Interim Results of a Phase 2 Clinical Study of Nusinersen (ISIS-SMNRx) in Patients with Infantile-Onset Spinal Muscular Atrophy (P5.004)
Interim Results of a Phase 2 Clinical Study of Nusinersen (ISIS-SMNRx) in Patients with Infantile-Onset Spinal Muscular Atrophy (P5.004)
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Nusinersen (ISIS-SMNRx) 在婴儿期发病的脊髓性肌萎缩症 (P5.004) 患者中的 2 期临床研究的中期结果
DOI：
10.1212/wnl.86.16_supplement.p5.004
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发表时间：
2016
期刊：
影响因子：
9.9
通讯作者：
K. Bishop
中科院分区：
文献类型：
--
作者：
R. Finkel;C. Chiriboga;J. Vajsar;J. Day;J. Montes;D. Vivo;M. Yamashita;F. Rigo;G. Hung;E. Schneider;D. Norris;S. Xia;F. Bennett;K. Bishop
目的：评估nusinersen（ISIS-SMNRx）在突发性脊髓性肌萎缩症（SMA）患者中的安全性、耐受性、药代动力学和临床疗效。
背景：婴儿型SMA是一种由运动神经元中运动神经元存活蛋白（Survival of Motor Neuron，SMN）缺陷引起的破坏性、持续进行性的神经退行性疾病，占所有SMA患者的一半以上，是婴儿期死亡的最常见遗传原因。Nusinersen是一种新型反义寡核苷酸药物，旨在改变SMN 2 mRNA的剪接，从而增加功能性SMN蛋白的量。
方法：这是一项正在进行的多中心、开放标签、II期临床研究的中期分析，旨在评价nusinersen多次鞘内给药在运动型SMA患者中的安全性/耐受性、药代动力学和临床效应。入组了20名受试者（低剂量队列中4名，高剂量队列中16名）。3例受试者的尸检组织能够进行药效学分析。
结果：截至2015年8月进行的中期分析，该研究已持续27个月。诺西那生耐受性良好，未发现安全性问题。可评价人群中19例受试者中有16例仍然存活（中位年龄20.1个月），与基线和已发表的自然史数据相比，运动功能评分显著改善（p=0.01），运动里程碑的增量实现，如头部控制（10例受试者）、滚动（9例受试者）、坐位（6例受试者）和神经肌肉电生理学改善。药效学数据支持药物递送、全长SMN 2转录物的增强和靶神经元中SMN蛋白的增加。
结论：在这项开放标签II期研究中，nusinersen表现出良好的安全性和耐受性，药理学与其预期作用机制一致，并有令人鼓舞的证据支持有意义的临床应答。重要的是，目前正在进行一项nusinersen治疗运动型SMA的关键性、假手术对照III期临床研究。披露：Finkel博士作为顾问和/或演讲者在Isis Pharmaceuticals和Voyager Therapeutics的活动中获得了个人报酬。Chiriboga博士已收到与最新，ISIS制药/Biogen和罗氏制药公司的活动的个人补偿。瓦杰萨博士没有什么可透露的。戴博士作为顾问与萨雷普塔治疗公司和PTC治疗公司合作，获得了个人报酬。蒙特斯博士作为顾问参加了Isis Pharmeceuticals的活动，并获得了个人报酬。De Vivo博士作为顾问在Isis制药公司的活动中获得了个人报酬。Yamashita博士作为Isis制药公司的雇员，因其活动而获得个人报酬。里戈博士没有什么可透露的。洪医生没什么可透露的施耐德博士没有什么可透露的。诺里斯博士因与伊西斯制药公司的活动而获得个人报酬。Xia博士作为Isis Pharmaceuticals的雇员，因其活动而获得个人报酬。班尼特博士因在Isis Pharmaceuticals，Inc.的活动而获得个人报酬。作为一名雇员Bishop博士已因作为Isis Pharmaceuticals员工的活动而获得个人报酬。
Objective:To assess the safety, tolerability, pharmacokinetics and clinical effects of nusinersen (ISIS-SMNRx) in patients with infantile-onset Spinal Muscular Atrophy (SMA).
Background:Infantile-onset SMA is a devastating and relentlessly progressive neurodegenerative disease caused by the deficiency of Survival of Motor Neuron (SMN) protein in motor neurons, accounts for over half of all patients with SMA, and is the most common genetic cause of death in infancy. Nusinersen is a novel antisense oligonucleotide drug designed to alter splicing of SMN2 mRNA thereby increasing the amount of functional SMN protein.
Methods:This is an interim analysis of an ongoing multicenter, open-label, Phase 2 clinical study designed to evaluate the safety/tolerability, pharmacokinetics, and clinical effects of multiple intrathecal doses of nusinersen in patients with infantile-onset SMA. Twenty participants (4 in a lower-dose cohort, 16 in a higher-dose cohort) were enrolled. Autopsy tissue in 3 participants enabled pharmacodynamic analyses.
Results:As of an interim analysis performed in August 2015, the study has been ongoing for 27 months. Nusinersen has been well tolerated with no safety concerns identified. Sixteen of 19 participants in the evaluable population remain alive (median age 20.1 months) and demonstrate significant (p=0.01) improvements in motor function scores, incremental achievement of motor milestones such as head control (10 participants), rolling (9 participants), sitting (6 participants), and improvements in neuromuscular electrophysiology compared to baseline and published natural history data. Pharmacodynamic data support drug delivery, enhancement of full-length SMN2 transcript, and an increase in SMN protein in target neurons.
Conclusions:In this open-label Phase 2 study, nusinersen exhibits good safety and tolerability, pharmacology that is consistent with its intended mechanism of action, and encouraging evidence supporting meaningful clinical response. Importantly, a pivotal, sham-controlled Phase 3 clinical study of nusinersen in infantile-onset SMA is currently ongoing. Disclosure: Dr. Finkel has received personal compensation for activities with Isis Pharmaceuticals and Voyager Therapeutics as a consultant and/or speaker. Dr. Chiriboga has received personal compensation for activities with Up To Date, ISIS pharmaceuticals/Biogen, and Roche pharmaceuticals. Dr. Vajsar has nothing to disclose. Dr. Day has received personal compensation for activities with Sarepta Therapeutics and PTC Therapeutics as a consultant. Dr. Montes has received personal compensation for activities with Isis Pharmeceuticals as a consultant. Dr. De Vivo has received personal compensation for activities with Isis Pharmaceuticals as a consultant. Dr. Yamashita has received personal compensation for activities with Isis Pharmaceuticals as an employee. Dr. Rigo has nothing to disclose. Dr. Hung has nothing to disclose. Dr. Schneider has nothing to disclose. Dr. Norris has received personal compensation for activities with Isis Pharmaceuticals. Dr. Xia has received personal compensation for activities with Isis Pharmaceuticals as an employee. Dr. Bennett has received personal compensation for activities with Isis Pharmaceuticals, Inc. as an employee. Dr. Bishop has received personal compensation for activities with Isis Pharmaceuticals as an employee.