B a c k g r o u n d• Maraviroc(Selzentry®/Celsentri®)isanapprovedCCR5antagonistwithanti-viralactivityagainstCCR5-tropic(R5)HIV-1.1• Theefficacyandsafetyofmaravirocintreatment-experiencedpatientswithR5virushavebeenassessedintworandomized,

double-blind,placebo-controlledPhase3studies;MOTIVATE1(USA,Canada)andMOTIVATE2(Europe,Australia,USA).2–5

• Inbothstudies,maraviroc(QDorBID)+optimizedbackgroundtherapy(OBT)demonstratedsignificantlygreatervirologicandimmunologicefficacyandasimilarsafetyprofilecomparedtoplacebo+OBTintheWeek48primaryanalysis.Thesedatahavebeenpresentedindependently.2,3

• Since thestudydesign, inclusion/exclusioncriteria,conduct,monitoring,andstatisticalanalysesofMOTIVATE1andMOTIVATE2wereidentical,poolingofdatafromthetwostudieswasappropriate,resultinginlargersamplesizesforsubgroupanalyses.6

• Wepresenttheresultsofaplannedanalysisofpooleddata,atWeek48,fromthetwoMOTIVATEstudies.

M e t h o d s• Patients with triple-class drug experience and/or triple-class drug resistance, R5 virus only (Trofile™, Monogram

Biosciences),andHIV-1RNA≥5,000copies/mLwererandomizedina1:2:2ratiotoplacebo,maravirocQD,ormaravirocBID,incombinationwithOBT.2–5

• OBTconsistedof3–6antiretrovirals+/– low-doseritonavir. Investigationalagents(includingdarunavir,etravirine,andraltegravir)werenotusedaspartoftheOBT.PatientsreceivingaPI(excepttipranavir)and/ordelavirdine–potentCYP3A4inhibitors–intheirOBTreceived150mgdosesofmaraviroc;allotherpatientsreceived300mgdosesofmaraviroc.

• Eachstudywasindividuallypoweredtoshowsuperiorityofeitherexperimentalarmcomparedtotheplacebo+OBTgroup.• Theprimaryendpointwasthechangefrombaselineinlog10-transformedplasmaHIV-1RNAlevelsat48weeks.Secondary

endpointsincludedcategoriesofvirologicresponse(percentageofpatientswithHIV-1RNAlevels<50and<400copies/mL),changefrombaselineinCD4+cellcount,andtimetotreatmentfailure.

R e s u l t s

Study population

• Thecombineddataset includedatotalof1,049patientswhoeachreceivedat leastonedoseofmaravirocQD+OBT(n=414),maravirocBID+OBT(n=426),orplacebo+OBT(n=209).

• Demographicsandbaselinecharacteristicsweresimilaracrossthethreetreatmentgroups(Table1).• ThemajorityofpatientshadtwoorfewerpotentiallyactivedrugsintheirOBTregimenaccordingtooverallsusceptibility

scoreatscreening(Table1).

Efficacy

• BothmaraviroctreatmentgroupsshowedgreaterreductionsfrombaselineinHIV-1RNAcopies/mLat48weeks(primaryendpoint)comparedtoplacebo+OBT(Table2).

• Foreachofthesecondaryvirologicendpoints,includingtheratesofvirologicsuppressionto<400and<50copies/mLatWeek48(Figure1),theresponsesinthemaravirocgroupswerealsosignificantlybetterthanintheplacebogroup(P<0.0001).

Figure 1: Percentage of patients with HIV-1 RNA suppression (solid lines, HIV-1 RNA <400 copies/mL; dashed lines, HIV-1 RNA <50 copies/mL)

*P<0.0001versusplacebo+OBT.HIV-1RNAvalueimputedasbaselineifmissingorifpatientdiscontinuedbefore48weeks.Includesallpatientswhoreceivedatleastonedoseofstudymedication;pooledanalysisofMOTIVATE1andMOTIVATE2.

