福泰製藥 (VRTX) 2018 Q4 法說會逐字稿

Welcome to the Vertex Full Year and Fourth Quarter 2018 Financial Results Conference Call. This is Michael Partridge, Senior Vice President of Investor Relations for Vertex. Tonight, we will review our continued efforts to develop new medicines for all people with cystic fibrosis, recent advances in our research and development pipeline and our 2018 financial results and 2019 guidance.

歡迎參加 Vertex 2018 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，我們將回顧我們為所有囊性纖維化患者開發新藥的持續努力、我們研發管線的最新進展以及我們 2018 年的財務業績和 2019 年的業績展望。

Making prepared remarks on the call tonight, we have Dr. Jeff Leiden, Chairman and CEO; Stuart Arbuckle, Chief Commercial Officer; and I would like to welcome to the call, Paul Silva, Vertex's Interim Chief Financial Officer. Paul has been Vertex's Corporate Controller and Chief Accounting Officer since 2008. And he and his team have worked closely with the Investor Relations group since that time.

今晚在電話會議上作發言的有：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；我還要歡迎Vertex的臨時首席財務官保羅·席爾瓦參加電話會議。自 2008 年以來，Paul 一直擔任 Vertex 公司的財務總監兼首席會計官。從那時起，他和他的團隊就與投資者關係部門密切合作。

Following prepared remarks from Jeff, Stuart and Paul, Dr. Reshma Kewalramani, Chief Medical Officer, will join us for Q&A. We recommend that you access the webcast slides on our website as you listen to this call. The conference call is being recorded and a replay will be on our website.

在 Jeff、Stuart 和 Paul 發表準備好的演講之後，醫療長 Reshma Kewalramani 博士將與我們一起進行問答環節。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，稍後將在我們的網站上提供回放。

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 ongoing development and potential 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潛在商業化、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. Over the past several years, I've shared with you Vertex's strategy to create multiple transformative medicines for different serious diseases by continuing to leverage our long track record of serial innovation. I'm pleased to review with you this evening the significant progress we made in 2018 on executing this strategy and to discuss the important growth drivers that we expect in 2019, which will include many important clinical, reimbursement and commercial milestones in CF, as well as clinical data from across our research and development pipeline. In CF, we expect to obtain the Phase III data for the VX-445 triple combination this quarter and remain on track to submit a new drug application for triple combination regimen no later than mid-year.

謝謝你，麥可。各位晚上好。在過去的幾年裡，我向大家介紹了Vertex的策略，即透過不斷利用我們長期以來在連續創新方面取得的成功，為不同的嚴重疾病創造多種變革性藥物。今晚我很高興與大家一起回顧我們在 2018 年執行該策略方面取得的重大進展，並討論我們預計在 2019 年實現的重要成長動力，其中包括 CF 領域許多重要的臨床、報銷和商業里程碑，以及來自我們整個研發管線的臨床數據。在 CF 方面，我們預計將在本季度獲得 VX-445 三聯療法的 III 期數據，並預計在年中之前提交三聯療法的新藥申請。

We also expect to see more patients initiating treatment with our medicines throughout 2019 as a result of global label expansions and from key reimbursement agreements reached in 2018, which will drive further revenue growth this year.

我們也預計，隨著全球標籤的擴大以及 2018 年達成的關鍵報銷協議，2019 年將有更多患者開始使用我們的藥物進行治療，這將推動今年的收入進一步成長。

In our non-CF pipeline, data expected in the first half of 2019 from our Phase IIb dose ranging study of VX-150 will inform our plans for potential Phase III development in pain. In our AAT program, we're advancing a portfolio of small molecule correctors, including our first molecule that entered Phase I development in late 2018, and a second that is expected to enter clinical development this year.

在我們的非 CF 產品線中，預計在 2019 年上半年將獲得 VX-150 IIb 期劑量範圍研究的數據，這將為我們潛在的 III 期疼痛治療開發計劃提供資訊。在我們的 AAT 專案中，我們正在推進一系列小分子矯正劑的研發，其中包括我們第一個於 2018 年底進入 I 期開發的分子，以及預計今年進入臨床開發的第二個分子。

And in sickle cell disease and beta-thalassemia, we have now initiated enrollment of both of our Phase I, II studies of the gene editing treatment of CTX001. I will briefly review each of these pipeline programs with you this evening.

針對鐮狀細胞疾病和β地中海貧血，我們現在已經啟動了基因編輯療法 CTX001 的 I 期和 II 期研究的入組工作。今晚我將簡單地向大家介紹這些人才培育計畫。

First, the cystic fibrosis. Today, approximately half of all people with CF are eligible for Vertex CF medicine. And we stand on the verge of yet another dramatic advance in the treatment of this disease with our triple combination regimens that hold the potential to treat up to 90% of all people with the disease. Our progress in CF in 2018 was marked by two important achievements. First, we saw significant increase in the number of patients being treated with our approved medicines. This was the result of the successful SYMDEKO launch in the U.S., multiple label expansions for KALYDECO and ORKAMBI and the completion of key reimbursement agreements around the world, which Stuart will review in a moment.

首先是囊性纖維化。目前，大約一半的囊性纖維化患者符合使用 Vertex CF 藥物的條件。我們即將迎來治療這種疾病的另一個重大進展，我們的三重療法有望治癒高達 90% 的該疾病患者。2018 年，我們在 CF 領域取得了兩項重要成就。首先，我們看到接受我們已獲批准藥物治療的患者人數顯著增加。這是 SYMDEKO 在美國成功上市、KALYDECO 和 ORKAMBI 多次擴大標籤範圍以及在全球範圍內完成關鍵報銷協議的結果，Stuart 稍後將對此進行回顧。

And second, we made excellent progress in advancing our two triple combination regimens through Phase III development. It was on this call one year ago that we announced our plans to initiate Phase III development for two different triple combination regimens that include a next-generation corrector, either VX-659 or VX-445. In just one year, we completed enrollment of approximately 1,000 patients across the four Phase III studies and obtained the first Phase III data for the VX-659 studies.

其次，我們在推動兩項三聯療法進入 III 期研發方面取得了卓越的進展。在一年前的這次電話會議上，我們宣布了啟動兩種不同的三重療法 III 期開發的計劃，這兩種療法都包含下一代矯正劑，即 VX-659 或 VX-445。僅一年時間，我們就完成了四項 III 期研究中約 1000 名患者的入組，並獲得了 VX-659 研究的首批 III 期數據。

These data showed clear and compelling evidence of the dramatic benefit that this regimen may offer patients with one F508del mutation and one minimal function mutation, as well as the significantly enhanced benefit that a triple combination regimen may provide for those with 2 F508del mutations who are already being treated with SYMDEKO or ORKAMBI. We will obtain data for the VX-445 triple combination regimen in the first quarter of this year, which will enable us to choose the best regimen to submit for regulatory approval. We remain on track to submit a New Drug Application for a triple combination regimen no later than mid-2019.

這些數據清晰有力地證明了該方案可能為攜帶一個 F508del 突變和一個最小功能突變的患者帶來顯著益處，以及三重療法可能為已經接受 SYMDEKO 或 ORKAMBI 治療的攜帶兩個 F508del 突變的患者帶來顯著增強的益處。我們將於今年第一季獲得 VX-445 三聯療法的相關數據，這將使我們能夠選擇最佳方案提交監管部門批准。我們仍按計畫推進，最遲將於 2019 年年中提交三聯療法的新藥申請。

We've set a high bar with the triple combination data, but we're also committed to creating even better CF medicines for the future, including once daily triple combination regimens and regimens that contain other next-generation correctors that may have enhanced profiles. We have multiple molecules in preclinical and clinical development that may provide future improvements for the treatment of CF.

我們已經透過三重療法的數據設定了很高的標準，但我們也致力於為未來創造更好的 CF 藥物，包括每日一次的三聯療法方案和包含其他可能具有增強特性的下一代矯正劑的方案。我們目前有多個處於臨床前和臨床開發階段的分子，這些分子未來可能會為囊性纖維化的治療帶來改進。

Now to our recent progress outside of CF, where we are rapidly advancing a portfolio of potential new medicines through late preclinical and early clinical development across a range of serious diseases with large unmet medical need. I'll start with our AAT program, where we recently initiated clinical development of our first small molecule corrector. The similarities between our AAT and CF programs are striking and we believe that we will be able to apply many of the lessons learned in our CF discovery and development efforts to accelerate and de-risk our activities targeting AAT. We believe that measurements of the circulating functional AAT protein in people with alpha-1 antitrypsin deficiency will provide us with an early and important marker for the potential of our medicines to treat the cause of this disease, just as the biomarker of sweat chloride did for us in CF.

現在來談談我們在 CF 以外的最新進展，我們正在快速推進一系列潛在新藥的研發，這些藥物涵蓋多種存在巨大未滿足醫療需求的嚴重疾病，目前正處於臨床前後期和臨床早期開發階段。我先從我們的 AAT 計畫說起，我們最近啟動了首個小分子矯正劑的臨床開發。我們的 AAT 和 CF 專案之間的相似之處非常顯著，我們相信，我們將能夠運用在 CF 發現和開發工作中學到的許多經驗教訓來加速和降低我們針對 AAT 的活動的風險。我們相信，對 α-1 抗胰蛋白酶缺乏症患者體內循環功能性 AAT 蛋白的測量，將為我們提供早期且重要的標誌物，以評估我們的藥物治療該疾病病因的潛力，就像汗液氯化物生物標誌物在囊性纖維化中為我們所做的那樣。

Turning to our research and development program in pain. We recently announced positive Phase II results for VX-150, showing a significant reduction of pain in people with small fiber neuropathy. These data marked the third positive proof-of-concept study for VX-150 in three different pain conditions and further validate the potential role of NaV1.8 inhibition in the treatment of pain. A Phase IIb dose ranging study of VX-150 in acute pain following bunionectomy surgery is now fully enrolled, and we expect data from this study in the first half of this year. Positive data from this study could support pivotal development of VX-150 in pain. We have a portfolio of multiple additional NaV1.8 inhibitors in late preclinical development and expect to advance the first of these molecules into clinical development in 2019. We are also continuing to invest in the discovery of additional potential pain molecules targeting other new mechanisms, given the significant need for new pain medicines.

