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Extending recombinant factor IX Fc fusion protein dosing interval to 14 or more days in patients with hemophilia B

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  • Indiana Hemophilia and Thrombosis Center
Article

Extending recombinant factor IX Fc fusion protein dosing interval to 14 or more days in patients with hemophilia B

Abstract

Background In the phase 3 B‐LONG study (NCT01027364), prophylaxis with recombinant factor IX Fc fusion protein (rFIXFc) every 7 to >14 days was associated with low annualized bleed rates (ABRs) in males aged ≥12 years with severe hemophilia B. The long‐term safety and efficacy of rFIXFc prophylaxis was confirmed in the B‐YOND study (NCT01425723), an extension of the B‐LONG clinical trial. Objective The aim of this post‐hoc analysis was to evaluate the efficacy of a ≥14‐day rFIXFc dosing interval in patients treated prophylactically during B‐LONG or B‐YOND. Methods The analysis included 22 patients aged ≥12 years who received prophylactic rFIXFc with a ≥14‐day dosing interval at any time during B‐LONG or B‐YOND up until the second interim analysis of B‐YOND (September 2015). Results The median (interquartile range [IQR]) rFIXFc exposure on the ≥14‐day dosing interval was 3.4 (1.8‐4) years. Patients treated with a ≥14‐day dosing interval were well controlled with a median (IQR) overall ABR of 1.6 (0.6‐2.7) and a median (IQR) spontaneous ABR of 0.7 (0.3‐1.1) in 18 evaluable patients. A rFIXFc dosing interval of ≥14 days was well tolerated, with no new safety concerns identified. Conclusion Most patients on rFIXFc prophylaxis, with a dosing interval of ≥14 days, remained well controlled; ABRs were consistent with those reported in the overall study population. A ≥14‐day dosing interval can be utilized in some well controlled individuals and reduces the burden imposed by frequent prophylactic injections while maintaining adequate bleed suppression.
Res Pract Thromb Haemost. 2018;1–5.    
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 1
wileyonlinelibrary.com/journal/rth2
Received:16May2018 
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  Accepted:5Octob er2018
DOI:10.10 02/rth 2.12163
BRIEF REP ORT
Extending recombinant factor IX Fc fusion protein dosing
interval to 14 or more days in patients with hemophilia B
Amy D. Shapiro MD1| K. John Pasi MD2| Margareth C. Ozelo MD, PhD3|
Roshni Kulkarni MD4| Christopher Barnowski MD5| Bent Winding MD6|
Johan Szamosi MSc6| Stefan Lethagen MD6,7
Thisisanop enaccessarti cleundertheter msoftheCreativeCommonsAttribution-NonCommercial-NoD erivsL icense,whichpermitsuseanddistrib utionin
anymedium,providedtheoriginalworkisproperlycited,theuseisno n-commercialandnomodi ficat ionsoradaptat ionsaremade.
©2018TheAut hors.Researc h and Prac tice in Thr ombosi s and Haem ostasispublishedbyWileyPeriodi cals,Inconbeh alfofInternationalSocietyonT hrombosis
and Haemostasis.
1IndianaH emoph ilia&ThrombosisCenter,
Indianapolis,Indiana
2RoyalLondonHaem ophiliaCentre,Barts
andTheLondonSc hoolofMe dicineand
Dentis try,London,UK
3INCTdoS angueH emocentro
UNICA MP,Universit yofCam pinas,
Campinas,Brazil
4Depar tmentofPediatr icsandHuman
Develop ment,M ichiga nStateUniversity,
EastLansing,Michigan
5Bioverativ,aSanofiCompany,Waltham,
Massachusetts
6Sobi,Sto ckholm,Sweden
7UniversityofCo penhagen,Cop enhage n,
Denmark
Correspondence
StefanLethagen ,Sobi,SE-11276Stockh olm,
Sweden.
Email:stefan.lethagen@sobi.com
Funding information
SobiandB ioverat iv,aSanoficompany
Abstract
Background:Inthephase3B-LONGstudy(NCT01027364),prophylaxiswithrecom-
binant factorIXFcfusion protein(rFIXFc)every7to>14dayswasassociatedwith
lowannualizedbleedrates(ABRs)inmalesaged≥12yearswithseverehemophiliaB.
The long-term s afety and effic acy of rFIXFc prophylaxis w as confirmed in the B-
YONDstudy(NCT01425723),anextensionoftheB-LONGclinicaltrial.
Objective:Theaimofthispost-hocanalysiswastoevaluatetheefficacyofa≥14-day
rFIXFc dosing interval in patients treated prophylactically during B-LONG or
B - Y O N D .
Methods:Theanalysisincluded22patientsaged≥12yearswhoreceivedprophylac-
ticrFIXFcwitha≥14-daydosingintervalatanytimeduringB-LONGorB-YONDup
untilthesecondinterimanalysisofB-YOND(September2015).
Results:Themedian(interquartilerange[IQR])rFIXFcexposureonthe≥14-daydos-
ing interv al was 3.4 (1.8-4)years. Pat ients treated with a ≥14-day dosing inte rval
werewellcontrolledwithamedian(IQR) overallABRof1.6(0.6-2.7) and a median
(IQR)spontaneousABRof0.7(0.3-1.1)in18evaluablepatients.ArFIXFcdosingin-
tervalof≥14dayswaswelltolerated,withnonewsafetyconcernsidentified.
