福泰製藥 (VRTX) 2017 Q3 法說會逐字稿

Good evening. This is Michael Partridge, Vice President of Investor Relations for Vertex. Welcome to our third quarter 2017 financial results conference call. (Operator Instructions) This call is recorded. A replay will be available later tonight on our website.

晚安.這是 Vertex 公司投資者關係副總裁 Michael Partridge。歡迎參加我們2017年第三季財務業績電話會議。（操作員指示）本次通話將會被錄音。今晚晚些時候，我們將在網站上提供重播。

Dr. Jeff Leiden, Chairman and CEO; Dr. Jeff Chodakewitz, Chief Medical Officer; and Ian Smith, Chief Operating Officer, will provide prepared remarks this evening. Stuart Arbuckle, Chief Commercial Officer, will join us for Q&A.

董事長兼執行長傑夫·萊頓博士、首席醫療官傑夫·喬達克維茨博士和首席營運長伊恩·史密斯將於今晚發表準備好的演講。首席商務官史都華·阿巴克爾將參加問答環節。

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, our 10-K and other filings with the Securities and Exchange Commission. These statements, including those regarding the ongoing development and commercialization of KALYDECO and ORKAMBI, 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 the reconciliation of GAAP to non-GAAP can be found in the financial results press release and in tonight's webcast slides, which have now been posted on our website.

我們將在本次電話會議上發表一些前瞻性聲明。這些聲明受到今天新聞稿、我們的 10-K 表格以及向美國證券交易委員會提交的其他文件中詳細討論的風險和不確定性的影響。這些聲明，包括有關 KALYDECO 和 ORKAMBI 的持續開發和商業化、Vertex 的其他囊性纖維化項目以及 Vertex 未來的財務業績的聲明，都是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。有關我們使用 GAAP 和非 GAAP 財務指標以及 GAAP 與非 GAAP 的調整的信息，請參閱財務業績新聞稿和今晚的網絡直播幻燈片，這些內容現已發佈在我們的網站上。

I will now turn the call over to Dr. Jeff Leiden.

現在我將把電話交給傑夫·萊頓博士。

Thanks, Michael. Good evening, everyone. 2017 has been a tremendous year for Vertex. We've made significant progress across all parts of our business and moved closer to realizing our long-term vision of treating all people with CF. During the year, we've increased the number of people eligible for and being treated with our approved medicines. More recently, we showed data from multiple triple combination regimens that demonstrate that we may be able to treat up to 90% of all CF patients. As a result of treating more people with our approved medicines, CF product revenues have increased quarter-to-quarter throughout this year. And tonight, we are increasing our full year guidance for total CF product revenues. Our financial strength has substantially increased, and we expect this revenue and earnings growth to continue going forward, creating significant value for shareholders.

謝謝你，麥可。各位晚上好。2017年對Vertex來說是碩果累累的一年。我們在業務的各個方面都取得了重大進展，並朝著實現治療所有囊性纖維化的長期願景邁進了一步。今年，我們增加了符合資格並正在接受我們批准藥物治療的人數。最近，我們展示了多個三聯療法的數據，這些數據表明我們或許能夠治療高達 90% 的囊性纖維化患者。由於使用我們核准的藥物治療了更多患者，今年以來，CF 產品的收入逐季成長。今晚，我們將上調全年CF產品總收入預期。我們的財務實力已大幅增強，我們預計未來收入和獲利成長動能將持續，為股東創造巨大價值。

Let me now briefly review our progress over the last 3 months. First, KALYDECO. On August 1, the FDA approved KALYDECO for use in more than 600 people with CF ages 2 and older who have 1 of 5 residual function mutations in the CFTR gene. KALYDECO continues to be a transformative medicine and is now labeled to treat approximately 6,000 people with CF globally. And we continue to increase the number of patients initiating treatment with KALYDECO.

現在讓我簡單回顧一下我們過去三個月的進展。首先是 KALYDECO。8 月 1 日，FDA 批准 KALYDECO 用於治療 600 多名 2 歲及以上患有 CF 的人群，這些人群的 CFTR 基因中存在 5 種殘餘功能突變中的 1 種。KALYDECO 繼續發揮變革性藥物的作用，目前已獲準用於治療全球約 6,000 名囊性纖維化患者。我們持續增加接受 KALYDECO 治療的患者人數。

Second, tezacaftor/ivacaftor. Based on the positive Phase III data we announced earlier this year, the FDA and the European Medicines Agency have accepted our applications for the use of the tezacaftor/ivacaftor combination treatment studied in 2 different CF patient populations: one, people with CF ages 12 and older who have 2 copies of the F508del mutation; and two, people who have 1 F508del mutation and 1 residual function mutation that is responsive to tezacaftor/ivacaftor. In the U.S., the FDA has granted priority review of the NDA and set an action date of February 28, 2018. We currently expect approval in Europe in the second half of 2018. Our commercial team in the U.S. is currently preparing to bring this medicine to the many patients who are eagerly awaiting its approval.

其次，tezacaftor/ivacaftor。根據我們今年稍早公佈的積極的 III 期數據，FDA 和歐洲藥品管理局已接受我們關於在兩種不同的 CF 患者群體中使用 tezacaftor/ivacaftor 聯合療法的申請：一是 12 歲及以上且攜帶 2 個 F508del 突變拷貝的 CF 患者；二是攜帶 1 個 F508del 突變和 1在美國，FDA 已授予該新藥申請優先審查權，並將審批日期定為 2018 年 2 月 28 日。我們目前預計將於 2018 年下半年在歐洲獲得批准。我們在美國的商業團隊目前正在準備將這種藥物帶給眾多熱切期盼其核准的患者。

Third, our triple combination regimens. In July, we announced clinical results for 3 different regimens, which included next-generation correctors, VX-152, VX-440 and VX-659. Across these regimens in 2- and 4-week studies, we saw significant clinical activity in both het/min and F508del homozygous patients across multiple measures: increases in FEV1, increases in sweat chloride and in the one study in which it's been evaluated thus far, increases in CFQ-R. We also saw good tolerability. We expect to continue to collect Phase II data for next-generation correctors, VX-152, VX-659 and VX-445, in triple-combination regimens into early next year. And pending data from these studies and discussions with regulatory agencies, we expect to begin pivotal development in the first half of 2018 of up to 2 triple-combination regimens. We expect that each of these triple regimens may have a different next-generation corrector and one of the regimens may be dosed once daily. These triple regimens may provide the opportunity for 90% of the CF population to be treated with a medicine that addresses the underlying cause of their disease.

第三，我們的三聯療法。7 月，我們公佈了 3 種不同治療方案的臨床結果，其中包括下一代矯正劑 VX-152、VX-440 和 VX-659。在為期 2 週和 4 週的研究中，這些治療方案均顯示出顯著的臨床活性，在 het/min 和 F508del 純合子患者中，多項指標均顯示出顯著的臨床活性：FEV1 增加、汗液氯化物增加，以及在迄今為止評估 CFQ-R 的一項研究中，CFQ-R 增加。我們也觀察到了良好的耐受性。我們預計在明年年初繼續收集下一代矯正劑 VX-152、VX-659 和 VX-445 在三聯療法中的 II 期數據。根據這些研究的數據以及與監管機構的討論，我們預計將在 2018 年上半年開始關鍵性開發至多 2 種三重療法。我們預計這三種治療方案中的每一種都可能採用不同的下一代矯正劑，其中一種方案可能每天只需服用一次。這些三聯療法可能使 90% 的囊性纖維化患者有機會接受針對其疾病根本原因的藥物治療。

We continue to invest in scientific innovations to bring forward life-changing medicines. We believe this creates the most value for patients, employees and shareholders. We're seeing good progress both internally and with our collaborations, and we expect to advance new medicines into clinical development in 2018. We look forward to updating you on this progress as well as helping you understand how we select our disease areas and potential investigational medicines.

我們將繼續投資科學創新，以研發改變生命的藥物。我們相信這能為病患、員工和股東創造最大價值。我們在內部研發和合作方面都取得了良好的進展，預計在 2018 年將新藥推進到臨床開發階段。我們期待向您報告這項進展，並幫助您了解我們如何選擇疾病領域和潛在的研究藥物。

We're very proud of the significant progress the company has made in increasing the number of people eligible for and being treated with our medicines around the world. And we are well positioned to meet our goals of consistently creating transformative medicines for patients and delivering significant and sustained revenue and earnings growth for our shareholders.

我們為公司在增加全球範圍內符合資格並接受我們藥物治療的人數方面取得的重大進展感到非常自豪。我們已做好充分準備，實現我們的目標，即持續為患者創造變革性藥物，並為股東帶來顯著且持續的收入和利潤成長。

I'll now turn the call over to Dr. Jeff Chodakewitz to make specific comments on some of our development programs.

現在我將把電話交給傑夫·喬達克維茨博士，讓他對我們的一些發展項目發表具體評論。

Thanks, Jeff, and good evening. We're very pleased with the clinical progress we've been able to make across multiple CF studies this year, which are bringing us closer to our goal of treating all patients with CF.

謝謝你，傑夫，晚上好。我們非常高興今年在多項 CF 研究中取得的臨床進展，這些進展使我們離治療所有 CF 患者的目標更近了一步。

First, I will review results from 3 different studies in CF that recently completed, then I will make comments on our ongoing triple-combination programs. I will start with the ORKAMBI clinical results. We are pleased to have announced tonight Phase III results of ORKAMBI in children 2 to 5 years of age with CF who have 2 copies of the F508del mutation. The primary endpoint of the study was safety, and the results showed that the treatment was well tolerated. In addition, the study also showed improvements in CF-related disease measures, including sweat chloride and nutritional status. These are the first findings to show the safety and benefit of ORKAMBI in children as young as 2. CF is a devastating and progressive disease, and our goal has been to evaluate our medicines in younger and younger patients so that we may establish a basis for intervening earlier with medicines that change the course of the disease. Based on the results from the ORKAMBI 2 to 5 study, we expect to submit for regulatory approval by regulatory authorities in the U.S. and Europe in the first quarter of 2018.

首先，我將回顧最近完成的 3 項不同的 CF 研究的結果，然後我將對我們正在進行的三重療法計畫發表意見。我將首先介紹 ORKAMBI 的臨床結果。我們很高興地宣布，ORKAMBI 在 2 至 5 歲患有 CF 且攜帶 2 個 F508del 突變拷貝的兒童中的 III 期試驗結果。研究的主要終點是安全性，結果顯示該治療耐受性良好。此外，研究也顯示，與 CF 相關的疾病指標有所改善，包括汗液氯化物和營養狀況。這是首次證明 ORKAMBI 對 2 歲兒童安全有效的研究結果。囊性纖維化是一種毀滅性的進行性疾病，我們的目標是評估我們的藥物對越來越年輕的患者的療效，以便我們能夠更早地使用藥物幹預，從而改變疾病的進程。根據 ORKAMBI 2 至 5 研究的結果，我們預計將於 2018 年第一季向美國和歐洲的監管機構提交監管批准申請。

Now to tezacaftor/ivacaftor. We announced top line data from a Phase III study evaluating the addition of tezacaftor in people with CF ages 12 and older with 1 copy of the F508del mutation and a second gating mutation who were already receiving ivacaftor monotherapy. The study did not meet its primary endpoint as there was no difference in FEV1 for those who added tezacaftor in addition to ivacaftor that they were already taking compared to those receiving placebo in addition to ivacaftor. Importantly, safety data from the study showed that the combination was generally well tolerated and the safety profile was consistent with that observed in prior studies of the tezacaftor/ivacaftor combination.

