1

IL-17a blockade and the

treatment of psoriasis

K. Alexander Papp MD, PhD, FRCPC

Probity Medical Research,

Canada (US, Australia, Chile)

2

Psoriasis

Perspective

3

Proposed Mechanism of Psoriasis Disease Initiation

and Maintenance

Nestle et al. N Engl J Med. 2009;361:496.

4

Key Cells and Mediators in Psoriasis

Keratinocyte

Myeloid

dendritic cell

Natural

killer T cell

Plasmacytoid

dendritic cell

Macrophage

IL-1

IL-6

TNF-

TNF-

TNF-

IFN-

IFN-

Innate Immunity

Adapted from Nestle et al. N Engl J Med. 2009;361:496.

5

Key Cells and Mediators in Psoriasis

Keratinocyte

Myeloid

dendritic cell

Natural

killer T cell

Plasmacytoid

dendritic cell

Macrophage

IL-1

IL-6

TNF-

TNF-

TNF-

IFN-

IFN-

Innate Immunity

Th1 cell

Th17 cell

IL-23

IL-17A/F

IL-22

Keratinocyte

IL-12

TNF-

IFN-

Adaptive Immunity

Activation

Adapted from Nestle et al. N Engl J Med. 2009;361:496.

6

Key Cells and Mediators in Psoriasis

Keratinocyte

Myeloid

dendritic cell

Natural

killer T cell

Plasmacytoid

dendritic cell

Macrophage

IL-1

IL-6

TNF-

TNF-

TNF-

IFN-

IFN-

Innate Immunity

Th1 cell

Th17 cell

IL-23

IL-17A/F

IL-22

Keratinocyte

IL-12

TNF-

IFN-

Adaptive Immunity

Activation

Antimicrobial peptides

IL-1

IL-6

TNF-

S100

CXCL8

CXCL9

CXCL10

CXCL11

CCL20

Innate Immunity

Adapted from Nestle et al. N Engl J Med. 2009;361:496.

7

Key Cells and Mediators in Psoriasis

Keratinocyte

Myeloid

dendritic cell

Natural

killer T cell

Plasmacytoid

dendritic cell

Macrophage

IL-1

IL-6

TNF-

TNF-

TNF-

IFN-

IFN-

Innate Immunity

Th1 cell

Th17 cell

IL-23

IL-17A/F

IL-22

Keratinocyte

IL-12

TNF-

IFN-

Adaptive Immunity

Activation

Antimicrobial peptides

IL-1

IL-6

TNF-

S100

CXCL8

CXCL9

CXCL10

CXCL11

CCL20

Innate Immunity

Adapted from Nestle et al. N Engl J Med. 2009;361:496.

8

Role of IL-17

9

Key Events in the History of IL-17 and TH171

1. Gaffen SL. Nat Rev Immunol. 2009;9:556-568

1986 1993 1995 2003 2005 2006 2007 2009

1986: Mosmann,

Coffman and

colleagues propose

the TH1- TH 2 cell

paradigm

CTLA8, later

renamed IL-17A, is

cloned

IL-17RA is cloned

IL-23 is shown to

stimulate CD4+ T cells

to produce IL-17

First demonstration that

TH17 cells are

pathogenic in

autoimmunity;

TH17 cells are shown to

arise as a separate

lineage from TH1 and

TH 2 cells

RORyt and STAT3 are shown

to drive TH17 cell

differentiation;

TGF-β and IL-6 are shown to

drive TH17 cell development;

TREG cells are shown to

arise in opposition to TH17

cells;

TH17 cells are shown to

produce IL-22

IL-17RC is found to

be the co-receptor

for IL-17A and IL-

17F;

TH17 cells are

shown to produce

IL-21

IL-17-specific antibodies

show efficacy in early

clinical trials for the

treatment of psoriasis

10

Genetic Experiments in

Nature

11

12

Chronic mucocutaneous candidiasis in humans with

inborn errors of interleukin-17 immunity

Puel A, et al Science 2011;

332(6025): 65-68

13

Chronic mucocutaneous candidiasis in humans with

inborn errors of interleukin-17 immunity

Puel A, et al Science 2011;

