HILL’S GLOBAL SYMPOSIUM 2021 | PROCEEDINGS

CANINE ATOPIC DERMATITIS:

HOW TO USE THE NEWEST DRUGS IN CLINICAL PRACTICE?

Wayne Rosenkrantz, DVM, DACVD

Animal Dermatology Clinic
Tustin, CA, USA

INTRODUCTION
Oclacitinib maleate (Apoquel®) is a synthetic Janus kinase (JAK) inhibitor developed for the treatment of allergic
skin diseases in dogs. It has a high degree of efficacy, a rapid speed of onset and fewer adverse effects than
corticosteroids. Studies have shown that oclacitinib is safe and efficacious for long-term use and improved
the quality of life for dogs with atopic dermatitis. Cytopoint™ is the first monoclonal antibody (mAb) therapy
approved for control of the clinical signs associated with atopic dermatitis in dogs. Cytopoint is an injectable
containing a caninized mAb specifically designed to target and neutralize cytokine interleukin-31 (IL-31). It works
by mimicking the activity of natural antibodies to selectively bind and neutralize IL-31. Having these drugs with
a comparably high degree of efficacy has been extremely beneficial for the management of atopic dermatitis in
dogs. The question of which drug to select for an individual patient will be based on many variables but should
occur on a case-by-case basis.

Oclacitinib oclacitinib in 436 dogs with a variety of allergic diseases.1

Oclacitinib maleate (Apoquel®) is a drug developed Pruritus scores decreased from 7.39 to 2.59 and 7.58
for the treatment of allergic diseases in dogs. It is a to 5.54 in the oclacitinib and placebo treated groups
synthetic drug of a relatively new class of drugs called respectively. The response in the treated group was
Janus kinase (JAK) inhibitors. Janus kinases are a significantly better than the placebo group. Another
group of four enzymes [Janus kinase 1-3 and tyrosine blinded placebo study performed by board certified
kinase (TK)] that function by facilitating the first step veterinary dermatologists evaluated oclacitinib for the
in transmitting intracellular signals, enabling a cytokine management of atopic dermatitis in 299 dogs.2 Pruritus
that has bound and activated a cell surface receptor to scores decreased from 7.8 to 2.6 and from 7.7 to 7.4
have an effect on that cell. They function in pairs with at the 14-day scoring in the oclacitinib and placebo
certain cytokine receptors being acted on by various treated groups respectively, with very significant
combinations of paired enzymes such as JAK 1 and differences between groups. All dogs participated in
3 or JAK 2 and 3 or JAK 3 and TK. Oclacitinib acts a subsequent open label study and at the end of 112
predominantly to inhibit JAK 1 and at higher serum days the pruritus score averaged 3.2. The skin lesions
levels to inhibit JAK 2. The Cmax of the drug relates as graded by the canine atopic dermatitis extent and
to the dose and the 90% confidence interval for the severity index (CADESI) reduced from a pre-treatment
Cmax at a dose of 0.6mg/kg administered daily for score of 62 to 32 and 58 to 57 in the oclacitinib and
168 days is 273-406 ng/ml. The Cmax at a dose of placebo groups respectively. When all dogs completed
0.4mg/kg is approximately 200ng/ml for beagle and the open label phase the CADESI was 26 at Day 112.
mongrel dogs after a single dose. The cytokines most Another study also demonstrated that oclacitinib has
sensitive to JAK 1 enzyme inhibition from the highest to efficacy in the management of flea allergy dermatitis.3
the lowest are IL-31, IL-2, IL-13, IL-14 and IL-6. At much Lastly the author finds oclacitinib helpful to use at the
higher oclacitinib serum levels other JAK 1 and JAK 2 beginning of dietary trials to aid in pruritus reduction
sensitive cytokines including erythropoietin (EPO) and until the dietary trial can be completed. Because of
granulocyte and macrophage colony stimulating factor its immediate effects and short duration of activity it
(GM-CSF) are affected. This drug has been considered can be utilized for the first part of diet trials to alleviate
an immunomodulator because its most potent effect pruritus and then discontinued once the elimination diet
is blocking the activity of IL-31, which controls pruritus is up and running to allow interpretation of any benefits
activity. from the ongoing diet trial. The dose of oclacitinib for
all allergic disease cases is 0.4 to 0.6mg/kg given 12hrs
Efficacy has been demonstrated in the management for 14 days then q 24hrs. It is available in 3.6, 5.4 and
of pruritus associated with allergic disease in many 16mg tablets. Although most dogs control at once daily
studies. A blinded placebo-controlled study evaluated dosing the author and other dermatologists have found

