福泰製藥 (VRTX) 2023 Q3 法說會逐字稿

Good day, and welcome to the Vertex Pharmaceuticals Third Quarter 2023 Conference Call.

大家好，歡迎參加 Vertex Pharmaceuticals 2023 年第三季電話會議。

(Operator Instructions) Please note this event is being recorded.

（操作說明）請注意，本次活動正在錄影。

I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead, ma'am.

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 as the Senior Vice President of Investor Relations, it is my pleasure to welcome you to our Third 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年第三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' future financial performance are based on management's current assumptions. Actual outcomes and events could differ materially.

我們將在本次電話會議上發表前瞻性聲明，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。

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.

我還想指出，今晚電話會議上我們將要討論的部分財務表現和指引是以非公認會計準則（non-GAAP）編制的。此外，外匯影響的列示已包含我們的外匯風險管理計畫。

I'll now turn the call over to Reshma.

現在我將把電話交給雷什瑪。

Thanks, Susie. Good evening all, and thank you for joining us on the call today. We've delivered another strong quarter and continue to drive execution across the company.

謝謝蘇西。各位晚上好，感謝大家今天參加我們的電話會議。我們又完成了一個強勁的季度，並將繼續在全公司範圍內推進各項工作的執行。

By reaching more CF patients, third quarter global product revenue grew 6% versus the prior year period, and we are raising full year 2023 CF product revenue guidance to approximately $9.85 billion. We are delivering on our marketed medicines in CF while simultaneously preparing for commercial excellence in multiple areas ahead of our potential near-term launches, including exa-cel in both severe sickle cell disease and transfusion-dependent beta thalassemia. VX-548 for acute pain and longer term in peripheral neuropathic pain and our vanzacaftor triple combination therapy for cystic fibrosis.

由於惠及更多囊性纖維化（CF）患者，第三季全球產品營收年增6%，我們將2023年全年CF產品營收預期上調至約98.5億美元。我們正全力推動已上市CF藥物的研發，同時也為近期可能推出的多個領域的商業化做好準備，包括用於治療重度鐮狀細胞病和輸血依賴型β地中海貧血的exa-cel，用於治療急性疼痛和長期治療周圍神經性疼痛的VX-548，以及用於治療囊性纖維化的vanzacaftor三聯療法。

Most notably, we are tracking towards an exa-cel PDUFA date for sickle cell disease on December 8 of this year and for TDT on March 30 of next year, with global regulatory reviews also underway in Europe and the U.K. Phase III pivotal trial readouts in early 2024, from both our vanzacaftor triple in CF and our VX-548 program in acute pain. A Phase II trial readout by year-end 2023 from our VX-548 trial in diabetic peripheral neuropathy and completion of enrollment in the Phase II portion of the VX-147, Phase II/III program in AMKD later this year.

最值得關注的是，我們正朝著今年12月8日獲得exa-cel治療鐮狀細胞疾病的PDUFA批准日期以及明年3月30日獲得TDT的PDUFA批准日期穩步邁進，同時，歐洲和英國的全球監管審查也在進行中。我們計劃在2024年初公佈vanzacaftor三合一療法治療囊性纖維化和VX-548治療急性疼痛的III期關鍵性試驗結果。此外，我們計劃在2023年底前公佈VX-548治療糖尿病週邊神經病變的II期試驗結果，並於今年稍後完成VX-147治療急性髓系白血病（AMKD）的II/III期臨床試驗的II期部分患者招募。

With that overview, let me now turn to a pipeline update. Starting with cystic fibrosis. For our next-in-class vanzacaftor triple combination therapy, we remain on track to complete all 3 Phase III studies, SKYLINE 102 and 103 in patients ages 12 years and above, and the RIDGELINE study in patients ages 6 to 11 by the end of 2023 and share results from these 3 pivotal studies in early 2024.

概述完畢，現在讓我來介紹一下產品線的最新進展。首先是囊性纖維化。對於我們下一代同類產品vanzacaftor三合療法，我們仍按計劃推進，將於2023年底前完成全部三項III期臨床試驗，包括針對12歲及以上患者的SKYLINE 102和103研究，以及針對6至11歲患者的RIDGELINE研究，並於2024年初公佈這三項關鍵性研究的結果。

We have high expectations that the vanzacaftor triple combination can deliver greater improvements in CFTR function than TRIKAFTA based upon the totality of evidence generated to date, including in vitro from our HBE assays and in Phase II studies. The vanzacaftor triple holds the potential for enhanced clinical benefit versus TRIKAFTA for patients and the convenience of once-daily dosing. It also carries a substantially lower royalty burden.

基於迄今為止所獲得的所有證據，包括我們體外HBE檢測和II期臨床研究的結果，我們對vanzacaftor三聯療法在改善CFTR功能方面比TRIKAFTA療法抱有很高的期望。 vanzacaftor三重療法可望為患者帶來比TRIKAFTA療法更顯著的臨床效益，每日一次給藥也更為便捷。此外，它的專利使用費也顯著降低。

In addition, we continue to make progress with another important program in our CF portfolio, VX-522, and -- our CFTR mRNA therapy in development with our partners at Moderna for the more than 5,000 CF patients who cannot benefit from CFTR modulators. We continue to expect to complete the single ascending dose portion and initiate the multiple ascending dose portion of this study by the end of the year.

此外，我們在囊性纖維化（CF）產品組合中的另一個重要項目VX-522以及與Moderna合作開發的CFTR mRNA療法方面也持續取得進展。該療法旨在為超過5000名無法從CFTR調節劑中獲益的CF患者提供治療。我們預計在年底前完成研究的單次遞增劑量部分，並啟動多次遞增劑量部分。

Turning now to exa-cel. Our CRISPR/Cas9-based gene editing program for sickle cell disease and transfusion-dependent beta thalassemia. This program holds the potential to be a onetime functional cure for these debilitating and life-shortening diseases. Exa-cel represents an enormous advancement for the estimated 32,000 people living with severe sickle cell disease and transfusion-dependent beta thalassemia across the U.S. and Europe. It is a large commercial opportunity.

現在我們來談談exa-cel。這是我們基於CRISPR/Cas9技術的基因編輯項目，旨在治療鐮狀細胞貧血症和輸血依賴型β地中海貧血。該計畫預計將一次性治癒這些致殘且縮短壽命的疾病。 Exa-cel的出現，對於美國和歐洲約32,000名患有重度鐮狀細胞貧血症和輸血依賴型β地中海貧血的患者而言，無疑是一項巨大的進步。它蘊藏著巨大的商業機會。

On the regulatory front, in the U.S., we were very pleased to have had the chance to discuss the exa-cel filing with members of the FDA Advisory Committee last week, and to hear the very compelling stories from patients. The meeting represented a significant milestone for Vertex and the first potential CRISPR/Cas9-based therapeutic. We look forward to our upcoming PDUFA dates and to the potential of bringing this precise, durable gene-editing therapy to patients. Internationally, in both the U.K. and the EU, we are also well into the regulatory review process and expect regulatory decisions in these jurisdictions in the coming months.

在監管方面，我們非常高興上周有機會與美國食品藥品監督管理局（FDA）諮詢委員會成員討論了exa-cel的申請，並聆聽了患者的感人故事。這次會議對Vertex公司以及首個潛在的基於CRISPR/Cas9技術的療法而言，都是一個重要的里程碑。我們期待即將到來的PDUFA審批日期，並期待將這種精準、持久的基因編輯療法帶給患者。在國際方面，我們在英國和歐盟的監管審查流程也進展順利，預計在未來幾個月內獲得這些地區的監管決定。

In addition, we recently submitted a marketing authorization application for exa-cel to the Saudi Food and Drug Authority or SFDA. I am pleased to share that exa-cel is the first medicine ever to receive breakthrough designation by the SFDA, reflecting both the high unmet need and the high enthusiasm for exa-cel in the Kingdom of Saudi Arabia. We look forward to updating you in the coming months.

此外，我們近期已向沙烏地阿拉伯食品藥物管理局（SFDA）提交了exa-cel的上市許可申請。我很高興地告訴大家，exa-cel是首個獲得SFDA突破性療法認定的藥物，這不僅反映了沙烏地阿拉伯王國巨大的未滿足醫療需求，也體現了市場對exa-cel的高度期待。我們期待在未來幾個月內向您報告最新進展。

Moving on to the pain program and VX-548, our novel, highly selective NaV1.8 inhibitor that holds the promise for effective pain relief without the side effects or addictive properties of opioids and, therefore, represents a significant commercial opportunity in both acute and neuropathic pain. The pace of the Phase III program in acute pain has been rapid, which we see as an indication of the high unmet need, and strong patient and physician interest in an efficacious non-opioid acute pain therapy.

接下來談談疼痛治療計畫和VX-548，這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，因此在急性疼痛和神經性疼痛領域都具有巨大的商業潛力。急性疼痛III期臨床試驗進展迅速，顯示市場存在巨大的未滿足需求，患者和醫生對有效的非鴉片類急性疼痛療法表現出濃厚的興趣。

We have completed the randomized controlled trial in abdominoplasty, the RCT in bunionectomy and a single-arm safety and efficacy study remain on track to complete by the end of this year. As previously discussed, we will unblind, analyze and share results on all 3 studies at the same time, and we expect to do so in early 2024.

我們已完成腹部整形術的隨機對照試驗，拇趾外翻切除術的隨機對照試驗以及一項單臂安全性和有效性研究也正按計劃進行，預計將於今年年底前完成。如前所述，我們將同時揭盲、分析並公佈這三項研究的結果，預計在2024年初完成。

This comprehensive Phase III program has been designed to support a broad, moderate-to-severe acute pain label and to enable prescribing and usage across multiple care settings. We're also studying VX-548 in peripheral neuropathic pain or PNP, yet another area of high unmet need. Recall, we previously demonstrated positive proof-of-concept with the predecessor molecule VX-150 in neuropathic pain.

這項全面的III期臨床試驗旨在支持VX-548獲準用於治療中重度急性疼痛，並使其能夠在多種醫療環境中進行處方和使用。我們也正在研究VX-548在周邊神經性疼痛（PNP）的應用，這是另一個亟待解決的重大醫療需求領域。回顧一下，我們之前已透過其前驅分子VX-150在神經性疼痛方面證實了其積極的概念驗證。

In diabetic peripheral neuropathy or DPN, I am pleased to share that we have completed our Phase II 12-week dose-ranging proof-of-concept study. We anticipate sharing the results from this Phase II trial by the end of this year. As we await the DPN results, we are excited to initiate a second Phase II peripheral neuropathic pain study of VX-548 by the end of the year in lumbosacral radiculopathy or LSR. It's a type of neuropathic pain caused by the impairment of nerve roots in the area of the lumbar spine.

