The 48-week outcomes from a Phase 2 clinical study of higher dose (9mg) mazdutide in Chinese subjects with obesity have demonstrated significant weight loss efficacy, favourable safety and multiple metabolic benefits. Innovent Biologics has said the results suggested that mazdutide 9mg may provide an alternative option to metabolic surgery for long-term weight management of Chinese subjects with moderate-to-severe obesity. Innovent plans to initiate a Phase 3 clinical study of mazdutide 9mg in Chinese patients with obesity by the end of 2023.
The Phase 2 study is a randomised, double-blind, placebo-controlled study intended to evaluate the efficacy and safety of higher dose 9mg mazdutide in Chinese subjects with obesity (mean baseline body mass index (BMI) of 34.3 kg/m2). Metabolic surgery is recommended for Chinese population with a BMI of 32.5 kg/m2 or above. A total of 80 subjects were enrolled and randomised in a 3:1 ratio to mazdutide 9mg or to placebo. The primary endpoint of the study is the percent change in body weight from baseline versus placebo after 24 weeks of treatment. The study also extended to 48 weeks in subjects that agreed to continue receiving additional 24 weeks of double-blind extension treatment.
In May 2023, Innovent announced that this clinical study met its 24-week primary endpoint, the placebo-adjusted mean percent change in body weight from baseline was -15.4% (-14.7 kg). Meanwhile, 31.7% and 21.7% of the subjects in the mazdutide 9mg group achieved 15% or more and 20% or more weight loss from baseline, respectively.
After reaching the 24-week primary endpoint, 59 subjects (43/60 in the mazdutide group and 16/20 in the placebo group; mean baseline BMI of 34.7kg/m2, mean baseline weight of 98.4kg) agreed to continue into the 24-week double-blind extension period of the study drug. After 48 weeks of treatment, the placebo-adjusted mean percent change in body weight from baseline was -18.6% (-17.8 kg). Meanwhile, 51.2% and 34.9% of the subjects in the mazdutide 9mg group achieved 15% or more and 20% or more weight loss from baseline, respectively.
"As a chronic disease with complex causes, obesity is an important risk factor of metabolic diseases, cardiovascular and cerebrovascular diseases and tumors. Obesity requires long-term treatment and management as well as the attention of the entire society. The 48-week results of mazdutide 9mg in Chinese subjects with obesity revealed robust weight loss efficacy of GLP-1R and GCGR dual agonists, which is at the forefront of the weight loss efficacy of GLP-1 drugs. We also observed cardiometabolic benefits after mazdutide 9mg treatment, including reductions in uric acid levels and liver fat content,” said Professor Linong Ji, the leading principal investigator of the study, Peking University People's Hospital. “Mazdutide has demonstrated strong and long-term efficacy, as well as good tolerability and safety, suggesting the advantages of mazdutide as a novel dual agonist of GLP-1 and GCG receptors. Mazdutide 9mg is anticipated to provide an effective and safe weight loss treatment for Chinese subjects with moderate-to-severe obesity and may offer a potential alternative to surgery. I am looking forward to the Phase 3 clinical study of mazdutide 9mg in Chinese subjects with obesity, and its translation into clinical applications in the future."
Corresponding to changes in body weight, the mean waist circumference and blood pressure of subjects in the mazdutide group also decreased. No subject in the mazdutide group discontinued treatment due to adverse events through 48 weeks of treatment. There were no serious adverse events occurred through 48 weeks of treatment.
Gastrointestinal adverse reactions (nausea, vomiting and diarrhoea) were the most common adverse events, most of mild or moderate severity. The incidence of gastrointestinal adverse reactions reduced during the extended treatment period to 48 weeks and most were mild.
The increase in heart rate in the mazdutide group was similar to that in the placebo group after 24 weeks of treatment, with no further increase in heart rate being observed during the extended treatment period to 48 weeks. No signal of increased cardiovascular risk was observed throughout the treatment period of 48 weeks.
The profile of adverse events through 48 weeks of treatment was consistent with that observed in previous studies of mazdutide and other GLP-1-based drugs, with no new safety signals observed.
In subjects with baseline liver fat content (as measured by MRI-PDFF) greater than 5%, the liver fat content was reduced by 73.3% after 24-week treatment of mazdutide. In the overall population, mazdutide induced 45.5% reductions in ALT levels relative to placebo after 24-week treatment. The above benefits were maintained during extended treatment period to 48 weeks.
After 24-weeks of treatment, mazdutide 9mg significantly reduced triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and serum uric acid (sUA) levels, and the reductions were maintained during the extended treatment period to 48 weeks. In addition, high-density lipoprotein cholesterol (HDL-C) levels were stable throughout the treatment period of 48 weeks.
Innovent entered into a licensing agreement with Eli Lilly and Company (Lilly) for the development and potential commercialization of OXM3 (also known as mazdutide), a GLP-1R and GCGR dual agonist, in China. As a mammalian oxyntomodulin (OXM) analogue, in addition to the effects of GLP-1 receptor agonists on promoting insulin secretion, lowering blood glucose and reducing body weight, mazdutide may also increase energy expenditure and improve hepatic fat metabolism through the activation of glucagon receptor.