CSL112 (Apolipoprotein A-I (human)) Infusion Rapidly Increases ApoA-I Exchange Rate via Specific Serum Amyloid-Poor HDL Sub-Populations When Administered to Patients Post Myocardial Infarction

Background: Apolipoprotein A-I (apoA-I) exchange rate (AER) into plasma high density lipoprotein (HDL) may represent a cell-free measure of HDL function, and predict recurrent major adverse cardiovascular events post-acute myocardial infarction (AMI). Purpose: To characterise the effects of CSL112 (apoA-I (human)) on AER and the relationships with specific HDL subpopulations when administered in the 90-day high-risk period post AMI. Methods: Patients from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study received either placebo, 2g or 6g CSL112 post AMI. The rate of apoA-I exchange into HDL was measured in AEGIS-I plasma samples incubated with fluorescent apoA-I-NBD (7-nitrobenz-2-oxa-1,3-diazole) lipid-sensitive reporter for 30 min at 37°C. HDL particle size distribution was assessed by native gel electrophoresis followed by fluorescent imaging and detection of apoA-I and serum amyloid A (SAA1/SAA2) by western blotting. Results: CSL112 infusion increased AER peaking 2 h post infusion and returning to baseline by 24 h. AER was correlated with cholesterol efflux capacity, HDL-C, apoA-I and phosphatidylcholine (all p<0.001). CSL112 infusion induced transient changes in HDL particle size distribution. Small remodelled HDL (S-HDL rem ) derived from CSL112 were detected in plasma 2-4 h after infusion. Large remodeled HDL species (L-HDL rem ) accumulated 2-12 h post infusion. The apoA-1-NBD reporter was confined to distinct HDL subpopulations that contained little SAA. In plasma samples characterized by the baseline pattern of HDL particle size distribution (0 h and 24-48 h post infusion), the apoA-I-NBD reporter predominantly exchanged into the HDL3 subpopulation, but not into large HDL2. Conclusion: Infusion of CSL112 increased AER via exchange into SAA-poor HDL particles. AER may represent a clinically amenable biomarker of HDL functionality. Figure: HDL particle remodelling and AER in a representative subject infused with 6g CSL112 .