Metabolomic responses to lumacaftor/ivacaftor in cystic fibrosis

Abstract Background Cystic fibrosis (CF) is a life‐limiting disease caused by a defect in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene. Lumacaftor/Ivacaftor is a novel CFTR modulator approved for patients that are homozygous for Phe508del CFTR , but its clinical effectiveness varies amongst patients, making it difficult to determine clinical responders. Therefore, identifying biochemical biomarkers associated with drug response are clinically important for follow‐up studies. Methods Serum metabolomics was performed on twenty patients with CF pre‐ and 6‐month post‐Lumacaftor/Ivacaftor response via Ultrahigh Performance Liquid Chromatography‐Tandem Mass Spectroscopy (UPLC‐MS/MS). Correlation with clinical variables was performed. Results Metabolomics analysis demonstrated 188 differentially regulated metabolites between patients pre‐ and post‐Lumacaftor/Ivacaftor initiation, with a predominance of lipid and amino acid alterations. The top 30 metabolites were able to differentiate pre‐ and post‐Lumacaftor/Ivacaftor status in greater than 90% of patients via a random‐forest confusion matrix. Alterations in bile acids, phospholipids, and bacteria‐associated metabolites were the predominant changes associated with drug response. Importantly, changes in metabolic patterns were associated with clinical responders. Conclusions Selected key lipid and amino acid metabolic pathways were significantly affected by Lumacaftor/Ivacaftor initiation and similar pathways were affected in clinical responders. Targeted metabolomics may provide useful and relevant biomarkers of CFTR modulator responses.