First-in-human study for londamocitinib (AZD4604), an inhaled selective JAK1 inhibitor

Background Janus kinase (JAK) 1 is a promising target for asthma treatment; it may address inflammation not controlled by inhaled corticosteroids. Londamocitinib (AZD4604) is a selective JAK1 inhibitor designed for inhaled delivery. Objective Three-part, randomised, placebo-controlled phase 1 study (NCT04769869) in healthy volunteers (N=85) and participants with mild asthma (N=18) investigating safety, tolerability, pharmacokinetics, and lung and systemic target engagement (TE) of londamocitinib. Methods Single (0.025-6mg) and multiple (0.4-3mg, inhaled) doses of londamocitinib were administered to healthy volunteers and participants with mild asthma for up to 10 days. Effect on fractional exhaled nitric oxide (FeNO), a type 2 inflammation marker, was assessed in participants with mild asthma with elevated FeNO. Results Londamocitinib was well-tolerated after single and multiple dosing. Post-inhalation, londamocitinib was quickly absorbed and systemic exposure increased approximately dose proportionally. Following twice-daily dosing to achieve steady state, 2- to 4-fold accumulation was observed. Approximately 50% reductions in mean FeNO were seen for 1.4 and 3mg doses of londamocitinib in participants with mild asthma after 3 days, which persisted to Day 10 of dosing, versus no significant reduction with placebo. Transient, minimal suppression of systemic TE (IL-4-induced STAT6 phosphorylation in peripheral CD3+ T cells) was seen with the 3mg but not the 1.4mg londamocitinib dose. Conclusion Twice-daily administration of londamocitinib provides rapid and effective reduction of FeNO in patients with mild asthma with elevated FeNO. Clinical Implication Londamocitinib demonstrates acceptable safety and tolerability, and shows potential as a candidate drug for future asthma treatment.