Hereditary angioedema (HAE) is a rare genetic condition that can be life-threatening
Associated with kallikrein-kinin system dysregulation, it causes unpredictable debilitating and painful episodes of swelling in, for example, the abdomen, larynx, face and extremities.
Although therapies are available, breakthrough attacks are common, so a more effective prophylactic treatment would be beneficial. A new potential treatment, garadacimab, is being developed by CSL to treat C1-esterase inhibitor deficient HAE.
The monoclonal antibody is a novel Factor XIIa inhibitor; when the serine protease Factor XII is activated to become FXIIa, it initiates a cascade that results in the formation of the oedema.
Garadacimab is designed to inhibit the HAE cascade at its origin — compared with other HAE therapies that target downstream mediators instead. After a successful first-in-human trial in volunteers, a double-blind, placebo-controlled Phase II trial was done in 32 adult patients with the disease.1,2
Patients had had at least four attacks during a 2-month period in the 3 months before screening. They were randomly assigned to receive 75, 200 or 600 mg of the antibody or a placebo, with an initial intravenous loading dose then a subcutaneous dose on day 6 and every 4 weeks thereafter for 12 weeks.
During the treatment period, the median number of monthly attacks was 4.6 with the placebo, 0.0 with both the 75 and 200 mg doses, and 0.3 with the highest dose. There were no serious adverse events.
In a multicentre, randomised, double-blind, placebo-controlled Phase III trial, 64 patients aged 12 or older with HAE were given a 400 mg loading dose of garadacimab or a placebo, and then five additional monthly doses of the antibody or the placebo.3
The primary endpoint was the number of HAE attacks per month during the trial period; and at a mean number of 0.27 with the antibody, it was significantly lower than the 2.01 observed with the placebo.
Protection from attacks was observed from the first dose, with nearly three quarters of the active group being attack free within the first 3 months and efficacy being sustained for the second 3 months.
The most common treatment-emergent adverse events were infections in the upper respiratory tract, nasopharyngitis and headaches. There was no increased risk of bleeding or thromboembolic events.
The company plans to file for regulatory approval this year. The antibody is also being investigated in other indications, including idiopathic pulmonary fibrosis, wherein FXIIa inhibition might also improve clinical outcomes.