Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study.
Design of a Randomized, Placebo-Controlled, Phase 3 Trial of Tofersen Initiated in Clinically Presymptomatic SOD1 Variant Carriers: the ATLAS Study.
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在临床症状前SOD 1变异携带者中启动的托福生随机、安慰剂对照、3期试验设计：ATLAS研究。
DOI：
10.1007/s13311-022-01237-4
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发表时间：
2022-07
影响因子：
5.7
通讯作者：
Fradette, Stephanie
中科院分区：
文献类型：
--
作者：
Benatar, Michael;Wuu, Joanne;Andersen, Peter M.;Bucelli, Robert C.;Andrews, Jinsy A.;Otto, Markus;Farahany, Nita A.;Harrington, Elizabeth A.;Chen, Weiping;Mitchell, Adele A.;Ferguson, Toby;Chew, Sheena;Gedney, Liz;Oakley, Sue;Heo, Jeong;Chary, Sowmya;Fanning, Laura;Graham, Danielle;Sun, Peng;Liu, Yingying;Wong, Janice;Fradette, Stephanie
尽管广泛的研究，肌萎缩侧索硬化症（ALS）仍然是一个渐进的和总是致命的神经退行性疾病。对ALS的根本原因的有限了解使得难以靶向疾病的上游生物学机制，并且治疗性干预通常在疾病过程中相对较晚施用。ALS的遗传形式为治疗开发提供了独特的机会，因为遗传关联可能揭示疾病病因的潜在见解。遗传性ALS也可能适合于研究早期干预，因为有可能鉴定出具有致病性遗传变异的临床症状前高危个体。越来越多的证据表明ALS存在症状前阶段，来自症状前家族性ALS（Pre-fALS）研究的生物标志物数据显示，血液神经丝轻链（NfL）的升高先于表型转化为临床表现疾病。Tofersen是一种研究中的反义寡核苷酸，旨在通过降解超氧化物歧化酶1（SOD 1）mRNA来减少SOD 1蛋白的合成。ATLAS研究（NCT 04856982）根据Pre-fALS和托费森临床开发项目的信息，旨在评估启动托费森对与高或完全转移和快速疾病进展相关的SOD 1变体前驱携带者的影响，这些患者也有疾病活动的生物标志物证据（血浆NfL升高）。ATLAS研究将调查tofersen是否可以延迟临床表现的ALS的出现。据我们所知，ATLAS是首个在症状前ALS中进行的干预性试验，有可能对症状前试验的设计和实施、高危个体的识别和监测以及ALS的未来治疗模式产生重要见解。在线版本包含补充材料，可通过10.1007/s13311-022-01237-4获得。
Despite extensive research, amyotrophic lateral sclerosis (ALS) remains a progressive and invariably fatal neurodegenerative disease. Limited knowledge of the underlying causes of ALS has made it difficult to target upstream biological mechanisms of disease, and therapeutic interventions are usually administered relatively late in the course of disease. Genetic forms of ALS offer a unique opportunity for therapeutic development, as genetic associations may reveal potential insights into disease etiology. Genetic ALS may also be amenable to investigating earlier intervention given the possibility of identifying clinically presymptomatic, at-risk individuals with causative genetic variants. There is increasing evidence for a presymptomatic phase of ALS, with biomarker data from the Pre-Symptomatic Familial ALS (Pre-fALS) study showing that an elevation in blood neurofilament light chain (NfL) precedes phenoconversion to clinically manifest disease. Tofersen is an investigational antisense oligonucleotide designed to reduce synthesis of superoxide dismutase 1 (SOD1) protein through degradation of SOD1 mRNA. Informed by Pre-fALS and the tofersen clinical development program, the ATLAS study (NCT04856982) is designed to evaluate the impact of initiating tofersen in presymptomatic carriers of SOD1 variants associated with high or complete penetrance and rapid disease progression who also have biomarker evidence of disease activity (elevated plasma NfL). The ATLAS study will investigate whether tofersen can delay the emergence of clinically manifest ALS. To our knowledge, ATLAS is the first interventional trial in presymptomatic ALS and has the potential to yield important insights into the design and conduct of presymptomatic trials, identification, and monitoring of at-risk individuals, and future treatment paradigms in ALS. The online version contains supplementary material available at 10.1007/s13311-022-01237-4.
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DOI：
10.1136/jnnp-2016-313521
发表时间：
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期刊：
Journal of neurology, neurosurgery, and psychiatry
影响因子：
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发表时间：
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DOI：
10.1093/brain/awab404
发表时间：
2022-03-29
期刊：
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影响因子：
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影响因子：
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