UTAH MEDICAID DUR REPORT FEBRUARY 2019

CRISABOROLE FOR THE TREATMENT OF MILD TO

MODERATE ATOPIC DERMATITIS

Crisaborole ointment, 2% (Eucrisa)

Report finalized: January 2019

Drug Regimen Review Center

Elena Martinez Alonso, B.Pharm., MSc MTSI, Medical Writer Valerie Gonzales, Pharm.D., Clinical Pharmacist Lauren Heath, Pharm.D., MS, BCACP, Assistant Professor (Clinical) Jacob Crook, MStat, Data and Statistical Analyst Joanne LaFleur, PharmD, MSPH, Associate Professor

University of Utah College of Pharmacy, Drug Regimen Review Center Copyright © 2019 by University of Utah College of Pharmacy Salt Lake City, Utah. All rights reserved

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Contents Introduction .................................................................................................................................... 3

Methods .......................................................................................................................................... 3

Disease Overview ............................................................................................................................ 4

Table 1. Revised Hanifin and Rajka Criteria for the Clinical Diagnosis of Atopic Dermatitis .. 4

Table 2. Examples of Atopic Dermatitis Severity Scales ......................................................... 5

Treatment Strategies and Guideline Recommendations ............................................................... 6

Table 3. Clinical Practice Guideline Recommendations for the Treatment of Atopic Dermatitis ............................................................................................................................... 7

Expert Opinion Recommendations ................................................................................................. 9

Table 4. Management Plan of Atopic Dermatitis (All Age Groups) for Primary Care Providers ................................................................................................................................. 9

Crisaborole for the Treatment of Mild to Moderate Atopic Dermatitis ....................................... 10

Table 5. Crisaborole Prescribing Information ....................................................................... 10

Safety .................................................................................................................................... 10

Clinical Trial Evidence .................................................................................................................... 11

Table 6. Investigator’s Static Global Assessment (ISGA) Scores and Definitions ................. 11

Utah Medicaid Utilization Data ..................................................................................................... 13

Table 7. Total FFS Pharmacy Data for Crisaborole (2016-2018) ........................................... 13

Table 8. Total ACO Pharmacy Data for Crisaborole (2016-2018) ......................................... 13

Table 9. Age Distribution for FFS Patients Receiving Crisaborole (2016-2018) .................... 13

Discussion Topics and Potential Prior Authorization Criteria for Crisaborole .............................. 14

Summary ....................................................................................................................................... 15

References .................................................................................................................................... 16

Appendix A: Literature Search Strategies ..................................................................................... 18

Appendix B: Key Findings in Published Clinical Trials ................................................................... 19

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Introduction Crisaborole (Eucrisa) is a non-steroidal, phosphodiesterase 4 (PDE-4) inhibitor approved by the U.S. Food and Drug Administration (FDA) in December 2016 for the treatment of mild to moderate atopic dermatitis (AD) in patients 2 years of age and older.1-3 Atopic dermatitis or atopic eczema is a chronic inflammatory skin disorder primarily affecting children, but can also affect adults.4-6 Clinical manifestations include pruritus, cutaneous eczematous plaques, xerosis, and pain.4,6,7 Crisaborole is a topical ointment applied twice daily to the affected area.1 It inhibits the enzyme PDE-4 causing an increase in the levels of intracellular cyclic adenosine monophosphate (cAMP).1,7 Its precise mechanism of action in AD is not fully understood.1

Current therapeutic options for mild to moderate AD include moisturizers, topical corticosteroids (TCSs), and topical calcineurin inhibitors (TCIs).6,8 TCSs have been used to manage AD for more than 60 years and are the mainstay of anti-inflammatory therapy in AD;8 however, they are related to short- and long-term adverse reactions including hypothalamic-pituitary-adrenal axis suppression, skin atrophy, striae, and telangiectasia.2,6,8 TCIs (tacrolimus and pimecrolimus) are approved as second-line treatments for patients with AD “who have failed to respond adequately to other topical prescription treatments for AD or when those treatments are not advisable.”8-10 They carry a black box warning regarding the long-term risk of cancer (eg, skin malignancy and lymphoma).6,9,10 Crisaborole has demonstrated favorable efficacy and safety in patients with mild to moderate AD and has recently become available as an additional therapeutic option for these patients.6 Phototherapy and systemic immunomodulatory agents (eg, cyclosporine) are typically used for patients with moderate to severe AD who have not adequately responded to conventional topical therapy.11

Currently, there are prior authorization criteria in place for topical immunomodulators (pimecrolimus, tacrolimus, and crisaborole).12 The purpose of this review is to provide evidence that can assist the Medicaid Drug Utilization Review (DUR) Board in assuring appropriate use of crisaborole in patient populations most likely to benefit.

