福泰製藥 (VRTX) 2013 Q4 法說會逐字稿

Good day, ladies and gentlemen, and welcome to Vertex Pharmaceuticals Fourth 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、先生，大家好，歡迎參加 Vertex Pharmaceuticals 2013 年第四季財務業績電話會議。目前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, this conference call is being recorded. I would now like to hand the conference over to Mr. Michael Partridge, Vice President of Investor Relations. Sir, you may begin.

提醒各位，本次電話會議將被錄音。現在我想將會議交給投資人關係副總裁 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; Stuart Arbuckle, Chief Commercial Officer; and Ian Smith, Chief Financial Officer. Our agenda tonight is as follows: Jeff will begin by reviewing Vertex's strategic business priorities for 2014, then Stuart will discuss fourth-quarter product revenue, and provide some commentary on the outlook for Kalydeco in 2014. To close, Ian will review the full-year 2013 financial results, and our 2014 financial guidance.

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；首席商務長 Stuart Arbuckle；以及財務長 Ian Smith。今晚議程如下：Jeff 將先回顧 Vertex 2014 年的策略性業務優先事項，接著 Stuart 將討論第四季產品營收，並就 2014 年 Kalydeco 的展望提供一些評論。最後，Ian 將回顧 2013 全年財務結果，以及我們 2014 年的財務指引。

Joining us for Q&A will be Dr. Bob Kauffman, Co-Chief Medical Officer; and Dr. Peter Mueller, Chief Scientific Officer. We plan to conclude tonight's call at approximately 5:45 p.m. Please be considerate and limit your questions to one, with a related follow-up.

問答環節將由 Bob Kauffman 博士（共同首席醫療長）與 Peter Mueller 博士（首席科學長）一同參與。我們預計今晚的電話會議將於下午 5:45 左右結束。請各位體諒，將問題限制為一題，並可加上一個相關追問。

I will note that information discussed on the conference call includes forward-looking statements which are subject to the risks and uncertainties discussed in detail in our reports, including our 10-K and 10-Q reports, which have been filed with the Securities and Exchange Commission. These statements, including without limitation those regarding the commercial performance of Kalydeco and Incivek, 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.

我提醒各位，本次電話會議所討論的資訊包含前瞻性陳述，並受我們報告中詳述之風險與不確定性影響，包括已向美國證券交易委員會提交的 10-K 與 10-Q 報告。這些陳述（包括但不限於關於 Kalydeco 與 Incivek 的商業表現、我們的開發計畫與預期，以及我們的指引）係基於管理層目前的假設，並受可能導致實際結果與事件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 fourth-quarter 2013 financial press release. The press release is on our website. I would also refer you to Slide 4 in this webcast. Thank you, and I'll now turn the call over to Jeff.

關於我們使用 GAAP 與非 GAAP 財務衡量指標的資訊，以及 GAAP 與非 GAAP 之間的調節表，已載於我們 2013 年第四季財務新聞稿。該新聞稿已發布於我們的網站。我也請各位參考本次網路直播的第 4 張投影片。謝謝，接下來我把電話交給 Jeff。

Thanks Michael. Good evening. We received approval for Kalydeco for patients six and older with the G551D mutation nearly two years ago. Since that time, we have made significant progress toward our broader goal of treating the vast majority of people with cystic fibrosis.

謝謝 Michael。各位晚安。我們在將近兩年前獲得 Kalydeco 核准，用於 6 歲及以上且帶有 G551D 突變的患者。自那時起，我們在朝向更宏大的目標——治療絕大多數囊性纖維化患者——方面取得了重大進展。

Kalydeco is a transformative medicine. I would like to thank all the patients, families, doctors, nurses, and caregivers who were involved in the treatment of CF for their continued support as we seek to help more people with this devastating disease over the coming year.

Kalydeco 是一款具變革性的藥物。我想感謝所有參與囊性纖維化（CF）治療的患者、家屬、醫師、護理人員與照護者，感謝你們持續的支持；在未來一年，我們將努力協助更多人對抗這種具毀滅性的疾病。

Our strategy is to reach as many people with CF as possible with our medicines, and to enhance the benefit for those that we treat. This will be a very important year for patients for Vertex and for our investors.

我們的策略是透過我們的藥物，盡可能觸及更多 CF 患者，並提升我們所治療患者所獲得的效益。這將是對患者、對 Vertex、以及對我們投資人而言都非常重要的一年。

I would like to briefly review Vertex's strategic priorities and goals for the year. The Management team and I see this year as a year of execution for the Company. If we are successful, this should deliver revenue and earnings growth for Vertex and its shareholders in 2015 and beyond.

我想簡要回顧 Vertex 本年度的策略性優先事項與目標。管理團隊與我將今年視為公司「執行落地」的一年。若我們能成功，這應可在 2015 年及之後為 Vertex 及其股東帶來營收與獲利成長。

This execution has three main components. First, we must remain focused on investing in priority development programs, particularly CF, in order to launch multiple transformative medicines globally in the near future. Secondly, we will continue to invest in early-stage research. Research has been a growth engine for Vertex for many years, and we expect it will produce many of our future medicines, including new clinical candidates in 2014.

這項執行包含三個主要面向。第一，我們必須持續聚焦於投資優先的開發計畫，尤其是 CF，以便在不久的將來於全球推出多款具變革性的藥物。第二，我們將持續投資於早期研究。研究多年來一直是 Vertex 的成長引擎，我們預期它將產出許多未來藥物，包括在 2014 年帶來新的臨床候選藥物。

Finally, we are committed to maintaining financial strength to support investments that create good medicines. We enter 2014 in a strong financial position to invest in our future. We have approximately $1.47 billion in cash, no convertible debt, and Kalydeco revenues that are expected to grow in 2014.

最後，我們致力於維持財務實力，以支持能創造優良藥物的投資。我們以強勁的財務狀況進入 2014 年，得以投資我們的未來。我們約有 14.7 億美元現金、沒有可轉換公司債，且預期 Kalydeco 營收在 2014 年將成長。

During 2013 we worked on each part of our financial platforms -- revenue, expenses, and the balance sheet. On the revenue side, we were able to launch Kalydeco successfully in Europe, and we're now reaching nearly all of the eligible G551D patients ages six and older in both the US and Europe. We expect further growth this year, pending Kalydeco geographic and label expansion.

在 2013 年，我們針對財務平台的各個部分——營收、費用與資產負債表——逐一推進。在營收方面，我們成功於歐洲推出 Kalydeco，目前在美國與歐洲，幾乎已觸及所有符合條件、年齡 6 歲及以上的 G551D 患者。在 Kalydeco 地理覆蓋與適應症標籤擴展獲准的前提下，我們預期今年仍將進一步成長。

From a balance sheet perspective, we converted all $400 million of our convertible debt in 2013. We start 2014 with a significantly stronger net cash position.

就資產負債表而言，我們在 2013 年將全部 4 億美元的可轉換公司債完成轉換。我們以顯著更強的淨現金部位展開 2014 年。

Finally, at the end of the year we restructured the business to provide significant expected savings in our operating expenses going forward, with the reduction of approximately $150 million to $200 million of non-GAAP OpEx in 2014 compared to 2013. We expect our current financial strength to allow us to invest in our key development programs, particularly in CF, and still maintain a strong balance sheet as we exit this year.

最後，在年底我們進行了業務重整，預期可在未來顯著節省營運費用；相較 2013 年，2014 年非 GAAP 營運費用（OpEx）預計將減少約 1.5 億至 2 億美元。我們預期目前的財務實力將使我們能投資於關鍵開發計畫（尤其是 CF），同時在今年結束時仍維持強健的資產負債表。

Looking back at 2013, I am proud of the execution that enabled us to meet or exceed these key goals which are shown on Slide 7 that we shared with you at the beginning of last year. We are outlining our key priorities from the start of 2014 so that you can again measure our performance as the year progresses. You can see these on Slide 8.

回顧 2013 年，我為我們的執行成果感到自豪；這使我們達成或超越這些關鍵目標，這些目標列於我們在去年年初與各位分享的第 7 張投影片。我們在 2014 年一開始就提出關鍵優先事項，讓各位能在年度推進過程中再次衡量我們的表現。各位可在第 8 張投影片看到。

I will point out a couple of things in particular. The Kalydeco label expansion efforts and related clinical data will be an important market of our progress in helping more people with CF. Results from the Phase III traffic and transport studies in the Delta 508 homozygous population that we expect to see mid-year are a key milestone for the Company, potentially enabling us to begin to treat an additional 28,000 patients or more.

