The FDA has launched a safety investigation into Novartis’ gene therapy Zolgensma following reports of tumors in patients, as concerns flare up over genomic insertion risks.
Friday, the FDA confirmed that it is evaluating cases of tumor formation in children previously treated with Zolgensma for spinal muscular atrophy (SMA). The agency’s diligence extends to Itvisma, a sister intrathecal formulation of the intravenously infused Zolgensma, as the two products contain the same vector and construct, even though Itvisma itself has no reported cases of tumor to date, the FDA said.
At the center of the investigation is a biological process known as insertional oncogenesis, where the viral vector used to deliver functional copies of the therapeutic material inserts itself into human genes.
Zolgensma relies on an adeno-associated virus vector to deliver a functional SMN1 gene to treat SMA. Rare integration is a known safety risk factor of the treatment.
Among more than 6,000 patients that Zolgensma has reached globally, Novartis disclosed nine reports of tumors since its regulatory approval in 2019. These include tumors of the central and peripheral nervous systems, spinal and paraspinal regions, and the kidney, according to the FDA.
Molecular analyses performed on tumor tissue from at least two of these patients revealed direct evidence of the therapeutic AAV vector integrating near or within the Glioma-Associated Oncogene Homolog 1(GLI1), a gene known to cause cancer when overexpressed or abnormally activated, the FDA noted. A third case of GLI1 overexpression is under investigation.
In its Nov. 6 communique, the FDA also flagged two recent reports of other gene therapy candidates where AAV vector integration drove tumor formation. One of them is a paraspinal neoplasm case in a 3-year-old boy with infantile-onset Krabbe disease who received FBX-101, developed by Forge Biologics, as part of a clinical trial. The program was discontinued last year as Forge turned its focus on contract manufacturing services following an acquisition by Ajinomoto.
In the other case, a neuroepithelial tumor developed in a five-year-old boy with severe mucopolysaccharidosis type I (MPS I) four years after injection with Regenxbio’s RGX-111 into the brain’s fluid-filled cavity. The RGX-111 clinical program has been placed under an FDA clinical hold since January.
Despite the investigation, the FDA maintained that the “overall benefits of Zolgensma and Itvisma continue to outweigh their potential risks” in SMA. Zolgensma’s current label already flags a “theoretical risk” of tumor formation due to integration of AAV into the human genome.
The FDA now said it’s re-evaluating whether existing label and long-term studies are sufficient to monitor and mitigate the serious risk of tumor.