福泰製藥 (VRTX) 2023 Q1 法說會逐字稿

Good day, and welcome to the Vertex Pharmaceuticals First Quarter 2023 Conference Call. (Operator Instructions) Please note, this event is being recorded. I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead.

大家好，歡迎參加Vertex Pharmaceuticals 2023年第一季電話會議。 （操作說明）請注意，本次會議正在錄音。現在我將會議交給Susie Lisa女士。請開始。

Good evening, all. My name is Susie Lisa, and as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our first quarter 2023 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. 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.

各位晚上好。我是蘇西·麗莎，身為投資者關係資深副總裁，我很高興歡迎各位參加我們2023年第一季財務業績電話會議。今晚，Vertex執行長兼總裁雷什瑪·凱瓦拉瑪尼博士、營運長史都華·阿巴克爾和財務長查理·瓦格納將發表事先準備好的演講。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。本次電話會議將進行錄音，錄音回放將在我們的網站上提供。

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. 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. In addition, the impact of foreign exchange is presented inclusive of our foreign exchange risk management program. I will now turn the call over to Reshma.

我們將在本次電話會議上發表前瞻性聲明，這些聲明受制於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。這些聲明，包括但不限於有關Vertex已上市的囊性纖維化藥物、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，我們今晚將在電話會議上討論的部分財務表現和指引是以非GAAP準則列示的。此外，外匯影響的列示已包含我們的外匯風險管理計畫。現在我將把電話會議交給Reshma。

Thanks, Susie. Good evening all, and thank you for joining us on the call today. We're pleased to have opened with a strong start to 2023, as first quarter global CF product revenues grew 13% versus the first quarter of 2022. In addition, we completed the exa-cel U.S. rolling BLA submissions for sickle cell disease and beta thalassemia, and secured U.S. approval for TRIKAFTA in patients 2 to 5 years of age. Now is an especially exciting time at Vertex because within our 5 launches in 5 years, or 5 in 5 goal, we see multiple programs with near-term launch potential, including exa-cel in sickle cell disease and transfusion-dependent beta thalassemia, the vanzacaftor triple in CF, and VX-548 for acute pain. In total, we now have programs in 8 disease areas in mid- and late-stage development, 6 of which are past the proof-of-concept stage, as depicted on Slide 5.

謝謝蘇西。各位晚上好，感謝大家今天參加我們的電話會議。我們很高興2023年開局強勁，第一季全球囊性纖維化（CF）產品營收較2022年第一季成長了13%。此外，我們完成了exa-cel在美國的滾動生物製品許可申請（BLA），用於治療鐮狀細胞病和β地中海貧血，並獲得了TRIKAFTA在美國2至5歲患者中的上市許可。現在對Vertex來說是一個令人振奮的時刻，因為我們在五年內推出5款新產品（即「五年內5款」的目標）的計劃中，有多個項目具有近期上市的潛力，包括用於治療鐮狀細胞病和輸血依賴型β地中海貧血的exa-cel、用於治療囊性纖維化的vanzacaftor三聯療法以及用於治療急性三聯療法以及用於治療急性疼痛的VX-548。目前，我們共有 8 個疾病領域的專案處於中後期開發階段，其中 6 個專案已經過了概念驗證階段，如投影片 5 所示。

With this breadth of compelling opportunities, we're investing accordingly to drive continued pipeline success, clinical trial progress and the build-out of commercialization capabilities. In addition, beyond the 8 disease areas already in the clinic, the next wave of innovation is advancing through preclinical development, including programs in Duchenne's muscular dystrophy, myotonic dystrophy type I, NaV1.7 for pain, and gentler conditioning agents for use with exa-cel. With a uniquely strong and durable CF franchise, multiple near-term commercial opportunities, a broad and rapidly advancing pipeline, a strong balance sheet and an exceptionally talented and committed team, Vertex has never been as well positioned to deliver for patients and shareholders for years to come.

憑藉如此廣泛且極具吸引力的機遇，我們正在進行相應的投資，以推動產品線持續成功、臨床試驗進展以及商業化能力的提升。此外，除了目前已進入臨床階段的8個疾病領域外，下一波創新浪潮正推進臨床前開發，包括杜氏肌肉營養不良症、I型強直性肌肉營養不良症、用於緩解疼痛的NaV1.7以及與exa-cel聯合使用的更溫和的調理劑等項目。憑藉強大且持久的囊性纖維化產品線、多個近期商業化機會、廣泛且快速推進的產品線、穩健的資產負債表以及一支才華橫溢且敬業的團隊，Vertex從未像現在這樣擁有如此優越的條件，能夠為患者和股東在未來數年內創造價值。

With that overview, I'll turn to the details of recent R&D progress, starting with CF. Our next-in-class vanzacaftor triple combination has completed enrollment in its 2 Phase III clinical trials in patients ages 12 years and above, known as SKYLINE 102 and 103, and is progressing well.

概述完畢後，我將詳細介紹近期研發進展，首先是囊性纖維化（CF）領域。我們新一代的vanzacaftor三合療法已完成兩項針對12歲及以上患者的III期臨床試驗（SKYLINE 102和103）的患者招募，目前進展順利。

Enrollment in patients ages 6 to 11, known as the RIDGELINE study, is also advancing rapidly. We continue to anticipate the completion of the SKYLINE studies by the end of this year, and I'm pleased to share we now project the completion of the RIDGELINE study at approximately the same time as the SKYLINE studies.

針對6至11歲患者的RIDGELINE研究的入組工作也迅速進行。我們仍然預期SKYLINE研究將於今年底完成，我很高興地宣布，我們現在預計RIDGELINE研究的完成時間將與SKYLINE研究大致相同。

Recognizing the very high bar set by TRIKAFTA, we have high expectations for the vanzacaftor triple program based on the totality of the evidence generated to date, and as was recently reported in Lancet Respiratory Medicine. Preclinically, our HBE assays, which have consistently proven to have robust translation from the bench into the clinic, showed greater restoration of chloride transport with the vanzacaftor triple than with TRIKAFTA. In the Phase II clinical program, the vanzacaftor triple drove greater CFTR function and correspondingly lower levels of sweat chloride than has been seen with TRIKAFTA. As such, we believe the vanzacaftor triple has the potential for enhanced clinical benefit along with the convenience of once-daily dosing. In addition, we expect the vanza triple to carry a substantially lower royalty burden.

鑑於 TRIKAFTA 樹立了極高的標桿，我們對 vanzacaftor 三聯療法計畫寄予厚望。這基於迄今為止所獲得的全部證據，正如近期《柳葉刀呼吸醫學》雜誌所報導的那樣。臨床前研究顯示，我們已證實能夠有效轉化臨床應用的 HBE 檢測方法表明，vanzacaftor 三聯療法在恢復氯離子轉運方面優於 TRIKAFTA。在 II 期臨床試驗中，vanzacaftor 三聯療法顯著提高了 CFTR 功能，並相應地降低了汗液氯化物水平。因此，我們相信 vanzacaftor 三聯療法具有增強臨床效益的潛力，同時兼具每日一次給藥的便利性。此外，我們預計 vanzacaftor 三聯療法的專利使用費負擔將大幅降低。

Another important study in our CF portfolio pertains to VX-522, our CFTR mRNA therapy that we're developing in partnership with Moderna for the more than 5,000 CF patients who cannot benefit from CFTR modulators. We have initiated the single ascending dose or SAD study of VX-522 and are actively enrolling and dosing CF patients. We anticipate completing the SAD portion of the study and initiating the multiple ascending dose portion of the study this year.

我們囊性纖維化（CF）產品組合中的另一項重要研究是關於VX-522的，這是我們與Moderna合作開發的CFTR mRNA療法，旨在為超過5000名無法從CFTR調節劑中獲益的CF患者提供治療。我們已啟動VX-522的單次遞增劑量（SAD）研究，並正在積極招募CF患者並進行給藥。我們預計今年完成SAD研究部分，並啟動多次遞增劑量研究部分。

Turning now to exa-cel, our gene editing program for severe sickle cell disease and transfusion-dependent beta-thalassemia. Exa-cel holds the potential to be the first CRISPR-based gene editing treatment to be approved, as well as the promise to be a onetime functional cure for these diseases. This is our most advanced program outside of CF, and we expect exa-cel to be our next commercial launch.

接下來我們來談談exa-cel，這是我們針對重度鐮狀細胞疾病和輸血依賴型β-地中海貧血的基因編輯計畫。 exa-cel有望成為首個獲準的基於CRISPR的基因編輯療法，並有望一次治癒這些疾病。這是我們在囊性纖維化以外的最先進項目，我們預期exa-cel將成為我們下一個商業化產品。

Per our prior guidance, we completed our BLA submissions for both sickle cell disease and TDT in the U.S. at the end of last quarter. We now await acceptance of our filings and assignment of the PDUFA date. Our filings include requests for priority review, which if granted, will result in an 8-month review by FDA from the time of submission.

根據我們先前的指導，我們已於上季末完成了在美國針對鐮狀細胞病和TDT的生物製品許可申請（BLA）提交。目前，我們正在等待FDA接受我們的申請並確定處方藥用戶付費法案（PDUFA）審批日期。我們的申請中包含優先審評請求，如果獲得批准，FDA將從提交之日起進行為期8個月的審查。

Internationally, as previously announced, both the EMA and MHRA have validated our exa-cel MAA submissions, and those filings are under review. We see a significant opportunity for exa-cel. Stuart will comment further on the market opportunity and our launch preparations in just a few minutes.

正如先前宣布的那樣，歐洲藥品管理局 (EMA) 和英國藥品和保健產品監管署 (MHRA) 已確認我們提交的 exa-cel 上市許可申請，​​目前正在審核中。我們認為 exa-cel 擁有龐大的市場機會。 Stuart 將在幾分鐘後就市場機會和我們的上市準備工作作進一步闡述。

Turning next to our pain program and VX-548, our novel, highly selective NaV1.8 inhibitor that holds the promise of effective pain relief without the side effects or addictive properties of opioids. We have confidence in the outlook for this program, given: one, NaV1.8 is a genetically and pharmacologically validated target; two, we have multiple positive proof-of-concept results with our predecessor NaV1.8 inhibitor, VX-150, across acute, neuropathic and musculoskeletal pain, and with VX 548 itself in acute pain; and three, our Phase III program with VX-548 in acute pain is substantially similar to the positive Phase II trials we have already concluded. VX 548 has been granted fast track and breakthrough therapy designations for acute pain in the U.S. We initiated pivotal development last year, and enrollment in dosing across the 3 Phase III studies continue to progress nicely. These studies have been designed to support our goal of a broad, moderate to severe acute pain label that would enable prescribing and usage across multiple care settings, including at the site of care, post-discharge and in the home.

