福泰製藥 (VRTX) 2014 Q1 法說會逐字稿

Good day, ladies and gentlemen, and thank you for your patience. You've joined the Vertex Pharmaceuticals Incorporated first-quarter 2014 financial results conference call.

各位女士、先生，大家好，感謝各位耐心等候。您已加入 Vertex Pharmaceuticals Incorporated 2014 年第一季財務業績電話會議。

(Operator Instructions)

(接線員指示)

As a reminder, this conference may be recorded. I would now like to turn the call over to your host, the Vice President of Investor Relations, Mr. Michael Partridge. Sir, you may begin.

提醒各位，本次會議可能會被錄音。現在我想把電話交給本次會議主持人——投資人關係副總裁 Michael Partridge 先生。先生，您可以開始了。

Thank you, operator, and good evening, everyone. Joining me on tonight's call are Dr. Jeff Leiden Chairman and CEO; Dr. Jeff Chodakewitz, Chief Medical Officer; Stuart Arbuckle, Chief Commercial Officer; and Ian Smith, Chief Financial Officer. Our agenda tonight is as follows.

謝謝，接線員，大家晚安。今晚與我一同參與電話會議的有：董事長兼執行長 Jeff Leiden 博士；首席醫療長 Jeff Chodakewitz 博士；首席商務長 Stuart Arbuckle；以及首席財務長 Ian Smith。今晚的議程如下。

Jeff Leiden will begin by reviewing Vertex's strategic business priorities for 2014 Then Jeff Chodakewitz will review our clinical progress in cystic fibrosis, including the results of the study of VX-661 in combination with KALYDECO and G551D F508del patients. Dr. Chodakewitz joined Vertex at the start of 2014 and we are happy to have him join us on this and future calls.

Jeff Leiden 將先回顧 Vertex 2014 年的策略性業務優先事項。接著 Jeff Chodakewitz 將回顧我們在囊性纖維化（CF）方面的臨床進展，包括 VX-661 與 KALYDECO 併用、以及在 G551D/F508del 患者中的研究結果。Chodakewitz 博士於 2014 年初加入 Vertex，我們很高興他能參與本次及未來的電話會議。

Next, Stuart will discuss KALYDECO product revenues and provide some commentary on the outlook for KALYDECO growth in 2014. To close, Ian will review the financial results and discuss our updated financial guidance. Joining us for Q&A are Dr. Bob Kauffman and Dr. Peter Mueller. We plan for the call to run for a total of one hour.

接下來，Stuart 將討論 KALYDECO 的產品營收，並就 2014 年 KALYDECO 成長展望提供一些評論。最後，Ian 將回顧財務結果並討論我們更新後的財務指引。參與問答的還有 Bob Kauffman 博士與 Peter Mueller 博士。我們預計本次電話會議總長為一小時。

(Caller Instructions)

(來電者指示)

This conference call will include forward-looking statements, which are subject to risks and uncertainties, including those discussed in detail in our reports filed with the Securities and Exchange Commission, including our 10-K and 10-Q. These statements, including without limitation, those regarding the performance of KALYDECO, our development plans and expectations, and our guidance are based on Management's current assumptions and are subject to risks and uncertainties that could cause actual outcomes and events to differ materially.

本次電話會議將包含前瞻性陳述，該等陳述受風險與不確定性影響，包括我們向美國證券交易委員會（SEC）提交之報告（含 10-K 與 10-Q）中所詳細討論者。這些陳述（包括但不限於）關於 KALYDECO 的表現、我們的開發計畫與預期，以及我們的指引，係基於管理階層目前的假設，並受可能導致實際結果與事件與所述內容出現重大差異之風險與不確定性影響。

Information regarding our use of GAAP and non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in our first-quarter 2014 financial results press release. This press releases is on our website and I would also refer you to slide 4 of tonight's webcast. Thank you. I will now turn the call over to Jeff Leiden.

關於我們使用 GAAP 與非 GAAP 財務衡量指標的資訊，以及 GAAP 與非 GAAP 的調節表，已載於我們 2014 年第一季財務業績新聞稿中。該新聞稿已發布於我們的網站，我也請各位參考今晚網路直播的第 4 張投影片。謝謝。現在我把電話交給 Jeff Leiden。

Thanks, Michael, and good evening, everyone. Vertex is in many ways a Company in transition. We have made cystic fibrosis a clear focus of our business and we've made a decision to no longer invest in hepatitis C. At the same time, we're continuing to invest in early-stage research to identify compounds in CF and other areas that could become transformative medicines for patients with serious diseases, as well as opportunities for Vertex growth.

謝謝你，Michael，大家晚安。Vertex 在許多方面正處於轉型之中。我們已將囊性纖維化明確作為業務重點，並決定不再投資於 C 型肝炎。同時，我們仍持續投資早期研究，以在 CF 及其他領域辨識可能成為治療嚴重疾病患者之突破性藥物的化合物，以及為 Vertex 帶來成長的機會。

This transition to Vertex business represents our continued execution against three strategic priorities for 2014. I talked about these priorities earlier this year and I'd like to review them again now. First, focus on driving forward our cystic fibrosis development programs to enable the launch of multiple transformative CF medicines globally. Our clinical and commercial teams have made significant progress in CF already this year.

這項 Vertex 業務轉型，代表我們持續落實 2014 年三項策略優先事項。我在今年稍早談過這些優先事項，現在我想再回顧一次。第一，專注推進我們的囊性纖維化開發計畫，以促成多款具突破性的 CF 藥物在全球上市。我們的臨床與商業團隊今年在 CF 領域已取得顯著進展。

For example, we have expanded the US KALYDECO label to include additional patients. We have now completed dosing in the Phase 3 studies of V-X809. We have recently received orphan status for VX-661 and we are today reporting positive clinical results for a study of VX-661 in patients heterozygous for G551D and F508del.

例如，我們已擴大美國 KALYDECO 的適應症標示，納入更多患者。我們現已完成 V-X809 第三期研究的給藥。我們近期已取得 VX-661 的孤兒藥資格，並於今日報告 VX-661 在 G551D 與 F508del 雜合子患者中的研究之正向臨床結果。

Second, continue to invest in research. Internal research is a critical growth engine for Vertex and we expect that it will produce more transformative medicines to provide sustainable growth in the future. And third, maintain financial strength so that we can continue to invest in the discovery and development of our new medicines. We ended the first quarter with more than $1.3 billion in cash and with KALYDECO revenues of approximately $100 million, that we expect to grow through the year and in future years. This financial position supports our investments for future growth.

第二，持續投資研發。內部研發是 Vertex 關鍵的成長引擎，我們預期它將產出更多突破性藥物，以在未來帶來可持續的成長。第三，維持財務實力，使我們能持續投資於新藥的發現與開發。第一季結束時，我們持有超過 13 億美元現金，且 KALYDECO 營收約為 1 億美元；我們預期該營收將在今年及未來年度持續成長。此一財務狀況支持我們對未來成長的投資。

Our goal in CF is to treat as many people as possible and to enhance the benefit for those that we treat. Jeff Chodakewitz will give you more detail on our recent CF clinical progress, but before I turn it over to him, I would like to acknowledge that today marks the start of CF Awareness Month and recognize all the patients, families, doctors, nurses, and caregivers who are involved in the treatment of CF. Thank you for your continued support as we seek to improve the lives of more people with this devastating disease. Our continued progress in CF clinical development is a strong sign that our commitment to people with CF is unwavering. With that, I'll turn it over to Jeff.

我們在 CF 的目標是治療盡可能多的人，並提升我們所治療患者的受益程度。Jeff Chodakewitz 將就我們近期 CF 臨床進展提供更多細節，但在把電話交給他之前，我想先提到今天是囊性纖維化關注月的開始，並向所有參與 CF 治療的患者、家屬、醫師、護理人員與照護者致敬。感謝各位在我們努力改善更多罹患此一毀滅性疾病之患者生活的過程中，持續給予支持。我們在 CF 臨床開發上的持續進展，強烈顯示我們對 CF 患者的承諾始終如一。接下來交給 Jeff。

Thanks, Jeff and good evening. It's a pleasure to speak with you all today. I'll provide an overview of some important progress we've made with our three CF development programs -- specifically ivacaftor monotherapy, lumacaftor and ivacaftor combination therapy, and VX-661 and ivacaftor combination therapy.

謝謝你，Jeff，大家晚安。很高興今天能與各位交流。我將概述我們三項 CF 開發計畫所取得的一些重要進展——具體而言，包括 ivacaftor 單藥治療、lumacaftor 與 ivacaftor 併用治療，以及 VX-661 與 ivacaftor 併用治療。

Let me begin with ivacaftor monotherapy -- our clinical and regulatory efforts are focused on demonstrating clinical activity in additional patients that may benefit from this medicine. In February, following approval from the US FDA, we began treating patients with eight additional mutations with KALYDECO. These are all mutations for which in vitro data predicted clinical responsiveness to KALYDECO. We submitted an MAA variation to the European Medicines Agency and expect to receive an opinion from the CHMP for these additional gating mutations around mid-year.

