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.

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.

• Authors: C Michael Gibson, Syed Hassan A Kazmi, Serge Korjian, Gerald Chi, Adam T Phillips, Sahar Memar Montazerin, Danielle Duffy, Bo Zheng, Mark Heise, Charles Liss, Lawrence I Deckelbaum, Samuel D Wright, Andreas Gille
• Journal: Journal of cardiovascular pharmacology and therapeutics (J Cardiovasc Pharmacol Ther) 2022 Jan-Dec Vol. 27 Pg. 10742484221121507 ISSN: 1940-4034 [Electronic] United States
• PMID: 36282079 (Publication Type: Clinical Trial, Phase II, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Apolipoprotein A-I
• Apolipoproteins B
• Biomarkers
• Cholesterol
• Cholesterol, HDL
• Cholesterol, LDL
• CSL112
• Phosphatidylcholines
• Triglycerides

Topics

• Humans
• Apolipoprotein A-I (adverse effects)
• Apolipoproteins B (therapeutic use)
• Biomarkers
• Cholesterol
• Cholesterol, HDL
• Cholesterol, LDL
• Myocardial Infarction (drug therapy)
• Phosphatidylcholines (therapeutic use)
• Triglycerides