Isis Pharmaceuticals, Inc announced positive top-line results from a phase-2 study evaluating the safety and efficacy of ISIS 113715 in patients with type-2 diabetes. ISIS 113715 is a novel insulin sensitizer that reduces the expression of protein tyrosine phosphatase-1B (PTP-1B). The study showed consistent and statistically significant reductions in multiple short and intermediate measures of glucose control.

In addition to lowering blood glucose, ISIS 113715 caused statistically significant and clinically meaningful reductions in LDL cholesterol. Consistent with the preclinical data with ISIS 113715, a tendency toward weight loss was observed even in this short-term study without strict dietary control. The effect of ISIS 113715 on weight was preceded by a statistically significant increase in circulating adiponectin, a hormone that is increased with weight loss. ISIS 113715 demonstrated a favourable safety profile with no exacerbation of sulfonylurea-induced hypoglycaemia or other clinically significant adverse effects. The full details of the data will be presented at a future medical meeting.

"Although the study completed is only 13 weeks in duration, I am encouraged by the safety and efficacy data," said Robert Henry, professor of Medicine, University of California at San Diego and chief, Section of Diabetes, Endocrinology and Metabolism at VA San Diego. "If the profile of ISIS 113715 seen in this study is confirmed in longer-term trials, the drug could be an important addition to the care of type-2 diabetic patients."

The analysis demonstrated statistically significant reductions in multiple indices of glucose control as compared to placebo in patients with type-2 diabetes on stable doses of sulfonylurea. The measures of glucose control evaluated were - fasting serum glucose (FSG), a spot measure of glucose control; weekly self monitored blood glucose (SMBG), a one-week average of daily fasting glucose measurements; fructosamine, a measure of glucose over the preceding two to four weeks; and glycated albumin, a measure of average glucose over the preceding four weeks. In the 200 mg/week cohort, there was a 25 mg/dL decrease in averaged weekly fasting SMBG (p=0.026 versus placebo) and a 25 umol/L decrease in serum fructosamine (p=0.009 versus placebo). Further, glycated albumin was also statistically significantly reduced and similar results were observed for fasting blood glucose.

Consistent, but less robust effects on all of these parameters were also observed in the 100 mg/week cohort. The fifth measure of glucose control in the study, haemoglobin A1c (HbA1c), a measure of average glucose control over the preceding eight to 12 weeks, failed to reach statistical significance due to the delay in onset of glucose control as accumulation of ISIS 113715 to active concentrations took more than six weeks.

ISIS 113715 was well tolerated. The most common adverse events were mild injection site reactions. There were no drug-related serious adverse events, no severe hypoglycaemia, no clinically significant alterations in kidney or liver function even in patients who entered the trial with mild renal dysfunction, and no other clinically significant adverse effects were observed in subjects exposed to ISIS 113715. From both the 100 mg and 200 mg per week treatment groups, there were only three terminations in the study due to adverse events: one for uncontrolled diabetes, one for a rash following the first subcutaneous dose and one for a moderate injection site reaction in a subject with inadequately controlled diabetes.

"We are pleased that this study has confirmed that ISIS 113715, a first in class PTP-1B inhibitor, is well tolerated and has a unique profile," said Sanjay Bhanot, vice president of Metabolic Disorders and Translational Medicine at Isis. "An insulin sensitizer that normalizes glucose without exacerbating hypoglycaemia, that also reduces LDL-C levels and weight would be a significant advance in the treatment of patients with type 2 diabetes, who frequently are obese and at high cardiovascular risk."

The trial was a randomized, double-blind, placebo-controlled phase-2 study that had 76 evaluable patients with well-established type-2 diabetes who had uncontrolled blood sugar despite treatment with stable doses of sulfonylurea. Patients were randomized 2:1 to receive either placebo (n=26) or ISIS 113715 100 mg (n=24), 200 mg (n=26) once-weekly subcutaneously for three months in addition to their stable doses of sulfonylurea. Patients entering the study had average HbA1c levels of 8.8%, average fasting glucose levels of approximately 196 mg/dL, and average LDL-C levels of approximately 128 mg/dL. The trial was conducted in several countries in Eastern Europe, including Romania, Poland and Russia. Study end points evaluated included HbA1c, FSG, SMBG, lipids, Apo B-100, adiponectin, fructosamine and glycated albumin.

ISIS 113715 is a second-generation antisense drug that inhibits PTP-1B, an enzyme that is a key mediator of insulin resistance. Insulin resistance is one of two main defects in patients with type 2 diabetes.

Isis is exploiting its expertise in RNA to discover and develop novel drugs for its product pipeline and for its partners.