vTv Therapeutics Inc. announced the publication of a paper in Science Translational Medicine showcasing the discovery and development of TTP399, an investigational, oral, small molecule, liver-selective glucokinase (GK) activator, as a potential treatment for diabetes. The paper reviews the scientific rationale underpinning the development of TTP399 and its progression from preclinical to clinical development concluding with the positive results of the AGATA study, a phase 2 study of TTP399 in patients with type 2 diabetes. In this 6-month study, TTP399 (800 mg/day) was associated with a statistically 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). Moreover, in patients weighing =100 kg, TTP399 decreased weight (-3.4 kg; p< 0.05) compared to placebo. No hypoglycemia, no detrimental effects on plasma lipids or liver enzymes, and no increased blood pressure were observed with TTP399 relative to placebo, highlighting the importance of tissue selectivity and preservation of physiological regulation when targeting key metabolic regulators such as GK. GK is a genetically validated target in the development of diabetes, making it an attractive therapeutic target. However, the use of GK as a therapeutic target for the treatment of type 2 diabetes has been historically 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 indicated that a hepatoselective GK activator (GKA) that does not activate GK in beta cells or affect the GK-GKRP interaction may reduce hyperglycemia in patients with type 2 diabetes, while limiting hypoglycemia and liver-associated adverse effects. Using its proprietary drug discovery platform, vTv identified and characterized small-molecule compounds, including TTP399, with the ability to increase GK activity in the liver without affecting the physiological role of GK.