我特別指出其中幾點。Kalydeco 的適應症標籤擴展工作及相關臨床數據，將是衡量我們協助更多 CF 患者進展的重要指標。我們預期於年中看到針對 Delta 508 同型合子族群之第三期「交通與運輸」研究結果，這是公司的一個關鍵里程碑，可能使我們得以開始治療額外 28,000 名或更多患者。

We plan to conduct a 12-week Phase II study of VX661 and Ivacaftor in Delta 508 homozygous patients in the first half of this year. Our goal is to potentially position VX661 to play a role in a triple combination with a next-generation corrector in the future. We are pleased that VX661 has now been granted breakthrough therapy designation from the USFDA.

我們計畫在今年上半年，於 Delta 508 同型合子患者中進行一項為期 12 週的 VX661 與 Ivacaftor 第二期研究。我們的目標是讓 VX661 未來有機會在與下一代校正劑的三重合併療法中扮演角色。我們很高興 VX661 現已獲得美國 FDA 授予突破性療法認定。

I had the opportunity to meet with many of our investors and analysts at the JPMorgan conference earlier this month, and I returned from the conference confident that investors and analysts are aligned with our key business priorities for the year. I look forward to speaking with you and updating you as we progress. With that, I will turn it over to Stuart.

本月稍早在摩根大通（JPMorgan）會議上，我有機會與許多投資人與分析師會面；我從會議返程時更有信心，投資人與分析師對我們今年的關鍵業務優先事項已達成一致。我期待與各位交流，並在我們推進過程中向各位更新進展。接下來，我把時間交給 Stuart。

Good evening, everyone. Tonight I am pleased to report our fourth-quarter product revenue, and outline our expectations for Kalydeco in 2014. First, Kalydeco generated $371 million in worldwide net revenues for the full year, and approximately $109 million in net revenues in the fourth quarter, including US sales of $56 million, and international sales of $53 million. These results are a testament both to the transformative nature of the medicine, and the benefit it brings to patients.

各位晚安。今晚我很高興報告我們第四季的產品營收，並概述我們對 Kalydeco 在 2014 年的預期。首先，Kalydeco 全年在全球創造了 3.71 億美元的淨營收，第四季約為 1.09 億美元的淨營收，其中包含美國銷售 5,600 萬美元，以及國際銷售 5,300 萬美元。這些成果證明了該藥物的變革性本質，以及它為病患帶來的效益。

It's worth noting that our fourth-quarter sales include approximately $8 million of inventory build, and one-time business adjustments that we do not expect to be repeated in future quarters.

值得注意的是，我們第四季的銷售包含約 800 萬美元的庫存建立，以及一次性的業務調整；我們預期未來季度不會重複出現。

We are now treating nearly all the eligible G551d patients in the US and EU. We're forecasting growth for Kalydeco revenue in 2014, as outlined in the guidance we provided at JPMorgan, based on the following anticipated key drivers. First, geographic expansion, from securing public reimbursement in Canada and Australia. We estimate that there are approximately 200 eligible G551D patients in Australia, and 100 in Canada. Secondly, label expansion into two potential patient populations. Other non-G551d gating mutations, and R117h patients.

我們目前在美國與歐盟幾乎已治療所有符合資格的 G551D 病患。我們預測 2014 年 Kalydeco 營收將成長，如同我們在摩根大通會議（JPMorgan）所提供的指引，係基於以下預期的關鍵驅動因素。第一，地理擴張，透過在加拿大與澳洲取得公共給付（reimbursement）。我們估計澳洲約有 200 名符合資格的 G551D 病患，加拿大約有 100 名。第二，適應症標籤擴展至兩個潛在病患族群。其他非 G551D 的閘控（gating）突變，以及 R117H 病患。

For the non-G551d gating population, we have submitted an SNDA to the FDA, with a FIDUFA date of March 27. We've also submitted an MAA variation to the EMA for a similar label expansion in Europe, and we are in discussions with regulators about that label expansion. We estimate there are approximately 150 patients in the US, and 200 patients in the EU who are six years and older with these gating mutations. We also see the potential to treat additional patients if we can successfully agree a regulatory path for people with CF who have the R117H mutation.

針對非 G551D 的閘控突變族群，我們已向 FDA 提交 SNDA，PDUFA 日期為 3 月 27 日。我們也已向 EMA 提交 MAA 變更申請，以在歐洲進行類似的標籤擴展，並正與監管機關就該標籤擴展進行討論。我們估計在美國約有 150 名、在歐盟約有 200 名年滿六歲且具有這些閘控突變的病患。若我們能成功就具有 R117H 突變的囊性纖維化（CF）患者取得可行的監管途徑，我們也看見治療更多病患的潛力。

To summarize, we expect these drivers to enable us to grow our Kalydeco revenue beginning in the second quarter, and continuing throughout the year. Our goal as always is to enable patients who could benefit from Kalydeco to access the medicine as fast as possible.

總結而言，我們預期這些驅動因素將使我們自第二季開始推動 Kalydeco 營收成長，並在全年持續。我們一貫的目標是，讓可能受益於 Kalydeco 的病患能以最快速度取得該藥物。

Turning briefly to Incivek. Fourth-quarter revenues in North America were approximately $19 million, bringing the total revenue for 2013 to $466 million. The continued decline in revenue throughout 2013 can be attributed to a decrease in new patient starts, inventory draw-downs throughout the extended channel, and a decrease in the realized price due to a change in the payer mix.

接著簡要談 Incivek。第四季北美營收約為 1,900 萬美元，使 2013 年總營收達 4.66 億美元。2013 年全年營收持續下滑，可歸因於新病患開始治療人數下降、延伸通路（extended channel）中的庫存去化，以及因付款方組合（payer mix）變化導致實現價格下降。

In summary, I am pleased with our results in making Kalydeco available to more patients who may benefit from this medicine, and I look forward to updating you on our continued progress in this area in 2014. I'll now turn it over to Ian.

總結來說，我對我們讓更多可能受益於 Kalydeco 的病患能取得此藥物的成果感到滿意，並期待在 2014 年向各位更新我們在此領域持續的進展。接下來交給 Ian。

Thanks Stuart, and good evening to everyone. Tonight I would like to discuss our current financial position, our 2013 results, and our financial strategies, including our 2014 financial guidance. For a detailed discussion of our 2013 financial results, please refer to our press release we issued earlier today.

謝謝 Stuart，也向各位道晚安。今晚我想討論我們目前的財務狀況、2013 年的結果，以及我們的財務策略，包括 2014 年的財務指引。如需 2013 年財務結果的詳細討論，請參閱我們今天稍早發布的新聞稿。

First to our financial position and the progress we expect to make through this year. As Jeff mentioned, we are entering 2014 with approximately $1.47 billion in cash. This balance-sheet strength, combined with our expected growth in Kalydeco revenues, and other revenue sources, enables us to both invest in our pipeline and products, and still exit the year with a strong balance sheet. Additionally, pending success with our late-stage CF products, we have the potential to generate substantial cash flow and earnings in 2015 and beyond.

首先談我們的財務狀況，以及我們預期今年將取得的進展。如 Jeff 所提到，我們進入 2014 年時，現金約為 14.7 億美元。這樣的資產負債表實力，加上我們預期 Kalydeco 營收成長及其他收入來源，使我們既能投資於研發管線與產品，同時仍能在年底維持強健的資產負債表。此外，若我們的後期 CF 產品取得成功，我們在 2015 年及之後有潛力產生可觀的現金流與獲利。

Now to the 2013 results. We generated $1.2 billion in total revenues in 2013, including $838 million in product revenue. This was made up of $371 million in Kalydeco revenue, and $466 million in Incivek revenue. There are also $157 million in royalty revenues, which includes $131 million in Incivek royalties. Lastly, we recorded an additional $218 million in collaborative revenues, including the $152-million HCV royalty sale to JMJ that we announced in November. Going forward, we will no longer receive Incivo royalties.

接著談 2013 年的結果。2013 年我們創造總營收 12 億美元，其中產品營收為 8.38 億美元。其中包括 Kalydeco 營收 3.71 億美元，以及 Incivek 營收 4.66 億美元。另有權利金收入 1.57 億美元，其中包含 Incivek 權利金 1.31 億美元。最後，我們另認列 2.18 億美元的合作收入，其中包含我們於 11 月宣布出售給 JMJ 的 1.52 億美元 HCV 權利金。展望未來，我們將不再收到 Incivo 的權利金。

Turning now to 2014. We expect our total revenues to be in the range of $570 million to $600 million. We anticipate that this total revenue will be made up of approximately $470 million to $500 million in Kalydeco revenue, which Stuart discussed earlier, and approximately $100 million which includes committed and contracted collaborative revenues, and Incivek revenues.

