Long-term tolerability, immunogenicity and efficacy of Nuwiq® (human-cl rhFVIII) in children with severe haemophilia A.

INTRODUCTION: Nuwiq® (human-cl rhFVIII, simoctocog alfa) is a 4th generation recombinant human FVIII, without chemical modification or fusion with any other protein, produced in a human cell line. AIM/METHODS: This study (GENA-13) was an extension of the GENA-03 study in which previously treated children aged 2-12 years with severe haemophilia A received Nuwiq® prophylaxis for ≥6 months. GENA-13 examined long-term tolerability, immunogenicity and efficacy of Nuwiq® prophylaxis in children. RESULTS: Of 59 patients enrolled in GENA-03, 49 continued Nuwiq® prophylaxis in GENA-13 for a median (range) of 30.0 (9.5-52.0) months. No patient withdrew due to drug-related adverse events or developed inhibitors. Only 2 of 20 518 infusions were associated with possibly related adverse events (dyspnoea, fever). The estimated annualized bleeding rate (ABR) was 0.67 (95% CI: 0.44, 1.02) for spontaneous and 2.88 (95% CI: 1.86, 4.46) for all bleeds. Younger children (2-5 years) had lower ABRs than children aged 6-12 years. Annualized bleeding rates were reduced in GENA-13 vs GENA-03, especially for spontaneous bleeds in younger children (71% reduction; ABR ratio 0.29 [95% CI: 0.11, 0.74]). Nuwiq® efficacy was rated as excellent/good in the treatment of 83.0% of 305 evaluated breakthrough bleeds. Surgical prophylaxis with Nuwiq® was rated as excellent for all 17 assessed procedures. CONCLUSION: Long-term treatment with Nuwiq® for the prevention of bleeds in children with severe haemophilia A was well tolerated, effective and reduced spontaneous bleeding by up to 70% compared with GENA-03.

Low incidence of factor VIII inhibitors in previously untreated patients with severe haemophilia A treated with octanate® : Final report from a prospective study.

INTRODUCTION: Octanate® is a human, plasma-derived, von Willebrand factor-stabilized coagulation factor VIII (FVIII) concentrate with demonstrated haemostatic efficacy in previously treated patients with haemophilia A. AIM: This prospective, open-label study aimed to assess the immunogenicity of octanate® in previously untreated patients (PUPs). METHODS: The study monitored development of FVIII inhibitors in 51 PUPs. Tolerability, viral safety, FVIII recovery and efficacy of octanate® for the prevention and treatment of bleeds and in surgical procedures were also assessed. RESULTS: Five (9.8%) of the 51 patients developed inhibitors during the study, 4 of which (7.8%) were high titre. Three inhibitor cases (5.9%) were considered clinically relevant; 2 were transient inhibitors that disappeared during regular octanate® treatment without a change in dose or treatment frequency. Amongst 45 patients with FVIII:C <1% at baseline and who received ≥20 exposure days (EDs) or had <20 EDs but developed an inhibitor, inhibitor incidence was 11.1% (6.7% clinically relevant). All clinically relevant inhibitors developed within 20 EDs of on-demand treatment. No inhibitors developed in PUPs receiving prophylaxis. All patients who developed inhibitors had either intron 22 inversions or large deletions. Irrespective of the reason for administration, haemostatic efficacy was rated as "excellent" in 99.6% of all infusions (4700 of 4717 infusions), and no complications were reported in 23 surgical procedures. Mean incremental in vivo recovery was 2.0%/IU/kg (±0.7) and 1.9%/IU/kg (±0.5) for the first and second assessments, respectively. Tolerability was rated "very good" in 99.9% of infusions. CONCLUSION: In PUPs with severe haemophilia A, octanate® demonstrated haemostatic efficacy with a low rate of inhibitor development.

Immunogenicity, efficacy and safety of Nuwiq® (human-cl rhFVIII) in previously untreated patients with severe haemophilia A-Interim results from the NuProtect Study.

