Advances in Treatments for Canine Atopic Dermatitis

Canine atopic dermatitis (AD) is a chronic, relapsing, and genetically predisposed allergic skin disease often associated with elevated immunoglobulin E antibodies to environmental allergens.¹ AD is common, with a prevalence of 3% to 15% in the general canine population and 58% among dogs with dermatologic conditions.² Clinical signs of AD include chronic skin inflammation, pruritus, and recurrent skin infections. The pathogenesis of canine AD is complex and not completely understood. Likely, a defective skin barrier allows microbial adherence; allergenic protein penetration; and initiation of an abnormal, cell-mediated, inflammatory response with excessive cytokine release.³

Canine AD triggers include food, flea, and environmental allergens; Malassezia yeast; and Staphylococcus bacteria.³ Treatment of canine AD involves a multifaceted approach with management of acute flares, chronic suppression of inflammation, trigger avoidance (when possible), restoration of the skin barrier, allergen desensitization, and treatment of secondary infections.⁴ The International Committee on Allergic Diseases of Animals (ICADA) produced an updated guideline for the treatment of canine AD in 2015.⁴ However, since the publication of this guideline, a new caninized monoclonal antibody, lokivetmab, was approved by the U.S. Department of Agriculture (USDA) for the treatment of canine AD. This article will discuss the role of lokivetmab in canine AD management, review mainstay and adjunct canine AD therapies, and discuss new literature supporting the use of oclacitinib and cyclosporine in canine AD.

Lokivetmab

Lokivetmab is a caninized monoclonal antibody against interleukin-31 (IL-31) approved by the USDA in December 2016 under the brand name Cytopoint (Zoetis, cytopoint.com).⁵ Overexpression of canine IL-31 has been implicated in the pathophysiology of pruritus in dogs with AD.⁶ The mechanism of action of lokivetmab is displayed in FIGURE 1.

Figure 1. The role of lokivetmab in stopping the itch cycle. Overexpression of canine interleukin-31 (IL-31) has been implicated in the pathophysiology of pruritus in dogs with atopic dermatitis.6 By neutralizing IL-31, lokivetmab inhibits pruritus and reduces inflammatory skin lesions.⁵ Illustration adapted from: Cytopoint interrupts the itch cycle. Zoetis United Kingdom. Accessed November 20, 2023. https://www.zoetis.co.uk/products/dogs/cytopoint/moa-itch-cycle.aspx. Designua/shutterstock.com

Dosing

Lokivetmab is commercially available in single-use, 1-mL vials in the following concentrations: 10, 20, 30, and 40 mg/mL. It is administered subcutaneously at a minimum dose of 2 mg/kg (0.9 mg/lb) of the patient’s body weight. Doses should be repeated every 4 to 8 weeks as needed based on the individual patient’s response.⁵ Manufacturer dosing recommendations are listed in TABLE 1.

Pharmacokinetics and Pharmacodynamics

After subcutaneous administration in dogs, lokivetmab remains in circulation for several weeks.⁵ The onset of action and duration of effect of lokivetmab were compared to those of placebo in 24 purpose-bred beagles with IL-31 experimentally induced pruritus. Lokivetmab, at a dose of 2 mg/kg SC, demonstrated a significant reduction in pruritus starting at 3 hours after injection that was sustained for up to 42 days.⁷ Onset of action and duration of efficacy of lokivetmab were further explored in 211 client-owned canine patients with AD. Subcutaneous administration of lokivetmab at 2 mg/kg once resulted in a greater reduction from baseline in owner-assessed pruritus at 1 to 49 days and a statistically significant reduction in pruritus for at least 1 month when compared to placebo.⁸ Like naturally occurring antibodies, lokivetmab is eliminated via physiologic protein degradation pathways.⁵

