Head-to-head superiority to high-dose dulaglutide: first phase III clinical trial of mazdutide in Chinese patients with type 2 diabetes met study endpoints

The study results suggested that mazdutide was superior compared with dulaglutide for glycaemic control, and mazdutide also showed multiple cardiometabolic benefits in T2D patients including weight loss, blood lipid, blood pressure, serum uric acid, liver enzymes, etc.

DREAMS-2 (ClinicalTrials.gov, NCT05606913) is a multi-center, randomized Phase III clinical study to compare the efficacy and safety of mazdutide and dulaglutide in Chinese subjects with T2D who have inadequate glycemic control with metformin monotherapy or combination therapy of metformin with other oral drugs. The study enrolled 731 subjects to receive either mazdutide 4.0 mg, mazdutide 6.0 mg or dulaglutide 1.5 mg for 28 weeks. The primary endpoint was the change from baseline to week 28 in glycated hemoglobin (HbA1c) levels. The study used a non-inferiority design, and further superiority testing was performed after non-inferiority was achieved.

The primary endpoint was successfully met , showing a robust glucose-lowering efficacy of mazdutide. After 28 weeks of treatment, mazdutide 4.0 mg and mazdutide 6.0 mg showed non-inferiority to dulaglutide 1.5 mg in terms of improvement in HbA1c level from baseline. Based on these results, the superiority test was further performed, and both mazdutide 4.0 mg and 6.0 mg achieved superiority to dulaglutide 1.5 mg.

The key secondary endpoints showed mazdutide’s superior benefits in both glucose-lowering and weight loss. Statistical superiority was achieved in the following endpoints in both mazdutide 4.0 mg and mazdutide 6.0 mg groups after 28 weeks of treatment, including the change from baseline in HbA1c (superiority), percent change from baseline in body weight, proportion of subjects with HbA1c less than 7.0% and weight loss of greater than 5%, and proportion of subjects with HbA1c less than 7.0%.

Mazdutide showed comprehensive benefits beyond glucose-lowering and weight loss in multiple cardiometabolic indicators (blood pressure, blood lipids, serum uric acid, and liver enzymes). Mazdutide also showed significant advantages compared with dulaglutide in various indicators, including the proportion of subjects with HbA1c less than 6.5%, changes in fasting blood glucose and seven-point fingerstick blood glucose from baseline, the proportion of subjects with body weight loss of greater than 5% and greater than 10%, absolute change in body weight from baseline, waist circumference, body mass index (BMI), systolic blood pressure (SBP), triglyceride (TG), serum uric acid (UA), alanine aminotransferase (ALT) and aspartate aminotransferase (AST), etc.

Favorable safety and tolerability profile: i. Gastrointestinal adverse reactions were the most common adverse events, most were mild to moderate in severity , transient, and mainly occurred during the first 12-week titration period. ii. No severe hypoglycemia occurred; the incidence of moderate or severe hypoglycemia was comparable to that of dulaglutide; and the incidence of hypoglycemia was lower in indirect comparison to reported in registrational studies of other GLP-1 drugs. iii. No signal of increased cardiovascular risk throughout the treatment period, similar to dulaglutide. iv. The overall safety profile was consistent with that observed in previous clinical studies of mazdutide and no new safety signals observed.

Mazdutide is the first GLP-1R/GCGR dual agonist in the regulatory review status, with the first new drug application (NDA) for chronic weight management under review by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA). DREAMS-2, as one of the registrational clinical studies of mazdutide, will provide high-quality evidence of mazdutide for Chinese population with T2D. Innovent plans to read out the results of another DREAMS-1 Phase III clinical study in mid-2024 and submit to the CDE an NDA for the treatment of T2D with mazdutide. Detailed data from the DREAMS-1 and DREAMS-2 studies will be further analyzed and published at academic congresses or in clinical journals.