INTRODUCTION: Nuwiq® (Human-cl rhFVIII) is a fourth generation recombinant FVIII, produced in a human cell line, without chemical modification or protein fusion. No inhibitors developed in studies with Nuwiq® in 201 previously treated patients with haemophilia A (HA). The immunogenicity, efficacy and safety of Nuwiq® in previously untreated patients (PUPs) with severe HA are being assessed in the ongoing NuProtect study. METHODS: The study, conducted across 38 centres worldwide, is evaluating 110 true PUPs of all ages and ethnicities enrolled for study up to 100 exposure days (EDs) or 5 years maximum. The primary objective is to assess the immunogenicity of Nuwiq® (inhibitor activity ≥0.6 BU) using the Nijmegen-modified Bethesda assay at a central laboratory. RESULTS: Data for 66 PUPs with ≥20 EDs from a preplanned interim analysis were analysed. High-titre (HT) inhibitors developed in 8 of 66 patients after a median of 11.5 EDs (range 6-24). Five patients developed low-titre inhibitors (4 transient). The cumulative incidence (95% confidence interval) was 12.8% (4.5%, 21.2%) for HT inhibitors and 20.8% (10.7%, 31.0%) for all inhibitors. During inhibitor-free periods, median annualized bleeding rates during prophylaxis were 0 for spontaneous bleeds and 2.40 for all bleeds. Efficacy was rated as "excellent" or "good" in treating 91.8% of bleeds. Efficacy of surgical prophylaxis was "excellent" or "good" for 8 (89%) procedures and "moderate" for 1 (11%). No tolerability concerns were evident. CONCLUSION: These interim data show a cumulative incidence of 12.8% for HT inhibitors and convincing efficacy and tolerability in PUPs treated with Nuwiq® .

Efficacy and safety of Nuwiq® (human-cl rhFVIII) in patients with severe haemophilia A undergoing surgical procedures.

INTRODUCTION: Haemophilia A patients are at a high risk of excess bleeding during surgeries. The aim of haemostatic therapy during the perioperative period is to normalize FVIII level perioperatively and postoperatively to maintain normal haemostasis until wound healing is complete. AIMS/METHODS: To examine the efficacy of Nuwiq® (simoctocog alfa, human-cl rhFVIII), a 4th generation recombinant FVIII produced in a human cell line, for surgical prophylaxis in patients with severe haemophilia A. This analysis assessed the efficacy of Nuwiq® during surgical procedures and in the postoperative period in seven clinical studies of previously treated patients (PTPs) with severe haemophilia A. RESULTS: Thirty-six patients, aged 3-55 years, received surgical prophylaxis with Nuwiq® for 60 surgeries (28 major and 32 minor). Efficacy was evaluated for 52 surgeries (25 major and 27 minor). The success rate of Nuwiq® treatment was 98.1% (51 of 52 evaluated surgeries); haemostatic efficacy was assessed as "excellent" or "good" in all but one major surgery (assessed as "moderate"). The number of infusions ranged from 1 to 19 for minor surgeries and from 3 to 76 for major surgeries. The median (range) daily doses were 42.0 (28.2-100.9) IU kg-1 for minor surgeries and 69.3 (43.3-135.6) IU kg-1 for major surgeries. There were no serious treatment-related adverse events, and none of the patients developed FVIII inhibitors. CONCLUSIONS: The results of this pooled analysis show that Nuwiq® was efficacious in maintaining haemostasis during and after major and minor surgical procedures in PTPs with severe haemophilia A.

Novel, human cell line-derived recombinant factor VIII (Human-cl rhFVIII, Nuwiq® ) in children with severe haemophilia A: efficacy, safety and pharmacokinetics.

INTRODUCTION: Nuwiq® (Human-cl rhFVIII) is a new-generation recombinant factor VIII (rFVIII) protein, without chemical modification or fusion to any other protein, produced in a human cell line. AIM/METHODS: This prospective, open-label, multinational phase III study assessed the efficacy and safety of Human-cl rhFVIII in 59 previously treated patients (PTPs) with severe haemophilia A aged 2-12 years (2-5 [N = 29]; 6-12 [N = 30]) during standard prophylaxis (≥50 exposure days and ≥6 months). Efficacy in treating breakthrough bleeds and during surgical prophylaxis was also assessed. RESULTS: An initial pharmacokinetic assessment (N = 13 per age subgroup) demonstrated comparable results with the one-stage and chromogenic assays. Mean (SD) half-life was 11.9 (5.4) and 13.1 (2.6) hours in children aged 2-5 years and 6-12 years respectively (one-stage assay). Prophylactic efficacy, based on mean monthly bleeding rate, was 'excellent' or 'good' in 91.5% of children for all bleeds and in 96.6% of children for spontaneous bleeds. Mean (SD) annualized bleeding rate was 4.12 (5.22) [median 1.9] for all bleeds, 1.50 (3.32) [median 0] for spontaneous bleeds and 2.34 (3.54) [median 1.57] for traumatic bleeds. There were no major, life-threatening bleeds. Efficacy was 'excellent' or 'good' in the treatment of 82.4% of breakthrough bleeds. Overall efficacy during five major surgeries was rated as 'excellent'. There were no FVIII inhibitors or treatment-related serious adverse events. CONCLUSION: These results in paediatric PTPs indicate that Human-cl rhFVIII is effective for the prevention and treatment of bleeds.