接下來，我們來談談我們的疼痛治療項目和VX-548。 VX-548是一種新型的高選擇性NaV1.8抑制劑，有望在不產生鴉片類藥物副作用或成癮性的情況下有效緩解疼痛。我們對該計畫的前景充滿信心，原因有三：第一，NaV1.8是一個經過基因和藥理學驗證的靶點；第二，我們的前代NaV1.8抑製劑VX-150在急性疼痛、神經性疼痛和肌肉骨骼疼痛方面均取得了多項積極的概念驗證結果，VX-548本身在急性疼痛方面也取得了積極結果的第三III期臨床試驗與我們已完成的積極II期臨床試驗基本相似。 VX-548已獲得美國快速通道和突破性療法認定，用於治療急性疼痛。我們於去年啟動了關鍵性開發，目前三項III期臨床試驗的給藥入組工作進展順利。這些研究旨在支持我們的目標，即建立一個廣泛的、適用於中度至重度急性疼痛的標籤，以便在多種護理環境中進行處方和使用，包括護理場所、出院後和家庭。

We continue to anticipate completing the acute pain Phase III pivotal program toward the end of this year or beginning of next, creating another potentially significant and near-term commercial opportunity. In addition, we continue to enroll and dose patients in a 12-week Phase II dose-ranging proof-of-concept study of VX-548 in diabetic peripheral neuropathy, a form of peripheral neuropathic pain. I'm pleased to share we also anticipate completing this Phase II study towards the end of this year or beginning of next.

我們預期急性疼痛III期關鍵性試驗將於今年底或明年年初完成，這將創造另一個潛在的、近期內可觀的商業機會。此外，我們正在繼續招募患者並進行為期12週的VX-548 II期劑量範圍概念驗證研究，該研究旨在評估VX-548治療糖尿病週邊神經病變（一種週邊神經性疼痛）的療效。我很高興地宣布，我們也預計這項II期研究將在今年年底或明年年初完成。

Transitioning now to inaxaplin, or VX-147, the first potential medicine to target the underlying cause of APOL1-mediated kidney disease, or AMKD. In March, we were very pleased with the publication of the Phase II results for inaxaplin in the New England Journal of Medicine. Importantly, the paper was accompanied by an editorial and a feature on the science behind the study. We see this coverage in the New England Journal of Medicine as underscoring the importance of the inaxaplin data and the medicine's potential. The Phase IIb dose-ranging portion of the global Phase II/III pivotal study remains on track to complete this year. Recall, this study has a preplanned interim analysis at 48 weeks of treatment which, if positive, could serve as the basis to seek accelerated approval in the U.S. With inaxaplin, we see the potential to bring a first-in-class treatment to the approximately 100,000 patients with AMKD in the U.S. and Europe and unlock a multibillion-dollar market opportunity.

現在我們來談談inaxaplin（VX-147），它是第一個針對APOL1介導的腎臟病（AMKD）根本病因的潛在藥物。今年3月，我們非常高興inaxaplin的II期臨床試驗結果發表在《新英格蘭醫學雜誌》。更重要的是，論文還附有社論和專題文章，闡述了研究背後的科學原理。我們認為，《新英格蘭醫學雜誌》的報導凸顯了inaxaplin資料的重要性及其藥物的潛力。全球II/III期關鍵性研究的IIb期劑量探索部分目前進展順利，預計今年完成。需要指出的是，該研究預先計劃在治療48週後進行中期分析，如果結果為陽性，則可作為在美國尋求加速審批的依據。我們相信，inaxaplin可望為美國和歐洲約10萬名AMKD患者帶來首創療法，並開啟數十億美元的市場機會。

Moving now to type 1 diabetes. There are more than 2.5 million people with type 1 diabetes in North America and Europe alone, and we are committed to delivering a transformative, if not curative medicine for this disease. We have 3 programs in our type 1 diabetes portfolio, all of which use the same fully differentiated insulin-producing islet cells, which have already demonstrated proof of concept.

接下來我們來談談第一型糖尿病。光是在北美和歐洲，就有超過250萬1型糖尿病患者，我們致力於為這種疾病提供變革性甚至治癒性的藥物。我們目前有三個1型糖尿病項目，所有項目都使用相同的完全分化的胰島素分泌胰島細胞，這些細胞的概念驗證已經成功。

Our first program, or VX-880, the naked cell program, uses standard immunosuppressives to protect the islet cells from the immune system. I am pleased to share that both Part A and Part B of the study are now fully enrolled and dosed. In both portions of the study, dosing of patients was staggered, with Part A patients receiving half dose and Part B patients receiving the full target dose. The next step in the program is Part C, in which patients will be treated concurrently with the full target dose. This should facilitate faster time lines. We look forward to sharing VX-880 data for more patients and with longer duration of follow-up at medical congresses this year, including the ADA scientific sessions in June.

我們的首個項目，即裸細胞項目VX-880，採用標準免疫抑制劑來保護胰島細胞免受免疫系統攻擊。我很高興地宣布，研究的A部分和B部分都已完成全部受試者招募和給藥。在兩個部分中，患者的給藥時間均分階段進行，A部分患者接受半劑量，B部分患者接受全劑量。此計畫的下一步是C部分，屆時患者將同時接受全劑量治療。這將有助於加快研究進程。我們期待在今年的醫學大會上，包括6月的美國糖尿病協會（ADA）科學會議，分享更多患者和更長時間追蹤的VX-880數據。

Our second program, VX-264, or the cells plus device program, encapsulates these same cells in a proprietary device that is designed to shield the cells from the body's immune system. And hence, there is no requirement for immunosuppressants. Both the IND in the U.S. and the CTA in Canada have cleared. Site activation and study initiation activities are underway in both the U.S. and Canada, and we look forward to enrolling and dosing patients in this Phase I/II study in the near term.

我們的第二個項目VX-264，即細胞+裝置項目，將這些細胞封裝在一個專有裝置中，該裝置旨在保護細胞免受人體免疫系統的攻擊。因此，無需使用免疫抑制劑。該計畫在美國的IND申請和在加拿大的CTA申請均已獲批准。目前，美國和加拿大的研究中心啟動和研究啟動工作正在進行中，我們期待在不久的將來開展這項I/II期臨床試驗，並開始招募患者並進行給藥。

Third, our hyperimmune program, in which we edit the same cells to cloak them from the immune system. This would represent another path to obviating the need for immunosuppressives. In March, we expanded our collaboration with CRISPR Therapeutics into type 1 diabetes, and this new licensing agreement will enable us to use CRISPR-Cas9 to edit the cells. This research stage program continues to make progress.

第三，我們的超免疫療法項目，即透過基因編輯使細胞免受免疫系統攻擊。這將是避免使用免疫抑制劑的另一條途徑。今年三月，我們擴大了與 CRISPR Therapeutics 的合作，將研究領域拓展至第 1 型糖尿病，這項新的授權協議將使我們能夠利用 CRISPR-Cas9 技術編輯細胞。該研究階段的專案正在持續推進中。

Lastly, also in the T1D portfolio, the ViaCyte-VCTX-211 hypoimmune program using a ViaCyte cell line remains on track. This program has finished enrollment and dosing in group 1 of the Phase I/II study.

最後，同樣在第1型糖尿病產品組合中，使用ViaCyte細胞株的ViaCyte-VCTX-211低免疫療法計畫進展順利。本計畫已完成I/II期臨床試驗第一組的受試者招募和給藥。

Let me conclude with our alpha-1 antitrypsin deficiency, or AATD, program, which continues to enroll both the Phase II study for VX-864 and the Phase I study for VX-634. The Phase II program for VX-864 is a 48-week study in patients with AATD that will assess both liver clearance of Z polymer and serum functional AAT levels. This study is projected to complete enrollment later this year. The Phase I healthy volunteer study of VX-634, the next-in-class molecule with multifold greater potency and better drug-like properties, is projected to complete this year. With that, I'll now turn over the call to Stuart.

最後，我想談談我們的α1-抗胰蛋白酶缺乏症（AATD）計畫。本計畫目前正在進行VX-864的II期臨床試驗和VX-634的I期臨床試驗，均持續招募受試者。 VX-864的II期臨床試驗是一項為期48週的AATD患者研究，旨在評估Z聚合物的肝臟清除率和血清功能性AAT水平。該研究預計將於今年稍後完成受試者招募。 VX-634是同類藥物中的佼佼者，具有更高的效力和更優的成藥特性，其I期健康志願者研究預計將於今年完成。接下來，我將把電話交給Stuart。

Thanks, Reshma. From a commercial perspective, our focus continues to be to reach all patients eligible for our CFTR modulators and maintain high levels of adherence among patients already on therapy, while also preparing for potential near-term launches for exa-cel, VX-548 in acute pain and the vanzacaftor triple combination in CF. I'll first review our CF first quarter commercial results and then the longer-term outlook for our CF portfolio. I will then comment on the exa-cel opportunity and our launch preparations, given that we have now completed our regulatory filings in the U.S., Europe and the U.K.

謝謝，Reshma。從商業角度來看，我們的重點仍然是涵蓋所有符合CFTR調節劑使用條件的患者，並保持已接受治療患者的高依從性，同時為近期可能推出的exa-cel、用於治療急性疼痛的VX-548以及用於治療囊性纖維化的vanzacaftor三聯療法做好準備。我將首先回顧我們囊性纖維化產品組合第一季的商業業績，然後展望我們囊性纖維化產品組合的長期前景。鑑於我們已完成在美國、歐洲和英國的監管申報，我將就exa-cel的市場機會和上市準備工作發表意見。

We had a strong first quarter, with growth predominantly driven by bringing our medicines to younger patients, including TRIKAFTA in children ages 6 to 11 in the U.S., plus Europe and Canada, and we remain confident in the growth outlook for 2023. Last week, as expected, we received FDA approval for TRIKAFTA in the U.S. for children ages 2 to 5 years, which adds approximately 900 new patients who, for the first time, will have a treatment to address the underlying cause of their disease.

