Overview of the Last Decade Inflammatory Skin Diseases. Mark Lebwohl, MD

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1 Overview of the Last Decade Inflammatory Skin Diseases Mark Lebwohl, MD ProfessorAnd Chairman Kimberly and Eric J. Waldman Department of Dermatology Icahn School of Medicine at Mount Sinai

2 Disclosure Mark Lebwohl is an employee of Mount Sinai which receives research funds from: Abbvie, Amgen, Boehringer Ingelheim, Celgene, Eli Lilly, Janssen / Johnson & Johnson, Kadmon, Medimmune/Astra Zeneca, Novartis, Pfizer, Valeant and ViDac. Dr. Lebwohl is also a consultant for Allergan, Aqua Leo-pharma,and Promius.

Pathogenesis of Psoriasis Innate immunity Adaptive immunity Innate immunity Natural killer T cell INF-γ Keratinocyt e TNF-α INF-γ IL-1β IL-6 TNF-α Myeloid dendritic cell IL-12 Activation Th1 cell

3 Pathogenesis of Psoriasis Innate immunity Adaptive immunity Innate immunity Natural killer T cell INF-γ Keratinocyt e TNF-α INF-γ IL-1β IL-6 TNF-α Myeloid dendritic cell IL-12 Activation Th1 cell IL-20 TNF-α INF-γ IL-20 Keratinocyt e IL-22 Antimicrobial peptides IL-1β IL-6 TNF-α S100 CXCL8 CXCL9 CXCL10 CXCL11 CCL20 Plasmacytoid dendritic cell TNFα IL-23 Th22 cell IL-17A IL-17F IL-17R Macrophage Adapted from: Nestle F, et al, NEJM 2009; 501. Th17 cell

4 Abnormal cell proliferation in psoriasis. Weinstein GD, Frost P. J Invest Dermatol. 1968;50(3): Autoradiographic analysis of turnover times of normal and psoriatic epidermis. Weinstein GD, Van Scott EJ. J Invest Dermatol. 1965;45:

5 Resistant severe psoriasis controlled with systemic cyclosporine therapy. Picascia DD, Garden JM, Freinkel RK, Roenigk HH Jr. Transplant Proc. 1988;20(3Suppl 4): Cyclosporine consensus conference: with emphasis on the treatment of psoriasis. Lebwohl M, Ellis C, Gottlieb A, Koo J, Krueger G,Linden K,Shupack J,Weinstein G. J Am Acad Dermatol. 1998; 39:

6 An international, randomized, doubleblind, placebo-controlled phase 3 trial of intramuscular alefacept in patients with chronic plaque psoriasis. Lebwohl M, Christophers E, Langley R, Ortonne JP, Roberts J, Griffiths CE; Alefacept Clinical Study Group. Arch Dermatol. 2003;139:

7 Efalizumab Study Group. A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, Walicke P, Dummer W, Wang X, Garovoy MR, Pariser D; N Engl J Med Nov 20;349(21):

8 Efficacy and safety of infliximab monotherapy for plaque-type psoriasis: a randomized trial. Chaudhari U, et al. Lancet 2002 June 9;357(9271):

9 Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with psoriasis: 52-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 2). Papp KA,et al. Lancet. 2008;371(9625): Efficacy and safety of ustekinumab, a human interleukin-12/23 monocl onal antibody, in patients with psoriasis: 76-week results from a randomised, double-blind, placebo-controlled trial (PHOENIX 1). Leonardi CL,et al. Lancet. 2008;371(9625):

10 Secukinumab in plaque psoriasis--results of two phase 3 trials. Langley RG, Elewski BE, Lebwohl M, Reich K, Griffiths CE, Papp K, Puig L, Nakagawa H, Spelman L, Sigurgeirsson B, Rivas E, Tsai TF, Wasel N, Tyring S, Salko T, Hampele I, Notter M, Karpov A, Helou S, Papavassilis C; ERASURE Study Group; FIXTURE Study Group. N Engl J Med Jul 24;371(4):

11 Comparison of ixekizumab with etanercept or placebo in moderate-to-severe psoriasis (UNCOVER-2 and UNCOVER-3): results from two phase 3 randomised trials. Griffiths CE, Reich K, Lebwohl M, van de Kerkhof P, Paul C, Menter A, Cameron GS, Erickson J, Zhang L, Secrest RJ, Ball S, Braun DK, Osuntokun OO, Heffernan MP, Nickoloff BJ, Papp K; UNCOVER-2 and UNCOVER-3 investigators. Lancet. 2015;386(9993):

12 Phase 3 Studies Evaluating Brodalumab Compared to Ustekinumab In Psoriasis MLebwohl, BStrober, AMenter, KGordon, JWeglowska, LPuig, KPapp, LSpelman, DToth, FKerdel, AArmstrong, G Stingl, AKimball, HBachelez, JWu, JCrowley, RLangley, TBlicharski,CPaul, JLacour,STyring,LKircik,SChimenti, KCallis Duffin, JBagel, JKoo, GAras, JLi, W Song, C Milmont, YShi, N Erondu, PKlekotka, BKotzin, A Nirula NEJM in press

