福泰製藥 (VRTX) 2022 Q3 法說會逐字稿

Good day, and welcome to the Vertex Pharmaceuticals Third Quarter 2022 Earnings Call.

大家好，歡迎參加Vertex Pharmaceuticals 2022年第三季財報電話會議。

(Operator Instructions)

（操作說明）

Please note this event is being recorded. I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead, ma'am.

請注意，本次會議正在錄影。現在我將會議交給蘇西·麗莎女士。請開始吧，女士。

Good evening, all. My name is Susie Lisa, and I'm thrilled to have joined Vertex as the new Senior Vice President of Investor Relations. Welcome to our third quarter 2022 financial results conference call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Stuart Arbuckle, Chief Operating Officer; and Charlie Wagner, Chief Financial Officer.

各位晚上好。我叫蘇西‧麗莎，非常榮幸能加入Vertex公司，擔任投資人關係資深副總裁。歡迎參加我們2022年第三季財務業績電話會議。今晚出席會議並發表演說的有：Vertex公司執行長兼總裁雷什瑪·凱瓦拉瑪尼博士、營運長史都華·阿巴克爾以及財務長查理·瓦格納。

We recommend that you access the webcast slides as you listen to this call. The 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 in our filings with the Securities and Exchange Commission.

我們建議您在收聽本次電話會議的同時查看網路直播投影片。本次電話會議將被錄音，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一些前瞻性聲明，這些聲明受制於今天新聞稿以及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。

These statements, including, without limitation, those regarding Vertex's marketed cystic fibrosis medicines, our pipeline and Vertex's future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially. I would also note that select financial results and guidance that we will review on the call this evening are presented on a non-GAAP basis. I will now turn the call over to Reshma.

這些聲明，包括但不限於有關Vertex已上市囊性纖維化藥物、我們的研發管線以及Vertex未來財務表現的聲明，均基於管理層目前的假設。實際結果和事件可能與這些假設有重大差異。我還想指出，今晚電話會議上我們將討論的部分財務表現和指引是以非GAAP準則編制的。現在我將把電話會議交給Reshma。

Thanks, Susie. We're delighted to have you on Board. Good evening all, and thank you for joining us on the call today. Vertex continues to execute exceptionally well and make significant progress towards our goals of: one, reaching all patients with cystic fibrosis resulting in strong sustainable growth; two, advancing our diverse mid- and late-stage clinical pipeline to develop transformative medicines in multiple disease areas; three, preparing for our next commercial launches; and four, progressing the next wave of innovation towards the clinic.

謝謝蘇西。我們非常高興您加入我們。各位晚上好，感謝大家今天參加電話會議。 Vertex 持續保持卓越的執行力，並在實現以下目標方面取得了顯著進展：第一，惠及所有囊性纖維化患者，從而實現強勁且可持續的增長；第二，推進我們多元化的中後期臨床研發管線，在多個疾病領域開發變革性藥物；第三，為下一輪商業化上市做好準備；第四階段，下一波創新進入臨床階段。

In the third quarter, global CF product revenues increased 18% year-on-year to $2.3 billion as more patients initiated treatment with our CFTR modulators. Based on the strong performance, we are raising full year 2022 product revenue guidance from $8.6 billion to $8.8 billion to $8.8 billion to $8.9 billion. Despite the growing numbers of CF patients on CFTR modulators, we still have many more patients to reach. And as you will hear from Stuart, we are working with focus and urgency to reach all patients around the globe who may benefit from our therapies.

第三季度，隨著更多患者開始使用我們的CFTR調節劑治療，全球囊性纖維化（CF）產品收入年增18%，達到23億美元。基於強勁的業績表現，我們將2022年全年產品營收預期從86億至88億美元上調至88億至89億美元。儘管使用CFTR調節劑的CF患者人數不斷增長，但我們仍有許多患者需要惠及。正如您將從Stuart那裡聽到的，我們正集中精力、爭分奪秒地工作，力求讓全球所有可能受益於我們療法的患者都能獲得治療。

As previously discussed, we are at an important inflection point for the company. Each of our clinical stage programs, sickle cell disease and beta-thalassemia, acute pain, AMKD, type 1 diabetes and AATD is a first-in-class or best-in-class approach that holds the promise to transform the disease and each represents a multibillion dollar opportunity. With a uniquely strong and durable CF franchise, a broad and deep R&D pipeline with multiple potentially near-term commercial opportunities, a strong balance sheet and the capacity to invest in both internal and external innovation and deeply talented people, Vertex is well positioned to deliver for patients and shareholders for years to come.

如同先前所述，我們正處於公司發展的重要轉捩點。我們所有處於臨床階段的項目，包括鐮狀細胞病和β地中海貧血、急性疼痛、AMKD、1型糖尿病和AATD，都是同類首創或同類最佳的療法，有望徹底改變疾病的治療格局，每個項目都蘊藏著數十億美元的商機。憑藉強大且持久的囊性纖維化產品線、廣泛而深入的研發管線（其中包含多個潛在的近期商業化機會）、穩健的資產負債表以及投資於內部和外部創新和人才的能力，Vertex 已做好充分準備，在未來幾年內為患者和股東創造價值。

With that overview, I'll turn to the details of recent R&D progress, starting with CF. TRIKAFTA sets a very high bar in terms of safety and efficacy in the registrational trials as well as in real world and long-term studies. That said, if it is possible to develop even more effective medicines for CF patients, we are determined to be the company that does so. Our next-in-class triple combination, VX-121/tezacaftor/VX-561, holds that potential.

概述完畢後，我將詳細介紹近期研發進展，首先從囊性纖維化（CF）領域開始。 TRIKAFTA 在註冊試驗、真實世界研究和長期研究中，其安全性和有效性都達到了極高的標準。即便如此，如果有可能開發出對 CF 患者更有效的藥物，我們決心成為引領這一目標的公司。我們下一代三重療法 VX-121/tezacaftor/VX-561 就具備這樣的潛力。

The triple now referred to as vanzacaftor, tezacaftor, deutivacaftor or the vanzacaftor triple is progressing rapidly through Phase III development with our studies in patients ages 12 and older, now projected to complete enrollment this year. As a reminder, this combination demonstrated greater activity in our human bronchial epithelial assay versus TRIKAFTA and greater clinical benefit in Phase II than we have seen with any of our prior medicines.

目前被稱為 vanzacaftor、tezacaftor 和 deutivacaftor 的三聯療法（簡稱 vanzacaftor 三聯療法）正快速推進 III 期臨床試驗，針對 12 歲及以上患者的研究預計將於今年完成入組。需要指出的是，與 TRIKAFTA 相比，該組合療法在我們的人類支氣管上皮細胞試驗中顯示出更高的活性，並且在 II 期臨床試驗中展現出比我們以往任何藥物都更顯著的臨床益處。

Additionally, it offers the convenience of once-daily dosing and royalties in the low single digits versus low double digits for TRIKAFTA. For the 5,000 patients who do not make any CFTR protein, we're working on an mRNA therapy with our partners at Moderna. We have completed IND-enabling studies, and we remain on track to submit an IND for this program this quarter with clinical trials starting thereafter, and we're not done. Our work continues to identify even better potential therapies that could bring more patients with CF to carrier levels of sweat chloride.

此外，它還具有每日一次給藥的便利性，且專利使用費僅為個位數，而TRIKAFTA的專利使用費則為兩位數。對於5000名無法產生CFTR蛋白的患者，我們正與Moderna的合作夥伴共同研發mRNA療法。我們已完成IND申報所需的各項研究，並預計在本季度提交該項目的IND申請，隨後啟動臨床試驗。但我們的工作並未止步。我們將繼續致力於尋找更有效的潛在療法，以使更多囊性纖維化患者的汗液氯化物水平達到攜帶者水平。

Turning to exa-cel, previously known as CTX001, our gene editing program for severe sickle cell disease and transfusion-dependent beta-thalassemia, or TDT. This is our most advanced program outside CF, and we expect exa-cel to be our next commercial launch. In June, we presented data from 75 patients with up to 37 months of follow-up from our pivotal trials of exa-cel. The data demonstrated exa-cel's potential to provide a onetime functional cure for these patients.

接下來我們來談談 exa-cel，它之前被稱為 CTX001，是我們針對重度鐮狀細胞疾病和輸血依賴型β-地中海貧血（TDT）的基因編輯計畫。這是我們在囊性纖維化以外的最先進項目，我們預計 exa-cel 將成為我們下一個商業化產品。今年 6 月，我們公佈了 exa-cel 關鍵性試驗中 75 名患者長達 37 個月的追蹤數據。這些數據表明，exa-cel 有潛力為這些患者提供一次性功能性治癒。

Last month, we announced that in addition to having granted virtually all available U.S. regulatory designations, the FDA has now also granted exa-cel a rolling review. We plan to begin our BLA submissions for both sickle cell disease and beta-thalassemia in the U.S. next month, and complete the submissions by the end of the first quarter of 2023. In Europe, we previously shared that we reached agreement on the filing package with the EMEA and MHRA in the EU and U.K., respectively. We remain on track to submit these MAAs by the end of this year. Our teams are intensely focused on preparing these multiple complex submissions with 3 separate regulatory agencies in order to bring exa-cel to patients as quickly as possible.

上個月，我們宣布，除了已獲得幾乎所有可用的美國監管機構認定外，FDA 還批准了 exa-cel 的滾動審查。我們計劃下個月開始向美國提交治療鐮狀細胞貧血症和β-地中海貧血的生物製品許可申請 (BLA)，並於 2023 年第一季末完成所有申請。先前，我們已宣布分別與歐盟的 EMEA 和英國的 MHRA 就申請資料達成協議。我們仍按計劃在今年年底前提交這些上市許可申請 (MAA)。我們的團隊正全力以赴地準備向三個不同的監管機構提交的這些複雜的申請，以便盡快將 exa-cel 帶給患者。

Given that priority, we will not be sharing new clinical data at ASH, but instead, look forward to sharing updated clinical data in the first half of 2023. Exa-cel holds the promise for a onetime curative therapy for thousands of patients with severe sickle cell disease and transfusion-dependent beta-thalassemia. This therapy, potentially the first CRISPR-based gene editing treatment to be commercialized for patients with a genetic disease also represents a near-term and significant market opportunity.

