Inhibitor of Activated Factor XII Garadacimab in Prophylaxis of HAE Attacks
Hereditary angioedema (HAE) is an autosomal dominant inherited disease characterized by a deficiency of C1 inhibitor. This condition leads to excessive production of bradykinin, which is responsible for the development of soft tissue edema. Garadacimab represents a human antibody, the first of its class, aimed at inhibiting activated factor XII, a key initiator of bradykinin formation. The phase II study presented below, whose results were recently published, evaluated the efficacy and safety of this innovative HAE therapy.
Possibilities of Influencing Bradykinin Production
HAE is a disease characterized by dysregulation in the kallikrein-kinin system. Activated factor XII (FXIIa) is a key initiator of excessive bradykinin production, which is the central mediator of soft tissue angioedema formation.
Garadacimab is a fully human recombinant antibody against FXIIa, developed to effectively prevent angioedema attacks in patients with hereditary angioedema with C1 inhibitor deficiency. The goal of the recently published phase II clinical study was to evaluate the efficacy and safety of garadacimab in the prophylactic therapy of HAE.
Methodology and Course of the Study
The double-blind, placebo-controlled phase II clinical study was conducted at 12 research centers in Israel, Canada, Germany, and the United States. Patients aged 18-65 who had developed at least 4 angioedema attacks of any severity in two consecutive months within 3 months prior to study entry or prior to initiating previous prophylaxis were included.
After an initial period of 4-8 weeks, participants were evenly randomized in a 1:1:1:1 ratio to receive placebo or garadacimab at doses of 75, 200, or 600 mg administered once every 4 weeks. The initial dose was given intravenously, followed by subcutaneous administration every 4 weeks for up to 12 weeks.
The primary goal of the study was to evaluate the number of monthly attacks in the treated population (ITT − intention-to-treat) during the 12-week subcutaneous therapy, comparing the 200 and 600 mg garadacimab groups with the placebo group. Treatment safety was assessed in each patient who received at least one dose of therapy.
Results
From October 29, 2018, to August 28, 2019, an initial screening of 54 patients was conducted, with 32 allocated to receive placebo (n = 8) or garadacimab at doses of 75 mg (n = 9), 200 mg (n = 8), or 600 mg (n = 7). The median age of participants was 39.5 years (28–52.5 years), and the study population included 18 women and 14 men.
The median number of monthly attacks during the 12-week subcutaneous therapy was 4.6 in the placebo group (interquartile range [IQR] 3.1–5.0), 0 in the 75 mg garadacimab group (IQR 0.0–0.4), 0 in the 200 mg garadacimab group (IQR 0.0–0.0), and 0.3 in the 600 mg garadacimab group (0.0–0.7). Compared to placebo, there was a significant reduction in attack rates in patients receiving 200 mg garadacimab (100% reduction; 95% confidence interval [CI] 98–101; p = 0.0002) and 600 mg garadacimab (93% reduction; 95% CI 54–110; p = 0.0003).
No cases of serious adverse events, deaths, or adverse events of special interest (anaphylaxis, thromboembolic, and bleeding events) were reported during the study.
Conclusion
The phase II clinical study results showed that prophylactic administration of garadacimab at doses of 200 and 600 mg once every 4 weeks significantly reduces the number of monthly HAE attacks compared to placebo. The therapy was well tolerated within the study, with no serious adverse events reported.
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Source: Craig T., Magerl M., Levy D. S. et al. Prophylactic use of an anti-activated factor XII monoclonal antibody, garadacimab, for patients with C1-esterase inhibitor-deficient hereditary angioedema: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 2022; 399 (10328): 945–955, doi: 10.1016/S0140-6736(21)02225-X.
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