Intrathecal Onasemnogene Abeparvovec for Sitting, Nonambulatory Patients with Spinal Muscular Atrophy: Phase I Ascending-Dose Study (STRONG)

Richard S. Finkel, Basil T. Darras, Jerry R. Mendell, John W. Day, Nancy L. Kuntz, Anne M. Connolly, Craig M. Zaidman, Thomas O. Crawford, Russell J. Butterfield, Perry B. Shieh, Gihan Tennekoon, John F. Brandsema, Susan T. Iannaccone, John Shoffner, Sarah Kavanagh, Thomas A. Macek, Sitra Tauscher-Wisniewski

Research output: Contribution to journalArticlepeer-review


BACKGROUND: Spinal muscular atrophy (SMA) is a neuromuscular disorder arising from biallelic non-functional survival motor neuron 1 (SMN1) genes with variable copies of partially functional SMN2 gene. Intrathecal onasemnogene abeparvovec administration, at fixed, low doses, may enable treatment of heavier patients ineligible for weight-based intravenous dosing. OBJECTIVE: STRONG (NCT03381729) assessed the safety/tolerability and efficacy of intrathecal onasemnogene abeparvovec for sitting, nonambulatory SMA patients. METHODS: Sitting, nonambulatory SMA patients (biallelic SMN1 loss, three SMN2 copies, aged 6-<60 months) received a single dose of intrathecal onasemnogene abeparvovec. Patients were enrolled sequentially into one of three (low, medium, and high) dose cohorts and stratified into two groups by age at dosing: younger (6-<24 months) and older (24-<60 months). Primary endpoints included safety/tolerability, independent standing ≥3 seconds (younger group), and change in Hammersmith Functional Motor Scale Expanded (HFMSE) from baseline (older group) compared with historic controls. RESULTS: Thirty-two patients were enrolled and completed the study (medium dose, n = 25). All patients had one or more treatment-emergent adverse events, with one serious and related to treatment (transaminase elevations). No deaths were reported. One of 13 patients (7.7%) in the younger group treated with the medium dose achieved independent standing. At Month 12 for the older group receiving the medium dose, change from baseline in HFMSE was significantly improved compared with the SMA historic control population (P < 0.01). CONCLUSIONS: Intrathecal onasemnogene abeparvovec was safe and well-tolerated. Older patients treated with the medium dose demonstrated increases in HFMSE score greater than commonly observed in natural history.

Original languageEnglish (US)
Pages (from-to)389-404
Number of pages16
JournalJournal of neuromuscular diseases
Issue number3
StatePublished - 2023


  • Adeno-associated virus
  • Hammersmith Functional Motor Scale Expanded
  • clinical trial
  • gene therapy
  • intrathecal administration
  • motor milestones
  • neurodegenerative disorders
  • onasemnogene abeparvovec
  • spinal muscular atrophy
  • vector genomes

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology


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