Semmelweis University 2nd Dept. of Paediatrics, 7-9. Tűzoltó street Budapest, 1094, Hungary.
Bethesda Children's Hospital, 3. Bethesda street, Budapest, 1146, Hungary.
Eur J Paediatr Neurol. 2020 Jul;27:37-42. doi: 10.1016/j.ejpn.2020.05.002. Epub 2020 May 14.
Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a homozygous deletion of the survival motor neuron (SMN) 1 gene. Nusinersen is an antisense oligonucleotide enhancing the production of the SMN protein. It has received approval by the European Medicines Agency (EMA) in 2017, based on the clinical trials demonstrating the effectiveness of nusinersen in several types of SMA. In Hungary, the first patient received nusinersen treatment in April 2018. Our aim is to summarize our experience regarding the efficacy, safety and tolerability of nusinersen in our patients.
Data were collected retrospectively in all types of SMA patients (type 1-3) starting treatment with nusinersen in Hungary between April 2018 and December 2019. Motor functions were evaluated at baseline, at the fourth and all following injections.
By 31 December 2019, nusinersen therapy was initiated in 54 patients at either of the two Hungarian treatment centres. Mean age of the patients at the start of the treatment was 6.3 years (±5,4 range 0.4-17.9). 13 patients are type 1 (mean 0.78 ± 0.27, range 0.4-1.5 yrs), 21 patients are type 2 (mean 4.5 ± 3.3, range 1.3-12 yrs), 23 patients are type 3 (mean 10.9 ± 5.2, range 2.9-17.9 yrs). Fourteen patients had severe scoliosis, four of them underwent spine stabilizing surgery. During the study period 340 injections were administered without any new safety concerns emerging. The data of 38 patients, who had completed the first six treatments, were included in the final statistical analysis. Motor function has improved in most of the children. By the 307th day visit, on average, a 14.9 (±5,1) point improvement was measured on the CHOP INTEND scale in type 1 patients (p = 0.016). All patients with type 1 SMA who performed the motor evaluation (7/10) have improved by more than four (7-21) points. Regarding type 2 patients, a 7.2 (range -2- 17) point increase from baseline (p < 0.001) on the Hammersmith Functional Motor Scale Expanded (HFMSE) and 4.3 (range: 2-9) point increase (p = 0.031) on the Revised Upper Limb Module (RULM) were found. The distance of the 6 min walk test also increased by 33.9 m on average (range -16 - 106), in type 3 patients.
According to our results nusinersen has the same safety and tolerability profile as in the clinical trials. In a heterogenic patient population of SMA type 1 and 2, nusinersen showed similar efficacy as seen in the pivotal studies. A clinically and statistically significant improvement of motor functions was also detectable in type 3 patients with heterogeneous age distribution.
脊髓性肌萎缩症（SMA）是一种常染色体隐性遗传病，由生存运动神经元（SMN）1 基因的纯合缺失引起。Nusinersen 是一种反义寡核苷酸，可增强 SMN 蛋白的产生。它基于临床试验表明 nusinersen 在几种类型的 SMA 中的有效性，于 2017 年获得欧洲药品管理局（EMA）的批准。在匈牙利，第一位患者于 2018 年 4 月接受了 nusinersen 治疗。我们的目的是总结我们在患者中使用 nusinersen 的疗效、安全性和耐受性方面的经验。
在 2018 年 4 月至 2019 年 12 月期间，我们在匈牙利开始使用 nusinersen 治疗的所有类型 SMA 患者（1 型-3 型）中，回顾性收集数据。在基线、第 4 次和所有后续注射时评估运动功能。
截至 2019 年 12 月 31 日，在匈牙利的两个治疗中心，54 名患者开始接受 nusinersen 治疗。患者开始治疗时的平均年龄为 6.3 岁（±5.4 范围 0.4-17.9）。13 名患者为 1 型（平均 0.78 ± 0.27，范围 0.4-1.5 岁），21 名患者为 2 型（平均 4.5 ± 3.3，范围 1.3-12 岁），23 名患者为 3 型（平均 10.9 ± 5.2，范围 2.9-17.9 岁）。14 名患者有严重脊柱侧凸，其中 4 名患者接受了脊柱稳定手术。在研究期间，共进行了 340 次注射，没有出现新的安全问题。在最终的统计分析中，纳入了完成前 6 次治疗的 38 名患者的数据。大多数儿童的运动功能都有所改善。在第 307 天的随访中，1 型患者的 CHOP INTEND 量表平均改善了 14.9（±5.1）分（p = 0.016）。所有接受运动评估的 1 型 SMA 患者（7/10）均改善了 4 分以上（7-21）。对于 2 型患者，Hammersmith 功能运动量表扩展版（HFMSE）的评分平均增加了 7.2（范围 -2-17）分（p < 0.001），修订后的上肢模块（RULM）的评分增加了 4.3（范围：2-9）分（p = 0.031）。3 型患者的 6 分钟步行测试距离也平均增加了 33.9 米（范围 -16-106）。
根据我们的结果，nusinersen 具有与临床试验相同的安全性和耐受性。在 SMA 1 型和 2 型的异质患者人群中，nusinersen 表现出与关键研究相似的疗效。在年龄分布不均的 3 型患者中，也可以检测到运动功能的临床和统计学显著改善。
