Clinical Trial and Postmarketing Safety of Onasemnogene Abeparvovec Therapy

Drug Saf. 2021 Oct;44(10):1109-1119. doi: 10.1007/s40264-021-01107-6. Epub 2021 Aug 12.

Abstract

Introduction: This is the first description of safety data for intravenous onasemnogene abeparvovec, the only approved systemically administered gene-replacement therapy for spinal muscular atrophy.

Objective: We comprehensively assessed the safety of intravenous onasemnogene abeparvovec from preclinical studies, clinical studies, and postmarketing data.

Methods: Single-dose toxicity studies were performed in neonatal mice and juvenile or neonatal cynomolgus nonhuman primates (NHPs). Data presented are from a composite of preclinical studies, seven clinical trials, and postmarketing sources (clinical trials, n = 102 patients; postmarketing surveillance, n = 665 reported adverse event [AE] cases). In clinical trials, safety was assessed through AE monitoring, vital-sign and cardiac assessments, laboratory evaluations, physical examinations, and concomitant medication use. AE reporting and available objective clinical data from postmarketing programs were evaluated.

Results: The main target organs of toxicity in mice were the heart and liver. Dorsal root ganglia (DRG) inflammation was observed in NHPs. Patients exhibited no evidence of sensory neuropathy upon clinical examination. In clinical trials, 101/102 patients experienced at least one treatment-emergent AE. In total, 50 patients experienced serious AEs, including 11 considered treatment related. AEs consistent with hepatotoxicity resolved with prednisolone in clinical trials. Transient decreases in mean platelet count were detected but were without bleeding complications. Thrombotic microangiopathy (TMA) was observed in the postmarketing setting. No evidence of intracardiac thrombi was observed for NHPs or patients.

Conclusions: Risks associated with onasemnogene abeparvovec can be anticipated, monitored, and managed. Hepatotoxicity events resolved with prednisolone. Thrombocytopenia was transient. TMA may require medical intervention. Important potential risks include cardiac AEs and DRG toxicity.

Trial registration: ClinicalTrials.gov NCT02122952 NCT03306277 NCT03505099 NCT03461289 NCT03837184 NCT03421977 NCT04042025.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biological Products* / adverse effects
  • Chemical and Drug Induced Liver Injury / drug therapy
  • Chemical and Drug Induced Liver Injury / etiology
  • Clinical Trials as Topic
  • Genetic Therapy* / adverse effects
  • Humans
  • Mice
  • Muscular Atrophy, Spinal* / drug therapy
  • Prednisolone / therapeutic use

Substances

  • Biological Products
  • Prednisolone

Associated data

  • ClinicalTrials.gov/NCT02122952
  • ClinicalTrials.gov/NCT03306277
  • ClinicalTrials.gov/NCT03505099
  • ClinicalTrials.gov/NCT03461289
  • ClinicalTrials.gov/NCT03837184
  • ClinicalTrials.gov/NCT03421977
  • ClinicalTrials.gov/NCT04042025