AZD0449, an inhaled JAK1 inhibitor, in healthy participants and patients with mild asthma

Inhaled corticosteroids (ICS) plus bronchodilator are recommended for the treatment of asthma. Targeting the JAK1-dependent pathway may be an alternative for asthma management in patients with incomplete response to ICS. The aim of this study was to investigate the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of AZD0449, a novel JAK1 selective inhibitor, following inhaled (dry powder, nebulized) and intravenous administration to healthy participants and patients with mild asthma. This was a randomized, single-blind, placebo-controlled Phase 1 study (NCT03766399) of single- and multiple-ascending doses conducted using a three-part design. Healthy participants and patients with mild asthma aged 18-55 years were recruited. The study evaluated safety, tolerability, PK and PD of AZD0449. PD was measured as the effect on fractional exhaled nitric oxide (FeNO). Systemic target engagement was measured using phosphorylation of signal transducer and activator of transcription 6 (pSTAT6). A total of 125 participants were included in the study. No drug-related safety concerns emerged. Following inhaled administration, AZD0449 showed low, dose-proportional, systemic exposures and elimination from plasma was partly absorption-limited, suggesting lung retention and supporting once-daily dosing. At the dose levels evaluated (1.2-5.0 mg), there was no significant anti-inflammatory effect (reduction in FeNO) with AZD0449 vs. placebo, following repeated dosing for 14 days. Furthermore, there was no significant suppression of pSTAT6. AZD0449 was safely administered via inhalation, with low systemic exposure and lung retention. This study provides a greater understanding of inhaled dosing of small molecule JAK1 inhibitors for the treatment of asthma. No effect on PD biomarkers (FeNO and STAT6) was observed.