GLORY-1 outcomes shows positive results for mazdutide - a dual glucagon GCG-1/GLP-1 receptor agonist

The results from GLORY-1 - a Phase 3 clinical study of mazdutide - a dual glucagon (GCG)/glucagon-like peptide-1 (GLP-1) receptor agonist, in Chinese adults with overweight or obesity, have revealed the mean percent change from baseline in body weight was −10.97%, −13.38%, and −0.24% at Week 32 and −12.05%, −14.84%, and −0.47% at Week 48 in the mazdutide 4 mg, 6 mg, and placebo groups, respectively.

China has the world's largest population of individuals with overweight or obesity, a trend that is likely to rise. Obesity is associated to multiple comorbidities, and is a major contributor to reduced life expectancy and quality of life. In 2019, overweight and obesity accounted for 11.1% of deaths from chronic non-communicable diseases in China, nearly doubling from 5.7% in 1990.

Innovent entered into an exclusive license agreement with Eli Lilly and Company (Lilly) for the development and potential commercialisation of OXM3 (also known as mazdutide), a GLP-1R and GCGR dual agonist, in China. As a mammalian oxyntomodulin (OXM) analogue, mazdutide may offer additional benefits beyond those of GLP-1 receptor agonists - such as promoting insulin secretion, lowering blood glucose and reducing body weight - by also activating the glucagon receptor to increase energy expenditure and improve hepatic fat metabolism.

Specifically, younger individuals in China exhibit metabolic dysfunction at rates comparable to or even exceeding those in older Western populations. The dual GCG/GLP-1 receptor agonist therapy demonstrated not only significant reductions in body weight and BMI but also comprehensive improvements in obesity-associated systemic health risks. Moreover, they emphasized that obesity interventions in China must adopt differentiated strategies tailored to local population features, with a focus on liver health and lipid management. Given the earlier onset of obesity in China and its heavier societal burden, earlier intervention is critical—and yields greater long-term benefits.

In the GLORY-1 study, a total of 610 participants with obesity (BMI ≥ 28 kg/m2) or overweight (24 kg/m2 ≤ BMI < 28 kg/m2) with at least one obesity-related comorbidity were enrolled and randomized to receive mazdutide 4 mg, 6 mg, or placebo, administered subcutaneously once weekly for 48 weeks. The co-primary endpoints were the percentage change in body weight from baseline and a weight reduction of ≥5% at week 32.

At baseline, the mean weight was 87.2 kg, and the mean BMI was 31.1 kg/m 2. The study results showed that mazdutide significantly reduced body weight compared to placebo at both 4 mg and 6 mg doses.

A total of 76.3% of participants in the mazdutide 4 mg group and 84.0% in the mazdutide 6 mg group had a weight reduction of ≥5% at week 32, compared with 10.9% in the placebo group; 37.0% of participants in the mazdutide 4 mg group and 50.6% in the mazdutide 6 mg group had a weight reduction of ≥15% at week 48, compared with 2.1% in the placebo group.

The primary endpoint and all key secondary endpoints of the study showed statistically significant superiority to placebo with p-values <0.001 (Table 1).

Table 1: Primary endpoint and all key secondary endpoints 1) Efficacy estimand aims to estimate the study treatment effect when participants adhered to the planned treatment regimen. 2) Treatment policy estimand aims to evaluate the efficacy regardless of intercurrent events (early discontinuation of study treatment and initiation of new anti-obesity medication or bariatric surgery).

Mazdutide also significantly reduced blood pressure, blood lipids (total cholesterol, triglycerides, and low-density lipoprotein cholesterol), serum uric acid, transaminase levels, and other cardiovascular and metabolic indicators.

In addition, mazdutide significantly reduced liver fat content:

• Among participants with baseline liver fat content ≥ 5%, the mean percent changes in liver fat content from baseline to week 48 were −63.26%, −73.18%, and +8.20% in the mazdutide 4 mg, 6 mg, and placebo groups, respectively;

• Among participants with baseline liver fat content ≥ 10%, the mean percent change from baseline in liver fat content to week 48 were −65.85%, −80.24%, and −5.27% in the mazdutide 4 mg, 6 mg, and placebo groups, respectively.

• Good overall safety and tolerability of mazdutide were reported.

The overall safety profile of the mazdutide group was consistent with findings from previous studies of mazdutide and aligned with that of other GLP-1 receptor agonists. The most frequently reported treatment-emergent adverse events included nausea, diarrhoea, and vomiting, which were mostly mild or moderate in severity.

At Week 48, both the mean change from baseline in heart rate was 2.6 beats per minute in both the mazdutide 4 mg and 6 mg groups. There were no safety signals of increased cardiovascular risk observed throughout the study.

"For decades, global obesity management guidelines have predominantly relied on data from Caucasian populations, resulting in limited applicability to Asian demographics. Meanwhile, China's overweight/obese population exhibits distinct clinical characteristics and therapeutic needs compared to Western populations, necessitating evidence-based weight management strategies specifically tailored for Chinese patients,” explained Professor Linong Ji, the Leading Principal Investigator of the Study, from the Peking University People's Hospital co-corresponding author of the study. “For most Chinese patients with overweight or obesity, the recommended weight loss target should be 5%-15% reduction maintained over 3-6 months. Moderate-to-severe obesity patients may require more ambitious goals. The GLORY-1 study, conducted in Chinese populations aligned with these targets, demonstrated promising outcomes: mazdutide achieved >15% weight reduction in nearly half of participants, indicating its efficacy across people living with overweight to severe obesity."

Mazdutide is expected to launch in China this year, with anticipated approvals for weight management and glycaemic control.

Mazdutide currently has two NDAs accepted for review by NMPA, including:

• For chronic weight management in adults with overweight or obesity

• For glycemia control in adults with type 2 diabetes

Mazdutide is currently being evaluated in six Phase 3 clinical studies, including:

• GLORY-1: A Phase 3 trial in Chinese participants with overweight or obesity

• GLORY-2: A Phase 3 trial in Chinese participants with moderate-to-severe obesity

• GLORY-3: A Phase 3 trial comparing mazdutide and semaglutide in Chinese participants with overweight/obesity and metabolic dysfunction-associated fatty liver disease (MAFLD)

• DREAMS-1: A Phase 3 trial in treatment-naïve Chinese patients with T2DM

• DREAMS-2: A Phase 3 trial comparing mazdutide and dulaglutide in Chinese T2DM patients with inadequate glycemic control on oral antidiabetic drugs

• DREAMS-3: A Phase 3 trial comparing mazdutide and semaglutide in Chinese patients with T2D and obesity

Among these, GLORY-1, DREAMS-1 and DREAMS-2 studies have all met their endpoints, and other studies are currently ongoing.

In addition, several new clinical studies of mazdutide are planned, including:  

• A Phase 3 trial in adolescents with obesity

• A Phase 3 trial in Chinese participants with moderate-to-severe obstructive sleep apnoea and obesity

• New studies in metabolic dysfunction-associated steatohepatitis (MASH) and heart failure with preserved ejection fraction (HFpEF)

  
  

The findings were reported in the paper, ‘Once-Weekly Mazdutide in Chinese Adults with Obesity or Overweight’, published in The New England Journal of Medicine. To access this paper, please click here