Simoctocog alfa (Nuwiq®) in children: early steps in life's journey for people with severe hemophilia A.

People with severe hemophilia A usually experience their first bleed early in life. In children with severe hemophilia A, primary prophylaxis is recommended to prevent recurrent and potentially life-threatening bleeds that significantly impact day-to-day life. Factor VIII (FVIII) prophylaxis is well-established in children and has been shown to reduce the development of hemophilic arthropathy. However, a major challenge of FVIII therapy is the development of neutralizing anti-FVIII antibodies (FVIII inhibitors). Simoctocog alfa (Nuwiq®) is a human cell line-derived recombinant FVIII (rFVIII) whose immunogenicity, efficacy, and safety have been studied in 167 children with severe hemophilia A across two prospective clinical trials and their long-term extensions. In 105 previously untreated children, the inhibitor rate of 16.2% for high-titer inhibitors (26.7% for all inhibitors) was lower than published rates for hamster cell line-derived rFVIII products. There was no inhibitor development in previously untreated children with non-null F8 mutations and in previously treated children. In a case series of 10 inhibitor patients, 8 (80%) underwent successful immune tolerance induction with simoctocog alfa with a median time to undetectable inhibitor of 3.5 months. In an analysis of 96 children who enrolled in the extension studies and received long-term simoctocog alfa prophylaxis for up to 5 years, median spontaneous, joint, and total annualized bleeding rates were 0.3, 0.4, and 1.8, respectively. No thromboembolisms were reported in any of the 167 children, and there were no treatment-related deaths. Optimal care of children should consider several factors, including minimization of inhibitor development risk, maintaining tolerance to FVIII, highly effective bleed prevention and treatment, safety, and impact on long-term outcomes such as bone and joint health. In this context we review the pediatric clinical data and ongoing studies with simoctocog alfa.

von Willebrand factor/factor VIII concentrate (Wilate) prophylaxis in children and adults with von Willebrand disease.

ABSTRACT: Long-term prophylaxis with a von Willebrand factor (VWF) concentrate is recommended in patients with von Willebrand disease (VWD) who have a history of severe and frequent bleeds. However, data from prospective studies are scarce. WIL-31, a prospective, noncontrolled, international phase 3 trial, investigated the efficacy and safety of Wilate prophylaxis in severe patients with VWD. Male and female patients 6 years or older with VWD types 1, 2 (except 2N), or 3 who had completed a prospective, 6-month, on-demand, run-in study (WIL-29) were eligible to receive Wilate prophylaxis for 12 months. At baseline, patients (n = 33) had a median age of 18 years. Six (18%) patients had severe type 1, 5 (15%) had type 2, and 22 (67%) had type 3 VWD. The primary end point of a >50% reduction in mean total annualized bleeding rate (TABR) with Wilate prophylaxis vs prior on-demand treatment was met; mean TABR during prophylaxis was 5.2, representing an 84.4% reduction. The bleeding reduction was consistent across age, sex, and VWD types. The mean spontaneous ABR was 3.2, representing an 86.9% reduction vs on-demand treatment. During prophylaxis, 10 (30.3%) patients had 0 bleeding events and 15 (45.5%) patients had 0 spontaneous bleeding events. Of 173 BEs, 84.4% were minor and 69.9% treated. No serious adverse events related to study treatment and no thrombotic events were recorded. Overall, WIL-31 showed that Wilate prophylaxis was efficacious and well-tolerated in pediatric and adult patients with VWD of all types. The WIL-29 and WIL-31 trials were registered at www.ClinicalTrials.gov as #NCT04053699 and #NCT04052698, respectively.

Safety, pharmacokinetics and efficacy of a subcutaneous recombinant FVIII (OCTA101) in adult patients with severe haemophilia A.

INTRODUCTION: Regular, prophylactic intravenous (i.v.) FVIII can be challenging for some patients with haemophilia A. Subcutaneous (s.c.) FVIII administration could provide an alternative treatment option with greater convenience and without the complications associated with venous access. AIM: To assess the safety, pharmacokinetics (PK), bioavailability and efficacy of s.c. OCTA101, a recombinant FVIII with a recombinant von Willebrand factor fragment dimer. METHODS: This was a single-centre, prospective, open-label, phase I/II study (NCT04046848). Previously treated male patients (≥18 years) with severe haemophilia A were eligible for the study. The primary objective of the study was to assess the safety (including immunogenicity) of OCTA101. Secondary objectives included assessments of PK, bioavailability, and the efficacy of prophylaxis. RESULTS: Thirty patients were treated with OCTA101. FVIII inhibitors developed in five (16.7%) patients during daily prophylaxis with 40-60 IU/kg (three cases) and 12.5 IU/kg (two cases) OCTA101. The trial was therefore terminated. OCTA101 had a 2.5-fold longer terminal half-life compared with i.v. rFVIII, and bioavailability was 16.6%. Efficacy data at study termination indicated that daily prophylaxis with 40-60 IU/kg OCTA101 was efficacious in the absence of FVIII inhibitors. CONCLUSIONS: Despite promising PK and efficacy results, the trial was terminated due to the incidence of FVIII inhibitors. The occurrence of inhibitors at two dose levels suggests that their development may be related to the subcutaneous route of administration.

