Psoriatic Arthritis: New and Emergent Therapies

Psoriatic Arthritis: New and Emergent Therapies Alice Bendix Gottlieb MD, PhD Professor of Dermatology New York Medical College Metropolitan Hospital New York, NY, USA

DISCLOSURE OF RELEVANT RELATIONSHIPS WITH INDUSTRY Current Consulting/Advisory Board Agreements/or Speakers Bureau: Janssen Inc.; Celgene Corp., Bristol Myers Squibb Co., Beiersdorf, Inc., Abbvie, UCB, Novartis, Incyte, Lilly, Reddy Labs, Valeant, Dermira, Allergan, Sun Pharmaceutical Industries Research/Educational Grants : Janssen, Incyte

Agenda Skin Matters IL-17 Blockade Ixekizumab Secukinumab IL-23 Blockade Guselkumab Abatacept Tofacitinib TNF Blockade Data shown will be from only PSA studies except for certolizumab

Skin Matters Arthur Kavanaugh, Alice Gottlieb, Akimichi Morita, Joseph Merola, Julie Birt, Chen-Yen Lin, Catherine Shuler, Diamant Thaçi ACR, 2017

Assess activity, impact, and prognostic factors NSAIDs and IA corticosteroids as indicated Physiotherapy and NSAIDs Physiotherapy Corticosteroid injections as indicated Topicals as indicated GRAPPA PsA Treatment Recommendations 2015 Assess which domains are involved Peripheral arthritis Axial disease Enthesitis Dactylitis Skin Nails csdmards, TNFi, or PDE-4i Biologics (TNFi, IL12/23i, IL17i) or PDE-4i Switch biologic (TNFi, IL12/23i, or IL17i) NSAIDs only TNFi, IL17i or IL12/23i Switch biologic (TNFi, IL17i or IL12/23i) No direct evidence for therapies in axial PsA; recommendations based on SpA literature NSAIDs Biologics (TNFi, IL12/23i, IL17i) or PDE-4i Switch biologic (TNFi, IL12/23i, IL17i) or PDE-4i CS injections: consider on individual basis due to potential for serious side effects; no clear evidence for efficacy NSAIDS csdmards, or PDE-4i Biologics (TNFi, IL12/23i) Switch biologic, (TNFi, IL12/23i, IL17i) or PDE-4i Topicals Phototx or csdmards or PDE-4i Biologics, (TNFi, IL12/23i, IL17i) or PDE-4i Switch biologic (TNFi, IL12/23i, IL17i) or PDE-4i Topical or procedural or csdmards Biologics, (TNFi, IL12/23i, IL17i) or PDE-4i Switch biologic, (TNFi, IL12/23i, IL17i) or PDE-4i IA=intraarticular; i=inhibitor. Yellow text=conditional recommendations (no current regulatory approval Treat, or periodically based on abstract re-evaluate data only. & Coates Consider LC et previous al. Arthritis therapy, Rheum. patient 2016;68(5):1060-1071. preference, other disease involvement & comorbidities modify Expedited therapy therapeutic as needed route CS: corticosteroid; csdmard: conventional synthetic disease-modifying antirheumatic drug; IA: intra-articular; IL: interleukin; NSAID: nonsteroidal anti-inflammatory drug; PDE-4i: phosphodiesterase-4 inhibitor; PsA: psoriatic arthritis; SpA: spondyloarthropathy; TNFi: tumor necrosis factor inhibitor.

Ixekizumab is FDA Approved forpsoriasis INDICATIONS AND USAGE TALTZ is a humanized interleukin-17a antagonist indicated for the treatment of adults with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy DOSAGE AND ADMINISTRATION Administered by subcutaneous injection Recommended dose is 160 mg (two 80 mg injections) at week 0, followed by 80 mg at weeks 2, 4, 6, 8, 10, and 12, then 80 mg every 4 weeks 90% PASI 75, 70% PASI 90, 40% PASI 100 at week 16 FDA: Food and Drug Administration; PASI: Psoriasis Area Severity Index.

