Estudio en humanos de londamocitinib (AZD4604), un inhibidor inhalado selectivo de JAK1

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.

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.

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.

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.

Twice-daily administration of londamocitinib provides rapid and effective reduction of FeNO in patients with mild asthma with elevated FeNO.

Londamocitinib demonstrates acceptable safety and tolerability, and shows potential as a candidate drug for future asthma treatment.