KineMed's Study of Merck's Ezetimibe (ZETIA) Invited to Join Best of AHA Specialty Conference Poster Session
EMERYVILLE, Calif.--(BUSINESS WIRE)--Aug 17, 2010 - The American Heart Association (AHA) has honored KineMed's abstract entitled “Ezetimibe Treatment Stimulates Transport of Plasma Cholesterol into Fecal Neutral Sterols in Hyperlipidemic Humans” with a position in the Best of AHA Specialty Conference Poster Session that will take place at the AHA Chicago meeting November 13-17, 2010. The study was performed in partnership with the University of California Berkeley, Radiant Research, Chicago Pritzker School of Medicine, and Merck/Schering Plough.
The study utilizing KineMed's proprietary stable isotope biomarker technology demonstrated that ezetimibe, which primarily blocks intestinal cholesterol absorption via NCP1L1, also increases reverse cholesterol transport (RCT) significantly in humans. The flow of cholesterol (C) from peripheral tissues into the bloodstream and out of the body as fecal sterols, or RCT, is the human body's major pathway for reducing cholesterol burden in tissues. Using a method for measuring key steps in the RCT pathway in vivo in humans, KineMed evaluated the effects of inhibition of NPC1L1-mediated cholesterol absorption with ezetimibe (10 mg/d) in a prospective, placebo-controlled double-blind cross-over trial in 27 hyperlipidemic patents. After 6 weeks of each ~7 week treatment period (ezetimibe or placebo), patients received 24 hour continuous IV infusions of [3,4-13C]-C followed by 7 days of outpatient stool collections. Three components of RCT were quantified, based on label incorporation curves into free C, C-ester (CE) and fecal sterols, with SAAM-II modeling: whole-body efflux rate of free C from tissues into blood; production and clearance rates of CE; and flux of plasma C into fecal sterols. Sterol mass excretion was quantified from stool samples using oral 2H4-sitostanol as internal standard. Ezetimibe significantly increased fecal neutral sterol output (50%) and increased the efficiency of plasma C excretion into fecal neutral sterols (113%) but not into fecal bile acids. Esterification rate of free C to CE (which equals CE clearance at steady-state) trended higher (7% increase, p=0.055). Fractional de novo synthesis of plasma C was increased by 57%, consistent with a response to negative sterol balance in tissues. Whole-body C efflux rate from tissues into plasma was unchanged by ezetimibe treatment, while calculated excretion of effluxed C into feces (a marker of global RCT flux) was significantly increased. Thus, ezetimibe stimulates the flow of endogenous (plasma) C into fecal neutral sterols, increases the production and clearance rate of CE and results in increased de novo synthesis of C. These effects on in vivo cholesterol fluxes are all consistent with increased rates of transport of tissue C through the plasma compartment and out of the body in response to ezetimibe in hyperlipidemic humans.
“These results add new and important information about the effects of ezetimibe on cholesterol biology in humans”, said Marc Hellerstein M.D., Ph.D., Chief of the Scientific Advisory Board at KineMed, Inc. and Professor (Calloway Chair), UC Berkeley and Professor of Medicine, UC San Francisco. “The flow of cholesterol in the body underlies the therapeutic mechanism of action of ezetimibe but had not previously been measurable in humans. The techniques used in this study provide a model for characterizing the actions of anti-atherogenic agents in man.” Michael H. Davidson, M.D., FACC, Founder and Executive Medical Director of Radiant Research and Clinical Professor and Director of Preventative Cardiology at the University Of Chicago Pritzker School of Medicine, commented, "This study emphasizes the important role of the intestines in RCT. The KineMed technology was able to demonstrate for the first time in humans that ezetimibe affects the removal of plasma cholesterol into the feces and supports the potential anti-atherosclerotic effect of this novel LDL-C lowering agent."
About KineMed, Inc.
KineMed, Inc. ("KineMed" or the "Company") is a drug discovery and development company employing its proprietary translational medicine technology (AquaTag™ and KineMarker™) to both identify active drug candidates preclinically and confirm their therapeutic activity and dose response in first-in-man studies. The Company is working to develop drugs both on its own and with pharmaceutical collaborators in therapeutic focus areas where it can demonstrate functional modulation of specific biological pathways that mediate disease.
KineMed's technology expedites the drug development process and provides real-time insight into conditions including metabolic disorders, cancer, fibrotic diseases, inflammation, and neurodegeneration.
For further information about KineMed, please visit: http://www.kinemed.com.
Contact: KineMed, Inc.
Lila Taylor, +1-510-655-6525 ext. 141
Director of Business Development
Scott Turner Ph.D., +1-510-655-6525 ext. 101
Vice President, Research Operations
Posted: August 2010