Mazdutide

BACKGROUND: Once-weekly dual glucagon and glucagon-like peptide-1 receptor agonist mazdutide, administered at 4 and 6 mg, provides substantial weight loss in Chinese adults with overweight or obesity. This trial aimed to evaluate the efficacy and safety of mazdutide 9 mg in Chinese adults with obesity. METHODS: In this randomized, double-blind, placebo-controlled phase 2 trial (NCT01904913), participants with a body mass index (BMI) ≥30 kg/m2 and without diabetes were randomized 3:1 to receive mazdutide 9 mg or placebo for 24 weeks. The primary endpoint was the percentage change in body weight from baseline to week 24. FINDINGS: Eighty participants were randomized and received mazdutide 9 mg (n = 60) or placebo (n = 20). At week 24, the mean percentage change in weight from baseline was -12.78% with mazdutide 9 mg and 1.80% with placebo (treatment difference: -14.58% [95% confidence interval (CI) -18.00, -11.16], p < 0.0001). Weight reduction ≥5% was achieved by 81.7% of participants with mazdutide after 24-week treatment, while no participants with placebo achieved this threshold. Mazdutide treatment was associated with greater improvements in cardiometabolic risk factors vs. placebo. The most common adverse events included nausea (50.0% with mazdutide vs. 0% with placebo), diarrhea (38.3% vs. 10.0%), and vomiting (36.7% vs. 10.0%), predominantly mild to moderate in severity. CONCLUSIONS: Mazdutide 9 mg was safe and led to substantial weight reductions in Chinese adults with a BMI ≥ 30kg/m2 but without diabetes after 24-week treatment. These results support further clinical development of mazdutide 9 mg for the treatment of obesity. FUNDING: This study was sponsored by Innovent Biologics.

Mazdutide is a once-weekly glucagon and glucagon-like peptide 1 receptor dual agonist developed for the treatment of type 2 diabetes (T2D)1. Here we report on a randomized phase III trial assessing the efficacy and safety of mazdutide, compared with dulaglutide, in participants with T2D who were also treated with background oral anti-diabetic drugs. In this study, 731 participants with T2D were randomized 1:1:1 to receive 4 mg mazdutide, 6 mg mazdutide or 1.5 mg dulaglutide for 28 weeks. Both doses of mazdutide showed non-inferiority and superiority to the 1.5-mg dose of dulaglutide in terms of the mean change in the diagnostic marker glycated haemoglobin A1c (HbA1c) from baseline to week 28, with a least-squares mean treatment difference of -0.24% (P = 0.0032) for 4 mg mazdutide and -0.30% (P = 0.0003) for 6 mg mazdutide, relative to 1.5 mg dulaglutide. Significantly greater reductions in body weight were achieved with mazdutide than with dulaglutide, with a least-squares mean treatment difference of -3.78% for 4 mg mazdutide and -5.76% for 6 mg mazdutide (both P < 0.0001), relative to dulaglutide. Moreover, significantly more participants who received mazdutide 4 mg or 6 mg reached the composite end point of HbA1c < 7.0% with a body-weight reduction of at least 5% at week 28 (both P < 0.0001), compared with those who received dulaglutide. The most common treatment-emergent adverse events were diarrhoea, nausea and vomiting. In summary, we found that in Chinese participants with T2D, 28 weeks of treatment with mazdutide (4 mg and 6 mg) provided reductions in HbA1c and body weight that were superior to those attained with 1.5 mg dulaglutide. Mazdutide was generally safe, although the incidence of gastrointestinal adverse events was higher for mazdutide than for dulaglutide.

Despite advances in type 2 diabetes (T2D) management, unmet needs remain for therapies that effectively control hyperglycaemia while addressing comorbid metabolic disorders1,2. Here we assessed the efficacy and safety of the dual glucagon receptor (GCGR)/glucagon-like peptide-1 receptor (GLP-1R) agonist mazdutide monotherapy versus placebo in Chinese adults with T2D controlled inadequately with diet and exercise alone. In this phase 3 trial, 320 participants (mean glycated haemoglobin A1c (HbA1c) of 8.24%, body mass index of 28.2 kg m-2 and diabetes duration of 1.9 years) were randomized 1:1:1 to receive weekly subcutaneous injections of mazdutide (4 mg or 6 mg) or placebo for 24 weeks, followed by a 24-week extended mazdutide treatment. At week 24, mazdutide significantly reduced HbA1c versus placebo (primary endpoint): -1.57% with mazdutide 4 mg and -2.15% with mazdutide 6 mg, versus -0.14% with placebo, with treatment differences of -1.43% and -2.02% (both P < 0.0001). Weight loss from baseline at week 24 occurred with -5.61% (4 mg) and -7.81% (6 mg) versus -1.26% (placebo) (both P < 0.0001). Furthermore, more participants with mazdutide achieved HbA1c < 7.0%, weight loss ≥ 5% (all P < 0.0001) and composite endpoints (HbA1c < 7.0% and weight loss ≥ 5%) versus placebo (P = 0.0006 for 4 mg; P < 0.0001 for 6 mg) at week 24. The most common adverse events-diarrhoea, decreased appetite and nausea-were consistent with GLP-1R agonists. These results establish mazdutide monotherapy as an effective intervention providing clinically meaningful glycaemic control and weight reduction alongside a favourable safety profile in this population.

