Recombinant human Lecithin-Cholesterol acyltransferase in patients with atherosclerosis: Phase 2a primary results and phase 2b design.

BACKGROUND Reverse cholesterol transport (RCT) removes cholesterol and stabilizes vulnerable plaques. In addition, high-density lipoprotein (HDL) may be cardioprotective in acute MI. Lecithin-cholesterol acyltransferase (LCAT) may enhance RCT. The objective of this study was to investigate the pharmacokinetics, pharmacodynamics, and safety of multiple ascending doses of recombinant human LCAT (MEDI6012) to inform a Phase 2 b program. METHODS This was a randomized, blinded, placebo-controlled, dose-escalation Phase 2a study of MEDI6012. Patients were randomized into 1 of 4 cohorts (40, 120, 300 mg IV weekly x3 doses, or 300 mg IV-push, 150 mg at 48-hours and 100 mg at 7 days). All cohorts were planned to randomize 6:2 (MEDI6012 vs placebo). The primary endpoints were baseline-adjusted AUC from 0-96 hours post dose-3 (AUC0-96hr) for HDL-C, HDL cholesteryl ester (HDL-CE), and total cholesteryl ester (CE). The primary safety endpoints were treatment-emergent adverse events (AEs). RESULTS A total of 32 patients were randomized. MEDI6012 significantly increased AUC0-96hr for HDL-C, HDL-CE and CE in a graded fashion with increasing doses. Relative to placebo, MEDI6012 increased HDL-C at Day 19 by 66% (95%CI 33-99, p = 0.014) with 120 mg and 144% (95%CI 108-181, p < 0.001) with 300 mg. An IV-push increased HDL-C by 40.8% at 30 minutes. Overall AEs were similar between groups with no severe, life-threatening/fatal AEs or neutralizing antibodies. CONCLUSIONS Multiple ascending doses of MEDI6012 were safe and well tolerated and significantly increased HDL-C, HDL-CE and CE in a dose-related manner. These data support the ongoing Phase 2 b program investigating MEDI6012 in ST-elevation MI.