Advisory Committee Briefing Document Preclinical Pharmacology and Toxicology Summary Drug: Pargluva® (muraglitazar, BMS-298,585) Drug class: Peroxisome Proliferator-Activated Receptor dual agonist Clinical Indication: Type 2 diabetes

The peroxisome proliferator-activated receptors (PPAR) are nuclear receptors that regulate gene expression in response to ligand binding. Three PPAR receptor subtypes, namely gamma, alpha and delta (beta), have been identified. The development of PPAR agonist pharmaceuticals for the treatment of type 2 diabetes, dyslipidemia, and obesity is currently an area of great interest. The FDA has received data for more than 40 compounds including PPAR gamma, PPAR alpha, PPAR delta, PPAR dual (alpha/ gamma) or PPAR pan agonists. This extensive database permits identification of the toxicity profile specific to each PPAR receptor subtype. This summary will provide a brief overview of the toxicity profiles associated with exaggerated PPAR gamma or PPAR alpha activation for the class in general in addition to the preclinical toxicology data for muraglitazar.