福泰製藥 (VRTX) 2017 Q1 法說會逐字稿

Good evening. This is Michael Partridge, Vice President of Investor Relations for Vertex. Welcome to our First Quarter 2017 Financial Results Conference Call. (Operator Instructions) This call is recorded, and a replay will be available following the conclusion of tonight's call 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年第一季財務業績電話會議。（操作員說明）此通話將會被錄音，今晚通話結束後，您可以在我們的網站上收聽錄音回放。

Dr. Jeff Leiden, Chairman and CEO; and Ian Smith, Chief Operating Officer and Chief Financial Officer, will provide prepared remarks this evening. Stuart Arbuckle, Chief Commercial Officer, will join us for Q&A. We will make forward-looking statements on this conference call. These statements are subject to the risks and uncertainties discussed in detail in today's press release, 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.

董事長兼執行長傑夫萊頓博士和營運長兼財務長伊恩史密斯將於今晚發表準備好的演講。首席商務官史都華·阿巴克爾將參加問答環節。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。

Information regarding our use of GAAP and non-GAAP financial measures and the reconciliation of GAAP to non-GAAP is available in the financial results press release. I would also refer you to Slide 3 of tonight's webcast.

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。我還想請您參考今晚網路直播的第三張投影片。

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, and good evening, everyone. 2017 is an important year for Vertex, and we've had a strong start to the year with excellent progress across all aspects of our business. This progress has advanced us significantly toward our goal of developing medicines for all people with CF.

謝謝大家，晚上好。2017 年對 Vertex 來說是重要的一年，我們開局強勁，業務的各個方面都取得了優異的進展。這項進展使我們在為所有囊性纖維化患者研發藥物的目標上邁出了重要一步。

In the first few months of 2017, we continued to increase the number of people eligible for and being treated with our approved medicines, KALYDECO and ORKAMBI. In September of 2016, we received approval for ORKAMBI in children ages 6 to 11 in the U.S., and we've seen rapid uptake and strong compliance and persistence in these patients.

2017 年的前幾個月，我們繼續增加符合條件並接受我們批准的藥物 KALYDECO 和 ORKAMBI 治療的人數。2016 年 9 月，我們獲得了美國對 6 至 11 歲兒童使用 ORKAMBI 的批准，我們看到這些患者對該藥物的接受度很高，依從性和堅持性也很強。

This quarter, we also submitted an MAA line extension to the European Medicines Agency for approval of ORKAMBI in children ages 6 to 11. There are approximately 3,400 children ages 6 to 11 who have 2 copies of the F508del mutation in Europe. We remain committed to expanding the eligibility for and access to ORKAMBI.

本季度，我們也向歐洲藥品管理局提交了 MAA 產品線擴展申請，請求批准 ORKAMBI 用於 6 至 11 歲兒童。歐洲約有 3400 名 6 至 11 歲的兒童攜帶 2 個 F508del 突變拷貝。我們將繼續致力於擴大 ORKAMBI 的適用範圍和使用管道。

We've also made significant progress across our CF pipeline. Last month, we shared positive results for 2 Phase III studies of the investigational tezacaftor/ivacaftor combination: 1 study in people with 2 copies of the F508del mutation and 1 study in people with 1 F508del mutation and a second residual function mutations. Both studies demonstrated the clinically meaningful benefits, favorable safety and tolerability profiles across multiple patient groups. We look forward to submitting an NDA and MAA for tezacaftor/ivacaftor in the third quarter of 2017.

我們在囊性纖維化產品線方面也取得了重大進展。上個月，我們分享了 2 項關於試驗性 tezacaftor/ivacaftor 組合的 III 期研究的積極結果：1 項研究針對攜帶 2 個 F508del 突變拷貝的人群，1 項研究針對攜帶 1 個 F508del 突變和第二個殘餘功能突變的人群。兩項研究均表明，該藥物在多個患者群體中具有臨床意義的益處、良好的安全性和耐受性。我們期待在 2017 年第三季提交 tezacaftor/ivacaftor 的 NDA 和 MAA。

In addition, we have 4 next-generation correctors currently in Phase I and Phase II studies. We believe a triple combination of a next-generation corrector with tezacaftor and ivacaftor could provide benefit for the approximately 90% of people with CF who have at least 1 F508del mutation. We expect to have data in people with CF from 3 of these combination regimens in the second half of 2017, and I look forward to updating you on this progress over the coming months.

此外，我們目前有 4 款新一代矯正器正在進行 I 期和 II 期研究。我們相信，下一代矯正劑與 tezacaftor 和 ivacaftor 的三重組合可以為大約 90% 的至少攜帶 1 個 F508del 突變的 CF 患者帶來益處。我們預計在 2017 年下半年獲得 3 例囊性纖維化患者接受這 3 種聯合治療方案的數據，我期待在接下來的幾個月向大家報告這一進展。

Lastly, we are focused on broadening our CF pipeline, and during the quarter, we announced an agreement to acquire CTP-656 from Concert Pharmaceuticals. Our goal is to develop the most effective and convenient medicines for people with CF, and CTP-656 has the potential to be used as part of a future once-daily combination regimen that can treat the underlying cause of CF.

最後，我們專注於擴大我們的 CF 產品線，在本季度，我們宣布了一項從 Concert Pharmaceuticals 收購 CTP-656 的協議。我們的目標是為囊性纖維化患者開發最有效、最方便的藥物，而 CTP-656 有潛力成為未來每日一次聯合治療方案的一部分，該方案可以治療囊性纖維化的根本原因。

These recent accomplishments give us tremendous conviction that we will achieve our vision of bringing new transformative medicines to people with CF around the world. Our continued progress has also positioned us well to meet our financial goals of delivering sustainable long-term revenue and earnings growth.

最近的這些成就讓我們堅信，我們將實現為世界各地的囊性纖維化患者帶來變革性新藥的願景。我們持續取得的進展也使我們有能力實現財務目標，即實現可持續的長期收入和獲利成長。

With that, I'll now turn the call over to Ian to discuss our financials.

接下來，我將把電話交給伊恩，讓他來討論我們的財務狀況。

Thanks, Jeff, and good evening to everyone. Tonight, I'll discuss the key aspects of our first quarter 2017 financials, and we'll also review our 2017 financial guidance.

謝謝你，傑夫，大家晚上好。今晚，我將討論我們 2017 年第一季財務狀況的關鍵方面，我們也將回顧我們 2017 年的財務預期。

Total CF product revenues of $481 million in the first quarter 2017 represents a 22% increase compared to $394 million we recorded in the first quarter of 2016. Additionally, it represented a $27 million increase compared to the total CF revenues of $454 million we recorded in the fourth quarter of 2016.

2017 年第一季 CF 產品總營收為 4.81 億美元，比 2016 年第一季的 3.94 億美元成長了 22%。此外，與我們在 2016 年第四季記錄的 4.54 億美元 CF 總收入相比，這代表增加了 2,700 萬美元。

For ORKAMBI, we reported first quarter 2017 product revenues of approximately $295 million, an increase of $18 million compared to the fourth quarter of 2016. This increase was primarily driven by the rapid uptake for ORKAMBI in the 6 to 11-year-olds as well as strong persistence in compliance with this medicine in this age group.

ORKAMBI 2017 年第一季產品營收約為 2.95 億美元，比 2016 年第四季增加了 1,800 萬美元。這一增長主要是由於 6 至 11 歲兒童對 ORKAMBI 的快速接受度以及該年齡層對該藥物的強烈依從性所致。

First quarter KALYDECO sales were $186 million compared to $177 million for the fourth quarter of 2016. I'd like to point out that $9 million of this increase was based on mainly onetime adjustments related to reimbursement agreements in Europe.

KALYDECO 第一季銷售額為 1.86 億美元，而 2016 年第四季為 1.77 億美元。我想指出，這筆成長中的 900 萬美元主要是基於與歐洲報銷協議相關的一次性調整。

We also continued to manage and prioritize our operating expenses. Our first quarter 2017 non-GAAP combined R&D and SG&A expenses were $313 million compared to $306 million in the first quarter of 2016 and compared to $295 million in the fourth quarter of 2016.

我們也繼續管理和優先安排營運支出。2017 年第一季非 GAAP 合併研發及銷售、一般及行政費用為 3.13 億美元，而 2016 年第一季為 3.06 億美元，2016 年第四季為 2.95 億美元。

This revenue and expense profile resulted in a non-GAAP net profit for the first quarter 2017 of $101 million or $0.41 per diluted share compared to a non-GAAP net profit of $22 million or $0.09 per diluted share for the first quarter of 2016 and compared to non-GAAP net profit of $88 million or $0.35 per diluted share in the fourth quarter of 2016.

根據此收入和支出情況，2017 年第一季非 GAAP 淨利為 1.01 億美元，即每股攤薄收益 0.41 美元，而 2016 年第一季非 GAAP 淨利為 2,200 萬美元，即每股攤薄收益 0.09 美元，2016 年第一季非 GAAP 淨收益為每股 803 萬美元，即每股盈餘為 803 萬淨利潤。

The significant growth in the net profit was largely driven by the strong growth in product revenues, while prioritizing and managing operating expenses.

淨利潤的顯著成長主要得益於產品收入的強勁成長，同時優先考慮並控制了營運費用。

From a balance sheet perspective, we ended the first quarter with approximately $1.4 billion in cash, cash equivalents and marketable securities. During the quarter, we received an upfront cash payment from Merck KGaA related to an out-licensing of our oncology portfolio. We also chose to repay $300 million that was outstanding under our revolving credit facility. Our financial position gives us significant flexibility to reinvest into the business to support our future growth.