13 Risankizumab versus Ustekinumab for Moderate-to-Severe Plaque Psoriasis. Papp KA, Blauvelt A, Bukhalo M, Gooderham M, Krueger JG, Lacour JP, Menter A, Philipp S, Sofen H, Tyring S, Berner BR, Visvanathan S, Pamulapati C, Bennett N, Flack M, Scholl P, Padula SJ. N Engl J Med. 2017;376:

14 TSLP Confidential Mechanism of Dupilumab Gittler JK and Guttman-Yassky E. J Allergy Clin Immunol Sep 2012

15 Dupilumab blocks the IL-4/IL-13 receptor/ligand system IL-4 IL-13 IL-4Rα γc IL-4Rα IL-13Rα1 JAK1 STAT6 JAK3 JAK1 TYK2 STAT6 STAT3 Type I receptor B cells, T cells, monocytes, eosinophils, fibroblasts Type II receptor Epithelial cells, smooth muscle cells, fibroblasts, monocytes, activated B cells Thaci D, et al. EADV 2013: FC03.3. Sponsored by Regeneron Pharmaceuticals, Inc. and Sanofi

Proportion (%) of Patients Patients Achieving EASI-75 Through Week 16 SOLO 1 & 2 1 CHRONOS 2, CAFÉ 3 50* 48* 13 71* 65* 23 63* 59* 30 Time (weeks) *P<0.

Patients who used rescue therapy or withdrew from the trial were classified as nonresponders in the statistical analysis. 1. Ferrándiz C et al.

16 Proportion (%) of Patients Patients Achieving EASI-75 Through Week 16 SOLO 1 & 2 1 CHRONOS 2, CAFÉ 3 50* 48* 13 71* 65* 23 63* 59* 30 Time (weeks) *P< vs placebo or placebo + TCS. Presented data are from the FAS-52 of patients who completed the study before the data cutoff. Week 16 statistics use the FAS. Patients who used rescue therapy or withdrew from the trial were classified as nonresponders in the statistical analysis. 1. Ferrándiz C et al. Presented at: EADV 2017; September 13 17, 2017; Geneva, Switzerland. Abstract FC Blauvelt A et al. Lancet 2017;389: De Bruin-Weller M et al. Presented at: EADV 2017; September 13 17, 2017; Geneva, Switzerland. Abstract D3T01.1B.

Proportion (%) of Patients Patients Achieving EASI-50 Through Week 16 SOLO 1 & 2 1 CHRONOS 2, CAFÉ 3

Presented data are from the FAS-52 of patients who completed the study before the data cutoff.

Patients who used rescue therapy or withdrew from the trial were classified as nonresponders in the

17 Proportion (%) of Patients Patients Achieving EASI-50 Through Week 16 SOLO 1 & 2 1 CHRONOS 2, CAFÉ 3 81* 85* 67* 77* 85* 61* Time (weeks) *Nominal P< vs placebo or placebo + TCS. Presented data are from the FAS-52 of patients who completed the study before the data cutoff. Week 16 statistics use the FAS. Patients who used rescue therapy or withdrew from the trial were classified as nonresponders in the statistical analysis. 1. Ferrándiz C et al. Presented at: EADV 2017; September 13 17, 2017; Geneva, Switzerland. Abstract FC Blauvelt A et al. Lancet 2017;389: Data on file.

% Change in EASI (LSM) Percent Change in EASI From Baseline Through Week 16 SOLO 1 & 2 1 CHRONOS 2, CAFÉ 3 Time (weeks) 34

Patients who used rescue therapy or withdrew from the trial were classified as nonresponders in the statistical analysis. 1.

18 % Change in EASI (LSM) Percent Change in EASI From Baseline Through Week 16 SOLO 1 & 2 1 CHRONOS 2, CAFÉ 3 Time (weeks) * 71* 81* 82 78* 80* *P< vs placebo or placebo + TCS. Nominal P< vs placebo + TCS. Presented data are from the FAS-52 of patients who completed the study before the data cutoff. Week 16 statistics use the FAS. Patients who used rescue therapy or withdrew from the trial were classified as nonresponders in the statistical analysis. 1. Ferrándiz C et al. Presented at: EADV 2017; September 13 17, 2017; Geneva, Switzerland. Abstract FC Blauvelt A et al. Lancet 2017;389: De Bruin-Weller M et al. Presented at: EADV 2017; September 13 17, 2017; Geneva, Switzerland. Abstract D3T01.1B.

