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.

Nonacog beta pegol in previously treated children with hemophilia B: results from an international open-label phase 3 trial.

UNLABELLED: Essentials Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life. This phase 3 trial investigated its safety/efficacy in previously treated hemophilia B boys ≤ 12 years. A 40 IU kg(-1) dose provided effective once-weekly prophylaxis and hemostasis when used to treat bleeds. Nonacog beta pegol was well tolerated in previously treated boys ≤ 12 years with hemophilia B. SUMMARY: Background Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life, developed to improve care for patients with hemophilia B. Objectives To investigate the safety, efficacy and pharmacokinetics of nonacog beta pegol for the prophylaxis and treatment of bleeds in previously treated children with hemophilia B. Patients/Methods This phase 3 trial, paradigm(™) 5, enrolled and treated 25 children (aged ≤ 12 years) with hemophilia B (FIX ≤ 2%). Patients were stratified by age (0-6 years and 7-12 years), and received once-weekly prophylaxis with 40 IU kg(-1) nonacog beta pegol for 50 exposure days. Results No patient developed inhibitors, and no safety concerns were identified. Forty-two bleeds in 15 patients were reported to have been treated; the overall success rate was 92.9%, and most bleeds (85.7%) resolved after one dose. The median annualized bleeding rates (ABRs; bleeds per patient per year) were 1.0 in the total population, 0.0 in the 0-6-year group, and 2.0 in the 7-12-year group; the estimated mean ABRs were 1.44 in the total population, 0.87 in the 0-6-year group, and 1.88 in the 7-12-year group. For 22 patients who had previously been receiving prophylaxis, the estimated mean ABR was 1.38 versus a historical ABR of 2.51. Estimated mean steady-state FIX trough levels were 0.153 IU mL(-1) (0-6 years) and 0.190 IU mL(-1) (7-12 years). Conclusion Nonacog beta pegol was well tolerated in previously treated children with hemophilia B; a 40 IU kg(-1) dose provided effective once-weekly prophylaxis and hemostasis when bleeds were treated.

Recombinant long-acting glycoPEGylated factor IX (nonacog beta pegol) in haemophilia B: assessment of target joints in multinational phase 3 clinical trials.

BACKGROUND: The paradigm(™) 2 and 4 phase 3 clinical trials investigated the safety and efficacy of nonacog beta pegol, a recombinant glycoPEGylated factor IX (FIX) with extended half-life, in previously treated haemophilia B patients. AIM: These post hoc analyses investigated the bleeding patterns in target joints. METHODS: Patients randomized to 40 or 10 IU kg(-1) once weekly prophylaxis who had at least one target joint were included. Baseline demographics and disease-specific data were collected. Bleeding patterns were assessed, and an International Society on Thrombosis and Haemostasis (ISTH) definition of target joints was used. RESULTS: A total of 67% and 8% of patients in the 40 and 10 IU kg(-1) arm, respectively, did not experience target joint bleeds during the paradigm(™) 2 trial. Twenty-four target joints were recorded in each prophylaxis arm at baseline. During the paradigm(™) 2 trial, no bleeds were reported in 17 (71%) and 7 (29%) target joints in the 40 and 10 IU kg(-1) arms respectively. All target joint bleeds in the 40 IU kg(-1) once weekly prophylaxis arm were controlled with a single injection of 40 IU kg(-1) nonacog beta pegol. By the latest ISTH definition, 90% and 58% of target joints in the 40 and 10 IU kg(-1) arms, respectively, were no longer considered target joints at the end of the paradigm(™) 2 trial. At the end of the paradigm(™) 4 extension trial, all target joints in the 40 IU kg(-1) arm were no longer considered target joints. CONCLUSION: Routine prophylaxis with 40 IU kg(-1) once weekly nonacog beta pegol has the potential for effective management of target joint bleeds in haemophilia B patients.

Long-term safety and efficacy of recombinant factor VIII Fc fusion protein (rFVIIIFc) in subjects with haemophilia A.

