福泰製藥 (VRTX) 2015 Q4 法說會逐字稿

This is Michael Partridge, Vice President of Investor Relations for Vertex. Welcome to our fourth-quarter and full-year 2015 financial results conference call.

我是 Vertex 投資人關係副總裁 Michael Partridge。歡迎參加我們 2015 年第四季暨全年財務結果電話會議。

(Operator Instructions)

(接線員指示)

As a reminder, this conference call is recorded.

提醒各位，本次電話會議將被錄音。

A replay will be available following the conclusion of tonight's call. Dr. Jeff Leiden, Chairman and CEO; and Ian Smith, Chief Financial Officer, will provide prepared remarks this evening. Stuart Arbuckle, Chief Commercial Officer; and Dr. Jeff Chodakewitz, Chief Medical Officer, will join us for the Q&A portion of the conference call.

今晚電話會議結束後將提供重播。董事長兼執行長 Jeff Leiden 博士，以及財務長 Ian Smith，將於今晚發表事先準備的談話。商務長 Stuart Arbuckle，以及醫務長 Jeff Chodakewitz 博士，將加入問答環節。

We recently presented at the annual JPMorgan Healthcare Conference, where we provided a comprehensive update on our business and had the opportunity to meet with many investors and analysts. As such, our remarks tonight will be brief. We expect to conclude the call by 5.45 p.m.

我們近期在一年一度的摩根大通醫療健康大會（JPMorgan Healthcare Conference）上發表，並就我們的業務提供了全面更新，也有機會與許多投資人與分析師會面。因此，今晚我們的談話將會簡短。我們預計在下午 5:45 結束本次電話會議。

On tonight's call, Jeff will review key priorities for our Business in 2016. Ian will review our fourth corner and full-year 2015 financial results and discuss our 2016 financial guidance, which we provided also earlier this month. As always, you can access the webcast slides on our website.

在今晚的電話會議中，Jeff 將回顧我們 2016 年業務的關鍵優先事項。Ian 將回顧我們 2015 年第四季與全年財務結果，並討論我們 2016 年財務指引；該指引我們也已於本月稍早提供。一如往常，您可在我們網站上取得網路直播簡報投影片。

I will remind you that we will make forward-looking statements on this conference call. These statements are subject to the risks and uncertainties discussed in detail in today's press release and our 10-K, which has been filed with the Securities and Exchange Commission. These statements, including without limitation those regarding the ongoing development and potential commercialization of our drug candidates, Vertex's other cystic fibrosis programs, and Vertex's future financial performance, are based on Management's current assumptions. Actual outcomes and events could differ materially.

我提醒各位，我們將在本次電話會議中作出前瞻性陳述。這些陳述受今日新聞稿及我們已向美國證券交易委員會（SEC）提交之 10-K 年報中所詳述的風險與不確定性影響。這些陳述（包括但不限於）關於我們藥物候選品的持續開發與潛在商業化、Vertex 其他囊性纖維化（CF）計畫，以及 Vertex 未來財務表現，係基於管理層目前的假設。實際結果與事件可能有重大差異。

Information regarding our use of GAAP and non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in today's financial results press release. Please also see slide 4 of tonight's webcast.

關於我們使用 GAAP 與非 GAAP 財務衡量指標的資訊，以及 GAAP 與非 GAAP 之間的調節表，已載於今日的財務結果新聞稿。也請參閱今晚網路直播的第 4 張投影片。

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

接下來我將把電話會議交給 Jeff Leiden 博士。

Thanks, Michael. Good evening, everyone.

謝謝你，Michael。各位晚上好。

Earlier this month I met with many of our investors and analysts at the annual JPMorgan healthcare conference and talked about the important transition has Vertex has made in the last few years. As we enter 2016, Vertex is on a path toward sustained earnings and revenue growth, driven by an increasing number of people being treated with our two approved medicines for cystic fibrosis, KALYDECO and ORKAMBI.

本月稍早，我在一年一度的摩根大通醫療健康大會上與許多投資人與分析師會面，並談到 Vertex 在過去幾年所完成的重要轉型。隨著我們進入 2016 年，Vertex 正走在持續獲利與營收成長的道路上；成長動能來自於接受我們兩款已核准囊性纖維化藥物 KALYDECO 與 ORKAMBI 治療的人數持續增加。

We have a broad and deep pipeline of investigational medicines for CF that we believe may allow us to reach our goal of treating all people with CF in the future. Additionally, our pipeline of medicines for other serious diseases, including cancer, pain and other neurologic diseases, continues to progress through early stage clinical development. In short, we are a very different Company than we were just four years ago.

我們在 CF 領域擁有廣泛且深厚的研發中藥物管線，我們相信這將使我們在未來得以達成治療所有 CF 患者的目標。此外，我們針對其他嚴重疾病（包括癌症、疼痛及其他神經系統疾病）的藥物管線，也持續在早期臨床開發階段取得進展。簡而言之，我們已是一家與四年前截然不同的公司。

This evening I will briefly review our key priorities for 2016 and provide some insight into upcoming milestones in CF and other parts of our Business. Our number one priority has been and continues to be to increase the number of people eligible for and treated with KALYDECO and ORKAMBI and to develop potential new medicines that may provide even greater benefit for all people with CF in the years ahead.

今晚我將簡要回顧我們 2016 年的關鍵優先事項，並就 CF 及我們業務其他部分即將到來的里程碑提供一些觀點。我們的首要優先事項一直是、也將持續是：增加符合 KALYDECO 與 ORKAMBI 治療資格並接受治療的人數，同時開發潛在新藥，期望在未來幾年為所有 CF 患者帶來更大的效益。

At this time last year, just over 3,000 people were eligible for treatment with KALYDECO. Today approximately 25,000 people are eligible for KALYDECO or ORKAMBI, and we expect the vast majority of these people will begin treatment with these medicines to treat the cause of their CF. We also expect to increase the number of people eligible for these medicines in 2016 through label expansion efforts that could include younger patients or patients with other mutations in the CFTR gene.

在去年此時，僅略高於 3,000 人符合 KALYDECO 的治療資格。如今約有 25,000 人符合 KALYDECO 或 ORKAMBI 的治療資格，我們預期其中絕大多數將開始使用這些藥物，以治療其 CF 的致病原因。我們也預期在 2016 年透過適應症標籤擴展（可能包括更年幼的患者或具有 CFTR 基因其他突變的患者）來增加符合這些藥物治療資格的人數。

Our second key priority for 2016 is to continue building a financial profile of sustained revenues and earnings growth and a strong balance sheet. In 2015, the continued expansion of the KALYDECO label and the approval of ORKAMBI resulted in a significant increase in the number of patients being treated with our medicines, which led to a significant increase in revenues. Our progress in 2015 has positioned us for continued growth, and we believe we are on the right path to achieve our goal of building a financial profile consistent with that of other global biotech companies.

我們 2016 年的第二項關鍵優先事項，是持續打造可帶來持續營收與獲利成長、並具備強健資產負債表的財務體質。在 2015 年，KALYDECO 適應症標籤的持續擴展以及 ORKAMBI 的核准，使接受我們藥物治療的患者人數大幅增加，進而帶動營收顯著成長。我們在 2015 年的進展使我們具備持續成長的有利位置；我們相信自己正走在正確道路上，以達成建立與其他全球生技公司一致之財務體質的目標。

And finally, our third key priority is to invest in our Business to create future medicines for other serious diseases. Continued investment in our pipeline is essential for creating additional breakthrough medicines for patients. I'll spend just a few minutes reviewing our recent progress and upcoming milestones that reflect these three priorities.

最後，我們的第三項關鍵優先事項，是投資於我們的業務，以創造未來可用於其他嚴重疾病的新藥。持續投資於我們的研發管線，對於為患者創造更多突破性藥物至關重要。我將用幾分鐘回顧我們近期進展與即將到來的里程碑，以反映這三項優先事項。

Our first CF medicine, KALYDECO, was approved by that FDA in January 2012 and since then our goal has been to bring this medicine to as many people as possible who may benefit. KALYDECO addresses the underlying cause of CF and is a significant medical advance for people with certain mutations in the CFTR gene. Today approximately 4,000 people are eligible for treatment with KALYDECO in North America, Europe and Australia.

我們第一款 CF 藥物 KALYDECO 於 2012 年 1 月獲美國 FDA 核准；自那時起，我們的目標一直是讓盡可能多、可能受益的人使用這款藥物。KALYDECO 針對 CF 的根本致病原因，對於具有 CFTR 基因特定突變的患者而言，是一項重大的醫療進展。目前在北美、歐洲與澳洲，約有 4,000 人符合 KALYDECO 的治療資格。

We are committed to bringing this medicine to even more patients who we believe may benefit in the years ahead. We are awaiting a decision from the US FDA on our application for approval of KALYDECO in people ages two and older with CF who have certain residual function mutations. There are approximately 1,500 people ages two and older in the US we have the residual function mutations represented in the supplemental new drug application for KALYDECO.

我們致力於在未來幾年讓更多我們認為可能受益的患者使用這款藥物。我們正等待美國 FDA 就我們的申請作出決定：核准 KALYDECO 用於 2 歲及以上、且具有某些殘餘功能突變之 CF 患者。在美國，約有 1,500 名 2 歲及以上患者具有該等殘餘功能突變，且已納入 KALYDECO 的補充新藥申請（sNDA）所涵蓋的突變範圍。

While our submission for approval in these mutations is primarily based on preclinical data, and on a phase 2-A clinical study in only 24 patients, we believe that KALYDECO would be beneficial to these patients, given the underlying science behind this precision medicine approach of using genetic markers and predictive assays to identify patients who are likely to benefit. Importantly, we chose to seek this approval knowing that these patients would otherwise have to potentially wait years before potential approval based on Phase 3 data.

雖然我們針對這些突變的核准申請主要基於臨床前數據，以及僅納入 24 名患者的第 2a 期臨床研究，但基於此精準醫療方法背後的科學原理（使用基因標記與預測性檢測來辨識可能受益的患者），我們相信 KALYDECO 將對這些患者有益。重要的是，我們選擇在明知若不如此，這些患者可能必須再等待多年、直到基於第 3 期數據才可能獲核准的情況下，仍尋求此次核准。

With more than four years of safety data, we believe that this path toward potential approval is in the best interest of people with CF. However, we also recognize that the application is based upon limited available clinical data in these rare mutations. The PDUFA date for a decision from the FDA is February 7.

基於超過四年的安全性數據，我們相信這條通往潛在核准的途徑符合 CF 患者的最佳利益。然而，我們也認知到，該申請係建立在這些罕見突變之有限臨床數據之上。FDA 作出決定的 PDUFA 日期為 2 月 7 日。

With ORKAMBI, we are working to bring this medicine to more patients who we believe would benefit, specifically children with two copies of the F Delta 508 mutation similar to the approach we took with KALYDECO. With the approval in the European Union at the end of last year, approximately 20,500 people, ages 12 and older, are now eligible for treatment with ORKAMBI in the US and Europe.

至於 ORKAMBI，我們正努力讓更多我們認為會受益的患者使用這款藥物，特別是具有兩份 F Delta 508 突變的兒童，做法類似我們對 KALYDECO 所採取的策略。隨著去年年底在歐盟獲得核准，目前在美國與歐洲，約有 20,500 名 12 歲及以上人士符合 ORKAMBI 的治療資格。

Today we announced that a Phase 3 study of ORKAMBI in children ages six to 11 met its primary safety endpoint and supports our planned submission of a supplemental new drug application in the second quarter of this year in the US. If approved, an additional 2,400 people in the US with CF would be eligible for treatment with ORKAMBI.

今天我們宣布，ORKAMBI 用於 6 至 11 歲兒童的第 3 期研究達成其主要安全性終點，並支持我們計畫於今年第二季在美國提交補充新藥申請（sNDA）。若獲核准，美國將另有 2,400 名囊性纖維化（CF）患者符合 ORKAMBI 治療資格。

While this was primarily a safety study, we also saw encouraging improvements in secondary and exploratory efficacy endpoints, including a statistically significant change in the exploratory endpoint of lung clearance index or LCI. Changes in LCI are also the primary endpoint of an ongoing Phase 3 study to support approval of ORKAMBI in this age group in Europe. There are approximately 3,400 children, ages six to 11, who have two copies of the Fdelta508 mutation in the European Union. Additional information on these data was provided in today's press release.