有鑑於此項優先事項，我們不會在ASH大會上公佈新的臨床數據，而是期待在2023年上半年分享更新的臨床數據。 Exa-cel預計將為數千名患有嚴重鐮狀細胞疾病和輸血依賴型β-地中海貧血的患者提供一次性治癒療法。該療法有望成為首個商業化的基於CRISPR的基因編輯療法，用於治療遺傳性疾病，也代表著近期巨大的市場機會。

Turning to VX-548 and our pain program. VX-548 is a novel selective NaV1.8 inhibitor that offers the potential of highly effective pain relief without the side effects or addictive potential of opioids. NaV1.8 is both a genetically and pharmacologically validated target. Recall that VX-150, an earlier-generation NaV1.8 inhibitor, demonstrated positive proof of concept in acute, neuropathic and musculoskeletal pain. VX-548 has been studied in 2 Phase II placebo-controlled acute pain studies and showed statistically significant and clinically meaningful pain relief compared to placebo and was generally well tolerated.

接下來我們來談談VX-548及其在疼痛治療中的作用。 VX-548是一種新型選擇性NaV1.8抑制劑，它有望在不產生鴉片類藥物副作用或成癮性的情況下，高效緩解疼痛。 NaV1.8是一個經過基因和藥理學驗證的標靶。回顧一下，VX-150，一種早期的NaV1.8抑制劑，已在急性疼痛、神經性疼痛和肌肉骨骼疼痛方面展現出積極的概念驗證。 VX-548已在兩項II期安慰劑對照急性疼痛研究中進行了評估，結果顯示，與安慰劑相比，VX-548在統計學上具有顯著意義，且臨床上也具有顯著療效，並且整體耐受性良好。

The study also included an opioid reference arm to support the evaluation of VX-548. With regard to the regulatory status, VX-548 has been granted fast track and breakthrough therapy designation in the U.S. We reached agreement with the FDA on the design of the Phase III program in support of a broad label in moderate to severe acute pain and recently initiated the pivotal studies.

該研究還設立了阿片類藥物對照組，以支持對 VX-548 的評估。在監管方面，VX-548 已在美國獲得快速通道資格和突破性療法認定。我們已與 FDA 就 III 期臨床試驗方案的設計達成一致，以支持其在中度至重度急性疼痛方面的廣泛適應症，並於近期啟動了關鍵性研究。

The Phase III development plan for VX-548 in acute pain consists of 2 randomized controlled trials. The design of the RCTs in the pivotal program is very similar to our Phase II completed studies, same pain states, post bunionectomy and post abdominoplasty. Same treatment duration, 48 hours and the same primary endpoint, the sum of pain intensity difference, or SPID, over 48 hours of VX-548 compared to placebo.

VX-548治療急性疼痛的III期開發計畫包括兩個隨機對照試驗。關鍵性項目中的隨機對照試驗設計與我們已完成的II期研究非常相似，疼痛狀態相同，均為拇趾外翻切除術後和腹部整形術後。治療時間相同，皆為48小時，主要終點也相同，即VX-548與安慰劑相比，48小時內疼痛強度差異總和（SPID）。

A third single-arm study rounds out the Phase III program. This study will enroll patients with multiple other types of moderate to severe acute pain with a treatment period of up to 14 days. Given our experience in executing these types of trials efficiently, the short treatment duration and the high unmet need for effective pain relief without the significant side effects or addictive potential of opioids, we view VX-548 as a near-term and significant market opportunity. We also plan to study VX-548 in neuropathic pain and remain on track to initiate a Phase II dose-ranging proof-of-concept study in patients with painful diabetic neuropathy towards the end of this year.

第三項單臂研究完善了III期臨床試驗項目。研究將招募患有多種其他類型中度至重度急性疼痛的患者，治療週期最長為14天。鑑於我們高效執行此類試驗的經驗，以及VX-548治療週期短、且在不產生阿片類藥物顯著副作用或成癮性的情況下有效緩解疼痛的巨大未滿足需求，我們認為VX-548具有近期且重要的市場機會。我們也計劃研究VX-548在神經性疼痛的應用，並按計畫於今年底啟動一項針對糖尿病性神經痛患者的II期劑量範圍概念驗證研究。

Moving to inaxaplin or VX-147, the first potential medicine to treat the underlying cause of APOL1-mediated kidney disease, or AMKD. Inaxiplin has breakthrough therapy designation in the U.S. and both prime and orphan drug designation in Europe. Inaxaplin is being studied in a single adaptive, randomized, double-blind, placebo-controlled, Phase II/III pivotal trial and the primary endpoint is a reduction in the rate of decline of kidney function in patients treated with inaxaplin on top of standard of care compared to standard of care for approximately 2 years.

伊那沙普林（Inaxaplin，又稱VX-147）是第一個有望治療APOL1介導的腎臟病（AMKD）根本病因的藥物。伊那沙普林已獲得美國突破性療法認定，並在歐洲獲得主要藥物認定和孤兒藥認定。目前正在一項適應性、隨機、雙盲、安慰劑對照的II/III期關鍵性試驗中研究伊那沙普林，該試驗的主要終點是：在標準治療的基礎上加用伊那沙普林治療的患者，其腎功能下降速度較僅接受標準治療的患者降低約2年。

Importantly, the trial is a preplanned interim analysis at 48 weeks of treatment, which if positive, could serve as the basis for accelerated approval in the U.S. This study is underway in enrolling patients. We now have more than 50 sites open for enrollment in the U.S. and internationally with a goal to open more than 150 sites in total. We look forward to updating you on the enrollment and study progress as the trial advances.

重要的是，該試驗是一項預先計劃的48週治療中期分析，如果結果為陽性，則可能成為美國加速審批的依據。目前，該研究正在招募患者。我們在美國和國際上已開放50多個招募中心，目標是最終開放150多個招募中心。隨著試驗的推進，我們將及時向您通報招募和研究進展。

Next, moving on to type 1 diabetes. We have been advancing 3 programs in our portfolio. First, VX-880, our stem cell-derived, fully differentiated insulin-producing islet cell replacement therapy, which is a mid-stage clinical development. In this program, we use standard immunosuppressive therapy to protect the cells from the immune system. These same cells are the foundation for our other 2 programs in type 1 diabetes. Next, the cells plus device program, which encapsulates these fully differentiated islet cells in a proprietary device that shields the cells from the body's immune system and does not require immunosuppressants.

接下來，我們來談談第1型糖尿病。我們一直在推進三個專案。首先是VX-880，這是一種源自幹細胞的、完全分化的胰島素分泌胰島細胞替代療法，目前處於臨床開發中期階段。在這個計畫中，我們採用標準的免疫抑制療法來保護細胞免受免疫系統的攻擊。這些細胞也是我們另外兩個1型糖尿病計畫的基礎。其次是細胞+裝置項目，該項目將這些完全分化的胰島細胞封裝在一個專有裝置中，該裝置可以保護細胞免受人體免疫系統的攻擊，並且無需使用免疫抑制劑。

We remain on track to file the IND for this program by the end of this year. Lastly, in our hypoimmune cells program, which is in preclinical development, we are editing the same fully differentiated insulin-producing islet cells to cloak them from the immune system, obviating the need for immunosuppressants. Earlier this year, we achieved proof of concept for VX-880 in type 1 diabetes with the first 2 patients dosed at half dose in Part A of the study. Part B of the study, which uses the full target dose is underway and enrolling patients. The type 1 diabetes program holds enormous potential. There are more than 2.5 million patients in the U.S. and EU alone with type 1 diabetes who may benefit from a treatment with the potential to provide glucose control without the fear of hypoglycemia or the need for insulin. We look forward to sharing additional data from more patients and longer duration of follow-up at the appropriate time.

我們仍按計畫於今年底前提交該項目的IND申請。此外，在我們目前處於臨床前開發的低免疫細胞計畫中，我們正在對完全分化的胰島素分泌胰島細胞進行基因編輯，使其免受免疫系統攻擊，從而避免使用免疫抑制劑。今年早些時候，我們在VX-880治療第1型糖尿病方面取得了概念驗證，在研究的A部分中，前兩名患者接受了半劑量給藥。目前，採用全劑量目標劑量的研究B部分正在進行中，並已開始招募患者。 1型糖尿病項目潛力大。光是在美國和歐盟就有超過250萬1型糖尿病患者，他們有望從這種能夠有效控制血糖且無需擔心低血糖或使用胰島素的療法中獲益。我們期待在適當的時候分享更多患者和更長時間追蹤的更多數據。

A last word on our type 1 diabetes program. Having recently closed the acquisition of Viacyte, I want to extend a warm welcome to our Viacyte colleagues. Let me close with our Alpha-1 antitrypsin deficiency, or AATD program. Earlier this month, we announced that the IND for VX-634, the first in a series of next wave AAT correctors has cleared, and VX-634 has entered first-in-human clinical trials. We also announced that a 48-week Phase II study of VX-864, our first-generation AAT corrector will soon initiate. This study will assess the impact of longer-term treatment on polymer clearance from the liver as well as on serum levels of functional AAT.

關於我們的第一型糖尿病項目，最後再補充幾點。我們最近完成了對Viacyte的收購，在此我謹代表公司熱烈歡迎Viacyte的同事們加入我們。接下來，我想談談我們的α1-抗胰蛋白酶缺乏症（AATD）計畫。本月初，我們宣布了下一代AAT矯正劑系列中的首個產品VX-634的IND申請已獲批准，並已進入首次人體臨床試驗。同時，我們也宣布即將啟動一項為期48週的II期臨床試驗，該試驗針對的是我們的第一代AAT矯正劑VX-864。這項研究將評估長期治療對肝臟清除聚合物以及血清中功能性AAT水平的影響。

With those R&D highlights, I'll hand it over to Stuart for a review of our commercial progress.

介紹完這些研發亮點後，我將把工作交給斯圖爾特，讓他來評估我們的商業進度。

Thanks, Reshma. I am pleased to review tonight our continued strong performance in CF as well as the multiple near-term commercial opportunities we see across our business, including the strong outlook in CF, significant progress made to prepare for the commercial launch of exa-cel and our view of the promising role of VX-548 in helping treat pain.