332(6025): 65-68

Recurrent or persistent infections

caused by Candida albicans and less

frequently Staphylococcus aureus

14

Chronic mucocutaneous candidiasis in humans with

inborn errors of interleukin-17 immunity

Puel A, et al Science 2011;

332(6025): 65-68 Recurrent or persistent infections

caused by Candida albicans and less

frequently Staphylococcus aureus

Autosomal recessive deficiency of

IL-17A

15

Chronic mucocutaneous candidiasis in humans with

inborn errors of interleukin-17 immunity

Puel A, et al Science 2011;

332(6025): 65-68 Recurrent or persistent infections

caused by Candida albicans and less

frequently Staphylococcus aureus

Autosomal recessive deficiency of

IL-17A

Autosomal dominant deficiencies of

IL-17F

16

TH Cell Differentiation Overview:IL-17 Is Produced by TH17 Cells Arising from CD4+ T Cell Progenitors1-9

Physiologic Targets

Defense against

intracellular pathogens

Defense against extracellular pathogens

Allergy and asthma

Defense against extracellular pathogens

Autoimmunity

Epithelial immunity and healing

Tolerance

Immune homeostasis

Defense against extracellular

pathogens

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

IL-21, IL-22

IL-1,TGF-,

IL-6, IL-23

Stress, injury

Recruitment

of neutrophils

Activated

APC

Naïve

CD4+T cell

IL-5, IL-13, IL-4IL-10,IL-25

Eosinophils, basophils,

T cells, B cells, APCs

IL-12,

IFN-

IFN-

TNF-α

IL-2

T cells, APCs

IL-17A,

IL-17F

IL-17A/F

IL-2,

TGF-

IL-10, TGF-

T cells

TH17

TH1 TREG

Keratinocytes, neutrophils, APCs, T cells

Innate

immune

cells

IL-25

APC = antigen-presenting cell; TGF- = transforming growth factor-beta; TREG = regulatory T.

1. Brand S. Gut. 2009;58:1152-1167. 2. Cools N, et al. Clin Dev Immunol. 2007;89195:1-11. 3. Miossec P, et al. N Engl J Med. 2009;361:888-898. 4. Lucey DR, et al. Clin

Microbiol Rev. 1996;9:532-562. 5. Gaffen SL. Nat Rev Immunol. 2009;9:556-568. 6. Abbas AK, et al. Cellular and Molecular Immunology. 6th ed. Philadelphia, Pa: Saunders.

2007:303-320. 7. Cua DJ, et al. Nat Rev Immunol. 2010;10:479-490. 8. van der Fits L, et al. J Immunol. 2009;182:5836-5845. 9. Létuvé S, et al. J Allergy Clin Immunol.

2006;117:590-596.

TH2

IL-4

17

IL-17 Cytokine Family

Gaffen. Nat Rev Immunol 2009;9(8):556-67(Updated 9: p 747).

18

IL-17 Signaling - Ligand/Receptor Combinations

1. Gaffen. Nat Rev Immunol 2009;9(8):556-67(Updated 9: p747).

2. Chang et al. Immunity 2011;35(4):611-21.

IL-17A IL-17A/F

IL-17F

IL-17C

IL-17D

IL-17E/IL-25IL-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-17RA

IL-17RE

IL-17RD/

SEF

19

IL-17 Receptor A Has an Important Role for

Function of Multiple IL-17 Family Cytokines1-7

IL-17 cytokines bind to and activate signaling through a family of receptors1-7

IL-17 receptor A forms a complex with other receptor subunits to bind with different IL-17 cytokines1,3

For example, IL-17A, IL-17F, and IL-17A/F bind to and activate signaling through a heteromeric

receptor complex comprised of IL-17 receptor A and IL-17 receptor C1-4,6,7

1. Toy D, et al. J Immunol. 2006;177:36-39. 2. Wright JF, et al. J Immunol. 2008;181:2799-2805. 3. Rickel EA, et al. J Immunol. 2008;181:4299-4310. 4. Chang

SH, et al. Cell Res. 2007;17:435-440. 5. Claudio E, et al. J Immunol. 2009;182:1617-1630. 6. Kuestner RE, et al. J Immunol. 2007;179:5462-5473. 7. Ramirez-

Carrozzi V, et al. Nat Immunol. 2011;12:1159-1166.

