福泰製藥 (VRTX) 2016 Q4 法說會逐字稿

Good evening. This is Michael Partridge, Vice President of Investor Relations for Vertex. Welcome to our fourth-quarter and full-year 2016 financial results conference call.

晚安.這是 Vertex 公司投資者關係副總裁 Michael Partridge。歡迎參加我們2016年第四季及全年財務業績電話會議。

(Operator Instructions)

（操作說明）

This call is recorded and a replay of the call will be available later tonight on our website. Dr. Jeff Leiden, Chairman and CEO and Ian Smith, Chief Operating Officer and Chief Financial Officer, will provide prepared remarks this evening. Stuart Arbuckle, Chief Commercial Officer will join us a little later for Q&A. I will remind you that we will make forward-looking statements on this conference call. The statements are subject to the risks and uncertainties discussed in detail in today's press release, our 10-K, and other filings with the Securities and Exchange Commission.

本次通話已錄音，通話回放將於今晚稍晚在我們的網站上提供。董事長兼執行長傑夫萊頓博士和營運長兼財務長伊恩史密斯將於今晚發表準備好的演講。首席商務官斯圖爾特·阿巴克爾稍後將與我們一起進行問答環節。我在此提醒各位，我們將在本次電話會議上發表一些前瞻性聲明。這些聲明受到今天新聞稿、我們的 10-K 表格以及向美國證券交易委員會提交的其他文件中詳細討論的風險和不確定性的影響。

The statements including those regarding the ongoing development and potential commercialization of our drug candidates and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

包括關於我們候選藥物的持續開發和潛在商業化以及Vertex未來財務表現的聲明均基於管理層目前的假設。實際結果和事件可能與此有重大差異。

Information regarding our use of GAAP and non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in the financial results press release. I will also refer you to Slide 4 of tonight's webcast. I will now turn the call over to Dr. Jeff Leiden.

有關我們使用 GAAP 和非 GAAP 財務指標的資訊以及 GAAP 與非 GAAP 的調整表，請參閱財務業績新聞稿。我還想請大家參考今晚網路直播的第 4 張投影片。現在我將把電話交給傑夫·萊頓博士。

Thanks Michael. Good evening everyone. Earlier this month, we met with many of our investors and analysts at the annual JPMorgan healthcare conference, where we outlined our priorities for 2017.

謝謝你，麥可。各位晚上好。本月初，我們在摩根大通年度醫療保健大會上與許多投資者和分析師會面，並在會上概述了我們 2017 年的優先事項。

We have three key goals as we enter the year. First, we remain focused on increasing the number of people eligible for and being treated with ORKAMBI. Our progress toward this goal in 2017, will be measured primarily by achieving reimbursement for ORKAMBI in Europe and by the subsequent growth in our 2017 revenues.

進入新的一年，我們有三個主要目標。首先，我們將繼續專注於增加符合 ORKAMBI 治療條件並接受治療的人數。2017 年，我們將主要透過 ORKAMBI 在歐洲獲得報銷以及 2017 年收入的相應增長來衡量我們在實現這一目標方面取得的進展。

Second, we're advancing multiple potential new medicines for CF that may improve treatment and also provide many more people with the first medicine to address the underlying cause of their disease. Over the coming year we expect to obtain data from across our CF pipeline that will mark our progress toward this goal. And third, we're committed to reinvesting in our pipeline to create future medicines for other serious specialty diseases beyond CF, while creating value for our shareholders.

其次，我們正在推動多種治療囊性纖維化的潛在新藥，這些新藥不僅可能改善治療效果，還能為更多人提供首個針對其疾病根本原因的藥物。在接下來的一年裡，我們預計將從我們的 CF 產品線中獲得數據，這將標誌著我們朝著這個目標的進展。第三，我們致力於對我們的研發管線進行再投資，以開發針對囊性纖維化以外的其他嚴重專科疾病的未來藥物，同時為我們的股東創造價值。

Tonight Ian and I will briefly review some of the key 2017 milestones and activities that support these goals and how our progress will position the Company for continued growth in 2017 and beyond. First to ORKAMBI and our anticipated revenue growth for 2017. With the approval for use in children ages six to 11, ORKAMBI is now approved for approximately 11,000 people with CF in the United States.

今晚，伊恩和我將簡要回顧 2017 年的一些關鍵里程碑和支持這些目標的活動，以及我們的進展將如何使公司在 2017 年及以後繼續保持成長。首先是 ORKAMBI 以及我們對 2017 年營收成長的預期。ORKAMBI 獲準用於 6 至 11 歲兒童，目前在美國已獲準用於治療約 11,000 名囊性纖維化患者。

Similar to the launch in those ages 12 and older, we've seen strong uptake of ORKAMBI in younger patients and believe that physicians recognize the importance of starting treatment as early as possible. Given the large number of eligible children and adults who have already started treatment in the US to date, we expect that further growth for ORKAMBI in 2017 will come primarily from eligible patients initiating treatment in European countries following the completion of reimbursement discussions.

與 12 歲及以上人群的上市情況類似，我們看到 ORKAMBI 在年輕患者中也得到了廣泛認可，並且相信醫生們認識到儘早開始治療的重要性。鑑於迄今為止美國已有大量符合條件的兒童和成人開始接受治療，我們預計 ORKAMBI 在 2017 年的進一步增長將主要來自歐洲國家在完成報銷討論後開始接受治療的符合條件的患者。

Across Europe, we've completed the clinical and health economic assessments of ORKAMBI in key countries and are actively engaged in reimbursement discussions that will enable patients to initiate treatment with ORKAMBI. Importantly, we recently reached a formal reimbursement agreement in Germany that we believe reflects the value that ORKAMBI provides to eligible patients.

在歐洲各地，我們已經完成了 ORKAMBI 在主要國家的臨床和衛生經濟評估，並且正在積極參與報銷討論，這將使患者能夠開始使用 ORKAMBI 進行治療。重要的是，我們最近在德國達成了一項正式的報銷協議，我們認為該協議體現了 ORKAMBI 為符合條件的患者提供的價值。

We expect to conclude additional reimbursement discussions in 2017 and anticipate rapid uptake of ORKAMBI following these reimbursement decisions; which will drive revenue growth beginning this year. We're confident that it is not a question of if we will achieve reimbursement outside the US, but a question of when.

我們預計將在 2017 年完成額外的報銷討論，並預計在這些報銷決定之後 ORKAMBI 將迅速得到推廣；這將從今年開始推動收入成長。我們有信心，在美國以外地區獲得報銷不是能否實現的問題，而是何時實現的問題。

Now to our pipeline of other potential new medicines for CF. Our goal is to create new medicines that treat the underlying cause of CF for all people with the disease. We have potential CF medicines in all stages of research and development and expect to obtain important, value-defining data from across our CF pipeline of eight approved and investigational medicines throughout 2017.

接下來，我們來看看其他可能用於治療囊性纖維化的新藥。我們的目標是研發出能夠治療囊性纖維化根本病因的新藥，造福所有囊性纖維化患者。我們擁有處於各個研發階段的潛在 CF 藥物，並期望在 2017 年全年從我們 8 種已獲批准和正在研究的 CF 藥物產品線中獲得重要的、具有價值意義的數據。

In the first half of this year, we expect to obtain data from the Phase 3 program of tezacaftor in combination with ivacaftor in two large groups of people with CF. Those with two copies of the F508del mutation and those with one copy of the F508del and one copy of a residual function mutation. These data are intended to support an NDA and MAA submission in the second half of this year.

今年上半年，我們預計將獲得 tezacaftor 與 ivacaftor 合併治療 CF 的 3 期臨床試驗數據，試驗對象為兩組大型 CF 患者。攜帶兩個 F508del 突變拷貝的人，以及攜帶一個 F508del 突變拷貝和一個殘餘功能突變拷貝的人。這些數據旨在支持今年下半年提交的NDA和MAA申請。

Additionally, the Phase 3 studies are together expected to enroll more than 1,000 people with CF and will thus provide a robust evaluation of the safety of the tezacaftor/ivacaftor combination; an important consideration for the ongoing development of our triple combination regimens that also contain a next-generation corrector.

此外，預計 3 期研究將招募 1000 多名 CF 患者，從而對 tezacaftor/ivacaftor 組合的安全性進行強有力的評估；這對於我們正在開發的包含下一代矯正劑的三聯療法來說是一個重要的考慮因素。

We have four next-generation correctors currently in clinical development, including two ongoing Phase 2 studies evaluating next generation correctors, VX-440 and VX-152 as part of a triple combination in people with one copy of the F508del mutation and one couple of a minimal function mutation and in people with two copies of the F508del mutation.

