福泰製藥 (VRTX) 2017 Q4 法說會逐字稿

Good evening. This is Michael Partridge, Vice President of Investor Relations for Vertex. We're pleased to be able to talk with you tonight about our fourth quarter and full year financial results for 2017 and about our continued progress to build long-term leadership in the treatment of cystic fibrosis. Dr. Jeff Leiden, Chairman and CEO; Dr. Jeff Chodakewitz, Chief Medical Officer; and Ian Smith, Chief Operating Officer, will provide prepared remarks this evening. Stuart Arbuckle, Chief Commercial Officer, will join us for Q&A.

晚安.這是 Vertex 公司投資者關係副總裁 Michael Partridge。我們很高興今晚能與大家談談我們 2017 年第四季和全年的財務業績，以及我們在囊性纖維化治療領域建立長期領導地位方面取得的持續進展。董事長兼執行長傑夫·萊頓博士、首席醫療官傑夫·喬達克維茨博士和首席營運長伊恩·史密斯將於今晚發表準備好的演講。首席商務官史都華·阿巴克爾將參加問答環節。

We recommend that you access the webcast live as a supplement to the information from today's press releases. These slides are available for download on the Investor Relations page on our website. This conference call is being recorded, and a replay will be available on our website.

我們建議您觀看網路直播，作為今天新聞稿資訊的補充。這些幻燈片可在我們網站的投資者關係頁面下載。本次電話會議正在錄音，錄音回放將在我們的網站上提供。

I will remind you that we will make forward-looking statements on this call. These statements 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 the ongoing development and potential commercialization of any triple-combination regimen for cystic fibrosis, Vertex' other cystic fibrosis programs and Vertex' future financial performance, are based on management's current assumptions. Actual outcomes and events could differ materially.

我在此提醒各位，我們將在本次電話會議上發表一些前瞻性聲明。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，包括但不限於有關囊性纖維化三聯療法的持續開發和潛在商業化、Vertex 的其他囊性纖維化項目以及 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. Today is a special day for everyone at Vertex and for the CF community as it marks the sixth anniversary of the FDA approval of our first CF medicine, KALYDECO. When KALYDECO was first approved in 2012, only 1,200 people worldwide were eligible for a medicine to treat the underlying cause of their disease. Today, the number of people eligible for one of our CF medicines has grown to 34,000 worldwide, and we will continue to expand the number of eligible patients in 2018 and beyond.

謝謝你，麥可。各位晚上好。今天對於 Vertex 的每個人以及 CF 群體來說都是一個特殊的日子，因為今天是我們第一款 CF 藥物 KALYDECO 獲得 FDA 批准六週年的日子。2012 年 KALYDECO 首次核准時，全球只有 1,200 人有資格獲得治療其疾病根本原因的藥物。目前，全球符合我們CF藥物使用條件的人數已增至34,000人，我們將繼續在2018年及以後擴大符合條件的患者人數。

In the past few years, and especially in 2017, we've made remarkable scientific progress that has moved us closer to achieving our ultimate goal in CF, to develop highly effective medicines for all people with the disease. And with today's announcement that we have selected 2 next-generation correctors to advance into Phase III development as part of 2 different triple-combination regimens, we've taken a significant step toward achieving that goal.

在過去的幾年裡，尤其是在 2017 年，我們在科學領域取得了顯著的進步，使我們離實現 CF 的最終目標更近了一步，那就是為所有患有這種疾病的人開發高效的藥物。今天我們宣布，我們已選定 2 種下一代矯正劑進入 III 期開發階段，作為 2 種不同的三聯療法的一部分，這標誌著我們朝著實現該目標邁出了重要一步。

I'd like to begin by acknowledging everyone who has helped to bring us to this important milestone in our more than 15-year journey to develop new CF medicines. I'd especially like to thank the patients, families and CF caregivers for their unwavering support as well as the employees at Vertex for their commitment to this program. The data announced today are remarkable and demonstrate the potential for significant and consistent clinical benefits in patients with one F508del mutation and a minimal function mutation when treated with a triple-combination regimen containing either VX-659 or VX-445. We remain focused on bringing forward the best triple-combination regimen to patients as quickly as possible.

首先，我要感謝所有幫助我們達成這項重要里程碑的人，這是我們在長達 15 年的 CF 新藥研發歷程中所取得的成就。我特別要感謝病患、家屬和囊性纖維化照護人員的堅定支持，以及 Vertex 的員工對該計畫所做的貢獻。今天公佈的數據非常出色，顯示對於攜帶一個 F508del 突變和一個最小功能突變的患者，使用包含 VX-659 或 VX-445 的三聯療法進行治療，有可能獲得顯著且持續的臨床益處。我們將繼續致力於盡快為患者提供最佳的三重療法。

Based upon the totality of the data collected today from 4 different triple-combination regimens in more than 200 people with CF, we believe that both the VX-659 and VX-445 regimens have highly compelling profiles for late-stage development. Therefore, we have decided to advance both regimens into Phase III, one of which we plan to evaluate as a once-daily regimen. We're having productive discussions with the FDA regarding Phase III programs for both triple-combination regimens. We look forward to finalizing the design of these programs and remain on track to begin the first Phase III studies of a triple-combination regimen in the first half of this year.

根據今天從 200 多名 CF 患者中收集到的 4 種不同的三聯療法的全部數據，我們認為 VX-659 和 VX-445 療法都具有非常令人信服的後期開發前景。因此，我們決定將兩種方案推進到 III 期，其中一種方案我們計劃評估為每日一次的方案。我們正在與 FDA 就兩種三重療法的 III 期項目進行富有成效的討論。我們期待最終確定這些方案的設計，並繼續按計劃在今年上半年啟動首個三聯療法的 III 期研究。

As I look back over the past year, we've made tremendous progress across all parts of our business and have positioned the company for further success. We continue to increase the number of patients eligible for and treated with our approved medicines, which is driving significant revenue growth. We expect this revenue growth to continue, which will, in turn, also drive significant earnings growth. We reported positive Phase III data for the combination of tezacaftor and ivacaftor and are awaiting FDA approval for this important new treatment option, which will be a significant contributor to revenue growth beginning this year.

回顧過去一年，我們在業務的各個方面都取得了巨大的進步，並為公司未來的成功奠定了基礎。我們不斷增加符合資格並使用我們已獲批准藥物進行治療的患者人數，這推動了收入的顯著增長。我們預計這種營收成長動能將持續下去，進而也將推動獲利的顯著成長。我們公佈了 tezacaftor 和 ivacaftor 聯合用藥的積極 III 期數據，目前正在等待 FDA 批准這一重要的新治療方案，該方案將從今年開始為收入成長做出重大貢獻。

Today, we've provided further hope for those still awaiting a new medicine for the cause of their CF with a selection of 2 next-generation correctors to move into Phase III development as part of triple-combination regimens.

今天，我們為那些仍在等待治療囊性纖維化病因的新藥的人們帶來了更多希望，我們選擇了 2 種下一代矯正劑進入 III 期開發階段，作為三聯療法的一部分。

And beyond CF, we are preparing to begin clinical development of CTX001 in 2 devastating diseases, beta-thalassemia and sickle cell disease, with our partner, CRISPR Therapeutics. We also expect to move one or more potential medicines from our internal research programs into clinical development in other diseases this year.

除了 CF 之外，我們正準備與合作夥伴 CRISPR Therapeutics 一起，開始對 CTX001 進行臨床開發，以治療兩種毀滅性疾病：β-地中海貧血和鐮狀細胞疾病。我們也預計今年將一種或多種來自我們內部研究計畫的潛在藥物推進到其他疾病的臨床開發階段。

I look forward to updating you on our continued progress over the coming year and will now turn the call over to Dr. Jeff Chodakewitz to review today's announcement in more detail.

我期待在未來一年向大家報告我們的持續進展，現在我將把電話交給傑夫·喬達克維茨博士，讓他更詳細地回顧今天的公告。

Thanks, Jeff, and good evening. I'm very pleased to share the initial results from the ongoing Phase II studies of the VX-659 and VX-445 triple-combination regimens and to review our plans to advance these 2 different triple-combination regimens into Phase III development.

謝謝你，傑夫，晚上好。我非常高興地與大家分享正在進行的 VX-659 和 VX-445 三聯療法 II 期研究的初步結果，並回顧我們推進這兩種不同的三聯療法進入 III 期開發的計劃。

The initial Phase II data reported today are extraordinary from both an efficacy and safety perspective. Collectively, our Phase II studies in more than 200 CF patients provide compelling evidence of the significant clinical benefits that triple combinations may provide to CF patients.

今天公佈的初步 II 期臨床試驗數據，無論從療效或安全性角度來看，都非常出色。總的來說，我們對 200 多名 CF 患者進行的 II 期研究提供了令人信服的證據，證明三聯療法可能為 CF 患者帶來顯著的臨床益處。

All 4 of our next-generation correctors were advanced into development out of our own labs based not only on their in vitro efficacy profile, but also on their drug-like properties, including PK profiles, minimal drug-drug interaction potential, ability to be coformulated with tezacaftor and ivacaftor and others. All of the Phase II data generated to date has validated the rigorous selection criteria we used.

我們所有 4 種下一代矯正劑都是在我們自己的實驗室中推進開發的，這不僅是基於它們的體外功效，還基於它們的類藥特性，包括 PK 特性、最小的藥物相互作用潛力、與 tezacaftor 和 ivacaftor 等藥物共同配製的能力。迄今為止產生的所有 II 期數據都驗證了我們使用的嚴格選擇標準。

We are today reporting top line safety and tolerability data as well as efficacy information as measured by mean absolute within group change in percent-predicted FEV1, sweat chloride and CFQ-R data for the patients with a minimal function mutation from each study.

今天，我們將報告主要安全性和耐受性數據，以及療效信息，這些信息通過每項研究中最小功能突變患者的預測 FEV1 百分比、汗液氯化物和 CFQ-R 數據的平均絕對組內變化來衡量。

First to the Phase II data for the VX-659 triple regimen. This study evaluated VX-659 in combination with tezacaftor and ivacaftor or triple placebo for 4 weeks. 53 patients received one of 3 doses of VX-659 in combination with tezacaftor and ivacaftor. Across the study, the combination was generally well-tolerated and the overall safety profile was favorable. The majority of adverse events were considered mild or moderate. There were no discontinuations due to adverse events. One patient interrupted triple-combination dosing due to a rash, which resolved following interruption of treatment. The patient restarted and completed triple-combination dosing without any further rash.

首先公佈VX-659三重療法的II期數據。本研究評估了 VX-659 與 tezacaftor 和 ivacaftor 合併使用或三重安慰劑治療 4 週的效果。53 名患者接受了 3 種不同劑量的 VX-659 與 tezacaftor 和 ivacaftor 合併治療。在整個研究過程中，此組合療法整體耐受性良好，整體安全性良好。大多數不良事件被認為是輕度或中度的。沒有因不良事件而停藥的情況。一名患者因皮疹而中斷了三聯療法，停藥後皮疹消退。患者重新開始並完成了三重療法，未再出現皮疹。

In the patients who received this triple combination, we observed significant improvements in lung function of 10.2, 11.6 and 13.3 percentage points across the 3 dose groups that were evident by the second week of the treatment period and sustained through the 4-week dosing period. These data are shown on Slide 10.

在接受這種三聯療法的患者中，我們觀察到肺功能在 3 個劑量組中分別有 10.2、11.6 和 13.3 個百分點的顯著改善，這種改善在治療期的第二週就顯現出來，並在 4 週的給藥期內持續存在。這些數據顯示在第10張投影片上。

With sweat chloride, we saw significant decreases of 45.8, 43.7 and 51.4 millimole per liter for the triple-combination dose groups. These were the largest decreases in sweat chloride observed for any of our triple-combination regimens to date. These data are shown on Slide 11.

對於汗液氯化物，我們發現三聯劑量組的氯化物含量顯著下降了 45.8、43.7 和 51.4 毫摩爾/公升。這是我們迄今觀察到的所有三聯療法中汗液氯化物含量下降幅度最大的一次。這些數據顯示在第11張投影片上。

We also observed significant improvements in patient-reported respiratory symptoms of 24.6, 19.8 and 21.8 points for those on the triple-combination regimens as reported in the CFQ-R respiratory domain score. These data are shown on Slide 12.

