Novel Approaches for Hemophilia Treatment

Jerry S. Powell, MD


March 19, 2015

In This Article

Hemophilia is a genetic disease caused by mutation of one of the genes for coagulation proteins. When severe (defined as clotting activity < 1%), patients are at risk for spontaneous, life-threatening bleeding episodes. Individuals with moderate hemophilia (between 2% and 7% clotting activity) or mild hemophilia will usually suffer abnormal bleeding only after minor trauma or surgery.

Over the past several decades, factor replacement therapy has reduced the morbidity and mortality of hemophilia through reduction in the frequency of bleeding episodes and improvement in the quality of life.[1,2,3,4,5] Compared with individuals with normal coagulation, however, deaths still occur at higher rates due to bleeding episodes.[6] Regular intravenous infusions of factor two to three times each week, termed prophylactic therapy, are now the standard of care for children and increasingly for adults.[7,8]

Current therapies are expensive, and with the frequent infusion schedule, adherence is difficult.[9] In addition, convenient access to peripheral veins is often a problem, and many children require use of central venous access devices, with the concomitant risks of infection and thrombosis.[10,11] Despite recent promising success in gene therapy for hemophilia B, a cure for hemophilia is not yet available.[12] Thus, improved factor preparations and/or novel approaches are needed.

Various methods are in development to improve the treatment of hemophilia, including the use of bioengineered coagulation factors, which require less frequent injections.[13,14,15,16,17,18] These are exciting times for new approaches to the treatment of hemophilia. The different approaches are summarized in the Table.

In 2014, antihemophilic factor (Recombinant), Fc fusion protein (rFVIII-Fc), and eftrenonacog alfa (rFIXFc) were approved for clinical use. These will be discussed in greater detail than the others still in development, but comparative clinical experience eventually will be necessary to determine the relative clinical advantages of the various new products.

Table. New Factor Products for Hemophilia

Factor Modification Clinical Benefit Status*
rFIX-Fc Fusion to FcIg 3-fold increase T1/2 Approved US and Canada
rFIX-FP Fusion to albumin 5-fold increase T1/2 Phase 3 completed
N9-GP 40 kDa PEG on activation peptide 4- to 5-fold increase T1/2 phase 3 completed
rFVIII-Fc Fusion to FcIg 1.8-fold increase T1/2 Approved in US and Canada
BAX855 20 kDa PEG/full length FVIII 1.5-fold increase T1/2 In phase 3
BAY94-9027 60 kDa PEG single site 1.7-fold increase T1/2 Phase 3 completed
N8-GP Single 40 kDa PEG attached to 21 amino acid B domain 1.5-fold increase T1/2 In phase 3
rhFVIII-SC Single-chain FVIII Higher affinity to vWF Phase 3 completed
rFVIII-huCL Produced in human cell line Human glycosylation of FVIII Approved in Canada
rFVIIa-FP Fusion of FVIIa to albumin 3- to 4-fold increase T1/2 In phase 3
rFVIIa-CTP Fusion of rFVIIa to CTP 3- to 4-fold increase T1/2 In phase 1
Other approaches primarily to treat persons with hemophilia with inhibitors
hBS23, ACE910 FXase mimetic, bypasses FVIII; bispecific mAb binds FIXa and FX In phase 1b/3
TFPI inhibitors Inhibit the inhibition of TFPI Several in preclinical development
ALN-AT3 siRNA reduces mRNA antithrombin Starting phase 1

*References in text. Clinical status updates available at

CTP = C-terminal peptide; F = factor; FcIg = Fc domain of immunoglobulin (Ig)G; kDa = kilodaltons; mAB = monoclonal antibody; mRNA = messenger RNA; PEG = polyethylene glycol; siRNA = small interfering RNA; T1/2 = circulating half-life; TFPI = tissue factor pathway inhibitor; vWF = von Willebrand factor


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