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Stelara (ustekinumab)-银屑病上市新药 生物制剂Stelara™(ustekinumab)近日通过了美国FDA批准，用于治疗成年人中重度银屑病。斑块状银屑病是一种免疫系统障碍性疾病，会导致皮肤细胞快速过度增殖，出现皮肤发红、炎症性斑片状增厚以及疼痛。美国约有600万人患有斑块状银屑病。 Stelara™是一种在实验室中通过模拟机体中自身抗体的特点合成的单克隆抗体，在体内通过抑制两种致病蛋白的功能达到治疗银屑病的目的，这两种蛋白能引起皮肤细胞过度增殖产生炎症。 目前有3项研究正在对其生物安全性和有效性进行评估，共2266名患者参与Stelara™通过抑制免疫系统功能对抗炎症，这将增加忠者的感染风险。接受该药治疗的患者已有出现严重感染的报道，部分患者甚至需要住院治疗。感染的病原体为机体广泛分布的细菌、病毒、真菌，同时也会增加癌症风险。 STELARA™(ustekinumab) 最近重要修改。 剂量和给药方法，对给药的一般考虑 剂量和给药方法, 为STELARA™给药指导装配针头安全保护预装注射器 一般描述 可得到以下规格STELARA：45mg ustekinumab在0.5mL和90mg ustekinumab在1mL中。STELARA是在一个有27号规格固定英寸针头的单次使用预装注射器，或一个单次使用2mL带有包被塞子的Type I型玻璃小瓶内无菌溶液中供应。注射器装配干天然橡胶(1种乳胶衍生物)制造的一个被动针头保护和一个针头复盖。 每支45 mgustekinumab预装注射器还含：L-组氨酸和L-组氨酸单盐酸盐一水物(0.5mg)，山梨醇80(0.02mg)，和蔗糖(38mg)装填至最终体积0.5mL。 每支90 mgustekinumab预装注射器还含：L-组氨酸和L-组氨酸单盐酸盐一水物(1mg)，山梨醇80(0.04mg)，和蔗糖(76 mg)装填至最终体积1.0mL。 每支45 mgustekinumab小瓶还含：L-组氨酸和L-组氨酸单盐酸盐一水物(0.5mg)，山梨醇80(0.02mg)，和蔗糖(38 mg)装填至最终体积0.5mL。 每支90 mgustekinumab小瓶还含：L-组氨酸和L-组氨酸单盐酸盐一水物(1mg)，山梨醇80(0.04mg)，和蔗糖(76mg)装填至最终体积1.0mL。 STELARA™溶液是无色至淡黄色外观和pH 5.7-6.3。STELARA?不含防腐剂. 作用机制 适应证和用途 剂量和给药方法 剂型和规格 禁忌证 特殊感染的理论风险：遗传上缺乏IL-12/IL-23患者曾报道来自分枝杆菌、沙门氏菌和卡介苗(BCG)免疫接种严重感染。临床情况指示应考虑诊断检验。 结核(TB)评价：开始用STELARA治疗前评价患者TB。给STELARA™前开始潜伏TB治疗。 恶性病：STELARA™可能增加恶性病风险。尚未评价有恶性病史或已知恶性病患者用STELARA™。 可逆性后脑白质脑病综合征(RPLS)：报道1例。如怀疑立即治疗和停用STELARA™。 不良反应 药物相互作用 活疫苗：用STELARA™不应给予活疫苗。 如何供应/贮存和装卸 储存及稳定性
Stelara™ PHARMACOLOGY Ustekinumab is a human monoclonal antibody that binds with high affinity and specificity to the shared p40 protein subunit of human interleukins 12 and 23, thereby preventing interaction with IL12Rβ1 receptor proteins expressed on the surface of immune cells.1 Abnormal regulation of IL-12 and IL-23 has been associated with immune-mediated diseases such as psoriasis. It is believed that by preventing IL-12 and IL-23 contributions to immune cell activation, ustekinumab interrupts signalling and cytokine cascades that are relevant to psoriasis pathology.1 CLINICAL STUDIES The safety and efficacy of ustekinumab in patients with moderate to severe plaque psoriasis was assessed in two double-blind placebo-controlled trials (PHOENIX 1 and 2).2,3 In PHOENIX 1 (n=766) patients were randomised to receive ustekinumab 45mg or 90mg at weeks 0 and 4, then every 12 weeks, or placebo at weeks 0 and 4 with crossover to ustekinumab (45mg or 90mg) at weeks 12 and 16, then every 12 weeks. At week 40, patients in the ustekinumab groups with at least 75 per cent improvement from baseline in psoriasis area and severity index score (PASI 75) at weeks 28 and 40 were re-randomised to continue maintenance treatment with ustekinumab or placebo. In PHOENIX 2 (n=1230), patients were randomised to ustekinumab or placebo as in PHOENIX 1. At week 28, partial responders (≥PASI 50, < PASI 75 response) were re-randomised to ustekinumab every 12 weeks or to intensified dosing every eight weeks.* In both trials significantly more patients receiving ustekinumab achieved a PASI 75 response at week 12 than did those receiving placebo. Onset of efficacy was rapid with significantly more patients in the ustekinumab groups achieving PASI 50 by week 2 and PASI 75 by week 4, compared with placebo. In PHOENIX 1, maintenance of PASI 75 response was significantly better in patients re-randomised at week 40 to receive maintenance therapy than in those receiving placebo through at least one year. In PHOENIX 2, dosing intensification in the ustekinumab 90mg group resulted in a higher PASI 75 response rate at week 52 than did continuing at 12-weekly dosing, an improvement not seen in the ustekinumab 45mg group. Treatment was well tolerated in both trials and clinical improvements were paralleled by improvements in patient-reported outcomes, as measured by dermatology life quality index. Ustekinumab was compared with etanercept in another trial involving 903 patients with moderate to severe plaque psoriasis where ciclosporin, methotrexate or PUVA were ineffective, not tolerated or contraindicated. Patients treated with two doses of 45mg or 90mg ustekinumab at weeks 0 and 4 demonstrated significantly superior response compared with those treated with etanercept 50mg twice weekly through week 12 (PASI 75 response at week 12 achieved by 68 per cent and 74 per cent of patients vs 57 per cent in the etanercept group). * Stelara SPC recommends a 12-week dosing interval.
