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