Mall Marcus A, Wainwright Claire E, Legg Julian, Chilvers Mark, Gartner Sylvia, Dittrich Anna-Maria, Stehling Florian, Conner Sarah, Grant Sebastian, Suresh Nina, Weinstock Tanya G, Davies Jane C
Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine, Charité - Universitätsmedizin Berlin, Berlin, Germany.
German Center for Child and Adolescent Health (DZKJ), partner site, Berlin, Germany.
Eur Respir J. 2025 Jul 14;66(1). doi: 10.1183/13993003.02435-2024. Print 2025 Jul.
BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in children aged 6-11 years with cystic fibrosis (CF) heterozygous for and a minimal function CF transmembrane conductance regulator () variant (/MF genotypes) in a 24-week, placebo-controlled trial. We conducted a 96-week open-label extension study for children who completed the 24-week parent study. METHODS: In this phase 3b extension study, dosing was based on weight and age, with children weighing <30 kg and aged <12 years receiving ELX 100 mg once daily, TEZ 50 mg once daily and IVA 75 mg every 12 h, and children ≥30 kg or ≥12 years receiving ELX 200 mg once daily, TEZ 100 mg once daily and IVA 150 mg every 12 h. The primary end-point was safety and tolerability. Secondary and other efficacy end-points included absolute changes from parent study baseline in sweat chloride concentration, lung clearance index (LCI), percentage predicted forced expiratory volume in 1 s (FEV) and Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score. RESULTS: A total of 120 children were enrolled and dosed. 118 children (98.3%) had adverse events (AEs), which for most were mild (43.3%) or moderate (48.3%) in severity. The most common AEs (≥20% of children) were COVID-19 (58.3%), cough (51.7%), nasopharyngitis (45.0%), pyrexia (40.0%), headache (37.5%), upper respiratory tract infection (30.8%), oropharyngeal pain (26.7%), rhinitis (24.2%), abdominal pain (22.5%) and vomiting (20.0%). Children who transitioned from the placebo and ELX/TEZ/IVA groups of the parent study had improvements from parent study baseline at Week 96 in mean sweat chloride concentration (-57.3 (95% CI -61.6- -52.9) and -57.5 (95% CI -62.0- -53.0) mmol·L), LCI (-1.74 (95% CI -2.09- -1.38) and -2.35 (95% CI -2.72- -1.97) units), FEV % pred (6.1 (95% CI 2.6-9.7) and 6.9 (95% CI 3.2-10.5) percentage points) and CFQ-R respiratory domain score (6.6 (95% CI 2.5-10.8) and 2.6 (95% CI -1.6-6.8) points). CONCLUSIONS: ELX/TEZ/IVA treatment was generally safe and well tolerated, with a safety profile consistent with the parent study and older age groups. After starting ELX/TEZ/IVA, children had robust improvements in sweat chloride concentration and lung function that were maintained through 96 weeks. These results demonstrate the safety and durable efficacy of ELX/TEZ/IVA in this paediatric population.
背景：在一项为期24周的安慰剂对照试验中，依列卡福/替扎卡福/依伐卡福（ELX/TEZ/IVA）对6至11岁患有囊性纤维化（CF）且携带一个最小功能CF跨膜电导调节因子（CFTR）变异（ΔF508/MF基因型）的儿童有效且安全。我们对完成24周母体研究的儿童进行了一项为期96周的开放标签扩展研究。 方法：在这项3b期扩展研究中，给药基于体重和年龄，体重<30 kg且年龄<12岁的儿童每天接受一次100 mg依列卡福、一次50 mg替扎卡福和每12小时一次75 mg依伐卡福，体重≥30 kg或年龄≥12岁的儿童每天接受一次200 mg依列卡福、一次100 mg替扎卡福和每12小时一次150 mg依伐卡福。主要终点是安全性和耐受性。次要及其他疗效终点包括与母体研究基线相比，汗液氯化物浓度、肺清除指数（LCI）、1秒用力呼气容积预测值百分比（FEV）和囊性纤维化问卷修订版（CFQ-R）呼吸领域评分的绝对变化。 结果：共纳入120名儿童并给药。118名儿童（98.3%）出现不良事件（AE），其中大多数为轻度（43.3%）或中度（48.3%）。最常见的不良事件（≥儿童的20%）是新冠病毒病（58.3%）、咳嗽（51.7%）、鼻咽炎（45.0%）、发热（40.0%）、头痛（37.5%）、上呼吸道感染（30.8%）、口咽痛（26.7%）、鼻炎（24.2%）、腹痛（22.5%）和呕吐（20.0%）。从母体研究的安慰剂组和ELX/TEZ/IVA组转入的儿童在第96周时，汗液氯化物浓度（分别为-57.3（95%CI -61.6- -52.9）和-
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