福泰製藥 (VRTX) 2016 Q3 法說會逐字稿

Good evening, this is Michael Partridge, Vice President of Investor Relations. Welcome to our third-quarter 2016 financial results conference call.

晚上好，我是投資人關係副總裁麥可‧帕特里奇。歡迎參加我們2016年第三季財務業績電話會議。

(Caller Instructions)

（來電者指示）

This conference call is recording, and there will be a replay available later tonight. You can access the webcast slides by going to our website.

本次電話會議正在錄音，今晚晚些時候將提供重播。您可以透過造訪我們的網站來查看網路直播幻燈片。

Dr. Jeff Leiden, Chairman and CEO; Stuart Arbuckle, Chief Commercial Officer; Dr. Jeff Chodakewitz, Chief Medical Officer; and Ian Smith, Chief Financial Officer, will provide prepared remarks on this call. They will be joined by Dr. David Altshuler, Chief Scientific Officer, for the Q&A portion of the call.

董事長兼執行長傑夫·萊頓博士、首席商務官斯圖爾特·阿巴克爾、首席醫療官傑夫·喬達克維茨博士和首席財務官伊恩·史密斯將在本次電話會議上發表準備好的演講。首席科學官大衛·阿爾特舒勒博士將加入電話會議的問答環節。

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 SEC. These statements, including without limitation those regarding the ongoing development and potential commercialization of our drug candidates, our expectations regarding our approved medicines, and Vertex's future financial performance, are based on management's current assumptions. Actual outcomes and events -- (technical difficulty).

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 10-K 文件中詳細討論的風險和不確定性的影響。這些聲明，包括但不限於關於我們候選藥物的持續開發和潛在商業化、我們對已獲批准藥物的預期以及Vertex未來財務業績的聲明，均基於管理層目前的假設。實際結果和事件－（技術難題）。

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. Vertex's strategy in cystic fibrosis is to treat as many people with CF as possible, and to continue to enhance the clinical benefits for those treated by our medicines. Our long-term goal is to reduce the progressive and irreversible effects of CF by treating the underlying cause of the disease.

謝謝你，麥可。各位晚上好。Vertex 在囊性纖維化領域的策略是盡可能多地治療囊性纖維化患者，並不斷提高接受我們藥物治療的患者的臨床效益。我們的長期目標是透過治療囊性纖維化的根本原因，來減少囊性纖維化帶來的進行性和不可逆轉的影響。

There are three key components to our strategy: first, to increase the number of eligible patients being treated with our approved medicines, mainly by obtaining reimbursement for ORKAMBI for more patients outside the US; second, to further expand the labels for KALYDECO and ORKAMBI around the world; and third, to develop new combination regimens of CFTR modulators designed to enhance benefit for all patients. This evening, I am pleased to report that we continue to make excellent progress on all of these fronts.

我們的策略包含三個關鍵組成部分：第一，增加接受我們已批准藥物治療的合格患者人數，主要透過為美國以外的更多患者爭取 ORKAMBI 的報銷；第二，進一步擴大 KALYDECO 和 ORKAMBI 在全球範圍內的適應症；第三，開發新的 CFTR 調節劑聯合療法，旨在增強所有患者的獲益。今晚，我很高興地報告，我們在所有這些方面都繼續取得了優異的進展。

Last month, the FDA approved ORKAMBI for the treatment of children with CF ages 6 through 11 who have two copies of the F508del mutation. With this approval, approximately 29,000 patients worldwide are now eligible for our medicine. Today, we are treating approximately 9,000 of these 29,000 eligible patients.

上個月，FDA 批准 ORKAMBI 用於治療 6 至 11 歲患有囊性纖維化且攜帶兩個 F508del 突變拷貝的兒童。隨著這項批准的通過，全球約有 29,000 名患者現在有資格使用我們的藥物。今天，我們正在治療這 29,000 名符合條件的患者中的大約 9,000 名。

Moving forward, we remain focussed on expanding access to ORKAMBI and KALYDECO for the many eligible patients who are still awaiting treatment, largely through obtaining reimbursement for ORKAMBI in Europe, Canada, and Australia. We are also continuing to make progress in our efforts to expand the labels for KALYDECO and ORKAMBI.

展望未來，我們將繼續專注於擴大 ORKAMBI 和 KALYDECO 的適用範圍，讓更多符合條件的患者能夠獲得治療，目前他們仍在等待治療，主要途徑是爭取在歐洲、加拿大和澳大利亞獲得 ORKAMBI 的報銷。我們也不斷努力擴大 KALYDECO 和 ORKAMBI 的品牌範圍，並且取得了進展。

In the US, we're focused on obtaining approval for KALYDECO in patients with residual function mutation. And in the EU, we expect data this quarter from our phase 3 trial of ORKAMBI in children ages 6 through 11 who are homozygous for the F508del mutation. If successful, these would represent approximately 5,000 additional patients who may benefit from our approved medicines.

在美國，我們正致力於獲得 KALYDECO 對具有殘餘功能突變患者的批准。在歐盟，我們預計本季將公佈 ORKAMBI 對 6 至 11 歲 F508del 突變純合子兒童的 3 期試驗數據。如果成功，這將意味著大約有 5,000 名患者可能受益於我們核准的藥物。

Beyond this important progress, our long-term goal is to treat all people with CF. During the last year, we have significantly advanced our CF pipeline, which now spans all phases of research and development.

除了這項重要進展之外，我們的長期目標是治療所有囊性纖維化患者。在過去一年中，我們取得了顯著的進展，我們的 CF 產品線現已涵蓋研發的各個階段。

Today, we announced the plan's initiation of two separate phase 2 studies of our next-generation correctors, VX-440 and VX-152 in people with CF, and also a phase 1 study with a third next-generation corrector, VX-659, as part of triple combination. These studies represent significant milestones in our efforts to treat as many people with CF as possible, and will provide the first safety and clinical efficacy data in patients, including het/min patients for a triple combination regimen that includes a next-generation corrector.

今天，我們宣布啟動兩項獨立的 2 期臨床試驗，分別針對患有囊性纖維化的患者的下一代矯正劑 VX-440 和 VX-152，以及一項 1 期臨床試驗，將第三種下一代矯正劑 VX-659 作為三聯療法的一部分。這些研究代表了我們在治療盡可能多的 CF 患者方面取得的重要里程碑，並將提供包括下一代矯正劑在內的三聯療法在患者（包括 het/min 患者）中的首個安全性和臨床療效數據。

We expect to have data from the phase 2 studies in the second half of 2017. Additionally, we look forward to obtaining phase 3 data for the combination regimen of VX-661, which now carries the generic name tezacaftor and ivacaftor, in the first half of 2017.

我們預計將於 2017 年下半年獲得 2 期研究的數據。此外，我們期待在 2017 年上半年獲得 VX-661 聯合療法的 3 期數據，該療法現在具有通用名 tezacaftor 和 ivacaftor。

As we enter the fourth quarter of 2016, Vertex is a global biotech Company that has discovered and developed two break-through medicines for people with CF, while broadening our pipeline of future medicine. A significant revenue growth and return to profitability over the past year are metrics of the kind of Company that we are becoming, a Company that consistently creates transformative medicines for patients and delivers significant and sustained revenue and earnings growth for our shareholders.

進入 2016 年第四季度，Vertex 是一家全球生技公司，已發現並開發出兩種治療囊性纖維化的突破性藥物，同時也不斷拓展未來藥物的研發管線。過去一年來的顯著收入成長和獲利能力恢復，是衡量我們正在成為的那種公司的指標，即一家不斷為患者創造變革性藥物，並為股東帶來顯著且持續的收入和利潤增長的公司。

With that, I'll hand the call over to Stuart to discuss the performance of our medicines.

接下來，我將把電話交給斯圖爾特，讓他討論我們藥物的療效。

Thanks, Jeff and hello, everyone. Tonight, I will review the performance of ORKAMBI, our ongoing efforts to obtain reimbursement in Europe, the label expansion for children ages 6 through 11 in the United States, and the outlook for KALYDECO.

謝謝傑夫，大家好。今晚，我將回顧 ORKAMBI 的表現、我們在歐洲爭取報銷的持續努力、美國 6 至 11 歲兒童的標籤擴展情況，以及 KALYDECO 的前景。

In the third quarter, global sales of ORKAMBI were $234 million, comprised of US sales of $211 million and ex-US sales of $23 million. This quarter, sales in the US declined compared to the second quarter of this year, largely due to a slowing in refills during the summer months of July and August. We have now seen the vast majority of these patients refill their prescriptions. The overall compliance and persistence rates we are observing remain as we outlined earlier in the year.

第三季度，ORKAMBI 的全球銷售額為 2.34 億美元，其中美國銷售額為 2.11 億美元，美國以外地區的銷售額為 2,300 萬美元。本季美國銷售額較今年第二季下降，主要原因是 7 月和 8 月夏季月份的補充裝需求放緩。現在我們已經看到絕大多數患者都續開了處方。我們觀察到的整體合規率和持續率與我們年初概述的情況一致。

During the quarter, patients in the US continued to initiate treatment at a slower rate, as we approach peak penetration in the US for patients age 12 and over. As of the end of September, approximately 6,400 patients in the US have initiated therapy on ORKAMBI.

本季度，美國患者開始接受治療的速度持續放緩，因為我們在美國 12 歲及以上患者的治療滲透率已接近高峰。截至 9 月底，美國約有 6,400 名患者開始接受 ORKAMBI 治療。

Last month, we revised our 2016 ORKAMBI revenue guidance to be between $950 million and $990 million for the full year, and we are reiterating that guidance today. US treatment trends were one reason for the revised guidance, and the other main driver was the ongoing launch in Germany which has been slower than expected.

上個月，我們將 2016 年 ORKAMBI 全年營收預期修訂為 9.5 億美元至 9.9 億美元，今天我們重申這項預期。美國治療趨勢是修訂指南的原因之一，另一個主要驅動因素是德國的持續推廣，但推廣速度比預期慢。

As of September 30, approximately 500 of the 2,500 eligible patients have initiated treatment in Germany. We remain confident that we will treat the vast majority of eligible patients over time in Germany, but it will take longer than we had originally anticipated to reach that goal.

