New therapies in ankylosing spondylitis: targeting the IL-17 pathway

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1 New therapies in ankylosing spondylitis: targeting the IL-17 pathway Dominique Baeten, MD, PhD Clinical Immunology and Rheumatology Academic Medical Center/University of Amsterdam

2 Immunological disease continuum Immune-mediated inflammatory diseases Autoinflammatory: Local factors at tissues sites predisposed to disease lead to activation of innate immune response, with production of cytokines and other inflammatory mediators causing target tissue damage (i.e., self-directed tissue inflammation) Rare monogenic autoinflammatory diseases Polygenic autoinflammatory diseases FMF Crohn s disease Ulcerative colitis Sarcoidosis Gout Idiopathic uveitis Mixed pattern diseases (with evidence of acquired component [MHC association] and autoinflammatory component) Ankylosing spondylitis Reactive arthritis Psoriasis/psoriatic arthritis Behcet syndrome HLA-B27-associated uveitis Polygenic autoimmune diseases (organ-specific and non-specific) Rheumatoid arthritis Multiple sclerosis Type I diabetes Systemic lupus erythematosus Rare monogenic autoimmune diseases Autoimmune lymphoproliferative disease Autoimmune: Aberrant dendritic and lymphocyte responses in lymphoid organs overcome tolerance, with development of immune reactivity to self antigens McGonagle D & McDermott MF. PLoS Med. 2006

3 Hypotheses for HLA-B27 HLA-B27 ERAP1 Bacterial stress Antigen presentation Autoreactive T cells Heavy chain homodimers NK cell activation Heavy chain misfolding Unfolded protein responses Mechanical stress TNFR1 TRADD TNF autoimmune autoinflammatory Dougados and Baeten, Lancet 2011

4 IL-23 Rather than IL-12 Drives T cell Dependent Autoimmune Disease IL-12 is formed from the p40 and p35 subunits IL-23 is formed from the p40 and p19 subunits Cua et al. Nature 2003 Murphy et al. J Exp Med 2003

5 Differentiation of Th17 Cells TGF + IL-6/IL-1 induce differentiation of Th17 cells, and IL-23 promotes their development and production of IL-17A Miossec et al. N Engl J Med. 2009;361: Bettelli et al. Nature Veldhoen et al. Immunity Mangan et al. Nature. 2006

6 Th17 Cells: A New Distinct Lineage of Effector Helper T cells Miossec et al. N Engl J Med. 2009;361: Park et al. Nat Immunol. 2005;6: Harrington et al. Nat Immunol. 2005;6:

7 The IL-23/IL-17 axis IL-23R SNP HLA-B27 Th17 cells Other IL-17 producing cells Animal models IL-17 blockade

8 1) IL-23R Locus Gene Function Associated with AS PsO IBD 6p21 HLA-B27 Antigen presentation Yes 5q15 ERAP1 Aminopeptidase Yes 1p31 IL23R Cytokine receptor Yes Yes Yes 2p15 Yes 21q22 Yes 12p13 TNFR1 Cytokine receptor Probable Yes 16q22 TRADD Signalling Probable 9q32 TNFSF15 Inflammatory cytokine Probable Yes IL1A Inflammatory cytokine Probable 2q11 IL1R2 Cytokine receptor Probable 9q34 CARD9 Innate immune defence Probable Yes 4q21 ANTXR2 Vascular morphogenesis Probable Dougados and Baeten, Lancet 2011

9 % Max pstat3 (fold MFI) IL-17A production (pg/ml) IL-17A mrna fold IL23R R381Q impairs IL-23 induced Th17 effector responses ** * G A G A pstat3 (fold MFI) * CTR IL pstat3 0.0 G A *p<0.05,**p<0.01 Di Meglio, Plos One 2011 Sarin, PNAS 2011

10 2) HLA-B27 induced UPR DeLay, Arthritis Rheum 2009 Goodall, PNAS 2010

11 Increased IL-23 production by AS macrophages Zeng L, Arthritis Rheum 2011

12 Fold relative expression (IFN- ) Fold relative expression (IFN- ) Relative expression (IFN- ) Relative expression (IFN- ) Increased IL-23 production by AS macrophages IL-23 p19 IL HD SpA RA 0 HD SpA- RA HLA-B27+ 0 HLA-B27- HLA-B27- HLA-B27+

