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TOPIC: FDA Investigating Serious Risk of Malignancy Linked to Zolgensma Gene Therapy: FDA Safety Communication
AUDIENCE: Patient, Health Care Professional, Medical Genetics, Pediatric, Neurology, Nephrology
ISSUE: The 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. 20261 and a PLAG1 integration event in the RGX-111 program (Ahrens-Nicklas et al. 20262).
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.
For more information about this alert, click on the red button "Read Alert" below.
BACKGROUND: Zolgensma is an adeno-associated virus (AAV) vector-based gene therapy, for spinal muscular atrophy (SMA).
RECOMMENDATIONS:
- If a tumor develops in a patient receiving ZOLGENSMA, or to report other suspected adverse reactions, healthcare providers should contact Novartis Gene Therapies, Inc. at 1-833-828-3947.
REFERENCES:
1 Vo JN, Wu YM, Heider A, Cao X, Wang R, Pham T, Teo GC, Magge SN, Parmar H, Mody R, Robinson DR, Chinnaiyan AM. Integration-Associated Paraspinal Neoplasm after AAV Gene Therapy. N Engl J Med. 2026 Oct 15;395(15):1555-1558. doi: 10.1056/NEJMc2607927. PMID: 42874111; PMCID: PMC13671263.
2 Ahrens-Nicklas RC, Kotch C, Roche AM, Everett JK, Reddy S, Santi M, Madsen PJ, Martos-Rus C, Yrigollen CM, Small JC, McCague S, Davidson BL, Samelson-Jones BJ, Surrey LF, Li M, Ficicioglu C, Wang R, Bushman FD, George LA. Neuroepithelial Tumor with AAV Integration after Intracisternal Magna Vector Delivery. N Engl J Med. 2026 Jun 4;394(21):2126-2133. doi: 10.1056/NEJMoa2601608. Epub 2026 May 13. PMID: 42127296.
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