Abstract 15780: CSL112, A Novel Formulation of Human Apolipoprotein A-I, Dramatically Increases Cholesterol Efflux Capacity in Patients With Stable Atherothrombotic Disease: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Study
Introduction: The ability of high-density lipoprotein (HDL) to remove cholesterol from macrophages in atherosclerotic plaque is thought to underlie its inverse correlation with cardiovascular risk. CSL112 is a novel formulation of apoA-I purified from human plasma and reconstituted to form HDL particles suitable for infusion. Two phase 1 studies have demonstrated favorable safety, pharmacokinetics (PK) and biomarker responses to single or multiple infusions of CSL112 in healthy subjects. The aim of the current study (NCT01499420) was to assess the effect of CSL112 on safety, PK, and lipid biomarkers in patients with stable atherothrombotic disease. Here, we report on the lipid biomarker results of the study.
Methods and Results: We studied markers of cholesterol movement in response to a single infusion of placebo or CSL112 at dose levels 1.7, 3.4 and 6.8 g in 44 subjects. Over this dose range, infusion of CSL112 caused approximately dose-proportional elevations in apoA-I. Biomarker changes included: formation of PreBeta1-HDL (HDL-VS), elevation of global cholesterol efflux capacity from macrophages, movement of free cholesterol to HDL in plasma, elevation of HDL-cholesterol, and elevation of lecithin-cholesterol acyltransferase (LCAT) activity as evidenced by a time-dependent change of the ratio of free cholesterol to esterified cholesterol. Several of the biomarker changes were maintained for at least 72 h after infusion of CSL112 at 3.4 g and 6.8 g. No increases were observed in plasma concentrations of apoB, lipoprotein(a), non-HDL cholesterol, and triglycerides.
Conclusion: A single infusion of CSL112 in patients with stable atherothrombotic disease 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.
- © 2013 by American Heart Association, Inc.