我們還觀察到，接受三聯療法的患者在 CFQ-R 呼吸領域評分中報告的呼吸道症狀有顯著改善，分別提高了 24.6 分、19.8 分和 21.8 分。這些數據顯示在第12張投影片上。

I will now turn to the Phase II data for the VX-445 triple regimen. This study evaluated VX-445 in combination with tezacaftor and ivacaftor or triple placebo for 4 weeks. 53 patients received one of 3 doses of VX-445 in combination with tezacaftor and ivacaftor. Across the study, the combination was generally well-tolerated and the overall safety profile was favorable.

接下來，我將介紹 VX-445 三聯療法的 II 期數據。本研究評估了 VX-445 與 tezacaftor 和 ivacaftor 合併使用或三重安慰劑治療 4 週的效果。53 名患者接受了 3 種不同劑量的 VX-445 與 tezacaftor 和 ivacaftor 合併治療。在整個研究過程中，此組合療法整體耐受性良好，整體安全性良好。

The majority of adverse events were considered mild or moderate. There were 2 discontinuations from the treatment groups due to adverse events and none in the placebo group. The treatment discontinuations occurred in the VX-445 100-milligram dose group. One of the treatment discontinuations was due to increased bilirubin without concomitant transaminase elevation, which was observed on the final day of dosing. The patient's bilirubin levels returned to baseline during the safety follow-up period after discontinuation of treatment. The second discontinuation was due to rash, and following discontinuation of treatment, the rash resolved.

大多數不良事件被認為是輕度或中度的。治療組有 2 例因不良事件而退出研究，安慰劑組則無一例。治療中斷發生在 VX-445 100 毫克劑量組。其中一例治療中斷是由於膽紅素升高而轉氨酶未同時升高，這是在最後一次給藥當天觀察到的。患者在停止治療後的安全追蹤期內，膽紅素水平恢復至基線水平。第二次停藥是因為出現了皮疹，停藥後皮疹消退了。

In those who received the VX-445 triple-combination regimen, we observed significant improvements in lung function of 11.1, 7.8 and 13.8 percentage points that were evident by the second week of the treatment period and sustained through the 4-week dosing period. These data are shown on Slide 15.

在接受 VX-445 三聯療法的患者中，我們觀察到肺功能顯著改善，分別提高了 11.1、7.8 和 13.8 個百分點，這些改善在治療期的第二週就已顯現，並在 4 週的給藥期內持續存在。這些數據顯示在第15張投影片上。

With sweat chloride, we saw significant decreases of 38.2, 33.2 and 39.1 millimole per liter for the triple-combination dose groups. These data are shown on Slide 16.

對於汗液氯化物，我們發現三聯劑量組的氯化物含量顯著下降了 38.2、33.2 和 39.1 毫摩爾/公升。這些數據顯示在第16張投影片上。

We also observed significant improvements in patient-reported respiratory symptoms of 20.8, 15.4 and 25.7 points for those on the triple-combination regimens as reported in the CFQ-R respiratory domain score. These data are shown on Slide 17.

我們還觀察到，接受三聯療法的患者在 CFQ-R 呼吸領域評分中報告的呼吸道症狀有顯著改善，分別提高了 20.8 分、15.4 分和 25.7 分。這些數據顯示在第17張投影片上。

I would also note that we conducted post-dose spirometry evaluations for both of the triple-combination regimens in these studies and saw no evidence of bronchoconstriction.

我還要指出，我們在這些研究中對兩種三重療法進行了給藥後肺功能測定評估，並沒有發現支氣管收縮的跡象。

The Phase II studies of the VX-659 and VX-445 triple-combination regimens are currently ongoing in patients with 2 F508del mutations. An additional part of each study is evaluating a potential once-daily regimen that contains the once-daily potentiator, VX-561, in place of twice-daily ivacaftor in patients with one F508del mutation and one minimal function mutation. These parts of the studies are fully enrolled, and the remaining data from each of the Phase II studies are expected in the first half of 2018.

目前，針對攜帶 2 個 F508del 突變的患者，正在進行 VX-659 和 VX-445 三重療法的 II 期研究。每項研究的另一部分是評估一種潛在的每日一次的治療方案，該方案包含每日一次的增強劑 VX-561，以代替每日兩次的伊伐卡托，用於治療具有一個 F508del 突變和一個最小功能突變的患者。這些研究部分已全部招募完畢，預計 2018 年上半年將獲得各 II 期研究的剩餘數據。

Data from across our portfolio of next-generation correctors received to date show that the potential benefits of treating the cause of CF with triple-combination regimens are clear and support the rapid advancement of the VX-659 and VX-445 triple-combination regimens into Phase III development.

迄今為止，我們收到的所有下一代矯正劑的數據表明，使用三聯療法治療 CF 病因的潛在益處是顯而易見的，並支持 VX-659 和 VX-445 三聯療法快速推進至 III 期開發。

Our strategy of advancing both VX-659 and VX-445 into Phase III gives us the opportunity to generate data from 2 different triple-combination regimens, including one that may be dosed once daily and pick the best regimen to bring to patients as quickly as possible.

我們將 VX-659 和 VX-445 都推進到 III 期，這使我們有機會從 2 種不同的三聯療法中產生數據，其中一種療法可能每天給藥一次，並選擇最佳療法盡快帶給患者。

Our discussions with the FDA regarding our Phase III program for triple-combination regimens have been productive, and we have already shared with the FDA the available data for the VX-659 and VX-445 triple-combination regimen. We are now focused on finalizing the design of the Phase III programs, and we remain on track to initiate the first Phase III program in the first half of 2018 upon completion of these discussions.

我們與 FDA 就三聯療法 III 期計畫的討論取得了富有成效，我們已經與 FDA 分享了 VX-659 和 VX-445 三聯療法的可用數據。我們現在正集中精力完成第三階段計劃的設計，並且我們仍按計劃在完成這些討論後於 2018 年上半年啟動第一個第三階段計劃。

We plan to conduct 2 separate studies for each triple-combination regimen, a study of each regimen in people with CF who have one F508del mutation and one minimal function mutation and a study in those with 2 F508del mutations.

我們計劃對每種三聯療法進行 2 項獨立的研究，一項研究針對患有 CF 且具有一個 F508del 突變和一個最小功能突變的患者，另一項研究針對患有 2 個 F508del 突變的患者。

Following the initiation of the Phase III studies for the VX-659 triple-combination regimen in the first half of 2018, we plan to initiate the Phase III studies for the VX-445 triple regimen in the middle of the year. We plan to evaluate VX-445 in combination with tezacaftor and the once-daily potentiator, VX-561, as a potential once-daily triple-combination regimen pending the Phase II data for this regimen and also the completion of a long-term nonclinical toxicology study for VX-445.

在 2018 年上半年啟動 VX-659 三聯療法的 III 期研究之後，我們計劃在年中啟動 VX-445 三聯療法的 III 期研究。我們計劃評估 VX-445 與 tezacaftor 和每日一次的增效劑 VX-561 聯合使用，作為一種潛在的每日一次的三聯療法，但前提是該療法的 II 期數據以及 VX-445 的長期非臨床毒理學研究已經完成。

In addition to evaluating each triple-combination regimen in the studies I just discussed, we also plan to evaluate each of these triple-combination regimens in patients who have one F508del mutation and a second gating or residual function mutation. These studies are planned to begin in the second half of 2018.

除了評估我剛才討論的研究中的每種三聯療法方案外，我們還計劃評估每種三聯療法方案在具有一個 F508del 突變和第二個門控或殘餘功能突變的患者中的療效。這些研究計劃於 2018 年下半年開始。

Once our FDA discussions are complete, we look forward to updating you with more details regarding the specific designs of the studies. Before I close, I'd like to thank everyone who took part in these studies for their commitment to helping us advance the treatment of CF.

一旦我們與FDA的討論結束，我們將期待向您提供有關研究具體設計的更多細節。在結束演講之前，我要感謝所有參與這些​​研究的人，感謝他們致力於幫助我們推進囊性纖維化的治療。

I'll now turn the call to Ian.

現在我將把電話轉給伊恩。

Thanks, Jeff, and good evening to everyone. 2017 was an outstanding year for Vertex, and tonight, I'm pleased to review our fourth quarter 2017 financials and our 2018 full year financial guidance for combined non-GAAP R&D and SG&A expenses.

謝謝你，傑夫，大家晚上好。2017 年對 Vertex 來說是傑出的一年，今晚，我很高興回顧我們 2017 年第四季度的財務狀況以及我們對 2018 年全年非 GAAP 研發和銷售、管理及行政費用的財務預期。

Revenues first. Total CF product revenues of $621 million in the fourth quarter of 2017 represent a 37% increase compared to $454 million we recorded in the fourth quarter of 2016. Our product revenues grew each quarter throughout 2017 as we increased the number of patients treated with our approved medicines. Today, we estimate we have initiated therapy in over 17,000 of the 34,000 patients eligible for our medicines. We expect eligibility and the number of patients we treat to continue to grow throughout 2018.

收入優先。2017 年第四季 CF 產品總營收為 6.21 億美元，比 2016 年第四季的 4.54 億美元成長了 37%。2017 年，隨著使用我們核准藥物治療的患者人數增加，我們的產品收入每季都實現了成長。據估計，目前我們已經對 34,000 名符合我們藥物使用條件的患者中的 17,000 多名開始了治療。我們預計 2018 年符合條件的患者人數和我們治療的患者人數將繼續增長。

For ORKAMBI, we reported fourth quarter 2017 product revenues of $365 million, a 32% increase compared to the fourth quarter of 2016.

ORKAMBI 2017 年第四季產品營收為 3.65 億美元，比 2016 年第四季成長了 32%。

The growth in 2017 was driven by the continued uptake of the medicine globally, particularly in children ages 6 to 11 in the U.S.

2017 年的成長是由該藥物在全球範圍內的持續普及所推動的，尤其是在美國 6 至 11 歲兒童中的普及。

Fourth quarter 2017 KALYDECO revenues were $256 million, a 44% increase compared to the fourth quarter of 2016. This significant growth in 2017 was driven by the rapid uptake of the medicine by patients in the U.S. with residual function mutations following the label expansion of these patients in mid-2017.

2017 年第四季 KALYDECO 的營收為 2.56 億美元，比 2016 年第四季成長了 44%。2017 年的顯著增長是由美國患者在 2017 年年中擴大適應症範圍後迅速接受該藥物所推動的，這些患者存在殘餘功能突變。

Our fourth quarter 2017 non-GAAP-combined R&D and SG&A expenses were $355 million compared to $295 million in the fourth quarter of 2016. This increase was primarily due to the continued acceleration and advancement of our portfolio of triple-combination regimens for CF and the investments to support the treatment of patients with our medicines globally.

2017 年第四季度，我們非 GAAP 合併研發及銷售、一般及行政費用為 3.55 億美元，而 2016 年第四季為 2.95 億美元。這一增長主要歸功於我們針對囊性纖維化的三聯療法產品組合的持續加速發展和進步，以及為支持全球患者使用我們的藥物進行治療而進行的投資。

Non-GAAP net profit for the fourth quarter 2017 was $158 million compared to non-GAAP net profit of $88 million for the fourth quarter 2016. The increase in non-GAAP net profit was largely driven by the strong growth in total CF product revenues.

2017 年第四季非 GAAP 淨利潤為 1.58 億美元，而 2016 年第四季非 GAAP 淨利潤為 8,800 萬美元。非GAAP淨利的成長主要得益於CF產品總收入的強勁成長。

Our financial performance in 2017 has resulted in a full year non-GAAP operating margins of 26% compared to 17% for the full year of 2016. And as we continue to increase the number of patients that we treat with our medicines, we expect our operating margins to continue to expand in the future.

2017 年，我們的財務業績實現了全年非 GAAP 營業利潤率 26%，而 2016 年全年為 17%。隨著我們使用藥物治療的患者人數不斷增加，我們預計未來的營業利潤率將繼續擴大。

We also strengthened our balance sheet during the year as we ended 2017 with approximately $2.1 billion of cash, cash equivalents and marketable securities compared to $1.4 billion at the beginning of the year. This increased cash position was after we paid down $300 million in the first quarter 2017 that was outstanding under our revolving credit facility.

