Background: GENEr8-1 is an ongoing phase 3 clinical study evaluating the safety and efficacy of valoctocogene roxaparvovec, an AAV5-mediated gene therapy encoding human B-domain-deleted FVIII (hFVIII-SQ) for the treatment of hemophilia A. Following administration, substantial increases in FVIII activity levels were observed with an acceptable safety profile. The most common adverse event was a mild, transient increase in ALT, which was managed using glucocorticoids.

Aims: Evaluate humoral and cellular immune responses following administration of valoctocogene roxaparvovec and assess impact on patient safety and therapeutic efficacy.

Methods: Plasma and PBMCs were collected at specified timepoints prior to and following administration of valoctocogene roxaparvovec from the first 16 patients with ≥26 weeks follow-up. FVIII inhibitors were assessed using the Nijmegen-modified Bethesda assay. FVIII and AAV5 total binding antibody (TAb) titers were determined by ECLA. Patients testing positive at screening for AAV5 TAb, or with a history of FVIII inhibitors, were excluded from the study. PBMCs were analyzed by IFN-γ ELISpot assay for capsid-specific and hFVIII-SQ-specific cellular immune responses.

Results: No patients developed FVIII inhibitors after dosing. All patients were AAV5 TAb positive by week 8 and remained positive at all subsequent timepoints. TAb titers were not associated with ALT elevations or FVIII activity measures. Most patients tested positive for cellular immune responses to AAV5; positivity was largely transient, self-limiting, and not consistently associated with changes in ALT or FVIII activity measures. Detection of FVIII-specific cellular immune responses was rare. Responses to both AAV5 and FVIII could be detected during and outside periods of glucocorticoid use.

Conclusions: The immune response to valoctocogene roxaparvovec is primarily directed toward the AAV5 capsid with only sporadic, transient responses toward hFVIII-SQ. These responses have not been associated with safety or efficacy outcomes. FVIII inhibitor responses have not been detected in any valoctocogene roxaparvovec recipient to date.

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/clinical-immunogenicity-of-valoctocogene-roxaparvovec-in-gener8-1-a-phase-3-study-of-aav5-mediated-gene-therapy-encoding-human-fviii-for-the-treatment-of-hemophilia-a/