福泰製藥 (VRTX) 2016 Q1 法說會逐字稿

Good evening. This is Michael Partridge, Vice President of Investor Relations. Welcome to our first quarter 2016 conference call.

晚安.這是投資者關係副總裁麥可·帕特里奇。歡迎參加我們2016年第一季電話會議。

(Operator Instructions)

（操作說明）

You can access the webcast slides by going to the events section of the Investor Relations page on our website, and a replay of tonight's call will also be available on the website once we have concluded.

您可以透過造訪我們網站投資者關係頁面的活動部分來查看網路直播幻燈片，今晚電話會議結束後，我們還將在網站上提供會議錄音回放。

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

董事長兼執行長傑夫·萊頓博士、首席商務官斯圖爾特·阿巴克爾和首席財務官伊恩·史密斯將於今晚發表準備好的演講。首席醫療官傑夫·喬達克維茨博士將加入電話會議的問答環節。

We will make forward-looking statements on this call. These statements are subject to the risks and uncertainties discussed in detail in today's press release, and our 10-K which has been filed with the SEC. These statements, including, without limitation, those regarding the ongoing development and potential commercialization of our drug candidates, our expectations regarding our approved medicines, and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

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以及我們向美國證券交易委員會提交的 10-K 文件中詳細討論的風險和不確定性的影響。這些聲明，包括但不限於關於我們候選藥物的持續開發和潛在商業化、我們對已獲批准藥物的預期以及Vertex未來財務業績的聲明，均基於管理層目前的假設。實際結果和事件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 tonight's press release. I would 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 財務指標的信息，以及 GAAP 與非 GAAP 的調整表，請參閱今晚的新聞稿。我還想請您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. Over the last four years, Vertex has delivered two transformative medicines to people with cystic fibrosis. Today, there are approximately 27,000 people eligible for one of our approved CF medicines, and we have a clear path toward our goal of helping potentially all people with this rare and life-shortening disease in the future.

謝謝你，麥可。各位晚上好。在過去的四年裡，Vertex 為囊性纖維化患者提供了兩種具有變革意義的藥物。目前，約有 27,000 人符合我們已批准的 CF 藥物的適用條件，我們朝著幫助未來所有患有這種罕見且縮短壽命疾病的人的目標邁出了清晰的步伐。

We're confident that our experience with ORKAMBI and KALYDECO, and our scientific leadership and progress in targeting the underlying biology of this disease, positions us well to increase the number of people treated with our approved medicines, and to develop new medicines in the years ahead that may provide even greater benefit for all people with CF.

我們相信，憑藉我們在 ORKAMBI 和 KALYDECO 方面的經驗，以及我們在針對該疾病潛在生物學方面的科學領先地位和進展，我們有能力增加接受我們已批准藥物治療的人數，並在未來幾年開發出可能為所有囊性纖維化患者帶來更大益處的新藥。

Tonight, I'll provide brief comments on three key areas, which serve as markers of our progress toward treating all people with CF, including first, the performance of our approved medicines, ORKAMBI and KALYDECO, and our road map toward treating more patients with these medicines that will drive revenue growth in 2016 and beyond.

今晚，我將簡要介紹三個關鍵領域，這些領域標誌著我們在治療所有囊性纖維化患者方面取得的進展，包括我們已獲批准的藥物 ORKAMBI 和 KALYDECO 的表現，以及我們使用這些藥物治療更多患者的路線圖，這將推動 2016 年及以後的收入增長。

Second, the role of VX-661 in helping to achieve our long-term goal in CF. And third, our pipeline of additional CFTR modulators and other mechanisms we are advancing as part of collaborations. These approaches include ENaC inhibition, and in the longer term, gene editing with CRISPR-Cas9, and may position us to help all people with CF.

其次，VX-661 在幫助我們實現 CF 長期目標方面發揮了作用。第三，我們正在推動其他 CFTR 調節劑和其他機制的研發，這是合作的一部分。這些方法包括 ENaC 抑制，從長遠來看，還包括使用 CRISPR-Cas9 進行基因編輯，這可能會使我們能夠幫助所有患有囊性纖維化的人。

We're approximately nine months into the launch of ORKAMBI in the US for people with two copies of the F508del CFTR mutation ages 12 and older. As of the end of March, approximately 65% or 5,500 of the 8,500 currently eligible patients in the US have initiated treatment with ORKAMBI. We expect the number of patients who have initiated treatment with ORKAMBI will continue to grow during 2016. And we continue to expect that by the end of the year, the vast majority of all eligible patients ages 12 and older in the US will have initiated treatment.

ORKAMBI 在美國上市至今已有約九個月，適用於 12 歲及以上、攜帶兩個 F508del CFTR 突變拷貝的族群。截至 3 月底，美國目前 8,500 名符合條件的患者中，約有 65%（即 5,500 人）已開始接受 ORKAMBI 治療。我們預計 2016 年接受 ORKAMBI 治療的患者人數將持續成長。我們仍然預計，到今年年底，美國所有 12 歲及以上符合條件的患者中的絕大多數都將開始接受治療。

We've seen excellent reimbursement and access for ORKAMBI from public and private payers in the US, and the feedback from the CF community continues to be very positive. Importantly, patients across the US have broad access to the medicine through public and private insurance, and we have assistance programs in place for eligible patients who need additional help. All major commercial insurers and all 50 state Medicaid programs are currently covering ORKAMBI, reflecting the important advance and value this medicine represents in the treatment of CF.

我們看到，ORKAMBI 在美國的公共和私人支付方都獲得了良好的報銷和使用，CF 患者群體也持續給予了非常正面的回饋。重要的是，全美各地的患者都可以透過公共和私人保險廣泛獲得這種藥物，我們也為需要額外幫助的符合條件的患者制定了援助計劃。目前所有主要商業保險公司和所有 50 個州的醫療補助計劃都在承保 ORKAMBI，這反映了該藥物在治療囊性纖維化方面所代表的重要進步和價值。

We're now moving forward toward bringing ORKAMBI to younger patients. And at the end of March, we submitted a supplemental new drug application to the FDA requesting approval for ORKAMBI for children ages 6 to 11 with two copies of the F508del mutation. We requested priority review, which if granted, would provide us with a decision on the application in the second half of this year. If approved, approximately 2,400 additional patients in the US would be eligible for treatment.

我們現在正努力將 ORKAMBI 帶給更年輕的患者。3 月底，我們向 FDA 提交了一份補充新藥申請，請求批准 ORKAMBI 用於治療 6 至 11 歲攜帶兩個 F508del 突變拷貝的兒童。我們請求優先審查，如果獲得批准，我們將在今年下半年收到申請結果。如果獲得批准，美國將有大約 2400 名患者符合治療條件。

Outside the US, we have commenced discussions with reimbursement agencies in various European and other countries. Given the clinical benefits of ORKAMBI and the severity of the disease for people with two copies of the F508del mutation, we believe that we will achieve reimbursement from key European and other government payers, just as we've seen in the US. ORKAMBI is already commercially available in Germany, and through early access programs in France.

在美國以外，我們已經開始與歐洲及其他國家的各種報銷機構進行討論。鑑於 ORKAMBI 的臨床益處以及攜帶兩個 F508del 突變拷貝的患者的病情嚴重性，我們相信我們將從主要的歐洲和其他國家政府支付方獲得報銷，就像我們在美國看到的那樣。ORKAMBI 已在德國上市，並透過法國的早期體驗計劃提供。

In the near term, the progress on our understanding of treating eligible patients with ORKAMBI gives us clarity on a revenue expectation for 2016. Later in the call, Stuart and Ian will talk about the ORKAMBI launch in detail, our guidance, and how we think about revenue trends from 2015, and growth into 2016 and further into the future.

短期來看，我們對使用 ORKAMBI 治療符合條件的患者所取得的進展，使我們對 2016 年的收入預期更加清晰。在稍後的通話中，Stuart 和 Ian 將詳細討論 ORKAMBI 的發布、我們的指導意見，以及我們如何看待 2015 年的收入趨勢，以及 2016 年和未來更遠時期的成長。

For KALYDECO, we're increasing our revenue guidance for 2016, which Stuart will discuss in his remarks. As we think about the future opportunities for ORKAMBI and KALYDECO, I want to emphasize that revenue growth in 2016 and beyond, is largely a function of additional patients who are currently eligible for ORKAMBI or KALYDECO initiating treatment with these medicines. On that basis alone, we believe there is significant growth ahead for both medicines.

對於 KALYDECO，我們提高了 2016 年的收入預期，Stuart 將在他的演講中討論這一點。當我們思考 ORKAMBI 和 KALYDECO 的未來機會時，我想強調的是，2016 年及以後的收入成長，很大程度上取決於目前符合 ORKAMBI 或 KALYDECO 使用條件的患者開始接受這些藥物治療的人數增加。光是這一點，我們就相信這兩種藥物未來都有很大的成長空間。

Consider that today ORKAMBI and KALYDECO are approved for approximately 27,000 people worldwide, but we're only currently treating approximately one-third of these patients. As we see additional uptake of ORKAMBI in the US, and achieve reimbursement for eligible patients outside the US, growth will continue as additional patients continue to initiate treatment.

目前，ORKAMBI 和 KALYDECO 已獲準用於全球約 27,000 名患者，但我們目前僅治療了其中約三分之一的患者。隨著 ORKAMBI 在美國的普及，以及符合條件的患者在美國以外地區獲得報銷，隨著更多患者開始接受治療，成長動能將持續。

In addition, there are many more patients not currently eligible for treatment who may benefit from either ORKAMBI or KALYDECO. In total, we believe there are approximately 44,000 people, an additional 17,000 people beyond those eligible today, who could benefit from one of these two medicines.

此外，還有許多目前不符合治療條件的患者可能會從 ORKAMBI 或 KALYDECO 中受益。我們認為，總共有大約 44,000 人（比目前符合資格的人數多出 17,000 人）可以從這兩種藥物中的一種中受益。

This additional group of patients is largely comprised of the following. First, approximately 12,000 people less than 12 years of age who have two copies of the F508del mutation, and who may be helped by ORKAMBI. And second, approximately 5,000 patients who may be helped by KALYDECO, comprised mostly of patients who have residual function mutation.

這部分新增患者主要包括以下幾類人群。首先，大約有 12,000 名 12 歲以下的兒童攜帶兩個 F508del 突變拷貝，他們可能會受到 ORKAMBI 的幫助。其次，大約有 5,000 名患者可能受益於 KALYDECO，其中大部分是具有殘餘功能突變的患者。

Treating a substantial portion of this additional group of 17,000 patients would further drive ORKAMBI and KALYDECO growth, if we obtain future approvals for these additional groups of patients. We have ongoing studies, regulatory submissions and development plans to support these efforts, including ongoing discussions with the FDA regarding our application for approval of KALYDECO in approximately 1,500 people ages 2 and older, with one of 23 residual function mutations, as well as our recent SNDA submission to the FDA for approval of ORKAMBI in children ages 6 to 11 with two copies of the F508del mutation.

如果未來我們能獲得針對這額外患者群體的批准，治療這額外 17,000 名患者中的相當一部分將進一步推動 ORKAMBI 和 KALYDECO 的成長。我們正在進行研究、監管申報和開發計劃以支持這些努力，包括與 FDA 就我們申請批准 KALYDECO 用於大約 1,500 名 2 歲及以上、攜帶 23 種殘餘功能突變之一的患者的申請進行持續討論，以及我們最近向 FDA 提交的 SNDA 申請，以批准 ORKAMBI 用於攜帶兩個 F508del 突變的兒童 11 歲。

While we are focused on getting ORKAMBI and KALYDECO to as many patients as possible, as soon as possible, we also recognize that there are many patients who are still waiting for treatment for the underlying cause of their disease. We hear from these patients often. So I'm particularly pleased to report that our CF pipeline is advancing. This gives us great confidence that we will ultimately be able to treat the vast majority of people with CF, and potentially enhance the benefit for those people currently taking our approved medicines.

雖然我們專注於盡快讓盡可能多的患者使用 ORKAMBI 和 KALYDECO，但我們也意​​識到，還有很多患者仍在等待治療其疾病的根本原因。我們經常收到這些患者的回饋。因此，我特別高興地報告，我們的 CF 產品線正在取得進展。這讓我們非常有信心，最終我們將能夠治療絕大多數囊性纖維化患者，並有可能提高目前正在服用我們已批准藥物的患者的益處。

I'll start with VX-661, which could play an important role in the treatment of people with CF, and is currently in Phase 3 development. In combination with ivacaftor, our Phase 2 data suggested that VX-661 may have an improved benefit risk profile compared to ORKAMBI in people with two copies of the F508del mutation, and may provide enhanced clinical benefits over ivacaftor monotherapy for other patients with gating mutations. We are on track to obtain the first data from the ongoing Phase 3 program for VX-661 in early 2017 from the study in people with two copies of the F508del mutation.

我先從 VX-661 開始，它可能在治療囊性纖維化患者方面發揮重要作用，目前正處於第 3 期開發階段。與 ivacaftor 聯合使用時，我們的 2 期數據表明，對於攜帶兩個 F508del 突變拷貝的患者，VX-661 可能比 ORKAMBI 具有更好的獲益風險特徵，並且對於其他攜帶門控突變的患者，VX-661 可能比 ivacaftor 單藥治療提供更強的臨床獲益。我們預計在 2017 年初獲得正在進行的 VX-661 3 期臨床試驗項目的第一批數據，該試驗針對的是攜帶兩個 F508del 突變拷貝的人群。

Additionally, VX-661 is positioned to play a key role in the development of a triple combination with a next generation corrector and ivacaftor. We believe that this triple combination approach will be fundamental for two reasons. First, triple combinations may allow us to treat a very large group of patients who are not helped today by either ORKAMBI or KALYDECO, including those with one F508del mutation, and a second mutation that causes minimal CFTR function. And second, these regimens could provide even greater benefit to patients currently eligible for our approved medicines who have at least one F508del mutation.

