Durability of efficacy, safety, and quality of life 5 years after valoctocogene roxaparvovec gene transfer for severe hemophilia A: final phase 3 GENEr8-1 trial results

Background: Valoctocogene roxaparvovec, a gene therapy for severe hemophilia A, enables endogenous factor VIII (FVIII) expression and confers bleed control. Objectives: To present the final 5-year efficacy and safety results from the phase 3 GENEr8-1 trial. Methods: Adult men (N = 134) with severe hemophilia A without inhibitors who were using FVIII prophylaxis received one 6 × 1013 vg/kg infusion of valoctocogene roxaparvovec. End points included annualized bleeding rate (ABR), FVIII infusion rate, FVIII activity, Haemophilia-Specific Quality of Life Questionnaire for Adults, adverse events, and immunosuppressant use. Results: Median follow-up was 261.1 weeks; 128 of 134 participants completed the study. For the 112 participants who enrolled from a previous noninterventional study (rollover population), mean ABR for treated bleeds declined by 83.3% (P < .0001), mean FVIII infusion rate declined by 94.9% (P < .0001), and mean ABR for all bleeds declined by 78.1% in the 5-year efficacy evaluation period vs baseline. In 132 modified intention-to-treat participants, mean and median FVIII activity at week 260 was 13.7 and 6.2 IU/dL, respectively (chromogenic assay). In year 5, 77.8% of rollover participants had 0 treated bleeds. One participant resumed prophylaxis since the 4-year data cutoff (25/134 across all follow-up). Haemophilia-Specific Quality of Life Questionnaire for Adults total score was improved from baseline at year 5. In year 5, alanine aminotransferase elevations occurred in 51 of 129 participants who entered year 5. Immunosuppressants were not used to manage them. No serious treatment-related adverse events occurred after year 1. Conclusion: Valoctocogene roxaparvovec provides durable hemostatic efficacy, FVIII activity, and improved health-related quality of life for ≥5 years, with no new safety signals.