The safety of pharmacologic options for the treatment of persons with hemophilia

ABSTRACT

Introduction: The mainstay of treatment of hemophilia A and B is the replacement of the congenitally deficient coagulation factor through the intravenous infusion of specific concentrates (factor VIII, FVIII, in hemophilia A; factor IX, FIX, in hemophilia B). Several commercial brands of FVIII or FIX products extracted from human plasma or engineered using recombinant DNA technology are available.

Areas covered: We analyze the safety aspects of plasma-derived and recombinant FVIII and FIX products licensed in Europe, focusing on their pathogen safety and inhibitor and thrombosis risks. The safety aspects of bypassing agents (i.e., activated prothrombin complex concentrates and recombinant activated factor VII) used for treatment of bleeding episodes in inhibitor patients will be also briefly discussed.

Expert opinion: The analysis of the published literature documents the high degree of safety from pathogen risk for both plasma-derived and recombinant products available for hemophilia treatment. The main threat to factor concentrate safety is represented by the development of neutralizing alloantibodies against the infused coagulation factor, which in hemophilia A seem to occur more frequently following the administration of recombinant than plasma-derived FVIII products. Great expectations are placed on newer products, particularly on those based upon mechanisms of action other than FVIII replacement.     

Haemophilia B: current pharmacotherapy and future directions

Introduction: Hemophilia B is a rare hereditary hemorrhagic disorder characterized by deficiency of the clotting factor IX (FIX). Hemophilia B patients experience mild to severe bleeding complications according to the degree of FIX defect. Nowadays, the most challenging complication of individuals with hemophilia B is the development of alloantibodies, which render the standard replacement therapy with FIX concentrates ineffective, exposing them to a significantly increased morbidity and mortality. Areas covered: This review summarizes the most important events leading to the development of the current FIX products available for the treatment of hemophilia B patients. In addition, it focuses on the more recent advances in the production of new FIX molecules aimed at improving the clinical management of such patients. Expert opinion: Although the availability of plasma-derived FIX concentrates has greatly improved the clinical management of hemophilia B patients, the introduction of FIX products using recombinant DNA technology has represented the most significant therapeutic progress in hemophilia B therapy, ensuring an advanced level of safety. The development of rFIX products with extended half lives will further improve the therapeutic armamentarium for hemophilia B patients.     

Haemophilia B: current pharmacotherapy and future directions

Introduction: Hemophilia B is a rare hereditary hemorrhagic disorder characterized by deficiency of the clotting factor IX (FIX). Hemophilia B patients experience mild to severe bleeding complications according to the degree of FIX defect. Nowadays, the most challenging complication of individuals with hemophilia B is the development of alloantibodies, which render the standard replacement therapy with FIX concentrates ineffective, exposing them to a significantly increased morbidity and mortality.

Areas covered: This review summarizes the most important events leading to the development of the current FIX products available for the treatment of hemophilia B patients. In addition, it focuses on the more recent advances in the production of new FIX molecules aimed at improving the clinical management of such patients.

Expert opinion: Although the availability of plasma-derived FIX concentrates has greatly improved the clinical management of hemophilia B patients, the introduction of FIX products using recombinant DNA technology has represented the most significant therapeutic progress in hemophilia B therapy, ensuring an advanced level of safety. The development of rFIX products with extended half lives will further improve the therapeutic armamentarium for hemophilia B patients.     

Recent advances in the development of coagulation factors and procoagulants for the treatment of hemophilia

Hemophilia is a family of rare bleeding disorders. The two primary types, hemophilia A and hemophilia B, are caused by recessive X-chromosome linked mutations that result in deficiency of coagulation factor VIII (FVIII) or factor IX (FIX), respectively. Clinically, hemophilia is manifested by spontaneous bleeding, particularly into the joints (haemarthrosis) and soft tissue, and excessive bleeding following trauma or surgery. The total overall number of hemophilia patients worldwide is approximately 400,000, however only about 100,000 of these individuals are treated. The first treatment of hemophilia was initiated when it was determined that the clotting deficiency could be corrected by a plasma fraction taken from normal blood. The discovery of factor VIII enrichment by cryoprecipitation of plasma opened a new era of therapy which eventually led to the production of factor concentrates and the subsequent development of highly purified forms of plasma factors. The most significant improvements have been the availability of recombinant forms of factors VIII and IX. Unfortunately, recombinant factors still retain some of the limitations of plasma concentrates. These limitations include development of antibody responses in patients and the relatively short half-life of the molecules requiring frequent injection to maintain effective concentration. Treatment beyond replacement of native factors has been tried. They include the development of modified factor VIII and IX molecules with improved potency, stability and circulating half-life and enhancement of a prothrombotic responses and/or stabilization of coagulation factors via inhibition of key negative regulatory pathways. These approaches will be reviewed in this commentary.     