INTRODUCTION: The safety, efficacy and prolonged half-life of recombinant factor VIII Fc fusion protein (rFVIIIFc) in previously treated patients with severe haemophilia A was demonstrated in the phase 3 A-LONG and Kids A-LONG studies. Here, we report interim safety and efficacy data from the rFVIIIFc extension study, ASPIRE (ClinicalTrials.gov #NCT01454739). METHODS: Eligible subjects could enrol in ASPIRE upon completing A-LONG or Kids A-LONG. There were four treatment groups: individualized prophylaxis; weekly prophylaxis; modified prophylaxis (for subjects in whom optimal treatment could not be achieved with individualized or weekly prophylaxis); and episodic treatment. The primary endpoint was development of inhibitors. RESULTS: A total of 150 A-LONG subjects and 61 Kids A-LONG subjects enrolled in ASPIRE. As of the interim data cut (6 January 2014), the median time on study was 80.9 (A-LONG) and 23.9 (Kids A-LONG) weeks. The majority of subjects (A-LONG, 92.0%; Kids A-LONG, 57.4%) had ≥100 cumulative rFVIIIFc exposure days. No inhibitors were observed. Adverse events were generally consistent with those expected in the general haemophilia A population. Median annualized bleeding rates (ABRs) were low with individualized [A-LONG: 0.66; Kids A-LONG: 0.00 (<6 years old), 1.54 (6 to <12 years old)], weekly (A-LONG: 2.03) and modified (A-LONG: 1.97) prophylaxis. There was no change in prophylactic infusion frequency or total weekly prophylactic dose in the majority of subjects from A-LONG and Kids A-LONG. CONCLUSION: Interim data from ASPIRE confirm the long-term safety of rFVIIIFc and the maintenance of a low ABR with extended-interval prophylactic dosing in patients with severe haemophilia A.

Recombinant factor VIII Fc fusion protein: extended-interval dosing maintains low bleeding rates and correlates with von Willebrand factor levels.

BACKGROUND: Routine prophylaxis with replacement factor VIII (FVIII) - the standard of care for severe hemophilia A - often requires frequent intravenous infusions (three or four times weekly). An FVIII molecule with an extended half-life could reduce infusion frequency. The A-LONG study established the safety, efficacy and prolonged pharmacokinetics of recombinant FVIII Fc fusion protein (rFVIIIFc) in previously treated adolescents and adults with severe hemophilia A. OBJECTIVE: In this post hoc analysis, we investigated the relationship between subjects' prestudy (FVIII) and on-study (rFVIIIFc) regimens. METHODS: We analyzed two subgroups of subjects: prior prophylaxis and on-study individualized prophylaxis (n = 80), and prior episodic treatment and on-study weekly prophylaxis (n = 16). Subjects' prestudy dosing regimens and bleeding rates were compared with their final rFVIIIFc regimens and annualized bleeding rates (ABRs) in the last 3 months on-study. Dosing regimen simulations based on population pharmacokinetics models for rFVIII and rFVIIIFc were performed. RESULTS: As compared with their prestudy regimen, 79 of 80 (98.8%) subjects on individualized rFVIIIFc prophylaxis decreased their infusion frequency. Overall ABRs were low, with comparable factor consumption. Longer dosing intervals, including 5-day dosing, were associated with higher baseline von Willebrand factor antigen levels. Simulated dosing regimens predicted a greater proportion of subjects with steady-state FVIII activity trough levels of ≥ 1 IU dL(-1) (1%) with rFVIIIFc than with equivalent rFVIII regimens. CONCLUSION: These results suggest that patients on rFVIIIFc prophylaxis can reduce their infusion frequency as compared with their prior FVIII regimen while maintaining low bleeding rates, affording more patients trough levels of ≥ 1 IU dL(-1) than with rFVIII products requiring more frequent dosing regimens.

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.

Clinical pharmacological study of a plasma-derived factor VIIa and factor X mixture (MC710) in haemophilia patients with inhibitors--phase I trial.

MC710, a combined product of plasma-derived activated factor VII (FVIIa) and factor X (FX) at a protein weight ratio of 1:10, is a novel bypassing agent for haemostasis in haemophilia patients with inhibitors. In this study, pharmacokinetic (PK), pharmacodynamic (PD) parameters and safety of single doses of MC710 were investigated in 11 male haemophilia patients with inhibitors in a non-bleeding state. This was a multi-centre, open-labelled, non-randomized, active controlled crossover, dose-escalation study of five doses (20-120 µg kg(-1) of FVIIa) with re-administration of different MC710 dosages to the same subjects. The active controls were NovoSeven (120 µg kg(-1)) and/or FEIBA (50 and 75 U kg(-1)) which were used to compare PD parameters. The area under the curve (AUC) and maximum plasma concentration (C(max)) of MC710 active ingredients increased dose-dependently within the range of 20 and 120 µg kg(-1). After administration of MC710, activated partial thromboplastin time (APTT) was dose-dependently improved and prothrombin time (PT) was shortened to approximately 6 s at 10 min, and APTT improvement and PT shortening effects were maintained until 12 h after administration of MC710 at all doses. No serious or severe adverse event was observed after administration of MC710; furthermore, several diagnostic marker values and those changes did not indicate any signs of disseminated intravascular coagulation (DIC). These results suggest that MC710 would have haemostatic potential equal to or greater than NovoSeven and FEIBA and was be tolerable when given at doses up to 120 µg kg(-1).