Comparison of coagulation parameters associated with fibrinogen concentrate and cryoprecipitate for treatment of bleeding in patients undergoing cytoreductive surgery for pseudomyxoma peritonei: Subanalysis from a randomized, controlled phase 2 study.

Background and Aims: The FORMA-05 study compared the efficacy and safety of human fibrinogen concentrate (HFC) versus cryoprecipitate for hemostasis in bleeding patients undergoing cytoreductive surgery for pseudomyxoma peritonei (PMP). This subanalysis explores coagulation parameters in the FORMA-05 patients, with a focus on the seven patients who developed thromboembolic events (TEEs). Methods: FORMA-05 was a prospective, randomized, controlled phase 2 study in which patients with predicted blood loss ≥2 L received HFC (4 g) or cryoprecipitate (two pools of five units), repeated as needed. Plasma fibrinogen, platelet count, factor (F) XIII, FVIII, von Willebrand Factor (VWF) antigen and ristocetin cofactor activity levels, EXTEM A20, FIBTEM A20, and endogenous thrombin potential (ETP) were measured perioperatively. Results: Fibrinogen, platelet count, EXTEM and FIBTEM A20, FXIII, FVIII, VWF levels, and ETP were maintained throughout surgery in both the HFC group (N = 21) and the cryoprecipitate group (N = 23). Seven TEEs were observed in the cryoprecipitate group. The two patients developing deep vein thromboses (DVT) appeared to have a procoagulant status preoperatively, with distinctively higher fibrinogen level, FIBTEM A20, and platelet levels, all of which persisted perioperatively. The five patients developing pulmonary embolism (PE) had slightly higher VWF levels preoperatively, with a disproportionate increase intraoperatively (postcryoprecipitate administration) and postoperatively. Conclusions: Patients treated with HFC versus cryoprecipitate showed broad overlaps in coagulation parameters. Patients with PE experienced a disproportionate VWF rise following cryoprecipitate administration, whereas patients developing DVT displayed a procoagulant status before and following surgery. Preoperative testing may allow these patients to be identified.

Simoctocog alfa (Nuwiq®) in previously untreated patients with severe haemophilia A-Final efficacy and safety results from the NuProtect study.

INTRODUCTION: Simoctocog alfa (Nuwiq®) is a 4th generation recombinant FVIII with proven efficacy for the prevention and treatment of bleeding episodes (BEs) in previously treated patients with severe haemophilia A. The NuProtect study assessed the immunogenicity, efficacy and safety of simoctocog alfa in 108 previously untreated patients (PUPs). The incidence of high-titre inhibitors was 16.2% and no patients with non-null F8 mutations developed inhibitors. AIM: To report the efficacy and safety results from the NuProtect study. METHODS: PUPs received simoctocog alfa for prophylaxis, treatment of BEs, or as surgical prophylaxis. The efficacy of prophylaxis (during inhibitor-free periods) was assessed using annualised bleeding rates (ABRs). The efficacy in treating BEs and in surgical prophylaxis was assessed using a 4-point scale. Adverse events were recorded throughout the study. RESULTS: Of 108 PUPs treated with simoctocog alfa, 103 received at least one prophylactic dose and 50 received continuous prophylaxis for at least 24 weeks. In patients on continuous prophylaxis, the median ABR was 0 (mean 0.5) for spontaneous BEs and 2.5 (mean 3.6) for all BEs. In 85 patients who had BEs, efficacy of BE treatment was excellent or good for 92.9% (747/804) of rated BEs; 92.3% of BEs were treated with 1 or 2 infusions. The efficacy of surgical prophylaxis was excellent or good for 94.7% (18/19) of rated procedures. There were no safety concerns and no thromboembolic events. CONCLUSION: Simoctocog alfa was efficacious and well tolerated as prophylaxis, surgical prophylaxis and for the treatment of BEs in PUPs with severe haemophilia A.

