Open Access

Bruce L. Zuraw, William R. Lumry, Douglas T. Johnston, Emel Aygören-Pürsün, Aleena Banerji, Jonathan A. Bernstein, Sandra C. Christiansen, Joshua S. Jacobs, Karl V. Sitz, Richard G. Gower, Remi Gagnon, H. James Wedner, Tamar Kinaciyan, Roman Hakl, Jana Hanzlíková, John T. Anderson, Donald L. McNeil, Stephen B. Fritz, William H. Yang, Raffi Tachdjian, Paula J. Busse, Timothy J. Craig, H. Henry Li, Henriette Farkas, Jessica M. Best, Desiree Clemons, Melanie Cornpropst, Sylvia M. Dobo, Heather A. Iocca, Deborah Kargl, Eniko Nagy, Sharon C. Murray, Phil Collis, William P. Sheridan, Marcus Maurer, Marc A. Riedl

• Background: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein in development for the prophylaxis of hereditary angioedema (HAE) attacks. Objective: Our aim was 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 receive once-daily berotralstat in a dose of 110 mg or 150 mg or placebo (Clinicaltrials.gov identifier NCT03485911). Patients aged 12 years or older with HAE due to C1 inhibitor deficiency and at least 2 investigator-confirmed HAE attacks in the first 56 days of a prospective run-in period were eligible. The primary efficacy end point was the rate of investigator-confirmed HAE attacks during the 24-week treatment period. Results: A total of 121 patients were randomized; 120 of them received at least 1 dose of the study drug (n = 41, 40, and 39 in the 110-mg dose of berotralstat, 150-mg of dose berotralstat, and placebo groups, respectively). Berotralstat demonstrated a significant reduction in attack rate at both 110 mg (1.65 attacks per month; P = .024) and 150 mg (1.31 attacks per month; P < .001) relative to placebo (2.35 attacks per month). The most frequent treatment-emergent adverse events that occurred more with berotralstat than with placebo were abdominal pain, vomiting, diarrhea, and back pain. No drug-related serious treatment-emergent adverse events occurred. 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 per day.