TTP399
Type 1 Diabetes and Hypoglycemia
Type 1 Diabetes (T1D) is an autoimmune disease with no cure affecting over 1.6 million people in the United States. Adult-onset T1D has become more common than childhood-onset with more than half of all new cases diagnosed in adult patients. The patient population is expected to grow worldwide, with an estimated projection of 5 million patients in the U.S. by 2050.
Hypoglycemia is the most common acute complication in T1D, and hypoglycemic control continues to be an unmet need in the patient population.
Our Compound
TTP399 is a novel, oral, small molecule, liver selective glucokinase activator being developed as an adjunct therapy to insulin in patients with T1D. In a recent phase 2 study, TTP399 showed a 40% reduction in hypoglycemic episodes compared to placebo. In April 2021, the FDA granted Breakthrough Therapy designation to TTP399 for the treatment of T1D. This past October, vTv announced results of our mechanistic study of TTP399 in patients with T1D demonstrating no increased risk of ketoacidosis. TTP399 has now been tested in almost 600 subjects and demonstrated a good safety and tolerability profile.
Mechanism of Action
TTP399 is a Glucokinase (GK) Activator, a mechanism entirely distinct from the action of antidiabetic therapies currently on the market. TTP399 restores the normal function of the liver in the presence of high glucose: it traps glucose inside liver cells, promotes further glucose uptake for energy and storage, and keeps the liver in a “fed” state, thereby preventing ketone production. You can read more about the mechanism of action here.
Clinical Trials
SimpliciT1 Phase 2 Study
TTP399 completed a phase 2 study in patients with T1D as an adjunctive treatment to insulin therapy. The study met its primary objective by demonstrating a statistically significant and clinically meaningful improvement to HbA1C, and treatment with TTP399 also showed a decrease in hypoglycemic episodes by 40%. TTP399 improved patients’ daily time in normal glycemic range with no reports of ketoacidosis during the study duration. Additionally, patients treated with TTP399 showed a reduction in their total daily mealtime bolus insulin dose.
You can read more about this study at ClinicalTrials.gov or read our article in Diabetes Care.
Mechanistic Study
In October 2021, vTv announced positive results for our mechanistic study of TTP399 in patients with T1D. The study demonstrated that patients taking TTP399 showed no increase in ketone levels relative to placebo during a period of acute insulin withdrawal, indicating no increased risk of ketoacidosis. TTP399 patients also showed improved fasting plasma glucose levels and fewer hypoglycemic events during the week of treatment prior to the insulin withdrawal test.
Publications
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
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- Vella A, Freeman J, Dunn I, Keller K, Buse J, Valcarce C. Targeting hepatic glucokinase to treat diabetes with TTP399, a hepatoselective glucokinase activator. Science Translational Medicine 16 Jan 2019
- Klein K., Freeman J., Dunn I., Dvergsten C., Kirkman S., MD1, Buse B., Valcarce C. The SimpliciT1 Study: Hepatoselective glucokinase activation via TTP399 for the treatment of type 1 diabetes mellitus. Presented at 100th anniversary of the University of Toronto’s discovery of insulin (Insulin100)
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
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- Klein K., Freeman J., Dunn I., Dvergsten C., Kirkman S., MD1, Buse B., Valcarce C. The SimpliciT1 Study: Hepatoselective glucokinase activation via TTP399 for the treatment of type 1 diabetes mellitus. Presented at 100th anniversary of the University of Toronto’s discovery of insulin (Insulin100)
- Freeman J, Dunn I, Valcarce C. Mechanism matters: preliminary evidence that activation of glucokinase by TTP399 does not increase plasma or urine ketones in type 1 diabetes. Presented at the 56th EASD Conference – Virtual, September 22, 2020.
- Valcarce C, Freeman J, Dunn I, Dvergsten C, Klein KR, Buse J. The Simplici-T1 trial: Activation of glucokinase by TTP399 improves glycemic control in patients with T1DM. Presented at the 56th EASD Conference – Virtual, September 22, 2020.
- Buse J, Klein K, Freeman J, Dunn I, Valcarce C. The Simplici-T1 Trial: Glucokinase Activator TTP399 Improves Glycemic Control in Patients with Type 1 Diabetes. Presented at the American Diabetes Association’s 80th Scientific Sessions – Virtual, June 13, 2020
- Valcarce C, Klein K, Freeman J, Dunn I, Buse B. The Simplici-T1 Trial: Relationship between Glycemic Control and Insulin Dose. Presented at the American Diabetes Association’s 80th Scientific Sessions – Virtual, June 13, 2020
- Valcarce C, Freeman J, Dunn I, Dvergsten C, Soeder T and Buse J. Results from the sentinel and learning phase of the Simplici-T1 study, the first clinical trial to test activation of glucokinase as an adjunctive treatment for type 1 diabetes. Presented at the 55th EASD conference, September 18, 2019, Barcelona, Spain
- Buse J, Valcarce C, Freeman J, Dunn I, Dvergsten C, Kirkman S, Alexander k, Jamie D and Bergamo K. Simplici-T1: First Clinical Trial to Test Activation of Glucokinase as an Adjunctive Treatment for Type 1 Diabetes; Presented at the American Diabetes Association 78th Scientific Sessions, June 25, 2018, Orlando, Florida
- Valcarce C. Selective Activation of Glucokinase (GK) in the Liver: Improves Glycemic Control and Reduces Insulin Need as Well as Risk of Ketoacidosis in Type 1 Diabetic Minipigs. Presented at the Keystone Symposia on Diabetes, January 22-26, 2017
- Valcarce C, Grimes I, and Freeman J. TTP399, a Novel, Liver Selective Glucokinase Activator: Results from a 10 Day Pilot Study in Patients with Type 2 Diabetes Mellitus (T2DM) Naïve to Drug; Presented at the American Diabetes Association 76th Scientific Sessions, June 12, 2016, New Orleans, Louisiana
- Valcarce C. The Importance of Tissue Selectivity and Preservation of the Physiological Regulation when Targeting Key Metabolic Regulators as Glucokinase; Presented at the Keystone Symposia on New Therapeutics for Diabetes and Obesity, April 19, 2016, La Jolla, California
- Valcarce C. TTP399, A Liver Selective Glucokinase Activator Increases Efficacy of Currently Marketed Therapies for Type 2 Diabetes; Presented at the 75th Annual Scientific Session of the American Diabetes Association, June 3, 2015, Boston Massachusetts
- Valcarce C. TTP399, a Liver-Selective Glucose Kinase Activator (GKA), Lowers Glucose and Does NOT Increase Lipids in Subjects with Type 2 Diabetes Mellitus (T2DM); (Abstract #122-OR). Presented at the 74th Annual Scientific Session of the American Diabetes Association, June 13, 2014, San Francisco California
- Valcarce C. TTP399, A Liver Selective Glucokinase Activator (GKA) that Preserves the Physiological Regulation of Glucokinase (GK) by GK Regulatory Protein (GKRP)
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