Motor gains achieved by 83% of paediatric SMA patients treated with onasemnogene abeparvovec

The phase 3b SMART study has shown that 83% of paediatric patients with spinal muscular atrophy (SMA) weighing between 8.5 and 21 kg achieved significant motor improvements following treatment with intravenous onasemnogene abeparvovec in a recent article published in Neurology.¹ SMA, specifically 5q-SMA, is a genetic neuromuscular disorder caused by mutations in both copies of the SMN1 gene, leading to reduced production of survival motor neuron (SMN) protein, which is essential for motor neuron survival.² Onasemnogene abeparvovec, a gene therapy that targets the underlying cause of SMA, has already demonstrated its efficacy and safety in five clinical trials involving patients with SMA type 1^3–6 or presymptomatic SMA with 2⁷ or 3⁸ SMN2 gene copies. However, this new research marks the first trial to extend its evaluation to a broader weight range, addressing a critical evidence gap for heavier SMA patients who had previously been excluded from trials focusing on those under 8.5 kg.

Conducted across 13 international sites, the study assessed 24 symptomatic children with SMA, including those who had been previously treated with disease-modifying therapies. Participants were stratified into three weight categories and received a single infusion of onasemnogene abeparvovec, followed by 52 weeks of monitoring. While the primary objective was to evaluate safety, secondary outcomes focused on motor function and developmental milestones.

All participants experienced at least one treatment-related adverse event, but most were mild or moderate. Serious treatment-related adverse events, including transient thrombocytopenia, were reported in 29% of patients, yet no cases of symptomatic hepatotoxicity or severe liver dysfunction occurred. Elevated liver enzyme levels were observed in 83% of participants but were effectively managed with corticosteroids, which were required for longer durations in heavier patients. Importantly, no patients met Hy’s law criteria for drug-induced liver injury.

Motor outcomes reinforced the treatment’s clinical benefits. At the end of the study, 61% of participants achieved a clinically significant improvement in their Hammersmith Functional Motor Scale–Expanded (HFMSE) scores, and 83% maintained or improved their motor milestones. Notably, some children achieved new developmental milestones, such as standing or walking with assistance.

The study also confirmed the safety profile of onasemnogene abeparvovec for this diverse patient population. While heavier patients experienced higher rates of aminotransferase elevations and required prolonged corticosteroid use, all adverse events were manageable with appropriate interventions. These findings underscore the importance of personalised corticosteroid regimens to mitigate immune responses to treatment in larger patients.

The SMART study offers new hope for families of children with SMA by demonstrating that onasemnogene abeparvovec can maintain or improve motor function in heavier and older patients. While further research is needed to address limitations such as the lack of a comparator group and small sample sizes, this study represents a significant step forward in the management of SMA, expanding access to effective treatment across a broader spectrum of patients.

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References:

1. McMillan HJ, Baranello G, Farrar MA, et al. Safety and Efficacy of IV Onasemnogene Abeparvovec for Pediatric Patients With Spinal Muscular Atrophy. Neurology. 2025:104. DOI: https://doi.org/10.1212/WNL.0000000000210268
2. Day JW, Howell K, Place A. et al. Advances and limitations for the treatment of spinal muscular atrophy. BMC Pediatr. 2022;22:632. DOI: https://doi.org/10.1186/s12887-022-03671-x.
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Disclosures: This article was created by the touchNEUROLOGY team utilizing AI as an editorial tool (ChatGPT (GPT-4o) [Large language model]. https://chat.openai.com/chat.) The content was developed and edited by human editors. No funding was received in the publication of this article.