Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
Trial of Antisense Oligonucleotide Tofersen for SOD1 ALS
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DOI：
10.1056/nejmoa2204705
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发表时间：
2022-09-22
影响因子：
158.5
通讯作者：
Fradette, Stephanie
中科院分区：
文献类型：
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作者：
Miller, Timothy M.;Cudkowicz, Merit E.;Fradette, Stephanie
BackgroundThe intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1（SOD1）protein and is being studied in patients with amyotrophic lateral sclerosis（ALS）associated with mutations in SOD1（SOD1 ALS）.MethodsIn this phase 3 trial，we randomly assigned adults with SOD1 ALS in a 2：1 ratio to receive 8 doses of tofersen（100 mg）or placebo over a period of 24 wk.主要终点是预测疾病进展较快的参与者中ALS功能评定量表修订版（ALSFRS-R;范围为0至48，评分越高表示功能越好）从基线至第28周的总评分变化。次要终点包括脑脊液（CSF）中SOD 1蛋白总浓度、血浆中神经丝轻链浓度、慢肺活量和16块肌肉的手持式测力仪的变化。对试验的随机部分和52周时开放标签扩展部分的综合分析比较了在试验开始时开始tofersen的参与者的结果（早期开始队列）与第28周从安慰剂转换为药物的参与者中的受试者结果共有72名受试者接受了tofersen治疗，（39人预测进展较快），36人接受安慰剂（21人预测进展较快）。与安慰剂相比，Tofersen导致CSF中SOD 1和血浆中神经丝轻链浓度的降低更大。在快速进展亚组（主要分析）中，ALSFRS-R评分至第28周的变化，托弗森组为-6.98，安慰剂组为-8.14（差异，1.2分; 95%置信区间[CI]，-3.2至5.5; P=0.97）。两组间次要临床终点的结果无显著差异。共有95例受试者（88%）进入开放标签扩展期。在第52周，ALSFRS-R评分的变化在早期开始队列中为-6.0，在延迟开始队列中为-9.5（差异为3.5分; 95%CI为0.4 - 6.7）;在其他终点观察到有利于早期开始托弗森的非多重校正差异。腰椎穿刺相关不良事件很常见。神经系统严重不良事件发生在7%的tofersen recipients.ConclusionsIn SOD 1 ALS的人，tofersen降低浓度的SOD 1在CSF和血浆中的神经丝轻链超过28周，但没有改善临床终点，并与不良事件。在扩展阶段，正在进一步评价较早和延迟开始托费生治疗的潜在影响。（由Biogen资助; VALOR和OLE ClinicalTrials.gov编号; EudraCT编号，2015-004098-33和2016-003225-41。）
BackgroundThe intrathecally administered antisense oligonucleotide tofersen reduces synthesis of the superoxide dismutase 1 (SOD1) protein and is being studied in patients with amyotrophic lateral sclerosis (ALS) associated with mutations in SOD1 (SOD1 ALS).MethodsIn this phase 3 trial, we randomly assigned adults with SOD1 ALS in a 2:1 ratio to receive eight doses of tofersen (100 mg) or placebo over a period of 24 weeks. The primary end point was the change from baseline to week 28 in the total score on the ALS Functional Rating Scale-Revised (ALSFRS-R; range, 0 to 48, with higher scores indicating better function) among participants predicted to have faster-progressing disease. Secondary end points included changes in the total concentration of SOD1 protein in cerebrospinal fluid (CSF), in the concentration of neurofilament light chains in plasma, in slow vital capacity, and in handheld dynamometry in 16 muscles. A combined analysis of the randomized component of the trial and its open-label extension at 52 weeks compared the results in participants who started tofersen at trial entry (early-start cohort) with those in participants who switched from placebo to the drug at week 28 (delayed-start cohort).ResultsA total of 72 participants received tofersen (39 predicted to have faster progression), and 36 received placebo (21 predicted to have faster progression). Tofersen led to greater reductions in concentrations of SOD1 in CSF and of neurofilament light chains in plasma than placebo. In the faster-progression subgroup (primary analysis), the change to week 28 in the ALSFRS-R score was -6.98 with tofersen and -8.14 with placebo (difference, 1.2 points; 95% confidence interval [CI], -3.2 to 5.5; P=0.97). Results for secondary clinical end points did not differ significantly between the two groups. A total of 95 participants (88%) entered the open-label extension. At 52 weeks, the change in the ALSFRS-R score was -6.0 in the early-start cohort and -9.5 in the delayed-start cohort (difference, 3.5 points; 95% CI, 0.4 to 6.7); non-multiplicity-adjusted differences favoring early-start tofersen were seen for other end points. Lumbar puncture-related adverse events were common. Neurologic serious adverse events occurred in 7% of tofersen recipients.ConclusionsIn persons with SOD1 ALS, tofersen reduced concentrations of SOD1 in CSF and of neurofilament light chains in plasma over 28 weeks but did not improve clinical end points and was associated with adverse events. The potential effects of earlier as compared with delayed initiation of tofersen are being further evaluated in the extension phase. (Funded by Biogen; VALOR and OLE ClinicalTrials.gov numbers, and ; EudraCT numbers, 2015-004098-33 and 2016-003225-41.)