我們目前有四種下一代矯正劑正在進行臨床開發，其中包括兩項正在進行的 2 期研究，評估下一代矯正劑 VX-440 和 VX-152 作為三聯療法的一部分，用於治療攜帶一個 F508del 突變拷貝和一對最小功能突變拷貝的患者，以及攜帶兩個 F508del 突變拷貝的患者。

The third next-generation corrector, VX659 is currently being evaluated in a Phase 1 study in healthy volunteers and CF patients and the fourth VX-445 is expected to enter a Phase 1 study next month. Most importantly, we expect to have data in people with CF from three of the studies in the second half of this year. We believe that based on our in vitro data, a triple combination of a next-generation corrector with tezacaftor and ivacaftor could provide benefit for any person with CF who has at least one F508del mutation; approximately 90% of all people with the disease.

第三代矯正劑 VX659 目前正在健康志願者和 CF 患者中進行 1 期臨床試驗評估，第四代矯正劑 VX-445 預計下個月進入 1 期臨床試驗。最重要的是，我們預計將在今年下半年獲得三項研究中囊性纖維化患者的數據。我們相信，根據我們的體外數據，下一代矯正劑與 tezacaftor 和 ivacaftor 的三重組合可以為任何至少攜帶一個 F508del 突變的 CF 患者帶來益處；大約 90% 的 CF 患者都攜帶這種突變。

2017 will be a year of multiple important data events that will inform us as to the potential of our CF pipeline to both enhance treatment and also treat many more people in the years ahead. We look forward to updating you on our progress in CF throughout the year.

2017 年將發生多起重要數據事件，這些事件將讓我們了解我們的 CF 研發管線在未來幾年內既能增強治療效果又能治療更多患者的潛力。我們期待今年內向您報告我們在囊性纖維化方面的進展。

Before turning the call over to Ian to discuss our financial position, I will briefly review the key pillars of our research strategy which is designed to support the creation of future medicines focused on serious specialty diseases that are aligned to Vertex's corporate strategy and core capabilities. First, we're going to focus on validated targets that address the underlying cause of disease, just like we did with CFTR in CF.

在將電話轉交給 Ian 討論我們的財務狀況之前，我將簡要回顧一下我們研究戰略的關鍵支柱，該戰略旨在支持未來藥物的研發，這些藥物專注於嚴重的專科疾病，與 Vertex 的企業戰略和核心能力相一致。首先，我們將專注於已驗證的靶點，以解決疾病的根本原因，就像我們之前針對 CF 中的 CFTR 所做的那樣。

Second, we're committed to developing assays both at the cell level and in humans that predict clinical efficacy. Third, we're only interested in discovering and developing transformative medicines for serious specialty diseases. Taken together, we believe this will allow us to identify rapid paths for clinical trials and registration just as we have in CF.

其次，我們致力於開發細胞層面和人體內的檢測方法，以預測臨床療效。第三，我們只對發現和開發治療嚴重特殊疾病的變革性藥物感興趣。綜上所述，我們相信這將使我們能夠像在 CF 領域一樣，找到臨床試驗和註冊的快速途徑。

With these principles in mind, we've refined our internal research focus to ensure that the types of molecules we may discover in research, would also be the types of medicines that we would seek to develop and commercialize ourselves. Today we are focused on diseases in our research labs that are consistent with these research principles, including Adrenoleukodystrophy, Alpha-1 Antitrypsin Deficiency, Sickle Cell Disease, and Polycystic Kidney Disease.

秉持這些原則，我們改進了內部研究重點，以確保我們在研究中發現的分子類型，也是我們自己尋求開發和商業化的藥物類型。今天，我們的研究實驗室專注於符合這些研究原則的疾病，包括腎上腺腦白質營養不良症、α-1抗胰蛋白酶缺乏症、鐮狀細胞疾病和多囊性腎病變。

We look forward to updating you on these and other similar programs as they progress over the coming years. With that I will now turn the call over to Ian.

我們將在未來幾年內，隨著這些項目和其他類似項目的進展，及時向您報告最新情況。接下來我將把電話交給伊恩。

Thanks Jeff and hello everyone. Tonight I will discuss our fourth-quarter and full-year CF revenues and revenues for ORKAMBI and KALYDECO. We will also review our 2017 financial guidance.

謝謝傑夫，大家好。今晚我將討論我們第四季和全年的 CF 收入以及 ORKAMBI 和 KALYDECO 的收入。我們也將對2017年的財務預期進行審查。

Our total CF product revenues in the fourth quarter of 2016 were $454 million, compared to $401 million for 2015. Our full-year 2016 CF product revenues, were approximately $1.68 billion; a significant increase compared to $982 million for 2015. For ORKAMBI, we reported fourth-quarter 2016 product revenues of approximately $277 million; a significant increase compared to $220 million for the fourth quarter of 2015.

2016 年第四季度，我們的 CF 產品總營收為 4.54 億美元，而 2015 年同期為 4.01 億美元。2016 年全年 CF 產品營收約為 16.8 億美元；與 2015 年的 9.82 億美元相比，成長顯著。ORKAMBI 2016 年第四季產品營收約為 2.77 億美元，與 2015 年第四季的 2.2 億美元相比，成長顯著。

Full-year product revenues for ORKAMBI grew to $980 million in 2016 from $351 million for 2015. 2015 revenues for ORKAMBI reflect two quarters of sales following the approval of the medicine in the US in July 2015. Fourth-quarter KALYDECO sales were $177 million, compared to $181 million for the fourth quarter 2015. Full year product revenues for KALYDECO grew to $703 million for 2016S from $632 million for 2015. Now to operating expenses.

ORKAMBI 2016 年全年產品營收從 2015 年的 3.51 億美元成長至 9.8 億美元。ORKAMBI 2015 年的收入反映了該藥物於 2015 年 7 月在美國獲得批准後的兩個季度的銷售額。KALYDECO 第四季銷售額為 1.77 億美元，而 2015 年第四季為 1.81 億美元。KALYDECO 2016 年全年產品收入從 2015 年的 6.32 億美元成長至 7.03 億美元。接下來是營運費用。

Our fourth-quarter 2016 non-GAAP combined R&D and SG&A expenses were $295 million, compared to $282 million for 2015. Our non-GAAP net profit for the fourth quarter of 2016 was $88 million, or $0.35 per diluted share compared to a non-GAAP net profit of $44 million or $0.18 per diluted share for 2015. From a balance sheet perspective, we ended 2016 with approximately $1.43 billion in cash, cash equivalents, and marketable securities.

2016 年第四季非 GAAP 合併研發及銷售、一般及行政費用為 2.95 億美元，而 2015 年同期為 2.82 億美元。2016 年第四季，我們的非 GAAP 淨利潤為 8,800 萬美元，即每股攤薄收益 0.35 美元，而 2015 年的非 GAAP 淨利潤為 4,400 萬美元，即每股攤薄收益 0.18 美元。從資產負債表的角度來看，截至 2016 年底，我們擁有約 14.3 億美元的現金、現金等價物和有價證券。

As part of the recently announced out licensing agreement with Merck KGaA for our oncology portfolio, we will receive an upfront cash payment of $230 million that would add to our current cash position in the first quarter of 2017, further strengthening our financial position.

作為最近宣布的與默克集團就我們的腫瘤產品組合達成的對外許可協議的一部分，我們將收到 2.3 億美元的預付款，這將增加我們 2017 年第一季的現金儲備，進一步增強我們的財務狀況。

This agreement and the related upfront payment is subject to the expiration of the waiting period under the Hart-Scott-Rodino Antitrust Improvements Act. As we significantly added to our cash position over the recent months, we remain highly focused on reinvestment into our business to support our future growth.

本協議及相關預付款須待《哈特-斯科特-羅迪諾反壟斷改進法案》規定的等待期屆滿後方可生效。由於近幾個月來我們的現金儲備大幅增加，我們將繼續高度重視對業務的再投資，以支持未來的成長。

Internally, this means we will continue to invest in key research programs to create future medicines and externally this means business development efforts will remain focused on bolstering our position in CF expanding our non-CF pipeline with early-stage external assets, and expanding our access to important scientific technologies that could represent transformative future changes to medicine. Now to the financial guidance for 2017, which we discussed in detail in our JPMorgan press release.

