福泰製藥 (VRTX) 2025 Q1 法說會逐字稿

Good day, and welcome to the Vertex Pharmaceuticals first quarter 2025 earnings call. (Operator Instructions) Please note this event is being recorded.

大家好，歡迎參加 Vertex Pharmaceuticals 2025 年第一季財報電話會議。（操作員指示）請注意，此事件正在被記錄。

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

現在我想將會議交給蘇西麗莎女士。請繼續，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 first quarter 2025 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; Charlie Wagner, Chief Financial Officer; and Duncan McKechnie, SVP North America Commercial Operations and come July 1, Chief Commercial Officer.

大家晚上好。我叫蘇西麗莎 (Susie Lisa)，擔任投資人關係資深副總裁。我很高興歡迎您參加我們的 2025 年第一季財務業績電話會議。在今晚的電話會議上，我們邀請了 Vertex 執行長兼總裁 Reshma Kewalramani 博士發表準備好的演講； Stuart Arbuckle，首席營運長；查理·瓦格納 (Charlie Wagner)，首席財務官；以及北美商業運營高級副總裁 Duncan McKechnie，7 月 1 日將出任首席商務官。

We recommend that you access the webcast slides as you listen to this call. The call is being recorded, and a replay will be available on our website. We will make forward-looking statements on this call that are subject to the risks and uncertainties discussed in detail in today's press release and in our filings with the Securities and Exchange Commission.

我們建議您在收聽此電話會議時存取網路廣播投影片。這次通話正在錄音，重播將在我們的網站上提供。我們將在本次電話會議上做出前瞻性陳述，這些陳述將受到今天的新聞稿和我們向美國證券交易委員會提交的文件中詳細討論的風險和不確定性的影響。

These statements, including, without limitation, those regarding Vertex's marketed medicines for cystic fibrosis, sickle cell disease, beta-thalassemia and moderate to severe acute pain, 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.

這些聲明包括但不限於有關 Vertex 上市的囊性纖維化、鐮狀細胞病、β-地中海貧血和中度至重度急性疼痛藥物、我們的產品線和 Vertex 未來財務業績的聲明，均基於管理層當前的假設。實際結果和事件可能會有重大差異。我還要指出的是，我們將在今晚的電話會議上審查的部分財務結果和指導都是按照非 GAAP 基礎呈現的。

I will now turn the call over to Reshma.

現在我將把電話轉給 Reshma。

Thanks, Susie. Good evening all, and thank you for joining us on the call today. Continuing the momentum from 2024, we've kicked off '25 with another quarter of strong performance across the board. Growing and diversifying revenue as we execute on multiple launches, accelerating programs in pivotal development and advancing the R&D pipeline.

謝謝，蘇西。大家晚上好，感謝您今天參加我們的電話會議。延續 2024 年的良好勢頭，我們以全面強勁的業績開啟了 2025 年。隨著我們執行多項發布、加速關鍵開發項目和推動研發管道，收入不斷增長且多樣化。

We continue to reach more patients with more products and delivered $2.77 billion in revenue in the first quarter, representing 3% growth versus Q1 2024. This year, we are keenly focused on commercialization, and we are pleased with the early launch dynamics and physician and patient feedback on ALYFTREK, our fifth CF medicine, and JOURNAVX, the first oral non-opioid for moderate to severe acute pain in more than two decades, both of which were approved in the US in just the last few months.

我們繼續透過更多產品覆蓋更多患者，第一季實現了 27.7 億美元的收入，比 2024 年第一季成長了 3%。今年，我們非常重視商業化，並且對我們的第五種 CF 藥物 ALYFTREK 和二十多年來第一種用於治療中度至重度急性疼痛的口服非阿片類藥物 JOURNAVX 的早期上市動態以及醫生和患者的反饋感到滿意，這兩種藥物都在過去幾個月內在美國獲得了批准。

With these approvals and the continued global launch of CASGEVY, our gene-edited therapy for sickle cell disease in beta thalassemia, we are significantly expanding the number of patients we serve. We are also sharply focused on advancing the four programs currently in pivotal development. Suzetrigine in diabetic peripheral neuropathy, zimislecel in type 1 diabetes, Inaxaplin in APOL1-mediated kidney disease and POV in IgA nephropathy. Importantly, Three of these Phase 3 programs are on track to complete enrollment of the interim analysis cohort or the full study this year, setting up a series of potential filings in 2026.

隨著這些批准以及我們針對β地中海貧血鐮狀細胞疾病的基因編輯療法 CASGEVY 的持續全球推出，我們正在大幅擴大我們服務的患者數量。我們也高度重視推進目前處於關鍵發展階段的四個項目。Suzetrigine 用於治療糖尿病週邊神經病變，zimislecel 用於治療第 1 型糖尿病，Inaxaplin 用於治療 APOL1 介導的腎臟疾病，POV 用於治療 IgA 腎病變。重要的是，其中三個 3 期項目預計將在今年完成中期分析隊列或全面研究的招募，為 2026 年的一系列潛在申請做好準備。

And as we approach the one-year anniversary of the acquisition of Alpine Immune Sciences, I wanted to highlight two big recent povetacicept related milestones First, we completed enrollment in the interim analysis cohort in the Phase 3 Ranir IgAN trial. And second, we reached agreement with the FDA to advance POV to pivotal development in a second indication, primary membranous nephropathy. This is a notable milestone as Pub continues to deliver on its promise as a pipeline in a product with best-in-class potential. The start of the POI membrane study will also mark our fifth program in pivotal development.

在我們收購 Alpine Immune Sciences 一週年之際，我想強調一下最近與 povetacicept 相關的兩個重大里程碑：首先，我們完成了第 3 階段 Ranir IgAN 試驗中期分析隊列的招募。其次，我們與 FDA 達成協議，將 POV 推進到第二個適應症原發性膜性腎病變的關鍵開發階段。這是一個值得注意的里程碑，因為 Pub 繼續履行其作為具有一流潛力的產品管道的承諾。POI膜研究的啟動也標誌著我們第五個計畫進入關鍵發展階段。

Tonight, I'll limit my R&D comments on the pipeline programs with the most significant new information to share, specifically CF, pain, type 1 diabetes and the kidney programs. Starting with CF. Following our December US approval of a lift truck, we have gained MHRA approval in the UK and a positive CHMP opinion in the EU. As a result, we expect potential approval from the European Commission for a lift truck in the second half of this year, along with potential approvals in Canada, Australia and Switzerland.

今晚，我將把我的研發評論限制在管道項目上，分享最重要的新訊息，特別是 CF、疼痛、 1 型糖尿病和腎臟項目。從 CF 開始。繼去年 12 月我們的堆高機在美國獲得批准後，我們又獲得了英國 MHRA 的批准以及歐盟 CHMP 的正面評價。因此，我們預計歐盟委員會可能會在今年下半年批准堆高機，同時加拿大、澳洲和瑞士也有可能批准堆高機。

These approvals are in addition to the European Commission's early April approval of KAFTRIO for rare mutations, which followed similar approvals for Trikafta rare mutations in the US and Canada late last year. adding hundreds of additional eligible patients in North America and thousands in Europe. These approvals are a direct result of the team's decades-long painstaking work to establish and verify the hypothesis that the three unique binding sites of our CFTR modulators results in overall protein stabilization and have the potential to transform the lives of nearly 95% of patients with CF. Stuart will share more on the US ALYFTREK launch shortly.

這項批准是繼歐盟委員會於 4 月初批准 KAFTRIO 用於治療罕見突變之後的另一項批准，去年年底，美國和加拿大也批准了 Trikafta 用於治療罕見突變。在北美增加了數百名符合條件的患者，在歐洲增加了數千名符合條件的患者。這些批准是該團隊數十年來艱苦工作的直接成果，旨在建立和驗證以下假設：我們的 CFTR 調節劑的三個獨特結合位點可實現整體蛋白質穩定，並有可能改變近 95% CF 患者的生活。史都華將很快分享有關美國 ALYFTREK 發布的更多資訊。

Next on the horizon for our CF small molecule program is the next Gen or NG 3.0 CFTR regimen. With this program, we seek to reach our long-standing goal of bringing most, if not all, patients with CF to normal levels of CFTR function. The backbone of this NG 3.0 combination is VX-828, the most efficacious CFTR corrector that we have ever studied in vitro. It is completing Phase 1 development, and we remain on track to initiate a study with VX-828 in patients with CF before the end of this year.

我們的 CF 小分子計畫的下一步是下一代或 NG 3.0 CFTR 方案。透過該計劃，我們力求實現我們的長期目標，即讓大多數（如果不是全部） CF 患者達到正常的 CFTR 功能水平。NG 3.0 組合的核心是 VX-828，這是我們體外研究過的最有效的 CFTR 校正劑。它即將完成第一階段的開發，我們仍有望在今年年底前啟動針對 CF 患者的 VX-828 研究。

For the ongoing Phase 1/2 study of VX-522 for the approximately 5,000 or so patients who cannot benefit from our CFTR modulators, we have recently implemented a temporary pause to the study as we assess the tolerability issue, given that this remains an active clinical trial, we won't be providing any additional details at this time so as to maintain study integrity. We will update you when we know more.

對於正在進行的 VX-522 第 1/2 期研究，該研究針對大約 5,000 名無法從我們的 CFTR 調節劑中受益的患者，我們最近暫時暫停了該研究，以評估耐受性問題，鑑於這仍然是一項活躍的臨床試驗，我們目前不會提供任何其他細節，以保持研究的完整性。一旦我們了解更多信息，我們將及時通知您。

Moving next to the pain programs. First, the Phase 3 study of Suzetrigine in diabetic peripheral neuropathy, a chronic peripheral neuropathic pain condition that affects over 2 million Americans annually, is well underway with ongoing enrollment and dosing. As a reminder, Suzetrigine has fast track designation for peripheral neuropathic pain and breakthrough designation for diabetic peripheral neuropathy. Next, I'm very pleased to share that the study of oral VX-993, another NaV1.8 inhibitor in acute pain post bunionectomy is on track to complete this quarter, and we expect to report results from this trial in the second half of this year. VX-993 has fast track designation for acute pain in both the oral and IV formulations.

接下來轉到疼痛程序。首先，Suzetrigine 治療糖尿病週邊神經病變的 3 期研究正在順利進行，目前正在進行患者招募和給藥。糖尿病週邊神經病變是一種慢性週邊神經性疼痛疾病，每年影響超過 200 萬美國人。提醒一下，Suzetrigine 已獲得治療週邊神經性疼痛的快速通道資格和治療糖尿病週邊神經病變的突破性資格。接下來，我很高興地告訴大家，另一種用於治療拇囊切除術後急性疼痛的 NaV1.8 抑制劑口服 VX-993 的研究即將在本季度完成，我們預計將在今年下半年報告該試驗的結果。VX-993 口服和靜脈注射劑型均已獲得急性疼痛的快速通道資格。

Lastly, we continue to make solid progress with additional NaV1.8 inhibitors beyond VX-993 as well as in our NAV 1.7 pain signal inhibitor program that may be used alone or in combination with NaV1.8 inhibitors, transitioning now to type 1 diabetes. Zimislecel remains on track to complete enrollment and dosing of its pivotal study this quarter, positioning us for global regulatory submissions in 2026 if the data are supportive. Recall, we expect about 60,000 severe type 1 diabetics who may potentially benefit from this first zimislecel submission.