Methods A literature search for systematic reviews addressing the efficacy and safety of crisaborole was conducted in the Cochrane Library and Ovid Medline. Additionally, clinical trials were reviewed in the Cochrane Controlled Register of Trials (CENTRAL). References of relevant search results were screened. Search strategies are provided in Appendix A. In addition, searches in The National Institute for Health and Care Excellence (NICE) website were performed.

Information concerning product labeling and FDA clinical review documents was obtained from the FDA website. Additional information was found in Micromedex, Lexicomp, and Up To Date. Treatment guidelines for the management of AD were identified by searching the American Academy of Dermatology (AAD) and the American Academy of Allergy, Asthma & Immunology (AAAAI) websites and checking the reference lists of relevant systematic reviews.

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Disease Overview Atopic dermatitis (AD), also called atopic eczema, is a chronic inflammatory skin disorder characterized by intense pruritus and inflammatory eczematous lesions due to skin barrier dysfunction and immune system imbalances.4,7,13 AD is usually an episodic disease with recurrent flare-ups and remissions.4,13,14 The term “atopic” is associated with a genetic trend toward allergic conditions.15 Several studies have demonstrated a high impact of AD on patient´s health-related quality of life due to symptoms (eg, skin itching and sleep problems) and visible eczemas.4,16,17 Additionally, regular visits to doctors, frequent treatment, and work and school absence are associated with a significant economic burden on families and the health care system.18

AD can occur in all age groups; however, it is more common in young children 5 years of age or below (90% of cases), particularly in infants between 3 and 6 months of age.4,13,18 AD is considered the most frequent inflammatory skin disease in the pediatric population.18,19 It affects up to 25% of children and approximately 2% to 3% of adults.13 Among all children with AD, approximately 80% have mild disease and up to 70% experience significant improvements or complete resolution in late childhood.4 AD can appear in any part of the body and distribution patterns of skin lesions are age-related (face and extensor surface of extremities in infants, flexural folds in children, and hands or flexures in adults).4

AD is a complex disorder influenced by genetic, immunologic, and environmental factors.13 AD is strongly associated with a personal or family history of atopic diseases such as type I allergies, allergic rhinitis, and asthma.4,8,13,20 Approximately 70% of patients with AD have a family history of atopic conditions.13 The presence of null mutations in the gene encoding for filaggrin, a key protein in the skin barrier function, is a strong risk factor for developing AD.4,7 In addition, some immune-related genes are important risk factors for AD.4 Environmental and lifestyle factors that are associated with the disease include living in urban areas with little sunlight and humidity, western diet with high sugar and polyunsaturated fatty acid amounts, tobacco smoke, soaps, and detergents.4,7,13

Diagnosis of AD is based on clinical findings such as pruritus, eczematous lesions and skin dryness.4,13 Morphology and distribution of cutaneous lesions are key in the clinical diagnosis of AD.4,13 The 1980 validated Hanifin and Rajka criteria have been widely used in clinical trials; however, they are cumbersome for use in clinical practice.13 A simplified version of Hanifin and Rajka criteria, proposed in a 2003 consensus conference, is recommended by the AAD for routine clinical practice.13 These criteria are useful to diagnose AD in all age groups and include several features, as shown in Table 1.

Table 1. Revised Hanifin and Rajka Criteria for the Clinical Diagnosis of Atopic Dermatitis13

1) Essential features that must be present: pruritus and eczema

2) Important features that are present in most cases: early age onset, dry skin, and atopy such as personal and/or family history and IgE reactivity

3) Associated features that are suggestive of AD: eg, atypical vascular responses and keratosis pilaris

4) Exclusionary conditions that should not be considered as AD: eg, scabies, seborrheic dermatitis, and contact dermatitis

Abbreviations: AD, atopic dermatitis; IgE, immunoglobulin E

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Regarding laboratory measures, elevated allergen-specific plasma concentrations of immunoglobulin E (IgE) are often observed in patients with AD; however, 20% of patients with AD do not show any change in IgE levels.13,21

There are currently 28 different scales to measure disease severity; however, none of these are considered the gold-standard.13 The most frequently used scales are the Scoring Atopic Dermatitis (SCORAD) Index, Eczema Area Severity Index (EASI), Investigator’s Global Assessment (IGA), and Six Area, Six Sign Atopic Dermatitis (SASSAD) severity score.13 These scales are mainly used in clinical trials and are not recommended for use in clinical practice by the AAD because they were not designed for this objective.13 Likewise, available tools to assess patients’ quality of life in clinical trials are not recommended for use in clinical practice.13 Available evidence suggests that some of these scales, including SCORAD index and EASI, have been appropriately validated and can be used in clinical practice when feasible.13,22 Table 2 includes further information regarding some of the AD assessment tools to evaluate disease severity. The 2014 AAD guideline on diagnosis and assessment of AD recommends “that clinicians ask general questions about itch, sleep, impact on daily activity, and persistence of disease, and currently available scales be used mainly when practical.”13

