Sebetralstat

Hereditary angioedema (HAE) is a rare genetic disease resulting in deficiency or dysfunction of C1 esterase inhibitor (C1INH) protein, leading to uncontrolled activation of the kallikrein-kinin system and episodic tissue swelling that can be life-threatening when affecting the airway. Sebetralstat is a competitive, reversible inhibitor of plasma kallikrein, a serine protease central to the pathophysiology of HAE attacks. Under normal conditions, C1INH regulates plasma kallikrein activity; however, in HAE patients with deficient or dysfunctional C1INH, uncontrolled plasma kallikrein cleaves high molecular weight kininogen (HK), releasing bradykinin, which increases vascular permeability through activation of bradykinin receptors, causing the characteristic angioedema. By competitively inhibiting plasma kallikrein, sebetralstat prevents the cleavage of HK, thereby reducing bradykinin production and treating the clinical symptoms of acute HAE attacks. Additionally, sebetralstat inhibits the positive feedback mechanism of the kallikrein-kinin system, whereby plasma kallikrein activates factor XII to factor XIIa, which in turn generates additional plasma kallikrein from prekallikrein, thus amplifying bradykinin production. This dual mechanism—direct inhibition of bradykinin generation and interruption of the amplification loop—enables sebetralstat to effectively control acute HAE attacks. The drug's oral bioavailability represents a significant advancement over previous parenteral treatments, as it allows patients to self-administer treatment at the earliest sign of an attack, aligning with treatment guidelines that recommend early intervention to prevent attack progression