福泰製藥 (VRTX) 2025 Q4 法說會逐字稿

Good day, and welcome to the Vertex Pharmaceuticals fourth quarter 2025 earnings call. (Operator Instructions) Please note this event is being recorded. I would now like to turn the conference over to Ms. Susie Lisa. Please go ahead.

大家好，歡迎參加 Vertex Pharmaceuticals 2025 年第四季財報電話會議。（操作說明）請注意，本次活動正在錄影。現在我將把會議交給蘇西·麗莎女士。請繼續。

Good evening, everyone. My name is Susie Lisa, and as Senior Vice President of Investor Relations, I'd like to welcome you to our fourth quarter and full year 2025 financial results conference call. On tonight's call, making prepared remarks, we have Dr. Reshma Kewalramani, Vertex's CEO and President; Charlie Wagner, Chief Operating Officer and Chief Financial Officer; and Duncan McKechnie, Chief Commercial Officer. We recommend that you access the webcast slides as you listen to this call.

各位晚上好。我叫蘇西·麗莎，身為投資者關係資深副總裁，我謹代表公司歡迎各位參加我們2025年第四季及全年財務業績電話會議。在今晚的電話會議上，我們將有Vertex公司執行長兼總裁Reshma Kewalramani博士、營運長兼財務長Charlie Wagner以及商務長Duncan McKechnie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，請查看網路直播投影片。

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. 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.

通話正在錄音，錄音回放將在我們的網站上提供。我們將在本次電話會議上發表前瞻性聲明，這些聲明受到今天新聞稿和我們向美國證券交易委員會提交的文件中詳細討論的風險和不確定性的影響。這些聲明，包括但不限於有關 Vertex 已上市的用於治療囊性纖維化、鐮狀細胞病、β 地中海貧血和中度至重度急性疼痛的藥物、我們的研發管線以及 Vertex 未來的財務業績的聲明，均基於管理層目前的假設。實際結果和事件可能與此有重大差異。我還要指出，我們今晚電話會議上將要討論的部分財務業績和指引是以非公認會計準則 (non-GAAP) 為基礎編制的。

I'll now turn the call over to Reshma.

現在我將把電話交給雷什瑪。

Thank you, Susie. Good evening all and thank you for joining us on the call today. 2025 was marked by excellent progress across the business, disciplined commercial execution in CF and the new product launches, meaningful pipeline progress and robust financial performance. Fourth quarter results wrapped up another strong year with 10% total revenue growth, and for the full year 2025, total revenue growth was 9%. As we executed on our plans for commercial diversification, full year '25 results included CASGEVY revenue of $116 million and JOURNAVX revenue of $60 million in the 8 months since launch.

謝謝你，蘇西。各位晚上好，感謝各位今天參加我們的電話會議。 2025年，公司各業務均取得了卓越進展，CF業務和新產品上市的商業執行嚴謹高效，產品線進展顯著，財務業績穩健。第四季業績為又一個強勁的年份畫上了圓滿的句號，總收入增長了 10%；2025 年全年總收入增長了 9%。隨著我們商業多元化計畫的實施，2025 年全年業績包括 CASGEVY 收入 1.16 億美元，JOURNAVX 收入 6,000 萬美元（自推出以來的 8 個月）。

Building on the momentum of our Q4 and full year 2025 results, in 2026, we are focused on increasing the number of patients we serve and further diversifying our revenue base. 2026 priorities include expanding leadership in CF, accelerating adoption of CASGEVY, growing JOURNAVX, both in prescriptions and revenue and advancing the emerging renal franchise, starting with pove in IgAN.

憑藉2025年第四季和全年業績的良好勢頭，2026年，我們將專注於增加服務患者數量並進一步拓展收入來源。 2026年的重點工作包括：鞏固在囊性纖維化領域的領先地位；加速CASGEVY的推廣應用；提升JOURNAVX的處方量和收入；以及推進新興的腎臟疾病業務，首先從IgA腎病的pove入手。

We are entering an exciting period, and Vertex is well positioned to deliver on the significant opportunities in front of us and drive sustained growth over the long term by combining commercial execution with serial innovation and rapidly advancing the pipeline across multiple serious disease areas. With that overview, I'll focus my R&D comments tonight on cystic fibrosis and the renal franchise. Beginning with cystic fibrosis, ALYFTREK is a next-generation 2.0 CFTR modulator and is the fifth approved CF therapy in our portfolio.

我們正進入一個令人興奮的時期，Vertex 已做好充分準備，把握擺在我們面前的重大機遇，並透過將商業執行與連續創新相結合，以及在多個嚴重疾病領域快速推進產品線，推動長期持續增長。有了以上概述，我今晚的研發評論將重點放在囊性纖維化和腎臟疾病領域。ALYFTREK 是一種新一代 2.0 CFTR 調節劑，用於治療囊性纖維化，也是我們產品組合中第五種核准的 CF 療法。

ALYFTREK brings many important benefits for patients, once-daily dosing, regulatory approval in additional mutations and the best CFTR protein function restoration in our CF portfolio. As continued evidence of this, I am pleased to share the top line results from the recently completed ALYFTREK Phase III trial, this one in two- to five-year-olds. All patients in this study were on TRIKAFTA and switched to ALYFTREK on entry into the study. ALYFTREK was safe and well tolerated, and the sweat chloride data showed a mean reduction of 9.6 millimoles from a TRIKAFTA baseline. Importantly, 65% of these ALYFTREK patients achieved levels of sweat chloride below the normal or carrier level of 30 millimoles when treated through 24 weeks.

ALYFTREK 為患者帶來許多重要益處，每日一次給藥，已獲監管部門批准用於治療其他突變，並且是我們 CF 產品組合中 CFTR 蛋白功能恢復效果最佳的藥物。作為這方面的持續證據，我很高興與大家分享最近完成的 ALYFTREK III 期試驗的主要結果，該試驗針對的是 2 至 5 歲的兒童。本研究中的所有患者在入組時均接受 TRIKAFTA 治療，並改用 ALYFTREK 治療。ALYFTREK 安全且耐受性良好，汗液氯化物數據顯示，與 TRIKAFTA 基線相比，平均減少了 9.6 毫摩爾。重要的是，65% 的 ALYFTREK 患者在接受 24 週治療後，汗液氯化物水平低於正常值或載體水平 30 毫摩爾。

This compares to 37.5% of patients at normal levels of sweat chloride at baseline on TRIKAFTA. This magnitude of sweat chloride reduction is unprecedented for this age group in cystic fibrosis. We are on track to initiate global regulatory submissions for ALYFTREK in the two- to five-year-old age group in the first half of this year. And as we continue to march down to younger age groups, I'm also pleased to share that the ALYFTREK one to two-year-old study has already initiated, and enrollment and dosing are underway. Turning now to our next wave of CFTR modulators or next-gen 3.0 medicines.

相較之下，服用 TRIKAFTA 的患者中，基線時汗液氯化物正常的患者佔 37.5%。對於囊性纖維化患者這個年齡層來說，這種程度的汗液氯化物減少是前所未有的。我們正按計劃於今年上半年啟動 ALYFTREK 針對 2 至 5 歲年齡層兒童的全球監管申報。隨著我們繼續向更年輕的年齡組推進，我也很高興地宣布，ALYFTREK 一至兩年的研究已經啟動，目前正在進行招募和給藥。現在讓我們來看看下一波 CFTR 調節劑或下一代 3.0 藥物。

In this class, VX-828 is the most efficacious corrector we have ever studied in vitro and advanced studies in patients. The VX-828 proof-of-concept study is on track to complete enrollment and dosing in the first half of 2026. VX-581, another corrector from this 3.0 class is currently in a Phase I healthy volunteer study. And beyond these two assets, we are advancing additional CF regimens. Shifting to the VX-522 program for the approximately 5,000 patients who do not make any CFTR protein and therefore cannot benefit from our CFTR modulators, our Phase I/II study of VX-522 is on track for readout in the second half of this year, and we aren't stopping there.

在本類矯正劑中，VX-828 是我們迄今為止在體外研究和患者高級研究中發現的最有效的矯正劑。VX-828 概念驗證研究正按計畫進行，預計 2026 年上半年完成入組和給藥。VX-581 是 3.0 類矯正器中的另一種，目前正在進行 I 期健康志願者研究。除了這兩項成果之外，我們還在推進其他囊性纖維化治療方案。針對約 5,000 名無法產生任何 CFTR 蛋白因而無法從我們的 CFTR 調節劑中獲益的患者，我們將轉向 VX-522 計畫。我們的 VX-522 I/II 期研究正按計畫進行，預計今年下半年公佈結果，但我們不會止步於此。

We are poised to continue to expand our CF leadership position driven by more than 20 years of serial innovation and enduring goal that if it is possible to do better for our CF patients, we are committed to doing so, an unmatched 200,000-plus patient years of real-world data and a proven ability to extend the benefits of our medicines to the youngest patients. Moving next to our renal pipeline, which is emerging as our fourth vertical alongside CF, heme and pain as a key engine for Vertex's next decade of growth.

我們已做好準備，繼續擴大我們在 CF 領域的領導地位。這得益於我們 20 多年來的持續創新和始終如一的目標：如果有可能為我們的 CF 患者做得更好，我們就致力於這樣做。我們擁有超過 20 萬名患者年的真實世界數據，並且有能力將我們藥物的益處擴展到最年輕的患者。接下來是我們的腎臟產品線，它正與囊性纖維化、血紅素和疼痛一起，成為我們第四個垂直領域，也是 Vertex 未來十年成長的關鍵引擎。

Povetacicept, a dual BAFF APRIL inhibitor is the most advanced asset in our renal pipeline with the first expected indication in IgA nephropathy or IgAN. IgAN is a progressive kidney disease with high unmet need that affects 330,000 people in the U.S. and Europe and more than 1 million people in Asia.

Povetacicept 是一種雙重 BAFF APRIL 抑制劑，是我們腎臟產品線中最先進的資產，其首個預期適應症是 IgA 腎病或 IgAN。IgA腎病是一種進行性腎病，目前存在大量未滿足的醫療需求，在美國和歐洲影響33萬人，在亞洲影響超過100萬人。

We see pove's dual BAFF APRIL inhibition as key to interdicting the underlying cause of IgA nephropathy because this is a disease driven by B cells and BAFF and APRIL are the key cytokines that play distinct roles in B cell proliferation, differentiation and survival. In addition to mechanism of action, pove's biophysical characteristics enable a differentiated profile. Pove was specifically engineered to achieve improvements in binding affinity, potency, pharmacokinetics and tissue distribution. This protein engineering translates to two key areas of downstream advantage. First, in terms of efficacy, through Phase II, pove has delivered substantial reductions in proteinuria and stabilization in GFR, supported by significant reductions in Gd-IgA1 and hematuria.

