Protein tyrosine phosphatase 1B (PTP1b) was first discovered in 1988. It is a counter-regulator to insulin and leptin signaling pathways. Given current endemic of insulin resistance via obesity and type 2 diabetes, it is natural to search for drugs that improve insulin and leptin sensitivities. PTP1b suppression is one of those options.
Here is a phase 2 clinical trial on an antisense inhibition of PTP1b (IONIS-PTP-1BRx). Results are promising but not profound: A1c and body weight dropped by 0.7% and 6 lbs in 27 to 36 weeks. No major adverse events were seen. A clearer picture of the drug will emerge in the future trials. At the same time the search for the other perfect PTP1b continues.
To evaluate safety and efficacy of IONIS-PTP-1BRx, a second-generation 2′-O-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) with type 2 diabetes (HbA1c 7.5-10.5%) on a stable dose of metformin alone or with sulfonylurea were randomized 2:1 to IONIS-PTP-1BRx 200 mg (n = 62) or placebo (n = 30) once weekly for 26 weeks.
Mean baseline HbA1c was 8.6% and 8.7% in placebo and active treatment, respectively.
At week 27, IONIS-PTP-1BRx reduced mean HbA1c levels by −0.44% (p = 0.074) from baseline and improved leptin −4.4 ng/mL (p = 0.007) and adiponectin 0.99 μg/mL (p = 0.026) levels compared with placebo.
By week 36, mean HbA1c was significantly reduced −0.69% (p = 0.034) and accompanied by reductions in fructosamine −33.2 μmol/L (p = 0.005) and glycated albumin −1.6% (p = 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-1BRx versus placebo −2.6 kg (p = 0.002) independent of HbA1c reduction (R2 = 0.0020).
No safety concerns were identified in the study.
Compared with placebo, IONIS-PTP-1BRx treatment for 26 weeks produced prolonged reductions in HbA1c, improved medium-term glycemic parameters, reduced leptin and increased adiponectin levels, and resulted in a distinct body weight–reducing effect.