從內部來看，這意味著我們將繼續投資關鍵研究項目，以創造未來的藥物；從外部來看，這意味著業務發展工作將繼續專注於鞏固我們在囊性纖維化領域的地位，透過早期外部資產擴展我們的非囊性纖維化產品線，並擴大我們獲取重要科學技術的管道，這些技術可能代表著未來醫學的變革。接下來是 2017 年的財務預期，我們在摩根大通的新聞稿中對此進行了詳細討論。

For ORKAMBI, we expect $1.1 billion to $1.3 billion in total net product revenues. The low end of this range reflects potential revenues from markets where ORKAMBI is currently reimbursed, including the US in eligible patients ages six and older and outside the US, mainly in Germany in eligible patients ages 12 and older.

對於 ORKAMBI，我們預計其產品淨收入總額為 11 億美元至 13 億美元。此範圍的下限反映了 ORKAMBI 目前已獲得報銷的市場（包括美國 6 歲及以上符合條件的患者）以及美國以外（主要是德國 12 歲及以上符合條件的患者）的潛在收入。

The high end of the range reflects an estimate of potential additional European revenues in 2017 that is largely dependent on which European countries complete reimbursement agreements in 2017 and when these agreements become effective. Stated differently, revenue growth for ORKAMBI will be driven primarily by the completion of reimbursement discussions in Europe later this year.

該範圍的高端反映了對 2017 年歐洲潛在額外收入的估計，這主要取決於哪些歐洲國家在 2017 年完成報銷協議以及這些協議何時生效。換句話說，ORKAMBI 的營收成長將主要取決於今年稍後在歐洲完成的報銷談判。

We continue to expect our first-quarter 2017 ORKAMBI revenues will be similar to the fourth quarter 2016, given the majority of eligible patients in the US have initiated treatment. For KALYDECO, we expect $690 million to $710 million in net product revenues; as the majority of all patients eligible for KALYDECO have initiated treatment.

我們仍預期 2017 年第一季 ORKAMBI 的營收將與 2016 年第四季類似，因為美國大多數符合資格的患者已經開始接受治療。對於 KALYDECO，我們預計淨產品收入為 6.9 億美元至 7.1 億美元；因為大多數符合 KALYDECO 治療條件的患者已經開始接受治療。

Further growth for KALYDECO revenues will only be driven by potential US approval for treatment of people with residual function mutations. Additionally, we expect to combine non-GAAP R&D and SG&A expenses of $1.25 billion to $1.3 billion for 2017 compared to $1.2 billion for 2016.

KALYDECO 收入的進一步增長只有在美國獲得批准用於治療具有殘餘功能突變的人群才能推動。此外，我們預計 2017 年非 GAAP 研發及銷售、管理及行政費用總計為 12.5 億至 13 億美元，而 2016 年為 12 億美元。

This reflects investment in our CF pipeline and in our global infrastructure for KALYDECO and ORKAMBI. Our path to treating many more people with CF, which will result in significant and sustained revenue growth, is clear. Importantly, as our revenues grow over future years we are committed to managing our operating expenses to drive earnings and operating margin growth.

這體現了我們對 CF 管道以及 KALYDECO 和 ORKAMBI 全球基礎設施的投資。我們治療更多囊性纖維化患者的道路很清晰，這將帶來顯著且持續的收入成長。重要的是，隨著未來幾年收入的成長，我們將致力於控制營運費用，以推動獲利和營業利潤率的成長。

With that I will open the line to questions.

接下來我將開放提問環節。

(Operator Instructions)

（操作說明）

Matthew Harrison, Morgan Stanley.

馬修·哈里森，摩根士丹利。

Great, good afternoon. I appreciate it. Thanks for taking the question. Can I ask on VX150, not an area that I think a lot of us are as familiar with, can you put in context what you see as the key competitive hurdles and how you plan to further develop that compound?

午安.謝謝。感謝您回答這個問題。關於 VX150，我想請教一下，這可能是我們許多人不太熟悉的領域，您能否介紹一下您認為該化合物面臨的主要競爭障礙是什麼，以及您計劃如何進一步開發該化合物？

This is Jeff, thanks for the question Matthew. This is the first time we've really spent a lot of time talking about this, the clinical results. To start off and take a step back and remind you that pain is an enormous indication, actually multiple indications around the world. There been a novel pain mechanism of action in 40 or 50 years and obviously the recent attention of some of the side effects of pain medicines like opioids has made that even a more urgent problem.

我是傑夫，謝謝你的提問，馬修。這是我們第一次花這麼多時間討論這個問題，也就是臨床結果。首先，讓我們退後一步，提醒大家疼痛是一個非常重要的徵兆，實際上在世界各地都是多種徵兆。在過去的四、五十年裡，出現了一種新的止痛機制，顯然，最近人們對阿片類藥物等止痛藥的一些副作用的關注，使得這個問題變得更加緊迫。

You probably also know that the Nav channels are interesting because both Nav1.7 and 1.8 have been validated genetically in humans. Meaning that patients who have homozygous lost function mutations in 1.7 really don't feel any pain, as those are the famous firewalkers, and patients who have various gain of functions in 1.8 have hyper acute pain syndromes.

您可能也知道，Nav 通道很有趣，因為 Nav1.7 和 1.8 都已在人類身上得到基因驗證。這意味著，在 1.7 中具有純合功能喪失突變的患者實際上感覺不到任何疼痛，因為他們就是著名的火行者，而 1.8 中具有各種功能獲得突變的患者則患有超急性疼痛綜合徵。

So one of the reasons they are exciting to us is they fit the Vertex strategy of having a validated target in an area of large unmet need, where if you had a medicine that could have that pain efficacy without the pain side effects some of the others you'd obviously have a very important new medicine for patients. So that's the background.

因此，它們讓我們感到興奮的原因之一是它們符合 Vertex 的策略，即在存在巨大未滿足需求的領域中擁有已驗證的目標，如果你有一種藥物可以具有止痛功效，而沒有其他一些藥物的疼痛副作用，那麼你顯然就擁有了一種對患者來說非常重要的新藥。以上就是背景狀況。

We have been working on 1.7 and 1.8 actually for some time in our San Diego labs. This is the first one of those molecules we're bringing forward, 150 to 1.8 inhibitor, and in this study which was a double-blind randomized placebo-controlled crossover study, which is I think the most powerful study in pain because of the placebo effects.

實際上，我們在聖地牙哥的實驗室裡已經研究 1.7 和 1.8 版本一段時間了。這是我們推出的這類分子中的第一個，150 至 1.8 抑制劑，這項研究是一項雙盲隨機安慰劑對照交叉研究，我認為這是疼痛領域最有力的研究，因為安慰劑效應。

What we saw was a statistically significant reduction in pain using the WOMAC scale and also a number of other secondary end-points that were all consistent with that. And a tolerability profile that actually looked quite good in 124 patients. So that tells us that it works in this chronic OA pain. Again that's very different as you know from acute pain and it's very different from neuropathic pain.

我們看到，使用 WOMAC 量表評估的疼痛有統計學意義上的顯著降低，許多其他次要終點也與此一致。在 124 名患者中，耐受性表現看起來相當不錯。這說明它對這種慢性骨關節炎疼痛有效。如你所知，這與急性疼痛非常不同，也與神經性疼痛非常不同。

So in order to fully understand the profile of this molecule our plan is to take it forward in a couple more exploratory studies. One in acute pain starting this year and then one in neuropathic pain probably starting later this year or early next year. When we have the results from those, we'll really understand what we have here.

因此，為了充分了解該分子的特性，我們的計劃是再進行幾項探索性研究。其中一人今年開始出現急性疼痛，另一人可能在今年稍後或明年年初出現神經性疼痛。等我們拿到這些結果後，我們才能真正了解我們這裡的狀況。

And then we can really make decisions about how to bring it forward to patients most quickly. Eyeing these different indications, what our involvement would be, what the potential involvement with the partner might be, et cetera. All those questions are a little bit premature. The thing you should really take away is, it's yet another novel mechanism of action potentially transformative medicine to come out of our labs and because of that and the large unmet need, we're excited about it.

然後我們就可以真正決定如何以最快的速度將這項技術推廣給患者。考慮到這些不同的跡象，我們的參與方式是什麼，與合作夥伴的潛在參與方式是什麼等等。這些問題現在問還為時過早。你應該記住的是，這是我們實驗室研發的又一種具有變革意義的新型作用機制藥物，正因為如此，再加上目前存在巨大的未滿足需求，我們對此感到非常興奮。

And just for clarity, why not move it ahead in OA right now? Is it because of the competitive landscape or because of commercial considerations including partnering?

