Monthly Garadacimab Reduces Hereditary Angioedema Attacks

Hereditary angioedema attacks in patients at least 12 years of age were significantly and safely reduced with monthly subcutaneous garadacimab, according to study findings published in The Lancet.

A fully-human, novel monoclonal antibody, garadacimab inhibits activated factor XII (FXIIa). Researchers sought to assess the efficacy and safety of subcutaneous garadacimab administered once-monthly as prophylaxis for hereditary angioedema. The primary outcome was the number of hereditary angioedema attacks per month during the 6-month treatment period.

In the VANGUARD (ClinicalTrials.gov Identifier: NCT04656418) randomized, double-blind, placebo-controlled, multicenter, phase 3 trial, researchers recruited patients at least 12 years of age from 7 countries (Israel, Japan, Hungary, Germany, Canada, the Netherlands, and the US) from January 2021 to June 2022. The study included 39 patients who received a 400 mg loading dose and 200 mg garadacimab once monthly for 6 months (self-administered or caregiver-administered) and 22 patients who received a loading dose and volume-matched placebo once monthly (59% women; 86% White, 9% Asian, 2% Black, 2% Pacific Islander).

Patients were stratified by age (≤17 years and >17 years). Those older than 17 years were additionally stratified by baseline attack rate (1 to <3 attacks/month vs ≥3 attacks/month). Patients, investigational staff, and funder representatives were masked to treatment assignment. Among all patients in the garadacimab group, 14 received either complement C1-INH (intravenous or subcutaneous; 6 patients), berotralstat dihydrochloride (4 patients), tranexamic acid (2 patients), danazol (1 patient), or landelumab (1 patient).

Researchers found patients in the garadacimab group had a significantly lower mean number of investigator-confirmed hereditary angioedema attacks/month (0.27; 95% CI, 0.05-0.49) than the placebo group (2.01; 95% CI, 1.44-2.57; P <.0001). This corresponds to a percentage difference in means of -87% (95% CI, -96% to -58%; P <.0001). The investigators noted the median number of hereditary angioedema attacks/month for garadacimab was 0.0 (interquartile range [IQR], 0.00-0.31) and for placebo was 1.35 (IQR, 1.00-3.20).

Patients treated with garadacimab vs placebo had a 90% reduction in the mean number of moderate or severe hereditary angioedema attacks/month. Notably, almost 75% of patients receiving garadacimab were attack-free during the first 3 months of treatment vs 10% of patients receiving placebo (P <.0001). Moreover, during the full 6 months of treatment, 62% of patients receiving garadacimab were attack-free, whereas none of the patients in the placebo group were attack-free for the entire 6-month period (P <.0001). Researchers noted patients in the garadacimab group had a 91% reduction from baseline in the number of hereditary angioedema attacks/month compared with patients in the placebo group, who exhibited a 20% reduction from baseline in the number of attacks/month.

Upper respiratory tract infections, nasopharyngitis, and headaches were the most common treatment-emergent adverse events. Inhibition of FXIIa was not associated with increased risk of thromboembolic events or bleeding. There were 3 patients in the garadacimab group who evaluated treatment response as “poor”; each of those patients had at least a 50% attack-rate reduction throughout the treatment period.

Significant study limitations include the underpowered sample size, the short treatment period, possible selection bias, and lack of generalizability due to inadequate racial and ethnic representation.

“Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favorable safety profile,” researchers concluded. “Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults.”

Disclosure: This research was supported by CSL Behring. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.