Vanzacaftor Calcium/Tezacaftor/Deutivacaftor

编者按：今年初，行业媒体Evaluate发布报告，梳理了预计于2025年上市的关键创新疗法。随着2025年进程已过三分之一，我们也对这些潜在重磅疗法的最新进展进行回顾。在报告列出的十项疗法中，有五款为小分子药物，充分体现了小分子药物在2025年生物医药创新格局中所占据的重要地位。在这五款小分子潜力疗法中，药明康德化学业务平台很高兴为其中两款提供了赋能服务，助力合作伙伴加速创新成果转化。面向未来，药明康德将持续发挥平台优势，携手全球客户，推动更多创新疗法早日惠及全球患者。图片来源：123RF在这份报告中所提到的10款潜在重磅疗法当中，已有5款率先获得美国FDA批准，包含由Vertex Pharmaceuticals所开发，在去年底获批用以治疗囊性纤维化（CF）患者的Alyftrek；由阿斯利康（AstraZeneca）与第一三共（Daiichi Sankyo）联合开发用以治疗乳腺癌的Trop2靶向抗体偶联药物（ADC）Datroway（datopotamab deruxtecan），以及同样由Vertex Pharmaceuticals所开发、用于治疗急性疼痛的Journavx（suzetrigine）则在今年1月分别接连获得FDA批准；而由GSK所开发的脑膜炎球菌疫苗Penmenvy（MenABCWY）则在2月获批；强生开发的抗体疗法Imaavy（nipocalimab）在4月底获批治疗全身性重症肌无力（gMG）。值得注意的是，在这些潜在重磅疗法当中，有不少具有显著的创新性。例如，由GSK所开发的depemokimab是在3期试验中进行评估的首个白细胞介素5（IL-5）靶向超长效生物制品。根据新闻稿，该疗法可能成为仅须每6个月给药一次、用于治疗严重哮喘的首个获批超长效生物制品。而Vertex Pharmaceuticals的新闻稿则指出，其NaV1.8抑制剂suzetrigine为二十多年来首个用于治疗急性疼痛的新机制药物。此外，强生（Johnson & Johnson）旗下新生儿Fc受体（FcRn）靶向单抗nipocalimab具有治疗多种免疫疾病的潜力，获批治疗gMG之外，它还是在干燥综合征（Sjögren’s disease，SjD）领域获得突破性疗法认定（BTD）的首款疗法。▲2025年10款潜在重磅疗法一览（图表来源：根据参考资料[1]整理制表）在列出的10款潜在重磅疗法中，小分子药物占据一半（5款，占比50%）；单克隆抗体疗法占据2款（占比20%）；而抗体偶联药物（ADC）、多肽药物及疫苗各自占据1款（各占比10%）。这一分布进一步印证了小分子药物在2025年生物医药创新版图中举足轻重的地位。2025年的十款潜在重磅疗法疗法：Alyftrek（vanzacaftor/tezacaftor/deutivacaftor）公司：Vertex Pharmaceuticals研发状态：2024年12月20日获美国FDA批准Alyftrek是一款下一代囊性纤维化跨膜电导调节因子（CFTR）调节剂三联疗法，该疗法在去年12月获FDA批准用于治疗6岁及以上、携带至少一个F508del突变或其他对Alyftrek有应答的CFTR基因突变的囊性纤维化患者。在两项随机双盲3期临床试验中，接受治疗24周后，基于一秒用力呼气量百分比（ppFEV1）数值的评估，Alyftrek的疗效与获批CF疗法Trikafta相当，达到试验的主要终点。此外，Alyftrek在降低汗液氯化物（SwCl）水平方面与活性对照药物相比表现出优效性，这是两项3期试验的关键次要终点之一。▲Alyftrek在SKYLINE 102和SKYLINE 103试验中达到主要终点（图片来源：Vertex公司官网）疗法：Datroway（datopotamab deruxtecan，Dato-DXd）公司：阿斯利康、第一三共研发状态：2025年1月17日获美国FDA批准Datroway是一款由人源化、靶向Trop2的单克隆抗体与创新DNA拓扑异构酶I抑制剂（DXd），通过可裂解的四肽连接子偶联生成的ADC。该疗法在今年1月获FDA批准上市，用于治疗无法切除或转移性HR阳性、HER2阴性的成年乳腺癌患者，这些患者曾接受过内分泌疗法和化疗。美国FDA的批准主要基于TROPION-Breast01临床3期试验的结果。分析显示，Datroway治疗组的中位无进展生存期（PFS）为6.9个月（95% CI：5.7，7.4），化疗组为4.9个月（95% CI：4.2，5.5），即Datroway相较于化疗，可将患者的疾病进展或死亡风险降低37%（HR=0.63，95% CI：0.52，0.76，p<0.0001）。Datroway与化疗组患者的确认客观缓解率（ORR）分别为36%（95% CI：31，42）和23%（95% CI：19，28）。今年1月，美国FDA授予Datroway优先审评资格用于治疗局部晚期或转移性表皮生长因子受体突变（EGFRm）的非小细胞肺癌（NSCLC）成人患者，预计将在2025年第三季度完成审评。疗法：Journavx（suzetrigine）公司：Vertex Pharmaceuticals研发状态：2025年1月30日获美国FDA批准Suzetrigine是一种口服选择性NaV1.8抑制剂，与其它NaV离子通道相比，它对NaV1.8具有高度选择性。根据关键性3期临床试验的积极结果，suzetrigine在急性疼痛治疗中表现出显著效果。具体来说，在接受腹部整形手术（abdominoplasty）患者中进行的3期临床试验结果显示，suzetrigine达到了试验的主要终点，与安慰剂相比，药物组患者48小时内疼痛强度差异的时间加权总和评分（SPID48）显著降低，SPID48的平均差异为48.4（95% CI：33.6，63.1；P<0.0001）。此外，患者在手术48小时后的数值疼痛评分量表（NPRS）评分与基线相比也显著降低。而在接受拇囊炎切除手术（bunionectomy）的患者中，该疗法亦达成主要终点，SPID48的平均差异为29.3（95% CI：14.0，44.6；P=0.0002）。▲Suzetrigine达成试验主要终点（图片来源：Vertex官网）疗法：Aficamten公司：Cytokinetics研发状态：PDUFA日期为2025年12月26日Aficamten是一种下一代心肌球蛋白抑制剂，用于治疗梗阻性肥厚型心肌病（HCM）。该药物的上市申请主要基于关键性3期临床试验SEQUOIA-HCM结果。分析显示，与安慰剂相比，aficamten治疗24周显著提高了患者的运动能力。通过心肺运动试验（CPET）测得的峰值氧气摄取量（pVO2）与基线相比，在aficamten治疗组增加了1.8 ml/kg/min，而安慰剂组为0.0 ml/kg/min。此外，接受aficamten治疗的患者在10个预先设定的次要终点中，均观察到了统计学上显著的改善。FDA曾于2021年12月授予aficamten治疗梗阻性HCM的突破性疗法认定。▲Aficamten达到SEQUOIA-HCM试验的主要终点（图片来源：Cytokinetics官网）疗法：Brensocatib公司：Insmed研发状态：PDUFA日期为2025年8月12日Brensocatib是一种口服、可逆性DPP1小分子抑制剂。DPP1是一种酶，负责激活中性粒细胞中的中性粒细胞丝氨酸蛋白酶（NSPs）。Brensocatib可通过抑制DPP1降低NSPs的活化，从而降低炎症性疾病（如支气管扩张）的组织损伤。这款疗法已经获得美国FDA授予的突破性疗法认定，用于治疗非囊性纤维化支气管扩张。一项包含1680名成人和41名青少年非囊性纤维化支气管扩张症患者的临床试验结果显示，试验达到主要终点，10 mg和25 mg剂量的brensocatib分别将患者的年化肺部症状恶化（PE）率降低21.1%和19.4%，统计学显著并具有临床意义。▲Brensocatib的3期临床试验疗效数据（图片来源：参考资料[4]）疗法：Tolebrutinib公司：赛诺菲（Sanofi）研发状态：PDUFA日期为2025年9月28日Tolebrutinib是一款在研口服、能穿越血脑屏障且具有生物活性的布鲁顿氏酪氨酸激酶（BTK）抑制剂，它能够达到足以调节B淋巴细胞和疾病相关小胶质细胞的脑脊液浓度。临床3期试验结果表明，tolebrutinib与安慰剂相比，可将非复发性继发进展型多发性硬化（nrSPMS）出现6个月确认残疾进展（CDP）的时间延缓31%（HR=0.69；95% CI，0.55-0.88；p=0.0026）。进一步的次要终点分析显示，接受tolebrutinib治疗的参与者中，确认残疾获得改善的患者比例（10%）是安慰剂组（5%）的两倍（HR=1.88；95% CI，1.10-3.21）。Tolebrutinib目前正在多个3期临床试验中评估其治疗多种类型多发性硬化的潜力。该疗法在2024年12月获得FDA授予突破性疗法认定，用于治疗nrSPMS成年患者。▲Tolebrutinib分子结构（图片来源：PubChem）疗法：玛仕度肽（Mazdutide，IBI362）公司：信达生物（Innovent）、礼来（Eli Lilly and Company）研发状态：在中国用于治疗肥胖与2型糖尿病治疗的监管申请结果预定分别在2025年上半年与下半年公布玛仕度肽是信达生物与礼来共同推进的一款胰高血糖素样肽-1受体（GLP-1R）和胰高血糖素受体（GCGR）双重激动剂。