Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: 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; Melissa Wigderson; Sitra Tauscher-Wisniewski; Bryan E. McGill; Thomas A. Macek

doi:10.1038/s41591-022-01867-3

Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: 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, Melissa Wigderson, Sitra Tauscher-Wisniewski, Bryan E. McGillThomas A. Macek

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1390-1397
Number of pages	8
Journal	Nature medicine
Volume	28
Issue number	7
DOIs	https://doi.org/10.1038/s41591-022-01867-3
State	Published - Jul 2022

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)

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10.1038/s41591-022-01867-3

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Strauss, K. A., Farrar, M. A., Muntoni, F., Saito, K., Mendell, J. R., Servais, L., McMillan, H. J., Finkel, R. S., Swoboda, K. J., Kwon, J. M., Zaidman, C. M., Chiriboga, C. A., Iannaccone, S. T., Krueger, J. M., Parsons, J. A., Shieh, P. B., Kavanagh, S., Wigderson, M., Tauscher-Wisniewski, S., ... Macek, T. A. (2022). Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial. Nature medicine, 28(7), 1390-1397. https://doi.org/10.1038/s41591-022-01867-3

Strauss, KA, Farrar, MA, Muntoni, F, Saito, K, Mendell, JR, Servais, L, McMillan, HJ, Finkel, RS, Swoboda, KJ, Kwon, JM, Zaidman, CM, Chiriboga, CA, Iannaccone, ST, Krueger, JM, Parsons, JA, Shieh, PB, Kavanagh, S, Wigderson, M, Tauscher-Wisniewski, S, McGill, BE & Macek, TA 2022, 'Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy: the Phase III SPR1NT trial', Nature medicine, vol. 28, no. 7, pp. 1390-1397. https://doi.org/10.1038/s41591-022-01867-3

@article{806343fd09554562ab75ea8e9e4dc271,

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

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.",

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

note = "Funding Information: The authors wish to thank the investigators, site coordinators, and study teams, administrators of newborn screening programs and, most importantly, the patients, families, and caregivers for their participation in these studies. The authors also thank M. Milton of Novartis Institutes for Biomedical Research, who provided critical review and input on content related to biodistribution, immune response and safety; S. P. Reyna of Novartis Gene Therapies, Inc., who provided critical review and input on SMA patient care; and M. Wolf of Novartis Gene Therapies, Inc., who provided functional outcome measure expertise and contributions to study conduct and oversight. Medical writing assistance and editorial support was provided by J. Gibson from Kay Square Scientific and M. Nissen of Novartis Gene Therapies, Inc. This support was funded by Novartis Gene Therapies, Inc. The NSW Pilot NBS study was funded by Luminesce Alliance, a not-for-profit cooperative joint venture across the Sydney Children{\textquoteright}s Hospital Network, Children{\textquoteright}s Medical Research Institute, and Children{\textquoteright}s Cancer Institute, established with the support of the New South Wales Government. Luminesce Alliance is also affiliated with UNSW Sydney and The University of Sydney. The SPR1NT study was designed and funded by Novartis Gene Therapies, Inc., which was involved in the study design, data collection, data analysis, data interpretation, and writing of all related reports and publications. Funding Information: The authors wish to thank the investigators, site coordinators, and study teams, administrators of newborn screening programs and, most importantly, the patients, families, and caregivers for their participation in these studies. The authors also thank M. Milton of Novartis Institutes for Biomedical Research, who provided critical review and input on content related to biodistribution, immune response and safety; S. P. Reyna of Novartis Gene Therapies, Inc., who provided critical review and input on SMA patient care; and M. Wolf of Novartis Gene Therapies, Inc., who provided functional outcome measure expertise and contributions to study conduct and oversight. Medical writing assistance and editorial support was provided by J. Gibson from Kay Square Scientific and M. Nissen of Novartis Gene Therapies, Inc. This support was funded by Novartis Gene Therapies, Inc. The NSW Pilot NBS study was funded by Luminesce Alliance, a not-for-profit cooperative joint venture across the Sydney Children{\textquoteright}s Hospital Network, Children{\textquoteright}s Medical Research Institute, and Children{\textquoteright}s Cancer Institute, established with the support of the New South Wales Government. Luminesce Alliance is also affiliated with UNSW Sydney and The University of Sydney. The SPR1NT study was designed and funded by Novartis Gene Therapies, Inc., which was involved in the study design, data collection, data analysis, data interpretation, and writing of all related reports and publications. Funding Information: 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{\textquoteright}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. Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = jul,

doi = "10.1038/s41591-022-01867-3",

language = "English (US)",

volume = "28",

pages = "1390--1397",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Publishing Group",

number = "7",

}

TY - JOUR

T1 - Onasemnogene abeparvovec for presymptomatic infants with three copies of SMN2 at risk for spinal muscular atrophy

T2 - the Phase III SPR1NT trial

AU - Strauss, Kevin A.

