已停止其 I 期開發。

Beyond our small molecule programs, we've made significant progress in building and progressing a portfolio of cell and genetic therapies in line with our research strategy, primarily through our business development activities. We are highly encouraged by our recent clinical data for our CRISPR-Cas9 ex vivo gene editing treatment, CTX001, for beta-thalassemia and sickle cell disease. Both studies continue to enroll, and we expect to provide additional data for this program in 2020.

除了我們的小分子計畫之外，我們還根據我們的研究策略，主要透過業務發展活動，在建構和推進細胞和基因療法組合方面取得了重大進展。我們最近獲得的 CRISPR-Cas9 體外基因編輯療法 CTX001 治療 β 地中海型貧血和鐮狀細胞疾病的臨床數據令我們倍感鼓舞。這兩項研究仍在繼續招募受試者，我們預計將在 2020 年提供該計畫的更多數據。

I'd also like to highlight our cell therapy approach for Type 1 diabetes. This program comes to us from our acquisition of Semma Therapeutics in October of 2019. The team of scientists at Semma have cracked the biology on both the production and scale-up of fully mature islet cells and has developed a novel implantable device to protect these cells from the immune system, while preserving cell health and function. We have set an ambitious goal to progress this program into clinical development in late 2020 or early 2021.

我還想重點介紹一下我們針對第 1 型糖尿病的細胞療法。此專案源自於我們於 2019 年 10 月收購的 Semma Therapeutics 公司。Semma 的科學家團隊已經破解了完全成熟的胰島細胞的生產和規模化生物學難題，並開發了一種新型植入式裝置，用於保護這些細胞免受免疫系統的攻擊，同時保持細胞的健康和功能。我們設定了一個雄心勃勃的目標，在 2020 年底或 2021 年初將該專案推進到臨床開發階段。

In summary, we've made outstanding progress in CF and multiple other diseases in 2019. And I look forward to updating you on our progress over the coming months and years.

總而言之，2019 年我們在囊性纖維化和其他多種疾病方面取得了顯著進展。我期待在未來的幾個月和幾年裡向您報告我們的進展。

I'll now turn the call over to Stuart.

現在我將把電話交給史都華。

Thanks, Reshma. I am pleased to review with you this evening, our strong commercial performance for 2019. Our full year 2019 CF revenues were $4 billion, up from $3 billion in 2018, which represents year-over-year growth of 32%. This growth in total revenues was driven primarily by the full year impact of the SYMDEKO launch in the U.S. and Germany, label expansions for our CF medicines globally and the early approval and launch of TRIKAFTA in the U.S.

謝謝你，雷什瑪。今晚我很高興與各位一起回顧我們2019年的強勁商業業績。2019 年全年 CF 營收為 40 億美元，高於 2018 年的 30 億美元，年增 32%。總收入的成長主要得益於 SYMDEKO 在美國和德國的全年上市、我們 CF 藥物在全球範圍內的標籤擴展以及 TRIKAFTA 在美國的提前批准和上市。

The launch of TRIKAFTA is off to a very strong start. Our fourth quarter total CF product revenues were approximately $1.25 billion, including TRIKAFTA revenues of $420 million, making TRIKAFTA already our top-selling medicine. I would note that our fourth quarter revenues include, as expected, launch-related stocking of approximately $100 million. Approximately 18,000 patients are eligible for TRIKAFTA in the U.S., which represents the largest patient population eligible for one of our CF medicines at the time of approval and launch. For 6,000 of these people, this is the first time they have had a medicine to treat the underlying cause of their CF. We are seeing strong interest from all groups of eligible patients, including new initiations as well as patients transitioning from our other CFTR modulators.

TRIKAFTA的推出取得了非常強勁的開局。我們第四季 CF 產品總收入約為 12.5 億美元，其中包括 TRIKAFTA 的收入 4.2 億美元，這使得 TRIKAFTA 成為我們最暢銷的藥物。我想指出，正如預期的那樣，我們第四季度的收入包括與產品上市相關的約 1 億美元的庫存費用。在美國，約有 18,000 名患者符合 TRIKAFTA 的用藥條件，這代表了在我們 CF 藥物獲批上市時，符合用藥條件的最大患者群體。對其中 6000 人來說，這是他們第一次獲得治療囊性纖維化根本病因的藥物。我們看到所有符合條件的患者群體都表現出濃厚的興趣，包括新患者以及從我們其他 CFTR 調節劑過渡到本產品的患者。

Our commercial supply, market access, patient support, marketing and field teams were ready for an early approval. And since October, these teams have been doing a phenomenal job with CF centers and commercial and government payers. The centers and their multidisciplinary teams have done a remarkable job responding to the high patient demand. And while still early in the launch, we are on track to obtain broad reimbursement for TRIKAFTA in the U.S., similar to what we have seen for our other CF medicines. Together, these factors have combined to produce the strong start to the launch.

我們的商業供應、市場准入、患者支援、行銷和現場團隊已做好儘早獲得批准的準備。自 10 月以來，這些團隊在與 CF 中心以及商業和政府支付方合作方面做得非常出色。各中心及其多學科團隊在應對患者的高需求方面做得非常出色。雖然 TRIKAFTA 的上市仍處於早期階段，但我們有望在美國獲得廣泛的醫療保險報銷，就像我們其他 CF 藥物所獲得的那樣。這些因素共同促成了此次發表會的強勁開局。

Outside the U.S., we reached multiple reimbursement agreements in 2019 in key countries, which will enable many thousands of patients to initiate treatment with certain Vertex medicines for the first time. While TRIKAFTA will be the main driver of Vertex's revenue growth in 2020, we also expect an increase in international revenues based on more patients initiating treatment with our medicines outside the U.S.

2019 年，我們在美國以外與多個主要國家達成了多項報銷協議，這將使成千上萬的患者能夠首次開始使用 Vertex 的某些藥物進行治療。雖然 TRIKAFTA 將是 Vertex 在 2020 年收入成長的主要驅動力，但我們也預計，隨著更多患者在美國以外開始使用我們的藥物進行治療，國際收入也將有所增長。

In summary, I am pleased that we are bringing our medicines to many more patients around the globe.

總之，我很高興我們能將我們的藥品帶給全球更多患者。

And with that, I'll now turn the call over to Charlie.

那麼，我現在就把電話交給查理。

Thanks, Stuart. I will provide additional remarks this evening regarding our 2019 financial results, and I will also discuss our 2020 financial guidance. All of the results and guidance I will discuss are non-GAAP.

謝謝你，斯圖爾特。今晚我將就我們 2019 年的財務表現作補充說明，並討論我們 2020 年的財務預期。我將要討論的所有結果和指導意見均不符合公認會計準則。

As Stuart mentioned, we had fourth quarter total CF product revenues of approximately $1.25 billion, a 45% increase compared to 2018. Our fourth quarter 2019 combined R&D and SG&A expenses were $496 million, including the operating expenses of Exonics and Semma compared to $400 million in the fourth quarter of 2018. Significant growth in revenues and disciplined spending in the fourth quarter resulted in operating income of $593 million, a 70% increase compared to the fourth quarter of 2018.

正如史都華所提到的，我們第四季CF產品總收入約為12.5億美元，比2018年成長了45%。2019 年第四季度，我們的研發和銷售、管理及行政費用合計為 4.96 億美元，其中包括 Exonics 和 Semma 的營運費用，而 2018 年第四季為 4 億美元。第四季營收大幅成長，加上支出控制得當，營業收入達到 5.93 億美元，比 2018 年第四季成長了 70%。

Net income for the fourth quarter of 2019 was $444 million compared to $337 million for the fourth quarter of 2018. Our full year financial results reflect a similar story of strong revenue growth and disciplined spending, resulting in exceptional operating income growth.

