From the Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston (B.T.D.); the Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (R.M., G.B.), and the Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genoa (C.B.) - both in Italy; the Department of Developmental Neurology, Medical University of Gdańsk, Gdańsk, Poland (M.M.-B.); the Paediatric Gait Analysis Service of New South Wales, the Children's Hospital at Westmead and the University of Sydney, Sydney (K.R.); the Department of Pediatrics, Peking University First Hospital, Beijing (H.X.), and Children's Hospital of Fudan University, Shanghai (Y.W.) - both in China; the Department of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo (E.Z.); the Dubowitz Neuromuscular Centre, National Institute for Health Research Great Ormond Street Hospital Biomedical Research Centre, University College London Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital for Children NHS Foundation Trust, London (G.B.), Roche Products, Welwyn Garden City (M.E.-K.), and the Muscular Dystrophy UK Oxford Neuromuscular Centre, the Department of Paediatrics, University of Oxford, Oxford (L.S.) - all in the United Kingdom; Russian Children Neuromuscular Center, Veltischev Clinical Pediatric Research Institute, Pirogov Russian National Research Medical University, Moscow (D.V.); Pharma Development, Safety (M.G.), Product Development Medical Affairs - Neuroscience and Rare Disease (K.G., P.F.), and Pharma Development Neurology (R.S.S.), F. Hoffmann-La Roche, and Roche Pharmaceutical Research and Early Development, Roche Innovation Center Basel (O.K., H.K.) - both in Basel, Switzerland; the Division of Child Neurology, Centre de Références des Maladies Neuromusculaires, the Department of Pediatrics, University Hospital Liege, University of Liege, Liege, Belgium (L.S.); and I-Motion, Institut de Myologie, Assistance Publique Hôpitaux de Paris, Hôpital Armand Trousseau, Paris (L.S.).
N Engl J Med. 2021 Jul 29;385(5):427-435. doi: 10.1056/NEJMoa2102047.
Type 1 spinal muscular atrophy (SMA) is a progressive neuromuscular disease characterized by an onset at 6 months of age or younger, an inability to sit without support, and deficient levels of survival of motor neuron (SMN) protein. Risdiplam is an orally administered small molecule that modifies pre-messenger RNA splicing and increases levels of functional SMN protein in blood.
We conducted an open-label study of risdiplam in infants with type 1 SMA who were 1 to 7 months of age at enrollment. Part 1 of the study (published previously) determined the dose to be used in part 2 (reported here), which assessed the efficacy and safety of daily risdiplam as compared with no treatment in historical controls. The primary end point was the ability to sit without support for at least 5 seconds after 12 months of treatment. Key secondary end points were a score of 40 or higher on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND; range, 0 to 64, with higher scores indicating better motor function), an increase of at least 4 points from baseline in the CHOP-INTEND score, a motor-milestone response as measured by Section 2 of the Hammersmith Infant Neurological Examination (HINE-2), and survival without permanent ventilation. For the secondary end points, comparisons were made with the upper boundary of 90% confidence intervals for natural-history data from 40 infants with type 1 SMA.
A total of 41 infants were enrolled. After 12 months of treatment, 12 infants (29%) were able to sit without support for at least 5 seconds, a milestone not attained in this disorder. The percentages of infants in whom the key secondary end points were met as compared with the upper boundary of confidence intervals from historical controls were 56% as compared with 17% for a CHOP-INTEND score of 40 or higher, 90% as compared with 17% for an increase of at least 4 points from baseline in the CHOP-INTEND score, 78% as compared with 12% for a HINE-2 motor-milestone response, and 85% as compared with 42% for survival without permanent ventilation (P<0.001 for all comparisons). The most common serious adverse events were pneumonia, bronchiolitis, hypotonia, and respiratory failure.
In this study involving infants with type 1 SMA, risdiplam resulted in higher percentages of infants who met motor milestones and who showed improvements in motor function than the percentages observed in historical cohorts. Longer and larger trials are required to determine the long-term safety and efficacy of risdiplam in infants with type 1 SMA. (Funded by F. Hoffmann-La Roche; FIREFISH ClinicalTrials.gov number, NCT02913482.).
1 型脊髓性肌萎缩症（SMA）是一种进行性神经肌肉疾病，其特征为 6 个月或更小年龄时发病，无法在没有支撑的情况下坐立，且生存运动神经元（SMN）蛋白水平不足。利司扑兰是一种口服小分子药物，可修饰前信使 RNA 剪接，并增加血液中功能性 SMN 蛋白的水平。
我们对 1 至 7 月龄、确诊为 1 型 SMA 的婴儿进行了利司扑兰的开放性标签研究。研究的第 1 部分（此前已发表）确定了第 2 部分（此处报告）的使用剂量，该部分评估了与历史对照相比，每日利司扑兰治疗的疗效和安全性。主要终点为治疗 12 个月后至少能在没有支撑的情况下坐立 5 秒。主要次要终点为费城儿童医院婴儿神经肌肉疾病测试（CHOP-INTEND；评分范围为 0 至 64，分数越高表示运动功能越好）评分达到 40 或更高、CHOP-INTEND 评分较基线增加至少 4 分、Hammersmith 婴儿神经学检查第 2 节（HINE-2）的运动里程碑反应以及无需永久性通气。次要终点的比较采用了 40 例 1 型 SMA 婴儿自然病史数据的 90%置信区间上限。
共纳入 41 例婴儿。治疗 12 个月后，12 例（29%）婴儿能够在没有支撑的情况下坐立至少 5 秒，这在该疾病中尚未达到。与历史对照相比，达到关键次要终点的婴儿比例为 56%，高于 CHOP-INTEND 评分 40 或更高的 17%，90%，高于 CHOP-INTEND 评分较基线增加至少 4 分的 17%，78%，高于 HINE-2 运动里程碑反应的 12%，85%，高于无需永久性通气的 42%（所有比较均 P<0.001）。最常见的严重不良事件为肺炎、细支气管炎、低张力和呼吸衰竭。
在这项涉及 1 型 SMA 婴儿的研究中，与历史队列相比，利司扑兰治疗使更多婴儿达到运动里程碑，运动功能得到改善。还需要进行更长和更大规模的试验来确定利司扑兰在 1 型 SMA 婴儿中的长期安全性和疗效。（由罗氏公司（F. Hoffmann-La Roche）资助；FIREFISH 临床试验.gov 编号：NCT02913482）。