此外，VX-661 將在與下一代矯正器和 ivacaftor 的三重組合開發中發揮關鍵作用。我們認為，這種三重組合方法至關重要，原因有二。首先，三合一療法或許能夠治療目前 ORKAMBI 或 KALYDECO 都無法幫助的一大群患者，包括那些攜帶一個 F508del 突變和第二個導致 CFTR 功能極低的突變的患者。其次，這些治療方案可能會為目前符合我們已批准藥物條件且至少攜帶一個 F508del 突變的患者帶來更大的益處。

Today, we have two next gen correctors in clinical development, VX-152 and VX-440. These potential medicines are currently being evaluated in Phase 1 studies in healthy volunteers. Successful completion of these studies would enable us to move rapidly into Phase 2 studies in the second half of 2016 to evaluate one or more next generation correctors with VX-661 and ivacaftor in people with CF.

目前，我們有兩種新一代矯正器正在進行臨床開發，分別是 VX-152 和 VX-440。這些潛在藥物目前正在健康志願者身上進行 I 期臨床試驗評估。這些研究的成功完成將使我們能夠在 2016 年下半年迅速進入 2 期研究，以評估一種或多種下一代矯正器與 VX-661 和 ivacaftor 在 CF 患者中的療效。

I'll now turn to our pipeline of other potential CF medicines that could be complementary to our portfolio of CFTR modulators, and it may enable us to treat more patients and provide greater clinical benefit in the years to come. The most advanced example of this is our lead ENaC inhibitor, VX-371. Today, we announced data from a Phase 2 14-day study of VX-371 in 142 people with CF who are not receiving ORKAMBI or KALYDECO. The study met its primary end point of safety, 96% of the patients who enrolled in the study completed all treatment, and the treatment regimens consisting of VX-371 were generally well-tolerated. There were no statistically significant changes from baseline in FEV-1 for those patients who received the VX-371, compared to placebo.

接下來，我將介紹我們其他潛在的 CF 藥物研發管線，這些藥物可以與我們的 CFTR 調節劑產品組合形成互補，並可能使我們能夠在未來幾年治療更多患者，帶來更大的臨床益處。這方面最先進的例子是我們領先的 ENaC 抑制劑 VX-371。今天，我們公佈了 VX-371 在 142 名未接受 ORKAMBI 或 KALYDECO 治療的囊性纖維化患者中進行的 14 天 2 期研究的數據。該研究達到了安全性的主要終點，96% 的入組患者完成了所有治療，且 VX-371 治療方案整體上耐受性良好。與安慰劑組相比，接受 VX-371 治療的患者的 FEV-1 值與基線相比沒有統計學意義上的顯著變化。

The data announced today are consistent with our in vitro data that did not show a meaningful change in cilia beat frequency, when VX-371 was used alone in human bronchial epithelial cells with two copies of the F508del mutation. In contrast, these in vitro data did show a meaningful change of cilia beat frequency when VX-371 was used in combination with ORKAMBI. Together, the in vitro and clinical safety data generated to date provide further support for our ongoing study of VX-371 in combination with ORKAMBI.

今天發表的數據與我們的體外數據一致，體外數據顯示，當在具有兩個 F508del 突變拷貝的人類支氣管上皮細胞中單獨使用 VX-371 時，纖毛擺動頻率沒有發生有意義的變化。相較之下，這些體外數據確實顯示，當 VX-371 與 ORKAMBI 聯合使用時，纖毛擺動頻率發生了有意義的變化。迄今為止產生的體外和臨床安全性數據共同為我們正在進行的 VX-371 與 ORKAMBI 聯合研究提供了進一步的支持。

This ongoing study began enrolling people with two copies of the F508del mutation ages 12 and older in the first quarter of this year. And the primary end points are safety and mean absolute change from baseline in lung function at day 28 of treatment, as compared to placebo. Additional information on these studies can be found in our first quarter press release issued today.

這項正在進行的研究於今年第一季開始招募 12 歲及以上、攜帶兩個 F508del 突變拷貝的人。主要終點是安全性以及治療第 28 天肺功能相對於基線的平均絕對變化（與安慰劑相比）。有關這些研究的更多信息，請參閱我們今天發布的第一季新聞稿。

Additionally, last year we entered into a collaboration with CRISPR Therapeutics, with a longer-term goal of discovering gene editing approaches for the treatment of genetic diseases, including CF. The use of this technology in people with CF may be many years away, but it is strategically important as we think about future advances that could fundamentally change the treatment of this disease in the years to come.

此外，去年我們與 CRISPR Therapeutics 展開合作，其長期目標是發現基因編輯方法來治療包括囊性纖維化在內的遺傳疾病。這項技術應用於囊性纖維化患者可能還需要很多年，但從策略角度來看，它非常重要，因為我們正在思考未來幾年可能從根本上改變這種疾病治療的進步。

Tonight, I've summarized how we think about our opportunity in CF, an opportunity that is unique, both in terms of the potential benefit that ORKAMBI and KALYDECO provide to people with CF today, and also for the long-term potential of our development stage medicines to treat the vast majority of people with CF in the future. In conclusion, I'll make just a few comments about the type of company we will become as we achieve the success in CF that I have just outlined.

今晚，我總結了我們如何看待我們在 CF 領域的機會。這是一個獨特的機遇，不僅體現在 ORKAMBI 和 KALYDECO 目前能為 CF 患者帶來的潛在益處，也體現在我們處於研發階段的藥物在未來治療絕大多數 CF 患者的長期潛力上。最後，我想就我們實現剛才概述的CF成功後，我們將成為什麼樣的公司做一些簡要說明。

Vertex is on a path toward sustained earnings and revenue growth, driven by increasing number of people being treated with KALYDECO and ORKAMBI. We believe our business model, one focused on significant investment to create value through innovation, research and development positions us to consistently discover and deliver transformative new medicines for patients, and to reinvest in scientific opportunities to create future medicines.

Vertex 正朝著持續獲利和收入成長的方向發展，這得益於越來越多的人接受 KALYDECO 和 ORKAMBI 的治療。我們相信，我們專注於透過創新、研發進行大量投資以創造價值的商業模式，使我們能夠不斷發現並為患者提供變革性的新藥，並將資金再投資於科學機遇，以創造未來的藥物。

With that, I'll turn the call over to Stuart to make more specific comments on the ORKAMBI launch.

接下來，我將把電話交給斯圖爾特，讓他對 ORKAMBI 的發布做更具體的評論。

Thanks, Jeff, and hello, everyone. Tonight I will review our progress with the launch of ORKAMBI, the basis of our 2016 guidance for ORKAMBI product revenues, and our ongoing efforts to obtain reimbursement outside the US to drive further growth of ORKAMBI in 2017 and beyond.

謝謝傑夫，大家好。今晚我將回顧我們在 ORKAMBI 上市方面取得的進展，這是我們 2016 年 ORKAMBI 產品收入指導的基礎，以及我們正在努力爭取在美國以外地區獲得報銷，以推動 ORKAMBI 在 2017 年及以後的進一步增長。

We are now just over nine months into the launch, and we are pleased that approximately 65% of eligible patients in the US have initiated treatment with ORKAMBI to date. Global sales of ORKAMBI in the first quarter were $223 million, comprised of US sales of approximately $214 million and ex-US sales of approximately $9 million, which were mainly from Germany.

目前產品上市已超過九個月，我們很高興地看到，迄今為止，美國約有 65% 的符合條件的患者已經開始接受 ORKAMBI 治療。ORKAMBI 第一季的全球銷售額為 2.23 億美元，其中美國銷售額約為 2.14 億美元，美國以外地區的銷售額約為 900 萬美元，主要來自德國。

At the beginning of the year, our intention was to provide financial guidance for 2016 ORKAMBI revenues, once we had gained sufficient understanding of the dynamics of the launch in the US. Today, we have a deeper understanding of how doctors and their patients are using the medicine, based on the real world treatment patterns we've observed in more than 4,500 patients who initiated treatment in the US in 2015.

年初，我們的目標是在充分了解 ORKAMBI 在美國上市的動態之後，為 2016 年 ORKAMBI 的收入提供財務指導。今天，我們根據對 2015 年在美國開始接受治療的 4500 多名患者的真實治療模式的觀察，對醫生及其患者如何使用這種藥物有了更深入的了解。

I'll now share with you our understanding of the launch dynamics that informed our guidance. First, uptake, defined as the total proportion of the 8,500 eligible patients in the US who will begin treatment with ORKAMBI by the end of 2016, and also the rate at which these patients initiate treatment. Second, the persistence rate, defined as the proportion of patients who start and remain on treatment. And third, the compliance rate, which reflects the number of pills actually taken by a patient in a given month.

現在我將與大家分享我們對產品上市動態的理解，這些理解也為我們制定指導方針提供了基礎。首先是接受率，定義為到 2016 年底，美國 8,500 名符合條件的患者中將開始接受 ORKAMBI 治療的總比例，以及這些患者開始接受治療的速度。其次，持續治療率定義為開始治療並堅持治療的患者比例。第三，依從率，它反映了患者在特定月份實際服用的藥片數量。

First, to uptake, to date approximately 65% of the 8,500 eligible patients in the US have initiated treatment with ORKAMBI, comprised of more than 3,000 patients who initiated treatment in the third quarter of 2015, more than 1,500 in the fourth quarter, and approximately 800 in the first quarter of 2016. We have seen further initiations in April, and expect that patient initiations will continue throughout 2016, albeit the lower rate than in the first three quarters post-launch. We continue to expect the vast majority of the eligible patients ages 12 and older in the US will initiate treatment with ORKAMBI by the end of this year.

首先，就接受度而言，迄今為止，美國 8,500 名符合條件的患者中約有 65% 已開始接受 ORKAMBI 治療，其中包括 2015 年第三季度開始治療的 3,000 多名患者、第四季度開始治療的 1,500 多名患者以及 2016 年第一季度開始治療的約 800 名患者。我們看到 4 月又有更多患者開始接受治療，預計 2016 年全年患者治療量將繼續增加，儘管速度會低於上市後前三個季度的水平。我們仍然預計，到今年年底，美國 12 歲及以上符合條件的絕大多數患者將開始接受 ORKAMBI 治療。

Second, persistence. Among patients who have initiated ORKAMBI since launch, we've seen that approximately 15% of patients discontinue treatment within three months of starting treatment. Our clinical trial and market research data indicate that these discontinuations are largely related to respiratory adverse events. After the first three months of treatment, the discontinuation rate then slows considerably.

第二，堅持不懈。自 ORKAMBI 上市以來，我們發現，在開始接受 ORKAMBI 治療的患者中，約有 15% 的患者在開始治療後的三個月內就停止了治療。我們的臨床試驗和市場調查數據表明，這些停藥主要與呼吸不良事件有關。治療開始後的前三個月，停藥率會大幅下降。

Based on what we've observed to date, from all patients taking ORKAMBI, including those who have been on commercial drug for up to nine months, and those who continue to receive ORKAMBI as part of our Phase 3 long-term extension study, we expect that the proportion of all patients who initiate and remain on treatment will stabilize at approximately 70% to 80%.

根據我們迄今為止的觀察，在所有服用 ORKAMBI 的患者中，包括服用商業藥物長達九個月的患者，以及作為我們 3 期長期擴展研究的一部分繼續接受 ORKAMBI 治療的患者，我們預計開始並繼續接受治療的所有患者的比例將穩定在 70% 到 80% 左右。

It is also important to point out that the pattern of patient initiations and discontinuations had an offsetting effect on our first quarter ORKAMBI revenues. Specifically, because more than 4,500 patients began treatment of ORKAMBI in 2015, the impact of approximately 15% of these patients discontinuing ORKAMBI was highly evident in the first quarter.

還需指出的是，患者的開始和停止治療模式對我們第一季的 ORKAMBI 收入產生了抵消作用。具體來說，由於 2015 年有超過 4,500 名患者開始接受 ORKAMBI 治療，其中約 15% 的患者停止使用 ORKAMBI 的影響在第一季非常明顯。

Therefore, while approximately 800 new patients initiated treatment in the first quarter, this growth was largely offset by the bolus of patients who discontinued treatment. This bolus of discontinuations began in the fourth quarter, but had a larger impact on the first quarter of 2016, where there were also fewer patient initiations to offset these discontinuations.

因此，雖然第一季約有 800 名新患者開始接受治療，但這一增長很大程度上被大量停止治療的患者所抵消。這波停用潮始於第四季度，但對 2016 年第一季的影響更大，因為當時新患者數量較少，無法抵消這些停用潮的影響。

And finally, compliance. Based on what we have observed to date from the launch, we expect the compliance rate with ORKAMBI to be between 70% and 80%.

最後，是合規性。根據我們迄今為止從產品上市以來的觀察，我們預計 ORKAMBI 的合規率將在 70% 到 80% 之間。

In summary, based on our understanding of the launch dynamics for ORKAMBI, and the fact that we have continued to see additional patients initiating treatment with ORKAMBI in April, we expect to deliver quarter-to-quarter revenue growth for ORKAMBI beginning in the second quarter, and continuing through the end of 2016 and into 2017.