Conclusion:MostpatientsonrFIXFcprophylaxis,withadosingintervalof≥14days,
remained wellcontrolled; ABRswere consistent with those reportedin the overall
study population. A ≥14-daydosing inter val canbeutilized in somewellcontrolled
individualsandreducestheburdenimposedbyfrequentprophylacticinjectionswhile
maintainingadequatebleedsuppression.
KEY WORDS
clinicaltrial,factorIX,hemophiliaB,prophylaxis,recombinantfusionproteins
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     SHAPIRO e t Al.
1 | INTRODUCTION
Comparedwithon-demandtreatment,prophylacticfactorreplace-
menttherapyimprovesclinicaloutcomesinpeoplewithhemophilia,
reducin g the frequenc y of bleeding epi sodes, and imp roving joint
outcomes andqualityoflife.1,2ForprophylaxisinhemophiliaB,the
use of conventi onal half-life f actor IX (FIX ) product s requires fre -
quent injections to maintain protective FIX levels. The burden im-
posedbyfrequentinjectionsisanimportantbarriertoadherencein
individualswithhemophiliatreatedprophylactically.3
RecombinantFIXFcfusionprotein(rFIXFc;eftrenonacogalfa)is
one of the approved extended half-lifeproductsfor hemophilia B.
rFIXFc is a fusionprotein comprising human coagulation FIXcova-
lently boundwithoutalinker to the Fc domainofhuman immuno-
globulinG1(IgG1)producedinawell-characterizedhumancellline.4
The Fc portion of rFIXFcbinds to theendogenous neonatal Fc re-
ceptorandusestheIgGrecyclingpathway,delayinglysosomaldeg-
radationofFc-containing proteins by recyclingthem backinto the
circulation,therebyresultinginprolongedhalf-lifeofrFIXFc.4rFIXFc
isapprovedforprophylaxisandtreatmentofbleedinginindividuals
ofallagegroupswhohavehemophiliaB.5
Thephase3B-LONGstudydemonstratedthatprophylaxiswith
rFIXFc is ass ociated with low ann ualized bleedin g rates (ABRs) in
malepatientsaged≥12yearswithseverehemophiliaB.6Theexten-
sion stud y,B-YOND, ha s confirmed t he long-ter m safety an d effi-
cacyofprophylaxiswithrFIXFc7;keyresultsuponcompletionofthe
B-YONDstudyareexpec tedin2018.
The appr oved indicati on for rFIXFc in th e EU was updated in
July2017toincludeadosingintervalof≥14daysforuseinpatients
with hem ophilia B who are well co ntrolled with rFIX Fc adminis-
tered ever y 10 days.5Theaimofthecurrentpost-hocanalysiswas
tocharacterizelong-termexperiencewithextendedintervaldosing
usingdatauptotheseconddatacutofB-YOND(September2015).
2 | METHODS
B-LON G (NCT01027364) was a phas e 3, non-rand omized, open-
label, multicenter study, with primary and secondary endpoints
reported previously.6 The stu dy enrolled 123 male p atients aged
≥12yearswithseverehemophiliaB(≤2%ofnormalFIXlevels)whose
priortreatmentregimenwaseitherprophylaxisorondemand.
In B - LONG,pat i e n t s w e r e a s signedt o o n e o ffourt r e a t m e n t g r o u p s:
Group 1 received prophylaxis with rFIXFc 50IU/kg weekly, with the
dose adjusted as needed(n=63); Group2received prophylaxiswith
rFIXFc 100IU/kg at an inter val of every 10days, with the inter val
adjustedasneeded basedonpharmacokinetics (PK)and/oroutcome
(n=29); Group 3 received on-demand treatment with rFIXFc 20-
100IU/kgforbleedingepisodes, with the dose adjustedaccordingto
bleedingseverity(n=27);andGroup4receivedtreatmentwithrFIXFc
as part of perioperative care (n=12). Theprimary efficacy endpoint
inB-LONGwastheABR, and primary safetyendpoints were the de-
velopmentofinhibitors(neutralizingantibodies)andadverseevents.
B-YOND (NCT01425723) was a non-randomized, open-label,
extensionstudythatenrolledpatientswhocompletedB-LONG6 or
KidsB-LONG.8In ter i md a t af r omO c tob e r20 14 haveb e enr e por t e d
previously.7Ofthe115patientswhocompletedB-LONG,93were
enrolledinB-YOND.DatafrompatientsenrolledinB-YONDfrom
B-LONGarereportedinthispost-hocanalysis;patientsenrolledin
B-YONDfromKidsB-LONGwerenotincludedastheKidsB-LONG
studydesigndidnotallowdosingintervalslongerthan1week.
