Psoriasis:Therapeu.cAdvancesBasedonIncreasedUnderstandingof

DiseasePathways

JamesG.Krueger,MDPhDProfessorandLaboratoryHeadTheRockefellerUniversity

Conflicts•  Researchsupport,consul.ng,orlecturefeesbymostpharmaandbiotechcompanieswithapsoriasisproductorinves.ga.onalagentduringthepast20years

•  Nopatents,ownership,orfinancialgainfromanypsoriasisproductordrug

Immune-MediatedInflammatoryDiseasesaffectatleast1:10PeopleWorldwide•  Skin:PsoriasisVulgaris,AtopicDerma..s,AlopeciaAreata,

Vi.ligoandnumerousothers•  Diges.veSystem:Crohn’sDisease,Ulcera.veColi.s,and

Type1Diabetes•  Skeletal:RheumatoidArthri.s,Psoria.cArthri.s•  CNS:Mul.pleSclerosis•  Respiratory:Asthma•  Mul.-organ:SystemicLupus,SystemicSclerosis

PsoriasisVulgaris

•  Themostsuccessfulcaseofmoleculartherapeu.ctarge.nginahumanimmune-mediateddisease

•  Withasingledrugcannowcontrolpsoriasisextremelywellin~80-90%ofpa.ents

•  Nowhavedrugsthatdirectlytargetelementsofgene.c/genomicdiseaserisk

Genera.onsofPathogenicModels•  1st-SimpleT-cellmodel(agnos.cofT-cellpolarity)•  2nd-PolarT-cellmodel(IL-12/Th1T-cells)•  3rd-InnateImmunityModel--ItsTNFandnotT-cells•  4th-ComplexT-cellModel(Th1,Th17&Th22T-cells)•  5th-IL-23/T17T-cellmodel--Type17T-cells(Th17,Tc17,innatelymphocytessynthesizeIL-17undercontrolofIL-23)

Psoriasisvulgaris

Anautoimmuneskindiseaseassociatedwithincreasedsystemicinflamma.onthatimpactsoverallhealthandlifespan

Phenotypesofpsoriasis•  Thecellular(histologic)diseasedefini.on•  Themoleculardefini.onbasedongeneexpression

Howarethesefeaturescreatedbyimmune-derivedcytokinesandhowdoestarge.ngthosecytokineswith

immuneantagonistschangethephenotypes?

Unaffected Skin of Patient Psoriasis Lesion

Histopathologyofnormalappearingbackgroundskinandapsoriasisplaque(bothatsamemagnifica.on).

CD3+T-cellsinPsoriasisUninvolvedSkin PsoriasisPlaque

Immunocompetentcellsinpsoriasis.Insituimmunophenotypingbymonoclonalan<bodies.BosJDetal.ArchDermatolRes.1983;275(3):181-9.Predominanceof"memory"Tcells(CD4+,CDw29+)over"naive"Tcells(CD4+,CD45R+)inbothnormalanddiseasedhumanskin.BosJDetalArchDermatolRes.1989;281(1):24-30.

NON-LESIONALLESIONAL

S100A7

Psoriasin(S100A7)isaproteinfirstisolatedfromscalesofpsoria.clesions.

NON-LESIONALLESIONAL

HBD-2

LCN-2

HBD2(β-defensin)andlipocalin2(LCN2)arean.-microbialproteins

NON-LESIONAL PSORIASIS PLAQUE

H&E

CD11c

Myeloid(CD11c+)Dendri.cCellsinPsoriasis

CD3 cell counts

NL LS

0

50

100

150

200

250

300

350

CD11c cell counts

NL LS

0

100

200

300

400

500

600

Langerin cell counts

NL LS

0

25

50

75

100

125

8-foldaverageincrease 7-foldaverageincrease

p<0.0001 p<0.0001nosignificantchange

Conceptofaninflammatorydendri.ccell.CD11c+DCsinpsoriasislesionshaddifferentmarkersanddifferentfunc.onsfromnormalskin

Theevolvingpsoriasistranscriptome—diseaseroadmapsbasedonstudyofskinbiopsies

2001n=24

2003n=24

2008n=26

2010n=90

159genes

800genes

2800genes

4175genes

Oestreicheretal Zhouetal Yaoetal Suarez-Farinasetal

FundamentalHypothesis:Psoriasisvulgarisisanimmune-mediateddiseasecausedbyT-lymphocytes(T-cells)andassociatedcytokines.

