c-edge co-star: efficacy of elbasvir / grazoprevir

c-edge co-star: efficacy of elbasvir / grazoprevir

C-EDGECO-STAR:EFFICACYOFELBASVIR/GRAZOPREVIR
INHCV-INFECTEDPERSONSWHOINJECTDRUGS
RECEIVINGOPIOIDAGONISTTHERAPY
GrebelyJ1,DoreGJ1,Al.ceF2,LitwinAH3,DalgardO4,GaneE5,ShiboletO6,
LuetkemeyerA7,NahassR8,PengCY9,ConwayB10,HoweA11,NguyenBY11,Wahl
J11,BarrE11,RobertsonM11,PlaSHL11
1TheKirbyIns.tute,UNSWAustralia,2YaleSchoolofMedicine,3Montefiore
MedicalCenterandAlbertEinsteinCollegeofMedicine,4Ins.tuteofClinical
Medicine,5AucklandClinicalStudies,6Tel-AvivMedicalCenter,7Universityof
California,SanFrancisco,8IDCare,9ChinaMedicalUniversityHospital,
10VancouverInfec.ousDiseasesCentre,11Merck&Co.,Inc.
DISCLOSURES
•  Consultant/advisorforandhasreceivedresearchgrantsfrom
AbbVie,Bristol-MyersSquibb,GileadSciencesandMerck/MSD
2
ACKNOWLEDGEMENTS
Weextendourgra.tudetothepa.ents,theirfamilies,inves.gatorsandsitepersonnelwho
par.cipatedinthisstudy.
•  Australia:GregDore,DavidIser,JosephSasadeusz,Mar.nWeltman;Canada:BrianConway,
RogerP.LeBlanc,DanieleLongpre;France:Jean-PierreBronowicki,JosephMoussalli,Fabien
Zoulim;Germany:AndreasTrein,AlbrechtStoehr;Israel:OrenShibolet;Netherlands:H.W.
Reesink;NewZealand:EdwardGane;Norway:OlavDalgard,HegeKileng;Romania:Adrian
OctavianAbagiu,EmanoilCeausu,AdrianStreinu-Cercel;Spain:JuanIgnacioArenasRuizTapiador,JoseLuisCallejaPanero,JuanAntonioPineda,ConradoFernandezRodriguez,Juan
TurnesVazquez;Taiwan:Wan-LongChuang,Cheng-YuanPeng,Sheng-ShunYang;United
Kingdom:KoshAgarwal,DavidBell,AshleyBrown,JohnDillon,DanielM.H.Forton,Andrew
Us.anowski;UnitedStates:FrederickL.Al.ce,DavidMichaelAsmuth,KathleenK.Casey,
JamesN.Cooper,StuartC.Gordon,PaulY.Kwo,JacobPaulLalezari,WilliamM.Lee,AlainH.
Litwin,AnnieLuetkemeyer,AndrewJ.Muir,RonaldG.Nahass,GrisellOr.z-Lasanta,K.
RajenderReddy,KennethE.Sherman,JihadSlim,MarkS.Sulkowski,AndrewH.Talal,Joesph
LeoYozviak
3
Thisstudyandmedicalwri.ngsupportwerefundedbyMerck&Co.,Inc.
BACKGROUNDANDAIM
•  Injec.ondruguseisthemajorriskfactorforHCVepidemicin
mosthighincomecountries,withpeoplewhoinjectdrugs
(PWID)accoun.ngfor50-80%ofHCVinfec.ons1
•  HCVtreatmentuptakeintheIFN-containingerahasbeenlow,
par.cularlyamongPWID2,3
•  DespitesimilarHCVtreatmentoutcomeswithIFN-containing
therapy4,5,PWIDwithcurrentdrugusehavebeenexcluded
fromIFN-freeDAAdevelopmentprograms
1.HajarizadehB,GrebelyJ,andDoreGJ.NatRevGastroHepatol2013;10:553-62.2.IversenJ,etal.JViral
Hepa..s2013;21:198-207.3.AlaviM,etal.LiverInterna.onal2014;34:1198-206.4.AspinallA,etal.Clin
InfectDis2013;57:S80-S89.5.GrebelyJ,etal.IntJDrugPolicy2015;26:1028-38.
