Mette H. Jensen , Samra J. Sanni , Ditte Riber , Jens J. Holst , Mette M. Rosenkilde , Alexander H. Sparre-Ulrich
{"title":"AT-7687 是一种新型 GIPR 肽拮抗剂，它与 GLP-1 激动剂结合使用，可促进猴的体重减轻和代谢改善。","authors":"Mette H. Jensen , Samra J. Sanni , Ditte Riber , Jens J. Holst , Mette M. Rosenkilde , Alexander H. Sparre-Ulrich","doi":"10.1016/j.molmet.2024.102006","DOIUrl":null,"url":null,"abstract":"<div><h3>Objectives</h3><p>Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment.</p></div><div><h3>Methods</h3><p>We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period.</p></div><div><h3>Results</h3><p>AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (<em>P</em> = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (<em>P</em> = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (<em>P</em> = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (<em>P</em> = 0.008), glucose by 30% (<em>P</em> = 0.02), triglycerides by 39% (<em>P</em> = 0.05), total cholesterol by 29% (<em>P</em> = 0.03), and LDL cholesterol by 48% (<em>P</em> = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects.</p></div><div><h3>Conclusions</h3><p>This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.</p></div>","PeriodicalId":18765,"journal":{"name":"Molecular Metabolism","volume":"88 ","pages":"Article 102006"},"PeriodicalIF":7.0000,"publicationDate":"2024-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2212877824001376/pdfft?md5=d4e3ed6d91b514b386ce580c9aecd09d&pid=1-s2.0-S2212877824001376-main.pdf","citationCount":"0","resultStr":"{\"title\":\"AT-7687, a novel GIPR peptide antagonist, combined with a GLP-1 agonist, leads to enhanced weight loss and metabolic improvements in cynomolgus monkeys\",\"authors\":\"Mette H. Jensen , Samra J. Sanni , Ditte Riber , Jens J. Holst , Mette M. Rosenkilde , Alexander H. Sparre-Ulrich\",\"doi\":\"10.1016/j.molmet.2024.102006\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Objectives</h3><p>Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment.</p></div><div><h3>Methods</h3><p>We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period.</p></div><div><h3>Results</h3><p>AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (<em>P</em> = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (<em>P</em> = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (<em>P</em> = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (<em>P</em> = 0.008), glucose by 30% (<em>P</em> = 0.02), triglycerides by 39% (<em>P</em> = 0.05), total cholesterol by 29% (<em>P</em> = 0.03), and LDL cholesterol by 48% (<em>P</em> = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects.</p></div><div><h3>Conclusions</h3><p>This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.</p></div>\",\"PeriodicalId\":18765,\"journal\":{\"name\":\"Molecular Metabolism\",\"volume\":\"88 \",\"pages\":\"Article 102006\"},\"PeriodicalIF\":7.0000,\"publicationDate\":\"2024-08-10\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S2212877824001376/pdfft?md5=d4e3ed6d91b514b386ce580c9aecd09d&pid=1-s2.0-S2212877824001376-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Molecular Metabolism\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S2212877824001376\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Molecular Metabolism","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2212877824001376","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
AT-7687, a novel GIPR peptide antagonist, combined with a GLP-1 agonist, leads to enhanced weight loss and metabolic improvements in cynomolgus monkeys
Objectives
Obesity represents a global health crisis with significant patient burdens and healthcare costs. Despite the advances with glucagon-like peptide-1 (GLP-1) receptor agonists in treating obesity, unmet needs remain. This study characterizes a novel glucose-dependent insulinotropic polypeptide receptor (GIPR) peptide antagonist, AT-7687, evaluating its potential to enhance obesity treatment.
Methods
We assessed the in vitro potency and pharmacokinetics of AT-7687, alongside its therapeutic effects when administered subcutaneously (SC) alone and in combination with liraglutide to high-fat-diet-fed obese non-human primates (NHP). The study spanned a 42-day treatment period and a 15-day washout period.
Results
AT-7687 demonstrated a subnanomolar cAMP antagonistic potency (pKB of 9.5) in HEK-293 cells and a 27.4 h half-life in NHPs. It effectively maintained weight stability in obese monkeys, whereas placebo recipients had an 8.6% weight increase by day 42 (P = 0.01). Monotherapy with liraglutide resulted in a 12.4% weight reduction compared to placebo (P = 0.03) and combining AT-7687 with liraglutide led to a 16.3% weight reduction (P = 0.0002). The combination therapy significantly improved metabolic markers, reducing insulin levels by 52% (P = 0.008), glucose by 30% (P = 0.02), triglycerides by 39% (P = 0.05), total cholesterol by 29% (P = 0.03), and LDL cholesterol by 48% (P = 0.003) compared to placebo. AT-7687 treatment was well tolerated and not associated with any side effects.
Conclusions
This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.
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.
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