截至9月30日，在德國，2500名符合條件的患者中約有500人已開始接受治療。我們仍然有信心，隨著時間的推移，我們將在德國治療絕大多數符合條件的患者，但實現這一目標所需的時間將比我們最初預期的要長。

In contrast to Germany, we continue to see strong demand in France, where approximately 900 of the 1,500 eligible patients have initiated therapy through early access programs as of the end of September. I would note that we are not recognizing revenue for these patients in France until we achieve a formal reimbursement agreement.

與德國的情況相反，我們在法國繼續看到強勁的需求，截至 9 月底，在 1500 名符合條件的患者中，約有 900 名通過早期准入計劃開始了治療。我想指出的是，在與法國達成正式的報銷協議之前，我們不會確認這些患者的收入。

Throughout Europe, reimbursement is progressing as anticipated. While there are unique aspects to each process, reimbursement typically falls into three phases: a clinical benefit assessment, an economic evaluation, and price negotiations.

整個歐洲的報銷工作都在預期中進行。雖然每個流程都有其獨特之處，但報銷通常分為三個階段：臨床效益評估、經濟評估和價格談判。

In several countries, benefit assessments and economic evaluations are complete. We are pleased that government payers across Europe recognize the severity of this disease and the broad clinical benefits of ORKAMBI.

在一些國家，效益評估和經濟評價已經完成。我們很高興歐洲各地的政府支付方認識到這種疾病的嚴重性以及 ORKAMBI 的廣泛臨床益處。

We have now entered the third phase of the reimbursement process, which includes price negotiations in many key countries. While the process takes time to complete, we believe that we will achieve broad reimbursement from key European and other government payers.

我們現在已經進入報銷流程的第三階段，其中包括與許多主要國家進行價格談判。雖然這個過程需要時間才能完成，但我們相信我們將從主要的歐洲和其他國家政府支付者獲得廣泛的報銷。

We expect our first pricing agreement in a major European market to come in Germany this December. Pricing and reimbursement approvals for patients eligible for ORKAMBI outside of the US are expected to drive significant revenue growth in 2017.

我們預計今年12月在德國與歐洲主要市場達成首個定價協議。預計 2017 年，美國以外符合 ORKAMBI 使用條件的患者的價格和報銷批准將推動收入大幅成長。

I will now turn to our recent sNDA approval for ORKAMBI announced last month. We were delighted the FDA approved ORKAMBI for the treatment of children ages 6 to 11 who have two copies of the F508del mutation, and since then, we have working to get the medicine to the approximately 2,400 eligible patients as rapidly as possible.

接下來，我將談談我們上個月宣布的 ORKAMBI 的 sNDA 批准。我們很高興 FDA 批准 ORKAMBI 用於治療 6 至 11 歲攜帶兩個 F508del 突變拷貝的兒童，從那以後，我們一直在努力盡快將這種藥物提供給大約 2400 名符合條件的患者。

Interest in ORKAMBI for this age group has been very high, and our interactions with public and private payers have been productive. We expect broad coverage of ORKAMBI for this patient population, as payers have already evaluated the product after approval last year in patients 12 years and older.

該年齡層對 ORKAMBI 的興趣非常高，我們與公共和私人支付方的互動也富有成效。我們預計 ORKAMBI 將廣泛涵蓋該患者群體，因為支付方在去年批准該產品用於 12 歲及以上患者後已經對其進行了評估。

Thanks to the commitment of healthcare providers at CF centers across the country, I am pleased to report the first children ages 6 through 11 are already receiving ORKAMBI. We expect the launch to drive revenue growth in the fourth quarter of 2016 and in 2017.

感謝全國各地 CF 中心醫護人員的辛勤付出，我很高興地宣布，首批 6 至 11 歲的兒童已經開始接受 ORKAMBI 治療。我們預計此次發布將推動 2016 年第四季和 2017 年的營收成長。

Turning to KALYDECO, net revenues for the product were $176 million in the third quarter. We are now treating the vast majority of currently eligible patients, and therefore, we expect this level of quarterly revenues to be maintained in the near term, unless KALYDECO is approved in CF patients with residual function mutations.

再來看 KALYDECO，該產品第三季的淨收入為 1.76 億美元。我們現在正在治療絕大多數符合條件的患者，因此，除非 KALYDECO 獲準用於治療具有殘餘功能突變的 CF 患者，否則我們預計短期內將維持這一季度收入水平。

Today, there are approximately 29,000 people eligible for ORKAMBI or KALYDECO globally, yet, we are only treating approximately one-third of these patients. Therefore, expanding access to both of our medicines for eligible patients around the world is our top priority.

目前，全球約有 29,000 人符合 ORKAMBI 或 KALYDECO 的治療條件，然而，我們只治療了其中約三分之一的患者。因此，讓世界各地符合資格的患者都能獲得我們這兩種藥物，是我們的首要任務。

With that, I'll turn the call over to Jeff Chodakewitz.

接下來，我將把電話交給傑夫·喬達克維茨。

Thanks, Stuart. Tonight, I'll review the significant progress we are making with our CF pipeline, and I'll start with the phase 3 program of tezacaftor.

謝謝你，斯圖爾特。今晚，我將回顧我們在 CF 藥物研發管線方面取得的重大進展，首先介紹 tezacaftor 的 3 期臨床試驗計畫。

We believe the investigational combination of tezacaftor and ivacaftor could play important role in the treatment of people with CF. Enrollment is now complete in the phase 3 study in F508del homozygous patients, and also in the study in people who have residual function mutations. Data from both studies are expected in the first half of 2017.

我們相信，tezacaftor 和 ivacaftor 的試驗性組合可能在治療囊性纖維化患者方面發揮重要作用。F508del純合子患者的第3期研究以及具有殘餘功能突變的人群的研究均已完成入組。預計這兩項研究的數據將於 2017 年上半年公佈。

The phase 3 study in people with gating mutations is expected to complete enrollment in early 2017. Pending data from the phase 3 program, we plan to submit an NDA in the US for tezacaftor and ivacaftor in the second half of 2017.

針對攜帶門控突變的族群所進行的 3 期研究預計將於 2017 年初完成招募。待 3 期臨床試驗數據公佈後，我們計劃於 2017 年下半年在美國提交 tezacaftor 和 ivacaftor 的新藥申請。

I'd like to turn now to the progression of our next-generation correctors and triple combination regimens. Our research and development strategy is to advance multiple compounds into development on the basis of our predictive preclinical assays and on phase 1 safety studies, so we can choose the best combinations to evaluate in phase 3 development. The advancement of VX-440 and VX-152 into phase 2 and the selection of VX-659 for clinical development reflect this strategy.

現在我想談談我們下一代矯正器和三聯療法的進展。我們的研發策略是根據我們的預測性臨床前試驗和 1 期安全性研究，推進多種化合物進入研發階段，以便我們能夠選擇最佳組合在 3 期研發中進行評估。VX-440 和 VX-152 進入第 2 期臨床試驗，以及 VX-659 被選為臨床開發藥物，都體現了這項策略。

VX-440 and VX-152 will evaluate triple-combination dosing for four weeks and two weeks respectively, and will evaluate both het/min and F508del homozygous patients. Data from both of these studies are expected in the second half of 2017.

VX-440 和 VX-152 將分別評估為期四週和兩週的三重劑量，並將評估 het/min 和 F508del 純合子患者。這兩項研究的數據預計將於 2017 年下半年公佈。

The phase 2 study of VX-440 includes three parts. Each has a different strategic objective, but shares the same primary endpoint of safety and efficacy, as measured by absolute change among function.

VX-440 的 2 期研究包括三個部分。每個專案都有不同的策略目標，但都以安全性和有效性為主要終點，即透過功能方面的絕對變化來衡量。

Slide 8 of the webcast outlines some of the studies' key features. Part A is focused on het/min patients and part B will enroll F508del homozygous patients. Parts A and B of the study will evaluate triple combination dosing for four weeks, and we expect to have the data in the second half of 2017. The potential initiation of phase 3 development will depend on these data and discussions with regulatory agencies.

網路直播的第 8 張投影片概述了該研究的一些關鍵特徵。A 部分重點關注 het/min 患者，B 部分將招募 F508del 純合子患者。研究的 A 部分和 B 部分將評估為期四週的三重療法，我們預計將在 2017 年下半年獲得數據。第三階段研發能否啟動將取決於這些數據以及與監管機構的討論。

Part C is designed to generate 12-week safety and efficacy data for triple-combination dosing in het/min patients, and will run largely in parallel with potential phase 3 development. And we'll evaluate the contribution of the individual components to the overall triple-combination regimen.

C 部分旨在產生 het/min 患者三聯療法 12 週的安全性和有效性數據，並將與潛在的 3 期開發基本並行進行。我們將評估各個組成部分對整體三合一療法的貢獻。

Slide 9 of our webcast outlines the phase 2 study of VX-152. This study includes two parts: the primary endpoint of safety and tolerability, but a key focus will also be looking at measures of efficacy, including absolute change in lung function and change in sweat chloride, among others. Part A will enroll het/min patients and part B will enroll F508del homozygous patients.

我們的網路直播投影片 9 概述了 VX-152 的 2 期研究。這項研究包括兩部分：主要終點是安全性和耐受性，但重點也將放在療效指標上，包括肺功能的絕對變化和汗液氯化物的變化等。A 部分將招募 het/min 患者，B 部分將招募 F508del 純合子患者。

The VX-152 study will evaluate triple-combination dosing for two weeks, and data are also expected in the second half of 2017 and are intended to support the potential initiation of a longer-duration phase 2B or registration program, pending data and discussions with regulatory agencies. Our phase 1 studies in healthy volunteers and other preclinical studies provide support for advancing both VX-440 and VX-152 into phase 2 development, and have informed the designs of the phase 2 studies we're announcing today. Based on phase 1 learnings, we believe VX-440 may have a wider therapeutic window, and this is the reason that the VX-440 study will evaluate four-week dosing from the outset.

VX-152 研究將評估三聯療法兩週的療效，預計 2017 年下半年將公佈相關數據，旨在支持啟動更長時間的 2B 期臨床試驗或註冊計劃，具體時間取決於數據和與監管機構的討論。我們在健康志願者中進行的 1 期研究和其他臨床前研究為推進 VX-440 和 VX-152 進入 2 期開發提供了支持，並為我們今天宣布的 2 期研究的設計提供了依據。根據 1 期臨床試驗的結果，我們認為 VX-440 可能具有更寬的治療窗口，因此 VX-440 研究將從一開始就評估四週給藥方案。

We also noted in our press release today a specific contraception requirement for females of child-bearing potential seeking to enroll in the VX-440 study. This enrollment criterion was based on recent results from preclinical development toxicology studies. Based on laboratory findings from our phase 1 study of VX-152, we're also excluding patients with the G6PD deficiency from the phase 2 studies of VX-152 and also VX-440.

