Update on non-TNFi therapies for spondyloarthritis Tse Sau Mei Tuen Mun Hospital

Pathogenesis of spondyloarthritis A heterogeneous group of chronic inter-related inflammatory arthropathies affecting the synovium, entheses and certain extra-articular sites Ankylosing spondylitis (AS), psoriatic arthritis (PsA), reactive arthritis (ReA), enteropathic arthritis, juvenile SpA, undifferentiated SpA Etiology is still largely unknown Complex interplay of genetics and environmental factors Histologically: infiltration of T cells ( CD4+ and CD8+), CD68+ macrophages, CD20+ B cells, proliferation of fibroblasts Cytokines: TNFα, IL-6, IL-1, IL-17 Emerging role of Th17 cells, IL-23/IL-17 axis EULAR Textbook on Rheumatic Disease Autoimmunity Reviews 2014;13:64–69

Unmet need in SpA Axial SpA Mainstay of treatment: NSAIDs, anti TNF Tolerability of NSAIDs Up to 40% on anti TNF do not respond sufficiently due to intolerance or inefficacy Lack of evidence on halting new bone formation DMARDs are not effective in axial SpA

Non-TNF inhibitor therapies for SpA Anti IL-12/23 Ustekinumab Anti IL-17 Secuknumab Brodalumab PDE4 inhibitors Apremilast Bisphosphonates Pamidronate, zoledonate, neridronate Targeting T/B cells Abatacept Rituximab Anti IL-6 Tocilizumab Sarilumab

The IL-23/IL-17 axis Nature 2007; 448;416

The IL-23/IL-17 axis in SpA Arthritis Rheum 2014;66(2):231–241 Schematic drawing depicting cells, effector cytokines, and possible contributions to spondyloarthritis (SpA) pathogenesis. Dendritic cells (DCs) and macrophages are major sources of interleukin-23 (IL-23), which is produced in response to microbes and their products signaling through pattern recognition receptors. Consequences of HLA–B27 misfolding and endoplasmic reticulum stress can augment IL-23 and IL-1 production, and CARD9 variants could affect production of this cytokine as well. Cells of both the adaptive and the innate immune response are implicated in SpA pathogenesis. CD4 Th17 cell expansion has been reported, and killer cell immunoglobulin-like receptor 3DL2 Th17 cells may be triggered by surface HLA–B27 dimers on DCs and macrophages to produce IL-17. Th17 development and survival may be influenced by variants of the IL-23 and IL-6 receptors (IL23R, IL6R), as well as IL-27 and Tyk-2– and STAT3-mediated cytokine responses. Tissue inflammation in SpA involves innate immune IL-17–expressing mast cells (synovium), neutrophils (facet joints), and CD3CD4CD8 entheseal-resident T cells. The latter produce IL-22, which can drive osteoproliferation in rodent models. Variants in IL6R, TYK2, and STAT3 may also affect tissue responses to cytokines. IFN interferon-; TNF tumor necrosis factor; iNKT invariant natural killer T; GI gastrointestinal. Arthritis Rheum 2014;66(2):231–241

Targeting IL-12/23 - Ustekinumab A fully human monoclonal antibody directed against the p40 subunit shared by IL-12 and IL-23 Approved for treatment of moderate-to-severe psoriasis In PsA, 2 phase 3 RCTs, PSUMMIT 1 and PSUMMIT 2 (n=927) significantly better clinical efficacy at week 24 , response maintained to week 50 Peripheral joint count, psoriasis, dactylitis, enthesitis, axial symptoms (BASDAI) Efficacy irrespective of MTX use Better response in <100kg Less improvement in TNFi experienced patients Significantly inhibited radiographic progression of joint damage UST (111) PBO (61) BASDAI20* 54·1% 26·2% BASDAI50* 27·9% 13·1% BASDAI70* 14·4% 0·0% Lancet 2013; 382: 780–89 Ann Rheum Dis 2014;73:990–999 Ann Rheum Dis Published Online First 19-2-2014

Ustekinumab – Axial SpA Study Subjects Treatment groups Results TOPAS study Open label single arm 28 weeks 20 Active AS TNF-naive UST 90mg at week 0, 4, 16 ASAS40 response= 65% Improvement in other clinical parameters and patient-reported outcomes ↓active inflammation on MRI ↓ NSAIDs intake Overall well tolerated Ann Rheum Dis 2014;73:817–823

