Description

Mazdutide: The Promising Dual-Receptor Agonist for Metabolic Disorders

Mazdutide (also known as IBI362 or LY3305677) represents a significant advancement in peptide therapeutics as a novel dual-action medication that simultaneously targets two key metabolic pathways. This once-weekly injectable has demonstrated remarkable efficacy for both weight management and glycemic control in clinical trials, positioning it as a potential leader in the growing field of metabolic medicines. With substantial weight loss results that approach surgical outcomes and favorable safety profiles, mazdutide is garnering attention as a next-generation therapy for obesity and type 2 diabetes.

Molecular Structure and Mechanism of Action

Mazdutide functions through a distinct dual-receptor mechanism that differentiates it from existing metabolic medications.

Dual Receptor Targeting

Mazdutide is classified as a glucagon-like peptide-1 receptor (GLP-1R) and glucagon receptor (GCGR) dual agonist, the first in its class to advance to late-stage clinical trials^[1]. This synthetic peptide analog of mammalian oxyntomodulin activates two complementary receptor systems:

·         GLP-1 receptors, which are widely distributed on pancreatic beta cells, brain tissues, and other organs

·         Glucagon receptors, which play important roles in energy metabolism and fat utilization

By simultaneously engaging both receptor types, mazdutide creates a unique pharmacological profile that combines the benefits of GLP-1 activation with the metabolic advantages of glucagon signaling^[1][2].

Metabolic Effects

This dual-receptor activation produces several complementary effects that contribute to mazdutide’s therapeutic benefits:

·         Enhanced insulin secretion from pancreatic beta cells in a glucose-dependent manner

·         Increased satiety and reduced appetite through central nervous system effects

·         Delayed gastric emptying, prolonging feelings of fullness after meals

·         Improved metabolic flexibility and energy expenditure

·         Enhanced fat oxidation and reduction in liver fat content

Importantly, while glucagon receptor activation alone would typically increase hepatic glucose production, the balanced dual-agonist approach prevents this unwanted effect while maintaining glucagon’s beneficial impacts on weight loss and metabolic function^[1].

Clinical Development and Research

Mazdutide has undergone extensive clinical testing, with compelling results from multiple trials in different patient populations.

Clinical Trial Program

The development program for mazdutide includes several key clinical trials:

·         A 12-week multiple-ascending-dose phase 1b study in Chinese patients with type 2 diabetes (NCT04466904)^[3]

·         A phase 1b trial evaluating 9 mg and 10 mg doses for 12 and 16 weeks respectively (NCT04440345)^[2]

·         A phase 2 trial in Chinese adults with overweight or obesity, evaluating doses up to 6 mg for 24 weeks, extended to 48 weeks for the 9 mg cohort^[4][5]

·         GLORY-1: A phase 3 randomized, double-blind, placebo-controlled trial enrolling 610 Chinese adults with overweight or obesity (NCT05607680)^[6][7]

·         DREAMS-2: A phase 3 trial comparing mazdutide to dulaglutide in 731 Chinese subjects with type 2 diabetes (NCT05606913)^[8][9]

·         DREAMS-3: A head-to-head study of mazdutide and Novo Nordisk’s semaglutide (Ozempic)^[10]

These trials have consistently shown significant benefits in both weight management and glycemic control across different patient populations and in comparison to established treatments.

Weight Loss Efficacy

Mazdutide has demonstrated dose-dependent weight loss across multiple studies:

·         In phase 1b trials, the 9 mg dose achieved a mean weight reduction of 11.7% at 12 weeks compared to 1.8% with placebo (treatment difference: -9.8%)^[2]

·         The 24-week phase 2 results showed mean weight reductions of 6.7% with 3 mg, 10.4% with 4.5 mg, and 11.3% with 6 mg compared to 1.0% with placebo^[4]

·         The extended 48-week treatment with 9 mg demonstrated a remarkable placebo-adjusted mean body weight loss of 18.6%^[5]

·         In the phase 3 GLORY-1 trial, patients achieved 10.97% and 13.38% reduction in body weight with 4 mg and 6 mg doses respectively, with over 50% of patients on high-dose mazdutide achieving at least 15% weight reduction at 48 weeks^[7]

These results position mazdutide among the most effective pharmacological approaches to weight management, with efficacy that researchers suggest may be comparable to bariatric surgery for certain doses^[2].

