introducing apoquel®: changing the way we manage allergic...

Introducing APOQUEL®:

Changing the way we manage allergic dermatitis

DR. ANDY HILLIERBVSc, MANZCVS (Canine Medicine)

Diplomate. AMERICAN COLLEGE VET. DERMATOLOGY

Director of Dermatology Medical StrategyDirector of Field Specialists

Zoetis Petcare (US)

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IgE, Mast cells, HistamineAtopic Dermatitis – pathomechanisms

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CYTOKINES PLAY KEY ROLE

Atopic Dermatitis – pathomechanisms

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Cytokines in Canine Allergic Skin Disease

McCandless et al. Production of IL-31 by canine Th2 cells and identification of inflammatory and neuronal target cells. Vet Dermatol 2012; 23(Suppl. 1): FC-64, p52

Langerhanscell

T-lymphocyte

IL-2

IL-4

IL-6

IL-13

IL-5

Activate Other Immune Cells Involved in Allergy

and Inflammation

Many Cytokines Implicated in Allergic Skin Disease (e.g. Atopic Dermatitis) Are Secreted from Activated T-lymphocytes

IL-31Induces

NeuronalItch Stimulation

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T-helper 2 cytokines all use the same intracellular signaling enzyme system

T helper-2 cell IL-31

The Janus kinase (JAK) signaling pathway

IL-2

IL-6IL-13

IL-4

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mRNA

JAK (Janus kinase)

1. Cytokine binds receptor

3. STAT phosphorylation

4. STAT dimerization

Cell membrane Nucleus

6. Translationof mRNAproducesproteins

7. Cell function changes:A. ↑IgE productionB. Lymphocyte proliferation C. ↑Cytokine productionD. ↑Cytokine receptor

expression E. ↑Chemokine production

2. Receptor dimerizationand JAK phosphorylation

STAT

DNA

Ribosome

Phosphates

5. RNA polymerasetranscription of DNA

Janus Kinase (JAK) Signaling Summary

JAK (Janus kinase)

PRURITUSINFLAMMATION

IL-31 binds to cutaneous neurons Activates JAK Sends neuronal signal to brain

Gonzales AJ, et al Interleukin-31: its role in canine pruritus and naturally occurring canine atopic dermatitis. Vet Dermatol. 24:48-e12, 2013

Neuronal Stimulation Through JAK: Key Component in Itch Cycle in Allergic Dogs

PRURITUSInflammatory milieu

IL-31

IL-31 Receptor

JAK Enzymes

Neuronal Cell Membrane

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APOQUEL® (oclacitinib tablet)(ok" la si' ti nib)

● Novel Janus Kinase inhibitor

● 4 JAK enzymes– JAK1– JAK2– JAK3– Tyk2

● APOQUEL selective for– JAK1 + JAK3

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JAK (Janus kinase)

1. JAK inhibitors bind JAK

2. Cytokine binds receptor

3. Receptor dimerizationJAK inhibitor

JAK inhibitor

3. JAK inhibitors block downstreamactivity in the cell

JAK inhibitors only work to block the activity in cells where activity is mediated by cytokines that work through JAK.

Cell membrane Nucleus

Janus Kinase (JAK) Inhibition

JAK1 JAK3 JAK1 JAK2 Tyk2

JAK1

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

JAK1 JAK2

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APOQUEL SELECTIVELY INHIBITS JAK1/JAK3

JAK2 Tyk2 JAK2 JAK2

ALLERGY Innate Immunity

ErythropoiesisMyelopoiesis

MINIMAL EFFECTS ON JAK2

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T helper-2 cell

IL-31

The Janus kinase(JAK)

signaling pathway

IL-2

IL-6

IL-13

IL-4

Apoquel Was Specifically Designed To Target Itch And Inflammation Associated With Allergic Dermatitis

INFLAMMATION

ITCH

APOQUEL JAK INHIBITOR

Gonzales AJ, Bowman JW, Fici GJ, et al. Oclacitinib (APOQUEL®) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy. J Vet Pharmacol Ther. 2014;37(4):317-324. doi:10.1111/jvp.12101.

