USTEKINUMAB and BRIAKINUMAB - PACIFIC DERMATOLOGIC ASSOCIATION

USTEKINUMABUSTEKINUMAB

andand

BRIAKINUMABBRIAKINUMABAndrew Blauvelt, M.D.Andrew Blauvelt, M.D.

Professor, Dept. of Dermatology andProfessor, Dept. of Dermatology and

Dept. of Molecular Microbiology & ImmunologyDept. of Molecular Microbiology & Immunology

Oregon Health & Science UniversityOregon Health & Science University

Chief, DermatologyChief, Dermatology ServiceService

VeteranVeteran’’s Affairs Medical Centers Affairs Medical CenterPortland, OregonPortland, Oregon

CONFLICTS OF INTERESTCONFLICTS OF INTEREST

•• Centocor: scientific advisor,Centocor: scientific advisor,

principal investigator for principal investigator for clinicalclinical

studies, received lab research fundsstudies, received lab research funds

•• Abbott: scientific advisor, Abbott: scientific advisor, principalprincipal

investigator for investigator for clinical studiesclinical studies

•• Lilly: Lilly: principalprincipal investigator forinvestigator for

clinical studiesclinical studies

PROMINENT T CELL INFILTRATIONPROMINENT T CELL INFILTRATION

ADJACENT TO HYPERPROLIFERATIVEADJACENT TO HYPERPROLIFERATIVE

KERATINOCYTES IN PSORIASISKERATINOCYTES IN PSORIASIS

REF: Jim Krueger, Rockefeller Univ. REF: Jim Krueger, Rockefeller Univ.

Triggers in geneticallyTriggers in genetically

predisposed personspredisposed persons

-- Trauma Trauma

-- Candida albicansCandida albicans

-- StreptococcusStreptococcus

NaNaïïveveTC

Th17Th17

DC ACTIVATION DC ACTIVATION ⇒⇒ TC TC ACTIVATIONACTIVATION ⇒⇒ KC ACTIVATION KC ACTIVATION

IL-17AIL-17A

IL-17FIL-17F

IL-22IL-22TNF-TNF-αα

NaNaïïveve

TCTC

KCKC

⇑⇑Antimicrobial pep-Antimicrobial pep-

tides (LL-37, HBD-2)tides (LL-37, HBD-2)

⇑⇑ProinflammatoryProinflammatory

cytokines (TNF- cytokines (TNF-αα))

MatureMature

DC DC

MatureMature

DC DC

IL-1IL-1ββ+ IL-6/IL-23+ IL-6/IL-23

Th1Th1

IL-23IL-23

IL-12IL-12

IL-12IL-12

IFN-IFN-γγTNF-TNF-αα

KCKC





⇑⇑CCL20CCL20 (CCR6 ligand)(CCR6 ligand)

⇑⇑ProliferationProliferationCCR6+CCR6+RORRORγγtt

Positive feedback loopsPositive feedback loops

Activation/proliferation of TCActivation/proliferation of TCActivation ofActivation of TNF-TNF-αα+ d+ dermal DCermal DC

((““inflammainflammatory DCtory DC””))Recruitment of CCR6+ Th17 cells via CCL20Recruitment of CCR6+ Th17 cells via CCL20Recruitment of CCR6+ blood DC via CCL20Recruitment of CCR6+ blood DC via CCL20

ImmatureImmature

DC DC

T-betT-bet



-- Trauma Trauma



NaNaïïveveTC

Th17Th17

DC ACTIVATION DC ACTIVATION ⇒⇒ TC TC ACTIVATIONACTIVATION ⇒⇒ KC ACTIVATION KC ACTIVATION

IL-17AIL-17A

IL-17FIL-17F


NaNaïïveve

TCTC

KCKC





MatureMature

DC DC

MatureMature

DC DC


Th1Th1

IL-23IL-23

IL-12IL-12

IL-12IL-12


KCKC






⇑⇑ProliferationProliferationCCR6+CCR6+RORRORγγtt

Positive feedback loopsPositive feedback loops

Activation/proliferation of TCActivation/proliferation of TCActivation ofActivation of TNF-TNF-αα+ d+ dermal DCermal DC


