Editor's note: Recently, the results of the Phase II clinical study of the class-leading GLP-1 receptor (GLP-1R)/glucagon receptor (GCGR) dual agonist Masdotide (R&D code: IBI362) in overweight/obese subjects in China were published in the journal Nature Communications[1]. Professor Ji Linong from Peking University People's Hospital served as the principal investigator of the study. The results of the study showed that the weight loss effect of Masdotide was rapid and robust, safe and well tolerated, and could bring comprehensive cardiometabolic benefits to patients.
It is worth noting that this study was recently selected by Nature Communications as one of the 50 most important studies in the field of clinical translational medicine in the world [2] and was listed as the Editor's Highlights [3], indicating that the research results have been recognized by the scientific community and have made significant contributions to clinical translational medicine in this field.
Overweight and obesity, often associated with hyperglycaemia, hypertension, dyslipidemia and hyperuricemia, are among the leading causes of increasing deaths associated with noncommunicable diseases and pose a significant threat to public health. Over the past 40 years, the prevalence of overweight and obesity has increased rapidly, and the prevalence of overweight/obesity among adults in China has now reached more than 50% [4].
Various evidence suggests that a weight loss of 5%~15% can significantly improve metabolic disorders and reduce the risk of type 2 diabetes, cardiovascular disease, metabolic liver disease, and other obesity-related comorbidities [5]. The Chinese expert consensus [6] suggests that for obese adults or overweight adults with weight-related comorbidities, if the weight is not fully controlled after 3~6 months of dietary or exercise intervention, drug therapy can be considered. However, the current approved bariatric treatment drugs in China are very limited and far from meeting the clinical needs.
Maxdotide is a first-in-class next-generation GLP-1R/GCGR dual agonist that has entered a phase III clinical trial. In addition to promoting insulin secretion, lowering blood glucose and weight loss by agitating GLP-1R, it can also increase energy expenditure, enhance weight loss efficacy, and improve liver fat metabolism by agitating GCGR. The results of the Phase II clinical trial were recently published in the journal Nature Communications [1].
A unique study design to explore the appropriate dose for overweight/obesity treatment
This 24-week clinical study aims to investigate the appropriate dose of marstopeptide in adult overweight/obese subjects and to observe the preliminary dose-related safety and efficacy results. The first phase of this publication aims to evaluate the efficacy and safety of three doses (3 mg, 4.5 mg, and 6 mg) of once-weekly subcutaneous administration of mestolitide for weight loss in overweight or obese subjects.
A total of 248 participants with obesity [body mass index (BMI) ≥28.0 kg/m2] or overweight (24.0 kg/m2≤ BMI<28.0 kg/m2) with ≥ 1 obesity-related complications were randomized to receive marstotide 3 mg, 4.5 mg, 6 mg, or placebo once weekly subcutaneous injection for 24 weeks.
The primary endpoint was the percentage change from baseline in body weight at week 24, and the secondary efficacy endpoints included: (1) the proportion of subjects who lost ≥5% and ≥10% from baseline to week 24, (2) change in weight, waist circumference, and BMI at week 24, (3) change in HbA1c, fasting blood glucose, and fasting insulin at week 24, and (4) cardiovascular risk factors (blood pressure, total cholesterol, LDL cholesterol, (5) changes in uric acid and alanine aminotransferase (ALT) at weeks 12 and 24, and changes in IWQOL-Lite score (assessing quality of life). Safety endpoints include safety, tolerability, and immunogenicity.
A total of 16.1% of overweight patients were included to enrich the evidence of GLP-1RA weight loss in the overweight population in China
Previous studies have shown that Chinese people may have higher body fat content and higher cardiovascular risk than Western populations at the same BMI level [7]. The BMI standards for overweight and obesity in China (24 kg/m2 and 28 kg/m2, respectively) are lower than those of the World Health Organization. According to the latest data, 34.3% of Chinese adults are overweight (BMI 24~28 kg/m2) [1]. Therefore, it is of great significance to study the therapeutic response of overweight adults in China to GLP-1RA.