PolarT-cellsubsets

IL-12 (TSLP, IL-33) IL-23

IFN-γ IL-4, IL-13 IL-17

Th1Tc1

Th2 Th17Tc17

(IL-23)

IL-22

Th22Tc22

AutoimmunityiscausedbyinappropriateactivationofoneormorepolarT-cellsubsets

PolarT-cellsubsets

IL-12 (TSLP, IL-33) IL-23

IFN-γ IL-4, IL-13 IL-17

Th1Tc1

Th2 Th17Tc17

(IL-23)

IL-22

Th22Tc22

AnearlyhypothesisproposedTh1T-cellscausedpsoriasis

Type1Devia<oninPsoriasis

Type1(γ-Interferon)

Type2(Interleukin-4)

Psoriasis

˜2-3foldexpansionofType1T-cellsJ.Invest.Dermatology113:752-759(1999)

Symbol Description FCH FDRCXCL10 chemokine (C-X-C motif) ligand 10 8285.866 0CXCL9 chemokine (C-X-C motif) ligand 9 7501.063 0CXCL11 chemokine (C-X-C motif) ligand 11 7427.648 0UBD ubiquitin D 5627.575 0CXCL11 chemokine (C-X-C motif) ligand 11 5515.316 0ICAM1 intercellular adhesion molecule 1 (CD54), human rhinovirus receptor1523.346 0C1S complement component 1, s subcomponent 1501.382 0HLA-DRA major histocompatibility complex, class II, DR alpha 1454.124 0HLA-DRB1 major histocompatibility complex, class II, DR beta 1 1237.32 0HLA-DPA1 major histocompatibility complex, class II, DP alpha 1 1191.56 0HLA-DRA major histocompatibility complex, class II, DR alpha 1079.847 0C1R complement component 1, r subcomponent 974.816 0HLA-DRB5 major histocompatibility complex, class II, DR beta 5 948.089 0RARRES3 retinoic acid receptor responder (tazarotene induced) 3 935.545 0CCL2 chemokine (C-C motif) ligand 2 895.502 0RSAD2 radical S-adenosyl methionine domain containing 2 807.346 0CTSS cathepsin S 800.808 0ISG20 interferon stimulated exonuclease gene 20kDa 716.4 0HLA-DMA major histocompatibility complex, class II, DM alpha 663.205 0PSMB9 proteasome (prosome, macropain) subunit, beta type, 9 (large multifunctional peptidase 2)645.756 0APOL3 apolipoprotein L, 3 616.127 0GBP2 guanylate binding protein 2, interferon-inducible 607.721 0CD74 CD74 molecule, major histocompatibility complex, class II invariant chain604.205 0HLA-DRB1 major histocompatibility complex, class II, DR beta 1 568.493 0ICAM1 intercellular adhesion molecule 1 (CD54), human rhinovirus receptor449.759 0ISG20 interferon stimulated exonuclease gene 20kDa 441.654 0BST2 bone marrow stromal cell antigen 2 415.635 0IRF1 interferon regulatory factor 1 380.93 0CTSS cathepsin S 379.723 0SERPING1 serpin peptidase inhibitor, clade G (C1 inhibitor), member 1, (angioedema, hereditary)375.298 0AIM2 absent in melanoma 2 372.634 0INDO indoleamine-pyrrole 2,3 dioxygenase 357.325 0APOL1 apolipoprotein L, 1 337.112 0HLA-DPA1 major histocompatibility complex, class II, DP alpha 1 334.534 0GLDC glycine dehydrogenase (decarboxylating) 256.429 0IL32 interleukin 32 256.145 0RARRES1 retinoic acid receptor responder (tazarotene induced) 1 236.388 0SECTM1 secreted and transmembrane 1 228.298 0ETV7 ets variant gene 7 (TEL2 oncogene) 196.912 0APOL6 apolipoprotein L, 6 187.719 0IL15 interleukin 15 179.367 0GBP1 guanylate binding protein 1, interferon-inducible, 67kDa 172.54 0IFI35 interferon-induced protein 35 160.635 0HLA-DRB4 major histocompatibility complex, class II, DR beta 4 160.437 0IFIT3 interferon-induced protein with tetratricopeptide repeats 3 146.128 0XAF1 XIAP associated factor-1 139.351 0CCL8 chemokine (C-C motif) ligand 8 133.609 0CFB complement factor B 132.853 0CEACAM1 carcinoembryonic antigen-related cell adhesion molecule 1 (biliary glycoprotein)128.47 0CFH complement factor H 125.194 0HCP5 HLA complex P5 117.354 0

