福泰製藥 (VRTX) 2018 Q1 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Vertex Pharmaceuticals First Quarter 2018 Conference Call. (Operator Instructions) As a reminder, today's conference may be recorded. There will be a brief pause and then the conference will begin.

各位女士、先生，大家好，歡迎參加 Vertex Pharmaceuticals 2018 年第一季電話會議。（操作說明）提醒各位，今天的會議可能會被錄音。短暫休息後，會議將正式開始。

Good evening. This is Michael Partridge, Senior Vice President of Investor Relations for Vertex. Tonight, we will discuss our first quarter 2018 financial results and our continued progress to build long-term leadership in the treatment of cystic fibrosis.

晚安.這是 Vertex 公司投資者關係資深副總裁 Michael Partridge。今晚，我們將討論我們 2018 年第一季的財務業績，以及我們在囊性纖維化治療領域建立長期領導地位的持續進展。

Dr. Jeff Leiden, Chairman and CEO; Dr. Reshma Kewalramani, 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. We recommend that you access the webcast slides as you listen to this call. The slides are available for download on our website. This conference call is being recorded, and a replay will be on our website starting later tonight.

董事長兼執行長傑夫·萊頓博士、首席醫療官雷什瑪·凱瓦拉馬尼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。我們建議您在收聽本次電話會議的同時，請查看網路直播投影片。幻燈片可在我們的網站上下載。本次電話會議正在錄音，稍後將在我們的網站上提供重播。

We will be making forward-looking statements on this call. These statements are subject to the risks and uncertainties discussed in detail in today's press release and our filings with the Securities and Exchange Commission. These statements including, without limitation, those regarding Vertex's marketed CF medicines, the ongoing development and potential commercialization of any triple combination regimen for cystic fibrosis, Vertex's other programs and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

我們將在本次電話會議上發表一些前瞻性聲明。這些聲明受到今天新聞稿和我們向美國證券交易委員會提交的文件中詳細討論的風險和不確定性的影響。這些聲明，包括但不限於有關 Vertex 已上市的 CF 藥物、任何囊性纖維化三聯療法的持續開發和潛在商業化、Vertex 的其他項目以及 Vertex 未來的財務業績的聲明，均基於管理層目前的假設。實際結果和事件可能與此有重大差異。

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, and good evening, everyone. 2018 is an important year for Vertex and in the first few months of this year, we've continued to build in our established track record of innovation to discover, develop and deliver transformative medicines to more people with CF.

謝謝你，邁克爾，大家晚上好。2018 年對 Vertex 來說是重要的一年，在今年的前幾個月裡，我們繼續鞏固了我們現有的創新記錄，為更多囊性纖維化患者發現、開發和提供變革性藥物。

The approval of SYMDEKO, our third disease-modifying CF medicine, offers many patients an important new treatment option, in particular, for those F508del homozygous patients who never started or who discontinued ORKAMBI. The SYMDEKO launch is off to a strong start in the U.S., and we anticipate approval in the EU in the second half of this year.

SYMDEKO 是我們第三種疾病修飾性 CF 藥物的核准，為許多患者提供了一種重要的新治療選擇，特別是對於那些從未開始或停止使用 ORKAMBI 的 F508del 純合子患者。SYMDEKO 在美國的上市取得了強勁的開局，我們預計今年下半年將在歐盟獲得批准。

Today, the number of people eligible for one of our approved CF medicines has grown to 34,000 worldwide and about half of these patients are currently on treatment. With the launch of SYMDEKO as a new treatment option and the completion of additional reimbursement agreements outside the U.S., we are positioned to see continuing significant revenue and earnings growth in 2018 and beyond. Our belief that we can treat many more patients in the future as well as to further enhance the benefit of CFTR modulators is based on our rapid progress in developing triple combination regimens that include a next-generation corrector.

目前，全球符合我們已批准的囊性纖維化藥物使用條件的人數已增加到 34,000 人，其中約一半患者正在接受治療。隨著 SYMDEKO 作為一種新的治療方案的推出，以及在美國以外地區完成額外的報銷協議，我們預計在 2018 年及以後繼續實現顯著的收入和利潤增長。我們相信，未來我們可以治療更多的患者，並進一步增強 CFTR 調節劑的療效，這是基於我們在開發包含下一代矯正劑的三重療法方面取得的快速進展。

Earlier this year, we announced that we had initiated Phase III studies to evaluate VF-659 in triple combination with tezacaftor and ivacaftor in 2 groups of patients: those with 1 F508del mutation and 1 minimal function mutation and those with 2 F508del mutations. The first sites are open for the Phase III study in patients who have only 1 minimal function mutation, and we have begun to dose patients in that study.

今年早些時候，我們宣布啟動了 III 期研究，以評估 VF-659 與 tezacaftor 和 ivacaftor 三聯療法在兩組患者中的療效：一組患者攜帶 1 個 F508del 突變和 1 個最小功能突變，另一組患者攜帶 2 個 F508del 突變。針對僅有 1 個最小功能突變的患者進行的 III 期研究的首批試驗點已經開放，我們已經開始給予該研究中的患者。

Today, we also announced the start of Phase III development for our second next-generation corrector, VX-445, as part of a triple combination regimen in the same groups of patients that we're evaluating with VX-659. This marks important progress toward our goal of advancing 2 different next generation triple combination regimens to allow us to choose and bring forward the best regimen to people with CF as quickly as possible.

今天，我們也宣布啟動第二代矯正劑 VX-445 的 III 期開發，作為三聯療法的一部分，用於與 VX-659 相同的患者群體。這標誌著我們在推進 2 種不同的下一代三聯療法的目標上取得了重要進展，以便我們能夠盡快選擇並為囊性纖維化患者提供最佳療法。

We're also making important progress in our research and development pipeline beyond CF. We are preparing to begin clinical development of CTX001, an investigational CRISPR-Cas9 gene editing treatment in 2 devastating diseases, beta-thalassemia and sickle cell disease with our partner, CRISPR Therapeutics. We also continue to make important progress with the selective NaV1.8 inhibitors, VX-150 and VX-128, for the treatment of pain. We look forward to generating additional data from ongoing studies of these potential pain medicines to inform future development plans.

除了囊性纖維化之外，我們在研發領域也取得了重要進展。我們正準備與合作夥伴 CRISPR Therapeutics 一起開始對 CTX001 進行臨床開發，這是一種用於治療兩種毀滅性疾病（β-地中海貧血和鐮狀細胞疾病）的在研 CRISPR-Cas9 基因編輯療法。我們在選擇性 NaV1.8 抑制劑 VX-150 和 VX-128 治療疼痛方面也持續取得重要進展。我們期待從這些潛在止痛藥的持續研究中獲得更多數據，以指導未來的研發計畫。

In 2018, we also expect to move one or more potential medicines from our internal research programs into clinical development in other diseases. I look forward to updating you on our continued progress during the year.

2018 年，我們也計劃將一種或多種潛在藥物從內部研究計畫推進到其他疾病的臨床開發階段。我期待在今年繼續向您報告我們的進展。

Tonight on the call, I'm pleased to have with us Dr. Reshma Kewalramani, our newly appointed Chief Medical Officer. Reshma joined Vertex in 2016, and her depth of medical knowledge paired with her experience and proven track record as a clinical leader make her an ideal successor to Dr. Jeff Chodakewitz, who will remain with us through early 2019 as a senior adviser as he transitions to his planned retirement. I'd like to personally thank Jeff for his extraordinary leadership and dedication to improving the lives of people with CF and other serious diseases.

在今晚的電話會議上，我很高興邀請到了我們新任命的首席醫療官雷什瑪·凱瓦拉馬尼博士。Reshma 於 2016 年加入 Vertex，她深厚的醫學知識、豐富的經驗以及作為臨床領導者的卓越成就，使她成為 Jeff Chodakewitz 博士的理想繼任者。 Jeff Chodakewitz 博士將繼續擔任高級顧問，直至 2019 年初，之後他將按計劃退休。我謹代表個人感謝傑夫，感謝他卓越的領導能力和對改善囊性纖維化及其他重症患者生活的奉獻精神。

I'll now turn the call over to Reshma to review the status of our CF clinical programs in more detail.

現在我將把電話交給雷什瑪，讓她更詳細地介紹我們囊性纖維化臨床計畫的進展。

Thanks, Jeff, and good evening, everyone. Tonight, I'm very pleased to review our progress in advancing VX-659 and VX-445 triple combination regimens into Phase III development and to share the initial results for once-daily triple combination regimens that include VX-561, a once-daily potentiator.

謝謝你，傑夫，大家晚上好。今晚，我非常高興地回顧我們在推進 VX-659 和 VX-445 三聯療法進入 III 期開發方面取得的進展，並分享每日一次三聯療法（包括每日一次的增效劑 VX-561）的初步結果。

First, to the VX-659 triple combination regimen. During the first quarter of 2018, we announced the initiation of 2 Phase III studies of VX-659, tezacaftor and ivacaftor, as an investigational triple combination regimen for people with CF. The first study is evaluating the VX-659 triple combination regimen versus placebo in approximately 360 patients ages 12 and older who have a minimal function mutation. A schematic of this design is shown on Slide 7.