Access to treatment among persons with hemophilia: A spatial analysis assessment in the Rhone-Alpes region,France

ObjectivesIn France, only hospital pharmacies can dispense clotting factor concentrates to persons with hemophilia, which limits the access to care for the treatment and the prevention of bleeding episodes. Moreover, the cost of clotting factor concentrates may restrain the maintenance of sufficient stocks in hospital pharmacies. The aim of this study was to investigate the accessibility of clotting factor concentrates to persons with hemophilia in the context of long-term prophylaxis and emergency treatment in the Rhone-Alpes region of France.MethodsA geographic information system was used for evaluating accessibility of clotting factor concentrates. Persons with hemophilia and hospital pharmacies were geolocalized with the use of postal data, and the evaluation of accessibility was based on the road network.ResultsApproximately 72% of the study area was accessible in less than 30 minutes to a hospital pharmacy. Eighty-five percent of persons with hemophilia had access to clotting factor concentrates for prophylactic treatment in less than 20 minutes. Most of them were patients with severe or moderate hemophilia. Regarding emergency doses, factor VIII was accessible in less than 30 minutes in 45.6% of the study area, and factor IX in 30.5%.ConclusionThis study highlights that spatial access to clotting factor concentrates by persons with hemophilia in the Rhône-Alpes region is good for prophylactic treatment but is more uneven for emergency doses.     

Pharmacokinetic drug evaluation of recombinant factor VIII for the treatment of hemophilia A

Introduction: The prevention of bleeding by prophylactic factor replacement is the recommended approach for the treatment of severe hemophilia. Prophylaxis should be individualized to provide the best clinical benefit to each patient. Therefore, a pharmacokinetic approach is crucial.

Areas covered: This review aims to concisely describe the basic principles of pharmacokinetics of FVIII, the role of population pharmacokinetic, the available different recombinant FVIII concentrates and the new extended half-life FVIII molecules with possible improvement in hemophilia A treatment.

Expert opinion: Pharmacokinetic is a useful tool to predict the outcome of replacement therapy, even though a large inter-individual variability exists, becauseof several factors: age, weight, von Willebrand factor level, blood group, active bleed, presence of inhibitors to FVIII, FVIII concentrate. Among the different recombinant FVIII concentrates pharmacokinetic differences are minor and clinically not significant. The extended half-life FVIII products brings only moderate advances, as half life extension is limited to 1.5–1.8-fold in comparison to that of native FVIII. Thus, infusions could be done every fourth, rarely fifth day to ensure a safe through level and a significant benefit can be offered only to patients treated every other day or three times weekly.     

Therapeutic approaches for haemophilia

The life-long episodic bleeding associated with inherited deficiencies of blood coagulation Factor VIII (FVIII) or Factor IX (FIX) can be well controlled with periodic iv. injections of FVIII or FIX concentrates. Either concentrate can be isolated from large human pools (i.e., plasma-derived FVIII or FIX concentrate) or from culture supernatants of recombinant cells engineered to secrete FVIII or FIX. The validated viral inactivation strategies used by manufacturers of FVIII and FIX concentrates have essentially eliminated the transmission of hepatitis B, hepatitis C and HIV viruses. The low yields and inherent instability of FVIII (and FVIIIa in particular) and the additional costs of viral inactivation methods make the annual cost/patient for prophylaxis and treatment of haemophilia very expensive. Several strategies have been adopted and proposed to improve yields of FVIII. These include: deletion of portions of FVIII which are not associated with function; mutations to prevent inactivation of FVIII by protease degradation; and synthesis of FVIII fragments to replace portions deleted in some FVIII deficient patients. An approach to improve FIX replacement involves the production of more coagulatively active FIX mutants. Another promising approach in both FVIII and FIX replacement is gene therapy. Two major issues that will have to be critically addressed before gene therapy for haemophilia can become widespread are whether the procedures will be well-tolerated in patients with significant liver impairment (due to previous exposure to hepatitis viruses) and whether consistent long-term delivery of the transgenes can be achieved.     