之前发布于eClinicalMedicine期刊上的一篇研究结果显示，接受每周一次9 mg玛仕度肽皮下注射治疗的受试者从基线至第12周体重的平均百分比变化为-11.7%，接受安慰剂治疗的受试者为-1.8%（估计治疗差异：-9.8%；95% CI：-14.4，-5.3；P=0.0002）。安全性方面，玛仕度肽的耐受性良好，并具有良好的安全性。未报告严重不良事件。所有治疗相关不良事件均为轻度或中度。疗法：Depemokimab公司：GSK研发状态：PDUFA日期为2025年12月16日Depemokimab是在3期试验中进行评估的首个白细胞介素5（IL-5）靶向超长效生物制品。SWIFT-1和SWIFT-2临床3期试验结果显示，试验达主要终点，depemokimab可显著降低严重哮喘患者的哮喘发作率达54%（HR=0.46，95% CI：0.36–0.59，p<0.001），这些患者具有2型炎症特征（以血液嗜酸性粒细胞计数为标志）。此外，试验亦达成次要终点。与安慰剂相比，患者需要住院或急诊救治的临床显著恶化减少达72%（HR=0.28，95% CI：0.13–0.61，p=0.002）。GSK预计在2025年启动该疗法用于治疗慢性阻塞性肺病（COPD）患者的3期临床试验。根据新闻稿，depemokimab可能成为仅须每6个月给药一次、用于治疗严重哮喘的首个获批超长效生物制品。疗法：Penmenvy（MenABCWY）公司：GSK研发状态：2025年2月14日获美国FDA批准五种脑膜炎球菌血清群（A，B，C，W和Y）占全球大部分地区的几乎所有侵袭性脑膜炎球菌病病例。GSK的五合一MenABCWY疫苗结合已获批的脑膜炎疫苗Bexsero和Menveo的抗原成分，可针对这五种血清群的脑膜炎球菌保护接种者。将两种有效疫苗合并为一种的目的是帮助简化免疫接种计划，进而增加疫苗覆盖率，帮助减少疾病的总负担。在3期试验中，MenABCWY疫苗成功达到所有主要终点，包括在免疫原性方面不劣于一剂GSK的A、C、Y和W群脑膜炎球菌疫苗，以及在对110种不同的B群脑膜炎球菌侵袭性菌株产生的免疫反应上，不劣于两剂GSK的B群脑膜炎球菌疫苗。此外，该疫苗显示出良好的耐受性，其安全性与上述两种疫苗一致。疗法：Nipocalimab公司：强生研发状态：2025年4月29日获美国FDA批准Nipocalimab是一款潜在“best-in-class”，靶向新生儿Fc受体的抗体疗法。它通过与FcRn结合，让被单核细胞和内皮细胞摄入的自身抗体不会重新释放到血液中，而是在细胞内被降解。已有研究显示，它可以将血液循环中包括致病自身抗体在内的IgG水平降低超过75%。它在4月29日获FDA批准，治疗抗AChR、抗MuSK抗体阳性的全身性重症肌无力（gMG）成人与12岁以上儿童患者。强生公司还在罕见自身抗体疾病、母体同种抗体介导的母胎疾病和风湿病领域探索nipocalimab的潜力。它在去年11月获得FDA授予突破性疗法认定，用于治疗中度至重度SjD成人患者。根据新闻稿，nipocalimab是在SjD领域获得突破性疗法认定的首个疗法。DAHLIAS临床2期试验结果显示，nipocalimab达到主要终点，从第4周开始，15 mg/kg nipocalimab组患者就开始获得缓解，并在整个24周的治疗期间持续增加。在第24周，与安慰剂相较，15 mg/kg组受试者在主要终点上，显示出平均系统性疾病活动程度相对于安慰剂超过70%的改善。▲DAHLIAS研究疗效结果摘要（图片来源：参考资料[5]）参考资料：[1] Top 10 most anticipated drug launches of 2025. Retrieved April 27, 2025 from https://www.fiercepharma.com/marketing/top-10-most-anticipated-drug-launches-2025[2] Insmed Provides Business Update at 43rd Annual J.P. Morgan Healthcare Conference. Retrieved January 21, 2025 from https://filecache.investorroom.com/mr5ir_insmed/371/2025-01-10-Insmed-Provides-Business-Update-at-43rd-Annual-J-P-Morgan-Healthcare-Conference.pdf[3] Delivering strong and sustained momentum. Retrieved January 21, 2025 from https://www.gsk.com/media/11750/gsk-2025-jpm-conf-presentation-14-january-2025.pdf[4] Insmed  Announces Positive Topline Results from Landmark ASPEN Study of  Brensocatib in Patients with Bronchiectasis. Retrieved May 28, 2024,  from  https://www.prnewswire.com/news-releases/insmed-announces-positive-topline-results-from-landmark-aspen-study-of-brensocatib-in-patients-with-bronchiectasis-302156279.html[5] LBA0010 EFFICACY AND SAFETY OF NIPOCALIMAB, AN ANTI-FcRn MONOCLONAL ANTIBODY, IN PRIMARY SJOGREN’S DISEASE: RESULTS FROM A PHASE 2, MULTICENTER, RANDOMIZED, PLACEBO-CONTROLLED, DOUBLE-BLIND STUDY (DAHLIAS). Retrieved November 12, 2024 from https://ard-bmj-com.libproxy1.nus.edu.sg/content/83/Suppl_1/240.2免责声明：本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。版权说明：欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

BOSTON--(BUSINESS WIRE)--Vertex Pharmaceuticals Incorporated (Nasdaq: VRTX) today reported consolidated financial results for the first quarter ended March 31, 2025, and raised the low end of its total revenue guidance range by $100 million, from $11.75 billion to $12 billion to a new range of $11.85 billion to $12 billion. “Vertex delivered a strong start to 2025 with notable execution across the business as we grow and diversify the revenue base, progress multiple launches and advance the R&D pipeline. We continued to expand our leadership in CF and build global momentum for CASGEVY, and we launched JOURNAVX in moderate-to-severe acute pain,” said Reshma Kewalramani, M.D., Chief Executive Officer and President of Vertex. “With multiple programs in pivotal development including povetacicept, which continues to make rapid progress in achieving its potential as a pipeline-in-a-product, and additional programs in early and mid-stage development, Vertex is poised to continue to deliver value for years to come.” First Quarter 2025 Results Total revenue increased 3% to $2.77 billion