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New Frontiers and Pivotal Clinical Advances for the

Pathoimmunobiology of Atopic Dermatitis

The Translational Path in Atopic Dermatitis and the Implications for Dermatology Practice

A Year 2016‐2017 Science‐to‐Practice Update for the Dermatological Specialist

PROFESSOR EMMA GUTTMAN, MD, PhD – Program ChairProfessor and Vice Chair, Dermatology

Director, Center for Excellence in Eczema and Laboratory for Inflammatory Skin DiseasesIcahn School of Medicine at Mount Sinai Medical Center

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CME‐certified symposium jointly provided by Advancing Knowledge in Healthcare (AKH) and CMEducation Resources, LLC

Commercial Support: Supported by an independent educational grant from Sanofi Genzyme and Regeneron Pharmaceuticals

Faculty disclosures: Listed in program materials

This CME activity may include discussions of off‐label or unapproved uses of specific agents

Welcome and Program Overview

We Request That You…

►PLEASE FILL OUT

QUESTION AND ANSWER (Q&A) CARDS as program proceeds so we can collect them and discuss during the Q&A session

COURSE SURVEY: Please hand all survey forms to staff at the desk outside following the program

CME CREDIT can be received by completing the online evaluation/claimed credit form atwww.akhcme.com/aderm (listed in your program materials)

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Continue Learning With UsEnduring Materials from This Symposium

• This entire program will be available as a CME Clinical Excellence WebCAST on multiple clinical websites, including www.BiologicsCAST.com

• PowerPoint slides from today’s program will be available for download

• Clinical questions about atopic dermatitis management may be submitted to www.iQandA‐CME.com

Distinguished Program Faculty

PROFESSOR EMMA GUTTMAN, MD, PhDProfessor and Vice Chair, DermatologyDirector, Center for Excellence in Eczema and Laboratory for Inflammatory Skin DiseasesIcahn School of Medicine at Mount Sinai Medical Center New York, NY

PROFESSOR MARK LEBWOHL, MD Sol and Clara Kest Professor and ChairmanKimberly and Eric J. Waldman Department of DermatologyIcahn School of Medicine at Mount SinaiNew York, NY

PROFESSOR LISA A. BECK, MDProfessor, Department of Dermatology and Medicine (Allergy/Immunology and Rheumatology) University of Rochester Medical Center School of Medicine and Dentistry Rochester, NY

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New Frontiers and Pivotal Clinical Advances for the

Pathoimmunobiology of Atopic Dermatitis

The Translational Path in Atopic Dermatitis and the Implications for Dermatology Practice




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Translational Revolution in AD

In the last decade there is a real revolution in atopic dermatitis research with rapid therapeutic development, further amplifying our current disease understanding

These therapeutic developments are giving our AD patients hope for a better future and quality of life

This symposium will present current data on disease pathogenesis, the unmet need and the emerging systemic nature of AD, suggesting the need for systemic treatments for patients with severe AD

It will also present data on disease control using systemic treatments

Translational Revolution in AD

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Overview

Overview of Therapeutic Advances in AD (Dr Mark Lebwohl)

Evolving Pathogenic Concepts On Atopic Dermatitis (AD) and Its Systemic Nature with Implications for Targeted Therapeutics (Dr. Emma Guttman‐Yassky)

Review of Published Clinical Trials and How This is Likely to Change Our Approach to the Treatment of AD (Dr. Lisa Beck)

Summary, future directions, questions (all)

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Therapeutic Advances inAtopic Dermatitis

A Year 2016‐2017 Mechanism‐to‐Practice UpdateFocused on Biologic Therapies

Professor Mark Lebwohl, MD Sol and Clara Kest Professor

and ChairmanKimberly and Eric J. Waldman Department of Dermatology

Icahn School of Medicine at Mount Sinai

Mount Sinai Gets Dollars From:

► Amgen

► Anacor

► Boehringer Ingleheim

► Celgene

► Lilly

► Janssen Biotech

► Kadmon

►LEO Pharmaceuticals

► Medimmune

► Novartis

► Pfizer

► Sun Pharmaceuticals

► Valeant

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Optimist: Glass is half fullPessimist: Glass is half emptyRealist: Glass is half full and half empty

The Clinical Dilemma in AD

► No universally accepted biomarker to define disease stages, severity or clinical success

► >20 instruments to assess disease severity in clinical trials that differ in items and domains they include and most have not been sufficiently validated● Treatment effects cannot be readily compared and meta‐analyses

are difficult

● Impacts evidence‐based management

Unmet need for effective therapy of moderate and severe atopic dermatitis

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IL-17AIL-17FIL-17R

IL-12

Antimicrobial peptidesIL-1βIL-6

TNF-αS100

CXCL8CXCL9

CXCL10CXCL11CCL20

ActivationNatural

killer T cell

Keratinocyte

Myeloiddendritic cell

Plasmacytoid dendritic cell

Macrophage

IL-1βIL-6

TNF-αTNF-αINF-γ

INF-γ

Th1 cell

Th17 cell

TNF-αINF-γ

Keratinocyte

TNF-α

Adaptive immunity

Innate immunityInnate immunity

IL-20

Adapted from: Nestle F, et al, NEJM 2009; 501.

Pathogenesis of PsoriasisMechanism of Alefacept

Th22 cell

IL-22

IL-20

IL-23

IL-17AIL-17FIL-17R

IL-12


TNF-αS100

CXCL8CXCL9

CXCL10CXCL11CCL20

ActivationNatural

killer T cell

Keratinocyte



Macrophage

IL-1βIL-6

TNF-αTNF-αINF-γ

INF-γ

Th1 cell

Th17 cell

TNF-αINF-γ

Keratinocyte

TNF-α

Adaptive immunity


IL-20


Mechanism of Cyclosporine

Th22 cell

IL-22

IL-20

IL-23

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IL-17AIL-17FIL-17R

IL-12


TNF-αS100

CXCL8CXCL9

CXCL10CXCL11CCL20

ActivationNatural

killer T cell

Keratinocyte



Macrophage

IL-1βIL-6

TNF-αTNF-αINF-γ

INF-γ

Th1 cell

Th17 cell

TNF-αINF-γ

Keratinocyte

TNF-α

Adaptive immunity


IL-20


Mechanism of TNF Blockers

Th22 cell

IL-22

IL-20

IL-23

IL-17AIL-17FIL-17R

IL-12


TNF-αS100

CXCL8CXCL9CXCL10CXCL11CCL20

ActivationNatural

killer T cell

Keratinocyte



Macrophage

IL-1βIL-6

TNF-αTNF-αINF-γ

INF-γ

Th1 cell

Th17 cell

TNF-αINF-γ

Keratinocyte

TNF-α

Adaptive immunity


IL-20


Mechanism of Secukinumab, Ixekizumab, Brodalumab

Th22 cell

IL-22

IL-20

IL-23

SecukinumabIxekizumab

Brodalumab

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Inborn errors of human IL‐17 immunity underlie chronic mucocutaneous candidiasis.

Puel A, et al. Allergy Clin Immunol. 2012;12:616‐22.

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Immunity to infection in IL‐17‐deficient mice and humans. Cypowyj S, Picard C, Maródi L, et alEur J Immunol. 2012;42:2246‐2254

Chronic mucocutaneous candidiasis in humans with inborn errors of interleukin‐17 immunity. Puel A, Cypowyj S, Bustamante J, et al.Science. 2011;332(6025):65‐68.