我很高興地宣布，在糖尿病週邊神經病變（DPN）領域，我們已完成為期12週的II期劑量範圍概念驗證研究。我們預計今年底公佈該II期試驗的結果。在等待DPN試驗結果的同時，我們也欣喜地宣布，將於今年底啟動VX-548治療腰骶神經根病變（LSR）的第二項II期週邊神經性疼痛研究。腰薦神經根病變是一種由腰椎區域神經根受損引起的神經性疼痛。

Given the limited therapeutic options, the significant opportunity to serve a large number of patients and the promise that the NaV1.8 mechanism holds, we are excited to pursue the potential of VX-548 in each of these neuropathic pain types.

鑑於治療選擇有限，為大量患者提供服務的巨大機會以及 NaV1.8 機制所蘊含的前景，我們很高興能夠探索 VX-548 在每種神經性疼痛類型中的潛力。

Next, on to type 1 diabetes, where we are evaluating stem cell-derived fully differentiated insulin-producing islet cells for people with type 1 diabetes. Our goal is to develop a potential onetime functional cure for the millions of people living with type 1 diabetes, including the more than 2.5 million patients in North America and Europe alone. The VX-880 or naked cell program, where we have already established proof-of-concept, is foundational to the type 1 diabetes program as a whole. Here, patients take standard immunosuppressants to protect the islet cells from the immune system.

接下來，我們將目光轉向第1型糖尿病，我們正在評估幹細胞衍生的完全分化的胰島素分泌胰島細胞對第1型糖尿病患者的療效。我們的目標是為數百萬1型糖尿病患者開發一種潛在的一次性功能性治癒方案，光是北美和歐洲就有超過250萬名患者。 VX-880（裸細胞）計畫是整個第1型糖尿病治療計畫的基礎，我們已經完成了概念驗證。在這個計畫中，患者需要服用標準的免疫抑制劑來保護胰島細胞免受免疫系統的攻擊。

At EASD last month, we presented positive updated clinical data from all patients in Parts A and B of the VX-880 study. With regard to study status, Part C of the study, which administers the full target dose with concurrent dosing is now fully enrolled. Our second program, VX-264, or the cells plus device program encapsulates these same cells in a proprietary immunoprotective device. And hence, there is no requirement for immunosuppressants. We have begun enrollment in dosing in Part A of the VX-264 study.

上個月的EASD會議上，我們公佈了VX-880研究A部分和B部分所有患者的最新積極臨床數據。關於研究進展，C部分（以同步給藥方式給予全劑量目標劑量）目前已完成全部入組。我們的第二個項目VX-264，即細胞+裝置項目，將這些相同的細胞封裝在專有的免疫保護裝置中。因此，無需使用免疫抑制劑。我們已開始VX-264研究A部分的給藥入組。

And finally, our third program, still in the research stage, is our hypoimmune cells, in which we added the same fully differentiated cells so as to obviate the need for immunosuppressants. Transitioning now to inaxaplin or VX-147, the first potential medicine to target the underlying cause of APOL1-mediated kidney disease or AMKD. The inaxaplin pivotal program for patients with AMKD is a single adaptive Phase II/III study with a pathway to accelerated approval in the U.S. The Phase IIb dose-ranging portion of the study continues to enroll in dose patients, and we expect to complete enrollment by the end of this year. We now expect to select a dose and move to Phase III of the study in Q1 of 2024.

最後，我們的第三個項目仍處於研究階段，即低免疫細胞療法。在該療法中我們添加了相同的完全分化細胞，從而避免了使用免疫抑制劑。接下來，我們將重點介紹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。 inaxaplin針對AMKD患者的關鍵性研究是一項適應性II/III期臨床試驗，旨在獲得美國加速審批。研究的IIb期劑量探索部分仍在招募不同劑量組的患者，預計今年底完成招募。我們預計在2024年第一季確定劑量並進入III期臨床試驗。

Now turning to alpha-1 antitrypsin deficiency or AATD. We have discontinued development of VX-864 due to non-serious rash events in some patients in the Phase II program. Our next-generation molecules VX-634 and VX-668 both have greater potency and better drug-like properties, and are both in Phase I clinical trials. These trials continue to enroll and dose healthy volunteers. We look forward to sharing more on AATD, including next steps as we learn more in the coming months.

現在我們來談談α1-抗胰蛋白酶缺乏症（AATD）。由於部分患者在II期臨床試驗中出現非嚴重皮疹，我們已停止VX-864的研發。我們的下一代分子VX-634和VX-668均具有更高的效力和較好的成藥性，目前均處於I期臨床試驗階段。這些試驗仍在繼續招募健康志願者並進行給藥。我們期待在未來幾個月內，隨著對AATD了解的深入，與大家分享更多相關信息，包括後續步驟。

With that, I'll turn it over to Stuart.

這樣，我就把麥克風交給史都華了。

Thanks, Reshma. I will focus my remarks tonight on CF, exa-cel and pain. We delivered strong third quarter commercial results with CF product revenue growing 6% globally versus the prior year as we continue to reach patients in younger age groups as a result of new regulatory approvals and via new reimbursement agreements.

謝謝，雷什瑪。今晚我的演講將重點放在囊性纖維化（CF）、Exa-Cel 和疼痛治療。我們第三季取得了強勁的商業業績，囊性纖維化產品收入在全球範圍內同比增長 6%，這得益於我們不斷獲得新的監管批准以及通過新的醫保報銷協議，持續拓展年輕患者群體。

Our strategy in CF has always been to develop medicines for all people living with CF and to serially innovate to deliver increased clinical benefit. We will continue to execute near term with a focus on younger age groups. And then our goal is to drive growth over the medium term with the vanzacaftor triple combination and longer term with our mRNA program, VX-522 that we are developing in partnership with Moderna.

我們在囊性纖維化領域的策略始終是為所有囊性纖維化患者研發藥物，並不斷創新以提升臨床療效。我們將繼續推進近期策略，重點關注年輕患者群。中期目標是透過vanzacaftor三聯療法推動成長，長期目標是透過與Moderna合作開發的mRNA計畫VX-522來實現成長。

Now turning to exa-cel, our next targeted launch and potential multibillion-dollar opportunity. This quarter, I will provide some insights as to launch readiness ahead of potential near-term regulatory approvals and then detail the patient journey. In the U.S. and Europe, we've previously highlighted that there are approximately 32,000 eligible patients with severe disease, 25,000 with sickle cell disease and 7,000 with beta thalassemia.

現在讓我們來談談exa-cel，這是我們下一個重點推廣的產品，也是一個潛在的數十億美元市場。本季度，我將就產品上市前的準備情況，以及可能在近期獲得監管部門批准的情況，提供一些見解，並詳細介紹患者的治療歷程。先前我們曾指出，在美國和歐洲，約有32,000名符合條件的重症患者、25,000名鐮狀細胞貧血患者和7,000名β地中海貧血患者。

The majority of sickle cell disease patients are in the U.S., while the majority of TDT patients are in Europe. Within Europe, approximately 75% of all eligible patients live in 4 countries: the U.K., France, Italy and Germany. Italy has by far the highest prevalence of eligible TDT patients, while France and the U.K. represent the majority of eligible patients with sickle cell disease.

鐮狀細胞疾病患者主要集中在美國，而TDT患者則主要集中在歐洲。在歐洲，約75%的符合條件的患者居住在四個國家：英國、法國、義大利和德國。義大利符合TDT條件的患者比例最高，而法國和英國則佔鐮狀細胞疾病符合條件患者的大多數。

In the U.S. and Europe, we are on track with our globally enabled supply network and launch preparations with authorized treatment centers and payers, including our recently completed application for a new technology add-on payment or NTAP, for Medicare patients in the U.S.

在美國和歐洲，我們正按計劃推進全球供應網絡和與授權治療中心和支付方的啟動準備工作，包括我們最近完成的針對美國醫療保險患者的新技術附加支付（NTAP）申請。

In addition, Reshma mentioned our exa-cel MAA submission in the Kingdom of Saudi Arabia or KSA. Our team is engaging with the Saudi health authorities and working on the processes to support ATC activation, access and reimbursement with the aim of bringing exa-cel to the thousands of patients with severe disease in KSA. We look forward to providing you with more information on future calls about this important additional opportunity.

此外，Reshma也提到了我們在沙烏地阿拉伯王國（KSA）提交的exa-cel上市許可申請（MAA）。我們的團隊正與沙烏地阿拉伯衛生部門積極溝通，並致力於推進相關流​​程，以支持ATC的活化、准入和報銷，旨在讓沙烏地阿拉伯王國成千上萬的重症患者能夠使用exa-cel。我們期待在未來的電話會議上與您分享更多關於這項重要機會的資訊。

As we prepare for approval and launch, it is important to understand the exa-cel patient journey, which can be broken down into 3 key phases, each of which can take several months. First, pretreatment. Initially, when a potential exa-cel patient and their hematologist decide the therapy is right for them, the patient is then referred to a transplant physician at an ATC. Once that referral is scheduled, the patient then undergoes a full workup to determine whether they are fit for treatment with exa-cel.

在準備審批和上市之際，了解 exa-cel 患者的治療歷程至關重要。此歷程可分為三個關鍵階段，每個階段可能持續數月。首先是預處理階段。最初，當潛在的 exa-cel 患者及其血液科醫生確定該療法適合患者時，患者將被轉診至移植中心 (ATC) 的移植醫生處。轉診安排妥當後，患者將接受全面的評估，以確定是否適合接受 exa-cel 治療。

Second, cell collection and manufacturing. This phase involves mobilization to move the blood stem cells from the bone marrow into the peripheral blood, where the cells can be collected through apheresis. The patient cells are then sent to our manufacturing facilities where they are edited and then tested for quality control. Cell collection takes longer for sickle cell disease patients given the need for 2 months of red blood cell transfusions prior to mobilization. And on average, 2 rounds of mobilization in apheresis. In contrast, TDT patients do not require premobilization transfusions and typically only require 1 round of mobilization in apheresis.

第二階段是細胞採集和製備。此階段包括動員，將造血幹細胞從骨髓轉移到週邊血，然後透過血球分離術採集細胞。採集到的患者細胞隨後被送往我們的製備中心進行編輯，並進行品質控制檢測。由於鐮狀細胞貧血症患者在動員前需要接受兩個月的紅血球輸注，因此他們的細胞採集時間更長。平均而言，鐮狀細胞貧血症患者需要進行兩輪血球分離術動員。相較之下，TDT 患者無需動員前輸血，通常只需進行一輪血球分離術動員。

The final phase is treatment. Once the edited cells are ready, the patient starts the treatment phase, which includes myeloablative conditioning, infusion of the edited cells at which point we will recognize revenue for the therapy, and then waiting for engraftment and post-infusion care. A critical timing factor in this phase is the patient's preferred timing for treatment as they must choose a time that works best for their lives given that this step involves an approximate 1-month hospital stay. This patient journey is consistent across all geographies.