compared to the first quarter of 2024, primarily driven by the continued performance of TRIKAFTA®/KAFTRIO® and an early contribution from the U.S. launch of ALYFTREK. In the U.S., total revenue increased 9% to $1.66 billion due to continued strong patient demand and higher net realized pricing. Outside the U.S., total revenue decreased 5% to $1.11 billion as strong patient demand in both established and newer markets was offset by the expected revenue decline in Russia, where Vertex is experiencing violation of its intellectual property rights. Vertex has strong intellectual property protection for its medicines around the world and believes this violation in Russia is a limited and isolated matter. Combined GAAP and Non-GAAP R&D, Acquired IPR&D and SG&A expenses were $1.4 billion and $1.2 billion, respectively, compared to $1.2 billion and $1.0 billion, respectively, in the first quarter of 2024. The increases were primarily due to continued R&D investment in support of multiple mid- and late-stage clinical development programs and increased commercial investment to support the launch of JOURNAVX. Intangible asset impairment charge of $379.0 million associated with VX-264 (the “cells plus device” program) in patients with type 1 diabetes, which will not be advancing further in clinical development, was included in GAAP operating income in the first quarter of 2025. GAAP effective tax rate was 11.5% compared to 14.0% for the first quarter of 2024. Non-GAAP effective tax rate was 18.8% compared to 17.4% for the first quarter of 2024. The difference between the GAAP and non-GAAP effective tax rates was primarily due to tax benefits related to stock-based compensation. GAAP net income was $646 million compared to $1.1 billion for the first quarter of 2024, as a result of increased operating expenses and the intangible asset impairment charge. Non-GAAP net income was $1.1 billion compared to $1.2 billion in the first quarter of 2024, as a result of increased operating expenses. Cash, cash equivalents and total marketable securities as of March 31, 2025, were $11.4 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 program. Full Year 2025 Financial Guidance Vertex today raised the low end of its full-year 2025 revenue guidance range from $11.75 to $12 billion to $11.85 billion to $12 billion, which assumes continued growth in CF, including the launch of ALYFTREK; as well as continued uptake of CASGEVY in multiple regions; and early contributions from the launch of JOURNAVX. Vertex reiterated its guidance for both combined GAAP and Non-GAAP R&D, AIPR&D and SG&A expenses, which includes expectations for continued investment in multiple mid- and late-stage clinical development programs and commercial capabilities, and AIPR&D expenses of approximately $100 million. This 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 FY 2025 Total revenue $11.85 to $12.0 billion $11.75 to $12.0 billion Combined GAAP R&D, AIPR&D and SG&A expenses * Unchanged $5.55 to $5.7 billion Combined Non-GAAP R&D, AIPR&D and SG&A expenses * Unchanged $4.9 to $5.0 billion Non-GAAP effective tax rate Unchanged 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 Cystic Fibrosis (CF) Portfolio Marketed Products 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 95 percent of all people living with CF in markets with the highest prevalence and are approved for patients as young as one month old. ALYFTREK, the newest marketed CFTR modulator, is approved in the U.S. and the United Kingdom (U.K.) for the treatment of patients 6 years and older. Vertex anticipates the number of CF patients taking its medicines will continue to grow through new approvals and reimbursement, treatment of younger patients, increased survival, and expansion into additional geographies. Recent and anticipated progress includes: ALYFTREK, the once-daily, next-in-class combination CFTR modulator 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 CFTR gene, is now approved