Allergic dermatitis

13Confidential and Internal to Zoetis

*Gonzales A, et al. J Vet Pharmacol Therap 2014

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Results

Proinflammatory (IL-2, IL-6), proallergic (IL-4, IL-13) and pruritogenic cytokines (IL-31)

Cytokines involved in hematopoiesis

Cytokines involved in innate immune response (IL-12, IL-23)

*Gonzales A, et al. J Vet Pharmacol Therap 2014

15Confidential and Internal to Zoetis

Collard WT, et al. J Vet Pharmacol Ther 2013

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Results: absolute bioavailability

Confidential and Internal to ZoetisCollard WT, et al. J Vet Pharmacol Ther 2013

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IL-6IL-13

Time (Hours)0 6 12 18 24

1

10

100

1000

10000

IL-31IL-2

IL-4

EPO, GM-CSF

IL-12, IL-23

Plasma Concentration APOQUEL 0.6 mg/kg BIDPlasma Concentration APOQUEL 0.6 mg/kg SIDJAK1 dependent cytokines IC50s

JAK 2 dependent cytokines IC50s

Dose Selected Maximizes Anti-pruritic Effects While Minimizing Immunosuppressive Effects

References: Studies 7960Z-60-11-B95, 7560W-60-06-626, 1462N-60-08-905, and 7960W-60-08-779

IC50

Con

cent

ratio

n oc

laci

tinib

(n

g/m

L)

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Results: effect of food

● Food - no effect on the rate/extent of absorption of oclacitinib


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Results: effect of breed

● No differences beagle vs mongrel dogs


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Results: absolute bioavailability


21*Gonzales A, et al. Vet Dermatol 2016: Collard WT, et al. J Vet Pharmacol Ther 2013 Confidential and Internal to Zoetis

Zoetis studied, cloned and sequenced canine IL-31 and produced identical

recombinant IL-31 for use in future studies.

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APOQUEL Inhibits IL-31-induced Pruritus Faster than Prednisolone

References: Study 7D61R-60-11-B64, Fleck T, et al. Vet Dermatol. 2012 Jul;23(Suppl. 1):38

APOQUEL or Prednisolone

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APOQUEL Inhibits IL-31-induced Pruritus Faster than Prednisolone

0

20

40

60

80

Leas

t Squ

ares

Mea

ns (L

SM +

/-SE

)

Treatment Group

PlaceboPF-03394197 @ 0.40 mg/kg SIDPrednisolone @ 0.25 mg/kg SIDPrednisolone @ 0.50 mg/kg SID

** p = 0.0013

PlaceboAPOQUEL @ 0.40 mg/kg SIDPrednisolone @ 0.25 mg/kg SIDPrednisolone @ 0.50 mg/kg SID

MEAN PRURITIC SCORES 1-3 HOURS POST DOSING (N=8 PER GROUP)

References: Study 7D61R-60-11-B64, Fleck T, et al. Vet Dermatol. 2012 Jul;23(Suppl. 1):38

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APOQUEL Inhibits IL-31-induced Pruritus Faster Than Injectable Dexamethasone

● Single dose study

● n = 8 beagle dogs per group

● Mean pruritic scores 1–3 hours post dosing are shown

0

20

40

60

80

100 Placebo,

Oclacitinib @0.4 mg/kg, oralDexamethasone @0.2 mg/kg, IM

Treatment group

Prur

itus

Scor

e(L

SM±

SEM

)

Pruritus Score (LSM ± SEM)

Placebo

Oclacitinib@ 0.4 mg/kg, oral

Dexamethasone@ 0.2 mg/kg, IM

Treatment Groups

* *

*

* * *

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APOQUEL® PROFILE§Novel, targeted, oral, selective Janus

kinase (JAK) inhibitor MOA

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§ Control of Pruritus Associated with Allergic Dermatitis in Dogs ≥ 12 mo.

§ Control of Atopic Dermatitis in Dogs ≥ 12 mo.Indications

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§ Control of Pruritus Associated with Allergic Dermatitis in Dogs > 12 mo.

§ Control of Atopic Dermatitis in Dogs > 12 mo.Indications

§Rapid decrease of itch within 1 day. Long-term efficacyEfficacy

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§0.4-0.6 mg/kg twice daily up to 14 days, then once daily with or without food

Dosing

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§0.4-0.6 mg/kg twice daily up to 14 days, then once daily with or without food

Dosing

§Minimal side effects; primarily GISafety

CLINICAL EFFICACY

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Measures of Efficacy:PRURITUS Visual Analog Score (PVAS)

0

100

50

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APOQUEL® Effectively Controlled Itch Within 24 Hours

Cosgrove, S. B., Wren, J. A., Cleaver, D. M., Martin, D. D., Walsh, K. F., Harfst, J. A., Follis, S. L., King, V. L., Boucher, J. F. and Stegemann, M. R. (2013), Efficacy and safety of oclacitinib for the control of pruritus and associated skin lesions in dogs with canine allergic dermatitis. Vet Dermatol 24: 479–e11

Efficacy for Treatment of Allergic Dermatitis

- 27%

- 65%

34Cosgrove SB et al 2013, Vet Dermatol.