我先從 ivacaftor 單藥治療談起——我們的臨床與法規工作重點在於證明更多可能受益於此藥物的患者具有臨床活性。2 月，在獲得美國 FDA 核准後，我們開始以 KALYDECO 治療另外八種突變的患者。這些突變皆為體外數據預測對 KALYDECO 具有臨床反應者。我們已向歐洲藥品管理局提交 MAA 變更申請，並預期約在年中取得 CHMP 對這些額外 gating 突變的意見。

An additional mutation for which we are seeking ivacaftor label expansion is R117H. As you may recall, we announced results in December from a Phase 3 trial in this population. We did not achieve statistical significance in the primary end point for the overall population of this trial but ivacaftor did produce a statistically and clinically significant improvement in FEV1 and other measures in a prespecified subpopulation of participants 18 years of age and older.

我們尋求擴大 ivacaftor 適應症標示的另一項突變是 R117H。各位或許記得，我們在 12 月公布了此族群第三期試驗結果。在該試驗的整體受試者族群中，我們未能在主要終點達到統計顯著性；但在預先指定、年齡 18 歲（含）以上的受試者次族群中，ivacaftor 在 FEV1 及其他指標上產生了具統計與臨床顯著性的改善。

We plan to submit an sNDA and MAA variation for people with CF ages 18 and older with at least one copy of the R117H mutation. The sNDA submission is planned for mid-year, with the MAA variation to follow in the second half of 2014. We expect to continue our discussions with the FDA following our sNDA submission. We estimate that there are more than 700 patients age 18 and older worldwide with the R117H mutation.

我們計畫針對 18 歲（含）以上、且至少帶有一個 R117H 突變拷貝的 CF 患者，提交 sNDA 與 MAA 變更申請。sNDA 預計於年中提交，MAA 變更申請則將於 2014 年下半年跟進。我們預期在提交 sNDA 後，將持續與 FDA 進行討論。我們估計全球 18 歲（含）以上帶有 R117H 突變的患者超過 700 人。

We also believe that ivacaftor may be able to help other patients who have residual CFTR function. We are conducting a proof-f-concept study in these patients and we are on track to report results later this quarter. In our view, a successful result in this study of approximately 20 participants would lay the groundwork for pivotal studies of ivacaftor in patients with residual CFTR function.

我們也相信，ivacaftor 可能能夠幫助其他仍保有殘餘 CFTR 功能的患者。我們正在這些患者中進行一項概念驗證研究，並按計畫於本季稍晚公布結果。我們認為，若這項約 20 名受試者的研究取得成功，將為在具殘餘 CFTR 功能患者中進行 ivacaftor 關鍵性試驗奠定基礎。

Finally, we expect to report results from our pediatric safety study of ivacaftor use in two- to five-year-olds with gating mutations in the third quarter. All patients in the pediatric study who have completed 24 weeks of treatment have now progressed into the rollover study.

最後，我們預期將於第三季公布一項兒科安全性研究結果，該研究評估 ivacaftor 用於具有閘門（gating）突變之 2 至 5 歲兒童。兒科研究中所有已完成 24 週治療的患者，現已進入延伸（rollover）研究。

Moving to our lumacaftor ivacaftor combination program, the six-month dosing period is complete for the Phase 3 traffic and transport studies in patients age 12 and older who are homozygous for the F508del mutation. We are on track to report 24-week results from these studies around mid-year. If these studies are successful, we expect to file an NDA and MAA later this year.

接著談我們的 lumacaftor 與 ivacaftor 聯合療法計畫：在 12 歲以上且 F508del 突變為同型合子（homozygous）的患者中，第 3 期 TRAFFIC 與 TRANSPORT 研究的 6 個月給藥期已完成。我們按計畫將於年中左右公布這些研究的 24 週結果。若研究成功，我們預期將於今年稍晚提交 NDA 與 MAA。

In traffic and transport, we are seeking to demonstrate a statistically and clinically significant improvement in absolute FEV1, the primary endpoint of the study, and also benefits in important secondary endpoints, including weight gain, pulmonary exacerbation and CF Q-R. We estimate that our studies are more than 90% powered for an absolute improvement in FEV1 of 3% from baseline compared to placebo at week 24.

在 TRAFFIC 與 TRANSPORT 研究中，我們希望證明主要終點（primary endpoint）——絕對 FEV1——具有統計學與臨床上顯著的改善，同時也在重要的次要終點上看到效益，包括體重增加、肺部惡化（pulmonary exacerbation）以及 CF Q-R。我們估計，這些研究對於在第 24 週相較安慰劑、從基線（baseline）起絕對 FEV1 改善 3% 的檢出力（power）超過 90%。

In addition to lumacaftor, we are developing another first-generation corrector, VX-661. Our principal strategy with VX-661 is to develop it as part of a future triple combination therapy with a next-generation corrector and a potentiator. Dosing has begun in our 12 week study of 661 plus ivacaftor in patients 18 and older who are homozygous for the F508del mutation.

除 lumacaftor 外，我們也在開發另一個第一代校正劑（corrector）VX-661。我們對 VX-661 的主要策略，是將其作為未來三重合併療法的一部分，與下一代校正劑及增效劑（potentiator）併用。我們已在一項為期 12 週的研究中開始給藥，該研究評估 661 加 ivacaftor 用於 18 歲以上且 F508del 突變為同型合子的患者。

We expect to enroll approximately 40 patients who will be treated with 661 plus ivacaftor or placebo. Our goal of this study is to assess the safety and efficacy of 661 plus ivacaftor over a longer duration of treatment. If successful, this study would be enabling for future development of VX-661 for use in a triple combination or potentially to progress it as part of a dual combination.

我們預期將納入約 40 名患者，接受 661 加 ivacaftor 或安慰劑治療。本研究目標是評估 661 加 ivacaftor 在較長治療期間的安全性與療效。若成功，本研究將有助於未來將 VX-661 用於三重合併療法的開發，或可能推進其作為雙重合併療法的一部分。

Today Vertex announced results from a proof-of-concept study of the corrector 661 in combination with ivacaftor in CF patients who have the G551D mutation on one allele and the F508del mutation on the other allele. The basis for exploring the VX-661 plus ivacaftor combination in this population is based on in vitro observations from HBE cells, in which adding VX-661 to ivacaftor improved chloride transport. The purpose of this trial was to see if the improvement in CFTR function that we observed in the lab could translate into a signal of clinical efficacy in the G551D F508del heterozygous population.

今日 Vertex 公布一項概念驗證研究結果：在 CF 患者中，校正劑 661 與 ivacaftor 併用；這些患者其中一個等位基因（allele）為 G551D 突變，另一個等位基因為 F508del 突變。在此族群探索 VX-661 加 ivacaftor 併用的依據，來自 HBE 細胞的體外（in vitro）觀察：加入 VX-661 後可改善 ivacaftor 的氯離子運輸。本試驗目的在於確認我們在實驗室觀察到的 CFTR 功能改善，是否能在 G551D/F508del 異型合子（heterozygous）族群中轉化為臨床療效訊號。

We dosed VX-661 as 100 milligrams daily in patients who were already taking 150 milligrams of KALYDECO twice daily for an average of one year. We were testing this clinical hypothesis for the first time and were not sure if we would be able to detect the signal. The patients that we enrolled were G551D patients who had already been receiving commercial KALYDECO and therefore we are likely to have already seen a significant clinical benefit from taking this medication. Also the study was small. We enrolled just 18 patients and the duration of therapy was short, just 28 days for which VX-661 would be added on top of ivacaftor.

我們在已平均服用 KALYDECO（每日兩次、每次 150 毫克）約一年的患者中，將 VX-661 以每日 100 毫克給藥。這是我們首次檢驗此臨床假設，且不確定是否能偵測到該訊號。我們納入的患者為 G551D 患者，且已在使用市售 KALYDECO，因此我們很可能已經看到服用該藥所帶來的顯著臨床效益。此外，本研究規模很小。我們僅納入 18 名患者，治療期間也很短，僅 28 天；VX-661 會在 ivacaftor 基礎上加用。

The results do, in fact, show a clear signal of efficacy. There was a mean 4.6 percentage point absolute improvement within group in PPFEV1 through 28 days. The relative FEV1 improvement was 7.3%. These improvements were both statistic statistically significant. We also saw a small reduction in sweat chloride on treatment within group on, with a P value of 0.053. FEV1 sweat chloride returned toward baseline in the four weeks following completion of the 661 treatment period. These off-treatment effects were statistically significant within group as well.

