Haggag Amina Z, Xu Jianfeng, Butcher Laurie, Pagnussat Sandra, Davies Graeme, Lundqvist Sara, Wang Wenyu, Van Zuydam Natalie, Nelander Karin, Jha Aruni, Yu Hongtao, Boianelli Alessandro, Lindmark Bosse, Ollerstam Anna, Sun Xuefeng, Wang Fan, Pan Xiaoliang, Liu Haihui, Chen Wengang, Xu Jianfeng, Wallenius Kristina, Zhou Jingye
Anaheim Clinical Trials LLC, Anaheim, California, USA.
Eccogene Inc., Cambridge, Massachusetts, USA.
Diabetes Obes Metab. 2025 Feb;27(2):551-562. doi: 10.1111/dom.16047. Epub 2024 Nov 4.
GLP-1 receptor agonists (GLP-1 RAs) are proven therapies for type 2 diabetes mellitus (T2DM) and overweight or obesity. We performed non-clinical and first-in-human (FIH) evaluation of ECC5004/AZD5004, an oral small-molecule GLP-1 RA.
ECC5004 was profiled in cell lines overexpressing human GLP-1R, in glucose-stimulated insulin secretion (GSIS) assays in a human β-cell line and non-human primates (NHPs). To evaluate safety, ECC5004 was orally administered to NHPs for 9 months and a phase I, double-blind, placebo-controlled FIH study was conducted. This study evaluated single doses of ECC5004 (1-300 mg) in healthy volunteers, and multiple daily doses (5, 10, 30 and 50 mg) in patients with T2DM for 28 days.
ECC5004 bound to the hGLP-1R (IC = 2.4 nM) augmented cAMP signalling without β-arrestin-2 recruitment or receptor internalization. ECC5004 potentiated GSIS in both EndoC-βH5 cells (EC = 5.9 nM) and in vivo in NHPs (EC = 0.022 nM). Dose-dependent body weight changes compared to control were seen in the 9-month NHP toxicity study. In the first-in-human study, ECC5004 was well tolerated with no serious adverse events. Dose-dependent reductions in glucose and body weight were observed with a dose-proportional exposure at doses ≥25 mg.
ECC5004 engaged the GLP-1R across the therapeutic dose range tested and had a safety and tolerability profile consistent with other GLP-1 RAs, along with a pharmacokinetic profile compatible with once-daily oral dosing. These data support continued development of ECC5004 as a potential therapy for T2DM and overweight or obesity.
NCT05654831.
胰高血糖素样肽-1受体激动剂（GLP-1 RAs）已被证实可用于治疗2型糖尿病（T2DM）以及超重或肥胖症。我们对口服小分子GLP-1 RA ECC5004/AZD5004进行了非临床和首次人体（FIH）评估。
在过表达人GLP-1R的细胞系、人β细胞系的葡萄糖刺激胰岛素分泌（GSIS）试验以及非人类灵长类动物（NHP）中对ECC5004进行了分析。为评估安全性，对NHP口服ECC5004达9个月，并开展了一项I期双盲、安慰剂对照的首次人体研究。该研究评估了健康志愿者单次服用ECC5004（1 - 300毫克）以及T2DM患者每日多次服用（5、10、30和50毫克），为期28天。
ECC5004与hGLP-1R结合（IC = 2.4纳摩尔），增强了cAMP信号传导，且未引起β-抑制蛋白2募集或受体内化。ECC5004在EndoC-βH5细胞（EC = 5.9纳摩尔）和NHP体内（EC = 0.022纳摩尔）均增强了GSIS。在为期9个月的NHP毒性研究中观察到与对照组相比体重出现剂量依赖性变化。在首次人体研究中，ECC5004耐受性良好，未出现严重不良事件。在剂量≥25毫克时观察到葡萄糖和体重呈剂量依赖性降低，且暴露量与剂量成比例。
在测试的治疗剂量范围内，ECC5004与GLP-1R结合，其安全性和耐受性与其他GLP-1 RAs一致，药代动力学特征也与每日一次口服给药相匹配。这些数据支持继续研发ECC5004，将其作为T2DM和超重或肥胖症的潜在治疗药物。
NCT05654831。
