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.

BACKGROUND: Hereditary angioedema is a rare and potentially life-threatening genetic disease that is associated with kallikrein-kinin system dysregulation. Garadacimab (CSL312), a novel, fully-human monoclonal antibody that inhibits activated factor XII (FXIIa), is being studied for the prevention of hereditary angioedema attacks. The aim of this study was to evaluate the efficacy and safety of once-monthly subcutaneous administrations of garadacimab as prophylaxis for hereditary angioedema. METHODS: VANGUARD was a pivotal, multicentre, randomised, double-blind, placebo-controlled, phase 3 trial that recruited patients (aged ≥12 years) with type I or type II hereditary angioedema across seven countries (Canada, Germany, Hungary, Israel, Japan, the Netherlands, and the USA). Eligible patients were randomly assigned (3:2) to receive garadacimab or placebo for 6 months (182 days) by an interactive response technology (IRT) system. Randomisation was stratified by age (≤17 years vs >17 years) and baseline attack rate (1 to <3 attacks per month vs ≥3 attacks per month) for the adult group. The randomisation list and code were kept by the IRT provider during the study, with no access by site staff and funding representatives. All patients and investigational site staff, and representatives from the funder (or their delegates) with direct interaction with the study sites or patients, were masked to treatment assignment in a double-blind fashion. Randomly assigned patients received a 400-mg loading dose of subcutaneous garadacimab as two 200-mg injections or volume-matched placebo on day 1 of the treatment period, followed by five additional self-administered (or caregiver-administered) monthly doses of 200-mg subcutaneous garadacimab or volume-matched placebo. The primary endpoint was the investigator-assessed time-normalised number of hereditary angioedema attacks (number of hereditary angioedema attacks per month) during the 6-month treatment period (day 1 to day 182). Safety was evaluated in patients who received at least one dose of garadacimab or placebo. The study is registered with the EU Clinical Trials Register, 2020-000570-25 and ClinicalTrials.gov, NCT04656418. FINDINGS: Between Jan 27, 2021, and June 7, 2022, we screened 80 patients, 76 of whom were eligible to enter the run-in period of the study. Of 65 eligible patients with type I or type II hereditary angioedema, 39 were randomly assigned to garadacimab and 26 to placebo. One patient was randomly assigned in error and did not enter the treatment period (no dose of study drug received), resulting in 39 patients assigned to garadacimab and 25 patients assigned to placebo being included. 38 (59%) of 64 participants were female and 26 (41%) were male. 55 (86%) of 64 participants were White, six (9%) were Asian (Japanese), one (2%) was Black or African American, one (2%) was Native Hawaiian or Other Pacific Islander, and one (2%) was listed as other. During the 6-month treatment period (day 1 to day 182), the mean number of investigator-confirmed hereditary angioedema attacks per month was significantly lower in the garadacimab group (0·27, 95% CI 0·05 to 0·49) than in the placebo group (2·01, 1·44 to 2·57; p<0·0001), corresponding to a percentage difference in means of -87% (95% CI -96 to -58; p<0·0001). The median number of hereditary angioedema attacks per month was 0 (IQR 0·00-0·31) for garadacimab and 1·35 (1·00-3·20) for placebo. The most common treatment-emergent adverse events were upper-respiratory tract infections, nasopharyngitis, and headaches. FXIIa inhibition was not associated with an increased risk of bleeding or thromboembolic events. INTERPRETATION: Monthly garadacimab administration significantly reduced hereditary angioedema attacks in patients aged 12 years and older compared with placebo and had a favourable safety profile. Our results support the use of garadacimab as a potential prophylactic therapy for the treatment of hereditary angioedema in adolescents and adults. FUNDING: CSL Behring.

Epidemiology of inhibitors and current treatment strategies.

The development of inhibitors is currently one of the most serious complications in the treatment of hemophilic children. Prospective studies of previously untreated patients (PUP) showed that up to 52% of patients with severe hemophilia A developed inhibitors during the first 50 exposure days (ED) (>100 for outliers). Inhibitor development is influenced by the type of hemophilia, the severity and the type of mutation. No significant differences in inhibitor incidence were found in prospective studies conducted with plasma-derived or recombinant products. However, no comparative study has been finished yet. A still ongoing prospective, multi-center PUP-study initiated by the German, Austrian and the Swiss Society of Thrombosis and Hemostasis Research (GTH) foresees the direct comparison of different types of concentrates with regard to inhibitor development. Preliminary results (update February 2002) show a slightly higher inhibitor development (p=0.08) in severely affected hemophilia A patients treated with recombinant factor (F) VIII concentrates. However, the groups are very small and statistically reliable statements cannot be made at the moment. In case of inhibitor development rapid inhibitor elimination and immune tolerance induction (ITI) is the preferred way to reduce the high risk of bleeding episodes. In this respect, various therapeutic regimens, such as the administration of high doses of FVIII twice daily (Bonn protocol), or lower doses three times weekly (van Creveld protocol), have been attempted. Elimination of inhibitors from plasma by immune adsorption followed by immune suppression (Malmö protocol) has also been used. The influence of the type of concentrate used for ITI has never been investigated comparatively. A longitudinal study of ITI at our center showed a significantly decreased success rate since the introduction of high purity plasma derived and recombinant FVIII products using the Bonn protocol. In inhibitor patients who showed an unsatisfactory response to treatment with FVIII concentrates with very little or no VWF the change to concentrates containing high amounts of von Willebrand factor (VWF) increased success rates up to 90%. These observations raise the question of whether VWF plays an important role in the induction of immune tolerance.

Inhibitor development in previously untreated patients with hemophilia A: a prospective long-term follow-up comparing plasma-derived and recombinant products.

In order to assess inhibitor development in previously untreated patients (PUPs) with severe (factor VIII [FVIII]<1%) and moderate (FVIII 1 to 5%) hemophilia A, a prospective study was initiated in 1976. During the 23-year study period, 72 hemophiliacs were frequently exposed prophylactically or on demand to plasma-derived (pd) (n = 51) or recombinant FVIII (rFVIII) (n = 21) concentrates (median 270 exposure days [ED]). Inhibitor testing was performed before the first exposure and at regular intervals thereafter. Of the 72 hemophilia A patients, 22 (32%) developed an inhibitor after 15 ED in median (range 4 to 195); 17 (77%) were high responders (>5 Bethesda Units [BU]), and the remaining 5 patients (23%) were low responders (>0.6 to 5 BU). The severely affected patients (n = 46) showed a significantly higher frequency of inhibitor formation (43%) than did the moderate ones (8%). Comparing the severely affected patients receiving pd products exclusively (n = 35) with those treated with recombinant concentrate (n = 11), 37% of the pd group developed a high-titer inhibitor (>5 BU, median 290 ED in noninhibitor patients) and 36% of the recombinant group (median 49 ED in the noninhibitor patients). However, the exposure status of the recombinant noninhibitor patients is rather low and therefore remains a high risk of developing further inhibitors in the future. The mutation type profile revealed no difference between the pd- and the recombinant-treated patients.