Daines Cori L, Polineni Deepika, Tullis Elizabeth, Costa Stefano, Linnemann Rachel W, Mall Marcus A, McKone Edward F, Quon Bradley S, Ringshausen Felix C, Selvadurai Hiran, Taylor-Cousar Jennifer L, Withers Nicholas J, Sawicki Gregory S, Lee Timothy, Ahluwalia Neil, Morlando Geiger Jessica, Jennings Mark, Tan Yaoyuan Vincent, Waltz David, Ramsey Bonnie, Griese Matthias
University of Arizona Medical Center - University Campus, Pediatrics, Tucson, Arizona, United States;
Washington University in St Louis, Pediatrics, St Louis, Missouri, United States.
Am J Respir Crit Care Med. 2025 Apr 10. doi: 10.1164/rccm.202411-2231OC.
Clinical and real-world studies show elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is efficacious and safe in people with cystic fibrosis (CF) ≥12 years of age with at least one allele.
Given the potential for life-long ELX/TEZ/IVA use, long-term safety and efficacy of ELX/TEZ/IVA was assessed.
In this phase 3, open-label, single-arm extension study, participants with -minimal function genotypes (from 24-week parent study 445-102 [n = 399]) or with the genotype (from 4-week parent study 445-103 [n = 107]) received ELX/TEZ/IVA (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours) over 192 weeks.
Primary endpoint was safety and tolerability. Mean exposure to ELX/TEZ/IVA was 172.6 weeks. Most participants had adverse events classified as mild (12.8%) or moderate (60.7%) in severity. Eighteen participants (3.6%) had adverse events that led to treatment discontinuation. After starting ELX/TEZ/IVA, participants had consistent increases in percent predicted FEV (ppFEV), Cystic Fibrosis Questionnaire-Revised respiratory domain score, and body mass index, with decreases in sweat chloride concentration and pulmonary exacerbations rates; these improvements were maintained through 192 weeks. The mean annualized rate of change in ppFEV was 0.02 percentage points (95% CI, -0.14 to 0.19) after initiation of ELX/TEZ/IVA.
During this 192-week open label extension study, the longest clinical study of a CFTR modulator to date, ELX/TEZ/IVA remained generally safe and well-tolerated. Participants had sustained improvements in lung function, respiratory symptoms, CFTR function, pulmonary exacerbation rates, and nutritional status. The estimated annualized rate of change in ppFEV suggests no evidence of pulmonary function loss across the study population over the 4-year treatment period. These results confirm the favorable long-term safety profile and durable disease-modifying clinical benefits of ELX/TEZ/IVA in adolescents and adults with CF. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/). Clinical trial registration available at www.
gov, ID: NCT03525574.
临床研究和真实世界研究表明，依列卡福/替扎卡福/依伐卡福（ELX/TEZ/IVA）对于年龄≥12岁且至少携带一个特定等位基因的囊性纤维化（CF）患者有效且安全。
鉴于ELX/TEZ/IVA可能需终身使用，对其长期安全性和有效性进行评估。
在这项3期、开放标签、单臂扩展研究中，具有最小功能基因型（来自24周的母研究445 - 102 [n = 399]）或特定基因型（来自4周的母研究445 - 103 [n = 107]）的参与者接受ELX/TEZ/IVA（依列卡福200 mg每日一次，替扎卡福100 mg每日一次，依伐卡福150 mg每12小时一次）治疗192周。
主要终点为安全性和耐受性。ELX/TEZ/IVA的平均暴露时间为172.6周。大多数参与者出现的不良事件严重程度分类为轻度（12.8%）或中度（60.7%）。18名参与者（3.6%）出现导致治疗中断的不良事件。开始使用ELX/TEZ/IVA后，参与者的预计FEV百分比（ppFEV）、囊性纤维化问卷修订版呼吸领域评分和体重指数持续增加，同时汗液氯化物浓度和肺部恶化率降低；这些改善在192周内得以维持。开始使用ELX/TEZ/IVA后，ppFEV的年化平均变化率为0.02个百分点（95% CI，-0.14至0.19）。
在这项为期192周的开放标签扩展研究中，这是迄今为止对CFTR调节剂进行的最长临床研究，ELX/TEZ/IVA总体上保持安全且耐受性良好。参与者在肺功能、呼吸道症状、CFTR功能、肺部恶化率和营养状况方面持续改善。ppFEV的估计年化变化率表明，在4年治疗期内，整个研究人群没有肺功能丧失的证据。这些结果证实了ELX/TEZ/IVA在青少年和成年CF患者中具有良好的长期安全性和持久的疾病改善临床益处。本文为开放获取文章，根据知识共享署名非商业性无衍生作品许可协议4.0（http://creativecommons.org/licenses/by-nc-nd/4.0/）发布。临床试验注册信息可在www.CLINICALTRIALS.gov查询，ID：NCT03525574。
