A Long Term Safety Study of BCX7353 in Hereditary Angioedema

• BCX7353 (Drug): BCX7353 mg oral capsules administered once daily

Primary outcomes

• Safety & Tolerability [Up to 96 weeks (US) / 216 weeks (Rest of World (ROW)).]: The number and percentage of subjects with treatment-emergent adverse events.

Secondary outcomes

• Incidence of Acute Attacks of Angioedema in Subjects During Treatment [Up to 96 weeks (US) / 216 weeks (ROW)]: Number of 'adjusted' attacks were assessed. 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 (i.e., allergic reaction, viral cold etc.)?', and were considered unique (attack began > 24 hours from the end of the prior attack). Any attack that began within 24 hours from the end of a prior attack was combined with the prior attack.
• The Durability of Response to Treatment [Up to 96 weeks (US) / 216 weeks (ROW)]: To evaluate if the rate of attacks remains consistent (durable) over time, the monthly attack rate was assessed at 0 to 24 weeks, 24 to 48 weeks, 48 to 96 weeks and 96 weeks until the end of the study. Monthly attack rate was defined as the total number of adjusted 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.
• Patient Reported Quality of Life (QoL) During Treatment [Up to 96 weeks (US) / 216 weeks (ROW)]: Quality of Life (QoL) specific to hereditary angioedema (HAE) was assessed at baseline and at each study visit until the end of the study. The questionnaire (i.e. AE-QoL) consisted of 17 questions spanning 4 domains (functioning, fatigue/mood, fear/shame, and nutrition). Each AE-QoL question had 5 answer options (scored 1-5), with lower and higher scores indicting less and more adverse impact, respectively. Per-subject scores for each domain were computed using the appropriate scoring algorithm applied to the question response scores for each domain. Per-subject total scores (including all 4 domains) were similarly computed using the question response scores for all 17 questions. The outputs from the scoring algorithm were normalized on a scale ranging from 0 (less adverse impact) to 100 (most adverse impact). The Mean change from baseline (CFB) in AE-QoL total score over time is presented below.
• Patient's Satisfaction With Medication During Long Term Administration of Berotralstat [Up to 96 weeks (US) / 216 weeks (ROW)]: 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. Scale 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. Note: Subjects in Hong Kong did not complete the TSQM.

Sex: All, ages: 12 Years to any

Key Inclusion Criteria:

* Subjects with HAE Type I or II who either have participated in a previous BCX7353 study or, in selected countries, in the opinion of the Investigator are expected to derive benefit from an oral treatment for the prevention of angioedema attacks.
* Access to appropriate medication for treatment of acute attacks
* 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
* Discontinuation of study drug due to a hypersensitivity reaction BCX7353 in a prior study
* Severe hypersensitivity to multiple medicinal products or severe hypersensitivity/ anaphylaxis with unclear etiology
* Unacceptable noncompliance in a previous BCX7353 study (if applicable) as assessed by the Sponsor or Investigator
* Investigational drug exposure, other than BCX7353, within 30 days prior to the screening visit (or baseline if no screening visit)

Participant flow

Outcome results

• Safety & Tolerability (Primary), Count of participants, Participants: 110 mg Followed by 150 mg Berotralstat 94; 150 mg Berotralstat 240
• Incidence of Acute Attacks of Angioedema in Subjects During Treatment (Secondary), Count of participants, Participants: 110 mg Followed by 150 mg Berotralstat 95; 150 mg Berotralstat 231
• The Durability of Response to Treatment (Secondary), Mean, HAE attacks per 28 days: 110 mg Followed by 150 mg Berotralstat 1.276 +/- 1.2254; 150 mg Berotralstat 1.079 +/- 1.4411
• Patient Reported Quality of Life (QoL) During Treatment (Secondary), Mean, AE-QoL score - change from baseline: 110 mg Followed by 150 mg Berotralstat -8.85 +/- 18.986; 150 mg Berotralstat -10.38 +/- 17.845
• Patient's Satisfaction With Medication During Long Term Administration of Berotralstat (Secondary), Mean, TSQM score - change from baseline: 110 mg Followed by 150 mg Berotralstat -4.1 +/- 35.51; 150 mg Berotralstat -1.3 +/- 30.48

Adverse events

Time frame: Adverse Events (AEs) were reported from time of Informed Consent Form signature until the last follow-up visit, approximately 3 weeks following the last dose of study drug; a period of up to 223 weeks in total. Grade 3 and 4 AEs or AEs deemed at least possibly related to use of study drug, were to be followed until the AE resolved or the subject was in a clinically stable condition with regards to the AE.

Serious adverse events by term

Other adverse events by term

• Results publication: Farkas H, Peter JG, Stobiecki M, Anderson J, Aygoren-Pursun E, Hagin D, Jesenak M, Kessel A, Kiani-Alikhan S, Kinaciyan T, Manning M, Reshef A, Wu A, Iocca HA, Johnston DT, Noble L, Tomita D, Banerji A. Long-term safety and efficacy of once-daily berotralstat in patients with hereditary angioedema: APeX-S final results. Ann Allergy Asthma Immunol. 2025 Sep;135(3):311-319.e6. doi: 10.1016/j.anai.2025.06.004. Epub 2025 Jun 7. PMID 40490218
• Results publication: Peter JG, Desai B, Tomita D, Collis P, Stobiecki M. Assessment of HAE prophylaxis transition from androgen therapy to berotralstat: A subset analysis of the APeX-S trial. World Allergy Organ J. 2023 Nov 6;16(11):100841. doi: 10.1016/j.waojou.2023.100841. eCollection 2023 Nov. PMID 38020288
• Results publication: Riedl MA, Soteres D, Sublett JW, Desai B, Tomita D, Collis P, Bernstein JA; APeX-S Study Investigators. Hereditary angioedema outcomes in US patients switched from injectable long-term prophylactic medication to oral berotralstat. Ann Allergy Asthma Immunol. 2024 Apr;132(4):505-511.e1. doi: 10.1016/j.anai.2023.11.016. Epub 2023 Nov 24. PMID 38006972
• Results publication: Farkas H, Balla Z. A review of berotralstat for the treatment of hereditary angioedema. Expert Rev Clin Immunol. 2023 Feb;19(2):145-153. doi: 10.1080/1744666X.2023.2150611. Epub 2022 Nov 29. PMID 36408587
• Results publication: Riedl MA, Neville D, Cloud B, Desai B, Bernstein JA. Shared decision-making in the management of hereditary angioedema: An analysis of patient and physician perspectives. Allergy Asthma Proc. 2022 Sep 1;43(5):397-405. doi: 10.2500/aap.2022.43.220050. Epub 2022 Jul 12. PMID 35820771
• Results publication: Farkas H, Stobiecki M, Peter J, Kinaciyan T, Maurer M, Aygoren-Pursun E, Kiani-Alikhan S, Wu A, Reshef A, Bygum A, Fain O, Hagin D, Huissoon A, Jesenak M, Lindsay K, Panovska VG, Steiner UC, Zubrinich C, Best JM, Cornpropst M, Dix D, Dobo SM, Iocca HA, Desai B, Murray SC, Nagy E, Sheridan WP. Long-term safety and effectiveness of berotralstat for hereditary angioedema: The open-label APeX-S study. Clin Transl Allergy. 2021 Jun;11(4):e12035. doi: 10.1002/clt2.12035. PMID 34161665

• Study Protocol (PDF, 2020-03-23)
• Statistical Analysis Plan (PDF, 2019-02-26)

• Henriette Farkas, MD, Principal investigator, Semmelweis University, Budapest, Hungary