ApoquelWhat You Should Know

Dr Rob Hilton BVSc (Hons) MANZCVS CertVD MRCVS

RCVS (UK) Recognised Advanced Practitioner and Certificate Holder in Veterinary

Dermatology.

Tele: 0433-853560

Web : www.skinvet.org

Oclacitinib Apoquel®, Zoetis

Indications:

For the treatment of

pruritus associated

with allergic

dermatitis and for the

treatment of the

clinical

manifestations of

atopic dermatitis in

dogs at least 12

months of age

New drug and

class Janus Kinase

inhibitor

Atopic dermatitis is a T-Cell disease, mediated by cytokines

Activated T cells,

histiocytic cells and

keratinocytes release

inflammatory cytokines :

• interleukins

• growth factors

• interferons

•Il-2 Clonal expansion,

inflammation

•Il-6 Inflammation

•Il-4 IL-13 Th2 shift

•Il-31 Pruritus

Cytokines and JAK’s

Selective Inhibition of JAK-1Gonzales et al 2014

0

10

20

30

40

50

60

70

80

90

100

JAK1 JAK2 JAK3 TYK-2

JAK1

JAK2

JAK3

TYK-2

No effect on 38 other tested kinases

Allergic Cytokine Receptors Utilize JAK 1

JAK1 JAK3JAK1

JAK2

Tyk2

JAK1

IL-2, IL-4 IL-6, IL-13 IL-31

JAK1 JAK2

Long term response may be more

impacted by other cytokine effects

The Itch Cycle – Zoetis

www.itchcycle.com

Interleukin-31 a newly identified culprit.

Apoquel blocks the response to interleukin-31 (IL-31) which, to date, is the only known DIRECT chemical mediator of pruritus in dogs.

FACTS• Produced by activated T-cells as part of the

inflammatory cascade associated with atopic dermatitis.

• Detectable in a high proportion of atopic dogs (and humans) and is not detected in normal dogs.

• Dogs injected with Il-31 will scratch! Pruritus does not occur when dogs are given histamine, IL-2, IL-6 and a variety of other known inflammatory cytokines.

• There are IL-31 receptors on nerve endings.

• Anti-IL-31 monoclonal antibodies are effective in reducing pruritus in the dog giving relief of pruritus for a period of weeks after injection.

IL-31• cIL-31 injected into dogs caused pruritic

behavior over a 2 h period compared with placebo 1

1 Gonzales et al(2013). Interleukin-31: its role in canine pruritus and

naturally occurring canine atopic dermatitis." Vet Dermatol 24(1): 48-53

• IL-31 dog model and in vitro inhibition data

• Direct correlation of plasma concentrations

and reduction in pruritus

The Pharmacokinetics of APOQUEL Correlates with Anti-itch Activity

Plasma

Concentration & % Pruritus Following

0.4 mg/kg Dose

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

0

50

100

150

200

250

0 6 12 18 24

Mean Plasma Concentration

Mean % Pruritus

Time (hours)

Reference: Fleck T et al., NAVDF 2013. Comparison of the onset and anti-pruritic activity of the JAK inhibitor oclacitinib to prednisolone and dexamethasone in an IL-31 canine model of pruritus.

Zoetis Study A160R-US-12-057

*

*****

APOQUEL Inhibited IL-31-induced Pruritus

Faster Than Injectable Dexamethasone

*p=0.065 Dexamethasone compared to placebo

**p=0.0001 APOQUEL compared to placebo

***p=0.0001 APOQUEL compared to dexamethasone

Plasma Concentration in Relationship to

IC50s

IL-6IL-13

Time (hours)

0 6 12 18 24

Co

nce

ntr

ati

on

(ng/m

L)

10

100

1000

Plasma Concentration (BID and SID)JAK1 dependent cytokines (itch & inflammation)JAK2 dependent cytokines (innate immunity & hematopoiesis)

IL-31IL-2

IL-4

EPO, GM-CSF

IL-12, IL-23

Cytokine Inhibition

0.6mg/kg

10

1

2

9

8

7

6

5

4

3

0

Vet Dermatol 2007, 18(5): 301-308

Vet Dermatol, 2009. 20(2): 115-122.

