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

  • J Allergy Clin Immunol. 2021 Jul;148(1):164-172.e9. doi: 10.1016/j.jaci.2020.10.015.
Bruce Zuraw  1 ,  William R Lumry  2 ,  Douglas T Johnston  3 ,  Emel Aygören-Pürsün  4 ,  Aleena Banerji  5 ,  Jonathan A Bernstein  6 ,  Sandra C Christiansen  1 ,  Joshua S Jacobs  7 ,  Karl V Sitz  8 ,  Richard G Gower  9 ,  Remi Gagnon  10 ,  H James Wedner  11 ,  Tamar Kinaciyan  12 ,  Roman Hakl  13 ,  Jana Hanzlíková  14 ,  John T Anderson  15 ,  Donald L McNeil  16 ,  Stephen B Fritz  17 ,  William H Yang  18 ,  Raffi Tachdjian  19 ,  Paula J Busse  20 ,  Timothy J Craig  21 ,  H Henry Li  22 ,  Henriette Farkas  23 ,  Jessica M Best  24 ,  Desiree Clemons  24 ,  Melanie Cornpropst  24 ,  Sylvia M Dobo  24 ,  Heather A Iocca  24 ,  Deborah Kargl  24 ,  Eniko Nagy  24 ,  Sharon C Murray  24 ,  Phil Collis  24 ,  William P Sheridan  25 ,  Marcus Maurer  26 ,  Marc A Riedl  1
Affiliations
  • 1. University of California San Diego, San Diego, Calif.
  • 2. Allergy & Asthma Specialists of Dallas, Dallas, Tex.
  • 3. Asthma and Allergy Specialists, Charlotte, NC.
  • 4. University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany.
  • 5. Massachusetts General Hospital, Harvard Medical School, Boston, Mass.
  • 6. University of Cincinnati, Cincinnati, Ohio.
  • 7. Allergy and Asthma Clinical Research, Walnut Creek, Calif.
  • 8. Little Rock Allergy and Asthma Clinical Research Center, Little Rock, Ark.
  • 9. University of Washington School of Medicine, Marycliff Clinical Research, Spokane, Wash.
  • 10. Clinique Spécialisée en Allergie de la Capitale, Québec, Canada.
  • 11. Washington University School of Medicine, St Louis, Mo.
  • 12. Medical University of Vienna, Department of Dermatology, Vienna, Austria.
  • 13. Department of Clinical Immunology and Allergology, St. Anne's University Hospital in Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
  • 14. Faculty Hospital, Department of Allergology and Immunology, Plzen, Czech Republic.
  • 15. Clinical Research Center of Alabama, Birmingham, Ala.
  • 16. Optimed Research Ltd, Columbus, Ohio.
  • 17. Portland Clinical Research, Portland, Ore.
  • 18. Ottawa Allergy Research Corporation, Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
  • 19. Department of Pediatrics, University of California, Los Angeles, Calif.
  • 20. Division of Clinical Immunology and Allergy, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY.
  • 21. Department of Medicine and Pediatrics, Penn State University, Hershey, Pa.
  • 22. Institute for Asthma and Allergy, Chevy Chase, Md.
  • 23. Hungarian Angioedema Reference Center, Third Department of Internal Medicine, Semmelweis University, Budapest, Hungary.
  • 24. BioCryst Pharmaceuticals, Durham, NC.
  • 25. BioCryst Pharmaceuticals, Durham, NC. Electronic address: [email protected].
  • 26. Dermatological Allergology, Department of Dermatology and Allergy, Charité Universitätsmedizin Berlin, Berlin, Germany.
PMID: 33098856 DOI: 10.1016/j.jaci.2020.10.015
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.

Keywords
BCX7353; C1 inhibitor; HAE; berotralstat; efficacy; hereditary angioedema; kallikrein inhibitor; long-term prophylaxis; prophylaxis; safety.
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