2019 年第四季淨收入為 4.44 億美元，而 2018 年第四季淨收入為 3.37 億美元。我們的全年財務表現也反映了類似的強勁營收成長和嚴格的支出控制，從而實現了卓越的營業收入成長。

Our total CF revenues for 2019 were $4 billion, a 32% increase over full year 2018. Our 2019 combined R&D and SG&A expenses were $1.69 billion compared to $1.53 billion for 2018. Our full year operating income was $1.79 billion for 2019 compared to $1.11 billion for 2018, a year-over-year increase of more than 60%.

2019 年，我們的 CF 總收入為 40 億美元，比 2018 年全年成長了 32%。2019 年，我們的研發與銷售、管理及行政費用合計為 16.9 億美元，而 2018 年為 15.3 億美元。2019 年全年營業收入為 17.9 億美元，而 2018 年為 11.1 億美元，較去年同期成長超過 60%。

As our profitability and cash flow increased as a result of treating more CF patients globally, we have deliberately reinvested in both internal and external innovation to create future medicines. In 2019, we invested approximately $1.6 billion in external innovation through new acquisitions and collaborations. Even with the significant BD activity, we ended the year with approximately $3.8 billion in cash and marketable securities compared to $3.2 billion at the end of 2018. As we look ahead to 2020 and beyond, we expect continued increases in cash flow to provide more flexibility for additional investments to fuel our long-term growth.

隨著我們在全球範圍內治療更多囊性纖維化患者，我們的盈利能力和現金流不斷增加，因此我們有意識地對內部和外部創新進行再投資，以創造未來的藥物。2019年，我們透過新的收購和合作，在外部創新方面投資了約16億美元。即使進行了大量的業務拓展活動，我們年底的現金和有價證券仍約為 38 億美元，而 2018 年底為 32 億美元。展望 2020 年及以後，我們預期現金流將持續成長，為進一步投資提供更大的靈活性，以推動我們的長期成長。

Now on to 2020 guidance. Today, we're providing 2020 financial guidance for total CF product revenues as well as for combined non-GAAP R&D and SG&A expenses and our anticipated effective tax rate. The strong uptake of TRIKAFTA and the recent completion of reimbursement agreements outside the U.S. have positioned Vertex for continued strong revenue growth in 2020. Our 2020 guidance for total CF product revenues is $5.1 billion to $5.3 billion, which at the midpoint reflects approximately 30% growth over 2019.

接下來是2020年的指導。今天，我們將提供 2020 年 CF 產品總收入的財務指導，以及非 GAAP 研發和銷售、管理及行政費用的綜合數據和我們預期的有效稅率。TRIKAFTA 的強勁普及以及近期在美國以外地區完成的報銷協議，使 Vertex 在 2020 年能夠繼續保持強勁的收入成長。我們對 2020 年 CF 產品總營收的預期為 51 億至 53 億美元，其中數值反映出比 2019 年成長約 30%。

I would note a few dynamics that are reflected in our 2020 guidance. As part of the strong launch of TRIKAFTA, that Stuart mentioned, we saw an expected launch-related inventory build of approximately $100 million in the fourth quarter that we do not expect to repeat in 2020. Also, as we move through 2020, as with all of our CFTR modulators, persistence and compliance dynamics will affect TRIKAFTA revenues, and therefore, our experience with our other CF medicines is factored into our guidance.

我想指出一些反映在我們 2020 年業績指引中的動態。正如 Stuart 所提到的，作為 TRIKAFTA 強勁啟動的一部分，我們在第四季度看到了與啟動相關的預期庫存增加約 1 億美元，我們預計 2020 年不會再出現這種情況。此外，隨著我們進入 2020 年，與我們所有的 CFTR 調節劑一樣，堅持性和依從性動態將影響 TRIKAFTA 的收入，因此，我們在其他 CF 藥物方面的經驗已納入我們的指導方針中。

Lastly, we expect gross to net adjustments of 13% to 14% for 2020. Focusing in on Q1 2020, we expect our revenues to be modestly higher than Q4 2019 revenues. This reflects the impact of the fourth quarter inventory build as well as gross-to-net adjustments in the first quarter of each year that are generally higher relative to the previous quarter.

最後，我們預期 2020 年毛利潤與淨利的調整幅度為 13% 至 14%。展望 2020 年第一季，我們預計營收將略高於 2019 年第四季的營收。這反映了第四季度庫存增加的影響，以及每年第一季毛利與淨利之間的調整，而第一季的調整通常比上一季高。

We expect 2020 combined R&D and SG&A expenses of $1.95 billion to $2 billion. The increase compared to 2019 is primarily driven by the launch of TRIKAFTA globally and the expansion of our R&D pipeline into additional diseases. Our R&D expense growth includes increased investment to advance our programs in cell and genetic therapies, including type 1 diabetes and DMD.

我們預計 2020 年研發與銷售、管理及行政費用總計為 19.5 億至 20 億美元。與 2019 年相比，成長主要得益於 TRIKAFTA 在全球範圍內的推出以及我們研發管線擴展到其他疾病領域。我們的研發支出成長包括加大投資，以推進我們在細胞和基因療法方面的項目，包括第 1 型糖尿病和 DMD。

Now to tax guidance, where we expect our full year non-GAAP tax rate to be 21% to 22%. The tax rate may fluctuate quarter-to-quarter, with the highest rate occurring in the fourth quarter. The vast majority of our tax provision will be noncash expense until we fully use our net operating losses. As Jeff noted, Vertex has a unique long-term growth potential that is based on continued revenue growth in CF and an expanding pipeline, and with continued spending discipline, we expect operating margins, earnings and cash flow to continue to increase.

現在來談談稅務方面的指導意見，我們預計全年非GAAP稅率為21%至22%。稅率可能會逐季波動，第四季的稅率最高。在我們完全利用淨營業虧損之前，我們的大部分稅收準備金將以非現金支出的形式存在。正如傑夫所指出的，Vertex 擁有獨特的長期成長潛力，這得益於 CF 業務的持續收入成長和不斷擴大的產品線，並且隨著支出紀律的持續，我們預計其營業利潤率、收益和現金流將繼續增長。

Now back to Jeff for a few concluding comments.

現在請傑夫作最後總結發言。

Thanks, Charlie. As this is my last quarterly call as CEO, I hope you'll indulge me for a couple of minutes for some final comments. First, it has been a tremendous pleasure and honor to lead Vertex for the past 8 years. I always say the drug discovery and development is the ultimate team sport. None of our successes would have happened without several incredible teams. First, I want to thank the entire Vertex team, including our senior leadership team, most of whom have been with me for the entire journey. I've never seen a stronger team in my 35 years in the industry, and I'm so proud and grateful for all of their work.

謝謝你，查理。由於這是我作為執行長的最後一次季度電話會議，希望大家能允許我再花幾分鐘時間做一些最後的總結發言。首先，在過去的8年裡，能夠領導Vertex公司，我感到無比榮幸和快樂。我一直認為藥物發現和開發是一項終極團隊運動。如果沒有幾個傑出的團隊，我們所有的成功都不可能實現。首先，我要感謝整個 Vertex 團隊，包括我們的高階領導團隊，他們中的大多數人一直陪伴我走過這段旅程。在我從事這個行業的 35 年裡，我從未見過如此強大的團隊，我為他們所做的一切感到無比自豪和感激。

The commitment of our outstanding senior leaders and employees to execute the Vertex strategy of serial innovation to deliver transformational medicines to patients and to grow the business is the driving force for our recent achievements and is also what will differentiate us and position us for long-term success for the future.