首先，我們來看看VX-659三重療法。2018 年第一季度，我們宣布啟動 VX-659、tezacaftor 和 ivacaftor 的 2 項 III 期研究，作為針對囊性纖維化患者的研究性三重療法。第一項研究正在評估 VX-659 三重療法與安慰劑在約 360 名 12 歲及以上、具有最小功能突變的患者中的療效。設計的示意圖如圖7所示。

The key feature of this study is that the efficacy assessments at 4 weeks and a safety assessment through 12 weeks will form the basis of a potential NDA submission. The 24-week assessment will generate data on key secondary endpoints as well as safety. Disease data are not required to complete the NDA submission. As Jeff mentioned, sites are open, patient enrollment in the study has begun and the first patients have been dosed.

本研究的關鍵特點是，4 週時的療效評估和 12 週時的安全性評估將構成潛在的 NDA 申請的基礎。為期 24 週的評估將產生關鍵​​次要終點以及安全性的數據。新藥申請無需提供疾病數據。正如傑夫所提到的，試驗點已經開放，患者招募工作已經開始，第一批患者已經接受了給藥。

A second study will evaluate the VX-659 triple combination in approximately 100 F508del homozygous patients ages 12 and older. The design of this study is shown on Slide 8. The key features of this study are a 4-week run-in where all patients received tezacaftor and ivacaftor and then a primary efficacy assessment after 4 weeks of additional dosing where VX-659 or placebo is added to tezacaftor and ivacaftor.

第二項研究將評估 VX-659 三聯療法對約 100 名 12 歲以上 F508del 純合子患者的療效。本研究的設計如投影片 8 所示。本研究的關鍵特徵是：首先進行為期 4 週的導入期，所有患者均接受 tezacaftor 和 ivacaftor 治療；然後在 4 週的額外給藥期後進行主要療效評估，在 tezacaftor 和 ivacaftor 的基礎上添加 VX-659 或安慰劑。

To support a regulatory submission in the U.S. to treat the F508del homozygous population, we anticipate using the 4-week efficacy data from this study in conjunction with 24-week safety data from the study in F508del minimal function patients. Data from these studies of VX-659 will also be used to support planned regulatory submissions in Europe and other regions.

為了支持在美國向監管機構提交治療 F508del 純合子族群的申請，我們預計將使用本研究的 4 週療效數據以及 F508del 最小功能患者的 24 週安全性數據。VX-659 的這些研究數據也將用於支持計劃在歐洲和其他地區提交的監管申請。

Turning to VX-445. Today, we announced the initiation of 2 Phase III studies of the VX-445 triple combination regimen for patients with CF. The study designs are similar to the Phase III program I just discussed for VX-659 and are shown on Slides 9 and 10, respectively.

轉向VX-445。今天，我們宣布啟動 2 項針對囊性纖維化患者的 VX-445 三聯療法的 III 期研究。研究設計與我剛才討論的 VX-659 的 III 期項目類似，分別在投影片 9 和 10 中顯示。

We recently obtained results from the nonclinical toxicology studies for VX-445, and we expect the FDA's review of these data prior to the start of our Phase III studies. Initiating Phase III studies with both VX-659 and VX-445 gives us the opportunity to generate data for 2 different triple combination regimens and pick the best regimen to bring to patients as quickly as possible. In addition to evaluating each triple combination regimen in the studies I just discussed, we also plan to evaluate each of these triple combination regimens in patients who have a gating or residual function mutation.

我們最近獲得了 VX-445 的非臨床毒理學研究結果，我們預計 FDA 將在開始我們的 III 期研究之前審查這些數據。同時啟動 VX-659 和 VX-445 的 III 期研究，使我們有機會獲得兩種不同的三聯療法的數據，並選擇最佳療法盡快帶給患者。除了評估我剛才討論的研究中的每種三聯療法外，我們還計劃評估每種三聯療法在具有門控或殘餘功能突變的患者中的療效。

Earlier this year, we announced Phase II results from VX-445 in F508del minimal function patients that support advancing VX-445 into Phase III studies for that population. Today, we are reporting the initial Phase II data for VX-445 in triple combination in F508del homozygous patients. Once again, the efficacy observed was impressive, and the safety profile of VX-445 was similar to that observed in previously reported parts of this study.

今年早些時候，我們公佈了 VX-445 在 F508del 最小功能患者中的 II 期試驗結果，支持將 VX-445 推進到針對該族群的 III 期試驗中。今天，我們報告 VX-445 在 F508del 純合子患者中進行三重療法的初步 II 期數據。再次觀察到的療效令人印象深刻，VX-445 的安全性與本研究先前報告的部分中觀察到的安全性相似。

This Phase II study evaluated VX-445 or placebo in combination with tezacaftor and ivacaftor for 4 weeks after a 4-week run-in of tezacaftor in combination with ivacaftor. In the patients who received this triple combination, we observed a significant improvement in lung function of 11 percentage points over what was obtained with tezacaftor and ivacaftor alone. This improvement was evident by the second week of the treatment period and sustained through the 4-week dosing period. These data are shown on Slide 11.

這項 II 期研究評估了 VX-445 或安慰劑與 tezacaftor 和 ivacaftor 聯合用藥 4 週，此前已進行了 4 週的 tezacaftor 與 ivacaftor 聯合用藥導入期。接受這種三聯療法的患者，其肺功能較單獨使用 tezacaftor 和 ivacaftor 時提高了 11 個百分點，有顯著改善。這種改善在治療期的第二週就顯現出來，並在為期 4 週的給藥期內持續存在。這些數據顯示在第11張投影片上。

The VX-445 triple combination was generally well tolerated, and the safety profile is consistent with what we've learned previously with this regimen. Today, we are also reporting the initial results for the once-daily potentiator, VX-561, when dosed as part of a triple combination regimen with VX-659 or VX-445 and tezacaftor in people with one minimal function mutation. In these Phase II studies, mean absolute improvements in ppFEV1 of 11.7 and 12.2 percentage points from baseline through week 4 of treatment were observed for the VX-445 and VX-659 triple combination regimens, respectively.

VX-445 三重療法整體耐受性良好，其安全性與我們先前對該療法的了解一致。今天，我們也報告了每日一次的增強劑 VX-561 與 VX-659 或 VX-445 和 tezacaftor 組成三聯療法，用於治療具有一個最小功能突變的患者的初步結果。在這些 II 期研究中，VX-445 和 VX-659 三合一療法從基線到治療第 4 週，ppFEV1 的平均絕對改善分別為 11.7 和 12.2 個百分點。

The once-daily triple combination regimens were generally well tolerated, and the safety results were consistent with what we have observed in triple combination studies that included ivacaftor. While we believe that the results clearly support the hypothesis that VX-561 has a role in future once-daily triple combinations, the FDA has requested additional dose ranging for VX-561 including potential evaluations of monotherapy before allowing evaluation of VX-561 in late-stage development. We look forward to updating you on our progress with our triple combination regimens as we advance these programs.

每日一次的三聯療法整體耐受性良好，安全性結果與我們在包含伊伐卡託的三聯療法研究中觀察到的結果一致。雖然我們認為結果清楚地支持了 VX-561 在未來每日一次的三重療法中發揮作用的假設，但 FDA 要求對 VX-561 進行額外的劑量範圍研究，包括在允許對 VX-561 進行後期開發評估之前，對單藥療法進行潛在的評估。隨著我們三聯療法計畫的推進，我們將期待向您報告我們的進展。

I'll now turn over the call to Ian.

現在我將把電話交給伊恩。

Thanks, Reshma, and good evening to everyone. 2018 is off to a strong start, and tonight, I'm pleased to review our first quarter 2018 financials, the SYMDEKO launch in the U.S. and our 2018 full year financial guidance.

謝謝雷什瑪，大家晚上好。2018 年開局強勁，今晚，我很高興回顧我們 2018 年第一季的財務狀況、SYMDEKO 在美國的上市情況以及我們 2018 年全年的財務預期。

Revenues first. Total CF product revenues of $638 million in the first quarter of 2018 represent a 33% increase compared to the $481 million we recorded in the first quarter 2017. Our total product revenues have continued to grow each quarter as we increase the number of patients treated with our approved medicines. Today, we estimate approximately 34,000 patients are eligible for our medicines, of which about half are being treated. We expect the eligibility and the number of patients we treat to continue to grow throughout 2018 and therefore continue to drive revenue growth.

收入優先。2018 年第一季 CF 產品總營收為 6.38 億美元，比 2017 年第一季的 4.81 億美元成長了 33%。隨著我們核准藥物的治療患者人數不斷增加，我們的產品總收入每季都在持續成長。據估計，目前約有 34,000 名患者符合我們藥物的使用條件，其中約一半正在接受治療。我們預計 2018 年符合資格的患者人數和接受治療的患者人數將繼續成長，從而繼續推動收入成長。

I'll make some brief comments on SYMDEKO launch in the U.S. Since the FDA approval on February 12, we have been educating health care providers on the medicine and working with payers to secure reimbursement. We are seeing broad coverage in access to SYMDEKO as the majority of commercial and government payers are reimbursing for the medicine. For the first quarter 2018, we reported SYMDEKO revenues of $34 million, which reflects the initial 7 weeks of sales. We continue to prepare for the anticipated approval of this medicine in the EU in the second half of 2018.