謝謝，雷什瑪。我很高興今晚能回顧我們在囊性纖維化領域持續強勁的業績，以及我們在業務中看到的多個近期商業機會，包括囊性纖維化領域的良好前景、為exa-cel商業化上市所做的重大準備工作，以及我們對VX-548在幫助治療疼痛方面所發揮的有前景的作用的看法。

Starting with CF. In the U.S., our focus is to maintain the very high persistence and compliance we have seen with our therapies and to extend the benefits of therapy to younger age groups. Outside the U.S., we have seen rapid growth driven by the uptake of KAFTRIO/TRIKAFTA in countries with recent reimbursement agreements. We've also seen strong uptake of KAFTRIO in children ages 6 to 11 in countries where this indication has reimbursed access. Today, our medicines are approved and reimbursed in more than 30 countries, benefiting tens of thousands of cystic fibrosis patients on 5 continents.

從囊性纖維化（CF）開始。在美國，我們的重點是保持我們療法的高堅持性和依從性，並將治療益處擴展到更年輕的年齡層。在美國以外，由於近期達成健保報銷協議的國家/地區對KAFTRIO/TRIKAFTA的需求增長，我們看到了快速增長。在已將KAFTRIO納入醫保報銷範圍的國家/地區，我們也看到6至11歲兒童對KAFTRIO的需求強勁。如今，我們的藥物已在30多個國家獲得批准並納入健保報銷範圍，惠及五大洲數萬名囊性纖維化患者。

However, there are still thousands of CF patients who are not yet on treatment. These patients fall primarily into the following categories: one, patients in countries where we are early on the launch curve, such as those with recently achieved reimbursement agreements or label extensions for younger patients; two, patients in younger age groups for whom we continue to pursue label and reimbursement extensions; and three, to a lesser extent, patients awaiting reimbursement for our medicines in a small number of countries.

然而，仍有數千名囊性纖維化患者尚未接受治療。這些患者主要分為以下幾類：第一類是那些我們處於產品上市早期階段的國家/地區的患者，例如那些近期已達成醫保報銷協議或針對年輕患者擴大適應症的國家/地區的患者；第二類是那些我們仍在努力爭取擴大適應症和醫保報銷範圍的年輕患者群體；第三類是少數國家/地區正在等待我們藥物數量較少的患者（醫藥數量）。

We are confident that we will reach the vast majority of these patients over time, which will drive continued revenue growth in the near and long term. We continue to make excellent progress expanding the label for our CFTR modulators to younger age groups. In September, ORKAMBI was approved for children ages 12 months to less than 24 months in the U.S. We expect to file for U.S. FDA approval of KALYDECO in children ages 1 month to less than 4 months before the end of 2022.

我們有信心，隨著時間的推移，我們將惠及絕大多數此類患者，這將推動我們近期和長期的收入持續成長。我們在拓展CFTR調節劑的適應症，使其適用於較年輕的年齡層方面，持續取得顯著進展。今年9月，ORKAMBI在美國獲準用於12個月至24個月以下的兒童。我們預計在2022年底前向美國FDA提交KALYDECO用於1個月至4個月以下兒童的上市申請。

Similarly, we will submit to the U.S. and other global regulatory authorities for approval of TRIKAFTA in children 2 to 5 years old by the end of the year. Finally, in CF, as Reshma mentioned, our CFTR mRNA program is progressing toward an IND submission this year. This program targets the underlying cause of disease in approximately 5,000 CF patients worldwide. Beyond CF, we have a broad, diverse and advanced R&D pipeline. I will focus my comments on our commercial readiness efforts and the market opportunity for our potential next product launches, exa-cel and VX-548.

同樣，我們將在年底前向美國和其他全球監管機構提交TRIKAFTA用於2至5歲兒童的上市申請。最後，如Reshma所提到的，在囊性纖維化（CF）領域，我們的CFTR mRNA計畫正朝著今年提交新藥臨床試驗申請（IND）的目標穩步推進。該計畫旨在解決全球約5000名CF患者的根本病因。除了CF領域，我們還擁有廣泛、多元且先進的研發管線。我將重點介紹我們的商業化準備工作以及我們潛在的下一代產品exa-cel和VX-548的市場機會。

Exa-cel holds curative potential for patients with sickle cell disease and transfusion-dependent beta-thalassemia, and we are making significant progress with launch preparation activities. Treatment with exa-cel is a process that takes months from start to finish, and we fully recognize both the significant opportunities and challenges in offering such a novel, potentially curative therapy for patients.

Exa-cel 預計將治癒鐮狀細胞疾病和輸血依賴型β地中海貧血患者，我們在上市準備方面取得了顯著進展。 Exa-cel 的治療過程從開始到結束需要數月時間，我們充分認識到為患者提供這種新型、潛在治癒性療法所面臨的巨大機會和挑戰。

We are creating the infrastructure and support required for physicians and patients that we believe will lead to commercial success upon potential regulatory approvals. Our commercial and medical science liaison field teams are hired and trained in the U.S. These teams have been actively engaging with key treatment centers, policymakers and payers and similar efforts are ongoing in Europe. Our initial launch of exa-cel will focus on the estimated 32,000 patients in the U.S. and Europe with severe forms of sickle cell disease and beta-thalassemia.

我們正在為醫生和患者建立必要的基礎設施和支援體系，我們相信這將有助於產品在獲得監管部門批准後取得商業成功。我們的商業和醫學聯絡團隊均在美國招募和培訓。這些團隊一直積極與重要的治療中心、政策制定者和支付者溝通，類似的努力也在歐洲進行。我們最初推出的exa-cel將聚焦在美國和歐洲約32,000名患有嚴重鐮狀細胞疾病和β-地中海貧血的患者。

Roughly 25,000 of these 32,000 patients are severe sickle cell disease patients, the vast majority of whom reside in the U.S. These patients are highly concentrated in certain geographies. And thus, we believe they can be served effectively with a network of approximately 50 qualified authorized treatment centers in the U.S. and approximately 25 in Europe. By way of context, we reached the vast majority of CF patients in the U.S. by calling on approximately 250 CF treatment centers. These centers have the medical and technical expertise to support the potential future use of exa-cel. Our field teams are already engaging with these centers on the needed administrative and logistical capabilities as well as the treatment capacity to support the launch.

在這32,000名患者中，約有25,000名是重度鐮狀細胞疾病患者，其中絕大多數居住在美國。這些患者高度集中在某些特定地區。因此，我們相信，透過在美國建立約50家合格的授權治療中心，並在歐洲建立約25家，就能有效地為他們提供服務。作為參考，我們透過聯繫約250家囊性纖維化（CF）治療中心，涵蓋了美國絕大多數CF患者。這些中心具備支援未來使用exa-cel所需的醫療和技術專長。我們的現場團隊已開始與這些中心接洽，以了解他們所需的行政和後勤能力以及治療能力，以支援產品的上市。

We've been encouraged by the early interest and engagement from the centers and their staff. In parallel to engaging with these treatment centers, we have been working closely with policymakers and with payers to ensure that these stakeholders understand the significant burden of these diseases. Payment models are an important consideration, given the value that a onetime potentially curative therapy like exa-cel can bring to patients and the healthcare system.

我們對各中心及其工作人員早期表現出的興趣和積極參與感到鼓舞。在與這些治療中心合作的同時，我們也與政策制定者和支付者密切合作，確保這些利害關係人了解這些疾病帶來的巨大負擔。考慮到像exa-cel這樣一次性、可能治癒的療法能夠為患者和醫療保健系統帶來的價值，支付模式是一個重要的考慮因素。

We are continuing to work with various stakeholders to ensure patients who may be eligible for exa-cel have access to this potentially curative therapy.

我們正繼續與各利益相關者合作，以確保符合 exa-cel 治療條件的患者能夠獲得這種可能治癒的療法。

Turning to pain. We believe that VX-548 has the potential to play an important role across the pain spectrum, including an acute, neuropathic and musculoskeletal pain. With the recent initiation of the VX-548 Phase III program and the short treatment period in these trials, acute pain is now an exciting potential near-term commercial opportunity. I'll focus my remarks around 3 key aspects, critical to framing the acute pain market for Vertex.

談到疼痛治療，我們相信VX-548有望在各種疼痛領域發揮重要作用，包括急性疼痛、神經性疼痛和肌肉骨骼疼痛。隨著VX-548 III期臨床試驗的啟動以及這些試驗中較短的治療週期，急性疼痛領域如今已成為一個令人振奮的潛在近期商業機會。我將重點闡述三個關鍵方面，這三個面向對於Vertex公司開拓急性疼痛市場至關重要。

One, the opportunity is significant, given the market today for acute pain in the U.S. is $4 billion, even though 90% of prescriptions are generic; two, prescribing is concentrated in the hospital setting and thus addressable with a specialty commercial infrastructure that fits the Vertex model; and three, there is a significant gap in the market for safe and effective treatment options for physicians and patients. Firstly, despite 90% generic penetration, the U.S. market is approximately $4 billion and patients received some 1.5 billion treatment days annually for the oral treatment of acute pain, a highly effective and well-tolerated new class of medicine, therefore, has multibillion dollar potential.

首先，鑑於目前美國急性疼痛市場規模達40億美元（儘管90%的處方藥為仿製藥），市場機會巨大；其次，處方主要集中在醫院，因此可以透過符合Vertex模式的專業商業基礎設施進行有效覆蓋；第三，目前市場上缺乏安全有效的治療方案，無法滿足醫生和患者的需求。首先，儘管仿製藥滲透率高達90%，但美國市場規模仍約為40億美元，患者每年接受口服急性疼痛治療​​的治療天數約為15億天，因此，高效且耐受性良好的新型藥物具有數十億美元的市場潛力。

Secondly, roughly 2/3 or $1 billion of these treatment days are driven by hospital prescribing following inpatient or outpatient procedures such as surgeries or emergency room visits. This includes the prescriptions written and filled in hospital during the patient's stay and those written at discharge to provide the patient with a multi-day course of medicine for ongoing pain management.

其次，這些治療日中約有三分之二（即10億美元）是由醫院在患者接受住院或門診手術或急診就診後開具的處方所驅動的。這包括患者住院期間在醫院開立和配發的處方，以及出院時開立的用於為患者提供多日療程藥物以進行持續疼痛管理的處方。

Given the concentration of pain treatment that is driven by hospital prescribing, we believe we can reach a large proportion of this market with a specialty sales and marketing infrastructure. And a third key consideration of this marketplace is the significant side effects of opioid therapy. Overdose deaths from opioids have continued to rise in the U.S. and opioid prescribing for the treatment of acute pain has been a clear contributing factor to the opioid epidemic. In response, hospitals, physicians and state agencies throughout the U.S. have limited or attempted to reduce the use of opioids for the treatment of acute pain. Many states as well as large hospital systems, such as Kaiser Permanente and John Hopkins Medicine, have enacted strict measures to reduce opioid prescribing.

