Ivacaftor/Lumacaftor

喜欢我们，设为星标，接收最新类器官进展与资讯！知识星球搜索“肠道类器官”获取更加专业的培养基配方、标准方案、AI类器官工具和技术手册。  传播科学知识 促进同行交流 推动产业发展 服务国家战略  本公众号由Organoid Agent智能体强力赋能，让您的类器官研究始终站在潮头浪尖！ 推荐语      HansClevers最新综述系统梳理了类器官作为 3D 体外平台在药物研发中的价值。其核心在于解决传统模型痛点：相比 2D 细胞系缺乏组织复杂性、动物模型存在物种差异与伦理争议，类器官能精准复刻人体组织架构与功能，可高效用于遗传疾病、癌症、传染病等疾病建模，还能实现药物效果与毒性的高通量筛选，甚至基于患者样本开展个性化用药评估。研究同时客观剖析了当前瓶颈，如类器官缺乏血管与免疫细胞、培养 可重复性不足及监管体系待完善等问题，并提出微流控整合、标准化培养等解决方案。这项综述不仅为药物研发提供了更贴近人体的新工具，更推动了从基础研究到临床转化的衔接，对减少无效实验、加速精准药物开发具有重要指导意义。 从类器官的本质与培育逻辑来看，研究明确类器官是源于干细胞的 3D 结构，能复刻对应组织的关键结构与功能 —— 这一特性使其相较传统 2D 细胞系更贴近人体生理状态，也避免了动物模型的物种差异与伦理争议。研究详细区分了两类核心培育路径：多能干细胞（PS 细胞，含胚胎干细胞与诱导多能干细胞 iPS 细胞）来源的类器官，需通过模拟胚胎发育的分步信号诱导，历经数周至数月分化为脑、视网膜、肝、肾等组织特异性结构；而组织干细胞（TSC）来源的类器官，直接取自患者活检样本，无需谱系定向，仅需特定生长因子与细胞外基质（如 Matrigel）即可实现扩增，更适合快速构建患者特异性模型，例如肠道、气道等含活跃干细胞的组织类器官。两种路径的差异与适配场景，为后续不同药物研发需求提供了清晰的技术选择依据。 在疾病建模这一核心应用领域，研究通过大量实例展现了类器官的独特优势。针对遗传疾病，以囊性纤维化（CF）为例，患者来源类器官（PDOs）可通过 forskolin 诱导肿胀实验评估 CFTR 通道功能 —— 健康类器官会因水分流入 lumen 而肿胀，CF 患者类器官则无此反应，且该反应可通过 CRISPR 纠正突变或有效 CFTR 调节剂（如 Orkambi）恢复，更关键的是，类器官药物反应与患者临床指标（如 1 秒用力呼气容积百分比 ppFEV1）高度相关，为个性化用药提供了精准依据。类似地，原发性纤毛运动障碍（PCD）的鼻气道类器官可直接观察纤毛摆动，α1 - 抗胰蛋白酶缺乏症的肝脏类器官能复刻蛋白聚集与 elastase 抑制受损，均为遗传疾病机制研究与治疗干预提供了 “人体替身”。 代谢疾病领域，研究重点分析了代谢功能障碍相关脂肪性肝炎（MASH）的建模突破。传统动物模型难以模拟人类 MASH 的脂质堆积、炎症与纤维化进程，而患者来源或代谢物诱导的肝脏类器官，不仅能呈现这些核心病理特征，还可通过共培养 Kupffer 细胞、肝星状细胞，还原炎症与纤维化的细胞间互作 —— 例如游离脂肪酸（FFA）处理后，类器官中会出现促炎因子上调、肝星状细胞活化及组织硬度增加，这为 MASH 药物筛选提供了更贴近临床的模型，研究中提及的 FGF19 可通过激活 FXR 减少脂质储存诱导的活性氧（ROS），正是基于类器官模型的重要发现。 传染病建模方面，类器官解决了传统细胞系无法支持病原体完整生命周期的痛点。例如，人类肠道类器官首次实现了诺如病毒（HuNoV）的体外培养，明确肠上皮细胞为其靶细胞，且能体现病毒对组织血型抗原（HBGA）的菌株特异性结合； Zika 病毒（ZIKV）研究中，人 iPS 细胞来源的脑类器官精准复刻了病毒对神经前体细胞的损伤 —— 导致皮质层紊乱、细胞增殖减少及神经元数量下降，甚至揭示了病毒蛋白 NS2A 破坏神经干细胞连接、NS5 抑制人类 STAT2 的分子机制，为抗 ZIKV 药物筛选（如发现 hippeastrine hydrobromide 可挽救微脑回表型）提供了关键平台。新冠疫情期间，气道类器官则明确了 ACE2 + 纤毛细胞为 SARS-CoV-2 的初始靶细胞，还证实了 TMPRSS2 在病毒入侵中的核心作用，且发现（羟）氯喹在类器官中无法抑制病毒复制，与后续临床无效结果一致，凸显了类器官在药物有效性验证中的关键价值。 癌症研究是类器官应用的另一重要场景。患者来源肿瘤类器官（PDTOs）能完整保留原发肿瘤的组织学、遗传学与转录组特征，且可稳定移植到小鼠体内进行体内验证。研究指出，PDTOs 可用于突变特异性药物测试 —— 例如 HER2 过表达的乳腺癌类器官对 HER 通路抑制剂敏感，BRCA1/2 突变的类器官对 PARP 抑制剂反应显著；更重要的是，PDTO 生物银行的建立，为肿瘤异质性研究与个性化治疗提供了支撑，如结直肠癌 PDTOs 能预测患者对 5 - 氟尿嘧啶、FOLFOX 化疗的响应差异，胰腺癌 PDTOs 的吉西他滨敏感性特征可用于患者分层，这些成果已推动多项临床试验（如 NCT03544047）评估 PDTO 指导治疗的价值。 在药物研发的转化安全应用层面，研究系统梳理了类器官在多器官毒性测试中的突破。肝脏作为药物代谢核心器官，类器官（无论 TSC 或 PS 细胞来源）能更精准预测药物诱导肝损伤（DILI）—— 例如对已退市的抗糖尿病药物曲格列酮、过量对乙酰氨基酚的肝毒性评估，敏感性显著高于传统 HepG2 细胞；肾脏类器官虽尚未完全具备肾小管滤过功能，但已能模拟顺铂、庆大霉素诱导的急性肾损伤，通过肾损伤分子 1（KIM1）的剂量依赖性上调，实现 nephrotoxicity 测试；胃肠道毒性测试中，回肠类器官构建的药物诱导腹泻模型，对 31 种参考药物的预测准确率达 90%，为临床前药物胃肠道安全性评估提供了高效工具。 类器官在药物吸收、分布、代谢与排泄（ADME）研究中的应用，是该研究关注的另一重点。肝脏类器官表达完整的 I 相（如 CYP3A4、CYP2D6）与 II 相（如尿苷二磷酸葡萄糖醛酸转移酶）代谢酶及药物转运体（如 OATP1B3、ABCB1），可用于药物代谢途径与胆汁排泄研究；肠道类器官通过 2D Transwell 系统，实现了药物跨上皮转运的双向评估，能区分高 / 低渗透性化合物，且可模拟肠道代谢的区段特异性差异；肾脏类器官则在近端小管转运体（如 OCT2、OAT1）研究中展现潜力，为药物肾清除评估提供了新模型。 针对类器官技术的现存挑战，研究并未回避，而是客观指出了关键瓶颈：多数类器官缺乏血管、免疫细胞与神经支配，限制了其功能成熟与对系统性疾病的模拟；培养过程中的变异性（如不同实验室的 protocol 差异、患者细胞的遗传多样性）影响了结果可重复性；规模化培养与高通量筛选（HTS）的技术门槛较高，制约了其在药物研发中的普及。对此，研究提出了针对性解决方案：通过微流控技术（如类器官芯片）构建血管网络、共培养免疫细胞，提升模型复杂性；利用自动化液体处理系统与 3D 生物打印，实现类器官的标准化、规模化生产；开发 matrix-free 悬浮培养、微孔阵列等技术，优化 HTS 兼容性 —— 例如微流体生成的类器官液滴，可实现病毒感染与 T 细胞渗透的高效评估，已应用于 SARS-CoV-2 药物筛选与 CAR-T 细胞 potency 检测。 监管层面，研究梳理了类器官作为 “新方法学”（NAMs）的政策环境进展。2022 年美国《FDA 现代化法案 2.0》与 2023 年《3.0》明确了动物实验并非药物研发的必需环节，FDA 更计划逐步淘汰单克隆抗体等药物的动物测试要求；OECD 则通过《良好体外方法实践指南》（GIVIMP）等文件，为类器官的验证与监管应用提供框架。但研究也指出，类器官的监管认可仍需突破 —— 多数研究仍处于临床前验证阶段，缺乏与体内数据、临床结果的大规模对比，且尚未形成统一的模型 qualification 标准，这些都需要跨行业联盟与监管机构的协同推进。 综上，该研究不仅是对类器官技术在药物研发中应用的系统性总结，更构建了 “问题 - 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— Total revenue of $3.08 billion , an 11% increase compared to Q3 2024 — — Refined full year financial guidance: total revenue guidance now $11.9 to $12.0 billion and total combined non-GAAP R&D, AIPR&D, and SG&A expense guidance now $5.0 to $5.1 billion — — R&D pipeline continues to make progress: five programs in pivotal development and povetacicept Phase 3 IgAN trial full enrollment complete; on track to submit first module of povetacicept IgAN BLA to FDA by end of 2025 — BOSTON --(BUSINESS WIRE)--Nov. 3, 2025-- Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today reported consolidated financial results for the third quarter ended September 30, 2025 , and refined full year 2025 financial guidance. “Vertex delivered strong results across the board in the third quarter, extending our leadership in CF, continuing to build global momentum for CASGEVY, and advancing the launch of JOURNAVX in acute pain,” said Reshma Kewalramani , M.D., Chief Executive Officer and President of Vertex . “We also delivered strong progress across the R&D pipeline, with completion of enrollment in the Phase 3 study of povetacicept in IgAN, initiation of the Phase 2/3 study of povetacicept in primary membranous nephropathy, as well as advancement of several programs in research and earlier-stage clinical development. For the remainder of 2025, we are focused on executing the ongoing launches, initiating the povetacicept BLA submission in IgAN for potential U.S. accelerated