Lasting power of new clotting proteins

Abstract

Hemophilia is a genetic disease caused by a deficiency of one of the coagulation proteins. The term usually refers to either hemophilia A, factor VIII (FVIII), with an incidence of ϳ1 in 5000 male births, or hemophilia B, factor IX (FIX), with an incidence of ϳ1 in 30 000 male births. When severe, the disease leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions of therapeutic factor concentrates. Most patients administer the infusions at home every few days and must limit their physical activities to avoid bleeding when the factor activity levels are below normal. In March 2014, a new therapeutic FIX preparation was approved for clinical use in Canada and the United States and, in June 2014, a new FVIII preparation was approved for clinical use in the United States. Over the next couple of years, other new factor products for FIX, FVIIa, and FVIII, which are currently in late stages of clinical trials, will likely also be approved. These new factors have been engineered to extend their half-life in circulation, thus providing major therapeutic advances for patients with hemophilia primarily by allowing treatment with fewer infusions per month. In the clinical trials so far, Ͼ500 patients have successfully used these extended half-life products regularly for Ͼ1 year to prevent spontaneous bleeding, to treat successfully any bleeding episodes, and to provide effective coagulation for major surgery. Essentially all infusions were well tolerated and effective. These promising new therapies should allow patients to use fewer infusions to maintain appropriate clotting factor activity levels in all clinical settings. Learning Objective• To be able to identify the new extended t 1/2 products for hemophilia A, B, and inhibitors and to understand the differences found to date between these products in clinical and preclinical studies

The Mystery of Antibodies Against Polyethylene Glycol (PEG) - What do we Know?

“…This question is of particular relevance because there are several PEGylated FVIII-and FIX products with extended half-life in development or already approved for the treatment of these patients (16,18). We analyzed plasma samples from 110 patients with hemophilia A or B.…”

“…Adynovate™ (16), the first PEGylated FVIII product for the treatment of patients with hemophilia A was approved by the FDA in December 2015. More PEGylated FVIII and factor IX (FIX) products for the treatment of patients with hemophilia A and B are in development (18,19). The half-life prolongation of FVIII and FIX products enables less frequent infusions, with the aim of decreasing bleeding rates and reducing the burden of treatment for patients (19).…”

“…We also included a cohort of patients with hemophilia A and B who have not received PEGylated biotherapeutics in this study. The potential presence of anti-PEG antibodies in the circulation of these patients is of particular interest because several PEGylated FVIII and FIX products are in development or were already approved (16,18,19).…”

Obstacles and future of gene therapy for hemophilia

“…It is also worthwhile to compare FIX gene therapy with the recently approved recombinant FIX Fc fusion protein and the other similar products employing various half-life extending technologies in late clinical trials (as reviewed in [104,105]). These novel protein therapeutics decrease the frequency of venipuncture needed to provide effective prophylaxis and will likely enhance the quality of life of patients, especially pediatric patients.…”

Innovative Pharmacological Therapies for the Hemophilias Not Based on Deficient Factor Replacement

“…Advances in our understanding of the molecular mechanisms of hemostasis have paved the way to the development of new therapeutic strategies for hemophilia, peculiar for being based on mechanisms other than the replacement of the deficient coagulation factor (►Table 1). 57 The rationale for their development lies in the need to improve patients' adherence to prophylaxis, meant to develop more effective therapies to treat and/or prevent bleeding in patients with inhibitors and possibly reduce the occurrence of inhibitors in patients at high risk. Some of these agents currently on the development pipeline act by inhibiting naturally occurring anticoagulant proteins such as antithrombin or TFPI, bypassing FVIII or IX in tenase formation, enhancing coagulation factor activity or rendering fibrin clots more resistant to degradation.…”