6/19/18. Emerging Challenges in Primary Care: Atopic Dermatitis: New Insights, New Therapies. Faculty. Disclosures

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1 Emerging Challenges in Primary Care: 2018 Atopic Dermatitis: New Insights, New Therapies 1 Faculty Brad P. Glick, DO, MPH, FAOCD Director, South Florida Psoriasis Treatment Centers Clinical Assistant Professor of Dermatology FIU Herbert Wertheim College of Medicine Miami, FL Adelaide A. Hebert, MD The University of Texas Professor, Department of Dermatology Director, Pediatric Dermatology Houston, TX Paul S. Yamauchi, MD, Ph.D. Clinical Assistant Professor of Dermatology David Geffen School of Medicine at UCLA Harbor- UCLA Medical Center Division of Dermatology Adjunct Associate Professor John Wayne Cancer Institute Dermatology Institute & Skin Care Center, Inc. Clinical Science Institute Santa Monica, CA 2 Disclosures Brad P. Glick, DO, MPH, FAOCD serves as a speaker, consultant and Investigator for Regeneron and Pfizer. Dr. Glick also serves as a speaker for Sanofi-Aventis. Adelaide A. Hebert, MD serves as a speaker for Pfizer, Amgen, and Valeant. Dr. Hebert also serves on the research grant team for Promins, GSK, Mayne, Sienna, Amgen, Medimetriks, Galderma, and Celgene. Additionally, she serves on the DSMB for GSK and Sanofi-Regeneron. Paul S. Yamauchi, MD, Ph.D. serves as a speaker for Lilly, Novartis, Abbvie, Sanofi, Regeneron, Leo, Celegne, Vanska, and Pfizer. Dr. Yamauchi also serves as an Advisor for Top MD. 33 1

2 Learning Objectives Review and characterize the clinical features of atopic dermatitis (AD) Discuss the current immuno-pathophysiology of AD Identify strategies for comprehensive treatment of atopic dermatitis in pediatric and adult populations Evaluate the clinical application of emerging therapies including topical and targeted biologic agents in the management of AD 4 PRE-TEST QUESTIONS 5 Pre-test ARS Question 1 How confident are you in your ability to manage patients with moderate-to-severe atopic dermatitis? 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 6 2

3 Pre-test ARS Question 2 How often do you use systemic therapy for patients with moderate-to-severe atopic dermatitis? 1.Never 2.Rarely 3.Sometimes 4.Often 5.Always 7 Pre-test ARS Question 3 Approximately how many patients with atopic dermatitis/eczema do you see on a weekly basis, in any clinical setting? 1. None > 20 8 Pre-test ARS Question 4 Which of the following features is a characteristic of atopic dermatitis? 1. Desquamation and plaques 2. Pruritic lesions without pain 3. Follows waxing and waning course 4. Commonly affects palms and soles 9 3

4 6/19/18 Atopic Dermatitis: A Chronic Inflammatory Disease M o s t c o m m o n fo rm o f e c z e m a A ff e c t s t h e f a c e, a r m s, l e g s, t r u n k C h r o n ic r e la p s in g c o u r s e o f p r u r itic a n d p a in fu l le s io n s P a p u la tio n E r y th e m a to u s, s c a ly p a tc h e s S k in b e c o m e s th ic k e n e d ( lic h e n ifie d ) fr o m e x c e s s iv e s c r a tc h in g E x c o r ia tio n s N o t c o n ta g io u s N o p e rm a n e n t c u re F o llo w s a w a x in g a n d w a n in g c o u r s e 1-2 S i g n i f i c a n t l y i m p a i r s q u a l i t y o f l i f e National Eczema3.Association. 2014;150: ; NuttenS. Ahttps://nationaleczem nnnutr Metab. 2015;66(suppl a.org/research/eczem 1): Ea-facts/. ichenfield 2018; LF, et2.al. Margolis JAmAJS cad, etdal. ermja atol. MA2014;71: Dermatol. 10 How Common is Atopic Dermatitis? 17.8 million Americans Starts in early childhood with 65% of children affected by 18 months of age Less than half of the patients have complete resolution by 7 years of age Only 60% have resolution by adulthood 3% of U.S. adults have moderate to severe eczema/atopic dermatitis requiring systemic therapy. Male:Female ratio (1:1.5) Higher incidence in Blacksinand compared to Caucasians U.S.Asians 11 Who Gets Atopic Dermatitis? Usually starts in the first six months of life. Approximately of18 adults had onset after the 20% age of years If one parent has atopic dermatitis, asthma, or hay fever: 60% chance each child will inherit one of these Increases to 80% if both parents are affected Increased prevalence noted in industrialized countries 12 4