我們認為，pove 的雙重 BAFF APRIL 抑制是阻斷 IgA 腎病根本原因的關鍵，因為這是一種由 B 細胞驅動的疾病，而 BAFF 和 APRIL 是在 B 細胞增殖、分化和存活中發揮不同作用的關鍵細胞因子。除了作用機制外，pove 的生物物理特性使其具有差異化的特性。Pove 經過專門設計，旨在提高結合親和力、效力、藥物動力學和組織分佈。這種蛋白質工程技術轉化為下游兩個關鍵優勢領域。首先，就療效而言，透過 II 期試驗，pove 已顯著降低了蛋白尿並穩定了 GFR，同時 Gd-IgA1 和血尿也顯著減少。

As importantly, pove's meaningful advantages in dosing. Pove is administered as a once-monthly small volume subcutaneous dose delivered via an auto-injector, a noteworthy consideration in the chronic biologics market where ease of use has repeatedly been shown to influence product choice. Pove is progressing through the BLA regulatory pathway where FDA has granted Breakthrough Therapy designation as well as Rolling Review.

同樣重要的是，pove 在劑量控制方面具有顯著優勢。Pove 每月一次透過自動注射器進行小劑量皮下注射，這在慢性生物製劑市場中是一個值得注意的考慮因素，因為易用性已被反覆證明會影響產品的選擇。Pove正在通過BLA監管途徑，FDA已授予其突破性療法認定以及滾動審查資格。

We used the priority review voucher to ensure an expedited time line for regulatory review and initiated our rolling BLA submission by submitting the first module in December of '25. We remain on track to complete the BLA submission in the first half of this year if the Phase III interim analysis results are supportive.

我們利用優先審查券確保監管審查的快速進行，並於 2025 年 12 月提交了第一個模組，啟動了滾動式 BLA 提交流程。如果 III 期中期分析結果支持，我們仍有望在今年上半年完成 BLA 的提交。

Switching to pove in membranous nephropathy, a disease that affects approximately 150,000 patients in the US and Europe and over 400,000 patients in Asia, where we've partnered with Zai and Ono for these markets as we did in IgAN. Membranous nephropathy, like IgAN, carries significant morbidity and lacks disease-modifying therapies. Accordingly, pove has FDA Fast Track and EMA PRIME designations and was recently granted Orphan Drug designation in the US. The OLYMPUS Phase II/III adaptive study of pove in membranous is enrolling and dosing patients.

轉而治療膜性腎病，這種疾病在美國和歐洲影響約 15 萬名患者，在亞洲影響超過 40 萬名患者。我們已與再鼎醫藥和小野藥品合作，在這些市場開展業務，就像我們在 IgAN 領域所做的那樣。膜性腎病變與 IgA 腎病一樣，會造成嚴重的併發症，並且缺乏疾病改善療法。因此，pove 獲得了 FDA 快速通道和 EMA PRIME 資格，並且最近在美國獲得了孤兒藥資格。奧林巴斯公司針對膜性乳癌患者進行的 II/III 期適應性研究正在招募並給予患者用藥。

I am pleased to share we remain on track to complete the Phase II portion of this study and advance to Phase III this summer. Before updating you on the two other renal programs in mid- and late-stage clinical development, let me shift focus briefly to neurology and pove's potential as a pipeline and a product with our plans in generalized myasthenia gravis.

我很高興地告訴大家，我們仍按計畫完成這項研究的第二階段，並在今年夏天進入第三階段。在向您介紹另外兩個處於中後期臨床開發階段的腎臟項目之前，讓我簡要地將重點轉移到神經病學以及我們在全身性重症肌無力方面的計劃和產品潛力上。

The rationale to study pove myasthenia is compelling. First, it's a serious disease with high morbidity. Second, there are approximately 175,000 patients with myasthenia in the US and Europe and an estimated 300,000 patients globally. Third, current therapies have limitations in terms of mechanism of action, specificity or the need for cyclical administration. This need for cyclical administration is particularly challenging as it can lead to disease relapse and progressive damage to neuromuscular junctions. In contrast, pove is dosed chronically and does not require cycling on and off. Lastly, recent human clinical pharmacology results provide strong evidence for dual BAFF APRIL inhibition as a transformative approach.

研究後發性重症肌無力的理由十分充分。首先，這是一種發病率很高的嚴重疾病。其次，美國和歐洲約有 175,000 名重症肌無力患者，全球估計有 30 萬名患者。第三，目前的療法在作用機轉、特異性或週期性給藥的必要性上有其限制。這種週期性給藥的需求尤其具有挑戰性，因為它可能導致疾病復發和神經肌肉接頭的進行性損傷。相較之下，pove 是長期給藥，不需要循環服用和停藥。最後，近期的人體臨床藥理學結果為雙重 BAFF APRIL 抑製作為一種變革性方法提供了強有力的證據。

Putting this all together, we believe pove's mechanism of action and specifically engineered protein format provide best-in-class potential in myasthenia. I am pleased to share that we're on track to initiate a proof-of-concept Phase II dose-ranging study of pove in myasthenia in the first half of 2026.

綜上所述，我們相信 pove 的作用機制和專門設計的蛋白質形式在重症肌無力治療方面具有一流的潛力。我很高興地宣布，我們正按計劃於 2026 年上半年啟動 pove 治療重症肌無力的 II 期劑量範圍概念驗證研究。

Now returning back to renal and inaxaplin for APOL1-mediated kidney disease or AMKD, where we completed enrollment in the interim analysis cohort of the AMPLITUDE pivotal study last fall. We anticipate several key upcoming inaxaplin milestones. First, completing enrollment in the AMPLITUDE full clinical trial cohort in the second half of this year; second, results from the AMPLITUDE interim analysis cohort either late this year or early next.

現在我們回到腎臟和伊那沙普林治療 APOL1 介導的腎臟疾病或 AMKD 的話題，我們去年秋天完成了 AMPLITUDE 關鍵研究的中期分析隊列的入組。我們預計 inaxaplin 將迎來幾個重要的里程碑。首先，在今年下半年完成 AMPLITUDE 全面臨床試驗隊列的招募；其次，在今年稍後或明年年初公佈 AMPLITUDE 中期分析隊列的結果。

And if the results are positive to file for US accelerated approval thereafter. Finally, in the AMPLIFIED study of inaxaplin in patients with AMKD and moderate proteinuria or patients with AMKD and type 2 diabetes, patient groups we did not study in AMPLITUDE, we expect results in mid-2026. The last program in renal to cover tonight is VX-407, which is being studied in a Phase II proof-of-concept trial for autosomal dominant polycystic kidney disease or ADPKD. This disease affects 300,000 patients in the US and Europe with no available disease-modifying treatments.

如果結果積極，則隨後申請美國加速審批。最後，在針對 AMKD 和中度蛋白尿患者或 AMKD 和 2 型糖尿病患者的 inaxaplin 的 AMPLIFIED 研究中（這些患者群體我們在 AMPLITUDE 中沒有研究過），我們預計將在 2026 年中期獲得結果。今晚要介紹的最後一個腎臟疾病計畫是 VX-407，它正在進行針對常染色體顯性多囊性腎病變 (ADPKD) 的 II 期概念驗證試驗。這種疾病影響美國和歐洲的 30 萬名患者，目前尚無有效的疾病緩解治療方法。

VX-407 is a small molecule protein folding corrector that targets the underlying cause of disease in up to 10% of people with ADPKD. The VX-407 Phase II proof-of-concept study is up and running, and we expect to complete enrollment this year. This study will evaluate the effect of VX-407 on height-adjusted total kidney volume, an important efficacy outcome given that it's an FDA-accepted surrogate endpoint in ADPKD. I'll close with two quick updates on a couple of other R&D programs.

VX-407 是一種小分子蛋白質摺疊矯正劑，可針對高達 10% 的 ADPKD 患者的根本病因進行治療。VX-407 II 期概念驗證研究已經啟動並進行，我們預計今年將完成招募工作。本研究將評估 VX-407 對身高調整後的總腎臟體積的影響，這是一個重要的療效結果，因為它是 FDA 認可的 ADPKD 替代終點。最後，我再簡單介紹一下另外兩個研發項目的最新進展。

For CASGEVY, we remain on track to file for US approval in patients ages 5 to 11 in the first half of this year. Recall, this has been granted a Commissioner's National Priority Voucher, and thus, we expect an expedited review. For JOURNAVX and acute pain, a pair of single-arm JOURNAVX Phase IV studies have been recently completed and will be presented at medical conferences this spring, one in aesthetics and reconstructive procedures and another in laparoscopic and arthroscopic procedures. In both studies, JOURNAVX was used as part of multimodal pain therapy.

對於 CASGEVY，我們仍按計劃於今年上半年向美國提交針對 5 至 11 歲患者的上市申請。請注意，該項目已獲得專員國家優先審批券，因此我們預計會加快審查。對於 JOURNAVX 和急性疼痛，最近完成了兩項單臂 JOURNAVX IV 期研究，並將於今年春季在醫學會議上發表，一項研究針對美容和重建手術，另一項研究針對腹腔鏡和關節鏡手術。在這兩項研究中，JOURNAVX 都被用作多模式疼痛治療的一部分。

The first study in plastic surgery procedures showed approximately 90% of patients remained opioid-free versus less than 10% opioid-free rates in the literature with standard of care for similar procedures. In the second study, which included arthroscopic knee and shoulder procedures as well as laparoscopic procedures, 76% of JOURNAVX patients remained opioid-free versus less than 50% opioid-free rates in the literature with standard of care for similar procedures. And in chronic neuropathic pain, our two suzetrigine Phase III studies in patients with diabetic peripheral neuropathy remain on track to complete enrollment by the end of this year.

首項整形外科手術研究表明，約 90% 的患者術後無需服用阿片類藥物，而文獻報導中類似手術的標準治療方案下，無需服用阿片類藥物的比例不到 10%。在第二項研究中，包括膝關節鏡和肩關節鏡手術以及腹腔鏡手術，76% 的 JOURNAVX 患者保持無鴉片類藥物狀態，而文獻中採用類似手術的標準護理，無鴉片類藥物狀態的比例不到 50%。在慢性神經性疼痛方面，我們針對糖尿病週邊神經病變患者的兩項蘇澤曲林 III 期研究仍按計畫進行，預計今年底完成入組。

With that, I'll turn the call over to Duncan to review the commercial highlights.

接下來，我會把電話交給鄧肯，讓他回顧廣告的精彩片段。

Thanks, Reshma. The focus of the commercial organization in 2025 was to drive multiple successful launches fueled by clear strategic intent, disciplined execution and targeted investments. We launched ALYFTREK in the US and Europe, built momentum behind the launch of CASGEVY in the US, Europe and the Middle East and successfully executed on the first year of launch for JOURNAVX here in the US. We're pleased with the progress we're making to diversify our revenue growth and treat patients in four diseases around the world.

