Lifitegrast Clinical Development Program: Key Findings ... · • In this presentation, we discuss...
Transcript of Lifitegrast Clinical Development Program: Key Findings ... · • In this presentation, we discuss...
LifitegrastClinicalDevelopmentProgram:KeyFindingsFrom3RandomizedControlledTrialsinAdultSubjects
WithDryEyeDiseaseWalterO.Whitley,1 EdwardJ.Holland,2 KennethSall,3
StephenS.Lane,4 AparnaRaychaudhuri,5 StevenZhang,6 AmirShojaei5
1VirginiaEyeConsultants,Norfolk,VA,USA;2CincinnatiEyeInstitute,Cincinnati,OH,USA;3SallResearchMedicalCenter,Artesia,CA,USA;4AssociatedEyeCare,Stillwater,MN ,USA;
5Shire,Chesterbrook,PA ,USA;6Shire,Lexington,MA ,USA
1PresentedattheAmericanAcademyofOptometry2015AnnualMeeting;October7–10,2015;NewOrleans,LA
Disclosures
• WalterO.WhitleyandKennethSall havereceivedsupportfromafor-profitcompany(Shire/SARcode)intheformofresearchfunding,materials,orservicesatnocost,forthesubjectmatterofthispresentation
• WalterO.Whitleyhasbeen,withinthelast3years,aconsultantforacompany(Shire)withabusinessinterestinthesubjectmatterofthispresentation,andhasreceivedspeakerfeesandservedonadvisoryboardsforShire
• EdwardJ.Hollandhasbeen,withinthelast3years,aconsultantforacompany(Shire/SARcode)withabusinessinterestinthesubjectmatterofthispresentation
• AparnaRaychaudhuri,StevenZhang,andAmirShojaeiareemployeesofacompany(Shire)withabusinessinterestinthesubjectmatterofthispresentation
• ThisstudywasfundedbyShire• TheauthorsthankLisaBaker,PhD,ofExcelScientificSolutions,whoprovided
medicalwritingassistancefundedbyShire
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Lifitegrast• Lifitegrastisasmallmoleculeintegrin
antagonistthatinterfereswithbindingofICAM-1totheintegrinLFA-1ontheTcellsurface,inhibitingTcellrecruitmentandactivationassociatedwithdryeyedisease(DED)
• Lifitegrastophthalmicsolution5.0%hasbeeninvestigatedin3(1phase2and2phase3)randomizedcontrolledtrialsfortreatmentofDED1–3
• Inthispresentation,wediscusstheclinical developmentoflifitegrastandthepatternofefficacyfindingsacrossthese3studies,includingfindingsofpreviouslyunreportedposthocanalyses
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ICAM-1,intercellularadhesionmolecule1;LFA-1,lymphocytefunction-associatedantigen1,MW,molecularweight(g/mol).1.SembaCP,etal.AmJOphthalmol.2012;153(6):1050-60. 2.SheppardJD,etal.Ophthalmology.2014;121(2):475–83.3.TauberJ,etal.Ophthalmology.2015Sep10.[Epub aheadofprint]
MW=615.5
StudyDesigns
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Study1 Study2 Study3Studytype Phase 2 Phase3(OPUS-1) Phase 3(OPUS-2)
Clinicaltrials.gov NCT00926185 NCT01421498 NCT01743729
Samplesize(availableforefficacyanalysis)
Lifitegrast5.0%, n=54;placebo,n=55*
Lifitegrast5.0%, n=293;placebo,n=294
Lifitegrast5.0%, n=358;placebo,n=360
(Co)primarysign ICSS(0–4scale) ICSS(0–4scale) ICSS(0–4scale)
Coprimarysymptom None Visual-relatedfunctionsubscale
EDS(VAS; 0–100scale;0=nodiscomfort)
Duration 84days 84days 84days
Keyinclusion criteria
• Adults withDED• Cornealstainingscore≥2(preCAE)• STT≥1and≤10mm• ChangeinICSS≥+1(postCAEminuspreCAE)
• Adults withDED• Cornealstainingscore≥2(preCAE)• STT≥1and≤10mm• ChangeinICSS≥+1(postCAEminuspreCAE)
• Adults withDED• Cornealstainingscore≥2• STT≥1and≤10mm• ICSS≥0.5• EDS≥40• Artificialtearuseinpast30days
CAE Yes Yes NoCAE,controlledadverseenvironment;EDS(VAS),eyedrynessscore(visualanaloguescale);ICSS,inferiorcornealstainingscore;STT,SchirmerTearTest(withoutanesthesia).*Study1alsoincludedgroupsreceivinglifitegrastophthalmicsolution0.1%and1.0%.Study1n’sshownforkeyefficacyanalysis,changefrombaselinetoday84inICSS.
