Advances in Management of Moderate to Severe Atopic … · 2019. 9. 3. · AD correlates with...

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Provided by Integrity Continuing Education, Inc.Supported by an educational grant from Sanofi Genzyme and Regeneron Pharmaceuticals.

Advances in Management of Moderate to Severe Atopic Dermatitis in Children and Adolescents

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Faculty and Affiliation

Michael S. Blaiss, MDClinical Professor of

PediatricsMedical College of Georgia

Augusta UniversityAugusta, Georgia

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Faculty Disclosures

Michael S. Blaiss, MDConsulting Fees:Sanofi Regeneron Pharmaceuticals Inc.

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Learning Objectives

Accurately diagnose and assess severity of disease in children and adolescents with atopic dermatitis (AD)

Utilize guidelines to design treatment plans for patients with AD based on disease severity

Identify patients with AD who are inadequately controlled on topical therapy and are candidates for treatment with biologic therapy

Discuss efficacy and safety of biologic therapies for the management of patients with AD and considerations for their use

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Burden of Pediatric AD

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Prevalence of AD in Children

9%–18% in the US1

~20% worldwide2

85% of cases present before 5 years of age3

30% of childhood cases persist into adult years3

AD often the first sign of long-term disease continuum4

– 60% develop asthma or allergic rhinitis later in life

– ~30% develop food allergies

1. Shaw TE, et al. Health J Invest Dermatol. 2011;131:67-73. 2. Nutten S. Ann Nutr Metab. 2015;66(Suppl 1):8-16. 3. Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. 4. Hill DA, Spergel JM. Ann Allergy Asthma Immunol. 2018;120:131-137.

The Atopic March

Dens

ity o

f Dis

ease

0 to 5 6 to 11 12 to 17 18 to 23 24 to 29 30 to 35 36 to 41 42 to 47 48 to 53 54 to 59

At a Diagnosis (mo)

0.8

0.6

0.4

0.2

0

Atopic dermatitisFood allergyAsthmaAllergic rhinitis

Figure adapted from: Ann Allergy Asthma Immunol. 2018;120:131-137.

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AD: Psychosocial/Health-Related Burden

Detrimental to QOL1,2

• Heavy psychosocial impact– Due to stigma, isolation, embarrassment, bullying,

unpredictability of flares

• Suicidal ideation reported by ~20% with severe disease3

• Negative impact on academic performance2

Infections• AD leads to invasive infections, including

eczema herpeticum, septicemia, osteomyelitis, and skin abscesses4

QOL, quality of life.

AD patient infected with eczema herpeticum. Photo courtesy of Peck Y. Ong, MD

1. Simpson EL. J Am Acad Dermatol. 2016;74:491-498. 2. Drucker AM. J Invest Dermatol. 2017;137:26-30. 3. Kimata H. Suicide Life Threat Behav. 2006;36:120-124. 4. Sun D, Ong PY. Immunol Allergy Clin North Am. 2017;37:75-93.

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AD: Psychosocial/Health-Related Burden

Negative effect on QOL1• Negative impact on sleep (mostly due to pruritus) in 47%–60%

of children2• Itching lasts ≥18 hours in ~42% of patients2• Leads to excessive daytime sleepiness, fatigue, reduced HRQOL• Study of 92,642 children found those with AD had significantly

increased risk for ADHD, depression, anxiety, conduct disorder, and autism3

Heavy care/financial burden for parents, caregivers• ~40% of parents/caregivers report interrupted sleep

>3×/week due to child’s AD4• Patients average 9 flares/year, each lasting ~15 days5• Out-of-pocket expenses for families estimated to be

approximately 35% of expendable income in the month before an office visit6

ADHD, attention deficit hyperactivity disorder; HRQOL, health-related quality of life.1. Simpson EL, et al. J Am Acad Dermatol. 2016;74:491-498. 2. Chang YS, Chiang BL. Int J Mol Sci. 2016;174:462. 3. Yaghmaie P, et al. J Allergy Clin Immunol. 2013;131:428-433. 4. National Eczema Association Caregiver Survey. https://nationaleczema.org/in-your-words-survey-series/. 5. Zuberbier T. J Allergy Clin Immunol. 2006;118:226-232. 6. Filanovsky MG, et al. J Pediatr. 2016;169:284-290.

