Alirocumab for hyperlipidemia: physiology of PCSK9 inhibition, pharmacodynamics and Phase I and II clinical trial results of a PCSK9 monoclonal antibody.

Statins have been the cornerstone of lipid therapy for the last two decades, but despite significant clinical efficacy in the majority of patients, a large residual risk remains for the development of initial or recurrent atherosclerotic cardiovascular disease. In addition, owing to side effects, a significant percentage of patients cannot tolerate any statin dose or a high enough statin dose to reach their recommended LDL cholesterol goals. Monoclonal antibodies (mAbs) to PCSK9 have recently been shown to be highly efficacious in lowering LDL cholesterol, while demonstrating a favorable adverse event profile in early clinical trials. This review of alirocumab (formerly REGN727/SAR236553) explains the physiology and pharmacodynamics of PCSK9 inhibition with a mAb, as well as the Phase I and II clinical trial results of alirocumab and the ongoing Phase III trial designs. Several mAbs to PCSK9 are currently in development and approval may be 1-3 years away. We will focus this review on alirocumab, but mAbs to PCSK9 are the most promising cholesterol-lowering medication since statins and have the potential to significantly reduce further the occurrence of atherosclerotic cardiovascular disease.