現在到 tezacaftor/ivacaftor。我們發表了一項 III 期研究的主要數據，該研究評估了在 12 歲及以上、攜帶 1 個 F508del 突變拷貝和第二個門控突變的囊性纖維化患者中，添加 tezacaftor 治療的效果，這些患者此前已接受 ivacaftor 單藥治療。研究未達到其主要終點，因為與服用安慰劑加 ivacaftor 的患者相比，服用 tezacaftor 加 ivacaftor 的患者在 FEV1 方面沒有差異。重要的是，該研究的安全數據顯示，該組合總體上耐受性良好，其安全性與先前對 tezacaftor/ivacaftor 組合的研究中所觀察到的安全性一致。

For secondary endpoints, we also looked at sweat chloride and CFQ-R. In sweat chloride, we saw a decrease of approximately 6 millimole compared to ivacaftor monotherapy that was statistically significant, and no difference in CFQ-R. Based on these results, we do not plan to seek approval for tezacaftor/ivacaftor in gating patients who also have an F508del mutation. The vast majority of all patients with a gating mutation around the world are receiving KALYDECO, and we expect that they will continue to do so.

對於次要終點，我們也研究了汗液氯化物和 CFQ-R。與伊伐卡托單藥治療相比，汗液氯化物含量下降了約 6 毫摩爾，具有統計學意義，而 CFQ-R 沒有差異。基於這些結果，我們不打算尋求批准 tezacaftor/ivacaftor 用於同時具有 F508del 突變的門控患者。全世界絕大多數患有門控突變的患者都在接受 KALYDECO 治療，我們預期他們將繼續接受治療。

Now to our ENaC inhibitor, VX-371. We've also announced the results from a Phase II 28-day study of an inhaled ENaC inhibitor, VX-371, when added to ORKAMBI. The study dosed 142 CF patients ages 12 and older who were homozygous for the F508del mutation. The study did not meet its primary efficacy endpoint. In these patients who were already receiving ORKAMBI, the addition of VX-371 did not produce changes in FEV1 when administered with or without hypertonic saline. Safety data from the study showed that the addition of VX-371 to ORKAMBI was generally well tolerated and the safety profile was consistent with that observed in prior studies of VX-371 monotherapy. We continue to conduct a Phase II study of VX-371 monotherapy in patients with primary ciliary dyskinesia.

現在來談談我們的 ENaC 抑制劑 VX-371。我們也發表了吸入式 ENaC 抑制劑 VX-371 添加到 ORKAMBI 中的 II 期 28 天研究結果。該研究對 142 名 12 歲及以上的 CF 患者進行了給藥，這些患者均為 F508del 突變的純合子。該研究未達其主要療效終點。對於這些已經接受 ORKAMBI 治療的患者，無論是否同時給予高滲透壓鹽水，添加 VX-371 都不會引起 FEV1 的變化。研究的安全數據顯示，在 ORKAMBI 中添加 VX-371 總體上耐受性良好，其安全性與先前 VX-371 單藥治療研究中觀察到的安全性一致。我們持續進行 VX-371 單藥治療原發性纖毛運動障礙患者的 II 期研究。

I will conclude with some remarks on our triple-combination regimens, as they continue to advance. We are well positioned with 4 different triple-combination regimens in Phase II, 3 of which have already demonstrated significant clinical activity and good tolerability in 2- to 4-week studies. We recently announced that we have included the experimental potentiator, VX-561, formerly CTP-656, into the Phase II studies of the next-generation correctors VX-659 and VX-445. VX-561 could play an important role in a future once-daily combination regimen that treats the underlying cause of CF. We remain on track to begin pivotal development for up to 2 triple regimens in the first half of 2018, and I look forward to updating you on our plans.

最後，我將就我們不斷取得進展的三聯療法發表一些看法。我們目前有 4 種不同的三重療法處於 II 期臨床試驗階段，其中 3 種療法已在 2 至 4 週的研究中顯示出顯著的臨床活性和良好的耐受性。我們最近宣布，我們已將實驗性增強劑 VX-561（以前稱為 CTP-656）納入下一代矯正劑 VX-659 和 VX-445 的 II 期研究。VX-561 可能在未來每日一次的聯合治療方案中發揮重要作用，該方案旨在治療囊性纖維化的根本原因。我們仍按計劃在 2018 年上半年啟動至多 2 種三聯療法的關鍵性開發，我期待著向您報告我們的計劃。

With that, I will now hand the call over to Ian.

接下來，我將把電話交給伊恩。

Thanks, Jeff, and good evening to everyone. 2017 has been a year of significant financial growth. We are poised to deliver continued revenue and earnings growth into 2018 and beyond. Tonight, I will discuss our third quarter 2017 financials, review our 2017 full year financial guidance and make further comments on the strength and the trajectory of our business.

謝謝你，傑夫，大家晚上好。2017年是經濟實現顯著成長的一年。我們已做好準備，在2018年及以後繼續實現營收和利潤的成長。今晚，我將討論我們 2017 年第三季的財務狀況，回顧我們 2017 年全年的財務預期，並就我們業務的實力和發展軌跡發表進一步評論。

Revenues first. Total CF product revenues of $550 million in the third quarter of 2017 reflects strong performance based on the demand for our medicines. This represents a 34% increase compared to $410 million last year. Our product revenues have grown each quarter throughout 2017 as we have increased the number of patients treated with the approved medicines. We expect this to continue in 2018 as we gain additional reimbursements in countries outside of the U.S. and we also have the potential to launch new medicines such as tezacaftor/ivacaftor.

收入優先。2017 年第三季 CF 產品總營收達 5.5 億美元，反映了基於​​市場對我們藥品需求的強勁業績。與去年的 4.1 億美元相比，這相當於成長了 34%。2017 年，隨著使用核准藥物治療的患者人數增加，我們的產品收入每季都在成長。我們預計這種情況將在 2018 年繼續，因為我們將在美國以外的國家獲得更多報銷，而且我們還有可能推出像 tezacaftor/ivacaftor 這樣的新藥。

Both ORKAMBI and KALYDECO have demonstrated strong growth in the quarter. For ORKAMBI, we reported third quarter 2017 product revenues of $336 million, an increase of $102 million compared to the third quarter of 2016. The quarterly growth this year has been driven by the continued uptake of the medicine globally, most specifically in the children ages 6 to 11 in the U.S.

ORKAMBI 和 KALYDECO 在本季度均實現了強勁成長。ORKAMBI 2017 年第三季產品營收為 3.36 億美元，比 2016 年第三季增加了 1.02 億美元。今年季度成長主要得益於該藥物在全球範圍內的持續普及，尤其是在美國 6 至 11 歲兒童中的普及。

Third quarter KALYDECO sales were $213 million compared to $176 million for the third quarter 2016. The quarterly growth this year has been driven by the strong uptake for the medicine by patients in the U.S. with residual function mutations following the recent FDA approvals.

KALYDECO 第三季銷售額為 2.13 億美元，而 2016 年第三季為 1.76 億美元。今年季度成長主要得益於美國FDA近期批准該藥物後，美國患有殘餘功能突變的患者對該藥物的強勁需求。

Our third quarter 2017 non-GAAP combined R&D and SG&A expenses were $334 million compared to $295 million in the third quarter 2016. This increase was primarily due to the continued acceleration and advancements of our portfolio of triple-combination regimens for CF and the investment to support the launch of our medicines globally. Strong growth in product revenues is driving an expansion in our operating margins. Operating margins were 26% for the third quarter 2017 compared to 16% for the third quarter 2016. And with our anticipated revenue growth, we expect our margin to continue to expand in the future.

2017 年第三季非 GAAP 合併研發及銷售、一般及行政費用為 3.34 億美元，而 2016 年第三季為 2.95 億美元。這一增長主要歸功於我們針對囊性纖維化的三聯療法產品組合的持續加速發展和進步，以及為支持我們藥物在全球範圍內上市的投資。產品收入的強勁成長帶動了我們營業利潤率的擴大。2017 年第三季營業利益率為 26%，而 2016 年第三季為 16%。隨著營收的預期成長，我們預計未來的利潤率將繼續擴大。

Non-GAAP net profit in the third quarter 2017 was $136 million compared to non-GAAP net profit of $43 million in the third quarter of 2016. The significant growth in non-GAAP net profit was largely driven by the strong growth in total CF product revenues.

2017 年第三季非 GAAP 淨利為 1.36 億美元，而 2016 年第三季非 GAAP 淨利為 4,300 萬美元。非GAAP淨利潤的顯著成長主要得益於CF產品總收入的強勁成長。

We have a strong balance sheet as we ended the third quarter with approximately $1.8 billion in cash, cash equivalents and marketable securities. This compares to $1.4 billion at the beginning of 2017. And during the third quarter, we paid $160 million to Concert Pharmaceuticals upon completing our asset purchase agreement for CTP-656, now VX-561.

我們的資產負債表非常穩健，截至第三季末，我們擁有約 18 億美元的現金、現金等價物和有價證券。相比之下，2017年初的數字為14億美元。第三季度，我們向 Concert Pharmaceuticals 支付了 1.6 億美元，完成了對 CTP-656（現為 VX-561）的資產收購協議。

Now turning to the full year financial guidance. Based on the strong underlying demand of our CF medicines and recent label expansions, we are increasing our total CF product revenue guidance to $2.1 billion to $2.15 billion in 2017. This was previously increased to $1.87 billion to $2.1 billion in August of this year. For ORKAMBI, we now expect $1.29 billion to $1.32 billion in net product revenues, which reflects the strong underlying demand for the medicine throughout the year among the people with CF ages 6 and older in the U.S., and is based on potential revenues in countries where ORKAMBI is currently reimbursed. I would note that this guidance does not assume the recognition of any ORKAMBI product revenues in France in 2017.

接下來是全年財務預期。鑑於我們 CF 藥物的強勁潛在需求以及近期標籤的擴展，我們將 2017 年 CF 產品總收入預期提高至 21 億美元至 21.5 億美元。今年8月，這一數字曾被提高到18.7億美元至21億美元。對於 ORKAMBI，我們現在預計淨產品收入為 12.9 億美元至 13.2 億美元，這反映了美國 6 歲及以上 CF 患者全年對該藥物的強勁潛在需求，並且是基於 ORKAMBI 目前已獲得報銷的國家的潛在收入。需要指出的是，該指南並未假定 2017 年 ORKAMBI 產品在法國獲得任何收入。

As to KALYDECO, we now expect $810 million to $830 million in net product revenues based on recent label expansions and the strong underlying demand we are seeing by eligible patients. As we think ahead to potential 2018 revenue guidance, we are mindful that the expected approval and launch of tezacaftor/ivacaftor will make it challenging to forecast revenue for individual products. Therefore, in early 2018, we anticipate providing full year total CF product revenue guidance but no individual product guidance.

至於 KALYDECO，根據最近的標籤擴展以及符合條件的患者所表現出的強勁潛在需求，我們現在預計其淨產品收入將達到 8.1 億美元至 8.3 億美元。展望 2018 年的潛在收入預期，我們意識到 tezacaftor/ivacaftor 的預期批准和上市將使預測單一產品的收入變得具有挑戰性。因此，我們預計在 2018 年初提供全年 CF 產品總收入指引，但不提供單一產品指引。

Now to operating expenses. We continue to expect combined non-GAAP R&D and SG&A expenses of $1.33 billion to $1.36 billion in 2017. As we plan for 2018, a key investment driver will be the initiation of pivotal studies for up to 2 triple-combination regimens, including clinical drug supply and the supply chain investment for potential commercial success of a triple-combination regimen. Therefore, non-GAAP operating expenses will see growth in 2018. At the same time, we do expect operating margins to expand in 2018 as our revenue growth will significantly exceed any increase in our operating expenses.

