Non-Factor Therapies in Haemophilia: The Era of Factor VIII Mimetics and Targeted Rebalancing Agents.

Background: Non-factor therapies have substantially reshaped the treatment landscape of haemophilia by restoring effective thrombin generation independently of factor replacement. By targeting key regulatory mechanisms of coagulation, these approaches address limitations of conventional therapy, including intravenous administration, fluctuating factor levels, and inhibitor development. Summary: Bispecific factor VIII mimetic antibodies enable stable haemostatic protection by functionally substituting the cofactor role of factor VIII, resulting in sustained thrombin amplification with subcutaneous administration. Several years of clinical experience with emicizumab have demonstrated durable efficacy, a favourable safety profile, and broad applicability across patients with haemophilia A with and without inhibitors, establishing factor VIII mimetics as a central component of modern prophylaxis. Next-generation mimetics aim to further optimize potency and haemostatic control. Targeted rebalancing agents enhance coagulation by attenuating endogenous anticoagulants such as tissue factor pathway inhibitor or antithrombin. These approaches provide factor-independent efficacy across haemophilia A and B but introduce distinct safety considerations related to excessive thrombin generation, necessitating dose mitigation and careful monitoring. In acquired haemophilia A, non-factor therapies offer particular advantages by bypassing neutralizing autoantibodies, with prospective data supporting the use of emicizumab for effective bleeding prophylaxis and potential deferral of immunosuppressive therapy in elderly and multimorbid patients. Key Messages: Non-factor therapies enable convenient haemophilia management through subcutaneous administration and sustained haemostatic control. Continued clinical experience will be essential to define the long-term positioning of rebalancing strategies.