從資產負債表的角度來看，我們第一季末擁有約 14 億美元的現金、現金等價物和有價證券。本季度，我們收到了默克集團 (Merck KGaA) 支付的一筆預付現金，這筆款項與我們腫瘤產品組合的對外授權有關。我們也選擇償還循環信貸額度下未償還的 3 億美元。我們良好的財務狀況使我們擁有相當大的靈活性，可以對業務進行再投資，以支持未來的成長。

Now turning to our full year guidance. For ORKAMBI, we continue to expect $1.1 billion to $1.3 billion in net product revenues. Where we land in this revenue range will be determined by the continued uptake and compliance of ORKAMBI in markets where it's been reimbursed as well as the completion of reimbursement agreements in individual countries within Europe. In particular, if we succeed in gaining reimbursements in France in 2017, this would be the major contributor to revenue growth this year.

現在來看看我們全年的業績預期。對於 ORKAMBI，我們仍然預計其淨產品收入為 11 億美元至 13 億美元。我們最終的收入將取決於 ORKAMBI 在已獲得報銷的市場中的持續普及和合規情況，以及歐洲各國報銷協議的完成情況。特別是，如果我們在 2017 年成功在法國獲得報銷，這將是今年營收成長的主要貢獻者。

After KALYDECO, we are increasing our full year guidance and now expect $710 million to $730 million in net product revenues due to the onetime reimbursement adjustments recognized in the first quarter and the strong underlying demand for the medicine.

繼 KALYDECO 之後，我們提高了全年業績預期，目前預計淨產品收入將達到 7.1 億美元至 7.3 億美元，這得益於第一季度確認的一次性報銷調整以及該藥物強勁的潛在需求。

Lastly, we continue to expect combined non-GAAP R&D and SG&A expenses of $1.25 billion to $1.3 billion for 2017, as we guided to earlier this year. This guidance reflects the rapid progression of our CF clinical development programs and the ongoing global launch of ORKAMBI. We do expect non-GAAP R&D and SG&A expenses to grow in the future quarters in 2017.

最後，我們仍然預期 2017 年非 GAAP 研發和銷售、管理及行政費用總計為 12.5 億至 13 億美元，與我們今年稍早的預期一致。該指南反映了我們 CF 臨床開發項目的快速進展以及 ORKAMBI 的持續全球上市。我們預計 2017 年未來幾季非 GAAP 研發及銷售、管理及行政費用將會成長。

Our goal is to increase the number of people eligible for and being treated with our medicines around the world. We expect this to result in significant long-term revenue growth, and we are committed to investing to create new medicines in other disease areas, while managing our operating expenses and delivering significant earnings growth.

我們的目標是增加世界各地符合資格並正在接受我們藥物治療的人數。我們預計這將帶來顯著的長期收入成長，我們致力於投資研發其他疾病領域的新藥，同時控制營運費用並實現顯著的獲利成長。

With that, I will open the line to questions.

接下來，我將開放提問環節。

(Operator Instructions) Our first question comes from the line of Phil Nadeau with Cowen and Company.

（操作說明）我們的第一個問題來自 Cowen and Company 的 Phil Nadeau。

Congratulations on the progress and the strong quarter. One question on the -- on what was disclosed in the press release moving one of the studies of the triple combo from 2-week dosing to 4-week dosing. Could you talk a little bit more about that decision? What were the data or analyses that you did to support the longer dosing? And what do you hope to achieve or demonstrate with it?

恭喜你們取得的進展和強勁的季度業績。關於新聞稿中披露的將三聯療法的一項研究從 2 週給藥週期改為 4 週給藥週期，有一個問題。能再詳細談談這個決定嗎？為了支持延長給藥時間，你們做了哪些數據或分析？你希望透過它達到什麼目的或展示什麼？

Phil, this is Jeff Leiden. I'll take that one. Maybe just to back up a little bit and remind you that we have 4 different triple regimen combos that are in clinical trials. We sort of think of them in 2 ways. VX-440 and VX-152 are the first wave. They're in Phase II trials. And as you know, those trials have 2 parts, both the het-min population and a homozygous population. And then the second wave is VX-659 and VX-445. And those are in Phase I trial, but the Phase I have a patient component as well. And before I answer your specific question, I would just say that we're very pleased with the progression of those, all 4 trials. They're all on time or actually a little ahead of schedule to deliver results for the first 3 in the second half of this year and the final one, VX-445, in the beginning of next year. With respect to VX-152 and your question now, the initial studies of VX-152, both parts, het-mins and homozygotes, were designed to be 2-week dosing studies. Based on the tolerability profile that we've seen so far, we've decided to extend the duration of the second trial, the homozygous trial, to 4 weeks. And the reason for that is it's just going to give us more patient information upon which to make the best decision about which one or several of these we're going to take forward into Phase III next year.

菲爾，我是傑夫‧萊頓。我選那個。也許需要稍微回顧一下，提醒您我們目前有 4 種不同的三聯療法組合正在進行臨床試驗。我們大致從兩個方面來看它們。VX-440 和 VX-152 是第一批。它們正處於二期臨床試驗階段。如您所知，這些試驗分為兩部分，分別是雜合子群體和純合子群體。第二波產品是 VX-659 和 VX-445。這些藥物目前處於 I 期試驗階段，但 I 期試驗也包含患者參與部分。在我回答你的具體問題之前，我想說我們對這 4 項試驗的進展都非常滿意。他們都按時或提前完成了計劃，前 3 個項目將於今年下半年交付成果，最後一個項目 VX-445 將於明年年初交付成果。關於 VX-152 和您現在的問題，VX-152 的最初研究，包括雜合子和純合子，都設計為 2 週的給藥研究。根據我們目前所看到的耐受性情況，我們決定將第二次試驗（純合子試驗）的持續時間延長至 4 週。原因在於，這將為我們提供更多患者信息，以便我們能夠做出最佳決定，確定明年我們將把其中一項或幾項研究推進到 III 期臨床試驗。

Got it. And one question we get about those Phase II trials is your plans for the Concert molecule? And then can you talk about your decision process there? How likely are you to move forward with ivacaftor/tezacaftor versus the Concert molecule in combination with tezacaftor?

知道了。我們經常被問到關於 II 期試驗的一個問題是：您對 Concert 分子有什麼計劃？那麼，您能談談您的決策過程嗎？您認為 ivacaftor/tezacaftor 合併治療與 Concert 分子合併 tezacaftor 治療的可能性有多大？

Yes. So our first priority is to get an excellent efficacy and tolerability regimen for patients who -- particularly het-mins, who have nothing today. In fact the BID regimen, everything that we've learned from those patients says that it will be well accepted because as you know those patients take many, many pills, 20 to 40 pills a day often. On the other hand, our ultimate goal is to get a highly effective and tolerable regimen that's once a day. And the good news there is that both VX-659 and VX-445 we believe are once-a-day regimens. We know that VX-661 is a once-a-day regimen. KALYDECO is a twice-a-day regimen, and so the impetus to acquire the deuterated KALYDECO from Concert was it's a once-a-day regimen, and we'd be able to combine it with VX-661 and either 659 or 445 to get a once-a-day, highly tolerable and highly efficacious regimen.

是的。因此，我們的首要任務是為患者（尤其是目前沒有任何治療方案的異質性低血壓患者）制定一個療效和耐受性都很好的治療方案。事實上，我們從這些患者身上學到的一切都表明，BID 方案將會被廣泛接受，因為正如你所知，這些患者經常一天要服用很多很多藥片，20 到 40 片。另一方面，我們的最終目標是獲得一種高效且耐受性良好的每日一次的治療方案。好消息是，我們認為 VX-659 和 VX-445 都是每日一次的用藥方案。我們知道 VX-661 是每天服用一次的方案。KALYDECO 是一種一天兩次的治療方案，因此我們從 Concert 公司購買氘代 KALYDECO 的動力在於它是一種一天一次的治療方案，我們可以將其與 VX-661 以及 659 或 445 結合使用，從而獲得一種一天一次、耐受性高且療效顯著的治療方案。

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

我們的下一個問題來自高盛的 Terence Flynn。

I was just wondering, a follow-up on the triple combos. Maybe can you talk about your disclosure plans? Will you plan to release those as a group? Or will they come in -- come out as they come in? And then regarding the ongoing Phase III trial of tezacaftor and KALYDECO and the F508del plus gating patients, can you remind us of the design there and what you're hoping to see?

我只是想問一下，關於三連擊的後續情況。您能否談談您的資訊揭露計畫？你們打算把這些作品當作一個整體來發布嗎？還是他們會進來，然後像進來一樣出來？關於正在進行的 tezacaftor 和 KALYDECO 的 III 期試驗以及 F508del 加門控患者，您能否提醒我們該試驗的設計以及您希望看到的結果？

Thanks for the question. I'll take the first part, the disclosure question. As we've done in the past, obviously, you're asking the question about future disclosures. I think our plan at this point would be to let the studies play out. We'll have a better visibility of the timing of the data coming from each of the studies in a couple of months from now, and I think at that point in time, we'll have a better understanding of how the data will roll out. Our intention actually is to provide you with a top line release probably in the form of a press release as usual and safety and efficacy data because these studies now are including patients with safety and efficacy data. And the data supports what the next steps are for each of the compounds in the triple combinations.

謝謝你的提問。我先回答第一部分，即資訊揭露問題。正如我們過去所做的那樣，顯然，您正在詢問有關未來披露的問題。我認為我們目前的計劃是讓研究結果自行揭曉。再過幾個月，我們就能更清楚地了解每項研究的數據發佈時間，我認為到那時，我們就能更了解數據將如何發布。我們的實際目的是向您提供一份概要信息，可能像往常一樣以新聞稿的形式發布，並提供安全性和有效性數據，因為這些研究現在包括了具有安全性和有效性數據的患者。數據也支持了三元組合中每種化合物的下一步研究方向。

And Terence, this is Jeff again. On your question on the gating -- [on the] gating F508 trial. Just to remind you, this is really the follow-up Phase III program to the Phase II results we've already published that showed in our case about a 4.6% additional increase in FEV1 when you add tezacaftor and ivacaftor in these patients. This obviously is a larger trial, more than 100 patients. It's an 8-week trial. The control is ivacaftor monotherapy versus tez/iva. We're completing enrollment of that trial, and we expect to have the results in the second half of this year. Based on those results, we'll decide the regulatory strategy. It's a little too early to tell until we see what the results are, and it could be a different regulatory strategy in the U.S. and in Europe, as you can imagine.

