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The therapeutic landscape in atopic dermatitis

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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The therapeutic landscape in atopic dermatitis

  1. 1. The Therapeutic Landscape in Atopic Dermatitis International Eczema Council 2019 Eric Simpson, MD, MCR Professor, Dermatology Oregon Health & Science University El Greco,1596 John Constable, 1821 Andrew Wyeth, 1948
  2. 2. Disclosures • Consultant and investigator for: • Regeneron/Sanofi • Genentech • Medimmune • GSK • Leo • Celgene • Pfizer • Chugai • I will be talking about off-label use • Dermira • Lilly • Tioga • Incyte • Abbvie • Kiniksa • Menlo • Ortho Dermatologica • Forte Biotech
  3. 3. Outline • Topicals • Biologics • Oral therapy
  4. 4. Current Guideline-recommended or Approved Therapies Cyclosporine Phototherapy Methotrexate Mycophenolate Azathioprine Dupilumab Pimecrolimus Corticosteroids Crisaborole Tacrolimus
  5. 5. Current Therapeutic Gaps Topical • Non-steroidal topical therapy with high efficacy AND without significant burning or safety concerns • Topical therapy that is infrequently dosed and easily applied Systemic • Systemic therapy with improved EASI 90s and lacks conjunctivitis • Less frequent dosing • Oral therapy option that is safe and effective 
  6. 6. Barrier Defects Barrier proteins, lipids, AMPs Keratinocyte Cytokines IL-25, IL-33, TSLP, IL-17C ILC2 LC Lichenification Th1 IL-17 Barrier structure proteins Hyperplasia Th17 Th22 Dysbiosis S aureus Th2 IL-22 TARGETS IN ATOPIC DERMATITIS Type 2 Cytokines IL-4, IL-5, IL-13, IL-31 IFN-γ Th2 Costimulatory Molecules
  7. 7. Microbiome as a Target Commensal bacteria- BACTERiAD I/II Trial • Gram neg present in flexures • G neg bacteria reduced in AD • Roseomonas mucosa from healthy volunteers improved dermatitis in mice • Strain-level differences in AD compared to NL • Mono-methyl glutarate, histidinal • Phosphatidylcholine (PC 37:2) • Phosphatidylethanol and PE-ceramides Myles IA, et al.. First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis. JCI Insight. 2018 May 3;3(9). Roseomonas mucosa
  8. 8. Myles IA, et al. First- in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis. JCI Insight. 2018 May 3;3(9). • 10 adults- • 6 weeks • Antecubitals • 5 children • 16 weeks • All areas • Decrease n S. aureus colonization
  9. 9. Microbiome as a Target Commensal bacteria • Coag- Staph make AMPs • Reduced number in AD patients • Screened for bacteria with anti-S. aureus activity • S.epidermidis and S. hominis • Lantibiotics synergize with AMPs • Clones identified and cultured and applied to AD skin S. Epidermidis S. hominis  Nonsteroidal, no burning, less frequent dosing
  10. 10. Barrier Defects Barrier proteins, lipids, AMPs Keratinocyte Cytokines IL-25, IL-33, TSLP, IL-17C ILC2 LC Lichenification Th1 IL-17 Barrier structure proteins Hyperplasia Th17 Th22 Dysbiosis S aureus Th2 IL-22 TARGETS IN ATOPIC DERMATITIS Type 2 Cytokines IL-4, IL-5, IL-13, IL-31 IFN-γ Th2 Costimulatory Molecules IL-23
  11. 11. Phase 2 study of topical delgocitinib (JTE-052) in adult AD % change in EASI • 327 Japanese 16-65 years • Mod-severe AD • 4 weeks of treatment • 5g of treatment allowed-20%BSA • Scalp excluded from treatment • LOCF for rescued pts • Sign reduction in itch • No increase in AEs • 1 case of burning • 3 cases of EH (1.1%) Nakagawa H, Nemoto O, Igarashi A, Nagata T. Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle- controlled clinical study. Br J Dermatol. 2018 Feb;178(2):424-432.
