TTP399

Overview

Glucokinase (GK) is a key regulator of glucose homeostasis. It is a member of the Hexokinase family (Hexokinase IV) and is expressed in the endocrine cells of the Langerhans islets, in the liver, in the L- and K- cells of the intestine, and in the neurons of the central nervous system, primarily in the hypothalamus. GK acts as the physiological glucose sensor, changing its conformation, activity, and/or intracellular location in parallel with changes in glucose concentrations. GK has two main distinctive characteristics that make it a good choice for blood glucose control. First, its expression is mostly limited to tissues that require glucose-sensing (mainly liver and pancreatic β-cells). Second, GK is able to sense changes in serum glucose levels and modulate changes in liver glucose metabolism that in turn regulate the balance between hepatic glucose production (HGP) and glucose consumption, and modulate changes in insulin secretion by the beta-cells.

Studies in humans, along with numerous animal studies, showing that mutations in the gene encoding GK can cause both hyperglycemia ([diabetes mellitus]) and hypoglycemia (glucose levels below normal) depending on the mutation, confirm the critical role of GK in the regulation of glucose control and provide genetic validation for this target.

The concept of GK activation for the treatment of diabetes is attractive because it has proven to be effective and safe in normalizing glycemia in animal models of type 1 and type 2 diabetes by a mechanism entirely distinct from the action of antidiabetic therapies currently on the market. Moreover, several lines of evidence have suggested that development of type 2 diabetes is related to functional impairment of the GK enzyme. Thus, GK activation may be a way to overcome an important underlying cause of type 2 diabetes progression and hence halt or delay the course of the disease.

Our approach to targeting GK is to use a small molecule, liver selective compound that only activates GK in the liver without affecting the interaction between GK and GKRP. Many competitors have tried to develop drugs that act as GKAs. Previously identified GKAs evaluated in the clinic for the treatment of type 2 diabetes demonstrate improved glucose control; however, these GKAs show increased incidence of hypoglycemia and hyperlipidemia and an apparent lack of durability. These liabilities have been correlated to hyperstimulation of the beta-cells in a glucose independent manner, and / or the accumulation of lipids in the liver, consistent with the disruption of GK and the GKRP interaction by these GKAs. Thus, liver selective compounds that do not activate GK in pancreatic beta-cells or affect the GK-GKRP interaction in the liver are expected to demonstrate a superior profile in comparison to previously identified GKAs.

TTP399 has been identified using TTP Translational Technology®, as the lead novel, potent, selective and orally available GK activator. This molecule has completed a 6 month phase 2 trial in patients with type 2 diabetes and is currently being studied in an adaptive phase 1/2 trial in patients with type 1 diabetes.

 


 

Presentations and Posters

Links to the following publications and presentations, which are located on outside websites, are provided for informational purposes only and do not constitute the opinions or views of vTv Therapeutics