Isis Pharmaceuticals, Inc. (NASDAQ: ISIS) announced today that it has initiated Phase 1 clinical studies for ISIS-GCGRRx and ISIS-GCCRRx, antisense drugs Isis is developing for the treatment of type 2 diabetes. Isis will develop both ISIS-GCGRRx and ISIS-GCCRRx to treat a broad population of diabetic patients. The unique mechanism of action of these new drugs could allow each drug to be used in combination with other therapies for type 2 diabetes.
"Type 2 diabetes is a progressive disease. More than half of all diabetic patients cannot reach acceptable glucose control with currently available therapies. Our goal is to develop safe, effective drugs with unique mechanisms of action that can provide significant therapeutic benefit," said B. Lynne Parshall, Chief Operating Officer, Chief Financial Officer and Secretary of Isis. "This year we have made significant progress toward this goal. Our ISIS-GCGRRx and ISIS-GCCRRx drugs are designed to reduce the activity of two critical hormones that oppose the action of insulin and cause increased glucose levels in diabetic patients. The initial clinical development for both of these drugs will focus on treating diabetic patients with moderate to severe diabetes who cannot achieve adequate glucose control with existing treatments. We believe that each drug could address a significant commercial market by providing long-term disease control in such patients."
ISIS-GCGRRx targets the glucagon receptor (GCGR) to reduce the effects of glucagon, a hormone that causes glucose production in the liver. Reducing GCGR also increases the production of active glucagon-like peptide (GLP-1), a hormone that preserves pancreatic function and enhances insulin secretion. "Glucagon plays a particularly significant role in increasing blood glucose levels in patients with advanced diabetes. Therefore ISIS-GCGRRx could work very well in those patients in whom most other therapies fail. In our preclinical studies, which were conducted in the most insulin-resistant models of type 2 diabetes, antisense reduction of GCGR produced robust glucose control and resulted in preservation of the pancreas without producing hypoglycemia," said Sanjay Bhanot, M.D., Ph.D., Vice President, Metabolic Disorders and Translational Medicine of Isis. "ISIS-GCGRRx has a significant effect in decreasing excessive liver glucagon action in these models. In addition, it increased active GLP-1 thereby improving pancreatic function. Due to this dual-action mechanism, ISIS-GCGRRx could be valuable for diabetic patients with severe hyperglycemia who are not controlled with current treatments."
Glucocorticoids are hormones that promote liver glucose production and fat storage. Reduction of the glucocorticoid receptor (GCCR) action specifically in the liver and fat tissues is an attractive therapeutic approach, because it provides the desired effects on glucose and lipid control without causing potential side effects associated with systemic GCCR inhibition. "In preclinical studies, we have demonstrated reduction of GCCR specific to the liver and fat with antisense drugs. These preclinical results were accompanied by robust lowering of blood glucose and lipid levels and a decrease in body fat in obese animals. Therefore ISIS-GCCRRx could be used in diabetic patients with moderate to severe hyperglycemia who are also obese and have high levels of lipids," concluded Dr. Bhanot.
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