• CD4+cellcountincreasesupto48weekswerealsomorefavorableinboththemaravirocgroupsthantheplacebogroup. - ThemeanchangefrombaselineinCD4+cellcount(last-observation-carried-forwardapproachusedtoimputemissing

values)was+61cells/mm3intheplacebogroup,comparedto+116and+124cells/mm3inthemaravirocQDandBIDgroups,respectively.

• TimetotreatmentfailurewassimilarinthemaravirocQDandBIDtreatmentgroupsandsignificantlylongerinthesegroupsthanintheplacebotreatmentgroup(Figure2).

Figure 2: Kaplan–Meier plot of time to treatment failure

Includesallpatientswhoreceivedatleastonedoseofstudymedication;pooledanalysisofMOTIVATE1andMOTIVATE2.

• WhentreatmentresponsewasanalyzedbyscreeningviralloadsandbaselineCD4+cellcounts,thebenefitofmaraviroc(QD or BID) + OBT over placebo + OBT remained constant across all strata, regardless of whether patients initiatedtreatmentwithhighviralloadsorlowCD4+cellcounts(Table3).

Safety• PooledanalysisrevealednoneworuniquesafetyfindingsatWeek48.• There were no clinically relevant differences in the safety profile between maraviroc (QD and BID) + OBT and

placebo+OBTover48weeksoftreatment(Table4,Figure3). - Thiswasdespitethelongerexposuretostudytreatmentinpatientsinthemaraviroctreatmentgroups(morethan300

patient-yearspergroup)versus theplacebogroup (111patient-years) (Table4),associatedwith thehigherrateofdiscontinuationintheplacebogroup.

• Adverseevents,seriousadverseevents,discontinuationsduetoadverseevents,andlaboratoryabnormalities(includinggrade3/4transaminaseelevations)occurredwithsimilarfrequencybetweentreatmentgroups(Table4).

• TheincidenceofCategoryC(AIDS-defining)eventswascomparableacrosstreatmentgroups(Table4).• The most common adverse events in all treatment groups were diarrhea, nausea, fatigue, and headache (Figure 3),

withsimilarratesforalltreatmentgroups.• Moredeathswererecordedinpatientsreceivingmaravirocversusthosereceivingplaceboduringthesafetyanalysis

reportingperiodorwithin28daysofdiscontinuingstudydrug.Deathswerefromvariouscausesandnoneofthedeathswereconsideredtoberelatedtostudymedication(Table4).

Figure 3: Percentage of adverse events occurring in ≥5% of patients in any group (unadjusted for study treatment exposure)

ISR=injectionsitereaction;RTI=respiratorytractinfection.PooledanalysisofMOTIVATE1andMOTIVATE2.

C o n c l u s i o n s• Maraviroc(QDorBID)+OBTdemonstratedsignificantlygreatervirologicsuppressionratesandincreasesfrombaseline

inCD4+cellcountsatWeeks24and48comparedtoplacebo+OBTinthiscombinedanalysis.• Thebenefitofmaraviroc+OBToverplacebo+OBTwasapparenteveninsubgroupsofpatientswithadverseprognostic

factors,suchashighscreeningviralloadorlowbaselineCD4+cellcount.• Maraviroc+OBTdemonstratedasimilarsafetyprofilecomparedtoplacebo+OBT,despiteconsiderablygreaterexposure

tostudytreatmentinthemaravirocgroups.• TherewasnoincreaseinAIDS-definingevents(infectionsormalignancies)ornon-AIDS-definingmalignanciesinmaraviroc

(QDorBID)+OBTversusplacebo+OBT.• Nodeathsreportedduringthestudyorupto28daysofstoppingstudydrugwereconsideredtoberelatedtostudymedication.• Inconclusion,theseresultsdemonstratethat,intreatment-experiencedpatientswithR5virus,maraviroccombinedwith

OBTprovidessustainedantiretroviralefficacyandtolerabilitythrough48weeks.

