福泰製藥 (VRTX) 2013 Q2 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Vertex Pharmaceuticals Incorporated second-quarter 2013 financial results conference call. At this time, all participants are in a listen-only mode. Later we will conduct a question and answer session, and instructions will be given at that time.

各位女士、各位先生，大家好，歡迎參加 Vertex Pharmaceuticals Incorporated 2013 年第二季財務業績電話會議。此刻，所有與會者皆處於僅收聽模式。稍後我們將進行問答環節，屆時將提供相關指示。

(Operator Instructions)

(接線員指示)

As a reminder, today's call is being recorded. I would now like to turn the call over to Michael Partridge. Please go ahead, sir.

提醒各位，今天的電話會議將被錄音。現在我想把電話會議交給 Michael Partridge。先生，請開始。

Thank you, operator, and good evening to everyone. Joining me on tonight's call are Dr. Jeff Leiden, Vertex's Chairman and CEO, Bob Kauffman, Chief Medical Officer, Stuart Arbuckle, Chief Commercial Officer, and Ian Smith, Chief Financial Officer. Jeff will begin with a few comments on the execution of our strategy to date in 2013. Then Bob will provide an update on our pipeline progress, including our mid and late stage programs in cystic fibrosis and hepatitis C.

謝謝，接線員，也向各位道晚安。今晚與我一同參與電話會議的有 Vertex 董事長兼執行長 Jeff Leiden 博士、首席醫療官 Bob Kauffman、首席商務官 Stuart Arbuckle，以及首席財務官 Ian Smith。Jeff 將先就我們在 2013 年迄今執行策略的情況發表幾點評論。接著 Bob 將就我們的研發管線進展提供最新資訊，包括囊性纖維化與 C 型肝炎的中後期計畫。

Stuart will follow with comments on trends for our key marketed medicines, KALYDECO and INCIVEK. And to close, Ian will review the second-quarter financial results and update our 2013 guidance. Following prepared remarks, Peter Mueller, Chief Scientific Officer, will join us for a question and answer period. After the call, we will be available in our offices for follow-up.

接下來 Stuart 將就我們主要已上市藥品 KALYDECO 與 INCIVEK 的趨勢發表評論。最後，Ian 將回顧第二季財務結果並更新我們 2013 年的財測指引。在預先準備的發言之後，首席科學官 Peter Mueller 將加入問答環節。會後，我們將在辦公室提供後續追蹤。

Before we begin, I will note that information discussed on this conference call includes forward-looking statements, which are subject to risks and uncertainties. These risks and uncertainties are discussed in detail in our 10-K and 10-Q reports filed with the Securities and Exchange Commission, and also in the press release announcing our financial results tonight. These statements, including without limitation, those regarding the commercial performance of INCIVEK and KALYDECO, our development plans and expectations, and our guidance are based on management's current assumptions. These statements are subject to risks and uncertainties that could cause actual outcomes and events to differ materially.

在開始之前，我要說明，本次電話會議所討論的資訊包含前瞻性陳述，並受風險與不確定性影響。這些風險與不確定性已在我們向美國證券交易委員會提交的 10-K 與 10-Q 報告中詳細說明，亦載於今晚公布財務結果的新聞稿中。這些陳述（包括但不限於關於 INCIVEK 與 KALYDECO 的商業表現、我們的開發計畫與預期，以及我們的財測指引）係基於管理層目前的假設。這些陳述受風險與不確定性影響，可能導致實際結果與事件與所述內容出現重大差異。

GAAP and non-GAAP financial measures will be discussed on this call. The information regarding our use of these measures and a reconciliation of GAAP to non-GAAP is available in our second-quarter 2013 financial press release, and is described on slide 4 of tonight's webcast. I will now turn it over to Jeff.

本次電話會議將討論 GAAP 與非 GAAP 財務衡量指標。關於我們使用這些指標的資訊，以及 GAAP 與非 GAAP 的調節表，已載於我們 2013 年第二季財務新聞稿中，並於今晚網路直播的第 4 張投影片中說明。現在我把時間交給 Jeff。

Thanks, Michael. Good evening, everyone. Tonight, I am pleased to discuss the progress that Vertex has made in the first half of 2013. At the start of this year, we outlined three strategic imperatives for our business that would position us for long-term growth.

謝謝你，Michael。各位晚安。今晚我很高興與各位分享 Vertex 在 2013 年上半年所取得的進展。在今年年初，我們提出三項策略要務，以使公司具備長期成長的定位。

First, prioritizing our development investment to advance our late-stage medicines for cystic fibrosis, hepatitis C and autoimmune diseases. Second, focus on continuing to discover innovative medicines for serious diseases from our research efforts. And third, maintaining our financial strength to support the investment required to realize our significant growth opportunities in the near future.

第一，優先配置我們的研發投資，以推進囊性纖維化、C 型肝炎與自體免疫疾病的後期藥物開發。第二，聚焦於持續透過研發工作發現針對嚴重疾病的創新藥物。第三，維持財務實力，以支持在不久的將來把握重大成長機會所需的投資。

Halfway through 2013, we have accomplished a great deal to advance our late-stage medicines, and we continue to reinvest in research to bring further ground-breaking therapies to patients, all while enhancing our financial strength. In cystic fibrosis, KALYDECO has been successfully launched for G551D patients in Europe this year. We have multiple studies under way that could potentially expand the KALYDECO label. Today, we are announcing the first clinical data for Ivacaftor monotherapy outside of G551D. Ivacaftor monotherapy has received breakthrough designation from the FDA, and we plan to submit regulatory filings in the US and the EU in the second half of 2013 to expand the use of Ivacaftor.

2013 年過了一半，我們在推進後期藥物方面已完成許多工作；同時我們持續再投資研發，為病患帶來更多突破性療法，並且進一步強化我們的財務實力。在囊性纖維化方面，KALYDECO 已於今年在歐洲成功上市，供 G551D 病患使用。我們正在進行多項研究，可能擴大 KALYDECO 的適應症標籤。今天，我們公布 Ivacaftor 單藥治療在 G551D 之外的首批臨床數據。Ivacaftor 單藥治療已獲 FDA 授予突破性療法認定，我們計畫於 2013 年下半年在美國與歐盟提交法規申請，以擴大 Ivacaftor 的使用。

Our Phase 3 program for VX-809 or Lumacaftor in combination with Ivacaftor is under way to evaluate six months of treatment in approximately 1,000 patients with homozygous for the F delta 508 mutation. We are on track to submit an NDA in the US with this combination in 2014. The combination of Lumacaftor and Ivacaftor has also received breakthrough designation from the FDA. In the second-quarter, we reported Phase 2 data with another corrector, VX-661 that further validated the strategy of combining a corrector and a potentiator to treat CF patients with two copies of the Delta 508 mutation.

我們針對 VX-809（或 Lumacaftor）與 Ivacaftor 併用的第 3 期計畫正在進行中，評估約 1,000 名 F delta 508 突變同型合子病患接受為期六個月治療的效果。我們正按計畫於 2014 年在美國就此併用療法提交 NDA。Lumacaftor 與 Ivacaftor 的併用療法亦已獲 FDA 授予突破性療法認定。在第二季，我們公布了另一款校正劑 VX-661 的第 2 期數據，進一步驗證將校正劑與增效劑併用，以治療帶有兩份 Delta 508 突變的囊性纖維化病患之策略。

In the second half of 2013, we plan to conduct a study of VX-661 in combination with Ivacaftor in G511D delta 508 heterozygous patients. Our in vitro data supports the potential for further benefit for these patients. In hepatitis C, we have generated nearly $450 million in hepatitis C revenues and royalties in the first half of this year. We have initiated multiple studies of VX-135 in combination with ribavirin, and separately in combination with daclatasvir. Despite the partial clinical hold placed on the US study, our strategy remains clear, to identify all oral and high viral cure regimens containing VX-135 with durations of 12 weeks or less in multiple genotypes.

在 2013 年下半年，我們計畫在 G511D/Delta 508 異型合子病患中，進行 VX-661 與 Ivacaftor 併用的研究。我們的體外數據支持這些病患可能獲得進一步療效的潛力。在 C 型肝炎方面，今年上半年我們已創造近 4.5 億美元的 C 型肝炎營收與權利金收入。我們已啟動多項 VX-135 與 ribavirin 併用的研究，並另行啟動 VX-135 與 daclatasvir 併用的研究。儘管美國研究被施加部分臨床暫停（partial clinical hold），我們的策略仍然明確：在多種基因型中，找出包含 VX-135 的全口服且高病毒治癒率之療程，療程時間為 12 週或更短。

Commercially, we continue to generate significant revenue in the hepatitis C market with INCIVO-based therapy, although the number of new patients initiating treatment continues to decline. In CF, KALYDECO reimbursement and uptake in Europe has been very strong, resulting in significant growth in our KALYDECO revenues.

在商業面，我們透過以 INCIVO 為基礎的療法，仍持續在 C 型肝炎市場創造可觀營收，儘管開始治療的新病患人數持續下降。在囊性纖維化方面，KALYDECO 在歐洲的給付核准與使用採納非常強勁，帶動我們 KALYDECO 營收顯著成長。

Financially, we enhanced our strength by seeking to maximize revenues while making prudent investments focused on R&D and controlling expenses. These actions are reflected in our Q2 results. Importantly, we ended the quarter with over $1.4 billion of cash, cash equivalents, and marketable securities, with no outstanding convertible debt. In summary, we are creating hope for people with CF and HCV, value for shareholders, and a platform for long-term growth by executing on our strategy. Now, I will turn it over to Bob.

在財務面，我們在審慎投資（聚焦研發）並控管費用的同時，致力於將營收最大化，以強化我們的財務實力。這些行動反映在我們第二季的業績中。重要的是，本季末我們持有超過 14 億美元的現金、約當現金與有價證券，且沒有任何未償還的可轉換債務。總結而言，透過執行我們的策略，我們正在為囊性纖維化（CF）與 C 型肝炎（HCV）患者帶來希望、為股東創造價值，並建立長期成長的平台。現在我把時間交給 Bob。

Thank you, Jeff, and good evening. Tonight, I will review the status and timing of our three ongoing studies with VX-135. Then, I will also review our CF development pipeline and provide a few updates based on our progress to date.

謝謝你，Jeff，各位晚安。今晚我將回顧我們三項正在進行的 VX-135 研究之狀態與時程。接著，我也會回顧我們的囊性纖維化研發管線，並根據目前進展提供幾項更新。

First, VX-135 for hepatitis C. We have initiated a 12-week study of 100-milligrams and 200-milligrams of VX-135, plus daclatasvir in 20 genotype 1 patients in New Zealand. Pending data from this initial cohort of patients, we plan to expand the study to enroll additional patients with both genotypes 1 and 3, and to evaluate an eight-week combination regimen in genotype 1. Safety and efficacy results from the first part of the study are expected to be available in early 2014.

