Pharmacological effects of pumecitinib nasal spray in a mouse model of allergic rhinitis

Background: Allergic rhinitis (AR) is an inflammation of the nasal mucosa primarily mediated by antigen-specific immunoglobulin E (IgE) and characterized predominantly by type 2 inflammation, in which the Janus kinase–signal transducer and activator of transcription (JAK-STAT) signaling pathway plays a critical role. Targeted inhibition of this pathway using small-molecule JAK inhibitor nasal sprays may represent a promising therapeutic strategy for AR. Objective: To evaluate the pharmacological profiles of pumecitinib (aka PG-011), a JAK inhibitor formulated as a nasal spray, for the treatment of AR in a mouse model. Methods: The inhibitory activity and selectivity of pumecitinib against JAK kinases were assessed in enzymatic assays. Its effects on cytokine-induced STAT phosphorylation (pSTAT) were evaluated in cellular assays. The pharmacological effects of pumecitinib nasal spray were investigated in an ovalbumin (OVA)-induced AR mouse model. Results: Pumecitinib was identified as a potent and selective inhibitor of JAK1 and JAK2 kinases relative to JAK3 and TYK2. It effectively suppressed pSTAT production induced by multiple cytokines, including interleukin (IL)-4, IL-31, and granulocyte-macrophage colony-stimulating factor. In the OVA-induced AR model, intranasal administration of 0.1% pumecitinib spray significantly reduced the frequency of sneezing episodes, as well as markedly attenuated nasal mucosal epithelial thickness, goblet cell hyperplasia, and eosinophil infiltration. The 0.05% concentration also produced significant reductions in epithelial thickness and eosinophil count. Both concentrations significantly lowered OVA-specific IgE levels in nasal lavage fluid. Conclusion: These findings demonstrate that pumecitinib nasal spray, through targeted inhibition of JAK1/2 kinases, exhibits pharmacological activity in a mouse model of AR, supporting its potential as a therapeutic candidate for further translational investigation in AR.