New Prophylactic Treatment for Hereditary Angioedema

Hereditary angioedema (HAE) is a genetic condition characterized by recurrent, unpredictable localized swelling of the skin and mucous membranes. Commonly affected areas include the neck, face, larynx, abdomen, genitals, hands, and feet. These episodes typically last from two to five days and can occur up to twice a week, often causing severe pain and, in cases where the airways are involved, can be life-threatening.

With an estimated prevalence of 1 in 50,000 individuals worldwide, HAE is classified as a rare disease. Most cases result from either a deficiency (Type I) or dysfunction (Type II) of the C1 inhibitor (C1-INH), a crucial regulator of the complement cascade and the kallikrein-kinin system (KKS). The KKS, an endogenous metabolic cascade, involves kallikrein and factor XII (or activated factor XIIa), leading to the increased release of bradykinin, which causes swelling.

Current treatments for HAE attacks include C1-INH preparations, the recombinant C1-INH Conestat alfa (Ruconest(TM)), or the bradykinin antagonist Icatibant (Firazyr®). For long-term prophylaxis, C1-INH preparations can be administered biweekly, while the plasma kallikrein inhibitor Berotralstat (Orladeyo®) is taken daily, and the anti-plasma kallikrein antibody Lanadelumab (Takhzyro®) is administered subcutaneously every two to four weeks. According to international guidelines, the goal of therapy is complete disease control, aiming for long-term freedom from attacks.

A new prophylactic option now available is Garadacimab (Andembry®), a fully human monoclonal IgG4 antibody targeting factor XIIa. By inhibiting factor XIIa, Garadacimab prevents the formation of kallikrein and bradykinin, thereby reducing the frequency of HAE attacks.

Garadacimab is not indicated for the treatment of acute HAE attacks; should a breakthrough attack occur during prophylactic treatment, it should be managed with an appropriate on-demand medication.

This treatment is intended for adults and adolescents aged 12 years and older. The regimen begins with a loading dose of 400 mg (administered as two injections of 200 mg each), followed by a maintenance dose of 200 mg once a month. The injection is administered subcutaneously into the abdomen, thigh, or outer upper arm, with rotation of injection sites recommended. Patients can self-administer Garadacimab after appropriate training.

It is important to note that coagulation tests may yield altered results for patients undergoing Garadacimab treatment, as the antibody may prolong the activated partial thromboplastin time (aPTT). This is due to the activation of factor XII by the reagents used in aPTT assays.

As a precaution, Garadacimab should not be used during pregnancy. Following childbirth, IgG antibodies can transfer into breast milk in the initial days; thus, there may be a risk for nursing infants if the mother is treated with Garadacimab. After this period, use during breastfeeding is considered acceptable.

The approval of Andembry was based on the results of the double-blind Phase III VANGUARD study, which included 58 adult and six pediatric patients aged 12 and older. All participants had HAE Type I or II and experienced at least two attacks during a two-month screening period. They were randomized in a 3:2 ratio to receive either Garadacimab or a placebo.

During the six-month treatment period, the primary endpoint measured was the time-normalized number of HAE attacks, which averaged 0.27 in the Garadacimab group compared to 2.01 in the placebo group, representing an 86.5% reduction. Furthermore, 71.8% of patients in the Garadacimab group were attack-free from day one to the end of the third month, while only 8.3% in the placebo group achieved this.

Common side effects associated with Garadacimab include injection site reactions, headaches, and abdominal pain.

Garadacimab should be stored in a refrigerator at 2 to 8 °C and kept in its original carton. It can be stored at room temperature (up to 25 °C) for a single period of up to two months.

In summary, while there are existing prophylactic treatments for HAE, Garadacimab represents a significant development as the first anti-factor XIIa antibody. The study data demonstrate the efficacy of this treatment in significantly reducing monthly HAE attacks compared to placebo, providing a rapid onset of protection. Although a direct comparison with other available therapies is lacking, Garadacimab shows promise in its effectiveness compared to oral prophylaxis with Berotralstat and is at least comparable to Lanadelumab and subcutaneous C1-INH.