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AD Mental Health Comorbidities

Common psychological comorbidities include1-3

– Anxiety– Depression– Poor self-image– ADHD– Behavioral/conduct problems

In GINIplus, children whose AD appeared to resolve in 1st or 2nd year of life still had emotional/behavioral difficulties by 10 years of age4

1. Brunner PM, et al. J Invest Dermatol. 2017;137:18-25. 2. Yaghmaie P, et al. J Allergy Clin Immunol. 2013;131:428-433. 3. Paller A, et al. Am J Clin Dermatol. 2018;19:821-838. 4. Schmitt J, et al. J Allergy Clin Immunol. 2010;125:404-410.

GINIplus, German Infant Nutrition Intervention plus.

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More Than Skin Deep: AD Comorbidities

Referred to as “atopic march,” comorbidities recognized as components of AD disease continuum usually begin early in life1

Systemic immune activation underlying AD correlates with common noncutaneous comorbidities2– Allergic rhinitis, asthma, conjunctivitis,

eosinophilic esophagitis The prevalence of food allergy increases

with AD severity in children– Approximately 40% of children with

moderate/severe AD have ≥1 food allergy compared with 8% in the general pediatric population3

1. Brunner PM, et al. J Invest Dermatol. 2017;137:18-25. 2. Vernon N, et al. Allergy Asthma Proc. 2014;35:409-414. 3. Silverberg NB, et al. Cutis. 2016;97:227-232.

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Diagnosis and Severity Assessment

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Diagnostic Criteria for AD

AD is currently diagnosed based on history and clinical presentation– Personal or family history of atopy is a risk factor– Biomarkers not specific enough to confirm diagnosis or assess severity

IgE, immunoglobin E.

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22; Eichenfield LF, et al. J Allergy Clin Immunol. 2017;139:S49-S57.

Essential (must be present)

• Pruritus• Eczema (acute, subacute, chronic)• Morphology: typical or atypical?• Age-specific patterns:

– Infants and children: facial, neck, extensor involvement

– Any age: current or previous flexural lesions; sparing of groin and axillary regions

• History: chronic or relapsing

Important(supports diagnosis)

• Early age of onset• Atopy• Personal and/or

family history• IgE reactivity• Xerosis

Differential/Exclusion Diagnoses(dermatologic manifestations of

alternate or concomitant diagnoses)

• Seborrheic dermatitis• Contact dermatitis (allergic or

irritant)• Scabies• Immunodeficiencies• Ichthyoses• Psoriasis• Photosensitivity dermatoses• Cutaneous T-cell lymphoma• Erythroderma of other causes

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Visual Representations of Moderate to Severe Pediatric AD

Xerosis Ill-defined erythema Papules, edema Erosions,

excoriations Oozing, crusting Lichenification Generally spares axillae and groin

Eichenfield LF, et al. J Am Acad Dermatol. 2014;70:338-351.

Photos courtesy of Mark Boguniewicz, MD, and Sheila F. Friedlander, MD.

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Clinical Features in Darker Skin Types

Erythema may be difficult to see Follicular accentuation Hypopigmentation Grayish-white skin discoloration (“ashy skin”)

Siegfried EC, et al. J Clin Med. 2015;4:884-917.

Photos courtesy of Mark Boguniewicz, MD, and Sheila F. Friedlander, MD.

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Distribution Patterns Vary with Age

InfantsForehead, cheeks,

and chin; trunk (except diaper area);

extensor surfaces

Young ChildrenFace, neck,

antecubital/popliteal fossae, wrists, ankles

AdolescentsPeriorbital area, neck, extensor surfaces, antecubital/popliteal

fossae, wrists, hands, ankles, feet

Simpson EL, et al. Semin Cutan Med Surg. 2016;35:S84-S88.

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Other Diseases Can Look Like AD

Photos courtesy of Sheila F. Friedlander, MD.

Contact Dermatitis (both photos) Scabies

AD

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Guidelines

Allergists: AAAAI/ACAAI

Joint Task Force published in

20131

Dermatologists: 4-part series

from AAD published in

20143-6

Simplified, integratedversion merging

recommendations published in 20177

1. Schneider L, et al. J Allergy Clin Immunol. 2013;131:295-299. 2. Eichenfeld LF, et al. Pediatrics. 2015;136:554-565. 3. Eichenfield LF, et al. J Am Acad Dermatol. 2014;70:338-351. 4. Eichenfield LF, et al. J Am Acad Dermatol. 2014;71:116-132. 5. Sidbury R, et al. J Am Acad Dermatol. 2014;71:327-349. 6. Sidbury R, et al. J Am Acad Dermatol. 2014;71:1218-1233. 7. Eichenfield LF, et al. J Allergy Clin Immunol. 2017;139:S49-S57.

