Abstract Text: Interleukin-1 receptor associated kinase 4 (IRAK4) is a key component of MyD88 dependent pathways, including signaling downstream of Toll-like receptors (TLRs) and IL-1 family cytokine receptors. EVO101 is a potent IRAK4 inhibitor currently in clinical development (NCT05579899) as a 0.1% topical cream formulation for the treatment of atopic dermatitis (AD). Leveraging our ex vivo human skin tissue model, we show that EVO101 can potently and dose-dependently inhibit inflammation induced by TLR and IL-1 family cytokine stimulation. Additionally, topically applied 0.1% cream formulation of EVO101 demonstrates robust anti-inflammatory activity in TLR and IL-1 stimulated human skin, with performance on par with high potency topical corticosteroids. As AD is known to have significant contributions from Th2 inflammation, we also evaluated EVO101 in Th2 stimulated human skin. 0.1% EVO101 topical cream performed on par, or superior to, other topical therapeutics, such as topical ruxolitinib (JAK inhibitor), topical tapinarof (AhR modulator), and topical calcineurin inhibitors. To interrogate this finding further, we evaluated if IL-1 family cytokines could drive Th2 inflammatory markers, and if Th2 inflammation resulted in upregulation of IL-1 family cytokines, thus providing a positive feedback loop. Indeed, individual IL-1 family cytokine stimulation of human skin resulted in upregulation of Th2-associated cytokines/chemokines. Additionally, Th2 stimulation of human skin resulted in upregulation of IL-1 family cytokines. These findings suggest that IL-1 family cytokines can drive and perpetuate Th2 inflammation, and that inhibition with an IRAK4 inhibitor (such as 0.1% EVO101 topical cream) may have positive impact in a heterogenous Th2 disease, such as AD.
