Valoctocogene roxaparvovec (AAV5-hFVIII-SQ) provides endogenous factor VIII (FVIII) production to prevent bleeding in people with severe hemophilia A. This study evaluated bleeding, FVIII activity and safety outcomes 3 years after receiving valoctocogene roxaparvovec.

The open-label, multicenter phase 3 GENEr8-1 trial (NCT03370913) evaluated 6 x 1013 vg/kg valoctocogene roxaparvovec in 134 adult men with severe hemophilia A (FVIII ≤1 IU/dL) without inhibitors. Bleeds and FVIII use were self-reported after regular prophylaxis ended (scheduled for week [W] 4) through data cutoff. Comparisons to baseline on FVIII prophylaxis were performed in a subset of 112 HIV-negative participants enrolling from a non-interventional study (rollover population). FVIII activity per chromogenic assay and quality of life (QOL) per Haemo-QOL-A were assessed in 132 HIV-negative participants (modified intent-to-treat [mITT] population). Safety was assessed in all participants.

Median follow-up was 162 weeks (n = 134); 131 participants completed W156. The mean annualized treated bleeding rate in 112 rollover participants over 3 years was 0.8 bleeds/year, mean annualized rate of all bleeds was 1.3 bleeds/year, and mean FVIII utilization was 125 IU/kg/year. During year 3, 73.2% of 110 rollover participants had zero treated bleeds and 61.6% had no bleeds (excluding surgeries/procedures). At W156, mean and median FVIII were 18.8 and 8.4 IU/dL (mITT, N = 132); 11.4%, 56.1%, and 32.6% of mITT participants had FVIII activity ≥40 IU/dL, ≥5 and <40 IU/dL, and <5 IU/dL, respectively. Overall, 10/132 (7.6%) participants resumed prophylaxis. Mean Haemo-QOL-A Total Score improvement from baseline to W156 was 6.6 (n = 122; p < 0.0001), exceeding the anchor-based clinically important difference (5.5). No new safety signals emerged. Since the previous data cut, 34/134 participants (25.4%) had alanine aminotransferase (ALT) elevation, mostly Grade 1, but none initiated immunosuppressants. Overall, 106/134 (79.1%) used corticosteroids for ALT elevation for median 33 weeks.

Valoctocogene roxaparvovec provided robust hemostatic efficacy relative to FVIII prophylaxis for 3 years, with QOL improvement and stable safety.