Hepatotoxicity following administration of onasemnogene abeparvovec (AVXS-101) for the treatment of spinal muscular atrophy.

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Spinal muscular atrophy (SMA) is an autosomal recessive, childhood-onset motor neuron disease, fatal in its most severe forms. In addition to neuromuscular degeneration, organ involvement, including the liver, may also be present. Onasemnogene abeparvovec (OA) is a gene therapy that addresses SMA's root cause. In pivotal mouse toxicology studies, the liver was identified a major target organ of toxicity for OA. Clinical data reflect elevations in serum aminotransferase concentrations, with some reports of serious acute liver injury. Prophylactic prednisolone mitigates these effects. We evaluated liver effects, with attention to clinical characteristics, to provide pragmatic, supportive guidance for identification, management, and risk mitigation of potential drug-induced liver injury.Data from 325 SMA patients who had received OA through 31 December 2019, in five clinical trials, a managed access program (MAP), and a long-term registry (RESTORE), and through commercial use, were analyzed. Liver-related adverse events (AEs), laboratory data, concomitant medications, and prednisolone use were analyzed.Based on adverse events and laboratory data, 90 of 100 patients had elevated serum aminotransferases concentrations. Of these, liver-associated AEs were reported for 34 of 100 (34%) and 10 of 43 (23%) patients in clinical trials and MAP/RESTORE, respectively. Two patients in MAP had serious acute liver injury, which resolved completely. While all events in the overall population resolved, prednisolone treatment duration varied (range: 33-229 days), with a majority receiving prednisolone 60-120 days. More than 60% had elevations in serum aminotransferases concentrations prior to dosing. Greater than 40% received potentially hepatotoxic concomitant medications.Hepatotoxicity is a known risk associated with OA use. Practitioners should identify contributing factors and mitigate risk through appropriate monitoring and intervention.


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