Sifalimumab, a human anti-interferon-α monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study.
Sifalimumab, a human anti-interferon-α monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study.
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DOI：
10.1002/art.37824
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发表时间：
2013-04
影响因子：
--
通讯作者：
Greth, Warren
中科院分区：
文献类型：
--
作者：
Petri, Michelle;Wallace, Daniel J.;Spindler, Alberto;Chindalore, Vishala;Kalunian, Kenneth;Mysler, Eduardo;Neuwelt, C. Michael;Robbie, Gabriel;White, Wendy I.;Higgs, Brandon W.;Yao, Yihong;Wang, Liangwei;Ethgen, Dominique;Greth, Warren
评估中度至重度系统性红斑狼疮（SLE）成人患者多次静脉注射（IV）剂量sifalimumab的安全性和耐受性。在这项多中心、双盲、安慰剂对照、顺序剂量递增的研究中，患者以3:1的比例随机分配，每2周至26周接受静脉注射西法利单抗（0.3、1.0、3.0或10.0 mg/kg）或安慰剂，然后随访24周。安全性评估包括记录治疗中出现的不良事件（ae）和严重ae。评估了药代动力学、免疫原性和药效学，并评估了疾病活动性。在161例患者中，121例接受了西法利单抗治疗（26例接受0.3 mg/kg； 25例接受1.0 mg/kg； 27例接受3.0 mg/kg； 43例接受10mg /kg）， 40例接受安慰剂治疗。患者以女性为主（95.7%）。基线时，患者具有中度至重度疾病活动性（SLE疾病活动性指数平均评分11.0），大多数（75.2%）具有高I型干扰素（IFN）基因特征。在西法利单抗组与安慰剂组中，≥1例治疗后突发AE的发生率为92.6%比95.0%，≥1例严重AE的发生率为22.3%比27.5%，≥1例感染的发生率为67.8%比62.5%；因不良事件而停药的发生率为9.1%比7.5%，死亡发生率为3.3% （n = 4）比2.5% （n = 1）。血清司伐利单抗浓度呈线性和剂量正比增加。在高基线标记的患者治疗期间，I型IFN基因标记的抑制持续存在。西法利单抗和安慰剂的临床活性（SLEDAI和不列颠群岛狼疮评估组评分）无统计学差异。然而，当调整过量爆裂类固醇时，SLEDAI从基线的变化随时间呈阳性趋势。与基线相比，司伐利单抗组在第26周补体C3或C4水平趋于正常。观察到的sifalimumab的安全性/耐受性和临床活性特征支持其在SLE的持续临床开发。
To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE). In this multicenter, double-blind, placebo-controlled, sequential dose-escalation study, patients were randomized 3:1 to receive IV sifalimumab (0.3, 1.0, 3.0, or 10.0 mg/kg) or placebo every 2 weeks to week 26, then followed up for 24 weeks. Safety assessment included recording of treatment-emergent adverse events (AEs) and serious AEs. Pharmacokinetics, immunogenicity, and pharmacodynamics were evaluated, and disease activity was assessed. Of 161 patients, 121 received sifalimumab (26 received 0.3 mg/kg; 25, 1.0 mg/kg; 27, 3.0 mg/kg; and 43, 10 mg/kg) and 40 received placebo. Patients were predominantly female (95.7%). At baseline, patients had moderate-to-severe disease activity (mean SLE Disease Activity Index score 11.0), and most (75.2%) had a high type I interferon (IFN) gene signature. In the sifalimumab group versus the placebo group, the incidence of ≥1 treatment-emergent AE was 92.6% versus 95.0%, ≥1 serious AE was 22.3% versus 27.5%, and ≥1 infection was 67.8% versus 62.5%; discontinuations due to AEs occurred in 9.1% versus 7.5%, and death occurred in 3.3% (n = 4) versus 2.5% (n = 1). Serum sifalimumab concentrations increased in a linear and dose-proportional manner. Inhibition of the type I IFN gene signature was sustained during treatment in patients with a high baseline signature. No statistically significant differences in clinical activity (SLEDAI and British Isles Lupus Assessment Group score) between sifalimumab and placebo were observed. However, when adjusted for excess burst steroids, SLEDAI change from baseline showed a positive trend over time. A trend toward normal complement C3 or C4 level at week 26 was seen in the sifalimumab groups compared with baseline. The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.
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影响因子：
2.6
作者：
Obermoser G;Pascual V
通讯作者：
Pascual V
影响因子：
12.8
作者：
Eisenberg R
通讯作者：
Eisenberg R
影响因子：
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作者：
Bauer, Jason W.;Petri, Michelle;Batliwalla, Franak M.;Koeuth, Thearith;Wilson, Joseph;Slattery, Catherine;Panoskaltsis-Mortari, Angela;Gregersen, Peter K.;Behrens, Timothy W.;Baechler, Emily C.
通讯作者：
Baechler, Emily C.
影响因子：
2.6
作者：
Bengtsson, AA;Sturfelt, G;Rönnblom, L
通讯作者：
Rönnblom, L
影响因子：
13.6
作者：
Strand, Vibeke
通讯作者：
Strand, Vibeke