Isis Pharmaceuticals Inc has initiated a Phase I clinical trial of ISIS 113715 for Type 2 diabetes. ISIS 113715 is a second-generation antisense drug designed to improve defective insulin signaling by targeting the gene, PTP-1B. PTP-1B reduces insulin's ability to regulate blood sugar levels. In preclinical studies, ISIS 113715 improved the regulation of blood sugar levels, an outcome critical in the management of Type 2 diabetes.

"We are excited to move Isis' first metabolic drug into clinical development. ISIS 113715 has demonstrated compelling activity in well- accepted animal models of diabetes without causing hypoglycemia or weight gain, effects commonly observed with other diabetes treatments," said Mark Wedel, Vice President, Clinical Research and Chief Medical Officer. "We are optimistic this compound may provide an improved treatment option for millions of people who have Type 2 diabetes."

The Phase I clinical trial will assess the safety and pharmacokinetic profile of several doses of ISIS 113715 by parenteral administration. The trial is planned to enroll 20 healthy volunteers.

In preclinical studies, ISIS 113715 demonstrated positive effects in five well-characterized and accepted models of diabetes. The drug normalized blood sugar levels in multiple rodent models and improved glucose tolerance in normal and obese monkeys. In addition, ISIS 113715 did not produce hypoglycemia or weight gain, a characteristic of many other Type 2 diabetes treatments. ISIS 113715 has demonstrated consistent reduction of PTP-1B mRNA and protein levels in liver and fat, key tissues known to be important in the regulation of blood sugar levels.

PTP-1B has long been considered an "undruggable" target. Pharmaceutical companies interested in diabetes research have actively pursued phosphatases, such as PTP-1B, for years as part of traditional small molecule discovery efforts. However, due to structural homologies among closely related enzymes it is often difficult to identify small molecule drugs that selectively inhibit one phosphatase without significantly affecting others.

With the exquisite specificity of antisense technology, Isis scientists were able to design a drug that targets PTP-1B. Antisense inhibition of PTP-1B expression enables insulin receptors to stay active longer, allowing for more sugar uptake into cells, and thereby lowering sugar levels in the bloodstream.

According to the National Institutes of Diabetes and Digestive and Kidney Diseases, approximately 17 million Americans are affected by diabetes, a metabolic disease that affects the body's use of sugars. Type 2 diabetes, also known as adult-onset diabetes, accounts for 90-95% of all diagnosed diabetes cases. Diabetes can lead to serious problems of the eyes, kidneys, nerves, gums and teeth. The most serious problem caused by diabetes is heart disease. People with diabetes are more than twice as likely as people without diabetes to have heart disease or a stroke.