First-in-human study for londamocitinib (AZD4604), an inhaled selective JAK1 inhibitor - 03/04/26
, Camille Riff, PharmD, PhD b, Julia Lund, MSc b, Zala Jevnikar, PhD c, Maria G. Belvisi, PhD d, e, Christina Keen, MD f, Jukka Mäenpää, MD g, John Mo, PhD g, Szilárd Nemes, PhD h, Pablo Forte Soto, MD i, Adam Platt, PhD j, Rajkumar Chetty, MD k, Dave Singh, MD l, Davinder P.S. Dosanjh, DPhil m, n, Pernilla Zingmark, MSc a, Kyriakos V. Konstantinidis, PhD o, Rod Hughes, DM mAbstract |
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 (F eno ), a type 2 inflammation marker, was assessed in participants with mild asthma with elevated F eno .
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 F eno 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 F eno in patients with mild asthma with elevated F eno .
Le texte complet de cet article est disponible en PDF.Key words : Asthma, Janus kinase inhibitors, JAKi, pharmacokinetics, fractional exhaled nitric oxide, inflammation, target engagement
Abbreviations used : AE, ALT, AST, ATS, AUC 0-24 , AUC τ , C max , CV, DPI, ERS, F eno , FEV 1 , ICS, JAK, PD, PK, PoM, STAT, T2, t max , TSLP
Plan
Vol 157 - N° 4
P. 858-867 - avril 2026 Retour au numéro
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