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

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.

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Journal
World Allergy Organization Journal
Published
2026-06-09
DOI
https://doi.org/10.1016/j.waojou.2026.101401
Primary Topic
Coagulation, Bradykinin, Polyphosphates, and Angioedema
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article
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article

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

Daniel Soteres, James Hao, Fotis Psarros, Roman Hakl et al.
World Allergy Organization Journal
Coagulation, Bradykinin, Polyphosphates, and Angioedema
article

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

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

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.

World Allergy Organization JournalVol. 19(7)
Semmelweis University (HU), Goethe University Frankfurt (DE), Jagiellonian University (PL), University of Leeds (GB), La Jolla Institute for Immunology (US), University of Padua (IT), University of Auckland (NZ), Chiba University (JP), Royal Free London NHS Foundation Trust (GB), Universidade do Porto (PT), University of Milan (IT), Washington University in St. Louis (US), Masaryk University (CZ), Alexandrovska Hospital (BG), Tel Aviv Sourasky Medical Center (IL), Sheba Medical Center (IL), American Association for Respiratory Care (US), Auckland City Hospital (NZ), Bellvitge University Hospital (ES), Medical University of Sofia (BG), Hospital de São João (PT), University of California San Diego (US), Humboldt-Universität zu Berlin (DE), Massachusetts General Hospital (US), IRCCS Policlinico San Donato (IT), National Hemophilia Foundation (US), Fraunhofer Institute for Translational Medicine and Pharmacology (DE), IMMUNOe Research Center (US), Bernstein Clinical Research Center (US), Bnai Zion Medical Center (IL), Institute for Asthma and Allergy (US), NIHR Leeds Musculoskeletal Biomedical Research Unit (GB), KalVista Pharmaceuticals (United States) (US), Medical University of Lodz (PL), University Hospital Frankfurt (DE), Allergy Associates Research Center (US), Amsterdam University Medical Centers (NL), Athens Naval & Veterans Hospital (GR), Medical University of Vienna (AT), Ss. Cyril and Methodius University in Skopje (MK), Icahn School of Medicine at Mount Sinai (US)
Openalex Percentile: Top 8%
Coagulation, Bradykinin, Polyphosphates, and Angioedema
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