  12. 12. Ruxolitinib (JAK 1/2) -Phase 2 in Adult AD • Primary endpoint: Mean % change from baseline in EASI score at Week 4 in ruxolitinib 1.5% bid group vs vehicle • Secondary and exploratory endpoints: IGA and EASI responder rates, itch NRS score and safety • Kim B, et al. EADV 2018, FC03.01. Sponsored by Incyte 1:1:1:1:1:1 N=307 Double-blind treatment period Vehicle bid Triamcinolone 0.1% bid Ruxolitinib 0.15% qd Ruxolitinib 0.5% qd Ruxolitinib 1.5% qd Ruxolitinib 1.5% bid Week 1 4 8 Vehicle bid Ruxolitinib 1.5% bid 12 16 Open-label period Safety follow-up Optional treatment Key inclusion criteria: • 18–70 years with active AD • AD duration >2 years • IGA 2/3 • BSA 3–20% Key exclusion criteria: • Active infections • Use of other topical treatments within 2 weeks of baseline • Systemic drug use within 4 weeks of baseline R
  13. 13. 4.8 40 29.9 46.2 49.9 52.7 15.5 59.8 45.4 52.2 67 71.6 26.9 50.7 58.5 67 78.5 0 20 40 60 80 100 Vehicle bid (n=52) TAC 0.1% bid (n=51) 0.15% qd (n=51) 0.5% qd (n=51) 1.5% qd (n=52) 1.5% bid (n=50) Meanchange(%) Week 2 Week 4 Week 8 Ruxolitinib cream Improvement from baseline in EASI score ‡ ‡ † ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ ‡ *P<0.05; †P<0.01; ‡P<0.001 vs vehicle; Error bars represent 95% confidence intervals; TAC, triamcinolone Kim B, et al. EADV 2018, FC03.01. Sponsored by Incyte • No increase in AEs in treatment groups • Rapid reduction in itch • Highest doses similar to triamcinolone 0.1 Ruxolitinib (JAK 1/2) -Phase 2 in Adult AD  No significant burning, high efficacy
  14. 14. Dose-finding study of tapinarof (GSK2894512) cream for the treatment of adults with moderate to severe AD AhR, aryl hydrocarbon receptor Peppers J, et al. EADV 2017, OP03.04 Sponsored by GlaxoSmithKline Inclusion criteria: • Age 12–65 years • Diagnosis of AD with active inflammation • BSA ≥5–≤35% (excl scalp) • IGA ≥3 • Primary efficacy analysis – Patients with IGA 0/1 and ≥2 grade improvement in IGA from baseline at Week 12 Tapinarof (GSK2894512), a novel non-steroidal anti-inflammatory agent, is a therapeutic AhR modulating agent cream 1:1:1:1:1:1 N=247 GSK2894512 cream 1.0% bid (n=40) GSK2894512 cream 1.0% qd (n=41) GSK2894512 cream 0.5% bid (n=43) GSK2894512 cream 0.5% qd (n=41) Vehicle cream bid (n=42) Vehicle cream qd (n=40) R Screening −4 BL 1 2 12 Double-blind treatment 16 Follow-up 4 148 Primary endpoint Week • Bacterial-derived • Polyphenol • Binds AhR • Anti-oxidant
  15. 15. Dose-finding study of tapinarof (GSK2894512) cream for the treatment of adults with moderate to severe AD IGA 0/1 and ≥2-point improvement 0.5% qd tapinarof 0.5% bid tapinarof 1% qd tapinarofVehicle qd 1% bid tapinarofVehicle bid Week 16 60 50 40 30 20 10 0 70 80 90 100 Patientsa(%) Follow-up period Treatment period 1 2 4 8 12 14  Nonsteroidal, modest efficacy Safety • More AEs in treatment groups • 10% with HA in highest dose • Some LFT increases (not AEs) • Some systemic effect at high doses? Peppers J, Paller AS, et al. . A phase 2, randomized dose-finding study of tapinarof (GSK2894512 cream) for the treatment of atopic dermatitis. J Am Acad Dermatol. 2019 Jan;80(1):89-98.e3.