特倫斯，我是傑夫。關於您提出的關於 F508 試驗的准入問題。提醒一下，這實際上是我們已發表的 II 期結果的後續 III 期項目，II 期結果顯示，在我們的病例中，當在這些患者中添加 tezacaftor 和 ivacaftor 時，FEV1 額外增加了約 4.6%。這顯然是一項規模更大的試驗，涉及超過 100 名患者。這是一項為期 8 週的試驗。對照組為伊伐卡托單藥治療與替扎尼定/伊伐卡托合併治療。我們正在完成試驗的受試者招募工作，預計今年下半年將獲得結果。我們將根據這些結果來決定監管策略。現在下結論還太早，要等到結果出來才行。而且，正如你所想，美國和歐洲的監管策略可能會有所不同。

And our next question comes from the line of Matthew Harrison from Morgan Stanley.

下一個問題來自摩根士丹利的馬修·哈里森。

So I have another follow-up on the triple, I guess 2 pieces. So first, should we infer from your comments that you saw better tolerability than you were expecting and that's what allowed you to increase from 2 weeks to 4 weeks? And then why only extend to 4 weeks in the homozygous arm as opposed to both the homo and heterozygote arm?

所以，關於三重奏，我還有後續，我想應該是兩個部分。首先，我們是否可以從你的評論中推斷出，你的耐受性比預期的要好，因此你才將療程從 2 週延長到 4 週？那麼，為什麼只在純合子組中延長至 4 週，而不是在純合子組和雜合子組中都延長？

Yes, thanks for the question. So I think I would say this sort of the way I said it before, which is based on the tolerability that we've seen we felt comfortable extending to 4 weeks. It's a little -- whether that better or same, that's sort of a speculation. We have solid data, and so we're comfortable extending to 4 weeks. And in terms of why only one, it's just a matter of we really would like to see 4-week results if we can with several of these so that we can compare them directly. I'm not sure we need to do that in every population, and so we just decided on that particular population for this study.

是的，謝謝你的提問。所以我想我會像之前那樣說，基於我們看到的耐受性，我們覺得可以放心地延長至 4 週。這有點……至於更好還是一樣，這只能說是猜測。我們有可靠的數據，因此我們認為延長至 4 週是合理的。至於為什麼只選一個，是因為我們真的很想看到幾個這樣的樣本在 4 週後的結果，這樣我們就可以直接比較它們。我不確定我們是否需要對每個群體進行這樣的研究，所以我們決定只針對這個特定群體進行研究。

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。

Also another triple question. Obviously, 440 and 152 are ahead in terms of the development. But assuming those look good, is -- we just want to know what's the thought process? Would you wait for de-risking data on 659 or 445 combos before you think about a pivotal? Or just what's the decision factor there? And I have a commercial follow-up.

還有一道三重問題。顯然，440 和 152 在發展方面處於領先地位。但假設這些看起來不錯，我們只是想知道背後的思考過程是什麼？在考慮關鍵指標之前，你會等待 659 或 445 種組合的去風險資料嗎？或者說，決定性因素究竟是什麼？我還有一個商業後續專案。

Sure. So first of all, we're thinking about the triple Phase III designs right now. So we're certainly not waiting even until we have data, Jeff. But the good news is because these trials are proceeding nicely, and in fact some of them ahead of schedule, we're going to have data from these -- at least the first 3 in a relatively short time frame, and the exact decision is going to be based on that data, obviously. It just depends on what we see in terms of making a decision to pull the trigger on one or more of these compounds. But I don't -- what I'm really trying to communicate to you is I don't think even in a case in which we wanted to wait, we're going to keep waiting very long because we're going to have the data in a relatively tight time frame, on at least 3 and maybe all 4 of the programs. And based on that data, we'll be able to make a good decision, I think, on taking one or more of them forward.

當然。首先，我們目前正在考慮三相 III 設計。所以，傑夫，我們肯定不會等到有了數據才行動。但好消息是，由於這些試驗進展順利，事實上其中一些試驗甚至提前完成，我們將在相對較短的時間內獲得這些試驗的數據——至少前 3 個試驗的數據，而最終的決定顯然將基於這些數據。這完全取決於我們觀察到的情況，然後再決定是否對其中一種或多種化合物進行投資。但我並不——我真正想傳達給你們的是，我認為即使在我們想要等待的情況下，我們也不會一直等下去，因為我們將在相對較短的時間內獲得數據，至少 3 個，甚至可能是全部 4 個項目。我認為，根據這些數據，我們將能夠做出一個好的決定，決定是否要推進其中一項或多項計畫。

I got you. Okay. And just on ORKAMBI, I know it's hard to say, you guys reiterated for the year. Is there -- are there any sort of gating factors that you're thinking about in terms of France or other countries that are going to contribute to the year? In other words, as the year moves on, are you guys going to update us on the process? Or is it more or less just this is the revenue guidance for the calendar '17?

我接到你了。好的。還有 ORKAMBI，我知​​道這很難說出口，但你們今年再次重申了這一點。您是否考慮過法國或其他將對今年做出貢獻的國家有任何限制因素？換句話說，隨著時間的推移，你們會向我們報告進度嗎？或者說，這基本上只是對 2017 年的收入預期？

So Jeff, thanks for the question. Yes, we did reiterate our guidance, $1.1 billion to $1.3 billion. We understand we had a good first quarter with ORKAMBI. A lot of that was actually driven by faster penetration into the 6 to 11 category in the U.S. And so with the first quarter behind us, we are looking at that guidance, and we're between $1.1 billion and $1.3 billion. But there's still uncertainty as we play out the year on top of what we've already recorded in the first quarter or the run rate coming out of the first quarter. And that does mainly relate to timing of reimbursements in Europe, and the major contributor outside of the U.S. would actually be France. And as you are aware, there is a lot of uncertainty in France. One is the political environment over there at this point. They're going through an election. And then also, it's an unusual markets in that the patients in France are already on drug, and we already receive cash for them, so we don't have this huge advocacy pull to get reimbursement for the drug to ensure that the patients can then receive the drug. So it's an unusual market. It is probably the largest contributor outside the U.S. for the 2017 revenues, but there is still significant uncertainty surrounding it, while we continue to collect the cash. So we felt comfortable keeping our guidance at $1.1 billion to $1.3 billion.

傑夫，謝謝你的提問。是的，我們重申了我們的預期，即 11 億美元至 13 億美元。我們知道，ORKAMBI 的第一個季度業績不錯。實際上，這很大程度上是由於美國市場對 6 至 11 歲年齡層產品的快速滲透所致。因此，隨著第一季的結束，我們正在審視這一預期，預計營收將在 11 億美元至 13 億美元之間。但是，隨著我們繼續推進這一年，除了第一季已經取得的成績或第一季的運行率之外，仍然存在不確定性。這主要與歐洲的報銷時間有關，而美國以外最大的貢獻者實際上是法國。如您所知，法國目前存在許多不確定因素。一是目前那裡的政治環境。他們正在進行選舉。此外，法國的市場也很特殊，因為法國的患者已經在服用這種藥物，我們也已經收到了現金，所以我們沒有強大的遊說力量去爭取藥物報銷，以確保患者能夠獲得這種藥物。所以這是一個不尋常的市場。它可能是 2017 年美國以外最大的收入來源，但圍繞它仍然存在很大的不確定性，因為我們仍在繼續收取現金。因此，我們認為維持11億至13億美元的預期不變是合理的。

And our next question comes from the line of Geoffrey Porges with Leerink Partners.

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

So just to follow up on the question about the European reimbursement. Ian, could you talk a little bit more about if various parts of the U.K. and Benelux for ORKAMBI because they could certainly move the needle. Are they in your plan for this year? Or is that something we should expect for next year? And then if Stuart's available, love to hear where you are in terms of the uptake and the ongoing adoption in the 6 to 11-year-olds in the U.S. and whether that's a template that we could look for in other markets over time.

那麼，我再跟進一下關於歐洲報銷的問題。伊恩，你能再多談談 ORKAMBI 在英國和比荷盧經濟聯盟的各個地區的情況嗎？因為他們肯定會對市場產生影響。它們在你今年的計劃之內嗎？或者這是我們明年應該期待的事？如果 Stuart 有空的話，我很想了解在美國 6 至 11 歲兒童中，這種產品的接受度和持續普及情況如何，以及這是否可以作為我們未來在其他市場借鑒的模板。

So I'll just take the front end of that, Geoff, and then Stuart is here, and Stuart can take the rest of the question. But I would just say the guidance that we gave of $1.1 billion to $1.3 billion does assume that we gain approval in certain markets, and they tend to be the smaller ones, and they also tend to be more impactful in the second half of the year. As of now, when we look at -- I'll just point out, when we look at Q2 for 2017, we actually see it to be very similar to Q1. But these other markets, even the smaller ones, we anticipate come on in the -- more in the second half of the year and contribute then, certainly France, as I just mentioned. But even the smaller markets as well, the ones you mentioned. And maybe Stuart could give commentary around those markets.

