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

Evaluating the Use of Actemra ® ( tocilizumab ) for the Treatment of Rheumatoid Arthritis. Brianna Borgia University of Pittsburgh School of Pharmacy PharmD Candidate 2011. Learning Objectives. Understand the epidemiology, pathophysiology , and clinical features of RA 

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

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  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

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