接著談 2014 年。我們預期總營收將落在 5.70 億至 6.00 億美元之間。我們預期該總營收將由約 4.70 億至 5.00 億美元的 Kalydeco 營收（Stuart 先前已討論）以及約 1.00 億美元所構成；後者包含已承諾與已簽約的合作收入，以及 Incivek 營收。

Now to our operating expense guidance. We anticipate 2014 non-GAAP operating expense to be $900 million to $950 million, a decrease of $150 million to $200 million from our 2013 non-GAAP OpEx of approximately $1.1 billion.

接著是我們的營業費用指引。我們預期 2014 年非 GAAP 營業費用為 9.00 億至 9.50 億美元，較 2013 年約 11 億美元的非 GAAP 營業費用減少 1.50 億至 2.00 億美元。

The operating expense will vary quarter to quarter; however, we expect Q1 2014 to be lower than Q4 2013. We expect the amount to be lower in the second half of this year, given the timing of planned clinical trials and the realization of our previously announced cost reductions.

營業費用將隨季度而變動；然而，我們預期 2014 年第一季將低於 2013 年第四季。考量規劃中的臨床試驗時程，以及我們先前宣布的成本削減逐步反映，我們預期今年下半年金額會更低。

The main components of our non-GAAP operating expenses are R&D expenses and SG&A expenses. Our guidance for these items is $665 million to $695 million, and $235 million to $255 million, respectively.

我們非 GAAP 營業費用的主要組成為研發（R&D）費用與銷售、一般及行政（SG&A）費用。我們對這兩項的指引分別為 6.65 億至 6.95 億美元，以及 2.35 億至 2.55 億美元。

I would now like to give you a break-down of the R&D investments of the Company. First, we plan to maintain our investments in basic research, with approximately $200 million to support the creation of future medicines. This is very similar to our 2012 and 2013 levels. Second, we expect to spend between $380 million and $410 million on late-stage development programs, mainly related to our multiple cystic fibrosis programs. This amount includes significant supply chain investments to prepare for commercial supply for the potential clinical success of Lumacaftor and Ivacaftor combination.

接下來我想為各位拆解公司在研發方面的投資。第一，我們計畫維持對基礎研究的投資，約 2.00 億美元，用以支持未來藥物的創製。這與我們 2012 年與 2013 年的水準非常接近。第二，我們預期在後期開發計畫上投入 3.80 億至 4.10 億美元，主要與我們多項囊性纖維化計畫相關。此金額包含顯著的供應鏈投資，以為 Lumacaftor 與 Ivacaftor 聯合療法在臨床可能成功後的商業供應做準備。

Finally, we expect to spend approximately $85 million on activities and obligations related to Kalydeco. These include safety, pharmaco-vigilance, medical affairs, quality, and the post-marketing commitments.

最後，我們預期在與 Kalydeco 相關的活動與義務上投入約 8,500 萬美元。這些包括安全性、藥物警戒（pharmacovigilance）、醫療事務、品質，以及上市後承諾事項。

Turning now to 2014 SG&A guidance of $235 million to $255 million. We expect a significant reduction in SG&A, compared with $309 million in 2013. This is the result of reduced US sales and marketing expenses for Incivek, as well as a continued focus on limiting spend to only necessary investments to support our CF medicines.

接著談 2014 年 SG&A 指引：2.35 億至 2.55 億美元。相較於 2013 年的 3.09 億美元，我們預期 SG&A 將大幅下降。這是因為 Incivek 在美國的銷售與行銷費用降低，以及我們持續聚焦於將支出限制在僅為支持 CF 藥物所需的必要投資。

Before I close, an item to note in our 2013 results is the asset write-down of VX135 and the related deconsolidation of our relationship with Alios. We are required to review all assets recorded on our balance sheet for potential impairment on a regular basis.

在我結束之前，2013 年結果中有一項值得注意：VX135 的資產減損，以及我們與 Alios 關係的相關除列合併（deconsolidation）。我們必須定期檢視資產負債表上所記錄的所有資產，以評估是否存在減損的可能。

Based on the information we have today, including the clinical data and market data, our assessment with the $250-million carrying value of this asset the process was no longer justified. This impairment and deconsolidation actually results in a gain of approximately $68 million attributed to Vertex, which represents the net of all amounts expensed to date versus the actual cash payments to Alios.

根據我們目前掌握的資訊，包括臨床數據與市場數據，我們評估認為以該資產2.5億美元的帳面價值來看，繼續推進該流程已不再合理。這項減損與去合併實際上為Vertex帶來約6,800萬美元的收益，代表截至目前為止已認列費用的所有金額與實際支付給Alios的現金款項之間的淨額。

Regarding the development of the VX135, our goal is to determine the best way to bring this medicine to patients and maximize the value. We remain in discussions with our two principal collaborators in HTB, Alios and BMS. Discussions are principally focused on the best way to advance this compound as part of our all-oral combinations, and the financial arrangements of each party. We recognize that time is of the essence in this area, and we hope to reach a conclusion on development plans soon.

關於VX135的開發，我們的目標是找出將此藥物帶給病患並使價值最大化的最佳方式。我們仍在與HTB領域的兩個主要合作夥伴Alios與BMS進行討論。討論主要聚焦於：在我們的全口服聯合療法中推進該化合物的最佳方式，以及各方的財務安排。我們理解在此領域時間至關重要，並希望能儘快就開發計畫達成結論。

In summary, we are committed to managing our operating expense at a decreased level compared to prior years, while maintaining our R&D investment to support future product creation, revenue growth, and earnings. We're committed to exiting this year with a strong balance sheet. We are optimistic that 2014 will be a transformative year for patients, for Vertex, and for our investors. With that, I'll ask the operator to please open the line for questions.

總結而言，我們致力於在維持研發投資以支持未來產品創造、營收成長與獲利的同時，將營運費用控制在較以往年度更低的水準。我們也致力於在今年結束時維持強健的資產負債表。我們樂觀認為2014年將是對病患、對Vertex以及對投資人而言具有轉型意義的一年。接下來，我請接線員開放提問。

(Operator Instructions)

(接線員指示)

Geoff Meacham, JPMorgan.

Geoff Meacham，摩根大通。

When you look at the data coming up in CF for Kalydeco monotherapy, and one of the bigger populations is the patients with residual function, my question is what is your early data tell you about the treatment effectiveness population relative to if G551 could be. I'm looking forward, how should we think about what a Phase III would look like, depending on the Phase II outcome?

當你們看囊性纖維化（CF）領域即將公布的Kalydeco單藥治療數據時，其中一個較大的族群是具有殘餘功能的病患；我的問題是，你們的早期數據對於該治療在這個族群的有效性，相較於G551可能的表現，透露了什麼訊息？往前看，依據第二期結果不同，我們應該如何思考第三期試驗可能會是什麼樣子？

This is Bob. Geoff. We haven't really looked at the data from that trial yet. It has not yet been analyzed, so I can't really comment on what we have seen so far. You are familiar with the population of patients who are either pancreatic sufficient or have only a modest (inaudible - background noise) chloride increase, and we will be anxious to see the results and I think our plans will come from there.

我是Bob。Geoff。我們其實還沒有看過那項試驗的數據。目前尚未完成分析，所以我無法就目前看到的情況發表評論。你熟悉那群病患：要嘛胰臟功能足夠，要嘛只有輕度的（聽不清楚—背景噪音）氯離子上升；我們會很期待看到結果，我想我們的計畫也會從那裡出發。

Good. Earlier data on that, when you look at some of your (inaudible) data, (inaudible - technical difficulty) measure the effect size and the (inaudible) activity relative to other mutations?

好的。就較早期的數據而言，當你們看一些（聽不清楚）的數據、（聽不清楚—技術問題）去衡量效應量以及（聽不清楚）的活性，相較於其他突變如何？

Yes, the effect size is in many cases comparable to what we see with the G551D with Kalydeco monotherapy in vitro. We expect that to be in many of the mutations that result in residual function, but we will see a similar level of activity. I will remind you though that we also saw this in R117h, and the results of that study were somewhat complicated, so we're waiting to see the results of the clinical trial of residual function to really get a sense of how to proceed.

是的，效應量在許多情況下與我們在體外看到的G551D病患使用Kalydeco單藥治療的結果相當。我們預期在許多導致殘餘功能的突變中，會看到類似程度的活性。不過我也要提醒你，我們在R117h上也曾看到這種情況，而那項研究的結果相對複雜，所以我們正在等待殘餘功能臨床試驗的結果，以真正掌握接下來該如何推進。

Last one on that, just because of the population being much bigger than G551d or R117h, do you imagine a Phase III would have to be a lot larger. Would this potentially be a 500- or even a 1,000-patient population in terms of the design of the Phase III, or do you feel like you can get this done in a relatively narrow study that would be, for example, like 12 weeks?