• 299 dogs, age: 1 – 13 years, weight: 3.4 –77.2 kg

• Client-owned dogs enrolled at 19 Dermatology Specialty Practices throughout the United States

After time 0 Oclacitinib is significantly different from Placebo

As much as (p < 0.0001)

Owner Assessed Pruritus VAS Scores

0

1

2

3

4

5

6

7

8

0 7 14 28 56 84 112

Oclacitinib

Placebo

VASSevere

Moderate

Mild

Very Mild

Normal

Day

99% placebo switch day 14-28

Dermatologist CADESI Scores

0

10

20

30

40

50

60

70

0 14 28 56 84 112

Oclacitinib

PlaceboCADESI-02

Day

99% placebo switch day 14-28

More Controlled Studies• 1 Gadeyne C, Little PR, King VL, et al (2014). 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 25(6), 512-e586

– single-masked, randomized controlled clinical trial

– 123 Client-owned dogs with allergic dermatitis

• 2 Little PR, King VL, Davis KR, et al (2015). 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, 26(1), 23-e28

– blinded, randomized clinical trial, noninferiority test at day 28.

– 226 client-owned dogs with a history of AD from eight sites

APOQUEL Improved Itch Faster than Cyclosporine in the First 14 days of the Study

References Study 6962R-14-10-025

Day of Study 0 1 2 7 14 28 56 84

LS Mean

(N)

Atopica73.84

(112)

69.06

(104)

67.07

(88)

56.84

(103)

51.81

(92)

42.97

(93)

32.42

(85)

26.97

(87)

APOQUEL74.37

(113)

55.60

(110)

44.02

(100)

32.29

(107)

27.55

(109)

36.75

(100)

34.60

(92)

28.77

(83)

P-value 0.7933 <0.0001 <0.0001 <0.0001 <0.0001 0.0694 0.5441 0.6129

Error bars indicate one standard error from the mean

* Treatment difference is significant at 0.05

Little et al, 2015

APOQUEL Provides Similar Itch Control to Prednisolone

0 4 hr 1 6 14 28

72 53 42 29 34 33

73 50 42 32 23 33

0.595 0.458 0.964 0.383 0.009 0.940

Day of Study

APOQUEL

Delta-Cortef

Extremely severe itching

Severe itching

Moderate itching

Mild itching

Very mild itching

Normal Dog

p value

*

* p=0.0087

LS-MEAN (±SE) PRURITUS VAS SCORES ASSESSED BY OWNERS

4 hours

Reference: Study A161R-AU-12-096

Dose Regimen

0.5-1.0 mg/kg SID up

to Day 6 (±1), followed by

0.5-1.0 mg/kg EOD up

to Day 28 (±2).

0.4-0.6 mg/kg BID for 14 days,

followed by 0.4-0.6 mg/kg SID up

to Day 28 (±2).

1 Gadeyne et al, 2014

Apoquel Side Effects

Little, et al (2014) Efficacy and safety of oclacitinib compared to ciclosporin for the

control of atopic dermatitis in client-owned dogs. NAVDF, Phoenix AZ

226 dogs with history of

chronic non-seasonal atopic dermatitis in an 84-day study

Case Studies

• Three cases presented are what we would call “nightmare” cases

• Refractory to all prior treatment except high risk dosing with corticosteroids.

• Illustrate the risks of medium/long term corticosteroid use

JackSignalment: • Male neutered

Labrador cross,

• 6 years of age

• Weight: 44 Kg

• Severe pruritus

Jack

•Severe pruritic dermatitis

•Age of onset approx 18

months of age

•Good flea control. No fleas

seen by observant owner

•Non seasonal

•Grade of pruritus severe

•Thighs, belly, flanks, feet and ears

•Developed severe pancreatitis

while receiving prednisolone which

did reduce the itch

Clinical History

Jack

•No response to single novel protein food elimination trial for 7

weeks

•Scrapings negative for ectoparasites.