Targeting IL-17 - Secukinumab A fully human monoclonal anti-IL17 antibody Demonstrated favorable safety and clinical efficacy in phase I and II studies in moderate to severe psoriasis In PsA, proof on concept study showed trend towards clinical improvement Ann Rheum Dis 2014;73:349–356

Secukinumab – Axial SpA Study Subjects Treatment groups Results Proof of concept study RCT Phase 2 28 weeks 30 Active AS (13 prior TNFi) Secukinumab (2x10mg/kg on D1 and D22) VS placebo ASAS20 response rate at wk 6: 59.2% vs 24.5% * Improved QoL Decrease in CPR, ESR Decrease in mean MRI scores Lancet 2013; 382: 1705–13

Targeting IL-17 - Brodalumab A human monoclonal antibody against interleukin-17 receptor A Promising results in patients with active PsA at 12 weeks in a phase 2 RCT (n=106), efficacy sustained through week 52, irrespective of prior biologic use Change in BASDAI in Brodalumab 280mg : -1.1 vs -0.2 (p<0.01) Not tested in axial SpA yet Ixekizumab – tested in PsO only N Engl J Med 2014;370:2295-306

Small molecule – PDE4 inhibitors Phosphodiesterases (PDEs) are enzymes responsible for the hydrolysis of cAMP, an intrinsic modulator of inflammatory responses PDE4 is the predominant PDE in inflammatory cells Inhibition of PDE4 elevates intracellular cAMP levels,  downregulates the inflammatory response through TNF, IL-23, IL-12, and other inflammatory cytokines Apremilast is a novel, orally available small molecule that specifically targets PDE4 In active PsA, RCTs ( including PALACE-1) confirmed efficacy including peripheral arthritis, enthesitis, psoriasis and physical function; irrespective of MTx use Side effects: nausea, diarrhoea, headache Arthritis Rheum 2012; 64(10):3156-67 Ann Rheum Dis 2014;73:1020–1026

Apremilast – Axial SpA Study Subjects Treatment groups Results RCT (Phase 2 pilot study) 12 weeks 36 active AS Activity on MRI (3 with prior TNFi) Apremilast 30mg bd Vs Placebo At week 12: Change in BASDAI: -1.59 vs -0.77 Numerically better improvement in BASFI, BASMI, fatigue, night pain Continued improvement without peaking of effects Acceptable safety profiles Primary endpoint not met Ann Rheum Dis 2013; 72:1475-80

Bisphosphonates Anti-inflammatory properties and analgesic effects Act on cells from the monocyte/macrophage lineage and may modulate the generation of pro-inflammatory cytokines Only intravenously administered bisphosphonates were used as a therapeutic agent in SpA as a high serum concentration and thus a more rapid response could be achieved Pamidronate Zoledronic acid Neridronate Curr Opin Rheumatol 2007;19(4):340-5

Bisphosphonates in SpA Study Subjects Treatment groups Results RCT 6 months 84 AS Pamidronate 60mg vs 10mg monthly infusion ↓in BASDAI: 2.22( 34.5%) vs 0.93(15%)*  Dose dependent effects 6 open label trials 99 AS, 9 peripheral SpA Pamidronate: mild and delayed clinical improvement (after 3rd infusion); more evident with higher dosage and shorter interval Placebo controlled trial 87 uSpA Pamidronate 60mg monthly x 6 m Vs placebo Superior ASAS20 and BASDAI-50 response Open label 11 AS with MRI osteitis Zoledronic acid 5mg infusion Improved MRI scores by 19-76%; Improved clinical parameters 60 AS Neridronate 10mg monthly infusion x 6 Standard infliximab therapy (5mg/kg) Comparable reduction in BASDAI ( -1.72, -1.62), BASFI and axial pain Arthritis Rheum 2002;46(3):776-73 Curr Opin Rheumatol 2007;19(4):340-5 Rheumatol Int 2012;32:3945–3950 Ann Rheum Dis 2014;73:1273–1274 Rheumatology 2014;53:90-94

Bisphosphonates in SpA In a local 48-week randomized controlled trial comparing the clinical efficacy and radiological inflammation of pamidronate vs golimumab in 30 axial SpA patients BASDAI improved in golimumab but not pamidronate; while pain relief occurred in both groups P = NS P <0.05 P < 0.01 P < 0.01 BASDAI Spinal pain Dr Mok CC

