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


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"The New Inflammation paradigm: What is it and what's the impact?" A slide deck presented by Dr. Michael George, VP & Inflammation Therapy Area Head at Covance.

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

  1. 1. The New Inflammation Paradigm:What is it and what’s the impact? p Dr Michael George g Vice President & Inflammation Therapy Area Head
  2. 2. The Area That Came in from the Cold.. Number of Active Studies by Therapeutic Area – Nov 2011 Phase I Phase II Phase III 0 1,000 2,000 3,000 ~ 7,000 Inflammation – a leading area of interest and activitySource: Covance Resource Management, TrialTrove, November 20112
  3. 3. A Few Key Numbers • Global Inflammation market valued at 60bn in 2016 - ~$55BN today* – Asthma COPD form largest share at 58% ($34bn) Asthma, – 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 2010Source: Business Insights “Asthma & COPD Market Outlook to 2012” , “The Immunomodulators Market Outlook to 2016”, 2011 3
  4. 4. Impact of DiseasesDebilitating, variable, organ-specific or multi-system presentationsUnderlying immune driven pathology which can present with overlappingfeatures 4
  5. 5. 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 System  Connective Tissues  Skin  Gastrointestinal SystemOthers: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) diseasesEyes (Uveitis) 5
  6. 6. Market Dynamics • Traditionally no specific therapies developed versus multiple inflammatory diseases • Many diseases intractable and relapsing despite high doses NSAIDsNSAIDs, steroids, cytotoxics, DMARDs • Then came TNF inhibitors • 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 and (e.g. Crohn’s disease and rarer autoimmune conditions) • What caused this dramatic development? Better understanding of Inflammation unlocked research & market potential6
  7. 7. 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 cascades p Allergy Autoimmune Immune system reacts to Immune system reacts to normal outside substance that it body tissues that it would would normally ignore normally ignore (Hypersensitivity) (Cross-Reactivity) In an autoimmune disorder, the immune system cant tell the difference between healthy body tissue and antigens. The result is an immune response that destroys normal body tissues7
  8. 8. 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 discovery th t clinically unrelated autoimmune conditions, e.g. rheumatoid The di that li i ll l t d t i diti h t id 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 8
  9. 9. Key Features of IMIDs: What Happens? IMIDs characterized by common underlying pathways leading to inflammation, which may result in: end organ damage, and are associated with increased morbidity and/or mortality Dysregulation of the Loss of ‘tolerance’ to the normal immune response body s body’s own auto-antigens to environmental antigens Immunomodulatory & immunosuppressive agents used to target these systems9
  10. 10. Loss of Immune Balance• Fundamental problem: imbalance between immune activation and control• Nature of disease is determined by the type of dominant immune response Many immunological diseases are chronic and self- perpetuating10
  11. 11. Why are IMIDs Chronic and Self-perpetuating? • Immunological diseases tend to be chronic and self- perpetuating, because: t ti b • 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 infections • The activated immune system can diversify to attack additional target sites on the triggering antigen “Epitope spreading” 11
  12. 12. 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 (autoimmunity) or microbial antigens (Crohn’s disease?)• Involve immune cells (T&B lymphocytes and g ( y p y granulocytes), y ), cytokines and antibodies• May be systemic or organ-specific A New Approach12
  13. 13. Plenty of Targets to Treat Key Steps IMMUNE SYSTEM Cellular Immunity Humoral ImmunityAg-Recognition(cross-reaction) Immune cell to cell Interactions Antigen Processing B Lymphocytes B-Lymphocytes Activation and Presentation differentiation (Receptor recognition & Cytokine signalling)Transformation Natural killer ll N t l kill cells Antigen specific Antibodies Proliferation Ag-specific cytotoxic T-Lymphos Macrophages & Granulocytes Recruitment Trafficking Immunocompetency I t 13
  14. 14. Unlocking The New ParadigmHuge 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, COPD RA SLE Psoriasis IBD)• Necessary to have scientific bench strength in these areas to be IMID development partner of choice14
  15. 15. Biomarkers Driving OpportunitiesPotential Uses – Improved patient stratification in clinical trials to increase the ability to detect a therapeutic effect with a novel agent d h i ff ih l – 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 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 toxicity – 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 15
  16. 16. Key Take Aways• Medical science and drug companies have come to understand Immune-mediated inflammatory diseases (IMIDs) represent a diverse group of chronic conditions th t share common pathways f h i diti that h th• 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 approaches (novel small molecule, biological and biosimilar development)• Inflammation means good Clinical ROI: any one compound may be re-applied versus multiple diseases pp p• Driving clinical activity and competition for patients• Crucial to understand the paradigm shift from organ-based p g g symptom relief to mechanism-based treatment, to systematically and effectively negotiate the impact on clinical development strategies and -trials16