我們第一季業績強勁，成長主要得益於將我們的藥物推廣至更年輕的患者群體，包括在美國、歐洲和加拿大為6至11歲兒童提供的TRIKAFTA。我們對2023年的成長前景依然充滿信心。如預期，上週我們獲得了美國FDA對TRIKAFTA的批准，用於治療2至5歲兒童，這將使約900名新患者首次獲得針對其疾病根本原因的治療。

Turning to the longer-term outlook. We see continued growth in CF beyond 2023. As Reshma mentioned, at the beginning of this year, there were more than 20,000 people in North America, Europe, Australia and New Zealand with CF who could benefit, but were not yet being treated with our approved medicines. Beyond the key growth driver of reaching younger patients through new approvals, we also continue to make progress in securing additional reimbursements. This includes multiple agreements spanning our CF portfolio for younger patients in Europe and, most recently, also Australia and New Zealand.

展望長期前景，我們預期囊性纖維化（CF）市場在2023年後將持續成長。正如Reshma所提到的，今年年初，北美、歐洲、澳洲和紐西蘭有超過2萬名CF患者，他們有望受益於我們已獲批准的藥物，但尚未接受治療。除了透過新藥獲準惠及更多年輕患者這項關鍵成長動力之外，我們還在爭取更多健保報銷方面持續取得進展。這包括在歐洲以及最近在澳洲和紐西蘭達成的多項針對年輕CF患者的健保報銷協議。

A second driver of CF product growth is the compelling portfolio of real-world outcome studies, including model data which validate the positive outlook for long-term growth in the overall CF population due to improved survival. Model data related to projected survival and long-term health outcomes were recently published in the Journal of Cystic Fibrosis, and include a 33.5 year increase in median projected survival with TRIKAFTA therapy versus the standard of care.

囊性纖維化產品成長的第二個驅動因素是一系列引人注目的真實世界療效研究，其中包括模型數據，這些數據驗證了由於生存期延長而帶來的囊性纖維化患者群體長期增長的積極前景。與預測存活期和長期健康結果相關的模型數據近期發表於《囊性纖維化雜誌》，數據顯示，與標準療法相比，TRIKAFTA療法可使中位預測生存期延長33.5年。

A third growth driver for our CF portfolio will be our next-generation vanzacaftor triple, which provides an opportunity to bring a new and potentially improved treatment option to patients, including those who discontinued therapy with our other medicines. We estimate that there are approximately 6,000 patients who have discontinued one of our existing CFTR modulators. And longer term, a fourth factor to help drive extended growth in our CF portfolio is VX-522, which is designed to provide mRNA therapy for the more than 5,000 patients who cannot benefit from CFTR modulators.

推動我們囊性纖維化產品組合成長的第三個因素是我們的下一代vanzacaftor三合療法，它為患者提供了一種新的、可能更有效的治療選擇，包括那些因其他藥物治療失敗而停止治療的患者。我們估計，目前約有6000名患者停止使用我們現有的CFTR調節劑。從長遠來看，推動我們囊性纖維化產品組合持續成長的第四個因素是VX-522，它旨在為超過5000名無法從CFTR調節劑中獲益的患者提供mRNA療法。

Shifting now to exa-cel, which holds curative potential for patients with sickle cell disease and transfusion-dependent beta thalassemia. With the recent completion of our exa-cel regulatory submissions in the U.S., Europe and U.K., our commercial teams are preparing for the potential approval and launch of this multibillion-dollar opportunity. Sickle cell disease and transfusion-dependent beta thalassemia are neither silent nor undiagnosed diseases. Our initial launch will focus on the approximately 32,000 most severe patients in the U.S. and Europe. These patients have been sick their entire lives with a chronic, often disabling disease that carries a high burden of care. They could soon have the opportunity for a potential lifetime cure.

現在我們來談談exa-cel，它有望治癒鐮狀細胞疾病和輸血依賴型β地中海貧血患者。隨著我們近期在美國、歐洲和英國完成exa-cel的監管申報，我們的商業團隊正在為這項價值數十億美元的產品的潛在批准和上市做準備。鐮狀細胞疾病和輸血依賴型β地中海貧血並非隱性疾病，也並非未確診的疾病。我們最初的上市將重點關注美國和歐洲約32,000名病情最嚴重的患者。這些患者終生飽受慢性疾病的折磨，這種疾病往往會導致殘疾，並給他們帶來沉重的護理負擔。他們或許很快就能迎來終身療癒的機會。

Our launch preparations are informed by extensive market research and insight generation, including through direct engagement with patients, providers and payers to understand their perceptions of gene therapy and the potential uptake of a product like exa-cel. We are encouraged by the strong interest and enthusiasm shown by all stakeholders for a genetic therapy that could provide transformative benefit for patients.

我們的上市準備工作以廣泛的市場研究和洞察分析為基礎，包括直接與患者、醫療服務提供者和支付方溝通，以了解他們對基因療法的看法以及像exa-cel這樣的產品的潛在市場接受度。所有利害關係人對這種可能為患者帶來變革性益處的基因療法所表現出的濃厚興趣和熱情令我們倍感鼓舞。

Starting with patients. The journey for someone to receive exa-cel can be summarized in 3 key phases: one, the pretreatment period where patients decide a genetic therapy is right for them and are referred to an authorized treatment center by their hematologists and begin the cell collection process; two, the manufacturing period where a patient cells are edited and become the exa-cel drug product; and three, the treatment period, where a patient receives myeloablative conditioning, then their edited cells and is followed for successful engraftment.

從患者開始。接受 Exa-Cel 治療的過程可以概括為三個關鍵階段：第一階段是預處理階段，患者在此階段確定基因療法適合自身情況，並由血液科醫生轉診至授權治療中心，開始細胞採集過程；第二階段是生產階段，患者細胞經過基因編輯，製成 Exa-Cel 藥物產品；第三階段是治療階段，患者接受清髓性預處理，然後進行基因檢測和移植是否成功移植後的細胞，患者是否接受清髓性預處理，然後進行基因檢測和移植是否成功。

Survey data from sickle cell and beta thalassemia patients indicate that more than 1/4 strongly believe genetic therapy is the right choice for them. Of the balance, the vast majority want to learn more about future treatment options through their own research and through the lived experiences of exa-cel patients and their treating physicians.

鐮狀細胞貧血症和β地中海貧血症患者的調查數據顯示，超過四分之一的患者堅信基因療法是他們的最佳選擇。其餘患者中，絕大多數希望透過自行研究以及了解exa-cel基因療法患者及其主治醫師的親身經歷，來了解更多未來的治療方案。

With providers, we've learned there is a clear recognition of the differences between various genetic therapy approaches and a strong preference for gene-edited therapies like exa-cel over gene insertion approaches using lentivirus. Our market research suggests that approximately 70% of providers prefer a gene-editing approach over other gene therapy mechanisms. Our teams are focused on providing access to key support and systems for both patients and providers to ensure the best possible treatment experience. Accordingly, we have made strong progress toward ensuring authorized treatment centers are administratively and logistically prepared to initiate the exa-cel treatment journey for patients upon approval. Approximately 50 U.S. centers are actively engaged in the process to become an ATC located in those areas with the highest prevalence of patients. Similarly, in all 4 key European markets, all 25 targeted ATC sites are in process.

我們與醫療服務提供者的溝通表明，他們清楚地認識到各種基因療法之間的差異，並且更傾向於使用基因編輯療法（例如exa-cel）而非慢病毒基因插入療法。我們的市場調查顯示，約70%的醫療服務提供者更傾向於基因編輯療法而非其他基因治療機制。我們的團隊致力於為患者和醫療服務提供者提供關鍵的支援和系統，以確保他們獲得最佳的治療體驗。因此，我們在確保授權治療中心在獲得批准後，能夠在行政和後勤方面做好充分準備，為患者啟動exa-cel治療流程方面取得了顯著進展。目前，約有50家美國中心正在積極申請成為授權治療中心（ATC），這些中心均位於患者數量最多的地區。同樣，在歐洲的四個主要市場，所有25個目標ATC中心也都在進行相關申請流程。

Payers are another important area of focus. We are actively engaging with key commercial and government payers and policymakers in the U.S. and Europe. First, with regard to commercial payers in the U.S., our conversations are focused on the patient need and clinical profile of exa-cel, including dramatic reductions in VOCs and hospitalizations for sickle cell disease patients and in transfusions for beta thalassemia patients.

支付方是另一個重要的關注領域。我們正積極與美國和歐洲的主要商業和政府支付方及政策制定者溝通。首先，就美國的商業支付方而言，我們的對話重點在於患者的需求以及exa-cel的臨床特性，包括顯著降低鐮狀細胞病患者的血管閉塞危象和住院率，以及減少β地中海貧血患者的輸血需求。

We are confident that payers will recognize exa-cel's value in patient populations where current lifetime cost of care can exceed $4 million. We are working with insurers to ensure broad access for the approximately 35% of sickle cell disease and transfusion-dependent thalassemia patients who are commercially insured.

我們相信，支付方會認可exa-cel在終生治療費用可能超過400萬美元的患者群體中的價值。我們正與保險公司合作，確保約35%的鐮狀細胞疾病和輸血依賴型地中海貧血患者（他們擁有商業保險）能夠廣泛獲得該藥物。

Now to government payers. Approximately 45% of severe sickle cell disease patients in the U.S. are ensured by Medicaid. And thus, we've also been working with state agencies to ensure Medicaid patients have broad access to exa-cel. We recognize that a critical element for adoption is ensuring a separate payment for the XL therapy in addition to the reimbursement already in place for the transplant procedure costs. Encouragingly, many states are already providing access to cell and gene therapies with separate payment policies for the procedure and the therapy, and we continue to engage with state agencies around payment models ahead of the launch.

現在來說說政府支付方。在美國，大約45%的重度鐮狀細胞貧血症患者由醫療補助計畫（Medicaid）提供醫療保障。因此，我們也一直在與各州機構合作，確保醫療補助計劃的患者能夠廣泛獲得exa-cel療法。我們意識到，推廣的關鍵在於確保在現有移植手術費用報銷之外，為XL療法單獨支付費用。令人鼓舞的是，許多州已經為細胞和基因療法提供了單獨的支付政策，分別針對手術和治療費用。在正式推出之前，我們將繼續與各州機構就支付模式進行溝通。

In addition, in February of this year, the Biden administration demonstrated their commitment to ensuring access to cell and gene therapies like exa-cel through the announcement of a CMS demonstration project called the Cell and Gene Therapy, or CGT, Access Model. The CGT Access Model will be administered through CMS' innovation center, which has a total budget of approximately $10 billion for the exploration and testing of novel delivery methods and approaches. Intended to accelerate and enhance broad Medicaid access for sickle cell disease patients, the CGT access model will, over time, facilitate this in 2 important ways: by creating a pathway for state Medicaid agencies to delegate authority to CMS to coordinate and facilitate innovative payment models, including outcomes-based agreements, or OBAs, with cell and gene therapy manufacturers like Vertex. And in addition, CMS has confirmed any outcomes-based arrangement for inpatient therapies requires payment separate from the hospital inpatient bundle.

