Antag Therapeutics Aps, Ole Maaløes Vej 3, 2200 Copenhagen N, Denmark.
Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Nørre Alle 14, 2200 Copenhagen N, Denmark.
Mol Metab. 2024 Oct;88:102006. doi: 10.1016/j.molmet.2024.102006. Epub 2024 Aug 10.
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.
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.
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.
This study underscores the potential of AT-7687 as a promising addition to current obesity treatments.
肥胖是全球健康危机，给患者带来沉重负担并耗费大量医疗保健成本。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，但仍存在未满足的需求。本研究描述了一种新型葡萄糖依赖性胰岛素促分泌多肽受体（GIPR）肽拮抗剂 AT-7687，评估其增强肥胖治疗的潜力。
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）给药和与利拉鲁肽联合给药治疗高脂肪饮食喂养肥胖非人类灵长类动物（NHP）的治疗效果。研究跨越了 42 天的治疗期和 15 天的洗脱期。
AT-7687 在 HEK-293 细胞中表现出亚纳摩尔级别的 cAMP 拮抗效力（pKB 为 9.5），在 NHP 中的半衰期为 27.4 小时。它有效地维持肥胖猴子的体重稳定，而安慰剂组在第 42 天体重增加 8.6%（P=0.01）。与安慰剂相比，利拉鲁肽单药治疗导致体重减轻 12.4%（P=0.03），而将 AT-7687 与利拉鲁肽联合治疗导致体重减轻 16.3%（P=0.0002）。联合治疗显著改善了代谢标志物，使胰岛素水平降低 52%（P=0.008），血糖降低 30%（P=0.02），甘油三酯降低 39%（P=0.05），总胆固醇降低 29%（P=0.03），低密度脂蛋白胆固醇降低 48%（P=0.003），与安慰剂相比。AT-7687 治疗耐受良好，与任何副作用无关。
本研究强调了 AT-7687 作为当前肥胖治疗方法的一种有前途的补充的潜力。
