Mazdutide

Mazdutide (IBI362 or LY3305677) is a synthetic peptide analogue of mammalian oxyntomodulin and a once-weekly GLP-1 and glucagon receptor dual agonist. In a 12-week multiple-ascending-dose phase 1b study in Chinese patients with type 2 diabetes (clinical trial reg. no. NCT04466904, clinicaltrials.gov), mean changes in HbA1c ranged from −1.46% to −2.23% with mazdutide (−1.98% with 1.5 mg dulaglutide and −0.87% with placebo). Mean changes in body weight were up to −5.4% with mazdutide, −0.9% with dulaglutide, and −1.1% with placebo. A 12- to 16-week phase 1b study in Western patients with type 2 diabetes (clinical trial reg. no. NCT03928379, clinicaltrials.gov) reported mean changes in HbA1c up to −2.16% with mazdutide (−0.70% with placebo) and mean changes in body weight up to −11.2 kg with mazdutide (−2.0 kg with placebo). In both studies, mazdutide was well tolerated, with gastrointestinal adverse events most frequently reported.

Mazdutide (also known as IBI362 or LY3305677), a novel once-weekly glucagon-like peptide-1 (GLP-1) and glucagon receptor dual agonist, achieved 12-week body weight loss of up to 6.4% at doses up to 6 mg in Chinese adults with overweight or obesity. It is the first GLP-1R/GCGR dual agonist to succeed in Phase 3 trials. As mazdutide's first registrational trial for weight management, the results of GLORY-1 not only further confirm the efficacy and safety of the mazdutide in a large population but also provide high-quality clinical evidence of long-term pharmacotherapy weight management specifically for the Chinese population with overweight or obesity[1].

Mazdutide (IBI-362; LY-3305677) is a long-acting synthetic oxyntomodulin analog. Mazdutide is also a co-agonist of glucagon-like peptide (GLP-1R) and glucagon receptor (GCGR). Mazdutide binds human and mouse GCGR (Ki: 17.7 nM and 15.9 nM, respectively) and GLP-1R (Ki: 28.6 nM and 25.1 nM, respectively) and stimulates insulin secretion from mouse islets (EC50: 5.2 nM). Mazdutide is used in studies of obesity and type 2 diabetes (T2D)[1][2][3].

As a mammalian oxyntomodulin (OXM) analog, 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. Mazdutide has demonstrated robust weight loss and glucose-lowering effects in clinical studies, as well as multiple cardio-metabolic benefits, including reducing waist circumference, blood lipids, blood pressure, blood uric acid, liver enzymes, liver fat content and improving insulin sensitivity.

Compared to placebo, it was also associated with reductions in fasting plasma glucose and HbA1c among patients with diabetes. Mazdutide was associated with more side effects, primarily gastrointestinal-related disorders, such as decreased appetite, nausea, vomiting and diarrhea. Moreover, all participants on Mazdutide experienced an increase in heart rates. However, these side effects were transient and mild to moderate in severity, and no participant discontinued treatment due to the side effects[2].

[1] Linong Ji. “Safety and efficacy of a GLP-1 and glucagon receptor dual agonist mazdutide (IBI362) 9 mg and 10 mg in Chinese adults with overweight or obesity: A randomised, placebo-controlled, multiple-ascending-dose phase 1b trial.” EClinicalMedicine (2022): 101691.
[2] LINONG JI. IBI362 (LY3305677), a weekly-dose GLP-1 and glucagon receptor dual agonist, in Chinese adults with overweight or obesity: A randomised, placebo-controlled, multiple ascending dose phase 1b study.[J]. EClinicalMedicine, 2021: 101088. DOI: 10.1016/j.eclinm.2021.101088