CHRONOS: Percent Change in EASI From Baseline Through Week 52 Dupilumab response plateaus at week 24 and sustained to week 52 47 61 82* 83 85 88 *P<0.0001 vs placebo or placebo + TCS. Nominal P<0.

19 CHRONOS: Percent Change in EASI From Baseline Through Week 52 Dupilumab response plateaus at week 24 and sustained to week * *P< vs placebo or placebo + TCS. Nominal P< vs placebo + TCS. Presented data are from the FAS-52 of patients who completed the study before the data cutoff. Week 16 statistics use the FAS. Patients who used rescue therapy or withdrew from the trial were classified as nonresponders in the statistical analysis. Blauvelt A et al. Lancet 2017;389:

20 Dupilumab in persistent asthma with elevated eosinophil levels. Wenzel S, et al. N Engl J Med May 21. [Epub ahead of print]

21 22

22 TREBLE: Effect of lebrikizumab on health-related quality of life at Week 12 Mean change from baseline (%) Pruritus VAS Week Sleep loss VAS Week * * ADIQ Week 12 Placebo Lebrikizumab 125 mg sd Lebrikizumab 250 mg sd Lebrikizumab 125 mg q4w ADIQ, AD Impact Questionnaire; sd, single dose; P=0.05 vs placebo; *P<0.05 vs placebo Eichenfield LF, et al. AAD 2017, Poster 5500 Sponsored by Genentech, Inc. and F. Hoffmann-La Roche Ltd.

23 Why interleukin-31 is important to AD? Itch-scratch-cycle: an exacerbating factor of AD IL-31 is a pruritogenic cytokine, involved in AD CIM331: Anti-IL-31RA antibody expected to improve pruritus and ameliorate dermatitis by breaking itch-scratch-cycle Mechanical trauma Scratch Skin CIM331 IL-31 C-fiber Inflammatory cells IL-31, etc Inflammation IL-31RA OSMR Target cells CIM331 Itch OSMR, Oncostatin M Receptor Nemoto O, et al. EADV 2013: FC03.9. Sponsored by Chugai Pharmaceutical Co., Ltd

24 Mean±SE change from basline (%) Efficacy of CIM331 (pruritus/dermatitis) Pruritus Mean percent change of pruritus VAS from baseline 0 PRE Week 4 Week Placebo 0.3 mg/kg 1.0 mg/kg 3.0 mg/kg Pruritus VAS imported rapidly and VAS reduction was kept Pruritus VAS reduction >50% improved dermatitis Nemoto O, et al. EADV 2013: FC03.9. Sponsored by Chugai Pharmaceutical Co., Ltd

25 g/w Efficacy of CIM331 (quality of life) Sleep efficiency = Sleep duration Total time in bed Weekly amount of hydrocort butyrate usage Good sleep % Poor sleep PRE Mean±SE Week 2 Week PRE Week 4 Week 8 Placebo 0.3 mg/kg 1.0 mg/kg 3.0 mg/kg Anti-IL-31RA antagonist (CIM331) was considered to be a promising novel therapeutic candidate for atopic dermatitis by breaking itch-scratch-cycle Nemoto O, et al. EADV 2013: FC03.9. Sponsored by Chugai Pharmaceutical Co., Ltd

26 Change in pruritus (%) Change in sleep disturbance (%) Phase 2 study of nemolizumab in patients with moderate to severe AD: Change in pruritus and sleep disturbance VAS Time course of percentage change in pruritus VAS 0 0 Week Time course of percentage change in sleep disturbance VAS 0 0 Week (n=25 46) Placebo 0.1 mg/kg q4w 0.5 mg/kg q4w 2.0 mg/kg q4w (n=32 46) (n=32 47) (n=34 45) Mean ± SE; Per-protocol population, no imputation, excluded data after rescue therapy Ruzicka T, et al. EADV 2016, FC04.02 Sponsored by Chugai Pharmaceutical Co. Ltd Baseline: mm

27 Mean % change from baseline Phase 2 study of nemolizumab in patients with moderate to severe AD PBO (n=43) Change in EASI at Week 12 (%) 0.1 mg/kg (n=44) P= mg/kg (n=43) P= Per protocol population, LOCF, excludes data after rescue therapy P-values as post hoc analysis vs placebo at Week mg/kg (n=46) P= Ruzicka T, et al. EADV 2016, FC04.02 Sponsored by Chugai Pharmaceutical Co. Ltd. Summary: Reduction in pruritus of up to 60% Improved quantity and quality of sleep Improved QoL Improvement in dermatitis Placebo 0.1 mg/kg q4w 0.5 mg/kg q4w 2.0 mg/kg q4w

Atopic Dermatitis: Emerging therapies. Melinda Gooderham MSc MD FRCPC

Atopic Dermatitis: Emerging therapies Melinda Gooderham MSc MD FRCPC SKiN Centre for Dermatology, Peterborough Assistant Professor, Queen s University, Kingston ON Investigator, Probity Medical Research,