A postmarketing surveillance study of the safety and efficacy of ReFacto® (St Louis-derived active substance) in patients with haemophilia A

This clinical trial evaluated the safety and efficacy of ReFacto (St Louis-derived active substance) in patients with severe or moderately severe haemophilia A over a period of 6 months or 50 exposure days (EDs), whichever occurred first. Sixty patients, 58 previously treated and two previously untreated, were enrolled into this study. This was an open-label, multicentre, postmarketing surveillance study in which patients received prophylaxis or on-demand treatment as determined by their doctor. Surgical prophylaxis was evaluated in seven patients requiring elective surgery. Thirty-two patients aged <1 to 66 years (median 19.5) received prophylaxis and 28 patients, aged 1-71 years (median 33.5), received on-demand treatment. The majority of patients had severe haemophilia A (FVIII:C < 2%): 84.4% in the prophylaxis group and 85.7% in the on-demand group. Prophylaxis with ReFacto was associated with a median of 6.7 bleeds per year (range: 0-37). The investigator's assessment of final outcome for prophylactic treatment was excellent or effective for 93.1% of patients. ReFacto resolved 92.8% of bleeds with one or two infusions. The investigator's assessment was excellent or good for 98.2% of bleeds treated with ReFacto. Haemostasis was achieved for all seven surgical cases and ReFacto gave an excellent or good response for each. The nature and incidence of adverse events was as expected and no new safety concerns emerged. One previously treated patient (PTP) developed a high-titre inhibitor (maximum 75 BU) and one minimally treated patient (MTP) developed a low-titre inhibitor while on the study but eventually achieved high titres (maximum 30 BU) after immune tolerance therapy was initiated with a plasma-derived FVIII product. One previously untreated patient (PUP) developed a transient low-titre inhibitor (0.4 BU). Other serious adverse events (SAEs) were unrelated to study treatment. There were no allergic events. The results of this study are consistent with the previously published ReFacto pivotal studies.     

Transmissible spongiform encephalopathy agent clearance by the immunoaffinity and anion-exchange chromatography steps of the ReFacto® manufacturing process

ReFacto (moroctocog alfa), a recombinant factor VIII approved for the treatment of haemophilia A, is produced by a mammalian cell-culture process that includes therapeutic-grade human serum albumin (HSA) in the cell-culture medium. While to date there have been no cases of transmissible spongiform encephalopathy (TSE) resulting from the clinical use of HSA, Wyeth conducted a study to demonstrate that the ReFacto manufacturing process has significant capacity to remove a TSE agent if it were present as a contaminant in the HSA. The immunoaffinity (8A4 Sepharose) and anion-exchange (Q Sepharose) chromatography steps were evaluated for the clearance of the hamster TSE agent, strain 263K. This Good Laboratory Practice study was performed using appropriately qualified, laboratory-scale chromatography systems. Filtered brain homogenate from TSE-infected hamsters was added to loads of both chromatographic columns, and the concentration of TSE agent in the loads and product pools were determined using a validated western blot quantitation method. Replicate chromatography runs were consistent, as demonstrated by the < or =0.7 log(10) difference observed in TSE agent reduction between each pair of runs. The immunoaffinity and anion-exchanges steps demonstrated 3.8 log reduction and >5.2 log reduction respectively. These data provide a high degree of assurance that in the unlikely event of a TSE contamination of the HSA used in the ReFacto cell-culture process, the purification steps have the potential to remove the infectious agent to extremely low levels, thereby significantly reducing the risk to patients receiving ReFacto.     

Performance of recalibrated ReFacto® laboratory standard in the measurement of FVIII plasma concentration via the chromogenic and one-stage assays after infusion of recalibrated ReFacto® (B-domain deleted recombinant factor VIII)