最後一個相關問題：因為這個族群比G551d或R117h大得多，你們是否認為第三期試驗必須做得大很多？就第三期設計而言，這是否可能會是500人、甚至1,000人的規模？還是你們覺得可以在相對較小、例如12週的研究中完成？

Yes, I can't really speculate on that, but I will point out obviously we have a fairly large safety database already on Kalydeco monotherapy that we'll be able to utilize to support the safety in this indication also. It is something we will have to discuss with the agency.

是的，我無法就此做太多推測；但我要指出的是，我們在Kalydeco單藥治療上已經累積了相當大的安全性資料庫，可用來支持此適應症的安全性。這是我們必須與主管機關討論的事項。

Geoffrey Porges, Bernstein.

Geoffrey Porges，Bernstein。

Just a quick follow-on question on R117h and then a financial question, Ian. The boundaries of R117h's contribution, is it -- are they in or out -- is R117h in or out of guidance for 2014? What are the potential outcomes of those discussions in terms of revenue contribution? Then Ian, could you clarify how much -- you were very clear about what was in the OpEx, but how much incremental cash burn will you have on top of the OpEx during the year, so we can back into where cash might be at year end? Thanks.

先就R117h追問一個簡短問題，然後再問一個財務問題，Ian。R117h貢獻的界線是什麼——也就是說——R117h是否已納入或未納入2014年的財測指引？就營收貢獻而言，這些討論可能的結果範圍是什麼？另外Ian，你能否釐清一下：你對OpEx包含哪些項目講得很清楚，但今年在OpEx之外，你們還會有多少額外的現金消耗（cash burn），讓我們可以回推年底現金可能落在哪裡？謝謝。

I am going to answer the second question first, Geoff. We haven't given guidance, as you can see, on where we expect our cash position to be at the end of the year. The way that we manage our balance sheet is looking to cash from multiple sources. If you look at the 2013 financials and also when we file our 10-K in a couple of weeks, you'll be able to see that we do get our cash from multiple sources.

Geoff，我先回答第二個問題。如你所見，我們尚未提供指引說明我們預期年底的現金部位會是多少。我們管理資產負債表的方式，是從多個來源取得現金。如果你看2013年的財務報表，以及我們在幾週後提交10-K時，你會看到我們確實有多元的現金來源。

The way that we like to measure our cash burn, and it's one of the reasons why we give non-GAAP guidance is that the non-GAAP loss tends to be a very good proxy for our cash burn. There are some non-cash items in there, but they are both positive and negative, things like option exercise money or capital expenditures.

我們衡量現金消耗的方式——這也是我們提供非GAAP指引的原因之一——是因為非GAAP虧損通常是我們現金消耗的一個非常好的替代指標。其中包含一些非現金項目，但有正有負，例如選擇權行使帶來的資金或資本支出等。

When you step back and look at our financials, what you tend to find is the non-GAAP guidance that we provide equates -- gives an approximate to our cash burn, because we are managing the balance sheet in that way. I will take a look at the K and understand it that way. Then also understand that the non-GAAP is a reasonable approximation.

當你退一步看我們的財務狀況時，通常會發現我們提供的非GAAP指引大致等同——可近似反映——我們的現金消耗，因為我們就是以這種方式在管理資產負債表。我建議你查看10-K並以這種方式理解。同時也請理解，非GAAP是一個合理的近似值。

Right. R117h?

好的。R117h呢？

Yes, if you could just remind me of that question again Geoff?

是的，Geoff，你可以再提醒我一次那個問題嗎？

Yes, is R117h in or out of the guidance for this year? Regardless, what are the potential boundaries of what you might get from your regulatory discussions with R117h and how much that revenue opportunity could be?

是的，R117h今年是否已納入或未納入指引？不論如何，就你們與監管單位針對R117h的討論而言，你們可能取得的結果範圍界線是什麼，以及那個營收機會可能有多大？

There is a piece of 117h in there. Consistent with the communication we made at the end of last year, we want to have a discussion with the FDA regarding a filing opportunity regarding patients 18 and older. We are proceeding ahead there, and somewhat optimistic. We look forward to a contribution from that patient population financially in 2014.

裡面有納入一部分117h。與我們去年底的溝通一致，我們希望就18歲以上病患的申請機會與FDA進行討論。我們正持續推進，且抱持一定程度的樂觀。我們期待該病患族群在2014年能帶來財務上的貢獻。

It's small, because you've got to go through the review period and the approval, and then you've got to launch in that patient population, and it's US-based principally. There is a slight delay of timelines in Europe, so it's a small contribution.

但貢獻會很小，因為你必須經過審查期與核准，之後還要在該病患族群中上市推廣，而且主要是以美國為主。歐洲的時程會稍微延後，所以貢獻不大。

Then I'd take the opportunity to your question, actually, to hand it over to Stuart, and maybe Stuart can give you an idea of how the revenue for Kalydeco builds through this. You can understand how we get to where we provided the guidance.

另外也藉由你的問題，我想把話交給Stuart，或許Stuart可以讓你了解Kalydeco的營收如何逐步建立。你就能理解我們如何達到所提供的指引。

Yes, so Geoff, I think the first thing is probably to ground people on what the run rate is as we exited 2013. As I said, we did $109 million in the fourth quarter, but as I mentioned in my prepared remarks, about $8 million of that was some inventory build towards the end of the year, and some other one-time business adjustments.

是的，所以 Geoff，我認為第一件事大概是先讓大家了解我們在 2013 年結束時的營運基準（run rate）是什麼。如我所說，我們第四季做了 1.09 億美元，但正如我在事先準備的發言中提到的，其中約 800 萬美元是年底前的一些庫存增加，以及其他一次性的業務調整。

Our run rate as we exit 2013 is just north of $100 million a quarter. As I outlined, we've really got two ways that we think we're likely to grow Kalydeco in 2014. The first one is geographic expansion, and we have ongoing discussions regarding reimbursement in Canada and Australia. There have been ongoing for a while, and we continue to be in very active negotiations with both of those reimbursement authorities.

我們在 2013 年結束時的 run rate，每季略高於 1 億美元。如我概述的，我們認為 2014 年 Kalydeco 的成長主要可能來自兩個方向。第一個是地理擴張，我們正就加拿大與澳洲的給付（reimbursement）進行持續討論。這些討論已進行一段時間，我們也持續與這兩個給付主管機關進行非常積極的協商。

We obviously have label expansions in the non-G551d gating. That's filed both in the European Union and here in the US. If successful, we would expect that to contribute to future growth. As Ian said, R117h is in the range of possibility. It's [encomprents] by our current guidance. But clearly we have to have discussions with the regulatory authorities, we have to put filings in, and then certainly in Europe, we've then got to secure reimbursement. As a contributor to our overall revenues in 2014, that's likely to be a very small contribution compared to some of those other growth drivers that I've mentioned.

我們顯然也有在非 G551d gating 適應症上的標籤擴增。這已在歐盟以及美國提出申請。若成功，我們預期這將對未來成長有所貢獻。如 Ian 所說，R117h 在可能範圍之內。它已被我們目前的財測所涵蓋。但很明顯我們必須與監管機關討論、提交申請文件，然後當然在歐洲還必須取得給付。就 2014 年整體營收的貢獻而言，相較於我提到的其他成長驅動因素，這可能只會是非常小的貢獻。

Mark Schoenbaum, ISI.

Mark Schoenbaum，ISI。

(inaudible) sitting in for Mark. Just had -- maybe change the topic a little bit. VX135, a few questions come to mind, but to just to stick to this one, maybe you can give us, if there is an understanding as to the relapse that occurred in the 200mg-plus [decladager] arm, whether there's an understanding as to the reasoning. Was there deep sequencing, was there a possible mutation we are seeing?

（聽不清）代替 Mark 發問。我有——也許稍微換個話題。關於 VX135，有幾個問題浮現，但先聚焦在這一個：你們是否已了解在 200mg 以上（加上 [decladager]）那一組出現復發（relapse）的情況，以及背後原因？是否做了深度定序（deep sequencing），是否可能看到某種突變？

This is Bob. Sequencing is ongoing in that study. We don't have any results yet, so I think we will report those likely at a medical meeting.

我是 Bob。該研究的定序仍在進行中。我們目前還沒有任何結果，所以我想我們可能會在某個醫學會議上公布那些結果。

Rachel McMinn, Merrill Lynch.

