Efficacy and Safety of Donidalorsen for Hereditary Angioedema

Hereditary 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. In this phas...

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Vydáno v:The New England journal of medicine Ročník 391; číslo 1; s. 21 - 31
Hlavní autoři: Riedl, Marc A., Tachdjian, Raffi, Lumry, William R., Craig, Timothy, Karakaya, Gül, Gelincik, Asli, Stobiecki, Marcin, Jacobs, Joshua S., Gokmen, Nihal M., Reshef, Avner, Gompels, Mark M., Manning, Michael E., Bordone, Laura, Newman, Kenneth B., Treadwell, Sabrina, Wang, Sophie, Yarlas, Aaron, Cohn, Danny M.
Médium: Journal Article
Jazyk:angličtina
Vydáno: United States Massachusetts Medical Society 04.07.2024
Témata:
Adolescent
Adult
Adverse events
Aged
Allergy
Angioedema
Angioedemas, Hereditary - drug therapy
Antisense oligonucleotides
Antisense therapy
Child
Clinical Medicine
Clinical Medicine General
Double-Blind Method
Emergency medical care
Emergency Medicine
Emergency Medicine General
Erythema
Female
Generalized linear models
Genetics
Genetics General
Hospital-Based Clinical Medicine
Humans
Immunology
Immunology General
Inflammatory Disease
Injections, Subcutaneous
Male
Middle Aged
Missing data
Oligonucleotides, Antisense - adverse effects
Oligonucleotides, Antisense - therapeutic use
Outpatient-Based Clinical Medicine
Patients
Pediatrics
Pediatrics General
Placebos
Prophylaxis
Quality of Life
Rheumatology
Rheumatology General
Rhinopharyngitis
Vasculitis
Young Adult
ISSN:0028-4793, 1533-4406, 1533-4406
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Shrnutí:Hereditary 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. In 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. A 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. Donidalorsen 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.).
Bibliografie:ObjectType-Article-1
SourceType-Scholarly Journals-1
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ISSN:0028-4793
1533-4406
1533-4406
DOI:10.1056/NEJMoa2402478