American guidelines for the management of AD do not specifically define mild, moderate, and severe AD.8,23 In general, mild AD typically affects less body surface area (BSA), is more likely to resolve, has less intense itching, and responds to basic management alone compared to severe cases.24,25 Moderate to severe AD often affects larger BSA, lasts longer, has more severe pruritus, and requires additional maintenance therapy.24,25 The National Institute for Health and Care Excellence (NICE) guideline on AD defines mild, moderate, and severe AD based on the extent and features of skin lesions, symptoms, and impact on quality of life.14

Table 2. Examples of Atopic Dermatitis Severity Scales13 SCORAD21,22,26 EASI22,27 IGA28

Items Measured in Each Scale - Severity of clinical signs:

erythema, edema/induration/papulation, oozing/crusting/weeping/exudation, excoriation, and lichenification (scores range from 0=absence to 3= severe)

- Disease extent: percentage of BSA - Symptoms: pruritus and sleep

disturbances (scores range from 0 to 10)

- SCORAD >50: Severe AD SCORAD 25-50: moderate AD SCORAD <25: mild AD

- Severity of clinical signs: erythema, edema/induration/ papulation, excoriation, and lichenification (scores range from 0=absence to 3= severe)

- Disease extent: percentage of BSA affected in 4 body regions (head and neck, upper extremities, lower extremities, and trunk)

- Total scores range from 0 to 72 (maximal severity)

- Severity of clinical signs: erythema, edema/induration/ papulation, oozing/ crusting/weeping/ exudation, excoriation, lichenification, and scaling

- Scores range from “clear” to “severe” or “very severe”

- Limitations: there is no standardized IGA. High variability in nomenclature, definitions, and scale size exists between clinical trials

Abbreviations: EASI, Eczema Area Severity Index; IGA, Investigator’s Global Assessment; SCORAD, Scoring Atopic Dermatitis

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Treatment Strategies and Guideline Recommendations The 2014 AAD guideline and the 2012 American Academy of Allergy, Asthma & Immunology (AAAI)/American College of Allergy, Asthma & Immunology (ACAAI) practice parameter consider topical agents as the cornerstone of AD therapy.8,23 In more severe cases of AD, topical agents are usually used in combination with systemic agents and/or phototherapy.8,11 According to the 2014 AAD guideline, AD management includes (1) non-pharmacologic interventions such as topical moisturizers, bathing practices, and wet wrap therapy, (2) pharmacologic topical treatment such as topical corticosteroids (TCSs) and topical calcineurin inhibitors (TCIs), and (3) phototherapy and systemic immunologic or anti-inflammatory agents.8,11,23

(1) Moisturizers are recommended as first-line treatment for mild AD and should be included in management plans for moderate to severe AD.8 In addition, they play an important role in the maintenance treatment and prevention of flares.8 Moisturizers include traditional moisturizers formulated as creams, ointments, oils, gels, and lotions, and prescription emollient devices that contain different proportions of lipids and are specifically designed to address deficiencies in skin barrier function.8

(2) TCSs are recommended when patients with AD do not respond to adequate skin care and frequent administration of moisturizers alone.8 TCSs are available at low, medium, or high potency and are considered the mainstay of anti-inflammatory treatment in AD.8 Short- and long-term adverse reactions associated with TCSs include hypothalamic-pituitary-adrenal axis suppression, skin atrophy, striae, and telangiectasia.2,6,8 The 2014 AAD guideline highlights that the selection of a particular TCS for AD depends on age, body regions affected, severity of xerosis, patient preference, and cost of therapy.8

TCIs (tacrolimus ointment 0.03% and 0.1% and pimecrolimus cream 1%) are anti-inflammatory agents approved by the FDA as second-line agents for the “short term and non-continuous chronic treatment of AD in non-immunocompromised individuals who have failed to respond adequately to other topical prescription treatments for atopic dermatitis, or when those treatments are not advisable.”8-10 The most commonly reported adverse events with TCIs are skin reactions including stinging and burning.8-10 A black box warning regarding the long-term risk of cancer (eg, skin malignancy and lymphoma) is included in the product labeling.8-10 TCIs may be preferred to TCSs in specific clinical situations (ie, steroid resistance, involvement of sensitive areas such as face, anogenital region, and skin folds, steroid-induced atrophy, and long-term and continuous use of TCSs).8 In addition, TCIs are recommended as steroid-sparing agents for AD management.8

If TCSs are co-administered with TCIs, TCSs are usually administered first to control flares (TCSs have greater potency than TCIs) and reduce skin reactions associated with TCIs.8 TCIs can be added as steroid-sparing agents and for the prevention of disease relapse.8

Topical phosphodiesterase inhibitors (TPIs) are mentioned as investigational anti-inflammatory drugs in the 2014 AAD guideline.8 This guideline predated FDA approval for crisaborole, a TPI agent.8 The 2018 consensus-based European guideline on AD highlights that crisaborole (currently not approved in Europe) was more efficacious than its vehicle in clinical trials including patients 2 years of age and older with mild to moderate AD; however, the efficacy of crisaborole compared with TCSs or TCIs is difficult to establish.21

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(3) Systemic immunomodulatory agents (eg, cyclosporine, azathioprine, methotrexate, and mycophenolate mofetil) and/or phototherapy (if feasible) are recommended in patients with AD resistant to conventional topical therapy (eg, moisturizers, TCSs, and TCIs).11 Dupilumab is an additional treatment option for these patients. This agent is an interleukin-4 receptor alpha antagonist that was approved in 2017 for “the treatment of adult patients with moderate-to-severe atopic dermatitis whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable.”29 Table 3 includes guideline recommendations for AD treatment.