綜上所述，根據我們對 ORKAMBI 上市動態的了解，以及我們持續看到更多患者在 4 月開始接受 ORKAMBI 治療的事實，我們預計 ORKAMBI 的收入將從第二季度開始逐季增長，並持續到 2016 年底和 2017 年。

I will now turn to the use of ORKAMBI to date outside the US. We are now well into the reimbursement process in all key European countries, Canada and Australia, specifically the clinical and cost effectiveness assessment portions of the reimbursement process. These discussions are going as expected, and have been productive.

接下來，我將介紹 ORKAMBI 在美國以外地區的使用情況。目前，我們已順利進入所有主要歐洲國家、加拿大和澳洲的報銷流程，特別是報銷流程中的臨床和成本效益評估部分。這些討論進展順利，且富有成效。

We believe that government payers across Europe recognize both the severity of this disease and the broad clinical benefits of ORKAMBI. These discussions will take time to complete. However, as Jeff mentioned earlier, we believe that we will achieve broad reimbursement from key European and other government payers, just as we've seen in the United States.

我們相信，歐洲各地的政府支付方都認識到這種疾病的嚴重性以及 ORKAMBI 的廣泛臨床益處。這些討論需要時間才能完成。不過，正如傑夫之前提到的那樣，我們相信我們將從歐洲和其他主要政府支付方獲得廣泛的報銷，就像我們在美國看到的那樣。

ORKAMBI is already available commercially in Germany, and through early access programs in France. We are only three months into the launch of ORKAMBI in Germany, and the uptake has been slower than we observed in the US. We attribute this to a number of factors, including that CF care in Germany is not concentrated in large centers as is seen in other countries, meaning there are many smaller centers, and also many centers and physicians who have not yet had personal experience with CFTR modulators.

ORKAMBI 已在德國上市銷售，並在法國透過早期體驗計畫銷售。ORKAMBI 在德國上市僅三個月，其市場接受度比我們在美國觀察到的要低。我們認為這歸因於多種因素，包括德國的 CF 治療不像其他國家那樣集中在大型中心，而是有很多較小的中心，以及許多中心和醫生還沒有使用 CFTR 調節劑的個人經驗。

In Germany, there are approximately 2,500 patients eligible for treatment. As of March 31, 2016, approximately 230 patients had initiated treatment. However, we expect the number of patients initiating treatment in Germany will grow through 2016 and into 2017.

在德國，約有2500名患者符合治療條件。截至 2016 年 3 月 31 日，約有 230 名患者開始接受治療。然而，我們預計 2016 年到 2017 年，德國開始接受治療的患者人數將會成長。

We do not expect what we are seeing in Germany will be representative of the uptake in other European countries. In fact, in France, where early access programs provide the opportunity for physicians to begin treating patients with ORKAMBI prior to formal reimbursement approval, we have already seen approximately 400 of the 1,500 eligible patients initiate treatment with ORKAMBI in 2016.

我們預期德國的情況並不能代表其他歐洲國家的接受程度。事實上，在法國，早期准入計畫讓醫生有機會在正式獲得報銷批准之前開始用 ORKAMBI 治療患者，我們已經看到 2016 年 1500 名符合條件的患者中約有 400 名開始接受 ORKAMBI 治療。

We took all of this information into account when we set 2016 revenue guidance for ORKAMBI of $1.0 billion to $1.1 billion. Our guidance reflects our understanding of the ongoing US launch as I just discussed, as well as expectations that we will receive both approval for ORKAMBI in the US for patients ages 6 to 11 in the second half of 2016, and certain revenues from sales of ORKAMBI outside the US, primarily from Germany. Taking a longer-term view, we expect significant further growth for ORKAMBI revenues in 2017, driven primarily by patients initiating treatment following the completion of reimbursement discussions outside the US.

我們在製定 ORKAMBI 2016 年營收預期（10 億美元至 11 億美元）時，已將所有這些資訊納入考量。正如我剛才所討論的，我們的指導意見反映了我們對正在進行的美國上市的理解，以及我們對以下兩方面的預期：一是 ORKAMBI 將於 2016 年下半年在美國獲得批准用於 6 至 11 歲的患者；二是 ORKAMBI 在美國以外地區（主要來自德國）的銷售將獲得一定的收入。從長遠來看，我們預計 ORKAMBI 2017 年的營收將大幅成長，這主要得益於美國境外病患在完成報銷談判後開始接受治療。

And now, to KALYDECO, today we are increasing our financial guidance for 2016 revenues. We now expect KALYDECO net revenues of $685 million to $705 million. The prior guidance provided on January 10, 2016 was for KALYDECO net revenues of $670 million to $690 million.

現在，對於 KALYDECO，我們今天提高了 2016 年的收入預期。我們現在預計 KALYDECO 的淨收入為 6.85 億美元至 7.05 億美元。2016 年 1 月 10 日給出的先前指導意見是，KALYDECO 的淨收入為 6.7 億美元至 6.9 億美元。

We increased our KALYDECO guidance based primarily on increasing number of patients initiating treatment with KALYDECO globally, and on expectations of a reduced impact this year from the VX-661 Phase 3 program. Our guidance for KALYDECO excludes any potential revenues from the approval of KALYDECO for people with residual function mutations. I'll now hand the call over to Ian.

我們提高 KALYDECO 指導價，主要依據是全球開始接受 KALYDECO 治療的患者人數不斷增加，以及預計今年 VX-661 3 期計畫的影響會減少。我們對 KALYDECO 的指導意見不包括 KALYDECO 核准用於治療具有殘餘功能突變的患者可能帶來的任何潛在收入。現在我將把電話交給伊恩。

Thank you, Stuart, and good evening to everyone. With the closing of the first quarter of 2016, and nine months into the launch of ORKAMBI, we are seeing significant progress across our business. Notably, we are seeing increasing number of patients being treated with our approved medicines, resulting in a growing revenue base that we expect to drive earnings growth.

謝謝你，斯圖爾特，大家晚上好。2016 年第一季即將結束，ORKAMBI 推出九個月後，我們看到公司業務取得了顯著進展。值得注意的是，我們看到越來越多的患者正在接受我們核准藥物的治療，從而帶來了不斷增長的收入基礎，我們預計這將推動獲利成長。

I will now review our first quarter financial results, and provide some specific comments about the long-term financial trajectory of our business. Financial results first.

接下來，我將回顧我們第一季的財務業績，並就我們業務的長期財務發展軌跡提出一些具體意見。首先看財務業績。

In the first quarter of 2016, we reported total CF product revenues of approximately $394 million, a significant increase compared to $130 million in the first quarter 2015. With ORKAMBI, we reported sales of $223 million for the first quarter 2016. We have recorded approximately $[574] million of ORKAMBI revenues in the first nine months since the US launch in July 2015. The first quarter KALYDECO sales of $171 million were up $41 million versus the first quarter of last year.

2016 年第一季度，我們報告的 CF 產品總收入約為 3.94 億美元，與 2015 年第一季的 1.3 億美元相比，成長顯著。2016 年第一季度，ORKAMBI 的銷售額為 2.23 億美元。自 2015 年 7 月在美國推出以來的前九個月，我們已記錄了 ORKAMBI 約 5.74 億美元的收入。KALYDECO 第一季銷售額為 1.71 億美元，比去年第一季成長了 4,100 萬美元。

Now to the operating expenses. Our first quarter non-GAAP operating expenses were $306 million, compared to non-GAAP operating expenses of $246 million for 2015. The increased operating expenses were primarily due to increased costs related to the progression of our CF pipeline, and to increased investment in global commercial support for the launch of ORKAMBI. Our non-GAAP net profit for the first quarter 2016 was $22 million, or $0.09 per diluted share, compared to a non-GAAP net loss of $148 million, or $0.62 per share for 2015.

接下來是營運費用。我們第一季的非GAAP營運支出為3.06億美元，而2015年的非GAAP營運支出為2.46億美元。營運費用增加主要是由於與 CF 產品線推進相關的成本增加，以及為 ORKAMBI 的上市而增加的全球商業支援投資。2016 年第一季度，我們的非 GAAP 淨利潤為 2,200 萬美元，即每股攤薄收益 0.09 美元，而 2015 年的非 GAAP 淨虧損為 1.48 億美元，即每股虧損 0.62 美元。

From a balance sheet perspective, we ended the first quarter with approximately $1.03 billion in cash, cash equivalents and marketable securities. Vertex also has $300 million outstanding from a credit agreement repayable by the end of the third quarter of 2017. The agreement also allows for the facility to increase to $500 million.

從資產負債表的角度來看，我們在第一季末擁有約 10.3 億美元的現金、現金等價物和有價證券。Vertex 還有 3 億美元的未償還貸款，這筆貸款是根據信貸協議支付的，應在 2017 年第三季末償還。該協議還允許將該設施的規模擴大到 5 億美元。

Now to financial trends. Stuart provided 2016 ORKAMBI and KALYDECO revenue guidance and the assumptions that drive our projections, and therefore, I will focus my comments on the longer-term growth opportunities that may come with treating more patients with our currently approved medicines.

接下來我們來看看金融趨勢。Stuart 提供了 2016 年 ORKAMBI 和 KALYDECO 的收入指導以及我們預測的假設，因此，我將重點評論使用我們目前已獲批准的藥物治療更多患者可能帶來的長期成長機會。

We expect ORKAMBI revenues will continue to grow as we treat more patients in the US, achieve reimbursement outside the US, and expand the ORKAMBI label to younger patients. KALYDECO's growth is based on gaining reimbursement for certain groups of patients outside the US, including those with R117H mutation, and the people ages 2 to 5 with gating mutations.

我們預計，隨著我們在美國治療更多患者、在美國以外地區獲得報銷以及將 ORKAMBI 的適用範圍擴大到更年輕的患者群體，ORKAMBI 的收入將繼續增長。KALYDECO 的成長是基於為美國以外的某些患者群體獲得報銷，包括 R117H 突變患者和 2 至 5 歲患有門控突變的患者。

In summary, as Jeff noted earlier, approximately 27,000 people are eligible for our CF medicines, yet we are only treating approximately one-third of these patients. As additional patients in the US start treatment, and we complete reimbursement discussions outside the US, we expect the number of patients treated with our medicines to increase significantly, and we expect revenue growth will follow.

總而言之，正如傑夫之前提到的，大約有 27,000 人符合我們 CF 藥物的使用條件，但我們只治療了其中大約三分之一的患者。隨著美國更多患者開始接受治療，以及我們完成美國以外地區的報銷談判，我們預計接受我們藥物治療的患者人數將大幅增加，我們預計收入成長也將隨之而來。

I will note that in 2015, we reported total CF revenues of $983 million. Based on 2016 guidance provided for ORKAMBI and KALYDECO, we anticipate the total CF revenues of approximately $1.7 billion to $1.8 billion, an approximate 75% increase over the prior year. As our revenues grow over future years, we are committed to managing our operating expenses to drive earnings growth, and we expect to deliver a financial profile as similar to many of our large cap biotech peers. With that, I open the line to questions.

我注意到，2015 年我們報告的總 CF 收入為 9.83 億美元。根據 2016 年 ORKAMBI 和 KALYDECO 的業績指引，我們預計 CF 總收入約為 17 億美元至 18 億美元，比上一年增長約 75%。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成長，並期望實現與許多大型生物技術同行類似的財務狀況。接下來，我開始接受提問。

(Operator Instructions)

（操作說明）

And our first question comes from the line of Michael Yee of RBC Capital Markets. Your line is now open.

我們的第一個問題來自加拿大皇家銀行資本市場的 Michael Yee。您的線路已開通。

Hi, good afternoon. Thanks for all the details. I really appreciate it, think it's very helpful for everyone.

您好，下午好。謝謝你提供的所有細節。我非常感謝，我覺得這對大家都很有幫助。

A two-part question. One is, you gave all of these discontinuation and persistence rates and compliance rates, which is in your guidance.

這是一個包含兩個部分的問題。一是，您在指導中給出了所有這些停藥率、持續用藥率和依從率。

Is there anything out there that you can do, to either improve these things, education, getting people to -- just get patients to take more drug, and can you apply any of this learnings to Europe? Are you seeing the same stuff in Germany? Are there any ways to improve it there?

有沒有辦法可以改善這些方面，例如教育，讓人們——讓病人服用更多藥物，以及可以將這些經驗應用到歐洲？你在德國也看到同樣的情況嗎？有什麼辦法可以改進嗎？

And then the second question, is a pipeline question on the 661 Het-min. You mentioned in the press release that you're changing the enrollment to do 200, instead of 300. But is that assuming you actually passed the futility? Can you just clarify that a little bit? I guess, why are we talking about changing the enrollment, if we haven't passed the futility?

第二個問題是關於 661 Het-min 的管道問題。你在新聞稿中提到，你們將招生人數從 300 人改為 200 人。但這前提是你真的通過了徒勞測試？您能再解釋一下嗎？我想，如果我們還沒有經歷徒勞無功的階段，為什麼還要討論改變招生製度？

Thanks.

謝謝。

Hey, Mike, it's Stuart here.

