福泰製藥 (VRTX) 2020 Q2 法說會逐字稿

Good evening. Welcome to the Vertex Second Quarter 2020 Financial Results Conference Call. This is Michael Partridge, Senior Vice President of Investor Relations for Vertex. Making prepared remarks on the call tonight, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Stuart Arbuckle, Chief Commercial Officer; and Charlie Wagner, Chief Financial Officer. We recommend that you access the webcast slides on our website as you listen to this call.

晚安.歡迎參加Vertex公司2020年第二季財務業績電話會議。這是 Vertex 公司投資者關係資深副總裁 Michael Partridge。今晚在電話會議上發表準備好的演講的有：Vertex 執行長兼總裁 Reshma Kewalramani 博士；商務長 Stuart Arbuckle；以及財務長 Charlie Wagner。我們建議您在收聽本次電話會議的同時，請造訪我們網站上的網路直播投影片。

This conference call is being recorded, and a replay will be available on our website. We will make forward-looking statements on this call that 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, our pipeline and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

本次電話會議正在錄音，錄音回放將在我們的網站上提供。我們將在本次電話會議上發表前瞻性聲明，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、我們的研發管線和 Vertex 未來財務業績的聲明，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 would also note that all of the financial results and guidance that we will review on this call this evening are non-GAAP.

我還要指出，我們今晚電話會議上將要討論的所有財務表現和指引均為非GAAP準則。

I will now turn the call over to Dr. Reshma Kewalramani.

現在我將把電話轉給雷什瑪·凱瓦拉瑪尼醫生。

Thanks, Michael. 2020 continues to be a year of remarkable progress for Vertex across all aspects of our business, as measured by the continued strong performance of the TRIKAFTA launch in the U.S.; the recent positive CHMP opinion for the triple combination regimen in Europe; completion of a landmark reimbursement agreement to expand access to the triple combination for patients in England; and the advancement of our late preclinical and clinical stage pipeline programs, most notably, our proof-of-concept data for CTX001 that underscores the curative potential of this therapy in both beta-thalassemia and sickle cell disease. I'm especially proud that the Vertex team has been able to accomplish all of this despite the challenges presented by the COVID-19 pandemic and want to acknowledge the resilience and commitment of all of our employees to continue to deliver on our goals for patients.

謝謝你，麥可。2020 年對於 Vertex 而言，在業務的各個方面都取得了顯著進展，這體現在 TRIKAFTA 在美國的持續強勁表現；歐洲三聯療法近期獲得 CHMP 的積極意見；完成一項具有里程碑意義的報銷協議，擴大了英國患者獲得三聯療法的機會；以及我們後期臨床前和臨床階段製定研發新計畫的數據，尤其值得驗證的數據，尤其值得在 CTX0101010101010119619616010010019963數據是解決了這種治療，尤其是這種治療的概念，尤其值得了該數據，尤其值得在 CTX 項目的數據，是這種治療的概念，尤其是這種治療的概念，這是在 CTX 項目的情況下提列數據，尤其值得在 CTX0101 之前是這種治療，這是強調了這種數據，尤其值得了這種治療的情況，尤其值得在 CTX 項目的情況下是這種治療，尤其值得了這種治療。 β-地中海貧血和鐮狀細胞疾病方面的治癒潛力。我特別感到自豪的是，儘管面臨 COVID-19 疫情帶來的挑戰，Vertex 團隊仍然能夠完成所有這些工作，我想感謝我們所有員工的韌性和奉獻精神，他們繼續為患者實現我們的目標。

Turning first to our CF medicines. Today, the vast majority of our eligible patients in the U.S. have begun treatment with TRIKAFTA, reflecting the significant and fundamental benefit that this medicine provides by addressing the underlying cause of disease. The rate of uptake for TRIKAFTA and the speed at which we have obtained broad reimbursement speak to the appreciation of the therapeutic profile of this medicine, which we believe will be the foundation of CF therapy for many years to come.

首先來看我們的囊性纖維化藥物。今天，我們在美國符合條件的絕大多數患者已經開始接受 TRIKAFTA 治療，這反映了這種藥物透過解決疾病的根本原因而帶來的重大而根本的益處。TRIKAFTA 的普及率以及我們廣泛報銷的速度，都顯示了人們對這種藥物治療效果的認可，我們相信它將成為未來多年囊性纖維化治療的基礎。

Outside the U.S., in June, we received a positive CHMP opinion for the triple combination regimen, which, if approved, will be known in Europe as KAFTRIO. This positions us for an earlier-than-expected approval in Europe in the coming months, which would provide up to 10,000 new patients with the first medicine to treat the underlying cause of their disease. Following the anticipated approval later this year in Europe, we plan to seek a potential expansion of the KAFTRIO label to include patients with one F508del mutation and a residual function or gating mutation based on the positive Phase III data reported earlier this month that showed KAFTRIO add significant additional benefit in these patients.

在美國以外，6 月我們收到了 CHMP 對三重療法的積極意見，如果獲得批准，該療法在歐洲將被稱為 KAFTRIO。這將使我們在未來幾個月內比預期更早在歐洲獲得批准，這將為多達 10,000 名新患者提供第一種治療其疾病根本原因的藥物。繼今年稍晚在歐洲獲得預期批准後，我們計劃尋求擴大 KAFTRIO 的適應症範圍，將患有一個 F508del 突變和殘餘功能或門控突變的患者納入其中。這是基於本月早些時候公佈的積極的 III 期數據，數據顯示 KAFTRIO 為這些患者帶來了顯著的額外益處。

We are also pleased that we were recently able to expand our reimbursement agreement with NHS England to include KAFTRIO, allowing thousands of patients in England to begin receiving this medicine once European Commission approval occurs. This is truly a landmark achievement for patients and builds on our other innovative reimbursement agreements, such as those in Ireland and Denmark that include KAFTRIO as well as our other medicines. Reaching these agreements in advance of regulatory approval is uncommon and reflects a shared belief in the value and benefit of our medicines in treating the underlying cause of cystic fibrosis.

我們也很高興最近能夠擴大與英國國家醫療服務體系 (NHS England) 的報銷協議，將 KAFTRIO 納入其中，一旦獲得歐盟委員會的批准，英國成千上萬的患者就可以開始接受這種藥物。這對患者來說確實是一項里程碑式的成就，它建立在我們其他創新報銷協議的基礎上，例如在愛爾蘭和丹麥達成的涵蓋 KAFTRIO 以及我們其他藥物的報銷協議。在獲得監管部門批准之前達成這些協議並不常見，這反映出我們對藥物在治療囊性纖維化根本原因方面的價值和益處的共同信念。

Based on our year-to-date performance, driven primarily by TRIKAFTA, we are again revising upward our 2020 revenue guidance, which Stuart and Charlie will discuss in more detail in a moment. Beyond 2020, we retain clear line of sight to reaching our long-standing goal of bringing the triple combination to 90% of all CF patients worldwide, as we obtain additional regulatory approvals, including approvals to treat younger patients and reimbursement agreements globally.

根據我們今年迄今為止的業績（主要歸功於 TRIKAFTA），我們再次上調了 2020 年的收入預期，Stuart 和 Charlie 稍後將對此進行更詳細的討論。展望 2020 年後，我們仍清楚地朝著實現長期目標邁進，讓全球 90% 的囊性纖維化患者都能接受三合一療法。我們將獲得更多監管批准，包括治療年輕患者的批准和全球報銷協議。

Turning to our programs beyond CF, where we are advancing a differentiated and broad pipeline of small molecule, cell and genetic therapies for a range of serious diseases. Despite the challenges of the COVID-19 pandemic, we have now been able to reinitiate enrollment and dosing in all of our clinical trials, and we've also been able to initiate new clinical studies during this period.

展望我們在 CF 以外的項目，我們正在推動一系列差異化且廣泛的小分子、細胞和基因療法，以治療多種嚴重疾病。儘管面臨 COVID-19 疫情帶來的挑戰，我們現在能夠重新啟動所有臨床試驗的招募和給藥，並且在此期間我們也能夠啟動新的臨床研究。

Let me go into more detail on a few of these programs. In our CRISPR-Cas9 gene editing program with CTX001, we and our partner, CRISPR Therapeutics, announced new clinical data at the EHA meeting last month that highlighted the curative potential of gene editing in 2 serious diseases, beta-thalassemia and sickle cell disease. A total of 7 patients had been treated with CTX001 as of the EHA meeting. And all of these patients had successfully engrafted, which is an important yet early sign of their potential response to treatment. Of note, we have now resumed conditioning and dosing in both studies of CTX001 and have dosed additional patients across the program in recent weeks. This program continues to gain momentum as we enroll and treat even more patients, and we expect to report additional data later in 2020.

讓我更詳細地介紹其中幾個項目。在我們的 CRISPR-Cas9 基因編輯計畫 CTX001 中，我們和我們的合作夥伴 CRISPR Therapeutics 上個月在 EHA 會議上公佈了新的臨床數據，突顯了基因編輯在兩種嚴重疾病（β-地中海貧血和鐮狀細胞疾病）中的治癒潛力。截至歐洲血液學協會 (EHA) 會議召開時，共有 7 名患者接受了 CTX001 治療。所有這些患者都成功植入了移植體，這是他們對治療可能產生反應的一個重要但早期的跡象。值得注意的是，我們現在已經恢復了 CTX001 兩項研究的預處理和給藥，並且在最近幾週內為該計畫中的其他患者進行了給藥。隨著我們招募和治療更多患者，該計畫持續發展壯大，我們預計將在 2020 年稍後公佈更多數據。

In AAT, we have now reinitiated enrollment in the Phase II study of VX-814 at all sites that have indicated the ability to resume clinical trials. This means that some, but not all clinical trial sites have been reopened and are screening and enrolling patients in the VX-814 study. We have also now initiated a similar Phase II study with our second AAT corrector, VX-864.

在 AAT，我們現在已經重新啟動了 VX-814 II 期研究的入組，所有表示有能力恢復臨床試驗的地點都已恢復入組。這意味著部分臨床試驗中心已經重新開放，正在篩選並招募病患參與 VX-814 研究。我們現在也針對我們的第二個 AAT 矯正器 VX-864 啟動了類似的 II 期研究。

Ultimately, the pace of enrollment will dictate the timing for data readouts from VX-814 and VX-864. We now expect data from the VX-814 study toward the end of 2020 or Q1 2021. In the next several months, we will have a much clearer picture of enrollment dynamics for these studies and when to expect data for each molecule. Our goal is to evaluate data from each Phase II study and to pick the best molecule to advance into late-stage development. This is consistent with our strategy of cracking the biology and then pouring on the chemistry to allow us to discover multiple molecules that we can simultaneously advance through proof-of-concept and pick the best molecule then for further development, just as we did in CF.

