A Yardstick for Managing Patients with Atopic Dermatitis

Transcription

1 AAIFNA 2018 Symposium A Yardstick for Managing Patients with Atopic Dermatitis Mark Boguniewicz, MD Professor, Division of Allergy-Immunology Department of Pediatrics National Jewish Health and University of Colorado School of Medicine

2 Disclosures Research Grants: NIH/NIAID, Anacor, Regeneron Consultant/Advisory Board: Regeneron, Sanofi-Genzyme, Pfizer Content will include discussion of offlabel uses of medications for atopic dermatitis

3 Learning Objectives At the conclusion of this presentation, participants should be able to: 1. Apply knowledge of the pathophysiology of AD to the selection of treatment options 2. Manage patients with AD in accordance with the latest treatment guidelines and expert recommendations

4 Practice Parameter Update: Flow chart of the diagnosis and management of AD Often still reactive therapy J Allergy Clin Immunol 2013;131:295 Non-recommended & non-approved systemic therapies

5 Global variations in prevalence of eczema symptoms in children from ISAAC Phase 3 Developed and developing countries Lancet 1998;351:1225; Odhiambo JA, et al. J Allergy Clin Immunol 2009;124

6 Characterization of different courses of atopic dermatitis in adolescent and adult patients >40% of patients with onset of AD before age 6 years will persist into adulthood Garmhausen D, et al. Allergy 2013;68:

7 Persistence of mild to moderate AD Cross-sectional & cohort study of a long-term registry of children with AD enrolled in PEER* 7157 pts enrolled in PEER with at least 2 yrs of f/u for 4248 and at least 5 yrs of f/u for 2416 At every age (2-26 yrs), >80% of PEER participants had symptoms of AD and/or were using medication to treat their AD It was not until age 20 yrs that 50% of pts had at least 1 lifetime 6-mo symptom- and treatment-free period Margolis JS, et al. JAMA Dermatol 2014;150:593 *Pediatric Eczema Elective Registry; ~ 16% of PEER subset with FLG mutations

8 US prevalence: adults 2010 and 2012 National Health Interview Survey data of US adults y Nationally representative cohort from all 50 states (n=27,157 and 34,613) 1-year prevalence was 10.2% (less specific question) and 7.2% (more specific question) 1-year prevalence of eczema with asthma or hay fever 3.2% 16 US AD PREVALENCE (%) Children: 12.0% ( %) Adults: 7.2% ( %) AGE (YR) Silverberg JI. Dermatol Clin 2017;35;283-9

9 Adult onset/recurrence of AD 54% with onset of AD after the age of 18 years AD n=6931 TNS household panel (n=60,000) Hanifin JM, Reed MI. Associations of childhood eczema severity: A US population based study. Dermatitis : 82-91

10 Clinical relevance Adult onset / recurrent AD is more common than previously recognized Important to rule out the differen;al diagnosis

11 Atopic dermatitis: a (systemic) disease of altered skin barrier and immune dysregulation Non-lesional Irritants Boguniewicz M, Leung DY. Immunol Rev 2011;242:233 >30% asthma, allergies & nonatopic co-morbidities

12 Association between adult atopic dermatitis, cardiovascular disease, and increased heart attacks in three population-based studies Data from NHANES (n = 4970) and NHIS 2010 & 2012 (n = 27, 157 & 34, 525) NHANES, flexural eczema in past yr associated with significantly higher odds of CAD (P 0.04), heart attack (P 0.01) and congestive heart failure (P 0.02) NHIS 2010 & 2012, 1-yr history of eczema associated with significantly higher odds of CAD (P 0.02), angina (P 0.02), heart attack (P 0.047), other heart disease (P < ), stroke (P 0.02), and PVD (<0.0001) Adults with AD may have increased cardiovascular disease, heart attack, and stroke Allergy 2015;70:1300