我將簡要評論 SYMDEKO 在美國的上市情況。自 2 月 12 日獲得 FDA 批准以來，我們一直在向醫療保健提供者普及這種藥物的相關知識，並與支付方合作以確保報銷。我們看到 SYMDEKO 的覆蓋範圍很廣，因為大多數商業和政府支付方都在報銷這種藥物。2018 年第一季度，SYMDEKO 的收入為 3,400 萬美元，這反映了最初 7 週的銷售情況。我們繼續為該藥物在歐盟於 2018 年下半年獲得批准做準備。

Our first quarter 2018 non-GAAP R&D and SG&A expenses were $360 million compared to $313 million in the first quarter of 2017. This increase was primarily due to the advancement of our portfolio of triple-combination regimens for CF and the investment to support the treatment of patients with our medicines globally.

2018 年第一季非 GAAP 研發及銷售、管理及行政費用為 3.6 億美元，而 2017 年第一季為 3.13 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推進，以及為支持全球患者使用我們的藥物進行治療而進行的投資。

Non-GAAP net income for the first quarter 2018 was $196 million compared to non-GAAP net income of $101 million for the first quarter of 2017. The increase in non-GAAP net income was largely driven by the strong growth in total CF product revenues. During the first quarter 2018, we also strengthened our balance sheet as we ended March with approximately $2.5 billion in cash, cash equivalents and marketable securities compared to $2.1 billion at the beginning of this year.

2018 年第一季非 GAAP 淨收入為 1.96 億美元，而 2017 年第一季非 GAAP 淨收入為 1.01 億美元。非GAAP淨利的成長主要得益於CF產品總收入的強勁成長。2018 年第一季度，我們的資產負債表也得到了加強，截至 3 月底，我們的現金、現金等價物和有價證券約為 25 億美元，而今年年初為 21 億美元。

Now turning to the guidance. We continue to expect full year 2018 total CF product revenues in the range of $2.65 billion to $2.8 billion comprised primarily of combined revenues from countries where our 3 approved medicines are currently reimbursed. The midpoint of this range represents approximately 26% growth over 2017 driven by the launch of SYMDEKO and an increased number of patients treated with our approved medicines. As we have commented on previous calls, we are focused on total CF product revenues in our guidance given that some patients on KALYDECO and ORKAMBI will switch to SYMDEKO. The timing and the amount of the switching is not yet known.

現在來看指導意見。我們繼續預計 2018 年全年 CF 產品總收入將在 26.5 億美元至 28 億美元之間，主要包括我們 3 種已獲批准藥物目前已納入醫保報銷範圍的國家的收入。該範圍的中點代表著比 2017 年增長約 26%，這主要得益於 SYMDEKO 的上市以及使用我們獲批藥物治療的患者人數的增加。正如我們在先前的電話會議中所提到的，鑑於一些使用 KALYDECO 和 ORKAMBI 的患者將轉而使用 SYMDEKO，我們在績效指引中重點關注 CF 產品的總收入。切換的時間和幅度目前尚不清楚。

We believe the overall growth of CF product revenues is the most important metric because it reflects revenue growth from treating more and more CF patients. We also continue to expect combined non-GAAP R&D and SG&A expenses of $1.5 billion to $1.55 billion. The key investment drivers are the execution of pivotal studies for 2 triple combination regimens, supply chain investment for the potential commercial success of a triple combination regimen and the incremental investment to support the launch of SYMDEKO.

我們認為 CF 產品收入的整體成長是最重要的指標，因為它反映了治療越來越多的 CF 患者所帶來的收入成長。我們也繼續預期非GAAP研發及銷售、管理及行政費用合計為15億美元至15.5億美元。關鍵的投資驅動因素包括：對 2 種三聯療法進行關鍵性研究；對三聯療法的潛在商業成功進行供應鏈投資；以及為支持 SYMDEKO 的上市而進行的增量投資。

Our financial profile has strengthened significantly over the past 2 years. Our continued execution across all parts of our business has positioned us to deliver sustainable revenue and earnings growth and to continue to expand our operating margin in 2018 and beyond as we significantly increase the number of patients we treat with our medicines.

過去兩年，我們的財務狀況顯著增強。我們在業務各個方面持續高效運作，使我們能夠實現可持續的收入和盈利增長，並在 2018 年及以後隨著我們用藥物治療的患者人數大幅增加而繼續擴大我們的營業利潤率。

With that, I will open the line to questions.

接下來，我將開放提問環節。

(Operator Instructions) And our first question comes from the line of Geoffrey Porges with Leerink.

（操作說明）我們的第一個問題來自 Geoffrey Porges 與 Leerink 的對話。

The only surprise really is that you're not going ahead with a pivotal trial with 561, and I'm wondering if you could give us a little bit more understanding as to the basis for the FDA's decision. It seems a little unusual given that it's just one of the isomers of -- well, actually, it's only a deuterated version, I beg your pardon, of KALYDECO. What's the basis for that caution? And should we assume that, that same standard of single-drug dose finding is going to be applied to every potentiator that might potentially enter the class?

唯一令人驚訝的是，你們沒有繼續進行 561 的關鍵性試驗，我想知道你們能否讓我們更了解 FDA 做出這項決定的依據。考慮到它只是 KALYDECO 的異構體之一，這似乎有點不尋常——好吧，實際上，它只是 KALYDECO 的氘代版本，恕我直言。這種謹慎的依據是什麼？我們是否應該假設，同樣的單藥劑量發現標準將適用於所有可能進入該類別的增強劑？

Hey, Geoff, it's Ian. Maybe we could actually separate that question to 2 parts, which maybe have Reshma talk about the data and Jeff Leiden talk about how we intend to incorporate 561 into our regimen as we go forward. I would remind you, back in early this year, this -- we look forward to getting results from 561. It was pending data and pending discussions with the FDA and maybe we can give you a little more insight into that. So Reshma, do you want to talk about the data first and then, Jeff, on the strategy for incorporation?

嘿，傑夫，我是伊恩。或許我們可以把這個問題分成兩部分，讓 Reshma 談談數據，讓 Jeff Leiden 談談我們打算如何將 561 納入我們未來的治療方案中。我想提醒各位，早在今年年初，我們就曾說過——我們期待從 561 號提案中獲得結果。這方面還需要一些數據，還要與美國食品藥物管理局（FDA）進行討論，或許我們可以提供更多相關資訊。雷什瑪，你想先談談數據，然後傑夫，談談公司成立的策略嗎？

Sure. Sure. So as you know, in both the VX-659 and the VX-445 proof of concept studies, we had one part that included VX-561 in place of ivacaftor. And let me walk you through the results in terms of efficacy and safety. On the efficacy side, as you heard in the prepared remarks, we had an improvement in ppFEV1 of 11.7 and 12.2 percentage points, respectively, for 445 and 659. Really impressive results that we were very pleased with. On the safety side, the results were remarkably similar to what we've seen in our ivacaftor studies. And when we looked at these results both on efficacy and safety, we were very impressed with what we saw and impressed with the consistency of the safety profile. Jeff?

當然。當然。如您所知，在 VX-659 和 VX-445 概念驗證研究中，我們有一個零件使用了 VX-561 來代替 ivacaftor。接下來，我將從療效和安全性兩方面為您詳細介紹結果。在療效方面，正如你們在準備好的演講稿中聽到的那樣，445 和 659 例患者的 ppFEV1 分別提高了 11.7 和 12.2 個百分點。結果非常出色，我們非常滿意。在安全性方面，結果與我們在伊伐卡托研究中看到的結果非常相似。當我們審視這些關於療效和安全性的結果時，我們對所看到的結果以及安全性的一致性都印象深刻。傑夫？

Yes, so Geoff, as you said, we got those results and obviously you need to have the Phase II results before you go and discuss Phase III design with the FDA, which we did over the last several weeks and months. And it became clear to us that the way the FDA was looking at 561, despite the fact that, as you say, it's really a deuterated version of KALYDECO, is as a new chemical entity. And the kind of information they're asking for, for instance, some of the dose ranging and potential monotherapy, is exactly the kinds of things that they would typically ask for a new chemical entity, particularly before it goes into a combination regimen. And so our decision was -- because our goal has always been to get the best regimen to patients as quickly as possible, we decided to move forward with 445 with KALYDECO because that's the quickest route and we didn't want to take a delay. Having said that, I also think that their decision was probably a bit influenced by the fact that KALYDECO has been so well studied in so many thousands of patients and frankly, it set a very, very high bar both in terms of efficacy and safety. And so they have a lot of comfort with it and that made it, I think, easier to enable us to move forward more quickly with that regimen. Having said all that, as Reshma said, the data for 561 is quite compelling. We do plan to take it forward into a once-a-day regimen. We're still in discussions with the FDA about exactly what data they're going to need in some of these Phase I and Phase II studies, but we think that's highly doable. We just don't want to wait. So as soon as we know that, we'll progress those studies and we'll work out a bridging strategy that allows us to bring 561 along with either 659 or 445, whichever one we choose, to patients.

