2011年3月9日美国FDA批准一新型生物制剂——贝利单抗(Benlysta)上市，成为该局近56年来首次批准治疗红斑狼疮的新药。贝利单抗作为一种新的靶向特异性生物制剂，其上市为狼疮的治疗提供了新的选择，给传统免疫抑制剂耐受或无效的狼疮患者也带来了新的希望。

贝利单抗是由HGS公司(Human Genome Sciences)和葛兰素史克(GSK)公司共同开发的人源单克隆抗体。它是一种Ｂ淋巴细胞刺激因子抑制剂，可通过抑制B淋巴细胞刺激因子(BLyS)的生物活性而发挥作用。贝利单抗的有效性和安全性已在BLISS-52 和BLISS-76两项研究中得到证实。贝利单抗联合标准药物治疗能够抑制狼疮患者的病情发展，部分患者病情突然复发风险降低，部分患者可降低激素用量。其主要不良反应包括恶心、腹泻和发热。注射反应也很常见，故在治疗前可用抗组胺药。希望不久的将来，我国能引进该产品。 

BENLYSTA

Manufacturer:
Human Genome Sciences and GlaxoSmithKline

Pharmacological Class:
Biologic (human IgG1gamma monoclonal antibody).

Active Ingredient(s):
Belimumab120mg/vial, 400mg/vial; pwd for IV infusion after recon­stitution and dilution.

Indication(s):
Systemic lupus erythematosus, in adults with active, autoantibody-positive SLE on standard therapy.

Pharmacology:
Belimumab is a human IgG1gamma monoclonal antibody specific for soluble human B lymphocyte stimulator protein (BLyS), a B cell survivor factor. It blocks the binding of soluble BLyS to its ­receptors on B cells, thus inhibiting the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells.

Clinical Trials:
Three randomized, placebo-­controlled studies involving 2133 patients with active, autoantibody positive SLE eva luated the safety and efficacy of belimumab. The patients were on a stable standard of care regimen (eg, corticosteroids, antimalarials, NSAIDs, and immunosuppressives); those with severe active lupus nephritis or severe active CNS lupus were excluded, as was the use of other biologics and IV cyclophosphamide.

In Trial 1, wherein several doses of belimu­mab were compared with placebo over 52 weeks, belimumab offered a benefit for patients with autoantibody-positive disease.

Trials 2 and 3 involved patients with active SLE and positive autoantibody tests at baseline. In both studies, more than half of the subjects had three or more organ systems with active disease at baseline. Patients were stratified by disease severity (measured by SELENA-SLEDAI scores), proteinuria level, and race. They were then randomized to receive either belimumab 1mg/kg, 10mg/kg, or placebo. The study drug was given by IV infusion on Days 0, 14, 28, and then every 28 days for 48 or 72 weeks in Trials 3 and 2, respectively, in addition to standard care.

The primary efficacy endpoint in both studies was the response rate at week 52 according to the SLE Responder Index (SRI), a composite endpoint that took into account the disease severity score, an organ domain score (which reflected significant worsening in any specific organ system), and a physician’s global assessment score.

In each trial, the proportion of patients achieving response was significantly higher in the belimumab 10mg/kg group than in the placebo group. At Week 76, the response rate with the 10mg/kg dose was not significantly different than placebo. The reductions in disease severity, as reflected in the SRI, were improvements in the most commonly involved organ systems (eg, mucocutaneous, musculoskeletal, and immunology).

Legal Classification:
Rx

Adults:
Give by IV infusion over 1 hour; slower if infusion reaction occurs. 10mg/kg every 2 weeks for 3 doses, then 10mg/kg every 4 weeks. May premedicate for infusion/hypersensitivity reactions (eg, APAP, diphenhydramine).

Children:
Not recommended.

Warnings/Precautions:
Severe active lupus nephritis or CNS lupus: not recommended. More deaths reported with Benlysta than ­placebo in clinical trials. Supervise infusion; have resuscitative equipment and trained personnel available in case of infusion/hypersensitivity ­reactions. Chronic infections: do not start ­therapy; if initiated, consider suspending if new infections develop and monitor closely. Monitor for malignancies, depression or other mood changes. Elderly. Black/African American. Pregnancy (Cat.C). Nursing mothers: not recommended.

Interaction(s):
Immunizations (may get sub­optimal response); avoid live vaccines for 30 days prior to and during treatment. Concomitant other biologicals or IV cyclophosphamide: not recommended.

Adverse Reaction(s):
Infections (eg, URI, UTI, nasopharyngitis, sinusitis, bronchitis, influenza; may be serious/fatal), psychological effects (eg, depression, insomnia, anxiety, suicide), GI upset, fever, migraine, extremity pain, ­infusion and/or hypersensitivity reactions.

How Supplied:
Single-use vials (120mg in 5mL, 400mg in 20mL)—1

Last Updated:3/31/2011

系统性红斑狼疮（SLE）的新药Benlysta(belimumab)，进入FDA快速审批通道，本药是一种蛋白质疗法药。预计在12月上旬，能得到审批结果。
上述决定基于该药物的两项关键Ⅲ期临床试验数据，参加这两次试验的受试者达1684人，均为SLE患者。Benlysta是一种BLyS抑制剂类新型药物，也是在同类药当中首个完成Ⅲ期临床试验的产品。试验结果显示，这种静脉注射制剂与目前的标准药联用之后，能够抑制SLE病情的发展，并且还能防止疾病的突然发作。
FDA批准了治疗系统性红斑狼疮的新药

Benlysta(贝利单抗)用于治疗正在接受标准治疗、自身抗体阳性的活动性系统性红斑狼疮(SLE)成人患者。Benlysta是一种冻干粉剂，单剂瓶装，仅适合静脉输注，在用药前医务人员须将其稀释还原。

