Two fatal cases of acute liver failure occurred in two children, aged 4 and 28 months, affected by spinal muscular atrophy (SMA) and treated with the drug Zolgensma (onasemnogene abeparvovec). The Italian Medicines Agency (Aifa) reports them on its website, publishing the information note of the manufacturer Novartis. Zolgensma is the first gene therapy against Sma, approved by AIFA in 2021 and paid for by the NHS for all children affected by the disease and weighing less than 13.5 kg. To date, the agency notes, there are about 3,000 patients treated with this drug, which when it was approved in 2021 went around the world because it was considered “the most expensive in history”. In fact, in the US it was given the go-ahead for 2.1 million dollars.
Damage reported
Hepatotoxicity, i.e liver toxicity, reported with onasemnogene abeparvovec, explains Aifa, often manifests itself as abnormal liver function or as an increase in aminotransferases. However, severe acute liver injury or acute liver failure, including with a fatal outcome, has been reported. The underlying mechanism, underlines the agency, is “probably related to an innate and/or vector-adaptive immune response”.
The recommendations
Aifa therefore recommends a prophylactic regimen with corticosteroids and monitoring of liver function for at least 3 months after the drug infusion. This includes the weekly monitoring for the first month and throughout the corticosteroid tapering period, followed by bi-weekly monitoring for an additional month and, if clinically indicated, at other time points as well. In addition, patients presenting with signs or symptoms indicative of liver dysfunction they should be promptly evaluated for liver injury. In the event that patients are not responding adequately to corticosteroids, a pediatric gastroenterologist or hepatologist should be consulted.
These are the common clinical characteristics of these two cases, as stated on the Aifa website: the initial manifestation of liver damage was the asymptomatic increase in liver aminotransferases within the first 1-2 weeks after the infusion; the clinical manifestation of hepatotoxicity included vomiting, weakness, and a second elevation of liver aminotransferases. This was followed by rapid deterioration of liver function and progression to hepatic encephalopathy and multiple organ failure. Death occurred 6-7 weeks after onasemnogene abeparvovec infusion during the period of corticosteroid tapering. Zolgensma, it is underlined, “is subjected to additional monitoring. This will allow the quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions.”