  16. 16. Outline • Topicals • Biologics • Oral therapy
  17. 17. Warning! Lack of standardization ahead! EASI 50 EASI %Δ EASI 75 SCORAD Endpoints None Run-in As needed Mandatory TCS Use
  18. 18. Standardization of Clinical Research in AD Core Outcome Sets for Trials and Practice1 Guidance Document for Industry2 Endpoint Training and Standardization Harmonizing Outcome Measures for Eczema 1 Spuls PI,et al. Patient-Oriented Eczema Measure (POEM), a core instrument to measure symptoms in clinical trials: a Harmonising Outcome Measures for Eczema (HOME) statement. Br J Dermatol. 2017 Apr;176(4):979-984. 2 Siegfried EC, et al.Developing drugs for treatment of atopic dermatitis in children (≥3 months to <18 years of age): Draft guidance for industry. Pediatr Dermatol. 2018 May;35(3):303-322. doi: 10.1111/pde.13452. Epub 2018 Mar 30. PubMed PMID: 29600515.
  19. 19. Barrier Defects Barrier proteins, lipids, AMPs Keratinocyte Cytokines IL-25, IL-33, TSLP, IL-17C ILC2 LC Lichenification Th1 IL-17 Barrier structure proteins Hyperplasia Th17 Th22 Dysbiosis S aureus Th2 IL-22 TARGETS IN ATOPIC DERMATITIS Type 2 Cytokines IL-4, IL-5, IL-13, IL-31 IFN-γ Th2 Costimulatory Molecules
  20. 20. • Epidermal “alarmin” • IL-1 cytokine family • Receptors on keratinocytes, Th2 cells, mast cells • Activates NfKb • Promotes type 2 inflammation (Th2 and ILC2) Rationale for Targeting IL-33 in AD IL-33 Inflammation Keratinocytes Cevikbas F, Steinhoff M. IL-33: a novel danger signal system in atopic dermatitis. J Invest Dermatol. 2012 May;132(5):1326-9.
  21. 21. Etokimab (anti-IL-33) • Open-label phase 2a • 12 adult patients • Mod-severe AD • Placebo at -7d • 1X 300mg infusion • Unclear TCS use 0 10 20 30 40 50 60 70 80 90 100 Day -21 Day 1 Day 15 Day 29 Day 57 Day 78 Day 113 Day 140 % patients achieving EASI-50 % patients achieving EASI-75* Average % EASI score reduction  High efficacy, infrequent dosing
  22. 22. • Produced by keratinocytes • Upregulated in psoriasis and AD • Initiates inflammatory cascade Rationale for Targeting IL-17C IL-17C Inflammation Keratinocytes MOR106, an anti-IL-17C mAb, a potential new approach for treatment of moderate-to-severe atopic dermatitis: Phase 1 study, AAD February 2018
  23. 23. MOR106 (anti-IL-17c mAB) Phase I Study • N=25 • 4 weekly infusions • Adults with mod- severe AD *Primary endpoint was safety; secondary endpoint was pharmacokinetics. 1. Thaçi D, et al. MOR106, an anti-IL-17c mAB, a potential new approach for treatment of moderate-to-severe atopic dermatitis: phase I study. Presented at: 2018 American Academy of Dermatology Meeting; February 16-20, 2018; San Diego, CA. 9 EASI-50 score % of patients with 50% EASI improvement 0 10 20 30 40 50 60 70 80 90 100 baseline 1 2 3 4 %ofsubjects Weeks since start of treatment Placebo MOR106 1mg/kg MOR106 4mg/kg MOR106 10mg/kg N = 7 N = 6 N = 6 N = 6 Infusion
  24. 24. • Produced by epithelium- lung and skin • Promotes Th2 responses via dendritic cell binding • Upregulated in skin in AD and lung in asthma • Tezepelumab works in asthma Rationale for Targeting TSLP TSLP Inflammation Keratinocytes