雖然這主要是一項安全性研究，但我們也在次要與探索性療效終點上看到令人鼓舞的改善，包括在探索性終點「肺清除指數」（lung clearance index，LCI）上出現具統計顯著性的變化。LCI 的變化同時也是一項正在進行的第 3 期研究之主要終點，該研究旨在支持 ORKAMBI 於歐洲核准用於此年齡族群。在歐盟，約有 3,400 名 6 至 11 歲、帶有兩份 Fdelta508 突變的兒童。關於這些數據的更多資訊已於今日新聞稿中提供。

Today KALYDECO and ORKAMBI are approved to treat approximately 25,000 people in North America, Europe and Australia. We believe that there are many more people who may benefit from these medicines and we have trials ongoing or planned that could expand the number of people eligible for treatment to approximately 44,000 in the years ahead.

目前，KALYDECO 與 ORKAMBI 已獲核准用於治療北美、歐洲與澳洲約 25,000 名患者。我們相信仍有更多人可能受益於這些藥物；我們正在進行或規劃中的試驗，未來數年可望將符合治療資格的人數擴大至約 44,000 人。

Beyond our approved medicines, we have a pipeline of investigational CF medicines from early-stage research programs such as gene editing with CRISPR, to late-stage development programs evaluating combinations of our CFTR modulators. This pipeline represents hope for the CF community and our goal is to one day treat all people with CF. We have a broad Phase 3 program underway evaluating the corrector VX-661 in combination with ivacaftor. And we are also advancing the development of two next-generation correctors that would be combined with the VX-661and ivacaftor as part of a Phase 2 study of triple combinations planned for later this year.

除已核准的藥物之外，我們亦擁有一系列研發中的 CF 候選藥物管線，涵蓋從早期研究計畫（例如使用 CRISPR 的基因編輯）到後期開發計畫（評估我們 CFTR 調節劑的組合）。這條管線為 CF 社群帶來希望，而我們的目標是有朝一日能治療所有 CF 患者。我們正進行一項廣泛的第 3 期計畫，評估校正劑（corrector）VX-661 與 ivacaftor 的合併使用。此外，我們也在推進兩種次世代校正劑的開發，將其與 VX-661 與 ivacaftor 合併，作為預計於今年稍晚展開之三合一組合第 2 期研究的一部分。

Both approaches are asking the same fundamental questions. First, can we enhance the benefit for patients already receiving KALYDECO or ORKAMBI? And second, can we provide benefit to new groups of people with CF not currently helped by KALYDECO or ORKAMBI, including a very large group of patients with one Fdelta508 mutation and a second mutation known to result in minimal CFTR function.

這兩種方法都在探討相同的根本問題。第一，我們能否提升已在使用 KALYDECO 或 ORKAMBI 的患者之治療效益？第二，我們能否讓目前尚未受益於 KALYDECO 或 ORKAMBI 的新 CF 患者族群獲得效益，其中包括一個非常龐大的族群：帶有一個 Fdelta508 突變，且第二個突變已知會導致 CFTR 功能極低（minimal CFTR function）的患者。

The VX- 661 program includes four Phase 3 studies in different groups of people with CF who have at least one copy of the Fdelta508 mutation. We will begin to see the first results from the VX-661 program by early 2017 and, importantly, this program is also meant to provide a significant amount of safety data to support evaluation of a next-generation corrector with VX-661and ivacaftor as part of an investigational triple-combination regimen.

VX-661 計畫包含四項第 3 期研究，涵蓋不同的 CF 患者族群，這些患者至少帶有一份 Fdelta508 突變。我們將於 2017 年初開始看到 VX-661 計畫的首批結果；且重要的是，此計畫亦旨在提供大量安全性數據，以支持評估將次世代校正劑與 VX-661 及 ivacaftor 合併，作為研究中的三合一組合療法。

At the end of 2015, we initiated clinical development of two next-generation correctors; VX-152 and VX-440. Phase 1 studies of each compound are ongoing in healthy volunteers and are evaluating single and multiple doses of VX-152 and VX-440, as well as triple combination with VX-661 and ivacaftor. Together with the safety data from the VX-661 program, these studies are designed to support the planned initiation of Phase 2 studies to evaluate triple-combination regimens in patients in the second half of 2016.

在 2015 年底，我們啟動了兩種次世代校正劑 VX-152 與 VX-440 的臨床開發。各化合物的第 1 期研究正在健康受試者中進行，評估 VX-152 與 VX-440 的單次與多次劑量，以及與 VX-661 與 ivacaftor 的三合一組合。結合 VX-661 計畫的安全性數據，這些研究旨在支持於 2016 年下半年按計畫啟動第 2 期研究，以評估患者中的三合一組合療法。

Our business model is unique. The success we have achieved in CF allows us to reinvest in the discovery and development of new transformative medicines. In parallel with CF, we are advancing a number of additional development programs for cancer, pain, and other serious diseases. We have significant flexibility in how we may advance these programs, either independently for these diseases we believe are aligned with the focus of our Business, specifically specialty diseases where G&A expenses are low, or in collaboration with other companies that we believe would be best suited to rapidly bring these potential medicines to patients.

我們的商業模式獨具特色。我們在 CF 領域取得的成功，使我們得以再投資於全新、具變革性的藥物之發現與開發。在推進 CF 的同時，我們也在推動多項額外的開發計畫，涵蓋癌症、疼痛及其他嚴重疾病。我們在推進這些計畫方面具有相當大的彈性：可選擇獨立推進（針對我們認為與公司業務重點一致的疾病，特別是一般與行政（G&A）費用較低的專科疾病），或與我們認為最適合能迅速將這些潛在藥物帶給患者的其他公司合作。

We believe our pipeline represents both potentially transformative future medicines for patients and significant value for our Business. We have begun to provide some additional insight and data for our pipeline programs and I look forward to providing updates on our progress throughout the coming year.

我們相信，我們的研發管線既代表未來可能為患者帶來變革的藥物，也為公司帶來顯著價值。我們已開始就管線計畫提供更多洞見與數據，並期待在未來一年持續就我們的進展提供更新。

I mentioned at the start of my remarks that Vertex has undergone an important transition in recent years. We are now a global biotech Company that has independently brought forward two breakthrough medicines to people with CF worldwide and is on the path to delivering significant earnings and cash flow. Our financial performance in 2015 and guidance for 2016 are metrics of the Company that we want to become, a Company that consistently creates transformative new medicines for patients, generates significant value for shareholders, and reinvests in scientific opportunities to create future medicines. This is our business model and I am pleased by our success to date and with our outlook for the coming years.

我在開場時提到，Vertex 近年來經歷了一項重要轉型。我們如今是一家全球性生技公司，已能獨立將兩款突破性藥物帶給全球 CF 患者，並正走在實現可觀獲利與現金流的道路上。我們 2015 年的財務表現與 2016 年的財務指引，正是我們希望成為之公司樣貌的衡量指標：一家能持續創造具變革性的新藥、為股東創造顯著價值，並再投資於科學機會以創造未來藥物的公司。這就是我們的商業模式；我對迄今的成功以及未來數年的展望感到欣慰。

With that I'll turn the call over to Ian.

接下來我把電話會議交給 Ian。

Thanks, Jeff. In my remarks today, I will review our fourth quarter and full-year 2015 financial results, and discuss our 2016 financial guidance for total KALYDECO net revenues and non-GAAP operating expenses, excluding cost of revenues. I will also discuss our expectation for providing ORKAMBI guidance in 2016.

謝謝，Jeff。在我今天的發言中，我將回顧我們 2015 年第四季與全年財務結果，並討論我們 2016 年關於 KALYDECO 總淨營收以及非 GAAP 營運費用（不含營收成本）的財務指引。我也將說明我們對於在 2016 年提供 ORKAMBI 指引的預期。

Financial results first: our 2015 net CF product revenues were approximately $983 million. This includes KALYDECO net revenues of $632 million and ORKAMBI net revenues of $351 million. Total CF product revenues increased by more than 110% compared to 2014.

先看財務結果：我們 2015 年 CF 產品淨營收約為 9.83 億美元。其中包括 KALYDECO 淨營收 6.32 億美元，以及 ORKAMBI 淨營收 3.51 億美元。與 2014 年相比，CF 產品總營收增加逾 110%。

In the fourth quarter of 2015, we reported total net CF product revenues of approximately $401 million, including KALYDECO net revenues of $181 million and ORKAMBI net revenues of $220 million. Fourth quarter KALYDECO sales of $181 million were up 45% versus the fourth quarter of last year and up 9% versus the third quarter of 2015. This included approximately $6 million in inventory stocking that occurred at the end of the fourth quarter.

在 2015 年第四季，我們報告 CF 產品總淨營收約為 4.01 億美元，其中包括 KALYDECO 淨營收 1.81 億美元與 ORKAMBI 淨營收 2.20 億美元。第四季 KALYDECO 銷售額 1.81 億美元，較去年第四季成長 45%，較 2015 年第三季成長 9%。其中包含約 600 萬美元於第四季末發生的庫存備貨（inventory stocking）。

Growth in KALYDECO was driven by both label expansion efforts, which increased the number of eligible patients to approximately 4,000, and by the completion of key reimbursement discussions in Europe. With ORKAMBI, more than 1,500 patients started in the fourth quarter, resulting in sales of $220 million, up 68% versus third quarter of 2015.

KALYDECO 的成長同時受惠於適應症標籤擴展的努力（使符合資格的患者人數增加至約 4,000 人），以及在歐洲完成關鍵的給付／報銷（reimbursement）協商。至於 ORKAMBI，第四季有超過 1,500 名患者開始用藥，帶動銷售額達 2.20 億美元，較 2015 年第三季成長 68%。

As expected, we saw a very rapid uptake for ORKAMBI in the period immediately following the FDA approval with more than 3,000 people starting treatment in the third quarter. Demand from patients and physicians has been strong. But, as expected, fewer patients started treatment in the fourth quarter compared to the third quarter, in line with our prior statements regarding expectations for the rate of uptake for ORKAMBI. We expect this trend to continue through the end of 2016, by which time we expect the vast majority of the 8,500 eligible patients in the US to have initiated treatment with ORKAMBI.

如預期，在 FDA 核准後的緊接期間，ORKAMBI 的採用速度非常快，第三季有超過 3,000 人開始治療。患者與醫師的需求一直很強勁。但也如預期，第四季開始治療的患者人數較第三季減少，符合我們先前對 ORKAMBI 採用速度之預期的說法。我們預期此趨勢將持續至 2016 年底；屆時我們預期美國 8,500 名符合資格的患者中，絕大多數將已開始使用 ORKAMBI 治療。

Gross to net adjustments were largely unchanged from the third quarter and were in the high single-digits due primarily to a greater proportion of patients within commercial plans initiating treatment in the first six months following the approval of ORKAMBI as compared to government-paid plans. Each of the 50-state Medicaid programs has now paid a claim for ORKAMBI, thus we expect gross to net adjustments will increase to the midteens by the end of 2016 to reflect an increase in patients treated being covered by Medicaid.

總額到淨額（gross to net）調整與第三季大致持平，維持在高個位數百分比，主要原因是相較於政府支付的保險方案，在 ORKAMBI 核准後的前六個月內啟動治療的患者中，商業保險方案的占比更高。目前全美 50 州的 Medicaid 計畫都已為 ORKAMBI 支付過一筆理賠，因此我們預期到 2016 年底，總額到淨額調整將上升至約 10% 多（midteens），以反映接受治療且由 Medicaid 承保的患者比例增加。

As we enter 2016, we are pleased with the launch of ORKAMBI to date, and remain focused on working to ensure those who need the medicine have access to it, educating healthcare providers and supporting adherence to ORKAMBI.

進入 2016 年之際，我們對 ORKAMBI 迄今的上市表現感到滿意，並將持續專注於確保需要此藥物的人能夠取得治療、教育醫療照護提供者，以及支持 ORKAMBI 的用藥依從性。

Now to operating expenses, our fourth quarter non-GAAP operating expenses were $282 million, including R&D expenses of $204 million and SG&A expenses of $78 million. The increased R&D expensed in the fourth quarter 2015 compared to 2014 were primarily the result of increased costs related to the pivotal Phase 3 program for VX-661 in combination with ivacaftor.

接著談營運費用，我們第四季非 GAAP 營運費用為 2.82 億美元，其中研發（R&D）費用 2.04 億美元，銷售、一般及行政（SG&A）費用 7,800 萬美元。2015 年第四季相較 2014 年第四季研發費用增加，主要是因 VX-661 與 ivacaftor 併用之關鍵性第三期（Phase 3）計畫相關成本上升所致。

The increased SG&A expenses were primarily the result of an increased investment in global commercial support for the launch of ORKAMBI. And tonight I am pleased to report that for the fourth quarter 2015 we recorded a non-GAAP net profit of $43 million, or $0.17 per diluted share compared to non-GAAP net loss of $132 million, or $0.55 per share for the fourth quarter of 2014. Our 2015 non-GAAP net loss was $268 million, or $1.11 per share, compared to non-GAAP net loss of $511 million or $2.17 per share for the full-year 2014.