謝謝你，雷什瑪。2025 年，商業組織的重點是推動多個產品成功上市，而實現這一目標的動力是明確的策略意圖、嚴謹的執行和有針對性的投資。我們在美國和歐洲推出了 ALYFTREK，為 CASGEVY 在美國、歐洲和中東的推出積蓄了力量，並在美國成功完成了 JOURNAVX 推出的第一年。我們對在實現收入成長多元化和治療全球四種疾病患者方面取得的進展感到滿意。

In cystic fibrosis, our goal has been to help patients get to carrier or normal levels of CFTR function as measured by sweat chloride. We've made incredible progress against this goal for patients with all mutations, all age ranges and all geographies. We now have five approved CFTR modulators, a decade plus of real-world evidence, over 77,000 patients on one of our CF therapies and access agreements in over 60 countries across six continents. We continue to drive growth from new patients, new launches, new geographies and new reimbursement agreements, all supported by an underlying 3% annual increase in the CF population over the last five years. Focusing now on ALYFTREK.

對於囊性纖維化，我們的目標是幫助患者達到帶因者或正常水平的 CFTR 功能，這可以透過汗液氯化物來衡量。對於所有基因突變、所有年齡層和所有地區的患者，我們在實現這一目標方面取得了令人矚目的進展。我們現在有五種核准的 CFTR 調節劑，十多年的真實世界證據，超過 77,000 名患者正在接受我們的 CF 療法，並在六大洲 60 多個國家/地區達成了准入協議。我們持續透過新增患者、新產品上市、新地域拓展和新的報銷協議來推動成長，所有這些都得益於過去五年囊性纖維化患者群體每年 3% 的成長。現在專注於 ALYFTREK。

The rollout in the US and Europe continues to progress well. The vast majority of treatment-naive patients in countries where we have reimbursement are already on ALYFTREK. We also see continued ongoing transitions from TRIKAFTA to ALYFTREK and the majority of ALYFTREK scripts continue to come from switches. ALYFTREK's improved sweat chloride profile and once-daily dosing versus TRIKAFTA are resonating with the clinical community even as we observe strong patient loyalty to TRIKAFTA.

在美國和歐洲的推廣工作持續順利進行。在我們能夠報銷費用的國家，絕大多數未接受過治療的患者已經在使用 ALYFTREK 治療。我們也看到 TRIKAFTA 向 ALYFTREK 的持續過渡，而 ALYFTREK 的大部分腳本仍然來自交換器。與 TRIKAFTA 相比，ALYFTREK 改善了汗液氯化物含量，並且每天只需服用一次，這引起了臨床界的共鳴，儘管我們觀察到患者對 TRIKAFTA 的忠誠度很高。

In Europe, we have already secured reimbursed access for ALYFTREK in key countries, for example, England, Ireland, Germany, Denmark and Norway. We also recently announced reimbursement for ALYFTREK in Australia, New Zealand and Italy, the latter enabling access for 1,500 patients to a CFTR modulator for the first time. Additionally, we continue to make excellent progress expanding geographically with meaningful contributions in 2025 from Brazil and Turkey.

在歐洲，我們已經確保在英國、愛爾蘭、德國、丹麥和挪威等主要國家獲得 ALYFTREK 的報銷資格。我們最近也宣佈在澳洲、紐西蘭和義大利對 ALYFTREK 進行報銷，其中義大利的報銷使 1500 名患者首次能夠獲得 CFTR 調節劑。此外，我們在地域擴張方面繼續取得優異進展，預計到 2025 年，巴西和土耳其將做出重要貢獻。

Overall, 2025 was another year of strong execution and growth in CF, and we will continue these efforts into 2026. Key drivers of growth for CF in '26 include continuing the launch of ALYFTREK globally, treating younger patients, expanding to additional geographies, securing access for patients and maintaining our comprehensive patient support programs.

總體而言，2025 年是 CF 業務強勁執行和成長的另一年，我們將繼續努力，直至 2026 年。2026 年 CF 成長的關鍵驅動因素包括繼續在全球推出 ALYFTREK、治療更年輕的患者、擴展到更多地區、確保患者獲得治療以及維持我們全面的患者支持計劃。

Turning now to CASGEVY, where we successfully moved from a foundational year in 2024 to a year of building significant momentum in 2025. You can see the evidence of this acceleration in our excellent quarter four '25 results, where CASGEVY had 111 new patient initiations, 37 patients with first cell collections and 30 patients receiving infusions, driving $54 million in quarterly revenue. We also reached some notable reimbursement agreements for CASGEVY in quarter four '25.

現在轉向 CASGEVY，我們成功地從 2024 年的基礎之年過渡到 2025 年的強勁發展勢頭之年。從我們 2025 年第四季優異的業績中，您可以看到這種加速成長的證據，CASGEVY 新增 111 名患者，37 名患者進行了首次細胞採集，30 名患者接受了輸液治療，推動了 5400 萬美元的季度收入。2025 年第四季度，我們也與 CASGEVY 達成了一些重要的報銷協議。

In the US, more than 30 states have joined the CMS cell and gene therapy access model, and there is now approximately 90% access for both Medicaid and commercial CASGEVY patients with the remainder having case-by-case access. In Europe, all countries and the UK are now providing reimbursed access and a recent landmark coverage decision by the Italian reimbursement body represents about 5,000 eligible TDT patients, half of Europe's beta thalassemia population.

在美國，已有超過 30 個州加入了 CMS 細胞和基因治療准入模式，目前 Medicaid 和商業 CASGEVY 患者約有 90% 的機會獲得治療，其餘患者則根據具體情況獲得治療。在歐洲，所有國家和英國現在都提供報銷服務，義大利報銷機構最近一項具有里程碑意義的承保決定惠及約 5,000 名符合條件的 TDT 患者，佔歐洲 β 地中海貧血患者的一半。

We anticipate seeing continued quarter-to-quarter variability in CASGEVY infusions in 2026 based on the duration of the patient journey and given the fact that patients themselves dictate when they wish to receive their infusion. We anticipate this will smooth out in 2027 and beyond as the number of patients at all stages of the treatment journey continues to build. Overall, we're very encouraged by the robust flow of patients in the US, in Europe and the Middle East moving from referral to cell collection and infusion as we drive towards realizing CASGEVY's multibillion-dollar potential.

我們預計，根據患者治療過程的持續時間以及患者自己決定何時接受輸液這一事實，2026 年 CASGEVY 輸液量將繼續出現季度間的波動。我們預計，隨著處於治療各階段的患者人數不斷增加，這種情況將在 2027 年及以後趨於平穩。總的來說，我們非常鼓舞地看到，在美國、歐洲和中東，越來越多的患者從轉診到細胞採集和輸注，我們正在努力實現 CASGEVY 數十億美元的潛力。

Moving to pain. I'm pleased to report that JOURNAVX achieved our 2025 launch objectives of: firstly, securing broad payer access; secondly, ensuring extensive hospital adoption; and thirdly, creating a broad prescriber base across both the hospital and retail segments. This launch strategy was designed to create a strong long-term foundation for years of growth with JOURNAVX.

走向痛苦。我很高興地報告，JOURNAVX 實現了我們 2025 年的上市目標：首先，確保廣泛的支付方准入；其次，確保醫院的廣泛採用；第三，在醫院和零售領域建立廣泛的處方醫生基礎。該發布策略旨在為 JOURNAVX 的多年發展奠定堅實的長期基礎。

More than 550,000 JOURNAVX prescriptions were filled in 2025 with a roughly 50-50 split between hospital and retail channels. There were as many prescriptions written in the fourth quarter of 2025 as there were in the prior three quarters cumulatively, although I would note that quarter four revenue growth does not yet fully reflect the strong prescription growth given the continued utilization of our patient support programs. Importantly, more than 35,000 physicians wrote prescriptions for JOURNAVX in 2025, including orthopedic surgeons, general surgeons, anesthesiologists, pain specialists, dentists and general practitioners.

2025 年，JOURNAVX 處方藥的配藥量超過 55 萬張，其中醫院通路和零售通路的配藥量大致各佔一半。2025 年第四季的處方量與前三個季度的累積處方量相當，但我注意到，由於我們的病患支援計畫仍在繼續使用，第四季度的收入成長尚未完全反映出強勁的處方量成長。值得注意的是，2025 年有超過 35,000 名醫生開立了 JOURNAVX 的處方，包括骨科醫生、普通外科醫生、麻醉師、疼痛專家、牙醫和全科醫生。

Over 200 million lives now have access across all three national PBMs. In addition, 21 states now provide unrestricted access for Medicaid recipients without prior authorization or step edit requirements. JOURNAVX has also been incorporated into formularies, order sets and/or discharge protocols across more than 950 hospitals and over 100 integrated delivery networks, a significant accomplishment in a short period of time and an indicator of the unmet need in this space.

目前已有超過 2 億人透過三大國家藥品福利管理機構取得藥品。此外，目前已有 21 個州為 Medicaid 受益人提供無限制訪問，無需事先授權或分級編輯要求。JOURNAVX 也被納入了 950 多家醫院和 100 多個綜合醫療服務網絡的處方集、醫囑集和/或出院方案中，這是在短時間內取得的重大成就，也顯示了該領域尚未滿足的需求。

Perhaps most importantly, we estimate that about 420,000 Americans benefited from the inclusion of JOURNAVX in their treatment journey as an effective, well-tolerated non-opioid option for moderate to severe acute pain. Looking ahead, given the strong adoption of JOURNAVX by hospitals and physicians and the progress we've made in securing payer coverage, we plan to double the size of our field force in quarter two.

或許最重要的是，我們估計約有 42 萬美國人會受益於將 JOURNAVX 納入他們的治療方案，JOURNAVX 是一種有效且耐受性良好的非鴉片類藥物，可用於治療中度至重度急性疼痛。展望未來，鑑於 JOURNAVX 在醫院和醫生中的廣泛應用，以及我們在獲得支付方覆蓋方面取得的進展，我們計劃在第二季將我們的銷售團隊規模擴大一倍。

We will also continue with a range of consumer engagement activities to drive meaningful prescription and revenue growth in 2026. This includes the recent launch of our first Vertex Connected TV campaign in January, which we are piloting in select markets. In 2026, we expect to more than triple the number of JOURNAVX prescriptions compared to approximately 550,000 written in 2025.

我們也將繼續進行一系列消費者互動活動，以推動2026年處方量和收入的顯著成長。這包括我們於 1 月推出的首個 Vertex 聯網電視廣告活動，我們正在部分市場進行試點。預計到 2026 年，JOURNAVX 的處方數量將比 2025 年的約 55 萬張增加三倍以上。

As we work to finalize access and gain coverage with additional payers, including Medicare Part D plans, we have made the strategic decision to maintain the patient support program for those patients not covered by their insurance. As this PSP program sunsets and gross to net normalizes in late 2026, early 2027, we expect prescription growth to increasingly drive meaningful revenue growth, especially in the latter half of the year.

