Efficacy and Safety Study of BCX7353 as an Oral Treatment for the Prevention of Attacks in HAE (APeX-2)

A Phase 3, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Efficacy and Safety of Two Dose Levels of BCX7353 as an Oral Treatment for the Prevention of Attacks in Subjects With Hereditary Angioedema

This is a phase 3, multicenter, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of oral BCX7353 in preventing acute angioedema attacks in patients with Type I and Type II HAE.

Study Overview

• Status: Completed
• Conditions: Hereditary Angioedema; HAE
• Intervention / Treatment: Drug: BCX7353 capsules; Drug: Placebo oral capsule

• Study Type: Interventional
• Enrollment (Actual): 121
• Phase: Phase 3

Contacts and Locations

Study Locations

• Austria
  • Vienna, Austria, 1090
    • Study Center
• Canada
  • Québec, Canada, G1V 4W2
    • Study Center
  • Ontario
    • Ottawa, Ontario, Canada, K1G 6C6
      • Study Center
    • Toronto, Ontario, Canada, M4V 1R2
      • Study Center
• Czechia
  • Brno, Czechia, 656 91
    • Study Center
  • Plzen, Czechia, 30460
    • Study Center
• France
  • Grenoble, France, 38043
    • Study Center
  • Paris, France, 75012
    • Study Center
• Germany
  • Berlin, Germany, 10117
    • Study Center
  • Frankfurt, Germany, D-60590
    • Study Center
• Hungary
  • Budapest, Hungary, H-1225
    • Study Center
• North Macedonia
  • Skopje, North Macedonia, 1000
    • Study Center
• Romania
  • Jud. Mureș
    • Sângeorgiu de Mureș, Jud. Mureș, Romania, 547530
      • Study Center
• Spain
  • Barcelona, Spain, 08907
    • Study Center
  • Madrid, Spain, 28046
    • Study Center
  • Seville, Spain, 41013
    • Study Center
• United Kingdom
  • Cambridge, United Kingdom, CB2 0QQ
    • Study Center
  • Frimley, United Kingdom, GU16 7UJ
    • Study Center
  • London, United Kingdom, E1 2ES
    • Study Center
  • Plymouth, United Kingdom, PL6 8DH
    • Study Center
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35209
      • Study Center
  • Arizona
    • Scottsdale, Arizona, United States, 85251
      • Study Center
  • Arkansas
    • Little Rock, Arkansas, United States, 72205
      • Study Center
  • California
    • San Diego, California, United States, 92122
      • Study Center
    • Santa Monica, California, United States, 90404
      • Study Center
    • Walnut Creek, California, United States, 94598
      • Study Center
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Study Center
  • Florida
    • Tampa, Florida, United States, 33613
      • Study Center
  • Maryland
    • Chevy Chase, Maryland, United States, 20815
      • Study Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02114
      • Study Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48106
      • Study Center
  • Minnesota
    • Plymouth, Minnesota, United States, 55446
      • Study Center
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Study Center
  • New Jersey
    • Belleville, New Jersey, United States, 07109
      • Study Center
    • Fair Lawn, New Jersey, United States, 07410
      • Study Center
    • Piscataway, New Jersey, United States, 08854
      • Study Center
  • New York
    • New York, New York, United States, 10029
      • Study Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28277
      • Study Site
    • Durham, North Carolina, United States, 27705
      • Study Center
  • Ohio
    • Cincinnati, Ohio, United States, 45231
      • Study Center
    • Columbus, Ohio, United States, 43235
      • Study Center
  • Oregon
    • Clackamas, Oregon, United States, 97015
      • Study Center
  • Pennsylvania
    • Hershey, Pennsylvania, United States, 17033
      • Study Center
  • Texas
    • Austin, Texas, United States, 78731
      • Study Center
    • Dallas, Texas, United States, 75231
      • Study Center
    • San Antonio, Texas, United States, 78229
      • Study Center
  • Washington
    • Spokane, Washington, United States, 99202
      • Study Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Key Inclusion Criteria:

• A clinical diagnosis of hereditary angioedema Type 1 or Type 2, defined as having a C1-INH functional level and a C4 level below the lower limit of the normal (LLN) reference range, as assessed during the Screening period.
• Subject weight of ≥ 40 kg
• Access to and ability to use one or more acute medications approved by the relevant competent authority for the treatment of acute attacks of HAE
• Subjects must be medically appropriate for on-demand treatment as the sole medicinal management for their HAE during the study.
• Subjects must have a specified number of investigator-confirmed attacks during the run-in period of a maximum of 56 days from the Screening visit.
• Acceptable effective contraception
• Written informed consent

