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 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 is in phase 2b trials assessing the effects of GKAs on glycemic control in patients with type 2 diabetes.

Clinical Data

TTP399 has been studied in a series of phase 1 and phase 2 clinical trials.  In all studies, TTP399 has been safe and well tolerated, with no increased incidence of hypoglycemia compared to placebo. The results of these trials, suggest that our approach to glucokinase activation will avoid safety and tolerability issues associated with other GKAs, such as activation of glucokinase in the pancreas, stimulation of insulin secretion independent of glucose, hypoglycemia, increased lipids and liver toxicity. Further, we believe that TTP399 will compare favorably with other products in the market, as our trials have indicated that TTP399 may have higher efficacy than competing products, the ability to normalize HbA1c, and no contraindication for renal impairment.
 
We have completed a Phase 2 clinical trial of TTP399, a randomized, double-blind, parallel-group, placebo-controlled, six-week, multiple dose study in 151 type 2 diabetic patients whose glycemic parameters were not well-controlled on metformin. The trial was designed to assess the pharmacokinetics, pharmacodynamics, safety and tolerability of TTP399 in formulation 1 and was conducted at 11 centers in the United States. Patients were randomized into four arms: TTP399 400 mg BID, TTP399 800 mg QD, TTP399 800 mg BID, and placebo.  All patients remained on consistent doses of metformin throughout the trial. 


 
In the trial, TTP399 demonstrated a statistically significant reduction in HbA1c levels in all TTP399 dose groups compared with placebo, without induction of hypoglycemia or hyperlipidemia and with no induction of insulin secretion in patients with type 2 diabetes. Within the high dose arm of TTP399, approximately 86% of patients with HbA1c levels ≤ 7.5% at baseline achieved blood glucose normalization, defined as HbA1c ≤ 6.5%, after only six weeks of treatment, while 50% of patients with HbA1c levels ≤ 8% at baseline achieved normalization after six weeks. For all doses combined, approximately 40% of patients with HbA1c levels ≤ 7.5% at baseline achieved blood glucose normalization while 25% of patients with HbA1c levels ≤ 8% at baseline achieved normalization. None of the patients receiving placebo reached HbA1c normalization.

AGATA Study

TTP399 is currently being studied in a six-month phase 2b trial, the AGATA study. The Add Glucokinase Activator to Target A1c (AGATA) trial is a multi-center, adaptive, randomized, double-blind, placebo- and active- controlled, parallel group, phase 2 study in subjects with T2DM to evaluate the effect of TTP399 on HbA1c following administration for 6 months. The primary endpoint will be the change from baseline in HbA1c at six months. The secondary endpoints will include subject achievement of HbA1c <7% at six months, subject achievement of HbA1c <6.5% at six months, plasma glucose, lipids (triglycerides (TG), total cholesterol, HDL cholesterol, and LDL cholesterol), insulin, lactate, C-peptide, glucagon, GLP-1 and body weight.



To learn more about the trial, visit the study page on clinicaltrials.gov or the AGATA study website www.myagata.com.

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