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HILL’S GLOBAL SYMPOSIUM 2021 | PROCEEDINGS
that some dogs need their once daily dosing divided lipid stores, leptin levels, IL-6 and glucose homeostasis.
BID for control of pruritus. There also seem to be dogs There are also anecdotal reports of increased tendency
that require their induction dosing to be maintained for for pyoderma, demodicosis and otitis externa. The
long-term control. This is not routinely recommended author typically avoids using Apoquel® in dogs with
as the incidence of adverse reactions could be more any history of pre-existing neoplasia and in dogs with
frequent at continued high dose therapy, however the deep infection, history of demodicosis or in severely
author and others have used induction dosing long immunocompromised dogs. It is contraindicated for
term and rarely are complications seen with this regime. use in breeding dogs or pregnant or lactating bitches.
It has been used in limited cases with concurrent low
Details regarding specific studies and frequency
dose glucocorticoids or cyclosporine (CSA) for short
of adverse events can be reviewed in the Apoquel®
periods of time.
Product Label information. The short-term safety
profiles based on data from multiple randomized- The author currently performs pre-Apoquel® chemistry
controlled clinical trials is very good. In a 28-day study profiles, complete blood counts and urinalysis testing.
with 436 dogs the incidence of diarrhea, vomiting, This is repeated at 6-month intervals in patients on
anorexia and polydipsia were low at 1.4-2.3%, which continuous therapy. Patients also need to be monitored
was similar to placebo-treated dogs (0-1.8%).1 In most for the development of clinical infections while on long
cases clinical signs are resolved while continuing the term therapy.
drug. A long-term compassionate care study evaluated
There is one 84-day randomized controlled trial
247 client-owned dogs with allergic skin disease that
comparing Apoquel® to Atopica® in 226 dogs.6 Dogs
had previously benefited from oclacitinib therapy.4
were evaluated for PVAS and CADESI-02 scoring on
Owners completed a quality-of-life survey and assessed
days 1, 2, 7, 14, 28, 56 and 84 days. Differences were
pruritus using a Visual Analog Scale (VAS) throughout
significant at all time points up to day 28 regarding
the study and veterinarians recorded adverse events,
PVAS scoring. Apoquel® treated dogs had a more rapid
concomitant medication and clinical pathology results
onset of activity regarding the pruritus reduction. More
were summarized. The percentage of dogs showing
adverse events were found in the Atopica® treated
>/=50% reduction from baseline on day 90 was 63.9%
group which was predominantly gastrointestinal
for PVAS and 66.4% for CADESI. Owners saw a positive
(vomiting and diarrhea) Atopica® group (44 and 15%)
impact on quality of life in >91% of all dogs. Urinary
vs Apoquel® group (14 and 4%). A retrospective study
tract infection/cystitis, vomiting, otitis, pyoderma and
compared the incidence of cutaneous histiocytoma
diarrhea were the most frequently reported (>5% of
development in atopic dogs treated with oclacitinib
dogs) abnormal clinical signs (UTI 11.3%, vomiting 10.1%,
(n=533) versus ciclosporin (n=654). There were 14/533
otitis 9.3%, pyoderma 9.3%, diarrhea 6.1%). Hematology
and 4/654 patients who developed histiocytomas while
and serum chemistry levels remained within the normal
on oclacitinib and ciclosporin, respectively. There was
reference ranges. Concomitant medications were well
a significantly higher percentage of histiocytomas on
tolerated, however, 16/247 dogs developed some type
oclacitinib (2.6%) versus ciclosporin (0.6%) (P=0.0041).7
of confirmed or suspected malignant neoplasia, and
However, in the previously mentioned study performed
10 of these dogs were euthanized. The association
at author’s practices comparing malignancies and non-
with Apoquel® and tumor formation in these cases
malignant skin masses in 339 allergic dogs receiving
is not known. A study performed at the author's
long-term (> 6 months) oclacitinib with age and breed
practices looked at a comparison of malignancies
matched control population, there was no statistically
and non-malignant skin masses in 339 allergic dogs
increase in histiocytomas in the Apoquel® treated
receiving long-term (> 6 months) oclacitinib with
group.5
age and breed matched control populations.5 The
incidence of malignancies in the oclacitinib group CytopointTM -Caninized Anti-cil-31 Monoclonal
(16.5%) versus controls (12.8%) was not statistically Antibody (Mab)
different (p=0.1742). The incidence of skin masses in Monoclonal antibodies are complex large protein
the oclacitinib group (56.6%) versus controls (58.3%) molecules that are developed by utilizing recombinant
was not statistically different (p=0.6743). The age DNA technology that mimics the natural immune
of death/euthanasia in the oclacitinib group (11.2 response in the body. They are inactivated by digestion
years, n=80) versus controls (11.8 years, n=72) was so are given by injection, rather than orally. They often
not statistically different (p=0.2077). There was no are therapeutically used at monthly or longer intervals.
statistical significance regarding the dose of oclacitinib They are designed to have target specificity and have
on cumulative incidence of malignancy or masses. minimal side-effects. They interact extracellularly with a
Adverse effects have been reported in published and free or cell surface target and cannot act intracellularly.
unpublished reports. UTIs incidence is variable, with They are degraded by normal protein catabolism to
some reports showing no cases and others showing a amino acids which are then reused by the body, with
low incidence of 6.5%. Anecdotal reports of weight gain minimal hepatic or renal metabolism and elimination.
have been observed in some patients on oclacitinib. It CytopointTM is a caninized anti-canine interleukin-31
is not entirely known whether weight gain is related (IL-31) monoclonal antibody. IL-31 has been shown
to reduced pruritus or other causes. The potential to induce pruritus in dogs in laboratory studies.
association of weight gain may reflect the impact of Lokivetmab is the active contained in Cytopoint.
JAK-STAT transcription factors involved with adipocyte Lokivetmab has the advantage of being extremely
metabolism including insulin action, modulation of