轉向我們的疼痛研究和開發項目。我們最近公佈了 VX-150 的積極 II 期臨床試驗結果，結果顯示該藥物能顯著減輕小纖維神經病變患者的疼痛。這些數據標誌著 VX-150 在三種不同疼痛狀況下的第三個積極概念驗證研究，並進一步驗證了 NaV1.8 抑制在疼痛治療中的潛在作用。VX-150 治療拇外翻切除術後急性疼痛的 IIb 期劑量範圍研究現已全面完成入組，我們預計將於今年上半年獲得該研究的數據。這項研究的積極數據可能為 VX-150 在疼痛治療領域的關鍵性開發提供支持。我們還有多個處於臨床前開發後期的NaV1.8抑制劑產品組合，預計2019年將其中第一個分子推進到臨床開發階段。鑑於對新型止痛藥的龐大需求，我們也將繼續投資於發現針對其他新機制的潛在止痛分子。

Moving on to the sickle cell disease and beta-thalassemia programs, where, with our partner, CRISPR Therapeutics, we have now initiated clinical studies of CTX001 for both of these important diseases. These studies represent the first clinical trials to evaluate a gene editing treatment using the CRISPR-Cas9 technology in these 2 serious diseases. As we advance these R&D efforts, we are constantly evaluating new external opportunities that could provide access to new technologies, platforms or development assets. We have entered into multiple agreements in recent years that are aligned with our strategy, including our collaboration with CRISPR Therapeutics, as well as recently announced collaborations with Arbor Biotechnologies, Merck KGaA, Genomics plc and X-Chem. We enter 2019 with increased flexibility to do more deals that would further broaden our pipeline and enable us to continue to explore serious diseases with multiple modalities and technologies.

接下來是鐮狀細胞疾病和β地中海貧血項目，我們與合作夥伴CRISPR Therapeutics一起，已經啟動了CTX001針對這兩種重要疾病的臨床研究。這些研究代表了首次利用 CRISPR-Cas9 技術對這兩種嚴重疾病進行基因編輯治療的臨床試驗。隨著我們推動這些研發工作，我們不斷評估可能提供新技術、平台或開發資產的新的外部機會。近年來，我們達成了多項符合我們策略的協議，包括與 CRISPR Therapeutics 的合作，以及最近宣布與 Arbor Biotechnologies、Merck KGaA、Genomics plc 和 X-Chem 的合作。進入 2019 年，我們擁有更大的靈活性，可以進行更多交易，從而進一步拓寬我們的產品線，使我們能夠繼續利用多種模式和技術探索嚴重疾病。

As we look towards future years, Vertex has the potential for significant revenue and earnings growth through the mid-2020s, based solely on treating more patients with our approved and future CF medicines. Importantly, we also have a rapidly advancing portfolio of potentially transformative medicines for other serious diseases and the ability to enhance our internal R&D efforts with external innovation to drive long-term future growth. At Vertex, we believe that real value for patients and shareholders is created through scientific innovation. And I'm pleased that Vertex continues to be at the forefront of transforming the treatment of CF and other serious diseases.

展望未來幾年，Vertex 有潛力在 2020 年代中期實現顯著的收入和利潤成長，這完全基於我們使用已獲批准和未來將要使用的 CF 藥物來治療更多患者。重要的是，我們還擁有快速發展、具有潛在變革意義的藥物組合，可用於治療其他嚴重疾病，並且能夠透過外部創新來加強我們的內部研發工作，從而推動未來的長期成長。在 Vertex，我們相信，透過科學創新才能為患者和股東創造真正的價值。我很高興Vertex公司繼續走在改變囊性纖維化和其他嚴重疾病治療的前端。

I will now turn the call over to Stuart to review our commercial progress.

現在我將把電話交給斯圖爾特，讓他回顧一下我們的商業進展。

Thanks, Jeff. I'm pleased to review with you this evening our strong commercial performance for 2018, driven by the launch of SYMDEKO in the U.S., and also our revenue guidance for 2019, which shows continued revenue growth as we treat more patients with our approved medicines globally. Approximately 18,000 patients are currently being treated with our CF medicines. And this resulted in CF product revenues of $868 million in the fourth quarter. The fourth quarter included $294 million in revenues from SYMDEKO in the U.S., which was the primary driver of the significant growth in CF revenues in the quarter and throughout 2018.

謝謝你，傑夫。今晚我很高興與大家一起回顧我們 2018 年強勁的商業業績，這主要得益於 SYMDEKO 在美國的上市。同時，我也很高興與大家分享我們對 2019 年的收入預期，該預期顯示，隨著我們在全球範圍內使用已獲批准的藥物治療更多患者，收入將繼續增長。目前約有 18,000 名患者正在接受我們的囊性纖維化藥物治療。這使得CF產品在第四季的營收達到了8.68億美元。第四季度，SYMDEKO 在美國的營收為 2.94 億美元，這是該季度以及 2018 年全年 CF 收入大幅成長的主要驅動力。

Our full year 2018 CF revenues were $3.04 billion, a 40% increase compared to the $2.17 billion for 2017, which is a direct result of treating many more patients globally. In the U.S., we saw a large number of patients initiate and remain on treatment with SYMDEKO in 2018. Demand for SYMDEKO has come from all eligible groups of patients, including those who previously discontinued or never initiated ORKAMBI and those who switched from ORKAMBI or KALYDECO to SYMDEKO. Given the profile of SYMDEKO, we had expected that persistence and compliance rates might be greater than those seen previously with ORKAMBI, and we are pleased to see this play out in the real world. While we are now well into the launch of SYMDEKO, we do anticipate additional patients will initiate treatment throughout 2019, including patients ages 12 years and older, as well as younger patients, following potential approval in children ages 6 to 11, which we anticipate during 2019 and is reflected in the guidance I will discuss in a moment.

2018 年全年 CF 收入為 30.4 億美元，比 2017 年的 21.7 億美元增長了 40%，這是全球範圍內治療更多患者的直接結果。2018 年，我們看到美國有大量患者開始接受 SYMDEKO 治療並持續接受治療。SYMDEKO 的需求來自所有符合條件的患者群體，包括先前停止使用或從未開始使用 ORKAMBI 的患者，以及從 ORKAMBI 或 KALYDECO 轉而使用 SYMDEKO 的患者。鑑於 SYMDEKO 的特性，我們曾預期其持久性和合規率可能會高於先前 ORKAMBI 的水平，我們很高興看到這一點在現實世界中得到了驗證。雖然 SYMDEKO 的上市已經取得了不錯的進展，但我們預計 2019 年將有更多患者開始接受治療，包括 12 歲及以上的患者，以及在 6 至 11 歲兒童中可能獲得批准後，年齡更小的患者。我們預計 2019 年內將獲得批准，這體現在我稍後將要討論的指導意見中。

KALYDECO revenues for 2018 were $1.01 billion, an increase of 19% compared to 2017. The increase in KALYDECO revenues is a direct result of treating more patients in the U.S. based on label expansions received in 2017. Outside the U.S., we reached important reimbursement agreements for our CF medicines in Australia, Sweden and Denmark in 2018, adding to the multiple agreements previously reached in Germany, Italy, The Netherlands, Ireland and other countries. These new reimbursement agreements allowed patients to have access to medicines that treat the underlying cause of their disease for the first time and provided a contribution to revenue growth for 2018. These agreements will also contribute to revenue growth in 2019 and beyond.

KALYDECO 2018 年的營收為 10.1 億美元，比 2017 年成長了 19%。KALYDECO 收入的成長是由於 2017 年獲得標籤擴展，從而在美國治療了更多患者。2018 年，我們在美國以外與澳洲、瑞典和丹麥就 CF 藥物達成了重要的報銷協議，此前我們已在德國、義大利、荷蘭、愛爾蘭和其他國家達成了多項協議。這些新的報銷協議使患者首次能夠獲得治療其疾病根本原因的藥物，並為 2018 年的收入成長做出了貢獻。這些協議也將有助於2019年及以後的收入成長。

Given the recent EU approval of SYMKEVI, known as SYMDEKO in the U.S., and our rapid progress in developing triple combination regimens, our ongoing reimbursement efforts remain focused on obtaining long-term portfolio agreements that not only provide immediate access to our approved medicines, but also a pathway to access and rapid reimbursement of future CF medicines. We've reached these types of agreements in multiple countries and view these agreements as win-wins for patients and governments, as they provide certainty to patients that they will have immediate access to current and future innovations in CF from Vertex and budget certainty to governments for the foreseeable future.

鑑於最近歐盟批准了 SYMKEVI（在美國被稱為 SYMDEKO），以及我們在開發三聯療法方面取得的快速進展，我們持續的報銷工作仍然專注於獲得長期產品組合協議，這些協議不僅可以立即提供我們已獲批准的藥物，還可以提供未來 CF 藥物的獲取和快速報銷途徑。我們已在多個國家達成此類協議，並將這些協議視為患者和政府的雙贏之舉，因為它們為患者提供了確定性，確保他們能夠立即獲得 Vertex 提供的當前和未來的囊性纖維化創新療法，並為政府在可預見的未來提供了預算確定性。

Our progress in 2018 in launching SYMDEKO, expanding the labels for KALYDECO and ORKAMBI and achieving important reimbursement agreements for our medicines outside the U.S. has positioned us for continued revenue growth in 2019. Our 2019 guidance for CF product revenues is $3.45 billion to $3.55 billion, which at the midpoint, reflects approximately 15% growth over 2018. As the timing of when we achieve future reimbursement agreements is not entirely in our gift, our 2019 revenue guidance only reflects anticipated revenues from regions where our medicines are currently reimbursed. Achieving additional reimbursement agreements in 2019 could provide upside to our revenues, and thus, we would update our guidance as appropriate at that time.

2018 年，我們在推出 SYMDEKO、擴大 KALYDECO 和 ORKAMBI 的適應症範圍以及在美國以外地區達成重要的藥品報銷協議方面取得了進展，這為我們 2019 年的持續收入增長奠定了基礎。我們對 2019 年 CF 產品收入的預期為 34.5 億美元至 35.5 億美元，其中數值約為 15%，比 2018 年成長約 15%。由於我們無法完全掌控何時達成未來的報銷協議，因此我們 2019 年的收入預期僅反映了我們藥品目前已獲得報銷的地區的預期收入。2019 年達成更多報銷協議可能會增加我們的收入，因此，屆時我們將視情況更新我們的業績指引。

I would note that we expect to see a negative impact in the first quarter of this year from channel inventory build of approximately $10 million that occurred at the end of 2018 and from higher gross-to-net adjustments, which we typically experience in the first quarter. We expect that these dynamics may more than offset revenue growth from new patients and that first quarter CF product revenues could be sequentially lower than the fourth quarter of 2018, despite our expectation for continued revenue growth for the full year, as noted in our guidance.

我想指出，由於 2018 年底通路庫存增加約 1000 萬美元，以及我們通常在第一季會遇到的毛利淨利調整幅度較大，我們預計今年第一季將出現負面影響。我們預計，這些動態因素可能會抵消新患者帶來的收入成長，儘管我們預計全年收入將持續成長（如我們在指導意見中所述），但第一季 CF 產品收入可能會比 2018 年第四季略低。

I'm pleased with the continued progress we have made in bringing our CF medicines to many more patients globally, which has resulted in strong revenue growth to support our investment in the creation of new medicines for CF and other diseases. I look forward to talking further with you throughout the coming year, and will now turn the call over to Paul to further review our financial results and guidance.