There were four treatment groups in B-YOND: Group 1 received
prophylaxiswithrFIXFc20-100IU/kgevery7days(weeklyprophylaxis);
Group 2 re ceived interval-adjusted p rophylaxis with r FIXFc 100IU/kg
every 8-16days wit h dosing based on th e patient’s clinic al profile ob-
servedintheparentstudyandindividual PKprofile,trough,and/orpeak
(recovery)values; Group 3 received modifiedprophylaxis with the pos-
sibilit y to furthe r personal ize dosing by eg, ch anging dosing f requenc y,
add ingpr eve ntiondosesbefor estre nu ousac ti vities,ortargetingatro ugh
FIXlevelof>5IU/dLifwarrantedbybleedinghistoryand/oractivit ylevel
toim proveprop hyl axis;andGro up4receivedo n-demandtreat ment.The
primar yendpointinB-YONDwasthedevelopmentofinhibitors.
Thispost-hocanalysisincludedpatientsaged≥12yearswhore-
ceivedprophylac ticrFIXFcwithadosinginter valof≥14daysatany
timeduringB-LONGorB-YOND,upuntilthetimeofthesecondin-
terimanalysis(September2015;seeFigure1).Descriptivestatistics
wereusedtosummarizedata.
3 | RESULTS AND DISCUSSION
Twenty-two patients received rFIXFcprophylaxis withados-
ing interval of ≥14days at any time during B-LONG or B-
YOND,until the time of the second interimB-YONDanalysis
(September2015). Themedianageatbaselinewas34.5years
with the vast majority of patients having <1% endogenous
FIX acti vity. The median t erminal half-life (t½) of rF IXFc was
99.8hours(Table1).
The majority of patients (18 of 22) whose dosing interval
wasextendedto≥14dayswereoninterval-adjustedprophylaxis
Essentials
• ProphylacticreplacementofcoagulationfactorIX(FIX)isrecommendedinseverehemophiliaB.
• RecombinantFIXFcfusionprotein(rFIXFc)iseffectiveandwelltolerated.
• Phase3post-hocanalysisshowsthatsomepatientsarewellcontrolledwithrFIXFcevery≥14days.
• A≥14-dayrFIXFcdosingintervalmayhelpreducetreatmentburdenforwell-controlledpatients.
    
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 3
SHAPIRO e t Al.
prior to th e extension (Fig ure1). The median (I QR) rFIXFc ex-
posure du ration before e xtending th e dosing inter val was 116
(61-205)days, the median (IQR) weekly consumption was 63
(59-72)IU/kg, and the median (IQR) dosing interval was 10
(10-12)days.
Patientshad amedianrFIXFcexposure onthe≥14-day dosing
intervalof3.4years, witha mediandose per injection of 100IU/
kg, andamedian dosing interval of14days(Table2).Six patients
haddosingintervalsthatextended beyond 14days:1 on15days,
3 on 16days, 1 on 17days, an d 1 on 21days. The m edian (IQR)
trough le vel while on ≥14-day dosin g was estimated to b e 2.80
(2.3-3.8)IU/dLbasedon149measurements.
The majority of patients treated prophylactically appeared
wellcontrolledandexperiencedzerobleedsduringtheperiodbe-
foretheirdosinginter valwasextendedto≥14days.However,5of
22patient sreturnedpermanentlytoadosingintervalof<14days
duetoaPKresult(n=1),patientrequest(n=3:twoofwhichwere
forp ers ona lr eas ons ,t het hi rdd ue to ble edi ng ),o rr epe atedb lee d-
ing(elbow;n=1).Amongthese fivepatients,onehadpreviously
beentreatedon-demandandthreeothershadeitheraveryshort
orno obser vationperiodonrFIXFcpriortoextendingthedosing
intervaland it is therefore uncertainifthese patients truly were
wellcontrolledbeforeextendingtheirdosingintervalto≥14days.
Theremainin g17ofth e22patie nts(77.3%)continuedonadosi ng
FIGURE1 StudyflowinB-LONGandtheB-YONDex tensionstudy
Subjects aged 12 years with a dosing interval of 14
days at any time during this period (N = 22)
At the time of extending the dosing interval:
18 patients were treated with individualized prophylaxis
1 patient was on once-weekly prophylaxis
2 patients were treated on demand
1 patient started B-LONG on a 14-day interval
Phase 3 study Phase 3 extension study
Group 4: Perioperative treatment
Primary
completion
2012
Second interim
analysis
Sep 2015
First interim
analysis
Oct 2014
Start
2009
Group 3: On-demand treatment
Group 4: On-demand treatment
Group 2: Interval-adjusted prophylaxis
Group 1: Dose-adjusted weekly prophylaxis
Group 3: Modified prophylaxis
Group 2: Interval-adjusted prophylaxis
Group 1: Dose-adjusted weekly prophylaxis
B-LONG B-YOND
TABLE1 Baselinepatientcharacteristics
Characteristic
Median (IQR) or n (%)
Patient s treated with ≥14- day
dosing inter val, N = 22
Age,y 34.5(23-48)
Race
White 13(59.1)
Black 2(9.1)
Asian 7(31.8)
Other 0
Severity
<1%endogenousFIXactivity 20(90.9)
1%-2%endogenousFIXactivity 2(9.1)
Genotype
Missense 16(72.7)
Nonsense 1(4.5)
Frame shif t 1(4.5)
Splicemutation 2(9.1)
Partialgenedeletion 1(4.5)
Largedeletions 0
Unknown 1(4.5)
rFIXFct½,h 99.8(86. 3-105.9)a
Data represent values at baselineofB-LONGfor patients treated with
≥14-day dosinginterval any time during B-LONGor B-YOND, untilthe
timeofthesecondinterimB-YONDanalysis.