是的，Geoff，正如你所說，我們得到了那些結果，顯然在與FDA討論III期設計之前，你需要有II期的結果，而我們在過去幾周和幾個月裡一直在做這件事。我們逐漸明白，儘管如你所說，561 實際上是 KALYDECO 的氘代版本，但 FDA 看待 561 的方式是將其視為一種新的化學實體。例如，他們所要求的信息，例如劑量範圍和潛在的單藥治療，正是他們通常會對一種新的化學實體提出的問題，尤其是在將其納入聯合治療方案之前。因此，我們的決定是——因為我們的目標始終是盡快為患者提供最佳治療方案，所以我們決定推進 445 與 KALYDECO 的聯合治療，因為這是最快的途徑，我們不想耽誤時間。話雖如此，我也認為他們的決定可能在一定程度上受到了以下事實的影響：KALYDECO 已在成千上萬的患者身上進行了非常充分的研究，坦白說，它在療效和安全性方面都樹立了非常非常高的標準。因此，他們對此感到非常放心，我認為這使我們能夠更快地推進該方案的實施。綜上所述，如雷什瑪所說，561號數據相當令人信服。我們計劃將其改為每日一次的用藥方案。我們仍在與 FDA 討論他們在一些 I 期和 II 期研究中究竟需要哪些數據，但我們認為這是完全可以實現的。我們就是不想等。所以一旦我們知道了這一點，我們就會推進這些研究，並制定一個過渡策略，使我們能夠將 561 與 659 或 445（無論我們選擇哪一個）一起帶給患者。

And our next question comes from the line of Geoff Meacham with Barclays.

下一個問題來自巴克萊銀行的傑夫·米查姆。

I just have a commercial one and then a clinical one. For SYMDEKO, when you look across the OUS approval trajectory, including Europe and Australia, down the road, just what are lessons to be learned from ORKAMBI? Can you help maybe abbreviate the process -- reimbursement process, I'm speaking about? And then I have a couple follow-ups on the clinical side.

我只有一台商用的，還有一台醫用的。對於 SYMDEKO 而言，放眼整個 OUS 審批流程，包括歐洲和澳大利亞，展望未來，我們能從 ORKAMBI 中學到哪些經驗教訓？您能否幫忙簡化流程－我指的是報銷流程？然後我還有一些臨床的後續工作要做。

Hey, Geoff, thanks for the question. So on SYMDEKO ex U.S., what can we learn from our experiences with ORKAMBI? Obviously, in many countries, we've been successful with getting ORKAMBI priced and reimbursed. And clearly, we'll be looking to build on those successes. In some of the markets where we haven't yet secured reimbursement for ORKAMBI, which we continue to very, very actively pursue, we have also begun discussions with some of those authorities about potential portfolio like agreements where we may be able to get accelerated access for patients to SYMDEKO. Obviously, those discussions with ORKAMBI are very, very active. And obviously, with SYMDEKO, they'll pick up more steam when, as we anticipate, we get the approval ex U.S., certainly in Europe, in the second half of this year. What I would stress though, Geoff, is we're not kind of waiting for SYMDEKO and then only really going to try and get reimbursement for SYMDEKO. That's not how we're thinking about it. As you know, patients with CF have a relentlessly progressive disease. We know that treating them as early as possible is incredibly important, certainly with disease-modifying agents like ORKAMBI. And so we're continuing to pursue, with every degree of urgency that we can, reimbursement for ORKAMBI. The other thing to remember, which I think is an important point, is that the SYMDEKO approval is likely to be for people 12 and over. And as you know, in recent years, we've expanded the indications for ORKAMBI, first, to 6 to 11 and hopefully subsequently down to 2 to 5. And so ORKAMBI is going to continue to play a very, very important role for those younger children with CF.

嘿，傑夫，謝謝你的提問。那麼，對於 SYMDEKO ex U.S.，我們可以從 ORKAMBI 的經驗中學到什麼？顯然，在許多國家，我們已經成功地讓 ORKAMBI 獲得定價和報銷。顯然，我們將力爭在這些成功的基礎上再創佳績。在一些我們尚未獲得 ORKAMBI 報銷的市場（我們仍在非常積極地爭取報銷），我們也已開始與一些相關機構討論潛在的投資組合協議，以便我們能夠讓患者更快地獲得 SYMDEKO。顯然，與 ORKAMBI 的討論非常非常活躍。顯然，隨著 SYMDEKO 的出現，正如我們所預期的那樣，一旦我們在今年下半年獲得美國以外的批准，尤其是在歐洲獲得批准，他們的發展勢頭將會更加強勁。不過，Geoff，我想強調的是，我們並不是等待 SYMDEKO 的出現，然後才去爭取 SYMDEKO 的賠償。我們不是那樣想的。如您所知，囊性纖維化患者的病情會持續惡化。我們知道，儘早治療這些疾病非常重要，尤其是使用像 ORKAMBI 這樣的疾病修飾劑。因此，我們將以一切可能的迫切性繼續爭取 ORKAMBI 的賠償。另一點需要記住，我認為這很重要，那就是 SYMDEKO 的批准對象可能是 12 歲及以上的人。如你所知，近年來，我們擴大了 ORKAMBI 的適應症範圍，首先擴大到 6 至 11 歲，希望隨後能縮小到 2 至 5 歲。因此，ORKAMBI 將繼續為患有囊性纖維化的低齡兒童發揮非常非常重要的作用。

And then just on the -- that's helpful. Thanks, Stuart. And then on the pipeline side, when you think about the future triples beyond 659 or 445, I get the strategy with 561, but what would be the real objective here? Do you -- are you guys still actively pursuing more novel combinations in Phase II? I'm trying to figure out -- if you have an assay that's predictive of FEV1, is it worth it to go into larger studies for just a few points of FEV1? In other words, is there an upper end that's kind of worth your investment or not?

然後就只是——這很有幫助。謝謝你，斯圖爾特。然後，在管道方面，當你考慮未來超過 659 或 445 的三倍增長時，我理解 561 的策略，但這裡的真正目標是什麼？你們——你們還在積極探索更多二期臨床試驗階段的新型組合療法嗎？我正在思考——如果你有一個可以預測 FEV1 的檢測方法，那麼為了獲得 FEV1 的幾個點而進行更大規模的研究是否值得？換句話說，是否存在一個值得投資的高端價位？

Yes, it's a great question, Geoff. As I said before, we have now reasonably large number of additional next-gen correctors that are flowing through research and into late preclinical development. And so the decision that we're going to make, and we'll have to start making it soon because some of those are moving along quickly, is are they significantly better than we believe than the 2 that are currently moving forward, 445 and 659. And significantly better is really the whole profile of the medicine, right? So it's certainly efficacy, but it's also once-a-day formulatability; dose, for instance; potency. All those things will go into our decision. But at the end of the day, the decision will be if we feel we have a molecule that's significantly better than the other 2, we'll take it forward into Phase I and certainly into early Phase II. That's easy and quick to do. If we don't, we won't.

是的，傑夫，這是一個很好的問題。正如我之前所說，我們現在有相當多的下一代矯正器正在進行研究並進入後期臨床前開發階段。因此，我們要做出的決定，而且我們必須盡快開始做出決定，因為其中一些進展很快，就是它們是否比我們認為目前正在推進的 445 和 659 這兩個項目要好得多。而顯著改善的正是這種藥物的整體效果，對吧？所以，療效固然重要，但每日一次的配方可行性、劑量、效力等因素也同樣重要。所有這些因素都會影響我們的決定。但最終的決定是，如果我們認為我們擁有的分子明顯優於其他兩種分子，我們將推進其進入 I 期臨床試驗，當然也會推進其進入 II 期臨床試驗早期階段。這很容易做到，而且很快。如果我們不這樣做，我們就做不到。

And our next question comes from the line of Michael Yee with Jefferies.

下一個問題來自 Jefferies 的 Michael Yee。

Congrats on the good SYMDEKO launch as well, to start off. Two-part question, I guess. Just to follow up on the whole concept of more dose-ranging studies needed for 561. I mean, I guess it would seem to be an important readthrough to what the regulators were saying on novel compounds. So just to clarify, are you implying that you need to actually prove it out as a full potentiator and run it as a monotherapy program and prove that it's an active potentiator for new compounds? Just wanted to clarify that. And then the second question was on the Phase IIIs that are ongoing, and it sounds like you started dosing patients. I mean, I presume that would be pretty fast. So while I wouldn't want you to necessarily guide on data, would you actually announce data when it's done after 4 and 12 weeks? Or do you need to file? I guess, what would be your disclosure policy be on these Phase IIIs that we're all looking forward to?

首先，恭喜 SYMDEKO 成功發售。我想，這應該是一個包含兩個部分的問題。關於 561 需要更多劑量範圍研究的整個概念，我想補充一點。我的意思是，我想這似乎是對監管機構關於新型化合物的表態的重要解讀。所以，為了澄清一下，你的意思是說，你需要實際證明它是一種完全的增效劑，並將其作為單一療法進行測試，以證明它對新化合物具有活性增效作用嗎？我只是想澄清一下。第二個問題是關於正在進行的 III 期臨床試驗，聽起來你們已經開始給病人用藥了。我的意思是，我估計那會很快。所以，雖然我並不想讓你對數據進行指導，但你會在 4 週和 12 週後公佈數據嗎？或是你需要提交文件嗎？我想問的是，對於我們都非常期待的這些三期臨床試驗，貴公司的揭露政策是什麼？

Yes, Mike, this is Jeff. I'll take the first part and maybe Ian will take the second one on the disclosure question. With respect to the first part, I never comment on what the FDA is going to want for other people's programs. We do think it's informative that they view 561 as a new chemical entity because as Geoff Porges mentioned, it's quite similar to KALYDECO, but clearly different. So I don't think it's unreasonable. Obviously, as compounds get more and more different and newer and newer, I think that they're going to have the same expectations for new chemical entities pretty much across the board, but obviously that's up to them.