所以我先回答前面的部分，傑夫，然後史都華來了，史都華可以回答剩下的部分。但我只想說，我們給出的 11 億至 13 億美元的預期是基於我們在某些​​市場獲得批准的前提，而這些市場往往規模較小，而且它們在下半年的影響也往往更大。截至目前，當我們查看——我只想指出，當我們查看 2017 年第二季度時，我們發現它實際上與第一季非常相似。但是，我們預期其他市場，即使是較小的市場，也會在今年下半年有所成長，並做出貢獻，當然，法國就是一個例子，正如我剛才提到的。但即使是較小的市場，例如你提到的那些市場也是如此。或許史都華可以對這些市場發表一些評論。

Yes. So as Ian said, the guidance incorporates the kind of range of possibilities because we can't be absolutely certain which countries we're going to reach agreements with and when. Certainly, we're pleased that we are beginning to see countries now strike pricing and reimbursement agreements with us. Obviously, Germany and Austria are already kind of online. We've added Denmark in the last few weeks, and we have an agreement in principle in Ireland. But as Ian said, those aren't really going to kick in, in terms of generating additional patients and therefore revenue until the second half. Discussions are then ongoing in those other markets that you mentioned like the Belgium, The Netherlands and the U.K., which is a particularly complicated market, not just because of the political situation there. But unlike many of these other countries, it doesn't really have a formal process that we can participate in to take it forward. And so we're really trying to develop with them a kind of bespoke process for ORKAMBI. In terms of the 6 to 11 launch, Geoff, which is the second part of your question, the launch is going well here in the U.S., as Ian referred to in his prepared remarks. The vast majority of the growth we saw between Q4 and Q1 was as a result of that 6 to 11 launch here in the U.S. And the launch trajectory in terms of uptake is very similar to the ORKAMBI launch, but we're also benefiting from what we expected, which is higher persistence and higher levels of compliance than we saw in the 12-plus population. And partly that's due to the profile of the drug in the 6 to 11 population that we saw in the clinical trials, and partly that's due to the fact that, not surprisingly, these patients are managed to a large extent by their parents in terms of compliance. So that's really how the launch dynamics are going for 6 to 11 here in the U.S.

是的。正如伊恩所說，該指導包含了各種可能性，因為我們無法完全確定我們將與哪些國家達成協議以及何時達成協議。當然，我們很高興看到一些國家開始與我們達成定價和報銷協議。顯然，德國和奧地利已經算是半聯網國家了。過去幾週我們新增了丹麥，並且與愛爾蘭也達成了原則協議。但正如伊恩所說，這些措施要到下半年才會真正發揮作用，帶來更多病患和收入。目前，您提到的其他市場，如比利時、荷蘭和英國，也正在進行相關討論。英國市場尤其複雜，不僅是因為那裡的政治局勢。但與其他許多國家不同，它並沒有一個我們可以參與的正式程序來推進此事。因此，我們正在努力與他們一起為 ORKAMBI 開發一種客製化流程。關於 6 點到 11 點的發射，Geoff，也就是你問題的第二部分，正如 Ian 在他準備好的發言稿中提到的那樣，發射在美國進行得很順利。第四季到第一季之間我們看到的大部分成長都歸功於美國 6 至 11 歲族群的推廣。就接受度而言，該推廣的軌跡與 ORKAMBI 的推廣非常相似，但我們也受益於我們預期的結果，即比 12 歲以上人群更高的堅持率和更高的依從性。部分原因是由於我們在臨床試驗中觀察到的 6 至 11 歲人群中該藥物的特性，部分原因是，不出所料，這些患者在很大程度上是由他們的父母負責管理其用藥依從性。所以，這就是美國6點到11點檔電影的發行動態。

You asked specifically was U.K. in our guidance for ORKAMBI for the year, and the answer is no.

您特別詢問英國是否在我們今年的 ORKAMBI 指導方針中，答案是否定的。

And 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。

My first question is actually on KALYDECO. Curious about the trends there. I mean, if the product is generally fully penetrated, how -- where is the bump in guidance coming from with regards to the strong underlying demand? And then I have a follow-up bigger picture question.

我的第一個問題其實是關於 KALYDECO 的。很好奇那裡的發展趨勢。我的意思是，如果產品已經基本完全滲透，那麼強勁的潛在需求又從何而來，業績指引的提升又從何而來呢？然後我還有一個更宏觀的問題。

So thanks for the question. I'll just walk you through kind of the math as to how we think about it and why we did increase the guidance. Obviously, we just recorded $186 million in the first quarter. There was some onetime items in there related to the settlement of contracts, and that's around $7 million or $8 million. But if you were to remove that amount out of the $186 million and then just say that's the run rate and multiply it by 4 and then add in the $6 million or $7 million, you're actually at $720 million. And so we decided to move the range up. We were once at $690 million to $710 million. So, obviously, even at our run rates plus the strong first quarter, we're above that guidance, so we moved it up, and we put a band around it. Because if there is better compliance and persistence, we have -- which we already have strong compliance and persistence, there may be a little upside. And if we have less compliance and persistence, maybe a little downside. So it was really a function of the math of the first quarter that puts you at $720 million, and we just put the guidance around $720 million, being $710 million to $730 million.

謝謝你的提問。我來給你解釋一下我們是如何考慮這個問題的，以及為什麼我們增加了指導。顯然，我們第一季就錄得了1.86億美元的收入。其中有一些與合約結算相關的一次性項目，金額約為 700 萬至 800 萬美元。但是，如果你從 1.86 億美元中減去這筆金額，然後假設這就是運行速度，再乘以 4，再加上 600 萬或 700 萬美元，實際上就是 7.2 億美元。因此，我們決定提高產品範圍。我們曾經達到 6.9 億美元到 7.1 億美元。所以，很顯然，即使按照我們目前的運行速度加上強勁的第一季業績，我們也超過了預期，所以我們提高了預期，並設定了一個區間。因為如果能提高合規性和堅持性，而我們目前已經具備很強的合規性和堅持性，那麼可能會有一些提升空間。如果服從性和堅持性降低，可能會有一些負面影響。所以，這其實是第一季的數學計算結果，讓收入達到 7.2 億美元，而我們給出的指導意見也正是 7.2 億美元左右，介於 7.1 億美元至 7.3 億美元之間。

Okay. Understood. And then bigger picture BD question. And now that you've out-licensed the oncology assets, I'm curious about your latest thoughts with regard to diversifying the business beyond CF? And kind of how do you prioritize building outside of that core competency versus continuing to build that fence around that vertical like your recent Concert deal?

好的。明白了。然後是更宏觀的BD問題。既然你們已經將腫瘤業務資產授權出去了，我很想知道你們對於將業務多元化拓展到囊性纖維化以外的領域有什麼最新想法？那麼，你如何權衡在核心競爭力之外進行業務拓展，而不是繼續圍繞核心業務領域（例如你最近與 Concert 達成的交易）構建壁壘呢？

Great question, Cory, and a very timely question. So I'll answer the second part of it first. This is Jeff. There's no higher priority here than executing on our CF strategy. We're obviously making great progress there in pretty much all respects, and we're not going to take our foot off the gas. We're going to put our foot down on the gas. We really believe now we're well in sight of being able to find one or more triple combinations that's going to allow us to treat 80% to 90% of all patients. That's clearly priority #1 for the entire organization, as well as for the BD organization, by the way. If we did see anything else out there that was complementary and that we think would make better a regimen, we would certainly be interested in it. However, we also are getting much closer to the end, again, really in CF, we believe. And so it's a great time, and we have started thinking quite a bit over the last even year or so about what's next in CF. And so let me answer it from a strategic standpoint, and then I'll let Ian it answer maybe from a more specific BD standpoint. So strategically, as you know, we've for a number of years now talk about the CF experience as being a model for what we want to do; meaning high unmet medical need, potentially transformative therapies where there are no therapies and specialty markets that have very low SG&A expend requirements, which allow us then to funnel most of our revenue, or OpEx anyway, into R&D and new diseases. And that's exactly the kinds of disease we're looking for whether it's internal investments or external investments for what's after CF. And I think as you know, David Altshuler joined us several years ago. He's spent a lot of time, I would say, tailoring our portfolio of internal research to diseases like that. And there are diseases like that we've talked about like sickle cell disease, Alpha-1 antitrypsin disease, adrenoleukodystrophy. They all look and smell a lot like CF in a whole variety of respects. And I think that's what you can expect our internal portfolio to look like, and we have a number of those programs that we haven't talked about as well. And the other part of the tail end of the portfolio has been that we've out-licensed several assets that didn't fit that strategy, so you saw us out-license our flu asset, which was a really interesting drug but a community drug, to J&J, and you saw as out-license recently our oncology portfolio. Again, some really interesting transformative assets that didn't really fit our commercial and development strategy. So I'm pleased with where the internal portfolio is now and our investments in the internal portfolio, but we've also, obviously, recognized that like most companies at our size and stage we're going to have to supplement our internal portfolio, as good as it is, with some external assets as well, and you've seen us starting to do that. I think the good news is as our financial situation has strengthened considerably and our cash accumulation has strengthened and will strengthen it gives us that much more firepower to go out and acquire other programs and assets to complement our internal portfolio. You're not going to see us go out and acquire revenues, products with revenues in 2018 and '19. We don't need to. But maybe I'll turn it over there to Ian to describe again our BD strategy, with the only change over time being that we have more firepower to execute that strategy.