首先是用於 C 型肝炎的 VX-135。我們已在紐西蘭啟動一項為期 12 週的研究，於 20 名基因型 1 病患中評估 100 毫克與 200 毫克的 VX-135 加上 daclatasvir 的併用療法。視這批初始受試者隊列的數據而定，我們計畫擴大研究，納入更多基因型 1 與 3 的病患，並在基因型 1 中評估為期 8 週的併用療程。該研究第一部分的安全性與療效結果預計將於 2014 年初取得。

In our European study of VX-135 plus ribavirin, 20 patients, 10 in each of the 100-milligram and 200-milligram arms have now completed 12 weeks of dosing. Both the 100-milligram and 200-milligram doses were well tolerated, with no discontinuations and no serious adverse events reported. 100% of patients achieved undetectable HCV RNA during the 12-week dosing period, and 70% and 80% of patients in the 100- and 200-milligram dosing arms, respectively, had undetectable virus within four weeks of initiating treatment. We expect to provide complete safety and efficacy results from the 100- and 200-milligram arms in the second half of 2013.

在我們於歐洲進行的 VX-135 合併利巴韋林（ribavirin）研究中，目前已有 20 名患者（100 毫克組與 200 毫克組各 10 名）完成 12 週給藥。100 毫克與 200 毫克兩種劑量的耐受性均良好，未出現停藥情形，亦未通報任何嚴重不良事件。在 12 週給藥期間，100% 的患者達到 HCV RNA 測不到；且在開始治療後四週內，100 毫克組與 200 毫克組分別有 70% 與 80% 的患者病毒測不到。我們預期將於 2013 年下半年提供 100 毫克與 200 毫克組的完整安全性與療效結果。

In the US, dosing and evaluation is ongoing in the study of 100-milligrams of VX-135 plus ribavirin. 10 patients with genotype 1 hepatitis C are enrolled in this dose group, and all patients have now completed at least 10 weeks of treatment. We are working to provide to the FDA the requested clinical, preclinical and pharmacokinetic data from ongoing VX-135 studies, with the goal of resolving the partial clinical hold, and supporting the evaluation of a 200-milligram dose of VX-135 in the US. We expect to complete submission of the requested data to the FDA in the fourth quarter. Safety and efficacy results for the 100-milligram arm of the study are expected to be available later this year.

在美國，100 毫克 VX-135 合併利巴韋林（ribavirin）的研究仍在持續給藥與評估中。此劑量組已納入 10 名基因型 1 丙型肝炎患者，且目前所有患者均已完成至少 10 週治療。我們正致力於向 FDA 提供其要求的、來自進行中 VX-135 研究的臨床、臨床前與藥物動力學資料，目標是解除部分臨床暫停（partial clinical hold），並支持在美國評估 200 毫克 VX-135 劑量。我們預期於第四季完成向 FDA 提交所要求資料。本研究 100 毫克組的安全性與療效結果預計將於今年稍晚取得。

In addition, our partner J&J has completed a drug-drug interaction study of VX-135 in combination with Simeprevir in healthy volunteers, and we expect dosing to commence in genotype 1 patients in the second half of 2013, pending data analysis and dose selection. Our strategy continues to be one of identifying high viral cure regimens of 12 weeks or less, effective in multiple genotypes, and we have multiple trials planned or underway to fulfill this strategy.

此外，我們的合作夥伴 J&J 已在健康受試者中完成 VX-135 與 Simeprevir 併用的藥物—藥物交互作用研究；在完成資料分析與劑量選擇後，我們預期將於 2013 年下半年開始對基因型 1 患者進行給藥。我們的策略仍是找出 12 週或更短、具有高病毒治癒率且對多種基因型有效的治療方案；為落實此策略，我們已規劃或正在進行多項試驗。

Now, moving to cystic fibrosis. Our most advanced compound is KALYDECO, which is indicated for the treatment of G551D patients over the age of six. We are studying this compound known generically as Ivacaftor in a number of additional patient populations that we believe have the potential to benefit from KALYDECO based on in vitro data along with our understanding of the disease biology and KALYDECO mechanism of action.

接下來談囊性纖維化。我們最先進的化合物是 KALYDECO，其適應症為治療 6 歲以上的 G551D 患者。我們正在多個額外的患者族群中研究此化合物（通用名 Ivacaftor），基於體外數據，以及我們對疾病生物學與 KALYDECO 作用機轉的理解，我們相信這些族群有潛力從 KALYDECO 中受益。

We have three Phase 3 label expansion studies underway, and we reported top line results in the first of these studies, the non-G551D gating study today. Ivacaftor produced statistically significant lung function improvements in patients with the nine characterized non-G551D gating mutations. This was a blinded cross-over study design.

我們目前有三項第 3 期擴大標籤適應症研究正在進行中，並且今天公布其中第一項研究——非 G551D 閘門（gating）研究——的主要（top line）結果。Ivacaftor 在具有九種已鑑定之非 G551D 閘門突變的患者中，帶來具統計顯著性的肺功能改善。本研究採盲性（blinded）交叉（cross-over）設計。

A schematic of the study is shown on slide 11 of the webcast. Patients were randomly assigned to receive either Ivacaftor or placebo for eight weeks, then go through a full week washout. And then receive the alternate treatment for eight weeks, that is through weeks 12 to 20. This study included 39 participants ages six and over, who have at least one of the nine characterized non-G551D gating mutations.

研究示意圖載於網路直播投影片第 11 張。患者被隨機分派接受 Ivacaftor 或安慰劑治療 8 週，之後進行完整 1 週的洗脫期（washout）。接著再接受另一種替代治療 8 週，也就是第 12 週至第 20 週。本研究共納入 39 名 6 歲以上受試者，且至少帶有九種已鑑定之非 G551D 閘門突變中的一種。

The primary end point was absolute change from baseline to percent predicted FEV1. In the study, the mean absolute treatment difference between Ivacaftor and placebo was 10.7%, with a p value of less than 0.0001. And the mean relative difference was 14.2%, again, with a p value of less than 0.0001, as measured by FEV-1 through the eight-week treatment period. The mean, absolute and relative FEV1 improvements during Ivacaftor treatment, that is the within group changes, were 7.5% and 10.8%, respectively. Both were highly significant, with p values of less than 0.0001.

主要終點為從基線到預測值百分比 FEV1 的絕對變化。研究中，Ivacaftor 相較安慰劑的平均絕對治療差異為 10.7%，p 值小於 0.0001。平均相對差異為 14.2%，同樣 p 值小於 0.0001；此為在 8 週治療期間以 FEV-1 測得。Ivacaftor 治療期間的平均 FEV1 改善（即組內變化）之絕對與相對改善分別為 7.5% 與 10.8%。兩者皆高度顯著，p 值均小於 0.0001。

We also achieved statistical significance for secondary end points of weight gain, and improvement in the respiratory domain of the CFQ-R, the patient-reported quality of life measure. Safety was similar to the experience to date with KALYDECO and G551D. Ivacaftor was well-tolerated. And in the study, the most common adverse events were pulmonary exacerbation, cough, headache, and abdominal pain, each occurring more frequently while patients received placebo.

我們亦在次要終點——體重增加，以及 CFQ-R（患者回報之生活品質量表）呼吸領域的改善——達到統計顯著性。安全性表現與迄今 KALYDECO 在 G551D 患者中的經驗相近。Ivacaftor 耐受性良好。在本研究中，最常見的不良事件為肺部惡化（pulmonary exacerbation）、咳嗽、頭痛與腹痛；且上述事件在患者接受安慰劑期間發生更為頻繁。

These results are another example of the correlation of clinical data with in vitro chloride transport data that we have seen across the CF program. In the second half of 2013, we expect to present full data from this study at a medical meeting. Also in the second half of 2013, we intend to file both an sNDA in the US and an MAA variation in Europe, for use of Ivacaftor in patients with other gating mutations.

這些結果再次顯示我們在囊性纖維化（CF）計畫中所觀察到的：臨床數據與體外氯離子運輸數據之間的相關性。我們預期於 2013 年下半年在醫學會議上發表本研究的完整數據。同樣在 2013 年下半年，我們計畫在美國提交 sNDA，並在歐洲提交 MAA 變更（variation），以將 Ivacaftor 用於其他閘門突變患者。

We have two additional Phase 3 label-expansion studies ongoing in CF patients, in patients with the R117H mutation, and in children ages two through five with the gating mutation, including G551D. Slide 12 shows the design of each of these studies. We expect the results from the R117H study in the second half of this year, and pending study results, we expect to submit an sNDA in early 2014.

我們另有兩項第 3 期擴大標籤適應症研究正在囊性纖維化患者中進行：一項針對 R117H 突變患者，另一項針對 2 至 5 歲、具有閘門突變（包含 G551D）的兒童。投影片第 12 張顯示這兩項研究各自的設計。我們預期於今年下半年取得 R117H 研究結果；視研究結果而定，我們預期於 2014 年初提交 sNDA。

In the study in children ages two through five, we have now completed the PK portion of the study and we have selected a dose. Enrollment in the 24-week dosing portion of this study is now ongoing, and we expect results in mid-2014.

在 2 至 5 歲兒童研究中，我們已完成研究的藥物動力學（PK）部分並選定劑量。目前該研究 24 週給藥部分的收案正在進行中，我們預期於 2014 年年中取得結果。

We are also conducting a proof-of-concept study in patients with residual CFT-R function, also known as the n-of-1 study. The design of this study is shown on slide 13. Like the gating study, the n-of-1 study has a cross-over design. Cross-over designs have increased power to show a treatment effect, by focusing on the drug-on and drug-off effects in individual patients, which may reduce variability. Data from this study are expected in the first half of 2014.

我們也正在對具有殘餘 CFTR 功能的患者進行概念驗證（proof-of-concept）研究，亦稱 n-of-1 研究。本研究設計載於投影片第 13 張。與閘門研究相同，n-of-1 研究採交叉設計。交叉設計可透過聚焦於個別患者的用藥期與停藥期效果來提升顯示治療效果的統計力，並可能降低變異性。本研究數據預期於 2014 年上半年取得。

Our CFT-R corrector, Lumacaftor or VX-809, is in two global Phase 3 studies, traffic and transport, to determine its efficacy and safety in people with two copies of the F508del mutation. Site initiation and recruitment is going well, and we expect to complete enrollment in both studies in the second half of 2013, and we are on track for reporting data and submitting an NDA and MAA in 2014.

我們的 CFTR 校正劑（corrector）Lumacaftor（或 VX-809）正在兩項全球第 3 期研究（traffic 與 transport）中進行，以評估其在帶有兩個 F508del 突變拷貝人群中的療效與安全性。各研究中心啟動與招募進展良好；我們預期於 2013 年下半年完成兩項研究的收案，並按計畫於 2014 年公布數據並提交 NDA 與 MAA。

As part of the Lumacaftor registration program, we are planning to start an 8-week study of Lumacaftor in combination with Ivacaftor in F508del heterozygous patients in the US in the second half of 2013. This placebo-controlled Phase 2 study is part of our registration package agreed with the FDA earlier this year, and is expected to enroll about 80 patients randomized between active and placebo arms. Based on our prior data in this population, we do not anticipate that the Lumacaftor and Ivacaftor combination will have a clinically meaningful benefit for heterozygous patients, but the study has been requested by the FDA for labeling purposes.

