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Res Pract Thromb Haemost. 2018;1–5.
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wileyonlinelibrary.com/journal/rth2
Received:16May2018
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Accepted:5Octob er2018
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
Thisisanop enaccessarti cleundertheter msoftheCreativeCommonsAttribution-NonCommercial-NoD erivsL icense,whichpermitsuseanddistrib utionin
anymedium,providedtheoriginalworkisproperlycited,theuseisno n-commercialandnomodi ficat ionsoradaptat ionsaremade.
©2018TheAut hors.Researc h and Prac tice in Thr ombosi s and Haem ostasispublishedbyWileyPeriodi cals,Inconbeh alfofInternationalSocietyonT hrombosis
and Haemostasis.
1IndianaH emoph ilia&ThrombosisCenter,
Indianapolis,Indiana
2RoyalLondonHaem ophiliaCentre,Barts
andTheLondonSc hoolofMe dicineand
Dentis try,London,UK
3INCTdoS angueH emocentro
UNICA MP,Universit yofCam pinas,
Campinas,Brazil
4Depar tmentofPediatr icsandHuman
Develop ment,M ichiga nStateUniversity,
EastLansing,Michigan
5Bioverativ,aSanofiCompany,Waltham,
Massachusetts
6Sobi,Sto ckholm,Sweden
7UniversityofCo penhagen,Cop enhage n,
Denmark
Correspondence
StefanLethagen ,Sobi,SE-11276Stockh olm,
Sweden.
Email:stefan.lethagen@sobi.com
Funding information
SobiandB ioverat iv,aSanoficompany
Abstract
Background:Inthephase3B-LONGstudy(NCT01027364),prophylaxiswithrecom-
binant factorIXFcfusion protein(rFIXFc)every7to>14dayswasassociatedwith
lowannualizedbleedrates(ABRs)inmalesaged≥12yearswithseverehemophiliaB.
The long-term s afety and effic acy of rFIXFc prophylaxis w as confirmed in the B-
YONDstudy(NCT01425723),anextensionoftheB-LONGclinicaltrial.
Objective:Theaimofthispost-hocanalysiswastoevaluatetheefficacyofa≥14-day
rFIXFc dosing interval in patients treated prophylactically during B-LONG or
B - Y O N D .
Methods:Theanalysisincluded22patientsaged≥12yearswhoreceivedprophylac-
ticrFIXFcwitha≥14-daydosingintervalatanytimeduringB-LONGorB-YONDup
untilthesecondinterimanalysisofB-YOND(September2015).
Results:Themedian(interquartilerange[IQR])rFIXFcexposureonthe≥14-daydos-
ing interv al was 3.4 (1.8-4)years. Pat ients treated with a ≥14-day dosing inte rval
werewellcontrolledwithamedian(IQR) overallABRof1.6(0.6-2.7) and a median
(IQR)spontaneousABRof0.7(0.3-1.1)in18evaluablepatients.ArFIXFcdosingin-
tervalof≥14dayswaswelltolerated,withnonewsafetyconcernsidentified.
Conclusion:MostpatientsonrFIXFcprophylaxis,withadosingintervalof≥14days,
remained wellcontrolled; ABRswere consistent with those reportedin the overall
study population. A ≥14-daydosing inter val canbeutilized in somewellcontrolled
individualsandreducestheburdenimposedbyfrequentprophylacticinjectionswhile
maintainingadequatebleedsuppression.
KEY WORDS
clinicaltrial,factorIX,hemophiliaB,prophylaxis,recombinantfusionproteins
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SHAPIRO e t Al.
1 | INTRODUCTION
Comparedwithon-demandtreatment,prophylacticfactorreplace-
menttherapyimprovesclinicaloutcomesinpeoplewithhemophilia,
reducin g the frequenc y of bleeding epi sodes, and imp roving joint
outcomes andqualityoflife.1,2ForprophylaxisinhemophiliaB,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-
posedbyfrequentinjectionsisanimportantbarriertoadherencein
individualswithhemophiliatreatedprophylactically.3
RecombinantFIXFcfusionprotein(rFIXFc;eftrenonacogalfa)is
one of the approved extended half-lifeproductsfor hemophilia B.
rFIXFc is a fusionprotein comprising human coagulation FIXcova-
lently boundwithoutalinker to the Fc domainofhuman immuno-
globulinG1(IgG1)producedinawell-characterizedhumancellline.4
The Fc portion of rFIXFcbinds to theendogenous neonatal Fc re-
ceptorandusestheIgGrecyclingpathway,delayinglysosomaldeg-
radationofFc-containing proteins by recyclingthem backinto the
circulation,therebyresultinginprolongedhalf-lifeofrFIXFc.4rFIXFc
isapprovedforprophylaxisandtreatmentofbleedinginindividuals
ofallagegroupswhohavehemophiliaB.5
Thephase3B-LONGstudydemonstratedthatprophylaxiswith
rFIXFc is ass ociated with low ann ualized bleedin g rates (ABRs) in
malepatientsaged≥12yearswithseverehemophiliaB.6Theexten-
sion stud y,B-YOND, ha s confirmed t he long-ter m safety an d effi-
cacyofprophylaxiswithrFIXFc7;keyresultsuponcompletionofthe
B-YONDstudyareexpec tedin2018.