我很高興看到我們在將 CF 藥物帶給全球更多患者方面取得了持續進展，這帶來了強勁的收入成長，從而支持我們對 CF 和其他疾病新藥研發的投資。我期待在未來一年與您進一步交流，現在我將把電話交給保羅，讓他進一步回顧我們的財務表現和指導。

Thanks, Stuart, and good evening, everyone. Vertex's financial performance in 2018 was marked by 40% growth in CF revenues, coupled with disciplined investment into our business, which drove significant increases in our operating margins, operating income and cash flow. In addition to Stuart's comments on 2018 revenues and 2019 revenue guidance, I will provide additional remarks this evening regarding our 2018 financial results. I will also discuss our 2019 financial guidance for R&D and SG&A expenses and for our effective tax rate. All of the results and guidance I will discuss are non-GAAP.

謝謝你，斯圖爾特，大家晚上好。Vertex 在 2018 年的財務表現以 CF 收入成長 40% 為標誌，同時對業務進行了有紀律的投資，這推動了我們的營業利潤率、營業收入和現金流的顯著增長。除了 Stuart 對 2018 年收入和 2019 年收入預期發表的評論外，我今晚還將就我們 2018 年的財務業績發表補充意見。我也會討論我們 2019 年的研發和銷售、管理及行政費用以及實際稅率的財務預期。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 noted, we saw a significant increase in CF product revenues, driven primarily by the launch of SYMDEKO in the U.S. KALYDECO label expansions also contributed to the revenue growth in 2018, where KALYDECO revenues reached $1 billion for the first time since its approval in 2012. This underscores both the important role that KALYDECO plays in the lives of thousands of patients around the globe and the continued strong demand for the medicine as we expand its label to new and younger patients.

正如 Stuart 指出的那樣，我們看到 CF 產品收入大幅增長，這主要得益於 SYMDEKO 在美國的推出。 KALYDECO 標籤的擴展也促進了 2018 年的收入成長，KALYDECO 的收入自 2012 年獲得批准以來首次達到 10 億美元。這不僅凸顯了 KALYDECO 在全球成千上萬患者生活中發揮的重要作用，也表明隨著我們將藥物的適應症擴展到新的、更年輕的患者群體，市場對該藥物的需求仍然強勁。

Our fourth quarter 2018 combined R&D and SG&A expenses were $400 million, compared to $355 million in the fourth quarter of 2017. Our full year 2018 R&D and SG&A expenses were $1.53 billion, compared to $1.33 billion for 2017. The increase in these expenses was primarily due to the advancement of our portfolio of triple combination regimens and investment to support the use of our medicines globally. The significant growth in CF revenues in 2018 resulted in full year operating margins of 37%, compared to 26% for 2017, as well as operating income of $1.11 billion, a 97% increase compared to 2017.

2018 年第四季度，我們的研發與銷售、管理及行政費用合計為 4 億美元，而 2017 年第四季為 3.55 億美元。2018 年全年研發及銷售、管理及行政費用為 15.3 億美元，而 2017 年為 13.3 億美元。這些費用的增加主要是由於我們三聯療法組合的推進以及為支持我們藥物在全球範圍內的使用而進行的投資。2018 年 CF 收入的顯著增長使得全年營業利潤率達到 37%，而 2017 年為 26%；營業收入達到 11.1 億美元，比 2017 年增長了 97%。

Net income for the fourth quarter of 2018 was $337 million, compared to $158 million in 2017. Our full year 2018 net income was $1.06 billion, compared to $495 million in 2017. The significant increase in our quarterly and full year net income was a result of the strong growth in CF product revenues. We also ended the year with approximately $3.17 billion in cash and marketable securities, compared to $2.09 billion at the end of 2017. We expect to continue to generate significant cash in 2019 and beyond.

2018 年第四季淨收入為 3.37 億美元，而 2017 年同期為 1.58 億美元。2018 年全年淨收入為 10.6 億美元，而 2017 年為 4.95 億美元。我們季度和全年淨收入的大幅成長是由於 CF 產品收入的強勁成長。截至年底，我們的現金和有價證券約為 31.7 億美元，而 2017 年底為 20.9 億美元。我們預計在2019年及以後將繼續產生大量現金流。

Now to our 2019 guidance. Today, we are providing financial guidance for CF product revenues, as Stuart discussed, as well as for combined R&D and SG&A expenses and our anticipated effective tax rate.

接下來是我們的2019年指導方針。今天，我們將提供 CF 產品收入的財務指導，正如 Stuart 所討論的那樣，以及研發和銷售、一般及行政費用的綜合情況和我們預期的有效稅率。

We expect combined R&D and SG&A expenses of $1.65 billion to $1.7 billion. The increase compared to 2017 primarily reflects CF development efforts, incremental investments to support the potential launch of a triple combination regimen, and investment to support the expansion of our pipeline into additional diseases.

我們預計研發銷售、管理及行政費用總計為 16.5 億至 17 億美元。與 2017 年相比，成長主要反映了 CF 開發工作、為支持三聯療法的潛在推出而進行的增量投資，以及為支持我們將產品線擴展到其他疾病而進行的投資。

Now to tax guidance. On a GAAP basis, we recorded a $1.5 billion noncash benefit in the fourth quarter of 2018, based on the reversal of the valuation allowance related to our net operating losses. Following the release of this valuation allowance, we will also begin recording a tax provision in 2019 and expect our full year GAAP and non-GAAP tax rates to be 21% to 22%. The tax rate will fluctuate quarter to quarter this year, 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 outlook that is based on continued revenue growth in CF, resulting in expanding operating margins and increases in earnings and cash flow.

接下來是稅務方面的指導。根據美國通用會計準則，由於衝回了與淨營業虧損相關的估值準備金，我們在 2018 年第四季確認了 15 億美元的非現金收益。在釋放該估值準備金後，我們也將在 2019 年開始提列所得稅準備，預計全年 GAAP 和非 GAAP 稅率將為 21% 至 22%。今年稅率將逐季波動，第四季稅率最高。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前景，其基礎是 CF 的持續收入成長，從而擴大營業利潤率，並增加收益和現金流。

I look forward to updating you on our progress. With that, I will turn the call back to Jeff.

我期待著向您報告我們的進展。這樣，我就把電話轉回給傑夫了。

Thanks, Paul. In closing, 2018 was a highly successful year of commercial and clinical execution across our business. Our achievements over recent months have positioned us for continued growth in revenue and operating income in 2019 and beyond and for important near-term milestones across our R&D portfolio, both in CF and in other diseases. Our strategy of creating transformative medicines through serial innovation is working exceptionally well, as evidenced by the rapid progress seen across our business, and I look forward to updating you over the coming year.

謝謝你，保羅。總之，2018 年是我們業務在商業和臨床執行方面取得巨大成功的一年。近幾個月來，我們所取得的成就使我們在 2019 年及以後能夠繼續實現收入和營業利潤的成長，並有望在 CF 和其他疾病的研發組合中實現重要的近期里程碑。我們透過連續創新來創造變革性藥物的策略取得了非常好的效果，我們業務的快速發展就證明了這一點，我期待在未來一年向大家報告最新進展。

With that, I will open the line to questions.

接下來，我將開放提問環節。

(Operator Instructions) Our first question comes from Michael Yee of Jefferies.

（操作說明）我們的第一個問題來自 Jefferies 的 Michael Yee。

Two topics I thought you could address. One is giving The Street some comfort about, obviously, what's been in the news recently, U.K. and more broadly speaking, the confidence that, that region will work itself out and to be specific, whether just a better pharmacoeconomic value drug will help solve that equation? And the second question is a pipeline question. You talked very nicely about AAT. You did say there's a second one coming in. Are those combinable? Are they similar? Just more potent? Maybe talk to how having 2 could actually be better than one or maybe I'm getting ahead of myself?

我想你可以談談這兩個主題。一方面，這顯然給華爾街帶來了一些安慰，因為最近新聞報道了英國乃至更廣泛的地區的情況，人們相信該地區會自行解決問題；另一方面，人們也想知道，一種藥效經濟價值更高的藥物是否能夠幫助解決這個問題。第二個問題與管道輸送有關。你對AAT的評價非常好。你之前說過還有第二輛即將到貨。它們可以組合使用嗎？它們相似嗎？只是效力更強？或許可以談談為什麼有兩個孩子其實比一個孩子好，還是我想得太遠了？

Mike, it's Stuart. I'll take the first question on the U.K. I mean, before I go on to the U.K., I do want to reference here, we made great progress from a reimbursement point of view in 2018. And that's reflected in the results we were able to share with you today, important agreements in places like Australia and Sweden and Denmark last year, and we've continued that momentum into 2019, where we have secured new agreements in places like Israel and Luxembourg and the pricing agreement for ORKAMBI for 6- to 11-year-old kids in Germany. So we continue to make great progress, getting access for patients around the world. Where we have been successful, in large part, is due to those countries using what we would consider to be appropriate methodologies to assess the value of these unique and transformative medicines. And because our goal is to get access for all eligible patients, we are continuing to pursue that with every bit of energy we can in the U.K. I think it's important to split the U.K. up. As you probably know, Mike, from a health care perspective, the U.K. is managed as a devolved country, so each country has its own process. So in Scotland, we've made great progress. We've reached an agreement with them about how they're going to assess our medicines, and we've submitted or on the verge of submitting ORKAMBI and SYMKEVI to the Scottish government. And we are optimistic we'll get access there, hopefully in 2019. In England, unfortunately, we are yet to reach an agreement with them on what we would consider to be an appropriate methodology, but we're certainly not going to give up on that. We're going to continue to fight to get access for patients in England, as we have for patients around the rest of the world. The last thing I'll say to you is that we know what the results will look like, even if we put the triple combination regimen through the existing NICE methodology, even if the results are as good as we saw with 659 in the Phase III study that we released in November. And even those results, when put into the NICE model, don't come out with a valuation, which we think in any way gets close to valuing the transformative nature of these medicines. And so even for the triple, we are going to continue to need to work with England to change the assessment methodology for our medicines. On the AAT question, I think I'll hand over to Jeff.