AIM: Mazdutide, an agonist of glucagon-like peptide-1 and glucagon receptors, significantly reduced weight in early phase trials at doses up to 10 mg. This randomized, double-blind, placebo-controlled Phase 1 trial evaluated the safety and efficacy of mazdutide up to 16 mg in adults with overweight or obesity. MATERIALS AND METHODS: Thirty-two adults with overweight/obesity without diabetes received once-weekly subcutaneous injections of mazdutide (n = 24) or placebo (n = 8) for 20 weeks. Two mazdutide dose escalation regimens (Cohorts 1 and 2, n = 12 each) were used to reach a 16-mg target dose. Data were analysed using descriptive statistics and mixed model repeated measures to estimate least square means with standard error (SE). RESULTS: At Week 20, mean percent change from baseline in body weight was -20.0% (SE: 1.9) for Cohort 1 and -21.0% (1.2) for Cohort 2 versus -0.1% (1.5) for placebo (p < 0.001). Weight loss of ≥15% was achieved by 66.7% of Cohort 1 and 75.0% of Cohort 2. No placebo participants achieved ≥5% weight loss. Mean percent change in waist circumference was -12.0% (SE: 1.7) in Cohort 1 and -17.0% (1.7) in Cohort 2 versus -0.8% (2.1) in placebo (p < 0.001). Improved fasting metabolic biomarker profiles and reduced appetite were associated with mazdutide treatment. No serious adverse events (AEs) were reported, and the most common AEs were mild or moderate gastrointestinal disorders. CONCLUSIONS: Mazdutide at 16 mg was well tolerated and associated with greater weight loss at higher doses than previously studied and improved metabolic regulation in adults with overweight or obesity. US Clinical Trials Registry: NCT05623839.

BACKGROUND: Evidence suggests that incretin-based dual agonist pharmacotherapy is helpful in persons with obesity. Mazdutide, a glucagon-like peptide-1 and glucagon receptor dual agonist, may have efficacy in persons with overweight or obesity. METHODS: In a phase 3, double-blind, placebo-controlled trial in China, we randomly assigned, in a 1:1:1 ratio, adults 18 to 75 years of age who had a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) of at least 28 or had a BMI of 24 to less than 28 plus at least one weight-related coexisting condition to receive 4 mg of mazdutide, 6 mg of mazdutide, or placebo for 48 weeks. The two primary end points were the percentage change in body weight from baseline and a weight reduction of at least 5% at week 32, as assessed in a treatment-policy estimand analysis (which assessed effects regardless of early discontinuation of mazdutide or placebo and the initiation of new antiobesity therapies). RESULTS: Among 610 participants, the mean body weight was 87.2 kg and the mean BMI was 31.1 at baseline. At week 32, the mean percentage change in body weight from baseline was -10.09% (95% confidence interval [CI], -11.15 to -9.04) in the 4-mg mazdutide group, -12.55% (95% CI, -13.64 to -11.45) in the 6-mg mazdutide group, and 0.45% (95% CI, -0.61 to 1.52) in the placebo group, and 73.9%, 82.0%, and 10.5% of the participants, respectively, had a weight reduction of at least 5% (P<0.001 for all comparisons with placebo). At week 48, the mean percentage change in body weight from baseline was -11.00% (95% CI, -12.27 to -9.73) in the 4-mg mazdutide group, -14.01% (95% CI, -15.36 to -12.66) in the 6-mg mazdutide group, and 0.30% (95% CI, -0.98 to 1.58) in the placebo group, and 35.7%, 49.5%, and 2.0% of the participants, respectively, had a weight reduction of at least 15% (P<0.001 for all comparisons with placebo). Beneficial effects on all prespecified cardiometabolic measures were seen with mazdutide. The most frequently reported adverse events were gastrointestinal and mostly mild to moderate in severity. The incidence of adverse events leading to discontinuation of the trial regimen was 1.5% with the 4-mg mazdutide dose, 0.5% with the 6-mg mazdutide dose, and 1.0% with placebo. CONCLUSIONS: In Chinese adults with overweight or obesity, once-weekly mazdutide at a dose of 4 mg or 6 mg for 32 weeks led to clinically relevant reductions in body weight. (Funded by Innovent Biologics; GLORY-1 ClinicalTrials.gov number, NCT05607680.).

OBJECTIVE: We conducted a randomized, double-blind, placebo-controlled phase 2 trial to evaluate the efficacy and safety of mazdutide, a once-weekly glucagon-like peptide 1 and glucagon receptor dual agonist, in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: Adults with type 2 diabetes inadequately controlled with diet and exercise alone or with stable metformin (glycated hemoglobin A1c [HbA1c] 7.0-10.5% [53-91 mmol/mol]) were randomly assigned to receive 3 mg mazdutide (n = 51), 4.5 mg mazdutide (n = 49), 6 mg mazdutide (n = 49), 1.5 mg open-label dulaglutide (n = 50), or placebo (n = 51) subcutaneously for 20 weeks. The primary outcome was change in HbA1c from baseline to week 20. RESULTS: Mean changes in HbA1c from baseline to week 20 ranged from -1.41% to -1.67% with mazdutide (-1.35% with dulaglutide and 0.03% with placebo; all P < 0.0001 vs. placebo). Mean percent changes in body weight from baseline to week 20 were dose dependent and up to -7.1% with mazdutide (-2.7% with dulaglutide and -1.4% with placebo). At week 20, participants receiving mazdutide were more likely to achieve HbA1c targets of <7.0% (53 mmol/mol) and ≤6.5% (48 mmol/mol) and body weight loss from baseline of ≥5% and ≥10% compared with placebo-treated participants. The most common adverse events with mazdutide included diarrhea (36%), decreased appetite (29%), nausea (23%), vomiting (14%), and hypoglycemia (10% [8% with placebo]). CONCLUSIONS: In Chinese patients with type 2 diabetes, mazdutide dosed up to 6 mg was generally safe and demonstrated clinically meaningful HbA1c and body weight reductions.