FIX,factorIX;IQR,interquartilerange;rFIXFc,recombinantfactorIXFc
fusionprotein;t½,terminalhalf-life.
aGeomet ric mean calcu lations (as repor ted in B-LON G6) are not pre-
sentedbecauseofdifferencesins amplingprofiles.
TABLE2 ExposuretorFIXFcona≥14-daydosinginterval
Parameter
Median (IQR) N = 22
Exposureduration,days 1261(648-1448)
Exposuredays,days 91(69-106)
Weeklyconsumption,IU/kg 50(46-51)
Doseperinjection,IU/kg 100(92-102)
Dosinginterval,days 14 (14-14)
IQR, interquar tile range; rFIXFc, recombinant factor IX Fc fusion
protein.
4 
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     SHAPIRO e t Al.
intervalof≥14daysatthetimeofthesecondinterimdatacut,al-
thoughthreeofthese17patientshadhadatemporaryreduction
(50, 30, an d 22days) in the dosi ng interv al to <14daysat s ome
point befo re the data cut be cause of bleedin g (n=1),r epeated
bleedingintothekneefollowingar throscopy(n=1)andPKresult
(n=1).
The ABR during theperiodwith a ≥14-daydosing intervalwas
estimatedforpatientsonpriorprophylaxiswhohadanobservation
period of ≥6mo nths on the exten ded dosing regimen . These pa-
tientshadamedian(IQR)overallABRof1.6(0.6-2.7)(Table3),which
isconsistentwiththeABRreportedfortheoverallstudypopulation.
Incomparison,themedian(IQR)overall ABR was1.4(0.0-3.4)with
interval-adjusted prophylaxis in B-LONG,6 2.25 (0.87-4.47) with
interval-adjusted prophylaxis and 2.42 (1.26-5.40) with modified
prophylaxistheinterimanalysisofB-YOND.7
The media n (IQR) spontan eous ABR during th e period with a
≥14-day dosing i nterval was 0 .7( 0.3-1.1) (Table3). This compa res
withamedian(IQR)spontaneousABRof0.9(0.0-2.3)withinterval-
adjusted prophylaxis in B-LONG,6 0.68 (0-2.58) with interval-
adjustedprophylaxisand0.41(0-1.84)withmodifiedprophylaxisin
theinter imana ly sisinB-YOND.7Thesedataprovidefurthersupport
thatpatient swith hemophilia Bcan remain wellcontrolledwithan
individualized14-daydosinginterval.
Intotal, fourpatientswere excludedfrom the ABRcalculation;
twobecausetheyhadanobservationperiodthatwastooshort(28
and 57days) to obt ain robust es timates of ABR a nd an additio nal
two patients because they had received on-demand treatment be-
forethedosinginter valwaschangedto≥14days.
A total of 120 bl eeding epis odes in 22 patie nts occurre d over
744patientmonthsofexposurewhileona≥14-daydosinginterval.
Approximately 60% ofthebleedsoccurred duringthefirst 10days
sincepreviousdosing.Themajorit yofbleedingepisodes(114[95%])
werecontrolledwitheitheroneortwoinjections.Themedian(IQR)
totalrFIXFcdoseusedtotreatableedwas56.3(37-99.1)IU/kg.
Theadverseeventprofile was consistent with thatexpectedin
ahemophiliaBpopulation,andnonewsafetyconcernswereidenti-
fied,c o m p a r e d w i t h t h e ove rall p o p u l a t i o n s i nB-LO N G 6o rB-YO ND.7
Therewerenor ep or t sofse ri ou sallergicre ac tions,an ap hy la xis,vas-
cularthromboticevents,ordevelopmentofinhibitors.6 ,7
In conclus ion, these da ta confirm th at patients w ho were well
controlled on a 10-day dosing interval of rFIXFc prophylaxis re-
mained wel l controlle d with low ABR s when treate d long-ter m on
a≥14-daydosing interval,and the treatment was welltolerated. A
rFIXFcdosingintervalof≥14daysallowsforbroadertreatmentflex-
ibilityand treatment individualizationcomparedwith conventional
FIX products, and further reduces the burden for patients, poten-
tiallypositivelyimpactingadherence.
ACKNOWLEDGMENTS
This study was sponsored by Sobi and Bioverativ, a Sanof i com-
pany. Writing assis tance was provid ed by Gillian Keating MB ChB
(Mudskip per Business , Ltd.), funded by S obi and editor ial support
was provided by Kristina Lindsten (Medical Writer,Sobi), all in ac-
cordancewithgoodpublicationpractice(GPP3)guidelines(http://
www.ismpp.org/gpp3).