最後階段是治療。一旦編輯後的細胞準備就緒，患者便開始接受治療，包括清髓性預處理、輸注編輯後的細胞（此時我們將確認治療收入），以及等待細胞植入和輸注後護理。此階段的關鍵時間因素在於患者對治療時間的偏好，因為考慮到此步驟需要約一個月的住院治療，患者必須選擇最適合自身生活的時間。所有地區的患者治療流程均相同。

Given the multiple steps and the duration of the journey, we expect 2024 to be a foundational year for exa-cel as the first patients begin this journey, and Vertex works to deliver transformative patient outcomes with the possibility of a lifetime of benefit.

鑑於該療法涉及多個步驟且療程較長，我們預計 2024 年將是 exa-cel 的奠基之年，因為首批患者將開始這段旅程，而 Vertex 將致力於為患者帶來變革性的治療效果，並有可能使患者終身受益。

Shifting now to VX-548, our highly selective NaV1.8 inhibitor for pain. Given the program's rapid pace of clinical advancement, we have developed our go-to-market strategies and are actively planning for a potential near-term launch. I'd like to share an outline of some of the work we've done to size each market opportunity.

現在我們來談談VX-548，這是一種高選擇性的NaV1.8抑制劑，用於治療疼痛。鑑於該計畫臨床進展迅速，我們已經制定了市場推廣策略，並正在積極籌備近期上市。我想簡要介紹一下我們為評估各個市場機會所做的一些工作。

Overall, the pain opportunity is massive. In the U.S. alone, each year, more than 90 million patients are treated for acute or peripheral neuropathic pain. Both acute and PNP are each multibillion-dollar markets today despite the fact that essentially all prescriptions are generic, and we see additional upside to these opportunities given the challenges of currently approved treatments. The unmet need in pain stems from the suboptimal benefit/risk profiles of existing agents such as the adverse effects and addiction potential of opioids and the lack of consistent efficacy for anticonvulsants like the gabapentinoids prescribed for neuropathic pain.

整體而言，疼痛治療市場潛力巨大。光是在美國，每年就有超過9000萬名患者接受急性或週邊神經性疼痛的治療。儘管幾乎所有處方藥都是仿製藥，但急性疼痛和周邊神經性疼痛如今都已成為數十億美元的市場。鑑於目前已獲批准的治療方法仍面臨許多挑戰，我們認為這些市場還有更大的成長空間。疼痛治療領域未被滿足的需求源自於現有藥物的療效/風險比不佳，例如鴉片類藥物的不良反應和成癮性，以及用於治療神經性疼痛的抗驚厥藥物（如加巴噴丁類藥物）療效不穩定。

We believe the innovation of VX-548 and its overall profile could provide a transformative option for millions of patients. In acute pain, we estimate approximately 80 million patients are prescribed a medicine for their moderate to severe acute pain every year in the U.S. More than 2/3 of patients receive acute pain treatment driven by an institution, either during a hospital or ambulatory surgery center visit or at discharge. As hospital-driven prescribing is concentrated amongst some 2,000 hospitals and 200 IDNs, we can reach a large proportion of the patient opportunity with a specialty sales force.

我們相信，VX-548 的創新性及其整體優勢將為數百萬患者帶來變革性的治療選擇。據估計，美國每年約有 8,000 萬中度至重度急性疼痛患者接受藥物治療。超過三分之二的患者在醫療機構的指導下接受急性疼痛治療​​，無論是在住院期間、門診手術中心就診時或出院時。由於醫院主導的處方主要集中在約 2000 家醫院和 200 個整合醫療網路 (IDN) 中，我們可以透過專業的銷售團隊接觸大部分潛在患者群體。

As Reshma mentioned, the peripheral neuropathic pain study in DPN is completed and the LSR study is about to begin. PNP is an exciting commercial opportunity given that approximately 10 million patients are prescribed in medicine for a PNP condition every year in the U.S. with chronic dosing but limited treatment options. PNP fits our Vertex specialty model perfectly. PNP is a collection of chronic conditions in which nerve impairment causes pain.

正如Reshma所提到的，DPN的周邊神經性疼痛研究已經完成，LSR研究即將開始。 PNP是一個令人振奮的商業機會，因為在美國，每年約有1000萬名患者因PNP接受長期用藥，但治療選擇有限。 PNP與我們的Vertex專科模式完美契合。 PNP是一系列由神經損傷引起的慢性疼痛疾病的總稱。

DPN and LSR are 2 of the largest patient segments. LSR represents over 40% of all PNP patients, while DPN represents approximately 20% of all PNP patients. Specialists play a critical role in treating PNP as patients can be on multiple treatments and are often in search of more effective pain control given the limited therapeutic options. Therefore, we believe the PNP segment is addressable with a specialty sales force and we look forward to bringing innovation to PNP patients.

糖尿病週邊神經病變 (DPN) 和腰椎間盤突出 (LSR) 是兩大主要患者群。 LSR 佔所有周邊神經病變 (PNP) 患者的 40% 以上，而 DPN 約佔所有 PNP 患者的 20%。由於 PNP 患者可能需要接受多種治療，鑑於治療選擇有限，他們往往尋求更有效的疼痛控制方法，因此專科醫​​生在 PNP 的治療中發揮著至關重要的作用。因此，我們認為可以透過組建專業的銷售團隊來拓展 PNP 患者群體，並期待為 PNP 患者帶來創新療法。

In conclusion, it's an exciting time at Vertex. We continue to make progress treating more CF patients and are on the verge of bringing a potential functional cure to patients with sickle cell disease or beta thalassemia with exa-cel. We're also preparing for multiple additional near-term launches, including the vanzacaftor triple in CF and VX-548 in acute pain, both of which have the potential to dramatically improve patients' lives and represent significant market opportunities for Vertex.

總之，Vertex正處於令人興奮的發展階段。我們在治療更多囊性纖維化（CF）患者方面持續取得進展，並且即將推出exa-cel，為鐮狀細胞疾病或β地中海貧血患者帶來潛在的功能性治癒方案。此外，我們也正在積極籌備近期多項新藥上市，包括用於治療CF的vanzacaftor三聯療法和用於治療急性疼痛的VX-548，這兩項療法都有望顯著改善患者的生活質量，並為Vertex帶來巨大的市場機會。

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 excellent results in the third quarter of 2023 demonstrate once again our consistent strong performance and attractive growth profile. Third quarter 2023 revenue increased 6% year-over-year to $2.48 billion. U.S. revenue grew 7% year-over-year following the recent FDA approval of TRIKAFTA in patients ages 2 to 5 and outside the U.S., revenue grew 6% year-over-year on continued strong uptake of TRIKAFTA/KAFTRIO in markets with recently achieved reimbursement as well as label extensions in younger age groups.

謝謝，斯圖爾特。 Vertex 2023年第三季的出色業績再次證明了我們一貫強勁的業績表現和極具吸引力的成長前景。 2023年第三季營收年增6%，達24.8億美元。在美國，由於近期FDA批准TRIKAFTA用於2至5歲患者，營收年增7%；在美國以外，由於TRIKAFTA/KAFTRIO在近期獲得醫保報銷的市場以及針對更年輕年齡組的適應症擴展，營收同比增長6%。

As anticipated, in Q3, we saw the drawdown of inventory in certain international markets in contrast to the increases in inventory that we experienced in the first half of the year. Year-to-date revenue of $7.35 billion represents 11% growth over the corresponding prior year period, including an approximate 150 basis point headwind from changes in foreign currency.

如預期，第三季我們在部分國際市場的庫存有所下降，這與上半年庫存增加的情況形成鮮明對比。今年迄今的營收為73.5億美元，較去年同期成長11%，其中包括約150個基點的匯率波動帶來的不利影響。

Overall, the primary drivers of revenue growth in 2023 have been in line with our expectations. Third quarter 2023 combined non-GAAP R&D, acquired IPR&D and SG&A expenses were $993 million compared to $758 million in the third quarter of '22. Q3 2023 results include $52 million of acquired IPR&D charges compared to $29 million of such charges in the third quarter of 2022.

整體而言，2023年營收成長的主要驅動因素符合我們的預期。 2023年第三季非GAAP研發、收購智慧財產權開發及銷售、管理及行政費用合計為9.93億美元，而2022年第三季為7.58億美元。 2023年第三季業績包含5,200萬美元的收購智慧財產權開發費用，而2022年第三季該項費用為2,900萬美元。

Operating expense growth was driven as expected by continued investment in research and our pipeline. Throughout 2023, the most significant areas of increased investment versus prior year included the clinical studies for VX-548 in acute pain, the vanzacaftor triple in CF and for type 1 diabetes as well as build-out of capabilities for our expanding pipeline. In addition, we continued our pre-commercial activities for exa-cel and other anticipated near-term launches.

如預期，營運費用成長主要得益於對研發和產品線的持續投入。 2023年全年，與前一年相比，投資增幅最大的領域包括：VX-548用於治療急性疼痛的臨床研究、vanzacaftor三聯療法用於治療囊性纖維化和1型糖尿病的臨床研究，以及不斷擴大的產品線所需的研發能力建設。此外，我們也持續推進exa-cel及其他預期近期上市產品的商業化前期工作。

Third quarter 2023 non-GAAP operating income was $1.17 billion, compared to $1.29 billion in the third quarter of 2022. Third quarter 2023 non-GAAP earnings per share were $4.08, representing 2% growth compared to $4.01 in the third quarter of 2022. We ended the quarter with $13.6 billion in cash and investments. Our priorities for cash deployment remain unchanged as we continue to prioritize investment in innovation, including external innovation via business development. Year-to-date, we have completed nearly 10 transactions with total consideration of over $500 million. We've also continued to allocate cash to share repurchases and year-to-date, we have spent approximately $285 million to repurchase approximately 900,000 shares.