結果確實顯示出明確的療效訊號。在 28 天期間，PPFEV1 的組內平均絕對改善為 4.6 個百分點。相對 FEV1 改善為 7.3%。這兩項改善皆具統計學顯著性。我們也觀察到治療期間組內汗氯（sweat chloride）小幅下降，P 值為 0.053。在完成 661 治療期後的四週內，FEV1 與汗氯皆回到接近基線。這些停藥後（off-treatment）效應在組內同樣具有統計學顯著性。

In this study, four patients already receiving KALYDECO were randomized to placebo to maintain study blinding. From a safety perspective, the regimen was generally well tolerated over 28 days and all 18 patients completed the treatment period. The most common adverse event in the treatment group were cough, pulmonary exacerbation, headache, and upper respiratory tract infection. And we expect to present more details on these results at a medical meeting in 2014.

在本研究中，為維持盲性（blinding），已有 4 名正在接受 KALYDECO 的患者被隨機分派至安慰劑組。就安全性而言，該療程在 28 天內整體耐受性良好，且 18 名患者皆完成治療期。治療組最常見的不良事件為咳嗽、肺部惡化、頭痛與上呼吸道感染。我們預期將於 2014 年的一場醫學會議上提出這些結果的更多細節。

For us there are really three important takeaways. First, once again in vitro data with our CFTR modulators has been predictive of a clinical benefit in a specific patient population. Second, correctors like 661 appear to be clinically active on a single F508del allele. And lastly, these results suggest to us that treatment for heterozygous patients may be further enhanced with CFTR modulators that are tailored toward each allele.

對我們而言，確實有三項重要重點。第一，我們的 CFTR 調節劑（modulators）之體外數據再次能夠預測特定患者族群的臨床效益。第二，像 661 這類校正劑似乎在單一 F508del 等位基因上具有臨床活性。最後，這些結果顯示，針對異型合子患者的治療，可能可透過依各等位基因量身打造的 CFTR 調節劑而進一步增強。

Based on the data announced today from this study and pending the results of the 12-week study, we could decide to develop VX-661 as part of the dual combination for certain heterozygous patient groups. Also based on these data, we plan to discuss with global regulatory authorities the potential approval pathway for VX-661 in combination with KALYDECO for people with CF who have the F508del mutation and another mutation known to respond to KALYDECO alone. In summary, I'm pleased with our progress with our CF development programs and I look forward to updating you throughout the year. With that, I'll turn it over to Stuart.

根據今日公布的本研究數據，並視 12 週研究結果而定，我們可能會決定將 VX-661 作為某些異型合子患者族群的雙重合併療法的一部分進行開發。此外，基於這些數據，我們計畫與全球監管機關討論 VX-661 與 KALYDECO 併用的潛在核准途徑，適用於具有 F508del 突變且另有一種已知可對單用 KALYDECO 產生反應之突變的 CF 患者。總結而言，我對我們 CF 開發計畫的進展感到滿意，並期待在今年持續向各位更新。接下來我把時間交給 Stuart。

Tonight I'll report on first-quarter product revenues and outline our expectations for KALYDECO revenue growth in 2014. KALYDECO generated $100 million in worldwide net revenues for the first quarter, including US sales of approximately $56 million and International sales of approximately $44 million. This represents an increase of 61% from revenues of $62 million that we reported for the first quarter of 2013.

今晚我將報告第一季產品營收，並概述我們對 2014 年 KALYDECO 營收成長的預期。KALYDECO 第一季全球淨營收為 1 億美元，其中美國銷售約 5,600 萬美元，國際銷售約 4,400 萬美元。相較於我們在 2013 年第一季所報告的 6,200 萬美元營收，這代表成長 61%。

The reason for the decline from the $109 million we reported in the fourth quarter of 2013 was the favorable impact of stocking and other nonrecurring business adjustments in the fourth quarter that we discussed on our quarterly call in January. We continue to see a very similar level of underlying demand and strong patient adherence to treatment.

相較於我們在 2013 年第四季所報告的 1.09 億美元，本季下滑的原因是：第四季因備貨（stocking）及其他一次性（nonrecurring）業務調整帶來的有利影響；我們已在 1 月的季度電話會議中討論過。我們持續看到非常相近的基本需求水準，以及患者對治療的高度依從性（adherence）。

We expect KALYDECO revenues to grow through 2014, beginning in the second quarter, based on the following anticipated key factors. First, label expansion. Since receiving approval from the FDA in late February for eight additional mutations, we have seen strong uptake, similar to what we saw in patients with the G551D mutation. We expect uptake to continue as we seek to reach the vast majority of the approximately 150 newly eligible patients in the US by year-end.

我們預期 KALYDECO 營收將在 2014 年持續成長，並自第二季開始，主要基於以下幾項預期的關鍵因素。第一，適應症標籤擴增（label expansion）。自 2 月底獲 FDA 核准新增 8 種突變後，我們看到強勁的採用（uptake），與我們在 G551D 突變患者中所見相似。我們預期採用將持續增加，因為我們希望在年底前觸及美國約 150 名新符合資格患者中的絕大多數。

We have filed an MAA variation with the EMA for a similar label expansion and currently anticipate approval in the second half of 2014. Following EMA approval, we will seek reimbursement for these new patients, both in countries where KALYDECO is already formally reimbursed such as France, and in new countries like Italy where, because there are so few G551D patients, the medicine has not yet been formally reviewed. There are approximately 250 eligible people with these additional mutations living in the EU.

我們已向 EMA 提交針對類似適應症標籤擴增的 MAA 變更申請，目前預期將於 2014 年下半年獲准。在 EMA 核准後，我們將為這些新病患爭取給付（reimbursement），包括在 KALYDECO 已正式獲得給付的國家（如法國），以及像義大利這類新國家；由於 G551D 病患人數極少，該藥物尚未在當地完成正式審查。在歐盟約有 250 名帶有這些額外突變且符合資格的人士。

A second key factor of KALYDECO growth is geographic expansion from securing public reimbursement in Canada and Australia. The reimbursement process is unfortunately taking longer than we, and more importantly, people with CF wanted. Reimbursement discussions in both countries are active and ongoing and our goal remains to get this transformational medicine to all eligible children and adults as quickly as possible. There are approximately 300 people with the G551D mutation in Canada and Australia, and we know they and their families are anxiously consciously awaiting a positive outcome from these discussions.

推動 KALYDECO 成長的第二個關鍵因素，是透過在加拿大與澳洲取得公費給付來進行地域擴張。很遺憾地，給付流程所花的時間比我們預期更久，更重要的是，也比囊性纖維化（CF）患者所期望的更久。兩國的給付討論都在積極且持續進行中，我們的目標仍是盡快讓這項具變革性的藥物提供給所有符合資格的兒童與成人。加拿大與澳洲約有 300 名帶有 G551D 突變的人士，我們知道他們及其家人正焦急地等待這些討論能有正面結果。

To summarize, we expect label and geographic expansion to enable us to grow our KALYDECO revenues beginning in the second quarter and continuing throughout the year. This growth is reflected in our KALYDECO net revenue guidance, which we are maintaining. I look forward to updating you on our continued progress throughout the year and I'll now turn it over to Ian.

總結而言，我們預期標籤與地域擴張將使我們自第二季起開始推動 KALYDECO 營收成長，並在全年持續。此成長已反映在我們維持不變的 KALYDECO 淨營收指引中。我期待在今年持續向各位更新我們的進展，接下來我把時間交給 Ian。

Thanks, Stuart and good evening to everyone. Tonight I would like to discuss our current financial position, our first-quarter 2014 results, and our updated 2014 financial guidance. During the first quarter, we further prioritized our development activities towards cystic fibrosis. Our financial results and guidance reflect this prioritization. As we enter the second quarter, we are a Business primarily funded by CF revenues in a strong cash position. We are investing in the discovery and development of medicines for CF and the creation of new medicines in other areas.

謝謝你，Stuart，也向各位道晚安。今晚我想討論我們目前的財務狀況、2014 年第一季業績，以及更新後的 2014 年財務指引。在第一季期間，我們進一步將研發活動的優先順序聚焦於囊性纖維化。我們的財務結果與指引反映了這項優先排序。進入第二季之際，我們是一家主要由 CF 營收支撐、且現金部位強勁的企業。我們正投資於 CF 藥物的探索與開發，以及在其他領域創造新藥。

Now to our cash position. We finished the quarter with over $1.3 billion in cash. This balance sheet strength, combined with the expected growth in our KALYDECO revenues, supports our business investment, but still allows us to exit 2014 with a strong balance sheet. We continue to manage this cash position as a priority, as it enables the transition of our Business to growth and profitability, driven by our CF medicines.

接著談我們的現金部位。本季結束時，我們持有超過 13 億美元現金。這樣的資產負債表強度，加上預期的 KALYDECO 營收成長，支持我們的業務投資，同時仍可讓我們在 2014 年底維持強健的資產負債表。我們持續將現金部位管理視為優先事項，因為這使我們的業務能在 CF 藥物帶動下，轉型走向成長與獲利。

An example of our prioritization to protect our financial strength is shown by our decision not to proceed with VX-135 in hepatitis C, amending our arrangement with Alios, and our decision to outlicense the compound. This is all reflected in our updated 2014 financial guidance that I'll discuss in a moment.

