EfficacyofGKT831inpatientswithprimarybiliarycholangitisandinadequateresponsetoursodeoxycholicacid:

Interimefficacyresultsofaphase2clinicaltrialGeorge Dalekos1, Pietro Invernizzi2, Frederik Nevens3, Van Vlierberghe Hans4, Ehud Zigmond5, Raul J. Andrade6, Ziv Ben Ari7, Michael Heneghan8,

Jonathan Huang9, Stephen Harrison10, Gerald Minuk11, PD Dr. Schattenberg Jörn12, Christophe Moreno13, John Vierling14, Catherine Vincent15, Christopher Bowlus16, Yoav Lurie17, Luigi Muratori18, Grazia Niro19, Gideon Hirschfield20, Anthony Post21, Stefan Zeuzem22, Tania Welzel22, Chin Lye Ch'ng23, Cynthia Levy24, Michael Miller25, Agustin Albillos26, Jane D. Collier27, Lynsey Corless28, Douglas Dieterich29, Andreas E Kremer30, George Papatheodoridis31, David Romeo32, Marina Silveira33, David Bernstein34, Michal Cohen-Naftaly35, Annarosa Floreani36, Brian Borg37, Elizabeth Carey38, Coral Hollywood39, Benedict Maliakkal40, Marco Marzioni41, Mordechai Rabinovitz42, Christian Rupp43, David Sheridan44, Carmen Stanca45, Mark G Swain46, Ella Veitsman47, P Spyridon Dourakis48, Philippe Wiesel49 1University of Thessaly, Greece; 2University of Milano-Bicocca, Italy; 3UZ Leuven, Belgium; 4Ghent University Hospital, Belgium; 5Tel Aviv Sourasky Medical Center/Medical Tourism,, Israel; 6Hospital Universitario Virgen de la Victoria, Spain; 7Sheba Medical Center, Israel; 8King's College Hospital NHS Foundation Trust, United Kingdom; 9University of Rochester Medical Center, United States; 10Pinnacle Clinical Research, United States; 11John Buhler Research Centre, Canada; 12Medical School, Johannes Gutenberg University Mainz, Germany; 13Hospital Erasme, Belgium; 14Baylor College of Medicine Medical Center, United States; 15University of Montreal, Canada; 16Uniersity of California Davis, United States; 17Shaare Zedek, Israel; 18Policlinico S. Orsola-Malpighi, Italy; 19IRCCS Ospedale Casa Sollievo della Sofferenza, Italy; 20Queen Elizabeth Medical Center, United Kingdom; 21University Hospitals Cleveland Medical Center, United States; 22Goethe University Frankfurt, Germany; 23Abertawe Bro Morgannwg University, United Kingdom; 24Schiff Center for Liver Diseases, United States; 25Tayside Medical Science Centre (TASC), United Kingdom; 26Hospital Ramón YCajal, Spain; 27John Radcliffe Hospital, United Kingdom; 28Hull Royal Infirmary, United Kingdom; 29Icahn School of Medicine at Mount Sinai, United States; 30University of Erlangen-Nuremberg, Germany; 31Laikο General Hospital of Athens, Greece; 32Dayton Gastroenterology- Sylvania, United States; 33Yale School of Medicine, United States; 34North Shore University Hospital, Israel; 36University of Padua, Italy; 37Southern Therapy and Advanced Research, United States; 38Mayo Clinic Hospital, United States; 39Gloucestershire Hospitals Nhs United Kingdom; 40Methodist University Hospital, United States; 41Marche Polytechnic University Faculty of Medicine, Italy; 42University of Pittsburgh Medical Center, United States; 43University Clinic Heidelberg, Germany; 44Plymouth Hospitals NHS Trust, United Kingdom; 45NYU Hepatology Associates, United States; 46University of Calgary, Canada; 47Rambam Healthcare Campus, Israel; 48General Hospital of Athens Hippocrates, Greece; 49Genkyotex, Plan-les-Ouates, Switzerland

Unmetneedsinprimarybiliarycholangitis(PBC)

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•  Definition-Chronic,cholestaticliverdiseasecharacterizedbynon-suppurativegranulomatouscholangitis;ductdestructionandductopenia,andportalfibrosisthatprogressesslowlytobiliarycirrhosis.

•  Etiology–Complexdisorder,causedbyacomplexoflargelyunknowngeneticandenvironmentalfactors.Putativeautoimmunepathogenesis.