科里，你問得好，而且問得非常及時。那我先回答第二部分。這是傑夫。目前最重要的事莫過於執行我們的CF策略。顯然，我們在幾乎所有方面都取得了巨大進展，我們不會放鬆努力。我們要全力以赴了。我們現在真的相信，我們很有可能找到一種或多種三重療法，使我們能夠治療 80% 到 90% 的患者。顯然，這對整個組織以及業務拓展部門來說，都是頭等大事。如果我們發現有其他互補的產品，並且我們認為可以改進治療方案，我們肯定會對此感興趣。然而，我們也越來越接近終點了，尤其是在 CF 領域，我們相信。所以現在正是時候，在過去一年左右的時間裡，我們已經開始認真思考 CF 的下一步發展方向。那麼，讓我從策略角度來回答這個問題，然後我會讓伊恩從更具體的業務拓展角度來回答。因此，如您所知，多年來，我們在策略上一直將囊性纖維化 (CF) 的經驗視為我們想要做的事情的典範；這意味著巨大的未滿足醫療需求、潛在的變革性療法（目前尚無療法）以及銷售、管理及行政費用要求非常低的專業市場，這使我們能夠將大部分收入（或者說運營支出）投入到研發和新疾病中。而這正是我們正在尋找的疾病類型，無論是針對囊性纖維化後的內部投資或外部投資。我想你們也知道，大衛‧阿爾特舒勒幾年前加入了我們。我認為他花了很多時間，調整我們的內部研究組合，使其能夠針對這類疾病進行研究。我們之前也討論過一些類似的疾病，像是鐮狀細胞疾病、α-1抗胰蛋白酶缺乏症、腎上腺腦白質營養不良症。它們在很多方面看起來和聞起來都很像 CF。我認為這就是你們可以預期我們的內部投資組合的樣子，而且我們還有一些項目還沒有談到。投資組合尾部的另一部分是，我們對外授權了一些不符合該策略的資產，例如，我們將流感資產（一種非常有趣的藥物，但屬於社區藥物）授權給了強生公司，最近我們也對外授權了我們的腫瘤產品組合。再次強調，有一些非常有趣且具有變革意義的資產，但它們並不適合我們的商業和發展策略。因此，我對目前的內部投資組合以及我們在內部投資組合中的投資感到滿意，但顯然我們也意識到，像大多數與我們規模和發展階段相同的公司一樣，我們必須用一些外部資產來補充我們現有的內部投資組合，儘管它已經很好了，你們也已經看到我們開始這樣做了。我認為好消息是，隨著我們的財務狀況大幅改善，現金累積也日益增強，並將繼續增強，這給了我們更大的實力去收購其他項目和資產，以補充我們的內部投資組合。你們不會看到我們在 2018 年和 2019 年出去收購有收入的產品。我們不需要這樣做。但也許我會把麥克風交給伊恩，讓他再次描述我們的業務拓展策略，隨著時間的推移，唯一的變化是我們擁有了更多執行該策略的實力。

Thank you. I actually don't have too much to add when it come down to the -- Jeff has said it many times on this call, the #1 strategy is look at everything in CF that complements our approach in CF. Number 2 is continue to think about adding new platforms and different modalities that gives us opportunity in other diseases that Jeff was describing. And then #3 is how do we just continue to expand our pipeline. And to Jeff's point, today we have $1.4 billion of cash. We don't have debt. We do have a revolver facility but we -- with $800 million, but we haven't drawn anything down on it. So we have significant financial capability to continue to invest in areas that would be consistently with where Vertex is focused.

謝謝。其實我沒什麼要補充的——傑夫在這次電話會議上已經多次說過，最重要的策略是關注CF中所有能與我們CF方法互補的東西。第二點是繼續思考如何增加新的平台和不同的治療方式，這為我們治療傑夫所描述的其他疾病提供了機會。第三點是，我們如何繼續擴大我們的產品線。正如傑夫所說，我們現在擁有 14 億美元的現金。我們沒有債務。我們確實有一個循環信貸額度，裡面有 8 億美元，但我們還沒有動用任何資金。因此，我們擁有雄厚的財力，可以繼續投資於與 Vertex 關注領域一致的領域。

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。

Can you talk about the U.S. versus ex U.S. revenue breakdown this quarter?

能否談談本季美國本土及美國以外地區的營收組成？

Yes, Ying. So for ORKAMBI, of the $295 million in total, the U.S. accounted for $264 million. And x U.S. was the balance, $31 million. For KALYDECO, of the $186 million, we recorded $102 million of that was in the U.S. and $84 million was x U.S.

是的，穎。因此，在 ORKAMBI 的 2.95 億美元總額中，美國貢獻了 2.64 億美元。剩餘部分為 x 美國，3100 萬美元。對 KALYDECO 而言，在 1.86 億美元的收入中，我們記錄到 1.02 億美元來自美國，8,400 萬美元來自其他國家。

And then also you've mentioned that you just reached reimbursement agreement in Denmark and also in Ireland in principle. Can you talk about roughly are they close to what the pricing you've got from Germany?

而且您也提到，您剛剛在丹麥和愛爾蘭原則上達成了報銷協議。您能大概說說它們和您從德國得到的價格接近嗎？

Yes, thanks for the question. Yes. So we're delighted that we are reaching increasing numbers of pricing and reimbursement agreements. Denmark is one. We have an agreement in principle, as you said, in Ireland, and we're really pleased that these are coming through and the patients in these countries are now going to have access to the product, which will begin to contribute in the second half. In terms of specifically commenting on pricing, we, obviously, can't do that. These are confidential agreements between us and the relevant authorities, and so we can't comment on the specific prices.

是的，謝謝你的提問。是的。因此，我們很高興能夠達成越來越多的定價和報銷協議。丹麥是其中之一。正如您所說，我們在愛爾蘭已經達成了一項原則性協議，我們非常高興這些協議能夠落實，這些國家的患者現在將能夠獲得該產品，這將在下半年開始發揮作用。至於具體評論價格問題，我們顯然不能這麼做。這些是我們與相關部門之間的保密協議，因此我們無法對具體價格發表評論。

And maybe, Ying, it may be an opportunity to talk about how we think about guidance going forward that -- talking about the price that we're getting, obviously, would be confidential, to Stuart's point. And so we are thinking more about helping you understand the revenue line by providing you guidance for a product. But then as we look into the future, obviously, we have the potential now to create more medicines that patients that may be on KALYDECO may move onto teza and iva, and those patients that once were on ORKAMBI may also move on teza/iva. So we're starting to think about how to help you understand our revenue trajectory. And a lot of the things that we're discussing here, obviously, we'll get some feedback from The Street as well. But what we're thinking about here is providing you kind of total CF revenues. So at the end of the day, our objective here is to use all the medicines to treat as many patients as possible. And ultimately, that's what important is treating as many patients as possible, which will translate to a total CF product revenue line. And so we're giving this some thought about how we provide guidance in the future as well.

英，或許我們可以藉此機會談談我們對未來指導的看法——當然，談到我們得到的價格，正如斯圖爾特所說，顯然是保密的。因此，我們正在考慮如何透過提供產品指導來幫助您了解收入來源。但展望未來，顯然，我們現在有潛力研發出更多藥物，讓正在服用 KALYDECO 的患者轉而服用 teza 和 iva，而曾經服用 ORKAMBI 的患者也可能轉而服用 teza/iva。因此，我們開始思考如何幫助您了解我們的營收成長軌跡。顯然，我們在這裡討論的很多事情，也會從華爾街得到一些回饋。但我們在這裡考慮的是向您提供總的 CF 收入。所以歸根結底，我們的目標是利用所有藥物治療盡可能多的患者。最終，重要的是盡可能多地治療患者，這將轉化為 CF 產品線的總收入。因此，我們也正在思考未來如何提供指導。

And our last question comes from the line of Tony Butler with Guggenheim.

我們的最後一個問題來自托尼·巴特勒與古根漢的合作。

Jeff, 2, if I may. In clin trials, the size of the cohorts for 440 were vastly different from that of 152. And I'm just curious that as you roll out the press release later in the second half, will there be sufficient patients to actually make a judgment -- for us to make a judgment between the 2 different molecules in the triple and more importantly, whether or not there is comparative activity in het-min as well as in the homozygous cohorts? And the second question is very simply, does teza bind at the same site as luma?

傑夫，2歲，如果可以的話。在臨床試驗中，440 位受試者的隊列規模與 152 位受試者的隊列規模截然不同。我很好奇，當您在下半年稍後發布新聞稿時，是否有足夠的患者來做出判斷——讓我們能夠對三聯療法中的兩種不同分子做出判斷，更重要的是，在雜合子和純合子群體中是否存在相對活性？第二個問題很簡單，teza 是否與 luma 結合在同一個位點？

Yes, so let me answer both of those. So first of all, with respect to the size of trial, it may be a little misleading in terms of what you're looking at on clinicaltrials.gov because you want -- the 440 trial actually has 3 parts to it. The first part, Part A and Part B, are the initial smaller trials, 40 patients het-min and 25 patients homozygotes. Part C is a 12-week trial with 130 patients. That's what's contributing to the big patient number that you're seeing there. But Part A and B are the parts that we'll be making the decisions on with the data this year. And those are actually quite similar to 152. 152 has 35 patients in Part A and about the same number, maybe slightly smaller, in Part B. And so, in fact, we will have an apples-to-apples comparison. We chose the size of those trials based upon how all the experience that we've had in Phase II trials, which is now many, many Phase II trials with the [CFTR] modulators. And as you know, if you go back and you look at those trials, this kind of size of trial with 20 to 35 patients each has been very, very informative, and every case essentially predicted the Phase III result almost precisely. So we do have a high level of confidence that we're going to be able to compare these and make decisions based on these trial sizes. 659 is slightly smaller. It's one cohort of patient. And 445, again, is slightly bigger. But even there, we think we're going to get pretty good reads to be able to make good decisions about which ones to take forward.