Analysis of fibrinogen concentrate pharmacokinetics and dosing for bleeds and surgery in adults, adolescents, and children with congenital afibrinogenaemia and hypofibrinogenaemia.

INTRODUCTION: Congenital afibrinogenaemia and hypofibrinogenaemia are rare coagulation disorders where clotting is impaired due to a lack of fibrinogen. Consequent bleeding episodes (BEs) are treated using human fibrinogen concentrate (HFC). AIM: This post-hoc analysis compared HFC pharmacokinetics (PK) and dosing between patient age groups and defined the in vivo recovery (IVR) for children with a- and hypofibrinogenaemia. METHODS: The analysis used data from the FORMA-01 (Phase 2), FORMA-02 and FORMA-04 (Phase 3) multinational, prospective, open-label studies in patients with a- and hypofibrinogenaemia. HFC PK in adults/adolescents (≥12 years; FORMA-01) and children (<12 years; FORMA-04) was examined. Haemostatic efficacy in BE treatment and perioperative prophylaxis was examined in FORMA-02 and FORMA-04 using an objective 4-point scale, with success defined as excellent/good. RESULTS: Median (range) age was 23 years for FORMA-01 (12-53; n = 22), 26.5 years for FORMA-02 (12-54; n = 25), and 6 years for FORMA-04 (1-10; n = 13). Mean PK parameters were lower for children (AUC, Cmax , IVR; p = .02), while clearance was higher. Median (range) total dose of HFC for all BEs was 59.41 mg/kg (32.12-273.80) in adults/adolescents and was 24% higher (ns) in children at 73.91 mg/kg (47.45-262.50). Treatment was successful in 98.9% of the 89 BEs in adults/adolescents and in 100% of the 10 BEs in children, with comparable results for perioperative prophylaxis. CONCLUSION: As expected, HFC PK differed between adults/adolescents and children. However, with the higher doses given to children, HFC showed similar efficacy across age groups. Dose adaptation based on age groups appears recommendable.

Immune Tolerance Induction (ITI) with a pdFVIII/VWF Concentrate (octanate) in 100 Patients in the Observational ITI (ObsITI) Study.

Background Immune tolerance induction (ITI) with repeated factor VIII (FVIII) administration is the only strategy proven to eradicate inhibitors. The observational ITI study is evaluating ITI with a range of FVIII products. Methods This subgroup analysis reports prospective interim data for patients treated with a plasma-derived, von Willebrand factor-stabilized FVIII concentrate (pdFVIII/VWF, octanate). Complete success (CS) of ITI required achievement of three criteria: inhibitor titer < 0.6 BU/mL; FVIII recovery ≥ 66%; FVIII half-life ≥6 hours. Partial success (PS) required achievement of two criteria and partial response (PR) one. ITI success was defined as CS or PS. Data were analyzed for patients who achieved CS, had 36 months' observation, or failed ITI. Results One-hundred prospectively enrolled patients were included in the analysis; 91 had poor prognosis factors for ITI success. The mean (standard deviation) daily ITI dose was 116.4 (61.1) IU FVIII/kg in 14 low responders (< 5 BU/mL) and 173.7 (112.0) IU FVIII/kg in 86 high responders (≥ 5 BU/mL). Inhibitor titers < 0.6 BU/mL were achieved in 71% of patients in a median of 4.01 months, accompanied by a 93% reduction in bleeding rate. ITI success was achieved by 70% of patients and 56 of 72 (78%) primary (first-line) ITI patients. PR was achieved by 5 patients; ITI failed in 25 patients. PS and CS were achieved in a median of 5.55 and 11.25 months, respectively. Conclusions ITI with pdFVIII/VWF led to rapid eradication of FVIII inhibitors, normalization of FVIII pharmacokinetics in the majority of patients, and a significant reduction in bleeding rates.

Simoctocog Alfa (Nuwiq) in Previously Untreated Patients with Severe Haemophilia A: Final Results of the NuProtect Study.