in the U.S. and the U.K. Vertex is working with the National Health Service (NHS) in the U.K. to secure coverage for eligible patients. In April, the European Medical Agency’s (EMA’s) Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion for ALYFTREK for the treatment of CF patients ages 6 years and older. European Commission approval is expected in the second half of 2025. Regulatory reviews are underway for ALYFTREK in Canada, Switzerland, Australia and New Zealand. Vertex secured European Commission approval for the label expansion of KAFTRIO in combination with ivacaftor for CF patients ages 2 years and older who have at least one non-class I mutation in the CFTR gene. With this approval, approximately 4,000 people in the European Union are newly eligible for a medicine that treats the underlying cause of their disease. Work to ensure access for all eligible patients is underway. CASGEVY for the treatment of 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), Canada, Switzerland and the United Arab Emirates (UAE) for the treatment of both SCD and TDT. Recent highlights include: In Europe, Vertex secured a formal reimbursement agreement with NHS England for SCD patients to access CASGEVY, following the agreement reached in August 2024 for eligible TDT patients to access CASGEVY. Vertex recently entered into a similar agreement in Wales for both eligible SCD and TDT patients. Following a positive assessment, Vertex also finalized national reimbursement in Austria. In the Middle East, following regulatory approval in the UAE, Vertex secured reimbursement in the majority of emirates. Since launch through May 1st, Vertex has activated more than 65 authorized treatment centers (ATCs) globally and approximately 90 patients have had their first cell collection. Vertex recently filed a manufacturing license submission with the FDA and expects to begin manufacturing CASGEVY in Portsmouth, NH, in the second half of 2025. This submission is part of the planned ramp of CASGEVY manufacturing capacity as demand for the therapy increases. 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. Vertex continues to advance a portfolio of selective NaV1.8 and NaV1.7 pain signal inhibitors for stand-alone use or in combination, with potential to provide effective pain relief without the limitations of opioids and other available medicines. On January 30, 2025, the FDA approved JOURNAVX for the treatment of adults with moderate-to-severe acute pain, and it is now available and stocked at pharmacies across the U.S., including major national and regional retail pharmacy chains. Since JOURNAVX became available in early March through April 18th, more than 20,000 prescriptions have been written and filled across the hospital and retail settings in different acute pain conditions, consistent with JOURNAVX’s broad label. As of May 1st, across commercial and government payers, approximately 94 million lives already have covered access to JOURNAVX, and approximately 42 million have unrestricted access (i.e., without the need for prior authorization or step edits). Vertex has reached a formal coverage agreement with a large national Pharmacy Benefit Manager (PBM) to make JOURNAVX available to their customers, representing approximately 22 million commercial lives. A total of ten state Medicaid plans are also providing unrestricted access to JOURNAVX and 20 more are currently evaluating their policies. More than 50 large healthcare systems have taken steps to initiate pharmacy and therapeutics (P&T) committee reviews of JOURNAVX, and some have already added it on formularies. Vertex recently initiated two Phase 4 studies in various moderate-to-severe acute pain conditions to provide additional data on the effectiveness and safety of JOURNAVX as part of real-world clinical practice, in both inpatient and outpatient settings. The Alternatives to Pain Act has been reintroduced in both the House and Senate of the new U.S. Congress, while nearly 35 