The SimpliciT1 Study: A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Adaptive Study of TTP399, a Hepatoselective Glucokinase Activator, for Adjunctive Treatment of Type 1 Diabetes

Abstract

Despite advances in exogenous insulin therapy, many patients with type 1 diabetes do not achieve acceptable glycemic control and remain at risk for ketosis and insulininduced hypoglycemia. We conducted a randomized controlled trial to determine whether TTP399, a novel hepatoselective glucokinase activator, improved glycemic control in people with type 1 diabetes without increasing hypoglycemia or ketosis. RESEARCH DESIGN AND METHODS SimpliciT1 was a phase 1b/2 adaptive study. Phase 2 activities were conducted in two parts. Part 1 randomly assigned 20 participants using continuous glucose monitors and continuous subcutaneous insulin infusion (CSII). Part 2 randomly assigned 85 participants receiving multiple daily injections of insulin or CSII. In both parts 1 and 2, participants were randomly assigned to 800 mg TTP399 or matched placebo (fully blinded) and treated for 12 weeks. The primary end point was change in HbA 1c from baseline to week 12. RESULTS The difference in change in HbA 1c from baseline to week 12 between TTP399 and placebo was 20.7% (95% CI 21.3, 20.07) in part 1 and 20.21% (95% CI 20.39, 20.04) in part 2. Despite a greater decrease in HbA 1c with TTP399, the frequency of severe or symptomatic hypoglycemia decreased by 40% relative to placebo in part 2. In both parts 1 and 2, plasma b-hydroxybutyrate and urinary ketones were lower during treatment with TTP399 than placebo. CONCLUSIONS TTP399 lowers HbA 1c and reduces hypoglycemia without increasing the risk of ketosis and should be further evaluated as an adjunctive therapy for the treatment of type 1 diabetes.

Diabetic vascular diseases: molecular mechanisms and therapeutic strategies

“…Activation of glucokinases (Dorzagliatin, PB-201, AZD-1656, etc.) has a regulatory effect on glucose homeostasis, 372 – 377 but no additional vascular protective value has been reported yet. 378 , 379

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Safety, tolerability, pharmacokinetics, and pharmacodynamics of the glucokinase activator PB-201 and its effects on the glucose excursion profile in drug-naïve Chinese patients with type 2 diabetes: a randomised controlled, crossover, single-centre phase 1 trial

“…In a glucose-dependent manner, glucokinase stimulates insulin secretion in the pancreas and regulates glucose production and utilization in the liver. Up to now, a number of GKA candidates have been developed; however, only four candidates are currently being investigated globally (TTP399 [ 6 , 7 ], dorzagliatin [8] , globalagliatin [9] , and PB-201 [ 10 , 11 ]). Issues prohibiting the entry of most GKAs into late clinical phases include hypoglycaemia [ 12 , 13 ], hyperlipidaemia [ 12 , 13 ], risk of fatty liver [14] , and loss of efficacy over time [ 13 , 15 ].…”

Why Glucagon Matters for Hypoglycemia and Physical Activity in Individuals With Type 1 Diabetes

“…If approved, it would be the first oral pill to treat T1D. In the SimpliciT1 study that reports on this drug ( 31 ), TTP399 use lowered A1C levels, along with overall insulin requirements over 12 weeks. Study participants needed 11 percent less insulin for meals and spent two more hours each day with blood glucose in optimal ranges.…”