Top50genes:IFNγ treatedKCs

Cytokine-drivenpathogenesis

ϒ-IFN

CXCL9CXCL10CXCL11IL-8ICAM-1MHC-IIImmuneamplifica.on

humankera.nocytes

(invitro)

Cytokine-drivenpathogenesis

ϒ-IFN

CXCL9CXCL10CXCL11IL-8ICAM-1MHC-IIImmuneamplifica.on

humankera.nocytes

(invitro)

PolarT-cellsubsets

IL-12 (TSLP, IL-33) IL-23

IFN-γ IL-4, IL-13 IL-17

Th1Tc1

Th2 Th17Tc17

(IL-23)

IL-22

Th22Tc22

In2005theTh17T-cellwasidentifiedasassociatedwithCNSautoimmunity

ExperimentsinmiceclearlyshowthatIL-23drivesac.va.on&expansionofTh17T-cells,

notTh1T-cells.γ-interferon

(Th1)IL-17(Th17)

p40

1.0

10.0

100.0

1,000.0

10,000.0

Rela

tive G

en

e E

xp

ress

ion

p19

1.0

10.0

100.0

1,000.0

10,000.0

Rela

tive G

en

e E

xp

ress

ion

Consistentup-regula.onofp40andp19mRNAs(IL-23subunits)inpsoriasisplaques,asdetectedbyreal-.meRT-PCR(normalizedtoHARP)

uninvolved uninvolvedlesion lesion

p<0.000001

LeeetalJEM(2005)Dendri.cCellsestablishedasmajorproducersofIL-23inpsoriasislesions

Gene.cBiomarkersofIncreasedRisk

O’ReilleyNatRevRheum(2011)

Th1

Th17

Blood

PsoriasisLesion

Th17T-cellsincreasedinpsoriasislesions

Loweset.al.J.Invest.Dermatol(2008)

Geneexpressionduringcyclosporinetreatment

T-cellproducedcytokinesactonkera.nocytestoinducespecificgeneproducts

IL-17AIL-17F

S100A7(psoriasin)CXCL1,2,3,8CCL20β-defensinandotheran.-microbialpep.des

humankera.nocytes

(invitro)

IL-23/Th17 pathway in psoriasis

neutT17DC

KC

Tcell DC

IL-23 IL-17

CCL20

CCR6+cells

CXCchemokinesCXCL1,2,3,5IL-8

An.-microbialpep.desβ-defensinsLipocalinLL-37S100A7,S100A8

Th17Tc17Tgamma-delta17ILC17

Butdoesnotexplainepidermalhyperplasia

PolarT-cellsubsets

IL-12 (TSLP, IL-33) IL-23

IFN-γ IL-4, IL-13 IL-17

Th1Tc1

Th2 Th17Tc17

(IL-23)

IL-22

Th22Tc22

TheTh22T-cellsubsetisalsoactivatedinpsoriasisandIL-22isakeratinocytemitogen

IL-22promotesacanthosisandimpairsterminaldifferen.a.on

NogralesKEetal,Bri<shJournalofDermatology,2008

Fullthicknessskinrars(epidermis+fibroblasts/dermis)

