Abstract 11851: CSL112, a Novel Formulation of Human Apolipoprotein A-I, Provides Sustained Increases in Biomarkers of Cholesterol Transport Following Repeat Dosing: A Placebo-Controlled, Randomized Multiple Ascending Dose Study in Healthy Subjects

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 IV infusion.

Methods and Results: We studied biomarkers of cholesterol movement following infusions of CSL112 in 36 healthy subjects (NCT01281774). Three dose regimens were studied: 4 once-weekly infusions of 3.4 g, 4 once-weekly infusions of 6.8 g, and 8 twice-weekly infusions of 3.4 g. Infusions of CSL112 caused immediate and profound elevations in cholesterol efflux capacity, PreBeta1-HDL, and HDL in serum or plasma. Elevations in PreBeta1-HDL were up to 20-fold. For all 3 regimens, all biomarker responses were dose dependent and had a similar magnitude and time course after the first and last infusions. PreBeta1-HDL and cholesterol efflux capacity peaked at the end of infusion and returned to near baseline at 24 h. Increases in HDL followed PreBeta1-HDL and peaked 24 to 48 h after infusion; elevations remained 72 h after infusion suggesting a sustained response. There was no change in the baseline-corrected AUC of apoA-I after multiple once-weekly infusions compared with a single infusion, but there was a notable increase in the AUC of HDL. This suggests that when compared to a single infusion of CSL112, multiple infusions of CSL112 may provide greater efflux of cholesterol from tissues to HDL. There were no changes from baseline observed in association with CSL112 for plasma apoB, triglycerides, or LDL suggesting that LDL clearance was not saturated in these regimens.

Conclusion: We conclude that single and multiple infusions of CSL112 in healthy human subjects rapidly elevate key biomarkers in the initiation of reverse cholesterol transport. CSL112 may thus provide a novel option to rapidly lower the burden of atherosclerosis and reduce the early excess of recurrent cardiovascular events following ACS.