我們今年的資產負債表也得到了加強，截至 2017 年底，我們擁有約 21 億美元的現金、現金等價物和有價證券，而年初時為 14 億美元。現金儲備增加是因為我們在 2017 年第一季償還了循環信貸額度下未償還的 3 億美元。

Now turning to guidance. We, today, provided financial guidance for combined non-GAAP R&D and SG&A expenses. As we have stated previously, we expect to provide 2018 revenue guidance when we receive FDA approval for the tezacaftor/ivacaftor combination. The FDA action date is February 28, 2018. When we provide revenue guidance, it will be for total CF product revenues and will not include guidance for individual products. We do expect significant CF product revenue growth in 2018, driven by the launch of tezacaftor/ivacaftor in the U.S. for eligible patients 12 and older and through treating more patients with ORKAMBI in countries outside the U.S.

現在進入指導環節。今天，我們提供了非GAAP研發和銷售、管理及行政費用合併後的財務指導。正如我們之前所說，我們預計在 tezacaftor/ivacaftor 組合獲得 FDA 批准後，我們將提供 2018 年的收入指引。FDA的決定日期為2018年2月28日。當我們提供收入預期時，將是指CF產品的總收入，不包括單一產品的預期收入。我們預計 2018 年 CF 產品收入將大幅成長，這主要得益於 tezacaftor/ivacaftor 在美國上市，適用於 12 歲及以上符合條件的患者，以及 ORKAMBI 在美國以外的國家治療更多患者。

As we think about the first quarter of 2018, we anticipate revenues will be impacted by higher gross-to-net revenue adjustments that we experienced in the first quarter of each year and by channel inventory build that occurred in the fourth quarter of 2017.

展望 2018 年第一季度，我們預期營收將受到每年第一季毛利淨利調整幅度增大以及 2017 年第四季通路庫存增加的影響。

Now to operating expenses. In 2018, we expect combined non-GAAP R&D and SG&A expenses of $1.5 billion to $1.55 billion. The key investment drivers are the execution of pivotal studies, the 2 triple-combination regimens, supply chain investment for the potential commercial success of the triple-combination regimen and incremental investment to support the planned launch of tezacaftor/ivacaftor. As we anticipate, our revenue growth will significantly exceed the increase in our operating expenses. We do expect operating margins and earnings to continue to expand in 2018.

接下來是營運費用。2018 年，我們預計非 GAAP 研發及銷售、管理及行政費用總計為 15 億至 15.5 億美元。關鍵投資驅動因素包括關鍵研究的執行、2 種三聯療法、為三聯療法的潛在商業成功而進行的供應鏈投資，以及為支持計劃推出 tezacaftor/ivacaftor 而進行的增量投資。正如我們預期的那樣，我們的收入成長將遠遠超出營運費用的成長。我們預計2018年營業利潤率和收益將持續成長。

2017 was a transformative year for Vertex, and the continued execution across all parts of our business has positioned us to deliver sustainable revenue and earnings growth as we significantly increase the number of patients we treat with our medicines.

2017 年是 Vertex 的變革之年，我們業務各個環節的持續執行，使我們能夠在大幅增加使用我們藥物治療的患者數量的同時，實現可持續的收入和利潤增長。

With that, I will now open the line to questions.

接下來，我將開放提問環節。

(Operator Instructions) Our first question comes from the line of Geoffrey Porges from Leerink.

（操作說明）我們的第一個問題來自 Leerink 的 Geoffrey Porges。

I was particularly struck by one number, which was the 51% sweat chloride response, which was quite remarkable. Perhaps, Jeff, could you comment a little bit about what appears to be the difference between 51% and 39% sweat chloride response? And is that suggesting to you that 659 might be a little bit more active and potent? And then could you also comment on why no 561 plan with 659 since it looks as though 659 is a little bit cleaner, a little bit more active? Why wouldn't you want to be planning on doing a 561 combination?

我特別注意到一個數字，那就是汗液氯化物反應率為 51%，這非常了不起。傑夫，您能否稍微解釋一下 51% 和 39% 的汗液氯化物反應之間似乎有哪些差異？這是否意味著 659 的活性和效力可能更強一些？另外，您能否解釋為什麼 659 沒有推出 561 計劃？因為 659 看起來更簡潔、更活躍一些。為什麼你不想計劃進行 561 組合呢？

Yes, Geoff. This is Jeff Leiden. Thanks for both questions. Let me answer the second one first. Actually, it's really a strategic portfolio question. And I'll just remind you that our approach here is to make sure that we get the best regimen to these patients as quickly as possible and that's one reason we're taking 2 regimens forward into Phase III because as you pointed out, both of them look really quite good. Both of them, in fact, all 4 of our regimens we feel were -- showed results that were certainly significant enough to take into Phase III. But we're taking 2 forward because that's one way of modifying one risk, and that's the risk of some rare-off target toxicity due to the next-gen corrector in one of these regimens, and obviously, by taking 2 forward, we mitigate that risk. And then to your question, what -- why take one forward with iva, one forward potentially with d-iva, and I say potentially because we still need to confirm that with our VX-561 results. And that is our plan, to take 659 forward with iva, and if it's supported by the data, 445 with d-iva. And the reason is the same, it's a way of mitigating risk, right? D-iva, although it's obviously very similar to iva, is a different chemical compound. We've only seen it in tens or less than 100 patients. And so I would hate to put all my eggs in that basket and find out there's some very rare tolerability or safety issue with d-iva that would set both programs back. So it mitigates that risk. And the way we feel better about that is let's assume that, at the end of the day, we decide VX-659 and iva is the best regimen, that's the one we're going to take forward and commercialize, we have the opportunity, we believe, to quickly bridge over to VX-561 into a once-a-day regimen simply with some bioequivalence type of data. And so I think we're just trying to use a portfolio approach to hedge both of those risks, and we have a strategy for eventually getting to that once-a-day regimen, whether it's 659 or 445 that turns out to be the winner at the end of the day.

是的，傑夫。這是傑夫·萊頓。謝謝你們的兩個問題。讓我先回答第二個問題。實際上，這確實是一個策略性投資組合問題。我還要提醒各位，我們在這裡的做法是確保盡快為這些患者提供最佳治療方案，這也是我們將兩種治療方案推進到 III 期的原因之一，因為正如您所指出的，這兩種方案看起來都非常好。事實上，我們認為我們所有的 4 種治療方案都顯示了足以進入 III 期臨床試驗的顯著結果。但我們之所以推進 2，是因為這是改變一種風險的方法，這種風險是由於這些方案中的下一代校正劑引起的罕見脫靶毒性，顯然，透過推進 2，我們可以降低這種風險。至於你的問題，為什麼——為什麼一個使用 iva，另一個可能使用 d-iva，我說“可能”，是因為我們還需要用 VX-561 的結果來確認。這就是我們的計劃，先用 iva 推進 659 項目，如果數據支持，再用 d-iva 推進 445 項目。原因也是一樣，這是一種降低風險的方式，對吧？D-iva 雖然與 iva 非常相似，但卻是不同的化合物。我們只在幾十到不到一百名患者身上見過這種情況。因此，我不想把所有的希望都寄託在這個藥物上，萬一發現 d-iva 存在一些非常罕見的耐受性或安全問題，導致兩個項目都受挫。所以它能降低這種風險。我們之所以感覺好一些，是因為假設最終我們決定 VX-659 和 iva 是最好的方案，我們將推進並商業化該方案，我們相信，我們有機會憑藉一些生物等效性數據，迅速過渡到 VX-561，使其成為每日一次的方案。所以我認為我們只是試圖透過投資組合的方法來對沖這兩種風險，並且我們有一個策略，最終實現每天一次的用藥方案，無論最終是 659 還是 445 哪個方案勝出。

And anything in the difference between the sweat chloride and the FEV1?

汗液氯化物和 FEV1 之間有什麼區別嗎？

Yes. So thanks for playing the sweat chloride out. We always talk about FEV1, and so sometimes, we ignore sweat chloride. One of the things that's really impressive to me about the next-gen data in general is the sweat chloride drops we're seeing. Remember, this is in men patients, the most difficult-to-treat patients with only one 508 allele, and we're seeing 40 to 50, and north of 50 even, millimole or drops in sweat chloride, which is truly remarkable. And I think it suggests that we are really very effectively getting at the underlying cause of this disease, which is what's so reassuring about the consistency of all this data. I don't think there are differences, honestly, between 40 and 50 millimoler in these number of patients that we would put our hat on because they're both really profound. And I would just remind you, with respect to picking regimens, it's really not any one value, it's not just sweat chloride, it's not just the FEV1 response, it's the totality of the profiles. The good news is they all look very, very good. So we are picking a bit between sirloin steak and filet mignon here, but we'll pick these -- in the end, pick the winner based upon the totality of the profile, both efficacy and safety and tolerability.

是的。所以，謝謝你幫我們把汗液中的氯化物都排出來。我們總是談論 FEV1，所以有時我們會忽略汗液氯化物。讓我印象深刻的下一代數據之一就是我們看到的汗液氯化物滴度。請記住，這是男性患者的情況，他們是最難治療的患者，只有一個 508 等位基因，我們看到他們的汗液氯化物濃度下降了 40 到 50 毫摩爾，甚至超過 50 毫摩爾，這真是令人矚目。我認為這表明我們正在非常有效地找到這種疾病的根本原因，而所有這些數據的一致性也正是令人安心的地方。說實話，我認為在這些患者中，40 毫摩爾和 50 毫摩爾之間沒有明顯的區別，因為它們的效果都非常顯著。我還要提醒大家，在選擇治療方案時，這真的不是某個單一數值的問題，不僅僅是汗液氯化物，也不僅僅是 FEV1 反應，而是所有指標的總和。好消息是，它們看起來都非常好。所以我們現在需要在西冷牛排和菲力牛排之間做出選擇，但最終我們會根據整體表現（包括功效、安全性和耐受性）來選出獲勝者。

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

我們的下一個問題來自傑富瑞集團的邁克爾葉。

A 2-part question. First was maybe just comment on the dose response and the tolerability profile of the 2 programs. It seems like there's sort of a dose response, but also maybe not really clinically meaningful. And then the second part of that is maybe just comment on the bilirubin case. And then as it relates to the Phase III design, rather than ask about the duration of efficacy of Phase III, maybe just remind us what the precedent is for filing on duration of safety and how much safety you would need to file these types of things or win these types of things.

這是一個包含兩個部分的問題。首先，或許可以對這兩個方案的劑量反應和耐受性情況做一些評論。似乎存在某種劑量反應關係，但可能並沒有真正的臨床意義。然後第二部分可能只是對膽紅素病例發表一些評論。至於 III 期臨床試驗設計，與其詢問 III 期臨床試驗的療效持續時間，不如提醒我們以往關於安全性持續時間的申請先例是什麼，以及申請或贏得此類申請需要多少安全性數據。

Thanks, Mike. I'll answer the first part on the tolerability of dose response. Maybe Jeff can talk to the bilirubin. And then I'll come back and talk about the safety and timing and the question there. First of all, with respect to dose response, again, one of the things that's very impressive to me is we've looked at 4 regimens, we've looked at multiple doses, and when you look at that totality across those 4 regimens, they are remarkably well-behaved considering we're talking about 20-, 22-, 40-, 50-patient studies. I mean, in every case, but one that we'll come back to, there's a pretty clear dose response, whether you're looking at sweat chloride or whether you're looking at FEV1. So the compounds are quite well-behaved in that way. The one outlier, which I think you're pointing out, is the 100-milligram dose of the 445 in which the FEV1 response and sweat chloride response, looked pretty similar to the 50-milligram dose. And then when you go up to 200, you see the jump again. And so we were interested in that, trying to understand it. And of course, what we're really interested in the end is the exposure response, right, not just the dose response. And so we went back and we looked at exposures in that -- in all the studies, but in -- particularly in that one, and what you see is interesting. If you look at the 50- and the 100-milligram doses of 445, the exposures are quite overlapping. And the FEV1 and sweat chlorides are quite overlapping, if you look at those confidence intervals. When you move up to 200, you see a clear differentiation, a jump in exposure, and you see a clear jump in FEV1 and sweat chloride. And so, actually, 445 turns out to be well behaved too as long as you're looking at the relevancy, which is exposure versus response. And with respect to tolerability, I'm going to let Jeff talk about bilirubin in a second. One of the things here that is very reassuring is that across all the doses, we're seeing excellent tolerability. There's really no evidence of a dose or exposure tolerability pattern or problem here with any one of these compounds, which is what makes us feel good about the therapeutic index or window. It's going to make it, I think, easier for us to go in and look at these doses and pick the best doses for each compound, which we will, which we're in the process of doing. And then maybe, Jeff, you want to talk about bilirubin?

