Phase 1 trial finds inhaled JAK1 inhibitor londamocitinib reduces Feno in mild asthma

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: A 3-part randomized placebo-controlled phase 1 study (NCT04769869) was conducted in healthy volunteers (n = 85) and participants with mild asthma (n = 18) investigating safety, tolerability, pharmacokinetics, and lung and systemic target engagement of londamocitinib. METHODS: Single (0.025-6 mg) and multiple (0.4-3 mg, 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. After inhalation, londamocitinib was quickly absorbed, and systemic exposure increased approximate dose proportionally. After twice-daily dosing to obtain steady state, 2- to 4-fold accumulation was observed. Approximately 50% reductions in mean Feno were seen for 1.4 and 3 mg 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 target engagement (IL-4-induced STAT6 phosphorylation in peripheral CD3 T cells) was seen with the 3 mg but not the 1.4 mg londamocitinib dose. CONCLUSION: Twice-daily administration of londamocitinib provides rapid and effective reduction of Feno in patients with mild asthma with elevated Feno.