Oclacitinib (APOQUEL^®) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy

Abstract

Janus kinase (JAK) enzymes are involved in cell signaling pathways activated by various cytokines dysregulated in allergy. The objective of this study was to determine whether the novel JAK inhibitor oclacitinib could reduce the activity of cytokines implicated in canine allergic skin disease. Using isolated enzyme systems and in vitro human or canine cell models, potency and selectivity of oclacitinib was determined against JAK family members and cytokines that trigger JAK activation in cells. Oclacitinib inhibited JAK family members by 50% at concentrations (IC50's) ranging from 10 to 99 nm and did not inhibit a panel of 38 non-JAK kinases (IC50's > 1000 nm). Oclacitinib was most potent at inhibiting JAK1 (IC50 = 10 nm). Oclacitinib also inhibited the function of JAK1-dependent cytokines involved in allergy and inflammation (IL-2, IL-4, IL-6, and IL-13) as well as pruritus (IL-31) at IC50's ranging from 36 to 249 nm. Oclacitinib had minimal effects on cytokines that did not activate the JAK1 enzyme in cells (erythropoietin, granulocyte/macrophage colony-stimulating factor, IL-12, IL-23; IC50's > 1000 nm). These results demonstrate that oclacitinib is a targeted therapy that selectively inhibits JAK1-dependent cytokines involved in allergy, inflammation, and pruritus and suggests these are the mechanisms by which oclacitinib effectively controls clinical signs associated with allergic skin disease in dogs.

Topically Administered Janus-Kinase Inhibitors Tofacitinib and Oclacitinib Display Impressive Antipruritic and Anti-Inflammatory Responses in a Model of Allergic Dermatitis

“…We found that mice treated orally with JAK inhibitors showed a significant decrease in scratching behavior; however, ear thickness was not significantly reduced. Our itching results are supported for oclacitinib by the recently published clinical study in dogs (Gonzales et al, 2014). For tofacitinib, Fujii and Sengoku (2013) reported an anti-inflammatory effect in the oxazolone-induced chronic dermatitis model in rats (effects on itch were not reported).…”

“…Nonetheless, there are still limited options and classic topical corticosteroids remain the primary foundation of topical treatment, with topical calcineurin inhibitors preferred for treatment of the face and intertriginous areas (Ring et al, 2012). To open up the option of therapeutic agents for allergic skin disorders, we focused on the Janus kinase (JAK) inhibitors, which have been recently developed for rheumatoid arthritis and pruritic inflammatory skin diseases (Cosgrove et al, 2013a,b;Fujii and Sengoku, 2013;Ports et al, 2013;Gonzales et al, 2014).…”

“…In addition, T H 2-derived cytokines, including IL-31 and thymic stromal lymphopoietin (TSLP), are ligands for murine and human sensory nerves and have a critical function to evoke itch (Cevikbas et al, 2014). Because these cytokines also interact with JAK, several JAK inhibitors have received a lot of attention recently as a therapeutic agent for major pruritic inflammatory skin diseases (Cosgrove et al, 2013a,b;Fujii and Sengoku, 2013;Ports et al, 2013;Gonzales et al, 2014). However, the exact mechanisms of the anti-inflammatory and anti-itch action of these JAK inhibitors are still not fully understood.…”

“…In a cellular setting where JAKs signal in pairs, tofacitinib preferentially inhibits signaling by heterodimers containing JAK3 and/or JAK1 with functional selectivity over receptors that signal via pairs of JAK2 (Meyer et al, 2010). Oclacitinib, currently licensed for the control of pruritus associated with allergic dermatitis in dogs (Gonzales et al, 2014), mainly displays activity against JAK1-dependent cytokines and shows minimal activity against JAK2-dependent cytokines in cellular assays (Gonzales et al, 2014).…”

Efficacy of APOQUEL® for the Control of Otitis Externa Secondary to Allergic Skin Disease in Client-Owned Dogs

“…Oclacitinib (APOQUEL®) is a novel Janus kinase (JAK) inhibitor that has been shown to inhibit cytokines involved in pruritus (IL-31) and allergy and inflammation (IL-2, IL-4, IL-6 and IL-13) [12]. Oclacitinib is currently approved for the control of pruritus associated with allergic dermatitis and for the control of atopic dermatitis in dogs that are at least 12 months of age [13].…”