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Novartis Reports Two Patient Deaths After Treatment with Zolgensma Gene Therapy

August 12, 2022

Novartis said that two children have died from acute liver failure after receiving its Zolgensma gene therapy to treat the neuromuscular disease spinal muscular atrophy.

The news of the deaths were first reported by STAT. They occurred in Russia and Kazakhstan. Novartis said the two fatal cases occurred at approximately five to six weeks post-Zolgensma infusion, and approximately 1 to 10 days following the initiation of corticosteroid taper, Novartis said in an emailed statement.

Novartis said it has notified health authorities in all markets where Zolgensma is used, including the U.S. Food and Drug Administration, and are communicating to relevant healthcare professionals as an additional step in markets where this action is supported by health authorities.

Acute liver failure is a known side effect that has been reported following treatment with Zolgensma and is highlighted in the product’s labeling including the Boxed Warning in the U.S. Prescribing Information. These are the first fatal cases of acute liver failure.

Following two recent patient fatalities, and in alignment with health authorities, will update the labeling 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, 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,” Novartis said in its statement.

Spinal muscular atrophy (SMA) is a rare, genetic neuromuscular disease caused by a lack of a functional SMN1 gene, resulting in the irreversible loss of motor neurons, affecting muscle functions, including breathing, swallowing and basic movement. The severity of SMA varies across a spectrum of types that each correspond to the copy number of the SMN2 gene, which produces a small fraction (approximately 10 percent) of functional SMN protein compared with SMN1. Left untreated, patients with SMA Type 2 are unable to walk and will require a wheelchair, and more than 30 percent will die by age 25. Loss of motor neurons cannot be reversed, so SMA patients with symptoms at the time of treatment will likely require some supportive respiratory, nutritional and/or musculoskeletal care to maximize functional abilities.

Zolgensma is an AAV9-based gene therapy that works by replacing the function of the missing or nonworking SMN1 gene with a new, working copy of an SMN gene. It was approved in the United States in May 2019 and has been shown to help patients reach developmental milestones that they wouldn’t otherwise have been able to achieve. Along with two other approved treatments, Spinraza from Biogen and Evrysdi from Roche, Zolgensma has improved the outlook for children born with SMA.

Despite the benefits, the two deaths spotlight the risks of gene therapy, in particular liver failure, and highlight safety issues related to the adeno-associated virus (AAV) delivery mechanism of these gene replacement therapies because they often end up in the liver.

It remains to be seen whether these two reported deaths will shape how regulators view the balance between a treatment’s benefits and risks.

Author: Rare Daily Staff

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