[Pharmacological characteristics and clinical trial results of garadacimab (anti-activated factor XII monoclonal antibody) for long-term prophylaxis of hereditary angioedema].

Abstract

Hereditary angioedema (HAE) is a rare life-threatening disease with recurrent edema. We outline the pharmacological characteristics and study results of a new drug, garadacimab (human anti-activated factor XII [FXIIa] monoclonal antibody), which has novel mechanism of action and suppresses acute HAE attacks. In HAE, excessive bradykinin production, an inflammatory mediator increasing vascular permeability, causes edema, and activation of factor XII initiates bradykinin production. Garadacimab suppresses bradykinin production by inhibiting FXIIa. HAE attacks include fatal laryngeal edema, and overall severity varies substantially among patients. There is an unmet medical need for treatment to reduce its frequency and severity. For prophylactic treatment, a convenient drug with long-administration interval is desired to reduce patients' burden. Based on results of Phase I study in healthy subjects and Phase II study of multiple doses in patients, efficacy and safety of monthly administration of 200 mg garadacimab were compared in 64 patients (ITT: 39 in garadacimab and 25 in placebo) in Phase III study. The primary endpoint, monthly attack frequency was significantly lower in garadacimab than placebo (0.27 vs. 2.01; P < 0.001), with relative reduction rate 87%. Monthly subcutaneous administration of 200 mg garadacimab showed favorable safety profile. The proportion of patients who remained attack-free during the 6-month was 62% in garadacimab and 0% in placebo, and effect after the first dose was maintained throughout the study period. Since this drug is administered subcutaneously once a month with autoinjector, reduction of patients' burden is also expected.