Small-Molecule Neutrophil Modulator ADS051 is Safe and Well-Tolerated in a Phase 1 Single Ascending Dose Study.

Introduction: 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.

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, 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.

Results: 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.

Discussion: 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.