Long-Term Data Reinforces Safety of Gene Therapy Zolgensma for Spinal Muscular Atrophy

Richard Finkel, MD

(Credit: St. Jude Children’s Research Hospital)

A long-term analysis from the global RESTORE registry (NCT04174157) provided real-world evidence supporting the safety of onasemnogene abeparvovec (Zolgensma; Novartis), a 1-time survival motor neuron gene replacement therapy, in patients with spinal muscular atrophy (SMA). The findings, based on up to 5 years of follow-up, aligned with previously reported clinical trial data, showing no unexpected safety concerns or late-onset toxicities.¹

The RESTORE registry, an ongoing noninterventional study initiated in 2018, evaluated long-term outcomes of SMA treatments, including onasemnogene abeparvovec. The latest analysis, Presented at the 2025 Muscular Dystrophy Association (MDA) Clinical & Scientific Conference, held March 16-19 in Dallas, Texas, included 140 patients with a median follow-up of nearly 34 months, assessing adverse events (AEs) and AEs of special interest (AESI) from treatment initiation.

Liver enzyme elevations were among the most commonly observed AEs, with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) increases reported in 29% and 25% of patients, respectively. Other frequent AEs included pyrexia (27%) and vomiting (24%). Serious AEs occurred in 41% of patients, though none led to changes in the therapy’s safety classification.

Among AESI, hepatotoxicity was the most prevalent (43%), primarily manifesting as isolated AST/ALT elevations without clinical symptoms. Thrombocytopenia (21%) and cardiac events (18%)—mainly elevated troponin I—were also documented, with all cases resolving without associated symptoms. Three patients (2%) developed thrombotic microangiopathy, and no instances of dorsal root ganglia toxicity were reported. One case of malignant spinal cord neoplasm was recorded but deemed unrelated to onasemnogene abeparvovec.²

Crucially, most AESI emerged in 3 months post-treatment, with no new late-onset safety concerns identified across the 5-year follow-up period. Led by Richard Finkel, MD, director of the Center for Experimental Neurotherapeutics at St. Jude Children’s Research Hospital, these findings reinforced the durability of onasemnogene abeparvovec’s safety profile and provide clinicians with valuable real-world insights into its long-term tolerability.

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Building on the long-term safety findings of onasemnogene abeparvovec, new research also presented at MDA 2025 underscored the evolving treatment landscape for SMA, particularly in infants with severe phenotypes. A case series, presented by lead author Julia Bassell-Hawkins, MD, PGY-4 Child Neurology at Stanford Medicine, suggested that despite early gene therapy, some patients may benefit from additional disease-modifying therapies (DMTs) to optimize motor function outcomes.³

The study examined 8 infants with genetically confirmed SMA type 1 (0 copies of SMN1, 2 copies of SMN2) who received onasemnogene abeparvovec in the first 2 months of life after being identified through newborn screening. The average age at gene therapy was 3.75 weeks, with 3 patients receiving risdiplam (Evrysdi; Genentech) as a bridging therapy prior to infusion. Over time, all patients required additional DMT—6 received risdiplam, 1 was treated with nusinersen (Spinraza; Biogen), and another switched from nusinersen to risdiplam.

Despite early intervention with onasemnogene abeparvovec, motor neuron symptoms still progressed in this high-risk population, reinforcing the need for a combination approach in select cases. Notably, all patients showed improvements after the addition of a second therapy, suggesting a potential benefit of early combination treatment.

These findings highlight an emerging challenge in SMA management: determining the optimal timing and necessity of supplemental DMTs following gene therapy. Although onasemnogene abeparvovec remains a cornerstone treatment, this real-world data suggested that combination strategies may be necessary for infants with severe disease phenotypes. Further research and clinical guidelines may be needed to define best practices for integrating multiple therapies in the evolving SMA treatment paradigm.

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REFERENCES
1. Finkel R, Alecu I, Lopez-Leon S, et al. Long-term Safety of Onasemnogene Abeparvovec for Patients with Spinal Muscular Atrophy: Real-world Findings from the RESTORE Registry. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. Abstract P280
2. Retson L, Tiwari N, Vaughn J, et al. Epithelioid neoplasm of the spinal cord in a child with spinal muscular atrophy treated with onasemnogene abeparvovec. Mol Ther. 2023;31(10):2991-2998. doi:10.1016/j.ymthe.2023.08.013
3. Bassell-Hawkins J, Rocha CT, Piccoli C. Outcomes and need for supplemental therapy after gene therapy in patients with spinal muscular atrophy type 1 identified by newborn screen. Presented at: 2025 MDA Clinical & Scientific Conference; March 16-19. Dallas, TX. Abstract P390