最終，VX-814 和 VX-864 的資料讀取時間將取決於招募速度。我們現在預計 VX-814 研究的數據將在 2020 年底或 2021 年第一季公佈。在接下來的幾個月裡，我們將對這些研究的招募動態以及何時可以預期獲得每種分子的數據有更清晰的了解。我們的目標是評估每項 II 期研究的數據，並挑選出最好的分子進入後期開發階段。這與我們攻克生物學難題，然後深入化學領域，從而發現多種分子，並同時推進概念驗證，最終選擇最佳分子進行進一步開發的策略相一致，就像我們在 CF 領域所做的那樣。

In APOL1-mediated FSGS, multiple clinical trial sites are now open for screening and enrollment in our Phase II study of VX-147, evaluating the reduction of proteinuria over 13 weeks. We expect to obtain data from this study in 2021.

在 APOL1 介導的 FSGS 中，多個臨床試驗中心現已開放，可供患者進行篩選和入組，參與我們的 VX-147 II 期研究，該研究旨在評估 13 週內蛋白尿的減少情況。我們預計將於 2021 年獲得這項研究的數據。

And with our cell therapy for type 1 diabetes, we are tracking for an IND submission in late 2020, to support initiation of our first study to evaluate the islet cells alone in patients with type 1 diabetes. The advancement of key IND-enabling activities and the generation of preclinical data to support the IND package in type 1 diabetes were key priorities in the first half of the year and have remained on track through the COVID-19 pandemic.

針對我們的 1 型糖尿病細胞療法，我們正計劃在 2020 年底提交 IND 申請，以支持啟動我們的第一項研究，該研究旨在單獨評估胰島細胞對 1 型糖尿病患者的療效。今年上半年，推進關鍵的 IND 申報活動和產生支持 1 型糖尿病 IND 申報包的臨床前數據是重點工作，並且在 COVID-19 疫情期間也保持了進度。

With that summary of the business and review of the R&D portfolio, let me turn it over to Stuart.

以上是對業務概況和研發組合的回顧，現在讓我把麥克風交給史都華。

Thanks, Reshma. I am pleased to review with you this evening our continued strong commercial performance. TRIKAFTA revenues for the second quarter were $918 million, reflecting very rapid uptake in the U.S. across the vast majority of all eligible patients. We have received rapid and broad reimbursement from both public and private payers, and feedback from patients and CF centers has been highly positive, consistent with the strong benefit/risk profile for this medicine.

謝謝你，雷什瑪。今晚我很高興與各位一起回顧我們持續強勁的商業表現。TRIKAFTA 第二季度的營收為 9.18 億美元，反映出該產品在美國絕大多數符合條件的患者中得到了非常迅速的推廣。我們已從公共和私人支付方獲得了快速而廣泛的報銷，患者和囊性纖維化中心的反饋也非常積極，這與該藥物的良好效益/風險比相符。

Our TRIKAFTA revenues to date in 2020 have also benefited from very strong persistence and compliance trends and from increased patient inventory levels as a result of early refills amidst the COVID-19 pandemic. I am proud of the teams that have worked tirelessly to execute such a phenomenal launch, which has exceeded even our own expectations. And I am thankful for the commitment of the CF community to working with us to help get so many patients on to TRIKAFTA since its approval in October last year.

2020 年至今，我們的 TRIKAFTA 收入也受益於非常強勁的持續性和合規性趨勢，以及 COVID-19 大流行期間患者提前續藥導致的庫存水準增加。我為辛勤工作的團隊感到自豪，他們成功完成瞭如此驚人的產品發布，甚至超出了我們自己的預期。我感謝 CF 社群與我們攜手合作，幫助眾多患者自去年 10 月 TRIKAFTA 獲準以來接受治療。

We now have the opportunity to build on this strong performance of the U.S. launch with an earlier-than-expected potential approval in Europe. This approval, which is anticipated to come in the next few months, will allow up to 10,000 new patients with a minimal function mutation to be treated with a medicine for the underlying cause of their disease for the first time. Further accelerating our ability to bring this medicine to patients is the recent expansion of our agreement with England to include immediate reimbursement of KAFTRIO for patients ages 12 and older upon EC approval, as well as reimbursement for all future label expansions for KALYDECO, ORKAMBI, SYMKEVI and KAFTRIO.

我們現在有機會憑藉美國市場強勁的上市表現，在歐洲獲得比預期更早的潛在批准。預計在未來幾個月內獲得的這項批准，將使多達 10,000 名患有最小功能突變的新患者首次能夠接受針對其疾病根本原因的藥物治療。為了進一步加速我們為患者提供這種藥物的能力，我們最近擴大了與英格蘭的協議，包括在獲得歐盟批准後立即為 12 歲及以上患者報銷 KAFTRIO，以及為 KALYDECO、ORKAMBI、SYMKEVI 和 KAFTRIO 的所有未來標籤擴展提供報銷。

This unique agreement provides the CF patient community in England with certainty that they will be among the first in Europe to receive our CF medicines. We are very pleased with this expanded agreement, which is a reflection of the importance and value of treating the underlying cause of CF with our medicines. We would like to thank NHS England and the CF patient community for their commitment to working collaboratively with us towards this agreement over recent months. And we are working with the other developed nations in the U.K. to finalize equivalent agreements as soon as possible.

這項獨特的協議讓英國的囊性纖維化患者群體確信，他們將成為歐洲首批獲得我們囊性纖維化藥物的患者群體之一。我們對這項擴大協議感到非常高興，這反映了用我們的藥物治療囊性纖維化根本病因的重要性和價值。我們衷心感謝英國國家醫療服務體系 (NHS England) 和囊性纖維化患者群體在過去幾個月與我們通力合作，促成了這項協議。我們正與英國其他已開發國家合作，盡快敲定同等協議。

As a result of our strong start to 2020, we are again raising our revenue guidance for the year. And I will offer the following perspective regarding launch dynamics in the U.S. and how we view the anticipated KAFTRIO launch in the EU. First, we are 9 months into the TRIKAFTA launch in the U.S., and the vast majority of all eligible patients have now begun treatment. Second, the compliance and persistence rates and patient inventory levels we have seen to date with the launch are high, and we expect them to normalize in the second half of the year. And third, we will be launching KAFTRIO in Europe amidst an ongoing and rapidly evolving global pandemic. This may significantly impact patients' ability to see their physicians for treatment initiation visits and to conduct important laboratory and clinical work to support initiation of KAFTRIO. It will also be the first time that our teams have had to execute a launch virtually.

由於 2020 年開局強勁，我們再次上調了全年的營收預期。我將就美國發射動態以及我們如何看待歐盟預期的 KAFTRIO 發射提供以下觀點。首先，TRIKAFTA 在美國推出已經 9 個月了，絕大多數符合條件的患者現在都開始接受治療。其次，就目前來看，產品上市後的依從率、持續使用率和病患庫存水準都很高，我們預期下半年這些指標將趨於正常化。第三，我們將在持續且迅速演變的全球疫情中在歐洲推出 KAFTRIO。這可能會嚴重影響患者就診進行治療啟動訪視以及進行重要的實驗室和臨床工作以支持 KAFTRIO 治療啟動的能力。這也將是我們的團隊首次進行線上產品發表。

As in the U.S., we ultimately expect to treat the vast majority of eligible patients in Europe. However, the exact trajectory of the launch in Europe is uncertain. All of these factors and their potential impact on future quarters are reflected in our revised revenue guidance, which Charlie will review in more detail momentarily.

與美國一樣，我們最終希望能夠治療歐洲絕大多數符合條件的患者。然而，該武器在歐洲的發射軌跡尚不確定。所有這些因素及其對未來幾季的潛在影響都已反映在我們修訂後的收入預期中，查理稍後將對此進行更詳細的審查。

We expect CF revenue growth beyond 2020. This growth will be driven primarily by additional approvals and reimbursement agreements for KAFTRIO outside the U.S. and by expanding the TRIKAFTA and KAFTRIO labels to treat younger patients. As markers of our continued progress to reach more patients with our medicines, our regulatory submissions for the triple combination are complete in Australia and Switzerland. And following potential EU approval of KAFTRIO later this year, we plan to begin discussions in countries where we are not yet reimbursed with the goal of providing access to this medicine for eligible patients as rapidly as possible.

我們預計 CF 收入在 2020 年以後將持續成長。這一增長主要得益於 KAFTRIO 在美國以外地區獲得更多批准和報銷協議，以及擴大 TRIKAFTA 和 KAFTRIO 的適應症範圍以治療更年輕的患者。作為我們不斷努力讓更多患者受益於我們的藥物的標誌，我們在澳洲和瑞士完成了三聯療法的監管申報。今年晚些時候，KAFTRIO 預計將獲得歐盟批准，屆時我們將開始與尚未獲得醫療保險報銷的國家展開討論，目標是盡快讓符合條件的患者獲得這種藥物。

We also remain on track to submit a supplemental new drug application for TRIKAFTA in the U.S. in the fourth quarter of 2020 for children ages 6 to 11 years of age with one F508del mutation. If approved, some 1,500 new patients in the U.S. would be eligible for a medicine to treat the cause of their CF beginning in 2021. We expect this submission would be followed rapidly by similar label expansion efforts outside the U.S. and by additional Phase III studies to support approval in even younger children.

我們也將繼續按計畫於 2020 年第四季在美國提交 TRIKAFTA 的補充新藥申請，用於治療 6 至 11 歲患有 F508del 突變的兒童。如果獲得批准，從 2021 年開始，美國將有約 1500 名新患者有資格獲得治療囊性纖維化病因的藥物。我們預計，在此次申請之後，美國以外地區將很快出現類似的標籤擴展申請，並將進行額外的 III 期研究，以支持批准該藥物用於更小的兒童。

In summary, Vertex remains on a trajectory of significant near-term and long-term revenue growth as we bring TRIKAFTA and KAFTRIO to more patients globally in the coming months and years. I am pleased with the significant commercial progress we've seen to date in 2020.

總而言之，隨著我們在未來幾個月和幾年內將 TRIKAFTA 和 KAFTRIO 帶給全球更多患者，Vertex 將繼續保持近期和長期收入顯著增長的勢頭。我對我們在2020年迄今取得的顯著商業進展感到滿意。

And we'll now turn the call over to Charlie.

