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OfficeofClinicalPharmacologyReview

NDA 21368,S‐030SubmissionDate 8/21/17SubmissionType EfficacySupplement(ResponsetoPediatricWrittenRequest)BrandName CialisTM

GenericName TadalafilDosageForm&Strength TabletsRouteofAdministration OralProposedIndication None.DuetofailedclinicalprograminboyswithDuchenne

MuscularDystrophy(DMD)Applicant EliLillyandCompanyOCPReviewTeam AtulBhattaram,Ph.D.,KevinKrudys,Ph.D.,Sreedharan

Sabarinath,Ph.D.

Reference ID: 4198880

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BackgroundEli Lilly and Company conducted a clinical trial with tadalafil in boys with DuchenneMuscularDystrophy(DMD)tofulfilltheWrittenRequestissuedbytheAgency.ThePediatricWritten Request (PWR) for tadalafil was originally issued on 11/16/2006 and wassubsequentlyamended(Formoredetails,refertothereviewbyDr.Rainer,MedicalOfficer,DivisionofNeurologyProducts,CDER).

Tadalafil is a selective, reversible inhibitor of cGMP‐specific phosphodiesterase type 5(PDE5).ItwashypothesizedthatbyinhibitingPDE5,theenzymeresponsiblefordegradingcGMP (cyclic guanosine monophosphate), tadalafil may enhance the residual NO (nitricoxide) signaling coming from active skeletal muscle by selectively boosting cGMPbioavailabilityandinducingvasodilationasneeded,inresponsetoexercise.

TheApplicantconductedarandomized,double‐blind,placebo‐controlledstudy(StudyH6D‐MC‐LVJJ [LVJJ]) to evaluate the efficacy and safety of tadalafil 0.3mg/kg and 0.6mg/kgadministeredorallyoncedailyinambulatoryboyswithDMDwhoarereceivingtreatmentwithcorticosteroids. A totalof331boyswithDMDwererandomized toreceiveplacebo(N=116), tadalafil0.3mg/kg(N=102),ortadalafil0.6mg/kg(N=113) for48weeks).ThemeanageofboyswithDMDwas9.6years.Mean6‐minutewalkdistance(6MWD)atbaselinewas329meters(54%ofthepredictedvalueforageandheight).Asrequiredforinclusioninthe study, all boys with DMD were taking a corticosteroid at baseline, eitherprednisone/prednisolone(53.8%)ordeflazacort(45.9%).Meandurationofcorticosteroidtherapywas40.6monthsatbaseline,andmost(71.9%)weretakingadailycorticosteroidregimen.

DoseselectionwasbasedonthesingledosesoftadalafilthatwereshowntorestorenormalhemodynamicresponsesinstudiesofadultswithBecker’sMuscularDystrophy(BMD)andboyswithDMD.Inarandomized,placebo‐controlled,crossoverstudyinadultmen(meanage,37years)withBMD,asingledoseof20mgtadalafilalleviatedmicrovascularischemiaandfullyrestoredbloodflowregulation(MartinEA,BarresiR,ByrneBJ,TsimerinovEI,ScottBL,WalkerAE,GurudevanSV,AneneF,ElashoffRM,ThomasGD,VictorRG.Tadalafilalleviatesmuscle ischemia in patients with Becker muscular dystrophy. Sci Transl Med.2012;4(162):162ra155). Based on an adult weight of 75 kg, this equates to a dose ofapproximately0.3mg/kg. Inaddition,singledosesof tadalafil (0.5mg/kgor1.0mg/kg)dose‐dependentlyrestorednormalmusclehemodynamicresponsestoexerciseinboyswithDMD assessed by both functional sympatholysis (that is, the NO‐dependent, exercise‐inducedattenuationofsympatheticvasoconstriction)andexercise‐inducedbrachialarteryhyperemia(NelsonMD,RaderF,TangX,TavyevJ,NelsonSF,MiceliMC,ElashoffRM,SweeneyHL,VictorRG.PDE5 inhibitionalleviates functionalmuscle ischemia inboyswithDuchenne

Reference ID: 4198880

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musculardystrophy.Neurology.2014;82(23):2085‐2091).Assuminga1.6‐foldaccumulationfactorduringmultipledosing(ForgueST,PattersonBE,BeddingAW,PayneCD,PhillipsDL,WrishkoRE,MitchellMI.Tadalafilpharmacokineticsinhealthysubjects.BrJClinPharmacol.2006;61(3):280‐288),theexposuresproducedbyasingledoseof0.5mg/kgor1.0mg/kgequatetoonce‐dailydosesofapproximately0.3mg/kgand0.6mg/kg,respectively.Theseonce‐dailydosesarepredictedtoachievesteady‐stateexposuresconsistentwiththosethatproducedpharmacologicaleffectsonskeletalmusclehemodynamicsinboyswithDMDafterasingledose.

InthestudyconductedbytheApplicantasperthePWR,tadalafildidnotshowefficacyinslowingthedeclineinambulationasmeasuredbytheprimary6MWDendpointat48weeks.RefertothereviewbyDr.Rainer,MedicalOfficer,DivisionofNeurologyProducts,CDERformoredetails.

