***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Current factor VIII ( FVIII ) products display a half-life ( t(1/2 ) ) of ∼ 8 - 12 hours , requiring frequent intravenous injections for prophylaxis and treatment of patients with hemophilia A.  rFVIIIFc is a recombinant fusion protein composed of a single molecule of FVIII covalently linked to the Fc domain of human IgG(1 ) to extend circulating rFVIII t(1/2 ) . This first-in-human study in previously treated subjects with severe hemophilia A investigated safety and pharmacokinetics of rFVIIIFc .  Sixteen subjects received a single dose of rFVIII at 25 or 65 IU/kg followed by an equal dose of rFVIIIFc .  Most adverse events were unrelated to study drug . None of the study subjects developed anti-rFVIIIFc antibodies or inhibitors . Across dose levels , compared with rFVIII , rFVIIIFc showed 1.54- to 1.70-fold longer elimination t(1/2 ) , 1.49- to 1.56-fold lower clearance , and 1.48- to 1.56-fold higher total systemic exposure . rFVIII and rFVIIIFc had comparable dose-dependent peak plasma concentrations and recoveries . Time to 1 % FVIII activity above baseline was ∼ 1.53- to 1.68-fold longer than rFVIII across dose levels . Each subject showed prolonged exposure to rFVIIIFc relative to rFVIII . Thus , rFVIIIFc may offer a viable therapeutic approach to achieve prolonged hemostatic protection and less frequent dosing in patients with hemophilia A. This trial was registered at www . clinical trials.gov as NCT01027377 Current management of hemophilia A includes prophylaxis with factor VIII ( FVIII ) replacement every 2 to 3 days . BAX 855 , Baxalta 's pegylated full-length recombinant FVIII ( rFVIII ) , was design ed to increase half-life and , thus , reduce the frequency of prophylactic infusions while maintaining hemostatic efficacy . BAX 855 was evaluated in previously treated patients with severe hemophilia A who were aged 12 to 65 years . A phase 1 study compared the pharmacokinetic ( PK ) profile of BAX 855 with that of licensed rFVIII ( Advate ) . In a pivotal study , the annualized bleeding rate ( ABR ) , PK parameters , and efficacy of bleeding treatment were assessed . In the phase 1 study , the mean half-life ( T1/2 ) and the mean residence time of BAX 855 compared with Advate were 1.4- to 1.5-fold higher . These results were confirmed in the pivotal study . The pivotal study met its primary endpoint : Prophylaxis with BAX 855 result ed in an ABR that was significantly lower than half the ABR of on-dem and treatment ( P < .0001 ) . The median ABR was 1.9 , and 39.6 % of compliant subjects had no bleeding episodes during prophylaxis , whereas subjects treated on-dem and had a median ABR of 41.5 . BAX 855 was also efficacious for the treatment of bleeding episodes , with 95.9 % of bleeding episodes treated with 1 to 2 infusions and 96.1 % having efficacy ratings of excellent/good . No FVIII inhibitory antibodies or safety signals were identified . These studies provide evidence that BAX 855 was safe and efficacious for on-dem and treatment and prophylaxis administered twice weekly in patients with hemophilia A. The trials were registered at www . clinical trials.gov as # NCT01736475 and # NCT01599819 Background BAY 94 - 9027 is a B-domain-deleted recombinant factor VIII ( rFVIII ) with site-specific attachment of poly(ethylene glycol ) that has shown an extended half-life in animal models of hemophilia . Objectives To assess the pharmacokinetics and safety of BAY 94 - 9027 after single and repeated administration in subjects with severe hemophilia A. Patients / Methods This 8-week , prospect i ve , multicenter , open-label , phase I trial was conducted in 14 subjects aged 21–58 years with FVIII of < 1 % , ≥ 150 days of exposure to FVIII , and no history of FVIII inhibitors . After a ≥ 3-day washout , subjects received a single dose of sucrose-formulated rFVIII ( rFVIII-FS ) ( cohort 1 [ n = 7 ] , 25 IU kg−1 ; cohort 2 [ n = 7 ] , 50 IU kg−1 ) for a 48-h pharmacokinetic ( PK ) study . After another ≥ 3-day washout , cohort 1 received twice-weekly BAY 94 - 9027 at 25 IU kg−1 ( 16 doses ) , and cohort 2 received once-weekly BAY 94 - 9027 at 60 IU kg−1 ( nine doses ) . A 168-h PK study was performed after the first and last BAY 94 - 9027 doses . Results BAY 94 - 9027 showed equivalent recovery and an improved PK profile vs. rFVIII-FS , with a half-life of ∼ 19 h ( vs. ∼ 13.0 h for rFVIII-FS ) . BAY 94 - 9027 was well tolerated , and no immunogenicity was observed . Conclusions This phase I study demonstrates that BAY 94 - 9027 has an extended half-life in subjects with hemophilia A and , after multiple dosing , was well tolerated with no immunogenicity during the 8-week trial . A phase III study in a larger number of subjects is underway to fully characterize how this prolonged half-life will permit less frequent prophylaxis dosing for patients with hemophilia This phase 3 pivotal study evaluated the safety , efficacy , and pharmacokinetics of a recombinant FVIII Fc fusion protein ( rFVIIIFc ) for prophylaxis , treatment of acute bleeding , and perioperative hemostatic control in 165 previously treated males aged ≥12 years with severe hemophilia A. The study had 3 treatment arms : arm 1 , individualized prophylaxis ( 25 - 65 IU/kg every 3 - 5 days , n = 118 ) ; arm 2 , weekly prophylaxis ( 65 IU/kg , n = 24 ) ; and arm 