現在我們將把電話交給查理。

Thanks, Stuart. Our financial performance for the second quarter was exceptional, highlighted by continued significant growth in CF product revenues following the launch of TRIKAFTA. Second quarter total CF product revenues were $1.52 billion, a 62% increase compared to 2019, bringing our year-to-date revenues to just over $3 billion. Our second quarter revenues included $1.21 billion in revenues in the U.S. and $314 million in revenues outside the U.S. Revenues from outside the U.S. in the second quarter grew 31% over the prior year, driven by strong patient uptake of ORKAMBI and SYMKEVI, following the completion of multiple reimbursement agreements in late 2019. Both in the U.S. and in countries outside the U.S. where our medicines are reimbursed, the vast majority of eligible patients have now initiated treatment with our medicines.

謝謝你，斯圖爾特。第二季的財務表現非常出色，尤其是在 TRIKAFTA 上市後，CF 產品收入持續大幅成長。第二季 CF 產品總營收為 15.2 億美元，比 2019 年成長了 62%，使我們今年迄今的營收略高於 30 億美元。我們第二季的營收包括美國境內的 12.1 億美元營收和美國境外的 3.14 億美元營收。第二季度美國境外的營收比去年同期成長了 31%，這主要得益於 ORKAMBI 和 SYMKEVI 在 2019 年底完成多項報銷協議後，患者對其的積極接受。無論是在美國還是在美國以外的、我們的藥物可以報銷的國家，絕大多數符合條件的患者現在都已經開始使用我們的藥物進行治療。

Our second quarter 2020 combined R&D and SG&A expenses were $467 million compared to $394 million for the second quarter of 2019, bringing our year-to-date expenses to $945 million. As we've said previously, our 2020 expenses reflect greater investment to support the use of our CF medicines globally and the expansion of our pipeline into new diseases. The significant growth in revenues, combined with more moderate growth in spending resulted in year-to-date operating margin of 58% and year-to-date operating income of $1.75 billion, an increase of 122% compared to operating income in the first half of 2019. Year-to-date net income for 2020 was $1.36 billion compared to $623 million for the first half of 2019.

2020 年第二季度，我們的研發和銷售、一般及行政費用合計為 4.67 億美元，而 2019 年第二季度為 3.94 億美元，使我們今年的累計費用達到 9.45 億美元。正如我們之前所說，2020 年的支出反映了我們加大了對全球 CF 藥物使用的支持力度，以及將我們的產品線擴展到新疾病領域的投入。收入的大幅增長，加上支出的較為溫和的增長，使得今年迄今為止的營業利潤率達到 58%，營業收入達到 17.5 億美元，比 2019 年上半年的營業收入增長了 122%。截至 2020 年 12 月 31 日，公司淨收入為 13.6 億美元，而 2019 年上半年為 6.23 億美元。

Now to guidance. Today, we are revising upward our 2020 financial guidance for total CF product revenues to a range of $5.7 billion to $5.9 billion, which at the midpoint, reflects 45% growth over 2019. Our guidance reflects the strong launch of TRIKAFTA to date in the U.S., the performance of our other CF medicines globally and the anticipated approval and uptake of KAFTRIO in Europe specifically in England, Ireland, Denmark and Germany. Even with the exceptional midyear results, it's important to reiterate a few of the moderating factors that Stuart mentioned in his remarks.

現在進入指導環節。今天，我們將 2020 年 CF 產品總收入的財務預期上調至 57 億美元至 59 億美元之間，其中價值較 2019 年成長 45%。我們的指導意見反映了 TRIKAFTA 迄今為止在美國的強勁上市，我們其他 CF 藥物在全球範圍內的表現，以及 KAFTRIO 在歐洲（特別是英國、愛爾蘭、丹麥和德國）的預期批准和推廣。即使年中取得了優異的成績，也有必要重申史都華在演講中提到的一些調節因素。

First, the persistence and compliance trends to date for TRIKAFTA are strong. And in fact, they're among the strongest and best we've seen for any of our medicines at this stage of the launch. However, we are still less than a year into the launch, and as such, we expect these metrics to reach a steady state during the second half of the year.

首先，TRIKAFTA 迄今為止的持續性和合規性趨勢都很強勁。事實上，就我們目前推出的所有藥物而言，它們是我們見過的最強、最好的之一。然而，距離產品發布不到一年，因此，我們預計這些指標將在今年下半年達到穩定狀態。

Second, as we previously noted, we saw a benefit from patients refilling their TRIKAFTA prescriptions early as the COVID-19 pandemic emerged. This resulted in patients having a higher amount of TRIKAFTA on hand at the end of both the first and second quarters. Our guidance assumes that this increased patient inventory normalizes throughout the second half of 2020.

其次，正如我們之前提到的，隨著 COVID-19 疫情的出現，我們發現患者儘早補充 TRIKAFTA 處方藥是有益的。這導致患者在第一季末和第二季末都擁有了較多的 TRIKAFTA。我們的指導意見假設，這種增加的患者數量將在 2020 年下半年恢復正常。

And finally, I would also note that while we have incorporated some incremental European revenues for KAFTRIO into our revised 2020 revenue guidance, the actual rate and level of uptake that we will see in 2020 in Europe is unpredictable, given the ongoing pandemic and the fact that we are conducting a virtual launch.

最後，我還想指出，雖然我們已將 KAFTRIO 的一些歐洲增量收入納入了我們修訂後的 2020 年收入預期，但考慮到持續的疫情以及我們正在進行虛擬發布，2020 年我們在歐洲看到的實際普及率和水平是無法預測的。

Our OpEx and tax guidance remains unchanged. I would note that we have recognized some savings on expenses as a result of the COVID-19 pandemic -- travel costs, for example -- however, we have also actively rebalanced our spending by making incremental investments in certain programs and in technology infrastructure to support both the remote operation of certain clinical trials and work-from-home capabilities for our global workforce.

我們的營運支出和稅務指導保持不變。我想指出，由於 COVID-19 疫情，我們在開支方面節省了一些費用——例如差旅費——但是，我們也積極地調整了支出，對某些項目和技術基礎設施進行了逐步投資，以支持某些臨床試驗的遠程操作以及我們全球員工的居家辦公能力。

With our strong revenue and profitability, we finished the second quarter with $5.5 billion in cash. And as in recent years, our top priority for capital allocation is to reinvest in our own internal R&D engine and to invest in external innovation to accelerate the creation of future medicines for the disease areas in which we are interested.

憑藉強勁的收入和獲利能力，我們第二季末的現金儲備為 55 億美元。與近年來一樣，我們資本配置的首要任務是再投資於我們自己的內部研發引擎，並投資外部創新，以加速開發我們感興趣的疾病領域的未來藥物。

Now back to Reshma for a few concluding remarks.

現在請雷什瑪做幾句總結性發言。

Thanks, Charlie. The first half of 2020 was a trying period for people, societies and businesses across the world as we grappled with the widespread impact of the COVID-19 pandemic. As a global business with thousands of employees, Vertex shared in these challenges. Yet despite the significant changes in how we work, interact and operate our business, Vertex continues to thrive, and our people continue to rise to the occasion with courage and determination.

謝謝你，查理。2020 年上半年，世界各地的人們、社會和企業都經歷了一段艱難時期，因為我們都在努力應對 COVID-19 疫情的廣泛影響。作為一家擁有數千名員工的全球性企業，Vertex 也面臨這些挑戰。儘管我們的工作方式、互動方式和業務運作方式發生了重大變化，但 Vertex 仍然蓬勃發展，我們的員工也繼續以勇氣和決心迎接挑戰。

As I said earlier this year, the future of Vertex remains brighter than ever. And this remains true today as we enter the second half of the year with continued strong commercial execution, increasing momentum across our pipeline with our type 1 diabetes program approaching the clinic and multiple upcoming data readouts in the next 6 to 12 months, and the financial strength to support both internal innovation and business development to discover and develop new medicines for patients and to support our long-term growth. I look forward to updating you as the year progresses.

正如我今年早些時候所說，Vertex 的未來依然一片光明。如今，隨著我們進入下半年，情況依然如此：我們繼續保持強勁的商業執行力，產品線發展勢頭強勁，1 型糖尿病項目即將進入臨床試驗階段，未來 6 至 12 個月內將有多項數據公佈，我們擁有雄厚的財力支持內部創新和業務發展，以發現和開發新藥造福患者，並支持我們的長期增長。隨著時間的推移，我會期待向您報告最新情況。

Thank you, and we'll now open the call to questions.

謝謝，現在開始接受提問。

(Operator Instructions) Our first question comes from the line of Cory Kasimov with JPMorgan.

（操作員說明）我們的第一個問題來自摩根大通的 Cory Kasimov。

I wanted to ask about the AAT program, now that the Phase II 864 study has initiated. Are there any key differences between this and the 814 study that's ongoing on CT.gov? It looks like 864 is 40 patients versus 50 patients for 814. So wondering if there's any specific rationale behind that and any other potential differences between the 2 trials?

我想詢問一下AAT計畫的情況，因為II期864研究已經啟動。這項研究與CT.gov網站上正在進行的814研究有什麼主要區別嗎？看起來 864 號病例有 40 名患者，而 814 號病例有 50 名患者。所以我想知道這背後是否有具體的理由，以及這兩次試驗之間是否有其他潛在差異？

Yes. Cory, it's Reshma. In essence, the 814 study, which is a study of about 28 days with a 1-month safety follow-up, a few different doses in the placebo group, is similar, if not exactly the same as our VX-864 study. Again, a few different doses of placebo group, 28 days of treatment and another 1 month of safety follow-up. You can think of them as very similar.

是的。科里，我是雷什瑪。從本質上講，814 研究（一項為期約 28 天、為期 1 個月的安全追蹤研究，安慰劑組採用幾種不同的劑量）與我們的 VX-864 研究相似，甚至完全相同。同樣，安慰劑組採用幾種不同的劑量，治療 28 天，然後進行 1 個月的安全性追蹤。你可以把它們看作非常相似。

And our next question comes from the line of Salveen Richter with Goldman Sachs.

下一個問題來自高盛的薩爾文·里希特。

On guidance for the CF franchise, how are you factoring in the positive CHMP decision with regard to countries coming on board in the second half? And how are you accounting for England? And then with regard to the pipeline, where do you stand with progress at the DMD, DM1 gene editing program?