最後，我們在 VX-993 以外的其他 NaV1.8 抑制劑以及 NAV 1.7 疼痛訊號抑制劑計畫方面繼續取得穩定進展，這些抑制劑可單獨使用或與 NaV1.8 抑制劑聯合使用，目前正在轉向治療 1 型糖尿病。Zimislecel 仍有望在本季度完成其關鍵研究的招募和給藥，如果數據支持，我們將在 2026 年提交全球監管申請。回想一下，我們預計大約有 60,000 名嚴重的 1 型糖尿病患者可能會從首次提交的 zimislecel 中受益。

Based on the high unmet need in T1D and the transformative nature of this therapy zimislecel has multiple global regulatory designations, including RMAT and fast track in the US prime in the EU and the innovation Passport in the UK. In our other T1D work following the recent data from VX-264 or the cells device program, we have returned this approach to the research stage. We continue to make preclinical progress on our other approaches to clock the VX-880 cells from the immune system. These cells have already demonstrated transformative efficacy.

基於第 1 型糖尿病 (T1D) 的巨大未滿足需求和這種療法的變革性質，zimislecel 擁有多項全球監管認證，包括美國的 RMAT 和快速通道、歐盟的 Prime 認證以及英國的創新護照。在我們根據 VX-264 或細胞設備程序的最新數據進行的其他 T1D 工作中，我們已將這種方法恢復到研究階段。我們繼續在其他方法上取得臨床前進展，以從免疫系統中抑制 VX-880 細胞。這些細胞已經顯示出轉化功效。

These approaches include alternative immunosuppressive regimens and gene editing to make hypoimmune-ilit cells, and we look forward to updating you as these programs advance. Finally, a few updates on our kidney portfolio, which now has clinical stage programs in four renal diseases, IgA nephropathy, AM KD membranous nephropathy and ADPKD, or autosomal dominant polycystic kidney disease, starting with polvetasecept, a potential best-in-class dual antagonist of the bath and April cytokines which play a key role in the pathogenesis of B cell-mediated autoimmune diseases.

這些方法包括替代免疫抑制方案和基因編輯以製造低免疫力細胞，我們期待隨著這些項目的進展向您通報最新情況。最後，對我們的腎臟產品組合進行一些更新，目前該組合針對四種腎臟疾病，即 IgA 腎病、AM KD 膜性腎病和 ADPKD（或常染色體顯性多囊腎病）開展臨床階段項目，首先是波維他塞普，它是潛在的最佳的巴斯和 April 細胞因子雙重拮抗劑，在 B 細胞介導的自身免疫性發病機制中的自身免疫性發病機制。

First, in IgAN, as mentioned earlier, I am very pleased to share that we have completed enrollment in the interim analysis cohort of the Rainier Phase 3 trial. Once this cohort completes 36 weeks of treatment, we will conduct the interim analysis and if positive, it will support filing in the first half of 2026 for potential accelerated approval in the US. In addition, our program to support the launch of POV with the subcutaneous auto injector for monthly at-home administration is well underway.

首先，在 IgAN 方面，如前所述，我很高興地告訴大家，我們已經完成了 Rainier 3 期試驗中期分析隊列的招募。一旦該群體完成 36 週的治療，我們將進行中期分析，如果結果呈陽性，將支持在 2026 年上半年提交申請，以獲得美國的潛在加速批准。此外，我們支持推出 POV 的計劃也在順利進行中，該計劃旨在透過皮下自動注射器實現每月在家給藥。

And for full approval, we are making strong progress towards our goal of enrolling the complete cohort of 480 patients in whom we will assess eGFR through week 104. Second, based on the positive results from the Ruby II basket study, we have reached agreement with the FDA to advance Poly to pivotal development in membranous nephropathy. Beginning in the second half of this year, we are planning to initiate a single Phase 2/3 adaptive study of POV versus standard of care with the primary endpoint of complete remission at week 72.

為了獲得全面批准，我們正在朝著目標邁進，即招募 480 名患者的完整隊列，我們將對他們進行到第 104 週的 eGFR 評估。第二，基於Ruby II籃子研究的正面成果，我們已與FDA達成協議，推動Poly在膜性腎臟病領域的關鍵性開發。從今年下半年開始，我們計劃啟動一項單獨的 2/3 期適應性研究，比較 POV 與標準治療，主要終點是第 72 週的完全緩解。

Next, two highlights on Inaxiplan for APOL1-mediated kidney disease or AMKD. First, we remain on track to complete enrollment in the interim analysis cohort of the amplitude pivotal trial this year. Amplitude is a study of primary AMKD. That is to say, patients with two APOL1 variants and no additional renal-related comorbidities. After completing enrollment, when this cohort reaches 48 weeks of treatment, we will conduct an interim analysis. If positive, we will be poised to file for potential accelerated approval in the US.

接下來，Inaxiplan 針對 APOL1 介導的腎臟疾病或 AMKD 的兩大亮點。首先，我們仍有望在今年完成振幅關鍵試驗的中期分析隊列的招募。Amplitude 是對原發性 AMKD 的研究。也就是說，患者有兩種 APOL1 變異體，且沒有其他腎臟相關合併症。完成招募後，當該隊列達到 48 週的治療時，我們將進行中期分析。如果結果為陽性，我們將準備向美國申請潛在的加速批准。

Second, based on the positive proof-of-concept results of inaxipline in primary AMKD, the momentum in the Phase 3 study and interest from the community, we recently initiated the amplified study, amplified is a Phase 2 proof-of-concept study of inaxaplin in patients with AMKD and other comorbidities, including type 2 diabetes. This study is enrolling in dosing patients.

其次，基於 inaxipline 在原發性 AMKD 中取得的積極概念驗證結果、第 3 階段研究的勢頭以及社區的興趣，我們最近啟動了擴大研究，擴大研究是針對 inaxipline 在患有 AMKD 和其他合併症（包括 2 型糖尿病）的患者中進行的第 2 階段概念驗證研究。此項研究正在招募給藥患者。

To close on our kidney pipeline, a few comments on VX-407 in autosomal dominant polycystic kidney disease or ADPKD. VX-407 is a first-in-class small molecule protein folding corrector that is designed to target the underlying cause of ADPKD by restoring PC1 protein function, thereby reducing total kidney volume and preventing progression to kidney failure. As a reminder, by way of its mechanism of action, VX-407 addresses up to 10% of ADPKD patients and as in CF, we will seek to expand the eligible patient population with serial innovation over time. We have completed the Phase 1 trial of VX-407 and the PK and safety are supportive of advancement.

最後，我們來總結我們的腎臟治療產品線，對 VX-407 在常染色體顯性多囊性腎病變 (ADPKD) 的應用做幾點評論。VX-407 是一流的小分子蛋白質折疊校正劑，旨在透過恢復 PC1 蛋白質功能來針對 ADPKD 的根本原因，從而減少腎臟總體積並防止進展為腎衰竭。提醒一下，透過其作用機制，VX-407 可治療多達 10% 的 ADPKD 患者，並且與 CF 一樣，我們將尋求隨著時間的推移透過連續創新來擴大符合條件的患者群體。我們已經完成了 VX-407 的第一階段試驗，並且 PK 和安全性支持研究的進展。

The Phase 2 proof-of-concept study is designed as a 52-week single-arm study of 24 patients that will evaluate the efficacy of VX-47 as measured by the height adjusted total kidney volume and we are on track to initiate this study in the second half of this year. For five years now, at the end of my remarks, I've turned the call over to Stuart. I'll do so for the final time tonight. Let me acknowledge and thank Stuart once again for the incredible run at Vertex and wish him the very best in retirement.

階段 2 概念驗證研究旨在對 24 名患者進行為期 52 週的單組研究，以身高調整後的總腎臟體積來評估 VX-47 的療效，我們計劃在今年下半年啟動這項研究。五年來，每次我結束演講時，我都會把發言權交給史都華。今晚我將最後一次這樣做。讓我再次感謝斯圖爾特在 Vertex 的出色表現，並祝他退休後一切順利。

With that, I'll now turn the call over to Stuart, And Duncan for a commercial update.

說完這些，我現在將電話轉給史都華和鄧肯，以了解商業更新情況。

Thanks very much, Reshma. I'll focus my comments tonight on the CF franchise, including the launch of a life and the continuing global launch of CASGEVY, building on the foundation we established in 2024. I'll then turn it over to Duncan to provide an update on the US launch of generics in acute pain.

非常感謝，Reshma。今晚我將重點介紹 CF 系列，包括生命的推出以及 CASGEVY 的持續全球推出，這一切都建立在我們於 2024 年建立的基礎之上。然後，我將把主題交給鄧肯，讓他介紹美國推出治療急性疼痛的仿製藥的最新情況。

Starting with CF with our existing portfolio of CF medicines, KALYDECO, ORKAMBI, SYMDEKO and TRIKAFTA we have continued to grow the number of eligible patients taking our CFTR modulators. As expected, we also continue to make regulatory and reimbursement progress that enables us to expand to younger patients. KALYDECO is now approved down to one month old. Patients with rare mutations, TRIKAFTA recently secured US and EMA approvals to expand the label for additional mutations, which means that the triple combination is now approved for mutations present in nearly 95% of all CF patients in our core markets and patients in new geographies such as Brazil.

從 CF 開始，我們現有的 CF 藥物組合包括 KALYDECO、ORKAMBI、SYMDEKO 和 TRIKAFTA，我們不斷增加服用 CFTR 調節劑的合格患者數量。正如預期的那樣，我們也繼續在監管和報銷方面取得進展，這使我們能夠擴展到更年輕的患者。KALYDECO 的核准時間現已縮短至一個月。患有罕見突變的患者，TRIKAFTA 最近獲得美國和 EMA 的批准，以擴大用於治療其他突變的標籤，這意味著三聯療法現已被批准用於治療我們核心市場中近 95% 的 CF 患者以及巴西等新地區的患者所患的突變。

In addition, as a result of better patient care, including the availability of our CFTR modulators, people with CF are now living longer than ever before. Now turning to the ALYFTREK launch. Our fifth CFTR modulator approved to treat the underlying cause of CF. In Phase 3 studies, when compared head-to-head with TRIKAFTA, ALYFTREK demonstrated noninferiority on lung function and further improvements in CFTR function as measured by sweat chloride. ALYFTREK was also approved by the FDA for an additional 31 mutations, not covered by the TRIKAFTA label and offers the convenience of once-daily dosing.