作為 Lumacaftor 註冊計畫的一部分，我們規劃於 2013 年下半年在美國啟動一項為期 8 週的研究，評估 Lumacaftor 與 Ivacaftor 併用於 F508del 雜合子（heterozygous）患者。此安慰劑對照第 2 期研究為我們今年稍早與 FDA 達成一致之註冊申請資料套件的一部分，預計收納約 80 名患者，並隨機分派至有效治療組與安慰劑組。根據我們先前在此族群的數據，我們不預期 Lumacaftor 與 Ivacaftor 的併用能為雜合子患者帶來具臨床意義的效益，但 FDA 為標示（labeling）目的要求進行此研究。

Tonight, we are also announcing a new study for VX-661, another corrector we have in clinical development. We plan to evaluate VX-661 plus Ivacaftor in a proof-of-concept clinical study for the mechanism of using a corrector and potentiator in heterozygous patients who have the G551D mutation, a gating mutation on one allele, and F508del on the other allele. The patients who enroll in this study will already be receiving KALYDECO, as labeled in the US and EU. We expect to start this four week Phase 2 study shortly in approximately 20 patients, and report data in late 2013, or early 2014.

今晚，我們也宣布針對 VX-661（我們另一項正在臨床開發中的校正劑）展開一項新研究。我們計畫在一項概念驗證臨床研究中評估 VX-661 加上 Ivacaftor，用以驗證在帶有 G551D 突變的異合子患者中，採用「校正劑 + 增效劑」機制的效果；這些患者在其中一個等位基因上具有 G551D（一種閘門型突變），另一個等位基因上則為 F508del。納入本研究的患者將已依美國與歐盟核准標示接受 KALYDECO 治療。我們預期將於近期在約 20 名患者中啟動這項為期四週的第 2 期研究，並於 2013 年底或 2014 年初公布數據。

In addition, we are planning to start a Phase 2 proof-of-concept study with the corrector VX-983, pending the outcome of ongoing studies and discussions with regulators. The results from these Phase 2 studies with VX-661 and VX-983 will be important factors, as we consider which molecule to prioritize for further development as part of dual or triple combination regimens.

此外，在視目前進行中的研究結果以及與監管機關討論的進展而定的前提下，我們也規劃啟動一項使用校正劑 VX-983 的第 2 期概念驗證研究。這些針對 VX-661 與 VX-983 的第 2 期研究結果，將是我們在考量後續開發（作為雙重或三重聯合療法方案的一部分）時，決定優先推進哪一個分子的關鍵因素。

We are also actively working to advance second-generation correctors that act on a different part of the CFT-R folding process and could be used as part of a dual corrector regimen, along with Ivacaftor to further enhance benefit for patients who are homozygous or heterozygous for F508del. Our goal is to bring a second-generation corrector into clinical development by the end of 2014.

我們也正積極推進第二代校正劑，這些藥物作用於 CFTR 摺疊過程的不同環節，並可與 Ivacaftor 一同作為雙校正劑方案的一部分，以進一步提升對 F508del 同型合子或異型合子患者的治療效益。我們的目標是在 2014 年底前將一項第二代校正劑推進至臨床開發。

At the recent ECSF meeting, Dr. Fred Van Goor of Vertex presented data that showed a combination of two correctors plus Ivacaftor nearly doubled chloride transport in human bronchial epithelial cells with two copies of the F508del mutation, compared to the use of a single-corrector plus Ivacaftor. In summary, we are pleased to have a full pipeline of medicines that may provide life-changing treatment for more people with CF. And now, I will turn it over to Stuart.

在近期的 ECSF 會議上，Vertex 的 Fred Van Goor 醫師發表的數據顯示：在帶有兩個 F508del 突變拷貝的人類支氣管上皮細胞中，「兩種校正劑 + Ivacaftor」的組合，與「單一校正劑 + Ivacaftor」相比，幾乎使氯離子運輸量倍增。總結而言，我們很高興擁有完整的藥物研發管線，這些藥物可能為更多囊性纖維化（CF）患者帶來改變人生的治療。接下來我把時間交給 Stuart。

Thank you, Bob, and good evening. I will provide some background and commentary on our improvements in INCIVEK for genotype 1 chronic hepatitis C infection, and KALYDECO for CF patients who have the G511D mutation. Starting with INCIVEK. Since launching INCIVEK in May 2011, we have treated more than 65,000 patients in the US and Canada, and recorded approximately $2.5 billion in cumulative revenues.

謝謝你，Bob，晚安。我將就我們在 INCIVEK（用於基因型 1 慢性 C 型肝炎感染）以及 KALYDECO（用於帶有 G511D 突變的 CF 患者）方面的改善，提供一些背景與評論。先從 INCIVEK 談起。自 2011 年 5 月推出 INCIVEK 以來，我們已在美國與加拿大治療超過 65,000 名患者，並累計錄得約 25 億美元營收。

While we see ongoing demand for hepatitis C treatment for motivated patients and those who need to be treated now, we are seeing a decline in the number of patients treated in anticipation of the next generation of medicines to treat hepatitis C. We expect this decline to continue for the remainder of the year. However, INCIVEK continues to generate significant revenues, and so is an important component of building the financial strength we need to fund our future opportunities. Our net revenues from INCIVEK in North America were $156 million in the second-quarter, as we maintained our market-leading position even in this declining market.

雖然我們仍看到對 C 肝治療的持續需求，來自於治療意願高的患者以及需要立即治療的患者，但我們也看到，因市場預期下一代 C 肝治療藥物即將到來，接受治療的患者人數正在下降。我們預期這一下降趨勢將在今年剩餘期間持續。然而，INCIVEK 仍持續帶來可觀營收，因此是我們建立所需財務實力、以資助未來機會的重要組成部分。第二季我們在北美的 INCIVEK 淨營收為 1.56 億美元；即使在這個下滑的市場中，我們仍維持市場領先地位。

Outside of the US, telaprevir performed well in the first half of 2013. The availability of INCIVO marketed by Janssen had expanded to additional countries, and based on Janssen's sales in the second-quarter, Vertex earned $44 million in royalties in Q2. This was largely driven by performance in Latin America. However, the outlook for INCIVO for the remainder of 2013 is difficult to forecast, due to seasonal prescribing patterns, and the potential reduction in patients initiating therapy in advance of new regimens entering the market.

在美國以外，telaprevir 在 2013 年上半年表現良好。由 Janssen 行銷的 INCIVO 已擴展至更多國家；根據 Janssen 第二季的銷售情況，Vertex 在第二季取得 4,400 萬美元權利金收入。這主要由拉丁美洲的表現所帶動。然而，由於處方具有季節性模式，以及在新療法方案進入市場前可能出現啟動治療患者數下降，2013 年剩餘期間 INCIVO 的展望難以預測。

Moving to KALYDECO, worldwide revenues were $99 million for the second-quarter of 2013, including US sales of $55 million based on the rapid adoption of KALYDECO in the US, following our launch in early 2012. Over the first half of this year, we have successfully completed reimbursement discussions in most of the major EU markets, including England, Scotland, Ireland, Northern Ireland, and Wales, and made KALYDECO available for the many patients who need it. Since then, we have seen a similar pattern of rapid uptake of KALYDECO, as we saw in the US last year. I am proud of the incredibly effective efforts of our field organization, which together with the dedicated healthcare providers who care for CF patients, have enabled us to begin treating nearly all the eligible G551D patients in the EU.

接著談 KALYDECO：2013 年第二季全球營收為 9,900 萬美元，其中美國銷售額為 5,500 萬美元，反映我們於 2012 年初在美國上市後，KALYDECO 在美國的快速採用。今年上半年，我們已在多數主要歐盟市場成功完成給付（報銷）協商，包括英格蘭、蘇格蘭、愛爾蘭、北愛爾蘭與威爾斯，並讓許多需要的患者得以使用 KALYDECO。此後，我們看到 KALYDECO 的快速採用模式與去年在美國所見相似。我為我們外勤團隊極其有效的努力感到自豪；在照護 CF 患者的醫療人員投入配合下，我們已能在歐盟開始治療幾乎所有符合條件的 G551D 患者。

We achieved approximately $44 million in KALYDECO sales outside of the US in the second-quarter, which represents significant growth over the first quarter. This figure does include approximately $2.5 million of inventory build in Europe.

第二季我們在美國以外的 KALYDECO 銷售額約為 4,400 萬美元，較第一季顯著成長。此數字包含歐洲約 250 萬美元的庫存增加。

We do not see further meaningful growth for KALYDECO in 2013. However, we do see three potential drivers for revenue growth beginning in 2014, subject to the successful completion of reimbursement and regulatory discussions, and likely to occur at different times throughout the year.

我們不預期 KALYDECO 在 2013 年會再出現具實質意義的成長。不過，在成功完成給付與監管協商的前提下，我們確實看到自 2014 年起有三項可能帶動營收成長的驅動因素，且很可能在一年中的不同時間點發生。

First, achieving public reimbursement in Australia and Canada. KALYDECO was approved in Australia earlier this month, and is the third largest potential market for KALYDECO after the US and England, with approximately 200 eligible G551D patients over the age of six. We estimate that there are approximately 100 eligible G551D patients in Canada.

第一，在澳洲與加拿大取得公費給付。KALYDECO 已於本月稍早在澳洲獲准；澳洲是繼美國與英格蘭之後，KALYDECO 的第三大潛在市場，約有 200 名年滿六歲且符合條件的 G551D 患者。我們估計加拿大約有 100 名符合條件的 G551D 患者。

Second, regulatory approvals for patients with non-G551D gating mutations, based on the data that Bob described earlier. This could allow for an expanded label as early as the first half of 2014, when we could begin to add as many as 400 additional cystic fibrosis patients globally, based on a label for all gating mutations.

第二，基於 Bob 先前描述的數據，針對非 G551D 的閘門型突變患者取得監管核准。這可能使適應症標示最早在 2014 年上半年擴大；若標示涵蓋所有閘門型突變，我們即可開始在全球新增多達 400 名囊性纖維化患者。

Third, potential for future growth in non-gating mutations, such as residual function patients, including R117H. This will be based on successful outcomes from the ongoing clinical trials that Bob described earlier. In summary, I am pleased with the progress we have made in the first half of 2013, and would like to thank all of those who have contributed to these results. And now I will turn it over to Ian.

第三，未來在非閘門型突變上的成長潛力，例如殘餘功能患者（包括 R117H）。這將取決於 Bob 先前提到之進行中臨床試驗的成功結果。總結而言，我對我們在 2013 年上半年取得的進展感到滿意，並想感謝所有為這些成果做出貢獻的人。接下來我把時間交給 Ian。

Thank you, Stuart. I will start by reaffirming our business and financial strategy. We are investing and advancing important medicines to drive sustained, long-term revenue and earnings growth. Our goal during this period is to maintain financial strength by prioritizing our spend towards R&D, and balancing our expenses with revenues while protecting our balance sheet. I am happy to report that we remain nicely on track.

謝謝你，Stuart。我將先重申我們的業務與財務策略。我們正投資並推進重要藥物，以帶動可持續的長期營收與獲利成長。我們在此期間的目標，是透過優先將支出投入研發（R&D），並在維持資產負債表穩健的同時，使費用與營收取得平衡，以維持財務實力。我很高興報告，我們仍然進展順利、符合規劃。

Now to the second-quarter of 2013 results. Total revenues were $311 million. Our GAAP -- total non-GAAP operating expenses, excluding cost of revenues and other charges, were $281 million for a non-GAAP loss of $6.2 million or $0.03 per share.

