Paradigm shift of the treatment in systemic autoimmune diseases

Review Talk 4 in JSI212 Paradigm shift of the treatment in systemic autoimmune diseases Yoshiya Tanaka, MD, PhD Professor and Chairman, Department of Internal Medicine-I, School of Medicine and Deputy Director, The University Hospital, University of Occupational & Environmental Health, Japan

Paradigm shift of the treatment in systemic autoimmune diseases 1. Dream comes true with TNF inhibitors? 2. TNF is only a target? 3. Emerging only for RA? 4. Biologics are enough? 5. Biologics need for a lifetime?

DMARD cannot stop progress of joint destruction in RA patients with stage I: radiographic changes after 2-year treatment Ⅰ Ⅱ DMARD (n=41) Ⅰ Ⅱ 62.9 Combined DMARD (n=38) Ⅰ Ⅱ 35.3 2 4 6 8 1 ( % ) *p<.5 Nakayamada S, et al Clin Rheumatol (23) 15, 27

Biologics purified from biological constructs in body (relative safety) pin-point therapy targeting certain molecule which is relevant to the disease (high efficacy)

Pathology of synovitis in rheumatoid arthritis osteoarthritis RA

Migration of lymphocytes into synovial tissue Rolling/tethering T-cell Activation of integrin High-affinity adhesion Vascular lumen chemokine Activated integrin Trans-endothelial migration TNF-α, IL-1, IL-6 Endothelial cells ICAM-1 TNF-α, IL-1, IL-6 Inhibition of a Activated disease lymphocyte process may lead to disease chemokine control macrophage Rheumatoid synovial tissue Tanaka Y, et al: Nature 361: 79, 1993

Biologics targeting RA launched in Japan infliximab etanercept adalimumab golimumab tocilizumab abatacept S Structure Chimeric IgG TNFR-IgG1 Human IgG Human IgG Humanized IgG CTLA4-IgG1 Target TNFα TNFα LTα TNFα TNFα Soluble and membrane-il-6r CD8/CD86 on APC Affinity 1.8x1 9 1 1 2.3x1 1 1.8x1 1.7x1 9 8.3x1 7 Half life 8-1 days 3-5.5 days ~14 days ~14 days 5.5-1 days 1 days administration DIV SC SC SC DIV DIV Amount 3 mg/kg (~1) 5 mg 4 mg(~8mg) 5mg 1mg 8 mg/kg 5mg, 75mg, 1g Interval q8w (~q4w) 1/W q2w q4w q4w q4w Marketed 23/7 25/3 28/6 211/9 28/4 21/9

Revolution of treatment of RA by biotherapies Improvement of signs and symptoms was a goal (~1999) methotrexate (MTX) as an anchor drug + TNF-inhibitors 1) Clinical remission and its maintenance (SDAI 3.3) no signs, no symptoms, no laboratory abnormality 2) Structural remission ( mtss<.5) no progress of joint destruction 3) Functional remission (HAQ.5) no progress in functional disturbance

Efficacy of infliximab for refractory RA: DAS28 (RECONFIRM-2: UOEH, Saitama MC, Tokyo Women s U RC) >4.1 2.7-4.1 High activity 9% are at the high disease activity after 6-12 months 4% improved at the low disease activity and 3% became in the clinical remission moderate 2.3-2.7 Low activity before At half a year At 1 year <2.3 DAS28-CRP (N=41, LOCF) Clinical remission Tanaka Y, et al. Mod Rheumatol (28) 18, 146

Efficacy of infliximab for refractory RA: ΔmTSS (RECONFIRM-2J: UOEH, Saitama MC, Tokyo Women s U RC) Ave.=21.33 Ave.=-.3 week week 54 week week 54 mtss of enrolled 67 patients were 14+87 at week Yearly progression of TSS (LOCF) Takeuchi T, et al. Mod Rheumatol (28) 18: 447

Role of TNF/IL-6 in joint destruction in RA MCP-1 Monocyte (precursor of osteoclast) migration RANK RANKL osteoclasts Maturation and activation LFA-1 ICAM-1 Activated osteoclasts NF-κB Synovial cells and T cells TNF, IL-6 TCZ, TNF-inhibitors Tanaka Y and Okada Y. Curr Drugs Targets (25) 4, 325

