福泰製藥 (VRTX) 2015 Q3 法說會逐字稿

Good afternoon, ladies and gentlemen, my name is Candace. Vertex third-quarter 2015 financial results call is about to begin.

各位女士、先生，下午好，我是 Candace。Vertex 2015 年第三季財務業績電話會議即將開始。

Good evening, everyone. This is Michael Partridge, Head of Investor Relations for Vertex Pharmaceuticals. Welcome to our third-quarter 2015 financial results conference call.

各位晚安。我是 Vertex Pharmaceuticals 投資人關係主管 Michael Partridge。歡迎參加我們 2015 年第三季財務業績電話會議。

(Operator Instructions)

(接線員指示)

As a reminder, this conference call is being recorded and a replay will be available following the conclusion of tonight's call on our website. Joining me on tonight's call are Dr. Jeff Leiden, Chairman and CEO; Stuart Arbuckle, Chief Commercial Officer; Ian Smith, Chief Financial Officer; and Dr. David Altshuler, our Chief Scientific Officer. Dr. Jeff Chodakewitz, Chief Medical Officer, will also be available for Q&A. Our agenda tonight is as follows: Jeff will review the progress with our cystic fibrosis medicines; Stuart will review the third-quarter sales performance of our marketed products; Ian will review the third-quarter 2015 financial results and update our 2015 guidance; and to close, David will discuss our research strategy and our early development pipeline. You can access the webcast slides by going to the Events section of the Investor Relations page on our website.

提醒各位，本次電話會議將進行錄音，並將於今晚會議結束後在我們網站提供重播。今晚與我一同參與電話會議的有：董事長兼執行長 Jeff Leiden 醫師；首席商務長 Stuart Arbuckle；財務長 Ian Smith；以及首席科學長 David Altshuler 醫師。首席醫療長 Jeff Chodakewitz 醫師也將出席並回答問答環節。今晚議程如下：Jeff 將回顧我們在囊性纖維化（CF）藥物方面的進展；Stuart 將回顧我們已上市產品的第三季銷售表現；Ian 將回顧 2015 年第三季財務結果並更新 2015 年財測指引；最後，David 將討論我們的研發策略與早期開發產品線。您可前往我們網站投資人關係頁面的「活動（Events）」區域取得網路直播簡報投影片。

I will remind you that we will make forward-looking statements on this conference 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 Securities and Exchange Commission. These statements, including without limitation, those regarding the ongoing development and potential commercialization of our drug candidates, those without Vertex's other cystic fibrosis programs, and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially. Information regarding our use of GAAP and non-GAAP financial measures and a reconciliation of GAAP to non-GAAP is available in our third-quarter 2015 financial results 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.

我提醒各位，我們將在本次電話會議中作出前瞻性陳述。這些陳述受今日新聞稿以及我們已向美國證券交易委員會（SEC）提交之 10-K 年報中所詳述的風險與不確定性影響。這些陳述（包括但不限於）關於我們藥物候選物的持續開發與潛在商業化、Vertex 其他囊性纖維化計畫，以及 Vertex 未來財務表現等，均係基於管理層目前的假設。實際結果與事件可能出現重大差異。有關我們使用 GAAP 與非 GAAP 財務衡量指標的資訊，以及 GAAP 與非 GAAP 之間的調節表，已載於我們 2015 年第三季財務業績新聞稿中。我也請各位參考今晚網路直播的第 4 張投影片。接下來我將把電話會議交給 Jeff Leiden 醫師。

Thank you, Michael. Good evening, everyone. Three years ago, we outlined a clear strategy designed to establish a foundation for sustainable business growth. This evening, I'm pleased to report that we continue to make excellent progress toward achieving our long-term vision for 2016 and beyond. Significant revenues and revenue growth from multiple high-value medicines, high operating margins, and a pipeline of additional transformational medicines. Our goal in CF is to reach the vast majority of people with this serious disease and to continue to enhance the benefit for the patients who we treat. We continue to build on a track record of innovation to discover, develop, and deliver transformative medicines to more people with CF. Let me summarize our recent commercial success and development progress in CF.

謝謝你，Michael。各位晚安。三年前，我們提出一項明確策略，旨在建立可持續業務成長的基礎。今晚我很高興向各位報告，我們持續朝著 2016 年及其後的長期願景取得卓越進展。包括：多款高價值藥品帶來的可觀營收與營收成長、高營業利潤率，以及一系列額外具變革性的藥物研發管線。我們在 CF 的目標，是觸及絕大多數罹患此嚴重疾病的人，並持續提升我們所治療患者的受益程度。我們將持續以創新成果為基礎，發現、開發並提供具變革性的藥物，讓更多 CF 患者受惠。我先總結我們近期在 CF 的商業成功與研發進展。

In July, ORKAMBI became the first FDA-approved medicine to treat the underlying cause of CF for the approximately 8,500 people in the US 12 years and older with two copies of the F508del mutation, and as of September 30, 2015, we already were treating more than 3,000 of these patients. Our sNDA has been accepted by the FDA for the expanded use of KALYDECO in people age two and older, with one of 23 residual function mutations that result in CF. This may accelerate access to KALYDECO for more than 1,500 patients in the US. The European Union CHMP recently issued threes positive opinions for KALYDECO and ORKAMBI, all with the potential to significantly expand the number of eligible patients for our CF medicines. In fact, at this time last year, we were approved to treat approximately 2,600 people with CF worldwide, whereas today, there are more than 25,000 patients approved or under regulatory submission for our medicines. We are currently conducting two phase 3 clinical studies of ORKAMBI in children ages 6 to 11 years old and plan to submit an sNDA to the FDA in the first half of 2016. There are approximately 5,500 children with CF in the US and Europe with two copies of the F508del mutation.

7 月，ORKAMBI 成為首款獲 FDA 核准、可治療 CF 潛在病因的藥物，適用於美國約 8,500 名 12 歲及以上、帶有兩個 F508del 突變拷貝的患者；截至 2015 年 9 月 30 日，我們已為其中超過 3,000 名患者提供治療。我們針對擴大 KALYDECO 適用範圍的補充新藥申請（sNDA）已獲 FDA 受理，適用於 2 歲及以上、帶有 23 種殘餘功能突變之一且導致 CF 的患者。這可能加速美國超過 1,500 名患者取得 KALYDECO 的治療可近性。歐盟 CHMP 近期就 KALYDECO 與 ORKAMBI 發出三項正面意見，皆有望大幅擴大符合我們 CF 藥物治療資格的患者人數。事實上，就在去年此時，我們在全球獲核准可治療的 CF 患者約為 2,600 人；而今天，已有超過 25,000 名患者的治療已獲核准或正處於我們藥物的法規申請審查中。我們目前正在進行兩項 ORKAMBI 的第三期臨床研究，對象為 6 至 11 歲兒童，並計畫於 2016 年上半年向 FDA 提交 sNDA。美國與歐洲約有 5,500 名 CF 兒童帶有兩個 F508del 突變拷貝。

Following closely behind ORKAMBI, we have the VX-661 plus ivacaftor pivotal phase 3 development program underway, which is expected to enroll more than 1,000 people with CF across four studies. We expect to complete enrollment in mid-2016. At the North American Cystic Fibrosis Conference, we announced that we are advancing two next-generation correctors, VX-152 and VX-440, into the clinic, and we expect to dose the first healthy volunteer with VX-440 this week. We believe these new correctors hold tremendous promise as part of a triple combination regimen for the 80% to 90% of CF patients with at least one F5808del allele, thereby possibly allowing us to treat patients we are not yet treating and also to enhance the benefit for those we already treat. The strength of the ORKAMBI launch to date and the continued expansion in the number of people eligible for KALYDECO are further evidence that we continue to execute against our key goal to become a Company that can reinvest to create future medicines and deliver returns to shareholders.

緊接在 ORKAMBI 之後，我們已啟動 VX-661 加 ivacaftor 的關鍵性第三期開發計畫，預計在四項研究中納入超過 1,000 名 CF 患者。我們預期於 2016 年年中完成收案。在北美囊性纖維化會議（NACF Conference）上，我們宣布將兩款次世代校正劑 VX-152 與 VX-440 推進至臨床階段，並預期本週將為首位健康受試者給予 VX-440 劑量。我們相信，這些新校正劑作為三聯合併療法的一部分，對於 80% 至 90% 至少帶有一個 F5808del 等位基因的 CF 患者具有巨大潛力，因而可能讓我們能治療目前尚未治療的患者，同時也提升我們已治療患者的受益程度。迄今 ORKAMBI 上市推進的強勁表現，以及符合 KALYDECO 治療資格人數的持續擴大，進一步證明我們正持續落實關鍵目標：成為一家能夠再投資以創造未來藥物並為股東帶來回報的公司。

As I noted at the NACF Conference, we also continue to advance early stage development programs outside of CF for the treatment of cancer, pain, and other diseases, which represents an important diversification of our development portfolio. Dr. David Altshuler, our Chief Scientific Officer, will discuss our research strategy and some of our emerging compounds later on this call. As you know, David was one of the four founding members of the Broad Institute of Harvard and MIT, where he served as Deputy Director and Chief Academic Officer. David is an experienced physician and human geneticist, and we tapped him to lead our research organization earlier this year so that we can bring his experience to bear as we continue to deliver transformational medicines to more people.

正如我在 NACF 會議上所提到的，我們也持續推進 CF 以外的早期開發計畫，用於治療癌症、疼痛及其他疾病，這代表我們研發組合的重要多元化。我們的首席科學長 David Altshuler 醫師將在稍後的會議中討論我們的研發策略以及部分新興化合物。如各位所知，David 是哈佛與麻省理工學院布羅德研究院（Broad Institute）的四位創始成員之一，並曾擔任副院長與首席學術長。David 是一位經驗豐富的臨床醫師與人類遺傳學家；我們在今年稍早邀請他領導研發組織，以便在我們持續為更多人提供具變革性藥物的過程中，充分運用他的經驗。

Before I turn the call over to Stuart, I wanted to mention how delighted we are to have entered into a research collaboration with CRISPR Therapeutics to discover and develop potential new treatments aimed at the underlying genetic causes of human disease. Gene editing represents a new and powerful technology platform that could represent a future paradigm shift in the treatment of CF, as well as other genetic diseases. And we're excited to be working with CRISPR, the Company at the forefront of using gene editing to create new treatments. With that, I'll hand it over to Stuart to discuss Vertex's third-quarter sales performance.

在我把電話會議交給 Stuart 之前，我想提到，我們非常高興已與 CRISPR Therapeutics 達成研究合作，以發現並開發針對人類疾病潛在遺傳根源的新療法。基因編輯是一個嶄新且強大的技術平台，可能在 CF 以及其他遺傳性疾病的治療上帶來未來典範轉移。我們也很興奮能與 CRISPR 合作，該公司正站在運用基因編輯創造新療法的最前沿。接下來我將交給 Stuart，請他討論 Vertex 第三季的銷售表現。

Thank you, Jeff, and hello, everyone. Tonight I will review KALYDECO performance in the third quarter and our progress in making ORKAMBI available to eligible patients in the US. Global sales of KALYDECO this quarter were $166 million, comprised of US sales of approximately $95 million and ex-US sales of approximately $71 million. This represents a 31% increase over the $127 million we recorded in the same quarter last year. The growth of KALYDECO is a result of continued geographic and label expansion. We have seen strong uptake in patients with the R117H mutation, following approve in the US in late 2014, and in children ages two to five with eligible mutations, following US approval at the end of March 2015. Internationally, there has also been rapid uptake of KALYDECO by eligible patients in Australia, and in patients with non-G551D gating mutations, in several European countries where these mutations are prevalent. We've made significant progress in securing reimbursement in Europe this year. As a result, the vast majority of eligible gating patients in Europe now have access to KALYDECO. We expect that growth in the number of patients receiving KALYDECO globally in the fourth quarter of 2015 and into 2016 will be tempered by enrollment in the VX-661 pivotal program, as previously described.