BaselineCharacteristics
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Study1 Study2 Study3LIF* PBO LIF PBO LIF PBO
Mean(SD)age,y 62.3(12.22)
60.4(12.93)
60.2(12.21)
61.1(11.77)
58.7(13.93)
58.9(14.26)
Female, % 81.0 77.6 78.2 73.6 79.6 73.6
Mean(SD)baseline ICSS 1.77(0.515)
1.65(0.513)
1.84(0.597)
1.81(0.599)
2.39(0.763)
2.40(0.722)
Mean(SD)baselineEDS 51.58(24.688)
51.81(23.552)
40.18(28.645)
41.62(29.690)
69.68(16.954)
69.22(16.761)
LIF,lifitegrast;PBO,placebo.*Groupreceiving5.0%formulationoflifitegrast.
Mildtomoderatebaselinesymptomatology
Moderatetoseverebaselinesymptomatology
Study1Findings• Primaryendpoint,ICSSatday84,wasnotmet• Prespecifiedsignendpoint,changefrombaselinetoday84inICSS:
treatmenteffect,0.35;95%CI,0.05–0.65;P=0.0209
• Onaprespecifiedsecondaryendpoint,changefrombaselinetoday84onvisual-relatedfunctionsubscaleofasymptomscale,thelifitegrastgrouphadgreaterimprovementthantheplacebogroup(P=0.0394)
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Study1ICSSFindings(ITTPopulationWithLOCF)
ITT,intenttotreat;LOCF,lastobservationcarriedforward.
LearningsFromStudy1
• Doseresponserelationshipforsignsandsymptoms,withgreatestefficacyfor5.0%solution(vs0.1%and1.0%)– 5.0%solutionchosenforfurtherevaluation
• InStudy1,subjectswithmild-tomoderatesymptomatology,lifitegrastimprovedICSSversusplacebo– Changefrombaselinetoday84inICSSchosenascoprimarysignendpointfor
Study2• Lifitegrastimprovedvisual-relatedfunctionsubscaleversusplacebo
– Changefrombaselinetoday84onvisual-relatedfunctionsubscalechosenascoprimarysymptomendpointforStudy2
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SIGNChangefromBaselinetoDay84inICSS
(SubjectsWith MildtoModerateSymptoms)
Study1:treatmenteffect,0.35;95%CI,0.05–0.65;P=0.0209
Study2Findings:Signs
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ChangeFrom BaselinetoDay84inICSS
FullStudy2Population(LIF, n=293;PBO,n=294)
BaselineEDS<40(PostHoc)(LIF, n=137;PBO,n=147)
Treatmenteffect(95%CI) 0.24 (0.10–0.38) 0.41(0.21–0.60)
P value 0.0007 <0.0001
• Metcoprimarysignendpoint,changefrombaselinetoday84inICSS
• EffectforICSSwasevenstrongeramonglesssymptomaticsubjects
Study2ICSSFindings(ITTPopulationWithLOCF)
Study2Findings:Symptoms• Coprimarysymptomendpoint(changefrombaselinetoday84onvisual-
relatedfunctionsubscaleofasymptomscale)wasnotmet• Inposthocanalysisofsubjectswithpriorartificialtearuseandbaseline
EDS≥40,lifitegrastimprovedEDSversusplacebo(treatmenteffect,13.34;95%CI,2.35–24.33;nominalP=0.0178;lifitegrast,n=63;placebo,n=67)
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Study2EDSFindings(SubjectsWithPriorArtificialTearUseand
EDS≥40,ITTPopulationWithLOCF)
LearningsFromStudy2
• Coprimarysignendpointmetsignificance,validatingStudy1– Effectonsignswasmorepronouncedinlesssymptomaticsubjects
• Effectonsymptomswasmorepronouncedinsubjectswithmoderatetoseverebaselinesymptomatology
• PopulationsenrolledinStudies1and2weremildlytomoderatelysymptomatic
• BasedonfindingsofStudies1and2,allsubjectsenrolledinStudy3hadpriorartificialtearuseandbaselineEDS≥40,andthusweremoderatelytoseverelysymptomatic
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SIGNChangefromBaselinetoDay84inICSS
(SubjectsWith MildtoModerateSymptoms)
SYMPTOMChangefromBaselinetoDay84inEDS
(SubjectsWith ModeratetoSevereSymptoms)
Study1:treatmenteffect,0.35;95%CI,0.05–0.65;P=0.0209
Study2(posthoc*):treatmenteffect,13.34;95%CI,2.35–24.33;nominalP=0.0178
Study2:treatmenteffect,0.24;95%CI,0.10–0.38;P=0.0007
*SubjectswithpriorartificialtearuseandbaselineEDS≥40.
