福泰製藥 (VRTX) 2018 Q2 法說會逐字稿

Good day, ladies and gentlemen, and welcome to the Vertex Pharmaceuticals Second Quarter 2018 Conference Call. (Operator Instructions) As a reminder, today's program may be recorded.

各位女士、先生，大家好，歡迎參加 Vertex Pharmaceuticals 2018 年第二季電話會議。（操作說明）提醒：今天的節目可能會被錄製。

I would now like to introduce your host for today's program, Michael Partridge, Vertex Pharmaceuticals Inc. Please go ahead.

現在我謹向大家介紹今天節目的主持人，來自 Vertex Pharmaceuticals Inc. 的 Michael Partridge。請繼續。

Thank you, and welcome to the Vertex Second Quarter 2018 Conference Call. This is Michael Partridge, Senior Vice President of Investor Relations for Vertex. Tonight, we will review our financial results and our continued progress to develop new medicines for all people with cystic fibrosis. Dr. Jeff Leiden, Chairman and CEO; and Ian Smith, Chief Operating Officer, will provide prepared remarks this evening. Stuart Arbuckle, Chief Commercial Officer; and Dr. Reshma Kewalramani, Chief Medical Officer, will join us for Q&A. We recommend that you access the webcast live as you listen to this call. The slides are available for download on our website. This conference call is being recorded, and the replay will be available on our website starting later tonight.

謝謝，歡迎參加 Vertex 2018 年第二季電話會議。這是 Vertex 公司投資者關係資深副總裁 Michael Partridge。今晚，我們將回顧我們的財務表現以及我們在為所有囊性纖維化患者開發新藥方面取得的持續進展。董事長兼執行長傑夫萊頓博士和營運長伊恩史密斯將於今晚發表準備好的演講。首席商務官斯圖爾特·阿巴克爾和首席醫療官雷什瑪·凱瓦拉馬尼博士將參加問答環節。我們建議您在收聽本次電話會議的同時，觀看網路直播。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錄音回放。

We will make forward-looking statements on this call. These statements are subject to the risks and uncertainties discussed in detail in today's press release and our 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. Good evening, everyone. In the first half of 2018, Vertex continued to make tremendous progress across our business, especially in the area of cystic fibrosis. Today, we are treating more patients with our CF medicines than ever before and delivering important clinical benefits to thousands of people around the world.

謝謝你，麥可。各位晚上好。2018 年上半年，Vertex 在各項業務中持續取得巨大進展，尤其是在囊性纖維化領域。如今，我們使用 CF 藥物治療的患者比以往任何時候都多，並為世界各地成千上萬的人帶來了重要的臨床益處。

First, to the launch of SYMDEKO in the U.S. The demand for this medicine has been strong across a wide range of eligible patients, including those who previously discontinued or never started ORKAMBI. Patient access to SYMDEKO is excellent and similar to prior launches in the U.S. for KALYDECO and ORKAMBI. And feedback from patients and physicians has been highly positive. Treating more patients is driving significant revenue growth. And on the basis of the rapid uptake of SYMDEKO in the first half of 2018, we are raising our total revenue guidance for 2018, which Ian will review in a moment.

首先，SYMDEKO 在美國上市。包括以前停止服用或從未開始服用 ORKAMBI 的患者在內的眾多符合條件的患者對這種藥物的需求都很強勁。SYMDEKO 的病患可近性極佳，與 KALYDECO 和 ORKAMBI 在美國的上市情況類似。患者和醫生的回饋都非常正面。治療更多患者推動了收入的顯著增長。鑑於 SYMDEKO 在 2018 年上半年迅速獲得市場認可，我們提高了 2018 年的總收入預期，Ian 稍後將對此進行審查。

Second, we are moving toward achieving our goal to treat CF patients at younger and younger ages, so we may help deliver transformative benefits early in life and slow or prevent the progression of disease. This progress is exemplified by the pending approvals for KALYDECO in children as young as 1 year of age and for ORKAMBI in children ages 2 to 5 years where we expect decisions from the FDA this summer. We're also evaluating SYMDEKO in children ages 6 to 11 and expect data from this study later this year.

其次，我們正朝著在越來越年輕的年齡治療 CF 患者的目標邁進，這樣我們就能幫助患者在生命早期獲得變革性的益處，並減緩或阻止疾病的進展。這項進展的例證是，KALYDECO 正在等待批准用於 1 歲及以上的兒童，ORKAMBI 正在等待批准用於 2 至 5 歲的兒童，我們預計 FDA 將於今年夏天做出決定。我們也正在對 6 至 11 歲兒童進行 SYMDEKO 評估，預計今年稍後將獲得該研究的數據。

Third, our 2 triple combination regimens that contain a next-generation corrector are proceeding rapidly through Phase III development. We expect to complete enrollment of our Phase III studies for both VX-659 and VX-445 triple combination regimens in the second half of this year.

第三，我們含有下一代矯正劑的 2 種三合一療法正在快速推進 III 期研發。我們預計今年下半年完成 VX-659 和 VX-445 三聯療法 III 期研究的患者招募工作。

Based on anticipated completion of enrollment for both programs, we expect to submit a new drug application no later than mid-2019. The VX-659 and VX-445 programs have moved exceptionally fast, advancing from first synthesis of the molecules all the way to late-stage development in a little over 2 years. I look forward to updating you on the continued progress for these programs in the coming months.

根據兩個計畫預計完成的招生工作，我們預計最遲將於 2019 年年中提交新藥申請。VX-659 和 VX-445 專案進展異常迅速，從分子的首次合成到後期開發，僅花了 2 年多一點的時間。我期待在接下來的幾個月向您報告這些專案的後續進度。

Beyond CF, we continue to invest to discover and develop medicines in other serious diseases. In our pain program, we have generated Phase II data for the selective NaV1.8 inhibitor, VX-150, representing the first proof of concept for NaV1.8 inhibition in the treatment of both acute pain and chronic inflammatory pain. These data provided important and clear clinical validation for this medicine. We expect to have Phase II results for VX-150 in a third type of pain, neuropathic pain, in early 2019.

除了囊性纖維化之外，我們還將繼續投資，以發現和開發治療其他嚴重疾病的藥物。在我們的疼痛治療計畫中，我們已經產生了選擇性 NaV1.8 抑制劑 VX-150 的 II 期數據，這代表了 NaV1.8 抑制在治療急性疼痛和慢性發炎性疼痛的第一個概念驗證。這些數據為該藥物提供了重要而明確的臨床驗證。我們預計將於 2019 年初獲得 VX-150 治療第三種疼痛類型（神經性疼痛）的 II 期臨床試驗結果。

We're no longer progressing VX-128, our first follow-on NaV1.8 inhibitor based on PK and tolerability findings from our Phase I study. We believe there is significant potential in the treatment of pain with the NaV1.8 inhibitor, and we continue to invest in research and development efforts to advance VX-150 in the clinic and to move additional NaV1.8 inhibitors into development.

