Cheifetz Adam S, Allegretti Jessica R, Quintas Megan, Dixit Bharat, Farquhar Ronald, Miller Benjamin W, Murphy Christopher K, Hershberger Ellie, Ghahramani Parviz, Stevens A C
Harvard Medical School, Boston, Massachusetts, USA.
Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.
Am J Gastroenterol. 2024 Nov 26;120(7):1585-1592. doi: 10.14309/ajg.0000000000003237.
A need for better treatment options for moderate to severe ulcerative colitis (UC) persists because of 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. The phase 1 single ascending dose study evaluated ADS051's safety, tolerability, and pharmacokinetics in healthy volunteers.
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, 1,500 mg, 3,500 mg, or placebo. Participants were followed until 30 days after dosing. Safety and pharmacokinetics of ADS051 in stool, blood, and urine were evaluated.
ADS051 was safe and well-tolerated. Adverse events (AEs) of constipation were reported by 2 participants (5.0%) in the ADS051 1,500 mg group vs none in the 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.
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.
由于目前治疗方法在疗效和安全性方面存在局限性，对中重度溃疡性结肠炎（UC）仍需要更好的治疗选择。中性粒细胞上皮迁移与特征性结肠黏膜炎症相关，并且很可能参与UC的发病机制和临床症状。ADS051是一种抑制中性粒细胞迁移和激活的小分子，这在UC中可能是重要的治疗靶点。1期单剂量递增研究评估了ADS051在健康志愿者中的安全性、耐受性和药代动力学。
50名健康成年人按4:1随机分为5个剂量递增队列，接受单次口服100 mg、300 mg、700 mg、1500 mg、3500 mg的ADS051或安慰剂。对参与者随访至给药后30天。评估ADS051在粪便、血液和尿液中的安全性和药代动力学。
ADS051安全且耐受性良好。在ADS051 1500 mg组中，2名参与者（5.0%）报告了便秘不良事件，而安慰剂组未报告。未报告严重不良事件，也没有因不良事件而停药的情况。在所有剂量组中，粪便中回收的ADS051剂量累计平均为10%-24%，大多在给药后48小时内。在440份血液样本中，只有2份可检测到ADS051（7.64和69.8 ng/mL）。平均而言，ADS051剂量的<0.035%经尿液排泄。
ADS051安全、耐受性良好，且在粪便中浓度高，全身暴露量最小。ADS051可能是一种安全有效的局部作用、靶向中性粒细胞的UC治疗药物。