此外，今年2月，拜登政府宣布啟動一項名為「細胞和基因療法（CGT）准入模式」的CMS示範項目，以此表明其致力於確保患者能夠獲得Exa-Cel等細胞和基因療法。 CGT准入模式將由CMS創新中心負責管理，該中心擁有約100億美元的預算，用於探索和測試新型的治療方式和方法。 CGT准入模式旨在加速和擴大鐮狀細胞疾病患者獲得醫療補助的途徑，並將透過以下兩個重要方面逐步實現這一目標：首先，它將為各州醫療補助機構提供授權，使其能夠委託CMS協調和促進創新的支付模式，包括與Vertex等細胞和基因療法生產商簽訂基於結果的協議（OBA）。其次，CMS已確認，任何針對住院治療的基於結果的安排都需要單獨支付，與醫院住院費用分開。

We view this CGT Access Model as an important indicator of the understanding of the severity of these diseases and the need to provide broad access to potentially transformative therapies for these historically underserved patient populations. We are extremely excited about the potential for exa-cel, our first commercial launch outside of CF in many years, and look forward to updating you further on our launch preparation activities on future calls.

我們認為，這種 CGT 進入模式是衡量我們對這些疾病嚴重性認知的重要指標，也反映了為這些長期以來服務不足的患者群體提供廣泛、可能具有變革意義的療法的必要性。我們對 exa-cel 的潛力感到無比興奮，這是我們多年來在囊性纖維化以外的首個商業化產品，期待在未來的電話會議上向您進一步匯報我們的上市準備工作。

I'm also looking forward to updating you on our continued progress to discover, develop and secure access to transformative medicines for all people living with CF. I will now turn the call over to Charlie to review the financials.

我也期待著向大家報告我們在發現、開發和確保所有囊性纖維化患者都能獲得變革性藥物方面取得的持續進展。現在我將把電話交給查理，讓他來回顧一下財務狀況。

Thanks, Stuart. Vertex's results in the first quarter of 2023 demonstrate our consistent strong performance and attractive growth profile regardless of macroeconomic conditions. First quarter 2023 revenue increased 13% year-over-year to $2.37 billion. Growth was led by a 33% year-over-year increase 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 grew 3% year-over-year with ongoing consistent performance.

謝謝，斯圖爾特。 Vertex 2023年第一季的業績表明，無論宏觀經濟環境如何，我們始終保持強勁的業績和可觀的成長前景。 2023年第一季營收年增13%，達23.7億美元。成長主要得益於美國以外地區年增33%，這主要歸功於TRIKAFTA/KAFTRIO在近期獲得醫保報銷的市場以及適應症擴展至更年輕年齡組的持續強勁增長。美國CF業務營收年增3%，業績持續穩健。

First quarter 2023 combined non-GAAP R&D, acquired IP R&D and SG&A expenses were $1.2 billion compared to $687 million in the first quarter of 2022. Q1 2023 results include $347 million of acquired IP R&D charges compared to just $2 million of such charges in the first quarter of 2022.

2023 年第一季非 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 12 億美元，而 2022 年第一季為 6.87 億美元。 2023 年第一季業績包括 3.47 億美元的收購智慧財產權研發費用，而 2022 年第一季此類費用僅為 200 萬美元。

First quarter 2023 IP R&D expenses resulted from several new collaborations, which augment our internal innovation efforts as detailed on Slide 15, including collaborations with Entrada Therapeutics and DM1 immunogen for gentler conditioning agents and the expansion of our relationship with CRISPR Therapeutics into type I diabetes. Aside from our investments in external innovation and the resulting higher acquired IP R&D charges, operating expense growth was driven as expected by continued investment in research and our advancing pipeline, which includes mid- and late-stage clinical assets across 8 different disease areas.

2023年第一季的智慧財產權研發費用主要來自幾項新的合作，這些合作增強了我們內部的創新能力（詳見幻燈片15），包括與Entrada Therapeutics和DM1免疫原公司合作開發更溫和的預處理劑，以及我們與CRISPR Therapeutics公司將合作關係拓展至I型糖尿病領域。除了對外部創新的投資以及由此產生的更高的收購知識產權研發費用外，營運費用的成長也如預期般主要來自對研發的持續投入以及我們不斷推進的研發管線，該管線涵蓋8個不同疾病領域的中後期臨床資產。

For example, these investments are directed towards clinical studies for the vanzacaftor triple in CF, VX-548 in acute pain and type I diabetes, as well as pre-commercial build-out activities for exa-cel and other potential near-term launches. Given the potentially transformative benefit to patients and multibillion-dollar market opportunities for our programs, we will continue to invest appropriately.

例如，這些投資將用於進行vanzacaftor三合一療法治療囊性纖維化、VX-548治療急性疼痛和I型糖尿病的臨床研究，以及exa-cel和其他潛在近期上市藥物的商業化前期準備工作。鑑於這些項目可能為患者帶來變革性益處，並蘊藏著數十億美元的市場機遇，我們將繼續進行適當的投資。

First quarter 2023 non-GAAP operating income was $902 million in the quarter compared to $1.17 billion in the first quarter of 2022. First quarter adjusted earnings per share were $3.05. We ended the quarter with $11.5 billion in cash and investments, as our cash flow generation and balance sheet remain very strong.

2023年第一季非GAAP營業收入為9.02億美元，而2022年第一季為11.7億美元。第一季調整後每股收益為3.05美元。截至季末，我們持有現金及投資115億美元，現金流和資產負債表依然非常強勁。

Now switching to guidance. Given our first quarter results and our consistent execution, there are no changes to our 2023 financial guidance as detailed on Slide 16. We continue to expect product revenue guidance of $9.55 billion to $9.7 billion, representing 7% to 9% growth year-over-year. Note that this guidance continues to include an expected approximate 1.5 percentage point headwind to our revenue growth, inclusive of our foreign exchange risk management program.

現在轉入業績指引。鑑於我們第一季的業績以及我們一貫的執行力，我們對2023年的財務指引（詳見第16頁）保持不變。我們仍預期產品收入為95.5億美元至97億美元，年增7%至9%。需要注意的是，該指引仍包含了我們預期約1.5個百分點的營收成長阻力，其中包括我們的外匯風險管理計畫。

As we mentioned in early February, given our years of experience in CF, we have strong visibility to our 2023 revenue guidance range, which is inclusive of expected new approvals like the TRIKAFTA U.S. approval in patients ages 2 to 5 and new reimbursements outside the U.S. Note too that 2023 product revenue guidance continues to reflect revenue from cystic fibrosis products only. Exa-cel is not included in guidance, as potential approval and launch dates in the EU, U.K. and U.S. are still to be determined.

正如我們在二月初提到的，憑藉我們在囊性纖維化領域多年的經驗，我們對2023年的收入預期範圍有清晰的把握，其中包括預期的新批准，例如TRIKAFTA在美國獲批用於2至5歲患者，以及美國以外地區的新醫保報銷。另請注意，2023年的產品收入預期仍僅反映囊性纖維化產品的收入。 Exa-cel未包含在預期範圍內，因為其在歐盟、英國和美國的潛在批准和上市日期尚未確定。

We are also reiterating our 2023 guidance for combined non-GAAP R&D, acquired IP R&D and SG&A in the range of $3.9 billion to $4 billion. Our 2023 non-GAAP operating expense guidance now includes approximately $400 million of upfronts in milestones from previously existing or recently completed BD transactions versus the $300 million that was anticipated at the beginning of the year. Our operating expenses continue to be more than 70% allocated to R&D and are funding the significant continued progress of our multiple mid- and late-stage clinical development programs. Additionally, we are funding the expansion of our commercialization capabilities in anticipation of the multibillion-dollar market opportunities represented by our programs with near-term launch potential.

我們重申2023年非GAAP研發支出、收購智慧財產權研發支出及銷售、管理及行政費用（SG&A）的預期，預計在39億美元至40億美元之間。我們2023年非GAAP營運支出預期目前包含約4億美元的里程碑付款，這些款項來自先前已完成或近期完成的業務拓展交易，而年初的預期為3億美元。我們的營運支出中，超過70%仍用於研發，為我們多個處於中後期臨床開發階段的專案持續取得顯著進展提供資金支持。此外，我們也正在為擴大商業化能力提供資金，以期抓住近期有望上市的項目所蘊含的數十億美元市場機會。

Our guidance for projected full year 2023 non-GAAP effective tax rate of 21% to 22% is also unchanged.

我們對 2023 年全年非 GAAP 實際稅率的預期仍為 21% 至 22%，這一預期保持不變。

In closing, Vertex performed exceptionally well in the first quarter of 2023. We delivered strong revenue growth, invested internally and externally, and accelerated programs across our diverse pipeline. We're also proud of our industry-leading culture of innovation that we believe will continue to drive long-term success. A few highlights from our recently published corporate responsibility report are found on Slide 17.

綜上所述，Vertex在2023年第一季表現優異。我們實現了強勁的營收成長，加大了內部和外部投資，並加速推進了多元化產品線中的各項計畫。我們也為我們行業領先的創新文化感到自豪，並相信這種文化將繼續推動我們的長期成功。我們近期發布的《企業社會責任報告》中的一些亮點內容請參閱第17頁投影片。

And as we continue to advance our programs in 2023, we anticipate further important milestones as highlighted on Slide 18 to mark our continued progress in multiple disease areas. We look forward to updating you on our progress on future calls, and I'll ask Susie to begin the Q&A period.

隨著我們在2023年繼續推進各項計劃，我們預計將取得更多重要里程碑式的進展，如幻燈片18所示，這些進展將標誌著我們在多個疾病領域持續取得進步。我們期待在未來的電話會議上向您報告最新進展，現在請Susie開始問答環節。

(Operator Instructions) And the first question will come from Salveen Richter with Goldman Sachs.