謝謝你，麥克。我將回答關於劑量反應耐受性的第一部分。或許傑夫可以和膽紅素對話。然後我會回來談談安全性、時機以及相關問題。首先，關於劑量反應，讓我印象非常深刻的一點是，我們研究了 4 種治療方案，研究了多種劑量，當你縱觀這 4 種治療方案的整體情況時，考慮到我們討論的是 20、22、40、50 名患者的研究，它們的表現非常出色。我的意思是，在所有情況下（除了我們稍後會提到的情況），無論是觀察汗液氯化物還是觀察 FEV1，劑量反應都非常明顯。所以這些化合物在這方面表現得相當好。唯一例外的情況，我想你也指出來了，就是 445 的 100 毫克劑量，其 FEV1 反應和汗液氯化物反應看起來與 50 毫克劑量非常相似。然後當你增加到 200 時，你會看到再次躍升。因此我們對此很感興趣，試圖了解它。當然，我們最終真正感興趣的是暴露反應，對吧，而不僅僅是劑量反應。因此，我們回顧了所有研究中的暴露情況，特別是那項研究中的暴露情況，結果很有意思。如果你看一下 445 的 50 毫克劑量和 100 毫克劑量，你會發現它們的暴露量相當重疊。如果你看一下信賴區間，你會發現 FEV1 和汗液氯化物之間有相當大的重疊。當劑量增加到 200 時，你會看到明顯的差異，暴露量會躍升，FEV1 和汗液氯化物也會明顯躍升。所以，實際上，只要你考慮相關性，也就是曝光與反應，445 的表現也相當不錯。至於耐受性方面，我稍後會讓傑夫談談膽紅素。令人非常欣慰的一點是，所有劑量組的耐受性都非常好。目前尚無證據表明這些化合物中存在劑量或暴露耐受性模式或問題，這讓我們對它們的治療指數或治療窗口感到放心。我認為，這將使我們更容易查看這些劑量，並為每種化合物選擇最佳劑量，我們將會這樣做，而且我們正在進行這項工作。那麼，傑夫，或許你想談談膽紅素？

Sure. I do think that consistency across the dose range is really very, very telling. Mike, in terms of your specific question on bilirubin, I think the really key point here is that this was an isolated finding. There were no evidence of transaminase elevations or any other findings about the liver. As you heard, actually with interruption that rapidly resolved and the -- and one patient actually restarted and continued on without any further elevation, so that's really a pattern that just isn't clinically concerning. So we don't see it as an issue.

當然。我認為劑量範圍內的一致性真的非常非常說明問題。麥克，關於你提出的膽紅素的具體問題，我認為關鍵在於這只是一個孤立發現。沒有發現轉氨酶升高或其他肝臟異常。正如你所聽到的，實際上中斷很快得到解決，而且——其中一位患者實際上重新開始並繼續治療，病情沒有進一步惡化，所以這實際上是一種臨床上並不令人擔憂的模式。所以我們認為這不是問題。

And then finally, your duration of safety data question, as you know, we don't really speculate. That's an FDA or European regulator decision at the end of the day. I can point you to our -- to some of our historical data, where you know we've been between 6 months and a year of safety data in most of these studies, but these are discussions we're having. I think the important point is this is a medicine -- these medicines will be things we're asking children to take for the rest of their lives, and so we do want to make sure that we have a complete safety data set that we're comfortable with and that regulators are comfortable with and it will be that -- the ratio, of course, of efficacy and safety, that at the end of the day, it will be the decision-making.

最後，關於您提出的安全資料持續時間的問題，如您所知，我們不會妄加猜測。最終，這要由美國食品藥物管理局（FDA）或歐洲監管機構決定。我可以向您展示我們的一些歷史數據，您知道在大多數研究中，我們已經收集了 6 個月到 1 年的安全數據，但這些是我們正在進行的討論。我認為重點在於，這是一種藥物——這些藥物是我們要讓孩子們終生服用的，因此我們希望確保我們擁有完整且令我們和監管機構都放心的安全數據集，最終的決策當然是療效和安全性的平衡。

Our next question comes from the line of Geoff Meacham from Barclays.

下一個問題來自巴克萊銀行的傑夫·米查姆。

I'll just ask the other 2 questions a little bit different way. I know the goal here ultimately is to maximize FEV1, but it's also obviously to get to a positive risk benefit as quickly as possible. So how do you guys balance those 2? And what do you think the upper end of an FEV1 could be? I'm just trying to think down the road competitively when you have, perhaps, gene therapy or other combinations available or in development.

我換個方式問另外兩個問題。我知道最終目標是最大限度地提高 FEV1，但顯然也要盡快達到正的風險收益比。你們是如何平衡這兩者之間的呢？你認為FEV1的上限值可能是多少？我只是想從競爭的角度考慮未來，當基因療法或其他組合療法出現或正在研發時，我們該如何應對。

Yes, let me answer those separately because they are a bit related, Geoff. So first of all, just to be clear, while FEV1 is an important indicator of acute benefit, our goal is actually bigger than that. And we measure efficacy in this disease not only by FEV1, but by long-term efficacy results that we've been seeing very clearly with both KALYDECO and ORKAMBI, and that includes decreases in the slope of the decline of the lung function curve, it includes hospitalizations, pulmonary exacerbations, IV, antibiotic use -- all of which are very favorably impacted by both KALYDECO and ORKAMBI. And at the end of the day, it's really the combination of what the acute response you can get, plus all of those chronic things that we would grade as a success in CF. And that's particularly true as you move back to the younger-age patients. Remember, there may be, and likely will be, a ceiling on acute FEV1. In a 30-year-old patient, it starts with an FEV1 of 50 because they have a fair amount of structural lung disease and you're not going to be able to reverse that. It's a very different story in a young 2-year old or 1-year-old who's starting with an FEV1 of 95 or 100. And you're really trying to do something different there. You're trying to prevent the disease or modify the course of the disease, and that, of course, is our ultimate goal. So acute FEV1 is one measurement. It depends a little bit on who you're treating as to what the ceiling will be. I don't think we have explored yet fully that ceiling. It's one of the things we want to do. But I do want to be really clear that the long-term goal is much more than acute FEV1. It's really modifying the course of the disease long-term as measured by all the things that I just told you about. One of the reasons we want to look at that with the triples is this may be the last time that anyone can do a placebo-controlled trial of a CFTR-modulating therapy, and obviously, those longer-term endpoints are going to be very, very useful and very interesting and important, I think, for us to measure.

是的，讓我分別回答這些問題，因為它們有點關聯，傑夫。首先，需要明確的是，雖然 FEV1 是急性獲益的重要指標，但我們的目標實際上比這更大。我們衡量這種疾病的療效不僅透過 FEV1，還透過長期療效結果來衡量，而我們已經非常清楚地看到 KALYDECO 和 ORKAMBI 都取得了這些療效，其中包括肺功能曲線下降斜率的降低、住院治療、肺部急性加重、靜脈注射、抗生素的使用——所有這些都受到了 KALYDECO 和 ORKAM 的非常有利的影響。歸根究底，真正衡量囊性纖維化治療成功的標準，是你能獲得的急性反應，以及所有那些我們認為是治療成功的慢性因素。對於年輕患者來說，這一點尤其如此。請記住，急性期 FEV1 可能存在上限，而且很可能存在上限。對於 30 歲的患者來說，FEV1 初始值為 50，因為他們有相當多的肺部結構性疾病，而這是無法逆轉的。對於 2 歲或 1 歲、FEV1 為 95 或 100 的幼兒來說，情況就完全不同了。你確實想在那裡做一些與眾不同的事情。你們試圖預防疾病或改變疾病的進程，而這當然也是我們的最終目標。因此，急性期FEV1是其中一項測量指標。服務對象的不同，這在一定程度上決定了服務價格的上限。我認為我們還沒有完全探索完這個極限。這是我們想做的事情之一。但我確實想明確指出，長期目標遠不止於急性 FEV1。從我剛才跟你說的這些方面來看，它確實從長遠角度改變了疾病的進展。我們想透過三聯體研究來探討這個問題的原因之一是，這可能是最後一次有人可以進行 CFTR 調節療法的安慰劑對照試驗，顯然，這些長期終點對我們來說將非常非常有用、非常有趣和重要，我認為值得我們去衡量。

And Jeff, just as a follow-up to that, since you guys have great technology looking at cellular assays and pulmonary assays, I mean, what's the -- once you get into the clinic with these Phase IIIs, what is the interest or focus level in getting some proof of concept data in things like IPF or COPD or something pulmonary but not quite CF? Or have you guys not gone down that path yet?

傑夫，作為後續問題，既然你們在細胞檢測和肺部檢測方面擁有很棒的技術，我的意思是，一旦你們進入臨床階段，進行這些 III 期試驗，你們對獲得一些概念驗證數據（例如 IPF、COPD 或其他肺部疾病，但又不是 CF）的興趣或關注程度是什麼？還是說你們還沒走過這條路？

Yes, yes. I thought you were going to actually ask me a different question. I thought you were going to ask me, are you still going to work on getting better correctors. So let me answer that question. The answer is yes, and the reason is because we know from sort of an experiment of nature, that if you're a carrier, and which means you have a one mutation but a normal allele, you have a chloride transport in your cells of about 80% of normal, somewhere right around there. And we know you don't get the disease. And so if we can drive everybody to carrier status with a triple regimen, and we are getting pretty close with some of these regimens now, we believe, and treat early, that we can actually turn patients into carriers, which, of course, is the ultimate goal. So we are going to continue to work on better and better next-gen correctors because we're seeing that we can still up the efficacy. With respect to IPF and COPD, we are totally focused here on finishing the journey in CF right now. We want to get these triples to everybody who has one 508 or 2 508 alleles. That's going to be plenty of work over the next couple of years. And when we finish that journey, of course, we'll consider other things that we might use these medicines for. But right now, we're pretty focused on CF.

是的，是的。我以為你會問我另一個問題。我以為你要問我，你是否還會繼續努力尋找更好的矯正器。那麼，讓我來回答這個問題。答案是肯定的，原因是我們從自然界的某種實驗中得知，如果你是攜帶者，這意味著你有一個突變但有一個正常的等位基因，那麼你細胞中的氯離子轉運能力大約只有正常的 80%，大概就在這個範圍內。我們知道你不會得這種病。因此，如果我們能夠透過三重療法讓所有人都成為攜帶者，而且我們現在在某些療法上已經非常接近這個目標了，我們相信，如果及早治療，我們實際上可以將患者變成攜帶者，這當然是最終目標。因此，我們將繼續致力於研發更好、更先進的下一代矯正器，因為我們發現我們仍然可以提高矯正效果。至於特發性肺纖維化和慢性阻塞性肺病，我們目前正全力以赴完成囊性纖維化的治療之旅。我們希望讓所有擁有一個或兩個 508 等位基因的人都能獲得這些三聯體。未來幾年，這將會是相當多的工作。當然，當我們完成這段旅程後，我們會考慮這些藥物還可以用於其他方面。但目前，我們主要關注的是囊性纖維化。

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

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

First, a scientific one and then a financial one. On the scientific side, you mentioned that the compounds are well tolerated, but you did note some pulmonary-type side effects in the adverse events. Can you talk a little bit about the characteristic of those pulmonary side effects? Were those kind of like what you've seen with KALYDECO, where it's clear that the lungs are getting cleared and that's what gives rise to the sputum and coughing? Or are they of a different characterization?