由於 I 期研究中的藥物動力學和耐受性結果，我們不再推進 VX-128 的研發，VX-128 是我們首個後續 NaV1.8 抑制劑。我們相信 NaV1.8 抑制劑在治療疼痛方面具有巨大的潛力，我們將繼續投資研發工作，以推進 VX-150 的臨床應用，並推動其他 NaV1.8 抑制劑的研發。

With our partner CRISPR Therapeutics, we're advancing CTX001. It's the first gene editing treatment for both sickle cell disease and beta-thalassemia using CRISPR-Cas9 technology. In beta-thalassemia, we obtained approval in the U.K. for a clinical trial application, or CTA, for CTX001 earlier this year and recently obtained the CTA approval in Canada. We remain on track to initiate the first study of CTX001 in beta-thalassemia later this year.

我們正與合作夥伴 CRISPR Therapeutics 一起推動 CTX001 的研發。這是第一個利用 CRISPR-Cas9 技術同時治療鐮狀細胞貧血症和β地中海型貧血的基因編輯療法。今年早些時候，我們在英國獲得了 CTX001 的臨床試驗申請（CTA）批准，用於治療 β-地中海貧血，最近在加拿大獲得了 CTA 批准。我們仍按計劃於今年稍後啟動 CTX001 在 β-地中海貧血的首次研究。

In sickle cell disease, we also recently obtained CTA approvals in Canada and the U.K. And we continue to work with the U.S. FDA to address the agency's questions regarding the IND for CTX001 that we submitted earlier this year.

在鐮狀細胞疾病領域，我們最近也在加拿大和英國獲得了 CTA 批准。我們將繼續與美國 FDA 合作，解決該機構對我們今年稍早提交的 CTX001 IND 提出的問題。

We also continue to make significant strides with our internal research efforts. We have compound from late-stage preclinical development for alpha-1-antitrypsin deficiency, or AAT, and focal segmental glomerulosclerosis, or FSGS. These early-stage programs demonstrate a strong fit with our business model and research strategy where we aim to develop transformative medicines for serious diseases in specialty markets to create the greatest value for both patients and shareholders. We choose diseases with well-understood biology where we can use or create early clinical markers that support the potential for transformative benefit and enable rapid development time lines. With both AAT and FSGS, we have the ability to design early-stage clinical studies that may provide initial proof-of-concept data in 2019 or 2020 to inform further development. This is very analogous to how we successfully advanced our CF portfolio.

我們在內部研究方面也持續取得顯著進展。我們有一種化合物處於臨床前開發的後期階段，用於治療α-1-抗胰蛋白酶缺乏症（AAT）和局部節段性腎小球硬化症（FSGS）。這些早期項目與我們的商業模式和研究策略高度契合，我們的目標是為專科市場的嚴重疾病開發變革性藥物，從而為患者和股東創造最大價值。我們選擇生物學特性已被充分理解的疾病，以便利用或創建早期臨床標誌物，從而支持變革性益處的潛力並實現快速開發時間表。借助 AAT 和 FSGS，我們有能力設計早期臨床研究，這些研究可能會在 2019 年或 2020 年提供初步的概念驗證數據，以指導進一步的發展。這與我們成功推進CF投資組合的方式非常相似。

In summary, we've made tremendous progress across our business in the first half of the year. In CF, it's remarkable that it was just 1 year ago when we announced the first Phase II data for a triple combination regimen. By this time next summer, we may have submitted for FDA approvals of one of these regimens, further defining the path toward treating up to 90% of all people with this devastating disease.

總而言之，今年上半年我們在各個業務領域都取得了巨大的進步。在囊性纖維化領域，值得一提的是，就在一年前，我們公佈了三聯療法的首個 II 期臨床數據。到明年夏天這個時候，我們或許已經向 FDA 提交了其中一種治療方案的批准申請，進一步明確了治療高達 90% 的這種毀滅性疾病患者的道路。

With our pipeline, we're advancing multiple new medicines that could fundamentally change the treatment of other serious diseases in the future. And financially, we continue to significantly increase our revenues, which will drive sustainable long-term earnings and operating margin growth and enable continued investment in the discovery of new future medicine.

憑藉我們的研發管線，我們正在推動多種新藥的研發，這些新藥未來可能會從根本上改變其他嚴重疾病的治療方式。在財務方面，我們的收入持續大幅成長，這將推動可持續的長期獲利和營業利潤率成長，並使我們能夠繼續投資於未來新藥的發現。

I'll now turn the call over to Ian.

現在我將把電話交給伊恩。

Thanks, Jeff, and good evening to everyone. I'm pleased to review our second quarter 2018 financial results, which are highlighted by the launch of SYMDEKO in the U.S. and our upward revision of the 2018 full year financial guidance for total CF revenues.

謝謝你，傑夫，大家晚上好。我很高興回顧我們 2018 年第二季度的財務業績，其中最引人注目的是 SYMDEKO 在美國的推出以及我們上調了 2018 年全年 CF 總收入的財務預期。

Revenues first. Total CF product revenues of $750 million in the second quarter of 2018 represents a 46% increase compared to the $514 million we recorded in the second quarter of 2017. We continue to see significant revenue growth as we increase the number of patients treated with our medicines globally. The second quarter included $186 million in revenues from the launch of SYMDEKO in the U.S., which is the primary driver of the rapid growth in total CF revenues. Demand for SYMDEKO is strong, and we are seeing favorable early trends in persistence and compliance and are receiving positive feedback from patients and physicians. 5 months into launch in the U.S., public and private insurance plans, representing 95% of covered lives, are processing claims for SYMDEKO, and nearly all state Medicaid programs are providing coverage for SYMDEKO.

收入優先。2018 年第二季 CF 產品總營收為 7.5 億美元，比 2017 年第二季的 5.14 億美元成長了 46%。隨著全球範圍內使用我們藥物治療的患者人數不斷增加，我們的收入也持續顯著增長。第二季營收為 1.86 億美元，主要得益於 SYMDEKO 在美國的上市，也是 CF 總營收快速成長的主要動力。對 SYMDEKO 的需求強勁，我們在堅持用藥和依從性方面看到了良好的早期趨勢，並收到了來自患者和醫生的正面回饋。在美國上市 5 個月後，公共和私人保險計劃（佔投保人數的 95%）正在處理 SYMDEKO 的理賠申請，幾乎所有州的醫療補助計劃都為 SYMDEKO 提供保險。

The demand has been particularly strong among the F508del homozygous patients initiating treatment for the first time and also in patients who discontinued ORKAMBI coming back to initiate therapy for SYMDEKO. We're also seeing patients switching from ORKAMBI to SYMDEKO as evidenced by ORKAMBI's revenues of $236 million in the U.S. for the second quarter compared to $282 million for the first quarter this year.

對於首次接受治療的 F508del 純合子患者以及停止使用 ORKAMBI 後重新開始接受 SYMDEKO 治療的患者來說，這種需求尤其強烈。我們也看到患者從 ORKAMBI 轉而使用 SYMDEKO，ORKAMBI 今年第二季在美國的收入為 2.36 億美元，而第一季為 2.82 億美元，這證明了這一點。

Based on the launch to date and our expectation for continued growth in SYMDEKO revenues as more patients initiate and remain on treatment over the coming months, we today revise our guidance for total CF product revenues to $2.9 billion to $3 billion from a prior range of $2.65 billion to $2.8 billion. The midpoint of this new range represents approximately 36% growth over 2017. Our guidance does not assume completion of new reimbursement agreements outside of the U.S. during 2018.