2023年第三季非GAAP營業收入為11.7億美元，而2022年第三季為12.9億美元。 2023年第三季非GAAP每股盈餘為4.08美元，較2022年第三季的4.01美元成長2%。截至本季末，我們持有現金及投資136億美元。我們現金部署的優先事項保持不變，我們將繼續優先投資於創新，包括透過業務拓展進行外部創新。今年迄今，我們已完成近10筆交易，總對價超過5億美元。此外，我們繼續將現金用於股票回購，今年迄今，我們已花費約2.85億美元回購了約90萬股股票。

Now switching to guidance. Given our strong year-to-date results and our consistent execution, we are increasing our 2023 revenue guidance as detailed on Slide 17. For the full year 2023, we now expect CF net product revenue of approximately $9.85 billion versus our prior range of $9.7 billion to $9.8 billion. Note that this revenue guidance continues to include an expected approximate 150 basis point headwind to our revenue growth rate from changes in foreign currency.

現在轉入業績指引。鑑於我們今年迄今的強勁業績和持續穩定的執行力，我們將上調2023年營收指引，詳情請見第17頁投影片。我們目前預計2023年全年CF淨產品營收約98.5億美元，高於先前97億至98億美元的預期。請注意，此營收指引仍包含了因匯率波動而導致的約150個基點的營收成長阻力。

We are maintaining our 2023 guidance for combined non-GAAP R&D, acquired IPR&D and SG&A expenses in the range of $4.1 billion to $4.2 billion. We continue to invest the majority of our operating expenses into R&D given the momentum in our multiple mid- and late-stage clinical development programs. We are also funding the expansion of our commercial capabilities in anticipation of the multibillion-dollar opportunities represented by our programs with near-term launch potential while continuing to leverage an attractive business model afforded by our focus in specialty markets.

我們維持2023年非GAAP研發、收購的智慧財產權開發及銷售、管理及行政費用總額41億至42億美元的預期。鑑於我們多個處於中後期臨床開發階段的專案進展順利，我們將繼續把大部分營運支出投入研發。同時，我們也加大對商業化能力的投入，以期抓住近期上市潛力巨大的項目所帶來的數十億美元商機。此外，我們將繼續利用專注於專業市場所帶來的極具吸引力的商業模式。

Due to an increase in our current year U.S. R&D tax credit estimate, we are lowering guidance for our projected full year 2023 non-GAAP effective tax rate by 100 basis points to a range of 20% to 21% versus the prior range of 21% to 22%.

由於我們對本年度美國研發稅收抵免的估計有所增加，我們將 2023 年全年非 GAAP 實際稅率的預期下調 100 個基點，從先前的 21% 至 22% 下調至 20% 至 21%。

In closing, Vertex delivered excellent results yet again in Q3 '23, achieving strong revenue growth, important regulatory milestones, continued clinical trial progress and ongoing investments, both internally and externally. As we continue to advance our programs to close out 2023 and head into 2024, we anticipate further important milestones as highlighted on Slide 18 to mark our continued progress in multiple disease areas.

綜上所述，Vertex在2023年第三季再次取得了卓越的業績，實現了強勁的營收成長、重要的監管里程碑、持續的臨床試驗進展以及持續的內部和外部投資。隨著我們繼續推進各項計劃，力爭在2023年底和2024年取得進展，我們預計將取得更多重要的里程碑，正如幻燈片18中所強調的，這些里程碑將標誌著我們在多個疾病領域持續取得進展。

We look forward to updating you on our progress on future calls, and I'll ask Susie to begin the Q&A period.

我們期待在以後的電話會議上向您報告我們的進度，現在我請 Susie 開始問答環節。

(Operator Instructions) And the first question will come from Geoff Meacham with Bank of America.

（操作員說明）第一個問題將來自美國銀行的傑夫·米查姆。

(technical difficulty)

（技術難題）

Geoff, sorry, you were garbled. We can't understand you.

傑夫，抱歉，你剛才說話含糊不清，我們聽不懂。

I am sorry. Is it better?

對不起。這樣好些了嗎？

Yes, that's better. Thanks.

是的，這樣好多了。謝謝。

So first question on AAT. It seems like a much more difficult indication than initially thought. At a high level, what would you characterize that as? Is it just a mechanism? Is it the bar for risk/benefit? Or is it the molecules itself?

關於AAT，第一個問題。它似乎比最初想的要難得多。從宏觀層面來說，您會如何描述它？它僅僅是一種機制嗎？是風險/效益的衡量標準嗎？還是分子本身的問題？

And the second question is when you look to vanzacaftor in the data, maybe help us with how rapidly you think you could roll reimbursement out across Europe and OUS indications? I know -- I wasn't sure if this was part of your portfolio agreements or if you had to renegotiate that.

第二個問題是，當您查看vanzacaftor的資料時，能否幫我們估算一下您認為在歐洲和美國以外地區推廣醫保報銷的速度會有多快？我知道——我不確定這是否包含在您的產品組合協議中，或者您是否需要重新談判。

Yes. Sure thing. This is Reshma. Let me break that into 2 questions. I'll take the first part on AAT, and I'll ask Stuart to comment on the vanzacaftor and our plans for launching globally.

好的，沒問題。我是雷什瑪。我把這個問題分成兩個部分來問。我先回答關於AAT的第一部分，然後我會請史都華談談vanzacaftor以及我們全球推廣計畫。

Geoff, the particular issue with the VX-864 molecule in AATD is a nonserious rash. That's it. That's what it is. And when you see this, it's almost always molecule-specific. So no, it's not the mechanism of action. This is where the portfolio strategy is really important and comes into play. VX-634 and VX-668, which are the next 2 molecules, they remain in Phase I development. And we're looking forward to getting those results and the data event will be a '24 data event when we get to see those results and select a molecule or molecules and settle on next steps.

傑夫，VX-864 分子在 AATD 治療中存在的特殊問題是輕微皮疹。僅此而已。就是這樣。而且這種情況幾乎總是特定於某個分子。所以，不，這與藥物的作用機制無關。這正是產品組合策略真正發揮作用的地方。接下來的兩個分子 VX-634 和 VX-668 目前仍處於 I 期臨床試驗階段。我們期待獲得這些結果，數據發布會將在 2024 年舉行，屆時我們將看到這些結果，並選擇一個或多個分子，確定下一步的研發方向。

Let me turn it over to Stuart to talk about Vanza. And to clarify, the study is a global study, and the intent is for global regulatory submissions and for a global launch.

讓我把麥克風交給史都華，讓他談談Vanza。需要澄清的是，這項研究是一項全球性研究，其目的是為了向全球監管機構提交申請，並最終在全球範圍內上市。

Stuart?

史都華？

Yes, Geoff. So on expectations for access and reimbursement outside of the U.S., as Reshma said, importantly, this study is a head-to-head comparison with TRIKAFTA. To your specific question, was vanzacaftor imagined when we embark on some of our portfolio agreements? It was. Some of them do include clauses to include increasingly better and better medicines, which is our anticipation of what vanzacaftor will prove to be. It isn't in all of our reimbursement agreements, just to be clear. But if the product can deliver the kind of profile that we expect, I would expect like we did with TRIKAFTA, that we will beat the kind of industry benchmarks for getting to access patients across ex-U.S. markets.

是的，Geoff。關於美國以外地區的市場准入和報銷預期，正如Reshma所說，重要的是，這項研究是與TRIKAFTA的直接對比。至於你提出的具體問題，vanzacaftor是否在我們簽訂一些產品組合協議時就已經被考慮？是的。其中一些協議確實包含條款，旨在納入越來越好的藥物，而這正是我們對vanzacaftor的預期。需要說明的是，並非所有報銷協議都包含此條款。但如果該產品能夠達到我們預期的效果，我預計就像我們之前推廣TRIKAFTA一樣，我們將超越行業基準，讓更多患者能夠在美國以外的市場獲得該藥物。

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

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

It sounds like '24, '25 is going to be a breakout year for Vertex, transformative in many ways. 2 questions for me. One on pain, Reshma, thanks for clarifying you're unblinding at the same time. But we get all these investor question, saying, are you having concerns about the [abdomectomy] trial? Maybe help us understand the strategy for why doing that at the same time and if you -- if there's any risks.

聽起來2024年和2025年對Vertex來說將是突破性的一年，在許多方面都將具有變革意義。我有兩個問題。第一個是關於疼痛的，Reshma，謝謝你澄清你們會同時揭盲。但我們常收到投資人的提問，例如，你們是否擔心腹部切除的試驗？能否請你解釋一下，為什麼你們要同時進行腹部切除試驗，以及是否有任何風險？

My second question is on PNP. So you said you'll have a specialty sales force. How do you market it in the context that Lyrica exists even though it's now a scheduled drug? Maybe some expectations for what you're looking for, for that data.

我的第二個問題是關於PNP的。您提到會組成專業的銷售團隊。鑑於Lyrica現在已被列為管制藥品，您打算如何進行市場推廣？您能否談談您希望獲得哪些數據？

Yes. Robyn, 2 questions on VX-548, one on the acute pain side and one on the neuropathic pain side. Let me tackle acute pain and I'll ask Stuart to comment on our commercialization approach on the neuropathic side.

是的。 Robyn，關於VX-548，我有兩個問題，一個是關於急性疼痛的，一個是關於神經性疼痛的。我先回答急性疼痛的問題，之後我會請Stuart談談我們在神經性疼痛上的商業化策略。

So to ground everyone, the acute pain program is, in its entirety, 3 pivotal trials. One is the abdominoplasty RCT, the second is the bunionectomy RCT, and the third is a single-arm safety and effectiveness trial. And the reason we are planning to unblind, analyze and share the results all at the same time is because our goal is to secure a broad moderate-to-severe acute pain label. And in order to do that, we need the results from all of these trials. So that's the reason for sharing the results all at the same time.

為了讓大家更能理解，急性疼痛治療​​項目總共包含三個關鍵性試驗。第一項是腹部整形術隨機對照試驗（RCT），第二項是拇趾外翻切除術隨機對照試驗，第三項是單臂安全性與有效性試驗。我們計劃同時揭盲、分析並公佈所有試驗結果，是因為我們的目標是獲得一項涵蓋中重度急性疼痛的廣泛適應症。為了實現這一目標，我們需要所有這些試驗的結果。這就是我們決定同時公佈所有結果的原因。

With regard to PNP, I'll just frame it up with what we are looking to do and how you may want to think about the profile, and then I'll turn it over to Stuart for commercialization. The Phase II study, that's the study we have completed and expect to share the results before the end of this year, it is a study that has a Lyrica reference arm. So it's not a comparison but it's there so that we can assess the magnitude of the treatment effect.

