Other safety alerts
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| The United States: FDA Investigating Serious Risk of Malignancy Linked to Zolgensma Gene Therapy |
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The Food and Drug Administration (FDA) has received postmarketing adverse event reports of malignancies in patients treated with Zolgensma, an adeno-associated virus (AAV) vector-based gene therapy, for spinal muscular atrophy (SMA), including confirmed reports of product-related insertional oncogenesis involving the GLI1 (Glioma-Associated Oncogene Homolog 1) gene. GLI1 is an oncogene that has the potential to cause cancer when overexpressed or abnormally activated.
Postmarketing reports of tumor formation (neoplasia) include tumors of the central and peripheral nervous systems, spinal/paraspinal regions, and kidney. Importantly, three cases involved tumors associated with the GLI1 oncogene. In two of those cases, molecular analysis of tumor tissue demonstrated Zolgensma AAV vector DNA integration into the host genome, with the promoter region of the onasemnogene abeparvovec construct inserted upstream of or within the GLI1 oncogene. The mechanism of GLI1 overexpression in the third case remains under investigation. Additionally, FDA is aware of two published reports of AAV vector integration-driven oncogenesis in other programs: a GLI1 integration event in the FBX-101 program (Vo et al. 2026) and a PLAG1 integration event in the RGX-111 program (Ahrens-Nicklas et al. 2026).
FDA has determined that the risk of neoplasia, including malignancy, is applicable to both onasemnogene abeparvovec products, Zolgensma (administered via intravenous infusion; indicated for the treatment of pediatric patients less than 2 years of age with SMA) and Itvisma (administered via intrathecal injection; indicated for the treatment of SMA in adult and pediatric patients 2 years of age and older) as the two products contain the same vector and construct. FDA is closely monitoring the risk of neoplasia, including malignancy, in other similar AAV vector-based gene therapy programs. There have been no reported cases of neoplasia following Itvisma administration to date. Initial approval of Zolgensma was May 24, 2019; initial approval of Itvisma was November 24, 2025.
The overall benefits of Zolgensma and Itvisma continue to outweigh their potential risks for their approved uses, though FDA is investigating the identified risk of neoplasia, including malignancy, with serious outcomes, and is evaluating whether regulatory action is appropriate.
The current U.S. prescribing information for Zolgensma and Itvisma indicates that there is a “theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome” under Warnings and Precautions. Novartis, the sponsor, is conducting long-term follow-up safety studies. FDA is expeditiously evaluating the adequacy of the current prescribing information and long-term follow-up studies to investigate and mitigate the serious risk of neoplasia based on the new safety information for product-related insertional oncogenesis for Zolgensma. Patients and clinical trial participants receiving treatment with these products should be monitored for tumor formation.
Please refer to the following website in FDA for details:
http://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-malignancy-linked-zolgensma-gene-therapy
In Hong Kong, there is one registered pharmaceutical product containing onasemnogene abeparvovec, namely Zolgensma Solution For Infusion 2 X 10^13 Vector Genomes/ml (HK-67654). The product is registered by Novartis Pharmaceuticals (HK) Limited, and is a prescription-only medicine. So far, the Department of Health (DH) has not received any case of adverse drug reaction related to onasemnogene abeparvovec. The registered package insert for Zolgensma Solution For Infusion 2 X 10^13 Vector Genomes/ml (HK-67654) has indicated that there is a “theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome” under Special Warnings and Precautions for Use. DH will remain vigilant on any further safety update of the drugs issued by the FDA and other drug regulatory authorities.
Ends/ Saturday, November 7, 2026
Issued at HKT 12:00
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