Long-Term Tofersen in SOD1 Amyotrophic Lateral Sclerosis.

Tofersen, an intrathecal antisense oligonucleotide designed to reduce SOD1 protein synthesis, is the first and only approved therapy for the treatment of ALS in adults who have a variant in the SOD1 gene.

Tofersen是一种设计用于减少SOD1蛋白合成的鞘内反义寡核苷酸，是首个也是唯一一个被批准用于治疗具有SOD1基因变异的成年ALS患者的疗法。

Background

To evaluate the long-term effects of tofersen in adults with SOD1-ALS.

评估托弗森在成年SOD1-ALS患者中的长期效果。

DESIGN, SETTING, AND PARTICIPANTS: The phase 3, randomized, double-blind, placebo-controlledVALOR trial (A Study to Evaluate Efficacy, Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Tofersen in SOD1-ALS; conducted from March 2019 to July 2021) evaluated tofersen use over 28 weeks in adults (18 years and older) with weaknesses attributable to ALS and a confirmed SOD1 pathogenic variant at 32 sites in 10 countries; participants could then enroll in an open-label extension (OLE; completed August 2024).

设计、设置和参与者：第三阶段、随机、双盲、安慰剂对照的VALOR试验（一项评估托弗森在SOD1-ALS中的疗效、安全性、耐受性、药代动力学和药效学的研究；从2019年3月到2021年7月进行）在32个地点的10个国家对成年（18岁及以上）因ALS导致的虚弱和确认的SOD1致病变异患者进行了28周的托弗森使用评估；参与者之后可以参加开放标签扩展研究（OLE；2024年8月完成）。

intervention_and_exposure

Adults with SOD1-ALS were randomly assigned 2:1 to receive tofersen (100 mg) or placebo over a 24-week period in the VALOR study.

在VALOR研究中，SOD1-ALS的成年患者被随机分配为2:1比例，接受24周的托弗森（100 mg）或安慰剂治疗。

All participants in the OLE were treated with tofersen.

所有在开放标签扩展（OLE）研究中的参与者均接受了托弗森治疗。

main_outcomes_and_measures

Integrated analysis of VALOR and the OLE study aimed to compare early start vs placebo/delayed start (approximately 6 months later) treatment with tofersen.

VALOR和OLE研究的综合分析旨在比较早期开始使用tofersen治疗与安慰剂/延迟开始（大约6个月后）治疗的效果。

Key efficacy end points included measures of axonal injury and neurodegeneration (neurofilament), function and strength, quality of life, and survival.

关键疗效终点包括轴突损伤和神经退行性变（神经丝蛋白）、功能和力量、生活质量以及生存情况的测量。

Results

VALOR enrolled 108 participants with 42 unique SOD1 pathogenic variants (mean [SD] age: placebo/delayed-start group 51.2 [11.6] [n = 36]; early-start group: 48.1 [12.6] [n = 72]) with 19 (53%) and 43 (60%) of participants being male in the placebo/delayed- and early-start groups, respectively.

VALOR项目招募了108名携带42种不同SOD1致病变异的参与者（平均[标准差]年龄：安慰剂/延迟开始组为51.2[11.6]岁[n=36]；早期开始组为48.1[12.6]岁[n=72]），其中安慰剂/延迟开始组和早期开始组分别有19名（53%）和43名（60%）参与者为男性。

Overall, 95/108 participants (88%) enrolled in the OLE, and 46 participants completed the OLE (early-start group, 34 [47%]; placebo/delayed-start group, 12 [33%]).

总体而言，108名参与者中有95名（88%）参加了开放标签扩展（OLE）研究，其中46名参与者完成了OLE研究（早期开始组34名[47%]；安慰剂/延迟开始组12名[33%]）。

At OLE completion, participants could have accumulated 3.5 years or more (range, 192-276 weeks) of follow-up from the start of VALOR.

在开放标签扩展研究(OLE)完成时，参与者可能已经从VALOR研究开始积累了3.5年或更长时间（范围，192-276周）的随访。

Over 148 weeks, earlier initiation of tofersen (compared to later initiation) was associated with numerically less decline in measures of clinical function (Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised score, -9.9 vs -13.5 points), respiratory function (slow vital capacity, -13.8% vs -18.1%), muscle strength (handheld dynamometry megascore, -0.38 vs -0.43 points), and quality of life (Amyotrophic Lateral Sclerosis Assessment Questionnaire 5 score, 17.0 vs 22.5 points; EuroQol 5 Dimension, 5 Level Questionnaire score, -0.1 vs -0.2 points).

在148周内，与晚期启动相比，早期启动tofersen与临床功能（肌萎缩侧索硬化症功能评级量表修订版评分，-9.9 vs -13.5点）、呼吸功能（缓慢肺活量，-13.8% vs -18.1%）、肌肉力量（手持测力计大分值，-0.38 vs -0.43点）和生活质量（肌萎缩侧索硬化症评估问卷5评分，17.0 vs 22.5点；欧洲五维五级健康量表评分，-0.1 vs -0.2点）的数值下降较少相关。

Tofersen prolonged survival relative to the expected natural history of SOD1-ALS.

Tofersen 延长了 SOD1-ALS 的预期自然病程相关的生存期。

Most adverse events were consistent with ALS progression or known procedural adverse effects.

大多数不良事件与 ALS 进展或已知程序性不良反应一致。

All serious neurological adverse events were reversible; few led to tofersen discontinuation.

所有严重的神经系统不良事件都是可逆的；少数导致了tofersen的停药。

conclusions_and_relevance

Final data from VALOR and the OLE demonstrated the benefit of tofersen in SOD1-ALS and provide clear rationale for its use in this population.

来自VALOR和开放标签扩展研究（OLE）的最终数据表明，tofersen对SOD1-ALS有益，并为在这一人群中使用提供了明确的理由。

trial_registration

ClinicalTrials.gov Identifier: VALOR NCT02623699; OLE NCT03070119.

临床试验注册号：VALOR NCT02623699; OLE NCT03070119。