Oral Plasma Kallikrein Inhibitor BCX7353 is Safe and Effective as an On-Demand Treatment of Angioedema Attacks in Hereditary Angioedema (HAE) Patients: Results of the ZENITH-1 Trial

In a phase 2 trial, BCX7353 was superior to placebo in reducing the angioedema attack rate (N Engl J Med 379: 352-362, 2018). We hypothesized that BCX7353 would also be superior to placebo in treating angioedema attacks. ZENITH-1 is a double-blind, placebo-controlled, randomized, cross-over, dose-ranging trial. Adults with HAE Type I or II self-administered a dose of blinded study drug for 3 attacks: 2 treated with active drug and 1 with placebo, in a randomized sequence. Subjects were free to use approved on-demand medications if needed, but were asked to wait 4h post-study drug if possible. Symptom diaries were completed prior to dosing and at 1, 2, 3, 4, 8 and 24h after study drug. Outcomes were compared using generalized logistic regression models. The completed first dose cohort (750mg) is reported; lower dose cohorts (500mg or 250mg) are in progress. 33 patients treated a total of 95 attacks; 30 treated all 3 attacks. At 4h postdose, 67.7% of BCX7353-treated angioedema attacks versus 46.7% for placebo were stable or improved by composite VAS (OR=2.771, p=0.0387). At 24h, subjects reported no or mild symptoms by patient global assessment in 64.1% of BCX7353-treated attacks versus 32.3% for placebo (OR=4.614, p=0.0038). Rescue medication was used in 29.7% of attacks treated with BCX7353 compared with 61.3% of placebo attacks (OR=0.196, p=0.0029). There were no Grade 3/4 AEs or laboratory abnormalities. BCX7353 750mg was superior to placebo and was well-tolerated. These results support further development of BCX7353 as an oral on-demand treatment for HAE attacks.