new immunomodulatory agents for inflammatory eye diseases

1: New Immunomodulatory Agents For Inflammatory Eye Diseases Gary Gilkeson, MD Professor of Medicine Medical University of South Carolina

2: Disclosures HGS/Genentech advisory board Taligen Therapeutics- complement related therapies- stockholder Grant support from NIH, VA, DOD, LFA, ALR and ACR REF Clinical Trials support- HGS, Genentech

3: Aims in Biologics in Opthamology Define critical components of the immune system in autoimmune diseases Describe new biologics being developed for old targets and new biologics targeting new targets Define which combination therapies may prove most effective Future targets based on latest research findings

4: Standard Immunosuppressants Methotrexate- liver toxicity, no alcohol Imuran- suppresses WBCs, hypersensitivity Cytoxan- infection, infertility, malignancy Mycophenylate (Cell Cept)- infection, nausea Cyclosporine- infection, hypertension, kidney Prograf- infection Rapamycin- infection

6: Therapeutic Target Areas in Inflammatory Diseases Cytokines/Chemokines B cells T cells Toll like receptors Adhesion molecules

8: Anti-IL6R (Actemra) in RA

10: New insight into the role of B cells in autoimmune diseases Efficacy of rituximab in RA, SLE, MS, and Wegeners has led to reexamination of the role of B cells in autoimmunity In most animal models of autoimmune diseases, eliminating B cells either therapeutically or genetically effectively ameliorates disease

11: What do B cells do in autoimmunity?

13: Rituximab in Autoimmune Diseases Proven efficacy in RA Pilot data suggesting efficacy in: Lupus ANCA+ vasculitides Poly/dermatomyositis Hepatitis C associated cryoglobulinemia MS Side effects: infections, infusion reactions Caveats- works best in combination with other drugs

14: Other isolated B cell directed therapies Anti-CD22- does not deplete B cells/modulates function- in trial in lupus Anti-CD19- depletes precursors back to the stem cell stage- prolonged B cell depletion- in trial in lymphoma Ocrelizumab- completely humanized anti-CD20- in trial in lupus and RA

15: BLyS terminology

16: Role of BLyS in B cell development

17: Other trials of agents targeting BLyS in RA/SLE TACI Ig Anti-April BAFF-R Will one be better than the other, less toxicity, more efficacy, work in combination with other agents better Side effects- immune suppression

18: Targeting cell-cell signalling

20: New Uses of Abatacept Approved for use in RA Trials in Lupus Trials in spondyloarthropathies Trials in Juvenile Idiopathic Arthritis Side effects- infections, slow onset of action

21: Toll like receptors (TLRs)

23: TLRs and Autoimmunity Clear evidence they play a role in SLE and RA Clear evidence that intrinsic molecules trigger TLRs in RA and SLE Targeted inhibitors of TLRs are in Phase II trials Agonists of TLRs are being used as vaccine and tumor adjuvants

26: Summary New research into the pathogenesis of autoimmune diseases has led to development of new biologic therapies. Literally hundreds of trials using dozens of new agents are in progress Challenges ahead are determining which therapy to use when and which combination of therapies may be most efficacious. Further challenge is how to make these agents affordable.