Department of Neurology, Stanford University Medical Center, Palo Alto, CA, USA.
Department of Pediatrics, Nemours Children's Hospital, Orlando, FL, USA; Center for Experimental Neurotherapeutics, St Jude Children's Research Hospital, Memphis, TN, USA.
Lancet Neurol. 2021 Apr;20(4):284-293. doi: 10.1016/S1474-4422(21)00001-6. Epub 2021 Mar 17.
Spinal muscular atrophy type 1 is a motor neuron disorder resulting in death or the need for permanent ventilation by age 2 years. We aimed to evaluate the safety and efficacy of onasemnogene abeparvovec (previously known as AVXS-101), a gene therapy delivering the survival motor neuron gene (SMN), in symptomatic patients (identified through clinical examination) with infantile-onset spinal muscular atrophy.
STR1VE was an open-label, single-arm, single-dose, phase 3 trial done at 12 hospitals and universities in the USA. Eligible patients had to be younger than 6 months and have spinal muscular atrophy with biallelic SMN1 mutations (deletion or point mutations) and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 10 vector genomes per kg) for 30-60 min. During the outpatient follow-up, patients were assessed once per week, beginning at day 7 post-infusion for 4 weeks and then once per month until the end of the study (age 18 months or early termination). Coprimary efficacy outcomes were independent sitting for 30 s or longer (Bayley-III item 26) at the 18 month of age study visit and survival (absence of death or permanent ventilation) at age 14 months. Safety was assessed through evaluation of adverse events, concomitant medication usage, physical examinations, vital sign assessments, cardiac assessments, and laboratory evaluation. Primary efficacy endpoints for the intention-to-treat population were compared with untreated infants aged 6 months or younger (n=23) with spinal muscular atrophy type 1 (biallelic deletion of SMN1 and two copies of SMN2) from the Pediatric Neuromuscular Clinical Research (PNCR) dataset. This trial is registered with ClinicalTrials.gov, NCT03306277 (completed).
From Oct 24, 2017, to Nov 12, 2019, 22 patients with spinal muscular atrophy type 1 were eligible and received onasemnogene abeparvovec. 13 (59%, 97·5% CI 36-100) of 22 patients achieved functional independent sitting for 30 s or longer at the 18 month of age study visit (vs 0 of 23 patients in the untreated PNCR cohort; p<0·0001). 20 patients (91%, 79-100]) survived free from permanent ventilation at age 14 months (vs 6 [26%], 8-44; p<0·0001 in the untreated PNCR cohort). All patients who received onasemnogene abeparvovec had at least one adverse event (most common was pyrexia). The most frequently reported serious adverse events were bronchiolitis, pneumonia, respiratory distress, and respiratory syncytial virus bronchiolitis. Three serious adverse events were related or possibly related to the treatment (two patients had elevated hepatic aminotransferases, and one had hydrocephalus).
Results from this multicentre trial build on findings from the phase 1 START study by showing safety and efficacy of commercial grade onasemnogene abeparvovec. Onasemnogene abeparvovec showed statistical superiority and clinically meaningful responses when compared with observations from the PNCR natural history cohort. The favourable benefit-risk profile shown in this study supports the use of onasemnogene abeparvovec for treatment of symptomatic patients with genetic or clinical characteristics predictive of infantile-onset spinal muscular atrophy type 1.
Novartis Gene Therapies.
脊髓性肌萎缩症 1 型是一种运动神经元疾病，导致 2 岁以下的患者死亡或需要永久通气。我们旨在评估onasemnogene abeparvovec（以前称为 AVXS-101）的安全性和疗效，onasemnogene abeparvovec 是一种基因治疗药物，可传递生存运动神经元基因（SMN），用于有症状的婴儿期发病的脊髓性肌萎缩症患者（通过临床检查确定）。
STR1VE 是一项在美国 12 家医院和大学进行的开放性、单臂、单次剂量、3 期试验。合格的患者必须年龄小于 6 个月，且具有双等位基因 SMN1 突变（缺失或点突变）和一个或两个 SMN2 拷贝的脊髓性肌萎缩症。患者接受一次静脉输注 onasemnogene abeparvovec（每公斤 1.1×10 个载体基因组），持续 30-60 分钟。在门诊随访期间，从输注后第 7 天开始，每周评估一次，持续 4 周，然后每月一次，直到研究结束（年龄 18 个月或提前终止）。主要疗效终点是在 18 个月的研究访视中独立坐 30 秒或更长时间（Bayley-III 项目 26）和 14 个月时无死亡或永久通气。安全性通过评估不良事件、伴随药物使用、体格检查、生命体征评估、心脏评估和实验室评估来评估。意向治疗人群的主要疗效终点与未经治疗的 6 个月或更小年龄的 23 名脊髓性肌萎缩症 1 型（双等位基因 SMN1 缺失和两个 SMN2 拷贝）婴儿进行比较，这些婴儿来自儿科神经肌肉临床研究（PNCR）数据集。该试验在 ClinicalTrials.gov 上注册，NCT03306277（已完成）。
从 2017 年 10 月 24 日至 2019 年 11 月 12 日，共有 22 名脊髓性肌萎缩症 1 型患者符合条件并接受了 onasemnogene abeparvovec 治疗。在 18 个月的研究访视中，13 名（59%，97.5%CI 36-100）患者实现了独立坐 30 秒或更长时间的功能（与未经治疗的 PNCR 队列中的 23 名患者相比为 0；p<0.0001）。20 名患者（91%，79-100%）在 14 个月时无永久性通气，无死亡（与未经治疗的 PNCR 队列中的 6 名患者相比为 26%，8-44%；p<0.0001）。所有接受 onasemnogene abeparvovec 治疗的患者均至少发生一次不良事件（最常见的是发热）。最常报告的严重不良事件是细支气管炎、肺炎、呼吸窘迫和呼吸道合胞病毒细支气管炎。有 3 例严重不良事件与治疗有关或可能有关（2 例患者肝转氨酶升高，1 例患者发生脑积水）。
这项多中心试验的结果建立在 1 期 START 研究的发现基础上，表明商业级 onasemnogene abeparvovec 的安全性和疗效。与 PNCR 自然史队列的观察结果相比，onasemnogene abeparvovec 显示出统计学上的优势和有临床意义的反应。该研究中显示出的有利风险状况支持使用 onasemnogene abeparvovec 治疗具有婴儿期发病脊髓性肌萎缩症 1 型预测遗传或临床特征的有症状患者。
诺华基因治疗公司。
