Three-year outcomes of valoctocogene roxaparvovec gene therapy for hemophilia A

Background Valoctocogene roxaparvovec transfers a human factor VIII (FVIII) coding sequence into hepatocytes of people with severe hemophilia A to provide bleeding protection. Objective Present 3-year efficacy and safety in the multicenter, open-label, single-arm, phase 3 GENEr8-1 trial. Methods GENEr8-1 enrolled 134 adult males with severe hemophilia A who were receiving FVIII prophylaxis. Efficacy endpoints included annualized bleeding rate (ABR), annualized FVIII utilization (AFU), FVIII activity (chromogenic substrate assay; imputed as 1 IU/dL at baseline and 0 IU/dL after discontinuation), and the Haemophilia-Specific Quality of Life Questionnaire for Adults (Haemo-QOL-A). Safety was assessed by adverse events (AEs). Results At week 156, 131/134 participants remained on study; overall, 17/134 resumed prophylaxis. Mean (standard deviation [SD]) treated ABR decreased from 4.8 (6.5) bleeds/year at baseline to 0.8 (SD, 2.3; P <0.0001) bleeds/year during post-prophylaxis (prophylaxis cessation to last follow-up) and 0.97 (SD, 3.48) bleeds/year during year 3. AFU decreased 96.8% from baseline post-prophylaxis and 94.2% during year 3. At week 156, mean and median FVIII activity were 18.4 (SD, 30.8) and 8.3 IU/dL, respectively. FVIII activity decrease was lower between years 2‒3 than 1‒2. At the end of year 3, clinically meaningful improvements in Haemo-QOL-A Total Score were observed (mean change from baseline, 6.6; 95% confidence interval, 4.24‒8.87; P <0.0001). Mild alanine aminotransferase elevations remained the most common AE during year 3 (23.7% of participants). A serious AE of B-cell acute lymphoblastic leukemia was considered unrelated to treatment. Conclusions Hemostatic efficacy was maintained, and safety remained unchanged from previous years.