在我們努力與更多支付方（包括聯邦醫療保險D部分計劃）達成最終協議並獲得承保的同時，我們做出了戰略決定，繼續為那些沒有保險的患者提供患者支持計劃。隨著 PSP 計劃在 2026 年底、2027 年初結束，毛利與淨利將恢復正常，我們預計處方增長將日益推動收入的顯著增長，尤其是在下半年。

Our expectation is that JOURNAVX gross to net will ultimately settle at levels comparable to other branded medicines. We're excited to continue to drive a transformation in the management of the 80 million Americans with moderate to severe acute pain each year by offering a safe and effective non-opioid treatment option and to build another multibillion-dollar franchise for Vertex.

我們預計 JOURNAVX 的毛利與淨利潤最終將穩定在與其他品牌藥品相當的水平。我們很高興能夠繼續推動每年 8000 萬遭受中度至重度急性疼痛的美國人的治療方式的變革，提供安全有效的非阿片類藥物治療方案，並為 Vertex 打造另一個價值數十億美元的特許經營權。

Turning now to our emerging renal business. We are partnering with and investing in the nephrology community for the long term, and povetacicept is the first in a series of potentially transformative medicines that tackle the underlying cause of several renal diseases, IgAN, PMN, AMKD and ADPKD. We anticipate that the renal franchise will ultimately rival the scale of our CF business, and we're seeking to bring the best elements of our success in CF to these kidney disease areas.

現在讓我們來談談我們新興的腎臟業務。我們正在與腎臟病學界建立長期合作關係並對其進行投資，而 povetacicept 是一系列可能具有變革意義的藥物中的第一種，這些藥物旨在解決多種腎臟疾病（IgAN、PMN、AMKD 和 ADPKD）的根本原因。我們預期腎臟疾病業務最終將與我們的囊性纖維化業務規模相媲美，我們正在努力將我們在囊性纖維化領域的成功經驗運用到腎臟疾病領域。

These best practices include an intense focus on the patient, an unrelenting commitment to serial innovation in R&D, a clear high science sell to specialist physicians and disciplined execution in securing reimbursed access here in the US and around the world. We will also offer comprehensive patient support programs for eligible patients to remove access challenges and enable them to more seamlessly obtain the medicine that HCPs prescribe.

這些最佳實踐包括：高度重視患者，堅持不懈地致力於研發領域的持續創新，向專科醫生清晰地推銷高水平的科學技術，以及在美國和世界各地確保獲得報銷的嚴格執行。我們還將為符合條件的患者提供全面的患者支持計劃，以消除獲取藥物的障礙，使他們能夠更順利地獲得醫護人員開具的處方藥。

We believe our experience, focus and capabilities equip us to win in renal and deliver substantial value to both patients and health care providers. Povetacicept's potential best-in-class profile enables us to clearly distinguish it within the IgA nephropathy landscape, setting it apart from other therapies.

我們相信，憑藉我們的經驗、專注和能力，我們能夠在腎臟領域取得成功，並為患者和醫療保健提供者帶來巨大的價值。Povetacicept 具有同類最佳的潛在優勢，使我們能夠將其在 IgA 腎臟病領域中清晰地區分開來，使其與其他療法區分開來。

As Reshma detailed, pove is an engineered fusion protein designed specifically to address B cell autoimmune diseases with a strong clinical profile that is further supported by an easy-to-use small volume auto-injector administered at home every four weeks. The importance of this insight has been borne out in our recent research with nephrologists who highlight the importance of payer access and preference for an auto-injector versus prefilled syringe in their treatment decisions. This market research with nephrologists reinforces what we've seen in the biologics space many times over.

正如雷什瑪詳細介紹的那樣，pove 是一種經過工程改造的融合蛋白，專門用於治療 B 細胞自體免疫疾病，具有強大的臨床療效，並且配備了易於使用的小容量自動注射器，每四周在家注射一次，進一步增強了其療效。我們最近與腎臟科醫生進行的一項研究證實了這一見解的重要性，他們強調了支付方的可及性以及在治療決策中對自動注射器與預填充注射器的偏好。這項針對腎臟科醫師的市場調查印證了我們在生物製劑領域多次觀察到的現象。

Commercial excellence, combined with patient convenience and ease of use of the medicine are critical drivers of market share. We began preparing for povetacicept's launch last year by building a commercial team for renal and engaging payers to ensure broad access.

商業上的卓越表現，加上患者的便利性和藥物的易用性，是市場份額的關鍵驅動因素。去年，我們開始為 povetacicept 的上市做準備，組建了一支腎臟疾病商業團隊，並與支付方接洽，以確保廣泛的市場准入。

We're completing the staffing of our teams, and the first contingent of our field team is already trained and actively engaging customers and providing disease education. As noted above, we're also developing a comprehensive renal patient support program based on our decade-plus of experience supporting cystic fibrosis patients.

我們正在完成團隊人員配備，第一批現場團隊成員已經接受培訓，並積極與客戶互動，提供疾病教育。如上所述，我們也正在根據我們十多年來支持囊性纖維化患者的經驗，制定一項全面的腎臟病患者支持計劃。

In summary, each of our commercialization areas reflects a clear strategic intent and an ambitious approach to both established and future launches. Our 2025 performance positions the portfolio for continued revenue growth, deeper market penetration and most importantly, broader patient impact across cystic fibrosis, hematological disorders, moderate to severe acute pain and potentially in the future, multiple renal diseases.

總而言之，我們的每個商業化領域都體現了清晰的策略意圖和對現有產品和未來產品上市的雄心勃勃的態度。我們 2025 年的業績將使產品組合能夠持續實現收入成長，更深入地滲透市場，最重要的是，對囊性纖維化、血液疾病、中度至重度急性疼痛以及未來可能出現的多種腎臟疾病等患者產生更廣泛的影響。

I'll now turn the call over to Charlie for our financial results and outlook.

現在我將把電話交給查理，讓他為大家介紹我們的財務表現和展望。

Thanks, Duncan. I'm pleased to share the details of Vertex's strong financial performance in the fourth quarter and for the full year 2025, which stands as a testament to our market leadership, the strength of our product portfolio and our disciplined approach to investment and operational management.

謝謝你，鄧肯。我很高興與大家分享 Vertex 在第四季度和 2025 年全年強勁的財務業績詳情，這證明了我們的市場領導地位、強大的產品組合以及我們嚴謹的投資和營運管理方法。

In the fourth quarter, total revenue reached $3.2 billion, a 10% increase compared to Q4 2024. For the full year, total revenue was $12 billion, an increase of 9% versus 2024. These results reflect our consistent commercial execution, durable CF franchise strength and expansion into new high-value disease areas.

第四季總營收達到 32 億美元，比 2024 年第四季成長 10%。全年總收入為 120 億美元，比 2024 年成長 9%。這些結果反映了我們持續的商業執行力、持久的 CF 特許經營實力以及向新的高價值疾病領域的擴張。

Our cystic fibrosis therapies remain the foundation of our revenue and cash flow with full year 2025 growth of 7% globally. CF revenue in the US grew 11% year-over-year, largely due to pediatric uptake, ongoing strength in TRIKAFTA and ALYFTREK, higher realized net prices and a modest benefit from channel inventory in the fourth quarter.

我們的囊性纖維化療法仍然是我們收入和現金流的基礎，預計到 2025 年全年全球成長率將達到 7%。CF 在美國的營收年增 11%，這主要歸功於兒科產品的普及、TRIKAFTA 和 ALYFTREK 的持續強勁表現、更高的實際淨價以及第四季度通路庫存帶來的適度收益。

Internationally, CF revenue grew 2% year-over-year, reflecting the ongoing penetration of Kaftrio in established markets and contributions from ALYFTREK in countries where reimbursed, partly offset by the previously communicated $200 million decline in Russia sales for the year. CASGEVY achieved $54 million in revenue in Q4 and $116 million for the full year 2025 and during Q4 demonstrated continued momentum in patient initiations and first cell collections.

在國際方面，CF 收入年增 2%，反映出 Kaftrio 在成熟市場的持續滲透以及 ALYFTREK 在已報銷國家的貢獻，但部分被此前公佈的俄羅斯銷售額下降 2 億美元所抵消。CASGEVY 第四季營收達 5,400 萬美元，2025 年全年營收達到 1.16 億美元，並在第四季度展現出患者啟動和首次細胞採集方面的持續成長勢頭。

JOURNAVX delivered $27 million in sales in the fourth quarter and $60 million for the full year, with substantial growth in quarterly prescriptions since its launch in Q1 of 2025. Note that JOURNAVX gross to net was significantly impacted by our patient support program in 2025, and that impact will diminish over the course of 2026.

JOURNAVX 第四季銷售額為 2,700 萬美元，全年銷售額為 6,000 萬美元，自 2025 年第一季推出以來，季度處方量大幅增加。請注意，JOURNAVX 的總利潤在 2025 年受到我們患者支持計畫的顯著影響，而這種影響將在 2026 年逐漸減弱。

Our increasingly diversified commercial portfolio now spanning four disease areas is driving new revenue streams and adding to our near- and long-term growth profile. Our fourth quarter gross margin of 85.7% reflects this product mix as well as investment in manufacturing optimization for our diversifying portfolio. I would add that Q4 gross margin is a reasonable proxy for what to expect in 2026.

我們日益多元化的商業組合現已涵蓋四大疾病領域，正在推動新的收入來源，並促進我們近期和長期的成長。我們第四季的毛利率為 85.7%，這反映了我們的產品組合以及對多元化產品組合的生產優化投資。我還要補充一點，第四季的毛利率可以合理地預測 2026 年的預期水準。

Turning to operating expenses. Q4 2025 combined non-GAAP R&D, acquired IP R&D and SG&A expenses totaled $1.4 billion, up 5% year-over-year and reflect our strategic investments in product launches, principally in pain and late-stage pipeline programs. Fourth quarter non-GAAP operating expenses included $56.5 million of AIPR&D expense or approximately $0.22 per share. This fourth quarter BD activity included an exclusive global license agreement with WuXi Biologics to develop and commercialize a trispecific T cell engager for B-cell-mediated autoimmune diseases. This asset is currently in preclinical development.

接下來談談營運費用。2025 年第四季非 GAAP 研發、收購 IP 研發和銷售、一般及行政費用總計達 14 億美元，年增 5%，反映了我們對產品上市的策略性投資，主要集中在疼痛治療和後期研發管線項目。第四季非GAAP營運費用包括5,650萬美元的AIPR&D費用，約合每股0.22美元。第四季業務拓展活動包括與藥明生物達成一項全球獨家許可協議，以開發和商業化用於治療 B 細胞介導的自身免疫性疾病的三特異性 T 細胞銜接器。該項目目前處於臨床前開發階段。

For the full year, combined non-GAAP R&D, acquired IPR&D and SG&A expenses totaled $5.1 billion, consistent with our previous guidance. Excluding acquired IPR&D, the increase versus prior year was primarily driven by the acceleration of late-stage clinical programs in renal medicine and ongoing expansion of commercial and marketing activities to support the launch of JOURNAVX and upcoming launches in renal.