我們在今天的新聞稿中也提到，對於希望參加 VX-440 研究的有生育能力的女性，有明確的避孕要求。此入組標準是基於近期臨床前開發毒理學研究的結果。根據我們對 VX-152 進行的 1 期研究的實驗室結果，我們也把患有 G6PD 缺乏症的患者排除在 VX-152 和 VX-440 的 2 期研究之外。

G6PD deficiency and CF prevalence have [limit] geographic overlap, and therefore, the incidence of G6PD in the CF population is very low. We estimate this impacts less than 1% of all CF patients overall.

G6PD 缺乏症和 CF 盛行率在地理上有重疊，因此，CF 族群中 G6PD 的發生率非常低。我們估計這會影響不到 1% 的囊性纖維化患者。

I will just make a few comments on the in-vitro profile for VX-659 highlighted here on slide 10. In our HPE assays, the use of triple combination that contains VX-659 with tezacaftor and ivacaftor resulted in maximal efficacy that was greater than that seen with VX-440 or VX-152 in triple combination. Additionally, VX-659 is highly potent in vitro, which makes it favorable for a combination with other molecules.

我只想對幻燈片 10 中重點介紹的 VX-659 的體外特性做一些評論。在我們的 HPE 試驗中，使用含有 VX-659 與 tezacaftor 和 ivacaftor 的三重療法，其療效最大，比 VX-440 或 VX-152 的三聯療法療效更大。此外，VX-659 在體外具有很高的效力，這使得它有利於與其他分子結合。

The phase 1 study of VX-659 will be very similar to those we conducted for VX-440 and VX-152. Pending data from healthy volunteers, we plan to conduct the first evaluation of VX-659 in CF patients as part of the initial phase 1 study. We expect to initiate phase 2 development for VX-659 in the second half of 2017, pending data from the phase 1 study.

VX-659 的 1 期研究將與我們先前對 VX-440 和 VX-152 進行的研究非常相似。在獲得健康志願者的數據後，我們計劃在初始 1 期研究的一部分中，對 CF 患者進行 VX-659 的首次評估。我們預計將於 2017 年下半年啟動 VX-659 的 2 期開發，時間取決於 1 期研究的數據。

Stepping back from the trial designs, we believe we are in a strong position to define the clinical activity of three different next-generation correctors in patients, and have data in 2017 that enhanced the probability of success for our next-generation corrector program. The studies we are conducting with VX-440 and VX-152 could provide data sufficient to move to pivotal development, accelerating our ability to deliver significant clinical benefits to even more patients than we treat today. I look forward to providing updates on our triple-combination regimens as they progress.

拋開試驗設計不談，我們相信我們有能力確定三種不同的下一代矯正器在患者中的臨床活性，並且在 2017 年獲得了數據，提高了我們下一代矯正器項目的成功機率。我們正在進行的 VX-440 和 VX-152 研究可以提供足夠的數據，從而推進到關鍵性開發階段，加快我們為比現在治療的更多患者帶來顯著臨床益處的能力。我期待著向我們報告三聯療法的進展。

Before I hand the call over to Ian, I do want to mention one additional clinical milestone we expect to achieve before the end of this year. Data from a phase 3 efficacy study to support approval for ORKAMBI in children ages 6 to 11 in Europe is expected in the fourth quarter. Pending data from this study, we plan to submit an MAA variation in the EU in the first half of 2017.

在將電話交給伊恩之前，我想提一下我們預計在今年年底前實現的另一個臨床里程碑。支持 ORKAMBI 在歐洲獲準用於 6 至 11 歲兒童的 3 期療效研究數據預計將於第四季度公佈。待本研究資料出爐後，我們計劃於 2017 年上半年向歐盟提交 MAA 變更申請。

With that, I'll hand the call over to Ian.

這樣，我就把電話交給伊恩了。

Thanks, Jeff, and good evening to everyone. As you've heard tonight, we continue to make significant progress across our business. In my remarks today, I will review our third-quarter financial results, review our 2016 financial guidance, and discuss our anticipated financial trajectory into 2017 and longer term.

謝謝你，傑夫，大家晚上好。正如你們今晚所聽到的，我們公司在各個業務領域都持續取得了重大進展。在今天的演講中，我將回顧我們第三季的財務業績，回顧我們 2016 年的財務預期，並討論我們對 2017 年及以後財務走勢的預期。

Financial results first. In the third quarter of 2016, we reported total net CF product revenues of approximately $410 million, growing 38% compared to the third quarter of last year, as the number of patients being treated with our medicines significantly increased with the launch for ORKAMBI in July of 2015. Our third-quarter non-GAAP operating expenses were $298 million, including R&D expenses of $214 million, and SG&A expenses of $84 million. The increased expenses for the third quarter of 2016 compared to 2015 were primarily the result of increased costs related to the progression of our CF pipeline and increased investment in global, commercial support for the launch of ORKAMBI.

首先看財務業績。2016 年第三季度，我們報告 CF 產品總淨收入約為 4.1 億美元，與去年第三季度相比增長了 38%，這主要得益於 2015 年 7 月 ORKAMBI 上市後，接受我們藥物治療的患者人數顯著增加。我們第三季的非GAAP營運費用為2.98億美元，其中包括研發費用2.14億美元及銷售、管理及行政費用8,400萬美元。2016 年第三季支出較 2015 年同期增加，主要是由於 CF 產品線推進成本增加以及為 ORKAMBI 的上市提供全球商業支援而增加的投資。

This quarter recorded a non-GAAP net profit of $40 million, or $0.16 per diluted share, compared to a non-GAAP net loss of $32 million, or $0.13 per share for third quarter of 2015. This turnaround to profit was driven by significant increase in revenues compared to the prior year, which outpaced a smaller increase in non-GAAP operating expenses.

本季錄得非GAAP淨利4000萬美元，即每股攤薄收益0.16美元，而2015年第三季非GAAP淨虧損為3200萬美元，即每股虧損0.13美元。與前一年相比，收入大幅增長，超過了非GAAP營運費用的小幅增長，從而實現了盈利的逆轉。

From a balance sheet perspective, we ended the third quarter with strong cash position of $1.1 billion. Additionally, earlier this month, we replaced our $300 million term loan with a credit agreement that will significantly lower our interest expense and increase our available credit up to $800 million, pending certain conditions. We will continue to build upon our strong financial position going forward.

從資產負債表的角度來看，我們在第三季末擁有11億美元的強勁現金儲備。此外，本月初，我們用一項信貸協議取代了 3 億美元的定期貸款，該協議將大幅降低我們的利息支出，並在滿足特定條件的情況下，將我們的可用信貸額度提高至 8 億美元。我們將繼續鞏固我們強勁的財務實力。

Now let's turn to 2016 financial guidance. We are reiterating our 2016 ORKAMBI revenue guidance of $950 million to $990 million. And within this guidance, we expect ORKAMBI revenues to grow from the third quarter to the fourth quarter of 2016, as children ages 6 through 11 initiate treatment in the US.

現在讓我們來看看2016年的財務展望。我們重申 2016 年 ORKAMBI 的營收預期為 9.5 億至 9.9 億美元。在這項指導原則下，我們預計 ORKAMBI 的收入將從 2016 年第三季到第四季成長，因為美國 6 至 11 歲的兒童開始接受治療。

As Stuart mentioned earlier, the initial signs of these patients initiating therapy are encouraging. And as we look into 2017, we see continued growth for ORKAMBI, primarily driven by gaining reimbursement approvals throughout Europe and continued pediatric launch in the US.

正如史都華之前提到的，這些患者開始接受治療的初步跡象令人鼓舞。展望 2017 年，我們看到 ORKAMBI 繼續成長，這主要得益於在歐洲獲得報銷批准以及在美國繼續推出兒科產品。

We continue to anticipate 2016 KALYDECO net revenues to be between $685 million and $705 million. As we look forward into 2017, we do not expect significant revenue growth for KALYDECO. If KALYDECO were to be approved in residual function patients, that would be the only significant driver of growth for KALYDECO in 2017.

我們繼續預期 2016 年 KALYDECO 的淨收入將在 6.85 億美元至 7.05 億美元之間。展望 2017 年，我們預期 KALYDECO 的營收不會有顯著成長。如果 KALYDECO 獲準用於殘餘功能患者，這將是 KALYDECO 在 2017 年唯一的顯著成長動力。

For our operating expenses, we continued to expect our combined non-GAAP R&D and SG&A expenses to between $1.18 billion and $1.23 billion for the full year. As we look forward to 2017, we anticipate modest growth in operating expenses to support the progression of our CF pipeline and our launch of ORKAMBI in new geographies.

對於我們的營運費用，我們繼續預計全年非GAAP研發和銷售、管理及行政費用合計將在11.8億美元至12.3億美元之間。展望 2017 年，我們預計營運費用將適度成長，以支援我們的 CF 產品線的推進以及 ORKAMBI 在新地區的推出。

As we continue to increase the number of patients that we treat, we expect our revenues to grow significantly in the coming years, while operating expenses will only increase modestly. We are well on track to deliver a financial profile that is similar to many of our large cap biotech peers, which includes high operating margins, sustainable earnings growth, and significant cash generation.

隨著我們治療的患者數量不斷增加，我們預計未來幾年我們的收入將大幅增長，而營運支出只會略有增長。我們正朝著與許多大型生技同行類似的財務狀況穩步前進，其中包括高營運利潤率、可持續的獲利成長和顯著的現金流。

I'll now open the line to questions.

現在開始接受提問。

(Operator Instructions)

（操作說明）

Michael Yee, RBC Capital Markets.

Michael Yee，加拿大皇家銀行資本市場。

Hi, good afternoon and thanks for the question and congratulations on the updates on everything, particularly the triple. My question on the next-generation compounds is, can you talk a little bit about what you mean by therapeutic window for VX-440, for VX-152, talk a little bit about safety and tolerability, what you saw in PK. Just give a little more color there, that would be helpful in between the two programs.