Table 3. Clinical Practice Guideline Recommendations for the Treatment of Atopic Dermatitis Guideline (Sponsoring

Organization, Year) Recommendations

Guidelines of Care for the Management of Atopic Dermatitis: Part 2: Management and Treatment of Atopic Dermatitis with Topical Therapies (AAD; 2014)8

- Topical agents are the backbone of AD therapy - In more severe cases, systemic agents or phototherapy are usually used in

combination with topical agents - Non-pharmacological interventions:

o Topical moisturizers with emollient, occlusive, and/or humectant ingredients. Moisturizers are the mainstay in mild AD, should be part of the regimen in moderate to severe AD, and are important in the maintenance treatment and prevention of flares

o Bathing practices, including additives o Wet wrap therapy

- TCS for both adults and children are “the mainstay of anti-inflammatory therapy” and are recommended for AD if patients do not respond to good skin care and repeated use of moisturizers alone

- TCIs (tacrolimus and pimecrolimus) “are recommended and effective for acute and chronic treatment, as well as maintenance, in both adults and children with atopic dermatitis, and are particularly useful in selected clinical situations.” TCIs are recommended in “actively affected areas as a steroid-sparing agent”

- Topical antistaphylococcal treatments are not recommended - Bleach baths and intranasal mupirocin are recommended for patients with

moderate to severe AD and bacterial infection - Topical antihistamines are not recommended in AD

Guidelines of Care for the Management of Atopic Dermatitis: Part 3: Management and Treatment with Phototherapy and Systemic Agents (AAD; 2014)11

- Phototherapy is recommended for acute and chronic AD in children and adults after failure of non-pharmacologic interventions (eg, moisturizers), topical therapies (TCS and TCI), and trigger avoidance

- Systemic immunomodulatory agents (eg, cyclosporine, azathioprine, methotrexate, and mycophenolate mofetil) are usually recommended for moderate to severe AD and in patients with greatly affected QoL. Systemic agents are used when moisturizers, TCS, TCI, adjunctive methods, and/or phototherapy have failed

- Systemic antihistamines and systemic antimicrobials may be beneficial for specific situations

The Joint Task Force on Practice Parameters on Atopic Dermatitis (AAAAI, ACAAI, and the JCAAI; 2012)23

First-line management and treatment: - Skin hydration with warm soaking baths and moisturizer. Moisturizers are

recommended as first-line therapy - TCS: TCS are recommended if AD is not well-controlled with moisturizers - TCI: the use of topical tacrolimus or topical pimecrolimus should be considered for

AD. Topical tacrolimus, “unlike topical steroids, does not cause atrophy for eczema on the face, eyelid, and skin folds that is unresponsive to low-potency topical steroids”. Topical pimecrolimus cream “safely decreases the number of flares,

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Table 3. Clinical Practice Guideline Recommendations for the Treatment of Atopic Dermatitis Guideline (Sponsoring

Organization, Year) Recommendations

reduces the need for corticosteroids, does not cause skin atrophy, and controls pruritus”

- Tar preparations are extensively used in AD, although no RCTs are available. Tar should not be recommended for acutely inflamed skin due to the potential for skin irritation

- Topical antihistamines are generally not recommended due to the potential for cutaneous sensitization; however, some patients may benefit

- Vitamin D may be helpful, especially in patients with low concentration or low intake of vitamin D

- Dilute bleach baths should be considered to diminish severity of AD, particularly in patients with recurrent infections

Intensification of management and treatment (eg, severe AD): wet dressings, hospitalization, phototherapy, systemic immunologic or anti-inflammatory therapies

Consensus-based European guidelines for treatment of atopic eczema (atopic dermatitis) in adults and children: part I (EDF, EADV, EAACI, ETFAD, EFA, ESPD, GA2LEN, UEMS; 2018)21

Adults: - Baseline (Basic therapy): “Educational programs, emollients, bath oils, avoidance of

clinically relevant allergens (encasings, if diagnosed by allergy tests)” - Mild (SCORAD <25 or transient eczema): “Reactive therapy with topical

glucocorticosteroids class II or depending on local cofactors: topical calcineurin inhibitors, antiseptics including silver, silver coated textiles”

