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

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 (<0.0001) despite slightly higher apoA-I levels when compared with healthy individuals (2 phase 1 studies pooled; ≤0.05), suggesting impaired HDL function. However, no differences were observed in apoA-I pharmacokinetics or in pre-β1-HDL (=0.5) or CEC (=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; =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.

© 2018 The Authors.