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FDA Investigates Tumor Risk After Novartis Zolgensma Gene Therapy
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FDA investigating risk of neoplasia linked to Zolgensma in children under two. Novartis reports nine tumor notifications since approval; two cases possible link to therapy.
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FDA opens probe
The US Food and Drug Administration said on Friday it was investigating a risk of neoplasia, or tumour formation including malignancy, associated with Novartis’ gene therapy Zolgensma. Novartis disclosed two cases in which tumours in children showed evidence of being linked to its gene therapy drug used to treat patients less than 2 years old with spinal muscular atrophy. Novartis said it had received nine reports overall of tumours in patients previously treated with Zolgensma since the therapy was first approved in 2019, and the FDA said the overall benefits of both Zolgensma and Itvisma continue to outweigh their potential risks for their approved uses.
The FDA said it was evaluating whether regulatory action was appropriate in light of the risk, and the agency said there have been no reported cases of neoplasia following administration of Novartis’ Itvisma, which was approved last year to treat patients with a rare muscle disorder. The Swiss drugmaker said in two of the cases doctors found evidence that the carrier used in the treatment had inserted its genetic material into the patients’ own DNA, pointing to a possible link between tumours and a one-time therapy that Novartis confirmed had been given to more than 6,000 children.
What Novartis and FDA say
Novartis said it had received nine tumor notifications since Zolgensma was approved in 2019, and the company said two of the reports showed evidence of a possible link to the drug. The FDA said it was investigating the risk of neoplasia, including malignancy, and the regulator stated that, for now, Zolgensma’s benefits still outweigh its risks while it evaluates potential measures. The overall benefits of both Zolgensma and Itvisma continue to outweigh their potential risks for their approved uses, while the agency evaluated whether regulatory action was appropriate in light of the risk.
The investigation aims to clarify the possible association and determine whether action is warranted, and the article added that the FDA’s assessment does not amount to a conclusion that the treatment caused the reported tumors. Novartis said the potential risk of tumours is included in Zolgensma’s prescribing information, and the company said it had notified health authorities in a timely and appropriate manner in both cases.
Mechanism and next steps
Zolgensma uses a modified virus to deliver a working copy of a gene into cells, and the cases described by Novartis involved evidence that the carrier inserted its genetic material into the patients’ own DNA. Viral vector DNA was detected in the patients' genomes in two cases, and the cases illustrate why assessing the safety of gene and cell therapies remains a particular challenge. The delivery vehicle is a genetically engineered, nonreplicating adeno-associated virus serotype 9 (AAV9) that transports the additional gene copy into target cells, where it is intended to compensate for the missing function.
AAV vector DNA can also integrate randomly into the human genome, and such integration events have been described in the scientific literature and are explicitly mentioned in the U.S. prescribing information for Zolgensma. A reliable risk assessment is not yet possible, and neither the tumor types nor the precise molecular findings and individual disease courses have been comprehensively documented publicly.