我們傑出的高階領導和員工致力於執行 Vertex 的連續創新策略，為患者提供變革性藥物並發展業務，這是我們近期取得成就的驅動力，也是我們將脫穎而出並在未來取得長期成功的關鍵所在。

Second, I want to thank our Board of Directors and our investors for their constant support, encouragement and advice. Even when I first became CEO, and we were still losing several hundred million dollars a year while trying to develop the first transformative CF medicines.

其次，我要感謝董事會和投資人一直以來的支持、鼓勵和建議。即使在我剛擔任執行長的時候，我們每年仍然虧損數億美元，同時還在努力開發第一批具有改變意義的囊性纖維化藥物。

And finally, and most importantly, I want to thank the entire CF community, patients, families and caregivers, for their courage, their persistent encouragement and their enthusiastic participation in this amazing journey toward a cure for all patients with this devastating disease. I look forward to continuing to work with all of you as Executive Chairman to bring more transformative medicines to patients with serious diseases who are waiting.

最後，也是最重要的一點，我要感謝整個囊性纖維化群體，包括患者、家屬和護理人員，感謝他們的勇氣、堅持不懈的鼓勵以及在這段為所有患有這種毀滅性疾病的患者尋求治癒的奇妙旅程中的熱情參與。我期待繼續以執行主席的身份與各位合作，為等待治療的重症患者帶來更多變革性的藥物。

I will now open the line to questions.

現在我將開放提問環節。

(Operator Instructions) Our first question comes from Phil Nadeau with Cowen and Company.

（操作說明）我們的第一個問題來自 Cowen and Company 的 Phil Nadeau。

Jeff, let me be the first to congratulate you on all that you and the Vertex team have achieved in your 8 years of the CEO tenure. It's really been quite something to watch. Then my question is just in terms of the numbers. First, Stuart, you mentioned really 3 buckets of TRIKAFTA patients, those transitioning from ORKAMBI and SYMDEKO, new patients being added to therapy who had no option prior and the new initiations, maybe among the holdout to dropouts in other populations. Could you give us some sense of the dynamics in those 3 markets? And of the $300 million in end user demand, where did that come from?

傑夫，讓我第一個祝賀你和Vertex團隊在你擔任CEO的8年任期內所取得的所有成就。這真是一場精彩的觀影體驗。那我的問題就只是關於數字的。首先，Stuart，你提到 TRIKAFTA 患者實際上分為三類：從 ORKAMBI 和 SYMDEKO 過渡的患者、之前沒有其他治療選擇的新患者以及新開始接受治療的患者，這些患者可能來自其他人群中堅持治療但最終退出治療的患者。您能否為我們介紹一下這三個市場的動態？終端用戶需求的 3 億美元來自哪裡？

And then second, just on the inventory, it seems like $100 million of inventory is really just 2 to 3 weeks of inventory given the current run rate. So to be clear on your comments, it's not that you expected inventory to come out of the channel during Q1. It's just that there's no subsequent inventory build, given that you're already at a kind of average run rate for inventory in the channel?

其次，就庫存而言，以目前的運行速度，1億美元的庫存似乎實際上只夠維持2到3週。所以，為了明確你的評論，你並不是預期庫存會在第一季從通路中流出。問題在於，鑑於通路中的庫存運行速度已達到平均水平，因此不會再進行後續的庫存建設。

Yes. Great, Phil. I'll take the question on the TRIKAFTA uptake, and then Charlie can talk to the inventory. So as you know, we had a very strong launch. There are a number of eligible patient populations, as you might tell from the strong launch. We have had a high level of interest from all patient groups and we've seen uptake in all of those patient groups, and we expect that to continue into 2020. And so to handle the inventory question, I'll throw that over to Charlie.

是的。太好了，菲爾。我來回答關於 TRIKAFTA 接受度的問題，然後查理可以談談庫存狀況。如你所知，我們的產品發布非常成功。從強勁的上市勢頭可以看出，符合條件的患者群體有很多。我們已經收到了來自所有患者群體的高度關注，我們看到了所有這些患者群體的接受度，我們預計這種情況將持續到 2020 年。所以，關於庫存問題，我將交給查理處理。

Yes. Phil, to your question, the -- first of all, the inventory build in the fourth quarter was expected. And I'd say the magnitude of the build is probably even a little bit less than what you mentioned. But therefore, I think it's fair to say that, that is a -- we commented that that's a build that won't repeat nor do we expect it to get drawn down significantly. Inventory bounces around a couple of -- a day or day 2 on any given quarter, but that's about the right level.

是的。Phil，關於你的問題，首先，第四季的庫存增加是預期之中的。而且我認為實際的建設規模可能比你提到的還要小。因此，我認為可以公平地說，我們評論說，這種建設不會重演，我們也不認為它會大幅縮水。庫存量在任何一個季度都會有幾天或兩天的波動，但這大致是合適的水平。

Our next question comes from Michael Yee with Jefferies.

下一個問題來自傑富瑞集團的麥可葉。

And obviously, Jeff, you are moving and leaving them with a great position. I guess I just wanted to ask, Stu, you made some comments just now on where the buckets were. But maybe you could just characterize how you think about the swapping dynamic and was there parts of that number for swapping? And how do you think what percent of swapping could happen throughout 2020, just so we can think about that?

很顯然，傑夫，你離開了，給他們留下了一個非常好的位置。我只是想問一下，Stu，你剛剛提到了水桶的位置。但或許您可以描述一下您是如何看待交換動態的，以及這個數字中是否有一部分是用於交換的？那麼，您認為2020年全年可能發生多少比例的互換交易呢？這樣我們就可以思考這個問題了。

And then maybe a question for Reshma. I mean I know that there'll be a lot of focus on AAT next. I know you're giving a broad guidance on 2020. Can you just talk about the speed of that study, it's a short study? What you're doing there and how fast we could get that data? It just seems like a very broad time line for 2020 data.

然後或許可以問雷什瑪一個問題。我的意思是，我知道接下來大家會非常關注AAT。我知道您是在對2020年給予總體指導。能談談這項研究的速度嗎？這是一項短期研究。你們在那裡做什麼？我們多久能拿到這些數據？2020 年的資料時間線似乎太廣泛了。

Yes. Mike, on the uptake of TRIKAFTA, as I said, we've seen interest across all of the patient groups and that includes those who are currently being treated with one of our existing CFTR modulators. Over time, where we have overlapping labels, given the superiority of the TRIKAFTA profile, we expect the vast majority of patients who are eligible for TRIKAFTA are going to switch to TRIKAFTA. Exactly how long that process will take? It's hard to tell. Obviously, we're early in the launch. But in terms of the destination, the vast majority of those patients are going to transition to TRIKAFTA.

是的。麥克，關於 TRIKAFTA 的接受度，正如我所說，我們已經看到所有患者群體都對此感興趣，其中包括目前正在接受我們現有 CFTR 調節劑治療的患者。隨著時間的推移，在標籤重疊的情況下，鑑於 TRIKAFTA 的優勢，我們預計絕大多數符合 TRIKAFTA 條件的患者將會轉而使用 TRIKAFTA。這個過程究竟需要多久？很難說。顯然，我們現在還處於產品發布初期。但就最終去向而言，絕大多數患者都會轉至 TRIKAFTA。

Mike, with regard to the alpha-1 antitrypsin deficiency program, I think the one you're referring to is VX-814. That's the one that's furthest ahead. It's the one we started Phase II proof-of-concept dose ranging towards the very tail end of 2019. So actually, it's really very early days. We're just getting going with that study. I am expecting that we'll have results from the program in 2020, but it's just way too early to give you more color around that.

