The FDA is investigating postmarketing reports of malignancies in patients treated with Zolgensma, Novartis' adeno-associated virus (AAV) vector-based gene therapy for spinal muscular atrophy (SMA), including confirmed cases of product-related insertional oncogenesis.
According to the agency, reported tumors have occurred in the central and peripheral nervous systems, spinal and paraspinal regions, and kidney. Three cases involved tumors associated with the GLI1 oncogene. In two of those cases, molecular analysis of tumor tissue showed that Zolgensma vector DNA had integrated into the host genome, with the construct's promoter region inserted upstream of or within GLI1. The mechanism behind GLI1 overexpression in the third case remains under investigation.
FDA said the risk applies to both onasemnogene abeparvovec products, intravenous Zolgensma (approved in 2019 for patients under 2) and intrathecal Itvisma (approved in November 2025 for patients 2 and older), because they share the same vector and construct. No neoplasia cases have been reported with Itvisma to date. The agency also cited two published reports of AAV integration-driven tumors in other programs, FBX-101 and RGX-111, and said it is monitoring similar gene therapies.
Current prescribing information lists a "theoretical risk of tumorigenicity" from vector integration. FDA is evaluating whether that labeling and Novartis' long-term follow-up studies are adequate, and whether regulatory action is warranted. The agency said the products' benefits continue to outweigh their risks for approved uses, and that treated patients and trial participants should be monitored for tumor formation.
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