(T-080) A phase I open-label sequential clinical trial and population oral minimal model to study pharmacodynamic interactions of dorzagliatin and empagliflozin in patients with type 2 diabetes and obesity

Yuanhui Zhang, NA – postdoctor, Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China; Lingge Feng, NA – Director, Research and Discovery Technology, Hua Medicine (Shanghai); Jiayi Zhang, NA – Director, Early Development, Hua Medicine (Shanghai); Yu Sun, NA – Medical Director, Early Development, Hua Medicine (Shanghai); Yu Zhao, NA – Sr. Director, Medical Science, Hua Medicine (Shanghai); Muhan Jiang, NA – master, Peking university of Third Hospital; Xiang Liu, NA – Biostatistics Director, Hua Medicine; Zhiyin Fang, NA – Sr. Biostatistics Manager, Hua Medicine; Gregory Tracey, NA – Medical Director at Frontage Laboratories, Frontage Clinical Services, Inc.; Li Chen, NA – CEO, Hua Medicine (Shanghai); Dongyang Liu, NA – Ph.D., Senior Researcher, Ph.D. Supervisor, Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China

OBJECTIVE Dorzagliatin, as the first marketed glucokinase activator, was recognized for its good clinical efficacy and safety profile in patients with type 2 diabetes mellitus . Empagliflozin, a sodium-dependent glucose transporters 2 inhibitor , exhibited advantages in lowering glucose and protecting renal and cardiovascular function. The main objective of this study is to evaluate the pharmacokinetic, pharmacodynamic characteristics of the combination of dorzagliatin and empagliflozin, and to assess whether the short-term combination use (4-5 days) of dorzagliatin and empagliflozin has a greater improvement in beta cell function and insulin sensitivity in patients with type 2 diabetes compared to monotherapy by population OMM. METHODS A phase I study (ClinicalTrials.gov, NCT03790787) was conducted in sixteen obese patients with T2DM from US. Empagliflozin, empagliflozin+ dorzagliatin and dorzagliatin were administered over five days sequentially, the PK (AUC (area under curve), Cmax (maximum concentration) for drug concentrations), PD (AUEC (area under effect curve) of blood glucose, C-peptide, and insulin concentrations after oral glucose tolerance test). Mechanistic parameters indicating different phase beta-cell function and overall insulin sensitivity were further estimated by a new method which is called population oral minimal model. RESULTS There were no significant PK DDI and obvious increase in frequency or severity of any adverse events after the combination of dorzagliatin and empagliflozin. Combination therapy significantly enhanced the glucose-lowering effect and C-peptide secretion levels (iAUC_0-4h). More importantly, the population OMM method more comprehensively and simply quantitatively evaluated the improvement of beta cell function and insulin sensitivity after short-term drug combination. The combination therapy significantly improved different phase insulin secretion capacity (φ_d, φ_s and φ_tot) and total insulin sensitivity compared to dorzagliatin/empagliflozin in diabetic patients.CONCLUTIONS The promising potential benefit of the combination of dorzagliatin and empagliflozin was found in lowering glucose, enhancing beta-cell function of glucose-stimulated insulin secretion, and improving insulin action with no PK characteristics change and good safety.

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