SG&A 費用增加主要是因為為支持 ORKAMBI 上市而加大對全球商業支援的投資。此外，我很高興報告，2015 年第四季我們錄得非 GAAP 淨利 4,300 萬美元，或稀釋後每股 0.17 美元；相較之下，2014 年第四季為非 GAAP 淨損 1.32 億美元，或每股 0.55 美元。我們 2015 年全年非 GAAP 淨損為 2.68 億美元，或每股 1.11 美元；相較之下，2014 年全年非 GAAP 淨損為 5.11 億美元，或每股 2.17 美元。

From a balance sheet perspective, we started 2016 with a strong cash position of $1.04 billion. Vertex also has $300 million outstanding from a credit agreement that provides for a secured loan of up to $500 million.

從資產負債表角度來看，我們在 2016 年初擁有強勁的現金部位，為 10.4 億美元。Vertex 亦有一項信貸協議下尚未償還的 3 億美元，該協議提供最高 5 億美元的擔保貸款額度。

Now let's turn to the 2016 financial guidance, which we first provided on January 10. We expect 2016 KALYDECO net revenues of $670 million to $690 million. Our guidance for KALYDECO revenues reflects the continued use of KALYDECO as was seen in the fourth quarter of 2015, which resulted in revenues of $181 million, and the expectation for up to approximately 200 patients with a gating mutation to enroll in a Phase 3 clinical study of VX-661 in combination with ivacaftor who would otherwise have received KALYDECO, which will thus reduce 2016 KALYDECO revenues.

現在我們來看 2016 年財務指引，我們已於 1 月 10 日首次提供。我們預期 2016 年 KALYDECO 淨營收為 6.70 億至 6.90 億美元。我們對 KALYDECO 營收的指引反映了 KALYDECO 的持續使用情況（如同 2015 年第四季所見，當季營收為 1.81 億美元），以及預期最多約 200 名具有 gating mutation 的患者將納入 VX-661 與 ivacaftor 併用的第三期臨床研究；這些患者若非參與研究原本會使用 KALYDECO，因此將降低 2016 年 KALYDECO 營收。

There was also an approximately $6 million inventory stocking that occurred at the end of the fourth quarter 2015. That is not expected to recur in future quarters and is thus accounted for in our guidance. Importantly, our current guidance excludes any potential revenues from the approval of KALYDECO for people with residual function mutations. We will update our KALYDECO guidance should we receive FDA approval for residual function mutations.

此外，2015 年第四季末亦發生約 600 萬美元的庫存備貨（inventory stocking）。預期未來季度不會再發生，因此已納入我們的指引考量。重要的是，我們目前的指引不包含 KALYDECO 若獲核准用於 residual function mutations 人群所帶來的任何潛在營收。若我們取得 FDA 對 residual function mutations 的核准，我們將更新 KALYDECO 指引。

With ORKAMBI, more than 4,500 people have begun treatment in the US by the end of 2015. There are four primary pieces of information regarding the launch that will inform our decision regarding ORKAMBI guidance. First, since all patients who initiated treatment with ORKAMBI in 2015 have been on treatment for approximately six months or less, we are waiting additional information on the compliance rate for patients taking ORKAMBI.

就 ORKAMBI 而言，截至 2015 年底，美國已有超過 4,500 人開始治療。關於上市進展，有四項主要資訊將影響我們對 ORKAMBI 指引的決策。第一，由於 2015 年開始使用 ORKAMBI 的所有患者用藥時間約為六個月或更短，我們正在等待更多關於患者服藥依從率（compliance rate）的資訊。

While we continue to expect that the vast majority of eligible patients in the US will begin treatment with ORKAMBI by the end of 2016, we are waiting additional information on the specific rate of uptake and on the specific proportion of the 8,500 eligible patients who begin treatment with ORKAMBI in 2016. And finally, additional information on the persistence rate, defined as how many patients remain on treatment will also be taken into account.

雖然我們仍預期美國絕大多數符合條件的患者將在 2016 年底前開始使用 ORKAMBI，但我們仍在等待更多關於實際採用速度（uptake rate）以及 8,500 名符合條件患者中於 2016 年開始使用 ORKAMBI 的具體比例之資訊。最後，我們也會納入更多關於持續用藥率（persistence rate）的資訊，其定義為有多少患者持續留在治療中。

These four factors, the compliance rate, the rate at which patients begin treatment, the total number of patients who initiate treatment, and the persistence rate, all are important in considering our guidance for ORKAMBI. In 2016, we expect to recognize revenues from sales of ORKAMBI in the US and Germany.

這四項因素——依從率、患者開始治療的速度、開始治療的患者總數，以及持續用藥率——在考量 ORKAMBI 指引時都很重要。2016 年，我們預期將認列來自美國與德國 ORKAMBI 銷售的營收。

In Germany, there are approximately 2,500 people with CF, ages 12 and older, with two copies of F508del mutation. In Europe, country to country reimbursement discussions are underway. However, we do not anticipate any significant ORKAMBI revenues from countries other than the US and Germany in 2016.

在德國，約有 2,500 名 12 歲以上、帶有兩個 F508del 突變拷貝的囊性纖維化（CF）患者。在歐洲，各國之間的給付／報銷（reimbursement）協商正在進行中。然而，我們不預期 2016 年來自美國與德國以外國家的 ORKAMBI 營收會有任何顯著貢獻。

The final component of our financial guidance is non-GAAP operating expenses, which are comprised of R&D and SG& A expenses and exclude cost of revenues. We expect our total 2016 non-GAAP operating expenses of $1.18 to $1.23 billion. As a reminder, our guidance for 2015 operating expenses was for $1.05 billion to $1.1 billion, and we reported 2015 operating expenses at the low end of this range of $1.06 billion, largely as a result of costs related to VX-661 that will now occur in 2016 as opposed to 2015.

我們財務指引的最後一個組成部分是非 GAAP 營運費用，其由研發與 SG&A 費用構成，並排除營收成本（cost of revenues）。我們預期 2016 年非 GAAP 營運費用總額為 11.8 億至 12.3 億美元。提醒一下，我們對 2015 年營運費用的指引為 10.5 億至 11.0 億美元，而我們實際報告的 2015 年營運費用為該區間低端的 10.6 億美元，主要是因與 VX-661 相關的部分成本將改在 2016 年發生，而非 2015 年。

The increase in expected operating expenses for 2016 as compared to 2015 is primarily a result of expanded development efforts related to the pivotal Phase 3 development program for VX-661 in combination with ivacaftor and for multiple Phase 1 and two studies of Vertex's early stage of mid-stage pipeline of potential CF medicines and anticipated SG&A costs to support the launch of ORKAMBI in new global markets.

2016 年預期營運費用相較 2015 年增加，主要是因為擴大了 VX-661 與 ivacaftor 併用之關鍵性第三期開發計畫的研發投入，以及針對 Vertex 早期至中期管線中多項潛在 CF 藥物的多個第一期（Phase 1）與兩項研究的開發工作，並且預期將增加 SG&A 成本以支援 ORKAMBI 在新的全球市場上市。

The components of Vertex's non-GAAP operating expenses include non-GAAP R&D expenses, which we expect to be in the range of $850 million to $880 million, and non-GAAP SG&A expenses, which we expect will be in the range of $330 million to $350 million. Vertex's expected non-GAAP R&D and SG&A expenses exclude stock-based compensation expense and certain other expenses.

Vertex 非 GAAP 營運費用的組成包括非 GAAP 研發費用（我們預期介於 8.50 億至 8.80 億美元）以及非 GAAP SG&A 費用（我們預期介於 3.30 億至 3.50 億美元）。Vertex 預期的非 GAAP 研發與 SG&A 費用不包含以股票為基礎的薪酬費用（stock-based compensation expense）及某些其他費用。

In summary, we are in a strong financial position as we enter 2016. We remain committed to delivering a financial profile that is similar to many of our large-cap biotech peers, which includes sustainable revenue and earnings growth, high operating margins and, most importantly, continued investment to create future medicines.

總結而言，我們在進入 2016 年時處於強勁的財務狀況。我們仍致力於提供與許多大型生技同業相近的財務輪廓，包括可持續的營收與獲利成長、高營業利潤率，以及最重要的——持續投資以創造未來的藥物。

Thank you. Operator, we are now ready to take questions.

謝謝。接線生，我們現在準備開始提問。

(Operator Instructions)

（接線生指示）

Geoff Meacham of Barclays.

Barclays 的 Geoff Meacham。

Hey, guys. Thanks for the question and congrats on profitability. I got a commercial and clinical question for you. I guess I will start with commercial. I wanted to know, Ian, if you can go into a little bit more detail about persistence rates over time with KALYDECO and whether this should be a real benchmark for ORKAMBI? I'm just curious if you guys have tracked people who have discontinued but later come back to therapy?

嗨，各位。謝謝讓我提問，也恭喜達成獲利。我有一個商業面和一個臨床面的問題。我想先從商業面開始。Ian，我想請你更詳細說明一下 KALYDECO 隨時間推移的持續用藥率（persistence rates），以及這是否應該作為 ORKAMBI 的一個真正基準？我也好奇你們是否有追蹤那些已停藥但之後又回到治療的人？

Geoff, maybe Stuart will take that question. Thanks for the comment on profitability (technical difficulty) quarter. Stuart is going to take the question. He might also comment on some of the other features that are affecting how we are thinking about the launch as well.

Geoff，也許 Stuart 會回答這個問題。謝謝你對獲利能力（技術難度）季度的評論。Stuart 會來回答這個問題。他也可能會就一些其他影響我們如何思考上市的特點一併評論。

Yes.

是的。

Geoff, hi. It is Stuart here. Let me just reiterate a couple of things that Ian said about ORKAMBI and the factors we are taking into account when thinking about the launch in the way of tracking very closely. One is obviously the peak penetration, so the number of eligible patients in total that get initiated on therapy over time. And we continue to expect the vast majority of the 8,500 patients will. Then there is the rate of uptake, how quickly we get to that peak penetration. As you know, at the end of December we had about 4,500 patients on therapy, that's about 55% of the total, and we expect we will get to peak penetration during the course of 2016.

Geoff，你好。我是 Stuart。我先重申 Ian 關於 ORKAMBI 所說的幾點，以及我們在思考上市時會非常密切追蹤的因素。其中一個顯然是峰值滲透率，也就是隨時間推移，符合資格的患者總數中有多少人開始接受治療。我們仍預期 8,500 名患者中的絕大多數都會開始治療。接著是採用速度，也就是我們多快能達到該峰值滲透率。如你所知，截至 12 月底約有 4,500 名患者正在接受治療，約占總數的 55%，我們預期在 2016 年期間達到峰值滲透率。

And then, as you said, one of the other key components is persistence. The number of patients who stay on therapy. And obviously it is pretty early days because whilst we've only been on the market for six months, we really don't have long-term experience with very many patients yet.

然後，如你所說，另一個關鍵組成要素是治療持續性（persistence）。也就是持續留在治療上的患者人數。而且顯然現在還很早，因為我們上市才六個月，對於很多患者我們還沒有很長期的使用經驗。

In the Phase 3 studies for ORKAMBI, at about 24 weeks in traffic and transport, about 5% of patients have discontinued; at 48 weeks in the open-label extension with ORKAMBI, we were at 15% of patients had discontinued. That's in the ORKAMBI clinical trials and time will tell whether we see a higher or lower number, but probably a higher number who are discontinuing in the real world.

在 ORKAMBI 的第 3 期研究中，大約 24 週時約有 5% 的患者已停止治療；在 ORKAMBI 的開放標籤延伸試驗中，48 週時停止治療的患者比例為 15%。這是在 ORKAMBI 臨床試驗中的結果；未來實際世界（real world）會是更高或更低仍有待觀察，但在真實世界中停止治療的人數可能會更高。

With KALYDECO, in the studies we looked at it was about 5% of patients, again, discontinued in the KALYDECO clinical trials. It was actually slightly higher than that in the real world. It got closer to 10%, so in the real world over time. And largely that was because it was over a longer period of time. We did see a slightly higher number, a higher percentage of patients on KALYDECO discontinue versus the clinical trials.

