Zhou Xiao-Hong, Prothon Susanne, Liathdale Engin, Ferrari Nicola, Hezaveh Kebria, Liu Zhi, Nemes Szilard, Almquist Joachim, Williams Michael L, Sobande Olami, Gottfridsson Christer, Gochuico Bernadette R, Platt Adam, Brohawn Zach, Belvisi Maria G, Goldwater Ronald, Hornberg Ellinor, Owen Caroline A
Patient Safety Biopharma, Chief Medical Office, Oncology R&D, AstraZeneca, Pepparedsleden 1, 431 51 Mölndal, Sweden.
Clinical Pharmacology & Quantitative Pharmacology, BioPharmaceuticals R&D, AstraZeneca, Pepparedsleden 1, 431 51 Mölndal, Sweden.
iScience. 2025 Jun 6;28(6):112602. doi: 10.1016/j.isci.2025.112602. eCollection 2025 Jun 20.
Excessive Wnt signaling contributes to the development of fibrotic diseases and cancer. Here, we report the findings of a phase 1 study evaluating AZD5055, an orally administered porcupine inhibitor, which inhibits Wnt signaling. The primary objective was to evaluate the safety and tolerability of AZD5055 in healthy volunteers. Secondary and exploratory objectives were the pharmacokinetics and pharmacodynamics of AZD5055, respectively. Sixty healthy volunteers were randomized to receive placebo or AZD5055 in single ascending doses of 7, 20, or 40 mg (part 1), or multiple ascending doses of 5, 15, or 20 mg once daily over 14 consecutive days of dosing (Part 2). AZD5055 was safe and well tolerated in both study parts. AZD5055 exposure increased dose-proportionally with a pharmacokinetic profile enabling once daily dosing. AZD5055 effectively inhibited Wnt signaling in skin, hair follicles, and serum samples. Thus, AZD5055 has therapeutic potential in Wnt-driven fibrotic diseases and cancers.
过度的Wnt信号传导会导致纤维化疾病和癌症的发展。在此，我们报告了一项1期研究的结果，该研究评估了口服给药的刺猬蛋白抑制剂AZD5055，它可抑制Wnt信号传导。主要目的是评估AZD5055在健康志愿者中的安全性和耐受性。次要目的和探索性目的分别是AZD5055的药代动力学和药效学。60名健康志愿者被随机分组，接受安慰剂或单次递增剂量为7、20或40毫克的AZD5055（第1部分），或在连续14天给药期间每天一次接受多次递增剂量为5、15或20毫克的AZD5055（第2部分）。在两个研究部分中，AZD5055均安全且耐受性良好。AZD5055的暴露量随剂量成比例增加，其药代动力学特征允许每日给药一次。AZD5055有效抑制皮肤、毛囊和血清样本中的Wnt信号传导。因此，AZD5055在Wnt驱动的纤维化疾病和癌症中具有治疗潜力。