13 Atopic dermatitis is associated with an increased risk for rheumatoid arthritis and inflammatory bowel disease, and a decreased risk for type 1 diabetes German National Health Insurance cohort aged 40 years or younger (n = 655,815) from Pts with AD (n = 49,847) at increased risk for incident RA (risk ratio [RR], 1.72; 95% CI, ) and/or IBD (CD: RR, 1.34; 95% CI, ; UC: RR, 1.25; 95% CI, ). After adjusting for health care utilization, there was a nominally significant inverse effect on T1D risk (RR, 0.72; 95% CI, ) No disproportionate occurrence of known RA, IBD, or T1D risk alleles in AD AD is a risk factor for development of RA and IBD. This excess comorbidity cannot be attributed to major known IBD and RA genetic risk factors Schmitt J, et al. J Allergy Clin Immunol 2016;137:130

14 Fig 1. Flow chart of the diagnosis and management of AD Differential diagnosis J Allergy Clin Immunol 2013;131:295

15 Differential diagnosis of AD Congenital disorders Netherton's syndrome Chronic dermatoses Seborrheic dermatitis Contact dermatitis (allergic or irritant) Nummular eczema Lichen simplex chronicus Infections and infestations Scabies HIV-associated dermatitis Malignancy Cutaneous T cell lymphoma (mycosis fungoides/sézary syndrome) Boguniewicz M, Leung DY. Middleton s Allergy 2014 Immunodeficiencies Wiskott-Aldrich syndrome SCID Hyper-IgE syndrome DOCK8 mutations IPEX Metabolic disorders Zinc deficiency Pyridoxine (vitamin B 6 ) and niacin deficiency Multiple carboxylase deficiency Phenylketonuria Proliferative disorder Letterer-Siwe disease

16 A pragmatic approach to patch testing atopic dermatitis patients: Clinical recommendations based on expert consensus opinion * *e.g. head/neck predominance, hand or foot, eyelid, perioral Chen JK, et al. Dermatitis 2016;27:186

17 Differential diagnosis of AD Congenital disorders Netherton's syndrome Chronic dermatoses Seborrheic dermatitis Contact dermatitis (allergic or irritant) Nummular eczema Lichen simplex chronicus Infections and infestations Scabies HIV-associated dermatitis Malignancy Cutaneous T cell lymphoma (mycosis fungoides/sézary syndrome) Boguniewicz M, Leung DY. Middleton s Allergy 2014 Immunodeficiencies Wiskott-Aldrich syndrome SCID Hyper-IgE syndrome DOCK8 mutations IPEX Metabolic disorders Zinc deficiency Pyridoxine (vitamin B 6 ) and niacin deficiency Multiple carboxylase deficiency Phenylketonuria Proliferative disorder Letterer-Siwe disease

18 Mycosis fungoides happens The most common form of CTCL Epidermotropic neoplasm of CD4+ T cells Robert C, Kupper TS. N Engl J Med 1999;341:1817

19 Moving beyond the Practice Parameter and Guidelines Topical PDE4 inhibitor J Allergy Clin Immunol 2013;131:295 MoAb vs IL-4 receptor alpha

20 The role of phosphodiesterase 4 inhibition in the pathophysiology of atopic dermatitis Guttman-Yassky E, et al. Br J Dermatol 2018 (submitted)

21 Crisaborole: targeting PDE4 Zane LT, et al. Immunotherapy 2016;8:853-66

22 Efficacy and safety of crisaborole ointment, a novel, nonsteroidal phosphodiesterase 4 (PDE4) inhibitor for the topical treatment of atopic dermatitis in children and adults To assess the efficacy and safety of crisaborole ointment, a PDE4 inhibitor in 2 phase III AD studies 2 identical VC, DB studies randomly assigned (2:1, crisaborole:vehicle) pts aged 2 yrs or older with an Investigator s Static Global Assessment (ISGA) score of mild or moderate for 2x/d application for 28 days Primary end point was ISGA score at day 29 of clear (0)/ almost clear (1) with 2-grade or greater improvement from baseline Paller AS, et al. J Am Acad Dermatol 2016;75: e4

