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Examining the Properties of Biologic Agents

Examining the Properties of Biologic Agents. Robert J Moots, MD, PhD Professor of Rheumatology University of Liverpool, UK. Academic Rheumatology Unit Clinical Sciences Centre University Hospital Aintree Liverpool, UK. Inflammatory Arthritis: Traditional Therapy. The Crime Scene. Cytokines.

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Examining the Properties of Biologic Agents

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  1. Examining the Properties of Biologic Agents Robert J Moots, MD, PhD Professor of Rheumatology University of Liverpool, UK

  2. Academic Rheumatology UnitClinical Sciences CentreUniversity Hospital AintreeLiverpool, UK

  3. Inflammatory Arthritis: Traditional Therapy

  4. The Crime Scene

  5. Cytokines Protein Inflammation

  6. Cytokines in Inflammation IL-1Ra IL-10 sTNFR IL-1b TNFa Pro-inflammatory Anti-inflammatory

  7. TACE TNF Production of TNF TM-TNF Activated Macrophage

  8. Target Cell sTNFR Signal TNF TNF Mode of Action Activated Mf

  9. Anti-TNF therapies ? Are they all the same

  10. Anti-TNFa Drugs • Conventional (eg, thalidomide) • Suppress production TNFa • Limited efficacy, side-effects • Biologics • Protein-based, made by biological technology • Specific effects, neutralise TNFa • High efficacy • Etanercept, infliximab, adalimumab

  11. Drug Structures and Kinetics

  12. Variable Constant (Fc) Infliximab Murine

  13. Adalimumab Human Variable Constant (Fc)

  14. Human p75 TNFareceptor Human antibody fragment Etanercept

  15. Activated Activated Target Target M M f Cell f Cell TNFR TNFR Signal Signal TNF TNF Infliximab/AdalimumabMode of Action

  16. sTNFR:Fc sTNFR:Fc Activated Activated M Etanercept Mode of Action Target Target M f Cell f Cell TNFR TNFR Signal Signal sTNFR sTNFR TNF TNF sTNFR:Fc sTNFR:Fc

  17. Other Properties TNF Lymphotoxin

  18. Pharmacokinetics

  19. Clinical Efficacy……..All the same?

  20. Clinical Efficacy…Inflammatory Arthritis • No head-to-head studies • Clinical trials: different study designs • Methodology • Inclusion/exclusion criteria • Demography • Geography • Disease severity/comorbidity • Placebo/active comparator

  21. Clinical Efficacy……..Can we compare? • Meta-analyses of published trials • Experience in normal clinical practice • No “perfect” way of comparing directly

  22. Meta-analysis: Published Trial Data

  23. Meta-analysis Hochberg et al ARD 2003 62(s2): 13-16

  24. Meta-analysis Hochberg et al ARD 2003 62(s2): 13-16

  25. Meta-analysis Hochberg et al ARD 2003 62(s2): 13-16

  26. Open Label Reports

  27. Geborek et al 57% of patients on infliximab had dose adjusted ARD 2002

  28. Discontinuations

  29. Differential Responses? • NICE (UK) “no switching of biologics” 2002 • Clinical practice - switching may work • Inefficacy or side effects • Etanercept/infliximab/adalimumab • ?mechanism • Efficacy etanercept after failure infliximab •   lymphotoxin on biopsy (Buch et al ARD 2004;63(10):1344-6)

  30. Toxicity?

  31. IJS reaction in 35% Rate of infections < MTX No extra serious infections Malignancy as per normal Haematological sfx < MTX No SLE/demyelination No neutralising antibodies Anaphylaxis/infusion reaction Rate of infections ~MTX No extra serious infections Malignancy as per normal Haematological sfx ~MTX No SLE/demyelination Autoantibodies Toxicity: in Clinical Trials Etanercept Infliximab

  32. IJS reaction in 35% Rate of infections > MTX Conventional bacterial No dose adjustment Malignancy? Haematological sfx ~ MTX No neutralising antibodies Toxicity: Real Life Etanercept Infliximab • Anaphylaxis/infusion reaction • Rate of infections > MTX • Frequency of TB etc • Dose adjustment • Malignancy? • Haematological sfx ~MTX • Autoantibodies

  33. IJS reaction in 35% Rate of infections > MTX Conventional bacterial No dose adjustment Malignancy? Haematological sfx ~ MTX No neutralising antibodies Toxicity: Real Life Etanercept Infliximab • Anaphylaxis/infusion reaction • Rate of infections > MTX • Frequency of TB etc • Often Dose adjustment • Malignancy? • Haematological sfx ~MTX • Autoantibodies

  34. Keane et al: NEJM 2001 • Infliximab • 121,000 treated • 70 TB cases reported by PASSIVE surveillance • 40 extrapulmonary • 17 disseminated • 64 from low-incidence countries • Etanercept • 95,493 treated patients • 9 TB cases reported by PASSIVE surveillance • Keane J, et al. N Eng J Med. 2001;345:1098-104

  35. FDA update on TB

  36. Infliximab Effective in Crohn’s  Recurrence TB Etanercept Not effective in Crohn’s No reports of TB Biologics as in vivo tools? • Bolus effect infliximab? • C’ fixation  cell lysis infliximab/adalimumab?

  37. Summary • Structural/kinetic/biological differences between biologics • Differential efficacy in various diseases • Subtle differences in adverse event profiles (TB) • Monoclonal antibodies vs p75 TNF receptor fusion protein • Dosage creep mAb • Differences between biologics: important research tools for inflammatory diseases

  38. Men die younger…. Don’t blame TNF……!

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