§ ConfirmseffectofIL-22onacanthosisofepidermis(SaetalJImmunology2007)§ *Parakeratosis

*

Three immune axes are activated in psoriasis

An.microbialpep.desIL-1βIL-6TNF-αS100CXCL8CXCL9CXCL10CXCL11CCL20

Th/Tc1

Th/Tc17

Th/Tc22

IL-23(p40/p19)

IL-12(p40/p35) TNF-α

IFN-γ

IL-17A/FIL-21

IL-22

kera.nocyte

kera.nocyte

NKTcell

plasmacytoidDendri.ccell

macrophage

ac<va<on

IL-1βIL-6

TNF-αTNF-αIFN-γ

TIP-DCIFN-α

TNF-α

LESIONFORMATION

Figureadaptedfrom:NestleFO,etal.NEnglJMed.2009;361:496-509

HoweverIL-23/Type-17axisdrivesthediseasephenotype

IL-17SignalingLigand/ReceptorCombina3ons

Gaffen.NatRevImmunol2009;9(8):556-67.

IL-17A IL-17A/F IL-17F

IL-17C

IL-17D

IL-17E/IL-25 IL-17B ??

??

FN1 FN2

SEFIR

TILL

CBAD IL-17RA IL-17RC

IL-17RA IL-17RB/ IL-25R

IL-17RA IL-17RD/

SEF

IL-17RB/ IL-25R

IL-17RE

IL-17RD/ SEF

X X X X

IxekizumabSecukinumab

Brodalumab

Anti-IL-17 Receptor Antibody AMG 827 Leads to Rapid Clinical Response in Subjects with Moderate to Severe Psoriasis: Results from a Phase I, Randomized, Placebo-Controlled Trial Kim A Papp, Cathy Reid, Peter Foley, Rod Sinclair, David H Salinger, Gary Williams, Hua Dong, James G Krueger, Chris B Russell and David A Martin JournalofInves3ga3veDermatology(2012)132,2466–2469;doi:10.1038/jid.2012.163;publishedonline24May2012

DatafirstpresentedatSocietyforInves.ga.veDermatologyin2010

Double-blind, placebo controlled study with a single dose of AMG827

Placebo(n=4)350mgSC(n=8)700mgIV(n=8)

Keyinclusioncriteria:ModeratetosevereplaquePsO≥6mos,PASIscore≥10, BSA≥10,eligibletoreceive phototherapyorsystemictherapy

Keyexclusioncriteria:Anyprioruseofbiologics;recentuseofsystemicsteroidsorcalcineurininhibitors

RussellCB,RandH,BiglerJ,KerkofK,TimourM,Bau.staE,KruegerJG,SalingerDH,WelcherAA,Mar.nDA.JImmunol.2014Apr15;192(8):3828-36.

IL-23/Th17 pathway in psoriasis

neutT17DC

KC

Tcell DC

IL-23 IL-17

CCL20

CCR6+cells

CXCchemokinesCXCL1,2,3,5IL-8

An.-microbialpep.desβ-defensinsLipocalinLL-37S100A7,S100A8

Th17Tc17Tgamma-delta17ILC17

RoleofIL-17Aprobedwithixekizumab

Expression of IL-17 Target Genes (RT-PCR)

log2(expression/hARP)=mRNAexpression(RT-PCR)normalizedtothehousekeepinggenehumanacidicribosomalproteingene(hARP)

Lipocalin2 Interleukin8

β-defensin2 CXCL1

Genes Modulated by ixekizumab (FCH>6)– very rapid effects and much faster response than etanercept

LS=LesionalSkinBiopsiesatBaseline

NL=Non-LesionalSkinBiopsiesatBaseline

Proportion of Patients with PASI 75

0

20

40

60

80

100

0 2 4 6 8 10 12 14 16 18 20

Placebo SC (n=8) LY 150 mg SC (n=8)