Summary.  The use of ReFacto Laboratory Standard ( RLS ) in the one-stage clotting assay was proposed to reduce the underestimation of factor VIII (FVIII) plasma concentration after the infusion of 'ReFacto^®' (B-domain deleted recombinant FVIII) in haemophilia A patients. Both ReFacto^® and RLS were recently recalibrated, with the resulting materials containing approximately 20% more protein than the previous products. The aim of this study was to evaluate the performance of recalibrated RLS in the measurement of FVIII plasma concentration after the infusion of recalibrated ReFacto^®. In 13 severe haemophilia A patients, 25 IU kg⁻¹ of ReFacto ^® were injected intravenously. Venous blood samples were collected at 0.25, 0.5, 1, 3, 6, 9, 24, 28 and 32 h after the end of the infusion. Pharmacokinetic parameters were measured for the chromogenic and one-stage assays using International Plasma Standard (IPS) and RLS for both assays and assuming a non-compartmental drug disposition. Comparisons among assays and standards were performed using anova . Pharmacokinetic estimates obtained with the chromogenic method were in agreement with those published in the literature. The one-stage method was confirmed to be more sensitive to lower plasma concentrations of FVIII. The measured maximum plasma concentration ( C _max ) was slightly higher than theoretical values and independent of the assay used. C _max , area under the curve ( AUC) and volume of distribution at steady state ( V _ss ) presented non-significant differences among the methods and standards used. The clinical utility of RLS in the evaluation of FVIII concentration after the infusion of ReFacto^® seems to be reduced since recalibration of the product.     

Efficacy, safety and tolerability of recombinant factor VIII (REFACTO®) in patients with haemophilia A: interim data from a postmarketing surveillance study in Germany and Austria

An open-label, multicentre, postmarketing surveillance study conducted in Germany and Austria with recombinant factor VIII (REFACTO) has enrolled 217 patients (mean age 26.3 years) from 38 haemophilia centres during the first 4.8 years. Most patients (188/217; 86.6%) had severe to moderately severe haemophilia A, of whom 153 completed sufficient diary information for the main efficacy analysis. These 153 patients experienced a median of 6.6 (interquartile range 1.4-18.6) bleeding episodes per year. Patients treated with prophylaxis experienced a median of 4.4 (1.1-9.3) bleeds per year, while patients treated on-demand experienced a median of 22.8 (11.3-29.0) bleeds per year. Overall, most physicians (41/43 [95.3%]) were 'very satisfied' or 'satisfied' with the efficacy of REFACTO in the treatment of bleeding episodes. A total of 137 non-serious adverse events have been reported in 52/217 patients (24.0%) to date. In addition, 129 serious adverse events in 87 patients (40%) were reported, including 41 cases of 'less than expected therapeutic effect' (LETE). Of these, 39 LETE cases were reported in one centre; however, patients in this centre experienced considerably fewer bleeding episodes per year than patients outside this centre. Overall, six patients (2.8%) have developed de novo inhibitors, three of which were considered high titre. Four of these patients were at high risk (0-50 exposure days [ED]) of inhibitor formation, one was at intermediate risk (51-100 ED) and one was at low risk (>100 ED). These results emphasize the benefit of postmarketing surveillance and, overall, this study confirms the efficacy, safety and tolerability of REFACTO in the treatment of patients with haemophilia A.     

Clinical efficacy, safety and pharmacokinetic properties of the factor VIII concentrate Haemoctin® SDH in previously treated patients with severe haemophilia A

Clinical efficacy, safety and pharmacokinetic properties of the high-purity double-virus inactivated plasma-derived factor VIII concentrate Haemoctin SDH (pdFVIII) were evaluated in three prospective open-label uncontrolled studies in previously treated patients (PTPs) with severe haemophilia A. The pharmacokinetic properties assessed at baseline and after 3 months of treatment are in accurate accordance with published data and remain unchanged over time (study A, n = 12). Mean terminal elimination half-life was 11.8 and 11.9 h, mean incremental recovery (IU dL(-1)/IU kg(-1)) was 2.3 and 2.0, respectively. Long-term efficacy and safety, in particular the potential immunogenicity, were investigated in a total of 53 PTPs (studies A and B) treated prophylactically and on-demand, as required. PdFVIII has shown to be effective in preventing and controlling bleeding episodes; 23.5% of patients were free of bleeding events. A total of 177 haemorrhages occurred with 74.0% resolving after a single infusion, 87.6% within two infusions. 98.3% of responses reported on haemorrhages were rated as 'excellent' or 'good'. Moreover, 'excellent' haemostatic efficacy has been demonstrated in 10 surgical procedures including general and severe orthopaedic interventions (study C). No complication occurred in any surgery. Few adverse events were reported, one patient developed a high-titre FVIII inhibitor without clinical relevance. In all three studies, over 6 million units were administered in nearly 4300 infusions, approximately 94% units or infusions were given for prophylaxis and only 6% for treatment on-demand. In conclusion, pdFVIII has shown to be effective, safe and well tolerated in long-term prophylaxis and treatment on-demand as well as after minor and major surgical procedures.     

