New and novel pharmacotherapies for hemophilia A: an update

Hemophilia A (HA) management has progressed significantly, yet standard and extended half-life (EHL) clotting factors present persistent limitations, including intravenous burden and suboptimal trough levels.

This narrative review highlights recently approved agents and phase III candidates for HA. In replacement therapy, efanesoctocog alfa maintains normal-to-near-normal factor VIII (FVIII) levels weekly by bypassing endogenous von Willebrand factor dependence. In non-replacement therapies, the focus centers on rebalancing agents - the anti-tissue factor pathway inhibitor (TFPI) monoclonal antibodies concizumab and marstacimab, and the antithrombin-targeting small interfering RNA (siRNA) fitusiran - as well as next-generation FVIII-mimetics like denecimig. With this objective, a structure literature search of the main original manuscripts and reviews published in English in major medical databases, including PubMed, EMBASE, and Cochrane Library from 2016 to now was conducted.

While these innovators promise near-zero bleeding rates and subcutaneous convenience, they introduce unique challenges. Rebalancing therapies present potential thromboembolic risks, complex breakthrough bleed protocols, and standard laboratory assay interference (requiring antithrombin monitoring or specialized assays). Critical goals for contemporary hemophilia management include tailoring therapies through multidisciplinary collaboration, monitoring subclinical joint disease via point-of-care ultrasound, and implementing standardized, real-world protocols for emergency hemostasis.