ClinicalPharmacokineticsandAntiviralActivityofCC-31244,aPan-genotypic,PotentNon-nucleosideNS5BPolymerase

Inhibitor(NNI)fortheTreatmentofHepatitisC

2017APASL,Shanghai

SamLee,Ph.D.

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CC-31244: Preclinical Background

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§ Potentialbest-in-classpan-genotypicHCVNS5BNNI

§ Highbarriertodrugresistance

§ ExcellentactivityagainstcommonNS5BNNIdrugresistantvariants

§ FavorablePKpropertiesinrats,dogs,andmonkeys

§ Livertargeting(>1,500-foldaboveEC50)inrats

CC-31244: Pan-genotypic NS5B NNI

Genotype CDI-31244EC50,µM

EC50Foldchange

SofosbuvirEC50,µM

EC50foldchange

1b 0.005 1.0 0.042 1.0

1a 0.009 1.8 0.034 0.8

2b 0.026 5.2 0.028 0.66

3a 0.011 2.2 0.14 3.2

4a 0.021 4.2 0.047 1.1

5a 0.002 0.4 0.075 1.7

§ CC-31244HCVrepliconEC50 foldchange,<6fold

HCVreplicon/chimericrepliconEC50 results

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CC-31244 Developed By Cocrystal’s Structure-based Drug Discovery Platform Technology

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Study Design and Objectives

§ Phase1a/1brandomized,placebocontrolled,double-blindstudy

§ SingleandmultipledosesofCC-31244inhealthyandHCVgenotype1-infectedpatientstoevaluatesafety/tolerability,PK,antiviralactivity,andfoodeffect

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Phase 1a Study Design: Healthy Volunteers

Singleascendingdoses(complete)

20mg 50mg 100mg 200mg* 400mg

N= 40;30CC-31244,10placebo;*foodeffectassessed

Multipleascendingdoses(complete)

200mg BID 400mg QD

N= 16;12CC-31244,4placebox7days

Endpoints§ Safety:adverseevents(AEs)andlaboratoryabnormalities

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Phase 1b Study Design: HCV GT1 Patients

HCVGT1HCVRNA≥5log10IU/ml

Naive

SingledosesQDorBIDx7days

200mgBID x7days Status

N= 4;3CC-31244,1placebo Complete

400mgQDx7days Status

N= 5;4CC-31244,1placebo Complete

600mgQDx7days Status

N= 5;4CC-31244,1placebo OngoingEndpoints§ Efficacy:changesinHCVRNAviralload§ Safety:adverseevents(AEs)andlaboratoryabnormalities

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Study Methods

§ Safetyassessmento Adverseeventso Hematology,bloodchemistry,urinalysiso ECGo Vitalsignso Physicalexamination

§ Efficacyassessmento HCVRNAquantitation(RocheTaqman HCVv2.0)o Days1-13,and35

§ PKassessmento Pre-dose,Days1-13

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CC-31244(N=42)

Placebo(N=14)

Age(years) Mean(SD) 41(13) 40(16)Median 41 36Min,Max 18,63 19,64

Gender[n(%)] Male 40(95) 10(71)Female 2(5) 4(29)

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CC-31244(N=7)

Placebo(N=2)

Age(years) Mean(SD) 50(13) 48(11)Median 51 48Min,Max 36,65 40,56

Gender[n(%)] Male 5(71) 2(100)Female 2(29) 0

Baselineviralload HCVRNAIU/mL(log10) 6.07(0.58) 6.37(0.49)Genotype[n(%)] GT1a 5(71) 1(100)

GT1b 2(29) 0

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Healthyvolunteers§ NoseriousAEsreported;nodiscontinuationduetoAEs§ AEincidencerate:SAD=23%(NNI),50%(placebo);MAD=25%(both)§ AEswithfrequency>1insubjectsreceivingCC-31244

Ø SAD:headache,2/30(6%);MAD:metallictaste,2/12(16%)

HCVGT1patients§ NoseriousAEsreported;nodiscontinuationduetoAEs§ AEincidencerate:57%(NNI),100%(placebo)§ NoAEswithfrequency>1inHCVGT1patientsreceivingCC-31244

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-3.5 -3.2 -2.9 -2.6 -2.3 -2

-1.7 -1.4 -1.1 -0.8 -0.5 -0.2 0.10.40.71

1 2 3 4 5 6 7 8 9 10 11 12 13HCVRN

AIU/m

L(lo

g10

)

Day

ViralLoadChangeFromBaseline(400mgQDor200mgBIDx7days)

Sub#1qd Sub#2qd Sub#4qd Sub#5qd

Sub#6bid Sub#7bid Sub#8bid

§ HCVRNAviralloaddeclineof3logsby48hours§ AftertheNNItreatment,theviralloadlevelswereslowlyincreased§ Drugresistanceanalysisongoing

● 400mgQD

● 200mgBIDNNI,QDorBID NoNNI

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Drug Genotype Dose(mg)

TreatmentDuration(days)

Viral loadreduction

(Log10IU/ml)

CC-31244 Genotype 1-6 400 7(QD) -3.0ABT-333*(Dasabuvir) Genotype1 400 3(BID) -1.08

800 3(BID) -0.95GS-9190(Tegobuvir) Genotype1 40 3(BID) -1.0

120 3(BID) -1.5

HCV NNIs: Viral Load Comparison

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(*:approvedDAA)

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Acknowledgements

Weextendourthankstothesubjectsandinvestigators

Cocrystalteam:LuzPascual,JudyPattassery,

IrinaJacobson,MicFeese,LotharUher,HongXiao,BiingLin,EmilSanchez,SteveCoats,JanetAldophson,Tami

McBrayer,Shuiyun Lan,TonyWhitaker,SamLee

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