為了更清楚地說明，為什麼不現在就在 OA 中推進呢？是因為競爭環境，還是因​​為包括合作在​​內的商業因素？

Yes great question. I think in pain, at least the experiences that I've had in my career is you really want to understand the molecule fully to understand how you develop it to it's fullest potential for patients. And while we could take it forward in OA now, which is a large study and actually would probably not be consistent with our commercializing it, I think we're going to create a lot more value if we first fully understand the mechanism across the three different types of pain and then we can make a really rational development plan. I still think we have a nice competitive position even when we do that.

問得好。我認為，至少就我職業生涯中的經驗而言，在疼痛治療方面，你真的需要充分了解分子，才能了解如何將其開發到最大潛力，造福患者。雖然我們現在可以將其應用於骨關節炎研究，這是一項大型研究，實際上可能與我們的商業化目標不符，但我認為，如果我們首先充分了解三種不同類型疼痛的機制，然後製定一個真正合理的開發計劃，我們將創造更大的價值。即使我們那樣做，我仍然認為我們擁有良好的競爭地位。

Okay, great thanks.

好的，非常感謝。

Geoff Meacham, Barclays.

巴克萊銀行的傑夫·米查姆。

Afternoon, thanks for taking the questions. When you look at the 661 combo data in the first half is it more important in the near term to have a new product cycle for ORKAMBI or are you thinking about this as being the cornerstone of a triple?

下午好，謝謝回答問題。從上半年的 661 組合數據來看，近期內對 ORKAMBI 而言，推出新的產品週期更為重要，還是將其視為三重奏的基石？

Is it more of a focus on limiting bronchoconstriction rather than higher FEV1. I have a follow-up too.

是否更注重限制支氣管收縮，而不是提高 FEV1？我還有一個後續問題。

Thanks Geoff. As you know, we've always talked about 661 as having at least three goals. One, exactly as you said is, if it had an enhanced benefit tolerability profile in the Delta-F508/double 508's that are currently being treated by ORKAMBI, I think that would be important because we do have a subset of those patients that had not been able to tolerate ORKAMBI due to respiratory effects and we'd be able to reach more of those patients with such a combo.

謝謝傑夫。如你所知，我們一直認為 661 至少有三個目標。一正如你所說，如果它能提高目前接受 ORKAMBI 治療的 Delta-F508/雙 508 患者的耐受性，我認為這將很重要，因為我們確實有一部分患者由於呼吸系統副作用而無法耐受 ORKAMBI，而這種組合療法將使我們能夠惠及更多此類患者。

The second purpose really is around those patients who are on KALYDECO monotherapy because they have regaiting and residual function mutation. Remember 90% of those patients have a Delta-F508 on the other allele. So if you could add tezacaftor to ivacaftor in those patients and produce enhanced benefit that would obviously be very, very important for those patients.

第二個目的實際上是針對那些接受 KALYDECO 單藥治療的患者，因為他們有恢復功能和殘餘功能突變。請記住，90% 的患者在另一個等位基因上都有 Delta-F508。因此，如果能將 tezacaftor 添加到 ivacaftor 中，並對這些患者產生增強的療效，那麼對這些患者來說顯然是非常非常重要的。

And you will remember that we actually published a Phase 2 study a couple of years ago, in a small number of patients but it was impressive in that it showed that adding tezacaftor to ivacaftor in those patients added an additional about 4.6% increase in FEV1. And that was a significant result. If we can reproduce that in our residual function and in gaiting mutations in this larger study, that's going to be very important for that population of patients and somewhat important competitively as well, since we tried to move most of those patients onto the double regimen.

您可能還記得，我們​​幾年前發表了一項 2 期研究，雖然患者人數不多，但結果令人印象深刻，研究表明，在這些患者中，在 ivacaftor 的基礎上加用 tezacaftor 可使 FEV1 額外增加約 4.6%。這是一個意義重大的結果。如果我們能夠在這項更大的研究中，在殘餘功能和門控突變中重現這一點，這對該患者群體來說非常重要，而且在競爭方面也具有一定的意義，因為我們試圖將大多數患者轉移到雙重治療方案中。

And then the final one, just as you said, is it the basis for the triple regimen. And here were going to have 1,000+ patients of safety data in particular on 661 plus ivacaftor, meaning that two of the three components would have been fully vetted in our combination and we would only have to add the one component, the next-gen corrector, which we think moves that program ahead considerably and also gives us a pretty nice competitive advantage. So I think about it with those three different perspectives and frankly all of them are important but anyone of them could be successful.

最後一點，正如你所說，是三重療法的基礎。我們將獲得 1000 多名患者的安全數據，特別是關於 661 加 ivacaftor 的數據，這意味著我們組合中的三個成分中的兩個已經過全面驗證，我們只需要添加一個成分，即下一代矯正劑，我們認為這將大大推進該項目，並給我們帶來相當不錯的競爭優勢。所以我從這三個不同的角度思考這個問題，坦白說，這三個角度都很重要，但任何一個角度都有可能成功。

Got you and Jeff I know you have talked about the productivity of your technology, when you look at generating new correctors. What would you say is the optimal number of leads or backups? Should we expect to see more going into Phase I? Just that JPM, obviously you added 445 to the pipeline but is four next-gen enough?

我知道你和傑夫討論過你們的技術在產生新的校正器方面的生產力。您認為最佳的潛在客戶或備用客戶數量是多少？我們是否應該預期會有更多項目進入第一階段？摩根大通，顯然你們在管道中增加了 445 個，但是四個下一代產品就足夠了嗎？

I mentioned that we literally have hundreds of these now. Obviously we're not going to bring hundreds forward into the clinic. We're bringing forward molecules that we think have particularly interesting and advantageous property compared to what is there.

我提到過，我們現在實際上有數百台這樣的機器。顯然，我們不可能把數百人送到診所。我們正在研發一些我們認為與現有分子相比具有特別有趣和有利特性的分子。

My hope is that at some point, maybe relatively soon, we will stop because one of these looks very, very good as it goes through Phase 2 and we're ready and off to the races and it's going to be hard to improve on it. Sort of like KALYDECO was as an example, but until we see the data I'm just happy to have multiple swings at the ball and I think you can expect potentially to see even another one come this year depending on the data that we start to generate.

我希望在某個時候，也許不久的將來，我們會停止研發，因為其中一款產品在第二階段的表現非常非常出色，我們已經準備就緒，即將投入生產，很難再有改進的空間了。就像 KALYDECO 那樣，但在我們看到數據之前，我很高興能有多次嘗試的機會，而且我認為，根據我們開始生成的數據，今年可能會出現另一個這樣的球員。

Okay, great thanks.

好的，非常感謝。

Michael Yee, RBC Capital Markets.

Michael Yee，加拿大皇家銀行資本市場。

Thanks, I have two questions. One is following up on 661, on the efficacy side of the equation, do you have confidence that it's at least as good as ORKAMBI? And if it was not for some reason, given there's only been short-term studies, is there a rationale for not filing in that situation and using it as a triple? If it was lower would that change your confidence on the triple overall?

謝謝，我有兩個問題。一是跟進 661，就療效而言，您是否有信心它至少與 ORKAMBI 一樣好？如果不是因為某些原因，考慮到目前只有短期研究，那麼在這種情況下不提交申請並將其用作三重申請的理由是什麼？如果賠率更低，會改變你對三連勝整體的信心嗎？

And then the second follow-up question is, you are mentioning a lot of comments around business development which we appreciate are you pretty focused on very early stage stuff or should we be not be surprised if you do something different than early stage? Thanks so much.

第二個後續問題是，您提到了許多關於業務發展的評論，我們對此表示讚賞。您是比較專注於早期階段的業務，還是說如果您從事與早期階段不同的業務，我們也不應該感到驚訝？非常感謝。

Yes Mike, this is Jeff, I'll take the first one and then Ian could take the BD question. With respect to 661 and efficacy, the reason we're doing the study is to get the final answer in a large number of patients but the reason we're doing the study is that our Phase 2 data did support the notion that it had an efficacy profile that was as good or better than ORKAMBI. And we're going to find out in a larger group of patients for longer now.

