Isis knocks diabetes receptor senseless
first-in-class antisense drug that aims to control blood glucose
levels in patients with Type II diabetes.
The drug, ISIS 325568, is a second generation antisense drug that inhibits the body's ability to produce the excessive amounts of glucose that can lead to hyperglycaemia in sufferers of Type II diabetes. The American Diabetes Association (ADA) has estimated that there are more than 230m people living with diabetes worldwide, with 90-95 per cent of cases being Type II diabetes, which is characterised by tissue-wide insulin resistance. The market for diabetes treatments was valued at $15bn (€11bn) in 2005 and is expected to increase dramatically as the addressable patient population continues to grow. Insulin and glucagon help to maintain blood glucose levels in a very narrow range, with insulin helping to transport glucose out of the blood stream and into tissue and glucagon working to release the stored glucose into the bloodstream. Glucagon exerts its physiological effects by signalling through the glucagon receptor (GCGR) to stimulate the conversion of stored energy into glucose. ISIS 325568 inhibits the expression of GCGR leading to a reduction in the ability of glucagon to produce glucose and cancelling out a lack of sensitivity to insulin. The antisense drug works by interrupting the translation phase of the protein production process by preventing the mRNA from reaching the ribosome. The chemically-modified complementary nucleotide chains developed by Isis hybridise to specific areas of the mRNA and cause it to be degraded and not translated into a functional protein. Preclinical research showed that ISIS 325568 improved glucose control and reduced levels of triglycerides in the blood without causing hypoglycaemia. In addition, treatment with the antisense drug led lo an increase in the levels of the glucagon-like peptide GLP-1, which is a hormone that helps to enhance insulin excretion by preserving pancreatic function. GLP-1 is a target that has been receiving interest recently with Pfizer and BioRexis both developing GLP-1 activators. In a bid to overcome this competition Pfizer bought out BioRexis earlier this year. In addition, Bristol Myers Squibb is developing saxagliptin, which aims to reduce glucose levels by inhibiting dipeptidyl peptidase-4's (DPP-4) ability to degrade GLP-1. "We are excited by the preclinical profile of ISIS 325568, a novel first-in-class drug that has demonstrated excellent glucose control and improved pancreatic function through a dual mechanism of action in insulin-resistant animal models," said Dr Sanjay Bhanot, vice president of Metabolic Diseases R&D at Isis Pharmaceuticals "Furthermore, the favourable effects on GLP-1 that we have seen exceed those observed with DPP IV inhibitors, and there was no evidence of hypoglycaemia or GI [glycaemic index] side effects. These preclinical findings suggest that ISIS 325568 could offer disease modifying effects and long-term disease control both as a single agent and in combination with other diabetes treatments." The company will be looking to demonstrate tolerability and safety in this initial study as well as monitoring a number of biomarkers that could provide evidence for the drug's activity or help inform dose selection in future studies. Isis already has another antisense insulin sensitizer drug in Phase II clinical development for Type II diabetes, ISIS 113715, which is an antisense inhibitor of protein tyrosine phosphatase 1b ( PTP-1b).