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Background: Berotralstat is a once-daily oral inhibitor of plasma kallikrein for the prophylaxis of hereditary angioedema (HAE) in patients ≥12 years. APeX-J aimed to evaluate the efficacy and safety of berotralstat in Japan. Methods: APeX-J was a Phase III trial comprising 3 parts (NCT03873116). Part 1 was a randomized, placebo-controlled evaluation of berotralstat 150 or 110 mg over 24 weeks. Part 2 was a 28-week dose-blinded phase in which berotralstat-treated patients continued the same dose and placebo patients were re-randomized to berotralstat 150 or 110 mg. In Part 3, all patients remaining on study received berotralstat 150 mg in an open-label manner for up to an additional 52 weeks. The primary endpoint of Parts 2 and 3 was long-term safety and tolerability, and secondary endpoints examined effectiveness. Results: Seventeen patients entered Part 2, and 11 continued into Part 3. Treatment-emergent adverse events (TEAEs) were reported by 14/17 patients (82.4%) in Parts 2 or 3; the most common were nasopharyngitis, abdominal pain, cystitis, influenza, and vertigo. One patient (5.9%) experienced a drug-related TEAE (Grade 4 increased hepatic enzyme). No drug-related serious TEAEs were reported. For patients who completed 26 months of treatment with berotralstat 150 mg (n = 5), mean (standard error of the mean) monthly HAE attack rates and on-demand medication use decreased from baseline by 1.15 (0.09) attacks/month and 2.8 (0.64) doses/month, respectively. Sustained improvements were also observed in patient quality of life and treatment satisfaction. Conclusions: Long-term prophylaxis with berotralstat raised no new safety signals and was effective at reducing attacks and improving patient-reported outcomes. Trial registration: ClinicalTrials.gov NCT03873116. Registered March 13, 2019. Retrospectively registered.

Background: Hereditary angioedema (HAE) is a rare and potentially life-threatening genetic disorder characterized by recurrent attacks of angioedema. HAE types I and II result from deficient or dysfunctional C1-esterase inhibitor (C1–INH). This Phase 3 study assessed the efficacy, pharmacokinetics (PK), and safety of subcutaneous (SC) C1–INH in Japanese patients with HAE. Methods: The prospective, open-label, multicenter, single-arm Phase 3 study recruited patients with HAE types I or II to an initial run-in period, followed by a 16-week treatment period where patients received 60 IU/kg C1–INH (SC) twice weekly. The two primary endpoints were the time-normalized number of HAE attacks per month and C1–INH functional activity at Week 16. Results: Nine patients entered the treatment period and completed the study. Treatment with C1–INH (SC) significantly reduced the mean monthly attack rate from 3.7 during the run-in period to 0.3 during treatment (exploratory p value of within-patient comparison = 0.004). After the last dose of C1–INH (SC) at Week 16, the mean trough concentration of C1–INH was 59.8%, and the mean area under the plasma concentration–time curve to the end of the dosing period and to the last sample were 5317.1 and 13,091.5 h•%, respectively. During the study, there were no deaths, serious adverse events, or adverse events leading to study discontinuation. Conclusions: C1–INH (SC) (60 IU/kg twice weekly) was efficacious and well tolerated as a prophylaxis against HAE attacks in Japanese patients with HAE types I or II, which was supported by the increased and maintained C1–INH functional activity.EudraCT Number 2019-003921-99; JapicCTI-205273