Average of HAQ score 1 years outcome of ETN for RA (US): HAQ 1.8 1.6 1.4 1.2 1..8.6.4 Long established RA (disease duration > 3Y, average=12.4 Y, #714) Early RA (disease duration < 3Y, average=.9y, #558).2. 1 2 3 4 5 6 7 8 9 1 Treatment with etanercept (years) Weinblatt M et al, Arthritis Care Res (211) 63, 373

IL-6 Mechanisms of actions of tocilizumab tocilizumab IL-6 Soluble IL-6 receptor (sil-6r) Membrane-bound IL-6 receptor (IL-6R) gp13 Outer space Cell membrane Inner space Jak-Stat signal pathway transcription DNA

Mechanism of action of CTLA4-Ig abatacept activated B cell antigen-presenting cell T cell autoantibody IL-6 MHC TCR antigen (main) signal TNF-α IL-2 CD8/86 CD28 co-stimulatory signal IFN-γ RANKL CTLA4-Ig abatacept activated macrophage IL-6 TNF-α IL-1

Biologics for autoimmune diseases Murine IgG CDR Soluble receptor p75 Human IgG PEG chimeric humanized human IgG PEG-IgG Ig-fusion protein TNF-α (infliximab) CD2 (rituximab) IL-6R (tocilizumab) CD2 (ocrelizumab) CD22 (epuratuzumab) TNF-α (adalimumab) (golimumab) BLyS (belimumab) CD2 (ofatumumab) IFNα (cifalimumab) IL-12/IL-23 (p4) (ustekinumab) RANKL (denosumab) TNF-α (certolizumab) TNFR2-Ig (etanercept) CTLA4-Ig (abatacept) TACI-Ig (atacicept)

Systemic manifestations of SLE Ocular (1%) Sicca (15%) Neuro-psychiatric (NPSLE) (6%) Systemic: fatigue, malaise fever, annorexia, weight loss (95%) Cutaneous (8%) Musculoskeletal (95%) Thrombosis (1%) Cardiopulmonary (6%) Renal (8%): lupus nephritis Gastrointestinal (4%) Hematologic (85%) Vasculitis (5%) Hahn BH. In Harrison s Principles of Internal Medicine, 18 th edition (211) 2724

Algorism of initial therapy of SLE Diagnosis, estimation of disease activity and organ involvement Not life- or organ-threatening Life- or organ-threatening QOL: acceptable QOL: not accepatable High dose GC + (MMF or IVCY) Conservative management Conservative treatment With low-dose GC response No response Maintenance By Low GC + MMF or AZ Developing agents (anti-cd2, anti-cd22, CTLA4-Ig, anti-baff, etc Hahn BH. In Harrison s Principles of Internal Medicine, 18 th edition (211) 2724

Biphasic reduction of B cells by rituximab in SLE CD4 absent µh-chain + stem cell pro-b cell µh-chain + pre-b cell CD2 + IgD + CD27 - naive B cell CD2 + IgD - CD27 + CD4 + CD8 + memory B cell CD2 high memory T cell CD4L + IgG + CD38 + VH4.34 + plasma cell rituximab [LONG-TERM EFFECT] Inhibition of differentiation of B cells Re-constitution of B cells Resetting immunity and remission-induction Humoral immunity (immune-complex-mediated) rituximab [RAPID EFFECT] Preferential reduction of CD2 high CD4 + CD8 + B cells Regulation of B-T cell activation Reduction of disease activity Cellular immunity (B and T cell-mediated) Ig

Emerging treatments for autoimmune diseases rituximab ocrelizumab ofatumumab Antigenpresenting cell CD8/CD86 atacicept CD2 TACI B cell APRIL BCMA belimumab BAFF-R Syk-i Fostamatinib BAFF (BLyS) CD4L CD28/CTLA-4 abatacept CD4 T cell Jak-i Tofacitinib CD8/CD86 CD22 epratuzumab anti-il-6 sirukumab sarilumab anti-il-17 secukinumab LY2439821 anti-gmcsf-r mavrilimumab anti-p4 (IL-12/23) ustekinumab anti-il-2 NNC19-12 anti-ifnα sifalimumab rontalizumab anti-ifnr MEDI-546 anti-rankl denosumab