In vivo recovery and safety of human factor VIII product AAFACT® in patients with haemophilia A

AAFACT, a monoclonal purified, solvent/detergent treated human plasma-derived coagulation factor VIII concentrate obtained from plasma of voluntary, non-remunerated blood donors, is manufactured and marketed in the Netherlands by Sanquin Plasma Products since 1995. In a postmarketing surveillance study, 70 previously treated haemophilia A patients were included (73% severe, 14% moderate and 13% mild haemophilia A). Most of these patients were followed during 4 years for the appearance of adverse events, possible transmissions of blood-borne viruses and the occurrence of antibodies against FVIII. The efficacy of treatment was determined in each patient by the in vivo recovery of FVIII. During this study, only six adverse events, possibly related to the use of AAFACT, were reported. None of these were indicated as serious. Transmissions of HIV, HAV, HBV and HCV in the seronegative patients have not been observed. In none of the patients, inhibitors to FVIII were detected. The in vivo recovery of FVIII during this study was not different from the in vivo recovery observed in eight patients during the preregistration study. There was a correlation of in vivo recovery with age and body weight. From these results, we conclude that the clinical usage of this human plasma-derived FVIII product is efficient and safe.     

Clinical efficacy of highly purified, doubly virus-inactivated factor VIII/von Willebrand factor concentrate (Fanhdi®) in the treatment of von Willebrand disease: a retrospective clinical study

The goal of therapy in patients with von Willebrand disease (vWD) is to correct the dual defect of primary haemostasis and intrinsic coagulation reflected by low levels of von Willebrand factor (vWF) and factor VIII coagulant activity (FVIII:C). Factor VIII/von Willebrand factor (FVIII/vWF) concentrates are currently the treatment of choice in vWD patients unresponsive to desmopressin (DDAVP). However, only few studies on their clinical use are available so far. The main objective of this study was to retrospectively evaluate the clinical efficacy of a highly purified, doubly virus-inactivated FVIII/vWF concentrate with a high content of FVIII/vWF (Fanhdi). Twenty-two patients with congenital vWD have been treated from 1999 to 2001 at eight specialized centres belonging to the Italian Association of Hemophilia Centers (AICE). Ten males and 12 females, median age 28.5 years, range 5-70 years) had type 3 vWD (six cases), DDAVP-unresponsive type 1 (nine cases) and type 2B (seven cases). The study drug was given to stop or prevent 12 bleeding episodes or to prevent excessive bleeding during 14 surgical or invasive procedures. Overall, replacement therapy with the concentrate showed an excellent to good clinical efficacy in 92% of bleeding episodes and in 93% of surgical procedures. No adverse events occurred during 1,601 infusions, accounting for a total of 304,500 IU of FVIII:C administered. These results confirm the efficacy and safety of this concentrate in the management of bleeding episodes and in the prevention of excessive bleeding during major and minor surgery.     

FEIBA®: mode of action

Summary.  FEIBA^® (factor eight inhibitor bypassing activity) has a history of more than 30 years of successful use in controlling bleeding in haemophilic patients who have developed inhibitory antibodies against factor (F)VIII or FIX. Recently it was shown that FEIBA^® contains the proenzymes of the prothrombin complex factors, prothrombin, FVII, FIX and FX, but only very small amounts of their activation products, with the exception of FVIIa, which is contained in FEIBA^® in greater amounts. FEIBA^® controls bleeding by induction and facilitation of thrombin generation, a process for which FV is crucial. A number of biochemical in vitro and in vivo studies have shown that FXa and prothrombin play a critical role in the activity of FEIBA^®. Consequently, they are considered to be key components of this product. The prothrombinase complex has been found to be a major target site for FEIBA^®. Apart from prothrombin and FXa, FEIBA^® contains other proteins of the prothrombin complex, which could also facilitate haemostasis in haemophilia patients with inhibitors.     

