FDA investigates malignancy risk with Zolgensma after GLI1-linked tumor findings and confirms vector DNA integration in two cases.
Written By: Siddhi Bhadekar, M. Pharm (QA)
Reviewed By: Pharmacally Editorial Team
The U.S. Food and Drug Administration (FDA) issued a safety communication on November 6, 2026, announcing an investigation into the risk of neoplasia, including malignancy, associated with onasemnogene abeparvovec, the adeno-associated virus (AAV) vector-based gene therapy marketed as Zolgensma for spinal muscular atrophy (SMA). The agency reported three GLI1-associated tumor cases, with molecular analysis confirming Zolgensma vector DNA integration into the host genome in two cases. The findings have prompted FDA to evaluate whether existing product labeling and long-term safety monitoring adequately address the risk. However, the agency stated that the overall benefits of Zolgensma and its sister product Itvisma continue to outweigh their potential risks for approved uses.
Postmarketing Tumor Reports and GLI1-Associated Insertional Oncogenesis
FDA identified postmarketing reports of tumors affecting the central and peripheral nervous systems, spinal and paraspinal regions, and kidney. Three cases involved tumors associated with GLI1 (Glioma-Associated Oncogene Homolog 1), an oncogene capable of promoting cancer when abnormally activated or overexpressed.
In two cases, molecular analysis of tumor tissue demonstrated integration of Zolgensma vector DNA into the host genome. The promoter region of the gene therapy construct was positioned upstream of or within GLI1, providing a plausible mechanism for abnormal oncogene activation. The mechanism responsible for GLI1 overexpression in the third case remains under investigation.
FDA also highlighted two published reports of integration-associated tumorigenesis involving other AAV gene therapy programmes. These included a GLI1 integration event in the FBX-101 programme, reported in the New England Journal of Medicine (NEJM) on October 15, 2026, and a PLAG1 integration event in the RGX-111 programme, published on June 4, 2026.
Although these reports involve separate gene therapy programmes and should not be considered additional Zolgensma cases, they reinforce the importance of evaluating insertional oncogenesis as a potential safety concern across AAV-based treatments.
FDA Extends Safety Assessment to Itvisma
FDA determined that the neoplasia risk is applicable to both onasemnogene abeparvovec products because they share the same vector and construct.
Zolgensma is administered through intravenous infusion and is indicated for pediatric patients younger than 2 years with SMA. Itvisma, administered through intrathecal injection, is approved for adults and pediatric patients aged 2 years and older. Their initial FDA approvals were granted on May 24, 2019, and November 24, 2025, respectively.
Importantly, FDA reported no cases of neoplasia following Itvisma administration to date. Its inclusion in the safety assessment reflects the shared vector and construct rather than an observed malignancy signal with Itvisma.
FDA is evaluating whether regulatory action is appropriate. No new prescribing restrictions, label changes or product withdrawals were announced in the communication.
Existing Tumorigenicity Warning Under Regulatory Review
Onasemnogene abeparvovec is a one-time gene replacement therapy that uses an AAV vector to deliver a functional copy of the SMN1 gene. The current U.S. prescribing information for both products already identifies a theoretical risk of tumorigenicity resulting from AAV vector DNA integration into the host genome under Warnings and Precautions.
The newly reported findings introduce a more substantial evidence base for this previously theoretical concern. FDA is therefore evaluating whether the existing labeling adequately communicates the risk and whether current long-term follow-up studies are sufficient to investigate and mitigate it.
Long-Term Safety Monitoring and Adverse Event Reporting
Novartis, the sponsor, is conducting long-term follow-up safety studies. One registered programme is AVXS-101-LT-002 (NCT04042025), an open-label follow-up study involving participants from previous Novartis-sponsored SMA trials who received intravenous or intrathecal onasemnogene abeparvovec. The study supports continued assessment of safety and treatment durability.
FDA has advised that patients and clinical trial participants receiving either product should be monitored for tumor formation.
Healthcare providers should contact Novartis Gene Therapies at 1-833-828-3947 if a tumor develops in a patient receiving Zolgensma. Other suspected adverse reactions can also be reported to FDA through 1-800-FDA-1088 or the MedWatch reporting programme.
Clinical Interpretation: Implications for AAV Gene Therapy Safety
The FDA communication marks an important development in the long-term safety assessment of AAV-based gene replacement therapies. The identification of vector DNA integration in tumor tissue from two Zolgensma-treated patients provides molecular evidence supporting product-related insertional oncogenesis, moving the concern beyond a theoretical risk.
Nevertheless, the available findings do not establish the incidence of malignancy among treated patients, and the mechanism in the third GLI1-associated case remains unresolved. The separate FBX-101 and RGX-111 reports also warrant broader scientific attention without establishing a uniform risk across AAV-based products.
For clinicians, the findings reinforce the importance of long-term surveillance, appropriate evaluation of suspected tumor formation and transparent patient counseling. FDA’s continued positive benefit-risk assessment indicates that the communication does not constitute a recommendation to discontinue or withhold either approved therapy. Instead, it highlights the need to strengthen long-term safety oversight as gene replacement treatments become established therapeutic options.
Reference
FDA Investigating Serious Risk of Malignancy Linked to Zolgensma Gene Therapy, US FDA, 06 November 2026
Long-term Follow-up Study of Patients Receiving Onasemnogene Abeparvovec-xioi ClinicalTrials.gov ID NCT04042025
Josh N. Vo, Ph.D., Integration-Associated Paraspinal Neoplasm after AAV Gene Therapy, N Engl J Med 2026;395:1555-1558, Published October 14, 2026, DOI: 10.1056/NEJMc2607927
Rebecca C. Ahrens-Nicklas, M.D., Ph.D. et al, Neuroepithelial Tumor with AAV Integration after Intracisternal Magna Vector Delivery, N Engl J Med 2026;394:2126-2133 DOI: 10.1056/NEJMoa2601608
About the Writer
Siddhi Rajendra Bhadekar (Linkedin) is an M.Pharm professional with expertise in medical and scientific writing, literature review, publication writing, and evidence synthesis, supported by four peer-reviewed publications.
She brings working knowledge of ICH-GCP, MedDRA, pharmacovigilance, ADR/AE reporting, clinical data management, and regulatory documentation.
With experience across pharmaceutical R&D, Quality Control, and Quality Assurance, she combines scientific research skills with strong attention to accuracy and detail.
Her background in manuscript development, publication planning, and scientific communication enables her to translate complex healthcare information into clear, reliable content.
