Mazdutide: A Research Overview

Introduction

Mazdutide (development designations IBI362 and LY3305677; referred to in early literature as OXM-3) is a synthetic peptide classified as a glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) dual agonist. Originated by Eli Lilly and Company and licensed to Innovent Biologics for development in China, mazdutide became the world's first molecule in its pharmacological class to receive regulatory approval for chronic weight management, an achievement that distinguished the dual GLP-1/glucagon agonist research program from earlier incretin pharmacology. This article provides an educational reference overview of mazdutide's chemical identity, pharmacological classification, and regulatory history based on published primary literature and official regulatory documents.

Background

The incretin axis — comprising intestinally derived peptide hormones that modulate insulin secretion in a glucose-dependent manner — has been a sustained focus of cardiometabolic research for several decades. Glucagon-like peptide-1 (GLP-1) is secreted by intestinal L cells in response to nutrient ingestion and functions as an incretin hormone. Research reviewed by Habegger and colleagues (2010) established that glucagon, produced by pancreatic alpha cells, also participates in the regulation of hepatic lipid metabolism and energy expenditure through its cognate receptor, adding scientific rationale for dual-receptor pharmacological approaches [1].

Oxyntomodulin (OXM), an endogenous peptide co-secreted with GLP-1 from intestinal L cells, was characterized in earlier research as a natural dual agonist of both GLP-1R and GCGR [2]. Human proof-of-concept work with native OXM demonstrated pharmacological activity at both receptors; however, the peptide's extremely short plasma half-life — measured in minutes due to rapid proteolytic cleavage — limited its direct research and therapeutic application. Mazdutide was designed as a long-acting synthetic analog of oxyntomodulin that retains dual receptor engagement while exhibiting a substantially extended pharmacokinetic profile suitable for once-weekly dosing intervals in clinical study designs.

Chemistry and Structure

Mazdutide is a 39-amino acid synthetic peptide structurally derived from mammalian oxyntomodulin. The molecule incorporates sequence modifications and a fatty acid side chain conjugated via a linker — a strategy that promotes reversible albumin binding in circulation and prolongs the plasma half-life to enable once-weekly dosing intervals in clinical investigations [3].

Both target receptors — GLP-1R and GCGR — belong to the class B1 subfamily of G protein-coupled receptors (GPCRs). Receptor binding characterizations reported by Ji and colleagues (2021) described nanomolar-range affinity at both human and murine forms of GCGR and GLP-1R, with Ki values in the range of 17–29 nM across receptor subtypes [3]. This balanced dual-receptor engagement profile distinguishes mazdutide from compounds that engage GLP-1R and GCGR at substantially different potency ratios.

Pharmacological Classification

Mazdutide is classified as a GLP-1R/GCGR dual agonist, also described in the scientific literature as a GLP-1/glucagon co-agonist or oxyntomodulin analog. This places it in a distinct pharmacological class from selective GLP-1 receptor agonists such as semaglutide or liraglutide, which engage only the GLP-1R subtype, and from selective glucagon receptor agonists. The dual-receptor pharmacological profile is designed to simultaneously engage GLP-1R-mediated insulinotropic and satiety signaling pathways alongside GCGR-mediated effects on energy expenditure and hepatic lipid metabolism as characterized in the primary literature.

Phase 1b clinical characterization of mazdutide under its designation IBI362 in Chinese adults with overweight or obesity was published in eClinicalMedicine in 2021, documenting safety, tolerability, pharmacokinetics, and early metabolic signals across ascending dose cohorts [3]. The receptor interactions underlying these clinical observations are examined in detail in the mazdutide mechanism of action article. Subsequent phase 1b investigation at higher doses was published in the same journal in 2022 [4], and parallel phase 1b work in Chinese patients with type 2 diabetes was reported in Nature Communications in 2022 [5]. Phase 2 and phase 3 programs built on these findings, with the phase 3 GLORY-1 result published in The New England Journal of Medicine in May 2025 [6].

Regulatory History and Milestones

Mazdutide received its first regulatory approval from China's National Medical Products Administration (NMPA) on June 27, 2025 — under the brand name Xinermei (信尔美) — for chronic weight management in Chinese adults with overweight or obesity accompanied by at least one weight-related comorbidity. This approval represented the world's first regulatory authorization of a GCG/GLP-1 dual receptor agonist for a weight management indication anywhere in the world [7].