此外，由於患者護理的改善，包括我們 CFTR 調節劑的可用性，CF 患者的壽命現在比以往任何時候都更長。現在轉向 ALYFTREK 發布。我們的第五種 CFTR 調節劑已獲準用於治療 CF 的根本病因。在 3 期研究中，與 TRIKAFTA 進行正面比較時，ALYFTREK 在肺功能方面表現出非劣效性，並且透過汗液氯化物測量進一步改善了 CFTR 功能。ALYFTREK 還獲得了 FDA 批准，可用於治療 TRIKAFTA 標籤未涵蓋的另外 31 種突變，並可方便地每日服用一次。

Recall too, that ALYFTREK carries a meaningfully lower royalty burden for Vertex and extends our composition of matter patent protection from 2037 for TRIKAFTA into 2039 for a lift track. We're pleased with the early US launch progress, and we're seeing uptake in all of the patient groups eligible for a ALYFTREK. Those naive to CFTR modulators or with newly approved rare mutations where we have seen the fastest initial uptake. Patients who've discontinued one of our other CFTR modulators and patients switching from TRIKAFTA who seek greater improvement in CFTR function and/or the convenience of once-daily dosing.

還記得，ALYFTREK 對 Vertex 來說具有顯著較低的專利費負擔，並且將 TRIKAFTA 的物質組成專利保護期從 2037 年延長至 2039 年（針對升降軌道）。我們對美國早期的推出進展感到滿意，我們看到所有符合 ALYFTREK 條件的患者群體都在接受該療法。對於對 CFTR 調節劑尚不熟悉或患有新批准的罕見突變的人來說，我們看到了最快的初始吸收。已停止使用我們的其他 CFTR 調節劑的患者和從 TRIKAFTA 轉換的患者，尋求 CFTR 功能的更大改善和/或每日一次給藥的便利性。

ALYFTREK prescriptions are off to a strong start as patients and physicians familiarize themselves with the ALYFTREK clinical data, including statistically significant lower sweat chloride than TRIKAFTA, the liver monitoring requirements when initiating therapy and the convenience of once-daily dosing. We continue to expect the majority of patients in the US who are currently on CFTR modulator therapy, will switch to ALYFTREK over time. We also look forward to launching a ALYFTREK later this year in the UK and other countries pending ongoing regulatory approvals.

隨著患者和醫生逐漸熟悉 ALYFTREK 的臨床數據，包括與 TRIKAFTA 相比具有統計學意義的更低的汗液氯化物含量、開始治療時的肝臟監測要求以及每日一次給藥的便利性，ALYFTREK 處方取得了良好的開端。我們繼續預計，目前接受 CFTR 調節劑治療的美國大多數患者將隨著時間的推移轉為接受 ALYFTREK 治療。我們也期待在今年稍後在英國和其他國家推出 ALYFTREK，等待監管部門的批准。

Transitioning now to CASGEVY, our transformative onetime treatment for patients with sickle cell disease and beta thalassemia and since regulatory approvals in late 2023 and early 2024, the rollout of CASGEVY is progressing as we expected and gathering momentum across all regions. ATC activations and patient initiations continue to increase. as we now have more than 65 authorized treatment centers, nearing our goal to activate approximately 75 total ATCs globally. We're also encouraged to see many ATCs have now collected cells from multiple patients.

現在我們轉向 CASGEVY，這是我們針對鐮狀細胞病和β地中海貧血患者的變革性一次性治療方法，自 2023 年底和 2024 年初獲得監管部門批准以來，CASGEVY 的推出正在按我們預期的方式進行，並在所有地區獲得發展勢頭。ATC 活化和患者啟動持續增加。現在我們擁有超過 65 個授權治療中心，已接近實現在全球範圍內啟動約 75 個 ATC 的目標。我們也很高興地看到許多 ATC 現在已經從多名患者身上收集了細胞。

As to specifics on the other important marker of our progress since launch, approximately 90 patients have now had their first cell collections, meaning they have begun the patient treatment journey. Encouragingly, more than twice that number of patients has been referred by their physicians to ATCs to initiate the treatment process. And in Q1, 8 patients completed their treatment journey and received their infusions of CASGEVY edited cells.

至於我們自推出以來取得進展的另一個重要標誌的具體情況，目前大約有 90 名患者已經進行了第一次細胞採集，這意味著他們已經開始了患者治療之旅。令人鼓舞的是，有兩倍多的患者被醫生轉介至 ATC 開始治療。在第一季度，有 8 名患者完成了治療並接受了 CASGEVY 編輯細胞的輸注。

With regard to access and reimbursement, we continue to make progress on the CASGEVY payer front. In the US, formal commercial coverage is either in place or provided through single case agreements. For Medicaid patients who represent about 45% of total patients, the majority of states have joined the CMMI demonstration project for cell and gene therapy access model, enabling fertility coverage for these patients and providing an alternative seamless approach for ATCs and states to the existing case-by-case coverage and state agreements.

關於訪問和報銷，我們在 CASGEVY 付款人方面繼續取得進展。在美國，正式的商業保險要么已經到位，要么通過單案協議提供。對於佔患者總數約 45% 的醫療補助患者，大多數州都加入了 CMMI 細胞和基因治療獲取模式示範項目，為這些患者提供了生育覆蓋，並為 ATC 和各州提供了一種替代的無縫方法，以取代現有的逐案覆蓋和州協議。

In Europe, we have now secured reimbursed access for both sickle cell disease and beta-thalassemia patients in England, Wales, Denmark, Austria and Luxembourg. And in the Middle East, we have reimbursement in Bahrain Saudi Arabia and recently added coverage in the majority of Emirates in the UAE. The interest in CASGEVY continues to be incredibly high in the sickle cell disease and beta thalassemia patient and physician communities globally, and uptake is accelerating as access and reimbursement is secured and familiarity with the process for collecting cells and infusing this truly transformative treatment growth.

在歐洲，我們現在已經為英格蘭、威爾斯、丹麥、奧地利和盧森堡的鐮狀細胞疾病和β地中海貧血患者提供了報銷服務。在中東，我們在巴林沙烏地阿拉伯獲得了報銷，最近在阿聯酋的大多數酋長國增加了保險範圍。全球鐮狀細胞疾病和β地中海貧血患者和醫生群體對 CASGEVY 的興趣持續高漲，隨著可及性和報銷的保障以及對收集細胞和注入過程的熟悉，這種真正具有變革性的治療增長正在加速。

The impact of CASGEVY is best captured by the real-world feedback from patients, caregivers and physicians. It's been inspiring to hear that caster patients now feel able to live their lives in ways they never have before. Whether that means having the energy to play with their kids, taking up snowboarding, without fear that the cold might bring on a pain crisis or investing in their education and careers given expectations now for a longer and healthier life. It is a privilege to be part of their journey.

CASGEVY 的影響最好透過來自患者、照護者和醫生的真實回饋來體現。聽到腳氣患者現在能夠以前所未有的方式生活，令人鼓舞。這是否意味著他們有精力陪孩子玩耍，去滑雪，而不用擔心寒冷會帶來疼痛危機，或者在人們期望更長壽、更健康的生活的情況下投資於他們的教育和事業。我很榮幸能夠參與他們的旅程。

I'll close my comments today by saying what a true honor it has been to serve patients, employees and shareholders as the Chief Commercial Officer and Chief Operating Officer at Vertex. The company has never been better positioned from a scientific, commercial, financial or people perspective, and I look forward to following its continued success, including with Duncan as the new Chief Commercial Officer.

今天，我想以以下這句話結束我的演講：作為 Vertex 的首席商務官和首席營運官，能夠為患者、員工和股東服務是我的榮幸。從科學、商業、財務或人員的角度來看，該公司從未處於如此有利的地位，我期待它繼續取得成功，包括鄧肯擔任新任商務長。

I'll now hand over to Duncan to provide an update on the latest chapter in our commercial diversification with the exciting launch of generics in moderate to severe acute pain.

現在我將把時間交給鄧肯，讓他介紹我們商業多元化的最新進展，包括令人興奮的中度至重度急性疼痛仿製藥的推出。

Thank you, Stuart. It has been a privilege to know you for over 35 years and work with you at Vertex for the last 12. I wish you every happiness in your retirement. JOURNAVX received FDA approval on January 30, and has been available at retailers since mid-March. Although it's early days, we are seeing a strong reception for a novel non-opioid option for the treatment of moderate to severe acute pain. We are pleased with the early launch, including broad retail pharmacy stocking, progress of reimbursement discussions and payer coverage, P&T committee reviews the breadth of usage to date and media coverage. To give you a sense of JOURNAVX progress thus far, I'll detail several key elements of our launch plan.

謝謝你，斯圖爾特。我很榮幸認識您 35 年多，並在過去的 12 年裡與您在 Vertex 共事。祝您退休後生活幸福快樂。JOURNAVX 於 1 月 30 日獲得 FDA 批准，並於 3 月中旬在零售商處發售。儘管還處於早期階段，但我們看到，對於治療中度至重度急性疼痛的新型非鴉片類藥物，人們的接受度很高。我們對早期的發布感到滿意，包括廣泛的零售藥局庫存、報銷討論和付款人覆蓋範圍的進展、P&T 委員會審查迄今為止的使用範圍和媒體報道。為了讓您了解 JOURNAVX 迄今為止的進展，我將詳細介紹我們的發布計劃的幾個關鍵要素。

One, let me start with retail pharmacy stocking, which is crucial given the acute nature of pain. By mid-March, JOURNAVX was available at approximately 33,000 pharmacy locations including nearly every location for the three largest pharmacy chains in the country as well as over a dozen regional chains nationwide; two, I'm also happy to report that we've made rapid progress with payers, which is a testament to their appreciation for the generics clinical profile and the importance of a non-opioid option in the treatment of acute pain.

首先，讓我先從零售藥局的庫存說起，考慮到疼痛的急性性質，這一點至關重要。截至 3 月中旬，JOURNAVX 已在約 33,000 家藥局提供，其中包括全國三大連鎖藥局的幾乎所有門市以及全國十幾家區域連鎖藥局；第二，我很高興地報告，我們與付款人的合作取得了快速治療，這證明了他們對仿製藥臨床概況以及非阿片類藥物在急性疼痛中的讚賞的重要性。

As of May 1, across commercial and government payers, 94 million lives already have covered access to JOURNAVX and 42 million have unrestricted access without the need to complete prior authorizations or step edits. With commercial payers, our negotiations continue to progress favorably. We've recently reached a formal coverage agreement with one of the large national pharmacy benefit managers to make generics available to their customers, collectively representing 22 million commercial lives.

截至 5 月 1 日，在商業和政府付款人中，已有 9400 萬人享受了 JOURNAVX 的訪問權限，4200 萬人可以不受限制地訪問，無需完成事先授權或分步編輯。我們與商業付款人的談判繼續取得良好進展。我們最近與一家大型全國性藥品福利管理公司達成了正式的承保協議，向其客戶提供仿製藥，總共惠及 2,200 萬商業生命。

In Medicare, we continue to engage with Medicare plans to secure off-cycle coverage in 2025 and 2026 coverage in line with Medicare bid cycle timing. For Medicaid patients, 10 state Medicaid plans and now providing unrestricted access to generics, meaning no prior authorization or step edit requirements and co-pays as low as $3 to $5 a as is common practice for Medicaid. We expect the coverage across commercial, Medicare and Medicaid payers will expand through 2025.

