Coagulation Factor VIII: Biological Basis of Emerging Hemophilia A Therapies.

Coagulation factor (F) VIII is essential for hemostasis. After activation, it combines with activated FIX (FIXa) on anionic membranes to form the intrinsic tenase enzyme complex, responsible for activating FX in the rate-limiting step of sustained coagulation. Hemophilia A and hemophilia B are due to inherited deficiencies in the activity of FVIII and FIX, respectively. Treatment of hemophilia A over the last decade has benefited from improved understanding of FVIII biology, including its secretion pathway, its interaction with von Willebrand factor in circulation, the biochemical nature of its FIXa cofactor activity, the regulation of FVIIIa by inactivation pathways, and its surprising immunogenicity. This has facilitated biotechnology innovations with first-in-class examples of several new therapeutic modalities recently receiving regulatory approval for hemophilia A, including FVIII mimetic bispecific antibodies and recombinant adeno associated viral (rAAV) vector-based gene therapy. Biological insights into FVIII are also guiding the development and use of gain-of-function FVIII variants aimed at addressing limitations of first-generation rAAV vectors for hemophilia A. Several gain-of-function FVIII variants designed to have improved secretion are currently incorporated in second-generation rAAV vectors and have recently entered clinical trials. Continued mutually reinforcing advancements in the understanding of FVIII biology and treatments for hemophilia A will be necessary to achieve the ultimate goal of hemophilia therapy: normalizing hemostasis and optimizing well-being with minimal treatment burden for all patients worldwide.