INTRODUCTION: FVIII inhibitor development is the most serious contemporary treatment complication in haemophilia A, particularly in previously untreated patients (PUPs). No inhibitors developed in clinical trials in previously treated patients treated with simoctocog alfa (Nuwiq), a fourth-generation recombinant FVIII produced in a human cell line. METHODS: The NuProtect study investigated the immunogenicity of simoctocog alfa in PUPs. NuProtect was a prospective, multinational, open-label, non-controlled, phase III study. PUPs with severe haemophilia A (FVIII:C <1%) of any age and ethnicity were treated with simoctocog alfa for 100 exposure days or a maximum of 5 years. Patients were true PUPs without prior exposure to FVIII concentrates or blood components. Inhibitor titres were measured with the Nijmegen-modified Bethesda assay; cut-off for positivity was 0.6 BU mL-1 (≥0.6 to <5 low-titre, ≥5 high titre). RESULTS: A total of 108 PUPs with a median age at first treatment of 12.0 months (interquartile range: 8.0-23.5) were treated with simoctocog alfa. F8 mutation type was known for 102 patients (94.4%) of whom 90 (88.2%) had null F8 mutations and 12 (11.8%) had non-null mutations. Of 105 PUPs evaluable for inhibitor development, 28 (26.7%) developed inhibitors; 17 high titre (16.2%) and 11 low titre (10.5%). No PUPs with non-null F8 mutations developed inhibitors. CONCLUSION: In the NuProtect study, the rate of inhibitor development in PUPs with severe haemophilia A treated with simoctocog alfa was lower than the rate reported for hamster-cell-derived recombinant factor VIII products in other recent clinical trials. No inhibitors were reported in PUPs with non-null F8 mutations.

Efficacy and safety of fibrinogen concentrate for on-demand treatment of bleeding and surgical prophylaxis in paediatric patients with congenital fibrinogen deficiency.

BACKGROUND: Congenital fibrinogen deficiency (CFD) is a rare, inherited disorder affecting normal blood clotting function, where patients can experience severe and/or frequent bleeding episodes (BEs). Treatment with human fibrinogen concentrate (HFC) can prevent/arrest bleeding. There is a need for more data on the efficacy, pharmacokinetics (PK) and safety of HFC treatment in paediatric patients with CFD. METHODS: Haemostatic efficacy of HFC (Fibryga® , Octapharma AG) for on-demand treatment of bleeding and surgical prophylaxis in patients <12 years old was assessed by investigators and an Independent Data Monitoring and Endpoint Adjudication Committee (IDMEAC) based on an objective 4-point efficacy scale. Maximum clot firmness (MCF; surrogate marker of haemostatic efficacy), single-dose PK and safety were also assessed. RESULTS: Of 14 patients receiving HFC (median [range] age 6.0 years [1.0-10.0]), eight received HFC for 10 BEs, three for surgical prophylaxis and 13 for PK. The IDMEAC rated haemostatic efficacy as 100% successful for on-demand BE treatment (95% CI 69.15-100.00) and surgical prophylaxis (95% CI 29.24-100.00). After a mean first dose of 70.78 mg/kg for BEs, mean (±SD) MCF significantly increased from pre-treatment to 1-hour post-infusion (3.3 mm [±1.77]; P = 0.0002), coinciding with haemostatic efficacy. PK parameters were favourable. Two possibly related adverse events occurred, including one serious (portal vein thrombosis). No allergic/hypersensitivity reactions or deaths were observed. CONCLUSION: HFC treatment for on-demand treatment of BEs and surgical prophylaxis was efficacious for this ultra-rare paediatric population with congenital afibrinogenaemia and showed a favourable PK and safety profile.

Efficacy of fibrinogen concentrate in major abdominal surgery - A prospective, randomized, controlled study in cytoreductive surgery for pseudomyxoma peritonei.

BACKGROUND: Cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei (PMP) is associated with excessive bleeding and acquired fibrinogen deficiency. Maintaining plasma fibrinogen may support hemostasis. OBJECTIVES: To compare hemostatic efficacy and safety of human fibrinogen concentrate (HFC) vs cryoprecipitate as fibrinogen sources for bleeding patients with acquired fibrinogen deficiency undergoing PMP CRS. METHODS: FORMA-05 was an off-label single-center, prospective, randomized, controlled phase 2 study. Patients undergoing PMP surgery with predicted intraoperative blood loss ≥2 L received human fibrinogen concentrate (HFC; 4 g) or cryoprecipitate (two pools of 5 units, containing approximately 4.0-4.6 g fibrinogen), repeated as needed. The primary endpoint was a composite of intraoperative and postoperative efficacy, graded using objective 4-point scales and adjudicated by an independent committee. RESULTS: One hundred percent of patients receiving HFC (95% confidence interval: 83.9-100.0, n = 21) or cryoprecipitate (84.6-100.0, n = 22) achieved hemostatic success. HFC demonstrated noninferior efficacy (P = .0095; post hoc) and arrived in the operating room 46 minutes faster. There were significantly greater mean increases with HFC vs cryoprecipitate in plasma fibrinogen (0.78 vs 0.35 g/L; P < .0001) and FIBTEM A20 (3.33 vs 0.93 mm; P = .003). Factor XIII, factor VIII, and von Willebrand factor activity were maintained throughout surgery. Only red blood cells were transfused intraoperatively (median units: HFC group, 1.0; cryoprecipitate group, 0.5). Thromboembolic events were detected with cryoprecipitate only. Safety was otherwise comparable between groups. CONCLUSIONS: Human fibrinogen concentrate was hemostatically efficacious in patients undergoing major abdominal PMP surgery, with a favorable safety profile. These results are relevant to other surgical settings where bleeding and acquired fibrinogen deficiency occur.