Rachel McMinn，Merrill Lynch。

I was a little bit surprised by the R&D numbers. It looks like there is a pretty big step-down there, just the split in OpEx, not the total OpEx. I guess I wanted to -- can you maybe walk through in a little bit more granularity what the -- how to think about that over the course of the year? As a follow up to that on the HCV side, if I'm understanding your comments there, should we assume at this point your guidance contains no HCV expenses, either legacy Telaprevir expenses or for 135? I guess in your ongoing discussions with Bristol, is that like a non-starter for you, you're not spending anything on (inaudible)?

我對研發（R&D）數字有點驚訝。看起來那裡有相當大的下滑，主要是營運費用（OpEx）的拆分，而不是總 OpEx。我想問——你能否更細緻地說明一下，該如何在全年期間理解這個趨勢？另外追問丙肝（HCV）方面，如果我理解你剛才的評論，目前的財測是否可以假設不包含任何 HCV 費用，不論是既有的 Telaprevir 費用或 135 的費用？我想在你們與 Bristol 的持續討論中，對你們而言是否等同於「不會啟動」，也就是你們不會在（聽不清）上花任何錢？

Thank you Rachel, I am scribbling down the questions so I can get to all of them. First of all, the trend of operating expense. I will start by saying what you see is our operating expense in Q4 of 2013. You should see a 5% to 10% decline as we go into Q1 of 2014. Then when you look through the year, it off-loads around based on the timing of certain clinical trials. However it's not significant.

謝謝你，Rachel，我正在把問題記下來，確保能逐一回答。首先談營運費用的趨勢。我先說明，你看到的是我們 2013 年第四季的營運費用。進入 2014 年第一季時，你應該會看到 5% 到 10% 的下降。接著看全年，費用會依某些臨床試驗的時程而有所起伏。不過幅度不大。

We do - we also just anticipate it might be a slightly lower run rate in Q3 and Q4. That's just given the timing of our major trial that we have ongoing with transport and traffic. In summary, there should be a slight tick down in Q1 compared to the prior quarter, and then as we go through the year you should anticipate less in Q3 and Q4, but not significantly.

我們也預期第三季與第四季的 run rate 可能會略低一些。這主要是因為我們正在進行的一項大型試驗在時程上的安排，與 transport 和 traffic 相關。總結來說，第一季相較前一季會小幅下滑；接著全年你應該預期第三、第四季會更少一些，但不會顯著。

As far as the questions on HCV, we have some small cost that we still incur in HCV relating to Telaprevir and those are like post-marketing commitments that unfortunately we're still contracted with the FDA to perform and complete. We actually exclude those as part of the restructuring of HCV so they don't get charged to the P&L. Most of these don't have any future benefits in our perspective, and that's why we don't incur them. Then as far as marketing and sales to the support of Incivek, that is absolutely negligible at this point in time.

至於丙肝（HCV）問題，我們仍有一些與 Telaprevir 相關的小額成本，這些屬於上市後承諾（post-marketing commitments），不幸的是我們仍與 FDA 有合約義務必須執行並完成。我們在丙肝重整（restructuring）中其實把這些排除在外，因此不會計入損益表（P&L）。從我們的角度看，這些大多不會帶來任何未來效益，這也是為什麼我們不會再投入。至於對 Incivek 的行銷與銷售支持，目前絕對可以忽略不計。

Ian, you might want to comment on how we are treating R&D expense for HCV in and out of the budget, we talked about that quite a bit (inaudible - low volume).

Ian，你可能想補充一下我們如何在預算內外處理丙肝的研發費用（R&D expense），我們對此討論了不少（聽不清——音量很低）。

Yes, I'm not sure Rachel. Did I answer your questions?

是的，我不確定，Rachel。我有回答到你的問題嗎？

Hello, can you hear me?

你好，你聽得到我嗎？

We can now.

現在可以了。

HCV, though, with 136. Is that completely out of your future?

不過丙肝方面，關於 136。那是否已完全不在你們未來規劃之內？

Okay, I see. Thank you for clarifying. As we discussed at JPMorgan, our OpEx operating expense guidance of $900 million to $950 million includes $40 million to $50 million. But that's still in there. We are not spending against that, though. I want to be clear on that. We're not spending against that at this point in time as we decide on the direction for the program.

好的，我明白了。謝謝你澄清。如同我們在 JPMorgan 會議上討論的，我們 9 億到 9.5 億美元的 OpEx（營運費用）指引中包含 4,000 萬到 5,000 萬美元。但那部分仍放在裡面。不過我們目前並沒有針對那部分在花錢。我想把這點講清楚。在我們決定該計畫方向之前，目前並沒有動用那筆支出。

As I said in some of my earlier remarks, we are in discussions with both our principal partners in this area, both BMS and Arias. As we work through those discussions, will be back to you -- not only just with the direction, but the impact on our operating expense, if any.

如我先前的一些發言所說，我們正與此領域的兩個主要合作夥伴進行討論，也就是 BMS 與 Arias。當我們推進這些討論後，我們會再回來向各位更新——不僅是方向，也包括（若有的話）對我們營運費用的影響。

Thank you.

謝謝。

We hope it to be soon.

我們希望會很快。

Michael Yee, RBC Capital Markets.

Michael Yee，RBC Capital Markets。

I had a question on 661, and obviously you are starting a Phase II study in homozygous there. It almost is like a small replication of a Phase III. I just wanted to get your updated thoughts on how you view the profile of that drug, and whether you'd expect it to be any different from an efficacy profile versus 809, which we are going to get a Phase III read-in on. The value and read-through, and what can we glean from that data, and whether you would expect that to be after the Phase III data,? Maybe you can run through your thoughts on 661.

我有一個關於 661 的問題，顯然你們正在同型合子（homozygous）族群啟動一項第二期研究。這幾乎像是一個小型的第三期重複驗證。我想聽聽你們對這個藥物特性（profile）的最新看法，以及你們是否預期它在療效表現上會與 809 有任何不同；我們將會看到 809 的第三期讀出。這些資料的價值與可讀性（read-through），我們能從中得到什麼，以及你們是否預期那會在第三期資料之後？也許你可以談談你們對 661 的想法。

This is Bob. The study that we're about to start is a 12-week study, safety, efficacy in PK661 plus Ivacaftor. I think our thoughts about the profile of that compound really haven't changed at all. This is just the next step in the process, and we continue to be quite pleased with the results that we have seen so far with 661.

我是 Bob。我們即將開始的研究是一項 12 週研究，評估 PK661 加上 Ivacaftor 的安全性、療效與藥物動力學（PK）。我認為我們對該化合物特性（profile）的看法其實完全沒有改變。這只是流程中的下一步，而我們對目前為止在 661 上看到的結果仍然相當滿意。

I wouldn't describe it as sort of a prelude to Phase III. It's a stand-alone Phase II-a study. The results will obviously help us going forward.

我不會把它形容為第三期的某種前奏。這是一項獨立的第二期a研究。這些結果顯然會在我們後續推進時提供幫助。

In terms of activity, it is very hard to speculate without seeing the data, but certainly we were pretty happy with the outcome of the 28-day study that we reported last spring. At the same time in vitro we think the activity of 809 and 661 are relatively similar in homozygous HBE cells. But until we see the clinical data with the longer dosing period, I think it's a little bit hard to speculate on that.

就活性而言，在未看到數據之前很難推測，但可以肯定的是，我們對去年春天報告的28天研究結果相當滿意。同時，在體外試驗中，我們認為809與661在同型合子HBE細胞中的活性相對相近。但在看到更長給藥期間的臨床數據之前，我認為要對此作出推測仍有些困難。

Michael, just strategically -- this is Jeff. I will remind you that how we are thinking about 661 as part of the portfolio. The primary way we are thinking about it is eventually as part of a triple, with a first- and second-generation corrector that would allows us to both increase activity in homozygous and potentially, plus pending the data, reach heterozygous, as well.

Michael，從策略角度來說——我是Jeff。我想提醒你我們如何把661視為產品組合的一部分。我們主要的思路是，最終把它作為三聯療法的一部分，搭配第一代與第二代校正劑，讓我們既能提高同型合子患者的活性，也可能——視數據而定——延伸到異型合子患者。

The other potential use of a 661 I guess is as a so-called backup for 809 in double therapy. Once we see the results of 809 next year, then we see the results of this Phase II trial, we will be positioned to give you a lot more strategic information about how we are to proceed.

我想661的另一個潛在用途，是作為809在雙聯療法中的所謂備援方案。等我們明年看到809的結果，再看到這項第二期試驗的結果後，我們就能提供更多關於後續推進方式的策略資訊。

Let me just ask that quick follow up. Obviously, we are planning for success. Were 809 not to work, there is some thinking that 661 would ultimately could still be used in the homozygous setting if you had a dual corrector, not just hetero but homo, so you would just be delayed. Is that the thinking there?