Mike，關於α-1抗胰蛋白酶缺乏症治療方案，我想你指的是VX-814。那是目前領先的那一個。這是我們在 2019 年底開始的第二階段概念驗證劑量範圍研究。所以實際上，現在還為時過早。這項研究我們才剛起步。我預計該項目將在 2020 年取得成果，但現在透露更多細節還為時過早。

Our next question comes from Salveen Richter with Goldman Sachs.

下一個問題來自高盛的薩爾文·里希特。

Jeff, congrats on all that you've achieved at Vertex. So firstly, could you just comment on how the 2019 TRIKAFTA launch will inform the cadence of uptake during 2020?

Jeff，恭喜你在Vertex取得的所有成就。首先，您能否談談 2019 年 TRIKAFTA 的推出將如何影響 2020 年的推廣節奏？

And then secondly, as we look at the pipeline, any new thoughts around the requirements for the regulatory pathway for alpha-1 antitrypsin here regarding the need for liver biopsy or not? And then secondly, with type 1 diabetes, what does the proof-of-concept study look like here?

其次，當我們檢視這條研發管線時，對於α-1抗胰蛋白酶的監管途徑，關於是否需要進行肝臟活檢，大家有什麼新的想法嗎？其次，對於第 1 型糖尿病，概念驗證研究是什麼樣的呢？

Yes. Salveen, it's Stuart. I'll take the question on the 2019 and impact on 2020. So obviously, given the results we've announced today, off to a very, very strong start. But having said that, there are many patients, we continue to need to get on to TRIKAFTA, so we are expecting continued growth through 2020 in terms of adding patients, and that's built into our guidance of $5.1 billion to $5.3 billion.

是的。薩爾文，我是史都華。我將回答有關 2019 年及其對 2020 年影響的問題。顯然，根據我們今天公佈的結果，我們取得了非常非常強勁的開局。但即便如此，仍有許多患者需要接受 TRIKAFTA 治療，因此我們預計到 2020 年患者數量將繼續增長，這已納入我們 51 億美元至 53 億美元的預期。

As Charlie said, one other factor to taking into account, as you think about the cadence or the shape of those revenues is the impact of persistence and compliance and how that will impact revenues, it does have an impact, although as we've seen with other CFTR modulators. Our expectation is the levels of persistence and compliance will be high with TRIKAFTA, particularly given the strong clinical profile.

正如查理所說，在考慮這些收入的節奏或形狀時，需要考慮的另一個因素是持續性和合規性的影響，以及這將如何影響收入，這確實會產生影響，儘管正如我們從其他 CFTR 調節劑中看到的那樣。鑑於 TRIKAFTA 具有良好的臨床療效，我們預期其堅持性和依從性水準會很高。

And then I think on the AAT and type 1, I think Reshma will take those.

然後我覺得關於AAT和第一型糖尿病，Reshma應該會接受這些治療。

Sure. Salveen, let me tackle the diabetes question first, and then I'll take AATD second. So with regard to the diabetes program, that's the cell therapy program that we acquired through the Semma acquisition. Salveen, the proof-of-concept, I imagine to be something you can think about more akin to sickle cell and our beta-thal program versus a small molecule program. And what I mean by that is, we are going to be able to go into the clinic right into patients. It's not going to have a healthy volunteer step. And whether we go with the cell program alone or the cell with the device, I think, the kind of endpoints you could expect are fairly straightforward ones, glucose levels, hemoglobin A1C. Clearly, hypoglycemic episodes on the safety side will be something that we're watching. But I think that kind of gives you a good sense for what we're going to be watching for.

當然。薩爾文，讓我先回答糖尿病的問題，然後再回答 AATD 的問題。所以，關於糖尿病項目，那是我們透過收購 Semma 公司所獲得的細胞療法項目。Salveen，這個概念驗證藥物，我認為更像鐮狀細胞貧血症和我們的β-地中海貧血治療方案，而不是小分子藥物治療方案。我的意思是，我們將能夠直接進入診所，接觸病人。它不會有一個健康的志願者步驟。無論我們單獨使用細胞程序還是使用細胞和設備，我認為，您可以預期的終點指標都是相當直接的，例如血糖水平、糖化血紅蛋白 A1C。顯然，在安全方面，低血糖事件是我們關注的重點。但我認為這能讓你大致了解我們將要關注的重點。

The other thing to mention is, I think, that you can, again, similar to beta-thal and sickle cell, I anticipate that the proof-of-concept studies are going to be a reasonable size and a very reasonable duration.

另一點要提及的是，我認為，與β-地中海貧血和鐮狀細胞貧血類似，我預計概念驗證研究的規模和持續時間將會相當合理。

With regard to the AATD program, we have not had further regulatory interaction. And so as I've commented on before, I was impressed with the October 2019 FDA conference. What the agency indicated was that they would work with each sponsor depending on their approach for what the regulatory enabling endpoint would be. And I anticipate that the key points that we would be looking for from this program that's ongoing is functional serum AAT levels. And as we think forward beyond that, we just need to get through the regulatory interactions. I will remind you that the augmentation companies receive their approval based on AAT levels. That's just a data point to look at.

關於 AATD 項目，我們沒有與監管機構進行進一步的溝通。正如我之前評論過的那樣，我對 2019 年 10 月的 FDA 會議印象深刻。該機構表示，他們將根據每個贊助商的具體方案，與他們合作，確定監管授權的最終目標。我預計，我們將從這個正在進行的項目中尋找的關鍵點是功能性血清 AAT 水平。展望未來，我們只需要應對監管方面的各種問題。我提醒各位，增強技術公司是根據 AAT 等級獲得批准的。那隻是一個值得關注的數據點。

And the last thing I'll say is our approach is obviously very different than those out there. In that, the small molecule corrector approach holds the opportunity to treat both the liver and lung manifestations. And so obviously, we're going to be talking through what those liver manifestations and what those endpoints would look like as well.

最後我想說的是，我們的方法顯然與市面上其他的方法截然不同。因此，小分子矯正劑方法有機會同時治療肝臟和肺部的病變。所以很顯然，我們接下來會討論這些肝臟表現以及最終的治療終點會是什麼樣子。

Our next question comes from Paul Matteis with Stifel.

下一個問題來自 Stifel 公司的 Paul Matteis。

Just 1 quick question on guidance. Even with considering inventories, when we just take your comments on 1Q, it looks like you're already pretty close to annualizing at the full year number you outlined. And so we just wanted to get a better understanding of the dynamics that go into your guidance. Are you just being conservative? Or is there a reason that uptake is slow?

關於指導方面，我還有一個小問題。即使考慮到庫存，僅就您第一季的業績而言，看起來您已經非常接近您概述的全年業績了。因此，我們只是想更了解您指導過程中的各種因素。你只是比較保守嗎？或者說，普及速度緩慢的原因是什麼？

And then just second, quickly, on the cell therapy program in diabetes, I was just curious, how do you think about a realistic clinical goal for that program? And do you feel like the bar for true commercial success is insulin independence? Or are there other ways we should think about a potential benefit?

