Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy
Nusinersen versus Sham Control in Later-Onset Spinal Muscular Atrophy
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DOI：
10.1056/nejmoa1710504
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发表时间：
2018-02-15
影响因子：
158.5
通讯作者：
Kim, Hyuna
中科院分区：
文献类型：
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作者：
Mercuri, E.;Darras, B. T.;Kim, Hyuna
背景Nusinersen是一种反义寡核苷酸药物，可调节运动神经元存活2（SMN 2）基因的前信使RNA剪接。它已被开发用于治疗脊髓性肌萎缩症（SMA）。方法我们在126名6个月后出现症状的SMA儿童中进行了一项多中心、双盲、假对照、III期nusinersen试验。在第1、29、85和274天，以2：1的比例将儿童随机分配接受nusinersen鞘内给药，剂量为12 mg（nusinersen组）或假手术（对照组）。主要终点是治疗15个月时Hammersmith功能运动量表-扩展（HFMSE）评分较基线的最小二乘平均变化; HFMSE评分范围为0 - 66，评分越高表示运动功能越好。次要终点包括HFMSE评分较基线有临床意义增加的儿童百分比（>= 3分），结果表明至少两种运动技能的改善。nusinersen组的HFMSE评分从基线至第15个月出现最小二乘均值增加（4.0分）和对照组的最小二乘均值降低（-1.9分），组间差异显著有利于nusinersen（变化的最小二乘均值差异，5.9分; 95%置信区间，3.7 - 8.1; P< 0.001）。这一结果促使试验提前终止。最终分析结果与中期分析结果一致。在最终分析中，nusinersen组57%的儿童与对照组26%的儿童相比，HFMSE评分从基线至第15个月至少增加3分（P< 0.001），诺西那生组和对照组不良事件的总体发生率相似（分别为93%和100%）。结论：在迟发型SMA儿童中，与对照组相比，接受nusinersen治疗的儿童运动功能有显著且有临床意义的改善。（由Biogen和Ionis Pharmaceuticals资助; CHERISH ClinicalTrials。政府编号，NCT 02292537。）
BACKGROUND Nusinersen is an antisense oligonucleotide drug that modulates pre-messenger RNA splicing of the survival motor neuron 2 (SMN2) gene. It has been developed for the treatment of spinal muscular atrophy (SMA).METHODS We conducted a multicenter, double-blind, sham-controlled, phase 3 trial of nusinersen in 126 children with SMA who had symptom onset after 6 months of age. The children were randomly assigned, in a 2: 1 ratio, to undergo intrathecal administration of nusinersen at a dose of 12 mg (nusinersen group) or a sham procedure (control group) on days 1, 29, 85, and 274. The primary end point was the least-squares mean change from baseline in the Hammersmith Functional Motor Scale-Expanded (HFMSE) score at 15 months of treatment; HFMSE scores range from 0 to 66, with higher scores indicating better motor function. Secondary end points included the percentage of children with a clinically meaningful increase from baseline in the HFMSE score (>= 3 points), an outcome that indicates improvement in at least two motor skills.RESULTS In the prespecified interim analysis, there was a least-squares mean increase from baseline to month 15 in the HFMSE score in the nusinersen group (by 4.0 points) and a least-squares mean decrease in the control group (by -1.9 points), with a significant between-group difference favoring nusinersen (least-squares mean difference in change, 5.9 points; 95% confidence interval, 3.7 to 8.1; P< 0.001). This result prompted early termination of the trial. Results of the final analysis were consistent with results of the interim analysis. In the final analysis, 57% of the children in the nusinersen group as compared with 26% in the control group had an increase from baseline to month 15 in the HFMSE score of at least 3 points (P< 0.001), and the overall incidence of adverse events was similar in the nusinersen group and the control group (93% and 100%, respectively).CONCLUSIONS Among children with later-onset SMA, those who received nusinersen had significant and clinically meaningful improvement in motor function as compared with those in the control group. (Funded by Biogen and Ionis Pharmaceuticals; CHERISH ClinicalTrials. gov number, NCT02292537.)