TSLP

Gittler JK…and Guttman-Yassky E. J Allergy Clin Immunol Sep 2012

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TSLP

Gittler JK…and Guttman‐Yassky E. J Allergy Clin Immunol Sep 2012Mechanism of cyclosporine

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Cyclosporine

►Nephrotoxicity

►Hypertension

►Hypomagnesemia, Hyperkalemia

►Hyperlipidemia

►Drug interactions

►Hypertrichosis

► Lymphoproliferative disease

► “Sexual Frenzy”

TSLP

Gittler JK…and Guttman-Yassky E. J Allergy Clin Immunol Sep 2012Mechanism of Dupilumab

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Th2 Cytokine (IL‐4/IL‐13) Effects on the Epidermis in AD

Inhibit terminal differentiation of KCs (IL‐4, IL‐13, IL‐31/Th2)

Inhibit lipid synthesis (Th2 cytokines/IL‐4, IL‐13, IL‐31)

Inhibit synthesis of antimicrobial peptides (Th2/IL‐4, IL‐13, IL‐33 cytokines)

Promote staph aureus binding and colonization (IL‐4, IL‐13)

Augment TSLP secretion by KCs (Th2 cytokines/IL‐4, IL‐13)

Sa et al. J Immunol 2007

Nograles KE. Br J Dermatol 2008

Guttman‐Yassky E. J Immunol 2008

Kim BE et al. Clin Immunol 2008;126:332‐7

Howell MD et al. J Invest Dermatol 2008;128:2248‐58

Cornelissen C et al. J Allergy Clin Immunol 2012;129(2):426‐33

DansoMO. JID July 2014

Th2 cytokines could link the barrier and immune defects in AD

IL‐4 Transgenic Mice Demonstrate Atopic Inflammatory Skin Disease Spontaneously

TgNon‐Tg4 mos

Tg 8 months

Tg 8 months Tg 8 months

Chan LS, et al. J Invest Dermatol 2001;117:977‐83

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Dupilumab Blocks Signaling Through the IL‐4/IL‐13 Receptor/Ligand System

Type I Receptor

IgE responses, Th2 –mediated inflammation, reduced antimicrobial

peptides

Type II Receptor

Reduced skin barrier function, increased Th2 responses

Dupilumab in persistent asthma with elevated eosinophil levels.

Wenzel S, et al. N Engl J Med. 2013 May 21. [Epub ahead of print]

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Dupilumab treatment in adults with moderate‐to‐severe atopic dermatitis.

Beck LA, Thaçi D, Hamilton JD, Graham NM, Bieber T, Rocklin R, Ming JE, Ren H, Kao R, Simpson E, Ardeleanu M, Weinstein SP, Pirozzi G, Guttman‐Yassky E, Suárez‐Fariñas M, Hager MD, Stahl N, Yancopoulos GD, Radin AR

N Engl J Med. 2014;371:130‐9.

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Evolving Pathogenic Concepts On Atopic Dermatitis (AD) and Its Systemic Nature with Implications for

Targeted Therapeutics




Speaker Disclosures

Research support, consulting or lecture fees on atopic dermatitis from Regeneron, Sanofi, Merck, Stiefel/GSK, Pfizer, Genentech, Bristol‐Myers Squibb, Galderma, Celgene, Leo Pharma, Janssen, Medimmune, Dermira, Anacor, AnaptysBio, Glenmark, Novartis, Celsus, Abbvie, Sun Pharma, Mitsubishi Tanabe, Vitae, Almirall

No patents, ownership, or financial gain from any atopic dermatitis drug

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Atopic Dermatitis

Most common inflammatory skin disease (3‐7% of adults and 15‐25% of children)

~ 1/3 of AD patients have moderate‐to severe disease

Large unmet need for safe and effective therapeutics in both adults and children

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Barrier Defects in AD (and Clinical Correlations)

Lichenification: Epidermal hyperplasia characterizes chronic lesional AD skin

Terminal Differentiation, Tight Junction, and Lipid Defects

Guttman‐Yassky, et al J Allergy Clin Immunol 2009

De Benedetto A et al JACI 2011; 127: 773‐786

N NL LS

N NL LS

28

A

B

C

D

E

Non-lesional Acute Chronic

CD3

CD11c

CD83

CD1a

! "#$ %

! &' $ %

0

20

40

60

80

100

120

140

*

*

Cel

ls/m

m

CD3

0

100

200

300

**

**

CD11c

0

100

200

300

400

**

****

CD83

0

50

100

150

200

250

*

*

CD1a

0

10

20

30

40

*

*

Acute and even more chronic AD are associated with large T cell and dendritic cell infiltrates

AD Skin Lesions are Invariably Characterized by Immune Activation

Gittler JK…and Guttman‐Yassky E J Allergy Clin Immunol 2012

Non‐lesionalAcute ADChronic AD

0

2

4

6

8

10

1

4

16

64

256

1024

IL−4

IL−5

IL−10

IL−13

IL−31

IL−33

CC

L17

CC

L18

CC

L22

CCL5

CC

L26

CC

L13

CC

L11

*

**

**

*

*** **

**

**

*

*

Non‐lesionalAcute ADChronic AD

IL‐4Th2

IL‐5Th2

IL‐10Th2

IL‐13Th2

IL‐31Th2

IL‐33Th2

CCL17Th2

CCL18Th2

CCL22Th2

CCL5Th2

CCL26Th2

CCL13Th2

CCL11Th2

ln(exp

ression/hARP)

Expression/hARP

ln(exp

ression/hARP)

IL‐22Th22

S100A7Th22

S100A8Th22

S100A9Th22

2 7 8 9

*

*** *

*** **** **

0

2

4

6

8

10

Th2

Th22

AD Lesions are Accompanied by Th2/Th22 Cytokine Activation

Gittler JK…and Guttman‐Yassky E J Allergy Clin Immunol 2012

S100A7

S100A8

Non‐lesional Acute Chronic

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Two Proposed Mechanistic Hypotheses for AD

“Outside‐in” ‐ AD is a disease of fixed (genetic) epidermal barrier defects, that may trigger abnormal keratinocyte hyperplasia and secondary immune activation

Supported by the FLG gene mutation in 10‐40% of AD patients

Palmer CAN, et al Nat Genet 2006; 48: 441‐446.

“Inside‐out”‐ The abnormal epidermal phenotype in lesional AD skin is driven by increased expression of cytokines produced by distinct T‐cell subsets

The Th2 Cytokines IL‐4 and IL‐13 Downregulate Epidermal Differentiation Proteins In Vitro

Howell MD et al. J Invest Derm 2008;128:2248–2258; Kim BE et al. Clin Immunol 2008;126:332–337.

Filaggrin Loricrin Involucrin

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Gittler JK…and Guttman‐Yassky E, JACI 2012

A Paradigm Shift in The Pathogenesis of AD….

Staph

Is the pediatric AD phenotype similar to adults?

