Chiriboga Claudia A, Swoboda Kathryn J, Darras Basil T, Iannaccone Susan T, Montes Jacqueline, De Vivo Darryl C, Norris Daniel A, Bennett C Frank, Bishop Kathie M
From the Departments of Neurology (C.A.C., J.M., D.C.D.) and Rehabilitative and Regenerative Medicine (J.M.), Columbia University, New York, NY; Department of Neurology (K.J.S.), University of Utah, Salt Lake City; Department of Neurology (B.T.D.), Boston Children's Hospital, Boston, MA; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical School, Dallas; and Ionis Pharmaceuticals, Inc. (formerly Isis Pharmaceuticals, Inc.) (D.A.N., C.F.B., K.M.B.), Carlsbad, CA.
Neurology. 2016 Mar 8;86(10):890-7. doi: 10.1212/WNL.0000000000002445. Epub 2016 Feb 10.
To examine safety, tolerability, pharmacokinetics, and preliminary clinical efficacy of intrathecal nusinersen (previously ISIS-SMNRx), an antisense oligonucleotide designed to alter splicing of SMN2 mRNA, in patients with childhood spinal muscular atrophy (SMA).
Nusinersen was delivered by intrathecal injection to medically stable patients with type 2 and type 3 SMA aged 2-14 years in an open-label phase 1 study and its long-term extension. Four ascending single-dose levels (1, 3, 6, and 9 mg) were examined in cohorts of 6-10 participants. Participants were monitored for safety and tolerability, and CSF and plasma pharmacokinetics were measured. Exploratory efficacy endpoints included the Hammersmith Functional Motor Scale Expanded (HFMSE) and Pediatric Quality of Life Inventory.
A total of 28 participants enrolled in the study (n = 6 in first 3 dose cohorts; n = 10 in the 9-mg cohort). Intrathecal nusinersen was well-tolerated with no safety/tolerability concerns identified. Plasma and CSF drug levels were dose-dependent, consistent with preclinical data. Extended pharmacokinetics indicated a prolonged CSF drug half-life of 4-6 months after initial clearance. A significant increase in HFMSE scores was observed at the 9-mg dose at 3 months postdose (3.1 points; p = 0.016), which was further increased 9-14 months postdose (5.8 points; p = 0.008) during the extension study.
Results from this study support continued development of nusinersen for treatment of SMA.
This study provides Class IV evidence that in children with SMA, intrathecal nusinersen is not associated with safety or tolerability concerns.
在儿童脊髓性肌萎缩症（SMA）患者中，研究鞘内注射诺西那生钠（以前称为ISIS - SMNRx）的安全性、耐受性、药代动力学及初步临床疗效。诺西那生钠是一种反义寡核苷酸，旨在改变SMN2信使核糖核酸（mRNA）的剪接。
在一项开放标签的1期研究及其长期扩展研究中，通过鞘内注射将诺西那生钠给予2至14岁、病情医学稳定的2型和3型SMA患者。在每组6 - 10名参与者的队列中研究了四个递增单剂量水平（1、3、6和9毫克）。对参与者进行安全性和耐受性监测，并测量脑脊液（CSF）和血浆药代动力学。探索性疗效终点包括哈默史密斯功能运动量表扩展版（HFMSE）和儿童生活质量量表。
共有28名参与者入组本研究（前3个剂量队列每组6名；9毫克队列10名）。鞘内注射诺西那生钠耐受性良好，未发现安全性/耐受性问题。血浆和脑脊液药物水平呈剂量依赖性，与临床前数据一致。延长的药代动力学表明，初始清除后脑脊液药物半衰期延长至4 - 6个月。在给药后3个月时，9毫克剂量组的HFMSE评分显著增加（3.1分；p = 0.016），在扩展研究期间给药后9 - 14个月进一步增加（5.8分；p = 0.008）。
本研究结果支持继续研发诺西那生钠用于治疗SMA。
本研究提供IV级证据，表明在SMA儿童中，鞘内注射诺西那生钠不存在安全性或耐受性问题。
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