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

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.

FIGURE 1

APeX‐J CONSORT diagram. ITT, intent‐to‐treat; TEAE, treatment‐emergent adverse event

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

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.