我再快速追問一下。顯然，我們是在以成功為前提做規劃。如果809未能奏效，有一種想法是：若你有雙校正劑，不僅可用於異型合子，也可用於同型合子，那麼661最終仍可能在同型合子情境中使用，只是進度會延後。這就是你們的想法嗎？

Correct.

沒錯。

Yes.

是的。

Matt Roden, UBS.

UBS的Matt Roden。

It's a logical extension of the earlier question on the R&D spend. Presumably if the CF program is positive, you will have more financial flexibility going forward. I was wondering if you can describe the bigger picture how you see a ramping up of R&D efforts again? Where do you get the programs, how fast can you ramp? Generally, what's your vision for R&D longer term?

這是對先前關於研發支出的問題的合理延伸。推測如果CF計畫結果正面，你們未來在財務上會更有彈性。我想請你們描述一下更宏觀的圖景：你們如何看待再次加速研發投入？你們從哪裡取得這些專案、能以多快速度擴張？整體而言，你們對長期研發的願景是什麼？

The vision for R&D, I will leave it to Jeff and Peter to talk about that, but in terms of the investment profile for the Company, we don't see -- we get asked this question frequently, which is if your revenues increased and increased significantly, do you spend more of them in R&D?

研發願景方面，我會交由Jeff和Peter來談；但就公司的投資輪廓而言——我們經常被問到這個問題：如果你們的營收增加且大幅增加，是否會把更多營收投入研發？

The way that we view our financial investments in the area of R&D in the Company right now is on a research basis, we are very comfortable with the level of investment in research. It's been productive and it's produced the pipeline that we have today, and hopefully will continue to provide new clinical candidates.

我們目前看待公司研發領域的財務投入方式是：在研究端，我們對現有的研究投資水準非常滿意。這些投入很有成效，並產出了我們今天所擁有的產品線，且希望能持續提供新的臨床候選藥物。

We see it as a nice profile and we have multiple size, the smaller class that are highly focused in certain areas, and so we don't see a significant change in research investment. From a development perspective, development is a function and really only changes if you are moving into late-stage development with significant trials.

我們認為這是一個不錯的配置輪廓；我們有多種規模的團隊，其中較小的團隊在特定領域高度聚焦，因此我們不認為研究投資會有顯著變化。從開發角度來看，開發支出是一項職能，真正會改變的情況主要是當你進入需要大型試驗的後期開發階段。

Again, it's not a function of a percentage of revenue, it's more of a function of opportunity. If there is the opportunity there that we believe can translate to future medicines, then we will be investing and those drugs.

同樣地，這不是營收百分比的函數，而更是機會的函數。如果存在我們相信能轉化為未來藥物的機會，那麼我們就會投資於那些藥物。

Overall, when you roll this into how we look at the operating expense profile for the Company, we see the ability to drive revenue growth, pending the success of the important trials this year, we really see the opportunity to drive significant revenue growth, while not seeing a significant increase in operating expense.

整體而言，當你把這些納入我們對公司營業費用輪廓的看法時，我們認為在今年重要試驗成功的前提下，我們確實有機會推動顯著的營收成長，同時不需要讓營業費用大幅增加。

We just don't see that, which therefore gives us the leverage from revenues on top of something that may marginally grow on operating expense. But it gives you the opportunity to generate significant earnings and cash flow. That's the profile that we are trying to manage to and be very selective about where we place our investments in R&D. I don't know whether Jeff or Peter want to make comments on R&D vision.

我們確實不認為會那樣，因此這讓我們能在營業費用可能僅小幅成長的情況下，從營收端取得槓桿效應。但這也讓你有機會產生可觀的獲利與現金流。這就是我們試圖管理的輪廓，同時在研發投資的配置上非常審慎、非常有選擇性。我不確定Jeff或Peter是否想對研發願景補充幾句。

Yes, Peter has been doing a lot of nice work on R&D vision and strategy going forward, so maybe Peter you could have a few comments on how you are thinking about that? This has been a very productive organization, but the environment's changing in very interesting ways, and we're going to change with it.

是的，Peter在研發願景與未來策略方面做了很多很好的工作，所以也許Peter你可以談幾點你是如何思考這件事的？這一直是一個非常有產出的組織，但外部環境正以非常有趣的方式改變，而我們也會隨之改變。

I want to be brief because there would be many things to visit what's going on. I think number one Ian phrased it nicely. I think we have a productive R&D research engine that basically produces on a continuous basis molecules, and I have high confidence that that will also happen as we go forward.

我想簡短一點，因為有很多事情可以談。我認為第一點，Ian說得很好。我認為我們有一個高產出的研發研究引擎，基本上能持續產出分子，我對未來也能持續如此很有信心。

Now in terms of focus, I think there is a change in the landscape out there that makes some adjustments necessary as we go forward in the future. It is not systematic regimen any longer that basically drives the show. It is transformational regimen that will drive the show, and driven by outcome and health care, visibility to outcome is basically the new hallmark that you have to shoot for. It drives us into diseases and disease approaches that deliver transformational outcome. That's our key focus, and adds security to what transformation, depending on what disease you are in.

至於聚焦方向，我認為外部格局正在改變，這使得我們未來需要做一些調整。不再是系統性的治療方案來主導全局。將主導全局的是具變革性的治療方案，而且是由療效結果與醫療照護所驅動；對結果的可見性基本上是你必須追求的新標誌。這會驅使我們進入那些能帶來變革性結果的疾病領域與疾病治療策略。這是我們的核心聚焦，也會在不同疾病領域中，為「何謂變革」增添確定性。

We will be very specific to basically look into those type of approaches and mechanisms. As we go forward, that will not be just limited to fundamentals more molecules approaches. There will be broader efforts now in terms of cell therapeutic approaches, gene therapies in any of those that you can imagine. We are currently looking into what might play a role here. In fact, I want a high level of vision. There's always a broader platform into transformational outcomes and diseases of specialty need. That type is what we are shooting for.

我們會非常具體地去檢視這類方法與作用機制。隨著我們往前走，這不會只侷限於以小分子為主的基礎方法。我們也會在細胞治療方法、基因治療等你能想像到的領域，展開更廣泛的努力。我們目前正在評估哪些可能在此扮演角色。事實上，我想提出一個高層次的願景。始終會有一個更廣泛的平台，聚焦於變革性結果以及具有專科未滿足需求的疾病。這就是我們努力的方向。

I appreciate the perspective there. Ian, a quick financial follow-up. You mentioned in the release a couple of weeks ago a $60-million in interest expense in 2014, if I'm not mistaken. I didn't see it today's release. Does that still stand? Can you clarify if that's GAAP or non-GAAP?

我很感謝你們提供這樣的觀點。Ian，我有一個快速的財務追問。你在幾週前的新聞稿中提到2014年有6,000萬美元的利息費用，如果我沒記錯的話。我在今天的新聞稿裡沒看到。這個數字仍然成立嗎？你能澄清那是GAAP還是非GAAP嗎？

Yes, that still stands. It is a GAAP and it's an interest charge the relates to -- well, it's actually a net interest charge, because it's partly -- it's an interest return from our invested capital that's on our balance sheet. It's principally driven by an interest charge on the lease of our building, and that's still there.

是的，仍然成立。那是GAAP口徑，且是一項與——嗯，實際上是淨利息費用，因為其中一部分——是來自我們資產負債表上投資資本的利息收益。主要是由我們大樓租賃的利息費用所驅動，這部分仍然存在。

But it is going to be non-GAAPed out?

但它會在非GAAP中被剔除嗎？

No, we will leave it in. It is a GAAP number.

不，我們會把它保留在內。那是一個 GAAP 數字。

I see. Okay, thank you.

我明白了。好的，謝謝。

Brian Abrahams, Wells Fargo.

Brian Abrahams，富國銀行。

Question for Bob about the long-term strategy in -- at 508 Dell and role of potentiators. What's the latest understanding of the channel-open probability in F508CFTR? I am wondering if your view is multiple correctors such as those within your portfolio could ultimately get the comparable activity without the need for Kalydeco? To that end, I'm wondering if you can give any more specific updates on the second -- the next-generation correctors you are presuming in terms of time line number we'll see move into the clinic this year? Thanks.

想請 Bob 談談 508 Del 的長期策略以及增效劑（potentiators）的角色。目前對 F508CFTR 的通道開啟機率（channel-open probability）最新的理解是什麼？我在想，是否你們投資組合中的多種校正劑（correctors）最終可以在不需要 Kalydeco 的情況下，達到相當的活性？就此而言，我想請你更具體更新一下第二個——你們所預期的下一代校正劑，今年我們會看到多少個、在什麼時間軸進入臨床？謝謝。

This is Bob. Just the last question first is our time line remains what we have said before. We expect to have a clinical candidate by the end of 2014. Depending on how things go there could be more than one clinical candidate, but that is likely the earliest one.