根據迄今為止的上市情況，以及我們對 SYMDEKO 收入在未來幾個月隨著更多患者開始並繼續接受治療而持續增長的預期，我們今天將 CF 產品總收入的預期從之前的 26.5 億美元至 28 億美元調整為 29 億美元至 30 億美元。該新區間的中點值比 2017 年增長了約 36%。我們的指導意見並未假設 2018 年在美國境外完成新的報銷協議。

With reimbursement outside the U.S., we remain focused on providing broad access to current and future medicines by establishing long-term reimbursement agreements. The latest example of this portfolio type of reimbursement agreement was announced with Sweden in June and provides immediate access to ORKAMBI and a framework for rapid access to future medicines. We established similar agreements in Ireland and other countries and are engaged in ongoing discussions with additional countries regarding long-term portfolio arrangements.

對於美國以外的報銷問題，我們仍然致力於透過建立長期報銷協議，為當前和未來的藥物提供廣泛的獲取途徑。6 月與瑞典宣布的最新此類組合式報銷協議，可立即獲得 ORKAMBI，並為未來快速獲得藥物奠定基礎。我們在愛爾蘭和其他國家達成了類似的協議，並正在與其他國家就長期投資組合安排進行持續磋商。

Now to expenses. Our second quarter 2018 non-GAAP combined R&D and SG&A expenses were $388 million compared to $333 million in the second quarter of 2017. This increase was primarily due to the advancement of the portfolio of triple combination regimens for CF and investment to support the treatment of patients with our medicines globally. Our guidance for a combined non-GAAP R&D and SG&A expense of $1.5 billion to $1.55 billion is unchanged. The key investment drivers continue to be the execution of pivotal studies for 2 triple combination regimens, supply chain investment for triple combination regimens and incremental investment to support the launch of SYMDEKO.

接下來是費用支出。2018 年第二季非 GAAP 合併研發及銷售、一般及行政費用為 3.88 億美元，而 2017 年第二季為 3.33 億美元。這一增長主要歸功於囊性纖維化三聯療法產品組合的推進以及對支持全球患者使用我們藥物進行治療的投資。我們對非GAAP研發及銷售、管理及行政費用的預期在15億美元至15.5億美元之間，維持不變。關鍵的投資驅動因素仍然是 2 種三聯療法的關鍵研究的執行、三聯療法的供應鏈投資以及支持 SYMDEKO 上市的增量投資。

Non-GAAP net income for the second quarter 2018 was $244 million, with an EPS of $0.94, compared to non-GAAP net income of $99 million and an EPS of $0.39 for the second quarter of 2017. The increase in non-GAAP net income and EPS was largely driven by the strong growth in total CF product revenues.

2018 年第二季非 GAAP 淨收入為 2.44 億美元，每股收益為 0.94 美元，而 2017 年第二季非 GAAP 淨收入為 9,900 萬美元，每股收益為 0.39 美元。非GAAP淨利和每股盈餘的成長主要得益於CF產品總收入的強勁成長。

We ended the quarter with approximately $2.8 billion in cash, cash equivalents and marketable securities compared to $2.1 billion in the beginning of this year.

本季末，我們持有約 28 億美元的現金、現金等價物和有價證券，而今年年初這一數字為 21 億美元。

The financial profile of our business is strong. We continue to see significant growth in revenues, expanding operating margins and increasing earnings. And we expect these trends to continue as we expand access to our medicines globally and increase the number of patients eligible for and treated with our medicines. We also continue to invest in internal R&D for CF and other diseases and in external innovation through business development activities to create future medicines that will continue to drive growth. I look forward to updating you as we -- as the year progresses.

我們公司的財務狀況良好。我們持續看到收入顯著增長、營業利潤率擴大和盈利增加。我們預計，隨著我們在全球擴大藥品的可及性，以及符合資格並接受我們藥品治療的患者人數的增加，這些趨勢將會持續下去。我們也將繼續投資於囊性纖維化和其他疾病的內部研發，並透過業務發展活動進行外部創新，以創造未來藥物，從而繼續推動成長。隨著時間的推移，我會期待著向大家報告最新情況。

And with that, I'll 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 Philip Nadeau from Cowen and Company.

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

Questions on the SYMDEKO launch. Congratulations on the number, it's really impressive. Curious to get a little bit more color around the trends there. So I guess, what were the U.S. sales for ORKAMBI in the quarter? And how did they compare to SYMDEKO? And given that they're probably not too far off, what is your sense of SYMDEKO's penetration of its U.S. opportunity given that the bottom end of the guidance could kind of be hit by flat quarters in H2? It seems like you'd suggest it's largely penetrated, but I'm curious to get a little bit more information there.

關於 SYMDEKO 發布的問題。恭喜你取得這樣的成績，真是令人印象深刻。很想了解更多關於那邊趨勢的資訊。所以我想問一下，ORKAMBI本季在美國的銷售額是多少？它們與SYMDEKO相比如何？鑑於他們的預測可能不會太離譜，考慮到下半年業績可能持平，您認為 SYMDEKO 在美國市場的滲透率如何？聽起來你似乎認為它已經相當普及了，但我很想了解更多。

Sure. Hey, Phil, it's Stuart. I'll try to answer all those. So for ORKAMBI in the U.S., we recorded net revenues of $236 million for the quarter compared to the $186 million that Ian referenced for SYMDEKO. In terms of how the launch is going, as Jeff said in his prepared remarks, we've actually seen strong uptake across the 3 different patient populations that we were anticipating that we'd see demand in: those who had tried ORKAMBI previously and discontinued; those who have never been exposed to a CFTR modulator, either ORKAMBI or KALYDECO; and we saw a fair amount of transitions from ORKAMBI to SYMDEKO. And that's the reason why you see the sequential decline for ORKAMBI from Q1 to Q2. In terms of for the balance of the year, whilst the launch is off to a strong start, we do continue to expect that there is further growth opportunity for SYMDEKO because we're not yet -- as you might expect, 4 or so months into the launch, we're not yet fully penetrated into those patient populations that were either naive or seen patients discontinue.

當然。嘿，菲爾，我是史都華。我會盡量回答所有這些問題。因此，ORKAMBI 在美國的季度淨收入為 2.36 億美元，而 Ian 提到的 SYMDEKO 的淨收入為 1.86 億美元。就產品上市情況而言，正如 Jeff 在事先準備好的發言稿中所說，我們實際上在預期會有需求的 3 個不同的患者群體中都看到了強勁的接受度：之前嘗試過 ORKAMBI 但後來停止使用的患者；從未接觸過 CFTR 調節劑（無論是 ORKAMBI 還是 KALYDECO）的患者；以及我們看到相當多的患者從 ORKAM 到 ORK。這就是為什麼你會看到 ORKAMBI 從第一季到第二季出現環比下降的原因。就今年剩餘時間而言，雖然上市開局強勁，但我們仍然預計 SYMDEKO 有進一步的增長機會，因為正如您可能預料到的那樣，上市 4 個月左右，我們還沒有完全滲透到那些以前從未接觸過該藥物或已經停止使用的患者群體中。

Our next question comes from the line of Robyn Karnauskas from Citi.

