Berotralstat Treatment in Children With Hereditary Angioedema (APeX-P)

A Phase 3 Study to Evaluate the Safety and Pharmacokinetics of Berotralstat Prophylaxis in Children With Hereditary Angioedema Who Are 2 to < 12 Years of Age

The purpose of this study is to evaluate the pharmacokinetics (PK), safety and effectiveness of berotralstat to determine the appropriate weight-based dose for pediatric participants 2 to < 12 years of age for prophylactic treatment to prevent attacks of hereditary angioedema (HAE).

Study Overview

• Status: Active, not recruiting
• Conditions: Hereditary Angioedema; Pediatric
• Intervention / Treatment: Drug: Berotralstat

Detailed Description

This is a single-arm, 3-part, open-label study designed to evaluate the PK, safety, and effectiveness of berotralstat weight-based treatment for the prevention of HAE attacks in pediatric participants 2 to < 12 years of age. Participation in this study is expected to be a minimum of 12 weeks in the standard of care (SOC) period, and in the berotralstat period, it is expected to be 12 weeks in Part 1, 36 weeks in Part 2, and 96 weeks in Part 3 of the study.

Participants were enrolled into 4 cohorts; participant weight at baseline was used to determine assignment to each cohort with the higher weight cohorts (Cohorts 1 and 2) enrolling first and in parallel. Safety assessments and PK modelling from all available PK data were then used to confirm the dose and weight bands for sequentially enrolling Cohorts 3 and 4. The safety and effectiveness of berotralstat in this population was summarized using descriptive statistical methods.

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Ontario
    • Vienna, Ontario, Austria
      • Investigative Site #1
• Canada
  • Ontario
    • Ottawa, Ontario, Canada
      • Investigative Site #1
• France
  • Grenoble, France
    • Investigative Site #3
  • Marseille, France
    • Investigative Site #2
  • Paris, France
    • Investigative Site #1
• Germany
  • Berlin, Germany
    • Investigative Site #1
  • Frankfurt, Germany
    • Investigative Site #2
• Israel
  • Haifa, Israel
    • Investigative Site #2
  • Tel Aviv, Israel
    • Investigative Site #1
• Italy
  • Padua, Italy
    • Investigative Site #1
• Poland
  • Krakow, Poland
    • Investigative Site #1
• Romania
  • Sângeorgiu de Mureş, Romania
    • Investigative Site #1
• Spain
  • Madrid, Spain
    • Investigative Site #1
  • Málaga, Spain
    • Investigative Site #2
• United Kingdom
  • Bristol, United Kingdom
    • Investigative Site #1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 2 years to 11 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male and non-pregnant, non-lactating females 2 to < 12 years of age
• Body weight ≥ 12 kg
• Clinical diagnosis of HAE
• In the opinion of the investigator, the participant would benefit from long term oral HAE prophylaxis
• For subjects who are not currently receiving prophylaxis for HAE, documented history of >= 2 HAE attacks in the 6 months prior to the enrollment visit.

Exclusion Criteria:

• Concurrent diagnosis of any other type of recurrent angioedema
• Known family history of sudden cardiac death at a young age (< 40 years of age)
• Creatinine clearance using the modified Schwartz formula of ≤ 30 mL/min/1.73 m^2
• Aspartate aminotransferase or alanine aminotransferase value ≥ 3 × the upper limit of the age-appropriate normal reference range value
• Clinically significant abnormal electrocardiogram (ECG) including but not limited to, a corrected QT interval using Fridericia's correction > 450 msec, or ventricular and/or atrial premature contractions that are more frequent than occasional, and/or as couplets or higher in grouping
• Current participation in any other investigational drug study or received another investigational drug within 30 days of enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1: ≥ 40 kg body weight (Berotralstat 150 mg); Participants received 150 milligram (mg) berotralstat capsule orally once daily for up to 144 weeks. Dose modifications were permitted due to weight changes, PK results, or safety.	Drug: Berotralstat; Administered orally once daily; Other Names: BCX7353; Orladeyo®
Experimental: Cohort 2: 32 to < 40 kg body weight (Berotralstat 108 mg); Participants received 108 mg berotralstat granules orally once daily for up to 144 weeks. Dose modifications were permitted due to weight changes, PK results, or safety.	Drug: Berotralstat; Administered orally once daily; Other Names: BCX7353; Orladeyo®
Experimental: Cohort 3: 24 to < 32 kg body weight (Berotralstat 96 mg); Participants received 96 mg berotralstat granules orally once daily for up to 144 weeks. Dose modifications were permitted due to weight changes, PK results, or safety.	Drug: Berotralstat; Administered orally once daily; Other Names: BCX7353; Orladeyo®
Experimental: Cohort 4: 12 to <24 kg body weight (Berotralstat 78 mg); Participants received 78 mg berotralstat granules orally once daily for up to 144 weeks. Dose modifications were permitted due to weight changes, PK results, or safety.	Drug: Berotralstat; Administered orally once daily; Other Names: BCX7353; Orladeyo®