5 What Makes Atopic Dermatitis Worse? Stress Food allergies Physical contact or inhaled allergens Weather Dry climate Wind Chemicals Hard water, detergents, solvents Wool or other rough material Skin infections Staphylococcus and streptococcus 13 Comorbidities Associated with Atopic Dermatitis Adjusted Odds Ratio of comorbidities stratified by disease severity in a Commercial population Shrestha S, et al. Adv Ther. 2017;34: Atopic Dermatitis Often Affects More Than the Skin Sleep Disruption 90% had at least 1 night of disrupted sleep per week 50% had at least 5 nights of disrupted sleep per week Burden of Care Time to access care Inconvenience Cost Managing side effects Persistent Itch 69% had itching lasting at least 12 hours a day 69% had severe itching 55% had itching for at least 10 years Psychological Distress 22% had Hospital Anxiety and Depression Scale (HADS) scores suggesting clinically relevant anxiety or depression n=380 patients with moderate-to-severe AD Simpson EL, et al. J AmAcad Dermatol. 2016;74:

6 Quality of Life Simpson dupilumabin Elet adults. al. Patient J AmAcadDermatol. burden of moderate 2016;74: to severe atopic dermatitis (AD): Insights froma phase 2b clinical trial of 16 Disease Severity in Children and Adults with AD Disease Severity in Children and Adults with AD Children 1 (0 to 17 years) National Survey of Children s Health 26% 7% 67% Adults 2-4 ( 18 years) Robust population-based estimates of the prevalence of moderate-to-severe AD in adults are lacking Extrapolation from other reports: Approximately million adults with diagnosed severe AD are receiving treatment 25% of adults with AD do not seek treatment for their condition Mild Moderate Severe 1. Silverberg JI, et al. Dermatitis. 2014;25: ; 2. Silverberg JI, et al. J Allergy Clin Immunol. 2013; ; 3. Silverberg JI, et al. J Invest Dermatol. 2015;135:56-66; 4. Eichenfield LF, et al. J Am Acad Dermatol. 2014;70: ARS Question 5 A 19- year- old woman presents with a chief complaint of eczema on her face, arms, and abdomen. The rashes have a dull red appearance with perceptible elevation and m ild excoriation. The patient says she scratches the rashes frequently and sometimes does not sleep well because of the itching. Using one palm, the clinician estim ates that 8% of her body surface area is affected. What is the best estimate of disease severity in this patient? 1. Mild 2. Moderate 3. Severe 4. Not possible to estimate severity from presented data 18 6

7 Assessing AD Severity in Clinical Practice Current AAD Treatment Guidelines Recommend Asking the Following Questions to Assess the Severity of a Patient s AD How long have you had AD? Is your AD active in bursts or all the time? How has your AD affected you emotionally? How has your AD affected your sleep? How had your AD affected your school or work? How has your AD affected your social life? What are your AD treatment goals? What treatment side effects have you experienced or are concerned about? Eichenfield LF, et al. J AmAcad Dermatol. 2014;70: Assessing Severity of Atopic Dermatitis Imagine 1 palm equal to 1% of your body surface area. Mild : 1-3% Moderate: 3-10% Severe: More than 10% 20 Eczema Area Scoring Index: EASI Scoring System EASI score ranges from

8 Investigator s Global Assessment (IGA) for AD 22 ARS Question 6 Which of the following pathophysiologic mechanisms is the fundamental abnormality underlying atopic dermatitis? 1. Overexpression of TNF alpha 2. Th2/Th22 immune abnormalities 3. Overproduction of IgM in response to allergens 4. Inflammation driving increased keratinocyte turnover 23 Genes and the Environment Influence the Natural History of AD AD is complex and multifactorial, characterized by genetic mutations, immune dysregulation, skin barrier dysfunction, and abnormal itch response Genes linked to AD 1,2 FLG (encodes profilaggrin, a skin barrier protein) CARD11 Genes that encode inflammatory cytokines (eg, IL-4, IL-5, IL-12, IL-13)11 gene Environmental Environmental factors factors (eg, soap, dust Scratching mite) Epigenetic regulation Genetics Barrier Impaired hypothesis: epithelial barrier 70% before 1 year old Skin barrierrelated genes Allergens Staphylococcus aureus AD Non-AD Acquired (IgE dermatitis sensitization Associated) (non-ige Associated) Immunologic hypothesis: Immune 30% before 1 (atopy)- year old related genes ~80% of patients with AD have personal or family history of atopy (elevated IgE) Ma Guttman-Yassky CA, et al. Nat E, Genet. et al. 2017;49: ; Expert Opin Biol Ther ;13: Nutten S. Ann Nutr Metab. 2015;66(suppl 1):8-16; 24 8