贝利单抗是B淋巴细胞刺激因子(BLyS)特异性抑制剂类新药，可阻断可溶性BLyS与B细胞上的相应受体结合。贝利单抗不直接与B细胞结合，而是通过与BLyS结合而抑制B细胞存活，其中包括自身反应性B细胞，并减少B细胞分化成合成免疫球蛋白的浆细胞。

FDA批准的Benlysta说明书中包含一些限制条件，不宜用于某些特定的情况。目前尚未在重度活动性狼疮肾炎患者和重度活动性中枢神经系统狼疮患者中对贝利单抗的疗效进行评估，亦未针对该药与其他生物制剂或静脉用环磷酰胺联用时的疗效进行研究。
在临床试验的对照期，贝利单抗治疗组的死亡例数多于安慰剂对照组。在3项临床试验所纳入的2,133例患者中，共有14例患者死于安慰剂对照、双盲治疗期，安慰剂对照组、贝利单抗1 mg/kg治疗组、贝利单抗4 mg/kg治疗组和贝利单抗10 mg/kg治疗组的死亡比例分别为3/675(0.4%)、5/673(0.7%)、0/111(0%)和6/674(0.9%)。死因包括感染、心血管疾病和自杀，没有任何单一死因占主导地位.

在接受贝利单抗等免疫抑制剂治疗的患者中已有严重感染甚至致死性感染的报告。对照临床试验的结果显示，贝利单抗治疗组与安慰剂对照组中重度感染的发生率分别为6%和5.2%。最常见的重度感染包括肺炎、泌尿系感染(UTI)、蜂窝织炎和支气管炎。最常见的感染有上呼吸道感染、UTI、鼻咽炎、鼻窦炎、支气管炎和流感。

在贝利单抗治疗组与安慰剂对照组中，过敏反应(包括过敏症)的发生率分别为13%和11%，与注射相关的不良事件的发生率分别为17%和15%。严重的注射反应包括心动过缓、肌痛、头痛、皮疹、荨麻疹和低血压。最常见的注射反应是头痛、恶心和皮肤反应。

临床试验中，贝利单抗治疗组精神病事件(主要是抑郁、失眠和焦虑)(16%)的发生率高于安慰剂对照组(12%)，另外还有严重精神病事件(贝利单抗治疗组0.8%，安慰剂对照组0.4%)、严重抑郁以及2例自杀事件的报告。目前还不明确贝利单抗治疗是否增加这些事件的风险。

贝利单抗治疗对恶性肿瘤的发生有何影响也属未知。与其他免疫调节剂一样，贝利单抗的作用机制可能会增加恶性肿瘤的风险。

Benlysta预计将于2011年3月底之前在美国上市。

重要安全性信息

BENLYSTA (贝利木单抗)禁用于曾经对贝利木单抗过敏的患者。

在临床试验的对照阶段，贝利木单抗组的死亡报告多于安慰剂组。在3项临床试验的2133例患者中，安慰剂对照双盲治疗期共出现14例死亡：安慰剂、贝利木单抗1毫克/千克、贝利木单抗4毫克/千克和贝利木单抗10毫克/千克组分别为3/675 (0.4%)、5/673 (0.7%)、0/111 (0%)和6/674 (0.9%)例死亡。未见突出的单一死因。病因包括感染、心血管疾病和自杀。

接受免疫抑制剂(包括贝利木单抗)的患者中已有严重甚至致死性感染的报告。在对照临床试验中，贝利木单抗组的严重感染发生率为6.0%，安慰剂组为5.2%。最常见的严重感染包括肺炎、尿路感染(UTI)、蜂窝组织炎和支气管炎。最常见(≥5%)的感染为上呼吸道感染、UTI、鼻咽炎、窦炎、支气管炎和流感。

贝利木单抗治疗对恶性肿瘤发生的影响尚属未知。与其他免疫调节剂一样，贝利木单抗的作用机制可增加恶性肿瘤的发生风险。

贝利木单抗组各类超敏反应报告率为13%，安慰剂组为11%，其中包括过敏反应(贝利木单抗组为0.6%，安慰剂组为0.4%)。输注相关的不良事件发生率贝利木单抗组为17%，安慰剂组为15%。严重输注反应包括心动过缓、肌痛、头痛、皮疹、荨麻疹和低血压。最常见(≥3%)的输注反应为头痛。恶心和皮肤反应。

贝利木单抗组报告的精神科事件 (主要是抑郁、失眠和焦虑) (16%)多于安慰剂组(12%)。同时报告的还有严重精神科事件、严重抑郁和2例自杀 (贝利木单抗组占0.8%，安慰剂组占0.4%)。贝利木单抗治疗与这些事件的风险增高有无关联尚属未知。

BENLYSTA组最常报告(≥5%)的不良反应为恶心、腹泻、发热、鼻咽炎、支气管炎、失眠、肢端疼痛、抑郁、偏头痛和咽炎。

关于 BENLYSTA

BENLYSTA (贝利木单抗)是一个称为BLyS特异性抑制剂的药物新类别中的第一个品种。贝利木单抗阻断可溶性BLyS (一种B细胞生存因子)与B细胞上的BLyS受体的结合。贝利木单抗与B细胞不直接结合，但通过与BLyS结合，贝利木单抗可抑制B细胞(包括自身反应性B细胞)的生存、减少B细胞向制造免疫球蛋白的浆细胞的分化。BLyS 是一种自然发生的蛋白质，1996年由HGS发现

BENLYSTA成品为冻干粉剂，采用一次性玻璃瓶包装，仅供静脉输注给药，