關於CF特許經營權的指導方針，您如何考慮CHMP關於下半年加入的國家的積極決定？那麼，你們如何解釋英格蘭的情況呢？那麼，關於研發管線，您在DMD、DM1基因編輯計畫的進展方面處於什麼階段？

Salveen, this is Reshma. Let me ask Charlie to take the first question about guidance, and how we're thinking about CHMP. And of course, there still is a step of European Commission approval, and then I'll come back and tackle DMD and DM1.

薩爾文，這位是雷什瑪。讓我請查理回答第一個關於指導的問題，以及我們如何看待 CHMP。當然，還需要獲得歐盟委員會的批准，之後我才會回來處理DMD和DM1的問題。

Charlie?

查理？

Sure. Thanks. Salveen, as we mentioned on the call, we have factored into our revised guidance an assumption of incremental revenues from approval in Europe, but as Reshma points out, we do not have the approval yet. And so the exact timing of that is not perfectly clear. We also highlighted that it will be a virtual launch because everybody is working from home, and the potential for the ongoing pandemics have an impact on the rate of uptake. That said, we feel very good about including it in the guidance, and that is factored into the number we gave today.

當然。謝謝。Salveen，正如我們在電話會議中提到的，我們在修訂後的業績指引中已經考慮了歐洲批准帶來的增量收入這一假設，但正如Reshma指出的那樣，我們尚未獲得批准。因此，具體時間尚不完全清楚。我們也強調，由於大家都在家辦公，而且持續的疫情可能會影響用戶接受度，因此本次發布會將以線上形式進行。儘管如此，我們仍然非常樂意將其納入指導方針中，這一點也已計入我們今天給出的數字中。

And with regard to the DMD and DM1 programs, you'll remember, of course, last year, around the summer time, we acquired Exonics and that's where we got the DMD and DM1 programs from. And then a few months after that, we acquired Semma, and that's where we're working on the type 1 diabetes program with. With regard to where we are with DMD, we're in late preclinical development. We have had our conversations with the FDA. We understand what they are looking for in terms of preclinical safety and clinical -- preclinical pharmacology, and we have a very good sense of what the IND package needs to look like. We are working through all of that. And I anticipate in the coming months, we're going to be able to give you further updates.

至於 DMD 和 DM1 程序，您當然會記得，去年夏天左右，我們收購了 Exonics，DMD 和 DM1 程序就是從那裡獲得的。幾個月後，我們收購了 Semma，現在我們正在與 Semma 合作 1 型糖尿病計畫。就 DMD 的研發進展而言，我們目前處於臨床前開發的後期階段。我們已經和FDA進行過溝通。我們了解他們在臨床前安全性和臨床（臨床前藥理學）所尋找的內容，我們非常清楚 IND 申請資料需要是什麼樣子。我們正在努力解決所有這些問題。我預計在接下來的幾個月裡，我們將能夠向大家提供更多最新消息。

I mean I'll just also just let you know that we're thinking very, very diligently and working hard on things like process development and analytical development. You've seen in the landscape that there is a real importance around dose and around getting the analytical development to make sure that you are very clear about what the dose is right. And so we're investing a good amount of our time and effort to make sure that we get all of that right as we make progress towards the clinic.

我的意思是，我也想讓你們知道，我們正在非常認真地思考和努力，致力於流程開發和分析開發等方面的工作。從目前的情況來看，劑量非常重要，分析發展也至關重要，以確保你非常清楚正確的劑量是多少。因此，我們投入了大量的時間和精力，以確保我們在診所籌建過程中所有環節都萬無一失。

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

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

Congratulations on the quarter. Just a couple of commercial ones and one brief follow-up on AAT. Commercial in Europe, Stuart, you mentioned that there'll be 10,000 patients who will be on label for TRIKAFTA when it's approved. Could you give us a sense of how many of those patients will have reimbursement at the time of approval? And then second, in the U.S., can you give us a sense as to the level of inventory that is being held by patients currently?

恭喜你本季取得佳績。只有幾篇商業文章和一篇關於 AAT 的簡短後續報導。Stuart，你提到，TRIKAFTA 獲準後，將有 10,000 名患者符合其適應症。您能否大致說明一下，在申請核准時，有多少患者能夠獲得報銷？其次，在美國，您能否大致介紹一下目前患者持有的庫存水準？

Sure, Phil. Thanks for the question. So yes, as you mentioned, with the label to include the F/MF patients, that's about 10,000 patients -- up to 10,000 patients across Europe who will be eligible for a CFTR modulator for the first time. Those patients are roughly split, not exactly, but roughly split as per the existing patient populations. And so the largest countries are the U.K. and Germany, places like France, Italy, Spain follow that. That's where the vast majority of patients are. And so obviously, the agreement in the U.K. is in England or subsequently in the other developed nations is excellent because that's the single biggest patient population. Then Germany, obviously, is a country where you get immediate access post- the EC approval. Other countries like France, Italy, Spain, et cetera, we will have to begin the reimbursement negotiations there. So that's how that kind of patient population splits out overall.

當然可以，菲爾。謝謝你的提問。所以，正如您所提到的，如果將 F/MF 患者納入其中，那麼大約有 10,000 名患者——歐洲各地多達 10,000 名患者將首次有資格接受 CFTR 調節劑治療。這些患者大致按照現有患者群體的比例進行劃分，雖然不是完全精確，但大致如此。因此，人口最多的國家是英國和德國，法國、義大利、西班牙等國緊追在後。絕大多數患者都在那裡。因此，很顯然，英國（英格蘭）或其他已開發國家達成的協議是極好的，因為那裡擁有最大的患者群體。那麼，很顯然，在獲得歐盟批准後，德國是一個可以立即獲得准入資格的國家。對於法國、義大利、西班牙等其他國家，我們將不得不從那裡開始進行賠償談判。所以，這就是這類患者群體整體的組成。

In terms of patient inventory, we didn't see any incremental inventory build from patients in the second quarter. It really was a carryover of the inventory build that patients had made when the pandemic first hit in the sort of first quarter and towards the end of the first quarter here in the U.S., and so we have not seen a drawdown on that inventory, we did not see an increase in that patient inventory in the second quarter.

就患者庫存而言，我們在第二季度沒有看到患者庫存增加。這實際上是疫情在美國第一季末期，患者累積的庫存的延續，因此我們沒有看到庫存減少，也沒有看到第二季度患者庫存增加。

That's very helpful. And a brief follow-up to Cory's question on AAT. What's your way of thinking on the next steps once you get the proof-of-concept data from the first 2 candidates. Could you move right into a pivotal study or would it be more likely that there will be an interim trial to further flesh out their profiles?

那很有幫助。對 Cory 關於 AAT 的問題，我做一個簡短的後續回答。從前兩個候選方案中獲得概念驗證資料後，您對下一步有何想法？可以直接進行關鍵性研究嗎？還是更有可能先進行中期試驗，以進一步完善他們的研究數據？

I had a little bit of a hard time hearing you, but I think it's about what is the next step once we have proof-of-concept data for VX-814 and can we go into pivotal development after that? So yes, I do anticipate that once we have the proof-of-concept data, and we have a sense for dose, and we get a look at the safety in patients with alpha-1 antitrypsin deficiency, we will be moving into pivotal development. Of course, we have 2 programs, VX-814 and VX-864. 814 is in the lead. And depending on exactly what the timing of each of those programs are, et cetera, we're going to have to make some decisions, but yes, I do anticipate after we are at a point of having POC, we would move right into Phase III pivotal development.

我剛才有點聽不清楚你說話，但我認為重點是，一旦我們獲得了 VX-814 的概念驗證數據，下一步是什麼，以及之後我們是否可以進入關鍵性開發階段？所以，是的，我預計一旦我們獲得了概念驗證數據，對劑量有了大致了解，並且了解了α-1抗胰蛋白酶缺乏症患者的安全性，我們將進入關鍵性開發階段。當然，我們有兩個程序，分別是 VX-814 和 VX-864。814 領先。具體來說，根據每個專案的具體時間表等等，我們將不得不做出一些決定，但是，是的，我預計在達到概念驗證階段後，我們將直接進入 III 期關鍵性開發階段。

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

下一個問題來自 Jefferies 的 Michael Yee。

Congrats on a great quarter. Two pipeline questions, one on AAT. Obviously, everyone's focused on functional AAT. I think we all know that, and we look forward to that. Is there anything in your secondary endpoints or any other biomarkers you would look at to help support the overall totality of what's going on? There is outstanding questions around trafficking to the lungs, et cetera, et cetera. So I think that's an interesting thing if there were any biomarkers to help support what's going on?

恭喜你本季表現出色。兩個管道相關問題，一個關於AAT。顯然，大家都在關注功能性AAT。我想我們都知道這一點，我們也期待著這一點。在您的次要終點或其他生物標記中，是否有任何內容可以幫助您全面了解情況？關於毒品販運至肺部等問題，仍存在一些懸而未決的問題。所以我覺得，如果有生物標記可以幫助我們理解正在發生的事情，那會是一件很有趣的事情？

And then my second question actually is on 147 for FSGS. You made some great comments, Reshma. I know you are an expert in renal disease. So I guess my question is, are you confident that a strong reduction of proteinuria can happen in a short amount of time? Or what amount of time do you need based on that mechanism to show that in a Phase II?

我的第二個問題其實是關於 FSGS 的 147。雷什瑪，你的評論很棒。我知道您是腎臟疾病的專家。所以我想問的是，您是否有信心在短時間內大幅減少蛋白尿？或者，根據該機制，您需要多少時間才能在 II 期臨床試驗中證明這一點？

Yes. Yes. Sure thing. Let me parse it out into the questions around AATD, and then I'll get to FSGS and proteinuria. So on the AATD program, be it for VX-814 or for VX-864, it is really about looking at the antigenic AAT levels and at the functional serum AAT levels. And if you ask me, what exactly are we looking for? What's the breadth of information that we can glean from the proof-of-concept studies. Besides those 2 things, the other 2 that I will point you to is safety. We can't minimize that. This is the first time that this medicine has been put into patients with this disease. And the last part is the PK/PD relationship and the relationship between the doses and the achievement of the exposure that we are seeking. So those are really the key elements that we will be able to glean when the study is complete.