我們為保護財務實力而進行優先排序的一個例子，是我們決定不再推進丙型肝炎領域的 VX-135、修訂我們與 Alios 的合作安排，並決定將該化合物對外授權（outlicense）。這些都反映在我稍後將說明的更新後 2014 年財務指引中。

Now to the first-quarter 2014 results. We generated $108 million in total non-GAAP revenues in the first quarter. $100 million of this was KALYDECO. Based on our decision to end further investment in hepatitis C, as announced this evening, the HCV-related revenues totaling approximately $10 million are excluded from non-GAAP revenues.

接著看 2014 年第一季業績。第一季我們的非 GAAP 總營收為 1.08 億美元。其中 1 億美元來自 KALYDECO。基於我們今晚宣布停止對丙型肝炎的進一步投資之決定，與 HCV 相關、合計約 1,000 萬美元的營收已自非 GAAP 營收中排除。

Now to our operating expense. Our first-quarter total non-GAAP operating expense was $234 million, down $41 million or 15%, from Q1 2013. The first-quarter non-GAAP operating expense includes $182 million of R&D expenses compared to $195 million in the first quarter of 2013 and $52 million of SG&A expenses compared to $80 million in the first quarter of 2013.

接著談營業費用。第一季非 GAAP 總營業費用為 2.34 億美元，較 2013 年第一季減少 4,100 萬美元或 15%。第一季非 GAAP 營業費用包括研發（R&D）費用 1.82 億美元（2013 年第一季為 1.95 億美元），以及銷售、一般及行政（SG&A）費用 5,200 萬美元（2013 年第一季為 8,000 萬美元）。

These reductions of 7% and 35%, respectively, reflect our commitment to prioritization towards the CF medicines and the protection of our financial position. Our GAAP net loss for the first quarter was $232 million or $1 per diluted share. Our non-GAAP net loss was $151 million or $0.65 per diluted share.

上述分別 7% 與 35% 的降幅，反映我們致力於將資源優先投入 CF 藥物並保護財務狀況。第一季 GAAP 淨損為 2.32 億美元，或每股稀釋後虧損 1 美元。第一季非 GAAP 淨損為 1.51 億美元，或每股稀釋後虧損 0.65 美元。

Turning now to our financial guidance and, firstly, our revenue guidance for the full-year 2014, we are maintaining our KALYDECO guidance of $470 million to $500 million that we provided earlier this year. Achieving this guidance depends on three key drivers of growth, the continued uptake for the eight additional mutations in the US, and achieving reimbursement for the G551D patients in Australia and Canada, and the approval for other additional gating type mutations in the EU.

接著談我們的財務指引；首先是 2014 全年營收指引。我們維持先前於今年稍早提供的 KALYDECO 指引：4.70 億至 5.00 億美元。達成此指引取決於三項關鍵成長動能：美國對新增八種突變的持續採用、在澳洲與加拿大為 G551D 病患取得給付，以及在歐盟取得其他新增 gating 類型突變的核准。

With the exclusion of our HCV revenues, we are revising our total non-GAAP revenue guidance to be in the range of $520 million to $550 million. This range includes some revenues for the potential R&D collaborations. Based on our move away from HCV and further focusing our investment towards CF, we are reducing our operating expense guidance. We now anticipate 2014 non-GAAP operating expenses to be $890 million to $930 million.

在排除 HCV 營收後，我們將非 GAAP 總營收指引修訂為 5.20 億至 5.50 億美元。此區間包含部分來自潛在研發合作的營收。基於我們退出 HCV 並進一步將投資聚焦於 CF，我們正在下調營業費用指引。我們目前預期 2014 年非 GAAP 營業費用為 8.90 億至 9.30 億美元。

Additionally, I will just note that Q1 non-GAAP OpEx for R&D and SG&A provide a reasonable basis for modeling our expenses during the rest of the year. Total spend may declined slightly towards the end of the year based on clinical development activities. In summary, we are committed to completing 2014 with a strong balance sheet and managing our operating expense at a decreased level compared to prior years, while we grow our CF revenues. With that, I'll ask the operator to please open the line for questions.

另外我也補充說明，第一季非 GAAP 的研發與 SG&A 營業費用，可作為建模今年其餘期間費用的合理基礎。依臨床開發活動而定，全年總支出可能在年底前略為下降。總結而言，我們致力於在 2014 年結束時維持強健的資產負債表，並在推動 CF 營收成長的同時，將營業費用控制在較往年更低的水準。接下來請接線員開放提問。

(Operator Instructions)

（接線員指示）

Geoff Meacham, JPMorgan.

Geoff Meacham，摩根大通（JPMorgan）。

Got a couple on the 661 KALYDECO combo study. I'm assuming that the patients on the placebo arm, on just a KALYDECO monotherapy, were stable. That data isn't in the slides but I'm assuming that, that has largely unchanged over the evaluation period?

我有幾個關於 661 與 KALYDECO 聯合用藥研究的問題。我假設安慰劑組的病患、也就是僅使用 KALYDECO 單藥治療的病患，狀況是穩定的。投影片裡沒有這些數據，但我假設在評估期間基本上沒有太大變化，對嗎？

Geoff, it's Jeff Chodakewitz. It's important to step back and say why those patients were in there. It's really -- it was only four patients, as we mentioned, and they were really there for blinding. So we really focused on the within group analysis that you saw. It wasn't really intended as a controlled trial with the placebo group. They were just there so maintaining the integrity of the blind.

Geoff，我是 Jeff Chodakewitz。重要的是先退一步說明為什麼那些病患會被納入。如我們提到的，其實只有四位病患，他們主要是為了盲法（blinding）而設。因此我們真正聚焦的是你所看到的組內分析。這並非原本就要設計成含安慰劑組的對照試驗。他們的存在只是為了維持盲法的完整性。

I see. Okay, that makes sense. And then does this data change your view ultimately about the need for a second corrector and I joined the call a little bit late so I wasn't sure if you guys gave on update on the next-gen corrector behind 661? Thanks.

了解。好，這樣就說得通。那麼，這些數據是否會改變你們對最終是否需要第二個校正劑（corrector）的看法？另外我稍晚才加入電話會議，所以不確定你們是否已更新 661 之後的下一代校正劑進展？謝謝。

Hi Geoff, it's Jeff Leiden. Our view of 661, first of all, has been enhanced by this data. We are learning a lot as we progress 661 and from this trial we learned a couple things. One, that it's possible to correct a single delta-508 allele, at least in these patients with a G551D on the other allele, and second, that you could do that on top of patients who have been stably on KALYDECO for quite a bit of time, most of the patients have been it on for a year or so. And that was an important finding.

嗨 Geoff，我是 Jeff Leiden。首先，我們對 661 的看法因這些數據而更加正面。隨著推進 661，我們學到很多，而從這項試驗我們學到幾件事。第一，至少在這些另一個等位基因帶有 G551D 的病患中，有可能校正單一的 delta-508 等位基因；第二，你可以在那些已穩定使用 KALYDECO 相當長一段時間的病患身上再加用來達成這點，多數病患已使用約一年左右。這是一項重要發現。

We're still thinking about 661 as part of a potential triple regimen to get the enhanced benefit for everybody, that's homozygotes and heterozygotes, but that what this data tells us that 661 one may also have a role in certain of these heterozygous patients and that's worth exploring. You'll remember, we talked about this being an interesting trial from that perspective a while ago.

我們仍在考慮將 661 納入一個潛在的三聯療法，以便讓所有人都能獲得更強的療效提升，包含同型合子與異型合子；但這些數據告訴我們，661 也可能在某些異型合子患者中扮演角色，這值得進一步探索。你會記得，我們之前曾從這個角度談到這是一項很有意思的試驗。

Got you. Okay. Thanks.

了解。好。謝謝。

Geoff Porges, Bernstein.

Geoff Porges，Bernstein。

I'd just like to follow up on the 661 combination. So first, Jeff Chodakewitz, you mentioned the control group, but could you tell us whether there was a difference in the cough, exacerbations, and other adverse events between the control group and the treatment group? And then, secondly, the G551 patients, are they typical of G551D patients? They seem to have a pretty low FEV1 as a starting point in this trial. And then, just to push a little bit more, why wouldn't you be contemplating now taking 661 with the standard dose of KALYDECO into a larger study in the homozygous delta-F508s?

