From the Division of Neurology, Department of Pediatrics, Nemours Children's Hospital, Orlando, FL (R.S.F.); the Department of Pediatric Neurology, Catholic University, Rome (E.M.); the Department of Neurology, Boston Children's Hospital, Boston (B.T.D.), and Biogen, Cambridge (Z.J.Z., S.G., W.F.) - both in Massachusetts; the Department of Neurology, St. Louis Children's Hospital, St. Louis (A.M.C.); the Department of Pediatrics, Ann and Robert H. Lurie Children's Hospital, Chicago (N.L.K.); the Department of Neuropediatrics and Muscle Disorders, Medical Center-University of Freiburg, Faculty of Medicine, Freiburg, Germany (J.K.); the Departments of Neurology (C.A.C., J.M.) and Rehabilitation and Regenerative Medicine (J.M.), Columbia University, and the Departments of Neurology and Pediatrics, Columbia University Medical Center (D.C.D.V.), New York; the Institute of Medical Genetics and Department of Pediatrics, Tokyo Women's Medical University, Tokyo (K.S.); the Institute of Motion, Paris (L.S.); the Department of Clinical and Molecular Genetics and Rare Diseases Unit, Hospital Vall d'Hebron, and Centro de Investigacíon Biomédica en Red Enfermedades Raras (CIBERER), Barcelona (E.T.); the Department of Pediatrics, Hacettepe University School of Medicine, Ankara, Turkey (H.T.); the Department of Pediatrics, Gothenburg University, Queen Silvia Children's Hospital, Gothenburg, Sweden (M.T.); the Department of Physical Therapy, Children's Hospital of Philadelphia, Philadelphia (A.M.G.); and Ionis Pharmaceuticals, Carlsbad, CA (K.B., C.F.B., E.S.).
N Engl J Med. 2017 Nov 2;377(18):1723-1732. doi: 10.1056/NEJMoa1702752.
Spinal muscular atrophy is an autosomal recessive neuromuscular disorder that is caused by an insufficient level of survival motor neuron (SMN) protein. Nusinersen is an antisense oligonucleotide drug that modifies pre-messenger RNA splicing of the SMN2 gene and thus promotes increased production of full-length SMN protein.
We conducted a randomized, double-blind, sham-controlled, phase 3 efficacy and safety trial of nusinersen in infants with spinal muscular atrophy. The primary end points were a motor-milestone response (defined according to results on the Hammersmith Infant Neurological Examination) and event-free survival (time to death or the use of permanent assisted ventilation). Secondary end points included overall survival and subgroup analyses of event-free survival according to disease duration at screening. Only the first primary end point was tested in a prespecified interim analysis. To control the overall type I error rate at 0.05, a hierarchical testing strategy was used for the second primary end point and the secondary end points in the final analysis.
In the interim analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (21 of 51 infants [41%] vs. 0 of 27 [0%], P<0.001), and this result prompted early termination of the trial. In the final analysis, a significantly higher percentage of infants in the nusinersen group than in the control group had a motor-milestone response (37 of 73 infants [51%] vs. 0 of 37 [0%]), and the likelihood of event-free survival was higher in the nusinersen group than in the control group (hazard ratio for death or the use of permanent assisted ventilation, 0.53; P=0.005). The likelihood of overall survival was higher in the nusinersen group than in the control group (hazard ratio for death, 0.37; P=0.004), and infants with a shorter disease duration at screening were more likely than those with a longer disease duration to benefit from nusinersen. The incidence and severity of adverse events were similar in the two groups.
Among infants with spinal muscular atrophy, those who received nusinersen were more likely to be alive and have improvements in motor function than those in the control group. Early treatment may be necessary to maximize the benefit of the drug. (Funded by Biogen and Ionis Pharmaceuticals; ENDEAR ClinicalTrials.gov number, NCT02193074 .).
脊髓性肌萎缩症是一种常染色体隐性神经肌肉疾病，由生存运动神经元（SMN）蛋白水平不足引起。诺西那生钠是一种反义寡核苷酸药物，可修饰 SMN2 基因的前信使 RNA 剪接，从而促进全长 SMN 蛋白的产生。
我们进行了一项随机、双盲、假手术对照、3 期疗效和安全性试验，评估诺西那生钠在脊髓性肌萎缩症婴儿中的应用。主要终点为运动里程碑反应（根据 Hammersmith 婴儿神经学检查的结果定义）和无事件生存（死亡或使用永久性辅助通气的时间）。次要终点包括总生存率和根据筛查时疾病持续时间进行的无事件生存亚组分析。仅在预先指定的中期分析中测试了第一个主要终点。为了将总体 I 型错误率控制在 0.05，使用分层测试策略对第二个主要终点和最终分析中的次要终点进行测试。
在中期分析中，接受诺西那生钠治疗的婴儿中运动里程碑反应的比例明显高于对照组（51 例婴儿中有 21 例[41%] vs. 27 例婴儿中 0 例[0%]，P<0.001），这一结果促使试验提前终止。在最终分析中，接受诺西那生钠治疗的婴儿中运动里程碑反应的比例明显高于对照组（73 例婴儿中有 37 例[51%] vs. 37 例婴儿中 0 例[0%]），接受诺西那生钠治疗的婴儿无事件生存率高于对照组（死亡或使用永久性辅助通气的风险比为 0.53；P=0.005）。接受诺西那生钠治疗的婴儿总生存率高于对照组（死亡风险比为 0.37；P=0.004），且筛查时疾病持续时间较短的婴儿比疾病持续时间较长的婴儿更有可能从诺西那生钠中获益。两组不良反应的发生率和严重程度相似。
在脊髓性肌萎缩症婴儿中，接受诺西那生钠治疗的婴儿比对照组更有可能存活且运动功能改善。早期治疗可能是最大限度发挥药物疗效的必要条件。（由 Biogen 和 Ionis 制药公司资助；ENDEAR ClinicalTrials.gov 编号，NCT02193074）。
