Background

Given the novelty of gene replacement therapy with onasemnogene abeparvovec in spinal muscular atrophy, efficacy and safety data are limited, especially for children older than 24 months, those weighing more than 8·5 kg, and those who have received nusinersen. We aimed to provide real-world data on motor function and safety after gene replacement therapy in different patient subgroups.

Methods

We did a protocol-based, multicentre prospective observational study between Sept 21, 2019, and April 20, 2021, in 18 paediatric neuromuscular centres in Germany and Austria. All children with spinal muscular atrophy types 1 and 2 receiving onasemnogene abeparvovec were included in our cohort, and there were no specific exclusion criteria. Motor function was assessed at the time of gene replacement therapy and 6 months afterwards, using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) and Hammersmith Functional Motor Scale-Expanded (HFMSE) scores. Additionally, in children pretreated with nusinersen, motor function was assessed before and after treatment switch. Off-target adverse events were analysed with a focus on liver function, thrombocytopaenia, and potential cardiotoxicity.

Findings

76 children (58 pretreated with nusinersen and 18 who were nusinersen naive) with spinal muscular atrophy were treated with onasemnogene abeparvovec at a mean age of 16·8 months (range 0·8–59·0, IQR 9–23) and a mean weight of 9·1 kg (range 4·0–15·0, IQR 7·4–10·6). In 60 patients with available data, 49 had a significant improvement on the CHOP-INTEND score (≥4 points) and HFMSE score (≥3 points). Mean CHOP INTEND scores increased significantly in the 6 months after therapy in children younger than 8 months (n=16; mean change 13·8 [SD 8·5]; p<0·0001) and children aged between 8 and 24 months (n=34; 7·7 [SD 5·2]; p<0·0001), but not in children older than 24 months (n=6; 2·5 [SD 5·2]; p=1·00). In the 45 children pretreated with nusinersen and had available data, CHOP INTEND score increased by 8·8 points (p=0·0003) at 6 months after gene replacement therapy. No acute complications occurred during infusion of onasemnogene abeparvovec, but 56 (74%) patients had treatment-related side-effects. Serious adverse events occurred in eight (11%) children. Liver enzyme elevation significantly increased with age and weight at treatment. Six (8%) patients developed acute liver dysfunction. Other adverse events included pyrexia (n=47 [62%]), vomiting or loss of appetite (41 [54%]), and thrombocytopenia (n=59 [78%]). Prednisolone treatment was significantly prolonged with a mean duration of 15·7 weeks (IQR 9–19), mainly due to liver enzyme elevation. Cardiac adverse events were rare; only two patients had abnormal echocardiogram and echocardiography findings.

Interpretation

This study provides class IV evidence that children with spinal muscular atrophy aged 24 months or younger and patients pretreated with nusinersen significantly benefit from gene replacement therapy, but adverse events can be severe and need to be closely monitored.

Funding

None.

Translation

For the German translation of the abstract see Supplementary Materials section.

中文翻译：

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onasemnogen abeparvovec 基因替代疗法治疗 24 个月或以下体重不超过 15 公斤的脊髓性肌萎缩症儿童：一项观察性队列研究

背景

鉴于 onasemnogene abeparvovec 基因替代疗法在脊髓性肌萎缩症中的新颖性，疗效和安全性数据有限，特别是对于 24 个月以上的儿童、体重超过 8·5 kg 的儿童以及接受过 nusinersen 的儿童。我们旨在提供不同患者亚组基因替代治疗后运动功能和安全性的真实数据。

方法

我们于 2019 年 9 月 21 日至 2021 年 4 月 20 日期间在德国和奥地利的 18 个儿科神经肌肉中心进行了一项基于方案的多中心前瞻性观察研究。所有接受 onasemnogene abeparvovec 的 1 型和 2 型脊髓性肌萎缩症儿童都包括在我们的队列中，并且没有具体的排除标准。使用费城儿童医院神经肌肉疾病婴儿测试 (CHOP INTEND) 和 Hammersmith 功能性运动量表扩展 (HFMSE) 评分在基因替代治疗时和 6 个月后评估运动功能。此外，在接受过 nusinersen 治疗的儿童中，在治疗转换前后评估了运动功能。分析了脱靶不良事件，重点关注肝功能、血小板减少和潜在的心脏毒性。

