Oclacitinib

Oclacitinib maleate (Apoquel®) is a novel targeted therapy that selectively inhibits key pathways involved in itch and inflammation associated with allergy. Oclacitinib selectively inhibits Janus kinase 1-dependent cytokines with minimal effects against Janus kinase 2-dependent cytokines involved in haematopoiesis. Janus kinase 1 enzyme activities play a central role in cytokine signaling and are involved in the signal transduction of many pro-inflammatory, pro-allergic, and pruritogenic cytokines implicated in atopic dermatitis, including interleukin (IL)-2, IL-4, IL-6, and IL-13. Janus kinases are also involved in the signaling of IL-31, a recently identified cytokine that has been shown to play a key role in canine pruritus. Oclacitinib has been shown to inhibit IL31 cytokine function in dogs.

Oclacitinib is indicated for control of acute or chronic pruritus in dogs over 12 months of age. The drug is not approved for dogs less than 12 months of age. Oclacitinib administered at a dose of 0.4 to 0.6 mg/kg orally twice daily for up to 14 days and then once-daily thereafter for dogs is highly effective for the management of pruritus and skin lesions in dogs with allergic dermatitis. Oclacitinib has been shown to reduce pruritus and clinical signs as effectively as prednisolone (Gadeyne 2014) and ciclosporin (Little 2015). The drug has a very rapid onset of action with relief sometimes apparent within hours of oral administration. Some dogs experience an increase in pruritus when switched from twice to once daily, related to the short half-life of the drug (4 hours). Overall, it appears that at least 60–70% of allergic dogs receiving the drug have rapid, substantial, and prolonged relief of their clinical signs. Veterinary dermatologists often use this drug as part of a multimodal treatment approach.

Short-term adverse effects of oclacitinib appear mild and include gastrointestinal side effects of vomiting and diarrhoea at an incidence of approximately 2%. The long-term administration of oclacitinib administered once-daily appears to be relatively safe. Results of a long-term compassionate use study support the safety of chronic use of oclacitinib and suggest an improved quality of life for the dog and the owner (Cosgrove 2015). Oclacitinib has been administered for as long as 3 years in some dogs; in longer-term studies, occasional patients have developed benign or malignant neoplasms, but no more often than would be expected for dogs in the studied age range.

The drug has been limited to use in dogs 12 months or older, predominantly because in one high-dose safety study, generalized demodicosis developed in some young laboratory dogs. Oclacitinib has not been evaluated in combination with other drugs such as systemic corticosteroids or ciclosporin; and concurrent use should be avoided with these drugs. It can be used safely in conjunction with antibiotics, antihistamines, antifungal drugs, NSAIDs, allergen-specific immunotherapy, and vaccination of treated dogs is effective. Oclacitinib does not appear to interfere with serologic or intradermal allergy tests. As with other immunosuppressive treatments, oclacitinib modulates the immune system and may increase susceptibility to infection and infestation and exacerbate neoplastic conditions. It is contraindicated in dogs with severe infections, demodicosis, or with active malignancy.

Lokivetmab

Lokivetmab (Cytopoint®, Canine Atopic Dermatitis Immunotherapeutic®) is a caninized anti-canine interleukin (IL)-31 monoclonal antibody that binds to and neutralises circulating IL-31, thereby inhibiting its binding to the IL-31 receptor. The subcutaneous administration of lokivetmab results in a dose related reduction in canine IL-31-induced pruritus in dogs for up to eight weeks following a single dose. A blinded placebo-controlled trial revealed a greater reduction in pruritus for at least one month compared to placebo and the level and duration of response was shown to increase with increased dose (Michels 2016). In a clinical trial involving client-owned dogs with atopic dermatitis, a single subcutaneous injection of lokivetmab at a dose of 2 mg/kg began to reduce pruritus within one day and was effective for a full month for 80% of affected dogs.

Lokivetmab has a good safety profile. Adverse effects are minimal and include vomiting, diarrhea, and lethargy (Michels 2016). In a field safety study, lokivetmab was well tolerated in dogs after two subcutaneous monthly injections. A wide variety of concomitant medications were safely used, including parasiticides, antibiotics, antifungals, corticosteroids, vaccines, immunotherapy, antihistamines, and other antipruritics, such as oclacitinib and cyclosporin (Michels 2016). Lokivetmab has also been demonstrated to be well tolerated in a laboratory safety study in which seven consecutive monthly subcutaneous injections were administered to laboratory beagle dogs at doses of 3.3 mg/kg or 10 mg/kg body weight (12 dogs per group) (Zoetis data).

References

1.  Cosgrove SB, Wren JA, Cleaver DM, et al. Efficacy and safety of oclacitinib for the control of pruritus and associated skin lesions in dogs with canine allergic dermatitis. Vet Dermatol. 2013;24(5):479.

2.  Cosgrove SB, Wren JA, Cleaver DM, et al. A blinded, randomized, placebo-controlled trial of the efficacy and safety of the Janus kinase inhibitor oclacitinib (Apoquel®) in client-owned dogs with atopic dermatitis. Vet Dermatol. 2013;24(6):587.

3.  Gonzales AJ, Humphrey WR, Messamore JE, Fleck TJ, Fici GJ, Shelly JA, et al. Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Vet Dermatol. 2013;24(1):48–53, e11–12.

4.  Gadeyne C, Little P, King VL, Edwards N, Davis K, Stegemann MR. Efficacy of oclacitinib (Apoquel®) compared with prednisolone for the control of pruritus and clinical signs associated with allergic dermatitis in client-owned dogs in Australia. Vet Dermatol. 2014;25(6):512.

5.  Krautmann M, Miller W, Walters R, Garcia-Tapia D, King V, Figueiredo J, Hoover D. Long-term laboratory safety study of lokivetmab (ZTS-00103289), a caninized, anti-canine IL-31 monoclonal antibody, in normal dogs. Vet Dermatol. 2016;27:73–74.

6.  Little PR, King VL, Davis KR, Cosgrove SB, Stegemann MR. A blinded, randomized clinical trial comparing the efficacy and safety of oclacitinib and ciclosporin for the control of atopic dermatitis in client-owned dogs. Vet Dermatol. 2015;26(1):23.

7.  Michels GM, Walsh KF, Kryda KA, Mahabir SP, Walters RR, Hoevers JD, Martinon OM. A blinded, randomized, placebo-controlled trial of the safety of lokivetmab (ZTS-00103289), a caninized anti-canine IL-31 monoclonal antibody in client-owned dogs with atopic dermatitis. Vet Dermatol. 2016;27(6):505.

8.  Michels GM, Ramsey D, Walsh K, et al. A blinded, randomized, placebo-controlled trial investigating three dose levels of lokivetmab (zts-00103289), a caninized anti-canine Il-31 monoclonal antibody, for the reduction of pruritus and associated skin lesions in dogs with atopic dermatitis. Vet Dermatol. 2016;27:55.

9.  Moyaert H, Van Brussel L, Borowski S, Escalada M, Mahabir SP, Walters RR, Stegemann MR. A blinded, randomized clinical trial evaluating the efficacy and safety of lokivetmab compared to ciclosporin in client-owned dogs with atopic dermatitis. Vet Dermatol. 2017;28(6):593.