嘿，麥克，我是史都華。

I'll take the first part of your question around the discontinuation and compliance rates. And then I'll have Jeff Chodakewitz to answer the pipeline question. So on discontinuation and compliance, and what we might be able to do to improve those: much as we did with KALYDECO, we will be continuing to generate data on the long-term benefits and even broader benefits of ORKAMBI when used in the real world. And I suspect that data, if it's compelling may lead physicians and patients to reconsider restarting ORKAMBI. So we'll continue to develop the overall clinical profile of ORKAMBI as we have more experience in the market.

我先回答你關於停藥率和依從率的問題的第一部分。然後我會請傑夫·喬達克維茨來回答管道問題。因此，關於停藥和依從性，以及我們可能採取哪些措施來改善這些方面：就像我們對 KALYDECO 所做的那樣，我們將繼續產生有關 ORKAMBI 在現實世界中使用時的長期益處甚至更廣泛益處的數據。我懷疑，如果數據令人信服，可能會促使醫生和患者重新考慮重新開始使用 ORKAMBI。因此，隨著我們在市場上累積更多經驗，我們將繼續改善 ORKAMBI 的整體臨床概況。

In terms of compliance, really many of the same things that we did with KALYDECO, we'll be doing with ORKAMBI. And that's really providing both providers and physicians with the educational materials to be able to understand how this is a product, which is treating the underlying cause of their disease. And so, is a product that they would want to try and stay compliant with as much as they possibly can. And we'll certainly be leveraging all the learnings we've had from KALYDECO with ORKAMBI and those programs are already in place.

在合規性方面，我們對 KALYDECO 所做的很多事情，我們也會對 ORKAMBI 做。這樣一來，就能真正為醫療服務提供者和醫生提供教育材料，讓他們了解這是一款能夠治療疾病根本原因的產品。因此，他們會盡可能地嘗試並遵守相關產品的規定。我們一定會將從 KALYDECO 專案中汲取的所有經驗運用到 ORKAMBI 專案中，這些專案已經到位。

And lastly, to your point about, to Germany, clearly one of the things we're going to be doing, is transferring all of the learnings from our launch experience in the US to all of the other markets that we're launching into. And that's in many ways, the benefits of those markets coming on stream a little bit later, is they can learn from our experiences here in the US.

最後，關於您提到的德國市場，很顯然，我們將要做的事情之一，就是把我們在美國上市的經驗教訓轉移到我們即將進入的所有其他市場。從很多方面來看，這些市場稍晚進入市場的好處在於，它們可以從我們在美國的經驗中學習。

With that, I'll hand it over to Jeff to have him answer the question on the pipeline.

接下來，我將把問題交給傑夫，讓他來回答關於輸油管的問題。

Hi, Mike. It's Jeff.

嗨，麥克。是傑夫。

Maybe just to clarify, we did provide some information about the timing of the interim analysis in the Het-min study, but there's been no other changes for that trial. The change in sample size comes from one of our other Phase 3 trials, looking at 661 ivacaftor in patients who have more of a residual function mutation on one of their alleles. We did look at that, and saw that there was some opportunity to maintain good power, but simplified and reduced the sample size. And that's what that was about.

或許需要澄清一下，我們確實提供了一些關於 Het-min 研究中期分析時間的信息，但該試驗沒有其他變化。樣本量的變化源自於我們的另一項 3 期試驗，該試驗研究了 661 名患者使用 ivacaftor 治療其等位基因上的殘餘功能突變的情況。我們確實研究過這個問題，發現有機會在保持良好功效的同時簡化並減少樣本量。事情就是這樣。

Okay. So still the Het-min interim in Q3; no change to that. Okay.

好的。所以第三季 Het-min 中期指標仍然保持不變；這一點沒有變化。好的。

That's the interim, that's correct.

那是過渡方案，沒錯。

Thank you. And our next question comes from the line of Terence Flynn of Goldman Sachs. Your line is now open.

謝謝。下一個問題來自高盛集團的特倫斯·弗林。您的線路已開通。

Hi. Thanks for taking the questions. Maybe just a follow-up on the discontinuation rate. I know you mentioned it's mainly due to respiratory events, but the 15% I think over three months is significantly higher than what you saw in the trials. I know you mentioned previously it could be higher.

你好。謝謝您回答問題。或許可以跟進一下停藥率的情況。我知道你提到這主要是由於呼吸系統事件，但我認為三個月內 15% 的發生率明顯高於你在試驗中看到的情況。我知道你之前提到價格可能會更高。

But any more color there on the drivers behind that, that you can expand on a little bit? And then on the ORKAMBI guidance, just wondering if you can provide a little bit more clarity there on the contributions from US rest of world, and then the patients 6 to 11 in terms of relative contribution?

但是，關於背後的驅動因素，您還有什麼可以補充說明的嗎？關於 ORKAMBI 指南，我想請您更清楚地說明美國和其他地區的貢獻，以及第 6 至 11 例患者的相對貢獻？

Thank you.

謝謝。

Sure, Terence.

當然可以，特倫斯。

So on the respiratory events, I think what I would say there is, now what we're reporting today, is what we're seeing in the real world usage of ORKAMBI in the broad population. Obviously, the clinical trial population that we studied in traffic and transport is a very controlled situation. That was patients with an FEV1 between 40 and 90.

所以關於呼吸系統事件，我認為現在我們報告的是，我們在 ORKAMBI 在廣大人群中的實際使用中看到的情況。顯然，我們在交通運輸領域研究的臨床試驗族群是一個受控程度很高的情況。這些患者的第一秒用力呼氣容積（FEV1）在 40 到 90 之間。

So really whilst, we tried to extrapolate from the clinical trial experience, the real world experience, that's one of the reasons -- that uncertainty is one of the reasons why we wanted to make sure we had sufficient time in market before we gave guidance, was because we really wanted to see how the product would get used in the real world.

所以，雖然我們試圖從臨床試驗經驗和真實世界經驗中進行推斷，但其中一個原因是——這種不確定性——這也是我們希望確保在給出指導意見之前有足夠的市場推廣時間的原因之一，因為我們真的想看看該產品在現實世界中是如何被使用的。

In terms of the contribution of the various different parts of the world to our ORKAMBI revenue guidance, as you might expect, the vast majority of these revenues is going to come from here in the US. There will be a contribution ex-US, but it's going to be relatively small. And then, incorporated within our guidance, as we said, is also an expectation that we will see an approval in 6 to 11 year-olds in the latter part of 2016, which would give us access to an eligible population of about 2.5 thousand. And that's also incorporated within our guidance. But that approval is not anticipated until the back end of 2016.

就世界各地對 ORKAMBI 收入預期的貢獻而言，正如您所預料的那樣，這些收入的絕大部分將來自美國。美國以外也會有貢獻，但金額相對較小。此外，正如我們所說，我們的指導方針中還包含一項預期，即在 2016 年下半年，我們將看到 6 至 11 歲兒童獲得批准，這將使我們能夠接觸到大約 2500 名符合條件的人群。這一點也已納入我們的指導方針中。但預計要到 2016 年底才能獲得批准。

Thank you. And our next question comes from the line of Geoff Meacham of Barclays. Your line is now open.

謝謝。下一個問題來自巴克萊銀行的傑夫·米查姆。您的線路已開通。

Hello. Thanks for taking the question. I got a couple.

你好。感謝您回答這個問題。我買了幾個。

I'm trying to get a sense, as to when you realized that compliance or persistent or discons were different for ORKAMBI versus KALYDECO, or commercial ORKAMBI versus Phase 3? You had a chance, 3Q call, JPM, 4Q call to be crystal clear on this. And it's 10 months almost into the launch, and now we're getting some detail.

我想了解一下，您是什麼時候意識到 ORKAMBI 與 KALYDECO，或者商業化 ORKAMBI 與第三期臨床試驗藥物在合規性、持續性或停藥方面存在差異的？你們本來有機會在第三季財報電話會議、摩根大通財報電話會議和第四季財報電話會議上把這個問題說清楚。距離產品發布已經過去了近 10 個月，現在我們終於獲得了一些細節資訊。

I just have a couple follow-ups.

我還有幾個後續問題。

So Geoff, thanks for the question. Let's see, so I just want to take us back a few months. Which as we went into JPMorgan, and also year end conference call at the end of January, we were very clear, with what we wanted to do regarding the ORKAMBI guidance. For us at that point in time, it was early in the launch.

傑夫，謝謝你的提問。嗯，我想帶大家回到幾個月前。正如我們在摩根大通會議上以及 1 月底的年終電話會議上所表達的那樣，我們非常清楚我們想對 ORKAMBI 的業績指引做些什麼。對我們來說，當時還處於產品發布的早期階段。

Yes, we had recruited a number of patients onto ORKAMBI, but it was still early in the launch to understand treatment patterns. We stated that very clearly.

是的，我們已經招募了一些患者加入 ORKAMBI，但當時還處於推廣初期，尚需了解治療模式。我們已經非常明確地闡述了這一點。

What we've been able to do now, as we sit here, as you point out just over nine months into the launch, we've been able to take a significant bolus of patients. For example, 3,000 patients that initiated in the first three months of, since approval. And we've been able to track those six to nine months.

正如你所指出的，在計畫啟動九個多月後，我們已經能夠接納大量病患。例如，自獲批以來的前三個月內，已有 3,000 名患者開始接受治療。我們已經能夠追蹤這六到九個月的情況。

What that allowed us to do was to understand the compliance rates, helped us to understand discontinuation rates, and also the pattern of discontinuation. As Stuart mentioned, that's been an important feature for us. So this was the -- we feel as though we're in this position at this point in time, where we've been able to track a substantial amount of patients over a good period of time, to have the confidence to provide guidance for 2016.

這使我們能夠了解依從率，幫助我們了解停藥率以及停藥模式。正如斯圖爾特提到的那樣，這對我們來說一直是一個重要的功能。所以，我們感覺目前我們已經能夠追蹤相當數量的患者一段時間，因此我們有信心為 2016 年提供指導。

The comparison to KALYDECO was less relevant, for us, it was more about the treatment patterns for ORKAMBI. ORKAMBI is a different medicine than KALYDECO, based on its clinical data and the patient population. But we now have enough confidence to provide you with the ORKAMBI guidance.

與 KALYDECO 的比較意義不大，對我們來說，更重要的是 ORKAMBI 的治療模式。根據臨床數據和患者群體來看，ORKAMBI 與 KALYDECO 是不同的藥物。但我們現在有足夠的信心為您提供 ORKAMBI 指南。

Okay.

好的。

And just a follow up to some earlier questions; to ask it a different way, for patients that are at low FEV1 at baseline and do experience bronchoconstriction, is there a treatment protocol in place? I mean, we've obviously heard of things like half dose, then up titrate, or dose skipping. Is there something that you can recommend to pulmonologists, a strategy for those that do experience the bronchoconstriction?

針對先前的一些問題，我再補充一下：對於基線 FEV1 較低且出現支氣管收縮的患者，是否有相應的治療方案？我的意思是，我們當然聽說過先減半劑量，然後逐漸增加劑量，或者跳過劑量之類的方法。您對肺科醫生有什麼建議，或者有什麼策略可以幫助那些有支氣管收縮症狀的患者？

Thank you.

謝謝。

Geoff, it's Jeff Chodakewitz, maybe just to give you a couple of comments about that. We don't have anything, in terms of very concrete specific guidance that we can give you, but we can make a couple of observations. First of all, what's clear from speaking to our investigators, and also to physicians in the field, that clearly the support for the patients, both setting expectations for the patient, and for the physician, and helping patients in those early weeks manage any symptoms, we think is very important. And something that goes back to some of the education questions that we've heard about earlier.

傑夫，我是傑夫·喬達克維茨，可能想就此事說幾點看法。就具體指導而言，我們沒有什麼可以給您的，但我們可以提出幾點看法。首先，透過與我們的調查人員以及該領域的醫生交談，我們清楚地認識到，對患者的支持，包括為患者和醫生設定預期，以及幫助患者在最初幾週內控制任何症狀，我們認為非常重要。而這又與我們之前討論過的一些教育問題有關。

We are also collecting information in our own study for patients whose FEV1s were less than 40, and we're in the process of summarizing that. We did in that study, give patients the option to start on a lower dose, and we'll get that data together and summarize it.

我們自己的研究也收集了 FEV1 小於 40 的患者的信息，目前正在進行總結。在那項研究中，我們允許患者選擇從較低劑量開始治療，我們將收集這些數據並進行總結。

But it's not going to be the kind of data that says, here's a specific recommendation. We know that that is being used. But it's really still about physicians, and their patients working together to manage.

但這並非那種會給出具體建議的數據。我們知道這種做法正在被使用。但歸根究底，還是醫生和患者共同努力進行治療。

Okay, thanks.

好的，謝謝。

Thank you. And our next question comes from the line of Mark Schoenebaum of Evercore. Your line is now open.

謝謝。我們的下一個問題來自 Evercore 樂團的 Mark Schoenebaum。您的線路已開通。

Hello. I really appreciate you taking the question on the call.

你好。非常感謝您在電話會議中回答這個問題。

Number one, I would just like to know, have you been surprised by the way the launch has unfolded? I'm sure you had some projections a year ago for persistence, [sully things] and have you been surprised?

首先，我想知道，你對這次發表會的進展方式感到驚訝嗎？我相信你一年前對堅持不懈、[糟糕的事情]有一些預測，結果讓你感到驚訝嗎？

Number two, I know you can't comment specifically on peak numbers, but the sell side consensus is around $4 billion at peak for ORKAMBI. I'm just wondering, can you just talk about that? And then finally, is there any opportunity for re-initiation in these patients that dropped out early?