Paradigm‐shifting AD discoveries have been based on adult biomarkers, reflecting decades of disease activity

But, 85% of AD cases begin before 5yo

We thus (collaboratively with Amy Paller’s group) aimed to:

Determine differences and similarities between early onset AD in children and chronic AD in adults with similar disease activity

We assessed blood and skin samples from 20 AD children<5yrs, within 6 month of disease onset, as well as 14 age‐matched controls

Pediatric vs Adult AD

31

0

10

20

30(%)

p=0.36p=0.88

* p=0.044 *** p<0.001

control AD control AD

children adults

0

1

2

3

4

5

(%)

p=0.38p=0.35

p=0.13 * p=0.028


children adults

0

10

20

30

40

(%)

** p=0.0056p=0.92

p=0.69 *** p<0.001


children adults

0

2

4

6

8

10

(%)** p=0.0021

*** p<0.001

p=0.91 * p=0.042


children adults

IL‐13+CLA+ IL‐13+CLA‐

CD4+ T‐cells

CD8+ T‐cells

Comparable Th2 activation in both pediatric and adult AD

In pediatric AD the Th2 imbalance is confined to skin homing/CLA+ T‐cells and does not extend to CD8+ T‐cells

In adults, Th2 activation extends into systemic/CLA‐ T‐cells and CD8+ T‐cells

Early AD Already Shows Strong Th2 Skewing in Blood

No Th1, Th22, Th17 or Th9 subset expansion was seen in

blood of AD children

Czarnowicki T…, Paller AS* and Guttman‐Yassky* E. JACI 2015

Pediatric AD Exhibits Profound Epidermal Hyperplasia

Bruner PM*, Esaki H*, ….. Paller AS* and Guttman‐Yassky*. JACI September 2016.

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Th2 Cytokines are Greatly Increased in Skin at Disease Initiation


Continuous Filaggrin Expression Characterizes Pediatric AD


33

There is early and potent Th2 activation in blood and skin of AD children, establishing the systemic nature of new onset disease

Pediatric non‐lesional skin is already hyperplastic, accompanied by significant inflammation and activated cytokines to levels often higher than in adults, possibly reflecting “true” AD initiation

FLG deficiency of adult AD is missing in early AD challenging the notion of filaggrin as central for disease elicitation and instigator of the atopic march

Conclusions

Can the Atopic March can be prevented by appropriate immune manipulations (using broad or specific T‐cell targeting) once the skin phenotype has developed?

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A prediction of the immune model is that immune suppression will reverse the epidermal pathology

The hypothesis can be rejected if immune suppression is achieved but the epidermal phenotype persists

Test of this hypothesis is our study with dupilumab, a specific immune antagonist

Testing the Immune Hypothesis of AD

Dupilumab, a Fully Human IL‐4Rα mAb, Potently Inhibits Both IL‐4 and IL‐13 Signaling

4 week study with weekly injections of dupilumab 75mg, 150 mg, 300 mg and placebo

A total of 67 patients, 18 participated in the biopsy study

Type I Receptor

B cells, T cells, Monocytes, Eosinophils, Fibroblasts

Type II Receptor

Epithelial cells, Smooth muscle cells, Fibroblasts, Monocytes, Activated B cells

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18.8

0

37.5

27.3

54.552.4

71.4

0

10

20

30

40

50

60

70

80

90

100

% Responders

2 40

Study Week

Placebo (n=16)

Dupilimab 75 mg (n=8)



*

*

*p<0.05; †p=0.003

*

†

Beck L….Guttman‐Yassky E et al, NEJM 2014

No differences in responses were seen between AD patients based on IgE or FLG mutation status

Dupilumab Response Rates

Dupilumab Significantly Reduced Epidermal Hyperplasia After Only Four Weeks of Treatment

Significant decreases in the expression of genes related to hyperplasia also by arrays (K16, Mki67)

K16K16

p=0.0026p=0.12

p=0.57

10

5

Dupilumab300mg

Dupilumab150mg

Placebo

Time

PrePost

Iog 2

(Exp

ression/hARP)

p=0.023

p=0.241

0.565

4

–4

Dupilumab300mg

Dupilumab150mg

Placebo

FCH (Post vs Pre)

0.122

0.003

2

–8

0

–16

–2

–32

Hamilton J…..and Guttman‐Yassly E. JACI Dec 2014

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Dupilumab Suppressed Inflammatory Pathways Beyond Th2

Placebo DPL_300DPL_150Down Up

Marked reductions in expression of:

Th2 chemokines (CCL17, CCL18, CCL13, CCL22, CCL26)

S100As (S100A8/9/12)

IL‐23/IL‐17 genes (elafin, IL‐23p19 and p40, IL‐17A)

hyperplasia related genes (K16, Mki67)

One possibility is through the inhibition of IL‐4 induced differentiation of dendritic cells


FCH (Post vs. Pre)

In vitro studies in KCs suggest that the Th2 cytokines (IL‐4, IL‐13, and IL‐31) inhibit differentiation genes

In vivo, IL‐4R blockade increases expression of LOR and FLG mRNAs, but the magnitude of the effect is small at 4 weeks; may also be confounded by reversal of epidermal hyperplasia

Trend for Increased Expression of Barrier Function Genes (LOR, FLG) with Dupilumab Treatment

FLG/K16 LOR/K16

Dupilumab300mg

Dupilumab150mg

PlaceboDupilumab300mg

Dupilumab150mg

Placebo

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Dupilumab Improved the AD Transcriptome in a Dose‐Dependent Manner

Drug Effect = Transcriptome‐specific changes with p<0.05 and FCH>2

PrePre Pre

PlaceboDupilumab 150mg

Dupilumab 300mg

PostPost Post

Placebo Dupilumab150mg

Dupilumab300mg

Avg % Improvement

‐21.5+24.7

+52

EASI

Time Point


Dupilumab Impacts Both the Inflammation and the Barrier Dysfunction of AD

Type 2 Immune Response

Chronic StageAcute StageInitiation

Skin Barrier DysfunctionEnvironmental Factors/Allergens

Innate Immune Response

Dupilumab

dupilumab

This establishes IL‐4 and IL‐13 as pathogenic cytokines in AD and cements AD as a reversible, immune‐driven disease, like psoriasis

Noda S et al. J Allergy Clin Immunol 2015;135:324–336.

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EASI‐75 Response in Phase III: Change from Baseline

† Censored analysis.

0

10

20

30

40

50

60

70

80

0 1 2 4 6 8 12 160

10

20

30

40

50

60

70

80

0 1 2 4 6 8 12 16

51.3*†

11.9†14.7†

44.2*†

52.5*†48.1*†

*P < 0.0001 vs placebo *P < 0.0001 vs placebo

Week Week

Patients (%)

SOLO 1 SOLO 2

Dupilumab 300 mg qw (censored)Dupilumab 300 mg qw (uncensored)

Dupilumab 300 mg q2w (censored)Dupilumab 300 mg q2w (uncensored)

Placebo qw (censored) Placebo qw (uncensored)

Pre‐Treatment Pictures (My Own Patient in Phase 2B)

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Post‐Treatment Pictures

Pre Treatment Pictures (My Own Patient in Phase 3)

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Post Treatment Pictures

What Features of AD May beExplained by Other Cytokines Effects

(IL‐22, and IL‐23/IL‐17)?