其次，關於糖尿病細胞療法項目，我很好奇，您認為該計畫的現實臨床目標是什麼？你認為真正的商業成功的標準是擺脫胰島素依賴嗎？或者，我們還可以從其他角度來考慮潛在的益處嗎？

Paul, this is Charlie. I'll take the first question on guidance. And I would not characterize the guidance as conservative. I think it's appropriate given what we know about the TRIKAFTA launch so far as well as the reimbursement agreements that we signed in the fourth quarter. Again, just to touch back on the inventory topic. It's tempting to look at the Q4 run rate and want to extrapolate from that. But if you take the $1.25 billion, back out $100 million for the inventory build, you're at $1.15 billion. And so the guidance obviously implies significant growth over that.

保羅，這是查理。我先回答第一個關於指導的問題。我不會將這些指導方針描述為保守的。我認為，考慮到我們目前對 TRIKAFTA 啟動情況的了解，以及我們在第四季度簽署的報銷協議，這樣做是合適的。再說一下庫存問題。人們很容易會根據第四季的運行速度進行推斷。但如果你從 12.5 億美元中減去 1 億美元用於庫存建設，那就剩下 11.5 億美元了。因此，該指引顯然意味著將實現顯著成長。

And then again, as we touched on in the remarks, the impact of persistence and compliance is meaningful and will come into the revenues over the course of 2020. So once you factor those things in, we think that the guidance is absolutely appropriate. And candidly, when you think about the $5.2 billion number at the midpoint, so $1.2 billion increase year-over-year, a 30% growth rate, it sets us up for another very strong year.

此外，正如我們在演講中提到的，堅持和合規的影響是意義重大的，並將在 2020 年期間體現在收入中。所以，考慮到這些因素，我們認為該指導意見是完全恰當的。坦白說，考慮到年中點的 52 億美元數字，比上年增長 12 億美元，成長率達 30%，這將使我們迎來另一個非常強勁的年份。

Paul, I'll take the question on the cell therapies program and type 1 diabetes. So if you think about the current approach to type 1 diabetes and whether you think about insulin just injection or you think about closed-loop systems or you think about really anything that's available there, what you realize is in these over 1 million people who have this disease, neither is the glucose control particularly good, whether you look at glucose or hemoglobin A1C, nor is it particularly safe on the other side, and that's the -- to speak to the hypoglycemic episodes. Then if you look at cadaveric transplants, that actually shows that people who have cadaveric transplants, islet cell transplants, they do very well in terms of glucose control and don't have the deficiencies with hypoglycemia.

保羅，我來回答關於細胞療法項目和第 1 型糖尿病的問題。所以，如果你想想目前治療第 1 型糖尿病的方法，無論是單純注射胰島素，還是閉環系統，或者任何可用的方法，你都會意識到，在超過 100 萬患有這種疾病的人中，血糖控制都不太好，無論是血糖還是糖化血紅蛋白 A1C，另一方面，低血糖發作也並不安全。如果你看看屍體移植，你會發現接受屍體移植、胰島細胞移植的人，在血糖控制方面表現得非常好，而且沒有低血糖的症狀。

Now the problem there of course is they're just [plain] aren't enough islets -- there are not enough cadavers for transplant and then there is the issue of immunosuppression. So the real beauty in this approach and why we're so very excited about this is Doug Melton and the Semma Group have come up with a way to not only produce, but to scale these islet cells and that holds the potential for really excellent glucose control like the cadaveric transplants, without the hypoglycemic episodes. So that's what the real goal here is.

當然，現在的問題是胰島數量不夠——沒有足夠的屍體可供移植，而且還有免疫抑制的問題。因此，這種方法的真正妙處以及我們對此感到非常興奮的原因在於，Doug Melton 和 Semma Group 不僅找到了一種生產這些胰島細胞的方法，而且還找到了一種可以大規模生產這些胰島細胞的方法，這有可能像屍體移植一樣實現非常出色的血糖控制，而不會出現低血糖發作。所以，這才是真正的目標。

Our next question comes from Alethia Young with Cantor Fitzgerald.

下一個問題來自 Cantor Fitzgerald 的 Alethia Young。

Congrats on the quarter. And Jeff, certainly, you will be missed in the CEO seat. Incredible run. I think that -- we call that CEO mic drop. So my 2 questions are, I guess, when you're thinking about in the field, what have been kind of the biggest surprises? I know you guys talked about bottlenecks and maybe potentially with just so much demand, have you seen that to be the case? Or has it been a little better?

恭喜你本季取得佳績。傑夫，你離開CEO的位置，我們肯定會非常想念你。精彩的奔跑。我覺得——我們稱之為CEO式的「麥克風掉落」。所以我的兩個問題是，我想，當你思考這個領域時，你遇到的最大驚喜是什麼？我知道你們討論過瓶頸問題，也可能是因為需求量太大，你們有沒有遇到這種情況？或者情況稍微好轉了一些？

And then my second question is, it might be a little early, but do you think the compliance and persistence are trending more like a KALYDECO? Or what kind of -- where are the puts and takes that you think about the [ever divine] dynamic in 2020?

我的第二個問題是，現在問這個問題可能有點早，但你認為合規性和持久性的發展趨勢更像 KALYDECO 嗎？或者，在2020年，你認為（永恆神聖的）動態中，有哪些值得關注的因素？

Yes. Alethia, thanks very much for the question. You're right, prior to the launch, there was a couple of potential bottlenecks as you described them that we were concerned about. One was -- concerns that CF centers had raised with us about the capacity constraints, they felt they might have given 18,000 patients were going to be eligible for TRIKAFTA. I have to say, they have done a spectacular job in responding to the higher level of patient demand. And whilst there have certainly been some bottlenecks at some centers, in general, the multidisciplinary teams have done just an amazing job working to get patients initiated on the medicine.

是的。阿萊西亞，非常感謝你的提問。你說得對，在發布之前，正如你所描述的，確實存在一些我們擔心的潛在瓶頸。其中之一是 CF 中心向我們提出的關於容量限制的擔憂，他們認為他們可能會給 18,000 名患者提供 TRIKAFTA 資格。我必須說，他們在應對不斷增長的患者需求方面做得非常出色。雖然有些中心確實出現了一些瓶頸，但總的來說，多學科團隊在幫助患者開始接受藥物治療方面做得非常出色。

The other potential bottleneck, as always, with a new product launch is, whether we are going to get support from payers. And again, our teams have done a great job working with both government and commercial payers. And clearly, we wouldn't have been able to deliver the results we have in the fourth quarter without very significant access. So both of those bottlenecks have actually -- we've been pleasantly surprised with how well those have turned out in Q4, and I expect that to continue in 2020.

與以往新產品發布一樣，另一個潛在的瓶頸是，我們能否獲得支付方的支持。再次強調，我們的團隊在與政府和商業支付方的合作中都做得非常出色。顯然，如果沒有非常重要的資源取得管道，我們不可能在第四季取得這樣的業績。所以，這兩個瓶頸問題實際上——我們對它們在第四季度取得的良好進展感到驚喜，我預計這種情況將在 2020 年繼續下去。

In terms of compliance and persistence, really, it's just too early to say in the real world, exactly what that is going to look like. We do expect it to be high. We do expect it to be in the range of our other CFTR modulators, which you know is very high for both of those aspects. And certainly, given the profile, we'd expect it to be similar with TRIKAFTA, it has been for our other medicines. But really too early to tell exactly what it's going to be like for this medicine in the real world.

