Abstract 11855: CSL112, a Novel Formulation of Human Apolipoprotein A-I, Dramatically Increases Cholesterol Efflux Capacity in Healthy Subjects: A, Placebo-Controlled, Double-Blinded, Randomized Single Ascending Dose Study

Abstract

Introduction: The ability of HDL to efflux cholesterol 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.

Method and Results: We studied markers of cholesterol movement in response to a single infusion of CSL112 at dose levels of 5 to 135 mg/kg in 57 healthy subjects (NCT01129661). Infusion of CSL112 caused a dose-proportional elevation in apoA-I and changes to key biomarkers of the early steps in reverse cholesterol transport. Biomarker changes included: formation of PreBeta1-HDL, elevation of global cholesterol efflux capacity from macrophages, movement of free cholesterol to HDL in plasma, elevation of HDL-cholesterol, and elevation of LCAT activity as evidenced by a time-dependent change of the ratio of free cholesterol to esterified cholesterol. These changes from baseline occurred in a dose- and time-dependent manner and were sustained for at least 72 hours after infusion of CSL112 at 40 mg/kg and higher. The elevations observed in PreBeta1-HDL (maximum = 3,600%) and global cholesterol efflux (maximum = 270%) were particularly marked, with an immediate rise to levels several-fold above baseline. There was no evidence to suggest that the effects of CSL112 on biomarkers of early steps in reverse cholesterol transport were saturated except for PreBeta1-HDL at the 135 mg/kg dose level. No changes from baseline were observed in association with CSL112 for the concentrations of apoB, non-HDL cholesterol, and non-HDL triglyceride.

Conclusion: We conclude that a single infusion of CSL112 in healthy subjects immediately enhances key biomarkers of the early steps in reverse cholesterol transport. CSL112 may thus provide a novel option to rapidly lower the systemic burden of atherosclerosis and to reduce the early excess of recurrent cardiovascular events following ACS.