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IL‐22 Promotes Hyperplasia and Impairs Terminal Differentiation

Nograles KE et al, British Journal of Dermatology, 2008

Full thickness skin rafts (epidermis + fibroblasts/dermis)

*S100As FCH S100A7 psoriasin 458.87Terminal DifferentiationLOR Loricrin 0.084FLG Filaggrin 0.032CALML5 Calmodulin 5 0.326KRT1 keartin 1 0.022KRT10 keratin 10 0.499

Genes up/down‐regulated by IL‐22 in keratinocytes

Targeting Th22/IL‐22 in AD

Since IL‐22 is involved in the epidermal hyperplasia and barrier defects in AD, we hypothesized that anti IL‐22 treatment might prove to be effective in chronic AD patients

We are conducting an NIH/NIAMS‐funded trial with an anti IL‐22 antibody (ILV‐094) in 60 moderate‐to‐severe AD patients (study completed, analyses in process)

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3 months Post ILV‐094

Pre ILV‐094/anti IL‐22

What is the Potential Significance of IL‐23/IL‐17 to AD Lesions?

Th17

Induction of S100As& EpidermalHyperplasia

Zheng et al. Nature 445: 648, 2007

Antimicrobiials and S100as FCH DEFB4 defensin, beta 4 238.549S100A7 psoriasin 189.381S100A12 S100 calcium binding protein A12 30.707Cytokines and Chemokines FCH IL8 interleukin 8 14.529CCL20 chemokine (C-C motif) ligand 20 28.306CXCL1 chemokine (C-X-C motif) ligand 1 (me 7.688CXCL2 chemokine (C-X-C motif) ligand 2 6.006CXCL3 chemokine (C-X-C motif) ligand 3 3.812Terminal DifferentiationLOR Loricrin 0.163

IL‐17 induces S100As and impairs differentiation in KCs

Th22

IL‐23

IL‐22 dependent

Nograles KE et al, BJD 2008 Sa et al. J Immunol 2007

IL‐22

IL‐17

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Pre Ustekinumab

Shroff A, and Guttman‐Yassky E. JAAD case reports January 2015

A Case Report of Successful Treatment of Refractory AD with High Dose Ustekinumab

Post Ustekinumab

Ustekinumab

Secukinumab

ILV-094

Tezepelumab

GBR 830

Dupilumab

Nemolizumab BMS-981164

Tralokinumab Lebrikizumab

JAK inhibitors

Apremilast

Other Pathways/Targets Under Investigation

Noda S, Krueger JG, and Guttman-Yassky E.J Allergy Clin Immunol 2015

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Summary….It is Not That Simple….

The AD phenotype cannot be explained by a single cytokine pathway like psoriasis

It is currently unclear how many immune axes need to be targeted and to what extent to fully reverse the pathogenic disease phenotype

Clinical trials with IL‐17/IL‐23, IL‐22, and IL‐4/IL‐13 antagonists (coupled with mechanistic studies) are needed to determine the relative contribution of each axis to AD in different AD phenotypes and in different parts of the world

AD Emerging As A Systemic Disease

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What is the Level of Systemic Immune Activation in AD vs Psoriasis (and Controls)?

Both atopic dermatitis (AD) and psoriasis are characterized by T‐cell activation in skin, but their comparable systemic T‐cell activation has been unclear

We recently evaluated T‐cell activation markers (ICOS and HLA‐DR) in central (Tcm/CCR7+CD45RO+) and effector memory (CCR7‐CD45RO+) skin homing (cutaneous lymphocyte antigen/CLA+) and CLA‐ subsets from psoriasis, AD and controls

Czarnowicki T…..Krueger JG, and Guttman‐Yassky E. JACI 2015

Compared with psoriasis, AD is characterized by increased levels of T‐cell activation (ICOS/HLA‐DR) among central and effector CD4+ and CD8+ CLA+ and CLA‐ memory subsets (p<0.01)

AD is Characterized by Excess Systemic T‐cell Activation Compared to Psoriasis

Czarnowicki T…. and Guttman‐Yassky E. JACI April 2015

46

Ungar B…Guttman‐Yassky E. J Invest Dermatol Nov 2016 (Epub ahead of print)

Systemic Cytokine Activation in AD

Serum cytokines levels were shown to be increased in AD patients compared to controls and correlated with disease activity (SCORAD)

IL‐22 CCL17 IL‐13 CCL22 CCL13 CCL2 IFNγ CXCL10 CCL4 CCL11 CCL26 CCL3

FCH (log 2)

‐3

‐2

‐1

0

1

2

3

4

5

…post CsA treatment …

Modifiable risk factors?

Ungar B…Guttman‐Yassky E. J Invest Dermatol Nov 2016 (Epub ahead of print)

IL‐22 CCL17 IL‐13 CCL22 CCL13 CCL2 IFNγ CXCL10 CCL4 CCL11 CCL26 CCL3

‐4.0

‐3.5

‐3.0

‐2.5

‐2.0

‐1.5

‐1.0

‐0.5

0.0

0.5

FCH (log 2)

47

AD and Cardiovascular Risk Factors

Higher odds of:

Smoking at least 100 cigarettes

Current smoker

Started smoking at younger age

Drinking >12 alcoholic beverages/yr

Greater odds of drinking

Higher BMI, esp. >35

Hypertension

Pre‐diabetes, high cholesterol

Especially with increased fatigue, sleep issues

Silverberg and Greenland. JACI 2015;135:721

Atopic Dermatitis and Cardiac Disease

National Health Interview Survey 2010 and 2012

1 year history of AD associated with:

● Coronary artery disease ‐‐ Stroke

● Angina ‐‐ Myocardial infarction

● Congestive heart failure ‐‐ Peripheral vascular disease

Silverberg J. Allergy 2015

48

Hjuler KF et al.: Am J Med. 2015 Dec;128(12):1325‐34

Increased Coronary Calcifications in Severe Psoriasis and AD

Percentage of

Analyzab

le segm

ents

Cardiac computedtomographyangiography (CCTA) showed plaques in 48.1% of AD patients vs. 38.3% in psoriasis and 21,2% in controls)

► Chronic inflammation accelerates atherosclerosis due to repetitive vascular injury/endothelial cell activation

–impaired vascular relaxation

–increased leukocyte adhesion

–increased endothelial permeability

–generation of a pro‐thrombotic state

Systemic inflammation and CVD

Steyers CM & Miller FJ: Int J Mol Sci. 2014 Jun 25;15(7):11324‐49Signorelli SS et al.: Int J Mol Med. 2014 Apr;33(4):777‐83

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Abnormal Cytokine Profile Already Exists in Non‐Lesional AD Skin (Unlike Psoriasis)

Suárez‐Fariñas M…Guttman E. J Allergy Clin Immunol 2011;127:954‐964.

