1112 An innovative phase 1b trial demonstrating proof-of-pharmacology for two novel IRAK4-inhibitors using a local (Imiquimod) and systemic (LPS) driven immune response

The purpose of this study was to evaluate and characterize the pharmacological activity two orally administered IRAK4-inhibitors BAY 1834845 1830839 in healthy volunteers. Prednisolone placebo were used as active non-active controls, respectively. Skin inflammation induced by topical application Imiquimod (IMQ) cream for up 3 days. Before after IMQ challenge effect on erythema microperfusion assessed. After 7 days treatment (b.i.d.), all participants received 1 ng/kg LPS an IV-infusion. Circulating inflammatory proteins, leukocyte differentiation, acute phase well clinical parameters investigated before challenge. Treatment with reduced mean skin perfusion response compared (p<0.05). or IMQ-challenge placebo. increase serum TNFa levels that occurred following i.v. LPS-challenge who treated either drug suppressed marker ≥80%. had inhibitory IL-6 concentrations seen group LPS-challenge. LPS-induced increases CRP, procalcitonin IL-8 also inhibited 1830839. This demonstrated effectiveness IRAK4-specific inhibitors suppressing systemic local upon specific challenges. results suggest both tested showed pharmacodynamic responses IMQ- LPS-challenges a similar size prednisolone.