是的，麥克，我是傑夫，我來回答第一個問題，然後伊恩可以回答BD問題。關於 661 和療效，我們進行這項研究的原因是為了在大量患者中獲得最終答案，但我們進行這項研究的原因是我們的 2 期數據確實支持了這樣一種觀點，即它的療效與 ORKAMBI 一樣好或更好。接下來，我們將對更大規模的患者群體進行更長的研究，以找出答案。

With respect -- I think you're sort of asking what would be a positive or what would be a good result as I interpret your question. A good result to me would be a drug that's approvable with an enhanced benefit tolerability profile in one of those groups of patients that I told you about. That would be a success and a safety database that was consistent with taking it forward as part of the triple.

恕我直言——我認為您似乎是在問，什麼樣的結果才算是正面或好的結果。對我來說，好的結果就是研發出一種藥物，它能夠獲得批准，並且在我之前提到的那幾類患者中具有更高的療效和耐受性。那將是一項成功，並且是一個與將其作為三重方案的一部分推進相一致的安全資料庫。

Michael to your BD question, as I have said many times on this call, it's really a three-pronged approach. Firstly, we look at most things pretty much everything that's involved with cystic fibrosis that maybe complementary to how we're progressing our own medicines and we usually get the opportunity to work with a lot of those, let's call them other ideas internally in our labs in San Diego and run them through our assays so we get a pretty good look at how to progress in the area of CF. That is number one priority.

Michael，關於你的業務拓展問題，正如我在這次通話中多次提到的，這實際上是一個三管齊下的方法。首先，我們會研究幾乎所有與囊性纖維化相關的事物，這些事物可能與我們自身藥物研發的進展相輔相成。我們通常有機會在聖地牙哥的實驗室內部研究許多這類想法，並透過我們的檢測方法進行測試，以便更好地了解如何在囊性纖維化領域取得進展。這是頭等大事。

Secondarily, I would say that last couple of years we have also understood how we may expand our scientific footprint in a couple of markers for progression there, the two deals recently one with Moderna Therapeutics and the other with CRISPR for gene editing. And they've allowed us different modalities, different approaches to solving some of the problems we're trying to solve.

其次，我想說，在過去的幾年裡，我們也了解如何擴大我們在幾個發展標誌上的科學影響力，最近達成的兩項協議分別是與 Moderna Therapeutics 的合作和與 CRISPR 基因編輯公司的合作。它們為我們提供了不同的模式、不同的方法來解決我們正在努力解決的一些問題。

And then to your point there is a third leg to our BD approach in corporate development and that is potentially in licensing, potentially smaller M&A but it's really focused on early stage. Our priorities today in the business as I said is about growing our -- as well as growing revenues but growing our cystic fibrosis franchise and expanding scientific modalities. Then if we can expand our efforts into other diseases, we will at the right time.

正如您所說，我們在企業發展方面的業務拓展方法還有第三個方面，那就是可能涉及許可，也可能涉及規模較小的併購，但它真正關注的是早期階段。正如我所說，我們今天的業務重點是發展壯大——除了增加收入外，還要發展我們的囊性纖維化業務，並擴展科學療法。如果時機成熟，我們將把研究範圍擴大到其他疾病領域。

Okay. Thanks that's helpful. I appreciate it.

好的。謝謝，這很有幫助。謝謝。

Brian Abrahams, Jefferies.

Brian Abrahams，傑富瑞集團。

Hi thanks very much for taking my questions. Two questions, first, I wonder if you had any updated sense of how compliance, persistence, and tolerability in the six- to 11-year-olds compares to adults? And secondly, I know you've mentioned the NDA for tezacaftor and KALYDECO would include data from the het/min study that was discontinued.

您好，非常感謝您回答我的問題。我有兩個問題，首先，我想知道您是否了解 6 至 11 歲兒童的服從性、堅持性和容忍度與成年人相比的最新情況？其次，我知道您曾提到 tezacaftor 和 KALYDECO 的新藥申請將包括已終止的 het/min 研究的數據。

Just wanted to follow up whether at this point you had received the data and if you could potentially provide any general sense as to trends on lung function or biomarkers or perhaps rates of AE's, including bronchoconstriction, how those looked relative to prior ORKAMBI Phase 2 and the het/min population.

我想跟進一下，您目前是否已收到數據，以及您是否可以提供一些關於肺功能或生物標記趨勢，或者不良事件發生率（包括支氣管收縮）的總體情況，以及這些情況相對於之前的 ORKAMBI 2 期試驗和 het/min 人群的情況如何。

Brian this is Stuart here, I'll take the question on six-to-11 compliance and persistence and really it's too early to tell in that population in terms of actual data from the real world as it were. There are some reasons to be optimistic that it could potentially be better than in the 12-plus population. A couple of reasons for that, one we know from the clinical data that we have generated for the six-to-11 population that we do see less of the respiratory adverse events that we know were so important to some of the early discontinuations we saw with ORKAMBI in the adult population.

Brian，我是Stuart，我來回答關於6到11歲人群的依從性和堅持性的問題，就現實世界中的實際數據而言，現在判斷這一人群的情況還為時過早。有一些理由讓我們樂觀地認為，它可能會比 12 歲以上人群的情況更好。原因有二：一是我們從針對 6 至 11 歲人群產生的臨床數據中了解到，呼吸系統不良事件發生率較低，而這些不良事件正是我們在 ORKAMBI 成人人群中觀察到的一些早期停藥的重要原因。

In addition, we also know from KALYDECO indeed for many other chronic therapies that compliance in the six-to-11 patient grew not surprisingly because of the parental supervision tends to be as high as it is if not higher than it is in any other patient group. So we don't have actual data really that's mature in the real world but I think there are some reasons to be optimistic that it could be higher than in the adult population. And for the second part of your question, I'll hand that over to Jeff.

此外，我們也從 KALYDECO 中了解到，對於許多其他慢性病治療而言，6 至 11 歲患者的依從性有所提高，這並不奇怪，因為家長的監督往往與其他任何患者群體一樣高，甚至更高。所以，我們還沒有真正成熟的現實世界數據，但我認為有一些理由樂觀地認為，兒童的盛行率可能高於成年人口的盛行率。至於你問題的第二部分，我將交給傑夫回答。

Brian, I think the second part of your question was around het/min data from the tez/iva trial. Yes. We have seen that data. By the way the data Safety Monitoring Board has also evaluated that data, at some point we will publish it. I am not going to go into detail, I would just say there were no new or concerning safety signals seen in that population of a little over 100 patients.

Brian，我認為你問題的第二部分是關於 tez/iva 試驗中的 het/min 數據。是的。我們已經看過這些數據了。順便一提，資料安全監測委員會也對這些數據進行了評估，我們會在某個時候公佈評估結果。我不打算詳細說明，我只想說，在這100多名患者中，沒有發現任何新的或令人擔憂的安全訊號。

Thank you.

謝謝。

Terence Flynn, Goldman Sachs.

特倫斯·弗林，高盛集團。

Hi, thanks for taking the question. Maybe first just on Stuart to follow up can you tell us what's embedded in your ORKAMBI guidance for assumptions on persistence and adherence in the younger population?

您好，感謝您回答這個問題。首先，Stuart，能否請您跟進一下，您在 ORKAMBI 指南中針對年輕人群的堅持性和依從性假設有哪些？

Terence, I'm actually going to take that question. We provided guidance for ORKAMBI at JPMorgan as you know and that was $1.1 billion to $1.3 billion. The assumptions that are underneath the model, we'll be more toward provide you with revenue guidance and then also updating you on timing as we gather reimbursement at the different markets.

特倫斯，我正好要回答這個問題。如您所知，我們曾為摩根大通的 ORKAMBI 提供業績指引，目標金額為 11 億至 13 億美元。模型背後的假設，我們將更傾向於向您提供收入指導，然後在我們收集不同市場的報銷款項時，也會向您更新時間表。

Just a quick commentary to the $1.1 billion to the $1.3 billion though. The $1.1 billion that's the low end of our guidance range. It's principally from the US market that does assume some growth in the six-to-11 population but also does assume there are some loss of patients due to the chronic nature of this medicine.

不過，我想簡單評論一下11億美元到13億美元之間的差額。11億美元是我們預期範圍的下限。主要來自美國市場，該市場確實假設 6 至 11 歲人群會有一些成長，但也假設由於這種藥物的慢性性質，會有一些患者流失。

And then the growth beyond the $1.1 billion up towards the $1.3 billion and potentially above it if it's possible, will be driven by European reimbursement and approvals in the different markets and a key contributor to the growth of the revenue line in 2017 would be France.

