Long-Term Safety and Efficacy of Elexacaftor/Tezacaftor/Ivacaftor in Children ≥6 Years with Cystic Fibrosis and at Least One <i>F508del</i> Allele: A 192-Week, Phase 3, Open-Label Extension Study

Abstract Rationale Elexacaftor (ELX)/tezacaftor (TEZ)/ivacaftor (IVA) was shown to be safe and efficacious in children 6 through 11 years of age with cystic fibrosis (CF) and at least one F508del allele in a 24-week phase 3 study. Children completing this study could enroll into a 192-week extension study. Objectives To evaluate the long-term safety and efficacy of ELX/TEZ/IVA in children ≥6 years of age. Methods In this two-part (part A [96 wk] and part B [96 wk]) phase 3 extension study, children &amp;lt;12 years of age weighing &amp;lt;30 kg received ELX 100 mg once daily/TEZ 50 mg once daily/IVA 75 mg every 12 hours, and children weighing ≥30 kg or aged ≥12 years received ELX 200 mg once daily/TEZ 100 mg once daily/IVA 150 mg every 12 hours. Measurements and Main Results Sixty-four children (F508del/minimal function [n = 36] and F508del/F508del [n = 28]) received at least one dose of ELX/TEZ/IVA. Mean exposure was 156.2 weeks, and 60.9% of children (n = 39) completed treatment in both parts of this 192-week study. The primary endpoint was safety. All children had adverse events, which for most were mild (31.3%) or moderate (64.1%) and generally consistent with common manifestations of CF. Two children (3.1%) had nonserious adverse events that led to treatment discontinuation (increased alanine aminotransferase [n = 1] and aggression [n = 1]). Secondary endpoints focused on efficacy. From parent study baseline, improvements were seen in percentage predicted FEV1 (9.6 percentage points [95% confidence interval (CI), 5.4 to 13.7 percentage points]), sweat chloride concentration (−57.9 mmol/L [95% CI, −63.3 to −52.5 mmol/L]), Cystic Fibrosis Questionnaire–Revised respiratory domain score (10.0 points [95% CI, 6.9 to 13.0 points]), lung clearance index at a 2.5% stopping point (−2.33 [95% CI, −2.87 to −1.79]), and body mass index z-score (0.39 [95% CI, 0.19 to 0.59]) at Week 192. The rate of pulmonary exacerbations per year was 0.05. The annualized rates of change in percentage predicted FEV1 and lung clearance index at a 2.5% stopping point were −0.09 percentage points (95% CI, −1.01 to 0.84 percentage points) and −0.07 units (95% CI, −0.12 to −0.01 units), respectively. Conclusions In this 4-year extension study in children ≥6 years of age, the longest clinical trial experience with a CFTR (cystic fibrosis transmembrane conductance regulator) modulator in this pediatric population, ELX/TEZ/IVA remained generally safe and well tolerated, with no new safety findings. Clinically meaningful improvements in lung function, CFTR function, and nutritional status reported in the parent study were maintained. These results confirm the long-term safety and efficacy of ELX/TEZ/IVA in children ≥6 years of age.Clinical trial registered with www.clinicaltrials.gov (NCT 04183790).