New Treatments in Atopic Dermatitis Lynda C. Schneider, MD Professor of Pediatrics, Harvard Medical School Boston Children s Hospital lynda.schneider@childrens.harvard.edu Disclosures: Lynda Schneider, MD Investigator Astellas (Protopic topical tacrolimus), Regeneron (Dupilumab) Grants Food Allergy Research & Education (FARE), Genentech, DBV Technologies, NIH/NIAID/DAIT (Atopic Dermatitis Vaccinia Network, Atopic Dermatitis Research Network, ADRN2) Pharmaceutical Advisory Board Pfizer (Crisaborole) Advisory Boards FARE Learning Objectives Upon completion of this session participants should be able to: Evaluate new therapies for atopic dermatitis 1
Pillars of AD therapy Dry skin Inflammation Infection Itching Identify Triggers Dry Skin Care - Moisturizers Ref. Lucky AW et al Pediatr Derm 1997 Szczepanowska J et al Ped Allergy Immunol 2008 Van Zuuren EJ et al British J Derm 2017 doi: 10.1111/bjd15602 Steroid sparing Improve xerosis & pruritus Patient/family preference - Ointments best, no lotions Absence of fragrance, dyes, food Time of day Age Pillars of atopic dermatitis therapy Repair Barrier Moisturize Inflammation Infection Itching Identify Triggers 2
Streamlined severity based treatment model Practical suggestions for treatment plans MILD DISEASE Basic Management Skin care Antiseptic measures Trigger avoidance Algorithm for Care of Atopic Dermatitis MODERATE TO SEVERE DISEASE Maintenance (Proactive) TCI (pimecrolimus/tacrolimus) TCI 2 3 x weekly OR if patient is non responsive 1 2 x daily Maintenance (Proactive) TC Medium potency TC (Class III IV) 1 2 x weekly (except for face/eyes) AND/OR Low potency TC (Class V VII) 1 2 x daily (including face/eyes) Acute Treatment Topical antiinflammatory applied to inflamed skin Low potency TC (Class VII) bid for up to 3 days beyond clearance Modified from Eichenfield LF et al. Pediatrics 2015; 136(3): 554 565. For relapsing course (frequent/persistent flares despite treatment) TC at first signs/symptom or maintenance Acute Treatment Topical anti inflammatory applied to inflamed skin Medium potency TC (Class III IV) bid for up to 3 days beyond clearance Flare not resolved in 7 days Consider nonadherence, infection, misdiagnosis Step wise Treatment Algorithm Recalcitrant moderate to severe AD Systemic immunosuppressive/ immunomodulatory (e.g. CSA, AZA, MTX, MMF, Dupilumab**) or UV therapy Moderate AD Activity of disease Mid high potency TCS &/or TCI*, Proactive TCS or TCI, Wet wraps Mild AD Low mid potency TCS and/or TCI * or Crisaborole * Basic treatment: Skin hydration, moisturizers, bleach baths, avoidance of irritants and triggers Adapted from Akdis CA et al. J Allergy Clin Immunol 2006;118:152 69 3
Dupilumab blocks the IL 4/IL 13 receptor/ligand system Type I Receptor B cells, T cells, Monocytes, Eosinophils, Fibroblasts Type II Receptor Epithelial cells, Smooth muscle cells, Fibroblasts, Monocytes, Activated B cells Phase III Study Design: SOLO 1 and SOLO 2 Objective: Assess efficacy and safety of dupilumab monotherapy vs. placebo in adults with moderate to severe AD SOLO 1: 671 patients SOLO 2: 708 patients Identical study design (randomized, double blind, placebo controlled, parallel group) Loading dose on Day 1 * Treatment period (16 weeks) Follow up period (12 weeks) Day 35 to 1 Baseline Week 16 Week 28 Screening R Placebo SC qw Dupilumab 300 mg SC q2w Dupilumab 300 mg SC qw Post treatment options: Maintenance study Open label extension Safety follow up through week 28 *Dupilumab, 600 mg; placebo, matching placebo; q2w, every other week; qw, weekly; R, randomization; SC, subcutaneously. Simpson EL et al. N Engl J Med 2016; 375:2335 48. Primary End Point and Key Secondary End Point Simpson EL et al. N Engl J Med 2016;375:2335 2348 4
