MEDI6012: Recombinant Human Lecithin Cholesterol Acyltransferase, High‐Density Lipoprotein, and Low‐Density Lipoprotein Receptor–Mediated Reverse Cholesterol Transport

Abstract

Background MEDI6012 is recombinant human lecithin cholesterol acyltransferase, the rate‐limiting enzyme in reverse cholesterol transport. Infusions of lecithin cholesterol acyltransferase have the potential to enhance reverse cholesterol transport and benefit patients with coronary heart disease. The purpose of this study was to test the safety, pharmacokinetic, and pharmacodynamic profile of MEDI6012. Methods and Results This phase 2a double‐blind study randomized 48 subjects with stable coronary heart disease on a statin to a single dose of MEDI6012 or placebo (6:2) (NCT02601560) with ascending doses administered intravenously (24, 80, 240, and 800 mg) and subcutaneously (80 and 600 mg). MEDI6012 demonstrated rates of treatment‐emergent adverse events that were similar to those of placebo. Dose‐dependent increases in high‐density lipoprotein cholesterol were observed with area under the concentration‐time curves from 0 to 96 hours of 728, 1640, 3035, and 5318 should be: mg·h/mL in the intravenous dose groups and 422 and 2845 mg·h/mL in the subcutaneous dose groups. Peak mean high‐density lipoprotein cholesterol percent change was 31.4%, 71.4%, 125%, and 177.8% in the intravenous dose groups and 18.3% and 111.2% in the subcutaneous dose groups, and was accompanied by increases in endogenous apoA1 (apolipoprotein A1) and non‐ATP‐binding cassette transporter A1 cholesterol efflux capacity. Decreases in apoB (apolipoprotein B) were observed across all dose levels and decreases in atherogenic small low‐density lipoprotein particles by 41%, 88%, and 79% at the 80‐, 240‐, and 800‐mg IV doses, respectively. Conclusions MEDI6012 demonstrated an acceptable safety profile and increased high‐density lipoprotein cholesterol, endogenous apoA1, and non‐ATP‐binding cassette transporter A1 cholesterol efflux capacity while reducing the number of atherogenic low‐density lipoprotein particles. These findings are supportive of enhanced reverse cholesterol transport and a functional high‐density lipoprotein phenotype. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02601560.

Influence of lecithin cholesterol acyltransferase alteration during different pathophysiologic conditions: A 45 years bibliometrics analysis

“…In the clinical trial, it was proved that ACP-501 infusion rapidly decreased small- and intermediate-sized HDL, whereas large HDL increased and it was thought well in terms of safety and tolerability in their test results ( Shamburek et al, 2016 ). Besides, another more active rhLCAT ( George et al, 2021 ), MEDI6012, was reported not only reverses HDL dysfunction in ACS patients caused by LCAT concentration/activity but also results in greater HDL function in a 2019 clinical trial ( Ossoli et al, 2019 ). Certainly, intense effort has been focused on developing ways to make a durable and stable plasma LCAT concentrations.…”

Identification of potential M2 macrophage-associated diagnostic biomarkers in coronary artery disease

“…Moreover, among the mainly enriched 13 cellular components, some of them were involved in cellular material transport (transmembrane transporter complex, transporter complex). The transport of substances by macrophages is also critical in the development of inflammation [ 27–29 ]. For example, members of the ABC transporter superfamily, ABCA1 and ABCG1, facilitate cholesterol efflux from foam cells to the extracellular cholesterol receptors Apolipoprotein AI (ApoA-I) and high density lipoprotein (HDL), respectively, restricting foam cell development and slowing the progression of atherosclerosis [ 30 , 31 ].…”

Alterations of HDL’s to piHDL’s Proteome in Patients with Chronic Inflammatory Diseases, and HDL-Targeted Therapies

“…Given that, administration of recombinant LCAT may lead to increased cholesterol esterification and enhanced RCT. Although some animal studies suggest that the overexpression of LCAT does not result in enhanced RCT [ 239 , 515 ], in clinical trials in patients with CHD, administration of the recombinant LCAT (ACP-501, another name MEDI6012) increased HDLc, favourably altered HDL metabolism, increased the apoA-I levels, CEC and raised the number of large HDL particles whilst small and intermediate-size HDL particles along with proatherogenic LDL particles decreased [ 516 , 517 ]. Many small-molecule LCAT activators , such as DS-8190a, have been successfully tested for the reduction in atherosclerotic lesions in animal models [ 518 ].…”