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Translating advances in therapeutics to pediatrics

Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.

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Translating advances in therapeutics to pediatrics

  1. 1. Translating Advances in Therapeutics to Pediatrics Amy S. Paller, MS, MD Professor of Dermatology and Pediatrics Northwestern Univ. Feinberg School of Medicine, Chicago Leslie Castelo-Soccio, MD, PhD Assistant Professor of Pediatrics and Dermatology University of Pennsylvania, Philadelphia Dr. Castelo-Soccio has no conflicts to discloseDr. Paller (related to AD or AA) has been an investigator for Galderma, Incyte, Leo, and Regeneron, and a consultant for AbbVie, Asana, Dermavant, Dermira, Galderma, Eli Lilly, Forte, Leo, Matrisys, Menlo, Morphosys/Galapagos, Novartis, Pfizer, and Sanofi-Regeneron
  2. 2. Children are not just little adults Different clinical features, differential diagnosis, course, and responses/tolerance of therapy
  3. 3. Children are not just little adults • Diagnosis largely clinical and more straightforward than adults 3 • Distribution in young child - Diaper area sparing - More cheek, chin, trunk - More exudation Atopic Dermatitis • In older child, adolescent - More periorbital, perioral, neck, flexural, hands, feet - More lichenification with chronicity • Environmental exposure (saliva, food, friction), microbiome effects, or inherent differences in skin at different sites at different ages?
  4. 4. Children are not just little adults • Similarly clinical diagnosis and resembles adult alopecia • Different needs based on age of patient/ developmental stage ….As in atopic dermatitis….. • Treatment is family oriented and care must be taken to treat child and not the care taker • Different tolerance for therapies (injections, irritants) • Consideration of weight based therapies and potential absorption due to high head surface area to body surface area 4 Alopecia areata/totalis/universalis
  5. 5. Differential diagnosis in children Alopecia areata • Tinea capitis • Telogen effluvium • Trichotillomania • Loose anagen syndrome • Temporal triangular alopecia • Genodermatoses with sparse, fragile hair Atopic Dermatitis • Immunodeficiencies (HIES, WAS) • Ichthyoses, esp Netherton • Seborrheic dermatitis • Psoriasis • Scabies • Allergic/ irritant contact dermatitis • Widespread tinea • Cutaneous T-cell lymphoma
  6. 6. Epidemiology / Natural History Alopecia areata • <20 y/o’s 2nd largest group presenting for care • 40% with AA experience 1st episode by age 20 • Younger age may predict more severe disease • Onset in childhood more frequent in girls (1.5:1) • Severe alopecia and early age higher in boys Atopic Dermatitis • Primarily in infants and young children - 10-20% of children overall - 90% start under 5 years of age - 60% by 1 year of age - Girls = boys Prevalence by age: Atopic Dermatitis Caldwell et al. JAAD 2017 Augustin et al. Dermatology 2015
  7. 7. Atopic Dermatitis  Percentage of children with mod- severe AD increases with age, esp. after 3 years (p<.0002) Disease Severity in Children Silverberg, Simpson. Pedi Allergy Immunol. 2013;24:476 Alopecia areata SALT 0-24% (17.9%) SALT 24-49% (11.6%) SALT 50-74% (9.2%) SALT 75-99% (15.8%) SALT 100% (45.6%) Wohlmuth-Wieser et al. Pediatr Dermatol. 2018;35:164 • Percentage within NAAF Registry • NAAF Registry is a skewed population • Population studies (eg, in Asian and middle Eastern populations) were mainly mild