接下來是營運費用。我們繼續預期 2017 年非 GAAP 研發及銷售、管理及行政費用總計為 13.3 億至 13.6 億美元。在規劃 2018 年時，一項關鍵的投資驅動因素將是啟動多達 2 種三聯療法的關鍵性研究，包括臨床藥物供應和供應鏈投資，以實現三聯療法的潛在商業成功。因此，2018 年非 GAAP 營運費用將會成長。同時，我們預計 2018 年營業利潤率將有所提高，因為我們的收入成長將遠遠超過營運費用的任何成長。

In conclusion, we are well on track to deliver a financial profile that includes high operating margins and sustainable earnings growth. Our success in increasing the number of CF patients that we treat with our medicines is driving the strong financial performance we have reported today. We are well positioned to realize our goal of treating many more patients and enhancing the benefit for those we treat with the CF pipeline assets that we are rapidly advancing in development. We look forward to continue to share our progress with you in the weeks and months ahead.

總之，我們正朝著實現高營業利潤率和永續獲利成長的財務目標穩步前進。我們成功增加了使用我們的藥物治療的囊性纖維化患者的數量，這正是我們今天公佈的強勁財務業績的驅動力。我們已做好充分準備，透過我們正在快速推進開發的 CF 管線資產，實現治療更多患者並提高我們所治療患者的益處的目標。我們期待在接下來的幾週和幾個月裡繼續與您分享我們的進展。

And with that, I open the line to questions.

接下來，我將開始接受提問。

(Operator Instructions) Our first question comes from the line of Michael Yee of Jefferies.

（操作說明）我們的第一個問題來自 Jefferies 公司的 Michael Yee。

Two-part question. One was, as you think about the triple and the strategy going forward, is there an expectation that the overall clinical Phase III program should pretty much look like ORKAMBI in both het/mins and homozygous in terms of a duration of the study? Or do you think you could figure out a way to accelerate that? And then the second question is around the uptake of 661 next year. While I appreciate it's early, are there opportunities there to significantly grow the overall doublet franchise? Where are the opportunities to grow that? Do you think it cannibalizes a bit? How do we think about that market?

問題分為兩部分。其中一個問題是，當您考慮三重奏和未來的策略時，是否預期整個臨床 III 期計畫在研究持續時間方面應該與 ORKAMBI 在 het/min 和純合子方面非常相似？或者你認為你能找到加速這進程的方法嗎？第二個問題是關於明年 661 的普及情況。雖然我知道現在還為時過早，但雙子星系列是否有機會大幅發展壯大呢？發展的機會在哪裡？你認為這會造成一些蠶食效應嗎？我們如何看待這個市場？

Michael, thanks for the question. Maybe given my comments, we expect to collect all that -- the data on the triple-regimen portfolio. We expect to have a really good view into that in early 2018. At that point, we can have a more, I'd say, detailed discussion. But for the strategy of how we're approaching the pivotal studies, the time lines, Jeff Leiden and maybe Stuart can talk to you about how we think about tezacaftor/ivacaftor launching in 2018.

邁克爾，謝謝你的提問。鑑於我的評論，我們或許應該收集所有這些數據——關於三重療法組合的數據。我們預計在 2018 年初就能對此有非常清楚的了解。到那時，我們可以進行更深入的討論。但對於我們如何進行關鍵研究的策略、時間安排，Jeff Leiden 和 Stuart 或許可以和您談談我們對 tezacaftor/ivacaftor 在 2018 年上市的看法。

Yes, Michael. It's Jeff. Let me sort of give you a high-level view. Again, we're just in regulatory discussions now, so obviously we won't be able to give you the final point of view until we finish those. But a couple of points, I think, worth making. One is, as I said and Jeff Chodakewitz said, our current plan, obviously, which will be based on the data, would be to take up to 2 programs forward. And those 2 programs would have different next-gen correctors in them. And our hope, again, based on the data that we'll see from Phase II, is that one of those programs might be a once-a-day regimen that would incorporate VX-561. That's one point. The second point is sort of to your question directly and the way you phrased it, which is we've obviously learned a lot as we've gone through multiple Phase III trials in CF. We've learned what the length of those trials needs to be, for instance, let's say, 8 to 12 weeks for collecting acute data and up to 24 weeks for long-term data. We've learned about the size of those trials, how they have to be powered to get the effects we want, and we've learned a lot about how to collect those endpoints.

是的，邁克爾。是傑夫。讓我簡單概括一下給你。再次強調，我們現在正處於監管方面的討論階段，所以顯然在我們完成這些討論之前，我們無法給出最終的觀點。但我認為有幾點值得一提。正如我和傑夫·喬達克維茨所說，我們目前的計劃顯然是基於數據，那就是推進最多 2 個項目。這兩個程式將採用不同的下一代糾錯器。我們再次希望，根據我們將從 II 期臨床試驗中看到的數據，其中一個項目可能是每天一次的治療方案，其中將包含 VX-561。這是一點。第二點其實是直接回答你的問題以及你的措辭，那就是，顯然，我們在進行 CF 的多項 III 期試驗的過程中學到了很多東西。我們已經了解了這些試驗需要持續多長時間，例如，收集急性數據需要 8 到 12 週，而收集長期數據則需要長達 24 週。我們已經了解了這些試驗的規模，如何才能使它們具有足夠的統計效力以達到我們想要的效果，並且我們還了解了很多關於如何收集這些終點指標的資訊。

So our strategy overall is to use all of that knowledge and, particularly, based on the strength of the results that we're seeing with the triple, to streamline these trials with the regulatory agencies as much as possible, so we can get these medicines as quickly as possible to patients, particularly the het/min patients who don't have anything right now. So more to come as we finalize those discussions. We'll certainly be able to explain those to you in the first half or the beginning of next year. But our intention is to streamline those trials and to think about how we get these drugs to those patients who are waiting for them as quickly as possible.

因此，我們的整體策略是利用所有這些知識，特別是基於我們從三聯療法中看到的強勁結果，盡可能簡化與監管機構的這些試驗，以便我們能夠盡快將這些藥物送到患者手中，特別是目前沒有任何藥物的雜合子/單核細胞增多症患者。待相關討論最終定稿後，我們將發布更多資訊。我們肯定會在明年上半年或年初向您解釋這些問題。但我們的目標是簡化這些試驗，並思考如何盡快將這些藥物送到等待這些藥物的患者手中。

And Michael, it's Stuart here. On the tezacaftor/ivacaftor, whether we think it's got the opportunity to grow the CF franchise, we certainly do. We think given the benefit-risk profile that it has, it really provides a tremendous new treatment option, which is going to allow more patients to be treated with a CFTR modulator. There's probably a couple of different kind of groups of patients I'd point you to. The first would be in the homozygous population. As you know, with ORKAMBI there, we've had a number of patients who've discontinued ORKAMBI, often due to adverse events. Given the benefit-risk profile of tezacaftor/ivacaftor, I think that's a population which is likely to see high demand for tezacaftor/ivacaftor. We also know that in the homozygous population, there's a number of patients who've never been initiated on ORKAMBI, often because of their views of the benefit-risk profile, and I think that's another population that potentially could be excited by a new treatment option. And then the third one would be in the residual function population. We obviously have the indication here for KALYDECO for those ivacaftor-responsive mutations. Not all of those patients are yet on KALYDECO, and so for those who are naïve, again, tezacaftor/ivacaftor could be a good option for those patients. And obviously, outside of the U.S., further down the line, the same in the homozygous population, but the residual function patients there outside the U.S. don't have any approved treatment to treat the underlying cause of their disease. So we certainly see tezacaftor/ivacaftor as a very important new treatment option, which can grow the number of patients being treated with a CFTR modulator.

邁克爾，我是斯圖爾特。關於 tezacaftor/ivacaftor，我們是否認為它有機會發展壯大 CF 系列，我們當然認為它有機會。我們認為，考慮到其益處和風險，它確實提供了一種巨大的新治療選擇，這將使更多患者能夠接受 CFTR 調節劑治療。我可能會向你推薦幾種不同類型的患者群體。第一種情況發生在純合子群體。如您所知，在使用 ORKAMBI 期間，我們有許多患者停止使用 ORKAMBI，通常是由於不良反應。鑑於 tezacaftor/ivacaftor 的獲益風險比，我認為這類人群對 tezacaftor/ivacaftor 的需求可能很高。我們也知道，在純合子族群中，有許多患者從未接受過 ORKAMBI 治療，這通常是因為他們對該藥物的益處風險比的看法。我認為這是另一個可能對新的治療方案感到興奮的人群。那麼第三個就屬於殘差函數群。顯然，KALYDECO 適用於那些對 ivacaftor 有反應的突變。並非所有患者都已開始使用 KALYDECO，因此對於那些未曾使用過 KALYDECO 的患者來說，tezacaftor/ivacaftor 可能是個不錯的選擇。顯然，在美國以外，更遠的地方，純合子人群的情況也是如此，但美國以外那些殘肢斷臂的患者沒有任何獲批的治療方法來治療他們疾病的根本原因。因此，我們當然認為 tezacaftor/ivacaftor 是一種非常重要的新治療選擇，可以增加接受 CFTR 調節劑治療的患者人數。

My final follow-up is just, is there anything magic about 6 months that they ask for ORKAMBI or why it couldn't be 3 months? Is there any magical reason that those were the numbers picked?

我最後的問題是，為什麼 ORKAMBI 要求 6 個月的時間，或者為什麼不能是 3 個月，這其中有什麼特別之處嗎？選中這些數字有什麼神奇的原因嗎？

Yes, Mike. I should have been a little clearer about that. There are 2 different -- or 3 different considerations. So there's the acute benefit. And as I said, we know we can see that pretty quickly within, certainly, 8 to 12 weeks. There's the long-term benefit in things like pulmonary exacerbations, hospitalizations, antibiotic use. When you look at that, that typically is going to take 6 months. And then there's, of course, the safety database, which we need to provide an adequate one. Having said that, obviously, what we're going to try to do is to come up with a regulatory strategy which fits that point of view, which means that we don't necessarily believe that we need to wait all the way to the end of all those measurements to file regulatory submissions, particularly for the patients who don't have anything today.

是的，麥克。我應該把這一點說得更清楚一些。這裡有兩到三個不同的考慮因素。這就是直接的好處。正如我所說，我們知道我們可以在 8 到 12 週內很快看到這一點。長遠來看，例如減少肺部疾病加重、住院和抗生素使用，都是有益的。你看，這通常需要6個月的時間。當然，還有安全資料庫，我們需要提供一個足夠完善的資料庫。話雖如此，顯然，我們要做的就是製定一個符合這種觀點的監管策略，這意味著我們不一定認為需要等到所有這些測量都結束才提交監管申請，特別是對於那些目前沒有任何治療方案的患者而言。

Our next question comes from Matthew Harrison of Morgan Stanley.

下一個問題來自摩根士丹利的馬修·哈里森。

I was hoping to ask sort of a non-CF pipeline question, and maybe I could ask it in 2 parts. So I guess, one, could you talk about some of the milestones that we might see over the course of next year for the non-CF pipeline and maybe specifically about your spinal cord injury asset? And then just help us think about how you plan to invest either internally or externally into the non-CF pipeline.