approval, advancing the pipeline, and preparing for new launches in additional disease areas.” Third Quarter 2025 Results Total revenue increased 11% to $3.08 billion compared to the third quarter of 2024, primarily driven by the continued performance of cystic fibrosis (CF) therapies and early contributions from the three ongoing launches. In the U.S. , total revenue increased 15% to $1.98 billion due to continued strong CF patient demand, including for ALYFTREK; contributions from CASGEVY and JOURNAVX; and favorable net pricing in CF versus the prior year. Outside the U.S. , total revenue increased 4% to $1.10 billion due to solid performance across multiple geographies. Combined GAAP and non-GAAP R&D, Acquired IPR&D and SG&A expenses were $1.5 billion and $1.3 billion , respectively, compared to $1.3 billion and $1.1 billion , respectively, in the third quarter of 2024. The increases were primarily due to increased R&D investment in support of multiple mid- and late-stage clinical development programs, increased commercial investment to support the launch of JOURNAVX in acute pain, and higher AIPR&D. GAAP and non-GAAP effective tax rates were 16.6% and 17.6%, respectively, compared to 14.6% and 19.8%, respectively, for the third quarter of 2024. In each of the third quarters of 2025 and 2024, the tax rate benefited from increased R&D tax credits. GAAP and non-GAAP net income were $1.1 billion and $1.2 billion , respectively, compared to $1.0 billion and $1.1 billion , respectively, for the third quarter of 2024, primarily driven by increased product revenue partially offset by increased operating expenses. Cash, cash equivalents, and total marketable securities as of September 30, 2025 , were $12.0 billion , compared to $11.2 billion as of December 31, 2024 . The increase was primarily due to cash flows from operating activities, partially offset by repurchases of Vertex’s common stock pursuant to its share repurchase programs. Full Year 2025 Financial Guidance Vertex today refined its full year 2025 revenue guidance with total revenue now expected to be $11.9 to $12.0 billion , which assumes continued growth in CF, including the global launch of ALYFTREK; continued uptake of CASGEVY in multiple regions; and early contributions from the U.S. launch of JOURNAVX. Vertex is also revising full year 2025 guidance for combined GAAP and non-GAAP operating expenses. Combined GAAP and non-GAAP R&D, AIPR&D, and SG&A expenses are now expected to be approximately $5.65 to $5.8 billion and $5.0 to $5.1 billion , respectively. This revised outlook accounts for acceleration of povetacicept programs and increased investment in sales and marketing initiatives for JOURNAVX in acute pain. In addition, Vertex lowered its prior non-GAAP effective tax rate guidance of 20.5% to 21.5% to a new range of 17% to 18% to incorporate several one-time tax benefits. These include one-time tax benefits recognized in the third quarter of 2025 from Alpine-related R&D tax credits, as well as anticipated recognition in the fourth quarter of 2025 of previously deferred tax benefits. This financial guidance also includes an immaterial cost impact from tariffs in 2025 based on currently known tariff rates and regulations. Vertex’s financial guidance is summarized below: Current FY 2025 Previous FY 2025 Total revenue $11.9 to $12.0 billion $11.85 to $12.0 billion Combined GAAP R&D, AIPR&D and SG&A expenses * $5.65 to $5.8 billion $5.55 to $5.7 billion Combined non-GAAP R&D, AIPR&D and SG&A expenses * $5.0 to $5.1 billion $4.9 to $5.0 billion Non-GAAP effective tax rate 17% to 18% 20.5% to 21.5% *The difference between the combined GAAP R&D, AIPR&D and SG&A expenses and the combined non-GAAP R&D, AIPR&D and SG&A expenses guidance relates primarily to $650 million to $700 million of stock-based compensation expense. **Combined GAAP and Non-GAAP R&D, AIPR&D and SG&A expenses guidance includes approximately $100 million of AIPR&D expenses. Key Business Highlights Marketed Products Cystic Fibrosis (CF) Portfolio Vertex has worked for more than 20 years to discover and develop medicines to treat the underlying cause of CF. Vertex CFTR modulators can treat nearly 95 percent of all people living with CF in core markets and are approved for patients as young as one month old. ALYFTREK, the newest marketed CFTR modulator, is approved in the U.S. , the United Kingdom ( U.K. ), the European Union (EU), Canada , New Zealand , and Switzerland for the treatment of patients 6 years and older. Vertex anticipates that the number of CF patients taking its medicines will continue to grow through new approvals and reimbursement agreements, treatment of younger patients, increased survival, and expansion into additional geographies. Recent progress includes: The U.S. launch of ALYFTREK is progressing well across all eligible patient groups, and launches outside the U.S. are showing a strong start in multiple markets. Vertex received approval