U.S. states to date have passed or introduced new legislation in support of non-opioid options. Vertex also expects JOURNAVX to be added to the list of treatments eligible for an add-on payment under the NOPAIN Act, which became effective on January 1, 2025. Select Clinical-Stage R&D Pipeline Cystic Fibrosis Vertex is enrolling and dosing studies in younger age groups — a Phase 3 study of TRIKAFTA/KAFTRIO in 1- to 2-year-olds and a Phase 3 study of ALYFTREK in 2- to 5-year-olds — to expand the labels and enable earlier treatment of children with CF. Consistent with its commitment to serial innovation and bringing as many patients as possible to normal levels of CFTR function, Vertex continues to advance new oral small molecule combination therapies through preclinical and clinical development. Vertex expects to advance the once-daily, next-generation 3.0 VX-828 combination into a clinical trial in people with CF this year. Vertex has implemented a temporary pause to the multiple ascending dose (MAD) portion of the Phase 1/2 study of VX-522, a nebulized CFTR mRNA therapy, in order to assess a tolerability issue. 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. Vertex continues to advance preclinical assets for gentler conditioning for CASGEVY, which could broaden the eligible patient population. Acute Pain Vertex expects to complete the Phase 2 study for an oral formulation of VX-993 this quarter. VX-993 is a next-generation selective NaV1.8 pain signal inhibitor, for the treatment of moderate-to-severe acute pain following bunionectomy surgery. Vertex expects to report results from the Phase 2 study in the second half of 2025. VX-993 has Fast Track designation for moderate-to-severe acute pain. Vertex has completed the Phase 1 study of an intravenous formulation of VX-993 in healthy volunteers. The FDA has granted the intravenous formulation of VX-993 Fast Track designation for moderate-to-severe acute pain. Peripheral Neuropathic Pain (PNP) Vertex continues to enroll and dose patients with diabetic peripheral neuropathy (DPN) in a Phase 3 pivotal trial of suzetrigine. The FDA has granted suzetrigine Fast Track designation in PNP and Breakthrough Therapy designation in DPN. Vertex continues to enroll and dose patients in a Phase 2 study for the oral formulation of VX-993 for the treatment of 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 continues to enroll and dose patients in the Phase 3 portion of the Phase 1/2/3 study of zimislecel in patients with T1D with severe hypoglycemic events and impaired awareness of hypoglycemia in the U.S., Canada, U.K., and EU. Vertex expects to complete enrollment and dosing of the pivotal study in the second quarter of 2025 and submit marketing applications to global regulators in 2026. 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 will present updated clinical data from the 12 participants who received the full dose of zimislecel as a single infusion with over one year of follow-up in the Phase 1/2 portion of the study in an oral presentation at the American Diabetes Association 85 th Scientific Sessions. Vertex will host an in-person investor event at the ADA conference on Friday, June 20, 2025 at 7:15 p.m. CT / 8:15 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. Vertex previously announced that it has discontinued development of the VX-264 (“cells plus device” program), as the Phase 1/2 study did not meet its efficacy endpoint. Vertex is pursuing research-stage programs to evaluate additional approaches that could provide transformative benefit to people with T1D and reduce or eliminate the need for standard immunosuppressive regimens. These approaches include alternative immunosuppressives, 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, a dual antagonist of the BAFF and APRIL cytokines, which play key roles in the pathogenesis of multiple B cell-mediated diseases. Pove represents a potentially best-in-class approach to treat IgAN and pMN and has