（操作員說明）第一個問題將來自高盛的薩爾文·里希特。

With regard to the exa-cel launch, you discussed the 3 steps that need to occur for patients to get treatment here. Could you just speak to the overall time that will be required in your mind after approval for a patient to actually be administered drug? And then secondly, the gene insertion competitor clearly has been doing work here and it's taken some time, but they've done foundational payer work. Just wondering what the read-through is from all the work they've done to your launch progress as well. And in the context of this, on the R&D and SG&A front as we look to next year, how do we think about how that SG&A line might inflect in the context of not just this launch, but also the pain launch as well?

關於Exa-Cel的上市，您提到了患者接受治療所需經歷的三個步驟。您能否簡要說明一下，從核准到患者實際接受藥物治療，您認為總共需要多長時間？其次，基因插入療法的競爭對手顯然也在這方面投入了大量精力，雖然耗時較長，但他們已經完成了基礎性的健保支付工作。我想了解一下，他們所做的這些工作對貴公司上市進展有何影響？此外，展望明年，在研發及銷售、管理及行政費用方面，我們該如何考慮銷售、管理及行政費用會如何影響此次上市以及疼痛治療藥物的上市？

Thanks very much for the question. I'm going to ask Stuart to talk about the exa-cel time lines and a little bit about the launch. Stuart?

非常感謝您的提問。我打算請史都華談談Exa-Cel的時間線以及發射方面的狀況。史都華？

Yes. So Salveen, as I outlined in my prepared remarks, this is a relatively extended process that takes multiple months from beginning to end, as I said, from the patient deciding with their physician that a genetic approach is the one that they would like to undertake through mobilization and the manufacturing. And then very, very importantly is the last step, which is obviously the most important because that's when they are infused with their edited cells, because of the nature of that last step where the patient has to undergo myeloablative conditioning and therefore, has a kind of multi-week stay in the hospital, whilst they're followed to see whether the product has engrafted. Before they are released in the hospital, they have to schedule that into their life.

是的。薩爾文，正如我在事先準備好的演講稿中所述，這是一個相對漫長的過程，從開始到結束需要幾個月的時間。正如我所說，這包括患者與醫生共同決定採用基因療法，以及動員和生產等環節。然後，非常非常重要的一步是最後一步，這顯然是最重要的，因為在這一步驟中，患者需要接受基因編輯細胞的輸注。由於最後一步的特殊性，患者必須接受清髓性預處理，因此需要在醫院住院數週，期間醫生會密切觀察細胞是否成功植入。在出院之前，患者必須將此過程安排進自己的生活中。

And so that is a -- obviously a very significant undertaking for an individual, but of course, the payoff there is they're looking to get a potential lifetime cure for that multi-month process. So it is a multi-month process with that last step, obviously, being one that they need to schedule into their life, hopefully, then to receive a lifetime of benefit from exa-cel.

所以，這對個人來說顯然是一項非常重要的挑戰，但回報當然是，他們希望透過這幾個月的療程獲得終身有效的治療。因此，這是一個持續數月的療程，最後一步顯然需要他們安排進自己的生活中，希望之後能夠從Exa-Cel中獲得終身益處。

In terms of kind of what are we learning from the marketplace from our interaction with payers, we're incredibly encouraged by the action we've had from payers, both their understanding of the severity of both sickle cell disease and transfusion-dependent thalassemia and the very significant burden that it has on patients, their families and of course, the broader health care system and the costs associated with that.

就我們從與支付方的互動中了解到的市場情況而言，我們對支付方的行動感到無比鼓舞，他們既了解鐮狀細胞病和輸血依賴型地中海貧血的嚴重性，也了解這些疾病給患者、他們的家庭以及更廣泛的醫療保健系統帶來的沉重負擔以及相關的成本。

Also, we're very encouraged by their reaction to the product profile that exa-cel has and how positive they appear to ne to be working with us to try and ensure that there is as near as possible access to exa-cel as close as possible post approval. So we're really very encouraged by the response from payers across the continuum, commercial payers, and very importantly for this population, both Medicaid and Medicare.

此外，我們對他們對Exa-cel產品特性的積極反應感到非常鼓舞，他們似乎也非常願意與我們合作，努力確保Exa-cel獲批後能盡快惠及更多患者。因此，我們對來自各級支付方的正面回饋感到非常振奮，包括商業保險公司，以及對這一人群而言尤為重要的醫療補助計劃（Medicaid）和聯邦醫療保險計劃（Medicare）。

I think you had a question on SG&A evolution. I think that's probably best handled by Charlie. So Charlie, do you want to take that one?

我想你之前問過關於銷售、管理及行政費用（SG&A）演變的問題。我覺得這個問題最好由查理來回答。查理，你願意回答這個問題嗎？

Yes. Salveen, thanks. Given that we've just reiterated our 2023 OpEx guidance, you can expect I'm not going to have much to comment on about 2024. I will say that the growth in OpEx in 2023, of course, is driven by the advancements in the pipeline. We've got multiple programs mid and late stage, including a few that are very close to commercialization. Even with that, the majority, over 70% of our OpEx is invested in R&D. Looking ahead, as we have more programs moving towards commercialization, you could see a little bit of a mix shift towards commercial spend. But importantly, with our model of focusing on transformative medicines in specialty populations, we'd always expect that the SG&A burden on the business would be quite low. It gives us the ability to drive significant profitability over time.

是的，Salveen，謝謝。鑑於我們剛剛重申了2023年的營運支出預期，您可以預料到我對2024年不會有太多評論。我只能說，2023年營運支出的成長當然是由在研產品的進展所推動的。我們有多個處於中後期階段的項目，其中一些已經非常接近商業化。即便如此，我們超過70%的營運支出仍投入研發。展望未來，隨著更多項目走向商業化，您可能會看到商業支出佔比略有增加。但重要的是，憑藉我們專注於為特定族群研發變革性藥物的模式，我們始終預期公司的銷售、管理及行政費用負擔會相當低。這使我們能夠隨著時間的推移實現顯著的獲利能力。

Next question will come from David Risinger with SVB Securities.

下一個問題將來自SVB證券的David Risinger。

Yes. Thank you for the updates. So I was hoping you could talk about your vision for VX-548 in chronic pain. So obviously, you're studying it in DPN. But specifically, what I'm interested in is, assuming that you succeed in your Phase II neuropathic pain trial, how might Vertex pursue Phase III development? How do you see the target product profile for the product? And would you consider development in musculoskeletal pain as well?

是的，謝謝您提供的最新資訊。我希望您能談談您對VX-548在慢性疼痛治療​​方面的願景。顯然，您正在研究它對糖尿病週邊神經病變（DPN）的療效。但我更感興趣的是，假設您在II期神經性疼痛試驗中取得成功，Vertex公司將如何進行III期研發？您認為該產品的目標產品特性為何？您是否也會考慮將其開髮用於治療肌肉骨骼疼痛？

This is Reshma. Let me take that one for you. We see 3 distinct areas for a drug like VX-548. One is acute pain. I'll put that aside for now and I'll come back to it. And instead of seeing the chronic market as 1 market, we actually see it as 2, the first being neuropathic pain and the second being, let's call it, musculoskeletal pain. In that chronic market, which we subdivide into 2, our immediate area of interest and where we are already in Phase II in the update on today's call is that we are now projecting the completion of that Phase II proof-of-concept study by the end of this year, early next.

我是雷什瑪。讓我來為您解答。我們認為像VX-548這樣的藥物有三個不同的應用領域。一是急性疼痛。我先暫且不談這個，稍後再詳細解釋。我們不會把慢性疼痛市場看成一個市場，而是將其細分為兩個：一是神經性疼痛，二是肌肉骨骼疼痛。在這個我們細分為兩個部分的慢性疼痛市場中，我們目前最關注的領域，也是我們在今天的電話會議上更新的二期臨床試驗進展，是預計將在今年年底或明年初完成的二期概念驗證研究。

We see that as a very substantial market, and we're pursuing that first because: One, there is high unmet need; two, because it fits our commercialization model, that is to say a specialty market. I fully expect that VX-548 and NaV1.8 inhibition in general will also be effective for musculoskeletal pain. And I say that not based on conjecture, but rather because the predecessor molecule, VX-150, we've already taken that into a form of musculoskeletal pain and it was positive there as well. So the way I see our pain portfolio progressing is acute pain first. We're already in Phase III. That program will be completed towards the end of this year, beginning of next. And I see that as the first pain opportunity in terms of nearest to market.

我們認為這是一個非常巨大的市場，因此我們首先著手開發這個市場，原因有二：第一，存在巨大的未滿足需求；第二，因為它符合我們的商業化模式，即專注於特定市場。我完全相信VX-548以及NaV1.8抑制劑整體對肌肉骨骼疼痛也有效。我這麼說並非基於臆測，而是因為我們的前驅分子VX-150已經用於治療肌肉骨骼疼痛，並且取得了正面的效果。因此，我認為我們疼痛產品組合的發展方向是先針對急性疼痛。我們已經進入III期臨床試驗階段。該項目將於今年年底或明年年初完成。我認為這是目前最接近上市的疼痛治療機會。

Second, the neuropathic pain program, and I do expect that 548 will work in musculoskeletal pain, I don't see that as a Vertexian disease because it requires a primary care outreach. But certainly, if the medicine can help, and I believe it will, we'll find a way to get it to patients, but that won't be through a Vertex commercialization enterprise.

其次，關於神經性疼痛項目，我確實認為548對肌肉骨骼疼痛有效，但我並不認為這是Vertex公司應該關注的疾病，因為它需要基層醫療機構的介入。當然，如果這種藥物有效（我相信它會有效），我們會找到辦法讓病人用上，但這不會通過Vertex的商業化途徑。

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。

Maybe a question on exa-cel, one more question on that. So I know -- I mean you are excited about the opportunity, and you're talking about 32,000 patients there and the drug clearly works. I mean it's pretty amazing. But when we talk to doctors, they talk about maybe initial opportunity will be 5,000 to 10,000 patients in the U.S. and they're a little bit worried about safety at this point, early on. And the investment community is also a little bit looking at it as a show-me story. So could you help us understand what we are missing in terms of when you talk to payers and prescribers, where do you think the disconnect is? And how do you think -- like what steps would need to happen for this disconnect to disappear? Obviously, launch would be an important factor.