Guidelines for assessing and treating

AD come from divergent clinical

perspectives

AAAAI, American Academy of Allergy, Asthma, and Immunology; AAD, American Academy of Dermatology; ACAAI, American College of Allergy, Asthma, and Immunology; PCPs, primary care providers.

AD guidelines designed for

PCPs and pediatricians2

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Testing Options

Test for1:

Secondary bacterial infections with disease

exacerbations

Food allergies for patients

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Severity Assessments

Accurate assessment of disease severity important for optimal treatment

Validated clinical scoring systems are not recommended by guidelines for general clinical use

Disease categorized into “mild,” “moderate,” and “severe” based on clinician assessment– IGA and ISGA scores that rank lesion severity from 0 (clear)

to 4 (severe) are most often used– Validated IGA score (vIGA-AD) recently introduced by

International Eczema Council

IGA, Investigator Global Assessment; ISGA, Investigator Static Global Assessment; vIGA-AD, validated Investigator Global Assessment-Atopic Dermatitis. Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. Validated IGA for atopic dermatitis. http://www.eczemacouncil.org/research/investigator-global-assessment-scale/.

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Severity Scoring in Clinical Practice

Guidelines recommend clinicians ask patients or their parents/caregivers general questions about itch, sleep, impact of disease on daily life– Incorporate patient-friendly scales only when practical

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. Eichenfield LF, et al. J Allergy Clin Immunol. 2017;139:S49-S57.

ItchSleep

Daily Life

At each visit, ask about impact of AD on:

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AD = Altered Epidermal Barrier + Immune Dysregulation

Nonlesional

CLA, cutaneous lymphocyte-associated; IDEC, inflammatory dendritic epidermal cells; IFN, interferon; IL, Interleukin; LC, Langerhans cells; MC, mast cell; MØ, macrophage; Th, T helper cell; TSLP, thymic stromal lymphopoietin. Adapted from: Boguniewicz M, et al. Immunol Rev. 2011;242:233-246.

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Treatment Approaches

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“Yardstick” Guidelines Published in 2018

Developed to reconcile differing recommendations from multidisciplinary guidelines

Emphasis is on practical, step-by-step, “how-to” strategies to ensure clear or almost-clear skin from all levels of severity

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22. 23

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Treatment Goals

Restore barrier integrity Control skin inflammation

and itch Decrease xerosis Treat secondary infection Recognize and prevent triggers Reduce frequency of flares Improve and maintain QOL

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Basic Management: bathing, moisturizers, avoid irritants

Soak for 20 minutes– With or without oatmeal or baking soda – Quickly clean with mild wash

Or Quick 10 min bath Apply occlusive emollient immediately

http://www.google.com/imgres?imgurl=http://common1.csnimages.com/lf/1/hash/1727/1673114/1/Fish+N+Fun+Bath+Toy.jpg&imgrefurl=http://www.csnstores.com/edushape-915018-EDS1086.html&usg=__-UT5Vs7r0N9z04a6m1gEzmpyuMA=&h=400&w=400&sz=31&hl=en&start=9&zoom=1&um=1&itbs=1&tbnid=LvGtWopyfWx1tM:&tbnh=124&tbnw=124&prev=/images?q=children+fun+bath&um=1&hl=en&sa=G&rlz=1T4ADRA_enUS357US359&tbs=isch:1&ei=qJNyTdK3JobNhAfy09Qu

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Basic management: Skin Hydration & Barrier Therapy