A second NMPA approval followed on September 19, 2025, authorizing mazdutide for glycemic control in adults with type 2 diabetes whose blood glucose remained inadequately controlled despite lifestyle interventions [8]. The achievement of two separate NMPA approvals within a single calendar year reflects the scope and pace of the GLORY and DREAMS phase 3 clinical programs.

As of this writing, mazdutide has not received approval from the US Food and Drug Administration (FDA) or the European Medicines Agency (EMA). Eli Lilly retains development and commercialization rights outside of China, and US-based clinical investigation of mazdutide has been reported as ongoing. The compound's regulatory approval status in China is distinct from its use as a research-use-only material in non-clinical research contexts. Research-grade Mazdutide from SpartaLabs is verified by third-party analytical testing and supplied with batch-specific Certificates of Analysis.

Discovery History

The scientific lineage of mazdutide traces through research on the incretin axis and through early investigations of oxyntomodulin as a dual GLP-1R and GCGR agonist. Human studies documenting OXM's pharmacological activity were published in the 2000s and 2010s [2], establishing the scientific rationale for long-acting engineered analogs. Mazdutide was originated within Eli Lilly's metabolic research pipeline under the designation LY3305677. In 2019, Innovent Biologics acquired the rights to develop, manufacture, and commercialize the compound in China, redesignating it IBI362, while Eli Lilly retained rights in all other territories. Phase 1b clinical investigations in Chinese populations were initiated and reported between 2021 and 2022 [3,4,5], followed by phase 2 randomized controlled trials reported in Nature Communications (2023) and Diabetes Care (2024) [9,10]. The phase 3 GLORY and DREAMS programs subsequently supported the NMPA approval submissions.

References

1. Habegger KM, Heppner KM, Geary N, Bartness TJ, DiMarchi R, Tschöp MH. The metabolic actions of glucagon revisited. Nat Rev Endocrinol. 2010;6(12):689-697. PMID: 21060334. DOI: 10.1038/nrendo.2010.187

2. Wynne K, Park AJ, Small CJ, Patterson M, Ellis SM, Murphy KG, et al. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes. 2005;54(8):2390-2395. PMID: 16046306. DOI: 10.2337/diabetes.54.8.2390

3. Ji L, Jiang H, Shi W, Wang H, Cheng Z, Pan T, et al. 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. 2021;40:101088. PMCID: PMC8374649. DOI: 10.1016/j.eclinm.2021.101088

4. Ji L, Luo X, Shi W, Wang H, Cheng Z, Pan T, et al. 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;53:101691. PMCID: PMC9561728. DOI: 10.1016/j.eclinm.2022.101691

5. Jiang H, Pang S, Zhang Y, Liu J, Chen Y, Yang L, et al. A phase 1b randomised controlled trial of a glucagon-like peptide-1 and glucagon receptor dual agonist IBI362 (LY3305677) in Chinese patients with type 2 diabetes. Nat Commun. 2022;13(1):3613. PMCID: PMC9232612. DOI: 10.1038/s41467-022-31328-x

6. Innovent Biologics / GLORY-1 investigators. Phase 3 clinical study of mazdutide in Chinese adults with overweight or obesity (GLORY-1). N Engl J Med. 2025;392(22):2215-2225. DOI: 10.1056/NEJMoa2411528

7. Innovent Biologics, Inc. Innovent announces mazdutide, first dual GCG/GLP-1 receptor agonist, received approval from China's NMPA for chronic weight management. Press release. June 27, 2025. Available at: https://www.prnewswire.com/news-releases/innovent-announces-mazdutide-first-dual-gcgglp-1-receptor-agonist-received-approval-from-chinas-nmpa-for-chronic-weight-management-302493152.html

8. Innovent Biologics, Inc. Innovent announces mazdutide received approval from China's NMPA for glycemic control in adults with type 2 diabetes. Press release. September 19, 2025. Available at: https://www.prnewswire.com/news-releases/innovent-announces-mazdutide-received-approval-from-chinas-nmpa-for-glycemic-control-in-adults-with-type-2-diabetes-302561434.html

9. Feng Z, Zhao C, Wang X, Gan L, Xia L, Han C, et al. A phase 2 randomised controlled trial of mazdutide in Chinese overweight adults or adults with obesity. Nat Commun. 2023;14(1):8156. DOI: 10.1038/s41467-023-44067-4

10. Shi W, Zhou X, Zhang D, Zou Y, Liu Y, Li X, et al. Efficacy and safety of mazdutide in Chinese patients with type 2 diabetes: a randomized, double-blind, placebo-controlled phase 2 trial. Diabetes Care. 2024;47(1):160-168. DOI: 10.2337/dc23-1287