關於Exa-Cel，我還有一個問題。我知道您對這個機會感到興奮，您提到有32000名患者，而且這種藥物顯然有效。這確實很了不起。但當我們與醫生溝通時，他們認為最初在美國的潛在患者可能只有5000到10000人，而且他們目前對藥物的安全性有些擔憂。投資界也對此持觀望態度，認為這是一個需要證明的故事。所以，您能否幫助我們理解，在您與支付者和處方醫生交流時，我們究竟忽略了什麼？您認為存在哪些脫節？您認為需要採取哪些措施才能消除這種脫節？顯然，上市是一個重要因素。

Sure, Mohit, this is Reshma. I think your question is about exa-cel and what do we really see as the real potential. I have very high confidence in the fact that there is significant unmet need. This is a disease that has really no therapy that can offer curative potential, full stop. There is no debate on that. With regard to the potential of our medicine, all of the data that we've showed to date show that this medicine has transformative, if not curative potential. And I'm going to ask Stuart to comment on what we've heard from patients, from payers and from stakeholders in general about their level of understanding and enthusiasm for this product.

當然，莫希特，我是雷什瑪。我想你的問題是關於Exa-Cel，以及我們真正認為它的​​潛力是什麼。我非常有信心，目前存在著巨大的未滿足醫療需求。這種疾病目前沒有任何療法能夠真正治愈，這一點毋庸置疑。至於我們藥物的潛力，我們迄今為止所展示的所有數據都表明，這種藥物具有變革性的潛力，甚至可能治癒疾病。接下來，我想請史都華談談我們從病人、支付方以及其他利害關係人那裡了解到的，他們對這款產品的理解和熱情程度。

And I'll also ask Stuart to remind what we see as the market size. What I'll say is that in the U.S. and Europe, there are 150,000 people with sickle cell and beta thalassemia. We are not targeting that full set with this the busulfan-based conditioning exa-cel program, we're targeting 32,000. Stuart?

我還要請史都華提醒一下我們對市場規模的看法。我想說的是，在美國和歐洲，有15萬人患有鐮狀細胞貧血症和β地中海貧血症。我們這個以白消安為基礎的預處理方案Exa-Cel的目標族群並非全部，而是3.2萬人。史都華？

Yes. As Reshma said, the 32,000 of those patients who are sort of the severe end of the spectrum, essentially, patients very similar to those that were enrolled in our clinical trials, these are patients who are having multiple occlusive crises per year for our sickle cell disease population and multiple transfusions in the year for those in the transfusion-dependent thalassemia patient population. So these are patients who -- whose lives are very, very significantly impacted by their disease, and it really impacts all aspects of their life, impacts their loved ones, impacts their ability to work, and they have a very, very significant burden of disease and also a very significant burden for the health care system. So in the discussions that we've had with both patients, payers and physician groups, the unmet need is very, very clearly well understood. The potential for curative onetime therapies is very, very much something that people are looking forward to.

是的。正如雷什瑪所說，這32,000名患者病情較為嚴重，與我們臨床試驗中的患者非常相似。這些鐮狀細胞貧血患者每年會經歷多次血管閉塞危象，而依賴輸血的地中海貧血患者每年需要多次輸血。因此，這些患者的生活深受疾病影響，疾病幾乎影響到他們生活的方方面面，影響到他們的親人，影響到他們的工作能力，他們承受著沉重的疾病負擔，也給醫療保健系統帶來了沉重的負擔。因此，在我們與患者、支付者和醫生團體進行的討論中，未滿足的需求得到了非常明確的認可。人們非常期待能夠一次性治癒的療法。

I think with any new technology and with any new product, there are always going to be some questions that people will have around things like safety, as these are really transformative and innovative therapies. And to some extent, for some people, that's something that can only get solved over the course of time and with their own lived experience. But certainly, the level of enthusiasm we're seeing from all stakeholders is very, very high, and we're very optimistic about this being a multibillion-dollar opportunity.

我認為任何新技術、任何新產品都會引發人們對安全性等方面的疑問，因為這些都是真正具有變革性和創新性的療法。在某種程度上，對某些人來說，這些問題只能隨著時間的推移和自身實踐經驗的累積才能得到解答。但可以肯定的是，我們看到所有利害關係人表現出了極高的熱情，我們非常樂觀地認為這將是一個價值數十億美元的商機。

The 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。

Just have a couple. Stuart, on the vanzacaftor triple, just curious on your updated view as to differentiation, obviously, beyond dosing. Just assuming that a patient is doing well on TRIKAFTA, would the argument be to switch, or I think you mentioned in the prepared remarks that patients have been -- have discontinued TRIKAFTA, what's the logic in them maybe responding to the new vanzacaftor triple? And then secondly, Charlie, or Reshma, you guys have almost $12 billion in cash, pretty good pipeline and no real urgent need for BD. So should we think about capital investments in areas that are probably in need of even more of a build-out, like gene or cell therapy? I'm just curious about uses of cash going forward?

就問幾個問題。 Stuart，關於vanzacaftor三合一療法，我很好奇你對差異化治療的最新看法，當然，除了劑量之外。假設患者服用TRIKAFTA效果良好，那麼是否應該考慮換藥？或者，我記得你在準備的發言稿中提到，有些病人已經停用TRIKAFTA，那麼他們為什麼可能對新的vanzacaftor三合一療法有反應呢？其次，Charlie或Reshma，你們有近120億美元的現金，研發管線也相當不錯，而且目前沒有迫切的業務拓展需求。那麼我們是否應該考慮對一些可能需要進一步發展的領域進行資本投資，例如基因療法或細胞療法？我只是好奇未來資金的用途。

Sure, Geoff. Let me ask Stuart to tackle vanzacaftor first, and then I'll ask Charlie to comment on capital allocation. Stuart?

當然，傑夫。我先請史都華處理vanzacaftor的問題，然後再請查理談談資本配置。史都華？

Geoff, So on vanzacaftor, just to remind everybody on the call, our goal in cystic fibrosis is to get as many people as possible to carrier levels of chloride transport as we can -- carrier levels of sweat chloride, pardon me, as we can because we believe if we can do that, we will essentially be able to prevent CF developing in people as we know it today. As you know, from our in vitro assays, but also from our clinical data with the vanzacaftor triple combination, we believe we can get to even higher levels than we've even been able to establish with TRIKAFTA which, as you know, sets a very, very high bar. And so the study that we have ongoing, both in 12-plus but also now 6 to 11 is aimed to do just that, to compare TRIKAFTA with vanzacaftor. And obviously, we' we're all looking forward to seeing the data when those studies read out.

傑夫，關於範扎卡夫托，我提醒一下各位，我們在囊性纖維化治療中的目標是盡可能讓更多患者的氯離子轉運達到載體水平——抱歉，我說的是汗液氯離子載體水平，因為我們相信，如果我們能做到這一點，就能從根本上預防囊性纖維化的發展。如你所知，從我們的體外試驗以及範扎卡夫托三聯療法的臨床數據來看，我們相信我們能夠達到比TRIKAFTA更高的水平，而TRIKAFTA的水平正如你們所知，已經非常非常高了。因此，我們正在進行一項研究，該研究不僅納入了12歲以上的患者，現在也納入了6至11歲的患者，其目的正是為了比較TRIKAFTA和範扎卡夫託的療效。顯然，我們都非常期待看到這些研究的結果。

As you identified, I think there's really going to be sort of 2 treatment opportunities for the vanzacaftor triple combination. If the efficacy is superior to what we see with TRIKAFTA, I think it's going to be a really exciting new treatment option, either for those people who are currently being treated with one of our existing CFTR modulators or for patients who have discontinued one of our CFTR modulators. And I said in my prepared remarks, globally, there are about 6,000 of those patients now.

正如您所指出的，我認為vanzacaftor三聯療法實際上將有兩種治療前景。如果它的療效優於TRIKAFTA，我認為它將成為一個非常令人振奮的新治療選擇，無論是對於目前正在接受我們現有CFTR調節劑治療的患者，還是對於已經停用我們現有CFTR調節劑的患者。我在事先準備好的演講稿中提到，目前全球約有6,000名這樣的病患。

Now your question is, well then why might they respond to vanzacaftor if they haven't responded to our other medicines. Actually, the major reason for discontinuation is not lack of efficacy, our products are amazingly efficacious in just about every patient, it tends to be for things like adverse events. And so I do think it's going to be an attractive treatment option for people to consider who may have discontinued one of our previous CFTR modulators. So obviously, the data will be very influential to all of this. We're looking forward to seeing that the studies are fully enrolled and ongoing. And so we're looking forward to seeing that data. But I do think vanza has the potential to be an even better treatment option for many patients even than TRIKAFTA is.

現在您的問題是，如果患者對我們其他藥物沒有反應，為什麼會對萬扎卡夫托（vanzacaftor）有反應？實際上，停藥的主要原因並非療效不佳——我們的產品對幾乎所有患者都非常有效——通常是由於不良反應等原因。因此，我認為對於那些可能已經停用我們先前CFTR調節劑的患者來說，萬扎卡夫托將是一個值得考慮的治療選擇。顯然，數據將對這一切產生非常重要的影響。我們期待看到研究順利完成招募並持續進行。因此，我們期待看到這些數據。但我確實認為，萬扎卡夫託有潛力成為許多患者比TRIKAFTA更好的治療選擇。

And then, Geoff, on capital allocation, no change at all in our strategy or priorities. Our priority continues to be investment in innovation, both internally and externally. You saw that we were active with BD in the first quarter. While it may be true that if you look back over the last 18 months or so, we've done a number of BD transactions in cell and gene therapy, I don't think you have to project forward that that's the only place we're focused. As you know, we've got a sandbox of disease areas, and we are modality agnostic and we'll do the deals that make sense for our program areas and fit our strategy. Lastly, I guess I would be remiss, just to point out, we do have an ongoing share buyback program as well. We've been at that for about 5 years or so. And that program continues to be a part of our capital allocation strategy.

傑夫，關於資本配置，我們的策略和優先事項沒有任何變化。我們的首要任務仍然是投資創新，包括內部和外部投資。您也看到了，我們在第一季積極開展業務拓展活動。雖然回顧過去18個月左右的時間，我們確實在細胞和基因治療領域完成了一些業務拓展交易，但我認為您不必就此斷定這是我們未來唯一的關注點。如您所知，我們涵蓋了多個疾病領域，我們對治療方式持開放態度，我們會進行那些符合我們專案領域和策略的交易。最後，我想我應該補充一點，我們還有一個持續進行的股票回購計畫。我們已經實施了大約5年。該計劃仍然是我們資本配置策略的一部分。

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

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

A few on VX-548 in acute pain. Can you talk a bit more about your target product profile? What level of (inaudible) do you want to achieve, with how many side effects? Then maybe as a follow-on to that, could you discuss the target patient population? Who would be the ideal patient for non-opioid option? And how many procedures per year, approximately, does that patient group have?

