Isis 113715, a novel PTP-1B antisense inhibitor, improves glycemic control and dyslipidemia and increases adiponectin levels in T2DM subjects uncontrolled on stable sulfonylurea therapy

Results: Protein tyrosine phosphatase 1B (PTP-1B) is a negative regulator of insulin action. Since reduction of PTP-1B activity enhances insulin sensitivity in preclinical models, PTP-1B inhibitors could be promising therapeutics for T2DM. However, the role of PTP-1B in human insulin resistance and T2DM remains undefined due to a lack of specific PTP-1B inhibitors. ISIS 113715, a specific antisense inhibitor of PTP-1B, is in development as a novel insulin sensitizer for T2DM, and we reported robust glucose lowering effects in mice, rats and monkeys. Further, ISIS 113715 reduced FSG in drug naïve T2DM patients and was safe and well-tolerated at 100-400 mg/week for 6-12 weeks. The present randomized double-blind, placebo-controlled, multi-center study evaluated the safety and efficacy of 100 or 200 mg doses of ISIS 113715 for 13 weeks in subjects with T2DM (duration ≤ 12 yrs, HbA1c ∼8.7%, FSG∼190 mg/dL) on stable, maximal doses of sulfonylureas. The efficacy analysis demonstrated statistically significant reductions in multiple indices of glucose control at 200 mg (n=26) compared to placebo (n=26), including FSG and SMPG (25 mg/dL, p=0.026), fructosamine (25 μmol/L, p=0.009) and glycated albumin (p=0.03). Consistent but less robust effects were observed in the 100 mg group. Additionally, an 11 mg/dL decrease in LDL-C (p=0.005) was observed in the 200 mg group, along with reductions in apoB and an increase in HDL-C, indicating improvement in metabolic dyslipidemia. Although this short-term study was not designed to assess body weight effects, a placebo-subtracted loss of >0.5 kg was seen in the 200 mg group, preceded by an increase in adiponectin. A 65% increase in adiponectin was seen by the end of the study (p=0.023). ISIS 113715 was safe and well-tolerated. There were no drug-related SAEs, no effects on vital signs, ECG, hepatic or renal function or severe hypoglycemia. Local, mild injection site erythema was the most common adverse event. These data validate PTP-1B as a novel target for T2DM patients and provide further support for a PTP-1B antisense approach in this population.