依库珠单抗治疗晚发性脊髓性肌萎缩症：1/2 期研究的长期结果。
Nusinersen in later-onset spinal muscular atrophy: Long-term results from the phase 1/2 studies.
机构信息
From the Department of Neurology (B.T.D.), Boston Children's Hospital, MA; Departments of Neurology (C.A.C., J.M., D.C.D.), Pediatrics (C.A.C., D.C.D.), and Rehabilitation and Regenerative Medicine (J.M.), Columbia University Irving Medical Center, New York, NY; Department of Pediatrics (S.T.I.), University of Texas Southwestern Medical Center, Dallas; Department of Neurology (K.J.S.), Massachusetts General Hospital, Boston; Ionis Pharmaceuticals, Inc. (L.M., S.X., C.F.B., E.S.), Carlsbad, CA; employee of Ionis Pharmaceuticals, Inc. (K.M.B.), Carlsbad, CA, during design and conduct of this study, current employee of Otonomy, San Diego, CA; Department of Neurology (J.M.S.), Barrow Neurologic Institute, Phoenix, AZ; Excel Scientific Solutions (A.M.G.), Southport, CT; and Biogen (P.S., I.B., S.G., W.F.), Cambridge, MA.
出版信息
Neurology. 2019 May 21;92(21):e2492-e2506. doi: 10.1212/WNL.0000000000007527. Epub 2019 Apr 24.
OBJECTIVE
To report results of intrathecal nusinersen in children with later-onset spinal muscular atrophy (SMA).
METHODS
Analyses included children from a phase 1b/2a study (ISIS-396443-CS2; NCT01703988) who first received nusinersen during that study and were eligible to continue treatment in the extension study (ISIS-396443-CS12; NCT02052791). The phase 1b/2a study was a 253-day, ascending dose (3, 6, 9, 12 mg), multiple-dose, open-label, multicenter study that enrolled children with SMA aged 2-15 years. The extension study was a 715-day, single-dose level (12 mg) study. Time between studies varied by participant (196-413 days). Assessments included the Hammersmith Functional Motor Scale-Expanded (HFMSE), Upper Limb Module (ULM), 6-Minute Walk Test (6MWT), compound muscle action potential (CMAP), and quantitative multipoint incremental motor unit number estimation. Safety also was assessed.
RESULTS
Twenty-eight children were included (SMA type II, n = 11; SMA type III, n = 17). Mean HFMSE scores, ULM scores, and 6MWT distances improved by the day 1,150 visit (HFMSE: SMA type II, +10.8 points; SMA type III, +1.8 points; ULM: SMA type II, +4.0 points; 6MWT: SMA type III, +92.0 meters). Mean CMAP values remained relatively stable. No children discontinued treatment due to adverse events.
CONCLUSIONS
Nusinersen treatment over ∼3 years resulted in motor function improvements and disease activity stabilization not observed in natural history cohorts. These results document the long-term benefit of nusinersen in later-onset SMA, including SMA type III.
CLINICALTRIALSGOV IDENTIFIER
NCT01703988 (ISIS-396443-CS2); NCT02052791 (ISIS-396443-CS12).
CLASSIFICATION OF EVIDENCE
This study provides Class IV evidence that nusinersen improves motor function in children with later-onset SMA.
目的
报告鞘内注射依替膦酸纳在晚发性脊髓性肌萎缩症（SMA）患儿中的结果。
方法
分析纳入了一项 1b/2a 期研究（ISIS-396443-CS2；NCT01703988）中首次接受依替膦酸纳治疗且有资格继续参加扩展研究（ISIS-396443-CS12；NCT02052791）的患儿。该 1b/2a 期研究为 253 天、递增剂量（3、6、9、12mg）、多剂量、开放标签、多中心研究，共纳入 2-15 岁 SMA 患儿。扩展研究为 715 天、单剂量水平（12mg）研究。每位参与者的研究间隔不同（196-413 天）。评估包括 Hammersmith 功能性运动量表扩展版（HFMSE）、上肢模块（ULM）、6 分钟步行试验（6MWT）、复合肌肉动作电位（CMAP）和定量多点递增运动单位数量估计。同时评估安全性。
结果
共纳入 28 例患儿（SMA Ⅱ型 11 例，SMA Ⅲ型 17 例）。第 150 天 HFMSE 评分、ULM 评分和 6MWT 距离均有所改善（HFMSE：SMA Ⅱ型，+10.8 分；SMA Ⅲ型，+1.8 分；ULM：SMA Ⅱ型，+4.0 分；6MWT：SMA Ⅲ型，+92.0 米）。CMAP 值无明显变化。无患儿因不良事件停药。
结论
依替膦酸纳治疗 3 年以上可改善运动功能，稳定疾病活动度，而这在自然病史队列中未见。这些结果证明了依替膦酸纳在晚发性 SMA，包括 SMA Ⅲ型中的长期获益。
临床试验.gov 标识符：NCT01703988（ISIS-396443-CS2）；NCT02052791（ISIS-396443-CS12）。
证据分类
本研究提供了 IV 级证据，表明依替膦酸纳可改善晚发性 SMA 患儿的运动功能。
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