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients.

BACKGROUND: Congenital fibrinogen deficiency is an ultra-rare disorder in which patients can experience severe and/or frequent bleeding episodes (BEs). Here, we present the largest prospective study to date on the treatment of this disorder. METHODS: Hemostatic efficacy of human fibrinogen concentrate (HFC; FIBRYGA® , Octapharma AG) for treatment of bleeding or surgical prophylaxis was assessed by investigators and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) according to a four-point scale, using objective criteria. Thromboelastometry maximum clot firmness (MCF) was also determined. RESULTS: Twenty-five afibrinogenemia patients were treated with HFC: 24 for on-demand treatment of 89 BEs, and nine as prophylaxis for 12 surgeries. For BEs, treatment success (rating of excellent or good) evaluated by investigators was 96.6% (90% confidence interval [CI], 0.92-0.99; two missing ratings, classified as failures) and by the IDMEAC was 98.9% (90% CI, 0.95-0.999). Mean ± standard deviation (SD) increase in MCF was 5.8 ± 2.5 mm one hour after the first HFC infusion (mean ± SD dose, 61.88 ± 11.73 mg/kg). For the 12 surgeries (median [range] HFC dose/surgery, 85.80 mg/kg [34.09-225.36]), intraoperative and postoperative treatment success were both rated 100% (90% CI, 0.82-1.00) by investigators and the IDMEAC. Three adverse events were possibly treatment related, including a moderate case of thrombosis. There were no deaths, no severe allergic or hypersensitivity reactions, and no clinical evidence of neutralizing antifibrinogen antibodies. CONCLUSIONS: Human fibrinogen concentrate was efficacious for on-demand treatment of bleeding and as surgical prophylaxis, with a favorable safety profile, in patients with congenital afibrinogenemia.

Efficacy and safety of simoctocog alfa (Nuwiq®) in patients with severe hemophilia A: a review of clinical trial data from the GENA program.

Simoctocog alfa (human-cl rhFVIII, Nuwiq®) is a 4th generation recombinant FVIII (rFVIII), without chemical modification or fusion with any other protein/fragment. Nuwiq® is produced in a human embryonic kidney cell line (HEK293F), which ensures human-specific post-translational protein processing. Nuwiq® was evaluated in seven prospective clinical studies in 201 adult and pediatric previously treated patients (PTPs) with severe hemophilia A. The NuProtect study in 110 previously untreated patients (PUPs) is ongoing. The mean half-life of Nuwiq® was 15.1-17.1 h in PTP studies with adults and adolescents, and 12.5 h in children aged 2-12 years. Clinical trials in PTPs demonstrated the efficacy and safety of Nuwiq® in the prevention and treatment of bleeds and as surgical prophylaxis. In the NuPreviq study of pharmacokinetic (PK)-guided personalized prophylaxis in 66 adult PTPs, 83% of patients had no spontaneous bleeds during 6 months of personalized prophylaxis and 57% were treated ⩽2 per week. No FVIII inhibitors were detected in PTPs after treatment with 43,267 injections and >80 million IU of Nuwiq®. Interim data for 66 PUPs with ⩾20 exposure days to Nuwiq® in NuProtect demonstrated a low cumulative high-titer inhibitor rate of 12.8% [actual incidence 12.1% (8/66)] and convincing efficacy and safety.

Efficacy and safety of a new human fibrinogen concentrate in patients with congenital fibrinogen deficiency: an interim analysis of a Phase III trial.

