近日，美国FDA批准Brineura（cerliponase alfa）作为一种特定形式Batten病的治疗方法。Brineura是第一个通过FDA批准的治疗方案，针对晚发婴儿型神经元蜡样脂褐质沉积症(CLN2)，以缓解3岁及以上呈现症状儿科患者行走能力的丧失，CLN2也被称为三肽基肽酶-1（TPP1）缺乏症。 CLN2疾病是一类蜡样脂褐质沉积症（NCLs），其被统称为Batten病。CLN2疾病是一种罕见的遗传性疾病，主要影响神经系统。在这种疾病的晚期婴儿形式中，体征和症状通常在2和4岁之间开始。最初的症状通常包括语言延迟、复发性癫痫发作和协调运动困难（共济失调）。受影响的儿童也会发展出肌肉抽搐（肌阵挛）和视力丧失等病情。CLN2疾病影响基本运动技能，如坐立和行走；具有这种情况的病人个人经常需要在童年时期使用轮椅，并且通常活不过青春期。Batten病比较罕见，在美国每10万名活产新生儿中估计有2-4名。 Brineura是一种酶替代疗法，其活性成分（cerliponase alfa）是人类TPP1的重组形式，而CLN2病患者恰恰缺乏这一重要的酶蛋白。医护人员通过特殊手术，植入储存器和导管到患者脑室内，于是可将Brineura施用于脑脊髓液中。Brineura必须在无菌条件下进行治疗，以减少感染的风险。3岁及其以上儿科患者的Brineura推荐剂量是300mg，每隔一周通过脑室内输注一次，然后输注电解质。完整的Brineura输液，包括所需的脑室内电解质输注持续约4.5小时。建议在开始输液前30至60分钟，预先施用抗组胺药物或皮质类固醇。 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。” 优先审评和突破性治疗指定。孤儿药物指定，罕见儿童疾病优先审评凭证。 批准日期：2017年4月27日  公司：BioMarin Pharmaceutical BRINEURA(cerliponase alfa)注射液，为静脉使用 美国初次批准：2017 作用机制 CLN2病是一种神经退行性变性疾病，CNS中溶酶体酶三肽氨基肽酶-1(TPP1)缺乏引起，该酶降解代谢多肽。TPP1无已知的底物特异性。在TPP1活性中缺乏导致在中枢神经系统(CNS)正常地被此酶代谢的物质溶酶体贮存的积蓄，导致运动功能渐进地下降。 Cerliponase alfa(rhTTP1)，一种前酶，被CNS中靶细胞摄取和通过阳离子独立的甘露糖-6-磷酸受体[the Cation Independent Mannose-6-Phosphate Receptor](CI-MPR，也被称为M6P/IGF2受体)转位至溶酶体。在溶酶体中Cerliponase alfa被活化和rhTPP1活化的蛋白th水解型的裂解来自蛋白N-端的三肽。 适应证和用途 Brineura是一种水解溶酶体N-端三肽氨基肽酶适用于在3岁和以上有婴儿晚期神经元蜡样脂褐质沉积症2型(CLN2)症状性儿童患者减慢步行的丧失，也被称为三肽氨基肽酶1(TPP1)缺乏。 剂量和给药方法 ● 无菌术：制备和给药期间必须严格地观察。Brineura应由在脑室给药中知识渊博的医生给药，或或在他的指导下给药。Brineura是通过输注经过一个外科地植入的贮存池和导管给予至脑脊液(CSF)。 ● 建议在输注开始前30至60分钟用抗组织胺类有或无解热药或皮质激素预先-治疗患者。 ● 推荐剂量是300mg每间隔一周给药一次作为一个脑室内输注接着通过脑室内输注电解质 历时约4.5小时。 ●对关于制备，特异性脑室内接入装置使用，和给药的完整资料，见完整处方资料. 剂型和规格 注射液：Brineura 150mg/5mL(30mg/mL)溶液，每纸盒两个单次-剂量小瓶与脑室内电解质注射液5mL在一个单次-剂量小瓶共包装。 禁忌证 ● 急性脑室内接入装置-相关并发症(如，渗漏，装置失效，或装置-相关感染)。 ●用脑室-腹膜分流术患者。 警告和注意事项 ●脑室内接入装置-相关并发症：检查头皮皮肤完整性和脑室内接入装置渗漏的迹象。如存在装置渗漏或感染的征象不要给药。 常规地输送CSF样品为测试检测亚临床装置相关感染。 ● 心血管不良反应：输注前，期间，和输注后监视生命征象。在有心动过缓，传导疾患，或有结构性心脏病病史患者，在输注期间监视心电图(ECG)。在无心脏异常患者，每6个月进行常规12-导联ECG评价。 ● 超敏性反应：输注期间和后观察患者。如发生一个严重的超敏性反应，立即地停止输注和开始适当的治疗。 不良反应 最常见不良反应(≥8%)是：发热，ECG异常，减低CSF蛋白，呕吐，癫痫，超敏性，增加CSF蛋白，血肿，头痛，易激惹，脑脊液细胞增多，装置-相关感染，心动过缓，感觉不舒服，和低血压。 供应/贮存和处置 Brineura被供应为一种无菌，清晰至略微乳白色和无色至浅黄色溶液为脑室内输注和脑室内电解质注射液被供应为一种清晰至无色溶液为脑室内输注；两者都被包括在2的包装1。为Brineura使用的给药药盒被分开供应为2的包装2[见剂量和给药方法(2.2)]。 2的包装1 每个Brineura(cerliponase alfa)注射液小瓶有一个绿色的翻转帽(塑料)，和含150 mg cerliponase alfa每5 mL(30 mg/mL)。 每个脑室内电解质注射液小瓶 有一个黄色翻转帽(塑料)，和含5mL溶液。 包装1的内容物 NDC号 Brineura(cerliponase alfa)注射液(2小瓶150mg/5mL) 脑室内电解质注射液(1小瓶，5mL) 68135-811-02 2的包装2 为Brineura使用给药药盒被分开供应和含以下一次性-使用, 无菌输注组分: ● 两个20-mL注射器 ● 两个注射器针头(21 G，25.4mm) ● 一条延伸线 ● 一个输注组件有0.2 mµ在线过滤器 ● 一个端口针(22 G，16mm) 贮存 Brineura(cerliponase alfa)注射液和脑室内电解质注射液: 贮存直立在冻结箱内(-25°C至 -15°C)在原始纸盒避光保护。 为与Brineura使用给药药盒: 与Brineura分开地贮存在原始纸盒。不要冻结 FDA Approves Brineura™ (cerliponase alfa) for the Treatment of CLN2 Disease, a Form of Batten Disease and Ultra-Rare Pediatric Brain Disorder in Children 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. These are not all of the possible side effects with Brineura. Talk to your child’s doctor if they have any symptoms that bother them or that do not go away.