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Comparative Study
. 2025 Oct 1;8(10):e2536348.
doi: 10.1001/jamanetworkopen.2025.36348.

Comparative Clinical Outcomes of Nusinersen and Gene Therapy in Spinal Muscular Atrophy Type 1

Juliette Ropars  1   2   3 , Claude Cances  4 , Rocio Garcia-Uzquiano  3   5 , Marta Gomez-Garcia de la Banda  5 , Christine Barnerias  6 , Frédérique Audic  1   7 , Julien Durigneux  8 , Cécile Halbert  7 , Lionelle Nkam  3 , Vincent Laugel  9 , Caroline Espil  10 , Ulrike Walther-Louvier  11 , Jean-Baptiste Davion  12 , Arnaud Isapof  13 , Laure Le Goff  14   15 , Isabelle Desguerre  6 , Susana Quijano-Roy  5   16 , Lamiae Grimaldi  3   17 ; French SMA Registry Study Group
Collaborators, Affiliations
Comparative Study

Comparative Clinical Outcomes of Nusinersen and Gene Therapy in Spinal Muscular Atrophy Type 1

Juliette Ropars et al. JAMA Netw Open. .

Abstract

Importance: Therapeutic advances have transformed the prognosis of spinal muscular atrophy (SMA). Given the lifelong implications of these innovative therapies, comparative data on their efficacy are urgently required.

Objective: To compare clinical outcomes of nusinersen and onasemnogene abeparvovec gene therapy as first-line treatments in children with SMA type 1 (SMA1).

Design, setting, and participants: This comparative effectiveness study used data from the French National SMA Registry from September 2016 to July 2024. The follow-up period started at treatment initiation and continued until July 22, 2024, or death. Children with genetically confirmed SMA1 (types a, b, or c) treated within 6 months of diagnosis with either nusinersen or gene therapy as first-line therapy and followed up for at least 24 months were included. Matching criteria included age, baseline score on the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders, and respiratory and nutritional status at treatment initiation.

Exposure: First-line treatment with either nusinersen or gene therapy.

Main outcomes and measures: Outcomes included respiratory and nutritional support needs, motor function, and unsatisfactory clinical response (UCR)- a composite of death, treatment switch (or, for gene therapy, addition) due to inadequate response, initiation of feeding support, and/or failure to achieve independent sitting.

Results: Among 1366 patients enrolled in the registry, 309 were diagnosed with SMA1. Twenty-four children in 12 matched pairs met inclusion criteria (14 [58%] male; mean [SD] age at treatment initiation, 6.1 [3.0] months [range, 2.3-11.9 months]). Three patients (1 receiving gene therapy [8%], 2 receiving nusinersen [17%]) died within the first year of treatment. At 2 years posttreatment, 1 of the 11 surviving patients treated with gene therapy (9%) required nutritional support vs 5 of 10 (50%) treated with nusinersen, and nocturnal ventilation was required in 5 of 11 (45%) receiving gene therapy vs 8 of 10 (80%) receiving nusinersen. Motor outcomes were comparable between groups (mean [SE] intrapair difference in CHOP-INTEND score evolution, -1.69 [1.24] points; P = .17). UCR occurred in 8 of 12 patients (67%) receiving nusinersen and 3 of 12 (25%) receiving gene therapy.

