Safety and Efficacy of Onasemnogene Abeparvovec in Pediatric SMA Across Expanded Weight Cohorts

The SMART trial provides important new data on intravenous onasemnogene abeparvovec—a gene replacement therapy for spinal muscular atrophy (SMA)—in children weighing 8.5–21 kg, a population that has been largely absent from earlier pivotal studies that focused on lighter, treatment-naïve patients (<8.5 kg). This broader weight range included many older children, some with prior exposure to other disease-modifying therapies, such as nusinersen or risdiplam.

Conducted as a phase 3b, single-arm, open-label, multinational study across 13 sites in 9 countries, SMART enrolled 24 participants with SMA types 1–3, most of whom had SMA type 2 (46 percent), three SMN2 gene copies (75 percent), and previous treatment exposure (88 percent).

Participants were divided into three weight cohorts (≥8.5–13 kg, >13–17 kg, and >17–21 kg) and received a one-time IV infusion of onasemnogene abeparvovec at 1.1 × 10¹⁴ vector genomes/kg. All began prednisolone prophylaxis 24 hours before infusion, tapered according to liver enzyme trends, and were followed for 52 weeks.

The trial’s primary endpoint assessed safety, including treatment-emergent adverse events, serious adverse events, and adverse events of special interest. Secondary endpoints evaluated changes in motor function and the achievement or maintenance of developmental milestones.

Safety Signals

Every participant experienced treatment-related adverse events, and nearly all (96 percent) had at least one adverse event of special interest:

• Hepatotoxicity: Seen in 83 percent, usually as asymptomatic transaminase elevations.
• 88 percent had ALT/AST >3× ULN; 58 percent exceeded 10× ULN; 21 percent exceeded 20× ULN.
• No cases met Hy’s law criteria or had symptomatic liver injury.
• Peak elevations often occurred in weeks 1–10, with 67 percent still mildly elevated at study end.
• Thrombocytopenia: Occurred in 71 percent, all asymptomatic, resolving without intervention.
• Cardiac events: Mild and rare (13 percent), all unrelated to treatment.

A key takeaway was heavier patients required longer corticosteroid courses (median 135–201 days versus 135 days in the lightest group), sometimes extending past the 1-year mark. About one-third of patients in the two heaviest groups were still on steroids at week 52. Corticosteroid-related side effects, including Cushingoid features, resolved by study end.

Motor Function: Gains and Stability Across Groups

Despite the heterogeneity of the cohort, motor outcomes were largely positive:

• HFMSE (n=20):
• Median gain: +4 points at weeks 26 and 52.
• 61 percent achieved ≥3-point gain; 44 percent ≥6 points; 11 percent ≥10 points.
• RULM (n=18):
• Median gain: +2 points at both 26 and 52 weeks.
• 41 percent achieved ≥3-point gain.
• Milestones: Most children maintained their baseline abilities; four achieved new milestones, such as standing or walking with assistance. Three participants lost a previously demonstrated skill, underscoring the variability in functional trajectories for older SMA patients.

Conclusion

The SMART study expands the evidence base for onasemnogene abeparvovec, showing that children up to 21 kg can safely receive the therapy with careful monitoring. While the incidence of asymptomatic hepatotoxicity and thrombocytopenia was high, these events were manageable and resolved without long-term sequelae.

Most importantly, motor stability or improvement was the norm—even in a diverse, older, and pretreated cohort—reinforcing the therapy’s role beyond the narrow confines of early-intervention SMA care.

Reference

McMillan HJ, Baranello G, Farrar MA, et al. Safety and Efficacy of IV Onasemnogene Abeparvovec for Pediatric Patients With Spinal Muscular Atrophy: The Phase 3b SMART Study. Neurology. 2025;104(2):e210268. doi:10.1212/WNL.0000000000210268