全年非GAAP研發、收購的智慧財產權研發及銷售、一般及行政費用合計為51億美元，與我們先前的預期一致。除收購的智慧財產權和研發外，與上年相比的成長主要得益於腎臟醫學後期臨床計畫的加速推進，以及為支持 JOURNAVX 的上市和即將推出的腎臟產品而持續擴大的商業和行銷活動。

The fourth quarter 2025 non-GAAP effective tax rate was 13.5%, reflecting increased utilization of onetime tax credits and our full year 2025 non-GAAP effective tax rate was 17.3%. Q4 '25 non-GAAP net income was $1.3 billion, up 24% year-over-year, delivering $5.03 of earnings per share, up 26% versus the prior year. Full year 2025 non-GAAP net income of $4.7 billion resulted in $18.40 of EPS.

2025 年第四季非 GAAP 實際稅率為 13.5%，反映出一次性稅收抵免的使用增加；2025 年全年非 GAAP 實際稅率為 17.3%。2025 年第四季非 GAAP 淨收入為 13 億美元，年增 24%，每股收益為 5.03 美元，比上年增長 26%。2025 年全年非 GAAP 淨收入為 47 億美元，每股收益為 18.40 美元。

Vertex ended 2025 with $12.3 billion in cash, cash equivalents and marketable securities. Our strong balance sheet positions us to continue investments in both internal and external innovation. During 2025, we increased our repurchase activity, buying approximately 4.8 million shares for roughly $2 billion. This reflects our ongoing commitment to returning value to shareholders while maintaining the flexibility to act on growth opportunities. Let me now turn to guidance for 2026.

Vertex 截至 2025 年底擁有 123 億美元的現金、現金等價物和有價證券。我們強勁的資產負債表使我們能夠繼續投資於內部和外部創新。2025 年，我們增加了回購活動，購買了約 480 萬股股票，價值約 20 億美元。這體現了我們持續致力於為股東創造價值，同時保持靈活性以抓住成長機會的承諾。現在讓我談談2026年的指導。

We expect full year 2026 total company revenue to be in the range of $12.95 billion to $13.1 billion, representing 8% to 9% growth versus the prior year. This outlook anticipates continued solid performance from our CF franchise and a $500 million or greater revenue contribution from non-CF products, including greater volumes of patient infusions for CASGEVY and a ramp of JOURNAVX prescriptions.

我們預計 2026 年全年公司總營收將在 129.5 億美元至 131 億美元之間，比前一年成長 8% 至 9%。該展望預計我們的 CF 產品線將繼續保持穩健表現，非 CF 產品將貢獻 5 億美元或更多的收入，包括 CASGEVY 患者輸注量的增加和 JOURNAVX 處方量的增加。

In Q1 2026, we anticipate year-over-year total revenue growth of approximately 7% with growth accelerating thereafter and building towards our full year guidance. Additionally, we expect combined non-GAAP operating expenses to be in the range of $5.65 billion to $5.75 billion as we continue to invest in our late-stage clinical pipeline and commercial buildouts in support of new launches and revenue diversification, particularly for JOURNAVX in acute pain and for renal. We anticipate our non-GAAP effective tax rate to be in the range of 19.5% to 20.5% for 2026 as we do not expect a repeat of the onetime tax benefits we experienced in 2025.

我們預計 2026 年第一季總營收年增約 7%，此後成長速度將加快，並朝著全年目標邁進。此外，我們預計合併後的非GAAP營運費用將在56.5億美元至57.5億美元之間，因為我們將繼續投資於後期臨床研發管線和商業建設，以支持新產品的上市和收入多元化，特別是針對急性疼痛和腎臟疾病的JOURNAVX。我們預計 2026 年的非 GAAP 有效稅率將在 19.5% 至 20.5% 之間，因為我們預計不會重現 2025 年的一次性稅收優惠。

In addition, based on our understanding of current rules, we do not expect a material impact from tariffs given our diversified supply chain and large US manufacturing presence, but this outlook is subject to change.

此外，根據我們對現行規則的理解，鑑於我們多元化的供應鏈和在美國龐大的製造規模，我們預計關稅不會產生實質影響，但這一預期可能會改變。

In summary, 2025 was a year of very strong performance, continued execution on our commercial priorities and clinical programs and further strengthening of our robust financial foundation. As we turn to 2026 and beyond, Vertex remains well positioned to continue expanding our impact for patients, investors and all stakeholders.

總而言之，2025 年是業績表現非常強勁的一年，我們在商業重點和臨床項目方面繼續推進，並進一步鞏固了我們穩健的財務基礎。展望 2026 年及以後，Vertex 仍處於有利地位，將繼續擴大我們對患者、投資者和所有利害關係人的影響。

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

我們期待在以後的電話會議中向您報告我們的進展情況，現在我請 Susie 開始問答環節。

(Operator Instructions) Cory Kasimov, Evercore ISI.

（操作說明）Cory Kasimov，Evercore ISI。

Probably not surprising that it's on pove. Curious how you view the risk of potential hypogamma adverse events and how this could ultimately impact the label, if at all?

它出現在 pove 上可能並不令人意外。我很想知道您如何看待潛在的低γ不良事件的風險，以及這最終會對標籤產生怎樣的影響（如果有的話）？

Cory, this is Reshma. Let me take that one. On hypogammaglobulinemia, that's to say low IgG levels. The way BAFF APRIL inhibitors work, you're going to see decrease in IgG. It's part and parcel of the mechanism of action.

科里，這位是雷什瑪。讓我來做吧。低丙種球蛋白血症，也就是 IgG 水準低。BAFF APRIL 抑制劑的作用機轉是降低 IgG 水準。這是作用機制不可或缺的一部分。

But the important question you're asking is what does that mean, if anything, on safety? So the data that we've shown is RUBY-3, the 80-milligram RUBY-3 cohort that we showed at ASN in November, what you see there is there are actually no SAEs, none of infection. It doesn't matter what IgG level you look at. There were simply none. That's good news.

但你提出的重要問題是，這對安全而言意味著什麼（如果有的話）？所以，我們展示的數據是 RUBY-3，也就是我們在 11 月 ASN 上展示的 80 毫克 RUBY-3 組，你可以看到，實際上沒有發生 SAE，也沒有發生感染。看哪個IgG水平都無所謂。根本沒有。這是個好消息。

There was a single patient with IgG levels of less than 300 milligrams. That was a threshold we used. It was not associated with any serious infection and there was no severe infection either. And on average, when you look at the IgG levels from the RUBY-3 IgAN study, the average value was within the normal range, so let's say, around 700 mg. So when I look at that, I don't really see anything there.

有一名患者的 IgG 水準低於 300 毫克。那是我們使用的一個閾值。它沒有引發任何嚴重感染，也沒有造成嚴重感染。平均而言，從 RUBY-3 IgAN 研究中的 IgG 水準來看，平均值在正常範圍內，比方說，大約為 700 毫克。所以當我查看時，我真的什麼也沒看到。

And I think that when you look at the overall benefit risk, including IgG levels, but look at everything as a whole, it looks really very good.

我認為，當你從整體上考慮收益風險，包括 IgG 水平，並將所有因素作為一個整體來看時，結果看起來真的非常好。

Salveen Richter, Goldman Sachs.

薩爾文·里克特，高盛。

With regard to the guidance here, is there any way you could help us understand what's baked into the guide for the CF component relative to ALYFTREK and TRIKAFTA? And on ALYFTREK in particular, you had a strong quarter. So walk us through the contributing factors here as we think of the trajectory for 2026.

關於這裡的指導，您能否幫助我們理解指南中關於 CF 組件相對於 ALYFTREK 和 TRIKAFTA 的具體內容？尤其是 ALYFTREK，你們本季表現強勁。那麼，請您為我們整理一下影響 2026 年發展軌跡的各種因素。

I'm going to split that question and ask Charlie to go first on the guide, and then I'll ask Duncan to comment on the market dynamics that led to the ALY numbers we shared.

我將把這個問題分成兩部分，先請查理就指南發言，然後再請鄧肯評論一下導致我們分享的 ALY 數據的市場動態。

Yes, Salveen, no additional color on the guidance. Obviously, total revenue guidance of $12.95 billion to $13.1 billion, so 8% to 9% for the year. Within that, a contribution -- a non-CF contribution of $500 million or more. Within CF, we're not going to break it down further in terms of ALY versus other products. Maybe Duncan can comment on the dynamics in ALY that we're seeing right now.

是的，薩爾文，指南中沒有其他補充說明。顯然，全年總營收預期為 129.5 億美元至 131 億美元，年增 8% 至 9%。其中，一筆捐款──一筆非CF捐款，金額為5億美元或以上。在CF領域，我們不會再根據ALY與其他產品進行更細緻的分析。或許鄧肯可以對我們目前在 ALY 看到的動態發表一些看法。

Sure. Thanks for the question, Salveen. So I'd say the fourth quarter was buoyed by the international launch. So we, as you know, secured reimbursement in Europe, in countries like the UK, Germany, Denmark, Ireland, Norway in 2025. So that really helped drive some of the numbers that we saw in the latter part of 2025, and we expect that to continue obviously into 2026.

當然。謝謝你的提問，薩爾文。所以我認為第四季業績得益於國際市場的推出。如您所知，我們已確保在 2025 年於歐洲（如英國、德國、丹麥、愛爾蘭、挪威等國家）獲得報銷。因此，這確實推動了我們在 2025 年下半年看到的一些數據，我們預計這種情況顯然會持續到 2026 年。

Geoff Meacham, Citibank.

傑夫‧米查姆，花旗銀行。

Just have a couple. The first one, you guys seem really excited about Pove's potential as well as the renal space. I guess the question is, is there work to do on the payer side when you think about access and reimbursement and maybe cost benefit? When you look historically, Reshma, renal hasn't been a category where you get higher realized value, but obviously, a new MOA can help that. And then just a follow-up on ALY.

就吃幾個吧。首先，你們似乎對Pove的潛力以及腎臟領域都非常興奮。我想問的是，從准入、報銷以及成本效益的角度來看，支付方是否還有工作要做？從歷史角度來看，Reshma，腎臟疾病並不是一個能獲得更高實際價值的類別，但顯然，新的作用機制可以改善這種情況。然後是關於 ALY 的後續報道。

Is there more interest in the US in using sweat chloride as a disease biomarker? And you mentioned the European launch. I mean, how would you characterize maybe the awareness and willingness to switch to ALY compared to the US.

美國對使用汗液氯化物作為疾病生物標記的興趣是否較大？你也提到了歐洲的發表會。我的意思是，與美國相比，您如何評估人們對 ALY 的認知和接受度？

All right. Jeff, I'm going to ask Duncan to comment on both, but we'll take it in two parts. Let's do ALY first, Duncan. How do folks -- how does the community think about sweat chloride US versus ex-US?