Although GLP-1RA drugs have been studied in many foreign countries for weight loss, the research data in the overweight population in China are very limited. As an example, semaglutide 2.4 mg in a weight-loss study in an Asian population included 80 percent of Chinese patients, but excluded participants with a BMI of < 27 kg/m2 (ie, overweight people with a BMI of 24~27 kg/m2) [8]. In this study of Masdopeptide, 16.1% of participants were overweight at baseline. Therefore, the results can provide important evidence for the applicability of marstotide in the weight management of overweight adults in China.
Weight loss is rapid and potent, making it competitive with GLP-1RA
The results showed that at week 24, the placebo group had a 1.0% increase in body weight from baseline, while the 3 mg, 4.5 mg, and 6 mg groups had a 6.7%, 10.4%, and 11.3% decrease in body weight (Figure 1), with treatment differences of -7.7%, -11.4%, and -12.3%, respectively, compared with the placebo group.
Figure 1. Weight efficacy endpoint
At week 24, 58.1%, 82.5%, and 80.3% of participants had a 5.0% ≥weight loss from baseline in the 3 mg, 4.5 mg, and 6 mg groups, compared with 4.8% in the placebo group, and 19.4%, 49.2%, and 50.8% in the placebo group with a ≥10.0% weight loss from baseline, compared with 0% in the placebo group (Figure 1).
BMI results were consistent with weight results. At week 24, the BMI of the 3 mg, 4.5 mg, and 6 mg groups decreased by 2.3 kg/m2, 3.3 kg/m2, and 3.6 kg/m2, respectively, and the placebo group increased BMI by 0.4 kg/m2 from baseline.
In this study, the weight-loss effect of Maxdotide was comparable to the results observed in clinical trials of other GLP-1RA drugs with excellent efficacy in weight loss.
Reduce cardiovascular risk factors such as waist circumference, blood pressure, and blood lipids, and bring comprehensive cardiometabolic benefits
Similar to the results of previous GLP-1RA clinical trials, this study also observed a certain degree of improvement in blood glucose, blood pressure, blood lipids, waist circumference, and aminotransferase levels after treatment with Mastotide (Table 1).
Table 1. Change in cardiometabolic risk factors at week 24
Among them, the results of the improvement of blood glucose and insulin levels showed that in Chinese adults who are overweight or obese but not accompanied by diabetes, the effect of marstotide has the effect of improving glucose metabolism and alleviating insulin resistance.
In addition, it is worth noting that at week 24, the average reduction of uric acid in the 3 mg, 4.5 mg, and 6 mg groups was 48.6 μmol/L, 54.9 μmol/L, and 72.6 μmol/L, respectively. To date, no blood uric acid decline has been reported in large-scale randomized controlled clinical studies of other GLP-1 drugs.
Since most of these metabolic indicators are independent risk factors for cardiovascular disease, the possibility that treatment with Mastotide may improve the cardiovascular outcomes of patients needs to be further verified by long-term clinical studies.
Safety and tolerability were good, and no drug-related serious adverse events occurred or led to permanent discontinuation
Chronic weight management often requires long-term medication, and intolerable gastrointestinal adverse events may lead to early discontinuation of the medication. Therefore, it is essential that the drug has a good safety and tolerability.
In this study, the most common adverse events caused by marstotide were mainly gastrointestinal symptoms, including nausea, diarrhea, and vomiting, consistent with the characteristics of GLP-1RAs. The vast majority of patients have gastrointestinal symptoms that occur during dose titrations, are mild/moderate and short-lived, and can be relieved by symptomatic treatment or decreasing the dose of marstalptide.
More importantly, there were no serious adverse events related to Masdotide or any adverse events leading to permanent discontinuation of the study drug as judged by the investigator to occur in this study. The well-tolerated and safe profile of Masdotide will ensure long-term benefits for patients to comply with treatment and maintain good adherence.
summary
As a class-leading next-generation GLP-1R/GCGR dual agonist, the results of the phase II clinical study published by Maxdotide this time demonstrate its significant weight loss efficacy, good safety and tolerability, and comprehensive cardiometabolic benefits. The study was selected as one of the 50 most important studies in the field of clinical translational medicine by Nature Communications, a top international journal, and was listed as the editor-in-chief's choice study, reflecting its important clinical significance. For Chinese overweight/obese patients, Maxotide will be a weight-loss treatment option that is worth looking forward to.
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2.https://www.nature.com/collections/ecgchegdhe
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