Valoctocogene roxaparvovec (AAV5-hFVIII-SQ), a gene transfer therapy for severe hemophilia A, enables endogenous factor VIII (FVIII) production to prevent bleeding. We present efficacy and safety outcomes 4-years post-valoctocogene roxaparvovec treatment in the GENEr8-1 trial.

In the open-label, multicenter, phase 3 GENEr8-1 trial (NCT03370913), 134 adult men with severe hemophilia A (FVIII ≤1 IU/dL) without FVIII inhibitors received 6E13 vg/kg valoctocogene roxaparvovec (Intention-To-Treat [ITT] population). Bleeds and FVIII use were self-reported after regular prophylaxis cessation (scheduled Week [W]4). The rollover population, which included 112 HIV-negative participants who enrolled from a non-interventional study, was used for comparisons with baseline FVIII use and bleeding rate. Chromogenic (CSA) and One-Stage Assay (OSA) FVIII activity were assessed in 132 HIV-negative participants (modified ITT [mITT] population). Safety was assessed in the ITT population.

In the ITT population, 118/134 participants completed W208; 24/134 participants resumed prophylaxis. In the rollover population, mean annualized treated bleeding rate was 0.8 bleeds/y, mean annualized bleeding rate for all bleeds was 1.3 bleeds/y, and mean annualized FVIII infusion rate was 6.1 infusions/y over 4-years. During year 4, 81/110 (73.6%) participants had 0 treated bleeds and 68/110 (61.8%) participants had 0 bleeds regardless of treatment. At W208, mean CSA and OSA FVIII activity were 16.1 and 27.1 IU/dL in the mITT population respectively. At W260, mean CSA and OSA FVIII activity were 18.0 and 25.5 IU/dL for the mITT subgroup dosed ≥ 5-years prior. FVIII activity (CSA) ≥ 40, ≥ 5 to < 40, ≥ 3 to < 5, and < 3 IU/dL was verified in 10/130 (7.7%), 68/130 (52.3%), 18/130 (13.8%), and 34/130 (26.2%) of participants, respectively. During year 4, the most common adverse event was alanine aminotransferase (ALT) elevation (56/131 participants; ALT > upper limit of normal or ≥ 1.5× baseline); no participants initiated immunosuppressants for ALT elevation.

At four years post valoctocogene roxaparvovec therapy, bleed control and FVIII expression were maintained in the majority of patients. No new safety signals emerged.