BACKGROUND: Fibrinogen concentrate is the preferred choice for fibrinogen replacement in congenital fibrinogen deficiency. This study investigated hemostatic efficacy of a new plasma-derived, double virus-inactivated (using two dedicated virus inactivation/elimination steps) human fibrinogen concentrate for on-demand treatment of bleeding episodes (BEs) and surgical prophylaxis. STUDY DESIGN AND METHODS: In this planned interim analysis of a prospective, multinational Phase III study (NCT02267226), 13 patients with afibrinogenemia (≥12 years) received fibrinogen concentrate (FIBRYGA, Octapharma AG). Hemostatic efficacy was assessed by investigators and an independent data monitoring and endpoint adjudication committee (IDMEAC) using objective four-point criteria and by thromboelastometry maximum clot firmness (MCF). RESULTS: Fibrinogen concentrate was used on-demand to treat 23 BEs in 11 patients, with 21 (91.3%) requiring a single infusion only. Treatment success was 95.7% (90% confidence interval [CI], 0.81-1.00; assessment missing for one BE) by investigators and 100% (90% CI, 0.88-1.00) by IDMEAC. Mean MCF increased significantly from 0.0 to 6.5 mm (95% CI, 5.65-7.40; p < 0.0001) at 1 hour postinfusion of a median (range) dose of 58.8 (33.9-101.7) mg/kg per BE. Four patients received fibrinogen concentrate as surgical prophylaxis, with intraoperative and postoperative treatment success rated 100% (90% CI, 0.50-1.00) by investigators and IDMEAC (median [range] dose per surgery 93.5 [34.1-225.4] mg/kg). No additional hemostatic interventions were required. No deaths, thromboses, or seroconversions were reported. CONCLUSION: These data showed that the new fibrinogen concentrate was efficacious for on-demand treatment of acute bleeding and surgical prophylaxis in congenital afibrinogenemia patients.

The first recombinant human coagulation factor VIII of human origin: human cell line and manufacturing characteristics.

INTRODUCTION: Since the early 1990s, recombinant human clotting factor VIII (rhFVIII) produced in hamster cells has been available for haemophilia A treatment. However, the post-translational modifications of these proteins are not identical to those of native human FVIII, which may lead to immunogenic reactions and the development of inhibitors against rhFVIII. For the first time, rhFVIII produced in a human host cell line is available. AIM: We describe here the establishment of the first human production cell line for rhFVIII and the manufacturing process of this novel product. METHODS AND RESULTS: A human cell line expressing rhFVIII was derived from human embryonic kidney (HEK) 293 F cells transfected with an FVIII expression plasmid. No virus or virus-like particles could be detected following extensive testing. The stringently controlled production process is completely free from added materials of animal or human origin. Multistep purification employing a combination of filtration and chromatography steps ensures the efficient removal of impurities. Solvent/detergent treatment and a 20 nm pore size nanofiltration step, used for the first time in rhFVIII manufacturing, efficiently eliminate any hypothetically present viruses. In contrast to hamster cell-derived products, this rhFVIII product does not contain hamster-like epitopes, which might be expected to be immunogenic. CONCLUSIONS: HEK 293 F cells, whose parental cell line HEK 293 has been used by researchers for decades, are a suitable production cell line for rhFVIII and will help avoid immunogenic epitopes. A modern manufacturing process has been developed to ensure the highest level of purity and pathogen safety.

Use of objective efficacy criteria for evaluation of von Willebrand factor/factor VIII concentrates.

von Willebrand disease (VWD) is the most common inherited coagulation disorder and is typically treated by restoring the deficient von Willebrand factor (VWF) with exogenous VWF or by stimulating release of endogenous VWF with desmopressin. Assessment of treatment efficacy is complex because there are no standardized criteria or consistent methodology in their application. The traditionally used four-point Likert scale, with criteria that are not clearly defined or easily quantifiable, relies on a subjective rating of efficacy, and is thus open to observer bias. This article presents a novel approach to assessing efficacy of VWF replacement therapy. A new objective scoring system for assessment of the treatment efficacy of bleeding episodes (objective set of criteria for evaluation of treatment efficacy in VWD) was developed to assess a new-generation human plasma-derived VWF/coagulation factor VIII concentrate (Wilate). This manuscript analyzes the results obtained using a traditional subjective scoring system for hemostatic efficacy and compares them with results obtained when a specifically developed set of stringent objective and well defined success/failure criteria are applied in a clinical trial setting. This new assessment tool provided improved objectification of the subjective judgments obtained from the recipients of the replacement therapy. A validated tool like this could ultimately be applied to clinical comparability studies for the multiplicity of new generation replacement products, as healthcare providers, regulatory agencies, and manufacturers must now consider the additional benefits conveyed by treatment modalities, such as treatment duration, alternative dosing regimens, and treatment frequency. The objective criteria appear to be more robust and present a more conservative assessment of treatment efficacy while avoiding observer and recipient bias and inconsistencies. This new approach may be a more suitable alternative for hemostatic assessment of coagulation products in VWD patients than the currently used subjective methods.

A retrospective study of Octaplex in the treatment of bleeding in patients with haemophilia A complicated by inhibitors.

