Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial
Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial
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DOI：
10.1016/s1474-4422(21)00251-9
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发表时间：
2021-10-01
期刊：
影响因子：
48
通讯作者：
Lavrov, Arseniy
中科院分区：
文献类型：
--
作者：
Mercuri, Eugenio;Muntoni, Francesco;Lavrov, Arseniy
研究背景脊髓性肌萎缩症是一种罕见的常染色体隐性遗传性神经肌肉疾病，由运动神经元生存基因1（SMN 1）的双等位基因缺失引起，导致运动神经元功能障碍。在这项STR1VE-EU研究中，我们的目的是评估onasemnogene abeparvovec基因替代疗法在1型脊髓性肌萎缩症婴儿中的安全性和有效性，使用比STR1VE-US中使用的更广泛的合格标准。方法STR1VE-EU是一项多中心，单臂，单剂量，开放标签的3期试验，在9个地点进行（医院和大学）在意大利（n = 4），英国（n = 2），比利时（n = 2），法国（n = 1）。我们招募了年龄小于6个月（180天）的1型脊髓性肌萎缩症患者，这些患者具有常见的双等位基因致病性SMN1外显子7 - 8缺失或点突变，以及1个或2个SMN2拷贝。患者接受onasemnogene abeparvovec（1.1 x 1014载体基因组[vg]/kg）的一次性静脉输注。门诊随访包括从输注后第7天开始每周评估一次，持续4周，然后每月评估一次，直至研究结束（18个月大或提前终止）。主要结局是在意向治疗人群中测量的在18个月龄研究访视之前的任何访视时独立坐位至少10 s（根据WHO多中心生长参考研究的定义）。将疗效与儿科神经肌肉临床研究（PNCR）自然史队列进行比较。该试验在www.example.com注册，NCT 03461289（已完成）。结果从2018年8月16日至2020年9月11日，对41例脊髓性肌萎缩症患者进行了合格性评估。Onasemnogene abeparvovec给药时的中位年龄为4.1个月（IQR 3.0 - 5.2）。33例患者中有32例（97%）完成了研究，并被纳入ITT人群（1例患者因第181天给药而被排除，尽管完成了研究）。32例患者中有14例（44%，97.5%CI 26 - 100）在18个月龄研究访视前的任何访视时达到了功能独立坐位至少10 s的主要终点（PNCR队列中23例未治疗患者中0例; p
Background Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US.Methods STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7-8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1.1 x 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed).Findings From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4.1 months (IQR 3.0-5.2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97.5% CI 26-100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p