20

Main Functions of IL-17A and IL-17F1-12*

Neutrophil recruitment4-6

Extracellular pathogen defense7,8

IL-17A is critical for memory

response against intracellular

pathogens9

Bone metabolism10,11

*Data regarding the IL-17A/F heterodimer are limited.12

1. Toy D, et al. J Immunol. 2006;177:36-39. 2. Wright JF, et al. J Immunol. 2008;181:2799-2805. 3. Chang SH, et al. Cell Res. 2007;17:435-440. 4. Hurst SD, et

al. J Immunol. 2002;169:443-453. 5. Kelly MN, et al. Infect Immun. 2005;73:617-621. 6. Fossiez F, et al. J Exp Med. 1996;183:2593-2603. 7. O’Connor W Jr, et

al. Nat Immunol. 2010;11:471-476. 8. Zelante T, et al. Eur J Immunol. 2007;37:2695-2706. 9. Pappu R, et al. Immunology. 2011;134:8-16. 10. Lubberts E, et al. J

Immunol. 2003;170:2655-2662. 11. Goswami J, et al. Eur J Immunol. 2009;39:2831-2839.12. Gaffen SL. Nat Rev Immunol. 2009;9:556-568.

21

Main Functions of IL-17C1,2

Neutrophil recruitment1,2

Extracellular pathogen defense1,2

Regulation of intestinal epithelial inflammation (protective function)1,2

Overlapping functions with IL-17A1,2

– Host defense

– Cytokine induction

G-CSF = granulocyte colony-stimulating factor.

1. Ramirez-Carrozzi V, et al. Nat Immunol. 2011;12:1159-1166. 2. Song X, et al. Nat Immunol. 2011;12:1151-1158.

22

Main Functions of IL-251-8

Promotes TH2 responses2-4

In preclinical models, modulates

allergic responses and asthma2-6

Protective immunity to extracellular

pathogens

(eg, parasitic infections)2-4,7,8

IL-17RAIL-17RB

IL-25

1. Rickel EA, et al. J Immunol. 2008;181:4299-4310. 2. Claudio E, et al. J Immunol. 2009;182:1617-1630. 3. Angkasekwinai P, et al. J Exp Med.

2007;204:1509-1517. 4. Angkasekwinai P, et al. Nat Immunol. 2010;11:250-257. 5. Zhao Y, et al. Int Arch Allergy Immunol. 2010;151:297-307. 6. Létuvé S, et

al. J Allergy Clin Immunol. 2006;117:590-596. 7. Hurst SD, et al. J Immunol. 2002;169:443-453. 8. Fallon PG, et al. J Exp Med. 2006;203:1105-1116.

23

The IL-17 Family Includes Unique

Receptors and Cytokines1-9

γδ = gamma-delta; LTi = lymphoid tissue inducer; Mϕs = macrophages; NK = natural killer; NKT = natural killer T;

PMN = polymorphonuclear.

1. Gaffen SL. Nat Rev Immunol. 2009;9:556-568. 2. Chang SH, et al. Cell Res. 2007;17:435-440. 3. Garley M, et al. Adv Med Sci. 2008;53:326-330. 4. Pappu R,

et al. Immunology. 2011;134:8-16. 5. Ramirez-Carrozzi V, et al. Nat Immunol. 2011;12:1159-1167. 6. Song X, et al. Nat Immunol. 2011;12:1151-1158. 7.

Moseley TA, et al. Cytokine Growth Factor Rev. 2003;14:155-174. 8. Ge D, et al. Int Arch Med. 2008;1:1-19. 9. Lee J, et al. J Biol Chem. 2001;276:1660-1664.