好的。傑夫，我會請鄧肯對這兩件事發表評論，但我們會分兩部分進行。鄧肯，我們先來做ALY吧。各位－社區如何看待美國和前美國地區的汗液氯化物含量？

How do you see the uptake? And then let's get to pove. Geoff, you are absolutely right to detect a ton of enthusiasm in our voice on Pove. It's not just about pove in IgAN, but it's pove in membranous and in myasthenia. And it is getting close to the time where we think we're going to have the results to share and close to the time where we think we're going to be able to file.

您如何看待市場接受度？然後我們開始吧。傑夫，你完全正確，從我們對Pove的語氣中聽出了極大的熱情。這不僅關乎 IgAN 中的 pove，也關乎膜性腎病變和重症肌無力的 pove。我們認為，公佈結果的時間已經接近尾聲，提交申請的時間也即將到來。

So enthusiasm is certainly building internally. Duncan, on the Pove question, it was about reimbursement and how you're seeing that.

所以，員工內部的熱情確實正在高漲。Duncan，關於 Pove 的問題，是關於報銷以及你如何看待這個問題的。

Yes. So ALY, first.

是的。首先是ALY。

Yes.

是的。

Thanks for the question, Geoff. So as far as the interest in sweat chloride is concerned, in general terms from a physician level, the level of sort of understanding and interest in the connection between sweat chloride and CFTR function is, by and large, similar in the US to Europe. There are no major differences in that regard. In terms of your question about willingness to switch, as you know, there are some different dynamics with regard to the labeling between the US and Europe, meaning that there are fewer liver function and liver monitoring requirements in Europe. So that has an impact on the dynamic.

謝謝你的提問，傑夫。因此，就汗液氯化物的研究而言，從醫生的角度來看，美國和歐洲對汗液氯化物與 CFTR 功能之間聯繫的理解和興趣程度總體上是相似的。在這方面沒有重大差異。關於您提出的轉換意願問題，如您所知，美國和歐洲在標籤方面存在一些不同的動態，這意味著歐洲對肝功能和肝臟監測的要求較少。所以這會對動態產生影響。

The other comment I would make as well is we always see more rapid uptake in naive patients and as per the prepared remarks, there are, for example, 1,500 naive patients in Italy that have just been reimbursed for CFTR modulator for the first time ever. So we would anticipate rapid uptake in that particular patient population. On the first part, actually of your question, povetacicept and our engagements with payers and the payer community, I would make just a couple of comments.

我還要補充一點，我們總是看到初次接受治療的患者接受得更快，根據準備好的發言稿，例如，義大利有 1500 名初次接受治療的患者首次獲得了 CFTR 調節劑的報銷。因此，我們預計該產品將在該特定患者群體中迅速普及。關於您問題的第一部分，即 povetacicept 以及我們與支付方和支付方群體的互動，我只想發表幾點評論。

Firstly, we started engaging with the payers in July last year. We've, at this point, had 74 engagements with multiple payers that cover over 210 million lives. And I would say those conversations are going extremely well. They are very well educated on IgAN, and they are very interested in the products that are coming to the market. So we feel really good about where we're at with our engagements with payers so far and where those will go in the future.

首先，我們從去年7月開始與付款方接洽。截至目前，我們已經與多家支付方進行了 74 次合作，覆蓋超過 2.1 億人。我認為這些對話進行得非常順利。他們對 IgAN 有非常深入的了解，並且對即將上市的產品非常感興趣。因此，我們對目前與支付方的合作進展以及未來的發展方向都感到非常滿意。

Tazeen Ahmad, Bank of America.

塔津·艾哈邁德，美國銀行。

With relation to pove, can we talk about what you're expecting to show on proteinuria? Like what results do you think would provide, in your mind, medically clinically differentiated data versus competitors?

關於尿蛋白檢測，我們可以談談你預期在尿蛋白檢測中會顯示什麼結果嗎？您認為什麼樣的結果才能提供與競爭對手相比具有醫學臨床差異化的數據？

Sure. On the magnitude of proteinuria response, I think we've talked about this before. But in every study that we've done, the depth of proteinuria response, the greater the depth, the better it is in terms of long-term outcomes, long-term outcomes being defined as death dialysis or time to transplantation. In this particular interim analysis, I would point you to the RUBY-3 80-milligram IgAN results. I think it's the best analog to look at to sort of get a sense for what we could see from the RAINIER trial.

當然。關於蛋白尿反應的程度，我想我們之前已經討論過這個問題了。但在我們所做的每一項研究中，蛋白尿反應的深度越大，長期結果就越好，長期結果定義為死亡、透析或移植時間。在本次中期分析中，我想向您推薦 RUBY-3 80 毫克 IgAN 的結果。我認為這是最好的類比，可以用來了解我們能從 RAINIER 試驗中看到什麼。

I say that because it's very similarly designed in the inclusion and exclusion criteria, the proteinuria thresholds, the GFR thresholds for entry, it's the same exact dose, 80 milligrams and the endpoint is exactly the same. And in RUBY-3, the 36-week proteinuria data was a 56% reduction in proteinuria. I think it's important to also note that the proteinuria reduction is something that I believe will have -- I think you could think of it as compounding effect over time.

我這麼說是因為它們的納入和排除標準、蛋白尿閾值、腎小球濾過率閾值都非常相似，劑量也完全相同，都是 80 毫克，終點也完全一樣。在 RUBY-3 研究中，36 週的蛋白尿數據顯示蛋白尿減少了 56%。我認為同樣重要的是要指出，蛋白尿減少是一個我認為會隨著時間的推移而產生累積效應的現象。

Even a little bit more improvement in proteinuria, better proteinuria reduction is going to be important because these patients are going to be on the medicine for their whole life. It takes something like 20 years for a person to develop end-stage renal disease from when they start having their GFR drop, or proteinuria starts to become heavy.

即使蛋白尿情況再改善一點點，蛋白尿減少得更好一些，也是非常重要的，因為這些患者需要終身服藥。從腎小球濾過率開始下降或蛋白尿開始增多，到發展為末期腎病，大約需要 20 年。

So over that course of time, improvements in proteinuria could really be very important. So if we see something like we saw in RUBY-3 Phase II, that would be incredibly important, very meaningful from a clinical perspective.

因此，隨著時間的推移，蛋白尿的改善可能真的非常重要。所以，如果我們看到類似 RUBY-3 II 期試驗中看到的結果，那將非常重要，從臨床角度來看意義非凡。

Evan Seigerman, BMO Capital Markets.

Evan Seigerman，BMO資本市場。

I'd love for you to expand on the rationale to study pove in gMG. Just seems to be a more crowded rare disease. I'd love for you to just touch on what differentiates this asset, what you saw potentially kind of in earlier studies and how you think it would compare to both assets that have been approved and are under investigation for the indication.

我希望你能詳細闡述一下在gMG中研究pove的理由。似乎只是罕見疾病患者比較多而已。我想請您談談這款產品的獨特之處，您在早期研究中看到了哪些潛在優勢，以及您認為它與已獲批准和正在研究用於該適應症的兩種產品相比如何。

Yes. Sure thing, Evan. I'll repeat a couple of things I said in my prepared remarks. It's a sizable population, right, nearing 200,000 patients in the US and Europe.

是的。當然可以，埃文。我再重複一下我在準備好的發言稿中說過的一些內容。這是一個相當龐大的群體，沒錯，光在美國和歐洲就有近 20 萬名患者。

It is clearly like one of the best examples of a B cell-mediated disease. That is how this disease happens. It's autoantibodies largely against the acetylcholine receptor. And the available treatments have some real limitations. One of the big limitations is for some of the treatments, you have to cycle on and cycle off.

這顯然是B細胞介導疾病的最佳例證之一。這種疾病就是這樣發生的。它主要是針對乙醯膽鹼受體的自身抗體。而且，現有的治療方法也存在一些限制。其中一個很大的限制是，某些治療方法需要週期性地開始和停止。

During the time where you cycle off the treatment where you're not taking the treatment, obviously, if you're not on the medicine, what happens is the autoantibodies come back and that can lead to the disease returning. Now what I'm about to tell you next is cross-study comparisons, so you have to take it with a grain of salt. But there's been a study in China, China-based study using a wild-type TACI. And using a wild-type TACI, if you do a side-by-side comparison of what's called the myasthenia gravis ADL score, that's the endpoint. It is remarkable what the wild-type TACI -- this is a wild-type TACI was able to accomplish.

在停藥期間，也就是停止服藥的那段時間，很顯然，如果你沒有服用藥物，就會出現自身抗體復發的情況，這可能導致疾病復發。接下來我要講的是跨研究的比較，所以你們要有所保留地看待。但是中國有一項研究，一項以中國為基地的研究，使用了野生型TACI。如果使用野生型 TACI，將所謂的重症肌無力 ADL 評分進行並排比較，那就是終點。野生型 TACI 所取得的成就令人矚目──這可是野生型 TACI 啊。

Again, these are cross-study comparisons, so take it with a grain of salt. But what that wild-type TACI tells me is that by mechanism of action, it is something to really hold close. So then you translate that to pove. Pove is not a wild-type TACI. Pove is this engineered fusion protein, better potency, better binding affinity, better pharmacokinetics, better tissue distribution.

再次強調，這些都是跨研究的比較，所以請謹慎看待。但這種野生型 TACI 告訴我，從作用機制來看，它確實值得我們密切關注。所以你把它翻譯成 pove。Pove 不是野生型 TACI。Pove 是一種經過基因工程改造的融合蛋白，具有更高的效力、更好的結合親和力、更好的藥物動力學和更好的組織分佈。

So I look at the wild-type TACI and then I think about what pove could bring to the table, and that's the reason I'm so excited about this. I think this is going to be a really important indication for pove. First thing first, we got to get through Phase II. That study should be up and running shortly. That is a dose-ranging study.

所以我觀察了野生型 TACI，然後思考 pove 能帶來什麼，這就是我對此如此興奮的原因。我認為這將是預測市場走勢的一個非常重要的指標。首先，我們得先度過第二階段。這項研究應該很快就會啟動。這是一項劑量範圍研究。

So we're going to study 80 mg and 240 mg and then we can take it from there and go to pivotal development. But it is one of the ones that I'm excited about.

所以我們將研究 80 毫克和 240 毫克的劑量，然後我們可以以此為基礎，進入關鍵性開發階段。但它是我非常期待的項目之一。

Michael Yee, UBS.

Michael Yee，瑞銀集團。

Two questions. First, on pove, can you remind us how to think about what rates of ADA are possible, either absolute rates or neutralizing rates? And do you expect that to be of any material number given it's a chronic drug that could be something to think about?

兩個問題。首先，關於 pove，您能否提醒我們如何思考 ADA 的可能速率，無論是絕對速率還是中和速率？考慮到這是一種需要長期服用的藥物，你認為這個數字會有多大意義？這值得我們深思。

And then I don't think anyone's asked on AMKD, but obviously, you have a very potent drug there, and that data could be in about a year or so. And just wanted to think about how you expect those results to play out. And given you have a more heterogeneous population rather than just FSGS, do you expect essentially the same results from the Phase II?