是的，麥克，我是傑夫。關於資訊揭露問題，我來回答第一部分，也許伊恩會回答第二部分。關於第一部分，我從不對FDA對其他人的計畫有何要求發表評論。我們認為他們將 561 視為一種新的化學實體是很有啟發性的，因為正如 Geoff Porges 所提到的，它與 KALYDECO 非常相似，但又明顯不同。所以我認為這並非不合理。顯然，隨著化合物變得越來越不同、越來越新，我認為他們對新的化學實體的期望基本上都會相同，但這顯然取決於他們自己。

And Mike, as to your question on disclosure, I don't really want to [design] the disclosure and what we include in that at this point in time. So it will be -- we'll complete the study. We'll gather the data, what does the data inform us of in terms of a filing strategy. And I think that's what you could imagine us disclosing. And the timing to that, we'll let you know when we're further into the studies. But as usual, it will be what we can we do with the data and we'll provide you that action and we'll provide you the data that supports it and we'll let you know when we have that.

麥克，關於你提出的資訊揭露問題，我目前並不想具體設計資訊揭露的內容以及揭露的具體形式。所以我們會完成這項研究。我們將收集數據，這些數據能告訴我們關於備案策略的哪些資訊。我想這就是你們能想像我們會揭露的內容。至於具體時間安排，我們會在研究進行到更深入的階段時通知您。但像往常一樣，我們會根據數據採取相應的行動，並提供支持該行動的數據，一旦有了這些數據，我們會立即通知您。

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

我們的下一個問題來自美國銀行美林證券的黃穎女士。

Maybe I'll ask one on the clinical trial design for the Phase IIIs. You're testing the Phase III for homozygous patients in about 100 patients where -- while you're testing on the, I guess, triple combo in the heterozygous patients in -- sorry, the 180 patients for the het/min trial. So I was wondering if the trial for homozygous patients is sufficiently powered to show security in efficacy, or it is most likely a supplemental trial to compare the efficacy. And then secondly, maybe commercial side on the SYMDEKO launch. Can you tell based on early experience who are the patients taking SYMDEKO today? Are those mostly patients who were not tolerant of ORKAMBI before? Or you're seeing also some other patients switching to SYMDEKO?

或許我會問一個關於 III 期臨床試驗設計的問題。您正在對大約 100 名純合子患者進行 III 期試驗，而您同時也在對雜合子患者進行三重療法試驗——抱歉，是 het/min 試驗的 180 名患者。所以我想知道，針對純合子患者的試驗是否有足夠的統計效力來證明療效的安全性，或者它很可能只是一項用於比較療效的補充試驗。其次，或許也要考慮 SYMDEKO 上市的商業面。根據早期經驗，你能判斷出目前服用 SYMDEKO 的患者族群是哪些人嗎？這些患者大多是先前對 ORKAMBI 不耐受的患者嗎？或者您也看到其他一些患者改用 SYMDEKO 了？

Ying, just before Reshma gives you the answer, I just want to correct one of your points, and we are obviously doing 2 different Phase III trials, 1 in het/min, 1 in 508, 508 patients. The het/min Phase III study does have 360 patients in, and the 508, 508 Phase III study has 100 patients in. And now maybe Reshma can help you understand how the het/min study will lead and how 508, 508 will follow.

穎，在雷什瑪給你答案之前，我想糾正你的一點，我們顯然正在進行兩項不同的 III 期試驗，一項針對 het/min，另一項針對 508 名患者。het/min III 期研究納入了 360 名患者，而 508, 508 III 期研究納入了 100 名患者。現在，或許 Reshma 可以幫助你理解 het/min 研究將如何進行，以及 508、508 將如何進行。

Sure. Sure. So for each of our programs, VX-659 and VX-445, the programs are actually very similar. So I'll use 659 as an example, but it's very similar to 445. In each program, there's going to be a study of 360 patients total for het/min patients and 100 patients total for homozygous F508del patients. Now the 360 patients for het/min, that comes from a desire that we have to look at things like pulmonary exacerbation, which is going to take more patients. With regard to the 508 homozygous study, that is well powered. Indeed, if you just look back at our proof of concept studies, you can see the fairly substantial improvement in things like sweat chloride, ppFEV1 and even CFQ-R.

當然。當然。因此，我們的每個程序，VX-659 和 VX-445，實際上都非常相似。所以我以 659 為例，但它與 445 非常相似。在每個項目中，將分別對 360 名雜合子/單核細胞患者和 100 名純合子 F508del 患者進行研究。現在，每分鐘有 360 名患者，這是因為我們希望研究肺部急性惡化等問題，而這需要更多的患者。關於這 508 例純合子研究，其統計效力充足。事實上，如果你回顧我們的概念驗證研究，你就可以看到汗液氯化物、ppFEV1 甚至 CFQ-R 等指標都有相當大的改善。

And Ying, on the SYMDEKO launch, obviously we're just 7 weeks in to the launch at the end of Q1, but we are able to tell in this early stage of the launch where those patients are coming from, and we see a mix. We are certainly seeing patients transition from ORKAMBI and KALYDECO based on the strength of the clinical data. But perhaps more importantly, we're also seeing use in patients who were not being treated with CFTR modulator prior to the approval of SYMDEKO, and that's really in 2 areas. One you mentioned, which is those homozygous who had been initiated on ORKAMBI but unfortunately had to discontinue the medicine. And then we're also seeing use in patients who were naive, who had never been initiated on a CFTR modulator, and we're also seeing SYMDEKO being used in those. And obviously, those last 2 patient groups are incredibly important because those are patients who are not being treated with a disease-modifying agent prior to the launch of SYMDEKO.

Ying，關於 SYMDEKO 的上市，顯然，在第一季末，我們才上市 7 週，但在這個上市的早期階段，我們已經能夠看出這些患者來自哪裡，我們看到的是混合型患者。基於臨床數據的可靠性，我們確實看到患者從 ORKAMBI 和 KALYDECO 轉而使用其他藥物。但或許更重要的是，我們也看到，在 SYMDEKO 核准之前未接受 CFTR 調節劑治療的患者中，也出現了這種用法，這主要體現在兩個方面。你提到的其中一例，就是那些已經開始服用 ORKAMBI 但不幸的是不得不停止服用該藥物的純合子患者。此外，我們也看到 SYMDEKO 被用於從未接受過 CFTR 調節劑治療的初治患者。顯然，最後這兩組患者非常重要，因為這些患者在 SYMDEKO 上市之前沒有接受過疾病修飾劑的治療。

Our next question comes from the line of Terence Flynn with Goldman Sachs.

我們的下一個問題來自特倫斯·弗林在高盛集團的經歷。

Maybe was just wondering if you could give us a little bit more detail on the couple cases of rash that you saw with -- in the triple combo Phase II that you just closed and just any idea which of the agents that might be tied to and anything you can say on that front. And then a question for Ian just on SYMDEKO. Can you quantify any inventory for the quarter?

我只是想問一下，您能否更詳細地介紹一下您剛結束的三聯療法 II 期臨床試驗中觀察到的幾例皮疹病例，以及您是否知道這些皮疹可能與哪些藥物有關，以及您在這方面有什麼看法。然後，我想問伊恩一個關於SYMDEKO的問題。您能能量化一下本季的庫存狀況嗎？

Sure. So let me start with the question that you had on the clinical side. Where we are right now is that we've completed our proof of concept studies for both VX-659 and VX-445, and what that means is we've treated about 200 patients. In that 200-patient experience, we have a low incidence of rash overall and a low severity. We have no serious events. These rashes have resolved with discontinuation of treatment or interruption. And interestingly, on that latter point, we've had a couple of cases where patients have interrupted their therapy for a period and then restarted and completed their course without trouble. To give you some context for this, KALYDECO and ORKAMBI, the rashes that we're seeing in our next-gen program are very similar in incidence and quality as what's been seen there. And you can look at the USPI and you'll see ORKAMBI is about 7% and KALYDECO is about 13% or so.

當然。那麼，就讓我先回答您所提出的臨床方面的問題吧。目前，我們已經完成了 VX-659 和 VX-445 的概念驗證研究，這意味著我們已經治療了約 200 名患者。在這 200 名患者的經驗中，皮疹的整體發生率較低，嚴重程度也較低。沒有發生任何重大事件。停藥或中斷治療後，這些皮疹已經消退。有趣的是，關於後一點，我們遇到過幾個病例，患者中斷治療一段時間後，又重新開始並順利完成了療程。為了讓您更好地理解這一點，KALYDECO 和 ORKAMBI，我們在下一代計畫中看到的皮疹，其發生率和品質與之前在那裡看到的非常相似。你可以查看美國石油指數（USPI），你會發現 ORKAMBI 的市佔率約為 7%，KALYDECO 的市佔率約為 13%。

Terence, to your question on SYMDEKO, I'll first draw you to the kind of top line revenues, CF total revenues and comment on that, which is the inventory in the channel at December 31, 2017, was similar to the inventory in the channel at March 31, 2018. So what that tells you is that the channels remained even for -- between those 2 periods, and therefore the revenue number is real demand in Q1. As to your question to SYMDEKO, there was some slight channel build, but that was offset to some channel decline on KALYDECO and ORKAMBI from December 31 period. In summary, total CF revenues in Q1 were the real demand and it was not channel build.