是的。是的。當然可以。讓我先把問題分解成 AATD 的問題，然後再討論 FSGS 和蛋白尿。因此，在 AATD 項目中，無論是 VX-814 或 VX-864，實際上都是在觀察抗原性 AAT 水平和功能性血清 AAT 水平。如果你問我，我們究竟在找什麼？我們能從概念驗證研究中獲得哪些資訊？除了這兩點之外，我還要提醒你的是安全問題。我們不能低估這一點。這是首次將這種藥物用於治療該疾病的患者。最後一部分是 PK/PD 關係以及劑量與我們所追求的暴露量之間的關係。所以，這些就是我們在研究完成後能夠了解的關鍵要素。

With regard to FSGS, so proteinuria is something that we in the renal community have talked about for a long, long time. There have been multiple workshops between nephrologists, academia, regulatory agencies, et cetera, to think about the relationship of proteinuria and outcomes like time to ESRD, as well as all of the questions you must be imagining with regard to onset of proteinuria, the duration of reduction in proteinuria, et cetera. And if I just sort of make a long story short, the reason you see our proof-of-concept Phase II study be of 12 weeks duration, is that I think it's going to take about that amount of time to start to see a reduction. And that sort of explains the duration of the study.

關於 FSGS，蛋白尿是我們腎臟病界長期以來一直在討論的問題。腎臟科醫師、學術界、監管機構等舉行了多次研討會，探討蛋白尿與終末期腎病 (ESRD) 時間等結果之間的關係，以及您可能正在思考的有關蛋白尿的發生、蛋白尿減少的持續時間等所有問題。長話短說，我們概念驗證 II 期研究持續 12 週的原因是，我認為大約需要這麼長時間才能開始看到效果。這也大致解釋了這項研究的持續時間。

And our next question comes from the line of Alethia Young with Cantor.

我們的下一個問題來自阿萊西亞·楊和坎托爾的傳承。

Congrats on the quarter. So I just want to talk a little bit about CTX001. And of course, there are a lot of medicines now in sickle cell and beta-thal and just how you think about positioning of a potential one-and-done versus like the Global Blood and Agioses and Novartises of the world?

恭喜你本季取得佳績。所以我想簡單談談 CTX001。當然，現在有很多治療鐮狀細胞貧血和β-地中海貧血的藥物，您認為一種潛在的「一次性」療法與像Global Blood、Agioses和諾華這樣的大型製藥公司相比，定位如何呢？

Yes. This is Reshma. Why don't I take that question. Alethia, I can't tell you how excited I am with the CTX001 program that we are conducting in conjunction with CRISPR Therapeutics. This is now a program that has achieved proof-of-concept in beta-thalassemia, right? We've dosed the first 2 patients. We've talked about the fact that they have engrafted. We've talked about the hemoglobin levels in these 2 patients, and it's well north of 11 grams per deciliter.

是的。這是雷什瑪。我為什麼不回答這個問題呢？Alethia，我無法告訴你我對我們與 CRISPR Therapeutics 共同進行的 CTX001 計畫有多興奮。現在這個計畫已經在β地中海貧血症領域實現了概念驗證，對吧？我們已經給前兩名患者註射了藥物。我們已經討論過它們已經成功植入的事實。我們已經討論過這兩位患者的血紅蛋白水平，他們的血紅蛋白水平遠高於每分升 11 克。

The first patient is at 14.2. The second patient is at 12.5 grams per deciliter at 5 months. The patients are going from the first patient, 34 units of blood transfused per year. The second patient, 61 units of blood transfused per year to no transfusions in the follow-up that we have observed. And while it is still a limited number of patients and a limited duration, patient #1 is now out 15 months. So we are really getting out there. We're past that 1-year point.

第一位患者在 14.2。第二名患者在 5 個月時血脂為 12.5 克/分升。從第一位患者開始，患者每年需要輸血 34 個單位。第二位患者，從每年輸血 61 單位到我們觀察到的追蹤期間無需輸血。雖然患者人數和治療時間仍然有限，但 1 號患者現在已經康復 15 個月了。所以我們真的要走出去。我們已經過了一年這個節點。

And we've also shared the data with regard to the first sickle cell patient who's also had hemoglobin F well north of 40% and has had no VOCs. So I think that there is a big difference between transforming a disease and treating a disease. There is a big difference between having no VOCs, no transfusions and having to manage some amount of chronic disease. And I think that there's a great importance in having a therapy that is one-time and then a person's life is restored. So I see enormous promise in this particular program.

我們也分享了首例鐮狀細胞貧血患者的數據，該患者的血紅素 F 遠高於 40%，且未發生 VOC 事件。所以我認為，改變疾病的本質和治療疾病之間存在著很大的差異。沒有血管閉塞危象、無需輸血和需要應對一定程度的慢性疾病之間有很大的區別。我認為，一次性治療能夠使人的生活重回正軌，這一點非常重要。所以我認為這個項目非常有潛力。

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

下一個問題來自美國銀行的傑夫‧米查姆。

Congrats on another good quarter in CF. So I have a commercial question and a pipeline one. Stuart, can you talk about for the quarter, the TRIKAFTA sales, the patients coming from switching versus new het/min patients? And maybe just -- I know maybe you don't want to give specifics, but how close are you to the 90% penetration that you've seen with other CF products.

恭喜CF又一個季度業績出色。我有一個商業方面的問題和一個管理方面的問題。Stuart，可以談談本季 TRIKAFTA 的銷售情況嗎？其中有多少患者是轉用 TRIKAFTA 治療的，又有多少是新加入的異質性低血壓/低血壓患者？或許——我知道您可能不想透露具體細節，但是您距離其他CF產品所達到的90%滲透率還有多遠？

And then for Reshma, I didn't see a lot of detail on the plan sort of the remaining 10% of CF patients. I know you guys are committed to 100%, but maybe just remind us of what the status is of the programs, for example, for premature stop, et cetera?

至於 Reshma，我沒有看到關於剩餘 10% 的囊性纖維化患者的計劃的具體細節。我知道你們致力於實現 100% 的目標，但或許可以提醒我們各項計畫的進展情況，例如，提前終止懷孕計畫等等？

Geoff, it's Stuart here. So thanks for the question. In terms of the source of TRIKAFTA prescriptions. When we say it's the vast majority of patients and it's the vast majority of patients across all segments, we mean just that. There really is not very much difference between the uptake in those who were naive to a CFTR modulator before TRIKAFTA was approved and those who were on either KALYDECO or ORKAMBI or SYMDEKO. So the level of uptake has been pretty universal and we are very much at the flat part of the launch curve, but there are still patients who are being initiated, but we are very much at the flat part of the launch curve now, which is why, as Charlie alluded to in talking about the guidance, it really is much more about the trends in persistence and compliance.

傑夫，我是史都華。謝謝你的提問。就 TRIKAFTA 處方來源而言。當我們說這是絕大多數患者，而且是所有群體中的絕大多數患者時，我們的意思就是如此。在 TRIKAFTA 獲批之前從未接觸過 CFTR 調節劑的人，與服用 KALYDECO、ORKAMBI 或 SYMDEKO 的人相比，其接受度並沒有太大差異。因此，接受度相當普遍，我們目前正處於啟動曲線的平穩階段，但仍有一些患者正在接受治療，但我們現在正處於啟動曲線的平穩階段，這就是為什麼，正如查理在談到指導方針時所暗示的那樣，這實際上更多地與堅持性和依從性的趨勢有關。

And for the pipeline question, I'll hand that over to Reshma.

至於輸油管的問題，我將交給雷什瑪來回答。

Yes. You are very right about the commitment to get to all patients. And what I'll tell you is, and just to remind everyone, for the last 10%, the underlying pathophysiology and the problem we have is that those patients make no protein, either because of premature or stop [codons], they just don't make any protein. And insofar as no protein is made, CFTR modulators cannot be helpful for these patients. So one way or another, a nucleic acid therapy is going to be needed, and we have programs in this area. And I see good progress with our partnership with Moderna in working on an mRNA approach to this last 10%. So more to come.

是的。您說的非常正確，我們必須致力於服務每一位患者。我要告訴大家的是，也提醒大家一下，對於最後 10% 的患者，其潛在的病理生理學問題在於，這些患者無法產生蛋白質，要么是因為過早終止密碼子，要么是因為終止密碼子，他們就是無法產生任何蛋白質。既然沒有蛋白質生成，CFTR 調節劑對這些患者就無濟於事。所以無論如何，核酸療法都是必要的，而我們在這方面也有相關的項目。我看到我們與 Moderna 的合作在利用 mRNA 方法攻克最後 10% 的難題方面取得了良好的進展。敬請期待更多內容。

The other point that we've made in the past and is worth repeating is, there's also an important delivery consideration here. The lung has a very large surface area. And of course, we're talking about trying to get delivery into a lung that has a large surface area, but is also very inflamed and full of mucus. So the delivery problem cannot be underestimated, but we have made good progress with our partners at Moderna, and I am optimistic about our ability to get there for our last 10% of patients.

我們過去曾提出過另一點，值得重申的是，這裡還有一個重要的交付考量。肺的表面積非常大。當然，我們現在討論的是要將藥物輸送到表面積很大，但又非常發炎且充滿黏液的肺部。因此，交付問題不容低估，但我們與 Moderna 的合作夥伴已經取得了良好的進展，我對我們能夠為最後 10% 的患者提供藥物充滿信心。

And our next question comes from the line of Evan Seigerman with Crédit Suisse.

我們的下一個問題來自瑞士信貸的 Evan Seigerman。

Congrats, again, on another fantastic quarter. So for Stuart, so you seem to be pretty cautious about the upcoming potential launch of KAFTRIO in Europe [starting] the pandemic. But the pandemic is arguably more of an issue here in the U.S. at the moment, so how are you able to overcome some of these commercialization issues domestically? And is there any reason to think that you won't have similar traction in Europe? And I understand kind of the ins and outs of the reimbursement agreements, say, for example, in Germany?

再次恭喜你們又取得了一個精彩的季度業績。所以對 Stuart 來說，你似乎對 KAFTRIO 即將在歐洲推出（尤其是在疫情爆發初期）持相當謹慎的態度。但目前疫情在美國可能是一個更大的問題，那麼你們要如何克服國內的一些商業化問題呢？那麼，有什麼理由認為你在歐洲不會獲得類似的成功呢？我大致了解報銷協議的來龍去脈，比如說，在德國的報銷協議？

Evan, thanks for the question. So I think your question, you were breaking up a little bit, was why are we concerned about the launch trajectory in Europe when the pandemic is kind of more of an issue in the U.S. now? And really, I would say 2 things.

