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Publications

Journal Article Epublish

PubMed: 42318595 DOI: 10.1016/j.waojou.2026.101401

Sebetralstat for on-demand treatment of hereditary angioedema: A pooled analysis of placebo-controlled clinical trials.

World Allergy Organ J 19(7):101401

Authors: Emel Aygören-Pürsün, Danny M Cohn, Nancy Agmon-Levin, Aleena Banerji, Jonathan A Bernstein, Paula Busse, Mauro Cancian, Eunice Dias de Castro, Henriette Farkas, Vesna Grivcheva-Panovska, David Hagin, Roman Hakl, Daisuke Honda, Aharon Kessel, Tamar Kinaciyan, Ifaad, Marcin Kurowski, H Henry Li, Ramon Lleonart, Hilary J Longhurst, William R Lumry, Markus Magerl, Inmaculada Martinez-Saguer, Isaac Melamed, Fotis Psarros, Sinisa Savic, Daniel F Soteres, Maria Staevska, Marcin Stobiecki, H James Wedner, Andrea Zanichelli, James Hao, Ketan Patil, Matthew Iverson, Samuel Owiredu-Yeboa, Michael D Smith, Christopher M Yea, Paul K Audhya, Marc A Riedl, Sorena Kiani-Alikhan, Marcus Maurer

Affiliations

  • University Hospital Frankfurt, Goethe University, Frankfurt, Germany.
  • Amsterdam UMC Location AMC, Amsterdam, Netherlands.
  • Clinical Immunology, Angioedema and Allergy Institute, The Center for Autoimmune Diseases, Sheba Medical Center, Tel Aviv, Israel.
  • Professor of Medicine, Harvard Medical School, Clinical Director, Allergy and Immunology, Massachusetts General Hospital, Boston, Massachusetts, United States.
  • University of Cincinnati College of Medicine, Division of Rheumatology, Allergy and Immunology, Advanced Allergy Services and Bernstein Clinical Research Center, Cincinnati, Ohio, United States.
  • Icahn School of Medicine at Mount Sinai, New York, New York, United States.
  • Departmental Unit of Allergology, University Hospital of Padua, Padua, Italy.
  • Allergy and Clinical Immunology Department, Centro Hospitalar Universitário de S. João EPE, Porto, Portugal.
  • Public Health and Forensic Sciences and Medical Education Department, Faculty of Medicine, University of Porto, Porto, Portugal.
  • Hungarian Angioedema Center of Reference and Excellence, Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary.
  • ACARE North Macedonia, PHI University Clinic of Dermatology, Ss Cyril and Methodius Skopje University, Skopje, Republic of North Macedonia.
  • Allergy and Clinical Immunology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel.
  • Department of Clinical Immunology and Allergology, St. Annés University Hospital in Brno, and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
  • Department of Nephrology, Graduate School of Medicine, Chiba University, Chiba, Japan.
  • Division of Allergy and Clinical Immunology, Bnai Zion Medical Center, Haifa, Israel.
  • Department of Dermatology, Medical University of Vienna, Vienna, Austria.
  • Department of Immunology and Allergy, Medical University of Łódź, Łódź, Poland.
  • Institute for Asthma and Allergy, Chevy Chase, Maryland, United States.
  • Allergology Department, Bellvitge University Hospital, Barcelona, Spain.
  • Department of Medicine, University of Auckland and Department of Immunology, Auckland City Hospital, Auckland, New Zealand.
  • AARA Research Center, Dallas, Texas, United States.
  • Angioedema Center of Reference and Excellence (ACARE), Institute of Allergology, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.
  • Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Immunology and Allergology, Berlin, Germany.
  • Hemophilia Center Rhine Main, Frankfurt, Germany.
  • IMMUNOe Research Center, Centennial, Colorado, United States.
  • Allergy Department, Naval Hospital, Athens, Greece.
  • Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds, United Kingdom.
  • Asthma & Allergy Associates, Colorado Springs, Colorado, Department of Internal Medicine, Division of Allergy and Immunology, University of Colorado Health Sciences Center, Denver, CO, United States.
  • Department of Allergology, Medical University of Sofia, Clinic of Allergology, University Hospital "Alexandrovska" Sofia, Sofia, Bulgaria.
  • Department of Clinical and Environmental Allergology, Jagiellonian University Medical College, Krakow, Poland.
  • Division of Allergy and Immunology, John T. Milliken Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, United States.
  • Operative Unit of Medicine, Angioedema Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy.
  • Department of Biomedical Science for Health, University of Milan, Milan, Italy.
  • KalVista Pharmaceuticals, Inc. Framingham, Massachusetts, United States.
  • KalVista Pharmaceuticals, Inc. Salisbury, United Kingdom.
  • Division of Allergy and Immunology, University of California - San Diego, La Jolla, California, United States.
  • Royal Free London NHS Foundation Trust, London, United Kingdom.

Abstract

BACKGROUND

Clinical trial designs evaluating on-demand therapies for hereditary angioedema attacks have evolved in response to changes in treatment guidelines. Sebetralstat, an oral plasma kallikrein inhibitor, was evaluated in 2 randomized, placebo-controlled clinical trials, which instructed early treatment of attacks with no minimum severity requirement.

OBJECTIVE

Characterize the efficacy and safety of sebetralstat by pooling data from phase 2 and 3 trials.

METHODS

This pooled analysis included participants (phase 2, aged ≥18 years; phase 3, aged ≥12 years) who received ≥1 dose of study drug (phase 2, sebetralstat 600 mg or placebo; phase 3, sebetralstat 300 mg or 600 mg, or placebo). Efficacy outcomes included times to beginning of symptom relief within 12 h, reduction in severity within 12 h, and complete attack resolution within 24 h. P values were not adjusted for multiplicity.

RESULTS

377 attacks were treated: 87 with sebetralstat 300 mg; 151 with sebetralstat 600 mg; 139 with placebo. Median (interquartile range) time to treatment was 32.5 min (8.0-94.0). Baseline severity was rated as "Mild" (46.2%), "Moderate" (40.6%), or "Severe"/"Very Severe" (12.7%). Compared with placebo, time to beginning of symptom relief was faster with sebetralstat (300 mg; 600 mg [P = 0.0001; P < 0.0001]), as was reduction in severity (P = 0.0038; P < 0.0001) and complete attack resolution (P = 0.0021; P < 0.0001). Median time to beginning of symptom relief was 1.6 h (0.8-7.0) and 1.8 h (1.0-4.3) with sebetralstat 300 mg and 600 mg, respectively, and 8.3 h (1.5 to >12) with placebo. Sebetralstat had a safety profile comparable to placebo.

CONCLUSION

Across phase 2 and 3 clinical trials, sebetralstat enabled early treatment, provided effective symptom relief versus placebo, and was well tolerated, regardless of attack location or baseline severity.

CLINICAL TRIAL REGISTRATION

ClinicalTrials.gov Identifier NCT04208412, registered on 2019-07-02; ClinicalTrials.gov Identifier NCT05259917 (KONFIDENT), registered on 2022-02-22.

MeSH

Safety, Angioedemas, Hereditary, Aged, Therapeutics, Angioedema