我們的下一個問題來自花旗銀行的 Robyn Karnauskas。

The question I had is a little bit about thinking of the company more long term now that cystic fibrosis is playing out and some of your competitors are jumping off. Can you help us think about capital allocation, business development, particularly where we can -- your pain and your antitrypsin and CRISPR, are more early-stage or Phase II? How do you think about how you might grow the business? Earlier, you're saying you (inaudible) capital.

我的問題是關於在囊性纖維化疫情肆虐、一些競爭對手紛紛退出市場的情況下，公司是否應該從長遠角度考慮問題。您能否幫助我們思考一下資本配置、業務發展，尤其是在我們力所能及的領域——您的痛點、您的抗胰蛋白酶和 CRISPR 技術，目前是處於早期階段還是 II 期？您是如何考慮發展業務的？之前，你說你（聽不清楚）資本。

Yes, Robyn. This is Jeff. I'll maybe take the first, long-term strategic part of it, and then I'll turn it over to Ian to talk a little more specifically about business development. So as we look at the business, and we talked about this a little bit before, mission one is to complete the journey in CF. And obviously, that really involves bringing the best triple regimen to patients as quickly as possible. We're well on track to do that. The good news today is that those trials are enrolling very rapidly. And if and when we do that, and we have a high level of confidence we will, we see growth coming from the CF franchise for a number of years going forward. So I think that's really the first important point. In both top line and bottom line growth, that's significant. Then, obviously, we're focusing a lot of attention on what comes after CF. And we divide that into 2 parts. Our internal pipeline, where we believe we have a very unique scientific innovation engine that has now generated multiple breakthrough medicines. And therefore, we're confident that we're going to do that again in some of the diseases we're talking about like AAT, sickle cell, pain and FSGS. And the good news about those is that I think we'll have a lot more visibility to them earlier than many people expect because the early-stage clinical trials, like in CF, give you a pretty good sense of where you are after 20 patients, 50 patients, et cetera. So in 2019, 2020, we expect to have a lot more visibility to the success of those programs. So that's the internal part. Obviously, we're also accumulating a lot of capital. And that gives us a lot of opportunity to invest externally more and more each quarter, as you're seeing. And so we are seeing our BD efforts ramp up pretty significantly. As I've said before, are we going to go out and buy short-term revenue? No, we really don't need to. But we certainly want to supplement our pipeline and invest in other kinds of innovation. And maybe I'll turn it over to Ian, he can review our strategy with you there.

是的，羅賓。這是傑夫。我可能會先談談其中的長期策略部分，然後再交給伊恩，讓他更具體地談談業務發展方面的問題。所以，當我們審視這項業務時（我們之前也稍微討論過這一點），首要任務是完成 CF 之旅。顯然，這確實意味著要盡快為患者提供最佳的三重療法。我們正朝著這個目標穩步前進。今天的好消息是，這些試驗的受試者招募工作進展非常迅速。如果並且當我們做到這一點時（我們非常有信心我們會做到），我們​​預計CF特許經營權將在未來幾年內實現增長。所以我認為這才是最重要的一點。無論從營收成長或利潤成長來看，這都意義重大。很顯然，我們現在非常關注囊性纖維化之後的發展。我們將它分為兩部分。我們擁有內部研發管線，我們相信我們擁有非常獨特的科學創新引擎，目前已經產生了多種突破性藥物。因此，我們有信心在我們正在討論的一些疾病中再次做到這一點，例如 AAT、鐮狀細胞貧血、疼痛和 FSGS。好消息是，我認為我們會比許多人預期的更早看到這些結果，因為像囊性纖維化這樣的早期臨床試驗，可以讓你在治療 20 名患者、50 名患者等等之後，對治療效果有一個相當清晰的了解。因此，在 2019 年和 2020 年，我們預計這些專案的成功情況將更加清晰可見。這就是內部結構部分。顯然，我們也在累積大量資本。正如你所看到的，這給了我們很多機會，讓我們每季都能增加對外投資。因此，我們看到我們的業務拓展工作正在顯著加強。正如我之前所說，我們是否要出去買短期收益？不，我們真的不需要。但我們當然希望補充我們的產品線，並投資其他類型的創新。或許我會把這個任務交給伊恩，讓他跟你一起檢視我們的策略。

Sure. And I'd first of all say that Jeff reviewed our broader strategy, and as we look outside the company, everything we look at is absolutely consistent to how we think about the company inside. We have 3 areas that we're focused on outside the company. Obviously, first is cystic fibrosis. We should look at everything in cystic fibrosis and see if it's complementary to our approaches to affecting the underlying course of the disease. And so we do look at everything that moves, and that includes different modalities and therapies for cystic fibrosis. Second area is really platforms and early-stage technologies. And you've seen us complete a couple of deals in the last couple of years that have been very important for us in terms of getting us into new areas of science and new modalities. And in particular, Jeff updated you on our CRISPR Therapeutics collaboration on the call this evening, where we've made really nice progresses in beta-thalassemia and sickle cell. And then the third area that we continue to look at is kind of more opportunistic in terms of products and medicines that would be consistent to our overall disease strategies, going from the underlying causal biology through to the disease itself and how those diseases may fit inside Vertex and be consistent to what we're working on inside Vertex. We're very active. We're more active than we've ever been. We're able to do that because today we do have capital that we can apply outside the company. So we look forward to advancing that efforts within our business and advising you when we close some transactions.

當然。首先我想說的是，傑夫審視了我們更廣泛的策略，當我們審視公司外部時，我們所看到的一切都與我們對公司內部的思考方式完全一致。我們公司外部有三個重點關注的領域。顯然，首先是囊性纖維化。我們應該全面審視囊性纖維化，看看它是否能與我們影響疾病根本進程的方法相輔相成。因此，我們會關注所有動態變化，包括囊性纖維化的不同治療方式和療法。第二個領域其實是平台和早期技術。在過去的幾年裡，你們也看到了我們完成了一些對我們來說非常重要的交易，這些交易讓我們進入了新的科學領域和新的治療方式。特別是，傑夫在今晚的電話會議上向大家介紹了我們與 CRISPR Therapeutics 的合作情況，我們在 β-地中海貧血和鐮狀細胞貧血方面取得了非常好的進展。然後，我們繼續關注的第三個領域，在產品和藥物方面更具機會主義色彩，這些產品和藥物將與我們的整體疾病策略保持一致，從潛在的致病生物學到疾病本身，以及這些疾病如何融入 Vertex 並與我們在 Vertex 內部正在進行的工作保持一致。我們非常活躍。我們比以往任何時候都更加活躍。我們之所以能夠做到這一點，是因為我們現在確實擁有可以用於公司外部的資金。因此，我們期待在公司內部推進這些工作，並在完成一些交易時向您提供建議。

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

我們的下一個問題來自摩根士丹利的馬修·哈里森。

This is Jeff Hung in for Matthew. I guess, first, for SYMDEKO, are you seeing patients come back to the market? Can you comment on persistence and compliance compared to ORKAMBI?

