Novartis has acknowledged that two patients have died of acute liver failure following treatment with its Zolgensma® (onasemnogene abeparvovec-xioi), a one-time gene therapy indicated for some forms of spinal muscular atrophy (SMA).

As a result, the company said, it will revise Zolgensma’s label to specify that fatal acute liver failure has been reported.

“While this is important safety information, it is not a new safety signal and we firmly believe in the overall favorable risk/benefit profile of Zolgensma,” Novartis said in a statement emailed to GEN and other news organizations.

Mani Foroohar, MD, Senior managing director, Genetic Medicines, and a senior research analyst with SVB Securities, wrote in a research note today that the deaths are expected to touch off renewed public discussion over the safety of adeno-associated virus (AAV) gene therapies such as Zolgensma.

“We expect these events to rekindle broader debates on safety and management of systemic AAV therapies in fragile or very young patients, one contributor to the overhang on gene therapy stocks across our coverage, which have underperformed the biotech sector as a whole YTD [year to date],” Foroohar wrote.

The label—including a Boxed Warning in the U.S. Prescribing Information for the gene therapy—has until now included acute liver failure as a known side effect that has been reported following treatment.

A 2020 paper published in The Journal of Pediatrics detailed two cases of transient, drug-induced subacute liver failure following treatment with Zolgensma. A 2021 study in Nature-published Gene Therapy showed that of nine children treated with the gene therapy in Qatar, none experienced failure—but all patients experienced elevated levels of the liver enzymes aspartate aminotransferase (AST) or alanine transaminase (ALT), two experienced high prothrombin time, and one experienced elevated bilirubin. One patient experienced vomiting after infusion.

First fatal cases

The deaths are the first fatal cases of acute liver failure that have been linked to Zolgensma, a gene therapy developed by AveXis. Novartis acquired AveXis for $8.7 billion in a deal completed in 2018.

A year later in May 2019, the FDA approved Zolgensma for the treatment of SMA in pediatric patients less than two years of age with SMA with bi-allelic mutations in the survival motor neuron 1 (SMN1) gene. Zolgensma was the second gene therapy authorized by the FDA for an inherited disease.

During the first half of this year, Zolgensma generated $742 million in net sales, up 17% from January–June 2021. Zolgensma finished last year with $1.351 billion in net sales, up 47% from 2020. Novartis considers Zolgensma among its “key growth brands.”

In trading today, Novartis shares dipped 1.16% on the SIX Swiss Exchange, to CHF 80.10 ($85.06).

To date, Novartis stated, Zolgensma has been used to treat more than 2,300 patients worldwide across clinical trials, managed access programs, and commercially.

“We have notified health authorities in all markets where Zolgensma is used, including FDA, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities,” Novartis added.

Novartis has long asserted that Zolgensma’s benefits in halting SMA and facilitating infant development milestones justify its $2.1 million list price, though the company has also long cited its discounted patient-access programs with insurers.

Novartis did not reveal information about the patients—who were both children according to STAT News, which first reported the deaths. However, the company did disclose that one of the fatal cases of acute liver failure took place in Russia and the other, in Kazakhstan.

Both cases occurred at approximately five to six weeks post Zolgensma infusion, and approximately 1–10 days following the initiation of corticosteroid taper, Novartis stated.