•  Therapy-Ursodeoxycholicacid(UDCA)isthefirst-linedrugeffectiveinthemajority(60-70%ofresponders).Obeticolicacid(OCA)isthelicensedsecond-linetherapy.

•  CurrentPBCtherapiestargetcholestasisbymodulatingbileacidmetabolism(UDCA,OCA)

•  Howeverinflammation&fibrosiscontributetocholestasis,bileduct&liverinjury

•  NADPHoxidasesNOX1&NOX4produceROSandmodulatesignalingthroughoxidationofsignalingproteins

•  NOX1/4drivemultipleinflammatory&fibrogenicpathways(TGFβ,PDGF,TLR4,ASK1,NF-κB,CCL2,…)

•  NOX1alsoactivatespathwaysthoughttomediateitching,suchasTRPV1

•  GKT831showsmarkedactivityinanimalmodels(bileductligation,MDR2KO,STAM,diet-inducedNASH,CCL4)

RationaleforNOX1/4inhibitionwithGKT831ininflammatoryandfibroticdisorders

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NOX1

ASK1

ASK1activation TGFβsignalingNOXstructure

Studydesign(objectives)�  24-weektreatmentperiod-4-weekfollowup�  Primaryefficacyendpointforinterimandfinalanalysis:PercentchangeinserumGGTfrombaseline�  KeysecondaryendpointisALPreduction�  Safetyandtolerability�  Interimanalysisatweek6andfinalanalysisatweek24

Keyeligibilitycriteria(population)�  MaleorfemalePBCpatientaged18-80years�  SerumALP≥1.5XULNandserumGGT≥1.5XULN(stratificationaccordingtobaselineGGT(>or<2.5XULN))�  OnUDCAfor≥6months&stabledosefor≥3months�  ExclusionofhistoryofcirrhosiswithcomplicationsorcurrentMELDscore≥15�  ALT>3XULNortotalbilirubin>1XULN�  Hepatorenalsyndromeorserumcreatinine>ULN�  Prohibitedmedications:fibratesandobeticholicacid(12-weekwashout)

GKT831inPBC:StudydesignandKeyeligibilitycriteria

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GSN000300–Alarge24-weekPhase2trialinpatientswithprimarybiliarycholangitis

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Placebo

GKT831400mgonceaday

GKT831400mgtwiceaday

Baseline Week6 Week24

InterimanalysisGGT,ALP

ALT,AST,bilirubinhsCRP

FIB-4,APRI

MainanalysisGGT,ALP

ALT,AST,bilirubin,CK-18hsCRP,IL-6

Fibroscan,ProC3,ELF,APRI,FIB-4PBC-40,pruritusVAS

IL-4,IL-12,IL-17A,IgM,IFNγFGF-19,C4,totalbileacids

Followup

Followup

Followup

111randomized(initialtarget102)

ALP≥1.5XULNGGT≥1.5XULN

InadequatebiochemicalresponsetoUDCA

GGT,ALP,bilirubin

ALT,ASThsCRP

FIB-4,APRI

GGT,ALP,bilirubinALT,AST,CK-18hsCRP,IL-6

Fibroscan,ProC3,ELF,FIB-4,APRIPBC-40,pruritusVAS

IL-4,IL-12,IL-17A,IgM,IFNγFGF-19,C4,totalbileacids

CholestasisLiverinjuryInflammationFibrosisQualityoflifeImmuneactivationBileacidmetabolism

InterimanalysisatWeek6:Baselinepatientcharacteristics

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Populationincludesveryactive,difficulttotreatPBCpatients

Placebo GKT831400mgOD1

GKT831400mgBID2 ALL

N 31 31 30 92

Age(years) 56(10) 56(10) 55(9) 56(9)

Females(%) 97 84 93 91

ALP(U/L) 304(151) 282(89) 350(177) 312(145)

GGT(U/L) 224(212) 215(154) 237(193) 225(187)

ALT(U/L) 44(18) 44(22) 55(34) 47(26)

AST(U/L) 44(19) 43(20) 50(33) 46(24)

Totalbilirubin(µmol/L) 11(5) 11(5) 10(4) 11(4)

hsCRP(mg/L) 5.0(4.9) 5.8(5.7) 4.7(5.1) 5.2(5.2)

Valuesexpressedasmean(SD).Baseline:Day1.Normalranges:GGTupto45and65U/L(F/M),ALPupto125U/L