就合規性和持續性而言，現在就斷言現實世界中究竟會是什麼樣子還為時過早。我們預計它會很高。我們預計它的性能將與我們其他 CFTR 調製器的性能相當，您也知道，它們的性能在這兩方面都非常出色。當然，根據其特性，我們預計它會與 TRIKAFTA 類似，就像我們其他藥物一樣。但現在判斷這種藥物在現實世界的表現還為時過早。

Our question comes from Whitney Ijem with Guggenheim.

我們的問題來自古根漢美術館的惠特尼·伊傑姆。

I wanted to follow-up on type 1 diabetes. So it sounded like it wasn't clear whether or not you'd be moving forward into the clinic with the naked cells or the encapsulation? And I'm wondering if you can give us any more color on what the exact encapsulation technology or devices at this point.

我想了解一下第1型糖尿病的情況。所以聽起來好像還不清楚你們會用裸細胞還是包覆細胞來做臨床試驗？我想知道您能否更詳細地介紹一下目前的具體封裝技術或裝置。

Sure. Thanks so much for the question. It's really one of my favorite late preclinical development programs to talk about for a few reasons. But with regard to your specific question, you're right. We have 2 shots on goal here, so to speak. One development pathway involves the cells alone. And for example, that is attractive in a couple of different potential areas. One of them would be patients who are renal transplant recipients, as an example, who are on immunosuppressive therapy anyway, and they have their renal transplant because of type 1 diabetes. So the naked cell approach or the cell alone approach there could be a nice pathway.

當然。非常感謝你的提問。出於幾個原因，這真的是我最喜歡談論的後期臨床前開發項目之一。但就你提出的具體問題而言，你是對的。可以說，我們現在有兩次射門機會。其中一種發育途徑僅涉及細胞本身。例如，這在幾個不同的潛在領域中都很有吸引力。例如，其中一類是腎臟移植受者，他們本來就在接受免疫抑制治療，而他們接受腎臟移植是因為患有第 1 型糖尿病。所以，裸細胞方法或單獨細胞方法可能是一條不錯的途徑。

The encapsulation is a device. The Semma Group has not only done amazing work with regard to the development and the maturation of cells and the industrial scale up, but they've done a really nice job with the device. The device has to be particular, and you know others have tried this in the past and it's a tough problem to solve. The device is different, and I think is -- really has the opportunity to succeed here for a few different reasons. It has to do with the geometry, it has to do with the material, it needs to allow glucose and insulin to free flow, but to keep the cells in their state. And it also has to do with ensuring that the device and the cells get sufficient oxygenation and that there isn't fibrosis. And the data that we have seen to date, including in large animals, tells us that, that's so.

封裝本身就是一種裝置。Semma 集團不僅在細胞的開發和成熟以及工業規模化方面取得了驚人的成就，而且在設備方面也做得非常出色。這個設備一定很特殊，你也知道以前有人嘗試過，這是一個很難解決的問題。這款設備與眾不同，我認為它——真的有機會在這裡取得成功，原因有幾個。這與幾何形狀有關，與材料有關，它需要允許葡萄糖和胰島素自由流動，但要保持細胞的狀態。這也與確保設備和細胞獲得足夠的氧氣以及防止纖維化有關。我們迄今為止所看到的數據，包括大型動物的數據，都顯示情況確實如此。

Got it. And just a quick follow-up. So will we be moving the encapsulation program forward into the clinic first and you sort of abandoned the naked cell approach? Or is it still up in the air as to which will go first?

知道了。還有一個後續問題。所以，我們會先將封裝技術推進到臨床階段，而你們則放棄了裸細胞方法嗎？或者說，究竟哪個先進行，目前還未確定？

Yes. You can think of it in terms of having 2 shots on go, and it's just a matter of which one goes first. But you can think of it as 2 programs.

是的。你可以把它想像成同時進行兩次射擊，問題只是哪一次先進行。但你可以把它看作是兩個程式。

Our next question comes from Robyn Karnauskas with SunTrust Robinson Humphrey.

下一個問題來自 SunTrust Robinson Humphrey 的 Robyn Karnauskas。

Thanks, Jeff for all the hard work you've put in. It's been great. So 2 questions. One for Charlie. First, you have cash that's accumulating. It looks like the studies that you're about to do may not be that expensive. They're very tight, and they may be small, at least for the next few years. So how are you thinking about thus maximizing cash without running the risk of having lazy balance sheet? And then for pain, you discontinued 1 program. What are you looking for versus the original VX-150?

傑夫，感謝你付出的所有辛勤努力。感覺很棒。所以有兩個問題。給查理一份。首先，你手邊有一筆正在累積的現金。看來你即將進行的研究可能不會太昂貴。它們非常緊湊，而且可能規模很小，至少在未來幾年內是如此。那麼，您打算如何最大限度地利用現金流，同時又不冒著資產負債表狀況不佳的風險呢？然後因為疼痛，你停止了 1 個項目。與原版 VX-150 相比，您想要的是什麼？

Sure. Robyn, thanks for the question. As you point out, the business model is running very well right now, and we are generating cash, which gives us flexibility. We continue to feel that the best use of our cash is to reinvest in the business, both in terms of internal innovation and also external innovation. Again, you saw us have a very active year in 2019 with $1.6 billion on a number of deals that got us access to some great enabling technology and some programs that are a perfect fit with our research strategy.

當然。羅賓，謝謝你的提問。正如你所指出的，目前我們的商業模式運作良好，並且我們正在產生現金流，這給了我們很大的靈活性。我們仍然認為，將現金用於再投資業務，包括內部創新和外部創新，才是對我們資金的最佳利用。再次強調，你們可以看到我們在 2019 年非常活躍，透過一系列交易獲得了 16 億美元的資金，從而獲得了一些很棒的賦能技術和一些與我們的研究策略完美契合的專案。

So going forward, we'll continue to be active in business development. To the extent that we have additional cash flow in 2020, that's where the priority will be. I'm not going to say that we're committing to a certain number of deals or a certain volume of cash flow, everything needs to be governed by the research strategy and the corporate strategy, we'll stay disciplined, but you'll continue to see us be active in 2020.

因此，接下來我們將繼續積極開展業務拓展工作。如果2020年我們有額外的現金流，那將是我們的首要任務。我不會說我們會承諾達成多少筆交易或產生多少現金流，一切都必須遵循研究策略和公司策略，我們會保持自律，但你們會看到我們在 2020 年繼續保持活躍。

Robyn, this is Reshma. I'll take a question about pain. So Robyn, I would think about pain just like CF, and frankly, all of our programs. The approach here in Vertex speak is first crack the biology, then pour on the chemistry. And where we are with the pain program is we've cracked the biology. And I feel confident saying that because of the VX-150 results that we saw in 3 Phase II studies, right, in acute pain, in neuropathic pain and in osteoporosis.

羅賓，這位是雷什瑪。我來回答一個關於疼痛的問題。所以 Robyn，我會像 CF 患者一樣思考疼痛，坦白說，我們所有的項目都會考慮到這一點。用 Vertex 的話來說，這裡的方法是先攻克生物學，然後再深入研究化學。而我們目前在疼痛治療方面的進展是，我們已經破解了其中的生物學原理。我之所以有信心這麼說，是因為我們在 3 項 II 期研究中看到了 VX-150 的結果，對吧，這些研究分別針對急性疼痛、神經性疼痛和骨質疏鬆症。

So what we're really doing now is part 2, which is pour on the chemistry. And this is about finding, let me call it, the ideal molecule, particularly in this disease state, safety and efficacy, of course, table stakes. But what we're really looking for is a molecule with the perfect PK, something that can be dosed once or twice a day, given that we're talking about a pain condition in this instance. We need to ensure that this medicine can be taken with food or without food. If you're talking about acute pain immediately post surgery, being able to take it without food is going to be really important. We're also thinking about DDIs and [COGS].

