Type 2 diabetes is generally characterized by insulin resistance, impaired insulin secretion and hyperglycemia. The pathophysiology is multifactorial with involvement of both genetic and lifestyle/environmental factors. Optimal glycemic control is the treatment goal in patients with type 2 diabetes, since the risk of long-term complications is associated with poor control.

Despite the availability of several oral anti-diabetic drugs and insulin, less than one third of type 2 diabetes patients achieve the recommended target levels of glycemic control. With the increasing incidence and prevalence of type 2 diabetes, there is a significant unmet medical need for treatment alternatives with improved efficiency and safety.

Protein tyrosine phosphatase-1B is a key negative regulator of the insulin signaling pathway.  Insulin binding to the insulin receptor, and autophosphorylation of tyrosine residues on the receptor, trigger a cascade of events including the mobilization of glucose transporters. This leads to increased glucose uptake and utilization in the liver, skeletal muscle and other peripheral tissues.  PTP1B negatively regulates the insulin receptor (IR) by reversing the effects of insulin by dephosphorylating these tyrosine residues and thus inactivating the receptor. Disruption of this enzyme would be expected to enhance IR activity, and improve glucose tolerance. Indeed, diabetic and obese mice administered PTP1B antisense oligonucleotide showed improved insulin sensitivity, lowering of HBA1c, and reduced levels of plasma and postprandial glucose levels. PTP1B null mice also showed a reduction in fat cell mass and were protected from diet-induced obesity. In addition, a single nucleotide polymorphism of the PTP1B gene has been identified in a group of Canadian Oji-Crees that is associated with a 40% reduction in risk of type 2 diabetes or impaired glucose tolerance. PTP1B has therefore been identified as a potential target for the treatment of type 2 diabetes and insulin resistance due to its role in the modulation of insulin sensitivity.

TTP814 has been identified, using TTP Translational Technology®, TransTech Pharma’s proprietary drug discovery engine, as a potent, novel, selective and orally available PTP1B inhibitor. Longer duration studies in combination with other oral antidiabetic agents are being planned.