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

Background: PB-201, a partial, pancreas/liver-dual glucokinase activator, showed good tolerance and glycaemic effects in multinational studies. This study determined its optimal dose, safety, pharmacokinetics, and pharmacodynamics in Chinese patients with type 2 diabetes. Methods: In this double-blind, randomised, four-period, crossover, phase 1 trial in China, conducted at the Peking University Third Hospital, adult patients with drug-naive type 2 diabetes were randomised (1:1:1:1) to four sequence groups using a computer-generated randomisation table. In each period, they received oral placebo or PB-201 (50+50, 100+50, or 100+100 mg split doses) for 7 days. Investigators and patients were masked to treatment assignment. The primary endpoints were safety and pharmacokinetics. Continuous glucose monitoring was used to delineate the glucose excursion profile. Trial registration number: NCT03973515. Findings: Between August 27, 2019 and December 19, 2019,16 patients were randomised. PB-201 showed a dose-proportional pharmacokinetic profile without apparent accumulation in the body and induced dose dependent lowering of blood glucose. PB-201 at 50+50, 100+50, and 100+100 mg increased mean time in range (49.210% [standard deviation 27], 56.130% [25], and 63.330% [20] with three doses, respectively) versus placebo (49.380% [27]) and reduced estimated glycated haemoglobin from baseline (-0.5445% [1.654],-1.063% [1.236], and-1.888% [1.381] vs-0.581% [1.200]). Fifteen patients (93.8%) had treatment-emergent adverse events, which were mild. No patients had hypoglycaemia with venous/capillary glucose <3.9 mmol/ L or nocturnal hypoglycaemia. Interpretation: PB-201 100 mg twice daily is identified as the optimal dose, which shows promising glucose lowering effects and low risks of hypoglycaemia and other side effects. Further investigation of PB-201 100 mg twice daily in confirmatory trials is warranted. Funding: PegBio. (c) 2021 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)