Clinical Trial

. 2022 Jul;28(7):1390-1397.

doi: 10.1038/s41591-022-01867-3. Epub 2022 Jun 17.

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

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, Melissa Wigderson²⁴, 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, NSW, Australia.
⁵ School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, NSW, 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 Department of Pediatrics, Neurology & Neurosurgery, Montreal Children's Hospital, McGill University, Montreal, QC, 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.

PMID: 35715567
PMCID: PMC9205287
DOI: 10.1038/s41591-022-01867-3

Clinical Trial

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

Kevin A Strauss et al. Nat Med. 2022 Jul.

. 2022 Jul;28(7):1390-1397.

doi: 10.1038/s41591-022-01867-3. Epub 2022 Jun 17.

Authors

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, NSW, Australia.
⁵ School of Clinical Medicine, UNSW Medicine and Health, UNSW Sydney, Sydney, NSW, 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 Department of Pediatrics, Neurology & Neurosurgery, Montreal Children's Hospital, McGill University, Montreal, QC, 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.

PMID: 35715567
PMCID: PMC9205287
DOI: 10.1038/s41591-022-01867-3

Abstract

Most children with biallelic SMN1 deletions and three SMN2 copies develop spinal muscular atrophy (SMA) type 2. SPR1NT ( NCT03505099 ), a Phase III, multicenter, single-arm trial, investigated the efficacy and safety of onasemnogene abeparvovec for presymptomatic children with biallelic SMN1 mutations treated within six postnatal weeks. Of 15 children with three SMN2 copies treated before symptom onset, all stood independently before 24 months (P < 0.0001; 14 within normal developmental window), and 14 walked independently (P < 0.0001; 11 within normal developmental window). All survived without permanent ventilation at 14 months; ten (67%) maintained body weight (≥3rd WHO percentile) without feeding support through 24 months; and none required nutritional or respiratory support. No serious adverse events were considered treatment-related by the investigator. Onasemnogene abeparvovec was effective and well-tolerated for presymptomatic infants at risk of SMA type 2, underscoring the urgency of early identification and intervention.

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Conflict of interest statement

Novartis Gene Therapies, Inc. sponsored this clinical trial. The authors declare the following competing interests. K.A.S. has received personal compensation from Novartis Gene Therapies, Inc. (formerly AveXis, Inc.) for serving as an advisory board member and from Biogen for serving as a visiting professor, and has received research support from clinical trials sponsored by Novartis Gene Therapies, Inc., and Biogen. M.A.F. has received honoraria for scientific advisory boards from Novartis Gene Therapies, Inc., Biogen, and Roche and research grants from Biogen. F.M. reports grants and personal fees from Novartis Gene Therapies, Inc., including participation in the STR1VE-EU grant and the SPR1NT study; grants, personal fees, and other (participation in the SHINE clinical trial and principal investigator of the investigator-initiated UK SMA REACH UK registry) from Biogen; and grants and personal fees from Roche, including participation in the JEWELFISH clinical trial of risdiplam and participation in the olesoxime clinical trial, during the conduct of the study. F.M. has also received honoraria for scientific advisory boards from Biogen, Novartis, Novartis Gene Therapies, Inc., PTC, Roche, and Sarepta Therapeutics. K.S. has served on advisory boards for Biogen, Novartis Gene Therapies, Inc./Novartis, and Chugai (Roche) and has received search funding from Biogen. J.R.M. has received personal compensation for clinical trial consulting and for serving on scientific advisory boards, as well as research support, from Novartis Gene Therapies, Inc. L.S. has received personal compensation as an advisory committee board member/consultant from Novartis Gene Therapies, Inc., Biogen, Biophytis, Cytokinetics, Dynacure, Roche, Santhera, and Sarepta Therapeutics, and has received research support from Novartis Gene Therapies, Inc., Biogen, Dynacure, and Roche. H.J.M. has received honoraria for scientific advisory boards from Novartis Gene Therapies, Inc., and has received research funding from Roche. R.S.F. has received personal compensation for advisory board participation from Novartis Gene Therapies, Inc., Biogen, Roche, and Scholar Rock, and for consulting from Novartis; editorial fees from Elsevier for co-editing a neurology textbook; license fees from the Children’s Hospital of Philadelphia; and research funding from Novartis Gene Therapies, Inc., Biogen, Roche/Genentech, and Scholar Rock. K.J.S. has received personal compensation for a speaking engagement from Biogen, and research funding as a principal investigator for clinical trials sponsored by Novartis Gene Therapies, Inc. and Biogen. J.M.K. was site principal investigator for clinical trials sponsored by Novartis Gene Therapies, Inc., Biogen, and Scholar Rock. C.M.Z. has received research support from Biogen. C.A.C. has served on advisory boards for Novartis Gene Therapies, Inc., and Roche/Genentech; has served as an educational speaker for Biogen; and has received research funding from Novartis Gene Therapies, Inc., Biogen, and Roche. S.T.I. has received personal compensation for service on advisory boards or consulting from Novartis Gene Therapies, Inc., Biogen, Roche/Genentech, and Sarepta Therapeutics; and research support from Novartis Gene Therapies, Inc., Biogen, Capricor, PTC, Scholar Rock, and Sarepta Therapeutics. J.M.K. is a principal investigator for clinical trials sponsored by Novartis Gene Therapies, Inc., Scholar Rock, and Roche/Genentech. J.A.P. has served as an investigator on clinical trials for Biogen, Novartis, PTC Therapeutics, and Scholar Rock, and has served in an advisory capacity for Biogen, Scholar Rock, Roche/Genentech, and Novartis. P.B.S. has served as a consultant for Alexion, Biogen, Genentech, Novartis Gene Therapies, Inc., and Sarepta and has served as a speaker for Alexion, Biogen, Genentech, Grifols, Novartis Gene Therapies, Inc., and PTC Therapeutics. S.K. is an employee of Novartis Gene Therapies, Inc., and receives consulting fees from UCB Pharma, Karuna Therapeutics, Worldwide Clinical Trials, CPC Clinical Research, Zosano Pharmaceuticals, PharPoint Research, and Nesos, Inc. M.W. is an employee of Novartis Gene Therapies, Inc., and owns Novartis stock or other equities. S.T.-W. is an employee of Novartis Gene Therapies, Inc., and owns Novartis stock or other equities. B.E.M. is an employee of Translational Medicine, Novartis Institutes for BioMedical Research (Cambridge), and owns Novartis stock or other equities. T.A.M. is an employee of Novartis Gene Therapies, Inc., and owns Novartis stock or other equities.