Safety of recombinant coagulation factors in treating hemophilia

Introduction: During the last decade, new FVIII/IX concentrates have been developed for the treatment of patients affected by hemophilia A/B. Significant progress has been achieved regarding their half-life, but the old issue of immunogenicity and new concerns about safety need to be addressed.

Areas covered: After the implementation of virucidal methods, both plasma-derived and recombinant clotting factor concentrates achieved a very safe profile. The development of anti-FVIII antibodies is the major adverse event of replacement therapy with both FVIII concentrates. Furthermore, the new extended half-life concentrates, protein fused or pegylated, raised some concerns about their side effects.

Expert Opinion: The treatment of hemophilia A with inhibitors by induction of immunotolerance and using by-passing concentrates, improved the quality of life of patients but did not allow them to have a life expectancy like that of patients without inhibitors. The new humanized monoclonal antibody (MAb) ACE910, mimicking FVIII function, seems to be able to reduce the bleedings of hemophilia A patients with inhibitors. The post-marketing surveillance will clarify if the adverse events observed during the phase III clinical trials and compassionate use were due to the association with a Prothrombin activated complex concentrate or to the prothrombotic effect of the drug itself.     

Pharmacokinetic drug evaluation of albutrepenonacog alfa (CSL654) for the treatment of hemophilia

Introduction: Replacement therapy for FVIII/IX in hemophilia A/B is more than 50 years old following the discovery of cryoprecipitate by Judith Pool in 1964. On-demand therapy and prophylaxis to treat or prevent bleedings is very demanding owing to the short half-life (HL) of factor concentrates (no more than 12–14 h for FVIII or 16–18 h for FIX). Patients are very eager to prolong the intervals between bolus. The enhanced HL of long-acting recombinant FIX (rFIX) concentrates seems to fulfill this expectance.

Areas covered: Great improvements have been achieved in the bio-engineering of new rFIX concentrates. Production, formulation, pharmacokinetics, pharmacodynamics, efficacy and tolerability of albutrepenonacog alfa (rIX-FP, trade name Idelvion) will be addressed. rIX-FP is produced by expression of genetically linked FIX and albumin in Chinese Hamster Ovary cells. rIX-FP exhibits a long HL, low clearance and small volume of distribution.

Expert opinion: There is no doubt that rIX-FP, as well as other long-acting rFIX concentrates, will facilitate and improve the adherence to therapy of younger hemophilia patients, toddlers and children. Efficacy, safety and immunogenicity of rIX-FP must be assessed not only during the regulatory clinical trials but also by post-marketing surveillance.     

The use of pharmacokinetics in dose individualization of factor VIII in the treatment of hemophilia A

Introduction: Hemophilia A is a bleeding disorder resulting from a lack of clotting factor VIII (FVIII), and treatment typically consists of prophylactic replacement of the deficient factor. However, high between subject variability precludes the development of a ‘one size fits all’ dosing strategy and necessitates an individualized approach. We sought to summarize the data on the pharmacokinetics of FVIII available as a basis for the development of population pharmacokinetic models to be used in dose tailoring.

Areas covered: We reviewed the pharmacokinetics of FVIII as used for the treatment of hemophilia A, with a focus on the variability observed between patients and the application of pharmacokinetic methods to dose individualization. We also explored the covariates affecting pharmacokinetic parameters, the differences between plasma-derived and recombinant FVIII and the development of extended half-life products.

Expert opinion: The pharmacokinetics of factor VIII in patients with hemophilia shows a high interpatient variability, and is affected by age, weight, level of von Willebrand factor, and blood group. A population approach to estimating individual pharmacokinetics is likely to provide the most successful strategy to tailor factor concentrate dosing to the individual needs and to ensure optimal patient outcomes, while also improving the cost-effectiveness of prophylactic replacement therapy.     

Chimeric proteins comprising the constant region of immunoglobulins for treating hemophilia B (WO2005001025)

The application (WO2005001025) details recombinant fusion proteins attached to the constant region of heavy chains of immunoglobulins. They are found to be particularly useful for the treatment of hemostatic disorders, such as hemophilia B. It aims at engineering chimeric proteins comprising of a single molecule of human factor IX (FIX) and the constant region (Fc domain) of one or two heavy chain(s) of human IgG (rFIXFc). cDNA for rFIXFc was generated by a PCR. rFIXFc protein was isolated and purified from stably transfected mammalian cells. The concentration and clotting activity of rFIXFc were assessed in mice, rats, monkeys, and FIX-deficient mice and dogs, after intravenous administration. The half-life of rFIXFc activity is prolonged by three to fourfold, compared with rFIX, when administered intravenously in all animals. The generation of chimeric proteins, comprised of FIX fused to the Fc domain of IgG, extends the clotting activity of the recombinant molecule. rFIXFc represents a promising candidate for the treatment of patients with hemophilia B. The application claims the methods of making recombinant chimeric proteins comprising of one biologically active molecule fused to the Fc region of the heavy chain(s) of immunoglobulins and their use for therapy.     

