Nemours Children's Hospital, Orlando, FL, USA; St Jude Children's Research Hospital, Memphis, TN, USA.
Columbia University Irving Medical Center, New York, NY, USA.
Lancet Child Adolesc Health. 2021 Jul;5(7):491-500. doi: 10.1016/S2352-4642(21)00100-0. Epub 2021 Jun 3.
Nusinersen showed a favourable benefit-risk profile in participants with infantile-onset spinal muscular atrophy at the interim analysis of a phase 2 clinical study. We present the study's final analysis, assessing the efficacy and safety of nusinersen over 3 years.
This phase 2, open-label, multicentre, dose-escalation study was done in three university hospital sites in the USA and one in Canada. Infants aged between 3 weeks and 6 months with two or three SMN2 gene copies and infantile-onset spinal muscular atrophy were eligible for inclusion. Eligible participants received multiple intrathecal loading doses of 6 mg equivalent nusinersen (cohort 1) or 12 mg dose equivalent (cohort 2), followed by maintenance doses of 12 mg equivalent nusinersen. The protocol amendment on Jan 25, 2016, changed the primary efficacy endpoint from safety and tolerability to reaching motor milestones, assessed using the Hammersmith Infant Neurological Examination section 2 (HINE-2) at the last study visit, in all participants who successfully completed the loading dose period and day 92 assessment. The statistical analysis plan was amended on Feb 10, 2016, to include additional analyses of the subgroup of participants with two SMN2 copies. Adverse events were assessed in all participants who received at least one dose of study treatment. The study is registered at ClinicalTrials.gov (NCT01839656).
Between May 3, 2013, and July 9, 2014, 20 symptomatic participants with infantile-onset spinal muscular atrophy (12 boys and 8 girls; median age at diagnosis 78 days [range 0-154]) were enrolled. Median time on study was 36·2 months (IQR 20·6-41·3). The primary endpoint of an incremental improvement in HINE-2 developmental motor milestones was reached by 12 (63%) of 19 evaluable participants. In the 13 participants with two SMN2 copies treated with 12 mg nusinersen, the HINE-2 motor milestone total score increased steadily from a baseline mean of 1·46 (SD 0·52) to 11·86 (6·18) at day 1135, representing a clinically significant change of 10·43 (6·05). At study closure (Aug 21, 2017), 15 (75%) of 20 participants were alive. 101 serious adverse events were reported in 16 (80%) of 20 participants; all five deaths (one in cohort 1 and four in cohort 2) were likely to be related to spinal muscular atrophy disease progression.
Our findings are consistent with other trials of nusinersen and show improved survival and attainment of motor milestones over 3 years in patients with infantile-onset spinal muscular atrophy, with a favourable safety profile.
Biogen and Ionis Pharmaceuticals.
在一项 2 期临床研究的中期分析中，nusinersen 显示出对婴儿期发病的脊髓性肌萎缩症患者有利的获益-风险特征。我们报告了该研究的最终分析，评估了 nusinersen 在 3 年中的疗效和安全性。
这是一项在美国的 3 家大学医院和加拿大的 1 家医院进行的 2 期、开放标签、多中心、剂量递增研究。年龄在 3 周到 6 个月之间、有 2 或 3 个 SMN2 基因拷贝和婴儿期发病的脊髓性肌萎缩症的婴儿有资格入组。合格的参与者接受多次鞘内负荷剂量的 6 毫克当量 nusinersen（队列 1）或 12 毫克剂量当量（队列 2），然后接受 12 毫克当量 nusinersen 的维持剂量。2016 年 1 月 25 日的方案修正案将主要疗效终点从安全性和耐受性改为在所有成功完成负荷剂量期和第 92 天评估的参与者中，使用最后一次研究访问时的 Hammersmith 婴儿神经学检查第 2 部分（HINE-2）达到运动里程碑。2016 年 2 月 10 日，对包含 2 个 SMN2 拷贝的参与者亚组的额外分析进行了修订。所有接受至少一剂研究治疗的参与者均评估了不良事件。该研究在 ClinicalTrials.gov 注册（NCT01839656）。
2013 年 5 月 3 日至 2014 年 7 月 9 日，纳入了 20 名患有婴儿期发病的脊髓性肌萎缩症的有症状参与者（12 名男孩和 8 名女孩；中位诊断年龄为 78 天[范围 0-154]）。中位研究时间为 36.2 个月（IQR 20.6-41.3）。19 名可评估参与者中有 12 名（63%）达到了 HINE-2 发育运动里程碑的递增改善的主要终点。在接受 12 毫克 nusinersen 治疗的 13 名有 2 个 SMN2 拷贝的参与者中，HINE-2 运动里程碑总评分从基线时的 1.46（SD 0.52）稳步增加到 1135 天时的 11.86（6.18），代表了 10.43（6.05）的临床显著变化。在研究结束（2017 年 8 月 21 日）时，20 名参与者中有 15 名（75%）存活。20 名参与者中有 16 名（80%）报告了 101 例严重不良事件；所有 5 例死亡（1 例在队列 1，4 例在队列 2）都可能与脊髓性肌萎缩症疾病进展有关。
我们的研究结果与 nusinersen 的其他试验一致，表明在 3 年内，婴儿期发病的脊髓性肌萎缩症患者的生存率和运动里程碑的改善，且具有良好的安全性。
Biogen 和 Ionis 制药公司。