Figures

**Fig. 1. Video-confirmed developmental motor milestones for children with three copies of *SMN2*.**
Months calculated as days / 30. Only the first observed instance of a milestone is included in this figure. Shaded areas indicate the World Health Organization Multicentre Growth Reference Study (WHO-MGRS) windows for normal development; the 99th percentile (that is, upper bound of normal development) of sits without support is 279 days, stands alone is 514 days, and walks alone is 534 days. ^aBayley Scales gross motor subtest item #26: child sits alone without support for at least 30 seconds. ^bBayley Scales gross motor subtest item #40: child stands alone. Child stands alone for at least 3 seconds after you release his or her hands. ^cBayley Scales gross motor subtest item #43: child walks alone. Child takes at least five steps independently, displaying coordination and balance. n = 6 males and n = 9 females; mean (s.d.) age at dosing, 28.7 (11.68) days.

**Fig. 2. Growth charts for children with three copies of *SMN2*.**
Ten (67%) children achieved the ability to maintain weight at or above the WHO 3rd percentile without the need for non-oral/mechanical feeding support at all visits up to 24 months of age. The ability to maintain weight at or above the 3rd percentile without the need for non-oral/mechanical feeding support was defined by meeting both of the following criteria at all visits: (1) does not receive nutrition through mechanical support (that is, feeding tube) and (2) maintains weight (≥3rd percentile for age and sex as defined by WHO guidelines) consistent with the patient’s age at the assessment. The gray shading represents WHO growth standards for the 3rd through 97th percentiles. n = 6 males and n = 9 females; mean (s.d.) age at dosing, 28.7 (11.68) days.

**Fig. 3. Bayley scales fine motor and gross motor raw scores.**
Improvements were observed in all children for both gross (a) and fine (b) subtests of the Bayley Scales of Infant and Toddler Development after onasemnogene abeparvovec infusion and up to 24 months of age. The gray shading represents Bayley-III gross and fine motor normal ranges (±2 s.d.). n = 6 males and n = 9 females; mean (s.d.) age at dosing, 28.7 (11.68) days.

See this image and copyright information in PMC

Comment in

Early treatment is a lifeline for infants with SMA.
Sumner CJ, Crawford TO. Sumner CJ, et al. Nat Med. 2022 Jul;28(7):1348-1349. doi: 10.1038/s41591-022-01889-x. Nat Med. 2022. PMID: 35840728 Free PMC article.
Timing is everything: Clinical evidence supports pre-symptomatic treatment for spinal muscular atrophy.
Motyl AAL, Gillingwater TH. Motyl AAL, et al. Cell Rep Med. 2022 Aug 16;3(8):100725. doi: 10.1016/j.xcrm.2022.100725. Cell Rep Med. 2022. PMID: 35977471 Free PMC article.

References

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1. Calucho M, et al. Correlation between SMA type and SMN2 copy number revisited: an analysis of 625 unrelated Spanish patients and a compilation of 2834 reported cases. Neuromuscul. Disord. 2018;28:208–215. - PubMed
1. Carson VJ, et al. Nusinersen by subcutaneous intrathecal catheter for symptomatic spinal muscular atrophy patients with complex spine anatomy. Muscle Nerve. 2022;65:51–59. - PubMed
1. Muntoni F, et al. Long-term follow-up of patients with type 2 and non-ambulant type 3 spinal muscular atrophy (SMA) treated with olesoxime in the OLEOS trial. Neuromuscul. Disord. 2020;30:959–969. - PubMed

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Comment in

References

Publication types

MeSH terms

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Associated data

LinkOut - more resources

Full Text Sources

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Medical