鑑於疼痛治療主要由醫院處方主導，我們相信憑藉專業的銷售和行銷體系，我們可以涵蓋該市場的大部分份額。該市場的第三個關鍵考慮因素是阿片類藥物治療的顯著副作用。在美國，阿片類藥物過量致死人數持續上升，而鴉片類藥物用於治療急性疼痛顯然是導致鴉片類藥物濫用危機的一個重要因素。為此，美國各地的醫院、醫生和州政府機構都已限製或試圖減少阿片類藥物在急性疼痛治療​​中的使用。許多州以及大型醫院系統，例如凱撒醫療集團和約翰霍普金斯醫學中心，都已採取嚴格措施來減少鴉片類藥物的處方量。

In addition, beyond the addictive potential, opioids have other negative side effects, including nausea, somnolence, constipation and can result in increased length of hospital stay until these problems resolve. These concerns and limitations with opioids create a significant gap in the market for the treatment of acute pain because of the lack of safe and effective treatment options for doctors and patients. Therefore, availability of a therapy like VX-548, a novel, highly effective, non-opioid treatment that does not have the addictive potential of opioids nor the significant side effect profile would be an extremely valuable new treatment option and could be used as the next step in a treatment strategy after prescription NSAIDs, relegating opioids to being used only as a last resort.

此外，除了成癮性之外，鴉片類藥物還有其他副作用，包括噁心、嗜睡、便秘，並可能導致住院時間延長，直到這些問題解決為止。阿片類藥物的這些弊端和局限性造成了急性疼痛治療​​市場的巨大空白，因為醫生和患者缺乏安全有效的治療選擇。因此，像VX-548這樣一種新型、高效、非阿片類藥物的療法，既沒有阿片類藥物的成癮性，也沒有顯著的副作用，將是一種極其寶貴的治療選擇，可以作為處方非類固醇抗發炎藥（NSAIDs）治療策略的下一步，從而使阿片類藥物僅作為最後的選擇。

I look forward to updating you further on our commercialization plans in pain, including our view of the opportunity in neuropathic pain over the coming months. In closing, I'm excited about the opportunity to extend the benefits of our CF medicines to more and more patients around the globe and with the near-term potential commercialize multiple transformative treatments for patients with serious diseases outside of CF.

我期待在未來幾個月內，向大家進一步介紹我們在疼痛治療領域的商業化計劃，包括我們對神經性疼痛領域機會的看法。最後，我很高興有機會將我們治療囊性纖維化的藥物惠及全球越來越多的患者，並且預計在近期內將多種變革性療法商業化，用於治療囊性纖維化以外的其他嚴重疾病。

I will now turn the call over to Charlie to review the financials.

現在我將把電話交給查理，讓他審核財務數據。

Thanks, Stuart. Vertex's third quarter and year-to-date 2022 results set us on pace for another year of exceptional financial performance and strong execution. Third quarter 2022 revenue increased 18% year-over-year to $2.3 billion, led by 46% growth outside the U.S. on continued strong uptake of TRIKAFTA/KAFTRIO in markets with recently achieved reimbursement as well as label extensions into younger age groups. U.S. CF revenue was up 5% with ongoing consistent performance aided by penetration into younger age groups. During the third quarter, CF revenue growth also benefited from an approximately $75 million increase in channel inventory in certain markets. We do not expect these purchases to recur in the fourth quarter, and this quarterly phasing is reflected in our updated full year guidance.

謝謝，Stuart。 Vertex 2022 年第三季及年初至今的業績表明，我們預計在新的一年裡繼續保持卓越的財務表現和強勁的執行力。 2022 年第三季營收年增 18% 至 23 億美元，其中美國以外地區成長 46%，主要得益於 TRIKAFTA/KAFTRIO 在近期獲得醫保報銷的市場以及產品標籤擴展至更年輕年齡層人群後持續強勁的市場需求。美國 CF 業務營收成長 5%，持續穩定的績效表現得益於產品在較年輕年齡層中的滲透。第三季度，CF 業務營收成長也得益於部分市場通路庫存增加約 7,500 萬美元。我們預計這些採購不會在第四季度再次出現，而這一季度分階段的安排已反映在我們更新後的全年業績預期中。

Third quarter 2022 combined non-GAAP R&D, acquired IP R&D and SG&A expenses were $758 million, an increase of 29% compared to the third quarter of 2021. Throughout 2022, we have continued to invest in our R&D pipeline, which now includes 7 programs, 5 of which are in pivotal development. The year-over-year increase in Q3 reflects stepped-up investments in these programs, notably pain, the new vanzacaftor triple in mRNA and CF and type 1 diabetes as well as the continued pre-commercial build-out activities for exa-cel.

2022年第三季非GAAP研發、收購智慧財產權研發及銷售、管理及行政費用合計為7.58億美元，較2021年第三季成長29%。 2022年全年，我們持續加大研發投入，目前已擁有7個研發項目，其中5個處於關鍵性開發階段。第三季年成長反映了我們對這些計畫的加大投入，特別是針對疼痛治療、mRNA和囊性纖維化及1型糖尿病的新型vanzacaftor三聯療法，以及exa-cel持續進行的商業化前期推廣活動。

Looking forward, we expect to continue to invest in research and our clinical stage pipeline as well as in commercial readiness activities for programs with near-term significant commercial potential, including exa-cel and VX-548 for pain. We also remain committed to augmenting our internal research efforts with external innovation aligned with our R&D strategy.

展望未來，我們將繼續投資於研發和臨床階段產品線，以及具有近期顯著商業潛力的項目（包括用於治療疼痛的exa-cel和VX-548）的商業化準備工作。同時，我們也將持續致力於透過與研發策略相符的外部創新來增強內部研發實力。

Third quarter 2022 non-GAAP operating margin was 55%. We generated non-GAAP operating income of $1.3 billion in the quarter, an increase of 11% versus the prior year period. Our non-GAAP effective tax rate in the third quarter of 2022 was 21%. We ended the quarter with $9.8 billion in cash and investments as our cash flow generation and balance sheet remain very strong. On the business development front, we closed the previously announced acquisition of ViaCyte for $320 million in cash and integration activities are underway.

2022年第三季非GAAP營業利益率為55%。本季非GAAP營業收入為13億美元，較上年同期成長11%。 2022年第三季非GAAP實際稅率為21%。本季末，公司持有現金及投資98億美元，現金流和資產負債表依然穩健。業務發展方面，我們已完成先前宣布的ViaCyte的收購，收購價格為3.2億美元現金，目前整合工作正在進行中。

Now switching to guidance. We are increasing our 2022 CF product revenue guidance by $150 million at the midpoint to a new range of $8.8 billion to $8.9 billion. The increase reflects the strong uptake of TRIKAFTA/KAFTRIO in markets with recent reimbursement agreements and continued performance in the U.S. At the midpoint, the increased guidance represents full year 2022 revenue growth of approximately 17% versus 2021 and will mark Vertex's 8th consecutive year of double-digit revenue growth. There is no change to our projected 2022 combined non-GAAP R&D, acquired IP R&D and SG&A expense range of $3 billion to $3.1 billion. There is also no change to our full year non-GAAP effective tax rate guidance range of 21% to 22%.

現在轉入業績指引。我們將2022年CF產品收入指引中位數調高1.5億美元，至88億美元至89億美元。此次上調反映了TRIKAFTA/KAFTRIO在近期達成健保報銷協議的市場中強勁的市場接受度，以及其在美國市場的持續良好表現。以中位數計算，上調後的指引意味著2022年全年營收較2021年成長約17%，這將是Vertex連續第八年實現兩位數的營收成長。我們預計2022年非GAAP研發、收購智慧財產權研發及銷售、管理及行政費用總額仍維持在30億美元至31億美元之間。此外，我們預期2022年全年非GAAP有效稅率指引仍維持在21%至22%之間。

Finally, a comment on movements in foreign exchange. The impact of the significant strengthening of the U.S. dollar versus the euro and other currencies since the start of the year is partially mitigated by our foreign exchange risk management program. For the full year 2022, at current rates, we estimate that changes in foreign exchange, net of program effects will have a negative impact of approximately 1% on our revenue growth, and this is reflected in our updated revenue guidance range for the year.

最後，我想就外匯波動做些說明。自年初以來，美元兌歐元和其他貨幣大幅走強，但我們的外匯風險管理計畫在一定程度上緩解了這種影響。以目前匯率計算，我們預計2022年全年，扣除計畫影響後，外匯波動將對我們的營收成長產生約1%的負面影響，這已反映在我們更新後的年度收入預期範圍內。

In closing, Vertex is performing exceptionally well despite the challenging macroeconomic climate. For the remainder of 2022 and into 2023, we look forward to further important milestones to mark our continued progress as highlighted on this slide. As Reshma noted, over the past year, Vertex has seen a significant acceleration in our R&D pipeline and we are well on our way to diversifying the company and adding to our long-term growth profile.

綜上所述，儘管宏觀經濟環境充滿挑戰，Vertex 的表現依然非常出色。展望 2022 年剩餘時間以及 2023 年，我們期待取得更多重要里程碑，以彰顯我們在本次投影片中所展現的持續進展。正如 Reshma 指出的，過去一年，Vertex 的研發專案顯著加速推進，我們正穩步推進公司多元化發展，並進一步提升公司的長期成長潛力。

As always, we look forward to updating you on our progress on future calls. Let me turn the call back to Susie to begin the question-and-answer period.

和往常一樣，我們期待在以後的電話會議上向您報告進度。現在我把電話交還給蘇西，讓她開始問答環節。

Thanks, Charlie. Chuck, will you begin the queue, please?

謝謝你，查理。查克，請你開始排隊好嗎？

(Operator Instructions)

（操作說明）

And the first question will come from Michael Yee with Jefferries.

第一個問題將來自 Jefferries 公司的 Michael Yee。

This is Dennis on for Mike. Congrats on the progress in the quarter. Can you just please remind us the status of the ongoing diabetes Phase 1, VX-880. And if we will get updated data this year? And if you can comment on where that will be great. And regarding the device program, is that something that we can see initial data in 2023? And like how should we think about the level of data disclosure for that program, given you only disclosed a single patient's worth of beta for VX-880?