在醫療保險方面，我們繼續與醫療保險計劃合作，以確保在 2025 年和 2026 年實現與醫療保險投標週期時間一致的非週期性覆蓋。對於醫療補助 (Medicaid) 患者，10 個州的醫療補助計劃現在提供不受限制的仿製藥使用權，這意味著無需事先授權或分步編輯要求，共同支付費用低至 3 至 5 美元，這是醫療補助的常見做法。我們預計到 2025 年，商業、醫療保險和醫療補助支付者的覆蓋範圍將擴大。

Three, a key area of focus is hospital P&T committees. As a reminder, we are prioritizing approximately 2,000 hospitals, many of which will add up to 150 health care systems or integrated delivery networks. More than one-third of these target health care systems have already taken steps to initiate P&T reviews of JOURNAVX and some have already added it on to their formulary.

三、重點關注領域是醫院P&T委員會。提醒一下，我們優先考慮大約 2,000 家醫院，其中許多醫院將組成 150 個醫療保健系統或綜合交付網路。超過三分之一的目標醫療保健系統已經採取措施啟動對 JOURNAVX 的 P&T 審查，有些系統已經將其添加到其處方集中。

Four, turning to patients. Our patient support programs are working as designed to provide a smooth and positive patient experience so that eligible patients who are prescribed genetics for their acute pain get access to the medicine for an interim period while payer coverage decisions are made; five, shifting to the policy landscape we are encouraged by the continued momentum and interest by federal and state policymakers to provide equal access to non-opioids. The critical need for non-opioid options was underscored by the presentation of new research at the American Academy of Pain Medicine in April.

四、轉向患者。我們的患者支援計劃正在按計劃進行，旨在為患者提供順暢、積極的體驗，以便符合條件的、因急性疼痛而接受基因治療的患者能夠在付款人承保決定做出期間暫時獲得藥物；五、轉向政策格局，我們對聯邦和州政策制定者繼續提供平等獲取非阿片類藥物的機會的勢頭和興趣感到鼓舞。今年 4 月，美國疼痛醫學學會公佈的一項新研究強調了非鴉片類藥物治療的迫切需求。

Our health economics analysis indicates that replacing just 25% of current acute pain prescriptions for opioids with nonopioids like JOURNAVX could deliver annual cost savings of $4.5 billion to the health care system and could prevent up to 260,000 cases of opioid use disorder and approximately 9,000 overdose deaths over the next 15 years.

我們的衛生經濟學分析表明，僅用 JOURNAVX 等非阿片類藥物取代目前 25% 的阿片類急性疼痛處方，就可以為醫療保健系統每年節省 45 億美元的成本，並可在未來 15 年內預防多達 260,000 例阿片類藥物使用障礙和約 9,000 例過量死亡。

With respect to state legislation, to date, nearly 35 states have already either enacted or proposed legislation to support the use of nonopioids. At the federal level, I'll highlight the NOPAIN Act, which in January, began providing an add-on payment for non-opioids used in Medicare patients in the hospital outpatient or ambulatory surgery center settings. We continue to expect JOURNAVX to be added near term to the list of medicines approved for this add-on payment.

在州立法方面，迄今為止，已有近 35 個州頒布或提出了支持使用非鴉片類藥物的法案。在聯邦層面，我要強調的是《NOPAIN法案》，該法案於今年1月開始為在醫院門診或門診手術中心接受醫療保險的患者使用的非阿片類藥物提供附加支付。我們繼續預期 JOURNAVX 將在近期內加入此項附加付款核准的藥品清單。

Lastly, an important indicator of our launch progress and a reflection of the unmet need in moderate to severe acute pain is that more than 20,000 prescriptions were successfully filled for JOURNAVX as of April 18. While it is early days in the launch, we are very encouraged by the breadth of physician types writing prescriptions for JOURNAVX as well as the wide range of pain types being treated, which is aligned with JOURNAVX broad label. We continue to execute on the opportunity to transform the treatment of pain while also creating another multibillion-dollar franchise for Vertex.

最後，我們推出進展的一個重要指標和中度至重度急性疼痛未滿足需求的反映是，截至 4 月 18 日，JOURNAVX 已成功配出超過 20,000 張處方。雖然推出尚處於初期階段，但我們對為 JOURNAVX 開處方的醫生類型的廣度以及所治療的疼痛類型的廣泛性感到非常鼓舞，這與 JOURNAVX 廣泛的標籤相一致。我們將繼續抓住機會，改變疼痛的治療方法，同時也為 Vertex 創造另一個價值數十億美元的特許經營權。

To conclude, we are in a new era of commercial diversification at Vertex, and we look forward to bringing our transformative therapies to more and more patients and to keeping you updated on our progress.

總而言之，Vertex 正處於商業多元化的新時代，我們期待為越來越多的患者帶來我們的變革性療法，並讓您了解我們的進展。

I'll now turn the call over to Charlie to review the financials.

我現在將電話轉給查理審查財務狀況。

Thanks, Duncan. Vertex's Q1 2025 results demonstrate our consistent strong performance and attractive growth profile. First quarter 2025 total revenue increased 3% year over year to $2.77 billion. US revenue growth of 9% year over year was driven by ongoing patient demand, higher net realized pricing and the early launch of a lift track. As expected, ex US revenue in the quarter declined and was down 5% year on year.

謝謝，鄧肯。Vertex 2025 年第一季的業績證明了我們持續強勁的業績和誘人的成長前景。2025 年第一季總營收年增 3%，達到 27.7 億美元。我們營收年增 9%，這得益於持續的患者需求、更高的淨實現價格以及早期推出的升降軌道。正如預期的那樣，本季除美國以外的收入下降，年減 5%。

Recall that outside the US, Q1 2024 benefited from increased channel inventory due to the majority of Russia shipments occurring early in that year. In Q1 2025, Russia revenue was negatively impacted by the availability of an illegal copy product. Excluding the impact of the revenue decline in Russia, ex US CF revenue growth would have increased in the low single digits. Included in Q1 total revenue was $14 million from CASGEVY and $10 million of collaboration revenue. First quarter 2025 combined non-GAAP R&D acquired IP R&D and SG&A expenses were $1.23 billion, an increase of 21% compared to $1.02 billion in the first quarter of 2024.

回想一下，在美國以外，由於俄羅斯的大部分出貨量發生在當年年初，因此 2024 年第一季受益於通路庫存的增加。2025 年第一季度，俄羅斯的收入受到非法複製產品的負面影響。排除俄羅斯收入下降的影響，除美國以外的CF收入成長率將達到低個位數。第一季總收入包括 CASGEVY 的 1,400 萬美元和 1,000 萬美元的合作收入。2025 年第一季非 GAAP 研發收購 IP 研發及銷售、一般及行政費用合計為 12.3 億美元，較 2024 年第一季的 10.2 億美元成長 21%。

The most significant increases in R&D and SG&A expenses versus prior year were due to rapid advancement of our broad pipeline, including clinical trials for IgAN, pain and type 1 diabetes as well as the build-out of commercial capabilities in pain. First quarter 2025 non-GAAP acquired IPR&D expenses were $20 million compared to $77 million in the first quarter of 2024. First quarter 2025 non-GAAP operating income was $1.18 billion compared to $1.34 billion in non-GAAP operating income in the first quarter of 2024. First quarter 2025 non-GAAP effective tax rate was 18.8%. First quarter 2025 non-GAAP earnings per share were $4.06 compared to $4.76 in the first quarter of 2024 and primarily due to increased operating expenses as well as lower interest income.

與前一年相比，研發和銷售、一般及行政費用的顯著增長是由於我們廣泛的產品線的快速發展，包括針對 IgAN、疼痛和 1 型糖尿病的臨床試驗以及疼痛商業能力的建設。2025 年第一季非 GAAP 收購的 IPR&D 費用為 2,000 萬美元，而 2024 年第一季為 7,700 萬美元。2025 年第一季非 GAAP 營業收入為 11.8 億美元，而 2024 年第一季非 GAAP 營業收入為 13.4 億美元。2025 年第一季非公認會計準則有效稅率為 18.8%。2025 年第一季非 GAAP 每股收益為 4.06 美元，而 2024 年第一季為 4.76 美元，主要原因是營運費用增加以及利息收入減少。

We ended the quarter with $11.4 billion in cash and investments after deploying approximately $425 million to repurchase more than 930,000 shares in the first quarter. Overall, our priorities for cash deployment remain unchanged. Now switching to guidance. Given the strong start and clear line of sight to the balance of the year, we are raising the low end of our 2025 total revenue guidance from $11.75 billion to a revised range of $11.85 billion to $12 billion, representing growth of approximately 8% at the midpoint at current exchange rates. This outlook reflects our expectation for continued growth from our portfolio of CF medicines, including the ongoing launch of ALYFTREK in the US, followed by other regions later this year.

在第一季投入約 4.25 億美元回購超過 93 萬股股票後，本季末我們擁有 114 億美元的現金和投資。整體而言，我們的現金部署重點保持不變。現在轉向指導。鑑於今年的強勁開局和清晰的預期，我們將 2025 年總收入預期的低端從 117.5 億美元上調至 118.5 億美元至 120 億美元的修訂範圍，按當前匯率計算，中間值增長率約為 8%。這一前景反映了我們對 CF 藥物組合持續成長的預期，包括正在美國推出的 ALYFTREK，以及今年稍後在其他地區推出的 ALYFTREK。

We believe the illegal copy issue is isolated to Russia and is fully included in our outlook. Guidance also includes a continued ramp-up in CASGEVY revenue as we treat more patients in geographies where we have secured regulatory approval and reimbursement. In addition, guidance reflects a revenue contribution from JOURNAVX primarily in the second half of 2025. And as a reminder, we expect volumes will ramp ahead of revenue due to financial assistance programs that are designed to provide eligible patients with immediate access while we work to secure broad sustainable payer coverage.

我們認為非法複製問題僅存在於俄羅斯，並且已完全納入我們的展望。該指引還包括，隨著我們在獲得監管部門批准和報銷的地區治療更多的患者，CASGEVY 收入將繼續增加。此外，該指引主要反映了 JOURNAVX 在 2025 年下半年的收入貢獻。需要提醒的是，我們預計，由於財政援助計劃旨在為符合條件的患者提供即時治療，同時我們努力確保廣泛且可持續的付款人覆蓋，因此治療量將超過收入。

Recently announced positive coverage decisions are included in our revenue guidance. As a result of these positive trends and as implied in our guidance range, we expect growth to accelerate over the remainder of the year delivering another strong year for Vertex in 2025. For combined non-GAAP R&D acquired IP R&D expenses and SG&A, there is no change to our guidance range of $4.9 billion to $5 billion for the full year 2025. Consistent with prior guidance, this includes approximately $100 million in projected IP R&D charges.

最近宣布的積極報道決定已包含在我們的收入指導中。由於這些正面趨勢以及我們的指導範圍所暗示，我們預計今年剩餘時間內的成長將加速，使 Vertex 在 2025 年再次取得強勁成長。對於非 GAAP 研發獲得的 IP 研發費用和銷售、一般及行政費用 (SG&A) 總額，我們對 2025 年全年 49 億美元至 50 億美元的指導範圍沒有變化。與先前的指引一致，這包括約 1 億美元的預計 IP 研發費用。

We will 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 with four and soon to be five Phase 3 studies ongoing and multiple Phase 2s. The planned increase in commercial costs in 2025 supports our increasingly diversified commercial portfolio, a full year of investments to support the launch of JOURNAVX and potential near-term launches.