關於PNP，我先簡單介紹一下我們的目標以及您可能對產品特性的理解，然後我會把它交給Stuart負責商業化事宜。我們已經完成了II期臨床試驗，預計在今年年底前公佈結果。這項研究設有Lyrica作為對照組。所以它並非直接比較，而是為了評估治療效果的程度。

And our goal here really is to have a medicine that can compete effectively and bring a better benefit/risk profile than Lyrica for this patient population. And just so that it's not missed, one of the comments I made in my prepared remarks is we're now expanding our progress into the peripheral neuropathic pain area with a study that we will initiate before end of year in what's called LSR or lumbosacral radiculopathy, another kind of neuropathic pain.

我們的目標是研發出一種能夠有效競爭，並且對這類患者群體具有比普瑞巴林（Lyrica）更優獲益/風險比的藥物。另外，為了避免大家忽略，我在事先準備好的演講稿中提到，我們正在將研究進展拓展到周圍神經性疼痛領域，我們將在年底前啟動一項針對腰骶神經根病（LSR）的研究，這是一種神經性疼痛。

Stuart?

史都華？

Yes. Just to expand on that, Robyn, very briefly. So PNP is kind of an umbrella term, which is used to describe a collection of conditions all of which have as their cause nerve impairment, which causes pain. DPN, which, as you know, is the study, which is ongoing with 548, obviously, there, the standard of care has been the gabapentinoids, and as Reshma said, what we're looking to do there because there are approved therapies there, which are generic, is demonstrate an improved benefit risk profile to be able to compete successfully in that market segment. And the Phase II study is obviously going to be very revealing in that regard.

是的。 Robyn，我再簡單補充一下。 PNP（週邊神經病變）是一個統稱，用來描述一系列以神經損傷為病因，從而引起疼痛的疾病。 DPN（糖尿病週邊神經病變），如你所知，目前正在進行的研究有548例患者參與。顯然，目前該領域的標準療法是加巴噴丁類藥物。正如Reshma所說，由於目前已有核准的仿製藥，我們希望證明我們的藥物具有更優的獲益風險比，從而能夠在該細分市場中成功競爭。而II期臨床試驗顯然將在這方面提供非常重要的資訊。

LSR is very different -- and DPN I should say, accounts for about 20% of all patients in the U.S. with PNP. That's 20% of approximately 10 million people. LSR accounts for over 40% of patients with PNP. There, there are no products which are specifically approved for LSR. So we see that as a very significant opportunity as well. There, obviously, with no approved therapies, it's likely that the comparator is going to be, can we demonstrate effective pain relief versus placebo.

LSR 的情況截然不同——更準確地說，DPN 約占美國所有 PNP 患者的 20%，也就是約 1,000 萬人中的 20%。而 LSR 則佔 PNP 患者的 40% 以上。目前，尚無專門核准用於治療 LSR 的產品。因此，我們也認為這是一個非常重要的機會。顯然，由於目前尚無核准療法，因此，比較的關鍵在於能否證明我們的產品能夠有效緩解疼痛，而安慰劑則無法與之相比。

And one follow-up, if I can. Do you have to look better? I know Lyrica has just a sidearm but I know a lot of doctors want it looking better for reimbursement. Do you have to look better or just safer? We obviously know the issues with safety with Lyrica.

還有一個後續問題，如果可以的話。你們的藥物外觀一定會更好嗎？我知道 Lyrica 只有一種側臂，但我也知道很多醫生為了獲得報銷，希望它的外觀更好。你們的藥物外觀必須更好，還是僅僅為了更安全？我們當然知道 Lyrica 的安全問題。

Yes, yes, yes. The point you make about the safety tolerability issues with Lyrica are real. The -- what we're looking for in the Phase II program is change from baseline at the various doses with Lyrica as a reference arm, not a comparator. But our goal here, to be clear, is to have a product, VX-548 that is a better benefit/risk profile than Lyrica.

是的，是的，是的。您提到的關於Lyrica安全性和耐受性的問題確實存在。 ——我們在II期臨床試驗中關注的是不同劑量下，以Lyrica為參照組（而非對照組）的基線變化。但要明確的是，我們的目標是研發出一種比Lyrica具有更優獲益/風險比的產品VX-548。

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。

One here on the pain side with the LSR trial. Can you help us understand why start this trial now versus waiting for the DPN trial to read out and get a better understanding of the profile there? And then a second question on the cells and device program here. That seems to be a partial dose with staggered enrollment. Again, and I'm just wondering why in the context of maybe the derisking that you saw on the naked cell approach?

這裡有一個關於LSR試驗疼痛的疑問。您能否解釋一下，為什麼現在就啟動這項試驗，而不是等到DPN試驗結果出來後再開始，以便更好地了解DPN試驗的情況？第二個問題是關於細胞和器械聯合治療方案的。這似乎是一種分階段入組的局部給藥方案。我再次想問，考慮到您在裸細胞治療方案中觀察到的風險降低，為什麼還要採用這種方案？

Sure thing. Let me start with the VX-264 question, and I'll go back to pain. The reason that we are at a partial dose with staggered dosing in the Part A part of the 264 program is because the cells plus device is a first-in-man program. And we are doing that to go slowly and ensure that we have sufficient time between patients to be able to assess safety and it is the way that the protocol is designed in consultation with global regulators. So that's the reason. It's because cells plus device is a first-in-man trial.

當然可以。我先回答VX-264的問題，然後再回到疼痛的話題。我們在264計畫A部分​​採用分階段給藥和部分劑量給藥的原因是，細胞聯合裝置療法是一項首次人體試驗。我們這樣做是為了循序漸進，確保在每位患者之間有足夠的時間評估安全性。這是在與全球監管機構協商後所製定的方案。這就是原因。因為細胞聯合裝置療法是一項首次人體試驗。

Let me go back now to VX-548 and LSR, and why now? It's really a very good question. The reason we started with DPN is because DPN or diabetic peripheral neuropathy has and has had an established regulatory pathway as well as an established commercial marketplace. So that's why we started with DPN. We started with it actually when we did the 150 program, and that's the first PNP or peripheral neuropathic pain indication, we pursued when we started with VX-548.

現在讓我回到VX-548和LSR的話題，以及為什麼選擇現在進行研究？這確實是個很好的問題。我們之所以從糖尿病週邊神經病變（DPN）著手，是因為DPN已經擁有成熟的監管途徑和商業市場。所以這就是我們選擇DPN的原因。實際上，我們在進行150計畫時就開始研究DPN，這也是我們研發VX-548時首先關注的周邊神經病變疼痛（PNP）適應症。

As the VX-548 study has gotten started and frankly, as we near that completion, we've turned our attention to LSR. It was always our intention to pursue a broad peripheral neuropathic pain label for VX-548, just like we're pursuing a broad label in the acute pain setting. We recently completed our regulatory discussions on the LSR pain type and gained confirmation that LSR from a regulatory perspective is a PNP pain type.

隨著VX-548研究的啟動，坦白說，隨著研究接近尾聲，我們已將注意力轉向LSR。我們一直計劃為VX-548申請廣泛的周邊神經性疼痛適應症，就像我們正在申請急性疼痛適應症一樣。我們最近完成了關於LSR疼痛類型的監管討論，並確認從監管角度來看，LSR屬於周圍神經性疼痛（PNP）的一種類型。

As Stuart said, medically, scientifically falls under that umbrella of a peripheral neuropathic pain type. And we completed our discussions with the regulators and confirmed that it is indeed, from a regulatory standpoint, also a PNP type. That's why we're starting the LSR Phase II study now. And I got to tell you, I'm terribly excited about that.

正如史都華所說，從醫學和科學角度來看，它屬於週邊神經性疼痛的範疇。我們已經與監管機構完成了討論，並確認從監管角度來看，它確實也屬於周圍神經性疼痛（PNP）的一種類型。這就是為什麼我們現在啟動LSR II期臨床試驗的原因。我必須告訴你，我對此感到非常興奮。

Your next question will come from Phil Nadeau with TD Cowen.

下一個問題將來自TD Cowen的Phil Nadeau。

A couple of follow-ups from us. First, on pain, investors saw The New England Journal of Medicine editorial over the summer that was somewhat skeptical of 548, and it's a topic of debate. Could you respond to that editorial? What do you think the author got wrong? Or where do you disagree with the author?

我們還有幾個後續問題。首先，關於疼痛管理，投資者在夏季看到了《新英格蘭醫學雜誌》的一篇社論，該社論對548公司持懷疑態度，這引發了一些爭議。您能否就此社論回應？您認為作者的哪些觀點是錯的？或者您在哪些方面與作者有分歧？

And then, second, a follow-up on Vanza. In the prepared remarks, you mentioned that Vanza was going to drive intermediate growth of the franchise. Can you elaborate on those comments a bit more, what new patient populations or opportunities could Vanza explore that TRIKAFTA currently can't?

其次，我想就Vanza進行後續討論。您在準備好的發言稿中提到，Vanza將推動整個產品線的中期成長。您能否進一步闡述一下，Vanza可以開拓哪些TRIKAFTA目前無法觸及的新病患群體或機會？

Yes, sure thing. Phil, when I think about the distillation of the editorial, I think it comes down to this is the holy grail of pain in terms of targets. There looks to be very promising results. It's a Phase II study, how should we think about the magnitude of the treatment effect, how should we think about it in terms of the effect and the potential not only versus placebo, but versus opioids and then maybe a desire to learn a little bit more about the secondary endpoints.

當然可以。菲爾，當我思考這篇社論的要點時，我認為歸根結底，這可以說是疼痛治療領域最關鍵的目標。目前看來，研究結果非常令人鼓舞。這是一項二期臨床試驗，我們該如何看待治療效果的強度？我們應該如何看待它與安慰劑和鴉片類藥物相比的療效和潛力？或許我們也希望能多了解次要終點。

And what I would say is we're going to have a far bigger study, 2,000 people in all. There's 1,000 people in the abdominoplasty study, another 1,000 people in the bunionectomy study and another 250 people in the safety and effectiveness study. And we'll have all the data we need to make a full assessment in this Phase III trial. So I think the best answer is let's look towards the Phase III trial. And I agree the Phase II results are very promising.

我想說的是，我們將進行一項規模更大的研究，總共2000人。其中1000人參與腹部整形手術研究，1000人參與拇趾外翻切除術研究，250人參與安全性和有效性研究。我們將獲得所有必要的數據，以便在三期臨床試驗中進行全面評估。所以我認為最好的方法是讓我們期待三期臨床試驗的結果。我也同意二期臨床試驗的結果非常令人鼓舞。

Let me turn it over to Stuart to talk about Vanza.

讓我把麥克風交給史都華，讓他談談範札。

Phil, on Vanza, I would really think about the opportunity for patients to be initiated on Vanza to be threefold. One is people who are currently on an existing CFTR modulator. But if we deliver the sort of profile with Vanza that we're hoping to versus TRIKAFTA, they may want to be switched onto vanzacaftor. Then you've got patients who have not yet been initiated on a CFTR modulator, that's a relatively small number of patients.