Th2

NormalAD nonlesional AD lesionalTh22

Nonlesional skin expression of Th2 and Th22 markers IL‐13, IL‐22, CCL22, and CCL18 showed high correlation with disease activity

Expression of terminal differentiation genes (EREG, PPL, and LOR) in nonlesional skin showed an inverse correlation with SCORAD

The Nonlesional Phenotype is Influenced by Disease Severity (SCORAD)

ANL AL

Suárez‐Fariñas M…Guttman‐Yassky E. J Allergy Clin Immunol 2011;127:954‐964. Down Up

50

Integrated Disease Severity Biomarker Models Highlight Systemic Immune Activation

LS NL

●●

●

●

●

●

●

●

●

●

●

● ●

●

●

●

●

●

●

●

●

● ●

●

r=0.63 p<0.01

-MX1, S100A12, S100A9, -PPL, IL17A

●●

●

●

●

●

●

●

●

●

●

●●

●

●

●

●

●

●

●

●

●●

●

r=0.73 p<0.01

-PPL, CD11c, CD3, IL13, E.Thickness

●

●

●

●

●

●●

●●

●

●●

●

●

●

●

●●

●

r=0.8 p<0.01

LS + NL + Serum

Ungar B…Guttman‐Yassky E.: J Invest Dermatol Nov 2016 (Epub ahead of print)

50 60 70 80

μScore

50 60 70 80 90

μScore

50 60 70 80

μScore

SCORAD

50

70

90

110

‐MX1, S100A12, S100A9, ‐PPL, IL17A

60

80

100SC

ORAD

‐PPL, CD11c, CD3, IL13, E. Thickness

r=0.73 p<0.01

100

80

60

40

SCORAD

r=0.8 p<0.01

EOS (serum), CCL11 (serum), S100A12 (LS), IL13 (NL), E. Thickness (NL)

AD Emerges as a Systemic Disease

1) High grade systemic immune activation in AD (T‐cells, B‐cells, circulating

cytokines) Czarnowicki T….Guttman‐Yassky E JACI 2015; Czarnowicki T… Guttman‐Yassky E JACI 2016; Ungar

B…..Guttman‐Yassky E J Invest Dermatol 2016.

2) Allergy, Asthma, and the Atopic March

3) Cardiovascular and other co‐morbidities

While Asthma and other comorbidities involve ~30% of AD patients, ALL moderate to severe AD patients are associated with systemic immune abnormalities (might be the common denominator that drives 2‐3)

51

Therapeutic Implications

The high level systemic immune activation in AD is reflected in the wide immune abnormalities seen in the NL AD skin (compared to psoriasis in which NL is closer to normal skin)

This emphasizes the need for systemic treatment approaches for patients with moderate‐to‐severe AD

52

A Review of Landmark Clinical Trials in Atopic Dermatitis

How Will the Data Change Our Approach to Treating Atopic Dermatitis?


LISA A. BECK, MDProfessor, Department of Dermatology and Medicine (Allergy/Immunology and Rheumatology)

University of Rochester Medical Center School of Medicine and Dentistry

Rochester, NY

Speaker Disclosures

• Abbvie – AD clinical trials / Consultant• Array Biopharma ‐ Consultant• Celgene, Inc. – Consultant• Hoffman‐ LaRoche ‐ Consultant• Genentech, Inc. ‐ Urticaria clinical trials / consultant• Janssen – Consultant• Novartis – Consultant• Regeneron, Inc. ‐ AD Clinical trials / consultant• Unilever ‐ Consultant• Pfizer & Medtronics ‐ Stock

53

Skin BarrierDefects

Th2AdaptiveImmunity

Itch

MicrobiomeDysbiosis

GeneralInflammation

10,000

1,000

100

10

1Hay fever

Total serum IgE(IU/m

L)

AD is the Most Type 2 Polarized Allergic DiseaseSerum IgE Values

Perennialrhinitis

Asthma Atopic Dermatitis

54

AD is the Most Type 2 Polarized Allergic Disease Serum TARC (CCL17)

AD is the Most Type 2 Polarized Allergic Disease Serum TARC (CCL17)

(J Allergy Clin Immunol. 2004;113:334.)

Asthma Asthma&

AR

AR HealthyControls

AD AD&

Asthma

AD&

AR

ADAAAR

Th2‐Mediated EffectsTh2‐Mediated Effects

Plasma Cell

IgE

Allergens

Itch

Scratch

TH2

IL-4 IL-5IL-13

Eosinophil

B Cell

Skin Barrier Function(↓FLG, LOR, IVL, TJ proteins)

Innate Immune Receptors(↓TLR1, TLR2, TLR6)

Anti-Microbial Peptides(↓HBD3, LL-37, S100s)

Epithelium

FLG=filaggrin; HBD3=human beta-defensin 3; IVL=involucrin; LL-37=cathelicidin;LOR=loricrin;TJ=tight junction; S100s=S100 calcium binding proteins; TLR 1, 2, 6=Toll-like receptor 1, 2, 6.Modified from Janeway CA et al. Immunobiology. 2008.

Dysbiosis

EpidermalThickening

55

SystemicTh2 Targeted

Therapies in ≥ Ph2 Development

SystemicTh2 Targeted

Therapies in ≥ Ph2 Development

Wang & Beck Am J Clin Dermatol. 2016 Oct;17:425

Dupilumab (anti‐IL‐4Rα) Blocks the IL‐4/IL‐13 Receptor/Ligand System

Type I Receptor

B cells, T cells, Monocytes, Eosinophils, Fibroblasts

Type II Receptor

Epithelial cells, Smooth muscle cells, Fibroblasts, Monocytes, Activated B

cells

IL‐4R, IL‐4 receptor‐alpha; IL‐13R, IL‐13 receptor‐alpha; JAK1, Janus kinase type 1; JAK3, Janus kinase type 3; STAT6, signal transducer and activator of transcription 6; TYK2, tyrosine kinase type 2; c, common cytokine receptor gamma chain.

• Dupilumab: a fully human mAb directed against IL‐4Rα subunit

• Blocks IL‐4 and IL‐13 intracellular signaling

• Efficacy in patients with moderate‐to‐severe asthma and increased IgE

(Wenzel et al. NEJM 2013;268:2455)

56

Five DBPC Trials of Dupilumabfor Atopic Dermatitis in US,

Europe, and Japan

Five DBPC Trials of Dupilumab for Atopic Dermatitis in US, Europe, and Japan

57

Baseline Demographics

Characteristic

4‐Wk Monotherapy

Placebo (n=16)

Dupilumab(n=51)

Age – yr 37.4±4.3 42.6±1.9

Male sex – no. (%) 11 (69) 28 (55)

White race – no. (%) 13 (81) 39 (76)

Body mass index 25.7±1.5 26.6±0.9

EASI score 22.8±3.0 30.0±2.0

Investigator’s global assessment score

3.6±0.2 2.8±0.1

Body‐surface area affected ‐ % 40.3±6.5 51.4±3.5

5‐D pruritus score 16.9±1.0 19.3±0.5

Pruritus numerical rating scale 5.98±0.5 6.0±0.2

(Beck et.al., N Engl J Med. 2014;371:130.)