您好，下午好，感謝您的提問，並祝賀您所有方面的更新，特別是三重奏的更新。關於下一代化合物，我的問題是，您能否談談 VX-440 和 VX-152 的治療窗口是什麼意思？能否談談安全性和耐受性，以及您在藥物動力學中觀察到的情況？在那裡添加一些色彩，這有助於銜接兩個節目。

And then just a commercial question for you is in the guidance you have given for the year in ORKAMBI, obviously you're launching the 6- to 11-year-olds. What type of cadence or ramp do you expect there? What's in your guidance? Is it a similar ramp to the 12 and up, even if these are healthier patients? Just want to understand what you're expecting there. Thanks so much.

那麼，還有一個商業方面的問題想問您，您在 ORKAMBI 提供的年度指導中，顯然是針對 6 至 11 歲兒童推出的。你預計那裡的踏頻或坡度是什麼樣的？你的指導原則是什麼？即使這些患者身體較健康，他們的病情發展曲線是否與 12 歲以上患者類似？我只是想了解你對那裡有什麼期望。非常感謝。

Hi Mike, it's Jeff Chodakewitz. Maybe I'll start and talk about the next-gen program. We are excited, as you said, to have both molecules progressing into phase 2. We think that based on our phase 1 results, and you know that given our ability to use our preclinical assays, we can look at the exposure and have a sense of where we're going to get to in the clinic. We think that both compounds are going to go into their phase 2 studies with doses that are both going to be well tolerated and efficacious, and I think that's very exciting.

嗨，麥克，我是傑夫·喬達克維茨。或許我可以先開始談談下一代計畫。正如您所說，我們很高興看到這兩個分子都進入了第二期臨床試驗。我們認為，基於一期臨床試驗的結果，而且您​​也知道，鑑於我們能夠利用臨床前檢測方法，我們可以觀察藥物暴露情況，並了解我們在臨床上將取得怎樣的進展。我們認為這兩種化合物都將進入二期臨床試驗，其劑量都將具有良好的耐受性和療效，我認為這非常令人興奮。

Maybe just to hone in a little bit on your question about therapeutic window, that really comes from both compounds being generally well-tolerated in VX-152. We did see some GI symptoms, mostly nausea and vomiting. That's the basis for that comment. So with VX-440 we're going right to four-week studies and with the potential therefore to accelerate quickly into a phase 3. And then for VX-152, because of that, we are starting with phase 2 studies and then can extend dosing from there.

或許可以稍微聚焦你關於治療窗口的問題，這其實是因為這兩種化合物在 VX-152 中普遍具有良好的耐受性。我們確實觀察到一些胃腸道症狀，主要是噁心和嘔吐。這就是我發表那番評論的依據。因此，對於 VX-440，我們將直接進入為期四週的研究，並有可能迅速進入第 3 期臨床試驗。而對於 VX-152，由於上述原因，我們將從第 2 期臨床試驗開始，然後逐步增加劑量。

Okay.

好的。

Mike, just to address your question on the 6 to 11 launch, obviously it's early days. We got the approval on the September 28, so we're less than a month in, but certainly the early signs are encouraging, as you might expect. Interest is high in using ORKAMBI in this younger patient population.

麥克，關於你提出的 6 點到 11 點的發射問題，顯然現在還為時過早。我們在9月28日獲得了批准，所以到現在還不到一個月，但正如你所預料的那樣，早期的跡象確實令人鼓舞。年輕患者族群對使用 ORKAMBI 的興趣很高。

We're making good progress with both public and commercial payers in terms of securing access and already have approval for about 50% of covered lives, which is obviously an important prerequisite to getting access to these younger patients. So as a result of all that, we are expecting a similarly robust uptake to that, which we saw with ORKAMBI in the 12-plus population, and that's what's incorporated into our overall guidance.

我們在確保獲得醫療服務方面，與公共和商業支付方都取得了良好進展，並且已經獲得了大約 50% 的參保人員的批准，這顯然是獲得這些年輕患者醫療服務的重要前提。因此，我們預計該產品將獲得與 ORKAMBI 在 12 歲以上人群中類似的強勁反響，而這正是我們整體指導方針中考慮的因素。

Okay. Great. Thank you so much.

好的。偉大的。太感謝了。

Geoff Meacham, Barclays.

巴克萊銀行的傑夫·米查姆。

Afternoon, guys, thanks for the question and congratulations on the plans for the triple. I just had a couple on that, for either VX-440 or VX-152, can you talk a little bit about what you're looking for FEV1-wise, just from a powering perspective? And then in either phase 2 is there a washout period for homozygous patients who have had prior exposure to ORKAMBI? And I have one follow-up.

下午好，各位，感謝你們的提問，也祝賀你們制定了三重計劃。我剛才也問過幾個關於 VX-440 或 VX-152 的問題，可以談談您對 FEV1 的期望嗎？就功率方面而言？那麼，在第二階段，對於先前接觸過 ORKAMBI 的純合子患者，是否有清洗期？我還有一個後續問題。

Hey, Geoff. It's Jeff Chodakewitz. I think that as you saw from our phase 2 designs, we're really going to be getting a pretty robust look at how both molecules are going to perform. We're really being able to look at both het/min patients and homozygous patients, which is I think very important, and the fact that we think that the doses we're going to be taking into phase 2 can deliver benefit for both populations. That is really critical.

嘿，傑夫。他是傑夫·喬達克維茨。我認為，正如您從我們的第二階段設計中看到的那樣，我們將真正全面地了解這兩種分子的性能。我們現在能夠同時觀察雜合子/隱性基因型患者和純合子基因型患者，我認為這非常重要，而且我們認為我們將在 2 期臨床試驗中使用的劑量能夠使這兩個群體都受益。這至關重要。

The -- our phase 2 studies are really not so much powered on any individual number. They're really giving us a good handle on being able to understand what the drugs are capable of doing. And to your point, we are going to actually leverage a washout from ORKAMBI so that people can participate. And we're going to, importantly, look after the end of dosing, and because we think that that follow-up period coming off of treatment actually has been -- can be very informative in terms of having confidence in the results. So that gives you a sense.

我們的二期研究其實並不是主要依據某個特定數字進行的。它們確實讓我們對藥物的作用機轉有了很好的了解。正如您所說，我們將利用 ORKAMBI 的取消，讓更多人參與其中。更重要的是，我們將關注停藥後的追蹤期，因為我們認為，治療結束後的追蹤期實際上對於增強對治療結果的信心非常有幫助。這樣你就能大概了解了。

Got you. Okay. And just real quick, in the past, you guys have talked about between VX-661 and VX-809, things like tissue penetration differences, half life differences. Any way to generally characterize what you would say are differences between VX-659, VX-440, and VX-152 just from maybe a PK or chemistry perspective?

抓到你了。好的。簡單提一下，過去你們討論過 VX-661 和 VX-809 之間的一些差異，例如組織穿透力差異、半衰期差異。能否從藥物動力學或化學角度，概括地描述 VX-659、VX-440 和 VX-152 之間的差異？

Geoff, maybe I'll just quickly take that, because that question is just frequently asked. There are small differences between compounds. I think the major difference is that they are structurally different.

傑夫，或許我就簡單回答吧，因為這個問題常被問到。化合物之間存在細微差別。我認為主要區別在於它們的結構不同。

Got you. Okay. Thanks, guys.

抓到你了。好的。謝謝各位。

Terence Flynn, Goldman-Sachs.

特倫斯·弗林，高盛集團。

Hi, thanks for taking the questions. Maybe two from me. Just on the second-gen correctors, can you give us any insight in terms of the dose-limiting talks in the animal models? Was the GI seen there? And then on VX-440, just wondering some more details on the design of part C of that trial. I was wondering if you have regulatory sign-off to run that as part of phase 2 rather than include in phase 3. Thanks.

您好，感謝您回答這些問題。也許我會給兩個。關於第二代矯正器，您能否就動物模型中的劑量限制問題提供一些見解？那個美國大兵當時在那裡嗎？關於 VX-440，我想了解該試驗 C 部分設計的更多細節。我想問一下，您是否已獲得監管部門的批准，可以將該項工作作為第二階段的一部分進行，而不是納入第三階段？謝謝。

So I think in terms of our phase 1, I think I've given you actually quite the flavor on what we've seen with the -- in the healthy volunteers, good tolerability overall. I mentioned the nausea and vomiting. I should clarify that that was at doses -- that was observed at doses higher than the doses that we're going to be taking into phase 2. That's how we think about being sure that we have a therapeutic window.

所以我覺得就我們的第一階段而言，我已經向你們展示了我們在健康志願者身上看到的整體良好耐受性。我提到了噁心和嘔吐的症狀。我應該澄清一下，那是在比我們將要進入二期臨床試驗的劑量更高的劑量下觀察到的。這就是我們確保存在治療窗口的方式。

In terms of preclinical data, I really can't comment on that level of detail. And of course, everything we do as we go forward will be confirmed with regulatory agencies.

至於臨床前數據，我真的無法對此細節發表評論。當然，我們今後所做的一切都將得到監管機構的確認。

Okay. And then on the VX-440 part C?

好的。那麼，VX-440 的 C 部分呢？

Oh, I'm sorry, I was -- sorry, Terence, I was going to that part of your question. We can't comment on the individual discussions we're having with regulatory agencies. I think as we talked about, that that is going to accomplish several things. It's going to help us understand the performance of the triple. It is importantly going to give us data on 12 weeks of dosing. And depending on the results that we're seeing, as we said, this data actually could be done basically in parallel with phase 3 studies.

哦，對不起，我——對不起，特倫斯，我正要回答你問題的那個部分。我們無法對與監管機構的具體討論發表評論。我認為正如我們之前討論的那樣，這樣做將會實現幾個目標。這將有助於我們了解三聯體的性能。更重要的是，它將為我們提供 12 週的給藥數據。正如我們所說，根據我們看到的結果，這些數據實際上可以與 3 期研究基本並行完成。

Okay. Is that the triple versus each of the sub component, each versus mono of each of the three drugs or is it versus a doublet?

好的。這是三聯體與每種子成分的比較，還是與三種藥物中的每種單藥的比較，還是與雙聯體比較？

No, it would really be primarily about triples versus doublets.

不，這主要還是三連擊和二連擊的差別。

Thank you.

謝謝。

Ying Huang, Bank of America.