First prospective report on immune tolerance in poor risk haemophilia A inhibitor patients with a single factor VIII/von Willebrand factor concentrate in an observational immune tolerance induction study.

INTRODUCTION/BACKGROUND: Development of neutralizing inhibitors against factor VIII (FVIII) is a major complication of haemophilia A treatment. AIM: The ongoing, international, open-label, uncontrolled, observational immune tolerance induction (ObsITI) study evaluates ITI, the standard of care in patients with inhibitors. PATIENTS/METHODS: Forty-eight prospective patients in this interim analysis received a single plasma-derived, von Willebrand factor-stabilized, FVIII concentrate (pdFVIII/VWF) for ITI. According to recommended Bonn protocol, 'low responders' at ITI start (<5 BU) received 50-100 IU FVIII kg(-1) daily, or every other day; 'high responders' (≥5 BU) received 100 IU FVIII kg(-1) every 12 h. RESULTS: Forty of 48 patients (83.3%), had at least one risk factor for poor ITI-prognosis at ITI start (i.e. age ≥7 years, >2 years since inhibitor diagnosis, inhibitor titre ≥10 BU at the start of ITI, or prior ITI failure). Nonetheless, 34 patients (70.8%) achieved complete success, 3 (6.3%) partial success, 1 (2.1%) partial response; ITI failed in 10 patients (20.8%), all with poor prognosis factors. All six low responders achieved complete success. ITI outcome was significantly associated with inhibitor titre level at ITI start (P = 0.0068), number of poor prognosis factors for ITI success (P = 0.0187), monthly bleeding rate during ITI (P = 0.0005) and peak inhibitor titre during ITI (P = 0.0007). Twenty-two of 35 high responder patients (62.9%) with ≥1 poor prognosis factor achieved complete success. CONCLUSION: Treatment with a single pdFVIII/VWF concentrate, mainly according to the Bonn protocol, resulted in a high ITI success rate in haemophilia A patients with inhibitors and poor prognosis for ITI success.

Clinical efficacy, safety and pharmacokinetic properties of the plasma-derived factor IX concentrate Haemonine in previously treated patients with severe haemophilia B.

Plasma-derived factor IX (FIX) concentrate remains an important choice for replacement therapy in haemophilia B patients. Haemonine is a high purity double-virus inactivated human plasma-derived coagulation FIX concentrate (pdFIX). Aim was to evaluate the clinical efficacy, safety and pharmacokinetic properties of Haemonine in three prospective, open-label uncontrolled studies and a compassionate use program in previously treated patients with severe haemophilia B. Long-term efficacy and safety were investigated in 29 patients treated prophylactically and, in addition, treatment on-demand (TOD) in the case of acute haemorrhage. Pharmacokinetic properties were assessed in 14 patients at baseline and after 3 months of regular treatment. Pharmacokinetic parameters were in accordance with published data and remained nearly unchanged over time, notably recovery and half-life. Mean terminal elimination half-life was 27.6 h and 25.0 h, mean incremental recovery (IU dL(-1) /IU kg(-1)) was 1.55 and 1.60, at baseline and 3 months, respectively. Haemonine was shown to be effective in preventing and controlling bleeds. 55.2% (16/29) of patients were free of bleeds under prophylaxis. 38 haemorrhages occurred, 42% (16/38) required treatment and 87.5% (14/16) resolved after a single infusion, 12.5% after 2 infusions. All responses reported on haemorrhages were rated as 'excellent' or 'good'. Moreover, 'excellent' haemostatic efficacy was demonstrated in 12 surgeries with no complications. Few adverse events (AEs) and no thrombogenic complication, nor induction of FIX inhibitory antibodies were observed. Haemonine is effective, safe and well tolerated in long-term prophylaxis, TOD and when applied after minor and major surgeries.