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APOQUEL Provides Similar Itch Controlto Prednisolone

Reference: Study A161R-AU-12-096

LS-mean (±SE) Pruritus VAS Scores Assessed by Owners

0

20

40

60

80

100

0 7 14 21 28

Mea

n VA

S Sc

ore

(mm

)

Day of Study

Delta-Cortef (prednisolone)

APOQUEL (oclacitinib)

EXTREMELY SEVERE

SEVERE

MODERATE

MILD ITCHING

VERY MILD

NORMAL

*

*p=0.0087

4 hours

37

0

20

40

60

80

100

0 7 14 21 28

Mea

n VA

S Sc

ore

(mm

)

Day of Study

Delta-Cortef (prednisolone)

APOQUEL (oclacitinib)

Extremely severe dermatitis

Severe dermatitis

Moderately severe dermatitis

Moderate dermatitis

Mild dermatitis

Normal Dog

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LS-MEANS(±SE) INVESTIGATOR ASSESSMENT OF ALLERGIC DERMATITIS VAS SCORES

* p=0.0022

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 Dec;25(6):512–e86.

APOQUEL WORKED AS WELL AS PREDNISOLONE AGAINST ALLERGIC DERMATITIS AND SKIN INFLAMMATION

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APOQUEL Provided Fast and Long Term Reduction in Itch in Dogs with Atopic Dermatitis

• Day 14- 28• Could withdraw if worsening clinical signs

• 86% (127/147) of the placebo –treated dogs

• 15% (23/152) of the APOQUEL-treated dogs

*Oclacitinib is significantly different from Placebo (p < 0.0001)

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Canine Atopic Dermatitis Extent Severity Index

CADESI-02

Erythema, lichenification, excoriations

Grades: 4

No. of body areas: 40

Max. score: 360

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APOQUEL Provided Rapid and Long Term Reduction in Dermatitis in Dogs with Atopic Dermatitis

*APOQUEL is significantly different from placebo (P

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APOQUEL® → Faster Onset of Action Than ATOPICA® in Control of Pruritus in Dogs with Atopic Dermatitis

Reference: Data on file, Study report 6962R-14-10-025, 2013, Zoetis Inc.

•Treatment difference is significant at 0.05•Atopica (cyclosporin) dosed at 3.1-6.7 mg/kg SID to Day 84 (± 2)•Apoquel dosed at 0.4-0.6 mg/kg BID for 14 days, then 0.4-0.6 mg/kg SID to Day 84 (±2)

SAFETY

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Safety Studies

Pivotal Margin of Safety Studies

Clinical Field Safety and Efficacy Studies

Continuation Field Study

Pivotal Margin of Safety of APOQUEL in Adult Dogs

– 4 groups of 8 adult dogs each● Placebo● 0.6 mg/kg (1x label dose)● 1.8 mg/kg (3x label dose)● 3.0 mg/kg (5x label dose)

– BID for 6 weeks, then SID for an additional 20 weeks

– Result● Effects in all groups consistent with the pharmacological action

of the drug class● Most effects were mild and nonprogressive● None were serious● None resulted in death

46 Reference: Study 1462N-60-10-A29

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Cosgrove, S. B., Wren, J. A., Cleaver, D. M., Martin, D. D., Walsh, K. F., Harfst, J. A., Follis, S. L., King, V. L., Boucher, J. F. and Stegemann, M. R. (2013), Efficacy and safety of oclacitinib for the control of pruritus and associated skin lesions in dogs with canine allergic dermatitis. Vet Dermatol. 24: 479–e11

● During the 30-day study, there were no deaths and no adverse reactions requiring hospital care. In most of these cases, signs spontaneously resolved with continued dosing

Adverse Reactions That Began During the Study Phase (Days 0–7)

Adverse Reactions

Number (%) of DogsPlacebo n = 220

Number (%) of DogsAPOQUEL Group

n = 216

Diarrhea 2 (0.9) 5 (2.3)

Vomiting 4 (1.8) 5 (2.3)

Anorexia 0 (0.0) 3 (1.4)

Polydipsia 0 (0.0) 3 (1.4)

The Side Effects of APOQUEL Are Similar to Placebo Without Many of the Side Effects of SteroidsALLERGIC DERMATITIS STUDY

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Adverse Reactions That Began During the Study Phase (Days 0–16)

Adverse Reactions

Number (%) of DogsPlacebo Group

n = 152

Number (%) of DogsAPOQUEL Group

n = 147

Diarrhea 5 (3.4) 7 (4.6)

Vomiting 6 (4.1) 6 (3.9)

Anorexia 0 (0.0) 4 (2.6)

New Dermal, Epidermal, or Subcutaneous Lump 4 (2.7) 4 (2.6)

Lethargy 2 (1.4) 3 (2.0)

The Side Effects of APOQUEL Are Similar to Placebo Without Many of the Side Effects of SteroidsATOPIC DERMATITIS STUDY

● In most cases, diarrhea, vomiting, anorexia, and lethargy spontaneously resolved with continued dosing

Cosgrove, S. B., Wren, J. A., Cleaver, D. M., Walsh, K. F., Follis, S. L., King, V. L., Tena, J-K S. andStegemann, M. R. (2013), 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 24: 587–e142.