Emollients• Improve skin barrier function• Reduce susceptibility to irritants• Adding emollients strengthens skin by delaying intercellular filaggrin

uncoiling• Regular use of topical CS can inhibit epidermal fatty acids synthesis* &

disrupt barrier function• alleviated by application of mixture of ceramides, free fatty acids &

cholesterol**• Support regular use of appropriate emollients

Darsow et al. ETFAD/EADV eczema task force 2009 position paper on diagnosis and treatment of atopic dermatitis. Journal compilation @2009 European Academy of Dermatology and Venereology 2010, 24, 317-328* Jensen JM, Pfeiffer S, Witt M, et al. Different effects of pimecrolimus and betamethasone on the skin barrier in patients with atopic dermatitis.J Allergy Clin Immunol 2009;124(3 Suppl 2):R19–28.** Kao JS, Fluhr JW, Man MQ, et al. Short-term glucocorticoid treatment compromises both permeability barrier homeostasis and stratum corneum integrity:inhibition of epidermal lipid synthesis accounts for functional abnormalities.J Invest Dermatol 2003;120(3):456–64.

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Topical Treatments for Mild Disease

Corticosteroids• TCS usually the first line

of treatment to reduce local inflammation

• Can cause skin atrophy and thinning if used inappropriately (eg, chronic use of high-potency TCS)

• No consensus regarding optimal dosing or frequency

PDE4 Inhibitor

• Crisaborole• Nonsteroidal• FDA approved in 2016,

first new treatment approved for AD in >15 years

• Inhibits cAMP levels • No data yet on

long-term use

Calcineurin Inhibitors

• TCIs: tacrolimus and pimecrolimus

• Nonsteroidal • Approved in 2000–2001• Inhibit

calcineurin-dependent T-cell activation

• No risk of skin atrophy• Use may be impeded

by black-box warning about increased risk for malignancy, despite lack of evidence to date

cAMP, cyclic adenosine monophosphate; FDA Food and Drug Administration; PDE4, phosphodiesterase 4; TCIs, topical calcineurin inhibitors; TCS, topical corticosteroids.Ahmed A, et al. Br J Dermatol. 2018;178:659-662; Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22; Paller AS, et al. J Allergy Clin Immunol. 2017;140:633-643.

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TCIs

Can be applied to face, extremities, and genital area Little systemic absorption Stinging/burning at application site most frequently cited adverse event Not indicated for:

– Children

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PDE4 Inhibition

PDE4 is a key regulator of inflammatory cytokines

Crisaborole 2% ointment, only PDE4 inhibitor approved for AD– Approved for mild to moderate

AD in adults and children ≥2 years Efficacy proven in 2 phase 3 studies

(N=1,522 patients >2 years old) with mild to moderate AD randomized 2:1 to crisaborole or placebo

Primary endpoint: ISGA score of clear (0) or almost clear (1) by day 29 with ≥2 grades improvement from baseline

Paller AS, et al. J Am Acad Dermatol. 2016;75:494-503.

51.748.5

40.6

29.7

0

10

20

30

40

50

60

AD-301 AD-302

Patie

nts w

ith IS

GA

of C

lear

(0)

or A

lmos

t Cle

ar (1

) at D

ay 2

9 (%

)

P=0.005 P

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Step-Care Management: Mild ADAc

ute

Trea

tmen

t

Basic Management1. Skin Care

• Moisturizer, liberal and frequent• Warm baths or showers using non-soap

cleansers, usually 1x/day followed by moisturizer (even on clear areas)

2. Trigger Avoidance• Common allergens and irritants

Basic Management1. Skin Care

• Moisturizer, liberal and frequent • Warm baths or showers using non-soap

cleansers, usually 1x/day followed by moisturizer (even on clear areas)

2. Antiseptic Measures• Dilute bleach bath (or equivalent)

≤2x/week according to severity (especially with recurrent infections)

3. Trigger Avoidance • Patient-specific proven allergens and

irritants• Consider comorbidities

Apply TCS to Inflamed SkinLow-to-medium potency TCS 2x/day for 3-7 days beyond clearance

(consider TCI, crisaborole)

Mai

nten

ance

Tr

eatm

ent

Nonlesional

Mild

Adapted from: Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22.

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Treatments for Moderate to Severe Disease

Systemic Immunosuppression

•Cyclosporine•Methotrexate•Mycophenolate mofetil•Azathioprine•Corticosteroids

Limitations:• All but corticosteroids are off-

label for AD• Not usable for long-term

maintenance because of multiple systemic adverse events

Phototherapy

•Primarily narrow-band UVB

Limitations:• Available only for patients ≥

12 years• Access/convenience (few

phototherapy centers)• Cost and travel time often not

covered by insurance• Very low risk for cutaneous

malignancies and cataracts

Biologics

•Dupilumab, only targeted biologic approved for moderate to severe AD

Limitations:• Currently approved only for

patients ≥12 years• Subcutaneous injection• Too new to be included

in guidelines• No data for optimal ways to

step down or discontinue after clear skin is achieved

UVB, ultraviolet B.