The nonactivated prothrombin complex concentrate (PCC) Octaplex (Octapharma PPGmbH, Vienna, Austria) has been used successfully for the treatment of congenital and acquired coagulation factor deficiencies and associated bleeding. The aims of this study were to assess retrospectively whether Octaplex is an effective treatment option for haemophilia A patients with high-titre inhibitors of factor VIII (FVIII) and to investigate the impact of Octaplex on thrombin generation in vitro and ex vivo. Retrospective data were collected from 15 haemophilia A patients with FVIII inhibitors who had been treated with Octaplex. Mild bleeds were treated for a median of 1 day with a median dose of 77 IU/kg and moderate bleeds for 3 days with 57 IU/kg. The physician's overall satisfaction with Octaplex, taking into account efficacy, safety and cost in comparison with other treatment options, was assessed for each bleed. The overall rating was good, very good or excellent for 29 of 41 (71%) bleeds. No adverse drug reactions were reported. In in-vitro studies of thrombin generation with normal plasma samples, experimental inhibition of FVIII activity prolonged the lag phase, diminished the peak thrombin concentration and decreased the area under the concentration-time curve, as expected. Marked improvement in thrombin generation parameters was achieved by adding 0.5-3 IU factor IX/ml PCC into the samples. The same held true when using plasma samples from haemophilia A patients with FVIII inhibitors. These results demonstrate that Octaplex overcomes inhibition of FVIII in in-vitro and ex-vivo assays of thrombin generation, and that Octaplex is an effective treatment option for haemophilia A patients with FVIII inhibitors.

Impact of infusion speed on the safety and effectiveness of prothrombin complex concentrate: a prospective clinical trial of emergency anticoagulation reversal.

Prothrombin complex concentrate (PCC) infusion is preferred for emergency reversal of coumarin therapy. Rapid infusion can potentially save crucial time; however, the possible impact of high infusion speed on PCC safety and effectiveness has not been delineated. In a prospective multinational clinical trial with 43 patients receiving PCC (Beriplex P/N) for emergency reversal of coumarin therapy, infusion speeds were selected by the investigators. In a two-phase statistical analysis, the influence of baseline patient variables and dose on selected infusion speed was assessed. Then, the effect of infusion speed on reduction in international normalized ratio (INR) and on thrombogenicity marker pharmacokinetics was evaluated. Infusion speed ranged widely from 2.0 to 40.0 mL min(-1) with a median of 7.5 mL min(-1). Selection of infusion speed was not significantly influenced by gender, age, body mass index, presence of acute bleeding, indication for coumarin therapy, baseline INR, or PCC dose. Infusion speed was higher by a median of 2.2 mL min(-1) (95% confidence interval, 1.0-4.3 mL min(-1)) among patients receiving Beriplex P/N volumes > or =80 mL compared with smaller infusion volumes. Infusion speed did not affect INR attained 30 min following PCC infusion. None of the evaluated thrombogenicity marker pharmacokinetic parameters was affected by infusion speed. Infusions in one patient with questionable hemostatic efficacy and another with a possibly PCC-related thromboembolic event were at moderate and slow speeds, respectively. This study provides the first direct evidence that Beriplex P/N can be rapidly infused for emergency coumarin therapy reversal without altering safety or effectiveness.

Rotational thromboelastography for monitoring of fibrinogen concentrate therapy in fibrinogen deficiency.

To characterize a functional assay for circulating fibrinogen based on rotational thrombelastography. Maximum clot firmness was determined by rotational thrombelastography in normal human plasma pool, fibrinogen-deficient plasma pool, normal whole blood, and individual plasma samples from 17 patients with fibrinogen deficiency. Plasma samples spiked with varying concentrations of exogenous fibrinogen were also measured. Results were compared with enzyme-linked immunosorbent assay and Clauss assay. The impact of sample freezing and filtration and use of cytochalasin D were also investigated. Over the tested range of 0-3 mg/ml added exogenous fibrinogen, the maximum clot firmness standard curve for determination of fibrinogen in plasma pools (n = 7) was linear (r2 = 0.97). Maximum clot firmness was highly linearly correlated both with Clauss assay (r2 = 0.93) and enzyme-linked immunosorbent assay (r2 = 0.95). In unspiked plasma samples from individual patients with fibrinogen deficiency, fibrinogen was undetectable by rotational thromboelastography. By all evaluated methods, the response to spiking with fibrinogen in such samples coincided closely in patients with afibrinogenemia and hypofibrinogenemia. In dysfibrinogenemia, smaller Clauss assay responses to spiking were observed, whereas the enzyme-linked immunosorbent assay response was variable. Maximum clot firmness was the only evaluated method of fibrinogen assessment to yield consistent results across all categories of fibrinogen deficiency. These in-vitro results suggest the potential clinical utility of rotational thromboelastography as a versatile method for monitoring the response to fibrinogen concentrate among patients with fibrinogen deficiency. Clinical investigations using rotational thromboelastography after in-vivo fibrinogen administration to patients with congenital fibrinogen deficiency are warranted.