我原本想問一個與 CF 流程無關的問題，也許我可以分成兩個部分來問。所以我想問，第一，您能否談談明年非囊性纖維化產品線可能會取得的一些里程碑，特別是關於您的脊髓損傷資產？然後，請您幫我們思考一下，您計劃如何對非CF產品線進行內部或外部投資。

Yes, Matt. This is Jeff Leiden. I'll take the first part, and maybe Ian and I can work on the second part together, sort of a BD question as well as an internal question. First, I'd remind you of something we've said many, many times, which is that we believe, at Vertex anyway, that investment in scientific innovation is where the real value is created in this industry, and that includes both our internal investment in R&D and our external investments in BD. With respect to our internal pipeline, we do expect to bring those programs -- and we've talked about 4 or 5 of them. We've talked about AAT. We've talked about adrenoleukodystrophy, sickle cell disease, pain. We've talked about 4 or 5. Those programs are actually advancing quite nicely. And what we've told you before is that as they enter the clinic, and we expect some of them to enter the clinic in 2018, you'll hear more about them. So I think you can anticipate hearing more about those programs next year. With respect to the external investment, you've seen us do a number of deals that both strengthen our technology platform, if you will, and also bring in early-stage products. You'll see us do more of those. But maybe -- Ian does a nice job of sort of summarizing our strategy for BD investments, which hasn't changed for the last several years and won't change going forward, except the fact that we have more financial firepower now.

是的，馬特。這是傑夫·萊頓。我來負責第一部分，也許我和伊恩可以一起負責第二部分，這既是一個業務拓展問題，也是一個內部問題。首先，我想提醒大家我們曾經多次說過的一點，那就是我們Vertex公司認為，對科學創新的投資才是這個產業真正創造價值的地方，這包括我們對研發的內部投資和我們對業務拓展的外部投資。就我們內部的人才培育計畫而言，我們確實希望推出這些計畫——我們已經討論過其中的四、五個項目。我們已經討論過AAT了。我們討論過腎上腺腦白質營養不良症、鐮狀細胞疾病和疼痛。我們已經討論過四、五個項目了。這些項目進展得相當順利。我們之前告訴過你們，當他們進入診所後（我們預計其中一些將在 2018 年進入診所），你們將會聽到更多關於他們的消息。所以我想明年你們應該會聽到更多關於這些項目的消息。關於外部投資，你們已經看到我們進行了許多交易，這些交易既加強了我們的技術平台，也引進了早期產品。你們會看到我們做更多這樣的事。但也許——伊恩很好地總結了我們 BD 投資策略，該策略在過去幾年中沒有改變，將來也不會改變，只是我們現在擁有了更多的財力。

Yes, sure. So I would actually start by, obviously, the company is in very different position today than it was a couple of years ago. One, where we were in capital preservation mode as we invested to create our medicines, whereas today, we do have significant cash flow. And I pointed in my prepared remarks that we have approximately $1.8 billion of cash on the balance sheet and without taking out any debt. And so we do have a significant access to capital, and to Jeff's point, I believe that we have to invest to create. And so externally, we have a strategy where it's got 3 points of approach. First is we do look at everything in CF. We should and we try to identify the approaches that are complementary to our own approach, where you have the disease-modifying agents, and they may be more orthogonal approaches as compared to CFTR modulation. But we really look at everything in CF. And we've done a couple of deals in that area, and most notably was the one we've done in Q3 with Concert, where we have the opportunity to potentially improve a regimen by going to a once-a-day regimen. And we'll see how that study plays out.

當然可以。所以，首先我要說的是，很顯然，公司現在的處境與幾年前截然不同。第一，我們當時處於資本保全模式，投資研發藥品，而如今，我們擁有大量現金流。我在事先準備好的演講稿中指出，我們的資產負債表上大約有 18 億美元的現金，而且我們沒有舉借任何債務。因此，我們確實擁有大量資金，而且正如傑夫所說，我認為我們必須投資才能創造。因此，在對外方面，我們的策略包含三個面向。首先，我們會關注CF中的所有內容。我們應該並且正在努力尋找與我們自身方法互補的方法，例如疾病修飾劑，它們可能與 CFTR 調節是更正交的方法。但我們確實會仔細研究囊性纖維化中的每一個細節。我們在這個領域已經達成了幾筆交易，其中最值得一提的是我們在第三季度與 Concert 達成的協議，我們有機會透過改為一天一次的治療方案來改進治療方案。我們將拭目以待這項研究的結果。

Secondly, as Jeff mentioned, scientific footprint. Vertex has been tremendously successful with small molecules over the last 20 years or so. But there's been a lot going on outside the world of Vertex, and we think it's time for us to plug into that. And we've already done transactions to give a different kind of modalities of actions to approach the diseases that we're interested in. And most notably, we've done collaborations with CRISPR Therapeutics, which is going very nicely, and we'll probably touch on that a little later on this call. And also Moderna. And then the third area is kind of more opportunistic, looking at disease areas -- still looking at disease areas that are consistent with who Vertex is and the disease areas that we focus on. And we look at those opportunities as well and consider whether to apply our capital. They tend to be earlier stage. I don't want people getting carried away with a large-scale deal at this point, but they tend to be earlier stage. So we can match our scientific approach and creation to developing these medicines, consistent with how we've done things in CF. So that's our approach, and applying enough capital as we generate it is important for us to grow our business.

其次，正如傑夫所提到的，科學足跡。在過去的20年左右的時間裡，Vertex在小分子藥物領域取得了巨大的成功。但是 Vertex 之外的世界發生了很多事情，我們認為現在是時候融入其中了。我們已經進行了一些交易，以提供不同的行動方式來應對我們感興趣的疾病。最值得一提的是，我們已經與 CRISPR Therapeutics 展開了合作，進展非常順利，我們稍後可能會在這次電話會議上談到這一點。還有 Moderna。第三個領域則更具機會主義色彩，著眼於疾病領域——仍然著眼於與 Vertex 的定位以及我們關注的疾病領域一致的疾病領域。我們也會關注這些機會，並考慮是否投入我們的資金。它們往往處於早期階段。我不想讓人們在這個階段沉迷於大規模交易，但它們往往處於早期階段。因此，我們可以將我們的科學方法和創造力應用於這些藥物的研發，這與我們在囊性纖維化領域所做的工作是一致的。這就是我們的方法，在我們獲得足夠的資金後立即投入使用，這對我們發展業務至關重要。

Okay, perfect. And then could I just ask specifically, I mean, will we see data on the spinal cord asset next year?

好的，完美。那麼，我可以具體問一下嗎？我的意思是，我們明年能看到脊髓資產的相關數據嗎？

Matt, it's Jeff Chodakewitz. Really, we don't expect that. I just would remind you that these are long-term studies and that the patients get treated acutely, and then we follow them for quite a bit of time. It's all going to depend on the rate of enrollment. And then even once the patient is enrolled, it takes some time to get data. So it's just really too early to tell, but I wouldn't expect any next year.

馬特，我是傑夫喬達克維茲。真的，我們並不指望那樣。我只想提醒各位，這些都是長期研究，患者會接受急性治療，然後我們會對他們進行相當長的一段時間的追蹤。這一切都取決於入學率。即使患者登記入組後，也需要一些時間才能取得數據。所以現在下結論還為時過早，但我預計明年不會有任何比賽。

Our next question comes from Geoffrey Porges of Leerink.

我們的下一個問題來自 Leerink 公司的 Geoffrey Porges。

Ian, a quick financial question, which is you mentioned that the revenue in France is still excluded from your updated guidance. Can you give us a sense of when -- what the cumulative cash from France is now and when you think that, that might actually be converted over into reported revenue? And potentially -- presumably, that will go through your non-GAAP numbers. And then secondly, maybe Jeff could help us understand the failure of tez/iva in the gating mutations. And how does that fit with the observed change in the sweat chloride and with the activity on the preclinical assay? And does that increase or decrease your confidence in the basis for assessing the triples?

伊恩，我有個關於財務的簡單問題，你提到法國的收入仍然不包含在你更新後的業績指引中。您能否大致說明一下，目前來自法國的累積現金流是多少，以及您認為這些現金流何時才能真正轉化為已公佈的收入？而且，這很可能——大概——會影響到你的非GAAP財務數據。其次，或許 Jeff 可以幫助我們理解 tez/iva 在門控突變中的失敗。這與觀察到的汗液氯化物變化以及臨床前試驗的活性如何吻合？這會增加還是減少你對評估三元組的信心？

Thanks for the question, Jeff. Let me just -- it's a complex answer, and we can get together after the call as well, so I'll just put my CPFA hat on. So first of all, France, we do not record revenue. We are getting paid for our medicines in France because -- through an early-access ATU program, and we accumulate that cash on the balance sheet. But because we don't have a definitive price in France, we have to keep that on the balance sheet because we may have to give some of it back if we agree to a price that's lower than the list price they're currently paying us now. If we were to receive an agreement for reimbursements in France in 2017, revenue recognition would allow that amount that's in the balance sheet to be recorded in the quarter that we got the reimbursements approved, and that would be a bolus. And it's about $130 million, $140 million that would actually be recorded on top of the revenues you would record going forward.

謝謝你的提問，傑夫。讓我簡單解釋一下——這個問題比較複雜，我們通話結束後也可以再討論，所以我先從我作為註冊專業財務分析師的角度來談談。首先，在法國，我們不記錄收入。我們之所以能在法國收到藥品款項，是因為——透過提前獲得 ATU 計劃，而且我們在資產負債表上累積了這筆現金。但由於我們在法國還沒有確定價格，所以我們必須把這筆錢保留在資產負債表上，因為如果我們同意的價格低於他們目前支付給我們的標價，我們可能不得不退還一部分。如果我們在 2017 年獲得法國的報銷協議，收入確認將允許將資產負債表中的金額記錄在我們獲得報銷批准的季度，這將是一筆可觀的收入。而且，這筆大約是 1.3 億美元到 1.4 億美元的收入，實際上是在您未來將要記錄的收入之外額外記錄的。

Now, the complexity in all of this is that if December 31 passes and we're now at January 1, there is no bolus in 2018 because the revenue recognition rules are actually changing. And this applies to all companies, not just Vertex, and you're probably aware of it already. But we will have to make an estimate, as of January 1, of what the value is we will be reimbursed at. That bolus of revenue that now sits -- or bolus of cash that now sits on the balance sheet actually goes through retained earnings. It does not go through the revenue line in 2018. So what happens in 2018, you don't get to record the backlog of cash. What you have to do is, going forward January 1, just start recording revenues as if you're getting paid for your medicines in France. Hopefully, that -- tried to keep it simple, but that's how we proceed. There will not be a bolus recognition in 2018. It will go through retained earnings, unfortunately.

現在，所有這一切的複雜之處在於，如果 12 月 31 日過去，到了 1 月 1 日，2018 年就不會有額外收入，因為收入確認規則實際上發生了變化。而且這適用於所有公司，不僅僅是 Vertex，你可能已經知道了。但截至 1 月 1 日，我們需要估算一下我們將獲得的補償金額。現在積壓在資產負債表上的那筆收入——或者說現在積壓在資產負債表上的那筆現金——實際上是透過留存收益實現的。2018 年，它不計入收入。所以，2018 年發生的一切都無法記錄積壓的現金。從 1 月 1 日起，你需要做的就是開始記錄收入，就像你在法國收到藥品款項一樣。希望如此——我盡量保持簡單，但這就是我們的行事方式。2018年將不再進行推注辨識。很遺憾，這筆費用將動用留存收益。

So Geoff, this is Jeff Leiden. I'm glad I got the easier part of the question. You really have 2 questions in there about the tez/iva results. Obviously, we've looked at this data very carefully. We believe that there are 2 reasons that sort of fit together, as you'll see, that explain why the study didn't show a clinical benefit. The first reason and maybe the most important reason is these patients who entered the study in KALYDECO were extremely well treated, as you might have expected. You can see that in their baseline characteristics. So the average patient has been on the drug for more than 3 years. They had a sweat chloride of 50, which is actually quite close to carrier levels, and they had a BMI of 24.5, which is normal, essentially. And so the very high bar that KALYDECO had set with those patients made it difficult to identify incremental acute improvements in FEV1 simply because when they entered the study, they were doing so well. The thing that goes along with that and the other part of that equation is, in this study, we're obviously adding a single first-gen corrector, tez, which only incrementally improves CFTR function. And you can see that clearly from the sweat chloride benefits, which, in the study, were about 7 -- about 6 to 7 millimolar. And so the combination of that, that the bar was so high when the study started and we're adding a single second-gen -- first-gen corrector which only improves sweat chloride a bit but only by about 7 millimole, just made it difficult to detect that incremental difference in acute FEV1.