RELATIONSHIP DISCLOSURES
A.D. ShapiroreportsclinicalresearchwithBioverativ,Octapharma,
NovoNordiskandShire,andadvisoryboardswithNovoNordiskand
Shire. K. Pasi reports research funding, fees for advisory boards
and travel grants from Bioverativ, Sobi and Biomarin, fees for lec-
tures and serving onadvisory boardsfromShire, research funding,
feesforlectures,servingonadvisoryboardsandtravelgrantsfrom
Octapharma,feesforlecturesfromNovoNordisk,researchfunding,
fees for lecturesand ser ving onadvisory boards for Alnylam, fees
forlectures from Pfizer,andfees for advisoryboard from Catalyst
Bio.M.C.OzeloreportsresearchsupportfromSobiandBioverativ,
research support and participation on advisory boards and on a
speakers bureaufrom NovoNordisk, Shire, Pfizer,participation on
aspeakersbureauandgrantreviewpanelforGrifols,participation
onadvisoryboardsforCSLBehring.R.Kulkarnireportsclinicaltrial
involvementwithBioverativ/Biogen,advisoryboardsforBioverativ,
BPL, NovoNordisk, Shire, Rocheand Kendrion. C. Barnowski is an
employeeofBioverativ,aSanoficompany.J.Szamosiisanemployee
ofSobiandholderofSobishares.B.WindingisanemployeeofSobi.
S.LethagenisanemployeeofSobi.
AUTHOR CONTRIBUTIONS
A.D. Shapiro: Investigator in the clinical trial and par ticipated in
draftingandrevisingthemanuscript,andreadandapprovedthefinal
version as submitted. K.J. Pasi: Investigator in the clinicaltrial and
parti cipated in dr afting and r evising the ma nuscript , and read and
approvedthefinalversionassubmitted.M.C.Ozelo:Investigatorin
theclinicaltrialandparticipated in draftingandrevisingthemanu-
script, and read and approved the final version as submitted. R.
Kulkarni:Investigatorintheclinicaltrialandpar ticipatedindrafting
andrevisingthemanuscript ,andreadandapprovedthefinalversion
TABLE3 Annualizedbleedingrateinpatientstreated
prophylacticallywitha≥14-daydosinginterval
Annualized bleeding rate
Median (IQR)
Patients treated
prophylactic ally with
≥14- day dosing
interval, N = 18a
Overall 1.6(0.6-2.7)
Joint 1.0(0.3-1.6)
Spontaneous 0.7(0.3-1.1)
Traumatic 0.5(0.3-1)
IQR,interquar tilerange.
aThisan alysisinclu dedpatientswhowereo nprophylaxisbeforee xte nd-
ing the do sing interval to ≥14day (ie, t he two patient s receiving on-
demand treatment were excluded), and who had been observed for
≥6mo(therebyexcludinganadditionaltwopatients).
    
|
 5
SHAPIRO e t Al.
assubmitted.C.Barnowski:Contributedtothedesignoftheanalysis
andthe interpretationof thedata, and par ticipatedindraftingand
revisingofthemanuscriptandreadandapprovedthefinalversionas
submitted.B.Winding:Substantiallycontributedtothedesignofthe
analysesandtheinterpretationofdata.Participatedindraftingand
revising of the manuscript and readandapproved thefinalversion
assubmitted. J.Szamosi:Performedallanalysesandpar ticipatedin
theinterpretationofdata.Participatedindraftingandrevisingofthe
manuscriptandreadandapprovedthefinalversionassubmitted.S.
Lethagen:Substantiallycontributedtothedesignoftheanalysesand
theinterpretationofdata.Participatedindraftingandrevisingofthe
manuscriptandreadandapprovedthefinalversionassubmit ted.
REFERENCES
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protein.Haemophilia.2014;20:e327–35.
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nant fac tor IX Fc fusion protein in hemophilia B. N Engl J Med.
2013;369:2313–23.
7. Pasi KJ,FischerK , RagniM , et al. Long-ter msafetyand eff icacyof
extended-interval prophylaxiswith recombinant factor IXFc fusion
protein (rFI XFc) in subjec ts with hae mophilia B. T hromb Haemo st.
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8. FischerK,KulkarniR,NolanB,etal.Recombinantf actorIXFcfusionpro-
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How to cite this article:ShapiroAD,PasiKJ,OzeloMC,etal.
ExtendingrecombinantfactorIXFcfusionproteindosing
intervalto14ormoredaysinpatientswithhemophiliaB.Res
Pract Thromb Haemost. 2018;00:1–5. ht t p s: //d o i .
org /10.10 02/rth2.12163
... Eftrenonacog-α, marketed as Alprolix ® , which is a Fc-fused-factor IX for treatment of haemophilia, is an example of recently approved Fc fusion therapeutic (Table 1) (Graf, 2018;Shapiro et al., 2012;Shapiro et al., 2019;Strohl, 2015). In addition, Eloctate ® (Fc fused factor VIII) has also been studied clinically for the treatment of haemophilia (Mahlangu et al., 2018). ...
