First report on the safety and efficacy of an extended half-life glycoPEGylated recombinant FVIII for major surgery in severe haemophilia A.

BACKGROUND: N8-GP (turoctocog alfa pegol) is an extended half-life glycoPEGylated recombinant factor VIII (FVIII) product developed for the prevention and treatment of bleeds in haemophilia A patients. AIM: This is a planned interim analysis of pathfinder™3, an international, open-label, Phase 3 trial evaluating the efficacy and safety (including immunogenicity) of N8-GP administered before, during and after major surgery in severe haemophilia A patients aged ≥12 years. METHODS: Sixteen patients who underwent 18 major surgical procedures (including synovectomy, joint replacement and ankle arthrodesis) were included here. Postoperative assessments were conducted daily for days 1-6, and once for days 7-14. Primary endpoint was N8-GP haemostatic efficacy, assessed after completion of surgery using a four-point scale ('excellent', 'good', 'moderate', 'none'). RESULTS: Haemostasis was successful (rated 'excellent' or 'good') on completion of surgery in 17 (94.4%) procedures and rated as 'moderate' (5.6%) for one surgery in a patient with multiple comorbidities who needed an intraoperative N8-GP dose (20.7 IU kg-1 ). In the postoperative period, three bleeds occurred (one during days 1-6; two during days 7-14); all were successfully treated with N8-GP. Mean N8-GP consumption on day of surgery was 80.0 IU kg-1 ; patients received a mean of 1.7 doses (median: 2, range: 1-3). No safety concerns were identified. CONCLUSION: The data showed that N8-GP was effective and well tolerated for the prevention and treatment of bleeds during major surgery; such FVIII products with extended half-lives may modify current treatment schedules, enabling fewer infusions and earlier patient discharge.

Usefulness of a simple self-administered joint condition assessment sheet to predict the need for orthopaedic intervention in the management of haemophilic arthropathy.

INTRODUCTION: Detecting signs of joint deterioration is important for early effective orthopaedic intervention in managing haemophilic arthropathy. AIM: We developed a simple, patient self-administered sheet to evaluate the joint condition, and assessed the predictive ability of this assessment sheet for the need for an orthopaedic intervention. METHODS: This was a single-centre, cross-sectional study. The association between the score of each of the four items of the assessment sheet (bleeding, swelling, pain and physical impairment) and the results of radiological findings and physical examinations based on Haemophilia Joint Health Score 2.1 was assessed. An optimal scoring system was explored by the area under the curve (AUC). The cut-off value for the need for surgery or physiotherapy was determined using the receiver operating characteristic curve procedure. RESULTS: Forty-two patients were included. The 'physical impairment' item showed the highest correlation coefficient with the results of radiographic and physical examinations (range: 0.57-0.76). The AUC of finally adjusted scoring indicates good ability to discriminate between patients with and without a need for orthopaedic intervention. The positive predictive value was the highest at a cut-off value of 4 points for knees (63.0%) and ankles (70.0%), at 5 points for elbows (66.7%) and the highest predictive accuracy at the cut-off value of 4 points for all the joints. The linear trend of the need for an orthopaedic intervention was observed with an increasing score. CONCLUSION: The joint condition assessment sheet can help clinicians assess the need for orthopaedic intervention for haemophilic arthropathy in Japanese patients with haemophilia.

A phase III clinical trial of a mixture agent of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors.

INTRODUCTION: MC710, a 1:10 protein weight ratio mixture of plasma-derived activated factor VII (FVIIa) and factor X (FX), is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. We evaluated the haemostatic efficacy and safety of one to two administrations of MC710 in 21 joint, muscle, and subcutaneous bleeding episodes in 14 male patients, in a multi-centre, open-label, non-randomized clinical trial. METHODS: Subjects were intravenously administered one or two doses of 60 or 120 µg kg-1 MC710 (as FVIIa) once or twice (to a maximum of 180 µg kg-1 ) over up to five bleeding episodes per subject. The haemostatic efficacy of MC710 was determined for each episode by investigator evaluation, using changes in visual analogue scale (VAS) for pain relief, and/or knee joint or muscle circumference for swelling reduction, and range of motion (ROM) for improvement of joint mobility. RESULTS: In 21 treatments for bleeding episodes, 19 were rated "excellent" or "effective" 8 h after the last treatment. VAS significantly decreased over time, and ROM significantly improved over time compared with the values before treatment. One mild adverse reaction, decreased blood potassium, and two serious adverse events, both knee joint bleeding, were observed within 1 week after first administration, with no significant effect on safety. Furthermore, diagnostic markers did not show any signs of disseminated intravascular coagulation (DIC). CONCLUSION: These results show that MC710 has sufficient haemostatic efficacy and safety, and can be used as a potential bypassing agent to control bleeding in haemophilia patients with inhibitors.

The features of clearance in recombinant factor IX (BeneFIX(®) ).