傑夫，這位是傑夫萊頓。我很慶幸自己答對了比較簡單的部分。你實際上有兩個關於 tez/iva 結果的問題。顯然，我們已經非常仔細地研究了這些數據。我們認為有兩個原因可以相互印證（您將會看到），這解釋了為什麼研究沒有顯示出臨床益處。第一個原因，或許也是最重要的原因，是參與 KALYDECO 研究的這些患者都得到了非常好的治療，正如你可能預料到的那樣。從他們的基線特徵可以看出這一點。因此，患者平均服用該藥物超過 3 年。他們的汗液氯化物含量為 50，這實際上非常接近攜帶者水平，他們的 BMI 為 24.5，基本上是正常的。因此，KALYDECO 為這些患者設定的非常高的標準，使得很難發現 FEV1 的漸進性急性改善，因為當他們進入研究時，他們的狀況非常好。與此以及等式的另一部分相關的是，在本研究中，我們顯然添加了一個第一代矯正器 tez，它只能逐步改善 CFTR 功能。從汗液氯化物含量的增加可以清楚看出這一點，研究顯示汗液氯化物含量約為 7 毫摩爾至 7 毫摩爾。因此，研究開始時標準非常高，而我們只添加了一個第二代——第一代矯正器，它只能稍微改善汗液氯化物，但只有大約 7 毫摩爾，這使得檢測急性 FEV1 的增量差異變得困難。

Our next question comes from Geoff Meacham of Barclays.

下一個問題來自巴克萊銀行的傑夫·米查姆。

When I look at kind of the development of your CF program, you've obviously developed very specific medicines for very specific mutations. And I guess, when you look at the triple data, it's entirely possible that, regardless if the patient is homozygous or heterozygous for Delta F, they could be treated with the triple just based on what we see today. So A, do you agree with that? Do you agree with sort of a one-size-fits-all Delta F508 allele single medicine? And then, B, what would be the -- what would you wait on the data in homozygous Delta F, a little bit more data from different triples than what you have already in place, to get that going? Or would you just go ahead and go with the strategy of, obviously, going out for het/mins first and then homozygous comes after? And I have one follow-up.

當我審視你們的囊性纖維化治療計畫的發展歷程時，很明顯，你們已經針對非常特定的基因突變開發了非常具體的藥物。我想，當你查看三聯療法數據時，完全有可能，無論患者是 Delta F 的純合子還是雜合子，僅根據我們今天所看到的，都可以用三聯療法進行治療。A，你同意嗎？你是否同意採用一種針對所有 Delta F508 等位基因的單一藥物進行治療？那麼，B，你會等待純合 Delta F 的數據，也就是比你目前擁有的更多的來自不同三聯體的數據，來啟動這項研究嗎？或者你會直接採用先進行雜合子/單倍體檢測，然後再進行純合子檢測的策略嗎？我還有一個後續問題。

Geoff, this is Jeff Leiden. Great question and really important question because I think you're pointing out something that we've talked about a lot internally, which is that our sort of whole concept and strategy here around how we're approaching CF has changed over the last, say, 12 months or so, particularly as we've gotten more triple data. We originally thought of this disease as 3 or 4 buckets of patients, each of whom might require different medicines. So KALYDECO monotherapy for 1, maybe doublet therapy for another, triple for another. That's changed dramatically with the results that we're seeing from our triples. And we do believe, just as you said, that whether you have 1 508 allele and you're het/min, let's say, or whether you have 2 508 alleles, you're a homozygous patient, you will be best treated with a triple regimen, and that's certainly what the Phase II data suggests. So if you take all that together, what it really means is that up to 90% of all patients, we believe, will be on the single triple.

傑夫，我是傑夫‧萊頓。這是一個很好的問題，也是一個非常重要的問題，因為我認為你指出了我們內部經常討論的一點，那就是在過去的12個月左右，特別是當我們獲得更多三重數據之後，我們圍繞CF的整個概念和策略發生了變化。我們最初認為這種疾病可以分為 3 到 4 類患者，每類患者可能需要不同的藥物。所以，KALYDECO 單藥療法可能適用於 1 例患者，雙藥療法可能適用於另一例患者，三藥療法可能適用於另一例患者。從我們的三重奏結果來看，情況已經發生了巨大變化。如您所說，我們相信，無論您是攜帶 1 個 508 等位基因且為雜合子/最小等位基因，還是攜帶 2 個 508 等位基因且為純合子患者，三聯療法都是最佳治療方案，而 II 期數據也確實表明了這一點。所以，綜合所有因素來看，我們認為高達 90% 的患者將接受單一三重療法。

There will be a small set of patients, likely, who remain on KALYDECO monotherapy because those are the patients who might, for instance, have a gating mutation on 1 allele, but not 508 or not a second-gen corrector-responsive mutation on the other allele. And so we believe those patients may be fully treated with KALYDECO, but we're talking a very small number, a few hundreds of patients, in that bucket. And then you're left with the final 10% of patients, and those are the patients who don't make any protein, largely because they have stop codons. And we believe those patients, obviously, will not benefit from any of the CFTR corrector strategies. They're going to need a genetic therapy, whether that's gene therapy or gene editing. We're obviously working on those, but those are farther away. So I think the way to think about it is just as you said, we're rapidly moving towards a world in which we believe that up to 90% of patients will be on a single triple regimen and getting maximum effect, hopefully, post the carrier effects. 10% are going to be waiting for genetic therapies and there will be a few, a small number, that will remain on KALYDECO monotherapy. That's how we see the world a few years from now.

可能有一小部分患者將繼續接受 KALYDECO 單藥治療，因為這些患者可能例如在一個等位基因上存在門控突變，但在另一個等位基因上沒有 508 突變或沒有對第二代矯正劑有反應的突變。因此，我們相信這些患者可能完全可以透過 KALYDECO 治療，但我們說的只是極少數患者，只有幾百名。最後剩下 10% 的患者，這些患者無法產生任何蛋白質，主要是因為他們的基因組中存在終止密碼子。我們認為，這些患者顯然不會從任何 CFTR 矯正策略中受益。他們需要接受基因治療，無論是基因療法或基因編輯。我們當然正在努力實現這些目標，但這還比較遙遠。所以我覺得思考這個問題的方式就像你說的，我們正在迅速走向這樣一個世界：我們相信，高達 90% 的患者將接受單一的三聯療法，並獲得最大療效，希望是在消除攜帶者效應之後。10% 的患者將等待基因療法，而少數患者將繼續接受 KALYDECO 單藥治療。這就是我們對幾年後世界的看法。

Okay. That's helpful. And then, when you -- you mentioned, Jeff, the nonsense mutation patients, and that still is a fairly large segment of the population and unaddressed. But are you comfortable with the gene editing technologies today and does that -- is that less of a priority for you than the full 90% kind of segment? And do you feel like the gene delivery systems today are good enough for you to address that population? Or do they need further optimization?

好的。那很有幫助。然後，你——你提到了傑夫，無義突變患者，這仍然是人口中相當大的一部分，而且這個問題還沒有解決。但您對目前的基因編輯技術是否感到放心？對您來說，這是否不如 90% 的市佔率重要？您認為目前的基因導入系統是否足以滿足該族群的需求？或者它們還需要進一步優化？

Yes. So first of all, for your first part of the question, we have been very consistent and insistent that we're committed to treating all patients with CF. So that's our priority, and one population is not higher than the other. I think what's different, just as you point out, is that we're actually quite close, I think, to that 90% of patients as we move our triples through. You're correct that the gene editing or gene therapy approaches are further way, and interestingly, not because of the gene editing or gene therapy technologies, but simply because of the difficulty of delivery, and particularly delivery to a lung that's occluded by mucus, that's full of nucleases. We already have to get to a live surface area. And then, of course, remember that most of those, if they're going to be inhaled deliveries, won't reach the other organs. And because CF is a systemic disease, we're going to have to make sure that we're treating all the organs.

是的。首先，對於您問題的第一部分，我們一直非常一致且堅持地表示，我們致力於治療所有患有囊性纖維化的患者。所以這是我們的首要任務，兩個群體的重要性沒有高低之分。我認為不同之處在於，正如你所指出的，隨著我們三聯療法的推進，我們實際上已經非常接近那 90% 的患者了。你說的沒錯，基因編輯或基因治療方法更進一步，有趣的是，這並不是因為基因編輯或基因治療技術本身，而是因為遞送的難度，特別是遞送到被充滿核酸酶的粘液阻塞的肺部的難度。我們必須先到達一個活體表面區域。當然，也要記住，如果藥物是透過吸入的方式輸送的，那麼大部分藥物都無法到達其他器官。因為囊性纖維化是一種全身性疾病，所以我們必須確保所有器官都進行治療。

So those patients who have stop codons, that is a difficult patient population to treat. We're absolutely committed to doing it. We're working hard on gene editing and gene therapy or Moderna types of approaches, but I do -- I don't want to give you the impression that that's an easy problem, that it's coming quickly because that's a longer-term problem. You also asked in the first part of your question whether we were going to wait to do homozygous after we had done het/min patients with the triples, and the answer to that is no. Our intention is to move forward with all of the eligible patients. Whether it's exactly on the same day timeline or week or month timeline, we plan to move forward simultaneously because we think that all of those patients are going to benefit from the triple.

因此，那些攜帶終止密碼子的患者，是一個難以治療的患者群體。我們絕對會盡力做到。我們正在努力研究基因編輯和基因療法，或者說 Moderna 類型的療法，但是——我不想讓你們覺得這是一個容易解決的問題，這個問題很快就能解決，因為這是一個長期問題。您在問題的第一部分也問到，我們是否會在對三聯體患者進行 het/min 治療後再進行純合子治療，答案是否定的。我們的目標是為所有符合條件的患者推進治療。無論是同一天、同一周還是同一個月，我們都計劃同時推進，因為我們認為所有這些患者都將從三聯療法中受益。

Your next question comes from Alethia Young of Crédit Suisse.

你的下一個問題來自瑞士信貸的阿萊西亞楊。

Just one on Europe actually. Kind of as we think about the process that you're going through with ORKAMBI and potential approval for teza/iva in second half 2018, I guess, I just kind of want to think about the dynamic of like both of these events kind of being somewhat relatively close to each other. Like how does that kind of drive the discussion? Or is there any kind of correlation at all?

