CSL112 (human apolipoprotein A-I) infusion rapidly increases apoA-I exchange rate (AER) when administered to patients post myocardial infarction

Abstract Background Cholesterol efflux capacity (CEC) measured using patient serum and cultured macrophages is considered a biomarker of high-density lipoprotein (HDL) functionality. This parameter is inversely related to incident cardiovascular events and declines in the days post-acute myocardial infarction (AMI). The apolipoprotein A-I (apoA-I) exchange rate (AER) may represent an alternative, clinically amenable cell-free measure of CEC, which has also been associated with incident cardiovascular events (1). Purpose To characterise the effects of human apoA-I (CSL112) infusion on AER over 48 hours when administered post AMI. Methods This analysis included 50 patients with available samples from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) randomized, double-blind, placebo-controlled, phase 2b pharmacokinetic/pharmacodynamic sub-study (2). Patients were randomized to receive four weekly infusions of either placebo (n=16), 2g (n=19) or 6g (n=15) CSL112 post AMI. Blood samples were drawn at baseline and at 2, 4, 6, 12, 24 and 48 hours post the first and fourth infusion for measurement of AER (1) as well as CEC (total, ABCA1 dependent and ABCA1 independent CEC) as previously described (3). Results CSL112 infusion increased AER dose-dependently, peaking at 2h (end of infusion) and returning to baseline by 24h post infusion (Figure 1). AER was significantly correlated with CEC (total, ABCA1 dependent and independent), HDL-cholesterol, apoA-I and phosphatidylcholine across all timepoints and similarly after both infusions (Table 1). Conclusion Infusion of CSL112 increased AER in a dose-dependent manner post AMI and may represent a clinically amenable biomarker of HDL functionality. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): CSL Ltd, Parkville, Australia Figure 1. Left: Time course data expressed as mean ± SEM and adjusted for baseline prior to each infusion. Using a linear mixed model for repeated measures, the 6g dose increased AER from baseline at timepoints from 2–12 hours (p<0.001), whereas the 2gm dose only increased AER between 2–6 hours (p<0.05). Right: Boxplots showing median, quartiles and min/max of Area Under the Curve (AUC) from 0–24 hours post infusion. Using one-way ANOVA the 6 g dose was significantly higher than placebo (p<0.05).Table 1