发现

76 名患有脊髓性肌萎缩症的儿童（58 名接受过 nusinersen 治疗，18 名未接受过 nusinersen 治疗）在平均 16·8 个月（范围 0·8-59·0，IQR 9-23）和平均年龄重量为 9·1 kg（范围 4·0–15·0，IQR 7·4–10·6）。在 60 名有可用数据的患者中，49 名 CHOP-INTEND 评分（≥4 分）和 HFMSE 评分（≥3 分）有显着改善。8 个月以下儿童（n=16；平均变化 13·8 [SD 8·5]；p<0·0001）和 8 至 24 个月（ n=34；7·7 [SD 5·2]；p<0·0001)，但不适用于 24 个月以上的儿童（n=6；2·5 [SD 5·2]；p=1·00） . 在接受过 nusinersen 预处理并有可用数据的 45 名儿童中，在基因替代治疗后 6 个月，CHOP INTEND 评分增加了 8·8 分 (p=0·0003)。在 onasemnogene abeparvovec 输注期间未发生急性并发症，但 56 名 (74%) 患者出现与治疗相关的副作用。八名（11%）儿童发生严重不良事件。肝酶升高随着治疗时的年龄和体重而显着增加。六名（8%）患者出现急性肝功能障碍。其他不良事件包括发热 (n=47 [62%])、呕吐或食欲不振 (41 [54%]) 和血小板减少症 (n=59 [78%])。泼尼松龙治疗显着延长，平均持续时间为 15·7 周（IQR 9-19），主要是由于肝酶升高。心脏不良事件很少见；只有两名患者有异常的超声心动图和超声心动图检查结果。在 onasemnogene abeparvovec 输注期间未发生急性并发症，但 56 名 (74%) 患者出现与治疗相关的副作用。八名（11%）儿童发生严重不良事件。肝酶升高随着治疗时的年龄和体重而显着增加。六名（8%）患者出现急性肝功能障碍。其他不良事件包括发热 (n=47 [62%])、呕吐或食欲不振 (41 [54%]) 和血小板减少症 (n=59 [78%])。泼尼松龙治疗显着延长，平均持续时间为 15·7 周（IQR 9-19），主要是由于肝酶升高。心脏不良事件很少见；只有两名患者有异常的超声心动图和超声心动图检查结果。在 onasemnogene abeparvovec 输注期间未发生急性并发症，但 56 名 (74%) 患者出现与治疗相关的副作用。八名（11%）儿童发生严重不良事件。肝酶升高随着治疗时的年龄和体重而显着增加。六名（8%）患者出现急性肝功能障碍。其他不良事件包括发热 (n=47 [62%])、呕吐或食欲不振 (41 [54%]) 和血小板减少症 (n=59 [78%])。泼尼松龙治疗显着延长，平均持续时间为 15·7 周（IQR 9-19），主要是由于肝酶升高。心脏不良事件很少见；只有两名患者有异常的超声心动图和超声心动图检查结果。肝酶升高随着治疗时的年龄和体重而显着增加。六名（8%）患者出现急性肝功能障碍。其他不良事件包括发热 (n=47 [62%])、呕吐或食欲不振 (41 [54%]) 和血小板减少症 (n=59 [78%])。泼尼松龙治疗显着延长，平均持续时间为 15·7 周（IQR 9-19），主要是由于肝酶升高。心脏不良事件很少见；只有两名患者有异常的超声心动图和超声心动图检查结果。肝酶升高随着治疗时的年龄和体重而显着增加。六名（8%）患者出现急性肝功能障碍。其他不良事件包括发热 (n=47 [62%])、呕吐或食欲不振 (41 [54%]) 和血小板减少症 (n=59 [78%])。泼尼松龙治疗显着延长，平均持续时间为 15·7 周（IQR 9-19），主要是由于肝酶升高。心脏不良事件很少见；只有两名患者有异常的超声心动图和超声心动图检查结果。主要是肝酶升高。心脏不良事件很少见；只有两名患者有异常的超声心动图和超声心动图检查结果。主要是肝酶升高。心脏不良事件很少见；只有两名患者有异常的超声心动图和超声心动图检查结果。

解释

这项研究提供了 IV 级证据，表明 24 个月或更年轻的脊髓性肌萎缩症儿童和接受过 nusinersen 治疗的患者显着受益于基因替代疗法，但不良事件可能很严重，需要密切监测。

资金

没有任何。

翻译

对于摘要的德语翻译，请参阅补充材料部分。