謝謝你，Jeff，大家好。今晚我將回顧第三季 KALYDECO 的表現，以及我們在美國讓符合資格的病患可取得 ORKAMBI 的進展。本季 KALYDECO 的全球銷售額為 1.66 億美元，其中美國銷售約 9,500 萬美元，美國以外地區銷售約 7,100 萬美元。這較去年同期我們記錄的 1.27 億美元成長 31%。KALYDECO 的成長來自持續的地理覆蓋與適應症標籤擴展。在美國於 2014 年底核准後，我們看到帶有 R117H 突變的病患採用情況強勁；此外，在 2015 年 3 月底美國核准後，具符合資格突變、年齡介於 2 至 5 歲的兒童也快速採用。在國際市場方面，澳洲符合資格的病患對 KALYDECO 的採用也很迅速；在若干歐洲國家（這些突變較為常見）中，帶有非 G551D 閘控突變的病患亦快速採用。今年我們在歐洲爭取給付方面取得重大進展。因此，目前歐洲絕大多數符合資格的閘控突變病患已可取得 KALYDECO。如先前所述，我們預期 2015 年第四季以及進入 2016 年，全球接受 KALYDECO 治療的病患人數成長，將因 VX-661 關鍵性試驗計畫的收案而有所趨緩。

Now turning to ORKAMBI. Since the FDA approval of ORKAMBI on July the 2nd, we have been focused on educating healthcare providers on the medicine and working with payers to secure reimbursement for the approximately 8,500 eligible patients in the US. Sales for the third quarter totaled $131 million. More than 3,000 patients have started treatment in the US, underscoring the important advance this medicine represents in the treatment of CF and the strong interest from both patients and their doctors. Our field teams around the country have visited all of the 275 CF centers in the US since approval, and virtually every center has initiated patients in ORKAMBI.

接著談 ORKAMBI。自 FDA 於 7 月 2 日核准 ORKAMBI 以來，我們一直專注於向醫療照護提供者宣導此藥物，並與付款方合作，為美國約 8,500 名符合資格的病患爭取給付。第三季銷售額合計為 1.31 億美元。美國已有超過 3,000 名病患開始治療，凸顯此藥物在囊性纖維化（CF）治療上的重要進展，以及病患與醫師雙方的高度興趣。自核准以來，我們在全國的外勤團隊已拜訪美國全部 275 家 CF 中心，且幾乎每一家中心都已讓病患開始使用 ORKAMBI。

As we anticipated, interest in the medicine is very high, which has put a significant administrative burden on centers as they work to initiate patients on treatment. As expected, we are seeing broad coverage of and access to ORKAMBI, which reflects payer understanding and appreciation of the seriousness of the disease and the significant value of a medicine that treats the underlying cause of CF. The majority of commercial and government payers with eligible patients are reimbursing for ORKAMBI. In those plans with published policies, and/or defined prior authorization criteria, almost all are reimbursing to label. There are a small number of plans not yet allowing access to ORKAMBI, and we anticipate they will complete their formal ORKAMBI reviews and define their final policies in the coming months. Our patient support team has been working diligently to help patients navigate the reimbursement process and is working to reduce the time it takes for patients to get their prescriptions filled. For any chronic medication, compliance and adherence are important facets of patient care, so they will be increasing their focus to ensure that patients are able to take ORKAMBI as prescribed, and so benefit from the medicine.

如我們所預期，對此藥物的興趣非常高，當各中心著手讓病患開始治療時，這也帶來顯著的行政負擔。同樣如預期，我們看到 ORKAMBI 具有廣泛的給付覆蓋與可近性，反映付款方理解並重視疾病的嚴重性，以及能治療 CF 根本原因之藥物所具備的重大價值。多數擁有符合資格病患的商業與政府付款方均對 ORKAMBI 予以給付。在已公布政策及／或已定義事前授權（prior authorization）標準的方案中，幾乎全部都依照核准標籤給付。仍有少數方案尚未允許取得 ORKAMBI，我們預期它們將在未來數月完成對 ORKAMBI 的正式審查並制定最終政策。我們的病患支援團隊一直努力協助病患因應給付流程，並致力縮短病患取得處方配藥所需的時間。對任何慢性用藥而言，服藥遵從性與持續性都是病患照護的重要面向，因此他們將加強投入，確保病患能依處方使用 ORKAMBI，從而受益於此藥物。

Outside of the US, we continue to expect approval in the EU in the fourth quarter of this year. Our EU commercial infrastructure is largely in place, and upon approval, we will then begin pricing and reimbursement discussions on a country-by-country basis to secure reimbursement for eligible patients who may benefit from ORKAMBI. With KALYDECO, the completion of reimbursement discussions took 9 to 20 months following approval. In summary, geographic and label expansion continue to drive significant growth in the number of patients we treat with KALYDECO. And with the launch of ORKAMBI, we are significantly expanding the number of eligible CF patients we treat. I'll now hand the call over to Ian.

在美國以外地區，我們仍預期今年第四季可在歐盟獲得核准。我們在歐盟的商業化基礎建設大致已就緒，待核准後，我們將按國別展開定價與給付談判，以為可能受益於 ORKAMBI 的符合資格病患爭取給付。以 KALYDECO 為例，核准後完成給付談判耗時 9 至 20 個月。總結而言，地理覆蓋與適應症標籤擴展持續推動我們以 KALYDECO 治療的病患人數顯著成長。而隨著 ORKAMBI 上市，我們正大幅擴增可治療的符合資格 CF 病患人數。接下來我把電話交給 Ian。

Thank you, Stuart, and good evening, everyone. Firstly, to the financials. Our CF revenues were $297 million this quarter, as we significantly increased the number of eligible people we treat with KALYDECO and ORKAMBI. KALYDECO sales of $166 million were up 31% versus the third quarter last year, and up 7% versus the second quarter of 2015. Now ORKAMBI, the launch in the US is off to a strong start. We recorded $131 million in net revenues. Inventory levels are normal, with one to two weeks in the channel. Gross to net adjustments were in the high single digits due to a more rapid uptake for patients within commercial plans as compared to government paid plans. We continue to expect Medicaid mix to be 35% to 40% in the longer term, which will increase gross to net adjustments into the mid-teens by late 2016. We expect continued revenue growth into 2016, as we approach peak penetration in the US market in the second half of 2016. As for Europe and other ex-US countries, we expect to recognize the first ORKAMBI revenues in Europe in the first half of 2016. These revenues will be mainly generated in Germany, given that pricing and reimbursement approvals in other countries will take some time to finalize. We do expect French regulatory authority to grant an ATU, or temporary authorization for use, for ORKAMBI in 2015. But we'll not recognize revenues from these sales until we receive formal reimbursement approval in France.

謝謝你，Stuart，大家晚安。首先談財務數字。本季我們的 CF 營收為 2.97 億美元，因為我們大幅增加了以 KALYDECO 與 ORKAMBI 治療的符合資格人數。KALYDECO 銷售額 1.66 億美元，較去年第三季成長 31%，較 2015 年第二季成長 7%。再來是 ORKAMBI，其在美國的上市開局強勁。我們記錄的淨營收為 1.31 億美元。庫存水位正常，通路端約為 1 至 2 週。由於商業保險方案內病患的採用速度較政府付費方案更快，毛額到淨額（gross-to-net）調整幅度為高個位數百分比。我們仍預期長期 Medicaid 組合占比為 35% 至 40%，這將使毛額到淨額調整在 2016 年底前提高至約十幾個百分點的中段。隨著我們在 2016 年下半年接近美國市場的滲透高峰，我們預期營收將持續成長至 2016 年。至於歐洲及其他美國以外國家，我們預期將在 2016 年上半年確認歐洲的首筆 ORKAMBI 營收。這些營收將主要來自德國，因為其他國家的定價與給付核准仍需一些時間才能定案。我們確實預期法國主管機關將於 2015 年核發 ORKAMBI 的 ATU（臨時使用授權）。但在法國取得正式給付核准之前，我們不會就這些銷售確認營收。

Our third-quarter non-GAAP R&D and SG&A expenses were $278 million, an increase of $66 million compared to last year. This increase is mainly attributable to an increase in sales and marketing expenses supporting the launch of ORKAMBI, and research and development costs to support the advancement of our CF medicines. The scale of our R&D organization and SG&A infrastructure is appropriate for our business. We expect modest increases in operating expense in 2016, and these will be driven by the progression of our CF medicines in development and geographic expansion to support the international launch of ORKAMBI. But we are rapidly moving towards steady state. While we expect to continue to invest significantly in R&D, we are committed to managing our operating expenses to ensure significant operating margins moving forward. Our non-GAAP net loss has narrowed to $32 million, compared to prior-year non-GAAP net loss of $86 million, and this is primarily driven by the significant increase in CF product revenues. From a balance sheet perspective, we maintained a strong position, with approximately $1 billion of cash at the end of the quarter.

我們第三季非 GAAP 的研發（R&D）與銷售、一般及行政（SG&A）費用為 2.78 億美元，較去年增加 6,600 萬美元。此增幅主要歸因於支持 ORKAMBI 上市的銷售與行銷費用增加，以及支持我們 CF 藥物推進的研發成本增加。我們的研發組織規模與 SG&A 基礎建設與我們的業務相稱。我們預期 2016 年營運費用將小幅增加，主要由開發中 CF 藥物的推進，以及為支持 ORKAMBI 的國際上市而進行的地理擴張所帶動。但我們正快速邁向穩態。雖然我們預期將持續大幅投資研發，但我們也致力於管理營運費用，以確保未來具備顯著的營業利益率。我們的非 GAAP 淨損已收斂至 3,200 萬美元，相較於前一年度非 GAAP 淨損 8,600 萬美元；這主要由 CF 產品營收的大幅增加所驅動。從資產負債表角度來看，我們維持強勁的財務狀況，季末現金約 10 億美元。

Now let's turn to the 2015 financial guidance, specifically KALYDECO revenues and the combined R&D and SG&A expenses. At the time of our second-quarter 2015 earnings call in July, we anticipated 2015 KALYDECO net revenues to be between $575 million and $590 million. We are now increasing KALYDECO net revenue guidance to be between $605 million and $620 million for the full year of 2015. For the non-GAAP operating expenses, we now expect our combined non-GAAP R&D and SG&A expense for the full year to be in the middle of the range we provided in January of this year of $1.05 billion to $1.1 billion. In summary, we're in a strong financial position today and focused on delivering financial profile that includes sustainable revenue and earnings growth, while continuing to invest to create more medicines and support access to those medicines already approved. Now over to David.

