2017年4月27日，美国食品和药品监管局今天批准Brineura(cerliponase_alfa)作为对一种特异性形式Batten病治疗。Brineura是第一个被FDA-批准减慢丧失走路能力(步行)在症状性儿童患者3岁和以上有婴儿晚期神经元蜡样脂褐质沉积症2型(CLN2)，也被称为三肽氨基肽酶-1 (TPP1)缺乏的治疗。
在FDA的药品评价和研究中心中药物评价III办公室主任Julie Beitz，M.D.说：“FDA承诺为有罕见病患者批准新和创新治疗，尤其是那里没有被批准的治疗选择,” “批准第一个为Batten病的这个形式治疗是对患这种情况患者是一个重要进展。”
CLN2病是一组被称为神经元蜡样质脂褐质沉积病(NCLs)之一，统称为Batten病。CLN2病是一种罕见遗传疾患主要地影响神经系统。在疾病的晚期婴儿型，体征和症状典型地在2和4岁间开始。初始症状通常地包括语言发育迟缓，复发性癫痫(癫痫)和困难协调运动(共济失调). 受影响的儿童还发生肌肉抽动(肌阵挛)和视力丧失。 CLN2病影响基本运动技能，例如坐和行走。有这个情况个体至童年后期往往需要使用轮椅和典型地不能活过青少年。Batten病是相对地罕见，在美国发生每十万活出生估计有2至4人。
Brineura是一种酶替代治疗。它的活性成分(cerliponase alfa)是一种重组型的人TPP1，在有CLN2病患者中缺乏该酶。Brineura被给予至脑脊液(CSF) 通过输注植入的贮存池和在头部中导管被一个特异性外科植入(脑室内进入装置[intraventricular access device])。Brineura必须在无菌条件下给予以减少感染的风险，而治疗应被由在脑室内给药方面知识渊博的卫生保健专业人员处理。在3岁和以上患儿中推荐Brineura的剂量是通过脑室内输注每间隔周一次300 mg，接着一个电解质输注。完整的Brineura 输注，包括要求的脑室内电解质输注，持续约4.5小时。建议在输注开始前30至60分钟用抗组织胺有或无解热药(为预防或治疗发热药物)或皮质激素预先-治疗患者。
一项非-随机化，单-臂剂量递升临床研究在22例有症状性CLN2病儿童患者和与来自42例有CLN2病来自一个天然史队列(一个独立的历史对照组)患者是至少3岁和有运动或语言症状未治疗患者比较确定Brineura的疗效。考虑患者年龄，基线行走能力和基因型，Brineura-治疗患者与在天然历史队列未治疗患者比较显示在走路能力较少下降。
在临床研究在24例有CLN2病年龄3至8岁患者至少接受一剂Brineura患者中评价Brineura的安全性。尚未在低于3岁患者中确定Brineura的安全性和有效性。
在用Brineura治疗患者最常见不良反应包括发热，ECG异常包括心率慢(心动过缓)，超敏性，在CSF蛋白中减低或增加，呕吐，癫痫，血肿(血管外血液异常集聚)，头痛，易激惹，CSF白细胞计数增加(脑脊液细胞增多)，装置-相关感染，感觉不舒服和低血压。
患者如有继续脑室内进取装置-相关并发症的征象(如，渗漏，装置失效或装置-相关感染的征象例如肿胀，头皮红斑，液体外渗，或脑室内接入装置周围或上头皮的隆起)时不应给予Brineura。在脑室内接入装置并发症的病例中，卫生保健提供者应终止Brineura的输注和参考装置制造商说明书为进一步指导。此外，卫生保健提供者应常规地测试患者CSF样品检测装置感染。在有脑室-腹膜分流术(医疗装置缓解液体积蓄引起对脑压力) 患者中也不应使用Brineura。
卫生保健提供者应还在卫生保健情况输注开始前，输注期间和输注后定期地监视生命征象(血压，心率，等)。卫生保健提供者应进行心电图(ECG)监视输注期间在有缓慢心率(心动过缓)，传导疾患病史患者(电脉冲通过心脏的进程受损)或结构性心脏病(心脏的缺陷或异常)，因为有些有CLN2病患者可能发生传导疾患或心脏病。在Brineura-治疗患者曽报道超敏性反应。由于对过敏反应潜能，当Brineura被给予时应容易得到适当医疗支持。如发生过敏反应，应立即终止输注和应开始适当治疗。
FDA将要求Brineura制造商进一步在2岁以下CLN2患者中评价Brineura的安全性，包括随常规使用装置相关不良事件和并发症。此外，一项长期安全性研究将评估Brineura治疗CLN2患者共最小10年。
FDA授权这项申请优先审评和突破性治疗指定。Brineura还接受孤儿药物指定，它提供激励帮助和鼓励对罕见疾病药物的开发。
承办单位还在一个程序意向鼓励为罕见儿童疾病预防和治疗新药和生物制品发展下，接受一个罕见儿童疾病优先审评凭证。一个承办单位在以后某个日期对一个不同产品随后的上市申请接受优先审评的凭证。这是FDA自该程序开始发出的第十个罕见儿童疾病优先审评凭证。
FDA授权Brineura的批准至BioMarin Pharmaceutical Inc。
https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm555613.htm
Brineura™ (cerliponase alfa) is approved to slow the loss of ability to walk or crawl (ambulation) in children with symptoms of CLN2 disease who are 3 years of age and older.
Brineura is the only enzyme replacement therapy to address the cause of CLN2 disease, a form of Batten disease. This approval marks the first time that a treatment is available for any type of Batten disease.
Indication
Brineura™ (cerliponase alfa) is a prescription medication used to slow loss of ability to walk or crawl (ambulation) in symptomatic pediatric patients 3 years of age and older with late infantile neuronal ceroid lipofuscinosis type 2 (CLN2), also known as tripeptidyl peptidase 1 (TPP1) deficiency.
