New Treatment in Haemophilia: Challenges, Controversies and Uncertainties

The therapeutic landscape for haemophilia is rapidly evolving beyond traditional factor replacement to include nonfactor therapies and adeno-associated virus (AAV) gene therapy. These innovations promise effective, long-term prophylaxis with reduced treatment burden but introduce new complexities in clinical management. This review provides a comprehensive analysis of these emerging treatments, focusing on key practical challenges. For nonfactor therapies-including emicizumab, concizumab, marstacimab and fitusiran-critical considerations for bleed management, surgical procedures, and transitioning between products, emphasizing that these agents are for prophylaxis only and require specific, often product-specific, concomitant factor or bypassing agent protocols for acute haemostasis. We further examine the safety profiles of these agents, with a focus on thrombotic risk, which can arise from drug-drug interactions, an excessive procoagulant effect, or the unmasking of baseline risk factors. Immunogenicity, while less frequent than with traditional factors, remains a consideration requiring ongoing pharmacovigilance. Finally, we address the central immunogenicity challenge in AAV gene therapy: managing cytotoxic T-cell-mediated hepatotoxicity that can threaten transgene expression. The role of corticosteroid immunomodulation-both prophylactic and reactive-is explored across clinical trials for haemophilia A and B, highlighting variable responses and the need for tailored strategies. This review synthesizes current evidence to help clinicians navigate this new therapeutic era, optimizing outcomes while mitigating the risks associated with these transformative treatments.