  25. 25. Tezepelumab (Anti-TSLP)- Phase 2a Alleviad • 113 adult pts with AD • 26 centers • 2 weeks of TCS run-in • Class 3 daily • 12 weeks of dosing • 280mg SQ q2 weeks Simpson EL, Parnes JR, She D, Crouch S, Rees W, Mo M, van der Merwe R. Tezepelumab, an anti-TSLP monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial. J Am Acad Dermatol. 2018 Dec 11. Percent Reduction in EASI
  26. 26. Tezepelumab (Anti-TSLP)- Phase 2a Alleviad • Some enhanced effects seen with biomarker subgroups: • DPP4-high • Periostin-low • TARC-low • IgE high • No significant AE signal • Positive signal in asthma Phase 2 with breakthrough status • Another Phase 2 planned! Simpson EL, Parnes JR, She D, Crouch S, Rees W, Mo M, van der Merwe R. Tezepelumab, an anti-TSLP monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: A randomized phase 2a clinical trial. J Am Acad Dermatol. 2018 Dec 11. pii: S0190-9622(18)33050-0. doi: 10.1016/j.jaad.2018.11.059. [Epub ahead of print] PubMed PMID: 30550828. Proportion of IGA 0/1
  27. 27. Barrier Defects Barrier proteins, lipids, AMPs Keratinocyte Cytokines IL-25, IL-33, TSLP, IL-17C ILC2 LC Lichenification Th1 IL-17 Barrier structure proteins Hyperplasia Th17 Th22 Dysbiosis S aureus Th2 IL-22 TARGETS IN ATOPIC DERMATITIS Type 2 Cytokines IL-4, IL-5, IL-13, IL-31 IFN-γ Th2 Costimulatory Molecules
  28. 28. Rationale for Targeting OX40 • OX40L is a co-stimulatory molecule that promotes Th2 polarization of naïve OX40-bearing T cells • OX40 antagonism: • Suppresses activated T cells (particularly atopic Th2 inflammation) • Potentially increases T regulatory cells, which may achieve immunologic tolerance  disease modification? Nygaard U, et al. Dermatol 2017;233:344–57; Dhingra N, et al. J Invest Dermatol 2013;133:2311–4
  29. 29. Anti-OX40 (KHK 4083) • KHK4083 is a fully human, non-fucosylated antagonistic anti-OX40 antibody Study design • A phase 1, single-center, open-label, three-dose study • KHK4083 10 mg/kg iv administered every other week (Weeks 0, 2, 4) • TCS/TCI, oral immunosuppressants and phototherapy were prohibited (Week –1 to Week 22) • Rescue treatment for AD was permitted at investigator’s discretion • 22 patients received the 3 doses of treatment; 20 were evaluated • 4 patients received rescue (documented as missing) BL 2 4 6 10 14 18 22 −60 −40 −20 −80 0 20 40 60 Meanchangefrom baseline(%) KHK4083 (q2w) • Nakagawa H, et al. EADV 2018, P0252. Sponsored by Kyowa Hakko Kirin Percent Reduction in EASI
  30. 30. 1. Glenmark Pharmaceuticals SA. GBR 830 AD Phase 2a press release Guttman-Yassky E, et al. AAD 2018, P7931 Sponsored by Glenmark Pharmaceuticals SA Phase 2a study of GBR 830 (anti-OX40 mAb) in adults with moderate to severe AD • Clinical improvement was associated with a reduction in mRNA biomarkers for disease activity, indicating an effect on acute and chronic stages of AD • In the GBR 830 cohort, 17 of 23 patients (74%) achieved EASI 50 scores at Day 57 vs baseline, a key secondary endpoint of the study1 Change in EASI score n=8 n=15 -80 -60 -40 -20 0 Changefrombaseline(%) DaysDose 1 Dose 2 Placebo GBR 830 1 4 8 15 22 29 32 36 43 50 57 71 85  Infrequent dosing, disease modification?