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Moderate

Step-Care Management: Moderate-to-Severe ADAc

ute

Trea

tmen

tM

aint

enan

ce

Trea

tmen

t

Basic Management + Topical Anti-inflammatory Medication

Maintenance TCS• Low potency 1×-2×/day (including face)• Medium potency 1×-2×/day (except face)

OR Maintenance TCIa• 1×-2×/day • 2×-3×/week (not an indicated dose)

OR Crisaborole 2%a• 2×/day

Basic Management + Referral to Specialist

Phototherapy (Not approved for ≤12 years)Dupilumabb (Available for ages ≥12 years)Systemic Immunosuppressants

• Cyclosporine Ac• Methotrexatec• Mycophenolate mofetilc• Azathioprined

Consider acute treatment for some patients• Wet-wrap therapy or hospitalization

Apply TCS to Inflamed SkinMedium-to-high potency TCS 2×/day for 3-7

days beyond clearance (consider TCI, crisaborole)

Adapted from: Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22.

If not resolved in 7 days, considernonadherence, misdiagnosis,

contact allergy to prescription, referral

aIndicated for patients at least 2 years old; bIndicated for patients at least 12 years old; cNot approved by FDA to treat AD; dNot recommended for long-term maintenance.

Severe

Rarely used in children

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Causes for Treatment Failure

Poor understanding of disease– Clinicians, caregivers, patients often unaware AD is

systemic, inflammatory disorder Poor adherence/incorrect medication use

– TCS phobia affects up to 80% of patients and caregivers1 Exacerbating factors/environmental triggers Secondary infection

– Bacterial, viral, dermatophyte Incorrect diagnosis Disease is severe

1. Li AW, et al. JAMA Dermatol. 2017;153:1036-1042.

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Biologic Therapy

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One Approved Biologic Agent: Dupilumab

Fully Human mAb Anti-IL-4Rα targets IL-4 and IL-13 receptor, blocking Th2 cytokine

signaling pathways

Approved as second-line treatment for moderate to severe AD after

topical treatments

Subcutaneous injection approved for patients ≥12 years

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018:120:10-22. Dupilumab (Dupixent®) PI June 2019.

mAb, monoclonal antibody.

Granted FDA approval in March 2017 based on short-term results in SOLO 1 and SOLO 2 trials and long-term

results in CHRONOS AD LIBERTY trial. Approved for adolescents ages 12–17 in March 2019

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Dupilumab Phase 3 Clinical Trials

Safety and efficacy demonstrated in 3 placebo-controlled clinical trials

SOLO 1, SOLO 2Evaluated dupilumab as monotherapy for

16 weeks

LIBERTY AD CHRONOSEvaluated dupilumab in

combination with TCS for 52 weeks

Blauvelt A, et al. Lancet. 2017;389:2287-2303. Simpson EL, et al. N Engl J Med. 2016;375:2335-2348.

Total of 2,119 adults with moderate to severe AD

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Efficacy in Global Assessment

Improvement in IGA Score (primary endpoint)

Adapted from: Simpson EL, et al. N Engl J Med. 2016;375:2335-2348.

0

10

20

30

40

50

60

70

80

SOLO 1 SOLO 2

Perc

enta

ge o

f Pat

ient

s with

Q

ualif

ying

IGA

Scor

e (%

)

Placebo Dupilumab Q2W Dupilumab QW

Investigator Global

Assessment (IGA) scoring system ranks

lesion severity from 0 (clear) to

4 (severe)

Q2W, every other week; QW, every week.

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Efficacy in Reducing Disease Severity

Improvement in EASI-75 Score (secondary endpoint)

Adapted from: Simpson EL, et al. N Engl J Med. 2016;375:2335-2348.

