Abstract 15426: CSL112 Enhances Cholesterol Efflux Equally in Patients with High and Low High Density Lipoprotein Functionality
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 in healthy subjects and one phase 2a study in coronary heart disease (CHD) patients have demonstrated favorable safety, pharmacokinetics and biomarker responses to single or multiple infusions of CSL112. The aim of the current study was to assess the influence of subject-specific HDL functionality, sometimes described as HDL dysfunction, on the pharmacodynamic effects of CSL112.
Methods and Results: To assess HDL functionality, we measured the specific cholesterol efflux activity of apoA-I (cholesterol efflux divided by apoA-I) in subjects at baseline. CHD patients (mean ± SD = 7.3 ± 0.3 %efflux per g/L apoA-I (n=43)) had lower activity (p<0.001) than healthy subjects (mean ± SD = 8.8 ± 0.2 % efflux per g/L apoA-I (n=93)), consistent with prior work showing impaired HDL function in CHD patients. Every subject infused with CSL112 responded, showing increased apoA-I plasma levels and serum cholesterol efflux. To assess changes in HDL functionality upon infusion of CSL112, we plotted changes in cholesterol efflux vs changes in apoA-I. To account for variations of these analytes over time and dose, we plotted area under curve (AUC) for 0 to 24 h after infusion of various doses of CSL112. In all three studies, AUC for apoA-I correlated with the AUC for cholesterol efflux, with coincident lines, indicating equal elevation in efflux among healthy and CHD patients. To further examine this relationship, subjects were stratified into tertiles based on specific activity. Infusion of CSL112 elevated efflux similarly in subjects in the highest HDL functionality and lowest HDL functionality tertiles.
Conclusion: ApoA-I from CHD patients compared to healthy subjects had lower specific activity in regards to cholesterol efflux. CSL112 causes strong elevation in cholesterol efflux regardless of HDL function and represents a promising candidate to rapidly remove plaque cholesterol and reduce recurrent atherothrombotic events.
Author Disclosures: A. Gille: Employment; Significant; CSL Limited. Ownership Interest; Significant; CSL Limited. G. Hartel: Employment; Significant; CSL Limited. D. D’Andrea: Employment; Significant; CSL Behring. Ownership Interest; Modest; CSL Behring. S.D. Wright: Employment; Significant; CSL Behring. Ownership Interest; Significant; CSL Behring.
- © 2014 by American Heart Association, Inc.