Background And Objectives: Safety and efficacy of IV onasemnogene abeparvovec has been demonstrated for patients with spinal muscular atrophy (SMA) weighing <8.5 kg. SMART was the first clinical trial to evaluate onasemnogene abeparvovec for participants weighing 8.5-21 kg.
Methods: SMART was an open-label, multicenter, phase 3b study conducted across 13 sites in 9 countries (NCT04851873). Symptomatic pediatric participants with SMA (any type; treatment-naïve or had discontinued prior treatment) were stratified into 3 weight cohorts (≥8.5-13, >13-17, and >17-21 kg), administered onasemnogene abeparvovec, and followed for 52 weeks. Corticosteroids were initiated 24 hours before infusion with dose increases in response to adverse events (AEs) and subsequent tapering at investigator discretion. The primary objective was safety. Secondary objective was efficacy (motor function/motor milestones).
Results: Twenty-four participants were enrolled; the majority had SMA type 2 (n = 11), 3 copies (n = 18), and prior treatment (n = 21). All participants completed the study; no deaths occurred. All participants had ≥1 treatment-related AE(s), 7 of 24 (29%) had serious treatment-related AEs, and 23 of 24 (96%) had ≥1 AE of special interest. Twenty of 24 participants (83%) had asymptomatic hepatotoxicity events, which were primarily transaminase elevations. No participant had bilirubin elevations >2× upper limit of normal, developed symptomatic hepatotoxicity, or met Hy law criteria. Transient asymptomatic thrombocytopenia events were reported in 17 of 24 participants (71%); all resolved spontaneously with no related bleeding events reported. Three of 24 participants (13%) had cardiac AEs (all unrelated to treatment). No thrombotic microangiopathy or dorsal root ganglionopathy-related AEs were reported. AE frequency and severity were similar across weight groups, although corticosteroid exposure was greater for the 2 heavier cohorts (median 135.0, 201.0, and 194.0 days, respectively) with 37% and 33% still on corticosteroids at the study end. By week 52, most participants maintained or improved motor function (Hammersmith Functional Motor Scale-Expanded 16/18; Revised Upper Limb Module 15/17); 4 participants (all 3 copies) achieved new motor milestones.
Discussion: Onasemnogene abeparvovec safety profile was similar across weight groups in this heterogenous participant population. Frequency and duration of asymptomatic aminotransferase elevations and thrombocytopenia are notable findings. Most participants demonstrated maintenance or improvement of motor function, suggesting clinical benefit for patients with SMA weighing up to 21 kg.
Trial Registration Information: ClinicalTrials.gov identifier (NCT04851873, clinicaltrials.gov/study/NCT04851873) submitted April 19, 2021. First participant enrolled on September 8, 2021.
Classification Of Evidence: This study provides Class IV evidence that intravenous onasemnogene abeparvovec is safe in pediatric patients with SMA who weigh 8.5-21 kg.
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http://dx.doi.org/10.1212/WNL.0000000000210268 | DOI Listing |
Neurology
January 2025
The Dubowitz Neuromuscular Centre, Developmental Neurosciences Department, University College London, Great Ormond Street Institute of Child Health, United Kingdom.
Background And Objectives: Safety and efficacy of IV onasemnogene abeparvovec has been demonstrated for patients with spinal muscular atrophy (SMA) weighing <8.5 kg. SMART was the first clinical trial to evaluate onasemnogene abeparvovec for participants weighing 8.
View Article and Find Full Text PDFGene Ther
January 2025
Departments of Pediatrics and Neurology, Emory University, Atlanta, 30322, Georgia.
Spinal muscular atrophy (SMA) is a progressive disease that affects motor neurons, with symptoms usually starting in infancy or early childhood. Recent breakthroughs in treatments targeting SMA have improved both lifespan and quality of life for infants and children with the disease. Given the impact of these treatments, it is essential to develop methods for managing treatment-induced changes in disease characteristics.
View Article and Find Full Text PDFTrends Mol Med
January 2025
MDUK Oxford Neuromuscular Centre, Department of Paediatrics, University of Oxford, Oxford, OX3 9DU, UK; NIHR Oxford Biomedical Research Centre, Oxford, OX3 9DU, UK; Neuromuscular Centre, Division of Paediatrics, University Hospital of Liège and University of Liège, 4000, Liège, Belgium. Electronic address:
Spinal muscular atrophy (SMA) is a devastating, degenerative, paediatric neuromuscular disease which until recently was untreatable. Discovery of the responsible gene 30 years ago heralded a new age of pioneering therapeutic developments. Three disease-modifying therapies (DMTs) have received regulatory approval and have transformed the disease, reducing disability and prolonging patient survival.
View Article and Find Full Text PDFValue Health
December 2024
CHOICE Institute, School of Pharmacy, University of Washington, Seattle, WA, USA.
Objective: Recent scientific breakthroughs have propelled the development of disease-modifying and potentially curative cell and gene therapies (CGTs) for rare diseases, including those diseases previously considered untreatable. However, the unique characteristics of CGTs pose challenges for the traditional methods of therapy value determination, reimbursement, and outcome evaluation used by regulatory and assessment agencies for product approval and market access. Notably, CGTs are one-time or short-course treatments, often first-in-class (precluding direct comparisons with effective alternatives), and have health benefits that are largely realized over time.
View Article and Find Full Text PDFEur Spine J
December 2024
Center for Musculoskeletal Surgery (CMSC), Charité Universitätsmedizin, Campus Mitte Charitéplatz 1, Berlin, Germany.
Purpose: 5q-spinal muscular atrophy (SMA) is a treatable neuromuscular disorder associated with scoliosis in up to 90% of patients. New SMA therapies could mark a paradigm shift in scoliosis management, but their effects on scoliosis development remain unclear. This study aims to observe scoliosis progression in the current treatment landscape to inform management strategies.
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