埃文，謝謝你的提問。所以我覺得你的問題，你剛才有點語無倫次了，是為什麼我們要關注歐洲的發射軌跡，而現在疫情在美國才是更大的問題？其實，我只想說兩件事。

The first one is that you'll remember, we got the approval for TRIKAFTA in October of last year. And as you'll remember from our Q4 and Q1 calls, we have seen very, very rapid uptake in the first few months of the -- post- the approval, when really the pandemic had not really been as big of a deal here in the U.S. as it already had been in Asia and obviously in Europe. And so we are launching, I think, into a very different situation where the pandemic is still a very, very dynamic issue, and we're seeing openings and re-lockdowns and things like that. So it is a very different situation, I think, that we are launching into when we get the approval by the European Commission.

首先，您可能還記得，我們​​在去年十月獲得了 TRIKAFTA 的批准。正如您在我們第四季和第一季的電話會議中記得的那樣，在獲得批准後的最初幾個月裡，我們看到了非常非常迅速的市場接受度，而當時疫情在美國的影響遠不如在亞洲和歐洲那麼嚴重。因此，我認為，我們正進入一個截然不同的局面，疫情仍然是一個非常、非常動態的問題，我們看到開放和重新封鎖等等情況。所以，我認為，當我們獲得歐盟委員會的批准時，我們將進入一個截然不同的情況。

The second thing that makes it different is that, like most businesses, the vast majority of our employees are working from home. Certainly, the commercial organization is all working from home. And so we will be launching this medicine virtually, which is a first for us as a company.

第二點不同之處在於，與大多數企業一樣，我們絕大多數員工都在家工作。當然，商業機構的所有員工都在家辦公。因此，我們將以線上方式推出這款藥物，這對我們公司來說尚屬首次。

The last thing I would say, which is linked to the pandemic is about patients and physicians and their ability to get together and see each other as a result of the pandemic. And so that's a dynamic which we have to take into consideration. And as we said in our prepared remarks, it's just uncertain how all that is going to play out. So I do think the situation we're launching into in Europe is very different to the situation we were fortunate enough to be able to launch into here in the U.S.

最後我想說的是，與疫情相關的一點是，由於疫情的影響，患者和醫生之間的見面和就診能力受到了影響。所以，這是我們必須考慮的動態因素。正如我們在準備好的演講稿中所說，這一切最終會如何發展，目前還不得而知。所以我認為我們在歐洲面臨的情況與我們有幸在美國面臨的情況截然不同。

And our next question comes from the line of Robyn Karnauskas with SunTrust.

我們的下一個問題來自 SunTrust 的 Robyn Karnauskas。

Congratulations on all the progress in this environment. I just wanted to ask a little bit about -- more about European dynamics. What were the lessons you learned just on the launch itself in the United States with TRIKAFTA and basically, what could be some positive reads to KAFTRIO for the launch in Europe, just regarding compliance and uptake because I think you just addressed the question around COVID. So it's just really more about do you think that this is more like KALYDECO launch versus ORKAMBI? And what are some positive reads that we might see when approved?

祝賀你們在這一領域取得的所有進展。我只是想稍微了解一下——更多關於歐洲局勢的內容。在美國推出 TRIKAFTA 的過程中，您學到了哪些經驗教訓？對於 KAFTRIO 在歐洲的推出，有哪些積極的啟示可以藉鑑，尤其是在合規性和接受度方面？因為我認為您剛剛談到了與 COVID 相關的問題。所以問題其實比較在於，你認為這更像是 KALYDECO 的發表會，還是 ORKAMBI 的發表會？如果獲得批准，我們可能會看到哪些正面的方面？

Yes. Robyn, it's Stuart here. Thanks for the question. In terms of the positives we can take from the U.S. experience, obviously, there's many of them because the launch has been such a terrific success. And so I think some of the positives would be, obviously, there's very high levels of awareness within the CF community of the triple combination regimen and its very positive benefit/risk profile. Secondly, that positive benefit/risk profile has played out in real-world exactly as we saw it play out in our pivotal and indeed, earlier studies. The efficacy is very, very strong. And the overall benefit/risk profile is really, really positive. So those are definitely positives that's resulted in high levels of persistence and compliance. So I think those are all very positive read-throughs.

是的。羅賓，我是史都華。謝謝你的提問。就我們可以藉鏡美國經驗的正面方面而言，顯然有很多，因為這次發布取得了巨大的成功。因此，我認為積極的一面顯然是，囊性纖維化患者群體對三合療法及其非常積極的益處/風險比有非常高的認識。其次，這種積極的收益/風險比在現實世界中得到了充分體現，正如我們在關鍵性研究以及更早的研究中所看到的那樣。療效非常非常強。整體而言，收益/風險比非常非常高。所以這些肯定是正面的因素，從而帶來了高度的堅持性和合規性。所以我認為這些都是非常正面的解讀。

The big uncertainty, as I say, is we are launching this into a very, very different situation environment than we were launching back in October of 2019, which in many ways seems a lifetime away, both in terms of the patients and physicians and their ability to get together and our ability to launch in a virtual world is just unproven. So that's clearly very different. We're thrilled to have got a reimbursement agreement in place in England in advance of the approval. That's clearly positive. And one of the positives here in the U.S. is that we got very rapid public and private reimbursement.

正如我所說，最大的不確定因素是，我們現在所處的環境與 2019 年 10 月啟動時的環境截然不同，從許多方面來看，那時的情況似乎已經過去了很久，無論是患者和醫生能否聚集在一起，還是我們在虛擬世界中啟動的能力都尚未得到證實。所以這顯然非常不同。我們很高興能在獲得批准之前就與英國方面達成報銷協議。這顯然是個好兆頭。在美國，一個正面因素是公共和私人醫療費用報銷速度非常快。

Obviously, though, there are a number of countries in Europe where we don't yet have reimbursement agreements in place, and we're going to have to begin that process. And that process is likely to take a bit longer in Europe than it did here in the U.S. So there's definitely many positives, but there are a number of things which are going to be different, which leads us to believe that the exact trajectory of the launch is difficult to call.

不過，顯然歐洲還有一些國家我們還沒有達成報銷協議，我們將不得不開始著手辦理相關手續。在歐洲，這個過程可能會比在美國花費更長的時間。所以肯定有很多積極因素，但也有一些事情會有所不同，這讓我們相信，發射的確切軌跡很難預測。

Having said that, I will leave you with this final thought: just as we have done in the U.S., we are confident that over time, the vast, vast majority of patients will be initiated on KAFTRIO over time.

說了這麼多，我最後想和大家分享一點：就像我們在美國所做的那樣，我們相信隨著時間的推移，絕大多數患者都會開始接受 KAFTRIO 治療。

And our next question comes from the line of Mohit Bansal with Citi.

下一個問題來自花旗銀行的 Mohit Bansal。

Congratulations from my end as well on the progress. My question is regarding the AAT and functionality. Given that this is -- these patients have a mutation. So even when you correct the misfolding, the protein which gets deleted is still going to be Z-AAT, and there's literature out there suggesting that the functionality of Z-AAT may not be as good as wild-type AAT. So to that end, do you think it could be an issue? And how exactly you are managing the functional AAT levels?

我這邊也祝賀你們取得的進展。我的問題與AAT及其功能有關。有鑑於此－這些患者都帶有基因突變。所以即使修正了錯誤折疊，刪除的蛋白質仍然是 Z-AAT，而且有文獻顯示 Z-AAT 的功能可能不如野生型 AAT。所以，從這個角度來看，你認為這可能會是個問題嗎？您具體是如何管理功能性AAT水準的？

Sure. Mohit, this is Reshma. So just to make sure that we're all grounded on the pathophysiology here. When you have alpha-1 antitrypsin deficiency, when you have that disease, you're right, this is a genetic mutation. It's a mutation of the SERPINA1 gene, and that mutation leads to a misfolded protein. The way our small molecule correctors work is they properly fold that misfolded protein. And in doing so, alleviate the congestion in the liver so that's how the liver part of this disease can be addressed with our approach. And because you have the corrected AAT protein now in the blood, that can go to the lung and do its job, which is to protect the lung from autodigestion, right? So the small molecule approach allows you to correct both the liver disease and the lung disease.

當然。莫希特，這位是雷什瑪。所以，為了確保我們都對這裡的病理生理學有基本的了解。當你患有α-1抗胰蛋白酶缺乏症，也就是患有這種疾病時，你說得對，這是一種基因突變。這是 SERPINA1 基因的突變，這種突變會導致蛋白質錯誤折疊。我們的小分子矯正劑的作用原理是使錯誤折疊的蛋白質正確折疊。這樣做可以緩解肝臟的充血，這就是我們用這種方法來解決這種疾病的肝臟部分的方法。因為血液中現在有了正確的 AAT 蛋白，它就可以到達肺部並發揮作用，保護肺部免受自身消化，對吧？因此，小分子療法可以同時治療肝臟疾病和肺部疾病。

The point that you're raising about how functional is this corrected AAT, people call it the competence of the molecule, and we have assessed that preclinically in our models and the competence is high. And we have assays, you can think of it as an ELISA assay, but we have assays that we can assess the functionality of the protein in neutralizing the neutrophil elastase and that looks good. So that's the reason we've entered into Phase II proof-of-concept development, and that's why in Phase II, we are measuring not only antigenic levels, but also functional level. So we don't have a direct readout.

您提出的關於這種修正後的 AAT 的功能性的問題，人們稱之為分子的活性，我們已經在我們的模型中進行了臨床前評估，活性很高。我們有檢測方法，你可以把它看作是 ELISA 檢測，但我們有檢測方法可以評估蛋白質中和嗜中性球彈性蛋白酶的功能，結果看起來不錯。所以這就是我們進入第二階段概念驗證開發的原因，也是為什麼在第二階段，我們不僅要測量抗原水平，還要測量功能水平。所以我們沒有直接的讀數。

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

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

Stuart, I just want to follow-up on the agreement that you have in place in England. Could you first give us a sense of what proportion of the 10,000 patients that you mentioned -- the incremental patient numbers -- are in England. And secondly, in that agreement, is it similar to the Irish agreement with a cap on the total potential spend for the government -- for the NHS in England? Or is it purely volume-dependent?

斯圖爾特，我只是想跟進一下你在英國達成的協議。您能否先簡單說明一下，您提到的 10,000 名患者（新增患者人數）中，有多少比例來自英格蘭？其次，該協議是否類似於愛爾蘭協議，對政府在英格蘭國民醫療服務體系 (NHS) 上的潛在總支出設定了上限？或者說，這完全取決於銷量？

Yes, Geoff, thanks for the question. So yes, the agreement in England, obviously, we're thrilled to have reached that agreement. The ratio of patients in the U.K. that are F/MF is roughly the same as you would see for the other mutations. And so you can broadly think that it's proportional to the population size of the U.K. versus others when you look at the CF population.

