Preclinical discovery and development of evolocumab for the treatment of hypercholesterolemia

摘要

Introduction: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a serine protease that binds and promotes the lysosomal degradation of the low-density lipoprotein receptors (LDLR). Upon its discovery in 2002, PCSK9 inhibition has subsequently emerged as a novel target for lowering LDL-cholesterol (LDL-C) and reducing coronary heart disease. Evolocumab, a monoclonal antibody directed against human PCSK9, was approved in 2015 as an adjunct to lipid-lowering therapy for treating patients with familial hypercholesterolemia (FH) or patients with high cardiovascular risk, who are treated with maximally tolerated lipid-lowering agents and have not reached the recommended LDL-C levels. Areas covered: The authors illustrate the rapid pace of the drug development process that monoclonal antibodies, including evolocumab, have demonstrated during the last decade. In less than 15 years from its discovery, this lipid-lowering target has successfully progressed from bench-side to clinical practice and has been recently approved to reduce cardiovascular events in patients with established atherosclerotic cardiovascular disease (ASCVD). Expert opinion: Evolocumab has demonstrated a good safety profile and robust efficacy in terms of its lipid-lowering effect and ASCVD risk reduction, yet affordability, accessibility, and cost-effectiveness of PCSK9 monoclonal antibodies remain a hurdle in the 'real-world' setting. These challenges facing the upcoming generation of precision medicine therapies must be addressed upfront.