1 Oncedaily;2Twicedaily

Asperprotocol,thepredefinedinterimanalysiswasconductedwhen>90patients(92)reachedWeek6

Percen

tcha

ngefrom

Baseline

-7%

-30

-25

-20

-15

-10

-5

0

0 1 2 3 4 5 6Treatmentduration(week)

-7%

-12%

Mean±SEMp<0.01-23%

-23%

Absolutecha

ngeinGGT(U/L)

Treatmentduration(week)

Mean±SEM

Primaryefficacyendpoint:GKT831achievesstatisticallysignificantreductionsinGGTatWeek6

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-12%

Primaryendpoint:percentchangeinGGT AbsolutechangeinGGTovertime

Placebo(n=31) GKT831400mgOD(n=31) GKT831400mgBID(n=30)

-80

-60

-40

-20

0

20

0 1 2 3 4 5 6

GreaterGGTreductionsinpatientswithhigherbaselineGGT(≥2.5XULN,n=68)GGT≥2.5XULNwasthepre-specifiedstratificationcut-off

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GKT831alsobenefitspatientswithmoreactivedisease

Placebo400mgOD 400mgBID

GKT831

Percen

tcha

ngefrom

Baseline

toweek6(%

)-40

-35

-30

-25

-20

-15

-10

-5

0

p=0.64

-29.4%

-11.2%-7.6%

Mean±SEM

n=21 n=24 n=23

p<0.01

Baseline

Week6

0

50

100

150

200

250

300

350

Placebo

GKT831400mgOD 400mgBID

MeanGGT(U/L)

Mean±SEM

n=21 n=24 n=23

MeanGGTlevels RelativechangesinGGT

GKT831alsoachievesstatisticallysignificantreductionsinALPatweek6

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-25

-20

-15

-10

-5

0

50 1 2 3 4 5 6

Relativ

echan

geinALP(%

)

MeanAL

P(U/L)

Treatmentduration(week) Treatmentduration(week)

Mean±SEMMean±SEMp<0.001

p=0.06

-2%

-17%

-8%

Keysecondaryendpoint:percentchangeinALP AbsolutechangeinALPlevels

-80-70-60-50-40-30-20-100

0 1 2 3 4 5 6

Placebo GKT831400mgOD

GKT831400mgBID

Proportionofpatientswith≥15%reductioninALPatWeek6 16.1% 25.8% 53.3%

GKT831achievesdosedependentreductionsinlivertransaminasesatweek6

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-12-10-8-6-4-20

-12-10-8-6-4-20

Percen

tcha

ngefrom

Ba

selin

etoW

eek6

Percentcha

ngefrom

Ba

selin

etoW

eek6

MedianvaluesMedianvalues

0102030405060

Placebo400mgOD 400mgBID

GKT831

n=31 n=31 n=30

MeanAS

T(U/L)

BaselineWeek6

Placebo400mgOD 400mgBID

GKT831

n=31 n=31 n=30

MeanAL

T(U/L)Meanvalues

0

20

40

60

80Meanvalues

SerumASTlevels SerumALTlevels

Nodetectablechangesintotalorconjugatedbilirubinfrombaselinetoweek6

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Meanconjugated

bilirubin(µml/L)

Meantotalbilirubin(µml/L)

0

2

4

6

8

10

12

14

0

2

4

6

8Mean±SEM Mean±SEM

Baseline

Placebo

GKT831400mgOD 400mgBIDBaseline

Week6

n=31 n=31 n=30 n=31 n=31 n=30Placebo

GKT831400mgOD 400mgBID

Totalbilirubin Conjugatedbilirubin

ReductionininflammatorymarkerhsCRPconsistentwithanti-inflammatorymechanism

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-30

-25

-20

-15

-10

-5

0

5

Percentcha

ngefrom

Ba

selin

etoW

eek6

Placebo400mgOD

400mgBID

GKT831

Medianvalues

0

2

4

6

8

10

p=NS

MeanhsCR

P(m

g/L)

