ArticlesAnti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial
Introduction
Ankylosing spondylitis is a chronic immune-mediated inflammatory disease, with an estimated prevalence of 0·2–0·5% worldwide. It is characterised by spinal inflammation, progressive spinal ankylosis due to new bone formation, peripheral arthritis and enthesitis, extra-articular manifestations, familial clustering, and a strong genetic association with human leucocyte antigen (HLA)-B27.1 Early onset of the disease in young adults, chronic spinal and extraspinal inflammation, and progressive irreversible structural damage can lead to important morbidity, functional deterioration, and socioeconomic burden.
Non-steroidal anti-inflammatory drugs (NSAIDs) and physiotherapy are the cornerstones of treatment for ankylosing spondylitis. Conventional disease-modifying anti-rheumatic drugs (DMARDs) are not effective for the axial symptoms of the disease. For patients with inadequate response to NSAIDs, treatment with tumour necrosis factor (TNF)-blockers has been recommended.2 However, no approved alternative therapies are available for the roughly 40% of patients who do not tolerate or respond to TNF-blockers. Thus, there is an unmet need for medicines with new modes of action.
Interleukin 17A (IL-17A) has emerged as a novel therapeutic target for ankylosing spondylitis. First, the disease shows a strong genetic association with a series of protective polymorphisms in the IL-23 receptor (IL23R) gene, including rs11209026 (Arg381Gln).3 Functional analyses have indicated that the Arg381Gln polymorphism impairs IL-23–dependent IL-17 production by Th17 cells, suggesting that genetically determined down-modulation of the IL-23/IL-17 axis could provide protection against ankylosing spondylitis.4 Second, intracellular HLA-B27 misfolding leads to an unfolded protein response that potentiates abnormal IL-23 production,5 and ankylosing spondylitis macrophages produce increased levels of IL-23.6 Third, the number of circulating CD4+IL-17+ cells is expanded in ankylosing spondylitis;7 this includes KIR3DL2-expressing T cells that respond to cell-surface HLA-B27 homodimers8 and IL-17–producing γ/δ T cells.9 Fourth, inflamed target tissues indicate an ankylosing spondylitis-specific increase in IL-17–producing innate immune cells.10, 11 Fifth, spondyloarthritis in HLA-B27 transgenic rats and experimental ankylosing enthesitis in (BXSB×NZB) F1 mice were associated with an expansion of Th17 cells and with up-regulated IL-17 expression, respectively.12 Moreover, IL-23 overexpression induces a spondyloarthritis-like disease in B10.RIII mice via RAR-related orphan receptor γt(+)CD3(+)CD4(–)CD8(–) T cells that produce IL-17 and IL-22.13 Finally, trials with anti-IL-12/IL-23 and anti-IL-17 agents have shown significant clinical efficacy in psoriasis, a disease closely related to ankylosing spondylitis.14, 15, 16, 17, 18, 19
We therefore undertook a proof-of-concept study to assess the efficacy and safety of secukinumab, a fully human anti-IL-17A monoclonal antibody, in patients with active ankylosing spondylitis.
Section snippets
Study design
We did a 28-week multicentre, randomised, double-blind, placebo-controlled study between March, 2009, and May, 2011, at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK; appendix). After a 4-week screening period, patients were randomly assigned (in a 4:1 ratio) to receive secukinumab or placebo at days 1 and 22.
The randomisation plan was generated by Novartis Drug Supply Management using a validated system. It was reviewed and approved by the Biostatistics
Results
Of 37 patients with active ankylosing spondylitis who were screened, 30 were enrolled in the study and randomly assigned to receive intravenous 2×10 mg/kg secukinumab (n=24) or placebo (n=6) on day 1 and day 22 (figure 1). Baseline demographics were similar between the two groups (table 1). 22 of the 24 (92%) secukinumab-treated patients and three of the six (50%) placebo-treated patients reached week 6. Of the 25 patients still in the study at week 6, 15 in the secukinumab group and all three
Discussion
Secukinumab was associated with rapid and significant reduction in the signs and symptoms of active ankylosing spondylitis in patients with inadequate response to NSAIDs.
60% of patients in the secukinumab group reached the primary endpoint of ASAS20 responses at week 6, indicating a 99·8% probability that secukinumab was more effective than placebo (table 2, figure 2). Favourable changes in secondary clinical outcomes, including quality-of-life measures, further supported clinical efficacy.
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