4
BACKGROUND
HCVNS5Ainhibitor,50mg
Elbasvir
(MK-8742)
HCVNS3/4Ainhibitor,100mg
Grazoprevir
(MK-5172)
§  Broadac.vityversusmostHCVgenotypesinvitro1-3
§  Efficaciousintreatment-naive&treatment-experiencedcirrho.candnoncirrho.cpa.entswithHCV,andinHIV/HCVco-infectedpa.ents4-6
§  All-oral,once-dailyregimen
1.SummaV,etal.An.microbialAgentChemother2012:56;4161;2.CoburnCA,,etal.ChemMedChem2013;8:1930;
3.HarperS,etal.ACSMedChemLel.2012Mar2;3(4):332;4.Zeuzemetal.,AnnIntMed2015;163:1;
5.Lawitzetal.,Lancet2015;385:1075;6.Rockstrohetal.,LancetHIV2015;2:e319
5
TRIALDESIGN
•  Phase3,randomized,parallel-group,placebo-controlled,double-blindtrial
•  Treatmentnaïve,GT1,4,6;mixedgenotypesof1,4,and6allowed
•  Onopiateagonisttherapy(OAT)foratleast3months,andconsistentlykeptat
least80%ofscheduledappointmentswhileonOAT
•  Goalof20%withcirrhosisandmaybeco-infectedwithHIV
Immediate
TreatmentArm
EBR/GZR,
n=201
Unblinding
Deferred
TreatmentArm
Placebo,
n=100
Unblinding
D1 W4 W8 W12
6
Follow-upfor24weeks
W16
Follow-up
for24weeks
EBR/GZR
W22
W28
W36
W52
EFFICACYANALYSES
•  Endpoints
–  Primaryendpoint:SVR12(HCVRNA<15IU/mL*)
–  Secondaryendpoint:SVR24
•  AnalysisPopula.ons
–  FullAnalysisSet(FAS)
•  Includesallpa.ents
•  Reinfec.onsarecountedasfailures
–  ModifiedFullAnalysisSet(mFAS):Primaryefficacyendpoint
•  Excludespa.entswhodiscon.nuedthetrialfornon-treatment
relatedreasons(e.g.,lost-to-follow-upandordiscon.nueddueto
reasonsotherthanvirologicfailure)
•  Pa.entswithdataconsistentwithclearanceofbaselineinfec.onand
HCVRNA>15IU/mLconsistentwithreinfec.onarecountedas
successes
7
*At12weeksaqerendoftreatment,HCVRNAdetermined
withCOBAS®AmpliPrep/COBAS®Taqman®HCVTest,v2.0®
DEMOGRAPHICS
Immediatetreatmentarm
(n=201)
n(%)
153(76)
48(23-66)
Male
Age[medianyrs;
(range)]
Race
White
158(79)
AfricanAmerican
31(15)
Asian/Other
12(6)
BaselineHCVRNA(IU/mL)
>2,000,000IU/mL
114(57)
HCVGenotype
1a
154(77)
1b
30(15)
412(6)
6
5(3)
Cirrhosis
Yes(F4)
40(20)
HCV/HIVCo-infected
16(8)
Urinedrugscreen(excludingopiateagonisttherapy)
posi.veatDay1
122(61)
8
Deferredtreatmentarm
Total
(n=100)
(N=301)
n(%)
n(%)
77(77)
230(76)
47(24-64)
48(23-66)
84(84)
242(80)
7(7)
38(13)
9(9)
21(7)
51(51)
165(55)
75(75)
229(76)
15(15)45(15)
6(6) 18(6)
4(4) 9(3)
22(22)
62(21)
5(5)
21(7)
52(52)
174(58)
SVR12INTHEIMMEDIATETREATMENTGROUP:
FULLANALYSISSET(FAS)
FullAnalysisSet
%SVR12(95%CI)
100
91.5
93.5
93.3
mFAS
91.7
80
95.5
20.0
60
40
20
0
AllGT
GT1a*
GT1b
GT4
GT6
mFAS
184/201
144/154
28/30
11/12
1/5
189/198
Reinfecdon
