Pharmacodynamic (PD) evaluation of Rezafungin...disseminated candidiasis model using an extended interval dosing regimen to mirror human dosing regimens •Efficacy was demonstrated

Pharmacodynamic (PD) evaluation of Rezafungin (CD101) against Candida auris in the persistently

neutropenic murine model of disseminated candidiasis

AlexanderJ.Lepak,MiaoZhao,DavidR.AndesUniversityofWisconsinSchoolofMedicineandPublicHealth

TransparencyDeclaration

• ThisstudywassupportedbyfundingfromCidara Therapeutics,Inc.

Candidaauris - Background• Globalemergingpathogen

• Mortalityrate40-60%

• Environmentalpersistenceandinterhuman transmission

• Drug-resistanceandmulti-drugresistanceistypical

• Fluconazoleresistance>90%

• AmphotericinBresistance30-50%

• Echinocandinresistance5-10%Lamoth F&Kontoyiannis DP.JInfec Dis2018

Rezafungin(CD101)

• Novelechinocandinwithtoxicologicalandpharmacokineticadvantagesincludingaprolongedterminalhalf-lifeof130-hoursinhumans

• Developedforextendedintervaldosing(i.e.once-weeklyintravenousinfusions)

• EchinocandinPK/PDstudieshave

demonstratedtheimportanceofboth

AUC/MICandCmax/MIC

• Rezafunginpharmacologicalproperties

allowformaximizingbothPDindices

Rezafungin Acetate

LepakAJetal,AAC2018LakotaEAatal,AAC2018

PreviousRezafungin MurinePK/PDTargetStudies

C.albicans C.glabrata C.parapsilosisStasis 1-logkill Stasis 1-logkill Stasis 1-logkill

24hfAUC/MIC* 2.89 5.14 0.20 0.66 ~3 NA

LepakAJ,etal.Antimicrob AgentsChemother 2018;62:e02154-17

*PDtargetsarenumericallylower(especiallynotableforC.glabrata)thancomparatorechinocandins

CurrentStudyAim: DeterminethepharmacodynamictargetfortreatmentofdisseminatedC.aurisinfectionintheneutropenicmurinemodelofinvasivecandidiasis

MethodsStrains:• 4C.aurisstrains(oneFKSmutantstrain)

Susceptibilitytesting:• MICsbyCLSImethods

MurinePK:• PlasmaPKfromgroupsofmiceafterIPadministrationofrezafunginat1,4,16,and64mg/kg

• Non-compartmentalmodel

InfectionModelandAnalysis:• 6-weekoldSwiss/ICRfemalemice(23-27g)• Neutropeniabycyclophosphamideinjectionatday-4,-1,+2and+4

• Inoculumof5.99±0.29log10CFU/mLinjectedintotailvein,2-hourslaterfirstdoseofdrugisadministered

• Rezafungindose(1,4,16or64mg/kg)IPonday0,3,6tomimiconce-weeklydosinginhumans

• Infectiousburdenenumeratedfromkidneysonday7byCFUcounts

• TreatmentdataandAUC/MICevaluatedbysigmoidEmaxmodel(Hillequation)

• Staticand1-logkilltargetexposuresweredetermined

StrainsandinvitroSusceptibilityTesting

Strain CountryofOrigin

Log10 growthinUntreatedControls(CFU/kidneys)

In vitroSusceptibilityResults(mg/L)Rezafungin Fluconazole Micafungin AmphotericinB

B11220 Japan 3.06 0.06 4 0.125 0.38B11785 Colombia 3.43 0.125 8 0.5 1.5B11799 Colombia 3.67 0.25 16 2 0.5B11211* India 3.17 2 256 4 1.5

*FKS1_HS1_S639F

MurinePharmacokinetics

Plasmaconcentrationsofrezafungin (CD101)inmicefollowingsingleIPdoses.Eachsymbolisthemeanandstandarddeviationforthreemice.Cmax,peakconcentration,AUC,areaunderconcentration-timecurvefromzerotoinfinity,T1/2,terminaleliminationhalf-life

TreatmentStudies

Rezafungin dose-responsecurvesagainstC.auris(left).Relationshipbetweentotal- (red)andfree- (blue)drugAUC/MICandtherapeuticeffect(right).Groupsofmiceweretreatedwithoneoffourrezafungin dosingregimensadministeredeverythreedaysoverthe7dayexperimentalperiod.Infectiousburdenwasenumeratedfromkidneyhomogenatesandcomparedtotheburdenattimepointzero(dashedline).Pointsabovethedashedhorizontallinerepresentnetincreaseinburdenovertimeandthosebelowthelinerepresentanetdecrease.PDparametersarealsoshowninthefigureontherightincludingregressionanalysis.

PDTargetExposuresAssociatewithNetStasisand1-logkillEndpoints

Strain MIC (mg/L)

Static Dose (mg/kg)

Stasis Ave 24 h AUC/MIC

Stasis Ave 24 h fAUC/MIC

1 log kill dose (mg/kg)

1 log kill Ave 24 h AUC/MIC

1 log kill Ave 24h fAUC/MIC

B11220 0.06 0.87 144.78 1.16 6.99 987.68 7.90B11785 0.125 6.09 421.39 3.4 10.65 685.80 5.49B11799 0.25 8.76 288.72 2.3 16.17 488.81 3.91B11211 2 23.04 82.95 0.66 NA*Mean 9.69 234.46 1.88 11.27 720.76 5.77Median 7.43 216.75 1.73 10.65 685.80 5.49Std Dev 9.48 151.53 1.21 4.62 251.26 2.01

*NA,notachieved

HumanExposure

• TranslatingPK/PDtargetstohumans

• Rezafungin 400mgIVonceweeklyinhumans

• TotalAUC0-168 1840mg*h/L,2.6%freedrug--->47.84mg*h/LfreeAUCoraverage24h

freedrugAUCofabout7mg*h/L

• UsinghumanfreedrugPKestimatesandstasisPDtargetsyieldsanMICceilingestimate

of2-4mg/L,for1-logkilltargettheMICceilingestimatewouldbe1-2mg/L

Conclusions

• Rezafungin demonstratedinvivopotencyagainstC.auris intheneutropenic

disseminatedcandidiasismodelusinganextendedintervaldosingregimentomirror

humandosingregimens

• Efficacywasdemonstratedagainstahighlyresistantstrain(B11211)withknownFKS1mutation

• PK/PDtargetexposuresoffreedrug24hAUC/MICof2and6ledtostasisand1-log

kill,respectively

• Rezafungin isavaluableadditiontotheantifungalarmamentarium,withPK

advantagesthatpermitachievementofoptimalPK/PDdrugexposuresinextended-

intervaldosingregimensandagainststrainswithelevatedechinocandinMICs