FDA首次批准红斑狼疮新药Benlysta上市

美国食品和药物管理局9日批准一种用于治疗红斑狼疮的静脉注射药物Benlysta上市，这是该局近56年来首次批准红斑狼疮药物上市。
Benlysta由美国人类基因组科学公司研制，由该公司和英国葛兰素史克公司联合销售。它是一种B淋巴细胞刺激因子抑制剂，需要与目前治疗红斑狼疮的标准药物如非甾体抗炎药、抗疟药、免疫抑制剂等一起服用，可减少患者体内异常B细胞的数量。
美国药管局表示，这一药物的安全性和有效性在1684名红斑狼疮患者参与的两个临床试验中得到验证。与同时接受安慰剂及红斑狼疮标准药物治疗相比，同时接受Benlysta及标准药物治疗能够抑制患者病情发展，部分患者病情突然发作的风险有所降低。不过，同时接受Benlysta及标准药物治疗的患者也出现更多的死亡和严重感染病例。Benlysta引发的不良反应主要包括恶心、腹泻和发烧。此外，非裔美国人在临床试验中对Benlysta没有反应。
红斑狼疮是一种自体免疫性疾病，患者的免疫系统错误地攻击自身的细胞和组织，导致炎症和组织损伤。这种疾病会累及身体多个系统和器官，临床症状主要表现为关节疼、发烧、起疹子和掉头发等，患者以中青年女性居多。目前尚无有效疗法，但可以控制症状。

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 evaluated 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

BENLYSTA的重要安全性信息
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。

【原产地英文商品名】BENLYSTA 400mg/vial
【原产地英文药品名】BELIMUMAB
【中文参考商品译名】
注：以下产品不同规格和不同价格，购买时请以电话咨询为准！
·BENLYSTA 400毫克/瓶
·BENLYSTA 120毫克/瓶
【中文参考药品译名】贝利木单抗
【生产厂家中文参考译名】：葛兰素史克/人类基因组科学公司
【生产厂家英文名】GSK/HGSI

BENLYSTA® (belimumab) 

BENLYSTA is an investigational human monoclonal antibody drug and the first in a new class of drugs called BLyS-specific inhibitors. On March 9, 2011, Human Genome Sciences and GlaxoSmithKline PLC (GSK) announced that the U.S. Food and Drug Administration (FDA) has approved BENLYSTA for the treatment of adult patients with active, autoantibody-positive systemic lupus erythematosus (SLE) who are receiving standard therapy.

The label for BENLYSTA includes the following limitations of use: The efficacy of belimumab has not been evaluated in patients with severe active lupus nephritis or severe active central nervous system lupus, and has not been studied in combination with other biologics or intravenous cyclophosphamide. Use of belimumab is therefore not recommended in these situations.

For full BENLYSTA (belimumab) prescribing information, please click here.  For the medication guide for BENLYSTA, please click here.

How BENLYSTA Works
Belimumab blocks the binding of soluble BLyS, a B-cell survival factor, to its receptors on B cells. Belimumab does not bind B cells directly, but by binding BLyS, belimumab inhibits the survival of B cells, including autoreactive B cells, and reduces the differentiation of B cells into immunoglobulin-producing plasma cells. BLyS is a naturally occurring protein which was discovered by HGS in 1996.

Collaboration with GlaxoSmithKline
In August 2006, HGS and GSK entered into a co-development and commercialization agreement under which HGS conducted the BENLYSTA Phase 3 trials, with assistance from GSK. The companies share equally in Phase 3/4 development costs, sales and marketing expenses, and profits of any product commercialized under the agreement.

How BENLYSTA Was Discovered
HGS first discovered the naturally occurring protein, BLyS or B-lymphocyte stimulator, in 1996 and published a preliminary description of its activity in the journal, Science, in July 1999. Following that discovery, HGS initiated a program to develop human monoclonal antibodies that would specifically recognize and inhibit the biological activity of BLyS. BENLYSTA is a human monoclonal antibody that HGS generated through a collaboration with Cambridge Antibody Technology.