現在讓我們轉到 2015 年的財務指引，特別是 KALYDECO 營收以及合併的研發（R&D）與銷售、一般及行政（SG&A）費用。在 7 月我們 2015 年第二季財報電話會議時，我們預期 2015 年 KALYDECO 淨營收介於 5.75 億至 5.90 億美元之間。我們現在將 2015 全年 KALYDECO 淨營收指引上調至 6.05 億至 6.20 億美元。就非 GAAP 營業費用而言，我們目前預期全年合併的非 GAAP 研發與 SG&A 費用將落在我們今年 1 月提供之 10.5 億至 11 億美元區間的中位數。總結來說，我們目前財務狀況穩健，並專注於交付包含可持續的營收與獲利成長的財務表現，同時持續投資以創造更多藥物，並支持已獲核准藥物的可近性。接下來交給 David。

Thank you, Ian. It's great to be here. Good evening, everyone. At Vertex, our strategy is to invest in science, to create transformative medicines for serious diseases in specialty markets. This is an enormous challenge, because doing anything for the first time involves considerable risk. But it's also a great opportunity, cause we live in a time of accelerating breakthroughs in science that can be applied to solve important problems that were previously thought to be intractable. There are three main points I would like to make about Vertex research, and I'll make comments on each of them. First, CF represents Vertex's most significant success to date, and is where we expect our research and early development will continue to have the biggest impact in the near term. Second, cystic fibrosis provides a good template to understand the diseases we expect to pursue in the future. And third, lessons from our work in CF are guiding our early clinical programs in other areas. I'll reference five different candidate medicines in pain and oncology that were discovered by Vertex scientists and that are progressing in early development.

謝謝你，Ian。很高興來到這裡。各位晚安。在 Vertex，我們的策略是投資科學，為專科市場中的嚴重疾病創造具變革性的藥物。這是一項巨大的挑戰，因為任何首次嘗試都伴隨相當大的風險。但這同時也是一個很好的機會，因為我們正處於科學突破加速的時代，這些突破可被應用來解決過去被認為難以攻克的重要問題。關於 Vertex 的研究，我想提出三個重點，並逐一加以說明。第一，囊性纖維化（CF）是 Vertex 迄今最重要的成功，也是我們預期在短期內研究與早期開發將持續產生最大影響的領域。第二，囊性纖維化提供了一個很好的範本，用以理解我們未來預期要投入的疾病。第三，我們在囊性纖維化上的工作所獲得的經驗，正在指引我們在其他領域的早期臨床計畫。我也會提到五個由 Vertex 科學家發現、目前在疼痛與腫瘤領域推進早期開發的候選藥物。

As you know, in CF, we are advancing two next-generation correctors, VX-152 and VX-440, out of our labs and into first in human studies. In vitro data show that in combination with VX-661 and ivacaftor, these compounds resulted in chloride transport that was approximately 3-fold greater than the use of lumacaftor/ivacaftor combination in these cells. These data give us optimism in that hopefully, one day we will be able to address the vast majority of CF patients with a triple-combination therapy, and also to continue to enhance the benefit for those we are already treating. Our research strategy with CF is not limited to our internal programs. We are also looking externally to bring in compounds that complement our CFTR modulators, and this is enabled by our CF research expertise. Our CF research platform allows us to robustly characterize the activity of external compounds and their potential to work in combination with our existing regimens. This approach form the basis for the collaboration we signed with Parion for ENaC inhibitors and we showed at NACF the ability of Parion's ENaC inhibitor to enhance the effects of ORKAMBI in vitro.

如各位所知，在囊性纖維化方面，我們正將兩個次世代校正劑（corrector）VX-152 與 VX-440 從實驗室推進至首次人體試驗。體外數據顯示，這些化合物與 VX-661 及 ivacaftor 併用時，在這些細胞中的氯離子運輸約為使用 lumacaftor/ivacaftor 組合的 3 倍。這些數據讓我們感到樂觀，希望有一天我們能以三重合併療法涵蓋絕大多數囊性纖維化患者，同時也能持續提升我們已在治療患者所獲得的效益。我們在囊性纖維化的研究策略不僅限於內部計畫。我們也在外部尋找可補強我們 CFTR 調節劑的化合物，而這得益於我們在囊性纖維化研究方面的專業能力。我們的囊性纖維化研究平台使我們能夠有力地表徵外部化合物的活性，以及其與我們既有療法合併使用的潛力。此一方法構成了我們與 Parion 就 ENaC 抑制劑所簽署合作的基礎；我們也在 NACF 上展示了 Parion 的 ENaC 抑制劑在體外可增強 ORKAMBI 效果的能力。

We are looking far into the future of CF treatment to understand what impact new treatment modalities could have. This week, we announced a collaboration with CRISPR Therapeutics to use the CRISPR-Cas9 gene-editing platform to create new medicines. CRISPR-Cas9 is an important scientific and technical breakthrough that holds significant promise for the future discovery of potentially transformative treatments. And this collaboration will evaluate the use of CRISPR-Cas9 across multiple diseases where targets have been validated through human genetics. We are excited to begin our initial gene-editing research on discovering treatments to address the mutations and genes known to cause and contribute to CF and sickle cell disease.

我們也把目光放得更長遠，以了解新的治療模式可能對囊性纖維化治療帶來何種影響。本週，我們宣布與 CRISPR Therapeutics 合作，使用 CRISPR-Cas9 基因編輯平台來創造新藥。CRISPR-Cas9 是一項重要的科學與技術突破，對於未來發現可能具變革性的治療具有重大前景。此合作將評估在多種疾病中使用 CRISPR-Cas9 的可行性，這些疾病的標的已透過人類遺傳學獲得驗證。我們很期待展開初期的基因編輯研究，以發現可針對已知會造成並促成囊性纖維化與鐮刀型細胞疾病之突變與基因的治療方法。

Thinking about CF more conceptually, the combination of what we learned through our CF research and the increasing flow of information from human genetics forms a template for our future discovery of precision medicines. First, our CF research program was directed at a target that was validated as an underlying cause based on human genetics. Second, by understanding the natural history of disease and using proprietary in vitro assays, we had a highly focused goal for CFTR modulation. Third, we had early markers of clinical effect that were highly predictive of late-stage success. And finally, these features have led to repeated success from the lab to the clinic. There are many lessons here that we can apply so that we can invest wisely and increase our chances of success in the future. Our investments are being evaluated based on insights from human biology, the therapeutic approach, and clinical development path criteria that we learned from our work in CF and can now apply to other diseases.

更概念性地思考囊性纖維化，我們從囊性纖維化研究中學到的內容，加上人類遺傳學資訊日益增加的流入，形成了我們未來發現精準藥物的範本。第一，我們的囊性纖維化研究計畫鎖定的標的，已基於人類遺傳學被驗證為根本原因。第二，透過理解疾病的自然病程並使用專有的體外測試，我們對 CFTR 調節有一個高度聚焦的目標。第三，我們擁有早期的臨床效果指標，且這些指標對於後期成功具有高度預測性。最後，這些特徵帶來了從實驗室到臨床的反覆成功。其中有許多經驗可供我們應用，使我們能更明智地投資並提高未來成功的機率。我們正依據從人類生物學洞見、治療方法，以及我們在囊性纖維化工作中學到並可套用至其他疾病的臨床開發路徑標準，來評估我們的投資。

In the area of pain, we have two compounds in early development, VX-150 and VX-241 target sodium channels,, with strong rationale for the treatment of pain, based on human genetics and well-documented roles in pain sensation. Specifically, the basis of our program is a key insight from human biology that gain or loss of function mutations in key sodium channels can increase or decrease pain sensation.

在疼痛領域，我們有兩個處於早期開發的化合物 VX-150 與 VX-241，鎖定鈉離子通道；基於人類遺傳學以及其在疼痛感受中有充分記載的角色，具備強而有力的疼痛治療理據。具體而言，我們計畫的基礎是一項來自人類生物學的關鍵洞見：關鍵鈉離子通道的功能獲得或功能喪失突變，可能會增加或降低疼痛感受。

In cancer, we have three compounds in early development, VX-970, VX-803, and VX-984, that target key cellular pathways responsible for DNA repair, a fundamental mechanism underlying the development and growth of cancer. In fact, DNA repair was recognized in 2015 with the Nobel Prize in Chemistry, citing three academic scientists for their pioneering efforts to map at a molecular level how cells repair damaged DNA. The Nobel Committee specifically cited the implication of this work for the development of new cancer treatments. In healthy cells, properly functioning DNA repair mechanisms protect against the development of problematic mutations. In cancer, however, these systems of DNA repair are known to go awry, allowing cancer cells to both accumulate mutations and increase their ability to survive and proliferate.

在癌症方面，我們有三個處於早期開發的化合物 VX-970、VX-803 與 VX-984，鎖定負責 DNA 修復的關鍵細胞途徑；DNA 修復是癌症發生與生長背後的基本機制。事實上，DNA 修復在 2015 年獲頒諾貝爾化學獎，表彰三位學術科學家在分子層級繪製細胞如何修復受損 DNA 的開創性努力。諾貝爾委員會特別指出此項工作對於開發新型癌症治療的意涵。在健康細胞中，正常運作的 DNA 修復機制可防止問題性突變的產生。然而在癌症中，這些 DNA 修復系統已知會失常，使癌細胞既能累積突變，也能提升其存活與增殖能力。

The new Vertex cancer medicines now in early development target two key nodes in the DNA repair systems, kinase is known as ATR and DNA, PK. Modulating activity of these two kinases is predicted to be critical to continued cancer cell survival in the face of DNA damage. In addition, we believe that these new compounds can be targeted to patients based upon a knowledge of the genomic alterations or characteristics in each patient's cancer, allowing a precision medicine approach to help increase benefit by targeting those patients more likely to respond. With the most advanced compound, VX-970, we and the National Cancer Institute are now conducting a number of early studies in tumor types that are predicted to be responsive to an ATR inhibitor. The first Phase 1 clinical data for VX-970 will be presented at the triple meeting in Boston in November.

Vertex 目前處於早期開發的新型癌症藥物，鎖定 DNA 修復系統中的兩個關鍵節點，其激酶分別稱為 ATR 與 DNA-PK。調節這兩種激酶的活性，預期對於癌細胞在面對 DNA 損傷時的持續存活至關重要。此外，我們相信可根據對每位患者癌症中基因體改變或特徵的了解，將這些新化合物鎖定於特定患者，採取精準醫療方法，透過鎖定較可能反應的患者來提升效益。就最先進的化合物 VX-970 而言，我們與美國國家癌症研究所（National Cancer Institute）目前正在多種預期對 ATR 抑制劑有反應的腫瘤類型中進行多項早期研究。VX-970 的第一期（Phase 1）臨床數據將於 11 月在波士頓的三方會議上發表。

In closing, we are pleased with the significant progress we are making in developing additional CF medicines, especially for the tens of thousands of patients living with CF who do not have a medicine that targets the underlying cause of their disease. We look forward to telling you more about our research strategy and our emerging clinical programs as they progress.

最後，我們對於在開發更多囊性纖維化藥物方面所取得的重大進展感到滿意，特別是針對數以萬計目前尚無可針對其疾病根本原因之藥物的囊性纖維化患者。隨著研究策略與新興臨床計畫的推進，我們期待向各位分享更多進展。

With that, I'll ask the operator to please open the line for questions.

那麼，我會請接線員開放提問專線。

Thank you.

