Infusion of CSL112, a novel formulation of human apolipoprotein A-I, in healthy subjects removes tissue cholesterol and directs its clearance

Abstract

Purpose: The ability of HDL to promote cholesterol efflux from atherosclerotic plaque is thought to underpin its potential for cardioprotection. CSL112 is apoA-I, the active component of HDL, purified from human plasma and reconstituted to form HDL-particles suitable for infusion. CSL112 is in development for the treatment of ACS, and this study measures the ability of CSL112 to promote cholesterol movement. Methods and results: We studied PK and biomarkers of cholesterol movement following a single infusion of 5 to 135 mg/kg CSL112 in 42 of 57 enrolled healthy subjects, all other subjects received placebo ([NCT01129661][1]). We previously showed that infusion of CSL112 caused an immediate and large elevation in serum cholesterol efflux capacity. Consistent with this finding, during the initial 24 h interval, HDL-cholesterol increased in a dose-dependent manner while non-HDL-cholesterol did not change. These observations demonstrate movement of tissue cholesterol to HDL. Here, we investigated the fate of that HDL cholesterol. During the first 24 h following the infusion we observed a progressive conversion of unesterified cholesterol (UC) in HDL to esterified cholesterol (EC), indicating the action of LCAT. The predominant clearance path for HDL EC involves transport to non-HDL cholesterol by CETP, an enzyme that removes HDL EC in exchange for triglyceride (TG). Two findings support the action of this pathway after infusion of CSL112. In the first 24 h we observed a transient, dose-dependent increase in TG in the HDL-fraction. Second, we observed a transient rise in CETP activity after the infusion of CSL112. Further studies showed that enhanced CETP activity did not lead to an increase in non-HDL-cholesterol indicating that there was no saturation of the hepatic LDL-receptor mediated catabolism of LDL. Conclusion: Infusion of CSL112 caused an immediate rise in apoA-I, cholesterol efflux capacity and exit of tissue cholesterol into plasma. Newly effluxed cholesterol appears to follow a normal route of clearance with passage to non-HDL lipoproteins via CETP. CSL112 may thus provide a novel option to rapidly transport cholesterol from atherosclerotic plaque to the liver and reduce early recurrent events following ACS. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01129661&atom=%2Fehj%2F34%2Fsuppl_1%2F1947.atom