PDF(Pubmed)
Abstract：
OBJECTIVE: 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.
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.
摘要：
目的：肥胖是一种全球性的健康危机，患者负担和医疗费用都很高。尽管胰高血糖素样肽-1-（GLP-1）受体激动剂在治疗肥胖方面取得了进展，未满足的需求仍然存在。这项研究表征了一种新型的葡萄糖依赖性促胰岛素多肽受体（GIPR）肽拮抗剂，AT-7687，评估其增强肥胖治疗的潜力。
方法：我们评估了AT-7687的体外效力和药代动力学，以及单独皮下（SC）和与利拉鲁肽联合应用于高脂饮食喂养的肥胖非人类灵长类动物（NHP）时的治疗效果。该研究跨越42天的治疗期和15天的清除期。
结果:AT-7687在HEK-293细胞中显示亚纳摩尔cAMP拮抗效力(pKB为9.5),在NHP中显示27.4小时的半衰期。它有效地保持了肥胖猴子的体重稳定性，而安慰剂组的体重在第42天增加了8.6%(P=0.01).利拉鲁肽的单一疗法导致安慰剂的体重减轻12.4％（P=0.03），而AT-7687与利拉鲁肽的组合导致体重减轻16.3％（P=0.0002）。联合治疗显著改善代谢标志物，胰岛素水平降低52%（P=0.008），葡萄糖减少30%（P=0.02），甘油三酯下降39%(P=0.05)，总胆固醇下降29%（P=0.03），和LDL胆固醇从安慰剂的48％（P=0.003）。AT-7687治疗耐受性良好，没有任何副作用。
结论：这项研究强调了AT-7687作为目前肥胖治疗的一个有希望的补充的潜力。
方法：我们评估了AT-7687的体外效力和药代动力学，以及单独皮下（SC）和与利拉鲁肽联合应用于高脂饮食喂养的肥胖非人类灵长类动物（NHP）时的治疗效果。该研究跨越42天的治疗期和15天的清除期。
结果:AT-7687在HEK-293细胞中显示亚纳摩尔cAMP拮抗效力(pKB为9.5),在NHP中显示27.4小时的半衰期。它有效地保持了肥胖猴子的体重稳定性，而安慰剂组的体重在第42天增加了8.6%(P=0.01).利拉鲁肽的单一疗法导致安慰剂的体重减轻12.4％（P=0.03），而AT-7687与利拉鲁肽的组合导致体重减轻16.3％（P=0.0002）。联合治疗显著改善代谢标志物，胰岛素水平降低52%（P=0.008），葡萄糖减少30%（P=0.02），甘油三酯下降39%(P=0.05)，总胆固醇下降29%（P=0.03），和LDL胆固醇从安慰剂的48％（P=0.003）。AT-7687治疗耐受性良好，没有任何副作用。
结论：这项研究强调了AT-7687作为目前肥胖治疗的一个有希望的补充的潜力。