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HILL’S GLOBAL SYMPOSIUM 2021 | PROCEEDINGS
targeted and having a very long half-life, remaining well. In one published study in 89 dogs, lokivetmab lead
in circulation for several weeks. The label allows for to a significant reduction of CADESI 04 and pruritus,
repeated administration, monthly, or as needed. Initial within four weeks but its maximum effect was achieved
experience suggests Cytopoint may be effective in after the second dose.11 In addition, recent Zoetis data
some canine patients that had an insufficient response suggests that it may take up to three monthly injections
to other forms of allergy therapy, including cases before the full benefit on pruritus reduction is seen.
that have failed oclacitinib therapy. In a clinical trial
In some cases, the duration of control is longer than
involving client-owned dogs with atopic dermatitis, a
one month. This may reflect seasonal atopic dermatitis
single injection of 2 mg/kg began to reduce pruritus
and individual case responses. In another report in 101
within 1 day and was effective for a full month.8 On day
dogs 73% responded to treatment and 37 (27%) were
3, greater than 80% of dogs administered Cytopoint
considered non-responders.12 Responders received
achieved treatment success (predefined as an owner-
a mean of 4.6 injections and the mean time between
assessed ≥20-mm reduction in pruritus as scored on
injections in the group of responders was 34 days. A
the pruritus Visual Analog Scale [VAS]). Mean pruritus
decrease in efficacy of treatment was not observed in
scores were very mild starting at day 1, continuing
a group of 32 dogs that received six or more injections.
for a full month. There was significantly greater
In a large multicentre clinical study, 181 veterinary
efficacy vs placebo in achieving treatment success in
clinics who purchased ≥20 vials of product were
improvement of skin lesion scores (predefined as a
asked to record the dates for the duration of effect.13
50% reduction from baseline in veterinarian- assessed
For dogs that received more than one injection during
skin condition) beginning on day 14 and continuing
the study, the mean treatment interval was 36.8 days
for 1 month (p≤0.05). Significant improvement in skin
(range, 12-101), 33.5 days (19-79), and 32.5 days (25-
condition was noted at the first visit on day 7. At day
56), respectively, for dogs that received two (n=293),
28, there was a nearly 50% decrease in dermatologist
three (n=92), or four injections (n=18). Of the dogs that
scores for treated dogs compared to placebo. In this
received two injections, 80.2% received the second
clinical trial side effects were minimal, manageable
dose between 28 and 56 days, 7.8% at >56 days, and
and similar to placebo. The most common side effects
11.9% at 27 days. The mean treatment interval was 36.8
were vomiting, diarrhea and lethargy. In another field
days. The impact of disease seasonality or concurrent
safety study Cytopoint was well tolerated in dogs after
therapy was not assessed.
subcutaneous injection.9 Adverse events occurred
at a similar frequency between treated and placebo The author uses Cytopoint commonly during the
groups in a study of 245 canine patients. Abnormal beginning of immunotherapy and at the start of diet
health events were self-limiting and not continuous trials in dogs less than 1 year of age, although it may not
throughout the length of the study. A wide variety of be as good as oclacitinib during dietary trials due to its
concomitant medications were safely used, including variable duration of activity. It can be used as a long-
parasiticides, antibiotics, antifungals, corticosteroids, term monotherapy or as part of multimodal therapy
vaccines, immunotherapy, antihistamines and other in chronic atopic dermatitis cases. It has appears very
antipruritics, such as oclacitinib and cyclosporine. safe, with minimal adverse reactions. An occasional
Cytopoint has also been demonstrated to be well dog may exhibit sensitivity or pain at the injection site
tolerated in a laboratory safety study in which seven and mild lethargy. In one review of 132 treated dogs,
consecutive monthly subcutaneous injections were adverse events were limited and mild and reported in
administered to laboratory Beagle dogs at doses of 3.3 11/132 (8.3%) dogs and included: lethargy (8), vomiting
mg/kg or 10 mg/kg body weight (12 dogs per group).10 (2), hyperexcitability (1), painful reaction at the injection
site (1) and urinary incontinence.14 A rare anecdotal
At one of the author’s practices, of the first 37 dogs that
anaphylactic reaction has been described by a couple
were closely followed and evaluated, 50% of the cases
of clinicians, some requiring hospitalization. Reduced
had good to excellent control, with 25% having a partial
efficacy after months of therapy is also rare and most
reduction in pruritus, while 20% of the cases showed
commonly is due to failure to control secondary
no improvement. In the cases that showed responses,
infection or other flare factors. To date the development
20% had relief for less than 4 weeks. More repetitive,
of autoantibodies has not been reported to occur at any
reduced interval of injections or higher dosing can help
significant degree.
in some of the cases that do not initially respond as