黃穎，美國銀行。

Hi, thanks for taking my questions, and it's great to hear the phase 2 advancing for other new (inaudible) correctors. So maybe for Stu, you mentioned that 6,400 patients now have started treatment in the US for ORKAMBI. That leaves about another 2,000 patients. Is there a reason we should think of why those 2,000 patients would not initiate therapy, if that's possible?

您好，感謝您回答我的問題，很高興聽到第二階段正在推進，以開發其他新的（聽不見的）矯正器。所以，Stu，你提到目前美國有 6400 名患者開始接受 ORKAMBI 治療。這樣還剩下大約2000名患者。我們是否應該思考一下，如果可能的話，為什麼這 2000 名患者不接受治療？

Secondly, I have a question on, maybe Jeff, on the phase 2 particle for these two molecules. Do you think as what we have seen with KALYDECO in G51D patients and also ORKAMBI in homozygous VX-508 deletion patients, two weeks or even four weeks should be long enough to see a significant improvement in lung function, given that these patients had het/min mutation? Thank you.

其次，我有一個問題，或許可以問 Jeff，關於這兩種分子的 2 相粒子。鑑於這些患者患有雜合/隱性突變，您是否認為，正如我們在 G51D 患者中使用 KALYDECO 以及在純合 VX-508 缺失患者中使用 ORKAMBI 所觀察到的那樣，兩週甚至四周的時間應該足以看到肺功能的顯著改善？謝謝。

Ying, so thanks for the question. Yes, over 6,400 patients have initiated therapy in ORKAMBI and we're obviously delighted with that. That's over 70% of the eligible patients. But as you said, that means that 2,000 are yet to be initiated.

瑩，謝謝你的提問。是的，已有超過 6400 名患者在 ORKAMBI 開始接受治療，我們對此感到非常高興。這佔符合條件患者的70%以上。但正如你所說，這意味著還有 2000 個項目尚未啟動。

Obviously, the individual decision about whether a physician and patient want to initiate therapy is one that thy have to come to themselves, but we're certainly continuing to see new patients being initiated. And as we deliver and develop more evidence about the long-term benefits of ORKAMBI, I think that's giving physicians and patients even more reasons to think about whether they would want to be initiated on ORKAMBI. And on the phase 2 questions, I'll hand that over to Jeff.

顯然，醫生和患者是否要開始治療是他們個人的決定，但我們確實看到越來越多的新患者開始接受治療。隨著我們提供和發展更多關於 ORKAMBI 長期益處的證據，我認為這將給醫生和病人更多理由去思考他們是否願意開始使用 ORKAMBI。至於第二階段的問題，我將交給傑夫回答。

Thanks, Stuart. Hi Ying, yes, as you note, we obviously don't have data yet for the triple. But everything that we've seen across our portfolio, as imodulating CFTR really suggests that both the two-week and the four-week studies are going to be able to give us valuable insights into the potential efficacy of the regimens.

謝謝你，斯圖爾特。嗨，穎，是的，正如你所指出的，我們顯然還沒有這三者的數據。但我們從整個產品組合中看到的一切，作為 CFTR 調節劑，都表明為期兩週和四週的研究將能夠為我們提供關於這些療法潛在療效的寶貴見解。

Great. Thank you.

偉大的。謝謝。

Alethia Young, Credit Suisse.

Alethia Young，瑞士信貸。

Hi guys, thanks for taking my question and congratulations on the progress in phase 2. On the corrector front with some of these new correctors, how do you think broadly about positioning these assets? And like with the VX-440 and VX-152 compounds, would you think about moving both into phase 3? And then I have one question about Europe.

大家好，感謝你們回答我的問題，並祝賀你們在第二階段的進展。關於這些新的校正器，你們如何看待這些資產的整體定位？就像 VX-440 和 VX-152 化合物一樣，您是否考慮將它們都推進到 3 期臨床試驗？然後我還有一個關於歐洲的問題。

Kelly, this is Jeff Leiden, that is more of a strategy question so maybe I'll take that. And first, I'll just remind you that our strategy all along has been to develop a portfolio of next-generation correctors, really for two reasons. One, they do have different properties, they come in different flavors, and we really want to see those different flavors in people and understand how they perform. And, two, there is a probability of success issued here, right? By bringing three or four of these different correctors into phase 1 and now, in this case, phase 2 studies, it increases the probability of success that we'll come up with the best regimen or each of the patient population.

凱莉，我是傑夫·萊頓，這更多的是一個策略問題，所以也許我會回答這個問題。首先，我要提醒大家，我們一直以來的策略都是開發一系列下一代矯正器，這主要有兩個原因。第一，它們確實具有不同的特性，它們有不同的口味，我們真的很想看看這些不同的口味在人們身上的表現，並了解它們是如何發揮作用的。其次，這裡存在一個成功機率，對吧？透過將三到四種不同的矯正劑引入 1 期臨床試驗，現在又引入 2 期臨床試驗，可以提高我們找到針對每位患者的最佳治療方案的成功機率。

And while we can predict an awful lot from our preclinical cellular-based assays, because they predicted quite well on the efficacy front, as a couple of folks noted before, there can be differences in potency, in maximal efficacy, in drug-like properties, and those are best seen really from these phase 1 and phase 2 trials. And we're learning a lot as we go about these different molecules.

雖然我們可以從臨床前細胞試驗中預測很多東西，因為它們在療效方面預測得相當好，但正如一些人之前指出的那樣，在效力、最大療效、類藥特性方面可能會存在差異，而這些差異最好從 1 期和 2 期試驗中看出。在研究這些不同分子的過程中，我們學到了很多。

Would we ever take two molecules into phase 3 development? It's absolutely possible just as you've seen with lumacaftor and VX-661, two first-generation correctors, because they may also have different protocols and profiles. It's just going to depend on the data that we see from these phase 2 studies. But I think the important thing is that strategy we're taking is this portfolio strategy.

我們是否會將兩種分子推進到第三期臨床試驗階段？這完全有可能，就像你從 lumacaftor 和 VX-661 這兩個第一代矯正器中看到的那樣，因為它們也可能具有不同的協定和配置。這完全取決於我們從這些二期臨床試驗中獲得的數據。但我認為重要的是，我們採取的策略是投資組合策略。

Great. Thanks. And then on Europe, for Stuart, perhaps, maybe with some of the reimbursement conversations, do you find them a different flavor as you go through each country? Is there similar themes on what payers are concerned about for ORKAMBI?

偉大的。謝謝。那麼對史都華來說，在歐洲，或許在報銷談判中，你覺得每個國家的報銷情況是否都有所不同？對於 ORKAMBI，支付方的擔憂是否也存在類似的主題？

Yes, I'd say the concerns and questions that we get, Alethia, are very consistent. As we've said a number of times, while each process is different, they tend to orate themselves around three phases. One is a discussion of the clinical benefits of ORKAMBI, and in general, while we've been pleased that payers across Europe have recognized the broad clinical benefits of ORKAMBI. Then there is an economic evaluation, and after that phase, you enter into the price negotiation.

是的，阿萊西亞，我認為我們收到的擔憂和問題非常一致。正如我們多次所說，雖然每個過程都不同，但它們往往圍繞著三個階段。一方面，我們討論了 ORKAMBI 的臨床益處；另一方面，我們很高興看到歐洲各地的支付方都認識到了 ORKAMBI 的廣泛臨床益處。然後進行經濟評估，評估結束後，就可以進入價格談判階段了。

And so while each process is different in each different country, they tend to follow that same pattern and they are proceeding as we anticipated. And the last thing is in addition to evaluating the clinical benefits, from an economic perspective, they're concerned about the overall budget impact it might have for them in their individual country.

因此，雖然每個國家的具體流程都不盡相同，但它們往往遵循相同的模式，並且正如我們預期的那樣進行。最後一點是，除了評估臨床效益外，從經濟角度來看，他們還擔心這可能會對他們各自國家的整體預算產生影響。

Brian Abrahams, Jefferies.

Brian Abrahams，傑富瑞集團。

Thank you for taking my questions and my congratulations as well on the progress of the next-gen correctors. Two questions. First, I was wondering if you might be able to expand on the comments you made regarding preclinical tox studies that led you to include contraception and exclude the G6PD deficiency patients for the VX-440 studies. Was that something just related to a hormonal interaction?

感謝您解答我的問題，也祝賀您新一代校正器取得了進展。兩個問題。首先，我想請您詳細解釋一下您先前關於臨床前毒理學研究的評論，這些研究促使您在 VX-440 研究中納入避孕措施，並將 G6PD 缺乏症患者排除在外。那是不是跟荷爾蒙相互作用有關？

And then on the commercial side, I realize it's very early days, but just wondering if you had any sense of compliance and persistence, or at least compliance in the 6- to 11-year-old patients relative to what you've seen in adults thus far.

至於商業方面，我知道現在還處於非常早期的階段，但我只是想知道，相對於您目前在成年人中觀察到的情況，您是否感覺到 6 至 11 歲患者的依從性和堅持性，或者至少依從性如何。

So, Brian, it's Jeff Chodakewitz. I'll start and then turn it over. Just want to be sure I understand your question. For the preclinical data for VX-440 and contraception, there are a set of standard studies that are done actually in rabbits. And they're -- we test the developmental toxicity, the effects of the drug, and we did find for VX-440 there were some abnormalities suggesting of potential deleterious effect on the fetus.

布萊恩，我是傑夫喬達克維茲。我先開始，然後再翻過來。我只是想確認一下我是否理解了你的問題。對於 VX-440 和避孕的臨床前數據，有一系列標準研究實際上是在兔子身上進行的。而且—我們測試了發育毒性，藥物的影響，我們發現 VX-440 存在一些異常，顯示其可能對胎兒產生有害影響。

We don't know whether that actually translates to people. But the prudent thing to do, clearly, is to ensure that women in the study are using highly effective contraception, and that's what we flagged that we'll be doing that in our phase 2 study with VX-440.

我們不知道這是否真的適用於人們。但顯然，謹慎的做法是確保研究中的女性使用高效的避孕措施，而這正是我們在 VX-440 的 2 期研究中要強調的。

And on your compliance question, as you say, it's very early days yet. We're just one month into the launch in 6- to 11-year-old children; however, I think there are some reasons to be optimistic that the compliance rates there could be higher than we see in teenagers and in young adults. Certainly, that's what we've seen with KALYDECO, and that's not atypical for what you see in other chronic diseases, where clearly, these young kids are largely, if not exclusively, under the supervision of their parents. And therefore, compliance rates appear to be at the higher end of the spectrum.