至於 KALYDECO，在我們檢視的研究中，大約也有 5% 的患者在 KALYDECO 臨床試驗中停止治療。在真實世界中其實略高一些。隨時間推移接近 10%。主要原因是觀察期間更長。因此我們確實看到，相較於臨床試驗，真實世界中停止使用 KALYDECO 的患者數與比例略高。

The last thing we are going to be thinking about then is obviously compliance, and that is the percentage of patients who actually take the pills that have been prescribed by their physician. As you know, KALYDECO is very, very high at 85%. Certainly the highest I've ever seen personally for a chronic medication. Other CF medicines are around about the 60% range. I would anticipate ORKAMBI is going to be in that range, probably towards the higher part of that range, but somewhere in that range.

最後一點我們會思考的，當然是用藥依從性（compliance），也就是實際按醫師處方服藥的患者比例。如你所知，KALYDECO 的依從性非常、非常高，達 85%。這肯定是我個人見過慢性用藥中最高的。其他囊性纖維化（CF）藥物大約在 60% 左右。我預期 ORKAMBI 會落在那個區間，可能偏向較高端，但大致會在那個範圍內。

The only other question we will have to look at very closely -- and, again, we just don't have data on it. We don't have data on it in the clinical program, Geoff, and we will have to see how it plays out in the real world is whether physicians and patients choose to reinitiate therapy if they have discontinued for some reason. And we just have no information from the clinical trials because they just weren't set up to look at that. If a patient discontinued, they were then excluded from further therapy. So we just don't have data on that right now, Geoff. Hopefully that gives you some perspective on what we are thinking.

另外還有一個問題我們必須非常密切地觀察——而且同樣地，我們目前沒有相關數據。在臨床計畫中也沒有這方面的數據，Geoff；我們必須看它在真實世界中如何發展：也就是若患者因某些原因停止治療後，醫師與患者是否會選擇重新啟動治療。我們從臨床試驗沒有任何資訊，因為試驗設計並不是為了評估這件事。如果患者停止治療，他們就會被排除在後續治療之外。所以目前我們確實沒有這方面的數據，Geoff。希望這能讓你更了解我們的思考方向。

That is helpful. And just real quick on the clinical side, when you look at the 152 and 440 study in healthies, has there been any evidence of drug/drug interactions with KALYDECO or 661? I'm trying to figure out whether you guys expect to take multiple doses of those two correctors into CF patients when you look to the back half of the year? Maybe just help us with the design of that 28-day study as you see it at this stage. Thank you.

這很有幫助。另外很快問一下臨床面：當你們看 152 與 440 在健康受試者的研究時，有沒有任何與 KALYDECO 或 661 的藥物／藥物交互作用證據？我想了解的是，當你們看今年下半年時，是否預期會在 CF 患者中使用那兩個校正劑（corrector）的多重劑量？也請你們就目前所見，協助我們理解那個 28 天研究的設計。謝謝。

Hi, Geoff, it's Jeff Chodakewitz. So in terms of the Phase 1 studies for VX-152 and 440, we are really in the midst of those studies and we obviously can't comment on the ongoing trials. Maybe just a comment on, though, then Phase 2 and we are in early days in terms of those designs. But I do think it's likely that we would look to take multiple doses of the compounds into those Phase 2 studies to learn as much as we can.

嗨，Geoff，我是 Jeff Chodakewitz。就 VX-152 與 440 的第 1 期研究而言，我們目前正進行這些研究中，因此顯然無法評論正在進行的試驗。不過我可以就第 2 期做個說明：我們在設計上仍屬早期階段。但我確實認為，我們很可能會在那些第 2 期研究中評估多重劑量，以盡可能獲取更多資訊。

Got you. Okay, thanks a lot, guys.

了解。好的，非常感謝各位。

Thanks.

謝謝。

Matt Roden of UBS.

UBS 的 Matt Roden。

Great, thanks very much for taking the question. I also wanted to congratulate you on the milestone of turning back to profitability.

很好，謝謝你們回答問題。我也想祝賀你們達成重回獲利的里程碑。

So regarding the pediatric study. I understand the primary endpoint is safety and the LCI data look really good, which the latter point being important for what is going on in Europe.

關於兒科研究。我了解主要終點是安全性，而 LCI 數據看起來非常好；後者對歐洲目前的情況很重要。

Just wanted to get your perspective on the 2.5% improvement in FEV. Have you talked to any experts or the FDA about that? I can't imagine that's going to be any kind of issue for you, but just wanted to see if there is anything to add on that side?

想請教你們對 FEV 改善 2.5% 的看法。你們有和任何專家或 FDA 討論過嗎？我不認為這會對你們造成任何問題，但想看看在這方面是否還有補充？

And then on the commercial side, wanted to ask, you have left the residual function mutations out of the KALYDECO guidance, but trying to get a sense for if that were to be approved, how should we think about the onboarding of those patients on to commercial drug? I would imagine you have a conversion of those that are on trial to commercial, but apart from that, would you characterize this as a highly motivated subset of patients or because they have a milder phenotype, could this be a slower rate of penetration? Thanks very much.

另外在商業面，我想問：你們在 KALYDECO 指引中把殘餘功能（residual function）突變排除在外；但我想了解如果未來獲批，我們應該如何看待這些患者轉入商業用藥（commercial drug）的導入（onboarding）？我想你們會把試驗中的患者轉換到商業用藥，但除此之外，你們會把這群人形容為高度積極的一小群患者，還是因為他們表型較輕（milder phenotype），滲透速度可能較慢？非常感謝。

Hi, Matt. It is Jeff Chodakewitz. Maybe I will start. In terms of the pediatric study, we were very pleased with the results of the study. Really meeting both the endpoints for exposure for PK and then for safety, as you said, so that was a nice outcome. The expectation with the FDA is that once you have established efficacy in the same disease in older children, that as you move to younger age groups, it's really about that exposure and safety consistent with the design of the study.

嗨，Matt。我是 Jeff Chodakewitz。也許我先回答。就兒科研究而言，我們對研究結果非常滿意。如你所說，研究確實同時達成了藥物動力學（PK）暴露的終點以及安全性終點，這是很好的結果。FDA 的預期是：一旦你已在同一疾病的較大年齡兒童中建立療效，當你往更年幼的年齡層推進時，重點就會放在暴露量與安全性是否一致，這也符合本研究的設計。

I will say that I think we were also quite pleased with the evidence of efficacy in the population where it gets harder to actually demonstrate that. And I think actually the FEV1 showing that strong trend was actually quite favorable, remembering that these kids started at a pretty high FEV1 percentage of baseline.

我也想說，我們對於在這個族群中看到的療效證據也相當滿意，因為在這個族群要實際證明療效會更困難。而且我認為 FEV1 顯示出強勁的趨勢其實相當有利，別忘了這些孩子起始時的 FEV1 基線百分比就相當高。

And as actually you noted, the fact that the LCI measure, which is in its earlier days, was nicely positive and that is our primary endpoint in the European study. And, lastly, the BMI measures as well. I think, overall, we were quite satisfied with the results of the trial.

而且正如你實際上所指出的，LCI 指標仍處於較早期階段，但結果相當正向，而這也是我們在歐洲研究中的主要終點。最後，BMI 指標也是如此。我認為整體而言，我們對這項試驗的結果相當滿意。

Matt, it is Stuart here. Just to comment on the residual function. So, as you said, residual function is not included within the KALYDECO guidance that we have provided. There is about 1,500 patients with the 23 mutations that we've asked for within our filing. In terms of patients transferring from clinical trials, clearly the clinical trial on which the application is based, or which is included in the clinical trial, is very small.

Matt，我是 Stuart。我想就殘餘功能（residual function）補充說明一下。如你所說，我們所提供的 KALYDECO 指引並未納入殘餘功能。就我們此次申報所涵蓋、我們提出的 23 種突變而言，大約有 1,500 名患者。至於從臨床試驗轉換的患者，顯然作為申請依據的臨床試驗（或納入申請的臨床試驗）規模非常小。

So it's not as if there is a huge bolus of patients to transition from clinical to supply to commercial supply. In terms of rate of uptake, the best analog, I think, for you there would be [arum] 17h which, by definition, is a residual function mutation. And so both in terms of heat penetration and rate of uptake, I think that's probably the best analog for you to think of in terms of the rate of uptake we might see if we are approved. And then just to (inaudible) what Ian said in his prepared remarks, if we are approved in residual function our anticipation is that we'd update our KALYDECO guidance to reflect that.

因此，並不存在一大批患者需要從臨床供藥轉換到商業供藥。就採用速度而言，我認為你可以參考的最佳類比是 [arum] 17h，因為按定義它屬於殘餘功能突變。因此，無論是在市場滲透程度或採用速度方面，我認為這大概是你用來思考若我們獲批後可能看到的採用速度的最佳類比。另外再補充（聽不清）Ian 在事先準備的發言中所說的，如果我們在殘餘功能適應症上獲批，我們預期會更新我們的 KALYDECO 指引以反映這一點。

Great; thanks very much.

很好；非常感謝。

Terrance Flynn of Goldman Sachs.

高盛（Goldman Sachs）的 Terrance Flynn。

Hi, this is Samir on for Terrance. Thanks for taking the question. Have all ORKAMBI clinical trial patients in the US transitioned to commercial drug? And if not, how many are left to transition? Thanks so much.

你好，我是代 Terrance 提問的 Samir。謝謝讓我提問。在美國，所有 ORKAMBI 臨床試驗患者是否都已轉換為商業用藥？如果沒有，還有多少人尚待轉換？非常感謝。

I'm not going to comment on exactly how many, but the vast majority of the patients who were on clinical trial supply have now transitioned to commercial drug. Just to orient you, there was approximately 500 in total of the patients in traffic and transport were in the US.

我不會評論確切人數，但先前使用臨床試驗供藥的患者中，絕大多數現在都已轉換為商業用藥。提供你一個背景資訊：在 TRAFFIC 與 TRANSPORT 試驗中，總計約有 500 名患者在美國。

Okay, great; thank you.

好的，很好；謝謝。

Matthew Harrison of Morgan Stanley.

摩根士丹利（Morgan Stanley）的 Matthew Harrison。

Great. Thanks for taking the question. I just had two quick ones. One, Ian, can you go back to the KALYDECO stocking comment that you made and just tell us if you think we should see some of that inventory come out of the channel this year and how that is in your guidance?

很好。謝謝讓我提問。我有兩個簡短問題。第一個，Ian，你能回到你提到的 KALYDECO 備貨（stocking）評論，告訴我們你是否認為今年會看到部分庫存從通路中消化掉，以及這在你們的指引中是如何反映的？

And then separately, just on the EU pediatric study, how will data from that influence maybe FDA perception of the filing that you guys have? And also how is timing of that related to when you would expect to have a PDUFA date for the label expansion in the US? Thanks.

另外，關於歐盟的兒科研究，該研究的數據可能會如何影響 FDA 對你們申報案的看法？以及該研究的時間點與你們預期在美國取得標籤擴增的 PDUFA 日期之間有何關聯？謝謝。

Yes. So I will take the first one and then Jeff Chodakewitz can take the second question. So firstly, the stocking question you ask is, first of all, [delorean] people, we had estimated there was approximately $6 million of inventory stocking in the fourth quarter for KALYDECO. What we mean by that is the inventory was higher at December 31 compared to September 30 by $6 million. That will then sell out of the channel, so it does impact future sales because it was in inventory. We have removed that from our guidance, so when we made an estimate for our 2016 KALYDECO guidance, we removed that.

好的。我先回答第一個問題，第二個問題由 Jeff Chodakewitz 回答。首先，關於你問的備貨問題，首先，[delorean] 各位，我們估計第四季 KALYDECO 約有 600 萬美元的庫存備貨。我們的意思是，截至 12 月 31 日的庫存相較於 9 月 30 日高出 600 萬美元。這些庫存之後會從通路售出，因此會影響未來銷售，因為它先前已在庫存中。我們已將這部分從我們的指引中剔除，所以在我們對 2016 年 KALYDECO 指引做估算時，已把這部分扣除。

In fact, when we all met in JPMorgan in San Francisco I gave people a simple calculation to think about how we got to our guidance for 2016, and I will refer to the again, which is in the fourth quarter of 2015, we did approximately $180 million worth of KALYDECO revenues. $181 million to be precise, but approximately $18 million.

事實上，當我們在舊金山的摩根大通（JPMorgan）會議上與大家見面時，我給了大家一個簡單的計算方式來理解我們如何得出 2016 年的指引；我再重申一次：在 2015 年第四季，我們的 KALYDECO 營收約為 1.80 億美元。精確來說是 1.81 億美元，但大約是 1.8 億美元。

If you take $6 million out of that and you get $174 million worth of fourth-quarter run-rate revenues and then multiply that by four. You then actually deduct the patients from that annualized number and you get to approximate range of the guidance that we provided which was $670 million to $690 million for KALYDECO. We did take account for that stocking.

