The New Inflammation Paradigm: What is it and what’s the impact?

Dr Michael George

p

gVice President & Inflammation

Therapy Area Head

The Area That Came in from the Cold..

Number of Active Studies by Therapeutic Area – Nov 2011

Phase IPhase IPhase IIPhase III

0 1,000 2,000 3,000 7,000~

Inflammation – a leading area of interest and activity

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Source: Covance Resource Management, TrialTrove, November 2011

A Few Key Numbers• Global Inflammation market valued at 60bn in 2016 - ~$55BN

today*Asthma COPD form largest share at 58% ($34bn)– Asthma, COPD form largest share at 58% ($34bn)

– Psoriasis, Lupus exhibit highest rate growth– Intense development activity to protect market shares/enter market

• Much at stake in Inflammation markets– The top 10 immunomodulator brands accounted for ~80% of sales p

in 2010– The leading 10 respiratory brands accounted for 50% of sales in

2010– The leading 5 companies in the respiratory arena accounted for

around 85% of sales in 2010

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Source: Business Insights “Asthma & COPD Market Outlook to 2012” , “The Immunomodulators Market Outlook to 2016”, 2011

Impact of Diseases

Debilitating, variable, organ-specific or multi-system presentationsUnderlying immune driven pathology which can present with overlapping features

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features

IMIDs: What’s Covered?

Immune mediated inflammatory diseases:• prevalence 2000 – 3000 per hundred thousand of the population • 80+ chronic autoimmune diseases targeting virtually any part of the body, including:

Respiratory SystemRespiratory System Connective Tissues Skin Gastrointestinal SystemGastrointestinal System

Others:Vascular System (vasculitides: Wegener’s, Giant Cell Arteritis, Churg-Strauss, Polyarteritis)Endocrine System (Type 1 diabetes, Addison’s disease, Thyroid disease)Nervous System (Demyelinating diseases Myasthenia gravis)

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Nervous System (Demyelinating diseases, Myasthenia gravis)Eyes (Uveitis)

Market Dynamics

• Traditionally no specific therapies developed versus multiple inflammatory diseases

• Many diseases intractable and relapsing despite high doses NSAIDs• Many diseases intractable and relapsing despite high doses NSAIDs, steroids, cytotoxics, DMARDs

• Then came TNF inhibitors• Another lull in development paradigms• Another lull in development paradigms• Today: explosion of new pharmacological approaches• Re-applicability of therapies to different diseases in different

categories (e g RA + Psoriasis + possibly Ulcerative Colitis andcategories (e.g. RA + Psoriasis + possibly Ulcerative Colitis and Crohn’s disease and rarer autoimmune conditions)

• What caused this dramatic development?

Better understanding of Inflammation unlocked research & market potential

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Allergy & Auto Immune Disease• Inflammation is the first response of the body’s immune system to infection

or irritation (antigen)• Inflammation has two main components: cellular and humoral cascadesp

Allergy Autoimmune

Immune system reacts to outside substance that it

Immune system reacts to normal body tissues that it wouldoutside substance that it

would normally ignore(Hypersensitivity)

body tissues that it would normally ignore

(Cross-Reactivity)

In an autoimmune disorder, the immune system can't tell the difference between healthy body tissue and antigens.

The result is an immune response that destroys normal body tissues

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The result is an immune response that destroys normal body tissues

Autoimmune Disease & IMID

• Traditionally, Inflammation diseases have been addressed in a piecemeal fashion, dictated by the physical site of the disease (e.g. lungs, gut, joints, etc) Th di th t li i ll l t d t i diti h t id• The discovery that clinically unrelated autoimmune conditions, e.g. rheumatoid arthritis and Crohn’s disease, share similar immune signalling dysregulation has led to a redefinition of these diseases as immune mediated inflammatory diseases (IMIDs)( )

• More than a name: this is also a significant shift in the management of these diseases:

organ-based symptom relief mechanism-based treatment

Anti-cytokine therapy has been effective in treating multiple inflammatory conditions and treatment evidence supports the

IMID paradigm

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Key Features of IMIDs: What Happens?

