1 / 19

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.

candra
Download Presentation

Today’s objectives

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript


  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

More Related