Oral Berotralstat Shows Strong Safety, Efficacy in Young Children with HAE

A study demonstrated that oral berotralstat was well-tolerated and resulted in early and sustained reductions in hereditary angioedema (HAE) attack rates.1

HAE affects approximately 1 in every 50,000 people globally, with an estimated prevalence of anywhere between 1 in 10,000 to 1 in 150,000 in the United States.2 An online survey of US physicians showed the average time to diagnosis for HAE ranged from 0 to 6 months in 5.8% cases and ≥ 10 years in another 5.8% cases.

This rare disease results in 15,000 to 30,000 US annual emergency department admissions. The US Food and Drug Administration (FDA) has approved several HAE treatments, including prevention medication, such as garadacimab-gxii (ANDEMBRY; subcutaneous), C1 esterase inhibitor (intravenous CINRYZE and subcutaneous), HAEGARDA), icatibant injection (FIRAZYR; subcutaneous), lanadelumab-flyo (subcutaneous), and berotralstat (ORLADEYO; oral capsules), as well as attack-targeting treatments, such as a human C1 esterase inhibitor (BERINERT; intravenous), sebetralstat (EKTERLY; oral capsule), ICATIBANT (aged ≥ 18 years; subcutaneous), ecallantide (KALBITOR; subcutaneous), and recombinant C1 esterase inhibitor (RUCONEST® (intravenous).3

Among current treatments, only plasma-derived C1 esterase inhibitor concentrates are approved for children aged ≤12 years. All approved long-term prophylaxis options for this age group require parenteral administration.3

In this recent trial, investigators evaluated oral berotralstat as a long-term prophylaxis for HAE in patients aged 2 – 11 years.1 Berotralstat, a small-molecule plasma kallikrein inhibitor, is currently approved to address HAE attacks in patients aged ≥ 12 years.

The study, called APeX-P, is the largest trial to examine long-term prophylaxis in children aged < 12 years.1 Led by Jolanta Bernatoniene, MD, PhD, from the pediatric immunology and infectious disease department at Bristol Royal Hospital for Children in the UK, the team evaluated the efficacy, safety, and pharmacokinetics of berotralstat in an interim analysis.

The sample included 29 children, with 48.3% females and a median age of 8 years. On average, patients were 2 years at HAE onset, and 82.8% of patients reported symptom onset before 6 years. Before starting berotralstat, patients received standard of care for 12 weeks.1

At a steady state, berotralstat reached peak concentration at a median of 3.9 hours (range, 0.9 – 6.0 hours), and the geometric mean Cmax was 204 ng/mL with a 40% coefficient of variation. The area under the curve from time 0 to the last measurable concentration was 915 ng•hr/mL with a 42% coefficient of variation, indicating moderate variability in drug exposure among participants.1

The most common treatment-emergent adverse events included nasopharyngitis, upper respiratory tract infection, and headache. Investigators observed no drug-related grade 3 or 4 reactions nor adverse event-related discontinuations.1

The median HAE attack rate when participants received standard of care was 0.96 attacks per the 4-week period. Median HAE attack rates for each 4-week period from day 1 to week 48 were 0, with a range of 0 to 4 attacks at week 4 and 0 to 1.7 attacks at week 48.1

“Oral berotralstat was well tolerated and resulted in early and sustained reductions in HAE attack rates,” investigators concluded.1

References

1. Bernatoniene J, Bourgoin-Heck M, Cancian M, et al. Oral berotralstat for hereditary angioedema prophylaxis in patients aged 2 to <12 years: APeX-P interim results. Ann Allergy Asthma Immunol. Published online July 18, 2025. doi:10.1016/j.anai.2025.07.012

2. Hereditary angioedema (HAE). Rare Disease Advisor. https://www.rarediseaseadvisor.com/disease-info-pages/hereditary-angioedema-epidemiology/. Accessed August 5, 2025.

3. Approved HAE Treatments. US Hereditary Angioedema Association. https://www.haea.org/pages/p/treatments. Accessed August 5, 2025.