from the European Commission and Health Canada in July and from Medsafe New Zealand and Swissmedic in October for ALYFTREK for the treatment of people with CF ages 6 years and older who have at least one F508del mutation or another responsive mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Regulatory review is underway for ALYFTREK in Australia . Eligible patients in England , Ireland , Germany , Denmark and Northern Ireland currently have reimbursed access to ALYFTREK, and Vertex is working to secure access for eligible patients in additional countries. In October at the North American Cystic Fibrosis Conference (NACFC), Vertex presented multiple abstracts on ALYFTREK as well as the association between lower sweat chloride with CFTR modulator use and improved clinical outcomes. ALYFTREK has shown greater reductions in sweat chloride compared to TRIKAFTA in Phase 3 trials, suggesting that ALYFTREK has the potential for even greater improvements in quality of life and other health-related outcomes. CASGEVY for the treatment of severe sickle cell disease (SCD) and transfusion-dependent beta thalassemia (TDT) CASGEVY is a non-viral, ex vivo, CRISPR/Cas9 gene-edited cell therapy for eligible patients with SCD or TDT that has been shown to reduce or eliminate vaso-occlusive crises (VOCs) for patients with SCD and transfusion requirements for patients with TDT. CASGEVY is approved in the U.S. , Great Britain , the EU, the Kingdom of Saudi Arabia (KSA), the Kingdom of Bahrain ( Bahrain ), Qatar , Canada , Switzerland , and the United Arab Emirates ( UAE ) for the treatment of both SCD and TDT. In total, there are more than 60,000 eligible patients in these countries, including approximately 37,000 in North America and Europe and more than 23,000 in the Middle East . Recent highlights include: In September, Vertex announced a reimbursement agreement for patients with SCD and TDT in Italy . Italy has the largest population of people living with TDT in Europe , with approximately 5,000 people 12 years and older with TDT and around 2,300 with SCD. Globally, since launch through September 30 th, 2025, approximately 165 people with SCD or TDT have had their first cell collection for CASGEVY, including 50 people in the third quarter of 2025; and 39 people with SCD or TDT have received infusions of CASGEVY, including 10 people infused in the third quarter of 2025. JOURNAVX (suzetrigine) for the treatment of moderate-to-severe acute pain JOURNAVX is a first-in-class, oral, selective, non-opioid NaV1.8 pain signal inhibitor, approved in the U.S. for the treatment of moderate-to-severe acute pain. Since JOURNAVX became available at pharmacies in early March, through mid-October more than 300,000 prescriptions for JOURNAVX have been written and filled across the hospital and retail settings in different acute pain conditions, consistent with JOURNAVX’s broad label. As of mid-October, across commercial and government payers, more than 170 million individuals already have covered access to JOURNAVX, representing more than half of U.S. covered lives. This includes formal coverage with two of the three large national pharmacy benefit managers (PBMs) and unrestricted access within 19 state Medicaid plans. Vertex expects access to JOURNAVX to continue to expand over the remainder of 2025 and into 2026. Approximately 90 of Vertex’s targeted 150 large healthcare systems and more than 750 individual hospitals of the 2,000 targeted institutions have added JOURNAVX to formularies, protocols or order sets. Select Clinical-Stage Pipeline Programs Cystic Fibrosis In October, Vertex completed the pivotal study of TRIKAFTA in children 12 months to <24 months of age. The data showed that TRIKAFTA was generally safe and well tolerated, consistent with the established safety profile. Treatment with TRIKAFTA in this age group resulted in rapid, robust, and clinically meaningful improvement in the secondary endpoint of sweat chloride reduction, with a mean reduction of 71.8 mmol/L through Week 24. Vertex expects to submit for approval with global regulators in the first half of 2026. Vertex recently completed enrollment in the global study of ALYFTREK in children 2 to 5 years of age. In this pivotal study, approximately 65 children will receive ALYFTREK for 24 weeks. The primary endpoint is safety and tolerability, and secondary endpoints include absolute changes in sweat chloride. Vertex expects to share results from this trial in the first half of 2026. Vertex has advanced VX-828, the once-daily, next-generation 3.0 corrector, into a cohort of patients with CF. Vertex has resumed dosing in the multiple ascending dose (MAD) portion of the Phase 1/2 study of VX-522, a nebulized CFTR mRNA therapy, for the approximately 5,000 patients who cannot benefit from CFTR modulators. Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia Vertex has completed enrollment of children 5 to 11 years of age with SCD or TDT in two global Phase 3 studies of CASGEVY and is on track to complete dosing this quarter. Vertex will share emerging data from these studies in an oral presentation at the American Society of Hematology (ASH) annual meeting on December 6 th, 2025. Peripheral Neuropathic Pain (PNP) Vertex previously initiated the first Phase 3 trial evaluating suzetrigine in diabetic peripheral neuropathy (DPN), a form of PNP, and is on track to start the second Phase 3 study later this month. Vertex expects to complete enrollment in both Phase 3 studies by the end of 2026. Vertex continues to enroll and dose patients in a Phase 2 study for the oral formulation of VX-993 for the treatment of painful DPN. Type 1 Diabetes (T1D) Vertex is evaluating stem cell-derived, fully differentiated islet cell therapies for patients suffering from T1D, with the goal of developing a potential one-time functional cure for this disease. Vertex has completed enrollment in the Phase 1/2/3 study of zimislecel in people with T1D. Vertex has temporarily postponed completion of dosing in the study, pending an internal manufacturing analysis. Zimislecel has been granted Regenerative Medicine Advanced Therapy (RMAT) and Fast Track designations from the U.S. Food and Drug Administration , Priority Medicines (PRIME) designation from the EMA, and has secured an Innovation Passport under the Innovative Licensing and Access Pathway (ILAP) from the UK Medicines and Healthcare products Regulatory Agency (MHRA). Vertex is pursuing research-stage programs to evaluate additional approaches that could provide transformative benefits to people with T1D and reduce or eliminate the need for standard immunosuppressive regimens. These approaches include improved immunosuppression, gene editing, and novel immunoprotection to encapsulate the islet cells. IgA Nephropathy (IgAN), Primary Membranous Nephropathy (pMN), and Other B Cell-Mediated Diseases Vertex is developing povetacicept for multiple diseases. Povetacicept is a dual inhibitor of the BAFF and APRIL cytokines, which play key roles in the pathogenesis of multiple B cell-mediated diseases. Povetacicept represents a potentially best-in-class approach to control B cell activity in IgAN and pMN and has pipeline-in-a-product potential. The U.S. Food and Drug Administration (FDA) has granted Breakthrough Therapy Designation (BTD) and a rolling review to the BLA submission for povetacicept for the treatment of IgAN. Vertex has completed enrollment of the interim analysis cohort for potential accelerated approval in the U.S. and has completed the studies to support the launch of povetacicept for monthly, at-home self-administration with an autoinjector. Vertex is on track to submit the first module of the IgAN BLA to the FDA before the end of 2025 and plans to complete the full BLA submission in the first half of 2026 for potential accelerated approval in the U.S. Vertex has now also completed full enrollment of the Phase 3 study in IgAN. Vertex recently initiated the Phase 2/3 pivotal study of povetacicept in patients with pMN. The FDA recently granted Fast Track designation for povetacicept in pMN. Vertex will have an oral presentation of updated Phase 1/2 data on povetacicept in IgAN and pMN at the American Society of Nephrology (ASN) Kidney Week . Vertex will host an in-person investor event at the ASN conference on Saturday, November 8, 2025 , at 7:00 p.m. CT / 8:00 p.m. ET . The investor event will also be webcast live and a link to the webcast can be accessed through Vertex’s website at www.vrtx.com in the “Investors” section. APOL1-Mediated Kidney Disease (AMKD) Vertex has discovered and advanced multiple oral, small molecule inhibitors of APOL1 function, pioneering a new class of medicines that targets the underlying cause of this genetic kidney disease. In September, Vertex completed enrollment in the interim analysis cohort of the AMPLITUDE Phase 2/3 trial of inaxaplin. Vertex will conduct the pre-planned interim analysis once this cohort has been treated for 48 weeks, with potential to file for accelerated approval in the U.S. if the results are supportive. Vertex is on track to complete enrollment in the AMPLIFIED Phase 2 study of inaxaplin by year end 2025. AMPLIFIED is a study of people with AMKD with moderate proteinuria, and people with AMKD and Type 2 diabetes — populations not being studied in the AMPLITUDE trial. Autosomal Dominant Polycystic Kidney Disease (ADPKD) Vertex is developing small molecule correctors that restore function to the variant polycystin 1 (PC1) protein, with the goal of addressing the underlying cause of ADPKD. Vertex recently initiated AGLOW, a Phase 2 proof-of-concept study of VX-407 in patients with a subset of variants in the PKD1 gene, which encodes the PC1 protein, estimated to be up to approximately 30,000 (or up to approximately 10%) of the overall patient population living with ADPKD. AGLOW is a 24-patient single-arm study that will evaluate the