首先是一個科學方面的問題，然後是一個財務方面的問題。從科學角度來看，您提到這些化合物耐受性良好，但您也注意到不良事件中出現了一些肺部類型的副作用。您能談談這些肺部副作用的特徵嗎？這些症狀是不是跟你之前在 KALYDECO 身上看到的類似，很明顯肺部正在被清理，而這正是產生痰液和咳嗽的原因？或它們具有不同的特徵？

So thanks. It's Jeff Chodakewitz. No, I think you have it exactly right. The impact, it was things like cough and sputum clearance that, really, they're reported as adverse events, but we actually think of them almost as a marker of potential effects of the underlying pharmacology that we're trying to get. So that's really the way it is. I would say just one other comment, that we look very specifically, as we mentioned in the prepared remarks, right from the beginning in these studies to be -- to look for any kind of post-dosing decreases in FEV1. We got all that data, and there is nothing there. So it's -- the pattern is exactly what you're describing.

謝謝。他是傑夫·喬達克維茨。不，我覺得你說得完全正確。影響方面，咳嗽和咳痰等症狀，雖然通常被報告為不良事件，但我們實際上認為它們幾乎可以作為我們正在嘗試達到的潛在藥理作用的標誌。事情就是這樣。我只想補充一點，正如我們在準備好的演講稿中提到的，從這些研究一開始，我們就非常具體地關注——尋找給藥後 FEV1 的任何下降情況。我們取得了所有數據，但裡面什麼都沒有。所以——這種模式正是你所描述的。

Okay. Then second one on the side effects. You mentioned that there's really nothing concerning about the bilirubin or rash. Was there anything confounding in those patients that could have given rise to those side effects that was not trigger-related?

好的。其次是關於副作用的第二個問題。您提到膽紅素或皮疹其實沒什麼大礙。這些患者是否有任何與誘因無關的混雜因素，導致這些副作用出現？

No. And I mean, you have to remember, we're talking about, which is a good thing, very small numbers of people with any of these adverse events we're talking about. I think to say were there any other confounders, I think it's really too early to tell. But again, the important thing is that they were generally mild to moderate, they resolved quickly, and as we told you, the safety profile, very favorable.

不。我的意思是，你必須記住，我們談論的是（這是一件好事），發生這些不良事件的人數非常少。我認為現在判斷是否有其他混雜因素還為時過早。但再次強調，重要的是這些症狀通常較輕微或中等，很快就消退了，而且正如我們所說，安全性非常好。

Great. And Ian, one last question for you on finances. I know you're not going to give guidance until tez/iva's approved, hopefully, next month. But can you give us some general sense about how you feel about the current consensus estimates for 2018. Based on my math, they seem to assume about 9% year-over-year growth versus Q4's run rate. Does that seem kind of reasonable? Can you discuss maybe what the drivers of growth will be for the franchise in 2018?

偉大的。伊恩，最後一個關於財務方面的問題。我知道在 tez/iva 獲得批准之前，你不會給予任何指導，希望下個月就能獲得批准。但您能否大致談談您對目前2018年普遍預期有何看法？根據我的計算，他們似乎假設同比增長約 9%，而第四季度的增長率與此相當。這聽起來是不是有點道理？您能否談談2018年該特許經營業務成長的驅動因素有哪些？

Sure. Thanks for the question, Phil. We did look at consensus coming into the call. Given that we won't be giving guidance, we thought that question may come up. And so, firstly, I would say that the number that we see in the consensus for 2018 does reflect growth, which is consistent with how we think about 2018. Obviously, we're waiting on the approval of tez/iva. That will be the major growth factor of the 2018 revenue line. And so as we look at that consensus number, we like where it is. It's consistent with how we're thinking about it. We'll give you greater clarity once we get the approval with tez/iva. I would take this opportunity to remind those on the call that it is our intent to give 2018 revenue guidance, but it would be a total CF revenue guidance. With the approval of tez/iva, we should see switches from ORKAMBI onto tez/iva. We should see going from KALYDECO to tez/iva. So for us, the guidance will be total CF revenues. And then also consistent with some of my remarks I made on the prepared remarks, I would just ask people to work with our IR group after the call to think about the models through the year. Q1, we do anticipate being affected by the inventory build that were -- occurred in Q4 of 2017, although we're still committed to a growth year driven by the approval of tez/iva.

當然。謝謝你的提問，菲爾。我們在電話會議前確實考慮了共識。鑑於我們不會提供指導，我們認為這個問題可能會被提出。因此，首先，我認為我們在 2018 年的共識中看到的數字確實反映了成長，這與我們對 2018 年的看法是一致的。顯然，我們正在等待 tez/iva 的批准。這將是2018年營收成長的主要因素。因此，當我們審視這個共識數字時，我們對它目前的狀態感到滿意。這與我們的想法一致。一旦我們獲得 tez/iva 的批准，我們將向您提供更清晰的說明。我想藉此機會提醒各位參加電話會議的人員，我們打算給出 2018 年的收入預期，但這將是現金流總收入預期。隨著 tez/iva 獲得批准，我們應該會看到使用者從 ORKAMBI 轉向 tez/iva。我們應該會看到從 KALYDECO 到 tez/iva 的轉變。因此，對我們來說，業績指引將是總現金流收入。此外，正如我在準備好的演講稿中提到的一些內容一樣，我希望大家在通話結束後與我們的投資者關係小組合作，思考今年的模型。第一季度，我們預計會受到 2017 年第四季度庫存增加的影響，儘管我們仍然致力於在 tez/iva 獲得批准後實現成長。

But could you give us a sense of the size of that inventory build?

能否大致介紹一下此次庫存建設的規模？

Yes. It wasn't very big, but I'll give you a comment of the nature of it. So in the U.S., given how the new year felt, there was some inventory stocking in the U.S. And overseas, there was some forward-buying around Europe that would normally have occurred in Q1 that was actually pulled forward into Q4. The size of it, it's around $10 million to $15 million. So if you think about how that gets pulled into Q4, it has a double impact in terms of helping Q4, but offsetting in Q1. Obviously, we still have a great Q4 number. So the demand is strong, more and more patients are going on drug, and compliance is good.

是的。它雖然不大，但我可以就它的性質做些評論。因此，鑑於新年伊始的氛圍，美國出現了一些庫存積壓的情況。而在海外，歐洲出現了一些原本應該在第一季進行的遠期採購，這些採購其實都提前到了第四季。它的規模大約在 1000 萬美元到 1500 萬美元之間。所以，如果你考慮一下這如何被納入第四季度，它會產生雙重影響：一方面有助於第四季度，另一方面又會抵消第一季的影響。顯然，我們第四季的業績依然非常出色。因此需求強勁，越來越多的患者開始服用該藥物，而且依從性良好。

Our next question comes from the line of Alethia Young from Crédit Suisse.

我們的下一個問題來自瑞士信貸的 Alethia Young。

Maybe we'll have the triple. Just when you talk about European reimbursement and the portfolio of deals, do you think the long-term data that you're kind of generating over time in real-world experience will drive those combinations? Or is it a combination -- or it's a kind of the combination of all things? And then the second question is just as far as the sickle cell program with CRISPR, what additional steps need to be taken in the U.S. for an IND filing? And can you give us any updated thoughts around design things?

或許我們會吃到三份。當您談到歐洲的報銷和交易組合時，您認為隨著時間推移在實際經驗中累積的長期數據是否會推動這些組合？或者說，它是兩者的結合──或者說，它是所有事物的一種結合？那麼第二個問題是，就使用 CRISPR 技術治療鐮狀細胞貧血症的計畫而言，在美國提交 IND 申請還需要採取哪些額外步驟？您能否就設計方面提出一些最新的想法？

Yes, Alethia. It's Stuart here. I'll take the first question, and then Jeff Leiden will take the question on sickle cell. So yes, I think one of the driving factors between -- behind governments being interested in these portfolio arrangements is the rapid progress they can see that we're making in developing treatments that treat the underlying cause of the disease in up to 90% of patients. And so yes, that's been one of the most compelling things to governments around the world and why they have been interested because they can see the rate of progress we're making and just how good the results are that we're seeing in these patients. So that's been certainly a very strong drive to them wanting to talk about portfolio-type arrangements.

是的，阿萊西亞。我是史都華。我先回答第一個問題，然後傑夫·萊頓將回答關於鐮狀細胞貧血症的問題。所以，我認為各國政府對這些投資組合安排感興趣的主要原因之一是，他們看到了我們在開發治療疾病根本原因的療法方面取得的快速進展，這些療法對高達 90% 的患者有效。所以，是的，這正是世界各國政府最為關注和感興趣的原因之一，因為他們看到了我們所取得的進展速度，以及我們在這些患者身上看到的良好療效。因此，這無疑是促使他們想要討論投資組合式安排的一個非常強烈的動力。

And it's Jeff Chodakewitz. Just a quick follow-up on the sickle cell. As you know, we've commented, we filed the, with CRISPR, the CTA for beta-thalassemia at the very end of '17. We're in the process with CRISPR of putting together that IND. And we expect to file that IND during this year, and then we'll be looking to initiate those studies in people with both sickle cell and beta-thal. Exactly when that will happen and the timing, we're going to have to be further along in that process and then we'll be able to give you a better sense.

他是傑夫·喬達克維茨。關於鐮狀細胞貧血症，我再補充一點。如您所知，我們已經評論過，我們在 2017 年底提交了使用 CRISPR 技術治療 β-地中海貧血的 CTA 申請。我們正在利用 CRISPR 技術來準備該 IND。我們預計今年將提交IND申請，然後我們將著手針對患有鐮狀細胞貧血症和β-地中海貧血的人群進行研究。至於具體何時發生以及時間安排，我們需要在這個過程中取得更大進展，然後才能給您一個更明確的答案。

Just a follow-up on that. I mean, is there any kind of different conversation around breaking these programs into the clients between U.S. and Europe?

關於這件事，我再補充一點。我的意思是，美國和歐洲的客戶在將這些項目拆分方面是否有任何不同的討論？

The beta-thal program will be done in Europe, and the sickle cell program will be done primarily in the U.S.

β-地中海型貧血治療計畫將在歐洲進行，而鐮狀細胞貧血治療計畫將主要在美國進行。

Our next question comes from the line of Ying Huang from Bank of America Merrill Lynch.

我們的下一個問題來自美國銀行美林證券的黃穎。

Maybe can I ask you a little bit differently on the FDA requirement on the Phase III? Given the data you have seen so far, including today's efficacy in Phase II as well as the Breakthrough Designation, do you guys think the FDA will require the same amount of safety data as well as the same duration for efficacy analysis in the Phase III? And then also, on rash and bilirubin, did that happen in the lower dose or higher dose of those 2 trials?

關於FDA對III期臨床試驗的要求，我能換個方式問您一個問題嗎？根據目前為止您所看到的數據，包括今天公佈的 II 期療效以及突破性療法認定，你們認為 FDA 是否會在 III 期臨床試驗中要求提供相同數量的安全性數據以及相同持續時間的療效分析？另外，關於皮疹和膽紅素，這兩項試驗中，低劑量組還是高劑量組出現了這種情況？

Yes. It's Jeff Leiden. I'll answer your first question. I think we've learned a lot about doing these CF trials as has the FDA as we've worked together over the last 6 or 7 years through a number of different medicines. As you know, as an example, we tend to see the full FEV1 effects within 4 to 8 weeks, and everything that we're seeing here suggests that, that is going to be true as well. So I think that, in general, the efficacy time-points can be on the shorter side, in other words, you don't need 6 months on your data. On the other hand, safety is obviously very important here as well, and you don't get a read on safety data in 4 weeks or 8 weeks, so it's likely going to be longer. And that's exactly what we're discussing now, which is what is the length of each one of those endpoints and in particular, that safety database, how big should it be and how long should it be. And as soon as we know that, we'll let you know.

是的。他是傑夫·萊頓。我先回答你的第一個問題。我認為，在過去的六、七年裡，我們和 FDA 一起合作，研究了許多不同的藥物，因此我們在進行這些 CF 試驗方面學到了很多東西。如您所知，例如，我們通常會在 4 到 8 週內看到 FEV1 的完全變化，而我們在這裡看到的一切都表明，這種情況也將如此。所以我認為，總的來說，療效觀察時間點可以比較短，換句話說，你的數據不需要6個月。另一方面，安全性顯然也非常重要，而安全資料不可能在 4 週或 8 週內得出，所以可能需要更長。而這正是我們現在正在討論的內容，也就是每個端點的長度，特別是安全資料庫，它應該有多大，應該要多長。一旦我們得知消息，我們會立即通知您。

And it's Jeff Chodakewitz. In terms of your question about dose, actually, it was mixed across doses. And so -- and exposure. There was no real linkage.

