PharmacovigilanceOfficial

FDA probes tumour reports with Zolgensma, citing confirmed AAV vector insertional oncogenesis involving GLI1

🇺🇸 FDA CBER · Fri 06 Nov 2026

CBER is assessing whether regulatory action is needed after postmarketing malignancy reports, and says the neoplasia risk applies to both onasemnogene abeparvovec products, Zolgensma and Itvisma.

The US Food and Drug Administration has said it is investigating postmarketing reports of malignancies in patients given Zolgensma, the AAV vector-based gene therapy for spinal muscular atrophy (SMA). The agency's notice, dated 6 November 2026, refers to confirmed reports of product-related insertional oncogenesis involving the GLI1 gene, an oncogene that can contribute to cancer when overexpressed or abnormally activated.

The 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 promoter region of the onasemnogene abeparvovec construct inserted upstream of or within GLI1. The mechanism of GLI1 overexpression in the third case is still under investigation.

FDA also pointed to two published reports of AAV integration-driven oncogenesis in other programmes: a GLI1 integration event in the FBX-101 programme and a PLAG1 integration event in the RGX-111 programme, both published in the New England Journal of Medicine in 2026. The agency says it is closely monitoring the neoplasia risk in other similar AAV vector-based gene therapy programmes.

FDA has concluded that the risk applies to both Zolgensma, given intravenously to children under 2 years, and Itvisma, given intrathecally to patients aged 2 years and older, because the two products share the same vector and construct. No neoplasia cases have been reported after Itvisma, which was first approved on 24 November 2025. Zolgensma was first approved on 24 May 2019.

FDA states that the benefits of both products continue to 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 reviewing whether that wording and the long-term follow-up studies run by sponsor Novartis are adequate. Patients and trial participants should be monitored for tumour formation, and clinicians are asked to report tumours to Novartis Gene Therapies or to FDA.

What it means for your team

  • Expect possible labelling changes or modified long-term follow-up requirements; FDA has not yet announced any regulatory action.
  • Review intake, coding and follow-up of neoplasia reports for AAV gene therapies, including requests for tumour molecular analysis where cases are reported.
  • Check signal evaluation procedures for class-wide implications, as FDA is monitoring other AAV programmes with similar integration concerns.
  • Teams handling Zolgensma or Itvisma should confirm that tumour monitoring and reporting routes to Novartis and FDA MedWatch are clear.

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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