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Haemophilia B (HB) is a rare disease which may lead to chronic disabling arthropathy, resulting in a significant clinical, social and economic impact. In recent years, new extended half-life (EHL) factor IX concentrates produced by recombinant technology (rFIX) have been developed. They have shown significantly prolonged half-life as compared to other rFIX products and improved bleeding control when used as prophylaxis. To date, EHL rFIX products reimbursed in Italy are a recombinant coagulation factor IX produced with Fc technology (rFIXFc) and a recombinant fusion protein containing rFIX fused with recombinant albumin (rIX-FP). The results of extension studies with injection intervals with a median of almost every 14 days for the complete individualized interval prophylaxis (IP) group on rFIXFc and 21 days for a selected subgroup of patients on rIX-FP have recently been published.The aim of this analysis was to estimate the cost of prophylactic treatment with rFIXFc and rIX-FP in adult patients, in the light of new clinical evidence and current average prices in Italy.The cost of therapy was estimated on the basis of the results of extension studies, the average prices reported in regional drug tenders and assuming an average patient weight of 70 kg.The analysis estimated a cost per patient/year between €224,407 and €230,355 for rFIXFc and between €242,259 and €368,587 for rIX-FP. The sensitivity analysis confirmed the robustness of the results.The use of rFIXFc over rIX-FP proves to be the least expensive choice for the treatment of HB in Italy.
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Purpose: In patients with hemophilia B, treatment with extended half-life (EHL) recombinant factor IX allows for longer dosing intervals while providing equal or superior bleeding protection compared with standard half-life products. This enables flexible, individualized treatment schedules, which reduce the burden of prophylaxis and improve patient outcomes. This analysis compared the efficacy of recombinant factor IX Fc fusion protein (rFIXFc) and recombinant factor IX albumin fusion protein (rIX-FP), two EHL therapies approved for prophylaxis and treatment of bleeding in hemophilia B. Patients and methods: Matching-adjusted indirect treatment comparison (MAIC) was used to adjust the between-treatment differences in baseline characteristics. Individual patient data for rFIXFc (B-LONG) were matched to aggregated data for rIX-FP (PROLONG-9FP) followed by statistical comparison for estimated annualized bleeding rate (ABR) using a Poisson regression model with adjustment for over dispersion. Data were analyzed according to treatment regimen prior to study entry: prior prophylaxis (rFIXFc, n=48; rIX-FP, n=40) or prior episodic treatment (n=43 and n=19, respectively). Relative treatment effects are presented as incidence rate ratios (IRR) with 95% confidence intervals (CI). Results: After adjustment for baseline characteristics, estimated ABR observed for rFIXFc and rIX-FP was not significantly different in patients on prior prophylaxis (1.87 versus 1.58; IRR 1.18, 95% CI 0.67-2.10) or prior episodic (2.25 versus 2.22; IRR 1.01 95% CI 0.40-2.57) regimens. Conclusion: This MAIC analysis shows that the estimated ABR for rFIXFc-treated patients from B-LONG was similar to that of rIX-FP-treated patients from PROLONG-9FP and, therefore, indicates that the two EHL therapies provide similar efficacy when used as prophylaxis for patients with hemophilia B. Trough levels differ between the two products (1-3% [targeted] versus 20% [observed], respectively), suggesting that trough level is not a surrogate indicator when ABR is used as a criterion for clinical efficacy when comparing these FIX products in hemophilia B.
Article
Extended half-life (EHL) products have shown robust efficacy in clinical trials, whilst allowing for less intense treatment regimens when compared with standard half-life products. Regimen optimisation with EHL products could lead to further improvements in bleeding rates, quality of life and reductions in treatment burden. Patients now expect good efficacy, a lower treatment burden and equivalent safety when compared with standard half-life products. As our knowledge base grows these expectations have evolved and targeting an annualised bleeding rate of zero has become a more realistic clinical goal. Personalised prophylaxis can help patients achieve these goals. However, a number of challenges still remain, including cost, challenges in predicting outcomes for patients and differences in patients' and clinicians' expectations. When switching a patient, comprehensive patient care can reduce the impact of these issues. This review presents in brief the protein therapeutics with an extended half-life, including key trial results, challenges of chronic care that impact on patients' outcomes and how the modified proteins might help address some of these issues. In addition, practical steps for managing the switch to EHL products are presented.
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Recombinant factor IX Fc (rFIXFc) fusion protein is the first of a new class of bioengineered long-acting factors approved for the treatment and prevention of bleeding episodes in haemophilia B. The aim of this work was to describe the manufacturing process for rFIXFc, to assess product quality and to evaluate the capacity of the process to remove impurities and viruses. This manufacturing process utilized a transferable and scalable platform approach established for therapeutic antibody manufacturing and adapted for production of the rFIXFc molecule. rFIXFc was produced using a process free of human- and animal-derived raw materials and a host cell line derived from human embryonic kidney (HEK) 293H cells. The process employed multi-step purification and viral clearance processing, including use of a protein A affinity capture chromatography step, which binds to the Fc portion of the rFIXFc molecule with high affinity and specificity, and a 15 nm pore size virus removal nanofilter. Process validation studies were performed to evaluate identity, purity, activity and safety. The manufacturing process produced rFIXFc with consistent product quality and high purity. Impurity clearance validation studies demonstrated robust and reproducible removal of process-related impurities and adventitious viruses. The rFIXFc manufacturing process produces a highly pure product, free of non-human glycan structures. Validation studies demonstrate that this product is produced with consistent quality and purity. In addition, the scalability and transferability of this process are key attributes to ensure consistent and continuous supply of rFIXFc.
