Allegretti Jessica R, Cheifetz Adam S, Dulai Parambir S, Stevens A C, Chapas-Reed Jillian, Chesnel Laurent, Dixit Bharat, Farquhar Ronald, Ghahramani Parviz, Miller Benjamin W, Murphy Christopher K, Quintas Megan, Tanase Raisa, Telia Tengiz, Woźniak-Stolarska Barbara, Gupta Renu
Brigham and Women's Hospital, Boston, Massachusetts, USA.
Harvard Medical School, Boston, Massachusetts, USA.
Am J Gastroenterol. 2024 Dec 31;120(7):1624-1635. doi: 10.14309/ajg.0000000000003269.
Ulcerative colitis (UC) is characterized by colonic inflammation, with neutrophils playing a key role in UC activity, prognosis, and response to therapies. Current UC therapeutics can have significant side effects and limited efficacy. ADS051 is a novel, oral, gut-restricted small molecule that modulates neutrophil migration and activation without in vitro suppression of T-cell activation. The primary objective of this Phase 1b multidose trial was to evaluate the safety of ADS051. Secondary objectives were clinical activity and pharmacokinetics assessment.
This trial enrolled 24 patients with moderate-to-severe UC in 3 sequential ascending dose cohorts with 3:1 randomization to ADS051 200 mg, 800 mg, or 3,200 mg, or placebo, administered orally once daily for 28 days. Safety, tolerability, and pharmacokinetics were assessed weekly, with clinical activity end points of clinical remission, endoscopic improvement, and histologic remission evaluated at Day 28.
ADS051 was well tolerated without severe or serious adverse events. High fecal concentrations were achieved with low systemic exposure, with <1% of the daily dose of ADS051 excreted in urine. On Day 28 of the trial, clinical remission was achieved in 22.2% of the pooled ADS051 group vs 0% of the pooled placebo group. Endoscopic response was achieved in 50.0% of ADS051-dosed vs 16.7% of placebo, and endoscopic improvement was achieved in 33.3% of ADS051-dosed vs 0% of placebo.
Phase 1b data in patients with UC indicate a favorable safety profile for ADS051 with encouraging signals of clinical activity, supporting the advancement to a Phase 2 trial.
溃疡性结肠炎（UC）的特征是结肠炎症，中性粒细胞在UC的活动、预后及对治疗的反应中起关键作用。目前的UC治疗方法可能有显著副作用且疗效有限。ADS051是一种新型口服、肠道靶向小分子，可调节中性粒细胞迁移和激活，且在体外不会抑制T细胞激活。这项1b期多剂量试验的主要目的是评估ADS051的安全性。次要目的是进行临床活性和药代动力学评估。
本试验纳入24例中重度UC患者，分为3个连续的递增剂量队列，以3:1的比例随机分配至ADS051 200mg、800mg或3200mg组，或安慰剂组，每日口服一次，共28天。每周评估安全性、耐受性和药代动力学，在第28天评估临床缓解、内镜改善和组织学缓解等临床活性终点。
ADS051耐受性良好，无严重不良事件。在全身暴露量较低的情况下，粪便中达到了高浓度，ADS051每日剂量的<1%经尿液排泄。在试验的第28天，合并ADS051组中22.2%达到临床缓解，而合并安慰剂组为0%。接受ADS051治疗的患者中有50.0%达到内镜反应，而安慰剂组为16.7%；接受ADS051治疗的患者中有33.3%达到内镜改善，而安慰剂组为0%。
UC患者的1b期数据表明ADS051具有良好的安全性，并有令人鼓舞的临床活性信号，支持推进至2期试验。