In vitro evaluation of B-domain deleted recombinant factor VIII (ReFacto®) stability during simulated continuous infusion administration

The administration of factor VIII (FVIII) by continuous infusion (CI) to manage severe haemorrhage or during major surgery appears pharmacokinetically and economically favourable when compared with intermittent bolus infusions. Successful clinical use of FVIII delivered by CI, however, requires a thorough assessment of product stability under conditions encountered during CI such as prolonged exposure to the delivery devices at ambient temperature and the low FVIII concentrations. This investigation has identified conditions under which ReFacto, a recombinant human B-domain deleted FVIII, can be successfully delivered under dilute conditions when using large volume parenteral polyvinyl chloride (PVC) bags without the addition of stabilizers or as an undiluted preparation delivered by ambulatory infusion pumps. ReFacto is stable for 36 h when stored in large volume parenteral PVC reservoirs at 3 and 8 IU mL(-1) or 72 h when delivered undiluted at 62 IU mL(-1) by CADD infusion pumps. The greatest concern with the delivery of ReFacto by CI is adsorptive losses to the contact surfaces of the delivery system. There was no significant binding of ReFacto to the PVC reservoirs overtime; however, there was appreciable binding to the administration set under certain conditions. The binding was influenced by the ionic strength of the solution, residence time in the tubing and protein concentration. The recovery and stability profile of ReFacto under certain conditions appears favourable when compared with that of full-length recombinant FVIII products, observed by other investigators.     

Evaluation of pharmacokinetics, efficacy and safety of Immunate® solvent detergent in previously treated patients with severe haemophilia A

Immunate Solvent Detergent (S/D) is a plasma derived, purified, human factor VIII (FVIII) - von Willebrand factor (VWF) complex subjected to two virus inactivation/removal processes: S/D and vapor heat treatment. This prospective, multicentre, three-part clinical study evaluated the pharmacokinetics (in comparison to the predecessor product Immunate), efficacy and safety of Immunate S/D in 56 previously treated patients with severe haemophilia A. Subjects received Immunate S/D on-demand, as a prophylactic regimen or both. The results of the pharmacokinetic population demonstrate that Immunate and Immunate S/D were equivalent with respect to the FVIII - and to the retrospectively VWF - parameters assessed. A total of 623 bleeding episodes were reported in 47/56 subjects. The duration of prophylaxis ranged from 0.1-5.2 months with a total of 175.6 months. The median number of bleeds per month in subjects on prophylaxis was 0 (range 0-10). Ninety-six percent of bleeding episodes were rated as having an excellent or good response. For most bleeding episodes (89%), subjects required only one infusion with a mean dose of 29.6 IU kg(-1). No FVIII inhibitory antibodies were observed in any subject. No related serious adverse events were reported. Thus, the introduction of S/D treatment did not alter the PK characteristics and function of VWF and FVIII molecules of Immunate S/D which is effective and safe for treatment of bleeding episodes, management of surgical procedures, and prophylaxis.     

Treatment and prevention of acute bleedings in von Willebrand disease – efficacy and safety of Wilate®, a new generation von Willebrand factor/factor VIII concentrate

Summary.  For many patients with von Willebrand disease (VWD), the replacement therapy with von Willebrand factor (VWF)/factor VIII (FVIII) concentrates is the treatment of choice. To evaluate clinical efficacy, safety and tolerability of Wilate^®, an albumin-free VWF/FVIII concentrate with a ratio of the two haemostatic moieties of approximately 1 to 1, a prospective clinical programme has been designed. The dataset on the treatment and prevention of bleedings is derived from 44 patients (20 males and 24 females) of all VWD types. Thousand and ninety five bleeding episodes were treated with an overall efficacy rating of excellent or good in 96%. The median dose per treatment day was 26 IU FVIII:C per kg. Eighty-one per cent of bleeds were stopped within 1 or 2 days. Gastrointestinal (GI) bleeds needed higher doses (mean 44 IU kg⁻¹) and longer treatment (mean 4 days). Efficacy and dosing data from eight children of 12 or less years of age did not differ significantly from the overall study population. Nineteen patients, including six children, were treated prophylactically for more than 3 months (mean 14.8, range 3–46) with a mean prophylactic dose of 27.4 IU kg⁻¹ and a mean frequency of 1.9 infusions per week. A drop of bleeding frequency from a mean of 4.5 to 1.4 bleeds per month was observed. The overall tolerability was very good. Adverse drug reactions were rare and were mild or moderate in their intensity. The large prospective clinical dataset shows that Wilate^® is efficacious and safe in the treatment and prevention of haemorrhages in all VWD types in both adult and paediatric patients.     

