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Cited by 295Neurogenetic and Muscular Disorders ResearchVirus-based gene therapy researchLysosomal Storage Disorders Research

The DOI matches its Crossref record; 23 of the 26 references it cites were found in a registry or an index.

Five-Year Extension Results of the Phase 1 START Trial of Onasemnogene Abeparvovec in Spinal Muscular Atrophy

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Mendell, Jerry R., Al-Zaidy, Samiah A., Lehman, Kelly J., McColly, Markus, Lowes, Linda P., Alfano, Lindsay N., Reash, Natalie F., Iammarino, Megan A., Church, Kathleen R., Kleyn, Aaron, Meriggioli, Matthew N., Shell, Richard·2021·JAMA Neurology
DOI 10.1001/jamaneurol.2021.1272PMC PMC8129901
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Abstract

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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Crossref · 10.1001/jamaneurol.2021.1272

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Figures

Figure 1. Disposition of Patients in the START LTFU Study aNo patient was treated with concomitant nusinersen during the START phase 1 trial. bTwo patients who did not enroll in the START long-term follow-up study are being followed up at the Nationwide Children’s Hospital Spinal Muscular Atrophy Clinic in Columbus, Ohio. Note that no visits were conducted in the START LTFU clinical trial from December 31, 2019, through June 11, 2020.
Figure 1. Disposition of Patients in the START LTFU Study aNo patient was treated with concomitant nusinersen during the START phase 1 trial. bTwo patients who did not enroll in the START long-term follow-up study are being followed up at the Nationwide Children’s Hospital Spinal Muscular Atrophy Clinic in Columbus, Ohio. Note that no visits were conducted in the START LTFU clinical trial from December 31, 2019, through June 11, 2020.CC BY-NC-ND · PubMed Central
Figure 2. Greatest Development Milestones Achieved During the START Long-term Follow-up Study Milestones are shown for the 10 patients in the therapeutic-dose cohort who received dosing early and had low baseline motor function (blue quadrant), those who received dosing early and had high motor function (orange quadrant), and those who received dosing late (gray quadrant). Values in parentheses are the age at which the milestone was achieved (in months). Patients were grouped according to baseline motor function (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores <20 points [low] or ≥20 points [high]) and age at dosing (<3 months [early] or ≥3 months [late]).5 This figure was adapted with author permission from Lowes LP et al.15
Figure 2. Greatest Development Milestones Achieved During the START Long-term Follow-up Study Milestones are shown for the 10 patients in the therapeutic-dose cohort who received dosing early and had low baseline motor function (blue quadrant), those who received dosing early and had high motor function (orange quadrant), and those who received dosing late (gray quadrant). Values in parentheses are the age at which the milestone was achieved (in months). Patients were grouped according to baseline motor function (Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders scores <20 points [low] or ≥20 points [high]) and age at dosing (<3 months [early] or ≥3 months [late]).5 This figure was adapted with author permission from Lowes LP et al.15CC BY-NC-ND · PubMed Central

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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)
DOI
10.1001/jamaneurol.2021.1272
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
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 (clinical) › Neurogenetic and Muscular Disorders Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Genetics (clinical) › 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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