23 More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with 2-grade improvement; AD-301: 32.8% vs 25.4%, P =.038; AD-302: 31.4% vs 18.0%, P<.001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P =.005; 48.5% vs 29.7%, P <.001) Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P.001) Treatment-related adverse events were infrequent and mild to moderate in severity Paller AS, et al. J Am Acad Dermatol 2016;75: e4

24 Crisaborole Improves ISGA at Day 29 Phase 3 Primary Outcome Baseline Characteris5cs Primary End Point Age groups (%) 2 6 yrs 7 11 yrs yrs 18 yrs Baseline ISGA (%) Mild (2) Moderate (3) Crisaborole (n = 503) AD- 301 Vehicle (n = 256) Crisaborole (n = 513) AD- 302 Vehicle (n = 250) PaQents achieving success at Day 29 (%)* P = P < % BSA Mean Range n = 503 n = 256 n = 513 n = 250 AD- 301 AD- 302 Crisaborole Vehicle * ISGA of 0 [clear] or 1 [almost clear] with 2 grade improvement from baseline. Paller AS, et al. J Am Acad Dermatol. 2016;75(3):

25 Crisaborole Improves Pruritus in Mild-to- Moderate AD Phase 3 Predefined Outcome A greater proporqon of crisaborole- treated paqents achieved improvement in pruritus across all study visits Median Qme to improvement = 1.37 days acqve vs 1.73 days control (P = 0.001) PaQents achieving improvement in pruritus (%)* * Score of 0 or 1 with 1 grade reducqon from baseline. Paller AS, et al. J Am Acad Dermatol. 2016;75(3): P < P < P < P = Baseline Day 8 Day 15 Day 22 Day 29 Crisaborole Vehicle 48 53

26 More crisaborole- than vehicle-treated patients achieved ISGA score success (clear/almost clear with 2-grade improvement; AD-301: 32.8% vs 25.4%, P =.038; AD-302: 31.4% vs 18.0%, P<.001), with a greater percentage with clear/almost clear (51.7% vs 40.6%, P =.005; 48.5% vs 29.7%, P <.001) Crisaborole-treated patients achieved success in ISGA score and improvement in pruritus earlier than those treated with vehicle (both P.001) Treatment-related adverse events were infrequent and mild to moderate in severity Crisaborole ointment 2% approved by FDA in Dec 2016 for treatment of mildmoderate AD in patients 2 years and older Paller AS, et al. J Am Acad Dermatol 2016;75: e4

27 Dupilumab, a fully human monoclonal Ab against IL-4 receptor alpha inhibits signaling of IL-4 & IL-13 Type I Receptor B cells, T cells, Monocytes, Eosinophils, Fibroblasts Type II Receptor Epithelial cells, Smooth muscle cells, Fibroblasts, Monocytes, Activated B cells

28 Two phase 3 trials of dupilumab vs placebo in atopic dermatitis 2 randomized, placebo-controlled, phase 3 trials of identical design (SOLO 1, n=671 and SOLO 2, n=708) Adults with moderate-to-severe AD (IGA 3-4) inadequately controlled by topical treatment randomly assigned in a 1:1:1 ratio to receive for 16 wks subcutaneous dupilumab (300 mg) or placebo weekly or dupilumab 300 mg qo wk alternating with placebo* Primary outcome was proportion of patients with IGA score of 0 or 1 (clear or almost clear) and reduction of 2 points in that score from baseline at week 16 *patients treated with dupilumab received 600 mg loading dose Simpson EL, et al. N Engl J Med 2016;375:

29 Demographic and clinical characteristics of patients at baseline Simpson EL, et al. N Engl J Med 2016;375:

30 Simpson EL, et al. N Engl J Med 2016;375: Efficacy outcomes

31 SOLO 1 & SOLO 2: 1 & key 2 end points Simpson EL, et al. N Engl J Med 2016;375: P<0.001 for all dupilumab vs placebo

32 SOLO 1 & SOLO 2: 2 end points Simpson EL, et al. N Engl J Med 2016;375: P<0.001 for all dupilumab vs placebo

33 Simpson EL, et al. N Engl J Med 2016;375: Adverse events

34 Adverse events For the 16 wk treatment period, overall rate of AEs (65-73% dupilumab vs 65-72% placebo) comparable between dupilumab and placebo groups Proportion of pts who completed treatment period was 88-94% for dupilumab and % for placebo Rate of serious AEs was 1-3% for dupilumab and 5-6% for placebo Serious and severe infections were numerically higher in placebo groups in both studies (0.5-1% dupilumab and 2-3% placebo) AEs noted to have higher rate with dupilumab treatment across both studies included injection site reactions (10-20% dupilumab; 7-8% placebo) and conjunctivitis (7-12% dupilumab; 2% placebo) approximately 26% of pts in both studies reported history of allergic conjunctivitis at study entry No patient discontinued therapy due to injection site reactions and only 1 patient discontinued therapy due to conjunctivitis Dupilumab approved by FDA on Mar 28, 2017 for the treatment of adult patients with moderate-to-severe AD whose disease is not adequately controlled with topical prescription therapies or when those therapies are not advisable

35 Lancet 2017;389:2287

36 Dupilumab + TCS efficacy at week 16 and week 52: CHRONOS Phase 3 results PaQents achieving IGA of 0 or 1 and 2 points Improvement from BL (Primary End Point) EASI- 75 (Key Secondary End Point) * P < vs placebo + TCS * P < vs placebo + TCS * PaQents (%) * * * * * * * Placebo qwk + TCS Dupilumab 300 mg q2wks + TCS Dupilumab 300 mg qwk + TCS Significant improvement in pruritus as early as Week 2 and sustained to Week 52 Co- primary end point in the EU and Japan Blauvelt A, et al. Lancet 2017; 389:

37 Chronos: EASI 50 & 75 over 52 weeks Blauvelt A, et al. Lancet 2017;389:2287

38 Dupilumab: Safety at 52 Weeks Event, n (%) Placebo qwk + TCS (n = 315) Dupilumab 300 mg q2wks + TCS (n = 110) Dupilumab 300 mg qwk + TCS (n = 315) 1 AE 226 (84) 97 (88) 261 (83) 1 SAE 16 (5) 4 (4) 9 (3) Death 0 0 1* (< 1) AEs leading to treatment disconqnuaqon 24 (8) 2 (2) 9 (3) AEs occurring in 5% of paqents Nasopharyngi;s 61 (19) 25 (23) 60 (19) URTI 32 (10) 11 (10) 43 (14) AD 144 (46) 20 (18) 52 (17) Injec;on site reac;on 24 (8) 16 (15) 60 (19) Asthma 19 (6) 5 (5) 2 (1) Herpes infec;ons 25 (8) 8 (7) 22 (7) Non- herpe;c skin infec;ons 56 (18) 12 (11) 26 (8) Conjuc;vi;s 25 (8) 15 (14) 61 (19) * Motor vehicle accident not considered related to study drug. Blauvelt A, et al. AAD 2017; Orlando, FL. Abstract 5267.

39 Br J Dermatol 2017; Nov 28 [Epub ahead of print]

40 CAFÉ study design To evaluate efficacy and safety of dupilumab with concomitant TCS in adults with AD with inadequate response to/intolerance of CsA or for whom CsA was medically inadvisable 16 wk, double-blind, randomized, placebo-controlled phase 3 trial with pts randomized 1:1:1 to subq dupilumab 300 mg qw:q2w:placebo All received concomitant medium-potency TCS from wk 2 through wk 16; dosage could be tapered if lesions cleared or stopped for adverse reactions to TCS de Bruin-Weller M, et al Br J Dermatol 2017; Nov 28 [Epub ahead of print]

