Biologics and Psoriasis: The Beat Goes On

Biologics and Psoriasis: The Beat Goes On Mark Lebwohl, MD Waldman Professor And Chairman Kimberly and Eric J. Waldman Department of Dermatology Icahn School of Medicine at Mount Sinai

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 and ViDac. Dr. Lebwohl is also a consultant for Allergan, Leopharma, and Promius.

Tildrakizumab Guselkumab Tremfya Brodalumab Siliq Ixekizumab Taltz Secukinumab Cosentyx Ustekinumab Stelara Adalimumab Humira Etanercept Enbrel Certolizumab - Cimzia Risankizumab/Mirikizumab

Strong The Ideal Biologic for Psoriasis Few injections Fast durable Safe Safe in pregnancy Effective in obese patients Work for PsA Pill Cheap Grow hair and muscles, increase libido, lose weight

Biologics for Psoriasis and Psoriatic Arthritis STRONG ETANERCEPT TILDRAKIZUMAB ADALIMUMAB RISANKIZUMAB MIRIKIZUMAB INFLIXIMAB CERTOLIZUMAB GOLIMUMAB USTEKINUMAB SECUKINUMAB IXEKIZUMAB BRODALUMAB GUSELKUMAB

PASI 75

PASI 90

PASI 100

Biologics for Psoriasis and Psoriatic Arthritis- FEW INJECTIONS ETANERCEPT ADALIMUMAB INFLIXIMAB CERTOLIZUMAB GOLIMUMAB USTEKINUMAB SECUKINUMAB IXEKIZUMAB APREMILAST METHOTREXATE CYCLOSPORINE ACITRETIN BRODALUMAB GUSELKUMAB TILDRAKIZUMAB RISANKIZUMAB MIRIKIZUMAB

Biologics for Psoriasis and Psoriatic Arthritis- FAST ETANERCEPT ADALIMUMAB INFLIXIMAB CERTOLIZUMAB GOLIMUMAB USTEKINUMAB SECUKINUMAB IXEKIZUMAB BRODALUMAB GUSELKUMAB TILDRAKIZUMAB RISANKIZUMAB MIRIKIZUMAB SPEED

ADALIMUMAB 36,37 INFLIXIMAB 28,29 ETANERCEPT (High Dose) 45,46 BRODALUMAB USTEKINUMAB Time to achieve 50% improvement in baseline PASI scores (NRI) in induction phase (baseline to week 12). Time estimates based on linear progression. Comparative biologics shown as weighted means based on individual study published results. IXEKIZUMAB 52 SECUKINUMAB (High Dose) 47,51 ETANERCEPT (Low Dose)40,45,48 0 1 2 3 4 5 6 7 8 9 10 11 12 Weeks

Biologics for Psoriasis and Psoriatic Arthritis DURABLE ETANERCEPT ADALIMUMAB INFLIXIMAB CERTOLIZUMAB GOLIMUMAB USTEKINUMAB SECUKINUMAB IXEKIZUMAB BRODALUMAB GUSELKUMAB TILDRAKIZUMAB RISANKIZUMAB MIRIKIZUMAB

Responders % Secukinumab Delivers High and Long-lasting Skin Improvement Through 5 Years 100 PASI PASI PASI 75 As observed MI LOCF 90 As observed MI LOCF 100 As observed MI LOCF 80 =~8% 60 =~7% 40 =~5% 20 As observed 0 Year 1 n = 162 Year 2 n = 152 Year 3 n = 139 Year 4 n = 132 Year 5 n = 122 LOCF, last observation carried forward; MI, multiple imputation; n, number of evaluable patients in the as-observed analysis (the number of evaluable patients in the MI and LOCF analyses was 168 at each time point); PASI, Psoriasis Area and Severity Index