是的，那我就來回答這兩個問題。首先，就試驗規模而言，你在 clinicaltrials.gov 上看到的內容可能會有點誤導，因為你想看到的——440 試驗實際上有 3 個部分。第一部分，A 部分和 B 部分，是最初的小規模試驗，包括 40 名雜合子患者和 25 名純合子患者。C 部分是一項為期 12 週的試驗，共有 130 名患者參與。這就是導致那裡患者數量龐大的原因。但今年我們將根據數據對 A 部分和 B 部分做出決定。實際上，它們與 152 非常相似。152號樣本A部分有35名患者，B部分患者人數大致相同，可能略少。因此，實際上，我們將進行公平的比較。我們根據我們在 II 期試驗中累積的所有經驗來選擇這些試驗的規模，目前我們已經進行了許多 II 期試驗，涉及 [CFTR] 調節劑。如您所知，如果您回顧這些試驗，您會發現這種規模的試驗（每例有 20 至 35 名患者）非常具有啟發性，而且每個病例基本上都幾乎準確地預測了 III 期試驗的結果。因此，我們非常有信心能夠對這些試驗規模進行比較，並根據這些試驗規模做出決策。659 略小一些。這是一組患者。而 445 又略大。但即便如此，我們認為我們也能獲得相當不錯的讀數，能夠對哪些項目值得推進做出正確的決定。

That's helpful. And again teza binds to the same site as luma?

那很有幫助。teza 再次與 luma 結合在同一個位點？

Yes. Thanks for asking again. Teza and luma do bind to the same site. They have the same, we believe, the same mechanism of action.

是的。謝謝你再次提問。Teza 和 luma 確實與同一位點結合。我們認為，它們具有相同的作用機制。

Our next question comes from the line of Liisa Bayko with JMP Securities.

我們的下一個問題來自 JMP Securities 的 Liisa Bayko。

As you think about rolling out tezacaftor/ivacaftor and how will that interact with ORKAMBI? Would this be -- are you thinking about sort of phasing out ORKAMBI over time and a switch strategy? Or how should we think about the interaction of those 2?

您在考慮推出 tezacaftor/ivacaftor 時，以及它將如何與 ORKAMBI 互動？你是打算逐步淘汰 ORKAMBI，並採取相應的替代策略嗎？或者我們應該如何看待這兩者之間的互動？

Yes, Liisa. It's Stuart here. Great question, thanks. Obviously, we're very pleased with the data that we saw earlier this year from the tezacaftor/ivacaftor Phase III program. Clearly, the agent has a very positive benefit-risk profile. In terms of patient populations that we think are likely to be the most interested in it, if we start with the F508 homozygous population, we're really thinking there that -- as we know, there are a large number of patients wanted to be on the CFTR modulator like ORKAMBI but unfortunately weren't able to stay on the product often because of adverse events. We think that's going to a population of patients and their physicians who are likely to be very keen to try the lumacaftor/ivacaftor combination. We also know there's a number of patients who are naïve to therapy, have never tried ORKAMBI, and we think they also may think more favorably about the benefit-risk profile of tezacaftor/ivacaftor. So those populations would both be additional patients who might be taking a CFTR modulator. And really, that's likely to be our focus with tezacaftor/ivacaftor. If there are patients who are already on ORKAMBI and who are doing really very well, I think that's going to be a decision for the physician and the patient whether they want to consider transitioning to tezacaftor/ivacaftor. And then the second population, obviously, which would also be an additional population is the residual function population. And at present in both the U.S. and in the EU, those patients have no product which can treat the underlying cause of their disease. So that, again, would be an entirely new population. And that's why we say that tezacaftor/ivacaftor in addition to being the basis for the triple combination is a really important medicine in its own right because it's totally in line with our strategy of bringing medicines forward which allow us to treat more patients with CF.

是的，莉莎。我是史都華。問得好，謝謝。顯然，我們對今年稍早從 tezacaftor/ivacaftor III 期試驗計畫中獲得的數據感到非常滿意。顯然，該代理人的收益風險比非常高。就我們認為最有可能對此感興趣的患者群體而言，如果我們從 F508 純合子群體開始，我們確實認為——正如我們所知，有很多患者想要使用像 ORKAMBI 這樣的 CFTR 調節劑，但不幸的是，由於不良事件，他們往往無法繼續使用該產品。我們認為，這將會吸引一部分患者及其醫生，他們很可能非常渴望嘗試 lumacaftor/ivacaftor 組合療法。我們也知道，有很多患者以前從未接受過治療，也從未嘗試過 ORKAMBI，我們認為他們可能也會對 tezacaftor/ivacaftor 的獲益風險比持更積極的態度。因此，這兩類人群都可能是正在服用 CFTR 調節劑的患者。而這很可能就是我們對 tezacaftor/ivacaftor 的重點。如果有些患者已經在使用 ORKAMBI 並且病情控制得非常好，我認為這將是由醫生和患者共同決定是否考慮過渡到 tezacaftor/ivacaftor。然後，顯然，第二個群體，也就是額外的群體，是殘差函數群體。目前，無論是在美國還是在歐盟，這些患者都沒有任何產品可以治療其疾病的根本原因。所以，那又將是一個全新的群體。因此，我們認為 tezacaftor/ivacaftor 除了是三重療法的基礎之外，本身也是一種非常重要的藥物，因為它完全符合我們推進藥物研發的策略，使我們能夠治療更多的囊性纖維化患者。

Okay. Great. And then as we move to triple, are you thinking this is a kind of one-size-fits-all more or less across the majority of the CF patients where this would be applicable? Or do you think you might have still some doublets or different triple combinations for different populations?

好的。偉大的。那麼，當我們轉向三倍劑量時，您是否認為這對於大多數適用的囊性纖維化患者來說，是一種比較通用的方案？或者您認為不同人群中可能還存在一些二重體或不同的三重體組合？

This is Jeff. That's a -- it's a great question and an important one. And I think there's still not a full understanding of this. I do want to spend a minute because our thinking has changed honestly too as we've started to see this data. The most important fact to sort of ground the answer in is that 80% to 90% of all patients with CF have at least one Delta F508 allele. That is they're either 50% homozygous 508-508 or they're 508 with something else on the other allele. It could be a minimal function mutation, could be a gating mutation, it could be residual function mutation. So there's really only about 10% of all the patients who don't have at least one 508 allele. And the reason that's important is because what we are learning is -- and I hope we'll see this result when we see the triple data in the second half of this year, that we believe a triple from all of our cellular data will allow us to address all of those patients maximally. That is if you think about the homozygous population, we believe that a triple will be better than any double. That's what our cell data tells us. And if you look at the het-min population, we believe that the triple, obviously, will be better than the doubles or the singles because right now those don't work. And if you look at the residual functions or the gating patients, 90% of those patients will have Delta 508 on the other allele, so a triple will be better for them too. And so once you get to that sort of insight, you realize that actually where this whole field is moving is away from the monotherapies and dual therapies to a single optimal triple therapy that's highly effective and tolerable that's going to treat these 80% to 90% of patients. And the patients who are left who don't have a 508, they'll be a small number of patients, for example, who have a gating mutation on one allele but not 508 on the other allele. They could be treated with KALYDECO monotherapy, but we're talking very small numbers here. And then the final 10% of those patients who don't have a 508 allele at all or a KALYDECO-responsive allele, likely stop codons for the most part, and they're going to need a genetic therapy like gene editing or gene therapy. So we believe this is going to very rapidly transition over to a single triple for 80% to 90% of the patients, a few patients left for us on KALYDECO monotherapy who don't have 508. And then the remaining 10%, 12% really will require genetic therapy, which, obviously, we're working on, but that's farther out.

這是傑夫。這是一個──這是一個很好的問題，也是一個重要的問題。我認為人們對此仍然沒有完全理解。我想花點時間談談這件事，因為當我們開始看到這些數據時，我們的想法也改變了。要得出這個結論，最重要的事實是，80% 到 90% 的 CF 患者至少攜帶一個 Delta F508 等位基因。也就是說，它們要不是 50% 的純合子 508-508，就是 508，但在另一個等位基因上有其他基因型。可能是最小功能突變，可能是門控突變，也可能是殘餘功能突變。所以實際上只有大約 10% 的患者不攜帶至少一個 508 等位基因。而這之所以重要，是因為我們正在學習的是——我希望我們能在今年下半年看到三重數據時看到這個結果——我們相信，從我們所有的細胞數據中提取的三重數據將使我們能夠最大限度地治療所有這些患者。也就是說，如果你考慮純合子群體，我們認為三合子會比任何雙合子都好。我們的細胞數據告訴我們這一點。如果你看看 het-min 人口，我們認為三重奏顯然會比雙重奏或單重奏更好，因為目前這些奏效不了。如果你觀察到殘餘功能或門控患者，會發現其中 90% 的患者在另一個等位基因上會有 Delta 508，因此三聯療法對他們來說也會更好。因此，一旦你有了這種洞察力，你就會意識到，整個領域的發展方向實際上是從單一療法和雙重療法轉向一種高效且耐受性良好的單一最佳三重療法，這種療法可以治療 80% 到 90% 的患者。而剩下的那些沒有 508 的患者，例如，少數患者在一個等位基因上有門控突變，但在另一個等位基因上沒有 508。他們可以接受 KALYDECO 單藥治療，但這裡指的是非常小的病例數。最後 10% 的患者完全沒有 508 等位基因或 KALYDECO 反應等位基因，很可能大部分情況下是終止密碼子，他們需要基因編輯或基因療法等基因療法。因此我們相信，對於 80% 到 90% 的患者來說，這將很快過渡到單一的三聯療法，剩下的少數患者將接受 KALYDECO 單藥治療，他們沒有 508。剩下的 10% 到 12% 的患者確實需要基因療法，我們當然正在研究這方面，但這還需要一段時間。

And then I think just my last question just along these lines as well, is targeting CFTR as a triple kind of at the upper end or do you think there might be a quad after that? Or do you really have to think about other mechanism like ENaC? And if there's any update there, that would be great too.

