Clinical utility and patient perspectives on the use of extended half-life rFIXFc in the management of hemophilia B

Figures & data

Figure 1 Expected FIX activity levels after doses of rFIXFc or rFIX (50 IU/kg body weight) were administered intravenously in multiple patients at time 0 hours.

Notes: FIX activity was followed for the specified intervals. The immediate post-dose recovery giving a FIX activity level of 50% is as expected for both the short-acting rFIX (black triangles) and the extended half-life rFIXFc (gray circles). The red line indicates the hours when the FIX activity level is <2% in this individual after taking the short-acting rFIX, and thus when the individual is at risk of bleeding. The vertical lines represent the standard deviation of FIX activity levels for 23 patients with hemophilia B. From N Engl J Med, Powell JS, Pasi KJ, Ragni MV, et al, Phase 3 study of recombinant factor IX Fc fusion protein in hemophilia B, 369:2313–2323. Copyright © 2013 Massachusetts Medical Society. Modified with permission. Available from http://www.nejm.org/doi/full/10.1056/NEJMoa1305074.²⁹
Abbreviations: FIX, factor IX; rFIXFc, recombinant factor IX fused with the fragment, crystallizable domain of IgG; Ig, immunoglobulin; rFIX, recombinant fix.

Table 1 New factor products for hemophilia

Factor	Modification	Clinical benefit/status*	Reference
FIX
rFIXFc	Fusion to Fc IgG	Approved in US, Canada, Australia and Japan	^Citation15, ^Citation17, ^Citation29
rFiX-FP	Fusion to albumin	3–5-fold increase in t1/2 Phase III completed	^Citation16, ^Citation18, ^Citation43
N9-GP	40 kDa PEG on activation peptide	Phase III completed	^Citation13
FVIII
rFVIII-Fc	Fusion to Fc IgG	1.8-fold increase in t1/2 Approved in US and Canada	^Citation44
BAX 855	20 kDa PEG/full length FVIII	1.5-fold increase in t1/2 In Phase III	^Citation57
BAY 94-9027	60 kDa PEG single site	1.7-fold increase in t1/2 Phase III completed	^Citation56
N8-GP	Single 40 kDa PEG attached to 21 amino acid B domain	1.5-fold increase in t1/2 In Phase III	^Citation58
rhFVIII-SC	Single chain FVIII	Higher affinity to vWF In Phase III	^Citation63
rFVIII-huCL	Produced in human cell line	Human glycosylation of FVIII In Phase III	^Citation60, ^Citation61
FVIIa
rFVIIa-FP	Fusion of FVIIa to albumin	3–4-fold increase in t1/2 In Phase III	^Citation64
Other approaches primarily to treat patients with hemophilia with inhibitors
mAB
hBS23	FXase mimetic, bypasses FVII	Bispecific mAb binds FIXa and FX	^Citation65
(ACE910)		In Phase I
TFPI
mAb2021	Blocks the action of TFPI	Several in preclinical development	^Citation66, ^Citation67
BAX 499	Blocks the action of TFPI	Several in preclinical development	^Citation68, ^Citation80
ATIII
ALN-AT3	siRNA reduces mRNA antithrombin	Starting Phase I	^Citation76

Notes: Clinical status updates are available at www.clinicaltrials.gov.

Abbreviations: AT, antithrombin; Fc, fragment, crystallizable; FIX, factor IX; FIXa, factor IXa; rFIXFc, recombinant factor IX fused to the Fc domain of IgG; FVII, factor VII; FVIII, factor III; FX, factor X; Ig, immunoglobulin; mAb, monoclonal antibody; mRNA, messenger RNA; PEG, polyethylene glycol; rFIX-FP, recombinant factor IX fused to albumin; rFVIIa, recombinant factor VIIa; rFVII-Fc, recombinant factor VII fused to the Fc domain of IgG; rFVIIa-FP, recombinant factor VIIa fused to albumin; rFVII-huCL, recombinant factor VII human cell line; rhFVII-SC, recombinant human factor VIII single chain; siRNA, short interfering RNA; t_1/2, half-life; TFPI, tissue factor pathway inhibitor; vWF, von Willebrand factor.

