Outcomes and management of invasive procedures in participants with hemophilia A post gene therapy: a post hoc analysis of the GENEr8-1 phase III trial

Background: Hemophilia A is caused by coagulation factor VIII (FVIII) deficiency and increases bleeding risk during invasive procedures.

Objectives: To investigate FVIII concentrate use and bleeding outcomes for invasive procedures after valoctocogene roxaparvovec gene transfer.

Design: This manuscript presents post hoc analysis of the phase III GENEr8-1 trial.

Methods: A post hoc analysis was performed for GENEr8-1, a global, single-arm, open-label, phase III trial that enrolled 134 adults with severe hemophilia A. FVIII activity and bleeding were evaluated after 2 years of follow-up. Invasive procedures were reviewed and categorized as major or minor. FVIII activity was measured with a chromogenic assay. Bleeding was self-reported by participants. Principal investigators completed questionnaires about perioperative management.

Results: In total, 111 invasive procedures were performed in 65 participants during GENEr8-1 as of the data cut. Procedures performed with FVIII treatment included 33 minor and 11 major procedures. The remaining 67 invasive procedures were minor and performed without FVIII treatment. When considering these 67 minor procedures, 43/46 investigators completing the questionnaires reported that the gene-therapy-derived FVIII activity was sufficient for the type of procedure. Minor procedures performed without FVIII treatment were associated with participants' higher mean endogenous FVIII activity (50.5 IU/dL) compared with major procedures (14.2 IU/dL) or minor procedures (16.4 IU/dL) performed with concomitant FVIII. Fourteen participants experienced 18 procedure-related bleeds (13 co-occurring with FVIII use). Participants who received FVIII treatment for procedure-related bleeds had numerically lower mean endogenous FVIII activity than those who did not receive FVIII treatment.

Conclusion: Invasive procedures were safely performed in participants following treatment with valoctocogene roxaparvovec. The questionnaire responses from investigators generally suggest they used endogenous FVIII activity derived from valoctocogene roxaparvovec to inform clinical decisions in a manner comparable to exogenously administered FVIII, and more commonly prescribed supplementary FVIII concentrate in the peri-procedural period for participants with lower FVIII activity levels.