IL-17A

IL-17F

IL-17A/F

heterodimer

IL-17C

IL-25

(IL-17E)

IL-17B

IL-17D

Ubiquitous (higher in hematopoietic tissues)

Most human tissues (preferentially on

nonhematopoietic tissues)

Ubiquitous (higher in hematopoietic tissues)

Selectively induced in epithelia by bacterial,

inflammatory stimuli

Ubiquitous (higher in hematopoietic tissues)

TH2 cells, TH9 cells, fibroblasts, basophils,

endocrine, kidney, and liver cells

TH2 cells, TH9 cells, fibroblasts, basophils,endocrine, kidney, and liver cells

Unknown

• TH17 cells

• CD8+ T cells

• γδ T cells

• PMN cells (low concentration)

Epithelial cells (trachea,

colon, skin)

• TH2 cells

• NKT cells

• Alveolar MФs

• PMN cells (lower concentration)

Unknown

Unknown

IL-17RA

IL-17RC

IL-17RA

IL-17RE

IL-17RA

IL-17RB

IL-17RB

Unknown

Cytokines Source of Cytokine Receptors Expression of Receptors

• NKT cells

• LTi cells

• NK cells

• Eosinophils

• Mast cells

• Basophils

24

The IL-17 Receptor and Cytokine

Family Is Implicated in Psoriasis1-4

Data suggest pathophysiology in psoriasis may be mediated by

interactions between IL-17 cytokine-producing cells and target cells

expressing IL-17 receptor A…1

…And lead to a cascade that results in inflammation and skin

manifestations1

1. Raychaudhuri SP. Clin Rev Allerg Immunol. 2013;44:183-193. 2. Miossec P, et al. N Engl J Med. 2009;361:888-898. 3. Miossec P, et al. Nat Rev Drug Discov.

2012. 4. Ouyang W, et al. Immunity. 2008;28:454-467.

Vessel activation,

angiogenesis

(erythema)

Keratinocyte

proliferation and

differentiation

(thickness and

scaling)

Inflammation

IL-17 producing cells(T cells, neutrophils, mast cells)

Target Cells Expressing IL-17RA(Keratinocytes, dermal fibroblasts and epithelial

cell, endothelial cells)

25

IL-17A Has Pathogenic Effects on Keratinocytes

1. Guttman-Yassky. J Allergy Clin Immunol 2011;127(6):1420-32.

2. Chiricozzi and Krueger. Expert Opin Investig Drugs 2013;22(8):993-1005.

3. Gaffen. Nat Rev Immunol 2009;9(8):556-67(Updated 9: p 747).

4. Lin et al. J Immunol 2011;187(1):490-500.

Th17

Cells

KC

IL-17A

Hyperproliferation and

acanthosis leading to psoriatic

plaques 1,2

Release proinflammatory

cytokines leading to increased

inflammation and recruitment

of Th17 cells and neutrophils1,2

Other cell types (not shown) that secrete IL-17 include γδ T cells, macrophages3,4

Neutrophils

KC

IL-17A

IL-17A

Mast

Cells

26

TH1- and TH17 -Associated Cytokines Are Present in

Psoriatic Plaques1,2

mRNA expression in

psoriatic plaques vs.

nonlesional psoriatic skin is:

– Increased 28- to 33-fold

(P < 0.01) for IL-17A,

IL-17C, and IL-17F

– Increased 9-fold (P < 0.01)

for IFN-γ mRNA

Pooled paired tissue samples from lesional and nonlesional psoriatic skin of subjects with moderate to severe chronic plaque psoriasis (n = 9).

*P < 0.01 compared with nonlesional psoriatic skin

RPLPO = housekeeping gene used as control in the analysis.

1. Johansen C, et al. Br J Dermatol. 2009;160:319-324. Figures: © 2009 John Wiley and Sons. © 2009 British Association of Dermatologists. 2. Zaba LC, et

al. J Exp Med. 2007;204:3183-3194.