R e f e r e n c e s1.DorrP,et al. Antimicrob Agents Chemother2005;49:4721–4732.2.LalezariJ,et al. 47th ICAAC2007;PresentationH-718a.3.FätkenheuerG,et al. 11th EACS2007;PresentationPS3/5.4.LalezariJ,et al. 14th CROI2007;Presentation104bLB.5.NelsonM,et al. 14th CROI2007;Presentation104aLB.6.GulickRM,et al. 4th IAS2007;PresentationWEPEB116LB.7.HoepelmanIM,et al. 11th EACS;PosterLBP7.9/1.

A c k n o w l e d g e m e n t sInvestigatorsandstudysitestaffPatientswhoparticipatedinthestudiesColleaguesfromMonogramBiosciences:JWhitcomb,ECoakley,CPetropoulosRHarrigan,BCCentreforExcellenceinHIVColleaguesfromQuintilesColleaguesfromPfizer:SFelstead,ABullivant,IOborska,KGeorge,MWestby,KTurner,DLindell,DPaige,SNuttall,JMerson,LKapili,MDunne,JSullivan,CRidgway,NRajicic,AParliyan

Efficacy and Safety of Maraviroc Plus Optimized Background Therapy in Treatment-experienced Patients Infected with CCR5-tropic HIV-1: 48-week Combined Analysis of the MOTIVATE Studies

Poster 79215th Conference on Retroviruses and Opportunistic InfectionsBoston, USA, February 3–6, 2008

DHardy1,JReynes2,IKonourina3,DWheeler4,SMoreno5,EvanderRyst3,WTowner6,AHorban7,HMayer8,andJGoodrich81DavidGeffenSchoolofMedicineatUCLA,LosAngeles,CA,USA;2UniversityHospitalofMontpellier,Montpellier,France;3PfizerGlobalResearchandDevelopment,Sandwich,UK;4InfectiousDiseasesPhysicians,Inc.,Annandale,VA,USA;5HospitalRamónyCajal,Madrid,Spain;6KaiserPermanente,LosAngeles,CA,USA;7SzpitalZakaznyCentrumDiagnostykiiTerapiiAIDS,Warsaw,Poland;8PfizerGlobalResearchandDevelopment,NewLondon,CT,USA

Table 1: Demographics and baseline characteristics

TotalN=1,049 Placebo+OBT MaravirocQD+OBT MaravirocBID+OBT N=209 N=414 N=426

Meanage,years(range) 45.7(29–72) 45.6(17–75) 46.3(21–73) Female,n(%) 24(11.5) 51(12.3) 44(10.3) White,n(%) 178(85.2) 336(81.2) 363(85.2) MeanCD4+count*,cells/mm3 187.2 195.7 189.2 MeanHIV-1RNA*,log10copies/mL 4.86 4.86 4.85 ≤2activedrugsinOBT†,% 66.0 66.0 69.7 EnfuvirtideinOBT†,% 43.5 40.6 42.7 TipranavirinOBT,% 13.9 15.9 14.8

*Calculatedforeachpatientasthemeanofuptothreepre-doseassessments(screening,randomization,andbaseline)(CD4+cellcount=meanoftwopre-doseassessments).†Accordingtooverallsusceptibilityscore.Includesallpatientswhoreceivedatleastonedoseofstudymedication;pooledanalysisofMOTIVATE1andMOTIVATE2.

Table 2: Mean change from baseline HIV-1 RNA at 48 weeks

TotalN=1,049 Placebo+OBT MaravirocQD+OBT MaravirocBID+OBT N=209 N=414 N=426

Meanchangefrombaseline –0.78 –1.68 –1.84inHIV-1RNAcopies/ml,log10*

Differencevsplacebogroup –0.89 –1.05(97.5%confidenceinterval) (–1.17,–0.62) (–1.33,–0.78)

*HIV-1RNAvalueimputedaszeroifpatientdiscontinuedbefore48weeks.

