Mazdutide: Discovery and Regulatory History

Introduction

Mazdutide (IBI362 / LY3305677) is a synthetic GLP-1R/GCGR dual agonist peptide with a scientific lineage traceable to foundational incretin research and, more directly, to early investigations of the endogenous gut hormone oxyntomodulin. The compound's development reflects a decades-long arc of inquiry into the pharmacology of simultaneous glucagon and GLP-1 receptor engagement, culminating in two separate regulatory approvals in China within a single calendar year — a trajectory that established the dual GCG/GLP-1 receptor agonist class as a clinically validated pharmacological framework. This article traces that history from its scientific antecedents through the development program and regulatory milestones achieved under the collaboration of Eli Lilly and Innovent Biologics.

Scientific Antecedents: Incretin and Glucagon Biology

The hormonal context underpinning mazdutide's development was established over several decades of parallel research programs. Glucagon, a pancreatic peptide hormone encoded by the proglucagon gene, was long characterized primarily as a counter-regulatory hormone for glucose homeostasis. Subsequent research reviewed by Habegger and colleagues (2010) expanded the biological characterization of glucagon receptor signaling, establishing its role in hepatic lipid and energy metabolism and adding scientific rationale for receptor-targeted metabolic pharmacology [1].

Glucagon-like peptide-1 (GLP-1) was characterized as a biologically active incretin in the 1980s through work on the proglucagon gene and its post-translational processing in intestinal L cells. Researchers including Joel Habener, Svetlana Mojsov, Daniel Drucker, and Jens Juul Holst contributed foundational characterization of GLP-1 as a potent glucose-dependent stimulator of insulin secretion [2]. The subsequent pharmaceutical development of GLP-1 receptor agonists for type 2 diabetes established incretin receptor pharmacology as a productive and durable research area.

Oxyntomodulin (OXM), a 37-amino acid peptide co-secreted with GLP-1 from intestinal L cells in response to nutrient ingestion, was characterized as a natural dual agonist of both GLP-1R and GCGR [3]. OXM's simultaneous engagement of GCGR was hypothesized to add effects on energy expenditure through the glucagon receptor component, making the dual-receptor activity of scientific interest as a means of achieving complementary metabolic effects from a single molecular entity.

Early Research: Oxyntomodulin and the Dual Agonist Concept

Human proof-of-concept studies with native oxyntomodulin, conducted in the 2000s, provided early evidence for the pharmacological hypothesis underlying mazdutide's design. Wynne and colleagues published a randomized, double-blind, placebo-controlled trial in Diabetes (2005) demonstrating that subcutaneous oxyntomodulin administration in overweight and obese human subjects was associated with reductions in body weight and appetite, and with increases in measured energy expenditure compared to placebo [3]. This early human study established the dual-receptor hypothesis in a clinical context.

The principal limitation of native oxyntomodulin for extended research application was its extremely brief plasma half-life — estimated at approximately 10 to 12 minutes in circulation — attributable to rapid enzymatic degradation by dipeptidyl peptidase-4 (DPP-4) and neutral endopeptidase 24.11. This pharmacokinetic characteristic required frequent administration in research settings and provided the rationale for engineering long-acting synthetic analogs retaining the dual receptor activity.

Preclinical research further established the dual agonist concept. Day and colleagues (2009) published early preclinical evidence in Nature Chemical Biology supporting the GLP-1/glucagon co-agonism approach in diet-induced obese rodent models, reporting metabolic outcomes at both receptor targets that were distinct from selective GLP-1R agonism [4]. This preclinical work informed the design parameters for subsequent engineered dual agonist molecules in the research pipeline.

Development at Eli Lilly and the Innovent Biologics Collaboration

Mazdutide was originated within Eli Lilly and Company's metabolic research and development pipeline under the designation LY3305677, as part of a broader program investigating long-acting incretin-related peptides. The molecule's structural design incorporated fatty acid side chain conjugation via a linker to extend plasma half-life through reversible albumin binding — a strategy informed by approaches employed across the long-acting peptide therapeutics literature.

In 2019, Innovent Biologics, a biopharmaceutical company headquartered in Suzhou, China, acquired rights from Eli Lilly to develop, manufacture, and commercialize mazdutide in China, where the compound was redesignated IBI362. Under the terms of that agreement, Eli Lilly retained development and commercialization rights outside of China. The bifurcated development structure — with Chinese-population phase data generated by Innovent and ex-China development managed by Lilly — positioned the compound for regulatory pursuit across two distinct development pathways simultaneously.

Clinical Development Milestones

Phase 1b clinical investigation of IBI362 / LY3305677 in Chinese adults with overweight or obesity was published by Ji and colleagues in eClinicalMedicine in August 2021, documenting the compound's first published human pharmacology data across ascending dose cohorts administered once weekly [5]. A follow-on phase 1b report at higher dose levels was published in eClinicalMedicine in October 2022 [6]. Concurrent phase 1b investigation in Chinese patients with type 2 diabetes was published in Nature Communications in June 2022 [7].