Chimeric proteins comprising the constant region of immunoglobulins for treating hemophilia B (WO2005001025)

The application (WO2005001025) details recombinant fusion proteins attached to the constant region of heavy chains of immunoglobulins. They are found to be particularly useful for the treatment of hemostatic disorders, such as hemophilia B. It aims at engineering chimeric proteins comprising of a single molecule of human factor IX (FIX) and the constant region (Fc domain) of one or two heavy chain(s) of human IgG (rFIXFc). cDNA for rFIXFc was generated by a PCR. rFIXFc protein was isolated and purified from stably transfected mammalian cells. The concentration and clotting activity of rFIXFc were assessed in mice, rats, monkeys, and FIX-deficient mice and dogs, after intravenous administration. The half-life of rFIXFc activity is prolonged by three to fourfold, compared with rFIX, when administered intravenously in all animals. The generation of chimeric proteins, comprised of FIX fused to the Fc domain of IgG, extends the clotting activity of the recombinant molecule. rFIXFc represents a promising candidate for the treatment of patients with hemophilia B. The application claims the methods of making recombinant chimeric proteins comprising of one biologically active molecule fused to the Fc region of the heavy chain(s) of immunoglobulins and their use for therapy.     

Role of Glycosylation in Conformational Stability, Activity, Macromolecular Interaction and Immunogenicity of Recombinant Human Factor VIII

Factor VIII (FVIII) is a multi-domain glycoprotein that is an essential cofactor in the blood coagulation cascade. Its deficiency or dysfunction causes hemophilia A, a bleeding disorder. Replacement using exogenous recombinant human factor VIII (rFVIII) is the first line of therapy for hemophilia A. The role of glycosylation on the activity, stability, protein–lipid interaction, and immunogenicity of FVIII is not known. In order to investigate the role of glycosylation, a deglycosylated form of FVIII was generated by enzymatic cleavage of carbohydrate chains. The biochemical properties of fully glycosylated and completely deglycosylated forms of rFVIII (degly rFVIII) were compared using enzyme-linked immunosorbent assay, size exclusion chromatography, and clotting activity studies. The biological activity of degly FVIII decreased in comparison to the fully glycosylated protein. The ability of degly rFVIII to interact with phosphatidylserine containing membranes was partly impaired. Data suggested that glycosylation significantly influences the stability and the biologically relevant macromolecular interactions of FVIII. The effect of glycosylation on immunogenicity was investigated in a murine model of hemophilia A. Studies showed that deletion of glycosylation did not increase immunogenicity.     

Pharmacokinetics of coagulation factors: clinical relevance for patients with haemophilia.

Haemophilia is a recessively inherited coagulation disorder, in which an X-chromosome mutation causes a deficiency of either coagulation factor VIII (FVIII) in haemophilia A, or factor IX (FIX) in haemophilia B. Intravenous administration of FVIII or FIX can be used to control a bleeding episode, to provide haemostasis during surgery or for long term prophylaxis of bleeding. In special cases, activated factor VII (FVIIa) may be used instead of FVIII or FIX. The aim of this work is to review the pharmacokinetics of FVIII, FIX and FVIIa and to give an outline of the use of pharmacokinetics to optimise the treatment of patients with haemophilia. The pharmacokinetics of FVIII are well characterised. The systemic clearance (CL) of FVIII is largely determined by the plasma level of von Willebrand factor (vWF), which protects FVIII from degradation. Typical average CL in patients with normal vWF levels is 3 ml/h/kg, with an apparent volume of distribution at steady state (Vss) that slightly exceeds the plasma volume of the patient, and the average elimination half-life (t1/2) is around 14 hours. There are still some discrepancies in the literature on the pharmacokinetics of FIX. The average CL of plasma-derived FIX seems to be 4 ml/h/kg, the Vss is 3 to 4 times the plasma volume and the elimination t1/2 often exceeds 30 hours. FVIIa has a much higher CL (average of 33 ml/h/kg), and a short terminal t1/2 (at 2 to 3 hours). The Vss is 2 to 3 times the plasma volume. Since the therapeutic levels of coagulation factors are well defined in most clinical situations, applied pharmacokinetics is an excellent tool to optimise therapy. Individual tailoring of administration in prophylaxis has been shown to considerably increase the cost effectiveness of the treatment. Dosage regimens for the treatment of bleeding episodes or for haemostasis during surgery are also designed using pharmacokinetic data, and the advantages of using a constant infusion instead of repeated bolus doses have been explored. The influence of antibodies (inhibitors) on the pharmacokinetics of FVIII and FIX is in part understood, and the doses of coagulation factor needed to treat a patient can tentatively be calculated from the antibody titre. In conclusion, therapeutic monitoring of coagulation factor levels and the use of clinical pharmacokinetics to aid therapy are well established in the treatment of patients with haemophilia.     

