本文由小咖机器人翻译整理

期刊来源：Lancet Neurol

文献发表时间：2024-01

原文链接：https://doi.org/10.1016/S1474-4422(23)00384-8

摘要内容如下：

背景

Cerliponase Alfa是一种重组人三肽基肽酶1（TPP1）酶替代疗法，用于治疗2型神经元蜡样质脂褐质沉积症（CLN2疾病），该疾病由TPP1基因突变引起。我们的目的是确定脑室内注射Cerliponase Alfa治疗儿童CLN2疾病的长期安全性和有效性。

方法

该分析包括在德国、意大利、英国和美国的五家医院进行的为期48周、单组、开放标签、多中心、剂量递增的主要研究（NCT01907087）和为期240周、开放标签、6个月安全性随访的累积数据。经基因分析和酶检测证实患有CLN2疾病的3-16岁儿童符合入选条件。治疗为每2周脑室内输注300mg Cerliponase Alfa。将DEM-CHILD数据库中患有未经治疗的CLN2疾病的历史对照作为对照组。主要疗效结果是CLN2临床评定量表的运动和语言联合领域中未逆转的2分下降或得分为0的时间。该扩展研究已在ClinicalTrials.gov（NCT02485899）注册，并已完成。

调查结果

在2013年9月13日至2014年12月22日期间，24名参与者参加了初步研究（15名女性和9名男性）。其中，23名参与者参加了2015年2月2日至2020年12月10日期间进行的扩展研究，并在平均272.1周（范围162.1-300.1周）的时间内接受了300 mg Cerliponase Alfa。17名参与者完成了延期，6名参与者提前中止。与既往未接受治疗的对照组相比，接受治疗的患者在联合运动和语言领域出现不可逆转的2分下降或得分为0的可能性显著降低（风险比0.14，95%CI 0.06~0.33；P<0.0001）。所有参与者都经历了至少一次不良事件，21人（88%）经历了一次严重不良事件；9名参与者经历了脑室内装置相关感染，其中6名参与者中有9起事件导致装置更换。没有因不良事件而中止研究，也没有死亡。

解释

在超过5年的平均治疗期内，Cerliponase Alfa被认为具有减缓CLN2疾病患儿运动和语言功能下降的临床意义。虽然我们的研究没有同期对照组，但研究结果为长期治疗的效果提供了重要的见解。

资金

生物标记药物。

英文原文如下：

Abstracts

BACKGROUND  Cerliponase alfa is a recombinant human tripeptidyl peptidase 1 (TPP1) enzyme replacement therapy for the treatment of neuronal ceroid lipofuscinosis type 2 (CLN2 disease), which is caused by mutations in the TPP1 gene. We aimed to determine the long-term safety and efficacy of intracerebroventricular cerliponase alfa in children with CLN2 disease.

METHODS  This analysis includes cumulative data from a primary 48-week, single-arm, open-label, multicentre, dose-escalation study (NCT01907087) and the 240-week open-label extension with 6-month safety follow-up, conducted at five hospitals in Germany, Italy, the UK, and the USA. Children aged 3-16 years with CLN2 disease confirmed by genetic analysis and enzyme testing were eligible for inclusion. Treatment was intracerebroventricular infusion of 300 mg cerliponase alfa every 2 weeks. Historical controls with untreated CLN2 disease in the DEM-CHILD database were used as a comparator group. The primary efficacy outcome was time to an unreversed 2-point decline or score of 0 in the combined motor and language domains of the CLN2 Clinical Rating Scale. This extension study is registered with ClinicalTrials.gov, NCT02485899, and is complete.

FINDINGS  Between Sept 13, 2013, and Dec 22, 2014, 24 participants were enrolled in the primary study (15 female and 9 male). Of those, 23 participants were enrolled in the extension study, conducted between Feb 2, 2015, and Dec 10, 2020, and received 300 mg cerliponase alfa for a mean of 272·1 (range 162·1-300·1) weeks. 17 participants completed the extension and six discontinued prematurely. Treated patients were significantly less likely than historical untreated controls to have an unreversed 2-point decline or score of 0 in the combined motor and language domains (hazard ratio 0·14, 95% CI 0·06 to 0·33; p<0·0001). All participants experienced at least one adverse event and 21 (88%) experienced a serious adverse event; nine participants experienced intracerebroventricular device-related infections, with nine events in six participants resulting in device replacement. There were no study discontinuations because of an adverse event and no deaths.

INTERPRETATION  Cerliponase alfa over a mean treatment period of more than 5 years was seen to confer a clinically meaningful slowing of decline of motor and language function in children with CLN2 disease. Although our study does not have a contemporaneous control group, the results provide crucial insights into the effects of long-term treatment.

FUNDING  BioMarin Pharmaceutical.

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