Novartis Confirms Nine Tumors in Children Treated with Zolgensma

Novartis has confirmed nine reports of tumors in children treated with its spinal muscular atrophy gene therapy Zolgensma (onasemnogene abeparvovec-xioi), seven of them newly disclosed, and two of the nine show evidence of viral vector integration into patient DNA.

"Of those, two cases to date have shown evidence of vector integration into the DNA of the patients. In both cases, the patients underwent treatment and continue to be monitored," Novartis said in a statement furnished to GEN and other outlets.

What does Novartis say about the risk?

"Patient safety is our priority. In each case, we timely and appropriately notified health authorities and will continue to work with them on next steps," the company added. More than 6,000 patients worldwide have received Zolgensma across clinical trials, managed access programs, and commercial treatment, according to Novartis.

The potential risk of tumors due to vector integration is already addressed in the prescribing information. The label carries a section titled "AAV Vector Integration and Risk of Tumorigenicity," which states: "There is a theoretical risk of tumorigenicity due to integration of AAV vector DNA into the genome." The label urges prescribers to report tumor cases to Novartis.

Zolgensma is an AAV9-based therapy for children under two with SMA caused by bi-allelic mutations in the SMN1 gene. The vector's DNA persists largely in episomal form, but Novartis has acknowledged that random integration of recombinant AAV DNA into human DNA has been reported with Zolgensma and with other AAV gene therapies in published studies.

"The clinical relevance of individual integration events is unknown, but it is acknowledged that individual integration events could potentially contribute to a risk of tumorigenicity," the label states.

How did the news surface?

Patient groups forced the disclosure. The Muscular Dystrophy Association issued a statement Thursday acknowledging the tumor reports, saying families "deserve transparent, timely, and science-based information as more is learned." MDA is reviewing the safety data with clinical experts and has reached out to Novartis.

SMA Europe said it learned of the cases "through confidential channels" and told Novartis the SMA community "now needs timely public communication." The groups spoke out after a hospice chaplain, Rev. Carolyn Philstrom, shared on LinkedIn a post from a private Facebook group in which a parent wrote that his neurologist said Novartis was withholding information and pursuing a "tiered rollout" of data.

The financial stakes are large. The Zolgensma Group, which includes the IV therapy and the intrathecal formulation Itvisma approved last year, generated $1.071 billion in net sales in the first three quarters of this year, up 16% from $925 million a year earlier. Q3 sales rose 34% to $404 million. The brand is one of Novartis' top 20. Shares on the SIX Swiss exchange dipped 0.1% to CHF 134.12 ($163.25); the ADRs slid 1.85% to $161.93.

What is the therapy's safety history?

In 2022, Novartis confirmed two deaths from acute liver failure, occurring five to six weeks after infusion and one to ten days after corticosteroid taper began. The label's black box warning was revised to specify that fatal acute liver failure had been reported.

Zolgensma was developed by AveXis, acquired by Novartis for $8.7 billion in 2018. The FDA approved it in 2019 as the second gene therapy authorized for an inherited disease. That same year, the FDA disclosed that AveXis had acknowledged a data manipulation affecting animal testing results supporting its production process in the BLA; AveXis replaced its two top scientific executives. A 2020 Journal of Pediatrics paper detailed two cases of transient drug-induced subacute liver failure, and a 2021 Gene Therapy study of nine children treated in Qatar found elevated liver enzymes in all patients.

Is this part of a wider pattern?

Three AAV-related tumor reports have surfaced this year. In January, the FDA placed clinical holds on Regenxbio's RGX-111 for MPS I after an intraventricular CNS tumor developed in a 5-year-old boy in a Phase I/II trial, and on the related RGX-121 for MPS II. Both holds remain in effect.

In May, Lindsey A. George, MD, of Children's Hospital of Philadelphia reported in the New England Journal of Medicine that the resected tumor case supports "the hypothesis that rare AAV integration can contribute to human oncogenesis," while noting more than 6,000 patients across three decades show a favorable overall safety profile.

In October, Michigan researchers led by Arul M. Chinnaiyan, MD, PhD, reported in NEJM a paraspinal neoplasm in a 3-year-old boy with Krabbe disease treated with Forbes Biologics' FBX-101. The patient remained asymptomatic at last follow-up; the authors called for cassette designs without splice donors and extended genomic surveillance after AAV therapy.

Novartis has committed to continue working with health authorities on next steps as monitoring of the nine patients continues.