Emerging drugs for the treatment of hemophilia A and B

Introduction: Replacement therapy with clotting factor concentrates is the most appropriate and effective way to treat bleedings of Hemophilia A&B to prevent chronic arthropathy. Unfortunately, the short half-life (HL) of FVIII/IX concentrates obliges the patients to receive frequent infusions, a big concern for children. The development of inhibitors in about 30–45% of hemophilia A and in 3–5% of hemophilia B patient is the major adverse event of replacement therapy.

Areas covered: In the last few years, new rFIX have been developed with HL. New rFVIII concentrates are displaying small increase of PK characteristics. The new bio-engineering methods allowed the production of molecules fused with Fc fragment of IgG or Albumin or linked to PEG. A new approach to improve hemostasis is represented by Mab against TFPI and small RNA interfering with Antithrombin synthesis. Another innovative drug seems to be the new bi-specific antibody which mimics FVIII function in linking FXa and FX to tenase production.

Expert opinion: The emerging drugs for hemophilia treatment seem to be very promising. The extended half-life will improve the adherence of patients to therapy. Accurate post-marketing surveillance studies will be necessary to check the efficacy, safety and immunogenicity of these new molecules.     

Coagulation products and their uses.

The indications, pharmacokinetics, and therapeutic guidelines for available coagulation products are reviewed. Patients with hemophilia, von Willebrand's disease (VWD), or acquired inhibitors to antihemophilic factor (AHF) cannot spontaneously stop an acute hemorrhage. Coagulation products used to manage bleeding in patients with these disorders include AHF concentrates, factor IX concentrates, factor VIIa concentrate, factor IX complexes, anti-inhibitor coagulant complexes, and desmopressin acetate. Typically, these commercially available products are used to manage acute bleeding or to prevent excessive bleeding during surgery. The dosage of the coagulation products and the duration of therapy depend on many variables, including the severity of the hemorrhage, the pharmacokinetics of the coagulation products, and patient-specific factors. Product purity and viral attenuation are also important considerations in determining an appropriate dosage regimen. Recombinant versions of some coagulant factors are available and can eliminate the risk of viral transmission. A thorough understanding of each coagulation product can guide product selection, dosing, and treatment duration and can reduce the risk of viral transmission.     

Efficacy and safety of a recombinant factor VIII produced from a human cell line (simoctocog alfa)

Introduction: The development of inhibitors against infused factor VIII (FVIII) has a detrimental impact on health and quality of life of patients with hemophilia A. Several observational studies and a recently published randomized trial indicate that the inhibitor risk in previously untreated patients (PUPs) is higher following the use of recombinant FVIII (rFVIII) products compared with plasma-derived FVIII concentrates. There is currently a great interest towards newer rFVIII products that adopt various technological solutions to reduce the inhibitor risk.

Areas covered: This review describes the efficacy and safety of simoctocog alfa (Nuwiq), a human cell-line derived rFVIII developed for the prevention and treatment of bleeding in hemophilia A patients. Particular relevance will be given to the safety aspects of this product, with special emphasis on the rate of inhibitor development, presenting the results of the phase II and III clinical trials on previously treated patients (PTPs) and the interim data from the phase III trial on PUPs.

Expert opinion: The final results from PTP studies and the preliminary data from the PUP study document the high efficacy and safety profile of this rFVIII product, which has the potential to reduce the inhibitor risk in PUPs with severe hemophilia A.     

