Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis
Secukinumab, an Interleukin-17A Inhibitor, in Ankylosing Spondylitis
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DOI：
10.1056/nejmoa1505066
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发表时间：
2015-12-24
影响因子：
158.5
通讯作者：
Richards, Hanno B.
中科院分区：
文献类型：
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作者：
Baeten, Dominique;Sieper, Joachim;Richards, Hanno B.
背景Secukinumab是一种抗白细胞介素17A的单抗，在2期试验中已被证明可以控制强直性脊柱炎的症状。我们在活动期强直性脊柱炎患者中进行了两个Suckinumab的3期试验。方法在两个双盲试验中，我们随机分配患者接受Suckinumab或安慰剂。在措施1中，共有371名患者在0、2和4周接受静脉注射安可单抗(每公斤体重10毫克)或匹配的安慰剂，随后从第8周开始每4周皮下注射安可单抗(150 mg或75 mg)或匹配的安慰剂。在措施2中，共有219名患者在基线时接受皮下注射安可单抗(150 mg或75 mg)或匹配的安慰剂；在第1、2和3周；从第4周开始每隔4周开始接受一次。在第16周，安慰剂组患者被随机分配到皮下给药150 mg或75 mg。结果在测量1中，皮下注射单抗150 mg和75 mg的ASAS20有效率分别为61%、60%和29%，安慰剂为29%(与安慰剂比较P<；0.001)；在测量2中，皮下注射150 mg、75 mg和安慰剂的ASAS20有效率分别为61%、41%和28%(P<；150毫克剂量为0.001，75毫克剂量P=0.1)。显著的改善持续了52周。在措施1的安慰剂控制期内，接受Secukinumab治疗的患者比服用安慰剂的患者更容易发生感染，包括念珠菌病。在整个治疗期间，接受Secukinumab治疗的患者合并暴露调整后的3级或4级中性粒细胞减少症、念珠菌感染和克罗恩病的发生率分别为每100人年0.7、0.9和0.7例。结论Secukinumab皮下剂量为150 mg，皮下或静脉给药，可显著减少16周时强直性脊柱炎的体征和症状。75 mg皮下剂量的Secukinumab只有在较高的静脉负荷量时才有显著改善。(由诺华制药提供资金；ClinicalTrials.gov编号，NCT01358175和NCT01649375。)
BACKGROUNDSecukinumab is an anti-interleukin-17A monoclonal antibody that has been shown to control the symptoms of ankylosing spondylitis in a phase 2 trial. We conducted two phase 3 trials of secukinumab in patients with active ankylosing spondylitis.METHODSIn two double-blind trials, we randomly assigned patients to receive secukinumab or placebo. In MEASURE 1, a total of 371 patients received intravenous secukinumab (10 mg per kilogram of body weight) or matched placebo at weeks 0, 2, and 4, followed by subcutaneous secukinumab (150 mg or 75 mg) or matched placebo every 4 weeks starting at week 8. In MEASURE 2, a total of 219 patients received subcutaneous secukinumab (150 mg or 75 mg) or matched placebo at baseline; at weeks 1, 2, and 3; and every 4 weeks starting at week 4. At week 16, patients in the placebo group were randomly reassigned to subcutaneous secukinumab at a dose of 150 mg or 75 mg. The primary end point was the proportion of patients with at least 20% improvement in Assessment of Spondyloarthritis International Society (ASAS20) response criteria at week 16.RESULTSIn MEASURE 1, the ASAS20 response rates at week 16 were 61%, 60%, and 29% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P< 0.001 for both comparisons with placebo); in MEASURE 2, the rates were 61%, 41%, and 28% for subcutaneous secukinumab at doses of 150 mg and 75 mg and for placebo, respectively (P< 0.001 for the 150-mg dose and P = 0.10 for the 75-mg dose). The significant improvements were sustained through 52 weeks. Infections, including candidiasis, were more common with secukinumab than with placebo during the placebo-controlled period of MEASURE 1. During the entire treatment period, pooled exposure-adjusted incidence rates of grade 3 or 4 neutropenia, candida infections, and Crohn's disease were 0.7, 0.9, and 0.7 cases per 100 patient-years, respectively, in secukinumab-treated patients.CONCLUSIONSSecukinumab at a subcutaneous dose of 150 mg, with either subcutaneous or intravenous loading, provided significant reductions in the signs and symptoms of ankylosing spondylitis at week 16. Secukinumab at a subcutaneous dose of 75 mg resulted in significant improvement only with a higher intravenous loading dose. (Funded by Novartis Pharma; ClinicalTrials.gov numbers, NCT01358175 and NCT01649375.)