pipeline-in-a-product potential. The global Phase 3 RAINIER trial of povetacicept in patients with IgAN has completed enrollment of the interim analysis cohort. The interim analysis will be conducted once this cohort reaches 36 weeks of treatment, with the potential to file for Accelerated Approval in the U.S. in the first half of 2026, if results are supportive. Studies to support the launch of povetacicept for home administration are underway. Based on positive results of povetacicept in primary membranous nephropathy (pMN) in the RUBY-3 study, Vertex has reached agreement with the FDA to advance povetacicept into pivotal development for this disease. Vertex will initiate a single, adaptive Phase 2/3 trial of povetacicept vs. standard-of-care this year. In the Phase 2 portion, both 80 mg and 240 mg of povetacicept will be assessed and the selected dose will advance to Phase 3, where the primary endpoint of complete clinical remission at 72 weeks of treatment will be evaluated. Vertex plans to present updated data from the IgAN and pMN cohorts of the RUBY-3 study at upcoming medical congresses. Vertex expects to share data and next steps from other RUBY-3 renal diseases and the hematologic conditions in the RUBY-4 study later this year. 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 genetic driver of this kidney disease. Vertex expects to complete enrollment in the interim analysis cohort of the Phase 3 portion of the AMPLITUDE trial of inaxaplin in the second half of 2025. 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 continues to enroll and dose patients in the AMPLIFIED Phase 2 study of inaxaplin in people with AMKD and diabetes or other co-morbidities. 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 address the underlying cause 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. 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 has completed the Phase 1 study of VX-407 in healthy volunteers. Vertex expects to advance VX-407 into a Phase 2 proof-of-concept study this year in patients with a subset of variants in the PKD1 gene, which encodes the PC1 protein, estimated to be up to ~30,000 (or ~10%) of the overall patient population. 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 (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 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 (unaudited, in millions, except per share amounts) Three Months Ended March 31, 2025 2024 Revenues: Product revenues, net $ 2,760.2 $ 2,690.6 Other revenues 10.0 — Total revenues 2,770.2 2,690.6 Costs and expenses: Cost of sales 363.0 342.6 Research and development expenses 979.7 789.1 Acquired in-process research and development expenses 19.8 76.8 Selling, general and administrative expenses 396.4 342.7 Intangible asset impairment charge 379.0 — Change in fair value of contingent consideration 2.2 (0.1 ) Total costs and expenses 2,140.1 1,551.1 Income from operations 630.1 1,139.5 Interest income 120.9 181.2 Interest expense (3.0 ) (10.4 ) Other expense, net (17.6 ) (31.2 ) Income before provision for income taxes 730.4 1,279.1 Provision for income taxes 84.1 179.5 Net income $ 646.3 $ 1,099.6 Net income per common share: Basic $ 2.52 $ 4.26 Diluted $ 2.49 $ 4.21 Shares used in per share calculations: Basic 256.9 258.2 Diluted 259.5 261.1 Vertex Pharmaceuticals Incorporated Total Revenues (unaudited, in millions) Three Months Ended March 31, 2025 2024 TRIKAFTA/KAFTRIO $ 2,535.5 $ 2,483.6 ALYFTREK 53.9 — Other product revenues (1) 170.8 207.0 Product revenues, net 2,760.2 2,690.6 Other revenues 10.0 — Total revenues $ 2,770.2 $ 2,690.6 1: In the first quarter of 2025, "Other product revenues" included $14.2 million from CASGEVY, and an insignificant amount from JOURNAVX. In the first quarter of 2024, there were no revenues for these products. 