Patients (%) UNCOVER-1, 2, 3: PASI responses up to Week 60 for initial non/partial responders to ixekizumab By Week 20 and Week 24, more than 60% of non/partial responders at Week 12 maintained PASI 50 response and more than 30% had PASI 75 response 100 90 80 70 60 50 40 30 20 10 0 68.5 63.0 28.8 8.2 63.0 61.6 60.3 32.9 15.1 35.6 45.2 23.3 23.3 57.5 37.0 2.7 2.7 5.5 6.8 6.8 50.7 32.9 17.8 16.4 6.8 54.8 54.8 39.7 41.1 21.9 17.8 6.8 9.6 50.7 53.4 54.8 53.4 35.6 35.6 37.0 38.4 20.5 9.6 16.4 16.4 9.6 6.8 19.2 12 16 20 24 28 32 36 40 44 48 52 56 60 Week 8.2 PASI 50 PASI 75 PASI 90 PASI 100 Subgroup of patients who did not respond/partially responded (spga 2 and no PASI 75 response) to IXE q2w during the 12-week induction period and who were assigned to IXE q4w (n=73) Kemény L, et al. EADV 2017, FC04.04 Sponsored by Eli Lilly and Company Nonresponders may benefit from continuing IXE q4w Maintenance of response Better on q2w?

Patients (%) PASI responses with brodalumab over 5 years 100 Patients off treatment a 80 60 PASI 75 PASI 90 PASI 100 40 20 0 Week 2 8 16 24 36 48 72 96 120 144 168 192 216 240 264 n= 173 175 169 159 153 148 144 141 136 131 128 106 As observed data Amendment (at Week 59): Amendment 65% of patients (at Week 123): (118/181) had dose 17% of patients (30/181) had decreased from dose increased back to 210 210 to 140 mg mg due to inadequate response Efficacy is maintained for up to 5 years a At week 264, patients had been off treatment for 6 weeks. Error bars represent 95% CI Papp K, et al. EADV 2017, P1798 Sponsored by LEO Pharma

Patients (%) resurface 1 and 2: Overall efficacy after 2 years of treatment 100 90 80 70 60 50 40 30 20 10 0 resurface 1 w.64 resurface 2 w.52 84 81 88 84 66 66 67 58 61 52 54 55 34 33 22 23 TIL 100 mg TIL 200 mg TIL 100 mg TIL 200 PASI 75 PASI 90 PASI 100 PGA (0/1) FAS (full analysis set; subjects with 1 dose of extension treatment based on assigned treatment); as observed data Patients entering OLE after 64 weeks (resurface 1) or 52 weeks (resurface 2) were at least partial responders (PASI 50). For resurface 1, patients had to have received active drug within 12 weeks of end of base study Papp K, et al. EADV 2017, D3T01.1H Sponsored by Merck & Co., Inc.

Patients (%) Patients (%) VOYAGE1: PASI 90 & PASI 100 response with guselkumab through 2 years 100 80 60 40 20 0 0 GUS Placebo ADA PASI 90 PASI 100 GUS GUS 80.1 78.9 50.5 82.3 82.1 81.1 NRI=72.3 4 12 20 28 36 44 52 60 68 76 84 92 100 Weeks n= 329 329 307 290 n= 174 165 161 158 n= 334 334 279 158 100 80 60 40 20 0 0 GUS Placebo ADA GUS GUS 50.5 46.6 24.0 NRI=43.2 55.1 49.0 4 12 20 28 36 44 52 60 68 76 84 92 100 Weeks n= 329 329 307 290 n= 174 165 161 158 n= 334 334 279 158 51.6 Griffiths CEM, et al. EADV 2017, D3T01.I Sponsored by Janssen Research and Development LLC

Mean Improvement in PASI (%) Mean PASI Improvement in Patients Treated with Subcutaneous RISANKIZUMAB (0.25 and 1.0 mg/kg) 100 90 80 70 60 50 40 30 20 10 0 Drug Administration (N =13) (N =13) (N =13) (N =13) (N =13) (N =13) (N =10) (N =9) (N =6) 6/9 (66%) of patients who entered long term follow up maintained PASI 100 for 41 66 weeks Primary Endpoint Optional Follow Up (N =7) (N =9) (N =9) (N =5) 0 4 8 12 16 20 24 28 32 36 40 44 48 52 Week after dose Krueger et al. J. Allergy Clinical Immunology. Published on line 12 March 2015 18

Biologic drug survival in Israeli psoriasis patients.. Shalom G, et al;j Am Acad Dermatol. 2017;4(76):662-9.