  8. 8. Immune Pathways in Skin and Blood 8 Atopic Dermatitis • Skin phenotypes early AD vs. adult AD - <5 year olds with AD for < 6 months - Strong Th2 skewing in skin - Th2 skewing in nonlesional skin much higher early vs. adult Esaki et al. JACI 2016;138:1639 Alopecia areata: Not investigated in children • More Th17 activation than adults • Persistently low Th1/Th2 ratios in AD vs. control children (skin and blood) Esaki et al. JACI 2016;138:1437 Czarnowicki et al. JACI 2015;136:941
  9. 9. Barrier Issues in Pediatric vs. Adult Skin 9 Atopic Dermatitis • Reduction in barrier proteins, such as filaggrin, in biopsies is reflective of chronicity and not in first 6 months (gene arrays, qRT-PCR, IHC) Brunner et al. JACI 2018;141:2094 Alopecia areata: Not investigated in children • Lipid and tight junction abnormalities present early on and likely major cause of barrier defects Esaki et al. JACI 2016;138:1639 Pedi AD Pedi control Adult controlAdult AD
  10. 10. QoL and Neuropsychiatric Comorbidities Atopic Dermatitis • Depression • Anxiety • Conduct disorder • Autism • ADHD - Esp. if severe/poor sleep • Children with AD and AA both have a poorer quality of life Alopecia areata • Depression • Anxiety • More prolonged disease duration or later disease onset = positive effects • Greater severity = negative effects • Study of impact of pediatric AD and AA on stigmatization, depression, anxiety and peer relationships ongoing [PeDRA Big Study]
  11. 11. Shared comorbidities in children Atopic Dermatitis • Atopic – Asthma, allergies (food, seasonal), urticaria • Infections of skin (S. aureus, herpes, molluscum) and other sites Alopecia areata • Atopic – AD (32.7%), asthma (20.7%), seasonal allergies (20.0%), other allergies (14.2%), urticaria (4.7%) • Autoimmune – Thyroid disease (1.4%) (Hashimoto’s; hypothyroid) – Vitiligo (1.5%) – Psoriasis (1.5%) – Diabetes – JIA – IBD • Emerging: Autoimmune – Alopecia areata – Vitiligo – IBD – Celiac disease – SLE Cipriano et al. JACI 2018;141:2094 National AA Registry; Wohlmuth- Wieser et al. Pedi Derm 2018;35:164
  12. 12. Alopecia areata • Case report of two people with AA improved after fecal transplant • Interest in compromised central and peripheral tolerance, and increased intestinal inflammation with enhanced gut permeability • Ongoing studies looking at fecal microbiome in children and adults with AA Microbiome Atopic Dermatitis • Increase in S. aureus and reduced diversity associated with flares • Interest in relationship between microbiome, barrier dysfunction and immunity • Emerging topical therapy with commensal organisms with anti-S. aureus activity (eg, Staphylococcus hominis and Roseomonas mucosa), including promising early studies in children
  13. 13. Therapy: shared pediatric responses to topical therapies • Topical steroids: Main topical treatment of AD and AA - More potent steroids required for treating AA vs. AD - Intralesional most effective is in adolescent AA - TCIs for sensitive areas, but more effective in AD than AA • Topical JAK inhibitors in adolescents to date - AD, adolescent (phase 3): ruxolitinib cream (NCT03745638 and NCT03745651) – AA: NCT 02812342, 02561585, 03800979- completed in 18years+ NCT 03354637 recruiting 18 years+; none recruiting for children currently • Disease-specific topicals: Crisaborole for AD; Minoxidil and topical immunotherapy for AA
  14. 14. Use of systemic therapies for pediatric AD • Most commonly used agents for pediatric atopic dermatitis in US • 1st-line choices are cyclosporine (45%), methotrexate (30%) and MMF (13%) - Most popular 2nd-line choice: Methotrexate and mycophenolate mofetil - Most popular 3rd-line choice: Azathioprine • Concerns: Side effect profiles and perceived risks of long-term toxicity • Use of systemic steroids rare (by pediatric dermatologists) because of toxicity and rebound issues 14 Totri et al. JAAD 2017;76:281
