HAE is a rare genetic disorder in which patients experience sudden onset of swelling in various locations of the body. Disease symptoms typically begin during childhood and become more pervasive during puberty and adulthood. Patients with HAE lack (type I) or have dysfunctional forms (type 2) of C1-inhibitor, a critical protein that controls the enzyme plasma kallikrein. Some number of patients, known as type 3, experience HAE attacks despite having normal levels of C1-inhibitor. In an HAE attack, lack of C1-inhibitor leads to excessive activation of plasma kallikrein that in turn generates the vasoactive peptide bradykinin, which is responsible for a sudden increase in vascular permeability and leakage of fluid into tissues. Swelling attacks can occur anywhere in the body, ranging from swelling of the abdomen which, if undetected, can lead to unnecessary surgery, to swelling of the airways, which can lead to asphyxiation and death. The disease occurs in approximately 1 in 10,000 to 1 in 50,000 people. Replacing C1-inhibitor or inhibiting activated plasma kallikrein or bradykinin has become the mainstay of therapy for HAE in the US since the early 2000s, although most of the currently approved therapies are delivered by injection or infusion.
Sebetralstat is in development for oral on-demand treatment of HAE with the phase 3 KONFIDENT trial initiated in March 2022.