Importance This ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy. Objective The primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained. Design, Setting, and Participants This study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017) at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 1013 vg/kg; or therapeutic dose, 1.1 × 1014 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020. Exposures Median time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort. Main Outcomes and Measures The primary outcome measure was the incidence of serious adverse events (SAEs). Results At data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen. Conclusions and Relevance The findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose. Trial Registration ClinicalTrials.gov Identifier: NCT03421977.

中文翻译：

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Onasemnogene Abeparvovec 在脊髓性肌萎缩症中的 1 期 START 试验的五年延长结果。

重要性 这项正在进行的研究评估了 1 型脊髓性肌萎缩 (SMA) 婴儿在接受 onasemnogene abeparvovec 基因替代疗法后的长期安全性和持久性反应。目的 这项正在进行的研究的主要目的是评估安全性。次要目标是确定在 START 1 期临床试验中取得的发展里程碑是否得以维持并获得了新的里程碑。设计、设置和参与者 本研究是一项持续的观察性随访研究，对全国儿童医院 START I 期研究（2014 年 5 月 5 日至 2017 年 12 月 15 日）的患者进行为期 15 年的持续安全监测在俄亥俄州哥伦布。参与者是 1 型 SMA 和 2 个 SMN2 拷贝的有症状婴儿，之前在 START 中接受过静脉内剂量的 onasemnogene abeparvovec（低剂量，6.7 × 1013 vg/kg；或治疗剂量，1.1 × 1014 vg/kg）治疗。该分析包括 15 名原始 START 患者中的 13 名；2例患者家属拒绝随访。数据分析时间为 2017 年 9 月 21 日至 2020 年 6 月 11 日。自给药以来的中位时间为 5.2（范围，4.6-6.2）年；低剂量组为 5.9（范围，5.8-6.2）年，治疗剂量组为 4.8（范围，4.6-5.6）年。主要结果和测量 主要结果测量是严重不良事件 (SAE) 的发生率。结果 在 2020 年 6 月 11 日数据截止时，本研究纳入了 13 名接受 START 治疗的患者（中位年龄，38.9 [范围，25.4-48.0] 个月；7 名女性；低剂量队列，n = 3；和治疗剂量队列，n = 10）。8 名患者 (62%) 发生严重不良事件，均未导致研究中止或死亡。最常报告的 SAE 是急性呼吸衰竭 (n = 4 [31%])、肺炎 (n = 4 [31%])、脱水 (n = 3 [23%])、呼吸窘迫 (n = 2 [15%] ]）和细支气管炎（n = 2 [15%]）。治疗剂量队列中的所有 10 名患者均存活且无需永久通气。在基线之前，治疗剂量队列中的 4 名患者 (40%) 需要无创通气支持，6 名患者 (60%) 不需要定期通气支持，这在长期随访中没有变化。接受治疗剂量治疗的所有 10 名患者都保持了先前获得的运动里程碑。两名患者达到“新里程碑”