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Background Prophylactic factor replacement in patients with hemophilia B improves outcomes but requires frequent injections. A recombinant factor IX Fc fusion protein (rFIXFc) with a prolonged half-life was developed to reduce the frequency of injections required. Methods We conducted a phase 3, nonrandomized, open-label study of the safety, efficacy, and pharmacokinetics of rFIXFc for prophylaxis, treatment of bleeding, and perioperative hemostasis in 123 previously treated male patients. All participants were 12 years of age or older and had severe hemophilia B (endogenous factor IX level of ≤2 IU per deciliter,or ≤2% of normal levels). The study included four treatment groups: group 1 received weekly dose-adjusted prophylaxis (50 IU of rFIXFc per kilogram of body weight to start), group 2 received interval-adjusted prophylaxis (100 IU per kilogram every 10 days to start), group 3 received treatment as needed for bleeding episodes (20 to 100 IU per kilogram), and group 4 received treatment in the perioperative period. A subgroup of group 1 underwent comparative sequential pharmacokinetic assessments of recombinant factor IX and rFIXFc. The primary efficacy end point was the annualized bleeding rate, and safety end points included the development of inhibitors and adverse events. Results As compared with recombinant factor IX, rFIXFc exhibited a prolonged terminal halflife (82.1 hours) (P<0.001). The median annualized bleeding rates in groups 1, 2, and 3 were 3.0, 1.4, and 17.7, respectively. In group 2, 53.8% of participants had dosing intervals of 14 days or more during the last 3 months of the study. In groups 1, 2 and 3, 90.4% of bleeding episodes resolved after one injection. Hemostasis was rated as excellent or good during all major surgeries. No inhibitors were detected in any participants receiving rFIXFc; in groups 1, 2, and 3, 73.9% of participants had at least one adverse event, and serious adverse events occurred in 10.9% of participants. These events were mostly consistent with those expected in the general population of patients with hemophilia. Conclusions Prophylactic rFIXFc, administered every 1 to 2 weeks, resulted in low annualized bleeding rates in patients with hemophilia B
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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 resulted in low ABRs when dosed prophylactically 1 to 2 times per week.
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Effective ways to prevent arthropathy in severe hemophilia are unknown. We randomly assigned young boys with severe hemophilia A to regular infusions of recombinant factor VIII (prophylaxis) or to an enhanced episodic infusion schedule of at least three doses totaling a minimum of 80 IU of factor VIII per kilogram of body weight at the time of a joint hemorrhage. The primary outcome was the incidence of bone or cartilage damage as detected in index joints (ankles, knees, and elbows) by radiography or magnetic resonance imaging (MRI). Sixty-five boys younger than 30 months of age were randomly assigned to prophylaxis (32 boys) or enhanced episodic therapy (33 boys). When the boys reached 6 years of age, 93% of those in the prophylaxis group and 55% of those in the episodic-therapy group were considered to have normal index-joint structure on MRI (P=0.006). The relative risk of MRI-detected joint damage with episodic therapy as compared with prophylaxis was 6.1 (95% confidence interval, 1.5 to 24.4). The mean annual numbers of joint and total hemorrhages were higher at study exit in the episodic-therapy group than in the prophylaxis group (P<0.001 for both comparisons). High titers of inhibitors of factor VIII developed in two boys who received prophylaxis; three boys in the episodic-therapy group had a life-threatening hemorrhage. Hospitalizations and infections associated with central-catheter placement did not differ significantly between the two groups. Prophylaxis with recombinant factor VIII can prevent joint damage and decrease the frequency of joint and other hemorrhages in young boys with severe hemophilia A. (ClinicalTrials.gov number, NCT00207597 [ClinicalTrials.gov].).
Article
Background: Kids B-LONG was a multicentre, open-label, phase 3 study assessing the safety, efficacy, and pharmacokinetics of recombinant factor IX Fc fusion protein (rFIXFc) in previously treated paediatric patients younger than 12 years with severe haemophilia B. Methods: The study enrolled 30 previously treated boys younger than 12 years with haemophilia B (≤2 IU/dL [≤2%] endogenous coagulation factor IX [FIX] activity). All patients were initially given rFIXFc prophylaxis (50-60 IU/kg) once per week with adjustments to dose (≤100 IU/kg per infusion) or dosing frequency (up to two times per week) as needed. The primary outcome measure was development of inhibitors (neutralising antibodies). Secondary outcomes were pharmacokinetics, annual bleeding rate (ABR), spontaneous joint ABR, the number of infusions and dose required to resolve a bleed, time from last infusion of rFIXFc to a bleeding episode, assessment of response to treatment, and total annualised rFIXFc consumption for prevention and treatment of bleeding episodes. All patients underwent sequential pharmacokinetic evaluations of their prestudy FIX and rFIXFc. The completed trial is registered with ClinicalTrials.gov, number NCT01440946. Findings: No patients developed inhibitors to rFIXFc; in the 30 enrolled patients the most common adverse events were nasopharyngitis (n=7; 23%) and fall (n=6; 20%); four patients (13%) had serious adverse events. Overall, rFIXFc exhibited a prolonged half-life of 68·6 h (95% CI 61·8-76·0), reduced clearance, and similar recovery compared with prestudy FIX. The median ABR was 2·0 (0·0-3·1) overall and 0·0 (0·0-0·0) for spontaneous joint bleeds; ten (33%) of 30 patients reported no bleeding, and 19 (63%) reported no joint bleeding on-study. The median average prophylactic dose of rFIXFc was 58·6 IU/kg (IQR 52·3-64·8) per week. Throughout the study, 29 (97%) of 30 patients remained on once per week infusions. Interpretation: Weekly infusions of rFIXFc were well tolerated and resulted in low bleeding rates in children with severe haemophilia B. Funding: Biogen, Sobi.