  31. 31. Barrier Defects Barrier proteins, lipids, AMPs Keratinocyte Cytokines IL-25, IL-33, TSLP, IL-17C ILC2 LC Lichenification Th1 IL-17 Barrier structure proteins Hyperplasia Th17 Th22 Dysbiosis S aureus Th2 IL-22 TARGETS IN ATOPIC DERMATITIS Type 2 Cytokines IL-4, IL-5, IL-13, IL-31 IFN-γ Th2 Costimulatory Molecules
  32. 32. Dupilumab IL-4/13 Blockade • IGA 0/1: ~38% • EASI reduction of ~80% • Itch reduction of ~50% • Improved QOL • Reduced anxiety and depression symptoms • Similar in ages 12-17 ↓ Th2 cyto/chemokines ↓ Th17 and 22 ↓ Proliferation ↓ Serum Th2 inflammation ↑ Epidermal differentiation
  33. 33. 36 0 20 40 60 80 100 0 1 2 4 6 8 12 16 Patients(%) Study week 35.0 76.6* 70.1* SOLO pooled * * Placebo (n = 460) Dupilumab 300 mg q2w (n = 457) Dupilumab 300 mg qw (n = 462) A higher proportion of patients achieved EASI-50 or NRS ≥ 3-point improvement or DLQI ≥ 4-point improvement with dupilumab monotherapy (SOLO pooled) *P < 0.0001 vs placebo Placebo Dupilumab q2w Dupilumab qw 16.1% 3.1% 22.4% 1.9% 19.9% 28.6% 8.1% 9.4% 0.3% 5.7% 5.4% 22.0% 50.6% 6.6% 11.1% 1.9% 5.2% 4.6% 14.5% 56.8% 5.9% EASI-50 NRS ≥ 3 DLQI ≥ 4 Week 16
  34. 34. 3 7 Example of a patient (48 years old; 8 years with AD) achieving EASI-50, NRS ≥ 3-point improvement and DLQI ≥ 4-point improvement (monotherapy) Point improvement % improvement EASI 34.7 72 NRS pruritus 6.1 61.4 DLQI 19 90 Baseline Week 16 4 IGA 2 58% BSA 22.5% 48 EASI 13.3 10 NRS pruritus 3.9 21 DLQI 2
  35. 35. Conjunctivitis at q2week dosing through Week 16: SOLO Pooled data: 10% vs 2% CHRONOS: 9% vs 5% (11.8 vs 6% at Week 52) CAFÉ: 28% vs 11%
  36. 36. Bakker DS, Ariens LFM, Van Luijk C, van der Schaft J, Thijs JL, Schuttelaar MLA, Van Wijk F, Knol EF, Balak DMW, van Dijk MR, the Bruin-Weller MS. Goblet cell scarcity and conjunctival inflammation during treatment with dupilumab in patients with atopic dermatitis. Br J Dermatol. 2018 Dec 30. doi:10.1111 / bjd.17538. [Epub ahead of print] PubMed PMID: 30597515.
