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.

Keywords: atherosclerosis; cholesterol efflux capacity; cholesterol homeostasis; cholesterol reverse cholesterol transport; high‐density lipoprotein cholesterol.

Conflict of interest statement

Dr George is an employee of AstraZeneca. Dr George, Dr Karathanasis, Dr She, Dr Buss, C. Jin, and Dr Hirshberg have stock ownership and/or stock options in AstraZeneca. Dr Abuhatzira and Dr Stoughton had stock ownership/options in AstraZeneca at the time the research was performed. Drs She and Abuhatzira are current employees of Viela Bio. Dr Karathanasis is an employee of NeoProgen and is a volunteer for the National Heart, Lung, and Blood Institute, National Institutes of Health. Dr Buss is an employee of REGENXBIO Inc. Dr Stoughton is an employee of C4 Medical Writing, LLC. C. Jin is an employee of Gilead Sciences. R. Bakker‐Arkema was a paid consultant for MedImmune (AstraZeneca) at the time the research was performed and is currently at BIA Clinical Group. Dr Koren received research funding from AstraZeneca to enroll subjects whose data are reported in this article.

Figures

Figure 1. Study flow diagram and additional design details.

pbo indicates placebo; PD, pharmacodynamics; and PK, pharmacokinetics.

Figure 2. Change from baseline (milligrams per deciliter) in serum concentration over time for HDL‐C (A), HDL‐CE (B), CE (C), ApoA1 (D), LDL‐C (E), and ApoB (F).

Mean baseline levels are listed in the following order: placebo intravenous, MEDI6012 intravenous group, placebo subcutaneous, MEDI6012 SC group, respectively. HDL‐C: 35, 34.7, 33.8, and 39.1 mg/dL; HDL‐CE: 28.9, 29, 28.8, and 33 mg/dL; CE: 108.3, 103.3, 114, and 110.4 mg/dL; apoA1: 127.0, 121.3, 116.3, and 129.5 mg/dL. LDL‐C: 82.7, 78, 80.5, and 78.2 mg/dL; apoB: 79.1, 74.1, 80.8, and 74.4 mg/dL. Error bars show standard error of the mean. ApoA1 indicates apolipoprotein A1; ApoB, apolipoprotein B; CE, cholesteryl ester; HDL‐C, high‐density lipoprotein cholesterol; HDL‐CE, high‐density lipoprotein cholesteryl ester; and LDL‐C, low‐density lipoprotein cholesterol.

Figure 3. Box and whisker plots for area under the curve (AUC) from 0 to 96 hours (milligrams per hour per deciliter) for high‐density lipoprotein cholesterol (HDL‐C) (A), high‐density lipoprotein cholesteryl ester (HDL‐CE) (B), cholesteryl ester (C), apolipoprotein A1 (D), low‐density lipoprotein cholesterol (LDL‐C) (E), and apolipoprotein B (F).

Results for other lipid measurements can be found in Table S2. Error bars show standard error of the mean. P‐IV indicates placebo (intravenous); and P‐SC, placebo (subcutaneous).

Figure 4. Change from baseline in small low‐density lipoprotein (LDL) particle concentration overall (A) and apolipoprotein B (ApoB) area under the curve from 0 to 96 hours (AUC0–96h) (B) according to statin intensity.

Statin intensity was classified according to the American College of Cardiology/American Heart Association guidelines on treatment of blood cholesterol.P values were calculated using the Mann‐Whitney nonparametric 2‐tailed t test.

Figure 5. Change from baseline in pre–beta‐1 high‐density lipoprotein (preB1‐HDL) (A), ATP‐binding cassette A1 (ABCA1) (B), Global (C), and non‐ABCA1 (D) cholesterol efflux capacity (CEC).

Figure 6. Effect of MEDI6012 on biomarkers of reverse cholesterol transport.

αHDL indicates alpha high‐density lipoprotein; ABCA1, ATP‐binding cassette A1; ABCG1, ATP‐binding cassette transporter G1; ApoA1, indicates apolipoprotein A1; ApoB, apolipoprotein B; CE, cholesteryl ester; CETP, cholesteryl ester transfer protein; FC, free cholesterol; HDL, high‐density lipoprotein; HDL‐C, high‐density lipoprotein cholesterol; HDL‐CE, high‐density lipoprotein cholesteryl ester; LCAT, lecithin cholesterol acyltransferase; LDL, low‐density lipoprotein; LDL‐C, low‐density lipoprotein cholesterol; LDLR, low‐density lipoprotein receptor; pre‐β‐HDL, pre‐beta high‐density lipoprotein; SRB1, Scavenger Receptor Class B type 1; TG, triglyceride; and VLDL, very low‐density lipoprotein.