美国波士顿儿童医院Basil T. Darras团队研究了Risdiplam治疗1型脊髓性肌萎缩症婴儿的疗效。2021年7月28日出版的《新英格兰医学杂志》发表了这项成果。

1型脊髓性肌萎缩症（SMA）是一种进行性神经肌肉疾病，发病年龄小于或等于6个月，患儿无法在没有支撑的情况下坐立，运动神经元（SMN）蛋白存活水平不足。Risdiplam是一种口服小分子，可修饰SMN2前信使RNA剪接，增加血液中功能性SMN蛋白的水平。

研究组对入组时1-7个月的1型SMA患儿进行了一项开放标签研究。该研究的第一部分（之前发表过）确定了第二部分（此处报道）中使用的剂量，该第二部分评估了每日进行Risdiplam治疗与历史对照组中未进行治疗的疗效和安全性。

主要终点是在治疗12个月后能够在没有支撑的情况下坐至少5秒钟。关键次要终点是费城儿童医院婴儿神经肌肉疾病测试（CHOP-INTEND，0-64分，得分越高表示运动功能越好）评分较基线至少增加4分，根据Hammersmith婴儿神经系统检查第2节（HINE-2）测量的运动里程碑缓解，以及无永久性通气的生存率。

研究组共纳入41例婴儿。经过12个月的治疗，12名婴儿（29%）能够在没有支撑的情况下坐至少5秒钟，这是该疾病从未达到的一个里程碑。与历史对照的置信区间上限相比，达到关键次要终点的婴儿百分比为56%，而CHOP-INTERNAL分数为40或更高的婴儿百分比为17%。

CHOP-INTEND评分较基线至少增加4分的婴儿百分比为90%，历史对照组仅为17%；HINE-2运动里程碑缓解的婴儿百分比为78%，历史对照组为12%；无永久性通气生存率为85%，而历史对照组为42%，组间差异均显著。最常见的严重不良事件是肺炎、毛细支气管炎、张力过低和呼吸衰竭。

研究结果表明，对于1型SMA婴儿，采用Risdiplam治疗与历史对照组相比，达到运动里程碑和运动功能改善的婴儿百分比显著提高。

附：英文原文

Title: Risdiplam-Treated Infants with Type 1 Spinal Muscular Atrophy versus Historical Controls

Author: Basil T. Darras, M.D.,, Riccardo Masson, M.D.,, Maria Mazurkiewicz-Bedzińska, M.D.,, Kristy Rose, Ph.D.,, Hui Xiong, M.D.,, Edmar Zanoteli, M.D.,, Giovanni Baranello, M.D., Ph.D.,, Claudio Bruno, M.D., Ph.D.,, Dmitry Vlodavets, M.D.,, Yi Wang, M.D., Ph.D.,, Muna El-Khairi, Ph.D.,, Marianne Gerber, Ph.D.,, Ksenija Gorni, M.D., Ph.D.,, Omar Khwaja, M.D., Ph.D.,, Heidemarie Kletzl, Ph.D.,, Renata S. Scalco, M.D., Ph.D.,, Paulo Fontoura, M.D., Ph.D.,, and Laurent Servais, M.D., Ph.D.

Issue&Volume: 2021-07-28

Abstract:

Background

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 SMN2 pre–messenger RNA splicing and increases levels of functional SMN protein in blood.

Methods

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.

Results

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.

Conclusions

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.

DOI: 10.1056/NEJMoa2102047

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2102047