Clinical trial to investigate the pharmacokinetics, pharmacodynamics, safety, and efficacy of recombinant factor VIIa in Japanese patients with hemophilia with inhibitors.

A multicenter and open-labeled clinical trial of human recombinant factor VIIa (rFVIIa) was conducted in Japanese patients with severe hemophilia A or B with inhibitors. The trial consisted of 2 parts. In study 1, the pharmacokinetics, pharmacodynamics, and safety of a single dose of 120 microg/kg of rFVIIa were investigated in 8 patients. In the subsequent study 2, the hemostatic effect and safety of rFVIIa were evaluated during a 24-week period in 10 patients. In study 1, the mean maximum FVII-coagulant activity (FVII:C) was found to occur after 10 minutes; activity then decreased rapidly and returned to the baseline within 24 hours after a single intravenous infusion of rFVIIa. The mean half-life of FVII:C was 3.5 hours. The activated partial thromboplastin time and prothrombin time in the patients were immediately shortened but returned to the baseline within 24 hours after dosing. In study 2, 86 microg/kg to 120 microg/kg of rFVIIa (mean, 97 microg/kg) was administered 1 to 85 times to 10 patients. A total of 58.0% (91/157) of bleeding episodes were treated excellently or effectively, with 5 (3.2%) ineffective episodes. There was no apparent trend in the relationship of the hemostatic effect with bleeding sites, mean dose, or number of injections. The efficacy rate, however, was significantly higher (90.0%) in bleeding episodes treated within 3 hours than in those treated at longer intervals (31.0%). No treatment-related adverse events were observed, and there was no evidence of antibody formation to rFVIIa. In conclusion. rFVIIa is an effective and well-tolerated option for treatment of bleeding episodes in hemophilia patients with inhibitors.

Pancytopenia in tuberous sclerosis.

A 46-year-old woman with edema and pancytopenia was referred for further evaluation. She was diagnosed as tuberous sclerosis with clinical manifestations such as facial adenoma sebaceous, ungual and periungual fibroma, subependymal nodules and renal angiomyolipoma. Her edema seemed due to hypercardiac function induced by massive anemia. X-ray revealed extraordinary thickening of the cortex of long bones of the extremities as well as patchy osteosclerotic findings in vertebra, suggesting that hematopoietic space was significantly reduced. Pancytopenia improved after splenectomy. Histological examination revealed several intrasplenic hemangiomas but its relationship to hypersplenism was not clear. It seemed that her massive pancytopenia was induced by a combination of hypersplenism and significant reduction in hematopoetic space. In tuberous sclerosis, various systemic complications sometimes induce severe hematological abnormalities. According to previous literatures, the present case of tuberous sclerosis manifested the most outstanding hematological complications.

An evaluation of semen processing methods for eliminating HIV-1.

OBJECTIVE: Whether artificial insemination can provide adequate protection for discordant couples where the man is HIV-1 positive and the woman is HIV-1 negative is uncertain because of the paucity of HIV-1 elimination data assessing current sperm-washing techniques. We evaluated how effectively these techniques eliminate HIV-1 RNA and proviral DNA from semen. METHODS: Spermatozoa were separated from semen samples from HIV-1-positive patients with haemophilia by discontinuous Percoll gradient centrifugation and the 'swim-up' method. The HIV-1 RNA and proviral DNA were measured by a highly sensitive PCR. In another test 5 x 10(6) copies of HIV-1 RNA (LAI strain) were added to semen from healthy donors and then assessed after single and combined procedures. RESULTS: Swim-up processing after Percoll gradient centrifugation reduced HIV-1 RNA and HIV-1 proviral DNA in semen to undetectable levels in the original specimen. Although discontinuous and continuous Percoll gradient centrifugation respectively reduced HIV-1 RNA added to seminal plasma specimens from healthy donors to less than < 1 copy from 10(5) and about 1 copy per 10(3) pre-separation copies, the discontinuous method left detectable HIV-1 RNA and proviral DNA in one out of 12 samples from patients with HIV-1 infection (8%). HIV-1 RNA and proviral DNA were decreased to undetectable levels after adding the swim-up procedure. CONCLUSIONS: Swim-up separation following Percoll gradient centrifugation should offer adequate protection for HIV-1-discordant couples.

