LATE-BREAKING ABSTRACT: Safety, pharmacokinetics and pharmacodynamics of BI 1060469, a novel oral CRTH2 antagonist

Introduction: BI 1060469, a novel oral antagonist of the chemo-attractant receptor-homologous molecule on T-helper-2 cells (CRTH2), targets airway inflammation in asthma by inhibiting prostaglandin D 2 (PGD 2 ) binding to CRTH2. Aim: Investigate the safety, pharmacokinetics (PK) and pharmacodynamics (PD) ofsingle rising doses of BI 1060469 in healthy males. Methods: Two Phase I, randomized, placebo-controlled, single-rising-dose studies (Study 1: BI 1060469, 1-250 mg; Study 2: BI 1060469, 10-250 mg). Primary endpoint was the percentage of patients with drug-related adverse event (AEs). PK (both studies) and PD (Study 1; exploratory) were also evaluated. Results: Fifty-two Caucasian (Study 1) and 80 Asian( Study2) volunteers were treated. Drug-related AEs were reported in 7.5% (Study 1) and 5% (Study 2) of volunteers (mild: headache, oropharyngeal pain, upper abdominal pain, rash, dry eyes). BI 1060469 exhibited dose-proportional PK from 3 to 25 mg (Study 1) and less than dose-proportional PK from 25 to 250 mg (Study 1) and 10 to 250 mg (Study 2). When considering body weight, the Caucasian and Asian PK data appear similar (mean body weight treated group: Caucasian, 81.2 to 87.6 kg; Asian, 63.8 to 69.7 kg). BI 1060469 dose-dependently inhibited PGD 2 binding to CRTH2 for ≥24 hours in two exploratory biomarker assays: eosinophil shape change was consistently inhibited ex vivo at a single 3-mg dose (95% inhibitory concentration [IC 95 ] 70 nmol/L) and CRTH2 receptor internalizationwas inhibited ex vivo at a single 75-mg dose (IC 95 691 nmol/L). Conclusion: BI 1060469 was well tolerated with a favourable PK profile and maximum inhibition, supporting once-a-day Phase II development.