我想就 661 的聯合用藥再追問一下。首先，Jeff Chodakewitz，你提到對照組，但你能否告訴我們，對照組與治療組在咳嗽、急性惡化以及其他不良事件方面是否有差異？其次，G551 的患者是否具有 G551D 患者的典型特徵？在這項試驗中，他們的起始 FEV1 似乎相當低。再進一步追問，為什麼你們現在不考慮把 661 與標準劑量的 KALYDECO 一起，用於 F508del 同型合子患者的更大型研究？

In terms of the placebo patients, again, it was really there for blinding. That's really what our intent was. In terms of the severity, it was a little bit lower, as you said, than perhaps we've seen in some of the studies but it's well within the range and the groups were -- it was pretty balanced and it was really just a -- we think it was really pretty representative of what we've seen in our 551D studies. I'm sorry. Your last question was around--?

就安慰劑患者而言，再次強調，它主要是為了盲法設計。這確實是我們的用意。至於嚴重程度，如你所說，可能比我們在某些研究中看到的略低一些，但仍完全落在合理範圍內，而且各組之間——相當平衡；我們認為它確實很能代表我們在 551D 研究中所見的情況。抱歉。你最後一個問題是關於——？

Why wouldn't you --

為什麼你們不——

Next question is 661, Jeff, and whether we consider going into a larger study for the delta-F508 homozygous?

下一個問題是關於 661，Jeff，以及你們是否考慮在 F508del 同型合子族群進入更大型研究？

For us, really, we think we're just getting this data. We really have to understand it a little bit better. It's early days. We also have the ongoing 12-week study for 661 and ivacaftor in the F508del homozygous population. And what we're going to do is really step back when we get those results and really say, what's the right path forward for 661?

對我們而言，我們其實才剛拿到這些數據。我們確實需要更深入理解它。目前仍是早期階段。我們也正在進行一項為期 12 週、針對 F508del 同型合子族群的 661 與 ivacaftor 聯合用藥研究。我們會在拿到那些結果後再退一步整體評估，並真正決定 661 接下來正確的推進路徑是什麼。

Okay. Look forward to that. Thanks.

好。期待看到結果。謝謝。

Robyn Karnauskas, Deutsche Bank.

Robyn Karnauskas，德意志銀行。

This is Alethia for Robyn. Just another 661 question, but just curious if this information that you have about 661, how does this change your perspective on acquiring or looking at complementary assets for your CF program?

我是 Alethia，代 Robyn 提問。再問一個關於 661 的問題：想請教你們目前掌握的 661 資訊，會如何改變你們對於為 CF（囊性纖維化）專案收購或評估互補性資產的看法？

Jeff's going to take that question in terms of our portfolio approach.

Jeff 會從我們的產品組合策略角度來回答這個問題。

We've said all along that we want to continue our leadership position in CF and that's going to come in two forms. One is to continue to develop our expanding portfolio of medicines, so not only 809 and 661, but next-gen correctors, which we think are going to be very important in both expanding the reach and expanding the benefit.

我們一直以來都說，希望持續維持在 CF 領域的領導地位，而這會以兩種形式呈現。第一是持續開發我們不斷擴充的藥物產品組合，不僅是 809 和 661，還包括下一代校正劑（next-gen correctors），我們認為這些在擴大可及人群與提升療效方面都非常重要。

But the other thing is we have a very active, as you can imagine, ongoing surveillance program of all of the potential other assets out there in CF. And we'll continue to watch that and make sure that we're either partnering, or acquiring, or doing whatever we can to get the best regimens we can in combination with our drugs.

但另一方面，如你所想像，我們也有一個非常積極、持續進行的監測計畫，關注 CF 領域所有其他潛在資產。我們會持續追蹤，並確保我們能透過合作、收購或任何必要方式，取得與我們藥物聯合使用時能形成最佳療法組合的方案。

Great. Thanks.

很好。謝謝。

Mark Schoenebaum, ISI Group.

Mark Schoenebaum，ISI Group。

Thanks for all the detail on the call. I find it helpful, especially the commercial commentary. I just wanted to -- on the placebo issue, would you guys be willing to characterize the behavior of -- I know it's only four -- but would you guys be willing to characterize the behavior of the four placebo patients, maybe give us some reassurance that they didn't behave as well as the treated patients or something like that? Then my second question was in the data where you removed the drug, were both drugs removed or was that just 661? Thanks a lot.

感謝電話會議提供這麼多細節。我覺得很有幫助，尤其是商業面的評論。我想問——關於安慰劑的問題，你們是否願意描述一下——我知道只有四位——你們是否願意描述那四位安慰劑患者的表現，或許讓我們更放心他們的表現並沒有像接受治療的患者那麼好之類的？第二個問題是，在你們移除藥物的那段數據中，是兩個藥都移除，還是只有移除 661？非常感謝。

Thanks, Mark. Sure. Let me try to give you a little more color. Again, it's four patients. I would say that what we observed in those patients was really that there were modest shifting around. It was variable, as you'd expect, in this disease with four patients getting placebo, and it was very typical of what we've seen in general with smaller cohorts of patients receiving placebo. So hopefully that gives you a little better flavor of that.

謝謝你，Mark。當然。我試著補充一些背景說明。再次強調，只有四位患者。我會說，我們在這些患者身上觀察到的，主要是一些幅度不大的波動。如你所預期，在這種疾病中，四位接受安慰劑的患者表現會有變異性；而這也非常符合我們一般在較小安慰劑隊列中所看到的典型情況。希望這能讓你對此有更具體的感受。

So modest would not be 4.6% on an absolute basis, I would imagine?

所以「幅度不大」應該不會是以絕對值計 4.6% 那種幅度吧？我想。

Correct. It's modest changes.

沒錯。是小幅變化。

Thank you.

謝謝。

The other piece in terms of the study design was really that we started and then stopped the VX-661. KALYDECO, which the patients were receiving in the marketed setting, was continued throughout the study. And in the follow-up period, they just stayed on their KALYDECO.

另外，就研究設計而言，我們實際上是先開始使用，之後再停止 VX-661。患者在上市用藥情境下原本就在使用的 KALYDECO，則在整個研究期間都持續使用。在追蹤期，他們也只是繼續使用他們的 KALYDECO。

Great. Thank you.

很好。謝謝。

It's Jeff Leiden. We've obviously had a number of questions on this and on the placebo group. And maybe let me take a step back, if you will, as I often do on these Phase 2 data, and tell you how we look at this data, which is we always look at the entirety of the results and we try to look at it from every direction to see if we're seeing a consistency and to see if we're seeing statistical significance. ¶ When I look at this data, the thing that is very convincing to me is that when you start by looking at what we saw in the lab in cells, which was this additive effect of 661 on KALYDECO in exactly these cells -- G551D, delta-508, that again has translated into what we're seeing in the clinic, and obviously now there were five, six, seven trials like that where the in vitro results translates into [these in vivo results].Then we saw the on effect when we added 661 to the patients who were stable on KALYDECO and, honestly, with only 14 patients, surprisingly we saw a statistically significant on effect.

我是 Jeff Leiden。顯然我們收到了不少關於這點以及安慰劑組的問題。也許我可以退一步，像我經常在談這些第二期數據時那樣，說明我們如何看待這些數據：我們總是看整體結果，並嘗試從各個角度檢視，看看是否呈現一致性，以及是否具有統計顯著性。¶ 當我看這些數據時，最令我信服的是：如果先從我們在實驗室、在細胞中看到的結果開始——也就是 661 在這些特定細胞（G551D、delta-508）中對 KALYDECO 的加成效應——這點已經轉化為我們在臨床上看到的結果；而且顯然現在已有五、六、七項試驗呈現同樣的情況：體外（in vitro）結果能轉化為[這些體內（in vivo）結果]。接著，我們看到在已穩定使用 KALYDECO 的患者加上 661 後的「on effect」，坦白說，在只有 14 位患者的情況下，我們竟然看到了具有統計顯著性的 on effect。

And then of course, the off effect is important. We removed the 661, left the patients on KALYDECO, and we saw a statistically significant decrease and that pattern in the Phase 2 trial is always very important. And then, finally, it correlated with sweat chloride, which always gives us confidence that what we're seeing is an on-mechanism effect. So when I look -- when I walk around the trial and look at it from all perspectives I see a consistency of statistical significance and this nice correlation from in vitro to [in vivo]. That's what really gives us the high level of confidence.

然後當然，「off effect」也很重要。我們移除 661，讓患者繼續使用 KALYDECO，並觀察到具有統計顯著性的下降；而在第二期試驗中，這種模式一向非常重要。最後，它也與汗氯（sweat chloride）呈相關性，這總是能讓我們更有信心，相信我們看到的是符合機轉的效果（on-mechanism effect）。所以當我——當我從各個角度檢視這項試驗時，我看到的是統計顯著性的一致性，以及從體外到[體內]的良好對應關係。這正是讓我們具備高度信心的原因。

Thanks so much.

非常感謝。

Michael Yee, RBC Capital.