然後，我認為還沒有人問過 AMKD 的問題，但顯然，這是一種非常有效的藥物，相關數據可能在一年左右就能獲得。我只是想思考你認為這些結果會如何發展。鑑於你們的研究對像是比單純的 FSGS 患者群體更加多樣化的患者，你們是否預期 II 期臨床試驗會得到基本上相同的結果？

Yes. Mike, let me take the AMKD results first, and then I'll come back to pove and ADA. So in AMKD, when I was listening to Duncan talk about AMKD, ADPKD, pove in IgAN, pove membranous, it really is a substantial renal franchise that's emerging. I do expect at the bottom line; I do expect that our results from the AMKD Phase III AMPLITUDE study will be very similar to what we saw in the Phase II AMKD study. Recall, though, Mike, that the readout, the primary endpoint for the Phase III study is GFR slope.

是的。麥克，讓我先看看AMKD的結果，然後再回來看pove和ADA的結果。所以，在 AMKD 中，當我聽 Duncan 談論 AMKD、ADPKD、IgAN 中的 pove、膜性 pove 時，這確實是一個正在興起的重要的腎臟疾病領域。我預計，從最終結果來看，AMKD III 期 AMPLITUDE 研究中獲得的結果將與我們在 II 期 AMKD 研究中看到的結果非常相似。不過，麥克，請記住，III 期研究的主要終點是 GFR 斜率。

Of course, we're going to measure proteinuria, but you'll recall that the FDA pathway to accelerated approval for AMKD is based on 48-week GFR. So there's that difference. And if you ask me, well, why do you think that even though the group that we studied in Phase II was something we called FSGS, which is a histologic diagnosis is what you see on biopsy. And the group that we studied in Phase III is AMKD, 2 APOL1 alleles. They are the same disease.

當然，我們會測量蛋白尿，但您應該記得，FDA 對 AMKD 的加速批准途徑是基於 48 週的 GFR。所以這就是差別所在。如果你問我，那麼你認為為什麼即使我們在第二階段研究的群體被我們稱為 FSGS，這是一種組織學診斷，也就是你在活檢中看到的疾病。我們在 III 期研究的組別是 AMKD，2 個 APOL1 等位基因。它們是同一種疾病。

It's just whether or not the patient with two APOL1 alleles, depressed renal function and proteinuria was sent to get a biopsy or not sent to get a biopsy. If you don't go to get a biopsy, you will never be able to see FSGS because that's simply a histological diagnosis. So net-net, I expect the results to be in line with Phase II. And I will reaffirm the time lines for data sharing tail end of this year, beginning of next. On pove and ADA and NAb, just to set the stage, and I know you know this, in biologics, ADAs, anti-drug antibodies are to be expected.

問題在於，患有兩個 APOL1 等位基因、腎功能減退和蛋白尿的患者是否被送去做腎臟切片檢查。如果不做活檢，就永遠無法發現 FSGS，因為那隻是組織學診斷。總的來說，我預計結果將與第二階段一致。我將再次確認數據共享的時間表，即今年年底或明年年初。關於 pove、ADA 和 NAb，首先要說明的是，我知道你們也知道，在生物製劑中，抗藥性抗體（ADA）是意料之中的。

If it doesn't have a consequence on efficacy, so you would know that by neutralizing antibodies, you would see it on the end point of interest, in this case, proteinuria, it is not something to be concerned about. And of course, on the other side, it could be an antibody that causes safety. But based on how this particular drug works, I don't have concerns in that domain. So it's really about a specific subset of antidrug antibodies, neutralizing antibodies that have an impact on outcomes. Based on everything that we saw in RUBY-3 that we shared with you at ASN in November, I don't expect that to be something of consequence.

如果它對療效沒有影響，那麼透過中和抗體，你就能在感興趣的終點（在本例中是蛋白尿）上看到它，這就不是什麼值得擔心的事情。當然，另一方面，它也可能是一種能帶來安全感的抗體。但就這種藥物的作用機製而言，我在這方面並不擔心。所以，這其實是關於一類特定的抗藥性抗體，即中和抗體，它們會對治療結果產生影響。根據我們在 11 月 ASN 大會上與大家分享的 RUBY-3 的所有內容，我不認為這會造成什麼重大影響。

ADA, that is.

也就是美國殘障法案（ADA）。

Eliana Merle, Barclays.

埃莉安娜·默爾，巴克萊銀行。

Just on JOURNAVX, how do you see the mix between retail and the hospital setting evolving over the course of the year? And how should we think about how that mix could impact gross to net as well as treatment duration?

就 JOURNAVX 而言，您認為零售業與醫院環境的融合將在今年如何演變？我們該如何考慮這種組合會對毛利淨利以及治療持續時間產生怎樣的影響？

Duncan, do you want to take that one?

鄧肯，你想接那個任務嗎？

Yes, sure. So as far as the mix is concerned, I would say that we did see it evolve over the course of 2025. We concluded the year at around about 50-50 between retail prescriptions and hospital prescriptions. And I would say that in the future, we anticipate that, that will move more towards the retail space proportionately compared to where it is right now. In terms of the impact on gross to net, there are a number of dynamics to that.

當然可以。所以就混合比例而言，我認為我們在 2025 年期間確實看到了它的演變。今年年底，零售處方和醫院處方的比例約為 50:50。而我認為，未來我們預計，與現在相比，零售領域的佔比將會更大。就毛利潤與淨利的影響而言，其中涉及諸多動態因素。

Obviously, the length of the prescription in hospital is usually shorter than the duration of the prescription in retail. But it also depends on the type of patient, for example, whether they're a commercial patient, whether they're a Medicare patient or a Medicaid patient and indeed, whether they're going through our patient support program or whether they're a self-pay patient. So there are a number of dynamics in terms of how the sort of prescription balance affects gross to net.

顯然，醫院處方藥的有效期限通常比零售處方藥的效期短。但這也要取決於患者的類型，例如，他們是商業患者、醫療保險患者還是醫療補助患者，以及他們是否正在接受我們的患者支持計劃，還是自費患者。因此，處方平衡如何影響毛利潤與淨利潤之間存在許多動態因素。

William Pickering, Bernstein.

威廉‧皮克林，伯恩斯坦。

I was wondering -- this is a pove one. If you could discuss how you expect the baseline GFR to impact the observed effect size, I think your Phase II patients had an average GFR about 10 mLs higher than the competitor Phase II or Phase III trials. And so if we were to see a Phase III baseline for pove, it's more similar to those competitor trials. Just wondering directionally, which way, if at all, that would influence effect size.

我在想——這是一個pove。如果您能討論一下您認為基線 GFR 將如何影響觀察到的效果大小，我認為您的 II 期患者的平均 GFR 比競爭對手的 II 期或 III 期試驗高出約 10 mL。因此，如果我們要查看 pove 的 III 期基線，它與那些競爭對手的試驗更為相似。我只是好奇，從方向上看，這會對效應大小產生什麼影響（如果有的話）。

Well, I think you're asking about what the impact of baseline GFR could be on proteinuria. Did I understand that correctly?

我想你是在問基線腎絲球濾過率對蛋白尿的影響。我理解得對嗎？

Yes, that's right.

是的，沒錯。

Okay. In general, when you're in the range of proteinuria where -- we're studying, so you have to be somewhere between 30, and I think the entry criteria is like 30 to 90 or something like that. When you're not at the very tail end close to dialysis, so what we would call a burnout kidney in the range that we're studying, it shouldn't have any great impact on proteinuria. When you have a burnt-out kidney, proteinuria could seemingly decrease because you don't have any renal function left. But in the range that we're talking about, it should be fine.

好的。一般來說，當你的蛋白尿處於我們正在研究的範圍內時，所以你的數值必須在 30 到 90 之間，我認為准入標準是 30 到 90 之類的。當你的病情還沒有到需要透析的地步，也就是我們研究的這個範圍內所謂的「腎臟衰竭」時，它應該不會對蛋白尿產生太大影響。當腎臟衰竭時，蛋白尿似乎會減少，因為腎臟功能已經完全失去。但在我們討論的範圍內，應該沒問題。

There's no real big impact there. I hope that helps.

那裡並沒有什麼真正的大影響。希望對您有幫助。

Brian Abrahams, RBC Capital Markets.

Brian Abrahams，加拿大皇家銀行資本市場。

Another one on pove. Just recognizing there are similar inclusion/exclusion criteria between RUBY-3 and RAINIER. I was just wondering if there are any differences such as proportion of patients from China or the degree of patients on SGLT2 inhibitors that might impact proteinuria response to povetacicept. And then also, is there any reason as we sort of think about a proxy for the potential magnitude of what we might see not to include the blend of UPCR reductions from both the 80 mg and 240 mg doses from RUBY-3 just to, I guess, get to a higher end. I'm just wondering if there's any reason 240 mg might have conferred lesser activity mechanistically.

另一個關於 pove 的。只是注意到 RUBY-3 和 RAINIER 之間存在類似的包含/排除標準。我只是想知道是否存在一些差異，例如來自中國的患者比例或使用 SGLT2 抑制劑的患者程度，這些差異可能會影響 povetacicept 對蛋白尿的反應。此外，當我們考慮如何估算我們可能看到的潛在影響程度時，是否有任何理由不將 RUBY-3 中 80 毫克和 240 毫克劑量下的 UPCR 降低量結合起來，以便獲得更高的數值？我只是想知道，從機制上講，240毫克的劑量是否有任何原因會導致活性降低。

Okay. On the differences between Phase II RUBY-3 and the Phase III RAINIER, I think the most important one is that the Phase II study was not placebo-controlled. The Phase III study, obviously, is placebo-controlled. In all the other dimensions, inclusion, exclusion criteria, the dose of the study, the endpoint, they're either exactly the same or very, very similar. The difference is the placebo arm.

好的。關於二期 RUBY-3 和三期 RAINIER 之間的區別，我認為最重要的區別是二期研究沒有安慰劑對照。顯然，III期研究是安慰劑對照研究。在其他所有方面，包括納入標準、排除標準、研究劑量、終點，它們要么完全相同，要么非常非常相似。差別在於安慰劑組。

So you do have to think about that. And at the ASN event, there was a question to one of the thought leaders who's worked in this space for a long time about, well, what do you think the placebo protein response could be over this period. And they said between 0% and 5%. I think that's about right. So I think that's the big one.

所以你確實需要考慮這一點。在 ASN 活動中，有人向長期從事該領域工作的思想領袖提出了一個問題，那就是，您認為在此期間安慰劑蛋白反應會是什麼樣的。他們說介於 0% 到 5% 之間。我覺得差不多就是這樣。所以我認為這是最重要的一點。

I don't have baseline characteristics, Brian, to share with you from the RAINIER study. Obviously, we'll have that for you when we share the results. I think there was another question about 80 mg and 240 mg. We did not study 240 mg any further after RUBY-2 and all of the 240 mg data that we had -- we shared with you at the ASCEND, and it did look on average about the same as 80 milligrams.

