A single infusion of MDCO-216 (ApoA-1 Milano/POPC) increases ABCA1-mediated cholesterol efflux and pre-beta 1 HDL in healthy volunteers and patients with stable coronary artery disease

Abstract

AimsApolipoprotein A-1 (ApoA-1), based on epidemiology, is inversely associated with cardiovascular (CV) events. Human carriers of the ApoA-1 Milano variant have a reduced incidence of CV disease. Regression of atherosclerotic plaque burden was previously observed on intravascular ultrasound (IVUS) with ETC-216, a predecessor of MDCO-216. MDCO-216, a complex of dimeric ApoA-1 Milano and 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, is being developed to reduce atherosclerotic plaque burden and CV events. We investigated the efficacy and safety of a single infusion of MDCO-216 in healthy volunteers and in patients with coronary artery disease (CAD).Methods and resultsTwenty-four healthy volunteers and 24 patients with documented CAD received a 2-h infusion of MDCO-216 in a randomized, placebo controlled, single ascending dose study. Five cohorts of healthy volunteers and four cohorts of CAD patients received ApoA-1 Milano doses ranging from 5 to 40 mg/kg. Subjects were followed for 30 days. Dose-dependent increases in ApoA-1, phospholipid, and pre-beta 1 HDL and decreases in ApoE were observed. Prominent and sustained increases in triglyceride, and decreases in HDL-C, endogenous ApoA-1 and ApoA-II occurred at doses >20 mg/kg and profound increases in ABCA1-mediated cholesterol efflux were observed. Other lipid and lipoprotein parameters were generally unchanged. MDCO-216 was well tolerated.ConclusionsMDCO-216-modulated lipid parameters profoundly increased ABCA1-mediated cholesterol efflux and was well tolerated. These single-dose data support further development of this agent for reducing atherosclerotic disease and subsequent CV events.

Persistent changes in lipoprotein lipids after a single infusion of ascending doses of MDCO-216 (apoA-IMilano/POPC) in healthy volunteers and stable coronary artery disease patients

“…Somewhat surprisingly we found only minimal changes in total plasma cholesterol (10). Other groups infusing other rec-HDL products in humans have described strong increases in plasma cholesterol after infusion of CER-001 (11) or CSL-112 (12), initially in the form of a rise in FC in HDL.…”

“…We recently reported time-and dose-dependent changes in plasma lipids, apolipoproteins and serum cholesterol efflux capacities (10). Somewhat surprisingly we found only minimal changes in total plasma cholesterol (10).…”

“…Since this correlation was not very strong we explored whether the increase in FC could also be related to the changes in cholesterol efflux capacities described in our previous paper (10). We found that delta FC at 8 h correlated strongly and positively with the increase of basal (Fig.…”

“…The study design and protocol were described in detail before (10). Briefly, the study protocol was developed by the Sponsor, The Medicines Company, and organized and executed by the Centre for Human Drug Research (CHDR) in Leiden, Netherlands, in compliance with the Declaration of Helsinki.…”

“…Changes in plasma levels of apoA-I (total and apoA-IMilano), apoB and apoE were reported before (10,16). The distribution of apoA-I, apoA-I Milano and apoE over lipoproteins was determined by Western blotting after FPLC separation.…”