IMIDs characterized by common underlying pathways leading to inflammation, which may result in: end organ damage, and areinflammation, which may result in: end organ damage, and are associated with increased morbidity and/or mortality

Dysregulation of the normal immune response

Loss of ‘tolerance’ to the body’s own auto-antigensnormal immune response

to environmental antigensbody s own auto-antigens

Immunomodulatory & immunosuppressiveagents used to target these systems

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Loss of Immune Balance

• Fundamental problem: imbalance between immune• Fundamental problem: imbalance between immune activation and control

• Nature of disease is determined by the type of dominantiimmune response

Many immunological diseases are chronic and self-perpetuating

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Why are IMIDs Chronic and Self-perpetuating?

• Immunological diseases tend to be chronic and self-t ti bperpetuating, because:

• The initiating trigger cannot be eliminated(self antigen, commensal microbes)( g )

• The immune system contains many built-in amplification mechanisms whose normal function is to optimize our ability to combat infectionsto combat infections

• The activated immune system can diversify to attack additional target sites on the triggering antigen “Epitope spreading”

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IMID Paradigm in Summary

• Chronic diseases with prominent inflammation, often caused by failure of tolerance or regulation

• RA, IBD, MS, psoriasis, many others• Affects 2-5% of population, incidence increasing

• May result from immune responses against self antigens• May result from immune responses against self antigens(autoimmunity) or microbial antigens (Crohn’s disease?)

• Involve immune cells (T&B lymphocytes and granulocytes), ( y p y g y ),cytokines and antibodies

• May be systemic or organ-specific

A New Approach

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Plenty of Targets to Treat

IMMUNE SYSTEMCellular Immunity Humoral Immunity

Key Steps

Ag-Recognition (cross-reaction)

Immunecell to cell

Interactions B-LymphocytesAntigen Processing

Transformation

Interactions(Receptor recognition &

Cytokine signalling)

ActivationB Lymphocytesdifferentiation

Antigen Processingand Presentation

N t l kill llAntibodies

Proliferation

Natural killer cellsAntigen specific

Ag-specific cytotoxic T-LymphosMacrophages & Granulocytes

Trafficking I t

Recruitment

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Trafficking Immunocompetency

Unlocking The New Paradigm

Huge Target Potential + New Technologies(Mechanism Based) (Biologics & Biomarkers)

Inflammatory signalling at a Cellular and Exudative level

• IMID pipeline growth is driving a wave of development opportunity across multiple areas simultaneously (Asthma, COPD RA SLE Psoriasis IBD)COPD, RA, SLE, Psoriasis, IBD)

• Necessary to have scientific bench strength in these areas to be IMID development partner of choice

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Biomarkers Driving Opportunities

Potential Uses– Improved patient stratification in clinical trials to increase the ability to

d h i ff i h ldetect a therapeutic effect with a novel agent– Allow expedited human proof of mechanism /concept studies to screen

out and fast track promising drug candidates– Identifying patient subgroups that may benefit from more intensiveIdentifying patient subgroups that may benefit from more intensive

immunosuppressive therapy or the use of novel therapy. Conversely, reducing the total immunosuppressive load in patients at low risk of disease relapse, reducing therapy associated toxicityPredicting subject response to treatment allowing closer monitoring of– Predicting subject response to treatment allowing closer monitoring of individuals judged to be most at risk of relapse

Increasing scope to leverage biomarkers to support rational expedited IMID drug development

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Key Take Aways

• Medical science and drug companies have come to understand Immune-mediated inflammatory diseases (IMIDs) represent a diverse

f h i diti th t h thgroup of chronic conditions that share common pathways• The new and enhanced understanding of Inflammation has attracted

massive client interest, R&D activity and investment explosion in new mechanism based targets and therapeutic approachesnew mechanism based targets and therapeutic approaches (novel small molecule, biological and biosimilar development)

• Inflammation means good Clinical ROI: any one compound may be re-applied versus multiple diseasespp p

• Driving clinical activity and competition for patients

• Crucial to understand the paradigm shift from organ-based p g gsymptom relief to mechanism-based treatment, to systematically and effectively negotiate the impact on clinical development strategies and -trials

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