Plasma Clearance of Coagulation Factor VIII and Extension of Its Half-Life for the Therapy of Hemophilia A: A Critical Review of the Current State of Research and Practice

Abstract

Factor VIII (FVIII) is an important component of blood coagulation as its congenital deficiency results in life-threatening bleeding. Current prophylactic therapy of the disease (hemophilia A) is based on 3–4 intravenous infusions of therapeutic FVIII per week. This poses a burden on patients, demanding reduction of infusion frequency by using FVIII with extended plasma half-life (EHL). Development of these products requires understanding FVIII plasma clearance mechanisms. This paper overviews (i) an up-to-date state of the research in this field and (ii) current EHL FVIII products, including recently approved efanesoctocog alfa, for which the plasma half-life exceeds a biochemical barrier posed by von Willebrand factor, complexed with FVIII in plasma, which results in ~1 per week infusion frequency. We focus on the EHL FVIII products’ structure and function, in particular related to the known discrepancy in results of one-stage clotting (OC) and chromogenic substrate (CS) assays used to assign the products’ potency, dosing, and for clinical monitoring in plasma. We suggest a possible root cause of these assays’ discrepancy that is also pertinent to EHL factor IX variants used to treat hemophilia B. Finally, we discuss approaches in designing future EHL FVIII variants, including those to be used for hemophilia A gene therapy.

Clinical efficacy of simoctocog alfa versus extended half‐life recombinant FVIII concentrates in hemophilia A patients undergoing personalized prophylaxis using a matching‐adjusted indirect comparison method

“…However, modifications to FVIII may affect its binding to platelets and interactions within the tenase complex; indeed, data from in vitro experiments have shown slower FX conversion with efmoroctocog alfa. 40 It was not possible to compare IPD from the NuPreviq study with IPD from the comparator studies as only aggregate data were published for the latter. If IPD were available for all studies, more advanced comparison methodologies such as propensity score matching could be used.…”

Factor VIII moiety of recombinant Factor VIII Fc fusion protein impacts Fc effector function and CD16+ NK cell activation

“…These biological products include plasma-derived FVIII concentrates, recombinant FVIII analogs, a bispecific FVIII mimetic, and an adeno-associated virus vector-based gene therapy ( 2 , 3 ). However, a major shortcoming of many plasma-derived and recombinant FVIII products is the relatively short circulating half-life (~12-15 hours), thus requiring frequent dosing ( 4 ). In the past two decades, drug manufacturers have designed novel protein products to overcome FVIII’s intrinsic short plasma FVIII half-life.…”

Special Issue “Genetic, Functional and Therapeutic Aspects of Procoagulant and Anticoagulant Factors”

“…The therapeutic options currently available for hemophilia A patients mainly include recombinant factor VIII concentrates [ 9 ] and gene therapy based on the delivery of a functional F8 gene into the liver using adeno-associated viral vectors [ 10 ]. A review contributed by Sarafanov presents strategies for favorable molecular modifications of FVIII to increase protein expression, potentially improving the therapeutic efficacy of both FVIII replacement products and constructs used in hemophilia A gene therapy [ 11 ]. Lastly, this Special Issue presents various aspects of the genetic diagnosis of antithrombin deficiency and hemophilia A, highlighting both historical evolution and future challenges [ 12 ].…”