鑑於我們多個中後期臨床開發項目的勢頭，我們將繼續將大部分營運費用投入到研發中，目前有四個、即將有五個 3 期研究正在進行中，還有多個 2 期研究正在進行中。2025 年商業成本的計劃增加支持了我們日益多樣化的商業組合，全年的投資將支持 JOURNAVX 的推出以及潛在的近期推出。

Given our differentiated business model and focus on specialty markets, we can make these targeted investments while maintaining attractive profitability and cash flow. We expect an immaterial cost impact from tariffs based on what we know today due to our low exposure to China and a geographically diverse supply chain. Additionally, much of our intellectual property is either in the US or the UK. Of course, given the dynamic nature of the tariff situation, including the potential for sector-specific tariffs, this outlook is subject to change.

鑑於我們差異化的商業模式和對專業市場的關注，我們可以進行這些有針對性的投資，同時保持有吸引力的獲利能力和現金流。由於我們對中國的依賴程度較低且供應鏈地理分佈廣泛，根據我們目前所知，我們預期關稅對成本的影響並不大。此外，我們的大部分智慧財產權都在美國或英國。當然，鑑於關稅情勢的動態性，包括特定行業關稅的可能性，這種前景可能會改變。

And finally, on guidance, there is no change to our expected full year 2025 non-GAAP effective tax rate in the range of 20.5% to 21.5%. In closing, Vertex yet again delivered strong results in line with our expectations in Q1 2025, growing and diversifying our revenue with the launch of two new products in the US, ALYFTREK and JOURNAVX continuing the global launch of CASGEVY and making significant pipeline progress across the portfolio. In addition, we now have five programs that are in Phase 3 or soon will be in multiple additional programs with first-in-class and/or best-in-class potential in the clinic in our early and mid-stage pipeline. These and other anticipated milestones of continued progress in multiple disease areas are detailed on slide 17.

最後，根據指引，我們預期 2025 年全年非 GAAP 有效稅率在 20.5% 至 21.5% 之間，不會改變。最後，Vertex 在 2025 年第一季再次取得了符合我們預期的強勁業績，透過在美國推出兩款新產品 ALYFTREK 和 JOURNAVX，繼續在全球推出 CASGEVY，並在整個產品組合中取得了重大的管道進展，實現了收入的成長和多樣化。此外，我們目前有五個項目處於第 3 階段，或很快就會進入多個其他項目，這些項目在我們的早期和中期研發管線中具有在臨床中具有一流和/或一流潛力。投影片 17 詳細介紹了這些以及多個疾病領域持續進展的其他預期里程碑。

We look forward to updating you on our progress on future calls. Before turning the call to Susie to begin the Q&A period, let me also add my thanks and congratulations to Stuart. Stuart is a talented executive and team player who has contributed enormously to Vertex. He's also a friend. As Stuart passes the baton, we look forward to welcoming Duncan to the executive team and to future earnings calls.

我們期待在未來的電話會議上向您通報我們的進展。在將電話轉給蘇西開始問答環節之前，我還要向史都華表示感謝和祝賀。史都華是一位才華橫溢的高管和團隊成員，為 Vertex 做出了巨大貢獻。他也是我的朋友。隨著史都華交接接力棒，我們期待歡迎鄧肯加入執行團隊並參加未來的收益電話會議。

I'll now ask Susie to begin the Q&A.

現在我請蘇西開始問答環節。

Thanks, Charlie. Chuck, can you get us started, please?

謝謝，查理。查克，你能幫我們開始嗎？

(Operator Instructions)

（操作員指示）

Geoffrey Meacham, Citibank.

花旗銀行的傑弗瑞‧米查姆。

Stuart, congrats again on the retirement, Duncan, looking forward to working together. I just had a couple of quick ones. One on ALYTREK track on the launch, what's been the feedback on utilizing sweat chloride as a biomarker more in practice. I wasn't sure if the conversations that you guys are having with pulmonologists on switching from TRIKAFTA is more related to the dosing differential or the sweat chloride or maybe a combination?

斯圖爾特，再次祝賀你退役，鄧肯，並期待與你一起合作。我剛剛吃了幾口。關於 ALYTREK 軌道的發布，在實踐中更多地利用汗液氯化物作為生物標誌物的反饋是什麼。我不確定你們與肺科專家就從 TRIKAFTA 轉換而來的對話是否更多地與劑量差異或汗液氯化物有關，或者兩者兼而有之？

And then just on JOURNAVX, to get an update -- maybe give us a sense for how you're thinking about the chronic pain indications and the design of those studies. I know you haven't had full FDA discussions, but as you look at the prior data maybe give us a sense for where you are with implementing maybe more novel strategies for that study.

然後就在 JOURNAVX 上獲取最新消息——也許可以讓我們了解一下您對慢性疼痛適應症和這些研究的設計的看法。我知道您還沒有與 FDA 進行過全面的討論，但是當您查看先前的數據時，也許我們可以了解您在實施這項研究的更多新穎策略方面所取得的進展。

Geoff, it's Reshma. Let me start with the dynamics and chronic pain work, and then I'll turn it over to Stuart to talk ALYTREK. Really no new news to report to you, Geoff. We're on track to have our end of Phase 2 meeting with the FDA this summer. I really like the study designs the team has come up with. We've done a lot of work on innovating and optimizing the clinical trial designs. And I do expect that we'll have an update for you this summer. Separately, but on a related note, the DPN study, the diabetic peripheral neuropathy study with tX548 is well underway enrollment dosing in that study is going well. Stuart, ALYTREK?

傑夫，我是雷什瑪。讓我先從動力學和慢性疼痛工作開始，然後我會把它交給史都華來談論 ALYTREK。確實沒有什麼新消息可以告訴你，傑夫。我們預計今年夏天與 FDA 結束第二階段會議。我真的很喜歡這個團隊提出的研究設計。我們在創新和優化臨床試驗設計方面做了大量工作。我確實希望今年夏天我們能為您提供最新消息。另外，但相關的是，DPN 研究，使用 tX548 的糖尿病週邊神經病變研究正在順利進行中，研究的入組劑量進展順利。斯圖爾特，ALYTREK？

Yeah, Geoff, on a lift rack, I would say sweatchloride is not routinely used in clinical practice to assess CFTR function, although it's well understood as a measure of CFTR function, but it's not something that's being increasingly adopted in clinical practice despite the ALYTREK data. And in terms of what do people find compelling about the ALYTREK profile, I would say it's really the sum of the parts, Geoff.

是的，傑夫，在升降架上，我想說汗氯化物在臨床實踐中並不常規用於評估 CFTR 功能，儘管它被很好地理解為 CFTR 功能的衡量標準，但儘管有 ALYTREK 數據，它並沒有在臨床實踐中得到越來越多的採用。至於人們認為 ALYTREK 簡介的哪些方面引人注目，我想說，它實際上是各個部分的總和，傑夫。

So it's firstly, the fact that it's demonstrated in large, long, robust clinical trials that it's noninferior to TRIKAFTA, which, as we all know, sets a very high bar in terms of -- and then it is the improvements in CFTR function that people have the potential to access as measured by sweat chloride -- then reinforcing that improved potential efficacy. It's the additional 31 mutations in the ALYTREK label that the FDA granted us versus the TRIKAFTA label.

因此，首先，事實證明，它不遜於 TRIKAFTA，眾所周知，TRIKAFTA 在這方面設定了非常高的標準——其次，人們有可能透過汗液氯化物來改善 CFTR 功能——這進一步增強了潛在療效。與 TRIKAFTA 標籤相比，FDA 授予我們的 ALYTREK 標籤增加了 31 個突變。

And then lastly, but still very importantly for CF patients, it's the once a day versus the twice a day for TRIKAFTA. So I wouldn't say it's one thing more than the others. It's really that combination of benefits that I think people are finding attractive about the ALYTREK profile.

最後，但對 CF 患者來說仍然非常重要的是，TRIKAFTA 是每天一次而不是每天兩次。所以我不會說這比其他事情更重要。我認為正是這些優勢的結合才使得人們發現 ALYTREK 的產品很有吸引力。

Jessica Fye, JPMorgan.

潔西卡費伊（Jessica Fye），摩根大通。

Stuart, congrats again. First, when you -- maybe for Charlie, when you said you expect a material impact from tariffs, just to confirm, is that from the current tariffs? Or is that if biopharma specific tariffs are implemented? And maybe just for our comfort, can you give us a little more detail on Vertex's manufacturing footprint, particularly for a ALYTREK, TRIKAFTA and JOURNAVX and how you think about the company's potential exposure to tariffs if they are implemented?

斯圖爾特，再次恭喜你。首先，當您——也許對於查理來說，當您說您預計關稅會產生重大影響時，只是為了確認一下，這是來自當前關稅的影響嗎？或如果實施生物製藥特定關稅？也許只是為了讓我們感到舒服，您能否向我們詳細介紹一下 Vertex 的製造足跡，特別是 ALYTREK、TRIKAFTA 和 JOURNAVX，以及您如何看待如果實施關稅，該公司可能面臨的關稅風險？

And then just separately on the CF business, can you recap how we should think about the impact of the Russia issue and just lapping last year sales that included Russia. Is that impact largely contained to 1Q? Or is it also impacts 2Q and subsequent quarters? Can you just quantify what that headwind is?

然後，就 CF 業務而言，您能否單獨回顧我們應該如何看待俄羅斯問題的影響，以及去年包括俄羅斯在內的銷售額。這種影響主要集中在第一季嗎？或者它也會影響第二季及後續季度嗎？您能量化一下這種逆風是什麼嗎？

Yeah, Jess, I'm going to start with the CF impact. Listen, the year is off to a great start, and it's very much in line with our internal expectations. We commented in the fourth quarter about this isolated issue in Russia. And it's worked out exactly as we expected. The impact in the first quarter is about $100 million. And for the full year, it's $200 million total. And so all of that is included in our current guidance, which, as you know, is 8% growth at the midpoint, which implies acceleration over the balance of the year.

是的，傑西，我將從 CF 影響開始。聽著，今年開局很好，而且非常符合我們的內部預期。我們在第四季度對俄羅斯的這一孤立問題發表了評論。並且它正如我們預期的那樣發揮作用。第一季的影響約為1億美元。全年總額為 2 億美元。所有這些都包含在我們目前的指導中，如你所知，中間值成長 8%，這意味著今年剩餘時間的成長將加速。

So we feel really good about where we're at, and we can talk more about some of the drivers. I'm going to move on to the second part of your question on tariffs. Given how dynamic the situation is, just I have to limit my comments to what we know today. And so for tariffs that have been announced and are in effect, there is an immaterial impact to Vertex. We have, I think, a very well-balanced global supply chain. We have minimal exposure to China.

因此，我們對目前的狀況感到非常滿意，並且我們可以更多地談論一些驅動因素。我將轉到您關於關稅問題的第二部分。鑑於情況的變化，我只能將我的評論限制在我們今天所知的範圍內。因此，對於已經宣布並生效的關稅，對 Vertex 的影響並不大。我認為，我們擁有非常均衡的全球供應鏈。我們對中國的接觸很少。

The vast majority of our drug product manufacturing for CF is in the United States and most of our IP is concentrated in the US and the UK. So for those reasons, the impact is immaterial. Again, there are all sorts of different tariff concepts that are being discussed including sector-specific tariffs until we know more about what might be implemented, I can't really size the impact for you.

