每日一次GLP-1/GIP/胰高血糖素受体三激动剂（NN1706）降低啮齿动物、猴子和人的体重。

IF 7 2区医学 Q1 ENDOCRINOLOGY & METABOLISM

Molecular Metabolism Pub Date : 2025-03-24 DOI:10.1016/j.molmet.2025.102129

Brian Finan , Jonathan D. Douros , Ronald Goldwater , Ann Maria Kruse Hansen , Julie B. Hjerpsted , Karina Rahr Hjøllund , Martin K. Kankam , Patrick J. Knerr , Anish Konkar , Stephanie A. Mowery , Timo D. Müller , John Rømer Nielsen , Sune Boris Nygård , Diego Perez-Tilve , Kirsten Raun , Bin Yang , Matthias H. Tschöp , Richard D. DiMarchi

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引用次数: 0

摘要

将互补作用模式与胰高血糖素样肽-1受体（GLP-1R）激动作用相结合的单分子是治疗肥胖的最佳药物。NN1706 （MAR423, RO6883746）是一种脂肪酰化的三激动剂，设计用于GLP-1R和葡萄糖依赖性胰岛素多肽受体（GIPR）的平衡活性，而胰高血糖素受体（GcgR）的相对效力较低。肥胖小鼠、大鼠和非人类灵长类动物服用NN1706后，体重明显减轻，血糖控制得到改善。在超重或肥胖的人类受试者中，每日皮下NN1706治疗以剂量依赖的方式显著减轻体重，而不损害血糖控制（NCT03095807, NCT03661879）。然而，在NN1706治疗队列中观察到心率增加，这对NN1706的进一步临床开发提出了挑战。

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A once-daily GLP-1/GIP/glucagon receptor tri-agonist (NN1706) lowers body weight in rodents, monkeys and humans

Single molecules that combine complementary modes of action with glucagon-like peptide-1 receptor (GLP-1R) agonism are best-in-class therapeutics for obesity treatment. NN1706 (MAR423, RO6883746) is a fatty-acylated tri-agonist designed for balanced activity at GLP-1R and glucose-dependent insulinotropic peptide receptor (GIPR) with lower relative potency at the glucagon receptor (GcgR). Obese mice, rats and non-human primates dosed with NN1706 showed significant body weight reductions and improved glycemic control. In human participants with overweight or obesity, daily subcutaneous NN1706 treatment resulted in substantial body weight loss in a dose-dependent manner without impairing glycemic control (NCT03095807, NCT03661879). However, increased heart rate was observed across NN1706 treatment cohorts, which challenges further clinical development of NN1706.

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来源期刊

Molecular Metabolism ENDOCRINOLOGY & METABOLISM-

CiteScore

14.50

自引率

2.50%

发文量

219

审稿时长

43 days

期刊介绍： Molecular Metabolism is a leading journal dedicated to sharing groundbreaking discoveries in the field of energy homeostasis and the underlying factors of metabolic disorders. These disorders include obesity, diabetes, cardiovascular disease, and cancer. Our journal focuses on publishing research driven by hypotheses and conducted to the highest standards, aiming to provide a mechanistic understanding of energy homeostasis-related behavior, physiology, and dysfunction. We promote interdisciplinary science, covering a broad range of approaches from molecules to humans throughout the lifespan. Our goal is to contribute to transformative research in metabolism, which has the potential to revolutionize the field. By enabling progress in the prognosis, prevention, and ultimately the cure of metabolic disorders and their long-term complications, our journal seeks to better the future of health and well-being.