Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator

Abstract

A hepatoselective glucokinase activator reduced hyperglycemia without hypoglycemia or adverse effects on lipids, liver enzymes, or blood pressure. Diabetes drug homing in on the liver Although glucokinase is a known therapeutic target in type 2 diabetes, previous attempts to activate it have not been clinically successful because of side effects and limited efficacy. To improve the effectiveness of the treatment while minimizing adverse reactions such as hypoglycemia, Vella et al. designed a hepatoselective activator of glucokinase for oral treatment. They tested this activator in rats and in minipigs and then ran a clinical trial with it in human patients, showing evidence of both efficacy and safety. The therapeutic success of interventions targeting glucokinase (GK) activation for the treatment of type 2 diabetes has been limited by hypoglycemia, steatohepatitis, and loss of efficacy over time. The clinical characteristics of patients with GK-activating mutations or GK regulatory protein (GKRP) loss-of-function mutations suggest that a hepatoselective GK activator (GKA) that does not activate GK in β cells or affect the GK-GKRP interaction may reduce hyperglycemia in patients with type 2 diabetes while limiting hypoglycemia and liver-associated adverse effects. Here, we review the rationale for TTP399, an oral hepatoselective GKA, and its progression from preclinical to clinical development, with an emphasis on the results of a randomized, double-blind, placebo- and active-controlled phase 2 study of TTP399 in patients with type 2 diabetes. In this 6-month study, TTP399 (800 mg/day) was associated with a clinically significant and sustained reduction in glycated hemoglobin, with a placebo-subtracted least squares mean HbA1c change from baseline of −0.9% (P < 0.01). Compared to placebo, TTP399 (800 mg/day) also increased high-density lipoprotein cholesterol (3.2 mg/dl; P < 0.05), decreased fasting plasma glucagon (−20 pg/ml; P < 0.05), and decreased weight in patients weighing ≥100 kg (−3.4 kg; P < 0.05). TTP399 did not cause hypoglycemia, had no detrimental effect on plasma lipids or liver enzymes, and did not increase blood pressure, highlighting the importance of tissue selectivity and preservation of physiological regulation when targeting key metabolic regulators such as GK.