Following 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 and was conditionally approved in Europe in August of 2022 and approved in the U.S. in June of 2023. Beyond Roctavian, there are ongoing pivotal trials of additional AAV vectors for HA and others that are progressing through pre-clinical development or early-phase clinical trial as well as non-AAV approaches also 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 observed stable FVIII expression in AAV HA gene therapy clinical trials with more modest initial FVIII expression. This observation has been qualitatively replicated in animal models. The development and approval of Roctavian is a landmark in HA therapeutics, though next-generation approaches are needed before HA gene therapy fulfills its promise of stable FVIII expression that normalizes hemostasis.
Review Article|
July 11, 2024
Roctavian Gene Therapy for Hemophilia A
Benjamin J Samelson-Jones,
Benjamin J Samelson-Jones
The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
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Juliana C. Small,
Juliana C. Small
The Children's Hospital of Philadeliphia, Philadelphia, Pennsylvania, United States
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Lindsey A. George
University of Pennyslvania School of Medicine, Philadelphia, Pennsylvania, United States
* Corresponding Author; email: georgel@email.chop.edu
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Blood Adv bloodadvances.2023011847.
Article history
Submitted:
April 17, 2024
Revision Received:
June 24, 2024
Accepted:
June 24, 2024
Citation
Benjamin J Samelson-Jones, Juliana C. Small, Lindsey A. George; Roctavian Gene Therapy for Hemophilia A. Blood Adv 2024; bloodadvances.2023011847. doi: https://doi.org/10.1182/bloodadvances.2023011847
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