41 CAFÉ results 325 pts randomized and 318 completed trial Significantly more pts on dupilumab qw+tcs/q2w+tcs achieved 75% improvement from baseline in EASI at wk 16 vs placebo+tcs (1 endpoint) (59.1%/62.6% vs 29.6%; P< vs placebo+tcs, both doses) Dupilumab qw+tcs/q2w+tcs significantly improved pruritus, pain, sleep disturbance, symptoms of anxiety and depression, and QOL Treatment groups had ~ overall rates of adverse events (69.1%/72.0%/69.4%; qw+tcs/q2w+tcs/placebo+tcs) and serious adverse events (1.8%/1.9%/1.9%) Conjunctivitis more frequent with dupilumab+tcs; skin infections more frequent with placebo+tcs de Bruin-Weller M, et al Br J Dermatol 2017; Nov 28 [Epub ahead of print]

42 CAFÉ Conclusions Dupilumab+TCS significantly improved signs and symptoms of AD and QOL in adults with history of inadequate response to/intolerance of CsA, or for whom CsA treatment was medically inadvisable No new safety signals were identified de Bruin-Weller M, et al Br J Dermatol 2017; Nov 28 [Epub ahead of print]

43 Dupilumab trials in adolescents & children with AD Study to determine safety and tolerability of dupilumab in patients aged 6 to <18 years with atopic dermatitis - Canada, Europe (NCT ) - completed Study to assess long-term safety of dupilumab administered in patients 6 to <18 years of age with atopic dermatitis Canada, Europe (NCT ) - ongoing FDA approval for pediatric dupilumab trials in US: Efficacy and safety of dupilumab in patients 12 to <18 years of age with moderate-to-severe atopic dermatitis (NCT ) enrollment complete Study to determine safety and tolerability of dupilumab in patients aged 6 to 11 years with atopic dermatitis Fitzpatrick s Dermatology in Gen Med 2012;170

44 Molecular changes in AD transcriptome Beck LA, et al. N Engl J Med 2014;371:130

45 Targeting pruritus H4R antagonist ZPL (oral) Phase 2a NK1R antagonists (oral) VLY-686/tradipitant Serlopitant TPRV1 Channel Antagonist PAC (cream) Paller AS, et al. J Allergy Clin Immunol 2017;140:

46

47 Boguniewicz M. J Allergy Clin Immunol Pract 2017;5:1477 Boguniewicz M, et al. J Allergy Clin Immunol Pract 2017;5:1519

48 Complex pathophysiology of atopic dermatitis and selected targets of biologics *IL-17 *IL-22 *IL-4Rα * *IL-13 *IL-31R *IL-12/ IL-23p40 Boguniewicz M. J Allergy Clin Immunol Pract 2017;5:1477

49 Atopic Dermatitis Yardstick: Practical recommendations for an evolving therapeutic landscape Boguniewicz M, et al. Ann Allergy Clin Immunol 2018;120:10 1 Indicated for patients with mild-to-moderate AD, ages 2 years and older ; 2 Indicated for patients with moderate-to-severe AD, ages 18 years and older; 3 Not FDA-approved to treat AD ; 4 FDA approved to treat AD, but not recommended for long-term maintenance

50 Atopic Dermatitis Yardstick: Practical recommendations for an evolving therapeutic landscape Boguniewicz M, et al. Ann Allergy Clin Immunol 2018;120:10

51 Atopic Dermatitis Yardstick: Practical recommendations for an evolving therapeutic landscape Boguniewicz M, et al. Ann Allergy Clin Immunol 2018;120:10

52 Atopic Dermatitis Yardstick: Practical recommendations for an evolving therapeutic landscape Boguniewicz M, et al. Ann Allergy Clin Immunol 2018;120:10

53 AD pts from phase 2 & 3 trials pre-/post-dupilumab Photos courtesy of Dr E Guttman-Yassky Boguniewicz M, et al. Ann Allergy Clin Immunol 2018;120:10

54 Atopic Dermatitis Program A multidisciplinary team approach

55 NIAID Atopic Dermatitis Research Network