所以我們現在真正要做的是第二部分，也就是加入化學反應。而這關乎找到，我姑且稱之為，理想的分子，尤其是在這種疾病狀態下，安全性和有效性當然是基本要求。但我們真正想要的是一種具有完美藥物動力學特性的分子，一種可以每天服用一次或兩次的藥物，因為我們在這裡討論的是疼痛疾病。我們需要確保這種藥物可以空腹或飯後服用。如果是指術後立即出現的急性疼痛，那麼能夠在不進食的情況下服用藥物就非常重要了。我們也在考慮DDI和[COGS]。

And so really, I guess, I would describe it to you as we're at the stage of pouring on the chemistry, and this is our search for the ideal molecule for this pain condition, or I should actually describe it's conditions. We think about it as 3 distinct groups in there.

所以，我想，我可以說是在向你描述我們目前所處的階段，也就是投入化學研究的階段，我們正在尋找治療這種疼痛症狀的理想分子，或者我應該更準確地說，是治療這種疼痛症狀的分子。我們認為它由三個不同的群體組成。

Our next question comes from Cory Kasimov with JPMorgan.

下一個問題來自摩根大通的科里·卡西莫夫。

Congrats on a great quarter. Only you pre-announced this a couple of weeks ago, you could have made that investor conference a little more exciting this year. But I guess, first question, I have for you is regarding AAT. As clinical work ramps, are you seeing any broader-based efforts to help with the diagnosis rate? And what kind of education can you do there to facilitate the process while in development?

恭喜你本季表現出色。如果你幾週前就提前宣布這件事，今年的投資人大會就會更精彩一些。不過，我想問您的第一個問題是關於AAT的。隨著臨床工作的增加，您是否看到任何更廣泛的措施來幫助提高診斷率？那麼，在發展過程中，你可以進行哪些類型的教育來促進這個過程呢？

Yes. Cory, let's take this in 2 parts, if you wouldn't mind. This is Reshma. I'll make a few comments, and then I'm going to turn it over to Stuart to tell us a little bit more about the market opportunity and such.

是的。科里，如果你不介意的話，我們分成兩部分來討論這個問題。這是雷什瑪。我先簡單說幾句，然後把麥克風交給斯圖爾特，讓他再詳細說說市場機會等等。

Cory, as we start our clinical trials and really start to engage with the community, which we've already started to do, what you realize and what you're alluding to is absolutely true. Unlike CF, this is a disease where there isn't newborn screening and there isn't 100% diagnosis. And while there is a 510 cleared CE marked assay for antigenic level, the diagnosis is not done that frequently. We are working with the community. We are engaged with the Alpha-1 Foundation. And I do see that group providing a real good amount of education, and I see an opportunity to do even more. Let me ask Stuart to comment from his vantage point.

科里，隨著我們開始臨床試驗並真正開始與社區互動（我們已經開始這樣做了），你所意識到的和你所暗示的都是完全正確的。與囊性纖維化不同，這種疾病目前沒有新生兒篩檢，也無法100%確診。雖然有 510 種獲得 CE 認證的抗原水平檢測方法，但這種診斷並不經常進行。我們正在與社區合作。我們正在與 Alpha-1 基金會合作。我確實看到這個團體提供了非常好的教育，而且我認為還有機會做得更多。讓我請史都華從他的角度發表一下看法。

Yes. Cory, so in terms of what we know about the market today, that's estimated to be about 100,000 people with the ZZ genotype in the U.S. and EU. Almost definitely, that's an underestimate, but let's just take that as a starting point. Only a fraction of those patients are currently diagnosed, to your point, and only a fraction of those that are diagnosed are actually actively treated with the current standard of care, which is the IV augmentation therapy.

是的。Cory，就我們目前對市場的了解而言，據估計，美國和歐盟約有 10 萬人擁有 ZZ 基因型。幾乎可以肯定，這還是低估了，但我們就以此為起點吧。正如您所說，目前只有一小部分患者得到診斷，而在得到診斷的患者中，只有一小部分人真正接受了目前的標準治療，即靜脈輸液增強療法。

So if we are able to bring to the market a product which treats the underlying cause of the disease, which has impact on both the lung and the liver and is an oral small molecule, we think there's multiple opportunities here. One is clearly potentially to replace some of the IV augmentation therapies. Another opportunity would be to increase the treatment rate in those patients who are already diagnosed, but we also do think there is a significant opportunity to increase the diagnosis rate.

因此，如果我們能夠推出一種治療疾病根本原因的產品，該產品對肺部和肝臟都有影響，並且是一種口服小分子藥物，我們認為這裡有很多機會。其中一項顯然有可能取代一些靜脈輸液增強療法。另一個機會是提高已確診患者的治療率，但我們也認為提高診斷率有很大的機會。

The diagnosis is not difficult to do. It's a simple blood test. It's currently included within treatment guidelines that should be done for patients diagnosed with COPD. But I think, as so often the case where you don't have a solution, people don't go looking for the problem. And so we do anticipate there could be an increase in those diagnosis rates if we are able to bring a better solution to the market.

診斷並不難。這是一個簡單的血液檢查。目前，它已被納入慢性阻塞性肺病患者的治療指南中。但我認為，很多時候，當沒有解決方案時，人們就不會去找問題所在。因此，我們預計，如果我們能夠向市場推出更好的解決方案，診斷率可能會提高。

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。

This is Kostas on for Matthew. Congratulations on the quarter. Two questions from me. The first one is, can you give us some sense for how to think about the dynamics of European revenues in 2020, please?

這裡是科斯塔斯替馬修解說。恭喜你本季取得佳績。我有兩個問題。第一個問題是，您能否為我們介紹2020年歐洲收入的動態變化趨勢？

Yes. I'll take that. We were able to finalize reimbursement agreements in a number of major European countries towards the back end of 2019. And as we anticipated, we did not see much of a contribution of those reimbursement agreements in 2019 because even having secured those agreements, you have to work through the administrative process before patients can be initiated. We are expecting our European revenues to grow in 2020 as more patients are able to access our CFTR modulators and that's incorporated in the $5.1 billion to $5.3 billion guidance that Charlie talked to earlier on the call.

是的。我接受。2019 年末，我們與多個歐洲主要國家最終敲定了報銷協議。正如我們預期的那樣，2019 年這些報銷協議並沒有帶來多大的貢獻，因為即使獲得了這些協議，在病人開始接受治療之前，你也必須完成行政程序。我們預計 2020 年歐洲的收入將有所增長，因為更多的患者能夠獲得我們的 CFTR 調節劑，這已包含在 Charlie 早些時候在電話會議上提到的 51 億美元至 53 億美元的指導方針中。

And my second question is on APOL1-mediated kidney disease program. You have mentioned that you are planning to use the protein urea as a clinical market. I was wondering whether you need more key efficacy endpoints or this would suffice?

我的第二個問題是關於 APOL1 介導的腎臟疾病計畫。您曾提到計劃將蛋白尿素應用於臨床市場。我想知道是否需要更多關鍵療效終點指標，還是這些就夠了？

Sure. Thanks, Kostas. This is Reshma. I'll take that one. So for those who may not be as familiar with this one, this is the VX-147 program, and this is going into patients into the clinic in Phase II now, actually. This is for APOL1-mediated FSGS. So Kostas, as you may know, the renal community, along with regulatory agencies have for the past many years thought and discussed what the appropriate regulatory enabling endpoint might be for a homogeneous proteinuric kidney disease, that's a mouthful.

