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Anti-Interleukin-17A Monoclonal Antibody Secukinumab in Treatment of Ankylosing Spondylitis: a Randomised, Double-Blind, Placebo-Controlled Trial

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Anti-Interleukin-17A Monoclonal Antibody Secukinumab in Treatment of Ankylosing Spondylitis: a Randomised, Double-Blind, Placebo-Controlled Trial Articles Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial Dominique Baeten, Xenofon Baraliakos, Jürgen Braun, Joachim Sieper, Paul Emery, Désirée van der Heijde, Iain McInnes, Jacob M van Laar, Robert Landewé, Paul Wordsworth, Jürgen Wollenhaupt, Herbert Kellner, Jacqueline Paramarta, Jiawei Wei, Arndt Brachat, Stephan Bek, Didier Laurent, Yali Li, Ying A Wang, Arthur P Bertolino, Sandro Gsteiger, Andrew M Wright, Wolfgang Hueber Summary Background Ankylosing spondylitis is a chronic immune-mediated infl ammatory disease characterised by spinal Published Online infl ammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key September 13, 2013 infl ammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We http://dx.doi.org/10.1016/ S0140-6736(13)61134-4 assessed the effi cacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active See Online/Comment ankylosing spondylitis. http://dx.doi.org/10.1016/ S0140-6736(13)61913-3 Methods We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two Department of Clinical in the Netherlands, and two in the UK). Patients aged 18–65 years were randomly assigned (in a 4:1 ratio) to either Immunology and intravenous secukinumab (2 × 10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer- Rheumatology, Academic Medical Center, University of generated block randomisation list without a stratifi cation process. The primary effi cacy endpoint was the percentage Amsterdam, Amsterdam, of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for Netherlands (D Baeten MD, improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered R Landewé MD, J Paramarta MD); with ClinicalTrials.gov, number NCT00809159. Rheumazentrum Ruhrgebiet, Herne, Germany (X Baraliakos MD, J Braun MD); Findings 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned Medicine/Rheumatology to receive either intravenous secukinumab (n=24) or placebo (n=6). The fi nal effi cacy analysis included 23 patients Department, Charité Campus receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, Benjamin Franklin, Berlin, Germany (J Sieper MD); Leeds ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99·8% probability that secukinumab Institute of Rheumatic and is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in Musculoskeletal Medicine, the secukinumab-treated group. University of Leeds, and NIHR Leeds Musculoskeletal Biomedical Research Unit, Interpretation Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well Leeds Teaching Hospitals NHS tolerated. It is the fi rst targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to Trust, Leeds, UK (P Emery MD); reach its primary endpoint in a phase 2 trial. Rheumatology Department, Leiden University Medical Center, Leiden, Netherlands Funding Novartis. (D van der Heijde MD); Glasgow Biomedical Research Centre, Introduction necrosis factor (TNF)-blockers has been recommended.2 University of Glasgow, Glasgow, UK (I McInnes MD); Ankylosing spondylitis is a chronic immune-mediated However, no approved alternative therapies are available Musculoskeletal Research infl ammatory disease, with an estimated prevalence of for the roughly 40% of patients who do not tolerate or Group, Institute of Cellular 0·2–0·5% worldwide. It is characterised by spinal respond to TNF-blockers. Thus, there is an unmet need Medicine, Newcastle infl am mation, progressive spinal ankylosis due to new for medicines with new modes of action. University, Newcastle upon Tyne, UK (J M van Laar MD); bone formation, peripheral arthritis and enthesitis, extra- Interleukin 17A (IL-17A) has emerged as a novel Atrium Medical Center, Heerlen, articular manifestations, familial clustering, and a strong therapeutic target for ankylosing spondylitis. First, the Netherlands (R Landewé); genetic association with human leucocyte antigen disease shows a strong genetic association with a series National Institute for Health (HLA)-B27.1 Early onset of the disease in young adults, of protective polymorphisms in the IL-23 receptor Research, Oxford 3 Musculoskeletal Biomedical chronic spinal and extraspinal infl ammation, and (IL23R) gene, including rs11209026 (Arg381Gln). Func- Research Unit, and Nuffi eld progressive irreversible structural damage can lead to tional ana lyses have indicated that the Arg381Gln Department