  15. 15. Q2 Week (200/300mg based on wt) Q4 week (300mg) Placebo Adverse Events (%) 72% 64% 69% Injection site reactions (%) 8.5% 6% 3.5% Conjunctivitis (%) 10% 11% 5% Skin Infections (%) 11% 13% 20% Q2 Week (200/300mg based on wt) Q4 week (300mg) Placebo IGA 0 or 1 24%* 18%** 2% EASI-75 41.5%* 38%* 8% EASI – mean % change from baseline 66%* 65%* 24% Itch NRS – mean % change from baseline 48%* 45.5%* 19% * p< 0.0001 **p<0.001 Placebo SC q2w Dupilumab 300mg SC q4w (no weight limit, 600mg load) Post-treatment options • Safety follow-up through Week 28 • Open-label extension enrollment Screening (5 weeks) Dupilumab 200 mg SC q2w <60Kg (400mg load) Dupilumab 300mg SC q2w >60Kg (600mg load) Day –35 to Day –1 Baseline Week 28Week 16 R 251 children >12 years old with IGA 3 or 4 (phase 3)AD: Dupilumab Press release, www.news.sanofi.us, May 16, 2018 Ongoing trials in children 6 months to 11 years of age Long-term risks unknown
  16. 16. Other emerging systemic therapies for pediatric AD 16 • Ongoing trial of tralokinumab for adolescents • Moderate to severe AD, adolescent (phase 3) NCT03526861 • Ongoing trials of systemic JAK1 inhibitors • Moderate-severe AD, adolescent (phase 3) – Abrocitinib/ PF-04965842, NCT03796676 – Upadacitinib/ ABT-494, NCT03569293 • Moderate-severe AD, 6-<12 years, 2-<6 years, phase 1 pharmacokinetic – Upadacitinib/ ABT-494: NCT03646604, NCT03568318, NCT03607422
  17. 17. Use of systemic therapy for pediatric AA • Systemic steroids for acute alopecia areata flares- mixed • Methotrexate • JAK inhibitors (off-label for children and adolescents) – NCT03732807 oral JAK inhibitor study recruiting 12+ years – Concerns about hematologic issues, coagulation/ thromboembolic events, malignancy with long-term use, especially aggressive B-cell lymphomas • Dupilumab • Two case reports: 13 y/o with totalis since age 2 and 28 y/o - treated for AD • Two reports of new AA within a few weeks after start of dupilumab 17 Landis and Pichardo-Geisenger. J Dermatol Treatment 2018;29:145; Lucas et al. Acta Derm 2016;96:102; Phan et al. JAAD 2019;80:120; Browne et al. Br J Dermatol 2018;179:609 Smogorzewski et al, 2019 JAAD Case Rep 2019;5:116; Darrigade et al. Br J Dermatol 2018;179:534 Flanagan et al. JAAD Case Rep 2018;5:54; Barroso-Garcia, 2018 J Invest Allergol Clin Immunol 2018;28:420
  18. 18. Unmet needs in pediatric AD and AA • Establishment of a prospective registry/ standardized patient data collection for both AD and AA • Better understanding of comorbidities – Impact on QoL and psychiatric issues for both disorders – Autoimmune associations with AA and AD – Risk factors for development of comorbidities
  19. 19. Unmet needs in pediatric AD and AA • Better understanding of mechanistic differences vs. adults – Overlap and differences between AD and AA – Underlying genetic factors that predispose to disease, affect natural history, or alter response to medications – Immune biomarker differences – Role of the microbiome – Sub-phenotypes and their differential response to intervention • Translating Advances in Therapeutics to Pediatrics – More therapeutic trials of JAK inhibitors, including attention to safety and best strategies for maintenance – Beyond JAK inhibition: More targeted approaches
  20. 20. ….Thanks for your attention Thanks for your attention! Philadelphia Chicago

Presented at the joint International Eczema Council and National Alopecia Areata Foundation Symposium, "Atopic Dermatitis and Alopecia Areata: Comparison and Contrast”, held during the 2019 Annual American Academy of Dermatology meeting in Washington, DC to explore the similarities and differences between these two common but complex skin diseases and the implications from bench to bedside.

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