Pasi, KJ;
Rangarajan, S;
Georgiev, P;
Mant, T;
Creagh, MD;
Lissitchkov, T;
Bevan, D;
Austin, S;
Hay, CR;
Hegemann, I;
et al.
Pasi, KJ; Rangarajan, S; Georgiev, P; Mant, T; Creagh, MD; Lissitchkov, T; Bevan, D; Austin, S; Hay, CR; Hegemann, I; Kazmi, R; Chowdary, P; Gercheva-Kyuchukova, L; Mamonov, V; Timofeeva, M; Soh, C-H; Garg, P; Vaishnaw, A; Akinc, A; Sørensen, B; Ragni, MV
(2017)
Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy.
N Engl J Med, 377 (9).
pp. 819-828.
ISSN 1533-4406
https://doi.org/10.1056/NEJMoa1616569
SGUL Authors: Austin, Steve
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Abstract
BACKGROUND: Current hemophilia treatment involves frequent intravenous infusions of clotting factors, which is associated with variable hemostatic protection, a high treatment burden, and a risk of the development of inhibitory alloantibodies. Fitusiran, an investigational RNA interference (RNAi) therapy that targets antithrombin (encoded by SERPINC1), is in development to address these and other limitations. METHODS: In this phase 1 dose-escalation study, we enrolled 4 healthy volunteers and 25 participants with moderate or severe hemophilia A or B who did not have inhibitory alloantibodies. Healthy volunteers received a single subcutaneous injection of fitusiran (at a dose of 0.03 mg per kilogram of body weight) or placebo. The participants with hemophilia received three injections of fitusiran administered either once weekly (at a dose of 0.015, 0.045, or 0.075 mg per kilogram) or once monthly (at a dose of 0.225, 0.45, 0.9, or 1.8 mg per kilogram or a fixed dose of 80 mg). The study objectives were to assess the pharmacokinetic and pharmacodynamic characteristics and safety of fitusiran. RESULTS: No thromboembolic events were observed during the study. The most common adverse events were mild injection-site reactions. Plasma levels of fitusiran increased in a dose-dependent manner and showed no accumulation with repeated administration. The monthly regimen induced a dose-dependent mean maximum antithrombin reduction of 70 to 89% from baseline. A reduction in the antithrombin level of more than 75% from baseline resulted in median peak thrombin values at the lower end of the range observed in healthy participants. CONCLUSIONS: Once-monthly subcutaneous administration of fitusiran resulted in dose-dependent lowering of the antithrombin level and increased thrombin generation in participants with hemophilia A or B who did not have inhibitory alloantibodies. (Funded by Alnylam Pharmaceuticals; ClinicalTrials.gov number, NCT02035605 .).
Item Type: |
Article
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Additional Information: |
From New England Journal of Medicine, Pasi, KJ; Rangarajan, S; Georgiev, P; Mant, T; Creagh, MD; Lissitchkov, T; Bevan, D; Austin, S; Hay, CR; Hegemann, I; Kazmi, R; Chowdary, P; Gercheva-Kyuchukova, L; Mamonov, V; Timofeeva, M; Soh, C-H; Garg, P; Vaishnaw, A; Akinc, A; Sørensen, B; Ragni, MV, Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy, 377:819-828. Copyright © 2017 Massachusetts Medical Society. Reprinted with permission. |
Keywords: |
Adult, Antithrombin III, Antithrombins, Dose-Response Relationship, Drug, Healthy Volunteers, Hemophilia A, Hemophilia B, Humans, Injections, Subcutaneous, Male, Middle Aged, RNAi Therapeutics, Single-Blind Method, Thrombin, Young Adult, Humans, Hemophilia A, Hemophilia B, Thrombin, Antithrombin III, Antithrombins, Injections, Subcutaneous, Single-Blind Method, Dose-Response Relationship, Drug, Adult, Middle Aged, Male, Young Adult, Healthy Volunteers, RNAi Therapeutics, 11 Medical and Health Sciences, General & Internal Medicine |
SGUL Research Institute / Research Centre: |
Academic Structure > Institute of Medical & Biomedical Education (IMBE) |
Journal or Publication Title: |
N Engl J Med |
ISSN: |
1533-4406 |
Language: |
eng |
Dates: |
Date | Event |
---|
31 August 2017 | Published |
|
Publisher License: |
Publisher's own licence |
PubMed ID: |
28691885 |
Web of Science ID: |
WOS:000408626400005 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/113574 |
Publisher's version: |
https://doi.org/10.1056/NEJMoa1616569 |
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