Secondary End Points Simpson EL et al. N Engl J Med 2016;375:2335 2348 Simpson EL et al. N Engl J Med 2016; 375:2335 48. Conclusions from Phase III Dupilumab Trials Both dose regimens of dupilumab showed clinically meaningful improvement and statistical significance vs. placebo in: AD signs & symptoms (including itch/pruritus and sleep) Health related quality of life Symptoms of anxiety/depression Most AEs were mild or moderate Injection site reactions and conjunctivitis were more frequent with dupilumab Fewer skin infections in dupilumab group Simpson EL et al. N Engl J Med 2016; 375:2335 48. Considerations for Prescribing Dupilumab Hypersensitivity reactions - Urticaria - Serum sickness or serum sickness like reactions reported 2/1472 subjects Patients should not adjust/stop their asthma treatments without consultation with their physicians. Patients with known helminth infections were excluded from participation in clinical studies. Avoid live viral vaccines. Ref: Package Insert 5
Prescribing Dupilumab Conjunctivitis should be promptly treated Can be used with topical steroids Topical calcineurin inhibitors may be used, but reserved for problem areas only, such as the face, neck, intertriginous and genital areas. Missed doses - within 7 days, administer & resume the patient s original schedule. - > 7 days, skip dose and give next dose on the original schedule. Ref: Package Insert Brunner, Guttman Yassky, Leung. J Allergy Clin Immunol;139:S65 76 Copyright 2017 American Academy of Allergy, Asthma & Immunology Selected Systemic Agents Agent Target Phase Comments Tralokinumab IL 13 3 Phase 3 in progress Lebrikizumab IL 13 2 Phase 2 completed; Phase 2b planned Nemolizumab IL 31RA 2 Phase 2 published NEJM; dose ranging study in progress. Ustekinumab IL 12/IL23 2 Approved for psoriasis. Missed primary endpoint in AD in 2 studies.* Tezepelumab TSLP 2 Phase IIa completed Secukinumab IL 17 2 Approved for psoriasis, psoriatic arthritis, and ankylosing spondylitis References: Brunner, Guttman Yassky, Leung. J Allergy Clin Immunol 2017;139:S65 76; Clinicaltrials.gov 9/1/17 *Khattri, Brunner, et al. Exp Dermatol 2017;26(1):28 35; 6
PDE 4 inhibitors for Atopic Dermatitis Topical PDE 4 inhibitors Crisaborole ointment approved Roflumilast (cream) RVT 501 (ointment) OPA 15406 (ointment) E6005 (ointment) Oral PDE 4 Inhibitor Apremilast (approved for psoriasis; development stopped) Figure from the Pharmaceutical Journal and Clinical Pharmacist 23 FEB 2017 Phase III trials Crisaborale Paller AS et al. J Am Acad Dermatol 2016;75:494 503 Primary Endpoint Percent of patients achieving ISGA clear or almost clear Paller AS et al. J Am Acad Dermatol 2016;75:494 503 7
Percent of Patients Achieving Improvement in Pruritus Paller AS et al. J Am Acad Dermatol 2016;75:494 503 JAK STAT signaling as Fig a therapeutic 2 target Paller AS, Kebashima K, Bieber T. Journal of Allergy and Clinical Immunology 2017 140, 633 643DOI: (10.1016/j.jaci.2017.07.006) Copyright 2017 American Academy of Allergy, Asthma & Immunology Copyright 2017 American Academy of Allergy, Asthma & Immunology Agent Target Route Comments Upadacitinib (ABT 494) JAK inhibitors in development for AD JAK 1 oral Met primary endpoint in Phase 2b study. Phase 3 planned for 2018. Baricitinib JAK 