接著是 2013 年第二季的業績。總營收為 3.11 億美元。依 GAAP -- 非 GAAP 口徑之總營運費用（不含營收成本與其他費用）為 2.81 億美元，對應非 GAAP 淨損 620 萬美元，或每股虧損 0.03 美元。

From a balance sheet perspective, we completed the quarter with over $1.4 billion of cash, cash equivalents and marketable securities, and no convertible debt. This was the result of the June debt to equity conversion. These results, and specifically our balance sheet strength, will enable us to continue to maintain our investment in our priority medicines.

從資產負債表角度來看，本季結束時我們持有超過 14 億美元的現金、約當現金與有價證券，且沒有可轉換債務。這是 6 月債轉股（債務轉換為股權）的結果。這些成果，特別是我們資產負債表的強勁實力，將使我們能夠持續維持對優先藥物的投資。

Now for the more detailed results. In the second-quarter, total KALYDECO revenues were approximately $99 million. EU uptake in the second-quarter exceeded our expectations, and KALYDECO is now treating nearly all of the eligible G551D patients in the US and EU. As such, we are raising our guidance for 2013 KALYDECO revenues to $345 million to $360 million.

現在來看更詳細的結果。第二季 KALYDECO 總營收約為 9,900 萬美元。第二季歐盟的採用情況超出我們的預期，而 KALYDECO 目前在美國與歐盟已幾乎治療所有符合資格的 G551D 病患。因此，我們將 2013 年 KALYDECO 營收指引上調至 3.45 億至 3.60 億美元。

INCIVEK revenues in the second-quarter were $156 million, reflecting ongoing demand for hepatitis C treatment even as the market anticipates the arrival of other regimens in 2014. INCIVO royalties were $44 million, and our combined hepatitis C revenues contributed approximately $200 million to our top line in the second-quarter. Finally, collaborative and other revenues in the second-quarter were $12 million.

第二季 INCIVEK 營收為 1.56 億美元，反映出即使市場預期 2014 年將有其他療法方案上市，丙型肝炎治療仍持續有需求。INCIVO 權利金為 4,400 萬美元，我們第二季合計的丙型肝炎營收約為 2.00 億美元，貢獻於我們的營收（top line）。最後，第二季合作及其他營收為 1,200 萬美元。

Because of the increased visibility into revenues for 2013, we are tightening our 2013 total revenue guidance range to $1.1 billion to $1.2 billion, which includes the increased KALYDECO guidance of $345 million to $360 million.

由於 2013 年營收的能見度提高，我們將 2013 年總營收指引區間收斂至 11 億至 12 億美元，其中包含上調後的 KALYDECO 指引 3.45 億至 3.60 億美元。

Now to our non-GAAP operating expense of $281 million, which includes cost of revenues and other charges. This is similar to the first quarter, made up of $191 million in R&D investments, and $90 million in SG&A expenses. Consistent with our financial strategy, we are prioritizing investment in R&D, and being disciplined with our SG&A spending. We are reiterating our non-GAAP operating expense of $1.09 billion to $1.15 billion for 2013.

接著談我們的非 GAAP 營業費用為 2.81 億美元，其中包含營收成本及其他費用。這與第一季相近，由 1.91 億美元的研發（R&D）投資，以及 9,000 萬美元的銷售、一般及行政（SG&A）費用所構成。依循我們的財務策略，我們優先投入研發，並對 SG&A 支出保持紀律。我們重申 2013 年非 GAAP 營業費用為 10.9 億至 11.5 億美元。

In summary, financially we are executing on our strategy, and prioritizing investment within our business to drive long-term growth. Our cash position and our financial strength will enable us to continue to maintain our investment to progress our medicines in development. I would now like to open the line to questions.

總結而言，在財務面我們正落實既定策略，並在業務內優先配置投資以推動長期成長。我們的現金部位與財務實力，將使我們能持續維持投資，以推進研發中的藥物。我現在想開放提問。

(Operator Instructions)

(接線員指示)

The first question comes from Geoff Meacham from JPMorgan.

第一個問題來自摩根大通（JPMorgan）的 Geoff Meacham。

Hi. Thanks for the question, and congrats on the CF data. One on CF and one on hep C. So for the 809 KALYDECO trial on heterozygous, are there any limitations on enrollment for genotype beyond G551D, that is on a non delta F allele? I just want to make sure there are maybe -- you are excluding patients that may have some residual KALYDECO function. And I guess the question there is, if there is a negative control for labeling, but you see a signal, then what is the path beyond that?

嗨。謝謝提問，也恭喜你們的囊性纖維化（CF）數據。我有一個關於 CF、另一個關於丙肝（hep C） 的問題。關於 809 的 KALYDECO 異型合子試驗，在基因型的收案上，除了 G551D 之外，對於另一個等位基因（也就是非 delta F 等位基因）是否有任何限制？我只是想確認，你們是否可能排除了一些仍可能保有部分 KALYDECO 功能的病患。我想問題是：如果作為標示（labeling）的陰性對照，但你們看到訊號，那接下來的路徑會是什麼？

This is Bob. It is hard to speculate on the path, until we actually see what the data show. But we choose the patients for this study who have mutations on the other allele, that would not, not respond to KALYDECO. So we obviously, try to keep our baseline at an absolute minimum. And that is what we have done throughout the heterozygous studies and we will do the same in this one.

我是 Bob。在我們實際看到數據顯示什麼之前，很難推測後續路徑。但我們在這項研究中選擇的病患，其另一個等位基因上的突變是那種不會、也不應該對 KALYDECO 有反應的突變。因此我們顯然會盡量把基線降到絕對最低。這也是我們在所有異型合子研究中一直採取的做法，這次也會同樣如此。

Got you. And just a real quick one on VX-135. I know you have been asked a lot about spend in Hep B. Is there a time to get off the partial hold from the FDA, or some data set that you view as a trigger for making future investments in 135? Thanks.

了解。再快速問一個關於 VX-135 的問題。我知道你們被問到很多關於在 B 肝（Hep B）上的支出。針對 FDA 的部分臨床暫停（partial hold），是否有一個解除的時間點，或是你們認為可作為觸發點、用來決定未來是否繼續投資 135 的某個數據集？謝謝。

This is Bob. I will answer sort of the first part of that. And that is, based on the particulars that the FDA has asked us for, we expect to be able to have a complete data set in the early part of the fourth quarter. And we then expect the FDA to review those data and then respond back to us. As to the other part, I will pass it on to Ian.

我是 Bob。我先回答其中第一部分。根據 FDA 要求我們提供的具體項目，我們預期在第四季初就能取得完整的數據集。接著我們預期 FDA 會審查這些數據，然後回覆我們。至於另一部分，我把問題交給 Ian。

Yes, hi, Geoff. Thanks for the question. The question has been asked a few times since Thursday night actually. And the way we -- we are very aware of the competitive nature of this market, this disease area. And we are always looking and making a decision to see whether we can compete in what is a significant market, and a global market.

是的，嗨 Geoff。謝謝你的問題。其實自週四晚上以來，這個問題已被問過好幾次。我們的看法是——我們非常清楚這個市場、這個疾病領域的競爭性。我們也一直在觀察並做出決策，評估我們是否能在一個重要且全球性的市場中競爭。

At this point in time, we have the assets, and we have the internal capability that we want to progress that opportunity. As we go through, there will be a very important Phase 2 period of establishing a potential regimen to compete in this market. We will be making those kind of decisions. But at this point in time, we plan to keep committed to HCV and drive forward for an all-oral regimen.

就目前而言，我們擁有相關資產，也具備內部能力，足以推進這個機會。在推進過程中，將有一段非常重要的第二期（Phase 2）期間，用來建立一個可能在此市場具競爭力的治療方案（regimen）。我們會在那時做出這類決策。但就目前而言，我們計畫持續投入丙型肝炎（HCV），並推進全口服療法方案。

Okay, thanks.

好的，謝謝。

The next question comes from Geoffrey Porges from Sanford Bernstein.

下一個問題來自 Sanford Bernstein 的 Geoffrey Porges。

Thanks very much for taking the question, and also, congrats on the additional CF Phase 3 data. Perhaps just to drill in a little bit more on 135, Bob, could you let us know, first, what the primary metabolic pathway if for VX-135? Secondly, the thinking behind taking it up to the 400-milligram dose? And then what the outcome was for those patients with the elevated liver functions? And lastly, can you just tell us whether you have seen any transaminase elevation, not enough to get to a [SAU] or discontinuation? But any at all at the 200-milligram dose?

非常感謝讓我提問，也恭喜你們新增的 CF 第三期數據。也許針對 135 再深入一點，Bob，你能否先告訴我們：第一，VX-135 的主要代謝途徑是什麼？第二，把劑量提高到 400 毫克背後的考量是什麼？第三，那些肝功能指數升高的病患最後的結果如何？最後，你能否說明在 200 毫克劑量下，你們是否看到任何轉胺酶（transaminase）升高——雖然不足以達到 [SAU] 或需要停藥——但是否有任何升高？

So I'll take -- if I can remember all four of those questions, I will take them in order. The pathway of metabolism is just primarily renal excreted as most [nucs] are.

我來回答——如果我能記得這四個問題的話——我會依序回答。代謝途徑主要是經腎臟排泄，和大多數 [nucs] 一樣。

Okay.

好的。

In terms of why we went to the 400-milligram dose, I would say that part of the Phase 2 evaluation of any compound really is to explore the dose range. When we had completed the 100- and 200-milligram doses in the European study we have very good tolerability, and therefore we decided to dose escalate. And we wanted to sort of maximize the viral kinetics in order to get the best response possible.

至於為什麼提高到 400 毫克劑量，我會說任何化合物的第二期評估，其中一部分就是探索劑量範圍。當我們在歐洲研究中完成 100 與 200 毫克劑量後，耐受性非常好，因此我們決定進行劑量遞增。我們希望在病毒動力學上達到最大化，以取得盡可能最佳的反應。

The outcome of the elevated transaminase patients, and then any at 200?

那肝轉胺酶升高的病患結果呢？以及 200 毫克是否有？

Yes. There were none in 200. More at 100. And they all resolved really quickly, within a week or so.

是的。200 毫克組沒有。100 毫克組反而更多。而且它們都很快恢復，大約一週左右就解決了。

Okay. Thank you.

好的。謝謝。

And in terms of the other transaminase elevations, I guess I just answered that by saying, we really haven't seen anything in the 100- and 200-milligram groups.

至於其他轉胺酶升高的情況，我想我剛剛已經回答了：在 100 與 200 毫克組，我們其實沒有看到任何明顯的情況。

Right. That's very helpful. Appreciate it.

了解。這非常有幫助。感謝。

The next question comes from Michael Yee from RBC Capital Markets.

下一個問題來自 RBC Capital Markets 的 Michael Yee。

Yes, hi, thanks. Question on Hep C and then on CF. On the 135, can you walk through what type of PK exposure you are seeing at 100, 200 and 400? And maybe whether there is any sort of overlap there? Just trying to think about exposure, 400 is only twice 200, so think about that.

是的，您好，謝謝。先問丙肝，然後問 CF。關於 135，您能否說明在 100、200 與 400 的 PK 暴露量大概是什麼樣的情況？以及那之間是否有任何程度的重疊？我只是想從暴露量的角度思考一下，400 只是 200 的兩倍，所以想了解這點。

And then on CF, can you explain the confidence in the other non-gating mutations. Excuse me, the, the residual function studies, where the confidence comes from then? And what I would say is obviously, that is a huge population. So just trying to understand whether there's any read-through in today's data into that study? Thanks.