effect of VX-407 on height-adjusted total kidney volume (htTKV). Myotonic Dystrophy Type 1 (DM1) Vertex is evaluating multiple approaches that target the underlying cause of DM1. Vertex’s lead approach, VX-670, is an oligonucleotide linked to a cyclic peptide, which holds the potential to promote effective delivery into cells and address the causal biology of DM1. Vertex continues to enroll and dose the MAD portion of the global Phase 1/2 clinical trial of VX-670 in people with DM1, which will assess both safety and efficacy. Vertex is on track to complete enrollment and dosing in the trial in the first half of 2026. Additional Earlier Stage R&D Programs Consistent with its overall strategy, Vertex takes a portfolio approach to all of its programs, with additional assets or approaches in CF, SCD, TDT, pain, AMKD, T1D, DM1, and ADPKD in earlier stages of development. Additionally, Vertex is working on preclinical molecules with the potential to expand its leadership in existing disease areas, including assets targeting improved immunosuppression for zimislecel, gentler conditioning for CASGEVY, and inhibition of NaV1.7 in pain. Non-GAAP Financial Measures In this press release, Vertex 's financial results and financial guidance are provided in accordance with accounting principles generally accepted in the United States (GAAP) and using certain non-GAAP financial measures. In particular, non-GAAP financial results and guidance exclude from Vertex 's pre-tax income (loss) (i) stock-based compensation expense, (ii) intangible asset amortization expense, (iii) gains or losses related to the fair value of the company's strategic investments, (iv) increases or decreases in the fair value of contingent consideration, (v) acquisition-related costs, (vi) an intangible asset impairment charge, and (vii) other adjustments. The company's non-GAAP financial results also exclude from its provision for income taxes the estimated tax impact related to its non-GAAP adjustments to pre-tax income (loss) described above and certain discrete items. These results should not be viewed as a substitute for the company’s GAAP results and are provided as a complement to results provided in accordance with GAAP. Management believes these non-GAAP financial measures help indicate underlying trends in the company's business, are important in comparing current results with prior period results and provide additional information regarding the company's financial position that the company believes is helpful to an understanding of its ongoing business. Management also uses these non-GAAP financial measures to establish budgets and operational goals that are communicated internally and externally, to manage the company's business and to evaluate its performance. The company’s calculation of non-GAAP financial measures likely differs from the calculations used by other companies. A reconciliation of the GAAP financial results to non-GAAP financial results is included in the attached financial information. The company provides guidance regarding combined R&D, AIPR&D and SG&A expenses and effective tax rate on a non-GAAP basis. Unless otherwise noted, the guidance regarding combined R&D, AIPR&D and SG&A expenses does not include estimates associated with any potential future business development transactions, including collaborations, asset acquisitions and/or licensing of third-party intellectual property rights. The company does not provide guidance regarding its GAAP effective tax rate because it is unable to forecast with reasonable certainty the impact of excess tax benefits related to stock-based compensation and the possibility of certain discrete items, which could be material. Vertex Pharmaceuticals Incorporated Consolidated Statements of Income (Loss) (unaudited, in millions, except per share amounts) Three Months Ended September 30 , Nine Months Ended September 30 , 2025 2024 2025 2024 Revenues: Product revenues, net $ 3,076.4 $ 2,771.9 $ 8,780.6 $ 8,108.1 Other revenues — — 30.7 — Total revenues 3,076.4 2,771.9 8,811.3 8,108.1 Costs and expenses: Cost of sales 414.8 392.6 1,185.3 1,107.1 Research and development expenses 977.7 875.9 2,935.8 2,631.6 Acquired in-process research and development expenses 54.5 15.0 76.5 4,540.9 Selling, general and administrative expenses 445.1 371.8 1,266.1 1,086.7 Intangible asset impairment charge — — 379.0 — Change in fair value of contingent consideration (1.9 ) 0.3 1.2 0.7 Total costs and expenses 1,890.2 1,655.6 5,843.9 9,367.0 Income (loss) from operations 1,186.2 1,116.3 2,967.4 (1,258.9 ) Interest income 125.7 132.2 369.0 469.9 Interest expense (3.3 ) (7.5 ) (10.0 ) (27.8 ) Other expense, net (9.8 ) (16.9 ) (14.2 ) (71.2 ) Income (loss) before provision for income taxes 1,298.8 1,224.1 3,312.2 (888.0 ) Provision for income taxes 215.9 178.7 550.1 560.6 Net income (loss) $ 1,082.9 $ 1,045.4 $ 2,762.1 $ (1,448.6 ) Net income (loss) per common share: Basic $ 4.24 $ 