近日，欧盟委员会批准治疗斑块型银屑病的新型生物制剂STELARA(TM) (ustekinumab)在欧洲27个国家上市销售。该药治疗成人中-重度斑块型银屑病，主要用于那些对其他全身性治疗药物（包括ciclosporin，methotrexate和PUVA等）应答不充分，有禁忌症候或耐受不好的患者。在欧洲国家，有2-3%的人深受银屑病困扰。 Ustekinumab has been authorised by the European Medicines Evaluation Agency (EMEA) for the treatment of moderate-to-severe plaque psoriasis in adults who failed to respond to, or have a contraindication to, or are intolerant to other systemic therapies including ciclosporin, methotrexate and PUVA (psoralen plus ultraviolet A light). Psoriasis is a chronic skin disease that can be itchy, painful and debilitating.牛皮癣是一种慢性皮肤疾病，可发痒，痛苦和破坏性。 Around 1.5 million people in the UK1, 2 have psoriasis and it is estimated that 20-30% of those have severe disease.3 Psoriasis is often associated with potentially serious co-morbidities and substantial physical and emotional burdens.4,5大约150万UK1，2牛皮癣患者和估计20-30％的人有严重的disease.3银屑病往往与合作有关的潜在的严重，人民的发病率和大量的身体和感情burdens.4，5 In Phase III clinical studies,treatmentwithustekinumabdemonstrated a significant, visible improvement in patients' psoriasis with convenient 12 weekly maintenance dosing, as well as demonstrating improvements in quality of life.6,7 This means that patients need just 5 doses a year versus up to 104 injections with currently available biologic therapies.在第三阶段的临床研究，治疗与ustekinumab表现出显着，在与维修方便给药12周患者的牛皮癣明显改善，以及展示的life.6质量的改善，7这意味着，病人只需要5年与剂量高达104利用现有生物药物注射。 About Ustekinumab 关于Ustekinumab Ustekinumab is a new, fully human monoclonal antibody with a novel mechanism of action that targets the p40 subunit of the cytokines interleukin-12 (IL-12) and interleukin-23 (IL-23). Clinical trials 临床试验 The authorisation of ustekinumab is based on data from two large pivotal Phase III, multi-centre, randomised, double-blind, placebo controlled trials (PHOENIX 1 & 2).在ustekinumab授权是基于两个大的至关重要的第三阶段，多中心的随机，双盲，安慰剂对照试验数据（凤凰城1＆2）。 6,7 These trials involved nearly 2,000 adult patients in whom the efficacy and tolerability of ustekinumab in the treatment of moderate-to-severe plaque psoriasis was evaluated.6,7 The primary endpoint of both trials was a reduction in psoriasis severity (measured using the Psoriasis Area and Severity Index, PASI) of at least 75% (PASI 75) by week 12. 6,7这些试验涉及近2000名成年患者的疗效和治疗的耐受性的ustekinumab中度至重度牛皮癣是evaluated.6，7这两个试验的主要终点是在牛皮癣的严重程度减少（衡量使用银屑病面积和严重程度指数，PASI）为至少75％（PASI 75的）的第12周。 Just over two-thirds of patients achieved this outcome in both studies (after two doses at weeks 0 and 4).6,7 Improvement in skin quality was seen after just two weeks in PHOENIX 1.短短的两年，三分之二的患者达到这两项研究的结果（后两个星期，0和4）.6,7剂量改善皮肤质量仅仅两年后，在凤凰城一周看到。 Findings from an additional Phase III (head-to-head), randomised, multi-centre trial comparing ustekinumab and etanercept ( Enbrel ®) for the treatment of moderate-to-severe psoriasis showed ustekinumab was more effective than etanercept.8 The primary endpoint of the trial was a reduction in PASI of at least 75% by week 12.从调查结果增加第三阶段（头对头），随机，多中心的试验对比用于治疗ustekinumab和依那西普（Enbrel的 ®）中度至重度牛皮癣显示ustekinumab超过etanercept.8有效的主要终点试验是在PASI评分的至少75％削减12周。 At week 12, after two subcutaneous injections at weeks 0 and 4, 68% and 74% of patients receiving ustekinumab 45 mg or ustekinumab 90 mg, respectively, achieved a PASI 75 compared with 57% of patients receiving etanercept 50 mg subcutaneous injections twice weekly.8 12周时，两个星期后0和4，68％和74接受ustekinumab 45毫克或90毫克ustekinumab分别皮下注射治疗％，实现PASI 75比57接受依那西普50毫克每周两次皮下注射％的患者.8 Tolerability profile 耐受性 Ustekinumab therapy was generally well-tolerated during Phase III clinical trials.6,7 The most common side effects reported in Phase III clinical trials were arthralgia, cough, headache , injection site erythema, nasopharyngitis and upper respiratory tract infection. Ustekinumab is a selective immunosuppressant. Ustekinumab是一种选择性的免疫抑制剂。 Centocor Ortho Biotech Inc. developed ustekinumab and has exclusive marketing rights to the product in the United States.
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