Elimination capacity of a TSE-model agent in the manufacturing process of Alphanate®/Fanhdi®, a human factor VIII/VWF complex concentrate

Summary.  The variant Creutzfeldt–Jakob disease (vCJD) is a transmissible spongiform encephalopathy (TSE), mainly present in the UK and is associated with the ingestion of bovine products affected with bovine spongiform encephalopathy. Manufacturers of biological products must investigate the ability of their production processes to remove TSE agents. We studied the purification steps in the manufacturing process of two FVIII/VWF concentrates (Alphanate^® and Fanhdi^®) in their ability to eliminate an experimental TSE-model agent. Hamster scrapie strain 263K brain-derived materials were spiked into samples of the solutions taken before various stages during its production: 3.5% polyethylene glycol (PEG) precipitation, heparin affinity chromatography and saline precipitation/final filtrations. PEG precipitation and affinity chromatography were studied both as isolated and combined steps. TSE agent removal was determined using a laboratory scale model representative of the industrial manufacturing process. The prion protein (PrP^Sc) was measured with Western blot and TSE infectivity was measured with bioassay. Western blot results were in agreement with those obtained by bioassay, showing a significant removal capacity in the production process: 3.21–3.43 log₁₀ for the PEG precipitation; about 3.45 log₁₀ for the affinity chromatography; and around 2.0 log₁₀ for the saline precipitation plus final filtrations. PEG precipitation and heparin affinity chromatography were demonstrated to be two complementary TSE-model agent removal mechanisms with total removal being the sum of the two. An overall reduction factor of around 8 log₁₀ can be deduced. The tests from the production process of FVIII/VWF complex concentrates have demonstrated their potential for eliminating TSE agents.     

Substitution of Arg527 and Arg531 in factor VIII associated with mild haemophilia A: characterization in terms of subunit interaction and cofactor function

The functional defect caused by substitution of Arg527 (--> Trp) and Arg531 (--> Gly, His) in factor VIII (FVIII), was explored by employing FVIII derived from patient plasma and recombinant FVIII variants. Mutation of these residues is associated with mild haemophilia A. For both FVIII-R527W and FVIII-R531H, activity was lower than antigen, indicating a functional defect for both variants. In contrast to FVIII-R527W, the amount of FVIII-R531H heterodimer present in plasma was reduced compared to heavy and light chain levels. Factor X (FX) activation experiments employing recombinant FVIII-R531G revealed that the activated FVIII-R531G heterotrimer was less stable than normal FVIIIa, apparently due to rapid dissociation of the A2 domain. These findings suggest that Arg531 is involved in maintaining the stability of both the heterodimer and the activated FVIII heterotrimer. Recombinant FVIII-R527W displayed reduced stimulation of FX activation, suggesting a defect in interaction with factor IXa (FIXa). The contribution of Arg527 in the interaction with FIXa was supported by the observation that FVIII-derived synthetic peptide Tyr511-Leu530 was able to inhibit FX activation and that this inhibition could be overcome by addition of increasing concentrations of FIXa. Furthermore, in the three-dimensional FVIII model residues Val517-Arg527 are located near the FIXa binding site Ser558-Gln565. Therefore we propose that Arg527 is part of an extended FIXa binding site, comprising residues Ser558-Gln565 and Val517-Arg527.     