我們的 CF 藥品生產絕大多數在美國進行，我們的大部分智慧財產權也集中在美國和英國。因此，基於這些原因，影響並不大。再次強調，目前正在討論各種不同的關稅概念，包括針對特定行業的關稅，在我們進一步了解可能實施的具體措施之前，我無法真正評估其影響。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

Just following up on ALYTREK. Could you just walk us through who the early adopters are, whether there's -- there seems to be a significant portion coming from a certain pool of patients. And then on JOURNAVX, with regard to the commercial payers here. Can you speak to the nuances with regard to tiered and preferred versus nonpreferred status in your overall plan for positioning.

只要跟進 ALYTREK。您能否向我們介紹一下早期採用者是誰，是否有—似乎有相當一部分來自特定的患者群體。然後是關於 JOURNAVX，關於這裡的商業付款人。您能否談談您在整體定位計劃中關於分級和優先與非優先地位的細微差別？

Sure thing, Salveen. Let me flip that question and ask Stuart to comment on lift Trek and the segments we've talked about on the kinds of patients. And then I'll ask Duncan to give you a little bit more color and texture behind the JOURNAVX launch in general, including where we are with payers. Stuart?

當然可以，薩爾文。讓我反過來問這個問題，請史都華對電梯迷航和我們討論過的有關病人類型的部分進行評論。然後，我會請鄧肯向您詳細介紹 JOURNAVX 的發布情況，包括我們與付款人的現況。史都華？

Yeah. So we are seeing uptake from ALYTREK in all of the patient groups that we identified. There are those that are newly eligible for a CFTR modulator, people who are sort of truly naive have never been on one previously, which includes the RAR mutations that TRIKAFTA was approved for and the additional mutations that ALYTREK track was approved for.

是的。因此，我們看到所有確定的患者群體都對 ALYTREK 的接受度有所提高。有些人剛剛有資格使用 CFTR 調節劑，有些人以前從未使用過這種藥物，其中包括 TRIKAFTA 獲批用於治療 RAR 突變，以及 ALYTREK 軌道獲批用於治療其他突變。

And perhaps not surprisingly, we're seeing the fastest uptake as a percentage of the total pool in that group. But we are also seeing patients who've discontinued coming back to a CFTR modulator, now that a new option like ALYTREK is available. And we are also seeing transitions primarily from TRIKAFTA because that is where the lion's share of CF patients are.

也許並不奇怪，我們看到該群體在總體中所佔比例的成長速度最快。但是，我們也看到已經停止使用 CFTR 調節劑的患者重新開始使用，因為現在有了像 ALYTREK 這樣的新選擇。我們也看到了主要來自 TRIKAFTA 的轉變，因為那裡有大部分 CF 患者。

And on those transitions, we continue to expect the majority of patients will transition to a lift track over time. So we're really seeing uptake in all three of those patient groups. The fastest perhaps not surprisingly in people who've never had a treatment option to treat the underlying cause of their disease before. Duncan?

在這些轉變過程中，我們繼續預期大多數患者將隨著時間的推移過渡到升降軌道。因此，我們確實看到這三組患者都得到了改善。對於那些以前從未有過治療手段來治療疾病根本原因的人來說，最快的可能並不奇怪。鄧肯？

Thank you, Stuart. So to provide you with a little bit of context to the overall launch of JOURNAVX to date, we are incredibly pleased with the early progress, although it's early days, we're seeing tremendous receptivity to a novel non-opioid option for the treatment of moderate to severe acute pain. And over the last 3 months, we've made great progress in terms of broad retail pharmacy stocking, advancing discussions with payers initiating P&T committee reviews as well as broad usage of the product by physicians in multiple different pain settings and conditions in line with the label. To get to your question specifically with regard to tiers and preferred versus nonpreferred, I would say there's an enormous number of payers in the US with an enormous number of different plan designs.

謝謝你，斯圖爾特。因此，為了向您提供迄今為止 JOURNAVX 整體發布情況的一些背景信息，我們對早期的進展感到非常高興，儘管還處於早期階段，但我們看到人們對一種用於治療中度至重度急性疼痛的新型非阿片類藥物表現出了極大的接受度。在過去的三個月裡，我們在廣泛的零售藥局庫存、推進與付款人的討論、啟動 P&T 委員會審查以及醫生根據標籤在多種不同疼痛環境和條件下廣泛使用該產品方面取得了巨大進展。為了具體回答您關於等級和優先與非優先的問題，我想說，美國有大量的付款人，並且有大量不同的計劃設計。

And even within the same payer different tiers can mean different things. So what I would focus on are our goals in this area, and that is to ensure that we have payer coverage in line with label, but to ensure that, that coverage has a few restrictions as possible for physician prescribing and that we ensure the product is affordable for patient -- patients and that we get to all of those outcomes whilst ensuring, of course, that we're optimizing the long-term value for Vertex.

即使對於同一個付款人，不同的層級也可能意味著不同的事情。因此，我要重點關注的是我們在這個領域的目標，那就是確保我們的付款人覆蓋範圍符合標籤，但要確保該覆蓋範圍對醫生處方有盡可能少的限制，並且我們要確保產品對患者來說是可以承受的——患者，而且我們要獲得所有這些結果，同時當然要確保我們正在優化 Vertex 的長期價值。

And so in terms of the progress to date, of the three big PBMs in the US. We have one of those three big PBMs now are covering JOURNAVX for a total of 4 million lives. And I can tell you that the progress that we're making is in line with those overall goals to minimize restrictions for physicians, maximize access for patients and optimize long-term value for Vertex.

就迄今為止美國三大 PBM 的進展而言。我們擁有三大 PBM 之一，目前它正在為 JOURNAVX 提供總共 400 萬人的覆蓋範圍。我可以告訴你們，我們所取得的進展符合這些總體目標，即盡量減少對醫生的限制，盡量增加患者的就醫機會，並優化 Vertex 的長期價值。

Tazeen Ahmad, Bank of America.

美國銀行的塔津·艾哈邁德（Tazeen Ahmad）。

I wanted to ask one a couple actually on JOURNAVX. You talk about the momentum that you've been seeing in the early innings of uptake I'm just curious as to what the profile of the patients are that are the earliest on borders and where in the treatment regimen are these scripts being written?

我實際上想在 JOURNAVX 上問幾個問題。您談到了在早期階段所看到的勢頭，我只是好奇最早到達邊界的患者的情況如何，以及這些腳本在治療方案的哪個階段編寫？

Are they being written for patients on their way home from the hospital? Are they being written while in the hospital for use in the hospital? Or is there any other scenario that we're not thinking about -- and as you think about the second half of the year, in terms of acceleration of recorded sales, would you expect to start to see that already in 2Q? Or is most of that going to be back-end loaded towards the end of the year?

這些是為從醫院回家的病人寫的嗎？這些是在醫院期間寫的，供醫院使用嗎？或者是否存在其他我們沒有考慮到的情況——當您考慮下半年時，就銷售記錄的加速而言，您是否預計會在第二季度開始看到這種情況？或者其中大部分將在年底前完成後端加載？

All right. Duncan, can I ask you a comment on settings of care types of pain on the one hand and then a comment on the volume versus revenue that we've talked about.

好的。鄧肯，我能否請您一方面評論一下疼痛護理類型的設置，然後評論一下我們討論過的數量與收入。

Absolutely. So in terms of the settings of care that we're seeing at this point, we're seeing JOURNAVX used in surgery settings, in non-surgery settings. So for example, we're seeing it used in knee, hip, shoulder replacement, for example, all the way through to ankle sprains, fractured risks, et cetera.

絕對地。因此，就我們目前看到的護理環境而言，我們看到 JOURNAVX 被用於手術環境和非手術環境。例如，我們看到它被用於膝蓋、臀部、肩膀置換，一直到腳踝扭傷、骨折風險等等。

So we're seeing broad uptake of genetics in line with its broad indication and it's being used by a broad range of physicians, for example, orthopedic surgeons, plastics, general surgeons, anesthesiologists and of course, pain specialists and perhaps Importantly, we're also seeing repeat use by physicians, and we're seeing very, very positive feedback from physicians in terms of the clinical effect of JOURNAVX to date.

因此，我們看到遺傳學的廣泛應用與其廣泛的適應症相一致，並且它被廣泛的醫生使用，例如骨科醫生、整形外科醫生、普通外科醫生、麻醉師，當然還有疼痛專家，也許重要的是，我們還看到醫生重複使用，並且我們看到醫生對 JOURNAVX 迄今為止的臨床效果給出了非常非常積極的反饋。

In terms of the recorded sales, I think we've always said that we would see volume ramp in the first half of the year and then revenue in the latter part of the year as we secure payer coverage and can thus pay back some of our patient support programs.

就記錄的銷售額而言，我想我們一直說，隨著我們確保付款人承保並因此能夠償還部分患者支持計劃，我們將在上半年看到銷量增長，然後在下半年看到收入增長。

Evan Seigerman, BMO Capital Markets.

埃文·塞格曼 (Evan Seigerman)，BMO 資本市場。

I really wanted to touch on the uptick of CASGEVY and really, what are some of the key hurdles that are accelerated that are kind of preventing the acceleration of the uptake? Is it fertility issues, health system trust issues I'm involved in intensity of the procedure. How can you really work to overcome those so we can see really this product hit its maximal potential?

我真的很想談談 CASGEVY 的上升趨勢，實際上，加速上升趨勢的一些關鍵障礙是什麼？是生育問題，還是醫療系統信任問題，我都參與了該程序的強度。您如何才能真正努力克服這些問題，以便我們能夠真正看到該產品發揮最大潛力？

Evan, let me ask Stuart to take that one.

埃文，我請史都華來接這個。

Yeah. Evan, thanks for the question. So we did see acceleration in CASGEVY in the first quarter, building on the foundation that we built in 2024. The things that I think are leading to that acceleration and that we expect to continue as we work through the balance of 2025 is firstly, establishing authorized treatment centers. Obviously, we need to have those so that patients can get treated. Securing access and reimbursement. We've done that in large part here in the US in both commercial and government paid.

是的。埃文，謝謝你的提問。因此，我們確實看到 CASGEVY 在第一季加速發展，這是在我們 2024 年建立的基礎之上的。我認為導致這一進程加速的因素以及我們預計在 2025 年餘下時間裡將繼續進行的因素首先是建立授權治療中心。顯然，我們需要這些，以便患者能夠得到治療。確保訪問和報銷。在美國，我們在很大程度上已經透過商業和政府資助的方式完成了這項工作。

And increasingly, we are securing reimbursed access for sickle cell disease and beta thalassemia outside of the US, and we announced a number of those in my prepared remarks. We're also seeing centers get more familiar with the treatment process. Clearly, this is a very innovative medicine. This is a very innovative a new treatment process for them and their patients to consider and as they get more experience with the process, then that's also encouraging them to treat more patients.