INTRODUCTION: Dosage adjustment is very important to perform continuous infusion (CI) of recombinant factor IX (rFIX) concentrates more effectively and economically, and clearance (CL) is strongly related to the infusion rate. However, previous reports have shown that the CL of rFIX concentrates varies widely (4.2-11.4 mL kg(-1) h(-1) ). AIM: The goal of this study was to gain a better understanding of the CL of the rFIX concentrate (BeneFIX(®) ) to precisely set the infusion rate of rFIX concentrates. METHODS: We estimated CLs by five different calculation approaches: from area under the blood concentration-time curve (AUC), from in vivo recovery (IVR) and half-life, from actual FIX activity value during CI, and from the simulation by one-compartment model in seven patients with haemophilia B. RESULTS: The mean CL calculated from AUC was 3.8 ± 0.4 mL kg(-1) h(-1) (range = 3.3-4.3 mL kg(-1) h(-1) ). CONCLUSION: The mean CL calculated from IVR and distribution half-life was 4.4 ± 0.4 mL kg(-1) h(-1) (range = 4.0-5.1 mL kg(-1) h(-1) ). The mean CL calculated from IVR and terminal half-life was 2.1 ± 0.5 mL kg(-1) h(-1) (range = 1.7-2.8 mL kg(-1) h(-1) ). The mean CL during CI was 4.9 ± 0.6 mL kg(-1) h(-1) (range = 4.2-5.6 mL kg(-1) h(-1) ). In addition, when we simulated the theoretical CL using a one-compartment model, the adjusted mean CL during CI was 4.8 ± 0.5 mL kg(-1) h(-1) (range = 4.0-5.4 mL kg(-1) h(-1) ). The CL obtained from distribution half-life was comparable to the CL during CI, while the CL calculated from terminal half-life did not reflect actual CL. Further, the rFIX concentrate was characterized by a one-compartment model under certain conditions.

Deep venous thrombosis was not detected after total knee arthroplasty in Japanese patients with haemophilia.

Combined thrombo-prophylaxis with mechanical and pharmacological methods is recommended in patients undergoing total knee or hip arthroplasty. As patients with 'untreated inherited bleeding disorders such as haemophilia' are at risk of bleeding, no prophylaxis has been prescribed for these patients. However, a retrospective study reported subclinical deep venous thrombosis (DVT) in 10% of patients with haemophilia undergoing major orthopaedic surgery. In this study, we aimed to evaluate the risk of DVT after total knee arthroplasty (TKA). We examined 38 TKA in 33 Japanese patients with haemophilia using ultrasonography. We did not detect DVT. The risk of DVT in patients with haemophilia after TKA may be lower than that in the general population. However, as patients with haemophilia progress in age, venous thromboembolism should be considered as a potential problem.

Ten-year experience of recombinant activated factor VII use in surgical patients with congenital haemophilia with inhibitors or acquired haemophilia in Japan.

Patients with congenital haemophilia with inhibitors or acquired haemophilia are at risk of bleeding complications during surgery. In these patients, replacement therapy for the missing coagulation factor is ineffective, and a bypassing agent such as recombinant activated factor VII (rFVIIa) is required to manage bleeding. To evaluate the safety and haemostatic efficacy of rFVIIa treatment in Japanese patients with congenital haemophilia with inhibitors to FVIII/FIX or acquired haemophilia undergoing surgery. Postmarketing surveillance data from May 2000 to March 2010 were analysed to assess the haemostatic efficacy of 38 procedures in 22 patients with congenital haemophilia A, 13 procedures in seven patients with congenital haemophilia B, and five procedures in five patients with acquired haemophilia. Postoperative bleeding control was judged to be effective (bleeding was stopped completely or reduced considerably) for 34/38 procedures (89%) in patients with congenital haemophilia A, 10/13 procedures (77%) in patients with congenital haemophilia B, and 4/5 procedures (80%) in patients with acquired haemophilia. Tranexamic acid was used concomitantly for 36/56 procedures (64%). Safety was analysed for 66 procedures in 37 patients. Adverse effects potentially related to rFVIIa treatment included mild superficial thrombophlebitis, mild decrease in platelet count, and mild elevation of the serum alanine transaminase level in one patient each. All adverse effects resolved without treatment. Administration of rFVIIa provided adequate haemostasis without serious adverse effects in the majority of cases. The efficacy and safety data in Japanese patients were similar to previously published data from other countries.

Self-monitoring has potential for home exercise programmes in patients with haemophilia.

