Abstract 15823: 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<0.001) and triglycerides (TG) (-33% to -36%, P<0.001) by reduction of the apoB-containing lipoproteins, and further decreased TC in combination with atorvastatin (-48% to -58%, P<0.001) as compared to the control. Rescue of LDLR degradation was verified by an increase in hepatic LDLR expression after alirocumab treatment (+80% to +178%, P<0.01). The combination treatment increased hepatic LDLR expression (+71% and +140%, P<0.01) and reduced TC (-36% and -48%, P<0.001) and TG (-40% and -51%, P<0.001) to a greater extent as compared to atorvastatin mono-treatment. Alirocumab alone dose-dependently decreased atherosclerotic lesion size (-70% and -87%, P<0.001) and severity and when added to atorvastatin enhanced the effects on lesion size (-88% and -98%, P<0.001; all compared to control). When compared to atorvastatin mono-treatment, the combination treatment further decreased lesion size (-82% and -97%, P<0.001) and severity. Results on atherosclerotic lesion composition are pending.
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.
- © 2013 by American Heart Association, Inc.