Abstract 9907: A Single Infusion of MDCO-216 (ApoA-1 Milano/POPC) Induces Marked Changes on the Lipid Profile
Introduction: Human carriers of the apolipoprotein A-1 Milano variant have a reduced incidence of cardiovascular disease. Regression of atherosclerosis was observed in a prior Phase II intra-vascular ultrasound study. MDCO-216 (ApoA-1 Milano/POPC) manufactured by a more efficient process is being developed to reduce cardiovascular events in acute coronary syndrome patients. We report the results of a Phase I single ascending dose study.
Methods: After signing informed consent and meeting all eligibility criteria, 24 healthy volunteers and 24 patients with documented CAD received a 2-hour infusion of MDCO-216 in a randomised, placebo controlled, single ascending dose study. 5 cohorts of healthy volunteers and 4 cohorts of CAD patients received doses ranging from 5 - 40 mg/kg. Subjects were followed for 30 days and returned throughout the study for safety assessments.
Results: In both healthy volunteers and stable CAD patients, dose dependent increases in ApoA-1, phospholipid and prebeta-1 HDL and decreases in Apo E were observed. Prominent sustained increases in triglyceride and decreases in HDL-C occurred at doses above 20 mg/kg in healthy volunteers and patients with CAD. In both subject populations, profound increases in ABCA1 mediated cholesterol efflux were observed. Other lipid and lipoprotein parameters were generally unchanged with increases in HDL particle size and a shift to larger HDL particles. MDCO-216 was well tolerated with no serious adverse events and no other significant adverse safety findings including laboratory parameters, vital signs and ECGs. The most common adverse events were headache and fatigue. No dose dependent effect on any safety parameter was noted and there was no difference in safety parameters between healthy volunteers and patients with CAD.
Conclusions: A single infusion of MDCO-216 modulated lipid parameters, profoundly increased ABCA1 mediated cholesterol efflux and was well tolerated. These single dose data are consistent with the lipid profile of carriers of the Apo A-1 Milano variant and support further development of this agent as a disease-modifying treatment for reducing atherosclerotic disease and subsequent cardiovascular events.
Author Disclosures: D.G. Kallend: Employment; Significant; The Medicines Company. Ownership Interest; Significant; The Medicines Company. A. Bobillier: Employment; Significant; Employee of The Medicines Company. S. Belibas: Employment; Significant; Employee of The Medicines Company. H. Kempen: Employment; Significant; Employee of The Medicines Company. J. Burggraaf: Employment; Significant; Employee of CHDR. J. Reijers: Employment; Significant; Employee of CHDR. M. Moerland: Employment; Significant; Employee of CHDR. P.L. Wijngaard: Employment; Significant; Employee of The Medicines Company.
- © 2014 by American Heart Association, Inc.