ImmatureImmature

DC DC

T-betT-bet

IL-23 AND IL-12 SHARE THE p40 SUBUNIT, YETIL-23 AND IL-12 SHARE THE p40 SUBUNIT, YET

EACH HAVE THEIR OWN UNIQUE SUBUNITEACH HAVE THEIR OWN UNIQUE SUBUNIT

REF: NairREF: Nair et al, Nat Genet, 2009et al, Nat Genet, 2009

POLYMORPHISMS IN POLYMORPHISMS IN p19p19, , p40p40, AND , AND IL-23RIL-23R LINKED TO LINKED TO

PROTECTION OF AND SUSCEPTIBILITY TO PSORIASISPROTECTION OF AND SUSCEPTIBILITY TO PSORIASIS

pp1919

p40p40

p35p35

INCREASED IL-23,INCREASED IL-23,

BUT NOT IL-12,BUT NOT IL-12,

mRNAmRNA

PRODUCTION PRODUCTION ININ

LESIONALLESIONAL

PSORIASISPSORIASIS

REF: Lee et al, J Exp Med, 2004REF: Lee et al, J Exp Med, 2004

IL-23IL-23

IL-12IL-12

NL LNL L

IL-23 POSITIVE DENDRITICIL-23 POSITIVE DENDRITIC

CELLS IN PSORIASISCELLS IN PSORIASIS

IL-23 IS CRITICAL FOR THE SURVIVALIL-23 IS CRITICAL FOR THE SURVIVAL

AND PROLIFERATION OF Th17 CELLSAND PROLIFERATION OF Th17 CELLS

Th17 CELLS ARE DISTINCTTh17 CELLS ARE DISTINCT

FROM Th1 AND Th2 CELLSFROM Th1 AND Th2 CELLS

REF: Blauvelt, Expert Rev Dermatol, 2007REF: Blauvelt, Expert Rev Dermatol, 2007

IL-17A+ LEUKOCYTES IN PSORIASISIL-17A+ LEUKOCYTES IN PSORIASIS

REF: Harper et al, J Invest Dermatol, 2009REF: Harper et al, J Invest Dermatol, 2009

⇑⇑CIRCULATING IL-17A+ ANDCIRCULATING IL-17A+ AND

IFN-IFN-γγ+ + CD4+ CELLS IN PSORIASISCD4+ CELLS IN PSORIASIS

Kagami et al, submittedKagami et al, submitted

T CELLS AND PSORIASIST CELLS AND PSORIASIS

(older data)(older data)

•• Many of the CD4+ and CD8+ T cells areMany of the CD4+ and CD8+ T cells are

type 1 T cells: Ttype 1 T cells: Th1 and Tc1 cellsh1 and Tc1 cells (i.e, they (i.e, theysecrete IFN-secrete IFN-γγ))

•• Thus, psoriasis is a Thus, psoriasis is a ““Th1 diseaseTh1 disease””

T CELLS AND PSORIASIST CELLS AND PSORIASIS

(newer data)(newer data)

•• Many of the CD4+ T cells are Th17 cells Many of the CD4+ T cells are Th17 cells (i.e, they(i.e, theysecrete IL-17Asecrete IL-17A) plus new genetics/mouse data) plus new genetics/mouse data

•• Thus, Thus, psoriasis is a psoriasis is a ““Th17 diseaseTh17 disease””

•• Or, more conservatively: psoriasis is a Or, more conservatively: psoriasis is a ““mixedmixedTh1/Th17 diseaseTh1/Th17 disease””

•• If If ““mixed,mixed,”” what is primary and what is what is primary and what issecondary?secondary?