Safety of factor VIII inhibitor bypass activity (FEIBA®): 10-year compilation of thrombotic adverse events

Published and unpublished spontaneously reported thrombotic adverse events (AEs) in factor VIII inhibitor bypass activity (FEIBA(R)) recipients were compiled for the most recent 10-year period during which FEIBA(R) units equivalent to 3.95 x 105 typical infusions were distributed worldwide. A total of 16 thrombotic AEs were documented over the 10-year period, corresponding to an incidence of 4.05 per 105 infusions (95% CI, 2.32-6.58 per 105 infusions). Disseminated intravascular coagulation (n=7) and myocardial infarction (n=5) were the most frequent thrombotic AEs. One fatality occurred in an 87-year-old metastatic cancer patient. In 13/16 (81%) patients known risk factors were present, most commonly FEIBA(R) overdose in 8/16 (50%), obesity in 3/16 (19%) and serum lipid abnormalities in 2/16 (12%). These findings indicate that thrombotic AEs in FEIBA(R) recipients are very rare. Recognition of risk factors and avoidance of FEIBA(R) overdosage may avert thrombotic AEs.     

In-vitro stability of porcine factor VIII (Hyate:C®)

The stability of porcine factor VIII (Hyate:C^®) 30 units mL^–1, 15 units mL^–1 and 5 units mL^–1 prepared aseptically in 0.9% sodium chloride injection was studied. Solutions were stored in plastic syringes at room temperature and ambient light, and at body temperature protected from light. Samples obtained immediately after mixing and at 4, 24, 48 and 72 h were assayed for FVIII activity using a one-stage FVIII assay. Samples were considered stable if FVIII activity did not decline more than 10% compared with baseline values.
Hyate:C^® 5 units mL^–1 stored at room temperature retained FVIII activity within 90% of baseline values for at least 24 h. When stored at body temperature, FVIII activity of Hyate:C^® 5 units mL^–1 declined to less than 90% of baseline values within 4 h. Stability of Hyate:C^® 15 units mL^–1 and 30 units mL^–1 stored at room temperature was retained for at least 72 h. When Hyate:C^® 15 units mL^–1 and 30 units mL^–1 were stored at body temperature, stability was retained for 24 h. Results of this study will permit further evaluation of Hyate:C^® stability when administered by ambulatory infusion pumps.     

FEIBA® safety profile in multiple modes of clinical and home-therapy application

Summary.  The development of neutralizing antibodies to factor VIII or IX therapeutic concentrates remains the most serious and challenging complication in the management of patients with haemophilia A and B. FEIBA ^® , Anti-Inhibitor Coagulant Complex, is an activated prothrombin complex concentrate that has been used to treat patients with such complications for almost 30 years. The mechanism of action of FEIBA^® has been proposed to involve simultaneous FVIII/FIX inhibitor bypassing action in the common, intrinsic and extrinsic coagulation pathways. FEIBA^® is derived from human plasma that undergoes stringent viral screening followed by significant viral inactivation and removal. To date, there have been no confirmed reports of transmission of hepatitis A, B or C, or of human immunodeficiency viruses associated with the use of the current, vapour-heat-treated FEIBA^® concentrate. The incidence of thrombotic adverse events recorded in the Baxter pharmacovigilance database for the 10-year postmarket period (1990–99) was approximately 4 : 100 000 infusions of FEIBA^®. Almost all documented thrombotic events with FEIBA^® occurred with doses that exceeded dosing recommendations, and known risk factors for cardiovascular disease were evident in more than 80% of the patients involved. Overall, clinical data have shown FEIBA^® to be safe and well-tolerated for use in a wide variety of clinical settings, including treatment of bleeding episodes, management of surgical procedures, home therapy, long-term prophylaxis, and prophylaxis during immune tolerance induction, when used according to dosing guidelines.     

Inhibitor development in patients receiving recombinant factor VIII (Recombinate rAHF/Bioclate®): a prospective pharmacovigilance study

