Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial,The Lancet Neurology

当前位置： X-MOL 学术 › Lancet Neurol. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Onasemnogene abeparvovec gene therapy for symptomatic infantile-onset spinal muscular atrophy type 1 (STR1VE-EU): an open-label, single-arm, multicentre, phase 3 trial
The Lancet Neurology ( IF 46.5 ) Pub Date : 2021-09-15 , DOI: 10.1016/s1474-4422(21)00251-9
Eugenio Mercuri ₁ , Francesco Muntoni ₂ , Giovanni Baranello ₃ , Riccardo Masson ₄ , Odile Boespflug-Tanguy ₅ , Claudio Bruno ₆ , Stefania Corti ₇ , Aurore Daron ₈ , Nicolas Deconinck ₉ , Laurent Servais ₁₀ , Volker Straub ₁₁ , Haojun Ouyang ₁₂ , Deepa Chand ₁₃ , Sitra Tauscher-Wisniewski ₁₂ , Nuno Mendonca ₁₄ , Arseniy Lavrov ₁₅ ,

Affiliation

Paediatric Neurology Unit and Nemo Clinical Centre, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Rome, Italy; Department of Child Neurology and Psychiatry, Catholic University, Rome, Italy.
Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, Great Ormond Street Institute of Child Health, London, UK; Great Ormond Street Hospital Trust, London, UK.
Dubowitz Neuromuscular Centre, UCL Great Ormond Street Institute of Child Health, London, UK; Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
I-Motion, Institut de Myologie, AP-HP Hopital Trousseau, Paris, France; Université de Paris, UMR 1141, Paris, France.
Center of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genoa, Italy.
Department of Pathophysiology and Transplantation, Dino Ferrari Centre, University of Milan, Milan, Italy; Neurology Unit, Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
Department of Pediatrics, Centre Hospitalier Universitaire de Liège, Liège, Belgium.
Neuromuscular Reference Center, Universitair Ziekenhuis Gent, Ghent, Belgium; Neuromuscular Reference Center, Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Brussels, Belgium.
I-Motion, Institut de Myologie, AP-HP Hopital Trousseau, Paris, France; Neuromuscular Reference Center, CHU de Liège, Hôpital de La Citadelle, Liège, Belgium; Department of Paediatrics, MDUK Oxford Neuromuscular Center, University of Oxford, Oxford, UK.
John Walton Muscular Dystrophy Research Centre, Newcastle University, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
Novartis Gene Therapies, Bannockburn, IL, USA.
Novartis Gene Therapies, Bannockburn, IL, USA; Department of Pediatrics, Washington University School of Medicine and St Louis Children's Hospital, St Louis, MO, USA.
Novartis Gene Therapies, Porto, Portugal.
Novartis Gene Therapies, Cambridge, UK.

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 × 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<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 [67%] of 33), upper respiratory infection (11 [33%]), and increased alanine aminotransferase (nine [27%]). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study.

Interpretation

STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline.

Funding

Novartis Gene Therapies.

中文翻译：

Onasemnogene abeparvovec 基因疗法治疗症状性婴儿型脊髓性肌萎缩 1 型 (STR1VE-EU)：一项开放标签、单臂、多中心、3 期试验

背景

脊髓性肌萎缩症是一种罕见的常染色体隐性遗传的神经肌肉疾病，由运动神经元存活 1 ( SMN1 ) 基因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，我们旨在使用比 STR1VE-US 中使用的更广泛的资格标准来评估 onasemnogene abeparvovec 基因替代疗法对 1 型脊髓性肌萎缩症婴儿的安全性和有效性。

方法

STR1VE-EU 是一项多中心、单臂、单剂量、开放标签的 3 期试验，在意大利 (n=4)、英国 (n=2)、比利时 (n= 2）和法国（n=1）。我们招募了年龄小于 6 个月（180 天）且患有 1 型脊髓性肌萎缩症和常见的双等位基因致病性SMN1外显子 7-8 缺失或点突变以及一到两个SMN2拷贝的患者。患者接受了一次性静脉输注onasemnogene abeparvovec (1·1 × 10 ¹⁴载体基因组 [vg]/kg)。门诊随访包括每周一次的评估，从输注后第 7 天开始，持续 4 周，然后每月一次，直到研究结束（18 个月大或提前终止）。根据世界卫生组织多中心生长参考研究的定义，主要结果是在意向治疗人群中测量的 18 个月大研究访问期间的任何访问中独立坐姿至少 10 秒。疗效与小儿神经肌肉临床研究 (PNCR) 自然史队列进行比较。该试验已在 ClinicalTrials.gov 注册，NCT03461289（已完成）。

发现

从 2018 年 8 月 16 日到 2020 年 9 月 11 日，对 41 名脊髓性肌萎缩症患者进行了资格评估。onasemnogene abeparvovec 给药的中位年龄为 4·1 个月 (IQR 3·0–5·2)。33 名患者中有 32 名 (97%) 完成了研究并被纳入 ITT 人群（尽管完成了研究，但由于 181 天的给药，一名患者被排除在外）。32 名患者中有 14 名（44%，97·5% CI 26-100）在直至 18 个月大的研究访问期间的任何访问中达到了功能性独立坐姿至少 10 秒的主要终点（对比PNCR 队列中 23 名未经治疗的患者中有 0 名；p<0·0001)。ITT 人群中 32 名患者中有 31 名（97%，95% CI 91-100）在 14 个月时无需永久通气支持而存活，而 PNCR 自然史队列中 23 名患者中有 6 名（26%，8-44 名）（p <0·0001)。33 名患者中有 32 名 (97%) 至少有 1 起不良事件，6 名 (18%) 有被认为严重且与 onasemnogene abeparvovec 相关的不良事件。最常见的不良事件是发热（33 例中的 22 例 [67%]）、上呼吸道感染（11 例 [33%]）和丙氨酸氨基转移酶升高（9 例 [27%]）。一名与研究药物无关的死亡是由于研究期间呼吸道感染导致的缺氧缺血性脑损伤。