至於你提出的合規性問題，正如你所說，現在還為時過早。這項活動在 6 至 11 歲兒童中開展才一個月；然而，我認為有理由樂觀地認為，他們的依從率可能會比青少年和年輕成年人的依從率更高。當然，我們在 KALYDECO 身上就看到了這一點，而且這在其他慢性疾病中並不罕見，很明顯，這些年輕的孩子在很大程度上（如果不是完全）是在父母的監督下。因此，合規率似乎處於較高水準。

Thanks very much.

非常感謝。

Matthew Harrison, Morgan Stanley.

馬修·哈里森，摩根士丹利。

Great. Thanks very much. I have two things that I just want to do ask, both on next-generation correctors. One, can you just compare and contrast what you would expect to learn from two weeks of dosing versus four weeks of dosing, and how you would correlate whatever signals you're going to get out of that to how you might move those compounds ahead? And then, second, can you just tell us the dose levels of VX-152 and VX-440 that you're using in these phase 2 studies?

偉大的。非常感謝。我有兩個問題想問一下，都是關於下一代校正器的。第一，你能否比較一下，兩週給藥和四周給藥分別能讓你了解什麼，以及你如何將從中獲得的任何信號與你如何推進這些化合物的研發聯繫起來？其次，您能否告知我們您在這些 2 期研究中使用的 VX-152 和 VX-440 的劑量等級？

Hi, Matthew, Jeff Chodakewitz. Let me talk about the two and the four weeks, because we are actually going to have very similar end points in both. And as we spoke about earlier actually, we think that both two and four weeks are going to be able to give us meaningful information. We're also going to have sweat chloride being evaluated in both trials, which will also be valuable.

嗨，馬修，我是傑夫喬達克維茲。讓我談談兩週和四周的情況，因為實際上這兩週的終點非常相似。正如我們之前討論過的，我們認為兩週和四周的時間都能夠為我們提供有意義的資訊。我們還將在兩項試驗中評估汗液氯化物含量，這也將很有價值。

Ultimately, what we're going to do is use all the information. We actually also have a lot of work being done to actually understand from a modeling perspective so that we can get the absolute most information out of our clinical trial. And so we're going to use all of that information across both to make the best decisions, and we think that that will contribute to both.

最終，我們將利用所有資訊。我們實際上也做了很多工作，從建模的角度去真正理解，以便從我們的臨床試驗中獲得絕對最多的資訊。因此，我們將綜合利用這兩方面的資訊來做出最佳決策，我們認為這將對雙方都有好處。

I think in terms of the specifics of the doses, as you may see in the design, we're going to go into patients with a small cohort; that's really just to confirm that exposure is the same in patients as it is in healthy volunteers. We don't have any reason to think that it will be different, but we're going to do that just to be sure we're taking the right approach. And then we'll choose our doses from there to confirm for the rest of the trial.

我認為，就劑量細節而言，正如您在設計中可能看到的那樣，我們將對一小部分患者進行試驗；這實際上只是為了確認患者和健康志願者的暴露情況相同。我們沒有任何理由認為情況會有所不同，但我們這樣做只是為了確保我們採取了正確的方法。然後我們將以此為基礎選擇劑量，以確認試驗剩餘部分的劑量。

Geoffrey Porges, Leerink Partners.

Geoffrey Porges，Leerink Partners。

Thanks very much for taking the questions, and congratulations on advancing some small CF compounds. First, just wondering if on slide 10 you could tell us where VX-152 [divid] compared to VX-440 in tezacaftor, in that assay.

非常感謝您回答這些問題，並祝賀您在一些小型CF化合物方面取得進展。首先，我想問一下，在第 10 張投影片中，您能否告訴我們，在 tezacaftor 的該項檢測中，VX-152 [divid] 與 VX-440 相比如何？

And then a couple of commercial questions, Ian, you've been fairly clear about what we should be expecting for KALYDECO in 2017, and there has certainly been some ups and downs in both consensus and in guidance this year for ORKAMBI. So wondering where you would suggest that we should be bracketing for next year for ORKAMBI. There are certainly a lot of variables with Europe, with the pediatric indication coming on line in the US, so that would be helpful.

接下來還有幾個商業問題。伊恩，你已經相當清楚地說明了我們應該對 KALYDECO 在 2017 年抱有怎樣的期望，而今年 ORKAMBI 的共識和預期也確實出現了一些起伏。所以我想知道您建議我們明年在 ORKAMBI 比賽中應該如何分組。歐洲的情況當然有很多變數，而美國兒科適應症即將上線，這將有所幫助。

And then, Stuart, lastly, as you're negotiating price in Europe, could you give us a sense of how you are thinking about having a portfolio of CF combination? Are you expecting to have them at different price points or should we be thinking that over time, they gravitate towards a ban, regardless of whether it's two or three drugs in the combination? Thanks.

最後，Stuart，既然你正在歐洲進行價格談判，你能否讓我們了解一下你是如何考慮建立CF組合投資組合的？您認為它們的價格會有所不同嗎？還是我們應該認為，隨著時間的推移，無論組合中是兩種還是三種藥物，它們最終都會被禁止？謝謝。

Thanks for the question. This is David Altshuler. I'll take the first part. As we showed last year in the het/min cells and also homozygous cells, VX-152 and VX-440 have very similar levels of max efficacy.

謝謝你的提問。這是大衛·阿爾特舒勒。我來回答第一部分。正如我們去年在 het/min 細胞和純合細胞中顯示的那樣，VX-152 和 VX-440 的最大療效水平非常相似。

All right. Thanks.

好的。謝謝。

Geoff, to your question on guidance, I was clear on KALYDECO in my prepared remarks, where KALYDECO is treating probably 90% of eligible patients that have -- and has a very good assistance rate and compliance rate. And we'd anticipate that continuing on into next year.

Geoff，關於你提出的指導問題，我在準備好的發言稿中已經明確說明了 KALYDECO 的情況，KALYDECO 可能正在治療 90% 符合條件的患者，並且具有非常好的輔助率和依從率。我們預計這種情況會持續到明年。

So as you see the current quarterly run rate for KALYDECO, we see that continuing on in 2017. The market for that potentially increasing would be if we were able to gather residual function approval. And as Jeff Chodakewitz explained, we are currently in discussions with the regulatory authorities in the US regarding that approval, and that continues that discussion.

從 KALYDECO 目前的季度運行率來看，我們看到這種情況在 2017 年繼續下去。如果我們能夠獲得剩餘功能批准，那麼該市場可能會成長。正如傑夫·喬達克維茨所解釋的那樣，我們目前正在與美國監管機構就該批准事宜進行討論，討論仍在繼續。

Regarding ORKAMBI, it's a little too early to say. We're very comfortable with the guidance we provided through the end of this year of $950 million to $990 million, and that does include the recent pediatric approval. As we look to 2017, we'll probably be thinking about how we give guidance around the US market and maybe Germany as well, because we do have visibility and knowledge to those markets.

至於 ORKAMBI，現在下結論還為時過早。我們對今年年底前給予的9.5億美元至9.9億美元的業績預期非常有信心，其中也包括最近獲得的兒科批准。展望 2017 年，我們可能會考慮如何為美國市場，或許還有德國市場提供指導，因為我們對這些市場確實有一定的了解和認識。

In terms of the other international markets of how quickly and the timing that they come off, we just need to give that some thought over the next few months of whether we actually try to provide a bracket around that guidance. There is a certain unknown element, as I'm sure you can appreciate, with these discussions, and sometimes the discussions push out because you are actually holding out for a price that you believe is appropriate for the medicine. And so it's about us getting to the right spot.

至於其他國際市場復甦的速度和時間，我們需要在接下來的幾個月仔細考慮一下，是否要嘗試給予相應的指導。我相信您也能理解，這些討論中存在一些未知因素，有時討論會因為您實際上堅持要一個您認為對這種藥物合適的價格而繼續進行。所以關鍵在於我們能否找到正確的位置。

And rather than putting guidance around it and be forced around guidance, we'll give it some consideration of how we put a bracket around that, and we'll get back to you early in 2017. And then to your third question, I'll pass it over to Stuart.

與其圍繞它制定指導方針，並被迫圍繞指導方針行事，不如我們考慮如何圍繞它設定一個框架，我們將在 2017 年初回复您。至於你的第三個問題，我會把它交給史都華來回答。

Geoff, in terms of pricing principles, obviously, we can't comment on the pricing of future products, but I'll talk to our pricing principles overall, which have been very consistent for how we price KALYDECO and ORKAMBI. The two primary drivers are really the number of patients that we're able to benefit with our medicines, and then the level of clinical benefit or value that we're able to bring.

Geoff，就定價原則而言，顯然我們不能評論未來產品的定價，但我可以談談我們整體的定價原則，這些原則對於 KALYDECO 和 ORKAMBI 的定價一直非常一致。兩個主要驅動因素實際上是我們的藥物可以使多少患者受益，以及我們能夠帶來的臨床益處或價值水平。

I think you've seen that we've adhered to those principles with ORKAMBI. And whilst we don't have formal pricing agreements in place across Europe yet, you have seen with the list prices of ORKAMBI that they are lower than they are for KALYDECO, which reflects the fact that clearly ORKAMBI has a much wider eligible patient population, despite the fact that that medicine has two different components within it. So I think you can expect that we'll be adhering to those pricing principles as we bring next-gen correctors and other medicines to market for eligible CF patients.

我想你已經看到，我們在 ORKAMBI 身上一直堅持這些原則。雖然我們目前還沒有在歐洲範圍內達成正式的定價協議，但您已經看到 ORKAMBI 的標價低於 KALYDECO，這反映出 ORKAMBI 的適用患者群體顯然要廣泛得多，儘管該藥物包含兩種不同的成分。因此，我認為您可以期待，我們將秉持這些定價原則，為符合條件的囊性纖維化患者推出下一代矯正器和其他藥物。

Thank very much.

非常感謝。

John Scotti, Evercore ISI.

John Scotti，Evercore ISI。

Congratulations on all the progress. I just want to ask on VX-659, if you were to compare the preclinical toxicity profile of that asset to VX-440 with regard to what potential thoratagenicity, et cetera, and then VX-152 with nausea, are you confident that the chemical structure of VX-659 is different enough where we won't see those issues in humans in the clinic with regard to what we see with VX-440 and VX-152?