Registry of inherited bleeding disorders in Poland--current status and potential role of the HemoRec database.

We present data collected in HemoRec, an Internet-based platform implemented in 2006 in 15 haemophilia treatment centres in Poland and compare them with the national registry of inherited bleeding disorders established since 1991 at the Institute of Haematology and Blood Transfusion in Warsaw. We also analyse the current status of haemophilia treatment in Poland as well as future perspectives. Data on 1102 patients registered in HemoRec were analysed and compared with 4294 patients in the national registry (status as at 17.08.2009). The number of patients with severe haemophilia, mild/moderate haemophilia and von Willebrand in HemoRec is 530, 328 and 54 (respectively), compared with 1199, 1167 and 1128 in the national registry. The mean age of all haemophilic patients registered in HemoRec is 26.2 years, compared with 37.3 years in the general Polish male population in 2008. The number of haemophilic patients with inhibitor registered in HemoRec is 102 compared with 155 in the national registry (resulting in a prevalence of 14.9% of all severe haemophilia A and 1.6% of all severe haemophilia B patients). HemoRec includes data on a representative group of Polish haemophilic patients, mostly with haemophilia and haemophilia with inhibitor. von Willebrand's disease is largely under-registered in Poland. The survival of Polish haemophilic patients is shorter than that in the general population. The number of inhibitor patients in Poland is relatively large and should be decreased by wider availability of immunotolerance induction in 2010.

Low incidence of factor VIII inhibitors in previously untreated patients during prophylaxis, on-demand treatment and surgical procedures, with Octanate®: interim report from an ongoing prospective clinical study.

For patients with haemophilia A (HA), lifelong replacement therapy with factor VIII (FVIII) concentrates is the treatment of choice. Octanate(®) is a plasma-derived, human, von Willebrand factor-stabilized FVIII product with demonstrated haemostatic efficacy in patients with HA. The aim of this ongoing study is to assess the immunogenicity of Octanate(®) in previously untreated patients (PUPs), monitoring for development of FVIII inhibitors. Interim data on 39 PUPs treated for bleeding, prophylactically and for surgical coverage are reported. Two of 39 subjects (5.1%) developed clinically relevant inhibitor titres over the course of the study. Another two displayed inhibitors that disappeared spontaneously without Octanate(®) dose change. All inhibitors developed under on-demand treatment and before exposure day (ED) 50. Remarkably, no inhibitor was observed in PUPs receiving prophylaxis with Octanate(®). Of 39 subjects, 30 had exceeded 50 EDs at the time of this analysis. All inhibitor subjects were found to have large FVIII gene defects, either intron 22-inversions or large deletions. Octanate(®) was well-tolerated and the adverse event profile was consistent with the population studied. The haemostatic efficacy of Octanate(®) in prophylaxis and treatment of bleeding were generally rated as 'excellent', and no complication was reported for surgery. Notable FVIII activity was present in blood at 15 min postadministration, and levels remained high at 1 h. Mean incremental in vivo recovery (IVR) was 2.0 (± 0.6) % IU(-1) kg(-1) . These interim results indicate Octanate(®) to be an efficacious, well-tolerated human FVIII product for management of HA in PUPs, associated with a minimal risk of inhibitors.

Modulation of factor VIII-specific memory B cells.

The development of inhibitory antibodies against factor VIII (FVIII) is the major complication in patients with haemophilia A who are treated with FVIII products. Memory B cells play an essential role in maintaining established antibody responses. Upon re-exposure to the same antigen, they are rapidly re-stimulated to proliferate and differentiate into antibody-secreting plasma cells (ASC) that secrete high-affinity antibodies. It is, therefore, reasonable to believe that memory B cells have to be eradicated or inactivated for immune tolerance induction therapy to be successful in patients with haemophilia A and FVIII inhibitors. The aim of our studies was the development of strategies to prevent FVIII-specific memory B cells from becoming re-stimulated. We established a 6-day in vitro culture system that enabled us to study the regulation of FVIII-specific murine memory-B-cell re-stimulation. We tested the impact of the blockade of co-stimulatory interactions, of different concentrations of FVIII and of ligands for toll-like receptors (TLR). The blockade of B7-CD28 and CD40-CD40 ligand interactions prevented FVIII-specific murine memory B cells from becoming re-stimulated by FVIII in vitro and in vivo. Furthermore, high concentrations of FVIII blocked re-stimulation of FVIII-specific murine memory B cells. Triggering of TLR7 amplified re-stimulation by low concentrations of FVIII and prevented blockade by high concentrations of FVIII. We conclude that we defined modulators that either amplify or inhibit the re-stimulation of FVIII-specific murine memory B cells. Currently, we are investigating whether the same modulators operate in patients with haemophilia A and FVIII inhibitors.

