Extended Half-Life Factor VIII and Factor IX Preparations

Abstract

In the last couple of years, several extended half-life factor VIII and factor IX preparations were intensively studied and gained approval. In order to extend half-lives, techniques like fusion to protein conjugates (Fc part of IgG₁ or albumin), chemical modification (PEGylation), and protein sequence modification are implemented. With these techniques, it is possible to extend half-lives of factor IX products 4- to 6- fold, while half-life extension of factor VIII products is limited to 1.5- to 2-fold due to their interaction with von Willebrand factor. Nevertheless, both extended half-life factor VIII and IX products have improved and facilitated prophylactic factor replacement therapy in hemophilia A and B, respectively. Extended half-life factor concentrates pose challenges to coagulation laboratories because accurate therapy monitoring is not possible with all factor activity assays currently used.

Laboratory testing in hemophilia: Impact of factor and non‐factor replacement therapy on coagulation assays

“…Rurioctocog alfa pegol (BAX‐855; Adynovate ® ), a PEGylated form of full‐length rFVIII, is licensed for the prevention and treatment of hemorrhage in hemophilia A 40 ; nonacog beta pegol (N9‐GP; Refixia ® ), a PEGylated version of the FIX activation peptide, is approved for the prevention and treatment of hemorrhage in adult hemophilia B 41 ; and turoctocog alfa pegol (N8‐GP; Esperoct ® ), which contains a truncated B‐domain attached to a PEG molecule, is approved for treatment and prophylaxis of bleeding in patients 12 years and above with hemophilia A 42 . Damoctocog alfa pegol (BAY94‐9027), a PEGylated form of B‐domain‐depleted rFVIII molecule, is undergoing clinical assessment 13,39. In terms of fusion proteins, eftrenonacog alfa (rFIX‐Fc; Alprolix ® ), a single recombinant FIX molecule fused to the Fc domain of IgG1, was the first EHL factor concentrate to gain FDA approval for the prophylaxis and treatment of hemophilia B 43 ; albutrepenonacog alfa (rFIX‐FP; Idelvion ® ), a fusion protein between rFIX and human albumin, was subsequently approved in this indication 39,44 .…”

“…Damoctocog alfa pegol (BAY94‐9027), a PEGylated form of B‐domain‐depleted rFVIII molecule, is undergoing clinical assessment 13,39. In terms of fusion proteins, eftrenonacog alfa (rFIX‐Fc; Alprolix ® ), a single recombinant FIX molecule fused to the Fc domain of IgG1, was the first EHL factor concentrate to gain FDA approval for the prophylaxis and treatment of hemophilia B 43 ; albutrepenonacog alfa (rFIX‐FP; Idelvion ® ), a fusion protein between rFIX and human albumin, was subsequently approved in this indication 39,44 . Lonoctocog alfa (rFVIII‐SC; Afstyla ® ) is approved for the treatment of hemophilia A across a number of countries 45…”

Evaluation of pre‐analytic heat treatment protocol used in the CDC Nijmegen‐Bethesda assay for heat inactivation of extended half‐life haemophilia treatment products

“…1 PHT has been previously shown to enable more accurate determination of the inhibitor titre without removing antibodies in the context of traditional factor replacement products. 3 Until recently, the ability of PHT to remove interfering factor activity for extended half-life F I G U R E 1 Effect of heating factor-deficient plasma specimens spiked with traditional or extended half-life recombinant factor VIII products at three concentrations (Dilution 1: 80 IU/dL, Dilution 2: 20 IU/dL and Dilution 3: 5 IU/dL) to 56°C for 30 minutes followed by centrifugation. 3 Until recently, the ability of PHT to remove interfering factor activity for extended half-life F I G U R E 1 Effect of heating factor-deficient plasma specimens spiked with traditional or extended half-life recombinant factor VIII products at three concentrations (Dilution 1: 80 IU/dL, Dilution 2: 20 IU/dL and Dilution 3: 5 IU/dL) to 56°C for 30 minutes followed by centrifugation.…”

“…2 Several modifications to traditional recombinant factor replacement products designed to extend product half-life have been introduced, including chemical modification through PEGylation, fusion to protein conjugates such as Fc fusion or albumin fusion, and protein sequence modification. 3 Until recently, the ability of PHT to remove interfering factor activity for extended half-life F I G U R E 1 Effect of heating factor-deficient plasma specimens spiked with traditional or extended half-life recombinant factor VIII products at three concentrations (Dilution 1: 80 IU/dL, Dilution 2: 20 IU/dL and Dilution 3: 5 IU/dL) to 56°C for 30 minutes followed by centrifugation. *Comparison of T0 (preheating) to T1 (postheating) by t test; P < .005 (EHL) factor products was untested.…”

Hemotherapy with New Blood Products

“…Therefore, this volume of Transfusion Medicine and Hemotherapy covers the latest developments in hemophilia therapy, with overviews on new factor concentrates for factor VIII and factor IX with extended half-life [1] as well as on the above mentioned new therapies [2]. Advances using cellular therapies in pa-…”