Ixekizumab is FDA approved for adults with active psoriatic arthritis DOSAGE AND ADMINISTRATION Plaque Psoriasis TALTZ is administered by subcutaneous injection. The recommended dose is 160mg (two 80 mg injections) at Week 0, followed by 80mg at Weeks 2, 4, 6, 8, 10, and 12, then 80mg every 4weeks. Psoriatic Arthritis The recommended dose is 160 mg by subcutaneous injection (two 80 mg injections) at week 0, followed by 80 mg every 4 weeks. For psoriatic arthritis patients with coexistent moderate-tosevere plaque psoriasis, use the dosing regimen for plaque psoriasis

Clinical Studies Cited in the PSA Package Insert Signs and Symptoms Control at weeks 12 and 24 Inhibition of Radiographic Progression at week 16 Improved Health Related Outcomes and Physical Function at weeks 12 and 16 Decreased CRP at weeks 12 and 16 Improved Dactylitis and Enthesitis (no data shown)

At wk 24 Peripheral Arthritis Axial Disease Enthesitis LEI 0% Dactylitis LDI-B%0 Skin %PASI 90 Nails % NAPSI 0 Bio Naïve* -Ixe q 4wks 57.9% ACR20 mtss 0.17 -Placebo 31.1% ACR20% mtss 0.49 -ADA Active control 57.4% ACR 20 mtss 0.10 42.6 (NS) 79.5 56.2 25.7 (NS) 19.3 25 6 18.9 33.3 77.8 38.6 39.4 Bio Exp.** -Ixe q 4wks 53% ACR20 -Placebo 19% ACR20 35 (NS) 75 44 20 22 21 12 7 *Mease et alann Rheum Dis 2016;0:1 9. doi:10.1136/annrheumdis-2016-209709, **Nash et al Lancet 2017; 389: 2317 27

Secukinumab is FDA Approved for Psoriasis Indication: for the treatment of moderate-to-severe plaque psoriasis in adult patients who are candidates for systemic therapy or phototherapy Dosage: Recommended dose is 300 mg by subcutaneous injection at weeks 0, 1, 2, 3, and 4, followed by 300 mg every 4 weeks. For some patients, a dose of 150 mg may be acceptable FDA: Food and Drug Administration.

Secukinumab is Indicated for PsA in the United States 2.2 Psoriatic Arthritis For psoriatic arthritis patients with coexistent moderate to severe plaque psoriasis, use the dosing and administration recommendations for plaque psoriasis [see Dosage and Administration (2.1)] For other psoriatic arthritis patients, administer secukinumab with or without a loading dosage by subcutaneous injection. The recommended dosage: o o o With loading dosage is 150 mg at weeks 0, 1, 2, 3, and 4 and every 4 weeks thereafter Without a loading dosage is 150 mg every 4 weeks If a patient continues to have active psoriatic arthritis, consider a dosage of 300 mg Secukinumab may be administered with or without methotrexate Package Insert. PsA: psoriatic arthritis.

IL-23 Blockade: Guselkumab PSA Phase 2 Clinical Trial

Guselkumab is FDA-approved for Psoriasis Indicated for the treatment of adults with moderate to severe plaque psoriasis who are candidates for systemic therapy or phototherapy Dosing: 100 mg sq at weeks 1,4 and every 8 weeks

Efficacy and Safety Results of Guselkumab, an Anti-IL23 Monoclonal Antibody, in Patients with Active Psoriatic Arthritis over 24 Weeks: A Phase 2a, Randomized, Double-Blind, Placebo- Controlled Study Atul A. Deodhar 1, Alice B Gottlieb 2, Wolf-Henning Boehncke 3, Bin Dong 4,Yuhua Wang 4, William Barchuk 5, Xie Xu 5, Elizabeth C. Hsia 4 1 Oregon Health & Science University, Portland, OR, USA; 2 Department of Dermatology, New York Medical College, Valhalla, NY, USA; 3 Department of Dermatology, Geneva University Hospital, Geneva, Switzerland, 4 Janssen Research & Development, LLC, Spring House, PA, USA; 5 Janssen Research & Development, LLC, San Diego, CA, USA, ACR,2016 Originally presented at ACR 2016 This presentation was supported by Janssen Research & Development, LLC

