Elexacaftor-Tezacaftor-Ivacaftor for Cystic Fibrosis with a Single Phe508del Allele

Abstract

Background: Cystic fibrosis is caused by mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein, and nearly 90% of patients have at least one copy of the Phe508del CFTR mutation. In a phase 2 trial involving patients who were heterozygous for the Phe508del CFTR mutation and a minimal-function mutation (Phe508del-minimal function genotype), the next-generation CFTR corrector elexacaftor, in combination with tezacaftor and ivacaftor, improved Phe508del CFTR function and clinical outcomes.

Methods: We conducted a phase 3, randomized, double-blind, placebo-controlled trial to confirm the efficacy and safety of elexacaftor-tezacaftor-ivacaftor in patients 12 years of age or older with cystic fibrosis with Phe508del-minimal function genotypes. Patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or placebo for 24 weeks. The primary end point was absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV₁) at week 4.

Results: A total of 403 patients underwent randomization and received at least one dose of active treatment or placebo. Elexacaftor-tezacaftor-ivacaftor, relative to placebo, resulted in a percentage of predicted FEV₁ that was 13.8 points higher at 4 weeks and 14.3 points higher through 24 weeks, a rate of pulmonary exacerbations that was 63% lower, a respiratory domain score on the Cystic Fibrosis Questionnaire-Revised (range, 0 to 100, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; minimum clinically important difference, 4 points) that was 20.2 points higher, and a sweat chloride concentration that was 41.8 mmol per liter lower (P<0.001 for all comparisons). Elexacaftor-tezacaftor-ivacaftor was generally safe and had an acceptable side-effect profile. Most patients had adverse events that were mild or moderate. Adverse events leading to discontinuation of the trial regimen occurred in 1% of the patients in the elexacaftor-tezacaftor-ivacaftor group.

Conclusions: Elexacaftor-tezacaftor-ivacaftor was efficacious in patients with cystic fibrosis with Phe508del-minimal function genotypes, in whom previous CFTR modulator regimens were ineffective. (Funded by Vertex Pharmaceuticals; VX17-445-102 ClinicalTrials.gov number, NCT03525444.).

Figure 1.. Absolute Change from Baseline in Percentage of Predicted FEV₁, and Rate of Pulmonary Exacerbations.

Panel A shows the absolute change from baseline in percentage of predicted forced expiratory volume in 1 second (FEV₁), based on a mixed-effects model for repeated measures. Data are least-squares means, and I bars indicate standard error of the mean; the dashed line indicates no change from baseline. Panel B shows a histogram of absolute change from baseline in percentage of predicted FEV₁ through week 24, according to trial group. Panel C shows the overall estimated annualized rate of pulmonary exacerbations, the estimated annualized rate of pulmonary exacerbations leading to hospitalization, and the estimated annualized rate of pulmonary exacerbations treated with intravenous antibiotics. CI denotes confidence interval.

Figure 2.. Absolute Change from Baseline in Sweat Chloride Concentration and CFQ-R Respiratory Domain Score.

Panel A shows the absolute change from baseline in sweat chloride concentration, based on a mixed-effects model for repeated measures; a reduction over time indicates improvement in CFTR function. Panel B shows a histogram of absolute change from baseline in sweat chloride concentration through week 24, according to trial group. Panel C shows the absolute change from baseline in the respiratory domain score on the Cystic Fibrosis Questionnaire–Revised (CFQ-R), based on a mixed-effects model for repeated measures. Scores are normalized to range from 0 to 100 points, with higher scores indicating a higher patient-reported quality of life with regard to respiratory symptoms; the minimum clinically important difference is 4 points. In Panels A and C, least-squares means at each visit are shown, and the I bars indicate the corresponding standard error; the dashed line indicates no change from baseline.