•• Data in mice suggest that IL-12/Th1 cells and IL-Data in mice suggest that IL-12/Th1 cells and IL-23/Th17 cells counter-regulate one another23/Th17 cells counter-regulate one another

THERAPUETICTHERAPUETIC

IMPLICATIONS:IMPLICATIONS:

DRUGS THAT BLOCK DRUGS THAT BLOCK IL-23IL-23

(e.g., (e.g., ustekinumabustekinumab and and

briakunumabbriakunumab))

USTEKINUMAB AND BRIAKINUMABUSTEKINUMAB AND BRIAKINUMAB(ABT-874) TARGET p40, THE(ABT-874) TARGET p40, THE SUBUNITSUBUNIT

SHARED BY IL-23 AND IL-12SHARED BY IL-23 AND IL-12

ANTI-IL-23/12 MONOCLONAL Abs UNDER EVALUATIONANTI-IL-23/12 MONOCLONAL Abs UNDER EVALUATION

FOR PSORIASIS AND OTHER DISEASESFOR PSORIASIS AND OTHER DISEASES

PsoriasisPsoriasis

(ph II)(ph II)88

Psoriasis (3 ph III)Psoriasis (3 ph III)2-42-4

PsorPsor. arthritis (ph II). arthritis (ph II)55

CrohnCrohn’’s disease (ph II)s disease (ph II)66

Multiple sclerosis (ph II)Multiple sclerosis (ph II)77

PublishedPublished

clinical dataclinical data

UnpublishedUnpublished20 days20 days11Half-lifeHalf-life

Phage displayPhage displayTransgenicTransgenicTypeType

Fully humanFully human

monoclonal IgG1 monoclonal IgG1 AbAbFully humanFully human

monoclonal IgG1 monoclonal IgG1 AbAbStructureStructure

BriakinumabBriakinumabUstekinumabUstekinumab (approved (approved

in Canada and Europe)in Canada and Europe)

1.1. Gottlieb AB, et al. Gottlieb AB, et al. CurrCurr Med Med Res OpinRes Opin 2007;23:10812007;23:1081; ; 2.2. Leonardi CL, et al. Leonardi CL, et al. LancetLancet 2008;371: 2008;371:

16651665; ; 3.3. Papp KA, et al. Papp KA, et al. LancetLancet 2008;371:1675; 2008;371:1675; 4.4. Griffiths C, et al. EADV 2008; Griffiths C, et al. EADV 2008; 5.5. Gottlieb Gottlieb

AB, et al. ACR 2007; AB, et al. ACR 2007; 6.6. Peyrin-Biroulet L, et al. Peyrin-Biroulet L, et al. LancetLancet 2008;372:67; 2008;372:67; 7.7. Se Segal BM, et al.gal BM, et al.

Lancet Lancet NeurolNeurol 2008; 7:796; 2008; 7:796; 8.8. Kimball AB, et al. Kimball AB, et al. Arch DermatolArch Dermatol 2008;144:200 2008;144:200

REFS: Leonardi et al, Lancet, 2008; Papp et al, Lancet, 2008REFS: Leonardi et al, Lancet, 2008; Papp et al, Lancet, 2008

Group 3

3a

3b

Group 1

Group 2 R

UstekinumabUstekinumab 45 mg 45 mg



Week-4 0 28 40

PlaceboPlacebo


164 12

Weeks 12–40Weeks 0–124 weeks

Placebo crossover and active treatmentPlacebo-

controlledScreen

PHOENIX 1 & 2: STUDY DESIGNPHOENIX 1 & 2: STUDY DESIGN

USTEKINUMAB PASI 75 RESPONSES ATUSTEKINUMAB PASI 75 RESPONSES AT

WEEK 12 (AFTER DOSES AT WEEKS 0, 4)WEEK 12 (AFTER DOSES AT WEEKS 0, 4)


Pati

en

ts (

%)

Pati

en

ts (

%)