當然。謝謝你，科斯塔斯。這是雷什瑪。我選那個。所以對於那些可能不太熟悉這個項目的人來說，這是 VX-147 項目，實際上，它現在已經進入第二階段的臨床試驗，進入患者體內。這是針對 APOL1 介導的 FSGS 的。所以，科斯塔斯，你可能知道，腎臟病界和監管機構在過去的許多年裡一直在思考和討論，對於同質性蛋白尿腎病來說，合適的監管授權終點是什麼，這可真是一言難盡。

But basically, what I'm saying is that there's a lot of support and what the idea here would be is to measure protein in the urine. That's a fairly simple thing to do. And when you have a disease that's a homogeneous protein leaking disease that most people believe, and this has been discussed extensively in the community that protein in the urine is the right measure for one to evaluate. So that's what we're going to be evaluating in this Phase II study. And that's the study that is now getting underway.

但基本上，我的意思是，有很多支持這種做法的人，而這裡的想法是測量尿液中的蛋白質。這很容易做到。當你患有一種同質性蛋白質外洩疾病時，大多數人認為（這一點在社區中也得到了廣泛的討論），尿蛋白是評估病情的正確指標。所以，這就是我們將在本次二期研究中評估的內容。這就是目前正在進行的研究。

Our next question comes from Liisa Bayko with JMP Securities.

下一個問題來自 JMP Securities 的 Liisa Bayko。

I wanted to also wish congratulations to the team and during the transition. Wanted to ask about the European rollout. Can you just get into a little more specifics on sort of timing of the different countries? And what do you think the on ramping could look like, given that this has been sort of a new therapy that's available in some countries, meaning they haven't had access to CFTR modulators in the past?

我還要向團隊表示祝賀，並祝福他們順利完成過渡。想問一下歐洲地區的推廣情況。能否更具體地說明各國的具體時間安排？考慮到這是一種在某些國家剛推出的新療法，這意味著他們過去無法獲得 CFTR 調節劑，您認為這種療法的推廣過程會是什麼樣的？

Yes. I think there's really 2 aspects to that question, Liisa. One is the timing in different countries of the uptake of our current medicines, which are approved in Europe, and clearly, we expect that, as I mentioned earlier, to begin now that we have reimbursement agreements in some of the major countries, U.K., Spain, France, et cetera, for existing CFTR modulators.

是的。莉莎，我認為這個問題實際上包含兩個面向。一是不同國家對我們目前在歐洲獲批的藥物的接受程度，顯然，正如我之前提到的，我們預計隨著我們與一些主要國家（英國、西班牙、法國等）就現有的 CFTR 調節劑達成報銷協議，這種情況將會開始改變。

In terms of how that might play out for the triple combination. Clearly, we have that submission in with the regulatory authorities. Our expectation is for an approval in Q4 of this year. And as you know, the regulatory approval is really the trigger to the beginning of reimbursement discussions. And so within our guidance for 2020, there is minimal triple combination regimen -- revenues included within that guidance.

至於這對於三巨頭組合可能會產生什麼樣的影響。顯然，我們已經向監管機構提交了這份文件。我們預計將於今年第四季獲得批准。如您所知，監管部門的批准才是啟動報銷討論的真正觸發點。因此，在我們對 2020 年的指導下，三聯療法的投入最少——收入也包含在該指導意見中。

Our final question comes from Brian Abrahams with RBC Capital Markets.

最後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 the quarter and congratulations, Jeff, to on all your accomplishments. What's been your feedback on real-world experience with TRIKAFTA efficacy and safety? To what degree that's been aligning with the clinical trial experience? Is anything unexpected or different there?

恭喜你本季取得佳績，也恭喜傑夫的所有成就。您在實際使用中對 TRIKAFTA 的功效和安全性有何回饋？這與臨床試驗經驗的吻合程度如何？那裡有什麼意料之外或不尋常的事情發生嗎？

And then secondarily, can you remind us of your plan to collect longer-term outcomes data with TRIKAFTA, things like exacerbations, the time line for updating that? And how important do you think that will be for full market penetration in the U.S. as well as European access?

其次，您能否提醒我們您利用 TRIKAFTA 收集長期結果數據的計劃，例如病情加重情況，以及更新這些數據的時間表？您認為這對於全面打入美國市場以及進入歐洲市場有多重要？

So in terms of the real-world experience, I said, I would say, has been very similar to what we saw in the Phase III program, Brian. The feedback we've had from physicians and patients has been almost universally positive. And when I say positive, their experience at the level of efficacy and the impact it's having on their lives is really inspiring.

所以就現實世界的經驗而言，我認為，它與我們在第三階段計劃中看到的情況非常相似，布萊恩。我們從醫生和患者那裡得到的回饋幾乎都是正面的。我說「正面」是指，他們在療效方面的體驗以及它對他們生活的影響真的非常鼓舞人心。

Obviously, safety is something which needs to play out over time. But certainly, we haven't seen anything in the real world that has surprised us, that has been different from what we saw in the Phase III programs. And as you know, those studies demonstrated a very, very strong benefit risk profile. In terms of outcomes data and what data we're going to be collecting, I'll hand that over to Reshma.

顯然，安全是一個需要時間慢慢累積的過程。但可以肯定的是，我們在現實世界中還沒有看到任何讓我們感到驚訝的事情，也沒有看到任何與我們在第三階段專案中看到的事情不同的事情。如您所知，這些研究表明，其收益風險比非常非常高。至於結果數據以及我們將要收集哪些數據，我會交給雷什瑪負責。

Sure. So Brian, you know that we -- in the Phase III program for the FMS patients, that was the program with about 400 patients that went out to 24 weeks. We already reported on pulmonary exacerbations, and it was a really large reduction of 63%. We are continuing to collect data. So patients in both the FS study and the FMS study rolled over into an open-label extension that goes out through 96 weeks. And in addition to that, we have additional studies that we're doing, collecting data from various registries not only here in the U.S., but as we've done with our other CFTR modulators around the globe as well. So we have more data to look forward to, not only from the clinical trials program in the open-label extension, but also registry data that we're collecting and we'll be collecting around the globe.

當然。所以布萊恩，你知道我們——在針對 FMS 患者的第三階段計畫中，該計畫有大約 400 名患者，持續了 24 週。我們之前已經報導過肺部疾病惡化的情況，其降幅非常大，達到了 63%。我們正在繼續收集數據。因此，FS 研究和 FMS 研究中的患者都進入了為期 96 週的開放標籤擴展研究。除此之外，我們也正在進行其他研究，收集來自各種註冊機構的數據，不僅包括美國的註冊機構，也包括我們在全球範圍內對其他 CFTR 調節劑所做的研究。因此，我們有更多數據可以期待，不僅來自開放標籤擴展的臨床試驗項目，還有我們正在收集和將要在全球範圍內收集的註冊數據。

Okay. On behalf of everyone here, thanks, everybody, for listening to tonight's call. Thanks also for all the kind words. We know that there are other earnings calls tonight. So we'll let you get to them. And at the same time, the IR team is in the office and happy to talk to you if you have additional questions.

好的。我謹代表在場的所有人，感謝大家收聽今晚的電話會議。也感謝大家的鼓勵與讚美。我們知道今晚還有其他財報電話會議。所以，我們讓你們去處理它們。同時，投資者關係團隊也在辦公室，如果您有任何其他問題，他們很樂意與您交談。

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. 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。