Important Safety Information
Brineura is a prescription medicine. Before treatment with Brineura, it is important to discuss your child’s medical history with their doctor. Tell the doctor if they are sick or taking any medication and if they are allergic to any medicines. Your child’s doctor will decide if Brineura is right for them. If you have questions or would like more information about Brineura, contact your child’s doctor.
Brineura is only given by infusion into the fluid of the brain (known as an intraventricular injection) and using sterile technique to reduce the risk of infection. An intraventricular access device or port must be in place at least 5 to 7 days prior to the first infusion. Intraventricular access device-related infections were observed with Brineura treatment. If any signs of infection occur, contact your child’s doctor immediately. Your child’s intraventricular access device may need to be replaced over time.
Brineura should not be used in patients with active intraventricular access device-related complications (e.g., leakage, device failure, or device-related infection) and with shunts used to drain extra fluid around the brain.
Low blood pressure and/or slow heart rate may occur during and following the Brineura infusion. Contact your child’s doctor immediately if these reactions occur.
Undesirable or hypersensitivity reactions related to Brineura treatment, including fever, vomiting, and irritability, may occur during treatment and as late as 24 hours after infusion. Your child may receive medication such as antihistamines before Brineura infusions to reduce the risk of reactions. Serious and severe allergic reactions (anaphylaxis) may occur. If a reaction occurs, the infusion will be stopped and your child may be given additional medication. If a severe reaction occurs, the infusion will be stopped and your child will receive appropriate medical treatment. If any signs of anaphylaxis occur, immediately seek medical care.
Safety and effectiveness in pediatric patients below 3 years of age have not been established.
The most common side effects reported during Brineura infusions included fever, problems with the electrical activity of the heart, decreased or increased protein in the fluid of the brain, vomiting, seizures, hypersensitivity, collection of blood outside of blood vessels (hematoma), headache, irritability, and increased white blood cell count in the fluid of the brain, device-related infection, slow heart rate, feeling jittery, and low blood pressure. Intraventricular device-related side effects included infection, delivery system-related complications, and increased white blood cell count in fluid of the brain.
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