Safety, tolerability, pharmacokinetics and pharmacodynamics of the spleen tyrosine kinase inhibitor BI 894416 in healthy volunteers and patients with asthma.

Spleen tyrosine kinase (SYK) has broad biological functions in inflammation and immunity. The orally administered SYK inhibitor BI 894416 was investigated in a single-rising-dose Phase I study in healthy volunteers and in a combined single- and multiple-rising-dose Phase Ib study in patients with mild asthma. The single-blinded, partially randomised, placebo-controlled Phase I study evaluated single doses of BI 894416 (3-70 mg) in healthy volunteers. The single-blinded, randomised, placebo-controlled Phase Ib study in patients with mild asthma evaluated three single doses (75-170 mg) and four multiple doses (10-60 mg) of BI 894416 over an interval of 9 days. The primary objective of both studies was safety and tolerability, assessing the proportion of participants with drug-related adverse events (AEs). Secondary endpoints related to pharmacokinetics and efficacy (Phase Ib study only). All except one randomised participant completed treatment (56 healthy volunteers and 68 mild asthmatics [29 received a single dose and 39 received multiple doses]). The most frequent drug-related AEs were headache, diarrhoea and nausea (all of mild/moderate intensity). No serious AEs occurred. BI 894416 was rapidly absorbed with median time-to-peak concentration 0.5-1.0 h; exposure increased in a dose-dependent manner. Basophils and nasal epithelial cells showed dose-dependent modulation of activation- and disease-associated genes and pathways. BI 894416 was safe and well tolerated in healthy volunteers and mild asthmatics. Results from target engagement biomarkers demonstrated treatment- and dose-dependent cellular modulation, potentially leading to decreased airway inflammation and airway obstruction.