Investigational once-daily pill reduces HbA1c in type 1 diabetes, without hypoglycemia
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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 presenter.
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.
“This may be the first adjunctive therapy that can help people improve their glycemic control without increasing the risk for hypoglycemia,” Carmen Valcarce, PhD, chief scientific officer of vTv Therapeutics, told Healio. “Fear of hypoglycemia is what keeps people from achieving their target goals. That is the major take-home message.”
Research for adjunctive, oral pharmacotherapies to treat type 1 diabetes has been limited by hypoglycemia and diabetic ketoacidosis, Valcarce said during an online presentation of the virtual European Association for the Study of Diabetes annual meeting. In a study of 190 people with type 2 diabetes, TTP399 was shown to reduce HbA1c by a mean of 0.9% vs. placebo, she said.
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 (greater than 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 a press 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 DKA in either treatment group. There was no severe hypoglycemia in the treated group and one incident in the placebo group.
TTP399 reduced severe and symptomatic hypoglycemic events by 40% compared with placebo, with 20% of participants assigned placebo and 12% of participants assigned TP399 experiencing at least one severe or symptomatic hypoglycemic event.
“Even though we did not expect to see an increase in hypoglycemia, we were very pleased to see that we could, in fact, decrease it,” Valcarce told Healio.
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.
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.
“This adds another tool in the toolbox for people with type 1 diabetes,” Valcarce told Healio. “Right now, they only have one tool, insulin, and it is a tricky tool to use. This will simplify treatment and reduce risk for hypoglycemia, and it will help people to achieve their target glucose, which will, in turn, reduce risk for long-term complications.”
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Valcarce C, et al. Abstract #50. Presented at: EASD Annual Meeting; Sept. 21-25, 2020 (virtual meeting).
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