- Moderate (SCORAD 25-50 / or recurrent eczema): “Proactive therapy with topical tacrolimus or class II or III topical glucocorticosteroids, wet wrap therapy, UV therapy (UVB 311 nm), psychosomatic counseling, climate therapy

- Severe (SCORAD >50 / or persistent eczema): “Hospitalization; systemic immunosuppression: cyclosporine A, short course of oral glucocorticosteroids, dupilumab, methotrexate, azathioprine, mycophenolate mofetil; PUVA; alitretinoin

Children: - Baseline (Basic therapy): same as adults - Mild (SCORAD <25 or transient eczema): same as adults - Moderate (SCORAD 25-50 / or recurrent eczema): same as adults - Severe (SCORAD >50 / or persistent eczema): “Hospitalization, systemic

immunosuppression: cyclosporine A, methotrexate, azathioprin, mycophenolate mofetil”

Guideline on Atopic Dermatitis; NICE 2013

Mild AD: Emollients, mild-potency TCS Moderate AD: Emollients, moderate-potency TCS, TCI, bandages Severe AD: Emollients, potent TCS, TCI, bandages, phototherapy, systemic therapy

Abbreviations: AAAAI, American Academy of Allergy, Asthma & Immunology; AAD, American Academy of Dermatology; ACAAI, American College of Allergy, Asthma & Immunology; AD, atopic dermatitis; EAACI, European Academy of Allergy and Clinical Immunology; EADV, European Academy of Dermatology and Venereology; EDF, European Dermatology Forum; EFA, European Federation of Allergy and Airways Diseases Patients’ Associations; ESDaP, European Society for Dermatology and Psychiatry; ESPD, European Society of Pediatric Dermatology; ETFAD, European Task Force on Atopic Dermatitis; GA2LEN, Global Allergy and Asthma European Network; IFN, interferon; JCAAI, Joint Council of Allergy, Asthma and Immunology; NICE, National Institute for Health and Care Excellence; PUVA, psoralen and ultraviolet A; QoL, quality of life; SCORAD, Scoring Atopic Dermatitis; TCI, topical calcineurin inhibitors; TCS, topical corticosteroids; UEMS, European Union of Medical Specialists; UVB, ultraviolet B

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Expert Opinion Recommendations An article published by Eichenfield et al in 2015 suggested a treatment management plan for pediatricians and other primary care providers treating patients with AD (see Table 4).24 This plan was based on the 2012 AAAI and ACAAI practice parameter, the 2014 AAD guideline, and the 2012 European Dermatology Forum (EDF) guideline.24

Table 4. Management Plan of Atopic Dermatitis (All Age Groups) for Primary Care Providers24 Mild Atopic Dermatitis Moderate to Severe Atopic Dermatitis

Basic Management: - Proper skin care: moisturizers and warm

baths or showers followed by moisturizers

- Antiseptic measures (ie, dilute bleach baths)

- Trigger avoidance

Maintenance Therapy: moisturizers

Basic Management PLUS:

Maintenance TCI:

- Tacrolimus or pimecrolimus

AND/OR

Maintenance TCS:

- Medium potency TCS (except for face and eyes) AND/OR

- Low potency TCS (face and eyes included)

Acute treatment for flaresa: low potency TCS; sometimes medium potency TCS can be used

Relapsing AD (“frequent/persistent flares”): administer topical anti-inflammatory agents “at first signs/symptoms or to flare-prone areas”

Acute treatment for flaresa: medium potency TCS. If flares are not resolved within 7 days, consider nonadherence, infection, misdiagnosis, or referral

Abbreviations: TCI, topical calcineurin inhibitors; TCS, topical corticosteroids a A flare is defined as an “acute worsening of symptoms necessitating escalation in treatment”

Eichenfield et al state that the selection of TCIs over TCSs depends on patient or provider preferences, medication accessibility, location of eczema (the use of TCSs in face and eyes should be restricted), and efficacy and safety of a specific agent.24

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Crisaborole for the Treatment of Mild to Moderate Atopic Dermatitis Crisaborole is a topical formulation administered twice daily. It inhibits the enzyme PDE-4 causing an increase in the levels of intracellular cyclic adenosine monophosphate (cAMP).1,7 Although the mechanism of action of crisaborole in AD is not fully characterized, it is believed that PDE-4 inhibition decreases the production of pro-inflammatory cytokines and controls the inflammation triggered in AD.1,2

Information from the FDA-approved Eucrisa label is summarized in Table 5.

Table 5. Crisaborole Prescribing Information1

FDA-Approval Date December 2016

Preparations Ointment (2%)

Mechanism of Action PDE-4 inhibitor

Indication “Topical treatment of mild to moderate atopic dermatitis in patients 2 years of age and older”

Dosage Apply twice daily to affected areas

Warnings Hypersensitivity reactions

Contraindications Patients with hypersensitivity to crisaborole or other ingredients of the formulations

Common Adverse Reactions

Dermatologic effects:

• ≥1%: Application site pain (crisaborole 4% vs. vehicle 1%) • <1%: Contact urticaria • Incidence unknown: Hypersensitivity reaction

Abbreviations: PDE, phosphodiesterase

Safety

The most common adverse reactions occurring in 1% of patients or greater include skin sensations such as burning and stinging at the application site.1 Contact urticaria was reported in less than 1% of patients.1

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Clinical Trial Evidence Appendix B outlines the efficacy and safety results from the main clinical trials with crisaborole.