Terence，關於你提出的 SYMDEKO 問題，我首先要帶你了解總收入，CF 總收入，並對此進行評論。截至 2017 年 12 月 31 日，通路庫存與截至 2018 年 3 月 31 日的通路庫存相似。這說明這兩個時期內各通路保持平衡，因此第一季的收入數字反映了實際需求。至於你向 SYMDEKO 提出的問題，頻道數量略有增加，但 KALYDECO 和 ORKAMBI 從 12 月 31 日起頻道數量有所下降，抵消了這一增長。總而言之，第一季 CF 總收入是實際需求，而不是通路建設帶來的收入。

And our next question comes from the line of Brian Abrahams with 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。

I guess first off on the triple combo Phase IIIs. Obviously, a lot of enthusiasm amongst sites, and we're hearing about sites needing to really filter patients as to who is eligible for the study. So I guess my first question is really how are you managing that operationally, the potential for healthier or more highly motivated patients to come into these Phase IIIs and maybe perhaps skew the results or reflect the different population studied in Phase II? And then I have a quick follow up on 561.

我想先談談三連擊第三階段。顯然，各研究中心都熱情高漲，我們也聽說各研究中心需要認真篩選符合研究條件的患者。所以我想我的第一個問題是，在操作層面上，你們是如何應對這種情況的？可能會有更健康或更有動力的患者進入這些 III 期臨床試驗，從而導致結果出現偏差，或反映出 II 期臨床試驗中研究的不同人群的情況？然後我還要快速跟進 561。

Sure. So we have the benefit of having worked with CF patients in this community for some time now and executing not only Phase II studies, but Phase III studies as well in the patient populations that we're studying now in VX-659 and VX-445. And the inclusion and exclusion criteria, the discussions with sites, the way that the sites are screening patients and such are fairly well described, and what we're doing in Phase III is similar to what we ourselves just completed in Phase II. So I feel very good about how the operations are running and the time line on which we are enrolling these studies.

當然。因此，我們很榮幸與該社區的 CF 患者合作了一段時間，並且不僅開展了 II 期研究，還在我們現在正在研究的 VX-659 和 VX-445 患者群體中開展了 III 期研究。納入和排除標準、與研究中心的討論、研究中心篩選患者的方式等等都得到了相當詳細的描述，我們在 III 期所做的工作與我們自己剛完成的 II 期工作類似。所以我對目前的營運情況以及我們招募這些研究的進度安排感到非常滿意。

Great. And then actually maybe a question on 445. You mentioned you're awaiting the FDA review of nonclinical tox. Just wondering if you could say whether there was any notable observations there or if that's just a box check.

偉大的。然後，或許還會有一個關於 445 的問題。您提到您正在等待 FDA 對非臨床毒性的審查。我只是想知道您是否能說說那裡是否有任何值得注意的發現，還是只是為了應付一下。

Sure. You know that the preclinical tox, the chronic tox results are standard fare. We've looked at it. We don't see anything in there, but of course, the agency has to review that.

當然。你知道，臨床前毒性、慢性毒性結果都是標準結果。我們已經看過了。我們沒在裡面看到任何內容，但當然，相關機構需要對此進行審查。

And our next question comes from the line of Phil Nadeau with Cowen and Company.

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

First one, question on 445 and the homozygous data. It didn't look like there were some liver enzyme elevations in that study. Is there anything to be concerned about there? Are those rates similar to what you've seen for other agents in the past?

第一個問題，關於 445 和純合資料。那項研究似乎沒有發現肝酵素升高的情況。那裡有什麼需要擔心的嗎？這些費率與您之前了解的其他經紀人的費率類似嗎？

Sure. So we've looked at the safety, as you can imagine, in great detail, and no, we don't see anything interesting or different there, very much what we've seen with our other trials.

當然。正如您所想，我們已經非常詳細地研究了安全性，但是，我們沒有發現任何有趣或不同的地方，這與我們在其他試驗中看到的情況非常相似。

Okay. And second on the qd regimen and when it can move forward, do you have a rough sense of how long the dose escalation that you need to do will take? Is that something that you think you could finish in 2018? Or is this possibly a multiyear process?

好的。其次，關於 qd 給藥方案以及何時可以推進，您大致了解需要進行的劑量遞增過程需要多長時間嗎？你認為這件事能在2018年完成嗎？或者這可能是需要數年時間的過程？

Yes, thanks, Phil. We're still in discussions with the agency, and so it's a little too early to give you a precise answer. I think we'll know very soon, and when we do, we'll let you know what the plan is. But most of what we're hearing about it is it's fairly straightforward so far. But until we finalize those discussions, I don't want to give you precise time lines.

是的，謝謝你，菲爾。我們仍在與相關機構進行磋商，因此現在給出確切答覆還為時過早。我想我們很快就會知道結果，一旦有了結果，我們會立即通知你們計劃是什麼。但我們目前聽到的大部分消息都表明，這件事相當簡單明了。但在我們最終敲定這些討論之前，我不想給出確切的時間表。

Our next question comes from Matthew Harrison with Morgan Stanley.

下一個問題來自摩根士丹利的馬修·哈里森。

I thought I'd change it up and ask about the CRISPR program for a second. So you've mentioned, and I think CRISPR has mentioned, that you filed the CTAs. You've gotten 1 approved. It sounds like some are still pending. Can you just talk a little bit about what the next steps are in terms of starting dosing and what items are left pending to get the other CTAs approved and open some more sites?

我想換個話題，問一下關於 CRISPR 計畫的問題。所以你提到過，而且我認為 CRISPR 也提到過，你們已經提交了 CTA。你已經獲得 1 項批准。聽起來有些還在等待審批。您能否簡要談談接下來在開始給藥方面有哪些步驟，以及為了獲得其他臨床試驗申請 (CTA) 的批准並開設更多站點，還有哪些事項需要完成？

Yes, Matt, this is Jeff. Thanks for the question. Maybe just to give folks a little background; I know you're aware of this. We're actually planning to study CTX001 in 2 related but different diseases, beta-thalassemia and sickle cell disease. On beta-thal, we've submitted multiple CTAs, as you mentioned, for beta-thal. One of those has been approved, and we expect to begin dosing later this year for beta-thal in Europe. In the U.S., we are on track to file an IND for sickle cell disease, and we'll also file outside the U.S. And again, depending on exactly when we do that, we anticipate starting dosing soon thereafter. So my hope is we'll be dosing in both diseases this year and that should allow us to start to generate some data in patients. As you know, these will likely be the first gene editing trials in people. We're pretty excited about that.

是的，馬特，這是傑夫。謝謝你的提問。也許只是想跟大家簡單介紹一下背景；我知道你們都了解這件事。我們實際上計劃研究 CTX001 在兩種相關但不同的疾病中的作用，即 β-地中海貧血和鐮狀細胞疾病。正如您所提到的，我們已經提交了多個關於β-地中海貧血的CTA。其中一種藥物已經獲得批准，我們預計今年稍後開始在歐洲進行β-地中海貧血的給藥試驗。在美國，我們正按計畫提交鐮狀細胞疾病的新藥臨床試驗申請（IND），我們也會在美國以外地區提交申請。同樣，具體提交時間取決於申請提交的日期，我們預計之後不久就會開始給藥。所以我希望我們今年能夠對這兩種疾病進行給藥，這將使我們能夠開始獲得一些患者數據。如你所知，這些很可能是第一次在人體上進行的基因編輯試驗。我們對此感到非常興奮。

And I will just actually add to it. We are very excited that it's the first gene edit trials in patients. But I'd also say, the -- this one came from a collaboration with CRISPR Therapeutics. Part of, let's say, expansion in growth opportunity is how we form these collaborations and give us product opportunities. And I just want to say that we're very happy with that collaboration with CRISPR Therapeutics, the progress we've made there and the partnership to progress this opportunity towards the clinic is -- it's pretty exciting for us at this stage and a very different disease than CF.

我還要補充一點。我們非常激動，因為這是首次在患者身上進行基因編輯試驗。但我還想說，這項技術是與 CRISPR Therapeutics 合作的成果。可以說，拓展成長機會的一部分在於我們如何建立這些合作關係，以及我們如何獲得產品機會。我只想說，我們對與 CRISPR Therapeutics 的合作非常滿意，我們在那裡取得的進展以及將這一機會推進到臨床階段的合作——在現階段這對我們來說非常令人興奮，而且這是一種與 CF 非常不同的疾病。

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

我們的下一個問題來自摩根大通的 Cory Kasimov。

This is Chuan on for Cory. Just another one maybe on the once daily. So understanding that the absolute difference for 445 and 659 was similar, but when looking at the placebo-adjusted data for 659, it looks to be quite a bit better at least on ppFEV1 since the placebo did quite poorly. Maybe if you could just comment on that. And then does this contribute at all to the decision not to move directly forward with 445 in the once daily? Just kind of thinking that given the 240-milligram dose for 659 is being used for the other trials, was there may be a desire to look at this specific dose rather than the 400 before making the final decision in addition to all the things that the FDA is asking for?