麥克，我是史都華。我先回答關於英國的第一個問題。我的意思是，在談到英國之前，我想先提一下，2018 年我們在報銷方面取得了巨大進展。這一點也體現在我們今天與大家分享的成果中，例如去年在澳洲、瑞典和丹麥等地達成的重要協議，並且我們在 2019 年繼續保持了這一勢頭，在以色列和盧森堡等地獲得了新的協議，以及在德國為 6 至 11 歲兒童制定的 ORKAMBI 定價協議。因此，我們持續取得巨大進展，讓世界各地的患者都能獲得醫療服務。我們之所以能夠取得成功，很大程度上是因為這些國家採用了我們認為合適的方法來評估這些獨特且具有變革意義的藥物的價值。因為我們的目標是讓所有符合資格的患者都能獲得醫療服務，所以我們正在英國竭盡全力地繼續推進這項工作。我認為將英國劃分成不同的地區非常重要。麥克，你可能知道，從醫療保健的角度來看，英國是一個權力下放的國家，因此每個國家都有自己的流程。所以在蘇格蘭，我們取得了巨大的進步。我們已經與他們就如何評估我們的藥物達成了協議，並且我們已經向蘇格蘭政府提交了 ORKAMBI 和 SYMKEVI，或者即將提交。我們樂觀地認為我們能夠獲得進入該區域的權限，希望能在 2019 年實現。遺憾的是，在英國，我們尚未與他們就我們認為合適的方法達成一致，但我們肯定不會放棄。我們將繼續為英國患者爭取醫療服務，就像我們為世界其他地區的患者爭取醫療服務一樣。最後我想告訴大家的是，即使我們按照現有的 NICE 方法對三聯療法進行評估，即使結果像我們在 11 月發布的 III 期研究中 659 例患者那樣好，我們也知道結果會是什麼樣子。即使將這些結果代入 NICE 模型，也無法得出我們認為能夠體現這些藥物變革性本質的估值。因此，即使是三聯療法，我們也需要繼續與英格蘭合作，改變我們藥物的評估方法。關於AAT的問題，我想我會把問題交給傑夫。

Mike, it's Jeff. Thanks for the question on AAT. In many ways, I think -- you can think of this as a very important lesson that we learned from our CFTR next gen program. And we sort of have this thing here at Vertex, crack the biology, then pour on the chemistry. We believe we have cracked the biology of AAT. We have multiple correctors that can refold the protein and caused it to be secreted from liver cells in a functional form. And so we started pouring on the chemistry about a year, 1.5 years ago and -- to create multiple molecules. And the reasoning is just that our experience, as with the CFTR next-gen correctors, is they get better and better, and we like to take more than one molecule into the clinic because it's a portfolio risk mitigation strategy, if you will. Obviously, these molecules have to not only be efficacious, they have to have the right PK, they have to have the right drug-drug interaction, they have to be tolerable. And so our strategy with AAT, and frankly with most of the programs you will see us bring forward, is going to be to pour the chemistry on, create multiple molecules, bring those forward in the clinic and compare them in early small studies, and we can get a pretty quick idea of which are the best molecules. And so these 2 AAT molecules, we don't think of them as additive. We really think of them as different molecules that we're going to compare. And by the way, you shouldn't be surprised to see us bringing a third one forward as well because, as I say, we just continue to get sort of better and better properties.

麥克，我是傑夫。感謝您提出關於AAT的問題。在很多方面，我認為——你可以把這看作是我們從 CFTR 下一代計劃中學到的一個非常重要的教訓。在 Vertex，我們有點這樣，先攻克生物學難題，再深入研究化學。我們相信我們已經破解了AAT的生物機制。我們擁有多種校正劑，可以重新折疊蛋白質，並使其以功能形式從肝細胞分泌出來。因此，大約一年半前，我們開始投入大量精力研究化學，以創造多種分子。理由很簡單，就像 CFTR 下一代矯正劑一樣，我們的經驗是它們會越來越好，我們喜歡將不只一種分子帶入臨床，因為這是一種投資組合風險緩解策略。顯然，這些分子不僅要有效，還要有合適的藥物動力學特性，要有合適的藥物交互作用，還要有良好的耐受性。因此，我們對 AAT 的策略，坦白說，對我們即將推出的大多數項目也是如此，就是投入大量化學研究，創造多種分子，將這些分子推進臨床研究，並在早期的小規模研究中進行比較，這樣我們就能很快了解哪些分子是最好的。因此，我們不認為這兩個 AAT 分子是相加的。我們實際上是將它們視為不同的分子，需要進行比較。順便說一句，你們也不應該對我們推出第三部作品感到驚訝，因為正如我所說，我們一直在不斷獲得越來越好的房產。

Our next question comes from Geoffrey Porges of Leerink.

我們的下一個問題來自 Leerink 公司的 Geoffrey Porges。

First, of the 18,000 patients, could you give us a sense of how many come from the U.S. and, ideally, how many come from Europe? And secondly, could you give us the breakout for KALYDECO, ORKAMBI and SYMDEKO by the main geographies? And then just a question for you Paul. Are you comfortable that we should model that 21% to 22% tax rate in our models going forward beyond 2019? I think that's what you suggested but wanted to clear about that.

首先，在這 18,000 名患者中，您能否大致說明有多少人來自美國，理想情況下，又有多少人來自歐洲？其次，能否請您依主要地區提供 KALYDECO、ORKAMBI 和 SYMDEKO 的細分資料？保羅，我還有一個問題想問你。您是否認為我們應該在 2019 年以後的模型中繼續採用 21% 至 22% 的稅率？我想這就是你建議的，但我想確認一下。

Jeff, it's Stuart. I'll take the first couple of questions there. Of the 18,000 patients who are actively treated now, it's about 2/3 in the U.S. and about 1/3 ex U.S. In terms of the breakout of the geographies in terms of the products, for Q4, for our Q4 revenues, for KALYDECO, the U.S. was $164 million, ex U.S. was $95 million. For ORKAMBI, the U.S. was $225 million and ex U.S. was $90 million. And for SYMDEKO in the U.S., it was $286 million and ex U.S. was $8 million, largely reflecting the launch that we just began to execute in Germany. So that's the breakout for the quarter. If you want to have the annual ones, I'd be happy to catch up with you after the call.

傑夫，我是史都華。我先回答前幾個問題。目前接受積極治療的 18,000 名患者中，約有 2/3 在美國，約有 1/3 在美國以外。就產品而言，第四季度我們 KALYDECO 的營收中，美國為 1.64 億美元，美國以外為 9,500 萬美元。ORKAMBI 在美國的銷售額為 2.25 億美元，在美國境外的銷售額為 9,000 萬美元。SYMDEKO 在美國的銷售額為 2.86 億美元，美國以外地區的銷售額為 800 萬美元，這主要反映了我們剛開始在德國執行的上市計畫。這就是本季的業績突破情況。如果你想進行年度例行檢查，我很樂意在通話結束後與你聯繫。

Jeff, it's Paul. Thanks for the question. And I'm going to give a little bit more detail than your specific question, just to kind of let you know how we're thinking about taxes. So in 2019, we expect the effective tax rate to be 21% or 22% for the full year and it's primarily driven by a noncash U.S. federal tax provision. And in future years, we expect that the rate could actually go lower due to geographic mix of income as our revenues continue to grow and our business advances globally. I'm not going to actually be able to give you what that rate is until we kind of get visibility of reimbursement in Europe. And then the other point I just want to make for everyone is that the majority of the guidance on the effective tax rate is noncash. And we expect to pay only approximately $25 million of cash taxes in 2019, compared to the $16 million that we're going to pay in 2018.

傑夫，我是保羅。謝謝你的提問。我還要就你提出的具體問題提供一些更詳細的信息，讓你了解我們是如何考慮稅收問題的。因此，我們預計 2019 年全年實際稅率為 21% 或 22%，這主要是由非現金的美國聯邦稅收準備金所驅動的。未來幾年，隨著收入持續增長和業務在全球範圍內發展，由於收入的地域組成變化，我們預計這一比率實際上可能會下降。在我們對歐洲的報銷情況有更清晰的了解之前，我無法準確地告訴你具體的報銷比例。還有一點我想跟大家強調，那就是關於實際稅率的大部分指引都是非現金的。我們預計 2019 年只需繳納約 2,500 萬美元的現金稅款，而 2018 年我們將繳納 1,600 萬美元。

Our next question comes from Phil Nadeau from Cowen and Company.

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

Just a couple on revenue growth drivers. So in the 2019 guidance, could you give us some sense of how much of the revenue growth is coming from existing geographies with existing labels and -- versus how much is coming from label expansions that you expect to get in 2019? And then second question on the portfolio agreements that you referenced, can you remind us which countries currently have portfolio agreements and how you go about negotiating portfolio agreements in the additional territories? Do you have to wait for an approval? Or is it something you can do proactively before, for example, the triples are approved?

僅舉兩例關於營收成長驅動因素的例子。那麼在 2019 年的業績指引中，您能否大致說明一下，營收成長有多少來自現有地區和現有品牌，又有多少來自您預計在 2019 年實現的品牌擴張？第二個問題是關於您提到的投資組合協議，您能否提醒我們目前哪些國家與其他國家簽訂了投資組合協議，以及您是如何在其他地區談判簽訂投資組合協議的？需要等待批准嗎？或者，這是否可以在三方協議獲得批准之前主動採取？

Yes. So I'll take both of those. In terms of the 2019 guidance, that reflects really 3 things. One is the sort of annualizing of the SYMDEKO launch in the U.S. into '19, also the annualizing effect of the label expansions we saw for both KALYDECO and ORKAMBI in 2018, and a contribution from countries where we were able to achieve new reimbursement agreements in 2018. In 2019, we are not expecting a large contribution from new launches because we don't have as many of those in 2019. Probably the most notable that we are assuming within our guidance is for the SYMDEKO in patients ages 6 to 11 and so that would be a new label expansion there. But the vast majority of it is coming from patients for whom we are labeled to get today. Just like to reiterate as well, it also assumes only revenues in geographies where we have reimbursement agreements today. But if we were able to get significant new reimbursement agreements in 2019 and if they were material, then we would potentially have an upside to our revenue and update our guidance at that time. In terms of which companies have portfolio agreements, if you've seen one portfolio agreement -- you've seen one portfolio agreement, Phil. So it would be difficult to describe them all, but we have them, for instance, in places like Ireland. We have an agreement in Australia, where we have a path to getting SYMDEKO reimbursed when it's approved by the TGA, Denmark, The Netherlands. And so there is a number of different portfolio agreements, they are all slightly different. In terms of do we need to have regulatory approvals to get portfolio agreements? Again, that varies country by country. But actually, many countries are well aware of how quickly our portfolio is advancing and how impressive the results look from our triple combination regimens. And so there's a significant interest from governments to be looking at these portfolio agreements, even in advance of regulatory approval. Indeed, one of the countries we were talking about early on, England, has been one of those markets that has expressed an interest in those portfolio agreements. And remember, the key to those is that they are a win-win-win for us, for patients and for the government. The win for us is that we would like to be able to have reimbursement agreements which kick in as soon as regulatory approval has been agreed. They're a win for physicians and patients who get to choose the best Vertex medicine as soon as they are approved. And they're a win for governments because they give them a level of budget certainty in treating their CF patients.