13 3) Th17 cells in SpA Jandus, Arthritis Rheum 2008 Shen, Arthritis Rheum 2009

14 Th17 cells in SpA Bowness, J Immunol 2011

15 Th17 cells in SpA Kenna, Arthritis Rheum 2012

16 4) Other IL-17 producing cells Natural killer cells NKT cells Lymphoid tissue inducer (LTi) cells Neutrophils Mast cells Awasthi, J Immunol 2009 Yeremenko, Arthritis Res Ther 2011

17 IL-17 producing cells in RA synovitis Hueber. J Immunol. 2010

18 % of total mast cells semiquantitative score IL-17 producing cells in SpA synovitis 3 c-kit+ cells SpA synovial tissue RA IL-17 expression p= IL-17 Mast cell tryptase RA PsA+SpA Noordenbos, Arthritis Rheum 2012

19 Mast cell targeting in SpA synovitis Noordenbos, Arthritis Rheum 2012

20 IL-17 producing cells in AS facet joints Ankylosing Spondylitis Osteoarthritis Appel, Arthritis Res Ther 2011

21 5) IL-23/IL-17 in experimental SpA Abe, Mod Rheumatol 2009

22 IL-17 in HLA-B27 tg rats Glatigny, Arthritis Rheum 2012

23 6) IL-17 Blockade Drug Mechanism Clinical status Secukinumab AMG 827 Fully human anti-il-17a monoclonal antibody Fully human anti-il-17r monoclonal antibody Phase III Phase II LY Humanized anti-il-17 monoclonal antibody Phase III

24 % Responders Hueber, Sci Transl Med Anti-IL17 Secukinumab Proof of concept trial in RA NS * NS NS Week 6 Week 16 DAS28 kinetics showed rapid and sustained improvements with Secukinumab compared to placebo for the full 16 weeks Fast and sustained responses were also identified in CRP levels, patient global assessment and HAQ scores until week 16

25 PASI 75 response rates (%) Secukinumab and other IL-17 blockers Proof of concept trials in Psoriasis 3 mg/kg 10 mg/kg 3x10 mg/kg Placebo Time (weeks) 83% 75% 40% 10% Hueber, Sci Transl Med Papp, N Engl J Med 2012 Leonardi, N Engl J Med 2012

26 Anti-IL17 Secukinumab Proof of concept trial in AS Demographics and Baseline Characteristics Safety Population Secukinumab (N=24) Placebo (N=6) Females, n (%) 10 (42) 1 (17) Age (years), Mean (SD) 41.1 (10.1) 45.0 (10.0) BMI (kg/m 2 ), Mean (SD) 27.1 (4.8) 25.3 (5.1) Disease duration (years), Median (range) Efficacy Population* 7.4 ( ) 8.4 ( ) Secukinumab (N=23) Placebo (N=6) BASDAI, Mean (SD) 7.1 (1.4) 7.2 (1.8) BASFI, Mean (SD) 6.4 (1.8) 5.3 (3.3) BASMI, Mean (SD) 4.3 (1.9) 3.7 (1.1) C-reactive protein (mg/l), Median (range) 7.0 ( ) 8.2 ( ) HLA B27 status positive n (%) 16 (70%) 5 (83.3%) Prior TNF inhibitor use n (%) 10 (43.5%) 3(50%) Concomitant immunosuppressants (MTX, SSZ) n(%) 7 (30.4%) 3 (50%)

27 Anti-IL17 Secukinumab Proof of concept trial in AS ASAS20 Response Rate (Bayesian Analysis) No of Responders n (%) Posterior mean response rate Posterior mean difference in response rates (Secukinumab vs. Placebo) 95% credible interval Probability (Secukinumab > Placebo) Secukinumab 14/23 (60.9) 59.2% 34.7% 11.5%, 56.3% 99.8% Placebo 1/6 (16.7) 24.5% Probability Density Plot

28 Primary Endpoint: ASAS20 Responses at Week 6 At week 6, a higher proportion of patients achieved ASAS20 response with secukinumab (61% [n=14/23]) compared to placebo (17% [n=1/6]) At the week 1 secondary endpoint, 39% [n=9/23] achieved ASAS20 response Secukinumab (AIN457) Induced ASAS20 Response

29 IL-23/IL-17 as therapeutic target in AS Conclusions Genetic, immunopathological and functional evidence for a role for IL-23/IL-17 in AS/SpA Direct evidence is often incomplete or inconclusive Role of IL-23R SNPs Link with HLA-B27 Cellular source of IL-17 IL-17 isotypes and associated cytokines IL-17 targets Role of IL-17 in structural damage First clinical evidence is strongly supportive Clinical development programs are ongoing It is time for reverse immunology!