4.05 $ 10.77 $ (5.61 ) Diluted $ 4.20 $ 4.01 $ 10.68 $ (5.61 ) Shares used in per share calculations: Basic 255.6 258.0 256.4 258.1 Diluted 257.6 261.0 258.6 258.1 Vertex Pharmaceuticals Incorporated Total Revenues (unaudited, in millions) Three Months Ended September 30 , Nine Months Ended September 30 , 2025 2024 2025 2024 TRIKAFTA/KAFTRIO $ 2,653.6 $ 2,585.0 $ 7,740.2 $ 7,517.8 ALYFTREK 247.0 — 457.7 — Other product revenues (1) 175.8 186.9 582.7 590.3 Product revenues, net 3,076.4 2,771.9 8,780.6 8,108.1 Other revenues — — 30.7 — Total revenues $ 3,076.4 $ 2,771.9 $ 8,811.3 $ 8,108.1 1: In the three and nine months ended September 30, 2025 , "Other product revenues" included $16.9 million and $61.5 million from CASGEVY, respectively, and $19.6 million and $32.9 million , respectively, from JOURNAVX. In the three and nine months ended September 30, 2024 , "Other product revenues" included $2.0 million from CASGEVY and no revenues from JOURNAVX. The remaining “Other product revenues” are related to KALYDECO, ORKAMBI, and SYMDEKO/SYMKEVI, our other CF products. Vertex Pharmaceuticals Incorporated Reconciliation of GAAP to Non-GAAP Financial Information (unaudited, in millions, except percentages) Three Months Ended September 30 , Nine Months Ended September 30 , 2025 2024 2025 2024 GAAP cost of sales $ 414.8 $ 392.6 $ 1,185.3 $ 1,107.1 Stock-based compensation expense (2.8 ) (1.9 ) (7.9 ) (5.5 ) Intangible asset amortization expense (5.0 ) (5.0 ) (15.1 ) (15.1 ) Non-GAAP cost of sales $ 407.0 $ 385.7 $ 1,162.3 $ 1,086.5 GAAP research and development expenses $ 977.7 $ 875.9 $ 2,935.8 $ 2,631.6 Stock-based compensation expense (116.0 ) (111.0 ) (315.7 ) (327.5 ) Intangible asset amortization expense (0.6 ) (0.9 ) (1.9 ) (0.9 ) Acquisition-related costs (2) — — — (172.3 ) Non-GAAP research and development expenses $ 861.1 $ 764.0 $ 2,618.2 $ 2,130.9 Acquired in-process research and development expenses $ 54.5 $ 15.0 $ 76.5 $ 4,540.9 GAAP selling, general and administrative expenses $ 445.1 $ 371.8 $ 1,266.1 $ 1,086.7 Stock-based compensation expense (76.1 ) (71.7 ) (204.7 ) (197.7 ) Acquisition-related costs (2) — — — (36.5 ) Non-GAAP selling, general and administrative expenses $ 369.0 $ 300.1 $ 1,061.4 $ 852.5 Combined non-GAAP R&D, AIPR&D and SG&A expenses $ 1,284.6 $ 1,079.1 $ 3,756.1 $ 7,524.3 GAAP other expense, net $ (9.8 ) $ (16.9 ) $ (14.2 ) $ (71.2 ) Decrease in fair value of strategic investments 2.6 10.8 12.2 50.5 Non-GAAP other expense, net $ (7.2 ) $ (6.1 ) $ (2.0 ) $ (20.7 ) GAAP provision for income taxes $ 215.9 $ 178.7 $ 550.1 $ 560.6 Tax adjustments (3) 47.8 104.0 240.0 283.8 Non-GAAP provision for income taxes $ 263.7 $ 282.7 $ 790.1 $ 844.4 GAAP effective tax rate 16.6 % 14.6 % 16.6 % (63.1 )% Non-GAAP effective tax rate 17.6 % 19.8 % 18.6 % (1,038.6 )% Vertex Pharmaceuticals Incorporated Reconciliation of GAAP to Non-GAAP Financial Information (continued) (unaudited, in millions, except per share amounts) Three Months Ended September 30 , Nine Months Ended September 30 , 2025 2024 2025 2024 GAAP operating income (loss) $ 1,186.2 $ 1,116.3 $ 2,967.4 $ (1,258.9 ) Stock-based compensation expense 194.9 184.6 528.3 530.7 Intangible asset impairment charge — — 379.0 — Intangible asset amortization expense 5.6 5.9 17.0 16.0 (Decrease) increase in fair value of contingent consideration (1.9 ) 0.3 1.2 0.7 Acquisition-related costs (2) — — — 208.8 Non-GAAP operating income (loss) $ 1,384.8 $ 1,307.1 $ 3,892.9 $ (502.7 ) GAAP net income (loss) $ 1,082.9 $ 1,045.4 $ 2,762.1 $ (1,448.6 ) Stock-based compensation expense 194.9 184.6 528.3 530.7 Intangible asset impairment charge — — 379.0 — Intangible asset amortization expense 5.6 5.9 17.0 16.0 Decrease in fair value of strategic investments 2.6 10.8 12.2 50.5 (Decrease) increase in fair value of contingent consideration (1.9 ) 0.3 1.2 0.7 Acquisition-related costs (2) — — — 208.8 Total non-GAAP adjustments to pre-tax income 201.2 201.6 937.7 806.7 Tax adjustments (3) (47.8 ) (104.0 ) (240.0 ) (283.8 ) Non-GAAP net income (loss) $ 1,236.3 $ 1,143.0 $ 3,459.8 $ (925.7 ) Net income (loss) per diluted common share: GAAP $ 4.20 $ 4.01 $ 10.68 $ (5.61 ) Non-GAAP $ 4.80 $ 4.38 $ 13.38 $ (3.59 ) Shares used in diluted per share calculations: GAAP and Non-GAAP 257.6 261.0 258.6 258.1 2: In the nine months ended September 30, 2024 , “Acquisition-related costs” were primarily related to compensation expense associated with cash-settled unvested Alpine equity awards. 