The appr oved indicati on for rFIXFc in th e EU was updated in
July2017toincludeadosingintervalof≥14daysforuseinpatients
with hem ophilia B who are well co ntrolled with rFIX Fc adminis-
tered ever y 10 days.5Theaimofthecurrentpost-hocanalysiswas
tocharacterizelong-termexperiencewithextendedintervaldosing
usingdatauptotheseconddatacutofB-YOND(September2015).
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
≥12yearswithseverehemophiliaB(≤2%ofnormalFIXlevels)whose
priortreatmentregimenwaseitherprophylaxisorondemand.
In B - LONG,pat i e n t s w e r e a s signedt o o n e o ffourt r e a t m e n t g r o u p s:
Group 1 received prophylaxis with rFIXFc 50IU/kg weekly, with the
dose adjusted as needed(n=63); Group2received prophylaxiswith
rFIXFc 100IU/kg at an inter val of every 10days, with the inter val
adjustedasneeded basedonpharmacokinetics (PK)and/oroutcome
(n=29); Group 3 received on-demand treatment with rFIXFc 20-
100IU/kgforbleedingepisodes, with the dose adjustedaccordingto
bleedingseverity(n=27);andGroup4receivedtreatmentwithrFIXFc
as part of perioperative care (n=12). Theprimary efficacy endpoint
inB-LONGwastheABR, and primary safetyendpoints were the de-
velopmentofinhibitors(neutralizingantibodies)andadverseevents.
B-YOND (NCT01425723) was a non-randomized, open-label,
extensionstudythatenrolledpatientswhocompletedB-LONG6 or
KidsB-LONG.8In ter i md a t af r omO c tob e r20 14 haveb e enr e por t e d
previously.7Ofthe115patientswhocompletedB-LONG,93were
enrolledinB-YOND.DatafrompatientsenrolledinB-YONDfrom
B-LONGarereportedinthispost-hocanalysis;patientsenrolledin
B-YONDfromKidsB-LONGwerenotincludedastheKidsB-LONG
studydesigndidnotallowdosingintervalslongerthan1week.
There were four treatment groups in B-YOND: Group 1 received
prophylaxiswithrFIXFc20-100IU/kgevery7days(weeklyprophylaxis);
Group 2 re ceived interval-adjusted p rophylaxis with r FIXFc 100IU/kg
every 8-16days wit h dosing based on th e patient’s clinic al profile ob-
servedintheparentstudyandindividual PKprofile,trough,and/orpeak
(recovery)values; Group 3 received modifiedprophylaxis with the pos-
sibilit y to furthe r personal ize dosing by eg, ch anging dosing f requenc y,
add ingpr eve ntiondosesbefor estre nu ousac ti vities,ortargetingatro ugh
FIXlevelof>5IU/dLifwarrantedbybleedinghistoryand/oractivit ylevel
toim proveprop hyl axis;andGro up4receivedo n-demandtreat ment.The
primar yendpointinB-YONDwasthedevelopmentofinhibitors.
Thispost-hocanalysisincludedpatientsaged≥12yearswhore-
ceivedprophylac ticrFIXFcwithadosinginter valof≥14daysatany
timeduringB-LONGorB-YOND,upuntilthetimeofthesecondin-
terimanalysis(September2015;seeFigure1).Descriptivestatistics
wereusedtosummarizedata.
3 | RESULTS AND DISCUSSION
Twenty-two patients received rFIXFcprophylaxis withados-
ing interval of ≥14days at any time during B-LONG or B-
YOND,until the time of the second interimB-YONDanalysis
(September2015). Themedianageatbaselinewas34.5years
with the vast majority of patients having <1% endogenous
FIX acti vity. The median t erminal half-life (t½) of rF IXFc was
99.8hours(Table1).
The majority of patients (18 of 22) whose dosing interval
wasextendedto≥14dayswereoninterval-adjustedprophylaxis
Essentials
• ProphylacticreplacementofcoagulationfactorIX(FIX)isrecommendedinseverehemophiliaB.
• RecombinantFIXFcfusionprotein(rFIXFc)iseffectiveandwelltolerated.
• Phase3post-hocanalysisshowsthatsomepatientsarewellcontrolledwithrFIXFcevery≥14days.