這裡是川，替科里報道。可能只是每天一次而已。因此，雖然 445 和 659 的絕對差異相似，但當查看 659 的安慰劑調整數據時，至少在 ppFEV1 上看起來要好得多，因為安慰劑的效果相當差。如果您能就此發表一下意見就好了。那麼，這是否對最終決定不直接推進每日一次的 445 號列車項目有所影響？我只是在想，鑑於其他試驗中使用的 659 劑量為 240 毫克，除了 FDA 要求的所有事項之外，在做出最終決定之前，是否有可能希望研究一下這個特定劑量，而不是 400 毫克？

Yes, thanks for the question. Actually, as we look at the data, the thing that's impressed us most, Shawn, is the consistency of the data. And it's pretty remarkable to me to see 4 to 6 different Phase II trials with different agents and different combinations that are all generating almost identical results, not only in terms of ppFEV1, by the way, but in terms of sweat chloride, in terms of CFQ-R, et cetera. And it's obviously very important that these are placebo-controlled studies and that we're seeing statistical significance in very small numbers of patients. So I guess our interpretation is what's remarkable is the consistency across the board between different regimens. We don't see a difference between 561. Any of those small differences are really just due to the patient numbers. And so no, that didn't drive any of our decision-making nor do I believe it drove the FDA's decision-making about how to proceed with 561. It's really just a matter of their view that this is a new chemical entity and their desire to have the appropriate early data set before we move into Phase III and we'll get that.

是的，謝謝你的提問。事實上，肖恩，當我們查看數據時，最讓我們印象深刻的是數據的一致性。令我非常驚訝的是，4 到 6 項不同的 II 期試驗，採用不同的藥物和不同的組合，都產生了幾乎相同的結果，不僅在 ppFEV1 方面如此，而且在汗液氯化物、CFQ-R 等方面也是如此。顯然，這些研究是安慰劑對照研究，而且我們在極少數患者中觀察到了統計意義，這一點非常重要。所以我認為，我們解讀為最引人注目的是不同治療方案之間的一致性。我們看不出 561 和 561 有什麼不同。這些細微的差異其實只是由於患者數量不同所造成的。所以，不，這並沒有影響我們的任何決策，我也不認為這影響了 FDA 對 561 號提案的決策。這實際上只是他們認為這是一種新的化學實體，並且希望在進入 III 期臨床試驗之前獲得適當的早期數據集的問題，我們會得到這個數據集的。

Okay. Great. And then sort of just a modeling question, can you maybe refresh our memories on the breakdown for the number of residual function patients qualified? It looks like the number of residual function mutations listed on the KALYDECO and the SYMDEKO labels are about the same: 16 for KALYDECO and 17 for SYMDEKO. So kind of just based on your announcement in conjunction with the approvals for KALYDECO in residual patients, it looks like there should be about 1,500 patients that are currently covered, ages 2 plus for KALYDECO in the U.S. Just wondering roughly how many patients is this for SYMDEKO given that this is in 12 plus. And then how many additional residual function patients are there OUS?

好的。偉大的。然後，還有一個建模方面的問題，您能否幫我們回顧一下符合條件的殘餘功能患者人數的細分情況？KALYDECO 和 SYMDEKO 標籤上列出的殘餘功能突變數量似乎大致相同：KALYDECO 為 16 個，SYMDEKO 為 17 個。根據您宣布的KALYDECO獲準用於剩餘患者的消息，目前美國大約有1500名2歲及以上的患者可以使用KALYDECO。我想知道SYMDEKO的適用人群是12歲及以上，那麼大約有多少患者可以使用它。那麼，還有多少其他殘肢患者（OUS）呢？

So Shawn, we'll get back to you after the call. You did ask for the -- well, just want to make sure what you asked was, what's the total number of RF patient population. We'll get back to you after the call on that.

肖恩，通話結束後我們會再聯絡你。您確實問過——嗯，我只是想確認一下，您問的是射頻消融患者的總人數是多少。通話結束後我們會盡快回覆您。

And our next question comes from the line of Dane Leone with BTIG.

下一個問題來自 BTIG 的 Dane Leone。

I want to ask -- it's kind of a follow-up to an earlier question regarding the rash appearance generally in your commentary about seeing it in around 13% of patients with KALYDECO. I was just curious. Could you elaborate any more in terms of the safety profile that you're seeing with 561? And is there any reason to think that the extended half-life of the molecule could exacerbate some of the safety profile that we've seen with KALYDECO?

我想問一下——這算是對您之前關於皮疹外觀問題的後續提問，您在評論中提到，大約 13% 的 KALYDECO 患者會出現皮疹。我只是好奇而已。您能否進一步詳細說明您觀察到的 561 的安全性能？是否有任何理由認為，該分子的延長半衰期可能會加劇我們在 KALYDECO 中看到的某些安全問題？

Sure. So when we looked at the data from VX-561 in either the 659 program or the 445 program, what we see is real consistency with regard to efficacy as well as the safety profile.

當然。因此，當我們查看 VX-561 在 659 計劃或 445 計劃中的數據時，我們發現其在療效和安全性方面都具有真正的一致性。

And just to be clear, as Reshma said before, both the incidence and severity of rash are very low here. They're similar to what we've seen with the other medicines. And as you know, that hasn't in any way affected the uptake or utility of those medicines. So we're very pleased with the overall benefit of this profile.

需要澄清的是，正如雷什瑪之前所說，這裡皮疹的發生率和嚴重程度都很低。它們與我們之前看到的其他藥物的情況類似。如您所知，這絲毫沒有影響這些藥物的吸收或使用。因此，我們對方案的整體效果非常滿意。

Our next question comes from Carter Gould with UBS.

我們的下一個問題來自瑞銀集團的卡特古爾德。

I guess 2, I guess, for Jeff. Now that you got clarity on the Phase III designs and you're entering a little bit more of an execution phase right now, any shifts in focus or attention on the BD front? And then just on the 445 once-a-day combo, just the quality of life data, the placebo arm looked a bit anomalous. Maybe just add some context around that. The active arm seems relatively consistent with the prior studies.

我猜是2，我猜是給傑夫的。既然您已經明確了第三階段的設計方案，現在正進入執行階段，那麼在業務拓展方面，您的關注點或重點是否有所轉移？然後，就每天一次的 445 組合而言，就生活品質數據而言，安慰劑組看起來有點異常。或許可以補充一些背景資料。活性組的結果似乎與先前的研究結果基本一致。

Yes, thanks for the questions, both good questions. First one, on BD. Really, there isn't a shift. As Ian said in his prepared remarks, we have been accelerating, revving up our BD efforts for the last several years with the same consistent strategy around CF platforms and early-stage transformative products. We continue to look and be very active in that space. You can expect to see us do more deals similar to the ones that we've done already, say, with CRISPR and Moderna, on Parion, et cetera. And because we have more firepower, we have more flexibility in terms of the size of those deals. And so some of them maybe even larger than the ones we've done already. So I don't think there's really a change, but there's certainly a very active effort. It's just part of our focus on diversifying our pipeline beyond CF, both through internal research and external collaborations or acquisitions. Maybe, Reshma, do you want to comment a little on the placebo arm and CFQ-R?

是的，謝謝你們的提問，兩個問題都很好。第一部，藍光版。實際上，並沒有什麼轉變。正如 Ian 在事先準備好的演講稿中所說，過去幾年，我們一直在加速推動業務拓展工作，並始終堅持圍繞 CF 平台和早期變革性產品採取一致的策略。我們將繼續關注並積極參與該領域。您可以期待我們會達成更多類似於我們已經達成的協議，例如與 CRISPR 和 Moderna 就 Parion 等達成的協議。因為我們擁有更強大的實力，所以我們在交易規模方面擁有更大的靈活性。所以其中一些甚至可能比我們已經完成的還要大。所以我認為並沒有真正的改變，但肯定有人在積極努力。這只是我們致力於將產品線多元化，使其超越囊性纖維化領域的一部分，這包括內部研究和外部合作或收購。雷什瑪，你或許想對安慰劑組和 CFQ-R 做一些評論？

Sure. Sure. So as we looked at the CFQ-R results across 659 and 445, actually across all the doses that we studied and in all the populations that we studied, what you see is big double-digit improvements in CFQ-R. In the study that -- the one 445 study, you rightly point out that there's anomaly in the placebo group. In essence, there are 2 patients that are just plain different, and that difference is what drove that CFQ-R value there. But you're right. It's an anomaly, and it comes from 2 patients out of 8, small numbers.

當然。當然。因此，當我們查看 659 和 445 的 CFQ-R 結果時，實際上在我們研究的所有劑量和所有研究人群中，我們看到 CFQ-R 有兩位數的顯著改善。在那項研究—那項 445 項研究中，你正確地指出安慰劑組有異常情況。從本質上講，這兩位患者的情況截然不同，而正是這種差異導致了 CFQ-R 值差異。但你說得對。這是一個異常現象，而且只出現在 8 名患者中的 2 名患者身上，數量很少。

Our next question comes from Alethia Young with Crédit Suisse.

我們的下一個問題來自瑞士信貸的 Alethia Young。

One on the NaV1.8, the VX-150, I just wanted to talk a little bit more about your strategy there. I know you have the data. Where do you plan on presenting it? And how do we think about moving forward in the Phase III and commercializing? And then just kind of also, can you just talk about if there's a preference at this point between true M&A or kind of doing more partnerships like you've done in the past?

