The FDA is investigating postmarket reports of malignancies in patients treated with Novartis’ gene therapy Zolgensma for spinal muscular atrophy, including confirmed cases of product-related insertional oncogenesis, according to a Nov. 6 agency safety communication. The agency said it is evaluating whether regulatory action is appropriate.
The reports include tumors of the central and peripheral nervous systems, spinal and paraspinal regions and kidney, the FDA said. Three cases involved tumors associated with the GLI1 oncogene. In two of them, tumor analysis showed Zolgensma’s viral vector DNA had integrated into the patient’s genome, with the promoter of the gene therapy’s construct inserted upstream of or within the GLI1 gene. The mechanism of GLI1 overexpression in the third case remains under investigation. The FDA also cited two published reports of similar vector integration events in other gene therapy programs, one involving GLI1 and one involving PLAG1, both in the New England Journal of Medicine.
The agency determined that the risk applies to both onasemnogene abeparvovec products: Zolgensma, an intravenous infusion for children younger than 2, and Itvisma, an intrathecal injection for patients 2 and older, because they contain the same vector and construct. There have been no reported cases of neoplasia after Itvisma to date, the FDA said. Zolgensma was approved in May 2019 and Itvisma in November 2025.
The FDA said the overall benefits of both products continue to outweigh their potential risks for approved uses. The current prescribing information lists a “theoretical risk of tumorigenicity” under warnings and precautions, and the agency said it is evaluating whether the label and Novartis’ long-term follow-up studies are adequate. Patients and trial participants receiving the products should be monitored for tumor formation, the FDA said.
Itvisma was approved last November as the first intrathecal gene therapy for SMA, and gene therapy safety has been in focus since the FDA investigated a boy’s death after Sarepta’s Elevidys in 2025.