是的。那我兩個都要。就 2019 年的指導方針而言，這實際上反映了 3 件事。一是 SYMDEKO 在美國的上市規模在 2019 年得以延續，二是 KALYDECO 和 ORKAMBI 在 2018 年的標籤擴展所帶來的年度化效應，三是我們在 2018 年達成新的報銷協議的國家所做出的貢獻。2019 年，我們預期新產品發表不會帶來太大貢獻，因為 2019 年新產品發表數量不多。在我們制定的指導原則中，最值得注意的可能是 SYMDEKO 用於 6 至 11 歲的患者，因此這將是一個新的適應症擴展。但絕大多數病例都來自我們今天被診斷為需要治療的患者。再次重申一下，這也只是假設了我們目前已簽訂報銷協議地區的收入。但是，如果我們在 2019 年能夠獲得重要的新的報銷協議，並且這些協議是實質性的，那麼我們的收入可能會有所增長，屆時我們將更新我們的業績指引。至於哪些公司擁有投資組合協議，如果你看過一份投資組合協議──菲爾，你就只看過一份投資組合協議。因此很難一一描述它們，但例如在愛爾蘭這樣的地方，我們確實能找到它們。我們在澳洲、丹麥和荷蘭都有一項協議，規定當 SYMDEKO 獲得 TGA 批准後，我們將獲得報銷。因此，存在許多不同的投資組合協議，它們都略有不同。就獲得投資組合協議而言，我們是否需要獲得監管部門的批准？同樣，這種情況因國家而異。但實際上，許多國家都清楚地意識到我們的產品組合發展速度有多快，以及我們的三聯療法的效果有多顯著。因此，各國政府對這些投資組合協議表現出了濃厚的興趣，甚至在獲得監管機構批准之前就已經開始關注。事實上，我們之前提到的國家之一——英國，就是對這些投資組合協議表示出興趣的市場之一。記住，關鍵在於這些措施對我們、病人和政府來說是三贏的。對我們來說，最大的好處是我們希望能夠達成報銷協議，一旦監管部門批准，該協議就能立即生效。對於醫生和患者來說，這是雙贏之舉，因為他們可以在 Vertex 藥物獲得批准後立即選擇最好的藥物。而且，這對政府來說也是一件好事，因為這能讓政府在治療囊性纖維化患者方面獲得一定程度的預算確定性。

That's helpful. Maybe just one follow-up on the portfolio agreements. You mentioned Ireland, Australia, Denmark and Netherlands. So as we model 2019 SYMKEVI sales, would it be reasonable to expect revenue from those 4 territories as well as Germany?

那很有幫助。或許只需要就投資組合協議做一次後續跟進。你提到了愛爾蘭、澳洲、丹麥和荷蘭。因此，在預測 2019 年 SYMKEVI 銷售額時，是否可以合理預期這 4 個地區以及德國都能帶來收入？

So in countries in the EU, where we have a regulatory approval for 12 plus, where those portfolio agreements are in place, we will be able to get access relatively quickly. I would remind you, though, that, in large part, SYMKEVI is indicated for the same population as ORKAMBI. And in places like Ireland, for instance, and the Netherlands, we've seen a very impressive uptake of ORKAMBI and very high persistence rate. So whilst patients and physicians will have a choice, essentially, they'll be trading up, which they think is the best medicine.

因此，在歐盟國家，如果我們獲得了 12 歲以上人口的監管批准，並且已經達成了投資組合協議，我們將能夠相對快速地獲得市場准入。不過，我要提醒您，SYMKEVI 在很大程度上適用於與 ORKAMBI 相同的人。例如在愛爾蘭和荷蘭等地，我們看到 ORKAMBI 的普及率非常高，而且持續使用率也非常高。因此，雖然患者和醫生將有選擇權，但本質上，他們將選擇更好的藥物，他們認為這是最好的藥物。

Our next question comes from Alethia Young of Cantor Fitzgerald.

我們的下一個問題來自 Cantor Fitzgerald 公司的 Alethia Young。

Can you hear me?

你聽得到我嗎？

Can hear you now.

現在能聽到你說話了。

Yes. Okay, cool. Maybe got the wrong -- my headset. Sorry, I apologize. I just wondered if you could talk a little bit about kind of your thoughts on the M&A. I mean, you have a pipeline that's coming together, obviously, internally, but I just wanted to talk a little bit about what you might think as supplemental and interesting around doing external M&A or anything like that. And then also, is that kind of delayed until you kind of figure out the CFO position as well?

是的。好的，明白了。可能是我拿錯了──我的耳機。對不起，我道歉。我只是想問您能否談談您對併購的看法。我的意思是，你們內部顯然已經有了一套正在逐步完善的管道，但我只是想稍微談談你們認為在進行外部併購或其他類似活動方面有哪些補充和有趣的想法。另外，是不是要等到你確定了財務長的職位之後，這件事才能提上日程呢？

Yes. Alethia, this is Jeff. I'll take those. As you know, for the last couple of years, we've been talking about a consistent, what I'll call, external innovation strategy, not just M&A but licensing, collaboration, et cetera. It's really focused around 3 areas. The first is obviously CF, where anything that we feel will be complementary or additive to our current regimens would be of great interest to us. Honestly, we're seeing less and less in that particular bucket simply because we've set such a high bar now with the triple combination data. The second area is what I'll call technology and tools. We've had a very concerted effort to build a complete toolbox of technologies that we think would allow us to address the kind of serious diseases and to some extent, genetic diseases that we're interested in on our pipeline. And you've seen us do a number of those deals. So CRISPR, Arbor, X-Chem and Genomics plc, those are all deals who you should think of as acquiring different tools that will let us optimally address the diseases that we're interested in. You should expect to see us continue to do that in areas of interest, nucleic acid therapies, gene therapies, et cetera. And then the third area would obviously be pipeline assets. And those pipeline assets would be consistent with our overall strategy of transformative medicines for serious diseases in specialty markets. And you should expect to see us do some of those as we find them. In general, they'll be earlier stage development assets, where we think we can add value through our clinical development, regulatory and commercial groups. What you won't see us doing is deals for on-market or late-stage products that are essentially there to buy revenue growth over the next 5 to 7 years, simply because we don't need that revenue growth. CF is going to provide that. And so you can expect to see us continue to do deals around those 3 focused areas. I would say that we're obviously building substantial financial firepower to do more of those deals, and we've ramped up our external innovation group to allow us to do that. And so I do think it's fair for you to expect to see us complement our very rapidly advancing internal pipeline with some external innovation as well.

是的。阿萊西亞，這位是傑夫。我收下那些。如你所知，在過去的幾年裡，我們一直在討論一種持續的、我稱之為外部創新策略的策略，它不僅包括併購，還包括授權、合作等等。它主要集中在三個方面。首先顯然是囊性纖維化（CF），任何我們認為可以補充或增強我們現有治療方案的東西都會引起我們的極大興趣。說實話，我們看到的這類數據越來越少，只是因為我們現在對三重組合數據的要求非常高。第二個領域我稱之為科技和工具。我們一直齊心協力地建造一套完整的技術工具箱，我們認為這些技術將使我們能夠解決我們研發管線中感興趣的各種嚴重疾病，以及在某種程度上解決遺傳性疾病。您也看到我們完成了不少這樣的交易。所以，CRISPR、Arbor、X-Chem 和 Genomics plc，這些都是你應該理解為收購不同工具的交易，這些工具將使我們能夠以最佳方式解決我們感興趣的疾病。你們應該會看到我們繼續在感興趣的領域進行這項工作，例如核酸療法、基因療法等等。第三個領域顯然是管道資產。這些在研產品與我們針對專科市場嚴重疾病研發變革性藥物的整體策略是一致的。你們應該會看到我們在發現這些機會後進行一些嘗試。一般來說，這些資產屬於早期開發階段，我們認為可以透過我們的臨床開發、監管和商業團隊為其增值。我們不會進行那些旨在未來 5 到 7 年內實現收入成長的已上市或後期產品的交易，因為我們不需要這種收入成長。CF將會提供這一點。因此，您可以期待我們繼續圍繞這三個重點領域開展交易。我認為，我們顯然正在累積雄厚的財力來達成更多此類交易，而且我們已經加強了外部創新團隊，使我們能夠做到這一點。因此，我認為你們有理由期待我們除了快速發展的內部研發管線之外，還會引進一些外部創新。

And our next question comes from Geoff Meacham of Barclays.

下一個問題來自巴克萊銀行的傑夫·米查姆。

I know the point is still, obviously, to select the NDA for the triple coming up in the first half. I just wanted to ask if your points of differentiation between the 2 or the metrics have changed at all. In other words, like is it still about FEV1 and maybe less about pulmonary exacerbations or the like? And then also when you look at the part of the package, is there anything that has yet to be done in terms of nonclinical or that could be perhaps a gating factor or something that could push you to the second half of the year versus the end of 2Q of your guidance? And I have one follow-up.

我知道重點顯然仍然是選擇上半年即將開始的三項任務的保密協議。我只是想問一下，你們對這兩者的區別判斷或衡量標準是否有所改變。換句話說，現在更關注的是 FEV1，而不是肺部急性惡化或其他類似情況嗎？此外，從方案的這一部分來看，非臨床方面是否還有什麼尚未完成，或者是否有任何可能成為阻礙因素或導致進度推遲到下半年而不是第二季末的因素？我還有一個後續問題。

Thanks, Geoff. This is Jeff. I'll take the first part, and Reshma maybe can take the second part. With respect to how we're going to compare the 2 assets, again, just -- I know you know this, but just a quick review. We -- now that the 445 trial is fully enrolled, we have very good line of sight to the timing of when we expect to see the top line data there, which is in the first quarter. So we're very confident that we'll have that kind of data that we can compare with the data that we've already reported for 659. As I said before, the way we're going to look at these 2 assets is the complete profile, if you will, of both programs. And that goes all the way back to preclinical work. It includes things like PK, PD, tolerability, drug-drug interactions as well as, of course, the efficacy measurements that you talked about with FEV1, but also things like sweat chloride. So this will be a very complete review of both assets. We're in the nice position of having a nice complete file on both assets once we get the 445 data, and I think we'll be able to then pick the best asset to move forward. And again, we're very much on track to do that in the first quarter. We're confident that we will be able to make that decision on schedule in the first quarter, which will allow that midyear NDA filing. But I'll let Reshma address the second part of the question with respect to the package and what's there.

謝謝你，傑夫。這是傑夫。第一部分我來做，第二部分或許可以給雷什瑪。關於我們如何比較這兩個資產，再次說明一下——我知道你們都知道，但還是簡單回顧一下。現在 445 試驗已全部招募完畢，我們對何時能看到主要數據的時間有了非常清晰的了解，預計會在第一季看到。因此，我們非常有信心能夠獲得可以與我們已經報告的 659 的數據進行比較的那種數據。正如我之前所說，我們將從這兩個項目的完整概況來看待它們。而這可以追溯到臨床前研究時期。它包括藥物動力學、藥效學、耐受性、藥物交互作用以及您提到的 FEV1 療效測量等內容，還包括汗液氯化物等內容。因此，這將是對這兩項資產的非常全面的評估。一旦我們獲得 445 數據，我們就能擁有關於這兩個資產的完整文件，這對我們來說是一個有利的位置，我認為我們屆時將能夠選擇最好的資產繼續推進。而且，我們很有可能在第一季實現這一目標。我們有信心在第一季按計劃做出決定，這將使我們能夠在年中提交新藥申請。但關於包裹及其內容，我會讓雷什瑪來回答問題的第二部分。

Sure, sure. Thanks, Jeff. So regardless of whether the selection is for VX-659 or for VX-445, we're going to have all of the data that we need in Q1. You know that we already shared the data for VX-659 late last year. The exact same package, the same amount of the data and the same kind of data, we're going to get very shortly for 445. And with regard to packaging that up, making sure that we have the CTD complete and the NDA file, that's going to happen by mid of this year. That is something that we are very much on track for, and I have high confidence that's going to happen.