我是丹尼斯，替麥克發言。恭喜本季取得的進展。能否請您簡單介紹一下正在進行的糖尿病一期臨床試驗VX-880的進展？我們今年能否獲得更新的數據？如果您能具體說明一下資料發布地點，那就太好了。關於器械項目，我們能否在2023年看到初步數據？鑑於您只揭露了VX-880一名患者的beta數據，我們該如何看待該計畫的數據揭露程度？

Thanks very much for that. Your question is about our type 1 diabetes program. And just to ground everyone, there are actually 3 programs within our type 1 diabetes portfolio. The first is VX-880, and that one is actually in Phase I/II. So it's a program that's already in patients. That's the program in which we've already achieved proof of concept based on the first 2 patients treated, importantly with half the targeted dose. That program is now continuing. We are enrolling and dosing patients at the full targeted dose and we do expect to share data next year at the appropriate conference or venue.

非常感謝。您的問題與我們的第1型糖尿病項目有關。為了讓大家更了解情況，我們目前在第1型糖尿病產品組合中實際上包含三個項目。第一個是VX-880，該計畫目前處於I/II期臨床試驗階段。也就是說，該計畫已經投入患者治療。基於前兩名患者的治療結果，我們已經驗證了該計畫的概念，值得注意的是，他們僅使用了目標劑量的一半。該項目目前正在繼續進行中。我們正在招募患者並按照目標劑量進行給藥，預計明年將在相應的會議或場合分享相關數據。

The second program in that portfolio is the cells plus device program. That program has its IND on track for later this year. With regard to what you should expect from that in terms of data disclosures and when we might be able to see data, I would think about the type 1 diabetes programs, whether it's cells alone or cells plus device closer to CTX001 and less similar to our small molecule programs. And what I mean by that is we go right into patients and with a reasonably small number of patients because you're right into patients with this potentially onetime curative therapy, we can tell a lot about the treatment effect and the emerging profile.

此項目組合中的第二個項目是細胞聯合器械項目。該項目的IND申請預計將於今年稍後提交。至於數據揭露方面，以及我們何時能夠看到相關數據，我想參考一下1型糖尿病項目，無論是單純的細胞療法還是細胞聯合器械療法，都更接近CTX001，而與我們的小分子藥物項目不太相似。我的意思是，我們會直接進入患者體內，而且由於這種療法可能只需一次即可治愈，因此即使患者數量相對較少，我們也能充分了解治療效果和潛在的療效特徵。

So it's a little bit too early to comment on exactly when we'll see data, but I would think about the program closer to CTX than to small molecules. And then lastly, just to round up the type 1 diabetes program, the third vertical or the third pillar in that program is the same exa-cel, these VX-880 cells that have already demonstrated benefit in the clinic, we are editing those cells in order to cloak them from the immune system, and that would allow us to not have to use immunosuppressants.

所以現在評論何時能看到數據還為時過早，但我認為這個項目更接近環磷酰胺（CTX）而非小分子藥物。最後，總結第1型糖尿病項目，該項目的第三個重點或支柱仍然是Exa-Cel公司研發的VX-880細胞。這些細胞已經在臨床試驗中展現出療效，我們正在對這些細胞進行基因編輯，使其能夠躲避免疫系統的攻擊，從而避免使用免疫抑制劑。

The next question will come from Mohit Bansal with Wells Fargo.

下一個問題將來自富國銀行的莫希特·班薩爾。

Congrats and welcome to Susie Lisa from my side as well. So maybe one question on the FEV benefit with these potentiators and correctors that you can extract the maximum benefit. And there was one expert who mentioned that probably at 14 percentage point improvement in TRIKAFTA, we are getting to the higher end there and maybe at 3, 4 percentage points more, you could be getting to a plateau of what is the maximum you can achieve with these kind of therapies. So assuming that next-generation combo does get there, do you think -- do you agree with that statement that this is probably the maximum you can get to with these kind of therapies?

恭喜蘇西·麗莎，我也非常歡迎她。關於這些增強劑和矯正劑對FEV1改善的益處，我想問一個問題，即如何才能最大限度地發揮其療效。一位專家提到，TRIKAFTA治療後，FEV1改善幅度達到14個百分點左右，可能已經接近上限，再提高3、4個百分點，就可能達到這類療法所能達到的極限。假設下一代聯合療法確實能達到這個目標，您是否同意這種說法，即FEV1改善幅度可能已經是這類療法所能達到的極限了？

Yes. Mohit, thanks for the kind words. Your question is about CFTR modulators in general? And what can we expect in terms of benefit? Let me just blow out that question a little bit more and broaden it. When you think about the benefit of CFTR modulators, it's important to realize that CF, as a disease, is a systemic disease. So the only manifestation is not the lung. It is a very prominent manifestation, but it's not the only manifestation. So what do I mean by that? CF patients also have difficulty with liver disease. They also have difficulty with endocrine and exocrine pancreatic disease, and you know about the difficulty in gaining weight, gaining height and living a high-quality life in the absence of CFTR modulators. So the real benefit of CFTR modulators, and we've seen this with KALYDECO to start with all the way up to TRIKAFTA, is certainly an improvement in lung function.

是的，莫希特，謝謝你的讚揚。你的問題是關於CFTR調節劑的整體情況嗎？以及我們可以期待哪些好處？讓我再詳細解釋一下這個問題。談到CFTR調節劑的益處，重要的是要認識到囊性纖維化（CF）是一種全身性疾病。所以它唯一的表現並非肺部。肺部受累是一個非常突出的表現，但並非唯一的表現。這是什麼意思呢？ CF患者也患有肝臟疾病，以及內分泌和外分泌胰臟疾病。你也知道，如果沒有CFTR調節劑，他們很難增重、長高，也難以擁有高品質的生活。因此，CFTR調節劑的真正益處——我們從最初的KALYDECO到後來的TRIKAFTA都看到了這一點——無疑是改善肺功能。

And the way we measure that acutely is indeed ppFEV1. Now your specific question is, is 14%, which is what TRIKAFTA achieved, is that the max? And I think the jury is still out on what the maximum ppFEV1 benefit could be. But I will tell you that the next in-class combination, that's the VX-121, tezacaftor, 561 combination. In the Phase II study, it had search in populations get up to 20% in benefits.

我們衡量急性期症狀改善的指標確實是 ppFEV1。現在您具體問的是，TRIKAFTA 達到的 14% 是否是最大值？我認為 ppFEV1 的最大獲益值目前尚無定論。但我可以告訴您，下一個同類聯合療法，即 VX-121、tezacaftor 和 561 的組合，在 II 期研究中，它使部分人群獲益高達 20%。

So I think the jury is still out, and we have the next wave of molecules to look forward to. And just to close out the benefits, there are some abstracts coming out at NACFC that include data from TRIKAFTA and some of our other CFTR modulators. And it's really encouraging to see that this benefit on ppFEV1 also translates to benefit in terms of mortality, lung transplantation, hospitalizations and pulmonary exacerbations.

所以我認為目前還不能下定論，我們還有下一波分子值得期待。最後補充一點，NACFC會議上將發表一些摘要，其中包含TRIKAFTA以及我們其他一些CFTR調節劑的數據。令人鼓舞的是，這種對ppFEV1的改善也轉化為在降低死亡率、肺移植率、住院率和肺部急性加重率方面的益處。

The next question will come from Salveen Richter with Goldman Sachs.

下一個問題將來自高盛的薩爾文·里希特。

Just 2 for me here. One on the type 1 diabetes program. Can you help us understand how that fully protects the cells from the immune system, but simultaneously maintains the integrity of the cells while in the device? And then secondly, you have about $10 billion in cash here. And so if you aren't -- and I guess your thoughts here, but if you aren't going to do value-creating business development, should we expect you to start to return that via stock buybacks or look to issue a dividend?

我這裡只有兩個問題。一個是關於1型糖尿病項目的。您能否幫我們理解一下，這個計畫是如何在完全保護細胞免受免疫系統攻擊的同時，又能維持細胞在設備內的完整性的？第二個問題是，你們手上有大約100億美元的現金。所以，如果您不打算進行創造價值的業務拓展——我猜您是這麼想的——那麼我們是否可以期待您透過股票回購或派發股息來回報這些資金？

Thanks, Salveen. Let me start with the type 1 diabetes question, and I'll just frame the capital allocation question, and I'll ask Charlie to give you more details.

謝謝，薩爾文。我先回答關於第一型糖尿病的問題，關於資本配置的問題我先簡單提一下，然後我會請查理提供更多細節。

On the type 1 diabetes program and the cells plus device combination, we have worked long and hard and all credit to the Semma team that worked on this even prior to the acquisition. There has been a long history of trying to use devices in this context and the traditional trouble that people have won into are the following: one, sufficient oxygenation and nutrients for the cells; two, prevent a foreign body reaction; and three, to have the cells protected where the nutrients and oxygen can get in, but not the immune cells and also to ensure that the sensing of glucose and the release of insulin can occur.

在1型糖尿病計畫以及細胞與設備結合的治療方案上，我們投入了大量的時間和精力，這要歸功於Semma團隊，他們在收購之​​前就已開始著手這項工作。長期以來，人們一直在嘗試將設備應用於這一領域，但傳統上遇到的難題主要有以下幾點：第一，如何確保細胞獲得充足的氧氣和營養；第二，如何防止異物反應；第三，如何保護細胞，使其能夠獲得營養和氧氣，同時又能阻止免疫細胞的入侵，並確保葡萄糖的感知和胰島素的釋放能夠正常進行。

The proprietary device that we have that it will be used with the VX-880 cell has the features to account for and address those issues, namely protect the cells, but allow the flow of nutrients and oxygen. Two, in all of our preclinical studies, including in large animal studies, we see no foreign body reaction. And three, to have the ability to sense glucose and release insulin.

我們擁有的這款專有裝置將與VX-880細胞配合使用，其具備解決這些問題的功能，即在保護細胞的同時，確保營養物質和氧氣的流通。其次，在我們所有的臨床前研究（包括大型動物研究）中，均未觀察到任何異物反應。第三，該裝置也具備感知葡萄糖並釋放胰島素的能力。

I will say, Salveen, the most challenging part of the type 1 diabetes program is actually having cells that are fully differentiated, insulin producing. And that part of this, we know we have gone past because of the proof-of-concept achievement in those first 2 patients treated at half dose. On the capital allocation question, our strategy on capital has not changed. The focus is on innovation, both internal and external.