他是傑夫·喬達克維茨。關於你問的劑量問題，實際上，劑量是混合使用的。因此——以及曝光。兩者之間並沒有真正的關聯。

Our next question comes from the line of Terence Flynn from Goldman Sachs.

我們的下一個問題來自高盛的 Terence Flynn。

Maybe 2 for me. Just was wondering, at a high level, if you can just give us some framework for how to think about tez/iva pricing, what are some of the key inputs. And then as we see the data today, again, does this change that discussion at all as you guys think about potential pricing? And then on the triple-combo Phase III program in homozygous patients, is -- will it definitively include a control arm? And what will that control arm be? Can you tell us at this point?

對我來說，或許是2。我只是想問一下，從宏觀層面來說，您能否給我們一個思考 Tez/Iva 定價的框架，其中有哪些關鍵的輸入因素？那麼，根據我們今天看到的數據，這是否會改變你們在考慮潛在定價時的討論？那麼，在針對純合子患者的三聯療法 III 期計畫中，是否會明確包含一個對照組呢？那麼，這個控制臂會是什麼呢？現在您可以告訴我們嗎？

Terence, on tez/iva pricing, obviously, I'm not going to comment specifically on it. We'll do that at the point that we get approval from the regulators. But in terms of the considerations we're taking into account, they really are the same as we've taken into account consistently for KALYDECO and ORKAMBI, and that is the magnitude of the clinical benefit that we're able to deliver. And as you know, we believe we've got a very strong profile with tezacaftor/ivacaftor. And then the other consideration is the size of the patient populations that were going to be able to benefit, and we'll be taking those same considerations into account when we come to making the pricing decision on tez/iva pending regulatory approval.

Terence，關於 tez/iva 的定價，顯然我不會對此發表具體評論。我們會在獲得監管機構批准後採取此行動。但就我們所考慮的因素而言，它們與我們一直以來對 KALYDECO 和 ORKAMBI 所考慮的因素完全相同，那就是我們所能提供的臨床益處的程度。如您所知，我們相信 tezacaftor/ivacaftor 具有非常強大的市場競爭力。另一個需要考慮的因素是能夠受益的患者群體規模，在獲得監管部門批准後，我們在製定 tez/iva 的定價決定時，也會考慮到這些因素。

With respect to the homozygous trial, we're still discussing that, but will it be a control arm, almost certainly yes. And at that point, remember, most of these homozygous patients will be on either ORKAMBI or tezacaftor/ivacaftor, and so it will likely not be a placebo control arm.

關於純合子試驗，我們仍在討論，但它是否會作為對照組，幾乎可以肯定是的。屆時，請記住，這些純合子患者中的大多數將接受 ORKAMBI 或 tezacaftor/ivacaftor 治療，因此很可能不會成為安慰劑對照組。

Our next question comes from the line of Brian Abrahams from 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。

On the triple, I guess I'm wondering, broadly speaking, what primarily drove your selection of these next-generation correctors over 440 and 152? What did you see with the additional dosing of 152? And could 152 and 440 still serve as backups? And then on the Phase III plans, I know these are still under discussion, but I'm just wondering if the right way to think about this is for the het/min group to -- for het/mins potentially coming through first just given the unmet need and possibly different regulatory barb versus the homozygous, or should we expect those to sort of follow through concurrently?

關於三重校正，我想問的是，總的來說，是什麼主要促使您選擇這些下一代校正器而不是 440 和 152 呢？追加152劑量後，你觀察到了什麼？152 和 440 還能當作備用機嗎？關於 III 期臨床試驗計劃，我知道這些仍在討論中，但我只是想知道，對於 het/min 組來說，正確的思考方式是否應該是——考慮到未滿足的需求以及與純合子不同的監管限制，het/min 組可能會率先獲得批准，還是我們應該預期它們會同時進行？

Yes, so with respect -- this is Jeff again, Jeff Leiden again. With respect to choosing between the 4 different regimens, it was really the totality of the data, and that means the acute FEV1, the sweat chloride on the efficacy side, certainly, the tolerability and safety profiles on the other side. But some additional factors as well, coformulatability, the dose that we need to give and "could we get that in one pill" manufacturability. All those went into the decision. As I said, it was a little bit of a hard decision because they were all quite good. We could have taken any of them into Phase III, and that's obviously a good problem to have. But there were some differences. I'd give you one just as an example. 659 and 445 have the potential to be once-a-day, whereas 152 and 440 were clearly going to be twice-a-day. Well, once-a-day in our mind is an advantage. You sort of put a check in that box. 440, in its preclinical data, as you know, had some teratogenicity. 659 and 445 didn't. So you can put a check in that box on the side of 659 and 445. So as we went down the whole list of benefits from an efficacy standpoint, safety and tolerability, coformulatability and manufacturability, these 2 won out. It was a little bit of a horse race. They didn't win out by 10 lengths, but we feel that they have the best overall profile from an efficacy, safety and formulation standpoint. And then your other question was about het/mins versus homozygous. I just want to step back and remind you again that we believe the data that we have strongly supports the notion that these triples should be used in anyone who has one 508 or 2 508 alleles, meaning het/mins or homozygous. And our plan is to pursue a clinical course to make sure that we get that done as quickly as possible. You're absolutely right, that the het/mins have the biggest unmet need because today, they don't have any CFTR modulation. But I would also remind you that when we looked at the triples in the homozygous patients, there was a very, very significant incremental effect on FEV1 when you add a next-gen corrector to tezacaftor/ivacaftor. And so while the acute need may not be as great, we feel that the benefit may be every bit as great in those patients. And so we don't want to leave any patients behind or slowdown in one of these populations, and we're just talking with regulators about how do we get that done most effectively and most quickly.

是的，尊敬的各位──我是傑夫，我是傑夫‧萊頓。至於在 4 種不同的治療方案中進行選擇，實際上是綜合考慮所有數據，這意味著在療效方面要考慮急性 FEV1 和汗液氯化物，當然，在耐受性和安全性方面也要考慮。但還有一些其他因素，例如共配製性、我們需要給予的劑量以及「我們能否將其製成一片藥丸」的生產可行性。所有這些因素都影響了最終決定。正如我所說，這是一個有點艱難的決定，因為他們都很優秀。我們可以把他們中的任何一個人帶入第三階段，這顯然是一個幸福的煩惱。但兩者之間也存在一些差異。我舉個例子而已。659 和 445 有可能每天只發一班，而 152 和 440 顯然是每天發兩班。嗯，我們認為一天一次是優勢。你相當於在那個方框裡打了個勾。如您所知，440 的臨床前數據顯示其具有一定的致畸性。659 和 445 沒有。所以你可以在 659 和 445 旁邊的方格裡打勾。因此，當我們從功效、安全性和耐受性、共配製性和可生產性等方面逐一評估所有優點時，這兩項最終勝出。這有點像賽馬比賽。雖然它們沒有以 10 個身位的優勢獲勝，但我們認為從功效、安全性和配方角度來看，它們擁有最佳的整體表現。然後你的另一個問題是關於雜合子/單倍體與純合子的差異。我只想退後一步，再次提醒大家，我們相信我們掌握的數據有力地支持了這樣一種觀點：對於任何擁有一個 508 或兩個 508 等位基因的人，即雜合子/單倍體或純合子，都應該使用這些三聯體。我們的計劃是參加臨床課程，以確保我們盡快完成這項任務。您說得完全正確，異質/單核細胞增多症患者的需求尚未得到滿足，因為目前他們沒有任何 CFTR 調節劑。但我還要提醒您，當我們觀察純合子患者的三重體時，當在 tezacaftor/ivacaftor 中添加下一代矯正劑時，FEV1 有非常非常顯著的增量效應。因此，雖然這些患者的迫切需求可能不那麼大，但我們認為他們從中獲得的益處可能同樣巨大。因此，我們不想讓任何患者落後，也不想放慢任何一個群體的治療速度，我們正在與監管機構討論如何以最有效、最快捷的方式完成這項工作。

Our next question comes from the line of Matthew Harrison from Morgan Stanley.

我們的下一個問題來自摩根士丹利的馬修·哈里森。

I guess I just wanted to ask one follow-up on safety and tolerability here. So you saw some rash across both studies. You've commented before about some GI tox. I guess what I was wondering is can you just talk to us a little bit about some of the clinical side effects you've seen versus what you've seen preclinically with these compounds, and do they match up at all. And I guess the basis for the question here is, preclinically, you saw some of the chest tightness before with ORKAMBI, and then it was unclear, where you didn't see it at a high frequency in some of the initial studies, so I'm just trying to understand your comfort around some of these issues.

我想再問一個關於安全性和耐受性的後續問題。所以兩項研究都出現了一些皮疹。你之前評論過一些腸胃毒素的問題。我想問的是，您能否和我們談談您在臨床上觀察到的一些副作用，以及您在臨床前研究中觀察到的這些化合物的副作用，它們之間是否有任何關聯。我想，提出這個問題的依據是，在臨床前研究中，您之前在使用 ORKAMBI 時觀察到了一些胸悶症狀，但後來情況變得不明朗，在一些早期研究中，您並沒有頻繁地觀察到這種症狀，所以我只是想了解您對這些問題的看法。

Hey, it's Jeff Chodakewitz. Maybe a couple of comments, one at a big picture level. I think that the adverse events profile that we've talked about tonight, I hope it's come through to you, that no matter how you look at it, whether you look at SAEs, clinical AEs, labs, all those things, that the profile for both of these regimens is actually very favorable. And that's great, combining with the efficacy, we're really excited about moving them forward. There's really nothing that particularly stands out. We've tried to give you a sense of the information. I do want to go to your question and your comment about bronchoconstriction. That was actually something that we saw clinically in ORKAMBI, and that's why I wanted to be sure we highlighted that. Even though we had no expectations about it, we think we don't see it in tezacaftor/ivacaftor. We did look for it very specifically in our Phase I and Phase II studies, and there was no evidence of that. So we feel very good.

嘿，我是傑夫·喬達克維茨。或許可以提幾點意見，其中一點是從宏觀層面來說。我認為，我們今晚討論的不良事件概況，我希望你們已經明白，無論從哪個角度來看，無論是嚴重不良事件、臨床不良事件、實驗室檢查結果，所有這些方面，這兩種治療方案的概況實際上都非常有利。太好了，再加上其功效，我們非常興奮能推動它們向前發展。其實沒有什麼特別突出的地方。我們已盡力向您傳達相關訊息。我想回應你關於支氣管收縮的問題和評論。實際上，我們在 ORKAMBI 的臨床實踐中也看到了這一點，所以我想確保我們強調這一點。儘管我們對此沒有任何期望，但我們認為在 tezacaftor/ivacaftor 中看不到它。我們在 I 期和 II 期研究中進行了非常專門的檢查，但沒有發現任何證據。我們感覺非常好。

Our next question comes from the line of Cory Kasimov from JPMorgan.

我們的下一個問題來自摩根大通的科里·卡西莫夫。

I guess I'd want to ask the question regarding potential duration of the Phase III studies another way. I'm curious if it's possible if they could be different durations from the standpoint of the tez/iva safety data you've already amassed relative to tez-561. So might the first one be shorter from that standpoint? And then my second question, I apologize if I missed this already on today's call, but how should we be thinking about the company's tax rate in 2018 and beyond given the tax reform?

我想換個方式問一下 III 期研究可能持續時間的問題。我很好奇，根據您已經累積的相對於 tez-561 的 tez/iva 安全數據，它們的持續時間是否有可能不同。那麼從這個角度來看，第一個版本會不會比較短呢？我的第二個問題是，如果我在今天的電話會議上已經錯過了這個問題，我深表歉意，但考慮到稅務改革，我們應該如何看待公司在 2018 年及以後的稅率？

Yes. With respect to your first question, Cory, in terms of tez/iva and how does that influence the duration here, the clean findings that we've seen with tez/iva are certainly major de-riskers of the safety profile of the triple, but as in any combination, when you add a new agent, the key is what about the new agent. That's what drives the length and the size of the safety database, and that won't be affected by the fact that tez/iva turns out to have a very good -- a very favorable safety and tolerability profile. So the discussion is really about we have a new combination with a completely new agent, actually, 2 of them, 659 and 445, what's the appropriate safety database, timing and duration to look at that new combination.