Brian，我沒有 RAINIER 研究的基線特徵可以與你分享。當然，我們會在公佈結果時一併告知大家。我想之前還有人問過關於 80 毫克和 240 毫克的問題。在 RUBY-2 之後，我們沒有對 240 毫克劑量進行進一步研究，我們所有的 240 毫克劑量數據——我們在 ASCEND 會議上與大家分享了——看起來平均而言與 80 毫克劑量大致相同。

Terence Flynn, Morgan Stanley.

Terence Flynn，摩根士丹利。

Maybe 2 for me. First one, unsurprisingly on Pove. I was wondering, Reshma, if you can comment at all about the blinded serious infection data you're seeing from the RAINIER study at this point? And then the second was on the WuXi deal. I know you mentioned you're developing this TCE for B cell-mediated autoimmune conditions.

對我來說，或許是2。不出所料，第一個是在Pove上。Reshma，我想問你，目前你從 RAINIER 研究中看到的盲法嚴重感染數據，你能不能發表一些評論？第二件事是關於與藥明康德的交易。我知道您曾提到您正在開發這種用於治療 B 細胞介導的自體免疫疾病的 TCE。

Just wondering how you think about differentiation there on the portfolio in terms of where you might carve out those indications relative to pove.

我想知道您是如何看待投資組合中的差異化問題的，以及您將如何將這些指標相對於投資組合進行劃分。

Yes. Yes. On the data for RAINIER, as you may know, there's an independent data safety monitoring committee that monitors that study. And maybe the most helpful thing I can share is that they review the data in an ongoing fashion. And of course, they review blinded and unblinded data.

是的。是的。如您所知，RAINIER 研究的資料由獨立的資料安全監測委員會負責監督。或許我能分享的最有幫助的一點是，他們會持續不斷地審查數據。當然，他們也會審查盲法數據和非盲法數據。

They review everything because they are the DSMB, they have not asked us to change anything in the study, and they've given the study clean bills of health as it goes through. Maybe that's the most helpful thing I can say to you with regard to what the ongoing data is. With regard to WuXi and indications, we specifically didn't share. So I'm going to keep that information under wraps for a little bit longer. I will say that the idea of having a medicine like pove pipeline and a product for multiple B cell-mediated diseases is exciting.

因為他們是資料安全監測委員會 (DSMB)，所以他們會審查所有內容；他們沒有要求我們更改研究中的任何內容；而且他們已經對研究進行了全面審查，確保其符合要求。關於目前的數據，或許我能給你的最有幫助的資訊就是這個了。關於藥明康德及其適應症，我們並沒有特別透露。所以，我打算暫時把這個消息保密。我想說，擁有像pove這樣的藥物研發管線，以及針對多種B細胞介導疾病的產品，這個想法令人興奮。

And our interest in serial innovation stands. And you put those two together, it's probably unsurprising to you that we're interested in these kind of trispecific engagers because they would work for a variety of diseases, not just the ones that we've talked about, IgAN, membranous, myasthenia, but other B cell-mediated diseases that we're interested in. But I'll keep the specifics under wraps for a little longer.

我們對持續創新的興趣依然不變。把這兩點結合起來，你可能就不會驚訝我們對這類三特異性銜接器感興趣了，因為它們可以用於治療多種疾病，不僅限於我們討論過的 IgAN、膜性肌無力症，還可以用於治療我們感興趣的其他 B 細胞介導的疾病。但我會暫時保密具體細節。

Debjit Chattopadhyay, Guggenheim.

查托帕迪亞 (Debjit Chattopadhyay)，古根漢。

This is Moritz on for Debjit. I have two about pove. First, looking at the RUBY-3 UPCR data, pove had a much larger standard error than atacicept, sibeprenlimab in their comparable studies. Any comment on what may have caused this variability? And second, as atacicept and sibeprenlimab's Phase III studies showed very different placebo rates in their UPCR interim analysis. What's your assumption for the placebo rate in the RAINIER interim?

這是莫里茲替德布吉特發言。我有兩個關於pove的問題。首先，查看 RUBY-3 UPCR 數據，在類似的研究中，pove 的標準誤差比 atacicept 和 sibeprenlimab 大得多。對於造成這種差異的原因，您有什麼看法？其次，atacicept 和 sibeprenlimab 的 III 期研究顯示，其 UPCR 中期分析中安慰劑率非常不同。您對 RAINIER 中期研究中安慰劑效應發生率的假設是什麼？

Yes. I don't have much more to add about the placebo rate other than what I said when this question was asked at ASN, the physician who had been involved in a number of trials and is a real IgAN expert offered that his idea was 0% to 5% for placebo. I think that's probably about right, and that sounds right to me. So I would keep that. On the idea of standard error, I have not looked at their data.

是的。關於安慰劑率，我沒有什麼要補充的了，除了我在 ASN 會議上被問到這個問題時所說的，那位參與過多次試驗的醫生，一位真正的 IgAN 專家，表示他認為安慰劑率應該在 0% 到 5% 之間。我覺得這大概是對的，聽起來還蠻合理的。所以我會保留它。關於標準誤差的概念，我還沒看過他們的數據。

I don't know that I have anything particularly helpful to say. As you know, the standard error is impacted by sample size. So I don't know exactly which data sets you're looking at, but that's one thing I would look at. And also matters what lab test you use, whether you're using 24-hour urine or you're using spot urine. So I could offer multiple explanations, but unfortunately, I haven't looked at the data you're looking at.

我不知道我有什麼特別有幫助的建議。如您所知，標準誤差受樣本大小的影響。所以我不太清楚你具體在查看哪些資料集，但這是我會關注的一個面向。此外，你使用的實驗室檢測方法也很重要，是使用 24 小時尿液或隨機尿液。所以，我可以提供多種解釋，但遺憾的是，我沒有看過你正在查看的數據。

But if you send it to Susie, I'm happy to look after the call.

但如果你把它發給蘇西，我很樂意接聽電話。

And just to be specific, the 0% to 5%, is that increase or decrease given that in the competitor Phase III studies, one of them showed a placebo increase and the other showed a decrease in UPCR.

具體來說，0% 到 5% 的增減幅度是指，在競爭對手的 III 期研究中，其中一項研究顯示安慰劑組尿蛋白/肌酸酐比值 (UPCR) 升高，而另一項研究顯示 UPCR 降低。

I was thinking about proteinuria -- the placebo group potentially having proteinuria improvement of somewhere between 0% to 5%. Obviously, if the proteinuria in the placebo group, if there was more proteinuria, it would be incrementally beneficial to pove because it is a comparison versus placebo. But of course, the placebo is equal opportunity, it could go up or down.

我當時在想蛋白尿——安慰劑組的蛋白尿改善幅度可能在 0% 到 5% 之間。顯然，如果安慰劑組的蛋白尿更多，那麼提高治療效果將是有益的，因為這與安慰劑組進行了比較。當然，安慰劑的效果是均等的，它可能會上升也可能下降。

Phil Nadeau, TD Cowen.

菲爾·納多，TD·考恩。

We want to ask about the $500 million guidance for products outside of CF. First, could you give us some sense of the breakdown between CASGEVY and JOURNAVX in that number? And then second, that is a big increase, a three-fold increase over 2025 and an approximate doubling versus the Q4 run rate. What gives you confidence in that level of growth? Is it CASGEVY infusions, CASGEVY self-harvest that are happening, visibility from payers on JOURNAVX?

我們想詢問一下關於 CF 以外產品 5 億美元的業績指引。首先，您能否簡單介紹一下 CASGEVY 和 JOURNAVX 在該數字中所佔的比例？其次，這是一個很大的成長，比 2025 年成長了三倍，比第四季的運行速度大約翻了一番。是什麼讓你對這樣的成長水準充滿信心？是否正在進行 CASGEVY 輸注、CASGEVY 自我採集，以及支付方在 JOURNAVX 上的可見性？

Can you give us some sense of what you're seeing to put that number out there?

您能否大致描述一下您觀察到的情況，以便我們能夠公佈這個數字？

I'll ask you to take that one.

我會請你來做這件事。

Sure. Yes. So the guidance includes a contribution from non-CF products of $500 million or more. We do feel very confident about that number and have great line of sight to the year for some of the reasons that you touched on. I won't break it down further in terms of CASGEVY or JOURNAVX, but you will see the CASGEVY and JOURNAVX results in our quarterly reporting after it's occurred.

當然。是的。因此，該指導意見包括來自非CF產品的5億美元或以上的貢獻。我們對這個數字非常有信心，並且由於你剛才提到的一些原因，我們對今年的前景非常樂觀。我不會進一步細分 CASGEVY 或 JOURNAVX，但您將在季度報告結束後看到 CASGEVY 和 JOURNAVX 的結果。

So you'll have a sense of where the contribution is coming from. With CASGEVY, we had a strong year with over -- with 300 or so patients initiating, 150 or so having first cell collections. And given the length of the patient journey, that gives us great visibility into the year. So we're very confident that CASGEVY will ramp up nicely compared to 2025. And then similarly, you've seen our previous commentary about JOURNAVX prescriptions tripling in 2026 compared to 2025.

這樣你就能了解捐款的來源。憑藉 CASGEVY，我們度過了強勁的一年，有超過 300 名患者開始接受治療，其中約有 150 名患者進行了首次細胞採集。考慮到患者就診過程的漫長，這讓我們對全年的情況有了很好的了解。因此，我們非常有信心，CASGEVY 的產能將比 2025 年大幅提升。同樣地，您也看到了我們先前的評論，即 JOURNAVX 處方量在 2026 年將比 2025 年增長三倍。

And with greater access in '26 versus '25, the revenue conversion on those prescriptions will be greater as well. So feeling confident about both. We have a nice trajectory heading into 2026 versus 2025 and look forward to reporting out on the results each quarter as we go forward.

而且，與 2025 年相比，2026 年的藥品取得管道將更加暢通，這些處方藥的收入轉換率也會更高。所以對這兩方面都很有信心。與 2025 年相比，我們 2026 年的發展軌跡良好，我們期待在接下來的每季都向大家報告結果。

Thanks, Jeff. If you could wrap it up for us, please.

謝謝你，傑夫。如果您能幫我們總結一下就太好了。

Yes, ma'am. This concludes our question-and-answer session as well as the conference call. Thank you for attending today's presentation. 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 replay access code 10206104. Again, that replay access code is 10206104.

是的，女士。我們的問答環節和電話會議到此結束。感謝各位參加今天的報告會。本次活動的重播將在電話會議結束後不久提供，撥打 1(877) 344-7529 或 1 (412) 317-0088，使用重播接入碼 10206104 即可收聽。再次提醒，重播存取代碼為 10206104。

Thank you for participating today. You may now disconnect.

感謝您今天的參與。您現在可以斷開連線了。