NOVEL THERAPIES FOR HEREDITARY ANGIOEDEMA

Hereditary angioedema (HAE) is a rare, autosomal dominant disease characterized by recurrent subcu-taneous (SC) and submucosal edema attacks. In recent years, significant progress has been made in the management of HAE, driven by a better understanding of its pathophysiology and the development of targeted therapies. Treatment approaches vary depending on the availability of drugs, clinical guide-lines, and individual patient needs. For on-demand treatment, plasma-derived C1 esterase inhibitor (pd-C1-INH), recombinant human C1-INH (rh-C1-INH), icatibant, ecallantide, and fresh frozen plasma are effective and safe options. Intravenous pd-C1-INH remains the first-line therapy for short-term prophy-laxis (STP), while attenuated androgens may serve as alternatives when pd-C1-INH is unavailable. For long-term prophylaxis (LTP), pd-C1-INH, lanadelumab, and berotralstat are strongly recommended as first-line agents. Androgens and antifibrinolytic agents may be considered as second-line options in selected cases. Several novel therapies have expanded the prophylactic options. Subcutaneous pd-C1-INH (Berinert 2000/3000®, Haegarda®) offers a concentrated formulation administered twice weekly. Lanadelumab (Takhzyro®), a SC monoclonal antibody targeting plasma kallikrein, has been safely used since 2018. Berotralstat (Orladeyo®), an oral plasma kallikrein inhibitor, provides a convenient once-daily regimen. Garadacimab (Andembry®), a monoclonal antibody targeting activated Factor XII, received approval in 2025 for monthly SC administration. Investigational agents under development include sebetralstat (an oral plasma kallikrein inhibitor for on-demand use), deucrictibant (an oral bradykinin B2 receptor antagonist for both on-demand and prophylactic use), and several emerging oral kallikrein inhibitors (ATN-249, vE-4666, vE-4062). Additionally, RNA interference (RNAi) ther-apies such as ALN-F12, ARC-F12, ADX-324, and donidalorsen (IONIS-PKK-LRx), as well as gene therapies like NTLA-2002 and monoclonal antibodies targeting plasma kallikrein (e.g., navenibart), offer promising future perspectives for potentially curative interventions. With the availability of these emerging targeted therapies and the implementation of personalized treatment approaches, achieving complete disease control and improving quality of life have become realistic goals in the management of HAE.