Rapid Plasma Kallikrein Inhibition Following Oral KVD900 is Associated With Early Symptom Relief in Patients With Hereditary Angioedema

Guidelines recommend availability of on-demand therapy for every patient with hereditary angioedema (HAE). We evaluated pharmacokinetics, pharmacodynamics, and time to symptom improvement of the oral plasma kallikrein (PKa) inhibitor KVD900. In a phase 2 study, adults with HAE type I/II were administered a single 600mg dose of open-label KVD900 in the clinic (Part 1), followed by a double-blind, placebo-controlled crossover trial treating HAE attacks (Part 2). Pharmacokinetic parameters were measured and inhibition of PKa activity was evaluated in dextran sulfate-stimulated whole plasma. Symptom improvement was measured using Patient Global Impression of Change (PGI-C). Among 42 patients with pharmacokinetic measurements, 600mg of orally administered KVD900 was rapidly absorbed with mean(SD) plasma concentration of 1710(2340)ng/mL at the first time point assessed (15 minutes). Plasma levels of KVD900 quickly reached maximum values (geometric mean Cmax: 6080ng/mL) with an observed median Tmax of 1.0 hour. Following administration of 600mg KVD900, PKa activity in plasma (n=12) was inhibited >50% within 15 minutes and was essentially completely inhibited (≥95%) within 1 hour. PKa inhibition was maintained for at least 4 hours after dosing. KVD900 treatment significantly (P<0.0001) reduced the time to symptom relief (HAE attack rated “A little better” or higher on PGI-C for 2 consecutive time points within 12 hours of study drug), with a median time of 1.6 hours, versus 9.0 hours following treatment with placebo. Oral administration of KVD900 achieved rapid plasma exposure and near complete inhibition of PKa activity in patients with HAE, which was associated with early symptom relief of attacks.