Conclusions and relevance: In this comparative effectiveness study of children with SMA1, gene therapy was associated with lower incidence of UCR and fewer supportive care needs vs nusinersen. These exploratory findings warrant confirmation in larger studies.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Ropars reported receiving honoraria for presentations and/or travel support from Novartis, Roche, and Biogen and participating on advisory boards of Novartis, Roche, Pfizer, and Italfarmaco. Dr Cances reported receiving honoraria or consulting fees for serving on boards of experts for Roche and Pfizer; travel paid by Novartis, Biogen, Roche, and Pfizer; and serving as principal investigator in therapeutic trials for Novartis, Biogen, Roche, and Scholar Rock. Dr Garcia-Uzquiano reported receiving honoraria for presentations and/or travel support from Roche and participating on advisory boards for Roche outside the submitted work. Dr Barnerias reported receiving personal fees from Novartis and Biogen outside the submitted work and funding of the French National SMA Registry contributed by Biogen and Novartis, which were not directly involved in this work. Dr Audic reported receiving honoraria and consulting fees from, serving on boards of experts for, and giving lectures and expert testimony for Novartis and Biogen and receiving travel paid by Novartis and Biogen. Dr Durigneux reported receiving personal fees from Novartis, Biogen, and Roche during the conduct of the study. Prof Laugel reported receiving grants and personal fees from Novartis, Roche, and Biogen and personal fees from Sarepta, Pfizer, PTC, Santhera, and Italfarmaco outside the submitted work. Dr Espil reported receiving honoraria for presentations and/or travel support from Novartis, Roche, and Biogen and participating on advisory boards of Novartis and Biogen. Dr Davion reported receiving personal fees from Novartis, Roche, and Biogen during the conduct of the study; receiving personal fees from Sanofi, PTC Therapeutics, LFB Biomedicaments, Alnylam, argenx, Pfizer SAS, Axelys Santé, Eisai SAS, Grifols, and Experf Nord outside the submitted work; and receiving travel grants and participating on advisory boards for Novartis, Roche, and Biogen. Dr Isapof reported receiving personal fees and honoraria from Novartis Gene Therapies and Biogen for consulting and speaking outside the submitted work. Dr Le Goff reported receiving nonfinancial support from Novartis Gene Therapies, Biogen, Roche, and Pfizer and personal fees from Novartis Gene Therapies and Roche outside the submitted work. Prof Desguerre reported serving on the scientific board and congress for Novartis and the scientific boards of Pfizer, Roche, and Sarepta outside the submitted work. Prof Quijano-Roy reported receiving honoraria and consulting fees from Novartis, Biogen, Roche, and Scholar Rock for serving on boards of experts and giving lectures and expert testimony; travel paid by Novartis, Biogen, and Roche; and serving as principal investigator in therapeutic trials for Novartis, Biogen, and Roche. Mr Grimaldi reported receiving grants from Biogen, Novartis, and Roche for financial support to the Registre SMA France to his institution, Assistance Publique–Hôpitaux de Paris (AP-HP), during the conduct of the study. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. Kaplan-Meier Curves Showing Time to Initiation of Ventilatory and Nutritional Support After Treatment Initiation
The graphs show time in months between treatment initiation and support initiation for patients alive at the cutoff date or between treatment initiation and death for patients who died by the cutoff date. At each time point, the number at risk included patients alive without ventilation or nutrition support; patients who had not reached the time point were censored. B, Two patients who required feeding support shortly before initiating treatment (13 days before nusinersen and 8 days before gene therapy) were excluded from the analysis.
Figure 2.
Figure 2.. Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) Score Evolution Over Time Since Initiation and by Matched Pairs
The CHOP INTEND score ranges from 0 to 64, with higher scores indicating better function. B, The patients treated with nusinersen in pairs 2 and 9 and the patient treated with gene therapy in pair 10 died during the first year of treatment, explaining the truncated follow-up. DMT indicates disease-modifying treatment.
Figure 3.
Figure 3.. Kaplan-Meier Curves Showing Time to Achievement of Supported Sitting and Standing and Independent Sitting
No statistical comparison between groups was performed, and CIs were omitted due to the limited number of events and small sample size. At each time point, the number of events reflects the number of surviving patients who achieved the analyzed motor ability. A, One patient with spinal muscular atrophy type 1c (SMA1c) in the nusinersen group and 1 with SMA1c in the gene therapy group achieved this milestone 42 days and 36 days, respectively, before treatment initiation and were excluded from the Kaplan-Meier analysis to avoid potential immortal time bias and ensure comparability across treatment groups. B, One patient in the nusinersen group did not achieve the milestone; this patient lacked motor capacity at baseline, gained the ability to sit with support 18 months after nusinersen initiation, and showed no further motor progress during 5 years of follow-up.
See this image and copyright information in PMC

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