Glycemic Control

In addition to weight loss, mazdutide shows significant benefits for glycemic control:

·         In Chinese patients with type 2 diabetes, mean reductions in HbA1c after 20 weeks ranged from 1.41% to 1.67% with mazdutide doses, compared to 1.35% with dulaglutide and 0.03% with placebo^[11]

·         The DREAMS-2 trial demonstrated that mazdutide was not only non-inferior but superior to dulaglutide for glycemic control^[8][9]

·         Importantly, mazdutide achieves glycemic improvements while simultaneously producing significant weight loss, offering comprehensive benefits for patients with type 2 diabetes^[3][11]

Additional Metabolic Benefits

Beyond weight loss and glycemic improvements, mazdutide demonstrates several additional metabolic benefits that enhance its therapeutic profile.

Cardiometabolic Improvements

Mazdutide treatment has been associated with broad cardiometabolic benefits:

·         Significant reductions in systolic blood pressure

·         Improvements in lipid profiles, including decreases in triglycerides and low-density lipoprotein (LDL) cholesterol

·         Reductions in alanine aminotransferase (ALT) levels, indicating potential liver benefits

·         Substantial reductions in liver fat content – up to 73.3% decrease after 24 weeks in people with elevated baseline liver fat^[5][7]

Novel Effects on Uric Acid

A particularly interesting finding has been mazdutide’s effect on uric acid levels:

·         Mazdutide produces significant reductions in serum uric acid, an effect not consistently seen with GLP-1 receptor agonists alone^[12]

·         In animal studies, the degree of hyperuricemia reduction by mazdutide was comparable to that of allopurinol, a standard uric acid-lowering medication^[12]

·         This effect was observed in both the low-dose and high-dose mazdutide studies, suggesting a consistent benefit across dosing regimens^[12]

This uric acid-lowering property could provide additional benefits for patients with metabolic syndrome, where hyperuricemia is often a comorbid condition.

Safety Profile and Tolerability

The safety profile of mazdutide appears consistent with other medications in its class, with predominantly mild to moderate adverse events.

Common Adverse Effects

The most frequently reported side effects include:

·         Gastrointestinal symptoms: diarrhea (36%), nausea (23%), vomiting (14%), abdominal distension

·         Decreased appetite (29%)

·         Upper respiratory tract infection

·         Urinary tract infection

·         Hypoglycemia (10% with mazdutide vs. 8% with placebo in diabetes trials)^[11][2][4]

These adverse events were generally mild or moderate in severity and often diminished over time.

Treatment Discontinuation

Mazdutide demonstrated favorable tolerability across trials:

·         In the GLORY-1 phase 3, adverse events leading to treatment discontinuation were reported in only 1.5% of participants with mazdutide 4 mg, 0.5% with mazdutide 6 mg, and 1.0% with placebo^[6]

·         No serious adverse events were reported in the phase 1b high-dose trial^[2]

·         Higher doses (9 mg and 10 mg) maintained favorable safety profiles similar to lower doses^[13]

Overall, mazdutide’s safety profile appears consistent with other GLP-1-based therapies, with no unexpected safety signals identified in trials to date.

Regulatory Status and Commercial Development

Mazdutide represents a significant collaboration between global and Chinese pharmaceutical companies, with important regulatory milestones on the horizon.

Development Partnership

The development of mazdutide involves a strategic partnership:

·         Originally developed by Eli Lilly, who licensed the China rights to Innovent Biologics in 2019

·         Innovent is developing mazdutide for the Chinese market, conducting multiple phase 3 trials

·         Lilly retains rights to the compound in all other countries, where it remains in phase 2 development for obesity^[10][14]

Regulatory Timeline

Mazdutide is approaching regulatory submissions in China:

·         Innovent has completed phase 3 trials for both obesity (GLORY-1) and type 2 diabetes (DREAMS-2)

·         The company plans to submit new drug applications (NDAs) to China’s National Medical Products Administration (NMPA) for both indications^[10][7]

·         If approved, mazdutide would be the first GLP-1R/GCGR dual agonist to reach the market

·         The development timeline for markets outside China would be determined by Eli Lilly

Comparison with Existing Therapies

Mazdutide enters a field with established competitors but offers potential advantages through its unique mechanism.

