FDA investigates malignancy risk with SMA gene therapy Zolgensma

The FDA is investigating a serious risk of malignancy with onasemnogene abeparvovec (Zolgensma; Novartis), the one-time adeno-associated virus (AAV) vector-based gene therapy for spinal muscular atrophy (SMA), after postmarketing reports confirmed product-related insertional oncogenesis involving the GLI1 oncogene.¹ The agency said it is evaluating whether regulatory action is appropriate but maintained that the overall benefits of the therapy continue to outweigh its potential risks for its approved uses.¹

The November 6 safety communication followed a November 5 disclosure by Novartis that it had received 9 reports of tumors in treated patients since the therapy's 2019 approval.² “Patient safety is our priority,” the company said in a statement, adding that it had notified health authorities of each case.²

Zolgensma tumor reports and GLI1 insertional oncogenesis findings

Postmarketing reports describe tumors of the central and peripheral nervous systems, spinal and paraspinal regions, and kidney.¹ Three cases involved tumors associated with GLI1, an oncogene capable of driving cancer when overexpressed or abnormally activated.¹ In 2 of those cases, molecular analysis of tumor tissue showed the promoter region of the onasemnogene abeparvovec construct integrated upstream of or within GLI1; the mechanism of GLI1 overexpression in the third case remains under investigation.¹

Novartis has said more than 6000 patients have received the therapy across clinical trials, managed access programs, and commercial use.² Two earlier case reports, published in 2023 and 2025, also described tumors in Zolgensma-treated children.² The FDA communication did not report patient ages or the interval from infusion to tumor diagnosis.¹

Malignancy risk extends to intrathecal onasemnogene abeparvovec (Itvisma)

FDA determined that the neoplasia risk applies to both onasemnogene abeparvovec products because they contain the same vector and construct.¹ Zolgensma is an intravenous infusion indicated for children younger than 2 years with SMA, first approved May 24, 2019; Itvisma is an intrathecal injection approved November 24, 2025, for patients 2 years and older.¹ No cases of neoplasia have been reported after Itvisma administration to date.¹

AAV vector integration and tumors in other gene therapy programs

The agency also cited 2 published reports of AAV integration-driven tumors in other programs.¹ Vo et al described a paraspinal neoplasm found incidentally on surveillance MRI 26 months after FBX-101 gene therapy in a child with Krabbe disease, with tumor GLI1 overexpression tied to vector integration.³ The authors called for vector cassettes designed without splice donors, closer attention to vector purity, and extended genomic surveillance after AAV gene therapy.³

Ahrens-Nicklas et al reported a neuroepithelial tumor that developed roughly 4 years after intracisternal magna AAV9 delivery in a child with severe mucopolysaccharidosis type I, with vector elements integrated into the PLAG1 gene.⁴ FDA said it is closely monitoring neoplasia risk across similar AAV vector-based programs.¹

Zolgensma monitoring and reporting guidance for pediatricians

Current US prescribing information for both products lists a theoretical risk of tumorigenicity from vector integration under Warnings and Precautions.¹ FDA is expeditiously reviewing whether that labeling and Novartis' ongoing long-term follow-up studies adequately address the newly identified risk.¹ In the interim, the agency advises that patients and clinical trial participants who received these products be monitored for tumor formation.¹

Clinicians should report suspected tumors or other adverse reactions to Novartis Gene Therapies at 1-833-828-3947 or to FDA MedWatch at 1-800-FDA-1088.¹

Limitations and open questions on Zolgensma cancer risk

The findings come from spontaneous postmarketing reports, which cannot establish incidence, and causality has been confirmed in only 2 cases.¹ Novartis' count of 9 reports among more than 6000 treated patients does not account for underreporting or differences in follow-up duration.² FDA has not specified surveillance intervals or imaging modalities for treated patients, and whether risk varies by dose, route, or age at treatment has not been addressed.¹ Further guidance is likely as the agency completes its review.

References

1. US Food and Drug Administration. FDA investigating serious risk of malignancy linked to Zolgensma gene therapy. November 6, 2026. Accessed November 9, 2026. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/fda-investigating-serious-risk-malignancy-linked-zolgensma-gene-therapy

2. Novartis confirms more reported tumor cases in Zolgensma patients as SMA groups seek details. Fierce Pharma. November 2026. Accessed November 9, 2026. https://www.fiercepharma.com/pharma/novartis-confirms-more-reported-tumor-cases-zolgensma-patients-sma-groups-seek-details

3. Vo JN, Wu YM, Heider A, et al. Integration-associated paraspinal neoplasm after AAV gene therapy. N Engl J Med. 2026;395(15):1555-1558. doi:10.1056/NEJMc2607927

4. Ahrens-Nicklas RC, Kotch C, Roche AM, et al. Neuroepithelial tumor with AAV integration after intracisternal magna vector delivery. N Engl J Med. 2026;394(21):2126-2133. doi:10.1056/NEJMoa2601608