Pharmacodynamics Post-Hoc Analysis of Glucose Kinase Activator Dorzagliatin (HMS5552)—Twelve Weeks Treatment in T2D Patients in China

In a phase II study, dorzagliatin, a novel glucokinase activator (GKA), demonstrated significant HbA1c reduction and safety profile in Chinese T2D patients. Two hundred fifty eight (258) T2D patients were randomly assigned to 5 groups (50mg BID, 75mg BID, 75mg QD, 100mg QD and placebo) for a 12 weeks treatment. Compared with placebo group, HbA1c changes from baseline was significantly lower in the 100mgQD (0.69%, P<0.05), 50mgBID (0.79%, P<0.01) and 75mgBID (1.12%, P<0.001) groups. Post-hoc analyses of the phase II results were conducted to investigate the effects of dorzagliatin on the composite response rate (defined as reaching HbA1c<7.0%, no weight gain and no hypoglycemia), efficacy response β cell functions (HOMA-IR and Disposition Index), and efficacy response in stratified subgroups. Post-hoc analysis showed that the composite response rate was 28.3% (P < 0·05) and 35.4% (P < 0·001), respectively for 50mgBID and 75mgBID groups. It was significantly higher than the placebo group. HOMA-IR and Disposition Index was improved at Week 12 for the 75 mg BID group compared with placebo. Improvement of HOMA-IR was maintained at Week 13, one week after treatment discontinuation. Subjects were stratified into subgroups according to their medical history, disease history, gender, age and BMI. In drug naïve subjects, HbA1c change from baseline was -0.85% in 75mgQD (P<0.05), -0.95% in 100mgQD (P<0.01), -1.04% in 50mgBID (P<0.01), -1.21% in 75mgBID (P<0.001), and -0.17% in placebo group. Significant HbA1c reduction was also observed in 75mgBID (-0.97%, P<0.05) in the subjects who were previously treated with other antidiabetic drugs. No significant trends were observed on HbA1c in subgroups stratified by disease history, gender, age and BMI. The post-hoc analysis demonstrated dorzagliatin provided a comprehensive disease management in T2D patients with benefits of β cell function and insulin resistance improvement in the early stage T2D patients.