vTv Therapeutics Inc. announced that the results from the JDRF-supported mechanistic study assessing effects of TTP399 on ketones during acute insulin withdrawal were published in the Diabetes Obesity and Metabolism journal and presented at The American Diabetes Association's 82nd Scientific Sessions (#ADA2022) on June 5th. This Phase 1, mechanistic study evaluated the effects of the GKA TTP399 on ketoacidosis risk in individuals with T1D on insulin pump therapy. The primary goal was to assess safety of TTP399 via a primary endpoint of non-inferiority of TTP399 compared to placebo regarding ketone levels during acute insulin withdrawal (IWT).

Indeed, TTP399 did not alter circulating concentrations of beta-hydroxybutyrate (BOHB) or time to cessation of IWT and confirmed non-inferiority. Pre-specified secondary analyses investigated the potential for benefit. No subject treated with TTP399 met the prespecified definition of DKA while 42% of placebo-treated subjects met this criterion.

Together, these data suggest that TTP399 does not increase, and may decrease, the risk of diabetic ketoacidosis (DKA) in subjects with T1D. This finding stands in direct contrast to other promising oral adjunctive therapies tested in T1D. During similar insulin withdrawal experiments, SGLT2i use significantly increased ketonemia in people with T1D during insulin withdrawal1.

Moreover, off-label use of SGLT2i in the real world is associated with substantially increased risk of euglycemic DKA2. That TTP399 did not result in increased BOHB during acute insulin withdrawal and instead demonstrated a trend toward lowering risk of metabolic acidosis suggests that TTP399 will not increase the risk of DKA when used in the real world. The data from this study support prior studies that demonstrate that TTP399 improves glucose control and reduces hypoglycemia and suggest a protective effect of TTP399 against acidosis in people with T1D.