Effects of Elexacaftor/Tezacaftor/Ivacaftor Therapy on Lung Clearance Index and Magnetic Resonance Imaging in Patients with Cystic Fibrosis and One or Two <i>F508del</i> Alleles

Abstract

<b>Rationale:</b> We recently demonstrated that triple-combination CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapy with elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) improves CFTR function in airway and intestinal epithelia to 40-50% of normal in patients with cystic fibrosis (CF) with one or two <i>F508del</i> alleles. In previous studies, this improvement of CFTR function was shown to improve clinical outcomes; however, effects on the lung clearance index (LCI) determined by multiple-breath washout and abnormalities in lung morphology and perfusion detected by magnetic resonance imaging (MRI) have not been studied. <b>Objectives:</b> To examine the effect of ELX/TEZ/IVA on LCI and lung MRI scores in patients with CF and one or two <i>F508del</i> alleles aged ⩾12 years. <b>Methods:</b> This prospective, observational, multicenter, postapproval study assessed LCI and lung MRI scores before and 8-16 weeks after initiation of ELX/TEZ/IVA. <b>Measurements and Main Results:</b> A total of 91 patients with CF, including 45 heterozygous for <i>F508del</i> and a minimal function mutation (MF) and 46 homozygous for <i>F508del</i>, were enrolled in this study. Treatment with ELX/TEZ/IVA improved LCI in <i>F508del</i>/MF (-2.4; interquartile range [IQR], -3.7 to -1.1; <i>P</i> < 0.001) and <i>F508del</i> homozygous (-1.4; IQR, -2.4 to -0.4; <i>P</i> < 0.001) patients. Furthermore, ELX/TEZ/IVA improved the MRI global score in <i>F508del</i>/MF (-6.0; IQR, -11.0 to -1.3; <i>P</i> < 0.001) and <i>F508del</i> homozygous (-6.5; IQR, -11.0 to -1.3; <i>P</i> < 0.001) patients. <b>Conclusions:</b> Our data demonstrate that improvement of CFTR function by ELX/TEZ/IVA improves lung ventilation and abnormalities in lung morphology, including airway mucus plugging and wall thickening, in adolescent and adult patients with CF and one or two <i>F508del</i> alleles in a real-world, postapproval setting. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).