實際上，歐洲那邊只有一張。當我們思考您與 ORKAMBI 的合作流程以及 teza/iva 在 2018 年下半年可能獲得的批准時，我想，我只是想思考這兩件事相對接近所帶來的動態。這種做法如何推動討論呢？或者說，兩者之間根本沒有任何關聯？

Yes, thanks for question, Alethia. It's Stuart here, I'll take that one. Our private negotiations on ORKAMBI are ongoing in multiple countries. As you know, we've had significant success through 2017 in places like Germany, Ireland, Italy and Denmark. And I'm pleased to say, just today, we reached an agreement in principle with The Netherlands, which is another important country for us. There's patients there who have been waiting a long time as well. So we're pleased with the progress we're making with ORKAMBI. It's never as fast as we or the CF community would like, obviously. We're also pleased with the prices that we are achieving in Europe. We think they reflect the value of this transformative medicine. And importantly, they're very consistent across the different countries in Europe, which is an important principle for us because we know that the value of ORKAMBI is the same for a patient, no matter what country they live in. So we're continuing to progress those and we want to conclude those pricing and reimbursement agreements as quickly as we possibly can because we know that CF is a [relentlessly] progressive disease and these patients are getting sicker and sicker, whilst they could be benefiting from ORKAMBI.

是的，謝謝你的提問，阿萊西亞。是斯圖爾特，我選他。我們正在多個國家就 ORKAMBI 專案進行私人談判。如您所知，我們在 2017 年在德國、愛爾蘭、義大利和丹麥等地取得了顯著的成功。我很高興地宣布，就在今天，我們與荷蘭達成了一項原則性協議，荷蘭對我們來說也是一個重要的國家。那裡也有一些病人已經等了很久了。我們對 ORKAMBI 目前的進展感到滿意。顯然，它永遠不會像我們或囊性纖維化社區希望的那樣快。我們對我們在歐洲取得的價格也感到滿意。我們認為它們體現了這種變革性醫學的價值。更重要的是，它們在歐洲各國之間非常一致，這對我們來說是一個重要的原則，因為我們知道，無論患者居住在哪個國家，ORKAMBI 的價值都是一樣的。因此，我們正在繼續推進這些工作，並希望盡快完成定價和報銷協議，因為我們知道囊性纖維化是一種不斷惡化的疾病，這些患者的病情越來越重，而他們本可以從 ORKAMBI 中受益。

Obviously, the filing of teza/iva and, indeed, the high level of awareness there is about the triple combination data has led a number of countries to inquire about portfolio-type arrangements like the one that we have struck in Ireland. And if we could strike those kind of arrangements, I would certainly do that with any country, obviously, at a reasonable price. Because I think that's a win for us as a company, and I certainly believe it's a win for patients and physicians because it allows access to the best Vertex medicines as soon as they're possibly available. So we'll continue to pursue pricing and reimbursement agreements with ORKAMBI with as much speed as we possibly can, but are certainly open to any government who wants to enter into a more portfolio-type agreement as well, but obviously, we don't want that to slow down access to ORKAMBI because those patients are waiting today.

顯然，TEZA/IVA 的備案，以及人們對三重合併數據的高度關注，促使許多國家詢問像我們在愛爾蘭達成的這種投資組合類型的安排。如果能夠達成這樣的協議，我當然願意與任何國家這樣做，當然，前提是價格合理。因為我認為這對我們公司來說是一件好事，而且我當然相信這對病人和醫生來說也是一件好事，因為它可以讓他們盡快獲得Vertex最好的藥物。因此，我們將繼續以最快的速度與 ORKAMBI 達成定價和報銷協議，當然，我們也歡迎任何希望達成更全面的協議的政府，但顯然，我們不希望這減慢 ORKAMBI 的供應，因為這些患者現在正在等待。

Our next question comes from Brian Abrahams of RBC Capital Markets.

下一個問題來自加拿大皇家銀行資本市場的布萊恩亞伯拉罕。

Two questions. First off, I recognize that you can't comment on ongoing FDA interactions around the triple combo path forward. But just wondering if you've done the same kinds of preclinical analyses for the triple combos, for instance, in FRT cells that had met the threshold for in vitro supportive approval for KALYDECO in the residual function setting. And then, secondly, you made some comments on the potential to move 1 once-daily triple-combo cocktail forward. I'm just wondering if we should take that to mean that you wouldn't likely move forward with both 659 and 445, or just that if you do take 2 cocktails forward, you'd probably mitigate the risk by having one be KALYDECO-based and one be 561-based.

兩個問題。首先，我知道您不能對 FDA 正在進行的關於三聯療法推進路徑的互動發表評論。但我只是想知道您是否對三聯療法進行了相同的臨床前分析，例如在 FRT 細胞中，這些細胞已達到 KALYDECO 在殘餘功能環境中體外支持批准的閾值。其次，您對推進每日一次的三重組合雞尾酒的推出潛力發表了一些評論。我只是想知道，這是否意味著你不太可能同時推進 659 和 445 的研發，或者只是說，如果你確實要推進兩款雞尾酒的研發，你可能會通過一款以 KALYDECO 為基礎，另一款以 561 為基礎來降低風險。

Two good questions. Thanks, Brian. The second question is our ABS, you're right on the money there. We would take, for instance -- or could take 659 and 445 forward, but almost certainly 1 of those would be once a day, one of them would be twice-a-day KALYDECO, for exactly the reason you said, just to mitigate the risk. So that's an easy answer. And then your other question about FRT cells, yes, we have and are continuing to accumulate data on the triple in FRT cells with all -- many of the different RF and other mutations. And certainly, those are part of our discussions with the regulators.

兩個好問題。謝謝你，布萊恩。第二個問題是關於我們的ABS，你問得完全正確。例如，我們可以採取——或者說可以採取 659 和 445，但幾乎可以肯定的是，其中 1 個每天一次，1 個每天兩次 KALYDECO，原因正如你所說，只是為了降低風險。答案很簡單。至於你提出的關於 FRT 細胞的另一個問題，是的，我們已經並且正在繼續累積關於 FRT 細胞中所有——許多不同的 RF 和其他突變的三重數據。當然，這些也是我們與監管機構討論的內容之一。

Our next question comes from 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。

This is Shawn on for Cory. I have 2, if I might. First, kind of just a follow-on and clarification. I just want to make sure I'm understanding correctly. So regarding the recognition of revenues from France, now, in the event that the reimbursement does not come online in 2018, and then -- sorry, does not come online in 2017, and we get into 2018 where we're subject to the new rules, would that backlog of revenue then be recorded by necessity in the first quarter of next year? And then, secondly, kind of in regards to the planned triple program, was the intention here to include a separate trial for gating mutation patients? And if so, kind of how do the results from the recent teza/iva trials change or not change your thinking around that?

這是肖恩替科里發言。如果可以的話，我想說我有兩個。首先，算是後續跟進和澄清。我只是想確認一下我的理解是否正確。那麼關於確認來自法國的收入，如果 2018 年的報銷款項沒有到位，然後——抱歉，是 2017 年也沒有到位，並且到了 2018 年我們開始受新規約束，那麼這部分積壓的收入是否必然會在明年第一季度確認呢？其次，關於計畫中的三重療法，是否打算單獨進行一項針對突變患者的試驗？如果是這樣，那麼最近的teza/iva試驗結果會如何改變或不改變你對此的看法？

So thanks for the questions, Shawn. Obviously, I'll take the first one, and Jeff Leiden can take over. The -- I'll try again on the revenue recognition. So if we do not get reimbursed in 2017, we still have that bolus of cash we received for providing medicines in France sitting on our balance sheet as we go into 2018. At the point -- starting January 1, we will record revenues going forward in 2018, and that will be at an estimated price that we anticipate that we would receive in France, and that will be recorded on the revenue line. That bolus of revenues from the prior period still sits on the balance sheet. At the point that we actually get reimbursement approval in France, that bolus of revenues will go through retained earnings. It will not go through revenues. And so we continue to record revenues at an estimated price on the top line in 2018, with or without approved reimbursement, but that bolus will no longer go through our revenue line. It's a function of the change in the GAAP for revenue recognition.

謝謝你的提問，肖恩。顯然，我會先做第一個，然後傑夫·萊頓可以接替他。我再嘗試確認收入。因此，即使我們在 2017 年沒有獲得補償，我們在 2018 年的資產負債表上仍然會有一筆因在法國提供藥品而收到的現金。自 2018 年 1 月 1 日起，我們將以預計在法國收到的價格記錄 2018 年的收入，並將該收入記錄在收入行中。上期那筆巨額收入仍保留在資產負債表上。一旦我們在法國獲得報銷批准，這筆收入將計入留存收益。這不會佔用收入。因此，無論是否獲得批准的報銷，我們都會繼續在 2018 年以估計價格記錄收入，但該筆額外支出將不再計入我們的收入。這是由於收入確認的公認會計準則（GAAP）發生了變化。

And Shawn, this is Jeff. Thanks for the question on gating because it's an important one, one that we've thought a lot about. As I said, what we learned from this trial was that the addition of a single first-generation corrector to KALYDECO in these very well-treated patients isn't enough to drive acute FEV1 benefit. However, we definitely want to test the hypothesis that with a first-generation and a second-generation corrector, which obviously drives a lot more activity from that single F508 allele, that we could potentially drive increasing acute FEV1, even in these well-treated patients. So our intention is to include those patients in our Phase III program. Just to be really clear, you said, would it be a separate trial? That I can't comment on because, obviously, the trial design we wouldn't talk about. But the fundamental question, are we going to include gating patients in our Phase III triple programs? Absolutely, because we really want to answer that question of can we produce even more acute FEV1 improvement?

肖恩，這位是傑夫。感謝您提出的關於准入門檻的問題，因為這是一個重要的問題，我們已經對此進行了深入思考。正如我所說，我們從這項試驗中了解到，對於這些治療非常成功的患者，在 KALYDECO 中添加一個第一代矯正器不足以帶來急性 FEV1 獲益。然而，我們絕對想檢驗這樣的假設：使用第一代和第二代矯正器，顯然可以從單一 F508 等位基因中驅動更多的活性，我們有可能即使在這些治療良好的患者中也能驅動急性 FEV1 的增加。因此，我們的目標是將這些患者納入我們的第三期臨床試驗項目。為了確認清楚，您剛剛問，這會是單獨的審判嗎？我無法對此發表評論，因為很顯然，我們不會討論試驗設計。但根本問題是，我們是否會在 III 期三聯療法項目中納入分流患者？當然，因為我們真的想回答這個問題：我們能否進一步提高 FEV1 值？

But equally important, I just want to remind you that this study really only looked at the acute improvement, and there's a whole different, very important aspect to these CFTR-corrector regimens, which is chronic improvement, seeing improvement in things like the slope of decline of the pulmonary function curve, the pulmonary exacerbations, the hospitalizations, the use of antibiotics, mortality, transplantation, et cetera. And one of the things we've learned from our trials, as you know, is that there's somewhat of a disconnect between the acute improvement that you see and the chronic improvement that you see. So as you know, in KALYDECO, we can see -- we see double-digit acute improvements in FEV1. With ORKAMBI, we see about a 2.8% to 3% improvement acutely. But when we look chronically, what we see is actually quite similar between the 2 medicines in terms of decreases in slope of decline and pulmonary exacerbations, et cetera.

但同樣重要的是，我想提醒大家，這項研究實際上只關注了急性改善，而這些 CFTR 矯正方案還有一個完全不同的、非常重要的方面，那就是慢性改善，觀察肺功能曲線下降斜率、肺部急性加重、住院治療、抗生素使用、死亡率、移植等方面的改善。如您所知，我們從試驗中學到的一件事是，您看到的急性改善和您看到的慢性改善之間存在某種脫節。如您所知，在 KALYDECO 中，我們可以看到 FEV1 有兩位數的急性改善。使用 ORKAMBI，我們看到急性改善約為 2.8% 至 3%。但從長遠來看，我們發現這兩種藥物在降低病情惡化斜率和減少肺部疾病惡化等方面實際上非常相似。

And that is really, really important for these patients over the long run. So what we want to do now with the triple -- well, we know we can drive a lot more activity off the single or double 508 alleles -- is to test the acute hypothesis, can we drive more activity even acutely by having a lot more 508 correction? And chronically, we want to ask, will these patients do better as we get them closer and closer to essentially carrier levels? We believe that, but we have to prove it in clinical trials. It's a really important thing because this may be some of the last times we can do these kinds of trials in these patients and compare them to placebo or simpler treatment. So we will want to improve those in the Phase III program.