然後，超過 11 億美元並有望達到 13 億美元甚至更高（如果可能的話）的成長，將受到歐洲報銷和不同市場批准的推動，而法國將是 2017 年收入成長的關鍵貢獻者。

Okay thanks Ian. Then just one on the pipeline, I think you are expecting VX371 plus ORKAMBI Phase 2 data in the mid-point of the year maybe just help remind us what you want to see to move forward with that combination or assuming you would move forward with 371 plus 661 KALYDECO?

好的，謝謝伊恩。那麼，目前只有一個在研項目，我想您預計 VX371 和 ORKAMBI 二期臨床試驗數據將在年中公佈，或許您可以提醒我們一下，您希望看到哪些數據才能推進該組合的研發，或者假設您會推進 371 和 661 KALYDECO 的研發？

I will take that Terence. First of all, I appreciate you recognizing that it was a transaction that we did in terms of an in-licensing because there was something that's going to one the questions that was earlier on the call, where we were able to scan the landscape for CF medicines and we were able to work with Parion Sciences and we saw in vitro by putting the ENaC inhibitor together with our own medicines we actually an additive benefit in our in vitro assay.

我接受那個，特倫斯。首先，感謝您認識到這是我們透過許可引進方式完成的交易，因為之前在電話會議上有人提出了一個問題，那就是我們能夠對囊性纖維化藥物市場進行調查，並與 Parion Sciences 合作，我們在體外試驗中發現，將 ENaC 抑製劑與我們自己的藥物結合起來，實際上在體外試驗中獲得了額外的益處。

That's why we moved forward with that transaction. We are happy to say we are now in Phase 2 where we are studying the ENaC inhibitor with our ORKAMBI combination in 508/508 patients and we expect that data in the second half of the year.

這就是我們推進那筆交易的原因。我們很高興地宣布，我們目前已進入 2 期臨床試驗階段，正在對 508/508 名患者進行 ENaC 抑制劑與 ORKAMBI 聯合用藥的研究，預計將在今年下半年獲得相關數據。

Data to move forward obviously we would want to see a proof of concept of the combination of the ENaC inhibitor with ORKAMBI in the 508/508 patient and we'll be looking for risk-benefits and progressing based on that proof of study concept.

顯然，為了推進研究，我們希望看到 ENaC 抑制劑與 ORKAMBI 在 508/508 患者身上聯合應用的概念驗證，我們將根據該研究概念驗證結果來評估其風險效益並推進研究。

Okay, thanks a lot.

好的，非常感謝。

Cory Kasimov JPMorgan.

科里·卡西莫夫，摩根大通。

Good afternoon, thanks for taking a question. I actually have two of them for you as well. First of all, now that the list price has been published in Germany, can you discuss how that may or may not impact or facilitate pricing discussions with other European countries and then the follow-up is when we could perhaps expect to start hearing of progress on the gene editing and/or mRNA fronts. Thanks.

下午好，謝謝您回答問題。我這裡其實也有兩個給你。首先，既然德國已經公佈了定價，您能否討論一下這可能會如何影響或促進與其他歐洲國家的定價討論？其次，我們什麼時候才能開始聽到基因編輯和/或mRNA的進展？謝謝。

Sure Corey. As we've said we have come to a pricing agreement with general authorities at the back end of last year, which became public in the middle of this month and we're pleased to have reached that point with the German authorities.

當然可以，科里。正如我們所說，我們在去年年底與相關部門達成了一項定價協議，該協議於本月中旬公開，我們很高興與德國當局達成了這項協議。

In terms of the impact it's likely to have on other negotiations, well firstly it shows that we are able to come to an agreement with a very major market in Europe. It certainly puts a benchmark out there in terms of a price because that price is in the public domain and I hope it's certainly going to encourage governments in the interests of the patients in their countries who were waiting to get access to this great medicine that it's going to encourage them to act with a sense of urgency.

就其可能對其他談判的影響而言，首先，這表明我們能夠與歐洲一個非常重要的市場達成協議。這無疑為價格設定了一個基準，因為這個價格是公開的，我希望這能夠促使各國政府為了本國等待獲得這種有效藥物的患者的利益，採取緊迫的行動。

Exactly what that means quantitatively, is really very hard to say, but hopefully it encourages other governments to act as the German government has.

這在數量上究竟意味著什麼，真的很難說，但希望這能鼓勵其他國家政府效法德國政府的做法。

And Corey I'll take the second part on gene editing and mRNA therapy, as you remember with the CRISPR collaboration in gene editing its a multi-indication collaboration. We have six indications that we can choose from, we have announced two; which is CF and hemoglobinopathies. You've probably seen that CRISPR has recently announced their intention to try to get the hemoglobinopathy program into the clinic later this year.

Corey，我將回答關於基因編輯和mRNA療法的第二部分。你還記得，CRISPR基因編輯合作是一項多適應症合作。我們有六種適應症可供選擇，目前已發表兩種：囊性纖維化和血紅素疾病。你可能已經看到，CRISPR 最近宣布他們打算在今年稍後嘗試將血紅蛋白病計畫推向臨床。

We have been really pleased with how that's going. That's obviously a bit of an easier problem because it affects the [emo] gene editing. We're continuing to work on CF and as we get products that we think are approaching the clinic, we will start to tell you about them. It was somewhat similar with Moderna, Moderna has been a more recent collaboration where we are looking at CF only right now and as we get products that actually we believe to move into the clinic, we will start to give you updates on some of those time lines.

我們對目前的進展非常滿意。這顯然是一個比較容易解決的問題，因為它涉及[emo]基因編輯。我們正在繼續研究囊性纖維化，一旦有我們認為即將進入臨床階段的產品，我們會開始向大家介紹。與 Moderna 的情況也有些類似，Moderna 是我們最近才開始合作的，目前我們只關注囊性纖維化領域，一旦我們有了真正認為可以進入臨床試驗的產品，我們會開始向大家提供一些時間表方面的更新。

Okay, thank you.

好的，謝謝。

Mark Schoenebaum Evercore ISI

Mark Schoenebaum Evercore ISI

Hi, thanks for taking the question. I was wondering back on ORKAMBI could you just give us an update as to where you are in French negotiations and remind us how big that market is? I think the news on 150 is great today, so just a question to make -- reduce my workload because I'm lazy, is there anything else outside of CF that we could see this year that could pop up like this that we should be aware of and thanks for everything while I was out. Thanks for helping out my team.

您好，感謝您回答這個問題。我想問一下，ORKAMBI，您能否向我們介紹一下您在法國的談判進展，並提醒我們法國市場有多大？我覺得今天關於 150 的消息很棒，所以我想問一個問題——因為我比較懶，所以想減少我的工作量，除了 CF 之外，今年還有什麼其他類似的事情可能會出現，我們應該注意的嗎？感謝我在不在期間所做的一切。感謝你幫助我的團隊。

Mark, first of all this is Jeff, welcome back that's most importantly. I am going to let Stuart answer your first question. I will come back on your second one.

馬克，首先這位是傑夫，歡迎回來，這才是最重要的。我將讓斯圖爾特來回答你的第一個問題。我會回覆你的第二個問題。

Mark, in terms of where we are in France. As you know these negotiations, while they are different country by country, all follow the same process, they have clinical benefit assessment, a health technology assessment, and then a pricing negotiation and in France, as with most of the other markets in the EU we are in that third phase of negotiations with France; talking about the specific pricing and reimbursement parameters, so that's the phase that we are in right now.

馬克，就我們目前在法國的位置而言。如您所知，這些談判雖然因國家而異，但都遵循相同的流程，包括臨床效益評估、健康技術評估，然後是定價談判。在法國，與歐盟大多數其他市場一樣，我們目前正處於與法國談判的第三階段；討論具體的定價和報銷參數，這就是我們目前所處的階段。

And we're looking forward to trying to bring those to a successful conclusion for the patients in France, many of whom are already enjoying the benefits of ORKAMBI.

我們期待著為法國的患者們成功完成這些治療，其中許多患者已經享受了 ORKAMBI 的好處。

Let me take the second part of your question mark. I don't want to steal all our thunder. We like some of these surprises but just give you a little bit of a survey of the landscape.

讓我來解答你問號的後半部。我不想搶走我們所有的風頭。我們喜歡這些驚喜，但也想先簡單介紹一下狀況。

First of all as you know out-licensed our flu compound to J&J. They have been progressing that compound nicely and so is it possible over the next year or so you'll start to hear some more proof of concept there, we're obviously going to let them speak for the time lines but I think it's possible. Oncology, we just out-licensed four assets to Merck KGaA. One of those is in Phase 2 and again depending on how they progress the program, I think you could hear some proof of concept there.