Jak3: role in cytokine signaling and SCID γc IL-2, IL-4, IL-7, IL-9, IL-15, IL-21 P P X SCID Stat P Jak1 Jak3 P Jak3-SCID P P CP-69,55 a Jak inhibitor Stat P P Stat transcription 312.4 Yamaoka K, O Shea JJ, et al. Blood. 25;16:3227

Syk (spleen tyrosine kinase) antigen, Ig B cell receptor Fc receptor integrin fostamatinib (R788 transmembrane adaptor PY SH2 phosphorylation by Src-family kinase ITAM PY SH2 Syk or ZAP-7 732.5 Downstream signaling Iwata S, et al. J Allergy Clin Invest (in press)

Significance of Syk in B cell activation Costimulatory molecule B cell receptor Syk-inhibitor Syk TLR CpG-DNAfor TLR9 (ssdna, dsdna) TRAF6 NFκB Ig IL-6 Iwata S, et al. J Allergy Clin Invest (in press)

Paradigm shift of treatment of RA w/ biologics Relief from joint pain MTX + TNF-inhibitors 1. Induction of clinical remission (SDAI < 3.3) Sustained remission 2. Structural remission ( mtss <.5) 3. Functional remission (HAQ <.5) Biologic-free remission?

A case who discontinued infliximab 35F (stage Ⅱ) MTX Infliximab 3mg/kg MS TJ# SJ# 24 24 24 15 26 5 9 2 1 1 1 1 1 1 MTX discontinued 1 1 2 1 1. IFX discontinued 6 CRP (mg/dl) DAS28 DAS28<2.6 DAS28 3 6/5 7 9 11 7/1 3 5 7 9 11 8/1 3 5 7 9 11 9/1 3 6

RRR study: study flow diagram and results Enrolled in RRR IFX was discontinued (n=114) withdrawn (n=12) RRR-achieved DAS28 at year 1 <3.2: n=56 (55%) remission (DAS28<2.6): n=44 (43%) LDA (2.6 DAS28<3.2): n=12 (12%) Estimated at year 1 (n=12) RRR-failed Failed from LDA for 1 year: n=46 (45%) DAS28 at year 1 3.2: n=17 (17%) flared up within 1 year: n=29 (28%) LDA: low disease activity Tanaka Y, et al. Ann Rheum Dis (21) 69:1286

Baseline factors affecting bio-free remission in RA treated with IFX: logistic multivariate analysis (in our department) estimated SE χ2 P-value gender.151943.2621.542922.461224 Disease duration.11635.4465 6.79151.9159 #SJC.61451.36662 2.89452.9371 CRP.4139.93878.19116.661997 DAS -.1125.23694.24789.619132 RF.182.173 1.15394.313614 Changes of positivity of RF by TNF-inhibitors By biologic-free 77% 52% By drug-free 4% % MMP-3.576.767.56478.452341 HAQ.633829.286998 4.877366.27211 MTX dose.14841.694 5.937255.14824 RF: (-), 1(+) -2.58378.584188 19.5616.1 PSL dose -.1434.3184.212917.644491 Is next target immunological remission?

1 Contribution of TNF-α to SKG Mice Incidence of arthritis (%) Arthritis severity scores TNF-α +/+ (n=24) 6 8 5 6 4 2 TNF-α +/- (n=28) TNF-α -/- (n=27) 4 3 2 1 8 12 16 2 24 28 32 8 12 16 2 24 28 32 Weeks Weeks Hata H, et al: J Clin Invest (24) 114: 582

Revolution of treatment of autoimmune diseases Improvement of signs and symptoms Anti-rheumatic drug methotrexate + Biologics TNF-inhibitors TCZ, ABT, RTX 1) Clinical remission 2) Structural remission 3) Functional remission RA Anti-lupus drug HGQ, MMF, AZ, CY, Syk-I + Biologics anti-cd2, CD22, BAFF? ABT, atacicept? 1) Clinical remission 2) improvement of organ damage 3) improvement of life span SLE