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 March 31, 2025 2024 GAAP cost of sales $ 363.0 $ 342.6 Stock-based compensation expense (2.6 ) (1.8 ) Intangible asset amortization expense (5.0 ) (5.0 ) Non-GAAP cost of sales $ 355.4 $ 335.8 GAAP research and development expenses $ 979.7 $ 789.1 Stock-based compensation expense (100.1 ) (119.4 ) Intangible asset amortization expense (0.6 ) — Non-GAAP research and development expenses $ 879.0 $ 669.7 Acquired in-process research and development expenses $ 19.8 $ 76.8 GAAP selling, general and administrative expenses $ 396.4 $ 342.7 Stock-based compensation expense (63.4 ) (70.7 ) Non-GAAP selling, general and administrative expenses $ 333.0 $ 272.0 Combined non-GAAP R&D, AIPR&D and SG&A expenses $ 1,231.8 $ 1,018.5 GAAP other expense, net $ (17.6 ) $ (31.2 ) Decrease in fair value of strategic investments 15.0 27.0 Non-GAAP other expense, net $ (2.6 ) $ (4.2 ) GAAP provision for income taxes $ 84.1 $ 179.5 Tax adjustments (2) 160.1 81.6 Non-GAAP provision for income taxes $ 244.2 $ 261.1 GAAP effective tax rate 11.5 % 14.0 % Non-GAAP effective tax rate 18.8 % 17.4 % Vertex Pharmaceuticals Incorporated Reconciliation of GAAP to Non-GAAP Financial Information (continued) (unaudited, in millions, except per share amounts) Three Months Ended March 31, 2025 2024 GAAP operating income $ 630.1 $ 1,139.5 Stock-based compensation expense 166.1 191.9 Intangible asset impairment charge 379.0 — Intangible asset amortization expense 5.6 5.0 Increase (decrease) in fair value of contingent consideration 2.2 (0.1 ) Non-GAAP operating income $ 1,183.0 $ 1,336.3 GAAP net income $ 646.3 $ 1,099.6 Stock-based compensation expense 166.1 191.9 Intangible asset impairment charge 379.0 — Intangible asset amortization expense 5.6 5.0 Decrease in fair value of strategic investments 15.0 27.0 Increase (decrease) in fair value of contingent consideration 2.2 (0.1 ) Total non-GAAP adjustments to pre-tax income 567.9 223.8 Tax adjustments (2) (160.1 ) (81.6 ) Non-GAAP net income $ 1,054.1 $ 1,241.8 Net income per diluted common share: GAAP $ 2.49 $ 4.21 Non-GAAP $ 4.06 $ 4.76 Shares used in diluted per share calculations: GAAP and Non-GAAP 259.5 261.1 2: In the first quarter of 2025 and 2024, “Tax adjustments” included the estimated income taxes related to non-GAAP adjustments to the company's pre-tax income and excess tax benefits related to stock-based compensation. Vertex Pharmaceuticals Incorporated Condensed Consolidated Balance Sheets (unaudited, in millions) March 31, 2025 December 31, 2024 Assets Cash, cash equivalents and marketable securities $ 6,201.2 $ 6,115.9 Accounts receivable, net 1,805.1 1,609.4 Inventories 1,359.7 1,205.4 Prepaid expenses and other current assets 642.8 665.7 Total current assets 10,008.8 9,596.4 Property and equipment, net 1,295.9 1,227.8 Goodwill and other intangible assets, net 1,529.2 1,913.9 Deferred tax assets 2,544.3 2,331.1 Operating lease assets 1,338.5 1,356.8 Long-term marketable securities 5,156.5 5,107.9 Other long-term assets 1,007.3 999.3 Total assets $ 22,880.5 $ 22,533.2 Liabilities and Shareholders' Equity Accounts payable and accrued expenses $ 3,396.8 $ 3,201.6 Other current liabilities 386.4 363.0 Total current liabilities 3,783.2 3,564.6 Long-term operating lease liabilities 1,537.7 1,544.4 Long-term finance lease liabilities 111.4 112.8 Other long-term liabilities 951.9 901.8 Shareholders' equity 16,496.3 16,409.6 Total liabilities and shareholders' equity $ 22,880.5 $ 22,533.2 Common shares outstanding 257.0 256.9 About Vertex Vertex is a global biotechnology company that invests in scientific innovation to create transformative medicines for people with serious diseases. The company has approved medicines that treat the underlying causes of multiple chronic, life-shortening genetic diseases — cystic fibrosis, sickle cell disease and transfusion-dependent beta thalassemia — and continues to advance clinical and research programs in these diseases. 