Garadacimab and the future of hereditary angioedema prophylaxis: a step upstream in the bradykinin pathway

Abstract

Hereditary angioedema (HAE) is a rare autosomal dominant disorder characterized by recurrent, potentially life-threatening episodes of bradykinin-mediated angioedema affecting the skin, gastrointestinal tract, and upper airway. Despite the availability of several prophylactic therapies, there is a need for effective and convenient treatment options. On 21 June 2024, the U.S. Food and Drug Administration approved Andembry™ (garadacimab-gxii), a first-in-class monoclonal antibody that inhibits activated Factor XII (FXIIa), for prophylaxis of HAE attacks in patients aged ≥12 years. By targeting FXIIa, garadacimab acts upstream in the kallikrein–kinin pathway, suppressing bradykinin generation and preventing vascular permeability associated with angioedema. Clinical trials demonstrated substantial reductions in attack frequency, with the phase 3 VANGUARD study reporting a 91.5% reduction in HAE attacks and that approximately 77% of patients remain attack-free during the study period. Garadacimab is administered as a 200-mg subcutaneous injection once monthly and has a favorable pharmacokinetic profile with an elimination half-life of approximately 18–20 days. Adverse events were generally mild, including headache, nasopharyngitis, and injection-site reactions. The approval of garadacimab represents an important advancement in HAE prophylaxis, offering a novel upstream mechanism, convenient dosing, and potential improvement in quality of life of the patients.