Adverse Effects, Safety, and Drug Interactions

The most common adverse effects of lokivetmab are listed in TABLE 2. Development of antidrug antibodies (ADAs) has been reported in up to 2.5% of dogs treated with lokivetmab.^9,10 ADAs may lead to the neutralization of lokivetmab, thus decreasing efficacy while potentially increasing the risk of hypersensitivity reactions. However, the true impact of ADAs on clinical outcomes is unknown.^9-11

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No drug interactions with lokivetmab have been noted. A variety of medications have been used concomitantly with lokivetmab in clinical trials, including parasiticides, antibiotics, antifungals, corticosteroids, vaccines, allergen-specific immunotherapy, antihistamines, oclacitinib, and cyclosporine, with no interactions reported.⁵

Role in Atopic Dermatitis Therapy

Due to its short onset of action and sustained response, lokivetmab can be used for acute flare management and chronic treatment of canine AD.¹² A study evaluating the efficacy of lokivetmab in 211 client-owned dogs with mild to severe AD highlights the benefit of lokivetmab at labeled doses in acute management. Lokivetmab efficacy was assessed through changes in the client pruritus visual analogue scale (pVAS) and the clinician-performed Canine Atopic Dermatitis Extent and Severity Index v3 (CADESI-03), with treatment success defined as ≥ 50% reduction in either score from baseline. A statistically significant reduction in pruritus in the lokivetmab group compared to the placebo group was seen as early as 1 day after treatment. A greater percentage of dogs achieved treatment success compared to those receiving placebo on days 1 to 56, with a success rate of 57% versus 14%, respectively, at 28 days based on the client pVAS and days 14 to 56, with a success rate of 46% versus 9%, respectively, at 28 days based on the clinician CADESI-03.⁸

In chronic management of canine AD, lokivetmab can be used to continuously decrease pruritus and skin inflammation.¹² A study evaluating proactive maintenance therapy with lokivetmab in 21 client-owned dogs with AD demonstrated an average time-to-flare of 63 days. One-quarter of dogs enrolled did not exhibit a flare for at least 1 year. Development of clinical signs was prevented in 43%, 33%, 28%, and 28% of dogs at 3, 6, 9, and 12 months, respectively.¹³ Furthermore, continued lokivetmab therapy has been shown to reduce the severity of lesions in atopic dogs over a 12-week treatment period, with significant reduction as early as 4 weeks.¹⁴

In terms of treatment comparisons, lokivetmab has only been directly compared to cyclosporine therapy in the chronic management of canine AD. In a randomized, noninferiority trial, monthly lokivetmab was compared to daily oral cyclosporine for 3 months. Lokivetmab was found to be noninferior to cyclosporine for pruritus reduction at 28 days, with an average pVAS reduction of 43.72%. However, lokivetmab did not achieve noninferiority compared to cyclosporine for lesion reduction at 28 days using CADESI-03, but the differences in CADESI-03 scores were never statistically significant between groups at any time point.¹⁰ The efficacy of lokivetmab compared to cyclosporine should be considered in the context of the favorable side effect profile of lokivetmab in contrast to the known toxicities of cyclosporine.

Ultimately, with its short onset of action, long duration of effect, and favorable safety profile, lokivetmab is an appealing choice for the acute and chronic management of canine AD. However, its mechanism of action is likely to provide the greatest benefit in pruritus reduction and fails to treat other components of acute flare and chronic canine AD, such as otitis externa.¹²

Mainstay Therapy

A summary of the mainstays of canine AD therapy can be found in TABLE 3, along with client considerations. New literature exploring the use of oclacitinib and cyclosporine since the release of the 2015 ICADA guidelines are highlighted below.

Oclacitinib

Oclacitinib (Apoquel; Zoetis, apoquel.com) labeling recommends twice-daily dosing for 2 weeks followed by once-daily dosing for long-term management,¹⁷ but some patients do not achieve adequate control with daily dosing. A recent trial evaluated the safety and efficacy of oclacitinib after prolonged twice-daily administration with a median dose of 0.5 mg/kg PO q12h and a median duration of 113 days. This small retrospective study revealed high efficacy rates, with treatment success in 72% of dogs, including dogs that failed to respond to daily therapy. Mildly decreased leukocytes, neutrophils, eosinophils, and monocytes; low rates of hypercholesterolemia; and gastrointestinal side effects were reported.¹⁸ Although this trial revealed the potential safety of oclacitinib given twice daily for a prolonged period, more data are necessary to support continued twice-daily administration.