當然，當然。謝謝你，傑夫。所以無論選擇的是 VX-659 還是 VX-445，我們都將在第一季獲得所需的所有數據。你知道，我們已經在去年底分享了 VX-659 的數據。我們很快就會收到完全相同的數據包，相同數量和相同類型的數據，用於 445。至於打包工作，確保我們完成 CTD 和 NDA 文件，這將在今年年中完成。這件事我們正按計劃穩步推進，我對此充滿信心。

Okay. And then just a follow-up. I know this was asked about the reimbursement OUS. I know in the past, you guys have had a pretty defined strategy of allowing kind of the patient community to sort of to escalate and maybe to put some pressure on the payers. And this, obviously, has been the case in the U.K. and in France. But I want to ask for the triple, is there a different methodology or just something you can do differently maybe to help accelerate your reimbursement looking OUS, maybe just do things a little bit differently that could help speed up a process?

好的。然後還有一個後續問題。我知道有人問過關於美國境外報銷的問題。我知道過去你們制定了一項相當明確的策略，允許患者群體逐步升級訴求，並可能對支付方施加一些壓力。很顯然，英國和法國的情況正是如此。但我想問的是，對於三重賠償，是否有不同的方法或您可以採取一些不同的措施來幫助加快您的報銷速度？對於美國境外的賠償，或許可以稍微改變處理方式，加速流程？

Yes, Geoff, it's Stuart here. I mean, I wouldn't say that it's our strategy to get patients to put pressure on people. As you know, our development plans in cystic fibrosis are no secret to anybody. The community is very well aware of the progress we're making, very well aware of the clinical benefits these products look like they are delivering. And so I think, quite rightly, they are calling on their elected officials to get access to these medicines. I'll refer back to what I said earlier. The key here from a kind of health technology assessment point of view is that the methodology needs to be appropriate for these types of medicines, which are going to be used very early in people's lives, hoping to restore them to normal levels of chloride transport and deliver benefits over the very, very long term. And frankly, the assessment methodologies are not really fit for purpose to assess those types of medicines. So from a health technology assessment point of view, that is what we are continuing to work on and where we've done that, which is, in many, many countries around the world, we've been successful. And then the other thing that I think is an important component of this is where we've been successful, I think, in a substantial portion of the time is because a senior government ministers have taken an interest in this issue, been able to see our portfolio and how fast it's developing, the kind of benefits it could bring to their population. And so to me, those are 2 of the most important success factors in the U.K. and everywhere else around the world.

是的，傑夫，我是史都華。我的意思是，我不會說我們的策略是讓病人給別人壓力。如您所知，我們在囊性纖維化領域的研發計畫已不是什麼秘密。社群非常清楚我們所取得的進展，也非常清楚這些產品似乎帶來的臨床益處。所以我認為，他們呼籲民選官員確保民眾能夠獲得這些藥物，這是完全正確的。我會再提及我之前說過的話。從健康技術評估的角度來看，關鍵在於該方法必須適用於這類藥物，因為這類藥物將在人們生命早期使用，希望能夠恢復他們正常的氯化物轉運水平，並在非常非常長的時間內帶來益處。坦白說，這些評估方法並不真正適合評估這類藥物。所以從衛生技術評估的角度來看，這就是我們正在繼續努力的方向，而且在世界許多國家，我們已經成功了。我認為另一個重要的部分是，我們之所以在相當長的一段時間內取得成功，是因為政府高級部長們對這個問題很感興趣，能夠看到我們的工作內容及其發展速度，以及它能為民眾帶來的好處。因此，在我看來，這是英國乃至全世界最重要的兩個成功因素。

And our next question comes from Paul Matteis of Stifel.

下一個問題來自 Stifel 公司的 Paul Matteis。

Two-part question on a VX-150. I guess, first of all, can you guys talk about the logic of doing more dose ranging work here? Given that you have a few positive Phase IIs, a low AE rate and there's a big unmet need for an opioid alternative, we were just wondering why not move faster into Phase III. And then secondarily, I was wondering if all strategic options for VX-150 are still on the table. And have you confirmed that you'll take this, as far as yourselves, at least to a targeted subset? Or is an out-licensing still a possibility?

關於VX-150的兩部分問題。我想，首先，你們能談談在這裡進行更多劑量範圍研究的邏輯嗎？鑑於你們已經取得了一些積極的 II 期臨床試驗結果，不良事件發生率較低，而且對阿片類藥物替代品的需求很大，我們只是想知道為什麼不加快進入 III 期臨床試驗。其次，我想知道 VX-150 的所有策略選擇是否仍然有效。你們是否已經確認，至少在你們自己看來，會將這項技術推廣到特定群體？或者，對外授權仍然是一種可能嗎？

Sure, thing. This is Reshma. Let me take the first half of your question, and then I'll pass it on to Jeff for the second half of your question. So with regard to VX-150, which is our NaV1.8 inhibitor that you pointed out we've had now 3 out of 3 successful studies in osteoarthritis, in small fiber neuropathy, as well as in bunionectomy. The reason that we're doing dose ranging is really 2 very simple points. One is regulatory. Regulators expected to do dose ranging, and really, what they're looking for us to do is to find the lowest efficacious dose. And so one is just a very practical point around the regulators. The second point is around just a good drug development. What we did in order to get a proof of mechanism readout is we chose a high dose. Now what we need to do is to figure out what is the exposure response relationship. Of course, that has important implications for picking not only the lowest efficacious dose, but also what the dose will be, which informs pill size and that informs COGS and other such things. So that's really what we're doing. I do want to let you know that the update on that one is that the Phase IIb is now fully enrolled, so we're going to be in a good spot to understand all of those pieces of information in the near future.

當然可以。這是雷什瑪。讓我來回答你問題的前半部分，然後我會把後半部分交給傑夫回答。所以，關於您提到的我們的 NaV1.8 抑制劑 VX-150，我們在骨關節炎、小纖維神經病變以及拇外翻切除術方面已經取得了 3 項研究全部成功的成果。我們進行劑量範圍測定的原因其實很簡單，就兩點。一是監管方面。監管機構希望進行劑量範圍測試，實際上，他們希望我們找到最低有效劑量。因此，其中一點是關於監管機構的非常實際的問題。第二點是關於如何進行良好的藥物研發。為了獲得機制讀數的證明，我們選擇了高劑量。現在我們需要做的是弄清楚暴露反應關係是什麼。當然，這不僅對選擇最低有效劑量有重要影響，而且對劑量本身也有重要影響，劑量決定了藥片的大小，而藥片的大小決定了成本和其他類似因素。所以，這才是我們正在做的。我想告訴大家，關於這項研究的最新進展是，IIb 期試驗現在已經全部招募完畢，所以我們很快就能了解所有這些資訊。

And maybe I'll take the second part. The question is really a commercial strategy question, I think. As I said before, we don't think of pain as a single commercial market. We think of it as multiple markets. As an example, acute pain, which is essentially postsurgical, post-procedural pain, mostly in hospitals, outpatient surgery centers or a dentist's office, is in itself a multibillion-dollar opportunity. Typically, you'd like to have both an IV and an oral form of the new analgesic in that market. That's very much a specialty market. We think we can address large parts of that market ourselves, and it would be our plan, as soon as we have the data that supports it, to pursue development and commercialization in that market ourselves. Small fiber neuropathy, similarly, a market that's typically in a set of pain specialist offices. It's a market that can be addressed. It's a specialty market, and it's one that, again, with appropriate data, we feel we could develop and commercialize ourselves, very, very different from the chronic inflammatory pain. That's OA, low back pain, et cetera. That's predominantly a primary care market and from our perspective, it's not a market that we would want to build a commercial presence in or develop, and that's one where you might see us go with a partner. We have had a fair amount of interest, as you might imagine, given this first or only class of analgesics from partners who have a lot of experience in these community pain markets. Does that answer your question about our commercial strategy?

或許我會選擇第二部分。我認為這實際上是一個商業策略問題。正如我之前所說，我們並不把疼痛視為單一的商業市場。我們將其視為多個市場。例如，急性疼痛（本質上是手術後、手術後疼痛，主要發生在醫院、門診手術中心或牙醫診所）本身就是一個價值數十億美元的商機。通常情況下，你希望市面上既有靜脈注射劑型的新型止痛藥，也有口服劑型的新型止痛藥。那是一個非常小眾的市場。我們認為我們可以自行開拓該市場的大部分領域，一旦我們掌握了支持這一想法的數據，我們的計劃就是在該市場自行進行開發和商業化。同樣，小纖維神經病變也屬於疼痛專科診所的範疇。這是一個可以開拓的市場。這是一個專業市場，而且，我們覺得，只要有適當的數據，我們就可以自行開發和商業化，這與慢性發炎疼痛非常非常不同。那是骨關節炎、腰痛等等。那主要是一個初級保健市場，從我們的角度來看，我們不想在這個市場建立商業存在或進行開發，你可能會看到我們與合作夥伴一起進入這個市場。正如您所料，由於這是首個（或唯一）類鎮痛藥，我們收到了相當多的關注，這些合作夥伴在社區疼痛市場擁有豐富的經驗。這樣回答了您關於我們商業策略的問題嗎？

Yes, it does.

是的，確實如此。

Our next question comes from Terence Flynn of Goldman Sachs.

下一個問題來自高盛的特倫斯·弗林。

I was just wondering if you can at all help us quantify the impact of improved persistence on SYMDEKO relative to ORKAMBI and maybe how this compares to KALYDECO, recognizing you have a lot more data on KALYDECO now. I think you've announced 5 years plus [in that].

我只是想問一下，您能否幫助我們量化 SYMDEKO 相對於 ORKAMBI 的持久性改進所帶來的影響，以及它與 KALYDECO 的比較情況，因為您現在掌握了更多關於 KALYDECO 的數據。我認為你已經宣布了五年以上的時間（在那件事上）。

Yes. Terence, without getting into the exact specifics and kind of the exact numbers because these things fluctuate over time and obviously SYMDEKO with 12 months into the launch, ORKAMBI or KALYDECO is more like 6 years, but certainly, the persistence we've seen on SYMDEKO is, as we anticipate, higher than we saw with ORKAMBI. It's not quite at the level that we saw with KALYDECO, which were the highest, personally, I've ever seen for any medicines in the many years I've been doing this. So it's somewhere between ORKAMBI and KALYDECO, but SYMDEKO is certainly is above ORKAMBI.

是的。Terence，我不想透露具體細節和確切數字，因為這些事情會隨著時間推移而波動，而且很明顯，SYMDEKO 上市 12 個月後，ORKAMBI 或 KALYDECO 上市時間更接近 6 年，但可以肯定的是，正如我們所預期的，SYMDEKO 的持久性高於 ORKAMBI。雖然還沒有達到 KALYDECO 的水平，但就我個人而言，KALYDECO 的水平是我從事這項工作多年來見過的所有藥物中最高的。所以它介於 ORKAMBI 和 KALYDECO 之間，但 SYMDEKO 肯定比 ORKAMBI 更勝一籌。

Okay. And then any more details you can give us on the patient mix for SYMDEKO? And have you guys seen any warehousing in the U.S. ahead of the triple combo potential launch?