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 acute and neuropathic pain, type 1 diabetes, APOL1-mediated kidney disease, IgA nephropathy, primary membranous nephropathy, autosomal dominant polycystic kidney disease, 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 14 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 Twitter/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) expectations for Vertex’s continued growth in CF, including by increasing the number of CF patients taking its medicines through new approvals and reimbursements, treatment of younger patients, increased survival, and expansion into additional geographies, (ii) expectations regarding securing coverage for ALYFTREK in the U.K., (iii) expectations regarding approval of ALYFTREK in the E.U. in the second half of 2025, (iv) beliefs regarding the anticipated benefits and commercial launch progress of CASGEVY, and with respect to increasing and initiating manufacturing activities for CASGEVY in the second half of 2025, (v) expectations regarding the potential benefits of JOURNAVX for the treatment of moderate-to-severe acute pain, including regarding the efficacy and safety of JOURNAVX, beliefs that JOURNAVX has potential to provide effective pain relief without the limitations of opioids and other available medicines, expectations with respect to the commercial launch progress and that commercial coverage of JOURNAVX will continue to expand throughout 2025, and expectations that JOURNAVX will be included on the list of treatments that quality for add-on payment under the NOPAIN Act, (vi) expectations to expand the labels for TRIKAFTA/KAFTRIO and ALYFTREK and enable earlier treatment of children with CF, (vii) expectations to advance the VX-828 combination into people with CF this year, (viii) expectations for the VX-522 clinical trial, (ix) expectations regarding Vertex’s SCD and TDT program, including with respect to gentler conditioning for CASGEVY broadening the eligible patient population, (x) plans with respect to the studies of the intravenous and oral formulation of VX-993 for the treatment of acute pain, including expectations to complete the Phase 2 study of the oral formulation of VX-993 in acute pain and expectations to report results from that study in the second half of 2025, (xi) expectations regarding the pivotal study evaluating zimislecel in T1D, including the expectations to complete enrollment and dosing during the fiscal quarter and submit marketing applications to global regulators in 2026, expectations to present updated data in upcoming medical conferences, and expectations and plans to pursue additional approaches to standard immunosuppression regimens, (xii) expectations with respect to povetacicept, including beliefs about its potential benefits and therapeutic scope, study designs, expectations regarding the Phase 3 RAINIER study, including plans to file for potential accelerated approval in the U.S. in the first half of 2026, beliefs with respect to the RUBY-3 basket study and plans to present updated data from this study at upcoming medical congresses, expectations and plans with respect to advancing povetacicept into pivotal development in pMN, beliefs with respect to the RUBY-4 basket study and expectations to share data and next steps later this year, (xiii) expectations regarding the AMPLITUDE trial in AMKD, including expectations to complete enrollment in the interim analysis cohort in the second half of 2025 and, assuming a positive interim analysis, apply for potential accelerated approval in the U.S., (xiv) expectations for the potential benefits and clinical status of VX-670 for the treatment in people with DM1, and (xv) expectations regarding the ADPKD program, including the potential benefits of VX-407 and expectations to advance VX-407 into a Phase 2 proof-of-concept study in 2025. 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 successfully commercialize ALYFTREK as a treatment for CF or JOURNAVX as a treatment for acute pain, 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 First 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)