Objectives: 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.
Methods: 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 3200 mg, or placebo, administered orally once daily for 28 days. Safety, tolerability, and pharmacokinetics were assessed weekly, with clinical activity endpoints of clinical remission, endoscopic improvement, and histologic remission evaluated at Day 28.
Results: 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 versus 0% of the pooled placebo group. Endoscopic response was achieved in 50.0% of ADS051-dosed versus 16.7% of placebo, and endoscopic improvement was achieved in 33.3% of ADS051-dosed versus 0% of placebo.
Conclusions: 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.
Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.