New therapies in ankylosing spondylitis: targeting the IL-17 pathway Dominique Baeten, MD, PhD Clinical Immunology and Rheumatology Academic Medical Center/University of Amsterdam
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
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
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
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;361:888-898 Bettelli et al. Nature. 2006 Veldhoen et al. Immunity. 2006 Mangan et al. Nature. 2006
Th17 Cells: A New Distinct Lineage of Effector Helper T cells Miossec et al. N Engl J Med. 2009;361:888-898 Park et al. Nat Immunol. 2005;6:1133-41 Harrington et al. Nat Immunol. 2005;6:1123-32
The IL-23/IL-17 axis IL-23R SNP HLA-B27 Th17 cells Other IL-17 producing cells Animal models IL-17 blockade
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
% Max pstat3 (fold MFI) IL-17A production (pg/ml) IL-17A mrna fold IL23R R381Q impairs IL-23 induced Th17 effector responses 345 245 145 45 40 30 15 0 ** 6 4 2 0 * G A G A pstat3 (fold MFI) 1.72 1.44 1.14 1.06 2.5 * 100 80 60 40 20 100 80 60 40 20 100 80 60 40 20 100 80 60 40 20 2.0 1.5 1.0 0.5 0 CTR IL-23 10 1 10 2 10 3 10 4 10 5 0 10 1 10 2 10 3 10 4 10 5 0 10 1 10 2 10 3 10 4 10 5 0 10 1 10 2 10 3 10 4 10 5 pstat3 0.0 G A *p<0.05,**p<0.01 Di Meglio, Plos One 2011 Sarin, PNAS 2011
2) HLA-B27 induced UPR DeLay, Arthritis Rheum 2009 Goodall, PNAS 2010
Increased IL-23 production by AS macrophages Zeng L, Arthritis Rheum 2011
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-10 25000 100 20000 80 15000 60 10000 40 5000 20 0 HD SpA RA 0 HD SpA- RA 40000 200 30000 150 20000 100 10000 50 0 HLA-B27+ 0 HLA-B27- HLA-B27- HLA-B27+
3) Th17 cells in SpA Jandus, Arthritis Rheum 2008 Shen, Arthritis Rheum 2009
Th17 cells in SpA Bowness, J Immunol 2011
Th17 cells in SpA Kenna, Arthritis Rheum 2012
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
IL-17 producing cells in RA synovitis Hueber. J Immunol. 2010
% of total mast cells semiquantitative score IL-17 producing cells in SpA synovitis 3 c-kit+ cells 2 1 0 SpA synovial tissue RA IL-17 expression p= 0.015 100 80 60 IL-17 Mast cell tryptase 40 20 0 RA PsA+SpA Noordenbos, Arthritis Rheum 2012
Mast cell targeting in SpA synovitis Noordenbos, Arthritis Rheum 2012
IL-17 producing cells in AS facet joints Ankylosing Spondylitis Osteoarthritis Appel, Arthritis Res Ther 2011
5) IL-23/IL-17 in experimental SpA Abe, Mod Rheumatol 2009
IL-17 in HLA-B27 tg rats Glatigny, Arthritis Rheum 2012
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 LY2439821 Humanized anti-il-17 monoclonal antibody Phase III
% Responders Hueber, Sci Transl Med. 2010 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
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 100 90 80 70 60 50 40 30 20 10 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Time (weeks) 83% 75% 40% 10% Hueber, Sci Transl Med. 2010 Papp, N Engl J Med 2012 Leonardi, N Engl J Med 2012
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 (1.6-51.4) 8.4 (1.7-33.4) 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 (0.2-61.7) 8.2 (1.4-44.3) 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%)
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
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
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!