3

67 66

0

20

40

60

80

100

Placebo 45 mg 90 mg

p < 0.001 vs placebo for each dose comparisonp < 0.001 vs placebo for each dose comparison

N = 255 N = 255 N = 256

4

6776

0

20

40

60

80

100

Placebo 45 mg 90 mgN = 410 N = 409 N = 411

PHOENIX 1 PHOENIX 2PHOENIX 1 PHOENIX 2

SIGNIFICANT EFFICACY AFTER TWO INJECTIONSSIGNIFICANT EFFICACY AFTER TWO INJECTIONS

Images courtesy of the PHOENIX 2 InvestigatorsImages courtesy of the PHOENIX 2 Investigators

Week 12Week 0

PASI = 23.7 PGA = 3 PASI = 1 PGA = 1

USTEKINUMAB PASI 75 RESPONSES ATUSTEKINUMAB PASI 75 RESPONSES AT

WEEK 28 (AFTER DOSES AT WEEKS 0, 4, 16)WEEK 28 (AFTER DOSES AT WEEKS 0, 4, 16)


PHOENIX 1 PHOENIX 2PHOENIX 1 PHOENIX 2

Patients

(%

)

100

20

40

60

80

Ustekinumab

45 mg

100

20

40

60

8071

79

0Ustekinumab

90 mg

Ustekinumab

45 mg

70

79

Ustekinumab

90 mg

0

USTEKINUMAB PASI 75USTEKINUMAB PASI 75

RESPONSES THROUGH WEEK 40RESPONSES THROUGH WEEK 40

REF: Leonardi et al, Lancet, 2008REF: Leonardi et al, Lancet, 2008

0

20

40

60

80

100

0 4 8 12 16 20 24 28 32 36 40

Pati

en

ts (

%)

Pati

en

ts (

%)

WeekWeek

Placebo

Placebo / Ustekinumab 45 mg

Placebo / Ustekinumab 90 mg

Ustekinumab 45 mg

Ustekinumab 90 mg

Median percentage improvement from baseline in PASI scoreMedian percentage improvement from baseline in PASI score

*All patients randomised to maintenance therapy or treatment interruption at week 40.*All patients randomised to maintenance therapy or treatment interruption at week 40.

Media

n p

erc

enta

ge

Media

n p

erc

enta

ge

100

20

40

60

80

400

Placebo

Ustekinumab 45 mg every 12 weeks

44 48 52 56 60 64 68 72 76

100

20

40

60

80

400

Placebo

Ustekinumab 90 mg every 12 weeks

44 48 52 56 60 64 68 72 76

MAINTENANCE TREATMENT WITH USTEKINUMABIS EFFECTIVE WITH EVERY 12 WEEKS DOSING

REF: Leonardi et al, Lancet, 2008REF: Leonardi et al, Lancet, 2008

TYPICAL CLINICAL RESPONSE TO USTEKINUMABTYPICAL CLINICAL RESPONSE TO USTEKINUMAB

PASI = 23.7 PGA = 3

Week 0Week 12

(2 injections)

Week 52

(6 injections)

PASI = 1 PGA = 1 PASI = 1.6 PGA = 1

Images courtesy of the PHOENIX 2 InvestigatorsImages courtesy of the PHOENIX 2 Investigators

DRUG AND CONDITIONS PASI 75 (%)

Ustekinumab (phase II): week 12, low dose 52

Ustekinumab (phase II): week 12, low-medium dose 59

Ustekinumab (phase II): week 12, medium-high dose 67

Ustekinumab (phase II): week 12, high dose 81

Ustekinumab (phase III): week 12, 45 mg 67

Ustekinumab (phase III): week 12, 90 mg 66-76

Ustekinumab (phase III): weeks 20-24, 45 mg 75-76


Briakinumab (phase II): week 12, low dose 60

Briakinumab (phase II): week 12, low-medium dose 90

Briakinumab (phase II): week 12, medium dose 87

Briakinumab (phase II): week 12, medium-high dose 90

Briakinumab (phase II): week 12, high dose 87

SUMMARY OF PASI 75 RESULTS FORSUMMARY OF PASI 75 RESULTS FOR

USTEKINUMAB AND BRIAKINUMABUSTEKINUMAB AND BRIAKINUMAB

200 mg x 1 dose (n=30)

100 mg eow (n=30)

200 mg/wk x 4 doses (n=30)

200 mg/wk (n=30)

Placebo (n=30)

Retreatment with original dosage except for placebo patients.

