托非生治疗在“真实世界”环境中对肌萎缩侧索硬化症患者的疗效——来自德国早期准入项目的一项为期12个月的多中心队列研究
Effects of tofersen treatment in patients with -ALS in a "real-world" setting - a 12-month multicenter cohort study from the German early access program.
作者信息
Wiesenfarth Maximilian, Dorst Johannes, Brenner David, Elmas Zeynep, Parlak Özlem, Uzelac Zeljko, Kandler Katharina, Mayer Kristina, Weiland Ulrike, Herrmann Christine, Schuster Joachim, Freischmidt Axel, Müller Kathrin, Siebert Reiner, Bachhuber Franziska, Simak Tatiana, Günther Kornelia, Fröhlich Elke, Knehr Antje, Regensburger Martin, German Alexander, Petri Susanne, Grosskreutz Julian, Klopstock Thomas, Reilich Peter, Schöberl Florian, Hagenacker Tim, Weyen Ute, Günther René, Vidovic Maximilian, Jentsch Martin, Haarmeier Thomas, Weydt Patrick, Valkadinov Ivan, Hesebeck-Brinckmann Jasper, Conrad Julian, Weishaupt Jochen Hans, Schumann Peggy, Körtvélyessy Peter, Meyer Thomas, Ruf Wolfgang Philipp, Witzel Simon, Senel Makbule, Tumani Hayrettin, Ludolph Albert Christian
机构信息
Department of Neurology, Ulm University, 89081, Ulm, Germany.
German Centre for Neurodegenerative Diseases (DZNE) Site Ulm, 89081, Ulm, Germany.
出版信息
EClinicalMedicine. 2024 Feb 15;69:102495. doi: 10.1016/j.eclinm.2024.102495. eCollection 2024 Mar.
BACKGROUND
In April 2023, the antisense oligonucleotide tofersen was approved by the U.S. Food and Drug Administration (FDA) for treatment of -amyotrophic lateral sclerosis (ALS), after a decrease of neurofilament light chain (NfL) levels had been demonstrated.
METHODS
Between 03/2022 and 04/2023, 24 patients with -ALS from ten German ALS reference centers were followed-up until the cut-off date for ALS functional rating scale revised (ALSFRS-R), progression rate (loss of ALSFRS-R/month), NfL, phosphorylated neurofilament heavy chain (pNfH) in cerebrospinal fluid (CSF), and adverse events.
FINDINGS
During the observation period, median ALSFRS-R decreased from 38.0 (IQR 32.0-42.0) to 35.0 (IQR 29.0-42.0), corresponding to a median progression rate of 0.11 (IQR -0.09 to 0.32) points of ALSFRS-R lost per month. Median serum NfL declined from 78.0 pg/ml (IQR 37.0-147.0 pg/ml; = 23) to 36.0 pg/ml (IQR 22.0-65.0 pg/ml; = 23; p = 0.02), median pNfH in CSF from 2226 pg/ml (IQR 1061-6138 pg/ml; = 18) to 1151 pg/ml (IQR 521-2360 pg/ml; = 18; p = 0.02). In the CSF, we detected a pleocytosis in 73% of patients (11 of 15) and an intrathecal immunoglobulin synthesis (IgG, IgM, or IgA) in 9 out of 10 patients. Two drug-related serious adverse events were reported.
INTERPRETATION
Consistent with the VALOR study and its Open Label Extension (OLE), our results confirm a reduction of NfL serum levels, and moreover show a reduction of pNfH in CSF. The therapy was safe, as no persistent symptoms were observed. Pleocytosis and Ig synthesis in CSF with clinical symptoms related to myeloradiculitis in two patients, indicate the potential of an autoimmune reaction.
FUNDING
No funding was received towards this study.
背景
2023年4月，反义寡核苷酸托非生（tofersen）经美国食品药品监督管理局（FDA）批准用于治疗肌萎缩侧索硬化症（ALS），此前已证实其可降低神经丝轻链（NfL）水平。
方法
在2022年3月至2023年4月期间，对来自德国10个ALS参考中心的24例肌萎缩侧索硬化症（ALS）患者进行随访，直至修订的ALS功能评定量表（ALSFRS-R）、进展率（每月ALSFRS-R的丧失）、NfL、脑脊液（CSF）中磷酸化神经丝重链（pNfH）以及不良事件的截止日期。
研究结果
在观察期内，ALSFRS-R的中位数从38.0（四分位间距32.0 - 42.0）降至35.0（四分位间距29.0 - 42.0），相当于每月ALSFRS-R丧失的中位数进展率为0.11（四分位间距 - 0.09至0.32）分。血清NfL的中位数从78.0 pg/ml（四分位间距37.0 - 147.0 pg/ml；n = 23）降至36.0 pg/ml（四分位间距22.0 - 65.0 pg/ml；n = 23；p = 0.02），脑脊液中pNfH的中位数从2226 pg/ml（四分位间距1061 - 6138 pg/ml；n = 18）降至1151 pg/ml（四分位间距521 - 2360 pg/ml；n = 18；p = 0.02）。在脑脊液中，我们在73%的患者（15例中的11例）中检测到细胞增多，在10例患者中的9例中检测到鞘内免疫球蛋白合成（IgG、IgM或IgA）。报告了两例与药物相关的严重不良事件。
解读
与VALOR研究及其开放标签扩展（OLE）一致，我们的结果证实了血清NfL水平的降低，此外还显示脑脊液中pNfH的降低。该治疗是安全的，因为未观察到持续症状。脑脊液中的细胞增多和Ig合成，以及两名患者出现与脊髓神经根炎相关的临床症状，表明存在自身免疫反应的可能性。
资金来源
本研究未获得资金支持。
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