Crisaborole ointment, 2% was FDA approved based on 2 identical 28-day pivotal trials (AD-301 and AD-302) including patients with mild to moderate AD.3 The following criteria were required for patients to enter these trials6:

• Patient is 2 years of age or older

• Clinical diagnosis of AD according to Hanifin and Rajka criteria

• Investigator’s Static Global Assessment (ISGA) score of 2 (mild AD) or 3 (moderate AD) at baseline

• At least 5% of BSA affected by AD (excluding scalp)

Several medications were prohibited during the trials including systemic medications (eg, oral corticosteroids or immunosuppressive agents) and other topical medications (eg, TCSs and TCIs).30

Regarding baseline characteristics, patients were between 2 to 79 years old with approximately 85% of patients between 2 and 17 years old.3 Around 40% of patients had mild AD (ISGA=2) and 60% had moderate AD (ISGA=3) at baseline.3 The mean percentage of BSA affected by AD was 18 to 19% (range 5% to 95%).3,30

The primary efficacy endpoint was the percentage of patients achieving success in ISGA at day 29 in the group treated with crisaborole compared to the vehicle group.6 Success in ISGA was defined as “a score of 0 (clear) or 1 (almost clear) with at least a 2-grade improvement from baseline.”6 ISGA is a 5-point rating scale that evaluates the severity of erythema, induration/papulation, and oozing/crusting.6 Scores range from 0 (clear) to 4 (severe). Clinical definitions for each ISGA score are described in Table 6.

Table 6. Investigator’s Static Global Assessment (ISGA) Scores and Definitions30 Grade (Score) Definition

Clear (0) - “Minor residual hypo/hyperpigmentation” - Erythema, induration/papulation and oozing/crusting: Absent

Almost clear (1) - “Trace faint pink erythema” - Induration/papulation: hardly perceptible - Oozing/crusting: absent

Mild (2) - Minimal pink erythema - Induration/papulation: mild - Oozing/crusting: absent

Moderate (3) - Pink-red erythema - Induration/papulation: moderate - Oozing/crusting: present or absent

Severe (4) - “Deep or bright red erythema” - Induration/papulation and oozing/crusting: severe

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The 2 pivotal trials showed a significantly higher percentage of patients achieving ISGA of 0 or 1 (with ≥ 2-grade improvement from baseline) at day 29 in the crisaborole group compared to vehicle group (Trial AD-301: 33% vs. 25%, Trial AD-302: 31% vs. 18%).3,30 The FDA reviewer highlighted in the Clinical Review that “…although the effect size is modest, it is clinically meaningful for patients seeking an alternative to chronic/intermittent treatment with topical corticosteroids.”30 In addition, significantly better outcomes at day 29 were reported with crisaborole compared to vehicle for all the secondary and exploratory endpoints (ie, time to reach success in ISGA, percentage of patients with ISGA of 0 or 1 at day 29, percentage change in severity of AD signs from baseline, and percentage of patients achieving improvements in pruritus and clinical signs of AD [erythema, exudation, excoriation, induration, and lichenification]).3 The safety profile of crisaborole was favorable.3 Application site pain was reported as the most common adverse event and hypersensitivity or contact urticaria was considered the most significant risk associated with the use of crisaborole ointment.6 The FDA reviewer considered crisaborole ointment 2% as an effective option for the treatment of AD without the long-term safety concerns associated with TCSs and TCIs.30

An additional study evaluated the long-term safety (up to 48 weeks) of crisaborole ointment 2% in patients with mild to moderate AD.31 Results showed a low incidence of treatment-related adverse events (TRAE).31 The most common TRAEs were dermatitis atopic, application site pain, and application site infection.31

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Utah Medicaid Utilization Data Utilization data for crisaborole for the last 3 years (January 2016 to December 2018) is presented as follows:

A. Total pharmacy data for fee-for-service (FSS) patients from January 2016 to December 2018

Table 7. Total FFS Pharmacy Data for Crisaborole (2016-2018)

Agent Brand name 2016 2017 2018 Total

Claims Patients Claims Patients Claims Patients Claims Patients

Crisaborole Eucrisa Ointment 2% 0 0 23 17 33 26 56 39

B. Total pharmacy data for accountable care organization (ACO) patients from January 2016 to December 2018

Table 8. Total ACO Pharmacy Data for Crisaborole (2016-2018)

