Elexacaftor/tezacaftor/ivacaftor in children aged ≥6 years with cystic fibrosis heterozygous for F508del and a minimal function mutation: results from a 96-week open-label extension study

Abstract

Background: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was efficacious and safe in children aged 6-11 years with cystic fibrosis (CF) heterozygous for F508del and a minimal function CF transmembrane conductance regulator (CFTR) variant (F/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_2.5), percentage predicted forced expiratory volume in 1 s (FEV₁) 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^-1), LCI_2.5 (-1.74 (95% CI -2.09- -1.38) and -2.35 (95% CI -2.72- -1.97) units), FEV₁ % 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.

Overview of the study. ELX: elexacaftor; TEZ: tezacaftor; IVA: ivacaftor; CFTR: cystic fibrosis transmembrane conductance regulator; BL: baseline; OL: open-label; LCI_2.5: lung clearance index; FEV₁: forced expiratory volume in 1 s; CFQ-R: Cystic Fibrosis Questionnaire-Revised (minimal clinically important difference shown as a green dashed line); AE: adverse event; events/100PY: number of events per 100 patient-years (336 days=48 weeks per year)=number of events/total duration of treatment-emergent period for each study in 100PY. Data in the graphs are presented as least squares mean±se.

FIGURE 1

Participant disposition. ELX: elexacaftor; TEZ: tezacaftor; IVA: ivacaftor; AE: adverse event.

FIGURE 2

Absolute change from parent study baseline in a) sweat chloride, b) lung clearance index (LCI_2.5), c) percentage predicted forced expiratory volume in 1 s (FEV₁) and d) Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score at each visit. Parent study baseline was defined as the most recent non-missing measurement before the first dose of study drug in the treatment period of the parent study. Data are presented as least squares mean±se. The minimal clinically important difference for CFQ-R respiratory domain score (4.0 points) is shown as a green dashed line in d). BL: baseline; OL: open-label.