首先，如您所知，我們已將我們的流感化合物授權給強生公司。他們一直在穩步推進該化合物的研發，因此在接下來的一年左右的時間裡，你可能會聽到更多相關的概念驗證。當然，具體時間表由他們自己決定，但我認為這是可能的。在腫瘤領域，我們剛剛將四項資產授權給了默克集團。其中一個專案處於第二階段，根據他們推進專案的進度，我認為你可能會在那裡聽到一些概念驗證。

The proof of concept -- most important thing for us is going to be the proof of concept studies with the next-gen correctors, which you will definitely hear in the second half of this year. And then I would say stay tuned for maybe another program or two to enter the clinic this year but we are going to surprise you with those.

概念驗證－對我們來說最重要的是下一代矯正器的概念驗證研究，你們肯定會在今年下半年聽到相關消息。然後我想說，敬請期待今年可能還有一兩個項目進入診所，但我們會給大家帶來驚喜。

Take care. Thanks.

小心。謝謝。

Geoffrey Porges, Leerink Partners.

Geoffrey Porges，Leerink Partners。

Thanks very much for taking the question. Stuart or Ian could you give us a breakout of revenue for KALYDECO and ORKAMBI, US and ex-US? And then the updated patient starts for the two products if you will? And then secondly just going back to the 150 and the pain target.

非常感謝您回答這個問題。Stuart 或 Ian，能否提供我們 KALYDECO 和 ORKAMBI 在美國和美國以外地區的收入明細？那麼，更新後的患者資料就開始用於這兩種產品了嗎？其次，回到150和疼痛目標。

I'm looking at your own pipeline strategy criteria Jeff and wondering how developing a treatment for osteoarthritis fits with these criteria, particularly given the target, it's early stage, it's really a widespread disease, it's a chronic indication. So should we assume that ultimately that that might be a partnering candidate as well given that strategic focus?

Jeff，我正在研究你的產品線策略標準，想知道開發骨關節炎的治療方法如何符合這些標準，特別是考慮到目標族群，它處於早期階段，這是一種非常普遍的疾病，而且是一種慢性疾病。鑑於這一戰略重點，我們是否應該假設它最終也可能是一個合作夥伴候選人？

So Geoff I will answer on the US, ex-US split. In Q4 of the $177 million that we reported for the fourth quarter, $101 million of that was in the US, $76 million of that was ex-US, so that's the KALYDECO Q4 numbers and that was essentially the same split for the full year. For ORKAMBI of the $277 million in Q4, $248 million of that was US and $29 million of that total was ex-US.

那麼，傑夫，我將回答關於美國和前美國分裂的問題。第四季度，我們報告的營收為 1.77 億美元，其中 1.01 億美元來自美國，7,600 萬美元來自美國以外地區。以上是 KALYDECO 第四季的數據，全年的收入組成基本上相同。ORKAMBI 第四季營收為 2.77 億美元，其中 2.48 億美元來自美國，2,900 萬美元來自美國以外地區。

And the 150 question, it's -- I think your question was about strategic fit and commercialization, sort of divided into two parts. There is our research strategy, that you probably heard me and David R Schuyler talk about that a fair amount over the last year or so that is a focus on serious diseases with unmet needs, to look at validated targets where you have assays that predict response, and where you can make a transformative medicine.

至於第 150 題，我認為你的問題是關於策略契合度和商業化，大致分為兩部分。我們的研究策略，你可能在過去一年左右的時間裡經常聽到我和 David R Schuyler 談論，就是專注於有未滿足需求的嚴重疾病，尋找已驗證的靶點，這些靶點有預測反應的檢測方法，可以研發出變革性的藥物。

And actually pain in general and mad channels fit those beautifully. They are fully validated targets on a serious disease with large unmet need where you can transformative medicine. Then you come to the commercial and development strategies. Pain is an area we can develop, but pain isn't really one disease as I said.

事實上，痛苦和瘋狂的頻道與這些非常契合。它們是針對一種存在巨大未滿足醫療需求的嚴重疾病的完全驗證靶點，可以帶來變革性醫學。接下來就是商業和發展策略。疼痛是我們能夠發展的一個領域，但正如我所說，疼痛並不是一種疾病。

Pain is a number of different diseases. OA is a very different disease as you know from neuropathic pain, mad's a very different disease from acute pain, and there are different medicines that work with different degrees of efficacy in those diseases. So I would think of pain as a legacy program that fits our scientific strategy extremely well and depending on what the profile of the drug is, might fit parts of our commercialization strategy or might be more appropriate with a partner, but until we know the whole profile which is easy and cheap to determine at this point, we won't be able to come up with a strategy for how to create the maximum value from the asset. Once we do I think it will be pretty straightforward actually.

疼痛是多種不同疾病的症狀。如你所知，骨關節炎與神經性疼痛是一種非常不同的疾病，中風也與急性疼痛是一種非常不同的疾病，針對這些疾病，不同的藥物也具有不同程度的療效。因此，我認為疼痛治療是一個傳承項目，它非常符合我們的科學策略，根據藥物的特性，它可能適合我們商業化策略的某些部分，或者可能更適合與合作夥伴合作，但在我們了解藥物的完整特性之前（目前確定藥物特性既容易又便宜），我們將無法制定如何從該資產中創造最大價值的策略。一旦我們這麼做了，我想其實會很簡單。

Great, thanks very much.

太好了，非常感謝。

Alethia Young, Credit Suisse

阿萊西亞楊，瑞士信貸

Thanks for taking my question. One on 661, when you thought about powering the study for 661 homozygotes were there different assumptions in how you thought about it with 809? The reason why I ask is, if I recall correctly, I thought the 809 had two arms where you split the power and then I have one quick question on the residuals.

謝謝您回答我的問題。在考慮以 661 位純合子進行研究時，您是否對 809 位純合子進行了不同的假設？我問這個問題的原因是，如果我沒記錯的話，我以為 809 有兩個臂，可以分配功率，然後我還有一個關於殘差的問題。

On the 661 strategy, the size of the homozygote study which I think is what you're really asking me about, was driven more by the necessary size of the safety database than it was by the powering for efficacy.

關於 661 策略，我認為你真正想問我的是純合子研究的規模，其驅動力更多地來自安全資料庫的必要規模，而不是療效的統計效力。

Because we need a total safety database which includes all the different trials, sufficiently large to get approval. And the biggest part of that turned out to be the homozygotes because they are the biggest population and therefore the easiest to enroll the fastest. So that's what really drives the size of that study, it is highly powered as it is.

因為我們需要一個包含所有不同試驗的完整安全資料庫，而且資料庫規模要夠大，才能獲得批准。而其中最大的一部分結果證明是純合子，因為他們是人數最多的群體，因此也是最容易、最快招募的。所以，這才是真正決定這項研究規模的原因，它本身就具有很高的統計效力。

And then on the residual study that's underway with 661, I know you said you were still in discussions with the FDA but can you help us think about what might be compelling data or fileable data more specifically?

關於正在進行的 661 的殘留研究，我知道您說過您仍在與 FDA 進行討論，但您能否更具體地幫助我們思考一下，哪些數據可能具有說服力或可提交申請？

Sure I do want to separate those two a little bit. The discussions that we're having with the FDA now are really around KALYDECO monotherapy, based upon our initial submission which contains a lot of in vitro data in the 23 different mutations as well as a small clinical study.

當然，我的確想把這兩者稍微分開一點。我們現在與 FDA 進行的討論實際上是圍繞 KALYDECO 單藥療法展開的，這是基於我們最初的提交，其中包含 23 種不同突變的大量體外數據以及一項小型臨床研究。

As you know we received a complete response letter from that initial application in February of last year and we been in discussions with them since then, because we feel there is sufficient data to very clearly show that the drug works. It's monotherapy in those patients, so that's one set of discussions which you should think of as separate from the new trials that we are talking about.

如您所知，我們去年二月收到了針對該申請的完整回覆函，從那時起我們就一直在與他們進行討論，因為我們認為有足夠的數據可以非常清楚地表明該藥物有效。對於這些患者來說，這是單藥治療，所以這是一組你應該將其與我們正在討論的新試驗分開的討論。

The new trials that you were talking about are part of the 661 program and in that particular residual function trial, there is a placebo arm, KALYDECO monotherapy arm, and a KALYDECO plus tezacaftor arm. So we are going to actually be able to see compare those three, if you will, and that data would hopefully provide the basis for submitting either KALYDECO monotherapy or dual therapy or both in the US and Europe and that's the data that we will see in the first half of this year. Is that clear how the two things are a little bit different?