如果你從中扣掉 600 萬美元，就得到第四季約 1.74 億美元的 run-rate 營收，然後再乘以四。接著你再從這個年化數字中扣除患者因素，就會得到我們所提供的指引的大致區間，也就是 KALYDECO 6.70 億至 6.90 億美元。我們確實已將這部分備貨因素納入考量。

Great. And this is Jeff. In terms of your questions around pediatrics, maybe starting with the US, as we said, we expect to submit our file in the second quarter of this year. We haven't yet had those discussions with the FDA, of course, but we are operating under the assumption of a six-month review time. The European study is still ongoing, it is enrolling. And I don't really see there being much interaction in terms of those processes.

很好。我是 Jeff。就你關於兒科的問題而言，先從美國說起，如我們所說，我們預期在今年第二季提交申報資料。當然我們尚未與 FDA 進行那些討論，但我們是以六個月審查期的假設在運作。歐洲研究仍在進行中，正在收案。我不太認為這些流程之間會有太多互動。

Operator, we're ready for the next question.

接線員，我們準備好下一個問題。

Michael Yee of RBC Capital Markets.

RBC 資本市場（RBC Capital Markets）的 Michael Yee。

Hi, thanks. Good afternoon. As it relates -- guidance for Ian. I know there is no formal guidance for ORKAMBI, but is the key message here -- when I look at the consensus of $1.6 billion, is the key message to think about the discontinuation is a little bit higher and compliance a little bit lower based on the comments that Stuart made in the US?

你好，謝謝。下午好。這與指引有關——給 Ian 的問題。我知道 ORKAMBI 沒有正式指引，但我看市場共識是 16 億美元；這裡的關鍵訊息是否是：根據 Stuart 對美國情況的評論，應該把停藥率想得稍微高一些、而依從性（compliance）稍微低一些？

And then on OUS, Ian, do I need to be clear that Germany is the only country being launched? Are there other things I need to think about when I look at the consensus of $345 million? Maybe you can make a comment about that and how consensus is modeling, just so I'm clear on that.

另外在美國以外（OUS）方面，Ian，我是否需要明確理解德國是唯一正在上市的國家？當我看共識的 3.45 億美元時，還有其他需要考量的因素嗎？也許你可以評論一下，以及共識是如何建模的，讓我更清楚。

And then the second question is just a quick clinical question on 152 and 440. In the Phase I, even though it is healthy, is there anything (inaudible) or any other biomarkers you're looking at that you will disclose that could give any hints of efficacy? Thanks.

第二個問題是一個簡短的臨床問題，關於 152 和 440。在第一期試驗中，即使受試者是健康人，你們是否有在看任何（聽不清）或其他生物標記，並且會揭露，從而提供任何療效線索？謝謝。

Thanks for the questions, Mike. Jeff Chodakewitz actually just stepped out while you asked that second question.

謝謝你的問題，Mike。Jeff Chodakewitz 在你問第二個問題時剛好離開了一下。

Might be able to tell, Jeff has a pretty bad cold. (Multiple speakers).

你可能聽得出來，Jeff 感冒得很嚴重。（多位講者）。

I just want to make sure he heard your question. I will take the first question so Jeff will take the second question.

我只是想確保他有聽到你的問題。我先回答第一個問題，第二個問題由 Jeff 來回答。

First of all, actually, no, we are not trying to say discontinuations is a bigger issue than compliance. I actually appreciate asking the question so we can clarify that. That is not what we are trying to say and it is not actually what we are seeing, even early on in this launch. But I appreciate the opportunity to comment on how people are thinking about the ORKAMBI launch and how we are seeing it reflected in sell-side models, and specifically the 2016, let's say, forecasts that are in the sell-side models.

首先，實際上不是的，我們並不是想說停藥比依從性更是個問題。我其實很感謝你提出這個問題，讓我們可以澄清。這不是我們想表達的，也不是我們所看到的情況，即使在這次上市初期也是如此。但我很感謝有機會評論大家如何看待 ORKAMBI 的上市，以及我們如何看到它反映在賣方模型中，特別是 2016 年（可以這麼說）賣方模型中的預測。

So obviously when you look at consensus, there a number of different models that are out there, a number of different numbers. And so there's some extreme numbers and then there's some that are more towards the normal. What I would say, I don't know the assumptions that are being put into other people's models, but I would ask you to listen carefully to Stuart's comments, where we touch on when do we believe we are going to get to peak penetration, the rate of uptake of ORKAMBI?

所以很明顯，當你看市場共識時，外面有許多不同的模型、許多不同的數字。因此會有一些極端的數字，也有一些更接近常態的數字。我想說的是，我不知道其他人模型中採用的假設是什麼，但我會請你仔細聽 Stuart 的評論，我們會談到我們認為何時會達到滲透率峰值，以及 ORKAMBI 的採用速度。

And then importantly the persistence and compliance, because specifically compliance, if people take six pills out of every ten, it's straightforward. You get $6 out of every $10 of your gross price. And then obviously there is a gross to net discount based on whether you have got Medicaid patients versus private payer patients. And so I just -- the opportunity to comment on this call to all people that want it, I want to make sure that people are giving thorough consideration to all the aspects of the launch. And we'd be happy to talk to you after the call as well.

然後很重要的是持續性與依從性，尤其是依從性；因為具體來說，如果病人每 10 顆只吃 6 顆，這很直接。你就只能拿到標價總額每 10 美元中的 6 美元。此外，還會因為 Medicaid 病人與商業保險病人的占比不同，而存在從毛額到淨額的折扣。所以我只是——藉由這通電話向所有想了解的人做個說明，我想確保大家在評估上市時，能充分考量上市的各個面向。我們也很樂意在會後再與你們交流。

As far as your question regarding Germany, Germany is the only country that we expect any significant revenues from outside of the US. And just to give you the background of Germany, Germany has an estimated 2,500 patients. We believe it could take 12 to 18 months to reach the peak penetration in those patients and we provided people with a price in Germany.

至於你關於德國的問題，德國是我們預期在美國以外唯一能帶來任何顯著營收的國家。簡單提供德國的背景：德國估計有 2,500 名病人。我們認為在這些病人中達到滲透率峰值可能需要 12 到 18 個月，而且我們也已向大家提供了德國的定價。

And it is one aspect of the sell-side model that I do struggle with, because when I look at an ex-US consensus of the sell-side model, a number that is close to $300 million, I find it very challenging for us to accrue that much revenue from Germany alone. I do appreciate you calling that out. And so I just hope that people are giving consideration to all these features when modeling the ORKAMBI launch. And then --

而這也是我在賣方模型中確實感到困擾的一點，因為當我看賣方模型對美國以外的共識預估時，接近 3 億美元的數字，我覺得要僅靠德國就累積到那麼多營收，對我們而言非常具挑戰性。我也很感謝你把這點提出來。所以我只是希望大家在建立 ORKAMBI 上市模型時，能把這些特徵都納入考量。然後——

Just very briefly about 152 and 440, I really can't go into the details of the ongoing studies but as you know, the main focus for Phase 1 studies has got to be exposure and safety and we learned a lot from those ongoing studies.

非常簡短地談一下 152 和 440，我真的無法深入說明正在進行的研究細節，但如你所知，第一期研究的主要重點必須是暴露量與安全性，而我們也從這些進行中的研究學到了很多。

Okay, thank you.

好的，謝謝。

Ying Huang of Bank of America.

美國銀行的 Ying Huang。

Hi, good afternoon. Thanks for taking my questions. Maybe first one is for Stu. So ORKAMBI, you're going to look at a much larger eligible patient population here. I know you guys have this clinical [alcom] base reimbursement agreement with Australian government for KALYDECO. Do you expect government payers to ask for some similar arrangement for ORKAMBI besides Australia?

嗨，下午好。謝謝回答我的問題。第一個問題可能給 Stu。關於 ORKAMBI，你們這次面對的是大得多的符合資格病人族群。我知道你們針對 KALYDECO 與澳洲政府有臨床（[alcom]）為基礎的給付協議。除了澳洲之外，你們是否預期政府付費方會要求針對 ORKAMBI 也採取類似的安排？

And second one is on clinical side is maybe for Jeff. Talking about the preclinical data you have, what's the metabolism and also secretion route for the two sets of next generation CFTR correctors? Do you expect any drug/drug interaction at all based on the way the drugs are metabolized and secreted with ORKAMBI? Thank you.

第二個問題在臨床面，可能給 Jeff。談到你們已有的臨床前數據，兩組下一代 CFTR 校正劑的代謝方式以及排泄途徑是什麼？基於這些藥物的代謝與排泄方式，你們是否預期與 ORKAMBI 會有任何藥物／藥物交互作用？謝謝。

Stuart here. I'll take your first question. Thanks for the question on reimbursement. And to cut to the chase, I really can't speculate on exactly what our arrangements are going to look like with governments around the world, because we really are just at the beginning of that process. And just to remind people, in most countries it is really a three-step process. There will be a clinical assessment of the risks and benefits of the agent. Then there is a pharmacoeconomic assessment and that really then is the starting point for then the price and contracting negotiations. And until we work our way through that process, it is really impossible to speculate on exactly what the nature of any relationship that we might come to with the various governments around the world. And for the clinical question, I will hand that over to Jeff.

我是 Stuart。我先回答第一個問題。謝謝你關於給付的提問。直接說結論，我真的無法推測我們與全球各國政府最終會是什麼樣的安排，因為我們才剛開始這個流程。也提醒大家，在多數國家這其實是三個步驟的流程。首先會對該藥物的風險與效益做臨床評估。接著會做藥物經濟學評估，而這才是後續價格與合約談判的起點。在我們走完整個流程之前，確實不可能推測我們可能與全球各國政府達成的任何關係之具體性質。至於臨床問題，我交給 Jeff。

Briefly you were asking about metabolism and so forth. And as you know, it's very hard from preclinical data to speculate, especially until you really understand exposures and so forth. We are going to understand that much better from our Phase 1 study. I would point back to what we have said all along about our NexGen molecules, that we wanted to get molecules that weren't just -- look good in the in vitro, but actually could be medicines. And that's the way we've approached it.

簡單回應你問到的代謝等問題。如你所知，僅憑臨床前數據很難推測，尤其是在你真正了解暴露量等資訊之前。我們會從第一期研究中更清楚地了解這些。我想回到我們一直以來對 NexGen 分子的說法：我們希望取得的分子不只是——在體外看起來很好，而是實際上能成為藥物。這就是我們的做法。

All right, thanks.

好的，謝謝。

Cory Kasimov of JPMorgan.

摩根大通的 Cory Kasimov。

Hey, thanks. Good afternoon, guys. I wanted to go back to the topic of ORKAMBI outside of the US. And obviously there's a lot of talk about reimbursement and time to roll out in Europe. But wanted to go to other regions such as Canada. And you just mentioned Australia, but following the approval in Canada and I know there's 1,500 patients there that meet the label criteria. Can you remind us of the market size in Australia as well?

嘿，謝謝。各位下午好。我想回到 ORKAMBI 在美國以外市場的話題。顯然大家談了很多關於歐洲的給付與推廣時程。但我想談談其他地區，例如加拿大。你們剛提到澳洲；在加拿大獲批之後，我知道那裡有 1,500 名病人符合標籤適應症條件。也請你們提醒一下澳洲的市場規模是多少？

Once you do have the reimbursement in place, what would you expect the anticipated pace of uptake and really just the overall relevance of these markets to be from a commercial standpoint? Thanks.

一旦給付到位，你們預期採用速度會是怎樣？從商業角度來看，這些市場整體的重要性會如何？謝謝。

Cory, Stuart here. As you said, the eligible patient population of F508del homozygotes in Canada is about 1,500 patients and that is out of about 4,000 total CF patients that we estimate in Canada. Now that we've got the regulatory approval, we can now begin to seek public reimbursement for ORKAMBI in Canada. And as you know, as I've just described, the process there is, again, a clinical assessment. There will be a pharmacoeconomic assessment and then there will be a price negotiation, probably through the Pan Canadian pricing alliance process that we went through with KALYDECO.

