| Affiliation: | 1. Cystic Fibrosis Research and Treatment Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA;2. Department of Medicine and the Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, AL, USA;3. Eudowood Division of Pediatric Respiratory Sciences, Johns Hopkins School of Medicine, Baltimore, MD, USA;4. Department of Medicine, Medical University of South Carolina, Charleston, SC, USA;5. Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA;6. Department of Medicine, Division of Respiratory Diseases, Boston Children''s Hospital, Boston, MA, USA;7. Ohio State University, Nationwide Children''s Hospital, Columbus, OH, USA;8. Department of Pediatrics, University of Colorado School of Medicine and Children''s Hospital Colorado, Aurora, CO, USA;9. Nivalis Therapeutics Inc., Boulder, CO, USA;10. Department of Pediatrics, Case Western Reserve University School of Medicine and Rainbow Babies and Children''s Hospital, Cleveland, OH, USA;11. Department of Internal Medicine, Pulmonary Division, National Jewish Health, University of Colorado Health Sciences Center, Denver, CO, USA;12. Department of Pediatrics, Pulmonary Division, National Jewish Health, University of Colorado Health Sciences Center, Denver, CO, USA |
| Abstract: | BackgroundCavosonstat (N91115), an orally bioavailable inhibitor of S-nitrosoglutathione reductase, promotes cystic fibrosis transmembrane conductance regulator (CFTR) maturation and plasma membrane stability, with a mechanism of action complementary to CFTR correctors and potentiators.MethodsA Phase I program evaluated pharmacokinetics, drug–drug interactions and safety of cavosonstat in healthy and cystic fibrosis (CF) subjects homozygous for F508del-CFTR. Exploratory outcomes included changes in sweat chloride in CF subjects.ResultsCavosonstat was rapidly absorbed and demonstrated linear and predictable pharmacokinetics. Exposure was unaffected by a high-fat meal or rifampin-mediated effects on drug metabolism and transport. Cavosonstat was well tolerated, with no dose-limiting toxicities or significant safety findings. At the highest dose, significant reductions from baseline in sweat chloride were observed (? 4.1 mmol/L; P = 0.032) at day 28. |