這是 Jeff Hung 代替 Matthew 出場。首先，我想問的是，對於 SYMDEKO 而言，你們是否看到患者重新回到市場上？您能否評價一下它在持久性和合規性方面與 ORKAMBI 相比的表現？

Yes, Jeff. This is Stuart. So yes, we are seeing patients who had previously been initiated on ORKAMBI but have discontinued. We are seeing a large number of those patients be reinitiated on a CFTR modulator, in this case, SYMDEKO. And it really is that growth in patients who have been treated with a CFTR modulator are those who had discontinued or those who were naive to therapy, have never been treated with ORKAMBI, that's driving the growth in revenues that you saw in the second quarter. And it's adding new patients, which is underlying the increase in our revenue guidance that we gave tonight to $2.9 billion to $3 billion.

是的，傑夫。這是斯圖爾特。是的，我們看到一些患者之前接受過 ORKAMBI 治療，但後來停止了治療。我們看到很多患者重新開始使用 CFTR 調節劑，在這種情況下，使用的是 SYMDEKO。確實，接受 CFTR 調節劑治療的患者人數的成長，包括那些已經停止治療或從未接受過 ORKAMBI 治療的患者，才是推動第二季營收成長的主要因素。而且，新增病患數量也在增加，這正是我們今晚將營收預期上調至 29 億至 30 億美元的原因所在。

Great. And then can you comment on -- if you view the U.K. pricing dispute as isolated or potentially broadening out to the rest of Europe. The pricing to me is obviously very low compared to your existing prices.

偉大的。那麼，您能否就以下問題發表評論——您認為英國的價格糾紛是孤立的，還是有可能蔓延到歐洲其他地區？在我看來，這個價格顯然比你們現有的價格低很多。

Yes. So -- and I'll just start by reminding you and others on the call that we've been successful in a large number of countries across Europe in securing pricing and reimbursement agreements, be it Germany, Italy, Ireland, the Netherlands. And as a result of that, I'm thrilled to say that thousands of patients have access to ORKAMBI today. But obviously, our goal is to sure -- ensure that all eligible patients in all countries have access to ORKAMBI and, indeed, our future medicines. And so we are absolutely focused on securing reimbursement in those markets where we don't yet have access to patients. There's a number of significant markets obviously defined by the number of patients there, places like Australia and the U.K. There are particularly large numbers of patients there. And so obviously, we're very focused on those as we are in all countries where we don't yet have access. And we know those patients have been waiting too long, and we're not going to stop until we get access for those people.

是的。所以——首先我要提醒各位以及電話會議上的其他人，我們已經在歐洲許多國家成功達成了定價和報銷協議，無論是德國、義大利、愛爾蘭還是荷蘭。因此，我很高興地宣布，如今成千上萬的患者可以使用 ORKAMBI。但很顯然，我們的目標是確保所有國家所有符合條件的患者都能獲得 ORKAMBI 以及我們未來的藥物。因此，我們目前正全力以赴地確保在那些我們尚未接觸到患者的市場獲得報銷。顯然，有一些重要的市場是由當地患者數量決定的，例如澳洲和英國。這些國家的患者數量尤其龐大。因此，很顯然，我們非常關注這些國家，就像我們關注所有我們尚未進入的國家一樣。我們知道這些患者已經等待了太久，我們不會停止努力，直到這些人都能接受治療。

Great. And maybe one last one on the CRISPR IND. Now that you have written comments from the FDA about the IND hold, can you comment on the difference between what the U.K. and Canada regulators ask and what the FDA is asking? And any comments about what you need to do to proceed in the U.S.?

偉大的。或許最後還有一個關於 CRISPR IND 的問題。既然您已經就 FDA 暫停 IND 一事發表了評論，您能否評論一下英國和加拿大監管機構的要求與 FDA 的要求之間的區別？關於在美國繼續下一步需要做些什麼，您有什麼建議嗎？

Yes. We're obviously in those discussions with the FDA to answer their questions. As you know, this is likely going to be the first gene editing trial outside of cancer to be approved for human trials. And so I think the FDA is being appropriately cautious and conservative. We're in the process of answering their questions. We obviously don't comment on that while we're in those discussions. But as soon as we've answered them and have a clear plan for it, we'll let you know.

是的。我們顯然正在與FDA進行討論，以回答他們的問題。如你所知，這很可能是癌症以外第一個獲準進行人體試驗的基因編輯試驗。所以我認為FDA採取的謹慎和保守態度是恰當的。我們正在回答他們的問題。顯然，在討論過程中，我們不會對此事發表評論。但一旦我們解答了這些問題並製定了明確的計劃，我們會立即通知您。

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。

This is Gavin on for Terence. And maybe just one on the triple combo. Can you give us any update? Is there upside to completing enrollment before the end of the year and potentially starting -- or getting a readout before mid-2019?

這裡是加文替特倫斯報道。或許三連擊中一個就夠了。請問有什麼最新進展嗎？在年底前完成註冊並有可能在 2019 年年中之前開始或獲得結果，是否有好處？

Oh, yes. This is Jeff. So what we've told you today is really what we know. We're obviously early on in the enrollment of the 445 trials, so it's just too early to give you any more specifics than that. But I think the good news is that we're going to be able to complete enrollment of both of those trials earlier than we thought by the end of the year. And we're very confident that will allow us to make a choice of the best regimen and submit that application to the FDA by mid-2019.

哦是的。這是傑夫。所以，我們今天告訴大家的，就是我們所知道的全部。顯然，445項試驗的招募工作還處於早期階段，所以現在提供更多細節還為時過早。但我認為好消息是，我們能夠在年底前比預期更早完成這兩項試驗的受試者招募工作。我們非常有信心，這將使我們能夠選擇最佳方案，並在 2019 年年中之前向 FDA 提交申請。

Our next question comes from the line of Michael Yee from Jefferies.

我們的下一個問題來自傑富瑞集團的邁克爾葉。

This is Andrew on for Mike. Actually, to follow up on the last question, would you consider disclosing the data for both triples at the same time? Or would they be staggered one by one? Or would they be disclosed once you submit the NDA?

這裡是安德魯，替麥克報道。實際上，為了跟進上一個問題，您是否考慮同時披露這兩個三元組的數據？還是會一個接一個地錯開時間？或者，一旦提交保密協議，這些資訊就會被揭露嗎？

Hey, Andrew, it's Ian. At this point in time, it's just really too early to -- for us to figure out how we're going to disclose this. As Jeff made -- just previously in the comments, we've just announced that we expect to complete enrollment in the second half of this year. We are comfortable, based on that though, saying that we expect to file an NDA in the U.S. by no later than mid next year or mid-2019. But to start talking about how we would disclose data and how it rolls out and whether these studies are close enough together to do it both together -- it's just a little too early. We do -- we know it's an important issue to you and to other investors. And as the year progresses and we talk to you more, we'll give you guidance on how we think about it when we have greater visibility.

