ATC Group: B06AC Drugs used in hereditary angioedema

Berotralstat is an inhibitor of plasma kallikrein. In patients with hereditary angioedema (HAE) due to C1-INH deficiency or dysfunction, normal regulation of plasma kallikrein activity is impaired, which leads to uncontrolled increases in plasma kallikrein activity and bradykinin release, resulting in HAE attacks consisting of swelling (angioedema).

C1 inhibitor is a single chain glycoprotein found in plasma and a member of the serine protease inhibitor, or serpin, superfamily of proteins. C1 inhibitor inhibits the complement system by binding C1r and C1s and is the most important inhibitor of contact activation, regulating the contact system and the intrinsic coagulation pathway by binding to and inactivating kallikrein and factor XIIa.

Conestat alfa, a recombinant human complement component 1 (C1) esterase inhibitor (rhC1-INH), is an analogue of human C1-INH and is obtained from the milk of rabbits expressing the gene coding for human C1-INH. C1-INH exerts an inhibitory effect on several proteases (target proteases) of the contact and complement systems.

Ecallantide is a potent (Ki=25 pM), selective, reversible inhibitor of plasma kallikrein. Ecallantide binds to plasma kallikrein and blocks its binding site, inhibiting the conversion of HMW kininogen to bradykinin.

Garadacimab is a fully human IgG4/lambda recombinant monoclonal antibody which binds to the catalytic domain of activated Factor XII (FXIIa and βFXIIa) and inhibits its catalytic activity. The inhibition of FXIIa, the first factor activated in the contact system, prevents HAE attacks by blocking the activation of prekallikrein to kallikrein and the generation of bradykinin, which is associated with inflammation and swelling in HAE attacks.

Icatibant is a selective competitive antagonist at the bradykinin type 2 (B2) receptor. It is a synthetic decapeptide with a structure similar to bradykinin, but with 5 non-proteinogenic amino acids. In HAE increased bradykinin concentrations are the key mediator in the development of the clinical symptoms.

Lanadelumab is a fully human, monoclonal antibody (IgG1/κ-light chain). Lanadelumab inhibits active plasma kallikrein proteolytic activity. Lanadelumab provides sustained control of plasma kallikrein activity and thereby limits bradykinin generation in patients with HAE.