Biologics for Psoriasis and Psoriatic Arthritis SAFE ETANERCEPT TILDRAKIZUMAB ADALIMUMAB RISANKIZUMAB MIRIKIZUMAB INFLIXIMAB CERTOLIZUMAB GOLIMUMAB USTEKINUMAB SECUKINUMAB IXEKIZUMAB BRODALUMAB GUSELKUMAB

Methotrexate Boxed Warning Fetal death/congenital anomalies bone marrow suppression and GI toxicity with concomitant NSAIDs hepatotoxicity, fibrosis, and cirrhosis Lung disease malignant melanomas infections Severe, occasionally fatal, skin reactions

Boxed Warning: Etanercept, Adalimumab, Golimumab Infections Malignancy

Infliximab Boxed Warning Bone marrow suppression, corticosteroid therapy, diabetes mellitus, fungal infection, herpes infection, immunosuppression, infection, mycobacterial infection, sepsis, tuberculosis, viral infection Cervical cancer, lymphoma, neoplastic disease, secondary malignancy, skin cancer

Efficacy and Safety of up to 10 years of Etanercept Therapy in North American Patients with Early and Longstanding Rheumatoid Arthritis Open label extensions of etanercept trials 1272 patients Poster presented at AAD, March 6-10 2009 San Francisco

Adalimumab: long-term safety in 23,458 patients from global clinical trials in rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, psoriasis and Crohn s disease G. Burmester, Panaccione R, Gordon KB, McIlraith MJ, Lacerda AP Ann Rheum Dis. 2013;72:517-24

Treatment with TNF blockers and mortality risk in patients with rheumatoid arthritis. Jacobsson LT et al. Ann Rheum Dis. 2007;66:670-675. Anti-TNF: 51 deaths/3177 pt yrs Controls: 137 deaths/3900 pt yrs

Treatment with tumor necrosis factor blockers is associated with a lower incidence of first cardiovascular events in patients with rheumatoid arthritis. Jacobsson LT et al. J Rheumatol. 2005;32:1213-8. First cardiac event: anti-tnf - 14.0/1000 pt yrs controls - 35.4/1000 pt yrs

Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumor necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Dixon WG, Watson KD, Lunt M, Hyrich KL; British Society for Rheumatology Biologics Register Control Centre Consortium, Silman AJ, Symmons DP; British Society for Rheumatology Biologics Register. Arthritis Rheum. 2007;56(9):2905-12.

Association Between Tumor Necrosis Factor Inhibitor Therapy and Myocardial Infarction Risk in Patients With Psoriasis. Wu JJ, Poon KY, Channual JC, Shen AY. Arch Dermatol. 2012 Aug 20:1-7. MI incidence TNF inhibitor/ oral or photorx /topical: 3.05, 3.85, and 6.73 per 1000 patient-years adjusted HR 0.50 vs topical Rx 95% CI, 0.32-0.7

Ustekinumab, Secukinumab, Ixekizumab, Brodalumab, Guselkumab: NO BOXED WARNING

Cumulative Rates per 100 PY (95% CI) PSOLAR Results: Age and Gender Adjusted Cumulative Rates of Malignancies (excluding NMSC) per 100 Patient-Years (PY) Based on Any Exposure to Therapy (Figure 1) 1.2 1.0 0.8 0.6 0.4 0.2 0.0 0.51 Ustekinumab (60/12472 PY) Figure 1. Cumulative Rates of Malignancies 0.81 0.73 0.75 0.68 Infliximab* (41/5176 PY) Other Biologics** (116/15991 PY) Nonbiologic (57/6749 PY) All*** (274/40388 PY) *This group Includes (n=36) patients exposed to golimumab only. **95.7% (n=4067) are adalimumab &/or etanercept patients, with the remainder exposed to other biologics. ***Adjustment used All population as reference. Fiorentino D, et al. AAD 2015. P1631.

