Abstract
Non-factor replacement therapies (NFTs) have been developed to address the limitations
of conventional replacement therapies, aiming to improve hemostasis and provide enhanced
protection against bleeding episodes and long-term joint damage for patients both
with and without inhibitors. Factor VIII (FVIII)-mimetic agents, such as emicizumab,
have transformed the management of hemophilia A with inhibitors, offering a lower
treatment burden and an effective alternative for those without inhibitors as well.
Rebalancing agents, including anti-tissular factor pathway inhibitor agents (concizumab
and marstacimab) and serpin inhibitors like fitusiran, have shown promising efficacy
for patients with hemophilia B with inhibitors and other hemophilia subtypes. Administered
subcutaneously, NFTs generate stable thrombin levels and feature a long half-life,
which can shift severe hemophilia toward a milder phenotype. These therapies are effective
regardless of inhibitor status and hold potential for application in other bleeding
disorders. Evaluating the potential thrombotic risk after implementing mitigation
measures, along with the development of anti-drug antibodies (ADAs), remain critical
areas for further analysis. NFTs pose additional challenges due to their complex mechanism
of action and the absence of a standardized laboratory assessment method. Unresolved
issues include optimal management strategies for major surgeries and tailored approaches
for safe use in older populations. This review highlights the progress and future
potential of NFTs in treating persons with hemophilia.
Keywords
hemophilia - non-factor replacement therapies - FVIII mimetics - rebalancing agents
