Two patients treated with Zolgensma, a Novartis gene therapy for a rare inherited disorder, have died, highlighting a known but rare side effect risk associated with this and other genetic medicines.

The children who died experienced acute liver failure at about five to six weeks following infusion with the gene therapy and within 10 days after the start of tapered dosing of corticosteroids to treat the liver problems, Novartis said in an emailed statement. The company did not further specify when those deaths occurred, other than to describe them as “recent patient fatalities.” Novartis did say that those cases occurred in Russia and Kazakhstan. The deaths were first reported Thursday by STAT.

Acute liver failure is a known complication of Zolgensma, and is flagged as a boxed warning on the drug’s prescribing information. Novartis said that the two deaths are the first fatal cases of acute liver failure associated with the gene therapy.

“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, which to date has been used to treat more than 2,300 patients worldwide across clinical trials, managed access programs, and in the commercial setting,” the company said.

Zolgensma treats spinal muscular atrophy (SMA), a rare muscle disorder caused by a genetic mutation that leads to insufficient levels of a protein key to the survival of motor neurons. SMA is classified across a range of types, but broadly, the disease leads to progressive muscle weakness that worsens with age. In the most severe type of SMA, the disease typically leads to death by age 2.

The Novartis gene therapy delivers a functioning version of the mutated gene. The one-time treatment is intended to get a patient’s cells to produce the needed muscle protein. Zolgensma is delivered to cells by adeno-associated virus (AAV), a commonly used vector for genetic medicines delivery. Liver toxicity is a known side effect risk of these engineered viruses. Such problems have been flagged in other clinical trials. Nearly a year ago, Astellas Pharma reported a fourth patient died in a study testing its gene therapy for X-linked myotubular myopathy, a different neuromuscular disorder. In that case, liver complications developed after dosing with the experimental Astellas gene therapy.

No deaths were reported in the clinical trials leading up to Zolgensma’s 2019 FDA approval. Those studies showed that following treatment, many young children were able to sit without support, stand, or even walk—development milestones that are missed when the disease progresses untreated. But results of the clinical research also noted that high levels of liver enzymes, a sign of drug toxicity, were common. The drug’s label also states that cases of liver injury and liver failure have been reported since the drug has reached the market. The prescribing information advises clinicians to monitor for such complications, which can be treated with corticosteroids.

Novartis said it is notifying health authorities and clinicians in the more than 40 markets where the drug is approved. The company added that it will update the drug label to specify the report of fatal acute liver failure. Zolgensma accounted for about $1.4 billion in global sales in 2021, a 47% increase compared to the prior year, according to Novartis’s financial reports.

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