謝謝。

(Operator Instructions)

(接線員指示)

Our first question comes from Michael Yee of RBC Capital Markets. Your line us now open.

我們的第一個問題來自 RBC Capital Markets 的 Michael Yee。您的線路現在已開通。

Thank you. Good afternoon. Congratulations on a great quarter. Two topics I wanted to get some more color on, the first, just on the launch, can you speak to more specifically how much inventory stocking that was? I think you said one to two weeks, is that $15 million to $20 million or so? Maybe help us there. And you said that centers were burdened. I just want to understand that comment a little bit and whether you thought there is any seasonality or things like that as we should be thinking about Q4. So talk a little about those things. And then my second question as a follow-up is on Europe. I know you just got a recommendation for approval, but broadly speaking, should we be thinking about price deltas, US and Europe, somewhat similar to what we see for ORKAMBI -- excuse me, for KALYDECO here? How should we think about any deltas there? Thank you

謝謝。下午好。恭喜本季表現亮眼。我想就兩個主題再多了解一些細節。第一個是關於上市初期，能否更具體談談那次庫存鋪貨的規模有多少？我想你們提到是一到兩週，那大概是 1,500 萬到 2,000 萬美元左右嗎？能否幫我們釐清一下。另外你們提到 CF 中心承受了負擔。我想更了解這句話的意思，以及在我們思考第四季時，是否存在任何季節性或類似因素。請談談這些。第二個追問是關於歐洲。我知道你們剛拿到建議核准，但整體而言，我們是否應該把美國與歐洲的價格差異，想成與我們在 ORKAMBI——抱歉，是在這裡的 KALYDECO——所看到的情況有些相似？我們應該如何看待其中的差異？謝謝。

Michael, thank you for the questions. On inventory, yes, your assessment's right. It's right in that $15 million to $20 million range was the initial inventory build for ORKAMBI. The rest is really driven by organic patient demand. In terms of our comments about the burden on CF centers, this is really just reflecting what we heard from centers actually prior to the launch, and we are seeing it play out during the launch. This is just a larger volume of patients than they had to try and get initiated on KALYDECO when we launched it. And so, that administrative purchase burden of helping patients through the payer reimbursement process is a very burdensome one for centers, and they certainly are relaying that to us. However, as we said in our prepared remarks, through the end of September, we have seen over 3,000 patients initiated on therapy. So the centers are really working through that process, and I don't think we really are seeing it as a seasonal impact. It really is just a function of working through a new launch with payers. In terms of the EU --

Michael，謝謝你的問題。關於庫存，是的，你的判斷沒錯。ORKAMBI 的初始庫存建立大約就在 1,500 萬到 2,000 萬美元的區間。其餘部分主要是由自然的病患需求所帶動。至於我們提到 CF 中心的負擔，這其實反映的是我們在上市前從中心聽到的回饋，而我們也看到在上市期間確實如此。這次需要啟動治療的病患量，比我們當初推出 KALYDECO 時要大得多。因此，協助病患走完付款方給付/報銷流程的行政與採購負擔，對中心而言非常沉重，他們也確實把這點回饋給我們。不過，如同我們在事先準備的發言中所說，截至 9 月底，我們已看到超過 3,000 名病患開始治療。所以中心確實正在推進這個流程，我不認為我們把它視為季節性影響。這更像是與付款方一起推進新產品上市流程的結果。至於歐盟——

Would you see seasonality in the fourth quarter? There's a lot of things going on in the fourth quarter. Do you expect any impact there?

你們會在第四季看到季節性嗎？第四季有很多事情在發生。你們預期會有任何影響嗎？

I don't think so, not in terms of patient visits and things like that. I wouldn't imagine though what we're going to see is a linear trend in terms of the launch. Launches just don't develop in that way. I think it's going to be a more [asyntopic] launch curve that you would normally see. But in terms of seasonality, I don't expect that to be much of a factor.

我想不會，至少在病患回診之類的事情上不會。不過我也不會預期上市推進會呈現線性趨勢。產品上市通常不會那樣發展。我認為會是你一般會看到的、較為[asyntopic]的上市曲線。但就季節性而言，我不預期會是很重要的因素。

In terms of in Europe, our approach to pricing is going to be very similar to that which it was here, perhaps with one exception. We're certainly going to be taking the same things into account, the seriousness of the disease, the clinical value we've demonstrated through treating the underlying cause of the disease, the investments we've made and continue to want to make in R&D to discover and develop future transformative medicines for CF patients and in other diseases. But we're also going to have to be sensitive to the economic environment in Europe, including the potential budget impact that ORKAMBI could have in almost all cases are single-payer markets. And so to finish on that and just to reiterate what Ian said in our prepared remarks, we do expect to recognize revenues for ORKAMBI in the EU in 2016, but these revenues are going to be primarily from Germany with minimal if any contribution from other countries.

至於歐洲，我們的定價方式將會與在這裡的做法非常相似，或許只有一個例外。我們當然會考量相同的因素：疾病的嚴重性、我們透過治療疾病根本原因所展現的臨床價值、以及我們已投入且仍希望持續投入於研發的資源，以便為 CF 病患及其他疾病發現並開發未來具變革性的藥物。但我們也必須對歐洲的經濟環境保持敏感，包括 ORKAMBI 可能帶來的預算影響；在幾乎所有情況下，歐洲都是單一付款方市場。最後補充並重申 Ian 在我們事先準備的發言中所說，我們確實預期在 2016 年於歐盟認列 ORKAMBI 的營收，但這些營收將主要來自德國，其他國家的貢獻即使有也會非常有限。

Okay. Thank you.

好的。謝謝。

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

謝謝。下一個問題來自 Barclays 的 Geoff Meacham。您的線路現在已開通。

Good afternoon, guys. Congratulations on the ORKAMBI launch and thank you for the question. A couple for Stuart and then some for David. For Stuart, just on ORKAMBI, wonder if you -- and I know it's early, but can you speak to the wait time to get a script approved? Does it differ among the different payers? And then, again it's early, but when you look at the feedback from the launch in the initial month or two in terms of the profile, is there any differences that you see commercially versus the traffic and transport phase 3s? Then I have some clinical follow-ups.

下午好，各位。恭喜 ORKAMBI 上市順利，也謝謝讓我提問。我有幾個問題想問 Stuart，然後也有一些想問 David。先問 Stuart，關於 ORKAMBI，我想知道——我知道現在還早——你能否談談處方核准的等待時間？不同付款方之間是否有差異？另外，同樣還早，但就上市頭一兩個月的回饋來看，從病患特徵輪廓而言，你們在商業端看到的情況，與 TRAFFIC 和 TRANSPORT 第三期試驗相比，有沒有任何差異？接著我還有一些臨床面的追問。

Sure, Geoff. In terms of wait time, the average time from a prescription being written to a patient actually initiating treatment or getting a pack through specialty pharmacies is about a month right now. Obviously, it's very early and so that number moves around a lot as patients move through the process, but right now, it's approximately a month. In terms of the profile, I'd say the only difference is that obviously traffic and transport had FEV1 criteria; inclusion, exclusion criteria, so the 40 to 90. And certainly, we are aware that there are patients who have been initiated with FEV1s below 40 and patients who have been initiated with FEV1s above 90, because the vast majority of payers are reimbursing to label and the label doesn't include any FEV1 restrictions. So that's really the major difference that I would suggest between what we're seeing in clinical practice and what we saw in traffic and transport.

當然可以，Geoff。就等待時間而言，從醫師開立處方到病患實際開始治療、或透過專科藥局拿到藥包的平均時間，目前大約是一個月。顯然現在還非常早，所以隨著病患在流程中推進，這個數字會有很大波動，但目前約為一個月。至於病患輪廓，我會說唯一的差異是：很明顯 TRAFFIC 和 TRANSPORT 有 FEV1 的標準；納入/排除條件是 40 到 90。而我們確實知道有些病患在 FEV1 低於 40 的情況下開始治療，也有些病患在 FEV1 高於 90 的情況下開始治療，因為絕大多數付款方是依照標籤適應症給付，而標籤並未包含任何 FEV1 的限制。所以這就是我認為臨床實務所見與 TRAFFIC/TRANSPORT 所見之間的主要差異。

Okay. And then for David, on the two next-gen correctors, and congratulations on getting those -- advancing those. Do they change the half-life of CFTR, mature CFTR that that's delta F? I know that was a little bit of a hot topic last year at NACF when you look at what the [VX-809] did to that. And then, not on the slide, but I was curious if you had looked directionally how the second-gen correctors also synergized with ORKAMBI versus the 661 KALYDECO combination.

好的。接著問 David，關於兩個下一代 corrector（校正劑），也恭喜你們推進了那些——它們是否會改變 CFTR（成熟 CFTR，也就是 delta F）的半衰期？我知道去年在 NACF 上，當你看 [VX-809] 對此的影響時，這曾是個相當熱門的話題。另外，雖然投影片上沒有，但我也好奇你們是否有方向性地看過第二代 corrector 與 ORKAMBI 的協同作用，相較於 661 與 KALYDECO 的組合？

Yes, Geoff, this is Jeff Leiden. Maybe I'll take those. So on the first question, at least so far, we're seeing that when you add all three drugs together, you don't get the effect on [correct and] CFTR half-life that we've see with the two drugs, at least with 152 and 440. Your second question was around ORKAMBI. I think we've shown the data with 661. We've shown the data compared to ORKAMBI, and it's really quite similar. We see about that 3-fold increase.

是的，Geoff，我是 Jeff Leiden。也許我來回答這些。第一個問題，至少到目前為止，我們看到當你把三種藥物一起加入時，並不會出現我們在兩種藥物組合（至少在 152 和 440 上）所看到的那種對 [correct and] CFTR 半衰期的影響。你的第二個問題是關於 ORKAMBI。我想我們已經展示了與 661 的數據。我們也展示了與 ORKAMBI 的比較數據，而結果其實非常相近。我們看到大約是 3 倍的提升。

I got you. Okay. Okay. Thank you

我明白了。好的。好的。謝謝

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

謝謝。我們的下一個問題來自高盛（Goldman Sachs）的 Terence Flynn。您的線路現在已開通。

This is Samir on for Terence. Can you provide any commentary regarding the prescribing trends, specifically in October? Thank you very much.

我是代替 Terence 的 Samir。您能否就處方趨勢提供一些評論，特別是 10 月的情況？非常感謝。

Samir, we're not going to really provide details on a month-by-month basis. Over the course of the quarter as we said, we saw just over 3,000 patients initiated. Obviously, that's been a fairly steep ramp, and I wouldn't anticipate that the launch trajectory is going to be linear. That's just not the way that product launches go.

Samir，我們不會真正按月提供細節。正如我們所說，在本季度期間，我們看到啟動治療的患者略超過 3,000 名。顯然，這是一個相當陡峭的爬坡，我不預期上市推進的軌跡會是線性的。產品上市通常不是這樣運作的。

Thank you.

謝謝。

Thank you. Our next question comes from Matt Roden of UBS. Your line is now open.

謝謝。我們的下一個問題來自瑞銀（UBS）的 Matt Roden。您的線路現在已開通。

Great. Thank you for taking the questions. Congratulations on a great launch. I just want to make sure we're crystal clear on the inventory part. With the levels of inventory that you have, it sounds to me like we should not expect that in the fourth quarter that there's any slack to come out of that system. Just want to verify that that's what you're telling us. And then related on the next quarter's trends, it seems like you're approaching already almost 50% penetration in a partial quarter of sales. Is there any reason that the homozygous F508del population won't be practically fully penetrated by next quarter?

