Innovent's Mazdutide, China's First Dual-Target GLP-1R/GCGR Agonist for Glycemic Control and Weight Loss, Meets Primary Endpoint in Phase III DREAMS-2 Trial

On May 9, Innovent Bio announced that its Phase III clinical trial (DREAMS-2) of mazdutide (development code: IBI362), a dual glucagon-like peptide-1 receptor (GLP-1R)/glucagon receptor (GCGR) agonist, conducted in Chinese patients with type 2 diabetes, had met its primary endpoint. The results indicated that mazdutide demonstrated significantly superior glycemic control compared with dulaglutide, and showed more favorable comprehensive benefits across multiple metabolic parameters, including body weight, blood lipids, blood pressure, serum uric acid, and liver enzymes.

In August 2019, Innovent Bio and Eli Lilly expanded their collaboration from the oncology field to the diabetes field. Innovent Bio was granted the rights to develop and commercialize in China a potential global best-in-class novel clinical-stage diabetes drug from Eli Lilly, namely IBI362.

Mazdutide is the GLP-1R/GCGR dual agonist with the most advanced global clinical development progress, and its first indication for weight management is currently under review by the Center for Drug Evaluation (CDE) of the National Medical Products Administration (NMPA). As one of the pivotal clinical studies for mazdutide’s glucose-lowering indication, DREAMS-2 will provide high-quality evidence-based medical data for patients with type 2 diabetes and inadequate glycemic control in China, while further demonstrating the efficacy and safety of mazdutide.

DREAMS-2 (NCT05606913) is a multicenter, randomized, Phase III clinical study comparing the efficacy and safety of mazdutide versus dulaglutide in Chinese patients with type 2 diabetes who have inadequate glycemic control on metformin monotherapy or in combination with other oral antidiabetic drugs. The study enrolled 731 participants, who were randomly assigned to receive either mazdutide 4.0 mg, mazdutide 6.0 mg, or dulaglutide 1.5 mg for 28 weeks. The primary endpoint of the DREAMS-2 study was the change in glycated hemoglobin (HbA1c) from baseline. The study employed a non-inferiority design, with superiority testing conducted subsequently upon demonstration of non-inferiority.

Data show that DREAMS-2 met its primary endpoint, with mazdutide demonstrating robust glycemic-lowering efficacy. Key secondary endpoints indicated that mazdutide was superior to dulaglutide in both glucose lowering and weight reduction.

After 28 weeks of treatment, both mazdutide 4.0 mg and mazdutide 6.0 mg demonstrated non-inferiority to dulaglutide 1.5 mg in terms of HbA1c improvement from baseline. Further superiority testing confirmed that both mazdutide 4.0 mg and 6.0 mg were superior to dulaglutide 1.5 mg in lowering blood glucose levels.

Statistical superiority was achieved* for the change from baseline in HbA1c (superiority), the percentage change from baseline in body weight, the proportion of subjects achieving both HbA1c <7.0% and ≥5% reduction in body weight from baseline, and the proportion of subjects achieving HbA1c <7.0% after 28 weeks of treatment with mazdutide 4.0 mg and mazdutide 6.0 mg.

Mazdutide demonstrates significant comprehensive advantages across a broader range of glycemic control, weight reduction, and cardiometabolic parameters (including blood pressure, blood lipids, serum uric acid, and liver enzymes). Compared with dulaglutide, mazdutide shows significant superiority in all measured outcomes, including: the proportion of subjects achieving HbA1c ≤6.5%; changes from baseline in fasting plasma glucose and seven-point capillary blood glucose profiles; the proportion of subjects achieving weight reductions of ≥5% and ≥10% from baseline; absolute change in body weight from baseline; as well as waist circumference, body mass index (BMI), systolic blood pressure (SBP), triglycerides (TG), serum uric acid (UA), alanine aminotransferase (ALT), and aspartate aminotransferase (AST).

Under conditions of superior efficacy, mazdutide demonstrated a favorable safety and tolerability profile with no additional safety signals. During treatment, gastrointestinal adverse reactions were the most common adverse events; these were mild to moderate in severity and transient in nature, primarily occurring during the 12-week titration period. No cases of severe hypoglycemia were reported. The incidence of moderate or higher hypoglycemia was comparable to that of dulaglutide, and the overall hypoglycemia rate was low compared with other GLP-1 receptor agonists in their respective registration trials. No safety signals indicating an increased cardiovascular risk were observed during treatment, consistent with the profile of dulaglutide. The overall safety profile was consistent with previous clinical studies of mazdutide, with no new safety signals identified.

Currently, the GLP-1 therapeutic landscape is highly competitive. Beyond demonstrating excellent efficacy in glucose lowering, these agents are capturing a larger market share in weight management. According to a recent report by IQVIA, approximately 120 drugs for the treatment of obesity are currently in clinical development, with more than one-third exerting their effects through the GLP-1 pathway.

To capture market share from the two giants, Eli Lilly and Novo Nordisk, latecomers must demonstrate differentiated advantages. This requires not only superior efficacy and safety in their investigational pipelines, but also strategic developments such as long-acting formulations, oral administration, and the exploration of novel targets and indications.

To further capture market share, Eli Lilly and Novo Nordisk are continuously developing new drugs. Eli Lilly has two new drugs in Phase III clinical trials: an oral GLP-1 agent named orforglipron, with key data to be released next year; and an injectable therapy named retatrutide, which targets GLP-1, GIP, and glucagon. In addition, Eli Lilly has four other drugs in Phase I or Phase II trials, while Novo Nordisk currently holds five related new drug candidates. Multinational corporations (MNCs) such as Pfizer, Boehringer Ingelheim, Amgen, and Roche are also intensively engaged in the research and development of GLP-1 medications.

In China, in addition to Innovent Bio and Hengrui Medicine, which are leading in progress, there are also listed pharmaceutical companies such as Huadong Medicine, Hansoh Pharma, and Borui Medicine. Many companies are focusing on dual-target agonists. Borui Medicine’s GLP-1/GIP dual agonist BGM0504 is currently undergoing Phase II clinical trials for the treatment of type 2 diabetes and weight loss. Hansoh Pharma’s GLP-1R/GIPR dual-target agonist HS20094 is currently undergoing Phase II clinical trials for obesity.

Innovent Bio’s mazdutide is currently the most advanced candidate in China. Its marketing application for weight management was accepted by the NMPA in February this year, making it the first GLP-1R/GCGR dual agonist to file for market approval globally and positioning it as a likely contender to become the first domestically produced dual-target weight-loss drug.

Innovent Bio plans to announce the results of another Phase III clinical trial, DREAMS-1, in mid-2024 and submit a New Drug Application (NDA) to the Center for Drug Evaluation (CDE) for mazdutide in the treatment of type 2 diabetes. Detailed study data from DREAMS-1 and DREAMS-2 will be further analyzed and presented at academic conferences or published in academic journals.

References:
1. Innovent Bio Announces That the National Medical Products Administration Has Officially Accepted Its New Drug Application for the First Weight-Loss Indication of Mazdutide