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Today’s objectives

Today’s objectives. Review the critical role that IL-6 plays in the pathogenesis of RA Explore the potential of IL-6 receptor (IL-6R) inhibition as a therapy in RA Discuss early clinical data from Phase II and III trials with tocilizumab (TCZ) – a humanised anti-IL-6R monoclonal antibody.

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Today’s objectives

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  1. Today’s objectives • Review the critical role that IL-6 plays in the pathogenesis of RA • Explore the potential of IL-6 receptor (IL-6R) inhibition as a therapy in RA • Discuss early clinical data from Phase II and III trials with tocilizumab (TCZ) – a humanised anti-IL-6R monoclonal antibody

  2. Agenda

  3. Agenda

  4. IL-6R inhibition: Advancing new therapeutic targets in RA Professor Ferdinand Breedveld Leiden University, Leiden, The Netherlands

  5. A continuing need for more effective therapies in rheumatoid arthritis • Rheumatoid arthritis (RA) affects 0.3–1.0% of the adult population worldwide1 • ~ 30–40% of patients do not achieve adequate disease control with currently available therapies2–4 • <50% achieve ACR50 • ~20% achieve ACR70 • Up to 40% of patients are unable to work within 5 years of diagnosis (50% at 10 years)5 • Life expectancy of RA sufferers is reduced 1. Alamanos Y, et al. Semin Arthritis Rheum 2006; 36:182–188.2. Shankar S and Handi R. J Postgrad Med 2004; 50:293–299.3. Smolen J, et al. Arthritis Res Ther 2006; 8(suppl 2):S5. 4. Olsen J, et al. NEJM 2004; 350:2167–2179. 5. NICE, Rheumatoid Arthritis Consultation Document; www.nice.org.uk.

  6. Cytokine targeted therapy in RA • IL-1 antagonists • Limited efficacy • TNF- antagonists • Patients frequently experience treatment failure • Novel therapies are still required to provide additional treatment options for patients with RA

  7. Properties of cytokines • Messenger molecules involved in cell-cell communication • Synthesised and secreted by many different cell types and tissues • Not stored in glands, unlike hormones • Released following stimulatory signal • Act on their target cells through specific surface receptors

  8. Cytokines activate their target cells by different mechanisms Target cell Production of mediators C Proliferation/cell division C Differentiation/maturation C Migration C

  9. C Cytokines activate their target cells by different mechanisms Target cell Apoptosis Most often cytokines exert an anti-apoptotic action

  10. C C C C C C C C Disregulated cytokine signalling IL-6 in RA Excessive production of mediators Too many receptors Inefficient shutdown of the signal cascade Mediator independent activation (mutations) C C C C C C Overshooting response of the target cell  possible disease development

  11. The growing awareness of IL-6: A key regulatory cytokine Publications with IL-6 in title and abstract 4000 3500 3000 2500 2000 Total number of publications 1500 1000 500 0 1987 1988 1989 1990 1991 1992 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 Pubmed search criteria: interleukin-6 [Title/Abstract] OR IL-6 [Title/Abstract]

  12. plasma cells B cells T cells cytotoxic T cells PC12cells nerve cells Pleiotropic effects of IL-6 Growth inhibition Proliferation plasmacytoma cells keratinocytes breast carcinoma cells mesangialcells melanoma cells APP expression IL-6 hepatocytes Regeneration Differentiation stem cells T cells Survival Migration Haematopoiesis

  13. IL-6 in rheumatoid arthritis • IL-6 secretion is induced by a variety of inflammatory mediators, including TNF-, IL-1β and IL-171 • IL-6 is produced by a range of cells, including macrophages, fibroblasts, T cells and B cells1–3 • IL-6 plays a central role4,5 • Elevated levels in the synovium and serum6 • Activation of T cells • Induction of acute-phase proteins • Maturation of megakaryocytes • Activation of osteoclasts • Induction of antibodies 1. Ishihara K and Hirano T. Cytokine Growth Factor Rev 2002; 13:357–368; 2. Kinne RW, et al. Arthritis Research 2000; 2:189–202; 3. Firestein GS. Nature 2003; 423:356–361; 4. Yoshizaki K, et al. Springer Semin Immunopathol 1998; 20:247–259; 5.Hirano T, et al. Eur J Immunol 1988;18:1797–1801; 6. Choy E, et al. Arthritis Rheum 2002; 46:3143–3150.

  14. Direct inhibition with anti-IL-6 antibody • Immune complex formation1 • Only transitory improvement in RA (2 months)2 • Serum IL-6 increased in 4 of 5 patients2 1. Lu ZY, et al. Eur J Immunol 1992; 22:2819–2824. 2. Wendling D, et al.J Rheumatol 1993; 20:259–262.

  15. Benefits of IL-6R inhibition with tocilizumab • Humanised monoclonal antibody • Binds to membrane-bound and soluble forms of IL-6R • Prevents IL-6 binding to its receptor • Inhibits IL-6R signalling and subsequent gene activation • Interruption of the inflammatory cycle in RA

  16. From mouse to man: The development of tocilizumab • Prevention of murine collagen-induced arthritis1,2 (CIA) • Effective treatment of CIA in Cynomolgus monkey with humanised anti-IL-6R3 • Reduction of joint swelling and stiffness • Suppression of joint destruction • Early clinical studies with TCZ confirm safety and efficacy in man4 1. Takagi N, et al. Arthritis Rheum 1998; 41:2117–2121. 2. Yoshizaki K, et al. Springer Semin Immunopathol 1998; 20:247–259. 3. Mihara M, et al. Clinical Immunology 2001; 98:319–326. 4. Nishimoto N, et al. Arthritis Rheum 2004; 50:1761–1769.

  17. Tocilizumab clinical development • SATORI • SAMURAI • CHARISMA • Global Phase III programme underway Japanese Phase III studies(monotherapy) European Phase II study

  18. Tocilizumab global Phase III clinical development programme Moderate to severe RA – 5 Phase III trials with 4200 patients vs S&S = signs & symptoms PJD = prevention of joint damage PF = physical function

  19. Summary • There remains a pressing medical need for alternative treatment options for patients with RA • IL-6 is a key regulatory cytokine with a pivotal role in the development of RA • The IL-6R therefore represents a novel and exciting therapeutic target for the treatment of RA

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