我們正在逐步確保美國境外的鐮狀細胞疾病和β地中海貧血的治療能夠得到報銷，並且我們在準備好的發言中宣布了其中的一些內容。我們也看到中心對治療過程越來越熟悉。顯然，這是一種非常創新的藥物。對於他們和他們的患者來說，這是一個非常創新的新型治療過程，隨著他們對過程的經驗越來越豐富，這也鼓勵他們治療更多的患者。

And I mentioned again in my prepared remarks that we've seen a number of our authorized treatment centers have treated multiple patients now. So I think all of those things contribute to the acceleration we saw in the first quarter, and we expect that to continue through the balance of and beyond, and it's that which gives me confidence that CASGEVY truly does have the potential to be a multibillion-dollar product for Vertex.

我在準備好的演講中再次提到，我們已經看到許多授權治療中心已經治療了多名患者。因此，我認為所有這些因素都促成了我們在第一季看到的加速成長，我們預計這種成長將持續到明年及以後，這讓我相信 CASGEVY 確實有潛力成為 Vertex 價值數十億美元的產品。

Michael Yee, Jefferies.

傑富瑞 (Jefferies) 的麥可餘 (Michael Yee)。

We had two questions on pain. I guess a lot of Wall Street is looking at third-party data, actually the script data in total ii with what you guys are talking about, but a lot of people are seeing it sort of decelerate week over week. So maybe could you just confirm or talk to what you see week-over-week -- and are you seeing an acceleration and don't pay too much attention to the data there. And then on 993, we have historically talked about with David and Fred about how that could have significantly better exposure than Susie. So could you just tell us about the data coming up in acute pain in the second half? And how would you compare that to the acute pain data we've already seen and figure out what to do with that?

我們有兩個關於疼痛的問題。我想很多華爾街人士都在關注第三方數據，實際上腳本數據總體上與你們談論的一致，但很多人都看到它每週都在減速。所以也許您能確認一下或談談您每週看到的情況——您是否看到了加速，而不要過多關注那裡的數據。然後在 993 上，我們曾與 David 和 Fred 討論過如何才能比 Susie 獲得更好的曝光率。那麼，您能否向我們介紹下半年出現的劇烈疼痛數據呢？您如何將其與我們已經看到的急性疼痛數據進行比較並找出如何處理這些數據？

Yeah. Mike, it's Reshma. I'll take your second question first on VX-993 and then I'll turn it over to Duncan to tell you a little bit about JOURNAVX, the momentum, the data we see and help you sort of think through the commonly available IMS data and the data that we see, which also includes hospital. On VX-993, so the big news from my prepared remarks on this one is the Phase 2 trial in acute pain post bunionectomy is going to complete in the near term. And I do expect to be able to share results with you in the second half of this year.

是的。麥克，我是雷什瑪。我先回答您關於 VX-993 的第二個問題，然後我會讓 Duncan 向您介紹 JOURNAVX、其勢頭、我們看到的數據，並幫助您思考常見的 IMS 數據和我們看到的數據，其中也包括醫院數據。關於 VX-993，我準備好的演講中提到的重大消息是，拇囊切除術後急性疼痛的 2 期試驗將在近期完成。我確實希望能夠在今年下半年與大家分享結果。

What we're looking for in this program, it is a more potent molecule. It is a molecule where we can dose higher. And so we're looking forward to exploring the full dose range of 993 and what we're really looking for here is two things. One is to have yet another safe and efficacious NaV1.8 inhibitor, and we want that because we are looking for options for NaV1.7, which is making its way preclinically. Certainly, our NaV1.7 inhibitor, when it makes its way into the clinic could be co-formulated with dynamics, that's one possibility and a different possibility is that we have additional options like VX-993. So that's one thing we're looking for.

我們在這個程式中尋找的是一種更有效的分子。這是一種我們可以給予更高劑量的分子。因此，我們期待探索 993 的全部劑量範圍，而我們真正在尋找的是兩件事。一是擁有另一種安全有效的 NaV1.8 抑制劑，我們想要這個是因為我們正在尋找 NaV1.7 的選擇，該抑制劑正在臨床前研究中。當然，我們的 NaV1.7 抑制劑在進入臨床時可以與動力學共同配製，這是一種可能性，另一種可能性是我們還有其他選擇，例如 VX-993。這就是我們正在尋找的東西。

And second is, of course, if it is possible to do better than JOURNAVX on efficacy, boy, we're going to be the ones who do that, and 993 is the first option behind JOURNAVX to tell us if that's possible. Clearly, that will require cross-study comparisons and the limits that come with that. But I'm really happy to see this program move as fast as it has and to share results when available. Duncan, can you say a few words about the momentum of the JOURNAVX scripts and the data sources.

第二，當然，如果它的功效有可能比 JOURNAVX 更好，那我們就要做到這一點，而 993 是 JOURNAVX 之後的第一個選擇，可以告訴我們這是否可能。顯然，這需要進行交叉研究比較以及隨之而來的限制。但我真的很高興看到這個項目進展如此迅速，並在可用時分享結果。鄧肯，您能否談談 JOURNAVX 腳本和資料來源的勢頭。

Yeah. Thank you, Mike, for the question. So maybe just to step back briefly quickly. Our goals in 2025 are really focused on securing payer coverage for generics as well as P&T wins whilst providing, of course, a seamless experience for patients. And as you've seen from our prepared remarks. We're incredibly encouraged by the progress we're making with payers and in terms of P&T coverage as well. In terms of the prescription data, I would make a couple of points. Firstly, the latest total prescription data ending the week of April 25, of Friday, April 25 is 25,000 prescriptions, but I suspect that in the data you're seeing, you're seeing the IMS retail date, which does not include usage in hospitals where we are seeing, of course, uptake.

是的。謝謝麥克提出的問題。因此也許只是短暫地快速退一步。我們 2025 年的目標實際上是集中在確保仿製藥的付款人覆蓋以及 P&T 勝利，同時為患者提供無縫體驗。正如您從我們準備好的發言稿中看到的。我們在付款人方面以及 P&T 覆蓋範圍方面取得的進展令我們感到非常鼓舞。就處方數據而言，我想提出幾點。首先，截至 4 月 25 日星期五當週的最新處方總數為 25,000 張處方，但我懷疑您看到的數據是 IMS 零售日期，其中不包括我們看到的醫院的使用情況，當然，醫院的使用情況也在增加。

So the total number we're giving you includes both the retail data as well as hospital usage. I would say also that we are incredibly early in the launch, and it is incredibly common to see variability week by week in prescription numbers, for example, actually last week's data showed the fastest growth in retail since JOURNAVX became available. So overall, I think as the payer coverage improves and our formulary adoption increases in hospitals, and as physicians get more experience with JOURNAVX, we'll continue to see growth of the products. So overall, we're incredibly happy with the progress, happy with the 25,000 prescriptions to date and looking forward to seeing those numbers grow over time.

因此，我們給您的總數包括零售數據和醫院使用情況。我還想說，我們正處於推出的早期階段，每週處方數量的變化是很常見的，例如，實際上上週的數據顯示，自 JOURNAVX 推出以來，零售量增長最快。所以總的來說，我認為隨著付款人覆蓋範圍的擴大和醫院對我們處方集的採用率的提高，以及醫生對 JOURNAVX 經驗的增加，我們將繼續看到產品的成長。總的來說，我們對進展感到非常高興，對迄今為止的 25,000 張處方感到滿意，並期待看到這些數字隨著時間的推移而增長。

Liisa Bayko, Evercore ISI.

Liisa Bayko，Evercore ISI。

Congratulations on the quarter. I wondering if you could just provide a little more granularity as a follow-up question to one of the earlier ones on JOURNAVX. In terms of the prescriptions, how many of those patients were kind of fully paying patients? What are gross to nets? And how do you anticipate that evolving as the year goes on? What should be the target gross to net, say, by the end of the year? And just then one on type 1 diabetes. If you could just give us a little bit of color on the product zimislecel the 600 patients. who those patients are exactly? I know there's a certain blood type within that as well.

恭喜本季。我想知道您是否可以提供更詳細的資訊作為 JOURNAVX 上早期問題的後續問題。就處方而言，有多少患者是全額付費患者？毛額和淨額是多少？您預計隨著時間的推移，這種情況將如何發展？比如說，到今年年底，毛利潤與淨利的目標應該是多少？接下來是一篇關於第 1 型糖尿病的文章。如果您能為我們簡單介紹一下 zimislecel 這款針對 600 名患者的產品的話。這些病人到底是誰？我知道其中也存在某种血型。

Yeah. Thanks so much, Lisa. Let me ask Charlie to comment on gross to net, and I'll come back and tell you a little bit about zimislecel.

是的。非常感謝，麗莎。讓我請查理對 gross to net 做出評論，然後我會回來告訴你一些關於 zimislecel 的事情。

Yeah, Lisa. Keep in mind that we're only reporting our first quarter results here and the approval was only in the first quarter as well. So -- gross to net is impacted by our patient assistance program. That's going to have a significant impact early in the launch while we work to secure broad and sustainable access as we gain access, the patient assistance programs will fall away and gross to net will start to normalize over the balance of the year. So I'm not going to get any more specific than that. But as we exit 2025 and into '26 we should be approaching something that's a bit more normalized.

是的，麗莎。請記住，我們在此僅報告第一季的業績，且批准也僅在第一季進行。因此，總額與淨額受到我們的患者援助計劃的影響。這將在啟動初期產生重大影響，同時我們將努力確保廣泛和可持續的訪問，隨著我們獲得訪問權，患者援助計劃將逐漸減少，總收入與淨收入將在今年餘下時間內開始正常化。所以我不會說得更具體了。但隨著我們走出 2025 年、進入 2026 年，我們應該會接近更正常化的狀態。

And then, Lisa, on the zimislecel program, -- you'll remember that this first program targets about 60,000 people in the US and Canada and Europe that are the most severe of our type 1 diabetics. These are people who have very brittle diabetes high highs in terms of sugar and low lows and multiple SHEs or symptomatic hypoglycemic episodes.

然後，麗莎，關於 zimislecel 計劃，你會記得，這個第一個計劃針對的是美國、加拿大和歐洲約 60,000 名病情最嚴重的 1 型糖尿病患者。這些人患有非常脆弱的糖尿病，血糖時高時低，並且會出現多次 SHE 或症狀性低血糖發作。

So this first filing that we're looking for, the enrollment in dosing should be done in the near term. I said by the end of the quarter, we'll set us up for that filing sometime next year that is for about 60,000 patients. We're then looking to expand that not only in terms of the patient numbers that can be served, including immunosuppression, but also then moving to alternative immunosuppression and then, of course, our gene-edited programs and other programs to clock our cells so that immunosuppression is not necessary. So that's sort of the trajectory that we're looking at first filings, I expect we'll start next year, and that's for about 60,000 patients. Those are the most severe of T1D patients.

因此，我們正在尋找的第一份文件，劑量登記應該在短期內完成。我說過，到本季末，我們將在明年某個時候為大約 6 萬名患者做好備案準備。我們希望擴大免疫抑制治療的範圍，不僅要增加可治療的患者數量，還要轉向替代免疫抑制治療，當然還有我們的基因編輯程序和其他程序來控制細胞，這樣就不需要免疫抑制了。這就是我們在研究第一批申請時的軌跡，我預計我們將從明年開始，大約有 60,000 名患者。這些是病情最嚴重的第 1 型糖尿病患者。

Eliana Merle, UBS.