我是 Bob。先回答最後一個問題：我們的時間表仍如先前所說。我們預期在 2014 年底前會有一個臨床候選藥物。視進展而定，可能不只一個臨床候選藥物，但那個很可能是最早的一個。

In terms of the channel-open probability, I think our general outlook at this point is that for F508Del with homozygotes and heterozygotes, the rate-limiting piece of this is the amount of correction that one can obtain, since potentiators are quite active on F508Del AFTR once they get to the cell surface.

至於通道開啟機率，我想我們目前的整體看法是：對於 F508Del 的同型合子與異型合子而言，限制速率的關鍵在於能達到多少校正效果，因為一旦 F508Del CFTR 到達細胞表面，增效劑對其作用相當活躍。

I think our general thinking is we likely will always be in a situation where we are going to be wanting to use a potentiator in combination with a corrector. Since I think just are looking at additive effects of all these molecules on one another. In order to really get substantial CHR activity, we are probably going to need basically three drugs -- two correctors and a potentiator.

我想我們的一般想法是，我們很可能會一直處於需要把增效劑與校正劑合併使用的情況。因為我認為我們看到的是這些分子彼此之間的加成效果。要真正獲得顯著的氯離子通道（CHR）活性，我們大概需要基本上三種藥——兩個校正劑加上一個增效劑。

Lisa Bayko, JMP Securities.

Lisa Bayko，JMP 證券。

Just wanted to get some commentary on what combination you think might be adequate to start targeting the heterozygotes?

想請你們評論一下，你們認為哪種組合可能足以開始鎖定異型合子？

Hi Lisa, it's Jeff. As we have said before, our thinking about this is really informed by the cell biology experiments. You will remember that in those experiments, double correctors -- I'm sorry, corrector plus potentiator, single correctors, 809 plus Kalydeco, 661 plus Kalydeco, really doesn't get you to the chloride transport that has been predictive of good clinical activity. That's been born out even in the clinical experiments we have done in the heterozygotes.

嗨 Lisa，我是 Jeff。如同我們先前所說，我們對此的想法主要是由細胞生物學實驗所驅動。你會記得在那些實驗中，雙校正劑——抱歉，是校正劑加增效劑、單一校正劑，809 加 Kalydeco、661 加 Kalydeco，確實都無法把氯離子運輸提升到可預測良好臨床活性的水準。這點也在我們於異型合子的臨床實驗中得到印證。

In contrast, when you use a first-generation corrector, a second-generation corrector, and Kalydeco, you get the levels of activity in the heterozygous cells that are similar to what you see with the single-corrector 809 plus Kalydeco, and that does read out in the clinic.

相較之下，當你使用第一代校正劑、第二代校正劑以及 Kalydeco 時，你在異型合子細胞中得到的活性水準，與單一校正劑 809 加 Kalydeco 所見相近，而這也能在臨床上反映出來。

That is really the basis of our assumption, that three drugs -- as Bob said, a first-gen corrector, a second-gen corrector and Kalydeco is going to be necessary to reach the heterozygotes, the only exception being those heterozygotes who might be 508 on one [aleo], and Kalydeco-responsive on the other aleo. As you know, we are testing those with the combination of 661 plus Kalydeco right now in a four-week study.

這就是我們假設的基礎：三種藥——如 Bob 所說，第一代校正劑、第二代校正劑與 Kalydeco——將是觸及異型合子所必需的；唯一的例外是某些異型合子可能一個等位基因是 508（原文：[aleo]），另一個等位基因對 Kalydeco 有反應。如你所知，我們目前正以 661 加 Kalydeco 的組合，在一項為期四週的研究中測試這些人。

Thanks. Can you remind us when we might see usage of Kalydeco in patients below age six and for the G551d population? Thanks.

謝謝。可以提醒我們，Kalydeco 何時可能會用於六歲以下患者以及 G551d 族群嗎？謝謝。

That study is supposed to read out in the second quarter and it is on track for that.

那項研究預計在第二季讀出結果，目前進度符合預期。

Thank you.

謝謝。

That's the two- to five-year-old study.

那是針對 2 到 5 歲的研究。

Terence Flynn, Goldman Sachs.

Terence Flynn，高盛。

I was just wondering if you can update us on the IP for the combination, with respect to maybe remind us on composition for 809 and 661, and then any combination patents that you might have? Thanks a lot.

我想請問你們能否更新一下該組合的智慧財產權（IP）狀況：也請提醒我們 809 與 661 的組成物（composition）專利，另外你們是否有任何組合專利？非常感謝。

Principally, the patent protection goes through mid-2020s. I can get the precise years for you, Terence, after we get off the call; but it is principally in the mid and late 2020s.

主要的專利保護會延續到 2020 年代中期。Terence，我可以在電話會議結束後給你精確年份；但主要是在 2020 年代中後期。

I think that is correct. In terms of combination, I think we have five in vitro prospective combination patents.

我想這是正確的。至於組合方面，我想我們有五項以體外（in vitro）為基礎、前瞻性的組合專利。

When would those go out, too? What would be the latest those -- the combo patents would cover to?

那些也會在什麼時候到期？也就是說，那些——組合專利最晚可涵蓋到什麼時點？

It would go to the mid-2020s, Terence. I can take a look at the dates and get back to you later.

會到 2020 年代中期，Terence。我可以再看一下日期，之後回覆你。

Ying Huang, Barclays.

Ying Huang，巴克萊。

Quick one is what should we expect from the four-week Phase II study for the Kalydeco and 661 combo, in one (inaudible) G501d and then one (inaudible) 508Del? Then, can you give us your thoughts about the importance of the secondary end points from the ongoing traffic and transport studies in terms of regulatory approval, and also reimbursement from the payers, such as (inaudible) reduction and (inaudible)? Thank you.

簡短一題：對於 Kalydeco 與 661 的四週第二期研究，我們應該期待看到什麼——一組是（聽不清）G501d，另一組是（聽不清）508Del？另外，你能否談談正在進行的 traffic 與 transport 研究中，次要終點的重要性：就法規核准以及付款方（payer）的給付/報銷而言，例如（聽不清）降低與（聽不清）？謝謝。

Ying to answer the question, I'm going to get Bob to talk to the 508, 551, 661 study, and maybe Stuart will follow up with the secondary (inaudible - background noise) that we're measuring.

Ying，為了回答這個問題，我會請 Bob 談談 508、551、661 的研究，然後也許 Stuart 會接著補充我們正在衡量的次要（聽不清——背景噪音）指標。

Again, we expect to have data in the second quarter on the Phase II study with Kalydeco and 661 in F50EDel, E551d heterozygotes. These are people that are already on Kalydeco commercially, and are enrolled in the study to add 661 on top for four weeks, and a four-week off period. Then the assessment, and we will have the results in the second quarter.

再次說明，我們預期在第二季取得 Kalydeco 與 661 用於 F50EDel、E551d 異型合子的第二期研究數據。這些受試者原本就已在商業用藥上使用 Kalydeco，並納入研究在其基礎上加用 661 四週，接著有四週停藥期。之後進行評估，我們將在第二季得到結果。

On the secondary end points, they're clearly going to be of interest to the regulators. Just to remind you in traffic and transport, we have things like exacerbations and weight gain, hospitalizations, quality of life; so that clearly of interest to the regulators while they still maintain a firm commitment to FUV1 as the primary regulatory end point.

至於次要終點，它們顯然會引起監管機關的興趣。提醒一下，在 traffic 與 transport 研究中，我們包含像是急性惡化（exacerbations）與體重增加、住院、生活品質等；因此這些顯然是監管機關關注的，同時他們仍堅定承諾以 FUV1 作為主要的法規終點。

As far as reimbursement authorities go, I would say they're even more important than FDV1 for a couple of reasons. Firstly, some of these secondary end points are of even more importance to providers and patients. From a payer's perspective, they are also very important that they are important from a cost-avoidance perspective.

就給付/報銷主管機關而言，我會說它們甚至比 FDV1 更重要，原因有幾點。第一，其中一些次要終點對醫療提供者與病患更為重要。從付款方角度來看，它們也非常重要，因為從避免成本的角度而言很關鍵。

If you can reduce exacerbations, if you can reduce hospitalizations, if you can be reducing concomitant medications, then clearly those are important cost offsets. The secondary end points are incredibly important, both from a regulatory point of view and from a reimbursement point of view.

