clinical pharmacokinetics and antiviral activity of …...cc-31244: preclinical background 2...
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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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