Towardsdetermining thepediatric exclusivity, theOfficeofClinicalPharmacology (OCP)reviewedrelevantaspectsthatwereintheWrittenRequest.ThereviewteamhasconcludedthattheApplicanthasfulfilleditemsinthePWRthatarerelevanttoclinicalpharmacologydiscipline.TherelevantPWRitemsalongwiththeresponsesfromtheApplicantandOCParediscussedbelow.

Reference ID: 4198880

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WrittenRequestItem#1:ClinicalStudy

Tadalafilpharmacokinetics(PK)andrelationshipsbetweentadalafilexposureandefficacyand safetywill be characterized using a population PK (PPK) approach. Patientswill berandomizedtooneoftwodosesoftadalafilorplaceboina1:1:1ratio.

InformationSubmitted/Applicant’sresponse

TadalafilpharmacokineticswerecharacterizedwithpopulationPKmethodsusingaone‐compartmentmodelestablishedinadults.PatientsinStudyLVJJwererandomizedtoeitherplacebotreatmentor0.3mg/kgor0.6mg/kgtadalafildose.

OCP’sComments

FulfilledasstatedinPWR

The Applicant conducted population pharmacokinetic analyses using acceptablemethodologythatincludedbasemodeldevelopmentalongwithscreeningofcovariatesfortheir influenceontadalafilpharmacokinetics.TheanalysisreportalongwiththedatahasbeensubmittedtotheAgency.

Reference ID: 4198880

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WrittenRequestItem#2:StudyEndpoints

Pharmacokinetic/PharmacodynamicEndpoints:

Thepharmacokineticendpoints in thepopulationpharmacokinetic analysismust includevolumeofdistributionandclearance.Sparsepharmacokineticsamplesmustbecollectedtoexploretherelationshipsbetweentadalafilexposureandefficacyandsafetyendpoints.

InformationSubmitted/Applicant’sresponse

PopPKReport:

CovariateSelectionandFinalModel

Source:Figure6.3onpage20inpopulation‐pk‐report.pdf

Reference ID: 4198880

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EstimatesofapparentclearanceandapparentvolumeofdistributioninthefinalpopulationPKmodelwere1.79L/hrand39.1L,respectively.

Source:Table6.4onpage21inpopulation‐pk‐report.pdf

PopPKReport:

Exposure‐Efficacy Relationship: The relationship between the study’s primary efficacyoutcomeandtadalafilexposurewasevaluatedfromascatterplotofchangefrombaselinein6‐minutewalkdistance(6MWD)atWeek48versustadalafilAUC.TherewasnodiscernablerelationshipbetweenAUCandchangein6MWD.

Reference ID: 4198880

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Source:Figure6.6onpage26inpopulation‐pk‐report.pdf

ResultsofstatisticalanalysesofrelationshipsbetweenadverseeventsandAUCquartilearealsoprovided.

Reference ID: 4198880

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Source:TableLVJJ.14.103onPage937inlvjj‐04‐body.pdf(ShownhereisoneofthetablesasprovidedbytheApplicant)

OCP’sComments

FulfilledasstatedinPWR

Thereviewerconductedgraphicalanalysistounderstandthedatacollectedtodescribethepharmacokineticsoftadalafil.AdequatedatahasbeencollectedthathelpstodescribethePKprofileusingaone‐compartmentmodel.

Reference ID: 4198880

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Source:Reviewer’sAnalysis

Noindependentexposure‐responseanalysiswasconductedbytheAgency.Sincethestudyfailed todemonstrateanybenefit from the twostudieddosesof tadalafil, nodiscernablerelationshipbetweenAUCandchangein6MWDisexpected.ThereportingofsafetyresultsbyAUCquartilesoftadalafilisacceptable.

Reference ID: 4198880

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WrittenRequestItem#3:Age‐AppropriateFormulation

Bioavailabilityofanyformulationusedinthestudiesmustbecharacterized,andasneeded,a relative bioavailability study comparing the approved drug to the age appropriateformulationmaybeconductedinadults.

InformationSubmitted/Applicant’sresponse

TheApplicantdidnotdevelopanewpediatricformulationforStudyLVJJ,asperEMEACHMPReflection Paper Formulation of Choice for the Pediatric Population dated 21 September2006,tadalafiltabletsareconsideredofappropriatesizefordosinginthepediatricpatientsage7‐14years.

Source:TableLVJJ.9.2onPage49inlvjj‐04‐body.pdf

Thetotaldailytadalafildoseforeachweightcategorywasachievedwithacombinationofexistingtadalafiltabletstrengths(2.5,5,10,and20mg)ormatchingplacebotablets.Thedosingalgorithmusedinthestudyisshownbelow.

Reference ID: 4198880

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Source:TableLVJJ.9.1onPage49inlvjj‐04‐body.pdf

OCP’sComments

FulfilledasstatedinPWR

Sincetheapprovedformulationsareusedinthestudy,noadditionalbioavailabilitystudiesarerequired.

Reference ID: 4198880

---------------------------------------------------------------------------------------------------------This is a representation of an electronic record that was signedelectronically and this page is the manifestation of the electronicsignature.---------------------------------------------------------------------------------------------------------/s/----------------------------------------------------

VENKATESH A BHATTARAM12/21/2017

KEVIN M KRUDYS12/21/2017

SREEDHARAN N SABARINATH12/21/2017

Reference ID: 4198880