KV998086

KV998086 is an orally bioavailable, potent, and selective small molecule inhibitor of activated Factor XII (FXIIa), currently under development by KalVista Pharmaceuticals for the treatment of hereditary angioedema (HAE). Identified through structure-based drug design using a fragment growth approach, the compound acts as a competitive inhibitor targeting the catalytic site of FXIIa with an IC50 of 7.2 nM. By blocking FXIIa, KV998086 prevents the activation of the kallikrein-kinin system (KKS), thereby suppressing the generation of plasma kallikrein and the subsequent cleavage of high molecular weight kininogen, which are key drivers of angioedema attacks. Preclinical studies have demonstrated that the drug possesses high oral bioavailability (78% in rats) and provides protection against edema in various animal models, representing a novel oral approach to managing KKS-mediated disorders.