關於 NaV1.8 和 VX-150，我想再多談談你們的策略。我知道你掌握這些數據。你打算在哪裡進行展示？那麼，我們如何考慮推進到第三階段並實現商業化呢？另外，您能否談談目前貴公司更傾向於真正的併購，還是像過去那樣更多地開展合作？

Yes, this is Jeff. Alethia, thanks for the questions. With respect to pain, as we've said before, we don't really think about pain as one disease. It's multiple diseases that are a little bit different: inflammatory, acute, neuropathic, et cetera; nor does our pain program have one compound in it. We have VX-150, as you know, for which we have positive data in both OA and in acute pain. We have VX-128, which is a fast follower that we're also very excited about. And I'd also remind you that in pain, both oral formulations and IV formulations are important, particularly for acute pain. So this is sort of a complicated chess game where we have to decide what's the best medicine for the best indication and the best formulation out of our pipeline, which is growing. And the way we're doing that is to do some exploratory studies in Phase II in these multiple indications. And I think we should have the data from those later this year, early next year, and that would allow us to make a decision about how to move forward. And I know -- some folks have asked me, "Wasn't that going to slow you down?" Actually, my answer would be it's going to actually speed us up because if we do Phase II correctly and we really understand the right dose, right medicine, right disease and right formulation, it's going to allow us to move much quickly in Phase III. And we're particularly excited about that because obviously, in areas like acute pain, we're sitting in the middle of this horrible opioid epidemic. And if we can demonstrate new oral agents, for example, that have the potency of opiates without the addictive potential, we think there's going to be a very favorable regulatory environment. But we want to make sure we have all the data we need to take advantage of that.

是的，這是傑夫。阿萊西亞，謝謝你的提問。關於疼痛，正如我們之前所說，我們並不真正把疼痛看作一種疾病。疼痛是由多種疾病引起的，這些疾病各有不同：發炎性、急性、神經性等等；我們的疼痛治療方案中也沒有單一的成分。如您所知，我們有 VX-150，我們在治療骨關節炎和急性疼痛方面都獲得了積極的數據。我們還有VX-128，它是一款快速跟隨器，我們也對此感到非常興奮。我也要提醒您，對於疼痛，口服製劑和靜脈注射製劑都很重要，特別是對於急性疼痛。所以這有點像是複雜的西洋棋比賽，我們必須從我們不斷增長的研發管線中，決定哪種藥物最適合哪種適應症，哪種配方才是最佳選擇。我們採取的方法是針對這些多種適應症進行一些 II 期探索性研究。我認為我們應該在今年稍後或明年年初獲得這些數據，這將使我們能夠決定如何繼續前進。我知道有些人問我：「這難道不會減慢你們的速度嗎？」 實際上，我的回答是，這反而會加快我們的速度，因為如果我們正確地完成了二期臨床試驗，真正了解了正確的劑量、正確的藥物、正確的疾病和正確的製劑，這將使我們能夠更快地進入三期臨床試驗。我們對此感到格外興奮，因為很明顯，在急性疼痛等領域，我們正處於這場可怕的鴉片危機中。例如，如果我們能夠證明新的口服藥物具有鴉片類藥物的效力，但沒有成癮性，我們認為將會有非常有利的監管環境。但我們希望確保我們擁有利用這項優勢所需的所有數據。

And Alethia, I'll take your second question, which is I'll first say that M&A versus licensing, we just view those as a tactic in terms of execution. And so as Jeff said earlier, we have 3 broader strategies in how we think about the outside world to Vertex, and that is look at everything in CF to see whether it complements our own approach; secondly, to have the possibility of expanding our scientific footprint beyond small molecules and maybe beyond gene editing now. And then secondly -- thirdly, sorry, what product opportunities are there, and if those product opportunities come in the way of licensing or M&A, again, that's just a tactic of how you incorporate those into the company. To Jeff's comment earlier, also, we do have more capital available today. As you saw in the first quarter, we added close to $500 million of capital, and that's from $2.1 billion to $2.5 billion of cash. And we have no debt. So we do have more capability today to add to our pipeline. The question is also do you think you're going to get involved in large M&A and utilization of our own share count? No, we don't believe that. We're focused on more earlier stage, high science ideas. As a company, we have lots of growth in front of us with CF, and that's where our focus is [on trying to] in terms of driving revenue growth and capital accumulation and we'll look at earlier stage opportunities in other disease areas.

阿萊西亞，我來回答你的第二個問題，首先我要說的是，關於併購與許可，我們只是把它們看作是執行策略的一種體現。正如 Jeff 之前所說，我們在思考 Vertex 的外部世界時有 3 個更廣泛的策略，首先是審視 CF 領域的一切，看看它是否與我們自己的方法互補；其次是有可能將我們的科學足跡擴展到小分子之外，甚至可能擴展到基因編輯之外。其次──抱歉，第三點，有哪些產品機會？如果這些產品機會阻礙了許可或併購，那麼這只是將這些機會融入公司的策略。另外，針對傑夫之前的評論，我們現在確實有更多可用資金。正如您在第一季所看到的，我們增加了近 5 億美元的資本，現金從 21 億美元增加到 25 億美元。而且我們沒有任何債務。所以，我們現在確實擁有更多能力來擴充我們的產品線。問題還在於，您是否認為您將參與大型併購活動並利用我們自身的股份數量？不，我們不這麼認為。我們更專注於早期階段的高科學理念。作為一家公司，我們在囊性纖維化領域還有很大的成長空間，這也是我們目前關注的重點，我們將努力推動收入成長和資本積累，同時我們也會關注其他疾病領域的早期投資機會。

And our last question will come from Robyn Karnauskas with Citi.

最後一個問題來自花旗銀行的 Robyn Karnauskas。

So I guess the first question is a follow-up where you're asked about what exactly -- when will we see the data. You're saying when you complete the study, you'll assess. When you say complete, is that 4 weeks? Or could that be 12, or could that even be 24? Just a sense of like, what do you define as complete? And how do you keep those placebo patients on the triple placebo for het/min? And the other, other question I had was you had a great quarter of SYMDEKO. What are you thinking about in the back end? Like, reasonable assumptions can get you above your guidance. So I was just kind of thinking, when you see a great, strong, robust 7 weeks of sales, how can you temper expectations going into the back of the year as the reason why you didn't raise guidance this quarter?

所以我想第一個問題是一個後續問題，就是我們究竟何時才能看到資料。你的意思是說，等研究結束後，你會進行評估。你說的「完成」是指4週嗎？或者可能是 12，甚至可能是 24？就想問一下，你如何定義「完整」？如何讓安慰劑組的患者在接受三重安慰劑治療期間保持健康？我還有一個問題，那就是你們的 SYMDEKO 季度表現非常出色。你們後端在考慮什麼？例如，合理的假設可以讓你超越指導原則。所以我就在想，當你看到連續 7 週的銷售業績強勁強勁時，你如何才能在進入下半年時降低預期，以此作為你沒有提高本季業績預期的理由呢？

Thanks, Robyn. So firstly, to your first question, just to remind you that the het/min study, which is the lead study with 659, our anticipation is that we'll provide you the data based on what we expect to file upon. And so when you look at the design of that study, it has a 4-week efficacy endpoint and a 12-week safety endpoint. So we would want it to run through the 12 weeks because that's the basis of the filing. So you would anticipate that we would run through that period of at least 12 weeks. We would collect the data. We would have to obviously analyze it, and we'll provide a disclosure on the 659 study in the het/min patients, which would complete using the 4- and 12-week data. As to your question regarding revenue expectations, we reiterated our guidance on the call tonight, $2.65 billion to $2.8 billion. We did have a strong first quarter. We've got to see how the year progresses. We have built in growth into that guidance. The main growth, we do anticipate, will come from those markets that we see that are already reimbursed from all 3 products and the main growth in terms of adding patients with [the placebo] will be through SYMDEKO. And so we're holding on our guidance at this point in time, and we'll see how the year goes. And the potential drivers of growth outside our guidance could be getting some of the markets where we're not currently reimbursed actually reimbursed and launching in those markets, and we'll update you at that time.

謝謝你，羅賓。首先，對於您的第一個問題，需要提醒您的是 het/min 研究，這是 659 的主要研究，我們預計我們將根據我們預期提交的文件向您提供資料。因此，當你查看研究的設計時，你會發現它有 4 週的療效終點和 12 週的安全性終點。所以我們希望它能持續 12 週，因為這是申報的基礎。所以，預計我們會經歷至少 12 週的這段時間。我們會收集數據。我們顯然需要進行分析，我們將對 659 名 het/min 患者的研究結果進行揭露，該研究將使用 4 週和 12 週的數據完成。關於您提出的營收預期問題，我們在今晚的電話會議上重申了我們的預期，即 26.5 億美元至 28 億美元。我們第一季表現強勁。我們得看看今年情況如何發展。我們在指導原則中融入了成長要素。我們預計，主要成長將來自那些已經透過這 3 種產品獲得報銷的市場，而增加安慰劑患者的主要成長將透過 SYMDEKO 實現。因此，目前我們暫時改變我們的指導方針，讓我們拭目以待今年的發展。而我們預期之外的潛在成長驅動因素可能是，在我們目前尚未獲得報銷的一些市場獲得報銷，並在這些市場推出產品，屆時我們會向您報告最新情況。

Thank you, and this concludes today's question-and-answer session. I would now like to turn the call back to Mr. Michael Partridge for closing remarks.

謝謝大家，今天的問答環節到此結束。現在我謹將電話轉回給麥可‧帕特里奇先生，請他作總結發言。

Thank you, Chelsea. Thank you, everybody, for tuning in to the call this evening. The Investor Relations team will be available tonight for any follow-up questions that you have. Good night.

謝謝你，切爾西。謝謝大家今晚收聽電話會議。投資者關係團隊今晚將解答您任何後續問題。晚安。

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

女士們、先生們，感謝各位參加今天的會議。程式到此結束，各位可以斷開連接了。祝大家今天過得愉快。