Haemophiliacs who have had to keep a physically inactive lifestyle due to bleeding during childhood are likely to have little motivation for exercise. The purpose of this study is to clarify the effectiveness of the self-monitoring of home exercise for haemophiliacs. A randomized controlled trial was conducted with intervention over 8 weeks at four hospitals in Japan. Subjects included 32 male outpatients aged 26-64 years without an inhibitor who were randomly allocated to a self-monitoring group and a control group. Individual exercise guidance with physical activity for improvement of their knee functions was given to both groups. The self-monitoring materials included an activity monitor and a feedback system so that the self-monitoring group could send feedback via the Internet and cellular phone. The self-monitoring was performed by checking exercise adherence and physical activity levels, bleeding history and injection of a coagulation factor. Both groups showed significant improvements in exercise adherence (P < 0.001) and physical function such as the strength of knee extension (P < 0.001), range of knee extension (P < 0.001), range of ankle dorsiflexion (P < 0.01), a modified Functional Reach (P < 0.05) and 10 metre gait time (P < 0.01). In particular, improvements in exercise adherence (P < 0.05), self-efficacy (P < 0.05), and strength of knee extension (P < 0.05) were significant in the self-monitoring group compared with those in the control group. No increase in bleeding frequency and pain scale was noted. The self-monitoring of home exercise for haemophilic patients is useful for the improvement of exercise adherence, self-efficacy and knee extension strength.

The risk of elective orthopaedic surgery for haemophilia patients: Japanese single-centre experience.

Haemophilic arthropathy causes pain and a severely restricted range of motion, and results in a significant reduction in quality of life. When conservative treatments have failed, orthopaedic surgery is recommended for these patients with severe haemophilic arthropathy. However, surgery for haemophilia patients is challenging due to high complication rate such as infection, delayed wound healing and mortality. The aim of this study was to evaluate the incidence of early complications and identify preoperative risk factors of surgery for haemophilia patients. We report a series of haemophilia patients undergoing elective orthopaedic surgery between 2006 and 2012. During this period, 119 surgeries in 81 patients were prepared and 118 surgeries in 80 patients were actually performed. Four deep bacterial infections and four delayed wound healings occurred within 6 months postoperatively. One patient died preoperatively and four patients died postoperatively. Only the presence of inhibitor was a significant risk factor for infection. We found no risk factor related to delayed wound healing. Our data revealed alkaline phosphatase, albumin, platelet, alpha-fetoprotein, presence of ascites and child classification C as predictors of perioperative mortality following elective orthopaedic surgery. Our role is to identify potential patients who present with risk factors for complications and attempt to seek the best determination of treatment strategy for these people.

A Phase II clinical trial of a mixture of plasma-derived factor VIIa and factor X (MC710) in haemophilia patients with inhibitors: haemostatic efficacy, safety and pharmacokinetics/pharmacodynamics.

MC710, a mixture of plasma-derived activated factor VII and factor X at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In a Phase II trial, we evaluated the haemostatic efficacy and safety of single doses of MC710, and investigated pharmacokinetic and pharmacodynamic parameters in nine joint bleeding episodes in six male haemophilia patients with inhibitors. This trial was a multi-centre, open-label, non-randomized study of two doses (60 and 120 µg kg(-1) as FVIIa dose), allowing the re-administration of different MC710 dosages to the same subjects. Haemostatic efficacy was assessed by evaluating reduction in pain and swelling, as well as increase in range of motion in a bleeding joint. The results of the study showed that in nine bleeding episodes, seven treatments were rated as 'excellent' or 'effective' according to investigator's rating system of efficacy at 8 h after administration. No serious or severe adverse events were observed after administration; furthermore, measurement of several diagnostic markers revealed no signs or symptoms of disseminated intravascular coagulation (DIC). The haemostatic potential of MC710 was confirmed at doses of 60 and 120 µg kg(-1) in this trial. MC710 is thus expected to be a safe and efficacious novel bypassing agent for controlling bleeding in haemophilia patients with inhibitors.

Results of clot waveform analysis and thrombin generation test for a plasma-derived factor VIIa and X mixture (MC710) in haemophilia patients with inhibitors--phase I trial: 2nd report.

We reported the results of a clinical pharmacological study of MC710 (a mixture of plasma-derived FVIIa and FX) in haemophilia patients with inhibitors during a non-haemorrhagic state. This report provides the results of a clot waveform analysis (CWA) and thrombin generation test (TGT) using blood samples obtained in this study. CWA and TGT were conducted using blood samples obtained from a pharmacokinetic and pharmacodynamic study in which MC710 (five dose rates: 20, 40, 80, 100 and 120 µg kg(-1)) was compared with NovoSeven (120 µg kg(-1)) and FEIBA (two dose rates: 50 and 75 U kg(-1)) as control drugs in 11 haemophilia patients with inhibitors without haemorrhagic symptoms. CWA showed that MC710 provided significantly greater improvement than the control drugs in activated partial thromboplastin time (APTT) at 80 µg kg(-1); maximum clot velocity and maximum clot acceleration were more enhanced by MC710 than by control drugs. TGT revealed that MC710 significantly shortened the initiation time of thrombin generation in comparison to FEIBA and induced greater thrombin generation potency than NovoSeven. It was not clear whether or not MC710 caused significant dose-dependent changes in the two measurements; however, differences between MC710 and the control drugs were clarified. MC710 was confirmed to have superior coagulation activity and thrombin productivity and is expected to have superior bypassing activity.