然後，我想問的最後一個問題也與此相關，將 CFTR 作為三靶點標靶治療是比較高端的策略，還是您認為之後可能會有四靶點標靶治療？或者你真的需要考慮像ENaC這樣的其他機制嗎？如果那方面有任何更新，那就太好了。

Yes. You have a little bit of both. So we certainly are still interested in looking at mechanisms, ENaC being the first one, whereas as you know, we'll see some data in the second half of this year. The reason being it is a completely different mechanism, and so one might predict that no matter how [good] you got, you could add ENaC in and get some additional benefit. So that's one way -- one important way that we're thinking about it. With respect to taking a triple to a quad, it's more CFTR correctors and potentiators. I think we're going to have to see the data from these compounds and also continue to get data from our new second-gen correctors because we have -- we continue to see improvements in those. But I have to say the levels we're seeing -- and we've shown you this from cells in both het-min and homozygous [are all current]. The next-gen correctors, those like 659 in particular, are really quite high. And so yes, we can probably raise the bar a little bit maybe with some others, but we're probably closing in on maximum kind of therapy. I think the question will be how does that translate in the clinic? In other words, is there a ceiling in the clinic? And we just don't know yet. We haven't reached it. We know we can get 15% improvements from gating patients -- gating 508 patients with tez/iva. The question is -- and we'll see it from the triple, can we go beyond that? And I think only the clinical data is going to tell us.

是的。你兩者兼具一點。所以我們當然仍然有興趣研究各種機制，ENaC 是第一個，正如你所知，我們將在今年下半年看到一些數據。原因在於它是一種完全不同的機制，因此可以預測，無論你變得多麼優秀，你都可以加入 ENaC 並獲得一些額外的好處。所以這是我們思考這個問題的一個重要方式。至於從三通道升級到四通道，更多的是CFTR矯正劑和增強劑。我認為我們需要查看這些化合物的數據，同時也要繼續獲取我們新的第二代校正劑的數據，因為我們——我們一直在看到這些校正劑的性能有所提升。但我必須說，我們看到的水平——我們已經向你們展示了來自雜合子和純合子細胞的水平[都是當前的水平]。下一代校正器，特別是像 659 這樣的校正器，精度真的很高。所以，是的，我們或許可以稍微提高一下標準，或許可以對其他一些療法進行改進，但我們可能已經接近最高水準的治療了。我認為問題在於，這在臨床上是如何轉化成臨床應用的？換句話說，診所的發展有上限嗎？我們現在還不知道。我們還沒到達那裡。我們知道，透過對患者進行分流，我們可以獲得 15% 的改善——對 ​​508 名患者使用 tez/iva 進行分流。問題是──我們將從三連勝中看出這一點──我們能否超越它？我認為只有臨床數據才能告訴我們答案。

And our next question comes from the line of Adam Walsh with Stifel.

我們的下一個問題來自 Stifel 的 Adam Walsh。

My first question is on CTP-656. Can you give us some guidance around whether you think there would be any antitrust issues on the acquisition of that molecule from Concert, given that you already have KALYDECO? I did notice in the Concert proxy documents that you had withdrawn and refiled your premerger notification report form with the U.S. regulatory authorities there. Can you just kind of explain that to us whether or not you anticipate any FTC issues and what the timing of clearance would do? That's the first one.

我的第一個問題是關於 CTP-656 的。鑑於貴公司已經擁有 KALYDECO，您能否就從 Concert 收購該分子是否會引發任何反壟斷問題提供一些指導意見？我在 Concert 的委託書中註意到，您已撤回並重新向美國監管機構提交了合併前通知報告表。您能否向我們解釋一下，您是否預計會遇到任何联邦貿易委員會（FTC）方面的問題，以及審批時間會造成什麼影響？這是第一個。

Yes. Well, we're actually -- Adam, thank you for the question. We're actually in the review period now, and we're working with the regulators as they have found questions. Let me just be clear of why we want to acquire CTP-656. It is a deuterated ivacaftor, which based on earlier studies and PK work suggests that it's a once-a-day potentiator. That interests us because we have once-a-day correctors that both -- that Jeff referred to earlier on this call. So ultimately, we would like to think about a combination pill that's a once-a-day regimen, and CTP-656 gives us that opportunity. It's -- that would be the best regimen for patients as long as we have safety and efficacy, and it would be the most convenient for patients, and that is the plan. And so as we go through this review period with the regulators, we'll be helping them understand that taking forward CTP-656 this is the best route forward for the compound.

是的。其實，我們是──亞當，謝謝你的提問。我們現在正處於審查期，我們正在與監管機構合作，因為他們發現了一些問題。讓我明確說明我們為什麼要收購 CTP-656。它是一種氘代伊伐卡托，根據早期的研究和藥物動力學工作表明，它是一種每日一次的增效劑。我們對此很感興趣，因為我們每天有一次糾錯程序，傑夫在之前的電話會議中也提到過這一點。所以最終，我們希望研發一種每天只需服用一次的複方藥片，而 CTP-656 為我們提供了這樣的機會。只要確保安全性和有效性，這將是對病人來說最好的治療方案，也是對病人來說最方便的方案，這就是我們的計畫。因此，在與監管機構進行審查期間，我們將幫助他們理解，推進 CTP-656 是該化合物的最佳途徑。

And any color on the timing of when that might conclude, the clearance?

關於何時完成清理工作，是否有任何具體資訊？

It can go on for a couple of months, few months. It's really subjective. We answer questions, and then they make their judgment. So it could move on. We do the -- Concert does also have an investor vote coming up, I believe it's in mid-May, on the approval of the transaction as well, subject to HSR.

這可能會持續幾個月。這完全是主觀的。我們回答問題，然後他們做出判斷。所以事情可能會繼續發展下去。我們相信，Concert 也將在 5 月中旬舉行投資者投票，以批准該交易，但需遵守 HSR 法規。

Right. And then different question on ORKAMBI the 6 to 11 population. You talked about strong compliance and persistence. When we think about that in the 6 to 11 population, should we be thinking compliance and persistence rates equivalent to, say, KALYDECO, maybe even a little bit better given the parents are involved? How should we think about those rates ultimately?

正確的。然後是關於 ORKAMBI 6 至 11 歲人群的另一個問題。你談到了嚴格的遵守和堅持。當我們考慮 6 至 11 歲族群時，我們是否應該認為依從性和堅持率與 KALYDECO 相當，考慮到父母的參與，甚至可能更好一些？我們最終該如何看待這些利率？

Yes, Adam, we're moving away really from kind of diagnosing and describing every patient dynamic for every patient population for every country. But suffice to say, they are higher in the 6 to 11 population than we have seen in the 12-plus population with ORKAMBI, and they're much more KALYDECO like. You'd expect that. The profile in the 6 to 11 age group of ORKAMBI is very strong. And also, as I've said, they are managed by their parents to a large degree in terms of compliance.

是的，亞當，我們正在逐漸擺脫對每個國家每個患者群體每個患者的動態進行診斷和描述的做法。但總而言之，在 6 至 11 歲人群中，它們的發生率比我們在 12 歲及以上人群中看到的 ORKAMBI 更高，而且它們更像 KALYDECO。這也不足為奇。ORKAMBI 6 至 11 歲年齡層的特徵非常鮮明。而且，正如我所說，他們在服從方面很大程度上是由他們的父母管理的。

Our next question comes from the line of Mohit Bansal from Citigroup.

我們的下一個問題來自花旗集團的莫希特·班薩爾。

Maybe a big picture -- maybe a question on your base case assumption for the triple-combination trials. So is it fair to assume that you would be looking for a comparator trial against ORKAMBI for the triple combo at least in homozygotes? And do you think it makes -- it maybe makes it a little bit easier in heterozygotes given that you will have to compete against a placebo as a comparator there?

或許可以放眼全局——或許可以問一下關於三聯試驗的基本假設的問題。那麼，是否可以合理地假設，您至少會在純合子中尋找針對三聯療法的 ORKAMBI 對照試驗？你認為這是否會讓雜合子更容易一些，因為在那裡你必須與安慰劑作為對照？

Thanks for the question. So let me start by just reminding you of our cellular results, right, which so far have translated into the clinic in pretty much every case. And those results show that a triple is clearly superior, quite superior. And we published those results in both homozygous cells and het-min cells to develop to either ORKAMBI or to VX-661 plus KALYDECO. So based upon those in vitro results, which as I said, have translated quite safely in the clinic, we expect -- actually expect the triple will be better in homozygous patients than the double, and expect it to be effective based on what we know so far. Obviously, we have to confirm all this in the clinic. In the het-min patients with both ORKAMBI and VX-661 and tez/iva, they have not been effective. So that's our expectation.

謝謝你的提問。首先，我想提醒大家我們的細胞檢測結果，到目前為止，這些結果幾乎在所有情況下都轉化成了臨床結果。這些結果表明，三重奏明顯更勝一籌，優勢非常明顯。我們發表了純合細胞和 het-min 細胞的這些結果，以開發 ORKAMBI 或 VX-661 加 KALYDECO。因此，根據我所說的體外試驗結果，這些結果在臨床上轉化得相當安全，我們預期——實際上預期三聯療法對純合子患者會比雙聯療法更好，並且根據我們目前所了解的情況，預期它會有效。顯然，所有這些都需要在診所進行確認。對於同時接受 ORKAMBI、VX-661 和 tez/iva 治療的 het-min 患者，這些藥物均無效。這就是我們的預期。

Our next question comes from the line of 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 in the wake of the positive tez/iva data, I was just curious how you guys are looking at the potential development scenarios for your ENaC inhibitor in case where there's positive Phase II data later this year? Would the plan still to be to move into a pivotal on top of ORKAMBI? Or would you pivot to teza/iva? Or is there's some other set of potential options we should be looking at?