薩爾文，我想說，1型糖尿病治療計畫中最具挑戰性的部分實際上是獲得完全分化、能夠產生胰島素的細胞。我們知道，我們已經克服了這個難題，因為在前兩名接受半劑量治療的患者身上，我們已經取得了概念驗證的成功。關於資金配置問題，我們的資金策略沒有改變。重點仍然是創新，包括內部創新和外部創新。

Charlie, anything you wanted to add to that?

查理，你還有什麼要補充的嗎？

No. You said it very well. The priority continues to be investment in innovation. I think we've been very active over the last few years and it shows. If you look at our pipeline now, 40% of the programs in the pipeline have benefited from BD that we've done in recent years. And so we continue to maintain an active function, looking at external innovation to support our internal efforts that will continue to be the priority. We have also maintained a share buyback program in recent years just to offset dilution, but the focus and the primary purpose is investment in innovation.

不，您說得很好。我們的首要任務仍然是投資創新。我認為過去幾年我們一直非常積極，這一點顯而易見。如果您看看我們目前的在研項目，您會發現其中40%的項目都受惠於我們近年來開展的業務拓展。因此，我們將繼續保持積極主動，尋求外部創新來支持我們內部的創新工作，而內部創新仍將是我們的首要任務。近年來，我們也一直維持股票回購計劃，以抵消股權稀釋的影響，但我們的重點和主要目的仍然是投資創新。

The next question will come from Phil Nadeau with Cowen and Company.

下一個問題將來自 Cowen and Company 的 Phil Nadeau。

I wanted to ask about the inaxaplin Phase II/III trial and specifically on the Phase II portion of the Phase II/III. What is Vertex's most recent thinking on whether data from that Phase II portion will be disclosed? And then maybe more generally, can you remind us what criteria by which you choose the dose that's advanced into Phase III? What measures will you be looking at to make that determination?

我想諮詢一下inaxaplin的II/III期臨床試驗，特別是其中的II期部分。 Vertex公司最近對於是否會公佈II期部分的數據有何想法？另外，能否更詳細說明一下，貴公司選擇進入III期臨床試驗的劑量標準為何？貴公司會參考哪些指標來做決定？

Sure. Phil, the inaxaplin trial, that's the VX-147 trial in AMKD or APOL1-mediated kidney disease is the program that's the adaptive Phase II/III study. And the criteria for dose selection, Phil, really centers around measures of efficacy seen at 12 weeks. And what that really means is proteinuria. Remember, proteinuria, we can see, change within that 12-week period. That is not possible for the change in GFR. Now the -- there is a committee that can look at the data to make that decision, that is done in the appropriate way, given the need to maintain trial integrity. But I would assume that we would share the fact that we've gotten past that important Phase II milestone and that a dose has been selected. But we are going to have to be careful about maintaining steady integrity, given that there are patients that are in the trial and will be continuing to the Phase III portion.

當然。菲爾，關於伊那沙普林（inaxaplin）的試驗，也就是VX-147在AMKD或APOL1介導的腎臟病中的試驗，是一個適應性II/III期研究計畫。菲爾，劑量選擇的標準主要圍繞在12週時的療效指標。而這實際上指的是蛋白尿。記住，我們可以在12週內觀察到蛋白尿的變化。腎絲球過濾率（GFR）的變化則無法做到這一點。現在，有一個委員會可以審查數據並做出決定，考慮到需要維護試驗的完整性，這個過程會以適當的方式進行。但我認為我們應該分享這樣一個事實：我們已經完成了重要的II期里程碑，並且已經選定了劑量。但是，鑑於還有一些患者正在參與試驗，並將繼續進行III期試驗，我們必須謹慎地維護試驗的完整性。

The next question will come from Evan Seigerman with BMO.

下一個問題將來自 BMO 的 Evan Seigerman。

Congrats on the strong quarter. I'd love for you to provide me some more color as to what you saw with 864 to reinitiate a clinical trial with this asset? Can you also highlight why 634 might be more successful than its predecessors?

恭喜貴公司本季業績強勁。我很想聽您詳細介紹一下您為何決定重啟864的臨床試驗？您能否也重點說明一下634為何可能比其前身藥物更成功？

Yes, Evan. So the question is on our alpha-1 antitrypsin deficiency or AATD program. And let me take one-half step back and remind everyone why we are so interested in this disease. So AATD fits the VERTEX strategy, our R&D strategy like a glove. It is a disease where we understand the causal human biology. We have a validated target, and we also have a biomarker that translates from bench to bedside. There are about 100,000 people in Europe and the U.S. who have this disease. And by the way, it happens to be a pulmonary disease that is a disease of protein misfolding, something we know a little bit about given our work in cystic fibrosis. So that's why this disease just fits us perfectly.

是的，埃文。所以問題是關於我們的α1-抗胰蛋白酶缺乏症（AATD）計畫。讓我先退一步，提醒大家我們為什麼對這種疾病如此感興趣。 AATD與VERTEX的研發策略完美契合。我們對這種疾病的致病機制有深入的了解，掌握了相關的生物學知識。我們已經找到了一個經過驗證的靶點，並且找到了一個可以從實驗室轉化為臨床應用的生物標記。在歐洲和美國，大約有10萬人患有這種疾病。順便一提，它是一種肺部疾病，屬於蛋白質錯誤折疊疾病，而我們對蛋白質錯誤折疊有一定的了解，這得益於我們在囊性纖維化領域的研究。所以，這種疾病對我們來說簡直是天作之合。

What we saw with the VX-864 Phase II trial, now 864 is the first-generation corrector for AAT is, for the first time, a small molecule was able to raise functional AAT levels. That has never been demonstrated before. And in the exploratory analysis, we were also able to see more than 90% reduction in serum polymer levels. When we put that all together, here's where we are. One approach that we're taking and we're taking both these approaches in parallel is to bring forward more potent medicines than 864. That is the VX-634. It's multifold, more potent. It has better drug-like properties, and it has initiated its Phase I study.

我們在VX-864的II期臨床試驗中觀察到，作為第一代AAT矯正劑，VX-864首次實現了小分子藥物提高功能性AAT水平，這在以前從未被證實過。在探索性分析中，我們也觀察到血清聚合物濃度降低了90%以上。綜合以上訊息，我們目前的情況是這樣的：我們正在採取的策略之一是研發比VX-864效力更強的藥物，也就是VX-634。 VX-634的效力是VX-864的數倍，具有更好的藥物特性，目前已啟動I期臨床試驗。

And in parallel, we're also advancing VX-864 because we have chronic tox coverage to study this molecule in a longer-term study. And in a longer-term study, we can assess liver clearance of polymer. This goes back to the serum polymer clearance that we saw. So we're looking for liver polymer clearance and the long-term impact on functional AAT. We're driving both of these programs forward in parallel. And I don't know, maybe around this time next year, we'll have the data that we need to assess which molecule or molecules should advance further. So that's really where we are with the AATD program.

同時，我們也在推動VX-864的研發，因為我們有針對慢性毒性的藥物，可以進行一項長期研究來考察該分子。在長期研究中，我們可以評估聚合物的肝臟清除率。這與我們先前觀察到的血清聚合物清除率有關。因此，我們正在研究聚合物的肝臟清除率及其對功能性AAT的長期影響。我們正在並行推進這兩個項目。我估計，也許明年這個時候，我們就能獲得所需的數據，從而評估哪些分子應該繼續推進後續研究。這就是我們目前在AATD項目上的最新進展。

The next question will come from David Risinger with SVB Securities.

下一個問題將來自SVB證券的David Risinger。

Thanks very much. And let me add my congrats on the results as well, particularly given the speculation today in the markets. So my question is regarding VX-548 and my take is that the product's opportunity in chronic pain is clearly tremendous since patients cannot be administered opioids long term, but could you help us understand your review of the acute market opportunity in the context of DRG codes and hospital system sensitivity?

非常感謝。也請容許我祝賀你們取得這樣的成績，尤其是在當前市場波動的情況下。我的問題是關於VX-548的，我認為該產品在慢性疼痛治療​​領域顯然具有巨大的潛力，因為患者無法長期服用鴉片類藥物。但是，您能否結合DRG編碼和醫院系統敏感性，幫助我們理解您對急性疼痛市場機會的評估？

Basically, the question is, will hospitals replace inexpensive generic drugs in patients who are not likely to be at risk of opioid addiction if they're prescribed opioids for less than a week unless, of course, they have a preexisting addiction issue.

基本上，問題是，如果患者服用阿片類藥物的時間不到一周，且不太可能出現阿片類藥物成癮的風險，醫院是否會用價格低廉的仿製藥來替代阿片類藥物，除非他們本身就有成癮問題。

David, I'm going to ask Stuart to tackle the question on acute pain, and I'll come back and just say a word on chronic pain. Stuart?

大衛，我打算請史都華來回答關於急性疼痛的問題，我稍後會簡單說說慢性疼痛。史都華？

Yes. So thanks for the question, David. Yes. So in terms of the market for acute pain, as I said in my prepared remarks, we do see this as a very significant opportunity for a number of reasons: one, the treatment of acute pain today is a very sizable market. I referenced the fact that there's 1.5 billion treatment days a year, and much of that is concentrated in the hospital environment despite the fact that the market is over 90% generic, as you referenced, is a $4 billion market today. So the real question is, what is the unmet need here. And the unmet need is actually very, very significant.

是的。謝謝你的提問，大衛。是的。就急性疼痛市場而言，正如我在準備好的演講稿中所說，我們認為這是一個非常重要的機遇，原因有很多：首先，如今急性疼痛的治療市場規模非常龐大。我提到過，每年有15億個治療日，其中大部分集中在醫院環境中，儘管正如你所提到的，該市場90%以上都是仿製藥，但如今的市場規模已達40億美元。所以真正的問題是，這裡存在著哪些未被滿足的需求。而未被滿足的需求其實非常非常巨大。

In contrast to your comments, actually, the acute use of opioids is a very prominent and well-recognized contributor to the opioid epidemic. And as a result of that, there have been significant constraints put in place on the use of opioids in many states and in many hospital systems. And that has substantially reduced the use of opioids.

