Evinacumab

Angiopoetin-like proteins (ANGPTL) are a diverse group of proteins involved in a number of physiological processes, including the regulation of lipoprotein metabolism. Loss-of-function mutations in ANGPTL3 and ANGPTL4 have been shown to result in hypolipidemia and a reduced risk of coronary artery disease, while increased levels of these proteins appear to be associated with cardiovascular risk. While these observations have made ANGPTLs as a class a desirable target in the treatment of hyperlipidemic disorders, ANGPTL3 is the first to be pharmacologically targeted for the purposes of lipid-lowering therapy. ANGPTL3 is expressed primarily in the liver and acts as an endogenous inhibitor of lipoprotein lipase (LPL) and endothelial lipase (EL) which are responsible, in part, for metabolizing triglycerides (TG) and HDL-C, respectively.

Evinacumab is monoclonal antibody that binds to and inhibits ANGPTL3, with the resulting disinhibition of LPL and EL reducing the levels of circulating TG and HDL-C. While the mechanism through which evinacumab reduces LDL-C is not entirely clear, this effect is independent of LDL receptor density and is therefore most likely due to the promotion of VLDL processing and upstream clearance of LDL formation.