Innovent Biologics has announced that the outcomes of high-dose cohorts in a phase 1 clinical trial of mazdutide (IBI362) - a glucagon-like petide-1 (GLP-1) and glucagon receptor dual agonist, in Chinese adults with overweight or obesity - showed that high-dose mazdutide may offer bariatric surgery-equivalent weight loss and potentially provides an encouraging treatment option for patients with severe obesity. The results were presented at ENDO 2022.
Mazdutide is a long-acting synthetic peptide related to mammalian oxyntomodulin (OXM), which uses a fatty acid side chain to prolong the duration of action and allow once-weekly administration. Mazdutide is thought to exert its biological effects by activating GLP-1 receptor and glucagon receptor in human beings, which is estimated to improve glucose tolerance and induce weight loss, mimicking the effects of endogenous oxyntomodulin.
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. The treatment of metabolic diseases by activating multiple metabolism-related targets simultaneously is currently the worldwide trend in drug development.
This randomised, double-blind, placebo-controlled multiple-ascending-dose study evaluated the safety, tolerability and PK/PD characteristics of mazdutide in Chinese participants with overweight or obesity. Twelve participants in each of the five cohorts were randomized 2:1 to receive subcutaneous 1.0-2.0-3.0mg (cohort 1), 1.5-3.0-4.5mg (cohort 2), 2.0-4.0-6.0mg (cohort 3), 2.5-5.0-7.5-10.0mg (cohort 4) or 3.0-6.0-9.0mg (cohort 5) mazdutide or placebo once weekly, with each dose level administered for four weeks. Each cohort of participants received administration for 12 weeks in total except that participants in cohort 4 received administration for 16 weeks.
In cohort 1-3 (low-dose), mazdutide demonstrated favourable tolerability and a safety profile, with mean percent reduction from baseline in body weight of up to 6.4% for participants receiving mazdutide at week 12. Meanwhile, improvements in BMI, waist circumference, blood pressure, lipid and serum uric acid were observed in participants receiving mazdutide. The results have been published in EclinicalMedicine (Ji L, Jiang H, An P, et al. (2021) 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. EClinicalMedicine 39: 101088. 10.1016/j.eclinm.2021.101088).
Results of cohort 4 and 5 (high-dose) were firstly presented at ENDO 2022. The mean reduction (percent reduction) from baseline in body weight were 7.62 kg (9.5%) for participants receiving mazdutide at week 16 in cohort 4, and 9.23 kg (11.7%) for participants receiving mazdutide at week 12 in cohort 5. Four participants (50%) receiving mazdutide in each cohort achieved ≥10% weight loss and two (25%) receiving mazdutide in each cohort achieved ≥15% weight loss during the study. Improvements in BMI, waist circumference, blood pressure, lipid and serum uric acid were similar with those observed in the low-dose cohorts.
Mazdutide up-titrated to 10mg and 9mg showed a similar safety profile with that of low-dose cohorts. No participant discontinued the study due to adverse events. No dose adjustment of mazdutide was made. No serious adverse event was reported.
"The obese population in China exceeded 100 million. Most patients failed to achieve weight loss goals by lifestyle intervention, underlying the urgent need for safe and highly efficacious weight loss treatments. We are delighted to see high-dose mazdutide showed a similar safety profile as low-dose mazdutide, while demonstrated more robust weight loss efficacy, as well as multiple benefits in metabolic parametersm” said Professor Linong Ji, the Principal Investigator of the Study, Peking University People's Hospital. “High-dose mazdutide may offer bariatric surgery-equivalent weight loss and potentially provides an encouraging treatment option for patients with severe obesity. Based on the current data and R&D progress, I believe that mazdutide has the full potential to become an innovative anti-obesity drug buster. I am also confident that mazdutide will achieve a great success in the phase III clinical studies scheduled in the second half of this year. I hope that mazdutide can be approved and launched-to-market and benefit patients in the foreseeable future."
"High-dose mazdutide showed favourable safety, tolerability, and robust efficacy on weight loss in Chinese adults with overweight or obesity. Mazdutide is the only molecule that achieve a 12-week weight loss by more than 11.5% among single-agent anti-obesity molecules approved or under development” added Dr Lei Qian, Vice President of Clinical Development of Innovent. “This result demonstrates the superiority of GLP-1 and glucagon receptor dual agonists over GLP-1 receptor mono-agonists in terms of weight loss efficacy. Meanwhile, this study further validated the multiple metabolic benefits offered by mazdutide to patients with overweight or obesity. We will continue to develop high-dose mazdutide in overweight or obesity and other potential indications and expect more exciting results."
Innovent entered into a licensing agreement with Eli Lilly and Company (Lilly) for the development and potential commercialisation of OXM3 (also known as IBI362, LY3305677 or mazdutide), a GLP-1 and glucagon receptor dual agonist, in China. In parallel, Lilly is developing OXM3 outside China.