•No response to Sarcoptes elimination trial Selamectin fortnightly

for 6 weeks

•20% reduction in pruritus in response to antibiotics (cephalexin

25mg/kg 2x day 3 weeks), weekly chlorhexidine shampoo and

conditioner plus daily moisturiser therapy

Clinical diagnosis: Atopic dermatitis with controlled

secondary infections

RESPONSE/LACK OF RESPONSE

TO INITIAL MANAGEMENT

Jack

•Intradermal test negative to all test allergens on two separate

occasions and two separate testers

•Owner not prepared to risk pancreatitis again by using

prednisolone

•No significant response to topical corticosteroids or antihistamines

•No response to cyclosporine 200 mg daily for 35 days

• No significant response to methotrexate 5mg weekly for 4 months.

INITIAL MEDICAL MANAGEMENT

Clinical diagnosis: Refractory low

IgE atopic dermatitis (intrinsic atopic

dermatitis, atopic- like dermatitis)

Jack

On APOQUEL now 2 years and 4 months

- Responded rapidly, within 24 hrs he was significantly improved

- On APOQUEL - pruritus and skin signs very mild to normal dog

- Has remained stable except for one incidence of quickly controlled

otits externa

- No evidence of side effects, very healthy throughout APOQUEL

treatment

- Monitored quarterly for signs related to immunosuppression

RESPONSE TO APOQUEL TREATMENT

JackHOW HAS DOG AND OWNER’S QUALITY

OF LIFE CHANGED POST APOQUEL?

Massive change in Jack's and owner's quality of life.

SafariSignalment: • Male neutered Labrador

cross,

• 5 years of age

• Weight: 26 Kg• Severe pruritic

dermatitis

Safari

- Age of onset approx 18 months of age

- Good flea control. No fleas seen by observant

owner

- Non-seasonal

- Grade of pruritus severe

- Belly, flanks lesser involvement feet and ears

- Heavily prednisolone dependent 20mg every

day.

Clinical History

Safari

•No response to 7 week single novel protein food

elimination trial for

•Scrapings negative for ectoparasites and no response

to Sarcoptes elimination trial Selamectin fortnightly

for 6 weeks

•20% reduction in pruritus in response to antibiotics

(cephalexin 25mg/kg 2x day 3 weeks), weekly

chlorhexidine shampoo and conditioner plus daily

moisturiser therapy

RESPONSE/LACK OF RESPONSE

TO INITIAL MANAGEMENT

Safari

RESPONSE/LACK OF RESPONSE

TO INITIAL MANAGEMENT

Clinical diagnosis of atopic dermatitis

•Intradermal test positive for dust mites

and other arthropods

•Allergy vaccine for 11 months. No

reduction in prednisolone dependence.

•No response to cyclosporine 150mg

for 35 days

•No significant response to

antihistamines (Fexofenadine 15mg/kg)

or topical corticosteroids

Help

Safari

- On APOQUEL now 2 years and 4 months

- Responded very quickly, within 24 hrs he was

significantly improved

- On APOQUEL pruritus and skin signs very mild

- Has remained stable except for one flare due to pyoderma.

Controlled with 900 mg cephalexin for 3 weeks

- No evidence of side effects, very healthy throughout APOQUEL

treatment

- Monitored quarterly for signs related to immunosuppression.

RESPONSE TO APOQUEL TREATMENT

SafariHOW HAS DOG AND OWNER’S QUALITY

OF LIFE CHANGED POST APOQUEL?Massive change in Safari's and owner's quality of life.

