• Marc A Riedl, Henriette Farkas, Emel Aygören-Pürsün, Fotis Psarros, Daniel F Soteres, Maria Staevska, Mauro Cancian, David Hagin, Daisuke Honda, Isaac Melamed, Sinisa Savic, Marcin Stobiecki, Paula J Busse, Eunice Dias de Castro, Nancy Agmon-Levin, Richard Gower, Aharon Kessel, Marcin Kurowski, Ramon Lleonart, Vesna Grivcheva Panovska, H James Wedner, Paul K Audhya, James Hao, Matthew Iverson, Michael D Smith, Christopher M Yea, William R Lumry, Andrea Zanichelli, Jonathan A Bernstein, Marcus Maurer, Danny M Cohn, and KONFIDENT Investigators.
• From the Division of Allergy and Immunology, University of California, San Diego, La Jolla (M.A.R.); the Hungarian Angioedema Center of Reference and Excellence, Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary (H.F.); University Hospital Frankfurt, Goethe University Frankfurt, Frankfurt (E.A.-P.), and the Institute of Allergology, Charité-Universitätsmedizin Berlin, Freie Universitätsmedizin Berlin and Humboldt-Universität zu Berlin, and Immunology and Allergology, Fraunhofer Institute for Translational Medicine and Pharmacology, Berlin (M.M.) - all in Germany; Naval Hospital of Athens, Athens (F.P.); Asthma and Allergy Associates, Colorado Springs (D.F.S.), and IMMUNOe Research Center, Centennial (I.M.) - both in Colorado; Clinical Center of Allergology, Clinic of Allergy and Asthma, University Hospital Alexandrovska, Medical University of Sofia, Sofia, Bulgaria (M.S.); the Department of Systems Medicine, University of Padua, Padua (M.C.), and Operative Unit of Medicine, Angioedema Center, IRCCS Policlinico San Donato, San Donato Milanese, and Dipartimento di Scienze Biomediche per la salute, University of Milan, Milan (A.Z.) - all in Italy; Tel Aviv Sourasky Medical Center (D.H.) and Sheba Medical Center (N.A.-L.), Tel Aviv, and Bnai Zion Medical Center, Haifa (A.K.) - all in Israel; Chiba University Hospital, Chiba, Japan (D.H.); the Leeds Institute of Rheumatic and Musculoskeletal Medicine, University of Leeds, Leeds (S.S.), and KalVista Pharmaceuticals, Salisbury (P.K.A., J.H., M.I., M.D.S., C.M.Y.) - both in the United Kingdom; Jagiellonian University Medical College, Krakow (M.S.), and Medical University of Lodz, Lodz (M.K.) - both in Poland; Icahn School of Medicine at Mount Sinai, New York (P.J.B.); Allergy and Clinical Immunology Department, Centro Hospitalar Universitário de S. João, and Faculty of Medicine, University of Porto, Porto, Portugal (E.D.); Marycliff Clinical Research, Spokane, WA (R.G.); Hospital Universitario Bellvitge de L'Hospitalet de Llobregat, Allergology Department, Barcelona (R.L.); University Clinic of Dermatology, School of Medicine, University Saints Cyril and Methodus, Skopje, North Macedonia (V.G.P.); Washington University School of Medicine, St. Louis (H.J.W.); KalVista Pharmaceuticals, Cambridge, MA (P.K.A., J.H., M.I., M.D.S., C.M.Y.); AARA Research Center, Dallas (W.R.L.); the University of Cincinnati College of Medicine and Bernstein Clinical Research Center, Cincinnati (J.A.B.); and the Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Center, University of Amsterdam, Amsterdam (D.M.C.).
• N. Engl. J. Med. 2024 Jul 4; 391 (1): 324332-43.

BackgroundApproved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy.MethodsIn this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours.ResultsA total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported.ConclusionsOral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).Copyright © 2024 Massachusetts Medical Society.

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