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Publications

Journal Article Epublish

PubMed: 42436759 DOI: 10.1016/j.jacig.2026.100750

Sebetralstat for breakthrough attacks in patients with hereditary angioedema receiving long-term prophylaxis in KONFIDENT-S.

J Allergy Clin Immunol Glob 5(5):100750

Authors: Tamar Kinaciyan, Emel Aygören-Pürsün, Inmaculada Martinez-Saguer, Daniel F Soteres, Daisuke Honda, Michael E Manning, H James Wedner, Atsushi Fukunaga, Henry J Kanarek, Kazumasa Ohmura, Isaac Melamed, Tariq El-Shanawany, Laurence Bouillet, William R Lumry, Marc A Riedl, Majed Koleilat, Bob Geng, Isao Ohsawa, Noemi Bara, Syed Rehman, Jonathan A Bernstein, Paula J Busse, Mauro Cancian, Danny M Cohn, Timothy J Craig, Henriette Farkas, Sorena Kiani-Alikhan, H Henry Li, Jason P Raasch, Raffi Tachdjian, Paul K Audhya, Paolo Bajcic, Ya-Hsiu Chuang, Matthew Iverson, Michael D Smith, Christopher M Yea, Andrea Zanichelli

Affiliations

  • Department of Dermatology, ACARE and Hereditary Angioedema Center Vienna and Burgenland, Medical University of Vienna, Vienna, Austria.
  • University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
  • HZRM Haemophilia Center Rhein Main, Frankfurt, Germany.
  • Asthma & Allergy Associates PC, Colorado Springs, Colo.
  • Department of Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Department of Internal Medicine, UA College of Medicine, Phoenix, Ariz.
  • Washington University School of Medicine, St Louis, Mo.
  • Department of Dermatology/OMPU Allergy Center, Division of Medicine for Function and Morphology of Sensory Organs, Faculty of Medicine, Osaka Medical and Pharmaceutical University, Osaka, Japan.
  • Kanarek Adult & Pediatric Allergy, Asthma & Immunology, Overland Park, Kan.
  • Institute of Preventive Medical Sciences, Health Sciences University of Hokkaido, Sapporo, Japan.
  • IMMUNOe Research Center, Centennial, Colo.
  • Department of Immunology, University Hospital of Wales, Cardiff, United Kingdom.
  • University of Grenoble Alpes, T-RAIG Unit, CNRS, UMR 5525, CHU Grenoble Alpes, TIMC, Grenoble, France.
  • French National Reference Center for Angioedema (CREAK), Internal Medicine Department, Grenoble University Hospital, Grenoble, France.
  • AARA Research Center, Dallas, Tex.
  • University of California-San Diego, La Jolla, Calif.
  • Deaconess Clinic, Evansville, Ind.
  • Allergy Asthma Medical Group & Research Center (AAMGRC), San Diego, Calif.
  • Department of Nephrology, Saiyu Soka Hospital, Saitama, Japan.
  • Hereditary Angioedema Expertise Center, Sangeorgiu de Mures, Romania.
  • Mediquest Clinical Research Center, Sangeorgiu de Mures, Romania.
  • Toledo Institute of Clinical Research, Toledo, Ohio.
  • University of Cincinnati College of Medicine and Bernstein Clinical Research Center, Cincinnati, Ohio.
  • Division of Allergy and Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY.
  • Departmental Allergy Division, Department of Systems Medicine, University of Padua, Padua, Italy.
  • Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, The Netherlands.
  • Department of Medicine, Pediatrics, MFM and Biomedical Sciences, Penn State University, Hershey, Pa.
  • Vinmec-VinUni Institute of Immunology, Vin University, Hanoi, Vietnam.
  • Center of Allergy and Clinical Immunology, Vinmec Times City Hospital, Hanoi, Vietnam.
  • Hungarian Angioedema Center of Reference and Excellence, Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary.
  • Division of Infection and Immunity, University College London, Royal Free London NHS Foundation Trust, London, United Kingdom.
  • Institute for Asthma and Allergy, Wheaton, Md.
  • Midwest Immunology Clinic, Plymouth, Minn.
  • Division of Allergy and Clinical Immunology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, Calif.
  • Allergy and Immunology, Providence Saint John's Health Center, Santa Monica, Calif.
  • KalVista Pharmaceuticals, Framingham, Mass.
  • Operative Unit of Medicine, Angioedema Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.
  • Dipartimento di Scienze Biomediche per la Salute, University of Milan, Milan, Italy.

Abstract

BACKGROUND

Although long-term prophylaxis (LTP) reduces attack frequency in hereditary angioedema, patients may experience breakthrough attacks. Oral sebetralstat demonstrated favorable safety and efficacy compared with placebo in the randomized phase 3 KONFIDENT trial (NCT05259917), including in patients receiving LTP. The safety and effectiveness of sebetralstat in participants receiving LTP are being assessed in the KONFIDENT-S open-label extension study (NCT05505916).

OBJECTIVE

This interim analysis of the KONFIDENT-S study evaluated long-term safety and effectiveness of oral sebetralstat 600 mg for attacks of hereditary angioedema with C1-inhibitor deficiency in participants receiving LTP with lanadelumab, berotralstat, or C1 inhibitor.

METHODS

Efficacy end points included times to beginning of symptom relief, reduction in severity, and complete attack resolution.

RESULTS

As of September 14, 2024, 35 participants receiving LTP experienced a mean ± standard deviation of 1.7 ± 1.5 attacks per month and treated 382 attacks with sebetralstat (1.3 ± 1.1 sebetralstat-treated attacks per month). Median (interquartile range) time from attack recognition to sebetralstat administration was 6 (1-40) minutes; time to beginning of symptom relief was 1.3 (0.8 to 3.8) hours, time to reduction in severity was 4.2 (1.3 to >12) hours, and time to complete attack resolution was 14.8 (4.6 to >24) hours. Effectiveness was similar for participants receiving berotralstat, lanadelumab, or C1 inhibitor. No serious or severe treatment-related treatment-emergent adverse events were reported.

CONCLUSION

Sebetralstat was well tolerated and enabled early on-demand treatment of attacks in patients with hereditary angioedema with C1-inhibitor deficiency receiving LTP. Treatment of breakthrough attacks with sebetralstat resulted in rapid symptom relief, reduction in attack severity, and complete attack resolution, regardless of LTP mechanism of action.

MeSH

Safety, Angioedemas, Hereditary, Therapeutics, Angioedema