9 Immunologic Dysregulation in AD Skin barrier dysfunction and Th2/Th22-deviated immune reactions are the fundam ental abnormality in AD Antigen-m ediated Th2 cell activation leads to cytokine release (e.g., IL-4, IL-13) leading to: Further disruptions in the skin barrier by decreased expression of FLG IL-31 activation of nerve term inals that m ediate itch Increased Th2 differentiation drives inflammation and im m une activation camp=cyclic adenosine monophosphate; FLG=filaggrin gene; IgE=immunoglobulin E; IL=interleukin; PDE4=phosphodiesterase 4; Th2=T helper cell 2; TSLP=thymic stromal lymphopoietin Furue M, et al. Allerg Int. 2017;66: ; Lee DE, et al. J Dermatolog Treat. 2017;19: Mechanisms of Pruritus in AD Pruritus in AD is induced by a variety of histam ine- dependent and independent pruritogens in clu d in g IL - 4, IL- 13, IL- 31 Proteases IL - 31 and nerve growth factors stim ulate an increase in the number of epidermal sensory nerve fibers Novel AD therapies such as IL- 4, IL- 13, and IL- 31 inhibitors exhibit antipruritic properties H1R = histamine receptor type 1; H4R = histamine receptor type 4; JAK = Janus kinase; NK1R = neurokinin 1 receptor Paller AS, et al. J Allerg Clin Immunol. 2017;140: Management of AD Has Historically Focused on Symptom Relief Treatm ent G oals Factors Associated with Poor Prognosis Reduce symptoms (e.g., itch, d e g re e o f skin in vo lve m e n t) Reduce inflammation Reduce frequency and severity of exacerbations Family history of AD Early age of onset Body surface area involved Atopy (flares) Avoid triggers Minimize treatment-related adverse events Follow severity- directed tre a tm e n t Eichenfield LF, et al. J AmAcad Dermatol. 2014;70:

10 Current Guideline-Recommended Approach to AD Treatment Non-pharmacologic Topical Therapy Systemic Agents* Emollients Moisturizers Phototherapy Corticosteroids Calcineurin inhibitors Cyclosporine Azathioprine Methotrexate Mycophenolate mofetil Mild Disease Severity Severe There is a need for practical guidance on the management of patients with moderate-to-severe AD requiring targeted/systemic therapy Eichenfield LF, et al. J AmAcad Dermatol. 2014;70: ; Lynde CCW, et al. J Cutan Med Surg. 2018;22: *not indicated for the treatment of atopic dermatitis published prior to the introduction of the targeted therapies crisaborole and dupilumab 28 Moisturizers Remain the Foundational Treatment of AD Used to combat xerosis and Gels/alcoholbased solutions Lotions Creams tra n se p id e rm a l w a te r lo ss Emollients lubricate and soften skin Occlusive agents prevent evaporation of water Humectrants attract and hold water Data defining the optimal amount or fre q u e n cy o f a p p lica tio n is la ckin g Generally thought that liberal and frequent reapplication is necessary AAD encourages incorporating Ointments patient preference when selecting a moisturizer Eichenfield LF, et al. J AmAcad Dermatol. 2014;70: Siegfried termsafety EC,Jaworski of topical JC,Kaiser corticosteroids JD,Hebert andtopical AA.Systematic calcineurininhibitors reviewof publishedtrials: inpediatric long- patients withatopic dermatitis. BMCPediatr Jun 7;16:75. doi: /s Topical Corticosteroids (TCS) Are Added if Moisturizers and Good Skin Care Fail to Control Symptoms Clas s Representative Steroids Descripti on Recommended Use Safety Clobetasol propionate 0.05% cream, ointment, gel Halobetasol propionate 0.05% cream Fluocinonide 0.1% cream Diflorasone diacetate 0.05% cream Fluocinonide 0.01% ointment Fluocinonide 0.05% cream Desoximetasone 0.05% cream Fluocinolone 0.025% cream Desoximetasone 0.05% cream Triamcinolone acetonide 0.1% cream, lotion Desonide 0.05% foam, gel Triamcinolone acetonide 0.025% cream, ointment Super potent Potent Upper midstrength Refractory lesions Tough-to-treat areas (hands, feet) Mid-strength Most commonly used Lower midstrength Mild 7 Hydrocortisone 2/2.5% cream, lotion Least potent Sensitive areas (face, axillae) Must weigh the risks and benefits when using TCS, particularly high potency agents, including Hypopigment ation Skin atrophy Slowed wound healing Formation of striae Burning or stinging upon application Erythema Edema National Eczema Association. Accessed March 2018; Eichenfield LF, et al. J AmAcad Dermatol. 2014;70:

11 Topical Calcineurin Inhibitors: Steroid Sparing Agents for Sensitive Areas Agent Comparative Efficacy Pimecrolimus 1% cream Comparable to lo w p o te n cy T C S Ta cro lim u s 0.3 % o in tm e n t Superior to pimecrolimus and low potency TCS Ta cro lim u s 0.1 % ointment Superior to ta cro lim u s %, TCIs have a slower onset vs. TCS pimecrolimus, and low potency TCS Equivalent to mid- potency TCS Approved for ages >2 years May cause skin burning and pruritus Label includes a boxed warning for possible risk of cancer No safety signals have been reported following 10 years of monitoring, however patients may express concern TCS=topical corticosteroid; TCI=topical calcineurin inhibitor National Eczema Association. Accessed March 2018; Eichenfield LF, et al. J AmAcad Dermatol. 2014;70: Questions to Consider 32 Treatment Strategies 33 11

12 ARS Question 7 26 y/o overweight woman with 15- yr hx of moderate- to- severe atopic dermatitis, asthma, and allergic rhinitis presents for a checkup Severity of atopic dermatitis is estimated to be 15% BSA with occasional trouble sleeping because of itching. Meds: fluticasone propionate, desloratadine, tacrolimus 0.1%, and moisturizers. Prior therapies include high- potency topical corticosteroids and pimecrolimus. S h e rep o rts g o o d ad h eren ce to th erap y. What might be an appropriate action at this time? 1. Consider initiating systemic therapy 2. Add high- potency steroid to tacrolimus 3. Recommend UVB or PUVA phototherapy 4. Maintain current therapies and discuss good skin care 34 Systemic Immunomodulatory Agents: Recommended if AD Remains Uncontrolled with Topical Therapy Agents Features Cyclosporine Methotrexate Azathioprine Ta cro lim u s Mycophenolate mofetil Variable efficacy To le ra b ility a n d sa fe ty concerns Must be used in lower doses and shorter durations than needed for long-te rm co n tro l of AD Not FDA-approved for tre a tm e n t o f A D Eichenfield LF, et al. J AmAcad Dermatol. 2014;70: With the Introduction of Targeted Therapies, AD Treatment is Evolving Rapidly Treatm ent has consisted of non- specific anti- in fla m m a to ry agents (e.g., topical Pimecrolimus Dupilumab corticosteroids and system ic im m u n o su p p re ssa n ts*) Tacrolimus Crisaborole Roflumilast Ustekinumab Tw o novel therapies (crisaborole, dupilum ab) have been recently approved These agents target the im m u n e d ysfu n ctio n underlying the pathogenesis of AD Topical in different corticosteroids vehicles (ointment, cream, lotion, spray, foam) Tralokinumab Lebrikizumab Upadacitinib Baricitinib Nemolizumab Apremilast Approved Investigational Topical Injection Oral *traditional systemic immunosuppressants are not indicated for the treatment of AD Paller AS, et al. J Allerg Clin Immunol. 2017;140:

13 Identifying Candidates for Systemic Therapy for Moderate-to-Severe AD Confirmed diagnosis of moderate-to-severe AD? Exacerbating factors/alternative diagnoses ruled out? Topical therapies optim ized? Is the patient adherent to Characteristics of patients who are candidates for newly introduced systemic therapy Itch that disrupts sleep Significant body surface area involvem ent (B S A 10%) Im paired quality of life Low risk for opportunistic infection treatm ent? Simpson EL, et al. J AmAcad Dermatol. 2017;77: ; Lynde CCW, et al. J Cutan Med Surg. 2018;22: ARS Question 8 The new biologic agent dupilumab acts through which of the following mechanisms? 1. Blocks JAK activity 2. Blocks IL-4 receptors 3. Attenuates IgE release 4. Inhibits phosphodiesterase 4 38 New and Emerging Therapies Target Specific Steps in the Th2 Pathway Integral to AD Pathogenesis IL-4 IL-4-specific blockers IL-5-specific blockers IL-5 IL-4 Dual IL-4 and IL-13 -specific blockers PDE-4-specific blockers PDE-4 IL-13 IL-13-specific blockers JAK JAK-specific blockers IgE-specific mabs Vakharia Gandhi NA, PP, et Silverberg al. Nat Rev JI. BioDrugs. Discov. 2017;31: ;15: Lee DE, et al. J Dermatolog Treat. 2017;19:

14 Recently Introduced Targeted Therapies Approved for the Treatment of AD Systemic Therapy1 Topical Therapy2 Agent: Dupilumab (Dupixent) MOA: IL - 4 receptor antagonist Approval: March 2017 In d ic a tio n : Treatm ent of adults with moderate- to - severe AD uncontrolled with topical therapies Administration: Subcutaneous in je ctio n (e ve ry- other-week) Agent: Crisaborole (Eucrisa 2% ointment) MOA: Phosphodiesterase (P D E )- 4 inhibitor Approval: December 2016 In d ic a tio n : To p ica l tre a tm e n t o f mild- to - moderate AD in patients 2 years Administration: To p ica l u se only (twice daily) 1. Inc.; Dupixent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc.; 2017; 2. Eucrisa [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, 40 Recently Approved Therapy: Dupilumab In d ic a tio n : Dupilumab is in d ica te d fo r th e tre a tm e n t o f a d u lts ( 18 years) with moderate- to - severe atopic derm atitis uncontrolled with topical th e ra p ie s. 41 Dupilumab Inhibition of IL-4 Intracellular Signaling Fully human IL- 4a monoclonal antibody1 Binds to the IL- 4 receptor α chain, a com ponent of receptors for both IL- 4 and IL- 131 Blocks both IL- 4 and IL- 13 signaling, cytokines that drive Th2- mediated inflammation Gandhi Vakharia NA, PP, et Silverberg al. Nat Rev J. BioDrugs. Discov. 2017;31: ;15: Lee DE, et al. J Dermatolog Treat. 2017;19: Dupixent [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, Inc;

15 Dupilumab Phase 2a Data Patients with Moderate-to-Severe AD Treated with Dupilumab Experienced Significant Skin Clearing by Week 16 Patients (%) Placebo Dupilumab 300 mg (q2 weeks) Dupilumab 300 mg (q week) Primary Endpoint IGA of 0 or 1 and 2 points decrease from baseline at Week *p<0.001 vs placebo *p<0.001 vs placebo * * * 60 * * * * * n=224 n=224 n=223 n=236 n=233 n=239 20n= n=224 n=223 n= n=233 n= S OL O 1 S OL O 2 S OL O 1 S OL O 2 Patients (%) Key Secondary Endpoint EASI-75 at Week 16 IGA=Investigator s 0 = clear ; Global =1 = almost Assessment; clear EASI-75=75%improvement in the Eczema Area and Severity Index. Simpson EL, et al. NEngl J Med. 2016;375: Dupilumab Phase 2a Data Patients with Moderate-to-Severe AD Treated with Dupilumab Experienced Significant Skin Clearing by Week 16 Placebo Dupilumab 300 mg (q2 weeks) Dupilumab 300 mg (q week) Primary Endpoint IGA of 0 or 1 and 2 points decrease from baseline at Week 16 Key Secondary Endpoint EASI-75 at Week 16 *p<0.001 vs placebo * * * * * * * * n=224 n=223 n=233 n=239 n=224 n=223 n=233 n=239 n=224 n=224 n=223 n=236 n=233 n=239 n=224 n=224 n=223 n=236 n=233 n=239 IGA=Investigator s 0 = clear ; Global =1 = almost Assessment; clear EASI-75=75%improvement in the Eczema Area and Severity Index. Simpson EL, et al. NEngl J Med. 2016;375: Combined Treatment with Dupilumab + TCS Elicited Significant Skin Clearing at Week 16 Which Was Maintained Through Week 52 Dupilumab Phase 3 CHRONOS Trials Combined Treatment with Dupilumab + TCS Elicited Significant Skin Clearing at Week 16 Which Was Maintained Through Week 52 Patients (%) Placebo + TCS Dupilumab 300 mg (q2 weeks) + TCS Dupilumab 300 mg (q week) + TCS Primary Endpoint IGA of 0 or 1 and 2 points decrease from baseline at Week 16 *p<0.001 vs placebo + TCS * 39 * 39 * 36 * n=315 n=106 n=319 n=264 n=89 n=270 n=315 n=106 n=319 n=264 n=89 n= Week 16 Week 52 Week 16 Week 52 IGA=Investigator s Global Assessment; EASI-75=75% improvement in the Eczema Area and Severity Index; TCS=topical corticosteroids. IGA 0 = clear ; IGA =1 = almost clear Blauvelt A, De bruin-weller M, Gooderham M, et al. Lancet. 2017;389(10086): Patients (%) *p<0.001 vs placebo + TCS * 69 Key Secondary Endpoint EASI-75 at Week 16 * * 65 *