0

10

20

30

40

50

60

70

80

SOLO 1 SOLO 2

Perc

enta

ge o

f Pat

ient

s

Achi

evin

g E

ASI-7

5 (%

)

Placebo Dupilumab Q2W Dupilumab QW

Eczema Area and Severity Index-75

(EASI-75) measures a 75% reduction from

baseline in extent and severity of erythema,

induration, papulation, edema, excoriations,

and lichenification

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Efficacy in Pruritus

Adapted from: Awosika O, et al. Clin Cosmet Investig Dermatol. 2018;11:41-49. Blauvelt A, et al. Lancet. 2017;389:2287-2303.

Patients (%) in phase 3 trials who achievedimprovement of ≥4 points on pruritus NRS

0 10 20 30 40 50 60 70

Week 16 Phase 3 CHRONOS trial


Week 16 Phase 3 SOLO 1 trial


Dupilumab Q2W

Dupilumab QW

Placebo

Dupilumab + TCS Q2W

Dupilumab + TCS QW

Placebo + TCS

NRS, numerical rating scale.

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Efficacy in QOL Improvements

Patients in phase 3 trials who demonstrated improvements in QOL (eg, sleep, anxiety, depression) as indicated by least squares* mean change in dermatology life quality index (DLQI) score

Adapted from: Awosika O, et al. Clin Cosmet Investig Dermatol. 2018;11:41-49; Blauvelt A, et al. Lancet. 2017;389:2287-2303.

-12-10-8-6-4-20





*Least squares incorporate percent change over time, primary analysis, and sensitivity analysis.

Dupilumab Q2W

Dupilumab QW

Placebo

Dupilumab + TCS Q2W

Dupilumab + TCS QW

Placebo + TCS

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Dupilumab: Trial Findings in Safety

Dupilumab found to be highly tolerable in both SOLO 1 and SOLO 2 – Only SAE was exacerbation of AD, reported in 2 patients

in SOLO 1 and 1 patient in SOLO 2• Same SAE experienced by patients taking placebo: 3 in SOLO 1,

5 in SOLO 2

– Other adverse events included infections: ~35% in both trials (non-skin infections: upper respiratory or oral) vs ~30% for those taking placebo

– Injection-site reactions also common: 13%–19% for those injecting the drug weekly vs 6% for placebo

Simpson EL, et al. N Engl J Med. 2016;375:2335-2348.

SAE, serious adverse event.

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Long-Term Efficacy

CHRONOS Study: Patients (%) showing sustained improvement over time in pruritus scores

Adapted from: Blauvelt A, et al. Lancet. 2017;389:2287-2303.

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52Study Week

100

90

80

70

60

50

40

30

20

10

0

18%

37%

59%54%

51%

27%

16%20%

16%

39%

13%8%

Perc

enta

geAc

hiev

ing

≥4 P

oint

s Im

prov

emen

t in

Peak

Pru

ritus

51%

44%

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Phase 3 Trial of Dupilumab in Adolescents

First biologic study of AD in ages 12–17 years (NCT03054428)– 251 patients with moderate to severe disease not controlled by

topicals randomized to dosing every 4 weeks, every 2 weeks, or placebo

– Coprimary endpoints EASI-75 response and IGA score of 0 (clear) or 1 (almost clear)

– Secondary endpoint improvement in pruritus NRS Preliminary phase 3 results presented September 2018 at

EADV showed statistically significant improvement in skin, pruritus, and QOL by week 16– Approval granted for use in ages 12–17 in March 2019

Simpson EL, et al. EADV abstract D3T01.1L. Presented September 15, 2018.

EADV, European Academy of Dermatology and Venereology.

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Phase 3 Dupilumab Trial in Adolescents: Results

17.9

38.1

45.5

24.4

41.5

47.9

2.4 8.2

19

0

10

20

30

40

50

60

IGA EASI-75 Pruritus NRS

Perc

enta

ge

16 Weeks

Q4W Q2W Placebo


Patients Achieving Trial Endpoints

Q4W, every 4 weeks.

45

Phase 3 Dupilumab Trial in Adolescents: Safety

1311

6

11 108.5

20

5 5

0

5

10

15

20

25

Skin Infections Conjunctivitis Injection-Site Reactions

Perc

enta

ge

16 Weeks

Q4W Q2W Placebo


Most Common Adverse Events

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Ongoing/Recruiting Clinical Trials of Dupilumab in Children

Trial Name*/ Number Focus # Pts/Ages Phase

Estimated Completion

NCT02612454† Long-term safety 765

≥6 mos to

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Considerations in Prescribing Dupilumab

Cost and coverage important considerations Method of administration (subcutaneous may be particularly

difficult for children) For insurance to cover, clinicians must document

– Diagnosis of AD (not just “eczema”)– Condition severity– Prior treatments and failures

• Specify the type of failure– Inadequate response to medium or high-potency TCS, suboptimal

improvement, failure to achieve long-term control, unacceptable adverse events

– Impact of disease on QOL

Boguniewicz M, et al. Ann Allergy Asthma Immunol. 2018;120:10-22.