Efficacy and safety of OCTANINE F in children with haemophilia B.

OCTANINE F is a high-purity blood clotting factor IX concentrate that has been shown to be effective and safe in adults with haemophilia B. At present, there are no prospective clinical study data on FIX replacement therapy in young children. The primary objective of this trial was to investigate the immunogenicity of OCTANINE F in children aged <6 years with haemophilia B. Secondary objectives were to assess the efficacy, viral safety and tolerability of OCTANINE F in this patient population. Twenty-five children aged <6 years with moderate or severe haemophilia B, including six who were previously untreated and 13 who had less than previous 50 exposure days were assigned to prophylactic or on-demand treatment with OCTANINE F over a 12- to 24-month period. Immunogenicity was assessed at baseline, during the treatment period and at the end of treatment by monitoring the levels of inhibitor. OCTANINE F was not associated with the development of an inhibitor in any patient during the study; all patients had a FIX inhibitor level of <0.4 Bethesda units (BU) for all samples taken throughout the study. The efficacy of OCTANINE F was rated as excellent in 96.4% of 499 bleeding episodes and tolerability was rated as very good in 97% of 1684 injections. OCTANINE F was shown to be effective and well tolerated in children aged <6 years with moderate or severe haemophilia B, including previously untreated patients, with no reported cases of FIX inhibitors or thrombotic events.

Pharmacokinetics, efficacy and safety of IMMUNATE solvent/detergent (IMMUNATE S/D) in previously treated patients with severe hemophilia A: results of a prospective, multicenter, open-label phase III study.

BACKGROUND: IMMUNATE Solvent/Detergent (S/D) is a plasma-derived, human factor VIII (FVIII)/von Willebrand factor (VWF) complex subjected to S/D and vapor heat treatment. METHODS: This prospective clinical study evaluated the pharmacokinetics (PK) (compared to IMMUNATE), efficacy and safety of IMMUNATE S/D in 56 previously treated patients with severe hemophilia A. Subjects received IMMUNATE S/D either on-demand (47/56), as a prophylactic regimen (49/56), or both (40/56). RESULTS: IMMUNATE and IMMUNATES/D were equivalent with respect to the FVIII and VWF PK parameters assessed. Bleeding episodes (623) were reported in 47/56 subjects. For 89% of episodes, subjects required only 1 infusion with a mean dose of 29.6 IU/kg and 96% of episodes had an excellent or good response. The duration of prophylaxis ranged from 0.1 to 5.2 months. The median number of bleeds per month in subjects on prophylaxis was 0 (range 0-10). No FVIII inhibitory antibodies were observed in 56 subjects after 2,646 treatment exposure days. No related serious adverse events were reported. CONCLUSION: The introduction of S/D treatment did not alter the PK characteristics and function of VWF and FVIII molecules in IMMUNATE S/D which is effective and safe for treatment of bleeding episodes, management of surgical procedures and prophylaxis.

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.

Management of oral bleedings with recombinant factor VIIa in children with haemophilia A and inhibitor.

Dental extraction in patients with haemophilia A and high-titre inhibitor is always a high-risk procedure, which often presents a lot of problems associated with bleeding. Prothrombin complex concentrates or recombinant activated factor VII (rFVIIa) has been used to control bleeding. rFVIIa was administered to five boys with severe haemophilia A complicated with inhibitor, who underwent seven dental extractions. The age of the patients ranged between 8 and 13 years (median 10 years). The concentrate was administered in doses of 90-100 microg kg(-1) body weight. Duration in the therapy and intervals between rFVIIa doses depended on the severity of bleeding. rFVIIa was proven to be highly effective and no side-effects of the product were observed.

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.