從長遠來看，這對這些患者來說真的非常重要。所以，我們現在想用三重基因——我們知道我們可以從單一或兩個 508 等位基因中驅動更多的活性——來檢驗急性假設，即我們能否透過更多的 508 校正來驅動更多的急性活性？從長遠來看，我們想問，當我們讓這些患者的病情越來越接近攜帶者水平時，他們的病情是否會好轉？我們對此深信不疑，但我們需要透過臨床試驗來證明這一點。這非常重要，因為這可能是我們最後一次能夠在這些患者身上進行此類試驗，並將結果與安慰劑或更簡單的治療方法進行比較。因此，我們希望改進第三階段專案中的那些專案。

Our next question comes from Phil Nadeau of Cowen & Company.

我們的下一個問題來自 Cowen & Company 的 Phil Nadeau。

First, just a housekeeping one for Ian. Ian, could you break down the revenue for KALYDECO and ORKAMBI by geographic region?

首先，給伊恩個家事。Ian，你能按地理區域細分KALYDECO和ORKAMBI的收入嗎？

Actually, I'll pass it on to Stuart. I think he has the numbers at his fingertips.

實際上，我會把它轉交給史都華。我認為他完全掌握了這些數據。

I do, Phil. So for KALYDECO, we had $133 million in the quarter in the U.S., $80 million ex U.S. And for ORKAMBI, it was $293 million in the U.S., and $43 million ex U.S. in Q3.

是的，菲爾。因此，KALYDECO 在本季在美國的營收為 1.33 億美元，在美國以外地區為 8,000 萬美元。而 ORKAMBI 在第三季在美國的營收為 2.93 億美元，在美國以外地區為 4,300 萬美元。

That's very helpful. And then, a second question on the triple development. In the past, you had suggested that the Concert molecule maybe wouldn't be ready to move forward into Phase III in the first half of next year, but that was going to be something that you looked at subsequently. So I'm kind of curious, what has changed over the last few months that gives you more confidence in moving Concert's molecule forward, right in the first half of the year in the initial Phase III program?

那很有幫助。然後，關於三重發展還有第二個問題。過去，您曾表示 Concert 分子可能在明年上半年還無法進入 III 期臨床試驗，但您之後會對此進行研究。所以我很好奇，在過去的幾個月裡，是什麼變化讓您更有信心在今年上半年推進 Concert 的分子，進入最初的 III 期臨床試驗計畫？

Yes, Phil. Nothing has changed, except we've been working really hard on that program to accumulate the data we would need to include it in these Phase II programs. And basically, what we're announcing today is that we feel we have an update and we feel comfortable in including it in the programs. We've done so. And so we do think it will allow us in the first half of next year to make that kind of decision about whether to include it or not, and with which regimens.

是的，菲爾。一切都沒有改變，只是我們一直在努力推進這個項目，以累積我們需要的數據，以便將其納入第二階段項目。基本上，我們今天宣布的是，我們認為我們有了更新，我們認為可以將其納入計劃中。我們已經做到了。因此，我們認為這將使我們能夠在明年上半年做出是否將其納入以及與哪些療法相結合的決定。

Phil, I would just add that our product communications around the inclusion in the Phase II and, therefore, in the Phase III potential was a lot to do with the speed of closure. We were going through Hart-Scott-Rodino review with that transaction, and we were unsure of when that would close and when we'd get a positive opinion. We did get that and it's allowed us to move quickly internally and, therefore, incorporate VX-561 into the Phase II programs to gather data to make the decision in early '18.

Phil，我只想補充一點，我們圍繞著產品納入 II 期臨床試驗，進而進入 III 期臨床試驗的宣傳，很大程度上與快速完成臨床試驗有關。那筆交易當時正在接受哈特-斯科特-羅迪諾審查，我們不確定何時才能完成審查，也不確定何時才能得到肯定的意見。我們確實得到了這一點，這使我們能夠在內部迅速推進，因此，可以將 VX-561 納入第二階段計劃，以收集數據，並在 2018 年初做出決定。

Great. And then, one last question on the Phase III programs. You've differentiated between the acute effects of the drugs and the chronic effects, and it seems like maybe you're going to try to make the case to the FDA that the acute effects are beneficial enough to patients to support an approval on their own. I'm kind of curious, though, on the safety side, how much safe -- what's the minimum amount of safety data that could potentially be supplied for a drug that's going to used chronically? Do you need a significant number of patients that are out to 12 months versus some way, some precedent for including shorter course of treatments in the safety package for chronic therapy?

偉大的。最後，還有一個關於第三階段計畫的問題。你已經區分了藥物的急性效應和慢性效應，看來你或許打算向 FDA 證明，藥物的急性效應對患者來說足夠有益，足以支持單獨批准該藥物。不過，我有點好奇，從安全角度來看，對於一種需要長期使用的藥物，至少需要提供多少安全數據？是否需要大量患者接受 12 個月的隨訪，而不是以某種方式或先例將較短療程的治療納入慢性病治療的安全方案中？

So Phil, you've identified all of the key questions, but that's exactly what we're discussing with the FDA, all of those that you talked about. As I said, we think we've learned a lot from our trials. It will allow us to streamline these trials, particularly for those patients who don't have anything today. But until we have those discussions finalized and we've seen all the data from the Phase IIs, it's just too early for me to give you any specific answers because we just don't have agreement yet from the regulators on each of those questions.

菲爾，你已經指出了所有關鍵問題，但這正是我們正在與 FDA 討論的問題，也就是你提到的所有問題。正如我所說，我們認為我們從這些嘗試中學到了很多。這將使我們能夠簡化這些試驗，特別是對於目前沒有任何治療方案的患者而言。但是，在相關討論最終完成，並且我們看到二期臨床試驗的所有數據之前，現在我無法給出任何具體答案，因為我們還沒有就這些問題與監管機構達成一致。

Our next question comes from Robyn Karnauskas of Citi.

下一個問題來自花旗銀行的 Robyn Karnauskas。

Two questions. First one may be really stupid. So besides a risk-mitigating strategy taking up to 2 products forward, is there anything else, any other reasons why you'd take 2 products forward? And if they both look good in their final analysis, would you launch both products? How are you thinking about that? And then, the second question is more of a big-picture question on your pipeline. I know you're all -- all focus is on getting these triple combos and moving them forward throughout '18, but when do you think you'll start to sort of talk to The Street about your pipeline, all the stuff you've been working on for a while, and your big-picture strategy for diversifying the company? I know you're -- Ian, you'd mentioned about doing deals and things like that, but when do you think that will become a big focus for you to communicate that to us?

兩個問題。第一個可能真的很愚蠢。除了將最多 2 款產品推向市場的風險緩解策略之外，還有其他原因導致你們選擇將 2 款產品推向市場嗎？如果最終分析結果顯示兩款產品都不錯，你會同時推出這兩款產品嗎？你對此有何看法？然後，第二個問題更著重於你的流程的整體情況。我知道你們所有人的注意力都集中在獲得這些三重組合並在整個 2018 年推進它們上，但是你們認為什麼時候會開始與華爾街談談你們的研發計劃、你們一直在努力的所有事情以及你們公司多元化的宏觀戰略呢？我知道你是──伊恩，你之前提到過做交易之類的事情，但你覺得什麼時候這才會成為你重點關注的領域，以便向我們傳達這些訊息呢？

Yes, Robyn, it's Jeff. So you're absolutely right, our #1 focus, for obvious reasons and for patient reasons, is to move the triples forward as quickly as we can. That doesn't mean that we're not focusing on the non-CF pipeline. We are, we're just not talking about it as much. Your question was, why take 2 forward? And it really is just what you said; it's a portfolio risk-mitigation strategy. As you know, Phase III is about both efficacy, multiple endpoints, as well as safety. And we would just -- we have multiple regimens. We would hate to take one regimen forward, get any kind of surprise in Phase III and be set back by 1 year or 2 for patients because these patients are waiting for the therapy. So by taking 2 forward, we just feel we're mitigating the risk, significantly, actually.

是的，羅賓，我是傑夫。所以你說得完全正確，出於顯而易見的原因以及為了病人著想，我們的首要任務是盡快推進三聯體計畫。但這並不意味著我們沒有關注非CF產品線。我們有，只是不怎麼談論而已。你的問題是，為什麼要向前推進 2？正如你所說，這是一種投資組合風險緩解策略。如您所知，III 期臨床試驗既要檢視療效（多個終點），也要檢視安全性。我們有很多治療方案。我們不希望推動一項治療方案，卻在 III 期臨床試驗中遇到任何意外情況，導致患者等待治療的時間延長 1 到 2 年。因此，透過推進第二步，我們感覺實際上大大降低了風險。

And then, with respect -- and yes, would we launch 2? Everything is going to depend on the data, but if you ask me today, our intention would be to pick the best regimen and launch 1 regimen, assuming there were no major differences in different patient populations. Because at the end of the day, it's just less confusing for patients, I think, if there's 1 regimen that treats 90% of patients. With respect to the pipeline, as I said, the programs are moving forward very nicely. We're very pleased. David Altshuler is really driving those programs forward at multiple sites. And we expect to bring some of them into the clinic next year. And I think, certainly, when we begin to bring them into the clinic, we'll begin to talk more about them and show you some of that data, so you should expect from us to hear more about several of these in 2018.

然後，恕我直言——是的，我們會推出 2 嗎？一切都取決於數據，但如果你今天問我，我們的目標是選擇最佳方案並推出一種方案，假設不同患者群體之間沒有重大差異。我認為，歸根結底，如果有一種治療方案可以治療 90% 的患者，那麼對患者來說就更不容易感到困惑。關於管線建設方面，如我所說，各項計畫進展非常順利。我們非常滿意。David Altshuler 正在多個地點大力推動這些項目。我們預計明年會將其中一些人引入診所。而且我認為，當然，當我們開始將它們引入臨床時，我們會開始更多地談論它們，並向你們展示一些數據，所以你們應該期待在 2018 年聽到更多關於其中幾種的信息。

Our next question comes from Ying Huang of Bank of America Merrill Lynch.

下一個問題來自美國銀行美林證券的黃穎。

This is (inaudible) on for Ying. So a couple. First is that, what is the compliance and persistence rate for ORKAMBI between 6 and 11? Do you think that you have any more room to grow? And secondly, for the 3Q numbers, should we see any inventory or seasonality impact from ORKAMBI? And lastly, the question is, given that the Phase II data of the triple is pretty strong, do you guys have a minimum number of patients required to enroll into the Phase III trial?

這是給英的（聽不清楚）。所以是一對。首先，ORKAMBI 在 6 到 11 之間的合規率和持續率是多少？你認為自己還有成長的空間嗎？其次，對於第三季的數據，我們是否會看到 ORKAMBI 帶來任何庫存或季節性影響？最後，鑑於此三聯療法的 II 期數據非常強勁，你們是否有 III 期試驗所需的最低患者人數？

So I just -- you didn't come through very clear, so if we could just make sure we've got the question, so the first question was does ORKAMBI has room to grow? Maybe Stuart.

所以，你剛才沒說清楚，所以我們想確認問題是否正確，第一個問題是 ORKAMBI 有沒有發展空間？或許是斯圖爾特。

It's compliance and persistence for patients aged from 6 to 11. I'm just wondering, for that particular subgroup of patients, do you still have more room to grow? Or do you think they could potentially just wait until newer therapies comes to the market?