Placebo patients treated with 200 mg eow.

Retreatment for 12 wks

Loss of PASI 50 Response

YES

NO Discontinue from study

Week 0 Week 12 Week 48

ABT-874 vs Placebo

Washout

4 Weeks

YE

S

PA

SI >

75

200 mg eow (n=30)

BRIAKINUMAB PHASE IIBRIAKINUMAB PHASE II

STUDY DESIGNSTUDY DESIGN

REF: Kimball et al, Arch Dermatol, 2008REF: Kimball et al, Arch Dermatol, 2008

3%

63%

93%90%

93%90%

0%

20%

40%

60%

80%

100%

*

**

**

ITT-NRI

*p<0.001 vs placebo

PBO 200 mg1 dose

100 mgeow

200 mg4 doses

200 mgeow

200 mgweekly

Pati

en

ts (

%)

BRIAKINUMAB PASI 75BRIAKINUMAB PASI 75

RESPONSES AT WEEK 12RESPONSES AT WEEK 12

REF: Kimball et al, Arch Dermatol, 2008REF: Kimball et al, Arch Dermatol, 2008

DRUG AND CONDITIONS PASI 75 (%)

Ustekinumab (phase II): week 12, low dose 52

Ustekinumab (phase II): week 12, low-medium dose 59

Ustekinumab (phase II): week 12, medium-high dose 67

Ustekinumab (phase II): week 12, high dose 81

Ustekinumab (phase III): week 12, 45 mg 67

Ustekinumab (phase III): week 12, 90 mg 66-76



Briakinumab (phase II): week 12, low dose 60

Briakinumab (phase II): week 12, low-medium dose 90

Briakinumab (phase II): week 12, medium dose 87

Briakinumab (phase II): week 12, medium-high dose 90

Briakinumab (phase II): week 12, high dose 87

SUMMARY OF PASI 75 RESULTS FORSUMMARY OF PASI 75 RESULTS FOR

USTEKINUMAB AND BRIAKINUMABUSTEKINUMAB AND BRIAKINUMAB

PHOENIX 1 & 2: SUMMARY OFPHOENIX 1 & 2: SUMMARY OF

USTEKINUMAB SAFETY/TOLERABILITYUSTEKINUMAB SAFETY/TOLERABILITY

•• Safety profiles seen in Phoenix 1 were consistent withSafety profiles seen in Phoenix 1 were consistent withthose seen in Phoenix 2, and together they support athose seen in Phoenix 2, and together they support afavorable favorable safety profile through 1 year of treatmentsafety profile through 1 year of treatment

–– Well-tolerated when administered up to 52 weeksWell-tolerated when administered up to 52 weeks

–– AEsAEs, serious , serious AEsAEs, and infection rates at 52 weeks, and infection rates at 52 weekscomparable to those seen at Week 12comparable to those seen at Week 12

–– Most commonly reported Most commonly reported AEs AEs ((!! 5% of 5% of ustekinumab ustekinumab--treated patients): treated patients): nasopharyngitisnasopharyngitis, upper respiratory, upper respiratorytract infection, headachetract infection, headache

–– No cases of active tuberculosisNo cases of active tuberculosis

–– No anaphylactic or serum sickness-like reactionsNo anaphylactic or serum sickness-like reactions

–– Mild injection-site reactionsMild injection-site reactions


WHAT IS THE NORMALWHAT IS THE NORMAL

FUNCTION OF Th17 CELLS?FUNCTION OF Th17 CELLS?

