Evaluating the Use of Actemra ® ( tocilizumab ) for the Treatment of Rheumatoid Arthritis

1. Evaluating the Use of Actemra® (tocilizumab) for the Treatment of Rheumatoid Arthritis Brianna Borgia University of Pittsburgh School of Pharmacy PharmD Candidate 2011

2. Learning Objectives • Understand the epidemiology, pathophysiology, and clinical features of RA  • List the current therapeutic options for treating RA • Discuss the clinical trials that evaluate the use of Actemra® (tolcilizumab) for the treatment of RA • Define the place in therapy of Actemra® (tolcilizumab) for the treatment of RA

3. Rheumatoid Arthritis

4. Epidemiology1-2 • Affects 1% of the adult population • Most frequent of all chronic inflammatory joint diseases • Ratio of women to men 3:1 • Risk factors • Genetic predisposition, smoking, exposure to environmental factors • Increased risk of mortality

5. Pathophysiology2 • Systemic autoimmune inflammatory disease • Chronic inflammation of synovial tissue lining of joint capsule http://www.abc.net.au/health/library/img/rheum_arth_diag.jpg

6. Clinical Features • Signs • Tenderness with warmth and swelling over joints • Symmetrical joint involvement • Rheumatoid nodules • Symptoms • Joint pain/stiffness • Muscle pain, fatigue, fever, loss of appetite • Joint deformity

7. Rheumatoid Nodules http://www.cedars-sinai.edu

8. Extraarticular Involvement • Rheumatoid nodules • Vasculitis • Pulmonary complications • Ocular manifestations • Cardiac involvement • Osteopenia • Anemia • Felty’s Syndrome

9. Laboratory Tests • Rheumatoid factor • Anticycliccitrullinated peptide antibody • anti-CCP • Elevated ESR, CRP • Antinuclear antibodies • ANA • Synovial fluid leukocytosis

10. Goals of Therapy • Achieve complete disease remission • Rare! • Control disease activity • Alleviate pain • Maintains ability to function at daily activities and work • Improve quality of life • Implement early and aggressive treatment

11. Current Therapy Options • Non-phamacologic • Pharmacologic • NSAIDS • Corticosteroids • DMARDs • Methotrexate, hydroxychloroquine, sulfasalazine, lefluomide • Azothiaprine, D-penicillamine, gold salts, minocycline, cyclosporine • Biologics

12. Methotrexate • Standard by which new DMARDs are evaluated • Dose 7.5-15mg/week • Inhibits cytokine production, purine biosynthesis → antiinflammatory effects • Folic acid antagonist • GI, hepatic, hematologic, and pulmonary toxicities

13. Biologics • Anti-TNF • Infliximab, etanercept, adalimumab, golimumab • IL-2 receptor antagonist • Anakinra • Depletion of peripheral B-cells • Rituximab • Costimulation modulator • Abatacept • Interleukin-6 receptor antagonist • Tocilizumab

14. Actemra® (tocilizumab)

15. Actemra® (tocilizumab) • First interleukin-6 receptor inhibitor FDA approved to treat adults with: • Moderate to severe active RA who have had an inadequate response to one or more TNF antagonist therapies • 4 mg/kg IV infusion over 1 hour q 4 weeks • Increase to 8 mg/kg based on clinical response

16. Mechanism of Action • Human monoclonal antibody • Binds specifically to both soluble and membrane bound IL-6 receptors • Elevated IL-6 is an important mediator of articular inflammation: • Proinflammatory cytokine • Involved in physiological processes

17. www.medscape.com

18. Pharmacokinetics • Concentration-dependent elimination • T1/2 for 4 mg/kg = 11 days • T1/2 for 8 mg/kg = 13 days • No dose adjustments needed for: • Age • Gender • Race

19. Warnings and Precautions

20. Summary • RA is a chronic inflammatory disease that affects patients quality of life and increases mortality risk • Tocilizumab is a new IL-6 inhibitor that is approved for the treatment of RA in patients who have failed

21. Literature Support • RADIATE • A multicenter, randomized, double-blind, placebo-controlled, parallel group study of tocilizumab, a humanized anti-IL-6 receptor monoclonal antibody • TOWARD • OPTION • AMBITION

