Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: a randomized, double-blind, placebo-controlled phase 3 trial

Abstract Background Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. Objective To determine the efficacy, safety, and tolerability of berotralstat in patients with HAE over a 24-week treatment period (the phase 3 APeX-2 trial). Methods APeX-2 was a double-blind, parallel-group study that randomized patients at 40 sites in 11 countries 1:1:1 to once-daily berotralstat 110 mg, 150 mg, or placebo (Clinicaltrials.gov, NCT03485911). Patients aged ≥12 years with HAE due to C1 inhibitor deficiency and ≥2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy endpoint was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. Results One-hundred twenty-one patients were randomized, and 120 received ≥1 dose of study drug (N=41, 40, and 39 for the berotralstat 110-mg, 150-mg, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks/month; p=0.024) and 150 mg (1.31 attacks/month; p Conclusion Both the 110-mg and 150-mg doses of berotralstat reduced HAE attack rates compared with placebo and were safe and generally well tolerated. The most favorable benefit-to-risk profile was observed at a dose of 150 mg/day.