3: In the three and nine months ended September 30, 2025 and 2024, “Tax adjustments” included the estimated income taxes related to non-GAAP adjustments to the company's pre-tax income (loss) and excess tax benefits related to stock-based compensation. “Tax adjustments” for the three and nine months ended September 30, 2024 also included a discrete benefit related to prior tax years resulting from a R&D tax credit study that was completed in the third quarter of 2024. Vertex Pharmaceuticals Incorporated Condensed Consolidated Balance Sheets (unaudited, in millions) September 30, 2025 December 31, 2024 Assets Cash, cash equivalents and marketable securities $ 6,287.0 $ 6,115.9 Accounts receivable, net 1,946.4 1,609.4 Inventories 1,626.8 1,205.4 Prepaid expenses and other current assets 709.4 665.7 Total current assets 10,569.6 9,596.4 Property and equipment, net 1,425.1 1,227.8 Goodwill and other intangible assets, net 1,517.8 1,913.9 Deferred tax assets 2,937.2 2,331.1 Operating lease assets 1,591.8 1,356.8 Long-term marketable securities 5,722.8 5,107.9 Other long-term assets 1,098.0 999.3 Total assets $ 24,862.3 $ 22,533.2 Liabilities and Shareholders' Equity Accounts payable and accrued expenses $ 4,033.8 $ 3,201.6 Other current liabilities 441.5 363.0 Total current liabilities 4,475.3 3,564.6 Long-term operating lease liabilities 1,834.8 1,544.4 Other long-term liabilities 1,233.4 1,014.6 Shareholders' equity 17,318.8 16,409.6 Total liabilities and shareholders' equity $ 24,862.3 $ 22,533.2 Common shares outstanding 254.0 256.9 About Vertex Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases and conditions. The company has approved therapies for cystic fibrosis, sickle cell disease, transfusion-dependent beta thalassemia and acute pain, and it continues to advance clinical and research programs in these areas. Vertex also has a robust clinical pipeline of investigational therapies across a range of modalities in other serious diseases where it has deep insight into causal human biology, including neuropathic pain, APOL1-mediated kidney disease, IgA nephropathy, primary membranous nephropathy, autosomal dominant polycystic kidney disease, type 1 diabetes, and myotonic dystrophy type 1. Vertex was founded in 1989 and has its global headquarters in Boston , with international headquarters in London . Additionally, the company has research and development sites and commercial offices in North America , Europe , Australia , Latin America , and the Middle East . Vertex is consistently recognized as one of the industry's top places to work, including 16 consecutive years on Science magazine's Top Employers list and one of Fortune’s 100 Best Companies to Work For. For company updates and to learn more about Vertex’s history of innovation, visit www.vrtx.com or follow us on LinkedIn, Facebook, Instagram, YouTube and X. Special Note Regarding Forward-Looking Statements This press release contains forward-looking statements that are subject to risks, uncertainties and other factors. All statements other than statements of historical fact are statements that could be deemed forward-looking statements, including all statements regarding the intent, belief, or current expectation of Vertex and members of the Vertex senior management team. Forward-looking statements are not purely historical and may be accompanied by words such as “anticipates,” “may,” “forecasts,” “expects,” “intends,” “plans,” “potentially,” “believes,” “seeks,” “estimates,” and other words and terms of similar meaning. Such statements include, without limitation, Dr. Kewalramani's statements in this press release, the information provided regarding future financial performance and operations, the section captioned “Full Year 2025 Financial Guidance” and statements regarding (i) the eligible patient population for Vertex’s CFTR modulators and expectations for continued growth in CF, including by increasing the number of CF patients taking its medicines through new approvals and reimbursement agreements, treatment of younger patients, increased survival, and expansion into additional geographies, (ii) beliefs regarding the clinical benefits, commercial launch progress, and access in additional countries for ALYFTREK, (iii) beliefs regarding the anticipated benefits, commercial launch progress, eligible patient population, and access to CASGEVY, (iv) expectations regarding the potential benefits and commercial launch progress for JOURNAVX, including expectations with respect to expanding access to JOURNAVX over the remainder of 2025 and into 2026, (v) expectations to expand the labels for TRIKAFTA/KAFTRIO and ALYFTREK and enable earlier treatment of children with CF, including expectations to submit regulatory approval applications for TRIKAFTA/KAFTRIO in children 12 to <24 months of age with global regulators in the first half of 2026 and to share results from the ALYFTREK clinical trial in children 2 to 5 years of age in the first half of 2026, (vi) expectations and plans with respect to the clinical trials evaluating VX-828 and VX-522, (vii) expectations regarding Vertex’s SCD and TDT program, including with respect to completing dosing in two Phase 3 studies of CASGEVY in the fourth quarter of 2025 and to share data from these studies in December 2025 , (viii) plans to start the second Phase 3 DPN study in November and to complete enrollment in both Phase 3 studies evaluating