Differentiation from Other GLP-1 Therapies

As a dual GLP-1/glucagon receptor agonist, mazdutide differs from popular GLP-1 receptor agonists like semaglutide (Ozempic/Wegovy) and tirzepatide (Mounjaro/Zepbound, which targets GLP-1 and GIP receptors):

·         Phase 3 data showed superior glycemic control compared to dulaglutide (Trulicity)^[8][10]

·         The ongoing DREAMS-3 trial is directly comparing mazdutide to semaglutide (Ozempic)^[10]

·         Early data suggests potential for weight loss efficacy comparable to or exceeding established therapies, particularly with the 9 mg dose^[2][5]

Positioning in Treatment Landscape

Based on available data, mazdutide may find its place in the treatment landscape through:

·         Robust weight loss efficacy, potentially approaching bariatric surgery results for certain patients

·         Comprehensive metabolic benefits beyond weight loss and glycemic control

·         Novel effects on uric acid levels, potentially benefiting patients with hyperuricemia

·         Favorable safety profile consistent with established GLP-1-based therapies

Conclusion

Mazdutide represents a promising advancement in the treatment of obesity and type 2 diabetes through its innovative dual-receptor mechanism of action. As the first GLP-1R/GCGR dual agonist to complete phase 3 trials, it has demonstrated remarkable efficacy for weight reduction—up to 18.6% placebo-adjusted weight loss at 48 weeks with the 9 mg dose—alongside significant improvements in glycemic control.

The compound’s broad metabolic benefits, including reductions in liver fat, blood pressure, lipids, and uniquely, serum uric acid, position it as a potentially valuable addition to the therapeutic armamentarium for metabolic disorders. With a safety profile consistent with established GLP-1-based therapies and regulatory submissions planned in China, mazdutide may soon offer a new option for patients struggling with obesity and diabetes.

As development continues, further data from comparative trials and real-world use will help clarify mazdutide’s ultimate place in the rapidly evolving landscape of metabolic medicines. With its promising combination of efficacy, safety, and comprehensive metabolic benefits, mazdutide represents an important step forward in addressing the global challenges of obesity and diabetes.

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1.       https://www.drugs.com/medical-answers/what-mazdutide-3573798/  

2.      https://pmc.ncbi.nlm.nih.gov/articles/PMC9561728/      

3.      https://pmc.ncbi.nlm.nih.gov/articles/PMC10733643/ 

4.      https://www.nature.com/articles/s41467-023-44067-4  

5.       https://www.clinicaltrialsarena.com/news/innovents-mazdutide-offers-weight-loss-in-phase-ii-obesity-trial/   

6.      https://diabetesjournals.org/diabetes/article/73/Supplement_1/1856-LB/155559/1856-LB-Efficacy-and-Safety-of-Mazdutide-in 

7.       https://www.clinicaltrialsarena.com/news/easd-2024-innovent-shows-off-mazdutides-efficacy-in-diabetes-and-obesity/   

8.      https://www.biospace.com/head-to-head-superiority-to-high-dose-dulaglutide-innovent-s-first-phase-3-clinical-trial-of-mazdutide-in-chinese-patients-with-type-2-diabetes-met-study-endpoints  

9.      https://synapse.patsnap.com/article/innovent-to-present-mazdutide-clinical-study-results-at-easd-2024 

10.   https://www.clinicaltrialsarena.com/news/innovent-mazdutide-china-superior-trulicity/    

11.    https://pubmed.ncbi.nlm.nih.gov/37943529/  

12.   https://diabetesjournals.org/diabetes/article/72/Supplement_1/77-LB/149939/77-LB-A-Novel-Glucagon-Like-Peptide-1-GLP-1R-and  

13.   https://pubmed.ncbi.nlm.nih.gov/36247927/

14.   https://www.fiercebiotech.com/biotech/next-gen-lilly-obesity-drug-secures-first-phase-3-win-innovent-readies-chinese-approval