Oral Sebetralstat for On-demand Treatment of Hereditary Angioedema: Phase 3 KONFIDENT Trial Results
Submission to EAACI 2024 (May 31-June 3, 2024; Valencia, Spain)
– Abstract text limit: 2500 characters, including spaces (not including title, authors, affiliations, headings)
– Current character count: 2496 of 2500 characters
Presentation type: Oral
Main/presenting author: Danny M. Cohn
Type: Oral Abstract Session (preferred); Thematic Poster Session
Category: Immune deficiencies and autoimmunity
Keywords: angioedema (selected in submitter), sebetralstat (custom term), on-demand treatment (custom term)
Acknowledgements: Editorial/medical writing assistance was provided under the direction of the authors by Richard W. Davis IV, PhD, CMPP, of ApotheCom, San Francisco, USA, and was supported by KalVista Pharmaceuticals.
Funding: This study was sponsored by KalVista Pharmaceuticals.
CONFIDENTIAL DRAFT
Oral Sebetralstat for On-demand Treatment of Hereditary Angioedema: Phase 3 KONFIDENT Trial Results
Marc A. Riedl,1 Henriette Farkas,2 Emel Aygören-Pürsün,3 Fotios Psarros,4 Daniel Soteres,5 Maria Staevska,6 Mauro Cancian,7 David Hagin,8 Daisuke Honda,9 Isaac Melamed,10 Sinisa Savic,11 Marcin Stobiecki,12 Paula J. Busse,13 Eunice Dias de Castro,14 Nancy Agmon-Levin,15 Richard Gower,16 Aharon Kessel,17 Marcin Kurowski,18 Ramon Lleonart,19 Vesna Grivcheva Panovska,20 H. James Wedner,21 Paul K. Audhya,22 James Hao,22 Matthew Iverson,22 Michael D. Smith,22 Christopher M. Yea,22 William R. Lumry,23 Andrea Zanichelli,24,25 Jonathan A. Bernstein,26,27 Marcus Maurer,28,29 Danny M. Cohn30
1UC San Diego, La Jolla, CA, USA; 2Hungarian Angioedema Center of Reference and Excellence, Semmelweis University, Budapest, Hungary; 3University Hospital Frankfurt, Frankfurt, Germany; 4Naval Hospital of Athens, Athens, Greece; 5Asthma & Allergy Associates PC, Colorado Springs, CO, USA; 6Clinical Center of Allergology, Clinic of Allergy and Asthma, University Hospital Alexandrovska, Medical University of Sofia, Sofia, Bulgaria; 7University of Padova, Padova, Italy; 8Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; 9Chiba University Graduate School of Medicine, Chiba, Japan; 10IMMUNOe Research Center, Centennial, CO, USA; 11University of Leeds, St James’s University Hospital, Leeds, United Kingdom; 12Jagiellonian University Medical College, Krakow, Poland; 13Icahn School of Medicine at Mount Sinai, New York, NY, USA; 14Centro Hospitalar Universitário de S. João EPE and University of Porto, Porto, Portugal; 15Sheba Medical Center, Tel Aviv, Israel; 16Marycliff Clinical Research, Spokane, WA, USA; 17Bnai Zion Medical Center, Haifa, Israel; 18Medical University of Lodz, Lodz, Poland; 19Hospital Universitario Bellvitge de L’Hospitalet de Llobregat, Allergy Section, Barcelona, Spain; 20University Clinic of Dermatology, School of Medicine, University Saints Cyril and Methodus, Skopje, North Macedonia; 21Washington University School of Medicine, St. Louis, MO, USA; 22KalVista Pharmaceuticals, Salisbury, United Kingdom, and Cambridge, MA, USA; 23AARA Research Center, Dallas, TX, USA; 24Operative Unit of Medicine, Angioedema Center, IRCCS Policlinico San Donato, San Donato Milanese, Milan, Italy; 25University of Milan, Milan, Italy; 26University of Cincinnati College of Medicine, Cincinnati, OH, USA; 27Bernstein Clinical Research Center, Cincinnati, OH, USA; 28Institute of Allergology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universitätsmedizin Berlin and Humboldt-Universität zu Berlin, Berlin, Germany; 29Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Berlin, Germany; 30Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
CONFIDENTIAL DRAFT
Introduction: Approved on-demand hereditary angioedema (HAE-C1INH) treatments (tx) require parental administration. Due to the administration burden and injection site reactions, many patients (pts) delay or withhold treatment, resulting in suboptimal outcomes. Sebetralstat, a plasma kallikrein inhibitor, is the first oral therapy investigated in a phase 3 trial for on-demand tx of HAE-C1INH.
Methods: In the phase 3, randomized, double-blind, placebo-controlled, 3-way crossover KONFIDENT trial (NCT05259917), pts aged ≥12 years with HAE-C1INH treated up to 3 eligible HAE attacks (any location) with 1 or 2 doses of sebetralstat 300 mg, sebetralstat 600 mg, or placebo (in 1 of 6 tx sequences). Primary endpoint: time to beginning of symptom relief (Patient Global Impression of Change rating of at least “A Little Better” for 2 time points in a row) within 12 hours of the first dose. Key secondary endpoints: time to reduction in severity (decrease from baseline in Patient Global Impression of Severity [PGI-S] for 2 time points in a row) within 12 hours and time to complete attack resolution (PGI-S rating of “None”) within 24 hours. Endpoints were tested hierarchically in a fixed sequence and adjusted for multiplicity.
Results: Of 136 randomized pts, 110 pts (97 [88.2%] adults; 24 [21.8%] receiving long-term prophylaxis) treated ≥1 eligible attack. Of 264 attacks, 87 were treated with sebetralstat 300 mg, 93 with sebetralstat 600 mg, and 84 with placebo. Median time from attack recognition to tx administration was 41 min (Q1, 6; Q3, 140). Compared with placebo, beginning of symptom relief was significantly faster with sebetralstat 300 mg (P<0.0001) and sebetralstat 600 mg (P=0.0013), as was reduction in severity (P=0.0036 and P=0.0032, respectively) and complete attack resolution (P=0.0022 and P<0.0001, respectively) (Table). Incidence of on-tx (ie, within 3 days of last attack dose) adverse events (AEs) were similar between sebetralstat (300 mg: 5.8%; 600 mg: 6.5%) and placebo (12.0%). On-tx tx-related AEs occurred in 2.3% of pts with sebetralstat 300 mg, 2.2% with sebetralstat 600 mg, and 4.8% with placebo; no serious tx-related AEs and no AEs that led to trial discontinuation were reported.
Conclusions: The efficacy and safety of sebetralstat 300 mg and 600 mg demonstrated in KONFIDENT support the use of sebetralstat for oral on-demand tx of HAE-C1INH, offering a pt-preferred route of administration, facilitating early tx, and providing rapid symptom relief.