of Orthopaedics, important morbidity, functional deterioration, and socio- polymorphism impairs IL-23–dependent IL-17 production Rheumatology and economic burden. by Th17 cells, suggesting that genetically determined Musculoskeletal Sciences, Nuffi eld Orthopaedic Centre, Non-steroidal anti-infl ammatory drugs (NSAIDs) and down-modulation of the IL-23/IL-17 axis could provide Oxford, UK (P Wordsworth MB); 4 physiotherapy are the cornerstones of treatment for protection against ankylosing spondylitis. Second, Division of Rheumatology, ankylosing spondylitis. Conventional disease-modifying intracellular HLA-B27 misfolding leads to an unfolded Schön Klinik Hamburg Eilbeck, anti-rheumatic drugs (DMARDs) are not eff ective for the pro tein response that potentiates abnormal IL-23 produc- Hamburg, Germany (J Wollenhaupt MD); Division of 5 axial symptoms of the disease. For patients with in- tion, and ankylosing spondylitis macro phages produce Rheumatology, Centre for adequate response to NSAIDs, treatment with tumour increased levels of IL-23.6 Third, the number of Infl ammatory Joint Diseases, www.thelancet.com Published online September 13, 2013 http://dx.doi.org/10.1016/S0140-6736(13)61134-4 1 Articles Munich, Germany circulating CD4+IL-17+ cells is expanded in ankylosing Randomisation was done by using a computer-generated (H Kellner MD); Novartis spondylitis;7 this includes KIR3DL2-expressing T cells block randomisation list without a stratifi cation process. Pharma AG, Shanghai, China that respond to cell-surface HLA-B27 homodimers8 and Data were accessible only to authorised personnel until (J Wei PhD); Novartis Institutes 9 for BioMedical Research, Basel, IL-17–producing γ/δ T cells. Fourth, infl amed target database lock. The unblinded pharmacist or designated Switzerland (A Brachat PhD, tissues indicate an ankylosing spondylitis-specifi c person (eg, study nurse) at each site received treatment S Bek PhD, D Laurent PhD, increase in IL-17–producing innate immune cells.10,11 allocation cards. When an eligible patient at a participating A P Bertolino MD, W Hueber MD); Fifth, spondyloarthritis in HLA-B27 transgenic rats and study site was to be entered into the study, the unblinded Novartis Institutes for BioMedical Research, experimental ankylosing enthesitis in (BXSB×NZB) pharmacist or designated person completed a random- Cambridge, MA, USA (Y Li PhD, F1 mice were associated with an expansion of Th17 cells isation request by email to Novartis. The assigned Y A Wang PhD); Novartis 12 and with up-regulated IL-17 expression, respectively. random isation number was returned to the pharmacist Pharma AG, Basel, Switzerland (S Gsteiger PhD, A M Wright MSc) Moreover, IL-23 overexpression induces a spondylo- within 24 h of the request. After inclusion of each new arthritis-like disease in B10.RIII mice via RAR-related patient, the pharmacist returned the email to confi rm the Correspondence to: Wolfgang Hueber, Translational orphan receptor γt(+)CD3(+)CD4(–)CD8(–) T cells that patient’s randomisation number and the date the patient Medicine—Autoimmunity, produce IL-17 and IL-22.13 Finally, trials with anti-IL-12/ received the fi rst administration of study medication. Novartis Institutes for IL-23 and anti-IL-17 agents have shown signifi cant Effi cacy and safety assessments were done up to week 28, BioMedical Research, clinical effi cacy in psoriasis, a disease closely related to with week 6 being the primary endpoint. All week-6 analyses WSJ 386.10.48, CH-4002, 14–19 Basel, Switzerland ankylosing spondylitis. were designated as interim analyses. All centres received wolfgang.hueber@novartis. We therefore undertook a proof-of-concept study to approval from independent ethics committees or institu- com assess the effi cacy and safety of secukinumab, a fully tional review boards, and the study was done in accordance human anti-IL-17A monoclonal antibody, in patients with with the principles of the Declaration of Helsinki. Signed active ankylosing spondylitis. informed consent for the main and pharmacogenetic studies was obtained from each patient before any study- Methods related procedures were undertaken. The full study Study design protocol is available from the sponsor. We did a 28-week multicentre, randomised, double- blind, placebo-controlled study between March, 2009, Patients and May, 2011, at eight centres in Europe (four in The study included 30 patients, 18–65 years of age, with Germany, two in the Netherlands, and two in the UK; defi nite ankylosing spondylitis as defi ned by the See Online for appendix appendix). After a 4-week screening period, patients were
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