With reduction to once-daily dosing, rebound pruritus has been noted in some dogs. A recent trial evaluated the addition of prednisolone 0.5 mg/kg PO q24h for 4 days when transitioning to oclacitinib daily compared to oclacitinib alone. This regimen reduced occurrence of rebound pruritus 1 week after oclacitinib dose reduction with few adverse effects.¹⁹ Therefore, short-term combination therapy may mitigate the need for continued twice-daily dosing and improve pruritus.

Oclacitinib chewable tablets were approved in 2023.²⁰ Acceptance of oclacitinib chewable tablets was evaluated for 7 days in 121 client-owned dogs with allergic or atopic dermatitis. Out of all administrations, 91.6% were accepted voluntarily within 5 minutes, demonstrating good palatability.¹⁵ The oclacitinib chewable tablet may reduce client burden and offers a promising new dosage form for the management of canine AD. Of note, the chewable tablets do contain pork and could cause an atopic flare in dogs with pork allergies.

Cyclosporine

The 2015 guidelines address the use of modified cyclosporine generic products and states that only generic cyclosporine formulations with proven bioequivalence to Atopica (Elanco, my.elanco.com/us/atopica-dog) should be used.⁴ Since publication of these guidelines, Cyclavance oral solution (Virbac, vet-us.virbac.com/cyclavance), a veterinary generic modified cyclosporine product, was approved for use in canine AD in 2020.¹⁶ This product demonstrated high acceptance rates in dogs, showed bioequivalence to Atopica capsules, and appears to be an acceptable alternative based on the guidelines’ standards.²¹

Several trials have also evaluated the use of human generic cyclosporine formulations. One small randomized controlled trial compared a human generic cyclosporine available in Europe, Equoral (Teva Pharmaceuticals, teva.cz/equoral), to prednisone and found that the generic product was as effective in reducing skin lesions and pruritus.²² In addition, a recent study compared the whole blood concentrations of the human-approved Teva cyclosporine generic modified formulation available in the United States to Atopica in research dogs. Generic modified cyclosporine achieved significantly higher concentrations at 1 hour, but no statistically significant difference was found at 1.5 hours.²³ With reduced cost, human generic cyclosporine modified formulations are a tempting, cost-saving alternative to Atopica, but true bioequivalence and efficacy have not been established.

Adjunct Therapy

A summary of adjuncts to canine AD therapy can be found in TABLE 4. These therapies are often used in combination with traditional mainstays of treatment in an attempt to provide better control of clinical signs.

The physical act of bathing has been shown to reduce pruritus in dogs. Although there are many shampoos with differing active ingredients, the frequency of bathing is one of the most important factors in relieving pruritus.⁴

Topical glucocorticoids should be used only for short periods and are beneficial for treating localized skin lesions. Glucocorticoid sprays are preferred over creams or ointments in many patients for treatment of flares. Long-term use of daily applications should be avoided as it places the patient at an increased risk for developing steroid-induced skin atrophy. However, this depends on the relative potency of the topical steroid being used.⁴

Studies have shown that oral supplements such as zinc methionine, Lactobacillus probiotics, and vitamin D₃ have demonstrated a decrease in Canine Atopic Dermatitis Lesion Index and pVAS scores when used in combination with traditional medication therapy over time.^24-26

Summary

Canine AD is a complex disease state requiring multimodal management to achieve control of clinical signs. Lokivetmab is an effective new agent with a favorable side effect profile that successfully treats pruritus and can be used in both acute and chronic canine AD management. Newly approved formulations of oclacitinib and cyclosporine as well as exploration into alternative dosing regimens of oclacitinib offers promising advances in the treatment of canine AD.