RELATIONSHIP OF TARGET CONCENTRATIONS WITH EFFICACY: RESULTS FROM THE APEX-1 STUDY OF BCX7353

Abstract

Introduction Hereditary angioedema (HAE) is characterized by unpredictable attacks of debilitating swelling. APeX-1 was a Phase 2, double-blind, placebo-controlled study to evaluate the prevention of attacks with BCX7353, a once daily oral kallikrein inhibitor, in patients with HAE. Methods Patients with Type I or II HAE with a history of at least 0.5 HAE attacks/week were randomized to four different BCX7353 doses (62.5mg, 125mg, 250mg, 350mg once daily) or placebo for 4 weeks. Subjects completed diaries to record angioedema attack details. A trough sample for BCX7353 analysis was drawn on Day 15. Results There was a dose-dependent reduction in mean HAE attack rate relative to the mean historical attack rate through 125mg (0.66 attacks/week reduction at this dose); efficacy at doses ≥250mg was likely confounded by drug-related adverse events misattributed as attacks. Mean plasma trough BCX7353 levels also increased by dose level with 57% of subjects in the 125mg group achieving the target trough concentration (≥4xEC50 at 24h post-dose). Subjects were individually classified by achieving or not achieving the target trough. The odds for subjects achieving ≥50%, ≥70%, or ≥90% reduction in attacks if the target trough was met or exceeded were 5.6-, 12.9- and 26.4-times higher, respectively, than for subjects who did not meet or exceed target trough level. Conclusions Maintenance of BCX7353 plasma concentrations above the target trough concentration increased the odds of reducing HAE attacks. A BCX7353 dose >125mg and