Efficacy and Safety of an Activated FXII Inhibitor in Preventing HAE Attacks

Introduction

Activated factor XII (FXIIa) is a key initiator of excessive bradykinin production in patients with HAE with a complement C1 inhibitor deficiency. In this condition, even minimal triggers, such as minor injuries, lead to the activation of the entire complement cascade, resulting in subcutaneous and mucosal edema. The disease poses a potentially life-threatening complication, most commonly due to swelling in the respiratory tract area.

The prevention of disease attacks is crucial in therapy. For this purpose, garadacimab has been developed, a human antibody – the first in its class – aiming to inhibit FXIIa. The efficacy and safety of prophylactic therapy with garadacimab in patients with HAE was evaluated in the VANGUARD clinical trial.

Methodology and Study Course, Patient Population

Participants aged ≥ 12 years with type I and II HAE from 7 countries (Israel, Japan, Canada, Hungary, Germany, the Netherlands, and the United States) were enrolled in a pivotal multicenter randomized double-blind placebo-controlled phase III clinical trial. Eligible patients were randomized in a 3:2 ratio to garadacimab or placebo therapy for 6 months. Randomization was stratified by age (≤ 17 years vs. > 17 years) and for adult patients by baseline attack frequency (1 to < 3 attacks vs. ≥ 3 attacks per month).

On the first day of therapy, patients received an initial dose of 400 mg garadacimab subcutaneously (in two 200 mg injections) or a volume-matching amount of placebo, followed by 5 doses of garadacimab at 200 mg or placebo administered monthly.

The primary objective of the study was to evaluate the time-normalized number of HAE attacks (per month) over 6 months of therapy. The safety of the therapy was assessed in patients who received at least one dose of garadacimab or placebo.

From January 27, 2021, to June 7, 2022, 80 patients underwent initial screening, of whom 76 met the inclusion criteria for the study's run-in period. Subsequently, 65 eligible patients were randomized to garadacimab therapy (n = 39) and placebo (n = 26; 1 patient was mistakenly included, thus 25 patients finally underwent therapy in this group). The study population included 38 women (59%) and 26 men (41%). The majority of patients were Caucasian (86%; n = 55).

Results

During the 6-month treatment period, the average number of HAE attacks confirmed by investigators was significantly lower in the garadacimab group (0.27; 95% confidence interval [CI] 0.05–0.49) compared to the placebo group (2.01; 95% CI 1.44–2.57; p < 0.0001). This finding corresponded to an average percentage difference of −87% (95% CI −96 to −58; p < 0.0001). The median number of HAE attacks per month was 0 in the garadacimab group (interquartile range [IQR] 0.00–0.31) and 1.35 in the placebo group (IQR 1.00–3.20).

The most common therapy-related adverse events included upper respiratory tract infections, nasopharyngitis, and headaches. Inhibition of activated factor XII was not associated with an increased risk of bleeding or thromboembolic events.

Conclusion

Results from the phase III clinical trial indicated that prophylactic administration of garadacimab significantly reduced the occurrence of HAE attacks in patients aged ≥ 12 years compared to placebo. Additionally, this therapy demonstrated a favorable safety profile. The study results support the use of garadacimab in the prophylaxis of HAE in adolescents and adults.

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Source: Craig T. J., Reshef A., Li H. H. et al. Efficacy and safety of garadacimab, a factor XIIa inhibitor for hereditary angioedema prevention (VANGUARD): a global, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2023; 401 (10382): 1079–1090, doi: 10.1016/S0140-6736(23)00350-1.