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HILL’S GLOBAL SYMPOSIUM 2021 | PROCEEDINGS
References dogs treated with oclacitinib and ciclosporin (2017), Abstracts of
1. Cosgrove SB, Wren JA, Cleaver DM, et al. Efficacy and safety of the North American Veterinary Dermatology Forum 26–29 April
oclacitinib for the control of pruritus and associated skin lesions 2017 Orlando, FL, USA. Vet Dermatol, 28: 426-455. https://doi.
in dogs with canine allergic dermatitis. Vet Dermatol 2013;24:479- org/10.1111/vde.12452.
e114. 8. Data on file SRNCR-U--, Zoetis LLC.
2. Cosgrove SB, Wren JA, Cleaver DM, et al. A blinded, randomized, 9. Data on file SRNCR-U--, Zoetis LLC.
placebo-controlled trial of the efficacy and safety of the Janus 10. Krautmann M, Miller, W, Walters, R, Garcia-Tapia, D, King, V,
kinase inhibitor oclacitinib (Apoquel(R)) in client-owned dogs figueriredo, J, Hoover, D. Long-term laboratory safety study
with atopic dermatitis. Vet Dermatol 2013;24:587-597, e141-582. of lokivetmab (ZTS-00103289), a caninized, anti-canine IL-31
3. Wheeler DW, Civil J, Payne-Johnson M, et al. Oclacitinib for the monoclonal antibody, in normal dogs. World Congress Veterinary
treatment of pruritus and lesions associated with canine flea- Dermatology. Bordeux, France, 2016.
allergic dermatitis. Vet Dermatol 2012;23(suppl 1 WCVD abst):38- 11. Szczepanik MP, Popiel J, Cekiera A, et al. Evaluation of the clinical
39. efficiency of lokivetmab in client privately owned atopic dogs
4. Cosgrove SB, Cleaver DM, King VL, et al. Long-term compassionate - multicenter study. Pol J Vet Sci. 2020 Jun;23(2):191-195. doi:
use of oclacitinib in dogs with atopic and allergic skin disease: 10.24425/pjvs.2020.132765. PMID: 32627992.
safety, efficacy and quality of life. Vet Dermatol 2015;26:171-e135. 12. Vincent AL, Lams ATH, Marcussi CS, et al. A retrospective study
5. Lancellotti B. Angus J, Edginton H, et al. Age- and breed-matched to assess anti-pruritic efficacy of lokivetmab in dogs with canine
retrospective cohort study of malignancies and benign skin masses atopic dermatitis. Procceding from NAVDF, Orlando, Fl 2017;42.
in 660 dogs with allergic dermatitis treated long-term with versus 13. Wright A, Amodie D and SousaC. Retrospective study of the
without oclacitinib. JAVMA 2020;257;5: 507-516. interval between injections of cytopoint in clinical practice.
6. Little PR, King VL, Davis KR, et al. A blinded, randomized Proceedings from NAVDF, Orlando, Fl 2017:226.
clinical trial comparing the efficacy and safety of oclacitinib and 14. Souza A, Schissler JR, Rosychuk R, et al. Lokivetmab in the control
ciclosporin for the control of atopic dermatitis in client-owned of pruritus in 135 dogs with allergic dermatitis. Proceedings from
dogs. Vet Dermatol 2015;26:23-30, e27-28. NAVDF Orlando, Fl. 2017;43.
7. High, EJ, Lam, ATH, Ferre, L. A retrospective study comparing
the incidence of cutaneous histiocytoma development in atopic