FDA probes reports of tumors linked to Zolgensma gene therapy

The FDA is investigating a serious risk of malignancy associated with Novartis’ spinal muscular atrophy (SMA) gene therapy Zolgensma following postmarketing reports of tumors in treated patients, including confirmed cases of treatment-related genetic integration involving an oncogene.

The agency said it had received reports of neoplasia, or abnormal tumor growth, affecting the central and peripheral nervous systems, spinal and paraspinal regions, and kidneys. Three cases involved tumors associated with GLI1 (Glioma-Associated Oncogene Homolog 1), a gene that can drive cancer when overexpressed or abnormally activated.

Molecular analysis of tumor tissue in two of the cases demonstrated integration of Zolgensma’s adeno-associated virus (AAV) vector DNA into the patients’ genomes. Specifically, the promoter region of the gene therapy construct was inserted upstream of or within GLI1. The mechanism behind GLI1 overexpression in the third case remains under investigation.

More than 6,000 patients have been treated with Zolgensma across clinical trials, managed access programs and commercial treatment. Novartis told media outlets that since first approval in 2019, the company has received 9 reports of tumors in patients previously treated with Zolgensma. 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 agency is evaluating whether regulatory action is warranted, including whether current prescribing information and Novartis’ long-term follow-up safety studies adequately address the newly identified risk. Both products already include a warning regarding the theoretical risk of tumorigenicity resulting from integration of AAV vector DNA into the genome.

The FDA said the overall benefits of Zolgensma and Itvisma (an intrathecal formulation of Zolgensma) continue to outweigh their potential risks for their approved uses. In the meantime, patients and clinical trial participants treated with either product should be monitored for tumor formation.

SMA is a rare, genetic neuromuscular disease caused by a mutated or missing SMN1 gene, which is responsible for producing most of the SMN protein a body needs for muscle function, including breathing, swallowing and basic movement. Zolgensma is gene replacement therapy that replaces the missing or nonworking SMN1 gene with a new, working SMN gene. The new SMN gene helps the body’s cells — particularly the motor neuron cells — to keep producing SMN protein.