Phil，關於Vanza，我認為患者開始使用Vanza的可能性主要有三個面向。首先是目前正在服用其他CFTR調節劑的患者。如果我們能使Vanza達到我們預期中相對於TRIKAFTA的療效水平，他們可能會希望轉而使用Vanzacaftor。其次是尚未開始使用CFTR調節劑的患者，這類患者數量相對較少。

But really, the big opportunity for growth is there's about 6,000 -- just over 6,000 patients globally now who've actually discontinued a CFTR modulator. So they wanted to be on a CFTR modulator but for a variety of reasons have had to discontinue. As I say, that's over 6,000 patients now around the world. We don't often talk about discontinuations from our CFTR modulators because it's actually a relatively small percentage compared to any other sort of chronic medication, but it's still a sizable number of patients. We know they would like to be on a CFTR modulator because they previously tried. And so we think they could be patients who are very interested in Vanza if we deliver the kind of profile that we're expecting.

但實際上，最大的成長機會在於，目前全球約有6,000多名患者（略多於6,000名）已經停止服用CFTR調節劑。他們原本想服用CFTR調節劑，但因為各種原因不得不停藥。正如我所說，目前全球有超過6000名患者面臨這種情況。我們很少談及CFTR調節劑的停藥情況，因為與其他類型的慢性藥物相比，停藥率實際上相對較低，但這仍然是一個相當可觀的數字。我們知道他們仍然希望服用CFTR調節劑，因為他們之前嘗試過。因此，我們認為，如果我們能提供預期的療效，他們可能會對Vanza非常感興趣。

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 on all the progress. One question, again, staying on DPN study. So could you remind us how prevalent is the opioid use in this setting? Because from our reading, it seems like it is more a third-line agent. And is the thought to replace Lyrica in that setting? Or is it more like to replace opioids in that setting? I mean how do you think about the profile of the drugs?

恭喜你們取得的所有進展。還有一個問題，還是關於DPN研究。您能否提醒我們一下，在這種情況下，阿片類藥物的使用有多普遍？因為根據我們所了解的情況，它似乎更像是三線藥物。那麼，在這種情況下，是否考慮用它來取代普瑞巴林（Lyrica）呢？或者更可能是替代鴉片類藥物？我的意思是，您如何看待這些藥物的特性？

Sure thing. I'll have Stuart talk about the -- what is being used in DPN today.

當然可以。我會讓史都華談談——DPN 目前都在使用哪些技術。

Yes. Mohit, there is a lot of polypharmacy going on in DPN right now, largely because the efficacy of the various classes of pain medicines, which are available today is pretty variable. So you do see patients who are on nonsteroidals. You see a lot of people who are on the gabapentinoids, which have been studied and approved there. And you also do see parents -- patients on opioids as well.

是的，莫希特，目前糖尿病週邊神經病變（DPN）患者普遍存在多種藥物聯合使用的情況，這主要是因為目前可用的各類止痛藥的療效差異很大。所以你會看到一些患者服用非類固醇類抗發炎藥，也會看到很多患者服用加巴噴丁類藥物（這類藥物已經過研究並獲批上市），甚至會看到一些患者及其父母同時服用鴉片類藥物。

So it really is a disease characterized by sort of polypharmacy largely due to either variable efficacy and/or the adverse events of the currently available therapies. That's why we're so excited about the prospect of 548 being able to establish a new standard of care for these patients.

因此，這種疾病確實以多種藥物聯合治療為特徵，這主要是由於現有療法的療效不一和/或不良反應所致。正因如此，我們對548有望為這些患者建立新的治療標準感到非常興奮。

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。

The press release makes mention of Vertex's portfolio approach to R&D and additional NaV1.8 and 1.7 inhibitors you're working on. How far along in development is the next most advanced 1.8 inhibitor behind VX-548? And do you have any dual 1.8 and 1.7 inhibitors?

新聞稿中提到了Vertex的研發組合策略，以及你們正在研發的其他NaV1.8和1.7抑制劑。 VX-548之後，下一個最先進的1.8抑制劑的研發進展如何？你們是否有任何同時具有1.8和1.7雙重抑製作用的抑制劑？

Yes. Welcome back, Jess. Really terrific question. The portfolio strategy, as you've seen it play out in CF is authentically and reproducibly extended across our R&D pipeline. So as it pertains to pain, the next NaV1.8 inhibitors are already in the clinic in Phase I trials. And we have more after that, making their way through the research part of our organization.

是的，歡迎回來，傑西。你問得真好。正如你所看到的，我們在囊性纖維化領域的投資組合策略，也真實可靠地延伸到了我們整個研發管線。就疼痛治療而言，下一代NaV1.8抑制劑已進入I期臨床試驗。而我們還有更多後續藥物正在研發階段。

In terms of NaV1.7, they are in the research stage and making very good progress. And we see the NaV1.7s as potentially for use as a single agent, and we also see the real opportunity for combining NaV1.7s and 1.8s. And just for all of the others who are following along, the reason I say that and the reason I think it's an excellent question, is that the way that the action potential works in the periphery in transducing the pain signal is that there is a stimulation of the action potential and then the propagation, and NaV1.7 works on that stimulation of the action potential and NaV1.8 works on that propagation. So, we see a lot of opportunity in the combination but we also see opportunity of NaV1.7 in and of itself.

就NaV1.7而言，它們目前處於研究階段，並且取得了非常顯著的進展。我們認為NaV1.7有潛力作為單一藥物使用，同時也看到了將NaV1.7與NaV1.8聯合使用的巨大潛力。對於所有關注此事的讀者，我之所以這樣說，並認為這是一個非常好的問題，是因為動作電位在外周傳遞疼痛信號的方式是：首先刺激動作電位，然後動作電位傳播。 NaV1.7作用於刺激動作電位，而NaV1.8作用於動作電位的傳播。因此，我們看到了聯合用藥的巨大潛力，同時也看到了NaV1.7本身的應用前景。

The next question will come from David Risinger with Leerink Partners.

下一個問題將來自 Leerink Partners 的 David Risinger。

Yes. I have 2 questions, please. First, if the VX-548 succeeds in Phase II in DPN in coming months, how do you plan to conduct Phase III? Do you plan to go it alone? And could you complete Phase III in '25 or likely not until '26? And then regarding VX-548 acute pain Phase III studies, how should we expect rescue medicine used to potentially benefit patients in the placebo arms? And how will rescue medicine use be disclosed?

是的。我有兩個問題。首先，如果VX-548在未來幾個月內成功完成DPN的II期臨床試驗，你們計劃如何進行III期臨床試驗？你們打算獨立進行嗎？你們能在2025年完成III期臨床試驗嗎？還是可能要等到2026年？其次，關於VX-548急性疼痛的III期臨床試驗，我們該如何預期安慰劑組病人會使用哪些急救藥物？急救藥物的使用將如何揭露？

Okay. David, let me start the answer to both of these questions. But the PNP question has a component of can we go at it alone. And so I want to make sure that Stuart touches on it.

好的。大衛，讓我先回答這兩個問題。但是PNP的問題包含一個面向，那就是我們能否獨立完成。所以我想確保斯圖爾特也談到這一點。

Let me cut to the punchline, for acute pain and for neuropathic pain, both in terms of diabetic neuropathy and in terms of LSR, this lumbosacral radiculopathy, we are going to do the development by ourselves and we are going to commercialize by ourselves. Both of these, acute pain and neuropathic pain, are absolutely Vertexian diseases, if I can call it that, in terms of commercialization.

讓我直奔主題，對於急性疼痛和神經性疼痛，無論是糖尿病性神經病變還是腰骶神經根病變（LSR），我們都將自主研發並實現商業化。就商業化而言，這兩種疾病——急性疼痛和神經性疼痛——都絕對是Vertexian的專長，如果我可以這樣稱呼它們的話。

I'll ask Stuart to comment a little bit more in commercializing neuropathic pain, and I'll come back to tell you about acute pain, rescue meds, et cetera.

我會請史都華就神經性疼痛的商業化問題再多發表一些看法，之後我會回來和大家談談急性疼痛、急救藥物等等。

David, so kind of building on what I said about this being a disease state, which unfortunately for patients is characterized by polypharmacy. And so patients are often seeking superior pain relief to what they are getting. It is heavily influenced and/or treated by specialists for DPN and indeed, for LSR as well. And so for both of those pain states within PNP overall, we believe we can achieve success commercially with a specialty sales force. As a result, of wanting to go it alone commercially, we're going to be doing the studies in DPN and hopefully, in LSR, Phase III studies are successful and Phase II ourselves as well.

大衛，我剛才說的關於這是一種疾病狀態，不幸的是，患者往往需要服用多種藥物，這算是對這種疾病狀態的補充。因此，患者通常希望獲得比目前更好的止痛效果。 DPN 和 LSR 的治療很大程度上依賴專科醫生。因此，我們相信，對於 PNP 中的這兩種疼痛狀態，我們可以透過組建專業的銷售團隊在商業上取得成功。正因如此，我們決定獨立進行商業活動，我們將自行進行 DPN 的研究，並希望 LSR 的 III 期臨床試驗和 II 期臨床試驗都能成功。

And David, to round it out with your questions on acute pain. The -- we have thought through very carefully as we did in the Phase II portion of the study, the same in the Phase III portion of the acute pain studies, about the use of rescue medicines and how to consider the statistical analysis plan in that light, and there are -- it's been very well considered in there.

最後，David，我想回答你關於急性疼痛的問題。我們已經非常仔細地考慮過，就像我們在二期研究和第三期急性疼痛研究中所做的那樣，關於使用急救藥物以及如何從這個角度考慮統計分析方案，這方面我們已經考慮得非常周全了。

So I don't have much more to say other than the use of rescue medicines, of course, will be disclosed in the publications and when we share the results, but how to think about it has been deeply considered and well accounted for just as it was in Phase II.

所以除了使用急救藥物的情況之外，我沒有什麼要補充的了。當然，急救藥物的使用情況會在出版物中揭露，並在我們分享結果時公佈。但是，如何考慮這個問題已經過深入思考和充分考慮，就像在 II 期臨床試驗中一樣。

I think there was a question in there about Phase III and the peripheral neuropathic pain structure. I'll focus my comments on DPN. That one will be designed with the FDA. We haven't yet had our end of Phase II meeting and therefore, I can't give you specifics on what that program will look like, but that's exactly what will be the next step once we have the Phase II DPN results, assuming they are positive.