Targeting T cells and B cells Immunohistiochemical stains of sacroiliac joint biopsies from SpA patients showed that T cells and macrophages were the most frequent infiltrates The number of CD20+ B cells in the persistently inflamed joints from AS patients has been reported to be significantly higher than joints from controls or from AS patient without active inflammation Ann Rheum Dis 2000;59:135-40 Arthritis Rheum 2006;54:2845-2851

Abatacept A fully humanized fusion protein that targets the co-costimulatory signal for full T-cell activation Effective in active PsA in phase II RCT ( n=170) Study Subjects Treatment groups Results Open label pilot study 24 weeks 30 active AS (15 TNFi-naïve 15 TNFi-failure) Abatacept 10mg/kg on days 1, 15, 29 then Q28D At week 24, ASAS40 reached in: 13% vs 0% in TNF naïve vs failure ASAS20: 27% vs 20% a major response was not observed Open label study 7 active AS/uSpA Who failed 2 TNFis None achieved BASDAI50 1 patient: 49.3% reduction in BASDAI IBP persisted Enthesitis improved  No strong efficacy in axial form Arthritis Rheum 2011;63(4):939–48 Ann Rheum Dis 2011;70:1108-10 Joint Bone Spine 2012;79:47-50

Rituximab A chimeric monoclonal antibody specific for human CD20 on mature B cells Maybe effective in PsA in an exploratory study of 9 patients Study Subjects Treatment groups Results RCT Phase 2 24 weeks 20 Active AS 10 – TNF-naive 10 – TNF-failure Rituximab 1g on days 1 and 15 Higher response in TNF-naïve: ASAS20 =50% vs 30% maybe effective in TNFi-naïve patients French Registry (Auto-immunity and Rituximab) 26 cases: AS – 10 uSpA – 7 PsA – 9 ( 23 prior TNFi) Mean number of rituximab course: 1.5 Efficacy was noted in 11 cases: 3/3 TNF-naïve patient responded 8/20 TNF-failure patient responded No predictive factor of response (eg axial vs peripheral)  moderate efficacy, more marked if TNFi-naïve Ann Rheum Dis 2012;71:1868-71 Arthritis Rheum 2010;62(5):1290-97 J Rheumatol 2012;39(12):2327-31

Targeting IL-6 Interleukin-6 (IL-6) is a pro-inflammatory cytokine found at elevated levels in serum and biopsy specimen from sacroiliac joint in AS patients Levels correlate with disease activity Clinical and radiological efficacy of TNF-blockade in AS is associated with significant reduction of IL-6 and CRP levels Tocilizumab and Sarilumab - Monoclonal antibody to the human IL-6 receptor Humanised vs fully human Inflamm Allergy Drug Targets 2012;11:262–5 Rheumatol 2007;26:211–15 Ann Rheum Dis 2008;67:511–17 Arthritis Rheum 2011;63:3789–800

Tocilizumab and Sarilumab Study Subjects Treatment groups Results Retrospective study N=21, TNFi failure Axial and peripheral SpA TCZ 4 or 8mg/kg monthly Reduction in acute-phase reactants but failed to substantially improve axial SpA and was inconsistently effective in peripheral SpA RCT Phase 2/3 102 TNFi-naïve active AS TCZ 8mg/kg monthly Vs placebo Week 12 ASAS20 response: no significant difference negative study ; terminated early Phase 2 301 Active AS Sarilumab 100, 150, 200mg SC biweekly 10, 150mg weekly Or placebo Week 12 no significant difference in ASAS20 response between placebo and any treatment groups negative study Arthritis Research & Therapy 2012, 14:R53 Ann Rheum Dis 2014;73:95–100 Ann Rheum Dis Published Online First: 18 Feb 2014

Summary √ (phase 3 RCTs) √ (proof of concept) √ (phase 2 RCT) PsA Axial SpA Other Ustekinumab √ (phase 3 RCTs) √ (proof of concept) PSO, IBD Secukinumab √ (phase 2 RCT) PSO, Uveitis, RA, Brodalumab √ (Phase 2 RCT) / PSO Apremilast √ (phase 3 RCT) Bisphosphonates √ (Open label / RCT) Abatacept X (open label) Rituximab √ (exploratory) √ (phase 2 RCT, registry) Tocilizumab/ Sarilumab X (RCT)

Conclusions Many of the non-TNFi biologics have proven efficacy in PsA Subgroup analysis on those with axial involvement (using BASDAI) shows improvement in back pain as well in these studies  For axial SpA patients, large scale studies are still lacking Phase II trials seem to be promising for agents that targets IL-17 and IL-23

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