48

Emerging Biologics Being Studied in Adolescents

Agent Name(s)Study ID # (Acronym)

Phase/StatusNo. Pts

Age Range, Study PopulationPrimary Endpoint(s)

IL-13 Inhibitor (subcutaneous)

Tralokinumab NCT03526861ECZTRA 63/Recruiting

29412–17 with moderate/severe ADIGA and EASI-75, baseline to week 16

IL-23 Inhibitor (subcutaneous)

Risankizumab NCT03706040 2/Recruiting155≥12 years with moderate/severe ADEASI-75, baseline to week 16

IL-31 RA (subcutaneous)

Nemolizumab

NCT03985943 3/Recruiting750

≥12 years with moderate/severe ADIGA ≥2 point reduction and EASI-75, baseline to week 16

NCT03989349 3/Recruiting750

≥12 years with moderate/severe ADIGA ≥2 point reduction and EASI-75, baseline to week 16

Source: ClinicalTrials.gov, using filters for “atopic dermatitis eczema,” “phase 2,” “phase 3,” “recruiting,” “active, not recruiting,” and “child (birth‒17)”.

IL, interleukin; RA, receptor antagonist.

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Emerging Small-Molecule Agents Being Studied in Children/Adolescents


Phase/StatusNo. Pts


JAK Inhibitors (Oral)

Abrocitinib (PF-04965842)

NCT03575871JADE Mono-2

3/Recruiting375

≥12 years with moderate/severe ADIGA and EASI-75, baseline to week 12

NCT03796676 JADE TEEN

3/Recruiting225

12–17 years with moderate/severe ADIGA and EASI-75, baseline to week 12

NCT03627767 3/Recruiting1,370≥12 years with moderate/severe ADLOR requiring rescue Tx, week 12 to week 52

NCT03422822 JADE EXTEND

3/Recruiting2,300

≥12 years with moderate/severe ADTEAEs, SAEs, and ∆ from baseline in lab values, ECG, and vital signs, up to 96 weeks

Baricitinib(LY3009104)

NCT03952559 BREEZE-AD-PEDS

3/Recruiting465

2–17 years with moderate/severe AD% achieving ≥2 point IGA improvement, up to 16 weeks; AUC and Cmax, baseline to 2 weeks

∆, change; AUC, area under curve; Cmax, maximum concentration; ECG, electrocardiogram; LOR, loss of response; SAEs, serious adverse events; TEAEs, treatment-emergent adverse events; Tx, treatment.


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Emerging Small-Molecule Agents Being Studied in Adolescents (cont)


Phase/StatusNo. Pts


JAK Inhibitors (Oral)

Ruxolitinib NCT03745638

TRuE AD13/Recruiting

600≥12 years with ADIGA-TS, baseline to week 8

NCT03745651 TRuE AD2

3/Recruiting600

≥12 years with ADIGA-TS, baseline to week 8

Upadacitinib

NCT03661138 3/Active272≥12 years with moderate/severe AD% experiencing AEs up to 141 weeks

NCT03569293Measure Up 1

3/Recruiting810

≥12 years with moderate/severe ADEASI-75 and vIGA with ≥2 grades of reduction, up to 16 weeks

NCT03607422 3/Recruiting810≥12 years with moderate/severe ADEASI-75 and vIGA with ≥2 grades of reduction, up to 16 weeks

NCT03568318AD Up

3/Recruiting810

≥12 years with moderate/severe ADEASI-75 and vIGA with ≥2 grades of reduction, up to 16 weeks

IGA-TS, Investigator Global Assessment Treatment Success.


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Considerations in AD Management

52

Improving Patient Satisfaction

Results from National Eczema Association’s “In Your Words” patient satisfaction survey (N=192) in 2016

Treatment Satisfaction:Overall, are you satisfied with the

treatment of AD?