好的。那麼，您能否提供更多關於SYMDEKO患者組成方面的資訊？你們有沒有在美國看到任何針對三合一產品潛在上市的倉儲情況？

So in terms of the uptake, we've actually seen broader uptake for SYMDEKO across all of the patient groups that you would expect. It's been taken up rapidly in naive patients, patients who've never been on ORKAMBI, those who were discontinued from ORKAMBI. And then we've also seen a fair number of patients switch from either ORKAMBI to KALYDECO. So we've really seen an uptake broadly across all of the eligible patient populations.

因此，就接受度而言，我們實際上已經看到 SYMDEKO 在所有預期的患者群體中得到了更廣泛的接受。它迅速地被初次接受治療的患者、從未服用過 ORKAMBI 的患者以及停用 ORKAMBI 的患者所接受。此外，我們也看到相當多的患者從 ORKAMBI 轉而使用 KALYDECO。因此，我們已經看到所有符合條件的患者群體都普遍接受了這種療法。

Our next question come from Robyn Karnauskas of Citi.

下一個問題來自花旗銀行的 Robyn Karnauskas。

So actually -- so first of all -- first, switching to SYMDEKO. What are you learning about ORKAMBI patients or KALYDECO patients that are switching on to SYMDEKO, given that there's a longer patent life for SYMDEKO and the triple going forward? Are you seeing the switching in line with expectations? Do you think it'll be captive suddenly? The second question is just a follow-up on Alethia's question. It seems like a change from JPMorgan that you might look externally for a pipeline asset. I remember, at JPMorgan, you discussed looking more for a platform to develop your -- if you have the science to develop new drugs. Are you just seeing something in the market? Or are things looking cheaper? What might have changed? Or how are you thinking about it differently?

所以實際上——所以首先——首先，切換到 SYMDEKO。鑑於 SYMDEKO 及其三重療法的專利保護期更長，您了解到 ORKAMBI 患者或 KALYDECO 患者轉而使用 SYMDEKO 的情況如何？您認為這種轉變符合預期嗎？你認為它會突然被俘虜嗎？第二個問題只是阿萊西亞問題的後續提問。這似乎與摩根大通的做法有所不同，他們可能會從外部尋找管道資產。我記得，在摩根大通的時候，你曾討論過要尋找一個平台來發展你的技術——如果你有研發新藥的科學技術的話。你只是在市場上看到了一些東西嗎？還是價格看起來更便宜了？可能有哪些變化？或者你有什麼不同的思考方式？

Robyn, it's Stuart here. I'll take the first question and then Jeff can take the pipeline and external innovation question. So in terms of what we're seeing with patients who switch from KALYDECO to SYMDEKO or ORKAMBI to SYMDEKO, I mean, generally, we're seeing those patients have a great experience. We aren't seeing many of those patients either discontinue or kind of go back to their original medication. As you know, from the data in the RF population, we saw tezacaftor add substantial clinical benefit on top of ivacaftor. So that, I think, is what's driving the majority of people who are making that transition. Obviously, with SYMDEKO or ORKAMBI, we don't have as much in the way of direct comparative data, but I think it's the overall benefit/risk profile of SYMDEKO that I think people are finding attractive. And that transition is going in line with our expectations. Then in terms of the external innovation, I'll hand that back to Jeff.

羅賓，我是史都華。我先回答第一個問題，然後傑夫可以回答關於產品線和外部創新的問題。所以就我們從 KALYDECO 換用 SYMDEKO 或 ORKAMBI 換用 SYMDEKO 的患者身上看到的，我的意思是，總的來說，我們看到這些患者的體驗都很好。我們沒有看到很多這樣的患者停止用藥或重新服用原來的藥物。如您所知，從 RF 族群的數據來看，我們發現 tezacaftor 在 ivacaftor 的基礎上增加了顯著的臨床效益。所以，我認為，這就是促使大多數人進行這種轉變的原因。顯然，對於 SYMDEKO 或 ORKAMBI，我們沒有那麼多直接的比較數據，但我認為 SYMDEKO 的整體收益/風險狀況正是人們覺得它有吸引力的地方。這一轉變符合我們的預期。至於外部創新方面，我會把這個任務交還給傑夫。

It's Jeff. Maybe just one other point on your question to Stuart about the switching because, obviously, this is relevant as well to the triples and it's going to depend on the data and the label and lots of other things. But I do think the strategy here is to continue to provide better and better medicines for more and more patients, including the patients who are already on our drugs. And so assuming that the data that we're seeing now in 659, which is significantly better, as you know, than SYMDEKO even in homozygous patients, we do expect, over the long terms, the vast majority of these patients will switch over to triple. So that's a sort of sideline for future. With respect to the pipeline and the BD strategy, I apologize if I miscommunicated that to you at JPMorgan, I obviously did. No, our strategy has been the same all along. So the 3 buckets of CF, as you point out, technology and tools -- and certainly, we've done lot of those deals and we'll continue to do them, but where we've always been interested in early-stage pipeline assets that meet our strategy, meaning they're potentially transformative drugs for serious diseases. As you know, they're not that easy to find, but we continue to look for them. And certainly, if we find them in diseases we're interested in, you should expect us to see -- to do in-licensing or acquisition deals on those early-stage assets.

是傑夫。關於你向 Stuart 提出的切換問題，或許還有一點需要補充，因為很明顯，這也與三元組有關，而且這取決於數據、標籤以及許多其他因素。但我認為，我們的策略是繼續為越來越多的患者提供越來越好的藥物，包括那些已經在使用我們藥物的患者。因此，假設我們現在在 659 中看到的數據（如您所知，即使在純合子患者中，它也明顯優於 SYMDEKO），我們預計，從長遠來看，絕大多數患者將會轉而接受三聯療法。所以這算是為未來發展的一個方向。關於專案儲備和業務拓展策略，如果我之前向摩根大通的各位傳達的訊息有誤，我深表歉意，顯然是我傳達錯了。不，我們的策略始終如一。正如您所指出的，CF 的三大要素是技術和工具——當然，我們已經做了很多這類交易，而且我們還會繼續做下去，但我們一直對符合我們策略的早期管線資產感興趣，這意味著它們是可能對嚴重疾病產生變革性影響的藥物。如你所知，它們並不容易找到，但我們會繼續尋找。當然，如果我們發現我們感興趣的疾病中存在這些早期資產，你們應該會期待我們進行許可引進或收購交易。

Our next question comes from Brian Abrahams with 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。

I was wondering if you could give us a little bit more color on the contribution of uptake in 2- to 5- year-olds to ORKAMBI revenues, maybe relative to background, the background dynamic of adults switching to SYMDEKO. And then separately on the triple, as you get more data in hand, I'm curious what type of translational or maybe educational work you'll need to do to bridge the shorter-term functional benefits from Phase IIIs to the long-term outcomes that you've seen with other treatments like KALYDECO that has been dosed over a course of years and whether you've had any preliminary payer discussions or feedback on that front.

我想請您詳細介紹一下 2 至 5 歲兒童的消費量對 ORKAMBI 收入的貢獻，也許可以結合背景情況，以及成年人轉向 SYMDEKO 的背景動態進行分析。另外，關於三聯療法，隨著您獲得更多數據，我很好奇您需要開展哪些類型的轉化或教育工作，才能將 III 期臨床試驗中獲得的短期功能性獲益與您在其他療法（如 KALYDECO，已持續多年給藥）中觀察到的長期療效聯繫起來，以及您是否已就此與支付方進行過任何初步討論或獲得反饋。

So Brian, I'll take the first question on ORKAMBI. So we have seen strong uptake with ORKAMBI in the 2- to 5-year-old patient groups. And as you might imagine, that kind of helped to lead to a very strong quarter for ORKAMBI and did, if you like, kind of compensate the fact that there are a number of patients who are switching from ORKAMBI to SYMDEKO. As you know, because of these dynamics with the patient populations and the same medicines being approved in those same patient populations, that's why we've really gone to getting total CF product guidance now because it's hard to be specific about each and every one of these patient population and exactly how many people are going to be on each medicine. And so that's why we've gone to total CF product revenues now. And then in terms of the triple data, I'll hand that over to Reshma.

那麼布萊恩，我來回答關於ORKAMBI的第一個問題。因此，我們看到 ORKAMBI 在 2 至 5 歲患者群體中獲得了強烈的接受度。正如你可能想像的那樣，這在一定程度上幫助 ORKAMBI 取得了非常強勁的季度業績，並在某種程度上彌補了許多患者從 ORKAMBI 轉用 SYMDEKO 的事實。如您所知，由於患者群體存在這些動態變化，而且同樣的藥物也在相同的患者群體中獲得批准，這就是為什麼我們現在真正開始尋求全面的囊性纖維化產品指導，因為很難具體說明每個患者群體以及每種藥物的確切使用人數。所以，這就是為什麼我們現在採用CF產品總收入作為統計指標的原因。至於三重數據，我會交給雷什瑪處理。

Sure. So with regard to triple combination, as you know, the primary endpoint in both the 445 and 659 programs for the FS studies are ppFEV1 at 4 weeks and in the FMS studies, the interim analysis at 4 weeks ppFEV1. Now what's very interesting in that is the reason we decided to go forward with a ppFEV1 at 4 weeks is because, as you can imagine, we have a treasure trove of data looking at ppFEV1 over time through our KALYDECO experience, ORKAMBI and SYMDEKO. And what you see is that there is a very consistent relationship with what you see with CFTR modulators at Week 4 and what you see later on, for example, at Week 24 or Week 52. And so I think that relationship is actually reasonably well understood amongst physicians as well as patients. And the other interesting thing to note is, of course, in the FMS studies for both 659 and 445, we're going to have the 24-week ppFEV1, so we can start to do some analyses of rate of decline and such. And we are also going to have pulmonary exacerbations, BMI, CFQ-R. So there's actually quite a bit of data that's coming. And I've been very impressed with how well these studies have been understood by the community, not just the physicians, but the patients as well.

當然。因此，關於三重療法，如您所知，FS 研究的 445 和 659 計劃的主要終點是 4 週時的 ppFEV1，而 FMS 研究的主要終點是 4 週時的中期分析 ppFEV1。現在，非常有趣的是，我們決定在 4 週時進行 ppFEV1 檢測的原因是，正如您所想，我們透過 KALYDECO、ORKAMBI 和 SYMDEKO 的經驗，累積了大量關於 ppFEV1 隨時間變化的數據。你會發現，在第 4 週 CFTR 調節劑中觀察到的情況與之後（例如，在第 24 週或第 52 週）觀察到的情況之間存在非常一致的關係。所以我認為，醫生和病人對這種關係其實都有相當清楚的認知。當然，還有一點值得注意，在 659 和 445 的 FMS 研究中，我們將有 24 週的 ppFEV1，因此我們可以開始對下降率等進行一些分析。我們也將進行肺部急性惡化、BMI、CFQ-R 等評估。所以實際上會有相當多的數據發布。令我印象深刻的是，這些研究成果不僅被醫生理解，也被廣大民眾所理解。

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 guess, I was wondering if you could talk a little bit about the operating margin progression. You've obviously moved up, I don't know, 7 or 8 points this year. How should we think about that relative to the revenue growth you're talking about in 2019 and beyond?