AU - Farrar, Michelle A.

AU - Muntoni, Francesco

AU - Saito, Kayoko

AU - Mendell, Jerry R.

AU - Servais, Laurent

AU - McMillan, Hugh J.

AU - Finkel, Richard S.

AU - Swoboda, Kathryn J.

AU - Kwon, Jennifer M.

AU - Zaidman, Craig M.

AU - Chiriboga, Claudia A.

AU - Iannaccone, Susan T.

AU - Krueger, Jena M.

AU - Parsons, Julie A.

AU - Shieh, Perry B.

AU - Kavanagh, Sarah

AU - Wigderson, Melissa

AU - Tauscher-Wisniewski, Sitra

AU - McGill, Bryan E.

AU - Macek, Thomas A.

N1 - Funding Information: The authors wish to thank the investigators, site coordinators, and study teams, administrators of newborn screening programs and, most importantly, the patients, families, and caregivers for their participation in these studies. The authors also thank M. Milton of Novartis Institutes for Biomedical Research, who provided critical review and input on content related to biodistribution, immune response and safety; S. P. Reyna of Novartis Gene Therapies, Inc., who provided critical review and input on SMA patient care; and M. Wolf of Novartis Gene Therapies, Inc., who provided functional outcome measure expertise and contributions to study conduct and oversight. Medical writing assistance and editorial support was provided by J. Gibson from Kay Square Scientific and M. Nissen of Novartis Gene Therapies, Inc. This support was funded by Novartis Gene Therapies, Inc. The NSW Pilot NBS study was funded by Luminesce Alliance, a not-for-profit cooperative joint venture across the Sydney Children’s Hospital Network, Children’s Medical Research Institute, and Children’s Cancer Institute, established with the support of the New South Wales Government. Luminesce Alliance is also affiliated with UNSW Sydney and The University of Sydney. The SPR1NT study was designed and funded by Novartis Gene Therapies, Inc., which was involved in the study design, data collection, data analysis, data interpretation, and writing of all related reports and publications. Funding Information: The authors wish to thank the investigators, site coordinators, and study teams, administrators of newborn screening programs and, most importantly, the patients, families, and caregivers for their participation in these studies. The authors also thank M. Milton of Novartis Institutes for Biomedical Research, who provided critical review and input on content related to biodistribution, immune response and safety; S. P. Reyna of Novartis Gene Therapies, Inc., who provided critical review and input on SMA patient care; and M. Wolf of Novartis Gene Therapies, Inc., who provided functional outcome measure expertise and contributions to study conduct and oversight. Medical writing assistance and editorial support was provided by J. Gibson from Kay Square Scientific and M. Nissen of Novartis Gene Therapies, Inc. This support was funded by Novartis Gene Therapies, Inc. The NSW Pilot NBS study was funded by Luminesce Alliance, a not-for-profit cooperative joint venture across the Sydney Children’s Hospital Network, Children’s Medical Research Institute, and Children’s Cancer Institute, established with the support of the New South Wales Government. Luminesce Alliance is also affiliated with UNSW Sydney and The University of Sydney. The SPR1NT study was designed and funded by Novartis Gene Therapies, Inc., which was involved in the study design, data collection, data analysis, data interpretation, and writing of all related reports and publications. Funding Information: 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. Publisher Copyright: © 2022, The Author(s).

PY - 2022/7

Y1 - 2022/7

N2 - 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.

AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=85132254873&partnerID=8YFLogxK

U2 - 10.1038/s41591-022-01867-3

DO - 10.1038/s41591-022-01867-3

M3 - Article

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AN - SCOPUS:85132254873

SN - 1078-8956

VL - 28

SP - 1390

EP - 1397

JO - Nature Medicine

JF - Nature Medicine

IS - 7

ER -

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

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