Innovent’s GLORY-1 trial assessing mazdutide meets its primary endpoints

Innovent Biologics has announced the key results of the first Phase 3 clinical trial of mazdutide in Chinese adults with overweight or obesity (GLORY-1) presented at the ADA Scientific Sessions 2024, show that the trial met its primary endpoints and all key secondary endpoints of GLORY-1, reconfirming the unique advantages of the GLP-1R/GCGR dual agonist.

Mazdutide is a glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) dual agonist. By activating GLP-1R, it reduces appetite and delays gastric emptying, thereby achieving weight loss. At the same time, through activation of GCGR, it increases energy expenditure, enhances fatty acid oxidation and lipolysis, and reduces liver fat.

"Overweight and obesity are risk factors for several comorbidities, the most frequent of which include fatty liver disease, prediabetes, dyslipidaemia, hypertension and hyperuricemia. Medical evidence suggests that lifestyle management combined with pharmacotherapy for weight loss can improve metabolic and cardiovascular risk factors and thereby improve health outcomes,” commented Professor Linong Ji, the leading principal investigator of the study, Peking University People's Hospital, Peking, China. “GLORY-1 is the first Phase 3 clinical study of mazdutide, which reconfirmed its excellent weight loss efficacy, multiple metabolic benefits improvement and good safety profile, and also indicated its potential to reduce obesity related comorbidities. I hope for the successful launch of mazdutide to swiftly benefit hundreds of millions of adults with overweight or obesity."

The results of the GLORY-1 study demonstrated that mazdutide not only induced robust weight loss in adults with obesity or overweight, but also reduced liver fat content and multiple cardiometabolic risk factors. Its first new drug application (NDA) for chronic weight management is under review by the CDE of the National Medical Products Administration (NMPA). Mazdutide, once approved, is expected to provide a safe and convenient medication for adults with obesity or overweight to effectively reduce body weight while providing cardiovascular and metabolic benefits.

Full results and analysis of GLORY-1 will be published at peer-reviewed academic journals. At present, over 1,500 subjects have received doses of mazdutide in 17 clinical trials, providing solid clinical evidence for weight management and diabetes treatment in China.

GLORY-1 is a multi-centre, randomised, double-blind, placebo-controlled Phase 3 clinical trial to evaluate the efficacy and safety of mazdutide in Chinese adults with overweight or obesity. A total of 610 participants were randomized to receive mazdutide 4mg, 6mg or placebo in the 48-week double-blind treatment period.

At week 32 and week 48, the weight loss efficacy of mazdutide 4mg and 6mg were superior to placebo in the mean percentage change in body weight from baseline, and percentage of participants achieved body weight reduction ≥5%, ≥10% and ≥15% (p<0.001). At week 48, the treatment difference for the mean percentage weight change between mazdutide 6mg and placebo was -14.31% for the treatment-policy estimand and -14.37% for the efficacy estimand. Further details can be found in the table below:

LS, least squares; * The treatment policy estimand represents the average treatment effect of mazdutide relative to placebo regardless of the adherence to treatment. For analyses related to the treatment-regimen estimand, analysis of covariance (ANCOVA) was used for continuous endpoints and logistic regression was used for binary endpoints. † The efficacy estimand represents the average treatment effect of mazdutide relative to placebo had participants remained on their randomized treatment for the entire planned 48 weeks treatment duration. Missing data were implicitly handled by using a mixed model for repeated measures (MMRM) under the assumption of missing at random. § The percentage was calculated with the use of Rubin's rules by combining the percentages of participants who met the target in imputed data sets. ¶ P<0.0001 (2-sided) for superiority comparison versus placebo, controlled for type I error rate.

For the efficacy estimand (P<0.001 for comparisons):

• At week 48, the change from baseline to week 48 in waist circumference was −9.48 cm with mazdutide 4 mg, −10.96 cm with mazdutide 6 mg and −1.48 cm with placebo;

• At week 48, pooled mazdutide group (4mg and 6mg) significantly reduced multiple indicators of cardiometabolic risk factors compared with placebo, including systolic blood pressure (−9.21 mmHg vs. −2.46 mmHg), triglycerides (−0.68 mmol/L vs. -0.16 mmol/L), total cholesterol (-0.32 mmol/L vs. 0.13 mmol/L), low-density lipoprotein cholesterol (-0.22 mmol/L vs. 0.09 mmol/L), serum uric acid (−44.79 µmol/L vs. 5.96 µmol/L) and ALT (−14.50 U/L vs.-4.50 U/L);

• As shown in an exploratory analysis of GLORY-1(1857-LB), in participants with baseline MRI-PDFF ≥10%, the liver fat content in mazdutide 6mg group was reduced by 80.2% on average, compared with 5.3% with placebo.

• The overall tolerability and safety profile of mazdutide was favorable with no new safety signals observed

• Mazdutide was well tolerated. 1.5%, 0.5% and 1.0% of participants in the mazdutide 4 mg group, mazdutide 6 mg group and placebo group discontinued the study drug prematurely due to AEs.

• The safety profile was consistent with that observed in previous studies of mazdutide, with no new safety signals observed. The most frequently reported adverse events were gastrointestinal (nausea, diarrhoea and vomiting), mostly mild or moderate in severity and occurring during dose escalation.

• The incidence of serious adverse events was low and comparable to placebo.

• Mean changes from baseline in heart rate were no more than 5 beats/min throughout the 48-week treatment period for both the mazdutide 4mg and 6mg groups. The mean change from baseline to week 48 in heart rate were 1.6 beats/min in both mazdutide 4 mg and 6 mg groups. No safety signal of increased cardiovascular risk was observed during treatment.
  

"We are excited to present GLORY-1 study results at ADA. GLORY-1 demonstrates that the GLP-1R/GCGR dual agonist mazdutide could be a safe and tolerable medication that aids obese or overweight individuals in reducing excess weight, liver fat content, and other risk factors associated with obesity-related comorbidities,” added Dr Lei Qian, Vice President of Clinical Development of Innovent. “We will also publish results of mazdutide in type 2 diabetes later this year. Innovent will continue to build out our next-generation product pipeline in the cardiovascular and metabolic therapeutic area, supporting people's pursuit of a healthier life."

Innovent entered into an exclusive license 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, with the effects of GLP-1 receptor agonists to promote 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.

Mazdutide has demonstrated robust weight loss and glucose-lowering effects in clinical studies as well as improvements in multiple cardio-metabolic indicators including reducing waist circumference, blood lipids, blood pressure, blood uric acid, liver enzymes, liver fat content and improved insulin sensitivity. Currently, five Phase 3 studies of mazdutide in Chinese adults with overweight or obesity (GLORY-1 and GLORY-2) and type 2 diabetic (DREAMS-1, DREAMS-2 and DREAMS-3) subjects are underway, where GLORY-1 and DREAMS-2 studies have met the primary and all key secondary endpoints.