是的。關於你的第一個問題，Cory，關於替尼/伊伐他汀以及它如何影響治療持續時間，我們看到替尼/伊伐他汀的良好結果當然大大降低了三聯療法的安全性風險，但與任何組合一樣，當你添加一種新藥物時，關鍵在於這種新藥物的效果如何。這正是安全資料庫的長度和規模所決定的，而 tez/iva 具有非常好的安全性和耐受性，這一事實並不會對此產生影響。所以討論的重點其實是，我們有了新的組合，其中包含兩種全新的藥物，分別是 659 和 445，那麼應該建立怎樣的安全資料庫、時間安排和持續時間來研究這種新的組合呢？

And Cory, on the taxes, I'll kind of just walk you through this. First of all, I'd remind you that we do have operating losses within the U.S., so as we create profits right now, those operating losses offset those profits. So we have minimal tax liability, minimal cash tax liability, and at this point, we're not recording an effective tax liability either. As we work through those NOLs and we get -- and the accounting allows for, we will start recording a tax rate and pay taxes. And we've set up our tax structure within the company that matches our global operations, and that actually results in us having a tax rate that would be in the low 20s once we start to pay. And so we have been benefited like many other companies in the -- that have a U.S. presence with the tax reform and the lowering of the U.S. domestic tax rate, but that benefit is small because we also accumulate profits outside of the U.S. as well.

科里，關於稅收方面，我這就給你詳細講解一下。首先，我要提醒各位，我們在美國確實存在經營虧損，所以當我們現在創造利潤時，這些經營虧損會抵銷這些利潤。因此，我們的納稅義務極少，現金納稅義務也極少，而且目前我們也沒有記錄實際納稅義務。當我們處理完這些淨經營虧損並獲得——而且會計允許的話——我們將開始記錄稅率並繳納稅款。我們已經建立了與公司全球營運相符的公司內部稅務架構，實際上，一旦我們開始繳納稅款，我們的稅率將只有 20% 左右。因此，像許多其他在美國設有分支機構的公司一樣，我們也受益於稅制改革和美國國內稅率的降低，但這種好處很小，因為我們在美國以外也累積了利潤。

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

我們的下一個問題來自羅伯特·貝爾德的布萊恩·斯科尼。

Just based on your commentary around plans to start pivotal programs for 440 and 152, should we take it as an understanding that you've now completed chronic tox at this point? And is there anything to speak of there? And can you comment on what species and duration you've seen and what, if any, end-organ tox there is?

僅根據您對啟動 440 和 152 關鍵項目的計劃的評論，我們是否可以理解為您現在已經完成了慢性毒理學研究？那裡有什麼值得一提的嗎？您能否描述一下您觀察到的物種、持續時間以及是否存在針對終末器官的毒性？

Brian, could we just clarify the question? You asked about 440 and 152? Could you -- so could you just reask the question again?

布萊恩，我們能把問題澄清一下嗎？你問的是440和152嗎？您能再問一次嗎？

Yes, yes. So on the 2 new ones, I was wondering your chronic tox, is it now complete? Is there anything in terms of what you're seeing in preclinical studies? How long have you gone out, and what end-organ tox are you seeing for those 2 outputs?

是的，是的。所以關於這兩個新病例，我想知道你的慢性中毒現在是否已經痊癒了？您在臨床前研究中觀察到了什麼？你外出多久了？對於這兩個輸出，你觀察到了哪些終末器官毒性？

So the chronic tox is complete for 659, and there was nothing there that in any way affected our plans to take it forward into Phase III. The chronic tox for 445 is not yet complete, but it will be very shortly.

因此，659 的慢性毒性試驗已經完成，沒有任何東西會影響我們將其推進到 III 期試驗的計劃。445 的慢性毒性研究尚未完成，但很快就會完成。

And then I just also wanted to confirm, on the go-forward strategy of combining 659 with ORKAMBI, this is a risk-mitigation strategy for 561, right? There's no concern about it at qd? Is it -- are you looking at it as a qd drug on top of tez/iva in Phase III?

然後我還想確認一下，將 659 與 ORKAMBI 合併的後續策略，對於 561 來說，這是一項風險緩解策略，對嗎？qd方面對此沒有擔憂嗎？你們打算把它當作每日一次的藥物，與 Tez/Iva 一起進行 III 期臨床試驗嗎？

Yes, correct. So this is all about KALYDECO being twice-a-day. Both 659 and 445 have clear once-a-day PK profiles.

是的，沒錯。所以，KALYDECO 每天使用兩次就夠了。659 和 445 都具有明顯的每日一次的藥物動力學特徵。

Our next question comes from the line of Robyn Karnauskas from Citigroup.

我們的下一個問題來自花旗集團的 Robyn Karnauskas。

So a big picture question for you. It's like you've been waiting for this data, I'm sure, for like a long time, and this is really remarkable. It's so exciting. When you think about your company big picture now, knowing this data, knowing likely that Phase III could replicate this, you have 2 shots on goals. How do you run the company differently? Does it change your -- you just gave the guide, doing M&A at $1 million to go out and find something new. And secondly, how do you start planning for converting results? Do you everyone is going to go on this sort of eventually? What can you do now to make that conversion fast once those trials are done?

所以，我想問你一個比較宏觀的問題。我相信你一定等這些數據很久了，這真是太棒了。太令人興奮了。現在，當你從公司大局出發，考慮到這些數據，考慮到 III 期臨床試驗很可能複製這一結果，你就有兩次機會實現目標。你們的公司運作方式有何不同？這會改變你嗎？ ——你剛剛給了指南，以 100 萬美元進行併購，然後出去尋找新的東西。其次，如何開始規劃如何提高轉換率？你們最終都會走上這條路嗎？試用期結束後，您現在可以做些什麼來快速實現轉換？

Yes. Great questions. So these are the questions -- good questions that we ask ourselves and we've been working on for a little while now, certainly as we see this data. They become quite relevant as you point out. And so I'll give you my impression and how I think about it, Robyn, and I hope the rest of the management team agrees. First of all, we need to finish this journey in CF, and as you point out, that is largely an execution task where we need to move as quickly as possible to get these Phase IIIs up and running, fully enrolled, get the data out there and really finish this journey for 90% of CF patients. And that's a very -- a responsibility we take very seriously for this community. As I said, we continue to work on even better next-gen correctors, and at some point, we need to make a decision about whether we're going to take those into the clinic to try to get carrier-like effects for everybody. And as we've said before, there's still 10% of patients with CF who won't be amenable to CFTR modulatory therapies because they have minimal -- they don't have any protein. And those patients are going to need a genetic approach, and we are working on that as well, although we feel that, that is considerably further out. So the first mission is finish the journey in CF, see if we can get some genetic therapies for the 10% of patients and really just change the course of this disease or prevent this disease. The second part of the journey is what's beyond CF. Can we do this again? And as I said at JPMorgan, I sometimes get asked the question, well, why do you think you can do this in another disease, you're a CF company, and sort of why should we trust you to invest in other diseases. And my answer is we have already done it before, many times, in this company. So starting with HIV, going to HCV, oncology, flu, you may have seen some of the news about the flu compound in the release today. It's -- and obviously, now with CF multiple times. So this is a company that has a very special innovation engine and create -- and can create these kinds of breakthrough drugs. And although we haven't talked about it, as you know, we've been working on that in 4 or 5 diseases, including sickle cell and AAT, [8 or more ones], some others that we've been talking -- starting to talk about. And those are moving along very nicely. So we want to use some of the revenue we have here to reinvest in our internal research programs. And then also, we want to use it because, as you pointed, we'll have a lot of financial firepower to supplement our innovation through external BD kinds of programs of many flavors. You've seen us do CRISPR, you've seen us do Moderna. You'll see more of those deals. And you could see some bigger ones, but still focused around the same strategy, making transformative drugs for serious diseases in specialty markets, expanding our therapeutic modality, capabilities into things like gene editing and gene therapy and other kinds of modalities and supplementing our early-stage pipeline. And so that's really the plan. In many ways, the strategy has gotten simpler. It's gotten to be more execution. We're really pleased with the way the team executes, and it's why we feel so confident about the future of the company.

是的。問得好。所以，這些都是我們一直在思考的問題——都是很好的問題，而且我們已經研究了一段時間了，尤其是在看到這些數據之後。正如你所指出的，它們變得非常重要。所以，羅賓，我會說說我的看法和想法，希望管理團隊的其他成員也能同意。首先，我們需要完成囊性纖維化（CF）的治療之旅，正如您所指出的，這在很大程度上是一項執行任務，我們需要盡快推進這些 III 期臨床試驗，完成患者招募，公佈數據，真正為 90% 的囊性纖維化患者完成治療之旅。這是我們為這個社區肩負的非常重要的責任，我們對此非常重視。正如我所說，我們將繼續努力研發更好的下一代矯正器，在某個時候，我們需要決定是否將這些矯正器投入臨床應用，以期為所有人帶來類似載體的效果。正如我們之前所說，仍有 10% 的 CF 患者不適合接受 CFTR 調節療法，因為他們體內的蛋白質含​​量極低——他們體內沒有任何蛋白質。這些患者需要採用基因治療方法，我們也正在研究這方面，儘管我們認為這還需要相當長的時間。因此，首要任務是完成囊性纖維化的研究，看看我們能否為 10% 的患者找到一些基因療法，真正改變疾病的進程或預防疾病。旅程的第二部分是囊性纖維化之後的故事。我們能再來一次嗎？正如我在摩根大通所說，我有時會被問到這樣一個問題：你為什麼認為你能在其他疾病領域做到這一點？你是一家專門研究囊性纖維化的公司，我們為什麼要相信你會投資其他疾病領域？我的回答是，我們公司以前已經這樣做過很多次了。所以，從 HIV 開始，到 HCV、腫瘤、流感，你可能已經看到了今天發布的一些關於流感化合物的新聞。而且很明顯，現在我已經多次患上囊性纖維化了。所以這家公司擁有非常特殊的創新引擎，能夠創造——並且能夠創造這類突破性藥物。雖然我們沒有談論過，但正如你所知，我們一直在研究 4 或 5 種疾病，包括鐮狀細胞貧血症和 AAT，[8 種或更多疾病]，還有一些我們一直在討論——開始討論的其他疾病。這些專案進展都非常順利。所以我們希望利用部分收入再投資於我們的內部研究計畫。此外，正如您所指出的，我們也想利用它，因為我們將擁有強大的財力，透過各種外部業務拓展計劃來補充我們的創新。你們都看到了我們開發 CRISPR 技術，也看到了我們開發 Moderna 技術。你會看到更多類似的優惠活動。你可能會看到一些更大的項目，但仍然圍繞著同樣的策略，即為專業市場中的嚴重疾病研發變革性藥物，將我們的治療模式和能力擴展到基因編輯、基因療法和其他類型的模式，並補充我們的早期研發管線。這就是計劃的全部內容。從很多方面來看，這項策略變得更簡單了。現在更多的是執行層面的問題了。我們對團隊的執行力非常滿意，這也是我們對公司未來充滿信心的原因。

Our next question comes from the line of Adam Walsh from Stifel.

我們的下一個問題來自 Stifel 的 Adam Walsh。

This is Neil on for Adam. Just wondering about what kind of preparations you guys are doing to ensure a successful launch of tez/iva. And then if you guys can just talk for a minute about how you expect the launch curve to play out and what you expect as far as uptake.

這裡是尼爾替亞當報道。想了解你們為了確保 tez/iva 的成功發布都做了哪些準備工作。然後，你們能否花一分鐘時間談談你們預期產品上市曲線會如何發展，以及你們對市場接受度的預期。

Yes. Thanks, Neil. The commercial team, I would say, here is pretty good at launching products. We've had the benefit of, as Jeff just described, an incredibly productive research and development engine here, which is in CF, has generated new products, new indications, new age groups time and time again. So the team is, I would say, pretty much a well-oiled machine when it comes to executing these launches. So they're ready to go. The teams are trained. We've scaled up here in the U.S. in our case management group because one of the most important things we can do is ensure patients are onboarded effectively. That group has been trained and expanded to account for the additional patients we are anticipating seeing. So we are as ready as we can be, and we're eagerly anticipating the approval in the near future. In terms of a launch trajectory, really difficult to say exactly how that's going to play out. It's going to depend on the, obviously, the timing of the approval. It's going to depend on us being able to secure access and reimbursement, which I'm confident we will do here in the U.S., as we have done for KALYDECO and ORKAMBI. And then we'll have to see how some of those launch dynamics play out in the real world in terms of persistence and compliance. Certainly, everything we know about KALYDECO and ORKAMBI would tell us we should expect to see great uptake, great persistence and great compliance, and that's what we're anticipating.

