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

RATIONALE

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children 6 through 11 years of age with cystic fibrosis (CF) and at least one allele in a 24-week phase 3 study. Children completing this study could enroll into a 192-week extension study.

OBJECTIVES

Evaluate long-term safety and efficacy of ELX/TEZ/IVA in children ≥6 years.

METHODS

In this 2-part (Part A [96-weeks] and Part B [96-weeks]) phase 3 extension study, children <12 years weighing <30 kg received ELX 100 mg once daily (qd)/TEZ 50 mg qd/IVA 75 mg every 12 hours (q12h) and children weighing ≥ 30 kg or aged ≥12 years received ELX 200 mg qd/TEZ 100 mg qd/IVA 150 mg q12h.

MEASUREMENTS AND MAIN RESULTS

Sixty-four children (/MF [n=36] and [n=28]) received ≥ 1 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 (AEs), which for most were mild (31.3%) or moderate (64.1%) and generally consistent with common manifestations of CF. Two children (3.1%) had non-serious AEs that lead 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 ppFEV (9.6 percentage points; 95% CI: 5.4, 13.7), sweat chloride concentration (-57.9 mmol/L; 95% CI: -63.3, -52.5), CFQ-R respiratory domain score (10.0 points; 95% CI: 6.9, 13.0), LCI (-2.33; 95% CI: -2.87, -1.79), and BMI z-score (0.39; 95% CI: 0.19, 0.59) at Week 192. Rate of pulmonary exacerbations per year was 0.05. The annualized rate of change in ppFEV and LCI was -0.09 percentage points (95% CI: -1.01, 0.84) and -0.07 units (95%CI: -0.12, -0.01), respectively.

CONCLUSIONS

In this 4-year extension study in children ≥6 years, the longest clinical trial experience with a CFTR 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. 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.

CLINICALTRIALS

gov, ID: NCT04183790.