A systematic overview of the first pasteurised VWF/FVIII medicinal product, Haemate P/ Humate -P: history and clinical performance.

Patients with von Willebrand disease (VWD) and haemophilia A (HA) lack, to varying degrees, the von Willebrand factor (VWF) and coagulation factor VIII (FVIII) that are critical for normal haemostasis. These conditions in turn make patients prone to uncontrolled bleeding. Historically, patients with severe forms of VWD or HA were crippled before adulthood and their life expectancy was significantly reduced. Over the past decades, specific coagulation factor replacement therapies including Haemate P, have been developed to help patients achieve and maintain normal haemostasis. Haemate P is a human, plasma-derived VWF/FVIII medicinal product, which was first licensed in Germany in 1981 for the treatment of HA-associated bleeding. It has since then come to be accepted as the gold standard for both the treatment and prophylaxis of bleeding in VWD, especially in cases where desmopressin [1-deamino-8-D-arginine vasopressin (DDAVP)] has been ineffective. Haemate P was the first effectively virus-inactivated (pasteurisation: 60 degrees C for 10 h in aqueous solution) FVIII product, whereby the risk of potentially threatening infective complications of plasma-derived products was reduced. Haemate P was also shown to have a VWF multimer profile remarkably close to that of normal plasma. This bibliographic review presents previously unpublished clinical data of Haemate P, based upon internal clinical study reports of the proprietor, CSL Behring, in addition to data already presented in other publications. The data demonstrate a predictable and well-characterised pharmacokinetic profile, and a proven record of short- and long-term safety, while effectively correcting the haemostatic defects in VWD and HA. Recently available data have also shown Haemate P to be of haemostatic value in exceptional clinical circumstances including surgical interventions. By virtue of its plasma-derived combination of VWF and FVIII, in addition to its high VWF:FVIII content ratio (2.4:1), Haemate P is also associated with successful immune tolerance induction in those patients developing inhibitor antibodies. Although the theoretical risk of thromboembolic complications does exist while receiving Haemate P, as it does with any FVIII replacement therapy, the incidence of such complications has remained notably low. Given the robust data that have accumulated for the use of Haemate P, dosing recommendations are also described in this review; the recommendations are tailored to patient-specific contexts including baseline VWF and FVIII levels in plasma and the type of surgical intervention being undertaken. A wide variety of studies have also provided data on paediatric and geriatric populations, all of which have suggested that Haemate P can be safely and effectively used in a wide variety of clinical circumstances.

Pharmacokinetics of Beriplex P/N prothrombin complex concentrate in healthy volunteers.

Prothrombin complex concentrates (PCCs) are widely administered for emergency oral anticoagulation reversal and for coagulation defects in liver disease. Pharmacokinetic data may help to optimize treatment. The objective of this study was to characterize the pharmacokinetics of a PCC (Beriplex P/N) containing coagulation factors II (FII), VII (FVII), IX (FIX) and X (FX) and anticoagulant proteins C and S. Fifteen healthy volunteers received a single rapid 50 IU/kg infusion of PCC and underwent frequent blood sampling until 144 hours (h) after infusion. Coagulation factors and anticoagulant protein pharmacokinetic parameters were estimated by non-linear regression. The mean infusion rate of PCC was 7.9 ml/min, equivalent to 196.4 IU/min. By the earliest post-infusion sampling point at 5 minutes (min), plasma FIX concentration increased by a median of 73%. Median increases in FII, FVII and FX at 5 min were 122%, 62% and 158%, respectively. Proteins C and S also increased rapidly. The median terminal half-life of FIX was 16.7 h, FII 59.7 h, FVII 4.2 h and FX 30.7 h. The median in-vivo recovery of FIX was 1.57 %/IU/kg and that of the other three coagulation factors > 2 %/IU/kg. Plasma concentration of thrombogenicity marker D-dimer did not increase, and there was no clinical evidence of thrombosis. Through up to 12 weeks follow-up there were no laboratory findings indicating PCC-related viral exposure. Rapid PCC infusion produced prompt sustained increases in coagulation factors and anticoagulant proteins with no clinical evidence of thrombosis or viral transmission.