Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial,Nature Medicine

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Onasemnogene abeparvovec for presymptomatic infants with two copies of SMN2 at risk for spinal muscular atrophy type 1: the Phase III SPR1NT trial
Nature Medicine ( IF 82.9 ) Pub Date : 2022-06-17 , DOI: 10.1038/s41591-022-01866-4
Kevin A Strauss _{1,

2,

3} , Michelle A Farrar _{4,

5} , Francesco Muntoni _{6,

7} , Kayoko Saito ₈ , Jerry R Mendell _{9,

10} , Laurent Servais _{11,

12} , Hugh J McMillan ₁₃ , Richard S Finkel _{14,

15} , Kathryn J Swoboda ₁₆ , Jennifer M Kwon ₁₇ , Craig M Zaidman ₁₈ , Claudia A Chiriboga ₁₉ , Susan T Iannaccone ₂₀ , Jena M Krueger ₂₁ , Julie A Parsons ₂₂ , Perry B Shieh ₂₃ , Sarah Kavanagh ₂₄ , Sitra Tauscher-Wisniewski ₂₄ , Bryan E McGill ₂₅ , Thomas A Macek ₂₄

Affiliation

Clinic for Special Children, Strasburg, PA, USA.
Penn Medicine-Lancaster General Hospital, Lancaster, PA, USA.
Departments of Pediatrics and Molecular, Cell & Cancer Biology, University of Massachusetts School of Medicine, Worcester, MA, USA.
Department of Neurology, Sydney Children's Hospital Network, Sydney, New South Wales, Australia.
School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
The Dubowitz Neuromuscular Centre, University College London, Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK.
National Institute of Health Research, Great Ormond Street Hospital Biomedical Research Centre, London, UK.
Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA.
Department of Pediatrics and Department of Neurology, The Ohio State University, Columbus, OH, USA.
Department of Paediatrics, MDUK Oxford Neuromuscular Centre, Oxford, UK.
Neuromuscular Reference Center, Department of Pediatrics, CHU & University of Liège, Liège, Belgium.
Departments of Pediatrics, Neurology & Neurosurgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
Department of Pediatrics, Nemours Children's Hospital, Orlando, FL, USA.
Center for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
Washington University School of Medicine, St. Louis, MO, USA.
Division of Pediatric Neurology, Columbia University Medical Center, New York, NY, USA.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Department of Neurology, Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
Novartis Gene Therapies, Inc., Bannockburn, IL, USA.
Translational Medicine, Novartis Institutes for BioMedical Research, Cambridge, MA, USA.

Abstract

SPR1NT (NCT03505099) was a Phase III, multicenter, single-arm study to investigate the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated at ≤6 weeks of life. Here, we report final results for 14 children with two copies of SMN2, expected to develop spinal muscular atrophy (SMA) type 1. Efficacy was compared with a matched Pediatric Neuromuscular Clinical Research natural-history cohort (n = 23). All 14 enrolled infants sat independently for ≥30 seconds at any visit ≤18 months (Bayley-III item #26; P < 0.001; 11 within the normal developmental window). All survived without permanent ventilation at 14 months as per protocol; 13 maintained body weight (≥3rd WHO percentile) through 18 months. No child used nutritional or respiratory support. No serious adverse events were considered related to treatment by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for children expected to develop SMA type 1, highlighting the urgency for universal newborn screening.

中文翻译：

Onasemnogene abeparvovec 用于有两个 SMN2 拷贝的有 1 型脊髓性肌萎缩风险的症状前婴儿：III 期 SPR1NT 试验

摘要

SPR1NT (NCT03505099) 是一项 III 期、多中心、单臂研究，旨在研究 onasemnogene abeparvovec 对出生 ≤ 6 周的双等位基因SMN1突变的症状前儿童的疗效和安全性。在这里，我们报告了 14 名携带两份SMN2的儿童的最终结果，这些儿童预计会发展为 1 型脊髓性肌萎缩 (SMA)。将疗效与匹配的儿科神经肌肉临床研究自然历史队列 ( n = 23) 进行比较。所有 14 名登记的婴儿在任何一次访问 ≤18 个月时独立坐姿 ≥30 秒（Bayley-III 项目 #26；P < 0.001; 11 在正常发育窗口内）。根据方案，所有患者在 14 个月时在没有永久通气的情况下存活；13 人在 18 个月内保持体重（≥WHO 第 3 个百分位）。没有儿童使用营养或呼吸支持。研究者认为没有与治疗相关的严重不良事件。Onasemnogene abeparvovec 对预计发展为 1 型 SMA 的儿童有效且耐受性良好，突显了普遍新生儿筛查的紧迫性。

更新日期：2022-06-17

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