16 Dupilumab Safety Profile Warning and Precautions Hypersensitivity Discontinue treatment Conjunctivitis and keratitis Report new onset or worsening eye symptoms Comorbid asthma Advise patients with comorbid asthma not to adjust or stop th e ir a sth m a tre a tm e n t w ith o u t Most Common Adverse Reactions (>1% in P h ase 3 Trials) In je ctio n site re a ctio n s Conjunctivitis Blepharitis Oral herpes Keratitis Eye pruritus Other herpes simplex virus Dry eye consultation with their physician Dupixent Inc.; [package insert]. Tarrytown, NY: Regeneron Pharmaceuticals, 46 Dupilumab Phase 2a Data Treatment with Dupilumab Resulted in Extensive Skin Clearing in Children and Adolescents EASI in Children (6-11 years) with Severe AD Dupilumab 2 mg/kg Dupilumab (n=18) 4 mg/kg (n=19) EASI in Adolescents (12-17 years) with Moderate- to - Severe AD Dupilumab (n=20) 2 mg/kg Dupilumab 4 mg/kg (n=20) EASI-75=75%improvement Cork MJ, et al. Presented at in the the American Eczema Academy Area and of Severity Dermatology Index. Annual Meeting. 2017; Orlando, FL. Abstract Recently Approved Therapy: Crisaborole In d ic a tio n : Crisaborole is in d ica te d fo r th e to p ica l tre a tm e n t o f mild- to - moderate atopic dermatitis in patients 2 years

17 Crisaborole A Non-steroidal Phosphodiesterase (PDE)-4 Inhibitor PDE-4 modulates production of inflammatory cytokines by its action on camp Healthy Skin Atopic Dermatitis PDE-4 Inhibition Low PDE-4 high camp low cytokine release low inflammation Increase PDE-4 low camp increase cytokine release increase inflammation PDE-4 inhibition increases camp and reduces cytokine release PDE4 JarnaginK, = phosphodiesterase et al. J Drugs Dermatol. 4; camp 2016;15: = cyclic adenosine monophosphate; AMP = adenosine monophosphate. 49 Patients with Mild-to-Moderate AD Treated with Crisaborole Experienced Significant Skin Clearing and Reduction of Itch Patients Achieving Success at Day 29 (%) Two identically designed, vehicle-controlled, double-blind studies enrolled patients 2 years with mild or moderate AD Vehicle Crisaborole 25.4 Primary Endpoint: ISGA of 0 or 1* p=0.038 AD p<0.001 n=256 n=503 n=250 n=513 AD-302 ISGA = Investigator s Static Global Assessment *ISGA of 0 [clear] or 1 [almost clear] with 2 grade improvement from baseline. Paller AS, et al. J Am Acad Dermatol. 2016;75: Called out endpoints Patients Achieving Improvements in Pruritus (%) Key Secondary Endpoint: Improvement in Pruritus Vehicle Crisaborole Baseline Day 8 Day 15 Day 22 Day Crisaborole Warnings and precautions Safety Profile Hypersensitivity reactions No treatment- related serious adverse events were reported in patients treated with crisaborole Majority of adverse events (AEs) were mild Adverse event Application site pain (%) Upper respiratory tract infection (%) Study Study Pooled AD-301 AD-302 Crisaborole Vehicle Crisaborole Vehicle Crisaborole Vehicle (n=502) (n=252) (n=510) (n=247) (n=1012) (n=499) Most common AE (occurring in >1% of subjects) was application site pain Eucrisa [package insert]. Palo Alto, CA: Anacor Pharmaceuticals, Inc;

