Nusinersen 治疗成人 5q 型脊髓性肌萎缩症的非干预性、多中心、观察性队列研究。

Nusinersen in adults with 5q spinal muscular atrophy: a non-interventional, multicentre, observational cohort study.

机构信息

Department of Neurology, University Hospital Essen, Essen, Germany.

Department of Neurology, Ulm University, Ulm, Germany.

出版信息

Lancet Neurol. 2020 Apr;19(4):317-325. doi: 10.1016/S1474-4422(20)30037-5. Epub 2020 Mar 18.

DOI:10.1016/S1474-4422(20)30037-5

PMID:32199097

Abstract

BACKGROUND

Nusinersen is approved for the treatment of 5q spinal muscular atrophy of all types and stages in patients of all ages. Although clinical trials have shown improvements in motor function in infants and children treated with the drug, data for adults are scarce. We aimed to assess the safety and efficacy of nusinersen in adults with 5q spinal muscular atrophy.

METHODS

We did an observational cohort study at ten academic clinical sites in Germany. Patients with genetically confirmed 5q spinal muscular atrophy (age 16-65 years) with a homozygous deletion of exons 7, 8, or both, or with compound heterozygous mutations were eligible for inclusion and received nusinersen treatment in accordance with the label for a minimum treatment time of 6 months to a follow-up of up to 14 months. The primary outcome was the change in the total Hammersmith Functional Motor Scale Expanded (HFMSE) score, assessed at months 6, 10, and 14, and based on pre-post comparisons. This study is registered with the German Clinical Trials Register (number DRKS00015702).

FINDINGS

Between July 13, 2017, and May 1, 2019, 173 patients were screened, of whom 139 (80%) were eligible for data analysis. Of these, 124 (89%) were included in the 6-month analysis, 92 (66%) in the 10-month analysis, and 57 (41%) in the 14-month analysis; patients with missing baseline HFMSE scores were excluded from these analyses. Mean HFMSE scores were significantly increased compared with baseline at 6 months (mean difference 1·73 [95% CI 1·05-2·41], p<0·0001), 10 months (2·58 [1·76-3·39], p<0·0001), and 14 months (3·12 [2·06-4·19], p<0·0001). Clinically meaningful improvements (≥3 points increase) in HFMSE scores were seen in 35 (28%) of 124 patients at 6 months, 33 (35%) of 92 at 10 months, and 23 (40%) of 57 at 14 months. To 14-month follow-up, the most frequent adverse effects among 173 patients were headache (61 [35%] patients), back pain (38 [22%]), and nausea (19 [11%]). No serious adverse events were reported.

INTERPRETATION

Despite the limitations of the observational study design and a slow functional decline throughout the natural disease course, our data provide evidence for the safety and efficacy of nusinersen in the treatment of adults with 5q spinal muscular atrophy, with clinically meaningful improvements in motor function in a real-world cohort.

FUNDING

None.

摘要

背景

nusinersen 获批用于治疗所有类型和阶段的 5q 型脊髓性肌萎缩症患者，年龄不限。虽然临床试验表明，接受该药治疗的婴儿和儿童的运动功能得到改善，但成人的数据却很少。我们旨在评估 nusinersen 在 5q 型脊髓性肌萎缩症成人患者中的安全性和疗效。

方法

我们在德国的十个学术临床地点进行了一项观察性队列研究。符合条件的患者为经基因检测证实的 5q 型脊髓性肌萎缩症（年龄 16-65 岁），携带外显子 7、8 或两者均缺失的纯合子缺失，或复合杂合突变，接受 nusinersen 治疗，治疗时间至少 6 个月，随访时间最长至 14 个月。主要结局是在 6、10 和 14 个月时基于治疗前后比较的总哈默史密斯功能运动量表扩展版（HFMSE）评分变化。该研究在德国临床试验注册处（DRKS00015702）注册。

结果

2017 年 7 月 13 日至 2019 年 5 月 1 日期间，共有 173 名患者接受了筛查，其中 139 名（80%）符合数据分析条件。这些患者中，124 名（89%）纳入 6 个月分析，92 名（66%）纳入 10 个月分析，57 名（41%）纳入 14 个月分析；未纳入分析的患者是因为基线 HFMSE 评分缺失。与基线相比，6 个月（平均差值 1.73，95%CI 1.05-2.41，p<0.0001）、10 个月（2.58，1.76-3.39，p<0.0001）和 14 个月（3.12，2.06-4.19，p<0.0001）的 HFMSE 评分显著升高。124 名患者中有 35 名（28%）在 6 个月时 HFMSE 评分增加≥3 分，92 名患者中有 33 名（35%）在 10 个月时 HFMSE 评分增加≥3 分，57 名患者中有 23 名（40%）在 14 个月时 HFMSE 评分增加≥3 分。在 173 名患者中，随访至 14 个月时最常见的不良反应为头痛（61 名[35%]患者）、背痛（38 名[22%]患者）和恶心（19 名[11%]患者）。未报告严重不良事件。