Efficacy and safety of valoctocogene roxaparvovec 4 years after gene transfer in GENEr8-1

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Introduction: Valoctocogene roxaparvovec (AAV5-hFVIII-SQ), a gene transfer therapy for severe hemophilia A, enables endogenous factor VIII (FVIII) production to prevent bleeding. The aim of this study was to evaluate efficacy and safety outcomes 4 years post-valoctocogene roxaparvovec treatment. Method: 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 was assessed in 132 HIV-negative participants (modified ITT [mITT] population). Safety was assessed in the ITT population. Results: 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 was 16.1 and 27.1 IU/dL, respectively, in the mITT population (18.0 and 25.5 IU/dL at W260 for the mITT subgroup dosed≥5 years prior); 10/130 (7.7%), 68/130 (52.3%), 18/130 (13.8%), and 34/130 (26.2%) participants had CSA FVIII activity≥40,≥5 to<40,≥3 to<5, and<3 IU/dL, respectively. During year 4, the most common adverse event was alanine aminotransferase (ALT) elevation (56/131 participants; ALT>upper limit of normal or≥1.5x baseline); no participants initiated immunosuppressants for ALT elevation. Conclusion: Bleed control and FVIII expression were maintained 4 years post-valoctocogene roxaparvovec treatment. No new safety signals emerged. Publication History Article published online: 13 February 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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