审判的反义寡核苷酸Tofersen SOD1 ALS。

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审判的反义寡核苷酸Tofersen SOD1 ALS。

郑传经地中海J。2022年9月22日,387 (12):1099 - 1110。doi: 10.1056 / NEJMoa2204705。

PubMed ID

36129998 (在PubMed

]

文摘

背景:鞘内注射超氧化物歧化酶的反义寡核苷酸tofersen降低合成1 (SOD1)正在研究蛋白质和肌萎缩性脊髓侧索硬化(ALS)患者与SOD1突变(SOD1肌萎缩性侧索硬化症)。方法:在这3期临床试验中,我们随机分配成人SOD1 ALS在2:1的比例获得八剂量的tofersen(100毫克)或安慰剂在24周。主要终点是改变从基线到星期28在总分ALS功能评定量表——(ALSFRS-R;范围0 - 48,得分越高表明更好的函数)参与者预测faster-progressing疾病。次要终点包括总浓度的变化SOD1脑脊液(CSF)、蛋白质浓度的神经丝轻链在等离子体,在缓慢的肺活量和手持测力法在16个肌肉。审判的随机组件相结合的分析方法及其开放的扩展在52周相比,参与者开始tofersen试验中的结果条目(早开始组)与参与者从安慰剂转向药物在28周(迟缓行动队列)。结果:共有72名参与者收到tofersen(39预计将有更快的发展),和36接受安慰剂(21预测更快进展)。Tofersen导致SOD1的浓度更大的削减在脑脊液和血浆中神经丝轻链的比安慰剂。更快的子群(主要分析),28周变化与tofersen ALSFRS-R分数为-6.98和-8.14与安慰剂(差异,1.2分;95%可信区间(CI), -3.2 - 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. CONCLUSIONS: In 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, NCT02623699 and NCT03070119; EudraCT numbers, 2015-004098-33 and 2016-003225-41.).

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药物

Tofersen