Agent Brand name 2016 2017 2018 Total

Claims Patients Claims Patients Claims Patients Claims Patients

Crisaborole Eucrisa Ointment 2% 0 0 5 5 59 37 64 40

C. Age distribution of patients for whom there were claims for crisaborole (only FFS patients from 2016 to 2018)

Table 9. Age Distribution for FFS Patients Receiving Crisaborole (2016-2018)

Age Unique Patients <18 28

18-64 11

01020304050

<18 18-64

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Discussion Topics and Potential Prior Authorization Criteria for Crisaborole The following prior authorization (PA) criteria may be considered for crisaborole:

- Patient is 2 years old or older

- Documentation for diagnosis of mild to moderate atopic dermatitis

o Currently, there is not a standard assessment tool to evaluate AD severity or laboratory tests confirming disease severity. The 2014 AAD guideline lists several rating scales, including EASI, SCORAD, IGA, and SASSAD severity score, to determine severity of AD or efficacy of treatment. However, these rating scales are not recommended by the AAD in routine clinical practice because they were designed for use in clinical trials.13 American guidelines for the management of AD do not specifically define mild, moderate, and severe AD. According to Eichenfield et al (2015), mild disease typically affects less BSA, is more likely to resolve, has less intense itching, and responds to basic management alone.24,25 Moderate to severe disease often affects larger BSA, lasts longer, has more severe pruritus, and requires additional maintenance therapy24

o Clinical trials with crisaborole selected patients with mild to moderate AD based on the Investigator’s Static Global Assessment (ISGA) scale. An ISGA score of 2 was considered as mild AD and ISGA score of 3 was moderate AD. Table 6 includes the clinical definitions for each ISGA score

- If a requirement of trial and failure of a certain number of agents is considered for eligibility, the following points may be taken into consideration:

o Good skin care and frequent administration of moisturizers are the non-pharmacological interventions recommended as first-line for patients with mild AD and as part of the management plan for moderate to severe AD. Patients not responding to these non-pharmacological interventions should receive topical pharmacological interventions such as TCSs and TCIs according to treatment guidelines published before the approval of crisaborole. Failure to respond to good skin care and frequent administration of moisturizers may be considered as a PA criterion

o TCSs are the mainstay of anti-inflammatory therapy in AD. TCIs are approved as second-line agents for the “short term and non-continuous chronic treatment of AD in non-immunocompromised individuals who have failed to respond adequately to other topical prescription treatments for atopic dermatitis, or when those treatments are not advisable.”8-10 However, the 2014 AAD guideline highlights that TCIs may be preferred over TCSs in specific clinical situations. Crisaborole is an alternative treatment for the management of mild to moderate AD; however, its place in therapy versus TCSs and TCIs has not been established

Re-authorization criteria

- Re-authorization approval may be established based on disease control and clinical improvements (eg, reduction of affected BSA, improvements in severity of eczematous lesions, and decrease in pruritus severity) with crisaborole therapy

- Clinical trials showed significant efficacy results with crisaborole therapy compared to vehicle at day 29

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Summary Crisaborole is a non-steroidal PDE-4 inhibitor approved for the treatment of mild to moderate AD in patients 2 years of age and older. Guidelines recommend the application of topical moisturizers as first-line therapy for mild AD and as part of management plans for moderate to severe AD. In patients not responding to proper skin care and frequent administration of moisturizers, the use of TCSs and/or TCIs are recommended. TCSs are the mainstay of anti-inflammatory therapy in AD and TCIs are approved as second-line agents for patient with AD “who have failed to respond adequately to other topical prescription treatments for AD or when those treatments are not advisable.”8-10 TCIs may be preferred over TCSs in specific clinical situations (eg, steroid resistance, steroid-induced atrophy, involvement of sensitive skin areas, and long-term use of TCSs). Crisaborole is an additional option for the management of mild to moderate AD; however, its place in therapy compared to TCSs or TCIs has not been established. For patients with AD resistant to conventional topical therapy, phototherapy or systemic agents should be considered.

In clinical trials, crisaborole ointment, 2% demonstrated greater efficacy compared to the ointment vehicle based on the percentage of patients achieving success in ISGA (ie, an ISGA score of 0 or 1 with at least a 2-grade improvement from baseline) at day 29. Safety profile appeared favorable with application site pain as the most frequent adverse reaction.

Utilization data for crisaborole documented that 39 FFS patients received this product in 2017 and 2018. Among them, 70% were pediatric patients.

Prior authorization criteria may include FDA approved indication and dosage, confirmation for diagnosis of mild to moderate AD, and failure to respond to frequent administration of moisturizers alone.

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8. Eichenfield LF, Tom WL, Berger TG, et al. Guidelines of care for the management of atopic dermatitis: section 2. Management and treatment of atopic dermatitis with topical therapies. Journal of the American Academy of Dermatology. 2014;71(1):116-132.

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26. Severity scoring of atopic dermatitis: the SCORAD index. Consensus Report of the European Task Force on Atopic Dermatitis. Dermatology (Basel, Switzerland). 1993;186(1):23-31.