• A≥14-dayrFIXFcdosingintervalmayhelpreducetreatmentburdenforwell-controlledpatients.
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SHAPIRO e t Al.
prior to th e extension (Fig ure1). 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.
Patientshad amedianrFIXFcexposure onthe≥14-day dosing
intervalof3.4years, witha mediandose per injection of 100IU/
kg, andamedian dosing interval of14days(Table2).Six patients
haddosingintervalsthatextended beyond 14days:1 on15days,
3 on 16days, 1 on 17days, an d 1 on 21days. 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/dLbasedon149measurements.
The majority of patients treated prophylactically appeared
wellcontrolledandexperiencedzerobleedsduringtheperiodbe-
foretheirdosinginter valwasextendedto≥14days.However,5of
22patient sreturnedpermanentlytoadosingintervalof<14days
duetoaPKresult(n=1),patientrequest(n=3:twoofwhichwere
forp ers ona lr eas ons ,t het hi rdd ue to ble edi ng ),o rr epe atedb lee d-
ing(elbow;n=1).Amongthese fivepatients,onehadpreviously
beentreatedon-demandandthreeothershadeitheraveryshort
orno obser vationperiodonrFIXFcpriortoextendingthedosing
intervaland it is therefore uncertainifthese patients truly were
wellcontrolledbeforeextendingtheirdosingintervalto≥14days.
Theremainin g17ofth e22patie nts(77.3%)continuedonadosi ng
FIGURE1 StudyflowinB-LONGandtheB-YONDex tensionstudy
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
TABLE1 Baselinepatientcharacteristics
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%endogenousFIXactivity 20(90.9)
1%-2%endogenousFIXactivity 2(9.1)
Genotype
Missense 16(72.7)
Nonsense 1(4.5)
Frame shif t 1(4.5)
Splicemutation 2(9.1)
Partialgenedeletion 1(4.5)
Largedeletions 0
Unknown 1(4.5)
rFIXFct½,h 99.8(86. 3-105.9)a
Data represent values at baselineofB-LONGfor patients treated with
≥14-day dosinginterval any time during B-LONGor B-YOND, untilthe
timeofthesecondinterimB-YONDanalysis.
FIX,factorIX;IQR,interquartilerange;rFIXFc,recombinantfactorIXFc
fusionprotein;t½,terminalhalf-life.
aGeomet ric mean calcu lations (as repor ted in B-LON G6) are not pre-
sentedbecauseofdifferencesins amplingprofiles.
TABLE2 ExposuretorFIXFcona≥14-daydosinginterval
Parameter
Median (IQR) N = 22
Exposureduration,days 1261(648-1448)
Exposuredays,days 91(69-106)
Weeklyconsumption,IU/kg 50(46-51)
Doseperinjection,IU/kg 100(92-102)
Dosinginterval,days 14 (14-14)
IQR, interquar tile range; rFIXFc, recombinant factor IX Fc fusion
protein.
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SHAPIRO e t Al.
intervalof≥14daysatthetimeofthesecondinterimdatacut,al-
thoughthreeofthese17patientshadhadatemporaryreduction
(50, 30, an d 22days) in the dosi ng interv al to <14daysat s ome
point befo re the data cut be cause of bleedin g (n=1),r epeated
bleedingintothekneefollowingar throscopy(n=1)andPKresult
(n=1).
The ABR during theperiodwith a ≥14-daydosing intervalwas
estimatedforpatientsonpriorprophylaxiswhohadanobservation
period of ≥6mo nths on the exten ded dosing regimen . These pa-
tientshadamedian(IQR)overallABRof1.6(0.6-2.7)(Table3),which
isconsistentwiththeABRreportedfortheoverallstudypopulation.
Incomparison,themedian(IQR)overall ABR was1.4(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
prophylaxistheinterimanalysisofB-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) (Table3). This compa res
withamedian(IQR)spontaneousABRof0.9(0.0-2.3)withinterval-
adjusted prophylaxis in B-LONG,6 0.68 (0-2.58) with interval-
adjustedprophylaxisand0.41(0-1.84)withmodifiedprophylaxisin
theinter imana ly sisinB-YOND.7Thesedataprovidefurthersupport
thatpatient swith hemophilia Bcan remain wellcontrolledwithan
individualized14-daydosinginterval.
Intotal, fourpatientswere excludedfrom the ABRcalculation;
twobecausetheyhadanobservationperiodthatwastooshort(28
and 57days) to obt ain robust es timates of ABR a nd an additio nal
two patients because they had received on-demand treatment be-
forethedosinginter valwaschangedto≥14days.
A total of 120 bl eeding epis odes in 22 patie nts occurre d over
744patientmonthsofexposurewhileona≥14-daydosinginterval.
