A phase 2 open-label extension study of prekallikrein inhibition with donidalorsen for hereditary angioedema.

Autor: Petersen RS; Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands., Bordone L; Ionis Pharmaceuticals, Inc., Carlsbad, California, USA., Riedl MA; University of California San Diego, La Jolla, California, USA., Tachdjian R; Department of Pediatrics, University of California, Los Angeles, California, USA.; Providence Saint John's Health Center, Santa Monica, California, USA., Craig TJ; Department of Medicine, Pediatrics, and Biomedical Sciences, Pennsylvania State University, Hershey, Pennsylvania, USA.; Vinmec International Hospital, Times City, Hanoi, Vietnam., Lumry WR; Allergy and Asthma Research Associates Research Center, Dallas, Texas, USA., Manning ME; Medical Research of Arizona, Scottsdale, Arizona, USA., Bernstein JA; Department of Internal Medicine, University of Cincinnati College of Medicine, and Bernstein Clinical Research Center, Cincinnati, Ohio, USA., Raasch J; Midwest Immunology Clinic, Plymouth, Minnesota, USA., Zuraw BL; Division of Rheumatology, Allergy, and Immunology, Department of Medicine, University of California San Diego, La Jolla, California, USA., Deng Y; Ionis Pharmaceuticals, Inc., Carlsbad, California, USA., Newman KB; Ionis Pharmaceuticals, Inc., Carlsbad, California, USA., Alexander VJ; Ionis Pharmaceuticals, Inc., Carlsbad, California, USA., Lui C; Ionis Pharmaceuticals, Inc., Carlsbad, California, USA., Schneider E; Ionis Pharmaceuticals, Inc., Carlsbad, California, USA., Cohn DM; Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.
Jazyk: angličtina
Zdroj: Allergy [Allergy] 2024 Mar; Vol. 79 (3), pp. 724-734. Date of Electronic Publication: 2023 Nov 27.
DOI: 10.1111/all.15948
Abstrakt: Background: Hereditary angioedema (HAE) is a potentially fatal disease characterized by unpredictable, recurrent, often disabling swelling attacks. In a randomized phase 2 study, donidalorsen reduced HAE attack frequency and improved patient quality-of-life (ISIS721744-CS2, NCT04030598). We report the 2-year interim analysis of the phase 2 open-label extension (OLE) study (ISIS 721744-CS3, NCT04307381).
Methods: In the OLE, the on-treatment study period consisted of fixed (weeks 1-13, donidalorsen 80 mg subcutaneously every 4 weeks [Q4W]) and flexible (weeks 17-105, donidalorsen 80 mg Q4W, 80 mg every 8 weeks [Q8W], or 100 mg Q4W) dosing periods. The primary outcome was incidence and severity of treatment-emergent adverse events (TEAEs). The secondary outcomes included efficacy, pharmacodynamic, and quality-of-life assessments.
Results: Seventeen patients continued in the OLE study. No serious TEAEs or TEAEs leading to treatment discontinuation were reported. Mean monthly HAE attack rate was 96% lower than the study run-in baseline rate (mean, 0.06/month; 95% confidence interval [CI], 0.02-0.10; median, 0.04 on-treatment vs. mean, 2.70/month; 95% CI, 1.94-3.46; median, 2.29 at baseline). Mean monthly attack rate for Q8W dosing (n = 8) was 0.29 (range, 0.0-1.7; 95% CI, -0.21 to 0.79; median, 0.00). Mean plasma prekallikrein and D-dimer concentrations decreased, and Angioedema Quality of Life Questionnaire total score improved from baseline to week 105 with donidalorsen.
Conclusion: The 2-year interim results of this phase 2 OLE study of donidalorsen in patients with HAE demonstrated no new safety signals; donidalorsen was well tolerated. There was durable efficacy with a 96% reduction in HAE attacks.
(© 2023 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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