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Curve From Time 0 to the Last Measurable Concentration (AUC0-last) of Berotralstat	AUC0-last is the area under the plasma concentration-time curve from time 0 to the time of the last measurable concentration.	Week 2
Area Under the Plasma Concentration-Time Curve From Time 0 to 6 Hours Post-dose (AUC0-6) of Berotralstat	AUC0-6 is the area under the plasma concentration-time curve from time 0 to 6 hours.	Predose and up to 6 hours post dose at Week 2
Concentration at the End of the Dosing Interval (Ctrough) of Berotralstat	Ctrough is the concentration at the end of a dosing interval of berotralstat.	Predose at Week 2
Maximum Observed Plasma Concentration (Cmax) of Berotralstat	Cmax is the maximum observed plasma concentration of berotralstat.	Predose and up to 6 hours post dose at Week 2
Time of Last Measurable Plasma Concentration (Tlast) of Berotralstat	Tlast is the time of the last measurable concentration (Clast) of berotralstat collected over the sampling interval.	Predose and up to 6 hours post dose at Week 2
Time to Maximum Plasma Concentration (Tmax) of Berotralstat	Tmax is the time taken to reach the maximum observed plasma concentration of berotralstat.	Predose and up to 6 hours post dose at Week 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (TEAEs)	An adverse event (AE) is any untoward medical occurrence in a clinical study participant. No causal relationship with study drug or with the clinical study itself is implied. An AE could be an unfavorable and unintended sign, symptom (including an abnormal laboratory finding), syndrome, or illness that developed or worsened during the clinical study. A serious adverse event (SAE) is any untoward medical occurrence resulting in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or other medically important event. TEAEs are AEs that occurred on/after first dose of berotralstat through 30 days post discontinuation of study treatment.	From first dose of study treatment up to approximately 73 weeks
Number of Adjusted Hereditary Angioedema (HAE) Attacks	Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?",were considered unique (attack began > 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of > 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack.	Week 1 through Week 12 and Week 1 through Week 48
Rate of Adjusted HAE Attacks	Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?",were considered unique (attack began > 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of > 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. The adjusted attack rate was calculated as the number of adjusted attacks observed during a given period and standardized to number of attacks per month, where 1 month is defined as a 28-day (4 week) period.	Week 1 through Week 12 and Week 1 through Week 48
Duration of Adjusted HAE Attack Symptoms	Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?",were considered unique (attack began > 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of > 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. The duration of each participant-reported attack was calculated in hours, based on the start, and stop date and time of the adjusted attack (time the attack finished).	Week 1 through Week 12 and Week 1 through Week 48
Incidence of Adjusted HAE Attack Based on Anatomical Location	Adjusted attacks were assessed based on anatomical location. Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?", were considered unique (attack began > 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of > 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. Anatomical locations were categorized as abdominal-only, non-abdominal peripheral, mixed, and laryngeal attacks.	Week 1 through Week 12 and Week 1 through Week 48
Number of Adjusted Attacks Requiring On-Demand Treatment	Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?", were considered unique (attack began > 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of > 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. Number of adjusted attacks treated with targeted HAE medications was assessed.	Week 1 through Week 12 and Week 1 through Week 48
Proportion of Adjusted Attacks Requiring On-Demand Treatment	Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?", were considered unique (attack began > 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of > 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. Proportion of adjusted attacks treated with targeted HAE medications was assessed.	Week 1 through Week 12 and Week 1 through Week 48
Number of Days With Angioedema Symptoms	Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc)?",were considered unique (attack began > 24 hours from the end of the prior attack),and if the entire adjusted attack was untreated, it had a duration of > 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. The number of days with angioedema symptoms is the number of the days during the reporting period for which at least 1 symptom is reported during an adjusted HAE attack based on the start date and resolution date of an attack.	Week 1 through Week 12 and Week 1 through Week 48
Proportion of Days With Angioedema Symptoms	Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc)?",were considered unique (attack began > 24 hours from the end of the prior attack),and if the entire adjusted attack was untreated, it had a duration of > 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. The proportion of days with angioedema symptoms was based on the number of days with reported symptoms and the number of days the participant was on treatment, where the number of days with angioedema symptoms is the number of the days during the reporting period for which at least 1 symptom is reported during an adjusted HAE attack based on the start date and resolution date of an attack.	Week 1 through Week 12 and Week 1 through Week 48
Assessment of Adjusted HAE Attack Severity	Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?", were considered unique (attack began > 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of > 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. The severity was assessed by the parent/caregiver as negligible, mild, moderate or severe.	Week 1 through Week 12 and Week 1 through Week 48
Number of Participants Who Discontinued Treatment Due to Perceived Lack of Efficacy	The total number of participants who discontinued the treatment due to perceived lack of efficacy of berotralstat were reported.	Week 1 through Week 12 and Week 1 through Week 48
Number of Hospitalizations and Clinic Visits Due to HAE	Adjusted attacks included at least 1 symptom of swelling, had a response of "no" to the diary question: "In retrospect, could there be an alternative explanation for your symptoms other than an HAE attack (that is, allergic reaction, viral cold etc.)?", were considered unique (attack began > 24 hours from the end of the prior attack), and if the entire adjusted attack was untreated, it had a duration of > 24 hours. Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack. Number of adjusted attacks that required hospitalization or clinic visits are reported.	Week 1 through Week 12 and Week 1 through Week 48