Approximately 60% ofthebleedsoccurred duringthefirst 10days
sincepreviousdosing.Themajorit yofbleedingepisodes(114[95%])
werecontrolledwitheitheroneortwoinjections.Themedian(IQR)
totalrFIXFcdoseusedtotreatableedwas56.3(37-99.1)IU/kg.
Theadverseeventprofile was consistent with thatexpectedin
ahemophiliaBpopulation,andnonewsafetyconcernswereidenti-
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 nB-LO N G 6o rB-YO ND.7
Therewerenor ep or t sofse ri ou sallergicre ac tions,an ap hy la xis,vas-
cularthromboticevents,ordevelopmentofinhibitors.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-daydosing interval,and the treatment was welltolerated. A
rFIXFcdosingintervalof≥14daysallowsforbroadertreatmentflex-
ibilityand treatment individualizationcomparedwith conventional
FIX products, and further reduces the burden for patients, poten-
tiallypositivelyimpactingadherence.
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-
cordancewithgoodpublicationpractice(GPP3)guidelines(http://
www.ismpp.org/gpp3).
RELATIONSHIP DISCLOSURES
A.D. ShapiroreportsclinicalresearchwithBioverativ,Octapharma,
NovoNordiskandShire,andadvisoryboardswithNovoNordiskand
Shire. K. Pasi reports research funding, fees for advisory boards
and travel grants from Bioverativ, Sobi and Biomarin, fees for lec-
tures and serving onadvisory boardsfromShire, research funding,
feesforlectures,servingonadvisoryboardsandtravelgrantsfrom
Octapharma,feesforlecturesfromNovoNordisk,researchfunding,
fees for lecturesand ser ving onadvisory boards for Alnylam, fees
forlectures from Pfizer,andfees for advisoryboard from Catalyst
Bio.M.C.OzeloreportsresearchsupportfromSobiandBioverativ,
research support and participation on advisory boards and on a
speakers bureaufrom NovoNordisk, Shire, Pfizer,participation on
aspeakersbureauandgrantreviewpanelforGrifols,participation
onadvisoryboardsforCSLBehring.R.Kulkarnireportsclinicaltrial
involvementwithBioverativ/Biogen,advisoryboardsforBioverativ,
BPL, NovoNordisk, Shire, Rocheand Kendrion. C. Barnowski is an
employeeofBioverativ,aSanoficompany.J.Szamosiisanemployee
ofSobiandholderofSobishares.B.WindingisanemployeeofSobi.
S.LethagenisanemployeeofSobi.
AUTHOR CONTRIBUTIONS
A.D. Shapiro: Investigator in the clinical trial and par ticipated in
draftingandrevisingthemanuscript,andreadandapprovedthefinal
version as submitted. K.J. Pasi: Investigator in the clinicaltrial and
parti cipated in dr afting and r evising the ma nuscript , and read and
approvedthefinalversionassubmitted.M.C.Ozelo:Investigatorin
theclinicaltrialandparticipated in draftingandrevisingthemanu-
script, and read and approved the final version as submitted. R.
Kulkarni:Investigatorintheclinicaltrialandpar ticipatedindrafting
andrevisingthemanuscript ,andreadandapprovedthefinalversion
TABLE3 Annualizedbleedingrateinpatientstreated
prophylacticallywitha≥14-daydosinginterval
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 tilerange.
aThisan alysisinclu dedpatientswhowereo nprophylaxisbeforee xte nd-
ing the do sing interval to ≥14day (ie, t he two patient s receiving on-
demand treatment were excluded), and who had been observed for
≥6mo(therebyexcludinganadditionaltwopatients).
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SHAPIRO e t Al.
assubmitted.C.Barnowski:Contributedtothedesignoftheanalysis
andthe interpretationof thedata, and par ticipatedindraftingand
revisingofthemanuscriptandreadandapprovedthefinalversionas
submitted.B.Winding:Substantiallycontributedtothedesignofthe
analysesandtheinterpretationofdata.Participatedindraftingand
revising of the manuscript and readandapproved thefinalversion
assubmitted. J.Szamosi:Performedallanalysesandpar ticipatedin
theinterpretationofdata.Participatedindraftingandrevisingofthe
manuscriptandreadandapprovedthefinalversionassubmitted.S.
Lethagen:Substantiallycontributedtothedesignoftheanalysesand
theinterpretationofdata.Participatedindraftingandrevisingofthe
manuscriptandreadandapprovedthefinalversionassubmit ted.
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ExtendingrecombinantfactorIXFcfusionproteindosing
intervalto14ormoredaysinpatientswithhemophiliaB.Res
Pract Thromb Haemost. 2018;00:1–5. ht t p s: //d o i .
org /10.10 02/rth2.12163
