Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy
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Importance: This ongoing study assesses long-term safety and durability of response in infants with spinal muscular atrophy (SMA) type 1 after dosing with onasemnogene abeparvovec gene replacement therapy. Objective: The primary objective of this ongoing study is to assess safety. The secondary objective is to determine whether developmental milestones achieved in the START phase 1 clinical trial were maintained and new milestones gained. Design, Setting, and Participants: This study is an ongoing, observational, follow-up study for continuous safety monitoring for 15 years in patients from the START phase I study (conducted May 5, 2014, through December 15, 2017) at Nationwide Children's Hospital in Columbus, Ohio. Participants were symptomatic infants with SMA type 1 and 2 copies of SMN2 previously treated with an intravenous dose of onasemnogene abeparvovec (low dose, 6.7 × 1013 vg/kg; or therapeutic dose, 1.1 × 1014 vg/kg) in START. Thirteen of 15 original START patients are included in this analysis; 2 patients' families declined follow-up participation. Data were analyzed from September 21, 2017, to June 11, 2020. Exposures: Median time since dosing of 5.2 (range, 4.6-6.2) years; 5.9 (range, 5.8-6.2) years in the low-dose cohort and 4.8 (range, 4.6-5.6) years in the therapeutic-dose cohort. Main Outcomes and Measures: The primary outcome measure was the incidence of serious adverse events (SAEs). Results: At data cutoff on June 11, 2020, 13 patients treated in START were enrolled in this study (median age, 38.9 [range, 25.4-48.0] months; 7 females; low-dose cohort, n = 3; and therapeutic-dose cohort, n = 10). Serious adverse events occurred in 8 patients (62%), none of which resulted in study discontinuation or death. The most frequently reported SAEs were acute respiratory failure (n = 4 [31%]), pneumonia (n = 4 [31%]), dehydration (n = 3 [23%]), respiratory distress (n = 2 [15%]), and bronchiolitis (n = 2 [15%]). All 10 patients in the therapeutic-dose cohort remained alive and without the need for permanent ventilation. Prior to baseline, 4 patients (40%) in the therapeutic-dose cohort required noninvasive ventilatory support, and 6 patients (60%) did not require regular ventilatory support, which did not change in long-term follow-up. All 10 patients treated with the therapeutic dose maintained previously acquired motor milestones. Two patients attained the new milestone of "standing with assistance" without the use of nusinersen. Conclusions and Relevance: The findings of this ongoing clinical follow-up of patients with SMA type 1 treated with onasemnogene abeparvovec supports the long-term favorable safety profile up to 6 years of age and provides evidence for sustained clinical durability of the therapeutic dose. Trial Registration: ClinicalTrials.gov Identifier: NCT03421977.
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A follow-up safety study revealed a favorable safety profile of Zolgensma following 6.2 years from dosing and provided evidence of sustained clinical durability.
“Additionally, a follow-up safety study has revealed a favorable safety profile of the therapy following 6.2 years from dosing, as well as providing evidence of sustained clinical durability [92].”
From Circumventing the packaging limit of AAV-mediated gene replacement therapy for neurological disorders (2022) · cites this paper as [92]
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Spinal Muscular Atrophy Update in Best Practices
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The 2021 yearbook of Neurorestoratology
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Advances and Challenges in Gene Therapy for Neurodegenerative Diseases: A Systematic Review
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Identifying Biomarkers of Spinal Muscular Atrophy for Further Development
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Impaired Neurodevelopment in Children with 5q-SMA - 2 Years After Newborn Screening
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Peeling back the layers of immunogenicity in Cas9-based genomic medicine
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Adeno-associated virus therapies: Pioneering solutions for human genetic diseases
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Taldefgrobep Alfa and the Phase 3 RESILIENT Trial in Spinal Muscular Atrophy
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Development of AAV-Mediated Gene Therapy Approaches to Treat Skeletal Diseases
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Onasemnogene Abeparvovec in Type 1 Spinal Muscular Atrophy: A Systematic Review and Meta-Analysis
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Continued safety and long-term effectiveness of onasemnogene abeparvovec in Ohio
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Experience and Perspectives in the US on the Evolving Treatment Landscape in Spinal Muscular Atrophy
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Progress in spinal muscular atrophy research
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An Overview of the Therapeutic Strategies for the Treatment of Spinal Muscular Atrophy
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Spinal astrocyte dysfunction drives motor neuron loss in late-onset spinal muscular atrophy
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Gene Therapy for Rare Neurological Disorders
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- Authors
- Mendell, J. R., Al-Zaidy, S. A., Lehman, K. J., McColly, M., Lowes, L. P., Alfano, L. N., Reash, N. F., Iammarino, M. A., Church, K. R., Kleyn, A., Meriggioli, M. N., & Shell, R.
- Affiliations
- Nationwide Children's Hospital (US)
- Al-Zaidy and Associates, LLC, Columbus, Ohio
- Novartis Gene Therapies, Inc. (United States) (GB)
- Corresponding author
- Mendell, Jerry R.
- ORCID
- Venue
- JAMA Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2021-07-01
- Volume
- 78
- Issue
- 7
- Pages
- 834
- ISSN
- 2168-6149 (ISSN-L)
- PMC
- PMC8129901
- OpenAlex
- W3160334825
- Cited by
- 295
- References
- 26
- Citations by year
- 2026: 42 · 2025: 51 · 2024: 74 · 2023: 54 · 2022: 53 · 2021: 19
- FWCI
- 28.08
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- Locations
- JAMA Neurology (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Genetics › Neurogenetic and Muscular Disorders Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Health Sciences › Medicine › Physiology › Lysosomal Storage Disorders Research
- Keywords
- onasemnogene abeparvovec, spinal muscular atrophy type 1, gene replacement therapy, START trial, long-term safety, serious adverse events, acute respiratory failure, pneumonia, developmental milestones, infants, durability of response, respiratory syncytial virus infection, influenza
- MeSH terms
- Biological Products, Child, Child, Preschool, Female, Follow-Up Studies, Humans, Male, Recombinant Fusion Proteins, Spinal Muscular Atrophies of Childhood, Genetic Therapy, Treatment Outcome
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