†A Cross-Study Comparison Investigating the Effect of CSL112 (Apolipoprotein A-I [Human]) on Cholesterol Efflux Capacity (Encore ACC 2022)

Abstract

Lead Author's Financial Disclosures Nothing to disclose. Study Funding CSL Behring, LLC. Background/Synopsis Following an acute myocardial infarction (AMI), patients are at high risk of secondary major adverse cardiovascular events (MACE) that are associated with increased morbidity and mortality. Cholesterol efflux capacity (CEC), a key marker of high- density lipoprotein (HDL) function, is inversely correlated with the incidence of MACE. CSL112 (human-derived apolipoprotein A-I [apoA-I]) is a novel agent in Phase III development, aimed to reduce the risk of MACE following AMI. In Phase I and II clinical trials, CSL112 has demonstrated significant increases in CEC; these studies were conducted across different patient populations, including healthy individuals of different ethnicities known to have variations in lipid metabolism, and have shown CSL112 is well tolerated with a favorable safety profile. Objective/Purpose This cross-study analysis aims to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of CSL112 across prior clinical studies, to assess the impact of ethnicity and disease status on apoA-I exposure and CEC. Methods Data from five CSL112 clinical trials were combined: single and multiple ascending dose Phase I studies in healthy volunteers (N=57 and N=36, respectively), a Phase I Japanese ethno-bridging study (N=52), a Phase IIa study in subjects with stable atherosclerotic disease (N=45), and a Phase IIb study in post-AMI subjects AEGIS-I (N=1267). Dose-normalized and baseline corrected PK parameters and CEC responses were compared between the subpopulations. Results Comparison of PK parameters confirmed that the dose-normalized exposures (measured by the maximum concentration [Cmax] and area under the curve [AUC]) of apoA-I were similar across healthy Caucasian and Japanese subjects, subjects with stable atherosclerosis, and subjects post-AMI. PD parameters were also comparable; dose-normalized baseline-corrected CEC were comparable between Japanese, Caucasian, and post-AMI subjects. In addition, following intravenous infusions of 6 g CSL112, similar fold elevations of apoA-I in Japanese, Caucasian and post-AMI subjects (median 2.08, 2.33, 2.08-fold increase, respectively) and total CEC (median of 2.74, 2.92 and 2.55 fold, respectively) were observed. Conclusions CSL112 induces comparable, immediate and robust increases in key biomarkers across different subpopulations. The comparable distribution range and patterns of CSL112 PK/PD parameters between the subpopulations suggests that disease status or ethnicity do not confer any clinically relevant differences on apoA-I exposure and CEC following CSL112 infusion. These results support the use of a fixed 6g dose in the ongoing global Phase III trial (AEGIS-II), investigating the impact of CSL112 on cardiovascular event risk reduction post- myocardial infarction. Nothing to disclose.