INTRODUCTION A need for better treatment options for moderate to severe ulcerative colitis (UC) persists due to the efficacy and safety limitations of current therapies. Neutrophil epithelial transmigration is associated with the characteristic colonic mucosal inflammation in and very likely involved with the pathogenesis and clinical symptoms of UC. ADS051 is a small-molecule inhibiting neutrophil migration and activation, which are potentially important therapeutic targets in UC. Phase 1, single ascending dose study evaluated ADS051's safety, tolerability, and pharmacokinetics in healthy volunteers. METHODS Fifty healthy adults were randomized 4:1 into 5 ascending dose cohorts to receive a single oral dose of ADS051 100 mg, 300 mg, 700 mg, 1500 mg, 3500 mg, or placebo. Participants were followed until 30 days post dose. Safety and pharmacokinetics of ADS051 in stool, blood, and urine were evaluated. RESULTS ADS051 was safe and well tolerated. Adverse event (AE) of constipation were reported by 2 participants (5.0%) in ADS051 1500 mg group versus none in placebo group. No serious AEs reported and no discontinuations due to AEs. In all dose groups, a cumulative average of 10%-24% of the ADS051 dose was recovered in stool, mostly within 48 hours after dosing. ADS051 was quantifiable in only 2 of 440 blood samples (7.64 and 69.8 ng/ml). On average, <0.035% of the ADS051 dose was excreted in urine. CONCLUSION ADS051 was safe, well tolerated, and achieved high stool concentrations with minimal systemic exposure. ADS051 could be a safe and effective, locally acting, neutrophil-targeting agent for the treatment of UC.

中文翻译：

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小分子中性粒细胞调节剂 ADS051 在 1 期单剂量递增研究中是安全且耐受性良好的。


引言 由于当前疗法的有效性和安全性限制，中度至重度溃疡性结肠炎 （UC） 仍然存在对更好治疗选择的需求。中性粒细胞上皮迁移与 UC 的特征性结肠粘膜炎症有关，并且很可能与 UC 的发病机制和临床症状有关。ADS051 是一种抑制中性粒细胞迁移和激活的小分子药物，这些是 UC 中潜在的重要治疗靶点。1 期单次递增剂量研究评估了 ADS051 在健康志愿者中的安全性、耐受性和药代动力学。方法 将 50 名健康成人以 4：1 的比例随机分为 5 个递增剂量组，接受单次口服剂量的 ADS051 100 mg、300 mg、700 mg、1500 mg、3500 mg 或安慰剂。参与者被随访至给药后 30 天。评价 ADS051 在粪便、血液和尿液中的安全性和药代动力学。结果 ADS051 安全且耐受性良好。ADS051 1500 mg 组有 2 名参与者 （5.0%） 报告了便秘的不良事件 （AE），而安慰剂组没有报告。没有报告严重的 AE，也没有因 AE 而停药。在所有剂量组中，ADS051 剂量的累积平均 10%-24% 在粪便中回收，多在给药后 48 小时内。ADS051 在 440 个血液样本中只有 2 个（7.64 和 69.8 ng/ml）可定量。平均而言，<0.035% 的 ADS051 剂量经尿液排泄。结论 ADS051 安全、耐受性好，大便浓度高，全身暴露最小。ADS051 可能是一种安全有效的局部作用中性粒细胞靶向剂，用于治疗 UC。