有些患者正在使用VX-548治療急性疼痛。能否詳細介紹一下您的目標產品特性？您希望達到怎樣的（聽不清楚）程度，以及預期的副作用？接下來，您能否談談目標患者群？哪些患者最適合使用非鴉片類藥物？該患者族群每年大約接受幾次治療？

Sure. Let me comment on the target product profile a bit, and then I'll ask Stuart to comment on the market size, both in terms of patient numbers and dollar potential. So Phil, if we recapitulate the results that we saw in Phase II, which you'll recall, is substantially similar to what we're doing in Phase III, that is to say, a study in abdominoplasty as a form of a soft tissue model, and bunionectomy as a form of a hard tissue pain model, that would be a home run for us. What I mean by that is efficacy, pain relief that's quick and durable, a benefit risk profile that is quite attractive, and by mechanism of action, that is to say the way 548 works is on the peripheral nervous system, not centrally, no addictive potential, that is an absolute home run. I'm going to ask Stuart to comment on market size in terms of dollars and patients. Stuart?

當然。我先簡單介紹一下目標產品概況，然後請Stuart談談市場規模，包括病患數量和潛在銷售額。 Phil，如果我們回顧一下二期臨床試驗的結果（您應該記得，這與我們正在進行的三期臨床試驗非常相似），也就是分別以腹部整形術（作為軟組織模型）和拇外翻切除術（作為硬組織疼痛模型）進行的研究，那對我們來說將是巨大的成功。我的意思是，療效顯著，能夠快速持久地緩解疼痛，獲益風險比也相當誘人，而且從作用機制來看，548的作用機制是作用於周圍神經系統而非中樞神經系統，沒有成癮性，這絕對是一次完美的成功。接下來，請Stuart談談市場規模，包括潛在銷售額和病患數量。 Stuart？

Yes. Thanks, Reshma. So the study program that we've got was to be designed, which Reshma just commented on, is designed to secure for us a label for moderate to severe acute pain. In contrast to a number of other relatively recent approvals in acute pain, which have been related to postsurgical pain and linked to certain procedure types, that's not the label we are seeking for. We are seeking a label for moderate to severe acute pain writ large. Could be post surgical and that's indeed the nature of our studies, but that is not the label we're seeking.

是的，謝謝，雷什瑪。正如雷什瑪剛才所提到的，我們正在設計的研究計畫旨在為我們爭取一個用於治療中度至重度急性疼痛的適應症。與近期核准的其他一些用於治療急性疼痛的藥物不同，這些藥物大多與術後疼痛相關，並限定於某些特定的手術類型，而我們尋求的適應症並非如此。我們尋求的適應症是更廣泛的中度至重度急性疼痛。術後疼痛也可能包含在內，這確實是我們研究的重點，但這並非我們最終尋求的適應症。

So we are not sizing the market based on the number of procedures or the number who's in surgery, it is for the broad treatment of acute pain which can't be controlled with kind of standard NSAIDs and things like that. When you look at that market opportunity in the U.S. alone, it's roughly 1.5 billion treatment days of medicine are utilized. And despite 90-plus percent of those prescriptions being generic, therefore, very, very cheap, it is a $4 billion market in the U.S. alone today. So we see a very, very significant commercial opportunity for VX-548 if it has the profile that Reshma described.

因此，我們並非根據手術數量或接受手術的患者人數來評估市場規模，而是著眼於廣泛治療無法用常規非類固醇抗發炎藥物等藥物控制的急性疼痛。光是在美國，這一市場就蘊藏著巨大的商機，每年大約需要15億個治療日的藥物。儘管其中90%以上的處方藥都是仿製藥，價格非常低廉，但光是在美國，這一市場如今的規模就高達40億美元。因此，如果VX-548具備Reshma所描述的特性，我們認為它將擁有非常巨大的商業潛力。

The next question will come from Michael Yee with Jefferies.

下一個問題將來自傑富瑞集團的邁克爾·伊。

Andrew Tsai on for Michael Yee. So I wanted to follow up on the acute and chronic pain study. So the first question we have is, do you think acute pain should have read-through to chronic pain and vice versa? And then second question for us is, for your Phase I CF program with Moderna, we understand this is a SAD data set coming up later this year. But just curious when we can expect to see longer-term that data? Is it possible that could come out later this year? Or should we be ruling out that scenario?

我是 Andrew Tsai，代替 Michael Yee。我想就急性疼痛和慢性疼痛研究進行後續探討。我們的第一個問題是，您認為急性疼痛的結果是否可以反映到慢性疼痛上，反之亦然？第二個問題是，關於您與 Moderna 合作的 I 期囊性纖維化 (CF) 項目，我們了解到今年稍後會公佈短期數據 (SAD)。但我們想知道何時才能看到更長期的數據？是否有可能在今年稍後公佈？或者我們應該排除這種可能性？

Sure. Let me take the mRNA question first, and then I'll come back around to pain. With regard to the program we have ongoing with Moderna, that's the VX-522 program. It is a program for the approximately last 5,000 patients or so who simply can't benefit from CFTR modulators. It is a SAD/MAD program with the SAD portion of it going on right now. When we did KALYDECO and TRIKAFTA, for example, our patients used to tell us that they knew from the first day that they were on placebo or active therapy. So I can't rule out when we will know whether we have efficacy. But in terms of time lines and what you can plan for, we expect to be done with the SAD this year, and we expect to be well into the MAD this year. So those are the time lines we're looking forward to.

當然。我先回答關於mRNA的問題，然後再談疼痛的問題。關於我們與Moderna公司正在進行的VX-522項目，這是一個針對大約最後5000名無法從CFTR調節劑中獲益的患者的項目。這是一個單次給藥/多次給藥（SAD/MAD）項目，目前正在進行SAD部分。例如，當我們進行KALYDECO和TRIKAFTA試驗時，我們的患者告訴我們，他們從第一天起就能分辨出自己接受的是安慰劑還是活性藥物。因此，我無法確定何時才能知道療效。但就時間安排和計劃而言，我們預計今年將完成SAD，並預計今年將進入MAD階段。這就是我們期待的時間安排。

With regard to the pain studies and what you could expect there, I don't really see read-through from acute to chronic neuropathic pain or vice versa. What I do see read-through is from the Phase II studies to Phase III. And I also see read-through from the NaV1.8 class, that is to say VX-150, which already showed efficacy in acute neuropathic and musculoskeletal. So as I look forward to the VX-548 pain study results and the VX-548 dose-ranging Phase II neuropathic range neuropathic study results, that's where I'm looking to for precedents, the Phase II program in 548 itself in acute pain, and the VX-150 program across the 3 pain types.

關於疼痛研究及其預期結果，我認為急性神經性疼痛和慢性神經性疼痛之間不太可能有直接關聯。我所看到的關聯是二期研究的結果可以推論到三期研究。此外，我也看到了NaV1.8類藥物（例如VX-150）的關聯，該藥物已顯示出對急性神經性疼痛和肌肉骨骼疼痛的療效。因此，我期待VX-548疼痛研究的結果，以及VX-548劑量範圍二期神經性疼痛研究的結果。我希望從中尋找先例：VX-548本身在急性疼痛方面的第二期研究，以及VX-150在三種疼痛類型中的研究。

The next question will come from Will Pickering with Bernstein.

下一個問題將由伯恩斯坦公司的威爾·皮克林提出。

Another one on pain. For the neuropathic pain study, could you talk about reasons to be optimistic that this drug will compare favorably to existing treatment options based on your experience with VX-150? And then very quickly on sickle cell and the CGT Access Model, how does the time line for that program compare to the expected launch time line for exa-cel?

關於疼痛問題。針對神經性疼痛研究，您能否根據您在VX-150方面的經驗，談談為什麼有理由樂觀地認為這種藥物與現有治療方案相比會更勝一籌？另外，關於鐮狀細胞貧血症和CGT准入模式，此計畫的進度安排與Exa-Cel的預期上市時間相比如何？

Sure. The first question on how do we think about VX-548 in neuropathic pain and what are our expectations. As I shared with you earlier, when we were waiting on the acute pain Phase II results, I had high expectations for the VX-548 program in general, and that extends to neuropathic pain. And the reasons for that are multifold, but here are 3 reasons. One, NaV1.8 as a target has often been called the holy grail in the pain setting because pain signals go through the NaV1.8 channel, and that's how these signals are propagated. So they are central to the perception of pain. That is for acute and that is the same for neuropathic. Two, VX-150, the predecessor molecule, already delivered positive proof of concept in neuropathic pain. That study had patients, the 150 study had patients with something called small fiber neuropathy, and it also had patients with diabetic neuropathy. That's the study we're doing now, diabetic neuropathy.

當然。第一個問題是關於我們如何看待VX-548在神經性疼痛中的應用，以及我們對此有何預期。正如我之前提到的，在我們等待急性疼痛II期臨床試驗結果時，我對VX-548項目整體抱有很高的期望，這同樣適用於神經性疼痛。原因有很多，這裡列舉三點。第一，NaV1.8作為靶點，常被譽為疼痛治療領域的“聖杯”，因為疼痛信號通過NaV1.8通道傳遞，這是這些信號傳播的方式。因此，NaV1.8通道在疼痛感知中扮演核心角色。無論是急性疼痛還是神經性疼痛，情況都是如此。第二，VX-548的前驅分子VX-150已經在神經性疼痛領域取得了積極的概念驗證。 VX-150的研究納入了患有小纖維神經病變和糖尿病性神經病變的患​​者。而我們目前正在進行的正是針對糖尿病性神經病變的研究。

And three, the VX-548 molecule is multifold, more potent and has better drug-like properties, which is why we went on to seek another molecule despite the success with 150. You put that all together and that sort of gives you a sense for why we have our high expectations for this. I think you had a second question on CGT. Let me ask Stuart to comment on that.

第三，VX-548 分子具有多重優勢，效力更強，且成藥性更好，這也是為什麼儘管 150 號分子取得了成功，我們仍然繼續尋找其他分子的原因。綜合以上幾點，您就能明白為什麼我們對它寄予厚望了。我想您還有關於 CGT 的第二個問題。我請 Stuart 對此進行說明。

Yes. Well, so on the CGT Access Model, I would consider this kind of complementary to our ongoing efforts with both government and commercial payers, secure access for exa-cel as close to approval as we possibly can. The model has only just been announced, and so it's obviously going to take a while for that to be fleshed out and then implemented. We're certainly not relying on that to be in place for a successful launch of exa-cel. As I said in my prepared remarks, we've been having extensive discussions with both government and commercial payers for the last few months, and we'll continue to up to and post the approval of exa-cel, and so we are working with them. We're not relying on the CDT Access Model for a successful launch. What I do think it is a signal of though, is just how important payers consider getting innovative therapies like exa-cel to these traditionally underserved patient populations. So to us, it's a real indicator of a groundswell of opinion that people want to get these transformative (inaudible) for a class that has been poorly treated in the past.