Article
The safety, efficacy, and prolonged half-life of recombinant factor IX Fc fusion protein (rFIXFc) were demonstrated in the Phase 3 B-LONG (adults/adolescents ≥12 years) and Kids B-LONG (children <12 years) studies of subjects with haemophilia B (≤2 IU/dl). Here, we report interim, long-term safety and efficacy data from B-YOND, the rFIXFc extension study. Eligible subjects who completed B-LONG or Kids B-LONG could enrol in B-YOND. There were four treatment groups: weekly prophylaxis (20–100 IU/kg every 7 days), individualised prophylaxis (100 IU/kg every 8–16 days), modified prophylaxis (further dosing personalisation to optimise prophylaxis), and episodic (ondemand) treatment. Subjects could change treatment groups at any point. Primary endpoint was inhibitor development. One hundred sixteen subjects enrolled in B-YOND. From the start of the parent studies to the B-YOND interim data cut, median duration of rFIXFc treatment was 39.5 months and 21.9 months among adults/adolescents and children, respectively; 68/93 (73.1 %) adults/adolescents and 9/23 (39.1 %) children had ≥100 cumulative rFIXFc exposure days. No inhibitors were observed. Median annualised bleeding rates (ABRs) were low in all prophylaxis regimens: weekly (≥12 years: 2.3; <6 years: 0.0; 6 to <12 years: 2.7), individualised (≥12 years: 2.3; 6 to <12 years: 2.4), and modified (≥12 years: 2.4). One or two infusions were sufficient to control 97 % (adults/adolescents) and 95 % (children) of bleeding episodes. Interim data from B-YOND are consistent with data from B-LONG and Kids B-LONG, and confirm the longterm safety of rFIXFc, absence of inhibitors, and maintenance of low ABRs with prophylactic dosing every 1 to 2 weeks. Supplementary Material to this article is available online at www.thrombosis-online.com.
Article
In the 1950s, Sweden initiated prophylaxis as a lifelong treatment for haemophilia. It was the first country to do so. To describe and evaluate dosing and outcome of prophylactic treatment in a large cohort of adult people with severe haemophilia who have been using prophylaxis most of their lives. Eighty-one patients born between 1932 and1992 were divided into two groups (Group A started prophylaxis at the age of ≤ 3 yr; Group B at three or more years of age) and evaluated retrospectively. Outcome was evaluated using the Hemophilia Joint Health Score (HJHS) and SF-36, a measure of quality of life. The median number of joint bleeds per year was 0 in both study groups; however, the annual number of joint bleeds during the final 3 yr of observation was higher in group B than in group A (P < 0.006). Twenty-five of 30 patients in group A and 27/51 patients in group B had no joint bleeds in that period. Group A had significantly better joint outcomes than group B. Patients in group A experienced better physical and social health than those in group B. This follow-up has provided for the first time more extensive and detailed information regarding the practice of prophylactic treatment in a large cohort of adults with severe haemophilia. The present study confirms that early start of prophylaxis continuing throughout the lifespan has been successful in virtually eliminating joint bleeds, preserving a close to normal joint status, and keeping patients healthy and able to live normal lives.
Article
Prophylaxis, or the practice of routine replacement infusions of clotting factor concentrate in persons with severe haemophilia, is a demanding medical regimen. Prophylactic infusions require direct venepuncture or sterile entry into a central venous access device on a regular basis. A telephone survey was conducted to elicit information regarding the barriers to compliance with prophylaxis. The Mountain States Regional Haemophilia and Thrombosis Center has recommended prophylaxis to 52 male patients with haemophilia A or B. The haemophilia nurse attempted to contact all of these patients or their parents, and contact was made with 38 (73.1%) of them. Respondents were asked about the following issues: their decision to initiate prophylaxis; their self-rated compliance; the challenges, barriers, and facilitators of prophylaxis; and their perceived value of the therapy. Four patients (10.5%) elected not to begin prophylaxis. Of the 34 persons who began prophylaxis, 20 respondents (58.8%) rated their compliance as excellent. Nearly one-third of the families with excellent compliance (giving 75-100% of prescribed infusions) stated that the time-consuming nature of prophylaxis was the most significant challenge of the regimen. In addition, 58.3% of the families that gave less than the prescribed number of infusions reported that the time commitment was the primary reason for missing infusions. Knowledge of the benefits of prophylaxis was the primary facilitator of compliance for 44.1% of families. Ninety-seven percent of respondents rated prophylaxis as very valuable. These data show that despite the known benefits of prophylaxis, it is a demanding medical regimen, and compliance is imperfect. In addition, this study underscores the importance of providing continuing support and education for patients and families who are implementing prophylaxis.