很好。謝謝讓我提問。恭喜上市表現非常出色。我只是想確認我們對庫存部分的理解完全清楚。以你們目前的庫存水位來看，聽起來第四季我們不應該預期系統中會釋放出任何「鬆動」的空間。只是想確認這就是你們要傳達的意思。另外，關於下一季的趨勢，看起來你們在一個不完整的銷售季度內就已接近 50% 的滲透率。是否有任何原因使得同型合子 F508del 族群在下個季度不會幾乎完全滲透？

Matt, I'll take the first question on the inventory levels. So I did mention on my prepared remarks that we are at normal inventory levels, which are between one and two weeks. We'd anticipate that being similar at the year end as well. The amount that was actually in the channel relating to one to two weeks at this stage of the launch was approximately [$17 million]; so that $15 million to $20 million that was mentioned before. I think the key takeaway is this a normal level of inventory as we move quarter to quarter or through the year end. And then on the actual number of eligible patients who are on it, it's actually more like 35% rather than the 50%, Matt; 3,000 patients out of the approximately 8,500 eligible patients here in the US. As we said, we wouldn't expect it to continue in a linear way. That's just not the way product launches go. There's obviously a lot of initial pent-up demand and patients and physicians excited about the launch. We still expect that we are going to get to the vast majority of patients over the course of 2016, but we wouldn't expect the launch trajectory to continue in a linear fashion.

Matt，我先回答第一個關於庫存水位的問題。我在事先準備的發言中提到，我們目前處於正常庫存水位，大約是一到兩週。我們預期到年底也會維持類似水準。在上市現階段，通路中實際對應一到兩週的庫存約為 [1,700 萬美元]；也就是先前提到的 1,500 萬到 2,000 萬美元。我認為關鍵重點是：這是正常的庫存水位，無論是季度之間或到年底都是如此。至於實際符合資格且已用藥的患者數，Matt，其實更接近 35% 而不是 50%；在美國約 8,500 名符合資格的患者中，有 3,000 名患者。如同我們所說，我們不預期它會以線性方式持續。產品上市通常不是這樣運作的。顯然，一開始會有大量累積需求，患者與醫師對上市也很興奮。我們仍預期在 2016 年期間能涵蓋絕大多數患者，但不預期上市軌跡會以線性方式持續。

Okay. Thank you for that. Really appreciate the comments. Ian, if I could just sneak in a quick capital allocation question. I'm sure you'll be getting a lot of these as your cash flows ramp up. I don't really mean this from a margin or profitability perspective. I'm just saying that if we do assume some robust margins in the business, can you talk about your priorities for the use of cash, maybe even rank order in terms of importance, allowing the balances to rise or getting involved in M&A end licensing or share repurchase activity? Just wanted to get a sense of your broad thinking as you approach the swing to cash flow positivity.

好的。謝謝你的說明。非常感謝這些評論。Ian，如果可以的話，我想再快速插問一個資本配置的問題。我相信隨著你們現金流快速成長，會收到很多這類問題。我不是從毛利或獲利能力的角度來問。我的意思是，如果我們假設公司有相當強勁的利潤率，你能談談你們使用現金的優先順序嗎？甚至可以按重要性排序，例如讓資產負債表上的現金餘額上升、或參與併購與授權、或進行庫藏股回購等？我想了解在你們即將轉為正向現金流之際，你們整體思考的方向。

Sure, thank you for the question, Matt. And just to comment, that's a great question because as we turn profitable, which we do anticipate in the fourth quarter, we're now cash accumulation and over the years we've been cash preservation while we reinvest in the business. So we are a different Company as we head into the fourth quarter. As we think about the allocation of cash, I start with the receipt of cash is actually the revenue, just to be basic about this, but the receipt of cash is the revenue. As we think about reinvestment and allocation of that capital, it does go towards R&D for our business, the internal R&D. But as we develop our business, we also consider the external investment in R&D, and I think you saw that with the example this week of signing a collaboration with CRISPR Therapeutics that we're very excited about. You've also seen it earlier this year where there's been licensing products that complement our approach in CF. So we're already starting to allocate that revenue capital towards internal R&D and also acquire products or expand our scientific footprint. And you should anticipate that to continue.

當然，謝謝你的問題，Matt。我也補充一下，這是個很好的問題，因為當我們轉為獲利（我們預期在第四季），我們就會開始累積現金；而過去多年我們是在保留現金，同時再投資於業務。因此，當我們邁入第四季時，公司已經不同以往。談到現金的配置，我先從最基本的說起：現金的收取其實就是營收的回收。在思考再投資與資本配置時，資金會投入我們業務的研發，也就是內部研發。但在發展業務的同時，我們也會考慮對外的研發投資；我想你們本週看到我們與 CRISPR Therapeutics 簽署合作協議的例子，我們對此非常興奮。你們也在今年稍早看到我們授權引進能補強我們在囊性纖維化（CF）策略的產品。因此，我們已開始把這些營收資本配置到內部研發，同時也用於取得產品或擴大我們的科學布局。你們應該預期這會持續下去。

As far as thinking about other allocation of capital, rather than just accumulate on the balance sheet, we do think about our capital structure and the shares outstanding, and we need to continue to think about that going forward. But it becomes a prioritization. And first, it is about investment in medicines for the future, which provides growth. However, if the capital becomes available that we would consider addressing our capital structure, we'd also make that choice as well.

至於其他資本配置的思考，而不只是把現金累積在資產負債表上，我們也會思考資本結構與流通在外股數，未來也需要持續考量。但這會牽涉到優先順序的取捨。首先，是投資於未來的藥物，這能帶來成長。然而，如果有可用資本，我們也會考慮處理資本結構，並可能做出那樣的選擇。

Really helpful. Thank you, Ian.

非常有幫助。謝謝你，Ian。

Thank you, and our next question comes from Cory Kasimov of JPMorgan. Your line is now open.

謝謝，下一個問題來自摩根大通（JPMorgan）的 Cory Kasimov。您的線路現在已開通。

This is Brittany on for Cory. Thank you for taking the questions. Is there anything you're seeing in the early launch of ORKAMBI in the US that changes your expectations for Europe? And then on the CRISPR collaboration, is there any early signs you're seeing in the applicability of gene therapy to CS? And then also, just what advantages did you see with CRISPR versus other gene-editing technologies? Thank you

我是代替 Cory 的 Brittany。謝謝讓我提問。你們在美國 ORKAMBI 早期上市中看到的任何情況，是否會改變你們對歐洲的預期？另外，關於與 CRISPR 的合作，你們是否看到任何早期跡象顯示基因治療可適用於 CS？還有，相較於其他基因編輯技術，你們認為 CRISPR 有哪些優勢？謝謝

In short, Brittany, the answer to your first part of the question is no, not really. We're seeing what we anticipated we'd see with the launch here in the US, which is a lot of enthusiasm from physicians and patients for the first drug that treats the underlying cause of their disease. And I expect there will be a similar level of enthusiasm from physicians and payers in the EU. So there's really nothing we're seeing here which is changing my view about how I think the launch is going to progress in the EU.

簡而言之，Brittany，你第一部分問題的答案是：不，並沒有。我們在美國這裡看到的上市情況與我們原先預期一致，也就是醫師與患者對於第一個能治療其疾病根本原因的藥物抱持高度熱忱。我預期在歐盟，醫師與付款方也會有類似程度的熱忱。因此，我們在這裡看到的情況並沒有改變我對歐盟上市進展方式的看法。

And with regard to CRISPR, we believe that CRISPR-cas9 is a powerful technology that holds really great promise for discovering transformative medicines for genetic diseases, including CF. And we're very excited to work with CRISPR Therapeutics as a leader in that field and it's a good fit for Vertex.

至於 CRISPR，我們相信 CRISPR-cas9 是一項強大的技術，對於發現可帶來變革的遺傳疾病療法（包括囊性纖維化（CF））具有非常大的潛力。我們也非常期待與該領域的領導者 CRISPR Therapeutics 合作，這與 Vertex 非常契合。

Great, thank you.

太好了，謝謝。

Thank you. Our next question comes from Ying Huang from 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的黃穎。您的線路現在已開通。

It's actually Katherine for Ying. A couple questions from us. On the payer mix, of the over 3,000 patients that started in 3Q, what percentage were Medicaid patients? And then can you speak to your expectations for compliance of the ORKAMBI patients versus those on KALYDECO? And then just lastly, for the triple combination, just want to clarify, are you planning to move both combinations forward or will you pick one? Thank you.

其實我是代替穎的 Katherine。我們有幾個問題。關於付款方組合，在第三季開始治療的 3,000 多名病患中，有多少百分比是 Medicaid 病患？另外，您能談談您對 ORKAMBI 病患相較於使用 KALYDECO 的病患，其用藥依從性的預期嗎？最後，關於三聯組合，我想確認一下，您是打算把兩個組合都往前推進，還是會選擇其中一個？謝謝。

So Katherine, a few questions there. Maybe I'll take the first one in terms of the revenue split, and Stuart will take the second, and Jeff Chodakewitz can clean up for us. So first to the split between the, let's call it the government channel and the private payer channel, it was about close to 20% in the government channel. That translated to a gross to net adjustment of our gross price of just below 10%. I did make some comments earlier that as this launch proceeds, we do anticipate that the government channel does rise up to somewhere close to 35%. And when we're at that steady state of 35% government and 65% private, then we would anticipate something in the mid-teens as a gross to net adjustment.

Katherine，你那裡有幾個問題。也許我先回答第一個、關於營收拆分的部分，Stuart 來回答第二個，然後 Jeff Chodakewitz 再幫我們補充。首先，就我們稱之為政府通路與私人付款方通路之間的拆分而言，政府通路約接近 20%。這換算成以我們的定價（gross price）計，毛額到淨額（gross-to-net）的調整幅度略低於 10%。我先前也提到，隨著這次上市推進，我們預期政府通路占比會上升到接近 35%。當我們達到政府 35%、私人 65% 的穩態時，我們預期毛額到淨額的調整幅度會在十幾個百分點的中段。

Katherine, in terms of compliance, obviously early days so far in the launch, but in terms of what we would anticipate, overall my anticipation is that our compliance with the therapy will be high, and that's because I think physicians will do a great job explaining to patients, and patients I think, on the whole, understand that this is a medicine that's treating the underlying cause of their disease. I think overall, the compliance rate is going to be high. I think the KALYDECO compliance would be the upper end of my expectations, if I'm perfectly honest. It's the highest compliance rate I've ever seen for any chronic medication. We'll certainly being doing everything we can to appropriately support patients to maintain a high level of compliance with ORKAMBI as well, but I think KALYDECO would be at the upper end of my expectation.

Katherine，就依從性而言，顯然目前上市時間還不長；但就我們的預期來看，我預期整體治療依從性會很高，因為我認為醫師會很清楚地向病患說明，而病患整體上也理解這是一種治療其疾病根本原因的藥物。我認為整體依從率會很高。如果坦白說，KALYDECO 的依從性會落在我預期的上緣。那是我見過任何慢性用藥中最高的依從率。我們當然會盡一切努力，適當地支持病患也能維持 ORKAMBI 的高依從性，但我認為 KALYDECO 會在我預期的上緣。

And in terms of next gen, as you know, we're going to move both of those molecules into [nan]. We're going to learn about the compounds as they go through the Phase 1 studies, but assuming the data supports it, we would plan to move both compounds into evaluation in patients.

