• Marc A Riedl, Raffi Tachdjian, William R Lumry, Timothy Craig, Gül Karakaya, Asli Gelincik, Marcin Stobiecki, Joshua S Jacobs, Nihal M Gokmen, Avner Reshef, Mark M Gompels, Michael E Manning, Laura Bordone, Kenneth B Newman, Sabrina Treadwell, Sophie Wang, Aaron Yarlas, Danny M Cohn, and OASIS-HAE Team.
• From the Division of Allergy and Immunology, University of California at San Diego, La Jolla (M.A.R.), the Division of Allergy, Immunology, and Rheumatology, University of California at Los Angeles, Los Angeles (R.T.), Allergy and Asthma Clinical Research, Walnut Creek (J.S.J.), and Ionis Pharmaceuticals, Carlsbad (L.B., K.B.N., S.T., S.W., A.Y.) - all in California; Asthma and Allergy Research Associates, Dallas (W.R.L.); the Department of Medicine, Pediatrics, and Biomedical Sciences, Penn State Health Allergy, Asthma, and Immunology, Hershey, PA (T.C.); Vinmec International Hospital, Hanoi (T.C.); the Division of Allergy and Immunology, Department of Chest Diseases, Hacettepe University School of Medicine, Ankara (G.K.), the Division of Immunology and Allergic Diseases, Istanbul Faculty of Medicine, Istanbul University, Istanbul (A.G.), and the Division of Allergy and Clinical Immunology, Department of Internal Medicine, Ege University Faculty of Medicine, Ege University, Izmir (N.M.G.) - all in Turkey; the Department of Clinical and Environmental Allergology, Jagiellonian University Medical College, Krakow, Poland (M.S.); the Angioedema Center, Barzilai University Medical Center, Ashkelon, Israel (A.R.); the Department of Immunology, Southmead Hospital, North Bristol National Health (NHS) Trust, Bristol, United Kingdom (M.M.G.); Medical Research of Arizona, Scottsdale (M.E.M.); and the Department of Vascular Medicine, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam (D.M.C.).
• N. Engl. J. Med. 2024 Jul 4; 391 (1): 213121-31.

BackgroundHereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression.MethodsIn this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25.ResultsA total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity.ConclusionsDonidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.).Copyright © 2024 Massachusetts Medical Society.

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