嘿，安德魯，我是伊恩。目前，我們還無法確定如何揭露此事。正如傑夫剛才在評論中提到的那樣，我們剛剛宣布，預計將在今年下半年完成招生工作。不過，基於此，我們有信心說，我們預計最遲將於明年年中或 2019 年年中在美國提交 NDA 申請。但是，現在就開始討論我們將如何揭露數據、如何發布數據，以及這些研究是否足夠接近，可以同時進行——還為時過早。我們當然知道——我們知道這對您和其他投資者來說是一個重要的問題。隨著時間推移，我們會與您進行更多交流，並在我們對這個問題有更清晰的認識時，向您提供我們的思考方向。

And just a quick follow-up on the Concert molecule, have you completed the dose-ranging studies? What else needs to happen basically to see that enter the Phase III?

關於 Concert 分子，還有一個後續問題，你們完成劑量範圍研究了嗎？要進入第三階段，基本上還需要發生什麼事？

This is Reshma. As you know, VX-561, which is the molecule we in-licensed from Concert, is an important part of our portfolio as we drive towards getting a medicine for 90% of patients with CF with a once-a-day pill. We are wrapping up our study design and discussing that with the FDA. And as soon as we finish all that up, we're going to be starting the trials.

這是雷什瑪。如你所知，VX-561 是我們從 Concert 公司引進的分子，是我們產品組合的重要組成部分，因為我們正在努力研發一種每天只需服用一次的藥物，就能讓 90% 的囊性纖維化患者受益。我們正在完善研究設計，並與FDA進行討論。一旦我們完成所有這些工作，我們將開始試驗。

Our next question comes from the line of Laura Chico from Raymond James.

我們的下一個問題來自 Raymond James 的 Laura Chico。

This is actually Timur Ivannikov for Laura. So I guess the first question we have is about seasonality of SYMDEKO. It looks like you've had a great launch, and the summer is halfway through in the U.S. And wondering if you can opine on the potential for any seasonal headwinds that might impact U.S. looking ahead. And how should we be thinking about this dynamic in 2H '18?

這其實是蒂穆爾·伊凡尼科夫為勞拉寫的。所以我想我們首先要問的是關於SYMDEKO的季節性問題。看來你們的啟動非常成功，而且美國的夏天已經過半。我想問你們能否就未來可能對美國市場產生影響的任何季節性不利因素發表一下看法。那麼，我們該如何看待2018年下半年的這種動態呢？

Yes, this is Stuart. So yes, it is not untypical to see a seasonal dip in compliance as people go on their vacations and their normal kind of routine, if I can call that, is disrupted. We've been focused on that for a number of years now. It certainly was a big focus of ours last year, it is again this year. And so we're going to be doing everything we can working with providers and directly with patients, where applicable, to try and maintain their compliance with their physicians' instructions. So exactly how that's going to play out, obviously, it's too early for us to say right now. But it's a phenomenon we're familiar with and one we certainly focused on very closely and will be doing that again this year.

是的，這是史都華。所以，是的，隨著人們度假，他們的正常生活節奏（如果可以稱之為正常生活節奏的話）被打亂，季節性的合規性下降並不罕見。我們多年來一直專注於此。這無疑是我們去年的重點工作，今年依然如此。因此，我們將盡一切努力與醫療服務提供者合作，並在適用情況下直接與患者合作，努力使他們遵守醫生的指示。所以，事情究竟會如何發展，顯然現在說還太早。但這是我們熟悉的現象，也是我們今年重點關注的現象，我們今年還會繼續關注。

Okay. And maybe a bigger question on -- bigger-picture question on reimbursement. Do you think the reimbursement landscape has changed or how the companies will continue to be rewarded for innovation has changed recently? Or has it always been a tough situation like it's been recently?

好的。或許還有一個更大的問題──一個關於報銷的更宏觀的問題。您認為近期健保報銷機制發生了變化嗎？或者說，企業因創新而獲得的獎勵方式改變了嗎？還是說情況一直都跟最近這樣艱難？

Yes, this is Jeff. So when we talk about reimbursement, we always separate the U.S. and Europe in that countries outside the U.S. are very, very different. In the U.S., we believe that innovation is rewarded. And that's really based on our own experience and those of others of breakthrough drugs like our 3 CF drugs that have very broad and very rapid coverage from all of the major players, including the government payers. And we don't see that changing over the coming years. In Europe, obviously, it's a very different environment. It's a single-payer environment. And again, over the last 2 to 3 years at least, it's been a difficult environment, I think, for all companies, including the innovative companies. I think one of the things we're pleased with, as Stuart said, is that we've been able to fairly rapidly secure reimbursement in a large number of European countries. And we're moving our discussions along in the several countries that remain, France, the U.K. and Australia being primary examples. It's always a bit of a difficult discussion, and we understand that those countries look at not only the price per patient but the total budget impact. But so far, we're pleased with what we're seeing. And we think that innovative, transformational breakthrough drugs will always be at the upper end of the reimbursement and price envelope. And those are the kind of drugs we're developing both in CF and beyond.

是的，這是傑夫。所以當我們談到報銷時，我們總是將美國和歐洲分開來看，因為美國以外的國家的情況非常非常不同。在美國，我們相信創新會得到獎勵。這實際上是基於我們自身以及其他突破性藥物的經驗，例如我們的 3 種 CF 藥物，這些藥物得到了包括政府支付方在內的所有主要參與者的廣泛且迅速的覆蓋。我們預計未來幾年這種情況不會改變。顯然，歐洲的環境截然不同。這是一個單一支付方制度。而且，至少在過去的2到3年裡，我認為對所有公司來說，包括創新公司在內，經營環境都非常艱難。正如史都華所說，我們感到欣慰的一點是，我們已經能夠相當迅速地在許多歐洲國家獲得報銷。我們正在與其餘幾個國家推進討論，其中法國、英國和澳洲是主要例子。這始終是一個比較棘手的話題，我們理解這些國家不僅要考慮每個病人的價格，還要考慮預算總影響。但就目前來看，我們對所看到的情況感到滿意。我們認為，具有創新性和變革性的突破性藥物，其報銷和價格範圍始終會處於較高水平。而這些正是我們正在研發用於治療囊性纖維化及其他疾病的藥物類型。

Our next question comes from the line of Geoffrey Porges from Leerink.

我們的下一個問題來自 Leerink 的 Geoffrey Porges。

Just real quick one, could you give us the U.S. sales of KALYDECO? Second, could you tell us the channel inventory contribution to this SYMDEKO revenue number? And then on the triple combination, you suggested no later than mid-2019. Could it be early 2019, given the fact that you're fully enrolled already? And regardless of when you file it, should we assume the same sort of accelerated review schedule that the FDA has given you for your previous combinations?

