Efficacy and Safety of Elexacaftor/Tezacaftor/Ivacaftor in Children 6 Through 11 Years of Age with Cystic Fibrosis Heterozygous for F508del and a Minimal Function Mutation: A Phase 3b, Randomized, Placebo-controlled Study

Abstract

Rationale The triple-combination regimen elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be safe and efficacious in children aged 6 through 11 years with cystic fibrosis and at least one F508del-CFTR allele in a phase 3, open-label, single-arm study. Objectives To further evaluate the efficacy and safety of ELX/TEZ/IVA in children 6 through 11 years of age with cystic fibrosis heterozygous for F508del and a minimal function CFTR mutation ( F /MF genotypes) in a randomized, double-blind, placebo-controlled phase 3b trial. Methods Children were randomized to receive either ELX/TEZ/IVA ( n = 60) or placebo ( n = 61) during a 24-week treatment period. The dose of ELX/TEZ/IVA administered was based on weight at screening, with children <30 kg receiving ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 hours, and children ⩾30 kg receiving ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 hours (adult dose). Measurements and Main Results The primary endpoint was absolute change in lung clearance index 2.5 from baseline through Week 24. Children given ELX/TEZ/IVA had a mean decrease in lung clearance index 2.5 of 2.29 units (95% confidence interval [CI], 1.97–2.60) compared with 0.02 units (95% CI, −0.29 to 0.34) in children given placebo (between-group treatment difference, −2.26 units; 95% CI, −2.71 to −1.81; P < 0.0001). ELX/TEZ/IVA treatment also led to improvements in the secondary endpoint of sweat chloride concentration (between-group treatment difference, −51.2 mmol/L; 95% CI, −55.3 to −47.1) and in the other endpoints of percent predicted FEV 1 (between-group treatment difference, 11.0 percentage points; 95% CI, 6.9–15.1) and Cystic Fibrosis Questionnaire-Revised Respiratory domain score (between-group treatment difference, 5.5 points; 95% CI, 1.0–10.0) compared with placebo from baseline through Week 24. The most common adverse events in children receiving ELX/TEZ/IVA were headache and cough (30.0% and 23.3%, respectively); most adverse events were mild or moderate in severity. Conclusions In this first randomized, controlled study of a cystic fibrosis transmembrane conductance regulator modulator conducted in children 6 through 11 years of age with F /MF genotypes, ELX/TEZ/IVA treatment led to significant improvements in lung function, as well as robust improvements in respiratory symptoms and cystic fibrosis transmembrane conductance regulator function. ELX/TEZ/IVA was generally safe and well tolerated in this pediatric population with no new safety findings.

A year in review (2022): Modulators and COVID19, the story goes on…

“…The most common adverse events were headaches and cough, and one child stopped treatment because of a rash. There were therefore no new safety findings and ETI was well tolerated in this age group [20] .…”

CFTR Modulators: Current Status and Evolving Knowledge

“…More recently, a randomized placebocontrolled trial evaluating the safety and efficacy of ELX/TEZ/ IVA in children 6 to 11 years of age heterozygous for F508del and a minimal function mutation confirmed the findings of the open-label study: ELX/TEZ/IVA led to significant improvements in lung function and respiratory symptoms, and was generally safe and well tolerated. 49 Use of ELX/TEZ/IVA in pwCF carrying one F508del mutation combined to gating or residual function mutation is also supported by a recent trial demonstrating greater clinical improvement in patient treated with ELX/TEZ/IVA versus treatment with either IVA alone or TEZ/IVA. 18 In the United States, in vitro data have led to expansion of Food and Drug Administration (FDA) approvals to an increasing number of mutations and populations.…”

Elexacaftor-Tezacaftor-Ivacaftor: A Life-Changing Triple Combination of CFTR Modulator Drugs for Cystic Fibrosis

“…Regarding efficacy, the triple combination therapy improved ppFEV 1 through week 24, LCI 2.5 , CFQ-R score, and BMI, and reduced SCC when compared to the pre-treatment baseline [ 35 ]. In parallel, a 24-week randomized, placebo-controlled, double-blind phase 3b trial was conducted to evaluate the efficacy and safety of ETI therapy in children aged 6–11 years old and heterozygous for F508del-CFTR and an MF mutation on the second allele [ 39 ]. The triple combination therapy led to improvements in absolute change in LCI 2.5 from baseline through week 24 (primary endpoint), in respiratory symptoms and CFTR function.…”

“…One child discontinued the therapy due to a rash that resolved after discontinuation. No new safety concerns were observed, and results provided further evidence that the triple combination therapy substantially improved CFTR function and clinical outcomes [ 39 ]. Overall, these results support the extend of ETI therapy for a younger CF population.…”