Safety, tolerability and pharmacokinetics of BT051, an oral inhibitor of neutrophil migration and activation in clinical development for Inflammatory Bowel Disease

Abstract Background BT051 is an oral, locally acting inhibitor of neutrophil trafficking and activation in clinical development for the treatment of patients with Inflammatory Bowel Disease (IBD). Herein we report the results of this first-in-human study of BT051 in healthy subjects. Methods This was a phase 1, randomised, double-blind, placebo-controlled, single-centre, single ascending dose (SAD) study. Healthy subjects (n=50) were randomised into 5 SAD cohorts to receive BT051 (100, 300, 700, 1500 or 3500 mg) or placebo (8 active:2 placebo in each cohort). A safety review committee evaluated any dose-limiting adverse events (AEs) through Day 3 before proceeding to the next cohort. Samples for pharmacokinetic (PK) analysis were collected from blood, stool and urine predose and up to 48 hours postdose; stool samples for PK analysis were also collected on Day 7. An exploratory endpoint of systemic immunosuppression was performed by assessing cytokine secretion induced from T-cells in subjects’ peripheral blood mononuclear cells (PBMC) at 4 and 24 hours postdose. Results Fifty healthy subjects were dosed with BT051 (n=40) or placebo (n=10). No dose-limiting toxicities, serious AEs or study discontinuations due to AEs were observed. Nine (22.5%) BT051 subjects and 2 (20%) placebo subjects experienced at least 1 mild or moderate AE with only vessel puncture site pain and constipation reported in more than 1 subject (n=2). Mean % of dose excreted in stool from partial collection ranged between 11.3–26.3%. At all doses tested, concentrations of BT051 in the large intestine were estimated to exceed >20x the threshold for inhibition of neutrophil transmigration and activation in vitro (1 μM) and continued to be detected out to 7 days postdose. Generally, blood concentrations of BT051 were undetectable except in two subjects at one time point each: one subject at 24 hours postdose who received 700 mg BT051 (70 ng/mL) and another subject at 12 hours postdose who received 1500 mg BT051 (8 ng/mL). Mean % of dose excreted in urine through 48 hours postdose ranged between 0.01–0.03%. No evidence of systemic T-cell immunosuppression was observed at any dose level. Conclusion Single ascending doses up to 3500 mg of BT051 were safe and well-tolerated in healthy subjects. Stool concentrations out to 7 days postdose that exceed the expected efficacious threshold, minimal to no systemic exposure and the lack of systemic immunosuppression support the continued development of BT051 as a gut-targeted therapy for patients with IBD.