第二，我知道你不能具體評論峰值數字，但賣方普遍認為 ORKAMBI 的峰值約為 40 億美元。我只是想問，您能談談這件事嗎？最後，對於這些早期退出治療的患者，是否有機會重新開始治療？

Thank you very much.

非常感謝。

We have a list of questions there. So if we don't get to all of them, please (multiple speakers)

我們那裡有一份問題清單。所以如果我們沒能全部回答到，請（多位發言者）

Sorry about that.

抱歉。

Yes, so we're all scribbling them down. But if we don't get to them, please say them again.

是的，所以我們都在把它們記下來。但如果我們沒能聽到這些，請再說一次。

So Mark, in terms of how we feel about the launch, I'd say we're very pleased with the way the launch has progressed here in the US. So from how we were able to work with payers, to get access and reimbursement from ORKAMBI from early on in the launch, to the rate of uptake that we've seen. I mean, to get close to 65% of eligible patients initiated within the first nine months is a fairly steep ramp, and so one we're pleased with.

所以馬克，就我們對這次發表會的感受而言，我想說我們對這次在美國的發表會進展非常滿意。因此，從我們如何與付款方合作，從 ORKAMBI 的早期推廣階段就獲得准入和報銷，到我們所看到的接受率。我的意思是，要在前九個月內讓近 65% 的符合條件的患者開始接受治療，這是一個相當陡峭的增長速度，因此我們對此感到滿意。

So I think overall, we're pleased, and the launch has played out much as we anticipated. In terms of the potential for re-initiations, we have heard anecdotally from physicians that they have tried re-initiating patients on ORKAMBI. We don't have much in the way of clinical data to be able to support that, but we are certainly aware that there are physicians who've done that successfully before for some of their patients. So that certainly is something that we'll continue to watch in the marketplace.

所以總的來說，我們很滿意，發表會的進展基本上符合我們的預期。至於重新開始治療的可能性，我們從醫生那裡聽說，他們曾嘗試讓病人重新開始使用 ORKAMBI。我們沒有太多臨床數據來支持這一點，但我們當然知道，有些醫生以前曾成功地為他們的一些病人這樣做過。所以，這無疑是我們將繼續在市場上關注的話題。

Mark, this is Jeff Leiden. Maybe I just add a little bit more of a 10,000-foot view, on both KALYDECO and ORKAMBI. Like you, I have been involved with many, many drug launches, and I think it's worth just putting those in perspective.

馬克，我是傑夫‧萊頓。或許我應該在 KALYDECO 和 ORKAMBI 這兩個項目上，再增加一些 10,000 英尺高的視角。和你一樣，我也參與過很多很多藥物的上市，我認為有必要把這些經驗放在一個更客觀的角度來看待。

From the standpoint, as an example in ORKAMBI of getting to 65% of the patients in nine months, and of course, with KALYDECO, it was close to 90%. That's a fairly unusually fast ramp. And from the standpoint of persistence, the kinds of numbers Stuart's talking about, lets say, 70% to 80% is the number that we settled out at, is still a very, very high number compared to most chronic medicines. And we believe that really represents the correct perception that both physicians and patients have about the value of these medicines, in treating the underlying cause of the disease for a long period of time.

以 ORKAMBI 為例，9 個月內有 65% 的患者獲得治療，而 KALYDECO 的治療率則接近 90%。那是一個相當不尋常的快速坡道。從堅持性的角度來看，史都華所說的數字，比如說，我們最終確定的 70% 到 80%，與大多數慢性病藥物相比，仍然是一個非常非常高的數字。我們相信，這真正代表了醫生和患者對這些藥物價值的正確看法，即長期治療疾病的根本原因。

And that really underlies our thinking about the pipeline as well, because as we develop this next set of medicines, including next gens, and [poclios] and [what we] things like CRISPR, we're talking about progressively increasing the benefit/risk profile of our portfolio of drugs that these patients can take. And that only, of course, will increase both persistence and compliance rates. So overall, very pleased with where we are. We know we have more work to do to get to more patients and improve therapy. But these two drugs have really performed quite well so far.

這也正是我們對研發管線思考的根本原因，因為隨著我們開發下一批藥物，包括下一代藥物、[poclios]以及[我們]像CRISPR這樣的技術，我們正在逐步提高我們藥物組合的益處/風險比，以便這些患者能夠服用。當然，這只會提高堅持率和依從率。總的來說，我們對目前的狀況非常滿意。我們知道，為了惠及更多患者並改善治療方案，我們還有更多工作要做。但到目前為止，這兩種藥物的表現確實相當不錯。

Thanks, Jeff.

謝謝你，傑夫。

Thank you. And our next question comes from the line of Geoffrey Porges of Leerink Partners. Please go ahead.

謝謝。我們的下一個問題來自 Leerink Partners 的 Geoffrey Porges。請繼續。

Thanks very much. Just a few questions. First, could you help us out? Just give us the breakdown between US and ex-US sales of KALYDECO, so we're all on the same page?

非常感謝。幾個問題。首先，您能幫我們一個忙嗎？請提供KALYDECO在美國本土和美國以外地區的銷售額明細，這樣我們才能了解清楚。

And then, I want to go back to Jeff's comments. And Jeff, could you really clarify this residual function change, and what has altered in terms of your statistical analysis, or your assumptions about the activity of the drug, or the combination? And give us a sense of what the hurdle there is for ORKAMBI's effect?

然後，我想回到傑夫的評論上來。Jeff，你能否詳細解釋一下殘差函數的變化，以及你的統計分析、藥物活性假設或藥物組合方面發生了哪些變化？請您介紹一下ORKAMBI效應面臨的障礙是什麼？

And then lastly, on this issue of persistence, is it reasonable to assume that about 50% of patients of the eligible pool are on drug right now? Because we keep going round and round about initiations and discontinuations. But surely what's important is the number of patients who remain on drug at the end of the quarter, and is 50% roughly the right number? Or perhaps slightly below that 45% to 50% of the eligibles? Is that the right way to think about it?

最後，關於堅持用藥的問題，假設符合條件的患者群體中約有 50% 目前正在服用該藥物是否合理？因為我們總是圍繞著開始和結束繞圈。但真正重要的是季度末仍繼續服用該藥物的患者人數，50% 大致是正確的數字嗎？或許略低於符合條件者的 45% 到 50%？這種思考方式正確嗎？

Thanks.

謝謝。

So Jeff, it's Stuart here.

傑夫，我是史都華。

I'll take your first question around KALYDECO revenues, and then I'll hand it over to Jeff Chodakewitz. So within the total KALYDECO revenues of $171 million for the first quarter of 2016, $95 million of that was in the US, and the balance of that $76 million, was in international.

我先回答你關於 KALYDECO 收入的第一個問題，然後我會把問題交給 Jeff Chodakewitz。因此，在 KALYDECO 2016 年第一季 1.71 億美元的總收入中，9,500 萬美元來自美國，其餘 7,600 萬美元來自國際市場。

Thank you.

謝謝。

And Jeff, in terms of the residual function study, we really stepped back and said, is there an opportunity to reduce the end of the study somewhat, without sacrificing the integrity of the trial? And we really looked at that two ways, that we saw opportunity. One is that we've really focused our statistical analyses on key parameters, and that really allows us to take care of that. The other thing is that we also looked at the line to data, and saw that the discontinuation rate from the trial was actually lower than what we had left room for, and that also was an opportunity to reduce the end.

傑夫，就殘餘功能研究而言，我們認真思考過，有沒有可能在不犧牲試驗完整性的前提下，稍微縮短研究的最後階段？我們從兩個方面考慮了這個問題，我們看到了機會。一方面，我們確實將統計分析的重點放在了關鍵參數上，這使我們能夠真正解決這個問題。另外，我們也查看了數據，發現試驗的終止率實際上低於我們預留的空間，這也是減少終止率的機會。

Great. Thanks very much.

偉大的。非常感謝。

And finally, Jeff, to your question on ORKAMBI, your back of envelope math is approximately right at the end of the third quarter. You're right, about 50% of the eligible population were on.

最後，傑夫，關於你提出的 ORKAMBI 問題，你粗略的計算結果大約在第三季末。你說得對，大約有 50% 的符合條件的人口參與了。

Clearly, that's a moving target, because it's a mix of the discontinuations and the initiation. The important thing I would add to that number is, that moving forward in Q2 and beyond, we do expect patient initiations, which we've continued to see in April in the US. And obviously we continue to see internationally in places like Germany, we expect to outpace discontinuations, which is why we are predicting quarter on quarter growth for the remainder of 2016 and beyond.

顯然，這是一個不斷變化的目標，因為它既包含停止，也包含開始。我想補充的重要一點是，展望第二季度及以後，我們預計患者啟動治療的情況會繼續增加，我們在4月的美國也看到了這種情況。顯然，我們在德國等國際市場上繼續看到，預計新增訂單將超過停產訂單，因此我們預測 2016 年剩餘時間及以後將實現季度環比增長。

Great. Thanks very much.

偉大的。非常感謝。

Thank you. And our next question comes from the line of Brian Abrahams of Jefferies. Your line is now open.

謝謝。下一個問題來自傑富瑞集團的布萊恩亞伯拉罕。您的線路已開通。

Hello. Thanks very much for all the granularity, and I appreciate you taking my question. My first question is I'm wondering if you're seeing any trends towards maybe less sick higher FEV1 patients going onto therapy over time, which could -- with ORKAMBI, which would theoretically improve persistence and compliance?

你好。非常感謝您如此詳細地解答，也感謝您回答我的問題。我的第一個問題是，我想知道您是否觀察到隨著時間的推移，病情較輕、FEV1 較高的患者接受治療的趨勢，這或許可以——使用 ORKAMBI——理論上提高治療的持續性和依從性？

And then on 661, if 661 looks better tolerated, but perhaps less efficacious than lumacaftor? I'm just wondering how you weigh which potential backbone to combine with the next generation corrector into a triple combo?

那麼，如果 661 看起來耐受性更好，但療效可能不如 lumacaftor 呢？我只是想知道，您是如何權衡將哪種潛在的骨架與下一代矯正器組合成三合一產品的？

Thanks.

謝謝。

In terms of trends of any trends to where the product is being used, in either sicker patients or less sick patients, to be honest with you, Brian, with 65% of eligible patients being initiated, it is being used across the board. Obviously, we've got a range of different physicians and centers here.

就產品使用趨勢而言，無論是病情較重的患者還是病情較輕的患者，坦白說，布萊恩，65% 的符合條件的患者都已開始使用該產品，這表明該產品已被廣泛使用。顯然，我們這裡有各種各樣的醫生和醫療中心。

Some started using it in their more severe patients. Others started using it in their less severe patients, but we are really seeing usage across the whole range of FEV1s of patients, as you would imagine with 65% of eligible patients having been initiated. And on the backbone, for the triple combination, I'll pass that over to Jeff Leiden.

有些醫生開始在病情較重的患者身上使用它。其他醫生開始在病情較輕的患者中使用該療法，但正如你所料，我們看到該療法已應用於所有 FEV1 值的患者，65% 的符合條件的患者已經開始使用該療法。至於主幹部分，也就是三連擊，我交給 Jeff Leiden 來解答。

Yes, just on the triple combination, obviously, we can't speculate there, exactly what will happen, but I would remind you there were a number of reasons that 661 is the preferable partner. Most of those have to do with drug-drug interactions and making it simpler to combine it into a triple regimen.

是的，就三重組合而言，顯然我們不能預測具體會發生什麼，但我提醒您，661 是更好搭檔的原因有很多。其中大部分與藥物交互作用有關，以及如何更輕鬆地將它們組合成三重療法。

So what I would say is, all things being equal, if 661 and lumacaftor had equal efficacy in combination with KALYDECO, we're certainly going to go with 661, because of those pharmacokinetic properties. Did that answer the question?

所以我想說的是，在其他條件相同的情況下，如果 661 和 lumacaftor 與 KALYDECO 聯合使用具有相同的療效，我們肯定會選擇 661，因為它具有良好的藥物動力學特性。這樣回答了這個問題嗎？

Yes. Well, not exactly.

是的。嗯，也不完全是。

I was wondering whether -- I mean, we know 661 has less CYP3A4 interactions. I was wondering whether some of the real world ORKAMBI side effects that you're seeing, are perhaps driven, by not only the respiratory AEs, but driven by CYP3A4, which we know is going to look better with 661 and how you weigh that, if efficacy is perhaps not as good?

我想知道——我的意思是，我們知道 661 與 CYP3A4 的相互作用較少。我想知道，您在現實世界中觀察到的一些 ORKAMBI 副作用，是否可能不僅是由呼吸系統不良反應引起的，還可能由 CYP3A4 引起。我們知道，CYP3A4 在 661 時會表現得更好。如果療效可能不如 661，您是如何權衡這一點的？

Yes, that's not the reason, just to be clear. So those AEs, are not driven by CYP interactions. We feel they are driven, as we said before, by off-target bronchoconstriction. It's unique to lumacaftor. We don't see or haven't seen with 661.

是的，澄清一下，那不是真正的原因。所以這些不良反應並非由 CYP 交互作用所引起。我們認為，正如我們之前所說，它們是由非靶向支氣管收縮引起的。這是lumacaftor獨有的。我們沒有看到或還沒看到 661。

Thanks.

謝謝。

Thank you. Our next question comes from the line of Adam Walsh of Stifel. Your line is now open.

