Roctavian gene therapy for hemophilia A

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After successful efforts in adeno-associated virus (AAV) gene addition for hemophilia B gene therapy, the development of valoctocogene roxaparvovec (Roctavian; Biomarin) over the past decade represents a potential new hemophilia A (HA) treatment paradigm. Roctavian is the first licensed HA gene therapy that was conditionally approved in Europe in August 2022 and approved in the United States in June 2023. Beyond Roctavian, there are ongoing pivotal trials of additional AAV vectors for HA, others that are progressing through preclinical development or early-phase clinical trial, as well as non-AAV approaches in clinical development. This review focuses on the clinical development of Roctavian for which the collective clinical trials represent the largest body of work thus far available for any licensed AAV product. From this pioneering clinical development, several outstanding questions have emerged for which the answers will undoubtedly be important to the clinical adaptation of Roctavian and future efforts in HA gene therapy. Most notably, unexplained year-over-year declines in factor VIII (FVIII) expression after Roctavian treatment contrast with stable FVIII expression observed in other AAV HA gene therapy clinical trials with more modest initial FVIII expression. This observation has been qualitatively replicated in animal models that may permit mechanistic study. The development and approval of Roctavian is a landmark in HA therapeutics, although next-generation approaches are needed before HA gene therapy fulfills its promise of stable FVIII expression that normalizes hemostasis.