另外關於 CF，您能否解釋對其他非 gating 突變的信心來源。不好意思，我是指殘餘功能研究（residual function studies），那麼信心是從哪裡來的？而且我想說的是，顯然那是一個非常龐大的人群。所以只是想了解，今天的數據是否能對那項研究提供任何延伸解讀？謝謝。

Okay. So in terms of 135, I will say the following. Firstly, in the three subjects who had LFT abnormalities in the 400-milligram group, the exposures in those three patients were essentially the highest of any of the 10 subjects that were enrolled in that dose group. And in addition, the exposures in the 200-milligram group differed on average by about twofold, with those in the 400-milligram group.

好的。就 135 而言，我會這麼說。首先，在 400 毫克組出現 LFT 異常的 3 位受試者中，這 3 位病人的暴露量基本上是該劑量組納入的 10 位受試者中最高的。此外，200 毫克組的暴露量與 400 毫克組相比，平均大約相差兩倍。

So there really is a fair spread between those subjects who had the LFT abnormalities in the 400-milligram group and the 200-milligram group. On the other hand, I will just say that this is a very small data set. And clearly, we have to establish this in larger numbers of patients to really understand this. But that is really where we are headed in the next set of evaluations.

因此，在 400 毫克組出現 LFT 異常的那些受試者與 200 毫克組之間，確實存在相當程度的差異分布。另一方面，我也要說，這是一個非常小的資料集。而且很明顯，我們必須在更多病人數中加以確認，才能真正理解這件事。但這正是我們下一階段評估要前進的方向。

Okay. And then on CF?

好的。那關於 CF 呢？

Yes. So you asked about our confidence in the patients with residual function. And I think that has largely to do with, first of all, both in vitro data that show that we can enhance the chloride transport in patients, in cells who carry the R117H mutation, and other mutations that result in residual function. And we have had a very good in vitro/in vivo correlation, correlating chloride transport in vitro and clinical results so far in the program, and we would expect that to continue in this group as well.

是的。您問到我們對殘餘功能病人的信心。我認為這主要來自於：首先，體外數據顯示，我們可以在攜帶 R117H 突變、以及其他會造成殘餘功能的突變之病人細胞中，提升氯離子運輸。而且到目前為止，在本計畫中，我們已經看到非常良好的體外/體內相關性，也就是體外的氯離子運輸與臨床結果之間的對應；我們預期在這一族群中也會延續。

Next question, please?

下一個問題，請？

The next question comes from Mark Schoenebaum from ISI Group.

下一個問題來自 ISI Group 的 Mark Schoenebaum。

Hi. Thanks for taking the question. Maybe the first one for Bob. Bob, I think the concern, I guess, for 135 is the potential for mitochondrial toxicity. Can you walk us through evidence we have thus far that this drug is not -- does not have mitochondrial toxicity? Maybe make an argument to try to convince us all?

您好。謝謝讓我提問。第一個問題可能給 Bob。Bob，我想大家對 135 的疑慮，應該是潛在的粒線體毒性。您能否帶我們回顧一下，到目前為止有哪些證據顯示這個藥物不是——不具有粒線體毒性？也許提出一個論點，試著說服我們大家？

And then number two is, the second question is an expense question. Maybe the first part for Jeff. And that is $1.4 billion of cash on the balance sheet is quite a bit, very formidable. Be curious to get your updated thoughts on what you are going to do with that cash? What kind of stuff conceptually is on the table versus off the table? And maybe I will just stop there. Thank you very much.

第二個問題是費用相關的問題。第一部分可能給 Jeff。資產負債表上有 14 億美元現金相當多，非常可觀。想請教您更新一下，您打算如何運用這筆現金？概念上有哪些事情在考慮範圍內、哪些不在？我先問到這裡。非常感謝。

So this is Bob. I will answer the first part. We have done an extensive evaluation of VX-135 for mitochondrial toxicity, using all state-of-the-art techniques. And in fact, we have seen no evidence for mitochondrial toxicity for this compound. And that is really about all I can say.

我是 Bob。我先回答第一部分。我們已使用所有最先進的技術，對 VX-135 的粒線體毒性做了廣泛評估。事實上，我們沒有看到任何證據顯示這個化合物具有粒線體毒性。我大概也只能說到這裡。

And Mark, as to your second question, I will just comment on the cash, and turn it over to Jeff about more strategically where we may go. But from a cash position, as you can see, we are in this position where we are accumulating. We want to maintain our strength from the balance sheet. That includes managing the liabilities on the balance sheet. So we are happy we have got over $1.4 billion at June 30, and we've been able to convert our debt into equity, so we don't have any significant liability or debt on the balance sheet.

Mark，至於您的第二個問題，我先就現金狀況簡單評論，然後把更策略性的方向交給 Jeff。但就現金部位而言，如您所見，我們目前處於持續累積的狀態。我們希望維持資產負債表的強健。這也包括管理資產負債表上的負債。因此，我們很高興截至 6 月 30 日現金超過 14 億美元，而且我們已將債務轉換為股權，所以資產負債表上沒有任何重大負債或債務。

So at this point, we are still in the phase of building. I think you will see that continuing for at least a short period of time. We are very aware as we go into 2014 that as -- sorry -- INCIVEK revenues decline, that we may need to apply some of the cash from the balance sheet to continue to invest in our medicines. As we come through that period, I think that is when your question becomes most pertinent, in terms of how do we put the capital to use? And we are starting to think about that in our business at this point.

所以在這個時間點，我們仍處於建置的階段。我想您會看到這種情況至少在短期內持續。我們非常清楚，進入 2014 年時，隨著——抱歉——INCIVEK 營收下滑，我們可能需要動用部分資產負債表上的現金，來持續投資我們的藥物。當我們度過那段期間後，我認為您的問題就會變得最切題：也就是我們要如何運用資本？我們目前也開始在業務上思考這件事。

Yes, Mike, this is Jeff. A quick comment to add to what Bob said on the mitochondrial toxicity. Yes, one of the other things that we learned from the 100- and 200-milligram trial that was done in Europe, was that we were monitoring those patients by both echo and EKG. And I think one of the important findings is, now that those patients have all concluded 12 weeks of therapy, we really didn't see any echo or EKG signs of cardiac pathology, which obviously, is the mitochondrial toxicity of the most interest, and frankly, the most worrying (inaudible).

是的，Mike，我是 Jeff。我補充 Bob 關於粒線體毒性的說法。是的，我們從在歐洲進行的 100 與 200 毫克試驗中學到的另一件事是，我們用心臟超音波（echo）與心電圖（EKG）同時監測那些病人。而我認為一個重要發現是，現在那些病人都已完成 12 週治療，我們確實沒有看到任何 echo 或 EKG 顯示心臟病理的跡象；而這顯然是粒線體毒性中最受關注、坦白說也最令人擔憂的部分（聽不清）。

Thanks a lot.

非常感謝。

With respect to the $1.4 billion, only thing I would add is what I have always said before. We are very pleased with our own pipeline, and we think that we have a number of interesting assets coming forward. But we are also always looking strategically for things that can complement what we have done, certainly in CF and HCV, but also in other areas that fit our specialty and transformative medicine strategy.

至於 14 億美元，我唯一要補充的是我以前一直說的。我們對自家的研發管線非常滿意，也認為有多個有趣的資產正在推進。但我們也一直在策略性地尋找能夠補強我們既有成果的機會，當然包括 CF 與 HCV，也包括其他符合我們專業領域與變革性醫療策略的領域。

The next question comes from Rachel McMinn from Bank of America Merrill Lynch.

下一個問題來自美國銀行美林（Bank of America Merrill Lynch）的 Rachel McMinn。

Thanks. I appreciate the question. So I guess, I wanted to ask Geoff's question a little bit differently. I mean, given the news on the VX-135 from last week, how should we think about your SG&A infrastructure going forward? I recognize that you are not ready to terminate the program. You are not saying anything of the sort. But I think you had previously alluded to keeping your HCV sales force through VX-135 development. How should we think about potential cost savings following the Gilead launch?

謝謝。我很感謝能提問。所以我想，我想用稍微不同的方式來問 Geoff 的問題。我是說，鑑於上週 VX-135 的消息，我們應該如何看待你們未來的 SG&A 基礎架構？我知道你們還沒準備要終止這個計畫。你們也沒有這樣說。但我記得你們之前曾提到，會在 VX-135 開發期間維持你們的 HCV 銷售團隊。在 Gilead 上市之後，我們應該如何看待可能的成本節省？

And then separately, I wanted to better understand the rationale for the study design for 661 in 551D patients. There is already a very strong benefit with KALYDECO alone. So I am just wondering if you think you will be hitting up against the ceiling, and why you wouldn't be looking at 809 in that setting. Thanks.

另外，我也想更了解在 551D 病人中 661 試驗設計的理由。單用 KALYDECO 就已經有非常強的效益。所以我只是想知道，你們是否認為會碰到天花板效應，以及為什麼不在那個情境下研究 809。謝謝。

So Rachel, it is Stuart here. I will take the first question on HCV SG&A, and then hand it over to Bob. So on our HCV investment, I mean we have an absolutely world-class HCV sales force. And although it is relatively small, one of the beauties of the specialty business model, is it's a small sales force. We know it has been instrumental in our success to date. However, as with all aspects of our business, we are constantly evaluating the return on investment we get for that sales force.

Rachel，所以我是Stuart。我先回答關於HCV SG&A的第一個問題，然後交給Bob。就我們在HCV上的投資而言，我們擁有絕對世界級的HCV銷售團隊。雖然規模相對不大，但專科業務模式的一大優點就是銷售團隊可以很精簡。我們知道，迄今為止它一直是我們成功的關鍵因素。不過，如同我們業務的所有面向一樣，我們也在持續評估這支銷售團隊所帶來的投資報酬。

And in our judgment, the sales force continues to be a really good investment, based on the revenues that they are generating today. What I would say though, is we are, as we say, looking at spend across all of our areas, and we have substantially reduced in the HCV area, our marketing expenses from 2012 into 2013. And that continues to be the case going into the second half of 2013, where we are looking very much at managing those expenses, in line with the trajectory of our revenues. And on the CF question, I will hand it over to Bob.

以我們的判斷，基於他們目前所帶來的營收，這支銷售團隊仍然是一項非常好的投資。不過我想說的是，我們如同所提到的，正在檢視各個領域的支出；而在HCV領域，我們已將2012到2013年的行銷費用大幅降低。而這種情況在2013年下半年仍會持續，我們會非常著重於依照營收走勢來管理這些費用。至於CF的問題，我交給Bob。

Right. So your question relates to the combination of 661 plus Ivacaftor. And the rationale for this is based on in vitro data, again which is generated Vertex to show that you can actually get a substantially greater effect on chloride transport in vitro in G551D F508del heterozygous cells in culture. And the rationale is whether in fact, in vivo, in humans, whether a greater clinical benefit could be obtained by this combination, again, going back to the correlation that we have seen between in vitro and in vivo.

好的。你的問題是關於661加上Ivacaftor的合併使用。其依據是體外數據，同樣是Vertex產生的數據，顯示在培養的G551D F508del雜合細胞中，體外的氯離子運輸確實可以得到顯著更大的改善效果。其背後的理由是：在體內、在人類身上，這種組合是否能帶來更大的臨床效益；這也回到我們所觀察到的體外與體內之間的相關性。

As to the choice of 661, I would just say that VX-809 is in an extensive program, a Phase 3 program with many, many studies. This is another opportunity for us to learn more about 661, and that is why we chose it for the combination.

