Signals of Toxicity Associated With Gene Therapy: The Case of Etranacogene Dezaparvovec in the Treatment of Hemophilia B

Abstract

Background: Etranacogene dezaparvovec is the first adeno-associated virus (AAV)–based gene therapy approved for the treatment of hemophilia B. Due to its recent market authorization, post-marketing surveillance is essential to characterize its safety profile in real-world clinical practice. Objective: To identify and characterize adverse drug reaction signals associated with etranacogene dezaparvovec using post-marketing pharmacovigilance data. Methods: A disproportionality analysis was performed using reports from the FDA Adverse Event Reporting System (FAERS) from Q1 2023 to Q3 2025, selecting cases in which etranacogene dezaparvovec was reported as the primary suspect drug. Signal detection was conducted with OpenVigil 2.1 using Reporting Odds Ratio (ROR), Proportional Reporting Ratio (PRR), Relative Reporting Ratio (RRR), and chi-square statistics. The Evans criteria were applied to identify probable associations. Results: A total of 26 reports including 35 suspected adverse drug reactions were identified. Strong and statistically significant disproportionality signals were observed for hepatic adverse events, particularly increased alanine aminotransferase, aspartate aminotransferase, and liver enzymes, all fulfilling the Evans criteria for probable adverse drug reactions. Moderate but significant signals were also detected for headache, fatigue, and influenza-like illness. Conclusion and Relevance: Post-marketing pharmacovigilance data confirm hepatic toxicity as the predominant safety signal associated with etranacogene dezaparvovec, consistent with clinical trial evidence and the known immunogenic profile of AAV-based gene therapies. These findings support the importance of careful hepatic monitoring in clinical practice and highlight the role of pharmacovigilance in evaluating the real-world safety of innovative gene therapies.