如果你能降低急性惡化、降低住院、減少併用藥物，那些顯然都是重要的成本抵減。次要終點非常重要，無論從法規角度或從給付/報銷角度皆然。

Bob, if I may have a follow up. I guess we should expect additional FEV1 from the four-week study, right? Maybe it's some incremental secondary benefits here?

Bob，如果我可以追問一下。我想我們應該可以期待四週研究會帶來額外的 FEV1，對吧？也許這裡還有一些逐步增加的次要效益？

Not to speculate, but obviously we're clearly looking at FEV1 as one of the read-outs to determine if the combination actually has a benefit over the individual agent. We will see how the results come when we get them.

不做揣測，但很明顯，我們確實把 FEV1 作為其中一個讀出指標，用來判斷該組合是否相較於單一藥物確實有額外效益。等我們拿到結果時，就會看到結果如何。

Robyn Karnauskas, Deutsche Bank.

Robyn Karnauskas，德意志銀行。

Quickly, just to be clear, if you hit your primary end point -- I'm talking about the 809 combo trial. If you hit the primary end point but miss secondary end points, and you maybe believe you won't feel the secure, strong reimbursement or good pricing because you missed the secondary end points, would you wait to file with maybe the combo or the triple?

很快地，為了確認清楚，如果你們達到主要終點——我指的是 809 組合試驗。如果達到主要終點但未達次要終點，而你們也許認為因為未達次要終點而無法獲得穩健、有力的給付或良好定價，你們會不會先不申請，改為等到可能是雙聯或三聯再送件？

The second question is, Ian you mentioned JPMorgan talking about looking at products that are synergistic and additive and competitive. Given the cash position, what kind of deals are you thinking are optimal == licensing, partnership, M&A? Thanks.

第二個問題是，Ian，你提到在摩根大通（JPMorgan）談到要看具有協同、加成以及具競爭力的產品。考量現金部位，你們認為什麼樣的交易最理想——授權、合作夥伴關係，還是併購（M&A）？謝謝。

I'll look for Bob to take the first question in terms of filing with when we meet the primary, if we meet the primary end point, she said.

第一個問題我請 Bob 來回答，關於若我們達到主要終點——如果我們達到主要終點——何時申請送件，她是這麼問的。

Yes. Obviously, we are hoping to hit on more than just the primary end point, but certainly if we hit the primary we will file and bring this medicine to patients who need it.

是的。很明顯，我們希望不只達到主要終點，但當然，如果我們達到主要終點，我們就會送件，並把這個藥帶給需要它的病人。

Robyn, on types of transactions or collaborations that we are looking for, clearly focus right now is on VX509 and VX787, 787 being the molecule for potentially to help with flu. We'll continue to have discussions. In particular, we just received the 20-colleague data with VX509. That allows us to continue those discussions and, as those progress through this year, we will advise you appropriately .

Robyn，關於我們在尋找的交易或合作類型，目前重點很明確是在 VX509 和 VX787 上，其中 787 這個分子可能用於協助治療流感。我們會持續進行討論。特別是，我們剛收到 VX509 的 20 位同事（colleague）資料。這讓我們能夠延續這些討論；隨著今年這些進展推進，我們會在適當時候向各位更新。

Just as a follow-up, just to be clear, if the 809 combination trial -- say you don't hit your secondary end points, would you then potentially begin exploring another homozygous trial with the other combo to maybe secure -- get a drug on the market, or a combo on the market in that population that maybe does have better value to the patient?

再追問一下，為了確認清楚，如果 809 組合試驗——假設你們沒有達到次要終點——你們是否可能開始探索用另一個組合在同型合子族群再做一個試驗，以便更有把握——在那個族群把一個藥或一個組合推上市場，而那個方案對病人可能有更好的價值？

Yes, and if I missed that in your first question, I'm sorry. I thought that's where you're focused. Also, part of our approach to this area is, as we mentioned back at NACF back in October, we're more active than we've ever been in terms of scouring the landscape. We want to look for technologies, assets, molecules, approaches that can be complementary, as well as maybe competitive. We have kind of a learning in this space when we were once in a prior disease. Today as we go out we look around, we do see some opportunities to enhance our position in CF.

是的，如果我在你第一個問題裡漏掉了這點，抱歉。我原以為你關注的是那個方向。另外，我們在這個領域的做法之一是——如同我們在去年十月的 NACF 上提到的——我們在掃描整個版圖方面比以往任何時候都更積極。我們想尋找能互補的技術、資產、分子與方法，也可能包括具競爭性的。我們在這個領域有一些學習，因為我們曾經在先前的一個疾病領域有過經驗。今天當我們向外看、四處評估時，確實看到一些機會可以強化我們在 CF 的地位。

As far as the particular question you were asking me about the 809, Jeff mentioned about the strategy with 661, that not only can that play a role in the triple-regimen where you've got dual correctors, but we also see that as a potential to play as a back-up, if needed.

至於你問我關於 809 的具體問題，Jeff 提到 661 的策略：它不僅能在三聯療法中發揮作用——也就是有雙重校正劑（dual correctors）的方案——我們也把它視為在需要時可作為備援方案的潛力。

I think that strategy, if you have more shots, it's better. We're committed to this disease long term. We think we've got a good understanding of the methods and actions, and how we can get these medicines to patients. We are going to keep going. We are committed to this space, and we think we are doing some incredible things for these patients. We want to broaden our efforts.

我認為這個策略是：如果你有更多次出手機會，就更好。我們長期承諾投入這個疾病領域。我們認為自己對機制與作用方式，以及如何把這些藥物帶給病人，有很好的理解。我們會持續推進。我們承諾深耕這個領域，也認為我們正在為這些病人做一些非常了不起的事情。我們希望擴大我們的努力。

Operator, it's now past our planned stop time for the call. We think we have time for two more questions.

接線員，我們現在已經超過原先規劃的電話會議結束時間。我們認為還有時間再回答兩個問題。

Ravi Mehrotra, Credit Suisse.

Ravi Mehrotra，瑞士信貸。

Thank you for taking my question, which is [Zukuroft] piece, but I'll give it a go. Can you give us any more color on your neurological disorder research efforts, in particular your MS program, specifically whether this program looks at remyelination?

謝謝讓我提問，這題有點像是 [Zukuroft] 的部分，但我還是試著問一下。你們能否多分享一些你們在神經疾病研究方面的進展，特別是你們的 MS 計畫；具體來說，這個計畫是否著眼於再髓鞘化（remyelination）？

I'll just quickly answer that actually, Ravi. it does look to remyelination. It's an early-stage program. It's in pre-clinical. As we progress in all these different areas that we have in research, we'll decide to the cover off at the appropriate time. We look forward to doing that, but yes we do have a program in MS, and it is a remyelination approach.

Ravi，我快速回答一下。是的，確實是著眼於再髓鞘化。這是一個早期階段的計畫。目前在臨床前階段。隨著我們在研究中各個不同領域的進展，我們會在適當的時間點再對外揭露更多細節。我們也期待能那樣做；但答案是，我們確實有一個 MS 計畫，而且是以再髓鞘化為方向的方法。

Katherine Xu, William Blair.

Katherine Xu，William Blair。

Just a very quick question. Now you have patients over six years old off G501d. They're pretty much all on drugs. Just curious, can you disclose the number of patients in the US versus Europe?

一個很快的小問題。現在你們有六歲以上、帶有 G501d 的病人。他們幾乎都已經在用藥。我只是好奇，你們能否揭露美國與歐洲各自的病人人數？

Yes, we think overall there are about 2,200 patients six years and older in the US, Europe, and also in Australia and Canada. As we have said nearly all of those have started therapy in the US and Europe, and we would hope to be able to do something similar in terms of bringing benefit to that same number of patients in Canada and Australia once we've been able to secure public reimbursement.

是的，我們認為整體而言，在美國、歐洲，以及澳洲和加拿大，六歲以上的病人大約有 2,200 人。如同我們所說，這些人在美國與歐洲幾乎都已開始治療；而一旦我們能夠取得公共給付，我們也希望能在加拿大與澳洲以類似方式，讓同樣數量的病人受益。

How much -- how many US versus Europe, each?

那美國與歐洲各是多少——各自的人數呢？

It is roughly a 50/50 split for G551d.

就 G551d 而言，大約是 50/50 的分布。

Thanks everyone for tuning in tonight. Kelly Willis and I are in our offices if you have any additional questions. Have a good night.

感謝各位今晚收聽。如果還有任何問題，Kelly Willis 和我都在辦公室。祝各位晚安。

Ladies and gentlemen, thank you for participating in today's conference. This concludes our program for today. You may all disconnect, and have a wonderful day.

各位女士、先生，感謝參與今天的會議。我們今天的議程到此結束。各位可以掛線，祝您有美好的一天。