瑞銀的 Eliana Merle。

For JOURNAVX, the retail pharmacy stocking you mentioned stocking now at around 30,000 retail locations. Can you put this in the context relative to the total number of retail locations you hope to be stocked at? And then in terms of the mix of scripts being filled in the retail versus the hospital setting? How do you expect that to trend over the course of the year? And then just lastly, what's the average duration for the script that you're seeing for JOURNAVX in terms of those that are being written so far?

對於 JOURNAVX，您提到的零售藥局庫存目前在約 30,000 個零售點有庫存。您能否將此與您希望庫存的零售點總數進行比較？那麼就零售店和醫院環境中填寫的處方組合而言呢？您預計這一趨勢在未來一年內會如何發展？最後，就目前編寫的腳本而言，您看到的 JOURNAVX 腳本的平均長度是多少？

Sure thing. Duncan, all three of you.

當然可以。鄧肯，你們三個。

Okay. Thank you for the question, Ali. So to take them in order, in terms of retail pharmacy stocking, -- it has always been a key part of our launch plan to ensure that genetics is easily available. for patients. Obviously, they are being treated for acute pain and need to be able to get the medicine rapidly. So at the point of retail stocking, we were in about 95% of retail locations across the US. Obviously, that number varies day by day. Depending on when JOURNAVX has been used and prescribed and comes out of the pharmacy store. But overall, we're looking for broad coverage and thus easy access in retail for patients throughout the year.

好的。謝謝你的提問，阿里。因此，就零售藥局的庫存而言，按順序進行操作——確保基因易於獲得一直是我們發布計劃的關鍵部分。為患者。顯然，他們正在接受急性疼痛治療​​，需要能夠迅速獲得藥物。因此，在零售庫存方面，我們的產品已覆蓋美國約 95% 的零售點。顯然，這個數字每天都在變化。取決於 JOURNAVX 的使用和處方時間以及從藥局購買的時間。但整體而言，我們希望獲得廣泛的覆蓋，讓患者全年都能輕鬆獲得零售服務。

In terms of the retail and hospital setting, maybe to step back a little bit, you may remember that in the acute pain market, about 15% of patients are in the pure hospital setting, about 35% of treatment days in discharge and about 50% are in retail, and we always communicated that we expected to see the initial prescriptions for JOURNAVX focused heavily in the discharge setting as the hospital formularies get up to speed. And that essentially is exactly what we are seeing. That trend will, we think, persist for the rest of the year.

就零售和醫院環境而言，也許稍微退一步來說，您可能還記得，在急性疼痛市場中，大約 15% 的患者在純醫院環境中，大約 35% 的治療日是在出院治療，大約 50% 的患者在零售中，我們總是傳達，隨著醫院處方集的加快，我們預計 JOURNAVX 的初始處方將主要集中在出院環境中。這實際上就是我們所看到的。我們認為，這一趨勢將在今年剩餘時間內持續下去。

And in terms of the average duration of a prescription in moderate to severe acute pain, it, of course, varies by setting of care as to whether someone is inpatient or whether they are outpatient or in the retail setting and also by type of medicines, say, an opioid versus an NSAID, but the average is about 14 days. And essentially, that is what we're seeing, the prescription duration for JOURNAVX at this point.

至於中度至重度急性疼痛的處方平均持續時間，當然會因護理環境而異，例如患者是住院、門診還是在零售環境中，以及藥物類型（例如阿片類藥物還是非類固醇抗發炎藥），但平均持續時間約為 14 天。基本上，這就是我們目前看到的 JOURNAVX 的處方期限。

David Risinger, Leerink.

David Risinger，Leerink。

Yeah. So I'm just hoping to clarify regarding the PBM with 22 million lives, are those within the $94 million figure or on top? And are they unrestricted or restricted lives. And then separately, just a higher-level question, please, Reshma. How is Vertex engaging with Washington leadership to educate elected leadership about the importance of both proven medical science and biotechnology innovation to the United States?

是的。因此，我只是希望澄清關於擁有 2200 萬人生命的 PBM 的問題，這些生命是在 9400 萬美元的數字之內還是在最高水平？他們的生活是不受限制的還是受限制的？然後另外，請問一個更高級別的問題，Reshma。Vertex 如何與華盛頓領導層合作，讓民選領導人了解成熟的醫學科學和生物技術創新對美國的重要性？

Yeah. David, thanks for the question. Let me take the second question first, and then I'll turn it over to Duncan to tell you a little bit more about the lives covered. We are and have been engaged with DC as well as with state governments on all of our medicines, CF, CASGEVY, JOURNAVX as well as the pipeline. I found those meetings to be constructive. And as far as our ability to ensure that the programs are reviewed in a timely fashion that we get feedback from regulators and that we are able to speak with those providing coverage, that has also continued. It's been business as usual and nothing out of the ordinary for us. Duncan, over to you.

是的。大衛，謝謝你的提問。讓我先回答第二個問題，然後我會讓鄧肯向你們稍微介紹一下報道中涉及的生命。我們目前和過去一直與華盛頓特區以及州政府就我們的所有藥品、CF、CASGEVY、JOURNAVX 以及研發管線進行合作。我發現這些會議很有建設性。至於我們確保及時審查這些計劃、從監管機構獲得反饋以及能夠與提供保險的人員交談的能力，我們也一直在繼續努力。對我們來說一切如常，沒有什麼特別的。鄧肯，交給你了。

Dave, thank you for the question. So yeah, the 22 million lives that you're referring to are included in the total 94 million and in general, those 22 million lives fall into our definition of unrestricted where we're looking for either no prior authorizations or no step edits.

戴夫，謝謝你的提問。是的，您提到的 2200 萬條生命包含在總數 9400 萬條生命中，並且總體而言，這 2200 萬條生命符合我們對不受限制的定義，即我們尋求無需事先授權或無需分步編輯。

Last question, Jack.

最後一個問題，傑克。

Gena Wang, Barclays.

巴克萊銀行的 Gena Wang。

Maybe one regarding the VX-522. I know you cannot comment too much. But for the temporary pause, -- was that due to the -- so I don't know if you can give a little bit more color regarding what are the tolerability issue that raised -- and then -- yes, so that's the first question.

也許其中一個與 VX-522 有關。我知道你不能評論太多。但是對於暫時的停頓，那是由於——所以我不知道您是否可以更詳細地說明一下由此引發的容忍度問題是什麼——然後——是的，這是第一個問題。

And then second question is regarding the ALYTREK. If we look at the first quarter revenue and when we compare to the other CF launch in the past, -- how do you see this compared to the past? And do you expect the trend to pick up in the next few quarters?

第二個問題是關於 ALYTREK 的。如果我們看一下第一季的收入，並與過去的其他 CF 發布進行比較——與過去相比，您如何看待這一情況？您預計未來幾季這趨勢會回升嗎？

Yeah. Gena, let me take the question on -- and then I'll ask Stuart to comment about the ALYTREK launch. Obviously, we have the great benefit of having Stuart here, who has been involved in every single CF launch that we'll have good line of sight on that. I don't have much more to add, Gena, because VX-522 is an active program. And because we want to maintain study integrity, I'll just leave it at the fact that the team is assessing a tolerability issue. And once we're able to say more, we certainly will. And I'll turn it over to Stuart to tell you about ALYTREK.

是的。吉娜，讓我來回答這個問題——然後我會請斯圖爾特對 ALYTREK 的發布發表評論。顯然，斯圖爾特的到來對我們有很大幫助，他參與了每一次 CF 的發布，因此我們可以很好地了解這些發布情況。我沒有什麼可補充的，Gena，因為 VX-522 是一個活躍的程式。因為我們想要保持研究的完整性，所以我只說團隊正在評估耐受性問題。一旦我們能夠說更多，我們一定會說的。接下來我將讓史都華向你們介紹 ALYTREK。

Yeah, Gena, I think it's a little bit difficult to compare a lift trek to other of our CFTR modulator approvals for one main reason, if you think about ORKAMBI when it was first approved, it was approved for mutations, which accounted for approximately 50% of CF patients where previously all we had was KALYDECO, which at the time, I think, was probably around 7%-ish of genotypes for all CF patients.

是的，Gena，我認為將 Lift Trek 與我們其他已批准的 CFTR 調節劑進行比較有點困難，主要原因是，如果你想想 ORKAMBI 首次獲得批准時的情況，它被批准用於治療突變，這佔 CF 患者的約 50%，而之前我們只有 KALYDECO，我認為當時它可能佔所有 CF 患者基因型的 7% 左右。

And then if you think when TRIKAFTA came along, TRIKAFTA took us from the sort of the 50% to the on its first approval to almost 90%. So there was such a lot of newly eligible patients who had never had a treatment to treat the underlying cause of their disease. ALYTREK slightly different to that, right? There are additional mutations. There are additional patients who are now eligible for a CFTR modulator with the approval of ALYTREK.

然後，如果你想想，當 TRIKAFTA 出現時，TRIKAFTA 將我們從第一次批准時的 50% 提高到了幾乎 90%。因此，有如此多的新符合條件的患者從未接受過針對其疾病根本病因的治療。ALYTREK 和這個稍微有點不同，對吧？還有其他突變。經 ALYTREK 批准，現在有更多的患者有資格使用 CFTR 調節劑。

I talked about the 31 additional mutations here in the US, but that's really hundreds of patients, whereas for ORKAMBI and TRIKAFTA, we were talking about thousands, if not tens of thousands of newly eligible patients. So I think it's really difficult to compare and contrast the approvals this early on. What I can tell you is we're seeing uptake in all the groups of patients that we anticipated naive patients, those who are discontinued and those who are already on a CFTR modulator. And so we're very pleased with the launch of ALYTREK to date, and we look forward to keeping you updated over coming quarters.

我談到了美國的 31 個額外突變，但這實際上是數百名患者，而對於 ORKAMBI 和 TRIKAFTA，我們談論的是數千名，甚至數萬名新符合條件的患者。所以我認為這麼早就對這些批准進行比較和對比確實很困難。我可以告訴你的是，我們看到所有患者群體的接受度都在上升，我們預期這些患者包括初治患者、停藥患者和已使用 CFTR 調節劑的患者。因此，我們對 ALYTREK 迄今為止的推出感到非常高興，並期待在未來幾季向您提供最新進展。

Thank you. That will conclude. Chuck, if you could please relay the information.

謝謝。那就結束了。查克，請你轉達一下這個訊息。

Yes, ma'am. This concludes our question-and-answer session as well as our conference call for today. Thank you for attending today's presentation. A replay of today's event will be available shortly after the call concludes here by dialing 1-877-344-7529 or 1-412-317-0088 using replay access code 101-96550. Thank you for your participation today. You may now disconnect.

是的，女士。今天的問答環節和電話會議到此結束。感謝您參加今天的演講。電話會議結束後不久，即可撥打 1-877-344-7529 或 1-412-317-0088（重播接入碼 101-96550）收聽今天活動的重播。感謝您今天的參與。您現在可以斷開連線。