就問一個問題，您能提供一下 KALYDECO 在美國的銷售額嗎？其次，能否告知我們通路庫存對 SYMDEKO 營收的貢獻？至於三重組合，您建議最遲在 2019 年中完成。鑑於你已經全部入學，會不會是 2019 年初？無論何時提交申請，我們是否應該假設會像FDA之前對您之前的組合藥物那樣，給予同樣的加速審查時間表？

So yes, this is Stuart. On the KALYDECO U.S. sales, recorded net revenues for the quarter were $161 million. And in terms of channel inventory, there was no meaningful channel build at all in our Q2 numbers. All of the growth we saw there was driven by organic patient growth, more patients going onto our medicines.

是的，他就是史都華。KALYDECO 美國銷售方面，該季度記錄的淨收入為 1.61 億美元。就通路庫存而言，我們第二季的數據中根本沒有出現任何有意義的通路建設。我們看到的所有成長都是由患者的自然成長所推動的，也就是更多患者開始使用我們的藥物。

Sorry, this is Jeff, just talk about the time line. It's just too early to give you much more than we've given you today, which is what we know, that we're now very confident, based on what we've seen with the 659 enrollment and the very beginning of the 445 enrollment, that both trials will complete. You made one statement, Geoff, I just want to make sure I do, do clarify, which, as you said, that we're -- we've completed enrollment. We actually have not completed enrollment of the 659 trial yet, so I do want to be accurate about that. But we do think both trials will complete -- or both programs will complete enrollment by the end of the year. And if you do the math on that then, that would allow us to compare the regimens, file an NDA in the U.S. by midyear. You asked about how the FDA will deal with these. Obviously, I don't speak for the FDA, and I can't. And it's going to depend on the data. So if the data is as promising as our Phase II data, we're obviously going to push very hard. And I think the FDA is very interested in moving as quickly as possible, taking all appropriate precautions. But I think we're going to have to see the data.

抱歉，我是傑夫，我們來談談時間線吧。現在透露更多資訊還為時過早，我們今天只能透露我們目前所知道的，根據 659 名受試者的入組情況和 445 名受試者入組的初期情況，我們非常有信心，這兩項試驗都將完成。傑夫，你剛才說過一句話，我只是想確認一下，就像你說的，我們已經完成了註冊。我們實際上還沒有完成 659 試驗的招募工作，所以我想確保這一點準確無誤。但我們認為這兩項試驗都將在年底前完成——或者說，這兩個項目都將在年底前完成招募。如果進行相應的計算，我們就可以比較這些方案，並在年中之前在美國提交新藥申請。你問到FDA將如何處理這些問題。顯然，我不能代表美國食品藥物管理局發言。這取決於數據。所以，如果數據和我們的二期數據一樣令人鼓舞，我們顯然會全力以赴。我認為美國食品藥物管理局（FDA）非常希望盡快採取行動，並採取一切適當的預防措施。但我認為我們還需要看看數據。

Our next question comes from the line of Brian Abrahams from 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。

Just want to go back to reimbursement internationally and just sort of wondering what your expectations are and sort of next steps for some of the key ex U.S. countries like U.K. and France. I guess, I'm curious, is there just a fundamental difference in the views on the value of disease-modifying medicines? Or do you believe that with additional negotiations or with additional data and perhaps triple combo data, you can sort of get past this, and this is resolvable?

我只是想回到國際報銷的問題上來，想知道您對一些主要的美國以外的國家（如英國和法國）的報銷有什麼期望以及下一步的步驟。我很好奇，對於疾病改善藥物的價值，是否存在根本性的觀點差異？或者您認為，透過進一步談判或獲得更多數據，甚至三重組合數據，就可以克服這個問題，這個問題是可以解決的？

Yes, so Brian, thanks for the question. So in terms of specifically where we are in the U.K. and Australia, the 2 countries that you referenced, in the U.K., obviously, we recently received a counteroffer from the NHS. We and many in the CF community believe that offer significantly undervalues both our current and our future medicines. And so we're not able to accept that offer. And in terms of next steps, we're looking to meet with those -- the head of the NHS and, indeed, the Minister of Health to try and progress those discussions. As I said, we're not certainly going to give up on fighting for access for those patients in the U.K. who've been waiting too long. In Australia, ORKAMBI, both the 6-11 indication and the 12-plus indication were reviewed by the Pharmaceutical Benefits Advisory Committee, PBAC, in Australia, which is the body that reviews both clinical effectiveness and cost effectiveness. We're yet to receive their formal minutes from that meeting. And when we do, which will be in the next few weeks, then that will help us determine what the path forward there is. What I would say is that, as I referenced in the answer to an earlier question, we have successfully secured pricing and reimbursement in a number of other countries in Europe where now thousands of patients are able to access ORKAMBI. And importantly, we were able there to strike pricing and reimbursement agreements, which we believe give us a fair price for the level of clinical benefit and innovation that ORKAMBI delivers. And we need that fair return to enable us to continue the journey in CF and other diseases, as Jeff was describing in his prepared remarks. So we are going to continue to fight for access in the U.K. and Australia to get access for those patients who've been waiting too long, but we can only do that at a price which fairly reflects the value of the medicines and the benefit they bring for patients.

是的，布萊恩，謝謝你的提問。所以就我們目前在英國和澳洲這兩個你提到的國家的具體情況而言，在英國，顯然，我們最近收到了來自英國國家醫療服務體系 (NHS) 的反提案。我們和許多囊性纖維化患者都認為，這種報價嚴重低估了我們目前和未來的藥物價值。因此，我們無法接受該提議。至於下一步措施，我們希望與英國國家醫療服務體系 (NHS) 的負責人以及衛生部長會面，以推進相關討論。正如我所說，我們絕不會放棄為英國那些等待時間過長的患者爭取治療機會。在澳大利亞，ORKAMBI 的 6-11 歲適應症和 12 歲及以上適應症均由澳大利亞藥品福利諮詢委員會 (PBAC) 進行審查，該委員會負責審查臨床療效和成本效益。我們尚未收到那次會議的正式會議記錄。而當我們在接下來的幾週內完成這項工作時，這將有助於我們確定未來的發展方向。我想說的是，正如我在對先前問題的回答中所提到的，我們已經成功在歐洲其他一些國家獲得了定價和報銷，現在成千上萬的患者能夠獲得 ORKAMBI 服務。更重要的是，我們在那裡達成了定價和報銷協議，我們認為這些協議為 ORKAMBI 帶來的臨床益處和創新水平提供了公平的價格。正如傑夫在事先準備好的演講稿中所描述的那樣，我們需要這種公平的回報，才能讓我們繼續在囊性纖維化和其他疾病領域進行研究。因此，我們將繼續在英國和澳洲爭取藥品獲取權，讓那些等待時間過長的患者能夠獲得藥品，但我們只能以能夠公平反映藥品價值及其給患者帶來的益處的價格來實現這一目標。

Our next question comes from the line of Geoff Meacham from Barclays.

下一個問題來自巴克萊銀行的傑夫·米查姆。

This is Olivia Brayer on for Geoff. Just a question on the triples, are you expecting 659 or 445 to yield better results in one population over the other? And maybe as a follow-up, have you given any more thought as to what your strategy and objective is in triple combinations beyond these 2?