Michael Yee，RBC Capital。

A quick question. First, I will ask a question not related to placebo, which is, in your ongoing traffic and transport study, I know they're still thinking about secondary end points and Wall Street is looking at how to evaluate that. Have you done any work around correlating weight gains and exacerbations and how that correlates to FEV1 effects? Obviously, we know what the results were in the KALYDECO monotherapy studies and the effects there and what that translated to for weight gain exacerbations, but given potentially less effect in the delta-508 homozygous population, how do you predict what would happen there where we [find a bit blind]? And I have a follow-up.

一個簡短的問題。首先，我想問一個與安慰劑無關的問題，也就是在你們正在進行的運輸與轉運研究中，我知道你們仍在考慮次要終點，而華爾街也在關注要如何評估它。你們是否做過任何工作，去關聯體重增加與急性惡化（exacerbations），以及這與 FEV1 效果之間的關聯？顯然，我們知道 KALYDECO 單藥研究的結果，以及其效果如何轉化為體重增加與急性惡化，但鑑於在 delta-508 同型合子族群中可能效果較小，你們如何預測在那裡會發生什麼情況，因為我們[有點看不清楚]？我還有一個追問。

It's Jeff Chodakewitz. Let me take a start your question. I don't think we looked, recently at least, at -- in a formal way at correlations between these different measures, but I do think you raise a couple of important points. First of all, that we have to really understand the totality of the disease and really we're assessing the benefit for patients on all of those endpoints.

我是 Jeff Chodakewitz。我先開始回答你的問題。我認為我們最近至少沒有以正式方式去看——在這些不同衡量指標之間的相關性，但我確實覺得你提出了幾個重要觀點。首先，我們必須真正理解疾病的整體面貌，而我們其實是在所有這些終點上評估對病人的效益。

It's really not just about any one of them, but as you imply, it's really about understanding all of them and then understanding the pattern and seeing what benefit the drug [brings]. We do have a set of secondary end points that we have preplanned and prespecified and that's going to include a number of important outcomes, like BMI as you're talking about, in terms of pulmonary exacerbations as well as patient reported outcomes like CF Q-R. So we're really going to take a look good look at all of that and take the time to really understand all the results.

這真的不只是其中任何一個指標，但如你所暗示的，重點是理解所有指標，然後理解其模式，看看藥物[帶來]什麼效益。我們確實有一套事先規劃並預先指定的次要終點，將包含多項重要結果，例如你提到的 BMI、肺部急性惡化，以及病人回報的結果，如 CF Q-R。因此我們會仔細檢視所有這些，並花時間真正理解所有結果。

Okay. And then the follow-up is, I'm sorry I have to sneak in one more, on the placebo [bled palm]. These patients in the study, they knew it was a randomized study versus placebo. They didn't know the exact randomization. I'm just trying to think about how much placebo effect there really would be given the randomization of seven to two?

好的。然後追問是，抱歉我得再塞一個問題，關於安慰劑[手掌出汗]。研究中的這些病人知道這是一個隨機分派、對照安慰劑的研究。他們不知道確切的隨機分派比例。我只是想了解，在 7 比 2 的隨機分派下，實際上會有多少安慰劑效應？

People were informed, of course, that was a placebo-controlled study. The patients knew that and they [formed] informed consent but as is the intent, we were very careful with the placebo so they would not be able to detect which one they were on.

當然，受試者被告知這是一項安慰劑對照研究。病人知道這點，並且[簽署]知情同意；但依照研究設計目的，我們對安慰劑非常謹慎處理，讓他們無法辨識自己使用的是哪一種。

Okay. Thanks.

好的。謝謝。

Terence Flynn, Goldman Sachs.

Terence Flynn，高盛。

First, just was wondering on the -- again, sorry to go back to it, but the placebo group in the 661 combo trial, can you give us any sense of the sweat chloride data in those patients? I know you said it was -- that it sounds like the data bounced around a little bit, but just wondering if you could characterize that on a basis versus what you saw in the treatment group? And then maybe just remind us -- I know you guys had changed the endpoint of the Phase 3 combo study for KALYDECO 809, can you just maybe give us some background there of what drove that decision again? Thanks a lot.

首先，我想問一下——再次抱歉回到這個話題——在 661 聯合試驗中的安慰劑組，你們能否讓我們大致了解那些病人的汗氯（sweat chloride）數據？我知道你們說過——聽起來數據有些波動——但想請你們描述一下，並與治療組所見相比如何？另外也請提醒我們——我知道你們更改了 KALYDECO 809 第三期聯合研究的終點——能否再提供一些背景，說明當初是什麼驅動了這個決定？非常感謝。

Sure. Again, in terms of the sweat chloride in the placebo patients it was quite -- it was variable. There were modest changes. Again, very typical of what you'd expect to see with a small number of patients receiving placebo, and that was true across all the measures.

當然。再次就安慰劑病人的汗氯而言，變異相當——相當大。有一些輕微的變化。同樣地，這非常符合你對少數接受安慰劑病人所預期會看到的情況，而且所有衡量指標都是如此。

Plus even KALYDECO was placebo.

另外，即使 KALYDECO 也是安慰劑。

Sorry. Yes. They received placebo on top of KALYDECO. In terms of the Phase 3 endpoint change, just maybe so I am clear, which -- can you say a little bit more about which aspect of it that you wanted me to comment on?

抱歉。是的。他們是在 KALYDECO 之上再接受安慰劑。至於第三期終點的變更，為了讓我更清楚，你能否再多說一點，你希望我評論的是哪個面向？

Sure. You guys had switched from a relative to an absolute improvement on that [Phase C]. Was just wondering again what drove that decision?

當然。你們把[第三期]的終點從相對改善改為絕對改善。我只是想再問一次，是什麼驅動了這個決定？

Right. We think, in fact, both measures are important. We -- the specifically shifting to absolute was based on a request that we got from the FDA, but we are going to have relative as a key secondary measure. That's really the basis for our change.

對。我們認為事實上兩種衡量方式都很重要。我們——特別改為絕對值，是基於我們收到 FDA 的要求，但我們會把相對值作為一個關鍵的次要衡量指標。這就是我們變更的主要原因。

Brian Abrahams, Wells Fargo.

Brian Abrahams，Wells Fargo。

First question on biology, do you believe that the increase in group FEV1 and the 661 KALYDECO study is due to enhancements of the G551D CFTR function or an action of the combo on the F508del CFTR? And then, just another question on placebo -- sorry about that -- but I realize the study wasn't powered or designed this way, but if you were to do a statistical test on the 661 group versus placebo, just given the variability you described for the placebo and the statistical significance on the in-group effect for the drug arm, would it be safe to say that placebo-adjusted mean FEV1 improvements would have been also been statistically significant? Thanks.

第一個是生物學問題：你們是否相信，在 G551D 的 661 KALYDECO 研究中，組別 FEV1 的上升是因為增強了 G551D CFTR 的功能，還是因為聯合療法對 F508del CFTR 的作用？另外，再一個關於安慰劑的問題——抱歉——我知道研究並非以此為統計效力或設計目的，但如果你對 661 組與安慰劑做統計檢定，考量你所描述的安慰劑變異性，以及藥物組組內效果的統計顯著性，是否可以說經安慰劑校正後的平均 FEV1 改善也會具有統計顯著性？謝謝。

It's Peter speaking. I'll answer the biology question. The belief that we have -- and there is some in vitro data that justifies that is that adding a corrector to the mix enhances trafficking of the CFTR protein to the surface. So part of the additional increase in activity that you see here is basically enhancing the amount of CFTR protein to the surface. When it is on the surface, it also gets potentiated by KALYDECO, so therefore you get basically a double effect. Enhancing, trafficking and--

我是 Peter。我來回答生物學問題。我們的看法——也有一些體外（in vitro）數據支持——是加入一個校正劑（corrector）會增強 CFTR 蛋白運輸到細胞表面的能力。因此你在這裡看到的額外活性增加，有一部分基本上是因為增加了到達表面的 CFTR 蛋白量。當它在表面時，也會被 KALYDECO 增效（potentiated），因此你基本上得到雙重效果。增強運輸以及——

Peter, the question was, do we believe the effect was predominantly on that G551D allele or the 508 allele and we believe the effect was predominantly on the 508 allele from everything we see have seen in vitro.

Peter，問題是：我們是否相信效果主要來自對 G551D 等位基因，還是 508 等位基因；而根據我們在體外看到的一切，我們相信效果主要在 508 等位基因上。

Yes. That's correct.

是的。沒錯。

Jeff, do you want to take the second question? Or the, I don't know, 100th question (laughter)?

Jeff，你要回答第二個問題嗎？或者說，我不知道，第 100 個問題（笑聲）？

I actually think that probably we've covered this quite completely. We think that the important analysis that we've talked about and that's Jeff Leiden has referred to as really the within-group analysis, both in terms of the sweat chloride and FEV1, the on and the off.

我其實認為我們大概已經把這點講得很完整了。我們認為我們已討論過的重要分析——Jeff Leiden 也提到——確實是組內分析（within-group analysis），無論是在汗氯還是 FEV1 上，也就是用藥與停藥的比較。

Okay. Thanks.