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Acceptability/palatability of berotralstat oral granules using a self-reported taste rating scale designed with images centered on taste	TASTY; 7-point scale [0 "worst" to 6 "best"]	Time of first dose (Day 1)

Collaborators and Investigators

• Sponsor: BioCryst Pharmaceuticals
• Investigators: Principal Investigator: Jolanta Bernatoniene, MD, Bristol Royal Hospital for Children

Publications and helpful links

General Publications

• Bernatoniene J, Bourgoin-Heck M, Cancian M, Yang W, Hagin D, Pagnier A, Stobiecki M, Kinaciyan T, Phillips-Angles E, Gayet S, Bara NA, Hunter J, Mateescu E, DeSpirito M, Johnston D, Long D, Iocca H, Petroni D, Aygoren-Pursun E. Oral berotralstat for hereditary angioedema prophylaxis in patients aged 2 to <12 years: APeX-P interim results. Ann Allergy Asthma Immunol. 2025 Dec;135(6):681-688.e3. doi: 10.1016/j.anai.2025.07.012. Epub 2025 Jul 25.

Study record dates

Study Major Dates

• Study Start (Actual): October 25, 2022
• Primary Completion (Actual): September 11, 2024
• Study Completion (Estimated): February 1, 2027

Study Registration Dates

• First Submitted: June 30, 2022
• First Submitted That Met QC Criteria: July 8, 2022
• First Posted (Actual): July 12, 2022

Study Record Updates

• Last Update Posted (Actual): February 25, 2026
• Last Update Submitted That Met QC Criteria: February 6, 2026
• Last Verified: February 1, 2026

More Information

Terms related to this study

• Keywords: Pediatric; Oral; once a day; Berotralstat; BCX7353; kallikrein inhibitor; Hereditary angioedema (HAE); Orladeyo
• Additional Relevant MeSH Terms: Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Vascular Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Immune System Diseases; Hypersensitivity, Immediate; Hypersensitivity; Immunologic Deficiency Syndromes; Skin Diseases; Urticaria; Skin Diseases, Vascular; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Skin and Connective Tissue Diseases; Angioedema; Angioedemas, Hereditary; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; berotralstat
• Other Study ID Numbers: BCX7353-304; 2021-005932-50 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No