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:

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.

• Authors: Bruce 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
• Journal: The Journal of allergy and clinical immunology (J Allergy Clin Immunol) Vol. 148 Issue 1 Pg. 164-172.e9 (07 2021) ISSN: 1097-6825 [Electronic] United States
• PMID: 33098856 (Publication Type: Clinical Trial, Phase III, Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

Chemical References

• Pyrazoles
• Plasma Kallikrein
• berotralstat

Topics

• Administration, Oral
• Adult
• Angioedemas, Hereditary (drug therapy)
• Double-Blind Method
• Female
• Humans
• Male
• Plasma Kallikrein (administration & dosage)
• Prospective Studies
• Pyrazoles (administration & dosage)
• Treatment Outcome