3 , episodic treatment ( 10 - 50 IU/kg , n = 23 ) . A subgroup compared recombinant FVIII ( rFVIII ) and rFVIIIFc pharmacokinetics . End points included annualized bleeding rate ( ABR ) , inhibitor development , and adverse events . The terminal half-life of rFVIIIFc ( 19.0 hours ) was extended 1.5-fold vs rFVIII ( 12.4 hours ; P < .001 ) . Median ABRs observed in arms 1 , 2 , and 3 were 1.6 , 3.6 , and 33.6 , respectively . In arm 1 , the median weekly dose was 77.9 IU/kg ; approximately 30 % of subjects achieved a 5-day dosing interval ( last 3 months on study ) . Across arms , 87.3 % of bleeding episodes resolved with 1 injection . Adverse events were consistent with those expected in this population ; no subjects developed inhibitors . rFVIIIFc was well-tolerated , had a prolonged half-life compared with rFVIII , and result ed in low ABRs when dosed prophylactically 1 to 2 times per week Radiological and orthopaedic outcome in severe and moderate haemophilia A and B patients undergoing long-term prophylactic treatment  were prospect ively investigated focusing on the age of onset of prophylaxis and the number of joint bleedings prior to treatment . We report on 21 patients with severe and moderate haemophilia A and B receiving prophylactic treatment of between 3.1 and 16.1 years ' duration . Three patient groups were evaluated according to the age at onset of prophylaxis . In group I prophylactic treatment was initiated in the first 2 years of life . Patients in group II received prophylaxis at the age of 3 - 6 years . Late-onset or secondary prophylactic treatment was started at the age of 6 years and above in seven patients ( group III ) . All patients received virus-inactivated F VIII or F IX concentrates at dosages of 30 - 50 IU/kg body weight i.v . three times per week for those with haemophilia A and twice per week for those with haemophilia B. Elbow , knee and ankle joints were investigated at 3 - 4-yearly intervals according to the radiological and orthopaedic scores recommended by the World Federation of Haemophilia . The total number of joint bleedings before and after start of prophylaxis were recorded in all patients . In group I 7/8 patients had unaffected joints with constant radiological and orthopaedic scores of zero or 1 , after a median of 11.25 years of prophylactic treatment . One patient in this group demonstrated mild radiological alterations ( score 4 ) . Patients in group II showed neither radiological nor orthopaedic alterations at study entry . Surprisingly , worsening joint scores could be detected despite ongoing prophylaxis after the 3-year interval ( median orthopaedic score 4 , median radiological score 8) . Treatment group III already showed considerable joint damage at study entry with a median radiological score of 11 ( 0 - 33 ) and a median orthopaedic score of 4 ( 0 - 11 ) . Despite prophylactic treatment , both radiological ( median 19.5 , range 2 - 47 ) and orthopaedic scores ( median 8 , range 2 - 12 ) deteriorated after 3 years . Prior to onset of prophylaxis , no or only one joint bleeding occurred in treatment group I. In group II , a median of six joint bleeds ( range 1 - 8 ) was reported before prophylaxis was started . Patients in group III usually experienced a median of more than 10 joint haemorrhages ( range 6 - 10 or more ) . Under prophylactic treatment the number of joint bleedings decreased significantly in groups II and III . However , radiological and orthopaedic scores increased as a sign of progressing osteoarthropathic alterations in patients reporting more than five joint haemorrhages onset of prophylaxis whereas no joint alterations could be assessed in patients with no or only one joint bleeding episode prior to prophylaxis . Even a small number of joint bleedings seems to cause irreversible osteoarthropathic alterations leading to haemophilic arthropathy . Once apparent , further progression of joint damage could not be arrested despite of prophylactic treatment ( groups II and III ) . In order to prevent haemophilic arthropathy , effective prophylaxis should be started before or at least after the first joint bleeding in severe haemophilia A and BACKGROUND Routine prophylaxis with replacement factor VIII ( FVIII ) - the st and ard 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 ' pre study ( 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 ' pre study 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 pre study 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 Willebr and 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 BACKGROUND N8-GP is a recombinant factor VIII ( FVIII ) with a site-directed glycoPEGylation for the purpose of half-life prolongation . OBJECTIVES To evaluate the safety and pharmacokinetic profiles of N8-GP in comparison with those of the patients ' previous FVIII products . PATIENTS / METHODS This dose-escalation trial included previously treated patients with severe hemophilia A who received one of three dose levels ( 
    Output:
    
In this systematic review , a pragmatic definition of EHL rFVIII has been proposed that should provide better clarity in clinical discussion s surrounding the appropriate use of rFVIII products .
At present , only products using PEGylation or Fc fusion half-life extension technology meet the proposed criteria for definition of EHL rFVIII