ORAL ADMINISTRATION OF A LIQUID FORMULATION OF BCX7353 RAPIDLY PROVIDES SUSTAINED CONCENTRATIONS AND KALLIKREIN INHIBITION

Abstract

Introduction BCX7353 is an investigational oral kallikrein inhibitor in Phase 3 studies for prevention of HAE attacks. A capsule formulation of BCX7353 is rapidly absorbed and exhibits a long half-life, which also may permit effective treatment of acute attacks in HAE patients. A Phase I study in HAE patients was conducted to determine whether a liquid formulation of BCX7353 may optimize on these attributes as an attack treatment. Methods Six subjects with HAE Type I or II were given a single 750 mg BCX7353 dose orally as a reconstituted solution in an intercritical period between attacks. The pharmacokinetic and kallikrein inhibition profiles were determined through 24h post-dose. BCX7353 plasma concentrations were determined using a validated mass spectrometry assay and kallikrein inhibition was assessed with an ellagic acid-initiated contact activation assay. Results Maximal concentrations were reached at approximately 2h post-dose across subjects (median). Mean concentrations exceeded the target concentration for plasma kallikrein suppression (i.e., 4x EC50) at 15 minutes post-dose; all subjects exceeded this target by at least 2.4-fold at 30 minutes post-dose and maintained concentrations over the target through 24h post-dose. A mean of 49% kallikrein inhibition relative to baseline activity was demonstrated at 15 minutes post-dose; >80% inhibition was measured between 1-8h, with 71% inhibition at 24h post-dose. Conclusions BCX7353 750 mg administered orally as a liquid formulation produced sustained plasma concentrations that potently inhibited kallikrein through at least 24 hours post-dose. These results support proof-of-concept studies to assess the efficacy of a liquid formulation of BCX7353 in the treatment of HAE attacks.