Mean±SEM

Placebo

GKT831

400mgOD 400mgBIDBaseline

Week6

n=31 n=31 n=30

n=31 n=31 n=30

MeanhsCRP PercentchangeinhsCRP

DosedependentreductionsinFIB-4andAPRI,consistentwithanti-fibroticmechanism

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-25

-20

-15

-10

-5

0

5

-25

-20

-15

-10

-5

0

5

Placebo400mgOD

400mgBID

GKT831

Med

ian%cha

ngeinFIB-4sc

ore

from

BaselinetoW

eek6

Med

ian%cha

ngeinAPR

Iscore

from

BaselinetoW

eek6

Placebo400mgOD

400mgBID

GKT831

Atweeks12&24,assessmentsofliverfibrosisincludePro-C3andtheELFscoreTransientelastography(Fibroscan®)performedatweek24

MedianvaluesMedianvalues

p<0.05p=NS

n=31 n=31 n=30n=31 n=31 n=30

PercentchangeinFIB-4score PercentchangeinAPRIscore

Clinicalsafetyprofile

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•  Positiverecommendationateachofthe3SafetyMonitoringboardmeetings•  3pre-planneddatareviewmeetingsbyIndependentSafetyMonitoringBoard•  Positiverecommendationtocontinuetrialasperprotocolaftereachofthe3reviewmeetings•  LastSMBreviewmeetingheldwhen87patientshadcompletedweek6and41hadcompletedweek24

•  Favorableclinicalsafetyprofileoverthefull24-weektreatmentperiod•  Hightreatmentcompletionrate(>96%ofpatientshavecompletedthefull24-weektreatment)•  4patientsdiscontinuedtreatmentprematurely;2foradministrativereasonsand2forsafetyreasons:

•  Onepatientwithdizziness,abdominalbloating,dyspnea,andpalpitationsafterasingledose•  Onepatientwithelevationsintransaminases(similarelevationsafewmonthspriortostudystart,

decisionmadetointerrupttreatment)•  2SAEs,bothunrelatedtostudydrug

— Onecaseofgrade1urinarytractinfection(subjecthospitalizedtoinitiateIVantibiotics)— Oncecaseofmultiplebonefracturesduetoatrafficaccident

•  Notreatmentinterruptionordiscontinuationsduetopruritusorfatigue

�  InpatientswithinadequateresponsetoUDCA,GKT831inducestimeanddosedependentreductioninGGTandALPafteronly6weeksoftreatment

�  GKT831isthefirstnon-anticholestaticcompoundtosignificantlyimprovemarkersofcholestasis,inflammationandfibrosisinPBC

�  GKT831appearstobewelltoleratedwithnosignalsrelatedtopruritusorfatigue

�  Finalresultsatafter24weeksoftreatmentwillprovideinformationaboutGKT831effectsonliverfibrosisandqualityoflife

KeyFindingsandConclusions

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Acknowledgements

PietroInvernizzi,Italy,GeorgeDalekos,Greece,FrederikNevens,Belgium,VanVlierbergheHans,Belgium,EhudZigmond,Israel,RaulJ.Andrade,Spain,ZivBenAri,Israel,MichaelHeneghan,UnitedKingdom,JonathanHuang,UnitedStates,StephenHarrison,UnitedStates,GeraldMinuk,Canada,JörnSchattenberg,Germany,ChristopheMoreno,Belgium,JohnVierling,UnitedStates,CatherineVincent,Canada,ChristopherBowlus,UnitedStates,YoavLurie,Israel,LuigiMuratori,Italy,GraziaNiro,Italy,GideonHirschfield,UnitedKingdom,AnthonyPost,UnitedStates,StefanZeuzem,Germany,TaniaWelzel,Germany,ChinLyeCh'ng,UnitedKingdom,CynthiaLEVY,UnitedStates,MichaelMiller,UnitedKingdom,AgustinAlbillos,Spain,JaneD.Collier,UnitedKingdom,LynseyCorless,UnitedKingdom,DouglasDieterich,UnitedStates,AndreasEKremer,Germany,GeorgePapatheodoridis,Greece,DavidRomeo,UnitedStates,MarinaSilveira,UnitedStates,DavidBernstein,UnitedStates,MichalCohen-Naftaly,Israel,AnnarosaFloreani,Italy,BrianBorg,UnitedStates,ElizabethCarey,UnitedStates,CoralHollywood,UnitedKingdom,BenedictMaliakkal,UnitedStates,MarcoMarzioni,Italy,MordechaiRabinovitz,UnitedStates,ChristianRupp,Germany,DavidSheridan,UnitedKingdom,CarmenStanca,UnitedStates,MarkGSwain,Canada,EllaVeitsman,Israel,SpyridonDourakis,Greece,PhilippeWiesel,Switzerland