BCX7353, a Potent Inhibitor of Plasma Kallikrein, Shows Sustained Maximal Enzyme Inhibition When Dosed Orally Once Daily: Results from a Phase I Trial in Healthy Subjects

Abstract

Plasma kallikrein is a proven target in the treatment of hereditary angioedema (HAE). A first-in-human study evaluated the pharmacokinetics, pharmacodynamics and safety of plasma kallikrein inhibitor BCX7353. Healthy subjects (n= 94 enrolled, n = 92 completed) received single (10, 30, 100, 250, 500 or 1000mg) or multiple (125, 250, 500mg x7 days or 350mg x14 days), once-daily (QD) oral doses of BCX7353 or placebo. Drug levels were measured in serial post-dose samples and plasma kallikrein enzyme activity was measured in a specific bioassay. Safety was evaluated by clinical and laboratory monitoring. BCX7353 exposure increased slightly greater than proportionally with increasing dose. The half-life of BCX7353 was 50-60 hours, and accumulation in AUCtau was approximately 4-fold after dosing to Day 7 or 14. Kallikrein inhibition was highly correlated to plasma concentrations, r=0.916. On Day 7, at doses ≥250mg QD, plasma concentrations were within or above the target therapeutic range and inhibition of plasma kallikrein was maximal and sustained throughout the dosing interval. Two subjects discontinued the study for gastrointestinal adverse events (AEs). One subject had a diffuse maculopapular rash that resolved with oral steroids. There were no serious AEs, and the maximum tolerated dose was not reached. Once daily BCX7353 has a generally well tolerated safety profile and provides sustained potent and maximal plasma kallikrein inhibition. Plasma concentrations met or exceeded the predicted therapeutic range over a 24 hour dosing interval. Clinical studies with HAE patients are planned to assess the efficacy of BCX7353 in reducing the occurrence of attacks.