Presentation number: OP0223 Abatacept in the Treatment of Active Psoriatic Arthritis: 1-year Results From a Phase III Study P Mease, 1 AB Gottlieb, 2 D van der Heijde, 3 O FitzGerald, 4 A Johnsen, 5 M Nys, 6 S Banerjee, 5 D Gladman 7 1 Swedish Medical Center and University of Washington, Seattle, WA, USA; 2 New York Medical College, Valhalla, NY, USA; 3 Leiden University Medical Center, Leiden, Netherlands; 4 St Vincent s University Hospital and University College Dublin, Dublin, Ireland; 5 Bristol-Myers Squibb, Princeton, NJ, USA; 6 Bristol-Myers Squibb, Braine-l Alleud, Belgium; 7 University of Toronto and Toronto Western Hospital, Toronto, ON, Canada EULAR Annual European Congress of Rheumatology 14 17 June 2017 Madrid, Spain

Introduction Unmet need exists for new targeted therapies for PsA PsA susceptibility is associated with Class I MHC molecules that are involved in antigen presentation to T cells 1 T cells are implicated in disease pathogenesis Abatacept, a selective T-cell co-stimulation modulator, 2 is a potential therapy for PsA with a distinct mechanism of action upstream of currently available agents 3 Abatacept is an approved treatment for RA with >10 years post-marketing experience CD80/86 Co-stimulatory pathway CD28 Abatacept Fully human soluble fusion protein Works early in the inflammatory process to reduce T-cell activation APC T cell MHC T-cell receptor APC=antigen-presenting cell; MHC=major histocompatibility complex; PsA=psoriatic arthritis 1. FitzGerald O, et al. Arthritis Res Ther 2009;11:214; 2. Cutolo M, et al. Autoimmun Rev 2013;12:758 67; 3. Ramiro S, et al. Ann Rheum Dis 2016;75:490 8. Figure adapted from Kremer JM. J Clin Rheumatol 2005;11:S55 62

Study Design Screening (7 42 days) Day 1 Randomization stratified by: MTX use prior TNFi use plaque psoriasis 3% BSA Double-blind phase Placebo SC weekly Abatacept 125 mg SC weekly Week 16 Early escape to open-label if <20% improvement in joint counts Week 24 1 Endpoint: ACR20 Open-label phase Abatacept 125 mg SC weekly Week 44 End of early escape open-label phase Week 52 Eligibility criteria Age 18 years Met CASPAR criteria Active arthritis ( 3 swollen and 3 tender joints) Active plaque psoriasis with 1 qualifying target lesion 2 cm in diameter Inadequate response or intolerance to 1 non-biologic DMARD May have failed TNFi agents Sample size calculation assumptions Estimates based on results of Phase II study of abatacept in PsA 1 BSA=body surface area; SHS=Sharp/van der Heijde score; TNFi=tumour necrosis factor inhibitor 1. Mease P, et al. Arthritis Rheum 2011;63:939 48

Baseline Patient Characteristics Data are mean (SD) unless indicated otherwise *n=124; n=123 Abatacept (n=213) Placebo (n=211) Age, years 51.0 (10.7) 49.8 (11.3) Female, n (%) 121 (56.8) 112 (53.1) Region, n (%) South America Europe North America Rest of World 95 (44.6) 53 (24.9) 44 (20.7) 21 (9.9) 80 (37.9) 59 (28.0) 40 (19.0) 32 (15.2) Prior TNFi, n (%) 129 (60.6) 130 (61.6) Concomitant MTX, n (%) 129 (60.6) 127 (60.2) MTX weekly dose, mg 17.1 (7.0)* 17.1 (9.2) Concomitant oral corticosteroid, n (%) 56 (26.3) 51 (24.2) PsA duration, years 8.3 (8.1) 8.8 (8.3) Psoriasis 3% BSA, n (%) 146 (68.5) 148 (70.1) Enthesitis, n (%) 140 (65.7) 132 (62.6) Dactylitis, n (%) 61 (28.6) 50 (23.7)