•• Mouse studies suggest that Th17 cells areMouse studies suggest that Th17 cells areimportant in fighting extracellular bacterialimportant in fighting extracellular bacterialinfections, especially at mucosal surfacesinfections, especially at mucosal surfaces

•• Th17 cytokines induce anti-microbial peptideTh17 cytokines induce anti-microbial peptideproduction and epithelial thickening at mucosalproduction and epithelial thickening at mucosalsurfacessurfaces

•• IndividualsIndividuals deficient in Th17 cells aredeficient in Th17 cells aresusceptible to susceptible to C. albicansC. albicans and and S. aureusS. aureus

infections (i.e., those with infections (i.e., those with JobJob’’s/hyper-IgEs/hyper-IgEsyndromesyndrome and and chronic mucocutaneouschronic mucocutaneouscandidiasiscandidiasis))

USTEKINUMAB BRIAKINUMAB:USTEKINUMAB BRIAKINUMAB: MAJORMAJOR

ADVANCES IN PSORIASIS THERAPYADVANCES IN PSORIASIS THERAPY

•• EfficacyEfficacy: 67-90% clear or near clear in: 67-90% clear or near clear in

both short-term and long-term studiesboth short-term and long-term studies

•• SafetySafety: minimal issues with over 3.5: minimal issues with over 3.5

years of use in over 3,000 patientsyears of use in over 3,000 patients

•• ConvenienceConvenience: given as SC shot once: given as SC shot once

every 1-3 monthsevery 1-3 months

•• CostCost: approximately $18,000 per year in: approximately $18,000 per year in

CanadaCanada

STATUS OF DRUGS THAT BLOCK THESTATUS OF DRUGS THAT BLOCK THE

IL-23/Th17 INFLAMMATORY PATHWAYIL-23/Th17 INFLAMMATORY PATHWAY

•• Ustekinumab (StelaraUstekinumab (Stelara®®)): long-term (>3.5: long-term (>3.5years) phase III studies on-going;years) phase III studies on-going;approved in Canada and Europe;approved in Canada and Europe;expected toexpected to be FDA-approved soonbe FDA-approved soon

•• BriakinumabBriakinumab: phase III studies began: phase III studies beganlate 2007late 2007

•• Anti-p19 mAbsAnti-p19 mAbs that target only IL-23 and that target only IL-23 andnot IL-12: phase I studies underwaynot IL-12: phase I studies underway

•• Anti-IL-17 mAbsAnti-IL-17 mAbs: phase II studies: phase II studiesunderwayunderway



-- Trauma Trauma



NaNaïïveveTC

Th17Th17

IL-17AIL-17A

IL-17FIL-17F


NaNaïïveve

TCTC

KCKC





MatureMature

DC DC

MatureMature

DC DC


Th1Th1

IL-23IL-23

IL-12IL-12

IL-12IL-12


KCKC






⇑⇑ProliferationProliferation

CCR6+CCR6+RORRORγγtt

Positive feedback loopsPositive feedback loopsActivation/proliferation of TCActivation/proliferation of TC

Activation ofActivation of TNF-TNF-αα+ d+ dermal DCermal DC


ImmatureImmature DC DC

T-betT-bet

USTEKINUMAB AND BRIAKINUMAB BLOCK p40, AND THUSUSTEKINUMAB AND BRIAKINUMAB BLOCK p40, AND THUS

BLOCK BOTH IL-23 (Th17 GROWTH FACTOR) AND IL-12BLOCK BOTH IL-23 (Th17 GROWTH FACTOR) AND IL-12

(Th1 GROWTH FACTOR)(Th1 GROWTH FACTOR)

XX

XX

THANKS!THANKS!

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USTEKINUMAB and BRIAKINUMAB - PACIFIC DERMATOLOGIC ASSOCIATION