title: 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: Apolipoprotein 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).
  
  
  
  Twenty-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.
  
  
  
  MDCO-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.
authors.affiliation: The Medicines Company (Schweiz) GmbH , Zürich , Switzerland.
authors.forename: D G
authors.initials: DG
authors.lastname: Kallend
authors.affiliation: Centre for Human Drug Research , Leiden , The Netherlands.
authors.forename: J A A
authors.initials: JA
authors.lastname: Reijers
authors.affiliation: The Medicines Company , Parsippany, NJ , USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Bellibas
authors.affiliation: The Medicines Company (Schweiz) GmbH , Zürich , Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Bobillier
authors.affiliation: The Medicines Company (Schweiz) GmbH , Zürich , Switzerland.
authors.forename: H
authors.initials: H
authors.lastname: Kempen
authors.affiliation: Centre for Human Drug Research , Leiden , The Netherlands.
authors.forename: J
authors.initials: J
authors.lastname: Burggraaf
authors.affiliation: Centre for Human Drug Research , Leiden , The Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Moerland
authors.affiliation: The Medicines Company (Schweiz) GmbH , Zürich , Switzerland.
authors.forename: P L J
authors.initials: PL
authors.lastname: Wijngaard
mesh_terms: D064286:ATP Binding Cassette Transporter 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D016632:Apolipoprotein A-I / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D001057:Apolipoproteins E / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000378:metabolism; D004338:Drug Combinations; D005260:Female; D064368:Healthy Volunteers; D053442:High-Density Lipoproteins, Pre-beta / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D010713:Phosphatidylcholines / Q000008:administration & dosage / Q000494:pharmacology*; D010743:Phospholipids / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D016632:Apolipoprotein A-I; D001057:Apolipoproteins E; D004338:Drug Combinations; D053442:High-Density Lipoproteins, Pre-beta; C000609591:MDCO-216; D010713:Phosphatidylcholines; D010743:Phospholipids; D014280:Triglycerides; D002784:Cholesterol
keywords: Atherosclerosis; Cholesterol efflux; Coronary disease; Lipids; Lipoproteins