謝謝。我們的下一個問題來自 Stifel 的 Adam Walsh。您的線路已開通。

Hey, thanks for taking my question.

嘿，謝謝你回答我的問題。

A few weeks ago, we published a 47-physician ORKAMBI survey, and a few things jumped out at us. I want to bounce them off of you. Most notably, our survey showed that if patients discontinue ORKAMBI due to drug-related side effects, 70% of doctors encouraged these patients to restart the drug. And then, a very meaningful percentage of those patients, not only successfully restart the drug, but also subsequently remain on the drug long-term.

幾週前，我們發布了一項針對 47 位醫生的 ORKAMBI 調查，其中有幾點引起了我們的注意。我想和你討論一下。最值得注意的是，我們的調查顯示，如果患者因藥物相關副作用而停止服用 ORKAMBI，70% 的醫生鼓勵這些患者重新開始服用該藥物。而且，相當一部分患者不僅成功地重新開始服用該藥物，而且隨後長期堅持服用該藥物。

So my questions are, is this consistent with your own internal research? Are patient restarts factored into your guidance? And if so, to what extent? Thank you.

所以我的問題是，這與你們自己的內部研究結果一致嗎？您的指導方案中是否考慮了病人重新入院的情況？如果屬實，程度如何？謝謝。

So Adam, it's Stuart here. Thanks for the question.

亞當，我是史都華。謝謝你的提問。

In terms of restarts, yes, your survey is consistent with what we've heard, in that we have heard from physicians that they are trying to restart ORKAMBI in some of their patients who they have, previously had to discontinue the product in, largely because, as you know, they are often firm believers that treating the underlying cause of the disease is clearly a good thing for those patients, if they can tolerate the medicine.

關於重新開始使用ORKAMBI的情況，是的，你們的調查結果與我們聽到的情況一致，我們從醫生那裡了解到，他們正在嘗試重新給一些之前不得不停止使用該產品的患者使用ORKAMBI，這主要是因為，正如你們所知，他們通常堅信，如果患者能夠耐受這種藥物，那麼治療疾病的根本原因顯然對這些患者來說是件好事。

In terms of the absolute volume of that, at the minute that's hard to quantify. We've certainly heard it anecdotally. We've certainly heard success stories.

就絕對數量而言，目前很難量化。我們確實從一些傳聞中聽說過這種說法。我們當然聽過一些成功案例。

It's fair to say, though, that within our guidance we've assumed a relatively minimal impact from restarts, because at this time, we really don't have evidence that it's happening in quite the numbers that perhaps people have said that they might do it in. So at the moment, within our guidance, a relatively minimal amount of restarting patients is assumed to happen in 2016 here in the US.

不過，公平地說，在我們的指導方針中，我們假設重啟的影響相對較小，因為目前我們確實沒有證據表明重啟的數量像人們所說的那麼多。因此，目前根據我們的指導，預計 2016 年美國重新開始治療的患者數量將相對較少。

Understood. Thank you.

明白了。謝謝。

Thank you. Our next question comes from the line of Phil Nadeau of Cowen and Company. Your line is now open.

謝謝。我們的下一個問題來自 Cowen and Company 的 Phil Nadeau。您的線路已開通。

Good afternoon. Thanks for taking my questions.

午安.謝謝您回答我的問題。

Two on commercial, then a quick one on the pipeline. On the commercial, can you give us a sense of how many lives outside of the US could gain reimbursement for ORKAMBI in 2017? I'm sure you have internal estimates and ranges. I'm curious what those are?

先跑兩班商業航班，然後快速跑一趟管道航班。關於這則廣告，您能否大致說明一下，2017 年美國以外有多少人可以透過 ORKAMBI 獲得報銷？我相信你們內部肯定有估算和範圍。我很好奇那些是什麼？

And then, similarly in the younger kids, do you expect any different penetration of ORKAMBI into that population than you've seen in the older kids and adults? Then last, on the triple, can you let us know if you've combined all three drugs in healthy volunteers yet? And what your disclosure strategy will be when you move into Phase 2? How much data from the Phase I will we get?

同樣地，對於年齡較小的孩子，您是否預期 ORKAMBI 在該族群中的滲透率會與在年齡較大的孩子和成年人中看到的情況有所不同？最後，關於三聯療法，您能否告知我們您是否已在健康志願者身上同時使用過這三種藥物？那麼，進入第二階段後，你們的資訊揭露策略是什麼？第一階段試驗我們能獲得多少數據？

Thanks.

謝謝。

So Phil, it's Stuart here. I'll take those two first commercial questions.

菲爾，我是史都華。我先回答這兩個商業問題。

In terms of the number of lives that might be eligible, so the number of patients with the F508del homozygous mutation 12 and above in Europe is somewhere around 12,000. Within our 2016 guidance, the only country that we're assuming we're going be able to recognize revenues for is in Germany.

就符合條件的生命數量而言，歐洲患有 F508del 純合突變 12 及以上患者的數量約為 12,000 人。在我們 2016 年的指導方針中，我們假設唯一能確認收入的國家是德國。

We're not in a position to be able to give 2017 guidance at this point. And trying to predict exactly when these reimbursement discussion is going to conclude is frankly, impossible to do, because clearly, it's a negotiation and the vast majority of countries don't have a formal time clock. And so, at this point, we're really not in a position to be able to speculate on when those might be concluded.

目前我們還無法提供 2017 年的業績指引。坦白說，要準確預測這些報銷討論何時結束是不可能的，因為很明顯，這是一場談判，而絕大多數國家都沒有正式的時間表。因此，目前我們還無法推測這些項目何時能夠完成。

In terms of what we would be anticipating in the 6 to 11-year-old population? If we are successful in gaining approval for that here in the US, then our anticipation would be much as we've seen with KALYDECO, that the uptake there is likely to be similarly robust as we have seen in adults. Although I would remind you, that from a 2016 perspective, that's likely to come in the second half, or in the second half of the second half of 2016.

那麼，我們對 6 至 11 歲兒童族群有何預期呢？如果我們在美國成功獲得批准，那麼我們預計，就像 KALYDECO 一樣，它的市場接受度可能會像我們在成年人中看到的那樣強勁。不過我要提醒各位，從 2016 年的角度來看，這很可能會在下半年，或是 2016 年下半年的下半年發生。

And Phil, I'll take the last question. So the Phase I study in healthy volunteers is still ongoing, so we can't make a comment on that. But as terms of disclosure and time line, still as we've discussed before, we expect to be in patients with triple combination in the second half of the year.

菲爾，我來回答最後一個問題。針對健康志願者的第一階段研究仍在進行中，所以我們無法對此發表評論。但就披露條款和時間表而言，正如我們之前討論過的，我們預計將在今年下半年開始對接受三聯療法的患者進行治療。

The disclosure, if I wrap up the Phase I around that, will be relevant information that supports the Phase 2 study design. At this point, that is too difficult to describe. And we'll let you know when we have that information, and we're initiating the Phase 2 study.

如果我圍繞這一點結束第一階段的研究，那麼披露的資訊將與第二階段的研究設計相關。目前，這種情況很難描述。我們會盡快通知您相關訊息，並啟動第二階段研究。

Great. Thanks for taking my questions.

偉大的。謝謝您回答我的問題。

Our next question comes from the line of Cory Kasimov of JPMorgan.

我們的下一個問題來自摩根大通的科里·卡西莫夫。

Hey, good afternoon. Thanks for taking the questions. I have two left for you.

嘿，下午好。謝謝您回答問題。我這裡還剩兩個給你。

So realize it's early, but wanted to ask about the potential of payer reauthorizations on ORKAMBI? How common is it, and how does it compare with the process you saw with KALYDECO?

我知道現在還為時過早，但還是想問一下 ORKAMBI 是否有可能獲得支付方的重新授權？這種做法有多普遍？它與您在 KALYDECO 中看到的流程相比如何？

And then, a capital allocation question for you. Now that you're profitable and growing and you're sitting on $1 billion in cash on your balance sheet, at what point would you consider buying back some of your stock?

接下來，我問你一個關於資本配置的問題。現在公司獲利成長，資產負債表上還有 10 億美元的現金，您會在什麼時候考慮回購部分股票？

Thanks.

謝謝。

So Cory, on the payer reauthorizations, not all payers have published policies that include their reauthorization criteria. So that's the first thing I'd say. Of the ones you have, most have a time clock of 6 to 12 months. So we're really only now beginning to get to the point of, patients getting to the time point when they are having to go through the reauthorization process.

所以，科里，關於付款方重新授權的問題，並非所有付款方都公佈了包含其重新授權標準的政策。這是我首先要說的。你擁有的那些，大多數都有 6 到 12 個月的期限。所以我們現在才真正開始接觸到病人需要經歷重新授權流程的階段。

Having said that, so the payers that have published policies or where their reauthorization criteria are known, the vast majority of them are either in line with the label, or reflect the systemic benefits of ORKAMBI. And by that, I mean they recognize that this product can have benefits across multiple end points, and either improvements or stabilization in those end points qualifies as a successful outcome. So whilst we are only now beginning to get into the period of seeing those reauthorizations, I feel good about the reauthorization criteria that we've seen to date. And to the last part of your question, they are not dissimilar at all to what we saw with KALYDECO.

也就是說，對於那些已經公佈政策或已知其再授權標準的支付方而言，絕大多數要么與標籤相符，要么反映了 ORKAMBI 的系統性益處。我的意思是，他們認識到該產品可以在多個終點產生益處，而這些終點的改善或穩定性都算作成功的結果。雖然我們現在才剛開始看到這些重新授權的階段，但我對迄今為止我們看到的重新授權標準感到滿意。至於你問題的最後一部分，它們與我們之前在 KALYDECO 中看到的情況完全一樣。

And to the last question, we have thought about stock buybacks in terms of capital allocation. But as we think about the priority of capital allocation for our business, I'll just give you a broader thought, which is we're still in this transitional period of moving into profitability and cash generation, and watching the revenue curve.

至於最後一個問題，我們已經從資本配置的角度考慮股票回購。但是，當我們考慮公司資本配置的優先事項時，我只想給大家一個更廣闊的思路，那就是我們仍處於向盈利和現金流過渡的時期，並且正在密切關注收入曲線。

As we go up the revenue curve, and we drive revenue growth and therefore earnings growth, which translates to more cash generation, we look to apply that capital to reinvest back in the business first, first internally into our pipeline.

隨著營收曲線的上升，我們推動營收成長，進而推動獲利成長，進而產生更多現金流。我們首先考慮將這些資金再投資於業務，首先是內部投資於我們的產品線。

But then potentially outside of the Company to diversify and expand our pipeline. And we've already done activities in that area, as you know, with CRISPR and our ENaC inhibitor. So those continue to be the priorities. It's the internal investment, it's the external investment.

但隨後可能會在公司外部尋求多元化和擴大我們的產品線。如您所知，我們已經在該領域進行了一些活動，例如使用 CRISPR 和我們的 ENaC 抑制劑。所以這些仍然是優先事項。既包括內部投資，也包括外部投資。

As we go up that revenue growth curve, and have greater capital to allocate, we will give consideration to capital strategies, such as share buybacks. But at this point in time, it's a little early for us. And if we were to move into something in the near future, it would be of a smaller scale to stop the shares outstanding creep that occurs each year through option exercises.

隨著收入成長曲線的上升，以及可分配資本的增加，我們將考慮資本策略，例如股票回購。但就目前而言，對我們來說還為時過早。如果近期我們要採取一些措施，那規模也會小一些，目的是為了阻止每年因選擇權行使而導致的流通股數量不斷增加。

All right. Thanks. Appreciate it.

好的。謝謝。謝謝。

Thank you. Our next question comes from the line of Alethia Young of Credit Suisse.

謝謝。我們的下一個問題來自瑞士信貸的 Alethia Young。

Hello. Thanks for taking my question. The three of them are around compliance. And I guess, when we looked at the math, we did over the quarters, it seemed like the first two quarters, the compliance was potentially higher, like 95%. And maybe in this quarter, based on our math, it would have gotten to about 80%. So one, is that analysis fair? Two, can you give us any color on, if the scripts are written in one or three-month increments?

你好。謝謝您回答我的問題。這三者都與合規性有關。我想，當我們查看各季度的數學數據時，似乎前兩個季度的合規率可能更高，達到 95%。根據我們的計算，本季或許能達到 80% 左右。所以，第一，這種分析公平嗎？第二，您能否透露一下劇本是按一個月還是三個月的周期編寫的？

And then, third, when you think about 70% to 80% range on compliance, which actually does move the model quite a bit, what qualitatively, do you think about that kind of gets you in the 70% range versus the 80% range? Should we think about like, amount of days that are people are taking? So there's a delta in the days they miss, and kind of adding that up and thinking about it? Or is there some other way, we should think about quantifying compliance?

第三，當您考慮合規率在 70% 到 80% 的範圍內時（這實際上會極大地改變模型），您認為從定性角度來看，是什麼因素導致合規率達到 70% 而不是 80% 呢？我們是否應該考慮人們需要花費多少天時間？所以他們缺勤的天數會有一個差值，把這些差值加起來仔細想想會怎麼樣？或者，我們是否應該考慮採用其他方法來量化合規性？

Thanks.

謝謝。

So let me try, and answer those sequentially.

那我就試著按順序回答這些問題吧。

In terms of the compliance trend, compliance is the metric that you need the longest period of time to measure, because clearly, this is a chronic medicine. And so, in the first prescription they get, your assumption is you're 100% compliant, and you have to wait until they get the second prescription to work out exactly what it is. So this is the one that really takes the longest period of time for us to get a good handle on.