Physician Satisfaction:Overall, do you think doctors know

how to treat AD?

National Eczema Association Caregiver Survey. https://nationaleczema.org/in-your-words-surveyseries/.

NO(91%)

YES(9%)

NO(86%)

YES(14%)

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Improving Patient Satisfaction (cont)

Participant recommendations from “In Your Words” survey to improve satisfaction– Pay attention to the mental health/QOL impact of AD– Demonstrate understanding that AD is more than just a

skin condition– Treat root cause, not just symptoms– Convey an attitude of caring about the patient– Don’t rely too heavily only on corticosteroids– Quickly recognize when patients should be referred for

more advanced treatments

National Eczema Association Caregiver Survey. https://nationaleczema.org/in-your-words-surveyseries/.

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Shared Decision Making

Expertise

Shared Decision

Healthcare Provider(pediatrician, nurse, NP, PA,

other clinicians)Patient/Caregiver

Diagnosis Treatment options Potential benefits Potential adverse events Treatment expectations

Values Lifestyle preferences

(may include schedule, socioeconomic factors)

Previous experience

Adapted from: Blaiss MS, et al. Ann Allergy Asthma Immunol. 2019;122:463-470.

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Important Patient Education Points

Written treatment

plan increases likelihood of adherence

Moisturize frequently throughout

the day

Topical medications do not take the place of moisturizers

Continue maintenance

therapies even when

skin appearshealthy

AD treatments will not work if they aren’t

used!

Eichenfield LF, et al. Pediatrics. 2015;136:554-565.

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Summary

AD is an inflammatory disease involving immune dysregulation and epidermal barrier breakdown

Disease negatively affects QOL of children and parents/caregivers Diagnosis based on clinical presentation AD leads to multiple comorbidities—even later in life Severity assessments are necessary to determine treatment Multiple treatments available depending on disease severity Systemic immunosuppression not suitable for long-term maintenance and

none approved in children Dupilumab the only biologic thus far available

– Trials show long-term efficacy– Recent phase 3 trial in adolescents yielded positive results

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Thank You!

Advances in Management of Moderate to Severe Atopic Dermatitis in Children and AdolescentsFaculty and AffiliationFaculty DisclosuresLearning ObjectivesBurden of Pediatric AD Prevalence of AD in ChildrenAD: Psychosocial/Health-Related Burden AD: Psychosocial/Health-Related Burden AD Mental Health ComorbiditiesMore Than Skin Deep: AD Comorbidities Diagnosis and Severity AssessmentDiagnostic Criteria for ADVisual Representations of Moderate to Severe Pediatric ADClinical Features in Darker Skin TypesDistribution Patterns Vary with AgeOther Diseases Can Look Like ADGuidelinesTesting OptionsSeverity AssessmentsSeverity Scoring in Clinical PracticeAD = Altered Epidermal Barrier + Immune Dysregulation Treatment Approaches��“Yardstick” Guidelines Published in 2018Treatment GoalsBasic Management: bathing, moisturizers, avoid irritantsBasic management: Skin Hydration & Barrier Therapy�Topical Treatments for Mild DiseaseTCIs PDE4 InhibitionStep-Care Management: Mild ADTreatments for Moderate to Severe DiseaseStep-Care Management: Moderate-to-Severe ADCauses for Treatment FailureBiologic Therapy��One Approved Biologic Agent: Dupilumab Dupilumab Phase 3 Clinical TrialsEfficacy in Global AssessmentEfficacy in Reducing Disease SeverityEfficacy in PruritusEfficacy in QOL ImprovementsDupilumab: Trial Findings in SafetyLong-Term EfficacyPhase 3 Trial of Dupilumab in AdolescentsPhase 3 Dupilumab Trial in Adolescents: ResultsPhase 3 Dupilumab Trial in Adolescents: SafetyOngoing/Recruiting Clinical Trials of Dupilumab in ChildrenConsiderations in Prescribing DupilumabEmerging Biologics Being Studied in AdolescentsEmerging Small-Molecule Agents Being Studied in Children/Adolescents Emerging Small-Molecule Agents Being Studied in Adolescents (cont)Considerations in �AD ManagementImproving Patient SatisfactionImproving Patient Satisfaction (cont)Shared Decision Making Important Patient Education PointsSummaryThank You!

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