好的。謝謝。

Ying Huang, Barclays.

Ying Huang，Barclays。

I'm not going to beat a dead horse by asking about placebo again. First of all, can you tell us, you plan to file R117H indicating here. Is that based on the recent feedback from FDA and also EMA? And then also secondly, also, I noticed that in this trial, you only tested 100 milligram dose for VX-661. Have you determined that, that's going to be the dose you will take VX-661 forward, going into a potential pivotal trial? And then lastly KALYDECO, can you talk to us about the underlying demand by, for example, bottle dispensed in 1Q over 4Q last year, and also maybe patients on therapy, even with though we know there's an inventory drawdown here? Thanks.

我不會再就安慰劑追問個沒完。首先，你能告訴我們，你們計畫在此申報 R117H 適應症。這是基於近期 FDA 與 EMA 的回饋嗎？其次，我也注意到在這項試驗中，你們只測試了 VX-661 的 100 毫克劑量。你們是否已確定這將是你們後續推進 VX-661、進入潛在關鍵性試驗（pivotal trial）的劑量？最後關於 KALYDECO，你們能否談談其潛在需求，例如第一季相較去年第四季的出貨瓶數（bottle dispensed），以及接受治療的病人人數，即使我們知道這裡有庫存去化？謝謝。

It's Jeff Chodakewitz. Let me take the first couple of those and I'll pass it on to Stuart. In terms of the R117H, we can't comment on our discussions with the FDA or speak on behalf of the FDA. As we presented, we think that the data coming out of that study for the patients who were greater than 18 was both statistically and clinically significant, recognizing that we did fail on the primary endpoint and we plan to file based on that analysis and we'll have ongoing dialogue with regulatory agencies.

我是 Jeff Chodakewitz。我先回答前面幾個問題，然後再交給 Stuart。就 R117H 而言，我們無法評論與 FDA 的討論內容，也不能代表 FDA 發言。如同我們所呈現的，我們認為該研究中年齡大於 18 歲患者的數據在統計上與臨床上都具有顯著性；同時也要承認我們在主要終點上未達標。我們計畫基於該分析提出申請，並將與監管機構保持持續對話。

In terms of the dose of 661, it was very early in our program. That was the dose that we studied, but I don't think we're in a position yet to say that we've decided on what a VX-661 dose would be.

至於 661 的劑量，當時在我們的計畫中仍非常早期。那是我們所研究的劑量，但我認為我們目前還不適合說我們已決定 VX-661 的劑量會是多少。

And on revenue, the fourth quarter of 2013 was inflated by some one-off business adjustments. The first quarter was negatively impacted by some of those same impacts such as increased stocking in the fourth quarter. The underlying patient demand is absolutely rock-solid and was very similar in terms of total patients, in terms of compliance, persistence, and all those sort of things between the two quarters.

至於營收，2013 年第四季因一些一次性的業務調整而被墊高。第一季則受到其中一些相同因素的負面影響，例如第四季增加備貨所帶來的影響。基本面的患者需求絕對非常穩固；就總患者數、用藥依從性、持續用藥情況以及各類相關指標而言，兩個季度之間都非常相近。

Thank you.

謝謝。

Katherine Xu, William Blair.

Katherine Xu，William Blair。

(Operator Instructions)

（接線員指示）

Howard Liang, Leerink.

Howard Liang，Leerink。

I have a couple of questions. One science question, the other one commercial. In the lab, can you remind us, did VX-661 have a bigger effect in the G551D F508del heterozygous cells or 508 homozygous cells? How do you think about the difference between G551D, 508 heterozygous versus homozygous? Why a positive signal that you saw here may or may not have read-through for the upcoming traffic transport studies?

我有幾個問題。一個是科學問題，另一個是商業問題。在實驗室裡，能否提醒我們，VX-661 在 G551D/F508del 雜合細胞中的效果較大，還是在 508 純合細胞中較大？你們如何看待 G551D、508 雜合與純合之間的差異？為什麼你們在這裡看到的正向訊號，可能或可能不會對即將進行的 traffic and transport 研究具有可延伸解讀（read-through）的意義？

Howard, it's Jeff. We don't mean to imply that this signal has implications directly that we can read out in the upcoming traffic and transport. So if you heard that, that's certainly not our implication. We believe that there's a lot of data that supports the upcoming traffic and transport results from the in vitro data to the in vivo data and that's really where our confidence comes for from for traffic and transport.

Howard，我是 Jeff。我們並不想暗示這個訊號會直接對即將到來的 traffic and transport 讀出有任何意涵。所以如果你聽起來是那樣，那絕對不是我們的意思。我們相信有大量數據支持即將到來的 traffic and transport 結果，從體外（in vitro）到體內（in vivo）的數據都一致，而我們對 traffic and transport 的信心主要就來自於此。

What we did learn here that was very, very important is the patients who are stably treated on KALYDECO, with all of the benefits they get on the G551D allele who also have 508 on the other allele can see enhanced clinical benefit by adding in a corrector. And that was obviously a big question in our minds -- could you translate that out to an improvement in FEV1 once you'd already fully treated the 551D allele? And the answer from this study is clearly yes and that does have implications for how we think about developing 661, but not the traffic and transport.

我們在這裡學到的一個非常、非常重要的點是：那些在 KALYDECO 上穩定治療的患者，因 G551D 等位基因而獲得所有益處，同時在另一個等位基因上帶有 508 的患者，加入一個校正劑（corrector）後可以看到更強的臨床獲益。這顯然是我們心中的一個重大問題——在你已經把 551D 等位基因充分治療之後，是否還能轉化為 FEV1 的改善？本研究的答案很清楚：可以；這確實會影響我們如何思考 661 的開發，但不涉及 traffic and transport。

Can I just follow-up? Why wouldn't it have read-through to traffic and transport?

我可以追問一下嗎？為什麼它不會延伸解讀到 traffic and transport？

The read-through that we had before, right? In other words, we know that corrector plus potentiator is effective in patients that have Delta F508 alleles and we've seen that in 809 and in multiple studies and five Phase 2 studies and we've seen it now with 661. So if you said we have yet one more study that shows a corrector plus a potentiator can enhance 508 function, yes, it does, but we had a lot of evidence there. Where we didn't have a lot of evidence is what happens when you add a corrector on top of KALYDECO in a 551D with one 508 allele? We just didn't know what was going to happen there. That's really what we learned from this trial.

我們之前所說的延伸解讀（read-through），對吧？換句話說，我們知道「校正劑加增效劑（potentiator）」在帶有 Delta F508 等位基因的患者中是有效的；我們在 809 上看到了，在多項研究與五個第二期試驗中也看到了，現在在 661 上也看到了。所以如果你說我們又多了一項研究顯示校正劑加增效劑可以增強 508 的功能，是的，確實如此，但我們原本就已經有很多證據。而我們缺乏大量證據的部分是：在一位 551D 且另一個等位基因為 508 的患者身上，在 KALYDECO 之上再加一個校正劑會發生什麼事？我們當時真的不知道會怎樣。這正是我們從這項試驗中學到的。

Okay. That makes sense. Can I follow, commercially, most G551D have delta-508 on the other allele, so when you add 661 to KALYDECO, do you expect to realize more revenue per patient, and do you think the market can bear higher costs than KALYDECO?

好的。這樣就說得通了。我想再追問商業面：多數 G551D 在另一個等位基因上是 delta-508，所以當你把 661 加到 KALYDECO 上時，你是否預期每位患者的營收會更高？你認為市場能承受比 KALYDECO 更高的成本嗎？

You're correct, about 70% of them have 508 on the other allele, the G551D patients. In terms of pricing, much too early to talk about that. We literally just got this data in the last few days. The thing we're really excited about is the fact that we appear to be able to be bringing additional benefit to patients who are already doing well on KALYDECO and that's about the maximum take-home you can take right now. It's really much too early to comment on what pricing implications that may have.

你說得沒錯，G551D 患者中約有 70% 在另一個等位基因上帶有 508。至於定價，現在談還太早。我們其實就是在過去幾天才拿到這些數據。我們真正感到興奮的是：看起來我們能為那些已經在 KALYDECO 上表現良好的患者帶來額外的益處；這是你目前能得到的最重要結論。現在評論這可能帶來的定價意涵，真的還太早。

Thanks very much.

非常感謝。

Matt Roden, UBS.

Matt Roden，UBS。

I had 12 placebo questions lined up, but you've answered all (laughter) so I'll ask something else. Congrats on the 661 data point. So if you integrate everything you know about the correctors, all the preclinical and clinical data, do you have any basis for thinking about how the benefit, assuming there is one, changes over time, once you get out past four weeks?

