CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients. Issue 4 (April 2018)

• Record Type: Journal Article
• Authors: Gille, Andreas; D'Andrea, Denise; Tortorici, Michael A.; Hartel, Gunter; Wright, Samuel D.
• Is Part Of: Arteriosclerosis, thrombosis, and vascular biology. Volume 38:Issue 4(2018)
• Publication Date: 2018-04
• Subjects: apolipoproteins -- atherosclerosis -- clinical trial -- coronary disease -- high density lipoprotein-1; Arteriosclerosis -- Periodicals; Thrombosis -- Periodicals; Blood-vessels -- Pathophysiology -- Periodicals; Electronic journals; 616.13
• DOI: 10.1161/ATVBAHA.118.310538
• Languages: English
• ISSNs: 1079-5642

Abstract

Abstract : Objective—: CSL112 (apolipoprotein A-I [apoA-I; human]) is a novel formulation of apoA-I in development for reduction of early recurrent cardiovascular events after acute myocardial infarction. Cholesterol efflux capacity (CEC) is a marker of high-density lipoprotein (HDL) function that is strongly correlated with incident cardiovascular disease. Impaired CEC has been observed in patients with coronary heart disease. Here, we determined whether infused apoA-I improves CEC when administered to patients with stable atherosclerotic disease versus healthy volunteers. Approach and Results—: Measurements of apoA-I, HDL unesterified cholesterol, HDL esterified cholesterol, pre–β1-HDL, and CEC were determined in samples from patients with stable atherosclerotic disease before and after intravenous administration of CSL112. These measures were compared with 2 prior studies in healthy volunteers for differences in CEC at baseline and after CSL112 infusion. Patients with stable atherosclerotic disease exhibited significantly lower ATP-binding cassette transporter 1–mediated CEC at baseline ( P <0.0001) despite slightly higher apoA-I levels when compared with healthy individuals (2 phase 1 studies pooled; P ⩽0.05), suggesting impaired HDL function. However, no differences were observed in apoA-I pharmacokinetics or in pre–β1-HDL ( P =0.5) or CEC ( P =0.1) after infusion of CSL112. Similar elevation in CEC was observed in patients with low or high baseline HDL function (based on tertiles of apoA-I–normalized CEC; P =0.1242). These observations were extended and confirmed using cholesterol esterification as an additional measure. Conclusions—: CSL112 shows comparable, strong, and immediate effects on CEC despite underlying cardiovascular disease. CSL112 is, therefore, a promising novel therapy for lowering the burden of atherosclerosis and reducing the risk of recurrent cardiovascular events. Abstract : Supplemental Digital Content is available in the text.