7
5
4
3
1
0
0
0
2
2
7
--
LTFUordiscondnued
unrelatedtoVF†
5
3
1
1
0
2(excluded)
Relapse
*Includesonesubjectwithmixedinfec.on(GT1aandGT1b)whoachievedSVR12
†IncludesonesubjectwithHCVRNA>LLoQconsistentwithreinfec.on;thissubjectwaslosttofollow-upanddid
notreturnforconfirma.onofHCVRNA;thissubjectwasdiscon.nuedforadministra.vereasonandcountedasa
9 failureintheFAS
GT=genotype;LTFU=losttofollow-up;VF=virologicfailure
SVR12INTHEIMMEDIATETREATMENTGROUP:
MODIFIEDFULLANALYSISSET(mFAS)
ModifiedFullAnalysisSet(mFAS)
%SVR12(95%CI)
100
95.5
96.1
96.6
100.0
AllGT†
GT1a*
GT1b
GT4
GT6
189/198
147/153
28/29
11/11
3/5
7
2
4
2
1
0
0
0
2
0
5
3
0
0
2
1
0
60.0
80
60
40
20
0
Failures
Relapse
Discondnuadon
Reinfecdon–countedassuccess
LTFUordiscondnuedunrelatedtoVirologicFailure–excludedfrommFASanalysis
3
10
1
1
*Includesonesubjectwithmixedinfec.on(GT1aandGT1b)whoachievedSVR12
SVR12INTHEIMMEDIATETREATMENTGROUP:
SUBGROUPANALYSISOFMODIFIEDFULLANALYSISSET(mFAS)
OverallSVR12=95.5%
n/m
SVR12
%(95%CI)
144/151
95.4(90.7,98.1)
Female
45/47
95.7(85.5,99.5)
≥50years
85/91
93.4(86.2,97.5)
<50years
104/107
97.2(92.0,99.4)
White
152/155
98.1(94.4,99.6)
29/31
6/9
93.5(78.6,99.2)
66.7(29.9,92.5)
GT1a
146/152
96.1(91.6,98.5)
GT1b
GT4
28/29
11/11
96.6(82.2,99.9)
100(71.5,100)
GT6
3/5
60.0(14.7,94.7)
Non-cirrhodc
Cirrhodc
151/158
38/40
95.6(91.1,98.2)
95.0(83.1,99.4)
HCVRNA≤2million
HCVRNA>2million
83/85
106/113
97.6(91.8,99.7)
93.8(87.7,97.5)
Posidvedrugscreen
127/133
95.5(90.4,98.3)
Negadvedrugscreen
62/65
95.4(87.1,99.0)
Subgroup
Male
African-American
Asian
10
11
20
30
40 50 60 70 80
%SVR12(Mean;95%CI)
90 100
PROBABLEREINFECTIONSINTHEIMMEDIATE
TREATMENTGROUP
•  5pa.entsweresuccessfullytreatedfortheirbaselinevirus,butatthe.me
ofvirologicfailurehadadifferentgenotype,subtype,orviralstraindetected
•  Inall5cases,popula.onsequencingandphylogene.canalysisofthe
nucleo.desequencessupportphylogene.callydis.nctviralstrainsat
follow-upcomparedtobaseline
Demographics
Fibrosis
Stage
GTat
Baseline
UDSat
Baseline*
UDSat
TW12*
Timepointof
detectableHCV
RNA
GTat
Follow-up
48yoAsianmale
NC
1a
BZP,OPA
BZP
FW8
6a
33yowhite
female
NC
1a
--
AMP,OPA
FW8
1a
55yowhite
female
C
1a
BZP,OPA
BZP,OPA
FW8
3a
45yoAsianmale
NC
6a
--
OPA
FW8
1b
37yoAsian
female
NC
6a
AMP,BZP,OPA
AMP,BZP,OPA
FW8
6a
*excludesopiateagonisttherapy;AMP=amphetamines;BZP=benzodiazepines;OPA=opiates
12
URINEDRUGSCREENRESULTS:
DAY1TOTREATMENTWEEK12
DeferredTreatmentArm;
PlaceboPhase
Anydruguseof8
classes*
60
Anydruguseof7
classes(excl.