我原本準備了 12 個關於安慰劑的問題，但你們都回答了（笑聲），所以我改問別的。恭喜 661 的數據點。如果把你們對校正劑的所有認知——所有臨床前與臨床數據——整合起來，你們是否有任何依據去思考：假設確實有獲益，當時間拉長、超過四週之後，這個獲益會如何隨時間變化？

We have two four-week observations of combination therapy. I'd like to get your thoughts as to whether or not you think there's a basis for believing the benefit can increase, stay the same, or maybe wane as you go out to 24 weeks past the four-week readout? I know we have to do the experiment, but I'm just wondering if you have a basis for a view on that?

我們目前對聯合療法有兩個為期四週的觀察。我想聽聽你們的看法：是否有任何理由相信，當你把時間拉到 24 週、也就是超過四週讀出之後，獲益可能會增加、維持不變，或可能減弱？我知道必須做實驗才能確定，但我只是想知道你們是否有任何依據形成看法？

I wish I could give you a real data-based answer. I just can't. At this point, what we have is four-week data. The only relevant piece of data I can give is what we know about KALYDECO, right? Which is now we have multiple years, up to four to five years in some patients, some of which has been recently published, in which we're seeing a tremendous stability of the response starting at two weeks and going out multiple years, but obviously that's KALYDECO, that's a potentiator, and unfortunately we just don't have longer data than that.

我希望我能給你一個真正以數據為基礎的答案。但我做不到。目前我們只有四週數據。我唯一能提供的相關數據是我們對 KALYDECO 的了解，對吧？也就是說，我們現在有多年的資料，在部分患者身上可長達四到五年，其中一些最近也已發表；我們看到反應從第二週開始就非常穩定，並可延續多年。但那畢竟是 KALYDECO，那是一個增效劑（potentiator）；很遺憾，我們目前沒有比這更長期的數據。

We'll see the first evidence of this, obviously, with traffic and transport. And then as Jeff said, the 661 plus KALYDECO three-month trial is going to be very, very important. First, obviously, for safety, but also because it's the first time we're going to see that three-month data with 661. Rather than speculate, I'd rather just show you the data when we have it.

我們將會在 traffic and transport 中看到第一個證據，這是很明顯的。然後如 Jeff 所說，661 加 KALYDECO 的三個月試驗將會非常、非常重要。首先，當然是安全性；但也因為這將是我們第一次看到 661 的三個月數據。與其推測，我寧可等我們拿到數據後再向各位展示。

Okay. And then, on the multiple sclerosis remyelinating program, you previously described this as further along than your other pre-clin programs, just wondering if this is something we could see in the clinic this year?

好的。接著，關於多發性硬化症再髓鞘化（remyelinating）計畫，您先前形容這項計畫比其他臨床前計畫更為超前；想請問今年是否有機會在臨床上看到進展？

Matt, you asked the same question on the last call, but yes, we do have program in this area. It is early and there will be a time when we give you more information on that.

Matt，你在上一次電話會議也問了同樣的問題；不過是的，我們在這個領域確實有一個計畫。目前仍處於早期階段，之後會有一個時間點我們會提供更多資訊。

Thanks very much.

非常感謝。

Liisa Bayko, JMP Securities.

JMP Securities 的 Liisa Bayko。

You talked about now exploring a regulatory pathway for the combination of 661 and KALYDECO in that ideal situation where you have someone that responds to KALYDECO -- an allele that responds to KALYDECO and another allele that's 508 -- sorry, another allele that's -- yes, 508. Can you maybe talk about what the patient population size is for that just so we can have a better sense?

您提到目前正在探索 661 與 KALYDECO 聯合用藥的法規申請途徑；在理想情況下，患者對 KALYDECO 有反應——也就是一個等位基因對 KALYDECO 有反應，另一個等位基因是 508——抱歉，另一個等位基因是——對，508。能否談談這類患者族群的規模，好讓我們更有概念？

There's two ways to think about that. One is in the G551D patients where Stuart mentioned before, somewhere between 65% and 70% or so of patients who had G551D on one allele had 508 on the other allele, so that's directly applicable to what we showed today. The other one, though, would be other KALYDECO-responsive allele, such as gating and residual function.

這可以從兩個角度來看。第一個是在 G551D 患者中，如 Stuart 先前提到的，大約有 65% 到 70% 左右的患者在一個等位基因是 G551D 的同時，另一個等位基因是 508，因此這與我們今天展示的內容直接相關。不過第二個角度則是其他對 KALYDECO 有反應的等位基因，例如 gating（閘門型）與 residual function（殘餘功能型）。

So the math that's a reasonable thing to do is to assume around 65% to 70% of all those patients with a KALYDECO-responsive allele on one side will have 508 on the other side. The thing we don't yet know is what is really the numerator there -- how many of all those residual functions are going to be responsive to KALYDECO? That's what we're going to figure out as we begin to get the results from these [other trials]. Did that answer your question okay?

因此，一個合理的估算方式是：假設所有在一側帶有對 KALYDECO 有反應等位基因的患者中，大約有 65% 到 70% 在另一側會是 508。但我們目前還不知道的是，真正的分子（numerator）是多少——也就是在所有那些殘餘功能型之中，有多少會對 KALYDECO 有反應？這就是我們在開始取得這些[其他試驗]結果後要釐清的。這樣有回答到你的問題嗎？

It does. Thank you very much.

有的。非常感謝。

Brian Skorney, Robert W. Baird.

Robert W. Baird 的 Brian Skorney。

Congrats on the data. Very compelling. The only thing I'm questioning -- I thought this was going to be a high hurdle because the patients were always on baseline KALYDECO. I would have expected them to be relatively healthy, but just on the FEV1 measurement, it actually looks like they're sicker than patients who are enrolled in the original KALYDECO Phase 3 study who are on nothing. So can just you help us put us in context how sick these patients really were, even though they were on KALYDECO, and how meaningful the improvement winds up being from the addition of 661?

恭喜這些數據。非常有說服力。我唯一的疑問是——我原本以為這會是一個很高的門檻，因為患者一直都在基礎治療 KALYDECO 上。我原本預期他們相對會比較健康，但從 FEV1 的測量來看，他們看起來其實比原始 KALYDECO 第 3 期研究中未使用任何治療的受試者還要更嚴重。所以能否協助我們理解：這些患者即使在使用 KALYDECO 的情況下，實際上病情有多嚴重？以及加上 661 後的改善幅度最終有多大的臨床意義？

It's Jeff, Brian. First of all, it is a high hurdle, as you said. We were not sure, given that and the fact that a very high proportion of patients who get KALYDECO, respond. We were not sure that we'd be able to show an improvement. In terms of the baseline, when we look back, we do see some variability, again, in terms of where patients end up after a period of time.

Brian，我是 Jeff。首先，正如你所說，這確實是一個很高的門檻。考量到這點，以及接受 KALYDECO 的患者中有非常高比例會有反應，我們並不確定是否能顯示出進一步的改善。就基線而言，回頭看時，我們確實看到一些變異性，亦即患者在一段時間後的狀態會有所不同。

The patient's baseline characteristics here were a little lower, but really not out of the range that we might expect to see. Again, the fact that they were on stable KALYDECO for an average of about a year, as we talked about, that's really -- just emphasizes the high hurdle that the small study had for showing a benefit. And that's why we're enthused about the results.

這裡患者的基線特徵確實稍微低一些，但其實仍在我們可能預期的範圍之內。再者，如我們所談到的，他們平均約一年都在穩定使用 KALYDECO，這點其實——更凸顯這個小型研究要顯示出效益所面臨的高門檻。也因此我們對結果感到振奮。

Okay. Thanks, Jeff.

好的。謝謝你，Jeff。

Ravi Mehrotra, Credit Suisse.

Credit Suisse 的 Ravi Mehrotra。

This is Koon, actually, asking a question on behalf of Ravi. I just wanted to know if you'd comment on the range in the changes you saw in the absolute FEV1 and sweat chloride? Thank you.

其實我是 Koon，代表 Ravi 提問。我想請問您是否能評論一下：您觀察到的絕對 FEV1 與汗氯（sweat chloride）變化幅度的範圍？謝謝。

I really think, as we said, this is really very early results. It's a small study. We're really going to have to continue to evaluate it. We will be presenting the data in a scientific forum in the coming year.

我認為，正如我們所說，這些確實是非常早期的結果。這是一項小型研究。我們確實需要持續評估。我們將在明年於科學會議上發表這些數據。

Okay. Thank you very much.

好的。非常感謝。

Thanks for joining us this evening. And we look forward to catching up with most of you soon.

感謝各位今晚加入。我們也期待不久後能與各位中的大多數再度交流。

Ladies and gentlemen, that does conclude Vertex Pharmaceuticals Incorporated first-quarter 2014 financial results conference call. You may disconnect your lines at this time. Have a great day.

各位女士、先生，Vertex Pharmaceuticals Incorporated 2014 年第一季財務結果電話會議到此結束。您現在可以掛斷電話線。祝您有美好的一天。