18 Agents in Late Phase Development for the Treatment of Atopic Dermatitis 52 Topical Agents in Developm ent for the Treatment of AD Target Compound Target Population AhR Ta p in a ro f/b e n vitim o d Moderate- to - Current Status (P h ase) 3 severe PDE- 4 Roflumilast Mild- to - moderate 2 PDE- 4 RVT- 501 Mild- to - moderate 2 JAK1, JAK2 To fa citin ib Moderate- to - severe JAK1, JAK2 Ruxolitinib Moderate- to severe JAK1, JAK3 LEO /JTE- 052 Moderate- to - severe 2 AhR=aryl hydrocarbon receptor; PDE-4=phosphodiesterase-4; JAK=Janus kinase Paller AS, et al. J Allerg Clin Immunol. 2017;140: Biologic Agents in Development for the Treatment of AD Target Compound Target Population Current Status (Phase) IL-13 Tralokinumab Moderate-to-severe 3 IL-13 Lebrikizumab Moderate-to-severe 3 TSLP Te ze p e lu m a b Moderate-to-severe 2 IL-4 Pitrakinra Moderate-to-severe 2 IL-5 Mepolizumab Moderate-to-severe 2 IgE Ligelizumab Moderate-to-severe 2 IL-12/IL-23 Ustekinumab Moderate-to-severe 2 IL-22 Fezakinumab Moderate-to-severe 2 IL-17A Secukinumab Moderate-to-severe 2 Il-31 Nemolizumab Moderate-to-severe 2 TSLP=thymic stromal lymphopoietin; IgE=immunoglobulin E Paller AS, et al. J Allerg Clin Immunol. 2017;140:

19 Small Molecules in Development for the Treatment of AD Target Compound Target Population Current Status (Phase) PDE-4 Apremilast Moderate-to-severe 2 H4R ZPL389 Moderate-to-severe 2 JAK1, JAK2 Baricitinib Moderate-to-severe 3 JAK1 PF Moderate-to-severe 3 JAK1 Upadacitinib Moderate-to-severe 3 (breakthrough therapy) NK1R Tradipitant Moderate-to-severe 2 NK1R Serlopitant Moderate-to-severe 2 PDE=phosphodiesterase; H4R=histamine receptor type 4; JAK=Janus kinase; NK1R=neurokinin 1 receptor Paller AS, et al. J Allerg Clin Immunol. 2017;140: Integrating New Therapies to Improve Disease Control 56 Patient Case: Mark Age and personal status: 9-year old student Disease history and diagnosis: 8-year history of mild atopic dermatitis Current therapy: Mid potency steroid. However, the parents want to minimize steroid usage. Past therapies: topical corticosteroids (midand high potency) Comorbidities: Allergic rhinitis Severity 5% BSA. IGA - Mild 57 19

20 Patient Case: Peter Age and personal status: 34 year old dentist Disease history and diagnosis: 10-year history of moderate atopic dermatitis Current therapy: Mid potency steroid Past therapies: topical corticosteroids Comorbidities: None Severity 10% BSA, IGA - Moderate 58 Patient Case: Angelina Age and personal status: 20-year old college student Disease history and diagnosis: 17-year history of moderate-to-severe atopic dermatitis Current therapy: tacrolimus 0.1%, moisturizers, and natural remedies; adherence to therapy is self-described as not perfect, but pretty good Past therapies: topical corticosteroids (mid- and high potency), pimecrolimus, cyclosporine Comorbidities: asthma treated with high dose inhaled corticosteroids and long-acting beta agonists Severity 25% BSA, IGA - Moderate 59 Where Do Targeted Therapies Fit into the Treatment Algorithm? Disease Severity Severe Moderate Mild Nonpharmacologic treatments Moisturizers Emollients Phototherapy Topical agents Corticosteroids Calcineurin inhibitors Phosphodiester ase-4 inhibitors Systemic treatments Cyclosporine Azathioprine Methotrexate Mycophenolate mofetil IL-4/IL-13 inhibitors IL-31 inhibitors* JAK inhibitors* *investigational Eichenfield Sidbury R, et LF, al. et J AmAcad al. J AmAcad Dermatol. Dermatol. 2014;71: ;70:

