Alexandra Masson1, Elena K Schneider-Futschik2, Nesrine Baatallah3, Thao Nguyen-Khoa4, Emmanuelle Girodon5, Aurélie Hatton6, Thomas Flament7, Muriel Le Bourgeois8, Frederique Chedevergne9, Céline Bailly10, Sylvia Kyrilli11, Diane Achimastos12, Alexandre Hinzpeter13, Aleksander Edelman14, Isabelle Sermet-Gaudelus15. 1. Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France; Centre de Référence et de Compétence de la Mucoviscidose, Hôpital Dupuytren, 8 avenue Dominique Larrey, 87042 Limoges, France. 2. Drug Delivery, Disposition and Dynamics, Monash Institute of Pharmacy and Pharmaceutical Sciences, Monash University, Parkville, Victoria 3052, Australia; Lung Health Research Center, Department of Pharmacology & Therapeutics, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, The University of Melbourne, Parkville, VIC, Australia. Electronic address: elena.schneider@monash.edu. 3. Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France. Electronic address: nesrine.baatallah@inserm.fr. 4. Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France; Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France; Laboratoire de Biochimie Générale, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de Sèvres, 75015 Paris, France. Electronic address: thao.nguyen-khoa@aphp.fr. 5. Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France; Service de Biochimie et Génétique Moléculaire, Hôpital Cochin, Assistance-Publique Hôpitaux de Paris, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France. Electronic address: emmanuelle.girodon@aphp.fr. 6. Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France. Electronic address: aurelie.hatton@inserm.fr. 7. Centre de Ressources et de Compétence de la Mucoviscidose Adulte, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire, 2 boulevard Tonnellé, 37000 Tours, France. Electronic address: t.flament@chu-tours.fr. 8. Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France. Electronic address: muriel.lebourgeois@aphp.fr. 9. Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France. Electronic address: frederique.chedevergne@aphp.fr. 10. Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France. Electronic address: celine.bailly@aphp.fr. 11. Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France. 12. Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France. Electronic address: diane.achimastos@aphp.fr. 13. Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France. Electronic address: alexandre.hinzpeter@inserm.fr. 14. Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France. Electronic address: aleksander.edelman@inserm.fr. 15. Centre Maladie Rare Mucoviscidose, Hôpital Necker-Enfants Malades, Assistance-Publique Hôpitaux de Paris, 149 rue de sèvres, 75015 Paris, France; Institut Necker-Enfants Malades, INSERM U1151, 149 rue de Sèvres, 75015 Paris, France; Université Paris Sorbonne, 75005 Paris, France. Electronic address: isabelle.sermet@aphp.fr.
Abstract
BACKGROUND: Ivacaftor-lumacaftor combination therapy corrects the F508 del-CFTR mutated protein which causes Cystic Fibrosis. The clinical response of the patients treated with the combination therapy is highly variable. This study aimed to determine factors involved in the individual's response to lumacaftor-ivacaftor therapy. METHODS: Sweat test was assessed at baseline and after 6 months of ivacaftor-lumacaftor treatment in 41 homozygous F508del children and young adults. β-adrenergic peak sweat secretion, nasal potential difference (NPD) and intestinal current measurements (ICM) were performed in patients accepting these tests. Seric level of lumacaftor and ivacaftor were determined and additional CFTR variant were searched. RESULTS: Sweat chloride concentration significantly decreased after treatment, whereas the β-adrenergic peak sweat response did not vary in 9 patients who underwent these tests. The average level of F508del-CFTR activity rescue reached up to 15% of the normal level in intestinal epithelium, as studied by ICM in 12 patients (p = .03) and 20% of normal in the nasal epithelium in NPD tests performed in 21 patients (NS). There was no significant correlation between these changes and improvements in FEV1 at 6 months. Serum drug levels did not correlate with changes in FEV1, BMI-Zscore or other CFTR activity biomarkers. Additional exonic variants were identified in 4 patients. The F87L-I1027T-F508del-CFTR complex allele abolished the lumacaftor corrector effect. CONCLUSION: This observational study investigates a number of potential factors linked to the clinical response of F508del homozygous patients treated with lumacaftor-ivacaftor combination therapy. Lumacaftor and ivacaftor blood levels are not associated with the clinical response. Additional exonic variants may influence protein correction.
BACKGROUND:Ivacaftor-lumacaftor combination therapy corrects the F508 del-CFTR mutated protein which causes Cystic Fibrosis. The clinical response of the patients treated with the combination therapy is highly variable. This study aimed to determine factors involved in the individual's response to lumacaftor-ivacaftor therapy. METHODS: Sweat test was assessed at baseline and after 6 months of ivacaftor-lumacaftor treatment in 41 homozygous F508delchildren and young adults. β-adrenergic peak sweat secretion, nasal potential difference (NPD) and intestinal current measurements (ICM) were performed in patients accepting these tests. Seric level of lumacaftor and ivacaftor were determined and additional CFTR variant were searched. RESULTS: Sweat chloride concentration significantly decreased after treatment, whereas the β-adrenergic peak sweat response did not vary in 9 patients who underwent these tests. The average level of F508del-CFTR activity rescue reached up to 15% of the normal level in intestinal epithelium, as studied by ICM in 12 patients (p = .03) and 20% of normal in the nasal epithelium in NPD tests performed in 21 patients (NS). There was no significant correlation between these changes and improvements in FEV1 at 6 months. Serum drug levels did not correlate with changes in FEV1, BMI-Zscore or other CFTR activity biomarkers. Additional exonic variants were identified in 4 patients. The F87L-I1027T-F508del-CFTR complex allele abolished the lumacaftor corrector effect. CONCLUSION: This observational study investigates a number of potential factors linked to the clinical response of F508del homozygous patients treated with lumacaftor-ivacaftor combination therapy. Lumacaftor and ivacaftor blood levels are not associated with the clinical response. Additional exonic variants may influence protein correction.
Authors: Scott C Bell; Marcus A Mall; Hector Gutierrez; Milan Macek; Susan Madge; Jane C Davies; Pierre-Régis Burgel; Elizabeth Tullis; Claudio Castaños; Carlo Castellani; Catherine A Byrnes; Fiona Cathcart; Sanjay H Chotirmall; Rebecca Cosgriff; Irmgard Eichler; Isabelle Fajac; Christopher H Goss; Pavel Drevinek; Philip M Farrell; Anna M Gravelle; Trudy Havermans; Nicole Mayer-Hamblett; Nataliya Kashirskaya; Eitan Kerem; Joseph L Mathew; Edward F McKone; Lutz Naehrlich; Samya Z Nasr; Gabriela R Oates; Ciaran O'Neill; Ulrike Pypops; Karen S Raraigh; Steven M Rowe; Kevin W Southern; Sheila Sivam; Anne L Stephenson; Marco Zampoli; Felix Ratjen Journal: Lancet Respir Med Date: 2019-09-27 Impact factor: 30.700
Authors: Susannah J King; Dominic Keating; Elyssa Williams; Eldho Paul; Brigitte M Borg; Felicity Finlayson; Brenda M Button; John W Wilson; Tom Kotsimbos Journal: ERJ Open Res Date: 2021-02-01
Authors: Maria Favia; Crescenzio Gallo; Lorenzo Guerra; Domenica De Venuto; Anna Diana; Angela Maria Polizzi; Pasqualina Montemurro; Maria Addolorata Mariggiò; Giuseppina Leonetti; Antonio Manca; Valeria Casavola; Massimo Conese Journal: Int J Mol Sci Date: 2020-03-31 Impact factor: 5.923