我想，鑑於 tez/iva 的積極數據，我只是好奇，如果今年稍後獲得積極的 II 期臨床試驗數據，你們是如何看待 ENaC 抑制劑的潛在開發方案的？計劃是否仍然是搬到 ORKAMBI 頂部的關鍵位置？或者你會轉向teza/iva嗎？或者，我們是否應該考慮其他一些潛在方案？

Yes. Great question. I think the way we're thinking about it is there are really 2 questions that we want to answer. I think the timing is going to work out pretty nicely here. The first question is really a biological question. It's if you add an ENaC inhibitor on top of CFTR modulation, do you see incremental results? So that's really a biologic question that is predicted by cell biology, but this cell biology is quite a bit more complicated than the simple chloride transport in HBEs. So we need to prove that. And I think we're going to get the answer to that in the second half of this year from this first trial. At the same time, we're going to get the answer to what happens with our triples clinically, how high can you drive FEV1 in both the homozygous and the heterozygous population. And so at the end of the day, what we're going to do with ENaC is going to really depend on looking at both those results together and basically asking ourselves a question, can we get a significant benefit over triple do we believe within an ENaC inhibitor? Because we do believe that quickly where everything is going to move to triples. So I think the ultimate question will be if you add an ENaC inhibitor on top of triple can you get significantly higher FEV1 responses? And that's really going to be dependent upon the magnitude of the FEV1 response to the triple and the magnitude of the improvement on the ENaC. The good news is we'll have both of those pieces of data toward the end of this year. I think we're going to be able to make a fairly straightforward decision.

是的。問得好。我認為我們現在的思考方式是，我們真正想要回答的是兩個問題。我認為時機把握得相當不錯。第一個問題其實是一個生物學問題。如果在 CFTR 調節的基礎上再加入 ENaC 抑制劑，是否能看到進一步的效果？所以這其實是一個生物學問題，可以透過細胞生物學來預測，但是細胞生物學比 HBE 中簡單的氯離子轉運要複雜得多。所以我們需要證明這一點。我認為我們將在今年下半年透過第一次試驗得到答案。同時，我們將得到關於三聯體在臨床上會發生什麼的答案，以及在純合子和雜合子人群中，FEV1 可以提高到多高。因此，歸根結底，我們對 ENaC 的處理方式將真正取決於將這兩個結果結合起來考慮，並問自己一個問題：我們能否在 ENaC 抑制劑中獲得超過三倍的顯著益處？因為我們確實相信，一切都會很快發展成三倍成長。所以我認為最終的問題是，如果在三聯療法的基礎上再加入 ENaC 抑制劑，能否獲得顯著更高的 FEV1 反應？這其實取決於 FEV1 對三重治療的反應幅度以及 ENaC 的改善幅度。好消息是，我們將在今年年底前獲得這兩項數據。我認為我們能夠做出一個相當簡單的決定。

Our next questions come from the line of Alethia Young with Crédit Suisse.

接下來的問題來自瑞士信貸的 Alethia Young。

Just maybe one that's a little more philosophical as well, like how many triple combinations do you kind of want to try? Like in this first tranche, you've kind of gone with the first 4. And then you'll see, and then you'll take a step back as to see whether you want to add mechanisms on top of that. Just maybe help -- give a little bit of color about what's going on in the lab and how you're thinking about kind of the progress beyond what you're doing with triples?

或許還可以問一個更具哲學性的問題，例如你想嘗試多少種三重組合？就像第一批產品一樣，你已經完成了前 4 個。然後你會看到，然後你會退後一步，看看是否要在此基礎上添加機制。或許可以幫忙——稍微介紹一下實驗室裡正在發生的事情，以及你對三重重複實驗以外的進展有何想法？

Yes. So, obviously, we're going to get a lot of information from these 4 triples, I believe, because we're going to have a very nice set of data sets that compares in vivo to in vitro results with 4 different combinations. And that in addition to the fact that we've derisked the teza/iva double combination, both from efficacy and safety standpoint, gives me a high level of confidence that one or more of these triples will proceed into Phase III. So hopefully, that answers that part of the question. And it's going to depend obviously on what we see in the second half of this year. Now to your other question on what's going on in the lab, we still have very active program looking at triples. I think I've talked about this before. We, I think, originally figured how we identify these. And we've identified tens if not hundreds of additional next-gen correctors. Obviously, the only ones that we're going to bring forward of those into the clinic is something that we feel has a favorable profile compared to the ones that we've already done. It could be efficacy, it could be PK, it could be tolerability. And if we see those sorts of things, it's entirely possible that we bring one or more of those new next-gen correctors forward into the clinic toward the end of this year or next year. But I think -- I don't want to give you the impression that we're dependent on that because I have a high level of confidence that one or more of these triples, assuming that they play out, will be able to proceed into Phase III.

是的。所以，顯然，我相信我們會從這 4 個三元組中獲得很多信息，因為我們將得到一組非常好的數據集，可以比較 4 種不同組合的體內和體外結果。此外，我們已經從療效和安全性兩方面降低了teza/iva雙重組合的風險，這讓我非常有信心，這三聯療法中的一種或多種將進入III期臨床試驗。希望這能解答這個問題的一部分。這顯然取決於我們今年下半年看到的情況。現在回答你關於實驗室裡正在發生的事情的另一個問題，我們仍然有一個非常活躍的專案在研究三重態。我想我以前談過這件事。我認為，我們最初是弄清楚如何識別這些的。我們已經發現了數十種甚至數百種新的下一代校正器。顯然，我們只會將那些我們認為比我們已經做過的試驗具有更好效果的試驗推進到臨床實踐中。可能是療效問題，可能是藥物動力學問題，也可能是耐受性問題。如果我們看到這類情況，我們完全有可能在今年年底或明年將一種或多種新一代矯正器引入臨床應用。但我認為——我不想讓你們覺得我們依賴於此，因為我非常有信心，假設這三項計劃都能順利進行，其中一項或多項將能夠進入第三階段。

And our last question comes from the line of Alan Carr with Needham.

最後一個問題來自艾倫·卡爾和尼達姆的論述。

A couple. One, what's your expectations for timing for the -- in the tez trial in 6 to 11 patients and when that data will be available? And then can you give us an update on Germany? That was one that -- a slow trajectory. I wonder if that's changed over time. And are you still have a high level of conviction that, that uptake was just restricted to Germany as opposed to some of the other countries in Europe?

一對夫婦。第一，您對 tez 試驗中 6 至 11 名患者的試驗時間有何預期？何時才能獲得相關數據？那麼，您能為我們介紹一下德國的最新情況嗎？那是一個——緩慢的軌跡。我想知道這種情況是否隨著時間推移而改變。您是否仍高度確信，這種普及僅限於德國，而不是歐洲其他國家？

Alan, it's Stuart here. Let me take the Germany question first. So yes, as you highlighted, we did see a slow uptake in Germany, and frankly it continues to be slow. We are continuing to add new patients day after day, week-after-week in Germany, but it continues to be relatively slow compared to France and to the U.S. We continue to believe that we will get to the majority of patients in Germany being initiated on ORKAMBI, but it continues to be slow progress. I do continue to believe that the uptake in other countries will be much more U.S. like and France like. And for instance, to give you an example, as a point that we are successful in signing a contract in Ireland where we have agreement in principle, I'm very confident based on the level of patient advocacy, the level of physician engagement with us and belief in the product that we'll see uptake there, which is much like we saw in the U.S. and in France. So I continue to believe that uptake in Germany is going to be a relative outlier for ORKAMBI. And you talked about teza/iva in 6 to 11, I'll hand the call off to Jeff.

艾倫，我是史都華。我先回答德國的問題。所以，正如你所指出的，我們在德國確實看到了緩慢的普及，坦白說，這種普及速度至今仍然很慢。我們在德國每天、每週持續增加新患者，但與法國和美國相比，速度仍然相對較慢。我們仍然相信，我們將使德國的大多數患者都能開始接受 ORKAMBI 治療，但進展仍然緩慢。我仍然相信，其他國家的接受程度會更像美國和法國。例如，舉個例子來說，假設我們在愛爾蘭成功簽署了一份合同，並且我們原則上達成了一致，基於患者權益倡導的程度、醫生與我們合作的程度以及對產品的信心，我非常有信心，我們將在那裡看到產品的普及，這與我們在美國和法國看到的情況非常相似。因此，我仍然認為，ORKAMBI 在德國的普及率將是一個相對例外。你在 6 到 11 點談到了 teza/iva，我把電話交給 Jeff 了。

Yes, so for the 6 to 11 teza/iva trial, just to remind you, this is really a safety, tolerability and PK trial in both homozygous patients and patients who have one Delta F508 allele with 1 ivacaftor-responsible allele. It's an open-label trial. It's currently enrolling. And once we see with the enrollment is, we'll be able to give you a sense of when we expect data. We actually haven't disclosed that because we just don't know yet.

是的，所以提醒一下，對於 6 至 11 teza/iva 試驗，這實際上是一項針對純合子患者和攜帶一個 Delta F508 等位基因和一個 ivacaftor 責任等位基因的患者的安全性、耐受性和藥物動力學試驗。這是一項開放標籤試驗。目前正在招生。一旦我們看到報名情況，我們就能告訴您我們預計何時能取得數據。我們還沒有透露，因為我們目前還不知道。

I'd like to turn the call back to Mr. Partridge for closing remarks.

現在我把電話轉回給帕特里奇先生，請他作總結發言。

Thanks, operator. Thank you, everybody, for dialing into our Q1 call. The IR team will be available tonight for any follow-up questions that you have. Have a good evening.

謝謝接線生。感謝各位撥入我們的第一季電話會議。投資者關係團隊今晚將隨時解答您的任何後續問題。祝你晚上愉快。

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