Long-term safety and efficacy of elexacaftor-tezacaftor-ivacaftor in children aged 6 and older with cystic fibrosis and at least one F508del allele: 144-week results of an open-label extension study

Abstract

Background: Elexacaftor-tezacaftor-ivacaftor (ETI) was shown to be safe and efficacious in children aged 6 to 11 with CF and at least one F508del- CFTR allele in a 24-week, open-label, Phase 3 clinical trial. Children who completed this pivotal trial could enroll in a 192-week open-label extension study.We present results from an interim analysis of this study at Week 144. Methods: In this Phase 3, two-part (part A and part B) extension study, children who weigh less than 30 kg receive 100 mg of elexacaftor and 50 mg of tezacaftor once daily and 75 mg of ivacaftor every 12 hours, and childrenweighing 30 kg or more receive 200 mg of elexacaftor and 100 mg of tezacaftor once daily and 150 mg of ivacaftor every 12 hours (adult dose). The primary endpoint is safety and tolerability; secondary endpoints include absolute changes from parent study baseline in ppFEV1, sweat chloride concentration, CF Questionnaire-Revised (CFQ-R) respiratory domain score, lung clearance index2.5, body mass index (BMI) and BMIfor- age z-score, weight and weight-for-age z-score, and height and heightfor- age z-score, as well as number of pulmonary exacerbations and CFrelated hospitalizations. Part A of the study (96 week) has been completed. Data collection for the 144-week interim analysis will be based on the date that the last participant reached the Week 144 visit. Results: 64 children (F508del/minimal function [F/MF] genotypes, n = 36; F508del/ F508del [F/F] genotype, n = 28) were enrolled and dosed in this extension study. At the 144-week interim analysis, mean exposure to ETI was 134.0 (SD, 32.7) weeks; 20 children discontinued the study due to commercial drug availability or completed Part A and did not participate in Part B. All children had adverse events,which for mostwere mild (35.9%) or moderate (60.9%) in severity. The exposure-adjusted rate of adverse events and serious adverse events (449.73 and 3.91 events/100 participant years, respectively)was lower than in the 24-week parent study (987.04 and 8.68 events/100 participant years, respectively). Two children (3.1%) discontinued due to adverse events: one child had a non-serious adverse event of increased alanine aminotransferase thatwas considered possibly related to ETI and another child had a non-serious adverse event of aggression that was considered unlikely to be related to ETI and which was previously reported. The improvements in ppFEV1, sweat chloride concentration, CFQ-R respiratory domain score, LCI2.5, and BMI z-score seen in the parent study were maintained through the 144-week interim analysis period. The annualized rate of PEx was 0.047. The annualized rate of change in ppFEV1 was +0.10 (95% CI: −0.92, 1.12). Conclusions: ETI continued to be generally safe and well-tolerated in children aged 6 years and older, with no new safety findings. The clinically meaningful improvements in lung function, CFTR function, and growth parameters seen in the parent study were maintained through an additional 144-weeks of ETI treatment. There was no decline in mean ppFEV1 during the 3.5-year treatment period. These results confirm the favorable safety profile and durable clinical benefits of ETI in this population.