AAV5 Gene Therapy for Severe Hemophilia A Successfully Enables FVIII Production

The phase 3 GENEr8-1 study demonstrated that valoctocogene roxaparvovec, an AAV5-vectored gene therapy, effectively enabled endogenous FVIII production in adults with severe hemophilia A without developing clinically meaningful FVIII inhibitors.

Findings published in Molecular Therapy examined the clinical immunogenicity outcomes of valoctocogene roxaparvovec, an adeno-associated virus serotype 5 (AAV5)–vectored gene therapy, in adults with severe hemophilia A enrolled in the GENEr-8 trial. The study followed 134 adult men who received a single intravenous infusion of valoctocogene roxaparvovec and were monitored for immune responses over 2 years.1

The study focused on the development of immune responses to both the AAV5 vector capsid and the transgene-expressed human factor VIII (FVIII) protein and the relationship of their response to liver inflammation, safety, and FVIII activity in the GENEr8-1 trial. The participants in the study had severe hemophilia A, defined as having FVIII activity levels below 1 IU/dL, and had no history of FVIII inhibitors or pre-existing anti-AAV5 antibodies.

Red blood drop with double helix | Image credit: Елена Бутусова -

The AAV5-vectored gene therapy aloctocogene roxaparvovec effectively enabled endogenous FVIII production in adults with severe hemophilia A without developing clinically meaningful FVIII inhibitors.

Image credit: Елена Бутусова -

No FVIII inhibitors were detected following the administration of valoctocogene roxaparvovec. All participants developed durable anti-AAV5 antibodies, and cellular immune responses specific for the AAV5 capsid were detected in most participants by interferon-g enzyme-linked immunosorbent spot assay 2 weeks following dose administration. These responses declined or reverted to negative over the first 52 weeks.

"Immune responses were predominantly directed toward the AAV5 capsid and showed no association with changes in FVIII activity," the authors wrote.

Data on FVIII-specific cellular immune responses were available for 123 of 134 participants. These responses were found to be less frequent and more sporadic than those specific for AAV5. The study found no association between FVIII-specific cellular immune responses and adverse events or changes in FVIII activity.

Participants were required to test negative for pre-existing anti-AAV5 antibodies at screening. The researchers noted that 3 participants developed detectable anti-AAV5 antibodies between screening and day 1 (25 to 42 days), were treated with valoctocogene roxaparvovec, and demonstrated effective transduction. "These participants still demonstrated effective transduction, with week 152 or 156 FVIII activity levels between 2.0 and 9.2 IU/dL compared with mean FVIII activity of 18.2 IU/dL and median FVIII activity of 8.2 IU/dL in the overall ITT population," stated the authors.

The study also assessed the impact of treatment-emergent AAV5 total antibodies (TAb) and transduction inhibitors (TI). By week 8, all participants were positive for AAV5 TAbs and TIs. "Mean AAV5 TAb titers first peaked at week 36 and were generally sustained thereafter," they wrote. Median FVIII activity showed no correlation with AAV5 TAB titers at week 8 or week 104.

The most common adverse event observed was elevated alanine aminotransferase (ALT) levels, occurring in 90.3% of participants through year 3.2 In year 1, 85.1% of study participants experienced ALT elevations, generally mild to moderate, and responded to steroids.

"These results suggest that early instances of liver inflammation, between 3- and 6-months post dose, may be related to adaptive immune responses in some individuals and therefore warrant corticosteroid treatment," the researchers noted. The incidence of ALT elevations declined in years 2 and 3, 29% and 23.7%, respectively. ALT elevations that started after 52 weeks were not associated with unanticipated drops in FVIII activity; thus, treatment with corticosteroids was not deemed beneficial.

"Later ALT elevations (R6 months post dose) may be mediated by other mechanisms that remain poorly defined and require further research. Consequently, the benefits of corticosteroid treatment for these secondary ALT elevations should be considered carefully,” the authors concluded.


1. Long BR, Robinson TM, Day JRS, et al. Clinical immunogenicity outcomes from GENEr8-1, a phase 3 study of valoctocogene roxaparvovec, an AAV5-vectored gene therapy for hemophilia A. Mol Ther. Published online May 24, 2024. doi:10.1016/j.ymthe.2024.05.033

2, Madan B, Ozelo MC, Raheja P, et al. Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A. J Thromb Haemost. Published online April 12, 2024. doi:10.1016/j.jtha.2024.04.001

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