PharmacovigilanceOfficial

FDA probes insertional oncogenesis risk with Zolgensma after confirmed GLI1-linked tumour cases

🇺🇸 FDA CBER · Mon 09 Nov 2026

FDA CBER says postmarketing reports include tumours with vector integration near the GLI1 oncogene, and it is weighing regulatory action on Zolgensma and Itvisma.

The US Food and Drug Administration has issued a safety communication on a serious risk of neoplasia, including malignancy, with Novartis's AAV-based gene therapy Zolgensma (onasemnogene abeparvovec) for spinal muscular atrophy. The agency cites postmarketing reports, including confirmed cases of product-related insertional oncogenesis involving the GLI1 gene.

Reported tumours affect the central and peripheral nervous systems, the spinal and paraspinal regions, and the kidney. Three cases involved GLI1-associated tumours. In two, molecular analysis of tumour tissue showed Zolgensma vector DNA integrated into the host genome, with the construct's promoter region inserted upstream of or within GLI1. The mechanism of GLI1 overexpression in the third case is still under investigation. FDA also points to two published reports of AAV integration-driven oncogenesis in other programmes: a GLI1 event in the FBX-101 programme and a PLAG1 event in the RGX-111 programme, both in the New England Journal of Medicine in 2026.

FDA has concluded that the neoplasia risk applies to both onasemnogene abeparvovec products, because they share the same vector and construct. Zolgensma is given intravenously to patients under two years old; Itvisma, approved on 24 November 2025, is given intrathecally to patients aged two and over. No neoplasia cases have been reported after Itvisma to date. The agency is also monitoring similar AAV vector-based programmes.

FDA says the benefits of both products still outweigh their risks for approved uses, but it is evaluating whether regulatory action is appropriate. Current US labelling lists a "theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome" under Warnings and Precautions. FDA is expeditiously assessing whether the prescribing information and Novartis's long-term follow-up studies are adequate. Patients and trial participants should be monitored for tumour formation, and clinicians are asked to report tumours or other suspected adverse reactions to Novartis Gene Therapies on 1-833-828-3947.

What it means for your team

  • Labelling changes, such as a move from "theoretical" to confirmed risk language, and revised follow-up requirements are under evaluation. Regulatory teams should track the FDA communication for updates.
  • PV teams should check case-processing and signal-detection workflows for neoplasia reports in AAV gene therapy recipients, including molecular and integration-site data where available.
  • Sponsors of other AAV vector programmes should note that FDA says it is closely monitoring the class for integration-related neoplasia, and should review their own long-term follow-up and risk-minimisation plans.

Official source: FDA CBER ↗

Article written by VigiEye from the official source (FDA CBER). AI-assisted; check the source before acting.

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