Clinical immunogenicity outcomes from GENEr8-1, a phase 3 study of valoctocogene roxaparvovec, an AAV5-vectored gene therapy for hemophilia A

Mol Ther. 2024 Jul 3;32(7):2052-2063. doi: 10.1016/j.ymthe.2024.05.033. Epub 2024 May 24.

Abstract

Gene transfer therapies utilizing adeno-associated virus (AAV) vectors involve a complex drug design with multiple components that may impact immunogenicity. Valoctocogene roxaparvovec is an AAV serotype 5 (AAV5)-vectored gene therapy for the treatment of hemophilia A that encodes a B-domain-deleted human factor VIII (FVIII) protein controlled by a hepatocyte-selective promoter. Following previous results from the first-in-human phase 1/2 clinical trial, we assessed AAV5-capsid- and transgene-derived FVIII-specific immune responses with 2 years of follow-up data from GENEr8-1, a phase 3, single-arm, open-label study in 134 adult men with severe hemophilia A. No FVIII inhibitors were detected following administration of valoctocogene roxaparvovec. Immune responses were predominantly directed toward the AAV5 capsid, with all participants developing durable anti-AAV5 antibodies. Cellular immune responses specific for the AAV5 capsid were detected in most participants by interferon-γ enzyme-linked immunosorbent spot assay 2 weeks following dose administration and declined or reverted to negative over the first 52 weeks. These responses were weakly correlated with alanine aminotransferase elevations and showed no association with changes in FVIII activity. FVIII-specific cellular immune responses were less frequent and more sporadic compared with those specific for AAV5 and showed no association with safety or efficacy parameters.

Keywords: adeno-associated virus; cellular immune response; clinical trial; factor VIII; gene therapy; hemophilia A; humoral immune response; immunogenicity; valoctocogene roxaparvovec.

Publication types

  • Clinical Trial, Phase III

MeSH terms

  • Adult
  • Antibodies, Viral / blood
  • Antibodies, Viral / immunology
  • Dependovirus* / genetics
  • Dependovirus* / immunology
  • Factor VIII* / genetics
  • Factor VIII* / immunology
  • Genetic Therapy* / methods
  • Genetic Vectors* / administration & dosage
  • Genetic Vectors* / genetics
  • Hemophilia A* / genetics
  • Hemophilia A* / immunology
  • Hemophilia A* / therapy
  • Humans
  • Male
  • Middle Aged
  • Transgenes
  • Treatment Outcome
  • Young Adult

Substances

  • Factor VIII
  • Antibodies, Viral

Supplementary concepts

  • Adeno-associated virus-5