至於為何選擇661，我只想說VX-809正處於一個非常龐大的計畫中，也就是包含許多、許多研究的第3期計畫。這是我們進一步了解661的另一個機會，因此我們選擇它來做組合。

Okay, thanks.

好的，謝謝。

The next question comes from Brian Abrahams from Wells Fargo.

下一個問題來自Wells Fargo的Brian Abrahams。

Thanks very much for taking my question, and congrats on all the progress in CF. Question on 135. I think what a lot of us are trying to figure out is whether the 100 or 200 mg dose is could potentially be sufficient. I know rapidity of [RNA] reductions are often seen as a surrogate for potency. You reported 70% and 80% RVRs. Obviously, comparing across small studies has limitations.

非常感謝讓我提問，也恭喜你們在CF方面的所有進展。我想問135的問題。我想我們很多人都在試著釐清，100或200毫克的劑量是否可能就已足夠。我知道RNA下降的速度常被視為效力的替代指標。你們報告了70%與80%的RVR。當然，跨小型研究做比較有其限制。

But I was wondering if you could help us understand how the population in this European study may have compared to that of the analogous study conducted for sofosbuvir plus ribavirin, and whether you had any details of characteristics of patients who were maybe a bit slower to respond in the study. And maybe could you possibly give us RVR results for those US patients on the 100 mg? That would help as well. Thank you.

但我想請你們協助我們理解，這項歐洲研究的人群與sofosbuvir加ribavirin所做的類似研究相比，可能有哪些差異；以及你們是否有關於研究中反應可能較慢的病患特徵的任何細節。另外，你們是否可以提供那些使用100毫克的美國病患的RVR結果？那也會很有幫助。謝謝。

Brian, I will just jump in front of Bob. We are not going to compare studies, cost studies actually. We are not going to compare patient demographics between a study that was run by another company and ourselves. We are waiting for the full data to be read out, and then you can do the analysis at that point in time. But maybe Bob would like to comment on how we think about 100 and 200, and (inaudible) as you said Brian. But maybe that is where it is coming from.

Brian，我先在Bob之前插一句。我們不會做研究之間的比較，跨研究的比較其實是有成本的。我們也不會把另一家公司執行的研究與我們自己的研究做病患人口學特徵的比較。我們會等完整數據讀出後，你就可以在那個時間點進行分析。不過也許Bob可以談談我們如何看待100與200（聽不清），如你所說Brian。也許問題就是從這裡來的。

Yes, so it is really impossible to ever match across studies when you don't have all the data. So I just -- we just can't really do that.

是的，所以在沒有所有數據的情況下，跨研究做匹配真的不可能。所以我只是——我們確實無法那樣做。

I would say that obviously in our, in our VK studies, we have seen very good antiviral activity, both 100 and 200. The results in our 200-milligram group compare favorably with the results that have been seen for sofosbuvir at 400 milligrams, and we consider both of those doses to be really, have very good activity.

我會說，很明顯在我們的VK研究中，我們在100與200兩個劑量都看到了非常好的抗病毒活性。我們200毫克組的結果，與400毫克sofosbuvir所見到的結果相比相當有利；我們認為這兩個劑量都確實具有非常好的活性。

As to the RVR rates that we saw in this trial, I would just remind you that our real primary development path for VX-135 is in combination with the other antiviral agents, not with ribavirin. And I think we should wait to see how our daclatasvir plus 135 study comes out, to really make judgments on 100- versus 200-milligrams and the efficacy we might see. I think it would be best to wait to see where there is more, in terms of more realistic studies in terms of ultimate development path, how they come out.

至於我們在這項試驗中看到的RVR比率，我只想提醒你，我們對VX-135真正的主要開發路徑是與其他抗病毒藥物合併使用，而不是與ribavirin合併。我認為我們應該等daclatasvir加135的研究結果出來後，再來對100毫克與200毫克以及我們可能看到的療效做出判斷。我認為最好等到有更多、更貼近最終開發路徑的、較為現實的研究結果出來，再看它們的表現。

Got you. No I understand. It might be a moot point when you end an NS5A anyway. Thanks very much.

了解。不，我明白。反正當你加入NS5A時，這可能就不是重點了。非常感謝。

Yes.

是的。

The next question comes from Liisa Bayko from JMP Securities.

下一個問題來自JMP Securities的Liisa Bayko。

Hi, thanks for taking my questions. I just wanted to know if you could comment at all on some of the other observations in terms of exacerbations of sweat chloride that you saw with the current study results in the non-G511D gating.

嗨，謝謝讓我提問。我想知道你們是否能對一些其他觀察結果做任何評論，例如在目前這項研究結果中，你們在非G511D gating族群看到的汗氯（sweat chloride）惡化情況。

So this is Bob. We have just really announced our top line results. We are obviously combing through the data of that study much more extensively now. And I think I would probably prefer to wait until those results are presented at a medical meeting to discuss any further details.

我是Bob。我們目前只公布了最上層（top line）的結果。我們顯然正在更深入地梳理那項研究的數據。我想我可能更傾向等到這些結果在醫學會議上發表後，再討論任何進一步的細節。

Okay. Fair enough. And then in the new study that you have initiated, the heterozygous study, G551D plus a background of delta 508. I am just curious of the G551D population, what percentage of them have F508 on the other allele?

好的。可以理解。另外，在你們已啟動的新研究中，也就是雜合子研究：G551D加上另一等位基因為delta 508的背景。我只是好奇，在G551D族群中，有多少比例的人在另一個等位基因上是F508？

About half of them do.

大約一半。

Okay. That's helpful. And then for the 400 patients, that R117H, can you maybe talk about the geographic distribution? I know you spoke about 400 patients.

好的。這很有幫助。另外，關於那400位病患、R117H，你能否談談地理分布？我知道你提到大約400位病患。

It's roughly evenly split between the US and EU. And it is actually probably slightly more in the European Union, but it's roughly evenly split.

美國與歐盟大致各半。實際上歐盟可能稍微多一些，但大致上是各半。

Okay.

好的。

Maybe we could -- I just want to clarify. I actually misspoke when I answered your question. In terms of G551D F508del -- probably close to 80% of those patients actually have F508del on the other allele. Sorry. Not 50%.

也許我們可以——我想澄清一下。我在回答你的問題時其實說錯了。就G551D F508del而言——這些病患中可能接近80%在另一個等位基因上其實是F508del。抱歉。不是50%。

That's what I thought. Okay.

我也是這麼想的。好的。

Yes. It's higher.

是的。比例更高。

Okay. And then just final question, again, on cystic fibrosis, for G551D, I know you said you have treated now the majority of patients in the US and Europe. Can you maybe talk about how many other patients might be in other world areas? Just trying to understand how much more upside there is in KALYDECO for the G551D population. Thanks.

好的。然後最後一個問題，同樣是關於囊性纖維化（CF），針對 G551D，我知道你說你們現在已經治療了美國和歐洲的大多數患者。你能否談談在世界其他地區可能還有多少患者？只是想了解 KALYDECO 在 G551D 族群上還有多少上行空間。謝謝。

Yes, the most significant other markets where we are yet to get full reimbursement are Canada, where we think there is about 100 eligible patients. And then Australia, where there is about 200 eligible patients.

是的，其他我們尚未取得全面給付（reimbursement）的最重要市場是加拿大，我們認為大約有 100 名符合資格的患者。然後是澳洲，大約有 200 名符合資格的患者。

And clearly, that has all to do with the G551D mutation being called kind of the Celtic mutation. Those are areas where there was obviously a lot of immigration. So those are really the remaining areas of growth for us for the G551D population, and really their reimbursement is going to be the key that will unlock the drug to be made available for those patients.

而且很明顯，這與 G551D 突變被稱為某種「凱爾特突變」有關。那些地區顯然有大量移民。因此，對我們而言，這些確實是 G551D 族群剩餘的成長區域，而他們的給付將是關鍵，能夠解鎖讓藥物可供那些患者使用。

Thanks a lot. Can I just sneak in one more question? Can you maybe talk about compliance so far on KALYDECO, kind of what -- now that it has been on the market for sometime at least in the US and some of the bigger European countries, what sort of normalized compliance rates are we observing? And that is my final question. Thank you.

非常感謝。我可以再偷偷問一個問題嗎？你能否談談目前 KALYDECO 的用藥依從性（compliance）？也就是說——現在它至少在美國以及一些較大的歐洲國家上市一段時間了，我們觀察到的常態化依從率大概是多少？這是我最後一個問題。謝謝。

Sure. So what I would say is that we are seeing rates of compliance which are as high as certainly I have ever seen in any therapy area. And I would say they are above 80% which is really pretty substantial.

當然。我會說，我們看到的依從率之高，至少是我在任何治療領域所見過的最高水準之一。我會說高於 80%，這確實相當可觀。

Thank you very much.

非常感謝。

The next question comes from Terence Flynn from Goldman Sachs.

下一個問題來自高盛（Goldman Sachs）的 Terence Flynn。

Hi. Thanks for taking the question. Just two for me. So in terms of the other gating trial that you reported today, are you -- can you give us any sense of if you collected data on pancreatic enzyme usage? And then with respect to the new trial of 661 KALYDECO, was wondering if that is going to include a KALYDECO control arm? Or I guess, how should we think about benchmarking the combo data when we see those results? Thanks.

你好。謝謝讓我提問。我有兩個問題。就你們今天公布的另一項 gating 試驗而言，你們——能否讓我們了解一下是否有收集胰臟酵素使用（pancreatic enzyme usage）的資料？另外，關於新的 661 KALYDECO 試驗，我想知道是否會包含一個 KALYDECO 的對照組？或者說，我們應該如何在看到結果時，去對這個聯合用藥（combo）的數據做基準比較（benchmarking）？謝謝。

This is Bob. In terms of the other gating mutations, obviously we collect data on concomitant medications, but we are not conducting sort of what I would consider a really rigorous assessment of the use of pancreatic enzymes. We would be able to get some sense of it from the data we have, but it is really not designed as a key end point of the study.

我是 Bob。就其他 gating 突變而言，我們當然會收集合併用藥（concomitant medications）的資料，但我們並沒有進行我所認為的那種對胰臟酵素使用的非常嚴謹評估。我們可以從現有資料中得到一些概念，但研究設計並不是把它作為主要終點（key end point）。

And in terms of 661 with KALYDECO, remember that we will have historical data on those patients because they are on KALYDECO already. So when you add 661 on top, we would be able to compare their change from their prior baseline, which we will have measured, rather than having a concurrent control.

至於 661 與 KALYDECO 的部分，請記得這些患者因為已經在使用 KALYDECO，所以我們會有他們的歷史資料。因此當你在其基礎上加上 661 時，我們可以比較他們相對於先前基線（prior baseline）的變化——那個基線我們會有量測——而不是設置一個同期對照（concurrent control）。

Thanks a lot.

非常感謝。

These are all people eligible that are for KALYDECO and are taking it commercially, so you can't take them off the treatment.

這些人都是符合 KALYDECO 資格且正在以商業用藥方式使用它的患者，所以你不可能讓他們停用治療。

The next question comes from Matthew Roden from UBS Securities.