Dose Dose Dose Weeks

Prop

or.o

nofPa.

ents

HighEfficacyofIL-17antagonistsinPhase3Studies

•  Secukinumab(an.-IL-17A)superiortoustekinumabinCLEARstudy,87%PASI75inJUNCTUREstudy2

•  Ixekizumab(an.-IL-17A)superiortoetanerceptinUNCOVERstudy,90%PASI75inbestperformingdosinggroup1

•  Brodalumab(an.-IL-17Receptor,Asubunit)superiortoustekinumabinAMAGINE-3study,386%PASI75inAMAGINE-2Study,bestperformingdosegroup4

1.‘Lilly'sIxekizumabSuperiortoEtanerceptandPlaceboinPhase3PsoriasisStudies’pressreleaseavailableat:h{ps://investor.lilly.com/releasedetail.cfm?releaseid=867193.Dateaccessed:May2015.2.PaulCetal.JEurAcadDermatolVenereol.2014[Epubaheadofprint].3.’AmgenandAstraZenecaannounceposi.veresultsfromsecondpivotalPhaseIIIstudyofBrodalumabinpa.entswithmoderate-to-severeplaquepsoriasis’pressrelease.Availableat:h{p://www.astrazeneca.com/Media/Press-releases/Ar.cle/11112014--amgen-and-astrazeneca-announce-posi.ve-results.‘AmgenandAstraZenecaannounceposi.veresultsfromthirdandfinalpivotalPhaseIIIstudyofBrodalumabinpa.entswithmoderate-to-severeplaquepsoriasis’pressrelease.Availableat:h{p://www.astrazeneca.com/Media/Press-releases/Ar.cle/20141125-amgen-and-astrazeneca-posi.ve-results-brodalumab.Dateaccessed:May2015.

AmgenhasterminatedbrodalumabpartnershipwithAstraZeneca.Brodalumabandixekizumabarenotcurrentlylicensedfortherapeu.cuse

Does IL-23 drive the Th17 pathway?

An.microbialpep.desIL-1βIL-6TNF-αS100CXCL8CXCL9CXCL10CXCL11CCL20

Th1

Th17

Th/Tc22

IL-23(p40/p19)

IL-12(p40/p35) TNF-α

IFN-γ

IL-17A/FIL-21

IL-22

kera.nocyte

kera.nocyte

NKTcell

plasmacytoidDendri.ccell

macrophage

ac<va<on

IL-1βIL-6

TNF-αTNF-αIFN-γ

TIP-DCIFN-α

TNF-α

LESIONFORMATION

Figureadaptedfrom:NestleFO,etal.NEnglJMed.2009;361:496-509

STAT1STAT3CEBP/NFkB

Adalimumab

Guselkumab

Blauvetetal.J.Am.Acad.Dermatol.76:405(2017)Voyage1Study

DiseaseProfileNeutralizedbyCNTO1959(Guselkumab)•  Diseaseprofile(lesionalvs.non-lesionalskin)–1224transcripts•  Highdose*broughttheexpressionlevelbacktonormalatWeek12

*Highdose=combined100&300mgtreatmentgroups

TreatmentvisitPASI50skinCNTO1959HighDay2yesNLCNTO1959HighDay2yesLSCNTO1959HighDay7yesLSCNTO1959HighDay84yesLS

-2.00 2.00

BaselineNon-Lesional

Week12Lesional

Week1Lesional

BaselineLesional

Sorenetal.J.AllergyClin.Immunol.133:1032(2014)

ustekinumab

risankizumab

Pappetal.NEJM376:1551(2017)

Kruegeretal.,J.AllergyClin.Immunol.136:116(2015).

HawkesJE,ChanTC,KruegerJG.JACI(2017).

TakeHomeMessage•  PsoriasisisdrivenbyapolarT-cell(Th17/Tc17)axis,regulatedbyIL-23

•  Kera.nocytesamplifytheresponse•  Alltherapiesthatimprovepsoriasisdirectlyorindirectlylowerexpressionorsignalingofthisimmune-responseaxis