至於下一代（next gen），如你所知，我們會把這兩個分子都推進到 [nan]。我們會在它們進入第一期研究的過程中進一步了解這些化合物；但假設數據支持，我們計畫將兩個化合物都推進到病患中的評估。

Great, thank you very much and congratulations on the quarter.

太好了，非常感謝，也恭喜本季表現。

Thank you.

謝謝。

Thank you. And our next question comes from 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 Matthew Harrison。您的線路現在已開通。

This is David Leibowitz in for Matt. You mentioned earlier in an answer to another question that it was taking about one month to get reimbursement for patients. And I was just curious, going forward as patients start to look to obtain refills, is there any expectation for how payers might address refills? Will there be some point where they want to re-evaluate?

我是代替 Matt 的 David Leibowitz。你先前在回答另一個問題時提到，為病患取得給付大約需要一個月。我想請教，往後當病患開始要取得續配（refills）時，對於付款方可能如何處理續配，是否有任何預期？他們是否會在某個時間點想要重新評估？

Yes. It's very common for payers to have reauthorization criteria. It will -- they differ from payer to payer, both in terms of the time to when they want to reassess a patient and look to reauthorize, and then also they differ in terms of the criteria. Of the reauthorization criteria that we've seen to date, which is a relatively limited number, but of the ones that we've seen to date, the vast majority have got criteria which effectively reflective of reimbursing to the label, or if the physician thinks that the patient has seen clinical benefit across a number of different dimensions, reflecting the fact that CF is a complicated multi-system disease.

是的。付款方設有重新授權（reauthorization）標準是很常見的。這些標準——不同付款方之間會有所差異，包括他們希望在何時重新評估病患並進行續授權，以及在標準內容上也會不同。就我們目前看到的重新授權標準而言，數量還相對有限；但在我們迄今所見的案例中，絕大多數的標準基本上反映的是依照標籤（label）給付，或是若醫師認為病患在多個不同面向上獲得臨床效益即可，這也反映了囊性纖維化（CF）是一種複雜的多系統疾病。

Thank you for answering that. And just to jump over to a different topic, there's been some data released recently from competitors on their triple combo, and I know you recently at NACF presented some data, some preclinical data on yours. And I was just curious if you could juxtapose yours versus theirs and make any overall comments and comparisons.

謝謝你回答。再跳到另一個主題，最近競爭對手釋出了一些他們三聯組合的數據；我知道你們最近在 NACF 也發表了一些你們的數據、一些臨床前數據。我想請教你是否能把你們的和他們的做個對照，並給出一些整體評論與比較。

So David, we'd prefer to keep our comments to our own compounds. So we are very excited about them. We provide you the [HBE] data. I would say that we like our position in terms of we already have two marketed medicines. We've got another corrector that is in Phase 3 development that we've characterized very well, given its stage of development. And then with our two next-generation correctors coming into the clinic, it provides us the opportunity to move quickly, given that we already understand the medicines that we would combine our next gens with. I'd also point out that we did take our time in choosing the right next-generation correctors, and the two of them to come into the clinic. And not only were they picked for their performance in pre-clinical assays for efficacy and safety, but also their pharmaceutical properties. So we believe that we're in a very good position to move those into the clinic very shortly, into the healthy studies, and then next year to move them into triple combination studies and see some results in patients. So we're looking forward to that.

David，我們比較希望把評論聚焦在我們自己的化合物上。我們對它們感到非常興奮。我們已向你提供 [HBE] 數據。我會說，我們很喜歡我們目前的定位，因為我們已經有兩個已上市的藥物。我們還有另一個校正劑（corrector）正在第三期開發中，基於其開發階段，我們已非常充分地對其進行特性描述。此外，隨著我們兩個下一代校正劑進入臨床，這讓我們有機會快速推進，因為我們已經了解要把下一代藥物與哪些藥物進行組合。我也要指出，我們在選擇合適的下一代校正劑上花了時間，並選定了這兩個進入臨床。它們不僅是基於在臨床前檢測中對療效與安全性的表現而被選出，也考量了其藥物製劑/藥學性質。因此，我們相信我們處於非常有利的位置，可以在很短時間內把它們推進到臨床、進入健康受試者研究，並在明年推進到三聯組合研究，在病患中看到一些結果。我們很期待。

Thank you for answering my questions.

謝謝你回答我的問題。

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

謝謝。我們的下一個問題來自 Jefferies 的 Brian Abrahams。您的線路現在已開通。

Hi. Thank you very much for taking my questions and congratulations on the strong ORKAMBI launch. So obviously, you have very rapid penetration, sounds like a lot of enthusiasm for ORKAMBI. I was wondering if you could tell us if there's any commonalities amongst patients who are not yet on treatment, if it's mostly administrative or reimbursement time lines, or if there's any particular reasons why physicians or patients may not be choosing the drug other than patients just not having gotten to their physician's office yet? And then on VX-970, I'm interested in the opportunity there, if you could tell us a little more about the biomarkers you might use for patient selection going forward, perhaps the proportion of common solid tumors that patients with common solid tumors that have complete ATM loss, which is I think the characteristic you saw in the complete response that was observed. Thank you.

嗨。非常感謝讓我提問，也恭喜 ORKAMBI 上市表現強勁。很明顯你們的滲透速度非常快，聽起來大家對 ORKAMBI 很有熱情。我想請教，對於尚未開始治療的病患，是否有任何共通點？主要是行政流程或給付時程的因素，還是醫師或病患不選擇該藥有任何特定原因（除了病患還沒去看診之外）？另外關於 VX-970，我對那裡的機會很感興趣；你能否多談一些你們未來可能用於病患篩選的生物標記（biomarkers），例如常見實體腫瘤中具有完整 ATM 缺失的病患比例——我認為那是你們在觀察到完全反應（complete response）時所看到的特徵。謝謝。

Brian, I'll take the first question on those patients not on treatment. Obviously, we're delighted that we're off to a promising start with over 3,000 patients initiated. But obviously, that means that there's somewhere near 5,000 or so who are not yet initiated. That's just such a large number of patients, it's hard to say there's one reason or two reasons why they haven't started on treatment yet. They really represent all types of eligible patients with the 508del mutation. And I just want to reiterate we do still anticipate that the vast majority of those patients will eventually be initiated on ORKAMBI over the course of the rest of this year and into 2016. So there's not really one or two things that are holding those patients back from initiating therapy.

Brian，我先回答第一個、關於尚未治療的病患。顯然，我們很高興目前有超過 3,000 名病患開始用藥，上市開局相當不錯。但這也表示大約還有接近 5,000 名左右尚未開始。病患數量這麼大，很難說他們尚未開始治療只有一個或兩個原因。他們其實涵蓋了所有類型、符合 508del 突變適應症的病患。我想再次強調，我們仍然預期其中絕大多數病患最終會在今年剩餘時間到 2016 年期間陸續開始使用 ORKAMBI。因此，並沒有一兩個特定因素在阻礙這些病患開始治療。

And hi, it's Jeff Chodakewitz. Maybe just a couple comments on your 970 question. You focused on ATM, but I would step back just a little bit because I think in my mind, that ATM deficiency is one of mutations that actually link to disorders of DNA repair in patients who have cancer. And so ATM is one. Another one that we're using as we go into our trial is mutations and deficiencies in P53, actually a more common one. The frequency of that varies widely across tumor cell. I can't give you a single number, but it certainly is observed in multiple types of cancer. And we think that does serve as an important foothold in our understanding of the science to tell us where to go clinically.

嗨，我是 Jeff Chodakewitz。也許就您關於 970 的問題補充幾點。您把焦點放在 ATM，但我會稍微退一步看，因為在我看來，ATM 的缺失其實是與癌症患者 DNA 修復障礙相關的一類突變之一。因此 ATM 是其中之一。我們在推進試驗時也在使用的另一項是 P53 的突變與缺失，實際上更為常見。其發生頻率在不同腫瘤細胞之間差異很大。我無法給出單一數字，但確實在多種癌症類型中都有觀察到。我們認為這確實可作為我們理解科學的重要立足點，指引我們在臨床上該往哪裡走。

Thank you so much.

非常感謝。

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

謝謝。下一個問題來自 Evercore ISI 的 Mark Schoenbaum。您的線路已開通。

Hi. This is (inaudible) actually sitting in for Mark. A lot of the questions are already asked. I wanted to take a step back and ask maybe just more big picture questions. The -- congratulations on what was a great quarter. But just trying to think about competition and perhaps, specifically, [galapagos], and thinking about the development and the development risk, just trying to think about how Vertex might see that, whether it's use of the drug, in particular or just the ability to combine those drugs, any thoughts on that. And then I had a question on, you mentioned reauthorization criteria and you mentioned clinical criteria. And I just wonder if you could comment on how high you see the bar for those clinical criteria, just because it seems early to be asking those kinds of questions. And then just based on the pipeline and number of products that are being moved forward, just maybe speaking to margins a little bit. So I know you've made comments before about expenses, but now just seems like a good time to ask again.

嗨。我是（聽不清），其實是代替 Mark 發問。很多問題都已經被問過了。我想退一步，問一些更宏觀的問題。— 恭喜，這是一個很棒的季度。但我想從競爭的角度思考，或許特別是 [galapagos]，以及研發與研發風險；想了解 Vertex 可能如何看待這件事，無論是藥物本身的使用，或是特別是這些藥物的聯合使用能力，您有什麼想法嗎？另外我還有一個問題，您提到重新授權（reauthorization）標準，也提到臨床標準。我想請您評論一下，您認為這些臨床標準的門檻會有多高，因為看起來現在就問這類問題似乎還很早。最後，基於產品線以及正在推進的產品數量，想請您談談毛利率/利潤率。我知道您之前談過費用，但現在似乎是個再次詢問的好時機。

Yes, (inaudible), this is Jeff Leiden. I'll start with the first one, Stuart can take the second, and Ian will take the third. With respect to Galapagos, just as Stuart emphasized, Ian said, we really don't comment on any of the competitor compounds or programs. I would just reiterate what Ian said about our program, which is we like our position really for three reasons. Number one, we have two drugs in the combination 661 in KALYDECO that are either approved or very well characterized, so when you put a three-drug combination together, we feel that's a nice position to be in. Number two, we've spent a lot of time optimizing the pharmaceutic properties of both next-gen correctors. That's important as you put a three-drug combination together. And number three, we showed you the chloride data from the HBE cells with that three drug combination, which are getting us levels which are at or north of what KALYDECO does in G551d. And so far, those assays have predicted quite well what we see in the clinic. We're excited to see the first Phase 2 results. We'll start those studies next year.

