Recombinant human lecithin-cholesterol acyltransferase in patients with atherosclerosis: phase 2a primary results and phase 2b design. Issue 3 (25th January 2021)

• Record Type: Journal Article
• Authors: Bonaca, Marc P; George, Richard T; Morrow, David A; Bergmark, Brian A; Park, Jeong-Gun; Abuhatzira, Liron; Vavere, Andrea L; Karathanasis, Sotirios K; Jin, ChaoYu; She, Dewei; Hirshberg, Boaz; Hsia, Judy; Sabatine, Marc S
• Is Part Of: European heart journal. Volume 8:Issue 3(2022)
• Page Start: 243
• Page End: 252
• Publication Date: 2021-01-25
• Subjects: LCAT -- Reverse cholesterol transport -- Atherosclerosis -- Lipids -- HDL -- Cholesterol ester -- Plaque regression; Cardiovascular pharmacology -- Periodicals; 615.71
• DOI: 10.1093/ehjcvp/pvab001
• Languages: English
• ISSNs: 2055-6837

Abstract

Abstract: Aims: Reverse cholesterol transport (RCT) removes cholesterol and stabilizes vulnerable plaques. In addition, high-density lipoprotein (HDL) may be cardioprotective in acute myocardial infarction (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 2b programme. Methods and results: This was a randomized, blinded, placebo-controlled, dose-escalation Phase 2a study of MEDI6012. Patients were randomized into one of four cohorts (40, 120, 300 mg IV weekly ×3 doses, or 300 mg IV-push, 150 mg at 48 h and 100 mg at 7 days). All cohorts were planned to randomize 6:2 (MEDI6012 vs. placebo). The primary endpoints were baseline-adjusted area under the curve (AUC) from 0 to 96 h post dose 3 (AUC 0–96 h) for HDL-C, HDL cholesteryl ester (HDL-CE), and total cholesteryl ester (CE). The primary safety endpoints were treatment-emergent adverse events. A total of 32 patients were randomized. MEDI6012 significantly increased AUC 0–96 h 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 min. Overall adverse events were similar between groups with no severe, life-threatening/fatal adverse events, 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 2b programme investigating MEDI6012 in ST-elevation MI.