Abstract 14267: Ncx 6560, a Novel Nitric Oxyde Donating Atorvastatin With a Promising Safety and Efficacy Profile: A Randomised, Double Blind Placebo and Active Control Study
Introduction: Evidence suggests that statins exert pleiotropic actions beyond lipid-lowering effects. Nonclinical studies have shown that NCX 6560, a nitric oxide (NO)-donating of atorvastatin was as effective as an equimolar dose of atorvastatin (ATV) on lipid lowering while exerting greater effects on anti thrombotic, anti inflammatory properties and endothelial function. The objectives of this FIM study were to assess the safety, tolerability, pharmacokinetics of NCX 6560 and to provide a proof of principle on its pharmacodynamic effects on lipids.
Design: Single and multiple ascending doses (MAD) of NCX 6560 were evaluated using an interwoven design in male healthy volunteers. In the MAD part, 48 subjects with high LDL- C ( between 130-180 mg/dL inclusive) were randomly assigned to 4 cohorts of 12 subjects, each receiving either NCX 6560 24, 48, 96 or 144 mg (n=8), ATV 40 mg (n=2) or placebo (n=2) for 2 weeks.
Results: A dose-related decrease from baseline in LDL-C (up to 57 %), total cholesterol (up to 45%), and Apo B levels (up to 49%) was observed after 2 weeks of treatment. The 48 mg NCX 6560 and 40 mg ATV doses were equipotent in decreasing these parameters after 2 weeks. The pharmacokinetic profile of ATV following NCX 6560 administration is dose proportional up to 96 mg. The bioavailability of ATV and its active metabolites after 48 mg of NCX 6560 was around 50% compared to that after an equimolar dose of ATV (40 mg). Treatment with NCX 6560 was generally safe and well tolerated. No SAEs or severe AEs were reported. No significant increase in liver enzymes was observed even at the highest dose (144 mg), which was not different from ATV 40 mg.
Conclusion: In this study, NCX 6560, 48 mg, had the same lipid-lowering effect as 40 mg ATV despite a lower exposure to ATV and its active metabolites (bioavailability of around 50%). This lower exposure, may lead to a better safety profile.
- © 2010 by American Heart Association, Inc.