21 Improving Disease Control in AD Traditionally, AD has been treated reactively, adjusting treatment in response to symptoms Accumulating evidence suggests AD is a chronic systemic disease active even when symptoms are absent Approaches to improving disease control while minimizing treatment-related AEs include Preventive therapy Scheduled intermittent therapy Alternating therapy Targeted therapies may remove a barrier to proactive systemic treatment for moderate-to-severe AD 1. Eichenfield LF, et al. J Am Acad Dermatol. 2014;71: Eichenfield LE, et al. American Academy of Dermatology Annual Meeting Multidisciplinary Management May Improve AD Treatment Outcomes Support Pharmacists Nurses NP/PA Educators Dietician Medical Care Dermatologist Immunologist Psychologist Comorbidities Allergist Ophthalmologist Internist PCP LeBovidge JS, et al. J Allergy Clin Immunol. 2016;138: A multidisciplinary approach to AD care may more effectively address the biological, psychological, behavioral, and dietary factors that affect disease control Available evidence suggests beneficial effects of multidisciplinary interventions in improving disease severity and quality of life, particularly for patients with moderate-tosevere AD 62 Summary AD is a chronically relapsing inflammatory skin disease with a complex pathogenesis involving epidermal barrier dysfunction and immune-mediated cutaneous inflammation Improved understanding of AD pathogenesis has led to targeted treatment strategies for moderate-to-severe disease A wide range of biologic agents are under investigation for treatment of AD The availability of targeted biologics may provide additional flexibility and personalization in the treatment in moderate-to-severe AD Proactive treatment has the potential to result in better disease control 63 21

22 POST-TEST QUESTIONS Post-test ARS Question 1 After completing this activity, how confident are you in your ability to manage patients with moderate-to-severe atopic dermatitis? 1. Not at all confident 2. Slightly confident 3. Moderately confident 4. Pretty much confident 5. Very confident 65 Post-test ARS Question 2 After completing this activity, how often do you intend to use systemic therapy for patients with moderate-to-severe atopic dermatitis? 1.Never 2.Rarely 3.Sometimes 4.Often 5.Always 66 22

23 Post-test ARS Question 3 Which of the following features is a characteristic of atopic dermatitis? 1. Desquamation and plaques 2. Pruritic lesions without pain 3. Follows waxing and waning course 4. Commonly affects palms and soles 67 Post-test ARS Question 4 19 y/o woman p/w chief complaint of eczema on her face, arms, and abdomen. Rashes - dull red appearance with perceptible elevation and mild excoriation. She scratches rash frequently and sometimes does not sleep well because of itching. Using one palm, the clinician estimates that 8% of body surface area is affected. What is the best estimate of disease severity in this patient? 1. Mild 2. Moderate 3. Severe 4. Not possible to estimate severity from presented data 68 Post-test ARS Question 5 Which of the following pathophysiologic mechanisms is the fundamental abnormality underlying atopic dermatitis? 1. Overexpression of TNF alpha 2. Th2/Th22 immune abnormalities 3. Overproduction of IgM in response to allergens 4. Inflammation driving increased keratinocyte turnover 69 23

24 Post-test ARS Question 6 26 y/o overweight wom an with 15- yr hx of m oderate- to - severe atopic derm atitis, asthm a, and allergic rhinitis Severity of atopic dermatitis is estimated to be 15% BSA with occasional trouble sleeping because of itching. Meds: fluticasone propionate, desloratadine, tacrolimus 0.1%, and m oisturizers. Prior therapies include high- potency topical corticosteroids and pim ecrolim us. She reports good adherence to therapy. What might be an appropriate action at this time? 1. Consider initiating systemic therapy 2. Add high- potency steroid to tacrolimus 3. Recommend UVB or PUVA phototherapy 4. Maintain current therapies and discuss good skin care 70 Post-test ARS Question 7 The new biologic agent dupilumab acts through which of the following mechanisms? 1. Blocks JAK activity 2. Blocks IL-4 receptors 3. Attenuates IgE release 4. Inhibits phosphodiesterase 4 71 Questions? 72 24