22. Objectives • The phase III RADIATE study examined the efficacy and safety of tocilizumab in patients with rheumatoid arthritis refractory to tumor necrosis factor antagonist therapy

23. Methods • 24 week phase III multicenter, randomized, double-blind, placebo-controlled, parallel group study • Conducted in accordance with the Declaration of Helsinki • Protocol approved by IRB’s, ethics committees and/or regulatory authorities • Funded by F. Hoffmann-La Roche Inc. and Chugai Pharmaceuticals

24. Inclusion Criteria • 18 years of age and older • Active RA for ≥ 6 months • SJC ≥ 6 • TJC ≥ 8 • CRP > 1.0mg/dl • ESR >28mm/h • Failure to respond or intolerance to ≥ 1 TNF antagonist within the past year

25. Inclusion Criteria • Discontinuation of: • Biologic DMARDs • Non-biologic DMARDs other than MTX • Stable methotrexate dose • Treatment with MTX for 12 weeks or more

26. Exclusion Criteria • Treatment with cell-depleting agents • Uncontrolled medical conditions • History of: • Other inflammatory diseases • Malignancies • 1° or 2° immunodeficiency • Hemoglobin > 8.5 g/dl • Leukopenia, Neutropenia, Thrombocytopenia • Abnormal liver function • Triglycerides > 10mmol/l • Active TB, hepatitis B, hepatitis C

27. Randomization

28. Concomitant Medications • Oral Corticosterioids • Stable dose ≤ 10mg/day of prednisone or equivalent • NSAIDS

29. Rescue Therapy • 8 mg/kg of TCZ + MTX was offered at week 16 in all cases of treatment failure • < 20% improvement in both SJC and TJC

30. Study Endpoints • Primary • ACR20 response at week 24 • Secondary • ACR50/70 • DAS28 • EULAR

31. ACR20 • ACR20 response defined as a ≥ 20% improvement in: • Swollen joint count (66 joints) and tender joint count (68 joints) • ≥ 20% improvement in 3 of the following 5 assessments • Patient’s assessment of pain • Patient’s global assessment of disease activity • Evaluator’s global assessment of disease activity • Patient’s assessment of physical function measured by the HAQ • CRP

32. Response to Treatment

33. Sample Size Calculation • To achieve > 80% power • Sample size of 450 patients neededto detect a difference of 20 points between TCZ and control arms at week 24 for the ACR20 response to enable reporting of safety and efficacy data

34. Statistical Analysis • Cochrane-Mantel-Haenszel χ2 test • Compared the proportion of patients in each of the TCZ + MTX groups vs. placebo with an ACR 20 response at 24 weeks

35. Results • Total of 499 patients randomly assigned to study treatment • Treatment groups were well-balanced • Baseline demographics • RA characteristics at baseline

36. Baseline Data

37. Baseline Data

38. Baseline Data

39. Efficacy for Primary Endpoints

40. Efficacy for Secondary Endpoints

41. Efficacy for Secondary Endpoints

42. Safety

43. Summary • TCZ + MTX provided rapid and sustained improvements in RA symptoms in patients who had previous inadequate response to TNF antagonist therapy • Safety profile of TCZ is manageable

44. Strengths of RADIATE • Randomized, double-blind, placebo controlled • Relevance of results can be applied to practice • Reported number of patients achieving disease remission • New shift in treatment goal for RA

45. Weaknesses of RADIATE • Funding bias • Short trial duration • Measurement of ACR20 response not widely used in clinical practice • Only assessed TCZ in combination with MTX

46. Other Supporting Literature

47. TOWARD • n = 1,220 • Examined the efficacy and safety of TCZ combined with conventional DMARDs in patients with active RA • Previous unsuccessful treatment with TNF antagonists or cell-depleting therapy excluded

48. Randomization

49. Primary Endpoint

50. OPTION • n = 623 • Assessed the therapeutic effects of blocking IL-6 by inhibition of the IL-6 receptor with TCZ in patients with RA • Patients who had an inadequate response to MTX were recruited