cannabinoids)
Cannabinoids
50
40
Benzodiazepines
30
Opiates
20
Cocaine
10
Amphetamines
0
Day1TW1 TW2 TW4 TW6 TW8TW10TW12
TimePoint
70
%ofPadentswithPosidveUrineDrugScreen
%ofPadentswithPosidveUrineDrugScreen
70
ImmediateTreatmentArm;
EBR/GZRTreatmentPhase
60
50
40
30
20
10
0
Day1 TW1 TW2 TW4 TW6 TW8TW10TW12
TimePoint
*8drugclasses:amphetamines,barbiturates,benzodiazepines,
cannabinoids,cocaine,opiates,phencyclidine,propoxyphene
13
ADHERENCE
%Adherence
>80%(>67doses)
100
90
80
70
60
50
40
30
20
10
0
100.0 99.0
199
199
197
199
>90%(>76doses)
96.5
192
199
Immediatetreatmentarm
(Ac.vestudymedica.on)
14
>95%(>79doses)
100.0 100.0 100.0
97
97
97
97
97
97
Deferredtreatmentarm
(Placebo)
PERCENTAGEOFPATIENTSWHOMISSED
DOSESOFSTUDYMEDICATION
Number(%)ofPadentswithNumberofMissedDoses
Numberof
misseddoses
0
1
2
3
4
5
6
7
8
9
10
11
≥12
15
Immediatetreatmentarm
(n=199)
153(76.9)
23(11.6)
8(4.0)
8(4.0)
1(0.5)
0
2(1.0)
1(0.5)
1(0.5)
0
0
2(1.0)
0
Deferredtreatmentarm
(n=97)
80(82.5)
8(8.2)
6(6.2)
0
3(3.1)
0
0
0
0
0
0
0
0
PERCENTAGEOFPATIENTSWHOMISSED
DOSESOFSTUDYMEDICATION
Number(%)ofPadentswithNumberofMissedDoses
Numberof
misseddoses
0
1
2
3
4
5
6
7
8
9
10
11
≥12
16
Immediatetreatmentarm
(n=199)
153(76.9)
23(11.6)
96.5%
8(4.0)
8(4.0)
1(0.5)
0
2(1.0)
1(0.5)
1(0.5)
0
0
2(1.0)
0
Deferredtreatmentarm
(n=97)
80(82.5)
8(8.2)
96.9%
6(6.2)
0
3(3.1)
0
0
0
0
0
0
0
0
SAFETYDURINGINITIALTREATMENTPERIOD
ANDFIRST14DAYSOFFOLLOW-UP
ImmediateTreatment
Arm(Acdve),n=201
DeferredTreatment
Arm(Placebo),n=100
Total
(n=301)
SeriousAEs,n(%)
7(3.5)
4(4.0)
11(3.7)
SeriousDrugRelatedAEs,n(%)
1(0.5)
1(1.0)
2(0.7)
Discon.nua.ons,n(%)
2(1.0)
2(2.0)
4(1.3)
0
1(1.0)
1(0.3)
166(82.6)
83(83.0)
249(82.7)
Fa.gue
32(15.9)
20(20.0)
52(17.3)
Headache
26(12.9)
14(14.0)
40(13.3)
Nausea
23(11.4)
9(9.0)
32(10.6)
Diarrhea
20(10.0)
9(9.0)
29(9.6)
LateALT/AST>5xULN,n(%)
0
0
0
Bilirubin>2.6xULN,n(%)
0
0
0
Hemoglobin<8.5gm/dL,n(%)
0
1(1.0)
1(0.3)
Crea.nine>2.5xbaseline,n(%)
0
0
0
Deaths,n(%)
Anyadverseevent,n(%)
17
CONCLUSIONS
•  EBR/GZRdemonstratedhighefficacyinGT1and4infectedpa.entsreceivingOpiateAgonistTherapy
–  LimitedbysmallnumberofGT6-infectedpa.ents
•  Acceptablesafetyprofilewithcomparableadverse
eventratesbetweentheimmediateanddeferred
treatmentarms
•  Highstudymedica.onadherence
•  Stableongoingdrugusethroughouttheini.al
treatmentphaseinbothgroups
•  Datademonstratesupportfortrea.ngHCVamong
subjectsreceivingOpiateAgonistTherapy
18