Inborn errors of human IL-17 immunity underlie chronic mucocutaneous candidiasis. Puel A, et al. Allergy Clin Immunol. 2012;12:616-22.

Immunity to infection in IL-17-deficient mice and humans. Cypowyj S, Picard C, Maródi L, et al Eur J Immunol. 2012;42:2246-2254. Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin- 17 immunity. Puel A, Cypowyj S, Bustamante J, et al. Science. 2011;332(6025):65-68.

Biologics for Psoriasis and Psoriatic Arthritis SAFE IN PREGNANCY ETANERCEPT ADALIMUMAB INFLIXIMAB CERTOLIZUMAB GOLIMUMAB USTEKINUMAB SECUKINUMAB IXEKIZUMAB BRODALUMAB GUSELKUMAB TILDRAKIZUMAB RISANKIZUMAB MIRIKIZUMAB

CRIB: Maternal and infant plasma and umbilical cord levels of certolizumab pegol CZP concentration ( g/ml) CZP concentration ( g/ml) 100 Plasma CZP levels (n=14 mother infant pairs a ) Mothers Infants 100 Plasma CZP levels in umbilical cord (n=15 c ) Mothers Infants Umbilical cord 10 10 1 1 infant had minimal CZP level of 0.042 μg/ml, mother s level was 49.4 μg/ml (infant/mother ratio: 0.0009) 1 The infant with a CZP level at birth of 0.042 μg/ml had a CZP level of 0.040 μg/ml in the umbilical cord 0.1 0.1 LLOQ = 0.032 g/ml LLOQ = 0.032 g/ml BLQ Delivery Week 4 Week 8 (±24 hours) (±7 days) b (±7 days) BLQ Delivery Umbilical (±24 hours) cords d a 2/16 infant samples excluded from per protocol analysis set (1 missing data at birth, 1 due to implausible PK data [ie, data not consistent with pediatric CZP PK model, based on expected range of clearance, volume of distribution, and subsequent elimination t ½ ]); b 2 samples not collected; c 1 umbilical cord excluded due to missing data; d Umbilical cords were collected within 1 h of delivery. BLQ, below limits of quantitation of the assay; LLOQ, lower limit of quantitation Kimball A, et al. EADV 2017, FC04.03 Sponsored by UCB Pharma

Biologics for Psoriasis and Psoriatic Arthritis OBESITY:ADJUST FOR WEIGHT ETANERCEPT ADALIMUMAB INFLIXIMAB CERTOLIZUMAB GOLIMUMAB USTEKINUMAB SECUKINUMAB IXEKIZUMAB BRODALUMAB GUSELKUMAB TILDRAKIZUMAB RISANKIZUMAB MIRIKIZUMAB

Biologics for Psoriasis and Psoriatic Arthritis OBESITY ETANERCEPT ADALIMUMAB INFLIXIMAB CERTOLIZUMAB GOLIMUMAB USTEKINUMAB SECUKINUMAB IXEKIZUMAB BRODALUMAB GUSELKUMAB TILDRAKIZUMAB RISANKIZUMAB MIRIKIZUMAB

Biologics for Psoriasis and Psoriatic Arthritis- PSA ETANERCEPT ADALIMUMAB INFLIXIMAB CERTOLIZUMAB GOLIMUMAB USTEKINUMAB SECUKINUMAB IXEKIZUMAB BRODALUMAB GUSELKUMAB TILDRAKIZUMAB RISANKIZUMAB MIRIKIZUMAB