KVD900, an oral on-demand treatment for hereditary angioedema: Phase 1 study results

Background: Attacks of hereditary angioedema are attributed to excessive plasma kallikrein (PKa) activity, which cleaves high-molecular-weight kininogen to generate the proinflammatory hormone bradykinin. Objective: We evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of KVD900, an orally administered inhibitor of PKa in healthy adults. Methods: KVD900 was administered in 2 clinical studies. In the first study, healthy adult men received single ascending doses (5-600 mg) of KVD900 capsule or placebo, single 100 mg doses of KVD900 tablet and KVD900 capsule (crossover), and single 600 mg doses of KVD900 (6 x 100 mg tablets) under fed and fasting conditions (crossover). In a second study, 3 cohorts of healthy adults were provided 600 mg of KVD900 tablets at 8-, 4-, and 2-hour intervals. Results: Overall, 98 healthy participants received KVD900. All adverse events (AEs) were mild, except for a single moderate AE (headache). Exposure to KVD900 was proportional to dose. The PK parameters for KVD900 600 mg in tablet form under fasted conditions were mean (coefficient of variation) maximum plasma concentration of 6460 (22.0) ng/mL, mean (coefficient of variation) area under the curve (AUC(0-24)) of 18,600 (22.5) h$ng/mL, and median (range) time to maximum plasma concentration of 0.5 (0.33-1.5) hours. Mean PKa inhibition was essentially complete (>98%) between 20 minutes and 3 hours, and >90% inhibition was maintained for at least 8 hours after dosing. High-molecular-weight kininogen cleavage protection at the 600 mg dose was attained within 20 minutes and maintained for 8 to 10 hours. Conclusion: These phase 1 studies evaluated the PK/PD profile of KVD900, showing that KVD900 rapidly achieves nearcomplete PKa inhibition and is generally safe and well tolerated.