학술논문
Recombinant human lecithin-cholesterol acyltransferase in patients with atherosclerosis: phase 2a primary results and phase 2b design
Document Type
Clinical report
Author
Source
European Heart Journal: Cardiovascular Pharmacotherapy. May 2022, Vol. 8 Issue 3, p243, 10 p.
Subject
Language
English
ISSN
2055-6837
Abstract
Introduction The essential role of atherogenic lipoproteins, particularly lowdensity lipoproteins (LDLs), in the pathogenesis of acute coronary syndromes (ACS) has led to the development of multiple therapeutic options, progressively lower [...]
Aims Reverse cholesterol transport (RCT) removes cholesterol and stabilizes vulnerable plaques. In addition, highdensity 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 x3 doses, or 300 mg IV-push, 150 mg at 48 h and 100mg at 7days). 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 treatmentemergent 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 120mg and 144% (95% CI 108-181, P 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. Keywords LCAT * Reverse cholesterol transport * Atherosclerosis * Lipids * HDL * Cholesterol ester * Plaque regression
Aims Reverse cholesterol transport (RCT) removes cholesterol and stabilizes vulnerable plaques. In addition, highdensity 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 x3 doses, or 300 mg IV-push, 150 mg at 48 h and 100mg at 7days). 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 treatmentemergent 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 120mg and 144% (95% CI 108-181, P 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. Keywords LCAT * Reverse cholesterol transport * Atherosclerosis * Lipids * HDL * Cholesterol ester * Plaque regression