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● 247 dogs

● Duration of treatment – Mean 401 days – Range 15-672 days

● Conclusion:– Safe + efficacious long-term

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0

20

40

60

80

100

0n=253

90n=226

180n=206

270n=194

360n=177

450n=169

540n=135

630n=142

720n=74

810n=81

900n=43

990n=64

1080n=10

VAS

Scor

e (m

m)

Day of Study

Extremely severe itching

Severe itching

Moderate itching

Mild itching

Very mild itching

Normal Dog

18/247 (7.3%) withdrew due to worsening of clinical signs

Pruritus relief was maintained throughout the study

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● Abnormal Health Events– Similar to what was observed in the clinical trials. – GI disturbances (emesis and diarrhea) were the most

frequently reported – Serious adverse events (including deaths and

neoplasms) occurred no more frequently than what is seen in the general population of dogs.

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Apoquel ® Important Safety Information

● APOQUEL® should not be used in dogs less than 12

months of age or in dogs with serious infections.

● APOQUEL may increase the susceptibility to infection and

demodicosis and may exacerbate neoplastic conditions.

● APOQUEL has not been evaluated in combination with

systemic immunosuppressive agents such as glucocorticoids or cyclosporine.

● APOQUEL should not be used in breeding dogs, or pregnant or lactating dogs.

● See full prescribing information at www.apoquel.com/apoquelPI

http://www.apoquel.com/apoquelPI

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● Comprehensive, post-approval surveillance program for reporting PV data to regulatory agencies (FDA)– Overall adverse reactions incidence rate is rareo>1 but < 10 animals reacting per 10,000 treated

– Individual adverse reactions were very rare●

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● Long-term continuation study1

– Rate of neoplasia (16/247 dogs ≈ 6%) ≈ expected in the general population of dogs

● 5-year post-approval PV safety review2

– Two most commonly reported neoplasias (papillomas and histiocytomas) were very rare incidence rates ● < 1 dog reacting out of 10,000 dogs treated

● Lancellotti NAVDF 2019 abstract– Incidence of malignancies and dermal masses in dogs with AD:

● Apoquel-treated group (339) vs “all other treatments” group (321)● No significant differences between groups

APOQUEL® AND NEOPLASIA

1. Cosgrove SB, Cleaver DM, King VL, et al. Long-term compassionate use of oclacitinib in dogs with atopic and allergic skin disease: safety, efficacy and quality of life. Vet Dermatol. 2015;26(3):171-179. doi:10.1111/vde.12194. 2. Data on file, A Five-Year Post-Approval Safety Review for APOQUEL® in the US (May 2013 to August 2018), Zoetis Inc

No evidence of higher risk for new neoplasms with APOQUEL

WHY IS APOQUEL A

GAME-CHANGER?

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iTP

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1. Data on file. Zoetis Pruritus Diary Study Wave 2, 2015, Zoetis Inc.2. Data on file. Pet Owner Quantitative Market Research, 2-013. Zoetis Inc.

Itch relief Great experienceTrust +

confidenceLoyalty + Best

Medicine

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Coe et al. JAVMA 2007https://www.avma.org/javma-news/2015-05-15/building-practice

● When discussing costs – Pet owners focused on

outcome– Their pet’s health– The value of the treatment

is most important

● 8/10 owners would probably say “YES” if the value of a

test or treatment were

explained

WHAT IS VALUE?

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COMMUNICATING THE VALUE

Instead of:“I’m giving Charlie APOQUEL for the itch and it will cost

R200 for X days!”

Rather say:“I understand how concerned you are about Charlie’s

scratching, APOQUEL will get him feeling comfortable within

a day without you having to worry about the side effects of

steroids.”

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CHANGING THE APPROACH TO THE PRURITIC DOG

PROTECTING THE BONDS THAT MATTER MOST

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IT IS A MASSIVE ADVANTAGE TO COMPLETE A

DIAGNOSTIC WORKUP

Find a curable disease

Scabies

Diagnose a Specific Cause →

Sustainable Long-Term Control

Flea Allergy

Fire Engine Medicine → Maybe Temporary Relief But…

Likely recurrence

Disease progression

Frustration +

disappointment

No long-term

solutions

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APOQUEL® use:- Stop the itch - During the diagnostic workup- Long-term for atopic dermatitis

introducing apoquel®: changing the way we manage allergic...

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