FDA Investigates Zolgensma Malignancy Risk, Puts Other AAV Gene Therapy Programs On Watch

By Elizabeth Urbanek, Executive Editor

The FDA is investigating a serious risk of malignancy in patients treated with Zolgensma, Novartis' gene therapy for spinal muscular atrophy (SMA). The agency also says it is closely monitoring other adeno-associated virus (AAV) vector-based gene therapy programs, which puts sponsors of AAV trials on notice alongside SMA programs.

In a safety communication published Nov. 6, the FDA said it has received postmarketing reports of tumors in patients treated with Zolgensma, including confirmed product-related insertional oncogenesis involving the GLI1 oncogene. Reported tumors occurred in the central and peripheral nervous systems, the spinal and paraspinal regions, and the kidney.

Three cases involved GLI1. In two of them, tumor tissue showed Zolgensma vector DNA integrated into the patient's genome near or within the gene. The third case remains under investigation. The FDA also cited published reports of integration-related tumors in two other AAV programs, FBX-101 and RGX-111.

The agency said the risk applies to both Zolgensma and Itvisma, the intrathecal version approved in November 2025, because they share the same vector and construct. No tumors have been reported after Itvisma to date. The FDA said benefits still outweigh risks for approved uses, but it is evaluating whether regulatory action is appropriate. It is also reviewing whether current labeling and long-term follow-up studies are adequate, and it said patients and clinical trial participants receiving these products should be monitored for tumors.

The FDA did not name the other AAV programs it is monitoring, say whether it expects changes to ongoing trials, describe new monitoring requirements, or set a timeline for any regulatory action.

What This Means For Clinical Supply

For clinical supply teams, the notice lands hardest on AAV gene therapy trials. Investigational medicinal products (IMPs) in these studies are typically made in small, costly batches, stored frozen, and shipped to sites against scheduled dosing visits.

The FDA has not changed any trial requirement. But naming other AAV programs could prompt sponsor safety reviews, institutional review board (IRB) questions, and updated informed consent before the next dose. Each step can delay dosing without a formal clinical hold.

When dosing slips, IMPs already at sites or depots keep aging. For lots with limited remaining shelf life, a delay of a few weeks could mean expiry, relabeling decisions, or write-offs, and AAV batches are rarely quick to replace.

That creates a tradeoff. Sponsors could keep shipping on the current calendar so sites can dose once cleared, or hold product centrally until each site has updated consent in place and accept slower first doses. The right call would depend on remaining expiry, cost per lot, and how fast sites can absorb changes.

The decision crosses clinical operations, safety, regulatory, quality, site pharmacies, and frozen-storage depots. If shipments are tied to consent status, interactive response technology (IRT) release rules and depot instructions would need the same trigger, and someone would need clear authority to pause and resume.

SMA programs face a separate question. Trials where prior onasemnogene abeparvovec treatment affects eligibility, or where it serves as background therapy, could see eligibility or monitoring changes that shift enrollment forecasts.

The notice does not establish risk for any other product, require trial changes, or give a timeline. For AAV sponsors, the operational question is whether to keep supply moving on the existing dosing calendar or tie shipments to confirmed site readiness while the FDA review plays out.

The Supply Question

Should AAV sponsors ship on the dosing calendar or wait until each site updates consent and protocol during FDA review?

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About The Author:

Elizabeth Urbanek is the Executive Editor for Clinical Supply Leader, where she works with clinical trial supply and logistics professionals across pharma and biotech to bring real-world perspectives, operational challenges, trends, scientific insights and regulatory strategy to the field.

Before joining life sciences media, Elizabeth spent more than 15 years in broadcast, digital and live-event storytelling, helping highly technical teams communicate complex ideas with clarity and impact. She brings that same approach to clinical supply, creating editorial space for experts to share what is happening across clinical trial operations.

Elizabeth is passionate about connecting people and ideas, identifying emerging themes and showcasing work that can move the clinical supply field forward.