  37. 37. Phase 2b Study of Tralokinumab (IL-13) A randomized, double-blind, placebo-controlled, multicenter, multidose study1 40 • Concomitant Class 3 once daily TCS were administered throughout the study and run-in† • Exploratory analyses: high serum DPP-4 levels and high periostin levels may be predictive of response • Safety: acceptable safety and tolerability profile • Did not meet asthma endpoints * Wollenberg A, Howell MD, Guttman-Yassky E, Silverberg JI, Kell C, Ranade K, Moate R, van der Merwe R. Treatment of atopic dermatitis with tralokinumab, an anti-IL-13 mAb. J Allergy Clin Immunol. 2019 Jan;143(1):135-141. Percent IGA 0/1
  38. 38. Phase 2 Study of Lebrikizumab in Moderate-to- Severe AD TREBLE: a randomized controlled study • Concomitant bid class 3 TCS were administered throughout the study†,1,2 • PRO endpoints: improvements in sleep loss VAS (125 mg, q4w and SD) and ADIQ (125 mg q4w)2 • Safety: rates of AEs were generally similar between treatment groups, and AEs were mostly mild or moderate in severity2 41 18.9 21.2 28.3 33.3 0 5 10 15 20 25 30 35 Placebo Lebrikizumab 125 mg SD Lebrikizumab 250 mg SD Lebrikizumab 125 mg q4w Proportionofpatients(%) Primary Endpoint: Patients Achieving IGA 0/1 EASI: 53.1% EASI: 58.5% EASI: 57.7% EASI: 70.5%
  39. 39. Rationale for Biologics Targeting IL-31 • The itch cytokine • Receptors on neurons • Increased expression in AD lesions1,2 • Correlations with disease severity3 1. Nemoto O et al. Br J Dermatol 2016;174:296–304. 2. Cevikbas F et al. J Allergy Clin Immunol 2014;233:448–460.e7. 3. Bieber T, D’Erme AM, Akdis CA et al. J Allergy Clin Immunol 2017;139:S58–S64. 42 IL-31 Th2 Itch1,2 Figure modified from Jones SA, et al. J Clin Investig 2011;121:3375–83 IL-31 receptor composition OSMRβIL-31RA
  40. 40. Phase 2a Study of Nemolizumab in Moderate-to-Severe AD “no imputation was performed for missing data. Data measured during or after rescue therapy were included in the analyses.” % reduction from baseline: NRS itch
  41. 41. Anti-OSM receptor β mAb (KPL-716) Pruritus visual analog scale (VAS)a Weeks Meanchangefrom baseline(%) 1 2 3 4 0 −20 −40 −60 −80 −100 −10.4% −55.4% EASI 1 2 3 4 Weeks 0 −20 −40 −60 −80 −100 −25% −42.3% Meanchangefrom baseline(%) Placebo (pooled iv) KPL-716 (7.5 mg/kg iv) • Phase 1b, dose-escalation study (AD patients): n=32 • Single IV infusion • KPL-716 simultaneously inhibits IL-31 and oncostatin M (OSM) signaling 1. Mikhak Z, et al. EADV 2018, late breaking news D3T01.1F. Sponsored by Kiniksa Pharmaceuticals, Ltd
  42. 42. The Great Wave off Kanagawa (1833) – Katsushika Hokusai
  43. 43. Barrier Defects Barrier proteins, lipids, AMPs Keratinocyte Cytokines IL-25, IL-33, TSLP, IL-17C ILC2 LC Lichenification Th1 IL-17 Barrier structure proteins Hyperplasia Th17 Th22 Dysbiosis S aureus Th2 IL-22 TARGETS IN ATOPIC DERMATITIS Type 2 Cytokines IL-4, IL-5, IL-13, IL-31 IFN-γ Th2 Costimulatory Molecules IL-23
  44. 44. JAK Inhibition- The Good and The Bad JAK1 Blockade Good Bad IL-4 IL-13 IL-22 IL-2 IL-6 IFN a/g IL-15 JAK1/2 Blockade Good Bad IL-4 EPO IL-13 TPO IL-22 GM-CSF IL-2 IL-6 IFN a/g IL-15 IL-5 IL-12 IL-23 JAK1/2/3 Blockade Good Bad IL-2 EPO IL-4 TPO IL-13 GM-CSF IL-6 IFN IL-15 IL-22 IL-5 IL-12 IL-23 Disclaimer: All JAK inhibitors inhibit all JAK signaling, just to greater or lesser extents. Dosing as important for efficacy and side effect profile as molecule. ? ? ? ?