1/2 oral Phase 2 completed PF 04965842 JAK 1 oral Phase 2 LEO 124249 Jak 1/3 oral Phase 2 trials in Japan Tofacitinib Jak 1/3 topical Phase 2a done; development stopped. Oral approved for RA & has risk of serious infections. Ruxolitinib, INCB018424 JAK 1/2 topical Phase 2 Brunner P, Guttman Yassky E, Leung DYM. J Allergy Clin Immunol 2017;139:S65 76. Clinicaltrials.gov 9/1/17 Paller AS, Kebashima K, Bieber T. J Allergy Clin Immunol 2017;140:633 643. Abbvie Data on file. Upadacitinib AD Phase 2b Press Release 05SEPT2017 8
Phase 2b Results for Oral Upadacitinib (ABT 494) Abbvie Data on file. Upadacitinib AD Phase 2b Press Release 05SEPT2017 Pillars of atopic dermatitis therapy Repair Barrier Moisturize Inflammation Infection Itching Identify Triggers Dysbiosis of the skin microbiome in AD is associated with S. aureus colonization Nakatsuji T et al., Sci Transl Med 2017; 9, eaah4680 9
Lack of antimicrobial activity in CoNS in Atopic Dermatitis Nakatsuji T et al., Sci Transl Med 2017; 9, eaah4680 Autologous Transplantation of Antimicrobial CoNS Reduces Survival of S. aureus Nakatsuji T et al., Sci Transl Med 2017; 9, eaah4680 Pillars of atopic dermatitis therapy Repair Barrier Moisturize Inflammation Infection Itching Identify Triggers 10
Antihistamines.evidence based review of 16 controlled studies revealed little objective evidence demonstrating the relief of pruritus when sedating or non sedating antihistamines were used in the treatment of AD. Reduction of skin inflammation with will often reduce pruritus. Schneider L, Tilles S, Lio P, Boguniewicz M, Beck L, et al. J Allergy Clin Immunol. 2013 Feb; 131:295 9. H4R antagonist ZPL 3893787 (oral) Phase 2a NK1R antagonists (oral) VLY 686/tradipitant Serlopitant TPRV1 Channel Antagonist PAC 14028 (cream) ANTI ITCH THERAPIES Paller AS, Kebashima K, Bieber T. Journal of Allergy and Clinical Immunology 2017 140, 633 643DOI: (10.1016/j.jaci.2017.07.006) Copyright 2017 American Academy of Allergy, Asthma & Immunology The clinician should recognize that AD has a significant impact on quality of life and patients have an increased risk for psychological distress. Schneider L, Tilles S, Lio P, Boguniewicz M, Beck L, et al. J Allergy Clin Immunol. 2013 Feb; 131:295-9. 11
The clinician should assess for sleep disturbances. Optimize sleep hygiene Treat AD inflammation aggressively to improve sleep and itching Refer to psychologist or sleep specialist if needed Schneider L, Tilles S, Lio P, Boguniewicz M, Beck L, et al. J Allergy Clin Immunol. 2013 Feb; 131:295 9. Improve Adherence Educate patients about AD & demonstrate skin care Give patients a written plan and assess understanding of skin care plan Develop a skin care schedule Assess concerns about medications Assess barriers What are the hardest parts for you/your child to follow? What parts do you skip/miss the most? Chou J et al. Allergy and Asthma Proceedings. 2011;32(5):377-83. http://www.aaaai.org/aaaai/media/medialibrary/pdf%20documents/libraries/atopicderm English.pdf 12
Rea, Corinna, et al. Pediatric Academic Societies Meeting, May, 2017. Summary Treat dry skin, Inflammation, Infection, Itching & Identify triggers Dupilumab and Crisaborale are two recently approved new therapies for AD Acknowledgements BCH AD Program Wendy Elverson, RD Jennifer LeBovidge, PhD Karol Timmons, RN, PNP Division of Immunology Raif S. Geha, MD Hans Oettgen, MD, PhD Janet Chou, MD Steve Gellis, MD Marilyn Liang, MD Jennifer Huang, MD 13
Thank you for your attention Enjoy Boston! 14