與您的評論相反，事實上，阿片類藥物的急性濫用是阿片類藥物濫用危機的一個非常突出且公認的因素。正因如此，許多州和許多醫院系統都對鴉片類藥物的使用實施了嚴格的限制。這些限制已大幅減少了阿片類藥物的使用。

However, what hasn't gone away is moderate to severe acute pain for those patients. And so there is a significant gap left in the marketplace for something that provides effective pain relief, but without the addictive potential and other side effects of opioids. So in the hospital setting, both in terms of the inpatient stay, which is probably on average 2, 3, 4 days, something like that, we think there's a substantial unmet medical need. And then obviously, those patients are discharged with a multi-day prescription for ongoing pain management, which they then fill in the retail setting. So overall, we're very, very excited both about the profile of the VX-548, but also the opportunity to make a real difference in the treatment of acute pain. And then Reshma, back to you on chronic.

然而，中度至重度急性疼痛仍困擾著這些患者。因此，市面上存在著巨大的空白，亟需一種能有效緩解疼痛，但又沒有鴉片類藥物成癮性及其他副作用的產品。在醫院環境中，無論是住院治療（平均住院時間約2、3、4天），我們認為都存在著巨大未滿足的醫療需求。此外，患者出院時通常會獲得持續止痛的多日處方，他們需要在零售藥局取藥。總而言之，我們對VX-548的特性以及它有望在急性疼痛治療​​領域帶來真正的改變，都感到非常興奮。接下來，Reshma，請繼續討論慢性疼痛問題。

Yes. David, I agree with you on the opportunity in chronic pain in addition to a very substantial opportunity in acute pain. And the reason for the opportunity in chronic pain is twofold. One is what you indicated around not wanting to use opioids over a chronic period, frankly, not wanting to use opioids even over an acute period. But second, opioids are actually not very good at all in terms of efficacy in the chronic setting and sort of -- for example, in neuropathic pain. And I just wanted to close by letting you know that the Phase II dose-ranging study of VX-548 in diabetic neuropathic pain, we'll also initiate this quarter. And we have high confidence for this one, not only because of the genetic validation of the target, but because of the pharmacological validation on neuropathic pain with the predecessor molecule, VX-150.

是的，David，我同意你關於慢性疼痛領域存在巨大機會的觀點，當然，急性疼痛領域也蘊藏著巨大的機會。慢性疼痛領域存在機會的原因有兩方面。首先，正如你所提到的，我們不希望長期使用鴉片類藥物，坦白說，即使在急性期，我們也不希望使用鴉片類藥物。其次，阿片類藥物在慢性疼痛治療​​中的療效其實並不理想，例如，在神經性疼痛方面。最後，我想告訴你，我們將在本季啟動VX-548治療糖尿病神經性疼痛的II期劑量探索研究。我們對這項研究充滿信心，不僅因為標靶的基因驗證，還因為其前驅分子VX-150在神經性疼痛治療​​方面的藥理驗證。

The next question will come from Robyn Karnauskas with Truist Securities.

下一個問題將來自 Truist Securities 的 Robyn Karnauskas。

This is Kripa on for Robyn. I just had 1 question on the AAT program. When do you think you can move from the Phase I into Phase II trial? How long do you think it will take to do the healthy volunteer study? And you previously talked about how you can maybe do really short trials to see activity. Given what you're doing with VX-864, has that thinking changed in any way?

我是Kripa，代表Robyn提問。我有一個關於AAT項目的問題。您認為什麼時候可以從I期臨床試驗進入II期臨床試驗？您覺得健康志願者研究需要多長時間？您之前提到過可以進行一些非常短期的試驗來觀察療效。鑑於您目前正在進行的VX-864研究，您的想法是否有所改變？

And another question on the mRNA program in CF. You said that IND will go in later this year. What's the earliest you see going into the clinic? Is there -- given that this is a new modality, is there any reason to anticipate delays for the IND acceptance?

關於囊性纖維化mRNA計畫還有一個問題。您提到IND申請將於今年稍後提交。您預計最早什麼時候可以進入臨床？考慮到這是一種新的治療方式，IND申請的審批是否有可能延遲？

Sure. So 2 separate questions in there. One about the mRNA program in cystic fibrosis and then about AAT. So let me tackle mRNA in cystic fibrosis first. So the approach here is to use an mRNA inhaled therapy for those 5,000 or so patients who don't make any CFTR protein and therefore, cannot benefit from CFTR modulators. The IND-enabling studies are complete. The IND will go in this year. And you're right, it is a more complex product than a small molecule.

當然。這裡面有兩個問題。一個是關於囊性纖維化中的mRNA療法，另一個是關於α1-抗胰蛋白酶（AAT）。我先來說說囊性纖維化中的mRNA療法。目前，針對約5,000名無法產生CFTR蛋白、因而無法從CFTR調節劑中獲益的患者，我們採用mRNA吸入療法。相關的IND申報研究已經完成，IND申請將於今年提交。你說得對，它比小分子藥物複雜得多。

And in the grand scheme of things, we've only been working on nucleic acid therapies and cell therapies for the last, let's say, 5 to 8 years, whereas we've been working on small molecules for many decades. That all being said, CF is a very serious life-shortening disease. And I do think that all parties invested are motivated to make sure that medicines that could bring benefit to patients rapidly. Of course, we'll be able to update you on the progress in future calls. But I'm very pleased with the progress, and I'm pleased to see that we're on track with the IND to go in this year.

從長遠來看，我們從事核酸療法和細胞療法的研究不過五到八年，而小分子藥物的研究卻有數十年歷史。儘管如此，囊性纖維化仍然是一種非常嚴重的、會縮短患者壽命的疾病。我認為所有相關方都積極致力於盡快研發出能夠造福患者的藥物。當然，我們會在以後的電話會議上向大家報告最新進展。但我對目前的進展非常滿意，也很高興看到我們正按計劃推進，預計今年提交新藥臨床試驗申請（IND）。

On the AAT program, we are doing 2 things in parallel: one is advancing VX-634 into the first-in-human study; and two, studying VX-864 for a longer duration of time. And we're doing this in parallel because we can, that is to say we have sufficient toxicology coverage to study VX-864 over an extended period. And I do think you need that extended period to evaluate liver clearance for this mechanism. But in terms of the first -- in humans, you've seen our track record, we tend to move at a good clip, I would say, let's say, around this time next year or so, we'll have the data from our first-in-human studies with 634, we'll have our data from the Phase II longer-term study.

在AAT計畫上，我們正​​在進行兩項工作：一是推動VX-634進入首次人體試驗；二是進行VX-864的長期研究。之所以並行這兩項工作，是因為我們擁有足夠的毒理學資料來對VX-864進行長期研究。我認為，評估這種機制的肝臟清除率確實需要較長的研究週期。至於首次人體試驗，如您所知，我們的進展速度很快。我估計，大約在明年這個時候，我們將獲得VX-634首次人體試驗的數據，以及VX-864 II期長期研究的數據。

And I fully expect more molecules behind 634 to enter the clinic. So I feel really good about where we are, and we're executing on the strategy of serial innovation and having a portfolio approach exactly as I would like in all of our programs, but particularly in AAT.

我完全預期634之後會有更多分子進入臨床試驗。所以我對我們目前的狀況感到非常滿意，我們正在執行連續創新和投資組合策略，這正是我希望在我們所有專案中，尤其是在AAT專案中實現的。

The next question will come from Jessica Fye with JPMorgan.

下一個問題將來自摩根大通的傑西卡·費伊。

Nice results tonight. Following up on an earlier question. Just to make sure I understand, are you generating this longer-term data with 864 to evaluate liver polymer clearance just to sort of further derisk 634, which has better drug-like properties?

今晚結果不錯。關於先前的問題，我想確認我的理解是否正確：您使用 864 產生這些長期數據是為了評估肝臟聚合物清除率，從而進一步降低 634 的風險嗎？ 634 具有更好的類藥特性。

And then second, with the trials in patients age 12 and up for new triple complete enrollment by year-end, can you set expectations for when we should expect top line data factoring in any analysis time that might be required?

其次，針對 12 歲及以上患者的試驗計劃在年底前完成三重入組，您能否預期何時能獲得初步數據，並考慮可能需要的分析時間？

Yes. Jessica, on the new triple combination, the vanzacaftor triple combination, that's 121-561 tezacaftor, we do project enrollment in that program, both studies in 12 plus will complete before the end of this year. As a reminder, these studies are 1 year in duration. So we will have all of the dosing complete at some point next year. And it does take a little bit of time, but we're pretty quick with closing out the study and having results thereafter. But the important point to know is that's a 1-year treatment duration. With regard to the 864 program and AATD, what are we really trying to accomplish there.

是的。傑西卡，關於新的三聯療法，也就是範扎卡托三合療法（121-561 替扎卡托），我們預計該計畫的入組人數將達到12歲以上人群，兩項研究都將在今年年底前完成。提醒一下，這些研究為期一年。因此，我們將在明年某個時候完成所有給藥。這確實需要一些時間，但我們很快就能結束研究並獲得結果。但要注意的是，治療週期為一年。關於864專案和AATD，我們真正想要實現的目標是什麼？

Here's the important thing to keep in mind. With 864, what we saw for the first time ever with a small molecule corrector is increases in functional AAT level. The magnitude of the treatment effect was insufficient for us to move that to Phase III, but that gave us proof of biological activity. The reason we want to study 864 for polymer clearance in the liver is because that post hoc analysis of Phase II showed us a 90% decrease in serum polymer levels, leading us to believe that longer-term treatment would indeed lead to clearance of the liver. That's the hypothesis we're testing there. And we're also going to evaluate where the longer-term treatment leads to elevations in functional AAT.

需要記住的關鍵一點是，864 首次在小分子矯正劑中觀察到功能性 AAT 水平的增加。雖然治療效果的強度不足以讓我們將其推進到 III 期臨床試驗，但這證明了其生物活性。我們之所以想研究 864 對肝臟中聚合物清除的影響，是因為 II 期臨床試驗的事後分析顯示血清聚合物水平降低了 90%，這使我們相信長期治療確實能夠清除肝臟中的聚合物。這就是我們正在驗證的假設。此外，我們還將評估長期治療是否會導致功能性 AAT 水平的升高。

If you're asking, is it possible that 864 is a molecule that moves forward into later stages of development based on this longer-term treatment? Yes, that's possible. Is it possible that VX-634 is the molecule we select because it's more potent and has better drug-like properties? Yes, that's possible. And that's why we're running both these programs in parallel. Ultimately, maybe the most important thing to take away is that the small molecule approach to this disease AATD is the only approach that holds the potential to treat both the liver and lung manifestations of this disease. And this pathway that we've drawn out allows us to assess both of those in parallel.

