Abstract 13324: Single Ascending Dose Pharmacokinetics and Pharmacodynamics of MDCO-216 (ApoA-I Milano/POPC) in Healthy Volunteers

• Published in: Circulation (New York, N.Y.) N.Y.), 2014-11, Vol.130 (suppl_2)
• Main Authors: Bellibas, S. Eralp, Kallend, David, Bobillier, Alain, Kempen, Herman, Wijngaard, Peter L
• Format: Article
• Language: English
• ISSN: 0009-7322; 1524-4539
• DOI: 10.1161/circ.130.suppl_2.13324

Abstract only Introduction: MDCO-216, a complex of dimeric recombinant apolipoprotein A-I Milano (apoA-I M) and a phospholipid (POPC), is currently under development to improve cardiovascular outcomes by reducing plaque burden in patients with atherosclerotic disease. An earlier version of MDCO-216 has been shown to reduce atherosclerotic plaque burden in animal models and in patients with ACS. The purpose of this study was to assess the pharmacokinetics (PK), pharmacodynamics (PD), safety and tolerability of newly manufactured MDCO-216 first time in healthy volunteers. Methods: 24 healthy volunteers received a single dose of MDCO-216 (5, 10, 20, 30 or 40 mg/kg) or placebo (in 2:1 ratio) as a 2 hour IV infusion in a double-blind, randomised design. Serial blood samples were collected for PK and anti-drug Ab (ADA) analysis. An ex-vivo cholesterol efflux assay was used as one of several exploratory PD biomarkers for MDCO-216 activity. Results: No ADA was detected with any dose at any time point. Plasma mean T 1/2 of MDCO-216 ranged from 48 to 61 hours (56 hr. in average) and median T max ranged between 2 to 4 hours. No obvious difference in CL was observed with increases in dose and ranged from 0.62 to 0.98 mL/hr/kg. Exposure parameters increased with dose in a slightly less than dose-proportional manner with a range of 138 to 794 μg/mL for C max and 3391 to 20788 μg.hr/mL for AUC 0-48 . Dose-dependent increases in ABCA1-mediated efflux capacity of up to 4-fold above baseline and smaller increases of SRB1-mediated efflux capacity occurred rapidly after infusion at all doses. The dose-response analysis for ABCA1-mediated efflux best fitted into a sigmoid E max (maximum effect) PD model and predicts an E max of 15.6% which saturates around a 30 mg/kg dose of MDCO-216. Conclusions: This data demonstrate that MDCO-216 can profoundly stimulate the first step of reverse cholesterol transport at clinically achievable doses with a predictable PK/PD profile.