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

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.