您提到的新試驗是 661 計畫的一部分，在該項殘餘功能試驗中，設有安慰劑組、KALYDECO 單藥治療組和 KALYDECO 加 tezacaftor 治療組。因此，我們將能夠對這三種療法進行比較，希望這些數據能夠為在美國和歐洲提交 KALYDECO 單藥療法、雙藥療法或兩者兼有的申請提供依據，而這些數據將在今年上半年公佈。這樣解釋清楚這兩件事的差別了嗎？

That's helpful. Thank you.

那很有幫助。謝謝。

Operator we have time for two more questions.

接線員，我們還有時間再回答兩個問題。

Ying Huang, Bank of America Merrill Lynch.

黃穎，美國銀行美林證券。

Thanks for taking my question. Number one I want to probe a little more about these six- to 11-year-old in the US. Given the number at 2,400 patients, I'm a little surprised you do not expect much incremental growth for ORKAMBI from 4Q 2016 to 1Q and another question on the VX-659, because the trial protocol has been posted on clinicaltrials.gov, you are excluding patients or healthy volunteers with any childbearing potential. So just curious did you observe any preclinical reproductive (inaudible) molecule or not? Thanks.

謝謝您回答我的問題。首先，我想更深入地了解美國 6 至 11 歲兒童的情況。鑑於病患人數為 2400 人，我有點驚訝您預期 ORKAMBI 從 2016 年第四季到 2017 年第一季不會有太大的成長。另外，關於 VX-659，由於試驗方案已發佈在 clinicaltrials.gov 上，您排除了任何有生育能力的患者或健康志願者。所以，我很好奇，您是否觀察到任何臨床前生殖（聽不清楚）分子？謝謝。

Hi Ying, it's Ian. Remember JPMorgan? I think you asked the very same question. We provided guidance in [4Q1] and that was we stated that we expected Q1 for ORKAMBI to be similar to that of Q4 2016.

嗨，瑩，我是伊恩。你還記得摩根大通嗎？我想你問的也是同樣的問題。我們在 [4Q1] 中提供了指導，即我們預計 ORKAMBI 的第一季業績將與 2016 年第四季類似。

And in that assumption, we are trying to help folks like yourself understand how the revenues may flow in 2017, with helping you understand that the low end of the guidance is still of revenues are coming from those approved markets, in those approved indications or patient categories that we're already in.

基於這種假設，我們試圖幫助像您這樣的人了解 2017 年的收入情況，並幫助您理解，指導意見的下限仍然是來自我們已經進入的那些已獲批准的市場、適應症或患者類別的收入。

Within that assumption there is some expectation of growth but we are already treating the vast majority of the patients within those categories, so even though we may add new patients in the growth, it is somewhat offset by the loss of patients that are already chronically on the medicine or were chronically on the medicine.

在這種假設下，我們預期會有成長，但我們已經治療了這些類別中的絕大多數患者，因此，即使我們可能會在成長過程中增加新患者，也會被那些已經長期服用該藥物或曾經長期服用該藥物的患者的流失所抵消。

We're also trying to help you understand that as we go out through the year, if the low end of the guidance is at $1.1 billion, we do expect that to be the exit run rate of 2016 and the earlier part of 2017, because we anticipate the growth which would be mainly from ex-US markets and principally Europe. That would be in the second half of the year, as I mentioned earlier on the call, a key contributor to that is actually France. So we're still in the same position and the same discussion we had back at JPMorgan.

我們也想幫助大家理解，隨著年底的臨近，如果預期下限為 11 億美元，我們預計這將是 2016 年末和 2017 年上半年的營運速度，因為我們預計成長將主要來自美國以外的市場，尤其是歐洲。那將在今年下半年發生，正如我之前在電話會議上提到的，而法國實際上是促成這一結果的關鍵因素。所以我們仍然處於同樣的立場，討論的話題也和我們在摩根大通時一樣。

So Ying on 659, a question on repro tox, we don't have the preclinical repro tox data yet and so the exclusion merely represents the typical caution until we have that data.

所以，Ying 在 659 號提問了關於生殖毒性的問題，我們還沒有臨床前生殖毒性數據，因此排除僅僅代表了在我們獲得該數據之前的典型謹慎態度。

Got it. Thank you.

知道了。謝謝。

Phil Nadeau, Cowen & Company.

Phil Nadeau，Cowen & Company。

Good afternoon, thanks for taking my questions and fitting me in. Just two, first on Germany, in the past at some point you thought that there was some hesitation among physicians to prescribe ORKAMBI to patients in Germany without a final price. I'm curious whether you think that impediment continues to exist and now that you have the final price will there be an uptick in the use in Germany? That's the first question.

下午好，感謝您抽空回答我的問題。就兩點而言，首先是關於德國，過去曾有一段時間，人們認為德國的醫生在沒有最終價格的情況下，對給患者開ORKAMBI處方有所猶豫。我很好奇您是否認為這種障礙仍然存在，現在您已經確定了最終價格，德國的使用量是否會上升？這是第一個問題。

And then the second question is on the study looking at KALYDECO plus tezacaftor versus KALYDECO and placebo, in the residual function patients. Is there any requirement for that study to show a benefit of KALYDECO plus tezacaftor over KALYDECO monotherapy alone or is it really the relevant compare versus placebo in order for that label to secured? Thank you.

第二個問題是關於一項研究，該研究比較了 KALYDECO 加 tezacaftor 與 KALYDECO 加安慰劑在殘餘功能患者中的療效。該研究是否需要證明 KALYDECO 合併 tezacaftor 治療優於 KALYDECO 單藥治療，還是說與安慰劑進行比較才是獲得該標籤的真正依據？謝謝。

It's Stuart here, I'll take your question on Germany. Actually we don't believe that the hesitation to prescribe has been due to uncertainty about the final price that we would agree in Germany. The relatively slow uptake we've seen a Germany I think is due to a couple of things.

我是斯圖爾特，我來回答你關於德國的問題。事實上，我們並不認為猶豫不決是因為我們不確定在德國最終能商定的價格。我認為德國的普及速度相對較慢，主要有兩個原因。

Notably the lack of experience, that many senses had with CFTR modulators at the launch of KALYDECO because of the fragmented nature of the market. And because in general a more conservative nature and approach to new medicines in Germany in many -- in that market compared to other markets in Europe.

值得注意的是，由於市場分散，KALYDECO 推出時，許多感官都缺乏對 CFTR 調製器的經驗。而且，與歐洲其他市場相比，德國在對待新藥方面整體上更加保守。

And so I'm not really expecting the fact we been able to reach a final pricing agreement with the German authorities significantly changed the perception of ORKAMBI in the eyes of German physicians.

因此，我並不認為我們能夠與德國當局達成最終定價協議這一事實會顯著改變德國醫生對 ORKAMBI 的看法。

This is Jeff on your 661 residual function question, with each of the arms KALYDECO monotherapy and 661 plus KALYDECO will be compared to the placebo arm and in terms of what would be required to get approvals, it's really going to depend on the profiles of each of those.

這是 Jeff 關於您提出的 661 殘餘功能的問題，KALYDECO 單藥治療組和 661 加 KALYDECO 治療組將分別與安慰劑組進行比較，至於獲得批准需要什麼，這實際上取決於每個治療組的具體情況。

It's not only about efficacy, it's about tolerability, it's about the overall profile. So when we see the data I think we will be able to give you a pretty good sense which directions we're going to take there.

不僅要看療效，還要看耐受性，還要看整體狀況。所以，當我們看到數據時，我想我們就能讓你對接下來要採取的方向有相當清晰的了解。

Great thanks for taking my questions.

非常感謝您回答我的問題。

Now we will conclude our call. This is Michael Partridge. Thanks for your questions tonight. Thanks for tuning in. The Investor Relations Team is available for any follow-up that you have after the call. Enjoy the rest of your evening.

現在我們的通話到此結束。這是邁克爾·帕特里奇。謝謝大家今晚提出的問題。感謝收看。投資者關係團隊隨時準備為您解答通話後的任何後續問題。祝您晚安。

Ladies and gentlemen, thank you for your participation in today's conference. This does conclude the program and you may now disconnect.

女士們、先生們，感謝各位參加今天的會議。程式到此結束，您可以斷開連線了。