Cory，我是 Stuart。如你所說，加拿大符合資格的 F508del 同型合子病人族群約為 1,500 人；而我們估計加拿大 CF 病人總數約為 4,000 人。現在我們已取得法規核准，就可以開始在加拿大為 ORKAMBI 申請公費給付。而如你所知、我剛剛也描述過，那裡的流程同樣是先做臨床評估。接著會做藥物經濟學評估，然後進行價格談判，可能會透過我們在 KALYDECO 上走過的泛加拿大定價聯盟（Pan Canadian pricing alliance）流程。

In terms of rate of uptake, much as we are seeing here in the US, I would anticipate that the relative rate of uptake will be slower for ORKAMBI than it was with KALYDECO in Canada or, indeed, other markets outside of the US for the same reason. It's just the sheer volume of patients is much larger than it is for KALYDECO and it's just more of an administrative burden to initiate patients. So much like we are seeing here in the US. I'd expect the relative rate of uptake for ORKAMBI to be less than it is for -- less rapid than it was for KALYDECO in Canada and, indeed, other markets outside of the US.

就採用速度而言，與我們在美國看到的情況類似，我預期 ORKAMBI 的相對採用速度會比 KALYDECO 在加拿大或其他美國以外市場更慢，原因相同。主要是病人數量龐大得多，相較於 KALYDECO，啟動病人用藥在行政作業上負擔更重。所以就像我們在美國看到的一樣。我預期 ORKAMBI 的相對採用速度會低於——也就是比 KALYDECO 在加拿大以及其他美國以外市場的採用速度更不迅速。

This is Jeff Leiden. Maybe just to add one comment. Obviously we have heard a lot from Ian and Stuart in some of the questions about the kenetics of the launch and some of the short-term modeling. I do think it's important to stand back as well and remember what the total opportunity is, which I think is where your question is going.

我是 Jeff Leiden。也許我只補充一點。顯然，在一些問題上，我們已從 Ian 和 Stuart 那裡聽到很多關於上市推進的動態（kinetics）以及一些短期模型的看法。但我確實認為也很重要的是退一步，記得整體機會到底有多大；我想這也是你的問題所指的方向。

If you think about where we are today versus where we were even six months ago, today we have approval for 8,500 patients in the US and we have a launch that we are really pleased with with more than 4,500 or 55% of the patients already on drug in the US, which I think is remarkable. We have reimbursement in the US that's gone actually better than we even expected, meaning every state Medicaid is now reimbursing the drug and the majority of the private insurers are.

如果你想想我們今天所處的位置，相較於甚至六個月前，今天我們在美國已獲核准可涵蓋 8,500 名病患，而且我們對上市表現非常滿意——在美國已有超過 4,500 名、也就是 55% 的病患已經用藥，我認為這相當了不起。我們在美國的給付（reimbursement）進展其實比我們預期的還要好，也就是說，目前每一個州的 Medicaid 都已開始給付該藥物，而且多數私人保險公司也已給付。

We have approval in Europe and are starting a launch in Germany, as you heard in the press release, and ATU in France. Now we have approval in Canada, which gives us access to 1,500 private patients and the ability to negotiate reimbursement, as Stuart said, to an additional, I think, 2,500 patients or so. And so when you look at the total opportunity, it's actually every bit of what we thought before and we have made significant progress and nothing of that has changed.

我們已在歐洲獲准，並如你在新聞稿中所聽到的，正開始在德國上市，且在法國取得 ATU。現在我們也在加拿大獲准，這讓我們可接觸到 1,500 名自費（private）病患，並且如 Stuart 所說，具備與額外、我想大約 2,500 名左右病患協商給付的能力。因此，當你看整體機會時，它其實完全符合我們先前的預期；我們已取得重大進展，而這些都沒有改變。

It's impossible to predict the exact kinetics, what's going to happen in the first quarter versus second quarter. But at least the way we look at it as we look out over the next couple of years, we see that opportunity intact and progressing really nicely. And I think it's important to see that in the big picture as well as the short term model. I hope that helps.

要精準預測確切的動態是不可能的——第一季相較第二季會發生什麼。但至少以我們的觀點，當我們把視野放到未來幾年，我們看到這個機會仍然完整，而且推進得非常順利。我認為在看短期模型之餘，也要從大局來看這一點。希望這能有所幫助。

Yes, helpful prospectus. Thanks.

是的，很有幫助的展望。謝謝。

Brian Abrahams of Jefferies.

Jefferies 的 Brian Abrahams。

Hi, thanks for taking my questions. Two questions. First on the clinical side on the six- to 11-year-old population. I was wondering if you could talk a little bit about the natural history of untreated patients on the lung clearance index end points. Where does it typically go over a six-month period in children of this age, balancing disease progression versus normal growth. Does it typically worsen or stay flat?

嗨，謝謝讓我提問。兩個問題。第一個是臨床面，關於 6 到 11 歲族群。我想請你談談未治療病患在肺清除指數（LCI）終點的自然病程。在這個年齡層的兒童，六個月期間通常會如何變化，需要在疾病進展與正常生長之間取得平衡。它通常會惡化還是維持持平？

And then on the clinical/commercial side, can you give us any more granularity on the ongoing Phase 3b study in low FEV1 patients, the doses, timeline, and potential impact that data might have to help these patients manage through the initial side effects and stay on therapy?

第二個是臨床/商業面：你們能否就低 FEV1 病患正在進行的第 3b 期研究提供更細的資訊，包括劑量、時程，以及這些數據可能帶來的影響——是否能幫助這些病患度過初期副作用並持續治療？

It is Jeff Chodakewitz. Let's maybe start with the LCI and as we talked about a little bit, this actually is an early measure. So the information that I can give you is somewhat imperfect, just so you know. And its advantage, we think, is being able, in children who have relatively normal FEV1s, but, as you know, they have significant underlying disease. Their pulmonary function really is far from normal. It allows you to measure that.

我是 Jeff Chodakewitz。我們先從 LCI 談起；如我們稍早提到的，這其實是一個較早期的衡量指標。所以我能提供的資訊會有些不完美，先讓你知道。我們認為它的優勢在於：在 FEV1 相對正常的兒童身上——但如你所知，他們其實有顯著的潛在疾病——他們的肺功能其實遠非正常。LCI 讓你能夠量測到這一點。

And over reasonably short periods of time, like a six-month period as we go in our clinical studies, there could be small decreases, but we think overall that that should be relatively stable. There may be modest shift over time, but we think we would be able to have a reasonable baseline for assessing it. So actually that is part of why the data that we had coming out of our pediatric study, even without the control arm, was encouraging to us.

在相對較短的時間區間內，例如我們臨床研究中的六個月期間，可能會看到些微下降，但我們整體認為應該會相對穩定。隨時間可能會有溫和的位移，但我們認為仍能建立合理的基線來評估。因此，這也是為什麼我們兒科研究所得到的數據——即使沒有對照組——仍讓我們感到鼓舞的一部分原因。

Maybe I will take a comment on the study in patients whose FEV1s are less than 40. We are still actually in the process of collecting all that data. We are still enrolling, but we think there is some useful information there just in terms of the experience that we have accrued. We did -- to your specific question, did give -- partway through, did give investigators the opportunity to start with a lower dose and then step up to full dose.

我再回應一下 FEV1 低於 40 的病患研究。我們其實仍在收集所有數據的過程中。我們仍在收案，但我們認為就目前累積的經驗而言，當中有一些有用的資訊。針對你具體的問題，我們在研究進行到一半時，確實讓研究者有機會先以較低劑量開始，之後再逐步增加到全劑量。

That would be -- it's not a perfect evaluation of that, but we were really trying to do what you said, which is to help explore what could help patients get through those early weeks of dosing. We are going to summarize all that data and present it and use it from an education perspective as well.

那會是——這不是對該作法的完美評估，但我們確實是在嘗試做你所說的：探索什麼能幫助病患度過用藥最初幾週。我們會彙整所有數據並加以發表，也會從教育的角度加以運用。

Great; thanks very much.

很好；非常感謝。

Alicia Young of Credit Suisse.

Credit Suisse 的 Alicia Young。

Thanks, guys, for taking my question and squeezing me in and congrats on the [9 grap] in the Green. Maybe just a couple. One, if something happens with the residual where the FDA may request information, do you guys have a strategy on how you might pursue that population going forward?

謝謝各位讓我提問、也把我塞進來，並恭喜你們在 Green 上的 [9 grap]。我可能有兩個。第一，如果在 residual 這一塊發生某些情況、FDA 可能要求補充資訊，你們是否有策略，未來打算如何推進這個族群？

And then also with the potential chest tightness that sometimes happens, our checks suggested that that happened earlier rather then later, like in the first couple of weeks. But is there a dynamic where it could happen later? And did you see similarities and differences though you probably titrated in the safeties in the younger population?

另外，關於有時會出現的胸悶（chest tightness），我們的查核顯示它似乎較早發生而非較晚，例如在前幾週。但是否存在一種動態，讓它也可能在較晚期才發生？以及在較年輕族群中，雖然你們可能在安全性上做了滴定（titrated），你們是否看到相似與差異之處？

It is Jeff Leiden. Maybe I'll take the first one, since it's a bit of a science and a policy question, strategy question, I think. And then Jeff C. can take the second question on the chest tightness.

我是 Jeff Leiden。第一個我先回答，因為我認為這有點是科學與政策、以及策略層面的問題。然後第二個關於胸悶的問題，Jeff C. 可以回答。

To give you little background. I know you are aware of this, but the RF application is a little bit unusual compared to the other applications that Vertex has submitted on KALYDECO and ORKAMBI, which are always based on large Phase 3 studies. This one's different. It is basically aimed at about 1,500 patients with 23 different mutations resulting in residual function.

先給你一些背景。我知道你也了解，但 RF 申請相較 Vertex 先前針對 KALYDECO 與 ORKAMBI 提交的其他申請案有點不一樣；那些通常都是以大型第 3 期研究為基礎。這一次不同。它基本上是針對約 1,500 名、帶有 23 種不同突變、導致殘餘功能（residual function）的病患。

And it is based predominantly on preclinical data. That is cell-based data from cells that have been engineered to have those 23 different mutations, supported by a very small Phase 2a study of about 24 patients that comprised eight or nine of those 23 mutations. And so what we are really asking the FDA to look at is both the science and the medicine that we are submitting. But also there is a policy question here, which is how do you extend the label of a drug like KALYDECO to very rare populations of mutations?

而且它主要是以臨床前數據為基礎。也就是細胞層級的數據：使用經工程化處理、帶有那 23 種不同突變的細胞所得到的結果；並由一個非常小型的第 2a 期研究支持，約 24 名病患，涵蓋那 23 種突變中的 8 或 9 種。因此，我們真正請 FDA 審視的是我們所提交的科學與醫學證據。但同時這裡也有一個政策問題：要如何把像 KALYDECO 這樣的藥物標籤適應症延伸到突變非常罕見的族群？

Some of these mutations only have four patients in the US or ten patients in the US. And that's a very important policy question in precision medicine that, as you know, the FDA is considering much more broadly than just in CF. And so part of the reason why it's a little more difficult to handicap this one is because it's this combination of clinical and policy sorts of things.

其中一些突變在美國可能只有 4 名病患，或只有 10 名病患。而這是在精準醫療中非常重要的政策議題；如你所知，FDA 正在比僅限於囊性纖維化（CF）更廣泛的範圍內加以考量。因此，這也是為什麼這一案比較難以判斷（handicap）：因為它結合了臨床面與政策面等多種因素。

We feel very strongly it is the right thing to do for patients, that's why we did it. There are 1,500 patients in the US that today don't have any CFTR correction therapy of any sort. And it would be years before they could get them based on large Phase 3 trials. And so, for us, this is definitely the right thing to do for patients.

我們非常堅定地認為，這麼做對病患而言是正確的事，這也是我們之所以這麼做的原因。在美國目前有1,500名病患，至今仍未能獲得任何形式的CFTR校正治療。而若要依賴大型第3期試驗，他們可能還要再等上好幾年才能取得治療。因此，對我們而言，這絕對是對病患正確的事。

And we believe in the science strongly, and in the clinical sport we have. But handicapping what the FDA's going to do, obviously is a bit more difficult. We will know by February 7. And then based upon what we do, we have obviously come up with a strategy. But, again, our goal was to try to get this medicine that has four years of safety data to these patients as soon as possible.

我們也非常相信科學，以及我們所擁有的臨床資料。但要推測FDA會怎麼做，顯然就比較困難一些。我們會在2月7日知道結果。然後基於結果，我們當然已擬定了一套策略。不過，再次強調，我們的目標是盡快把這款已累積四年安全性資料的藥物提供給這些病患。

Great. And Jeff Chodakewitz. Just to comment on your question about the chest tightness. Maybe first step back to our Phase 3 results, which I think are the most finitive information. As you noted, those adverse events did occur very early. They were manageable in the vast majority of people and they did decrease over time. Usually the average duration was approximately two weeks.