27. Hanifin JM, Thurston M, Omoto M, Cherill R, Tofte SJ, Graeber M. The eczema area and severity index (EASI): assessment of reliability in atopic dermatitis. EASI Evaluator Group. Experimental dermatology. 2001;10(1):11-18.

28. Futamura M, Leshem YA, Thomas KS, Nankervis H, Williams HC, Simpson EL. A systematic review of Investigator Global Assessment (IGA) in atopic dermatitis (AD) trials: Many options, no standards. Journal of the American Academy of Dermatology. 2016;74(2):288-294.

29. Dupixent (dupilumab) injection, for subcutaneous use [package insert]. Bridgewater, NJ: Sanofi-aventis U.S. LLC.; Revised October 2018.

30. McCord, M. Center for Drug Evaluation and Research (Application Number: 207695Orig1s000). Medical Review. Eucrisa (crisaborole) ointment 2%. November 11, 2016. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2016/207695Orig1s000MedR.pdf. Accessed January 3, 2018.

31. Eichenfield LF, Call RS, Forsha DW, et al. Long-term safety of crisaborole ointment 2% in children and adults with mild to moderate atopic dermatitis. Journal of the American Academy of Dermatology. 2017;77(4):641-649.e645.

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Appendix A: Literature Search Strategies

Table 1. Cochrane Library Search Strategy Search Date: January 01, 2019 #1 MeSH descriptor: [Dermatitis, Atopic] this term only 1518 #2 (crisaborole):ti,ab,kw (Word variations have been searched) 30 #3 (atopic dermatitis):ti,ab,kw (Word variations have been searched) 3030 #4 #1 OR #3 3030 #5 #4 AND #2 30 trials and 0 Cochrane Reviews

Table 2. Ovid Medline Literature Search Strategy for Systematic Reviews Database: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily <1946 to January 09, 2019> Search Strategy: -------------------------------------------------------------------------------- 1 crisaborole.ti,ab,kw,kf. (54) 2 eucrisa.ti,ab,kw,kf. (3) 3 atopic dermatitis.ti,ab,kw,kf. (18514) 4 Dermatitis, Atopic/ (18285) 5 1 or 2 (54) - Agent 6 3 or 4 (24821) - Indication 7 5 and 6 (48) - Agent and indication 8 Meta-Analysis/ (95977) 9 (metaanaly$ or meta-analy$).ti,ab,kw,kf. (141668) 10 (cochrane$ or systematic review?).jw. (16175) 11 (systematic adj3 review).ti,ab,kw,kf. (129705) 12 (MEDLINE or systematic review).tw. or meta analysis.pt. (229451)a 13 8 or 9 or 10 or 11 or 12 (277413) - Systematic review filter 14 7 and 13 (1)b – Total number of potential systematic reviews a Search filter for “Reviews” (Maximizes specificity) in Ovid Medline from McMaster University (https://hiru.mcmaster.ca/hiru/hiru_hedges_medline_strategies.aspx) b The article identified in Ovid Medline was a post-hoc pooled analysis from 4 phase 1 and phase 2 trials. Results from this analysis were not included in this report

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Appendix B: Key Findings in Published Clinical Trials

Table 1. Main Clinical Trials With Crisaborole Reference/

Clinical Study

Study Design/ Intervention Participants/

Study Duration

Results for Efficacy/Safety Endpoints

Paller, 20163

(AD-301, AD-302)

2 identical multicenter randomized, double-blind, vehicle-controlled phase 3 clinical studies (AD-301 and AD-302) Crisaborole 2% topical ointment BID for 28 days vs. vehicle

Patients ≥2 years with mild or moderate AD based on ISGA score Study duration: 28 days

Primary endpoint: % of patients achieving ISGA of clear (0) or almost clear (1) with ≥ 2-grade improvement from baseline at day 29 • AD-301 study: CRI 32.8% vs VEH 25.4%;

p = 0.038 • AD-302 study: CRI 31.4% vs VEH 18.0%;

p < 0.001

Secondary endpoint: % of patients achieving ISGA 0 or 1 • AD-301 study: 57.1% vs. 40.6%; p<0.001 • AD-302 study: 48.5% vs. 29.7%; p<0.001

Eichenfield, 201731

(AD-303)

Multicenter, open-label, 48-week safety study Patients continued treatment with crisaborole after finishing the 28-day phase 3 studies (AD-301 and AD-302)

Patients ≥2 years with mild or moderate AD Study duration: 48 weeks

48-week safety results: • Most patients experienced mild to moderate

TEAEs • 93.1% TEAEs were unrelated to treatment • Most common treatment-related AEs

(10.2%): o Dermatitis atopic (3.1%) o Application-site pain (2.3%) o Application-site infection (1.2%)

Abbreviation: AD, atopic dermatitis; AE, adverse events; CRI, crisaborole; ISGA; Investigator’s Static Global Assessment; TEAE, treatment-emergent adverse events; VEH, vehicle