Phase 2 randomized controlled trials in Chinese patients with obesity/overweight and with type 2 diabetes followed, reported in Nature Communications (December 2023) and Diabetes Care (January 2024), respectively [8,9]. These 24-week studies provided dose-ranging data and longer-duration safety and metabolic characterization that informed phase 3 study design.

The phase 3 GLORY-1 trial in Chinese adults with overweight and obesity met its co-primary endpoints and was published in The New England Journal of Medicine in May 2025 [10] — a milestone publication for the dual GCG/GLP-1 agonist compound class. The phase 3 DREAMS-1 and DREAMS-2 trials in Chinese adults with type 2 diabetes were published back-to-back in Nature in late 2025 [11], and DREAMS-3 reported head-to-head superiority data against semaglutide on a composite primary endpoint [11].

Regulatory Milestones

The first New Drug Application for mazdutide for the chronic weight management indication was accepted for review by China's National Medical Products Administration (NMPA) in February 2024.

On June 27, 2025, the NMPA granted approval for mazdutide — marketed in China 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 first regulatory authorization of a GCG/GLP-1 dual receptor agonist for a weight management indication anywhere in the world [12]. Sourcing specifications and quality standards for the research-use form of the compound are described in the mazdutide sourcing and quality article. The milestone marked the dual agonist pharmacological class as clinically validated by a major regulatory authority.

On September 19, 2025, the NMPA granted a second approval for mazdutide for glycemic control in adults with type 2 diabetes whose blood glucose remained inadequately controlled despite lifestyle interventions [13]. Two separate regulatory approvals in distinct indications within a single calendar year reflected the breadth of the clinical development program.

In November 2025, a supplementary application for a higher mazdutide dose for chronic weight management in adults with moderate-to-severe obesity was accepted for review by the NMPA Center for Drug Evaluation [14]. As of this writing, mazdutide has not received approval from the US Food and Drug Administration or the European Medicines Agency; both represent active development and regulatory frontiers for the compound. The Mazdutide product page provides batch-specific Certificate of Analysis documentation for research procurement.

Current Research Landscape

Eli Lilly is conducting US-based clinical investigation of mazdutide as part of a phase 2 master protocol study, building toward a potential regulatory program in ex-China territories. Lilly's parallel development of retatrutide (LY3437943), a GLP-1/GIP/glucagon triple receptor agonist, provides additional context for the broader research interest in multi-receptor incretin pharmacology at the same organization. A parallel regulatory and discovery timeline for another dual-receptor incretin compound in the GLP-1 cluster is covered in the cagrilintide history article.

Research interest in mazdutide extends into preclinical mechanistic inquiry: 2025 publications examined the compound's pharmacological effects in models of diabetic cognitive dysfunction [15] and cardiorenal and hepatic endpoints, with the eBioMedicine multi-omics study [15] identifying molecular pathway alterations beyond those observed with selective GLP-1R agonism. These preclinical investigations expand the scientific characterization of the dual GLP-1R/GCGR pharmacological profile and inform future research directions for the compound class.

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. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409-1439. PMID: 17928588. DOI: 10.1152/physrev.00034.2006

3. 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

4. Day JW, Ottaway N, Patterson JT, Gelfanov V, Smiley D, Gidda J, et al. A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol. 2009;5(10):749-757. PMID: 19668196. DOI: 10.1038/nchembio.209

5. 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

6. 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

7. 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

8. 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

9. 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

10. 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

11. Innovent Biologics, Inc. Nature — Two phase 3 clinical results of mazdutide (GLP-1/GCG dual receptor agonist) in Chinese adults with type 2 diabetes have been back-to-back published in Nature. Press release. December 2025. Available at: https://www.prnewswire.com/news-releases/nature--two-phase-3-clinical-results-of-mazdutide-glp-1gcg-dual-receptor-agonist-in-chinese-adults-with-type-2-diabetes-have-been-back-to-back-published-in-nature-302644606.html

12. 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

13. 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

14. Innovent Biologics, Inc. Mazdutide 9mg supplementary application accepted for review by China's NMPA. Press release. November 2025. Available at: https://www.prnewswire.com/news-releases/mazdutide-9mg-supplementary-application-accepted-for-review-by-chinas-nmpa-potentially-offering-a-novel-drug-option-for-moderate-to-severe-obese-population-302625421.html

15. Peng J, Li M, Zhao Z, Wang R, Huang Y, Zhang H, et al. Mazdutide, a dual agonist targeting GLP-1R and GCGR, mitigates diabetes-associated cognitive dysfunction: mechanistic insights from multi-omics analysis. eBioMedicine. 2025;107:105791. PMID: 40479843. DOI: 10.1016/j.ebiom.2025.105791