祝賀你們取得的所有進展。我想問一下關於 VX-659 的問題，如果您將該藥物的臨床前毒性特徵與 VX-440（例如潛在的致胸膜炎等）以及 VX-152（例如噁心）進行比較，您是否確信 VX-659 的化學結構與 VX-440 和 VX-152 的化學結構我們不會在臨床中看到所引起的這些問題？

And then just quickly on timing, given the trials are small, and if we assume they enroll quickly, is it unreasonable to assume that we could see data more towards mid-next year rather than towards the end of the year. I know you've guided (inaudible). Thanks.

然後，關於時間安排，鑑於試驗規模較小，如果我們假設他們能很快招募到受試者，那麼假設我們可能在明年年中而不是年底才能看到數據，這是否不合理？我知道你已經指導過（聽不清楚）。謝謝。

So, John, first of all, I just want to pass on the team's best wishes to Mark, and we look forward to hearing back from Mark at some point. And I'm sure I share everybody else's thoughts that are on the phone.

約翰，首先，我謹代表全隊向馬克致以最美好的祝愿，我們期待馬克在某個時候回复我們。我相信我的想法也和電話那頭的其他人一樣。

In terms of the question, I'm actually going to ask Jeff Leiden to answer it because there is a whole portfolio approach here that we have, starting from VX-659, and a methodology of how we pick our molecules and what that basis is. And you should anticipate [that the world] will be more molecules coming. So, Jeff?

關於這個問題，我其實打算請 Jeff Leiden 來回答，因為我們這裡有一個完整的投資組合方法，從 VX-659 開始，以及我們選擇分子的方法和依據。你應該預料到，世界上將會出現更多的分子。所以，傑夫？

Thanks for the question, John. Maybe just to go back one step and remind you of how we look at these molecules and select them. The first real asset test for these molecules is our human HB cells, the het/min cells and homozygous cells from multiple donors. And as we showed you, I think in one of the slides today, VX-659 actually has efficacy as measured by chloride transport, which is maximal efficacy that's significantly higher than what we were seeing for VX-440 and VX-152, which were also quite high by themselves, by the way.

謝謝你的提問，約翰。或許我們應該回顧一下，提醒您我們是如何看待和選擇這些分子的。對這些分子進行的第一個真正的資產測試是我們的人類 HB 細胞、het/min 細胞和來自多個捐贈者的純合細胞。正如我們今天在幻燈片中展示的那樣，VX-659 的療效（以氯離子轉運衡量）實際上比我們看到的 VX-440 和 VX-152 的療效要高得多，順便說一句，VX-440 和 VX-152 本身的療效也相當高。

We've also measured a number of other things in that assay, like (inaudible) frequency and others, and we see the same kind of difference between VX-659 and VX-440. We then put the molecules through a pretty rigorous screen with respect to PK, tox, co-formulability, really making sure that we're bringing drugs to the clinic as opposed to molecules.

我們還在該檢測中測量了許多其他方面，例如（聽不見的）頻率等等，我們發現 VX-659 和 VX-440 之間存在相同的差異。然後，我們對這些分子進行了相當嚴格的篩選，包括藥物動力學、毒理學、共製劑性等方面，真正確保我們帶入臨床的是藥物，而不是分子。

And we're done with most but not all of that for VX-659. We're certainly done with enough that so we feel very comfortable that we have a tox profile and PK profile that we're confident in taking into the phase 1 studies, both in normal and in patients this time as well. We have not done yet with the developmental studies in rabbits, so we don't have that data yet. And obviously, we don't have any human data, which is the final test of PK and safety, and we'll only see that in the phase 1 study.

VX-659 的大部分工作已經完成，但還有一些工作尚未完成。我們已經完成了足夠的工作，因此我們非常有信心獲得毒理學特徵和藥物動力學特徵，並將其用於 1 期研究，這次既包括正常人群也包括患者。我們還沒有完成對兔子的發育研究，所以我們還沒有那部分數據。顯然，我們沒有任何人體數據，而人體數據是藥物動力學和安全性的最終檢驗，我們只能在 1 期研究中看到這一點。

In addition, just as Ian mentioned, just to lead you to clear expectations, we have a number of other next-gen correctors in our late preclinical pipeline. We expect to bring at least one of those forward into the clinic in the first half of next year and maybe more. And the reason for that, again, is that these molecules come in a number of different flavors, different potencies, different properties, and we want to bring multiple of them into humans as part of triple combinations to understand how they interact. I hope that gives you a flavor of where VX-659 fits, and what we know and some things that we don't yet know but will know soon.

此外，正如 Ian 所提到的，為了讓大家對預期有清晰的了解，我們還有許多其他下一代矯正器處於臨床前研發後期階段。我們預計明年上半年至少會有一名患者進入臨床治療，也許還會有更多。原因在於，這些分子具有多種不同的類型、不同的效力、不同的特性，我們希望將多種分子以三重組合的形式引入人體，以了解它們之間的相互作用。我希望這能讓您大致了解 VX-659 的定位，以及我們已知的資訊和一些我們尚不了解但很快就會知道的資訊。

That's really helpful. Thank you so much.

這真的很有幫助。太感謝了。

Brian Skorney, Robert W Baird.

Brian Skorney，Robert W Baird。

Good afternoon, guys. I just have two questions. Why start both programs in het/min? It seems like you'd potentially get more information out of adding this on top of VX-661 ivacaftor in patients with two F508del alleles. And also, when we look at the relative differences in the four generations, is it reasonable to assume that two correctors within the same generation still are redundant? And is there any obvious redundancy to cross-combining correctors of those different generations?

下午好，各位。我只有兩個問題。為什麼兩個程式都以 het/min 模式啟動？對於攜帶兩個 F508del 等位基因的患者，在 VX-661 ivacaftor 的基礎上添加此藥物似乎可能會獲得更多資訊。此外，當我們觀察四代之間的相對差異時，是否可以合理地假設同一代中的兩個校正器仍然是冗餘的？將不同世代的校正器交叉組合使用是否有明顯的冗餘？

Brian, it's Jeff again. Let me answer both; both are really good questions. Maybe I'll answer your second question first. Really the portfolio approach is based upon the fact that while the molecules may bind to the same set, may even have the same mechanism of action, there are obviously a number of other properties that are going to be really important in picking the best regimen.

布萊恩，我是傑夫。讓我來回答這兩個問題；這兩個問題都非常好。或許我可以先回答你的第二個問題。實際上，投資組合方法基於這樣一個事實：雖然分子可能與同一組結合，甚至可能具有相同的作用機制，但顯然還有許多其他特性在選擇最佳方案時非常重要。

They include potency, because the more potent the molecule is, the easier it is to combine into a triple combination and formulate. May include national efficacy, obviously, and we showed you the VX-659 as an example, has greater maximal efficacy. But they also include things like PK properties, tissue penetration, drug interactions, all of those things.

其中包括效力，因為分子效力越強，就越容易組合成三元化合物並配製製劑。顯然，可能包括國家效力，我們以 VX-659 為例，它具有更高的最大效力。但它們也包括藥物動力學特性、組織滲透性、藥物交互作用等等。

And so when you think about this portfolio, think about it not only in terms of mechanism of action and not only in terms of efficacy and potency, but think about it as how do we create the best triple regimen with one or more of these molecules going forward. Does that make sense to you in terms of how we're thinking about it?

因此，在考慮這個產品組合時，不僅要考慮其作用機制，不僅要考慮其功效和效力，還要考慮我們如何利用其中一種或多種分子來創造最佳的三聯療法。你覺得我們這樣想有道理嗎？

Yes, that is helpful.

是的，這很有幫助。

And then repeat your first question for me.

然後請你再重複一次你的第一個問題。

Just on the strategy of going in het/mins first.

就先按策略進入 het/mins。

Yes, just to be clear about what we're doing here, first of all, het/mins obviously is the big group of patients with the largest unmet need. And so as we think about taking these molecules forward, that's the patient population that we're most focussed on. But I do want to be clear that we're essentially doing these things in parallel. So we will have results both in the het/min population and the homozygous population, essentially at the same time with very little delay. That's going to let us let us really design the best phase 3 study here.

是的，為了明確我們在這裡所做的事情，首先，het/mins 顯然是未滿足需求最大的患者群體。因此，當我們考慮推進這些分子的研發時，這便是我們最關注的患者群。但我確實想明確一點，我們基本上是在並行這些工作。因此，我們將在雜合子/純合子群體和純合子群體中基本上同時獲得結果，延遲時間非常短。這將使我們能夠真正設計出最好的第三期臨床試驗。

One of the things I've really been pleased with over the past four or five years is as we developed these molecules, we've learned an awful lot about how to take the development forward most quickly, most efficiently, and then how to start to think about phase 3 trials perhaps a little differently.

在過去的四、五年裡，我真正感到欣慰的一件事是，隨著我們開發這些分子，我們學到了很多關於如何以最快、最有效的方式推進開發，以及如何以可能略有不同的方式開始思考 3 期試驗的知識。

And so, I do think you're seeing the results of that here as we streamline these phase 2 trials, do them in parallel as opposed to in series as we've done them in the past, and then hopefully, based on the results, launch into phase 3 in a much broader fashion than we've done previously.

所以，我認為你們現在看到的成果就是我們簡化了這些二期試驗，採用並行而非像過去那樣串行的方式進行試驗的結果，然後希望根據試驗結果，以比以往更廣泛的方式啟動三期試驗。

Thanks, Jeff. That's helpful.

謝謝你，傑夫。那很有幫助。

Liisa Bayko, JMP Securities.

Liisa Bayko，JMP Securities。

Hi, thanks for taking the question. Just to clarify, there is no intention to formulate maybe a quad or something? You wouldn't add some of your next-generation correctors together, and why not would be the question?

您好，感謝您回答這個問題。澄清一下，我們並沒有打算組成一個四元組之類的組織嗎？你不會把一些下一代校正器加在一起，問題是，為什麼不呢？

So as a theoretical question, Liisa, of course, we would think about quads. As you know, we're also looking at some other mechanisms of action, things like ENaC inhibitors that could be combined. So there is nothing a priori that we wouldn't look at four-drug combinations. Obviously, an ENaC inhibitor is inhaled, so it wouldn't be co-formulated.

