Pharmacological suppression of the kallikrein kinin system with KVD900: An orally available plasma kallikrein inhibitor for the on‐demand treatment of hereditary angioedema

BACKGROUND: Hereditary angioedema (HAE) is a rare genetic disease that leads to recurrent episodes of swelling and pain caused by uncontrolled plasma kallikrein (PKa) activity. Current guidelines recommend ready availability of on‐demand HAE treatments that can be administered early upon attack onset. This report describes the pharmacological and pharmacodynamic properties of the novel oral small‐molecule PKa inhibitor KVD900 as a potential on‐demand treatment for HAE. METHODS: Pharmacological properties of KVD900 on PKa and closely related serine proteases were characterized using kinetic fluorogenic substrate activity assays. Effects of KVD900 on PKa activity and kallikrein kinin system activation in whole plasma were measured in the presence of dextran sulphate (DXS)‐stimulation using a fluorogenic substrate and capillary immunoassays to quantify high molecular weight kininogen (HK), plasma prekallikrein and Factor XII cleavage. Pharmacodynamic effects of orally administered KVD900 were characterized in plasma samples from six healthy controls in a first in human phase 1 clinical trial and from 12 participants with HAE in a phase 2 clinical trial. RESULTS: KVD900 is a selective, competitive and reversible inhibitor of human PKa enzyme with a K(i) of 3.02 nM. The association constant (K(on)) of KVD900 for PKa is >10 × 10(6) M(−1) s(−1). Oral administration of KVD900 in a first‐in‐human clinical trial achieved rapid and near complete inhibition of DXS‐stimulated PKa enzyme activity and HK cleavage and reduced plasma prekallikrein and Factor XII activation in plasma. In individuals with HAE, orally administered KVD900 inhibited DXS‐stimulated PKa activity in plasma by ≥95% from 45 min to at least 4 h post‐dose and provided rapid protection of HK from cleavage. CONCLUSION: KVD900 is a fast‐acting oral PKa inhibitor that rapidly inhibits PKa activity, kallikrein kinin system activation and HK cleavage in plasma. On‐demand administration of KVD900 may provide an opportunity to halt the generation of bradykinin and reverse HAE attacks.