2 deaths after Novartis' Zolgensma put gene therapy's liver safety in the spotlight once again

Novartis has recorded two deaths after treatment with its spinal muscular atrophy gene therapy Zolgensma, once again bringing gene therapy’s safety into attention.

Two children in Russia and Kazakhstan died about five to six weeks after receiving Zolgensma, Novartis confirmed to Fierce Pharma. Both patients died of acute liver failure, a known side effect of Zolgensma that’s included in a boxed warning on the one-time therapy’s label. Both had received corticosteroid taper to restore liver function.

While serious liver injury is a known risk of Zolgensma, these two are the first reports of fatal cases, Novartis said. The deaths were first reported by Stat.

Novartis will ask regulators, including the FDA, to update Zolgensma’s labeling to specify that fatal acute liver failure has been reported, Novartis said in a statement.

“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.

Liver toxicity is one of the most common side effects of gene therapies like Zolgensma, which rely on adeno-associated viruses (AAVs) as vectors to deliver therapeutic genes. AAVs are mostly directed at the liver and are currently the most commonly used platform for gene therapies.

One of the best-known cases of serious liver toxicities happened in a clinical trial of Astellas’ AT132, designed for a rare neuromuscular disease called X-linked myotubular myopathy. Initially, three of 17 children who received a high dose of the investigational therapy died after developing liver failure. After the FDA lifted a clinical hold to allow Astellas to pursue a lower—and potentially safer—dose, a fourth patient again showed abnormal liver function and later died in September 2021.

The FDA last September held an advisory committee meeting to specifically discuss safety risks of gene therapies. During the conference, the FDA noted that about one-third of the 500 patients who had received Zolgensma at that time had experienced a liver-related side effect.

Besides liver toxicity, AAV-based gene therapies have also raised concerns that they might cause cancer. Preclinical studies have shown that AAVs can incorporate genomes into certain animals, but the problem hasn’t been proven in humans.

Meanwhile, Zolgensma has also recorded some blood system problems, including irregular platelet counts. An animal study of an experimental spinal-injection formula of Zolgensma previously also flagged a neuroinflammation problem.

Since an initial FDA nod in 2019, Zolgensma has been cleared in over 40 countries and has become a blockbuster therapy. It reeled in $379 million in sales in the second quarter, a 26% increase year-over-year. The one-time gene therapy squeezed Biogen’s Spinraza but also faces competition from Roche’s oral drug Evrysdi.

Aside from Zolgensma's current infusion form, Novartis is also pursuing the intrathecal version, which would allow older SMA patients to receive the gene therapy.