Clinical trials to date have not been adequately powered to assess comparatively infrequent events such as inhibitor development in previously treated patients (PTPs). Comprehensive large-scale pharmacovigilance studies can be useful for this purpose. We prospectively collected inhibitor development reports worldwide among recipients of Recombinate rAHF recombinant factor VIII (rFVIII), also formerly distributed under the product name Bioclate, for the entire postlicensure period from 1993 through 2002. To determine level of exposure to rFVIII we also compiled the Recombinate rAHF/Bioclate International Units (IU) distributed annually. To estimate inhibitor incidence separately for previously untreated or minimally treated patients (PUPs) with 1-50 exposure days and PTPs with >50 exposure days, we used haemophilia A incidence and prevalence data and pooled mean annual rFVIII consumption per PUP and PTP from international multicentre prospective clinical trials. Documented inhibitor cases totalled 89, and the total quantity of Recombinate rAHF/Bioclate rFVIII distributed was 6.48 x10(9) IU. No lot association or other clustering of inhibitor events was evident in PTPs. The incidence of all reported inhibitors, expressed as a percentage of patients treated, was 11.9% (CI: 5.05-28.0%) for PUPs when compared with 0.123% (CI: 0.030-0.512%) for PTPs. The rates for high-titre inhibitors (>5 BU) only were 5.96% (CI: 3.00-11.8%) for PUPs and 0.0554% (CI: 0.0113-0.271%) for PTPs. Thus, incidence rates for both all inhibitors and high-titre inhibitors in PTPs were 1% of the corresponding rates in PUPs. Data from prospective PUP clinical trials involving intensive active monitoring suggest that true inhibitor incidence may be approximately twice that estimated in this pharmacovigilance study. Nevertheless, inhibitor development in PTPs receiving Recombinate rAHF/Bioclate is infrequent.     

Reformulated BeneFix®: efficacy and safety in previously treated patients with moderately severe to severe haemophilia B

BeneFix, the only recombinant factor IX (FIX), has been reformulated. The reformulation involves a change in diluent and allows for more concentrated infusions of recombinant FIX. A double-blind, randomized, pharmacokinetic (PK) crossover study demonstrated that reformulated BeneFix was bioequivalent to original BeneFix and follow-up PK evaluation after 6 months of treatment demonstrated the PK stability of reformulated BeneFix after multiple exposures. Favourable efficacy and safety profiles, consistent with those already well-established for original BeneFix, were observed: 81.1% of haemorrhages resolved with only a single infusion; 85.3% of initial treatment response ratings were Excellent or Good; more than half of the subjects using reformulated BeneFix for routine prophylaxis (11 of 17, 64.7%) had no spontaneous haemorrhages during their 6-12 month course of prophylactic treatment, with an overall spontaneous bleeding rate of 0.72 year(-1); and for the single surgical procedure (knee washing), treatment was rated Useful. In addition, there was no FIX inhibitor development, allergic-type manifestations, or thrombogenic complications with more than 1100 infusions (nearly 5.2 million IUs) administered in this trial. All efficacy and safety outcomes from this study were achieved with more concentrated recombinant protein infusions than that possible with original BeneFix, and utilization of the 2000 IU per vial dosage strength, newly introduced with the reformulated product, was high (>62%). The reformulation of BeneFix allows smaller delivery volumes and an increased choice of dosage strengths without altering the PK properties (including incremental recovery and half-life) or the established efficacy and safety profile of recombinant FIX.     

Safety and efficacy of KOGENATE® Bayer in previously untreated patients (PUPs) and minimally treated patients (MTPs)

Summary.  Safety and efficacy of KOGENATE^® Bayer (Kogenate^® FS), a second-generation full-length recombinant factor VIII formulated with sucrose as stabilizer and produced without the addition of human albumin during purification and the final formulation, was assessed in a prospective, international clinical trial including 31 previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe haemophilia A in home therapy and surgery. Factor VIII inhibitor development was monitored and mutation type profiles were analysed. As of 30 June 2000, the patients received a total of 2.729 infusions (mean 88; range 6–274) for bleeding episodes, surgery or prophylactic treatment. No unexpected drug-related adverse events were observed. Four patients developed an inhibitor after 3–12 exposure days (EDs). One patient successfully underwent immune tolerance treatment; inhibitors in two patients disappeared spontaneously with on-demand treatment, while the inhibitor titre remains low in one patient. Twenty-nine patients (93%) with more than 20 EDs can be regarded as at low risk for inhibitor development. In conclusion, KOGENATE^® Bayer is efficacious and well-tolerated for treatment of children with severe haemophilia A. The incidence of inhibitor formation is not different to that observed with other recombinant or plasma-derived products.