The FDA is investigating a serious risk of malignancy associated with Novartis’ spinal muscular atrophy gene therapy Zolgensma after molecular testing linked two tumors to integration of the therapy’s adeno-associated virus vector.
In a safety communication, the regulator said it had received postmarketing reports of tumors involving the central and peripheral nervous systems, spinal and paraspinal regions, and kidney.
Three cases involved abnormal activity of GLI1, an oncogene that can promote cancer when overexpressed. In two, analysis showed that Zolgensma vector DNA had integrated into the patient’s genome, placing the therapy’s promoter upstream of or within GLI1. The mechanism responsible for GLI1 overexpression in the third case remains under investigation. FDA
Novartis said it has received nine reports of tumors among more than 6,000 patients treated with Zolgensma since the therapy was first approved in 2019. Two have shown evidence of vector integration into the patients’ DNA. Both patients received treatment for their tumors and remain under monitoring, according to a company statement shared by SMA Europe. sma-europe.eu
Zolgensma uses an AAV9 vector to deliver a functional copy of SMN1, the gene deficient in spinal muscular atrophy. Although recombinant AAV DNA largely persists outside chromosomes, rare integration into the host genome can occur. US prescribing information currently describes tumorigenicity resulting from integration as a theoretical risk.
The FDA has determined that the newly identified risk also applies to Itvisma, Novartis’ intrathecally administered onasemnogene abeparvovec product, because it contains the same vector and genetic construct. No tumors have been reported following Itvisma treatment to date.
Zolgensma is administered intravenously and is approved in the US for children younger than two. Itvisma was approved in November 2025 for pediatric and adult patients aged two and older.
The safety signal also has implications for other AAV-based programs. The FDA cited two published cases of integration-associated oncogenesis involving different investigational therapies. One involved integration near GLI1 following treatment in the FBX-101 program, while another involved the oncogene PLAG1 in the RGX-111 program.
The regulator is monitoring similar AAV therapies and assessing whether Zolgensma and Itvisma require changes to their prescribing information or long-term follow-up requirements. Novartis is already conducting long-term safety studies.
The FDA said the benefits of both approved therapies continue to outweigh their potential risks. It advised that patients and clinical trial participants receiving the products should be monitored for tumor formation.
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