這裡是奧莉薇亞·布雷耶，替傑夫為您報道。關於三聯體的問題，您認為在某個群體中，659 還是 445 會產生更好的結果？或許可以作為後續問題，除了這兩種組合之外，您是否進一步思考過您的三重組合策略和目標是什麼？

Yes, this is Jeff. So let me answer each of those. Just to take you back to the Phase II data, you'll remember that 445 and 659, in fact, all 4 of our triple combinations, were remarkably similar. In fact, the consistency and the similarity of the data was quite striking. That's really the only data we have to make assumptions about Phase III. That's why we're doing the Phase III studies. But based on that data, we would expect 659 and 445 from an efficacy standpoint to be quite similar. Beyond these 2, your next part of the question, I said before we continue to develop additional next-generation correctors. And it's actually fairly remarkable, we have many of them, and they continue to improve over time. And so that we're left with a sort of a good problem, which is which of these do we take into the clinic? We obviously can't take them all because we have 20 or 30 of them at this point that are better. Which of them -- will we take -- how much better do they have to be? Our goal is to get everyone to carrier level. And as you know, even with 659 and 445, we're quite close in some population. And so you should expect to see one or more of them come into the clinic. We're just trying to choose which one and put a threshold on for how much better it needs to be before we bring them in. But they're moving forward pretty quickly, so I think you can expect to see additional compounds entering the clinic.

是的，這是傑夫。讓我逐一回答這些問題。回顧一下 II 期數據，您應該記得 445 和 659，實際上，我們所有的 4 個三聯體，都非常相似。事實上，數據的一致性和相似性非常驚人。這其實是我們唯一可以用來對第三階段做出假設的數據。這就是我們進行 III 期研究的原因。但根據這些數據，從療效的角度來看，我們預期 659 和 445 會非常相似。除了這兩項之外，關於你問題的下一部分，我之前說過，我們會繼續開發更多下一代矯正器。事實上，這相當了不起，我們有很多這樣的項目，而且隨著時間的推移，它們還在不斷改進。因此，我們就面臨一個比較好的問題，那就是我們應該把這些方法中的哪些應用在臨床實務上呢？我們顯然不能全部拿下，因為目前我們有二三十個更好的選擇。我們該選擇哪一個？它們需要比我們好多少？我們的目標是讓每個人都達到職業選手水準。如你所知，即使我們的票數分別為 659 和 445，在某些人口統計方面，我們的票數也相當接近。因此，您應該會看到他們中的一個或多個來診所就診。我們只是想選出一個合適的，並設定一個標準，說明在引進他們之前，他們需要改進多少。但他們的進展非常迅速，所以我認為可以期待看到更多化合物進入臨床試驗階段。

Our final question then comes from the line of Cory Kasimov from JPMorgan.

那麼，我們最後一個問題來自摩根大通的科里·卡西莫夫。

This is Carmen on for Cory. Most of my questions have been answered, but just one more. We've recently seen some data from some of your competitors, and we're likely to see more in the coming months. What are your latest thoughts on competitive positioning of your franchise? And what continues to give you confidence in maintaining your leadership position?

這裡是卡門替科里發言。我的大部分問題都已得到解答，但還有一個問題。我們最近看到了一些來自你們競爭對手的數據，而且我們很可能在未來幾個月看到更多。您對貴公司特許經營的競爭定位有何最新看法？是什麼讓你對維持領導地位充滿信心？

Yes, thanks for the question, it's obviously an important one. As you know, we don't comment on individual competitors. You'll have to ask them about their programs, and we've seen some of those results recently. I would comment on where we think we are, and your second part of the question, what gives us so much confidence. We're really pleased with where we are. As I said in my prepared remarks, actually, I've been within this industry for 35, 40 years. I don't think I've ever seen 2 molecules progress from synthesis into -- well into Phase III or a completion of Phase III in 2 to 2.5 years. It's been a really remarkably accelerated journey for these 2 triple combinations. And so we feel better and better about our competitive position, both based on the data and based on the speed at which we're moving. As I said, we should be in a position to file an NDA in the U.S. and also an application in Europe shortly thereafter for the best of these triple regimens that can provide therapy to up to 90% of patients at very high levels of efficacy. What gives us confidence? It's really our 20 years of understanding of the biology of this disease, the ability that we've run our HB assay several hundred thousand times and they predict the human results virtually perfectly, quantitatively. That's held up with the triples as well. And we're making better and better triples as we go, and so we're actually getting very close to our goal of getting to carrier levels. And as you know, when you're at carrier levels, carriers don't get the disease. So our goal is very simple, get a medicine, a triple medicine to patients that provides carrier levels for everyone. Get it to them as young as possible, and we believe they won't develop cystic fibrosis as we know the disease today. And we're well down that road.

是的，謝謝你的提問，這顯然是一個重要的問題。如您所知，我們不對個別競爭對手發表評論。你需要向他們詢問他們的專案狀況，我們最近也看到了一些成果。我想就我們認為我們所處的位置以及你問題的第二部分——是什麼讓我們如此自信——發表一些看法。我們對目前的狀況非常滿意。正如我在準備好的演講稿中所說，實際上，我從事這個行業已經有35到40年了。我從未見過兩個分子從合成到進入 III 期臨床試驗，或在 2 到 2.5 年內完成 III 期臨床試驗的情況。對於這兩組三重組合來說，這真是令人矚目的快速發展歷程。因此，無論從數據或從我們前進的速度來看，我們都對自己的競爭地位越來越有信心。正如我所說，我們應該能夠在美國提交新藥申請，並在此之後不久在歐洲提交申請，申請的是這些三聯療法中最好的一種，這種療法能夠以非常高的療效為高達 90% 的患者提供治療。是什麼讓我們充滿信心？這實際上是我們 20 年來對這種疾病生物學的了解，以及我們進行了數十萬次 HB 檢測，並且能夠幾乎完美地定量預測人類檢測結果的能力。三分球的情況也一樣。而且我們一直在不斷改進三重奏，所以我們實際上已經非常接近達到承運商水準的目標了。如你所知，當病毒攜帶者處於攜帶水平時，攜帶者本身不會生病。所以我們的目標很簡單，就是為患者提供一種藥物，一種三效合一的藥物，可以為每個人提供載體水平。儘早讓他們接受治療，我們相信他們不會患上我們今天所知的囊性纖維化這種疾病。我們在這方面已經走得很遠了。

This does conclude the question-and-answer session of today's program. I'd like to hand the program back to Michael Partridge for any further remarks.

今天的問答環節到此結束。我謹將發言權交還給麥可‧帕特里奇，請他再作發言。

Thank you very much, everybody, for joining us this evening. The Investor Relations team will be here if you have any additional questions. We'd be happy to talk to you. Thanks.

非常感謝各位今晚的到來。如有任何其他疑問，投資者關係團隊將隨時為您解答。我們很樂意與您交談。謝謝。

Thank you, ladies and gentlemen, for your participation in today's conference. This does conclude the program. You may now disconnect. Good day.

感謝各位女士、先生參加今天的會議。節目到此結束。您現在可以斷開連線了。再會。