很好。接著是Jeff Chodakewitz。就您關於胸悶的問題補充說明一下。也許先回到我們的第3期結果，我認為那是最具決定性的資訊。如您所指出，那些不良事件確實在非常早期就發生。在絕大多數人身上是可管理的，而且會隨時間下降。通常平均持續時間約為兩週。

So I think all of that really comes out of our Phase 3 data and suggests that it is an early event. And the experience in our pediatric study was actually completely consistent with that. It was a small number, it happened early and, in fact, nobody discontinued because of that.

所以我認為這些都確實反映在我們的第3期資料中，並顯示這是一個早期事件。而我們在兒科研究中的經驗也完全一致。發生的人數不多、出現得早，而且事實上沒有人因此停藥。

Great, thanks.

很好，謝謝。

Lisa Bayko of JMP Securities.

JMP Securities的Lisa Bayko。

Hi. Thanks for taking the question. I wanted to better understand what you were describing with Canada in terms of the private payers. I know there are 1,500 patients that would be eligible for ORKAMBI. Can you break that down into how many of those would be private?

嗨。謝謝讓我提問。我想更清楚了解您提到加拿大在私人支付方（private payers）方面的情況。我知道有1,500名病患符合ORKAMBI的適用資格。您能否拆分一下其中有多少人屬於私人保險？

Yes, Lisa, it is Stuart here. There is 1,500 patients in total who are 12 and over who are homozygously F508del mutation. And we estimate there's about 30% of those would be covered by some form of private insurance. Private insurance may take some time to kick in in Canada. It is not necessarily quite as rapid for them to come to a decision. Certainly that was our experience with KALYDECO. But approximately 30% of the 1,500 patients, we estimate, will have some form of private insurance.

好的，Lisa，我是Stuart。總共有1,500名12歲以上、且為F508del突變同型合子（homozygously）的病患。我們估計其中約30%會由某種形式的私人保險承保。在加拿大，私人保險啟動承保可能需要一些時間。他們做出決策未必那麼迅速。這確實是我們在KALYDECO上的經驗。但我們估計，這1,500名病患中約30%會有某種形式的私人保險。

Okay thanks. That's helpful. And then the data on the kids look really impressive. With the LCI, can you maybe comment on the clinical meaningfulness of that number? Obviously we are not as used to seeing that number as we are with FEV. I would be curious if you could put some context around that? Thanks.

好的，謝謝。這很有幫助。另外，兒童的數據看起來非常亮眼。關於LCI，您能否評論一下這個數值在臨床上的意義？顯然我們不像看FEV那樣習慣看這個指標。我想知道您是否能提供一些背景脈絡？謝謝。

Sure. It is Jeff Chodakewitz. I will say that in terms of that validation of saying what the minimally clinically important difference, it doesn't exist for that tool. I will say, based on our discussions with people who are experts in the methodology, we were -- we targeted a 0.7 decrease.

當然。我是Jeff Chodakewitz。我想說的是，就「最小臨床重要差異」（minimally clinically important difference）的驗證而言，這個工具目前並不存在這樣的標準。不過我可以說，根據我們與方法學專家的討論，我們—我們設定的目標是下降0.7。

Remember in this measure, actually a negative number is an improvement because of the way the test is done. So I can't give you an exact number, but hopefully that gives you some context in why we were pleased with the results.

請記得在這個量測中，因為測試方式的關係，負值其實代表改善。所以我無法給您一個精確的門檻數字，但希望這能讓您理解我們為何對結果感到滿意。

Lisa, this is Jeff. Maybe to reiterate one thing that Jeff C. said before because I think it's important. And I remember you and I talking about this at one point, that we are very interested in some of these alternative endpoints for a couple of reasons.

Lisa，我是Jeff。也許重申Jeff C.先前提到的一點，因為我認為這很重要。我記得你我曾在某個時點談過這件事：我們對其中一些替代性終點（alternative endpoints）非常感興趣，原因有幾個。

One, as Jeff said, these may be much more applicable to populations in which it is difficult to measure FEV1, like the kids, particularly as they get younger. But also because, as you know, FEV1, which is a measure of midsize airway resistance, is quite a bit downstream or upstream, if you will, from the problem in CF, which is really a distal airway gas exchange problem.

第一，如Jeff所說，這些指標可能更適用於難以量測FEV1的人群，例如兒童，尤其是年齡越小越是如此。但另外一個原因是，如你所知，FEV1是衡量中等大小氣道阻力的指標；相較於囊性纖維化（CF）的核心問題—其實是遠端氣道的氣體交換問題—FEV1所反映的位置相當下游（或如果你願意，也可以說相當上游）。

And actually LCI is probably a much more sensitive measure closer to the actual physiology of what is going on in CF. And so we have been very eager to start to see results from these kinds of studies to tell whether LCI could actually turn out to be as good or better an endpoint than FEV1. And obviously we need to provide agencies with clinical data to support that, and this is the first step in that process.

而LCI其實可能是更敏感、也更貼近CF實際生理機轉的量測指標。因此我們一直非常期待開始看到這類研究的結果，以判斷LCI是否可能成為與FEV1同樣好、甚至更好的終點指標。當然，我們需要向主管機關提供臨床資料來支持這一點，而這是該流程的第一步。

Okay, thanks a lot.

好的，非常感謝。

Phil Nadeau of Cowen and Company.

Cowen and Company的Phil Nadeau。

Thanks for taking my questions. Just to -- as we begin to model the younger kids -- penetration of ORKAMBI to the kids age six to 11, are there any issues with compliance persistence or uptake in that population that you want to point out or do you expect similar rates of those elements in the younger kids as in the older?

謝謝讓我提問。想請教—當我們開始對較年幼兒童建立模型時—ORKAMBI在6到11歲兒童族群的滲透率（penetration），在該族群是否有任何依從性（compliance）、持續用藥（persistence）或採用率（uptake）方面的問題需要特別指出？還是你們預期這些要素在較年幼兒童會與較年長者相近？

And then second, on the pipeline, I think we are expecting the ENaC monotherapy data midyear. Can you give us some idea of where you are looking for in that data set and what would be proof of concept? Thank you.

第二個問題關於研發管線：我想我們預期ENaC單藥治療（monotherapy）的數據會在年中出來。你們能否說明在那組資料中你們會關注哪些重點，以及什麼會構成概念驗證（proof of concept）？謝謝。

In terms of modeling the kids, were we lucky enough to get an approval this year, I'd certainly recommend that people take into account the same considerations. That's the peak penetration, time to peak, persistence rate and compliance, and model those each individually.

就兒童族群的建模而言，如果我們今年有幸獲得核准，我會建議大家把相同的考量納入：也就是峰值滲透率（peak penetration）、達到峰值所需時間（time to peak）、持續率（persistence rate）以及依從性（compliance），並分別對每一項單獨建模。

In terms of what we have seen with KALYDECO, we have seen that the worst compliance we see tends to be in that teenage to young adults-ville. And so because kids -- our assumption because kids are very closely monitored by their parents, particularly in that six- to 11-year age group, perhaps not surprisingly, we see high levels of compliance with that particular patient group. We tend to see a bit of a dip, perhaps unsurprisingly, in the teenage to young adults group. So we might anticipate in the six to 11 group that that would be our best complying patient population and that is certainly what we have seen with KALYDECO.

就我們在KALYDECO所看到的情況而言，依從性最差的族群往往是青少年到年輕成人這一段。因此，我們的假設是：由於兒童—特別是6到11歲這個年齡層—會被父母密切監督，所以不令人意外地，我們在這個病患族群看到很高的依從性。而在青少年到年輕成人族群，我們往往會看到一些下滑，這也不太令人意外。因此我們可能會預期，在6到11歲族群中，這會是我們依從性最佳的病患族群，而這也確實是我們在KALYDECO上所觀察到的。

It is Jeff Chodakewitz. Just maybe a couple of comments on the ENaC program. First of all, there is an ongoing Phase 2 study that [Perrion] has the lead on. That study is across all different types of genotypes in terms of the patient population and so we are going to be really looking for early evidence of activity in that study. And not just looking overall, but we are going to be trying to learn looking among the different subpopulations and we still expect the results of that to come out around midyear.

我是Jeff Chodakewitz。我再就ENaC計畫補充幾點。首先，目前有一項正在進行的第2期研究，由[Perrion]主導。該研究涵蓋各種不同基因型的病患族群，因此我們會在這項研究中尋找早期的活性證據。而且不只是看整體結果，我們也會嘗試在不同子族群之間進一步學習；我們仍預期其結果會在年中左右公布。

At the same time, we are going to be starting our study, which is very complementary to the study that is ongoing this quarter, and that study is going to be in 508 homozygous patients who already are going to be receiving ORKAMBI. And then looking to see whether the ENaC inhibitor can add to the efficacy for that population. And actually the preclinical data in our hands actually suggests that that may be the best way to get activity and benefit for patients from that mechanism. And so ultimately it is going to be learning from both of those trials as we better understand what the potential for that mechanism may be.

同時，我們將開始我們的研究，這與本季正在進行的研究高度互補；該研究將納入508同型合子患者，而這些患者已經會接受ORKAMBI治療。接著我們會觀察ENaC抑制劑是否能為該族群帶來額外的療效。而且，實際上我們手上的臨床前數據確實顯示，這可能是讓患者從該作用機制獲得活性與臨床受益的最佳方式。因此，最終我們將從這兩項試驗中學習，並在更深入了解該機制的潛力時加以整合。

That is very helpful. Thank you.

這非常有幫助。謝謝。

Adam Walsh of Stifel Nicolaus.

Stifel Nicolaus 的 Adam Walsh。

Adam, are you there?

Adam，你在線嗎？

Yes, I'm here. Hi. Thanks a lot for taking my question. I really appreciate it. I guess I have two questions. The first one is for Jeff Leiden. We have been out talking to docs and, according to them, your GPS reimbursement support program is really terrific. I will start with that. Some of these docs also note that the total out-of-pocket cost burden for a lot of CF patients is really quite high, even before they try to get on ORKAMBI or KALYDECO.

是的，我在。嗨。非常感謝讓我提問。我真的很感激。我想我有兩個問題。第一個是問 Jeff Leiden。我們一直在和醫師交流，根據他們的說法，你們的 GPS 給付/報銷支援計畫真的非常出色。我先從這點開始。其中一些醫師也提到，許多囊性纖維化（CF）患者的自付費用負擔其實相當高，甚至在他們嘗試使用 ORKAMBI 或 KALYDECO 之前就已如此。

And I am just curious in terms of -- with that in mind, how do you think about how far you can go to support patients, given the fact that if a co-pay is, say, 20%, and that adds quite a bit of out-of-pocket expense, where is -- how far can you go in supporting the patients there both with your own medicines and thinking about this in the context of the portfolio medicines they may already be on?

因此我想請教的是——在這樣的背景下，你們如何看待在支援患者方面能做到什麼程度？考量到若自付額（co-pay）例如是20%，就會增加相當可觀的自付支出；那麼——你們在支援患者方面（不論是針對你們自家藥品，或是放在患者可能已在使用的整體產品組合用藥脈絡下）究竟能做到多遠？

That's one. And then I have a question for Jeff Chodakewitz as well. It mentioned in the press release that two patients discontinued treatment in the ORKAMBI six-to-1 study because of adverse events. If you could comment briefly on those two patients, that would be great. Thank you.

這是第一個。另外我也有一個問題要問 Jeff Chodakewitz。新聞稿提到，在 ORKAMBI 的六比一研究中，有兩位患者因不良事件而停止治療。如果你能簡要評論一下這兩位患者的情況就太好了。謝謝。

Thanks for the questions. This is Jeff Leiden. I'm actually going to turn that one over to Stuart, because he is really responsible for the GPS program and he will also be able to describe the patient assistance program that has allowed us to help patients who do have high co-pays.

謝謝你的提問。我是 Jeff Leiden。這題我其實要交給 Stuart 回答，因為他確實負責 GPS 計畫；他也能說明我們的患者協助計畫，該計畫讓我們得以協助那些自付額很高的患者。

Yes, Adam, thanks for the question and thanks for the positive feedback. The GPS program, just so everybody is aware of it, is a service which is there to help patients and help them navigate the reimbursement process and there to provide them with ongoing education if they choose to opt in. It is great to get the feedback on that.

