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

Kevin A Strauss; Michelle A Farrar; Francesco Muntoni; Kayoko Saito; Jerry R Mendell; Laurent Servais; Hugh J McMillan; Richard S Finkel; Kathryn J Swoboda; Jennifer M Kwon; Craig M Zaidman; Claudia A Chiriboga; Susan T Iannaccone; Jena M Krueger; Julie A Parsons; Perry B Shieh; Sarah Kavanagh; Sitra Tauscher-Wisniewski; Bryan E McGill; Thomas A Macek

doi:10.1038/s41591-022-01866-4

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

Nat Med. 2022 Jul;28(7):1381-1389. doi: 10.1038/s41591-022-01866-4. Epub 2022 Jun 17.

Authors

Kevin A Strauss^{1

2

3}, Michelle A Farrar^{4

5}, Francesco Muntoni^{6

7}, Kayoko Saito⁸, Jerry R Mendell^{9

10}, Laurent Servais^{11

12}, Hugh J McMillan¹³, Richard S Finkel^{14

15}, Kathryn J Swoboda¹⁶, Jennifer M Kwon¹⁷, Craig M Zaidman¹⁸, Claudia A Chiriboga¹⁹, Susan T Iannaccone²⁰, Jena M Krueger²¹, Julie A Parsons²², Perry B Shieh²³, Sarah Kavanagh²⁴, Sitra Tauscher-Wisniewski²⁴, Bryan E McGill²⁵, Thomas A Macek²⁴

Affiliations

¹ Clinic for Special Children, Strasburg, PA, USA. kstrauss@clinicforspecialchildren.org.
² Penn Medicine-Lancaster General Hospital, Lancaster, PA, USA. kstrauss@clinicforspecialchildren.org.
³ Departments of Pediatrics and Molecular, Cell & Cancer Biology, University of Massachusetts School of Medicine, Worcester, MA, USA. kstrauss@clinicforspecialchildren.org.
⁴ Department of Neurology, Sydney Children's Hospital Network, Sydney, New South Wales, Australia.
⁵ School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, New South Wales, Australia.
⁶ The Dubowitz Neuromuscular Centre, University College London, Great Ormond Street Institute of Child Health & Great Ormond Street Hospital, London, UK.
⁷ National Institute of Health Research, Great Ormond Street Hospital Biomedical Research Centre, London, UK.
⁸ Institute of Medical Genetics, Tokyo Women's Medical University, Tokyo, Japan.
⁹ Center for Gene Therapy, Nationwide Children's Hospital, Columbus, OH, USA.
¹⁰ Department of Pediatrics and Department of Neurology, The Ohio State University, Columbus, OH, USA.
¹¹ Department of Paediatrics, MDUK Oxford Neuromuscular Centre, Oxford, UK.
¹² Neuromuscular Reference Center, Department of Pediatrics, CHU & University of Liège, Liège, Belgium.
¹³ Departments of Pediatrics, Neurology & Neurosurgery, Montreal Children's Hospital, McGill University Health Centre, Montreal, Quebec, Canada.
¹⁴ Department of Pediatrics, Nemours Children's Hospital, Orlando, FL, USA.
¹⁵ Center for Experimental Neurotherapeutics, St. Jude Children's Research Hospital, Memphis, TN, USA.
¹⁶ Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
¹⁷ Department of Neurology, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA.
¹⁸ Washington University School of Medicine, St. Louis, MO, USA.
¹⁹ Division of Pediatric Neurology, Columbia University Medical Center, New York, NY, USA.
²⁰ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
²¹ Department of Neurology, Helen DeVos Children's Hospital, Grand Rapids, MI, USA.
²² Department of Pediatrics, University of Colorado School of Medicine, Aurora, CO, USA.
²³ Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
²⁴ Novartis Gene Therapies, Inc., Bannockburn, IL, USA.
²⁵ 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.

Publication types

Clinical Trial, Phase III
Multicenter Study
Research Support, Non-U.S. Gov't

MeSH terms

Child
Humans
Infant
Infant, Newborn
Muscular Atrophy, Spinal* / drug therapy
Muscular Atrophy, Spinal* / genetics
Neonatal Screening
Spinal Muscular Atrophies of Childhood* / drug therapy
Spinal Muscular Atrophies of Childhood* / genetics
Survival of Motor Neuron 2 Protein / genetics

Substances

SMN2 protein, human
Survival of Motor Neuron 2 Protein

Associated data

ClinicalTrials.gov/NCT03505099