Oral berotralstat for the prophylaxis of hereditary angioedema attacks in patients in Japan: A phase 3 randomized trial

Isao Ohsawa, Daisuke Honda, Yusuke Suzuki, Tomoo Fukuda, Keisuke Kohga, Eishin Morita, Shinichi Moriwaki, Osamu Ishikawa, Yoshihiro Sasaki, Masaki Tago, Greg Chittick, Melanie Cornpropst, Sharon C Murray, Sylvia M Dobo, Eniko Nagy, Sharon Van Dyke, Lacy Reese, Jessica M Best, Heather Iocca, Phil Collis, William P Sheridan, Michihiro Hide, Isao Ohsawa, Daisuke Honda, Yusuke Suzuki, Tomoo Fukuda, Keisuke Kohga, Eishin Morita, Shinichi Moriwaki, Osamu Ishikawa, Yoshihiro Sasaki, Masaki Tago, Greg Chittick, Melanie Cornpropst, Sharon C Murray, Sylvia M Dobo, Eniko Nagy, Sharon Van Dyke, Lacy Reese, Jessica M Best, Heather Iocca, Phil Collis, William P Sheridan, Michihiro Hide

Abstract

Background: With no approved treatments in Japan for the prevention of hereditary angioedema (HAE) attacks, there is a significant unmet need for long-term prophylactic therapies for Japanese patients with HAE. Berotralstat (BCX7353) is an oral, once-daily, highly selective inhibitor of plasma kallikrein in development for prophylaxis of angioedema attacks in HAE patients.

Methods: APeX-J is a phase 3, randomized, double-blind, placebo-controlled, parallel-group, 3-part trial conducted in Japan (University Hospital Medical Information Network identifier, UMIN000034869; ClinicalTrials.gov identifier, NCT03873116). Patients with a clinical diagnosis of type 1 or 2 HAE underwent a prospective run-in period of 56 days to determine eligibility, allowing enrollment of those with ≥2 expert-confirmed angioedema attacks. Patients were randomly assigned (1:1:1) and stratified by baseline attack rate (≥2 vs. <2 expert-confirmed attacks/month between screening and randomization) to receive once-daily berotralstat 110 mg, berotralstat 150 mg, or placebo. The primary endpoint was the rate of expert-confirmed angioedema attacks during dosing in the 24-week treatment period.

Results: Nineteen patients were randomized to receive once-daily berotralstat 110 mg (n = 6), berotralstat 150 mg (n = 7), or placebo (n = 6). Treatment with berotralstat 150 mg significantly reduced HAE attacks relative to placebo (1.11 vs. 2.18 attacks/month, p = .003). The most frequently reported treatment-emergent adverse events (TEAEs) in berotralstat-treated patients (n = 13) were nasopharyngitis (n = 4, 31%), abdominal pain, cough, diarrhea, and pyrexia (n = 2 each, 15%).

Conclusions: Orally administered, once-daily berotralstat 150 mg significantly reduced the frequency of HAE attacks and was safe and well tolerated, supporting its use as a prophylactic therapy in patients with type 1 or 2 HAE in Japan.

Keywords: Japan; berotralstat; hereditary angioedema; kallikrein inhibitor; prophylaxis.

Conflict of interest statement

DH reports speaker fees from CSL Behring, Kyowa Kirin, Otsuka, Shire, and Takeda outside the submitted work. GC, MC, SCM, SMD, EN, SVD, LR, JB, HI, PC, and WPS are employees of BioCryst Pharmaceuticals. GC, EN, LR, and WPS hold stock options in BioCryst Pharmaceuticals. MH reports personal fees from BioCryst Pharmaceuticals during the conduct of the study; personal fees from Shire/Takeda; and grants and personal fees from CSL Behring, outside the submitted work; and a grant of the Ministry of Health, Labour and Welfare of Japan. IO, YSuzuki, TF, KK, EM, SM, OI, YSasaki, and MT have nothing to disclose.

© 2020 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

Figures

FIGURE 1
FIGURE 1
APeX‐J CONSORT diagram. ITT, intent‐to‐treat; TEAE, treatment‐emergent adverse event
FIGURE 2
FIGURE 2
(A) Mean expert‐confirmed attack rate; (B) change from baseline in expert‐confirmed attack rate by month at week 24. Abbreviations: HAE, hereditary angioedema; SEM, standard error of the mean
FIGURE 3
FIGURE 3
Angioedema quality of life scores, week 24 compared with baseline. Abbreviations: AE‐QoL, angioedema quality of life; CFB, change from baseline; MCID, minimal clinically important difference; QoL, quality of life; SEM, standard error of the mean. The AE‐QoL scores range from 0 to 100, and a decrease (change with a negative value) in AE‐QoL questionnaire scores indicates an improvement in the patient's QoL. The MCID for the AE‐QoL total score is 6 points.

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