Advances in the treatment of bleeding disorders

Abstract

Historically, the bleeding episodes in subjects with coagulation disorders were treated with substitution therapy, initially with whole blood and fresh frozen plasma, and more recently with specific factor concentrate. Currently, patients with hemophilia have the possibility of choosing different effective and safe treatments, including novel extended half-life and alternative hemostatic drugs. The availability of novel extended half-life products could probably overcome current prophylaxis limitations, particularly in hemophilia B patients, by reducing the frequency of injections, achieving a higher trough level, and improving the quality of life of the patients. In addition, subcutaneous administration of alternative therapeutics would simplify prophylaxis in patients with hemophilia A and B with and without inhibitors. Regarding von Willebrand disease, a recombinant von Willebrand factor was recently developed to control bleeding episodes in patients with this disease, in addition to available von Willebrand factor/factor VIII concentrates. The management of patients affected by rare bleeding disorders (RBDs) is still a challenge, owing to the limited number of specific products, which are mainly available only in countries with high resources. Some improvements have recently been achieved by the production of new recombinant factor (F) XIII A subunit-derived and FX plasma-derived products for the treatment of patients affected by FXIII and FX deficiency. In addition, the development of novel alternative therapeutics, such as anti-tissue factor pathway inhibitor, ALN-AT3, and ACE910, for patients with hemophilia might also have a role in the treatment of patients affected by RBDs.

Targeting of Antithrombin in Hemophilia A or B with RNAi Therapy

“…[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.…”

Real‐life experience in switching to new extended half‐life products at European haemophilia centres

“…4 Over the last 10 years, recombinant factor (F) VIII products for haemophilia A and FIX products for haemophilia B have been remodelled to prolong their half-lives by chemical modification using polyethylene glycol (PEG) polymers and fusion to the fragment crystallizable (Fc) region of an IgG 1 or, alternatively, to human albumin. [8][9][10] These prophylaxis schemes maintain a higher trough FVIII level than standard products: ~3 IU/dL (3%). [8][9][10] These prophylaxis schemes maintain a higher trough FVIII level than standard products: ~3 IU/dL (3%).…”

“…[8][9][10] Moreover, an ongoing clinical trial with recombinant FIX albumin fusion is investigating whether the dosing interval could be extended to 21 days (clinicaltrials.gov: NCT02053792). [8][9][10] Moreover, an ongoing clinical trial with recombinant FIX albumin fusion is investigating whether the dosing interval could be extended to 21 days (clinicaltrials.gov: NCT02053792).…”

The current state of adverse event reporting in hemophilia

“…In order to reduce the frequency of infusion, extended half-life products are becoming available with the first products currently licensed, and many others in the pipeline [55,56].…”

“…A bispecific antibody specifically binding factor IX and X and mimicking the cofactor activity of FVIII (ACE910) has been produced and is injected subcutaneously [62]. Other approaches exploit the inhibition of natural anticoagulants [55,63,64], for instance via a monoclonal antibody (mAb) targeting tissue factor pathway inhibitor (TFPI) [65], a mAb blocking the interaction between FX and TFPI [66], or RNA interference therapeutic targeting antithrombin [67]. These technologies may prevent inhibitor development, and provide a mechanism for reducing or eliminating exposure to the deficient factor.…”