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

Abstract

<b>Rationale:</b> The CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to improve clinical outcomes and sweat chloride concentration in patients with cystic fibrosis (CF) and one or two <i>F508del</i> alleles. However, the effect of ELX/TEZ/IVA on CFTR function in the airways and intestine has not been studied. <b>Objectives:</b> To assess the effect of ELX/TEZ/IVA on CFTR function in airway and intestinal epithelia in patients with CF and one or two <i>F508del</i> alleles aged 12 years and older. <b>Methods:</b> This prospective, observational, multicenter study assessed clinical outcomes including FEV₁% predicted and body mass index and the CFTR biomarkers sweat chloride concentration, nasal potential difference, and intestinal current measurement before and 8-16 weeks after initiation of ELX/TEZ/IVA. <b>Measurements and Main Results:</b> A total of 107 patients with CF including 55 patients with one <i>F508del</i> and a minimal function mutation and 52 <i>F508del</i> homozygous patients were enrolled in this study. In patients with one <i>F508del</i> allele, nasal potential difference and intestinal current measurement showed that ELX/TEZ/IVA improved CFTR function in nasal epithelia to a level of 46.5% (interquartile range [IQR], 27.5-72.4; <i>P</i> < 0.001) and in intestinal epithelia to 41.8% of normal (IQR, 25.1-57.6; <i>P</i> < 0.001). In <i>F508del</i> 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; <i>P</i> < 0.001) in nasal and 45.9% (IQR, 19.7-66.6; <i>P</i> < 0.001) in intestinal epithelia. <b>Conclusions:</b> 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 <i>F508del</i> alleles. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).