Abstract 18589: Safety and Tolerability of CSL112 in Subjects With Stable Atherothrombotic Disease: Results From a Phase 2a, Multicenter, Randomized, Double-Blind, Placebo-Controlled, Ascending-Dose Study

Purpose: CSL112 is a novel formulation of apoA-I purified from human plasma and reconstituted to form HDL particles. Based on the ability of infused apoA-I to rapidly remove cholesterol from atherosclerotic plaque, CSL112 is being developed to reduce CV events following ACS. This phase 2a trial assessed the safety profile and pharmacokinetics (PK)/pharmacodynamics (PD) of CSL112 after a single IV infusion and is the first study of CSL112 in pts with stable atherothrombotic disease. Methods: 45 subjects were randomized to either CSL112 (1.7, 3.4, 6.8 g) or matching placebo in a 3:1 ratio. The primary safety profile was assessed by the frequency of elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3x ULN) and study-drug-related adverse events (AEs). PK/PD assessments included apoA-I plasma concentration and serum cholesterol efflux capacity. Results: Of the 45 subjects randomized, 33 received CSL112 and 11 received placebo; 1 patient (6.8 g group) did not receive study drug and was excluded from the safety analyses. Elevations (>3x ULN) in AST or ALT were not observed in any treatment group. AEs occurring within 72 h of infusion or considered drug-related by investigators were nonserious and mild except for one case of atrial fibrillation in the placebo group. AEs were reported in 5 of 7 (71.4%), 5 of 12 (41.7%), and 6 of 14 (42.9%) subjects in the CSL112 1.7, 3.4, and 6.8 g groups, respectively, compared with 3 of 11 (27.3%) subjects in the placebo group. The numeric imbalance in AEs for CSL112 groups was attributable to vessel puncture site/infusion site bruising and headache. Evaluations of mean levels and absolute change of serum creatinine over time were similar across CSL112 and placebo groups. Robust and immediate dose-related increases in baseline-corrected apoA-I AUC and Cmax were observed, resulting in similar dose-related increases in baseline-corrected total cholesterol efflux capacity. Conclusion: CSL112 was well tolerated and did not adversely impact hepatic or renal function in subjects with stable atherothrombotic disease. CSL112 represents a novel investigational approach to raise apoA-I levels and to reduce cholesterol content in atherosclerotic plaque. Additional clinical studies of CSL112 are warranted.