Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial
Anti-interleukin-17A monoclonal antibody secukinumab in treatment of ankylosing spondylitis: a randomised, double-blind, placebo-controlled trial
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DOI：
10.1016/s0140-6736(13)61134-4
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发表时间：
2013-11-23
期刊：
影响因子：
168.9
通讯作者：
Hueber, Wolfgang
中科院分区：
文献类型：
--
作者：
Baeten, Dominique;Baraliakos, Xenofon;Hueber, Wolfgang
强直性脊柱炎是一种慢性免疫介导的炎症性疾病，以脊柱炎症、进行性脊柱强直和外周关节炎为特征。白细胞介素17（IL-17）被认为是强直性脊柱炎（脊柱关节炎的典型形式）发展中的关键炎性细胞因子。我们评估的疗效和安全性的抗IL-17 A的单克隆抗体Rakkinumab治疗活动性强直性脊柱炎患者。方法我们做了一个随机双盲的概念验证研究在欧洲的8个中心（4个在德国，两个在荷兰，两个在英国）。年龄在18-65岁之间的患者被随机分配（以4：1的比例）接受静脉注射阿基诺单抗（2 x 10 mg/kg）或安慰剂，间隔3周。使用计算机生成的区组随机化列表进行随机化，未进行分层过程。主要疗效终点是第6周时根据国际脊柱关节炎协会改善标准（ASAS 20）缓解率20%的患者百分比（贝叶斯分析）。安全性评估持续至第28周。该研究注册于ClinicalTrials.gov，编号NCT 00809159。结果筛选了37例中重度强直性脊柱炎患者，其中30例随机分配接受静脉注射阿基诺单抗（n=24）或安慰剂（n=6）。最终的疗效分析包括23名接受阿基诺单抗的患者和6名接受安慰剂的患者，安全性分析包括所有30名患者。第6周时，阿基诺单抗的ASAS 20应答估计值为59%，安慰剂为24%（阿基诺单抗上级于安慰剂的概率为99.8%）。一个严重的不良事件（由金黄色葡萄球菌引起的皮下脓肿）发生在治疗组secukinumab的解释迅速减少活动性强直性脊柱炎的临床或生物学体征，耐受性良好。这是我们所知的第一种靶向治疗，它是肿瘤坏死因子抑制的替代品，在2期试验中达到其主要终点。
Background Ankylosing spondylitis is a chronic immune-mediated inflammatory disease characterised by spinal inflammation, progressive spinal rigidity, and peripheral arthritis. Interleukin 17 (IL-17) is thought to be a key inflammatory cytokine in the development of ankylosing spondylitis, the prototypical form of spondyloarthritis. We assessed the efficacy and safety of the anti-IL-17A monoclonal antibody secukinumab in treating patients with active ankylosing spondylitis.Methods We did a randomised double-blind proof-of-concept study at eight centres in Europe (four in Germany, two in the Netherlands, and two in the UK). Patients aged 18-65 years were randomly assigned (in a 4: 1 ratio) to either intravenous secukinumab (2 x 10 mg/kg) or placebo, given 3 weeks apart. Randomisation was done with a computer-generated block randomisation list without a stratification process. The primary efficacy endpoint was the percentage of patients with a 20% response according to the Assessment of SpondyloArthritis international Society criteria for improvement (ASAS20) at week 6 (Bayesian analysis). Safety was assessed up to week 28. This study is registered with ClinicalTrials.gov, number NCT00809159.Findings 37 patients with moderate-to-severe ankylosing spondylitis were screened, and 30 were randomly assigned to receive either intravenous secukinumab (n=24) or placebo (n=6). The final efficacy analysis included 23 patients receiving secukinumab and six patients receiving placebo, and the safety analysis included all 30 patients. At week 6, ASAS20 response estimates were 59% on secukinumab versus 24% on placebo (99.8% probability that secukinumab is superior to placebo). One serious adverse event (subcutaneous abscess caused by Staphylococcus aureus) occurred in the secukinumab-treated group.Interpretation Secukinumab rapidly reduced clinical or biological signs of active ankylosing spondylitis and was well tolerated. It is the first targeted therapy that we know of that is an alternative to tumour necrosis factor inhibition to reach its primary endpoint in a phase 2 trial.