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

J Hepatol. 2021 Mar;74(3):560-566. doi: 10.1016/j.jhep.2020.11.001. Epub 2020 Nov 10.


Background & aims: Spinal muscular atrophy (SMA) is an autosomal recessive, childhood-onset motor neuron disease. Onasemnogene abeparvovec (OA) is a gene therapy designed to address SMA's root cause. In pivotal mouse toxicology studies, the liver was identified as a major site of OA toxicity. Clinical data reflect elevations in serum aminotransferase concentrations, with some reports of serious acute liver injury. Prophylactic prednisolone mitigates these effects. Herein, we aim to provide pragmatic, supportive guidance for identification, management, and risk mitigation of potential drug-induced liver injury.

Methods: Data from 325 patients with SMA who had received OA through 31 December 2019, in 5 clinical trials, a managed access program (MAP), and a long-term registry (RESTORE), and through commercial use, were analyzed. Liver-related adverse events, laboratory data, concomitant medications, and prednisolone use were analyzed.

Results: Based on adverse events and laboratory data, 90 of 100 patients had elevated liver function test results (alanine aminotransferase, and/or aspartate aminotransferase, and/or bilirubin concentrations). Of these, liver-associated adverse events 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 for 60-120 days. More than 60% had elevations in either alanine aminotransferase, aspartate aminotransferase, or bilirubin concentrations prior to dosing. Greater than 40% received potentially hepatotoxic concomitant medications.

Conclusions: Hepatotoxicity is a known risk associated with OA use. Practitioners should identify contributing factors and mitigate risk through appropriate monitoring and intervention.

Lay summary: Onasemnogene abeparvovec is a type of medicine called a "gene therapy," which is used to treat babies and young children who have a rare, serious inherited condition called "spinal muscular atrophy" (SMA). It works by supplying a fully functioning copy of the survival motor neuron or SMN gene, which then helps the body produce enough SMN protein. However, it can cause an immune response that could lead to an increase in enzymes produced by the liver. This article provides information about the liver injury and how to prevent and recognize if it happens, so that it may be treated properly.

Keywords: AAV9; Gene therapy; Hepatotoxicity; Onasemnogene abeparvovec; Safety.

Publication types

  • Case Reports
  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alanine Transaminase / blood
  • Aspartate Aminotransferases / blood
  • Bilirubin / blood
  • Biological Products / administration & dosage*
  • Biological Products / adverse effects*
  • Chemical and Drug Induced Liver Injury / etiology*
  • Cohort Studies
  • Female
  • Genetic Therapy / methods*
  • Glucocorticoids / therapeutic use
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Muscular Atrophy, Spinal / blood
  • Muscular Atrophy, Spinal / drug therapy
  • Muscular Atrophy, Spinal / therapy*
  • Prednisolone / therapeutic use
  • Recombinant Fusion Proteins / administration & dosage*
  • Recombinant Fusion Proteins / adverse effects*
  • Registries*
  • Treatment Outcome


  • Biological Products
  • Glucocorticoids
  • Recombinant Fusion Proteins
  • Zolgensma
  • Prednisolone
  • Aspartate Aminotransferases
  • Alanine Transaminase
  • Bilirubin