suzetrigine for the treatment of DPN, (ix) expectations for the Phase 2 study of the oral formulation of VX-993 in DPN, (x) expectations regarding the clinical benefits and goals for zimislecel in T1D, and expectations and plans with respect to additional approaches that could provide transformative benefits to people with T1D and reduce or eliminate the need for standard immunosuppression regimens, (xi) expectations with respect to povetacicept, including beliefs about its potential benefits and therapeutic scope, its potential to be a best-in-class approach to control B cell activity in IgAN and pMN, and its potential to be a pipeline-in-a-product, expectations regarding BLA submissions for IgAN, including with respect to submitting the first module to the FDA before the end of 2025 and completing the full submission in the first half of 2026, expectations with respect to the ongoing trials in pMN, and plans to present updated Phase 2 data for IgAN and pMN at an upcoming medical conference, (xii) expectations regarding the AMPLITUDE Phase 2/3 trial of inaxaplin in AMKD, including expectations to conduct the pre-planned interim analysis and apply for potential accelerated U.S. if results are supportive, and expectations to complete enrollment in the AMPLIFIED Phase 2 study of inaxaplin by year-end, (xiii) expectations regarding the ADPKD program and the Phase 2 proof-of-concept study of VX-407, and (xiv) beliefs regarding the potential benefits and clinical status of VX-670 for the treatment in people with DM1 and expectations to complete enrollment and dosing in the first half of 2026. While Vertex believes the forward-looking statements contained in this press release are accurate, these forward-looking statements represent the company's beliefs only as of the date of this press release and there are a number of risks and uncertainties that could cause actual events or results to differ materially from those expressed or implied by such forward-looking statements. Those risks and uncertainties include, among other things, that the company's expectations regarding its 2025 full year revenues, expenses and effective tax rates may be incorrect (including because one or more of the company's assumptions underlying its expectations may not be realized), that we may be unable to further successfully commercialize ALYFTREK as a treatment for CF, JOURNAVX as a treatment for acute pain, and CASGEVY as a treatment for SCD and TDT, that external factors may have different or more significant impacts on the company's business or operations than the company currently expects, that data from preclinical testing or clinical trials, especially if based on a limited number of patients, may not be indicative of final results or available on anticipated timelines, that patient enrollment in the company’s trials may be delayed, that the company may not realize the anticipated benefits from collaborations with third parties, that data from the company's development programs may not support registration or further development of its potential medicines in a timely manner, or at all, due to safety, efficacy or other reasons, and that anticipated commercial launches may be delayed, if they occur at all. Forward-looking statements in this press release should be evaluated together with the many uncertainties that affect Vertex’s business, particularly those risks listed under the heading “Risk Factors” and the other cautionary factors discussed in Vertex’s periodic reports filed with the SEC , including Vertex’s annual report on Form 10-K and its quarterly reports on Form 10-Q and current reports on Form 8-K, all of which are filed with the Securities and Exchange Commission (SEC) and available through the company's website at www.vrtx.com and on the SEC’s website at www.sec.gov. You should not place undue reliance on these statements, or the scientific data presented. Vertex disclaims any obligation to update the information contained in this press release as new information becomes available. Conference Call and Webcast The company will host a conference call and webcast at 4:30 p.m. ET . To access the call, please dial (833) 630-2124 ( U.S. ) or +1(412) 317-0651 (International) and reference the “Vertex Pharmaceuticals Third Quarter 2025 Earnings Call.” The conference call will be webcast live and a link to the webcast can be accessed through Vertex 's website at www.vrtx.com in the "Investors" section. To ensure a timely connection, it is recommended that participants register at least 15 minutes prior to the scheduled webcast. An archived webcast will be available on the company's website. (VRTX-E) View source version on businesswire.com: https://www.businesswire.com/news/home/20251103308960/en/ Vertex Contacts: Investor Relations: Susie Lisa , CFA, 617-341-6108 Manisha Pai , 617-961-1899 Miroslava Minkova , 617-341-6135 Media: 617-341-6992 mediainfo@vrtx.com Source: Vertex Pharmaceuticals Incorporated