LONDAMOCITINIB, an inhaled selective Janus kinase (JAK) 1 inhibitor, demonstrated encouraging early signals of efficacy and acceptable safety in a first-in-human Phase I study involving healthy volunteers and participants with mild asthma.
Researchers reported that twice-daily inhaled londamocitinib produced rapid and sustained reductions in airway inflammation, measured by fractional exhaled nitric oxide, without meaningful systemic immune suppression at lower doses. These findings positioned the therapy as a potential future option for patients whose asthma remains inadequately controlled with inhaled corticosteroids.
Londamocitinib Reduced Inflammation in Asthma Patients
JAK1 plays a central role in signalling pathways that drive Type 2 airway inflammation. Targeting this pathway through inhalation aimed to maximise lung effects while limiting systemic exposure, a long-standing challenge for oral JAK1 inhibitors.
The randomised, placebo-controlled study enrolled 85 healthy volunteers and 18 participants with mild asthma. Single doses ranging from 0.025–6 mg and multiple doses of 0.4–3 mg were administered for up to 10 days. In participants with mild asthma and elevated baseline inflammation, londamocitinib produced approximately 50% reductions in fractional exhaled nitric oxide at the 1.4 mg and 3 mg doses after just three days. These reductions persisted through Day 10, whereas no significant change was observed with placebo.
Fractional exhaled nitric oxide is widely used as a non-invasive biomarker of Type 2 airway inflammation and treatment response in asthma. Its reduction suggested meaningful local target engagement within the lungs. Further pharmacokinetic analysis showed rapid absorption after inhalation, with dose-proportional systemic exposure and two- to four-fold accumulation at steady state.
Importantly, systemic target engagement, assessed through interleukin-4-induced STAT6 phosphorylation in peripheral CD3-positive T cells, was minimal and transient, occurring only with the 3mg dose. This finding supported the rationale for inhaled delivery to limit systemic effects.
Implications for Future Asthma Treatment
Asthma affects more than 300 million people worldwide, and a substantial proportion continue to experience symptoms despite standard inhaled therapies. By selectively inhibiting JAK1 directly in the airways, londamocitinib asthma treatment could represent a novel anti-inflammatory approach.
The investigators noted that the study was short in duration and included a small number of participants with mild disease. Larger and longer trials will be required to confirm clinical benefits.
Reference
Jensen TJ et al. First-in-human study for londamocitinib (AZD4604), an inhaled, selective JAK1 inhibitor. J Allergy Clin Immunol. 2026; DOI:10.1016/j.jaci.2025.12.1008.
