Berotralstat for long-term prophylaxis of hereditary angioedema in Japan: Parts 2 and 3 of the randomized APeX-J Phase III trial

Abstract

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.

Keywords: Angioedemas; Berotralstat; Hereditary; Japan; Plasma kallikrein; Quality of life.

Fig. 1

APeX-J patient disposition. Patients were considered to have completed the study if they continued study drug dosing to study Week 104. Specific reasons for withdrawal of consent were not provided. TEAE, treatment-emergent adverse event

Fig. 2

Adjusted patient-reported HAE attack rates from baseline to 26 months of active berotralstat treatment for patients who entered Part 2 of APeX-J (n = 17). A. Mean (SEM) values for the All 150 mg group, B. Mean (SEM) values for the All 110 to 150 mg group, C. Median values for the All 150 mg group, and D. Median values for the All 110 to 150 mg group. Baseline attack rates are based on the number of attacks that occurred during the 56-day run-in period before study entry. For patients who received berotralstat following placebo, months are adjusted according to the date of the first berotralstat dose. Two patients in the All 110 to 150 mg group who experienced attacks during the last month were not on study for the full 28 days of the month and, as such, their attack rate for this month was calculated using a denominator smaller than 28 days. BL, baseline; HAE, hereditary angioedema; SEM, standard error of the mean

Fig. 3

Adjusted number of on-demand HAE attack medication doses administered per month from baseline to 26 months of active berotralstat treatment for patients who entered Part 2 of APeX-J (n = 17). Mean (SEM) values for the A.All 150 mg group and B.All 110 to 150 mg group. Baseline rates are based on medication use during the run-in period before study entry and are adjusted for the length of a month. For patients who received berotralstat following placebo, months are adjusted according to the date of the first berotralstat dose. BL, baseline; HAE, hereditary angioedema; SEM, standard error of the mean

Fig. 4

Patient-reported outcomes from baseline to 26 months of active berotralstat treatment for patients who entered Part 2 of APeX-J (n = 17). Mean (SEM) AE-QoL and TSQM scores for the All 150 mg group (A. and C.) and the All 110 to 150 mg group (B. and D.). Baseline values represent values on Day 1 before study drug administration. For TSQM, baseline values are based on the patient's reflection of the last treatment received. For patients who received berotralstat following placebo, months are adjusted according to the date of the first berotralstat dose. The black dotted line represents the MCID for the AE-QoL Total score. AE-QoL, Angioedema Quality of Life Questionnaire; BL, baseline; MCID, minimal clinically important difference; SEM, standard error of the mean; TSQM, Treatment Satisfaction Questionnaire for Medication