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Dorzagliatin monotherapy in Chinese patients with type 2 diabetes: a dose-ranging, randomised, double-blind, placebo-controlled, phase 2 study

– 2018-05-04

On May 4, 2018, the results of phase II clinical study of the glucokinase activator Dorzagliatin (HMS5552) were published in The Lancet Diabetes & Endocrinology, a wellknown British academic journal. This marked the first time The Lancet Diabetes & Endocrinology has published the achievements of a clinical research in China on novel drugs for type 2 diabetes.

The Lancet Diabetes & Endocrinology was established in 2013. As one disease area focused journal of The Lancet series, it covers multiple fields such as diabetes, obesity, metabolism and nutrition. Up to now, more than a thousand articles of various categories have been published. In the 2016 Journal Citation Reports published by Clarivate Analytics, the impact factor of The Lancet Diabetes & Endocrinology was 19.74, ranking it the number one clinical research journal in the field of diabetes and endocrinology.

The discovery of diabetes can date back to 3,500 years ago and it can be categorized into type 1 and type 2 diabetes. In 2017, there were approximately 450 million diabetic patients worldwide, of whom more than 120 million were from China. At present, the basic management of diabetes in China is still far behind the management of other chronic diseases. Current glucose lowering drugs have poor control over the fluctuation of blood glucose. The incidence of complications is high in patients at late stage of different types of diabetes.

Dorzagliatin, a glucokinase activator, is an oral anti-diabetic drug with novel mechanism and structure. It activates the glucokinase in the liver, islets, and intestines through allosteric effects, repairs the impaired glucose sensor and processor function of glucokinase in patients with type 2 diabetes and exerts the physiological synergistic control on glucose homeostasis.

The Hua Medicine (Shanghai) Ltd. (hereinafter referred to as: Hua Medicine) was the sponsor of the phase II clinical study of Dorzagliatin and completed the study in cooperation with 22 clinical research sites in China. This was the first phase II clinical study of Dorzagliatin. A total of 258 patients were randomized to five groups: placebo, 75 mg QD, 100 mg QD, 50 mg BID and 75 mg BID. After 12-week treatment, the reduction in glycated hemoglobin (HbA1c) in the 50 mg BID and 75 mg BID groups was 0.79% and 1.12% and the reduction was statistically significant compared with the placebo group. The incidence of adverse events was similar between the groups and no drug-related serious adverse events or severe hypoglycemia was reported.

Further analyses also demonstrated that, after 12-week treatment, the homoeostasis model assessment of insulin resistance and disposition index in the 75 mg BID group improved compared with placebo group and this effect was still observed at one week after the discontinuation of treatment, indicating that Dorzagliatin had a good and lasting effect on improving islet βcell function.

Treatment of type 2 diabetes is associated with the risk of inducing hypoglycemia and weight gain, and patients with type 2 diabetes may suffer from complications such as hypertension, dyslipidemia, and obesity. Therefore, some new treatment guidelines set new therapeutic goals on the basis of hyperglycemia control. For example, in 2009, the American Diabetes Association defined three different goals for the treatment of type 2 diabetes: HbA1c < 7%; avoid hypoglycemia; control or reduce weight. The single efficacy endpoint commonly used in the past cannot be used to evaluate multiple therapeutic goals. Therefore, some clinical studies on the treatment of type 2 diabetes have begun to use the composite endpoint as an efficacy endpoint. The composite endpoint consists of two or more conventional efficacy or safety endpoints, all of which must be met simultaneously before the composite endpoint can be used to evaluate clinical efficacy. The advantage of composite endpoint is to increase statistical power and to assess the efficacy and safety of certain treatment comprehensively.

In the phase II study of Dorzagliatin, the composite endpoint was defined as the proportion of patients with HbA1c < 7%, no weight gain, and no hypoglycemia. The results showed that the proportion of patients who reached the composite endpoint in the 50 mg BID and 75 mg BID groups was significantly higher than that in the placebo group. In addition, compared with the results from composite endpoints of other glucose lowering agents, data showed that the Dorzagliatin response rate of composite endpoint was much higher than other oral glucose lowering medications, and also looks better than some injectable glucose lowering agents such as liraglutide 1.2 mg, exenatide and insulin glargine.

Note: Data from Diabetes, Obesity and Metabolism 14:  77–82, 2012 and Lancet Diabetes Endocrinol 2018 (https://doi.org/10.1016/S2213-8587 (18) 30105-0), remapping.

Sponsored by Hua Medicine, several pre-clinical studies and five Phase I clinical studies on Dorzagliatin (a dual-acting full glucokinase activator) have been completed. The results showed that Dorzagliatin had good human pharmacokinetics and enzyme kinetics and good safety and could effectively reduce 24-hour plasma glucose levels and increase the early phase insulin secretion. The Dorzagliatin phase II clinical study, which was sponsored by Hua Medicine, demonstrated for the first time that Dorzagliatin had good control on blood glucose and good safety in Chinese patients with type 2 diabetes. Dorzagliatin can be used in patients with type 2 diabetes to increase the blood glucose sensor function of glucokinase and achieve excellent control on blood glucose. In addition, Dorzagliatin does not increase the risk of hypoglycemia, dyslipidemia, hepatic injury, and body weight. The gastrointestinal side effects were not found during the study.

The results of the phase II clinical study of Dorzagliatin support the future study on Dorzagliatin as a monotherapy in patients at early stage of type 2 diabetes and support the study on combined therapy with existing drugs such as metformin. At present, two phase III clinical studies of Dorzagliatin in Chinese patients are ongoing. The patient populations for the two studies are Chinese drug naive patients with type 2 diabetes and patients in whom metformin failed to keep sufficient glycemic control. Dorzagliatin is the first glucokinase activator in the world that entered into the Phase III clinical study.


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