Efficacy Correlates with Plasma Levels in Opus-1, a Proof-of-Concept Study of Oral Kallikrein Inhibitor BCX4161 As a Prophylaxis Against Attacks of Hereditary Angioedema (HAE)

Abstract

BCX4161 is an oral kallikrein inhibitor in development as a prophylactic agent in HAE. BCX4161 significantly reduced the mean HAE attack rate versus placebo in the OPuS-1 study. We evaluated the relationships between clinical efficacy, plasma BCX4161 concentrations, pharmacodynamic markers of activity and safety in OPuS-1 subjects. OPuS-1 was a double-blind, placebo-controlled, randomized 2-period crossover study conducted in 24 HAE subjects who received 28 days of treatment with BCX4161 400 mg TID and placebo. Subjects recorded HAE attack incidence daily. Pharmacokinetic and pharmacodynamic samples were drawn at trough (Ctrough) and a PK profile (0.5, 1, 2 and 3 hours post-dose) was assessed on Day 14. PT and aPTT samples were drawn throughout the study. Plasma kallikrein inhibitory levels were highly correlated with Ctrough (r= 0.73, p = 0.002). Ctrough was significantly correlated with the percent difference in HAE attack rate (Pearson correlation coefficient -0.42, p = 0.04), with an IC50 of approximately 34 ng/mL. The BCX4161 EC80 for kallikrein inhibition was 51 ng/mL. Four of 6 subjects (67%) with Ctrough greater than 51 ng/mL had an attack reduction on BCX4161 of at least 0.5 attacks/week compared to 5 of 18 subjects (33%) with concentrations below 51 ng/mL. Cmax and AUC0-3did not correlate with efficacy. There were no effects of BCX4161 on aPTT or PT. Despite a small sample size of 24 subjects, there were relationships suggestive of a pharmacokinetic/pharmacodynamic/efficacy association, and adequate, maintained BCX4161 exposure correlated with degree of benefit. BCX4161 did not affect coagulation parameters.