Henriette Farkas1, Marcin Stobiecki2, Jonny Peter3,4, Tamar Kinaciyan5, Marcus Maurer6, Emel Aygören-Pürsün7, Sorena Kiani-Alikhan8, Adrian Wu9, Avner Reshef10, Anette Bygum11,12,13, Olivier Fain14, David Hagin15, Aarnoud Huissoon16, Miloš Jeseňák17, Karen Lindsay18, Vesna Grivcheva Panovska19, Urs C Steiner20, Celia Zubrinich21, Jessica M Best22, Melanie Cornpropst22, Daniel Dix22, Sylvia M Dobo22, Heather A Iocca22, Bhavisha Desai22, Sharon C Murray22, Eniko Nagy22, William P Sheridan22. 1. Hungarian Angioedema Center of Reference and Excellence, Department of Internal Medicine and Hematology, Semmelweis University, Budapest, Hungary. 2. Department of Clinical and Environmental Allergology, Jagiellonian University Medical College, Krakow, Poland. 3. Allergy and Immunology Unit, University of Cape Town Lung Institute, Cape Town, South Africa. 4. Division of Allergy and Clinical Immunology, Department of Medicine, University of Cape Town, Cape Town, South Africa. 5. Department of Dermatology, Medical University of Vienna, Vienna, Austria. 6. Dermatological Allergology, Department of Dermatology and Allergy, Charité - Universitätsmedizin Berlin, Berlin, Germany. 7. Department for Children and Adolescents, University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt, Germany. 8. Department of Immunology, Barts Health NHS Trust, Royal London Hospital, London, UK. 9. Center for Allergy and Asthma Care, Central, Hong Kong, China. 10. Angioderma Center, Barzilai University Medical Center, Ashkelon, Israel. 11. Department of Dermatology and Allergy Centre, Odense University Hospital, Odense, Denmark. 12. Department of Clinical Genetics, Odense University Hospital, Odense, Denmark. 13. Clinical Institute, University of Southern Denmark, Odense, Denmark. 14. Sorbonne Université, Service de Médecine Interne, AP-HP, Hôpital Saint-Antoine, Paris, France. 15. Allergy and Clinical Immunology Unit, Department of Medicine, Tel Aviv Sourasky Medical Center and Sackler Faculty of Medicine, University of Tel Aviv, Tel Aviv, Israel. 16. Department of Immunology, Birmingham Heartlands Hospital, University Hospitals Birmingham, UK. 17. National Center for Hereditary Angioedema, Department of Pediatrics, Department of Pulmonology and Allergology, Comenius University in Bratislava, Jessenius Faculty of Medicine, Martin, Slovakia. 18. Auckland DHB Clinical Immunology and Allergy, Auckland, New Zealand. 19. University Clinic of Dermatology, Ss Cyril and Methodius University, Skopje, Macedonia. 20. Department of Immunology, University Hospital Zurich, Zurich, Switzerland. 21. Allergy, Asthma and Clinical Immunology, Alfred Health, Melbourne, Victoria, Australia. 22. BioCryst Pharmaceuticals, Durham, North Carolina, USA.
Abstract
BACKGROUND:Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE. METHODS: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness. RESULTS:Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11-540) and 307 (14-429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. CONCLUSIONS: In this analysis, both berotralstat doses, 150 and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov (NCT03472040).
RCT Entities:
BACKGROUND:Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE. METHODS:APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness. RESULTS: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11-540) and 307 (14-429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. CONCLUSIONS: In this analysis, both berotralstat doses, 150 and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov (NCT03472040).
Authors: Marcus Maurer; Markus Magerl; Stephen Betschel; Werner Aberer; Ignacio J Ansotegui; Emel Aygören-Pürsün; Aleena Banerji; Noémi-Anna Bara; Isabelle Boccon-Gibod; Konrad Bork; Laurence Bouillet; Henrik Balle Boysen; Nicholas Brodszki; Paula J Busse; Anette Bygum; Teresa Caballero; Mauro Cancian; Anthony J Castaldo; Danny M Cohn; Dorottya Csuka; Henriette Farkas; Mark Gompels; Richard Gower; Anete S Grumach; Guillermo Guidos-Fogelbach; Michihiro Hide; Hye-Ryun Kang; Allen P Kaplan; Constance H Katelaris; Sorena Kiani-Alikhan; Wei-Te Lei; Richard F Lockey; Hilary Longhurst; William Lumry; Andrew MacGinnitie; Alejandro Malbran; Inmaculada Martinez Saguer; Juan José Matta Campos; Alexander Nast; Dinh Nguyen; Sandra A Nieto-Martinez; Ruby Pawankar; Jonathan Peter; Grzegorz Porebski; Nieves Prior; Avner Reshef; Marc Riedl; Bruce Ritchie; Farrukh Rafique Sheikh; William B Smith; Peter J Spaeth; Marcin Stobiecki; Elias Toubi; Lilian Agnes Varga; Karsten Weller; Andrea Zanichelli; Yuxiang Zhi; Bruce Zuraw; Timothy Craig Journal: World Allergy Organ J Date: 2022-04-07 Impact factor: 5.516
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