是的，Adam，謝謝你的問題，也謝謝你給予正面的回饋。GPS 計畫——讓大家都了解一下——是一項服務，旨在協助患者並幫助他們掌握給付/報銷流程；若患者選擇加入（opt in），我們也會提供持續性的衛教。很高興收到這方面的回饋。

Now dealing with the question you raised about out-of-pocket costs. For both KALYDECO and ORKAMBI we have comprehensive patient assistance programs in terms of co-pay assistance for eligible patients. The program is such that no patient who has a co-pay who is eligible for the program would have a monthly co-pay for either KALYDECO or ORKAMBI about $15 per month. And then for those patients who have coinsurance, we will cover coinsurance up to 30% of the price of the medicines. And the program is to keep things simple for people, identical for both KALYDECO and ORKAMBI.

接著談你提出的自付費用問題。針對 KALYDECO 與 ORKAMBI，我們都有完整的患者協助計畫，包含符合資格患者的自付額補助（co-pay assistance）。該計畫的設計是：任何有自付額且符合計畫資格的患者，其每月針對 KALYDECO 或 ORKAMBI 的自付額都不會高於每月約15美元。另外，對於採共保（coinsurance）的患者，我們將補助共保費用，最高可達藥品價格的30%。此計畫的目的在於讓流程對大家更簡單，且 KALYDECO 與 ORKAMBI 兩者的規則完全一致。

And it's Jeff Chodakewitz. In terms of the pediatric study, as we pointed out, the overall profile was actually quite favorable. If there were two patients who discontinued, one of them was because of abnormal liver function tests and one of them was because of a rash.

我是 Jeff Chodakewitz。就兒科研究而言，如同我們指出的，整體概況其實相當正面。若談到那兩位停止治療的患者，其中一位是因肝功能檢測異常，另一位則是因出疹。

Great, thanks a lot.

很好，非常感謝。

Operator, we have time for two more questions.

接線員，我們還有時間再回答兩個問題。

Mark Schoenebaum of Evercore ISI.

Evercore ISI 的 Mark Schoenebaum。

Hey, guys, first question is on guidance. Should we assume your financial guidance is more or less conservative than Partridge's statement that this call would end by 5:45? Because you missed that pretty badly, so I'm a little concerned here.

嘿，各位，第一個問題是關於財測指引（guidance）。我們是否應該假設你們的財務指引大致上比 Partridge 說這通電話會在5:45結束更保守或更不保守？因為你們在那點上錯得挺離譜，所以我有點擔心。

Anyway, just really quick ones. I know it's getting late. Number one, can you just tell us when to expect data from the Phase 2 triple combo that you are going to start this year? I assume that is a mid-2017 event? Let me know if I'm wrong on that.

總之，幾個很快的問題。我知道時間很晚了。第一，你們今年要啟動的第二期三聯合併療法（Phase 2 triple combo），大概什麼時候可以期待看到數據？我猜是2017年年中左右的事件？如果我猜錯請告訴我。

And then, number two, I apologize if you addressed this. If you did I missed it. But can you confirm the timing and your disclosure intentions around the -- what I believe is the futility analysis in the [hetmin] trial?

第二，我先道歉，如果你們已經回答過這題。如果有的話我可能漏聽了。但你們能否確認一下——我認為是在 [hetmin] 試驗中的無效性分析（futility analysis）——其時程以及你們對外揭露的意圖？

It's Ian. I'll take both of those questions.

我是 Ian。這兩個問題我都來回答。

I want an answer to the Partridge question, please. (Laughter).

我想要 Partridge 那題的答案，拜託。（笑聲）。

In his prepared remarks he said the call would be brief as well. So he was wrong there as well.

他在事先準備的發言中也說這通電話會很簡短。所以他在那點上也錯了。

Pretty embarrassing.

挺尷尬的。

Luckily he doesn't give financial guidance for us. (Laughter).

幸好他不負責替我們提供財務指引。（笑聲）。

So your first question was regarding the triple. So, first of all, the timing of getting data from the triple or disclosing the data from the triple is really subject to how fast we move through the Phase 1. And we've mentioned this before. The longer our Phase 1 takes, actually the better it is because it means we are escalating the dose and we're getting greater exposure of the drug into the healthy volunteers.

所以你的第一個問題是關於三聯。首先，取得三聯數據或對外揭露三聯數據的時點，確實取決於我們推進第一期（Phase 1）的速度。我們之前也提過。第一期做得越久其實越好，因為這代表我們正在進行劑量遞增，並讓健康受試者獲得更高的藥物暴露量。

And based on where we expect this to go, we anticipate in the second half of the year we will be in the proof-of-concept triple studies, which will probably push us into early 2017 to get that data. That's how we are trying to set a timing expectation. And then your second question was on the disclosure regarding which? Futility.

依照我們預期的進展，我們預計在今年下半年會進入概念驗證（proof-of-concept）的三聯研究；這可能會把我們推到2017年初才取得那些數據。這就是我們試圖設定的時間預期。然後你的第二個問題是關於哪一項的揭露？無效性（futility）。

The [hat man] terms of recruitment to that trial is actually going very nicely, as you might anticipate, given that these patients have no other alternative medicine. And so we anticipate that we will be completed enrollment around the middle of the year. And, therefore, we do expect the futility study to be done in the second half of the year. Obviously we won't be disclosing that unless we have to curtail the study. So no news would be good news on that assessment.

[hat man] 試驗在招募方面其實進展得非常順利，這也如你所預期，因為這些患者沒有其他替代藥物選擇。因此我們預期大約在年中完成收案。也因此，我們確實預期無效性分析會在下半年完成。顯然，除非我們必須縮減或終止該研究，否則我們不會對外揭露該結果。所以在那項評估上，沒有消息就是好消息。

Okay. Thanks a lot. And congrats on the Pats' loss.

好的。非常感謝。也恭喜愛國者隊輸球。

Now you're hurting us.

你現在是在傷害我們。

Tony Butler of Guggenheim Securities.

Guggenheim Securities 的 Tony Butler。

Thanks very much for allowing me to squeeze one in. There are number of respiratory articles that actually support the use of LCI as an endpoint because it does demonstrate greater sensitivity. I guess the question is really what is the correlation between LCI and FEV, given that LCI apparently becomes abnormal earlier than spirometry and yet, in the later stage disease, it seems to correlate. And then, therefore, can you only use LCI in children?

非常感謝讓我插問一題。其實有不少呼吸領域的文章支持使用 LCI 作為終點，因為它確實展現出更高的敏感度。我想問題真正是：LCI 與 FEV 的相關性是什麼？因為看起來 LCI 會比肺量測定更早出現異常，但在疾病後期似乎又會相關。因此，你們是否只能在兒童中使用 LCI？

My last question -- I guess that's for Jeff C. And my last question really for Jeff L. Are you going to publish the kinetics and functionality of 152 and 440 soon? Or I guess ever, in a peer-reviewed journal? Thank you.

我最後一個問題——我想這是問 Jeff C. 的。以及我最後一個問題其實是問 Jeff L. 的：你們會很快發表 152 和 440 的動力學與功能性資料嗎？或者說，是否會在同儕審查期刊上發表？謝謝。

I will quickly say we will make the appropriate steps in terms of where we publish data regarding our molecules as we move forward. Obviously you've seen a lot of publications at NACF, which is in the fall and then overseas the ECFS conference, so you'll probably expect to see more data at those conferences. And then to your other question, Jeff.

我先簡短回覆：隨著我們往前推進，我們會採取適當步驟，決定在何處發表與我們分子相關的資料。顯然你已經在 NACF（秋季）以及海外的 ECFS 會議上看到很多發表，所以你大概可以預期在那些會議上會看到更多資料。至於你另一個問題，Jeff。

A couple more comments on LCI. And as you point out, they do have overlapping but somewhat different sweet spots, if you will, in terms of the best way to use them. And I do think, as a field, this links back to Jeff Leiden's comments that we are continuing to learn the best way to use each of them. Obviously LCI has that potential sensitivity advantages in children. But right now there are only some centers that actually have the expertise to do that well. And, of course, a great tool used poorly doesn't really help anybody. So I think there are still -- there is still a lot of work to be done.

再補充幾點關於 LCI。如你所說，就最佳使用方式而言，它們的適用區間（如果你願意這麼說）有重疊但也略有不同。我也確實認為，從整個領域來看，這呼應了 Jeff Leiden 的評論：我們仍在持續學習如何最好地使用各項指標。顯然 LCI 在兒童方面具有潛在的敏感度優勢。但目前真正具備把這項檢測做好的專業能力的中心仍然只有一些。當然，再好的工具如果用得不好，對任何人都沒有幫助。所以我認為仍然——還有很多工作要做。

And then there is the other part of your question about regulatory recognition. And I can't speak for the regulators, but I think it was encouraging that in Europe, LCI was accepted as our primary endpoint in our study. So I think there is, in general an openness to continue to advance the field and hopefully we can contribute to that.

然後你問題的另一部分是關於監管機構的認可。我無法代表監管單位發言，但我認為令人鼓舞的是，在歐洲，LCI 在我們的研究中被接受作為主要終點。因此我想整體而言，監管端對於持續推動這個領域是持開放態度的，希望我們也能對此有所貢獻。

Thank you both.

謝謝你們兩位。

Great. Well, thank you again for joining us tonight. Apologies for running over; it was all Michael's fault. At the risk of running for one or two more minutes, I did want to make a couple of concluding remarks.

很好。再次感謝各位今晚加入我們。抱歉超時；這全都是 Michael 的錯。冒著再多占用一兩分鐘的風險，我想做幾點結語。

And, again, I always like to do this sort of in retrospect and say where are we today as a Company as compared to where we were six or 12 months ago. And I must say, from a personal standpoint and from the standpoint of CF patients, I am very, very encouraged with the progress that we've made. I think it's now clear that KALYDECO and ORKAMBI together are approved for about 25,000 patients or almost one-third of all patients, CF patients, in the world.

而且，我一向喜歡用回顧的方式來看：相較於六個月或十二個月前，公司今天處於什麼位置。我必須說，從個人角度以及從囊性纖維化（CF）患者的角度來看，我對我們取得的進展感到非常、非常振奮。我想現在已經很清楚，KALYDECO 與 ORKAMBI 合計已獲核准可用於約 25,000 名患者，或接近全球所有 CF 患者的三分之一。

As we discussed with JPMorgan, there is a fairly straightforward strategy through label expansion in the younger populations and others to take that number from 25,000 to 44,000 patients in the next couple of years. And then we have a clear strategy with multiple prongs, actually, to get to the vast of majority patients. And they include the ENaC inhibitors which are in Phase 2, so they can move very rapidly if we see positive results there in combination with ORKAMBI.

正如我們與 JPMorgan 討論的，透過在更年幼族群及其他族群擴大適應症標籤，有一個相當直接的策略，可在未來幾年把這個數字從 25,000 提升到 44,000 名患者。接著我們也有一個清晰、實際上多管齊下的策略，來覆蓋絕大多數患者。其中包括已進入第 2 期的 ENaC 抑制劑；若與 ORKAMBI 聯合用藥看到正面結果，它們就能非常快速地推進。

They include the NextGen correctors, which are moving along in Phase 1, and which we hope to have in patients in the second half of this year. And we think those have the potential to both increase the efficacy for the patients we are treating today, but also to let us get to that large subset of hetmin patients that don't have anything today.

也包括 NextGen 校正劑（correctors），目前正於第 1 期推進，我們希望在今年下半年讓患者開始使用。我們認為它們不僅有潛力提升我們目前治療患者的療效，也能讓我們覆蓋到那一大群目前沒有任何治療選項的 hetmin 患者。

And then finally the progress we have made with some of our deals, particularly the CRISPR deal here. And although that's the Holy Grail, 10 or 15 years down the road, we do have a vision of potentially correcting the underlying mutation and curing patients with CF. And so as I look at the world from our perspective, obviously, I'm tremendously encouraged about the future opportunity, particularly the future opportunity for patients.

最後，是我們在一些交易上取得的進展，特別是這裡的 CRISPR 交易。雖然那是聖杯、可能要 10 到 15 年後才會實現，但我們確實有一個願景：有機會校正根本突變，並治癒 CF 患者。因此，從我們的角度看這個世界，我對未來的機會當然感到極為振奮，尤其是對患者而言的未來機會。

And I am pleased with the progress we are making and we'll look forward to updating you over the next year as we continue that.

我也對我們正在取得的進展感到滿意，並期待在未來一年持續推進的同時，向各位更新最新情況。

Thanks very much, everybody. That concludes tonight's call. The IR team will be available in our offices for additional questions if you have them. Thank you.

非常感謝各位。今晚的電話會議到此結束。若各位還有其他問題，投資人關係（IR）團隊會在辦公室提供協助。謝謝。

Ladies and gentlemen, you may disconnect your lines at this time. Have a great day.

各位女士、先生，您現在可以掛斷電話。祝您有美好的一天。