PowellJSPasiKJRagniMVPhase 3 study of recombinant factor IX Fc fusion protein in hemophilia BN Engl J Med2013369242313232324304002

 PubMed Web of Science ®Google Scholar

ShapiroADRagniMVValentinoLARecombinant factor IX-Fc fusion protein (rFIXFc) demonstrates safety and prolonged activity in a Phase I/IIa study in hemophilia B patientsBlood2012119366667222110246

 PubMed Web of Science ®Google Scholar

PetersRTLowSCKamphausGDProlonged activity of factor IX as a monomeric Fc fusion proteinBlood2010115102057206420056791

 PubMed Web of Science ®Google Scholar

MetznerHJPipeSWWeimerTSchulteSExtending the pharmacokinetic half-life of coagulation factors by fusion to recombinant albuminThromb Haemost2013110593193924178510

 PubMed Web of Science ®Google Scholar

SantagostinoENegrierCKlamrothRSafety and pharmacokinetics of a novel recombinant fusion protein linking coagulation factor IX with albumin (rIX-FP) in hemophilia B patientsBlood2012120122405241122859609

 PubMed Web of Science ®Google Scholar

SantagostinoEPROLONG-9FP clinical development program – Phase I results of recombinant fusion protein linking coagulation factor IX with recombinant albumin (rIX-FP)Thromb Res2013131Suppl 2S7S1023537724

 PubMed Web of Science ®Google Scholar

NegrierCKnobeKTiedeAGiangrandePMossJEnhanced pharmacokinetic properties of a glycoPEGylated recombinant factor IX: a first human dose trial in patients with hemophilia BBlood2011118102695270121555744

 PubMed Web of Science ®Google Scholar

MahlanguJPowellJSRagniMVPhase 3 study of recombinant factor VIII Fc fusion protein in severe hemophilia ABlood2013123331732524227821

 PubMed Web of Science ®Google Scholar

TurecekPLBossardMJGraningerMBAX 855, a PEGylated rFVIII product with prolonged half-life. Development, functional, and structural characterisationHamostaseologie201232Suppl 1S29S3822961422

 PubMed Web of Science ®Google Scholar

CoyleTERedingMTLinJCMichaelsLAShahAPowellJPhase I study of BAY 94-9027, a PEGylated B-domain-deleted recombinant factor VIII with an extended half-life, in subjects with hemophilia AJ Thromb Haemostat2014124488496

 PubMed Web of Science ®Google Scholar

TiedeABrandBFischerREnhancing the pharmacokinetic properties of recombinant factor VIII: first-in-human trial of glycoPEGylated recombinant factor VIII in patients with hemophilia AJ Thromb Haemost201311467067823398640

 PubMed Web of Science ®Google Scholar

ZollnerSBRaquetEMuller-CohrsJPreclinical efficacy and safety of rVIII-SingleChain (CSL627), a novel recombinant single-chain factor VIIIThromb Res2013132228028723830969

 PubMed Web of Science ®Google Scholar

SandbergHKannichtCStenlundPFunctional characteristics of the novel, human-derived recombinant FVIII protein product, human-cl rhFVIIIThromb Res2012130580881723010293

 PubMed Web of Science ®Google Scholar

KannichtCRamstromMKohlaGCharacterisation of the post-translational modifications of a novel, human cell line-derived recombinant human factor VIIIThromb Res20131311788823058466

 PubMed Web of Science ®Google Scholar

ZollnerSSchuermannDRaquetEPharmacological characteristics of a novel, recombinant fusion protein linking coagulation factor VIIa with albumin (rVIIa-FP)J Thromb Haemost201412222022824641308

 PubMed Web of Science ®Google Scholar

MutoAYoshihashiKTakedaMAnti-factor IXa/X bispecific antibody (ACE910): hemostatic potency against ongoing bleeds in a hemophilia A model and the possibility of routine supplementationJ Thromb Haemostat2014122206213

 Web of Science ®Google Scholar

HildenILauritzenBSorensonBBHemostatic effect of a monoclonal antibody mAb 2021 blocking the interaction between FXa and TFPI in a rabbit hemophilia modelBlood2012119245871587822563084

 PubMed Web of Science ®Google Scholar

AgersoHOvergaardRVPetersonMBPharmacokinetics of an anti-TFPI monoclonal antibody (concizumab) blocking the TFPI interaction with the active site of FXa in cynomolgus monkeys after iv and sc administrationEur J Pharm Sci201456656924568891

 PubMed Web of Science ®Google Scholar

GorczycaMENairSCJilmaBInhibition of tissue factor pathway inhibitor by the aptamer BAX499 improves clotting of hemophilic blood and plasmaJ Thromb Haemost20121081581159022632032

 PubMed Web of Science ®Google Scholar

ParunovLASoshitovaNPFadeevaOADrug-drug interaction of the anti-TFPI aptamer BAX499 and factor VIII: Studies of spatial dynamics of fibrin clot formation in hemophilia AThrombo Res20141331112119

 PubMed Web of Science ®Google Scholar

AkincASehgalAHettingerJAn RNAi Therapeutic Targeting Antithrombin Increases Thrombin Generation in Nonhuman Primates Available from: http://www.alnylam.com/web/wp-content/uploads/2012/12/ALNY-ASH-AT3posterXpanel-Dec2012-r.pdfAccessed 18 July, 2014

 Google Scholar