Simon Y Graeber1,2,3, Constanze Vitzthum1,3, Sophia T Pallenberg4,5, Lutz Naehrlich6,7, Mirjam Stahl1,2,3, Alexander Rohrbach1,3, Marika Drescher1,3, Rebecca Minso4, Felix C Ringshausen5,8, Claudia Rueckes-Nilges6, Jan Klajda6, Julian Berges9,10, Yin Yu9,10, Heike Scheuermann9,10, Stephanie Hirtz9,10, Olaf Sommerburg9,10, Anna-Maria Dittrich4,5, Burkhard Tümmler4,5, Marcus A Mall1,2,3. 1. Department of Pediatric Respiratory Medicine, Immunology and Critical Care Medicine and Cystic Fibrosis Center, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. 2. Berlin Institute of Health at Charité-Universitätsmedizin Berlin, Berlin, Germany. 3. German Center for Lung Research, associated partner site, Berlin, Germany. 4. Department of Pediatric Pneumology, Allergology and Neonatology. 5. Biomedical Research in Endstage and Obstructive Lung Disease Hannover, German Center for Lung Research, and. 6. Department of Pediatrics, Justus-Liebig-University Giessen, Giessen, Germany. 7. Universities of Giessen and Marburg Lung Center, German Center for Lung Research, Giessen, Germany; and. 8. Department of Respiratory Medicine, Hannover Medical School, Hannover, Germany. 9. Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics, and. 10. Department of Translational Pulmonology, Translational Lung Research Center Heidelberg, German Center for Lung Research, University of Heidelberg, Heidelberg, Germany.
Abstract
Rationale: 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 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 sweat chloride concentration, nasal potential difference, and intestinal current measurement 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, 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; 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 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. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).
Rationale: 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 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 sweat chloride concentration, nasal potential difference, and intestinal current measurement 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, 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; 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 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. Clinical trial registered with www.clinicaltrials.gov (NCT04732910).
Authors: Mette F Olsen; Maria S Kjøller-Svarre; Grith Møller; Terese L Katzenstein; Bibi U Nielsen; Tacjana Pressler; Jack I Lewis; Inger H Mathiesen; Christian Mølgaard; Daniel Faurholt-Jepsen Journal: Nutrients Date: 2022-03-22 Impact factor: 5.717