對於 6 至 11 歲的患者而言，依從性和堅持性至關重要。我只是想問一下，對於這部分特定的患者群體，你們是否還有進一步發展的空間？或者你認為他們可能會等到更新的療法上市？

So yes, okay, Stuart will take that.

好的，史都華會接受的。

So yes, in the 6 to 11 age group here in the U.S., we've seen very robust uptake in that patient group. And we've seen, as we anticipated, persistence levels which are quite high and compliance levels which are quite high, both of them actually higher than we've seen in the older patients. And that was as we anticipated. It was based on the clinical profile that we saw in the studies that we did in this patient population where the respiratory adverse events and dropout rates were very low. And we know in these younger patients, because they're largely under the supervision of their parents, their compliance rates tend to be higher. In terms of further growth, yes, I anticipate we are going to see further growth in that 6 to 11 population, both here in the U.S., because I don't think we've yet reached peak penetration in that patient group, and then, obviously, we're still awaiting the approval of that indication outside of the U.S. And that will also give us an opportunity to further grow ORKAMBI in that population.

是的，在美國，在 6 至 11 歲年齡層的患者群體中，我們看到了非常強烈的接受度。正如我們所預期的那樣，我們看到患者的堅持率和依從性都相當高，而且這兩個指標實際上都高於我們在老年患者中看到的水平。正如我們所預料的。這是基於我們在該患者群體中進行的研究中觀察到的臨床特徵，即呼吸系統不良事件和脫落率非常低。我們知道，由於這些年輕患者大多在父母的監督下接受治療，他們的依從性往往較高。就進一步增長而言，是的，我預計在 6 至 11 歲人群中，無論是在美國還是在其他地方，我們都將看到進一步的增長。因為我認為我們尚未達到該患者群體的滲透率峰值，而且顯然，我們仍在等待美國以外地區批准該適應症。這將給我們一個機會，進一步擴大 ORKAMBI 在該族群中的應用。

I think your second question was around seasonality. Did we see any seasonality in Q3, or inventory impacts for Q3? We really didn't see anything out of the ordinary in terms of inventory impacts in Q3. One thing we didn't experience this year that we had experienced last year with ORKAMBI was a compliance dip during the summer months. I think we learned the lessons of why that happened. The team put a number of programs in place, and we didn't see any compliance dip with ORKAMBI in Q3, and that was one of the reasons why we saw such strong demand during the quarter.

我認為你的第二個問題是關於季節性的。第三季是否有季節性因素或庫存影響？第三季度，我們在庫存影響方面並沒有看到任何異常情況。今年我們沒有遇到去年 ORKAMBI 出現的情況，那就是夏季期間合規率下降。我認為我們已經吸取了教訓，並明白為什麼會發生這件事。團隊實施了多項計劃，我們在第三季度沒有看到 ORKAMBI 的合規性下降，這也是我們在該季度看到如此強勁的需求的原因之一。

I think your second question was are there enough patients for the clinical trials of triple. Is that your question or...

我認為你的第二個問題是三聯療法的臨床試驗是否有足夠的病人。這是你的問題嗎？

Yes. I'm speaking about (inaudible), like how many do you need?

是的。我指的是（聽不清楚），例如你需要多少？

Yes. So in the homozygous and het/min patients, where we've had a lot of experience now enrolling our Phase II trials with triples, we're very, very confident that not only are there enough patients, but the demand to get into these clinical trials and try these regimens, given the strength of the results that we're seeing, is very, very high. I think there's enough patients in the other population as well. The only thing I would note to you is in the KALYDECO-treated gating patients, for example, it has been a little more difficult to recruit those trials, as you know, because the patients are so well treated. And so to convince them to come back in takes a little more convincing. We'll see how that goes when we get to those patients, but that's certainly not going to slow down any sort of regulatory filings.

是的。因此，對於純合子和雜合子/min 患者，我們在使用三聯療法進行 II 期試驗方面積累了豐富的經驗，我們非常有信心，不僅有足夠的患者，而且鑑於我們所看到的結果的強大效果，參與這些臨床試驗並嘗試這些療法的需求也非常非常高。我認為其他人群中也有足夠的病人。我唯一要提醒您的是，例如，對於接受 KALYDECO 治療的門控患者，招募這些試驗參與者就比較困難，您也知道，因為這些患者得到了很好的治療。因此，要說服他們回來還需要更多說服工作。等我們接觸到這些患者時，情況會如何發展，但這肯定不會減緩任何監管文件的提交。

Our next question comes from Adam Walsh of Stifel.

我們的下一個問題來自 Stifel 公司的 Adam Walsh。

This is for Jeff C. On the ENaC inhibitor, I think your earlier assays had suggested that the combination therapy with ORKAMBI might work. I'm just wondering if there's any read-through to the primary ciliary dyskinesia study that's ongoing, how we should think about the assay performance there and whether or not we would think of any readthrough from the ORKAMBI combo study?

這是給 Jeff C 的。關於 ENaC 抑制劑，我認為你先前的試驗表明，與 ORKAMBI 聯合治療可能有效。我只是想知道，對於正在進行的原發性纖毛運動障礙研究，是否有任何解讀，我們應該如何看待那裡的檢測性能，以及我們是否應該考慮從 ORKAMBI 聯合研究中得出任何結論？

Yes, maybe I'll take that, this is Jeff Leiden. So first, the question just in CF, just to remind you that the ENaC inhibitor, obviously, is a complementary mechanism. It doesn't work through chloride transport. It works through sodium transport. And therefore, we can't do the kinds of HB assays on chloride transport that we typically do with any of our CFTR modulators. But the best that we can do and did do in the HB assays was to do the height of the hydration layer and the frequency of ciliary beating. And in those assays, with ORKAMBI, it looked like adding ENaC enhanced the activity of ORKAMBI to increase the fluid layer and the ciliary beat frequency, which is why we went ahead to do the Phase III trial. Which, I think, taught us that there isn't a clinical benefit that we're seeing in that population after addition of ORKAMBI. How does that read through to primary ciliary dyskinesia? I'm not sure you can make a direct comparison. The question is, again, does increasing the fluid layer improve pulmonary function in primary ciliary dyskinesia, and the reason we're doing the trial is there's theoretical reasons to think so, but the only way to really answer the question is in patients, and that trial is ongoing. And when we finish, I think we'll have a pretty definitive answer about the role of ENaC inhibitors in that disease as well.

是的，也許我會接受，這位是傑夫萊頓。首先，關於 CF 的問題，需要提醒大家的是，ENaC 抑制劑顯然是一種補充機制。它並非透過氯離子運輸發揮作用。它的作用機轉是透過鈉離子轉運。因此，我們無法像通常使用 CFTR 調節劑那樣，對氯離子轉運進行 HB 檢測。但在 HB 檢測中，我們能做的最好的事情就是測量水合層的高度和纖毛擺動的頻率。在這些試驗中，使用 ORKAMBI 時，添加 ENaC 似乎增強了 ORKAMBI 的活性，增加了液層和纖毛擺動頻率，這就是我們繼續進行 III 期試驗的原因。我認為，這告訴我們，在添加 ORKAMBI 後，我們並沒有在該族群中看到臨床益處。這如何解釋原發性纖毛運動障礙？我不確定能否進行直接比較。問題仍然是，增加液層是否能改善原發性纖毛運動障礙患者的肺功能，我們進行這項試驗的原因是，理論上認為可以，但真正回答這個問題的唯一方法是在患者身上進行試驗，而這項試驗正在進行中。等我們完成這項研究後，我想我們就能對 ENaC 抑制劑在疾病中的作用有相當明確的答案了。

When will that finish?

什麼時候才能完成？

We haven't -- it depends a little bit on how it enrolls. It's enrolling now well, but we'd like to sort of finish and see the enrollment complete and understand how that plays out in the timeline. We'll let you know when we get there.

我們還沒有——這在一定程度上取決於它的招生方式。目前招生工作進展順利，但我們希望完成招生工作，看看招生結果如何，並了解這在時間安排上會如何發展。我們到達後會通知你。

And our final question comes from Tony Butler of Guggenheim Securities.

最後一個問題來自古根漢證券的托尼巴特勒。

Briefly, Jeff, you alluded to the notion of once the triple data come in and -- a single medicine would be selected to move forward and file, and that makes total sense for all populations. But if I think back to the July time period when you did reveal data on -- at least the early data on the triples, there did seem to be some distinguishing characteristics among some medicines, some triples, which looked better in 508 homozygous patients, yet some others that look better in het/mins. And that may not necessarily bear out longer term for longer-term studies, so I'm just curious if, in fact, that is not only correct, but more importantly, is there a hierarchical decision based upon populations that may make more sense?

簡而言之，傑夫，你提到一旦三重數據到位，就會選擇一種藥物繼續推進並提交申請，這對所有人群來說都是完全合理的。但如果我回想一下 7 月你公佈數據的時候——至少是三聯療法的早期數據——一些藥物、一些三聯療法之間似乎確實存在一些區別特徵，有些藥物在 508 名純合子患者中看起來更好，而另一些藥物在雜合子/單核細胞患者中看起來更好。而從長遠來看，這可能並不一定適用於更長期的研究，所以我只是好奇，這是否不僅是正確的，更重要的是，是否存在基於人群的層級決策，這可能更有意義？

Yes. Great question. Let me take it in 2 parts. First of all, just to give you our view of the early Phase II data, we don't believe that you can actually distinguish yet between the different triple combinations with respect to FEV1 or population. They were all in the close to double-digit range, and given the size of those trials, distinguishing between 9% and 10% in a trial like that is probably not a good idea. We may or may not have enough data once we get through all the Phase II trials to make those decisions and distinguish that way, and we'll see.

是的。問得好。讓我分成兩部分來解釋。首先，就我們對早期 II 期數據的看法而言，我們認為目前還無法根據 FEV1 或族群來區分不同的三重療法組合。它們都接近兩位數，考慮到這些試驗的規模，在這樣的試驗中區分 9% 和 10% 可能不是一個好主意。等我們完成所有二期臨床試驗後，我們可能有足夠的數據來做出這些決定並進行區分，也可能不會，我們拭目以待。

And your second part of the question, which is absolutely right, is, of course, the final decision will depend upon the data. And the Phase III data will be, hopefully, quite robust and give us the ability to really distinguish both on the efficacy and the safety side. Having said all that, my hope, and it's a hope, is that what we'll see is a pretty clear best regimen, if you will, which would allow us to launch 1 regimen. As you say, in the chance or the possibility that we saw significant and reproducible differences between the different regimens in different populations, of course, we would always launch the best population -- the best regimen into each population. So it will depend on what we see, but I'm just trying to give you a little bit of crystal ball-gazing on what we'd like to do.

你問題的第二部分完全正確，那就是最終的決定當然取決於數據。希望 III 期臨床試驗數據能夠相當可靠，使我們能夠真正區分療效和安全性兩方面。說了這麼多，我希望（這只是一個希望），我們會看到一個非常明確的最佳方案，這樣我們就可以推出一個方案了。正如你所說，如果我們發現不同人群中不同治療方案之間存在顯著且可重複的差異，我們當然總是會將最佳人群——最佳治療方案——引入到每個人群中。所以這取決於我們觀察到的情況，但我只是想稍微預測一下我們想做什麼。

Okay. Thanks, everybody, for joining us this evening. The Investor Relations team is going to be in the office if you have additional questions. This concludes the call, and you may now disconnect.

好的。謝謝各位今晚的到來。如有其他疑問，投資者關係團隊將在辦公室為您解答。通話結束，您可以斷開連線了。