是的，（聽不清），我是 Jeff Leiden。我先回答第一個，Stuart 回答第二個，Ian 回答第三個。關於 Galapagos，正如 Stuart 強調、Ian 也說過的，我們確實不評論任何競爭對手的化合物或計畫。我只想重申 Ian 對我們計畫的說法：我們喜歡我們目前的位置，主要有三個原因。第一，我們的聯合療法中有兩個藥物——661 與 KALYDECO——要麼已獲核准、要麼已有非常充分的特性描述，因此當你把三藥聯合放在一起時，我們認為這是一個不錯的起點。第二，我們花了很多時間去最佳化兩個下一代校正劑（next-gen correctors）的藥物製劑/藥學性質。當你要把三藥聯合放在一起時，這點很重要。第三，我們向各位展示了在 HBE 細胞中使用該三藥聯合的氯離子數據，其達到的水準等同於或高於 KALYDECO 在 G551d 中的效果。而到目前為止，這些測試相當能預測我們在臨床上看到的結果。我們很期待看到第一批第二期（Phase 2）結果。我們將在明年啟動這些研究。

On reauthorization criteria, just to reiterate what I said, so far we've seen a limited number of plans which have published their reauthorization criteria. We're really talking about a small [an] at this stage. Our knowledge of those will increase, obviously, as plans publish those criteria or make those criteria known. Of the ones that's we've seen so far, they aren't really setting a really very high clinical bar, to use your terminology. Most of them are essentially just ensuring that the patients continue to be within our label or show improvement across a number of clinical parameters in the opinion of the treating physician. So but as I say, that's on a limited basis right now, because it is early for plans to be publishing reauthorization criteria.

關於重新授權標準，我再重申一次我剛才說的：到目前為止，我們只看到少數保險計畫公布了其重新授權標準。現階段我們談的樣本數其實很小。當然，隨著各計畫公布或讓外界得知其標準，我們對這些標準的了解會增加。就我們目前看到的那些而言，它們並沒有設定非常高的臨床門檻（用您的說法）。多數基本上只是確保病人仍符合我們的適應症標籤，或在主治醫師的判斷下，在多項臨床參數上有所改善。但如我所說，這目前仍是基於有限資訊，因為現在確實還太早，保險計畫不一定會公布重新授權標準。

I would say just to round out your questions, I'll just state again, we're committed to driving this business forward and having high operating margins. We get to that position by revenue growth and controlling our operating expenses. We have a business and we're in an area where we can do that. And so for us it's execution on the launch, both in the US and then in Europe, continue to reinvest for growth of the future, yet still having significant operating margins.

我想為了完整回答您的問題，我再說一次：我們致力於推動這項業務向前發展，並維持高營業利潤率。我們透過營收成長與控制營業費用來達成這個目標。我們所處的領域與我們的業務模式，讓我們有能力做到這點。因此對我們而言，關鍵在於上市執行力——不論是在美國或歐洲——同時持續再投資以支持未來成長，但仍能維持可觀的營業利潤率。

Thank you.

謝謝。

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

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

Good evening. Thank you for taking my question and congratulations on the progress. First one on European reimbursement. In the prepared remarks, you noted that KALYDECO took I think between 9 and 20 months to get country-by-country reimbursement. I'm curious whether you think that could go faster this time around, given that you've gone back to the same payers, in some cases, probably several times with the different KALYDECO label expansions?

晚安。謝謝讓我提問，也恭喜你們的進展。第一個問題關於歐洲給付/報銷。在事先準備的發言中，你們提到 KALYDECO 取得各國逐一的給付/報銷大概花了 9 到 20 個月。我想知道，考量你們這次在某些情況下已經多次帶著不同的 KALYDECO 適應症擴增回到同一批支付方，你們是否認為這次可能會更快？

Yes, Phil, Thank you for the question. I won't really know until our team over in Europe begins those reimbursement discussions with the relevant authorities. That's why I say it's really, really difficult to predict. They all have different processes. A number of them, those processes are changing. They're not even the same process that we went through with KALYDECO. So I really can't predict with any sense of confidence or accuracy whether we're going to go faster or slower with ORKAMBI. We won't really know until we begin that process after we receive regulatory approval, which we continue to anticipate will happen later this quarter.

是的，Phil，謝謝你的問題。在我們歐洲團隊開始與相關主管機關進行那些給付/報銷討論之前，我其實不會知道。這也是我說真的、真的很難預測的原因。各國流程都不同。其中不少國家的流程正在改變。甚至已經不是我們當初為 KALYDECO 所走過的同一套流程。因此我無法以任何把握或準確度來預測，我們在 ORKAMBI 上會更快還是更慢。我們要等到取得法規核准後、開始那個流程才會真正知道；我們仍預期核准會在本季稍晚發生。

And then second question, also in your prepared remarks you mentioned that the reimbursement assistance team is beginning to shift to impact persistence and contact the patients. Can you talk a little bit more about that? What exactly is involved in impacting the persistence and what type of methods do you find most effective?

第二個問題，在你們的事先準備發言中也提到，給付/報銷協助團隊正開始轉向影響治療持續性（persistence）並與病患聯繫。你能再多談一點嗎？所謂影響治療持續性具體包含哪些內容？你們認為哪些方法最有效？

Yes, Thank you for the question. So obviously, they do a number of things. One is to help patients who are initiating on treatment navigate the reimbursement process, and they'll obviously need to continue to do that. Because while there are over 3,000 patients initiated, there's still a lot more patients that physicians are going to want to initiate on ORKAMBI. But for those who are now started on therapy, then we have a number of programs. And essentially, it's really helping educate patients on the mode of action of ORKAMBI, how it treats the underlying cause of their disease, and providing them to the extent they want to receive educational materials and refill reminders and things of that nature. And so we tailor that to the individual patients as they desire.

是的，謝謝你的問題。很明顯，他們會做很多事情。其中之一是協助剛開始治療的病患了解並完成給付/報銷流程，而他們當然也需要持續做這件事。因為雖然已經有超過 3,000 名病患開始用藥，但仍有更多病患是醫師會希望開始使用 ORKAMBI 的。但對於那些已經開始治療的人，我們也有一些計畫。基本上，是協助教育病患了解 ORKAMBI 的作用機轉、它如何治療其疾病的根本原因，並在病患願意的範圍內提供衛教資料、續配/補藥提醒等類似服務。因此我們會依照個別病患的需求來量身調整。

Great. Thank you for taking my questions.

很好。感謝讓我提問。

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

謝謝。下一個問題來自 Guggenheim 的 Tony Butler。您的線路現在開通。

Yes, thank you very much. Stuart, I recognize the commentary around the approval in the EU toward the end of the quarter, but if I make assumptions that as you alluded to earlier, Germany's the first country to be purchasing. Can you comment on the number of 5508del08 Del patients in Germany? And then my second question is more scientifically oriented. Beyond the correctors of 440 and 152, I had the impression that you may put additional correctors, second-gen correctors into the clinic. Is that still you true or did I misinterpret that? Thank you very much.

是的，非常感謝。Stuart，我理解你提到本季末在歐盟獲批的相關評論，但如果我做一些假設，正如你先前提到的，德國會是第一個開始採購的國家。你能評論一下德國 5508del08 Del 患者的人數嗎？第二個問題比較偏科學。除了 440 和 152 這兩個校正劑（correctors）之外，我的印象是你們可能會把額外的校正劑、第二代校正劑帶入臨床。這仍然屬實，還是我誤解了？非常感謝。

Yes, in Germany, Tony, there's about 2,500 patients who are 12 and over who are homozygous for the f508del mutation. And so assuming that our approval comes through at the end of this quarter, and that that's our labeled indication, that will be the eligible patient population in Germany.

是的，在德國，Tony，大約有 2,500 名 12 歲及以上、且為 f508del 突變純合子（homozygous）的患者。因此，假設我們在本季末獲得核准，且那就是我們標示適應症（labeled indication），那將會是德國符合資格的患者族群。

Thank you, Stuart.

謝謝你，Stuart。

I'll take the second one, which is about the additional correctors. Maybe I'll broaden it out just a little bit, if you don't mind. Our goal is to create the best portfolio of medicines for each one of these patient populations. So certainly a big part of that is going to be next-gen correctors, and as I've said several times before, we have multiple -- we have discovered multiple next-gen correctors. These are the first two, but there are others behind them. And assuming they pan out as they go through lead off and [tox], yes, our intent would be to put additional correctors in, particularly if they have different and interesting properties so that we can study them. Beyond that, I'd also remind you of things like the ENaC inhibitors, like gene editing, we're really looking at a variety of modalities, and so over the next few years, you can expect to see us bring multiple compounds, and frankly, multiple modalities into the clinic to try to create the best combinations.

我來回答第二個，也就是關於額外校正劑的問題。如果你不介意，我可能把範圍稍微擴大一點。我們的目標是為每一個患者族群建立最佳的藥物組合（portfolio）。因此，下一代校正劑當然會是其中很重要的一部分；而且如我之前多次提到，我們已經發現多個下一代校正劑。這是前兩個，但後面還有其他候選。並且假設它們在先導（lead off）與 [tox] 的過程中表現良好，是的，我們的意圖是導入更多校正劑，特別是如果它們具有不同且有趣的特性，讓我們可以加以研究。除此之外，我也提醒你，像 ENaC 抑制劑、基因編輯等，我們正在評估多種治療模式（modalities）；因此在未來幾年，你可以預期我們會把多個化合物，坦白說也包括多種治療模式帶入臨床，以嘗試打造最佳的組合療法。

Understood. Thank you.

了解。謝謝。

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

謝謝。下一個問題來自 JMP Securities 的 Liisa Bayko。您的線路現在開通。

Hi. Congratulations from me as well. You mentioned that there were a couple of plans that are not yet covering ORKAMBI. Can you maybe give us a sense of what percentage of lives that matter to you that represents?

嗨。我也要恭喜你們。你提到有幾個保險計畫尚未涵蓋 ORKAMBI。你能否讓我們了解一下，這大約代表你們所關注的「受保人數（lives）」的百分比是多少？

Yes, Liisa, it's a small number of plans. It's in the single digits in terms of the number of lives that they are responsible for. And essentially, they are not reimbursing yet. And we know they're continuing to work through the process of evaluating the product, and we're sure they'll come to a formal conclusion over the next few months. But it's -- at the minute, it is single digits in terms of the number of lives covered by those plans.

是的，Liisa，這只是少數幾個保險計畫。以它們所涵蓋的受保人數（lives）來看，是個位數的比例。基本上，它們目前尚未開始給付。我們知道它們仍在進行產品評估流程，我們也相信它們會在未來幾個月內做出正式結論。但就目前而言，這些計畫所涵蓋的受保人數占比是個位數。

Thank you. That's helpful. And then just on CMS, can you walk us through the timing there in getting coverage for the Medicare, Medicaid population? Thank you.

謝謝。這很有幫助。另外關於 CMS，你能帶我們了解一下，取得 Medicare、Medicaid 人群涵蓋（coverage）的時程嗎？謝謝。

Well, in terms of payer mix, we already have had patients both in Medicare and Medicaid who have got access and have been reimbursed for ORKAMBI. The vast majority, in fact, state Medicaids have already reimbursed patients. And so, we already have effectively reimbursement in a number of states and through Medicare as well.

嗯，就付款方組合（payer mix）而言，我們其實已經有 Medicare 與 Medicaid 的患者取得 ORKAMBI 的用藥機會，且已獲得給付。事實上，絕大多數州的 Medicaid 都已經為患者給付。因此，我們在多個州以及透過 Medicare 也已經實質上取得給付。

Okay. So there's not really any gating factor there, then?

好的。所以那邊其實沒有什麼關卡因素（gating factor）了，對嗎？

There are some Medicaid plans who are still considering the product and have decided that they're not going to cover ORKAMBI until they've come to a formal decision. So it really is on a state-by-state basis on Medicaid; there really isn't one answer, one decision. It really happens on a state-by-state basis.