New insights into the coagulation system and implications for new therapeutic options with recombinant factor VIIa

The classical model of the coagulation cascade is to be replaced by a new, cell based model of coagulation emphasizing the interaction of coagulation proteins with cell surfaces of platelets subendothelial cells and the endothelium. According to current knowledge hemostasis is initiated by the formation of a complex between tissue factor (TF) exposed as a result of a vessel wall injury, and already activated factor (F) VII (FVIIa) normally present in the circulating blood. The TF-FVIIa complexes convert FX into FXa on the TF bearing cell. FXa then activates prothrombin (FII) into thrombin (FIIa). This limited amount of thrombin activates FVIII, FV, FXI and platelets. Thrombin-activated platelets change shape and as a result will expose negatively charged phospholipids, which form the perfect template for full thrombin generation involving FVIIIa and FIXa. Thrombin also converts fibrinogen into fibrin, it activates the fibrin stabilizing FXIII, as well as the thrombin activatable fibrinolysis inhibitor (TAFI). The fibrin structure has been found to be dependent on the amount of thrombin formed and the rate of thrombin generation. Full thrombin generation is necessary for the formation of a tight, stable fibrin hemostatic plug resistant to premature fibrinolysis which is required for full and sustained hemostasis. Since thrombin has such a crucial role in providing hemostasis, any agent that enhances thrombin generation in situations with impaired thrombin formation may be characterized as a 'general hemostatic agent' - a term that has been applied to recombinant activated FVII. Recombinant coagulation factor VIIa (rFVIIa; NovoSeven(R)) was originally developed and approved for the treatment of bleeding episodes and the prevention of bleeding during surgery in hemophilia patients with inhibitors and in patients with auto-antibodies against FVIII or FIX (acquired hemophilia). As rFVIIa in pharmacological doses enhances thrombin generation on activated platelets, it has been suggested that rFVIIa may also help to improve hemostasis in other situations involving impaired thrombin generation. This is substantiated by the accumulation of published data indicating that rFVIIa is able to control bleeding in patients with thrombocytopenia or platelet function deficiencies as well as in patients without pre-existing coagulopathies.     

PEGylation of a Factor VIII–Phosphatidylinositol Complex: Pharmacokinetics and Immunogenicity in Hemophilia A Mice

Hemophilia A is an X-linked bleeding disorder caused by the deficiency of factor VIII (FVIII). Exogenous FVIII is administered therapeutically, and due to a short half-life, frequent infusions are often required. Fifteen to thirty-five percent of severe hemophilia A patients develop inhibitory antibodies toward FVIII that complicate clinical management of the disease. Previously, we used phosphatidylinositol (PI) containing lipidic nanoparticles to improve the therapeutic efficacy of recombinant FVIII by reducing immunogenicity and prolonging the circulating half-life. The objective of this study is to investigate further improvements in the FVIII-PI formulation resulting from the addition of polyethylene glycol (PEG) to the particle. PEGylation was achieved by passive transfer of PEG conjugated lipid into the FVIII-PI complex. PEGylated FVIII-PI (FVIII-PI/PEG) was generated with high association efficiency. Reduced activity in vitro and improved retention of activity in the presence of antibodies suggested strong shielding of FVIII by the particle; thus, in vivo studies were conducted in hemophilia A mice. Following intravenous administration, the apparent terminal half-life was improved versus both free FVIII and FVIII-PI, but exposure determined by area under the curve was reduced. The formation of inhibitory antibodies after subcutaneous immunization with FVIII-PI/PEG was lower than free FVIII but resulted in a significant increase in inhibitors following intravenous administration. Passive transfer of PEG onto the FVIII-PI complex does not provide any therapeutic benefit.     

Treating haemophilia A with recombinant blood factors: a comparison

The mainstay in the treatment of haemophilia A is replacement therapy with repeated infusions of plasma-derived Factor VIII (FVIII) concentrates or recombinant FVIII products. While modern plasma-derived FVIII concentrates have an excellent safety profile, there is an inexorable shift towards the use of recombinant products, especially in affluent countries. Recombinant FVIII products have demonstrated excellent haemostatic efficacy and higher safety with regard to the transmission of blood-borne pathogens. The experience in haemophilia A treatment with five currently available recombinant FVIII products, including the first third-generation product, Advate, which is completely free from human or animal proteins, is summarised. Some unresolved problems concerning the efficacy and assaying of recombinant factors and future perspectives of both recombinant and plasma-derived FVIII products in global haemophilia care, are also discussed.