Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on CFTR Function in Patients with Cystic Fibrosis and One or Two F508del Alleles

Science and Research

RATIONALE: The CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to improve clinical outcomes and sweat chloride concentration (SCC) in patients with cystic fibrosis (CF) and one or two F508del alleles. However, the effect of ELX/TEZ/IVA on CFTR function in the airways and intestine has not been studied. OBJECTIVES: To assess the effect of ELX/TEZ/IVA on CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles aged 12 years and older. METHODS: This prospective observational multicenter study assessed clinical outcomes including FEV1 %predicted and body mass index, and the CFTR biomarkers SCC, nasal potential difference (NPD) and intestinal current measurement (ICM) before and 8-16 weeks after initiation of ELX/TEZ/IVA. MEASUREMENTS AND MAIN RESULTS: A total of 107 patients with CF including 55 patients with one F508del and a minimal function mutation and 52 F508del homozygous patients were enrolled in this study. In patients with one F508del allele, NPD and ICM showed that ELX/TEZ/IVA improved CFTR function in nasal epithelia to a level of 46.5% (IQR, 27.5-72.4; P<0.001) and in intestinal epithelia to 41.8% of normal (IQR, 25.1-57.6; P<0.001). In F508del homozygous patients, ELX/TEZ/IVA exceeded improvement of CFTR function observed with TEZ/IVA and increased CFTR-mediated Cl- secretion to a level of 47.4% of normal (IQR, 19.3-69.2; P<0.001) in nasal and to 45.9% (IQR, 19.7-66.6; P<0.001) in intestinal epithelia. CONCLUSIONS: Treatment with ELX/TEZ/IVA results in effective improvement of CFTR function in airway and intestinal epithelia in patients with CF and one or two F508del alleles.