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 Trial

Abstract

Background: PB-201, a partial, pancreas/liver-dual glucokinase activator, showed good tolerance and glycaemic effects in multinational studies. We aimed to determine its optimal dose and to evaluate its 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 (NCT03973515), 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. Findings: Between July 18, 2019 and September 05, 2019, 16 patients were randomised. PB-201 showed a dose-proportional pharmacokinetic profile and dose-dependent lowering of blood glucose, similar to findings in non-Chinese populations. PB-201 at 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]). All treatment-emergent adverse events 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. Trial Registration: This trial was registered with ClinicalTrials.gov, number NCT03973515. Funding: PegBio. Declaration of Interest: YD and MX are employees of PegBio, and HZ is an ex-employee of PegBio. LJ has received fees for lecture presentations from AstraZeneca, Merck, Novartis, Lilly, Roche, Sanofi-Aventis and Takeda; consulting fees from AstraZeneca, Merck, Novartis, Lilly, Roche, Sanofi-Aventis and Takeda; and grants/research support from AstraZeneca, Bristol-Myers Squibb, Merck, Novartis and Sanofi-Aventis. All other authors declare no competing interests. Ethical Approval: The study protocol and informed consent information were approved by the ethics committee at Peking University Third Hospital.