是的。謝謝你，尼爾。我認為，這裡的商業團隊在產品上市方面做得相當出色。正如傑夫剛才所描述的那樣，我們這裡擁有一個極其高效的研發引擎，尤其是在囊性纖維化領域，它一次又一次地創造出新產品、新適應症和新的年齡層。所以我覺得，這支團隊在執行這些產品發表方面，就像一台運作良好的機器。他們準備出發了。各隊都經過了訓練。在美國，我們擴大了個案管理團隊的規模，因為我們能做的最重要的事情之一就是確保病人能夠有效地入院。該團隊已接受培訓並擴充規模，以應對我們預計會接診的額外患者。所以我們已經做好了萬全準備，並熱切期希望在不久的將來獲得批准。至於發射軌跡，真的很難準確預測結果。這顯然取決於審批的時間。這取決於我們能否獲得准入和報銷，我相信我們在美國能夠做到這一點，就像我們為 KALYDECO 和 ORKAMBI 所做的那樣。接下來，我們也要看看這些推廣動態在現實世界中能否在使用者持久性和合規性方面得到體現。當然，我們對 KALYDECO 和 ORKAMBI 的了解表明，我們應該期待看到巨大的市場接受度、極強的持久性和極高的依從性，而這正是我們所期待的。

All right. And just one other one. For tez/iva in the EU, how do you think the agreement is going to work out there with those countries that already have agreements on ORKAMBI? How should we think about that?

好的。還有一個。對於歐盟的 tez/iva 協議，您認為該協議在那些已經就 ORKAMBI 達成協議的國家中會如何運作？我們該如何看待這個問題？

Well, I think that really goes to the kind of the different processes of different countries. It's hard to give you one answer for kind of Europe as a whole, in countries where we have an individual pricing reimbursement agreement around ORKAMBI, there's really going to be 2 parts, either kind of the standard sort of sequential approach, where you apply product-by-product, and obviously, we're preparing to do that in line with getting our regulatory approval for tez/iva in the second half of this year, which is what we're planning for in the EU. In some markets, for instance, like in Ireland where we have a portfolio agreement, there we are anticipating, in line with that agreement, that we will get access for those patients at the time we get the regulatory approval for tez/iva. And that to me is one of the great benefits for patients and physicians of these portfolio agreements. And I think, as I mentioned earlier, in answer to somebody else's question, I think the tez/iva data and now the triple combination data is only going to further interest in these kinds of portfolio agreements.

我認為這確實與不同國家的不同流程有關。很難就整個歐洲的情況給出一個統一的答案。在那些我們與 ORKAMBI 簽訂了單獨定價報銷協議的國家，實際上會分為兩個部分：一是標準的順序方法，即逐個產品應用；二是，我們正準備在今年下半年獲得 tez/iva 的監管批准後實施這一方法，這也是我們在歐盟的計劃。例如，在某些市場，例如我們在愛爾蘭達成了一項投資組合協議，根據該協議，我們預計，當我們獲得 tez/iva 的監管批准時，這些患者就能獲得該藥物。在我看來，這正是這些投資組合協議對病人和醫生帶來的巨大好處之一。而且我認為，正如我之前在回答其他人的問題時提到的那樣，我認為 tez/iva 數據以及現在的三重組合數據只會進一步激發人們對這類投資組合協議的興趣。

Our next question comes from the line of Carter Gould from UBS.

我們的下一個問題來自瑞銀集團的卡特古爾德。

First on the pivotal triple-combo studies, can you maybe just talk about your level of comfort that U.S. and EU regulators will be aligned on the safety duration you need to see? And then just on the internal non-CF pipeline, beyond the VX-150 data and acute pain, are there any other internal clinical data we should expect to come out over the course of 2018?

首先，關於關鍵的三聯療法研究，您能否談談您對美國和歐盟監管機構在您需要看到的安全性持續時間方面達成一致的信心程度？那麼，就內部非 CF 研發管線而言，除了 VX-150 數據和急性疼痛數據之外，在 2018 年期間，我們是否應該預期其他內部臨床數據公佈？

Yes. This is Jeff Leiden. So we're talking with both European regulators and U.S. regulators about all the same issues that we've discussed on the call. And of course, our goal is to align those studies as much as possible between those. And when we get agreement with both of them, we'll let you know exactly how they look. And with respect to the non-CF pipeline, as you know, we have said that we expect to start Phase I studies in our sickle cell and beta-thal program. This year, those will be in patients. We expect one or more other programs from our internal research group to also enter the clinic this year. It's a little early to predict exactly when we'll start to see the first clinical data.

是的。這是傑夫·萊頓。所以，我們正在與歐洲監管機構和美國監管機構討論我們在電話會議上討論的所有相同問題。當然，我們的目標是盡可能地使這些研究相互協調一致。等我們和他們雙方都達成一致後，我們會告訴你最終效果如何。至於非 CF 產品線，如您所知，我們已經說過，我們預計將啟動鐮狀細胞貧血和 β-地中海貧血計畫的 I 期研究。今年，這些都將在患者身上進行。我們預計今年我們內部研究團隊的一個或多個其他項目也將進入臨床試驗階段。現在預測何時才能看到第一批臨床數據還為時過早。

Our final question then comes from the line of Navin Jacob from Deutsche Bank.

那麼，我們最後一個問題來自德意志銀行的納文·雅各布。

Navin Jacob, Deutsche Bank. Maybe 2 quick questions here, if I may. The first is which doses of 659 and 445 are you taking into Phase III? And then I have a follow-up commercial question.

納文·雅各布，德意志銀行。恕我冒昧，我想問兩個問題。首先，您在 III 期臨床試驗中服用的是 659 和 445 的劑量嗎？然後我還有一個後續的商業問題。

Yes. We haven't yet finalized the doses. That's one of the things that we're discussing with regulators. One of the reasons that we did the studies the way we did, and that we're actually very pleased with the results, is we do feel we have a very nice dose and exposure response set of curves for both of these compounds that will make it easier for us to pick the best dose.

是的。我們尚未最終確定劑量。這是我們正在與監管機構討論的問題之一。我們之所以採用這種方式進行研究，並且對結果非常滿意，其中一個原因是，我們認為我們已經獲得了這兩種化合物非常好的劑量和暴露反應曲線，這將使我們更容易選擇最佳劑量。

And then, very quickly, on commercial, if I may, apologies. But how do you think about the value that you're going to be generating here for het/min patients? Oftentimes, people think that as you expand populations in orphan disease, you have to cut price, but yet, at the same time, you -- Vertex has spent a significant amount of capital investing in brand-new drugs for these severe diseases. And so I guess the question is how should we be thinking about the economic value that you're providing, especially given the actual efficacy that you're showing here? Should our base case assumption be flat pricing versus KALYDECO or even a discount? Or is there -- do you actually see the value that you're providing here to patients?

然後，請容許我插播一則廣告，向大家致歉。但您認為您將為異質性/單核細胞增多症患者創造什麼樣的價值？人們常常認為，隨著罕見疾病患者族群的擴大，就必須降低價格，但同時，Vertex 公司卻投入了大量資金研發治療這些嚴重疾病的全新藥物。所以我想問的是，我們應該如何看待你所提供經濟價值，特別是考慮到你在這裡展現的實際效果？我們的基本假設應該是與 KALYDECO 的價格持平，還是給予折扣？或者說，你真的看到了你在這裡為患者提供的價值嗎？

Well, having just released the Phase II data and announced that we're moving forward into clinical development, we're not about to start speculating on those, specifically about pricing. Obviously, the data we've released today demonstrates that we think these triple combinations have the opportunity to provide tremendous value, certainly for patients in the first instance based on the efficacy and safety profile that we've shown. In terms of economic value for them, clearly, that's something that's going to be considered way down the line. We'll take into account the same considerations that I've said we always have, which is the magnitude of the benefit that we're providing and the number of patients that we are able to benefit, and those are the 2 considerations that we will continue to take into consideration as we move forward. The most important thing is, with the data we've released today, is it gives us a clear path to be able to provide CFTR modulators for up to 90% of patients. And that's our primary goal.

鑑於我們剛剛發布了 II 期臨床試驗數據並宣布將進入臨床開發階段，我們目前還不打算對此進行猜測，特別是關於定價方面的問題。顯然，我們今天發布的數據表明，我們認為這些三聯療法有機會帶來巨大的價值，首先，根據我們所展示的療效和安全性，這些療法對患者來說尤其如此。就其經濟價值而言，顯然，這是以後才會考慮的問題。我們將一如既往地考慮同樣的因素，即我們提供的益處的大小以及我們能夠受益的患者數量，這兩個因素也是我們未來將繼續考慮的。最重要的是，根據我們今天發布的數據，它為我們提供了一條清晰的道路，使我們能夠為高達 90% 的患者提供 CFTR 調節劑。這就是我們的首要目標。

Thank you, and this does conclude the question-and-answer session of today's program. I'd like to hand the program back to Michael Partridge for any further remarks.

謝謝，今天的問答環節到此結束。我謹將發言權交還給麥可‧帕特里奇，請他再作發言。

Thanks, I'll actually turn it back over to Jeff Leiden.

謝謝，我會把這件事交還給傑夫·萊頓。

Yes. Thanks, Michael. Maybe just 2 remarks, one an internal remark and one an external remark, and I'll start with the external one. I do want to come back and just remind you that in CF, we have been working with this community of patients and caregivers and the foundation for almost 20 years now. It's been an incredible journey. And to me, this is a special day because it's one more important step forward towards finishing that journey, which we are absolutely committed to. And I just want to thank again all the people, parents and families and caregivers and Vertex employees who stuck with it for 20 years to get to where we are today. It's a very special thing, and you don't see that often in one disease. And then from an internal standpoint, maybe just to echo what I said before, I do think -- and I'm pleased with the fact that we're seeing the strategy really play out nicely here, meaning the investment in scientific innovation leading to further understanding of disease, leading to breakthrough products that get better and better and then being able to reinvest the revenues that we make from those breakthrough products into more medicines in different diseases. And that's a model that all of us had as a dream, 6, 7 years ago when we started this strategy. We're certainly not done with that, but I think you can see the progress, and we're very pleased because we think it bodes very well for the future in other diseases.

是的。謝謝你，麥可。或許只有兩點要補充，一點是內部意見，一點是外部意見，我先從外部意見說起。我想再次提醒大家，在囊性纖維化領域，我們已經與患者、照護者和基金會合作了近 20 年。這是一段不可思議的旅程。對我而言，今天是個特別的日子，因為這是我們朝著完成這段旅程邁出的又一個重要步伐，而我們對此矢志不渝。我再次衷心感謝所有的人，包括家長、家人、照顧者以及 Vertex 的員工，感謝你們 20 年來的堅持，才讓我們取得了今天的成就。這是非常特殊的情況，在一種疾病中並不常見。從內部角度來看，也許只是重申我之前說過的話，我確實認為——而且我很高興看到我們的策略在這裡真正取得了良好的效果——這意味著對科學創新的投資將帶來對疾病的進一步了解，從而帶來不斷改進的突破性產品，然後能夠將我們從這些突破性產品中獲得的收入再投資於治療不同疾病的更多藥物。而這正是我們所有人六、七年前開始製定這項策略時所夢想的模式。我們當然還沒有完成這項工作，但我認為你可以看到取得的進展，我們非常高興，因為我們認為這預示著未來在其他疾病方面會有非常好的進展。

Thank you, Jeff. This concludes tonight's call. I'd like to thank everybody for joining us and for your questions. The Investor Relations team is in the office tonight to answer any additional questions that you have. Have a good evening.

謝謝你，傑夫。今晚的電話會議到此結束。感謝各位的參與與提問。投資者關係團隊今晚在辦公室，可以解答您提出的任何其他問題。祝你晚上愉快。

Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.

感謝各位女士、先生參加今天的會議。節目到此結束。您現在可以斷開連線了。再會。