Median hereditary angioedema attack rates fall to zero for children with berotralstat
Key takeaways:
- Children took daily doses of berotralstat that ranged from 78 mg to 150 mg.
- There were no grade 3 or 4 adverse events related to the drug.
- Findings indicate that oral granules may be appropriate for children.
SAN DIEGO — Children with hereditary angioedema saw early and sustained reductions in monthly attack rates with berotralstat, with a median of zero after the first month and at 12 months, according to a poster presented here.
These findings also indicate a favorable benefit-risk profile for the use of oral granules in long-term prophylactic treatment, researchers reported at the 2025 American Academy of Allergy, Asthma & Immunology/World Allergy Organization Joint Congress.
Disease and treatment burden
Symptoms of hereditary angioedema (HAE) often begin before puberty, Jolanta Bernatoniene, FRCPCH, PhD, consultant, pediatric infectious disease department, Bristol Royal Hospital for Children, told Healio.
“Pediatric patients with HAE can experience significant disease-related and treatment-related burdens, including HAE attacks requiring urgent medical care,” Bernatoniene said.
HAE also can have a negative impact on daily activities, she continued, such as missed school days, diminished academic performance and missed engagement in sports and social opportunities.
“In addition to physical burden, there can be a significant impact on mental health and other developmental aspects of life experienced by children with HAE,” Bernatoniene said.
Berotralstat (Orladeyo; BioCryst Pharmaceuticals) is currently approved as a prophylaxis for HAE attacks for adults and adolescents aged 12 years and older.
“There are currently limited therapeutic options for pediatric patients with HAE under the age of 12, which are on-demand or long-term prophylaxis therapies administered either through subcutaneous injection or intravenous infusion,” Bernatoniene said.
Bernatoniene called these administration methods challenging, burdensome and time-consuming for patients and caregivers alike.
“Treatment through these routes of administration may cause caregivers and pediatric patients with HAE to feel nervous, overwhelmed and stressed, which can become problematic because these emotions are known to trigger HAE attacks,” she said. “This can also cause some physicians to hesitate to prescribe long-term prophylaxis to their young patients.”
The oral granule formulation of berotralstat could reduce the treatment burden on children and be easier for caregivers to administer, Bernatoniene said.
“The granules, housed in a packet, are sprinkle-like in appearance and size and can be poured directly into the mouth and swallowed immediately with water or milk, or sprinkled over a spoonful of soft, non-acidic food, like pudding, for more convenient treatment that fits into daily routines,” Bernatoniene said.
Treatment results
The ongoing, open-label APeX-P study included 29 children (51.7% boys; 75.9% white) aged 3 to 11 years with HAE with C1-inhibitor deficiency and two or more attacks in the 6 months before enrollment. It explored the impact of daily administration of berotralstat in both oral capsule and oral granule formulations.
“In APeX-P, we observed that children with HAE are experiencing severe swelling attacks at a very young age,” Bernatoniene said.
The median age of symptom onset was 2 years for the study population, with 83% of these symptoms appearing and 90% of diagnoses occurring before age 6 years. Also, 89.7% of the population had a family history of HAE-C1INH.
“These findings support an earlier age of symptom onset and need for HAE prophylaxis than has generally been understood,” Bernatoniene said.
Eleven patients (38%) had used prophylactic treatment for HAE before the study, including 3.4% who used lanadelumab (Takhzyro, Takeda), 20.7% who used tranexamic acid and 27.6% who used a C1-esterase inhibitor.
Cohort 1 included seven children (median age 10 years) who weighed 40 kg or more and received a 150 mg capsule of berotralstat each day for a median of 1 year. The nine children in cohort 2 (median age 9 years) weighed between 32 and 40 kg and received a 108 mg dose of berotralstat in oral granules each day for a median of 0.92 year.
In cohort 3, nine children (median age 8 years) who weighed between 24 and 32 kg received a daily 96 mg dose of oral granules for a median of 0.71 year. The four children in cohort 4 (median age 4.5 years) who weighed between 12 and 24 kg received a daily 78 mg dose of oral granules for a median of 0.46 year.
While receiving the standard of care during the 12 weeks prior to initiating treatments, patients experienced a median monthly attack rate of 0.96, with a range of monthly attacks. At 1 month, the median fell to 0 (range 0-4), which persisted through 12 months (range 0-1.7).
The researchers also assessed berotralstat’s pharmacokinetic (PK) impact to enable the determination of appropriate granule dosing for pediatric patients based on established modeling, Bernatoniene said, which she called a common methodology.
“Using this approach, doses are selected to match drug exposure shown to be safe and effective in adults and adolescents,” she said.
When cohorts 13 were in steady state, which Bernatoniene described as the physiological state at which the drug was at equilibrium with the body, the median time to peak plasma concentration after dosing was 3.9 hours.
Also, the geometric mean maximum concentration was 204 ng/mL, and the total berotralstat exposure from the time of first measurable drug concentration to last measurable drug concentration for a given dose was 915 ng*hr/mL.
“Assessment of PK parameters during this time gives a better picture of what can be expected with longer-term use of the drug,” Bernatoniene said.
Nasopharyngitis (27.6%), upper respiratory tract infections (24.1%) and headache (13.8%) were the most common treatment-emergent adverse events. There were no grade 3 or 4 adverse events related to the drug, nor were there any serious adverse events, during the first 48 weeks of the trial. Also, there were no deaths or discontinuations related to any adverse events.
Next steps
Based on these findings, the researchers classified reductions in monthly attack rates among these children as early and sustained, with a benefit-risk profile that was favorable for oral granules of berotralstat in long-term prophylaxis for pediatric patients.
“These results show berotralstat was well tolerated in pediatric patients enrolled in the trial, with early and sustained reductions in monthly attack rates, and no new safety signals identified beyond those previously described in prior adult and adolescent trials,” Bernatoniene said.
Bernatoniene also noted that APeX-P is the largest trial of a prophylactic therapy for children aged 2 to 12 years with HAE. Enrollment was completed ahead of schedule with more than the initial target number of participants as well.
“I am excited by the interest we have seen in APeX-P and the prospect of an oral, once-daily prophylactic therapy that could help children with HAE and their caregivers better manage their disease and participate in daily activities that are important to them,” she said.
BioCryst reports that it will submit a new drug application to the FDA for its oral granule formulation for pediatric patients this year.
“These results will be included in regulatory submissions to seek approval for berotralstat for the treatment of patients with HAE aged 2 to 12 years,” Bernatoniene said.
The researchers are planning additional analyses from the study, she continued.
“Once approved, berotralstat oral granules for long-term prophylaxis can be incorporated into the shared decision-making process to select optimal treatment for children with HAE,” Bernatoniene said. “This new formulation of berotralstat has the potential to significantly reduce the treatment burden for children and families impacted by HAE.”
Reference:
- BioCryst announces positive results from APeX-P trial for Orladeyo (berotralstat) in pediatric patients with hereditary angioedema aged 2 to <12 years. https://ir.biocryst.com/news-releases/news-release-details/biocryst-announces-positive-results-apex-p-trial-orladeyor. Published Feb. 24, 2025. Accessed Feb. 24, 2025.