所以，莉薩，作為一個理論問題，我們當然會考慮四邊形。如您所知，我們也正在研究其他一些作用機制，例如可以合併使用的 ENaC 抑制劑。因此，沒有任何先驗理由阻止我們考慮四種藥物的組合。顯然，ENaC 抑制劑是吸入式的，所以不會與其他藥物合併配製。

But I think there is one difference here that is worth mentioning, and I think it would be unlikely that, for instance, that we would put VX-152 and VX-440 together because they do appear to have the same mechanism of actions. So adding them together would be not expected to produce a lot more benefit.

但我認為這裡有一個值得一提的區別，例如，我們不太可能將 VX-152 和 VX-440 放在一起，因為它們的作用機制似乎相同。因此，將它們加在一起預計不會產生更多好處。

Okay. And then can you maybe talk about where you're going to be enrolling patients for some of these preliminary studies for the next generation? Is it going to be North America, ex-US?

好的。那麼，您能否談談您將在哪裡招募患者參與下一代的一些初步研究？是指北美地區，不包括美國嗎？

It's Jeff Chodakewitz. We're actually going to be doing studies in sites both in the US and in Europe.

他是傑夫·喬達克維茨。我們實際上將在美國和歐洲的多個地點進行研究。

Okay. Great. Thank you. And then just wanted to get a little bit more clarity on the hormonal component. I think you had maybe talked about this earlier for VX-440 and what you've seen there in your preclinical stuff, and then what that would just mean if you were to take it forward. Thank you.

好的。偉大的。謝謝。然後，我還想更清楚地了解荷爾蒙方面的因素。我想你之前可能談到 VX-440，以及你在臨床前研究中看到的情況，還有如果繼續推進這項研究意味著什麼。謝謝。

Sure, Liisa, it's Jeff Chodakewitz, again. So just to clarify perhaps, we've already talked about the rapid toxicity and why we're putting the contraceptive language in place. The hormonal wording doesn't actually come from preclinical studies.

沒錯，莉薩，又是傑夫‧喬達克維茲。為了澄清一下，我們已經討論過快速毒性以及我們為什麼要加入避孕相關的措辭。這種關於荷爾蒙的措詞其實並非來自臨床前研究。

With VX-440 at higher doses, there was some evidence of liver enzyme induction, and that can actually somewhat lower the exposure to the hormones in contraceptives. Therefore, again, to ensure that we're using highly reliable contraception, we're excluding that as being the primary method.

使用較高劑量的 VX-440 時，有證據表明存在肝酵素誘導作用，這實際上可能會在一定程度上降低避孕藥中荷爾蒙的暴露量。因此，為了確保我們使用高度可靠的避孕方法，我們再次排除將其作為主要方法。

Okay. Great. Thank you.

好的。偉大的。謝謝。

Tony Butler, Guggenheim Partners.

東尼巴特勒，古根漢合夥公司。

Thanks very much. Two questions briefly and cohort 1A, can you help me understand the notion of using the low dose first before you move forward? While it may be intuitive, you don't do that for VX-152.

非常感謝。簡單問兩個問題，還有，1A組，你們能幫我理解一下先使用低劑量再進行下一步的概念嗎？雖然這樣做很直觀，但對於 VX-152 來說，你不能這樣做。

And then the second question is really around VX-152. To me, you've outlined very well the portfolio strategy. Why certainly you're moving forward with VX-440 and VX-659, but is the only reason for VX-152 the fact that it does not have teratogenicity? Thanks again.

第二個問題其實與 VX-152 有關。在我看來，你已經非常清楚地闡述了投資組合策略。為什麼你們肯定會繼續推進 VX-440 和 VX-659 的研發，而推進 VX-152 的唯一原因只是因為它沒有致畸性嗎？再次感謝。

Hi, Tony, Jeff Chodakewitz. So two comments, one, the 1A, as we go back to a prior conversation, the intent of 1A is to go -- make the transition from healthy volunteers to patients, and be sure basically, as the exposure is similar in the two groups. And since it could potentially go up or down, although, we don't expect it to do either, that's why you wouldn't want to go in at a high dose and then have the exposure actually end up higher. That's why we always start in this kind of situation with the low dose and then expand, which is the intent.

嗨，東尼，我是傑夫·喬達克維茨。所以有兩點要說明，第一點是 1A，當我們回到之前的討論時，1A 的目的是——從健康志願者過渡到患者，並確保基本上兩組的暴露情況相似。而且由於它有可能上升或下降，雖然我們預計它不會上升或下降，所以你不想以高劑量進入，然後導致實際暴露量更高。這就是為什麼我們總是從小劑量開始，然後逐漸增加劑量，這正是我們的目的。

In terms of your broader question about VX-152 and VX-440, I think it goes back to Jeff Leiden's comment, that we think both molecules will have the potential to be well tolerated at doses that can deliver benefit to patients, including, excitingly, both homozygous patients and het/min patients who don't have a treatment option. And that's really why we're taking both forward and will continue to learn as we add other molecules to our portfolio.

關於您提出的關於 VX-152 和 VX-440 的更廣泛的問題，我認為這要追溯到 Jeff Leiden 的評論，我們認為這兩種分子都有可能在能夠為患者帶來益處的劑量下具有良好的耐受性，令人興奮的是，包括沒有治療選擇的純合子患者和雜合子/隱性基因型患者。正因如此，我們才會繼續推進這兩項研究，並在將其他分子添加到我們的產品組合中的過程中不斷學習。

Operator, this is Michael Partridge. We have time for one more question.

接線員，這裡是麥可·帕特里奇。我們還有時間回答最後一個問題。

Alan Carr, Needham & Company.

艾倫·卡爾，尼德姆公司。

Thanks for taking my question and congratulations on your progress. I wonder if you can clarify a bit some of the timing around VX-152, VX-440, the results from those and the results from your VX-659 phase 2, are you trying to -- are you going to be able to position these three data from three phase 2 trials at the same time in order to decide which one or two to bring into phase 3?

感謝您回答我的問題，也祝賀您的進步。我想請您澄清一下 VX-152、VX-440 的時間安排，以及它們的結果和您的 VX-659 二期臨床試驗的結果。您是否打算同時整合這三項二期臨床試驗的數據，以便決定將哪一項或哪兩項推進到第三期臨床試驗？

So, Alan, this is Jeff Chodakewitz. Let me review how that winds up. Of course, in the end, all these time lines, particularly the phase 2 studies, are going to be dependent on the rate of (inaudible). But what we expect would be that for both VX-152 and VX-440, that we will be getting results, as we said, in the second half of 2017.

艾倫，這位是傑夫喬達克維茨。讓我回顧一下最終結果。當然，最終所有這些時間表，特別是 2 期研究，都將取決於（聽不清楚）的速度。但我們預計，VX-152 和 VX-440 都將在 2017 年下半年取得成果，正如我們所說。

At that point, we will also have the phase 1 results from VX-659, and as we talked about, that's given everything we learned about the relationship from preclinical to exposure to benefit of patients, we think that we will be able to understand a lot about all three compounds as we're looking forward to make decisions at that point.

屆時，我們也將獲得 VX-659 的第 1 期臨床試驗結果。正如我們之前討論過的，考慮到我們從臨床前研究到藥物暴露再到患者獲益等各方面所了解到的信息，我們認為屆時我們將能夠更好地了解這三種化合物，並期待屆時做出相應的決定。

This is Jeff Leiden. I just want to be clear that we don't think about VX-659 as being on exactly the same time frame as VX-152 and VX-440. As Jeff said, it's a little difficult to give you precision, because it depends on how fast users enroll; VX-659 will only have a small cohort of patients in the phase 1, and so we'll have to see what we learn from that.

這是傑夫·萊頓。我只想澄清一點，我們並不認為 VX-659 與 VX-152 和 VX-440 處於完全相同的時間段。正如傑夫所說，很難給出精確的結果，因為這取決於用戶入組的速度；VX-659 在第一階段只會招募一小部分患者，所以我們還要看看從中能學到什麼。

If you were to ask me just to put a marker on the table, I think of VX-659 myself is about six months behind VX-152 and VX-440. So we're not going to be waiting, obviously, if we see positive results with VX-152 and VX-440, before taking those into phase 3 to wait for VX-659, if that's really the question.

如果讓我隨便舉個例子，我認為 VX-659 比 VX-152 和 VX-440 落後大約六個月。所以，顯然，如果我們看到 VX-152 和 VX-440 的正面結果，我們不會等到 VX-659 的結果出來才將它們推進到第三階段，如果這真的是問題所在的話。

Yes. Okay. That helps. And then one other one. Can you give us an update on VX-371, where things stand with your CF program and cilliary dyskinesia there?

是的。好的。那很有幫助。然後還有另一個。能否向我們介紹 VX-371 的最新進展，以及你們的囊性纖維化計畫和纖毛運動障礙治療的進展？

So it's Jeff Chodakewitz. For both of our studies, both the study in CF where we're looking at the ENaC inhibitor on top of ORKAMBI in people who are homozygous for F508del, and the study in patients with PCD, both are actively enrolling.

原來是傑夫·喬達克維茨。我們正在積極招募兩名患者，一名是 CF 患者，研究在 ORKAMBI 的基礎上加用 ENaC 抑制劑治療 F508del 純合子；另一名是 PCD 患者，目前都在積極招募患者。

And timing for results, what's the latest on that?

成績公佈時間方面，最新進展如何？

It's always going to be of course until we end up getting the study fully enrolled, it's just too hard to give you any precision on the time.

當然，在研究完全招募到受試者之前，情況總是如此，很難給出精確的時間。

Thanks very much. Appreciate you taking my questions.

非常感謝。感謝您回答我的問題。

Okay, everybody, thanks for joining us tonight. For those of you going to the North American CF Conference, we look forward to seeing you there on Thursday night of this week. We will also be webcasting our presentation there starting 6:30 PM Eastern Time on Thursday. Tonight, the Investor Relations Team will remain in the office if you have any additional questions. Thank you.

好了，各位，感謝你們今晚收看我們的節目。對於那些將要參加北美囊性纖維化大會的朋友們，我們期待在本週四晚上見到你們。我們也將於週四美國東部時間下午 6:30 開始在那裡進行網路直播。今晚，投資者關係團隊將在辦公室恭候您的詢問。謝謝。

Ladies and gentlemen, that does conclude your call. You may disconnect at this time. Have a great day.

女士們、先生們，通話到此結束。您現在可以斷開連線了。祝你有美好的一天。