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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