Novel once-daily pill reduces HbA1c in type 1 diabetes
An investigational, once-daily pill added to optimized insulin therapy was shown to reduce HbA1c among adults with type 1 diabetes during a 12-week trial when compared with placebo plus insulin, according to a press release from vTv Therapeutics.
In announcing findings from the phase 2 Simplici-T1 trial, researchers said the pill, a novel, liver-selective glucokinase activator known as TTP399, was associated with a placebo-subtracted HbA1c reduction of 0.32% at 12 weeks when compared with placebo.
“Further studies are required to define the role of TTP399 in the management of type 1 diabetes,” John Buse, MD, PhD, director of the Diabetes Center, director of the North Carolina Translational and Clinical Sciences Institute, executive associate dean for clinical research at the University of North Carolina School of Medicine in Chapel Hill and a principal investigator for the study, told Healio. “Whether it will provide for moderate benefits in all patients or big benefits in particular subgroups is an area of great interest to me. We are in the process of doing analyses to try to understand that better.”
Role of insulin
Researchers used two statistical approaches to evaluate the effects of 800 mg TTP399 in 85 adults. The primary statistical analysis evaluated the effect on HbA1c regardless of treatment adherence or notable changes in insulin administration. Under the primary statistical analysis, the trial achieved its primary objective by demonstrating improvements in HbA1c for TTP399 compared with placebo at week 12 (P = .03).
To eliminate the possibility that the reduction in HbA1c was driven by administration of excess insulin ( 3 U per day), researchers conducted a second estimand analysis. Based on this analysis, participants treated with TTP399 achieved a placebo-subtracted reduction in HbA1c of 0.32% (P = .001), according to the release. Participants assigned TTP399 experienced a mean 0.21% reduction in HbA1c; those assigned placebo experienced a 0.11% increase in HbA1c. Mean baseline HbA1c was 7.6% after the insulin optimization period.
Researchers said the drug was well tolerated, with no between-group differences in treatment-emergent adverse events overall or when stratified by system organ class. There was no diabetic ketoacidosis in either treatment group. There was no severe hypoglycemia in the treated group and one incident in the placebo group.
Improved glucose response
Participants assigned TTP399 experienced fewer symptomatic hypoglycemic episodes compared with those assigned placebo (2 vs. 8).
Daily time spent in the recommended glucose range improved by approximately 2 hours among participants who received TTP399 vs. placebo (P = .03). Those assigned TTP399 also reduced their total daily mealtime bolus insulin dose by a mean of 11% relative to baseline (P = .02), whereas participants assigned placebo experienced a mean 3% decrease relative to baseline.
“The development of a safe and effective therapy that improves glucose control is a critical step toward eliminating the dangerous highs and lows associated with type 1 diabetes,” Sanjoy Dutta, PhD, vice president of research for JDRF, said in the release. “The results from the Simplici-T1 trial indicate that TTP339 is a promising oral treatment option to help people with type 1 diabetes keep their HbA1c levels within a healthy range, and stay in a desirable glucose range for most of the day, while simplifying the daily management of the disease.”
TTP399 selectively activates glucokinase, a key regulator of glucose metabolism, in the liver. This activation has been shown to increase glucose utilization, which in turn lowers blood glucose. Simplici-T1 is the first study to test activation of glucokinase in patients with type 1 diabetes, evaluating daily oral TTP399 as an adjunct to insulin therapy.
Simplici-T1 is a randomized, double-blind, adaptive study assessing the safety and efficacy of TTP399 as an adjunct to insulin therapy for adults with type 1 diabetes. The primary endpoint was change in HbA1c at week 12.
The phase 2 study was conducted in two parts under the same protocol to evaluate the safety and efficacy of TTP399 for adults with type 1 diabetes during 12 weeks of daily dosing after a multiweek insulin optimization and placebo run-in period. For part 1, researchers enrolled 19 participants using insulin pump therapy and continuous glucose monitors. For part 2, researchers enrolled 85 participants using pump therapy or multiple daily injections; CGMs were allowed for participants using the devices for at least 3 months before the start of the study.
“Consistent with FDA guidance, a 0.3% improvement in HbA1c is considered clinically meaningful, and coupled with the well-controlled population of patients and favorable safety data from our clinical trials to date, this provides a strong basis for moving this potential first-in-class program forward,” Steve Holcombe, president and CEO of vTv Therapeutics, said in the release.
In the spring, the European Commission approved two noninsulin oral agents for use as adjuncts to insulin for adults with type 1 diabetes: dapagliflozin, an SGLT2 inhibitor previously approved for type 2 diabetes, and sotagliflozin, a first-in-class dual SGLT1 and SGLT2 inhibitor. The FDA, however, has been hesitant to accept such noninsulin options in the United States. As Healio previously reported, the agency rejected sotagliflozin (Zynquista, Sanofi and Lexicon) in March and, in July, declined to expand the indication for dapagliflozin (Farxiga, AstraZeneca) for use in type 1 diabetes.
Holcombe said the company plans to work with the FDA to develop a pathway for TTP399 and initiate a registration trial this year. – by Regina Schaffer
Disclosures: JDRF supported this study. Buse reports he receives research support from or serves as an adviser for Adocia, AstraZeneca, Boehringer Ingelheim, Dexcom, Elcelyx Therapeutics, Eli Lilly, Intarcia, Johnson & Johnson, Lexicon, Metavention, NovaTarg, Novo Nordisk, Sanofi, Senseonics, Theracos and vTv Therapeutics, and holds stock options in Mellitus Health and PhaseBio Pharmaceuticals. Dutta is vice president of research for JDRF.