我認為其中有一個關於三期臨床試驗和周邊神經性疼痛結構的問題。我將重點討論糖尿病週邊神經病變（DPN）。該試驗方案將與FDA共同製定。我們尚未召開二期臨床試驗結束會議，因此我無法提供該方案的具體細節，但一旦我們獲得DPN二期臨床試驗的結果（假設結果是積極的），這將是我們下一步的計劃。

The next question will come from Evan Seigerman with BMO Capital Markets.

下一個問題將來自 BMO 資本市場的 Evan Seigerman。

Congrats on the progress as always. I wanted to talk about the implications of the recently released U.K. NICE appraisal of TRIKAFTA essentially indicating that was not cost-effective for the U.K. system. Because I was under the impression that this was settled in 2019. Could you maybe expand on the impact to your U.K. franchise and steps to resolve to ensure access in the U.K.?

一如既往地祝賀你們的進展。我想談談英國國家衛生與臨床優化研究所（NICE）最近發布的關於TRIKAFTA的評估報告的影響，該報告基本上表明TRIKAFTA對英國醫療體係而言並不具有成本效益。因為我之前以為這個問題在2019年就已經解決了。您能否詳細說明這對您在英國的業務有何影響，以及為確保TRIKAFTA在英國的正常使用，您將採取哪些措施來解決？

Yes, Evan. So the first thing I'll say about the ongoing NICE review is that this was an expected part of the contract that we negotiated with the NHS in 2019. So this isn't a surprise that NICE is reviewing our medicines after 4 years on the market. So that's the first thing to say. As a part of the original contract, we agreed with the NHSE and with NICE that we would collect and submit data after a period of being on the market. And we have done just that. We submitted clinical trial data, open-label extension data and real-world data from the U.K.

是的，埃文。關於正在進行的NICE審查，首先我要說的是，這是我們在2019年與NHS談判簽訂的合約中預期的一部分。因此，NICE在我們的藥物上市4年後對其進行審查並不令人意外。這是第一點。作為原始合約的一部分，我們與NHS英格蘭和NICE達成一致，在藥物上市一段時間後收集並提交數據。我們也確實這麼做了。我們提交了臨床試驗數據、開放標籤擴展數據以及來自英國的真實世界數據。

And I think -- it's unusual, I think, to see a medicine, which is what I think we've seen with TRIKAFTA, that performs perhaps even better in the real world than you expected having seen the Phase III results because the results we've seen in the real world, as you well know, are absolutely extraordinary, including things like reductions in exacerbations, increases in life expectancy, reductions in hospitalizations, a virtual elimination of lung transplants.

我認為——很不尋常的是，我們看到一種藥物（就像我們在 TRIKAFTA 身上看到的那樣），其在現實世界中的表現甚至可能比您在看到 III 期結果後所預期的還要好，因為我們在現實世界中看到的結果，正如您所知，絕對是非凡的，包括減少病情加重、延長壽命、減少住院治療、幾乎完全消除肺移植。

So we're pretty disappointed, it's fair to say, with the draft guidance from NICE. It is just that, though, it's draft guidance. There was a period of consultation. There's going to be a second NICE Committee Meeting, and I certainly feel confident that the full value of our medicines will be reflected at the end of this process.

坦白說，我們對NICE的指導草案相當失望。不過，它畢竟只是指導草案。之前已經進行了一段時間的公眾諮詢。 NICE委員會也將召開第二次會議，我相信最終我們藥物的全部價值將會充分體現。

The next question will come from Liisa Bayko with Evercore ISI.

下一個問題將來自 Evercore ISI 的 Liisa Bayko。

I wanted to circle back to pain and just 2 questions from me. First of all, the article -- so the editorial in The New England Journal of Medicine did focus in on overwhelmingly more females in the 2 acute pain indications that you're using as examples. So maybe you can just speak to that and addressing sort of the underrepresentation of males.

我想再回到疼痛這個話題，我有兩個問題。首先，關於您提到的那篇文章——《新英格蘭醫學雜誌》的社論——確實重點關注了您舉例的兩種急性疼痛適應症中女性患者遠多於男性患者。您能否就此談談，以及男性患者比例偏低的問題？

And then finally, just if you could comment on any capabilities that you've been working on developing. This is obviously a much different market to commercialize into than CF with a lot of generic competition and the need to get on hospital formulary, et cetera. And how are you building sort of those capabilities as you're waiting for data?

最後，能否請您談談您正在開發的一些功能？顯然，這個市場與囊性纖維化市場截然不同，面臨大量的仿製藥競爭，而且需要進入醫院處方集等等。在等待資料的同時，您是如何建立這些功能的呢？

Sure thing. Liisa, this is Reshma. Let me start, and then I'll pass it over to Stuart. Most companies, including our own want to ensure that we have more people of color in our trials, more women in our trials and I guess we have succeeded. So I see the fact that 548 has many women as a positive. Perhaps one point to make underneath -- just underlying that comment is, remember, in the acute pain study, one was an abdominoplasty study, and abdominoplasty is a procedure involving fat in the belly kind of surgery. It's -- some people call it a tummy tuck. And that is a surgical procedure that more women undergo.

當然可以。莉薩，我是雷什瑪。我先說，然後把麥克風交給史都華。大多數公司，包括我們公司，都希望確保臨床試驗中有更多有色人種和女性參與，我想我們已經成功了。所以我認為548試驗中有很多女性參與者是一個正面的訊號。或許還有一點需要補充——就我剛才的評論而言，請記住，在急性疼痛研究中，有一項是腹部整形手術研究，腹部整形手術是一種涉及腹部脂肪的手術。有些人稱之為腹部拉皮手術。而這種手術女性參與的比例更高。

With regard to the commercialization of pain, I'll turn it over to Stuart, but I want to frame up the following concept. In the acute pain setting one of the most important elements that VX-548 could address is effective pain relief without the addiction potential of opioids. And that part of it, this addiction potential of opioids is something that is not only of interest to Vertex but it's of interest to the community, the policymakers, to physicians, and we see a lot of tailwinds.

關於疼痛治療的商業化，我將把發言權交給斯圖爾特，但我想先闡述以下概念。在急性疼痛治療​​中，VX-548 最重要的優點之一在於，它能夠在有效緩解疼痛的同時，避免鴉片類藥物的成癮性。而鴉片類藥物的成癮性不僅是 Vertex 公司關注的重點，也是整個社會、政策制定者和醫生們關注的焦點，我們看到了許多有利因素。

And so as I turn it over to Stuart, I'll ask him to comment on our commercialization efforts but also the tailwinds we see. Stuart?

接下來，我將把發言權交給斯圖爾特，請他談談我們的商業化努力以及我們目前看到的有利因素。史都華？

Yes. So to your question about capabilities, I think we're trying to get the best of both worlds. We are trying to leverage the capabilities that have made us be successful to date, and much of that is based around our ability to get reimbursement and access for our medicines and also work with policymakers, with guideline institutions, et cetera, to support the appropriate use of effective medicines like ours.

是的。至於你問到的能力問題，我認為我們正在努力兼顧兩方面的優勢。我們試圖充分利用迄今為止讓我們取得成功的能力，而這些能力很大程度上取決於我們獲得藥品報銷和准入的能力，以及與政策制定者、指南機構等合作，以支持像我們這樣有效藥物的合理使用。

And as Reshma said, we're already seeing tailwinds if we can call them that, in the pain market with people looking to kind of move away from the sort of restrictions that they've previously put in place for things like opioids in terms of who can prescribe them, for how long, for which patients in which settings, to people looking at policy changes like the NOPAIN Act, which we highlighted a couple of quarters ago now where people are looking to make sure that there are no financial barriers or disincentives to people doing the right thing and using a non-opioid effective pain medicine just because there are generic medicines available. So that's something that we're going to be looking to build on some of the capabilities that we've used to help us be successful.

正如雷什瑪所說，我們已經看到一些利多因素（如果可以這麼說的話），尤其是在疼痛治療市場。人們希望擺脫先前對鴉片類藥物的限制，例如誰可以開處方、處方時長、適用於哪些患者以及在哪些情況下使用。同時，人們也關注政策變革，例如我們幾個季度前重點介紹的《非鴉片類藥物止痛法案》（NOPAIN Act）。該法案旨在確保不會因為有仿製藥而阻礙人們使用非鴉片類有效止痛藥。因此，我們將利用我們已有的優勢，繼續發展這方面的業務。

Having said that, we are going to be selling into a different segment of the market. This is obviously going to be a very hospital institution-driven sale. And so we are looking to bring in and have brought in new capabilities as we brought on our pain business unit, people who are experienced in that kind of institutional setting. So I would say we are trying to get the best of both worlds, leverage what we've been good at in the past, while bringing in people who bring new knowledge, skills and experience to the company as well.

話雖如此，我們將進軍一個不同的市場區隔。顯然，這將是一次以醫院機構為主導的銷售。因此，我們正在引進新的能力，正如我們組建疼痛治療業務部門時所引進的那樣，我們引進了在醫療機構環境中經驗豐富的人才。所以，我認為我們正在努力做到兩全其美，既要發揮我們過去的優勢，又要引進能為公司帶來新知識、技能和經驗的人才。

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葉。

Congrats on a great quarter. We had a follow-up question on pain and then a question on Vanza.

恭喜你們本季表現出色。我們收到了一個關於疼痛的後續問題，以及一個關於Vanza的問題。

On the acute and chronic pain, can you just remind me since you've never disclosed doses, should we expect that it's the same doses used in the Phase II and also the Lyrica and Vicodin doses as a control or basically the doses from the label? And is that pretty well understood? And then from a safety tolerability standpoint, I think there was a QT study that had completed. So was there anything to disclose there? That would be great to hear if that was the case, that would be a positive.

關於急性和慢性疼痛，您能否提醒一下，因為您從未公開過劑量，我們是否可以預期劑量與二期臨床試驗中使用的劑量相同，並且與作為對照的普瑞巴林（Lyrica）和維可丁（Vicodin）的劑量相同，或者基本上與藥品說明書上的劑量相同？這一點大家是否都清楚？另外，從安全性和耐受性的角度來看，我記得之前有一項QT間期研究已經完成了。請問這方面有什麼需要說明的嗎？如果是這樣的話，那就太好了，那將是一個積極的信號。

And then on Vanza, I know that there was questions around noninferiority and superiority. And I know it's powered potentially for superiority. But can you just remind us, is there a magnitude of clinical meaningfulness on FEV, et cetera, that you would deem to be meaningful? Or is it more the totality of everything as well, like sweat chloride and the benefits that, that may provide?