KiayaSignalment: • Signalment: Female

desexed, Staffordshire

• Bull Terrier, 3.5 years of age

• Severe pruritus and owner complained of “lumpy” skin

Kiaya

- Severe pruritic dermatitis

- Age of onset approx 20 months of age

- Good flea control. No fleas seen by observant

owner

- Non seasonal severe grade pruritus

-Thighs, belly, flanks and feet

- Pot belly

- Receiving prednisolone 10mg every second day

for last 9 months. Referred because of recent loss

of efficacy and "lumps" in skin under the coat.

Clinical History

Kiaya

10-13

Severe calcinosis cutis due to iatrogenic Cushing's

syndrome. Confirmed by biopsy

- Skin scrapings negative for Demodex spp

- Differential diagnoses of underlying condition: atopic

dermatitis and/or adverse food reaction "food allergy"

- Treatment for calcinosis cutis: topical DMSO and

systemic minocycline 5mg/kg twice daily

- Cyclosporine 75mg daily for 40 days reduced pruritus

from severe to moderate but still unacceptable.

Assessment and

initial management

Kiaya

RESPONSE TO APOQUEL

TREATMENT

• On APOQUEL now for 4 weeks

• Responded rapidly, within 24 hrs the itch was significantly improved

• On APOQUEL pruritus is very mild to mild

(as good as prednisolone was prior to calcinosis cutis).

KiayaFuture Strategy

• When calcinosis cutis resolved plan to conduct a

7 week novel protein food elimination trial using

a periodic APOQUEL withdrawal strategy

• When steroid washout complete and if not

resolved by diet, allergen test for desensitisation.

• If vaccine possible use a periodic APOQUEL

withdrawal strategy (every 2 months) to assess

efficacy of desensitisation

• Monitor for signs related to mmunosuppression.

Using Apoquel• 0.4-0.6mg/kg q12h for up to two weeks

then q24h

• Poor response could be secondary infections, fleas?, food allergy?

KEY POINTOclacitinib is NOT a cure for canine allergic skin disease.

It provides a rapid means of reducing pruritus in most cases of non-infected allergic dermatitis. A proper dermatological work up MUST BE DONE

Using Apoquel

• Pruritus flares after two weeks BID dosing

– Is there pyoderma or a non-allergic cause?

– With more time may be good

• so wait

• or longer q12h

– Consider how long stays better and timing of administration

• Morning versus evening sometimes makes a difference

– Can dose be raised– Remember the dose range

» Sometimes helpful to calculate and put in the record

– Give BID but make daily dose lower in the range

Use in elimination trials and during immunotherapy

Rapid action and short half life (4hrs) mean no suffering during trial/lag phases

• Food and parasite elimination trials withdraw every 10-14 days

• During ASIT withdraw every 6 weeks

Then restart if pruritus returns

• Dogs should be screened by scraping and hair pluck for demodicosis before starting Oclacitinib and monitored for this during treatment.

• Review and monitoring should be regular as would be indicated for the age of the dog and the fact that they are receiving an immunosuppressive agent.

• Relapses most commonly related to pyoderma

• Oclacitinib is reported not to interfere with intradermal allergen testing.

When Not To Use Apoquel• Dog is doing well on another treatment that

has high safety profile and similar cost

– ASIT

– Antihistamines

– Low dose (not daily) cyclosporine

– Prednisolone load 4-5mg/kg per month and no

adverse effects with monitoring

• Dog under one year age

• Demodex history ?/present ? - Isoxolaners

• Uncontrolled pyoderma

Apoquel is not likely to be effective initially in these cases.

Why?

Summary• Apoquel® provide a means of rapidly controlling pruritus

of allergic skin disease in most dogs . • It is the most significant breakthrough in the symptomatic

management of canine allergic skin disease the author has seen in his 40 years of practice.

• It buys time for dermatological diagnosis and workup. It does NOT replace the need for the cornerstones of management :– Food trials to eliminate adverse food reactions

– Parasite control trials– Allergen testing and immunotherapy

– Barrier repair

– Control of infection