达利珠单抗 HYP 与干扰素β-1a 治疗复发型多发性硬化症的比较。
Daclizumab HYP versus Interferon Beta-1a in Relapsing Multiple Sclerosis.
机构信息
From the Neurologic Clinic and Policlinic, the Departments of Medicine, Clinical Research, and Biomedicine and Biomedical Engineering, University Hospital, Basel, Switzerland (L.K.); the Department of Neurology, University of Münster, Münster, Germany (H.W.); the Department of Neurology, Medical University of Lodz, Lodz, Poland (K.S.); NeuroRx Research and Montreal Neurological Institute, McGill University - both in Montreal (D.L.A.); the Department of Neurology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic (E.H.); the Department of Neurology and Neurosurgery, Russian National Research Medical University, and Moscow Multiple Sclerosis Center - both in Moscow (A.B.); Cole Neurological Institute, University of Tennessee, Knoxville (M.K.); the Department of Neurology and the Neurovirology Research Laboratory, University of Utah, and the Veterans Affairs Salt Lake City Health Care System - both in Salt Lake City (J.R.); AbbVie Biotherapeutics, Redwood City, CA (S.G.); and Biogen, Cambridge, MA (M.S., K.R., G.O., J.E.).
出版信息
N Engl J Med. 2015 Oct 8;373(15):1418-28. doi: 10.1056/NEJMoa1501481.
BACKGROUND
Daclizumab high-yield process (HYP) is a humanized monoclonal antibody that binds to CD25 (alpha subunit of the interleukin-2 receptor) and modulates interleukin-2 signaling. Abnormalities in interleukin-2 signaling have been implicated in the pathogenesis of multiple sclerosis and other autoimmune disorders.
METHODS
We conducted a randomized, double-blind, active-controlled, phase 3 study involving 1841 patients with relapsing-remitting multiple sclerosis to compare daclizumab HYP, administered subcutaneously at a dose of 150 mg every 4 weeks, with interferon beta-1a, administered intramuscularly at a dose of 30 μg once weekly, for up to 144 weeks. The primary end point was the annualized relapse rate.
RESULTS
The annualized relapse rate was lower with daclizumab HYP than with interferon beta-1a (0.22 vs. 0.39; 45% lower rate with daclizumab HYP; P<0.001). The number of new or newly enlarged hyperintense lesions on T2-weighted magnetic resonance imaging (MRI) over a period of 96 weeks was lower with daclizumab HYP than with interferon beta-1a (4.3 vs. 9.4; 54% lower number of lesions with daclizumab HYP; P<0.001). At week 144, the estimated incidence of disability progression confirmed at 12 weeks was 16% with daclizumab HYP and 20% with interferon beta-1a (P=0.16). Serious adverse events, excluding relapse of multiple sclerosis, were reported in 15% of the patients in the daclizumab HYP group and in 10% of those in the interferon beta-1a group. Infections were more common in the daclizumab HYP group than in the interferon beta-1a group (in 65% vs. 57% of the patients, including serious infection in 4% vs. 2%), as were cutaneous events such as rash or eczema (in 37% vs. 19%, including serious events in 2% vs. <1%) and elevations in liver aminotransferase levels that were more than 5 times the upper limit of the normal range (in 6% vs. 3%).
CONCLUSIONS
Among patients with relapsing-remitting multiple sclerosis, daclizumab HYP showed efficacy superior to that of interferon beta-1a with regard to the annualized relapse rate and lesions, as assessed by means of MRI, but was not associated with a significantly lower risk of disability progression confirmed at 12 weeks. The rates of infection, rash, and abnormalities on liver-function testing were higher with daclizumab HYP than with interferon beta-1a. (Funded by Biogen and AbbVie Biotherapeutics; DECIDE ClinicalTrials.gov number, NCT01064401.).
背景
达利珠单抗高产量工艺（HYP）是一种人源化单克隆抗体，与白细胞介素-2 受体的α亚单位（CD25）结合，调节白细胞介素-2 信号。白细胞介素-2 信号的异常与多发性硬化症和其他自身免疫性疾病的发病机制有关。
方法
我们进行了一项随机、双盲、阳性对照、3 期研究，纳入了 1841 例复发缓解型多发性硬化症患者，比较达利珠单抗 HYP（皮下注射，剂量为 150mg，每 4 周一次）与干扰素 β-1a（肌肉注射，剂量为 30μg，每周一次），治疗时间长达 144 周。主要终点是年化复发率。
结果
达利珠单抗 HYP 的年化复发率低于干扰素 β-1a（0.22 比 0.39；达利珠单抗 HYP 降低 45%；P<0.001）。在 96 周期间，新的或新增大的 T2 加权磁共振成像（MRI）高信号病变数量，达利珠单抗 HYP 组低于干扰素 β-1a 组（4.3 比 9.4；达利珠单抗 HYP 组病变数量减少 54%；P<0.001）。在 144 周时，在 12 周时确认的残疾进展估计发生率为 16%的达利珠单抗 HYP 组和 20%的干扰素 β-1a 组（P=0.16）。达利珠单抗 HYP 组和干扰素 β-1a 组分别有 15%和 10%的患者出现除多发性硬化症复发以外的严重不良事件。达利珠单抗 HYP 组的感染发生率高于干扰素 β-1a 组（65%比 57%，包括 4%比 2%的严重感染），皮肤事件如皮疹或湿疹的发生率也高于干扰素 β-1a 组（37%比 19%，包括 2%比 <1%的严重事件），以及肝转氨酶水平升高超过正常范围上限 5 倍的发生率也高于干扰素 β-1a 组（6%比 3%）。
结论
在复发缓解型多发性硬化症患者中，与干扰素 β-1a 相比，达利珠单抗 HYP 在年化复发率和 MRI 评估的病变方面显示出更好的疗效，但在 12 周时确认的残疾进展风险降低方面没有显著差异。感染、皮疹和肝功能检查异常的发生率在达利珠单抗 HYP 组高于干扰素 β-1a 组。（由 Biogen 和 AbbVie Biotherapeutics 资助；DECIDE 临床试验.gov 编号，NCT01064401。）
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