關於Vanza，我知道之前有人質疑其非劣效性和優效性。我也知道它的潛在優勢在於其強大的統計功效。但您能否提醒我們一下，在FEV1等指標上，是否存在一個您認為具有臨床意義的顯著數值？或者，是否需要綜合考慮所有因素，例如汗液氯化物及其可能帶來的益處？

Sure thing. Mike, let me start, and then I will ask Stuart (inaudible) the market research that Stuart and the team have done on Vanza and what is valued vis-a-vis sweat chloride, et cetera. But I'll go back to 548 to start and then I'll set up the clinical trial structure for Vanza.

當然可以。麥克，我先開始，然後我會問史都華（聽不清楚）他和他的團隊對Vanza做的市場調查，以及它相對於汗液氯化物等指標的價值。不過，我先回到548這個主題，然後再建立Vanza的臨床試驗架構。

So to confirm, on the VX-548 acute pain Phase III trials, it is exceptionally similar to the VX-548 Phase II trials. Same pain conditions, abdominoplasty and bunionectomy. We selected the high dose, the dose that showed the benefit in the Phase II trial for the Phase III trial. And you are correct, standard labeled doses for the opioid.

因此，為了確認，VX-548 急性疼痛 III 期臨床試驗與 VX-548 II 期臨床試驗非常相似。疼痛情況相同，皆為腹部整形術和拇外翻切除術。我們在 III 期臨床試驗中選擇了高劑量，即在 II 期臨床試驗中顯示出療效的劑量。您說得對，這是阿片類藥物的標準標籤劑量。

And on the Phase II diabetic peripheral neuropathy trial, correct, the Lyrica is standard doses from the label. The doses in the peripheral neuropathy Phase II study are different than the acute pain doses, obviously, because one has chronic dosing and one has acute, and we need to make the appropriate adjustments so that we have the exposure we seek. But with regard to the reference arm, correct, it is the standard dosing from the label.

在糖尿病週邊神經病變的II期臨床試驗中，Lyrica的劑量是依照說明書建議的標準劑量，沒錯。週邊神經病變II期研究的劑量顯然與急性疼痛研究的劑量不同，因為前者是慢性用藥，後者是急性用藥，我們需要進行相應的調整，以達到我們想要的藥物暴露量。但就對照組而言，劑量是依照說明書建議的標準劑量，沒錯。

Lastly, on vanzacaftor, this is -- remember, this is a study that is head-to-head versus TRIKAFTA. The primary endpoint is ppFEV1 because that's the regulatory enabling endpoint. And recall, we have a key secondary endpoint that is on sweat chloride and this is very important because sweat chloride is the direct -- it's the most direct readout of CFTR function. You know that there have been great debates about whether or not there is a ceiling on ppFEV1, we can't have better than normal lung function, right? But in terms of sweat chloride, that is how patients are diagnosed with the disease, and it is very well understood that if we provide better CFTR function benefit that would show up in terms of sweat chloride, that is a secondary endpoint in the Phase III trial, and that's what we've already studied and reported out in a variety of Phase II trials, and it does indeed look to be the case that the Vanza triple is even better than -- I know that's a tall order, but it's even better than TRIKAFTA.

最後，關於Vanzacaftor，請記住，這是一項與TRIKAFTA進行頭對頭比較的研究。主要終點是ppFEV1，因為這是監管機構批准的終點。另外，我們還有一個關鍵的次要終點，即汗液氯化物水平，這非常重要，因為汗液氯化物是CFTR功能的直接指標。您知道，關於ppFEV1是否存在上限，我們無法達到優於正常水平的肺功能，一直存在激烈的爭論，對吧？但就汗液氯化物而言，它是診斷該疾病的依據，而且人們普遍認為，如果我們能改善CFTR功能，那麼汗液氯化物水平就會有所提高，這是III期試驗的次要終點，也是我們在多項II期試驗中已經研究和報告的內容。 Vanza三聯療法似乎確實比TRIKAFTA更好——我知道這要求很高，但它確實比TRIKAFTA更好。

Over to you, Stuart, on the marketplace with that in mind.

接下來就看你的了，斯圖爾特，帶著這種想法去關注市場吧。

Yes. So Mike, just as Reshma said on the study, the primary endpoint is noninferiority versus TRIKAFTA on FEV1, which, as we know, is an incredibly high bar but we will be able to see how vanzacaftor does versus TRIKAFTA in the study. So that's the first thing, just to remind you. As Reshma said, we're also looking at measures of superior CFTR function in patients. And when we've done research with physicians, even if the FEV1 benefit is the same with vanzacaftor. If we can demonstrate improved CFTR function, which, as Reshma said, the pharmacodynamic measure of that is sweat chloride. There is a lot of enthusiasm from physicians for a product which has that profile.

是的。 Mike，正如Reshma在研究中提到的，主要終點是FEV1方面不劣於TRIKAFTA，我們都知道，這是一個非常高的標準，但我們將在研究中觀察vanzacaftor與TRIKAFTA的比較結果。這是第一點，提醒一下。正如Reshma所說，我們也關注患者CFTR功能的改善情況。我們與醫生合作進行的研究表明，即使vanzacaftor在FEV1方面的獲益與TRIKAFTA相同，但如果我們能夠證明CFTR功能有所改善（正如Reshma所說，其藥效學指標是汗液氯化物），那麼醫生們對這種具有上述特徵的產品會非常感興趣。

In addition, just to remind you, vanzacaftor is also going to be a once-a-day regimen as well, which is also considered to be a benefit, particularly for those patients who have compliance challenges as well. So we're very much looking forward to the Phase III results and think there's going to be -- if the results come out as we expect them to, a high level of enthusiasm for vanzacaftor.

此外，需要提醒的是，vanzacaftor 也將採用每日一次的給藥方案，這也被認為是一項優勢，尤其對於那些依從性較差的患者而言。因此，我們非常期待 III 期臨床試驗的結果，並認為如果結果符合預期，vanzacaftor 將會受到廣泛關注和認可。

Super helpful. Could you clarify on the QT, that was a study that's out. Is that -- can you say that, that was completed and offset?

非常有用。關於QT間期，您能解釋一下嗎？那是一項已經公佈的研究。您能說一下，那項研究已經完成並結束了嗎？

Yes. Nothing new to report there. This is -- the QT is a study we do for cardiac function. It's one of our standard studies that we do in the clinical pharmacology around.

是的，沒什麼新的進展。 QT間期是我們用來評估心臟功能的檢查，也是我們臨床藥理學中常用的標準檢查之一。

Last question please, Jack.

傑克，最後一個問題。

The last question will come from Terence Flynn with Morgan Stanley.

最後一個問題將由摩根士丹利的特倫斯·弗林提出。

I was just wondering if, let's say, the theoretical situation where one of the randomized controlled Phase III acute trials is positive and the other is not. Can you still file for approval on that data set? Or do you need 2 positive trials?

我想問的是，假設存在這樣一種理論情況：一項隨機對照III期急性試驗的結果為陽性，而另一項結果為陰性。在這種情況下，是否仍可以基於這組數據申請批准？還是必須有兩項試驗結果均為陽性？

And then, Stuart, I just wondered if you could clarify your comments on 2024 being a foundational year for exa-cel, what that means. Is that -- does that mean you're comfortable with consensus where it stands? Or you think it's going to be somewhat more measured launch? Just want to clarify what foundational means.

斯圖爾特，我想請你解釋一下你關於2024年是exa-cel奠基之年的說法，這具體意味著什麼？是指你對目前的共識感到滿意嗎？還是你認為屆時會採取更謹慎的發布方式？我只是想弄清楚「奠基」的具體意義。

Yes. Terence, this is Reshma. Let me comment on the acute pain, and then I'll turn it over to Stuart. We are very close to having the results from the acute pain program and I'll just leave it at our goal is to have a positive set of 3 studies. And our goal is to file for a broad moderate-to-severe acute pain label.

是的，特倫斯，我是雷什瑪。我先就急性疼痛發表一下看法，然後把麥克風交給史都華。我們很快就能拿到急性疼痛項目的結果了，我只想說，我們的目標是獲得三項研究的陽性結果。我們的目標是申請一個涵蓋中度至重度急性疼痛的廣泛適應症。

Stuart?

史都華？

Yes. And on exa-cel and the comment we made about it being a foundational year, that has nothing to do with consensus. I actually couldn't tell you what consensus is for 2024 for exa-cel to be perfectly honest with you, Terence. It was really a response. We've been asked a lot of questions about what the launch dynamics will look like for exa-cel. And so we thought it was important to remind people of what the patient journey is, and that's obviously going to begin, hopefully, later this year when we get regulatory approval, and it was really to try and provide some context around that multistage journey that patients need to go through to get exa-cel.

是的。關於exa-cel，以及我們之前提到的“奠基之年”，這與共識無關。坦白說，特倫斯，我真的無法告訴你2024年exa-cel的共識是什麼。這其實是一種回應。我們被問了很多關於exa-cel上市策略的問題。所以我們認為有必要提醒大家患者的就醫流程，這顯然會在今年稍後獲得監管部門批准後開始。我們這樣做是為了幫助大家了解患者獲得exa-cel所需的多階段流程。

So that was really the reason for the comment. I was responding to questions we've had about launch dynamics. I do want to reiterate something which I said in my prepared remarks as well, whatever the journey to get there, we see this as being a very large commercial opportunity. There are tens of thousands of patients with severe sickle cell disease and beta thalassemia who could benefit and despite the journey being relatively long, this is a journey that, at the end of it, that has the potential for a lifetime of benefit. So we feel very optimistic about the exa-cel opportunity and we're looking forward to launching.

這就是我發表那番評論的真正原因。我是在回應一些關於產品上市動態的問題。我想重申一下我在事先準備好的發言稿中也提到過的內容：無論實現目標的路途多麼漫長，我們都認為這是一個巨大的商業機會。成千上萬患有嚴重鐮狀細胞貧血症和β地中海貧血的患者有望從中受益，儘管這條路相對漫長，但最終他們可能會終身受益。因此，我們對exa-cel的前景非常樂觀，並期待它的上市。

Thanks, Jack. If you could give the details, please, for callbacks.

謝謝，傑克。如果你能提供詳細信息，以便我們回電，那就太好了。

Yes, ma'am. 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 using the replay access code 2047491. The conference has now concluded. Thank you for attending today's presentation. You may now disconnect.

是的，女士。本次活動的錄音回放將在通話結束後不久提供，您可以撥打 1 (877) 344-7529 或 1 (412) 317-0088，並使用回放接入碼 2047491 收聽。會議現已結束。感謝您參加今天的示範。您可以掛斷電話了。