下一個問題來自瑞銀證券（UBS Securities）的 Matthew Roden。

Great. Thanks for taking the question. Bob, if I understood your comments on the VX-135 study with daclatasvir, it sounds like you are looking to expand the -- beyond the 20 patients that you're initially going to be expecting once you have those data.

很好。謝謝讓我提問。Bob，如果我理解你對 VX-135 與 daclatasvir 研究的評論，聽起來你們打算在取得初步資料後，把研究擴大——超過最初預期的 20 名患者。

The question I am trying to get to is, what you need to see in order to advance the molecule into registrational studies in terms of either SVRs or duration of therapy? And also related to that, when would that decision be taken? Sounds to me like regardless of what you see in the first 20 patients, that given the small sample size, you would be -- it would be warranted to take that into larger studies.

我想問的是，你們需要看到什麼，才會把這個分子推進到註冊性研究（registrational studies）？例如在 SVR 或治療療程長度方面需要達到什麼？另外，相關決策會在何時做出？在我看來，不論前 20 名患者看到什麼結果，考量樣本數很小，你們——似乎都有理由把它帶入更大型的研究。

So yes, this is Bob. Yes, I agree. We would likely expand that study just to get a better sense of the treatment effect before launching into a pivotal program. The initial 20 patients are really primarily a safety PK and preliminary efficacy read assessment. We know the bar is very high in this therapeutic area. So obviously we would like to see very good efficacy, as well as good tolerability, but it may be that we will have to see some more patients before we really get a complete handle on that.

是的，我是 Bob。是的，我同意。在啟動關鍵性（pivotal）計畫之前，我們很可能會擴大該研究，以便更好地掌握治療效果。最初的 20 名患者主要是用來評估安全性、藥物動力學（PK）以及初步療效讀出。我們知道在這個治療領域門檻非常高。因此我們當然希望看到非常好的療效以及良好的耐受性，但也可能需要再看更多患者，才能真正完整掌握情況。

Okay. That's very helpful. Just real quick on CF--

好的。這很有幫助。再很快問一下 CF——

This is Peter speaking. On top of that, I think it's really important for all of those studies we need in our safety database to move forward to longer-term pivotal type of studies. And I think that is another reason why we have to basically enhance the population in the regimen that you are going to consider later. And so this is outside of efficacy, an equally important component that you have the right safety description.

我是 Peter。此外，我認為對於所有這些研究而言，我們需要在安全性資料庫中累積足夠資料，才能推進到更長期、偏關鍵性類型的研究。我想這也是為什麼我們基本上必須擴大你之後要考慮的治療方案中的受試人群。因此，除了療效之外，同樣重要的一點是，你必須有正確的安全性描述。

Yes. Thank you, Peter. And then a quick one for Ian or Stuart on CF. I just want to make sure that I understand the KALYDECO guidance. It looks like you have already done about $160 million, $161 million year-to-date. And if you just had sequentially flat sales in the second half, from 2Q run rate, you would already hit the top end of guidance. I heard what you said, in terms of inventory in Europe. Just trying to understand, under what scenarios you could possibly -- the bottom of the guidance could possibly be in play? Thanks.

是的。謝謝你，Peter。然後我想就 CF 問 Ian 或 Stuart 一個快問。我只是想確認我對 KALYDECO 財測（guidance）的理解。看起來你們年初至今已經做到大約 1.60 億美元、1.61 億美元。如果下半年銷售只是相對第二季的 run rate 持平，你們就已經會達到財測上緣。我聽到你提到歐洲的庫存（inventory）。我想了解的是，在什麼情境下，你們的財測下緣才有可能發生？謝謝。

Yes. Good question, Matt. So as we set the guidance, I mean, the numbers you called out are right on. And but there was a $2 million to $3 million inventory build, and therefore the demand in the second-quarter, even though we record $99 million of sales, the demand is maybe close to $95 million, $96 million.

是的。好問題，Matt。我們在設定財測時，你指出的數字是正確的。不過有 200 萬到 300 萬美元的庫存增加，因此第二季即使我們認列了 9,900 萬美元的銷售額，實際需求（demand）可能接近 9,500 萬、9,600 萬美元。

And then if you do flat line that out, it puts you at around the $350 million or just above the $350 million mark, if you are doing the math that you are doing. That $350 million mark is, or just north of $350 million is actually right in the middle of the guidance we gave of $345 million to $360 million. So that's how we gave it.

然後如果你把它持平推算，大約會落在 3.50 億美元左右或略高於 3.50 億美元——如果你用你剛才那樣的算法。而 3.50 億美元左右或略高於 3.50 億美元，其實正好落在我們給出的 3.45 億到 3.60 億美元財測區間的中間。所以我們就是這樣給出財測的。

We didn't want to put a precise number. But we do think it is appropriate and conservative to put a range around the trajectory of the number of patients which we are treating at this point in time.

我們不想給出一個精確數字。但我們確實認為，針對目前我們正在治療的患者數量之成長軌跡，給出一個區間是合適且保守的做法。

I would just say that even though we're commenting on that range and saying we are treating nearly all the patients, the G551 patients in US and Europe now, the growth, as Stuart mentioned on the call, the growth we do anticipate to start again in 2014, and that does come from these other geographies that we start to sell drug into that we have been approved and we are looking for reimbursement. And that it comes with label expansion, to the study we are announcing today, and then the other studies that we are running. And those can come throughout 2014, giving us kind of a nice growth trajectory of an important revenue line item in 2014.

我只想說，儘管我們在評論那個區間並表示我們現在幾乎在美國與歐洲治療了所有患者、也就是G551患者，但如Stuart在電話會議中提到的，我們預期成長將在2014年再次開始，而這將來自我們開始在其他已獲核准、且正在尋求給付/報銷的地理市場銷售藥品。此外，成長也會來自適應症標籤擴大，包括我們今天宣布的研究，以及我們正在進行的其他研究。而這些都可能在2014年陸續發生，讓我們在2014年於一個重要的營收項目上形成相當不錯的成長軌跡。

Great. Thanks, and congrats on the progress in CF.

很好。謝謝，也恭喜你們在CF方面的進展。

The next question comes from Robin Karnauskas from Deutsche Bank.

下一個問題來自德意志銀行（Deutsche Bank）的Robin Karnauskas。

Thanks for taking my question. So I guess if you were to see a really significant improvement by adding 661 to KALYDECO in these patients, do you have a sense of how nimble you can be to advancing the program forward for approval, now that you have had some more time to understand what breakthrough designation gives you?

謝謝讓我提問。所以我想，如果在這些患者中把661加到KALYDECO後看到非常顯著的改善，你們是否能評估在推進該計畫以取得核准方面可以有多靈活/迅速？畢竟你們現在也有更多時間了解突破性療法認定能帶來什麼？

And then the second question I have, how many patients do you think that you need to see with 135, say at 100 milligrams or 200 milligrams to be comfortable you will not see the liver tox you saw in the 400-milligram dose? Thanks.

然後我的第二個問題是，你們認為需要看到多少名使用135（例如100毫克或200毫克）的患者，才會有把握不會出現你們在400毫克劑量中看到的肝毒性？謝謝。

I will take the second one first. In terms of how many patients, it is very hard to say. Obviously, statistically, if you study 300 patients and you don't see it, you can say that it's a rate of less than 1%. It all just depends on the end.

我先回答第二個問題。就需要多少名患者而言，這很難說。顯然，從統計上看，如果你研究了300名患者而沒有看到該事件，你可以說其發生率低於1%。這一切都取決於最終結果。

I think as Peter mentioned, as we begin to build our safety database towards pivotal studies, we will be in the 100s range for patient numbers. And that will give us a fair amount of confidence that we are not going to see it at any substantial rate.

我想如Peter提到的，當我們開始為關鍵性試驗建立安全性資料庫時，患者人數會在數百人的範圍。這將讓我們相當有信心，認為不會以任何顯著的比率看到該情況。

And Robyn, for the first question with 661 and 770, in those heterozygous 551 508, patients if we see a positive signal, I think the first thing is we have to basically show enough safety data for 661, which we haven't at this given point in time. And what that means is you have to at least conduct a trial risk, a couple hundred patients at the end of the day, to be in a label position that the agencies might accept.

Robyn，關於第一個問題，針對661與770，在那些異合子551/508的患者中，如果我們看到正向訊號，我認為第一件事是我們必須基本上展示足夠的661安全性資料，而就目前這個時間點我們還沒有。這意味著你至少必須進行一項試驗，最終累積到數百名患者，才能在標籤（適應症）上達到主管機關可能接受的程度。

That's helpful. And just as a follow-up, do you feel that the fact that the liver signal was not predicted preclinically that the -- and the mechanism of the tox is not fully understood, that that could be a hurdle with the FDA? Or is it really just all about statistics and showing that the incidence is well below a certain number to get people comfortable at the FDA?

這很有幫助。再追問一下，你是否覺得肝臟訊號在臨床前並未被預測到、且毒性機轉尚未完全理解，這可能會成為FDA的障礙？還是說其實就是統計問題，只要證明發生率遠低於某個數字，就能讓FDA的人放心？

That is 135 now, I was talking about --

那是135，我剛剛在講的是——

Yes, sorry, I was going back and forth.

是的，抱歉，我剛剛來回切換了。

Right.

對。

Yes, with 135, I think obviously the clinical data will likely trump any other information. And I think that is really what we are largely focused on. As I mentioned, in terms of in vitro data, we have done a very extensive evaluation for mitochondrial effects and there just don't seem to be any. So we are pretty confident in that regard.

是的，針對135，我認為臨床數據顯然很可能會凌駕於其他任何資訊之上。我想這也正是我們主要聚焦的地方。如我提到的，就體外數據而言，我們已對粒線體效應做了非常廣泛的評估，而看起來並沒有任何影響。因此在這方面我們相當有信心。

Thanks.

謝謝。

The next question comes from Yaron Werber from Citi.

下一個問題來自花旗（Citi）的Yaron Werber。

This is [Kumar] in for Yaron. Thank you for taking my question. What is the strategy for VX-809 JAK inhibitor? And also, can the time line for the non-G551D label expansion be shorter given the breakthrough designation?

我是代替Yaron的[Kumar]。謝謝讓我提問。對於VX-809 JAK抑制劑的策略是什麼？另外，鑑於突破性療法認定，非G551D的標籤擴大時程是否可以更短？

And so, I will ask Peter to talk about the breakthrough designation, how that affects time line for VX-809. And I think your first question, I didn't quite catch your name, but--

那麼，我會請Peter談談突破性療法認定，以及它如何影響VX-809的時程。至於你的第一個問題，我沒有太聽清楚你的名字，但——

Kumar.

Kumar。

Kumar? The first question, I think you are referring to VX-509, the JAK inhibitor. And our strategy remains as we described at the beginning of this year is that we think the most value can be captured from VX-509 by -- and recruiting partner help. So it is something that we are evaluating, partnering opportunities to drive that molecule forward in multiple disease areas.

Kumar？第一個問題，我想你指的是VX-509，也就是JAK抑制劑。我們的策略仍如今年年初所描述：我們認為VX-509能創造的最大價值在於——引入合作夥伴的協助。因此，我們正在評估合作機會，以推動這個分子在多個疾病領域向前發展。

We are aware the market is competitive and the disease areas are broad and big, and it's a global market. And we believe to get the maximum benefit from this molecule, the best decision is for an out licensing and we are currently looking at and evaluating opportunities to do that. To the, to VX-809 in CF, I will ask Peter to comment on how breakthrough designation may affect it.

