CSL112 (Apolipoprotein A-I [Human]) Strongly Enhances Plasma Apoa-I and Cholesterol Efflux Capacity in Post-Acute Myocardial Infarction Patients: A PK/PD Substudy of the AEGIS-I Trial. (25th October 2022)

• Record Type: Journal Article
• Authors: Gibson, C. Michael; Kazmi, Syed Hassan A.; Korjian, Serge; Chi, Gerald; Phillips, Adam T.; Montazerin, Sahar Memar; Duffy, Danielle; Zheng, Bo; Heise, Mark; Liss, Charles; Deckelbaum, Lawrence I.; Wright, Samuel D.; Gille, Andreas
• Is Part Of: Journal of cardiovascular pharmacology and therapeutics. Volume 27(2022)
• Publication Date: 2022-10-25
• Subjects: cholesterol -- HDL -- CSL112 -- infusible therapy -- acute myocardial infarction -- cholesterol efflux; Cardiovascular pharmacology -- Periodicals; Cardiovascular system -- Diseases -- Treatment -- Periodicals; 616
• DOI: 10.1177/10742484221121507
• Languages: English
• ISSNs: 1074-2484

Abstract

Introduction: Cholesterol efflux capacity (CEC) is impaired following acute myocardial infarction (AMI). CSL112 is an intravenous preparation of human plasma-derived apoA-I formulated with phosphatidylcholine (PC). CSL112 is intended to improve CEC and thereby prevent early recurrent cardiovascular events following AMI. AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) was a multicenter, randomized, double-blind, placebo-controlled, dose-ranging phase 2b study, designed to evaluate the hepatic and renal safety of CSL112. Here, we report an analysis of a pharmacokinetic (PK) and pharmacodynamic (PD) substudy of AEGIS-I. Methods: AMI patients were stratified by renal function and randomized 3:3:2 to 4, weekly, 2-hour infusions of low- and high-dose (2 g and 6 g) CSL112, or placebo. PK/PD assessments included plasma concentrations of apoA-I and PC, and measures of total and ABCA1-dependent CEC, as well as lipids/lipoproteins including high density lipoprotein cholesterol (HDL-C), non-HDL-C, low density lipoprotein cholesterol (LDL-C), ApoB, and triglycerides. Inflammatory and cardio-metabolic biomarkers were also evaluated. Results: The substudy included 63 subjects from AEGIS-I. CSL112 infusions resulted in rapid, dose-dependent increases in baseline corrected apoA-I and PC, which peaked at the end of the infusion (Tmax ≈ 2 hours). Similarly, there was a dose-dependent elevation in both total CEC and ABCA1-mediated CEC. Mild renal impairment did not affect the PK or PD of CSL112. CSL112 administration was also associated with an increase in plasma levels of HDL-C but not non-HDL-C, LDL-C, apoB, or triglycerides. No dose-effects on inflammatory or cardio-metabolic biomarkers were observed. Conclusion: Among patients with AMI, impaired CEC was rapidly elevated by CSL112 infusions in a dose-dependent fashion, along with an increase in apoA-I plasma concentrations. Findings from the current sub-study of the AEGIS-I support a potential atheroprotective benefit of CSL112 for AMI patients.