Role of enhanced half‐life factor <scp>VIII</scp> and <scp>IX</scp> in the treatment of haemophilia

Mahdi, Ali Jassem; Obaji, Samya; Collins, Peter William

doi:10.1111/bjh.13360

Cited by 52 publications

(68 citation statements)

References 44 publications

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“…[9][10][11][12] The development of a new generation of factor concentrates with an extended half-life [13][14][15] has reduced the frequency of administration, most notably for factor IX products. [16][17][18] However, these products still require intravenous infusion. Finally, treatment with factor-replacement products can result in the development of inhibitory alloantibodies in up to 30% of patients with severe hemophilia A 19 and in 5% of those with hemophilia B, 20 which renders factor treatment ineffective.…”

Section: Resultsmentioning

confidence: 99%

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

et al. 2017

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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. ( BACKGROUNDCurrent 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.

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Section: Resultsmentioning

confidence: 99%

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

et al. 2017

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“…Several extensive comparative reviews of EHL recombinant (r)FVIII, rFIX, and rFVIIa products are available. [1][2][3] Half-life (t 1/2 ) prolongation techniques include the following: (1) site directed or non-site-specific pegylation, [4][5][6] (2) fusion with prolonged half-life proteins, such as IgG-Fc or albumin, [7][8][9][10][11][12] and (3) protein modifications.…”

Section: Ehl Factor Productsmentioning

confidence: 99%

Novel approaches to hemophilia therapy: successes and challenges

Arruda

Doshi

Samelson-Jones

2017

Blood

100

106

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New therapies for hemophilia A and hemophilia B will likely continue to change clinical practice. Ranging from extended half-life to nonfactor products and gene therapy, these innovative approaches have the potential to enhance the standard of care by decreasing infusion frequency to increase compliance, promoting prophylaxis, offering alternatives to inhibitor patients, and easing route of administration. Each category has intrinsic challenges that may limit the broader application of these promising therapies. To date, none specifically address the challenge of dispersing treatment to the developing world.

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“…The most common treatment for HA is the frequent intravenous infusion of FVIII (from plasma or recombinant protein), which is expensive and inconvenient [36,37]. Most hemophilia patients worldwide still cannot access this treatment [4].…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the activity levels of rat FVIII and human FVIII delivered by adeno-associated viral vectors both in vitro and in vivo

Zhang

Mao

Shen

et al. 2018

Blood Cells, Molecules, and Diseases

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The development of a novel coagulation factor VIII (FVIII) expression cassette with an enhanced activity for gene therapy of hemophilia A (HA) is essential. The biological properties of several non-human FVIII sequences, such as porcine and canine, have been evaluated. Here, we compared the activity level of rat FVIII (rFVIII) and human FVIII (hFVIII) by using single-chain and dual-chain strategies in 293 T cells and the HA mice. In both in vitro and hydrodynamic injection studies, the activity of rFVIII detected by the activated partial thromboplastin time assay was higher than that of hFVIII both by single-chain (~2.96-fold and ~1.72-fold, respectively) and dual-chain (~7.69-fold and ~2.35-fold, respectively). Moreover, the dual chain exerted a potentially higher delivery efficacy compared with the single chain (~4.96-fold and ~2.99-fold, respectively). The blood loss of HA mice administrated with rFVIII was less than those with hFVIII. AAV-delivered rFVIII and hFVIII also exerted longterm therapeutic effects on HA mice and caused a transient ALT elevation. These data might help to the development of novel, optimized FVIII expression cassettes based on the amino acid difference between rFVIII and hFVIII. These data indicate that the dual-chain strategy would likely enhance the delivery efficiency of the AAV-mediated FVIII gene therapy.

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Role of enhanced half‐life factor VIII and IX in the treatment of haemophilia

Cited by 52 publications

References 44 publications

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

Novel approaches to hemophilia therapy: successes and challenges

Evaluation of the activity levels of rat FVIII and human FVIII delivered by adeno-associated viral vectors both in vitro and in vivo

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