是的，傑夫，謝謝你的提問。所以，是的，關於在英國達成的協議，我們當然非常高興能夠達成這項協議。在英國，F/MF 患者的比例與其他突變患者的比例大致相同。因此，從整體來看，囊性纖維化患者群體與英國的人口規模相比，其比例大致相當。

In terms of the exact terms of the agreement, I can't talk about the exact terms of the agreement. It is similar to others that it does include access to our existing medications, including KAFTRIO, once approved and additional indications for those approved medicines. So that would include going down into the age groups. And it does include a cap on total expenditure to give some certainty to the U.K. government and in this case, NHS England specifically.

至於協議的具體條款，我無法透露。它與其他藥物類似，包括獲得我們現有藥物（包括 KAFTRIO）的途徑（一旦獲得批准）以及這些已批准藥物的其他適應症。所以這其中也包括細分到各個年齡層。而且它也規定了總支出上限，以給英國政府，特別是英國國家醫療服務體系（NHS England）帶來一些確定性。

And our next question comes from the line of Gena Wang with Barclays.

下一個問題來自巴克萊銀行的王晶娜。

I also would like to add my congratulations on a very strong quarter. So I have 2 questions. The first one is regarding the revenue -- quarter revenue, if assuming no refill rate that would translate to roughly 12,000 patients. So my question is, can you share the percentage of a patient that was refilled? And also what is the discontinuation rate? And the second question is regarding the beta-thalassemia sickle cell. What would be your plan for registration trial, specifically, what you could learn from bluebird experience?

我還要祝賀你們本季業績非常出色。所以我有兩個問題。第一個問題與收入有關——季度收入，假設沒有續藥率，則大約相當於 12,000 名患者。所以我的問題是，您能否分享一下患者的續藥率？另外，停用率是多少？第二個問題與β-地中海貧血鐮狀細胞有關。您對註冊試用有什麼計畫？具體來說，您能從藍鳥的​​經驗中學到什麼？

Yes. Gena, I'm not sure I entirely heard all of your question. I think you were asking about the percentage of patients that are on the medicine and have stayed on the medicine, if I'm hearing you right. So...

是的。吉娜，我不太確定我是否完全聽清了你的問題。如果我理解正確的話，我想你是在問服用這種藥物並堅持服用該藥物的患者所佔的百分比。所以...

As amount of the refill rate, so like the persistence, the refill rate?

作為補充率的量，就像持久性一樣，補充率是多少？

Yes. Persistence rate. So yes, there's approximately 18,000 patients in the U.S. who were eligible for TRIKAFTA on its approval with the very broad [FNE] label. Of those, the vast majority of those have initiated therapy. And the persistence rates, as we call it, the number of patients who stayed on the medicine -- i.e., the opposite of those have discontinued -- the persistence rates are very, very high, some of the highest we've seen for any of our medicines at this time in the launch. And so whilst we're not getting into the exact specifics of what that is, you can imagine they are very, very high. Obviously, the discontinuation rate only increases over time, right? There aren't -- it doesn't go the other way, but it's very, very high. And I think that's not surprising given the benefit/risk profile we saw of this medicine in our pivotal trial.

是的。持續率。所以，是的，在美國，大約有 18,000 名患者符合 TRIKAFTA 核准的條件，其適應症範圍非常廣泛 [FNE]。其中絕大多數人已經開始接受治療。而我們稱之為持續用藥率的指標，即繼續服用該藥物的患者人數（與停止用藥的患者人數相反），持續用藥率非常非常高，是我們目前為止所有藥物上市初期所見過的最高水平之一。所以，雖然我們不打算深入探討具體細節，但你可以想像，這些數字非常非常高。顯然，隨著時間的推移，停產率只會增加，對吧？沒有——情況並非相反，但比例非常非常高。考慮到我們在關鍵性試驗中觀察到的這種藥物的益處/風險比，我認為這並不令人驚訝。

And on beta-thal and sickle cell, the question there, I'll hand that over to Reshma.

至於β-地中海貧血和鐮狀細胞貧血，這個問題我將交給雷什瑪來回答。

Gena, with regard to the beta-thal and sickle trial and what do we need to show in terms of the Phase III pivotal trials, I think the trials that you see that we've designed are right for the job. In terms of the endpoints, I think, very clearly in beta-thalassemia, transfusion independence is key. And in sickle cell, it's all about the reduction of VOCs, obviously, both metrics on which CTX001 has performed very well. Early stages, few patients all of those caveats but I think that the studies that we've designed are the right ones and I think those are the endpoints to watch.

Gena，關於β-地中海貧血和鐮狀細胞貧血的試驗，以及我們需要在 III 期關鍵性試驗中證明什麼，我認為我們設計的試驗是合適的。就終點而言，我認為，很明顯，在β地中海貧血中，輸血獨立性是關鍵。而對於鐮狀細胞貧血症來說，顯然一切都與減少 VOC 有關，而 CTX001 在這兩個指標上都表現得非常好。早期階段，患者數量少，有許多限制，但我認為我們設計的研究是正確的，我認為這些是需要關注的終點。

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

下一個問題來自摩根士丹利的馬修·哈里森。

I guess 2 for me. One, Stuart, can you just comment on the residual patients on SYMDEKO and ORKAMBI? Is that mainly age groups which are not approved for TRIKAFTA yet? Or have you noticed any groups that are staying on that drug that may surprise you. And then I guess the second question is just related to AAT. I was hoping you could comment on if you think the Phase III program or the regulatory strategy would look different if you observed carrier levels of the protein versus, say, level similar to what replacement therapy has?

我選2。Stuart，你能否談談 SYMDEKO 和 ORKAMBI 的剩餘病患狀況？主要是那些尚未獲得 TRIKAFTA 資格的年齡層嗎？或者，你有沒有註意到一些長期服用這種藥物的群體，這可能會讓你感到驚訝？那麼，我想第二個問題就跟AAT有關。我希望您能就以下問題發表一下看法：如果您觀察到載體蛋白水平與替代療法中類似的蛋白質水平相比，您認為 III 期臨床試驗方案或監管策略是否會有所不同？

Yes, Matt, thanks for the question. So the vast majority of patients who are on ORKAMBI, SYMDEKO or KALYDECO who are eligible for TRIKAFTA -- just as for the other patient groups -- are transitioning or have transitioned to TRIKAFTA. So what you see in the performance of the business is that the patients who are remaining on that are either those who are less than 12, so the younger age groups, where we continue to expand our indications there. And so we continue to initiate new patients here in the U.S. And as Charlie referenced in his remarks, growth that we've seen outside the U.S. where following the reimbursement agreements we put in place, patients have been -- or countries have been launching SYMDEKO and in some cases, or SYMKEVI, I should say, outside the U.S. and ORKAMBI. So -- but that's what's driving the existing KALYDECO, ORKAMBI and SYMDEKO/SYMKEVI business. It's either younger age groups or outside of the U.S.

是的，馬特，謝謝你的提問。因此，絕大多數正在服用 ORKAMBI、SYMDEKO 或 KALYDECO 且符合 TRIKAFTA 條件的患者——就像其他患者群體一樣——正在過渡到或已經過渡到 TRIKAFTA。因此，從業務表現來看，繼續使用該藥物的患者要么是 12 歲以下的兒童，要么是年齡較小的群體，而我們也在不斷擴大該群體的適應症。因此，我們繼續在美國招收新患者。正如查理在他的演講中提到的，我們在美國以外也看到了增長，在我們制定的報銷協議之後，患者或國家已經開始在美國以外推出 SYMDEKO，在某些情況下，或者應該說是 SYMKEVI 和 ORKAMBI。所以——這就是 KALYDECO、ORKAMBI 和 SYMDEKO/SYMKEVI 現有業務的驅動力。要嘛是年輕群體，要嘛是美國以外的群體。

And AAT, I think that will be Reshma.

AAT，我覺得應該是Reshma。

Thanks, Stuart. All right. On the question of AAT and what are we thinking about in terms of our Phase III plans? Let me just take one step back and just link what we're doing in Phase II to Phase III and give you a sense of how that strings together. So in Phase II, we're obviously looking at safety, and we're looking at the functional AAT levels and the serum antigenic AAT levels. And what we're trying to do there is to get the best estimation of dose, right? We are studying a number of different doses versus placebo. We're going to evaluate the dose exposure relationship and select the right dose.

謝謝你，斯圖爾特。好的。關於 AAT 的問題，以及我們在第三階段計畫中考慮的是什麼？讓我退後一步，把我們在第二階段所做的工作與第三階段連結起來，讓你們了解它們是如何銜接起來的。因此，在第二階段，我們顯然要關注安全性，並且要關注功能性 AAT 水平和血清抗原性 AAT 水平。我們現在想做的就是盡可能準確地估算劑量，對吧？我們正在研究多種不同劑量與安慰劑的比較。我們將評估劑量暴露關係，並選擇合適的劑量。

Assuming that we are in a position to move forward to Phase III based on these Phase II results, which obviously we haven't seen, but assuming that that is the next step, what we're going to do in Phase III is evaluate a few different measures. And as I've said before, we haven't had our meeting with the FDA yet. We haven't had that end of Phase II meeting. So this is a conceptual framework, but obviously, we need to go through those meetings and come out the other end with an agreement with the agency, but the framework would be that we would indeed be looking at antigenic levels. We would be looking at serum functional levels.

假設我們能夠根據這些 II 期結果推進到 III 期，雖然我們顯然還沒有看到這些結果，但假設這是下一步，那麼我們將在 III 期評估一些不同的措施。正如我之前所說，我們還沒有和FDA開會。我們還沒有召開第二階段結束會議。所以這是一個概念框架，但顯然，我們需要開會討論，最終與相關機構達成協議，但框架的核心是我們確實要關注抗原水平。我們會檢測血清功能水準。

We are planning to have an assessment of clearance of the liver from these polymers. And remember, again, with the small molecule approach, we have this opportunity to treat both the liver and the lung. So we plan to do that, and we are going to have that be a package. We need to go through the discussions with the agency. We need to confirm that that package would be acceptable. And as I've said a number of times previously, the companies that make augmentation therapy, about 5 of them have gotten their approvals in the U.S. based on levels of AAT. And so we need to go through that.