我想請您談談營業利潤率的變化。你今年的排名顯然上升了，我不知道，大概上升了7到8分吧。我們應該如何看待這一點與您所說的 2019 年及以後的收入成長之間的關係？

Matt, it's Jeff. Actually, maybe I'll take it. It's a little more of a strategic question since we've given you the guidance for 2019. So as we look forward and you've seen over the last couple of years, there's a pretty consistent trend here of growing revenues considerably faster than operating expenses, which obviously results in operating margin expansion and increases in operating income. I think, as Paul mentioned, as we look forward to next year, we expect to see our current guidance 15% top line revenue growth, but a 21% growth in operating margin, reflecting exactly the same pattern going forward in 2019. Obviously, as we get to triples, that only accelerates because revenue grows even faster during -- after the triple launches and operating expenses, we've maintained a pretty disciplined approach. So I think as you think about this long term, without giving you long-term guidance, you should think about continued operating margin and -- expansion and operating income increases, which also results in the cash flows that Paul mentioned. Does that give you enough detail on sort of how we think of it going forward?

馬特，我是傑夫。其實，也許我會接受。既然我們已經給了 2019 年的指導方針，那麼這個問題就更具策略性了。展望未來，正如您在過去幾年中所看到的，這裡存在一個相當一致的趨勢，即收入成長速度遠超營運支出，這顯然會導致營運利潤率擴大和營運收入增加。我認為，正如保羅所提到的那樣，展望明年，我們預計目前的營收成長預期為 15%，營業利潤率成長預期為 21%，這與 2019 年的趨勢完全一致。顯然，隨著產品線的更新換代，這種情況只會加速，因為在產品線更新換代和營運支出之後，收入成長速度會更快——我們一直保持著相當嚴謹的態度。所以我認為，在考慮長期發展時，雖然我不會給予長期指導，但你應該考慮持續的營業利潤率和擴張以及營業收入的成長，這也會帶來保羅提到的現金流。這樣是否足以讓您了解我們未來的想法？

Yes, that's very helpful. And then if I can just ask one follow-up. I mean, I -- other people have asked about ex-U. S. reimbursement on the cost. I was just wondering if you can just specifically address some of the news around compulsory licensing in some ex U.S. countries and what you see is the path forward there or the likelihood of anything happening there.

是的，這很有幫助。然後，我能再問一個後續問題嗎？我的意思是，其他人也問過關於前美國的事情。S. 報銷費用。我只是想問您能否具體談談一些前美國國家強制許可的新聞，以及您認為這些國家未來的發展方向或未來可能發生的事情。

Yes. So Matt, it's Stuart here. I mean, the compulsory license issue has probably most recently been discussed. In the U.K. yesterday, there was a debate on Crown use, as they call it, in the U.K. I think it's fair to say that the government itself in that debate recognize this is a very complicated issue. It's not entirely a viable option for multiple reasons, including that it's inconsistent with their desire to foster a vibrant life sciences ecosystem. We certainly agree with their perspective on that. I would say we're not really focused or particularly concerned, frankly, about compulsory licensing. What we're focused on is finding a solution in the short term for patients that provides access to ORKAMBI as soon as we can and our pipeline of future medicines as soon as they're approved.

是的。嗨，馬特，我是史都華。我的意思是，強制駕照問題可能是最近討論得最熱烈的話題。昨天英國就英國所謂的「王室使用」問題展開了辯論。我認為可以公平地說，政府在辯論中也承認這是一個非常複雜的問題。由於多種原因，這並非一個完全可行的選擇，其中包括這與他們希望培育充滿活力的生命科學生態系統的願望不符。我們完全同意他們的觀點。坦白說，我們並沒有真正關注或特別關心強制許可製度。我們現在的重點是盡快為患者找到短期解決方案，讓他們能夠盡快獲得 ORKAMBI，並儘快獲得我們未來研發的藥物。

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。

I wanted to ask about AAT and wondering if you can talk about the potential cadence of initial clinical data and what you might expect to learn from healthy volunteers. And then I realized this is putting the cart before the horse a little here, but assuming the early clinical stage work goes well, what might a registrational pathway for this indication potentially look like? I'm curious, would you expect it to be biomarker or outcome driven? I'm just trying to broadly understand what this program may encompass.

我想問一下關於AAT的問題，想知道您是否可以談談初步臨床數據的潛在節奏，以及您可能期望從健康志願者身上了解到什麼。然後我意識到這有點本末倒置，但假設早期臨床階段的工作進展順利，那麼該適應症的註冊途徑可能會是什麼樣的呢？我很好奇，您認為它會以生物標記為導向還是以結果為導向？我只是想大致了解這個項目可能包含哪些內容。

Sure. This is Reshma. Let me take both halves of that question. With regard to the cadence of the trial, so let me describe the trial. It's a fairly typical small molecule approach that we're taking here, SAD, single ascending dose, followed by MAD, multiple ascending dose. That's going to be done in healthy volunteers. And as soon as we get through that, we're going to be ready to go into patients. The good news on this program is that it's going to be a reasonably efficient program. I don't know if it's 30, 40 people, but a reasonably efficient program for us to be able to see whether our molecule's going to have the intended effect, which is elevations in AAT level and in activity. This is a fairly standard readout, and so we expect to have that in hand in the near future as soon as we get through our healthy volunteer studies. With regard to the registration path, we're early in here, but what I can tell you is that the existing therapies, which you know are augmentation therapies, so it's an infusion of the protein, those were approved and about 4 of them are available on the market and those were approved based on AAT levels. So that's one data point that you have to start with. We have to go through our conversations with regulators to see what the Phase III registration enabling endpoints are going to be here, but I do think that's an important data point to look at.

當然。這是雷什瑪。讓我來回答這個問題的兩個部分。關於審判的節奏，讓我來描述審判過程。我們在這裡採用的是一種相當典型的小分子方法，即 SAD（單次遞增劑量），然後是 MAD（多次遞增劑量）。這項研究將在健康的志願者身上進行。一旦我們完成這些，我們就可以開始接觸病人了。這個項目的好消息是，它將是一個相當有效率的項目。我不知道是 30 人還是 40 人，但這確實是一個相當有效的計劃，讓我們能夠看到我們的分子是否會產生預期的效果，即提高 AAT 水平和活性。這是一個相當標準的讀數，因此我們預計在不久的將來，一旦我們完成健康志願者研究，我們就能獲得該讀數。關於註冊途徑，我們還處於早期階段，但我可以告訴你的是，現有的療法，也就是增強療法，也就是蛋白質輸注，已經獲得批准，其中大約有 4 種已經上市，這些療法都是根據 AAT 水平獲得批准的。所以這是你必須先掌握的數據點。我們需要與監管機構進行溝通，看看 III 期註冊的終點是什麼，但我認為這是一個值得關注的重要數據點。

And our next question comes from Hartaj Singh of Oppenheimer & Co.

下一個問題來自奧本海默公司的哈塔吉·辛格。

Just a question on the 2 triplets. I know that in November you'd also indicated you had 12-week data and 26-week data that 659 had gone through. Can you just give us an update as to how you report that, the safety data also for both the projects as the efficacy readouts are coming up?

關於那兩組三胞胎，我有個問題。我知道您在 11 月也曾表示您有 659 例病例的 12 週數據和 26 週數據。能否請您更新報告方式，以及這兩個項目在療效數據公佈前的安全數據？

Sure. So if I go back to our 659 release from late last year, I think that gives you a very good template for how you can expect to hear our share of the data for 445, which will be coming this quarter in terms of both safety and efficacy. So on the efficacy side, you're going to hear us tell you about the ppFEV1 at 4 weeks from both the FS and the FMS trial and with regard to safety. Now on this one, we're going to give you the top line with regard to discontinuations, the overall tolerability, but we're going to be very, very thoughtful about maintaining study integrity and we're not going to go very far beyond that, just like you saw us do with 659.

當然。所以，如果我回顧我們去年底發布的 659 數據，我認為這可以很好地幫助您了解我們將在本季度發布的 445 數據（包括安全性和有效性數據）。因此，在療效方面，我們將向您介紹 FS 和 FMS 試驗中 4 週時的 ppFEV1 值，以及安全性的情況。現在，我們將向您介紹有關中止情況和整體耐受性的要點，但我們會非常非常謹慎地維護研究的完整性，不會超出這個範圍，就像您在 659 研究中看到的那樣。

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

最後一個問題來自 JMP Securities 的 Liisa Bayko。

Well, a lot of my questions have been asked, but I did want to ask about the triple and sort of if you could describe the patent life around the triple, that would be helpful.

嗯，我的許多問題已經被問過了，但我確實想問一下關於三重奏的問題，如果您能描述一下三重奏的專利壽命，那就太好了。

Liisa, thank you so much for asking that. I knew you'd get to that. So as you know, our plan is to co-formulate these into a single pill, in which case the patent life around the medicine is actually determined by the longest patent life of the ingredients, single ingredients. And in the case of VX-659 and 445, which both have pending patent applications, the patent expiry, if granted, would be 2037 in both the U.S. and Europe.

莉莎，非常感謝你問這個問題。我就知道你會說到那一步。如您所知，我們的計劃是將這些成分共同配製成一種藥丸，在這種情況下，藥物的專利期限實際上取決於成分中最長的專利期限，即單一成分的專利期限。至於 VX-659 和 445，它們都有正在申請的專利，如果獲得批准，其在美國和歐洲的專利到期日都將是 2037 年。

And any extensions on that? Or that would be before any extensions?

還有其他進展嗎？或者說，那是在任何擴展之前的情況？

Gosh, by 2037, I'm going to be way too old to even think about extensions. No, we're -- obviously, we're pleased with that patent life and really can't speculate on any extensions at this point.

天哪，到 2037 年，我就太老了，根本沒時間考慮接發的事了。不，顯然，我們對目前的專利期限感到滿意，現在真的無法猜測是否會延長專利期限。

Okay. Thank you, everybody, for joining us tonight. The Investor Relations team is in the office and happy to do any further follow-up questions.

好的。謝謝各位今晚的到來。投資者關係團隊已在辦公室，樂意解答任何後續問題。

Thank you. Ladies and gentlemen, thank you for participating in today's conference. This concludes today's program. You may all disconnect. Everyone, have a great day.

謝謝。女士們、先生們，感謝各位參加今天的會議。今天的節目到此結束。你們可以斷開連結了。祝大家今天過得愉快。