부산대학교 도서관

Introduction:Even with marked lowering of LDL-C, patients with CAD remain at significant risk of CV events. Elevated HDL-C is one of the strongest epidemiologic surrogates for protection against CHD but functional HDL particles that facilitate cholesterol efflux may be the main driver of cardioprotection. Endothelial lipase (EL) hydrolyzes HDL phospholipids resulting in catabolism of HDL and renal excretion. Loss-of-function EL gene mutations are associated with higher HDL-C, increased cholesterol efflux and lower CV risk. MEDI5884 is a selective, humanized, monoclonal EL neutralizing antibody. The benefit of pharmacologic inhibition of EL in patients with CAD is unknown.Methods:LEGACY was a phase 2a, double-blind, placebo-controlled, trial that randomized 132 subjects 45-80 years of age with stable CAD receiving high-intensity statin therapy with an LDL-C ? 100 mg/dL to 3 monthly doses of one of 5 dose levels of the EL inhibitor MEDI5884 (50, 100, 200, 350, or 500 mg SC) or matching placebo. The primary endpoint was the safety and tolerability of MEDI5884 through the end of the study (Day 151), and additional endpoints included change in HDL-C and cholesterol efflux from baseline to Day 91.Results:AEs and antidrug antibodies were balanced between placebo and MEDI5884 groups and there were no drug-related SAEs. In a dose-dependent manner, MEDI5884 increased HDL-C up to 48% (p<0.0001) (Fig A) and non-ABCA1 cholesterol efflux by 45% (p<0.001) (Fig B). MEDI5884 also increased apoA1 (37%, p<0.0001), HDL particle number (15%, p<0.001) and size (5.4%, p<0.0001). A small increase in LDL-C but a decrease in small dense LDL was observed in MEDI5884 treated groups.Conclusions:Inhibition of EL by MEDI5884 increases the quantity of functional HDL in subjects with stable CAD on high-intensity statin therapy without an adverse safety signal and warrants further clinical investigation to determine if it prevents progression of atherosclerosis.