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The role of emicizumab, a bispecific factor IXa- and factor X-directed antibody, for the prevention of bleeding episodes in patients with hemophilia A.

ABSTRACT: Hemophilia A, characterized by impaired or absent expression of factor VIII, has long been managed via direct factor replacement. Functionally, factor VIII acts as a cofactor for factor IXa and allows activation of factor X, which, in combination with factor V, generates thrombin. Bispecific antibodies such as emicizumab are recombinant, monoclonal antibodies capable of recognizing and binding to two distinct antigenic targets simultaneously; emicizumab binds factors IXa and X, resulting in spatial approximation and activation of factor X, thereby mimicking the actions of factor VIII. Critically, the presence of antifactor VIII antibodies, for example, inhibitors, impacts neither the mechanism nor the efficacy by which emicizumab functions. The results and interim analyses of the emicizumab clinical trials, HAVEN 1, 2, 3, and 4, are additionally reviewed and discussed.

SUBMITTER: Knight T

PROVIDER: S-EPMC6187429 | biostudies-literature | 2018 Oct

REPOSITORIES: biostudies-literature

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The role of emicizumab, a bispecific factor IXa- and factor X-directed antibody, for the prevention of bleeding episodes in patients with hemophilia A.

Knight Tristan T Callaghan Michael U MU

Therapeutic advances in hematology 20181010 10

Hemophilia A, characterized by impaired or absent expression of factor VIII, has long been managed <i>via</i> direct factor replacement. Functionally, factor VIII acts as a cofactor for factor IXa and allows activation of factor X, which, in combination with factor V, generates thrombin. Bispecific antibodies such as emicizumab are recombinant, monoclonal antibodies capable of recognizing and binding to two distinct antigenic targets simultaneously; emicizumab binds factors IXa and X, resulting ...[more]

PMID: 30344994

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Project description:Hemophilia B management has improved considerably since the introduction of high-purity plasma-derived factor IX (pdFIX) products in the early 1990s. Recombinant FIX (rFIX) was introduced more recently and has potential safety advantages over the older blood-based products. Until recently, only one such product, nonacog alfa (BeneFIX(®), Pfizer, Inc.), has been available. However, a new rFIX product, BAX326 (RIXUBIS, Baxter Healthcare Corp.), has now been approved by the US Food and Drug Administration. BAX326 undergoes rigorous virus elimination and purification steps during manufacture, and has low activated FIX activity, which confers low thrombogenic potential in humans. Preclinical studies showed promising pharmacokinetic and safety profiles, and these early findings have since been expanded in a series of prospective, multicenter, clinical studies. Foremost among these is a pivotal phase I/III study of BAX326 and its use in routine prophylaxis or on-demand treatment in patients aged 12-65 years with severe (FIX level <1%) or moderately severe (FIX level ≤2%) hemophilia B. This study confirmed the pharmacokinetic equivalence of BAX326 and nonacog alfa, and showed a significant reduction in annualized bleeding rate with BAX326 prophylaxis compared with on-demand treatment (79% versus historic controls; p < 0.001). The hemostatic efficacy of BAX326 was rated as 'excellent' or 'good' in 96% of bleeds. BAX326 was also associated with statistically significant and clinically meaningful improvements in physical health-related quality of life. Results are similarly encouraging in a pediatric study in children aged up to 12 years and in a study in hemophilia B patients undergoing surgery. A further study showed safe transition, with no inhibitor formation in any patient, from treatment with a pdFIX product to BAX326. Overall, the safety profile of BAX326 in clinical trials has been strong, with no inhibitor or specific antibody formation, thrombosis, or treatment-related serious adverse events or anaphylaxis.

Dataset Information

The role of emicizumab, a bispecific factor IXa- and factor X-directed antibody, for the prevention of bleeding episodes in patients with hemophilia A.

Publications

The role of emicizumab, a bispecific factor IXa- and factor X-directed antibody, for the prevention of bleeding episodes in patients with hemophilia A.

Similar Datasets

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