A&R：全人源化抗IFN-α单克隆抗体西法木单抗治疗SLE安全有效

来自美国巴尔的摩约翰斯·霍普金斯大学医学院的Michelle Petri等人进行了一项研究，该研究的目的是评价中至重度的成人系统性红斑狼疮（SLE）患者多次静脉（IV）使用西法木单抗安全性和耐受性。研究结果在线发布在2013年4月的ARTHRITIS & RHEUMATISM（关节炎与风湿病）上。研究者发现，该项针对西法木单抗的观察性安全性/耐受性和临床活动的研究结果支持其可能进一步发展为SLE的治疗用药。

这是一项多中心，双盲，安慰剂对照，连续性剂量递增性研究，受试者按照3：1比例被随机分接受四个不同剂量西法木单抗治疗（0.3、1.0、3.0或10.0mg/kg）或者安慰剂治疗，西法木单抗和安慰剂均是每两周静脉使用一次，共使用26周，总共随访24周。安全性评估包括治疗相关的紧急相关不良事件（AEs）和严重AEs。药代动力学、免疫原性和药效性均是评价指标，疾病活动度也被记录下来。

研究结果如下，该研究共纳入161位受试者，121位接受西法木单抗治疗（其中26位的西法木单抗治疗剂量为0.3mg/kg，25位为1.0mg/kg，27位为3.0mg/kg，43位为10mg/kg），40位接受了安慰剂治疗。受试者以女性为主（95.7%）。在基线时，患者系统性红斑狼疮活动度为中至重度（平均SLE疾病活动指数[SLEDAI]积分为11.0），绝大多数（75.2%）患者高表达Ⅰ型干扰素基因型。西法木单抗组 vs 安慰剂组：≥1个治疗相关AE的发生率是92.6% vs 95.0%，≥1个严重AE的发生率是22.3% vs 27.5%，≥1次感染的发生率是67.8% vs 62.5%；由于不良事件而停药的概率是9.1% vs 7.5%，死亡发生率是3.3%（n=4） vs 2.5%（n=1）。血清西法木单抗浓度以剂量依赖性线性递增。治疗过程中，基线高表Ⅰ型干扰素的患者的Ⅰ型干扰素表达的受到持续抑制。西法木单抗组和安慰剂组相比，在临床疾病活动度（SLEDA和英国狼疮评估小组得分）方面无统计学差异。但是，校正类固醇冲击后，SLEDAI从基线开始，随时间变化，出现积极趋势。与基线时相比，西法木单抗组患者的补体C3或者C4水平，在26周时趋于正常。

该项针对西法木单抗的观察性安全性/耐受性和临床活动的研究结果支持其可能进一步发展为SLE的治疗用药。

Sifalimumab, a human anti-interferon-α monoclonal antibody, in systemic lupus erythematosus: a phase I randomized, controlled, dose-escalation study.
OBJECTIVE
To evaluate the safety and tolerability of multiple intravenous (IV) doses of sifalimumab in adults with moderate-to-severe systemic lupus erythematosus (SLE).
METHODS
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.
RESULTS
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.
CONCLUSION
The observed safety/tolerability and clinical activity profile of sifalimumab support its continued clinical development for SLE.