• Coprimarysignendpoint(ICSS)wasnotmet• Oncoprimarysymptomendpoint,lifitegrastsignificantlyimprovedEDS
versusplacebo(treatmenteffect,12.61;95%CI,8.51–16.70;P<0.0001)
• Allprespecifiedsecondarysymptomendpointsachievedstatisticalsignificance
Study3Findings
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Study3EDSFindings(ITTPopulationWithLOCF)
LearningsFromStudy3
• Coprimarysymptomendpointmetsignificance,validatingStudy2findingsinthispopulationofmoderatelytoseverelysymptomaticsubjects(baselineEDS≥40)withhistoryofartificialtearuse
• Coprimarysignendpointfailedtoseparatefromplacebointhismoresymptomaticpopulation,suggestingadiscordantbehaviorbetweenthe2coprimaryvariables
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SIGNChangefromBaselinetoDay84inICSS
(SubjectsWith MildtoModerateSymptoms)
SYMPTOMChangefromBaselinetoDay84inEDS
(SubjectsWith ModeratetoSevereSymptoms)
Study1:treatmenteffect,0.35;95%CI,0.05–0.65;P=0.0209
Study2(posthoc*):treatmenteffect,13.34;95%CI,2.35–24.33;nominalP=0.0178
Study2:treatmenteffect,0.24;95%CI,0.10–0.38;P=0.0007
Study3:treatmenteffect:12.61;95%CI,8.51–16.70;P<0.0001
*SubjectswithpriorartificialtearuseandbaselineEDS≥40.
Summary
• In2studies,lifitegrastimprovedsigns ofDEDinsubjectswithmildtomoderatebaselinesymptomatology
• In2studies,lifitegrastimprovedsymptoms ofDEDinsubjectswithmoderatetoseverebaselinesymptomatology
• Lifitegrastappearedtobewelltoleratedinthesestudieswithnoseriousoculartreatment-emergentadverseevents
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SIGNChangefromBaselinetoDay84inICSS
(SubjectsWith MildtoModerateSymptoms)
SYMPTOMChangefromBaselinetoDay84inEDS
(SubjectsWith ModeratetoSevereSymptoms)
Study1:treatmenteffect,0.35;95%CI,0.05–0.65;P=0.0209
Study2(posthoc*):treatmenteffect,13.34;95%CI,2.35–24.33;nominalP=0.0178
Study2:treatmenteffect,0.24;95%CI,0.10–0.38;P=0.0007
Study3:treatmenteffect:12.61;95%CI,8.51–16.70;P<0.0001
*SubjectswithpriorartificialtearuseandbaselineEDS≥40.
Observations
• AsinpreviousDEDresearch,outcomesforsignsandsymptomsofDEDarepoorlycorrelatedinthelifitegrastclinicaltrials
• ForEDS,theremaybea“flooreffect”(seeninStudy2)inwhichefficacycanbedemonstratedonlywhenbaselinesymptomsaresufficientlysevere
• Incontrast,subjectswithhighbaselineICSSgradesmayhaveunderlyingconditionsnotresponsivetoashortcourseoftreatment,ortheremaybedifficultiesingradingICSS
• BecauseoftheparadoxicalrelationshipbetweensignsandsymptomsofDEDobservedinthelifitegrastclinicaltrials,itmaynotbepossibletoachievestatisticalsuccesswithcoprimary(signandsymptom)endpointsinthesamestudy
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Conclusions
• In3randomized,double-masked,controlledtrials,lifitegrastimprovedinferiorcornealstainingscoreinsubjectswithmildtomoderatesymptomatologyandeyedrynessscoreinsubjectswithmoderatetoseveresymptomatologyatbaseline
• LifitegrastmeritsconsiderationasatreatmentforsignsandsymptomsofDED
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