Safety, Pharmacokinetics, and Clinical Efficacy of ADS051, a Neutrophil Modulator, in Ulcerative Colitis: Results of a Randomized Phase 1b Trial

Abstract

Introduction: 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 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.

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 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.

Discussion: 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.

Trial registration: ClinicalTrials.gov NCT05084261.

Keywords: ADS051; gut-restricted; neutrophils; ulcerative colitis.

Graphical abstract

Figure 1.

Phase 1b clinical trial design. A total of 8 participants per cohort were randomized to receive either ADS051 (n = 6) or placebo (n = 2) in a 3:1 randomization scheme. The sample sizes were selected empirically based on having a reasonable number of participants to assess safety and tolerability. The doses were selected based on safety, tolerability, and PK data from a single-dose trial of ADS051 (28). SRC review of safety and tolerability on Day 14 for each cohort allowed the subsequent cohorts to proceed. Patients from the lower cohort did not escalate to the next cohort. D, day; PBO, placebo; PK, pharmacokinetic; SRC, safety review committee.

Figure 2.

Consolidated Standards of Reporting Trials participant flow diagram.

Figure 3.

Pharmacokinetic analyses of stool, blood, and urine. D, day; IC50, half-maximal inhibitory concentration; LLOQ, lower limit of quantification. ^aStool concentrations up to 8,000-fold above the target IC50 (3.3 μg/mL or 1 μM). ^bOnly 1 positive sample. All other samples < LLOQ (LLOQ = 2.5 ng/mL).

Figure 4.

Efficacy assessments. (a) Clinical remission. (b) Endoscopic response. (c) Endoscopic improvement. As part of efficacy assessments for the MAD trial, clinical remission, endoscopic response, and endoscopic improvement were measured for pooled ADS051 and pooled placebo per the criteria shown. MAD, multiple ascending dose; MCS, Mayo Clinic score; MES, Mayo endoscopic subscore; RBS, Mayo rectal bleeding subscore; SFS, Mayo stool frequency subscore; UCEIS, Ulcerative Colitis Endoscopic Index of Severity.