Journal
JOURNAL OF CYSTIC FIBROSIS
Volume 16, Issue 3, Pages 371-379Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jcf.2017.01.009
Keywords
GSNOR; F508del-CFTR; Homozygous; Cystic fibrosis; CFTR stabilizer; Modulator
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Funding
- Nivalis Therapeutics, Inc.
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Background: Cavosonstat (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. Methods: A Phase I program evaluated pharmacokinetics, drug-drug interactions and safety of cavosonstat in healthy and cystic fibrosis (CF) subjects homozygous for F508de1-CFTR. Exploratory outcomes included changes in sweat chloride in CF subjects. Results: Cavosonstat 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. Conclusions: The favorable safety and clinical profile warrant further study of cavosonstat in CF. (C) 2017 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.
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