NEW YORK (Reuters Health) - MB06322, a selective inhibitor of fructose 1,6-bisphosphatase (FBPase), lowers plasma glucose levels in a rat model of type 2 diabetes, according to a report in the May 31st issue of the Proceeding of the National Academy of Science.
“Our approach is designed to reduce the amount of glucose produced by the liver through direct and specific inhibition of the pathway responsible for this overproduction, namely the gluconeogenesis pathway,” Dr. Mark D. Erion from Metabasis Therapeutics, Inc., San Diego, told Reuters Health. “Clearly, much work remains in determining whether this approach will ultimately prove to be both safe and effective.”
Dr. Erion and colleagues investigated the effects of MB06322 (also known as CS-917) on basal and postprandial blood glucose levels in the Zucker diabetic fatty rat model of type 2 diabetes.
MB06322 fully inhibited glucose production in human hepatocytes at concentrations of 1 micromolar, the authors report.
In rats, oral administration of MB06322 to mildly or overtly diabetic rats resulted in dose-dependent glucose lowering, the report indicates, with maximal effects 2.5 to 5 hours after dosing.
Treatment with MB06322 was also associated with increased blood lactate levels in about three quarters of the older rats, the researchers note.
“Initial evidence for efficacy in humans was demonstrated in two Phase IIa studies (a 14-day and a 28-day),” Dr. Erion said. “Both studies showed that oral administration of MB06322 to patients with type 2 diabetes resulted in significant reductions in plasma glucose levels. In addition, these and earlier studies in human volunteers showed MB06322 to be well tolerated.”
“However, in March, we announced that two cases of lactic acidosis were observed during a phase I drug-drug interaction study that combined MB06322 with the commonly used diabetes drug metformin,” Dr. Erion added. “These findings led to the termination of two recently started phase II studies so that Metabasis and Sankyo, together and separately, could assess the program and determine its future. That review is continuing at this time.”
Source: PNAS 2005;102:7970-7975. [ Google search on this article ]
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