Antisense Inhibition of Protein Tyrosine Phosphatase 1B With IONIS-PTP-1B_Rx Improves Insulin Sensitivity and Reduces Weight in Overweight Patients With Type 2 Diabetes.

Abstract

To evaluate safety and efficacy of IONIS-PTP-1B_Rx, a second-generation 2'-<i>O</i>-methoxyethyl antisense inhibitor of protein tyrosine phosphatase 1B, as add-on therapy in overweight patients with type 2 diabetes inadequately controlled with metformin with or without sulfonylurea therapy. In this phase II, double-blind, randomized, placebo-controlled, multicenter trial, overweight and obese patients (BMI ≥27 kg/m²) with type 2 diabetes (HbA_1c ≥7.5% [58 mmol/mol] and ≤10.5% [91 mmol/mol]) on a stable dose of metformin alone or with sulfonylurea were randomized 2:1 to IONIS-PTP-1B_Rx 200 mg (<i>n</i> = 62) or placebo (<i>n</i> = 30) once weekly for 26 weeks. Mean baseline HbA_1c was 8.6% (70 mmol/mol) and 8.7% (72 mmol/mol) in placebo and active treatment, respectively. At week 27, IONIS-PTP-1B_Rx reduced mean HbA_1c levels by -0.44% (-4.8 mmol/mol; <i>P</i> = 0.074) from baseline and improved leptin (-4.4 ng/mL; <i>P</i> = 0.007) and adiponectin (0.99 μg/mL; <i>P</i> = 0.026) levels compared with placebo. By week 36, mean HbA_1c was significantly reduced (-0.69% [-7.5 mmol/mol]; <i>P</i> = 0.034) and accompanied by reductions in fructosamine (-33.2 μmol/L; <i>P</i> = 0.005) and glycated albumin (-1.6%; <i>P</i> = 0.031) versus placebo. Despite both treatment groups receiving similar lifestyle counseling, mean body weight significantly decreased from baseline to week 27 with IONIS-PTP-1B_Rx versus placebo (-2.6 kg; <i>P</i> = 0.002) independent of HbA_1c reduction (<i>R</i>² = 0.0020). No safety concerns were identified in the study. Compared with placebo, IONIS-PTP-1B_Rx treatment for 26 weeks produced prolonged reductions in HbA_1c, improved medium-term glycemic parameters, reduced leptin and increased adiponectin levels, and resulted in a distinct body weight-reducing effect.