Key Exclusion Criteria:

• Pregnancy or breast-feeding
• Any clinically significant medical condition or medical history that, in the opinion of the Investigator or Sponsor, would interfere with the subject's safety or ability to participate in the study
• Any laboratory parameter abnormality that, in the opinion of the Investigator, is clinically significant and relevant for this study
• Severe hypersensitivity to multiple medicinal products or severe hypersensitivity/ anaphylaxis with unclear etiology
• Use of C1-INH within 14 days or use of androgens or tranexamic acid within 28 days prior to the Screening visit for prophylaxis of HAE attacks, or initiation of these drugs during the study
• Current participation in any other investigational drug study or received another investigational drug within 30 days of the Screening visit
• Prior enrollment in a BCX7353 study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BCX7353 110 mg once daily; BCX7353 administered as oral capsules once daily	Drug: BCX7353 capsules; BCX7353 oral capsules administered once daily; Other Names: Berotralstat
Experimental: BCX7353 150 mg once daily; BCX7353 administered as oral capsules once daily	Drug: BCX7353 capsules; BCX7353 oral capsules administered once daily; Other Names: Berotralstat
Placebo Comparator: Placebo; Matching placebo administered as oral capsules once daily	Drug: Placebo oral capsule; Matching oral capsules administered once daily

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: The Rate of Investigator-confirmed HAE Attacks During Dosing in the Entire 24-week Treatment Period (Day 1 to Day 168)	Treatment comparisons between each berotralstat dose and placebo in the rate of investigator-confirmed HAE attacks during the Part 1 dosing period were analyzed using a negative binomial model. The number of investigator-confirmed attacks was included as the dependent variable, the treatment was included as a fixed effect, the stratification variable (baseline attack rate) was included as a covariate, and the logarithm of duration on treatment was included as an offset variable. The estimated attack rate for each treatment group, the treatment differences expressed as the attack rate ratio (berotralstat over placebo rate ratio), and the associated 95% confidence intervals (CIs) were provided from the negative binomial model.	24 weeks
Part 2 & 3: To Evaluate the Long-term Safety and Tolerability of Berotralstat 110 and 150 mg in Subjects With HAE	The safety data was assessed for the safety population, for subjects who entered Part 2 and Part 3, and includes TEAEs that began in Part 2 or 3, respectively, for these subjects. Safety data for Part 2 and Part 3 is combined to clearly show TEAEs occurring in subjects as the proceeded through the 2 study parts. TEAEs are defined as AEs that occurred on or after first dose of study treatment, whether in Part 1 or 2, and were assigned to the relevant treatment depending on when the TEAE began (Part 2 or Part 3 treatment). No statistical analysis was performed on this safety data.	Part 2: 24 weeks (Days 169 to 337). Part 3: 48 weeks (Days 338 to 674).

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part 1: Change From Baseline in Angioedema Quality of Life Questionnaire at Week 24 (Total Score)	Change in Quality of Life, on a 1-100 scale, where higher scores indicate more impairment and a decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). The AE-QoL is only validated for adults; however, data were collected on all adult and adolescent study subjects.	Baseline and 24 weeks
Part 1: Proportion of Days With Angioedema Symptoms Through 24 Weeks	Assessment of proportion of days subjects had angioedema symptoms from expert-confirmed HAE attacks during Part 1.	24 weeks
Part 1: Rate of Expert-confirmed Angioedema Events During Dosing in the Effective Treatment Period	The rate of expert-confirmed HAE attacks for the effective treatment period gives an analysis of the efficacy of active treatment after berotralstat had reached steady-state concentrations, given the effective half-life of 150 mg berotralstat in Study BCX7353-106 (Study 106) of 89 hours.	Day 8 through to 24 weeks (or or the last dose date/time in Part 1 + 24 hours for subjects who discontinued drug in Part 1)
Part 2: To Assess the Effectiveness of Berotralstat Over a 24- to 48 Week Period	Monthly Attack Rate was defined as the total number of investigator-confirmed HAE attacks experienced during the treatment period adjusted for the length of a month (defined as 28 days) and the number of days the subject was on treatment during that month. The end of Month 6 was defined as the start of Part 2 treatment. Baseline investigator-confirmed attack rate was defined as the total number of investigator-confirmed HAE attacks experienced in the period between screening and first dose of study drug adjusted for the length of a month (defined as 28 days) and the number of days during that period.	24 weeks (Days 169 to 337)
To Evaluate Angioedema Quality of Life Questionnaire (Total Score) Following Berotralstat Administration for up to 144 Weeks	Angioedema-specific QoL was assessed by the AE-QoL, consisting of 4 domains (i.e., functioning, fatigue/mood, fears/shame, and nutrition) and a total score. The AE-QoL scores range from 0 points (best QoL) to 100 points (worst QoL). A decrease (change with a negative value) in AE-QoL questionnaire scores indicates an improvement in the subject's QoL. The minimum clinically important difference (MCID) for the AE-QoL questionnaire is -6 (total score). The AE-QoL was completed by the subjects at each visit starting at baseline, and questions were answered with regard to the previous 28 days. For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment.	Up to 144 weeks
To Evaluate Treatment Satisfaction Questionnaire for Medication (TSQM) Following Berotralstat Administration for up to 144 Weeks	The Treatment Satisfaction Questionnaire for Medication (TSQM) was completed by subjects at baseline and at each study visit until the end of the study. TSQM scores consisted of 14 items of which 13 items were made up of 3 specific scales (Effectiveness, Side Effects, and Convenience) and 1 global satisfaction scale (Global Satisfaction). At baseline, TSQM questionnaires were completed based on subject's satisfaction with usual medications. At all other time points for collection of TSQM, subjects were asked about their level of satisfaction or dissatisfaction with the study drug. Scales scores were calculated for each scale and were transformed into scores ranging from 0 to 100, with higher scores indicating higher satisfaction. TSQM score and corresponding change from baseline values were calculated at each visit. For subjects who received active treatment following placebo, visits were adjusted according to the date of the first dose of active treatment.	Up to 144 weeks