是的。關於CGT准入模式，我認為這可以作為我們與政府和商業支付方持續努力的補充，旨在盡可能在Exa-Cel獲批後儘快確保其准入。該模式剛剛公佈，顯然還需要一段時間才能完善並實施。我們當然不會依賴該模式來確保Exa-Cel的成功上市。正如我在準備好的演講稿中所說，過去幾個月我們一直在與政府和商業支付方進行廣泛的討論，我們將繼續與他們合作，直至Exa-Cel獲批後。我們不會依賴CGT准入模式來確保Exa-Cel的成功上市。但我認為這確實表明，支付方非常重視將Exa-Cel等創新療法提供給這些傳統上服務不足的患者群體。所以對我們來說，這真正表明了一種強烈的民意，即人們希望為過去受到不公平對待的群體帶來這些變革性的（聽不清楚）改變。

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。

I have a commercial question on VX-548. I believe the randomized Phase III trials have a primary analysis against placebo, but there's also an opioid comparator arm. How do you think about the commercial implications if the pain efficacy looks better or worse than the opioid arm?

我有一個關於VX-548的商業問題。我知道隨機III期臨床試驗的主要分析是與安慰劑組比較，但同時也有一個鴉片類藥物對照組。如果VX-548的止痛效果優於或劣於鴉片類藥物組，您認為這會對VX-548的商業影響為何？

Yes, this is Reshma. You're right about the study design. It is a study that has a primary endpoint of VX-548 versus placebo just like the Phase II study, and there is a secondary endpoint with regard to the opioid comparator arm. And you'll remember in the Phase II study, we also had an opioid arm, but in the Phase II program, given the reasonably efficient study design, it was not for comparison, but for context. But I will point you to the press release that we put out to give you if you want to get a sense for what the magnitude of the treatment effect was and how it compares. And I'll just say that it compares favorably,. Of course, it was not there for comparison. Let me turn it over to Stuart to comment on the commercial implications.

是的，我是雷什瑪。您對研究設計的說法是對的。這項研究的主要終點是VX-548與安慰劑的比較，就像第二期研究一樣，此外還有一個關於鴉片類藥物對照組的次要終點。您可能還記得，在二期研究中，我們也設置了一個阿片類藥物組，但由於二期研究的設計相當高效，它並非用於比較，而是為了提供背景資訊。如果您想了解治療效果的程度以及比較情況，我建議您參考我們發布的新聞稿。我只能說，它的效果令人滿意。當然，它並非用於比較。接下來，我請史都華談談這項研究的商業意義。

Yes. So Jessica, if you offered people today a medicine, which had opioid-like efficacy but without all of the associated baggage, including addictive potential, they would tell you that, that is a very, very attractive treatment option for them to be considering. If we were superior to an opioid, then probably that would be additionally beneficial and something that we would obviously be very pleased about. However, I don't want people to take away anything other than if you have opioid-like efficacy without the baggage, that is a very, very attractive treatment option. And I think that would be a very commercially successful option.

是的。傑西卡，如果你今天向人們提供一種藥物，它具有類似阿片類藥物的療效，但沒有所有相關的副作用，包括成癮性，他們會告訴你，這對他們來說是一個非常非常有吸引力的治療選擇。如果我們的藥物比鴉片類藥物更有效，那當然會更有益處，我們也會為此感到非常高興。但是，我只想讓大家明白，如果一種藥物具有類似鴉片類藥物的療效，卻沒有那些副作用，那它就是一個非常非常有吸引力的治療選擇。而且我認為這將是一個非常成功的商業選擇。

And if I could just seek a follow-up. Are there any side effects that we should be keeping an eye out for with this mechanism as we approach that Phase III readout?

我可否再問一個後續問題？在接近三期臨床試驗結果公佈時，這種機制有哪些副作用是我們應該密切關注的？

Jess, this is Reshma. If you look at the Phase II data, both in abdominoplasty and bunionectomy, the benefit risk profile looks very good. And when you look specifically at safety and tolerability, it compares very, very well to placebo. So a really good-looking side effect profile.

傑西，我是雷什瑪。如果你看一下二期臨床試驗數據，無論是腹部整形還是拇外翻切除術，其獲益風險比都非常理想。尤其是在安全性和耐受性方面，它與安慰劑相比也表現得非常好。所以，副作用情況看起來非常理想。

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。

Congrats on the quarter and all the progress. Maybe first on the pipeline and CRISPR-based DMD therapy. Could you give us any more color on the progress of the IND filing? And is it reasonable for us to expect any clinical data in 2024? And then second, on VX-880, what should we expect to see at ADA in terms of patient numbers and cohorts? And then just a follow-on from that, with regards to 264. Now the IND is cleared, could you give us any more color in terms of the materials or the design of the device?

恭喜本季取得的各項進展。首先，關於研發管線和基於 CRISPR 的 DMD 療法，您能否詳細介紹一下 IND 申請的進展？我們是否可以預期在 2024 年獲得臨床數據？其次，關於 VX-880，在 ADA 會議上，我們應該預期看到哪些患者數量和隊列數據？最後，關於 264，既然 IND 申請已經獲批，您能否詳細介紹一下該設備的材料或設計？

Sure. Colin, there were a couple of questions in there. Let me talk about the type 1 diabetes questions first, and then I'll come back around to DMD. With regard to the type 1 diabetes portfolio at Vertex, we really have 3 programs. The first is VX-880. That's the naked cell program that uses off-the-shelf immunosuppressive. That's the program that has completed, and I'm very pleased to share completed Part A and Part B, and that's the program where we're going to share the results at multiple congresses through the year, starting with ADA. What you should expect there is the full cohort of Part A and Part B patients, and you should expect that, that is to say, more patients' worth of data than we've previously shared and longer-term data, including some patients that are out more than a year.

當然。科林，剛才有幾個問題。我先來談談第1型糖尿病的問題，然後再談杜氏肌肉營養不良症（DMD）。關於Vertex的第一型糖尿病產品組合，我們實際上有三個項目。第一個是VX-880。這是一個使用現成免疫抑制劑的裸細胞計畫。這個項目已經完成，我很高興地宣布A部分和B部分都已完成。我們將在今年的多個會議上分享該專案的結果，首先是ADA年會。屆時，您將看到A部分和B部分的全部患者數據，也就是說，我們將分享比之前更多的患者數據，以及更長期的追蹤數據，包括一些追蹤超過一年的患者數據。

Those same cells, the VX-880 cells, are the foundation for Program 2, which is the cells plus device program, and those same cells are the foundation for Program 3, which is the hypoimmune program. And that's really important because, as you know, there are 2 parts to this. The first is having cells that are fully differentiated and insulin producing. We've got that. And the second is how to evade the immune system. In the 264 program, we evade the immune system with a device. I'm not going to share any more details than we have in the past. But I will say that it's a proprietary device that has a particular material, geometry and structure that allows for oxygenation and nutrient transport as well as sensing of glucose and release of insulin without worry of the immune system coming into the cells, and from what we've seen to date in large animal models and small, no fibrosis. And of course, the third is the cells with the edits so that the edited cells evade the immune system.

這些VX-880細胞是第二階段（細胞加裝置階段）的基礎，也是第三階段（低免疫階段）的基礎。這一點至關重要，因為正如您所知，該階段包含兩個部分。第一部分是獲得完全分化且能產生胰島素的細胞。我們已經實現了這一點。第二部分是如何逃避免疫系統的攻擊。在264階段，我們使用一種裝置來逃避免疫系統的攻擊。我不會透露比過去更多的細節。但我可以透露的是，這是一種專有裝置，它採用特殊的材料、幾何形狀和結構，能夠在不引起免疫系統攻擊的情況下，實現氧合作用和營養物質的運輸，以及葡萄糖的感知和胰島素的釋放。根據我們目前在大型動物模型和小型動物模型中的觀察，沒有出現纖維化現象。當然，第三部分是對細胞進行基因編輯，使這些編輯後的細胞能夠逃避免疫系統的攻擊。

With regard to when we can see data from VX-264, we haven't guided to that, but we are very pleased with the clearance of the CTA and IND and we expect the trial to start dosing patients in the near future. With regard to the DMD program, you'll recall that our approach is different than the approach being taken by many in the field. That is to say our approach is grounded in human genetics, and what we see is that if you have near full-length or full-length dystrophin, which is the goal of our program, you have a very mild version of the disease. There is no such human genetic validation for an approach using microdystrophin. We're excited about the program. It is in its IND-enabling studies, and we are on track to complete those studies and get the IND filed towards the second half of this year.

關於何時能看到VX-264的數據，我們目前還沒有給出具體時間，但我們對臨床試驗申請（CTA）和新藥臨床試驗申請（IND）的獲批感到非常滿意，並預計該試驗將在不久的將來開始對患者進行給藥。關於杜氏肌肉營養不良症（DMD）項目，您可能還記得，我們​​的方法與該領域許多其他研究者的方法有所不同。也就是說，我們的方法是基於人類遺傳學，我們發現，如果患者擁有接近全長或全長的肌肉營養不良蛋白（這也是我們計畫的目標），那麼他們的疾病症狀會非常輕微。目前，使用微型肌肉營養不良蛋白的方法尚無此類人類遺傳學驗證。我們對該專案充滿信心。它目前正處於IND申報前的準備階段，我們正按計劃推進，預計在今年下半年完成這些研究並提交IND申請。

Thanks, Colin. Just that brings us to time. So can you wrap it up, please?

謝謝，科林。這就說到時間了。那麼，你能總結一下嗎？

Yes, ma'am. That will conclude our question-and-answer session as well as our conference call for today. A replay of today's event will be available shortly after the call concludes by dialing 1 (877) 344-7529 or 1 (412) 317-0088 and you can use the replay access code 8384718. Everyone, have a great day.

是的，女士。今天的問答環節和電話會議到此結束。會議結束後不久，您可以撥打 1 (877) 344-7529 或 1 (412) 317-0088 收聽會議錄音，錄音回放的存取碼為 8384718。祝大家今天愉快。