我們計劃評估肝臟對這些聚合物的清除。再次提醒大家，透過小分子療法，我們有機會同時治療肝臟和肺部疾病。所以我們計劃這樣做，而且我們會把它作為一個整體方案來推出。我們需要和該機構進行一番討論。我們需要確認該包裹是否可接受。正如我之前多次說過的那樣，生產增強療法的公司中，大約有 5 家已經根據 AAT 的水平獲得了美國批准。所以我們需要經歷這個過程。

Separately, we are very interested in, and I'm sure others might be interested in understanding the impact of our small molecule correctors on lung function measured by imaging or something like a pulmonary function test, and those are all considerations that we continue to talk and think about. But the framework for our package really is functional AAT levels, antigenic AAT levels and the clearance of the polymers from the liver.

另外，我們非常感興趣，我相信其他人也可能感興趣，了解我們的小分子矯正劑對透過影像或肺功能測試等方式測量的肺功能的影響，這些都是我們一直在討論和思考的問題。但我們方案的框架實際上是功能性 AAT 水平、抗原性 AAT 水平以及聚合物從肝臟的清除。

Operator, this is Michael. We have just a few minutes left. We'll take 2 more questions.

接線員，我是麥可。我們只剩下幾分鐘了。我們再回答兩個問題。

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

下一個問題來自加拿大皇家銀行資本市場的布萊恩亞伯拉罕。

My congratulations as well on the quarter. A couple on AAT also. Can you talk about the importance of smoother AAT or functional AAT levels that a corrector like 814 could confer versus the high peak to trough from an exogenous augmentation that -- and really the ways to assess the potential benefits of this. And then thinking longer term, you've laid out sort of a schematic for what a pivotal could look like? I'm also curious, your level of interest in exploring combinations with complementary mechanisms, either internally or externally to potentially optimize outcomes. Have you done preclinical work along those lines? And where might heterozygous patient population fit into the future development plan?

我也要祝賀你本季取得佳績。AAT上也有一對夫婦。您能否談談像 814 這樣的矯​​正劑能夠帶來的更平穩的 AAT 或功能性 AAT 水平的重要性，以及外源性增強劑帶來的高峰到低谷的波動——並真正評估這種潛在益處的方法。長遠來看，您是否已經勾勒出一個關鍵事件可能呈現的雛形？我也很好奇，您對探索內部或外部互補機制的組合以期優化結果的興趣程度如何。你是否做過這方面的臨床前研究？那麼，雜合子患者群體在未來的發展計畫中可能扮演什麼角色呢？

Okay. There's a lot packed into that question, but let me maybe try to tackle a little bit about where we are in terms of how we think about augmentation therapy or exogenous, what is basically protein replacement versus our approach with the small molecule. A couple of what I think are basic, but it's often hard to keep all of these things in mind, and it's important. So let me start there.

好的。這個問題包含了很多訊息，但我想嘗試稍微探討一下，就我們如何看待增強療法或外源性療法（基本上是蛋白質替代療法）與我們的小分子療法而言，我們目前處於什麼階段。我覺得有些事情很基本，但要記住所有這些事情往往很困難，而記住這些事情又很重要。那就讓我從這裡開始吧。

One critical element to point out with regard to exogenous augmentation therapy is that the only effect it could have is on the lung. And the reason I say that is because exogenous therapy is doing nothing for the production of misfolded protein, which gets stuck in the liver, if you will, and that is what causes fibrosis and could lead to cirrhosis. So one big concept about exogenous therapy that the only possible organ that it could help is the lung, very different than the small molecule approach.

關於外源性增強療法，需要指出的一個關鍵點是，它唯一可能產生的影響就是對肺部的影響。我之所以這麼說，是因為外源性療法對錯誤折疊蛋白質的產生沒有任何作用，而錯誤折疊蛋白質會滯留在肝臟中，這會導致纖維化，並可能導致肝硬化。因此，外源性療法的一個重要概念是，它唯一可能幫助的器官是肺，這與小分子療法非常不同。

The second is, you raise a good point around the PK and the peak-to-trough. The way augmentation therapy works is you go to a center and once a week, you get an infusion of this protein therapeutic. And during the course of that week, you have the augmentation that you received, let's say you went to the center on a Friday. So from Friday to Friday, what you have is what you received. And in that intervening period, you don't have any more AAT. This is very important because in you and me, in people who don't have alpha-1 antitrypsin deficiency, what happens is that AAT production changes in accordance to what your body needs. So for example, in times of stress, inflammation, infection, your body produces multifold more AAT in order to have the AAT medicine do its job, which is this need to prevent autodigestion. None of that can happen when you go into center for once-a-week therapy.

第二點是，你提出了關於 PK 和峰谷的一個很好的觀點。增強療法的原理是，你去中心，每週一次，接受這種蛋白質療法的輸液。在那一週期間，你接受了增強治療，假設你在星期五去了中心。所以從週五到週五，你所擁有的就是你所收到的。在此期間，你將不再有任何 AAT。這非常重要，因為在你我這樣的人身上，在沒有α-1抗胰蛋白酶缺乏症的人身上，AAT的產生會根據身體的需要而改變。例如，在壓力、發炎、感染等情況下，你的身體會產生數倍的 AAT，以便 AAT 藥物發揮作用，即防止自身消化。如果你每週去中心接受一次治療，這些情況都不會發生。

So there are many other differences we could talk about, but maybe the 3 for today is that the small molecule approach allows you to treat both lung and liver. It has this ability to change depending on what the needs of the body are as you can think of it as being under control of its own promoter. And the third point is around the fact that the augmentation therapy is just dose once a week and it has its decay over that week, and that is not how AAT works in the body. I hope that helps.

所以還有很多其他不同之處我們可以討論，但今天就先說說第三點吧：小分子療法可以同時治療肺部和肝臟疾病。它能夠根據身體的需要而改變，你可以把它想像成受自身啟動子控制。第三點是，這種增強療法每週只服用一次，而且效果會在一周內逐漸減弱，但這並不是 AAT 在體內發揮作用的方式。希望對您有幫助。

And our last question comes from the line of Paul Matteis with Stifel.

最後一個問題來自保羅·馬泰斯 (Paul Matteis) 與 Stifel 的合作。

Great. I'll continue the trend with 2 AAT questions. One, I was curious, based on genetic data or natural history data, what range of AAT production do you think you'd need to increase a ZZ mutant patient to in order to clinically derisk the next study? And then second, I was wondering if you could just comment now that you're going to Phase II with 864, some of the product differences as it relates to pharmacokinetics and potency and I guess, are you confident that that is a molecule that should be materially more potent?

偉大的。我將繼續推出 2 道 AAT 問題。首先，我很好奇，根據基因數據或自然史數據，您認為需要將 ZZ 突變患者的 AAT 產量提高到什麼範圍，才能在臨床上降低下一項研究的風險？其次，我想問一下，既然你們即將進入 864 的 II 期臨床試驗，能否談談該產品在藥物動力學和效力方面的一些差異？您是否確信這是一個效力顯著增強的分子？

Okay. We'll -- we've had a lot of AAT questions. So I guess it's fitting for our last question to be about AAT. I think the question behind your question is what are we really looking for in Phase II. And a little bit of that is around what levels are we looking at? And how does 814 compared to 864, right? So let me just tell you what we're really looking for in terms of the proof-of-concept study. Remember that this is a molecule, and this is a target that we have not studied before. No one has done what we're doing. We are the first ones there, and we are going to learn about the translation to patients with AATD with this trial. When we were doing CF, we'd obviously already gone through the translation from the bench to the bedside with KALYDECO and ORKAMBI and SYM by the time TRIKAFTA came along. And now this is like our translation to AATD to KALYDECO.

好的。我們收到了很多關於AAT的問題。所以我覺得我們最後一個問題問AAT（動物輔助治療）還挺合適的。我認為你問題背後的真正問題是，我們在第二階段真正想要的是什麼。其中一部分內容是關於我們正在關注的水平是多少？那麼，814 與 864 相比如何呢？那麼，讓我來告訴你們，我們在概念驗證研究中真正想要的是什麼。請記住，這是一個分子，而且這是我們以前從未研究過的目標。沒有人做過我們正在做的事情。我們是第一批進入這個領域的，我們將透過這項試驗來了解AATD患者的治療效果。當我們進行 CF 治療時，很明顯，在 TRIKAFTA 出現之前，我們已經透過 KALYDECO、ORKAMBI 和 SYM 完成了從實驗室到臨床應用的轉化。現在這就好比我們把 AATD 翻譯成 KALYDECO。

So here's what we're looking for from that proof-of-concept study: first, safety; second, we're looking for the relationship between PK/PD and dose and exposure to ensure that we get to the exposure levels that we need to get to; and third, I'm looking for a movement upward in AAT levels, both antigenic and in functional AAT levels because what that will tell us is that we have met proof-of-concept, right? We have put the drug into patients with this disease, and what we see is good safety exposure that we're looking for and movement up. Then we know -- once we know we've cracked the biology, and I'm not saying it's easy, but between cracking the biology and pouring on the chemistry, pouring on the chemistry is easier. And so once we have that proof-of-concept, then we can think about taking those next steps. So that's what I'm really looking for from that Phase II study.

所以，我們希望從這項概念驗證研究中得到以下幾點：首先是安全性；其次，我們希望了解 PK/PD 與劑量和暴露量之間的關係，以確保達到所需的暴露水平；第三，我希望看到 AAT 水平（包括抗原水平和功能性 AAT 水平）的上升，因為這將告訴我們，我們已經達到了概念驗證的目標，對吧？我們已經將這種藥物用於患有這種疾病的患者身上，我們看到了我們所期望的良好安全性和療效提升。那時我們就知道——一旦我們知道我們已經破解了生物學，我不是說這很容易，但在破解生物學和應用化學之間，應用化學更容易。因此，一旦我們有了概念驗證，我們就可以考慮採取下一步措施了。所以，這就是我真正希望從二期臨床試驗中獲得的結果。

Okay. Thank you all for joining us. We appreciate you tuning in. The Investor Relations team is available tonight if you have additional questions. Stay safe, and have a good evening.

好的。感謝各位的參與。感謝您的收看。如果您還有其他疑問，投資者關係團隊今晚可以為您解答。注意安全，祝你晚安。

Ladies and gentlemen, this concludes today's conference call. Thank you for participating, and you may now disconnect.

女士們、先生們，今天的電話會議到此結束。感謝您的參與，您現在可以斷開連接了。