Collaborators and Investigators

• Sponsor: BioCryst Pharmaceuticals
• Investigators: Principal Investigator: Bruce Zuraw, MD, UC San Diego School of Medicine, US HAE Angioedema Center

Publications and helpful links

General Publications

• Beard N, Frese M, Smertina E, Mere P, Katelaris C, Mills K. Interventions for the long-term prevention of hereditary angioedema attacks. Cochrane Database Syst Rev. 2022 Nov 3;11(11):CD013403. doi: 10.1002/14651858.CD013403.pub2.
• Wedner HJ, Aygoren-Pursun E, Bernstein J, Craig T, Gower R, Jacobs JS, Johnston DT, Lumry WR, Zuraw BL, Best JM, Iocca HA, Murray SC, Desai B, Nagy E, Sheridan WP, Kiani-Alikhan S. Randomized Trial of the Efficacy and Safety of Berotralstat (BCX7353) as an Oral Prophylactic Therapy for Hereditary Angioedema: Results of APeX-2 Through 48 Weeks (Part 2). J Allergy Clin Immunol Pract. 2021 Jun;9(6):2305-2314.e4. doi: 10.1016/j.jaip.2021.03.057. Epub 2021 Apr 15.
• Zuraw B, Lumry WR, Johnston DT, Aygoren-Pursun E, Banerji A, Bernstein JA, Christiansen SC, Jacobs JS, Sitz KV, Gower RG, Gagnon R, Wedner HJ, Kinaciyan T, Hakl R, Hanzlikova J, Anderson JT, McNeil DL, Fritz SB, Yang WH, Tachdjian R, Busse PJ, Craig TJ, Li HH, Farkas H, Best JM, Clemons D, Cornpropst M, Dobo SM, Iocca HA, Kargl D, Nagy E, Murray SC, Collis P, Sheridan WP, Maurer M, Riedl MA. Oral once-daily berotralstat for the prevention of hereditary angioedema attacks: A randomized, double-blind, placebo-controlled phase 3 trial. J Allergy Clin Immunol. 2021 Jul;148(1):164-172.e9. doi: 10.1016/j.jaci.2020.10.015. Epub 2020 Oct 21.

Study record dates

Study Major Dates

• Study Start (Actual): February 6, 2018
• Primary Completion (Actual): April 10, 2019
• Study Completion (Actual): April 6, 2022

Study Registration Dates

• First Submitted: March 15, 2018
• First Submitted That Met QC Criteria: March 30, 2018
• First Posted (Actual): April 3, 2018

Study Record Updates

• Last Update Posted (Actual): June 26, 2023
• Last Update Submitted That Met QC Criteria: May 31, 2023
• Last Verified: May 1, 2023

More Information

Terms related to this study

• Keywords: Berotralstat; BCX7353
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hypersensitivity, Immediate; Genetic Diseases, Inborn; Skin Diseases, Vascular; Hypersensitivity; Urticaria; Hereditary Complement Deficiency Diseases; Primary Immunodeficiency Diseases; Angioedema; Angioedemas, Hereditary; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Serine Proteinase Inhibitors; Berotralstat
• Other Study ID Numbers: BCX7353-302

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