就依從性趨勢而言，依從性是需要最長時間才能衡量的指標，因為很明顯，這是一種慢性病。因此，在他們拿到的第一張處方中，你假設你 100% 遵醫囑，你必須等到他們拿到第二張處方才能弄清楚到底是什麼。所以，這是我們需要花費最長時間才能真正掌握的。

I don't know obviously, the intricacies of your model. I'll just reiterate that we are, based on the trends that we've seen to date, and the experience we've got with the patients who have been treated to date, our expectation for the year, and the assumption on which our guidance is built, is that it will be somewhere between 70% and 80% for ORKAMBI this year.

我當然不了解你模型的複雜細節。我只想重申，根據我們迄今為止看到的趨勢，以及我們迄今為止治療的患者的經驗，我們對今年的預期，以及我們制定指導方針所依據的假設，是今年 ORKAMBI 的成功率將在 70% 到 80% 之間。

In terms of the one- or three-month script, the vast majority are written for one month. There are some three month prescriptions written, but the vast majority of prescriptions are written for -- on a monthly basis.

就一個月或三個月的劇本而言，絕大多數劇本都是為一個月的時間而寫的。有些處方是三個月的，但絕大多數處方都是每月開立的。

And in terms of qualitatively, what would lead you to one end versus the other? To me this is all about education, and our ability to help providers to give to their patients information which educates them on the nature of the disease, the underlying defect, the fact that ORKAMBI is designed to treat those underlying defects. And to the extent they believe in the science, believe in the long-term benefits that ORKAMBI could provide to them, then I think that's only likely to lead for patients having a higher compliance rate.

從定性角度來看，是什麼因素會讓你選擇其中一個結果而不是另一個結果？對我來說，這一切都與教育有關，我們有能力幫助醫療服務提供者向患者提供信息，讓他們了解疾病的性質、潛在的缺陷，以及 ORKAMBI 旨在治療這些潛在缺陷的事實。如果他們相信科學，相信 ORKAMBI 能為他們帶來長期的益處，那麼我認為這只會讓病人的依從性更高。

We're very focused on that. We're certainly taking all the learnings we can from our experience from KALYDECO, to support patients to take their prescriptions in line with their physician's recommendations.

我們非常關注這一點。我們一定會從 KALYDECO 的經驗中汲取一切可以學到的東西，以幫助患者按照醫生的建議服用處方藥。

Thanks.

謝謝。

Thank you. Our next question comes from the line of Matthew Harrison of Morgan Stanley. Your line is now open.

謝謝。我們的下一個問題來自摩根士丹利的馬修·哈里森。您的線路已開通。

Great. Thanks for taking the question. I had two, which are somewhat follow-ups on Phil's question.

偉大的。感謝您回答這個問題。我有兩個問題，算是對 Phil 問題的後續探討。

Just on next generation correctors and those studies, can you just tell us if you saw a safety event, what kind of safety event would be disclosable, versus not disclosable? And then, there is a point in time that we're going to see PK data from healthy volunteers, which might help us better understand how the drug levels that we saw on HB data might compare in patients?

關於下一代矯正器和相關研究，您能否告訴我們，如果您發現安全事件，哪些安全事件需要揭露，哪些不需要揭露？然後，在某個時間點，我們將看到來自健康志願者的藥物動力學數據，這可能會幫助我們更好地了解我們在 HB 數據中看到的藥物水平在患者體內的比較情況？

And then, a separate commercial question, just in the 6 to 12 pool for ORKAMBI, are your assumptions for persistence and discontinuation rate, the same as what you're seeing now in the older population? And if they are not the same, can you just explain why? Thanks.

另外，還有一個商業問題，僅針對 ORKAMBI 的 6 至 12 歲人群，您對持續性和停藥率的假設是否與您現在在老年人群中看到的情況相同？如果它們不一樣，你能解釋一下原因嗎？謝謝。

So maybe I'll take the first couple of questions.

那我先回答前幾個問題吧。

So with the next-gen disclosure, what would be require disclosure, it's reg FD. And if there was a material adverse event, we would have to disclose that. If you wanted me to give you an example, that would be a discontinuation of the trial, for example, and we would have to disclose that.

因此，下一代資訊揭露要求，即 reg FD，需要揭露的內容。如果發生重大不利事件，我們必須予以揭露。如果要我舉個例子，例如試驗中止，我們就必須揭露這件事。

Other than that, it's an ongoing trial. We need to complete the trial, gather the data. That will inform us, as I said earlier, for the Phase 2 trial in patients with triple combination. And we will provide relevant information at that point in time, that supports the design of that trial.

除此之外，這還是一項正在進行的試驗。我們需要完成試驗，收集數據。正如我之前所說，這將為三重療法患者的 2 期試驗提供資訊。屆時我們將提供相關信息，以支持該試驗的設計。

Can you just remind me of your second question? Disclosures? Is that -- (multiple speakers)

你可以提醒我你的第二個問題是什麼嗎？披露資訊？那是——（多人發言）

I was just wondering, will we see PK data, so that we can compare the drug levels that you can achieve in healthy volunteers, versus the drug levels that you were achieving in the HB] assay, so we have some sort of comparison on relative drug levels?

我只是想知道，我們是否能看到藥物動力學數據，以便我們可以將您在健康志願者身上達到的藥物濃度與您在 HB] 檢測中達到的藥物濃度進行比較，從而對相對藥物濃度進行某種比較？

So we'll provide you the relative information that helps you understand the design of the Phase 2 study. However, it is not our practice to provide that kind of detail on a Phase I study, and there's a number of reasons for that. And I would just give you one, that there is a specific competitive reason that would, we would prefer not to provide that information on a Phase 1 study.

因此，我們將為您提供相關信息，幫助您了解 2 期研究的設計。然而，我們通常不會在 I 期研究中提供這種細節，原因有很多。我只想告訴你一個原因，那就是出於特定的競爭原因，我們寧願不提供 1 期研究的相關資訊。

And Matt, in the 6 to 11, I mean, really the contribution of the 6 to 11 population if we're successful in getting approval, as I said, it's really going to be in the, likely to be in the fourth quarter. So really the contribution there, within our overall guidance is more about uptake than it is around persistence and compliance. And much as we did with the 12 and above population, I think we'll obviously be watching that very, very closely, just as we have done since the launch in July.

馬特，在 6 到 11 歲這個年齡段，我的意思是，如果我們成功獲得批准，6 到 11 歲這個年齡段的人口的貢獻，正如我所說，很可能會在第四季度。因此，在我們整體指導方針中，真正起作用的是推廣，而不是堅持和遵守。就像我們對待 12 歲及以上人群一樣，我認為我們顯然會非常非常密切地關注這一群體，就像自 7 月啟動以來我們一直在做的那樣。

And that will give us an ability to learn how the product performs with those patients in the real world. Again, one of the things we have seen with the younger population with KALYDECO, is they tend to be slightly more compliant than the average. Not surprisingly, because they have got a lot of parental and caregiver supervision.

這將使我們能夠了解該產品在現實世界中對這些患者的表現。再次，我們發現，使用 KALYDECO 的年輕族群往往比一般人更順從一些。這並不奇怪，因為他們受到父母和監護人的嚴格監督。

But really, those assumptions that we've given you, are much really more related to the 12 and above population. But we'll see how the 6 to 11 patients play out in the real world, in the course of time after the approval.

但實際上，我們給出的這些假設，更與 12 歲及以上的人群相關。但我們將拭目以待，看看這 6 至 11 名患者在獲得批准後的一段時間內，在現實世界中會如何發展。

Thank you. Our next question comes from the line of Ying Huang of Bank of America Merrill Lynch. Your line is now open.

謝謝。我們的下一個問題來自美國銀行美林證券的黃穎女士。您的線路已開通。

Hello. Thanks for taking my questions. Number one, I want to know if you have seen an uptick in discontinuations due to lack of efficacy, or it's all due to the chest tightness? And then secondly, for the ATU pricing you get in France, how does that compared to the German pricing of EUR159,000 per year per patient?

你好。謝謝您回答我的問題。首先，我想知道您是否發現因療效不佳而導致的停藥人數增加，還是全部都是由於胸悶引起的？其次，法國的 ATU 定價與德國每位患者每年 159,000 歐元的定價相比如何？

And lastly, I have a question on your gross to net. Is that consistent with what you have guided before, which is like mid-teens in 1Q 2015?

最後，我還有一個關於你們毛利與淨利的問題。這與您先前指導的情況一致嗎？您之前的指導是在 2015 年第一季達到十幾個百分點。

Thank you.

謝謝。

So Ying, in terms of discontinuations, the -- based on our clinical trial experience, and also what we are seeing in the market, the vast majority of those discontinuations are for adverse events, and most commonly that's for chest tightness. In terms of the ATU, we haven't disclosed the price within the ATU program. And in terms of the gross to net, the gross to net that we've seen and are predicting is potentially slightly lower than we originally thought.

所以，Ying，就停藥情況而言，根據我們的臨床試驗經驗以及我們在市場上看到的情況，絕大多數停藥都是由於不良事件，其中最常見的是胸悶。關於ATU，我們尚未在ATU方案中公佈價格。就毛利潤與淨利潤的比率而言，我們目前看到和預測的毛利潤與淨利潤比率可能比我們最初預想的要略低一些。

That's largely due to the fact that the Medicaid patient population that we're seeing is slightly lower than we anticipated. This is really as a result of many of those Medicaid patients that we thought would be covered by Medicaid are actually qualifying for disability benefit under Medicare. As a result of that, we're seeing a lower Medicaid population. And as a result, we're seeing, we're predicting a slightly lower gross to net of somewhere around 12% for the year.

這主要是因為我們看到的醫療補助患者人數略低於我們的預期。這其實是因為我們原本以為會享有許多醫療補助的醫療補助患者，其實符合醫療保險的殘障福利資格。因此，我們看到享受醫療補助的人口數量下降。因此，我們預測今年的毛利潤率與淨利潤率將略有下降，約 12%。

Yes, I might just add to that Stuart, which is in the, coming into 2016 and 2015, where the gross to net on ORKAMBI was close to 7%. As we moved into the Q1 of 2016, it's increased to 9%. So it is moving up slightly, as we expected. But as we plan out, and we look at the patients that are coming onto drug, we anticipate that it could end the year around 12%, as it eventually creeps up to that 12% level. That's also placed into our guidance.

是的，我還要補充一點，Stuart，在 2016 年和 2015 年，ORKAMBI 的總收入與淨收入比接近 7%。進入 2016 年第一季後，這一比例上升至 9%。正如我們預期的那樣，價格略有上漲。但根據我們的計劃，以及我們對正在接受藥物治療的患者的情況來看，我們預計到年底，藥物使用率可能會達到 12% 左右，最終會緩慢上升到 12% 的水平。這一點也已納入我們的指導原則中。

Thanks for the color.

謝謝你提供的色彩。

Thank you. And our next question comes from the line of Liisa Bayko of JMP Securities. Your line is now open.

謝謝。下一個問題來自 JMP Securities 的 Liisa Bayko。您的線路已開通。

Hi. Just a couple technical questions. Were there any inventory changes in the quarter?

你好。幾個技術問題。本季庫存是否有任何變化？

No. (laughter)

不。（笑聲）

Okay.

好的。

The ORKAMBI inventory at the end of March was, to all intents and purposes, identical to that which it was at the end of January 31. So there was really no inventory change for ORKAMBI at all.

3 月底的 ORKAMBI 庫存實際上與 1 月 31 日的庫存完全相同。所以 ORKAMBI 的庫存其實根本沒有任何變化。

Okay, great. And then can you comment on gross to net: where were you for the quarter? And would that be relatively consistent for the rest of the year? Will it change in some way?

好的，太好了。那麼，您能否就毛利潤和淨利潤談談：您本季的毛利潤和淨利潤分別是多少？這種情況在今年剩下的時間會相對穩定嗎？它會以某種方式改變嗎？

Are you referring to ORKAMBI, Liisa?

Liisa，你指的是ORKAMBI嗎？

Yes. Sorry. Thank you.

是的。對不起。謝謝。

Yes. So I actually just mentioned this, which is that in Q1 we were at approximately 9% gross to net discount.

是的。我剛才其實提到了這一點，那就是第一季我們的毛利淨利差約為 9%。

Okay.

好的。

In Q4 of last year, we were at 7%. We actually expect the Q1 level of 9% to trend up, to be something closer to 12% by the end of the year.

去年第四季度，我們的成長率為 7%。我們預計第一季的9%水準將呈上升趨勢，到年底將接近12%。

Okay, great. That's helpful. Thank you.

好的，太好了。那很有幫助。謝謝。

And then when you say, 15% of 65% have discontinued, that's like a 10% discontinuation rate roughly? Is that the right way to think about that?

那麼，當你說65%的人中有15%已經停止使用時，這大約相當於10%的停止使用率？這樣想對嗎？

No, Liisa. So -- and it's really important, so thanks for asking the question. It is of the patients who have initiated, 15% of them have discontinued ORKAMBI within approximately the first three months. The -- and so if you think about 4,500 patients who initiated between July and December, 15% of those patients who would have discontinued within the first three months. And then that rate of discontinuations slows considerably.