Table 3: Percentage of patients with HIV-1 RNA <50 copies/mL at Week 48 by screening HIV-1 RNA* and by baseline† CD4+ cell count

n/N(%)bysubgroup Placebo+OBT MaravirocQD+OBT MaravirocBID+OBT N=209 N=414 N=426

ScreeningHIV-1RNA,copies/mL <100,000 32/123(26) 140/238(59) 142/243(58) ≥100,000 8/84(10) 55/170(32) 61/176(35) BaselineCD4+count,cells/mm3 <50 1/38(3) 13/84(15) 14/85(16) 50–100 3/25(12) 19/51(37) 20/55(36) 101–200 12/55(22) 39/95(41) 59/104(57) 201–350 13/62(21) 79/115(69) 67/116(58) >350 10/26(38) 44/62(71) 43/59(73)

*PatientswerestratifiedattimeofrandomizationbyscreeningHIV-1RNA(<or≥100,000copies/mL).†BaselineCD4+cellcountcalculatedastheaverageofallpre-dosemeasurements.Includesalltreatedpatientswithvalidbaselineandon-treatmentmeasurements;pooledanalysisofMOTIVATE1andMOTIVATE2.Missingvaluesimputedusinglastobservationcarriedforward.

Table 4: Safety analysis (unadjusted for study treatment exposure)

Allcausalitiesandseverities,n(%) Placebo+OBT MaravirocQD+OBT MaravirocBID+OBT N=209 N=414 N=426

Totalexposuretostudy 111 300 309treatment,patient-years

Treatment-emergentadverseevents 177(84.7) 375(90.6) 393(92.3) Discontinuationduetoadverseevents 11(5.3) 24(5.8) 21(4.9) Seriousadverseevents 35(16.7) 62(14.9) 72(16.9) Grade3adverseevents 46(22.0) 84(20.3) 104(24.4) Grade4adverseevents 16(7.7) 37(8.9) 45(10.6) CategoryCevents 16(7.7) 29(7.0) 23(5.4) CategoryCmalignancies 5(2.4) 3(0.7) 4(0.9) Non-HIVmalignancies 11(5.3) 12(2.9) 19(4.5) Deaths* 2†(1.0) 6(1.4) 9(2.1) Maximumliverfunctiontestvalueswithoutregardtobaseline§(allcausalities),n(%)‡

Aspartatetransaminase Grade3:>5–10xULN 6(2.9) 12(2.9) 14(3.3) Grade4:>10xULN 0 4(1.0) 6(1.4) Alaninetransaminase Grade3:>5–10xULN 6(2.9) 16(3.9) 7(1.7) Grade4:>10xULN 1(0.5) 2(0.5) 4(1.0) Totalbilirubin Grade3:>2.5–5xULN 8(3.9◊) 28(6.9) 21(5.0◊) Grade4:>5xULN 3(1.5◊) 5(1.2) 2(0.5◊)

*Deathsreportedupto28daysafterstoppingstudydrug;nodeathswererelatedtostudydrugaccordingtoinvestigator.†Onepatientreceivedopen-labelmaravirocpriortodeath.‡N=207,408,and421forplacebo,maravirocQD,andmaravirocBIDgroups,respectively.§Patientswithgrade1and2liverfunctiontestscouldbeenrolledinthestudies.7

◊ Datamissingforonepatient.ULN=upperlimitofnormal.PooledanalysisofMOTIVATE1andMOTIVATE2.

0

100

Time (Weeks)

56.1%*51.7%*45.5%*43.2%*

22.5%*16.7%*

Patie

nts

(%)

90

80

70

60

50

40

30

20

10

04 8 12 16 20 24 28 32 36 40 44 48

Placebo + OBT (N=209)Maraviroc QD + OBT (N=414)Maraviroc BID + OBT (N=426)

0

1.0

Time to Treatment Failure (Days)

Surv

ival

Est

imat

e

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0100 200 300 400

Placebo + OBTMaraviroc QD + OBTMaraviroc BID + OBT

Diarrhea

Nausea

Fatig

ue

Headache

Upper RTI

Pyrexia

Vomiting

ISRCough

Dizziness

Rash

Insomnia

Nasopharyn

gitis

Bronchitis

Constipatio

n

Sinusitis

Arthralgia

Patie

nts

(%)

0

5

10

15

20

25 Placebo + OBTMaraviroc QD + OBTMaraviroc BID + OBT