FDA Investigating Serious Malignancy Risk Linked to Gene Therapy

 

The FDA is investigating a serious risk of malignancy in patients treated with onasemnogene abeparvovec (Zolgensma) for spinal muscular atrophy (SMA), the agency said Friday.

The announcement came soon after drugmaker Novartis acknowledged that there were nine reports of tumors in patients who received the treatment. Two of the tumor cases were linked to the drug, the company said.

Zolgensma, an adeno-associated virus (AAV) vector-based gene therapy, was approved in 2019 to treat pediatric patients under 2 years of age with SMA and bi-allelic SMN1 mutations.

The FDA said it received confirmed reports of product-related insertional oncogenesis involving the glioma-associated oncogene homolog 1 (GL1) gene. GLI1 has the potential to cause cancer when overexpressed or abnormally activated.

The reports of neoplasia include tumors of the central and peripheral nervous systems, spinal or paraspinal regions, and kidney, the FDA said.

"Importantly, three cases involved tumors associated with the GLI1 oncogene," the agency noted. "In two of those cases, molecular analysis of tumor tissue demonstrated Zolgensma AAV vector DNA integration into the host genome, with the promoter region of the onasemnogene abeparvovec construct inserted upstream of or within the GLI1 oncogene." The mechanism of GLI1 overexpression in the third case is under investigation.

The FDA said the risk of neoplasia, including malignancy, applies to two onasemnogene abeparvovec products: Zolgensma, which is administered by intravenous infusion, and Itvisma, an intrathecal injection to treat adult and pediatric SMA patients ages 2 and older approved in 2025.

Both products contain the same vector and construct, the FDA said. To date, there have been no reports of neoplasia with Itvisma, the agency added.

"Since first approval in 2019, Novartis has received 9 reports of tumors in patients previously treated with Zolgensma," a Novartis spokesperson wrote in an email to MedPage Today.

"Of those, two cases to date have shown evidence of vector DNA integration into the DNA of the patients. In both cases, the patients underwent treatment and continue to be monitored," the spokesperson continued. "In each case, we timely and appropriately notified health authorities and will continue to work with them on next steps."

The spokesperson did not say when tumors may have developed in the other seven cases, or when they were identified.

SMA is caused by reduced levels of the survival motor neuron (SMN) protein due to deletions or mutations in the SMN1 gene. A nearly identical gene, SMN2, produces low levels of functional SMN protein.

Onasemnogene abeparvovec uses an AAV vector to replace the SMN1 gene. Its prescribing information notes a theoretical risk of tumorigenicity from the integration of AAV vector DNA into the genome.

"The potential risk of tumors due to vector integration is currently included in the Zolgensma prescribing information," Novartis said.

Advocates recently raised concerns on social media after learning from their doctors that Novartis had received reports of tumors in patients treated with the gene therapy. SMA Europe, an umbrella organization of SMA patient groups in Europe, acknowledged the reports in a news release early Thursday.

"We understand that the relevant regulatory authorities are actively involved and are currently assessing the available evidence and determining what further steps may be needed," SMA Europe stated. "We trust in the regulatory processes established to evaluate safety signals and to take the necessary measures to protect patients and ensure the continued safety of medicines on the market."

In the U.S., the Muscular Dystrophy Association (MDA) said it was "seeking additional information, reviewing the available scientific and safety data with clinical and research experts, and has reached out to Novartis."

The MDA added that "limited information is available currently about the timing of events, nature of the tumors, and any future monitoring of treated individuals that may become appropriate."

A 2023 case report described a 16-month-old boy with SMA who was diagnosed with an epithelioid neoplasm of the spinal cord 14 months after receiving onasemnogene abeparvovec; the finding was considered inconclusive. A 2025 case report detailed a pilocytic astrocytoma in a child with SMA treated with onasemnogene abeparvovec; a molecular analysis suggested tumorigenesis was causally independent of the gene therapy.

Earlier this year, researchers identified vector integration in a brain tumor in a 5-year-old boy with severe mucopolysaccharidosis type I (Hurler syndrome) who received another AAV gene therapy, describing the case in the New England Journal of Medicine. A correspondence last month described an integration-associated paraspinal neoplasm after AAV gene therapy in a 3-year-old boy with Krabbe disease.

More than 6,000 patients have been treated with Zolgensma in clinical trials, managed access programs, and commercial treatment, Novartis said.

The tumor reports are not the first controversy involving Zolgensma. Soon after the therapy was approved, the FDA criticized the Novartis AveXis unit over data manipulation that affected the accuracy of animal product-testing results.

https://www.medpagetoday.com/neurology/generalneurology/123769