不，莉莎。所以——而且這個問題非常重要，謝謝你提出這個問題。在開始使用 ORKAMBI 的患者中，有 15% 的患者在大約前三個月內停止了使用。因此，如果你考慮 7 月到 12 月期間開始接受治療的 4500 名患者，其中 15% 的患者會在前三個月內停止治療。然後，停售率會大幅下降。

The 65% is the number of patients who have initiated therapy by the end of March. So the 15%, you need to apply to all of the patients who initiated. It's -- you don't -- it's not 15% of 65% is 10%; it is 15% of the 65% who have initiated, they will discontinue therapy is our belief.

65% 是指截至 3 月底已開始接受治療的患者人數。所以這 15% 的優惠政策，需要適用於所有開始治療的患者。不是——你不知道——不是 65% 的 15% 等於 10%；我們認為，是 65% 已經開始治療的人中有 15% 會停止治療。

And Lisa--

還有麗莎——

Right, but that gets you 10%, doesn't it? If you multiply [65 by 15] -- ?

沒錯，但那樣你就能拿到 10% 的佣金，不是嗎？如果將 [65 乘以 15] 呢？

Liisa, we'll jump on the phone with you after the call, and we'll do the math.

莉莎，我們通話結束後會馬上跟你通電話，我們會一起算算。

All right. Okay Thank you.

好的。好的，謝謝。

And then I just had a question about the Rho inhibitor. Can you give us a little detail on that trial? What are the end points you're looking at, what is the timing for data?

然後我還有一個關於 Rho 抑制劑的問題。您能給我們詳細介紹一下那場審判嗎？你們關注的終點是什麼？資料採集的時間節點是什麼？

And that's my final question. Thank you.

這是我的最後一個問題。謝謝。

Hi, Liisa. It's Jeff.

你好，莉莎。是傑夫。

So the Rho inhibitor trial is really specifically in patients who had a pretty catastrophic injury to their cervical spine, and really have very poor function immediately following that injury. In the study then, we follow those patients.

因此，Rho 抑制劑試驗實際上是專門針對頸椎遭受嚴重損傷，並且在受傷後立即出現功能障礙的患者。在這項研究中，我們將對這些患者進行追蹤研究。

At the time of surgery, they have either placebo, or one of two doses of active drug. It's about 150 patients total. And then we follow them for six months, looking at particularly how their upper extremities function, because that's so important to how patients, the quality of life of patients. And then, we do some other measures of disability.

手術時，他們要么服用安慰劑，要么服用兩種活性藥物中的一種。總共有大約150名患者。然後我們會對他們進行六個月的追蹤觀察，尤其關注他們的上肢功能，因為這對患者的生活品質來說非常重要。然後，我們也會進行一些其他的殘障評估。

And it's very hard right now. We just started the study, as we've said. So I think it's very hard to predict in that kind of population, in particular, exactly when we're going to get results.

現在的情況非常艱難。正如我們所說，這項研究才剛開始。所以我覺得，尤其是在這種人口規模下，很難準確預測何時才能得到結果。

Thank you.

謝謝。

Operator, we have time for two more questions.

接線員，我們還有時間再問兩個問題。

Thank you. Our next question comes from the line of Tony Butler of Guggenheim. Your line is now open.

謝謝。我們的下一個問題來自古根漢美術館的托尼巴特勒。您的線路已開通。

Yes, thanks very much.

是的，非常感謝。

Briefly, Stuart, in France, again the early access patients which receive ORKAMBI, I think you mentioned 400, I understand reimbursement has not occurred. But given the uptake being fairly strong, if one assumes that the majority of that 1,500 will be treated by year end, and you do get reimbursement, let's say next year, does that come in a bolus payment for that which has occurred, or is that payment then amortized assuming those patients stay on drug for 2017 and beyond?

簡而言之，Stuart，在法國，再次提到接受 ORKAMBI 治療的早期患者，我想你提到過 400 人，據我了解，他們還沒有獲得報銷。但鑑於接受治療的患者人數相當多，假設到年底前這 1500 名患者中的大多數都能得到治療，並且確實獲得了報銷，比如說明年，這筆報銷是針對已經發生的情況一次性支付，還是假設這些患者在 2017 年及以後繼續服用該藥物，然後分期支付？

Thanks very much.

非常感謝。

Yes, thanks for the question, Tony.

是的，謝謝你的提問，托尼。

So the way the accounting works in France is that, for the cash that we get for those patients before we get reimbursed, those are recognized as cash, not as revenue. At the point that we have certainty about the selling price, or very close to certainty about the selling price in France, then we will be able to, in a one-term adjustment, convert that cash to revenues. And then, from that point forward, all of those will be counted as revenues going forward. That's because the, whatever rebate you agree with the French government is retroactive, to the sales that you've had from the point that you launched the product.

因此，法國的會計運作方式是，在我們收到報銷之前，我們為這些病人收取的現金會被確認為現金，而不是收入。當我們能夠確定法國的售價，或非常接近確定法國的售價時，我們可以透過一次調整，將現金轉化為收入。從那時起，所有這些收入都將被計入未來的收入中。這是因為，無論你與法國政府達成何種退稅協議，該退稅都將追溯至你推出產品之日起的銷售額。

And that's helpful, thank you. And finally, you would call that out as an item in the quarter in which it occurs, I assume?

那很有幫助，謝謝。最後，我想您應該會把它作為一項內容列入它發生的季度中吧？

So maybe I'll follow on from Stuart. I'll just validate Stuart's answer as a CPA, so nice job, Stuart. (laughter)

所以也許我會接替史都華的工作。作為一名註冊會計師，我可以驗證一下史都華的回答，幹得好，史都華。（笑聲）

In terms of revenue recognition, many of you that are on this call, probably have seen other companies go through this with the ATU in France. And then absolutely, at the point that we are, we get to a point where we're confident with the price in France, yes, we would call it out in the quarter specifically. And at that same point of time, we would recognize all the revenue in that very quarter.

就收入確認而言，在座各位可能都看過其他公司在法國經歷 ATU 的類似過程。當然，當我們對法國的價格有信心時，我們會在季度報告中特別指出這一點。同時，我們會確認該季度的所有收入。

Thank you.

謝謝。

Thank you.

謝謝。

And our final question comes from the line of Katherine Xu of William Blair. Your line is now open.

最後一個問題來自威廉布萊爾的凱瑟琳徐的家族。您的線路已開通。

Hi, good evening. Thanks for squeezing me in.

您好，晚上好。謝謝你擠出時間幫我。

So I just have one question on the CRISPR program. Based on the research that you have ongoing right now, what kind of mutations are the most amenable for the technology first? And how difficult is it to eventually correct those FFO8, which is a deletion. You have to add back the [space] there.

我只有一個關於 CRISPR 專案的問題。根據您目前正在進行的研究，哪些類型的突變最適合首先應用該技術？最終要修正這些 FFO8 刪除操作有多難？你需要把那裡的空格加回去。

Yes, this is Jeff Leiden. Thanks for the question.

是的，這位是傑夫·萊頓。謝謝你的提問。

I think as you know, right -- if you look today, CRISPR is most amenable to actually inactivating treatment, making cleavages, because that's what it does most efficiently. And obviously, that's not what we would want to do in the delta 508 case. Then you move to making corrections, and then you move to more complex deletions and insertions.

我想你也知道，對吧——如果你看看現在，CRISPR 最適合用於真正地使治療失活，進行切割，因為這是它最有效的做法。顯然，在 Delta 508 案例中，我們並不想這樣做。然後你開始進行更正，然後你開始進行更複雜的刪除和插入。

And so, there's no doubt that there are still challenges to conquer, both in terms of how we correct deletions like in delta 508, but also in how we deliver this. Because obviously, this has to be delivered efficiently to large numbers of cells in the lungs, and we don't know how to do that yet.

因此，毫無疑問，我們仍然面臨著許多挑戰，包括如何修正像 delta 508 這樣的刪除操作，以及如何交付這些操作。顯然，這種物質必須有效地輸送到肺部的大量細胞中，而我們目前還不知道該如何做到這一點。

So that's why we said, while we think CRISPR is an incredibly powerful technology for the future, it's going to take a number of years to conquer, both the, some of the editing challenges, but also in particular, the delivery challenges. And that's what we're working on in CF.

所以這就是為什麼我們說，雖然我們認為 CRISPR 是一項非常強大的未來技術，但要克服一些編輯方面的挑戰，尤其是遞送方面的挑戰，還需要數年時間。這就是我們在CF團隊正在努力的方向。

Now we're also -- I'd just remind you that this CRISPR) Cas9 collaboration, we have a right to several targets, fixed targets, and some of those will be in other diseases, where some of these issues like delivery and editing are much more straightforward. So I think you can expect to hear from us over the next couple of years on our progress, in some of those other diseases.

現在我們還要提醒大家，關於 CRISPR) Cas9 合作，我們有權針對多個目標，固定目標，其中一些目標將針對其他疾病，在這些疾病中，像遞送和編輯這樣的問題要簡單得多。所以我認為在接下來的幾年裡，你們將會聽到我們在其他一些疾病方面取得的進展。

So at this point, are there mutations that are easier than others to edit? Do we know that?

那麼目前來看，是否存在比其他突變更容易編輯的突變呢？我們知道這一點嗎？

Yes, as I said, I think single-base payer corrections are going to be a lot easier than complex deletions and insertions to correct. But nevertheless, I mean, there are still some pretty significant challenges in diseases like CF. When you move ex Vivo therapy, and you move to inactivation in ex Vivo therapy, you're in a whole different world, in terms of efficiency. And so, you will see those I think from us and others, as being the first application.

是的，正如我所說，我認為單一支付方更正比複雜的刪除和插入更正要容易得多。但即便如此，我的意思是，像囊性纖維化這樣的疾病仍然面臨一些相當大的挑戰。當你採用體外療法，並採用體外療法中的滅活方法時，就效率而言，你就進入了一個完全不同的世界。因此，我認為你會看到我們和其他人提交的這些申請，作為第一個申請。

Thanks.

謝謝。

So I'll turn it back over to Jeff maybe for some final comments tonight.

那麼今晚我可能會把話題交還給傑夫，讓他做一些最後的總結。

Yes. First of all, thanks for your questions. Thanks for your patience.

是的。首先，感謝你們的提問。感謝您的耐心等待。

I know it was a long call, but we did want to give you, not only our guidance, but the detailed rationale for the guidance, so that you understand our model. And we appreciate your questions on that.

我知道通話時間很長，但我們不僅想向您提供指導，還想詳細解釋提供指導的理由，以便您理解我們的模式。我們感謝您提出的這些問題。

And as I look at our progress as a Company over the last year, I would call out three things that I think are important. First, the continuous increase in the number of patients that we can treat, and actually a fairly dramatic increase in the number of patients that we can treat with KALYDECO and ORKAMBI. And as we look forward, the increasing number of patients that we can treat with today's approval. So as I mentioned, 27,000 eligible. We're still only treating a third of those, and I think we have a clear path to get to the majority of those patients, both in the US and Europe over 2016 and 2017 and beyond.

回顧公司過去一年的發展歷程，我認為有三件事非常重要。首先，我們能夠治療的患者數量持續增加，而且使用 KALYDECO 和 ORKAMBI 治療的患者數量實際上出現了相當大的增長。展望未來，隨著今天這項批准的出台，我們可以治療的患者數量將會不斷增加。正如我之前提到的，有 27,000 人符合資格。我們目前只治療了其中三分之一的患者，我認為我們有明確的途徑在 2016 年和 2017 年及以後，在美國和歐洲治療大多數患者。

Second thing I would say, is the pipeline progression, we're pleased with 661, progressing well into Phase 3 of multiple trials, of multiple patient populations. But equally importantly, the next gen correctors which are progressing through Phase I with our -- and still on a time line to get into patients as triple combinations later this year. We think that's going to be very important, both for the patients we treat, and potentially for additional subsets of patients.

第二點我想說的是研發管線的進展，我們對 661 的進展感到滿意，它已順利進入多個試驗的 3 期，涉及多個患者群體。但同樣重要的是，我們正在進行第一階段試驗的下一代矯正器——並且仍然計劃在今年稍後以三聯療法的形式應用於患者。我們認為這對於我們治療的患者以及可能對其他患者群體都非常重要。

And then finally, the progression of the science. We didn't talk about that a lot today, but the science of CF I think has progressed significantly, and we have a much better understanding of the folding correction process. And the science that David Altshuler is driving, and the rest of the research group in some of the new diseases.

最後，是科學的發展歷程。我們今天沒有過多討論這個問題，但我認為 CF 的科學已經取得了顯著進展，我們對折疊校正過程有了更深入的了解。還有大衛·阿爾特舒勒 (David Altshuler) 領導的科學研究，以及其他研究小組在一些新疾病方面的研究。

And we've touched on those a little bit with CRISPR Cas9, but also others, that I hope we will be able to have a chance to talk to you about over the rest of 2016 and 2017, is an important long-term growth engine for the Company. So with that, maybe I'll close the call, and thanks again for joining us.

我們已經用 CRISPR Cas9 稍微談到了這些技術，但還有其他一些技術，我希望我們能在 2016 年和 2017 年的剩餘時間裡有機會和大家談談這些技術，它們是公司重要的長期成長引擎。那麼，或許我該結束通話了，再次感謝各位的參與。

Ladies and gentlemen, thank you for participating in today's conference. This does conclude the program. You may all disconnect. Everyone, have a great day.

女士們、先生們，感謝各位參加今天的會議。節目到此結束。你們可以斷開連結了。祝大家今天過得愉快。