Baseline Disease Characteristics Abatacept (n=213) Placebo (n=211) TJC 68 21.0 (13.4) 19.3 (13.1) SJC 66 12.1 (7.8) 11.1 (7.2) DAS28 (CRP) 5.0 (1.1) 4.9 (1.1) Leeds Enthesitis Index (range: 0 6) 2.1 (2.0) 1.9 (2.0) Leeds Dactylitis Index Basic 20.3 (56.0) 16.9 (45.7) PASI in patients with psoriasis 3% BSA 7.4 (8.0) 7.2 (7.8) HAQ-DI 1.3 (0.7) 1.3 (0.7) Total SHS, PsA-modified 20.0 (46.8) 17.7 (39.6) CRP, mg/l 14.0 (20.9) 14.3 (30.3) Elevated CRP >ULN (3 mg/l), n (%) 146 (68.9) 131 (62.7) Data are mean (SD) unless indicated otherwise Patient numbers in the abatacept and placebo arms were 210 and 208 for DAS28 (CRP), 145 and 148 for PASI, 212 and 211 for HAQ-DI, 205 and 202 for PsA-modified total SHS, and 212 and 209 for elevated CRP PASI=Psoriasis Area and Severity Index; ULN=upper limit of normal

Abatacept At week 24 Peripheral Arthritis Axial Disease Enthesitis- % Complete Resolution Dactylitis-% Complete Resolution Skin %PASI75 Nails Abatacept 39.4 % ACR20; %non progression xray 42.7% 32.9% complete resolution 44.3% complete resolution 16.4% PBO % 22.3 ACR 20; %non progression xray 32.7% 21.7% complete resolution 34.0% complete resolution 10.1% Peripheral Arthritis p <0.001; All others could not be analyzed because in hierarchy they were below HAQ-DI which did not meet statistical significance. Philip Mease, Alice B Gottlieb, Désirée van der Heijde, Oliver FitzGerald, Alyssa Johnsen,Marleen Nys,Subhashis Banerjee, Dafna Gladman:ARD Online First, published on May 4, 2017 as 10.1136/annrheumdis-2016-210724.

Tofacitinib JAK kinase inhibitor FDA approved for rheumatoid arthritis

Tofacitinib @ 3 months Except xray data Biologics Naive Peripheral Arthritis: % ACR 20/% Non progression on mtss at 12 months Axial ND Enthesitis Change in LEI Index Dactylitis Change in dactylitis score 5 mg BID 50/96-0.4+0.2 NS -3.5+1.0 43 10 mg BID 61/95-0.8+0.2-5.5+0.9 44 Adalimumab 55/98-1.1+0.2-4.0+1.0 39 Placebo (x 3 months) 33 /xrays not done for placebo at 12 months -0.4+0.2-2.0+1.1 15 Skin % PASI 75 Nails ND Mease et al NEJM 377:16 15371550, 2017; Inhibition of radiographic progression at 12 months; all patients on a cdmard; adalimumab = active control; no stats on dactylitis and xray non progression

TNF- Blockers

Comparative Data at Primary Endpoint Adalimumab Etanercept Infliximab Golimumab/ Certolizumab % PASI 75 75 49 80 58 (tested in only PSA)/80 (PSO) % ACR 20 58 59 58 51/58 Safety (Perceived) 4+ 4+ 2+ 3+ Adalimumab (A), Etanercept (E), Certolizumab and Infliximab (I) are FDA approved for controlling signs and symptoms, inhibition of radiographic progression and improvement of quality of life in PSA; A, E, I also for moderate to severe psoriasis. Golimumab is FDA approved for controlling signs and symptoms in PSA

Conclusion Class Peripheral Arthritis: Signs/Symptoms Inhibition of XRAY Progression Enthesitis Dactylitis Skin Nails IL-17 Mabs yes yes yes yes 4+ Yes IL-23 Mab yes? yes yes 4+ Probably yes Tofacitinib yes??yes?yes 1-2+?yes Abatacept yes??? no? TNF inhibitors yes yes yes yes 2-3.5+ yes