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.
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。