Interleukin 18 and interleukin 1beta production is decreased in HIV type 1-seropositive hemophiliacs but not in HIV type 1-seropositive nonhemophiliacs.

In Japan, the proportion of hemophiliacs infected with human immunodeficiency virus type 1 (HIV-1) is 40%, whereas more than 90% are infected with hepatitis C virus (HCV). To evaluate the immunological status of hemophiliacs infected with HIV-1, we investigated the pattern of cytokine production in peripheral blood mononuclear cells (PBMCs) of HIV-1-seropositive and -seronegative hemophiliacs, HIV-1-seropositive non-hemophiliacs, and healthy individuals. The production of IL-18 and IL-1beta from PBMCs stimulated with Staphylococcus aureus Cowan strain 1 (SAC) in the HIV-1-seropositive hemophiliacs was significantly decreased in comparison with the other groups. On the other hand, IL-12 production in both HIV-1-seropositive groups was significantly lower than in HIV-1-seronegative groups. TNF-alpha and IL-6 production was similar among the four groups. In contrast, plasma levels of TGF-beta1 were increased in HIV-1-seropositive hemophiliacs, HIV-1-seropositive nonhemophiliacs, and HIV-1-seronegative hemophiliacs, with the highest levels being in HIV-1-seropositive hemophiliacs, suggesting that coinfection with HIV-1 and HCV increases the level of plasma TGF-beta in HIV-1-seropositive hemophiliacs. Treatment of PBMCs from healthy individuals with TGF-beta1 inhibited IL-18 and IL-1beta production without affecting IL-6, IL-10, or TNF-alpha production. Suppression of the expression of caspase 1 mRNA, which is known to be an IL-1beta-converting enzyme and which also cleaves the precursor of IL-18, was observed in the SAC-stimulated PBMCs from healthy individuals after treatment with TGF-beta1 and in the SAC-stimulated PBMCs from HIV-1-seropositive hemophiliacs, suggesting that the decreased production of IL-18 and IL-1beta in HIV-1-seropositive hemophiliacs may be related to the downregulation of caspase 1 mRNA induced by high levels of TGF-beta1 in plasma.

Mucocutaneous manifestations in Japanese HIV-positive hemophiliacs.

BACKGROUND: Although various mucocutaneous manifestations have been reported in patients infected with HIV by sexual transmission or intravenous drug use, the prevalence and characteristics of skin disorders in HIV-positive hemophiliacs coinfected with hepatitis C virus (HCV) have rarely been described. OBJECTIVE: The purpose of this study was to clarify the characteristics of skin disorders in HIV-positive hemophiliacs and to identify differences in comparison with other HIV-positive groups. METHODS: A prospective study of the prevalence of mucocutaneous manifestations in 110 Japanese hemophiliacs (53 HIV-positive hemophiliacs including 24 AIDS and 57 HIV-negative hemophiliacs) was performed from July 1997 to July 1998. RESULT: None of the hemophiliacs developed Kaposi's sarcoma or sexually transmitted skin diseases. Eosinophilic folliculitis was observed in 3 AIDS patients. The incidence of folliculitis, common warts, seborrheic dermatitis, generalized eczema, oral candidiasis and herpes zoster was higher in HIV-positive than in HIV-negative hemophiliacs (p < 0.05). Although anti-HCV antibody was positive in all HIV-positive hemophiliacs, HCV-related dermatoses such as lichen planus and porphyria cutanea tarda were not observed. CONCLUSION: Although Kaposi's sarcoma and sexually transmitted skin diseases such as molluscum contagiosum, condyloma, and scabies are frequently associated with HIV, they were not found in the HIV-positive hemophiliacs in our study. HIV infection-related mucocutaneous manifestations are influenced not only by the presence of HIV but also by other factors such as the mode of transmission and sexual habit.