Evaluation of patient‐reported outcome measures for on‐demand treatment of hereditary angioedema attacks and design of KONFIDENT, a phase 3 trial of sebetralstat

Author:

Cohn Danny M.1ORCID,Aygören‐Pürsün Emel2,Bernstein Jonathan A.3,Farkas Henriette4,Lumry William R.5,Maurer Marcus67ORCID,Zanichelli Andrea89,Iverson Matthew10,Hao James10,Smith Michael D.10,Yea Christopher M.11,Audhya Paul K.10,Riedl Marc A.12

Affiliation:

1. Department of Vascular Medicine, Amsterdam Cardiovascular Sciences Amsterdam UMC University of Amsterdam Amsterdam The Netherlands

2. Department for Children and Adolescents University Hospital Frankfurt Frankfurt Germany

3. Division of Rheumatology, Allergy and Immunology Department of Internal Medicine University of Cincinnati College of Medicine Cincinnati Ohio USA

4. Hungarian Angioedema Center of Reference and Excellence Department of Internal Medicine and Haematology Semmelweis University Budapest Hungary

5. AARA Research Center Dallas Texas USA

6. Institute of Allergology Charité ‐ Universitätsmedizin Berlin Corporate Member of Freie Universität Berlin and Humboldt‐Universität zu Berlin Berlin Germany

7. Allergology and Immunology Fraunhofer Institute for Translational Medicine and Pharmacology ITMP Berlin Germany

8. Operative Unit of Medicine Angioedema Center IRCCS Policlinico San Donato Milan Italy

9. Department of Biomedical Sciences for Health University of Milan Milan Italy

10. KalVista Pharmaceuticals Cambridge Massachusetts USA

11. KalVista Pharmaceuticals Salisbury UK

12. Division of Rheumatology, Allergy & Immunology University of California San Diego San Diego California USA

Abstract

AbstractBackgroundHereditary angioedema (HAE) with C1‐inhibitor deficiency (HAE‐C1‐INH) is characterized by recurrent, debilitating episodes of swelling. Sebetralstat, an investigational oral plasma kallikrein inhibitor, demonstrated promising efficacy for on‐demand treatment of HAE‐C1‐INH in a phase 2 trial. We describe the multipronged approach informing the design of KONFIDENT, a phase 3 randomized, placebo‐controlled, three‐way crossover trial evaluating the efficacy and safety of sebetralstat in patients aged ≥12 years with HAE‐C1‐INH.MethodsTo determine an optimal endpoint to measure the beginning of symptom relief in KONFIDENT, we engaged patients with HAE on clinical outcome measures and subsequently conducted analyses of phase 2 outcomes. Sample size was determined via a simulation‐based approach using phase 2 data.ResultsPatient interviews revealed a strong preference (71%) for the Patient Global Impression of Change (PGI‐C) over other measures and indicated a rating of “A Little Better” as a clinically meaningful milestone. In phase 2, a rating of “A Little Better” demonstrated agreement with attack severity improvement and resolution on the Patient Global Impression of Severity and had better sensitivity than “Better.” Simulations indicated that 84 patients completing treatment would ensure at least 90% power for assessing the primary endpoint of time to beginning of symptom relief defined as a PGI‐C rating of at least “A Little Better” for two time points in a row.ConclusionsPatient feedback and phase 2 data support PGI‐C as the primary outcome measure in the phase 3 KONFIDENT trial evaluating sebetralstat, which has the potential to be the first oral on‐demand treatment for HAE‐C1‐INH attacks.

Publisher

Wiley

Subject

Immunology and Allergy,Immunology,Pulmonary and Respiratory Medicine

Reference31 articles.

1. The international WAO/EAACI guideline for the management of hereditary angioedema – The 2021 revision and update

2. Breakthroughs in hereditary angioedema management: a systematic review of approved drugs and those under research;Niccola S;Drugs Context,2019

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