6000

5000

4000

3000

2000

1000

0

Nonlesional Lesional

IL-1

7A/R

PL

PO

mR

NA *IL-17A

6000

5000

4000

3000

2000

1000

0

Nonlesional Lesional

IL-1

7C/R

PL

PO

mR

NA *

IL-17C

7000

5000

4000

3000

2000

1000

0

Nonlesional Lesional

IL-1

7F/R

PL

PO

mR

NA

*IL-17F6000

1600

1200

1000

800

600

400

0

Nonlesional Lesional

IFN

-/R

PL

PO

mR

NA

*IFN-1400

200

27

Targeting: IL-171

1. Adapted from Nestle et al. N Engl J Med. 2009;361:496.

2. Tausend et al. J Cutan Med Surg. 2014;18:156.

Th1 cell

Th17 cell

Keratinocyte

Myeloid

dendritic cell

IL-17A

Natural

killer T cell

Plasmacytoid

dendritic cell

Keratinocyte

Macrophage

Antimicrobial peptidesIL-1

IL-6

TNF-

S100

CXCL8

CXCL9

CXCL10

CXCL11

CCL20Activation

Secukinumab

Ixekizumab2

IL-17R

Brodalumab2

Original Article

Secukinumab in Plaque Psoriasis — Results of Two Phase 3 Trials

Richard G. Langley, M.D., Boni E. Elewski, M.D., Mark Lebwohl, M.D., Kristian Reich, M.D., Ph.D., Christopher E.M. Griffiths, M.D., Kim Papp, M.D., Ph.D., Lluís Puig, M.D., Ph.D., Hidemi Nakagawa, M.D., Ph.D., Lynda Spelman, M.B., B.S., Bárður Sigurgeirsson, M.D., Ph.D., Enrique Rivas, M.D., Tsen-Fang Tsai, M.D.,

Norman Wasel, M.D., Stephen Tyring, M.D., Ph.D., Thomas Salko, B.A., Isabelle Hampele, Ph.D., Marianne Notter, M.S., Alexander Karpov, Ph.D., Silvia Helou, M.D.,

Ph.D., Charis Papavassilis, M.D., Ph.D., for the ERASURE and FIXTURE Study Groups

N Engl J MedVolume 371(4):326-338

July 24, 2014

Study Overview

• In two trials in patients with moderate-to-severe plaque psoriasis, the anti–interleukin-17A monoclonal antibody secukinumab was more effective than placebo and etanercept.

• Infectious complications occurred more often with secukinumab than with placebo.

Speed of Response.

Langley RG et al. N Engl J Med 2014;371:326-338

Efficacy over Time.

Langley RG et al. N Engl J Med 2014;371:326-338

Demographic and Baseline Clinical Characteristics of the Patients.

Langley RG et al. N Engl J Med 2014;371:326-338

Efficacy End Points in ERASURE.

Langley RG et al. N Engl J Med 2014;371:326-338

Efficacy End Points in FIXTURE.

Langley RG et al. N Engl J Med 2014;371:326-338

Adverse Events during the Induction Period and the Entire 52-Week Study Period in FIXTURE.

Langley RG et al. N Engl J Med 2014;371:326-338

Conclusions

• Secukinumab was effective for psoriasis in two randomized trials, validating interleukin-17A as a therapeutic target.

37

38

5 5 3

7267

60

8277

83

0

20

40

60

80

100

PASI 75 Response for IL-17 Inhibitors

1. Langley et al. N Engl J Med 2014;371:326-38.

2. Amgen and AstraZeneca. 2014. Phase 3 Study of Brodalumab [News release]. Accessed September 2, 2014.

3. Eli Lilly and Company. 2014. Phase 3 Study of Ixekizumab [News Release]. Accessed September 2, 2014.

Pa

tie

nts

ach

ievin

g a

PA

SI 7

5 r

esp

on

se

, %

Secukinumab1

Phase 3

Time Point 12 weeks

150 mg, 300 mg 140 mg, 210 mgDose

Low Dose High Dose

Brodalumab2

Phase 3

12 weeks

ERASURE FIXTURE AMAGINE-1

Placebo Group

160 mg starting dose, 80 mg every 2 or 4 weeks

12 weeks

Ixekizumab3

Phase 3

UNCOVER

0

20

40

60

80

100

Pa

tie

nts

ach

ievin

g a

PA

SI 7

5 r

esp

on

se

, %

Between

78% to 90%

of patients

achieved a

response

39

Key Cells and Mediators in Psoriasis

Keratinocyte

Myeloid

dendritic cell

Natural

killer T cell

Plasmacytoid

dendritic cell

Macrophage

IL-1

IL-6

TNF-

TNF-

TNF-

IFN-

IFN-

Innate Immunity

Th1 cell

Th17 cell

IL-23

IL-17A/F

IL-22

Keratinocyte

IL-12

TNF-

IFN-

Adaptive Immunity

Activation

Antimicrobial peptides

IL-1

IL-6

TNF-

S100

CXCL8

CXCL9

CXCL10

CXCL11

CCL20

Innate Immunity

Adapted from Nestle et al. N Engl J Med. 2009;361:496.