如果您問的是，基於這種長期治療，864 分子是否有可能進入後續研發階段？是的，有可能。 VX-634 分子是否有可能因為其效力更強、成藥性更好而被我們選中？是的，有可能。正因如此，我們才同時推進這兩個項目。最終，或許最重要的是，小分子藥物療法是目前唯一有可能同時治療 AATD 肝臟和肺部病變的療法。而我們所製定的這條研發路徑，使我們能夠同時評估這兩種病變。

Next question will come from Geoff Meacham with Bank of America.

下一個問題將來自美國銀行的傑夫·米查姆。

This is Joe on for Geoff. I had a question on exa-cel. Can you walk us through how we should be thinking about the eventual commercial rollout? And after filing in the EU and the U.S., what is the rough timeline for first revenue? Should we be thinking late 2023? Or is that more early 2024?

我是Joe，替Geoff提問。我有一個關於Exa-Cel的問題。您能為我們講講最終的商業推廣計劃嗎？在歐盟和美國提交申請後，大概什麼時候能實現首次獲利？是2023年底？還是2024年初？

Sure. Let me start with where we are today and the immediate next milestones that we're working towards. And then I'm going to ask Stuart to comment on the prelaunch activities. So we are intensely focused on getting our filings in for the EU, the U.K. and the U.S. We are on track to start the rolling submission in the U.S. next month in November, and we're on track for our EU and U.K. submissions to complete by the end of this year. Stuart, do you want to talk a little bit about our prelaunch activities from there?

當然。首先，我想先介紹一下我們目前的進展以及接下來要努力實現的幾個重要里程碑。然後，我想請Stuart談談上市前的準備工作。我們目前正全力以赴地準備向歐盟、英國和美國提交申請。我們計劃下個月，也就是11月，開始在美國進行滾動提交，並預計在今年年底前完成歐盟和英國的申請。 Stuart，你接下來要談談我們的上市前準備工作嗎？

Yes. So much of our prelaunch activities is focused in 2 areas: one is with policymakers and payers; and the other one is with the authorized treatment centers who would be the ones who would be actually administering exa-cel with payers and policymakers. As you can imagine, a lot of this is about making sure that the right conditions are in place so that patients can get as early as possible access to exa-cel pending, obviously, regulatory approval. This is a disease of significant unmet need that's well recognized by the payer and policymaker community. And so the discussions we've been having with them have been really very productive and fruitful.

是的。我們上市前的大部分工作都集中在兩個方面：一是與政策制定者和支付方溝通；二是與獲得授權的治療中心溝通，這些中心將與支付方和政策制定者共同負責實際的Exa-Cel治療。如您所想，這些工作的關鍵在於確保各項條件到位，以便患者在獲得監管部門批准後，能夠儘早獲得Exa-Cel治療。支付者和政策制定者都充分認識到，這種疾病存在著巨大的未滿足醫療需求。因此，我們與他們的討論非常有成效。

On the authorized treatment center side, it really is identifying authorized treatment centers, which are close to where patients are concentrated. And patients are concentrated in relatively discrete geographies in about 25 states here in the U.S. where about 90% of the patients are located. In the EU, about 75% of patients are in 4 countries, the U.K., France, Italy, and Germany. And so we're looking at the potential to establish treatment centers, about 50 or so here in the U.S., about 25 or so in those 4 countries in Europe, which we think could serve the vast majority of patients, as I say, pending regulatory approval. Again, our engagement with the centers has been very positive. They're clearly very excited about the prospect of something like exa-cel, which has the potential to provide a onetime functional cure to their patients.

在授權治療中心方面，我們實際上是在確定靠近患者集中區域的授權治療中心。在美國，患者主要集中在約25個州的相對獨立的區域，約佔總患者人數的90%。在歐盟，約75%的患者集中在英國、法國、義大利和德國這四個國家。因此，我們正在考慮在美國建立約50家治療中心，在歐洲這四個國家建立約25家治療中心，我們認為這些中心可以服務絕大多數患者，正如我所說，前提是獲得監管部門的批准。再次強調，我們與這些中心的溝通非常正面。他們顯然對像exa-cel這樣的藥物的前景感到非常興奮，因為它有可能為他們的患者提供一次性的功能性治癒。

The next question will come from Colin Bristow with UBS.

下一個問題將來自瑞銀集團的柯林布里斯托。

This is (inaudible) on for Colin. Congrats on the strong quarter and pipeline progress. So we have 2 questions. The first one is on your CF based business. So how do you believe the competitive threat from AbbVie's latest triple with tezacaftor just appeared on the clinicaltrials.gov?

現在（聽不清楚）是科林的發言。恭喜你們本季業績強勁，研發管線也取得了進展。我們有兩個問題。第一個問題是關於你們的囊性纖維化業務。您認為艾伯維公司最新三重臨床試驗（tezacaftor）剛出現在clinicaltrials.gov網站上，構成了什麼樣的競爭威脅？

And the second question is on the CRISPR-based DMD therapy. So you have already noted the IND filing will be next year. So when do you think we could see the first clinical data for the program. Would you consider, for example, like release in the single patient data as you have already done with the VX-880 program for diabetes?

第二個問題是關於基於 CRISPR 的 DMD 療法。您已經提到 IND 申請將於明年提交。那麼，您認為我們何時能看到該計畫的首批臨床數據？例如，您是否會考慮像先前 VX-880 糖尿病計畫一樣，公佈單一患者的數據？

There are 2 questions in there. One on CF and one on DMD. Let me take the DMD question first. So to give everyone a little bit of a quick backgrounder. Recall that our approach to DMD is different than most of the approaches out there, which focus on microdystrophin. Our approach is an in vivo gene editing approach that is centered on exon skipping and producing full length, if not near full-length dystrophin. And the reason we believe in this approach is because of the human genetics that we see. So for example, Becker's muscular dystrophy where patients have near full length dystrophin, that disease is a much, much milder form of DMD. The microdystrophin approach simply doesn't have that kind of human genetics behind it.

裡面有兩個問題，一個是關於囊性纖維化（CF），一個是關於杜氏肌肉營養不良症（DMD）。我先回答關於DMD的問題。首先，先跟大家簡單介紹一下背景。我們治療DMD的方法與目前大多數專注於微型肌肉營養不良蛋白的方法不同。我們採用的是一種體內基因編輯方法，其核心是外顯子跳躍，目的是產生全長或接近全長的肌肉營養不良蛋白。我們相信這種方法的原因在於我們所觀察到的人類遺傳學特徵。例如，貝克爾肌肉營養不良症患者的肌肉營養不良蛋白接近全長，這種疾病是一種比DMD輕微得多的類型。微型肌肉營養不良蛋白療法缺乏這種人類遺傳學特徵的支持。

I'm really pleased with the progress of the program. We are in our IND-enabling studies now. We expect to finish those up and file our IND next year. There was a question in there about when you could expect data really a little bit too early to call, but I would think about this program in that cell and gene space, so with a reasonably small number of patients over a reasonable amount of time, very similar to CTX001, very similar to the type 1 diabetes program, we're going to know where we are.

我對專案的進展非常滿意。我們目前正在進行IND申報所需的各項研究。我們預計明年完成這些研究並提交IND申請。之前有人問到何時能獲得數據，現在下結論還為時過早，但考慮到這個項目屬於細胞和基因領域，在合理的時間內納入數量適中的患者，這與CTX001以及1型糖尿病項目非常相似，我們很快就能了解項目的進展情況。

On the CF business, we've talked about this many times in the past, TRIKAFTA has set an enormously high bar. It can treat up to 90% of patients with this disease. We have already advanced the next program. This is the vanzacaftor program. It's going to complete Phase III enrollment this year. If it is possible -- and it is a tall order, but if it is possible to be better than TRIKAFTA, the vanzacaftor triple program holds that potential. It has better chloride transport than TRIKAFTA in our human bronchial epithelial assays and in Phase II studies. We have to do some cross-study comparisons. But in Phase II studies, it looks like it is potentially even better than TRIKAFTA. And we are now on the brink of bringing the mRNA therapy for the first time having a therapy for the last 5,000 patients with CF. We've never had more patients benefit from our CFTR modulators and we've never been in this position of being right on the cup of having something for all patients. I like our hand, and I'm looking forward to sharing more data.

關於囊性纖維化（CF）領域，我們過去曾多次談到，TRIKAFTA 樹立了極高的標竿。它可以治療高達 90% 的 CF 患者。我們已經推進了下一個項目，即 vanzacaftor 項目。該計畫將於今年完成 III 期臨床試驗的患者招募。如果有可能——這的確是一個艱鉅的任務——但要超越 TRIKAFTA，vanzacaftor 三聯療法計畫就具備這樣的潛力。在我們的人體支氣管上皮細胞試驗和 II 期臨床試驗中，vanzacaftor 的氯離子轉運能力優於 TRIKAFTA。我們還需要進行一些交叉研究的比較。但在 II 期臨床試驗中，vanzacaftor 的療效似乎甚至可能優於 TRIKAFTA。我們現在即將首次推出 mRNA 療法，為最後 5,000 名 CF 患者提供治療方案。我們的CFTR調節劑惠及的患者數量從未如此之多，我們也從未像現在這樣，幾乎能夠為所有患者提供有效的治療方案。我對目前的進展充滿信心，並期待分享更多數據。

This concludes our question-and-answer session. I would like to turn the conference back over to Ms. Susie Lisa for any closing remarks. Please go ahead.

問答環節到此結束。現在我將會議交還給蘇西·麗莎女士，請她作總結發言。請開始吧。

Thank you, Chuck, and thanks very much, everyone, for their questions. We look forward to taking your follow-up and meeting with you soon.

謝謝查克，也非常感謝大家的提問。我們期待盡快與您進行後續溝通並與您會面。

The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

會議已結束。感謝您參加今天的報告。您可以斷開連線了。