vTv Therapeutics Inc. announced positive results of a mechanistic study of TTP399 in patients with type 1 diabetes (T1D). The study demonstrated that patients with T1D taking TTP399 experienced no increase in ketone levels relative to placebo during a period of acute insulin withdrawal, indicating no increased risk of ketoacidosis. Consistent with previous clinical studies, improved fasting plasma glucose levels and fewer hypoglycemic events were observed in the TTP399 treated group during the week of treatment prior to the insulin withdrawal test. The U.S. Food and Drug Administration (FDA) has declined to approve SGLT2 inhibitors as an adjunctive therapy in T1D, with concerns over the potential risks of diabetic ketoacidosis (DKA) in focus. DKA can lead to hospitalization and, if untreated, death. In order to address these concerns, vTv, following the FDAs recommendation, conducted this mechanistic study to demonstrate that treatment with TTP399, a liver-selective glucokinase activator, will not result in increased production of ketones, a precursor to ketoacidosis. The study enrolled 23 people with type 1 diabetes using insulin pumps, randomized to receive TTP399 (n=12) or placebo (n=11) orally once daily for approximately seven days. On the last day of dosing, an acute insulin withdrawal test was performed by stopping the patients insulin pumps and measuring levels of beta-hydroxybutyrate (BOHB) and other key metabolic markers over a period of up to 10 hours or until certain safety stopping criteria were met. The design of this study was based on similar studies, which showed significant increases in BOHB in patients taking SGLT2 inhibitors relative to those taking placebo. The demographics between the two arms of the study were well balanced, with approximately 80% of patients in the study utilizing closed-loop or hybrid-closed loop systems during the treatment period. The average HbA1c levels at baseline were 6.8% and 7.1% in the placebo and TTP399 arms, respectively. The study achieved its primary endpoint by demonstrating non-inferiority relative to placebo in the proportion of subjects reaching pre-specified concentration limits of BOHB, a biomarker for ketoacidosis, over the period of acute insulin withdrawal. BOHB is the primary ketone body found in blood. During the insulin withdrawal phase of the study, no significant differences were observed between the active and placebo arms in the patients BOHB profiles or the mean duration of the test. All patients completed at least three hours of the insulin withdrawal test. During this initial period of time, the area under the curve for the levels of BOHB was numerically lower for the TTP399 treated group than that for placebo. In addition, the concentration of bicarbonate, an important buffer that regulates acidity levels in blood, was higher in the TTP399 treated group than in the placebo group, indicating a lower risk of ketoacidosis in the group taking TTP399. In addition to data collected during the insulin withdrawal test, data collected during the week-long treatment period preceding the insulin withdrawal test demonstrated that patients taking TTP399 experienced reductions in fasting plasma glucose (-27mg/dL in the TTP399 group vs -4mg/dL in the placebo group p=0.03). Furthermore, no increases in BOHB or free fatty acid, a precursor to BOHB, were observed. Consistent with previous clinical studies of TTP399, the drug was well tolerated with fewer subjects reporting treatment-emergent adverse events in the group taking TTP399 than in the placebo group. Importantly, patients taking TTP399 reported no events of hypoglycemia, while four events of hypoglycemia were reported in the placebo group.