PCSK-9 Monoclonal Antibody Alirocumab Dose-Dependently Decreases Atherosclerosis Development and Enhances the Effects of Atorvastatin in APOE*3Leiden.CETP Mice

Introduction: Serum proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease responsible for low density lipoprotein receptor (LDLR) degradation in the liver, thereby increasing LDL cholesterol levels. PCSK9 inhibition is a potential novel strategy for treatment of CVD, especially in combination with statins which increase PCSK9 expression. Alirocumab (also known as SAR236553/REGN727) is a fully human PCSK9 monoclonal antibody currently in phase 3 clinical development. Hypothesis: Alirocumab alone reduces progression of atherosclerosis in APOE*3Leiden.CETP mice and adds to the atheroprotective effect of atorvastatin in this model. Methods: Mice were fed a Western-type diet alone or were treated by weekly subcutaneous injection with alirocumab (3 or 10 mg/kg) with or without atorvastatin (3.6 mg/kg/d) for 18 weeks. Effects on plasma lipids, hepatic LDLR expression and atherosclerotic lesion size and severity were assessed. Results: Alirocumab dose-dependently decreased total cholesterol (TC) (-37% to -46%, P Conclusions: A PCSK9 monoclonal antibody, alirocumab, dose-dependently decreases plasma lipids and progression of atherosclerosis and enhances the beneficial effects of atorvastatin in APOE*3Leiden.CETP mice.