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AASLD-FDA-NIH-PhRMA Hepatotoxicity Steering Group Meeting, 2006 Presentations: The Liver Toxicity Biomarkers Study CRADA

Robert N. McBurney, PhD
Senior Vice President, Research & Development and Chief Scientific Office, BG Medicine, Inc.
The Liver Toxicity Biomarkers Study CRADA [PDF]

The overall goal of the Liver Toxicity Biomarkers Study (LTBS) is to achieve a scientific understanding of the mechanisms of liver toxicity and to create new tools, such as molecular biomarkers, that can be used in pre-clinical and clinical studies to predict potentially harmful effects of drugs in humans. The LTBS will employ a molecular systems toxicology approach in a standard 28-day rat toxicity study towards this goal. The project is to be carried out under a cooperative research and development agreement (CRADA) between BG Medicine and the National Center for Toxicology Research (NCTR) of the FDA.

The primary objective of the LTBS is to make available, for preclinical drug development, a biomarker set that predicts probable occurrence of signs of hepatocellular injury in drug development or following approval for marketing, when no conventional signs of liver toxicity can be observed in animal toxicity studies. Additional objectives include elucidation of mechanisms of toxicity and provision of monitoring biomarkers for clinical studies. The LTBS will analyze liver tissue, blood plasma and urine samples derived from the rat toxicity study with microarray-, LC-MS- and NMR-based bioanalytical platforms at including: gene expression, proteomic and metabolomic methods for liver tissue; proteomic and metabolomic methods for blood plasma; and, metabolomic methods for urine. Prior results will be discussed from studies in which multivariate statistical and bioinformatic techniques were used with datasets derived from such platforms.

Five “Clean Compound / Toxic Compound” pairs of similar structure and therapeutic mechanism will be studied. A differential biomarker set will be obtained for all compound pairs and the overlap of these differential biomarker sets will yield a consensus biomarker set for predicting the liability of a compound for generating hepatocellular injury in a clinical trial. The sensitivity and specificity of the consensus biomarker set will be evaluated in subsequent validation studies.

Biographical Sketch

Dr. McBurney joined BG Medicine in 2003 following his position as Founder, President and CEO of Differential Proteomics, Inc., an emerging proteomics company. From 2000-2001, he held the position of President of CeNeS Pharmaceuticals, Inc., and from 1990-2000 was Chief Scientific Officer and then President of Cambridge NeuroScience, Inc. (CNSI). While at CNSI, Dr. McBurney was responsible for multiple drug discovery and development projects focused on treating stroke, traumatic brain injury, neuropathic pain and multiple sclerosis. Dr. McBurney's former academic positions include: Benjamin Meaker Visiting Industrial Professor in the Medical School at Bristol University (UK); Assistant Director of the Medical Research Council’s Neuroendocrinology Unit (UK); Reader in Neurobiology at the Medical School of the University of Newcastle-upon-Tyne (UK); Visiting Associate in Neurophysiology at the National Institutes of Health (USA); and, Florey Fellow of the Royal Society in Sir Alan Hodgkin's laboratory at Cambridge University (UK). He was awarded a BSc with first-class honours and a PhD from the University of New South Wales, Australia.