我們知道市場競爭激烈、疾病領域廣泛且規模龐大，而且是全球市場。我們相信要讓這個分子獲得最大效益，最佳決策是對外授權（out-licensing），我們目前正在尋找並評估這方面的機會。至於囊性纖維化（CF）中的VX-809，我會請Peter評論突破性療法認定可能如何影響它。

So Kumar, there are many different ways how breakthrough works. So the first, the first is you have basically more frequent interactions with regulatory authorities with the clear goal to come forward with an acceptable fast development program that authorities can accept.

Kumar，突破性療法有很多不同的運作方式。第一點是，你基本上會與主管機關更頻繁互動，明確目標是提出一個主管機關可接受的快速開發計畫。

In that context, we already got an acceleration because as you well know, we went down from 48 weeks or 52 weeks to a 24-week regimen, which basically cuts it substantially faster. And then also the clear-cut agreement about several doses. And no basically mono arm and all those types of things basically accelerated the overall program by about a year and a half. That is already good news.

在這個脈絡下，我們已經獲得加速，因為如你所知，我們把療程從48週或52週縮短到24週，基本上大幅加快。此外，也就多個劑量達成明確協議。而且不採用單臂（mono arm）等各種設計，基本上讓整體計畫加速了大約一年半。這已經是好消息。

Now obviously, the next piece is the registration and the approval process. And what regulatory authorities normally do is they talk with you about how you basically can file, so that this may be more accelerated. But it doesn't set a time line. It doesn't give you, it is two months or three months or five months or eight months. It is dependent on the data set that you have.

接下來當然是註冊申請與核准流程。主管機關通常會與你討論如何提交申請，讓流程可能更為加速。但它不會設定一個固定時程。它不會告訴你是兩個月、三個月、五個月、或八個月。這取決於你擁有的數據集。

What might happen, which just might be a benefit that you do not have to do an [add port] -- which is something they basically sort of say at different meetings, which could also be beneficial and going positive to the time line. That's about what it is. It is the closing direction with the agency on a daily basis to make good progress.

可能會發生的一件事——也許是一項好處——是你不必做一個[add port]——這是他們在不同會議上可能會提到的事情——這也可能對時程帶來正面幫助。大致就是這樣。也就是與主管機關保持更緊密、幾乎是日常的溝通方向，以取得良好進展。

That's very helpful. Thank you.

非常有幫助。謝謝。

The next question comes from Ying Huang from Barclays.

下一個問題來自巴克萊（Barclays）的Ying Huang。

Thanks for taking my questions as well. So I have a couple on VX-135 first. Were there any [Hyatt's law] cases reported or observed in that 400-milligram dose cohort in Europe? And then also, do you guys still plan to start a pivotal, given by the end of 2014, if assuming 100 milligrams just goes well?

也謝謝讓我提問。我先問幾個關於VX-135的問題。在歐洲那個400毫克劑量隊列中，是否有任何[Hyatt's law]案例被通報或觀察到？另外，如果假設100毫克進展順利，你們是否仍計畫在2014年底前啟動一項關鍵性試驗？

So this is Bob, in terms of your first question, no, there were no cases of Hyatt's law in any of the subjects, who had elevated liver function tests. Can you repeat the second question?

我是Bob，針對你的第一個問題，沒有，在任何出現肝功能檢測值升高的受試者中，都沒有Hyatt's law的案例。你可以重複一下第二個問題嗎？

Yes, if 100-milligram actually looks good and everything goes well, do you still plan to start a pivotal development of VX-135 by the end of next year?

是的，如果100毫克看起來確實不錯而且一切進展順利，您是否仍計畫在明年年底前啟動VX-135的關鍵性開發？

Yes. I mean, our goal is to, as we have said, to get the results of these studies, to provide them to the FDA in the hopes of resolving the clinical hold, so that we can assess higher doses in the US. And at the same time, to expand the study once we are able to -- the daclatasvir study in particular. And I think our ultimate regimen will be guided by the data. If 100 milligrams looks good, we will consider taking that into Phase 3. It really is just very data-driven.

是的。我的意思是，我們的目標是，如同我們所說的，取得這些研究的結果，並提供給FDA，希望能解除臨床暫停（clinical hold），以便我們能在美國評估更高劑量。同時，一旦我們能夠——特別是daclatasvir研究——也會擴大該研究。我認為我們最終的治療方案將由數據來指引。如果100毫克看起來不錯，我們會考慮將其推進到第三期。這確實是非常以數據為導向的。

Thanks, Bob. And then I have one more on VX-661 here. Anything you have seen in the preclinical model that leads you to believe this compound should behave differently from VX-809 in heterozygous patients or not?

謝謝你，Bob。接著我還有一個關於VX-661的問題。你們在臨床前模型中是否看到任何跡象，讓你們相信這個化合物在雜合子患者中的表現會與VX-809不同，或是不會？

No, I don't think there is anything particular that would make one think that one way or the other, in terms of 809 versus 661.

不，我不認為有任何特別之處會讓人覺得在809與661之間會有哪一種或另一種差異。

Okay, great. Oh, if I may ask just one more. Should we expect anything reported at AASLD for 135?

好的，很好。噢，如果可以的話我再問一個。我們是否應該期待在AASLD上有關於135的任何報告？

I can't really comment on where our data are going to be presented at this stage of the game. Have to just stay tuned.

在目前這個階段，我無法評論我們的數據將會在哪裡發表。只能請大家拭目以待。

We can say that when the certain study is complete, we generally provide a top line press release in terms of those study results when we have both safety and efficacy. So you can expect that and generally more complete data at the medical conferences to follow.

我們可以說的是，當某項研究完成時，我們通常會在同時具備安全性與有效性數據後，就該研究結果發布一份重點摘要的新聞稿。所以你可以期待會有這個，並且通常在後續的醫學會議上會公布更完整的數據。

Thank you, Ian.

謝謝你，Ian。

Operator, this is Michael. It's now nearly 6.00. We have time for two more questions.

接線員，我是Michael。現在已經快6點了。我們還有時間再回答兩個問題。

Thank you. The next question comes from David Friedman from Morgan Stanley.

謝謝。下一個問題來自Morgan Stanley的David Friedman。

Hi, thanks for taking the question. It's a question on 983. I was wondering if you could just talk a little bit about what the -- what final steps are necessary until that is in humans. And then also, if you have any more detail beyond just the brief sentence in the press release about your thoughts on some initial studies with that, with that drug?

嗨，謝謝讓我提問。這是一個關於983的問題。我想請你談談——在它進入人體試驗之前，還需要哪些最後步驟。另外，除了新聞稿中那句簡短的描述之外，你是否能提供更多細節，談談你們對於該藥物一些初步研究的想法？

All right. This is Peter. So first is basically, as it is true for all experimental medicines, you have to do a serious pre-clinical and early clinical assessments, which means tox studies, PK studies, any of those. And we are currently conducting these, and we'll see what the outcome is, and come back to you and see what strategy we can do. It's all data driven.

好的。我是Peter。首先，基本上，正如所有實驗性藥物一樣，你必須進行嚴謹的臨床前與早期臨床評估，包括毒理研究、藥物動力學（PK）研究等等。我們目前正在進行這些工作，會看看結果如何，之後再向各位回報，並評估我們可以採取什麼策略。一切都以數據為導向。

Hypothetically, 983 acts very similar to 809 and 661. And you can assume a similar development path as you have seen for 809 or 661 as we go forward, in case everything goes positive. (Inaudible). It already in humans anyhow. So -- but I think it is not in our POC study, if that is what you mean.

假設而言，983的作用方式與809和661非常相似。如果一切進展順利，你可以假設其開發路徑會與你們所看到的809或661相近。(聽不清楚)。不管怎樣，它已經在人體中進行過了。所以——但我認為它不在我們的POC研究中，如果你指的是這個的話。

Yes. We've completed the Phase 1 healthy volunteer study.

是的。我們已完成第一期健康受試者研究。

Yes.

是的。

And right now, we are considering what the next study would be with the compounding in combination with KALYDECO. And also having, kind of the normal regulatory discussions about what study we may proceed ahead with. And we will be back to you later this year when we have greater clarity on that.

而目前我們正在考慮下一項研究會是什麼，也就是該化合物與KALYDECO合併使用的研究。同時也在進行一般性的法規（監管）討論，評估我們可能會推進哪一項研究。等到今年稍晚我們更清楚之後，會再向各位回報。

Great. Thanks a lot.

太好了。非常感謝。

The final question comes from Salveen Richter from Canaccord.

最後一個問題來自Canaccord的Salveen Richter。

Thanks for squeezing us in. Just two qualitative questions really briefly. Given the -- for CF, given in vitro to in vivo correlation, how do the in vitro results for the R117H and residual mutation data look versus the non-G551D gating mutation?

謝謝讓我們插進來。我有兩個定性問題，簡短問一下。就囊性纖維化（CF）而言，考量體外到體內的相關性，R117H與殘餘突變（residual mutation）的體外結果，相較於非G551D的閘門型（gating）突變，看起來如何？

Peter, do you just want to close on this?

Peter，你要不要用這個問題做個收尾？

Yes. So basically, from a sensitivity in vitro 117 is highly sensitive, and we have therefore some hopes that it might also work at the end of the day in the clinic. Now in general, the comment is we have your gating type of mutations. I might just make a general comment. It's not the same for each and every class of mutations, and I want to just put that word of precaution out, because there's a difference between [drastic] mutations and gating mutations.

好的。基本上，從體外敏感性來看，117的敏感性非常高，因此我們也抱持一些希望，認為它最終在臨床上也可能有效。一般而言，我的評論是，我們有所謂閘門型突變。我可能做一個一般性的說明。不同類別的突變並不完全相同，我想提醒大家要謹慎，因為[嚴重]突變與閘門型突變之間是有差異的。

Got you. And then just briefly for the gating trial, the data today. Was the eight-week data in line with the 20-week data? The pre cross-over eight-week data, that is?

了解。接著簡短問一下關於閘門型試驗、也就是今天的數據。八週的數據是否與二十週的數據一致？我是指交叉前（pre cross-over）的八週數據。

You mean each, each period?

你是指每一個、每一個期間嗎？

Yes.

是的。

Yes.

是的。

Yes, so yes, so we looked at that specifically to see whether there was any carry-over effect after the washout period, and in fact there was no carry-over effect. The results whether you gave it first or second, were very comparable to each other.

是的，所以是的，我們特別檢視了這一點，看看在洗脫期（washout period）之後是否有任何殘留效應（carry-over effect），而事實上並沒有殘留效應。不論先給藥或後給藥，結果彼此都非常相近。

Great. Thanks so much.

太好了。非常感謝。

So thanks, everybody, for tuning in tonight. If you have additional questions, we are in our offices. We'll be happy to take your call. Have a good evening.

那麼今晚謝謝各位收聽。如果你們還有其他問題，我們都在辦公室。很樂意接聽你們的來電。祝各位晚安。

Ladies and gentlemen, that does conclude the conference for today. Again, thank you for your participation. You may all disconnect. Have a good day.

各位女士先生，今天的電話會議到此結束。再次感謝各位的參與。各位現在可以掛線。祝各位有美好的一天。