Physicians' Academy for Cardiovascular Education

Investigational drug has remodeling effect on HDL particles and induces cholesterol efflux

May 22, 2015 - news

New Data Showing Remodeling Effect of MDCO-216 on HDL Particles in Coronary Artery Disease Patients

Presented by: Herman Kempen (Zurich, Switzerland), S. Eralp Bellibas (Parsippa, USA), David Kallend (Zurich, Switzerland)

At ISA, results of a phase 1 study for MDCO-216 were presented that showed that this novel drug had a significant remodeling effect on HDL particles, which correlated with increased ABCA1-mediated cholesterol efflux. This mechanism of HDL remodeling and increased cholesterol efflux may drive the removal of deposited cholesterol from vessel walls to reduce plaque burden in patients with atherosclerotic disease.  
 
MDCO-216 is a complex of dimeric recombinant apolipoprotein A-1 Milano (ApoA-1 Milano) and a phospholipid (POPC) which was developed in an attempt to mimic pre-beta HDL and induce cholesterol efflux, the first step in reverse cholesterol transport, causing removal of cholesterol from the artery walls.     
 
A single infusion of MDCO-216 was shown to produce a rapid increase in ABCA1 mediated efflux, a potential marker of reverse cholesterol transport, and a marked increase in pre-beta 1 HDL. This was followed by and correlated with a decrease in smaller HDL particles and an increase in larger HDL particles which suggests significant and rapid HDL remodeling. This data provides a hypothesis for the mechanism by which MDCO-216 as a single infusion may increase the physiological process of reverse cholesterol transport and potentially reduce atherosclerotic plaque burden.    
 
“This new data suggests that MDCO-216 may have a profound impact on the body’s ability to remove cholesterol from arterial walls,” said Clive Meanwell, MD, PhD, Chairman and CEO, The Medicines Company. “We continue to be excited about the potential of MDCO-216 to rapidly reverse atherosclerotic plaque buildup. Together with our first-in-class PCSK9 inhibitor, ALN-PCSsc, we look forward to advancing these important compounds through clinical development.”
 
In other presentations at ISA 2015 of the Phase 1 data for MDCO-216, investigators compared the pharmacokinetics and pharmacodynamics of MDCO-216 in healthy volunteers (HV’s) and CAD patients. MDCO-216 was found to profoundly stimulate the first step of reverse cholesterol transport at clinically achievable and well tolerated doses with similar PK profiles in both HV’s and coronary artery disease (CAD) patients, but with higher potency in terms of ABCA1 efflux in CAD patients. 
 
In a separate presentation, investigators assessed the safety of newly manufactured MDCO-216 in HV’s and CAD patients. MDCO-216 was shown to be well tolerated with no serious events and no significant adverse safety findings. The most common adverse events were headache and fatigue. No dose dependent effect on any safety parameter was noted, including inflammatory markers, and there were no differences in safety parameters between HV’s and CAD patients.  
 

Source:

ISA2015 Clinical Breakthroughs press release