Keratin 16

Molecular Changes in the Atopic Dermatitis Transcriptome in Studies M4A and M4B

58

Two 4‐week monotherapy placebo‐controlled dose‐finding studies (Europe and US)

4‐week trial monotherapy vs. placebo + topical steroids allowed ad lib C4

16‐week monotherapy placebo‐controlled (US, Europe, Japan)

12‐week monotherapy placebo‐controlled (Europe)


Characteristic (Day 29)

4‐Wk Combination Therapy

Placebo and Topical Glucocorticoids

(n=10)

Dupilumab and Topical

Glucocorticoids (n=21)

EASI‐50 ‐ no. of patients (%) 5 (50%) 21 (100%)

EASI‐75 ‐ no. of patient (%) 4 (40%) 13 (62%)

Change in Pruritus NRS ‐ % ‐24.7 ± 15.0 ‐70.7 ± 4.7

IGA 0‐1 ‐ no. of patients (%) 3 (30%) 11 (52%)

Change in IGA ‐ % ‐30.6 ± 12.3 ‐52.5 ± 4.7

Change in EASI ‐% ‐52.5 ± 12.5 ‐75.6 ± 2.9

Beck L, Thaci D, Hamilton JD, et al. (2014) N Engl J Med 371: 130‐139

Efficacy Endpoints

59

Beck L, Thaci D, Hamilton JD, et al. (2014) N Engl J Med 371: 130‐139

TCS use

TCS Use Was About Half in Dupilumab Group

Two 4‐week monotherapy placebo‐controlled dose‐finding studies (Europe and US)

4‐week trial monotherapy vs. placebo + topical steroids allowed ad lib

16‐week monotherapy placebo‐controlled (US, Europe, Japan) M16

12‐week monotherapy placebo‐controlled (Europe)


60


International Dose‐Ranging, Phase 2b Study

SC dupilumab × 16 weeks in adult patients with moderate‐to‐severe AD inadequately controlled by topical medications

Primary endpoint: % change in EASI ‐ baseline to Week 16

Secondary endpoints: Changes from baseline to Week 16 in: Pruritus score; SCORAD; Proportion of patients achieving EASI‐50/75/90; Proportion of patients achieving IGA 0–1; Safety

Lancet. 2016 Jan 2;387(10013):40-52

61

Study treatment(weekly SC injection for 16 weeks after a

loading dose*)

Screening Safety follow‐up (16 weeks)

Study Design and Objective

*Loading doses: • 600 mg for 300 mg dose regimens • 400 mg for the 200 mg and 100 mg dose regimens

Dupilumab 100 mg q4w (n = 65)

Placebo (n = 61)




Dupilumab 300 mg weekly (n = 63)

q4w, every 4 weeks; q2w, every 2 weeks; SC, subcutaneous.

Lancet. 2016 Jan 2;387(10013):40-52

Placebo Dupilumab

n = 61

100 mg q4w

n = 65

300 mg q4w

n = 65

200 mg q2w

n = 61

300 mg q2w

n = 64

300 mg weeklyn = 63

Age (years), mean 37 37 37 36 39 36

Male sex, % 66 52 62 59 64 68

AD duration (years), mean 31 28 27 26 29 26

BSA %, mean (SD) 51 (23.5) 49 (23.9) 51 (22.6) 51 (25.4) 53 (24.8) 48 (20.9)

SCORAD [range 0–103], mean (SD) 67 (13.6) 68 (15.0) 67 (12.3) 68 (14.0) 69 (12.6) 65 (12.2)

EASI [range 0–72], mean (SD) 33 (13.8) 32 (13.5) 29 (11.5) 33 (15.5) 34 (14.5) 30 (11.2)

Peak pruritus NRS [0–10 scale], mean (SD)

6.3 (1.8) 6.7 (1.9) 6.8 (1.9) 7.0 (2.3) 6.7 (2.1) 6.5 (1.5)

Patients with IGA score, %

IGA score = 3 52.5 52.3 56.9 50.8 53.1 50.8

IGA score = 4 47.5 47.7 43.1 49.2 46.9 49.2

Baseline Characteristics

and Clinical Symptoms

Placebo Dupilumab

n = 61

100 mg q4w

n = 65

300 mg q4w

n = 65

200 mg q2w

n = 61

300 mg q2w

n = 64

300 mg

weekly

n = 63

Age (years), mean 37 37 37 36 39 36

Male sex, % 66 52 62 59 64 68

AD duration (years), mean 31 28 27 26 29 26

BSA %, mean (SD) 51 (23.5) 49 (23.9) 51 (22.6) 51 (25.4) 53 (24.8) 48 (20.9)

SCORAD [range 0–103], mean (SD) 67 (13.6) 68 (15.0) 67 (12.3) 68 (14.0) 69 (12.6) 65 (12.2)

EASI [range 0–72], mean (SD) 33 (13.8) 32 (13.5) 29 (11.5) 33 (15.5) 34 (14.5) 30 (11.2)

Peak pruritus NRS [0–10 scale],

mean (SD)6.3 (1.8) 6.7 (1.9) 6.8 (1.9) 7.0 (2.3) 6.7 (2.1) 6.5 (1.5)

Patients with IGA score, %

IGA score = 3 52.5 52.3 56.9 50.8 53.1 50.8

IGA score = 4 47.5 47.7 43.1 49.2 46.9 49.2

Baseline Demographics and Disease Characteristics

Moderate AD, IGA = 3; Severe AD, IGA = 4; NRS, Numeric Rating Scale; SCORAD, SCORing in Atopic Dermatitis; SD, standard deviation.

62

Proportion of Patients Achieving EASI‐50/75/90 over 16 Weeks

EASI‐50 EASI‐75 EASI‐90

0

20

40

60

80

100

123

0

20

40

60

80

100

*P < 0.0001, †P < 0.001, and ‡P < 0.05 (vs placebo, Week 16)

Week

Pro

po

rtio

n o

f p

atie

nts

(%

)

*†

**

‡

****

***

‡

*

4 8 12 160 4 8 12 1600

20

40

60

80

100

4 8 12 160

Placebo Dupilumab 100 mg q4w Dupilumab 300 mg q4w

Dupilumab 200 mg q2w Dupilumab 300 mg q2w Dupilumab 300 mg weekly

EASI-50, 50% improvement in EASI score; EASI-75, 75% improvement in EASI score; EASI-90, 90% improvement in EASI score

Lancet. 2016 Jan 2;387(10013):40‐52

Mean % Change in EASI to Week 32 (All Observed Values with Censoring After Rescue Medication Use)

-100

-90

-80

-70

-60

-50

-40

-30

-20

-10

00 1 2 3 4 6 8 10 12 14 15 16 18 20 22 24 26 28 30 32

124

Placebo Dupilumab 100 mg q4w Dupilumab 300 mg q4w

Dupilumab 200 mg q2w Dupilumab 300 mg q2w Dupilumab 300 mg weekly

*Week 16, P < 0.001 vs placebo; †Week 16, P < 0.0001 vs placebo; ‡Week 32, P < 0.05 vs placebo

*

†

‡

†

††

Mea

n %

ch

ang

e fr

om

bas

elin

e

Week

End of Treatment

EASI

Lancet. 2016 Jan 2;387(10013):40‐52

63

TEAEs over 32 Weeks (16 Weeks Treatment + 16 Weeks Follow Up)

125125

Placebo Dupilumab

n = 61

100 mg q4w

n = 65

300 mg q4w

n = 65

200 mg q2w

n = 61

300 mg q2w

n = 64

300 mg weeklyn = 63

All dupilumab

doses combined

n = 318Total number of TEAEs 184 249 212 207 207 256 1,131

Total number of serious TEAEs 4 7 3 3 2 1 16

Any TEAE, %* 80.3 81.5 86.2 75.4 78.1 84.1 81.1

Any serious TEAE, %* 6.6 7.7 4.6 1.6 3.1 1.6 3.8

Discontinuation due to TEAE, %* 4.9 15.4 4.6 4.9 6.3 1.6 6.6

Any infection, %* 59.0 63.1 63.1 49.2 56.3 61.9 58.8

Upper respiratory tract infection 41.0 38.5 43.1 29.5 37.5 38.1 37.4

Bacterial infections (NEC) 11.5 9.2 6.2 6.6 6.3 11.1 7.9

Herpes viral infections 1.6 12.3 6.2 9.8 7.8 4.8 8.2

Skin structures & soft tissue infections 8.2 7.7 4.6 8.2 7.8 4.8 6.6

Urinary tract infections 6.6 7.7 6.2 9.8 4.7 1.6 6.0Viral infections (NEC) 9.8 4.6 4.6 3.3 6.3 7.9 5.3