有一些 Medicaid 計畫仍在評估該產品，並決定在做出正式決定之前不會涵蓋 ORKAMBI。所以在 Medicaid 方面確實是逐州（state-by-state）而定；並沒有單一答案、單一決策。它確實是逐州發生的。

Okay, fair enough. And then just one question about the oncology portfolio. Can you maybe at all describe some of the data? I see in triple negative breast cancer patients and non-small cell lung, you're going to enhance maybe some of those populations, and it seems like maybe you have some data there. Could you comment at all on that? And that's my final question. Thank you.

好的，可以理解。最後一個問題關於腫瘤產品組合。你能否稍微描述一些數據？我看到在三陰性乳癌患者與非小細胞肺癌方面，你們將可能擴充其中一些族群，看起來你們可能已經有一些數據。你能否評論一下？這是我最後一個問題。謝謝。

Hi, it's Jeff Chodakewitz. I think it actually goes back to the question that was asked by someone else earlier about how are we selecting the right subset of patients. And that those factors are present actually in patients with multiple kinds of tumors. What we've done in those two small sets of studies -- of patients is actually to hone in on patients who we expect or will require to have some of those kinds of mutations that we spoke about, those deficiencies in DNA repair. And then, by doing that, we think we are being able to get a very focused, relatively rapid answer to the question about how the drug will work. So that's what that represents that you're seeing in our study description.

嗨，我是 Jeff Chodakewitz。我想這其實回到先前其他人問過的問題：我們如何選擇正確的患者子族群。而這些因素其實存在於多種腫瘤的患者身上。我們在那兩個小型研究的患者族群中所做的，是聚焦於我們預期會具有、或需要具有我們剛才談到的那類突變的患者，也就是 DNA 修復缺陷。透過這樣做，我們認為能以非常聚焦、相對快速的方式回答藥物將如何發揮作用這個問題。所以你在我們研究描述中看到的內容，就是在代表這件事。

Thanks a lot.

非常感謝。

Thank you. And our next question comes from Katherine Xu of William Blair. Your line is now open.

謝謝。下一個問題來自 William Blair 的 Katherine Xu。您的線路現在開通。

I just have a few questions on the CRISPR program. How far is it from the clinic? From a scientific perspective are there difficulties in levels of research between inserting these pairs versus correcting the base pairs? Then also, why did you choose CRISPR Therapeutics? There are a few other companies with similar technologies. And if you could comment on the IP side, that would be great as well.

我有幾個關於 CRISPR 計畫的問題。距離進入臨床還有多遠？從科學角度來看，插入這些鹼基對（base pairs）與校正鹼基對之間，在研究層面是否存在難度差異？另外，你們為什麼選擇 CRISPR Therapeutics？還有幾家公司也有類似技術。如果你也能評論一下智慧財產權（IP）方面，那也會很棒。

Katherine, David, will take the first two questions and then I'll answer the third question once David is through it on the process we went through.

Katherine，David 會先回答前兩個問題，然後等 David 講完後，我會回答第三個問題，也就是我們所走過的流程。

Thank you for the question. I would say that it's still early days in this, and so we really can't comment or predict exactly how long it will take. And in terms of things like the different methods of using CRISPR to modify the DNA, again, that will all be subject to research we're doing and look forward to updating you when we have progresses to report.

謝謝你的提問。我會說目前仍在非常早期階段，因此我們真的無法評論或精確預測需要多久時間。至於使用 CRISPR 修改 DNA 的不同方法等問題，同樣都將取決於我們正在進行的研究；等我們有進展可報告時，也期待再向各位更新。

In terms of process, on previous calls, when asked about our business and corporate development strategy, we've always had three main approaches. One was to complement what we're doing in cystic fibrosis, two was to be opportunistic in licensing and M&A, and then a third area was always to broaden our scientific platform. And that's what we're doing here. We've been very good in small molecules for a long time at Vertex. And with David's help in coming on board about a year ago, we were able to consider other technologies and how we may expand our scientific footprint. This was an area that rose to the top as a priority for us. And so we then went through the process, as you usually do, as there are a number of companies that have access to this technology. We did our usual diligence process, and based on the structure of the arrangement, the collaboration between people and the opportunity of fit with what we want to do at Vertex, our choice was with CRISPR Therapeutics. And we're very happy to be a partner of theirs as we move forward.

就流程而言，在先前的電話會議中，當被問到我們的業務與公司發展策略時，我們一直有三個主要做法。第一是補強我們在囊性纖維化（cystic fibrosis）領域正在做的事；第二是在授權與併購（M&A）方面把握機會；第三個領域則一直是擴大我們的科學平台。而這正是我們在這裡所做的。Vertex 長期以來在小分子方面一直做得非常好。在 David 約一年前加入並提供協助後，我們得以考量其他技術，以及我們如何擴大我們的科學版圖。這個領域成為我們的優先事項之一。因此我們接著走完通常會走的流程，因為有多家公司能取得這項技術。我們進行了一如往常的盡職調查流程，並基於合作架構、人員之間的協作，以及與 Vertex 想做的事情之契合度，我們選擇了 CRISPR Therapeutics。隨著我們向前推進，我們非常高興能成為他們的合作夥伴。

Operator, it's now --

接線員，現在——

We don't comment on IP, Katherine. Thank you.

Katherine，我們不評論智慧財產權（IP）。謝謝。

Operator, it's now 6:00. We will take two more questions.

接線員，現在是 6:00。我們再接受兩個問題。

Thank you. And our next question will come from the line of Ed Tenthoff of Piper Jaffray. Your line is now open.

謝謝。下一個問題來自 Piper Jaffray 的 Ed Tenthoff。您的線路已開通。

Great. Thank you very much. My congratulations on a really nice launch with ORKAMBI. Question, just with respect to differentiation between triple therapy with a second-gen corrector and also the ENaC inhibitor, how ultimately, do you see patient selection there? Obviously, it's going to be data driven, but is this something where maybe the ENaC inhibitors would be used in different patients? What's your general thinking along those lines?

很好。非常感謝。恭喜 ORKAMBI 的上市表現非常亮眼。問題是，關於第二代校正劑（second-gen corrector）的三聯療法與 ENaC 抑制劑之間的差異，最終您如何看待病患的選擇？顯然這會由數據驅動，但 ENaC 抑制劑是否可能用在不同的病患身上？您在這方面的整體想法是什麼？

Thank you for the question, and you're absolutely right, it will obviously in the end be driven by the data, which is why we're going to explore these in Phase 2. If you think about it at a high level, from a high level strategic standpoint, second-generation correctors in a triple combination would be expected to address anybody who has a single or a double delta 508 allele, so that's about 80% to 90% of all patients. ENaC inhibitors, again, theoretically and we're going to have to demonstrate this in the clinic, should be us useful for anybody with any mutation. In fact, as you know, Parion is running an initial Phase 2 trial with an all comer trial. We're going to run a Phase 2 trial with ENaC plus ORKAMBI. Based on the data there, we'll be able to determine you how to craft these regimens for each patient subset. That would be the theoretical expectations based on what we've seen in HBE cell. Does that make sense?

謝謝你的問題，你說得完全正確，最終顯然會由數據來決定，這也是我們要在第二期（Phase 2）試驗中探索的原因。從較高層次來看，從策略角度而言，第二代校正劑的三聯組合預期可涵蓋任何帶有單一或雙重 delta 508 等位基因的患者，約占所有患者的 80% 到 90%。ENaC 抑制劑同樣地，理論上——而我們必須在臨床上證明——應該對任何突變型別的患者都有用。事實上，如你所知，Parion 正在進行一項初步的第二期試驗，採用不設限入組（all-comer）的設計。我們將進行一項 ENaC 加上 ORKAMBI 的第二期試驗。根據那裡的數據，我們將能夠決定如何為各個患者子群設計這些治療方案。這些是基於我們在 HBE 細胞中所見結果的理論預期。這樣說清楚嗎？

Absolutely. I appreciate that color.

完全清楚。感謝你提供的補充說明。

Sure.

當然。

Thank you. Our last question comes from the line of Brian Skorney of Robert W Baird. Your line is now open.

謝謝。我們最後一個問題來自 Robert W Baird 的 Brian Skorney。您的線路已開通。

This is Nina in for Brian. Thank you for taking the questions. I just have a question on the ORKAMBI launch. Do you have a sense of what percentage of treating physicians actually started patients on ORKAMBI and have you seen any hurdles in terms of getting physicians to prescribe the product?

我是 Nina，代替 Brian 提問。謝謝讓我提問。我想問關於 ORKAMBI 上市的問題。你們是否掌握實際開立 ORKAMBI 並讓病患開始用藥的醫師比例？在讓醫師開立這個產品方面，你們是否看到任何障礙？

I can't tell you exactly how many physicians have actually have a patient on ORKAMBI. What I do know is that just about every CF center in the United States has put a patient on ORKAMBI. So we are really seeing, again, what we anticipated, which is broad interest in using the medicine both with physicians and with patients.

我無法告訴你確切有多少位醫師確實有病患正在使用 ORKAMBI。但我知道的是，美國幾乎每一家囊性纖維化（CF）中心都已讓病患使用 ORKAMBI。因此我們確實看到——再次——如同我們所預期的，無論是醫師或病患，對使用這項藥物都有廣泛的興趣。

Great. And one last question. So I know you said that there has been good feedback from payers in terms of getting ORKAMBI covered. Has there been any pushback at all? And if so, what was -- could you give us some color around that? And that's all.

很好。最後一個問題。我知道你提到在 ORKAMBI 的給付涵蓋方面，來自付款方（payers）的回饋不錯。是否有任何反對或阻力？如果有的話，能否提供一些背景說明？以上。

Yes, I'd say the end product of our discussions has been good, and that's reflected in the fact that we have good access, the vast majority of which is to label. Obviously, there's been a lot of discussion there, but a lot of it, as I said, been very productive. Because payers I do think understand how serious a disease this is and how this is a disease that is -- this is a product which is treating the underlying cause of the disease. And the fact that it's an orphan, if not ultra orphan indication, and so they have relatively few patients in each of their individual plans. So the discussions have been very productive, and I think that's reflected in the good and broad access that we have.

是的，我會說我們討論的最終結果是好的，這也反映在我們擁有良好的可及性（access）上，其中絕大多數都符合適應症標籤（label）。顯然過程中有很多討論，但如我所說，其中很多都非常有建設性。因為我確實認為付款方了解這是一種多麼嚴重的疾病，而這也是一項——這是一個治療疾病根本原因的產品。再加上這是罕見疾病（orphan），甚至可說是超罕見（ultra orphan）適應症，因此在各自的保險計畫中，患者人數相對不多。所以這些討論非常有成效，我認為這也反映在我們所擁有的良好且廣泛的可及性上。

Great. Thank you.

很好。謝謝。

You're welcome.

不客氣。

We appreciate everyone joining us on the call tonight. The Investor Relations team will be in the office if you have additional questions. Thank you and have a good evening.

感謝各位今晚參加本次電話會議。若您有其他問題，投資人關係團隊將在辦公室。謝謝，祝各位晚安。

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

各位女士、先生，感謝您參與今天的會議。本次議程到此結束，您可以掛線。祝各位有美好的一天。