  45. 45. Phase 2 study of baricitinib (JAK1/2) in adults with moderate to severe AD Change from baseline in EASI score over timea • Steroid run-in X 4 weeks and TCS use during study • Phase 3 studies underway
  46. 46. Phase 2b study of Abrocitinib (JAK1) IGA response of 0/1 and ≥2-point improvementa Week 41 2 6 8 12 13 14 16 100 80 60 40 20 0 LSmeanchangefrombaseline(%) Mean change from baseline in EASI scoreb PF-04965842 10 mg qd (n=49) PF-04965842 30 mg qd (n=51) PF-04965842 100 mg qd (n=56) PF-04965842 200 mg qd (n=55) Placebo (n=55) Patients(%) Dosing Follow-up 1 2 4 6 8 12 13 14 16 0 20 40 60 80 100 Week 27.8% 44.5% 6.3% * * • No TCS use • Phase 3 studies underway
  47. 47. *P<0.05; †P<0.01; ‡P<0.001 UPD vs placebo Guttman-Yassky E, et al. AAD 2018, Late-breaking Research: Clinical Trials Phase 2b Trial Upadacitinib (JAK1) in Adult AD 0 20 40 60 80 100 0 2 4 6 8 10 12 14 16 Week UPD 30 mg (n=42) UPD 15 mg (n=42) UPD 7.5 mg (n=42) Placebo (n=39, 37 Week 2) ‡ ‡ ‡ ‡ 74.4 61.7 ‡‡ ‡ ‡ ‡ ‡ ‡ * 39.4 23.0 ‡ ‡ * Change from baseline in EASI score (LOCF) Meanimprovement(%) 1o EP
  48. 48. *P<0.05; †P<0.01; ‡P<0.001; LOCF imputation for continuous variables Guttman-Yassky E, et al. EADV 2018, P0236 Phase 2b trial: Change from baseline in EASI score with upadacitinib through 32 weeks 12 Period 2 Entry 20 24 322 0 20 40 100 60 80 4 8 73.5 53.5† 51.6† 43.6* 11.812.714.3 61.3 12 Period 2 Entry 20 24 322 0 20 40 100 60 80 4 8 72.9 74.6‡ 69.3† 22.320.724.6 72.3 70.8‡ 0 Weeks Weeks UPD 15 mg/placebo (n=19) UPD 15 mg/UPD 15 mg (n=18) UPD 30 mg/placebo (n=19) UPD 30 mg/UPD 30 mg (n=19) Meanchange(%) Meanchange(%)
  49. 49. 0 20 40 60 80 100 Day 1 Day 15 Day 29 ASN002 (JAK/SYK inhibitor) in Adult AD • Guttman-Yassky E, et al. EADV 2018, Late-breaking news D3T01.1H. Sponsored by Asana BioSciences Patients(%) * * ‡ † Patients achieving EASI 50 • Blocking Syk blocks IL-17 signaling • 4 weeks study of 9 active, 2 placebo for each dose • Blood and transcriptome improvements • No TCS use SYK JAK1 JAK2 JAK3 TYK2 5 46 4 11 8 ASN002 inhibition of kinase activity, IC50 (nM)
  50. 50. Summary of Adverse Events for JAKs • Total AEs increase for all JAKs as doses increase • Mainly driven by lab abnormalities • Transient thrombocytopenia occurred with abrocitinib at highest dose • Serious infections in AD populations are low and similar to placebo for all JAKs at all doses • Black box warning for infection and malignancy for all JAKs likely, although AD data will likely be much safer than for RA • If companies push doses for efficacy, will they get burned?
  51. 51. Summary and Conclusions • Numerous targeted therapies being developed for AD with early studies showing a promising signal • Blockade of IL-4/IL-13 very effective and safe strategy • Blockade of other extracellular targets appear to have activity • JAK inhibition promising, but efficacy will need careful balancing with side effect profile • Exciting and hopeful time for patients suffering from AD!
  52. 52. Thank you for listening! Wanderer above the Sea of Fog (1818) – Caspar David Friedrich
  • khinezaw758

    Oct. 20, 2019
  • Vikrantedula

    Apr. 29, 2019

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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