AD or eczema exacerbation, %* 19.7 24.6 18.5 14.8 21.9 19 19.8

Headache, %* 3.3 10.8 7.7 14.8 7.8 12.7 10.7

Nausea & vomiting symptoms, %* 6.6 3.1 1.5 6.6 1.6 3.2 3.1

Injection site reactions, %* 3.3 4.6 7.7 6.6 4.7 9.5 6.6

Musculoskeletal & connective tissue pain, %* 8.2 6.2 4.6 1.6 6.3 4.8 4.7

Conjunctival infections, irritations, & inflammations, %* 3.3 1.5 6.2 9.8 4.7 11.1 6.6

*%, percent of patients. NEC, not otherwise classified; TEAE, treatment-emergent adverse event.

Lancet. 2016 Jan 2;387(10013):40‐52

Dupilumab Summary

► Dupilumab (anti‐IL‐4Rα) 300 mg dosing schedules provides rapid, marked and sustained improvement in EASI, SCORAD, IGA, and BSA%, and pruritus

► Dupilumab lead to statistically superior clinical outcomes compared to the placebo group in all measures of disease activity and pruritus

► The most common TEAEs were nasopharyngitis, headache, conjunctivitis and possibly Herpes infections.

64

SOLO 1 and 2 TrialsSOLO 1 and 2 Trials

Presented at late‐breaker session at EADV Congress, 2016.

Objective: Demonstrate efficacy and assess safety of dupilumab monotherapy vs placebo in adults with moderate-to-severe AD inadequately controlled with or medically inadvisable for topical therapy

671 patients in SOLO 1 and 708 patients in SOLO 2

Objective: Demonstrate efficacy and assess safety of dupilumab monotherapy vs placebo in adults with moderate-to-severe AD inadequately controlled with or medically inadvisable for topical therapy

671 patients in SOLO 1 and 708 patients in SOLO 2

SOLO 1 & SOLO 2: Pivotal Phase 3 Studies with Identical Study Design

SOLO 1 & SOLO 2: Pivotal Phase 3 Studies with Identical Study Design

* Dupilumab, 600 mg; placebo, matching placebo. q2w, every other week; qw, weekly; R, randomization; SC, subcutaneously.

Placebo SC qw

Dupilumab 300 mg SC qw

Post-treatment options:

• Maintenance study

• Open-label extension

• Safety follow-up through Week 28

Screening Dupilumab 300 mg SC q2w

Treatment period (16 weeks)

Follow-up period (12 weeks)

Loading dose on Day 1*

Day –35 to –1 Baseline Week 28Week 16

R

GZUS.DUP.16.09.2128

65

Baseline Disease CharacteristicsBaseline Disease Characteristics

SOLO 1 SOLO 2

EventPlacebo

qw(n = 224)

Dupilumab 300 mg q2w

(n = 224)

Dupilumab 300 mg qw(n = 223)

Placeboqw

(n = 236)


(n = 233)


Duration of AD, median, years 28.0 26.0 26.0 26.0 24.5 24.0

BSA affected, median, % 57.0 53.4 54.5 53.3 50.0 50.0

EASI score, median 31.8 30.4 29.8 30.5 28.6 29.0

IGA score (range 0–4), %

3 (moderate) 50.4 51.8 52.5 51.3 50.6 53.1

4 (severe) 49.1 48.2 47.5 48.7 49.4 46.9

Peak pruritus NRS, median 7.7 7.6 7.7 7.7 7.8 7.8

Total SCORAD score, median 67.0 65.1 65.9 68.9 67.8 67.4

DLQI score, median 14.0 13.0 14.0 15.0 15.0 16.0

BSA, body surface area; DLQI, Dermatology Life Quality Index; NRS, numerical rating scale; SCORAD, SCORing Atopic Dermatitis. GZUS.DUP.16.09.2128

IGA 0 or 1 and EASI‐75 ResponseIGA 0 or 1 and EASI‐75 Response

† Co-primary endpoint in EU and Japan; key secondary endpoint in other regions.

14.711.9

51.3

44.2

52.548.1

0

10

20

30

40

50

60

70

80

SOLO 1 SOLO 2

10.3 8.5

37.9 36.137.2 36.4

0

10

20

30

40

50

60

70

80

SOLO 1 SOLO 2

* * * *

* ** *

* P < 0.0001 vs placebo * P < 0.0001 vs placebo

EASI‐75† at Week 16IGA = 0 or 1 and ≥ 2 points reduction

from baseline at Week 16

Pa

tie

nts

(%

)

Dupilumab 300 mg qwDupilumab 300 mg q2wPlacebo qw

GZUS.DUP.16.09.2128

66

EASI: % Change from BaselineEASI: % Change from Baseline

LS, least squares; SE, standard error.

-80

-70

-60

-50

-40

-30

-20

-10

00 1 2 4 6 8 12 16

-80

-70

-60

-50

-40

-30

-20

-10

00 1 2 4 6 8 12 16

−37.6−30.9

−72.3*

−67.1*−72.0*

−69.1*

* P < 0.0001 vs placebo* P < 0.0001 vs placebo

SOLO 1 SOLO 2

LS

mea

n p

erce

nt

chan

ge

in E

AS

I fr

om

ba

se

lin

e (

±S

E)

WeekWeek

Dupilumab 300 mg qw (censored)Dupilumab 300 mg q2w (censored)Placebo qw (censored)

GZUS.DUP.16.09.2128

Peak Pruritus NRS: % Change from BaselinePeak Pruritus NRS: % Change from Baseline

NRS, numerical rating scale.

-80

-70

-60

-50

-40

-30

-20

-10

00 2 4 6 8 10 12 14 16

-80

-70

-60

-50

-40

-30

-20

-10

00 2 4 6 8 10 12 14 16

*

−15.4

−44.3*

−48.3*

*

* P < 0.0001 vs placebo * P < 0.0001 vs placebo

LS

mea

n p

erce

nt

chan

ge

inp

eak

pru

ritu

s N

RS

fro

m b

asel

ine

(±S

E)

WeekWeek

Dupilumab 300 mg qw (censored)Dupilumab 300 mg q2w (censored)Placebo qw (censored)

−26.1

−51.0*

−48.9*

*

*

GZUS.DUP.16.09.2128

SOLO 1 SOLO 2

67

DLQI and POEM: Proportions of Patients Achieving Improvement ≥ 4 (MCID) from Baseline at Week 16 DLQI and POEM: Proportions of Patients Achieving Improvement ≥ 4 (MCID) from Baseline at Week 16

DLQI, Dermatology Life Quality Index; MCID, minimal clinically important difference; POEM, Patient-Oriented Eczema Measure.

30.527.6

64.1

73.1

58.462.0

0

10

20

30

40

50

60

70

80

SOLO 1 SOLO 2

26.924.4

67.671.7

63.1 64.0

0

10

20

30

40

50

60

70

80

SOLO 1 SOLO 2

** *

*

* Nominal P < 0.0001 vs placebo * Nominal P < 0.0001 vs placebo

**

**

DLQI POEMP

ati

en

ts (

%)


GZUS.DUP.16.09.2128

HADS‐A (Anxiety) and HADS‐D (Depression): Proportions of Patients Achieving Score < 8 at Week 16

HADS‐A (Anxiety) and HADS‐D (Depression): Proportions of Patients Achieving Score < 8 at Week 16

1. Bjelland I, et al. J Psychosom Res. 2002;52:69-77. HADS, Hospital Anxiety and Depression Scale; HADS-A, HADS Anxiety subscale; HADS-D, HADS Depression subscale.


12.4

6.1

41.0 39.536.3

41.2

0

10

20

30

40

50

60

70

80

SOLO 1 SOLO 2

* Nominal P < 0.0001 vs placebo† Nominal P = 0.0001 vs placebo

* † * *

Pa

tie

nts

(%

)

• Analysis conducted in patients with clinical symptoms of anxiety or depression at baseline (i.e., HADS-A or HADS-D ≥ 8)1

GZUS.DUP.16.09.2128

68

Adverse Events Reported in ≥ 5% of Patients in Any Treatment Group

Adverse Events Reported in ≥ 5% of Patients in Any Treatment Group

SOLO 1 SOLO 2

Event*Placebo

qw(n = 222)


(n = 229)


Placeboqw

(n = 234)


(n = 236)


Patients, n (%)

Nasopharyngitis 17 (8) 22 (10) 25 (12) 22 (9) 20 (9) 20 (8)

Conjunctivitis 2 (1) 11 (5) 7 (3) 1 (< 1) 9 (4) 9 (4)

Upper respiratory tract infection

5 (2) 6 (3) 11 (5) 5 (2) 7 (3) 9 (4)

Injection-site reaction 13 (6) 19 (8) 41 (19) 15 (6) 32 (14) 31 (13)

Atopic dermatitis 67 (30) 30 (13) 21 (10) 81 (35) 32 (14) 38 (16)

Headache 13 (6) 21 (9) 11 (5) 11 (5) 19 (8) 22 (9)

Allergic conjunctivitis 2 (1) 12 (5) 7 (3) 2 (1) 2 (1) 3 (1)

* MedDRA Preferred Term.

GZUS.DUP.16.09.2128

In the pivotal phase 3 studies the primary endpoints were met Both dose regimens of dupilumab showed clinically meaningful improvement and statistical significance versus placebo in: AD signs and symptoms (including itch/pruritus and sleep) Health‐related quality of life Symptoms of anxiety/depression

Significant improvement in itch was observed as early as Week 2 Most AEs were mild or moderate

Injection site reactions and conjunctivitis were more frequent with dupilumab Overall, there were no observed increases in infections with dupilumab

SOLO 1 & 2: Conclusions

69

TH Subsets in Atopic DermatitisTH Subsets in Atopic Dermatitis

DC=dendritic cell; AMPs= Antimicrobial peptides.Hamid Q et al. J Clin Invest. 1994 Aug;94(2):870-876.Werfel T et al. J Invest Dermatol. 1996 Dec;107(6):871-876.Gittler JK et al. J Allergy Clin Immunol. 2012 Dec;130(6):1344-1354.

Non-lesional

Dermal DC

LangerhansCell

TH17

TH2

Antigens

Onset of Hyperplasia/ RegenerativeEpidermal Growth

Acute stage

TH22TH2

Disrupted Barrier

IL-22

IL-31 IL-4IL-13

AMPs (HBD3, LL-37)

Itch Scratch Lichenification

TH22

TH2

Intensification ofCytokine Effects

Chronic stage

TH1

Systemic Anti‐Cytokine Therapies in Development for ADSystemic Anti‐Cytokine Therapies in Development for AD

Blocking Th17 or Th1/Th17 pathways

Blocking Th2 pathway

Blocking Th22 pathway

Blocking a pruritogen


70

OC459 – Phase 2

Skin BarrierDefects

Th2AdaptiveImmunity

Itch

MicrobiomeDysbiosis

GeneralInflammation

71

Other Systemic Rxs

Wang & Beck Am J Clin Dermatol. 2016;17:425

Name of Agent Route Mechanism Phase Clinical Trials ID

Omalizumab SC Anti‐IgE mAb 2 NCT02300701

Ligelizumab SC Anti‐IgE mAb 2 NCT01552629

MEDI4212 SC/IV Anti‐IgE mAb 1 NCT01544348

XmAb7195 IV Anti‐IgE mAb 1b NCT02148744

Apremilast Oral PDE‐4 inhibitor 2 NCT02087943

AQ‐1125 POSHIP1 activator

(small molecule)

2 NCT02324972

DS106/DS107 PO/TopicalDGLA‐bioactive

lipid2

Paller et al., JAAD. 2016;75:494

• Two Phase III, RDBPC study (>1400) mild‐to‐moderate AD (> 2yrs of age) randomized 2:1 to crisaborole or vehicle

• Primary endpoint: SGA score at day 29 of clear (0)/almost clear (1) with 2‐grade or greater improvement from baseline

• Improvement in Itch was earlier in crisaborole‐treated pts.

• TEAE were infrequent and mild

72

JAK Kinase InhibitorsJAK Kinase Inhibitors

(Nat Rev Drug Discov. 2016;15:35-50Am J Clin Dermatol. 2016 Oct;17:425J Am Acad Dermatol 2015;73:395)

ABT-494 PO JAK 1 inhibitor(small molecule)

2b NCT02925117

Oral JAK 1 and 3 inhibitor

(BJD. 2016; 175:902BJD. 2016;175:86)

• 4 wk, Phase IIa, RDBPC study 69 adults with mild‐to‐moderate AD

• randomized 1:1 to 2% tofacitinib or vehicle ointment twice daily

• Primary endpoint: % change of EASI from baseline (LS Means 81.7% Tofavs 28.9% Veh)

• Improvement in Itch• No safety signals

EASI50

EASI75

73

Skin BarrierDefects

Th2AdaptiveImmunity

Itch

MicrobiomeDysbiosis

GeneralInflammation

The Itch that RashesThe Itch that Rashes

Systemic & Topical Anti‐Itch Rxs


74

Skin BarrierDefects

Th2AdaptiveImmunity

Itch

MicrobiomeDysbiosis


Systemic & Topical Barrier Repair RxsSystemic & Topical Barrier Repair Rxs

75

Conclusions

► Last FDA‐approved therapy for AD was 15 yrs ago.

► Many new topical and systemic Rxs are in the pipeline for AD treatment.The only ones that have reported Phase 3 data are:

Dupilumab – biologic targeting IL‐4Ralpha chain (moderate‐severe AD)

Crisaborole – topical PDE4 inhibitor

A major focus is on inhibiting components of the Type 2 (Th2) pathway:• DPL is effective at reducing the signs, symptoms and S. aureus levels (?barrier)

Whether there are AD endotypes that might respond better to Th17 or Th22 antagonists is currently being explored.

A number of more general anti‐inflammatory therapies show great promise (PDE4 inhibitors, JAK inhibitors, H4R inhibitors)